WO1999009021A1 - Process for selective derivatization of taxanes - Google Patents
Process for selective derivatization of taxanes Download PDFInfo
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- WO1999009021A1 WO1999009021A1 PCT/US1998/017016 US9817016W WO9909021A1 WO 1999009021 A1 WO1999009021 A1 WO 1999009021A1 US 9817016 W US9817016 W US 9817016W WO 9909021 A1 WO9909021 A1 WO 9909021A1
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- hydrocarbyl
- hydroxy
- hydrogen
- heteroaryl
- taxane
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- 0 CC(C)([C@@](C1)([C@@](C([C@]2([C@@](C[C@@]3*)OC2)OC(C)=O)[C@]3(C)C([C@@]2OC(C)=O)=O)O)O)C2=C(C)[C@]1O Chemical compound CC(C)([C@@](C1)([C@@](C([C@]2([C@@](C[C@@]3*)OC2)OC(C)=O)[C@]3(C)C([C@@]2OC(C)=O)=O)O)O)C2=C(C)[C@]1O 0.000 description 4
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
Definitions
- the present invention is directed, in general, to a process for the preparation of taxol and other taxanes, and in particular, to such a process in which the C(7) or C(10) hydroxyl group of a taxane is selectively derivatized.
- Taxotere both of which are potent anticancer agents. Conversion of 10-DAB to taxol, Taxotere ® and other taxanes having antitumor activity requires protection or derivatization of the C(7) and C(10) hydroxyl groups followed by esterification of the C(13) hydroxyl group to attach an appropriate side chain at that position.
- the C(7) hydroxyl group must be protected (or derivatized) before the C(10) hydroxyl group is protected or derivatized.
- taxol may be prepared by treating 10-DAB with triethylsilyl chloride to protect the C(7) hydroxyl group, acetylating the C(10) hydroxyl group, attaching the side chain by esterification of the C(13) hydroxyl group, and, finally, removal of protecting groups .
- taxanes having various substituents bonded to either the C(10) or the C(7) oxygens show anticancer activity.
- the present invention is directed to a process for the acylation of the C(10) hydroxy group of a taxane .
- the process comprises forming a reaction mixture containing the taxane and an acylating agent which contains less than one equivalent of a base for each equivalent of taxane, and allowing the taxane to react with the acylating agent to form a C(10) acylated taxane .
- the present invention is further directed to a process for the silylation of the C(10) hydroxy group of a taxane having a C(10) hydroxy group.
- the process comprises treating the taxane with a silylamide or a bissilylamide to form a C(10) silylated taxane.
- the present invention is further directed to a process for converting the C(7) hydroxy group of a 10-acyloxy-7-hydroxytaxane to an acetal or ketal .
- the process comprises treating the 10-acyloxy-7-hydroxytaxane with a ketalizing agent in the presence of an acid catalyst to form a C(10) ketalized taxane.
- the present invention is further directed to a taxane having the structure :
- M is a metal or comprises ammonium:
- R x is hydrogen, hydroxy, protected hydroxy, or together with R 14 or R 2 forms a carbonate;
- R 2 is keto, -0T 2 , acyloxy, or together with x forms a carbonate;
- R 4 is -OT 4 or acyloxy
- R 7 is -OSiR j R ⁇ R L ;
- R 9 is hydrogen, keto, -OT 9 , or acyloxy;
- R 10 is hydrogen, keto, -OT 10 , or acyloxy
- R 13 is hydroxy, protected hydroxy, keto, or MO-;
- R 14 is hydrogen, -OT 14 , acyloxy, or together with R ⁇ forms a carbonate;
- Rj, R ⁇ , R L are independently hydrocarbyl, substituted hydrocarbyl, or heteroaryl, provided, however, if each of R j , R ⁇ and R L are alkyl, at least one of Rj, R ⁇ and R L comprises a carbon skeleton having at least four carbon atoms ; and
- T 2 , T 4 , T 9 , T 10 , and T 14 are independently hydrogen or hydroxy protecting group.
- the present invention enables the selective derivatization of the C(10) hydroxyl group of a taxane without first protecting the C(7) hydroxyl group. Stated another way, it has been discovered that the reactivities previously reported for the C(7) and C(10) hydroxyl groups can be reversed, that is, the reactivity of the C(10) hydroxyl group becomes greater than the reactivity of the C(7) hydroxyl group under certain conditions.
- 7, 10-dihydroxytaxanes which may be selectively derivatized in accordance with the present invention correspond to the following structure:
- R- L is hydrogen, hydroxy, protected hydroxy, or together with R 14 or R 2 forms a carbonate;
- R 2 is keto, -OT 2 , acyloxy, or together with R x forms a carbonate;
- R 4 is -OT 4 or acyloxy
- R 9 is hydrogen, keto, -OT 9 , or acyloxy
- R 13 is hydroxy, protected hydroxy, keto, or
- R 14 is hydrogen, -OT 14 , acyloxy or together with x forms a carbonate
- T 2 , T 4 , T 9 , and T 14 are independently hydrogen or hydroxy protecting group;
- X x is -OX 6 , -SX 7 , or -NX 8 X 9 ;
- X 2 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heteroaryl
- X 3 and X 4 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heteroaryl;
- X 5 is -X 10 , -OX 10 , -SX 10 , -NX 8 X 10 , or -S0 2 X 1X ;
- X 6 is hydrocarbyl, substituted hydrocarbyl, heteroaryl, hydroxy protecting group or a functional group which increases the water solubility of the taxane derivative;
- X 7 is hydrocarbyl, substituted hydrocarbyl, heteroaryl, or sulfhydryl protecting group;
- X 8 is hydrogen, hydrocarbyl, or substituted hydrocarbyl ;
- X 9 is an amino protecting group
- X 10 is hydrocarbyl, substituted hydrocarbyl, or heteroaryl ;
- X xl is hydrocarbyl, substituted hydrocarbyl, heteroaryl, -OX 10 , or -NX 8 X 14 ;
- X 14 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heteroaryl.
- the C(10) hydroxyl group of a taxane can be selectively acylated in the absence of a base, preferably in the absence of an amine base.
- amine bases such as pyridine, triethylamine, dimethylaminopyridine and 2,6- lutidine, if present at all, are present in the reaction mixture in relatively low concentration.
- the molar ratio of the amine base to the taxane is preferably less than 1:1, more preferably less than 10:1, and most preferably less than 100:1.
- Acylating agents which may be used for the selective acylation of the C(10) hydroxyl group of a taxane include anhydrides, dicarbonates, thiodicarbonates, and isocyanates.
- the anhydrides, dicarbonates, and thiodicarbonates correspond to structure 4 and the isocyanates correspond to structure 5 :
- R 1 is -OR a , -SR a , or R a
- R 2 is -OC(0)R b , -OC(0)OR b , -OC(0)SR b , -OPOR b R c , or -OS(0) 2 R b
- R 3 is hydrocarbyl, substituted hydrocarbyl, or heteroaryl
- R a , R b , R c are independently hydrocarbyl, substituted hydrocarbyl, or heteroaryl.
- suitable carboxylic acid anhydride acylating agents include acetic anhydride, chloroacetic anhydride, propionic anhydride, benzoic anhydride, and other carboxylic acid anhydrides containing substituted or unsubstituted hydrocarbyl or heteroaryl moieties;
- suitable dicarbonate acylating reagents include dibenzyl dicarbonate, diallyl dicarbonate, dipropyl dicarbonate, and other dicarbonates containing substituted or unsubstituted hydrocarbyl or heteroaryl moieties;
- suitable isocyanate acylating agents include phenyl isocyanate, and other isocyanates containing substituted or unsubstituted hydrocarbyl or heteroaryl moieties.
- anhydrides, dicarbonates, and thiodicarbonates used as acylating agents may be mixed, it is generally preferred that they be symmetrical; that is, R 1 and R 2 are selected such that the molecule is symmetrical (e.g., if R 1 is R a , R 2 is-OC(0)R b with R a being the same as R b ) .
- R 1 and R 2 are selected such that the molecule is symmetrical (e.g., if R 1 is R a , R 2 is-OC(0)R b with R a being the same as R b ) .
- the reaction rate may be increased by including a Lewis acid in the reaction mixture.
