DE3910667A1 - PEPTIDE DERIVATIVES - Google Patents

Abstract

Somatostatin polypeptides containing at least one radical of the formula (a), (b) or (c) <IMAGE> in which Y1 is hydrogen, Y2 is hydrogen or hydroxyl, f and g are, independently of one another, 0 or 1, X1 is hydrogen, X2 is hydrogen or an amino protective group, and X3 is C2-6-alkylene, where the free valency in the radical (a), (b) or (c) is linked to the N-terminal amino group of the peptide, and the physiologically acceptable ethers and physiologically hydrolysable and acceptable esters thereof when the peptide contains at least one radical of the formula (a) or (b), in free form or in the form of an acid addition salt or complex. Compounds of this type have valuable pharmaceutical properties, in particular inhibiting GH, gastric and pancreatic secretion.

Description

The present invention relates to peptide derivatives, their preparation, their application as pharmaceuticals and pharmaceutical Preparations containing them.

The invention relates to somatostatin peptides that at least contain a radical of formula (a), (b) or (c)

wherein
Y₁ for hydrogen
Y₂ represents hydrogen or hydroxy,
f and g are independently 0 or 1
X₁ hydrogen
X₂ is hydrogen or an amino protecting group, and
X₃ is C _2-6 alkylene,
where the free valence in residue (a), (b) or (c) is bound to the N-terminal amino group of the peptide,
and the physiologically acceptable ethers and physiologically hydrolyzable and acceptable esters thereof if the peptide contains at least one radical of the formula (a) or (b),
in free form or in the form of an acid addition salt or complex.

The term somatostatin peptides also includes analogue and Derivatives of the natural somatostatine tetradecapeptide. Under Analogue and derivatives become straight chain or cyclic, from which understood natural somatostatin-derived polypeptides which lack one or more amino acid units and / or through one or more amino acid residues are replaced and / or one or more functional groups by one or more others functional groups are replaced and / or several groups by one or more other isosteric groups have been replaced. in the in general, all modified derivatives are biological active peptides, which has a qualitatively similar efficacy like the unmodified somatostatin peptide. Preferred somatostatin peptides are those, for example, from Contain 4 to 9 amino acids. Such connections and their manufacture are known and for example in the European Patent applications EP-A3-1295; EP-A2-215 171; 203 031; 214 872; 277,419 and 298,732.

These somatostatin peptides are used as Connections called.

The compounds of the invention also include compounds wherein the N-terminal amino group is represented by radicals of the formula (a) and / or (b) and / or (c) is disubstituted, preferably the Formula (a) and / or (b).

In the rest of the formula (a), g is preferably 0 or g and f is both 0.

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

In the rest (c), the alkylene as X₃ can be straight-chain or branched. X₃ is preferably C _2-4 alkylene, especially straight chain C _2-4 alkylene.

As examples of amino protecting groups for X₂ such can be mentioned are used as usual in peptide chemistry, e.g. B. Benzyl, acyl such as formyl, acetyl, benzoyl, p-toluenesulfonyl or benzenesulfonyl, benzyloxycarbonyl such as, for example substituted benzyloxycarbonyl, e.g. B. in aromatic Ring through halogen, nitro and / or lower alkyl or Alkoxy substituted, cycloaliphatic oxycarbonyl or aliphatic Oxycarbonyl such as tert-butoxycarbonyl or 9-fluorenylmethoxycarbonyl.

In the rest of formula (c) X₁ and X₂ are preferably Hydrogen.

The rest of formula (a) is very preferred.

The expression "physiologically acceptable ether" as used for the compounds according to the invention which contain at least one radical of the formula (a) or (b) is understood to mean ethers in which the hydroxyl groups of the radical (a) or (b) are etherified and the lead to no side effects at a desired dose level. Such include straight chain, branched or cyclic ethers such as C _1-4 alkyl ethers, e.g. B. Compounds in which the OH groups present in the rest (a) or (b) are methylated, or cyclic ethers in which 2 adjacent OH groups by z. B.

are substituted.  

