GB1587427A

GB1587427A - Polypeptide derivatives

Info

Publication number: GB1587427A
Application number: GB29877/77A
Authority: GB
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 1976-07-19
Filing date: 1977-07-15
Publication date: 1981-04-01
Also published as: BE856899A; NL7707894A; FR2359120B1; FR2359120A1; DE2730851A1; JPS5312839A

Description

(54) POI,YPETIDE DERIVATIVES (71) We, SANDOZ LTD., of 35 Lichtstrasse, 4002 Basle, Switzerland, a Swiss Body Corporate, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following. statement: The present invention relates to polypeptide derivatives.

More particularly, the present invention provides compounds of the formula I, A - B - Gly - D - E - F I wherein A is a residue of the formula

wherein R, is hydrogen or alkyl of 1 to 4 carbon atoms, R2 is hydrogen or, together with R1, forms an ethylene bridge and R3 is hydrogen, alkyl of 1 to 4 carbon atoms or an R4CO- group wherein R4 is saturated or unsaturated branched or unbranched alkyl residue of l to 17 carbon atoms; or phenylor phenylalkyl of 7 to 12 carbon atoms in each of which the phenyl residue may be mono- or di-substituted with fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms; whereby the RsO group is in a position meta- or para- to the

residue, and Z is hydrogen, alkyl of l to 5 carbon atoms, alkenyl of 3 to 5 carbon atoms, cyclopropylmethyl, cyclobutylmethyl, R4CO- wherein R4 is as previously defined, or a residue of a natural (L)-amino acid or of a dipeptide formed from natural (L)-amino acids, whereby instead of a natural (L)-amino acid, (L)methioninesulphoxide or (L)-methioninesulphone may be used, B is -Gly-, -(D)-Ala, -(D)-Met-, -(D)-methioninesulphoxide- or -(D)-methioninesulphone-, -(D)-S-methylcysteine, -(D)-S-methylcysteinesulphoxide- or -(D)-S-methylcysteine-sulphone, D is a residue of formula

wherein R5 is hydrogen or alkyl of 1 to 4 carbon atoms, R6 is hydrogen, fluorine, chlorine, bromine, nitro, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms and z is I or 2, E is -Leu-, -Nle-, -Nva-, -lle-, -Val- or

wherein r is 0, 1 or 2 and s is 0, 1 or 2, and F is 1 ) a residue of the formula

werein R'3 is hydrogen or R4CO# wherein R4 is as previously defined, R7 is hydrogen or alkyl of 1 to 4 carbon atoms and R8 is a)

b) #(CH2)m # CH2OR'3 wherein R'3 is as previously defined, and m is from 0 to 6,

wherein R3 is as previously defined, d) -CH2-SH,

wherein R9 is alkyl of 1 to 5 carbon atoms, r is 0, 1 or 2 and s is 0, 1 or 2, f) #(CH2)4#NH2,#(CH2)4#NHCOR4 wherein R4 is as previously defined,

g) (CH2)nCONH2 wherein n is 1 or 2, h) (CH2)COOR10 wherein n is as previously defined and R10 is hydrogen or alkyl of 1 to 5 carbon atoms, or i) together with R7 is #(CH2)3#, or 2 ) a residue of the formula

wherein n and R7 are as previously defined, whereby the A, D and E residues possess either the (L)- or (DL)- configuration and the residue F possesses the (L)-, (D)- or (DL)- configuration.

When R, is alkyl, this is preferably methyl. R, preferably is hydrogen or, together with R2, forms an ethylene bridge.

When R3 is alkyl, this is preferably methyl.

R3 especially signifies hydrogen.

R3O is preferably in a position para- to the

residue.

When Z is alkyl, this is preferably methyl. When Z is a natural amino acid, this is preferably H-Arg-, H-Lys-, H-Phe-, H-Tyr- or H-Ala-. Z is preferably hydrogen, alkyl, a natural (L)-amino acid or a dipeptide formed from natural (L)-amino acids.

