IE910819A1

IE910819A1 - Amino acid derivatives

Info

Publication number: IE910819A1
Application number: IE081991A
Authority: IE
Original assignee: Merck Patent Gmbh
Priority date: 1990-03-13
Filing date: 1991-03-12
Publication date: 1991-09-25
Also published as: EP0446706A2; JPH0578390A; EP0446706A3; HUT56580A; CA2037990A1; PT97019A; AU7276091A; DE4007869A1; KR910016768A; ZA911849B

Abstract

Amino-acid derivatives of the formula I p-Cl-C6H4-CH2-CO-Z-NR<1>-CR<2>R<3>-CO-NR<4>-CHR<5>-CO-Y-R<6> I in which Y, Z, R<1>, R<2>, R<3>, R<4>, R<5> and R<6> have the meaning stated in Claim 1, have tachykinin-agonistic (e.g. vasodilating) and/or tachykinin-antagonistic (e.g. analgesic) effects.

Description

MERCK PATENT GESELLSCHAFT MIT BESCHRANKTER HAFTUNG, a company organised under the laws of the Federal Republic of Germany, of Frankfurter Strasse 250, 61 Darmstadt, Federal Republic of Germany -1IE 91819 Merck Patent Gesellschaft mit beschrankter Haftung 6100 Darmstadt Amino acid derivatives The invention relates to new amino acid derivatives of the formula I P-C1-C6H4-CH2-CO-Z-NR1-CR2R3-CO-NR4-CHR5-CO-Y-R6 I wherein Z is 0, 1 or 2 amino acid radicals attached to one another by a peptide linkage and selected from the group consisting of Ala, Arg, Asn, Asp, Asp (OBut), Gin, Glu, Gly, His, lie, Leu, Lys, Met, aNal, bNal, Orn, Phe, Pro, Ser, Tcc, Thr, Tic, Trp, Tyr, Val, Ca-Me-aNal, Ca-Me-Phe, Ca-Me-Tcc, Ca-Me-Tic, Ca-Me-Trp, Ca-Me-Tyr, where functional groups of the amino acid side chain can also be protected by a protective group, R1, R2, R3, R4 and R5 are each H, A, alkenyl or alkynyl having in each case up to 4 C atoms, Ar, Aralkyl, Het, Het-alkyl, cycloalkyl having 3-7 C atoms, cycloalkylalkyl having 4-11 C atoms, each of which is unsubstituted or monosubstituted or polysubstituted by A, AO and/or Hal, R1 and R2, R1 and R4 or R2 and R4 together each can also form an alkylene chain which has 2-6 C atoms and can be saturated or unsaturated, unsubstituted or monosubstituted or polysubstituted by A, OH, OA, Ar, Ar-alkyl, Het and/or Het-alkyl, Y is Cys, lie, Leu, Met, Met(O), Met(O2), Nle, Phe IE 91819 - 2 or a radical of an analogous thio-amidated amino acid, R6 is OH, OA, NH2, NHA or NA2, Ar is phenyl which is unsubstituted or mono5 substituted or polysubstituted by A, AO, Hal, CF3, OH and/or NH2, or unsubstituted naphthyl, Het is a saturated or unsaturated 5-membered or 6membered heterocyclic radical which has 1-4 N, and/or S atoms, which can be condensed with a benzene ring or a pyridine ring and/or can be monosubstituted or polysubstituted by A, AO, Hal, CF3, HO, O2N, carbonyl oxygen, H2N, HAN, A2N, ACNH, AS, ASO, ASO2, AOOC, CN, H2NCO, ANHC0, A2NC0, ArNHCO, Ar-alkyl-NHCO, H2NSO2, AS02NH, Ar, Ar-alkyl, Ar-alkenyl, hydroxyalkyl and/or aminoalkyl having in each case 1-8 C atoms, and/or in which the N and/or S hetero atoms can also be oxidized, -alkyl- is an alkylene chain having 1-4 C atoms, Hal is F, Cl, Br or I, Ac is H-CO-, A-CO-, Ar-CO-, A-NH-CO- or Ar-NH-COand A is alkyl having 1-8 C atoms, wherein it is also possible for Y to be absent and/or 25 for one or more -ΝΑ-CO- groups to replace one or more -NH-CO- groups, and to salts thereof.

Similar compounds are known from DE-A-3711335, EP-A0176436 and from US-A-4472305.

IE 91819 The invention was based on the object of finding new compounds having valuable properties, especially those compounds which can be used for the preparation of medicaments.

It has been found that the compounds of the formula I and their salts possess very valuable properties. Above all, they have a tachykinin-agonistic action (for example vasodilating) and/or a tachykinin-antagonistic action (for example analgesic). These effects can be demonstrated, for example, by the methods indicated in US-A-4472305, the vasodilator action is, for example, also demonstrated by the method of F. Lembeck et al., Biochem. Res. Comm. 103. 1318-1321 (1981), and the analgesic action is demonstrated, for example, in the writhing test on rats or mice (experimental method, compare C. Vander Wende and S. Margolin, Fed. Proc. 15, 494 et seq. (1956); E. Siegmund et al., Proc. Soc. exp. Biol. (NY) 95, 729-731 (1957); L.L. Hendershot and J. Forsaith, J. Pharmacol, exp. Ther. 125. 237-240 (1959)). Furthermore, in the case of the agonists, stimulation in motoricity and falls in blood pressure occur, and in the case of the antagonists, anti-inflammatory and/or spasmolytic effects occur. Furthermore, the compounds of the formula I exhibit stimulating effects on tear secretion, in particular when applied locally.

The compounds can also be employed as active compounds for medicaments in human and veterinary medicine, in particular for prophylaxis and treatment of cardio30 vascular disorders, spastic disorders, pain, inflammations, disorders of the central nervous system and/or of the circulation, of asthma (e.g. of asthma attacks) and/or for the stimulation of tear secretion.

