LU87496A1 - NOVEL SOMATOSTATIN PEPTIDES, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS - Google Patents

Description

"

The present invention relates to new somatostatin peptides, their preparation and their use as medicaments.

The invention relates in particular to somatostatin peptides comprising at least one residue of formula (a), (b) or (c)

Yi Xi I \ H0H2C- (CH0H) £ - (C) „- CH2- H0H2C- (CH0H) £ -CH-CH20H> -X3- II / Y2 X2 (a) (b) (c) in which one symbols Yi and Y2 mean hydrogen and the other a hydroxy group or both symbols Yx and y2 mean hydrogen, f and g independently mean 0 or 1, one of the symbols Xi and X2 means hydrogen and the other signifies hydrogen or a protective group of the amino group and X3 signifies a C2-C6 alkylene group, the free valence in each residue (a), (b) or (c) being located on the amino group N -terminal of the peptide, and the physiologically acceptable ethers and the physiologically hydrolysable and physiologically acceptable esters of these compounds when the peptide contains at least one residue of formula (a) or (b), "in free form or in the form of a salt or a complex.

The term "somatostatin peptides" includes analogs and derivatives of somatostatin. By derivatives and analogues is meant linear, bridged or cyclic peptides in which one or more amino acid residues have been deleted and / or substituted by one or more other amino acid residues and / or in which one or more several functional groups have been replaced by one or more other functional groups and / or in which one or more groups have been replaced by one or more other isosteric groups.

In general, the term encompasses all modified derivatives of a biologically active peptide which exerts an effect qualitatively similar to that of the unmodified somatostatin peptide. Preferred somatostatin peptides are those containing for example 4 to 9 amino acids. Such compounds are described, for example, in European patent applications EP-A3-1295, EP-A2-203 031, 214 872, 215 171, 277 419 and 298 732, the content of which is incorporated into the present application by way of reference.

These compounds will be designated below the compounds of the invention.

The compounds of the invention also include those in which the N-terminal amino group is disubstituted by residues of formula (a) and / or (b) and / or (c), preferably of formula (a) and / or (b).

In the rest of formula (a), g preferably means 0 or else g and f each signify 0.

In the remainder of formula (b), f preferably means 0.

The alkylene groups represented by X3 in the remainder of formula (c) may be linear or branched.

X3 preferably signifies a C2-C4 alkylene group, more particularly a linear C2-C4 alkylene group.

"7 The protecting groups of the amino group represented by Xj. Or x2 can be any group usually used in peptide chemistry and include, for example, benzyl, acyl, such as formyl, acetyl, benzoyl, p-toluene -sulfonyl or benzenesulfonyl, substituted benzyloxycar-bonyl, benzyloxycarbonyl groups, for example substituted in the aromatic residue by halogen or ~. '3 by nitro and / or lower alkyl or lower alkoxy groups, R-oxycarbonyl groups in which R signifies an aliphatic or cyclic residue such as tert.-butoxycarbonyl or 9-fluorenylmethoxy-carbonyl groups.

Preferably, Xx and X2 each signify hydrogen.

The rest of formula (a) is particularly preferred.

The expression "physiologically acceptable ether" as applied to the compounds of the invention containing at least one residue of formula (a) or (b) means compounds in which the hydroxyl group (s) in the residue (a ) or (b) are etherified and are non-toxic at the doses administered. Such ethers include linear, branched or cyclic ethers, for example C 1 -C 4 alkyl ethers, for example ethers in which one or all of the hydroxy groups present are substituted by methyl groups, and cyclic ethers in which two hydroxy groups located on two adjacent carbon atoms are substituted for example by the remainder of formula / ^ -CHj

By the expression "physiologically hydro-lysable and physiologically acceptable ester" as applied to the compounds of the invention containing at least one '· residue of formula (a) or (b), is meant compounds in which •, two or all of the hydroxy groups in the remainder (a) or (b) are esterified and which are hydrolyzable under physiological conditions to give an acid which is itself physiologically acceptable, for example non-toxic, at the doses administered. Such esters include, for example, esters with aliphatic carboxylic acids containing from 2 to 8> 4 carbon atoms.

In the compounds of the invention, any of the free hydroxy groups in the remainder of formula (a) or (b) can also be linked by a glucosidic bond to a reducing mono-, di- or oligosaccharide or to an amino sugar.

Depending on the degree of substitution, the remainder of formula (a) or of formula (b) may contain one or two asymmetric carbon atoms and the compounds of the invention may therefore exist in the form of racemates or optical isomers or in the form mixtures of diastereoisomers (without taking into account the stereochemistry of the peptide chain). The racemates and mixtures of diastereoisomers can be separated into their individual isomers according to known methods. According to another alternative, optically active end products can be obtained by using optically active starting materials. The invention covers all forms.

The compounds of the invention can be in free form or in the form of salts or complexes.

Acid addition salts can be formed, for example, with organic acids, including polymeric acids, and mineral acids. Such acid addition salts include, for example, hydrochlorides and acetates. By complexes is meant compounds of known type, formed from the compounds of the invention by the addition of mineral substances, for example mineral salts or hydroxides such as the calcium and zinc salts, and / or addition organic substances; polymers.

