WO1998010786A2

WO1998010786A2 - Pharmaceutical composition for the treatment of syndrome x of reaven

Info

Publication number: WO1998010786A2
Application number: PCT/IL1997/000301
Authority: WO
Inventors: Yarom Cohen
Original assignee: Yarom Cohen
Priority date: 1996-09-12
Filing date: 1997-09-10
Publication date: 1998-03-19
Also published as: AU4133997A; WO1998010786A3

Abstract

The present invention relates to a pharmaceutical composition comprising as active ingredient a compound selected among somatostatin or one of its analogs, diazoxide or one of its analogs, cyclothiazide or one of its analogs and metformin, for the treatment of syndrome X of Reaven (also called 'Hyper Insulinemia syndrome' or 'The Deadly Quartet').

Description

PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF SYNDROM X OF REAVEN

The present invention relates to a pharmaceutical composition comprising as active ingredient a compound selected among somatostatin or one of its analogs (as herein defined) , diazoxide or one of its analogs (as herein defined) , cyclothiazideor one of its analogs (as herein defined) and metformin, for the treatment of syndrome X of Reaven (also called "Hyper Insulinemia syndrome" or "The Deadly Quartet") .

Somatostatin and its analogs, e.g. octreotide, are known for the treatment of the reduction of the secretion of Insulin caused by insulimonas. Moreover, they are known for the treatment of certain tumors, gastrointestinal diseases, etc. However, their effectivity for the reduction of the resistance to insulin has so far not been known.

It is also known that Diazoxide, Cyclothiazide and Metformin achieve the reduction of the resistance to Insulin. Moreover, it is known that Metformin is used in the treatment of Diabetes and reduces risk factors in carbovascular diseases in NIDDM.

Diazoxide, Cyclothiazide and Metformin have the following formulae: a. Diazoxide: 7-chloro-3-methyl-24-l,2,4-benzothio- diazine' 1,1-dioxide. b. Cyclothiazide: 3-bicyclo[2.2.1]hept-5-en-2y1-6-chloro-

3,4-dihydro-2H-l,2,4-benzothiadiazine- 7-sulfona ide 1, 1-dioxide. c. Metformin: N,N-Dimethylimidodicarbonimide diamide. However, those compounds have so far not been known for the treatment of the risk factors of syndrome X of Reaven.

Syndrome X includes, inter alia, the following risk factors: a. excessive blood pressure; b. dislipidemia, i.e. increase of the amount of Triglycerides in the blood, reduction of the amount of HDL and increase of the amount of LDL, c. excessive blood coagulation due to Plas inogen Activator Inhibitor-1 (PAI-1) increased in the blood; d. central obesity; e. Glucose intolerances - from ocult Diabetes to overt Diabetes f. increase of Insulin in the blood, i.e. the pancreas secretes more Insulin in order to overcome high Insulin resistance.

All the risk fators of syndrome X of Reaven are, inter alia, caused by a high resistance to Insulin. Thus, apparently said symptoms could be treated simultaneously if there would be a reduction to the resistance to Insulin.

Said risk factors either separately but mostly in combination are decisive factors in the appearance of Ischemic Heart disease, e.g. Angina Pectoris, Myocard Infarct; Cerebral Vascular Diseases and the like.

Until now, all said risk factors had to be treated separately as there was no pharmaceutical composition which could treat simultaneously all of them. However, said separate treatments are not always effective as very often the treatment of one risk factor severes the condition of another risk factor. It has therefore been desirable to find a pharmaceutical composition which can treat simultaneously all the various risk factors which are included in syndrome X of Reaven.

We have now found that due to the fact that the reduction of the resistance to Insulin can be achieved by administering a compound selected among somatostatin or one of its analogs (as herein defined) , diazoxide or one of its analogs (as herein defined), cyclothiazide or one of its analogs (as herein defined) and metformin, said treatment may enable the treatment of all risk factors of syndrome X of Reaven simultaneously.

The present invention thus consists in pharmaceutical preparations for the treatment of the risk factors of syndrome X of Reaven comprising as active ingredient a compound selected among somatostatin or one of its analogs (as herein defined) , diazoxide or one of its analogs (as herein defined) , cyclothiazi- deor one of its analogs (as herein defined) and metformin.

The present invention also comprises the use of a compound selected among somatostatin or one of its analogs (as herein defined) , diazoxide or one of its analogs (as herein defined) , cyclothiazideor one of its analogs (as herein defined) and metformin in the preparation of a pharmaceutical preparation for the treatment of the risk factors of syndrome X of Reaven.

Analogs of somastostatin in connection with the present invention mean any analog compound of somatostatin which biologically activate one or more somastostatin receptors. Said receptors cause the reduction of the resistance to Insulin and thus enable the combined treatment of all risk factors of syndrom X of Reaven and are thus effective in primarily & secondary preventing and/or treating Ischemic Heart disease, such as, Angina Pectoris, Myocard Infarcts ; Cerebral Vascular Diseases, etc.

As receptors there should be mentioned, inter alia, the following human somatostatin receptors, which are described in Steven W.J. Lamberts, et al. 1996. Octreotide.. The New England Journal Med. Jan. 25. pp. 246-54. These receptors are:

1. hSSTRl

Present in the brain, lung, stomach, jejunum, kidneys, liver and pancreas. It is located on chromosom 14ql3. It has 391 amino acids and its formula is given in Yamada et. al., Biochemical and Biophysical Research Communications, 1993, Vol. 195, No. 2., pages 844-852.

2. hSSTR2

Present in the brain and in the kidneys, It is located on chromosom 17q24. It has 369 amiono acids and its formula is given in Yamada.

3. hSSTR3

Present in the brain and in the pancreas. It is located on chromosome 22ql3.1. It has 418 amino acids and its formula is given in Yamada.

4. hSSTR4

Present in the brain and in the lung. It is located on chromosome 20. It has 388 amino acids and its molecular weight is 41,867. Its formula is given in Yamada.

5. hSSTR4

Present in the brain, heart, adrenal glands, placenta, pituitary, small intestines and skeletal muscles. It is located on chromosome 20pll.2. It has 364 amino acids, 4 its molecular weight is 39,176 and its formula is given in Yamada. All receiptors have common features:

1. They have a similarity in the configuration in the seven areas which do extend out of the membrane TM1 TM7)

2. Asp-Arg-Tyr at the end of the NH -terminal of the second loop which is in the cell.

3. Aspartic acid (Asp) is located in the third loop outside the cell.

The receptors which are especially important in reducing the Insulin resistance are receptors 2 and 5, also but less receptor 3. Receptors 1 and 4 are less important in this respect.

The use of somatostatin is not always satisfactory as it is effective only for a short time. Therefore the use of Octreoide, the most known analog of somatostatin or of another long acting Somatostatin, is preferred.

The analogs of somastostatin should comprise the chain D- Trp-Lys . Said chain constitute the critical core of the active analogs and is essential for the activation of the receptors.

Most analogs comprise the chain Phe-D-Trp-Lys.

Many analogs comprise the chain Phe-D-Trp-Lys-Thr being present in positions 7 - 10 of Somatostatin 14.

Suitable analogs of somatostatin being part of the pharmaceutical composition according to the present invention are, for example, : 1. Octreotide. 2'. Vapreotide.

