US20070060530A1 - Administration of dipeptidyl peptidase inhibitors - Google Patents

Administration of dipeptidyl peptidase inhibitors Download PDF

Info

Publication number
US20070060530A1
US20070060530A1 US11/531,671 US53167106A US2007060530A1 US 20070060530 A1 US20070060530 A1 US 20070060530A1 US 53167106 A US53167106 A US 53167106A US 2007060530 A1 US2007060530 A1 US 2007060530A1
Authority
US
United States
Prior art keywords
compound
pharmaceutical composition
administering
single dose
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/531,671
Inventor
Ronald Christopher
Paul Covington
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
DEVELOPMENT PARTNERS LLC
Takeda Pharmaceutical Co Ltd
Original Assignee
DEVELOPMENT PARTNERS LLC
Takeda Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=37564046&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20070060530(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by DEVELOPMENT PARTNERS LLC, Takeda Pharmaceutical Co Ltd filed Critical DEVELOPMENT PARTNERS LLC
Priority to US11/531,671 priority Critical patent/US20070060530A1/en
Assigned to TAKEDA SAN DIEGO, INC. reassignment TAKEDA SAN DIEGO, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHRISTOPHER, RONALD J.
Assigned to TAKEDA SAN DIEGO, INC. reassignment TAKEDA SAN DIEGO, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DEVELOPMENT PARTNERS, LLC
Assigned to DEVELOPMENT PARTNERS, LLC reassignment DEVELOPMENT PARTNERS, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: COVINGTON, PAUL
Assigned to TAKEDA PHARMACEUTICAL COMPANY LIMITED reassignment TAKEDA PHARMACEUTICAL COMPANY LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: TAKEDA SAN DIEGO, INC.
Publication of US20070060530A1 publication Critical patent/US20070060530A1/en
Priority to US13/091,460 priority patent/US20110192748A1/en
Priority to US13/773,282 priority patent/US8906901B2/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425Thiazoles
    • A61K31/4261,3-Thiazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22Hormones
    • A61K38/26Glucagons
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2013Organic compounds, e.g. phospholipids, fats
    • A61K9/2018Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • A61P31/18Antivirals for RNA viruses for HIV
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/48Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • the invention relates to the method of administering compounds used to inhibit dipeptidyl peptidase IV as well as treatment methods based on such administration.
  • Dipeptidyl Peptidase IV (IUBMB Enzyme Nomenclature EC.3.4.14.5) is a type II membrane protein that has been referred to in the literature by a wide a variety of names including DPP4, DP4, DAP-IV, FAP ⁇ , adenosine deaminase complexing protein 2, adenosine deaminase binding protein (ADAbp), dipeptidyl aminopeptidase IV; Xaa-Pro-dipeptidyl-aminopeptidase; Gly-Pro naphthylamidase; postproline dipeptidyl aminopeptidase IV; lymphocyte antigen CD26; glycoprotein GP110; dipeptidyl peptidase IV; glycylproline aminopeptidase; glycylproline aminopeptidase; X-prolyl dipeptidyl aminopeptidase; pep X; leukocyte antigen CD26; glycylproly
  • DPP-IV is a non-classical serine aminodipeptidase that removes Xaa-Pro dipeptides from the amino terminus (N-terminus) of polypeptides and proteins. DPP-IV dependent slow release of dipeptides of the type X-Gly or X-Ser has also been reported for some naturally occurring peptides.
  • DPP-IV is constitutively expressed on epithelial and endothelial cells of a variety of different tissues (intestine, liver, lung, kidney and placenta), and is also found in body fluids. DPP-IV is also expressed on circulating T-lymphocytes and has been shown to be synonymous with the cell-surface antigen, CD-26.
  • DPP-IV is responsible for the metabolic cleavage of certain endogenous peptides (GLP-1 (7-36), glucagon) in vivo and has demonstrated proteolytic activity against a variety of other peptides (GHRH, NPY, GLP-2, VIP) in vitro.
  • GLP-1 (7-36) is a 29 amino-acid peptide derived by post-translational processing of proglucagon in the small intestine.
  • DPP-IV has been shown to be the primary degrading enzyme of GLP-1 (7-36) in vivo.
  • GLP-1 (7-36) is degraded by DPP-IV efficiently to GLP-1 (9-36), which has been speculated to act as a physiological antagonist to GLP-1 (7-36).
  • Inhibiting DPP-IV in vivo is therefore believed to be useful for potentiating endogenous levels of GLP-1 (7-36) and attenuating the formation of its antagonist GLP-1 (9-36).
  • DPP-IV inhibitors are believed to be useful agents for the prevention, delay of progression, and/or treatment of conditions mediated by DPP-IV, in particular diabetes and more particularly, type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis, appetite regulation and obesity.
  • diabetes in particular diabetes and more particularly, type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis, appetite regulation and obesity.
  • ITT impaired glucose tolerance
  • IGF impaired fasting plasma glucose
  • metabolic acidosis ketosis
  • ketosis ketosis
  • appetite regulation and obesity are believed to be useful agents for the prevention, delay of progression, and/or treatment of conditions mediated by DPP-IV, in particular diabetes and more particularly, type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose
  • a method comprising: administering a daily dose of between 1 mg/day and 250 mg/day of Compound I to a patient, optionally between 2.5 mg and 200 mg of Compound I, optionally between 2.5 mg and 150 mg of Compound I, and optionally between 5 mg and 100 mg of Compound I.
  • a daily dose of 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg or 100 mg of Compound I is administered.
  • a once-per-week dose of 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg or 100 mg of Compound I is administered.
  • administering is performed 1 time per day and may optionally be performed 1 time per day as a single dosage.
  • administering is performed 1 time per day for a period of at least 30 days and optionally for a period of at least 60 days.
  • administering is performed 1 time per day in the morning and optionally is performed 1 time per day in the morning prior to a first meal of the day for the patient.
  • administering is performed 1 time per week and may optionally be performed 1 time per week as a single dosage.
  • administering is performed 1 time per week for a period of at least 30 days and optionally for a period of at least 60 days.
  • administering is performed 1 time per week in the morning and optionally is performed 1 time per week in the morning prior to a first meal of the day for the patient.
  • Administering may be performed by a wide range of routes of administration including, but not limited to a route selected from the group consisting of orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, intraperitoneally and intrathecally. In one particular variation, administering is performed orally.
  • Compound I may be used to treat a range of diseases. In one variation, administering Compound I is performed to treat type I or type II diabetes disease state of the patient. In another variation, administering Compound I is performed to treat a pre-diabetic patient. In still another variation, administering Compound I is performed to treat an inflammatory bowel disease, Crohn's disease, chemotherapy-induced enteritis, oral mucositis or Shortened Bowel syndrome.
  • administering Compound I is performed to treat a patient suffering from conditions mediated by DPP-IV such as diabetes and more particularly, type 2 diabetes mellitus; diabetic dislipidemia; impaired glucose tolerance (IGT); impaired fasting plasma glucose (IFG); metabolic acidosis; ketosis; appetite regulation; obesity; complications associated with diabetes including diabetic neuropathy, diabetic retinopathy and kidney disease; hyperlipidemia including hypertriglyceridemia, hypercholesteremia, hypoHDLemia and postprandial hyperlipidemia; arteriosclerosis; hypertension; myocardial infarction, angina pectoris, cerebral infarction, cerebral apoplexy and metabolic syndrome.
  • diabetes and more particularly, type 2 diabetes mellitus; diabetic dislipidemia; impaired glucose tolerance (IGT); impaired fasting plasma glucose (IFG); metabolic acidosis; ketosis; appetite regulation; obesity; complications associated with diabetes including diabetic neuropathy, diabetic retinopathy and kidney disease; hyperlipidemia including hypertriglyceridemia, hypercholesteremia, hypoHDL
  • a method for administering Compound I in combination with one or more antidiabetic or incretin compounds other than Compound I is also provided.
  • such combination therapy method is performed where a daily dose of between 1 mg/day and 250 mg/day of Compound I, optionally between 2.5 mg and 200 mg of Compound I, optionally between 2.5 mg and 150 mg of Compound I, and optionally between 5 mg and 100 mg of Compound I, is administered to a patient.
  • a daily dose of 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg or 100 mg of Compound I is administered to a patient in combination with one or more antidiabetic compounds other than Compound I.
  • such combination therapy method is performed where a once-per-week dose of between 1 mg and 250 mg of Compound I, optionally between 2.5 mg and 200 mg of Compound I, optionally between 2.5 mg and 150 mg of Compound I, and optionally between 5 mg and 100 mg of Compound I, is administered to a patient.
  • a once-per-week dose of 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg or 100 mg, 150 mg or 200 mg of Compound I is administered to a patient in combination with one or more antidiabetic compounds other than Compound I.
  • Combination of Compound I with one or more antidiabetic compounds other than Compound I provides excellent effects such as 1) enhancement in therapeutic effects of Compound I and/or the antidiabetic compounds; 2) reduction in side effects of Compound I and/or the antidiabetic compounds; and 3) reduction in a dose of Compound I and/or the antidiabetic compounds.
  • the one or more antidiabetic or incretin compounds administered in combination with Compound I may optionally be selected from the group consisting of insulin signaling pathway modulators, compounds influencing a dysregulated hepatic glucose production, insulin sensitivity enhancers, and insulin secretion enhancers.
  • the one or more antidiabetic or incretin compounds administered in combination with Compound I may also optionally be selected from the group consisting of protein tyrosine phosphatase inhibitors, glutamine-fructose-6-phosphate amidotransferase inhibitors, glucose-6-phosphatase inhibitors, fructose-1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glucagon receptor antagonists, phosphoenolpyruvate carboxykinase inhibitors, pyruvate dehydrogenase kinase inhibitors, alpha-glucosidase inhibitors, inhibitors of gastric emptying, glucokinase activators, GLP-1 receptor agonists, GLP-2 receptor agonists, UCP modulators, RXR modulators, GSK-3 inhibitors, PPAR modulators, metformin, insulin, and ⁇ 2 -adrenergic antagonists.
  • protein tyrosine phosphatase inhibitors glut
  • the one or more antidiabetic or incretin compounds administered in combination with Compound I may also optionally be selected from the group consisting of GSK-3 inhibitors, retinoid X receptor agonists, Beta-3 AR agonists, UCP modulators, antidiabetic thiazolidinediones, non-glitazone type PPAR gamma agonists, dual PPAR gamma/PPAR alpha agonists, antidiabetic vanadium containing compounds and biguanides.
  • the one or more antidiabetic or incretin compounds administered in combination with Compound I may also optionally be thiazolidinediones selected from the group consisting of (S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolidine-2,4-dione, 5- ⁇ [4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxo-propyl)-phenyl]-methyl ⁇ -thiazolidine-2,4-dione, 5- ⁇ [4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl ⁇ -thiazolidine-2,4-dione, 5- ⁇ [4-(2-(1-indolyl)ethoxy)phenyl]methyl ⁇ -thiazolidine-2,4-dione, 5- ⁇ 4-[2-(5-methyl-2-phenyl-4-oxazoly)-ethoxy)
  • the one or more antidiabetic compounds administered in combination with Compound I includes metformin.
  • the metformin in this combination comprises one or more pharmaceutically acceptable salts thereof.
  • the metformin in this combination comprises a metformin HCl salt.
  • the metformin in this combination is administered in a daily dose of between 125 and 2550 mg.
  • the metformin in this combination is administered in a daily dose of between 250 and 2550 mg.
  • the one or more antidiabetic compounds administered in combination with Compound I includes one or more sulphonyl urea derivatives.
  • the one or more antidiabetic compounds administered in combination with Compound I may also optionally be selected from the group consisting of glisoxepid, glyburide, glibenclamide, acetohexamide, chloropropamide, glibornuride, tolbutamide, tolazamide, glipizide, carbutamide, gliquidone, glyhexamide, phenbutamide, tolcyclamide, glimepiride and gliclazide, including any pharmaceutically acceptable salts thereof.
  • the one or more antidiabetic compounds administered in combination with Compound I includes glimepiride.
  • the one or more antidiabetic compounds administered in combination with Compound I may also optionally be selected from the group consisting of incretin hormones or mimics thereof, beta-cell imidazoline receptor antagonists, and short-acting insulin secretagogues.
  • the one or more antidiabetic compounds administered in combination with Compound I includes insulin.
  • the one or more antidiabetic compounds administered in combination with Compound I may also optionally be one or more GLP-1 agonists including, for example, extendatide.
  • the one or more antidiabetic compounds administered in combination with Compound I may also optionally be one or more GLP-2 agonists including, for example, human recombinant GLP-2.
  • the one or more antidiabetic compounds administered in combination with Compound I may also optionally be one or more antidiabetic D-phenylalanine derivatives.
  • the one or more antidiabetic compounds administered in combination with Compound I may also optionally be selected from the group consisting of repaglinide, mitiglinide and nateglinide, including any pharmaceutically acceptable salts thereof.
  • the one or more antidiabetic compounds administered in combination with Compound I includes mitiglinide calcium salt hydrate.
  • the one or more antidiabetic compounds administered in combination with Compound I may also optionally be one or more alpha-Glucosidase inhibitors.
  • the one or more antidiabetic compounds administered in combination with Compound I may also optionally be selected from the group consisting of acarbose, voglibose and miglitol, including any pharmaceutically acceptable salts thereof.
  • the one or more antidiabetic compounds administered in combination with Compound I includes voglibose.
  • the voglibose in this combination is administered in a daily dose of between 0.1 and 1 mg.
  • the one or more antidiabetic compounds administered in combination with Compound I may also optionally be rosiglitazone, including any pharmaceutically acceptable salts thereof.
  • the rosiglitazone in this combination comprises a rosiglitazone maleate salt
  • the one or more antidiabetic compounds administered in combination with Compound I may also optionally be tesaglitazar, muraglitazar or naveglitazar, including any pharmaceutically acceptable salts thereof.
  • the one or more antidiabetic compounds administered in combination with Compound I may also optionally be pioglitazone, including any pharmaceutically acceptable salts thereof.
  • the pioglitazone in this combination comprises a pioglitazone HCl salt.
  • the pioglitazone in this combination is administered in a daily dose of between 7.5 and 60 mg.
  • the pioglitazone in this combination is administered in a daily dose of between 15 and 45 mg.
  • the one or more antidiabetic compounds administered in combination with Compound I may also optionally comprise metformin and pioglitazone.
  • the pioglitazone in this combination comprises one or more pharmaceutically acceptable salts thereof.
  • the pioglitazone in this combination comprises a pioglitazone HCl salt.
  • the pioglitazone in this combination is administered in a daily dose of between 7.5 and 60 mg.
  • the pioglitazone in this combination is administered in a daily dose of between 15 and 45 mg.
  • the metformin in this combination comprises one or more pharmaceutically acceptable salts thereof.
  • the metformin in this combination comprises a metformin HCl salt.
  • the metformin in this combination is administered in a daily dose of between 125 and 2550 mg.
  • the metformin in this combination is administered in a daily dose of between 250 and 2550 mg.
  • Compound I may be administered as a free base or as a pharmaceutically acceptable salt thereof.
  • Compound I is administered as a HCl, methanesulfonate, succinate, benzoate, toluenesulfonate, R-( ⁇ )mandelate or benzenesulfonate salt of Compound I.
  • compositions are also provided.
  • a pharmaceutical composition is provided that is formulated in a single dose form wherein such single dose form comprises between 1 mg/day and 250 mg/day of Compound I, optionally between 2.5 mg and 200 mg of Compound I, optionally between 2.5 mg and 150 mg of Compound I, and optionally between 5 mg and 100 mg of Compound I.
  • the pharmaceutical composition comprises 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg or 100 mg of Compound I.
  • a pharmaceutical composition is provided that is formulated in a single dose form wherein such single dose form comprises between 1 mg/week and 250 mg/week of Compound I, optionally between 2.5 mg and 200 mg of Compound I, optionally between 2.5 mg and 150 mg of Compound I, and optionally between 5 mg and 100 mg of Compound I.
  • the pharmaceutical composition comprises 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg or 100 mg of Compound I on a once per week basis.
  • a pharmaceutical composition that comprises Compound I and one or more antidiabetic or incretin compounds other than Compound I in a single dose form.
  • Compound I is present in the single dose form in a dosage amount between 1 mg/day and 250 mg/day of Compound I, optionally between 2.5 mg and 200 mg of Compound I, optionally between 2.5 mg and 150 mg of Compound I, and optionally between 5 mg and 100 mg of Compound I.
  • the pharmaceutical composition comprises 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg or 100 mg of Compound I.
  • Combination of Compound I with one or more antidiabetic compounds other than Compound I provides excellent effects such as 1) enhancement in therapeutic effects of Compound I and/or the antidiabetic compounds; 2) reduction in side effects of Compound I and/or the antidiabetic compounds; and 3) reduction in a dose of Compound I and/or the antidiabetic compounds.
  • the one or more antidiabetic compounds comprised in the pharmaceutical composition may optionally be selected from the group consisting of insulin signaling pathway modulators, compounds influencing a dysregulated hepatic glucose production, insulin sensitivity enhancers, incretins and insulin secretion enhancers.
  • the one or more antidiabetic compounds comprised in the pharmaceutical composition may optionally be selected from the group consisting of protein tyrosine phosphatase inhibitors, glutamine-fructose-6-phosphate amidotransferase inhibitors, glucose-6-phosphatase inhibitors, fructose-1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glucagon receptor antagonists, phosphoenolpyruvate carboxykinase inhibitors, pyruvate dehydrogenase kinase inhibitors, alpha-glucosidase inhibitors, inhibitors of gastric emptying, glucokinase activators, GLP-1 receptor agonists, GLP-2 receptor agonists, UCP modulators, RXR modulators, GSK-3 inhibitors, PPAR modulators, metformin, insulin, and ⁇ 2 -adrenergic antagonists.
  • protein tyrosine phosphatase inhibitors glutamine-fructos
  • the one or more antidiabetic compounds comprised in the pharmaceutical composition may optionally be selected from the group consisting of GSK-3 inhibitors, retinoid X receptor agonists, Beta-3 AR agonists, UCP modulators, antidiabetic thiazolidinediones, non-glitazone type PPAR gamma agonists, dual PPAR gamma/PPAR alpha agonists, antidiabetic vanadium containing compounds and biguanides.
  • the one or more antidiabetic compounds comprised in the pharmaceutical composition may optionally be thiazolidinediones selected from the group consisting of (S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolidine-2,4-dione, 5- ⁇ [4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxo-propyl)-phenyl]-methyl ⁇ -thiazolidine-2,4-dione, 5- ⁇ [4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl]-thiazolidine-2,4-dione, 5- ⁇ [4-(2-(1-indolyl)ethoxy)phenyl]methyl ⁇ -thiazolidine-2,4-dione, 5- ⁇ 4-[2-(5-methyl-2-phenyl-4-oxazoly)-ethoxy)]]
  • the one or more antidiabetic compounds comprised in the pharmaceutical composition includes metformin.
  • the metformin in this combination comprises one or more pharmaceutically acceptable salts thereof.
  • the metformin in this combination comprises a metformin HCl salt.
  • the metformin in this combination is administered in a daily dose of between 125 and 2550 mg.
  • the metformin in this combination is administered in a daily dose of between 250 and 2550 mg.
  • the one or more antidiabetic compounds comprised in the pharmaceutical composition includes one or more sulphonyl urea derivatives.
  • the one or more antidiabetic compounds comprised in the pharmaceutical composition includes an antidiabetic compound selected from the group consisting of glisoxepid, glyburide, glibenclamide, acetohexamide, chloropropamide, glibornuride, tolbutamide, tolazamide, glipizide, carbutamide, gliquidone, glyhexamide, phenbutamide, tolcyclamide, glimepiride and gliclazide, including any pharmaceutically acceptable salts thereof.
  • the one or more antidiabetic compounds comprised in the pharmaceutical composition includes glimepiride.
  • the one or more antidiabetic compounds comprised in the pharmaceutical composition includes an antidiabetic compound selected from the group consisting of incretin hormones or mimics thereof, beta-cell imidazoline receptor antagonists, and short-acting insulin secretagogues.
  • the one or more antidiabetic compounds comprised in the pharmaceutical composition includes insulin.
  • the one or more antidiabetic compounds comprised in the pharmaceutical composition includes one or more GLP-1 agonists.
  • the one or more antidiabetic compounds comprised in the pharmaceutical composition includes one or more GLP-2 agonists, including human recombinant forms of GLP-2.
  • the one or more antidiabetic compounds comprised in the pharmaceutical composition includes one or more antidiabetic D-phenylalanine derivatives.
  • the one or more antidiabetic compounds comprised in the pharmaceutical composition includes an antidiabetic compound selected from the group consisting of repaglinide and nateglinide, including any pharmaceutically acceptable salts thereof.
  • the one or more antidiabetic compounds comprised in the pharmaceutical composition includes mitiglinide calcium salt hydrate.
  • the one or more antidiabetic compounds comprised in the pharmaceutical composition includes one or more alpha-Glucosidase inhibitors.
  • the one or more antidiabetic compounds comprised in the pharmaceutical composition includes an antidiabetic compound selected from the group consisting of acarbose, voglibose and miglitol, including any pharmaceutically acceptable salts thereof.
  • the one or more antidiabetic compounds comprised in the pharmaceutical composition includes voglibose.
  • the voglibose in this combination is administered in a daily dose of between 0.1 and 1 mg.
  • the one or more antidiabetic compounds comprised in the pharmaceutical composition includes rosiglitazone, including any pharmaceutically acceptable salts thereof.
  • the rosiglitazone in this combination comprises a rosiglitazone maleate salt.
  • the one or more antidiabetic compounds comprised in the pharmaceutical composition may also optionally be tesaglitazar, muraglitazar or naveglitazar, including any pharmaceutically acceptable salts thereof.
  • the one or more antidiabetic compounds comprised in the pharmaceutical composition includes pioglitazone, including any pharmaceutically acceptable salts thereof.
  • the pioglitazone in this combination comprises a pioglitazone HCl salt.
  • the pioglitazone in this combination is administered in a daily dose of between 7.5 and 60 mg.
  • the pioglitazone in this combination is administered in a daily dose of between 15 and 45 mg.
  • the one or more antidiabetic compounds comprised in the pharmaceutical composition includes metformin and pioglitazone.
  • the pioglitazone in this combination comprises one or more pharmaceutically acceptable salts thereof.
  • the pioglitazone in this combination comprises a pioglitazone HCl salt.
  • the pioglitazone in this combination is administered in a daily dose of between 7.5 and 60 mg.
  • the pioglitazone in this combination is administered in a daily dose of between 15 and 45 mg.
  • the metformin in this combination comprises one or more pharmaceutically acceptable salts thereof.
  • the metformin in this combination comprises a metformin HCl salt.
  • the metformin in this combination is administered in a daily dose of between 125 and 2550 mg.
  • the metformin in this combination is administered in a daily dose of between 250 and 2550 mg.
  • Compound I may be administered as a free base or as a pharmaceutically acceptable salt thereof.
  • Compound I is administered as a HCl, methanesulfonate, succinate, benzoate, toluenesulfonate, R-( ⁇ )mandelate or benzenesulfonate salt of Compound I.
  • the pharmaceutical composition may optionally be a single dose form adapted for oral administration, optionally a solid formulation adapted for oral administration, and optionally a tablet or capsule adapted for oral administration.
  • the pharmaceutical formulation may also be an extended release formulation adapted for oral administration.
  • the pharmaceutical composition may be employed to prevent or treat conditions mediated by DPP-IV such as diabetes and more particularly, type 2 diabetes mellitus; diabetic dislipidemia; impaired glucose tolerance (IGT); impaired fasting plasma glucose (IFG); metabolic acidosis; ketosis; appetite regulation; obesity; complications associated with diabetes including diabetic neuropathy, diabetic retinopathy and kidney disease; hyperlipidemia including hypertriglyceridemia, hypercholesteremia, hypoHDLemia and postprandial hyperlipidemia; arteriosclerosis; hypertension; myocardial infarction, angina pectoris, cerebral infarction, cerebral apoplexy and metabolic syndrome.
  • the pharmaceutical composition may optionally be a single dose form adapted for parenteral (subcutaneous, intravenous, subdermal or intramuscular) administration, optionally a solution formulation adapted for parenteral administration, and optionally a suspension formulation adapted for parenteral administration.
  • the pharmaceutical formulation may also be an extended release formulation adapted for oral administration.
  • kits comprising multiple doses of pharmaceutical composition according to the present invention.
  • kits further comprise instructions which comprise one or more forms of information selected from the group consisting of indicating a disease state for which the pharmaceutical composition is to be administered, storage information for the pharmaceutical composition, dosing information and instructions regarding how to administer the pharmaceutical composition.
  • articles of manufacture comprising multiple doses of pharmaceutical composition according to the present invention.
  • the articles of manufacture further comprise packaging materials such as a container for housing the multiple doses of the pharmaceutical composition and or a label indicating one or more members of the group consisting of a disease state for which the compound is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
  • the embodiments should be interpreted as being open ended in the sense that the methods may comprise further actions beyond those specified including the administration of other pharmaceutically active materials to a patient.
  • the pharmaceutical compositions, kits and articles of manufacture may further include other materials including other pharmaceutically active materials.
  • FIG. 1 illustrates DPP IV inhibition in plasma after a single oral administration of Compound I in monkey.
  • Disease specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition that may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the “side effects” of such therapy.
  • “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
  • “Pharmaceutically acceptable salts” means salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include, but are not limited to, acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethane
  • Pharmaceutically acceptable salts also include, but are not limited to, base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases.
  • Acceptable inorganic bases include, but are not limited to, sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide.
  • Acceptable organic bases include, but are not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
  • “Therapeutically effective amount” means that amount of a compound which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.
  • Treatment or “treating” means any administration of a therapeutically effective amount of a compound and includes:
  • the present invention relates generally to the administration of 2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile (referred to herein as “Compound I”) whose structure is provided below.
  • Example 1 describes one method for synthesizing Compound I. It is noted that other methods for synthesizing Compound I may be used as would be appreciated to one of ordinary skill in the art.
  • Compound I may be administered in its free base form and may also be administered in the form of salts, hydrates and prodrugs that are converted in vivo into the free base form of Compound I.
  • Compound I is intended to encompass salts, hydrates and prodrugs of Compound I unless otherwise specified.
  • a pharmaceutically acceptable salt of Compound I preferably confers improved pharmacokinetic properties as compared to the free base form Compound I.
  • Pharmaceutically acceptable salts may also initially confer desirable pharmacokinetic properties on Compound I that it did not previously possess, and may even positively affect the pharmacodynamics of the compound with respect to its therapeutic activity in the body.
  • salts, hydrates and prodrugs of Compound I include, but are not limited to salt forms formed by inorganic or organic acids, e.g., hydrohalides such as hydrochloride, hydrobromide, hydroiodide; other mineral acids and their corresponding salts such as sulfate, nitrate, phosphate, etc.; alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate; and other organic acids and their corresponding salts such as acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate and ascorbate.
  • hydrohalides such as hydrochloride, hydrobromide, hydroiodide
  • other mineral acids and their corresponding salts such as sulfate, nitrate, phosphate, etc.
  • alkyl and monoarylsulfonates such as ethanes
  • Further acid addition salts include, but are not limited to: adipate, alginate, arginate, aspartate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptaoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate, lactobionate, malate, malonate, mandelate, meta
  • Compound I is administered as a HCl, methanesulfonate, succinate, benzoate, toluenesulfonate, R-( ⁇ )mandelate or benzenesulfonate salt of Compound I.
  • Example 1 describes the preparation of the succinate salt form of Compound I.
  • the present invention relates generally to a method comprising administering Compound I to a patient at a daily dose of between 1 mg/day and 250 mg/day of Compound I to a patient, optionally between 2.5 mg and 200 mg of Compound I, optionally between 2.5 mg and 150 mg of Compound I, and optionally between 5 mg and 100 mg of Compound I (in each instance based on the molecular weight of the free base form of Compound I).
  • Specific dosage amounts that may be used include, but are not limited to 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg and 100 mg of Compound I per day. It is noted that unless otherwise specifically specified, Compound I may be administered in its free base form or as a pharmaceutically acceptable salt. However, the dosage amounts and ranges provided herein are always based on the molecular weight of the free base form of Compound I.
  • the present invention also relates to a method comprising administering Compound I to a patient at a once per week dose of between 1 mg/day and 250 mg/day of Compound I, optionally between 10 mg and 200 mg of Compound I, optionally between 10 mg and 150 mg of Compound I, and optionally between 10 mg and 100 mg of Compound I (in each instance based on the molecular weight of the free base form of Compound I).
  • Specific dosage amounts that may be used include, but are not limited to 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg and 100 mg of Compound I per week on a once-per-week regimen. It is noted that unless otherwise specifically specified, Compound I may be administered in its free base form or as a pharmaceutically acceptable salt. However, the dosage amounts and ranges provided herein are always based on the molecular weight of the free base form of Compound I.
  • Compound I may be administered by any route of administration.
  • the method of the present invention is practiced by administering Compound I orally. This type of administration is advantageous in that it is easy and may be self-administered by the patient.
  • Compound I may be administered one or more times per day.
  • An advantage of the present invention is that Compound I can be effectively administered at the dosage levels specified herein one time per day and may also be administered as a single dosage form one time a day.
  • Compound I is suitable for prolonged continuous use and may be administered to patients for an extended period of time. Accordingly, the method may be performed where Compound I is administered to a patient each day (optionally 1 time daily) for a period of at least 1 month, optionally for at least 3 months, and, if necessary, optionally for the duration of the patients disease profile. Because of the long acting DPP-IV inhibitory affects of Compound I, it is envisioned that a dosing regiment less frequent than once per day may be employed.
  • Compound I may be administered at any time during the day.
  • Compound I is administered daily one time a day where administration occurs in the morning before meals. Because Compound I can stimulate insulin secretion when blood glucose level reaches levels above 100 mg/dl, it may be beneficial to have Compound I in systemic circulation before an elevation in blood glucose levels occurs postprandially.
  • Compound I may be administered to any patient who would benefit from a course of treatment leading to the reduction of in vivo DPP-IV activity.
  • FIG. 1 illustrates and Example 3 describes the observed effect that administering Compound I has on monkey plasma DPPIV activity after a single oral administration.
  • Compound I can be effectively used relative to disease states where it is desired to reduce plasma DPPIV activity.
  • the patient's plasma DPPIV activity may be reduced by greater than 60% relative to baseline for a period of at least at least 6 hours, 12 hours, 18 hours and even 24 hours following administration.
  • Examples of particular applications for administering Compound I include, but are not limited to the prevention, delay of progression, and/or treatment of conditions mediated by DPP-IV, in particular diabetes and more particularly, type 2 diabetes mellitus, diabetic dislipidemia, impaired glucose tolerance (IGT), impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis, appetite regulation, obesity and complications associated with diabetes including diabetic neuropathy, diabetic retinopathy, inflammatory bowel disease, Crohn's disease, chemotherapy-induced enteritis, oral mucositis, Shorthened Bowel Syndrome and kidney disease.
  • type 2 diabetes mellitus diabetic dislipidemia
  • IIGT impaired glucose tolerance
  • IGF impaired fasting plasma glucose
  • ketosis ketosis
  • obesity obesity and complications associated with diabetes including diabetic neuropathy, diabetic retinopathy, inflammatory bowel disease, Crohn's disease, chemotherapy-induced enteritis, oral mucositis, Shorthened Bowel Syndrome and kidney disease.
  • the conditions mediated by DPP-IV further includes hyperlipidemia such as hypertriglyceridemia, hypercholesteremia, hypoHDLemia and postprandial hyperlipidemia; arteriosclerosis; hypertension; myocardial infarction, angina pectoris, cerebral infarction, cerebral apoplexy and metabolic syndrome.
  • hyperlipidemia such as hypertriglyceridemia, hypercholesteremia, hypoHDLemia and postprandial hyperlipidemia; arteriosclerosis; hypertension; myocardial infarction, angina pectoris, cerebral infarction, cerebral apoplexy and metabolic syndrome.