Under the expression "physiologically hydrolyzable and acceptable Ester "as applied to the compounds of the invention, the contain at least one radical of formula (a) or (b) Understood esters, in which the hydroxyl groups of the radical (a) or (b) are esterified and hydrolyzable under physiological conditions are, whereby an acid is obtained, which none undesirable side effects at a desired dose level leads. These esters can e.g. B. by acylation of free Hydroxy groups in the residue (a) or (b) can be derived. Suitable Esters include e.g. B. esters with carboxylic acids, the 2 to Contain 8 carbon atoms.

The compounds according to the invention also include those in which any of the free hydroxy groups in the rest of formula (a) or (b) glycosilic to a reducing monosaccharide, disaccharide or oligosaccharide or an aminosugar.

Depending on the substitution, the radicals of the formula (a) or (b) contain one or two asymmetric carbon atoms and thus the compounds according to the invention can be correspondingly optical Show isomerism. It is understood that the present Invention both the individual isomeric forms and the Mixtures, e.g. B. racemic and diastereoisomeric compounds, includes.

The compounds according to the invention can be in free form or in a pharmaceutically acceptable salt or complex form. As acid addition salts come those with organic Acids, polymeric acids or inorganic acids in question. As Examples of acid addition salts are the hydrochlorides and Called Acetate. Complexes include those known per se To understand compounds when adding inorganic Substances such as salts or hydroxides (e.g. Ca, Zn salts) and / or with the addition of polymeric organic substances.  

One class of compounds according to the invention relates to those which contain at least one radical of the formula (a) or (b).

Preferred compounds according to the invention are those of Formula (I)

wherein
R₁ for a radical of the formula (a), (b) or (c) as defined above,
R₂ is hydrogen, C _1-12 alkyl, C _1-4 alkanoyl, C _7-10 phenylalkyl or a radical of the formula (a), (b) or (c) as defined above,
<N-CH (Z₁) -CO for

• a) optionally with halogen, NO₂, NH₂, OH, alkyl with 1 up to 3 carbon atoms and / or alkoxy with 1 to 3 carbon atoms (L) - or (D) -phenylalanine residue or
• b) the rest of a natural lipophilic a- amino acid other than that specified under i), a corresponding (D) -amino acid or a synthetic amino acid,

in which
Z 1 in <N-CH (Z 1) -CO- represents the residue of an amino acid residue defined under i) or ii),
A 'for hydrogen or alkyl with 1 to 3 carbon atoms
Y'₁ and Y'₂ independently of one another for hydrogen or for

where m is an integer from 1 to 4
R _a CH₃ or C₂H₅ and
R _{b is} H, CH₃ or C₂H₅, or

wherein n is an integer from 1 to 5, or

3) -CO-NHR _c

wherein R _{c is} a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, or

wherein R _{d is} the residue of a natural or synthetic a- amino acid (incl. hydrogen) on the α- C atom and
R _{e represents} an alkyl radical with 1 to 5 carbon atoms,

wherein R ' _a and R' _{b are} independently hydrogen, CH₃ or C₂H₅
R₈ and R₉ independently of one another hydrogen, halogen, alkyl with 1 to 3 C atoms or alkoxy with 1 to 3 C atoms
p 0 or 1,
q 0 or 1 and
r is 0, 1 or 2,
or Y′₁ and Y′₂ together represent a bond,
B for Phe or in the phenyl radical substituted by halogen, NO₂, NH₂, OH, alkyl having 1 to 3 C atoms or alkoxy having 1 to 3 C atoms, or 3- (2-naphthyl) alanine
C for L- or D-Trp optionally substituted in the benzene ring by halogen, NO₂, NH₂, OH, alkyl having 1 to 3 C atoms or alkoxy having 1 to 3 C atoms, it being possible for the α- amino group to be substituted by methyl
D for Lys, Lys in which the side chain contains an O or S in the β position, γ F-Lys, δ F-Lys or Orn, where the α- amino group can be substituted by methyl, or 4-aminocyclohexylAla or 4-aminocyclohexylGly
E for Thr, Ser, Val, Phe, Ile, aminobutyric acid or aminoisobutyric acid residue