- Lewis acids which may be used include triflates and halides of elements of groups IB, IIB, IIIB, IVB, VB, VIB, VIIB, VIII, IIIA, IVA, lanthanides, and actinides of the Periodic Table (American Chemical Society format) .
- Preferred Lewis acids include zinc chloride, stannic chloride, cerium trichloride, cuprous chloride, lanthanum trichloride, dysprosium trichloride, and ytterbium trichloride.
- Zinc chloride or cerium trichloride is particularly preferred when the acylating agent is an anhydride or dicarbonate .
- Cuprous chloride is particularly preferred when the acylating agent is an isocyanate.
- the solvent for the selective acylation is preferably an ethereal solvent such as tetrahydrofuran. Alternatively, however, other solvents such as ether or dimethoxyethane may be used.
- the temperature at which the C(10) selective acylation is carried out is not narrowly critical. In general, however, it is preferably carried out at room temperature or higher in order for the reaction to proceed at a sufficiently high rate.
- acylating reactions involving dibenzyl dicarbonate, diallyl dicarbonate, acetic anhydride, chloroacetic anhydride and phenyl isocyanate are illustrated in Reaction Schemes 1 through 5 below.
- the taxane which is selectively acylated at the C(10) position is 10-deacetylbaccatin III. It should be understood, however, that these reaction schemes are merely illustrative and that other taxanes having a C(10) hydroxy group, in general, and other 7, 10-dihydroxytaxanes, in particular, may be selectively acylated with these and other acylating agents in accordance with the present invention.
- the C(10) hydroxyl group of a taxane may be selectively silylated.
- the silylating agent is selected from the group consisting of silylamides and bissilyamides .
- Preferred silylamides and bissilyamides correspond to structures 6 and 7, respectively:
- the silylating agents are selected from the group consisting of tri (hydrocarbyl) silyl- trifluoromethylacetamides and bis tri (hydrocarbyl) - silyltrifluoromethylacetamides, with the hydrocarbyl moiety being substituted or unsubstituted alkyl or aryl .
- the preferred silylamides and bissilylamides include N,0-bis- (trimethylsilyl) trifluoroacetamide, N,0-bis- (triethylsilyl) trifluoroacetamide,
- N-methyl-N-triethylsilyltrifluoroacetamide N-bis (t-butyldimethylsilyl) trifluoroacetamide.
- the silylating agents may be used either alone or in combination with a catalytic amount of a base such as an alkali metal base.
- a base such as an alkali metal base.
- Alkali metal amides such as lithium amide catalysts, in general, and lithium hexamethyldisilazide, in particular, are preferred.
- the solvent for the selective silylation reaction is preferably an ethereal solvent such as tetrahydrofuran. Alternatively, however, other solvents such as ether or dimethoxyethane may be used.
- the temperature at which the C(10) selective silylation is carried out is not narrowly critical. In general, however, it is carried out at 0 °C or greater.
- Selective C(10) silylation reactions involving N,0-bis (trimethylsilyl) trifluoroacetamide and N,0-bis (triethylsilyl) trifluoroacetamide are illustrated in Reaction Schemes 6 and 7 below. In these reaction schemes, the taxane which is selectively silylated at the C(10) position is 10-deacetylbaccatin III.
- the C(7) hydroxyl group can readily be protected or otherwise derivatized selectively in the presence of the C(l) and C(13) hydroxyl groups (and a C(14) hydroxy group, if present) .
- Selective acylation of the C(7) hydroxyl group of a C(10) acylated or silylated taxane can be achieved using any of a variety of common acylating agents including, but not limited to, substituted and unsubstituted carboxylic acid derivatives, e.g., carboxylic acid halides, anhydrides, dicarbonates, isocyanates and haloformates .
- the C(7) hydroxyl group of baccatin III, 10-acyl-lO-deacetylbaccatin III or 10-trihydrocarbylsilyl-lO-deacetyl baccatin III can be selectively acylated with dibenzyl dicarbonate, diallyl dicarbonate, 2, 2, 2-trichloroethyl chloroformate , benzyl chloroformate or another common acylating agent.
- acylation of the C(7) hydroxy group of a C(10) acylated or silylated taxane are more efficient and more selective than are C(7) acylations of a 7,10- dihydroxy taxane such as 10-DAB, i.e., once the C(10) hydroxyl group has been acylated or silylated, there is a significant difference in the reactivity of the remaining C(7), C(13), and C(l) hydroxyl groups (and the C(14) hydroxyl group, if present) .
- These acylation reactions may optionally be carried out in the presence or absence of a base .
- Examples of selective C(7) acylation of a taxane having an acylated or silylated C(10) hydroxy group are shown in Reaction Schemes 8 through 11.
- the taxane which is selectively acylated at the C(7) position is baccatin III or 10-triethylsilyl-lO-deacetylbaccatin III. It should be understood, however, that these reaction schemes are merely illustrative and that taxanes having other acyl and silyl moieties at C(10) as well as other substituents at other taxane ring positions may be selectively acylated at C(7) with these and other acylating agents in accordance with the present invention.
- the C(7) hydroxyl group of a C(10) acylated taxane derivative can be selectively protected using any of a variety of hydroxy protecting groups, such 0 as acetal, ketal, silyl, and removable acyl protecting groups.
- the C(7) hydroxyl group may be silylated using any of a variety of common silylating agents including, but not limited to, tri (hydrocarbyl) silyl halides and tri (hydrocarbyl) silyl triflates .
- the hydrocarbyl moieties of these compounds may be substituted or unsubstituted and preferably are substituted or unsubstituted alkyl or aryl.
- the C(7) hydroxyl group of baccatin III can be selectively silylated using silylating agents such as tribenzylsilyl chloride, trimethylsilyl chloride, triethylsilyl chloride, dimethyl isopropylsilyl chloride, dimethyl phenylsilyl chloride, and the like.
- silylating agents such as tribenzylsilyl chloride, trimethylsilyl chloride, triethylsilyl chloride, dimethyl isopropylsilyl chloride, dimethyl phenylsilyl chloride, and the like.
- silylations of the C(7) hydroxy group of a C(10) acylated taxanes are more efficient and more selective than are silylations of a 7, 10-dihydroxy taxane such as 10-DAB, i.e., once the C(10) hydroxyl group has been acylated, there is a significant difference in the reactivity of the remaining C(7), C(13), and C(l) hydroxyl groups (and the C(14) hydroxyl group, if present) .
- the C(7) silylation reaction may be carried out under a wide range of conditions, including in the presence or absence of an amine base . Examples of selective C(7) silylation of C(10) acylated taxanes are shown in Reaction Schemes 12 through 15.
- the taxane which is selectively silylated at the C(7) position is baccatin III or another C (10) -acyloxy derivative of 10- deacetylbaccatin III. It should be understood, however, that these reaction schemes are merely illustrative and that other taxanes may be selectively silylated with these and other silylating agents in accordance with the present invention.
- the C(7) hydroxyl group of C(10) acylated taxanes can be selectively protected using any of a variety of common reagents including, but not limited to, simple acetals, ketals and vinyl ethers, in the presence of an acid catalyst .
- These reagents (whether acetal, ketal, vinyl ether or otherwise) are referred to herein as "ketalizing agents" and are described in "Protective Groups in Organic Synthesis" by T. W. Greene, John Wiley and Sons, 1981.
- the acid catalyst used may be an organic or inorganic acid, such as toluenesulfonic acid or camphorsulfonic acid, in at least a catalytic amount.
- the C(7) hydroxyl group of baccatin III can be selectively ketalized using 2-methoxy propen .
- suitable reagents for the preparation of acetals and ketals include methyl vinyl ether, ethyl vinyl ether, tetrahydropyran, and the like.
- Selective ketalization of the C(7) substituent of a C(10) acylated taxane is more efficient and more selective than it is with 10-DAB, i.e., once the C(10) hydroxyl group has been acylated, there is a large difference in the reactivity of the remaining C(7), C(13), and C(l) hydroxyl groups (and the C(14) hydroxyl group, if present) .
- Reaction Scheme 16 An example of selective formation of a C(7) ketal from baccatin III is illustrated in Reaction Scheme 16. It should be understood, however, that this reaction scheme is merely illustrative and that other taxanes may be selectively ketalized with this and other ketalizing agents in accordance with the present invention.