  • cardiac measurements that may be improved include, but are not limited to a decrease in mean systolic blood pressure, an increase in HDL cholesterol, improvement in LDL/HDL ratio and a reduction in triglycerides.
  • cardiovascular measurements examples include, but are not limited to a decrease in mean systolic blood pressure, an increase in HDL cholesterol, improvement in LDL/HDL ratio and a reduction in triglycerides.
  • Compound I in combination with one or more antidiabetic or incretin compounds to patients with gastrointestinal inflammatory disorders (including, but not be limited to inflammatory bowel disease, Crohn's disease, chemotherapy-induced enteritis, oral mucositis and Shortened Bowel Syndrome) following a minimum treatment of at least 30 days will improve the health of the mucosal lining of the gastrointestinal tract. Improvement in the health of the mucosal lining of the gastrointestinal tract may be demonstrated by, but is not limited to, an increase in the intestinal surface area, reduced inflammation, and/or increases in absorption of nutrients.
  • gastrointestinal inflammatory disorders including, but not be limited to inflammatory bowel disease, Crohn's disease, chemotherapy-induced enteritis, oral mucositis and Shortened Bowel Syndrome
  • Compound I is administered to a patient with type 2 diabetes. Patients receiving Compound I may also have a malfunction in insulin secretion from pancreatic islets rather than patients who have developed insulin resistance in peripheral insulin sensitive tissues/organs.
  • administering Compound I one time per day, or one time per week, at the dosage levels specified herein may also be used to treat patients who are prediabetic. It is believed that administering Compound I in a patient who is prediabetic serves to delay development of type II diabetes in that patient. Sustained increase in blood glucose desensitizes pancreatic islet function and impairs insulin secretion. By improving cyclic AMP levels and the calcium dynamics in beta cells, the cells activate genes repairing damaged cell components and are less vulnerable to glucose toxicity.
  • Administering Compound I one time per day, or one time per week, at the dosage levels specified herein is expected to have a range of desirous biological effects in vivo. For example, administering Compound I one time per day, or one time per week, at the dosage levels specified herein reduces the patient's blood glucose level when compared with placebo control. Such a decrease in postprandial blood glucose levels helps diabetic patients to maintain lower glucose levels.
  • Administering Compound I one time per day, or one time per week, at the dosage levels specified herein is also expected to have the affect of increasing the patient's insulin level or insulin sensitivity.
  • Insulin facilitates entry of glucose into muscle, adipose and several other tissues. The mechanism by which cells can take up glucose is by facilitated diffusion through stimulation of insulin receptor.
  • C-peptide and insulin are protein chains created by the activation and division of proinsulin (an inactive precursor to insulin). C-peptide and insulin are created and stored in the beta cells of the pancreas. When insulin is released into the bloodstream, equal amounts of C-peptide also are released. This makes C-peptide useful as a marker of insulin production.
  • Administering Compound I according to the present invention is expected to increase the patient's C-peptide level.
  • Administering Compound I one time per day at the dosage levels specified herein is also expected to have the affect of decreasing the patient's hemoglobin A1c level by greater than 0.5% when compared to placebo control after extended treatment with Compound I. Further, administering Compound I one time per week at the dosage levels specified herein is also expected to have the affect of decreasing the patient's hemoglobin A1c level by greater than 0.2% when compared to placebo control after extended treatment with Compound I.
  • Hb-A1c values are known to be directly proportional to the concentration of glucose in the blood over the life span of the red blood cells. Hb-A1c thus gives an indication of a patient's blood glucose levels over the previous last 90 days, skewed to the most recent 30 days. The observed reduction in the patient's hemoglobin A1c level thus verifies the sustained reduction in the patient's blood glucose levels as a result of administering Compound I one time per day at the dosage levels specified herein.
  • the present invention also relates to the use of Compound I in combination with one or more other antidiabetic and/or incretin compounds.
  • other antidiabetic compounds include, but are not limited to insulin signaling pathway modulators, like protein tyrosine phosphatase (PTPase) inhibitors, and glutamine-fructose-6-phosphate amidotransferase (GFAT) inhibitors; compounds influencing a dysregulated hepatic glucose production, like glucose-6-phosphatase (G6 Pase) inhibitors, fructose-1,6-bisphosphatase (F-1,6-BPase) inhibitors, glycogen phosphorylase (GP) inhibitors, glucagon receptor antagonists and phosphoenolpyruvate carboxykinase (PEPCK) inhibitors; pyruvate dehydrogenase kinase (PDHK) inhibitors; insulin sensitivity enhancers (insulin sensitizers); insulin secretion enhancers (insulin secret
  • PTPase inhibitors that may be used in combination with Compound I include, but are not limited to those disclosed in U.S. Pat. Nos. 6,057,316, 6,001,867, and PCT Publication Nos. WO 99/58518, WO 99/58522, WO 99/46268, WO 99/46267, WO 99/46244, WO 99/46237, WO 99/46236, and WO 99/15529.
  • GFAT inhibitors examples include, but are not limited to those disclosed in Mol. Cell. Endocrinol. 1997, 135(1), 67-77.
  • G6 Pase inhibitors that may be used in combination with Compound I include, but are not limited to those disclosed in PCT Publication Nos. WO 00/14090, WO 99/40062 and WO 98/40385, European Patent Publication No. EP682024 and Diabetes 1998, 47, 1630-1636.
  • F-1,6-BPase inhibitors that may be used in combination with Compound I include, but are not limited to those disclosed in PCT Publication Nos. WO 00/14095, WO 99/47549, WO 98/39344, WO 98/39343 and WO 98/39342.
  • Examples of GP inhibitors that may be used in combination with Compound I include, but are not limited to those disclosed in U.S. Pat. No. 5,998,463, PCT Publication Nos. WO 99/26659, WO 97/31901, WO 96/39384 and WO 9639385 and European Patent Publication Nos. EP 978279 and EP 846464.
  • glucagon receptor antagonists that may be used in combination with Compound I include, but are not limited to those disclosed in U.S. Pat. Nos. 5,880,139 and 5,776,954, PCT Publication Nos. WO 99/01423, WO 98/22109, WO 98/22108, WO 98/21957, WO 97/16442 and WO 98/04528 and those described in Bioorg Med. Chem. Lett 1992, 2, 915-918, J. Med. Chem. 1998, 41, 5150-5157, and J. Biol. Chem. 1999, 274; 8694-8697.
  • PEPCK inhibitors that may be used in combination with Compound I include, but are not limited to those disclosed in U.S. Pat. No. 6,030,837 and Mol. Biol. Diabetes 1994, 2, 283-99.
  • PDHK inhibitors examples include, but are not limited to those disclosed in J. Med. Chem. 42 (1999) 2741-2746.
  • insulin sensitivity enhancers examples include, but are not limited to GSK-3 inhibitors, retinoid X receptor (RXR) agonists, Beta-3 AR agonists, UCP modulators, antidiabetic thiazolidinediones (glitazones), non-glitazone type PPAR gamma agonists, dual PPAR gamma/PPAR alpha agonists, antidiabetic vanadium containing compounds and biguanides such as metformin.
  • RXR retinoid X receptor
  • Beta-3 AR agonists beta-3 AR agonists
  • UCP modulators antidiabetic thiazolidinediones (glitazones), non-glitazone type PPAR gamma agonists, dual PPAR gamma/PPAR alpha agonists, antidiabetic vanadium containing compounds and biguanides such as metformin.
  • GSK-3 inhibitors include, but are not limited to those disclosed in PCT Publication Nos. WO 00/21927 and WO 97/41854.
  • RXR modulators include, but are not limited to those disclosed in U.S. Pat. Nos. 4,981,784, 5,071,773, 5,298,429 and 5,506,102 and PCT Publication Nos. WO89/05355, WO91/06677, WO92/05447, WO93/11235, WO95/18380, WO94/23068, and WO93/23431.
  • Beta-3 AR agonists include, but are not limited to CL-316,243 (Lederle Laboratories) and those disclosed in U.S. Pat. No. 5,705,515 and PCT Publication Nos. WO 99/29672, WO 98/32753, WO 98/20005, WO 98/09625, WO 97/46556, and WO 97/37646.
  • UCP modulators include agonists of UCP-1, UCP-2 and UCP-3.
  • UCP modulators include, but are not limited to those disclosed in Vidal-Puig et al., Biochem. Biophys. Res. Commun., Vol. 235(1) pp. 79-82 (1997).
  • Examples of antidiabetic, PPAR modulating thiazolidinediones include, but are not limited to, (S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolidine-2,4-dione (englitazone), 5- ⁇ [4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxo-propyl)-phenyl]-methyl ⁇ -thiazolidine-2,4-dione (darglitazone), 5- ⁇ [4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl]-thiazolidine-2,4-dione (ciglitazone), 5- ⁇ [4-(2-(1-indolyl)ethoxy)phenyl]methyl ⁇ -thiazolidine-2,4-dione (DRF2189), 5- ⁇ 4-[2-(5-methyl
  • non-glitazone type PPAR gamma agonists include, but are not limited to N-(2-benzoylphenyl)-L-tyrosine analogues, such as GI-262570, reglixane (JTT501) and FK-614 and metaglidasen (MBX-102).
  • Examples of dual PPAR gamma/PPAR alpha agonists include, but are not limited to omega.-[(oxoquinazolinylalkoxy)phenyl]alkanoates and analogs thereof including those described in PCT Publication No. WO 99/08501 and Diabetes 2000, 49(5), 759-767; tesaglitazar, muraglitazar and naveglitazar.
  • Examples of antidiabetic vanadium containing compounds include, but are not limited to those disclosed in the U.S. Pat. No. 5,866,563.
  • Metformin dimethyldiguanide
  • GLUCOPHAGETM hydrochloride salt
  • insulin secretion enhancers include but are not limited to glucagon receptor antagonists (as described above), sulphonyl urea derivatives, incretin hormones or mimics thereof, especially glucagon-like peptide-1 (GLP-1) or GLP-1 agonists, beta-cell imidazoline receptor antagonists, and short-acting insulin secretagogues, like antidiabetic phenylacetic acid derivatives, antidiabetic D-phenylalanine derivatives, and mitiglinide and pharmaceutical acceptable salts thereof.
  • GLP-1 glucagon-like peptide-1
  • beta-cell imidazoline receptor antagonists beta-cell imidazoline receptor antagonists
  • short-acting insulin secretagogues like antidiabetic phenylacetic acid derivatives, antidiabetic D-phenylalanine derivatives, and mitiglinide and pharmaceutical acceptable salts thereof.
  • sulphonyl urea derivatives include, but are not limited to, glisoxepid, glyburide, glibenclamide, acetohexamide, chloropropamide, glibornuride, tolbutamide, tolazamide, glipizide, carbutamide, gliquidone, glyhexamide, phenbutamide, tolcyclamide; glimepiride and gliclazide.
  • Tolbutamide, glibenclamide, gliclazide, glibornuride, gliquidone, glisoxepid and glimepiride can be administered in the form that they are marketed under the trademarks RASTINON HOECHSTTM, AZUGLUCONTM, DIAMICRONTTM, GLUBORIDTM, GLURENORMTM, PRO-DIABANTM and AMARYLTM, respectively.
  • GLP-1 agonists include, but are not limited to those disclosed in U.S. Pat. Nos. 5,120,712, 5,118,666 and 5,512,549, and PCT Publication No. WO 91/11457.
  • GLP-1 agonists include those compounds like GLP-1 (7-37) in which compound the carboxy-terminal amide functionality of Arg 36 is displaced with Gly at the 37 th position of the GLP-1 (7-36)NH 2 molecule and variants and analogs thereof including GLN 9 -GLP-1 (7-37), D-GLN 9 -GLP-1 (7-37), acetyl LYS 9 -GLP-1 (7-37), LYS 18 -GLP-1 (7-37) and, in particular, GLP-1 (7-37)OH, VAL 8 -GLP-1 (7-37), GLY 8 -GLP-1(7-37), THR 8 -GLP-1 (7-37), GLP-1 (7-37) and 4-imidazopropionyl-G
  • GLP-1 agonist a 39-amino acid peptide amide, which is marketed under the trademark BYETTATM.
  • Exenatide has the empirical formula C 184 H 282 N 50 O 60 S and molecular weight of 4186.6 Daltons.
  • amino acid sequence for Exenatide is as follows: H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2
  • GLP-2 glucagon-like peptide-2
  • GLP-2 agonists include, but are not limited to those disclosed in U.S. Pat. No. 7,056,886 and PCT Publication Nos. WO 00/53208, WO 01/49314 and WO 03/099854.
  • a GLP-2 agonist is TEDUGLUTIDETM, a 39-amino acid peptide amide (NPS Pharmaceuticals, Inc.).
  • beta-cell imidazoline receptor antagonists include, but are not limited to those described in PCT Publication No. WO 00/78726 and J. Pharmacol. Exp. Ther. 1996; 278; 82-89.
  • An example of an antidiabetic phenylacetic acid derivative is repaglinide and pharmaceutically acceptable salts thereof.
  • Examples of antidiabetic D-phenylalanine derivatives include, but are not limited to nateglinide (N-[(trans4-isopropylcyclohexyl)-carbonyl]-D-phenylalanine, EP 196222 and EP 526171) and repaglinide ((S)-2-ethoxy-4- ⁇ 2-[[3-methy-1-1-[2-(1-piperidinyl)phenyl]butyl]-amino]-2-oxoethyl ⁇ benzoic acid, EP 0 147 850 A2 and EP 0 207 331 A1).
  • Nateglinide is intended to include the particular crystal forms (polymorphs) disclosed in U.S. Pat. No. 5,488,510 and European Patent Publication No. EP 0526171 B1.
  • Repaglinide and nateglinide may be administered in the form as they are marketed under the trademarks NOVONORMTM and STARLIXTM, respectively.
  • alpha-Glucosidase inhibitors include, but are not limited to, acarbose, N-(1,3-dihydroxy-2-propyl)valiolamine (voglibose) and the 1-deoxynojirimycin derivative miglitol.
  • Acarbose is 4′′,6′′-dideoxy-4′-[(1S)-(1,4,6/5)-4,5,6-trihydroxy-3-hydroxymethyl-2-cyclo-hexenylamino)maltotriose.
  • acarbose can as well be described as O-4,6-dideoxy-4- ⁇ [1S,4R,5S,6S]-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl]-amino)-alpha-D-glucopyranosyl-(1-4)-O-alpha-D-glucopyranosyl-(1-4)-D-glucopyranose.
  • Acarbose and miglitol may be administered in the forms that they are marketed under the trademarks GLUCOBAYTM and DIASTABOL 50TM respectively.
  • inhibitors of gastric emptying other than GLP-1 include, but are not limited to those disclosed in J. Clin. Endocrinol. Metab. 2000, 85(3), 1043-1048, and Diabetes Care 1998; 21; 897-893, especially Amylin and analogs thereof such as pramlintide. Amylin is described in Diabetologia 39, 1996, 492-499.
  • ⁇ 2 -adrenergic antagonists include, but are not limited to midaglizole which is described in Diabetes 36, 1987, 216-220.
  • the insulin that may be used in combination with Compound I include, but are not limited to animal insulin preparations extracted from the pancreas of bovine and pig; human insulin preparations genetically synthesized using Escherichia coli or yeast; zinc insulin; protamine zinc insulin; fragment or derivative of insulin (e.g., INS-1) and an oral insulin preparation.
  • the antidiabetic compound administered in combination with Compound I is selected from the group consisting of nateglinide, mitiglinide, repaglinide, metformin, extendatide, rosiglitazone, tesaglitazar, pioglitazone, glisoxepid, glyburide, glibenclamide, acetohexamide, chloropropamide, glibornuride, tolbutamide, tolazamide, glipizide, carbutamide, gliquidone, glyhexamide, phenbutamide, tolcyclamide, glimepiride and gliclazide, including any pharmaceutically acceptable salts thereof.
  • PTPase inhibitors examples include GSK-3 inhibitors, non-small molecule mimetic compounds, GFAT inhibitors, G6 Pase inhibitors, glucagon receptor antagonists, PEPCK inhibitors, F-1,6-BPase inhibitors, GP inhibitors, RXR modulators, Beta-3 AR agonists, PDHK inhibitors, inhibitors of gastric emptying and UCP modulators are disclosed in the patents, applications and references provided herein.
  • the other antidiabetic compound may be administered (e.g., route and dosage form) in a manner known per se for such compound.
  • Compound I and the other antidiabetic compound may be administered sequentially (i.e., at separate times) or at the same time, either one after the other separately in two separate dose forms or in one combined, single dose form.
  • the other antidiabetic compound is administered with Compound I as a single, combined dosage form.
  • the dose of the antidiabetic compound may be selected from the range known to be clinically employed for such compound.
  • therapeutic compounds of diabetic complications can be used in combination with Compound I in the same manner as the above antidiabetic compounds.
  • therapeutic compounds of diabetic complications include, but are not limited to, aldose reductase inhibitors such as tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, CT-112 and ranirestat; neurotrophic factors and increasing compounds thereof such as NGF, NT-3, BDNF and neurotrophin production-secretion promoters described in WO01/14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole); neuranagenesis stimulators such as Y-128; PKC inhibitors such as ruboxistaurin mesylate; AGE inhibitors such as ALT946, pimagedine
  • antihyperlipemic compounds include, but are not limited to, HMG-CoA reductase inhibitors such as pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin and pitavastatin; squalene synthase inhibitors such as compounds described in WO97/10224 (e.g., N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic acid); fibrate compounds such as bezafibrate, clofibrate, simfibrate and clinofibrate; ACAT inhibitors such as avasimibe and eflucimibe; anion exchange resins such as colestyr
  • antiobestic compounds include, but are not limited to, dexfenfluramine, fenfluramine, phentermine, sibutramine, amfepramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonists such as SB-568849 and SNAP-7941; neuropeptide Y antagonists such as CP-422935; cannabinoid receptor antagonists such as SR-141716 and SR-147778; ghrelin antagonist; 11 ⁇ -hydroxysteroid dehydrogenase inhibitors such as BVT-3498; pancreatic lipase inhibitors such as orlistat and ATL-962; Beta-3 AR agonists such as AJ-9677; peptidic anorexiants such as leptin and CNTF (Ciliary Neurotropic Factor); cholecystokinin agonists such as lintitript and FPL-15849; and feeding de
  • antihypertensive compounds examples include angiotensin converting enzyme inhibitors such as captopril, enalapril and delapril; angiotensin II antagonists such as candesartan cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan, olmesartan medoxomil, tasosartan and 1-[[2′-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid; calcium channel blockers such as manidipine, nifedipine, nicardipine, amlodipine and efonidipine; potassium channel openers such as levcromakalim, L-27152, AL0671 and NIP-121; and clonidine.
  • Compound I may be comprised within a pharmaceutical composition adapted for a variety of routes of administration.
  • Compound I may be comprised within a pharmaceutical composition adapted to be administered by a route selected from the group consisting of orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, intraperitoneally and intrathecally.
  • Compound I may be formulated in a variety of pharmaceutically acceptable compositions including injectable forms (e.g.
  • compositions can be manufactured by known techniques conventionally used in the pharmaceutical industry with a pharmaceutically acceptable carrier conventionally used in the pharmaceutical industry.
  • compositions comprising Compound I are intended to encompass the free base form of Compound I, salts, hydrates and prodrugs of Compound I, as well as other materials that may be included in such composition for its intended purpose, including other active ingredients, unless otherwise specified.
  • Particular salt forms of Compound I include, but are not limited to, the HCl, methanesulfonate, succinate, benzoate, toluenesulfonate, R-( ⁇ )mandelate or benzenesulfonate salt forms of Compound I.
  • Compound I may advantageously be used when administered to a patient at a daily dose of between 1 mg/day and 250 mg/day of Compound I to a patient, optionally between 2.5 mg and 200 mg of Compound I, optionally between 2.5 mg and 150 mg of Compound I, and optionally between 5 mg and 100 mg of Compound I (in each instance based on the molecular weight of the free base form of Compound I).
  • Specific dosage amounts that may be used include, but are not limited to 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg and 100 mg of Compound I per day.
  • compositions of the present invention may be in the form of a single dose form comprising between 1 mg/day and 250 mg/day of Compound I, optionally between 2.5 mg and 200 mg of Compound I, optionally between 2.5 mg and 150 mg of Compound I, and optionally between 5 mg and 100 mg of Compound I.
  • the pharmaceutical composition comprises 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg or 100 mg of Compound I.
  • compositions of the present invention may optionally be adapted for oral administration.
  • such pharmaceutical composition is a solid formulation adapted for oral administration.
  • the composition for example, may be in the form of a tablet or capsule.
  • Example 2 provides examples of solid formulations comprising Compound I adapted for oral administration.
  • such pharmaceutical composition is a liquid formulation adapted for oral administration.
  • compositions of the present invention may optionally be adapted for parenteral administration.
  • such pharmaceutical composition is a solution formulation adapted for parenteral administration.
  • such pharmaceutical composition is a suspension formulation adapted for parenteral administration.
  • compositions of the present invention may optionally comprises Compound I in combination with one or more other antidiabetic or incretin compounds in a combined, single dose form.
  • such combined, single dose form comprising Compound I in combination with one or more other antidiabetic and/or incretin compounds is adapted for oral administration and optionally is a solid oral dose form.
  • such combined, single dose form comprising Compound I in combination with one or more other antidiabetic and/or incretin compounds can be adapted for parenteral administration and optionally is a solution dose form.
  • such combined, single dose form comprising Compound I in combination with one or more other antidiabetic compounds comprises between 1 mg/day and 250 mg/day of Compound I to a patient, optionally between 2.5 mg and 200 mg of Compound I, optionally between 2.5 mg and 150 mg of Compound I, and optionally between 5 mg and 100 mg of Compound I (in each instance based on the molecular weight of the free base form of Compound I).
  • such combined, single dose form comprising Compound I in combination with one or more other antidiabetic compounds comprises 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, and 100 mg of Compound I.
  • any antidiabetic compound, or set of antidiabetic compounds may be combined with Compound I to form such combined, single dose form.
  • such combined, single dose form includes Compound I and one or more members of the group consisting of insulin signaling pathway modulators, like protein tyrosine phosphatase (PTPase) inhibitors, and glutamine-fructose-6-phosphate amidotransferase (GFAT) inhibitors, compounds influencing a dysregulated hepatic glucose production, like glucose-6-phosphatase (G6 Pase) inhibitors, fructose-1,6-bisphosphatase (F-1,6-BPase) inhibitors, glycogen phosphorylase (GP) inhibitors, glucagon receptor antagonists and phosphoenolpyruvate carboxykinase (PEPCK) inhibitors, pyruvate dehydrogenase kinase (PDHK) inhibitors, insulin sensitivity enhancers (insulin sensitizers), insulin secret
  • such combined, single dose form comprises Compound I and an antidiabetic thiazolidinedione.
  • thiazolidinediones that may be used in this variation include, but are not limited to (S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolidine-2,4-dione (englitazone), 5- ⁇ [4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxo-propyl)-phenyl]-methyl ⁇ -thiazolidine-2,4-dione (darglitazone), 5- ⁇ [4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl ⁇ -thiazolidine-2,4-dione (ciglitazone), 5- ⁇ [4-(2-(1-indolyl)ethoxy)phenyl]methyl ⁇ -thiazolidine-2,4-
  • the thiazolidinedione in such combined, single dose form is 5- ⁇ [4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl ⁇ -thiazolidine-2,4-dione (pioglitazone) and its hydrochloride salt which is marketed under the trademark ACTOSTM.
  • the thiazolidinedione is 5- ⁇ [4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl ⁇ -thiazolidine-2,4-dione (rosiglitazone) and its maleate salt.
  • such combined, single dose form comprises Compound I and a non-glitazone type PPAR gamma agonist.
  • such combined, single dose form comprises Compound I and a biguanide.
  • a biguanide that may be used in this variation is Metformin (dimethyldiguanide) and its hydrochloride salt which is marketed under the trademark GLUCOPHAGETM.
  • such combined, single dose form comprises Compound I and a sulphonyl urea derivative.
  • sulphonyl urea derivatives that may be used in this variation include, but are not limited to glisoxepid, glyburide, glibenclamide, acetohexamide, chloropropamide, glibornuride, tolbutamide, tolazamide, glipizide, carbutamide, gliquidone, glyhexamide, phenbutamide, tolcyclamide; glimepiride and gliclazide.
  • Tolbutamide, glibenclamide, gliclazide, glibornuride, gliquidone, glisoxepid and glimepiride can be administered in the form as they are marketed under the trademarks RASTINON HOECHSTTM, AZUGLUCONTM, DIAMICRONTTM, GLUBORIDTM, GLURENORMTM, PRO-DIABANTM and AMARYLTM, respectively.
  • such combined, single dose form comprises Compound I and an antidiabetic D-phenylalanine derivative.
  • antidiabetic D-phenylalanine derivatives include, but are not limited to repaglinide and nateglinide which may be administered in the form as they are marketed under the trademarks NOVONORMTM and STARLIXTM, respectively.
  • such combined, single dose form comprises Compound I and an alpha-Glucosidase inhibitor.
  • alpha-Glucosidase inhibitors include, but are not limited to acarbose, miglitol and voglibose which may be administered in the form as they are marketed under the trademarks GLUCOBAYTM, DIASTABOL 50TM and BASENTM, respectively.
  • the antidiabetic compound administered in combination with Compound I in such combined, single dose form is selected from the group consisting of nateglinide, repaglinide, metformin, extendatide, rosiglitazone, pioglitazone, glisoxepid, glyburide, glibenclamide, acetohexamide, chloropropamide, glibornuride, tolbutamide, tolazamide, glipizide, carbutamide, gliquidone, glyhexamide, phenbutamide, tolcyclamide, glimepiride and gliclazide, including any pharmaceutically acceptable salts thereof.
  • the pharmaceutical composition may optionally be adapted for oral administration and in this regard may optionally be a solid formulation such as a tablet or capsule or may alternatively be in a liquid formulation adapted for oral administration.
  • the dose of the antidiabetic compound may be selected from the range known to be clinically employed for such compound. Any of therapeutic compounds of diabetic complications, antihyperlipemic compounds, antiobestic compounds or antihypertensive compounds can be used in combination with Compound I in the same manner as the above antidiabetic compounds.
  • Examples of therapeutic compounds of diabetic complications include, but are not limited to, aldose reductase inhibitors such as tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, CT-112 and ranirestat; neurotrophic factors and increasing compounds thereof such as NGF, NT-3, BDNF and neurotrophin production-secretion promoters described in WO01/14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole); neuranagenesis stimulators such as Y-128; PKC inhibitors such as ruboxistaurin mesylate; AGE inhibitors such as ALT946, pimagedine, N-phenacylthiazolium bromide (ALT766), ALT-711, EXO-226, pyridorin and pyridoxamine; reactive oxygen scavengers such as
  • antihyperlipemic compounds include, but are not limited to, HMG-CoA reductase inhibitors such as pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin and pitavastatin; squalene synthase inhibitors such as compounds described in WO97/10224 (e.g., N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic acid); fibrate compounds such as bezafibrate, clofibrate, simfibrate and clinofibrate; ACAT inhibitors such as avasimibe and eflucimibe; anion exchange resins such as colestyr
  • antiobestic compounds include, but are not limited to, dexfenfluramine, fenfluramine, phentermine, sibutramine, amfepramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonists such as SB-568849 and SNAP-7941; neuropeptide Y antagonists such as CP-422935; cannabinoid receptor antagonists such as SR-141716 and SR-147778; ghrelin antagonist; 11 ⁇ -hydroxysteroid dehydrogenase inhibitors such as BVT-3498; pancreatic lipase inhibitors such as orlistat and ATL-962; Beta-3 AR agonists such as AJ-9677; peptidic anorexiants such as leptin and CNTF (Ciliary Neurotropic Factor); cholecystokinin agonists such as lintitript and FPL-15849; and feeding de
  • antihypertensive compounds examples include angiotensin converting enzyme inhibitors such as captopril, enalapril and delapril; angiotensin II antagonists such as candesartan cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan, olmesartan medoxomil, tasosartan and 1-[[2′-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid; calcium channel blockers such as manidipine, nifedipine, nicardipine, amlodipine and efonidipine; potassium channel openers such as levcromakalim, L-27152, AL0671 and NIP-121; and clonidine.
  • kits comprising a pharmaceutical composition according to the present invention comprising Compound I (and optionally one or more other antidiabetic compounds) where such kit further comprises instructions that include one or more forms of information selected from the group consisting of indicating a disease state for which the pharmaceutical composition is to be administered, storage information for the pharmaceutical composition, dosing information and instructions regarding how to administer the pharmaceutical composition.
  • the kit may also comprise packaging materials.
  • the packaging material may also comprise a container for housing the pharmaceutical composition.
  • the container may optionally comprise a label indicating the disease state for which the pharmaceutical composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
  • the kit may also comprise additional components for storage or administration of the composition.
  • the kit may also comprise the composition in single or multiple dose forms.
  • the pharmaceutical composition in the kit comprises multiple doses of a pharmaceutical composition according to the present invention wherein such pharmaceutical composition is a single dose form that comprises Compound I in one of the dosage ranges specified herein.
  • the pharmaceutical composition in the kit comprises multiple doses of a pharmaceutical composition according to the present invention wherein such pharmaceutical composition is a single dose form that comprises Compound I and one or more of the other antidiabetic compounds specified herein.
  • the present invention also relates to articles of manufacture comprising a pharmaceutical composition according to the present invention comprising Compound I (and optionally one or more other antidiabetic compounds) where such articles of manufacture further comprise packaging materials.
  • the packaging material comprises a container for housing the composition.
  • the invention provides an article of manufacture where the container comprises a label indicating one or more members of the group consisting of a disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
  • the pharmaceutical composition in the article of manufacture comprises multiple doses of a pharmaceutical composition according to the present invention wherein such pharmaceutical composition is a single dose form that comprises Compound I in one of the dosage ranges specified herein.
  • the pharmaceutical composition in the article of manufacture comprises multiple doses of a pharmaceutical composition according to the present invention wherein such pharmaceutical composition is a single dose form that comprises Compound I and one or more of the other antidiabetic compounds specified herein.
  • the packaging material used in kits and articles of manufacture according to the present invention may form a plurality of divided containers such as a divided bottle or a divided foil packet.
  • the container can be in any conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a “refill” of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule.
  • the container that is employed will depend on the exact dosage form involved. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle that is in turn contained within a box.
  • Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material (preferably stiff transparent plastic material) covered with a foil. During the packaging process recesses are formed in the stiff material. The recesses have the size and shape of individual tablets or capsules to be packed or may have the size and shape to accommodate multiple tablets and/or capsules to be packed. Next, the tablets or capsules are placed in the recesses accordingly and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed.
  • the tablets or capsules are individually sealed or collectively sealed, as desired, in the recesses between the foil and the sheet.
  • the strength of the sheet is preferably such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the foil at the place of the recess. The tablet or capsule can then be removed via said opening.
  • the benzonitrile product may be isolated as the free base if desired, but preferably, the product may be further converted to a corresponding acid addition salt.
  • the benzonitrile product (approximately 10 mg) in a solution of MeOH (1 mL) was treated with various acids (1.05 equivalents). The solutions were allowed to stand for three days open to the air. If a precipitate formed, the mixture was filtered and the salt dried. If no solid formed, the mixture was concentrated in vacuo and the residue isolated.
  • salts of 34 were prepared from the following acids: benzoic, p-toluenesulfonic, succinic, R-( ⁇ )-Mandelic and benzenesulfonic.
  • isolation and/or purification steps of the intermediate compounds in the above described process may optionally be avoided if the intermediates from the reaction mixture are obtained as relatively pure compounds and the by-products or impurities of the reaction mixture do not interfere with the subsequent reaction steps.
  • one or more isolation steps may be eliminated to provide shorter processing times, and the elimination of further processing may also afford higher overall reaction yields.
  • tablet formulations that may be used to administer succinate salt of 2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile (Succinate salt of Compound I) according to the present invention. It is noted that the formulations provided herein may be varied as is known in the art.
  • the exemplary tablet formulations are as follows: 12.5 mg of Compound I (weight of free base form) per tablet Core Tablet Formulation (1) 2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4- 17.0 mg dioxo-3,4-dihydro-2H-pyrimidin-1- ylmethyl]-4-fluoro-benzonitrile (succinate salt) (2) Lactose Monohydrate, NF, Ph, Eur 224.6 mg (FOREMOST 316 FAST FLO) (3) Microcrystalline Cellulose, NF, Ph, Eur 120.1 mg (AVICEL PH 102) (4) Croscarmellose Sodium, NF, Ph, Eur 32.0 mg (AC-DO-SOL) (5) Colloidal Silicon Dioxide, NF, Ph, Eur 3.2 mg (CAB-O-SIL M-5P) (6) Magnesium Stearate, NF, Ph, Eur 3.2 mg (MALLINCKRODT, Non-bovine Hyqual) TOTAL 400.0 mg
  • FIG. 1 illustrates the observed effect that administering Compound I has on the monkey's plasma DPPIV activity post dosing.
  • Compound I reduced DPP-IV activity in monkey's plasma by greater than 90% relative to baseline at 12 hours post dosing.
  • Compound I can be effectively used relative to disease states where it is desired to reduce plasma DPPIV activity.
  • the patient's plasma DPPIV activity may be reduced by greater than 60% relative to baseline for a period of at least at least 6 hours, 12 hours, 18 hours and even 24 hours following administration.
  • Group A had free access to CE-2 powder chow (CLEA Japan) for 21 days.
  • Group B had free access to CE-2 powder chow (CLEA Japan) containing 0.03% (w/w) of succinate salt of Compound I for 21 days.
  • the dose of Compound I in Group B was calculated to be 74.8 ⁇ 2.5 (mean ⁇ SD) mg/kg body weight/day.
  • Group C had free access to CE-2 powder chow (CLEA Japan) containing 0.0075% (w/w) of pioglitazone hydrochloride for 21 days.
  • the dose of pioglitazone in Group C was calculated to be 17.7 ⁇ 0.6 (mean ⁇ SD) mg/kg body weight/day.
  • Group D had free access to CE-2 powder chow (CLEA Japan) containing 0.03% (w/w) of succinate salt of Compound I in combination with 0.0075% (w/w) of pioglitazone hydrochloride for 21 days.
  • the doses of Compound I and pioglitazone in Group D were calculated to be 63.1 ⁇ 1.9 (mean ⁇ SD) mg/kg body weight/day and 15.8 ⁇ 0.5 (mean ⁇ SD) mg/kg body weight/day, respectively.
  • 21 days of administration of the powder chow there were not significant differences in the administration amount of the powder chow in the above 4 groups.
  • blood samples were taken from the orbital veins of the mice by capillary pipette under feeding condition, and plasma glucose levels were enzymatically measured by using Autoanalyzer 7080 (Hitachi, Japan).