The abbreviations of amino acid radicals listed above and below stand for the radicals -NR-CR'R-CO- (wherein R, R' and R” have the specific meanings known for each IE 91819 A* amino acid) of the following amino acids: Aib Ala Arg Asn Asp Asp(OBut) Cie Ca—Me—aNal Ca-Me-Phe Ca-Me-Tcc Ca-Me-Tic Ca-Me-Trp Ca-Me-Tyr Cys Deg Dpg Gin Glu Gly His lie Leu Lys Lys(BOC) Lys(CBZ) Met . Met(O) Met(O2) aNal bNal Nle N-Me-Phe N-Me-Trp Orn 2- aminoisobutyric acid alanine arginine asparagine aspartic acid mono-tert.-butyl aspartate cyclo-leucine (1-amino-cyclopentanecarboxy1ic acid) C-a-methyl-3-(a-naphthyl)-alanine C-a-methyl-phenylalanine 3- methyl-l,2,3,4-tetrahydro-b-carboline-3 carboxylic acid 1-methyl-1,2,3,4-tetrahydroisoquinoline-l carboxylic acid C-a-methyl-tryptophan C-a-methyl-tyrosine cysteine diethylglycine (2-amino-2-ethyl-butyric acid) dipropylglycine (2-amino-2-propylvaleric acid) glutamine glutamic acid glycine histidine isoleucine leucine lysine N5-tert.-butoxycarbonyl-lysine N5-benzyloxycarbonyl-lys ine methionine methionine S-oxide methionine S,S-dioxide 3-(a-naphthyl)-alanine 3-(b-naphthyl)alanine norleucine N-methyl-phenylalanine N-methyl-tryptophan ornithine Phe phenylalanine Pro proline Ser serine Tcc 1,2,3,4-tetrahydro-b-carboline-3-carboxylic 5 acid Thr threonine Tic 1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid Trp tryptophan 10 Tyr tyrosine Val valine The abbreviations below also have the following meanings: BOC tert.-butoxycarbonyl 15 BOM benzyloxymethyl imi-BOM benzyloxymethyl in the 1-position of the imidazole ring CBZ benzyloxyc arbony1 Clp p-chlorophenylacetyl 20 DCC I dicyclohexylcarbodiimide DMF dimethylformamide DNP 2,4-dinitrophenyl imi-DNP 2,4-dinitrophenyl in the 1-position of the imidazole ring 25 EDCI N-ethyl-N'- (3-dimethylaminopropyl)-carbodiimide hydrochloride FMOC 9-fluorenylmethoxycarbony1 HOBt 1-hydroxybenzotriazole Me methyl 30 OMe methyl ester OEt ethyl ester POA phenoxyacetyl TFA trifluoroacetic acid Insofar as the amino acids mentioned above can exist in 35 several enantiomeric forms, all these forms and also mixtures thereof (for example the DL-forms) are IE 91819 - Ί included in the above and following text, for example as a constituent of the compounds of the formula I. The L-forms are preferred. Where individual compounds are listed in the following text,* the abbreviations of these amino acids relate in each case to the L-form, unless anything to the contrary is expressly indicated.

The invention also relates to a process for the preparation of an amino acid derivative of the formula I and salts thereof, characterised in that it is liberated from one of its functional derivatives by treatment with a solvolysing or hydrogenolysing agent, or in that a carboxylic acid of the formula II p-Cl-C6H4-CH2-CO-G1-OH II wherein G1 is (a) (b) -Z1-, (c) -Z-, (d) -Z-NR^CRV-CO-, (e) -Z -NR1-CR2R3-CO-NR4-CHR5-CO-, ( f) -z-nr1-cr2r3-co-nr4-chr5-co-yis reacted with an amino compound of the formula III H-G2 III wherein G2 is (a) - z -nr1-cr2r3-co-nr4-chr5-co-y-r6 , (b) -z2-nr1-cr2r3-co-nr4-chr5-co-y-r6 , (c) -nr1-cr2r3-co-nr4-chr5-co-y-r6 , (d) -nr4-chr5-co-y-r6 , (e) -Y-R6, (f) -NH2, NHA or NA2 and Z1 + Z2 together are Z, and in that, if appropriate, a functionally modified amino and/or hydroxyl group in a compound of the formula I is liberated by treatment with solvolysing or - 8 hydrogenolysing agents and/or a free amino group is acylated and/or a radical R6 is converted into another radical R6 by treatment with esterifying, solvolysing or amidating agents and/or a thioether group is oxidized to a sulfoxide group or sulfone group and/or a sulfoxide group is reduced to a thioether group and/or a compound of the formula I is converted into one of its salts by treatment with an acid.

In the preceding and following text, the radicals or 10 parameters Y, Z, R1 to R6, Ar, Het, Hal, Ac, A, G1, G2, Z1 and Z2 have the meanings indicated in the formulae I, II or III, unless anything to the contrary is expressly indicated.

In the formulae above, A has 1-8, preferably 1, 2, 3 15 or 4, C atoms. A is preferably methyl and also ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl or tert.-butyl, and also perityl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethyl-butyl, 1-ethylbutyl, 2-ethylbutyl, 1-ethyl-l-methylpropyl, l-ethyl-2-methylpropyl, 1,1,2trimethylpropyl, 1,2,2-trimethylpropyl, heptyl or octyl.

Cycloalkyl is preferably cyclopropyl, cyclobutyl, cycl25 opentyl, cyclohexyl or cycloheptyl, but is also, for example, 1-, 2- or 3-methylcyclopentyl or 1-, 2-, 3- or 4-methylcyclohexyl.

Accordingly, cycloalkylalkyl is preferably cyclopropylmethyl, 2-cyclopropylethyl, eyelobutyImethyl, 2-cyclo30 butylethyl, eyelopentyImethyl, 2-cyclopentylethyl, eyelohexyImethyl or 2-cyclohexylethyl, but is also, for example, 1-, 2- or 3-methyleyelopentyImethyl or 1-, 2-, 3- or 4-methyleyelohexyImethy1.

Hal is preferably F, Cl or Br, but also I.

IE 91819 - 9 Ac is preferably H-CO-, A-CO-, such as acetyl, propionyl or butyryl, Ar-CO-, such as benzoyl, ο-, mor p-methoxybenzoyl or 3,4-dimethoxybenzoyl, A-NH-CO-, such as N-methylcarbamoyl or N-ethylcarbamoyl, or ArNH-CO-, such as N-phenylcarbamoyl.

Ar is preferably phenyl and also preferably ο-, m- or p-tolyl, ο-, m- or p-ethylphenyl, ο-, m- or p-methoxyphenyl, ο-, m- or p-fluorophenyl, ο-, m- or p-chlorophenyl, ο-, m- or p-bromophenyl, ο-, m- or p-iodophenyl, ο-, m- or p-trifluoromethylphenyl, ο-, m- or p hydroxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5dimethoxyphenyl, 3,4,5-trimethoxyphenyl, ο-, m- or paminophenyl, 1-naphthyl or 2-naphthyl.

Accordingly, Ar-alkyl is preferably benzyl, 1-phenylethyl, 2-phenylethyl, ο-, m- or p-methylbenzyl, l-o-, -m- or -p-tolylethyl, 2-0-, -m- or -p-tolylethyl, ο-, m- or p-ethylbenzyl, l-ο-, -m- or -p-ethylphenylethyl, 2- 0-, -m- or -p-ethylphenylethyl, ο-, m- or p-methoxybenzyl, l-ο-, -m- or -p-methoxyphenylethyl, 2-o-, -mor -p-methoxyphenylethyl, ο-, m- or p-fluorobenzyl, Ιο-, -m- or p-fluorophenylethyl, 2-0-, -m- or -p-fluoro phenylethyl, ο-, m- or p-chlorobenzyl, l-ο-, -m- or -p chlorophenylethyl, 2-ο-, -m- or -p-chlorophenylethyl, ο-, m- or p-bromobenzyl, l-ο-, -m- or -p-bromophenylethyl, 2-0-, -m- or -p-bromophenylethyl, ο-, m- or piodobenzyl, l-ο-, -m- or -p-iodophenylethyl, 2-ο-, -mor -p-iodophenylethyl, ο-, m- or p-tri-fluoromethylbenzyl, ο-, m- or p-hydroxybenzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, ο-, m- or p-aminobenzyl, 1-naphthylmethyl or 2-naphthylmethyl. 1 Het is preferably 2-furyl, 3-furyl, 2-thienyl, 3thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazo lyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3- , 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 410 or 5-isothiazolyl, 2-, 3- or 4-pyridyl or 2-, 4-, 5- or 6-pyrimidyl, and is also preferably 1,2,3-triazol-l-yl, -4-yl or -5-yl, 1,2,4-triazol-l-yl, -3-yl or -5-yl, 1tetrazolyl, 5-tetrazolyl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-cxadiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,3,4-thiadiazol-5yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 2,l,5-thiadiazol-3-yl, 2,l,5-thiadiazol-4-yl, 2-, 3-, 4- , 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3-pyridazinyl, 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 3- , 4-, 5-, 6- or 7-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzthiazolyl, 2-, 4, - , 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8or 9-acridinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolyl, 2-, 4- , 5-, 6-, 7- or 8-quinazolyl. The heterocyclic radicals can also be partly or completely hydrogenated.