3. Lanreotide.

4. Cyclopeptide somatostatin analogues selected among : Cyclo[Pro-Phe-D-Trp-Lys-Thr-Phe] Cyclo[N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe] Cyclo[Pro-Ala-D-Trp-Lys-Thr-Phe] Cyclo[Pro-Tγr-D-Trp-Lys-Thr-Phe] Cyclo[Pro-Phe-D-Trp-Lys-i-aminobutyric-Phe] Cyclo[N-Me-Ala-Phe-D-Trp-Lys-Thr-Phe] Cyclo[Pro-Phe-D-Trp-Lys-Val-Phe] Cyclo[D-Ala-D-Phe-D-Trp-L-Lys-D-Thr-N-Me-D-Phe] 5

Cyclo [ Pro-Phe-D-Trp-Lys-Thr (Bz 1 ) } (Bzl = (a)

Cyclo[Pro-Phe-D-Trp-Lys-Thr-Phe]

Cyclo [Pro-D-Phe-D-Trp-Lys-Thr (Bzl) ]

Cyclo [Ahep-Lys-Asn-Phe-Phe-Trp-Lys-Thr-

Tyr-Thr-Ser] (Ahep =(b)

Cyclo [Ahep-Phe-D-Trp-Lys-Thr (Bzl) ]

Cyclo [Ahep-Phe-D-Trp-Lys-Thr]

Cyclo [Ahep-Phe-D-Trp-Lys-Ser (Bzl) ]

Cyclo [Ahex-Phe-D-Trp-Lys-Thr (Bzl) ] (Ahex = (c)

Cyclo[Aoct-Phe-D-Trp-Lys-Thr (Bzl) ] (Aoct = (d)

Cyclo [Ala-Cys-Phe-D-Trp-Lys-Thr-Cys]

(a) Bzl = benzyl

(b) Ahep = 7-aminoheptanoyl

(c) Ahex = 6-aminohexanoyl

(d) Aoct = 8-amino-octanoyl;

5. D-Phe- [Cys-Phe-D-Trp-Lys-Thr-Cys] -Thr-ol

6. D-Nal- [Cys-Tyr-D-Trp-Lys-Val-Cys] -Thr-NH₂ (Nal = (1)

7. D-Phe-[Cys-Tyr-D-Trp-Lys-Val-Cys]-Nal-NH₂

8. D-Phe-[Cys-Tyr-D-Trp-Lys-Thr-Cys]-Nal-NH₂ 9. D-Phe- [Cys-Tyr-D-Trp-Lys-Abu-Cys] -Nal-NH₂ (Abu = (2)

10. D-Phe- [Cys-Tyr-D-Trp-Lys-Ser-Cys] -Nal-NH₂

11. D-Nal- [Cys-Tyr-D-Trp-Lys-Val-Cys]-Nal-NH₂

12. c (Ahep-Trp-D-Trp-Lys-Thr-Phe) (Ahep = (3)

13. D-Phe-Cpa-Tyr-D-Trp-Lys-Thr-Phe-Thr-NH₂ (Cpa = (4)

14. D-Phe-Cpa-Tyr-D-Trp-Lys-Val-Phe-Thr-NH₂

15. D-Phe-Phe-Phe-D-Trp-Lys-ThrτPhe-Thr-NH₂

16. D-Phe-Phe-Phe-D-Trp-Lys-Val-Phe-Thr-NH₂

17. D-Phe-Phe-Tyr-D-Trρ-Lys-Val-Phe-D-Nal-NH₂

18. D-Phe-Ala-Phe-D-Trp-Lys-Ala-Nal-NH₂

19. D-Phe-Phe-Phe-D-Trp-Lys-Val-Phe-Thr-NH₂

20. D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH₂

21. D-Phe-Phe-Tyr-D-Trp-Lys-Val-Phe-D-Nal-NH₂

(1) Nal L-3 (2-naphthyl)alanine

(2) Abu L-α-amino-n-butyric acid

(3) Ahep 7,aminoheptanoic acid

(4) Cpa L-p-chlorophenylalanine 22. Polypeptides of the formula:

X-Lys-Asn-Phe-Phe-A-Lys-Thr-Phe-Thr-Ser-Y wherein A is L- or D-Trp,

X is H-(Aeg)_m-Cys- or H-(Aeg)_m-Ala-Gly-Cys-,

Y is -Cys-(Aeg)_n-OH or

X and Y taken together are a 2-aminoethyl-glycyl group in the ring position and m and n are 0, 1, 2, provided that m and n are at least 1, and their cyclic disulfide derivatives.

23. A peptide of the formula:

Bmp-Lys-X-Phe-Phe-trp-Lys-Thr-Phe-Thr-Y-Cys-OH 3 4 5 6 7 8 9 10 11 12 13 14 in which

Bmp represents the desa inocysteine radical,

X represents Asn, trp represents D-Trp that may be substituted in the benzene ring by a halogen atom, and

Y represents the radical of an alpha-(lower alkyl) amino- (lower alkyl) -carboxylie acid having a minimum of 4 and a maximum of 8 carbon atoms, in which the two lower alkyl radicals can be connected to one another witha single C-C bond, an oxygen atom or a sulphur (II) atom.

24. Cyclic octapeptides of the formula

^■•^■Asn-Phe-Phe-Trp-Lys-Thr-Phe-Gaba (Ar) ^■*^■ 5 6 7 8 9 10 11 12 in which

Trp represents L-Trp or D-Trp, in which the benzene ring may be substituted by a fluorine atom, and

Gaba(Ar) represents the residue of a -aminobutyric acid substituted by a cyclic hydrocarbyl radical Ar selected from the group consisting of cyclohexyl; phenyl optionally substituted by halogen, nitro or phenoxy; and naphthyl optionally substituted by halogen. 25. A compound of formula

H-Ser-Ala-Asn-Ser-Asn-Pro-Ala-R₈

-Ala-Pro-Arg-Glu-Arg-Lys-Ala-Gly-Cys-R_l8-R₁₉-Phe-Phe-D

-Trp-Lys-Thr-R₂₅-R₂₆-R₂₇-R_2β-OH wherein R₈ is

Met or Leu , R₁₃ is Lys or des R₁₈ , R₁₉ is Asn or

des R₁₉ , R ₂₅ is Phe or Tyr , R₂₆ is Thr or des

R₂₆ , R₂₇ is Ser or D-Ser and R₂₈ is D-Cys or Cys . 26 . A compound of formula

H-Ser-Ala-Asn-Ser-Asn-Pro-Ala-R₈-Ala-Pro

-Arg-Glu-Arg-Lys-Ala-Gly-Cys-R₁₈-R₁₉-Phe-Phe-D-Trp-Lys

-Thr-R₂₅-R₂₆-R₂₇-R_2β-OH wherein R_a is Met or

Leu, R₁₈ is Lys or des R_ιa, R₁₉ is Asn or des

R₁₉, R ₂₅ is Phe or Tyr, R₂₆ is Thr or des R₂₆,

R₂₇ is Ser or D-Ser and R₂₃ is D-Cys or Cys, or the linear version thereof where the disulfide bridge is replaced by hydrogen. 27. A cyclic hexapeptide of the formula -X - Phe-D-Trp-Lys-Y-Pheτ i I in which X represents the radical of an L-aminoacid of the formula

in which A and B are identical or different and denote alkyl having 1 to 3 carbon atoms, or A and B together represent a saturated, unsaturated or aromatic monocyclic or bicyclic structure having 3 to 6 carbon atoms, n denotes 0 or 1, and

Y represents an aliphatic or aromatic L-aminoacid the side- chair of which can be hydroxylated, said amino acid being selected from the group consisting of L-alanine, L-serine, L-valine, L-leucine, L-isoleucine, L-phenylalanine and L- tyrosine. 28. An N-acyl-polypeptide of formula,

F

1 2 3 4 5 6 7 wherein

"Acyl" is a group of formula RXo- wherein R¹ is C₁₂₀ alkyl or phenyl; a group of formula R^πS0₂- wherein R¹¹ is C₁₂₀- alkyl, phenyl or tolyl; a group

_RIII

N-CO- wherein R^IV R^ι and R^IV are each independently hydrogen or C_1-l0alkyl; or biotinyl, A is hydrogen or C^alkyl,

>N-CH(Z)-CO- is an (L) - or (D) -phenylalanine residue optionally ring-substituted by N0₂, or an (L) or (D)-norleu- cine residue, whereby

Z in ^*^N-CH(Z) -CO- represents the remainder of said residue, B is -Phe- optionally ring-substituted by N0₂, F is a group of formula

wherein R„ is hydrogen or a group of formula

-CH (R₅) -X, R₅ is CH₃CH (OH) - , i-butyl or benzyl X is a group of formula -COOR_! , -CH₂OR₂ or R<

^■CO-N

R₇

wherein R_x, R₆ and R₇ are each hydrogen or C^alkyl, and R₂ is hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester, the group -CH(R₅)-X having the (D)- or (L) -configuration, and