R₇ for hydrogen or alkyl with 1 to 3 carbon atoms
R₁₀ for hydrogen or the rest of a physiologically acceptable, physiologically hydrolyzable ester
R₁₁ represents hydrogen, alkyl having 1 to 3 C atoms, phenyl or phenylalkyl having 7 to 10 C atoms, but if R₁₂ represents -CH (R₁₃) -X₄, only hydrogen or methyl
R₁₂ for hydrogen, alkyl with 1 to 3 carbon atoms or

R₁₃ for the residue of a natural or synthetic amino acid (including hydrogen) on the α- C atom or for a CH₂OH, HO-CH₂-CH₂, HO (CH₂) ₃ or -CH (CH₃) OH residue,

R₁₄ for hydrogen or alkyl having 1 to 3 carbon atoms
R₁₅ for hydrogen, alkyl with 1 to 3 carbon atoms, phenyl or phenylalkyl with 7 to 10 carbon atoms, and
R₁₆ represent hydrogen or hydroxy,

where the radicals B, D and E in L-form and the radicals in positions 2 and 7 and the radicals Y'₁4) and Y'₂4) can be in D- or L-form,
and the physiologically acceptable ethers and the physiologically hydrolyzable and acceptable esters thereof if the compounds of the formula I contain at least one radical of the formula (a) or (b),
as well as the salts and complexes of these polypeptide derivatives.

In the present description and the claims "Halogen" preferably for fluorine, chlorine or bromine.  

A 'is preferably hydrogen or methyl, especially Hydrogen.

If <N-CH (Z₁) -CO- has the meaning a), this radical is preferably for a (L) - or (D) -phenylalanine, pentafluorophenylalanine or a (L) - or (D) -tyrosine residue (where Z₁ Benzyl or p-OH-benzyl means), especially for the (D) -phenylalanine residue.

If <N-CH (Z₁) -CO- has the meaning b), this radical is preferred lipophilic. Accordingly, those residues are preferred in which Z₁ for alkyl with 3, preferably 4 or more carbon atoms or for is a radical -CH₂-A₂, wherein A₂ is naphthyl, pyridyl or 3-indolyl means.

The <N-CH (Z₁) CO radical is particularly preferably for the under a) defined residues.

Y'₁ and Y'₂ are preferably together for a bond or are preferably, independently of one another, hydrogen or a radical of the formula (1) or (3). Y'₁ and are very preferably Y'₂ for a bond.

If B in the ring means Phe substituted by halogen, then also understood to include pentafluoroalanine.

The following meanings are preferred, either individually, together or in any combination or sub-combination:

B is preferably Phe or Tyr.
C is preferably (D) -Trp, or 5-halo- (D) Trp, especially D-Trp.
D is preferably Lys or 4-aminocyclohexylalanine, especially Lys.
E is preferably Thr, Ser or Val, especially Thr or Val.

especially a group of the formula

wherein R₁₁ is hydrogen, R₁₂ is as defined above, R₁₃ -CH₂OH, -CH (CH₃) OH, CH₂CH₂OH, (CH₂) ₃OH or as an α- bonded radical of an α- amino acid for i-propyl, i-butyl or a radical derived from Trp, 5-FluoroTrp, 3- (2-naphthyl) alanine, Ala, MeAla or Gly, especially CH₂OH or CH (CH₃) OH, very particularly CH (CH₃) OH, and

and
R₁₀ represents hydrogen or, as the residue of a physiologically acceptable, physiologically hydrolyzable ester, preferably HCO, alkylcarbonyl having 2 to 12 carbon atoms, phenylalkylcarbonyl having 8 to 12 carbon atoms or benzoyl, the group -CH (R₁₃) -X₄ preferably has the L configuration.

The residues in positions 2 and 7 preferably have the (L) configuration.

Further preferred compounds are those of the formula (I) in which R₁ and / or R₂ represent a radical of formula (a).

