GB1601754A

GB1601754A - Pharmacologically active aligopeptide derivatives

Info

Publication number: GB1601754A
Application number: GB19202/78A
Authority: GB
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 1977-05-16
Filing date: 1978-05-12
Publication date: 1981-11-04
Also published as: NZ187280A; AU3611378A; DK199578A; BE867121A; JPS53141236A; NL7805165A; DE2819277A1; PT68036A; IT7849374A0; FR2391191A1; PT68036B; IL54714A0

Description

(54) PHARMACOLOGICALLY ACTIVE OLIGOPEPTIDE 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 formula I, A - B - Gly - D - E I wherein A is a residue of formula

wherein Rl is hydrogen or alkyl or 1 to 4 carbon atoms, R. is hydrogen or, together with R1, a -CH2-CH2- group, R3 is hydrogen, alkyl of 1 to 4 carbon atoms or a R4CO- group, R4 is a saturated or unsaturated, linear or branched hydrocarbon group of up to 17 carbon atoms, phenyl or phenylalkyl of 7 to 12 carbon atoms whereby the phenyl residue of said phenyl or phenylalkyl may be mono- or disubstituted with halogen, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, and the R30 group is in the meta- or paraposition to the

residue, Z1 is hydrogen, alkyl of 1 to 5 carbon atoms, alkenyl of 3 to 5 carbon atoms, cyclopropylmethyl, cyclobutylmethyl or a R4CO- or R4'CO- group, Z2 is hydrogen or alkyl of 1 to 4 carbon atoms, R4,CO- is the radical of a natural L-amino acid or a dipeptide radical, derived from two natural L-amino acids whereby one of the natural amino acids in the dipeptide may be replaced by L-methionine sulphoxide, L-methionine sulphone or L-3,4dihydroxyphenylalanine and the amino groups in the R4 residue may be substituted with alkyl of 1 to 4 carbon atoms with the condition that R4CO- is other than a basic amino acid radical or a dipeptide comprising two basic amino acid radicals and, when Z2 is hydrogen and B is D-Ala, R4'CO- is other than Phe or Tyr, B is D-Ala, D-Ser, D-Thr, Aib, D-Met, D-methionine sulphoxide or D-methionine 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, Z is 1 or 2, E 1 ) is a residue of formula

wherein R; is hydrogen or R4CO-, R7 is hydrogen or alkyl of 1 to 4 carbon atoms, R8 is

b) -(CH2)m-CH2OR3' wherein m is () to 6,

wherein R@ is alkyl of 1 to 5 carbon atoms, r is 0, 1 or 2, s is 0, 1 or '. f) -(CH2)4-NH2, -(CH2)4-NHCOR4,

g) -(CH2)n-CONH2 n is 1 or 2, h) -(CH2)n-COOR10 wherein n is 1 or 2, and R", is hydrogen or alkyl of 1 to 5 carbon atoms, i) R8 together with R7 is -(CH2)3-, -CH2-S-CH2- or -CH2-SO-CH2-, 2 ) is a residue of formula

wherein n is 1 or 2. or 3 ) when Z1 is R4'CO- and/or B is D-methionine sulphoxide or D-methionine sulphone and/or R1 and R2 together signify -(CH2)2, E may also be -Met-X, -Leu-X, -Nva-X, -Ile-X, -Val-X, -Nle-X, -Pro-X,

N COX (wherein b is 0 or 1) b NK NH or CH3'S(O) -CH2-CH co-x (wherein a is 1 or 2) wherein X is

wherein each of R, R" and R"' independently signifies hydrogen or alkyl of 1 to 5 carbon atoms, and the residue A has the L, DL or, when R1 and R2 together are -(CH2)2-, also the D configuration, the residue D has the L or DL configuration, and the residue E has the L, D or DL configuration, with the proviso that B a) is D-Ala- only when (i) Z is R4,CO- or (ii) residue A has the D configuration and R1 and R, together are -(CH2)2- or (iii) residue A has the L or DL configuration or R1 and R2 are -(CH2)2- and E is -Pro-X, or (iv) E is

and b) is Aib only when (i) R, and R2 are -(CR2)2- or (ii) E is

wherein r' is 1 or 2.