A group of compounds according to the invention comprises the compounds containing at least one residue of formula (a) or (b).

The preferred compounds of the invention are those corresponding to formula I

*, '1 5

Zi A 'CH2-S-Yj' Y2'-S-CH2

III I

Rx —N — CH — CO — N CH — CO — B — C — D — E — NH — CH — F (I) r2 in which

R 1 signifies a residue of formula (a) f (b) or (c) as defined above, R 2 signifies hydrogen, a C 1 -C 2 alkyl group, C 1 -C 4 alkanoyl, C 7 -C 10 phenylalkyl or a residue of formula (a), (b) or (c) as defined above,> N-CH (Zi) -CO signifies a) a residue (L) - or (D) -phenylalanine optionally substituted in the ring by halogen or by groups NO2, NH2, OH, C1-C3 alkyl and / or C1-C3 alkoxy, or b) the remainder of a natural α-amino acid or of a (D) -amino - corresponding acid, other than that defined under a), or of a synthetic α-amino acid, Ζχ in the remainder> N-CH (Zi) -CO- represents the residue of the amino acid residue as defined under a) and b), A 'signifies hydrogen or a C1-C3 alkyl group,

Yx 'and Y2' together signify a direct bond, or

Yx 'and Y2' mean, independently of one another, hydrogen or a residue corresponding to one of the following formulas (1) to (5): * · 6

Ra ^ / CH2 -CO-C- (CH2) m-H -CO-CH -CO-NHRe

Rb \ (CH2) n (1) (2) (3) 'Ra ^ -CO-NH-CH-COOR, -CO- (NH) p- C - (CH2) r-ÎCjJ *

Rd Rb '/ q (4) (5) in which

Ra signifies a methyl or ethyl group Rb signifies hydrogen or a methyl or ethyl group m signifies an integer from 1 to 4 inclusive n signifies an integer from 1 to 5 inclusive

Rc signifies a C1-C6 alkyl group R <j represents the substituent attached to the carbon atom a of a natural α-amino acid (including hydrogen) R, signifies a C1-C5 alkyl group Ra 'and Rb' each signify, independently of one another, hydrogen or a methyl or ethyl group, r8 and Rg each signify, independently of each other, hydrogen, a halogen or a group C1-C3 alkyl or C1-C3 alkoxy 'p signifies 0 or 1, q signifies 0 or 1, and r signifies 0, 1 or 2, B signifies -Phe- optionally substituted in the ring by halogen or by groups NO2, NH2, OH, C1-C3 alkyl and / or C1-C3 alkoxy, or a naphthylalanine residue, "1 ^ 7 C signifies (L) -Trp- or - (D) Trp- optionally α -Ν-methylated and optionally substituted in the benzene ring by halogen or by groups NO2, nh2, OH, C1-C3 alkyl and / or C! -C3 alkoxy, D stands for -Lys-, Lys in which the side chain contains 0 or S in position 0, γΡ-Lys, SF-Lys or Orn, possibly α-Ν-methylated, or a 4-aminocyclohexyl-Ala or 4-aminocyclohexyl-Gly E residue means Thr, Ser, Val, Phe, Tyr, Ile, or an amino-isobutyric or aminobutyric acid residue F signifies a group of formula

Ri 6 Λ -C00R7, -CH2OR10, -GON 'or -CO-NL-X4 XRl2 in which R7 signifies hydrogen or a C1-C3 alkyl group Rio signifies hydrogen or the remainder of a physiologically hydrolysable ester and physiologically acceptable

Ru signifies hydrogen or a C1-C3 alkyl group, phenyl or phenyl-C7-Ci0alkyl Ri 2 signifies hydrogen, a C1-C3 alkyl group or a residue of formula -CH (R13) -x4 Ri 3 signifies -CH2OH, - (CH2) 2-OH, - (CH2) 3-OH, or -CH (CH3) OH or represents the substituent attached to: the carbon atom a of a natural or synthetic α-amino acid (including hydrogen) and X4 signifies a group of formula

Ri

-C00R7, -CH2ORio. -CO-N ^ 14 or \ R

K15 δ '% in which R7 and Rio have the meanings given above,

Ri4 signifies hydrogen or a C1-C3 alkyl group, and Ris signifies hydrogen or a C1-C3 alkyl group, phenyl or phenyl C1-C3 radical and Ri6 signifies hydrogen or a hydroxy group,

Ru must signify hydrogen or a methyl group when R12 represents a residue -CH (Ri3) -X4, and in formula I the residues B, D and E have the configuration L, and the residues in position 2 and 7 and the residues Yi 4) and Y2 4) each have, independently, the configuration (L) or (D), and the physiologically acceptable ethers and the physiologically hydrolysable and physiologically acceptable esters of these compounds when the compounds of formula I contain at least one residue of formula (a) or (b).