Very preferred compounds according to the invention are those two residues of formula (a) and / or (b) at the N-terminal Have amino group, for example compounds of formula II

wherein
Z₁, A ', Y'₁, Y'₂, B, C, D, E and F have the meanings given above
and R₁₇ and R₁₈ independently of one another represent a radical of the formula (a) or (b), preferably a radical of the formula (a),
and their physiologically acceptable ethers or physiologically hydrolyzable and acceptable esters.

The present invention includes methods of making compounds of the invention. For example, the connections be made by

• a) at least one protecting group in a protected with at least one radical of formula (a), (b) or (c) substituted Polypeptide is present, removed or
• b) a compound of formula III wherein either
  g is 0 or 1,
  Y₁ and Y₂ have one of the meanings given above, and
  Z₂ stands for -CHO, or
  g for 1,
  Z₂ for CH₂OH and -CY₁Y₂ together represent carbonyl,
  the free hydroxyl groups can be etherified or esterified,
  or a compound of formula IVX'₁-NH-X'₃-CHO (IV) wherein
  X'₁ an amino protecting group, and
  X′₃ is C _1-5 alkylene,
  reductively aminated with a compound of formula V, P-NH₂ (V) wherein P is a somatostatin peptide residue in protected form, e.g. B. a compound of formula V ' wherein Z₁, Y'₁, Y'₂, A ', B, C, D, E and F have the meanings given above, the rest is in a protected form,
  and then, if appropriate, process step a) is carried out;
• c) two peptide units, each of which has at least one amino acid or an amino alcohol in protected or unprotected Form and one unit a residue of formula (a), (b) or (c) contains, through an amide bond with each other linked, the peptide binding taking place in the manner is that the amino acid sequence according to the invention prepared and then, if necessary, the process stage a) is executed, or
• d) a functional group of an unprotected or protected Polypeptides transferred to another functional group, being an unprotected or protected somatostatin peptide is obtained and in the latter case process step a) is performed,
• e) at least one possibly protected group in an unprotected or introduces protected polypeptide, followed by if necessary, process stage a) is carried out becomes,
• f) optically active isomers, starting from mixtures of such Isomers which are obtained according to process stage a) to e) are separating

the compounds in free form, salt form or as complexes can be obtained.

These are known per se in peptide chemistry Methods; they can be analogous to those in the examples below described procedures are carried out.

If desired, protective groups such as Common in peptide chemistry to protect functional groups that are not used in the implementation. Such  Protecting groups also include polymeric resins with functional ones Groups.

The reductive amination step b) can be carried out in the usual manner as for an aldose or ketosis can be performed. The reductive Amination can be accomplished, for example, with NaBH₃CN. An acidic pH, for example of 5-7, is preferred. The temperature can range from room temperature to 100 ° C be. The reaction can also be advantageous in the presence of a inert solvent, such as water, an alcohol, Dioxane or dimethylformamide can be carried out.

The end product can be cleaned in the usual way.

The unmodified polypeptides that are used as starting materials in Stage b) or c) can be used, according to known Methods are prepared, for example in solution or by Solid phase, e.g. B. as described in US Patent 43 95 403 also Oxidation stage of a straight-chain polypeptide into a bridged one Peptide. The peptide units that have at least one residue of the formula (a), (b) or (c) and as the starting product in Stage (c) can be used analogously to the manufacturing stage b) are produced.

Insofar as the production of the starting products is not particularly described the connections are known or can according to known methods, e.g. B. analogous to that in the following Processes described examples prepared and cleaned will.

In the following examples, all temperatures are given in degrees Celsius and the [ α ] _D values are uncorrected. The following abbreviations are used:

BOC = tert. Butyloxycarbonyl
DMF = dimethylformamide
AcOH = acetic acid
MeOH = methanol
Thr-ol = threoninol residue = CH₃-CHOH-CH (CH₂OH) -NH-
TFA = trifluoroacetic acid

All peptides are obtained as polyacetate polyhydrates with a peptide content of 70 to 90%.