- the C(7) hydroxyl group of a taxane further comprising a C(10) hydroxyl group can be selectively silylated.
- these silylations are not limited to silyl groups bearing alkyl substituents having three carbons or less.
- the C(7) hydroxyl group of a taxane can be selectively silylated with a silylating agent which includes the -SiRjR ⁇ R L moiety wherein R ⁇ , R ⁇ and R L are independently substituted or unsubstituted hydrocarbyl or heteroaryl, provided that any substituents are other than hydroxyl.
- a silylating agent which includes the -SiRjR ⁇ R L moiety wherein R ⁇ , R ⁇ and R L are independently substituted or unsubstituted hydrocarbyl or heteroaryl, provided that any substituents are other than hydroxyl.
- R ⁇ , R ⁇ and R L is alkyl
- at least one of R j , R k , and R L comprises a carbon skeleton (i.e., carbon chain or ring(s)) having at least four carbon atoms.
- Suitable silylating agents include silyl halides and silyl triflates, for example, tri (hydrocarbyl) silyl halides and tri (hydrocarbyl) silyl triflates.
- the hydrocarbyl substituents of these silylating agents may be substituted or unsubstituted and preferably are substituted or unsubstituted alkyl or aryl .
- the selective silylation of the C(7) hydroxy group may be carried out in a solvent, such as dimethyl formamide (“DMF") or pyridine and in the presence of an amine base, such as imidazole or pyridine.
- Reaction Schemes 17 - 20 illustrate the silylation of the C(7) hydroxy group of 10-DAB in high yield by treating 10-DAB with t-butyldimethylsilyl chloride, tribenzylsilyl chloride, dimethyl-isopropylsilyl chloride, and dimethylphenylsilyl chloride, respectively.
- Silylation 0 under these conditions was surprising in view of the report by Denis, et . al . (J " . Am. Chem. Soc , 1988, 110, 5917) that selective formation of 7-TBS-lO-DAB was not possible .
- the process of the present invention can also be used to protect the C(7) and C(10) hydroxy groups of a 7, 10-dihydroxytaxane with different silyl protecting groups. By selecting groups which can be removed under different conditions, the C(7) and C(10) hydroxy groups can be separately accessed for derivatization. These reactions, therefore, increase the flexibility of the overall process and, enable a higher yield for many of the individual protecting reactions relative to the yield obtained using currently available processes.
- the triethylsilyl protecting group is more readily removed from C(10) than is the t-butyldimethylsilyl protecting group from C(7) and the dimethylphenylsilyl protecting group is more readily removed from C(7) than is the t-butyldimethylsilyl protecting group from C(10) .
- the preparation of 7-t- butyldimethylsilyl-10-triethylsilyl-10-DAB and 7-dimethylphenylsilyl-10-t-butyldimethylislyl-10-DAB are illustrated in Reaction Schemes 21 and 22.
- the methods disclosed herein may be used in connection with a large number of different taxanes obtained from natural or synthetic sources to prepare a wide variety of taxane intermediates which may then be further derivatized.
- the methods of the present invention may be effectively used to protect the C(7) and/or C(10) hydroxy functional group prior to the coupling reaction between a C(13) side chain precursor and a taxane to introduce a C(13) / 8-amido ester side chain, and also prior to the reactions for preparing taxanes having alternative substituents at various locations on the taxane nucleus.
- the attachment of a C(13) side chain precursor to a taxane may be carried out by various known techniques .
- a side chain precursor such as an appropriately substituted ⁇ -lactam, oxazoline, oxazolidine carboxylic acid, oxazolidine carboxylic acid anhydride, or isoserine derivative may be reacted with a tricyclic or tetracyclic taxane having a C(13) hydroxy, metallic oxide or ammonium oxide substituent to form compounds having a j ⁇ -amido ester substituent at C(13) as described, for example, Taxol: Science and Applications, M. Suffness, editor, CRC Press (Boca Rotan, FL) 1995, Chapter V, pages 97-121.
- the synthesis of taxol from 10-DAB is illustrated in reaction scheme 23. It should be noted that while a 3-lactam and 10 -DAB are used in this reaction scheme, other side chain precursors and other taxanes could be substituted therefor without departing from the present invention.
- Taxol ( 89% over al I )
- the process illustrated in Reaction Scheme 23 is significantly more efficient than any other currently known process, due to the high yields and selectivity of the cerium trichloride catalyzed acetylation of the C(10) hydroxyl group of 10-DAB and the subsequent silylation of the C(7) hydroxyl group.
- the synthesis proceeds in four steps and 89% overall yield.
- Reaction schemes 24 and 25 illustrate the preparation of taxanes having substituents appended to the C(7) hydroxyl group and a free C(10) hydroxyl group.
- the method of the current invention provides flexibility so that the substituent attached to the C(7) hydroxyl group can be put in place either before or after attachment of the C(13) side chain.
- Reaction scheme 24 outlines the preparation of a taxane which has been found to be a potent chemotherapeutic radiosensitizer, illustrating attachment of the substituent at the C(7) hydroxyl group before introduction of the C(13) side chain. According to the process of reaction scheme 7, 10-DAB is first converted to 10-TES-10-DAB.
- the C(7) hydroxyl group is then converted to an intermediate imidazolide by treatment with carbonyl diimidazole, and the intermediate imidazolide subsequently reacts, without isolation, with metronidazole alcohol to provide 7-metro-10-TES-10-DAB.
- Coupling of 7-metro-lO-TES-lO-DAB with a ⁇ -lactam to introduce the side chain at C(13) is followed by removal of the TES groups at C(10) and C(2') by treatment with HF and pyridine .
- Reaction scheme 25 outlines the preparation of a taxane useful in identifying proteins which form bioconjugates with taxanes. It illustrates a protocol for attachment of a substituent at the C(7) hydroxyl group after introduction of the C(13) side chain.
- 10-DAB is first converted to 7-p-nitrobenzyloxycarbonyl- 10-TES-10-DAB.
- the C(13) side chain is attached employing a TES protected j ⁇ -lactam, and the p-nitrobenzyloxycarbonyl protecting group is then selectively removed by treatment with hydrogen and a palladium catalyst, producing 2 ' , 10- (bis) -TES-taxotere .
- the C(7) hydroxyl group then reacts with carbonyl diimidazole and the derived imidazolide is treated with 1,4-diamino butane to give a primary amine.
- Taxanes having C(2) and/or C(4) substituents other than benzoyloxy and acetoxy, respectively, can be prepared from baccatin III, 10-DAB and other taxanes as more fully described in PCT Patent Application WO 94/01223.
- the C(2) and C(4) acyloxy substituents are treated with lithium aluminum hydride or another suitable reducing agent to from hydroxy groups at C(2) and C(4) which may then be reacted, for example, with carboxylic acid halides (optionally after protection of the C(2) hydroxy group together with the C(l) hydroxy group with a 1, 2-carbonate protecting group) to obtain the desired C(2) and C(4) derivatives.
- Taxanes having C(7) substituents other than hydroxy and acyloxy as described herein can be prepared from baccatin III, 10-DAB, and other taxanes as more fully described in PCT Patent Application WO 94/17050.
- a C(7) xanthate may be subjected to tin hydride reduction to yield the corresponding C(7) dihydro taxane.
- C(7) fluoro-substituted taxanes can be prepared by treatment of C (13) -triethylsilyl-protected baccatin III with 2-chloro-l, 1, 2-trifluorotriethylamine at room temperature in THF solution.
- Other baccatin derivatives with a free C(7) hydroxyl group behave similarly.
- 7-chloro baccatin III can be prepared by treatment of baccatin III with methanesulfonyl chloride and triethylamine in methylene chloride solution containing an excess of triethylamine hydrochloride .
- Taxanes having C(9) substituents other than keto can be prepared from baccatin III, 10-DAB and other taxanes as more fully described in PCT Patent Application WO 94/20088.
- the C(9) keto substituent of the taxane is selectively reduced to yield the corresponding C(9) jS-hydroxy derivative with a borohydride, preferably tetrabutylammonium borohydride (Bu 4 NBH 4 ) or triacetoxy- borohydride.