By halogen is meant in the present application preferably fluorine, chlorine or bromine. According to usual practice, the amino acid residues designated by an abbreviation, for example -Phe-, -Cys- etc ...., should be understood as having the configuration (L), unless otherwise indicated. The term natural amino acid refers to an amino acid originating from a natural source or produced in another way, for example by synthesis or cell culture. The term "synthetic amino acid" refers to an amino acid obtained by synthesis and which does not exist; not in nature.

A 'preferably means hydrogen or a methyl group, especially hydrogen.

When> N-CH (Zi) -C0- has the meaning given under (a), it preferably means a residue (L) - or (D) -phenylalanine, pentafluorophenylalanine or (L) - or (D) -tyrosine ( where z2 signifies a benzyl group or "T i 9 p-OH-benzyl), more preferably a residue (D) -phenyl-alanine.

When> N-CH (Zl) -CO- has the meaning given under b), the defined residue is preferably lipophilic. The preferred radicals b) are the radicals in which Ζχ denotes an alkyl group having 3, preferably 4 or more carbon atoms, or a residue -CH2-A2 in which A2 denotes a naphthyl, pyridyl or 3-indolyl group.

More preferably> N-CH (Ζχ) -C0- has the meaning given under a).

Preferably, Υχ 'and Y2' together represent a direct bond or else each symbol Yi 'and Y2' signifies, independently of one another, hydrogen or a residue of formula (1) or (3). More preferably, Υχ 'and Y2' together represent a direct bond.

When B signifies -Phe- substituted in the cycle by halogen, it may be a pentafluoroalanine residue.

In the compounds of formula I, the following meanings are preferred, taken individually or in combination: B means Phe or Tyr, C means (D) Trp or 5-halo- (D) Trp, in particular D-Trp, D means Lys or 4-aminocyclohexylalanine, E means Thr, Ser or Val, in particular Thr or Val, 'F means -CO-n especially-CO-Ir \ \ R12 CH (R13) X4 where Ru means hydrogen, Rx2 has the meaning given previously, R13 signifies CH2OH, CH (CH3) OH, CH2 CH2 OH, (CH2) 3 OH, isopropyl, isobutyl, or a residue derived from Trp, 5-fluoro-Trp, (3-Nal, Ala, MeAla or Gly , Preferably CH2OH or CH (CH3) OH, especially CH (CH3) OH, x4 means -CO-N "'or CH2or10, \ \ 5 especially CH2ORi0 Rio signifies hydrogen,

Rio as the ester residue preferably means a formyl group, C2-C12 alkylcarbonyl, C8-C12 phenylalkylcarbonyl or benzoyl, the group -CH (Ri3) -X4 preferably has the L configuration.

The remains in position 2 and 7 preferably have the L configuration.

The compounds of formula I are for example the following: R, (-1 a · ^ (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Cys-Thr-ol r2

Ri 1 1 b. ^ (D) Phe-Cys-Tyr- <D) Trp-Lys-Val-Cys-ThrNH2 R2

Ri! -, c. '^ (D) Phe-Cys-Tyr- (D) Trp-Lys-Val-Cys-TrpNH2 I ‘r2

RXv. I --— I

d · '^ (D) Trp-Cys-Phe- (D) Trp-Lys-Thr-Cys-ThrNH2 R2 11

Rl I --—-- 1 e. ^ (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Cys-ThrNH2 R2

Ri I 1 f. ^ 3- (2- (Naphthyl) - (D) Ala-Cys-Tyr- (D) Trp-Lys-Val-Cys-ThrNH2 R2

I I

g. ^ (D) Phe-Cys-Tyr- (D) Trp-Lys-Val-Cys-ß-Nal-NH2 R2

Riv ^ (1 hr. ^ 3- (2-naphthyl) -Ala-Cys-Tyr- (D) Trp-Lys-Val-Cys- ß-Nal-NH2 R2

Ri I ---- 1 i. D) Phe-Cys-ß-Nal- (D) Trp-Lys-Val-Cys-Thr-NH2 r2

The compounds of the invention which are particularly preferred are the compounds of formula I where Rt and / or r2 signify a residue of formula (a).

The especially preferred compounds of the invention are those which contain two residues of formula (a) and / or "(b) on the N-terminal amino group, for example the

compounds of formula II

Zi A 'CH2-S-Yi' Y2'-S-CH2

III I

Rx 7 — N — CH — CO — N CH — CO — B — C — D — E — NH — CH — F (II)

Rie - 1b 12 in which

Zi / A ', Y2', B, C, D, E, F and Y2 'are as defined above and the symbols R17 and Ri8 signify residues of formula (a) or (b), preferably residues of formula (a), more preferably identical, and their physiologically acceptable ethers and their physiologically hydrolysable and physiologically acceptable esters.