Abstract

Pharmaceutical compositions comprising 2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile and pharmaceutically acceptable salts thereof are provided as well as kits and articles of manufacture comprising the pharmaceutical compositions as well as methods of using the pharmaceutical compositions.

Description

    RELATED APPLICATION
  • This application claims the benefit of U.S. Provisional Application No. 60/717,560 filed Sep. 14, 2005 and U.S. Provisional Application No. 60/747,280 filed May 15, 2006, each of which is incorporated herein by reference.
  • FIELD OF THE INVENTION
  • The invention relates to the method of administering compounds used to inhibit dipeptidyl peptidase IV as well as treatment methods based on such administration.
  • DESCRIPTION OF RELATED ART
  • Dipeptidyl Peptidase IV (IUBMB Enzyme Nomenclature EC.3.4.14.5) is a type II membrane protein that has been referred to in the literature by a wide a variety of names including DPP4, DP4, DAP-IV, FAPβ, adenosine deaminase complexing protein 2, adenosine deaminase binding protein (ADAbp), dipeptidyl aminopeptidase IV; Xaa-Pro-dipeptidyl-aminopeptidase; Gly-Pro naphthylamidase; postproline dipeptidyl aminopeptidase IV; lymphocyte antigen CD26; glycoprotein GP110; dipeptidyl peptidase IV; glycylproline aminopeptidase; glycylproline aminopeptidase; X-prolyl dipeptidyl aminopeptidase; pep X; leukocyte antigen CD26; glycylprolyl dipeptidylaminopeptidase; dipeptidyl-peptide hydrolase; glycylprolyl aminopeptidase; dipeptidyl-aminopeptidase IV; DPP IV/CD26; amino acyl-prolyl dipeptidyl aminopeptidase; T cell triggering molecule Tp103; X-PDAP. Dipeptidyl Peptidase IV is referred to herein as “DPP-IV.”
  • DPP-IV is a non-classical serine aminodipeptidase that removes Xaa-Pro dipeptides from the amino terminus (N-terminus) of polypeptides and proteins. DPP-IV dependent slow release of dipeptides of the type X-Gly or X-Ser has also been reported for some naturally occurring peptides.
  • DPP-IV is constitutively expressed on epithelial and endothelial cells of a variety of different tissues (intestine, liver, lung, kidney and placenta), and is also found in body fluids. DPP-IV is also expressed on circulating T-lymphocytes and has been shown to be synonymous with the cell-surface antigen, CD-26.
  • DPP-IV is responsible for the metabolic cleavage of certain endogenous peptides (GLP-1 (7-36), glucagon) in vivo and has demonstrated proteolytic activity against a variety of other peptides (GHRH, NPY, GLP-2, VIP) in vitro.
  • GLP-1 (7-36) is a 29 amino-acid peptide derived by post-translational processing of proglucagon in the small intestine. GLP-1 (7-36) has multiple actions in vivo including the stimulation of insulin secretion, inhibition of glucagon secretion, the promotion of satiety, and the slowing of gastric emptying. Based on its physiological profile, the actions of GLP-1 (7-36) are believed to be beneficial in the prevention and treatment of type II diabetes and potentially obesity. For example, exogenous administration of GLP-1 (7-36) (continuous infusion) in diabetic patients has been found to be efficacious in this patient population. Unfortunately, GLP-1 (7-36) is degraded rapidly in vivo and has been shown to have a short half-life in vivo (t1/2=1.5 minutes).
  • Based on a study of genetically bred DPP-IV knock out mice and on in vivo/in vitro studies with selective DPP-IV inhibitors, DPP-IV has been shown to be the primary degrading enzyme of GLP-1 (7-36) in vivo. GLP-1 (7-36) is degraded by DPP-IV efficiently to GLP-1 (9-36), which has been speculated to act as a physiological antagonist to GLP-1 (7-36). Inhibiting DPP-IV in vivo is therefore believed to be useful for potentiating endogenous levels of GLP-1 (7-36) and attenuating the formation of its antagonist GLP-1 (9-36). Thus, DPP-IV inhibitors are believed to be useful agents for the prevention, delay of progression, and/or treatment of conditions mediated by DPP-IV, in particular diabetes and more particularly, type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis, appetite regulation and obesity.
  • Several compounds have been shown to inhibit DPP-IV. Nonetheless, a need still exists for new DPP-IV inhibitors and methods of administering such inhibitors for the treatment of disease.
  • SUMMARY OF THE INVENTION
  • A method is provided comprising: administering a daily dose of between 1 mg/day and 250 mg/day of Compound I to a patient, optionally between 2.5 mg and 200 mg of Compound I, optionally between 2.5 mg and 150 mg of Compound I, and optionally between 5 mg and 100 mg of Compound I. In one variation, a daily dose of 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg or 100 mg of Compound I is administered. In another variation, a once-per-week dose of 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg or 100 mg of Compound I is administered.
  • In one variation, administering is performed 1 time per day and may optionally be performed 1 time per day as a single dosage. Optionally, administering is performed 1 time per day for a period of at least 30 days and optionally for a period of at least 60 days.
  • In one variation, administering is performed 1 time per day in the morning and optionally is performed 1 time per day in the morning prior to a first meal of the day for the patient.
  • In one variation, administering is performed 1 time per week and may optionally be performed 1 time per week as a single dosage. Optionally, administering is performed 1 time per week for a period of at least 30 days and optionally for a period of at least 60 days.
  • In one variation, administering is performed 1 time per week in the morning and optionally is performed 1 time per week in the morning prior to a first meal of the day for the patient.
  • Administering may be performed by a wide range of routes of administration including, but not limited to a route selected from the group consisting of orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, intraperitoneally and intrathecally. In one particular variation, administering is performed orally.
  • Compound I may be used to treat a range of diseases. In one variation, administering Compound I is performed to treat type I or type II diabetes disease state of the patient. In another variation, administering Compound I is performed to treat a pre-diabetic patient. In still another variation, administering Compound I is performed to treat an inflammatory bowel disease, Crohn's disease, chemotherapy-induced enteritis, oral mucositis or Shortened Bowel syndrome.
  • In another variation, administering Compound I is performed to treat a patient suffering from conditions mediated by DPP-IV such as diabetes and more particularly, type 2 diabetes mellitus; diabetic dislipidemia; impaired glucose tolerance (IGT); impaired fasting plasma glucose (IFG); metabolic acidosis; ketosis; appetite regulation; obesity; complications associated with diabetes including diabetic neuropathy, diabetic retinopathy and kidney disease; hyperlipidemia including hypertriglyceridemia, hypercholesteremia, hypoHDLemia and postprandial hyperlipidemia; arteriosclerosis; hypertension; myocardial infarction, angina pectoris, cerebral infarction, cerebral apoplexy and metabolic syndrome.
  • A method is also provided for administering Compound I in combination with one or more antidiabetic or incretin compounds other than Compound I. In one variation, such combination therapy method is performed where a daily dose of between 1 mg/day and 250 mg/day of Compound I, optionally between 2.5 mg and 200 mg of Compound I, optionally between 2.5 mg and 150 mg of Compound I, and optionally between 5 mg and 100 mg of Compound I, is administered to a patient. In one variation, a daily dose of 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg or 100 mg of Compound I is administered to a patient in combination with one or more antidiabetic compounds other than Compound I.
  • In one variation, such combination therapy method is performed where a once-per-week dose of between 1 mg and 250 mg of Compound I, optionally between 2.5 mg and 200 mg of Compound I, optionally between 2.5 mg and 150 mg of Compound I, and optionally between 5 mg and 100 mg of Compound I, is administered to a patient. In one variation, a once-per-week dose of 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg or 100 mg, 150 mg or 200 mg of Compound I is administered to a patient in combination with one or more antidiabetic compounds other than Compound I.
  • It is noted that several different dosage ranges for particular antidiabetic and incretin compounds are provided herein. It is intended for the scope of the present invention to include drug combinations covering any of the disclosed ranges for Compound I in combination with any of the dosage ranges described herein for other antidiabetic or incretin compounds.
  • Combination of Compound I with one or more antidiabetic compounds other than Compound I provides excellent effects such as 1) enhancement in therapeutic effects of Compound I and/or the antidiabetic compounds; 2) reduction in side effects of Compound I and/or the antidiabetic compounds; and 3) reduction in a dose of Compound I and/or the antidiabetic compounds.
  • The one or more antidiabetic or incretin compounds administered in combination with Compound I may optionally be selected from the group consisting of insulin signaling pathway modulators, compounds influencing a dysregulated hepatic glucose production, insulin sensitivity enhancers, and insulin secretion enhancers.
  • The one or more antidiabetic or incretin compounds administered in combination with Compound I may also optionally be selected from the group consisting of protein tyrosine phosphatase inhibitors, glutamine-fructose-6-phosphate amidotransferase inhibitors, glucose-6-phosphatase inhibitors, fructose-1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glucagon receptor antagonists, phosphoenolpyruvate carboxykinase inhibitors, pyruvate dehydrogenase kinase inhibitors, alpha-glucosidase inhibitors, inhibitors of gastric emptying, glucokinase activators, GLP-1 receptor agonists, GLP-2 receptor agonists, UCP modulators, RXR modulators, GSK-3 inhibitors, PPAR modulators, metformin, insulin, and α2-adrenergic antagonists.
  • The one or more antidiabetic or incretin compounds administered in combination with Compound I may also optionally be selected from the group consisting of GSK-3 inhibitors, retinoid X receptor agonists, Beta-3 AR agonists, UCP modulators, antidiabetic thiazolidinediones, non-glitazone type PPAR gamma agonists, dual PPAR gamma/PPAR alpha agonists, antidiabetic vanadium containing compounds and biguanides.
  • The one or more antidiabetic or incretin compounds administered in combination with Compound I may also optionally be thiazolidinediones selected from the group consisting of (S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolidine-2,4-dione, 5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxo-propyl)-phenyl]-methyl}-thiazolidine-2,4-dione, 5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl}-thiazolidine-2,4-dione, 5-{[4-(2-(1-indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione, 5-{4-[2-(5-methyl-2-phenyl-4-oxazoly)-ethoxy)]benzyl}-thiazolidine-2,4-dione, 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione, bis{4-[(2,4-dioxo-5-thiazolidinyl)-methyl]phenyl}methane, 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]-benzyl}-thiazolidine-2,4-dione, 5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]-thiazolidine-2,4-dione, 5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenylmethyl)-thiazolidine-2,4-dione, 5-[3-(4-chloro-phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4-dione, 5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl)thiazolidine-2,4-dione, 5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,4-dione, 5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}-thiazolidine-2,4-dione, 5-{[4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)-phenyl]-methyl)-thiazolidine-2,4-dione, 5-[6-(2-fluoro-benzyloxy)-naphthalen-2-ylmethyl]-thiazolidine-2,4-dione, 5-([2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4-dione and 5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl-benzyl)benzamide, including any pharmaceutically acceptable salts thereof.
  • In one variation, the one or more antidiabetic compounds administered in combination with Compound I includes metformin. In one particular variation, the metformin in this combination comprises one or more pharmaceutically acceptable salts thereof. In another particular variation, the metformin in this combination comprises a metformin HCl salt. In still another particular variation, the metformin in this combination is administered in a daily dose of between 125 and 2550 mg. In yet another variation, the metformin in this combination is administered in a daily dose of between 250 and 2550 mg.
  • In another variation, the one or more antidiabetic compounds administered in combination with Compound I includes one or more sulphonyl urea derivatives.
  • The one or more antidiabetic compounds administered in combination with Compound I may also optionally be selected from the group consisting of glisoxepid, glyburide, glibenclamide, acetohexamide, chloropropamide, glibornuride, tolbutamide, tolazamide, glipizide, carbutamide, gliquidone, glyhexamide, phenbutamide, tolcyclamide, glimepiride and gliclazide, including any pharmaceutically acceptable salts thereof. In one variation, the one or more antidiabetic compounds administered in combination with Compound I includes glimepiride.
  • The one or more antidiabetic compounds administered in combination with Compound I may also optionally be selected from the group consisting of incretin hormones or mimics thereof, beta-cell imidazoline receptor antagonists, and short-acting insulin secretagogues.
  • In another variation, the one or more antidiabetic compounds administered in combination with Compound I includes insulin.
  • The one or more antidiabetic compounds administered in combination with Compound I may also optionally be one or more GLP-1 agonists including, for example, extendatide.
  • The one or more antidiabetic compounds administered in combination with Compound I may also optionally be one or more GLP-2 agonists including, for example, human recombinant GLP-2.
  • The one or more antidiabetic compounds administered in combination with Compound I may also optionally be one or more antidiabetic D-phenylalanine derivatives.
  • The one or more antidiabetic compounds administered in combination with Compound I may also optionally be selected from the group consisting of repaglinide, mitiglinide and nateglinide, including any pharmaceutically acceptable salts thereof. In one variation, the one or more antidiabetic compounds administered in combination with Compound I includes mitiglinide calcium salt hydrate.
  • The one or more antidiabetic compounds administered in combination with Compound I may also optionally be one or more alpha-Glucosidase inhibitors.
  • The one or more antidiabetic compounds administered in combination with Compound I may also optionally be selected from the group consisting of acarbose, voglibose and miglitol, including any pharmaceutically acceptable salts thereof. In one variation, the one or more antidiabetic compounds administered in combination with Compound I includes voglibose. In another variation, the voglibose in this combination is administered in a daily dose of between 0.1 and 1 mg.
  • The one or more antidiabetic compounds administered in combination with Compound I may also optionally be rosiglitazone, including any pharmaceutically acceptable salts thereof. In one variation, the rosiglitazone in this combination comprises a rosiglitazone maleate salt
  • The one or more antidiabetic compounds administered in combination with Compound I may also optionally be tesaglitazar, muraglitazar or naveglitazar, including any pharmaceutically acceptable salts thereof.
  • The one or more antidiabetic compounds administered in combination with Compound I may also optionally be pioglitazone, including any pharmaceutically acceptable salts thereof. In one variation, the pioglitazone in this combination comprises a pioglitazone HCl salt. In another variation, the pioglitazone in this combination is administered in a daily dose of between 7.5 and 60 mg. In still another variation, the pioglitazone in this combination is administered in a daily dose of between 15 and 45 mg.
  • The one or more antidiabetic compounds administered in combination with Compound I may also optionally comprise metformin and pioglitazone. In one variation, the pioglitazone in this combination comprises one or more pharmaceutically acceptable salts thereof. In another variation, the pioglitazone in this combination comprises a pioglitazone HCl salt. In still another variation, the pioglitazone in this combination is administered in a daily dose of between 7.5 and 60 mg. In yet another variation, the pioglitazone in this combination is administered in a daily dose of between 15 and 45 mg. In another variation of each of the above variations, the metformin in this combination comprises one or more pharmaceutically acceptable salts thereof. In one particular variation, the metformin in this combination comprises a metformin HCl salt. In another particular variation, the metformin in this combination is administered in a daily dose of between 125 and 2550 mg. In still another variation, the metformin in this combination is administered in a daily dose of between 250 and 2550 mg.
  • In regard to each of the above embodiments and variations thereof, Compound I may be administered as a free base or as a pharmaceutically acceptable salt thereof. In particular variations, Compound I is administered as a HCl, methanesulfonate, succinate, benzoate, toluenesulfonate, R-(−)mandelate or benzenesulfonate salt of Compound I.
  • Pharmaceutical compositions are also provided.
  • In one embodiment, a pharmaceutical composition is provided that is formulated in a single dose form wherein such single dose form comprises between 1 mg/day and 250 mg/day of Compound I, optionally between 2.5 mg and 200 mg of Compound I, optionally between 2.5 mg and 150 mg of Compound I, and optionally between 5 mg and 100 mg of Compound I. In particular variations, the pharmaceutical composition comprises 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg or 100 mg of Compound I.
  • In one embodiment, a pharmaceutical composition is provided that is formulated in a single dose form wherein such single dose form comprises between 1 mg/week and 250 mg/week of Compound I, optionally between 2.5 mg and 200 mg of Compound I, optionally between 2.5 mg and 150 mg of Compound I, and optionally between 5 mg and 100 mg of Compound I. In particular variations, the pharmaceutical composition comprises 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg or 100 mg of Compound I on a once per week basis.
  • In another embodiment, a pharmaceutical composition is provided that comprises Compound I and one or more antidiabetic or incretin compounds other than Compound I in a single dose form. Optionally, Compound I is present in the single dose form in a dosage amount between 1 mg/day and 250 mg/day of Compound I, optionally between 2.5 mg and 200 mg of Compound I, optionally between 2.5 mg and 150 mg of Compound I, and optionally between 5 mg and 100 mg of Compound I. In particular variations, the pharmaceutical composition comprises 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg or 100 mg of Compound I.
  • Combination of Compound I with one or more antidiabetic compounds other than Compound I provides excellent effects such as 1) enhancement in therapeutic effects of Compound I and/or the antidiabetic compounds; 2) reduction in side effects of Compound I and/or the antidiabetic compounds; and 3) reduction in a dose of Compound I and/or the antidiabetic compounds.
  • According to above embodiment, the one or more antidiabetic compounds comprised in the pharmaceutical composition may optionally be selected from the group consisting of insulin signaling pathway modulators, compounds influencing a dysregulated hepatic glucose production, insulin sensitivity enhancers, incretins and insulin secretion enhancers.
  • Also according to above embodiment, the one or more antidiabetic compounds comprised in the pharmaceutical composition may optionally be selected from the group consisting of protein tyrosine phosphatase inhibitors, glutamine-fructose-6-phosphate amidotransferase inhibitors, glucose-6-phosphatase inhibitors, fructose-1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glucagon receptor antagonists, phosphoenolpyruvate carboxykinase inhibitors, pyruvate dehydrogenase kinase inhibitors, alpha-glucosidase inhibitors, inhibitors of gastric emptying, glucokinase activators, GLP-1 receptor agonists, GLP-2 receptor agonists, UCP modulators, RXR modulators, GSK-3 inhibitors, PPAR modulators, metformin, insulin, and α2-adrenergic antagonists.
  • Also according to above embodiment, the one or more antidiabetic compounds comprised in the pharmaceutical composition may optionally be selected from the group consisting of GSK-3 inhibitors, retinoid X receptor agonists, Beta-3 AR agonists, UCP modulators, antidiabetic thiazolidinediones, non-glitazone type PPAR gamma agonists, dual PPAR gamma/PPAR alpha agonists, antidiabetic vanadium containing compounds and biguanides.
  • Also according to above embodiment, the one or more antidiabetic compounds comprised in the pharmaceutical composition may optionally be thiazolidinediones selected from the group consisting of (S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolidine-2,4-dione, 5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxo-propyl)-phenyl]-methyl}-thiazolidine-2,4-dione, 5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl]-thiazolidine-2,4-dione, 5-{[4-(2-(1-indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione, 5-{4-[2-(5-methyl-2-phenyl-4-oxazoly)-ethoxy)]benzyl}-thiazolidine-2,4-dione, 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione, bis{4-[(2,4-dioxo-5-thiazolidinyl)-methyl]phenyl}methane, 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]-benzyl}-thiazolidine-2,4-dione, 5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]-thiazolidine-2,4-dione, 5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenylmethyl)-thiazolidine-2,4-dione, 5-[3-(4-chloro-phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4-dione, 5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl)thiazolidine-2,4-dione, 5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,4-dione, 5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}-thiazolidine-2,4-dione, 5-{[4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)-phenyl]-methyl)-thiazolidine-2,4-dione, 5-[6-(2-fluoro-benzyloxy)-naphthalen-2-ylmethyl]-thiazolidine-2,4-dione, 5-([2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4-dione and 5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl-benzyl)benzamide, including any pharmaceutically acceptable salts thereof.
  • In one variation, the one or more antidiabetic compounds comprised in the pharmaceutical composition includes metformin. In one particular variation, the metformin in this combination comprises one or more pharmaceutically acceptable salts thereof. In another particular variation, the metformin in this combination comprises a metformin HCl salt. In still another particular variation, the metformin in this combination is administered in a daily dose of between 125 and 2550 mg. In yet another variation, the metformin in this combination is administered in a daily dose of between 250 and 2550 mg.
  • In another variation, the one or more antidiabetic compounds comprised in the pharmaceutical composition includes one or more sulphonyl urea derivatives.
  • In another variation, the one or more antidiabetic compounds comprised in the pharmaceutical composition includes an antidiabetic compound selected from the group consisting of glisoxepid, glyburide, glibenclamide, acetohexamide, chloropropamide, glibornuride, tolbutamide, tolazamide, glipizide, carbutamide, gliquidone, glyhexamide, phenbutamide, tolcyclamide, glimepiride and gliclazide, including any pharmaceutically acceptable salts thereof. In one variation, the one or more antidiabetic compounds comprised in the pharmaceutical composition includes glimepiride.
  • In another variation, the one or more antidiabetic compounds comprised in the pharmaceutical composition includes an antidiabetic compound selected from the group consisting of incretin hormones or mimics thereof, beta-cell imidazoline receptor antagonists, and short-acting insulin secretagogues.
  • In another variation, the one or more antidiabetic compounds comprised in the pharmaceutical composition includes insulin.
  • In another variation, the one or more antidiabetic compounds comprised in the pharmaceutical composition includes one or more GLP-1 agonists.
  • In another variation, the one or more antidiabetic compounds comprised in the pharmaceutical composition includes one or more GLP-2 agonists, including human recombinant forms of GLP-2.
  • In another variation, the one or more antidiabetic compounds comprised in the pharmaceutical composition includes one or more antidiabetic D-phenylalanine derivatives.
  • In another variation, the one or more antidiabetic compounds comprised in the pharmaceutical composition includes an antidiabetic compound selected from the group consisting of repaglinide and nateglinide, including any pharmaceutically acceptable salts thereof. In one variation, the one or more antidiabetic compounds comprised in the pharmaceutical composition includes mitiglinide calcium salt hydrate.
  • In another variation, the one or more antidiabetic compounds comprised in the pharmaceutical composition includes one or more alpha-Glucosidase inhibitors.
  • In another variation, the one or more antidiabetic compounds comprised in the pharmaceutical composition includes an antidiabetic compound selected from the group consisting of acarbose, voglibose and miglitol, including any pharmaceutically acceptable salts thereof. In one variation, the one or more antidiabetic compounds comprised in the pharmaceutical composition includes voglibose. In another variation, the voglibose in this combination is administered in a daily dose of between 0.1 and 1 mg.
  • In another variation, the one or more antidiabetic compounds comprised in the pharmaceutical composition includes rosiglitazone, including any pharmaceutically acceptable salts thereof. In one variation, the rosiglitazone in this combination comprises a rosiglitazone maleate salt.
  • The one or more antidiabetic compounds comprised in the pharmaceutical composition may also optionally be tesaglitazar, muraglitazar or naveglitazar, including any pharmaceutically acceptable salts thereof.
  • In another variation, the one or more antidiabetic compounds comprised in the pharmaceutical composition includes pioglitazone, including any pharmaceutically acceptable salts thereof. In one particular variation, the pioglitazone in this combination comprises a pioglitazone HCl salt. In another particular variation, the pioglitazone in this combination is administered in a daily dose of between 7.5 and 60 mg. In still another particular variation, the pioglitazone in this combination is administered in a daily dose of between 15 and 45 mg.
  • In another variation, the one or more antidiabetic compounds comprised in the pharmaceutical composition includes metformin and pioglitazone. In one particular variation, the pioglitazone in this combination comprises one or more pharmaceutically acceptable salts thereof. In another particular variation, the pioglitazone in this combination comprises a pioglitazone HCl salt. In still another particular variation, the pioglitazone in this combination is administered in a daily dose of between 7.5 and 60 mg. In yet another particular variation, the pioglitazone in this combination is administered in a daily dose of between 15 and 45 mg. In a further variation of each of the above variations, the metformin in this combination comprises one or more pharmaceutically acceptable salts thereof. In still a further variation, the metformin in this combination comprises a metformin HCl salt. In yet a further variation, the metformin in this combination is administered in a daily dose of between 125 and 2550 mg. In still a further variation, the metformin in this combination is administered in a daily dose of between 250 and 2550 mg.
  • In regard to each of the above embodiments and variations thereof regarding pharmaceutical compositions, Compound I may be administered as a free base or as a pharmaceutically acceptable salt thereof. In particular variations, Compound I is administered as a HCl, methanesulfonate, succinate, benzoate, toluenesulfonate, R-(−)mandelate or benzenesulfonate salt of Compound I.
  • Also in regard to each of the above embodiments and variations thereof regarding pharmaceutical compositions, the pharmaceutical composition may optionally be a single dose form adapted for oral administration, optionally a solid formulation adapted for oral administration, and optionally a tablet or capsule adapted for oral administration. The pharmaceutical formulation may also be an extended release formulation adapted for oral administration.
  • Also in regard to each of the above embodiments and variations thereof regarding pharmaceutical compositions, the pharmaceutical composition may be employed to prevent or treat conditions mediated by DPP-IV such as diabetes and more particularly, type 2 diabetes mellitus; diabetic dislipidemia; impaired glucose tolerance (IGT); impaired fasting plasma glucose (IFG); metabolic acidosis; ketosis; appetite regulation; obesity; complications associated with diabetes including diabetic neuropathy, diabetic retinopathy and kidney disease; hyperlipidemia including hypertriglyceridemia, hypercholesteremia, hypoHDLemia and postprandial hyperlipidemia; arteriosclerosis; hypertension; myocardial infarction, angina pectoris, cerebral infarction, cerebral apoplexy and metabolic syndrome.
  • Also in regard to each of the above embodiments and variations thereof regarding pharmaceutical compositions, the pharmaceutical composition may optionally be a single dose form adapted for parenteral (subcutaneous, intravenous, subdermal or intramuscular) administration, optionally a solution formulation adapted for parenteral administration, and optionally a suspension formulation adapted for parenteral administration. The pharmaceutical formulation may also be an extended release formulation adapted for oral administration.
  • Also provided are kits comprising multiple doses of pharmaceutical composition according to the present invention.
  • In one variation, the kits further comprise instructions which comprise one or more forms of information selected from the group consisting of indicating a disease state for which the pharmaceutical composition is to be administered, storage information for the pharmaceutical composition, dosing information and instructions regarding how to administer the pharmaceutical composition.
  • Also provided are articles of manufacture comprising multiple doses of pharmaceutical composition according to the present invention. In one variation, the articles of manufacture further comprise packaging materials such as a container for housing the multiple doses of the pharmaceutical composition and or a label indicating one or more members of the group consisting of a disease state for which the compound is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
  • It is noted in regard to all of the above embodiments that the embodiments should be interpreted as being open ended in the sense that the methods may comprise further actions beyond those specified including the administration of other pharmaceutically active materials to a patient. Similarly, unless otherwise specified, the pharmaceutical compositions, kits and articles of manufacture may further include other materials including other pharmaceutically active materials.
  • BRIEF DESCRIPTION OF THE FIGURE
  • FIG. 1 illustrates DPP IV inhibition in plasma after a single oral administration of Compound I in monkey.
  • DEFINITIONS
  • Unless otherwise stated, the following terms used in the specification and claims shall have the following meanings for the purposes of this application.
  • “Disease” specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition that may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the “side effects” of such therapy.
  • “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use.
  • “Pharmaceutically acceptable salts” means salts which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include, but are not limited to, acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like.
  • Pharmaceutically acceptable salts also include, but are not limited to, base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include, but are not limited to, sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include, but are not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.
  • “Therapeutically effective amount” means that amount of a compound which, when administered to an animal for treating a disease, is sufficient to effect such treatment for the disease.
  • “Treatment” or “treating” means any administration of a therapeutically effective amount of a compound and includes:
  • (1) preventing the disease from occurring in an animal which may be predisposed to the disease but does not yet experience or display the pathology or symptomatology of the disease,
  • (2) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the disease (i.e., arresting further development of the pathology and/or symptomatology), or
  • (3) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the disease (i.e., reversing the pathology and/or symptomatology).
  • DETAILED DESCRIPTION OF THE INVENTION 1. 2-[6-(3-AMINO-PIPERIDIN-1-YL)-3-METHYL-2,4-DIOXO-3,4-DIHYDRO-2H-PYRIMIDIN-1-YLMETHYL]-4-FLUORO-BENZONITRILE and Compositions thereof
  • The present invention relates generally to the administration of 2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile (referred to herein as “Compound I”) whose structure is provided below.
    Figure US20070060530A1-20070315-C00001
  • Example 1 describes one method for synthesizing Compound I. It is noted that other methods for synthesizing Compound I may be used as would be appreciated to one of ordinary skill in the art.
  • Compound I may be administered in its free base form and may also be administered in the form of salts, hydrates and prodrugs that are converted in vivo into the free base form of Compound I. For example, it is within the scope of the present invention to administer Compound I as a pharmaceutically acceptable salt derived from various organic and inorganic acids and bases in accordance with procedures well known in the art. As used herein, Compound I is intended to encompass salts, hydrates and prodrugs of Compound I unless otherwise specified.
  • A pharmaceutically acceptable salt of Compound I preferably confers improved pharmacokinetic properties as compared to the free base form Compound I. Pharmaceutically acceptable salts may also initially confer desirable pharmacokinetic properties on Compound I that it did not previously possess, and may even positively affect the pharmacodynamics of the compound with respect to its therapeutic activity in the body.
  • Particular examples of salts, hydrates and prodrugs of Compound I include, but are not limited to salt forms formed by inorganic or organic acids, e.g., hydrohalides such as hydrochloride, hydrobromide, hydroiodide; other mineral acids and their corresponding salts such as sulfate, nitrate, phosphate, etc.; alkyl and monoarylsulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate; and other organic acids and their corresponding salts such as acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate and ascorbate. Further acid addition salts include, but are not limited to: adipate, alginate, arginate, aspartate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate, galacterate (from mucic acid), galacturonate, glucoheptaoate, gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate, lactobionate, malate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate and phthalate.
  • In particular variations, Compound I is administered as a HCl, methanesulfonate, succinate, benzoate, toluenesulfonate, R-(−)mandelate or benzenesulfonate salt of Compound I. Example 1 describes the preparation of the succinate salt form of Compound I.
  • 2. Administration and Use of Compound I
  • The present invention relates generally to a method comprising administering Compound I to a patient at a daily dose of between 1 mg/day and 250 mg/day of Compound I to a patient, optionally between 2.5 mg and 200 mg of Compound I, optionally between 2.5 mg and 150 mg of Compound I, and optionally between 5 mg and 100 mg of Compound I (in each instance based on the molecular weight of the free base form of Compound I). Specific dosage amounts that may be used include, but are not limited to 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg and 100 mg of Compound I per day. It is noted that unless otherwise specifically specified, Compound I may be administered in its free base form or as a pharmaceutically acceptable salt. However, the dosage amounts and ranges provided herein are always based on the molecular weight of the free base form of Compound I.
  • The present invention also relates to a method comprising administering Compound I to a patient at a once per week dose of between 1 mg/day and 250 mg/day of Compound I, optionally between 10 mg and 200 mg of Compound I, optionally between 10 mg and 150 mg of Compound I, and optionally between 10 mg and 100 mg of Compound I (in each instance based on the molecular weight of the free base form of Compound I). Specific dosage amounts that may be used include, but are not limited to 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg and 100 mg of Compound I per week on a once-per-week regimen. It is noted that unless otherwise specifically specified, Compound I may be administered in its free base form or as a pharmaceutically acceptable salt. However, the dosage amounts and ranges provided herein are always based on the molecular weight of the free base form of Compound I.
  • Compound I may be administered by any route of administration. In particular embodiments, however, the method of the present invention is practiced by administering Compound I orally. This type of administration is advantageous in that it is easy and may be self-administered by the patient.
  • Compound I may be administered one or more times per day. An advantage of the present invention, however, is that Compound I can be effectively administered at the dosage levels specified herein one time per day and may also be administered as a single dosage form one time a day. By being able to administer Compound I at the dosage levels specified herein only one time per day and orally, it is easier for patients to self-administer Compound I, thus improving the compliance of usage among patients requiring in vivo inhibition of DPP-IV activity.
  • Advantageously, Compound I is suitable for prolonged continuous use and may be administered to patients for an extended period of time. Accordingly, the method may be performed where Compound I is administered to a patient each day (optionally 1 time daily) for a period of at least 1 month, optionally for at least 3 months, and, if necessary, optionally for the duration of the patients disease profile. Because of the long acting DPP-IV inhibitory affects of Compound I, it is envisioned that a dosing regiment less frequent than once per day may be employed.
  • Advantageously, Compound I may be administered at any time during the day. Optionally, Compound I is administered daily one time a day where administration occurs in the morning before meals. Because Compound I can stimulate insulin secretion when blood glucose level reaches levels above 100 mg/dl, it may be beneficial to have Compound I in systemic circulation before an elevation in blood glucose levels occurs postprandially.
  • Compound I may be administered to any patient who would benefit from a course of treatment leading to the reduction of in vivo DPP-IV activity. FIG. 1 illustrates and Example 3 describes the observed effect that administering Compound I has on monkey plasma DPPIV activity after a single oral administration.
  • As can be seen from the data shown in FIG. 1, by administering Compound I one time per day at the dosage levels specified herein, Compound I can be effectively used relative to disease states where it is desired to reduce plasma DPPIV activity. In view of the data presented, it is believed that when at least 2.5 mg of Compound I is administered to a patient, the patient's plasma DPPIV activity may be reduced by greater than 60% relative to baseline for a period of at least at least 6 hours, 12 hours, 18 hours and even 24 hours following administration.
  • Examples of particular applications for administering Compound I include, but are not limited to the prevention, delay of progression, and/or treatment of conditions mediated by DPP-IV, in particular diabetes and more particularly, type 2 diabetes mellitus, diabetic dislipidemia, impaired glucose tolerance (IGT), impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis, appetite regulation, obesity and complications associated with diabetes including diabetic neuropathy, diabetic retinopathy, inflammatory bowel disease, Crohn's disease, chemotherapy-induced enteritis, oral mucositis, Shorthened Bowel Syndrome and kidney disease. The conditions mediated by DPP-IV further includes hyperlipidemia such as hypertriglyceridemia, hypercholesteremia, hypoHDLemia and postprandial hyperlipidemia; arteriosclerosis; hypertension; myocardial infarction, angina pectoris, cerebral infarction, cerebral apoplexy and metabolic syndrome.
  • It is believed that administration of Compound I to type I or type II diabetic patients following a minimum treatment of at least 30 days will improve one or more cardiovascular measurements. Examples of cardiac measurements that may be improved include, but are not limited to a decrease in mean systolic blood pressure, an increase in HDL cholesterol, improvement in LDL/HDL ratio and a reduction in triglycerides.
  • It is also believed that administration of Compound I in combination with one or more antidiabetic compounds to type I or type II diabetic patients following a minimum treatment of at least 30 days will improve one or more cardiovascular measurements. Examples of cardiac measurements that may be improved include, but are not limited to a decrease in mean systolic blood pressure, an increase in HDL cholesterol, improvement in LDL/HDL ratio and a reduction in triglycerides.
  • It is also believed that administration of Compound I in combination with one or more antidiabetic or incretin compounds to patients with gastrointestinal inflammatory disorders (including, but not be limited to inflammatory bowel disease, Crohn's disease, chemotherapy-induced enteritis, oral mucositis and Shortened Bowel Syndrome) following a minimum treatment of at least 30 days will improve the health of the mucosal lining of the gastrointestinal tract. Improvement in the health of the mucosal lining of the gastrointestinal tract may be demonstrated by, but is not limited to, an increase in the intestinal surface area, reduced inflammation, and/or increases in absorption of nutrients.
  • In one variation, Compound I is administered to a patient with type 2 diabetes. Patients receiving Compound I may also have a malfunction in insulin secretion from pancreatic islets rather than patients who have developed insulin resistance in peripheral insulin sensitive tissues/organs.
  • Advantageously, administering Compound I one time per day, or one time per week, at the dosage levels specified herein may also be used to treat patients who are prediabetic. It is believed that administering Compound I in a patient who is prediabetic serves to delay development of type II diabetes in that patient. Sustained increase in blood glucose desensitizes pancreatic islet function and impairs insulin secretion. By improving cyclic AMP levels and the calcium dynamics in beta cells, the cells activate genes repairing damaged cell components and are less vulnerable to glucose toxicity.
  • Administering Compound I one time per day, or one time per week, at the dosage levels specified herein is expected to have a range of desirous biological effects in vivo. For example, administering Compound I one time per day, or one time per week, at the dosage levels specified herein reduces the patient's blood glucose level when compared with placebo control. Such a decrease in postprandial blood glucose levels helps diabetic patients to maintain lower glucose levels.