- the C(9) j ⁇ -hydroxy derivative can then be protected at C(7) with a hydroxy protecting group and the C(9) hydroxy group can be acylated following the methods described herein for acylation of the C(7) hydroxy group.
- reaction of 7-protected-9/3-hydroxy derivative with KH causes the acetate group (or other acyloxy group) to migrate from C(10) to C(9) and the hydroxy group to migrate from C(9) to C(10), thereby yielding a 10-desacetyl derivative, which can be acylated as described elsewhere herein.
- Taxanes having C(10) substituents other than hydroxy, acyloxy or protected hydroxy as described herein may be prepared as more fully described in PCT Patent Application WO 94/15599 and other literature references.
- taxanes having a C(10) keto substituent can be prepared by oxidation of 10-desacetyl taxanes.
- Taxanes which are dihydro substituted at C(10) can be prepared by reacting a C(10) hydroxy or acyloxy substituted taxane with samarium diiodide.
- Taxanes having a C(14) substituent other than hydrogen may also be prepared.
- the starting material for these compounds may be, for example, a hydroxylated taxane (14 -hydroxy-10-deacetylbaccatin III) which has been discovered in an extract of yew needles (C&EN, p 36- 37, April 12, 1993) .
- Derivatives of this hydroxylated taxane having the various C(2), C(4), C(7), C(9), C(10), C3' and C5' functional groups described above may also be prepared by using this hydroxylated taxane.
- C(14) hydroxy group together with the C(l) hydroxy group of 10-DAB can be converted to a 1, 2-carbonate as described in C&EN or it may be converted to a variety of esters or other functional groups as otherwise described herein in connection with the C(2), C(4), C(9) and C(10) substituents.
- M comprises ammonium or is a metal
- R 1 is hydrogen, hydroxy, protected hydroxy, or together with R 14 or R 2 forms a carbonate;
- R 2 is keto, -OT 2 , acyloxy, or together with R ⁇ forms a carbonate;
- R 4 is -OT 4 or acyloxy;
- R 7 is hydrogen, halogen, -OT 7 , or acyloxy
- R 9 is hydrogen, keto, -OT 9 , or acyloxy
- R 10 is hydrogen, keto, -OT 10 , or acyloxy
- R 7 , R 9 , and R 10 independently have the alpha or beta stereochemical configuration
- R 13 is hydroxy, protected hydroxy, keto, MO- or
- R 14 is hydrogen, -OT 14 , acyloxy, or together with R x forms a carbonate; T 2 , T 4 , T 7 , T 9 , T 10 and T 14 are independently hydrogen or hydroxy protecting group;
- X x is -OX 6 , -SX 7 , or -NX 8 X 9 ;
- X 2 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heteroaryl
- X 3 and X 4 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heteroaryl;
- X 5 is -X 10 , -OX 10 , -SX 10 , -NX 8 X 10 , or -S0 2 X li;
- X 6 is hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroaryl, hydroxy protecting group, or a functional group which increases the water solubility of the taxane derivative;
- X 7 is hydrocarbyl, substituted hydrocarbyl, heteroaryl, or sulfhydryl protecting group
- X 8 is hydrogen, hydrocarbyl, or substituted hydrocarbyl ;
- X 9 is an amino protecting group
- X 10 is hydrocarbyl, substituted hydrocarbyl, or heteroaryl
- X X1 is hydrocarbyl, substituted hydrocarbyl, heteroaryl, -OX 10 , or -NX 8 X 14 ;
- X 14 is hydrogen, hydrocarbyl, substituted hydrocarbyl , or heteroaryl .
- the substituents of the taxane correspond to the substituents present on baccatin III or 10-DAB. That is, R 14 is hydrogen, R 9 is keto, R 4 is acetoxy, R 2 is benzoyloxy, and R- L is hydroxy.
- the taxane has a structure which differs from that of taxol or Taxotere ® with respect to the C(13) side chain and at least one other substituent.
- R 14 may be hydroxy;
- R 2 may be hydroxy, -OCOZ 2 or -OCOOZ 22 wherein Z 2 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heteroaryl and Z 22 is hydrocarbyl, substituted hydrocarbyl, or heteroaryl;
- R 4 may be hydroxy, -0C0Z 4 or -OCOOZ 44 wherein Z 4 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heteroaryl and Z 44 is hydrocarbyl, substituted hydrocarbyl, or heteroaryl;
- R 7 may be hydrogen, hydroxy, -OCOZ 7 or -OCOOZ 77 wherein Z 7 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heteroaryl and Z 77 is hydrogen, hydrocarbyl, substituted hydrocarbyl, or heteroaryl,
- R 9 may be hydrogen, hydroxy, -OCOZ 9 or -OCOOZ 99 wherein Z 9 is hydrogen, hydrocarbyl, substituted hydrocarbyl
- P x0 is acyl, said acyl comprising at least three carbon atoms or two carbon atoms and a nitrogen, oxygen or sulfur atom.
- R A is substituted or unsubstituted alkyl or aryl, said unsubstituted alkyl comprising at least two carbon atoms; and R B and R c are independently substituted or unsubstituted alkyl or aryl.
- the taxane has the formula
- P 7 and P 10 are independently substituted or unsubstituted acyl.
- P 7 and P 10 are preferably different.
- the terms “selective” and “selective derivatization” shall mean that the desired product is preferentially formed over any other by-product.
- the desired product is present in a molar ratio of at least 9:1 relative to any other by-product and, more preferably, is present in a molar ratio of at least 20:1 relative to any other by-product.
- Ph means phenyl
- Bz means benzoyl
- Bn means benzyl
- Me means methyl
- Et means ethyl
- iPr means isopropyl
- Ac means acetyl
- TES means triethylsilyl
- TMS means trimethylsilyl
- TSS means Me 2 t-BuSi-
- CDI means carbonyl diimidazole
- BOM means benzyloxymethyl
- DBU means diazabicycloundecane
- DMAP means p-dimethylamino pyridine
- LHMDS means p-dimethylamino pyridine
- LHMDS
- Other hydroxyl protecting groups may be found in "Protective Groups in Organic Synthesis" by T. W. Greene, John Wiley and Sons, 1981, and Second Edition, 1991.
- hydrocarbon and “hydrocarbyl” moieties described herein are organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbyl groups, and include alkaryl, alkenaryl and alkynaryl . Preferably, these moieties comprise 1 to 20 carbon atoms.
- alkyl groups described herein are preferably lower alkyl containing from one to six carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight, branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like. They may be substituted with aliphatic or cyclic hydrocarbyl radicals.
- alkenyl groups described herein are preferably lower alkenyl containing from two to six carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like. They may be substituted with aliphatic or cyclic hydrocarbyl radicals.
- the alkynyl groups described herein are preferably lower alkynyl containing from two to six carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like. They may be substituted with aliphatic or cyclic hydrocarbyl radicals .
- the aryl moieties described herein contain from 6 to 20 carbon atoms and include phenyl. They may be hydrocarbyl substituted with the various substituents defined herein. Phenyl is the more preferred aryl.
- heteroaryl moieties described are heterocyclic compounds or radicals which are analogous to aromatic compounds or radicals and which contain a total of 5 to 20 atoms, usually 5 or 6 ring atoms, and at least one atom other than carbon, such as furyl, thienyl, pyridyl and the like.
- the heteroaryl moieties may be substituted with hydrocarbyl, heterosubstituted hydrocarbyl or hetero-atom containing substituents with the hetero-atoms being selected from the group consisting of nitrogen, oxygen, silicon, phosphorous, boron, sulfur, and halogens.
- substituents include hydroxy; lower alkoxy such as methoxy, ethoxy, butoxy; halogen such as chloro or fluoro; ethers; acetals; ketals; esters; heteroaryl such as furyl or thienyl; alkanoxy; acyl; acyloxy; nitro; amino; and amido.
- the substituted hydrocarbyl moieties described herein are hydrocarbyl moieties which are substituted with at least one atom other than carbon and hydrogen, including moieties in which a carbon chain atom is substituted with a hetero atom such as nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogen atom.
- substituents include hydroxy; lower alkoxy such as methoxy, ethoxy, butoxy; halogen such as chloro or fluoro; ethers; acetals; ketals; esters; heteroaryl such as furyl or thienyl; alkanoxy; acyl; acyloxy; nitro; amino; and amido.