Y_x and Y₂ are each hydrogen or together represent a direct bond, whereby the residue resides in the 2- and 7-position each indepen-dently have the (L)- or (D) -configuration, and with the proviso that: i) (L)- and/or (D) -cysteine residues are present at the 2- and 7-positions only. 29. A polypeptide of the formula

wherein

A is C₁.₁₂alkyl , C₇.₁₀phenylalkyl or a group of formula RCO- , whereby i) R is hydrogen, c^_na-lkyl , phenyl or

C_{7 10}phenyl alkyl, or ii) RCO- is a) an L- or D-phenylalanine residue optionally ring-substituted by halogen and/or C^alkyl , b) H-Asn- , or c) H-Nle-Asn- , the α-amino group of amino acid residues a) and b) and the N-terminal amino group of dipeptide residues c) being optionally ono- or di-C_{1 12}alkylated, A' is hydrogen or, when A is C_{1 12}alkyl or

C_{7 10}phenylalkyl, also C_{1 12}alkyl or C₇.₁₀phenylalkyl, B is -Phe-optionally ring-substituted by halogen and/or

C_{x 3}alkyl , C is - (L) - or - (D) -Trp- optionally α-N-methylated and optionally benzene-ring-substituted by halogen and/ or

C_{x 3}alkyl , D is -Lys- optionally α-N-methylated and optionally

Σ-N-C₁.₃-alkylated , E is -Thr- or -Ala- each in (D) - or (L) -form and each being optionally α-N-methylated,

F is a group o or

wherein R_x is hydrogen or C₁ alkyl,

R₂ is hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester, R₃ is hydrogen, C^alkyl, phenyl or C₇.₁₀- phenylalkyl, R„ is hydrogen, Cj ₃alkyl or, when R₃ is hydrogen or methyl, also a group of formula -CH(R_S)-X, R₅ is hydrogen, -(CH₂)₂-OH, -(CH₂)₃ -OH,

-CH₂-OH, -CH(CH₃)-OH, isobutyl or benzyl X is a group of formula -COO _! , -CH₂OR₂ or

/

-CO-N

^ ₇ wherein

R_: and R₂ have the meanings given above, R_e is hydrogen or C_halky1 and R₇ is hydrogen, C₁ alkyl, phenyl or C₇.₁₀phenylalkyl, the group -CH(R₅)-X having the D- or L- configuration, and Y_t and Y₂ are each hydrogen or together represent a direct 11 bond, whereby the residues in the 1- and 6-position each independently have the L- or D-configuration. 30. A compound of formula

wherein A is C_{x 12}alkyl, C_{7 10}phenylalkyl or a group of formula RCO-

, whereby i) R is hydrogen, C_{t u}alkyl, phenyl or C_{7 10}phenylalkyl or ii) RCO- is a) an L- or D-phenylalanine residue optionally ring-substituted by F, Cl, Br, No₂, NH₂ ,

OH, C_{j. 3}alkyl and/or C_{t 3}alkoxy; b) the residue of a natural or synthetic α-a-mino acid other than defined under a) above or of a corresponding D-amino acid, or c) a dipeptide residue in which the individual amino acid residues are the same or different and are selected from those defined under a) and/or b) above,

C ₈alkanoyl, A' is hydrogen,

Y_j and Y₂ represent together a direct bond or each of Y_: and Y₂ is independently hydrogen or a radical of formulae (1) to (5) .

-CO- -CO-NHR_r

( i ) ( 2 ) ( 3 )

-C0-NH-

( 4 ) ( 5 ) wherein

R_a is methyl or ethyl

R_b is hydrogen, methyl or ethyl m is a whole number from 1 to 4 n is a whole number from 1 to 5 e is (Ci ₆) alkyl

R_d represents the substituent attached to the α-carbon atom of a natural or synthetic α- a ino acid (including hydrogen)

R_e is (Cj.₅) alkyl

R_a' and R_b' are independently hydrogen, methyl or ethyl,

R₈ and R₉ are independently hydrogen, halogen, (C_{1 3}) alkyl or (C_{1 3})alkoxy,

P is 0 or 1, q is 0 or l, and r is 0, 1 or 2,

B is -Phe- optionally ring-substituted by halogen,

N0₂, NH₂, OH, C_{t 3}alkyl and/or C_{λ 3}alkoxy (including pentafluoroalanine) , or β-naphthyl-Ala

C is (L)-Trp- or (d)-Trp- optionally α-N-methylated and optionally benzene-ring-substituted by halogen, N0₂, NH₂ OH, C_{x 3}alkyl and/or C_{x 3} alkoxy,

D is Lys, Lys in which the side chain contains O or

S in β-position, J-F-Lys or <SF-Lys, optionally α- N-methylated, or a 4-aminocyclohexylAla or 4- aminocyclohexylGly. residue

E is The, Ser, Val, Phe, lie or an aminoisobutyric or aminobutyric acid residue

G is a group of formula

wherem

R₇ is hydrogen or C_{t 3}alkyl , R₁₀ is hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester, is hydrogen, C_{x 9}alkyl, phenyl or C_{7 10}phenyl-alkyl,

R₁₂ is hydrogen, C_{x 3}alkyl or a group of formula -CH(R₁₃)-X₁,

Ri: is CH₂OH, - (CH₂)₂-OH, -(CH₂)₃-OH, or -CH(CH₃)OH or represents the substituent attached to the a- carbon atom of a natural or synthetic α-amino acid (including hydrogen) and

X_; is a group of formula -COOR₇ , -CH₂OR₁₀ or

wherein

R₇ and R_l0 have the meanings given above, R is hydrogen or C_{L 3}alkyl and R₁₅ is hydrogen, C_{x 3}alkyl, phenyl or

C_{7 10}phenylalkyl, and R₁₆ is hydrogen or hydroxy, with the proviso that when R₁₂ is -CH(R₁₃)-X_! then R_u is hydrogen or methyl, wherein the residues B, D and E have the L-confi- guration, and the residues in the 2-and 7-posi- tion and any residues Y 4) and Y₂ 4) each independently have the (L)- or (D)- configuration.

31. A somatostatin analog selected from the compounds of the following formulae

wherein

_S or _(CH₂)₉ where s is 0 , 1 or 2 ; is one of X and Z is _S and the other is S or CH₂; _S or (_CH₂)_t where t is 0 , 1 or 2 ;

Y is in_depen_dently of the other, is ^C _{1 5} each of R_x and R₂ alkyl, _benzyl, benzyl having one or two _{C1 5} alkyl, halogen, hydroxy, amino, nitro, and/or C, .₅ alkoxy substituents, or _Ci.5 alkyl substituted with 5- or ⁶- me _bere_d heterocyclic ring; R₃ is 3-indolymethyl, either unsubstituted or having C _s alkyl, C_{x 5} alkoxy or halogen substitution;

R„ Cj ₅ alkyl, C _s hydroxyalkyl, benzyl, carboxy- (C_{x 5} alkyl) , amino (C_{1 5} alkyl) or benzyl having a C_{x 5} alkyl, halogen, hydroxy, amino, nitro and/or C_{L 5} alkoxy substituent;

R₅ is Cj ₅ alkyl, benzyl, or benzyl having a

C_{x 5} alkyl, halogen, hydroxy, amino, nitro, and/or C_{x 5} alkoxy substituent, compounds of Formula

wherein

A is C_{λ 12} alkyl, C_{7 10} phenylalkyl or a group of formula RCO-, whereby i) R is hydrogen, C_{x ;1} alkyl, phenyl or C_{7 10} phenylalkyl, or ii) RCO-is a) an L- or D-phenylalanine residue optionally ring- substituted by F, Cl, Br, N0₂, NH₂, OH, C_{x 3} alkyl and/or C_{x 3} alkoxy b) the residue of a natural α-amino acid other than defined under a) above -or of a corresponding D-amino acid, or c) a dipeptide residue in which the individual amino acid residues are the same or different and are selected from those defined under a) and/or b) above, the α-amino group or amino acid residues a) and b) and the N-terminal amino group of dipeptide residues c) being optionally mono- or di-Cj ₁₂ alkylated,