B is preferably -(D)-Ala-,-(D)-Met-,-(D)-methioninesulphoxide-or-(D)-meth- ioninesulphone-.

When R5 is alkyl, this is preferably methyl. R5 is preferably methyl or hydrogen.

R6 is preferably hydrogen, nitro or chlorine, especially hydrogen or nitro.

As an amino acid residue, E is preferably (L)-methionine-, (L)-methioninesulphoxide- or (L)-methioninesulphone-, especially (L)-methioninesulphoxide-.

R7 is especially hydrogen.

R3 is preferably hydrogen.

R9 is preferably methyl. r is preferably l or 2, especially 1. s is preferably 0 or l, especially 1. n is preferably 2.

F is preferably -serinol, -asparaginol or -threoninol. F preferably has the (L)configuration.

In one group of compounds, R4 is alkyl of 1 to 17 carbon atoms, preferably 1 to 12 carbon atoms, most preferably from 1 to 6 carbon atoms, for example, methyl, ethyl, propyl and butyl. When R4 is alkyl of two or more carbon atoms, this moiety may be unsaturated.

When R4 is phenyl or phenylalkyl of 7 to 12 carbon atoms, e.g. tolyl or benzyl, the phenyl residue may be mono- or di-substituted with fluorine, chlorine or bromine. The phenyl residue may also be substituted with alkyl of I to 4 carbon atoms or alkoxy of I to 4 carbon atoms.

In a second group of compounds, Z is hydrogen, alkyl of 1 to 5 carbon atoms, alkenyl of 3 to 5 carbon atoms, cyclopropylmethyl or cyclobutylmethyl.

In a third group of compounds, Z is R4CO wherein R4 is as previously defined.

In a fourth group of compounds, R6 is hydrogen, fluorine, chlorine, bromine or nitro.

In a fifth group of compounds, R6 is alkyl of I to 4 carbon atoms or alkoxy of I to 4 carbon atoms.

In a sixth group of compounds, E is -Leu-, -Nle-, -Nva-, -Ile- or -Val-. In another group of compounds,

wherein r and s are as previously defined.

In a seventh group of compounds, F as previously defined under i) is

wherein R3 and R7 are as previously defined and R8 is as previously defined under a), b) and c). In another group of compounds, Ra is as previously defined under d) and e). In a further group of compounds, Rc is (CH2)4-NH2, -(CH2)4-NHCOR4 wherein R4 is as previously defined, or R8 is as previously defined under g), h) and i). In three further groups of compounds, R8 is

In an eighth group of compounds, F is as previously defined under 2").

A peptide of formula I may be obtained by methods which are conventional in the art of peptide synthesis.

Accordingly, the present invention provides a process for the production of a peptide of formula I which comprises: a) removing at least one protective group from a protected peptide having the sequence indicated in formula I, or b) linking together by an amide bond two peptide units, each of which contains at least one amino acid and which is in protected or unprotected form, the peptide units being such that the amino acid sequence given in formula I is obtained, and then, if necessary, effecting process variant a), or c) converting a group A, B, E and/or F of an unprotected or protected peptide into another group A, B, E and/or F, and if necessary, effecting process variant a).

The above methods are known in peptide chemistry and may be effected in manner analogous to the processes described in the following Examples.

Insofar as the production of the starting materials is not particularly described, these compounds are known or may be produced and purified in accordance with known methods. These compounds may also be produced in a manner analogous to the processes described in the following Examples.

The compounds may exist in salt, including acid addition salt, forms or in the form of complexes, for example, complexes with metals.

Suitable metals for complex formation include calcium, magnesium, aluminium, and especially zinc.

In the following Examples, all temperatures are indicated in degrees Celsius, The following abbreviations are used: Ac = acetyl Boc = tert.-butyloxycarbonyl Bzl = benzyl CBO = benzyloxycarbonyl DMF =dimethylformamide Me = methyl MePhe = N-methylphenylalanine TFA = trifluoroacetic acid decomp. = decomposition temperature THF = tetrahydrofuran Asn-ol = asparaginol.