It is to be understood that throughout the present specification and claims abbreviations for individual optically active amino acid radicals (e.g. Phe, Tyn, Met, Lev etc.) represent the L-forms in accordance with conventional nomenclature, unless otherwise indicated.

When R, is alkyl, this is preferably methyl. R1 is preferably hydrogen or, together with R2, forms an ethylene bridge.

R is preferably hydrogen.

When R3 is alkyl this is preferably methyl. R3 is preferably hydrogen or methyl, especially hydrogen.

R3O is preferably in a position para- to the

residue. When Z and Z2 are each alkyl, these are preferably methyl, Zl is preferably hydrogen or R4,CO-, especially hydrogen.

B is preferably -D-Ala,-D-methionine sulphoxide or D-methionine sulphone, especially -D-Ala or -D-methionine sulphoxide.

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

R6 is preferably hydrogen, NO2 or chlorine, especially hydrogen or NO2.

R, is preferably hydrogen.

RX is preferably hydrogen.

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

When E is an amino acid residue this is preferably methionine, methionine sulphoxide or methionine sulphone, especially methionine sulphoxide.

X is preferably -NR'R", especially -NH2.

E is preferably a residue as hereinbefore defined under E 1"). The residues defined under e), wherein r is 1 or 2, preferably 1 and s is 0 or 1, preferably 1 are especially preferred.

The compounds wherein E is a residue as hereinbefore defined under 1 )g) or serinol are also of interest. The residues, E, preferably have the L-configuration.

R30 is preferably in a position meta- to the -CH2CR1NZ1CO- residue.

R4 may be an alkyl group of from 1 to 17 carbon atoms, preferably from 1 to 12 carbon atoms, most preferably from 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl and n-butyl.

When R4 is phenyl or phenylalkyl of 7 to 12 carbon atoms, e.g. tolyl or benzyl and the phenyl residue is monosubstituted or disubstituted by halogen this is preferably fluorine, chlorine or bromine.

B is preferably D-Ser, D-Thr or Aib.

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

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 if necessary, effecting process variant a), or c) converting a group A, B and/or E of an unprotected or protected peptide into another group A, B and/or E having the definition previously indicated, and, if necessary effecting process variant a).

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

The compounds may exist in salt form, including acid addition salt forms or in the form of complexes. for example, complexes with metals. Acids for acid addition salt formation include organic acids, polmeric acids and inorganic acids. Complexes may, for example, be formed with inorganic metal ions such as calcium ions or magnesium ions.

In the following Examples, all temperatures are indicated in degrees Celsius.

The following abbreviations are used: Aib a-aminoiosobutyric acid Boc tert-butyloxycarbonyl DMF dimethylformamide Dopa 3 ,4-dihydroxyphenylalanine radical Leu-ol leucinol radical Met (0) methionine sulphoxide radical Met (02) methionine sulphone radical Met-ol methioninol radical Met (O)-ol methioninol sulphoxide radical MePhe N-methylphenylalanine radical MeTrp Na-methyltryptophan radical MeTyr N-methyltyrosine radical ONp 4-nitrophenoxy Pro-ol prolinol radical TFA trifluoroacetic acid Thz-ol 4-hydroxymethyl-thiazolidinyl-3-radical Thz(O)-ol 4-hydroxymethyl-thiazolidinyl-sulphoxide-3-radical M.P. melting point.

EXAMPLE 1: H-Tyr-D-Met-Gly-MePhe-Met-ol (trifluoroacetate) 7.5 g of Boc-Tyr-D-Met-Gly-MePhe-Met-ol is dissolved in 100 ml of TFA/methylene chloride [1:1 (v/v)j at room temperature. After 5 minutes, the volume of the mixture is considerably reduced in vacuo and the title product obtained by precipitation with diethyl ether. Decomposition point 90 ; [α]D20 = -4.5 (C = 1.2 in CH3COOH 95% by volume).