The HPLC analysis shows that the polypeptides are less than 5% other peptides.

The factor "F" given in the following examples gives the peptide content in the products obtained (F = 1 comes with 100% peptide content). The difference to 100% [(1-F) × 100] consists of acetic acid and water.

Example 1

3 ml of trifluoroacetic acid (100%)

added and the mixture is kept at room temperature until all starting products are dissolved (about 5 minutes). After the addition of 20 ml of diisopropyl ether, the title compound precipitates. It is filtered and washed with diisopropyl ether. The title compound is purified by means of silica gel chromatography (CHCl₃ / MeOH / AcOH / H₂O 7/3 / 0.5 / 0.5) and obtained as a white lyophilisate.
[ α ] = 24.5 ° (c = 1 in AcOH 95%) F = 0.83

The starting products are obtained as follows:

2.25 g of di-tert-butyl pyrocarbonate, dissolved in 30 ml of DMF slowly, drop by drop, at room temperature a solution of

added in 100 ml DMF. After two hours at room temperature the solvent is evaporated under vacuum and 200 ml of diisopropyl ether are added to the residue. The precipitate formed is filtered, washed with diisopropyl ether and dried. The crude product is purified by means of silica gel chromatography (CH₂Cl₂ / MeOH 9/1) and obtained as a white amorphous powder.
[ a ] = 29.8 ° (c = 1.28 in DMF)

Method A

0.5 g of the product obtained in stage a), in 30 ml of dioxane / H₂O 3: 7 are treated with 50 mg of NaBH₃CN and 130 mg of glyceraldehyde. The pH of the mixture is adjusted to 7 with 0.1 ml of HCl and the mixture is treated at 100 ° C. for 6 hours. The mixture is subsequently cooled, frozen and liophilized. The residue is taken up in 50 ml of ethyl acetate and shaken with water. The organic phase is dried and evaporated in vacuo. The title compound is obtained as an amorphous product.
[ α ] = 23.2 ° (c = 1.2 in DMF)

Method B

Instead of a mixture of dioxane / water, a mixture can Methanol / water (2/1 V / V) used and the reaction mixture be adjusted to pH 5 with a phosphate buffer. After 4 up to 6 hours at 50 ° C, then adding water, Filtration and drying over P₄O₁₀, the title compound b) isolated as an amorphous powder.

Example 2

Analogously to Example 1, the title compound is obtained starting from 130 mg (D) -glyceraldehyde.
[ α ] = -25.1 ° (c = 1 in 95% AcOH), F = 0.86.

Example 3

Analogously to Example 1, the title compound is obtained starting from 130 mg (L) -glyceraldehyde.
[ α ] = -18.4 ° (c = 1 in 95% AcOH), F = 0.90.

Example 4

Analogously to Example 1, starting from glycolaldehyde in appropriate amount of the following compounds:

[ α ] = -28.8 ° (c = 1 in 95% AcOH), F = 0.90.

[ α ] = -21.9 ° (c = 1 in 95% AcOH), F = 0.83.

Example 5

Analogously to Example 1, 2-methoxyacetaldehyde is obtained the following compounds in appropriate quantities:

[ α ] = -8.5 ° (c = 0.25 in 95% AcOH), F = 0.76
and

[ α ] = -5 ° (c = 0.5 in 95% AcOH), F = 0.79.

In the examples below, the expression SMS has the following Importance:

Example 6 2,3-propionyloxy (2S) propyl SMS

Analogously to Example 1, the title compound is obtained starting from 2,3-di-O-propionyl- (D) -glyceraldehyde.
[ α ] = -21.7 ° (c = 0.9 in 95% AcOH), F = 0.88.

Example 7 2,3-Di-hexanoyloxy (2S) propyl SMS

Analogously to Example 1, the title compound is obtained starting from 2,3-di-O-hexanoyl- (D) -glyceraldehyde.
[ α ] = -18.8 ° (c = 0.25 in 95% AcOH), F = 0.79.