A' is hydrogen or, when A is C_{α 12} alkyl or C_{7 10} phenylalk- also C_{x 12} alkyl or C_{7 10} phenylalkyl, Y_j and Y₂ represent together a direct bond or each of Y_; and Y₂ is independently hydrogen or a radical of the formulae -CO- -CO-NHR_r

_n

( 1 ) ( 2 ) ( 3 )

-CO-NH-

( 4 ) ( 5 )

wherein R_a is methyl or ethyl

R_b is hydrogen, methyl or ethyl m is a whole number from 1 to 4 n is a whole number from 1 to 5 R_c is (C_1-6) alkyl

R_d represents the substituent attached to the α-carbon atom of a natural α-amino acid (including hydrogen) R_e is (C^_s) alkyl

R_a' and R_b' are independently hydrogen, methyl or ethyl, R₈ and R, are independently hydrogen, halogen, (C₁ ) alkyl or ( C_x .₃) alkoxy, p is 0 or 1, q is 0 or 1, and r is 0, 1 or 2, B is -Phe- optionally ring-substituted by halogen, No₂, NH₂,

OH, C^alkyl and/or C^alkoxy, or naphthylalanine. C is (L)-Trp- or (D)-Trp- optionally α-N-methylated and optionally benzene-ring-substituted by halogen, No₂, NH₂, OH, C_j.₃ alkyl and/or C₁₃ alkoxy, D is -Lys-, ThiaLys, F-Lys, «SF-Lys or Orn, optionally α-N- methylated, or a 4-aminocyclohexyl Ala or 4-aminocyclo- hexyl Gly residue, E is Thr, Ser, Val, Phe, lie or an aminoisobutyric acid residue

wherein R₇ is hydrogen or C^alkyl,

R₁₀ is hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester, R_n is hydrogen, C₁₃alkyl, phenyl or C_{7 10}-phenylal- kyl,

R₁₂ is hydrogen, C^alkyl or a group of for ula-

R₁₃ is CH₂OH, -(CH₂)₂-OH, -(CH₂)₃-OH, or -CH(CH₃)0H or represents the substituent attached to the α-carbon atom of anatural α-amino acid (including hydrogen) and X_: is a group of formula -COOR₇ , -CH₂OR₁₀ or

wherein

R₇ and R₁₀ have the meanings given above,

R_l4 is hydrogen or C_halky1 and

R₁₅ is hydrogen, C₁₃alkyl, phenyl or C₇.₁₀phenylalkyl, and

R₁₆ is hydrogen or hydroxy, with the proviso that when R₁₂ is -CHfRj_jJ-X_j then R is hydrogen or methyl, wherein the residues B, D and E have the L-configuration, and the residues in the 2- and 7-position and any residues

Y_j 4) and Y₂ 4) each independently have the (L)- or (D)- configuration

and compounds of the following formulae H-Cys-Phe- (D) Trp-Lys-Thr-Phe-Cys-OH

τAsn-Phe-Phe- ( D) Trp-Lys-Thr-Phe-Gaba-

-MeAla-Tyr- (D) Trp-Lys-Val-Ph

NM e-Phe-His- (D) Trp-Lys-Val-Ala .

32 . Somatostatin analogs

X-Cys-D-o-Trp-E-F-Cys-Y I

I L

X-Cys-Lys-Asn-Phe-D-o-Trp-E-F-Phe-Thr-Ser-Cys-Y II

I, II, X = N-terminus anchor; Y = C-terminus anchor, G-I or its ale; wherein at least I of X, Y = cationic anchor; D = Phe Tyr, 3- (p-fluorophenyl) alanine or 3 (p-chlorophenyl) alanine residue; E = Lys, Lys(R') ; R¹ = c_x._β (fluoro) alkyl ; F = Thr, Val, Ser; G = D- or L-Thr, Phe, or 3- (2-naphthyl) alanine residue; I = OH, NH₂, NHRX

33. Peptides RR^lNCHR²CONHCH(CH₂SR⁴) CO-Phe-Trp-Lys-X-NHCHR^CH.SR⁵ [R = inorg. or org. acyl group, R¹ = H, alkyl, NCHR²CO moiety = I.

Me (CH₂) ₈CO-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol I or D-Phe (optionally ring substituted by halo, N0₂, OH, alkyl. alkoxy) ; Phe, Trp, (D or L) ,may be ring substituted by N0₂, NH₂, OH, alkyl, alkoxy; Lys may be α-N-methylated and Σ-N-alkylated; X = D- or L-α-amino acid residue optionally α-N-methylated; R³ = C0₂H, CH₂OH, carbamoyl, R" = R⁵ = H, RR⁵ = bond] 34. H-Ser-Ala-Asn-Ser-Asn-Pro-Ala-X-Ala-Pro-Arg-Glu-Arg-Lys-Ala- Gly-

Cys-X^x^Phe-Phe-D-Trp-Lys-Tys-Thr-X'-X'-X'-r-OH 35. H-Ser-Ala-Asn-Ser-Asn-Pro-Ala-Leu-Ala-Pro-Arg-Glu-Arg-Lys -Ala-Gly-

C ιys-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Tyr-Thr-Ser-C1ys-OH

Said compounds (34 and 35) appear in Chemical Abstracts 98, 1983 1 43839 q

36. c(Spacer-Phe-D-Trp-Lys-Thr) Spacer may stand for:

b) R-α-Bn-NMe-o-AMPA c) Phe-Pro

Said cmpounds and similar ones appear in Brecx et al., Lett. Pept. Sci.1995, 2 (3/4): 165-8 , "Somatostatin analogs contai- ning 0-amino methyl phenyl acetic acid as a bridge unit"; and Tourwe, Lett. Pept. Sci. 1995, 2 (3/4): 182-6, "Conformation directed design of cyclic Somatostatin containing a BVI-turn mimetic". 37. H₂N-Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys- OH

38. H₂N-Ser-Ala-Asn-Ser-Asn-Pro-Ala-Met-Ala-Pro-Arg-Glu-Arg-Lys- Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys-OH

39. D-β-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂

40. Ac-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂

41. D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Trp-NH₂

42. D-Trp-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂

43. D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂

44. D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH₂

45. 3-(2-naphthyl) -D-Ala-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂

46. c (Aha-Phe-p-Cl-Phe-D-Trp-Lys-Thr-Phe) Aha = 7 -amino heptanoic acid.

Analogs of Diazoxide and Cyclothiazide are compounds which affect the receptor being adenosine 5'- triphosphate sensitive K^* channels.

Suitable analogs of Diazoxide and of Cyclothiazide are indicated, for example, in a paper of Bertolino et al., appearing in Receptor-Channels 1993 1(4) : 267-78 "Modulation of AMPA/Kainate Receptors by Analogs of diazoxide and cyclothiazide in thin slices of rat hippocampus". However, the analogs which may be used in the pharmaceutical composition according to the present invention are not restricted to the analogs given in said paper and any other analog having the proper properties may be used.

The pharmaceutical preparation according to the present invention may also comprise additional compounds such as compounds having an additional pharmaceutical effect, carriers, solvents, emulgamators, etc.

In view of the fact that diazoxide sometimes has undesired salt and water retention, which may be relieved by certain thiazide diuretics, e.g. 6-chloro-2H-l, 2 , 4-benzothiadiazine-7- sulfonamide 1,1-dioxide (Chlorothiazide) ; 6-chloro-3 , 4-dihydro- 2H-1, 2, 4-benzothiadiazine-7-sulfonamide 1, 1-dioxide (Hydrochlort- hiazide) ; 6-chloro-3- (dichloromethyl) -3 , 4-dihydro-2H-l, 2 , 4- benzothiadiazine-7-sulfonamide 1,1-dioxide (Trichlormethiazide) ; or 6-chloro-3 , 4-di-hydro-2-methyl-3 [(2,2 , 2-trifluoroethyl) thiome- thyl]-2H-l, 2 , 4-benzothiadiazine-7-sulfonamide 1, 1-dioxide (Polythiazide) , the pharmaceutical compositions according to the present invention may comprise, in addition to Diazoxide and/or one of its analogs, as an additional compound having a pharmaceutical effect, one or more of the above thiazides or a thiazide having similar properties. Said thiazide diuretics may prevent the salt and water retention.