The Boc-Tyr-D-Met-Gly-MePhe-Met-ol used as starting material, is obtained as follows: a) Boc-D-Met-Gly-OH A solution of 9 g of glycine and 4.8 g of NaOH in 35 ml of water is added to 37 g of Boc-D-Met-ONp in 150 ml of 1,2-dimethoxyethane. After two hours the reaction mixture is diluted with 300 ml of water and repeatedly extracted with ethyl acetate. The aqueous phase is covered with ethyl acetate and acidified with 4N H2S04. The organic phase is repeatedly washed with dilute KHSO4 solution and then with water and the solvent removed under vacuum. The residue is crystallised from ethyl acetate/petroleum ether.

Decomposition point 126 [o:iD2 = +12.0 (C = 1.1 in DMF). b) Boc-Tyr-D-Met-Gly-OH A solution of 3.8 g of H-D-Met-Gly-OH (trifluoroacetate) [previously prepared by treatment of Boc-D-Met-Gly-OH with TFA [1:1 (v/v)] in 40 ml of DMF and 3.3 ml of DMF and 3.3 ml of trimethylamine are added at room temperature to 40 g of Boc-Tyr-ONp dissolved in 40 ml of DMF. After two hours, the volume of the reaction mixture is considerably reduced in vacuo, diluted with 150 ml of water and worked up in the manner previously described in a). The title compound crystallises from methanol/petroleum ether.

Decomposition point 195 [a]D(' = +11.6 (C = 1.0 in DMF). c) Boc-MePhe-Met-ol 3.1 g Boc-MePhe-OH are dissolved in 30 ml of tetrahydrofuran, cooled to 200 and 1.45 ml of N-ethylmorpholine followed by 1.45 ml of chloroformic acid butyl ester are added whilst stirring. The mixture is stirred for a further 5 minutes at -200C. A cold solution of 1.80 g of methioninol in 8 ml of tetrahydrofuran is added and the mixture left to stand for 2 hours at -5 to 0 and then a further 2 hours at room temperature with stirring. The reaction mixture is diluted with ca 350 ml of ethyl acetate and repeatedly washed with water. 1N citric acid, 10% by volume KHCO3 and 30% by volume NaCl solution. The organic phase is dried with Na2SO4 and evaporated to yield Boc-MePhe-Met-ol as an amorphous product. [a]D" = -54 (C = 1.24 in methanol). d) H-MePhe-Met-ol (trifluoroacetate) 40 ml of 98% by volume TFA is added to a solution of 4.3 g of Boc-MePhe-Met-ol in 20 ml of CH2Cl2, 5 ml of CH3-S-CH2-CH3 and 0.2 ml of HS-CH2-CH2-OH at 0 . The mixture is left to stand for 1 hours at room temperature and the volume reduced to 5-10 ml in vacuo. The oily product is precipitated twice from diethyl ether/petroleum ether and dried under high vacuum to yield H-MePhe-Met-ol (trifluoroacetate) as an amorphous product, [C:iD = +3.2 (C = 0.98 in methanol). e) Boc-TYr-D-Met-Gly-MePhe-Met-ol 2.3 g of dicyclohexylcarbodiimide is added to 4.7 g of Boc-Tyr-D-Met-Gly-OH, 2.7 g of t-hydroxybenzotriazole, 4.1 g of H-MePhe-Met-ol (trifluoroacetate) and 1.1 ml of N-methylmorpholine in 40 ml of DMF at 00. After standing for one hour at 0 and 15 hours at room temperature, the reaction mixture is filtered and the volume considerably reduced under vacuum. The residue is taken up in ethyl acetate and washed repeatedly with dilute KHCOR solution. hydrochloric acid and water, and the solvent taken off under vacuum.

The residue is purified by column chromatography on Kieselgel using a mixture of methylene chloride/methanol. The title compounds is obtained as an amorphous product.