  • Administering Compound I one time per day, or one time per week, at the dosage levels specified herein is also expected to have the affect of increasing the patient's insulin level or insulin sensitivity. Insulin facilitates entry of glucose into muscle, adipose and several other tissues. The mechanism by which cells can take up glucose is by facilitated diffusion through stimulation of insulin receptor. C-peptide and insulin are protein chains created by the activation and division of proinsulin (an inactive precursor to insulin). C-peptide and insulin are created and stored in the beta cells of the pancreas. When insulin is released into the bloodstream, equal amounts of C-peptide also are released. This makes C-peptide useful as a marker of insulin production. Administering Compound I according to the present invention is expected to increase the patient's C-peptide level.
  • Administering Compound I one time per day at the dosage levels specified herein is also expected to have the affect of decreasing the patient's hemoglobin A1c level by greater than 0.5% when compared to placebo control after extended treatment with Compound I. Further, administering Compound I one time per week at the dosage levels specified herein is also expected to have the affect of decreasing the patient's hemoglobin A1c level by greater than 0.2% when compared to placebo control after extended treatment with Compound I. Hb-A1c values are known to be directly proportional to the concentration of glucose in the blood over the life span of the red blood cells. Hb-A1c thus gives an indication of a patient's blood glucose levels over the previous last 90 days, skewed to the most recent 30 days. The observed reduction in the patient's hemoglobin A1c level thus verifies the sustained reduction in the patient's blood glucose levels as a result of administering Compound I one time per day at the dosage levels specified herein.
  • 3. Combination Therapy Including Compound I
  • The present invention also relates to the use of Compound I in combination with one or more other antidiabetic and/or incretin compounds. Examples of such other antidiabetic compounds include, but are not limited to insulin signaling pathway modulators, like protein tyrosine phosphatase (PTPase) inhibitors, and glutamine-fructose-6-phosphate amidotransferase (GFAT) inhibitors; compounds influencing a dysregulated hepatic glucose production, like glucose-6-phosphatase (G6 Pase) inhibitors, fructose-1,6-bisphosphatase (F-1,6-BPase) inhibitors, glycogen phosphorylase (GP) inhibitors, glucagon receptor antagonists and phosphoenolpyruvate carboxykinase (PEPCK) inhibitors; pyruvate dehydrogenase kinase (PDHK) inhibitors; insulin sensitivity enhancers (insulin sensitizers); insulin secretion enhancers (insulin secretagogues); alpha-glucosidase inhibitors; inhibitors of gastric emptying; glucokinase activators, GLP-1 receptor agonists, GLP-2 receptor agonists, UCP modulators, RXR modulators, GSK-3 inhibitors, PPAR modulators, metformin, insulin; and α2-adrenergic antagonists. Compound I may be administered with such at least one other antidiabetic compound either simultaneously as a single dose, at the same time as separate doses, or sequentially (i.e., where one is administered before or after the other is administered).
  • Examples of PTPase inhibitors that may be used in combination with Compound I include, but are not limited to those disclosed in U.S. Pat. Nos. 6,057,316, 6,001,867, and PCT Publication Nos. WO 99/58518, WO 99/58522, WO 99/46268, WO 99/46267, WO 99/46244, WO 99/46237, WO 99/46236, and WO 99/15529.
  • Examples of GFAT inhibitors that may be used in combination with Compound I include, but are not limited to those disclosed in Mol. Cell. Endocrinol. 1997, 135(1), 67-77.
  • Examples of G6 Pase inhibitors that may be used in combination with Compound I include, but are not limited to those disclosed in PCT Publication Nos. WO 00/14090, WO 99/40062 and WO 98/40385, European Patent Publication No. EP682024 and Diabetes 1998, 47, 1630-1636.
  • Examples of F-1,6-BPase inhibitors that may be used in combination with Compound I include, but are not limited to those disclosed in PCT Publication Nos. WO 00/14095, WO 99/47549, WO 98/39344, WO 98/39343 and WO 98/39342.
  • Examples of GP inhibitors that may be used in combination with Compound I include, but are not limited to those disclosed in U.S. Pat. No. 5,998,463, PCT Publication Nos. WO 99/26659, WO 97/31901, WO 96/39384 and WO 9639385 and European Patent Publication Nos. EP 978279 and EP 846464.
  • Examples of glucagon receptor antagonists that may be used in combination with Compound I include, but are not limited to those disclosed in U.S. Pat. Nos. 5,880,139 and 5,776,954, PCT Publication Nos. WO 99/01423, WO 98/22109, WO 98/22108, WO 98/21957, WO 97/16442 and WO 98/04528 and those described in Bioorg Med. Chem. Lett 1992, 2, 915-918, J. Med. Chem. 1998, 41, 5150-5157, and J. Biol. Chem. 1999, 274; 8694-8697.
  • Examples of PEPCK inhibitors that may be used in combination with Compound I include, but are not limited to those disclosed in U.S. Pat. No. 6,030,837 and Mol. Biol. Diabetes 1994, 2, 283-99.
  • Examples of PDHK inhibitors that may be used in combination with Compound I include, but are not limited to those disclosed in J. Med. Chem. 42 (1999) 2741-2746.
  • Examples of insulin sensitivity enhancers that may be used in combination with Compound I include, but are not limited to GSK-3 inhibitors, retinoid X receptor (RXR) agonists, Beta-3 AR agonists, UCP modulators, antidiabetic thiazolidinediones (glitazones), non-glitazone type PPAR gamma agonists, dual PPAR gamma/PPAR alpha agonists, antidiabetic vanadium containing compounds and biguanides such as metformin.
  • Examples of GSK-3 inhibitors include, but are not limited to those disclosed in PCT Publication Nos. WO 00/21927 and WO 97/41854.
  • Examples of RXR modulators include, but are not limited to those disclosed in U.S. Pat. Nos. 4,981,784, 5,071,773, 5,298,429 and 5,506,102 and PCT Publication Nos. WO89/05355, WO91/06677, WO92/05447, WO93/11235, WO95/18380, WO94/23068, and WO93/23431.
  • Examples of Beta-3 AR agonists include, but are not limited to CL-316,243 (Lederle Laboratories) and those disclosed in U.S. Pat. No. 5,705,515 and PCT Publication Nos. WO 99/29672, WO 98/32753, WO 98/20005, WO 98/09625, WO 97/46556, and WO 97/37646.
  • Examples of UCP modulators include agonists of UCP-1, UCP-2 and UCP-3. Examples of UCP modulators include, but are not limited to those disclosed in Vidal-Puig et al., Biochem. Biophys. Res. Commun., Vol. 235(1) pp. 79-82 (1997).
  • Examples of antidiabetic, PPAR modulating thiazolidinediones (glitazones) include, but are not limited to, (S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolidine-2,4-dione (englitazone), 5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxo-propyl)-phenyl]-methyl}-thiazolidine-2,4-dione (darglitazone), 5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl]-thiazolidine-2,4-dione (ciglitazone), 5-{[4-(2-(1-indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione (DRF2189), 5-{4-[2-(5-methyl-2-phenyl-4-oxazoly)-ethoxy)]benzyl}-thiazolidine-2,4-dione (BM-13.1246), 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione (AY-31637), bis {4-[(2,4-dioxo-5-thiazolidinyl)-methyl]phenyl}methane (YM268), 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]-benzyl}-thiazolidine-2,4-dione (AD-5075), 5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]-thiazolidine-2,4-dione (DN-108) 5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenylmethyl)-thiazolidine-2,4-dione, 5-[3-(4-chloro-phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4-dione, 5-[3-(4-chlorophenyl])—2-propynyl]-5-(4-fluorophenyl-sulfonyl)thiazolidine-2,4-dione, 5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,4-dione (rosiglitazone), 5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}-thiazolidine-2,4-dione (pioglitazone; marketed under the trademark ACTOS™), 5-[6-(2-fluoro-benzyloxy)-naphthalen-2-ylmethyl]-thiazolidine-2,4-dione (MCC555), 5-([2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4-dione (T-174), edaglitazone (BM-13-1258), rivoglitazone (CS-011), and 5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl-benzyl)benzamide (KRP297).
  • Examples of non-glitazone type PPAR gamma agonists include, but are not limited to N-(2-benzoylphenyl)-L-tyrosine analogues, such as GI-262570, reglixane (JTT501) and FK-614 and metaglidasen (MBX-102).
  • Examples of dual PPAR gamma/PPAR alpha agonists include, but are not limited to omega.-[(oxoquinazolinylalkoxy)phenyl]alkanoates and analogs thereof including those described in PCT Publication No. WO 99/08501 and Diabetes 2000, 49(5), 759-767; tesaglitazar, muraglitazar and naveglitazar.
  • Examples of antidiabetic vanadium containing compounds include, but are not limited to those disclosed in the U.S. Pat. No. 5,866,563.
  • Metformin (dimethyldiguanide) and its hydrochloride salt is marketed under the trademark GLUCOPHAGE™.
  • Examples of insulin secretion enhancers include but are not limited to glucagon receptor antagonists (as described above), sulphonyl urea derivatives, incretin hormones or mimics thereof, especially glucagon-like peptide-1 (GLP-1) or GLP-1 agonists, beta-cell imidazoline receptor antagonists, and short-acting insulin secretagogues, like antidiabetic phenylacetic acid derivatives, antidiabetic D-phenylalanine derivatives, and mitiglinide and pharmaceutical acceptable salts thereof.
  • Examples of sulphonyl urea derivatives include, but are not limited to, glisoxepid, glyburide, glibenclamide, acetohexamide, chloropropamide, glibornuride, tolbutamide, tolazamide, glipizide, carbutamide, gliquidone, glyhexamide, phenbutamide, tolcyclamide; glimepiride and gliclazide. Tolbutamide, glibenclamide, gliclazide, glibornuride, gliquidone, glisoxepid and glimepiride can be administered in the form that they are marketed under the trademarks RASTINON HOECHST™, AZUGLUCON™, DIAMICRONT™, GLUBORID™, GLURENORM™, PRO-DIABAN™ and AMARYL™, respectively.
  • Examples of GLP-1 agonists include, but are not limited to those disclosed in U.S. Pat. Nos. 5,120,712, 5,118,666 and 5,512,549, and PCT Publication No. WO 91/11457. In particular, GLP-1 agonists include those compounds like GLP-1 (7-37) in which compound the carboxy-terminal amide functionality of Arg36 is displaced with Gly at the 37th position of the GLP-1 (7-36)NH2 molecule and variants and analogs thereof including GLN9-GLP-1 (7-37), D-GLN9-GLP-1 (7-37), acetyl LYS9-GLP-1 (7-37), LYS18-GLP-1 (7-37) and, in particular, GLP-1 (7-37)OH, VAL8-GLP-1 (7-37), GLY8-GLP-1(7-37), THR8-GLP-1 (7-37), GLP-1 (7-37) and 4-imidazopropionyl-GLP-1.
  • One particular example of a GLP-1 agonist is Extendatide, a 39-amino acid peptide amide, which is marketed under the trademark BYETTA™. Exenatide has the empirical formula C184H282N50O60S and molecular weight of 4186.6 Daltons. The amino acid sequence for Exenatide is as follows: H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
  • Examples of glucagon-like peptide-2 (GLP-2) or GLP-2 agonists include, but are not limited to those disclosed in U.S. Pat. No. 7,056,886 and PCT Publication Nos. WO 00/53208, WO 01/49314 and WO 03/099854. One particular example of a GLP-2 agonist is TEDUGLUTIDE™, a 39-amino acid peptide amide (NPS Pharmaceuticals, Inc.).
  • Examples of beta-cell imidazoline receptor antagonists include, but are not limited to those described in PCT Publication No. WO 00/78726 and J. Pharmacol. Exp. Ther. 1996; 278; 82-89.
  • An example of an antidiabetic phenylacetic acid derivative is repaglinide and pharmaceutically acceptable salts thereof.
  • Examples of antidiabetic D-phenylalanine derivatives include, but are not limited to nateglinide (N-[(trans4-isopropylcyclohexyl)-carbonyl]-D-phenylalanine, EP 196222 and EP 526171) and repaglinide ((S)-2-ethoxy-4-{2-[[3-methy-1-1-[2-(1-piperidinyl)phenyl]butyl]-amino]-2-oxoethyl}benzoic acid, EP 0 147 850 A2 and EP 0 207 331 A1). Nateglinide is intended to include the particular crystal forms (polymorphs) disclosed in U.S. Pat. No. 5,488,510 and European Patent Publication No. EP 0526171 B1. Repaglinide and nateglinide may be administered in the form as they are marketed under the trademarks NOVONORM™ and STARLIX™, respectively.
  • Examples of alpha-Glucosidase inhibitors include, but are not limited to, acarbose, N-(1,3-dihydroxy-2-propyl)valiolamine (voglibose) and the 1-deoxynojirimycin derivative miglitol. Acarbose is 4″,6″-dideoxy-4′-[(1S)-(1,4,6/5)-4,5,6-trihydroxy-3-hydroxymethyl-2-cyclo-hexenylamino)maltotriose. The structure of acarbose can as well be described as O-4,6-dideoxy-4-{[1S,4R,5S,6S]-4,5,6-trihydroxy-3-(hydroxymethyl)-2-cyclohexen-1-yl]-amino)-alpha-D-glucopyranosyl-(1-4)-O-alpha-D-glucopyranosyl-(1-4)-D-glucopyranose. (U.S. Pat. No. 4,062,950 and European Patent Publication No. EP 0 226 121). Acarbose and miglitol may be administered in the forms that they are marketed under the trademarks GLUCOBAY™ and DIASTABOL 50™ respectively.
  • Examples of inhibitors of gastric emptying other than GLP-1 include, but are not limited to those disclosed in J. Clin. Endocrinol. Metab. 2000, 85(3), 1043-1048, and Diabetes Care 1998; 21; 897-893, especially Amylin and analogs thereof such as pramlintide. Amylin is described in Diabetologia 39, 1996, 492-499.
  • Examples of α2-adrenergic antagonists include, but are not limited to midaglizole which is described in Diabetes 36, 1987, 216-220. The insulin that may be used in combination with Compound I include, but are not limited to animal insulin preparations extracted from the pancreas of bovine and pig; human insulin preparations genetically synthesized using Escherichia coli or yeast; zinc insulin; protamine zinc insulin; fragment or derivative of insulin (e.g., INS-1) and an oral insulin preparation.
  • In one particular embodiment, the antidiabetic compound administered in combination with Compound I is selected from the group consisting of nateglinide, mitiglinide, repaglinide, metformin, extendatide, rosiglitazone, tesaglitazar, pioglitazone, glisoxepid, glyburide, glibenclamide, acetohexamide, chloropropamide, glibornuride, tolbutamide, tolazamide, glipizide, carbutamide, gliquidone, glyhexamide, phenbutamide, tolcyclamide, glimepiride and gliclazide, including any pharmaceutically acceptable salts thereof.
  • Examples of the preparation and formulation of PTPase inhibitors, GSK-3 inhibitors, non-small molecule mimetic compounds, GFAT inhibitors, G6 Pase inhibitors, glucagon receptor antagonists, PEPCK inhibitors, F-1,6-BPase inhibitors, GP inhibitors, RXR modulators, Beta-3 AR agonists, PDHK inhibitors, inhibitors of gastric emptying and UCP modulators are disclosed in the patents, applications and references provided herein.
  • In the case of combination therapy with Compound I, the other antidiabetic compound may be administered (e.g., route and dosage form) in a manner known per se for such compound. Compound I and the other antidiabetic compound may be administered sequentially (i.e., at separate times) or at the same time, either one after the other separately in two separate dose forms or in one combined, single dose form. In one particular embodiment, the other antidiabetic compound is administered with Compound I as a single, combined dosage form. The dose of the antidiabetic compound may be selected from the range known to be clinically employed for such compound. Any of therapeutic compounds of diabetic complications, antihyperlipemic compounds, antiobestic compounds or antihypertensive compounds can be used in combination with Compound I in the same manner as the above antidiabetic compounds. Examples of therapeutic compounds of diabetic complications include, but are not limited to, aldose reductase inhibitors such as tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, CT-112 and ranirestat; neurotrophic factors and increasing compounds thereof such as NGF, NT-3, BDNF and neurotrophin production-secretion promoters described in WO01/14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole); neuranagenesis stimulators such as Y-128; PKC inhibitors such as ruboxistaurin mesylate; AGE inhibitors such as ALT946, pimagedine, N-phenacylthiazolium bromide (ALT766), ALT-711, EXO-226, pyridorin and pyridoxamine; reactive oxygen scavengers such as thioctic acid; cerebral vasodilators such as tiapride and mexiletine; somatostatin receptor agonists such as BIM23190; and apoptosis signal regulating kinase-1 (ASK-1) inhibitors. Examples of antihyperlipemic compounds include, but are not limited to, HMG-CoA reductase inhibitors such as pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin and pitavastatin; squalene synthase inhibitors such as compounds described in WO97/10224 (e.g., N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic acid); fibrate compounds such as bezafibrate, clofibrate, simfibrate and clinofibrate; ACAT inhibitors such as avasimibe and eflucimibe; anion exchange resins such as colestyramine; probucol; nicotinic acid drugs such as nicomol and niceritrol; ethyl icosapentate; and plant sterols such as soysterol and γ-oryzanol. Examples of antiobestic compounds include, but are not limited to, dexfenfluramine, fenfluramine, phentermine, sibutramine, amfepramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonists such as SB-568849 and SNAP-7941; neuropeptide Y antagonists such as CP-422935; cannabinoid receptor antagonists such as SR-141716 and SR-147778; ghrelin antagonist; 11β-hydroxysteroid dehydrogenase inhibitors such as BVT-3498; pancreatic lipase inhibitors such as orlistat and ATL-962; Beta-3 AR agonists such as AJ-9677; peptidic anorexiants such as leptin and CNTF (Ciliary Neurotropic Factor); cholecystokinin agonists such as lintitript and FPL-15849; and feeding deterrent such as P-57. Examples of the antihypertensive compounds include angiotensin converting enzyme inhibitors such as captopril, enalapril and delapril; angiotensin II antagonists such as candesartan cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan, olmesartan medoxomil, tasosartan and 1-[[2′-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid; calcium channel blockers such as manidipine, nifedipine, nicardipine, amlodipine and efonidipine; potassium channel openers such as levcromakalim, L-27152, AL0671 and NIP-121; and clonidine.
  • The structure of the active agents identified herein by code nos., generic or trade names may be taken from the actual edition of the standard compendium “The Merck Index” or from databases, e.g. Patents International (e.g. IMS World Publications). The corresponding content thereof is hereby incorporated by reference. Any person skilled in the art is fully enabled to identify the active agents and, based on these references, likewise enabled to manufacture and test the pharmaceutical indications and properties in standard test models, both in vitro and in vivo.
  • 4. Compositions Comprising Compound I
  • Compound I may be comprised within a pharmaceutical composition adapted for a variety of routes of administration. For example, Compound I may be comprised within a pharmaceutical composition adapted to be administered by a route selected from the group consisting of orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery (for example by catheter or stent), subcutaneously, intraadiposally, intraarticularly, intraperitoneally and intrathecally. As such, Compound I may be formulated in a variety of pharmaceutically acceptable compositions including injectable forms (e.g. subcutaneous, intravenous, intramuscular and intraperitoneal injections), drip infusions, external application forms (e.g. nasal spray preparations, transdermal preparations; ointments, etc.), and suppositories (e.g. rectal and vaginal suppositories). These different pharmaceutically acceptable compositions can be manufactured by known techniques conventionally used in the pharmaceutical industry with a pharmaceutically acceptable carrier conventionally used in the pharmaceutical industry.
  • As used herein, a composition comprising Compound I is intended to encompass the free base form of Compound I, salts, hydrates and prodrugs of Compound I, as well as other materials that may be included in such composition for its intended purpose, including other active ingredients, unless otherwise specified. Particular salt forms of Compound I that may be employed include, but are not limited to, the HCl, methanesulfonate, succinate, benzoate, toluenesulfonate, R-(−)mandelate or benzenesulfonate salt forms of Compound I. As noted above, Compound I may advantageously be used when administered to a patient at a daily dose of between 1 mg/day and 250 mg/day of Compound I to a patient, optionally between 2.5 mg and 200 mg of Compound I, optionally between 2.5 mg and 150 mg of Compound I, and optionally between 5 mg and 100 mg of Compound I (in each instance based on the molecular weight of the free base form of Compound I). Specific dosage amounts that may be used include, but are not limited to 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg and 100 mg of Compound I per day. As also noted above, it is desirable for Compound I to be administered one time per day. Accordingly, pharmaceutical compositions of the present invention may be in the form of a single dose form comprising between 1 mg/day and 250 mg/day of Compound I, optionally between 2.5 mg and 200 mg of Compound I, optionally between 2.5 mg and 150 mg of Compound I, and optionally between 5 mg and 100 mg of Compound I. In specific embodiments, the pharmaceutical composition comprises 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg or 100 mg of Compound I.
  • As also noted above, Compound I may advantageously be used when administered orally. Accordingly, the compositions of the present invention may optionally be adapted for oral administration. In one variation, such pharmaceutical composition is a solid formulation adapted for oral administration. In this regard, the composition, for example, may be in the form of a tablet or capsule. Example 2 provides examples of solid formulations comprising Compound I adapted for oral administration. In another variation, such pharmaceutical composition is a liquid formulation adapted for oral administration.
  • As also noted above, Compound I may advantageously be used when administered parenterally. Accordingly, the compositions of the present invention may optionally be adapted for parenteral administration. In one variation, such pharmaceutical composition is a solution formulation adapted for parenteral administration. In another variation, such pharmaceutical composition is a suspension formulation adapted for parenteral administration.
  • As noted above, Compound I may advantageously be used in combination with one or more other antidiabetic and/or incretin compounds. Accordingly, the compositions of the present invention may optionally comprises Compound I in combination with one or more other antidiabetic or incretin compounds in a combined, single dose form.
  • Optionally, such combined, single dose form comprising Compound I in combination with one or more other antidiabetic and/or incretin compounds is adapted for oral administration and optionally is a solid oral dose form. Alternatively, such combined, single dose form comprising Compound I in combination with one or more other antidiabetic and/or incretin compounds can be adapted for parenteral administration and optionally is a solution dose form.
  • In one variation, such combined, single dose form comprising Compound I in combination with one or more other antidiabetic compounds comprises between 1 mg/day and 250 mg/day of Compound I to a patient, optionally between 2.5 mg and 200 mg of Compound I, optionally between 2.5 mg and 150 mg of Compound I, and optionally between 5 mg and 100 mg of Compound I (in each instance based on the molecular weight of the free base form of Compound I). In specific embodiments, such combined, single dose form comprising Compound I in combination with one or more other antidiabetic compounds comprises 2.5 mg, 5 mg, 6.25 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, and 100 mg of Compound I.
  • Any antidiabetic compound, or set of antidiabetic compounds may be combined with Compound I to form such combined, single dose form. In particular embodiments, such combined, single dose form includes Compound I and one or more members of the group consisting of insulin signaling pathway modulators, like protein tyrosine phosphatase (PTPase) inhibitors, and glutamine-fructose-6-phosphate amidotransferase (GFAT) inhibitors, compounds influencing a dysregulated hepatic glucose production, like glucose-6-phosphatase (G6 Pase) inhibitors, fructose-1,6-bisphosphatase (F-1,6-BPase) inhibitors, glycogen phosphorylase (GP) inhibitors, glucagon receptor antagonists and phosphoenolpyruvate carboxykinase (PEPCK) inhibitors, pyruvate dehydrogenase kinase (PDHK) inhibitors, insulin sensitivity enhancers (insulin sensitizers), insulin secretion enhancers (insulin secretagogues), alpha-glucosidase inhibitors, inhibitors of gastric emptying, glucokinase activators, GLP-1 receptor agonists, GLP-2 receptor agonists, UCP modulators, RXR modulators, GSK-3 inhibitors, PPAR modulators, metformin, insulin, and α2-adrenergic antagonists. Compound I may be administered with such at least one other antidiabetic compound either simultaneously as a single dose, at the same time as separate doses, or sequentially (i.e., where on is administered before or after the other is administered).
  • In one variation, such combined, single dose form comprises Compound I and an antidiabetic thiazolidinedione. Particular examples of thiazolidinediones that may be used in this variation include, but are not limited to (S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolidine-2,4-dione (englitazone), 5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxo-propyl)-phenyl]-methyl}-thiazolidine-2,4-dione (darglitazone), 5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl}-thiazolidine-2,4-dione (ciglitazone), 5-{[4-(2-(1-indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione (DRF2189), 5-{4-[2-(5-methyl-2-phenyl-4-oxazoly)-ethoxy)]benzyl}-thiazolidine-2,4-dione (BM-13.1246), 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione (AY-31637), bis{4-[(2,4-dioxo-5-thiazolidinyl)-methyl]phenyl}methan-e (YM268), 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]-benzyl}-thiazolidine-2,4-dione (AD-5075), 5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]-thiazolidine-2,4-dione (DN-108) 5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenylmethyl)-thiazolidine-2,4-dione, 5-[3-(4-chloro-phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4-dione, 5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl)thiazolidine-2,4-dione, 5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,4-dione (rosiglitazone), 5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}-thiazolidine-2,4-dione (pioglitazone), 5-[6-(2-fluoro-benzyloxy)-naphthalen-2-ylmethyl]-thiazolidine-2,4-dione (MCC555), 5-([2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4-dione (T-174), edaglitazone (BM-13-1258), rivoglitazone (CS-011) and 5-(2,4-dioxothiazolidin-5-ylmethyl)-2-met-hoxy-N-(4-trifluoromethyl-benzyl)benzamide (KRP297).
  • In one particular variation, the thiazolidinedione in such combined, single dose form is 5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}-thiazolidine-2,4-dione (pioglitazone) and its hydrochloride salt which is marketed under the trademark ACTOS™.
  • In another particular variation, the thiazolidinedione is 5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,4-dione (rosiglitazone) and its maleate salt.
  • In another variation, such combined, single dose form comprises Compound I and a non-glitazone type PPAR gamma agonist.
  • In another variation, such combined, single dose form comprises Compound I and a biguanide. A particular example of a biguanide that may be used in this variation is Metformin (dimethyldiguanide) and its hydrochloride salt which is marketed under the trademark GLUCOPHAGE™.
  • In another variation, such combined, single dose form comprises Compound I and a sulphonyl urea derivative. Particular examples of sulphonyl urea derivatives that may be used in this variation include, but are not limited to glisoxepid, glyburide, glibenclamide, acetohexamide, chloropropamide, glibornuride, tolbutamide, tolazamide, glipizide, carbutamide, gliquidone, glyhexamide, phenbutamide, tolcyclamide; glimepiride and gliclazide. Tolbutamide, glibenclamide, gliclazide, glibornuride, gliquidone, glisoxepid and glimepiride can be administered in the form as they are marketed under the trademarks RASTINON HOECHST™, AZUGLUCON™, DIAMICRONT™, GLUBORID™, GLURENORM™, PRO-DIABAN™ and AMARYL™, respectively.
  • In another variation, such combined, single dose form comprises Compound I and an antidiabetic D-phenylalanine derivative. Particular examples of antidiabetic D-phenylalanine derivatives that may be used in this variation include, but are not limited to repaglinide and nateglinide which may be administered in the form as they are marketed under the trademarks NOVONORM™ and STARLIX™, respectively.
  • In another variation, such combined, single dose form comprises Compound I and an alpha-Glucosidase inhibitor. Particular examples of alpha-Glucosidase inhibitors that may be used in this variation include, but are not limited to acarbose, miglitol and voglibose which may be administered in the form as they are marketed under the trademarks GLUCOBAY™, DIASTABOL 50™ and BASEN™, respectively.
  • In one particular embodiment, the antidiabetic compound administered in combination with Compound I in such combined, single dose form is selected from the group consisting of nateglinide, repaglinide, metformin, extendatide, rosiglitazone, pioglitazone, glisoxepid, glyburide, glibenclamide, acetohexamide, chloropropamide, glibornuride, tolbutamide, tolazamide, glipizide, carbutamide, gliquidone, glyhexamide, phenbutamide, tolcyclamide, glimepiride and gliclazide, including any pharmaceutically acceptable salts thereof.
  • In regard to each of the above embodiments and variations regarding a combined, single dose form comprising the combination of Compound I and one or more other antidiabetic compounds, the pharmaceutical composition may optionally be adapted for oral administration and in this regard may optionally be a solid formulation such as a tablet or capsule or may alternatively be in a liquid formulation adapted for oral administration. The dose of the antidiabetic compound may be selected from the range known to be clinically employed for such compound. Any of therapeutic compounds of diabetic complications, antihyperlipemic compounds, antiobestic compounds or antihypertensive compounds can be used in combination with Compound I in the same manner as the above antidiabetic compounds. Examples of therapeutic compounds of diabetic complications include, but are not limited to, aldose reductase inhibitors such as tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, CT-112 and ranirestat; neurotrophic factors and increasing compounds thereof such as NGF, NT-3, BDNF and neurotrophin production-secretion promoters described in WO01/14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole); neuranagenesis stimulators such as Y-128; PKC inhibitors such as ruboxistaurin mesylate; AGE inhibitors such as ALT946, pimagedine, N-phenacylthiazolium bromide (ALT766), ALT-711, EXO-226, pyridorin and pyridoxamine; reactive oxygen scavengers such as thioctic acid; cerebral vasodilators such as tiapride and mexiletine; somatostatin receptor agonists such as BIM23190; and apoptosis signal regulating kinase-1 (ASK-1) inhibitors. Examples of antihyperlipemic compounds include, but are not limited to, HMG-CoA reductase inhibitors such as pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin and pitavastatin; squalene synthase inhibitors such as compounds described in WO97/10224 (e.g., N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]piperidine-4-acetic acid); fibrate compounds such as bezafibrate, clofibrate, simfibrate and clinofibrate; ACAT inhibitors such as avasimibe and eflucimibe; anion exchange resins such as colestyramine; probucol; nicotinic acid drugs such as nicomol and niceritrol; ethyl icosapentate; and plant sterols such as soysterol and γ-oryzanol. Examples of antiobestic compounds include, but are not limited to, dexfenfluramine, fenfluramine, phentermine, sibutramine, amfepramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonists such as SB-568849 and SNAP-7941; neuropeptide Y antagonists such as CP-422935; cannabinoid receptor antagonists such as SR-141716 and SR-147778; ghrelin antagonist; 11β-hydroxysteroid dehydrogenase inhibitors such as BVT-3498; pancreatic lipase inhibitors such as orlistat and ATL-962; Beta-3 AR agonists such as AJ-9677; peptidic anorexiants such as leptin and CNTF (Ciliary Neurotropic Factor); cholecystokinin agonists such as lintitript and FPL-15849; and feeding deterrent such as P-57. Examples of the antihypertensive compounds include angiotensin converting enzyme inhibitors such as captopril, enalapril and delapril; angiotensin II antagonists such as candesartan cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan, olmesartan medoxomil, tasosartan and 1-[[2′-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid; calcium channel blockers such as manidipine, nifedipine, nicardipine, amlodipine and efonidipine; potassium channel openers such as levcromakalim, L-27152, AL0671 and NIP-121; and clonidine.
  • 5. Kits and Articles of Manufacture Comprising Compound I
  • The present invention also relates to kits comprising a pharmaceutical composition according to the present invention comprising Compound I (and optionally one or more other antidiabetic compounds) where such kit further comprises instructions that include one or more forms of information selected from the group consisting of indicating a disease state for which the pharmaceutical composition is to be administered, storage information for the pharmaceutical composition, dosing information and instructions regarding how to administer the pharmaceutical composition. The kit may also comprise packaging materials. The packaging material may also comprise a container for housing the pharmaceutical composition. The container may optionally comprise a label indicating the disease state for which the pharmaceutical composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition. The kit may also comprise additional components for storage or administration of the composition. The kit may also comprise the composition in single or multiple dose forms.
  • In one embodiment, the pharmaceutical composition in the kit comprises multiple doses of a pharmaceutical composition according to the present invention wherein such pharmaceutical composition is a single dose form that comprises Compound I in one of the dosage ranges specified herein.
  • In another embodiment, the pharmaceutical composition in the kit comprises multiple doses of a pharmaceutical composition according to the present invention wherein such pharmaceutical composition is a single dose form that comprises Compound I and one or more of the other antidiabetic compounds specified herein.
  • The present invention also relates to articles of manufacture comprising a pharmaceutical composition according to the present invention comprising Compound I (and optionally one or more other antidiabetic compounds) where such articles of manufacture further comprise packaging materials. In one variation, the packaging material comprises a container for housing the composition. In another variation, the invention provides an article of manufacture where the container comprises a label indicating one or more members of the group consisting of a disease state for which the composition is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
  • In one embodiment, the pharmaceutical composition in the article of manufacture comprises multiple doses of a pharmaceutical composition according to the present invention wherein such pharmaceutical composition is a single dose form that comprises Compound I in one of the dosage ranges specified herein.
  • In another embodiment, the pharmaceutical composition in the article of manufacture comprises multiple doses of a pharmaceutical composition according to the present invention wherein such pharmaceutical composition is a single dose form that comprises Compound I and one or more of the other antidiabetic compounds specified herein.
  • It is noted that the packaging material used in kits and articles of manufacture according to the present invention may form a plurality of divided containers such as a divided bottle or a divided foil packet. The container can be in any conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a “refill” of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule. The container that is employed will depend on the exact dosage form involved. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle that is in turn contained within a box.
  • One particular example of a kit according to the present invention is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material (preferably stiff transparent plastic material) covered with a foil. During the packaging process recesses are formed in the stiff material. The recesses have the size and shape of individual tablets or capsules to be packed or may have the size and shape to accommodate multiple tablets and/or capsules to be packed. Next, the tablets or capsules are placed in the recesses accordingly and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are individually sealed or collectively sealed, as desired, in the recesses between the foil and the sheet. The strength of the sheet is preferably such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the foil at the place of the recess. The tablet or capsule can then be removed via said opening.
  • EXAMPLES 1. Preparation of 2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile and Pharmaceutically Acceptable Salts
  • Figure US20070060530A1-20070315-C00002
  • A mixture of 2-bromo-5fluorotoluene (2) (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) was refluxed for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO4 and the solvent removed to give product 3 (yield 60%). 1H-NMR (400 MHz, CDCl3): δ 7.60 (dd, J=5.6, 8.8 Hz, 1H), 6.93-7.06 (m, 2H), 2.55 (s, 3H).
  • 2-Bromomethyl-4-fluorobenzonitrile (4)
  • A mixture of 4-fluoro-2-methylbenzonitrile (3) (2 g, 14.8 mmol), NBS (2.64 g, 15 mmol) and AIBN (100 mg) in CCl4 was refluxed under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give crude product as an oil, which was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.68 (dd, J=5.2, 8.4 Hz, 1H), 7.28 (dd, J=2.4, 8.8 Hz, 1H), 7.12 (m, 1H), 4.6 (s, 2H).
  • 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (6)
  • A mixture of crude 3-methyl-6-chlorouracil (5) (0.6 g, 3.8 mmol), 2-Bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and K2CO3 (0.5 g, 4 mmol) in DMSO (10 mL) was stirred at 60° C. for 2 hours. The reaction was diluted with water and extracted with EtOAc. The organics were dried over MgSO4 and the solvent removed. The residue was purified by column chromatography. 0.66 g of the product was obtained (yield: 60%). 1H-NMR (400 MHz, CDCl3): δ 7.73 (dd, J=7.2, 8.4 Hz, 1H), 7.26 (d, J=4.0 Hz, 1H), 7.11-7.17 (m, 1H), 6.94 (dd, J=2.0, 9.0 Hz, 1H), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [m+H] calc'd for C13H9ClFN3O2, 293.68; found 293.68.
  • 2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile, TFA salt (1) (TFA Salt of Compound I)
  • Figure US20070060530A1-20070315-C00003
  • 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (5) (300 mg, 1.0 mmol), (R)-3-amino-piperidine dihydrochloride (266 mg, 1.5 mmol) and sodium bicarbonate (500 mg, 5.4 mmol) were stirred in a sealed tube in EtOH (3 mL) at 100° C. for 2 hrs. The final compound was obtained as a TFA salt after HPLC purification. 1H-NMR (400 MHz, CD3OD): δ. 7.77-7.84 (m, 1H), 7.16-7.27 (m, 2H), 5.46 (s, 1H), 5.17-5.34 (ABq, 2H, J=35.2, 15.6 Hz), 3.33-3.47 (m, 2H), 3.22 (s, 3H), 2.98-3.08 (m, 1H), 2.67-2.92 (m, 2H), 2.07-2.17 (m, 1H), 1.82-1.92 (m, 1H), 1.51-1.79 (m, 2H). MS (ES) [m+H] calc'd for C18H20FN5O2, 357.38; found, 357.38.
  • 2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile, HCl Salt
  • Figure US20070060530A1-20070315-C00004
  • The TFA salt of Compound I was suspended in DCM, and then washed with saturated Na2CO3. The organic layer was dried and removed in vacuo. The residue was dissolved in acetonitrile and HCl in dioxane (1.5 eq.) was added at 0° C. The HCl salt was obtained after removing the solvent. 1H-NMR (400 MHz, CD3OD): δ. 7.77-7.84 (m, 1H), 7.12-7.26 (m, 2H), 5.47 (s, 1H), 5.21-5.32 (ABq, 2H, J=32.0, 16.0 Hz), 3.35-3.5 (m, 2H), 3.22 (s, 3H), 3.01-3.1 (m, 1H), 2.69-2.93 (m, 2H), 2.07-2.17 (m, 1H), 1.83-1.93 (m, 1H), 1.55-1.80 (m, 2H). MS (ES) [m+H] calc'd for C18H20FN5O2, 357.38; found, 357.38.
  • General Procedure for the Preparation of Salts of Compound I.
  • The benzonitrile product may be isolated as the free base if desired, but preferably, the product may be further converted to a corresponding acid addition salt. Specifically, the benzonitrile product (approximately 10 mg) in a solution of MeOH (1 mL) was treated with various acids (1.05 equivalents). The solutions were allowed to stand for three days open to the air. If a precipitate formed, the mixture was filtered and the salt dried. If no solid formed, the mixture was concentrated in vacuo and the residue isolated. In this way, salts of 34 were prepared from the following acids: benzoic, p-toluenesulfonic, succinic, R-(−)-Mandelic and benzenesulfonic.
  • The isolation and/or purification steps of the intermediate compounds in the above described process may optionally be avoided if the intermediates from the reaction mixture are obtained as relatively pure compounds and the by-products or impurities of the reaction mixture do not interfere with the subsequent reaction steps. Where feasible, one or more isolation steps may be eliminated to provide shorter processing times, and the elimination of further processing may also afford higher overall reaction yields.
  • 2. Exemplary formulations comprising succinate salt of 2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile
  • Provided are examples of tablet formulations that may be used to administer succinate salt of 2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile (Succinate salt of Compound I) according to the present invention. It is noted that the formulations provided herein may be varied as is known in the art.
  • The exemplary tablet formulations are as follows:
    12.5 mg of Compound I (weight of free base form) per tablet
    Core Tablet Formulation
    (1) 2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4- 17.0 mg
    dioxo-3,4-dihydro-2H-pyrimidin-1-
    ylmethyl]-4-fluoro-benzonitrile (succinate salt)
    (2) Lactose Monohydrate, NF, Ph, Eur 224.6 mg
    (FOREMOST 316 FAST FLO)
    (3) Microcrystalline Cellulose, NF, Ph, Eur 120.1 mg
    (AVICEL PH 102)
    (4) Croscarmellose Sodium, NF, Ph, Eur 32.0 mg
    (AC-DO-SOL)
    (5) Colloidal Silicon Dioxide, NF, Ph, Eur 3.2 mg
    (CAB-O-SIL M-5P)
    (6) Magnesium Stearate, NF, Ph, Eur 3.2 mg
    (MALLINCKRODT, Non-bovine Hyqual)
    TOTAL 400.0 mg
    (per tablet)
    Film Coat (12.0 mg in total)
    (1) Opadry II 85F18422, White - Portion 1 (COLORCON)
    (2) Opadry II 85F18422, White - Portion 2 (COLORCON)
    (3) Opadry II 85F18422, White - Portion 3 (COLORCON)
  • 25 mg of Compound I (weight of free base form) per tablet
    Core Tablet Formulation
    (1) 2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4- 34.0 mg
    dioxo-3,4-dihydro-2H-pyrimidin-1-
    ylmethyl]-4-fluoro-benzonitrile (succinate salt)
    (2) Lactose Monohydrate, NF, Ph, Eur 207.6 mg
    (FOREMOST 316 FAST FLO)
    (3) Microcrystalline Cellulose, NF, Ph, Eur 120.1 mg
    (AVICEL PH 102)
    (4) Croscarmellose Sodium, NF, Ph, Eur 32.0 mg
    (AC-DO-SOL)
    (5) Colloidal Silicon Dioxide, NF, Ph, Eur 3.2 mg
    (CAB-O-SIL M-5P)
    (6) Magnesium Stearate, NF, Ph, Eur 3.2 mg
    (MALLINCKRODT, Non-bovine Hyqual)
    TOTAL 400.0 mg
    (per tablet)
    Film Coat (12.0 mg in total)
    (1) Opadry II 85F18422, White - Portion 1 (COLORCON)
    (2) Opadry II 85F18422, White - Portion 2 (COLORCON)
    (3) Opadry II 85F18422, White - Portion 3 (COLORCON)
  • 50 mg of Compound I (weight of free base form) per tablet
    Core Tablet Formulation
    (1) 2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2, 68.0 mg
    4-dioxo-3,4-dihydro-2H-pyrimidin-1-
    ylmethyl]-4-fluoro-benzonitrile (succinate salt)
    (2) Lactose Monohydrate, NF, Ph, Eur 173.6 mg
    (FOREMOST 316 FAST FLO)
    (3) Microcrystalline Cellulose, NF, Ph, Eur 120.1 mg
    (AVICEL PH 102)
    (4) Croscarmellose Sodium, NF, Ph, Eur 32.0 mg
    (AC-DO-SOL)
    (5) Colloidal Silicon Dioxide, NF, Ph, Eur 3.2 mg
    (CAB-O-SIL M-5P)
    (6) Magnesium Stearate, NF, Ph, Eur 3.2 mg
    (MALLINCKRODT, Non-bovine Hyqual)
    TOTAL 400.0 mg
    (per tablet)
    Film Coat (12.0 mg in total)
    (1) Opadry II 85F18422, White - Portion 1 (COLORCON)
    (2) Opadry II 85F18422, White - Portion 2 (COLORCON)
    (3) Opadry II 85F18422, White - Portion 3 (COLORCON)