Example 1.

H-Tyr-(D)-Ala-Gly-Phe-Met-serinol (trifluoroacetate) 2 g of Boc-Tyr-(D)-Ala-Gly-Phe-Met-serinol are dissolved at room temperature in 10 ml of CF3COOH/CH2CI2 (1:1 v/v). After 30 minutes, the mixture is concentrated under vacuum and the residue triturated with diethyl ether. The solid product is recrystallized from methanol/diethyl ether to yield the title compound.

M.P. 200 (decomp.). [a]DO = +2.1 (C = 1.0 in DMF).

The Boc-Tyr-(D)-Ala-Gly-Phe-Met-serinol employed as starting material is produced as follows: a) Boc-Tyr-(D)-s;ila-Gly-Phe-OCH3 53 g of CBO-(D)-Ala-Gly-Phe-OCH3 are dissolved in 400 ml of dioxane and 50 ml of water after the addition of 5 g of a platinum catalyst and hydrogenated at room temperature under normal pressure until no further hydrogen is absorbed.

The catalyst is filterd off, the mixture concentrated and the residue taken up in 200 ml of DMF. 15 g of hydroxysucccinimide, 30 g of Boc-(L)-Tynosine and 26 g of dicyclohexylcarbodiimide are added to the solution at OOC. After one day at 0 C and one day at room temperature, the dicyclohexyl urea which separates out if filtered off and the filtrate concentrated and taken up in ethyl acetate. The mixture is washed with dilute HCI and water and concentrated. On adding diethyl ether, the title product crystallizes ou fot eh concentrated solution.

M.P. 100 (decomp.). [α]D20 = -9.5 (C = 1 in DMF). b) Boc-Tyr-(D)-Ala-Gly-phe-NHNH2 43 g of Boc-Tyr-(D)-Ala-Gly-Phe-OCH3 are dissolved in 300 ml of methanol and 35 ml of hydrazine hydrate are added. After one day at room temperature, the mixture is evaporated and the residue is triturated with water which has been acidified to pH 3 with HCI. The precipitated product is filtered and dried to yield the title compound. M.P. 195 (decomp.). [aS]DO = @ 20.9 (C = I in DMF). c) Boc-Tyr-(D )-Ala-Gly-Phe-Met-serinol To 2.5 g of Boc-Tyr-(D)-Ala-Gly-Phe-NHNH2 in 40 ml of DMF are added 2.7 ml of 5.6 M HCI in dioxane and 0.52 ml of tert.butylnitrite at -20 and, after 10 minutes, 3,4 ml of triethylamine and 2 g of H-met-serinol trifluoroacetate. After 4 hours at 0 and 15 hours at room temperature, the mixture is concentrated under vacuum, the residue taken up in ethyl acetate and washed repeatedly with dilute HCI and water and the organic phase evaporated. The residue crystallizes from methanol/diethyl ether to yield the title compound. M.P. 140 (decomp.).

[a]2O = -15 (C = 1 in DMF).

Example 2.

H-Tyr-(D)-Ala-Gly-Phe-methioninesulphoxide-serinol (trifluoroacetate) To a solution of I g of H-Tyr-(D)-Ala-Gly-Phe-Met-serinol (trifluoroacetate) in 10 ml of water are added 1.8 ml of a 0.1 M solutionof hydrogen peroxide. After one hour at room temperature, the solution is lyophilised to yield the title compound. M.P. 225 (decomp.). [α]D20 = +0.3 (C = 1 in DMF).

Example 3.

H-Tyr-(D)-Ala-Gly-MePhe-Leu-Asn-ol (hydrochloride) 0.88 g of CBO-Tyr(Bzl)-(D)-Ala-Gly-MePhe-Leu-Asn-ol are dissolved, with one equivalent of aqueous hydrochloric acid, in 40 ml of acetic acid/water (8:2 v/v), 100 mg of Pd (10% by weight on active charcoal) are added and hydrogenation effected at normal pressure and room temperature. After 4 hours, the catalyst is filtered off, the solvent removed under vacuum and the residue triturated with ether to yield the title compound. [α]D20 = -10.7 (C = 0.97 in CH3COOH 95%).