[α]D20 = -23.3 (C = 1.2 in DMF).

EXAMPLE 2: H-Tyr-D-Met(O)-Gly-MePhe-Met(O)-ol (trifluoroacetate) 7.9 g of Boc-Tyr-D-Met(O)-Gly-MePhe-Met(O)-ol is dissolved in 100 ml of TFA/ methylene chloride (1:1 v/v) at 22 . After 5 minutes the volume of the mixture is considerably reduced under vacuum and the title compound precipitated with diethyl ether.

[a]2(' = -8.1 (C = 1 in 95% by volume acetic acid).

The Boc-Tyr-D-Met(O)-Gly-MePhe-Met(O)-ol employed as starting material is prepared as follows: 20 ml of 11 M H2O2 are added to a solution of 7.5 g of Boc-Tyr-D-Met-Gly-MePhe-Metowl in 75 ml of acetic acid at 220. After 5 minutes the reaction mixture is stirred into 1.5 1 of diethyl ether and the precipitated raw product is separated by filtration. The raw product is purified by chromatography on Kieselgel using a mixture of methane/methylene chloride.

The title compound is isolated in amorphous form and treated directly with TFA.

The following compounds can be prepared in manner analogous to that described in Examples 1 or 2 using appropriate starting materials in approximately equivalent amounts TABLE 1 Compounds of formula: A-B-Gly-D-E Ex. Salt c in A B D E [α]D20 No. form AcOH 95% 3 H-Tyr D-Met(O) MePhe Met-ol TFA - 6,9 1,2 4 H-Tyr D-Met MePhe Met(O)-ol TFA - 3,6 1,2 5 H-Tyr D-Met(O2) MePhe Met(O)-ol TFA - 3,1 1 6 H-MeTyr D-Met(O) MePhe Met(O)-ol TFA - 6,5 1 7 H-Ala-Tyr D-Ala MePhe Met(O)-ol HCl -22,2 2,7 8 H-Dopa-Tyr D-Ala MePhe Met(O)-ol HCl -10,3 2,2 9 H-Glu-Tyr D-Ala MePhe Met(O)-ol HCl - 9,2 2,1 10 H-Met-Tyr D-Ala Phe Leu-ol TFA +23,8 1,2 11 H-Met(O)-Tyr D-Ala Phe Leu-ol TFA +24,9 1,1 12 H-Trp-Tyr D-Ala MePhe Met(O)-ol HCl + 5,9 0.85 13 H-Tyr D-Ala Phe Thz-ol TFA +25,3 1,0 14 H-Tyr D-Ala Phe Thz(O)-ol TFA + 1,0 0,5 15 H-Tyr D-Ala Phe Pro-ol TFA +28,6 1,0 16 H-Tyr D-Ala MePhe Pro-ol TFA + 2,9 1,1 17 H-Tyr D-Met Phe Pro-ol TFA +26,5 1 18 H-Tyr D-Met(O) Phe Pro-ol TFA +23,7 1 19 H-Phe-MeTyr D-Ala MePhe Met(O)-ol HCl -53,5 0,9 20 H-MePhe-Tyr D-Ala MePhe Met(O)-ol TFA -18,2 1,05 21 H-MeTrp-Tyr D-Ala MePhe Met(O)-ol TFA -15,1 1,1 22 H-Tyr Aib Phe Met(O)-ol TFA +17,2 1,0 23 H-Tyr D-Ser MePhe Met(O)-ol TFA - 8,1 1,0 TABLE 2 Compounds of formula

Ex. Salt c in Z1 Z2 [α]D20 No. form AcOH 95% (by vol.)

24 H H TFA -35.7 1.1 25 -CH24 H HC1 -18.9 0.55 The compounds of formula I exhibit pharmacological activity. In particular, the compounds exhibit analgesic activity, as indicated by their activity 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.

The compounds of formula I also exhibit central nervous system activity in psychothera- peutic properties as indicated by their ability to inhibit spontaneous motor activity in mice.