- acyl moieties and the acyloxy moieties described herein contain hydrocarbyl, substituted hydrocarbyl or heteroaryl moieties. In general, they have the formulas -C(0)G and -OC(0)G, respectively, wherein G is substituted or unsubstituted hydrocarbyl, hydrocarbyloxy, hydrocarbylamino, hydrocarbylthio or heteroaryl.
- the ketal moieties described herein have the general formula
- X 31 , X 32 , X 33 and X 34 are independently hydrocarbyl, substituted hydrocarbyl or heteroaryl moieties. They may be optionally substituted with the various substituents defined herein.
- the ketal moieties are preferably substituted or unsubstituted alkyl or alkenyl, and more preferably substituted or unsubstituted lower (C ⁇ Cg) alkyl. These ketal moieties additionally may encompass sugars or substituted sugars and include ketal moieties prepared from sugars or substituted sugars such as glucose and xylose .
- a ketal moiety is incorporated into a taxane of the present invention as a C(7) hydroxy protecting group, then either X 31 or X 32 represents the taxane moiety.
- X 31 , X 32 and X 33 are independently hydrocarbyl, substituted hydrocarbyl or heteroaryl moieties. They may be optionally substituted with the various substituents defined herein other than hydroxyl.
- the acetal moieties are preferably substituted or unsubstituted alkyl or alkenyl, and more preferably substituted or unsubstituted lower (Ci-Cg) alkyl. These acetal moieties additionally may encompass sugars or substituted sugars and include acetal moieties prepared from sugars or substituted sugars such as glucose and xylose .
- taxane denotes compounds containing the A, B and C rings (with numbering of the ring positions shown herein) :
- Example 1 A. Selective acylation of a C(10) hydroxyl group:
- 10-Cbz-l O-DAB To a solution of 10-DAB (30 mg, 0.055 mmol) in THF (1 mL) at room temperature was added dibenzyl pyrocarbonate (320 mg, 1.1 mmol, 20 equiv) under N 2 . The reaction mixture was stirred at room temperature for 24 h. EtOAc (10 mL) was added, and the solution was quickly filtered through a short column of silica gel. The silica gel was washed with EtOAc (100 mL) , and the solution was concentrated under reduced pressure.
- 10-Propionyl -lO -DAB To a solution of 10-DAB (47 mg, 0.086 mmol) in THF (2 mL) at room temperature was added a mixture of propionic anhydride anhydride (4 mL) and ZnCl 2 / THF solution (0.5 M, 350 mL, 0.173 mmol, 2 equiv) under N 2 . The reaction mixture was stirred at room temperature for 14 h. Then the reaction mixture was diluted with EtOAc (150 mL) , exhaustively washed with saturated aqueous NaHC0 3 solution (50 mLx3), brine. The organic layer was dried over Na 2 S0 4 , concentrated under reduced pressure.
- 10-TMS-10-DAB To a solution of 10-DAB (100 mg, 0.18 mmol) in THF (10 mL) at 0 °C was slowly added N, O-bis (trimethylsilyl) trifluoroacetamide (1.0 mL, 3.7 mmol, 20 equiv) under N 2 . The reaction mixture was stirred at 0 °C for 5 h. EtOAc (20 mL) was added, and the solution was filtered through a short column of silica gel. The silica gel was washed with EtOAc (100 mL) , and the solution was concentrated under reduced pressure.
- Triethylamine (0.5 mL) was added, and the solution was warmed to room temperature, diluted with EtOAc (100 mL) , washed with saturated aqueous NaHC0 3 solution, dried over Na 2 S0 4 , and concentrated under reduced pressure. The residue was dried in vacuo overnight to give 112 mg (99%) of crude product.
Abstract
Description
Claims
Priority Applications (20)
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DK01203287T DK1170292T3 (en) | 1997-08-18 | 1998-08-17 | Process for selective derivatization of taxanes |
DE69836072T DE69836072T2 (en) | 1997-08-18 | 1998-08-17 | METHOD FOR THE SELECTIVE DERIVATIZATION OF TAXANESE |
JP51349899A JP2001504864A (en) | 1997-08-18 | 1998-08-17 | Selective derivatization of taxanes |
EP98942080A EP0956284B1 (en) | 1997-08-18 | 1998-08-17 | Process for selective derivatization of taxanes |
PL98377990A PL193674B1 (en) | 1997-08-18 | 1998-08-17 | Method of selectively deriving taxanes |
CA002268662A CA2268662A1 (en) | 1997-08-18 | 1998-08-17 | Process for selective derivatization of taxanes |
BR9806145-3A BR9806145A (en) | 1997-08-18 | 1998-08-17 | Process for selective derivatization of taxanes |
AU90211/98A AU744987B2 (en) | 1997-08-18 | 1998-08-17 | Process for selective derivatization of taxanes |
DK98942080T DK0956284T3 (en) | 1997-08-18 | 1998-08-17 | Process for selective derivatization of taxanes |
IL12938698A IL129386A0 (en) | 1997-08-18 | 1998-08-17 | Process for selective derivatization of taxanes |
DK01203288T DK1170293T3 (en) | 1997-08-18 | 1998-08-17 | Process for selective derivatization of taxanes |
HU0300425A HUP0300425A3 (en) | 1997-08-18 | 1998-08-17 | Process for selective derivatization of taxanes |
KR1019997003388A KR100596989B1 (en) | 1997-08-18 | 1998-08-17 | Process for selective derivatization of taxanes |
NO19991838A NO325139B1 (en) | 1997-08-18 | 1999-04-16 | Process for acylating a C (10) hydroxy group in a taxane having C (7) and C (10) hydroxy groups |
IL166175A IL166175A (en) | 1997-08-18 | 2005-01-06 | Process for selective derivatization of taxanes |
NO20054512A NO20054512L (en) | 1997-08-18 | 2005-09-29 | taxanes |
NO20054514A NO20054514L (en) | 1997-08-18 | 2005-09-29 | taxanes |
NO20054513A NO20054513L (en) | 1997-08-18 | 2005-09-29 | taxanes |
IL184321A IL184321A0 (en) | 1997-08-18 | 2007-07-01 | Process for selective derivatization of taxanes |
IL184320A IL184320A0 (en) | 1997-08-18 | 2007-07-01 | Process for selective derivatization of taxanes |
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US09/063,477 US7288665B1 (en) | 1997-08-18 | 1998-04-20 | Process for selective derivatization of taxanes |
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EP (6) | EP1671960A2 (en) |
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CN (3) | CN1974563A (en) |
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NO (4) | NO325139B1 (en) |
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---|---|---|---|---|
EP0918764A1 (en) * | 1996-07-11 | 1999-06-02 | Napro Biotherapeutics, Inc. | Method for acylating 10-deacetylbaccatin iii selectively at the c-10 position |
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US6359154B2 (en) | 2000-02-02 | 2002-03-19 | Fsu Research Foundation, Inc. | C7 carbamoyloxy substituted taxanes |
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US6596737B2 (en) | 2000-02-02 | 2003-07-22 | Fsu Research Foundation, Inc. | C10 carbamoyloxy substituted taxanes |
US6610860B2 (en) | 2000-02-02 | 2003-08-26 | Fsu Research Foundation, Inc. | C7 ester substituted taxanes |
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US6673833B2 (en) | 2000-02-02 | 2004-01-06 | Fsu Research Foundation, Inc. | C7 heterosubstituted acetate taxanes |
US6780879B2 (en) | 2000-02-02 | 2004-08-24 | Fsu Research Foundation, Inc. | C7 carbonate substituted taxanes |