The CBO-Tyr(Bzl)-(D)-Ala-Gly-MePhe-Leu-Asn-ol is prepared as follows: a) Boc-Mephe-Leu-OMe To a solution of 28 g of Boc-MePhe-OH and 11.2 ml of N-methylmorpholine in 400 ml of THF are added 13.2 ml of chloroformic acid isobutyl ester at -250.

After 5 minutes, at -250, 18 g of H-Leu-OMe and 11.2 ml of N-methyl morpholine in 200 ml of DMF are added to the solution. After 2 hours, at -150, the mixture is diluted with ethyl acetate, washed with dilute aqueous KHCO3 solution,hydrochloric acid, water, dried and the solvent removed under vacuum to yield the title compound as a viscous oil. b) Boc-(D)-Ala-Gly-MePhe-Leu-OMe To a solution of 24.6 g of Boc-(D)-Ala-Gly-OH and 11.2 ml of N-methyl morpholine in 400 ml of THF are added 13.2 ml of chloroformic acid isobutyl ester at 250. After 5 minutes, at 250, 11.2 ml of N-methylmorpholine and 42.1 g of H-MePhe-Leu-OMe (trifluoroacetate) in DMF [which has previously been prepared by the treatment of Boc-MePhe-Leu-OMe with TFA-methylene chloride (1:1 v/v)] are added. After 2 hours, at -150, the title compound is isolated as described under a) above, as a solid foam. c) CBO-Tyr-(Bzl)-(D )-Ala-Gly-MePhe-Leu-OMe To a solution of 4.1 g of CBO-Tyr(Bzl)-OH and 1.1 ml of N-methylmorpholine in 40 ml of THF are added 1.3 ml of chloroformic acid isobutyl ester at -250 are added a solution of 1.1 ml of N-methylmorpholine and 5.5 g of H-(D)-Ala-Gly MePhe-Leu-OMe (trifluoroacetate) in 20 ml of DMF [previously produced by treatment of Boc-(D)-Ala-Gly-MePhe-Leu-OMe with T -methyl ene chloride]. After 2 hours at -15 , the isolation described under a) above is effected to yield the title compound as a solid foam. d) CBO-Tyr(Bzl)-(D)-Ala-Gly-MePhe-Leu-NHNH2 7.6 g of CBO-Tyr(Bzl)-(D)-Ala-Gly-MePhe-Leu-OMe and 5 ml of hydrazine hydrate are dissolved in methanol. After 6 hours at 00, the product is precipi tated by the addition of water. The product is washed with a large quantity of water to remove the base to yield the title compound. M.P. 96" (decomp.).

[a]020 = 29.60 (C = 1.0 in DMF). e) CBO- Tyr(Bzl)-(D )-A la-Gly-MePhe-Leu-Asn-ol To 7.6 g of CBO-Tyr(Bzl)-(D)-Ala-Gly-MePhe-Leu-NHNH2 in 40 ml of DMF are added, at -30 , 5.4 ml of 5.6 M HCI in dioxane, 1.2 ml of tert.-butylnitrite and, after 10 minutes, 6.7 ml of N-methylmorpholine and 1.5 g of asparaginol hydrochloride. After 15 hours at 00, the mixture is concentrated under vacuum.

The residue is taken up in ethyl acetate, hydrochloric acid and water, and the organic phase evaporated. The raw product is purified by column chroma tography on kieselgel. Elution is effected with a mixture of methylene chloride/methanol to yield the title compound. M.P. 103 (decomp.).

[a]O = 32.50 (C = 1.0 in DMF).

The following compounds can be prepared in manner analogous to those described in Examples 1, 2 or 3 using appropriate starting materials in approximately equivalent amounts.