The invention also relates to a process for the preparation of the compounds of the invention, process according to which a) at least one protective group is eliminated in a protected peptide containing at least one residue of formula (a), (b) or (c) previously defined, or

b) subjecting to a reducing amination either a compound of formula III

Yi H0H2C- (CH0H) f- (C) g-Z2 (III) Ï2 in which f has the meaning given above, g means 0 or 1,

Yx and Y2 have one of the meanings given above and Z2 signifies -CHO, or else g signifies 1, s Z2 signifies CH2OH and -CYiY2 together form a group; carbonyl, the free hydroxy groups being able to be etherified or esterified,

either a compound of formula IV

X'x-NH-X'a-CHO (IV) in which Λ * 13

Xi 'signifies a protective group for the amino group, and

X3 'signifies a Cx-C5 alkylene group, with a compound of formula V

P - nh2 (V) in which P signifies the remainder of a somatostatin peptide in protected form, for example a compound of formula V 'Ζχ A'

I I

H2N — CH — CO — N CH — CO — B — C — D — E — NH — CH — F (V ')

I I

CH2-S-Yx 'y2'-s-ch2 in which Ζχ, Υχ', Y2 ', A', B, C, D, E and F are as defined above, the free amino groups present in the remainder of formula CH2-S-Yx 'Y2'-S-CH2

I I

—CH — CO — N-CH — CO — B — C — D — E — NH — CH — F

I I

Ζχ A 'being in protected form, and, if necessary, step a) of the process is implemented, c) two peptide fragments are paired by an amide bond, each of which contains at least one "amiao-acid or one of its derivatives, in protected or unprotected form, at least one of the peptide fragments containing at least one residue of formula (a), (b) or (c) as defined above and the peptide fragments being such that obtains a protected or unprotected polypeptide sequence, and, if necessary, step a) of the process is carried out, or d) a functional group is eliminated or transformed

V

14 protected or unprotected polypeptide into another functional group such that a protected or unprotected polypeptide is obtained and, ... when it is. protected, step a) of the process is carried out, e) at least one optionally protected residue is introduced into a protected or unprotected peptide and, if necessary, step a) of the process is implemented, f) the optically active isomers are separated from any mixture of such isomers obtained according to steps a) to e), and the compound thus obtained is recovered in free form or in the form of a salt or a complex.

The above method can be carried out for example in a manner analogous to the methods described below in the examples.

Steps a), c), d) and e) of the process can be carried out according to the methods known in peptide chemistry.

If desired, the protecting groups which are suitable for protecting the peptides can be used in these reactions to protect functional groups which do not participate in the reaction. The term protective group also includes a polymer resin having functional groups.

Step b) of the process can be carried out according to known methods for the reductive amination of an aldose or a ketose. The reaction can be carried out for example in the presence of NaBH3CN. The operation is preferably carried out at an acidic pH, for example a pH of between 5 and 7, and i at a temperature of, for example, between room temperature and 100 ° C. It may be advantageous to carry out the reaction in an inert solvent, for example water, an alcohol, dioxane or dimethylformamide, or mixtures thereof.

The products of the invention thus obtained can be purified and isolated according to known methods.

'i 15

The unmodified polypeptides, used as starting materials in steps b) and c) of the process, can be prepared according to known methods in solution or by a solid phase process, for example as described in US Pat. No. 4,395,403, including oxidation of the linear polypeptide to obtain a monocyclic polypeptide. The peptide fragment containing at least one residue of formula a), b), c), used as starting material in step c) of the process, can be prepared in a similar manner to step b) of the process.

The compounds used as starting materials are known or can be obtained according to known methods or in a similar manner to the methods described in the literature.

The following examples illustrate the present invention without in any way limiting its scope. All temperatures are given in degrees Celsius and the values [ot] 20D are not corrected. The following abbreviations have been used.

BOC = tert.-butyloxycarbonyl DMF = dimethylformamide

MeOH = methanol

AcOH - acetic acid.

All peptides are obtained in the form of polyacetate polyhydrate having a peptide content of 70 to 90%, unless otherwise indicated. The polypeptides contain less than 5% of other peptides (analysis by HPLC chromatography).

- The factor "F" used below indicates the content: of peptide in the product (F = 1 indicates a peptide content of 100%). The difference up to 100% [(1 - F) x 100] is made up of acetic acid and water.

Example 1 l-1 2,3-dihydroxypropyl- (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Cys-Thr-ol

'J

16 _A 300 mg 2,3 dihydroxy-1-propyl- (D) Phe-

Cys-Phe- (D) Trp-Lys (BOC) -Thr-C ^ s-Thr-ol, add 3 ml of trifluoroacetic acid (100%) and keep at room temperature until everything starting material is dissolved (5 minutes). After addition of 20 ml of diisopropyl ether, the title compound which has precipitated is filtered and washed with diisopropyl ether. The title compound thus obtained is purified by chromatography on silica gel (eluent: CHC13 / MeOH / AcOH / H2O 7/3 / 0.5 / 0.5) and is isolated in the form of white lyophilisate.

[a] D20 = - 24.5 ° (c = 1 in AcOH at 951), F = 0.83.