Het can, therefore, also be, for example: 2,3-dihydro25 2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or - furyl, tetrahydro-2-furyl, tetrahydro-3-furyl, tetrahydro-2 -thienyl, tetrahydro-3-thienyl, 2,3-dihydro-1, 2-, -3-, -4- or -5-pyrryl, 2,5-dihydro-l-, -2-, -3-, 4- or -5-pyrryl, 1-, 2- or 3-pyrrolidinyl, tetrahydro30 1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4or -5-pyrazolyl, 2,5-dihydro-1-, -2-, -3-, -4- or 5pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4dihydro-Ι-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro1- , -2-, -3-, -4-, -5- or -6-pyridyl, 1,2,3,6-tetra35 hydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro2- , -3- or -4-pyranyl, 1,4-dioxanyl, l,3-dioxan-2-, -4or -5-yl, hexahydro-Ι-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidyl, 1-, 2- or 311 piperazinyl, 1,2,3,4-tetrahydro-l-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-l-, -2-, -3-, -4-, -5-, -6-, -7- or 8-isoquinolyl.

The heterocyclic radicals can also be substituted as 5 indicated. Het can, therefore, preferably also be: 2amino-4-thiazolyl, 4-carboxy-2-thiazolyl, 4-carbamoyl2-thiazolyl, 4-(2-aminoethyl)-2-thiazolyl, 2-aminc-5,6dimethyl -3 -pyrazinyl or 4-carbamoylpiperidino, and also, for example, 3-, 4- or 5-methyl-2-furyl, 2-, 410 or 5-methyl-3-furyl, 2,4-dimethyl-3-furyl, 5-nitro-2furyl, 5-styryl-2-furyl, 3-, 4- or 5-methyl-2-thienyl, 2-, 4- or 5-methyl-3-thienyl, 3-methyl-5-tert.-butyl-2thienyl, 5-chloro-2-thienyl, 5-phenyl-2- or -3-thienyl, 1-, 3-, 4- or 5-methyl-2-pyrrolyl, l-methyl-4-nitro-215 pyrrolyl, l-methyl-5-nitro-2-pyrrolyl, 3,5-dimethyl-4ethyl-2-pyrrolyl, 4-methyl-5-pyrazolyl, 4-methyl-2thiazolyl, 5-methyl-2-thiazolyl, 2-methyl-4-thiazolyl, - methyl-4-thiazolyl, 2-methyl-5-thiazolyl, 4-methyl-5thiazolyl, 2,4-dimethyl-5-thiazolyl, 3-, 4-, 5- or 620 methyl-2-pyridyl, 2-, 4-, 5- or 6-methyl-3-pyridyl, 2or 3-methyl-4-pyridyl, 3-, 4-, 5- or 6-chloro-2pyridyl, 2-, 4-, 5- or 6-chloro-3-pyridyl, 2-chloro-4pyridyl, 3-chloro-4-pyridyl, 2,6-dichloropyridyl, 2hydroxy-3-, -4-, -5- or -6-pyridyl (= lH-2-pyridon-3, 25 4-, -5- or -6-yl), 5-phenyl-lH-2-pyridon-3-yl, 5-pmethoxyphenyl-lH-2-pyridon-3-yl, 2-methyl-3-hydroxy-4hydroxymethyl-5-pyridyl, 2-hydroxy-4-amino-6-methyl-3pyridyl, 3-N'-methylureido-lH-4-pyridon-5-yl, 5-methyl4-pyrimidyl, 6-methyl-4-pyrimidyl, 2,6-dihydroxy-430 pyrimidyl, 5-chloro-2-methyl-4-pyrimidyl, 2-methyl-4amino-5-pyrimidyl, 3-methyl-2-benzofuryl, 2-ethyl-3benzo-furyl, 7-methyl-2-benzothienyl, 1-, 2-, 4-, 5-, 6- or 7-methyl-3-indolyl, l-methyl-5- or -6-benzimidazolyl, l-ethyl-5-benzimidazolyl, l-ethyl-6-benzimida35 zolyl and 3-, 4-, 5-, 6-, 7- or 8-hydroxy-2-quinolyl.

R1 and R4 are preferably each H or together form an alkylene chain having 2-6, in particular 2 C atoms, in which case R2 and R3 are preferably each H.

R1 and R2 together can also represent an alkylene chain having 2-6, in particular 3, C atoms; in this case, R3 and R4 are preferably H.

R2 and R3 are otherwise preferably identical and are preferably each A, in particular methyl, and also ethyl, propyl, isopropyl, butyl, or isobutyl.

Furthermore, R2 and R4 together preferably form an alkylene chain having 2-6, in particular 2 or also 3, C atoms; in this case R3 is preferably H.

Accordingly, the group -NR1-CR2R3-CO-NR4- is preferably -NH-C(A)2-CO-NH-, in particular -NH-C(CH3)2-CO-NH-(= Aib-NH-), and also -NH-C(C2H5)2-CO-NH-(= Deg-NH-) or -NH-C(C3H7)2-CO-NH- (= -Dpg-NH-); The group -NR1-CR2R3-CO-NR4-CHR5-CO is particularly preferably -CH [ CH2CH (CH3) 2 ] -C0(Pip-Leu).

R5 is preferably H or A, in particular alkyl having 1-4 C atoms, particularly preferably isobutyl, and also preferably n-butyl, sec.-butyl or isopropyl.

R6 is preferably NH2, also preferably OMe or OEt.

A particularly preferred group of compounds of the formula I is that in which the group Y is absent. Otherwise, Y is preferably Phe, also preferably Ile, Leu, Met or Nle.

Z is preferably 2, but also 0 or 1 amino acid radicals 5 which are attached to one another by a peptide linkage in particular one of the groups Trp-Ile, Trp-D-Ile, DTrp-Ile, D-Trp-D-Ile, Trp-Phe, Trp-D-Phe, D-Trp-Phe, D Trp-D-Phe, furthermore preferably one of the groups Phe-Phe, Phe-D-Phe, Phe-Val, Phe-D-Val, Tcc-Phe, Tcc-D Phe, D-Tcc-Phe, D-Tcc-D-Phe, Trp-Tyr, Trp-D-Tyr, D-Trp Tyr, D-Trp-D-Tyr, N-Me-Trp-Phe, N-Me-Trp-D-Phe.