    6. Effect of Administration on Plasma DPP-IV Activity
  • A single dose of Compound I was administered orally to monkey at a dosage of 0.3 mg/kg. FIG. 1 illustrates the observed effect that administering Compound I has on the monkey's plasma DPPIV activity post dosing. As can be seen, Compound I reduced DPP-IV activity in monkey's plasma by greater than 90% relative to baseline at 12 hours post dosing. Thus, as can be seen from the data shown in FIG. 1, by administering Compound I one time per day at the dosage levels specified herein, Compound I can be effectively used relative to disease states where it is desired to reduce plasma DPPIV activity. In view of the data presented, it is believed that when at least 25 mg of Compound I is administered to a patient, the patient's plasma DPPIV activity may be reduced by greater than 60% relative to baseline for a period of at least at least 6 hours, 12 hours, 18 hours and even 24 hours following administration.
  • 7. Effect of Co-Administration with Pioglitazone on Plasma Glucose
  • The effect of administering Compound I in combination with pioglitazone was investigated by measuring plasma glucose levels in mice. Male db/db (BKS.Cg-+Leprdb/+Leprdb) mice (6 weeks of age, CLEA Japan (Tokyo, Japan)) were divided into 4 groups (n=7 in each group) comprising Group A to Group D. Group A had free access to CE-2 powder chow (CLEA Japan) for 21 days. Group B had free access to CE-2 powder chow (CLEA Japan) containing 0.03% (w/w) of succinate salt of Compound I for 21 days. The dose of Compound I in Group B was calculated to be 74.8±2.5 (mean±SD) mg/kg body weight/day. Group C had free access to CE-2 powder chow (CLEA Japan) containing 0.0075% (w/w) of pioglitazone hydrochloride for 21 days. The dose of pioglitazone in Group C was calculated to be 17.7±0.6 (mean±SD) mg/kg body weight/day. Group D had free access to CE-2 powder chow (CLEA Japan) containing 0.03% (w/w) of succinate salt of Compound I in combination with 0.0075% (w/w) of pioglitazone hydrochloride for 21 days. The doses of Compound I and pioglitazone in Group D were calculated to be 63.1±1.9 (mean±SD) mg/kg body weight/day and 15.8±0.5 (mean±SD) mg/kg body weight/day, respectively. During 21 days of administration of the powder chow, there were not significant differences in the administration amount of the powder chow in the above 4 groups. After 21 days of administration of the powder chow, blood samples were taken from the orbital veins of the mice by capillary pipette under feeding condition, and plasma glucose levels were enzymatically measured by using Autoanalyzer 7080 (Hitachi, Japan).
  • The results are shown in Table 1. The values in the table means average (n=7)±standard deviation.
    TABLE 1
    Plasma Glucose
    Group (mg/dL)
    Group A (control) 472.9 ± 74.6
    Group B (Compound 1) 410.3 ± 47.9
    Group C (Pioglitazone) 394.4 ± 47.9
    Group D (Compound I + Pioglitazone) 256.1 ± 62.5
  • As shown in Table 1, the combination of Compound I with pioglitazone showed excellent effects of lowering plasma glucose levels.
  • It will be apparent to those skilled in the art that various modifications and variations can be made to the compounds, compositions, kits, and methods of the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention cover the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents.

Claims (92)

1. A method comprising:
administering a daily dose of between 1 mg/day and 250 mg/day of Compound I to a patient.
2. A method according to claim 1, wherein the daily dose of Compound I administered to the patient is between 5 mg and 200 mg.
3. A method according to claim 1, wherein the daily dose of Compound I administered to the patient is between 5 mg and 150 mg.
4. A method according to claim 1, wherein the daily dose of Compound I administered to the patient is between 5 mg and 100 mg.
5. A method according to claim 1, wherein the daily dose of Compound I administered to the patient is 5 mg.
6. A method according to claim 1, wherein the daily dose of Compound I administered to the patient is 6.25 mg.
7. A method according to claim 1, wherein the daily dose of Compound I administered to the patient is 10 mg.
8. A method according to claim 1, wherein the daily dose of Compound I administered to the patient is 20 mg.
9. A method according to claim 1, wherein the daily dose of Compound I administered to the patient is 25 mg.
10. A method according to claim 1, wherein the daily dose of Compound I administered to the patient is 50 mg.
11. A method according to claim 1, wherein the daily dose of Compound I administered to the patient is 100 mg.
12. A method according to claim 1, wherein administering is performed 1 time per day.
13. A method according to claim 1, wherein administering is performed 1 time per day as a single dosage.
14. A method according to claim 1, wherein administering is performed 1 time per day for a period of at least 30 days.
15. A method according to claim 1, wherein administering is performed 1 time per day for a period of at least 60 days.
16. A method according to claim 1, wherein administering is performed 1 time per day in the morning.
17. A method according to claim 1, wherein administering is performed 1 time per day in the morning prior to a first meal of the day for the patient.
18. A method according to claim 1, wherein administering is performed by a route selected from the group consisting of orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery, subcutaneously, intraadiposally, intraarticularly, intraperitoneally and intrathecally.
19. A method according to claim 1, wherein administering is performed orally.
20. A method according to claim 1, wherein administering is performed to treat type I or type II diabetes disease state of the patient.
21. A method according to claim 1, wherein said patient has type II diabetes.
22. A method according to claim 1, wherein said patient is prediabetic.
23. A method according to claim 1, wherein administering comprises administering Compound I in combination with one or more antidiabetic compounds other than Compound I.
24. A method comprising:
administering a daily dose of Compound I to a patient in combination with one or more antidiabetic compounds other than Compound I.
25. A method according to claim 24, wherein administering comprises administering Compound I in combination with one or more antidiabetic compounds selected from the group consisting of insulin signaling pathway modulators, compounds influencing a dysregulated hepatic glucose production, insulin sensitivity enhancers, and insulin secretion enhancers.
26. A method according to claim 24, wherein administering comprises administering Compound I in combination with one or more antidiabetic compounds selected from the group consisting of protein tyrosine phosphatase inhibitors, glutamine-fructose-6-phosphate amidotransferase inhibitors, glucose-6-phosphatase inhibitors, fructose-1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glucagon receptor antagonists, phosphoenolpyruvate carboxykinase inhibitors, pyruvate dehydrogenase kinase inhibitors, alpha-glucosidase inhibitors, inhibitors of gastric emptying, glucokinase activators, GLP-1 receptor agonists, GLP-2 receptor agonists, UCP modulators, RXR modulators, GSK-3 inhibitors, PPAR modulators, insulin, and α2-adrenergic antagonists.
27. A method according to claim 24, wherein administering comprises administering Compound I in combination with one or more antidiabetic compounds selected from the group consisting of GSK-3 inhibitors, retinoid X receptor agonists, Beta-3 AR agonists, UCP modulators, antidiabetic thiazolidinediones, non-glitazone type PPAR gamma agonists, dual PPAR gamma/PPAR alpha agonists, antidiabetic vanadium containing compounds and biguanides.
28. A method according to claim 24, wherein administering comprises administering Compound I in combination with one or more antidiabetic compounds selected from the group consisting of (S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolidine-2,4-dione, 5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxo-propyl)-phenyl]-methyl}-thiazolidine-2,4-dione, 5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl}-thiazolidine-2,4-dione, 5-{[4-(2-(1-indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione, 5-{4-[2-(5-methyl-2-phenyl-4-oxazoly)-ethoxy)]benzyl}-thiazolidine-2,4-dione, 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione, bis {4-[(2,4-dioxo-5-thiazolidinyl)-methyl]phenyl}methane, 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]-benzyl}-thiazolidine-2,4-dione, 5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]-thiazolidine-2,4-dione, 5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenylmethyl)-thiazolidine-2,4-dione, 5-[3-(4-chloro-phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4-dione, 5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl)thiazolidine-2,4-dione, 5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,4-dione, 5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}-thiazolidine-2,4-dione, 5-([2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4-dione and 5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl-benzyl)benzamide, including any pharmaceutically acceptable salts thereof.
29. A method according to claim 24, wherein administering comprises administering Compound I in combination with metformin, including any pharmaceutically acceptable salts thereof.
30. A method according to claim 24, wherein administering comprises administering Compound I in combination with one or more sulphonyl urea derivatives.
31. A method according to claim 24, wherein administering comprises administering Compound I in combination with one or more antidiabetic compounds selected from the group consisting of glisoxepid, glyburide, glibenclamide, acetohexamide, chloropropamide, glibornuride, tolbutamide, tolazamide, glipizide, carbutamide, gliquidone, glyhexamide, phenbutamide, tolcyclamide, glimepiride and gliclazide, including any pharmaceutically acceptable salts thereof.
32. A method according to claim 24, wherein administering comprises administering Compound I in combination with one or more antidiabetic compounds selected from the group consisting of incretin hormones or mimics thereof, beta-cell imidazoline receptor antagonists, and short-acting insulin secretagogues.
33. A method according to claim 24, wherein administering comprises administering Compound I in combination with insulin.
34. A method according to claim 24, wherein administering comprises administering Compound I in combination with one or more GLP-1 agonists.
35. A method according to claim 24, wherein administering comprises administering Compound I in combination with one or more GLP-2 agonists.
36. A method according to claim 24, wherein administering comprises administering Compound I in combination with extendatide.
37. A method according to claim 24, wherein administering comprises administering Compound I in combination with one or more antidiabetic compounds selected from the group consisting of repaglinide, mitiglinide and nateglinide, including any pharmaceutically acceptable salts thereof.
38. A method according to claim 24, wherein administering comprises administering Compound I in combination with one or more alpha-Glucosidase inhibitors.
39. A method according to claim 24, wherein administering comprises administering Compound I in combination with one or more antidiabetic compounds selected from the group consisting of acarbose, voglibose and miglitol, including any pharmaceutically acceptable salts thereof.
40. A method according to claim 24, wherein administering comprises administering Compound I in combination with rosiglitazone, including any pharmaceutically acceptable salts thereof.
41. A method according to claim 24, wherein administering comprises administering Compound I in combination with pioglitazone, including any pharmaceutically acceptable salts thereof.
42. A method according to claim 41, wherein the pioglitazone comprises pioglitazone HCl.
43. A method according to claim 24, wherein administering comprises administering Compound I in combination with metformin and pioglitazone, including any pharmaceutically acceptable salts thereof.
44. A method according to claim 43, wherein the pioglitazone comprises pioglitazone HCl.
45. A method according to claim 1, wherein Compound I is administered as a free base.
46. A method according to claim 1, wherein Compound I is administered as a pharmaceutically acceptable salt.
47. A method according to claim 1, wherein Compound I is administered as a succinate salt.
48. A pharmaceutical composition formulated in a single dose form wherein such single dose form comprises between 1 mg and 250 mg of Compound I.
49. A pharmaceutical composition according to claim 48, wherein such single dose form comprises between 5 mg and 200 mg of Compound I.
50. A pharmaceutical composition according to claim 48, wherein such single dose form comprises between 5 mg and 150 mg of Compound I.
51. A pharmaceutical composition according to claim 48, wherein such single dose form comprises between 15 mg and 100 mg of Compound I.
52. A pharmaceutical composition according to claim 48, wherein such single dose form comprises 5 mg of Compound I.
53. A pharmaceutical composition according to claim 48, wherein such single dose form comprises 6.25 mg of Compound I.
54. A pharmaceutical composition according to claim 48, wherein such single dose form comprises 10 mg of Compound I.
55. A pharmaceutical composition according to claim 48, wherein such single dose form comprises 20 mg of Compound I.
56. A pharmaceutical composition according to claim 48, wherein such single dose form comprises 25 mg of Compound I.
57. A pharmaceutical composition according to claim 48, wherein such single dose form comprises 50 mg of Compound I.
58. A pharmaceutical composition according to claim 48, wherein such single dose form comprises 100 mg of Compound I.
59. A pharmaceutical composition according to claim 48, wherein such single dose form further comprises one or more antidiabetic compounds other than Compound I.
60. A pharmaceutical composition formulated in a single dose form wherein such single dose form comprises Compound I and one or more antidiabetic compounds other than Compound I.
61. A pharmaceutical composition according to claim 60, wherein such single dose form comprises one or more antidiabetic compounds selected from the group consisting of insulin signaling pathway modulators, compounds influencing a dysregulated hepatic glucose production, insulin sensitivity enhancers, and insulin secretion enhancers.
62. A pharmaceutical composition according to claim 60, wherein such single dose form comprises one or more antidiabetic compounds selected from the group consisting of protein tyrosine phosphatase inhibitors, glutamine-fructose-6-phosphate amidotransferase inhibitors, glucose-6-phosphatase inhibitors, fructose-1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glucagon receptor antagonists, phosphoenolpyruvate carboxykinase inhibitors, pyruvate dehydrogenase kinase inhibitors, alpha-glucosidase inhibitors, inhibitors of gastric emptying, insulin, and α2-adrenergic antagonists.
63. A pharmaceutical composition according to claim 60, wherein such single dose form comprises one or more antidiabetic compounds selected from the group consisting of GSK-3 inhibitors, retinoid X receptor agonists, Beta-3 AR agonists, UCP modulators, antidiabetic thiazolidinediones, non-glitazone type PPAR gamma agonists, dual PPAR gamma/PPAR alpha agonists, antidiabetic vanadium containing compounds and biguanides.
64. A pharmaceutical composition according to claim 60, wherein such single dose form comprises one or more antidiabetic compounds selected from the group consisting of (S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolidine-2,4-dione, 5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxo-propyl)-phenyl]-methyl}-thiazolidine-2,4-dione, 5-{[4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl}-thiazolidine-2,4-dione, 5-{[4-(2-(1-indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione, 5-{4-[2-(5-methyl-2-phenyl-4-oxazoly)-ethoxy)]benzyl}-thiazolidine-2,4-dione, 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione, bis{4-[(2,4-dioxo-5-thiazolidinyl)-methyl]phenyl}methane, 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]-benzyl}-thiazolidine-2,4-dione, 5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]-thiazolidine-2,4-dione, 5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenylmethyl)-thiazolidine-2,4-dione, 5-[3-(4-chloro-phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4-dione, 5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl)thiazolidine-2,4-dione, 5-{[4-(2-(methyl-2-pyridinyl-amino)-ethoxy)phenyl]methyl}-thiazolidine-2,4-dione, 5-([2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4-dione and 5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl-benzyl)benzamide, including any pharmaceutically acceptable salts thereof.
65. A pharmaceutical composition according to claim 60, wherein such single dose form comprises metformin, including any pharmaceutically acceptable salts thereof.
66. A pharmaceutical composition according to claim 60, wherein such single dose form comprises a sulphonyl urea derivative.
67. A pharmaceutical composition according to claim 60, wherein such single dose form comprises one or more antidiabetic compounds selected from the group consisting of glisoxepid, glyburide, glibenclamide, acetohexamide, chloropropamide, glibornuride, tolbutamide, tolazamide, glipizide, carbutamide, gliquidone, glyhexamide, phenbutamide, tolcyclamide, glimepiride and gliclazide, including any pharmaceutically acceptable salts thereof.
68. A pharmaceutical composition according to claim 60, wherein such single dose form comprises one or more antidiabetic compounds selected from the group consisting of incretin hormones or mimics thereof, beta-cell imidazoline receptor antagonists, and short-acting insulin secretagogues.
69. A pharmaceutical composition according to claim 60, wherein such single dose form comprises insulin.
70. A pharmaceutical composition according to claim 60, wherein such single dose form comprises one or more GLP-1 agonists.
71. A pharmaceutical composition according to claim 60, wherein such single dose form comprises one or more GLP-2 agonists.
72. A pharmaceutical composition according to claim 60, wherein such single dose form comprises extendatide.
73. A pharmaceutical composition according to claim 60, wherein such single dose form comprises one or more antidiabetic compounds selected from the group consisting of repaglinide, mitiglinide and nateglinide, including any pharmaceutically acceptable salts thereof.
74. A pharmaceutical composition according to claim 60, wherein such single dose form comprises one or more alpha-Glucosidase inhibitors.
75. A pharmaceutical composition according to claim 60, wherein such single dose form comprises one or more antidiabetic compounds selected from the group consisting of acarbose, voglibose and miglitol, including any pharmaceutically acceptable salts thereof.
76. A pharmaceutical composition according to claim 60, wherein such single dose form comprises rosiglitazone, including any pharmaceutically acceptable salts thereof.
77. A pharmaceutical composition according to claim 60, wherein such single dose form comprises pioglitazone, including any pharmaceutically acceptable salts thereof.
78. A pharmaceutical composition according to claim 77, wherein the pioglitazone comprises pioglitazone HCl.
79. A pharmaceutical composition according to claim 60, wherein such single dose form comprises metformin and pioglitazone, including any pharmaceutically acceptable salts thereof.
80. A pharmaceutical composition according to claim 79, wherein the pioglitazone comprises pioglitazone HCl.
81. A pharmaceutical composition according to claim 48, wherein such single dose form is adapted for oral administration.
82. A pharmaceutical composition according to claim 48, wherein such single dose form is a solid formulation adapted for oral administration.
83. A pharmaceutical composition according to claim 48, wherein such single dose form is a tablet or capsule adapted for oral administration.
84. A pharmaceutical composition according to claim 48, wherein such single dose form comprises an extended release formulation adapted for oral administration.
85. A pharmaceutical composition according to claim 48, wherein Compound I is present in the pharmaceutical composition as a free base.
86. A pharmaceutical composition according to claim 48, wherein Compound I is present in the pharmaceutical composition in a pharmaceutically acceptable salt.
87. A pharmaceutical composition according to claim 48, wherein Compound I is present in the pharmaceutical composition in a succinate salt.
88. A kit comprising:
multiple doses of a pharmaceutical composition according to claim 48; and
instructions which comprise one or more forms of information selected from the group consisting of indicating a disease state for which the pharmaceutical composition is to be administered, storage information for the pharmaceutical composition, dosing information and instructions regarding how to administer the pharmaceutical composition.
89. An article of manufacture comprising:
multiple doses of a pharmaceutical composition according to claim 48; and
packaging materials.
90. An article of manufacture according to claim 89, wherein the packaging material comprises a container for housing the multiple doses of the pharmaceutical composition.
91. An article of manufacture according to claim 90, wherein the container comprises a label indicating one or more members of the group consisting of a disease state for which the compound is to be administered, storage information, dosing information and/or instructions regarding how to administer the composition.
92. A method for treating conditions mediated by DPP-IV, which comprises administering a therapeutically effective amount of Compound I in combination with one or more antidiabetic compounds other than Compound I.
US11/531,671 2005-09-14 2006-09-13 Administration of dipeptidyl peptidase inhibitors Abandoned US20070060530A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US11/531,671 US20070060530A1 (en) 2005-09-14 2006-09-13 Administration of dipeptidyl peptidase inhibitors
US13/091,460 US20110192748A1 (en) 2005-09-14 2011-04-21 Administration of Dipeptidyl Peptidase Inhibitors
US13/773,282 US8906901B2 (en) 2005-09-14 2013-02-21 Administration of dipeptidyl peptidase inhibitors

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US71756005P 2005-09-14 2005-09-14
US74728006P 2006-05-15 2006-05-15
US11/531,671 US20070060530A1 (en) 2005-09-14 2006-09-13 Administration of dipeptidyl peptidase inhibitors

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/091,460 Continuation US20110192748A1 (en) 2005-09-14 2011-04-21 Administration of Dipeptidyl Peptidase Inhibitors

Publications (1)

Publication Number Publication Date
US20070060530A1 true US20070060530A1 (en) 2007-03-15

Family

ID=37564046

Family Applications (3)

Application Number Title Priority Date Filing Date
US11/531,671 Abandoned US20070060530A1 (en) 2005-09-14 2006-09-13 Administration of dipeptidyl peptidase inhibitors
US13/091,460 Abandoned US20110192748A1 (en) 2005-09-14 2011-04-21 Administration of Dipeptidyl Peptidase Inhibitors
US13/773,282 Active US8906901B2 (en) 2005-09-14 2013-02-21 Administration of dipeptidyl peptidase inhibitors

Family Applications After (2)

Application Number Title Priority Date Filing Date
US13/091,460 Abandoned US20110192748A1 (en) 2005-09-14 2011-04-21 Administration of Dipeptidyl Peptidase Inhibitors
US13/773,282 Active US8906901B2 (en) 2005-09-14 2013-02-21 Administration of dipeptidyl peptidase inhibitors

Country Status (31)

Country Link
US (3) US20070060530A1 (en)
EP (1) EP1942898B2 (en)
JP (1) JP5027137B2 (en)
KR (1) KR101345316B1 (en)
CN (1) CN101374523B (en)
AR (1) AR055435A1 (en)
AT (1) ATE532518T1 (en)
AU (1) AU2006290205B2 (en)
CA (1) CA2622472C (en)
CR (1) CR9874A (en)
CY (1) CY1112281T1 (en)
DK (1) DK1942898T4 (en)
EA (1) EA015169B1 (en)
ES (1) ES2376351T5 (en)
GE (1) GEP20135838B (en)
HK (1) HK1119086A1 (en)
HR (1) HRP20120004T4 (en)
IL (1) IL190131A (en)
MA (1) MA29795B1 (en)
ME (2) ME02005B (en)
MY (1) MY147393A (en)
NO (1) NO340910B1 (en)
NZ (1) NZ566799A (en)
PE (1) PE20070522A1 (en)
PL (1) PL1942898T5 (en)
PT (1) PT1942898E (en)
RS (1) RS52110B2 (en)
SI (1) SI1942898T2 (en)
TW (1) TWI432200B (en)
WO (1) WO2007033350A1 (en)
ZA (2) ZA200802857B (en)

Cited By (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050065145A1 (en) * 2003-09-08 2005-03-24 Syrrx, Inc. Dipeptidyl peptidase inhibitors
US20050065144A1 (en) * 2003-09-08 2005-03-24 Syrrx, Inc. Dipeptidyl peptidase inhibitors
US20050070531A1 (en) * 2003-08-13 2005-03-31 Syrrx, Inc. Dipeptidyl peptidase inhibitors
US20050277945A1 (en) * 2004-06-14 2005-12-15 Usgi Medical Inc. Apparatus and methods for performing transluminal gastrointestinal procedures
US20070066635A1 (en) * 2005-09-16 2007-03-22 Mark Andres Polymorphs of benzoate salt of 2-[[6-[(3r)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2h)-pyrimidinyl]methyl]-benzonitrile and methods of use therefor
US20080227798A1 (en) * 2006-11-29 2008-09-18 Kelly Ron C Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2h-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
US20080249089A1 (en) * 2002-08-21 2008-10-09 Boehringer Ingelheim Pharma Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
WO2008134425A1 (en) * 2007-04-27 2008-11-06 Cedars-Sinai Medical Center Use of glp-1 receptor agonists for the treatment of gastrointestinal disorders
US20090012059A1 (en) * 2004-03-15 2009-01-08 Jun Feng Dipeptidyl peptidase inhibitors
WO2009022007A1 (en) * 2007-08-16 2009-02-19 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivative
WO2009022009A1 (en) * 2007-08-16 2009-02-19 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a pyrazole-o-glucoside derivative
US20090275750A1 (en) * 2005-09-16 2009-11-05 Jun Feng Dipeptidyl peptidase inhibitors
US20100029941A1 (en) * 2006-03-28 2010-02-04 Takeda Pharmaceutical Company Limited Preparation of (r)-3-aminopiperidine dihydrochloride
WO2010018217A2 (en) * 2008-08-15 2010-02-18 Boehringer Ingelheim International Gmbh Organic compounds for wound healing
US20100105710A1 (en) * 2007-03-13 2010-04-29 Takeda Pharmaceutical Company Limited Solid preparation comprising 2-[[6-[(3r)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2h)-pyrimidinyl]methyl]-4-fluorobenzonitrile
WO2010079197A1 (en) 2009-01-07 2010-07-15 Boehringer Ingelheim International Gmbh Treatment of diabetes in patients with inadequate glycemic control despite metformin therapy comprising a dpp-iv inhibitor
WO2010086411A1 (en) 2009-01-29 2010-08-05 Boehringer Ingelheim International Gmbh Dpp-iv inhibitors for treatment of diabetes in paediatric patients
WO2010092163A2 (en) 2009-02-13 2010-08-19 Boehringer Ingelheim International Gmbh Antidiabetic medications
US7820815B2 (en) 2004-11-05 2010-10-26 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(-3-aminopiperidin-1-yl) xanthines
US7872124B2 (en) 2004-12-21 2011-01-18 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
WO2011064352A1 (en) 2009-11-27 2011-06-03 Boehringer Ingelheim International Gmbh Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin
WO2011113947A1 (en) 2010-03-18 2011-09-22 Boehringer Ingelheim International Gmbh Combination of a gpr119 agonist and the dpp-iv inhibitor linagliptin for use in the treatment of diabetes and related conditions
WO2011138421A1 (en) 2010-05-05 2011-11-10 Boehringer Ingelheim International Gmbh Combination therapy
WO2011161161A1 (en) 2010-06-24 2011-12-29 Boehringer Ingelheim International Gmbh Diabetes therapy
US8093236B2 (en) 2007-03-13 2012-01-10 Takeda Pharmaceuticals Company Limited Weekly administration of dipeptidyl peptidase inhibitors
US8106060B2 (en) 2005-07-30 2012-01-31 Boehringer Ingelheim International Gmbh 8-(3-amino-piperidin-1-yl)-xanthines, their preparation, and their use as pharmaceuticals
US8232281B2 (en) 2006-05-04 2012-07-31 Boehringer Ingelheim International Gmbh Uses of DPP-IV inhibitors
US20120219623A1 (en) * 2009-10-02 2012-08-30 Boehringer Ingelheim International Gmbh Pharmaceutical compositions comprising bi-1356 and metformin
US8324383B2 (en) 2006-09-13 2012-12-04 Takeda Pharmaceutical Company Limited Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile
US8513264B2 (en) 2008-09-10 2013-08-20 Boehringer Ingelheim International Gmbh Combination therapy for the treatment of diabetes and related conditions
WO2013174767A1 (en) 2012-05-24 2013-11-28 Boehringer Ingelheim International Gmbh A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference
WO2013183784A1 (en) 2012-06-05 2013-12-12 Takeda Pharmaceutical Company Limited Solid preparation
US8697868B2 (en) 2004-02-18 2014-04-15 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions
US8853156B2 (en) 2008-08-06 2014-10-07 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients inappropriate for metformin therapy
US8865729B2 (en) 2008-12-23 2014-10-21 Boehringer Ingelheim International Gmbh Salt forms of a xanthine compound
US8883800B2 (en) 2011-07-15 2014-11-11 Boehringer Ingelheim International Gmbh Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions
US8907086B2 (en) 2011-03-03 2014-12-09 Merck Sharp & Dohme Corp. Fused bicyclic heterocycles useful as dipeptidyl peptidase-IV inhibitors
US8906901B2 (en) 2005-09-14 2014-12-09 Takeda Pharmaceutical Company Limited Administration of dipeptidyl peptidase inhibitors
US9034883B2 (en) 2010-11-15 2015-05-19 Boehringer Ingelheim International Gmbh Vasoprotective and cardioprotective antidiabetic therapy
US9155705B2 (en) 2008-04-03 2015-10-13 Boehringer Ingelheim International Gmbh DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation
US9266888B2 (en) 2006-05-04 2016-02-23 Boehringer Ingelheim International Gmbh Polymorphs
US9486526B2 (en) 2008-08-06 2016-11-08 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients inappropriate for metformin therapy
US9526730B2 (en) 2012-05-14 2016-12-27 Boehringer Ingelheim International Gmbh Use of a DPP-4 inhibitor in podocytes related disorders and/or nephrotic syndrome
US9526728B2 (en) 2014-02-28 2016-12-27 Boehringer Ingelheim International Gmbh Medical use of a DPP-4 inhibitor
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
US20180185291A1 (en) 2011-03-07 2018-07-05 Boehringer Ingelheim International Gmbh Pharmaceutical compositions
US10155000B2 (en) 2016-06-10 2018-12-18 Boehringer Ingelheim International Gmbh Medical use of pharmaceutical combination or composition
US10406172B2 (en) 2009-02-13 2019-09-10 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US11033552B2 (en) 2006-05-04 2021-06-15 Boehringer Ingelheim International Gmbh DPP IV inhibitor formulations
US11911388B2 (en) 2008-10-16 2024-02-27 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral or non-oral antidiabetic drug