Additionally, the compounds exhibit a stimulative effect on the secretion of growth hormone and prolactin as indicated in standard tests in mice.

The compounds are therefore indicated for use as analgesic and psychotherapeutic agents and as stimulants for the secretion of growth hormone and prolactin.

For these uses an indicated daily dose is from 0.5 to 400 mg, suitably from 30 to 350 mg, conveniently administered in unit dosage form, containing from 0.1 to 200 mg, suitably from 7.5 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 formation include organic acids such as trifluoroacetic acid and mineral acids such as hydrochloric acid. Suitable metal ions for complex formation include calcium and magnesium. The present invention also provides a pharmaceutical composition comprising a compound of formula I, in free base form or in the form of a pharmaceutically acceptable salt or complex, in association with a pharmaceutically acceptable carrier or diluent. Such compositions may be in the form of, for example, a solution or capsule.

Claims

WHAT WE CLAIM IS:

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

wherein R, is hydrogen or alkyl or 1 to 4 carbon atoms, R2 is hydrogen or, together with Rl, a -CH2-CH2- group, RX is hydrogen, alkyl of 1 to 4 carbon atoms or a R4CO- group, 1:4 is a saturated or unsaturated, linear or branched hydrocarbon group of up to 17 carbon atoms, phenyl or phenylalkyl of 7 to 12 carbon atoms whereby the phenyl residue of said phenyl or phenylalkyl may be mono- or disubstituted with halogen, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, and the R30 group is in the meta- or paraposition to the

residue, Z1 is hydrogen, alkyl of 1 to 5 carbon atoms, alkenyl of 3 to 5 carbon atoms, cyclopropylmethyl, cyclobutylmethyl or a R4CO- or R4'CO- group, Z2 is hydrogen or alkyl of 1 to 4 carbon atoms, R41CO- is the radical of a natural L-amino acid or a dipeptide radical, derived from two natural L-amino acids whereby one of the natural amino acids in the dipeptide may be replaced by L-methionine sulphoxide, L-methionine sulphone or L-3,4dihydroxyphenylalanine and the amino groups in the R4 residue may be substituted with alkyl of 1 to 4 carbon atoms with the condition that 1:4 CO- is other than a basic amino acid radical or a dipeptide comprising two basic amino acid radicals and, when Z2 is hydrogen and B is D-Ala, R4'CO- is other than Phe ot Tyr, B is D-Ala, D-Ser, D-Thr, Aib, D-Met, D-methionine sulphoxide or D-methionine 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, Z is 1 or 2, E 1 ) is a residue of formula

wherein 1:3' is hydrogen or R4CO-, R? is hydrogen or alkyl of 1 to 4 carbon atoms, R8 is

b) -(CH2)m-CH2OR3' wherein m is 0 to 6,

d) -CH2-S-H

wherein Rg is alkyl of 1 to 5 carbon atoms, r is 0, 1 or 2, s is 0, 1 or 2, f) -(CH2)4-NH2, -(CH2)4-NHCOR4,

g) -(CH2)n-CONH2 wherein n is 1 or 2, h) -(CH2)n-COOR10 wherein n is 1 or 2, and R10 is hydrogen or alkyl of 1 to 5 carbon atoms, i) R8 together with R7 is -(CH2)3-, -CH2-S-CH2- or -CH2-SO-CH2-, 2 ) is a residue of formula

wherein n is 1 or 2, or 3 ) when Z1 is R4'CO- and/or B is D-methionine sulphoxide or D-methionine sulphone and/or R1 and R2 together signify -(CH2)2, E may also be -Met-X, -Leu-X, -Nva-X, -Ile-X, -Val-X, -Nle-X, -Pro-X,