Accordingly, the invention relates particularly to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by means of the partial formulae la to If following, which correspond to the formula I, but wherein the group -NR1-CR2R3-CO-NR420 in la is -NH-C(A) 2-CO-NH-; in lb is -Aib-ΝΗ-, -Deg-NH alkylene in Ic is -NH-—l-Cf---CO-NH-; in Id is -Cle-NH-; in Ie is -NH-L ; and in If is -ΐΛΆϊParticularly preferred are compounds of the formulae I and Ia' to If', which correspond to the formulae I and Ia to If, but wherein in addition R5 is H or A and/or Y is absent, or is Met, lie, Leu, Nle or Phe and/or R6 NH2, OMe or OEt, and also compounds of the formulae I and la to If, which correspond to the formulae I and Ia to If, but wherein in addition R5 is isobutyl and/or Y is absent, or is Phe or Met and/or R6 is NH2 or OMe.

Especially preferred among the compounds of the formulae I, I', I, Ia to If, Ia' to If' and Ia to If are those in which Y is absent and/or in which Z is D-Trp-Ile, D-Trp-D-Ile or D-Trp-D-Phe.

The compounds of the formula I and also the starting materials for their preparation are, incidentally, prepared by methods known per se, such as are described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart; compare also DE-A-37 11 335, EP-A-0176436, and US-A-4 472 305), in particular under reaction conditions which are known and suitable for the reactions mentioned. In this regard, it is also possible to make use of variants which are known per se, but are not mentioned here in detail.

If desired, the starting materials can also be formed in situ, so that they are notisolated from the reaction mixture, but are immediately reacted further to give the compounds of the formula I.

The compounds of the formula I can be obtained by liberating them from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolysis .

Preferred starting materials for the solvolysis or 10 hydrogenolysis are those which, instead of one or more free amino and/or hydroxyl groups, contain corresponding protected amino and/or hydroxyl groups, preferably groups of this type which, instead of an H atom attached to an N atom, carry an amino protective group, for example those which correspond to the formula I, but, instead of an His group, contain an N(im)-R7-His group (wherein R7 is an amino protective group, for example BOM or DNP).

Preferred starting materials are also those which, instead of the H atom of a hydroxyl group, carry a hydroxyl protective group, for example those which correspond to the formula I, but, instead of one Ser or Asp group, contain an -NH-CH (CH2OR8)-CO or -NH-CH(CH2COOR8)-CO group (wherein R8 is a hydroxyl protective group).

It is also possible for several - identical or different - protected amino and/or hydroxyl groups to be present in the molecule of the starting material. If the protective groups present are different from one another, they can in many cases be split off selectively.

The term amino protective group is generally known and relates to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which can be removed readily after the desired chemical reaction has been carried out at another point on the molecule. Typical representatives of groups of this kind are, in particular, unsubstituted or substituted acyl, aryl (for example DNP), aralkoxy5 methyl (for example BOM) or aralkyl (for example benzyl, 4-nitrobenzyl or triphenylmethyl) groups. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their nature and size is, incidentally, not critical; groups having 1-20, in particular 1-8, C atoms are, however, preferred. In the context of the present process, the term acyl group, is to be understood in the widest sense. It embraces acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids and also, in particular, alkoxycarbonyl, aryloxycarbonyl and, above all, aralkoxycarbonyl groups. Examples of acyl groups of this type are alkanoyl, such as acetyl, propionyl or butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl or toluyl; aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC or 2-iodoethoxycarbonyl; and aralkyloxycarbonyl, such as CBZ (carbobenzoxy), 4methoxybenzyloxycarbonyl or FMOC. Preferred amino protective groups are DNP and BOM, and also CBZ, FMOC, benzyl and acetyl.

The term hydroxyl protective group is also generally known and relates to groups which are suitable for protecting a hydroxyl group against chemical reactions, but which can be removed readily after the desired chemical reaction has been carried out at another point in the molecule. Typical representatives of such groups are the unsubstituted or substituted aryl, aralkyl or acyl groups mentioned above, and also alkyl groups. The nature and size of the hydroxyl protective groups is not critical, since they are removed again after the desired chemical reaction or reaction sequence; groups having 1-20, in particular 1-10, C atoms are preferred.

Examples of hydroxyl protective groups are, inter alia: benzyl, p-nitrobenzoyl, p-toluenesulfonyl and acetyl, benzyl and acetyl being particularly preferred.

The functional derivatives of the compounds of the 5 formula I to be used as starting materials can be prepared by customary methods of amino acid and peptide synthesis, such as are described, for example, in the standard works and patent applications mentioned, and also, for example by the Merrifield solid phase method.

The liberation of the compounds of the formula I from their functional derivatives is effected - depending on the protective group used - with, for example, strong acids, preferably TFA or perchloric acid, but also with other strong inorganic acids, such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, or sulfonic acids, such as benzenesulfonic or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are preferably organic solvents, for example carboxylic acids, such as acetic acid, ethers, such as tetrahydrofuran or dioxane, amides, such as DMF, halogenated hydrocarbons, such as methylene chloride, and also alcohols, such as methanol, ethanol or isopropanol, and also water. Mixtures of the abovementioned solvents are also suitable. TFA is preferably used in excess without the addition of a further solvent; perchloric acid is used in the form of a mixture of acetic acid and 70% perchloric acid in a 9 : 1 ratio. The reaction temper30 atures for the cleavage are preferably between about 0 and about 50°; the reaction is preferably carried out between 15 and 30° (room temperature). ; The BOC group can be split off, for example, preferably by means of 40% trifluoroacetic acid in methylene chlo35 ride or by means of about 3 N to 5 N HCI in dioxane at 15-30°, while the FMOC group can be split off by means of an approximately 5 to 20% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30°. Splitting off the DNP group is possible, for example, also by means of an approximately 3 to 10% solution of 2-merc5 aptoethanol in DMF/water at 15-30°.

Protective groups which can be removed by hydrogenolysis (for example BOM, CBZ or benzyl) can be split off, for example, by treatment with hydrogen in the presence of a catalyst (for example a noble metal catalyst such as palladium, preferably on a support such as charcoal). Suitable solvents for this reaction are those indicated above, in particular, for example, alcohols such as methanol or ethanol, or amides, such as DMF. As a rule, the hydrogenolysis is carried out at temperatures between about 0 and 100° and pressures between about 1 and 200 bar, preferably at 20-30° and 1-10 bar. Hydrogenolysis of the CBZ group can be effected readily, for example, over 5 to 10% Pd/C in methanol or with ammonium formate (in place of H2) over Pd-C in methanol/DMF at 20-30°.

Compounds of the formula I can also be obtained by direct peptide synthesis from a carboxylic acid component (formula II) and an amine component (formula III). Examples of suitable carboxylic acid components are those of the partial formulae Clp-OH (p-chlorophenylacetic acid),( Clp-Z-OH, Clp-Z-NR1-CR2R3-COOH, ClpZ-NR1-CR2R3-CO-NR4-CHR5-COOH or Clp-Z-NR1-CR2R3-CO-NR4CHR5-CO-Y-OH, while suitable amine components are those of the partial formulae H-Z-NR1-CR2R3-CO-NR4-CHR5-CO-Y30 R6, H-NR1-CR2R3-CO-NR4-CHR5-CO-Y-R6, H-NR4-CHRS-CO-Y-R6, HY-R6 or HR6 (wherein R6 is NH2, NHA or NA2) . The peptide bond can, however, also be made within the group Z; in this case a carboxylic acid of the formula Clp-Z1-OH is reacted with an amino compound of the formula H-Z2-NR135 CR2R3-CO-NR4-CHR5-CO-Y-R6, Z1 + Z2 being Z. This reaction is preferably carried out by customary methods of peptide synthesis, such as are described, for example, in Houben-Weyl, loc. cit., volume 15/11, pages 1 to 806 (1974).