The starting material can be prepared as follows: 1 1 a) H-DPhe-Cys-Phe-DTrp-Lys (SOC) -Thr-Cys-Thr-ol To a solution of 10 g of H-DPhe-Cys-Phe -DTrp-Lys-Thr-Cys-Thr-ol in 10 ml of DMF, 2.25 g of di-tert.-butyl pyrocarbonate dissolved in 30 ml of DMF is added dropwise at room temperature. After 2 hours at room temperature, the solvent is removed under reduced pressure and 200 ml of diisopropyl ether are added to the residue. The precipitate which has formed is filtered, washed with diisopropyl ether and dried. The crude product is purified by chromatography on silica gel (eluent: CH2Cl2 / MeOH 9/1) and is then isolated in the form of a white amorphous powder. [a] 2oD “29.8 ° (c * 1.28 in DMF).

b) 2,3-dihydroxy-1-propyl- (P) Phe-Cys-Phe- (D) Trp-Lys (BOC) -Thr- —ï

Cys-Thr-ol Method A

To 0.5 g of the product of step a) in 30 ml of a ‘i * 17 3: 7 mixture of dioxane and water, 50 mg of NaBH3CN and 130 mg of glyceraldehyde are added. The pH of the reaction mixture is adjusted to 7 with 0.1 ml of HCl and the mixture is heated at 100 ° for 6 hours. The mixture is cooled, frozen and lyophilized. The residue is taken up in ethyl acetate (50 ml) and extracted with water. The organic phase is dried and evaporated in vacuo to give the title compound in amorphous form. [a] 20D = 23.2 ° (c 1.2 in DMF)

Method B

Instead of a mixture of water and dioxane, a mixture of methanol and water (2/1, volume / volume) can be used and the reaction mixture is adjusted to pH 5 with a phosphate buffer. After a reaction time of 4 to 6 hours at 50 °, the title compound can be isolated in the form of an amorphous powder after addition of water, filtration and drying over P40iO.

Example 2 I | 2,3-dihydroxy- (2S) -propyl- (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Cys-Thr-ol

The process of Example 1 is repeated, but 130 mg of (D) -glyceraldehyde is used.

[ot] 20D = - 25.1 ° (c = 1 in 95% AcOH), F = 0.86.

Example 3 i-1 2,3-dihydroxy- (2R) -propyl- (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Cy3-Thr-ol

The process of Example 1 is repeated, but 130 mg of (L) -glyceraldehyde is used.

[a] 20d ”- 18.4 ° (c * 1 in 95% AcOH), F = 0.90.

Example 4

The process of Example 1 is repeated but the glyceraldehyde is replaced by an equivalent amount of 18 t I.

glycolaldehyde. The following compounds are obtained:, -1 a) 2-hydroxyethyl- (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Qys-Thr-ol [al20 = - 28.8 0 (c = 1 in AcOH at $ 95) ÿF = 0.90.

D

I I

b) Bis- (2-hydroxyethyl) - (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Cys-Thr-ol [a] 20 = - 21.9 0 (c = 1 in AcOH ä 95%), F = 0.83.

D

Example 5

By proceeding as described in Example 1 but using 2-methoxy-acetaldehyde, the following compounds are obtained: „„ I --- 1 a) 2-Me thoxye thy1- (D) Phe-Cys-Phe- ( D) Trp-Lys-Thr-Cys-Thr-ol [aj20 = - 8.5 0 (c = 0.25 in AcQH at ^ 951)? F ~ 0.76.

and, i-1 b) Bl3- (2-nethoxyethyl) - (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Cyg-Thr-ol [a] 20 = - 5 0 (c = 0.5 in 95% AcOH), F = .0.79 D 1

In the following compounds, SMS means the peptide residue r i -DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol.

Example 6

2,3-di-propionyloxy- (2S) -propyl-SMS

The procedure is as described in Example 1, but using 19 2,3-di-O-propionyl-D-glyceraldehyde: [a] 20D - - 21.7 ° (c * 0.9 in 95% AcOH ), F = 0.88.

Example 7

2.3- di-hexanoyloxy- (2S) -propyl-SMS

The procedure is as described in Example 1, but 2,3-di-O-hexanoyl-D-glyceraldehyde is used: [a] 20D = -18.8 ° (c * 0.25 in 95% AcOH), F = 0.79.

Example 8

2.3- di-0-isopropylidene-2,3-dihydroxy- (2S) -propyl-SMS

The procedure is as described in Example 1, but 2,3-di-O-isopropylidene-D-glyceraldehyde is used: (al20D = -38 ° (c = 0.25 in 95% AcOH), F = 0, 76.

Example 9

2,3,4-tri-hydroxy- (2S, 3R) -butyl-SMS

The procedure is as described in Example 1, but the D (-) erythrosis is used: [a] 20D = -29.2 ° (c 0.25 in 95% AcOH), F = 0.81.

Example 10

2- aminoethyl-SMS

The procedure is as described in Example 1, but N-Boc-2-amino-acetaldehyde is used: [cx] 20d = -32 ° (c "0.13 in 95% AcOH), F = 0.84.

Example 11

3- aminopropyl-SMS

The procedure is as described in Example 1, but N-Boc-3-amino-propionaldehyde is used.