The present invention also comprises a method for the treatment of the risk factors of syndrome X of Reaven by applying to a patient a pharmaceutically effective dosage of a pharmaceutical preparation according to the present invention comprising a pharmaceutically effective dosage of a compound selected among somatostatin or one of its analogs (as herein defined) , diazoxide or one of its analogs (as herein defined) , cyclothiazide or one of its analogs (as herein defined) and metformin.

Said dosage should preferably not exceed 50μg/kg/day of the active ingredient (calculated on Octreotide) , preferably not exceeding 40μ/kg/day. Said dosage is given in any suitable manner. It may be given as one portion once a day or even in two days or more when given in slow release form, or being divided into 3-4 dosages which are applied in equal periods of time for Octreotide, or 1 - 2 times a day for analogs with a higher t^. Said dosage should preferably not exceed 8 mg/kg/day in the treatment of the active ingredient (calculated on diazoxide) in adults, and preferably not exceed 15/rag/day in the treatment of children. The amount of Metformin applied should preferably not exceed 2.5 g/day divided into 2 - 3 portions.

Should any of the above thiazide diuretics be added the added amounts are, for example, the following:

Chlorothiazide: 500 - 2000 mg a day;

Hydrochlorothiazide: 50 - 200 mg a day;

Trichloromethiazide: 12.5 - 50 mg a day;

Polythiazide: 1- 4 mg a day.

Said dosage has to be re-calculated on the basis of the analog being the active ingredient. Moreover, the exact dosages have to be adapted to the condition of the patients and to its specific properties e.g. weight, age, etc.

The composition may be administered in various manners. This depends in particular on the analog being the active ingredient. Thus octreotide is advantageously injected sub-cutaneously as a saline solution. Cyclo (N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe) is advantageously administered per os.

The treatment is performed, as indicated above, against the risk factors of syndrome X of Reaven, in particular against the following diseases in order to primarily and secondarily prevent and to treat:

A. 1. Ische ic Heart diseases, e.g. Angina Pectoris and

Myocard Infarcts;

2. Cerebral vascular diseases in order to prevent Transient Ischemic attack (TIA) and Cerebrovascular accident (CVA) ;

3. Intermittent Claudication;

4. Ischemic Bowel disease; and

5. Impotence due to a Periferal vascular disease.

B. Prevent excessive blood coagulation (high PAI-1 in the blood) in order to primarily prevent MI, CVA, Renal vein trombosis, etc.

C. Lower body weight (which is also a risk factor for high blood pressure, Glucose Intolerance, etc.)

Said diseases are mainly caused, as indicated above, by a high resistance to Insulin.

The present invention will now be illustrated with reference to the following experiment (all injections are given into the hollow space of the Peritoneum) :

60 fat male rats of the Zucker species, aged 7 weeks having an average weight of 225 g. 54 rats of same are divided into 3 groups :

Group A receives injections of Octreotide in a 0.9% NaCl saline solution in a high dosage (40μg/kg/day) ;

Group B receives injections of Octreotide in a 0.9% NaCl saline solution in a low dosage (20 μg/kg/day) ; and

Group C the control group, receives an injection of a 0.9% saline solution. The volume of the 0.9% NaCl is identical with the volume being injected into Group A and B (At the beginning of the tests the rats have approximately the identical weight and they therefore receive the identical volume of injections) .

All rats receive the same amount of Food (Pair Fed) . Said amount is chosen according to the group eating the lowest amount. Thus, the influence of the drug is isolated.

The rats are located in a room changing light and darkness in order to simulate natural surroundings, as in general they eat in darkness. The rats drink water freely.

The rats are weighed twice a week. At the end of the experiment the rate change of the weight is being calculated. The amount of food eaten per week is measured and the amount eaten each day is calculated. (The influence of the Octreotide on the amount of food eaten by the rats is not checked. They eat the identical amount of food.)

Six rats are tested before the beginning of the experiment. Six rats from each group are separated after 2 weeks, 4 weeks and 8 weeks and an Intra-Peritoneal Glucose Tolerance Test (GTT l.Og Glucose/kg BW) is performed after a fast of 12 hours during which the rats do not receive any medicament or food.

Blood is taken from the Supra-orbital sinus with slow anaesthesia with C0₂.

At zero time, i.e. before the Glucose load 2 cc of blood are taken from each rat. cc of blood is put into a test tube which contains Heparin and the concentrations of Glucose and Insulin are determined; and

1 cc of blood is put into a test tube which contains Na₂EDTA 0.1% and the concentrations of Cholesterol, Triglycer- ides, HDL and LDL are determined.

At 15, 30 and 60 minutes after the Glucose load, cc of blood is taken from each rat and put into a test tube which contains Heparin and the concentrations of Glucose and Insulin are determined.

After the Glucose tolerance test each tested rat "leaves" the experiment.

The materials used in the experiments:

Octreoide manufactured by Sandoz Basel.

0.9% NaCl

30% Glucose

Not sterilized food for mice and rats manufactured by Kopolk, Petach Tikva. Catalogue No. 19510. Gross energy 3,950 kCal/kg. Digestibality energy of the food in rats 3,150 kCal/kg.

The laboratory tests are performed as follows:

1. Glucose is tested by the Glucose Oxidase method in a kit of Boehringer Mannheim called Glucose GOD-Perid Method 2 x 300ml catalogue No. 124028. The test is performed on the day or the following day on which the blood is taken.

2. The Insulin is tested by the Radio Immuno Assay (RIA) by a SB INSIK-5 kit of Sorin Biomedica.

The method is performed by the general method known for the test of Insulin by said kit.

3. The total Cholesterol is tested by the CHOD-PAP method. The total cholesterol comprises VLDL + LDL + HDL. The kit with which the test is performed is manufactured by Boehringer Mannheim and the cholesterol reagent is MPA3 catalogue No. 236691 4 x 500ml.

The HDL is tested by precipitating LDL and VLDL with Heparin MnCl₂ and then the total cholesterol is tested. VLDL is calculated by T.G./5. LDL is calculated by the formula

LDL = totaL cholesterol - (VLDL + HDL)

4. The Triglycerides are being tested by the peridochrom T.G. GPO-PAP method. The kit is manufactured by Boehringer Mannheim and the reagent has catalogue No. 701904 15 x 32ml.

The data received are worked up by standard methods for this purpose. The results show that the Insulin resistance is significantly lowered, there is an increase in the level of HDL and a decrease in the level of LDL and of the Triglycerides. A decrease in the rate of weight gain of young obese rats is observed, which implies a decrease in the weight of adult obese rats.

The Insulin resistance (Insulin Sensitivity Index) is determined using the dynamic test - the Glucose Tolerance Test (GTT) . An integration of the area under the curve (AUC) of Glucose and Insulin in the period of 1 hours is measured and the determination of the ratio between them gives a good estimate of the Insulin resistance.

Claims

Claims :

1. A pharmaceutical composition for the treatment of the risk factors of syndrome X of Reaven comprising as active ingredient a compound selected among somatostatin or one of its analogs (as herein defined) , diazoxide or one of its analogs (as herein defined) , cyclothiazideor one of its analogs (as herein defined) and metformin.

2. A pharmaceutical composition comprising an additional compound.

3. A pharmaceutical composition comprising an additional compound having an additional pharmaceutical effect.

4. A pharmaceutical composition according to Claim 2 or 3 wherein the additional compound is selected among carriers, solvents and emulgamators.