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101616673A (en) * 2006-09-13 2009-12-30 武田药品工业株式会社 2-[6-(3-amino-piperadine-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-ylmethyl]-purposes of 4-fluoro-benzonitrile
WO2009099171A1 (en) * 2008-02-07 2009-08-13 Takeda Pharmaceutical Company Limited Pharmaceutical product
WO2009099172A1 (en) * 2008-02-07 2009-08-13 Takeda Pharmaceutical Company Limited Pharmaceutical product
WO2009128360A1 (en) * 2008-04-18 2009-10-22 大日本住友製薬株式会社 Therapeutic agent for diabetes
PE20100156A1 (en) * 2008-06-03 2010-02-23 Boehringer Ingelheim Int NAFLD TREATMENT
CN103664873B (en) 2009-12-30 2016-06-15 深圳信立泰药业股份有限公司 As 3-(3-amino piperidine-1-yl)-5-oxo-1 of DPP IV (DPP-IV) inhibitor, 2,4-pyrrolotriazine derivatives
US11813275B2 (en) 2013-04-05 2023-11-14 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US20140303097A1 (en) 2013-04-05 2014-10-09 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
US20140303098A1 (en) 2013-04-05 2014-10-09 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
WO2014170383A1 (en) 2013-04-18 2014-10-23 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
CN104402832A (en) * 2014-11-04 2015-03-11 广东东阳光药业有限公司 Preparation method for dihydropyrimidine derivative
CN106474128A (en) * 2016-11-15 2017-03-08 河南大学 The new opplication of succinum love song Ge Lieting
CN108836973B (en) * 2018-08-28 2022-12-02 常州市阳光药业有限公司 Metformin-glibenclamide capsule and preparation method thereof
CN110156750A (en) * 2019-05-13 2019-08-23 无锡贝塔医药科技有限公司 Pyrimidine ring14The preparation method of the amber love song Ge Lieting of C flag
CN114983958A (en) * 2022-07-13 2022-09-02 青海夏都医药有限公司 Trelagliptin succinate tablet and preparation method thereof

Citations (91)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3960949A (en) * 1971-04-02 1976-06-01 Schering Aktiengesellschaft 1,2-Biguanides
US4494978A (en) * 1976-12-30 1985-01-22 Chevron Research Company Herbicidal N-(N'-hydrocarbyloxycarbamylalkyl)-2,6-dialkyl-alpha-haloacetanilides
US4935493A (en) * 1987-10-06 1990-06-19 E. I. Du Pont De Nemours And Company Protease inhibitors
US5002953A (en) * 1987-09-04 1991-03-26 Beecham Group P.L.C. Novel compounds
US5387512A (en) * 1991-06-07 1995-02-07 Merck & Co. Inc. Preparation of 3-[z-benzoxazol-2-yl)ethyl]-5-(1-hydroxyethyl)-6-methyl-2-(1H)-pyridinone by biotransformation
US5512549A (en) * 1994-10-18 1996-04-30 Eli Lilly And Company Glucagon-like insulinotropic peptide analogs, compositions, and methods of use
US5601986A (en) * 1994-07-14 1997-02-11 Amgen Inc. Assays and devices for the detection of extrahepatic biliary atresia
US5614379A (en) * 1995-04-26 1997-03-25 Eli Lilly And Company Process for preparing anti-obesity protein
US5614492A (en) * 1986-05-05 1997-03-25 The General Hospital Corporation Insulinotropic hormone GLP-1 (7-36) and uses thereof
US5624894A (en) * 1992-09-17 1997-04-29 University Of Florida Brain-enhanced delivery of neuroactive peptides by sequential metabolism
US5885997A (en) * 1996-07-01 1999-03-23 Dr. Reddy's Research Foundation Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
US6011155A (en) * 1996-11-07 2000-01-04 Novartis Ag N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6172081B1 (en) * 1999-06-24 2001-01-09 Novartis Ag Tetrahydroisoquinoline 3-carboxamide derivatives
US6184020B1 (en) * 1997-12-16 2001-02-06 Novo Nordisk Biotech, Inc. Polypeptides having aminopeptidase activity and nucleic acids encoding same
US6201132B1 (en) * 1993-12-03 2001-03-13 Ferring B.V. Inhibitors of DP-mediated processes, compositions, and therapeutic methods thereof
US6214340B1 (en) * 1997-11-18 2001-04-10 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Physiologically active substance sulphostin, process for producing the same, and use thereof
US6235493B1 (en) * 1997-08-06 2001-05-22 The Regents Of The University Of California Amino acid substituted-cresyl violet, synthetic fluorogenic substrates for the analysis of agents in individual in vivo cells or tissue
US6251391B1 (en) * 1999-10-01 2001-06-26 Klaire Laboratories, Inc. Compositions containing dipepitidyl peptidase IV and tyrosinase or phenylalaninase for reducing opioid-related symptons
US6335429B1 (en) * 1997-10-10 2002-01-01 Cytovia, Inc. Fluorogenic or fluorescent reporter molecules and their applications for whole-cell fluorescence screening assays for caspases and other enzymes and the use thereof
US6337069B1 (en) * 2001-02-28 2002-01-08 B.M.R.A. Corporation B.V. Method of treating rhinitis or sinusitis by intranasally administering a peptidase
US20020006899A1 (en) * 1998-10-06 2002-01-17 Pospisilik Andrew J. Use of dipeptidyl peptidase IV effectors for lowering blood pressure in mammals
US20020016100A1 (en) * 2000-07-25 2002-02-07 Yazaki Coroporation Connector supporting structure
US20020019411A1 (en) * 2000-03-10 2002-02-14 Robl Jeffrey A. Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method
US6355614B1 (en) * 1998-06-05 2002-03-12 Point Therapeutics Cyclic boroproline compounds
US20020037829A1 (en) * 2000-08-23 2002-03-28 Aronson Peter S. Use of DPPIV inhibitors as diuretic and anti-hypertensive agents
US20020041871A1 (en) * 2000-06-01 2002-04-11 Brudnak Mark A. Genomeceutical and/or enzymatic composition and method for treating autism
US20020049153A1 (en) * 1999-05-17 2002-04-25 BRIDON Dominique P. Long lasting insulinoptropic peptides
US20020049164A1 (en) * 1998-06-24 2002-04-25 Hans-Ulrich Demuth Prodrugs of DP IV-inhibitors
US6380398B2 (en) * 2000-01-04 2002-04-30 Novo Nordisk A/S Therapeutically active and selective heterocyclic compounds that are inhibitors of the enzyme DPP-IV
US20020061839A1 (en) * 1998-03-09 2002-05-23 Scharpe Simon Lodewijk Serine peptidase modulators
US20020071838A1 (en) * 1998-07-31 2002-06-13 Hans-Ulrich Demuth Method for raising the blood glucose level in mammals
US20020077340A1 (en) * 2000-11-20 2002-06-20 Richard Sulsky Pyridone inhibitors of fatty acid binding protein and method
US20030008905A1 (en) * 2000-03-31 2003-01-09 Hans-Ulrich Demuth Method for the improvement of islet signaling in diabetes mellitus and for its prevention
US20030008925A1 (en) * 1997-11-19 2003-01-09 Marc Esteve Treatment of drug-induced sleepiness
US20030023946A1 (en) * 2001-07-24 2003-01-30 Ming-Te Lin Standard cell library generation using merged power method
US20030027282A1 (en) * 1997-10-06 2003-02-06 Huber Brigitte T. Quiescent cell dipeptidyl peptidase: a novel cytoplasmic serine protease
US6521644B1 (en) * 1999-03-23 2003-02-18 Ferring Bv Compositions for promoting growth
US20030040478A1 (en) * 1999-12-08 2003-02-27 Drucker Daniel J Chemotherapy treatment
US6528486B1 (en) * 1999-07-12 2003-03-04 Zealand Pharma A/S Peptide agonists of GLP-1 activity
US20030045464A1 (en) * 1997-12-16 2003-03-06 Hermeling Ronald Norbert Glucagon-like peptide-1 crystals
US20030055052A1 (en) * 2000-11-10 2003-03-20 Stefan Peters FAP-activated anti-tumor compounds
US20030060434A1 (en) * 1997-02-18 2003-03-27 Loretta Nielsen Combined tumor suppressor gene therapy and chemotherapy in the treatment of neoplasms
US20030060412A1 (en) * 2000-01-27 2003-03-27 Prouty Walter Francis Process for solubilizing glucagon-like peptide 1compounds
US6545170B2 (en) * 2000-04-13 2003-04-08 Pharmacia Corporation 2-amino-5, 6 heptenoic acid derivatives useful as nitric oxide synthase inhibitors
US20030069234A1 (en) * 2001-06-06 2003-04-10 Medina Julio C. CXCR3 antagonists
US6548529B1 (en) * 1999-04-05 2003-04-15 Bristol-Myers Squibb Company Heterocyclic containing biphenyl aP2 inhibitors and method
US6548481B1 (en) * 1998-05-28 2003-04-15 Probiodrug Ag Effectors of dipeptidyl peptidase IV
US6555519B2 (en) * 2000-03-30 2003-04-29 Bristol-Myers Squibb Company O-glucosylated benzamide SGLT2 inhibitors and method
US6559188B1 (en) * 1999-09-17 2003-05-06 Novartis Ag Method of treating metabolic disorders especially diabetes, or a disease or condition associated with diabetes
US20030087935A1 (en) * 1999-09-22 2003-05-08 Cheng Peter T. Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US20030087950A1 (en) * 2001-03-28 2003-05-08 Denanteuil Guillaume New alpha-amino acid sulphonyl compounds
US20030089935A1 (en) * 2001-11-13 2003-05-15 Macronix International Co., Ltd. Non-volatile semiconductor memory device with multi-layer gate insulating structure
US20030092697A1 (en) * 2001-05-30 2003-05-15 Cheng Peter T. Conformationally constrained analogs useful as antidiabetic and antiobesity agents and method
US20030092630A2 (en) * 1999-08-24 2003-05-15 Probiodrug Ag New effectors of dipeptidyl peptidase iv for topical use
US20030096857A1 (en) * 1999-11-30 2003-05-22 Evans David Michael Novel antidiabetic agents
US20030100563A1 (en) * 2001-07-06 2003-05-29 Edmondson Scott D. Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US20040002609A1 (en) * 2002-06-04 2004-01-01 Pfizer Inc. Synthesis of 3,3,4,4-tetrafluoropyrrolidine and novel dipeptidyl peptidase-IV inhibitor compounds
US20040002495A1 (en) * 2002-05-20 2004-01-01 Philip Sher Lactam glycogen phosphorylase inhibitors and method of use
US6673829B2 (en) * 2001-09-14 2004-01-06 Novo Nordisk A/S Aminoazetidine,-pyrrolidine and -piperidine derivatives
US6673815B2 (en) * 2001-11-06 2004-01-06 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US20040006062A1 (en) * 2002-05-06 2004-01-08 Smallheer Joanne M. Sulfonylaminovalerolactams and derivatives thereof as factor Xa inhibitors
US20040009972A1 (en) * 2002-06-17 2004-01-15 Ding Charles Z. Benzodiazepine inhibitors of mitochondial F1F0 ATP hydrolase and methods of inhibiting F1F0 ATP hydrolase
US20040009998A1 (en) * 2001-10-01 2004-01-15 Dhar T. G. Murali Spiro-hydantoin compounds useful as anti-inflammatory agents
US6686337B2 (en) * 2000-10-30 2004-02-03 Ortho-Mcneil Pharmaceutical, Inc. Combination therapy comprising anti-diabetic and anticonvulsant agents
US20040034014A1 (en) * 2000-07-04 2004-02-19 Kanstrup Anders Bendtz Heterocyclic compounds, which are inhibitors of the enzyme DPP-IV
US6703238B2 (en) * 1997-09-29 2004-03-09 Point Therapeutics, Inc. Methods for expanding antigen-specific T cells
US6706742B2 (en) * 2001-05-15 2004-03-16 Les Laboratories Servier Alpha-amino-acid compounds
US20040054171A1 (en) * 2002-07-04 2004-03-18 Jensen Anette Frost Polymorphic forms of a 4H-thieno[3,2-E]-1,2,4-thiadiazine 1,1-dioxide derivative
US20040053369A1 (en) * 2000-10-27 2004-03-18 Abbott Catherine Anne Dipeptidyl peptidases
US6710040B1 (en) * 2002-06-04 2004-03-23 Pfizer Inc. Fluorinated cyclic amides as dipeptidyl peptidase IV inhibitors
US20040058876A1 (en) * 2002-09-18 2004-03-25 Torsten Hoffmann Secondary binding site of dipeptidyl peptidase IV (DP IV)
US20040063935A1 (en) * 2000-10-06 2004-04-01 Kosuke Yasuda Aliphatic nitrogenous five-membered ring compounds
US20040072892A1 (en) * 2000-11-10 2004-04-15 Hiroshi Fukushima Cyanopyrrolidine derivatives
US20040072874A1 (en) * 2002-09-30 2004-04-15 Nagaaki Sato N-substituted-2-oxodihydropyridine derivatives
US20040077645A1 (en) * 2001-02-24 2004-04-22 Frank Himmelsbach Xanthine derivatives,production and use thereof as medicament
US6727261B2 (en) * 2001-12-27 2004-04-27 Hoffman-La Roche Inc. Pyrido[2,1-A]Isoquinoline derivatives
US20040082497A1 (en) * 2000-04-26 2004-04-29 Evans David Michael Inhibitors of dipeptidyl peptidase IV
US20040082607A1 (en) * 2001-02-02 2004-04-29 Satoru Oi Fused heterocyclic compounds
US20040092478A1 (en) * 2001-03-19 2004-05-13 Rothermel John D. Combinations comprising an antidiarrheal agent and an epothilone or an epothilone derivative
US20040097510A1 (en) * 2002-08-21 2004-05-20 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US20050014732A1 (en) * 2003-03-14 2005-01-20 Pharmacia Corporation Combination of an aldosterone receptor antagonist and an anti-diabetic agent
US20050014946A1 (en) * 2001-11-09 2005-01-20 Hans-Ulrich Demuth Substituted amino ketone compounds
US20050020574A1 (en) * 2002-12-03 2005-01-27 Boehringer Ingelheim Pharma Gmbh Co. Kg New substituted imidazo-pyridinones and imidazo-pyridazinones, the preparation thereof and their use as pharmaceutical compositions
US20050026921A1 (en) * 2003-06-18 2005-02-03 Boehringer Ingelheim International Gmbh New imidazopyridazinone and imidazopyridone derivatives, the preparation thereof and their use as pharmaceutical compositions
US20050032804A1 (en) * 2003-06-24 2005-02-10 Cypes Stephen Howard Phosphoric acid salt of a dipeptidyl peptidase-IV inhibitor
US20050038020A1 (en) * 2003-08-01 2005-02-17 Hamann Lawrence G. Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods
US20050043292A1 (en) * 2003-08-20 2005-02-24 Pfizer Inc Fluorinated lysine derivatives as dipeptidyl peptidase IV inhibitors
US20050043299A1 (en) * 2001-10-23 2005-02-24 Ferring B. V. Inhibitors of dipeptidyl peptidase iv
US6861440B2 (en) * 2001-10-26 2005-03-01 Hoffmann-La Roche Inc. DPP IV inhibitors
US6867205B2 (en) * 2002-02-13 2005-03-15 Hoffman-La Roche Inc. Pyridine and pyrimidine derivatives
US20050058635A1 (en) * 2003-05-05 2005-03-17 Hans-Ulrich Demuth Use of effectors of glutaminyl and glutamate cyclases