[All amino acid residues with the exception of glycyl, as well as all the amino alcohols with the exception of serinol, have, unless otherwise stated, the (L)-configuration. An amino alcohol is assigned to the (L)-series if the -CM2-OM group occupies the position of the cr-COOH group in the corresponding L-amino acid. In the case of a lactone defined under F 2") (Examples 5 and 11), the series to which this belongs is resolved after hydrolytic opening of the lactone ring.] TABLE

Compounds of formula H-Tyr-(D)-Ala-Gly-Phe-E-F Ex. No. E - F Salt Form [α]D22 C 4 Methionine-asparaginol TFA - 2.1 0.33% W/V in DMF 5 Methionine-3-aminobutyrolactone TFA -14.8 0.27% W/V in DMF 6 Methionine-glutaminol TFA - 3.0 0.4% W/V in DMF 7 Methionine-threoninol TFA + 4.7 1% W/V in DMF 8 methioninesulphoxide-threoninol TFA +25.6 1.07% W/V in AcOH 95% 9 Methioninesulphoxide-asparaginol TFA +12.8 1.1% W/V in AcOH 95% 10 Methioninesulphoxide-glutaminol TFA +18.5 0.93% W/V in AcOH 95% 11 methioninesulphoxide-3-amino- TFA + 4.5 0.94% W/V in AcOH 95% butyrolactone The compounds of formula I exhibit pharmacological activity. In particular, the compounds exhibit analogesic activity, as indicated by their affinity for the opiate receptors in rat brains as indicated by the method of C. B. Pert and S. H.

Snyder [Molecular Pharmacology 10, 868 (1974)] and also in the Tail Flick Test in mice.

Additionally, the compounds exhibit antipsychotic activity, as indicated by their ability of inhibit spontancous motor activity in mice.

The compounds are therefore indicated for use as analgesic and as antipsychotic agents. For this use, an indicated daily dose is form 30 to 350 mg, conveniently administered in unit dosage form containing from 7 to 175 mg, or in sustained release form.

The compounds may be administered in pharmaceutically acceptable salt forms, including acid addition salt forms, or in the form of complexes. Such forms exhibit the same order of activity as the free base forms and are readily prepared in conventional manner. Representative acids for acid addition salt forms include organic acids such as trifluoroacetic acid and mineral acids such as hydrochloric acid. Suitable metals for complex formation include zinc. The present invention also provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt or compex thereof in association with a pharmaceutically acceptable carrier or diluent. Such compositions may be in the form of, for example, a solution or a capsule.

Claims

WHAT WE CLAIM IS:

1. A process for the production of a compound of the formula I, A - B - Gly - D - E - F I wherein A is a residue of the formula

wherein Rl is hydrogen or alkyl of 1 to 4 carbon atoms, R2 is hydrogen or, together with R1, forms an ethylene bridge and R2 is hydrogen, alkyl of I to 4 carbon atoms or an R4CO- group wherein R4 is a saturated or unsaturated branched or unbranched alkyl residue of I to 17 carbon atoms; or phenyl or phenylalkyl of 7 to 12 carbon atoms in each of which the phenyl residue may be mono- or di-substituted with fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms; whereby the R3O group is in a position meta- or para- to the

residue, Z is hydrogen, alkyl of I to 5 carbon atoms, alkenyl of 3 to 5 carbon atoms, cyclopropylmethyl, cyclobutylmethyl, R4CO- wherein R4 is as previously defined, or a residue of a natural (L)-amino acid or of a dipeptide formed from natural (L)-amino -acids, whereby instead of a natural (L)-amino acid, (L)methioninesulphoxide or (L)-methioninesulphone may be used, B is -Gly-, -(D)-Ala, -(D)-Met-, -(D)-methioninesulphoxide or -(D)methioninesulphone-, -(D)-S-methylcysteine-, -(D)-S-methylcysteinesulphoxide- or -(D)-S-methylcysteine-sulphone, D is a residue of the formula