Example 8 2,3-di-isopropylidene-2,3-dihydroxy- (2S) propyl SMS

Analogously to Example 1, the title compound is obtained starting from 2,3-di-O-isopropylidene (D) -glyceraldehyde.
[ α ] = -38 ° (c = 0.25 in 95% AcOH), F = 0.76.

Example 9 2,3,4-tri-hydroxy (2S, 3R) butyl SMS

Analogously to Example 1, the title compound is obtained starting from D - (-) - erythrose.
[ α ] = -29.2 ° (c = 0.25 in 95% AcOH), F = 0.81.

Example 10 2-Aminoaethyl SMS

Analogously to Example 1, the title compound is obtained starting from N-Boc-2-aminoacetylaldehyde.
[ α ] = -32 ° (c = 0.13 in 95% AcOH), F = 0.84.

Example 11 3-aminopropyl SMS

Analogously to Example 1, the title compound is obtained starting from N-Boc-3-aminopropionaldehyde.
[ a ] = -21 ° (c = 0.29 in 95% AcOH), F = 0.76.

The compounds according to the invention have valuable results in animal experiments pharmacodynamic properties and are therefore suitable as a therapeutic agent. In particular, they cause an inhibition the GH secretion z. B. by reducing the GH content can be detected in the serum of the rat.

This inhibition of GH secretion can be determined as follows:

Male rats are given an hour after s. c. Administration of the to testing compound in several logarithmically graded doses Blood drawn. The GH level in serum is determined medium radioimmunoassay (RIA). In these experiments they are Compounds according to the invention active in doses of 0.02 to 100 µg / kg s. c.

The GH-lowering effect of the compound according to the invention also became apparent also after oral application on male rats Oestradiol implants examined. This test is as follows carried out:

Male OFA rats weighing approx. 300 g are subjected to ether anesthesia a tube (length 50 mm, ⌀ 3 mm) made of Silastic with 50 mg Oestradiol implanted under the dorsal skin. To different Times (1 to 6 months later) these animals are repeated for Attempts used. The test substance is administered orally, the animals about 16 hours before the experiment without food being held. The GH level in the blood serum is 1 and 2 hours determined by oral administration by RIA. In these attempts the compounds of the invention are active in cans from 10 to 5000 µg / kg orally.

The compounds of the invention are therefore used for all indications in which an inhibition of GH secretion is desired. The focus is on use in acromegaly,  as well as diabetes mellitus, especially the complications of which, e.g. B. angiopathy, proliferative retinopathy, Twilight disorders and kidney problems.

The compounds of the invention also inhibit gastric and Pancreatic secretion and also the secretion of various Peptides of the gastrointestinal tract, as from standard experiments Rats with gastric and pancreatic fistula emerges. In these attempts the compounds of the invention are active in cans from 0.1 to 10 mg / kg orally.

The compounds of the invention are therefore also suitable for Treatment of gastrointestinal disorders, such as for the treatment of Gastric ulcers, pancreatic fistulas, intestinal inflammation, dumping Syndrome, acute pancreatitis and gastrointestinal hormones secreting tumors (e.g. vipomas, glucagonomas, insulinomas etc.) and gastrointestinal bleeding.

The compounds of the invention also inhibit proliferation and / or keratinization of epidermal cells and are therefore suitable also for the treatment of dermatological diseases with a pathological proliferation and / or keratinization of epidermal Cells are related, especially for the treatment of Psoriasis.

The compounds according to the invention can also be used for treatment a degenerative senile dementia including the senile dementia of the Alzheimer type (SDAT).

The compounds of the invention are also useful in the Treatment of various tumors, especially tumors with Somatostatin receptors, as from proliferation experiments with various Cancer cell lines and tumor growth attempts in the bare mouse with hormone-dependent tumors (e.g. stomach-dependent  Colon cancer). The compounds of the invention are therefore used in the treatment of z. B. breast, Prostate, colon, pancreatic and brain cancer.