The reaction is preferably carried out in the presence of a dehydrating agent, for example a carbodiimide, such as DCCI or EDCI, and also propanephosphonic anhydride (compare Angew. Chem. 92., 129 (1980)), diphenylphosphoryl azide or 2-ethoxy-N-ethoxycarbonyl-l,2dihydroquinoline, in an inert solvent, for example a halogenated hydrocarbon, such as methylene chloride, an ether, such as tetrahydrofuran or dioxane, an amide, such as DMF or dimethylacetamide, or a nitrile, such as acetonitrile, or in mixtures of these solvents, at temperatures between about -10 and 40, preferably between 0 and 30°.

Instead of II or III, it is also possible to employ in the reaction suitable reactive derivatives of these compounds, for example compounds in which reactive groups are blocked in the meantime by protective groups. The amino acid derivatives III can, for example, be used in the form of their activated esters, which are preferably formed in situ, for example by the addition of HOBt or N-hydroxysuccinimide.

The starting materials of the formulae II and III are for the most part known. Insofar as they are not known, they can be prepared by known methods, for example the abovementioned methods of peptide synthesis and of splitting protective groups.

If desired, a functionally modified amino and/or hydroxyl group in a compound of the formula I can be liber30 ated by solvolysis or hydrogenolysis in accordance with one of the methods described above.

Thus it is possible, in particular, to convert a compound of the formula I wherein functional groups in group Z are protected by a protective group into a compound of the formula I with an unprotected group Z, expediently by hydrogenolysis, if the protective group is CBZ, otherwise by selective solvolysis. It is possible, for example, to convert com5 pounds which contain an Lys(CBZ) group into corresponding compounds which contain instead an Lys group.

It is also possible to acylate a free amino group (for example on a radical Het) in customary manner, by reacting it with an acid of the formula Ac-OH (wherein Ac has the given meaning) or with a reactive derivative of an acid of this type. Suitable reactive derivatives are, for example, the chlorides (for example acetyl chloride), bromides (for example benzoyl bromide) or anhydrides (for example acetic anhydride) of the above15 mentioned acids. The acylation is preferably carried out in one of the abovementioned inert solvents, where the addition of a base such as triethylamine or pyridine can be advantageous.

Furthermore, it is possible to convert a radical R6 into another radical R6 by treatment with esterifying, solvolysing, or amidating agents. In this manner, an acid of the formula I (R6 = OH) can be esterified, for example with the aid of an alcohol of the formula A-OH or of a diazoalkane, for example diazomethane, or an ester of the formula I (R6 = OA) can be hydrolysed to the corresponding acid of the formula I (R6 = OH), for example, using aqueous dioxane-containing sodium hydroxide solution at room temperature. It is also possible, for example, to convert one of the abovementioned esters into the corresponding amide of the formula I (R6 = NH2, NHA or NA2) by treatment with ammonia or with an amine of the formula A-NH2 or A2NH.

It is also possible to oxidize a thioether group to a sulfoxide group, in particular a group Y = Met to a group Y = Met(O), for example, by feeding air into a solution of the compound of the formula I (Y = Met) in acetonitrile/water at temperatures between 0 and 30°.

Conversely, it is possible to reduce a sulfoxide group (for example in I, Y = Met(0)) to a thioether group (for example in I, Y = Met), for example by means of NH4I in aqueous TFA at temperatures between -10 and 25° A base of the formula I can be converted into the appropriate acid addition salt by means of an acid. Acids suitable for this reaction are, in particular, those which afford physiologically acceptable salts. Thus it is possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrogen halide acids, such as hydrochloric or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, or sulfamic acid, and also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionic acid, 3-phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, 225 hydroxyethanesulfonic acid, benzenesulfonic acid, ptoluenesulfonic acid, naphthalenemonosulfonic and naphthalenedisulfonic acids or laurylsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used to isolate and/or purify the compounds of the formula I.

The new compounds of the formula I and their physiologically acceptable salts can be used for the preparation of pharmaceutical formulations by bringing them into a suitable dosage form together with at least one excipient or auxiliary and, if desired, together with one or more further active compound(s). The formulations thus obtained can be employed as medicaments in human or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral or rectal) administration, parenteral or local (for example topical) administration or for administration in the form of an inhalation spray, and which do not react with the new compounds, for example water, lower alcohols, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate and other fatty acid glycerides, gelatine, soya lecithin, carbohydrates, such as lactose or starch, magnesium stearate, talc, cellulose or vaseline. Tablets, coated tablets, capsules, syrups, elixirs or drops are especially used for oral administration; lacquered tablets and capsules having coatings or capsule casings resistant to gastric juices are of particular interest. Suppositories are used for rectal administration; solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants are used for parenteral administration. Suitable formulations for topical administration are, for example, solutions which can be used in the form of eye drops, and also for example, suspensions, emulsions, creams, ointments or compresses. Sprays containing the active compound either dissolved or suspended in a propellant gas mixture (for example fluorochlorohydrocarbons) can be used for administration as an inhalation spray. It is preferable in this regard to use the active compound in a micronized form, and one or more additional physiologically tolerable solvents can be present, for example ethanol. Inhalation solutions can be administered by means of customary inhalers. The new compounds can also be lyophilized and the resulting lyophilisates can be used, for example, for the preparation of injection formulations. The formulations indicated can be sterilized and/or can contain auxiliaries, such as preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants and/or aroma substances. If desired, they can also contain one or more further active compounds, for example one or more vitamins.

As a rule, the substances according to the invention are administered analogously to other known, commercially available peptides, but, in particular, analogously to the compounds described in US-A-4 472 305, . preferably in dosages between about 0.05 and 500, especially between 0.5 and 100 mg, per dosage unit. The daily dosage is preferably between about 0.01 and 2 mg/kg of body weight. The particular dose for each specific patient depends, however, on a very wide variety of factors, for example on the efficacy of the particular compound employed, on the age, body weight, general state of health, sex, diet, time and means of administration, excretion rate, combination of medicaments and the severity of the particular disorder to which the therapy applies. Parenteral administration is preferred.

In the preceding and following text all temperatures are quoted in °C. In the following examples, customary working up means as follows: if necessary, water is added, the mixture is neutralized and extracted with ether or methylene chloride, the phases are separated, the organic phase is dried over sodium sulfate, filtered and evaporated, and the residue is purified by chromatography over silica gel and/or crystallization. RT - retention time (minutes) for HPLC on an RP 18 250-4 column, unless otherwise stated; mobile phase: a = water, b = 0.3% TFA in water, c = acetonitrile.