[a] 2 0 D - -21 ° (c »0.29 in 95% AcOH), F = 0.76.

In the tests carried out on laboratory animals, the compounds of the invention, in free form> or in the form of a pharmaceutically acceptable salt or complex, are distinguished by interesting pharmacological properties and can therefore be used in therapeutic as drugs.

In particular, they exert an inhibitory activity on the secretion of growth hormone (GH), as can be seen for example from the drop in plasma k 1 GH levels in rats.

The test is carried out with male rats. The test substance is administered in various doses increasing logarithmically, using at least 5 rats per dose. One hour after the subcutaneous administration of the test substance, blood is taken and the GH levels in the blood are determined using the radioimmunoassay method. In this test, the compounds of the invention are active after administration by the subcutaneous route at doses of between 0.02 and 100 μ / kg, for example at 30 μg / kg.

In addition, the inhibitory activity of the compounds of the invention on the secretion of GH was also examined after oral administration to male rats having estradiol implants. The test is carried out as follows:

A tube of silastic (length 50 mm, diameter 3 mm) at 50 mg of estradiol is implanted under ether anesthesia under the dorsal skin of a male rat of OFA strain weighing approximately 300 g. At various time intervals (1 to 6 months later), the fasted animals are used repeatedly for the tests. In this test, the compounds are active after oral administration at doses of between 10 and 5000 // g / kg (the level of GH in the serum is determined according to the radioimmunology assay method 1 hour and 2 hours after oral administration).

The compounds of the invention are therefore indicated * for therapeutic use in the treatment of disorders having an etiology comprising or associated with excessive secretion of GH, for example in the treatment of acromegaly as well as for the treatment of diabetes. sweet, especially from its vascular complications, for example angiopathy, proliferative retinopathy, dawn phenomenon and nephropathy.

The compounds of the invention also inhibit "* 21 gastric secretion and exocrine and endocrine pancreatic secretion and the release of various peptides from the gastrointestinal tract, as is apparent from conventional tests carried out on rats having a gastric or pancreatic fistula. In this test, the compounds are active after oral administration at a dose of between 0.1 and 10 mg / kg.

The compounds of the invention are therefore also indicated for use in therapy in the treatment of gastrointestinal disorders, for example for the treatment of ulcer, enterocutaneous and pancreaticocutaneous fistula, irritable bowel syndrome, syndrome dumping, watery diarrhea, acute pancreatitis and hormone-producing gastrointestinal tumors (eg, vipoma, glucagonoma, insulinoma, carcinoid tumors, etc.) as well as gastrointestinal bleeding.

The compounds of the invention also inhibit the proliferation and / or keratinization of epidermal cells and are therefore indicated for use in therapy in the treatment of dermatological diseases associated with proliferation and / or pathological keratinization of cells of the epidermis, especially in the treatment of psoriasis.

In addition, the compounds of the invention are indicated for therapeutic use in the treatment of degenerative senile dementia, also known as senile dementia of the Alzheimer type (DSTA).

The compounds of the invention are also effective in the treatment of various types of tumors, in particular of tumors containing somatostatin receptors, as emerges from the proliferation tests with different cancer cell lines and in the tests for tumor growth in nude mice with hormone-dependent tumors (eg, gastric hormone-dependent colon cancer). The compounds of the invention can therefore be used in therapy, for example for the treatment of breast, prostate, colon, pancreas and brain cancer.

For all the above indications, the appropriate daily dose is between about 2 yug and about 20 mg, preferably between about 0.01 and about 20 mg, for example about 10 to about 5000 // g subcutaneously and between approximately 300 and 20,000 // g orally, the compounds of the invention being advantageously administered in divided doses up to 4 times a day in the form of unit doses containing for example from approximately 0.5 μς to approximately 10 mg of active substance, for example about 2 µg to 10 mg, or in a sustained release form.

The compound of Examples 1, 4b and 10 are the preferred compounds.

The compounds of the invention can be administered in free form or in the form of a pharmaceutically acceptable salt or complex. Such salts or complexes can be prepared according to the usual methods and have the same activity as the free form. The invention also relates to the compounds of the invention for use as medicaments, especially for the treatment of disorders having an etiology comprising or associated with excessive secretion of growth hormone, for example diabetes mellitus, for prophylaxis and the treatment of nephropathy, angiopathy and proliferative rethinopathy, acromegaly, gastrointestinal disorders, for example ulcer, pancreatic fistula, irritable bowel syndrome, dumping syndrome , watery diarrhea syndrome, gastrointestinal bleeding, acute pancreatic and hormone-producing gastrointestinal tumors, for the treatment of dermatological diseases associated with pathological cell proliferation and / or keratinization epidermis, for the treatment of degenerative senile dementia and the treatment of various types of tumors.

As medicaments, the compounds of the invention can be administered in the form of a pharmaceutical composition containing, as active substance, a compound of the invention in free form or in the form of a pharmaceutically acceptable salt or complex , in combination with a pharmaceutically acceptable carrier or diluent. Such compositions, which also form part of the invention, can be prepared according to the usual methods. The compounds can be administered according to any of the usual routes, for example parenterally, for example in the form of solutions or injectable suspensions, enterally, preferably orally, for example in the form of tablets or capsules, or in a form suitable for nasal administration or in the form of suppositories.