Family Cites Families (327)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB699812A (en) 1950-11-29 1953-11-18 British Ind Solvents Ltd Manufacture of substituted pyrimidones
GB1053063A (en) 1963-05-18
DE1670912C3 (en) 1967-08-18 1981-06-11 Bayer Ag, 5090 Leverkusen Herbicidal agents based on 1,2,4-triazin-5-ones
GB1377642A (en) 1971-01-14 1974-12-18 Koninklijke Gist Spiritus Penicillanic and cephalosporanic acid derivatives
DE2150686A1 (en) 1971-10-12 1973-04-19 Basf Ag 6-amino-uracil-5-carboxylic acid thioamides - inters for dyestuffs and pharmaceuticals
BE792206A (en) 1971-12-02 1973-06-01 Byk Gulden Lomberg Chem Fab
AU5996573A (en) 1972-09-11 1975-03-06 Commonwealth Scientific And Industrial Research Organisation Pyridinium salts
US3823135A (en) 1972-12-26 1974-07-09 Shell Oil Co Pyrimidone herbicides
GB1464248A (en) 1973-11-01 1977-02-09 Ici Ltd Substituted triazinediones their preparation and use as herbicides
DE2361551A1 (en) 1973-12-11 1975-06-19 Basf Ag Watersol. azo dyes derived from substd. pyridinium chlorides - dyeing natural and synthetic polyamides yellow-violet shades
DE2500024A1 (en) 1975-01-02 1976-07-08 Basf Ag Soluble azo dyes for dying polyamides - prepd. by coupling of 4,6-diaminopyridone derivs
JPS535180A (en) 1976-07-01 1978-01-18 Sumitomo Chem Co Ltd Preparation of 3,4-dihydro-2 (1h) quinazoline derivatives
DE2720085A1 (en) 1977-05-05 1978-11-16 Hoechst Ag PYRIMIDO (6.1-A) ISOCHINOLIN-2-ON DERIVATIVES
CH657851A5 (en) 1983-06-28 1986-09-30 Ciba Geigy Ag CHROMOGENEOUS CHINAZOLONE COMPOUNDS.
AR240698A1 (en) * 1985-01-19 1990-09-28 Takeda Chemical Industries Ltd Process for the preparation of 5-(4-(2-(5-ethyl-2-pyridil)-ethoxy)benzyl)-2,4-thiazolodinedione and their salts
WO1989010701A1 (en) 1988-05-05 1989-11-16 Basf Aktiengesellschaft Substances based on uracil-derivates for stimulating growth and reducing fat in animals
GB8900382D0 (en) 1989-01-09 1989-03-08 Janssen Pharmaceutica Nv 2-aminopyrimidinone derivatives
US5433955A (en) 1989-01-23 1995-07-18 Akzo N.V. Site specific in vivo activation of therapeutic drugs
IE63502B1 (en) 1989-04-21 1995-05-03 Zeneca Ltd Aminopyrimidine derivatives useful for treating cardiovascular disorders
CA2073856C (en) 1990-01-24 2002-12-03 Douglas I. Buckley Glp-1 analogs useful for diabetes treatment
JPH05504969A (en) 1990-02-13 1993-07-29 メルク・エンド・カムパニー・インコーポレーテツド Angiotensin 2 antagonists containing substituted benzyl elements
US5366862A (en) 1990-02-14 1994-11-22 Receptor Laboratories, Inc. Method for generating and screening useful peptides
US5814460A (en) 1990-02-14 1998-09-29 Diatide, Inc. Method for generating and screening useful peptides
US5162326A (en) 1990-02-15 1992-11-10 Takeda Chemical Industries, Ltd. Pyrimidinedione derivatives, their production and use
US5462928A (en) 1990-04-14 1995-10-31 New England Medical Center Hospitals, Inc. Inhibitors of dipeptidyl-aminopeptidase type IV
DE4110019C2 (en) 1991-03-27 2000-04-13 Merck Patent Gmbh Imidazopyridines, processes for their production and pharmaceutical preparations containing them
US6825169B1 (en) 1991-10-22 2004-11-30 Trustees Of Tufts College Inhibitors of dipeptidyl-aminopeptidase type IV
CA2121369C (en) 1991-10-22 2003-04-29 William W. Bachovchin Inhibitors of dipeptidyl-aminopeptidase type iv
US5350752A (en) 1991-12-16 1994-09-27 E. R. Squibb & Sons, Inc. Dihydropyrimidine derivatives
DE4141788A1 (en) 1991-12-18 1993-06-24 Merck Patent Gmbh imidazopyridines
TW229142B (en) 1992-04-15 1994-09-01 Nissan Detrochem Corp
US5602102A (en) 1992-05-29 1997-02-11 Board Of Regents, The Univ. Of Tx System Dipeptidyl peptidase-I inhibitors and uses thereof
DE4305602A1 (en) 1992-06-17 1993-12-23 Merck Patent Gmbh imidazopyridines
AU4794393A (en) 1992-07-31 1994-03-03 Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services, The Producing increased numbers of hematopoietic cells by administering inhibitors of dipeptidyl peptidase iv
ZA936492B (en) 1992-09-10 1995-03-02 Lilly Co Eli Compounds useful as hypoglycemic agents and for treating Alzheimer's disease.
US5811281A (en) 1993-07-12 1998-09-22 Cornell Research Foundation, Inc. Immortalized intestinal epithelial cell lines
DE4341453A1 (en) 1993-12-06 1995-06-08 Merck Patent Gmbh imidazopyridines
EP0749974B1 (en) 1994-03-08 2001-06-27 Otsuka Pharmaceutical Factory, Inc. Phosphonic diester derivative
US5580979A (en) 1994-03-15 1996-12-03 Trustees Of Tufts University Phosphotyrosine peptidomimetics for inhibiting SH2 domain interactions
US5543396A (en) 1994-04-28 1996-08-06 Georgia Tech Research Corp. Proline phosphonate derivatives
AU2790895A (en) 1994-06-10 1996-01-05 Universitaire Instelling Antwerpen Purification of serine protease and synthetic inhibitors thereof
WO1995035031A1 (en) 1994-06-17 1995-12-28 La Trobe University Biological control of insects
DE4432860A1 (en) 1994-09-15 1996-03-21 Merck Patent Gmbh imidazopyridines
ATE226574T1 (en) 1995-04-13 2002-11-15 Taiho Pharmaceutical Co Ltd 4,6-DIARYLPYRIMIDINE DERIVATIVES AND SALTS THEREOF
US6325989B1 (en) 1995-06-01 2001-12-04 Dana-Farber Cancer Institute, Inc. Form of dipeptidylpeptidase IV (CD26) found in human serum
JP2002515724A (en) 1995-06-01 2002-05-28 ダナ−ファーバー キャンサー インスティテュート インコーポレイテッド Novel form of dipeptidyl peptidase IV (CD26) found in human serum, antibodies and uses thereof
EP0748800B1 (en) 1995-06-09 2001-05-09 F. Hoffmann-La Roche Ag Pyrimidinedione, pyrimidinetrione, triazinedione derivatives as alpha-1-adrenergic receptor antagonists
JPH0928376A (en) 1995-07-21 1997-02-04 Ajinomoto Co Inc New dipeptidyl peptidase iv and its production
DE122010000020I1 (en) 1996-04-25 2010-07-08 Prosidion Ltd Method for lowering the blood glucose level in mammals
JPH09295977A (en) 1996-04-30 1997-11-18 Terumo Corp Pyridopyrimidine derivative and medicinal composition containing the same
US5965532A (en) 1996-06-28 1999-10-12 Trustees Of Tufts College Multivalent compounds for crosslinking receptors and uses thereof
KR100579765B1 (en) 1996-07-01 2006-12-28 닥터 레디스 레보러터리즈 리미티드 Methods for the preparation of novel heterocyclic compounds, their pharmaceutical compositions and their use in the treatment of diabetes and related diseases
US6006753A (en) 1996-08-30 1999-12-28 Eli Lilly And Company Use of GLP-1 or analogs to abolish catabolic changes after surgery
US7235627B2 (en) 1996-08-30 2007-06-26 Novo Nordisk A/S Derivatives of GLP-1 analogs
US6458924B2 (en) 1996-08-30 2002-10-01 Novo Nordisk A/S Derivatives of GLP-1 analogs
AU4721897A (en) 1996-10-25 1998-05-22 Tanabe Seiyaku Co., Ltd. Tetrahydroisoquinoline derivatives
TW492957B (en) 1996-11-07 2002-07-01 Novartis Ag N-substituted 2-cyanopyrrolidnes
JP2002514196A (en) 1996-12-05 2002-05-14 アムジエン・インコーポレーテツド Substituted pyrimidinone and pyridone compounds and methods of use
GB9702701D0 (en) 1997-02-01 1997-04-02 Univ Newcastle Ventures Ltd Quinazolinone compounds
US6100234A (en) 1997-05-07 2000-08-08 Tufts University Treatment of HIV
JP4050329B2 (en) 1997-05-16 2008-02-20 ノボザイムス,インコーポレイテッド Polypeptide having prolyl pipetidyl aminopeptidase activity and nucleic acid encoding the same
EP0897012A1 (en) 1997-07-05 1999-02-17 Societe Des Produits Nestle S.A. Cloning of the prolyl-dipeptidyl-peptidase from aspergillus oryzae
IL125950A0 (en) 1997-09-05 1999-04-11 Pfizer Prod Inc Methods of administering ampa receptor antagonists to treat dyskinesias associated with dopamine agonist therapy
AU9602198A (en) 1997-10-06 1999-04-27 Trustees Of Tufts College Cytoplasmic dipeptidylpeptidase iv from human t-cells
WO1999018856A1 (en) 1997-10-10 1999-04-22 Cytovia, Inc. Novel fluorescent reporter molecules and their applications including assays for caspases
WO1999028474A2 (en) 1997-12-01 1999-06-10 The Government Of The United States Of America, Represented By The Secretary Of Health And Human Services Chemokine variants and methods of use
EP2583675A1 (en) 1998-02-02 2013-04-24 Trustees Of Tufts College Use of dipeptidylpeptidase inhibitors to regulate glucose metabolism
WO1999046272A1 (en) 1998-03-09 1999-09-16 Fondatech Benelux N.V. Serine peptidase modulators
AU3357299A (en) 1998-03-20 1999-10-11 Sloan-Kettering Institute For Cancer Research Use of dipeptidyl peptidase (dpp4) for suppressing the malignant phenotype of cancer cells
WO1999050249A2 (en) 1998-04-01 1999-10-07 Du Pont Pharmaceuticals Company Pyrimidines and triazines as integrin antagonists
CN1295570A (en) 1998-04-08 2001-05-16 诺瓦提斯公司 N-pyriconyl herbicides
FR2777283B1 (en) 1998-04-10 2000-11-24 Adir NOVEL GLUCAGON-PEPTIDE- 1 (7-37) ANALOGUE PEPTIDE COMPOUNDS, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME
DE19828114A1 (en) 1998-06-24 2000-01-27 Probiodrug Ges Fuer Arzneim Produgs of unstable inhibitors of dipeptidyl peptidase IV
US6129911A (en) 1998-07-10 2000-10-10 Rhode Island Hospital, A Lifespan Partner Liver stem cell
AU5027299A (en) 1998-07-31 2000-02-28 Novo Nordisk A/S Use of glp-1 and analogues for preventing type ii diabetes
EP1105460B1 (en) 1998-08-10 2009-10-07 THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES Differentiation of non-insulin producing cells into insulin producing cells by glp-1 or exendin-4 and uses thereof
WO2000010549A1 (en) 1998-08-21 2000-03-02 Point Therapeutics, Inc. Regulation of substrate activity
CA2344246A1 (en) 1998-09-17 2000-03-23 Akesis Pharmaceuticals, Inc. Combinations of chromium or vanadium with antidiabetics for glucose metabolism disorders
DE19845153A1 (en) 1998-10-01 2000-04-06 Merck Patent Gmbh Imidazo [4,5] pyridin-4-one derivatives
US20030176357A1 (en) 1998-10-06 2003-09-18 Pospisilik Andrew J. Dipeptidyl peptidase IV inhibitors and their uses for lowering blood pressure levels
CO5150173A1 (en) 1998-12-10 2002-04-29 Novartis Ag COMPOUNDS N- (REPLACED GLYCLE) -2-DIPEPTIDYL-IV PEPTIDASE INHIBITING CYANOPIRROLIDINS (DPP-IV) WHICH ARE EFFECTIVE IN THE TREATMENT OF CONDITIONS MEDIATED BY DPP-IV INHIBITION
DE19900471A1 (en) 1999-01-08 2000-07-13 Merck Patent Gmbh Imidazo [4,5c] pyridin-4-one derivatives
KR100787254B1 (en) 1999-01-22 2007-12-20 기린 홀딩스 가부시키가이샤 Quinoline Derivatives and Quinazoline Derivatives
AU779745C (en) 1999-02-10 2005-08-25 Curis, Inc. Methods and reagents for treating glucose metabolic disorders
AU3960400A (en) 1999-03-05 2000-09-28 Molteni L. E C. Dei Fratelli Alitti Societa' Di Esercizio S.P.A. Use of metformin in the preparation of pharmaceutical compositions capable of inhibiting the enzyme dipeptidyl peptidase iv
GB9906714D0 (en) 1999-03-23 1999-05-19 Ferring Bv Compositions for improving fertility
AU4031500A (en) 1999-03-26 2000-10-16 Akesis Pharmaceuticals, Inc. Edible solids for treatment of glucose metabolism disorders
WO2000063209A1 (en) 1999-04-20 2000-10-26 Novo Nordisk A/S New compounds, their preparation and use
DE19926233C1 (en) 1999-06-10 2000-10-19 Probiodrug Ges Fuer Arzneim Production of thiazolidine, useful as pharmaceutical intermediate, comprises reacting hexamethylenetetramine with cysteamine
US6107317A (en) 1999-06-24 2000-08-22 Novartis Ag N-(substituted glycyl)-thiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6110949A (en) 1999-06-24 2000-08-29 Novartis Ag N-(substituted glycyl)-4-cyanothiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6617340B1 (en) 1999-07-29 2003-09-09 Novartis Ag N-(substituted glycyl)-pyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
JP4748908B2 (en) 1999-09-10 2011-08-17 ザ・ユニバーシティ・オブ・シドニー Dipeptidyl peptidase
EP1216233A1 (en) 1999-09-28 2002-06-26 MERCK PATENT GmbH Quinazolinones
US6447772B1 (en) 1999-10-01 2002-09-10 Klaire Laboratories, Inc. Compositions and methods relating to reduction of symptoms of autism
WO2001027090A1 (en) 1999-10-08 2001-04-19 Meiji Seika Kaisha, Ltd. m-SUBSTITUTED BENZOIC ACID DERIVATIVES EXHIBITING INTEGRINαvβ3 ANTAGONISM
US6261794B1 (en) 1999-10-14 2001-07-17 Saint Louis University Methods for identifying inhibitors of methionine aminopeptidases
US7230000B1 (en) 1999-10-27 2007-06-12 Cytokinetics, Incorporated Methods and compositions utilizing quinazolinones
US20040152745A1 (en) 1999-11-12 2004-08-05 Guilford Pharmaceuticals, Inc. Dipeptidyl peptidase IV inhibitors and methods of making and using dipeptidyl peptidase IV inhibitors
CA2390231A1 (en) 1999-11-12 2001-05-17 Paul Jackson Dipeptidyl peptidase iv inhibitors and methods of making and using dipeptidyl peptidase iv inhibitors
PT1248604E (en) 2000-01-21 2007-01-31 Novartis Ag Combinations comprising dipeptidylpeptidase-iv inhibitors and antidiabetic agents
AU2001228309A1 (en) 2000-01-24 2001-08-07 Novo-Nordisk A/S N-substituted 2-cyanopyroles and -pyrrolines which are inhibitors of the enzyme dpp-iv
JP4931314B2 (en) 2000-01-25 2012-05-16 ニューロクライン バイオサイエンシーズ,インコーポレイテッド Gonadotropin releasing hormone receptor antagonist and related methods
US6569901B2 (en) 2000-01-28 2003-05-27 Novo Nordisk A/S Alkynyl-substituted propionic acid derivatives, their preparation and use
US7217722B2 (en) 2000-02-01 2007-05-15 Kirin Beer Kabushiki Kaisha Nitrogen-containing compounds having kinase inhibitory activity and drugs containing the same
JP2003523396A (en) 2000-02-25 2003-08-05 ノボ ノルディスク アクティーゼルスカブ Inhibition of beta cell degeneration
US6448045B1 (en) 2000-03-10 2002-09-10 The Regents Of The University Of California Inducing insulin gene expression in pancreas cells expressing recombinant PDX-1
US6608038B2 (en) 2000-03-15 2003-08-19 Novartis Ag Methods and compositions for treatment of diabetes and related conditions via gene therapy
EP1136482A1 (en) 2000-03-23 2001-09-26 Sanofi-Synthelabo 2-Amino-3-(alkyl)-pyrimidone derivatives as GSK3beta inhibitors
US6573096B1 (en) 2000-04-01 2003-06-03 The Research Foundation At State University Of New York Compositions and methods for inhibition of cancer invasion and angiogenesis
US20030105118A1 (en) 2000-04-18 2003-06-05 Shuji Masumoto Tricyclic quinazolinediones
GEP20084317B (en) 2000-04-25 2008-02-25 Icos Corp Inhibitors of human phosphatidyl-inositol 3-kinase delta
GB0010183D0 (en) 2000-04-26 2000-06-14 Ferring Bv Inhibitors of dipeptidyl peptidase IV
DE10025464A1 (en) 2000-05-23 2001-12-06 Inst Medizintechnologie Magdeb Combined use of enzyme inhibitors for the therapy of autoimmune diseases, in transplants and tumor diseases, as well as combinations of pharmaceutical preparations comprising enzyme inhibitors
WO2001094597A1 (en) 2000-06-09 2001-12-13 Prozymex A/S Purified proenzyme of dipeptidyl peptidase i (pro-dppi)
TW583185B (en) 2000-06-13 2004-04-11 Novartis Ag N-(substituted glycyl)-2-cyanopyrrolidines and pharmaceutical composition for inhibiting dipeptidyl peptidase-IV (DPP-IV) or for the prevention or treatment of diseases or conditions associated with elevated levels of DPP-IV comprising the same
US6432969B1 (en) 2000-06-13 2002-08-13 Novartis Ag N-(substituted glycyl)-2 cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6627636B2 (en) 2000-06-15 2003-09-30 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
US6620821B2 (en) 2000-06-15 2003-09-16 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
US7078397B2 (en) 2000-06-19 2006-07-18 Smithkline Beecham Corporation Combinations of dipeptidyl peptidase IV inhibitors and other antidiabetic agents for the treatment of diabetes mellitus
GB0014969D0 (en) 2000-06-19 2000-08-09 Smithkline Beecham Plc Novel method of treatment
WO2002004610A2 (en) 2000-07-10 2002-01-17 Bayer Aktiengesellschaft Regulation of human dipeptidyl-peptidase iv-like enzyme
TW535080B (en) 2000-07-24 2003-06-01 Ten Square Co Ltd Method and apparatus for optimal fitting activities into customer idle time
AR032360A1 (en) 2000-08-01 2003-11-05 Pharmacia Corp COMPOUND DERIVED FROM HEXANOIC HOMOIMINOPIPERIDINIL ACID, PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND INTERMEDIARY COMPOUNDS USED IN THEIR PREPARATION
US7022711B2 (en) 2000-08-04 2006-04-04 Warner-Lambert Company 2-(4-Pyridyl)amino-6-dialkoxyphenyl-pyrido[2,3-d]pyrimidin-7-ones
ES2334858T3 (en) 2000-08-10 2010-03-16 Mitsubishi Tanabe Pharma Corporation DERIVATIVES OF PROLINA AND USE OF THE SAME AS PHARMACOS.
US20020165237A1 (en) 2000-08-11 2002-11-07 Fryburg David Albert Treatment of the insulin resistance syndrome
US6900226B2 (en) 2000-09-06 2005-05-31 Hoffman-La Roche Inc. Neuropeptide Y antagonists
AU3815102A (en) 2000-09-08 2002-03-22 Prozymex As Dipeptidyl peptidase I crystal structure and its uses
AU9287401A (en) 2000-09-27 2002-04-08 Merck & Co Inc Benzopyrancarboxylic acid derivatives for the treatment of diabetes and lipid disorders
US20020064736A1 (en) 2000-09-27 2002-05-30 Fuji Photo Film Co., Ltd. Dye-forming coupler, silver halide photographic light-sensitive material, and method for producing an azomethine dye
GB0023983D0 (en) 2000-09-29 2000-11-15 Prolifix Ltd Therapeutic compounds
SE0003599D0 (en) 2000-10-05 2000-10-05 Thomas Johansson Moisture absorption device
IL155245A0 (en) 2000-10-12 2003-11-23 Ferring Bv Novel serine protease genes related to dppiv
AU2177302A (en) 2000-10-27 2002-05-06 Probiodrug Ag Method for the treatment of neurological and neuropsychological disorders
EP1347755A2 (en) 2000-10-31 2003-10-01 Merck & Co., Inc. Benzopyrancarboxylic acid derivatives for the treatment of diabetes and lipid disorders
AU2002246568A1 (en) 2000-10-31 2002-08-06 Vanderbilt University Biological markers and diagnostic tests for angiotensin converting enzyme inhibitor- and vasopeptidase inhibitor-associated angioedema
AU2002225954A1 (en) 2000-11-08 2002-05-21 The University Of Georgia Research Foundation, Inc. Dipeptidylpeptidases and methods of use
US20020155565A1 (en) 2000-11-10 2002-10-24 Pilar Garin-Chesa FAP-activated anti-tumor compounds
US20030203946A1 (en) 2000-11-17 2003-10-30 Carsten Behrens Glucagon antagonists/inverse agonists
WO2002083143A1 (en) 2000-12-11 2002-10-24 Tularik Inc. Cxcr3 antagonists
JPWO2002051836A1 (en) 2000-12-27 2004-04-22 協和醗酵工業株式会社 Dipeptidyl peptidase-IV inhibitor
DE10100053A1 (en) 2001-01-02 2002-08-22 Keyneurotek Ag I G Use of enzyme inhibitors of dipeptidyl peptidase IV and aminopeptidase N and pharmaceutical preparations therefrom for the prevention and / or therapy of ischemia-related acute and chronic neurodegenerative processes and diseases
EP1349576B1 (en) 2001-01-02 2011-11-23 IMTM GmbH Combined use of enzyme inhibitors for the treatment and prevention of allergic reactions of type i according to the gell and coombs classification, and for the treatment and prevention of dermatological diseases associated with follicular and epidermal hyperkeratosis and reinforced keratinocyte proliferation
WO2002059301A1 (en) 2001-01-27 2002-08-01 K.U. Leuven Research And Development Chemokines
TWI255817B (en) 2001-02-14 2006-06-01 Kissei Pharmaceutical Glucopyranosyloxybenzylbenzene derivatives and medicinal use thereof
WO2002066627A1 (en) 2001-02-16 2002-08-29 Bayer Aktiengesellschaft Regulation of human dipeptidyl peptidase 8
JP4178816B2 (en) 2001-03-15 2008-11-12 田辺三菱製薬株式会社 Pharmaceutical composition
EP1385508B1 (en) 2001-03-27 2008-05-21 Merck & Co., Inc. Dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
DE10115921A1 (en) 2001-03-30 2002-10-02 Boehringer Ingelheim Pharma Process for the preparation of 4,6-diaminopyrimido [5,4-d] pyrimidines
US6890905B2 (en) 2001-04-02 2005-05-10 Prosidion Limited Methods for improving islet signaling in diabetes mellitus and for its prevention
GB0109146D0 (en) 2001-04-11 2001-05-30 Ferring Bv Treatment of type 2 diabetes
PE20021080A1 (en) 2001-04-12 2003-02-12 Boehringer Ingelheim Int A SPECIFIC ANTIBODY FAPO BIBH1 IN THE TREATMENT OF CANCER
US6573287B2 (en) 2001-04-12 2003-06-03 Bristo-Myers Squibb Company 2,1-oxazoline and 1,2-pyrazoline-based inhibitors of dipeptidyl peptidase IV and method
JP2004533449A (en) 2001-05-11 2004-11-04 ボード オブ リージェンツ, ザ ユニバーシティ オブ テキサス システム Anti-CD26 monoclonal antibodies for the treatment of diseases associated with cells expressing CD26
US20030060494A1 (en) 2001-05-18 2003-03-27 Nobuyuki Yasuda Pharmaceutical use of N-carbamoylazole derivatives
IL143366A0 (en) 2001-05-24 2002-04-21 Harasit Medical Res Services & Treatment of renal fibrosis
WO2003000181A2 (en) 2001-06-20 2003-01-03 Merck & Co., Inc. Dipeptidyl peptidase inhibitors for the treatment of diabetes
AU2002344820B2 (en) 2001-06-20 2006-12-14 Merck & Co., Inc. Dipeptidyl peptidase inhibitors for the treatment of diabetes
GB0115517D0 (en) 2001-06-25 2001-08-15 Ferring Bv Novel antidiabetic agents
WO2003002531A2 (en) 2001-06-27 2003-01-09 Smithkline Beecham Corporation Fluoropyrrolidines as dipeptidyl peptidase inhibitors
JP2004534836A (en) 2001-06-27 2004-11-18 プロバイオドラッグ アーゲー Novel use of dipeptidyl peptidase IV inhibitors
DE10150203A1 (en) 2001-10-12 2003-04-17 Probiodrug Ag Use of dipeptidyl peptidase IV inhibitor in treatment of cancer
DE10154689A1 (en) 2001-11-09 2003-05-22 Probiodrug Ag Substituted amino ketone compounds
US7368421B2 (en) 2001-06-27 2008-05-06 Probiodrug Ag Use of dipeptidyl peptidase IV inhibitors in the treatment of multiple sclerosis
US20030130199A1 (en) 2001-06-27 2003-07-10 Von Hoersten Stephan Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents
US20030135023A1 (en) 2001-06-27 2003-07-17 Hans-Ulrich Demuth Peptide structures useful for competitive modulation of dipeptidyl peptidase IV catalysis
ATE380175T1 (en) 2001-06-27 2007-12-15 Smithkline Beecham Corp PYRROLIDINE AS DIPEPTIDYL PEPTIDASE INHIBITORS
WO2003002553A2 (en) 2001-06-27 2003-01-09 Smithkline Beecham Corporation Fluoropyrrolidines as dipeptidyl peptidase inhibitors
DE60225556D1 (en) 2001-07-03 2008-04-24 Novo Nordisk As DPP-IV INHIBITING PURINE DERIVATIVE FOR THE TREATMENT OF DIABETES
US6869947B2 (en) 2001-07-03 2005-03-22 Novo Nordisk A/S Heterocyclic compounds that are inhibitors of the enzyme DPP-IV
US20030144350A1 (en) 2001-07-20 2003-07-31 Adipogenix, Inc. Fat accumulation-modulation compounds
WO2003010197A2 (en) 2001-07-25 2003-02-06 Genset S.A. Gmg-1 polynucleotides and polypeptides and uses thereof
WO2003010314A2 (en) 2001-07-26 2003-02-06 Genset S.A. Gmg-2 polynucleotides and polypeptides and uses thereof
CZ2004133A3 (en) 2001-07-30 2004-06-16 Novo Nordisk A/S Derivatives of vinyl carboxylic acid, pharmaceutical composition in which the derivative is comprised and use thereof
JP2004536152A (en) 2001-07-30 2004-12-02 ノボ ノルディスク アクティーゼルスカブ Novel vinyl N- (2-benzoylphenyl) -L-tyrosine derivatives and their use for antidiabetic agents and the like
ATE536881T1 (en) 2001-07-31 2011-12-15 Us Gov Health & Human Serv GLP-1, EXENDIN-4, PEPTIDE ANALOGS AND USES THEREOF
AU2002327430A1 (en) 2001-08-08 2003-02-24 Genzyme Corporation Methods for treating diabetes and other blood sugar disorders
US7279550B2 (en) 2001-08-13 2007-10-09 Probiodrug Ag Irreversible cysteine protease inhibitors of legumain
EP1285922A1 (en) 2001-08-13 2003-02-26 Warner-Lambert Company 1-Alkyl or 1-cycloalkyltriazolo[4,3-a]quinazolin-5-ones as phosphodiesterase inhibitors
JP2003128551A (en) 2001-08-15 2003-05-08 Sankyo Co Ltd New antidiabetic pharmaceutical composition
DE10143840A1 (en) 2001-09-06 2003-03-27 Probiodrug Ag New acylated hydroxamates useful for the treatment of e.g. wound healing
US6844316B2 (en) 2001-09-06 2005-01-18 Probiodrug Ag Inhibitors of dipeptidyl peptidase I
TWI246510B (en) 2001-09-14 2006-01-01 Mitsubishi Pharma Corp Thiazolidine derivatives and pharmaceutical uses thereof
US20030186963A1 (en) 2001-09-14 2003-10-02 Dorwald Florencio Zaragoza Substituted piperidines
WO2003024965A2 (en) 2001-09-19 2003-03-27 Novo Nordisk A/S Heterocyclic compounds that are inhibitors of the enzyme dpp-iv
HUP0401898A3 (en) 2001-09-21 2005-08-29 Sanofi Aventis 3-substituted-4-pyrimidone derivatives, pharmaceutical compositions containing them and their intermediates
US7427615B2 (en) 2001-09-21 2008-09-23 Mitsubishi Pharma Corporation 3-substituted-4-pyrimidone derivatives
MEP58108A (en) 2001-09-21 2011-05-10 Bristol Myers Squibb Co Lactam-containing compounds and derivatives thereof as factor xa inhibitors
US7019010B2 (en) 2001-09-27 2006-03-28 Novertis Ag Combinations
WO2003030946A1 (en) 2001-10-09 2003-04-17 Novartis Ag Regulation of insulin production
US7064135B2 (en) 2001-10-12 2006-06-20 Novo Nordisk Inc. Substituted piperidines
KR20040054729A (en) 2001-10-18 2004-06-25 브리스톨-마이어스 스큅 컴퍼니 Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions
TWI301834B (en) 2001-10-22 2008-10-11 Eisai R&D Man Co Ltd Pyrimidone compound and pharmaceutical composition including the same
GB0125446D0 (en) 2001-10-23 2001-12-12 Ferring Bv Novel anti-diabetic agents
CN1604968A (en) 2001-10-31 2005-04-06 诺瓦提斯公司 Methods to treat diabetes and related conditions based on polymorphisms in the TCF-1 gene
MXPA04004956A (en) 2001-11-26 2004-08-11 Schering Corp Piperidine-based mch antagonists for treatment of obesity and cns disorders.
EP2769715A3 (en) 2001-11-26 2014-09-17 Trustees Of Tufts College Methods for treating autoimmune disorders, and reagents related thereto
CA2468192A1 (en) 2001-11-26 2003-06-05 Trustees Of Tufts College Peptidomimetic inhibitors of post-proline cleaving enzymes
WO2003048081A2 (en) 2001-12-04 2003-06-12 Bristol-Myers Squibb Company Glycinamides as factor xa inhibitors
US7279470B2 (en) 2001-12-14 2007-10-09 Novo Nordisk A/S Compounds and uses thereof for decreasing activity of hormone-sensitive lipase
GB0129988D0 (en) 2001-12-14 2002-02-06 Ferring Bv Imidazolidineacetic acid derivatives
SE0104340D0 (en) 2001-12-20 2001-12-20 Astrazeneca Ab New compounds
MXPA04006048A (en) 2001-12-21 2004-09-27 Novo Nordisk As Amide derivatives as gk activators.
TW200301698A (en) 2001-12-21 2003-07-16 Bristol Myers Squibb Co Acridone inhibitors of IMPDH enzyme
WO2003057144A2 (en) 2001-12-26 2003-07-17 Guilford Pharmaceuticals Change inhibitors of dipeptidyl peptidase iv
AU2002351753A1 (en) 2001-12-29 2003-07-30 Novo Nordisk A/S Combined use of a glp-1 compound and a modulator of diabetic late complications
WO2003057200A2 (en) 2002-01-11 2003-07-17 Novo Nordisk A/S Compositions comprising inhibitors of dpp-iv and nep enzymes for the treatment of diabetes
US7101898B2 (en) 2002-02-01 2006-09-05 Novo Nordisk A/S Amides of aminoalkyl-substituted azetidines, pyrrolidines, piperidines and azepanes
WO2003063903A2 (en) 2002-02-01 2003-08-07 Probiodrug Ag Modulation of t lymphocytes using dp iv inhibitors
DE60317631T2 (en) 2002-02-01 2008-09-25 Merck & Co., Inc. 11-BETA-HYDROXYSTEROID DEHYDROGENASE-1 HEMMER FOR THE TREATMENT OF DIABETES, ADIPOSITAS AND DYSLIPIDEMIA
BR0307576A (en) 2002-02-13 2005-01-11 Hoffmann La Roche Compounds; process for the manufacture of compounds; pharmaceutical compositions; method for the treatment and / or prophylaxis of diseases associated with dpp iv; and use of compounds
KR20040095239A (en) 2002-02-27 2004-11-12 화이자 프로덕츠 인코포레이티드 Acc inhibitors
NZ534877A (en) 2002-02-28 2006-05-26 Prosidion Ltd Glutaminyl based DPIV inhibitors
HUP0200849A2 (en) 2002-03-06 2004-08-30 Sanofi-Synthelabo N-aminoacetyl-pyrrolidine-2-carbonitrile derivatives, pharmaceutical compositions containing them and process for producing them
WO2003076418A1 (en) 2002-03-07 2003-09-18 X-Ceptor Therapeutics, Inc. Quinazolinone modulators of nuclear receptors
BR0308316A (en) 2002-03-11 2004-12-28 Novartis Ag Nateglinide Salts
IL163940A0 (en) 2002-03-13 2005-12-18 Euro Celtique Sa Aryl substituted pyrimidines and the use thereof
DE10211555A1 (en) 2002-03-15 2003-10-02 Imtm Inst Fuer Medizintechnolo Use of the inhibitors of enzymes with activities of the aminopeptidase N and / or the dipeptidyl peptidase IV and pharmaceutical preparations thereof for the therapy and prevention of dermatological diseases with sebocytic hyperproliferation and changed differentiation states
TW200305415A (en) 2002-03-22 2003-11-01 Novartis Ag Combination of organic compounds
WO2003082817A2 (en) 2002-03-25 2003-10-09 Merck & Co., Inc. Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US7348318B2 (en) 2002-03-25 2008-03-25 Nippon Kayaku Kabushiki Kaisha α-Amino-N-(diaminophosphinyl)lactam derivatives
US20030232761A1 (en) 2002-03-28 2003-12-18 Hinke Simon A. Novel analogues of glucose-dependent insulinotropic polypeptide
AR039209A1 (en) 2002-04-03 2005-02-09 Novartis Ag INDOLILMALEIMIDA DERIVATIVES
US20040106802A1 (en) 2002-04-08 2004-06-03 Torrent Pharmaceuticals Ltd. Novel compounds and therapeutic uses thereof
EP1492777A1 (en) 2002-04-08 2005-01-05 Torrent Pharmaceuticals Ltd Thiazolidine-4-carbonitriles and analogues and their use as dipeptidyl-peptidase inhibitors
CA2484551A1 (en) 2002-04-30 2003-11-13 Trustees Of Tufts College Smart pro-drugs of serine protease inhibitors
TW200407143A (en) 2002-05-21 2004-05-16 Bristol Myers Squibb Co Pyrrolotriazinone compounds and their use to treat diseases
DE60333937D1 (en) 2002-05-23 2010-10-07 Novartis Vaccines & Diagnostic SUBSTITUTED QUINAZOLINONE COMPOUNDS
GB0212412D0 (en) 2002-05-29 2002-07-10 Novartis Ag Combination of organic compounds
WO2003101958A2 (en) 2002-06-04 2003-12-11 Pfizer Products Inc. Flourinated cyclic amides as dipeptidyl peptidase iv inhibitors
EP1514552A4 (en) 2002-06-06 2008-04-02 Eisai R&D Man Co Ltd Novel fused imidazole derivative
AR040241A1 (en) 2002-06-10 2005-03-23 Merck & Co Inc INHIBITORS OF 11-BETA-HYDROXIESTEROID DEHYDROGRENASE 1 FOR THE TREATMENT OF DIABETES OBESITY AND DISLIPIDEMIA
HUP0202001A2 (en) 2002-06-14 2005-08-29 Sanofi-Aventis Azabicyclo-octane and nonane derivatives with ddp-iv inhibiting activity
PL374963A1 (en) 2002-06-17 2005-11-14 Smithkline Beecham Corporation Chemical process
SE0201976D0 (en) 2002-06-24 2002-06-24 Astrazeneca Ab Novel compounds
US20040006004A1 (en) 2002-06-27 2004-01-08 Markku Koulu Method for prevention and treatment of diseases or disorders related to excessive formation of vascular tissue or blood vessels
US7105526B2 (en) 2002-06-28 2006-09-12 Banyu Pharmaceuticals Co., Ltd. Benzimidazole derivatives
JP2006506442A (en) 2002-07-09 2006-02-23 ポイント セラピューティクス, インコーポレイテッド Boroproline compound combination therapy
KR101120337B1 (en) 2002-07-09 2012-02-29 브리스톨-마이어스 스큅 컴퍼니 Substituted heterocyclic derivatives useful as antidiabetic and antiobesity agents and method
JP4579681B2 (en) 2002-07-09 2010-11-10 ブリストル−マイヤーズ スクイブ カンパニー Substituted heterocycloderivatives and methods useful as antidiabetic and antiobesity agents
AU2003248259A1 (en) 2002-07-10 2004-02-02 Yamanouchi Pharmaceutical Co., Ltd. Novel azetidine derivative or salt thereof
CA2490818A1 (en) 2002-07-15 2004-01-22 Merck & Co., Inc. Piperidino pyrimidine dipeptidyl peptidase inhibitors for the treatment of diabetes
JP2004099600A (en) 2002-07-19 2004-04-02 Sankyo Co Ltd Pharmaceutical composition containing bicyclic amino-substituted compound
EP1525306A1 (en) 2002-07-29 2005-04-27 Tanabe Seiyaku Co., Ltd. Three-dimensional structure of dipeptidyl peptidase iv
EP1527049B8 (en) 2002-08-08 2008-10-29 Takeda Pharmaceutical Company Limited Fused heterocyclic compounds as peptidase inhibitors
DK1528931T3 (en) 2002-08-09 2008-09-08 Prosidion Ltd Dipeptidyl peptidase IV inhibitors to reduce the rate of chronic weight gain
DK1532149T3 (en) 2002-08-21 2010-05-10 Boehringer Ingelheim Pharma 8- [3-Amino-piperiden-1-yl] -xanthines, their preparation and their use as a drug
US7495005B2 (en) 2002-08-22 2009-02-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, their preparation and their use in pharmaceutical compositions
DE10238470A1 (en) 2002-08-22 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg New xanthine derivatives, their production and their use as medicines
DE10238477A1 (en) 2002-08-22 2004-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg New purine derivatives, their production and their use as medicines
NZ538956A (en) 2002-08-29 2006-08-31 Taisho Pharmaceutical Co Ltd Benzenesulfonate salt of 4-fluoro-2-cyanopyrrolidine derivative used to inhibit dipeptidyl peptidase IV (DPPIV)
US6998502B1 (en) 2002-09-05 2006-02-14 Sabinsa Corporation Convenient process of manufacture for difluoromethylornithine and related compounds
EP1398032A1 (en) 2002-09-10 2004-03-17 PheneX Pharmaceuticals AG 4-Oxo-quinazolines as LXR nuclear receptor binding compounds
WO2004024184A1 (en) 2002-09-11 2004-03-25 Takeda Pharmaceutical Company Limited Sustained release preparation
JP2004123738A (en) 2002-09-11 2004-04-22 Takeda Chem Ind Ltd Sustained-release preparation
ATE461212T1 (en) 2002-09-18 2010-04-15 Prosidion Ltd SECONDARY BINDING SITE OF DIPEPTIDYLPEPTIDASE IV (DP IV)
US7262207B2 (en) 2002-09-19 2007-08-28 Abbott Laboratories Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
PL374732A1 (en) 2002-09-19 2005-10-31 Abbott Laboratories Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-iv (dpp-iv)
RU2328280C2 (en) 2002-09-26 2008-07-10 Эйсай Ар Энд Ди Менеджмент Ко., Лтд. Combinative medicinal agent
ES2291680T3 (en) 2002-10-07 2008-03-01 MERCK & CO., INC. BETA-AMINO HETEROCICLIC INHIBITING ANTIDIABETICS OF DIPEPTIDIL PEPTIDASA.
WO2004033455A2 (en) 2002-10-08 2004-04-22 Novo Nordisk A/S Hemisuccinate salts of heterocyclic dpp-iv inhibitors
AU2003282510A1 (en) 2002-10-11 2004-05-04 Bristol-Myers Squibb Company Hexahydro-benzimidazolone compounds useful as anti-inflammatory agents
KR20050067418A (en) 2002-10-18 2005-07-01 머크 앤드 캄파니 인코포레이티드 Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
AU2003301662A1 (en) 2002-10-21 2004-05-13 Bristol-Myers Squibb Company Quinazolinones and derivatives thereof as factor xa inhibitors
ES2344057T3 (en) 2002-10-23 2010-08-17 Bristol-Myers Squibb Company INHIBITORS OF DIPEPTIDIL PEPTIDASA IV BASED ON GLICINE NITRILS.
AU2003286776A1 (en) 2002-10-30 2004-06-07 Guilford Pharmaceuticals Inc. Novel inhibitors of dipeptidyl peptidase iv
AU2003290577B2 (en) 2002-11-07 2008-12-11 Merck Sharp & Dohme Corp. Phenylalanine derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US7482337B2 (en) 2002-11-08 2009-01-27 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions
BR0316327A (en) 2002-11-18 2005-09-27 Pfizer Prod Inc Dipeptidylpeptidase inhibiting cyclic fluorinated amides iv
DE10254304A1 (en) 2002-11-21 2004-06-03 Boehringer Ingelheim Pharma Gmbh & Co. Kg New xanthine derivatives, their production and their use as medicines
AU2002952946A0 (en) 2002-11-27 2002-12-12 Fujisawa Pharmaceutical Co., Ltd. Dpp-iv inhibitor
UY28103A1 (en) 2002-12-03 2004-06-30 Boehringer Ingelheim Pharma NEW IMIDAZO-PIRIDINONAS REPLACED, ITS PREPARATION AND ITS EMPLOYMENT AS MEDICATIONS
DE10256264A1 (en) 2002-12-03 2004-06-24 Boehringer Ingelheim Pharma Gmbh & Co. Kg New trisubstituted dihydro-imidazo-pyridazinone or imidazo-pyridinone derivatives, useful as dipeptidylpeptidase-IV inhibitors for e.g. treating diabetes mellitus type I or II, arthritis or obesity
US7309714B2 (en) 2002-12-04 2007-12-18 Merck & Co., Inc. Phenylalanine derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
WO2004050656A1 (en) 2002-12-04 2004-06-17 Eisai Co., Ltd. 1,3-dihydroimidazole fused-ring compound
US7420079B2 (en) 2002-12-09 2008-09-02 Bristol-Myers Squibb Company Methods and compounds for producing dipeptidyl peptidase IV inhibitors and intermediates thereof
JP4504924B2 (en) 2002-12-20 2010-07-14 メルク・シャープ・エンド・ドーム・コーポレイション 3-Amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment and prevention of diabetes
WO2004062613A2 (en) 2003-01-13 2004-07-29 Bristol-Myers Squibb Company Hiv integrase inhibitors
CA2512546A1 (en) 2003-01-17 2004-08-05 Merck & Co., Inc. 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
JP2006516573A (en) 2003-01-31 2006-07-06 メルク エンド カムパニー インコーポレーテッド 3-Amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment and prevention of diabetes
ES2587885T3 (en) 2003-01-31 2016-10-27 Sanwa Kagaku Kenkyusho Co., Ltd. Useful cyanopyrrolidines for the treatment of metabolic syndrome, among others
WO2004071454A2 (en) 2003-02-13 2004-08-26 Guilford Pharmaceuticals Inc. Substituted azetidine compounds as inhibitors of dipeptidyl peptidase iv
DE10308351A1 (en) 2003-02-27 2004-11-25 Aventis Pharma Deutschland Gmbh 1,3-substituted cycloalkyl derivatives having acidic, usually heterocyclic groups, processes for their preparation and their use as medicaments
DE10308356A1 (en) 2003-02-27 2004-09-09 Aventis Pharma Deutschland Gmbh Cycloalkyl substituted alkanoic acid derivatives, process for their preparation and their use as medicaments
US7148246B2 (en) 2003-02-27 2006-12-12 Sanofi-Aventis Deutschland Gmbh Cycloalkyl derivatives having bioisosteric carboxylic acid groups, processes for their preparation and their use as pharmaceuticals
DE10308353A1 (en) 2003-02-27 2004-12-02 Aventis Pharma Deutschland Gmbh Diarylcycloalkyl derivatives, processes for their preparation and their use as medicines
AU2003207881A1 (en) 2003-02-28 2004-09-17 Aic Dipeptidyl peptidase inhibitors
WO2004076434A1 (en) 2003-02-28 2004-09-10 Aic Dipeptidyl peptidase inhibitors
EP1626981A4 (en) 2003-03-04 2006-11-22 Biorexis Pharmaceutical Corp Dipeptidyl-peptidase protected proteins
AR043443A1 (en) 2003-03-07 2005-07-27 Merck & Co Inc PROCEDURE FOR THE PREPARATION OF TETRAHYDROTRIAZOLOPIRAZINS AND INTERMEDIATE PRODUCTS
AR043505A1 (en) 2003-03-18 2005-08-03 Merck & Co Inc PREPARATION OF BETA-CETOAMIDS AND REACTION INTERMEDIARIES
WO2004085661A2 (en) 2003-03-24 2004-10-07 Merck & Co., Inc Process to chiral beta-amino acid derivatives
US20040242568A1 (en) 2003-03-25 2004-12-02 Syrrx, Inc. Dipeptidyl peptidase inhibitors
JP2006521400A (en) 2003-03-26 2006-09-21 バイエル・フアーマシユーチカルズ・コーポレーシヨン Compounds for the treatment of diabetes and related disorders and their use
TWI357408B (en) 2003-03-26 2012-02-01 Mitsubishi Tanabe Pharma Corp 3-substituted-4-pyrimidone derivatives
WO2004087650A2 (en) 2003-03-27 2004-10-14 Merck & Co. Inc. Process and intermediates for the preparation of beta-amino acid amide dipeptidyl peptidase-iv inhibitors
WO2004089362A1 (en) 2003-04-11 2004-10-21 Novo Nordisk A/S 2-cyanopyrroles and their analogues as ddp-iv inhibitors
WO2004096806A1 (en) 2003-04-30 2004-11-11 Sumitomo Pharmaceuticals Co. Ltd. Fused imidazole derivative
WO2004098591A2 (en) 2003-05-05 2004-11-18 Probiodrug Ag Inhibitors of glutaminyl cyclase and their use in the treatment of neurological diseases
ATE464889T1 (en) 2003-05-05 2010-05-15 Probiodrug Ag MEDICAL USE OF GLUTAMINYL AND GLUTAMATIC CYCLASE INHIBITORS
WO2004099134A2 (en) 2003-05-05 2004-11-18 Prosidion Ltd. Glutaminyl based dp iv-inhibitors
AU2003902260A0 (en) 2003-05-09 2003-05-29 Fujisawa Pharmaceutical Co., Ltd. Dpp-iv inhibitor
EP1625122A1 (en) 2003-05-14 2006-02-15 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
US7560455B2 (en) 2003-05-14 2009-07-14 Merck & Co., Inc. 3-Amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
KR20060009933A (en) 2003-05-15 2006-02-01 다이쇼 세이야꾸 가부시끼가이샤 Cyanofluoropyrrolidine derivative
WO2004104215A2 (en) 2003-05-21 2004-12-02 Bayer Healthcare Ag Diagnostics and therapeutics for diseases associated with dipeptidylpeptidase 7 (dpp7)
EP1631680A2 (en) 2003-05-21 2006-03-08 Bayer HealthCare AG Diagnostics and therapeutics for diseases associated with dipeptidylpeptidase iv (dpp4)
CA2526770A1 (en) 2003-06-06 2004-12-23 Merck & Co., Inc. Fused indoles as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
AU2003902946A0 (en) 2003-06-12 2003-06-26 Fujisawa Pharmaceutical Co., Ltd. Dpp-iv inhibitor
CA2527806A1 (en) 2003-06-17 2004-12-29 Merck & Co., Inc. Cyclohexylglycine derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
DE10327439A1 (en) 2003-06-18 2005-01-05 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel imidazopyridazinone and imidazopyridone derivatives, their production and their use as pharmaceuticals
NZ543863A (en) 2003-06-20 2009-05-31 Hoffmann La Roche Hexahydropyridoisoquinolines as DPP-IV inhibitors
AU2004251830B8 (en) 2003-06-20 2009-11-26 F. Hoffmann-La Roche Ag Pyrido[2, 1-A]-isoquinoline derivatives as DPP-IV inhibitors
DE10330842A1 (en) 2003-07-08 2005-02-10 Institut für Medizintechnologie Magdeburg GmbH, IMTM Use of the inhibitors of enzymes with activities of aminopeptidase N and / or dipeptidyl peptidase IV and pharmaceutical preparations thereof for the therapy and prevention of dermatological diseases with hyperproliferation and altered differentiation states of fibroblasts
JP2007500704A (en) 2003-07-31 2007-01-18 メルク エンド カムパニー インコーポレーテッド Hexahydrodiazepinone as a dipeptidyl peptidase IV-inhibitor for the treatment or prevention of diabetes
US20050065148A1 (en) * 2003-08-13 2005-03-24 Syrrx, Inc. Dipeptidyl peptidase inhibitors
JP2007505121A (en) 2003-09-08 2007-03-08 武田薬品工業株式会社 Dipeptidyl peptidase inhibitor
EP1697342A2 (en) 2003-09-08 2006-09-06 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
WO2005075436A2 (en) 2004-02-05 2005-08-18 Probiodrug Ag Novel inhibitors of glutaminyl cyclase
KR101071390B1 (en) 2004-03-15 2011-10-07 다케다 야쿠힌 고교 가부시키가이샤 dipeptidyl peptidase inhibitors
KR101210730B1 (en) 2004-07-02 2012-12-10 코어셉트 쎄라퓨틱스, 잉크. Modified pyrimidine glucocorticoid receptor modulators
US7872124B2 (en) 2004-12-21 2011-01-18 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
CN102908350B (en) 2005-09-14 2014-07-23 武田药品工业株式会社 Dipeptidyl peptidase inhibitors for treating diabetes
RS52110B2 (en) 2005-09-14 2018-05-31 Takeda Pharmaceuticals Co Dipeptidyl peptidase inhibitors for treating diabetes
US20070060529A1 (en) 2005-09-14 2007-03-15 Christopher Ronald J Administration of dipeptidyl peptidase inhibitors
TW200745079A (en) 2005-09-16 2007-12-16 Takeda Pharmaceuticals Co Polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile and methods of use therefor