US7160919B2 (en) | 2004-03-05 | 2007-01-09 | Florida State University Research Foundation, Inc. | C7 lactyloxy-substituted taxanes |
US7186851B2 (en) * | 2004-05-14 | 2007-03-06 | Immunogen, Inc. | Facile method for synthesizing baccatin III compounds |
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US8242166B2 (en) | 2008-03-31 | 2012-08-14 | Florida State University Research Foundation, Inc. | C(10) ethyl ester and C(10) cyclopropyl ester substituted taxanes |
US8314261B2 (en) | 2004-01-16 | 2012-11-20 | Guilin Huiang Biochemistry Pharmaceutical Co. Ltd. | Process for the preparation of synthetic taxanes |
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WO2017115301A1 (en) | 2015-12-30 | 2017-07-06 | Syncore Biotechnology Co., Ltd. | Treatment of breast cancer using a combination of a cationic liposomal formulation of taxane, a non-liposomal formulation of taxane and a further active agent |
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5405972A (en) * | 1993-07-20 | 1995-04-11 | Florida State University | Synthetic process for the preparation of taxol and other tricyclic and tetracyclic taxanes |
US5616739A (en) * | 1992-10-05 | 1997-04-01 | Rhone-Poulenc Rorer, S.A. | Method of preparing taxane derivatives |
Family Cites Families (61)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US569666A (en) * | 1896-10-20 | Brake-beam | ||
FR2601676B1 (en) | 1986-07-17 | 1988-09-23 | Rhone Poulenc Sante | PROCESS FOR THE PREPARATION OF TAXOL AND DESACETYL-10 TAXOL |
USRE34277E (en) | 1988-04-06 | 1993-06-08 | Centre National De La Recherche Scientifique | Process for preparing taxol |
FR2629818B1 (en) * | 1988-04-06 | 1990-11-16 | Centre Nat Rech Scient | PROCESS FOR THE PREPARATION OF TAXOL |
JPH01309997A (en) * | 1988-06-09 | 1989-12-14 | Kanto Kasei Kogyo Kk | Method for obtaining copper-nickel-chromium bright electroplating having excellent corrosion resistance and plating film obtained thereby |
US4960790A (en) | 1989-03-09 | 1990-10-02 | University Of Kansas | Derivatives of taxol, pharmaceutical compositions thereof and methods for the preparation thereof |
US5175315A (en) * | 1989-05-31 | 1992-12-29 | Florida State University | Method for preparation of taxol using β-lactam |
US5136060A (en) | 1989-11-14 | 1992-08-04 | Florida State University | Method for preparation of taxol using an oxazinone |
FR2678930B1 (en) * | 1991-07-10 | 1995-01-13 | Rhone Poulenc Rorer Sa | PROCESS FOR THE PREPARATION OF DERIVATIVES OF BACCATIN III AND DESACETYL-10 BACCATIN III. |
US5990325A (en) | 1993-03-05 | 1999-11-23 | Florida State University | Process for the preparation of 9-desoxotaxol, 9-desoxobaccatin III and analogs thereof |
US5714513A (en) | 1991-09-23 | 1998-02-03 | Florida State University | C10 taxane derivatives and pharmaceutical compositions |
SG46582A1 (en) | 1991-09-23 | 1998-02-20 | Univ Florida State | 10-Desacetoxytaxol derivatives |
US5284864A (en) | 1991-09-23 | 1994-02-08 | Florida State University | Butenyl substituted taxanes and pharmaceutical compositions containing them |
US5399726A (en) | 1993-01-29 | 1995-03-21 | Florida State University | Process for the preparation of baccatin III analogs bearing new C2 and C4 functional groups |
US5654447A (en) | 1991-09-23 | 1997-08-05 | Florida State University | Process for the preparation of 10-desacetoxybaccatin III |
US5430160A (en) | 1991-09-23 | 1995-07-04 | Florida State University | Preparation of substituted isoserine esters using β-lactams and metal or ammonium alkoxides |
US5229526A (en) * | 1991-09-23 | 1993-07-20 | Florida State University | Metal alkoxides |
US5489601A (en) | 1991-09-23 | 1996-02-06 | Florida State University | Taxanes having a pyridyl substituted side-chain and pharmaceutical compositions containing them |
FR2687145B1 (en) | 1992-02-07 | 1994-03-25 | Rhone Poulenc Rorer Sa | NEW ANHYDRIDES OF ACIDS, THEIR PREPARATION AND THEIR PACKAGE AND |
US5200534A (en) | 1992-03-13 | 1993-04-06 | University Of Florida | Process for the preparation of taxol and 10-deacetyltaxol |
US5416225A (en) | 1992-03-30 | 1995-05-16 | Sloan-Kettering Institute For Cancer Research | Total synthesis of taxol |
US5254703A (en) | 1992-04-06 | 1993-10-19 | Florida State University | Semi-synthesis of taxane derivatives using metal alkoxides and oxazinones |
US5440056A (en) | 1992-04-17 | 1995-08-08 | Abbott Laboratories | 9-deoxotaxane compounds |
CA2130578A1 (en) | 1992-04-17 | 1993-10-28 | Geewananda P. Gunawardana | Taxol derivatives |
US5269442A (en) * | 1992-05-22 | 1993-12-14 | The Cornelius Company | Nozzle for a beverage dispensing valve |
US5470866A (en) | 1992-08-18 | 1995-11-28 | Virginia Polytechnic Institute And State University | Method for the conversion of cephalomannine to taxol and for the preparation of n-acyl analogs of taxol |
WO1994005282A1 (en) | 1992-09-04 | 1994-03-17 | The Scripps Research Institute | Water soluble taxol derivatives |
US5478854A (en) | 1992-10-01 | 1995-12-26 | Bristol-Myers Squibb Company | Deoxy taxols |
FR2696460B1 (en) | 1992-10-05 | 1994-11-25 | Rhone Poulenc Rorer Sa | Process for the preparation of taxane derivatives. |
US5412116A (en) | 1992-11-06 | 1995-05-02 | Hauser Chemical Research, Inc. | Oxidation of glycoside substituted taxanes to taxol or taxol precursors and new taxane compounds formed as intermediates |
FR2698363B1 (en) | 1992-11-23 | 1994-12-30 | Rhone Poulenc Rorer Sa | New taxane derivatives, their preparation and the compositions containing them. |
US5380751A (en) | 1992-12-04 | 1995-01-10 | Bristol-Myers Squibb Company | 6,7-modified paclitaxels |
FR2698871B1 (en) * | 1992-12-09 | 1995-02-24 | Rhone Poulenc Rorer Sa | New taxoids, their preparation and the pharmaceutical compositions containing them. |
US5646176A (en) | 1992-12-24 | 1997-07-08 | Bristol-Myers Squibb Company | Phosphonooxymethyl ethers of taxane derivatives |
US5948919A (en) * | 1993-02-05 | 1999-09-07 | Napro Biotherapeutics, Inc. | Paclitaxel synthesis from precursor compounds and methods of producing the same |
FR2702212B1 (en) | 1993-03-02 | 1995-04-07 | Rhone Poulenc Rorer Sa | New taxoids, their preparation and the pharmaceutical compositions containing them. |
US5547981A (en) | 1993-03-09 | 1996-08-20 | Enzon, Inc. | Taxol-7-carbazates |
US5703247A (en) | 1993-03-11 | 1997-12-30 | Virginia Tech Intellectual Properties, Inc. | 2-Debenzoyl-2-acyl taxol derivatives and methods for making same |
US5475011A (en) | 1993-03-26 | 1995-12-12 | The Research Foundation Of State University Of New York | Anti-tumor compounds, pharmaceutical compositions, methods for preparation thereof and for treatment |
US5336684A (en) | 1993-04-26 | 1994-08-09 | Hauser Chemical Research, Inc. | Oxidation products of cephalomannine |
IL109926A (en) * | 1993-06-15 | 2000-02-29 | Bristol Myers Squibb Co | Methods for the preparation of taxanes and microorganisms and enzymes utilized therein |
FR2718137B1 (en) * | 1994-04-05 | 1996-04-26 | Rhone Poulenc Rorer Sa | Process for the preparation of trialcoylsilyl-7 baccatine III. |