Claims (9)

24, * * 1.- A somatostatin peptide comprising at least one residue of formula (a), (b) or (c) Ti * HOH2C- (CHOH) £ - (C) g-CH2- HOH2C- (CHOH) £ -CH -CH2OH ^ N-X3- Y2 χ2 (a) (b) (c) in which one of the symbols Υχ and Y2 signifies hydrogen and the other a hydroxy group or else the two symbols Υχ and Y2 signify the hydrogen, f and g independently signify 0 or 1, one of the symbols Χχ and X2 signifies hydrogen and the other signifies hydrogen or a protective group for the amino group and X3 signifies a C2-C6 alkylene group free valence in each residue (a), (b) or (c) being located on the N-terminal amino group of the peptide, and the physiologically acceptable ethers and the. physiologically hydrolyzable and physiologically acceptable esters of these compounds when the peptide contains at least one residue of formula (a) or (b), in free form or in the form of a salt or a complex. - .2.- A somatostatin peptide of formula I Ζχ A 'CH2-S-Yx' Y2'-S-CH2 III I Rx — N — CH — CO — N CH — CO — B — C — D — E —NH — CH — F (I) r2 25, λ t in which Ri signifies a residue of formula (a), (b) or (c) as defined in claim 1, R2 signifies hydrogen, an alkyl group Ci-Ci2, C1-C4 alkanoyl, C7-C10 phenylalkyl or a residue of formula (a), (b) or (c) as defined in claim 1,> N-CH (Zx) -CO means a) a residue (L) - or (D) -phenylalanine optionally substituted in the ring by halogen or by NO2 "NH2, OH, C1-C3 alkyl and / or C1-C3 alkoxy, or b ) the remainder of a natural α-amino acid or of a corresponding (D) -amino acid, other than that defined under a), or of a synthetic α-amino acid, Zi in the rest> N -CH (zx) -CO- represents the residue of the amino acid residue as defined under a) and b), A 'signifies hydrogen or a C1-C3 alkyl group, Yi' and y2 'signify together a direct bond, or else Yi 'and Y2' means independently, hydrogen or a residue corresponding to one of the following formulas (1) to (5): R. ^ / CH2 -C0-C- (CH2) bH -CO- CH -C0-NHRc IX • Rb x (CH2) n * (1) (2) (3) I »26 D Λ f Λ / nk ^ -CO-NH-CH-COOR. -C0- (NH) p- C - (CH Rd 'q (4) (5) in which Ra signifies a methyl or ethyl group Rb signifies hydrogen or a methyl or ethyl group m signifies an integer from 1 to 4 inclusive n signifies an integer from 1 to 5 inclusive Rc signifies a C 1 -C 6 alkyl group represents the substituent attached to the carbon atom a of a natural α-amino acid (including hydrogen) Re, means a C1-C5 alkyl group Ra 'and Rb' each mean, independently of one another, hydrogen or a methyl or ethyl group, r8 and Rg each signify, independently of one another, hydrogen, halogen or C1-C3 alkyl or C1-C3 alkoxy p signifies 0 or 1, q signifies 0 or 1, and r signifies 0, 1 or 2, B signifies -Phe- optionally substituted in the ring with halogen or with groups NO2, NH2, OH, 4 C1-C3 alkyl and / or Cx-C3 alkoxy, or a residue * naphthylalanine, J. 27 C signifies (L) -Trp- or - (D) Trp- optionally α-Ν-methylated and optionally t substituted in the benzene ring by halogen or by NO2, NH2, OH, C1-C3 alkyl and / or Oχ-03 alkoxy groups, D stands for -Lys-, Lys in which the side chain contains 0 or S in position β, γΡ-Lys, δΡ-Lys or Orn, optionally α-Ν-methylated, or a 4-aminocyclohexyl-Ala or 4-aminocyclohexyl-Gly E residue means Thr, Ser, Val, Phe, Tyr, Ile, or a residue of amino-isobutyric or aminobutyric acid F signifies a group of formula Ri 6 ✓Rn or * v -COOR ,, -CH20Ri0 t -C0N (-CO-N-l_X4> Rl2 in which R7 signifies hydrogen or a C1-C3 alkyl group Rio signifies hydrogen or the remainder of a physiologically hydrolyzable and physiologically acceptable ester Ri 1 signifies hydrogen or a C1-C3 alkyl group, phenyl or phenyl-C7-C10 sign Ri2 signifies the hydrogen, a C1-C3 alkyl group or a residue of formula -CH (Ri3) -X4 Ri 3 means -CH2OH, - (CH2) 2-OH, - (CH2) 3-OH, or? -CH {CH3) 0H or represents the substituent attached to the carbon atom a of a natural or synthetic α-amino acid (including hydrogen) and X4 signifies a group of formula -C00R7, -CH2ORi0 or / R14 -CO-N 'XRis i' · 28 ψ in which r7 and Rio have the meanings given above, Ri4 means hydrogen or a C1-C3 alkyl group, and Ri 5 means hydrogen or a Cx alkyl group -C3, phenyl or phenylalkyl in C7-Ci0 and Ri6 means hydrogen or a hydroxy group, Rii having to signify hydrogen or a methyl group when Ri2 represents a residue -CH (Ri3) -x4, and in formula I the residues B, D and E have the configuration L, and the residues in position 2 and 7 and the residues Yi 4) and Y2 4) each have, independently, the configuration (L) or (D), and the ethers physiologically acceptable and the physiologically hydrolysable and physiologically acceptable esters of these compounds when the compounds of formula I contain at least one residue of formula ( a) or (b). 