The compounds according to the invention are intended for all of these indications in a daily dose of about 2 µg to 20 mg, preferably from about 0.01 to 20 mg, e.g. B. from about 10 to 5000 µg s. c. and from about 300 µg to 20 mg p. o., can be used. If desired the compounds can also be divided into doses up to 4 times a day in unit dosage form or in extended release form be administered. Such unit doses can be about 0.5 µg up to 10 mg, e.g. B. from about 2 ug to 10 mg, of the respective active ingredient contain.

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

The invention also relates to the polypeptides according to the invention in free form or as pharmaceutically acceptable salts or complexes for use as a pharmaceutical.

The invention also includes pharmaceutical preparations which contain compounds of the invention. These contain the mentioned compounds or their pharmacologically acceptable Salts or complexes e.g. B. mixed with a liquid or solid carrier material. You can e.g. B. together in a capsule can be administered with the usual carriers. These Preparations can and should be produced in the usual way e.g. B. for injection, suppositories or nasal, but especially for oral administration, e.g. B. like tablets or capsules be. Depot preparations can also be used.

The invention also relates to a method for the treatment of Disorders associated with excess GH secretion gastrointestinal disorders, dermatological disorders  Diseases with pathological profiling and / or Keratinization related to epidermal cells, degenerative senile dementia and tumors in a patient who such treatment is required, which requires the administration of a effective amount of a compound of the invention or a pharmaceutically acceptable salt or complex thereof to which mentioned patient includes.

Claims (8)

1. A somatostatin peptide, characterized in that it contains at least one radical of the formula (a), (b) or (c) wherein
Y₁ for hydrogen
Y₂ represents hydrogen or hydroxy,
f and g are independently 0 or 1
X₁ hydrogen
X₂ is hydrogen or an amino protecting group, and
X₃ is C _2-6 alkylene,
where the free valence in residue (a), (b) or (c) is bound to the N-terminal amino group of the peptide,
and the physiologically acceptable ethers and physiologically hydrolyzable and acceptable esters thereof if the peptide contains at least one radical of the formula (a) or (b),
in free form or in the form of an acid addition salt or complex. 2. A compound according to claim 1, characterized in that they have at least one radical of the formula (a) or (b) as in Claim 1 contains defined. 3. A compound according to claim 1, of formula I. wherein
R₁ for a radical of the formula (a), (b) or (c) as defined above,
R₂ is hydrogen, C _1-12 alkyl, C _1-4 alkanoyl, C _7-10 phenylalkyl or a radical of the formula (a), (b) or (c) as defined above,
<N-CH (Z₁) -CO for

• a) an optionally substituted by halogen, NO₂, NH₂, OH, alkyl having 1 to 3 carbon atoms and / or alkoxy having 1 to 3 carbon atoms (L) - or (D) -phenylalanine or
• b) the rest of a natural lipophilic α- amino acid other than that specified under i), a corresponding (D) -amino acid or a synthetic amino acid,