JPH10508022A (en) * | 1994-10-28 | 1998-08-04 | ザ リサーチ ファウンデーション オブ ステート ユニバーシティ オブ ニューヨーク | Taxoid derivatives, their production and their use as antitumor agents |
US6100411A (en) * | 1994-10-28 | 2000-08-08 | The Research Foundation Of State University Of New York | Taxoid anti-tumor agents and pharmaceutical compositions thereof |
US5489589A (en) | 1994-12-07 | 1996-02-06 | Bristol-Myers Squibb Company | Amino acid derivatives of paclitaxel |
JPH08253465A (en) * | 1995-03-17 | 1996-10-01 | Dai Ichi Seiyaku Co Ltd | Tetracyclic compound |
US5847170A (en) * | 1995-03-27 | 1998-12-08 | Rhone-Poulenc Rorer, S.A. | Taxoids, their preparation and pharmaceutical compositions containing them |
MA23823A1 (en) * | 1995-03-27 | 1996-10-01 | Aventis Pharma Sa | NEW TAXOIDS, THEIR PREPARATION AND THE COMPOSITIONS CONTAINING THEM |
US5780653A (en) | 1995-06-07 | 1998-07-14 | Vivorx Pharmaceuticals, Inc. | Nitrophenyl, 10-deacetylated substituted taxol derivatives as dual functional cytotoxic/radiosensitizers |
US5760251A (en) | 1995-08-11 | 1998-06-02 | Sepracor, Inc. | Taxol process and compounds |
FR2743074B1 (en) * | 1995-12-27 | 1998-03-27 | Seripharm | METHOD FOR THE SELECTIVE PROTECTION OF BACCATIN DERIVATIVES AND ITS USE IN THE SYNTHESIS OF TAXANES |
US5688977A (en) | 1996-02-29 | 1997-11-18 | Napro Biotherapeutics, Inc. | Method for docetaxel synthesis |
JP4172726B2 (en) * | 1996-05-22 | 2008-10-29 | ルイトポルド・ファーマシューティカルズ・インコーポレーテッド | Formulation containing a covalent complex of cis-docosahexaenoic acid and docetaxel |
US5773461A (en) | 1996-06-06 | 1998-06-30 | Bristol-Myers Squibb Company | 7-deoxy-6-substituted paclitaxels |
FR2750989B1 (en) | 1996-07-09 | 1998-09-25 | Rhone Poulenc Rorer Sa | PROCESS FOR MONOACYLATION OF HYDROXY TAXANES |
US5750736A (en) | 1996-07-11 | 1998-05-12 | Napro Biotherapeutics, Inc. | Method for acylating 10-deacetylbaccatin III selectively at the c-10 position |
US5811452A (en) | 1997-01-08 | 1998-09-22 | The Research Foundation Of State University Of New York | Taxoid reversal agents for drug-resistance in cancer chemotherapy and pharmaceutical compositions thereof |
US6017935A (en) * | 1997-04-24 | 2000-01-25 | Bristol-Myers Squibb Company | 7-sulfur substituted paclitaxels |
SI0875508T1 (en) | 1997-05-02 | 2004-04-30 | Pharmachemie B.V. | Method for the preparation of baccatin III and derivatives thereof from 10-deacetylbaccatin III |
US7288665B1 (en) | 1997-08-18 | 2007-10-30 | Florida State University | Process for selective derivatization of taxanes |
US5914411A (en) | 1998-01-21 | 1999-06-22 | Napro Biotherapeutics, Inc. | Alternate method for acylating 10-deacetylbaccatin III selectively at the C-10 position |
-
1998
- 1998-04-20 US US09/063,477 patent/US7288665B1/en not_active Expired - Fee Related
- 1998-08-17 DK DK01203288T patent/DK1170293T3/en active
- 1998-08-17 ES ES98942080T patent/ES2274579T3/en not_active Expired - Lifetime
- 1998-08-17 PL PL98377990A patent/PL193674B1/en not_active IP Right Cessation
- 1998-08-17 DE DE69834584T patent/DE69834584T2/en not_active Expired - Fee Related
- 1998-08-17 JP JP51349899A patent/JP2001504864A/en not_active Ceased
- 1998-08-17 CN CNA2006101492418A patent/CN1974563A/en active Pending
- 1998-08-17 AT AT01203288T patent/ATE326455T1/en not_active IP Right Cessation
- 1998-08-17 DK DK98942080T patent/DK0956284T3/en active
- 1998-08-17 AT AT01203287T patent/ATE360624T1/en not_active IP Right Cessation
- 1998-08-17 CA CA002268662A patent/CA2268662A1/en not_active Abandoned
- 1998-08-17 CN CNB2005100641228A patent/CN100351246C/en not_active Expired - Fee Related
- 1998-08-17 KR KR1019997003388A patent/KR100596989B1/en not_active IP Right Cessation
- 1998-08-17 BR BR9806145-3A patent/BR9806145A/en not_active Application Discontinuation
- 1998-08-17 EP EP05108674A patent/EP1671960A2/en not_active Withdrawn
- 1998-08-17 PT PT01203287T patent/PT1170292E/en unknown
- 1998-08-17 EP EP01203286A patent/EP1193262A1/en not_active Withdrawn
- 1998-08-17 CA CA002597799A patent/CA2597799A1/en not_active Abandoned
- 1998-08-17 ID IDW990217A patent/ID21654A/en unknown
- 1998-08-17 CZ CZ0133299A patent/CZ296580B6/en not_active IP Right Cessation
- 1998-08-17 IL IL12938698A patent/IL129386A0/en not_active IP Right Cessation
- 1998-08-17 DK DK01203287T patent/DK1170292T3/en active
- 1998-08-17 EP EP07104179A patent/EP1795528A1/en not_active Withdrawn
- 1998-08-17 AT AT98942080T patent/ATE341540T1/en not_active IP Right Cessation
- 1998-08-17 HU HU0300425A patent/HUP0300425A3/en unknown
- 1998-08-17 PL PL98332723A patent/PL332723A1/en not_active IP Right Cessation
- 1998-08-17 PT PT98942080T patent/PT956284E/en unknown
- 1998-08-17 PL PL377991A patent/PL201641B1/en not_active IP Right Cessation
- 1998-08-17 ES ES01203288T patent/ES2259646T3/en not_active Expired - Lifetime
- 1998-08-17 AU AU90211/98A patent/AU744987B2/en not_active Ceased
- 1998-08-17 PT PT01203288T patent/PT1170293E/en unknown
- 1998-08-17 DE DE69837684T patent/DE69837684T2/en not_active Expired - Lifetime
- 1998-08-17 EP EP01203287A patent/EP1170292B1/en not_active Expired - Lifetime
- 1998-08-17 ES ES01203287T patent/ES2286073T3/en not_active Expired - Lifetime
- 1998-08-17 EP EP01203288A patent/EP1170293B1/en not_active Expired - Lifetime
- 1998-08-17 NZ NZ335156A patent/NZ335156A/en not_active IP Right Cessation
- 1998-08-17 DE DE69836072T patent/DE69836072T2/en not_active Expired - Lifetime
- 1998-08-17 SG SG200006873A patent/SG97986A1/en unknown
- 1998-08-17 ZA ZA987394A patent/ZA987394B/en unknown
- 1998-08-17 CN CNB98801341XA patent/CN1205196C/en not_active Expired - Fee Related
- 1998-08-17 WO PCT/US1998/017016 patent/WO1999009021A1/en active Application Filing
- 1998-08-17 EP EP98942080A patent/EP0956284B1/en not_active Expired - Lifetime
- 1998-08-17 RU RU99110384/04A patent/RU2225402C2/en not_active IP Right Cessation
-
1999
- 1999-04-16 NO NO19991838A patent/NO325139B1/en not_active IP Right Cessation
- 1999-06-17 US US09/335,408 patent/US6191287B1/en not_active Expired - Lifetime
-
2000
- 2000-06-07 US US09/588,933 patent/US6291691B1/en not_active Expired - Fee Related
- 2000-09-28 US US09/672,270 patent/US6706896B1/en not_active Expired - Fee Related
-
2005
- 2005-06-09 US US11/148,833 patent/US20050272944A1/en not_active Abandoned
- 2005-09-29 NO NO20054513A patent/NO20054513L/en unknown
- 2005-09-29 NO NO20054514A patent/NO20054514L/en unknown
- 2005-09-29 NO NO20054512A patent/NO20054512L/en unknown
-
2006
- 2006-06-26 CY CY20061100861T patent/CY1105399T1/en unknown
-
2007
- 2007-07-01 IL IL184321A patent/IL184321A0/en unknown
- 2007-07-01 IL IL184320A patent/IL184320A0/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5616739A (en) * | 1992-10-05 | 1997-04-01 | Rhone-Poulenc Rorer, S.A. | Method of preparing taxane derivatives |
US5405972A (en) * | 1993-07-20 | 1995-04-11 | Florida State University | Synthetic process for the preparation of taxol and other tricyclic and tetracyclic taxanes |
Non-Patent Citations (1)
Title |
---|