Patent Citations (99)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3960949A (en) * 1971-04-02 1976-06-01 Schering Aktiengesellschaft 1,2-Biguanides
US4494978A (en) * 1976-12-30 1985-01-22 Chevron Research Company Herbicidal N-(N'-hydrocarbyloxycarbamylalkyl)-2,6-dialkyl-alpha-haloacetanilides
US5614492A (en) * 1986-05-05 1997-03-25 The General Hospital Corporation Insulinotropic hormone GLP-1 (7-36) and uses thereof
US5002953A (en) * 1987-09-04 1991-03-26 Beecham Group P.L.C. Novel compounds
US4935493A (en) * 1987-10-06 1990-06-19 E. I. Du Pont De Nemours And Company Protease inhibitors
US5387512A (en) * 1991-06-07 1995-02-07 Merck & Co. Inc. Preparation of 3-[z-benzoxazol-2-yl)ethyl]-5-(1-hydroxyethyl)-6-methyl-2-(1H)-pyridinone by biotransformation
US5624894A (en) * 1992-09-17 1997-04-29 University Of Florida Brain-enhanced delivery of neuroactive peptides by sequential metabolism
US6201132B1 (en) * 1993-12-03 2001-03-13 Ferring B.V. Inhibitors of DP-mediated processes, compositions, and therapeutic methods thereof
US5601986A (en) * 1994-07-14 1997-02-11 Amgen Inc. Assays and devices for the detection of extrahepatic biliary atresia
US5512549A (en) * 1994-10-18 1996-04-30 Eli Lilly And Company Glucagon-like insulinotropic peptide analogs, compositions, and methods of use
US5614379A (en) * 1995-04-26 1997-03-25 Eli Lilly And Company Process for preparing anti-obesity protein
US5885997A (en) * 1996-07-01 1999-03-23 Dr. Reddy's Research Foundation Heterocyclic compounds, process for their preparation and pharmaceutical compositions containing them and their use in the treatment of diabetes and related diseases
US6011155A (en) * 1996-11-07 2000-01-04 Novartis Ag N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US20030060434A1 (en) * 1997-02-18 2003-03-27 Loretta Nielsen Combined tumor suppressor gene therapy and chemotherapy in the treatment of neoplasms
US6235493B1 (en) * 1997-08-06 2001-05-22 The Regents Of The University Of California Amino acid substituted-cresyl violet, synthetic fluorogenic substrates for the analysis of agents in individual in vivo cells or tissue
US6703238B2 (en) * 1997-09-29 2004-03-09 Point Therapeutics, Inc. Methods for expanding antigen-specific T cells
US20030027282A1 (en) * 1997-10-06 2003-02-06 Huber Brigitte T. Quiescent cell dipeptidyl peptidase: a novel cytoplasmic serine protease
US6342611B1 (en) * 1997-10-10 2002-01-29 Cytovia, Inc. Fluorogenic or fluorescent reporter molecules and their applications for whole-cell fluorescence screening assays for capsases and other enzymes and the use thereof
US6335429B1 (en) * 1997-10-10 2002-01-01 Cytovia, Inc. Fluorogenic or fluorescent reporter molecules and their applications for whole-cell fluorescence screening assays for caspases and other enzymes and the use thereof
US6214340B1 (en) * 1997-11-18 2001-04-10 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Physiologically active substance sulphostin, process for producing the same, and use thereof
US20030008925A1 (en) * 1997-11-19 2003-01-09 Marc Esteve Treatment of drug-induced sleepiness
US6184020B1 (en) * 1997-12-16 2001-02-06 Novo Nordisk Biotech, Inc. Polypeptides having aminopeptidase activity and nucleic acids encoding same
US20030045464A1 (en) * 1997-12-16 2003-03-06 Hermeling Ronald Norbert Glucagon-like peptide-1 crystals
US6555521B2 (en) * 1997-12-16 2003-04-29 Eli Lilly And Company Glucagon-like peptide-1 crystals
US20020061839A1 (en) * 1998-03-09 2002-05-23 Scharpe Simon Lodewijk Serine peptidase modulators
US6548481B1 (en) * 1998-05-28 2003-04-15 Probiodrug Ag Effectors of dipeptidyl peptidase IV
US6355614B1 (en) * 1998-06-05 2002-03-12 Point Therapeutics Cyclic boroproline compounds
US20020049164A1 (en) * 1998-06-24 2002-04-25 Hans-Ulrich Demuth Prodrugs of DP IV-inhibitors
US20020071838A1 (en) * 1998-07-31 2002-06-13 Hans-Ulrich Demuth Method for raising the blood glucose level in mammals
US20020006899A1 (en) * 1998-10-06 2002-01-17 Pospisilik Andrew J. Use of dipeptidyl peptidase IV effectors for lowering blood pressure in mammals
US6521644B1 (en) * 1999-03-23 2003-02-18 Ferring Bv Compositions for promoting growth
US6548529B1 (en) * 1999-04-05 2003-04-15 Bristol-Myers Squibb Company Heterocyclic containing biphenyl aP2 inhibitors and method
US20020049153A1 (en) * 1999-05-17 2002-04-25 BRIDON Dominique P. Long lasting insulinoptropic peptides
US6172081B1 (en) * 1999-06-24 2001-01-09 Novartis Ag Tetrahydroisoquinoline 3-carboxamide derivatives
US6528486B1 (en) * 1999-07-12 2003-03-04 Zealand Pharma A/S Peptide agonists of GLP-1 activity
US20030092630A2 (en) * 1999-08-24 2003-05-15 Probiodrug Ag New effectors of dipeptidyl peptidase iv for topical use
US6559188B1 (en) * 1999-09-17 2003-05-06 Novartis Ag Method of treating metabolic disorders especially diabetes, or a disease or condition associated with diabetes
US20030087935A1 (en) * 1999-09-22 2003-05-08 Cheng Peter T. Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US6727271B2 (en) * 1999-09-22 2004-04-27 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US20030096846A1 (en) * 1999-09-22 2003-05-22 Cheng Peter T. Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US6251391B1 (en) * 1999-10-01 2001-06-26 Klaire Laboratories, Inc. Compositions containing dipepitidyl peptidase IV and tyrosinase or phenylalaninase for reducing opioid-related symptons
US20030096857A1 (en) * 1999-11-30 2003-05-22 Evans David Michael Novel antidiabetic agents
US20030040478A1 (en) * 1999-12-08 2003-02-27 Drucker Daniel J Chemotherapy treatment
US6380398B2 (en) * 2000-01-04 2002-04-30 Novo Nordisk A/S Therapeutically active and selective heterocyclic compounds that are inhibitors of the enzyme DPP-IV
US20030060412A1 (en) * 2000-01-27 2003-03-27 Prouty Walter Francis Process for solubilizing glucagon-like peptide 1compounds
US20020019411A1 (en) * 2000-03-10 2002-02-14 Robl Jeffrey A. Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method
US6395767B2 (en) * 2000-03-10 2002-05-28 Bristol-Myers Squibb Company Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method
US6555519B2 (en) * 2000-03-30 2003-04-29 Bristol-Myers Squibb Company O-glucosylated benzamide SGLT2 inhibitors and method
US20030008905A1 (en) * 2000-03-31 2003-01-09 Hans-Ulrich Demuth Method for the improvement of islet signaling in diabetes mellitus and for its prevention
US6545170B2 (en) * 2000-04-13 2003-04-08 Pharmacia Corporation 2-amino-5, 6 heptenoic acid derivatives useful as nitric oxide synthase inhibitors
US20040082497A1 (en) * 2000-04-26 2004-04-29 Evans David Michael Inhibitors of dipeptidyl peptidase IV
US20020041871A1 (en) * 2000-06-01 2002-04-11 Brudnak Mark A. Genomeceutical and/or enzymatic composition and method for treating autism
US20040034014A1 (en) * 2000-07-04 2004-02-19 Kanstrup Anders Bendtz Heterocyclic compounds, which are inhibitors of the enzyme DPP-IV
US20020016100A1 (en) * 2000-07-25 2002-02-07 Yazaki Coroporation Connector supporting structure
US20020037829A1 (en) * 2000-08-23 2002-03-28 Aronson Peter S. Use of DPPIV inhibitors as diuretic and anti-hypertensive agents
US20040063935A1 (en) * 2000-10-06 2004-04-01 Kosuke Yasuda Aliphatic nitrogenous five-membered ring compounds
US20040053369A1 (en) * 2000-10-27 2004-03-18 Abbott Catherine Anne Dipeptidyl peptidases
US6686337B2 (en) * 2000-10-30 2004-02-03 Ortho-Mcneil Pharmaceutical, Inc. Combination therapy comprising anti-diabetic and anticonvulsant agents
US20040072892A1 (en) * 2000-11-10 2004-04-15 Hiroshi Fukushima Cyanopyrrolidine derivatives
US20030055052A1 (en) * 2000-11-10 2003-03-20 Stefan Peters FAP-activated anti-tumor compounds
US20020077340A1 (en) * 2000-11-20 2002-06-20 Richard Sulsky Pyridone inhibitors of fatty acid binding protein and method
US20040082607A1 (en) * 2001-02-02 2004-04-29 Satoru Oi Fused heterocyclic compounds
US20040077645A1 (en) * 2001-02-24 2004-04-22 Frank Himmelsbach Xanthine derivatives,production and use thereof as medicament
US20040087587A1 (en) * 2001-02-24 2004-05-06 Boehringer Ingelheim Pharma Gmbh & Co. Kg Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions
US6337069B1 (en) * 2001-02-28 2002-01-08 B.M.R.A. Corporation B.V. Method of treating rhinitis or sinusitis by intranasally administering a peptidase
US20040092478A1 (en) * 2001-03-19 2004-05-13 Rothermel John D. Combinations comprising an antidiarrheal agent and an epothilone or an epothilone derivative
US6716843B2 (en) * 2001-03-28 2004-04-06 Les Laboratoires Servier Alpha-amino acid sulphonyl compounds
US20030087950A1 (en) * 2001-03-28 2003-05-08 Denanteuil Guillaume New alpha-amino acid sulphonyl compounds
US6706742B2 (en) * 2001-05-15 2004-03-16 Les Laboratories Servier Alpha-amino-acid compounds
US20030092697A1 (en) * 2001-05-30 2003-05-15 Cheng Peter T. Conformationally constrained analogs useful as antidiabetic and antiobesity agents and method
US20030069234A1 (en) * 2001-06-06 2003-04-10 Medina Julio C. CXCR3 antagonists
US20030100563A1 (en) * 2001-07-06 2003-05-29 Edmondson Scott D. Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US6699871B2 (en) * 2001-07-06 2004-03-02 Merck & Co., Inc. Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US20030023946A1 (en) * 2001-07-24 2003-01-30 Ming-Te Lin Standard cell library generation using merged power method
US6673829B2 (en) * 2001-09-14 2004-01-06 Novo Nordisk A/S Aminoazetidine,-pyrrolidine and -piperidine derivatives
US20040009998A1 (en) * 2001-10-01 2004-01-15 Dhar T. G. Murali Spiro-hydantoin compounds useful as anti-inflammatory agents
US20050043299A1 (en) * 2001-10-23 2005-02-24 Ferring B. V. Inhibitors of dipeptidyl peptidase iv
US6861440B2 (en) * 2001-10-26 2005-03-01 Hoffmann-La Roche Inc. DPP IV inhibitors
US6673815B2 (en) * 2001-11-06 2004-01-06 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
US20050014946A1 (en) * 2001-11-09 2005-01-20 Hans-Ulrich Demuth Substituted amino ketone compounds
US20030089935A1 (en) * 2001-11-13 2003-05-15 Macronix International Co., Ltd. Non-volatile semiconductor memory device with multi-layer gate insulating structure
US6727261B2 (en) * 2001-12-27 2004-04-27 Hoffman-La Roche Inc. Pyrido[2,1-A]Isoquinoline derivatives
US6867205B2 (en) * 2002-02-13 2005-03-15 Hoffman-La Roche Inc. Pyridine and pyrimidine derivatives
US20040006062A1 (en) * 2002-05-06 2004-01-08 Smallheer Joanne M. Sulfonylaminovalerolactams and derivatives thereof as factor Xa inhibitors
US20040002495A1 (en) * 2002-05-20 2004-01-01 Philip Sher Lactam glycogen phosphorylase inhibitors and method of use
US6710040B1 (en) * 2002-06-04 2004-03-23 Pfizer Inc. Fluorinated cyclic amides as dipeptidyl peptidase IV inhibitors
US20040002609A1 (en) * 2002-06-04 2004-01-01 Pfizer Inc. Synthesis of 3,3,4,4-tetrafluoropyrrolidine and novel dipeptidyl peptidase-IV inhibitor compounds
US20040009972A1 (en) * 2002-06-17 2004-01-15 Ding Charles Z. Benzodiazepine inhibitors of mitochondial F1F0 ATP hydrolase and methods of inhibiting F1F0 ATP hydrolase
US20040054171A1 (en) * 2002-07-04 2004-03-18 Jensen Anette Frost Polymorphic forms of a 4H-thieno[3,2-E]-1,2,4-thiadiazine 1,1-dioxide derivative
US20040097510A1 (en) * 2002-08-21 2004-05-20 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US20040058876A1 (en) * 2002-09-18 2004-03-25 Torsten Hoffmann Secondary binding site of dipeptidyl peptidase IV (DP IV)
US20040072874A1 (en) * 2002-09-30 2004-04-15 Nagaaki Sato N-substituted-2-oxodihydropyridine derivatives
US20050020574A1 (en) * 2002-12-03 2005-01-27 Boehringer Ingelheim Pharma Gmbh Co. Kg New substituted imidazo-pyridinones and imidazo-pyridazinones, the preparation thereof and their use as pharmaceutical compositions
US20050014732A1 (en) * 2003-03-14 2005-01-20 Pharmacia Corporation Combination of an aldosterone receptor antagonist and an anti-diabetic agent
US20050058635A1 (en) * 2003-05-05 2005-03-17 Hans-Ulrich Demuth Use of effectors of glutaminyl and glutamate cyclases
US20050026921A1 (en) * 2003-06-18 2005-02-03 Boehringer Ingelheim International Gmbh New imidazopyridazinone and imidazopyridone derivatives, the preparation thereof and their use as pharmaceutical compositions
US20050032804A1 (en) * 2003-06-24 2005-02-10 Cypes Stephen Howard Phosphoric acid salt of a dipeptidyl peptidase-IV inhibitor
US20050038020A1 (en) * 2003-08-01 2005-02-17 Hamann Lawrence G. Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods
US20050043292A1 (en) * 2003-08-20 2005-02-24 Pfizer Inc Fluorinated lysine derivatives as dipeptidyl peptidase IV inhibitors

Cited By (126)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8664232B2 (en) 2002-08-21 2014-03-04 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US9108964B2 (en) 2002-08-21 2015-08-18 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US8119648B2 (en) 2002-08-21 2012-02-21 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US8178541B2 (en) 2002-08-21 2012-05-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US20080249089A1 (en) * 2002-08-21 2008-10-09 Boehringer Ingelheim Pharma Kg 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US10023574B2 (en) 2002-08-21 2018-07-17 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US9321791B2 (en) 2002-08-21 2016-04-26 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US9556175B2 (en) 2002-08-21 2017-01-31 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and thier use as pharmaceutical compositions
US10202383B2 (en) 2002-08-21 2019-02-12 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
US20050070531A1 (en) * 2003-08-13 2005-03-31 Syrrx, Inc. Dipeptidyl peptidase inhibitors
US7790736B2 (en) 2003-08-13 2010-09-07 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7723344B2 (en) 2003-08-13 2010-05-25 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
US7790734B2 (en) 2003-09-08 2010-09-07 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US20050065145A1 (en) * 2003-09-08 2005-03-24 Syrrx, Inc. Dipeptidyl peptidase inhibitors
US20050065144A1 (en) * 2003-09-08 2005-03-24 Syrrx, Inc. Dipeptidyl peptidase inhibitors
US8697868B2 (en) 2004-02-18 2014-04-15 Boehringer Ingelheim International Gmbh 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions
US20090012059A1 (en) * 2004-03-15 2009-01-08 Jun Feng Dipeptidyl peptidase inhibitors
US8173663B2 (en) 2004-03-15 2012-05-08 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7781584B2 (en) 2004-03-15 2010-08-24 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US8329900B2 (en) 2004-03-15 2012-12-11 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US8288539B2 (en) 2004-03-15 2012-10-16 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US7906523B2 (en) 2004-03-15 2011-03-15 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US8188275B2 (en) 2004-03-15 2012-05-29 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US20050277945A1 (en) * 2004-06-14 2005-12-15 Usgi Medical Inc. Apparatus and methods for performing transluminal gastrointestinal procedures
US9499546B2 (en) 2004-11-05 2016-11-22 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)-xanthines
US9751855B2 (en) 2004-11-05 2017-09-05 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)-xanthines
US8541450B2 (en) 2004-11-05 2013-09-24 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(3-aminopiperidin-1yl)-xanthines
US7820815B2 (en) 2004-11-05 2010-10-26 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(-3-aminopiperidin-1-yl) xanthines
US8883805B2 (en) 2004-11-05 2014-11-11 Boehringer Ingelheim International Gmbh Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)-xanthines
US7872124B2 (en) 2004-12-21 2011-01-18 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US8637530B2 (en) 2005-07-30 2014-01-28 Boehringer Ingelheim International Gmbh 8-(3-amino-piperidin-1-yl)-xanthines, their preparation, and their use as pharmaceuticals
US8106060B2 (en) 2005-07-30 2012-01-31 Boehringer Ingelheim International Gmbh 8-(3-amino-piperidin-1-yl)-xanthines, their preparation, and their use as pharmaceuticals
US8906901B2 (en) 2005-09-14 2014-12-09 Takeda Pharmaceutical Company Limited Administration of dipeptidyl peptidase inhibitors
US8222411B2 (en) 2005-09-16 2012-07-17 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US20070066635A1 (en) * 2005-09-16 2007-03-22 Mark Andres Polymorphs of benzoate salt of 2-[[6-[(3r)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2h)-pyrimidinyl]methyl]-benzonitrile and methods of use therefor
US20090275750A1 (en) * 2005-09-16 2009-11-05 Jun Feng Dipeptidyl peptidase inhibitors
US20100029941A1 (en) * 2006-03-28 2010-02-04 Takeda Pharmaceutical Company Limited Preparation of (r)-3-aminopiperidine dihydrochloride
US9266888B2 (en) 2006-05-04 2016-02-23 Boehringer Ingelheim International Gmbh Polymorphs
US11033552B2 (en) 2006-05-04 2021-06-15 Boehringer Ingelheim International Gmbh DPP IV inhibitor formulations
US9493462B2 (en) 2006-05-04 2016-11-15 Boehringer Ingelheim International Gmbh Polymorphs
US8673927B2 (en) 2006-05-04 2014-03-18 Boehringer Ingelheim International Gmbh Uses of DPP-IV inhibitors
US10301313B2 (en) 2006-05-04 2019-05-28 Boehringer Ingelheim International Gmbh Polymorphs
US8232281B2 (en) 2006-05-04 2012-07-31 Boehringer Ingelheim International Gmbh Uses of DPP-IV inhibitors
US11291668B2 (en) 2006-05-04 2022-04-05 Boehringer Ingelheim International Gmbh Uses of DPP IV inhibitors
US9173859B2 (en) 2006-05-04 2015-11-03 Boehringer Ingelheim International Gmbh Uses of DPP IV inhibitors
US9815837B2 (en) 2006-05-04 2017-11-14 Boehringer Ingelheim International Gmbh Polymorphs
US10080754B2 (en) 2006-05-04 2018-09-25 Boehringer Ingelheim International Gmbh Uses of DPP IV inhibitors
US11084819B2 (en) 2006-05-04 2021-08-10 Boehringer Ingelheim International Gmbh Polymorphs
US11919903B2 (en) 2006-05-04 2024-03-05 Boehringer Ingelheim International Gmbh Polymorphs
US8324383B2 (en) 2006-09-13 2012-12-04 Takeda Pharmaceutical Company Limited Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile
US8084605B2 (en) 2006-11-29 2011-12-27 Kelly Ron C Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
US20080227798A1 (en) * 2006-11-29 2008-09-18 Kelly Ron C Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2h-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
US20100105710A1 (en) * 2007-03-13 2010-04-29 Takeda Pharmaceutical Company Limited Solid preparation comprising 2-[[6-[(3r)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2h)-pyrimidinyl]methyl]-4-fluorobenzonitrile
US7994183B2 (en) 2007-03-13 2011-08-09 Takeda Pharmaceutical Company Limited Solid preparation comprising 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-4-fluorobenzonitrile
US8093236B2 (en) 2007-03-13 2012-01-10 Takeda Pharmaceuticals Company Limited Weekly administration of dipeptidyl peptidase inhibitors
WO2008134425A1 (en) * 2007-04-27 2008-11-06 Cedars-Sinai Medical Center Use of glp-1 receptor agonists for the treatment of gastrointestinal disorders
AU2008288407B2 (en) * 2007-08-16 2012-04-05 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivative
US8551957B2 (en) 2007-08-16 2013-10-08 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivate
WO2009022007A1 (en) * 2007-08-16 2009-02-19 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivative
WO2009022009A1 (en) * 2007-08-16 2009-02-19 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a pyrazole-o-glucoside derivative
EP3106156A1 (en) * 2007-08-16 2016-12-21 Boehringer Ingelheim International GmbH Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivative
EA018608B1 (en) * 2007-08-16 2013-09-30 Бёрингер Ингельхайм Интернациональ Гмбх Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivative and dpp iv inhibitor
EP3939577A1 (en) 2007-08-16 2022-01-19 Boehringer Ingelheim International GmbH Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivative
US20110195917A1 (en) * 2007-08-16 2011-08-11 Boehringer Ingelheim International Gmbh Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivate
EP2187879B1 (en) 2007-08-16 2016-10-12 Boehringer Ingelheim International GmbH Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivative
EP2698152A1 (en) 2007-08-16 2014-02-19 Boehringer Ingelheim International GmbH Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivative
US9415016B2 (en) 2008-04-03 2016-08-16 Boehringer Ingelheim International Gmbh DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation
US10973827B2 (en) 2008-04-03 2021-04-13 Boehringer Ingelheim International Gmbh DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation
US10022379B2 (en) 2008-04-03 2018-07-17 Boehringer Ingelheim International Gmbh DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation
US9155705B2 (en) 2008-04-03 2015-10-13 Boehringer Ingelheim International Gmbh DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation
US8853156B2 (en) 2008-08-06 2014-10-07 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients inappropriate for metformin therapy
US9486526B2 (en) 2008-08-06 2016-11-08 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients inappropriate for metformin therapy
EP3598974A1 (en) 2008-08-06 2020-01-29 Boehringer Ingelheim International GmbH Treatment for diabetes in patients inappropriate for metformin therapy
US10034877B2 (en) 2008-08-06 2018-07-31 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients inappropriate for metformin therapy
EP2990037A1 (en) 2008-08-06 2016-03-02 Boehringer Ingelheim International GmbH Treatment for diabetes in patients inappropriate for metformin therapy
WO2010018217A3 (en) * 2008-08-15 2010-05-20 Boehringer Ingelheim International Gmbh Purin derivatives for use in the treatment of fab-related diseases
EP3626238A1 (en) 2008-08-15 2020-03-25 Boehringer Ingelheim International GmbH Dpp-4 inhibitors for use for the treatment of wound healing in diabetic patients
EA031225B1 (en) * 2008-08-15 2018-12-28 Бёрингер Ингельхайм Интернациональ Гмбх Dpp-4 inhibitors for wound healing
WO2010018217A2 (en) * 2008-08-15 2010-02-18 Boehringer Ingelheim International Gmbh Organic compounds for wound healing
US8513264B2 (en) 2008-09-10 2013-08-20 Boehringer Ingelheim International Gmbh Combination therapy for the treatment of diabetes and related conditions
US11911388B2 (en) 2008-10-16 2024-02-27 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral or non-oral antidiabetic drug
US9212183B2 (en) 2008-12-23 2015-12-15 Boehringer Ingelheim International Gmbh Salt forms of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine
US8865729B2 (en) 2008-12-23 2014-10-21 Boehringer Ingelheim International Gmbh Salt forms of a xanthine compound
US8846695B2 (en) 2009-01-07 2014-09-30 Boehringer Ingelheim International Gmbh Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy comprising a DPP-IV inhibitor
WO2010079197A1 (en) 2009-01-07 2010-07-15 Boehringer Ingelheim International Gmbh Treatment of diabetes in patients with inadequate glycemic control despite metformin therapy comprising a dpp-iv inhibitor
WO2010086411A1 (en) 2009-01-29 2010-08-05 Boehringer Ingelheim International Gmbh Dpp-iv inhibitors for treatment of diabetes in paediatric patients
US10406172B2 (en) 2009-02-13 2019-09-10 Boehringer Ingelheim International Gmbh Pharmaceutical composition, methods for treating and uses thereof
WO2010092163A2 (en) 2009-02-13 2010-08-19 Boehringer Ingelheim International Gmbh Antidiabetic medications
US20120219623A1 (en) * 2009-10-02 2012-08-30 Boehringer Ingelheim International Gmbh Pharmaceutical compositions comprising bi-1356 and metformin
US10092571B2 (en) 2009-11-27 2018-10-09 Boehringer Ingelheim International Gmbh Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin
WO2011064352A1 (en) 2009-11-27 2011-06-03 Boehringer Ingelheim International Gmbh Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin
US9457029B2 (en) 2009-11-27 2016-10-04 Boehringer Ingelheim International Gmbh Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin
EP3646859A1 (en) 2009-11-27 2020-05-06 Boehringer Ingelheim International GmbH Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin
WO2011113947A1 (en) 2010-03-18 2011-09-22 Boehringer Ingelheim International Gmbh Combination of a gpr119 agonist and the dpp-iv inhibitor linagliptin for use in the treatment of diabetes and related conditions
WO2011138421A1 (en) 2010-05-05 2011-11-10 Boehringer Ingelheim International Gmbh Combination therapy
KR101927068B1 (en) * 2010-05-05 2018-12-10 베링거 인겔하임 인터내셔날 게엠베하 Sequential Combination Therapy by the Weight Reducing Treatment Followed by the DPP-4 Inhibitor
US10004747B2 (en) 2010-05-05 2018-06-26 Boehringer Ingelheim International Gmbh Combination therapy
EA033415B1 (en) * 2010-05-05 2019-10-31 Boehringer Ingelheim Int Methods for treating obesity, use of dpp-4 inhibitor in these methods and method for treating patients suffering from type 2 diabetes mellitus
US9186392B2 (en) 2010-05-05 2015-11-17 Boehringer Ingelheim International Gmbh Combination therapy
KR101819609B1 (en) * 2010-05-05 2018-01-17 베링거 인겔하임 인터내셔날 게엠베하 Sequential Combination Therapy by the Weight Reducing Treatment Followed by the DPP-4 Inhibitor
US9603851B2 (en) 2010-05-05 2017-03-28 Boehringer Ingelheim International Gmbh Combination therapy
EP2566469B1 (en) 2010-05-05 2022-12-21 Boehringer Ingelheim International GmbH Combination therapy
EP3366304B1 (en) * 2010-06-24 2020-05-13 Boehringer Ingelheim International GmbH Diabetes therapy
US20120165251A1 (en) * 2010-06-24 2012-06-28 Boehringer Ingelheim International Gmbh Diabetes therapy
WO2011161161A1 (en) 2010-06-24 2011-12-29 Boehringer Ingelheim International Gmbh Diabetes therapy
US9149478B2 (en) * 2010-06-24 2015-10-06 Boehringer Ingelheim International Gmbh Diabetes therapy
US11911387B2 (en) 2010-11-15 2024-02-27 Boehringer Ingelheim International Gmbh Vasoprotective and cardioprotective antidiabetic therapy
US9034883B2 (en) 2010-11-15 2015-05-19 Boehringer Ingelheim International Gmbh Vasoprotective and cardioprotective antidiabetic therapy
US8907086B2 (en) 2011-03-03 2014-12-09 Merck Sharp & Dohme Corp. Fused bicyclic heterocycles useful as dipeptidyl peptidase-IV inhibitors
US11564886B2 (en) 2011-03-07 2023-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical compositions
US10596120B2 (en) 2011-03-07 2020-03-24 Boehringer Ingelheim International Gmbh Pharmaceutical compositions
US20180185291A1 (en) 2011-03-07 2018-07-05 Boehringer Ingelheim International Gmbh Pharmaceutical compositions
US8962636B2 (en) 2011-07-15 2015-02-24 Boehringer Ingelheim International Gmbh Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions
US8883800B2 (en) 2011-07-15 2014-11-11 Boehringer Ingelheim International Gmbh Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions
US9199998B2 (en) 2011-07-15 2015-12-01 Boehringer Ingelheim Internatioal Gmbh Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions
US9555001B2 (en) 2012-03-07 2017-01-31 Boehringer Ingelheim International Gmbh Pharmaceutical composition and uses thereof
US10195203B2 (en) 2012-05-14 2019-02-05 Boehringr Ingelheim International GmbH Use of a DPP-4 inhibitor in podocytes related disorders and/or nephrotic syndrome
US9526730B2 (en) 2012-05-14 2016-12-27 Boehringer Ingelheim International Gmbh Use of a DPP-4 inhibitor in podocytes related disorders and/or nephrotic syndrome
WO2013174767A1 (en) 2012-05-24 2013-11-28 Boehringer Ingelheim International Gmbh A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference
US9713618B2 (en) 2012-05-24 2017-07-25 Boehringer Ingelheim International Gmbh Method for modifying food intake and regulating food preference with a DPP-4 inhibitor
WO2013183784A1 (en) 2012-06-05 2013-12-12 Takeda Pharmaceutical Company Limited Solid preparation
US9486411B2 (en) 2012-06-05 2016-11-08 Takeda Pharmaceutical Company Limited Solid preparation
KR20150021544A (en) 2012-06-05 2015-03-02 다케다 야쿠힌 고교 가부시키가이샤 Solid preparation
US9757377B2 (en) 2012-06-05 2017-09-12 Takeda Pharmaceutical Company Limited Solid preparation
US9526728B2 (en) 2014-02-28 2016-12-27 Boehringer Ingelheim International Gmbh Medical use of a DPP-4 inhibitor
US10155000B2 (en) 2016-06-10 2018-12-18 Boehringer Ingelheim International Gmbh Medical use of pharmaceutical combination or composition

Also Published As

Publication number Publication date
EP1942898B1 (en) 2011-11-09
PL1942898T3 (en) 2012-04-30
CR9874A (en) 2008-08-01
SI1942898T1 (en) 2012-03-30
NO20081592L (en) 2008-05-23
IL190131A (en) 2013-08-29
ME01960B (en) 2015-05-20
AU2006290205B2 (en) 2012-12-13
ES2376351T3 (en) 2012-03-13
NO340910B1 (en) 2017-07-10
PL1942898T5 (en) 2014-10-31
RS52110B2 (en) 2018-05-31
MY147393A (en) 2012-11-30
ZA200802857B (en) 2009-09-30
EA015169B1 (en) 2011-06-30
PT1942898E (en) 2011-12-20
CN101374523B (en) 2012-04-11
HRP20120004T4 (en) 2014-06-06
HRP20120004T1 (en) 2012-03-31
CY1112281T1 (en) 2015-12-09
KR101345316B1 (en) 2013-12-27
ATE532518T1 (en) 2011-11-15
WO2007033350A1 (en) 2007-03-22
US20110192748A1 (en) 2011-08-11
SI1942898T2 (en) 2014-08-29
ZA200901814B (en) 2010-06-30
TW200744602A (en) 2007-12-16
CA2622472A1 (en) 2007-03-22
BRPI0616055A2 (en) 2011-06-07
CA2622472C (en) 2013-11-19
HK1119086A1 (en) 2009-02-27
AR055435A1 (en) 2007-08-22
MA29795B1 (en) 2008-09-01
JP5027137B2 (en) 2012-09-19
DK1942898T4 (en) 2014-06-02
RS52110B (en) 2012-08-31
DK1942898T3 (en) 2012-01-09
CN101374523A (en) 2009-02-25
EP1942898B2 (en) 2014-05-14
KR20080055875A (en) 2008-06-19
ME02005B (en) 2012-08-31
AU2006290205A1 (en) 2007-03-22
PE20070522A1 (en) 2007-07-11
JP2009507930A (en) 2009-02-26
US8906901B2 (en) 2014-12-09
ES2376351T5 (en) 2014-07-15
IL190131A0 (en) 2008-11-03
NZ566799A (en) 2011-04-29
US20130172377A1 (en) 2013-07-04
EP1942898A1 (en) 2008-07-16
GEP20135838B (en) 2013-06-10
TWI432200B (en) 2014-04-01
EA200800726A1 (en) 2008-08-29

Similar Documents

Publication Publication Date Title
US8906901B2 (en) Administration of dipeptidyl peptidase inhibitors
US20190314352A1 (en) Administration of dipeptidyl peptidase inhibitors
EP2073810B1 (en) Use of 2-6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2h-pyrimidin-1-ylmethyl-4-fluoro-benzonitrile for treating diabetes, cancer, autoimmune disorders and hiv infection
US8093236B2 (en) Weekly administration of dipeptidyl peptidase inhibitors
US20070060529A1 (en) Administration of dipeptidyl peptidase inhibitors

Legal Events

Date Code Title Description
AS Assignment

Owner name: TAKEDA SAN DIEGO, INC., CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:CHRISTOPHER, RONALD J.;REEL/FRAME:018503/0554

Effective date: 20061101

Owner name: TAKEDA PHARMACEUTICAL COMPANY LIMITED, JAPAN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:TAKEDA SAN DIEGO, INC.;REEL/FRAME:018503/0597

Effective date: 20061109

Owner name: TAKEDA SAN DIEGO, INC., CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:DEVELOPMENT PARTNERS, LLC;REEL/FRAME:018503/0578

Effective date: 20061101

Owner name: DEVELOPMENT PARTNERS, LLC, NORTH CAROLINA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:COVINGTON, PAUL;REEL/FRAME:018503/0352

Effective date: 20061102

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION