GB2224280A

GB2224280A - Modified somatostatin

Info

Publication number: GB2224280A
Application number: GB8907902A
Authority: GB
Inventors: Rainer Albert; Wilfried Bauer; Francois Cardinaux; Janos Pless
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 1988-04-11
Filing date: 1989-04-07
Publication date: 1990-05-02
Anticipated expiration: 2009-04-07
Also published as: SE8901278L; DK171489D0; FR2629824B1; CH677795A5; BE1003200A4; IL89897A0; IT8947833A0; AU3263989A; GB2224280B; IT1231943B; FR2629824A1; JPH01305098A; ES2013431A6; DE3910667A1; GB8907902D0; SE8901278D0; LU87496A1; DK171489A; NL8900882A

Abstract

Somatostatin peptides containing at least one residue of formula (a), (b) or (c> <IMAGE> wherein one of Y1 and Y2 is hydrogen and the other is hydroxy or both are hydrogen, each of f and g independently is 0 or 1, one of X1 and X2 is hydrogen and the other is hydrogen or an amino protecting group, and X3 is C2-4 alkylene, the free bond in each residue (a), (b) or (c) being located at the N-terminal group of the peptide, and the physiologically-acceptable others and physiologically-hydrolysable and - acceptable esters thereof when the peptide contains at least one residue of formula (a) or (b), in free form, salt form or complex form have pharmacological activity, in particular GH-, gastric and pancreatic secretion inhibiting activity.

Description

PEPTIDE DERIVATIVES The present invention relates to somatostatin peptides, processes for their production, pharmaceutical preparations containing them and their use as medicaments.

More particularly the present invention provides a somatostatin peptide comprising at least one residue of formula (a), (b) or (c)

wherein one of Y1 and Y2 is hydrogen and the other is hydroxy or both are hydrogen, each of f and g independently is O or 1, one of X1 and X2 is hydrogen and the other is hydrogen or-an amino protecting group, and X3 is C26alkylene, the free bond in each residue (a), (b) or (c) being located at the N-terminal group of the peptide, and the physiologically-acceptable ethers and physiologicallyhydrolysable and -acceptable esters thereof when the pep tide contains at least one residue of formula (a) or (b), in free form or acid addition salt form or complex form.

The term 11somatostatin peptides" includes its analogues or derivatives thereof. By derivatives and analogues is understood straight-chain, bridged or cyclic polypeptides wherein one or more amino acid units have been omitted and/or replaced by one or more other amino radical(s) and/or wherein one or more functional groups have been replaced by one or more other functional groups and/or one or more groups have been replaced by one or several other isosteric groups. In general, the term covers all modified derivatives of a biologically active peptide which exhibit a qualitatively similar effect to that of the unmodified somatostatin pep tide. Preferred somatostatin peptides are those containing e.g. of from 4 to 9 amino-acids.Such compounds are disclosed e.g. in EP Specifications EP-A3-1295, EP-A2-203 031, 214 872, 215 171, 277 419 and 298 732, the contents of which including the examples thereof are incorporated herein by reference.

Hereinafter these compounds are referred to as compounds of the invention.

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

In the residue of formula (a), either g is preferably 0 or g and f are each 0.

In the residue of formula (b), f is preferably 0.

Any alkylene as X3 in the residue of formula (c) may be linear or branched. X3 iS preferably C2,lalkylene, more particularly linear C2,4alkylene, Examples of amino protecting groups as X1 or X2 may be any such groups as used e.g. in peptide chemistry, and include for example benzyl, acyl groups such as formyl, acetyl, benzoyl, p-toluenesulphonyl or benzenesulphonyl, benzyloxycarbonyl, substituted benzyloxycarbonyl groups, e.g. substituted in the aromatic radical by halogen, nitro and/or lower alkyl or alkoxy, cycloaliphatic oxycarbonyl groups and aliphatic oxycarbonyl groups such as tert.-butoxycarbonyl or 9-fluorenylmethoxycarbonyl.

Preferably X1 and X2 are each hydrogen.

Residue of formula (a) is most preferred.

By the term "physiologically-acceptable ethers as applied to compounds of the invention containing at least one residue of formula (a) or (b), is meant ethers in which the hydroxy group(s) in residue (a) or (b) is(are) etherified and which are not toxic at desired dosage levels.Such ethers include linear, branched or cyclic ethers, e.g. C14alkyl ethers, for example ethers in which one or all hydroxy present are substituted by methyl, and cyclic ethers in which 2 vicinal hydroxy groups are substituted by

By the term "physiologically-hydrolysable and -acceptable esters" as applied to compounds of the invention containing at least one residue of formula (a) or (b), is meant esters in which one, two or all hydroxy groups in residue (a) or (b) are esterified and which are hydrolysable under physiological conditions to yield an acid which is itself physiologically acceptable, e.g. non-toxic, at desired dosage levels. Such esters include e.g. esters with aliphatic carboxylic acids having 2 to 8 carbon atoms.

In the compounds of the invention any one of the free hydroxy groups in the residue of formula (a) or (b) may also be bound in glycosydic manner to a reducing mono-, di- or oligosaccaride or amino sugar.

Depending on the substitution pattern, the residue of formula (a) or of formula (b) may contain one or two asymetric carbon atoms and thus the compounds of the invention may exist in racemic or isomeric form or as diastereoisomers (without taking into account the stereochemistry of the peptide chain). Racemic and diastereoisomeric mixtures may be separated into individual isomers in conventional manner. Alternatively optically active starting materials may be employed. The invention covers all forms.

The compounds of the invention may exist in free form or in salt form or in the form of complexes thereof. Acid addition salts may be formed with e.g. organic acids, including polymeric acids and inorganic acids. Such acid addition salt forms include e.g. the hydrochlorides and acetates. By complexes are to be understood compounds of known type, formed from compounds of the invention on addition of inorganic substances, e.g. inorganic salts or hydroxides such as Ca- and Zn-salts, and/or on addition of polymeric organic substances.

One group of compounds in accordance with the invention is that containing at least one residue of formula (a) or (b). Preferred compounds of the invention are compounds of formula I

wherein R1 is a residue of formula (a), (b) or (c) as defined above, R2 is hydrogen, alkyl with 1 to 12 C-atoms, alkanoyl with 1 to 4 C-atoms, C10phenalkyl or a residue of formula (a), (b) or (c) as defined above > N-CH(Z1)-CO is a) a (L)- or (D)-phenylalanine residue which is optionally substituted by halogen, NO2, NH2, OH, alkyl with 1 to 3 C-atoms and/or alkoxy with 1 to 3 C-atoms, or b) the residue of a natural a-amino acid or of a corresponding (D)-amino acid, other than that given under a), or of a synthetic a-amino acid, wherein Z1 in > N-CH(Z1)-CO- represents the residue of an amino acid residue as defined under a) and b), A' is hydrogen or alkyl with 1 to 3 C-atoms, Y1' and Y2t represent together a direct bond or each of Y1' and Y2' is independently hydrogen or a radical of formulae (1) to (5)

wherein R. is methyl or ethyl Rb is hydrogen, methyl or ethyl m is a whole number from 1 to 4 n is a whole number from 1 to 5 Rc is (C16)alkyl Rd represents the substituent attached to the a-carbon atom of a natural a-amino acid (including hydrogen) R. is (C1,s)alkyl Ra' and Rb' are independently hydrogen, methyl or ethyl, R8 and R9 are independently hydrogen, halogen, (C1-3)alkyl or (C1-3)alkoxy, p is O or 1, q is O or 1, and r is 0, 1 or 2, B is -Phe- optionally ring-substituted by halogen, NO2, NH2, OH, Cl~3alkyl and /or C1-3alkoxy, or naphthylalanine, C is (L)-Trp- or -(D)Trp- optionally a-N-methylated and optionally benzene-ring-substituted by halogen, NO2, NH2, OH, C1,3alkyl and/or C13 alkoxy, D is -Lys-, Lys in which the side chain contains 0 or S in ss position, yF-Lys, SF-Lys or Orn, optionally a-N-methylated, or a 4-aminocyclohexylAla or 4-aminocyclohexylGly residue E is Thr, Ser, Val, Phe, Tyr, Ile, an aminoisobutyric or aminobutyric acid residue F is a group of formula

wherein R7 is hydrogen or C13alkyl, R10 is hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester, R11 is hydrogen, C1~3alkyl, phenyl or C710phenyl-alkyl, R12 is hydrogen, C1-3alkyl or a group of formula -CH(R13)-X4, R13 is CH20H, -(CH2)2-OH, -(CH2)3-OH, or -CH(CH3)0H or represents the substituent attached to the a-carbon atom of a natural or synthetic a-amino acid (in cluding hydrogen) and X4 is a group of formula

wherein R7 and R10 have the meanings given above, R14 is hydrogen or C13alkyl and R15 is hydrogen, C13alkyl, phenyl or C7-lophenylalkyl, and R16 is hydrogen or hydroxy, with the proviso that when R12 is -CH(R13)-X4 then R11 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 Y1 4) and Y2 4) each independently have the (L)- or (D)- configuration, and the physiologically-acceptable ethers and physiologicallyhydrolysable and -acceptable esters thereof when the compounds of formula I contain at least one residue of formula (a) or (b).

Throughout the present specification and claims by "halogen" is meant preferably fluorine, chlorine and bromine. In accordance with conventional practice, amino acid residues referred to by abbreviation, e.g. -Phe-, -Cys- etc., are to be understood as having the (L)-configuration unless otherwise indicated. The term natural amino acid refers to amino acids derived from natural sources or produced otherwise e.g. by synthesis or cell culture.

A' is preferably hydrogen or methyl, especially hydrogen.

When > N-CH(Z1)-CO- has the meaning a), it is preferably an (L) or (D)-phenylalanine, pentafluorophenyl alanine or (L)- or (D)-tyrosine residue (wherein Z1 is benzyl or p-OH-benzyl), most preferably a (D)-phenylalanine residue.

When > N-CH(Z1)-CO- has the meaning b), the defined residue is preferably lipophilic. Preferred residues b) are residues in which Z1 is alkyl having 3, preferably 4 or more carbon atoms, or is a radical -CH2-A2 wherein A2 is naphthyl, pyridyl or 3-indolyl.

Most preferably > -N-CH(Z1)-CO- has the meaning a).

Preferably Y'1 and Y'2 together represent a direct bond or each of Y'1 and Y'2 is independently hydrogen or a radical of formula (1) or (3). More preferably Y'1 and Y'2 together represent a direct bond.

Examples of B as -Phe- ring-substituted by halogen may also include pentafluoroalanine.

In the compounds of formula I, the following significances are furthermore preferred either individually or in any combination or sub-combination: B is Phe or Tyr; C is -(D) Trp or 5-halo-(D)Trp, particularly D-Trp; D is Lys or 4-aminocyclohexylalanine; E is Thr, Ser or Val, particularly Thr or Val;

especially

wherein R11 is hydrogen;R12 is as defined above, R13 is CH20H, CH(CH3)0H, CH2CH2OH, (CH2)30H or as the substituent attached to the a-carbon atom of an a-amino-acid is i-propyl, i-butyl, a residue derived from Trp, 5-fluoro-Trp, ss-Nal, Ala, MeAla or Gly, preferably CH2OH or CH(CH3)OH, especially CH(CH3)0H; X4 is

especially CH2OR10 Rlo is hydrogen R10 as an ester residue is preferably formyl, C2-12alkylcar bonyl, C~ 12 phenylalkylcarbonyl or benzoyl; the group -CH(R13)-X4 has preferably the L-configuration.

Preferably the residues in the 2- and 7-positions have the L-configuration.

Individual compounds of formula I are for example:

More preferred compounds of the invention are the compounds of formula I in which R1 and/or R2 are a residue of formula (a).

Especially preferred compounds of the invention are those which have two residues of formula (a) and/or (b) on the N-terminal amino group, e.g. compounds of formula II

wherein Z1, A', Y1', B, C, D, E, F and Y2' are as defined above, and each of R17 and Rie is a residue of formula (a) or (b), preferably a residue of formula (a), more preferably identical, and their physiologically ethers and physiologically-hydrolysable and -acceptable esters.

The present invention in another aspect provides a process for the production of the compounds of the invention, comprising a. removing at least one protecting group from a protected peptide containing at least one residue of formula (a), (b) or (c) as defined above; or b. reductively aminating either a compound of formula III

wherein either f is as defined above, g is O or 1, Y1 and Y2 have one of the significances given above and Z2 is -CHO, or g is 1, Z2 is CH2OH and -CY1Y2-form together carbonyl, and the free hydroxy groups thereof may be etherified or esterified or a compound of formula IV X'1-NH-X'3-CHO (IV) wherein X'l is an amino protecting group, and X'3 is C1~5alkylene, with a compound of formula V P-NH2 (V) wherein P is a somatostatin peptide residue in protected form, e.g. a compound of formula V'

wherein Z1, Y'1, Y'2, A', B, C, D, E and F are as defined above, the free amino groups present in

being in protected form, and, if necessary, carrying out process step a); c. coupling together by an amide bond two peptide fragments, each of which contains at least one amino-acid or a deri vative thereof in protected or unprotected form, and at least one peptide fragment contains at least one residue of formula (a), (b) or (c) as defined above, the peptide frag ments being such that a protected or unprotected polypeptide sequence is obtained and, if necessary, carrying out process step a); or d. removing or converting a functional group of an unprotected or a protected polypeptide into another functional group so that an unprotected or a protected polypeptide is obtained, and in the latter case stage a) of the process is effected; e. introducing at least one optionally protected residue into a protected or unprotected peptide and if necessary carrying out process step a); f. separating optically active isomers from any mixture of such isomers obtained in accordance with steps (a) to (e); and recovering a compound thus obtained in free or salt form or in the form of a complex.

The above process may for example be carried out analogously to the processes described in the accompanying examples.

Process steps a), c), d) and e) may be carried out by methods known in the art of peptide chemistry.

Where desired, in these reactions, protecting groups which are suitable for use in pep tides may be used for functional groups which do not participate in the reaction. The term protecting group may also include a polymer resin having functional groups.

Process step b) may be effected in a conventional manner for the reductive amination of an aldose or ketose. It may be performed for example in the presence of NaBH3CN, preferably at an acidic pH, e.g. from pH 5 to 7. The temperature of the reaction may be e.g. from room temperature to 100 C. It may be advantageous to carry out the reaction in an inert solvent, e.g. water, an alcohol, dioxane or DMF or a mixture thereof.

The final compounds may be purified in accordance with known methods.

The non-modified polypeptides used as starting products for processes b) or c) may be produced in known manner in solution or by the solid phase process, e.g. as disclosed in US Patent 4,395,403 including the oxidising of straight-chain polypeptide to provide a mono-cyclic polypeptide. The peptide fragment containing at least one residue of formula (a), (b) or (c), used as starting material in step c) may be produced by analogy to process step b).

Insofar as the production of the starting materials is not particularly described, the compounds are known or may be produced and purified in accordance with methods known in the art.

In the following examples all temperatures are in C and [a]20- D values are uncorrected. The following abbreviations are employed.

BOC = tert.-butyloxycarbonyl DMF = dimethylformamide MeOH = methanol AcOH = acetic acid All peptides are obtained as a polyacetate polyhydrate except where otherwise stated with a peptide content of from 70 to 90 %.

The polypeptides contain less than 5 X of other pep tides by HPLCanalysis.

"F" as used herein after refers to the proportion of polypeptides (= peptide content) in the preparations obtained (F = 1 corresponds to 100 per cent), the difference to 100 Z corresponds to acetic acid and water.

EXAMPLE 1

3 ml of trifluoroacetic acid (100 %) are added to 300 mg of

Thr-ol and kept at room temperature until all the starting material has dissolved (5 minutes). After adding 20 ml of diisopropylether, the title compound is precipitated and subsequently filtered off and washed with diisopropylether. The title compound is purified by chromatography on silica gel (eluant: CHCl3/MeOH/AcOH/H20 7/3/0.5/0.5) and is isolated as a white lyophilisate.

[a]20 = - 24.50 (c = 1 in AcOH 95 ), F = 0.83.

D The starting material may be produced as follows:

2.25 g of di-tert.butyl-pyrocarbonate, dissolved in 30 ml of DMF, are slowly added in drops at room temperature to a solution of 10 g of

acetate in 100 ml of DMF. After two hours at room temperature, the solvent is drawn off under vacuum, and 200 ml of diisopropylether are added to the residue. The deposit which is being formed is filtered off, washed with diisopropylether and dried. The crude product is purified by chromatography over silica gel (eluant: CH2Cl2/MeOH 9/1) and is then isolated as a white amorphous powder.

[a]20 = 29.8 0 (c = 1.28 in DMF).