DENIS J.-N., GREENE A. E.: "A HIGHLY EFFICIENT, PRACTICAL APPROACH TO NATURAL TAXOL.", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, US, vol. 110., 1 January 1998 (1998-01-01), US, pages 5917 - 5919., XP002915026, ISSN: 0002-7863, DOI: 10.1021/ja00225a063 * |
Cited By (86)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0918764A4 (en) * | 1996-07-11 | 1999-09-01 | Napro Biotherapeutics Inc | Method for acylating 10-deacetylbaccatin iii selectively at the c-10 position |
EP0918764A1 (en) * | 1996-07-11 | 1999-06-02 | Napro Biotherapeutics, Inc. | Method for acylating 10-deacetylbaccatin iii selectively at the c-10 position |
US6191287B1 (en) | 1997-08-18 | 2001-02-20 | Florida State University | Process for selective derivatization of taxanes |
JP2002538155A (en) * | 1999-03-02 | 2002-11-12 | インデナ エッセ ピ ア | Method for preparing taxanes from 10-deacetylbacatin III |
US7186849B2 (en) | 2000-02-02 | 2007-03-06 | Fsu Research Foundation, Inc. | C7 ester substituted taxanes |
US6906088B2 (en) | 2000-02-02 | 2005-06-14 | Fsu Research Foundation, Inc. | Taxanes having a C10 carbamoyloxy substituent |
US6610860B2 (en) | 2000-02-02 | 2003-08-26 | Fsu Research Foundation, Inc. | C7 ester substituted taxanes |
US6649632B2 (en) | 2000-02-02 | 2003-11-18 | Fsu Research Foundation, Inc. | C10 ester substituted taxanes |
US6660866B2 (en) | 2000-02-02 | 2003-12-09 | Psu Research Foundation, Inc. | C10 carbonate substituted taxanes |
US6664275B2 (en) | 2000-02-02 | 2003-12-16 | Fsu Research Foundation, Inc. | C10 heterosubstituted acetate taxanes |
US6359154B2 (en) | 2000-02-02 | 2002-03-19 | Fsu Research Foundation, Inc. | C7 carbamoyloxy substituted taxanes |
US6750245B2 (en) | 2000-02-02 | 2004-06-15 | Fsu Research Foundation, Inc. | C7 carbamate substituted taxanes |
US6780879B2 (en) | 2000-02-02 | 2004-08-24 | Fsu Research Foundation, Inc. | C7 carbonate substituted taxanes |
US6861446B2 (en) | 2000-02-02 | 2005-03-01 | Fsu Research Foundation, Inc. | C7 heterosubstituted acetate taxane compositions |
US6872837B2 (en) | 2000-02-02 | 2005-03-29 | Fsu Research Foundation, Inc. | Taxanes having a c10 Heterosubstituted acetate substituent |
US7524869B2 (en) | 2000-02-02 | 2009-04-28 | Florida State University Research Foundation, Inc. | Taxanes having a C10 ester substituent |
US6992104B2 (en) | 2000-02-02 | 2006-01-31 | Fsu Research Foundation, Inc. | C7 carbonate taxane compositions |
US7056946B2 (en) | 2000-02-02 | 2006-06-06 | Fsu Research Foundation, Inc. | C10 carbonate taxane compositions |
US7157474B2 (en) | 2000-02-02 | 2007-01-02 | Fsu Research Foundation, Inc. | C10 heterosubstituted acetate taxane compositions |
US7226944B2 (en) | 2000-02-02 | 2007-06-05 | Fsu Research Foundation, Inc. | Taxanes having a C7 carbonate substituent |
US7183312B2 (en) | 2000-02-02 | 2007-02-27 | Fsu Research Foundation, Inc. | Taxanes having a C7 heterosubstituted acetate substituent |
US7230013B2 (en) | 2000-02-02 | 2007-06-12 | Florida State University Research Foundation, Inc. | C10 carbamoyloxy substituted taxane compositions |
US6673833B2 (en) | 2000-02-02 | 2004-01-06 | Fsu Research Foundation, Inc. | C7 heterosubstituted acetate taxanes |
US6596737B2 (en) | 2000-02-02 | 2003-07-22 | Fsu Research Foundation, Inc. | C10 carbamoyloxy substituted taxanes |
US7256213B2 (en) | 2000-02-02 | 2007-08-14 | Florida State University Research Foundation, Inc. | Taxanes having a C10 carbonate substituent |
CZ300793B6 (en) * | 2000-11-28 | 2009-08-12 | Indena S. P. A. | Process for preparing taxane derivative |
EP1982720A1 (en) | 2002-05-20 | 2008-10-22 | The Regents of the University of California | Ribaviren for use to treat cancer |
EP2108362A2 (en) | 2002-06-26 | 2009-10-14 | Medigene AG | Method of producing a cationic liposomal preparation comprising a lipophilic compound |
US8075913B2 (en) | 2002-06-26 | 2011-12-13 | Medigene Ag | Method of producing a cationic liposomal preparation comprising a lipophilic compound |
US8663606B2 (en) | 2002-06-26 | 2014-03-04 | Medigene Ag | Method of producing a cationic liposomal preparation comprising a lipophilic compound |
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US7794747B2 (en) | 2002-06-26 | 2010-09-14 | Medigene Oncology Gmbh | Method of producing a cationic liposomal preparation comprising a lipophilic compound |
US9238021B2 (en) | 2002-06-26 | 2016-01-19 | Medigene Ag | Method of producing a cationic liposomal preparation comprising a lipophilic compound |
EP2390262A1 (en) | 2003-05-16 | 2011-11-30 | Intermune, Inc. | Synthetic chemokine receptor ligands and methods of use thereof |
US8314261B2 (en) | 2004-01-16 | 2012-11-20 | Guilin Huiang Biochemistry Pharmaceutical Co. Ltd. | Process for the preparation of synthetic taxanes |
US8003812B2 (en) | 2004-02-13 | 2011-08-23 | Florida State University Research Foundation, Inc. | C10 cyclopentyl ester substituted taxanes |
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US7160919B2 (en) | 2004-03-05 | 2007-01-09 | Florida State University Research Foundation, Inc. | C7 lactyloxy-substituted taxanes |
US7186851B2 (en) * | 2004-05-14 | 2007-03-06 | Immunogen, Inc. | Facile method for synthesizing baccatin III compounds |
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US8242166B2 (en) | 2008-03-31 | 2012-08-14 | Florida State University Research Foundation, Inc. | C(10) ethyl ester and C(10) cyclopropyl ester substituted taxanes |
WO2009143454A2 (en) | 2008-05-22 | 2009-11-26 | Kereos, Inc. | Combination antitumor therapy |
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WO2010005850A1 (en) | 2008-07-08 | 2010-01-14 | The J. David Gladstone Institutes | Methods and compositions for modulating angiogenesis |
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WO2014160185A2 (en) | 2013-03-14 | 2014-10-02 | The Board Of Trustees Of The Leland Stanford Junior University | Mitochondrial aldehyde dehydrogenase-2 modulators and methods of use thereof |
WO2014191989A1 (en) * | 2013-05-26 | 2014-12-04 | Idd Therapeutics Ltd. | Conjugate of a taxane and biotin and uses thereof |
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WO2015127137A1 (en) | 2014-02-19 | 2015-08-27 | Aldea Pharmaceuticals, Inc. | Mitochondrial aldehyde dehydrogenase 2 (aldh2) binding polycyclic amides and their use for the treatment of cancer |
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WO2017115301A1 (en) | 2015-12-30 | 2017-07-06 | Syncore Biotechnology Co., Ltd. | Treatment of breast cancer using a combination of a cationic liposomal formulation of taxane, a non-liposomal formulation of taxane and a further active agent |
WO2017178456A1 (en) | 2016-04-11 | 2017-10-19 | Greenaltech, S.L | Uses of a carotenoid in the treatment or prevention of stress induced conditions |
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WO2018136570A1 (en) | 2017-01-18 | 2018-07-26 | F1 Oncology, Inc. | Chimeric antigen receptors against axl or ror2 and methods of use thereof |
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