wherein R5 is hydrogen or alkyl of 1 to 4 carbon atoms, Ra is hydrogen, fluorine, chlorine, bromine, nitro, alkyl of I to 4 carbon atoms or alkoxy of I to 4 carbon atoms, and z is I or 2, E is -Leu-, -Nle-, -Nva-, -Ile-, -Val- or

wherein R'3 is hydrogen or R4CO# wherein R4 is as previously defined, R7 is hydrogen or alkyl of 1 to 4 carbon atoms and R8 is a)

b) #(CH2)m#CH2OR'3 wherein R3 is as previously defined, and m is from 0 to 6,

wherein R3 is as previously defined, d) #CH2#SH4

wherein R9 is alkyl of 1 to 5 carbon atoms, r is 0, 1 or 2, and s is 0, 1 or 2 f) #(CH2)4#NH2, #(CH2)4#NHCOR4 wherein R4 is as previously defined,

g) #(CH2)n#COHN2 wherein n is 1 or 2, h) #(CH2)n#COOR10 wherein n is as previously defined and R10 is hydrogen or alkyl of I to 5 carbon atoms, or i) together with R7 is #(CH2)3#, or 2 ) a residue of the formula

wherein n and R7 are as previously defined, whereby the A, D and E residues possess either the (L)- or (DL)- configuration and the residue F possesses the (L)-, (D)- or (DL)- configuration, which process comprises a) removing at least one protective group from a protected peptide having the sequence indicated in formula I, or b) linking together by an amide bond two peptide units, each of which contains at least one amino acid and which is in protected or unprotected form, the peptide units being such that the amino acid sequence given in formula I is obtained, and then, if necessary, effecting process variant a), or c) converting a group A, B, E and/or F of an unprotected or protected peptide into another group A, B, E and/or F and, if necessary, effecting process variant a).

2. A process for the production of a compound of formula I, as defined in Claim 1, as hereinbefore described with reference to the Examples.

3. A compound of formula I, as defined in Claim I, whenever produced by a process as claimed in claim I or claim 2.

4. A compound of formula I, as defined in Claim 1.

5. A compound of formula I as defined in Claim 1, wherein A is a residue of the formula defined in Claim 1, wherein R, and R2 are as defined in Claim 1, R2 is hydrogen, and Z is hydrogen, alkyl of I to 5 carbon atoms, alkenyl of 3 to 5 carbon atoms, cyclopropylmethyl or cyclobutylmethyl, B is -Gly- or -(D)-Ala, D is -Phe-, E is -methioninesulphoxide, and F is a residue of the formula

wherein R7 is hydrogen or methyl, and Ra is

b) --(CH,),,-CH,OH wherein m is from 0 to 6,

e) -CM2-CH2-S-CH3,

wherein Ra is alkyl of 1 to 5 carbon atoms,

g) #(CH2)n#CONH2 wherein n is 1 or 2, h) (CH2)nCOOR10 wherein n is as previously defined, and R10 is hydrogen or alkyl of I to 5 carbon atoms, wherein A, D and E possess the (L)-configuration and F possesses either the (D)- or (L)-configuration.

6. A compound according to Claim 5, wherein R1 and R2 are hydrogen, Z is hydrogen, alkyl of 1 to 5 carbon atoms or alkienyl of 3 to 5 carbon atoms, and F is a residue of the formula

wherein Ra is

7. A compound of the formula I, as defined in Claim 1, wherein A is a residue of the formula defined in Claim 1, wherein R1 and R2 are as defined in Claim 1, R3 is an R4CO- group, wherein R3 is as defined in Claim 1, and Z is hydrogen, alkyl of I to 5 carbon atoms, alkenyl of 3 to 5 carbon atoms, cyclopropylmethyl, cyclobutylmethyl or R4CO- wherein R4 is as defined in Claim 1, B is -Gly- or (D)-Ala, D is -Phe-, E is -methionine- or -methioninesulphoxide- and F is a residue of the formula