D

Procedure A 0.5 g of the end product of stage a) in 30 ml dioxane/H20 3 : 7 are treated with 50 mg Na BH3CN and 130 mg glyceral dehyde are added. The pH of the mixture is adjusted to 7 with 0.1 ml HCl and the mixture heated to 100 C for 6 hours. The mixture is cooled, freezed and lyophilized. The residue is taken up in ethyl acetate (50 ml) and shaken with water. The organic phase is dried and evaporated in a vacuum to give the title compound in amorphous form.

[a]20 = 23.2 (c = 1.2 in DMF) D Procedure B Instead of a mixture of water/dioxane, a mixture of methanol/water (2/1, v/v) can be used and the reaction mixture will be adjusted to pH 5 with a phosphate buffer.

After a reaction time of 4 to 6 hours at 50 C the title compound can be isolated as an amorphous powder after addition of water, filtration and drying over P40lo.

EXAMPLE 2

The procedure of Example 1 is repeated but using 130 mg (D)-glyceraldehyde.

[a]20 = - 25.1 0 (c = 1 in 95 % AcOH), F = 0.86.

D EXAMPLE 3

The procedure of Example 1 is repeated but using 130 mg (L)-glyceraldehyde.

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

D EXAMPLE 4 The procedure of Example 1 is repeated but replacing the glyceraldehyde by an equivalent amount of glycolaldehyde. The following compounds are obtained:

[a]20 = - 28.80 (c = 1 in 95 AcOH), F = 0.90. D

[a]20 = - 21.9 0 (c = 1 in 95 % AcOH), F = 0.83.

D EXAMPLE 5 In repeating the procedure of Example 1 but using 2-methoxyacetaldehyde, the following compounds are obtained:

[a]20 = - 8.5 (c = 0.25 in 95 X AcOH), F = 0.76.

D and

[a]20 = - 5 (c = 0.5 in 95 AcOH) F = 0.79.

D In the following compounds, SMS denotes the polypeptide radical

EXAMPLE 6 2,3-Di-propionyloxy-(2S)-propyl-SMS The procedure of Example 1 is repeated but using 2,3-di-0propionyl-D-glyceraldehyde: [a]20 = - 21.7 0 (c = 0.9 in 95 % AcOH), F = 0.88.

D EXAMPLE 7 2,3-Di-hexanoyloxy-(2S)-propyl-SMS The procedure of Example 1 is repeated but using 2,3-di-0hexanoyl-D-glyceraldehyde: [a]20 = - 18.80 (c = 0.25 in 95 X AcOH), F = 0.79.

D EXAMPLE 8 2,3-Di-O-isopropyliden-2,3-dihydroxy-(2S)-propyl-SMS The procedure of Example 1 is repeated but using 2,3-di-0-isopropyliden-D-glyceraldehyde: [a]20 = - 380 (c = 0.25 in 95 AcOH), F = 0.76.

D EXAMPLE 9 2,3,4-Tri-hydroxy-(2S,3R)-butyl-SHS The procedure of Example 1 is repeated but using D(-)-erythrose: [a]20 = - 29.2 0 (c = 0.25 in 95 X AcOH), F = 0.81.

D EXAMPLE 10 2-Aminoethyl-SHS The procedure of Example 1 is repeated but using N-Boc-2-aminoacetaldehyde: [a]20 = - 32 0 (c = 0.13 in 95 % AcOH), F = 0.84.

D EXAMPLE 11 3-Aminopropyl-SnS The procedure of Example 1 is repeated but using N-Boc-3-aminopropionaldehyde: [a]20 = - 210 (c = 0.29 in 95 X AcOH), F = 0.76.

D The compounds of the invention in free form or in the form of pharmaceutically acceptable salts and complexes exhibit valuable pharmacological properties as indicated in animal tests and are, therefore, indicated for therapy.

In particular, the compounds of the invention show GH-release inhibiting activity as indicated e.g. by depression of serum GH-levels in the rat.

This test is carried out employing male rats. The test-substance is administered at varying, logarithmically staggered doses employing at least 5 rats per dose. 1 hour after s.c. administration of the test substance blood is taken. The determination of the blood serum GH-level is effected by radio-immuno-assay.

The compounds of the invention are active in this test when administered at a dosage in the range of from 0.02 to 100, e.g.

to 30, ug/kg s.c..

Furthermore, the GH-reducing activity of the compounds of the invention was also examined after oral application to male rats with oestradiol implants. This test is carried out as follows: A loop (length 50 mm 8 3 mm) of silastic with 50 mg of oestradiol is implanted under the dorsal skin of anaesthetized male OFA rats which have a weight of ca. 300 g. At various times (1 to 6 months later), these animals, in a fasted state, are used repeatedly for tests. The test substances are active in this test at doses from 10 to 5000 ug/kg, when GH level in the blood serum is determined by radio-immuno-assay 1 and 2 hours after oral administration.

The compounds of the invention are accordingly indicated for use in the treatment of disorders with an aetiology comprising or associated with excess GH-secretion, e.g. in the treatment of acromegaly as well as in the treatment of diabetes mellitus, especially complications thereof, e.g.angiophathy, proliferative retinopathy, dawn phenomenon and nephropathy.

The compounds of the invention, also inhibit gastric- and exocrine and endocrine pancreatic secretion and the release of various peptides of the gastrointestinal tract, as indicated in standard tests using e.g. rats with gastric or pancreatic fistulae, wherein the compounds are active orally at a dose from 0.01 to 10 mg/kg.

The compounds of the invention additionally are thus indicated for use in the treatment of gastro-intestinal disorders, for example in the treatment of peptic ulcers, enterocutaneous and pancreaticocutaneous fistula, irritable bowel syndrom, dumping syndrom, watery diarrhea syndrom, acute pancreatitis and gastrointestinal hormone secreting tumors (e.g. vipomas, glucagonomas, insulinomas, carcinoids and the like) as well as gastrointestinal bleeding.

The compounds of the invention are also effective in inhibiting the proliferation and/or keratinisation of epidermal cells and are thus indicated for use in the treatment of dermatological diseases involving morbid proliferation and/or keratinisation of epidermal cells, in particular in the treatment of psoriasis.

Furthermore the compounds of the invention are indicated for use in the treatment of degenerative senile dementia, also known as senile dementia of the Alzheimer type (SDAT).

The compounds of the invention are also effective in the treatment of varous kinds of tumors, particularly the somatostatin receptor positive tumors, as indicated in proliferation tests with various different cancer cell lines and in tumor growth experiments in nude mice with hormone dependent tumors (e.g.

gastric dependent colon cancer). Thus the compounds of the invention can be used in the treatment of, for example, cancers of the breast, the prostate, the colon, the pancreas and the brain.

For all the above uses an indicated daily dosage is in the range from about 2 ijg to about 20 mg, preferably about 0.01 to about 20 mg, e.g. about 10 to about 5000 ug s.c. and from about 300 to 20000 ug p.o. of the compound conveniently administered in divided doses up to 4 times a day in unit dosage form containing for example from about 0.5 ug to about 10 mg, e.g. from about 2 ug to 10 mg, of the compound or in sustained release form.

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

The compounds of the invention may be administered in free form or in pharmaceutically acceptable salt form or complexes. Such salts and complexes may be prepared in conventional manner and exhibit the same order of activity as the free compounds. The present invention also provides a pharmaceutical composition comprising a compound of the invention in free base form or in pharmaceutically acceptable salt form or complex form in association with a pharmaceutically acceptable diluent or carrier. Such compositions may be formulated in conventional manner. The compounds may be administered by any conventional route, for example parenterally e.g. in form of injectable solutions or suspensions, enterally, preferably orally, e.g. in the form of tablets or capsules or in a nasal or a suppository form.

In accordance with the foregoing the present invention further provides: a) a somatostatin peptide containing at least one residue of formula (a), (b) or (c), e.g. a compound of formula I or II, or a pharmaceutically acceptable salt or complex thereof for use as a pharmaceutical; b) a method of treating disorders with an aetiology comprising or associated with excess of GH-secretion, e.g. diabetes mellitus, prevention and treatment of nephropathy, angiopathy and proliferative retinopathy, acromegaly, of treating gastro-intestinal disorders, e.g. peptic ulcers, entero cutaneous and pancreaticocutaneous fistulae, irritable bowel syndrom, dumping syndrom, watery diarrhea syndrom, gastro intestinal bleeding, acute pancreatitis and gastro-intestinal hormone secreting tumours, of inhibiting proliferation and/or keratinisation of epidermal cells, of treating degenerative senile dementia as well as of treating tumors in a subject in need of such treatment, which method comprises administering to said subject an effective amount of a compound according to the invention, e.g. a compound of formula I or II, or a pharmaceutically acceptable salt or complex thereof.

Claims

1. A somatostatin peptide comprising at least one residue of formula (a), (b) or (c)

wherein one of Y1 and Y2 is hydrogen and the other is hydroxy or both are hydrogen, each of f and g independently is O or 1, one of X1 and X2 is hydrogen and the other is hydrogen or an amino protecting group, and X3 is C26alkylene, the free bond in each residue (a), (b) or (c) being located at the N-terminal group of the peptide, and the physiologically-acceptable ethers and physiologi cally-hydrolysable and -acceptable esters thereof when the peptide contains at least one residue of formula (a) or (b), in free form or acid addition salt form or complex form.

2. A somatostatin peptide comprising at least one residue of formula (a) or (b)

wherein one of Y1 and Y2 is hydrogen and the other is hydroxy or both are hydrogen, and each of f and g independently is O or 1, the free bond in each residue (a) or (b) being located at at the N-terminal group of the peptide, and the physiologically-acceptable ethers and physiologi cally-hydrolysable and -acceptable esters thereof when the peptide contains at least one residue of formula (a) or (b), in free form or acid addition salt form or complex form.

3. A somatostatin peptide according to claim 1 or 2, in which the N-terminal amino group is disubstituted by said residues.

4. A somatostatin peptide of formula I

wherein R1 is a residue of formula (a), (b) or (c) as defined in claim 1, R2 is hydrogen, alkyl with 1 to 12 C-atoms, alkanoyl with 1 to 4 C-atoms, C7-lophenalkyl or a residue of formula (a), (b) or (c) as defined in claim 1, > N-CH(Z1)-CO is a) a (L)- or (D)-phenylalanine residue which is optionally substituted by halogen, NO2, NH2, OH, alkyl with 1 to 3 C-atoms and/or alkoxy with 1 to 3 C-atoms, or b) the residue of a natural a-amino acid or of a corresponding (D)-amino acid, other than that given under a), or of a synthetic a-amino acid, wherein Z1 in > N-CH(Zi)-CO- represents the residue of an amino acid residue as defined under a) and b), A' is hydrogen or alkyl with 1 to 3 C-atoms, Y1' and Y2' represent together a direct bond or each of Y1' and Y2' is independently hydrogen or a radical of formulae (1) to (5)

wherein R. is methyl or ethyl Rb is hydrogen, methyl or ethyl m is a whole number from 1 to 4 n is a whole number from 1 to 5 Rc is (C1-6)alkyl Rd represents the substituent attached to the a-carbon atom of a natural a-amino acid (including hydrogen) R. is (C1-5)alkyl R' and Rb' are independently hydrogen, methyl or ethyl, Ra and Rg are independently hydrogen, halogen, (C13)alkyl or (C13)alkoxy, p is O or 1, q is O or 1, and r is 0, 1 or 2, B is -Phe- optionally ring-substituted by halogen, NO2, NH2, OH, C1-3alkyl and /or C13alkoxy, or naphthylalanine, C is (L)-Trp- or -(D)Trp- optionally a-N-methy lated and optionally benzene-ring-substituted by halogen, NO2, NH2, OH, C1-3alkyl and/or C13alkoxy, D is -Lys-, Lys in which the side chain contains O or S in ss position, yF-Lys, SF-Lys or Orn, optionally a-N-methylated, or a 4-aminocyclo hexylAla or 4-aminocyclohexylGly residue E is Thr, Ser, Val, Phe, Tyr, Ile, an aminoiso butyric or aminobutyric acid residue F is a group of formula

wherein R7 is hydrogen or C1.3alkyl, R10 is hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester, R11 is hydrogen, C1~3alkyl, phenyl or C7-10phenyl- alkyl, R12 is hydrogen, C1-3alkyl or a group of formula -CH(R13)-X4, R13 is CH20H, -(CH2)2-OH, -(CH2)3-OH, or -CH(CH3)0H or represents the substituent attached to the a-carbon atom of a natural or synthetic a-amino acid (including hydrogen) and x4 is a group of formula -COOR7, -CH20R1o or

wherein R7 and R10 have the meanings given above, R14 is hydrogen or C1-3alkyl and R15 is hydrogen, C1,3alkyl, phenyl or C7-10phenyl- alkyl, and R16 is hydrogen or hydroxy, with the proviso that when R12 is -CH(R13)-X4 then R11 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 Y1 4) and Y2 4) each independently have the (L)- or (D)- confi guration, and the physiologically-acceptable ethers and physiologi cally-hydrolysable and -acceptable esters thereof when the compounds of formula I contain at least one residue of formula (a) or (b).