5. A pharmaceutical composition according to any of Claims 1 to 4, wherein the analog of somatostatin is Octreotide.

6. A pharmaceutical composition according to any of Claims 1 to 4, wherein the analog of somatostatin is Vapreotide.

7. A pharmaceutical composition according to any of Claims 1 to 4, wherein the analog of somatostatin is Lanreotide.

8. A pharmaceutical composition according to any of Claims 1 to , wherein the analogs of somatostatin are Cyclopeptide somatostatin analogues selected among :

Cyclo[Pro-Phe-D-Trp-Lys-Thr-Phe]

Cyclo [N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe]

Cyclo [Pro-Ala-D-Trp-Lys-Thr-Phe]

Cyclo[Pro-Tyr-D-Trp-Lys-Thr-Phe]

Cyclo [Pro-Phe-D-Trp-Lys-_<J-aminobutyric-Phe]

Cyclo[N-Me-Ala-Phe-D-Trp-Lys-Thr-Phe]

Cyclo[Pro-Phe-D-Trp-Lys-Val-Phe]

Cyclo[D-Ala-D-Phe-D-Trp-L-Lys-D-Thr-N-Me-D-Phe]

Cyclo[Pro-Phe-D-Trp-Lys-Thr(Bzl) ] (Bzl = (a)

Cyclo[Pro-Phe-D-Trp-Lys-Thr-Phe]

Cyclo[Pro-D-Phe-D-Trp-Lys-Thr (Bzl) ]

Cyclo[Ahep-Lys-Asn-Phe-Phe-Trp-Lys-Thr-

Tyr-Thr-Ser] (Ahep =(b)

Cyclo[Ahep-Phe-D-Trp-Lys-Thr(Bzl) ]

Cyclo[Ahep-Phe-D-Trp-Lys-Thr] Cyclo [Ahep-Phe-D-Trp-Lys-Ser (Bzl ]

Cyclo[Ahex-Phe-D-Trp-Lys-Thr (Bzl) ] (Ahex = (c)

Cyclo [Aoct-Phe-D-Trp-Lys-Thr (Bzl) ] (Aoct = (d)

Cyclo[Ala-Cys-Phe-D-Trp-Lys-Thr-Cys]

(a) Bzl = benzyl

(b) Ahep = 7-aminoheptanoyl

(c) Ahex = 6-aminohexanoyl

(d) Aoct = 8-amino-octanoyl;

9. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is: D-Phe- [Cys-Phe-D-Trp-Lys-Thr-Cys] -Thr-ol

10. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is:

D-Nal- [Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH₂ (Nal = (1)

11. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is:

D-Phe- [Cys-Tyr-D-Trp-Lys-Val-Cys] -Nal-NH₂

12. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is:

D-Phe- [Cys-Tyr-D-Trp-Lys-Thr-Cys ] -Nal-NH₂ 13. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is: D-Phe- [Cys-Tyr-D-Trp-Lys-Abu-Cys]-Nal-NH₂ (Abu = (2)

14. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is:

D-Phe-[Cys-Tyr-D-Trp-Lys-Ser-Cys]-Nal-NH₂

15. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is:

D-Nal- [Cys-Tyr-D-Trp-Lys-Val-Cys]-Nal-NH₂

16. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is: c(Ahep-Trp-D-Trp-Lys-Thr-Phe) (Ahep = (3)

17. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is: D-Phe-Cpa-Tyr-D-Trp-Lys-Thr-Phe-Thr-NH₂ (Cpa = (4)

18. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is: D-Phe-Cpa-Tyr-D-Trp-Lys-Val-Phe-Thr-NH₂ 19. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is: D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH₂

20. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is: D-Phe-Phe-Phe-D-Trp-Lys-Val-Phe-Thr-NH₂

21. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is: D-Phe-Phe-Tyr-D-Trp-Lys-Val-Phe-D-Nal-NH₂

22. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is: D-Phe-Ala-Phe-D-Trp-Lys-Ala-Nal-NH₂

23. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is: D-Phe-Phe-Phe-D-Trp-Lys-Val-Phe-Thr-NH₂

24. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is: D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH₂

25. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is: D-Phe-Phe-Tyr-D-Trp-Lys-Val-Phe-D-Nal-NH2

26. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analogs are polypeptides of the formula: X-Lys-Asn-Phe-Phe-A-Lys-Thr-Phe-Thr-Ser-Y wherein A is L- or D-Trp,

X is H-(Aeg)_m-Cys- or H-(Aeg)_m-Ala-Gly-Cys-,

Y is -Cys-(Aeg)_n-0H or

X and Y taken together are a 2-aminoethyl-glycyl group in the ring position and m and n are 0, 1, 2, provided that m and n are at least l, and their cyclic disulfide derivatives.

27. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analogs are peptides of the formula: 28

B p represents the desaminocysteine radical,

Y represents the radical of an alpha- (lower alkyl) amino- (lower alkyl) -carboxylic acid having a minimum of 4 and a maximum of 8 carbon atoms, in which the two lower alkyl radicals can be connected to one another with a single C-C bond, an oxygen atom or a sulphur (II) atom. 28. A pharmaceutical composition according to any of Claims 1 to

4, wherein the somatostatin analogs are cyclic octapeptides of the formula

^LAsn-Phe-Phe-Trp-Lys-Thr-Phe-Gaba (Ar) -¹ 5 6 7 8 9 10 11 12 in which

Gaba(Ar) represents the residue of a^-aminobutyric acid substituted by a cyclic hydrocarbyl radical Ar selected from the group consisting of cyclohexyl; phenyl optionally substituted by halogen, nitro or phenoxy; and naphthyl optionally substituted by halogen. 29. A pharmaceutical composition according to any of Claims 1 to

4 , wherein the somatostatin analogs are compounds of formula

H-Ser-Ala-Asn-Ser-Asn-Pro-Ala-R_a

-Ala-Pro-Arg-Glu-Arg-Lys-Ala-Gly-Cys-R₁₈-R₁₉-Phe-Phe-D

-Trp-Lys-Thr-R_2S-R₂₆-R₂₇-R₂₃-OH wherein R₈ is Met or Leu, R₁₈ is Lys or des R_ιa, R₁₉ is Asn or

des R₁₉, R _2S is Phe or Tyr, R₂₆ is Thr or des

R_{26/ 2}7 is ^{Ser or} D-Ser and R₂₃ is D-Cys or Cys. 30. A pharmaceutical composition according to any of Claims 1 to 4 , wherein the somatostatin analogs are compounds of formula

H-Ser-Ala-Asn-Ser-Asn-Pro-Ala-R_a-Ala-Pro

-Arg-Glu-Arg-Lys-Ala-Gly-Cys-R₁₈-R₁₉-Phe-Phe-D-Trp-Lys

-Thr-R₂₅-R₂₆-R₂₇-R₂₈-OH wherein R₈ is Met or

Leu, R₁₈ is Lys or des R₁₈, R₁₉ is Asn or des

R₁₉, R ₂₅ is Phe or Tyr, R₂₆ is Thr or des R₂₆,

R₂₇ is Ser or D-Ser and R_2β is D-Cys or Cys, or the linear version thereof where the disulfide bridge is replaced by hydrogen. 31. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analogs are cyclic hexapeptides of the formula

-X - Phe-D-Trp-Lys-Y-Pheτ

L — in which X represents the radical of an L-aminoacid of the formula

Y represents an aliphatic or aromatic L-aminoacid the side- chair of which can be hydroxylated, said amino acid being selected from the group consisting of L-alanine, L-serine, L-valine, L-leucine, L-isoleucine, L-phenylalanine and L- tyrosine. 32. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analogs are N-acyl-polypeptides of formula,

Acyl-

1 2 3 4 5 6 7 wherein

"Acyl" is a group of formula R'CO- wherein R¹ is Cj ₂₀ alkyl or phenyl; a group of formula R^πS0₂- wherein R^π is

alkyl, phenyl or tolyl; a group

wherein

R¹¹¹ and R^IV are each independently hydrogen or Cj .^alkyl ; or biotinyl , A is hydrogen or C_{1 3}alkyl,

>N-CH ( Z) -CO- is an (L) - or (D) -phenylalanine residue optionally ring-substituted by N0₂ , or an (L) or (D) -norleu- cine residue , whereby

Z in ^>N-CH ( Z ) -CO- represents the remainder of said residue ,

B is -Phe- optionally ring-substituted by N0₂ , F is a group of formula

wherein R₄ is hydrogen or a group of formula

-CH(R₅)-X, R₅ is CH₃CH(OH)-, i-butyl or benzyl X is a group of formula -COOR -CH₂OR₂ or

wherein _: , R^ and R₇ are each hydrogen or C₁.₃alkyl, and R₂ is hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester, the group -CH(R₅)-X having the (D) - or (L) -configuration, and