in which
Z 1 in <N-CH (Z 1) -CO- represents the residue of an amino acid residue defined under i) or ii),
A 'for hydrogen or alkyl with 1 to 3 carbon atoms
Y'₁ and Y'₂ independently of one another for hydrogen or for where m is an integer from 1 to 4
R _a CH₃ or C₂H₅ and
R _{b is} H, CH₃ or C₂H₅, or where n is an integer from 1 to 5, or 3) -CO-NHR _c where R _{c is} a straight-chain or branched alkyl radical having 1 to 6 carbon atoms, or wherein R _{d is} the residue of a natural or synthetic α- amino acid (including hydrogen) located on the α- C atom and
R _{e represents} an alkyl radical with 1 to 5 carbon atoms, wherein R ' _a and R' _{b are} independently hydrogen, CH₃ or C₂H₅
R₈ and R₉ independently of one another hydrogen, halogen, alkyl with 1 to 3 C atoms or alkoxy with 1 to 3 C atoms
p 0 or 1,
q 0 or 1 and
r is 0, 1 or 2,
or Y′₁ and Y′₂ together represent a bond,
B for Phe or in the phenyl radical substituted by halogen, NO₂, NH₂, OH, alkyl having 1 to 3 C atoms or alkoxy having 1 to 3 C atoms, or 3- (2-naphthyl) alanine
C for L- or D-Trp optionally substituted in the benzene ring by halogen, NO₂, NH₂, OH, alkyl having 1 to 3 C atoms or alkoxy having 1 to 3 C atoms, it being possible for the a -amino group to be substituted by methyl
D for Lys, Lys in which the side chain contains an O or S in the β position, γ F-Lys, δ F-Lys or Orn, where the α- amino group can be substituted by methyl, or 4-aminocyclohexylAla or 4-aminocyclohexylGly
E for Thr, Ser, Val, Phe, Ile, aminobutyric acid or aminoisobutyric acid residue R₇ for hydrogen or alkyl with 1 to 3 carbon atoms
R₁₀ for hydrogen or the rest of a physiologically acceptable, physiologically hydrolyzable ester
R₁₁ represents hydrogen, alkyl having 1 to 3 C atoms, phenyl or phenylalkyl having 7 to 10 C atoms, but if R₁₂ represents -CH (R₁₃) -X₄, only hydrogen or methyl
R₁₂ for hydrogen, alkyl with 1 to 3 carbon atoms or R₁₃ for the residue of a natural or synthetic amino acid (including hydrogen) on the α- C atom or for a CH₂OH, HO-CH₂-CH₂, HO (CH₂) ₃ or -CH (CH₃) OH residue, R₁₄ for hydrogen or alkyl having 1 to 3 carbon atoms
R₁₅ for hydrogen, alkyl with 1 to 3 carbon atoms, phenyl or phenylalkyl with 7 to 10 carbon atoms, and
R₁₆ represent hydrogen or hydroxy,
where the radicals B, D and E in L-form and the radicals in positions 2 and 7 and the radicals Y'₁4) and Y'₂4) can be in D- or L-form,
and the physiologically acceptable ethers and the physiologically hydrolyzable and acceptable esters thereof if the compounds of the formula I contain at least one radical of the formula (a) or (b),
as well as the salts and complexes of these polypeptide derivatives. 4. A method for producing a somatostatin peptide according to claim 1, characterized in that

• a) at least one protective group which is present in a protected polypeptide which is substituted by at least one radical of the formula (a), (b) or (c) is removed or
• b) a compound of formula III wherein either
  g is 0 or 1,
  Y₁ and Y₂ have one of the meanings given above, and
  Z₂ stands for -CHO, or
  g for 1,
  Z₂ for CH₂OH and -CY₁Y₂ together represent carbonyl,
  the free hydroxyl groups can be etherified or esterified,
  or a compound of formula IVX'₁-NH-X'₃-CHO (IV) wherein
  X'₁ an amino protecting group, and
  X′₃ is C _1-5 alkylene,
  reductively aminated with a compound of formula V, P-NH₂ (V) where P is a somatostatin peptide residue in protected form,
  and then, if appropriate, process step a) is carried out;
• c) two peptide units, each of which contains at least one amino acid or an amino alcohol in protected or unprotected form and one unit contains a radical of the formula (a), (b) or (c), are linked to one another by an amide bond, the peptide bond in the It should be done in such a way that the amino acid sequence according to the invention is produced and process step a) is then carried out, if appropriate, or
• d) converting a functional group of an unprotected or protected polypeptide into another functional group, an unprotected or protected somatostatin peptide being obtained and, in the latter case, process step a) being carried out,
• e) introducing at least one optionally protected group into an unprotected or protected polypeptide, process step a) then optionally being carried out,
• f) separates optically active isomers, starting from mixtures of those isomers which are obtained in process step a) to e)

the compounds in free form, salt form or as Complexes can be obtained. 5. A compound according to any one of claims 1 to 3, or one pharmaceutically acceptable salt or complex thereof, for use as a pharmaceutical. 6. A pharmaceutical composition containing a compound according to one of claims 1 to 3, or a pharmaceutical acceptable salt or complex thereof, along with a pharmaceutically acceptable diluent or carrier therefor.