Example 1 The pH of a mixture of 949 mg of p-chlorophenylacetylL-(N-imi-2,4-dinitrophenyl-histidyl)-L-phenylalanyl-aaminoisobutyryl-L-leucyl-methionine-amide [Clp-(imi5 DNP-His)-Phe-Aib-Leu-Met-NH2; obtainable from Clp-(imiDNP-His)-OH and H-Phe-Aib-Leu-Met-NH2 analogously to Example 3, see below], 2 g of 2-mercaptoethanol, 20 ml of DMF and 20 ml of water is adjusted to 8 by stirring with aqueous Na2CO3 solution at 20°, and the mixture is stirred for 2 hours at 20°. Working up in the customary manner gives p-chlorophenylacetyl-L-histidyl-L-phenylalanyl-a-aminoisobutyryl-L-leucyl-methionine-amide (Clp-His-Phe-Aib-Leu-Met-NH2) .

Example 2 1 g of Clp-Phe-(imi-BOM-His)-Aib-Leu-Nle-NH2 [obtainable from Clp-Phe-(imi-BOM-His)-OH and H-Aib-Leu-Nle-NH2 analogously to Example 3, see below] is dissolved in 25 ml of methanol, and the mixture is hydrogenated for 3 hours over 0.5% Pd/C at 20° and 1 bar; after fil20 tration, the mixture is evaporated and worked up in the customary manner to give Clp-Phe-His-Aib-Leu-Nle-NH2.

Example 3 1.01 g of N-methylmorpholine is added to a solution of 1.71 g of p-chlorophenylacetic acid (Clp-OH) in 60 ml of methylene chloride with cooling. 6.59 g of D-TrpIle-Pip-Leu-Phe-NH2, 1.35 g of HOBt and a solution of 1.92 g of EDCI in 50 ml of methylene chloride are added with stirring, the mixture is stirred for 14 hours at 4’ and evaporated. Customary working up gives Clp-D30 Trp-Ile-Pip-Leu-Phe-NH2, RT 22.64 (b/c 57:43).

The following are obtained analogously: Clp-Phe-Val-Pip-Leu-Met-NH2, RT 10.93 (a/c 55:45) Clp-Phe-Val-Pip-Leu-Met(0)-NH2 Clp-Phe-Val-Pip-Leu-Met(O2) -NH2 Clp-D-Tcc-Phe-Pip-Leu-OMe, RT 34.91 (a/c 1:1) Clp-D-Tcc-Phe-Pip-Leu-Phe-NH2, RT 18.46 (a/c 1:1) Clp-D-Tcc-D-Phe-Pip-Leu-Phe-NH2, RT 10.53 (a/c 45:55) Clp-Trp-Phe-Pip-Leu-Leu-NH2, RT 11.45 (a/c 1:1) Clp-Trp-D-Phe-Pip-Leu-Leu-NH2, RT 11.51 (a/c 1:1) Clp-D-Trp-Ile-Pip-Leu-Phe-OMe Clp-D-Trp-D-Ile-Pip-Leu-Phe-NH2, RT 21.40 (b/c 57:43) Clp-D-Trp-D-Ile-Pip-Leu-Phe-OMe Clp-D-Trp-Phe-Pip-Leu-NH2 Clp-D-Trp-Phe-Pip-Leu-OMe, RT 23.3 (b/c 1:1) Clp-D-Trp-Phe-Pip-Leu-Ile-NH2, RT 14.46 (a/c 1:1) Clp-D-Trp-Phe-Pip-D-Leu-Ile-NH2, RT 21.37 (a/c 1:1) Clp-D-Trp-Phe-Pip-Leu-Leu-NH2, RT 9.11 (b/c 1:1) Clp-D-Trp-Phe-Pip-Leu-Met-NH2 Clp-D-Trp-Phe-Pip-Leu-Met(0)-NH2 Clp-D-Trp-Phe-Pip-Leu-Met (O2)-NH2, RT 11.50 (b/c 55:45) Clp-D-Trp-Phe-Pip-Leu-D-Met-NH2, RT 12.56 (a/c 1:1) Clp-D-Trp-Phe-Pip-D-Leu-D-Met-NH2, RT 15.54 (a/c 1:1) Clp-D-Trp-Phe-Pip-Leu-Phe-NH2, RT 18.38 (b/c 55:45) Clp-D-Trp-Phe-Pip-Leu-Phe-OMe, RT 32.76 (a/c 45:55) Clp-D-Trp-Phe-Pip-D-Leu-Phe-OMe, RT 39.76 (a/c 45:55) Clp-D-Trp-D-Phe-Pip-Leu-Phe-NH2, RT 20.92 (b/c 55:45) Clp-D-Trp-Tyr-Pip-Leu-Phe-NH2, RT 12.28 (b/c 6:4) Clp-D-Trp-D-Tyr-Pip-Leu-Phe-NH2, RT 12.36 (b/c 6:4) Clp-D-N-Me-Phe-Phe-Pip-Leu-OMe Clp-N-Me-Trp-Phe-Pip-Leu-Leu-NH2, RT 16.18 (a/c 1:1) Clp-N-Me-Trp-D-Phe-Pip-Leu-Leu-NH2, RT 15.92 (a/c 1:1) Clp-D/L-N-Me-Trp-Ile-Pip-Leu-OMe, RT 19.54 (a/c 1:1) Clp-D-N-Me-Trp-Phe-Pip-Leu-OMe Clp-D-N-Me-Trp-Phe-Pip-Leu-NH2 Clp-D-N-Me-Trp-Phe-Pip-Leu-Leu-OMe Clp-D-N-Me-Trp-Phe-Pip-Leu-Leu-NH2, RT 18.42 (a/c 1:1) Clp-D-N-Me-Trp-D-Phe-Pip-Leu-Leu-NH2, RT 17.68 (a/c 1:1) Clp-D-N-Me-Trp-Phe-Pip-Leu-Met(O2) -OMe Clp-D-N-Me-Trp-Phe-Pip-Leu-Met(02) -NH2 Clp-D-N-Me-Trp-Phe-Pip-Leu-Nle-OMe Clp-D-N-Me-Trp-Phe-Pip-Leu-Nle-NH2 Clp-D-N-Me-Trp-Phe-Pip-Leu-Phe-OMe Clp-D-N-Me-Trp-Phe-Pip-Leu-Phe-NH2.

Example 4 23-[3-Benzyl-4-(Clp-D-Trp-Phe)-2-oxopiperazino]-4methylvaleryl-Phe-NH2 [Clp-D-Trp-Phe-(3-benzyl-PipLeu)-Phe-NH2], RT 44.34 (b/c 1:1), is obtained analo10 gously to Example 3 from Clp-D-Trp-OH and 2S-(3-benzyl4-L-phenylalanyl-2-oxopiperazino)-4-methyIvaleryl-PheNH2. 2-[4-(Clp-D-Trp-Ile)-2-oxohexahydro-1H-1,4-diazepino]4-methy 1 valeryl-Met-NH2, 2 isomers, RT 27.28 and 21.25 (a/c 55:45), is obtained analogously using 2-(4-Ile-2oxohexahydro-lH-1,4-diazepino)-4-methylvaleryl-Met-NH2.