Y_x and Y₂ are each hydrogen or together represent a direct bond, whereby the residue resides in the 2- and 7-position each indepen-dently have the (L)- or (D) -configuration, and with the proviso that: i) (L)- and/or (D)-cysteine residues are present at the 2- and 7-positions only. 33. A pharmaceutical composition according to any of Claims 1 to 4 , wherein the somatostatin analogs are polypeptides of the formula

wherein

A is C^^alkyl, C₇.₁₀phenylalkyl or a group of formula RCO-, whereby i) R is hydrogen, C^nalkyl, phenyl or

C₇._1Qphenylalkyl, or ii) RCO- is a) an L- or D-phenylalanine residue optionally ring-substituted by halogen and/or C₁ alkyl, b) H-Asn-, or c) H-Nle-Asn-, the α-amino group of amino acid residues a) and b) and the N-terminal amino group of dipeptide residues c) being optionally ono- or di-Ci ₁₂alkylated, A' is hydrogen or , when A is C ₁₂alkyl or

C₇._1Qphenylalkyl , also C^^alkyl or C_{7 10}phenylalkyl , B is -Phe-optionally ring-substituted by halogen and/or

C₁.₃alkyl , C is - (L) - or - (D) -Trp- optionally α-N-methylated and optionally benzene-ring-substituted by halogen and/or

Ci ₃alkyl , D is -Lys- optionally α-N-methylated and optionally

Σ-N-C_{! 3}-alkylated, E is -Thr- or -Ala- each in (D) - or ( L) -form and each being optionally α-N-methylated ,

F is a group of formula -COO _! , -CH₂OR₂ , or

wherein R is hydrogen or C₁ alkyl,

R₂ is hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester, R₃ is hydrogen, C^alkyl, phenyl or C_{7 10}- phenylalkyl, R„ is hydrogen, C_halky1 or, when R₃ is hydrogen or methyl, also a group of formula -CH(R₅)-X, R₅ is hydrogen, -(CH₂)₂-OH, -(CH₂)₃ -OH,

-CH₂-OH, -CH(CH₃)-OH, isobutyl or benzyl X is a group of formula -COORi , -CH₂OR₂ or

wherein

R_: and R₂ have the meanings given above , R₆ is hydrogen or C_halky 1 and R₇ is hydrogen, C^alkyl , phenyl or C₇.₁₀phenylalkyl , the group -CH(R_S)-X having the D- or L- configuration, and Y_j and Y₂ are each hydrogen or together represent a direct bond, whereby the residues in the 1- and 6-position each independently have the L- or D-configuration. 34. A pharmaceutical composition according to any of Claims 1 to 4 , wherein the somatostatin analog is a compound of formula A' CK₂-S-Y_l Y₂-S-CH₂

N-C IH-CO-B-C-D-E-NH-CIH-G A wherein A is C_x.₁₂alkyl, C_{7 10}phenylalkyl or a group of formula

RCO- , whereby i) R is hydrogen, C₁._ualkyl, phenyl or C₇.₁₀phenylalkyl or ii) RCO- is a) an L- or D-phenylalanine residue optionally ring-substituted by F, Cl, Br, No₂, NH₂,

OH, C^alkyl and/or C^alkoxy; b) the residue of a natural or synthetic α-a-mino acid other than defined under a) above or of a corresponding D-amino acid, or c) a dipeptide residue in which the individual amino acid residues are the same or different and are selected from those defined under a) and/or b) above,

Cj.galkanoyl, A' is hydrogen,

Yi and Y₂ represent together a direct bond or each of Y_x and Y₂ is independently hydrogen or a radical of formulae (1) to (5) .

-CO -CO-NHR

)_n

(1) (2) (3) -CO-NH-

(4) (5)

wherein

R_a is methyl or ethyl

R_b is hydrogen, methyl or ethyl m is a whole number from 1 to 4 n is a whole number from 1 to 5

R_c is (C_1-6) alkyl

R_d represents the substituent attached to the α-carbon atom of a natural or synthetic α- amino acid (including hydrogen)

R_e is (Ci.s) alkyl

R_a' and R_b' are independently hydrogen, methyl or ethyl,

R_a and Rg are independently hydrogen, halogen,

(C₁ ) alkyl or (C_{1 3}) alkoxy,

P is 0 or 1, q is 0 or 1, and r is 0, 1 or 2,

B is -Phe- optionally ring-substituted by halogen, N0₂, NH₂, OH,

(including pentafluoroalanine)-, or β-naphthyl-Ala

C is (L)-Trp- or (d)-Trp- optionally α-N-methylated and optionally benzene-ring-substituted by halogen, N0₂, NH₂ OH, C₁₃alkyl and/or C^-, alkoxy,

D is Lys, Lys in which the side chain contains O or S in β-position, F-Lys or SF-Lys, optionally α- N-methylated, or a 4-aminocyclohexylAla or 4- aminocyclohexylGly residue

E is The, Ser, Val, Phe, lie or an aminoisobutyric or aminobutyric acid residue

G is a group of formula

wherein

R₇ is hydrogen or C_{γ 3}alkyl,

R₁₀ is hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester, R_u is hydrogen, C_{x 9}alkyl, phenyl or C_{7 10}phenyl-alkyl, R₁₂ is hydrogen, C_{x 3}alkyl or a group of formula

-CH(R₁₃)-X₁, R₁₃ is CH₂OH, - (CH₂)₂-OH, -(CH₂)₃-OH, or -CH(CH₃)OH or represents the substituent attached to the α- carbon atom of a natural or synthetic α-amino acid (including hydrogen) and Xi is a group of formula -COOR₇ , -CH₂OR₁₀ or

wherein

R₇ and R₁₀ have the meanings given above,

R₁₄ is hydrogen or C_{λ 3}alkyl and

R₁₅ is hydrogen, Cj ₃alkyl, phenyl or

C₇.₁₀phenylalkyl, and R₁₆ is hydrogen or hydroxy, with the proviso that when R₁₂ is -CH(R₁₃)-Xi then R_n is hydrogen or methyl, wherein the residues B, D and E have the L-confi- guration, and the residues in the 2-and 7-position and any residues _: 4) and Y₂ 4) each independently have the (L)- or (D)- configuration. 35. A pharmaceutical composition according to any of Claims 1 to

4, wherein the analog is a somatostatin analog selected from the compounds of the following formulae 36

wherein

W is S or (CH₂)_S where s is 0, l or 2; one of X and Z is S and the other is S or CH₂;

Y is S or (CH₂)_C where t is 0, 1 or 2 ; each of R_t and R₂ independently of the other, is C_{x 5} alkyl, benzyl, benzyl having one or two C_{x 5} alkyl, halogen, hydroxy, amino, nitro, and/or C_l ._s alkoxy substituents, or Cj.₅ alkyl substituted with 5- or 6- embered heterocyclic ring;

R₃ is 3-indolymethyl , either unsubstituted or having C_λ .₅ alkyl, C_{x 5} alkoxy or halogen substitution;

R₄ C_{j 5} alkyl, C^ hydroxyalkyl, benzyl, carboxy- (C_{x 5} alkyl) , amino (C_{x s} alkyl) or benzyl having a C_{x 5} alkyl, halogen, hydroxy, amino, nitro and/or C_{x 5} alkoxy substituent;

R₅ is Cj.₅ alkyl, benzyl, or benzyl having a

Cj ₅ alkyl, halogen, hydroxy, amino, nitro, and/or C ₅ alkoxy substituent, compounds of formula

wherein

A is C_{x 12} alkyl, C₇.₁₀ phenylalkyl or a group of formula RCO-, whereby i) R is hydrogen , C₁._ll alkyl , phenyl or C₇.₁₀ phenylalkyl , or ii) RCO-is a) an L- or D-phenylalanine residue optionally ring- substituted by F, Cl, Br, N0₂, NH₂, OH, C₁ alkyl and/or C₁ alkoxy b) the residue of a natural α-amino acid other than defined under a) above or of a corresponding D-amino acid, or c) a dipeptide residue in which the individual amino acid residues are the same or different and are selected from those defined under a) and/or b) above, the α-amino group or amino acid residues a) and b) and the N-terminal amino group of dipeptide residues c) being optionally mono- or di-C_{1 12} alkylated,

A ' is hydrogen or , when A is C_x. _l2 alkyl or C_{7 1Q} phenylalk- also C_x .₁₂ alkyl or C₇.₁₀ phenylalkyl , Y_x and Y₂ represent together a direct bond or each of Y_x and Y₂ is independently hydrogen or a radical of the formulae

-CO- -CO-NHR

( 1 ) ( 2 ) . ( 3 )

(4) (5) wherein R_a is methyl or ethyl

R_b is hydrogen, methyl or ethyl is a whole number from 1 to 4 n is a whole number from 1 to 5

R_c is (C^_e) alkyl

R_d represents the substituent attached to the α-carbon atom of a natural α-amino acid (including hydrogen)

R_β is (C^) alkyl

R_a' and R_b' are independently hydrogen, methyl or ethyl,

R₈ and g are independently hydrogen, halogen, (C_{1 3}) alkyl or (C_j.₃) alkoxy, p is 0 or 1, q is 0 or l, and r is 0 , 1 or 2 , B is -Phe- optionally ring-substituted by halogen , No₂ , NH₂ , OH, C_halky1 and/or C_{x 3}alkoxy, or naphthylalanine.