T---COX' (wherein b is 0 or 1) b ,NH or CH -S(O) -CH, (wherein a is 1 or 2) CO-X R' wherein X is -N or -OR"' R" wherein each of R, R" and R"' independently signifies hydrogen or alkyl of 1 to 5 carbon atoms, and the residue A has the L, DL or, when R1 and 1:2 together are -(CH2)2-, also the D configuration, the residue D has the L or DL configuration, and the residue E has the L, D or DL configuration, with the proviso that B a) is D-Ala- only when (i) Z1 is R;CO - or (ii) residue A has the D configuration and R1 and R2 together are -(CH2)2- or (iii) residue A has the L or DL configuration or R1 and R2 are -(CH2)2- and E is -Pro-X, or (iv) E is

and b) is Aib only when (i) Rl and R2 are (CH2)s or (ii) E is

wherein r' is 1 or 2. 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, if necessary, effecting process variant a), or c) converting a group A, B and/or E of an unprotected or protected peptide into another group A, B and/or E having the definition previously indicated 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 1, whenever produced by a process as claimed in Claim 1 or 2.

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

5. H-Tyr-D-Met-Gly-MePhe-Met-ol.

6. H-Tyr-D-Met(O)-Gly-MePhe-Met(O)-ol.

7. A compound of formula I, as defined in Claim 1, wherein A is H-Tyr, B is D-Met(O), D is MePhe and E is Met-ol.

8. A compound of formula I, as defined in Claim 1, wherein A is H-Tyr, B is D-Met, D is MePhe and E is Met(O)-ol.

9. A compound of formula I. as defined in Claim 1, wherein A is H-Tyr, B is D-Met(O2), D is MePhe and E is Met(O)-ol.

10. A compound of formula I, as defined in Claim 1, wherein A is H-MeTyr, B is D-Met(O), D is MePhe and E is Met(O)-ol.

11. A compound of formula I, as defined in Claim 1, wherein A is H-Ala-Tyr, B is 1)-Ala, D is MePhe and E is Met(O)-ol.

12. A compound of formula I, as defined in Claim 1, wherein A is H-Dopa-Tyr, B is 1)-Ala, D is MePhe and E is Met(O)-ol.

13. A compound of formula I, as defined in Claim 1, wherein A is H-Glu-Tyr, B is 1)-Ala, D is MePhe and E is Met(O)-ol.

14. A compound of formula I, as defined in Claim 1, wherein A is H-Met-Tyr, B is D-Ala, D is Phe and E is Leu-ol.

15. A compound of formula I, as defined in Claim 1, wherein A is H-Met(O)-Tyr, B is D-Ala, D is Phe and E is Leu-ol.

16. A compound of formula I, as defined in Claim 1, wherein A is H-Trp-Tyr, B is D-Ala, D is MePhe and E is Met(O)-ol.

17. A compound of formula I, as defined in Claim 1, wherein A is H-Tyr, B is 1)-Ala, D is Phe and E is Thz-ol.

18. A compound of formula I, as defined in Claim 1, wherein A is H-Tyr, B is 1)-Ala, D is Phe and E is Thz(O)-ol.

19. A compound of formula I, as defined in Claim 1, wherein A is H-Tyr, B is 1)-Ala, D is Phe and E is Pro-ol.

20. A compound of formula I, as defined in Claim 1, wherein A is H-Tyr, B is 1)-Ala, D is MePhe and E is Pro-ol.

21. A compound of formula I, as defined in Claim 1, wherein A is H-Tyr, B is D-Met, D is Phe and E is Pro-ol.

22. A compound of formula I, as defined in Claim 1, wherein A is H-Tyr, B is D-Met(O), D is Phe and E is Pro-ol.

23. A compound of formula I, as defined in Claim 1, wherein A is H-Phe-MeTyr, B is 1)-Ala, D is MePhe, E is Met(O)-ol.

24. A compound of formula I, as defined in Claim 1, wherein A is H-MePhe-Tyr, B is 1)-Ala, D is MePhe and E is Met(O)-ol.

25. A compound of formula I, as defined in Claim 1, wherein A is H-MeTrp-Tyr, B is 1)-Ala, D is MePhe and E is Met(O)-ol.