Example 5 Clp-D-Trp-Phe-(N-benzyl-Gly)-Leu-Met-NH2, rt 28.02 (b/c 1:1), is obtained analogously to Example 3 from Clp-D20 Trp-Phe-OH and (N-benzyl-Gly)-Leu-Met-NH2. 2S-[4-(Clp-D-Trp-Phe)-2-oxohexahydro-IH-1,4-diazepino] 4-methylvaleramide .is obtained analogously using 2S-(2oxohexahydro-lH-1,4-diazepino)-4-methylvaleramide.

Example 6 Clp-D-Trp-D-Phe-(N-benzyl-Gly)-Leu-Phe-NH2, RT 37.56 (b/c 1:1) is obtained analogously to Example 3 from Clp-D-Trp-D-Phe-(N-benzyl-Gly)-OH and H-Leu-Phe-NH2.

Example 7 Clp-Phe-Val-D-Pro-Leu-Met-NH2, RT 22.92 (b/c 55:45), is obtained analogously to Example 3 from Clp-Phe-Val-D-Pro-Leu-OH and H-Met-NH2.

Clp-D-Trp-Phe-Pip-Leu-Met-thioamide (Clp-D-Trp-PhePip-Leu-Met-CS-NH2) or Clp-D-N-Me-Trp-Phe-Pip-Leu-Met5 thioamide is obtained analogously from Clp-D-Trp-PhePip-Leu-OH (or Clp-D-N-Me-Trp-Phe-Pip-Leu-OH) and methionine thioamide (Met-CSNH2).

Example 8 Clp-D-Trp-Ile-Pip-Leu-Phe-N(C2H5)2 is obtained analo10 gously to Example 3 from Clp-D-Trp-Ile-Pip-Leu-Phe-OH and diethylamine.

The following are obtained analogously using the corresponding amines: Clp-D-Trp-Ile-Pip-Leu-Phe-NHCH3 15 Clp-D-Trp-Ile-Pip-Leu-Phe-N(CH3) 2 Clp-D-Trp-Ile-Pip-Leu-Phe-NHC2H5 Clp-D-Trp-Ile-Pip-Leu-Phe-N(C4H9)2 Clp-D-Trp-Ile-Pip-Leu-Phe-N (C8H17) 2.

Example 9 A solution of 1 g of Clp-Lys(BOC)-Phe-Pip-Leu-Phe-NH2 [obtainable from Clp-OH and H-Lys(BOC)-Phe-Pip-Leu-PheNH2] in 100 ml of a 40% solution of TFA in dichloromethane is allowed to stand at 10° for 16 hours. Evaporation and purification by chromatography give Clp-Lys25 Phe-Pip-Leu-Phe-NH2.

Example 10 A solution of 1 g of Clp-Asp(OBut)-Phe-Pip-Leu-Phe-NH2 [obtainable from Clp-OH and H-Lys(OBut)-Phe-Pip-LeuPhe-NH2] in 15 ml of 4 N HCI in dioxane is stirred at ° for 2 hours. The mixture is evaporated and subjected to customary work-up, to give Clp-Asp-PhePip-Leu-Phe-NH2.

Example 11 mg of 10% Pd-C and then 10 mg of ammonium formate are 5 added under N2 to a solution of 50 mg of Clp-Lys(CBZ)Phe-Pip-Leu-Phe-NH2 [obtainable from Clp-OH and HLys(CBZ)-Phe-Pip-Leu-Phe-NH2] in 5 ml of methanol and 5 ml of DMF, the reaction vessel is sealed, and the mixture is stirred at 20’ for 5 days, filtered and evaporated to give Clp-Lys-Phe-Pip-Leu-Phe-NH2.

Example 12 A solution of diazoethane in dioxane is added to a solution of 100 mg of Clp-D-Trp-Phe-Pip-Leu-OH in 60 ml of dioxane until a yellow coloration remains. The mixture is evaporated and subjected to customary workup to give Clp-D-Trp-Phe-Pip-Leu-OEt.

Example 13 A mixture of 1 g of Clp-D-Trp-Phe-Pip-Leu-OMe in a mixture of 100 ml of 0.1 N aqueous sodium hydroxide solution and 100 ml of dioxane is stirred at 20° for 24 hours. 1 N hydrochloric acid is added to pH 1, and the mixture is evaporated and subjected to customary work-up to give Clp-D-Trp-Phe-Pip-Leu-OH, RT 11.3 (b/c lil).

The following are obtained analogously by hydrolysis of the corresponding methyl esters: Clp-D-Tcc-Phe-Pip-Leu-OH, RT 16.03 (a/c lil) Clp-D-Trp-Ile-Pip-Leu-Phe-OH Clp-D-Trp-D-Ile-Pip-Leu-Phe-OH Clp-D-Trp-Phe-Pip-Leu-Met-OH Clp-D-Trp-D-Phe-Pip-Leu-Met-OH Clp-D-Trp-Phe-Pip-Leu-Phe-OH Clp-D-Trp-D-Phe-Pip-Leu-Phe-OH Clp-D-N-Me-Phe-Phe-Pip-Leu-OH, RT 16.99 (a/c 1:1) Clp-D-N-Me-Trp-Phe-Pip-Leu-OH Clp-D-N-Me-Trp-Phe-Pip-Met(O2) -OH Clp-D-N-Me-Trp-Phe-Pip-Nle-OH Clp-D-N-Me-Trp-Phe-Pip-Phe-OH.

Example 14 A solution of 50 mg of Clp-D-Trp-Phe-Pip-Leu-Phe-OMe in 5 ml of methanol and 5 ml of 25 % aqueous NH3 solution is saturated with NH4C1. NH3 is passed in for 24 hours, and the solution is concentrated and subjected to customary work-up to give Clp-D-Trp-Phe-Pip-Leu-PheNH2, RT 18.38 (b/c 55:45).

Example 15 Air is passed through a solution of 1 g of Clp-D-TrpPhe-Pip-Leu-Met-NH2 in 50 ml of acetonitrile and 50 ml of water until the reaction is complete. Customary work-up gives the corresponding sulfoxide Clp-D-TrpPhe-Pip-Leu-Met(0)-NH2.

Example 16 ml of 2 M NH4I solution is added at 0° to a solution of 1 g of Clp-Phe-Val-Pip-Leu-Met(0)-NH2 in 50 ml of TFA. After the mixture has been stirred at 0° for 1 hour, the iodine produced is reduced by adding thio25 glycolic acid, and the mixture is subjected to customary work-up to give Clp-Phe-Val-Pip-Leu-Met-NH2, RT 10.93 (a/c 55:45).

The examples below relate to pharmaceutical formulations .

Example A: injection vials The pH of a solution of 100 g of Clp-D-Trp-D-Phe-PipLeu-Phe-NH2 and 5 g of disodium hydrogenphosphate in 3 1 of twice distilled water is adjusted to 6.5 with 2N hydrochloric acid, and the solution is filtered under sterile conditions and filled into injection vials.

These are lyophilized under sterile conditions and closed in a sterile manner. Each injection vial contains 5 mg of active compound.

Example B: suppositories A mixture of 20 g of Clp-D-Trp-Ile-Pip-Leu-Phe-NH2 with 100 g of soya lecithin and 1,400 g of cocoa butter is melted, poured into moulds and allowed to cool. Each suppository contains 20 mg of active compound.