3. A somatostatin peptide according to claim 2, and corresponding to formula II Zi A 'CHj-S-Yi' Y2'-S-CH2 I 1! I Ri 7 —N — CH — CO — N CH — CO — B — C — D — E — NH — CH — F (II) Rl 8 "in which Zi, A ', Yi', B, C, D, E, F and Y2 'are as defined in claim 2 and the symbols Ri 7 and Rx8 mean residues of formula (a) or (b) as defined in claim 1, and their physiologically acceptable ethers and their physiologically esters hydrolyzable and physiologically acceptable. r * 29 _4, - 2,3-dihydro- (2R) -propyl- (D) Phe- Cys-Phe- (D) Trp-Lys-Thr-C ^ s-Thr-ol, in free form or in as a salt or a complex. 5. The I- | 2-hydroxyethyl- (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Cys-Thr-ol in free form or in the form of a salt or a complex. 6. „i-1 Bis- (2-hydroxyethyl) - (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Cys-Thr-o1 in free form or in the form of a salt or d 'a complex. 7. A somatostatin peptide chosen from i - ia) 2,3-dihydroxypropyl- (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Cys-Thr-ol, - b) 2, 3-dihydroxy- (2S) -propy1- (D) Phe-Cys-Phe- (D) Trp-Lys-Thr- Cys-Thr-ol iic) 2-Methoxyethyl- (D) Phe-Cys-Phe- (D ) Trp-Lys-Thr-Cys-Thr-ol J-- | d) Bis- (2-methoxyethyl) - (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Cys-Thr-ol e) 2,3-Di-propionyloxy- (2S) -propyl-SMS f) 2,3-Di-hexanoyloxy- (2S) -propyl-SMS * 30 g) 2,3-Di-O-isopropylidene-2,3-dihydroxy- (2S) -propyl-SMS h) 2,3, 4-Tri-hydroxy- (2S, 3R) -butyl-SMS i) 2-Aminoethyl-SMS j) 3-Aminopropyl-SMS where SMS means -DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol , in free form or in the form of a salt or a complex. 8, - A process for the preparation of a somatostatin peptide as defined in claim 1, characterized in that a) at least one protective group is eliminated in a protected peptide containing at least one residue of formula (a), (b) or (c) defined in claim 1, or b) subjecting to a reductive amination is a compound of formula III Ti H0H2C- (CH0H) c- (C) g-Z2 (III) Y2 in which fa the meaning given in claim 1, g signifies 0 or 1, Yi and Y2 have one of the meanings given in claim 1, and Z2 signifies -CHO, or g signifies 1, Z2 signifies CH2OH and -CY1Y2 together form a group carbonyl, the free hydroxy groups being able to be etherified or esterified, or a compound of formula IV r, * 31 X'i-NH-X's-CHO (IV) in which Xx 'signifies a protective group for the amino group, and X3' signifies a C1-C5 alkylene group, with a compound of formula VP - NH2 (V) in which P signifies the remainder of a som peptide atostatin in protected form, and if necessary, step a) of the process is implemented, c) two peptide fragments, each of which contains at least one amino acid or one of its derivatives, are coupled by an amide bond, in protected or unprotected form, at least one of the peptide fragments containing at least one residue of formula (a), (b) or (c) as defined in claim 1 and the peptide fragments being such that one obtains a protected or unprotected polypeptide sequence, and, if necessary, step a) of the method is carried out, or d) a functional group of a protected or unprotected polypeptide is eliminated or transformed into another functional group of such that a protected or unprotected polypeptide is obtained and, when it is protected, step a) of the process is implemented, - e) at least one optionally protected residue r is introduced into a protected or unprotected peptide protected and, if necessary, step a) of the process is implemented, f) the optically active isomers from any mixture of such isomers obtained according to steps a) to e), and the compound thus obtained is recovered in free form or in the form of a salt or a complex. - ,. ·· * 32 9. A somatostatin peptide according to any one of claims 1 to 7, in free form or in the form of a pharmaceutically acceptable salt or complex, for use as a medicament. 10. A pharmaceutical composition, characterized in that it comprises a somatostatin peptide according to any one of claims 1 to 7, in free form or in the form of a pharmaceutically acceptable salt or complex, in combination with a pharmaceutically acceptable vehicle or diluent.