5. A somatostatin peptide according to any one of the preceding claims wherein in the residue of formula (a), either g is O or g and f is 0.

6. A somatostatin peptide according to any one of claims 1 to 4 wherein in the residue of formula (b) f is 0.

7. A somatostatin peptide according to claim 1, 3 and 4, wherein in the residue of formula (c) X1 and X2 are each hydrogen.

8. A somatostatin peptide according to claim 4 of formula II

wherein Z1, A', Y1', B, C, D, E, F and Y2, are as defined in claim 4, and R17 and Ria are each a residue of formula (a) as defined in claim 1, and the physiologically ethers and physiologicallyhydrolysable and -acceptable esters thereof.

Thr-ol in free form, salt form or complex form.

free form, salt form or complex form.

Thr-ol in free form, salt form or complex form.

12. A somatostatin peptide selected from

e) 2,3-Di-propionyloxy-(2S)-propyl-SMS f) 2,3-Di-hexanoyloxy-(2S)-propyl-SMS g) 2, 3-Di-0-isopropyliden-2, 3-dihydroxy-(25)-propyl-SMS h) 2,3,4-Tri-hydroxy-(2S,3R)-butyl-SMS i) 2-Aminoethyl-SMS j) 3-Aminopropyl-SMS in free form, salt form or complex form.

13. A process for the production of a somatostatine pep tide according to claim 1, in free form or in salt form or complex form, which process comprises a. removing at least one protecting group from a protected peptide containing at least one residue of formula (a), (b) or (c) as defined above; or b. reductively aminating either a compound of formula III

wherein either g is O or 1, Y1 and Y2 have one of the significances given above and Z2 is -CHO, or g is 1, Z2 is CH20H and -CY1Y2-form together carbonyl, and the free hydroxy groups thereof may be etherified or esterified or a compound of formula IV X'1-NH-X'3-CHO (IV) wherein X'1 is an amino protecting group, and X'3 is CI,Salkylene, with a compound of formula V P-NH2 (V) wherein P is a somatostatin peptide residue in protected form, and, if necessary, carrying out process step a); c. coupling together by an amide bond two peptide frag ments, each of which contains at least one amino-acid or a derivative thereof in protected or unprotected form, and at least one peptide fragment contains at least one residue of formula (a), (b) or (c) as defined above, the peptide fragments being such that a protected or un protected polypeptide sequence is obtained and, if necessary, carrying out process step a); or d. removing or converting a functional group of an un protected or a protected polypeptide into another functional group so that an unprotected or a protected polypeptide is obtained, and in the latter case stage a) of the process is effected; e. introducing at least one optionally protected residue into a protected or unprotected peptide and if necessary carrying out process step a); f. separating optically active isomers from any mixture of such isomers obtained in accordance with steps (a) to (e); and recovering a compound thus obtained in free or salt form or in the form of a complex.

14. A compound according to any one of Claims 1 to 12 in free form or in pharmaceutically acceptable salt form or complex form for use as a pharmaceutical.

15. A compound according to any one of Claims 1 to 12 in free form or in pharmaceutically acceptable salt form or complex form for use in the treatment of disorders with an aetiology comprising or associated with excess growth hormone secretion.

16. A compound according to any one of Claims 1 to 12 in free form or in pharmaceutically acceptable salt form or complex form for use in the treatment of gastro-intestinal disorders.

17. A compound according to any one of Claims 1 to 12 in free form or in pharmaceutically acceptable salt form or complex form for use in the treatment of dermatological diseases involving morbid proliferation and/or keratinisation of epidermal cells.

18. A compound according to any one of Claims 1 to 12 in free form or in pharmaceutically acceptable salt form or complex form for use in the treatment of degenerative senile dementia.

19. A compound according to any one of Claims 1 to 12 in free form or in pharmaceutically acceptable salt form or complex form for use in the treatment of tumours.

20. A pharmaceutical composition comprising a compound of any one of Claims 1 to 12 in free form, or in pharmaceutically acceptable salt form or complex form in association with a pharmaceutically carrier or diluent.

21. A compound substantially as herein before described with reference to any of Examples 1 to 11.