Example C: solution A solution is prepared from 1 g of Clp-D-Trp-D-Ile-PipLeu-Phe-NH2, 9.38 g of NaH2PO4 . 2 H2O, 28.48 g of Na2HPO4 . 12 H20 and 0.1 g of benzalkonium chloride in 940 ml of twice distilled water. The pH is adjusted to 6.8 and the solution is made up to 1 1 and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D: ointment 500 mg of Clp-D-Trp-Phe-Pip-Leu-OMe is mixed with 99.5 g of vaseline under aseptic conditions.

Merck Patent Gesellschaft mit beschrankter Haftung 6100 Darmstadt

Claims

1. Patent claims: 5 1. Amino acid derivatives of the formula I p-Cl-C 6 H 4 -CH 2 -CO-Z-NR 1 -CR 2 R 3 -CO-NR 4 -CHR 5 -CO-Y-R 6 I wherein Z is 0, 1 or 2 amino acid radicals attached to one another by a peptide linkage and selected 10 from the group consisting of Ala, Arg, Asn, Asp, Asp (OBut), Gin, Glu, Gly, His, lie, Leu, Lys, Met, aNal, bNal, Orn, Phe, Pro, Ser, Tcc, Thr, Tic, Trp, Tyr, Val, Ca-MeaNal, Ca-Me-Phe, Ca-Me-Tcc, Ca-Me-Tic, Ca-Me15 Trp, Ca-Me-Tyr, where functional groups of the amino acid side chain can also be protected by a protective group, R 1 , R 2 , R 3 , R 4 and R 5 are each H, A, alkenyl or alkynyl having in each case up to 4 C atoms, 20 Ar, Ar-alkyl, Het, Het-alkyl, cycloalkyl having 3-7 C atoms, cycloalkylalkyl having 411 C atoms, each of which is unsubstituted or monosubstituted or polysubstituted by A, AO and/or Hal, 25 R 1 and R 2 , R 1 and R 4 or R 2 and R 4 together each can also form an alkylene chain which has 2-6 C atoms and can be saturated or unsaturated, unsubstituted or monosubstituted or polysubstituted by A, OH, OA, Ar, Ar-alkyl, Het and/or Het-alkyl, 30 Y is Cys, He, Leu, Met, Met(O), Met(O 2 ), Nle, Phe or a radical of an analogous thio-amidated amino acid, R 6 is OH, OA, NH 2 , NHA or NA^, Ar is phenyl which is unsubstituted or monosubstituted or polysubstituted by A, AO, Hal, CF 3 , OH and/or NH 2 , or unsubstituted naphthyl, 5 Het is a saturated or unsaturated 5-membered or 6-membered heterocyclic radical which has 14 N, 0 and/or S atoms, which can be condensed with a benzene ring or a pyridine ring and/or can be monosubstituted or polysubstituted by 10 A, AO, Hal, CF 3 , HO, 0 2 N, carbonyl oxygen, H 2 N, HAN, AjN, AcNH, AS, ASO, ASO 2 , AOOC, CN, H 2 NC0, ANHCO, AaNCO, ArNHCO, Ar-alkyl-NHCO, H 2 NSO 2 , AS0 2 NH, Ar, Ar-alkyl, Ar-alkenyl, hydroxyalkyl and/or aminoalkyl having in each 15 case 1-8 C atoms, and/or in which the N and/or S hetero atoms can also be oxidized, -alkyl- is an alkylene chain having 1-4 C atoms, Hal is F, Cl, Br or I, Ac is H-C0-, Α-CO-, Ar-CO-, A-NH-CO- or Ar-NH- 20 CO- and A is alkyl having 1-8 C atoms, wherein it is also possible for Y to be absent and/or for one or more -ΝΑ-CO- groups to replace one or more -NH-CO- groups, 25 and to salts thereof. (a) p-Chlorophenylacetyl-D-Trp-D-Phe-Pip-Leu-PheNH 2 ; (b) p-chlorophenylacetyl-D-Trp-Ile-Pip-Leu-PheNH 2 ;

2. (c) p-chlorophenylacetyl-D-Trp-D-Ile-Pip-LeuPhe-NH 2 .

3. Process for the preparation of an amino acid derivative of the formula I and salts thereof, charac5 terised in that it is liberated from one of its functional derivatives by treatment with a solvolysing or hydrogenolysing agent, or in that a carboxylic acid of the formula II p-Cl-C 6 H 4 -CH 2 -CO-G 1 -OH II 10 wherein G 1 is (a) (b) absent -Z 1 -, (c) -Z-, (d) -Z-NR^CR^-CO-, (e) -Z-NR l -CR 2 R 3 -CO-NR 4 -CHR 5 -CO- 15 (f) -z-nr 1 -cr 2 r 3 -co-nr 4 -chr 5 -co- Y- is reacted with an amino compound of the formula III H-G 2 III 20 wherein G 2 is (a) -Z-NR 1 -CR 2 R 3 -CO-NR 4 -CHR 5 -CO- Y-R 6 , (b) -Z 2 -NR 1 -CR 2 R 3 -CO-NR 4 -CHR 5 -CO- Y-R 6 , (c) -nr 1 -cr 2 r 3 -co-nr 4 -chr 5 -co-y- 25 (d) R 6 , -nr 4 -chr 5 -co-y-r 6 , ( e ) -Y-R 6 , (f) -NH 2 , NHA or NAj and Z 1 + Z 2 together are z, 30 and in that, if appropriate, a functionally modified amino and/or hydroxyl group in a compound of the formula I is liberated by treatment with a solvolysing or hydrogenolysing agent and/or a free amino group is acylated and/or a radical R 6 is converted into another radical R 6 by treatment with an esterifying, solvolysing or amidating agent and/or a thioether group is oxidized to a sulfoxide group or sulfone group and/or a sulfoxide 5 group is reduced to a thioether group and/or a compound of the formula I is converted into one of Its salts by treatment with an acid.

4. Process for the preparation of pharmaceutical formulations, characterised in that a compound of 10 the formula I and/or one of its physiologically acceptable salts is brought into a suitable dosage form together with at least one solid, liquid or semi-liquid excipient or auxiliary and, if appropriate, in combination with one or more further 15 active compound(s).

5. Pharmaceutical formulation characterised in that it contains at least one compound of the formula I and/or one of its physiologically acceptable salts.

6. The use of compounds of the formula ologically acceptable salts thereof preparation of a medicament. I or of physi for the

7. The use of compounds of the formula I or of physiologically acceptable salts thereof in combating 25 cardiovascular disorders, spastic disorders, pain, inflammations, disorders of the central nervous system and/or of the circulation, and/or for the stimulation of tear secretion. 8.

8. 9.

9. 10.

10.

11. . 11 .

12. 12.

13. 13. An amino acid derivative of the formula I given and defined in Claim 1 or a salt thereof, substantially as hereinbefore described and exemplified. A process for the preparation of an amino acid derivative of the formula I given and defined in Claim 1 or a salt thereof, substantially as hereinbefore described and exemplified. An amino acid derivative of the formula I given and defined in Claim 1 or a salt thereof, whenever prepared by a process claimed in Claim 3 or 9. A pharmaceutical formulation according to Claim 5, substantially as hereinbefore described and exemplified. Use according to Claim 6, substantially as hereinbefore described. Use according to Claim 7, substantially as hereinbefore described.