wherein R4 is as defined in Claim I, R7 is hydrogen or methyl, and R8 is

b) #(CH2)m#CH2O#OCR4 wherein Ra is as defined in Claim 1, and m is from 0 to 6,

wherein R4 is as defined in Clairn I

wherein Rg is alkyl of I to 5 carbon atoms, f) #(CH2)4#NH2, #(CH2)4#NHCOR4, wherein R4 is as defined in Claim 1,

when Z is other than R4CO-,

g) #(CH2)n#CONH2 wherein n is I or 2, h) #(CH2)n#COOR10, wherein n is as previously defined and R10 is hydrogen or alkyl of I to 5 carbon atoms, wherein A, D and E possess the (L)-configuration and F possesses either the (D)- or (L)-configuration.

8. A compound according to Claim 7 wherein R1 and R2 are hydrogen, Z is hydrogen, alkyl of I to 5 carbon atoms, alkenyl of 3 to 5 carbon atoms or R4CO- wherein R4 is as defined in Claim 1, E is -methioninesulphoxide- and F is a residue of the formula

wherein R4 is as defined in Claim 1, and Ra is b) -CH2O-OCR4 wherein R4 is as defined in Claim 1,

wherein R4 is as defined in Claim I, f) - (CH2)4-NH2 or when Z is other than R4CO-,

9. A compound of formula I, as defined in Claim 1, wherein A is a residue of the formula defined in Claim I, wherein R1 and R2 are as defined in Claim 1, R3 is R'3 as defined in Claim 1, and Z is hydrogen, alkyl of I to 5 carbon atoms, alkenyl of 3 to 5 carbon atoms, cyclopropylmethyl, cyclobutylmethyl or R4CO- wherein R4 is as defined in Claim 1, B is -Gly- or -(D)-Ala-, D is -Phe-, E is -methioninesulphoxide- and F is a residue of the formula

wherein R'3 is as defined in Claim 1, R7 is hydrogen or methyl, and R8 is

b) #(CH2)m#CH2#OR'3 wherein R'3 is as defined in Claim 1, and m is from 0 to 6,

wherein R2 is as defined in Claim 1,

wherein Ra is alkyl of I to 5 carbon atoms, f) -(CH2)4-NH2,

g) #(CH2)n#CONH2 wherein n is I or 2 h) #(CH2)N#COOR10 wherein n is as previously defined, and R10 is hydrogen or alkyl of I to 5 carbon atoms, wherein A, D and E possess the (L)-configuration, and F possesses either the (D)or (L)-configuration.

10. A compound according to Claim 9, wherein R, and R2 are hydrogen, Z is hydrogen, alkyl of 1 to 5 carbon atoms, alkenyl of 3 to 5 carbon atoms or R4CO- wherein R4 is as defined in Claim 1, and F is a residue of the formula

@@@@@ @' is as defined in Claim 1 and Ra is b) -CH2-OR2, wherein R'3 is as defined in Claim 1,

wherein R'3 is as defined in Claim 1, f) -(CH2)4-NH2,

11. A compound of the formula I, as defined in Claim 1, wherein A is a residue of the formula defined in Claim 1, wherein R1 and R2 are as defined in Claim 1, R2 is hydrogen or an R4CO- group, wherein R4 is as defined in Claim 1, and Z is hydrogen, alkyl of I to 5 carbon atoms, alkenyl of 3 to 5 carbon atoms, cyclopropylmethyl, cyclobutylmethyl, or R4CO- wherein R4 is as defined in Claim I, B is -Gly- or -(D)-Ala-, D is a residue of the formula defined in Claim 1, wherein R5 is hydrogen or methyl, and Ra and Z are as defined in Claim 1, E is -methionine-, -methioninesulphoxide- or -methioninesulphone-, and F is a residue of the formula

wherein R2 is as defined in Claim 1, R, is hydrogen or methyl, and Ra is

b) - (CH2)m-CH2OR2, wherein R'3 is as defined in Claim 1, and m is from 0 to 6,

wherein R3 is as defined in Claim 1,

wherein Ra is alkyl of 1 to 5 carbon atoms, and r is 0, 1 or 2, f) - (CH2)4-NH2,

g) #(CH2)n#CONH2 wherein n is 1 or 2, h) #(CH2)n#COOR10 wherein n is as previously defined, and R10 is hydrogen or alkyl of I to 5 carbon atoms, wherein A, D and E possesses the (L)-configuration and F possesses either the (D)or (L)-configuration.