26. A compound of formula I, as defined in Claim 1, wherein A is H-Tyr, B is Aib, D is Phe and E is Met(O)-ol.

27. A compound of formula I, as defined in Claim 1, wherein A is H-Tyr, B is D-Ser, D is MePhe and E is Met(O)-ol.

28. A compound of formula

wherein Z1 and Z are as defined in claim 1.

29. A compound of claim 28, wherein Z1 and Zo are each H.

30. A compound of claim 28, wherein Z1 is cyclobutylmethyl and Z2 iS H.

31. A compound of formula I as defined in claim 1, wherein Z2 is hydrogen, R4'CO is the radical of a natural L-amino acid or a dipeptide radical derived from two natural L-amino acids, B is D-Met, D-methionine sulphoxide or D-methionine sulphone, E has the meaning 1") wherein 1:8 has the meaning a), b), c), d), e), f), g) or h); the meaning 2 ); or the meaning 3 ) excluding -Val-X, -Pro-X and

and the residue A has the L or DL-configuration.

32. A compound of formula I as defined in claim 1, wherein A is H-Tyr, B is D-methionine sulphoxide or D-methionine sulphone, D is MePhe and E is Met-ol or Met(O)-ol.

33. A compound of formula I as defined in claim 1 wherein Z is a R4'CO-group, Z is hydrogen, 1:4,CO- is the radical of a natural L-amino acid or a dipeptide radical derived from two natural L-amino acids whereby one of the natural amino acids in the dipeptide may be replaced by L-methionine sulphoxide or L-methionine sulphone, B is D-Ala, E has the meaning given in claim 31, and the residue A has the L or DL-configuration.

34. A compound of formula I as defined in claim 1 wherein Z, is hydrogen, R4'CO has the meaning given in claim 33, B is D-Ala, D-Met, D-methionine sulphoxide or D-methionine sulphone, and E has the meaning

and the residue A has the L or DL-configuration.

35. A compound of formula I as defined in claim 1, wherein Z, is a R4'CO- group, either (i) R4'CO- is the radical of a natural L-amino acid, the amino group in the R4' residue being mono-substituted with alkyl of 1 to 4 carbon atoms, or (ii) Z is alkyl of 1 to 4 carbon atoms and R4'CO- is the radical of a natural L-amino acid, B is D-Ala, D-Met, D-methionine sulphoxide or D-methionine sulphone, E has the meaning 1 ), 2 ) or 3 ) excluding -Val-X and the residue A has the L or DL-configuration,

36. A compound of formula I as defined in claim 1, wherein - 1:4,CO- is the radical of a natural L-amino acid, the amino group in the R4' residue being optionally mono-substituted with alkyl of 1 to 4 carbon atoms.

B is D-Ala, D-Met, D-methionine sulphoxide or D-methionine sulphone, E has the meaning given in claim 35 and the residue A has the D configuration.

37. A compound of formula I as defined in claim 1, wherein Z2 is hydrogen, 1:4,CO- is the radical of a natural L-amino acid or a dipeptide radical derived from two natural amino acids, whereby one of the natural amino acids in the dipeptide may be replaced by L-methionine sulphoxide, L-methionine sulphone or L-3,4dihydroxyphenylalanine.

B is D-Ser or 1)-Thr, E has the meaning 1") and the residue A has the L or DL-configuration.

38. A compound according to any one of the claims 3, 31, 33, 35 and 36, wherein E has the meaning 1 ) or 2 ) with the proviso that when R8 has the meaning a) or the meaning e) wherein Rg is methyl, r is 0 and s is 1, B is D-methionine sulphoxide or D-methionine sulphone.

39. A compound according to any one of claims 3 to 38 in complex form.

40. A compound according to any one of claims 3 to 38 in salt form.

41. A pharmaceutical composition comprising a compound according to any one of claims 3 to 38 in free base form or in the form of a pharmaceutically acceptable salt or complex, in association with a pharmaceutically acceptable diluent or carrier.