C is (L) -Trp- or (D)-Trp- optionally α-N-methylated and optionally benzene-ring-substituted by halogen, No₂, NH₂, OH, C_{x 3} alkyl and/or C_ι.₃ alkoxy,

D is -Lys-, ThiaLys, F-Lys, £F-Lys or Orn, optionally α-N- methylated, or a 4-aminocyclohexyl Ala or 4-aminocyclo- hexyl Gly residue,

E is Thr, Ser, Val, Phe, lie or an aminoisobutyric acid residue

F is a group of formula -COOR₇ , - CH₂OR_1Q, or

wherein R₇ is hydrogen or C^alkyl,

R₁₀ is hydrogen or the residue of a physiologically acceptable,physiologically hydrolysable ester, R_π is hydrogen, C₁.₃alkyl, phenyl or C₇.₁₀-phenylalkyl, R₁₂ is hydrogen, C_halky1 or a group of formula-CH(R₁₃) -

R₁₃ is CH₂OH, -(CH₂)₂-OH, -(CH₂)₃-OH, or -CH(CH₃)OH or represents the substituent attached to the α-carbon atom of anatural α-amino acid (including hydrogen) and X_x is a group of formula -C00R₇ , -CH₂OR₁₀ or

wherein

R₇ and R₁₀ have the meanings given above,

R₁₄ is hydrogen or C₁₃alkyl and

R₁₅ is hydrogen, C^alkyl, phenyl or C₇.₁₀phenylalkyl, and

R₁₆ is hydrogen or hydroxy, with the proviso that when R₁₂ is -CH(R₁₃)-X_! then R is hydrogen or methyl, wherein the residues B, D and E have the L-configuration, and the residues in the 2- and 7-position and any residues Y_t 4) and Y₂ 4) each independently have the (L)- or (D)- configuration and compounds of the following formulae

H-Cys-Phe- (D) Trp-Lys-Thr-Phe-Cys-OH

-Asn-Phe-Phe- (D) Trp-Lys-Thr-Phe-Gaba-,

I !

NMe-Phe-His- (D) Trp-Lys-Val-Ala . I /

36. A pharmaceutical composition according to any of Claims 1 to 4, wherein the analogs are Somatostatin analogs i 1

X-Cys-D-o-Trp-E-F-Cys-Y I

X-Cys-Lys-Asn-Phe-D-o-Trp-E-F-Phe-Thr-Ser-Cys-Y II I, II, X = N-terminus anchor; Y = C-terminus anchor, G-I or its ale; wherein at least I of X, Y = cationic anchor; D = Phe Tyr, 3- (p-fluorophenyl) alanine or 3 (p-chlorophenyl) alanine residue; E = Lys, LysfR¹) ; R¹ = C_{1 8} (fluoro) alkyl; F = Thr, Val, Ser; G = D- or L-Thr, Phe, or 3-(2-naph- thyl) alanine residue; I = OH_T NH₂, NHRX 37. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analogs are peptides: RR^CHR^ONHCH(CH₂SR⁴) CO-Phe-Trp-Lys-X-NHCHR³CH₂SR⁵ [R - inorg. or org. acyl group, R¹ = H, alkyl, NCHR²CO moiety = I.

Me (CH₂) ₈CO-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol I or D-Phe (optionally ring substituted by halo , N0₂ , OH, alkyl . alkoxy) ; Phe, Trp , (D or L) ,may be ring substituted by N0₂ , NH₂ , OH , alkyl , alkoxy ; Lys may be α-N-methylated and Σ-N-alkylated ; X = D- or L-α-amino acid residue optionally α-N-methylated; R³ = C0₂H , CH₂OH , carba oyl , R⁴ = R⁵ = H, R⁴R⁵ = bond ]

38. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is:

H-Ser-Ala-Asn-Ser-Asn-Pro-Ala-X-Ala-Pro-Arg-Glu-Arg-Lys-Ala- Gly

Cys-X¹-x²-Phe-Phe-D-Trp-Lys-Tys-Thr-X³-X⁴-X⁵-X⁶-OH

39. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is:

H-Ser-Ala-Asn-Ser-Asn-Pro-Ala-Leu-Ala-Pro-Arg-Glu-Arg-Lys- Ala-Gly-

I — 1

Cys-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Tyr-Thr-Ser-Cys-OH

40. A pharmaceutical composition according to any of Claims 1 to 4 , wherein the somatostatin analog is c (Spacer-Phe-D-Trp-Lys-Thr) Spacer may stand for: a) R,S-c5-Bn-o-AMPA b) R-α-Bn-NMe-o-AMPA c) Phe-Pro

41. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is:

H₂N-Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys- OH

42. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is:

H₂N-Ser-Ala-Asn-Ser-Asn-Pro-Ala-Met-Ala-Pro-Arg-Glu-Arg-Lys- Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys-OH

43. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatim analog is: D-^β-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂

44. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is: Ac-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂

45. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is: D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Trp-NH₂

46. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is: D-Trp-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH₂

47. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is: D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂

48. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is: D-Phe-Cys-Tyr-D-Trp-Lys-Val-cys-Trp-NH₂

49. A pharmaceutical composition according to any of Claims l to 4 , wherein the somatostatin analog is :

3- (2-naphthyl) -D-Ala-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH₂

50. A pharmaceutical composition according to any of Claims 1 to 4, wherein the somatostatin analog is: c(Aha-Phe-p-Cl-Phe-D-Trp-Lys-Thr-Phe) Aha = 7 -amino heptanoic acid.

51. A pharmaceutical composition according to any of Claims 1 to 4, wherein the active ingredient is diazoxide and comprises in addition a thiazide selected among chlorothiazide, hydro- chlorothiazide, trichloromethiazide and polythiazide.

52. A method for the treatment of symptoms of syndrome X by applying to a patient a pharmaceutical composition according to any of Claims 1 to 51 comprising a pharmaceutically effective dosage of a compound selected among somatostatin or one of its analogs (as herein defined) , diazoxide or one of its analogs (as herein defined) , cyclothiazideor one of its analogs (as herein defined) and metformin.

53. A method according to Claim 52, wherein the pharmaceutically effective dosage (calculated on octreotide) does not exceed 50μ/kg/day.

54. A method according to Claim 53, wherein said dosage does not exceed 40μ/kg/day.

55. A method according to any of Claims 52 to 54 wherein the analog is octreotide which is applied in the form of an injection in a 0.9% saline solution.

56. A method according to Claim 52 , wherein said dosage does not exceed 8 g/kg/day in the treatment of the active ingredient (calculated on diazoxide) in adults, and does not exceed 15/mg/day in the treatment of children.

57. A method according to Claim 52, wherein the amount of metformin applied does not exceed 2.5 g/day divided into 2 - 3 portions.

58. Use of a compound selected among somatostatin or one of its analogs (as herein defined) , diazoxide or one of its analogs (as herein defined), cyclothiazide or one of its analogs (as herein defined) and metformin in a preparation for the treatment of the risk factors of syndrome X of Reaven substantially as described in the specification.