12. A compound according to Claim 11, wherein R1 and R2 are hydrogen, Z is hydrogen, alkyl of I to 5 carbon atoms, alkenyl of 3 to 5 carbon atoms, or R4CO-, wherein R4 is as defined in Claim 1, Rs is hydrogen, E is -methioninesulphoxide- or -methioninesulphone-, and F is a residue of the formula

wherein R2 is as defined in Claim 1, and Ra is b) -CH2OR2 wherein R3 is as defined in Claim 1,

wherein R'3 is as defined in Claim 1, f) #(CH2)4#NH2,

13. H-Tyr-(D)-Ala-Gly-Phe-Met-(L)-serinol.

14. H-Tyr-(D)-Ala-Gly-Phe-(L)-methioninesulphoxide-(L).serinol.

15. H-Tyr-(D)-Ala-Gly-MePhe-Leu-(L)-asparaginol.

16. H-Tyr-(D)-Ala-Gly-Phe-(L)-methionine-(L)-asparaginol.

17. H-Tyr-(D)-Ala-Gly-Phe-(L)-methionine-3-aminobutyrolactone.

18. H-Tyr-(D)-Ala-Gly-Phe-(L)-methionine-(L)-glutaminol.

19. H-Tyr-(D)-Ala-Gly-Phe-(L)methionine-(L)-threoninol.

20. H-Tyr-(D)-Ala-Gly-Phe-(L)-methioninesulphoxide-(L)-threoninol.

21. H-Tyr-(D)-Ala-Gly-Phe-(L)-methioninesulphoxide-(L)-asparaginol.

22. H-Tyr-(D)-Ala-Gly-Phe-(L)-methioninesulphoxide-(L)-glutaminol.

23. H - Tyr - (D) - Ala - Gly - Phe - (L) - methioninesulphoxide - 3 - amino butyrolacetone.

24. A compound according to any one of Claims 3 to 4 and 14 to 23, in complex form.

25. A compound according to Claim 5, 6 or 13, in complex form.

26. A compound according to Claim 7 or 8, in complex form.

27. A compound according to Claim 9 or 10, in complex form.

28. A compound according to Claim 11 or 12, in complex form.

29. A compound according to any one of Claims 3 to 4 and 14 to 23, in salt form.

30. A compound according to Claims 5, 6 or 13, in salt form.

31. A compound according to Claim 7 or 8, in salt form.

32. A compound according to Claim 9 or 10, in salt form.

33. A compound according to Claim 11 or 12, in salt form.

34. A pharmaceutical composition comprising a compound according to any one of Claims 3 to 4, and 14 to 23 or a pharmaceutically acceptable salt or complex thereof, in association with a pharmaceutically acceptable diluent or carrier.

35. A pharmaceutical composition comprising a compound according to any one of Claims 5, 6 or 13, or a pharmaceutically acceptable salt or complex thereof, in association with a pharmaceutically acceptable diluent or carrier.

36. A pharmaceutical composition comprising a compound according to Claim 7 or 8, or a pharmaceutically acceptable salt or complex thereof, in association with a pharmaceutically acceptable diluent or carrier.

37. A pharmaceutical composition comprising a compound according to Claim 9 or 10, or a pharmaceutically acceptable salt or complex thereof, in association with a pharmaceutically acceptable diluent or carrier.

38. A pharmaceutical composition comprising a compound according to Claim 11 or 12, or a pharmaceutically acceptable salt or complex thereof, in association with a pharmaceutically acceptable diluent or carrier.