Peptide antagonists of neurotensin

Details Peptide antagonists of neurotensin Peptide antagonists of neurotensin

1996-11-19

1998-11-24

Spector, Lorraine

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

530333, 530335, 530337, 530344, 530317, 435106, 435119, 435120, 435127, A61K 3812

Patent

active

058406824

DESCRIPTION:

BRIEF SUMMARY
This application is the U.S. national stage of PCT/FR95/00643 filed May 17, 1995.
The present invention relates to amino acid derivatives of formula: ##STR2## to their preparation, to their salts and to the medicaments containing them.
In the formula (I), radical, norbornylacetyl, norbornylphenoxycarbonyl, benzoyl, nicotinoyl, 4-phenylbenzoyl, 4-tert-butylbenzoyl or 2-pyrrolidinecarbonyl radical or a protective group for an amine functional group, or 1, it being understood that, when R.sub.1 is a hydrogen atom, the sum m+n+p is at least equal to 1, radical and radical.
The present invention also encompasses the equivalents of the compounds of formula (I) in which one or a number of peptide bonds (CO--NH) between two amino acid residues are replaced by --CH.sub.2 --NH bonds and/or the peptide bond (CO--NH) between the R.sub.2 and R.sub.3 amino acid residues is replaced by a CH.dbd.CH bond.
In the preceding and following definitions, the alkyl and alkyloxy radicals and portions contain 1 to 4 carbon atoms in a straight or branched chain, Arg means arginine, Lys means lysine, Pro means proline, Fmoc means 9-fluorenylmethoxycarbonyl, Pmc means 2,2,5,7,8-pentamethylchroman-6-sulphonyl and Boc means tert-butoxycarbonyl.
In the formula (I), each amino acid residue can be in the L or D configuration.
Use is preferably made, as protective group for the amine functional group, of the 9-fluorenylmethoxycarbonyl, tert-butoxycarbonyl, acetyl, pivaloyl and benzyloxycarbonyl groups, the phenyl in the benzyloxycarbonyl group being optionally substituted by halogen, alkyl, alkyloxy or nitro.
The peptide compounds of formula (I) in which the sum m+n+p is equal to at least 1 can be prepared by reaction of a derivative of formula: ##STR3## in which R has the same meanings as in the formula (I), R' and R" are identical and each represent a hydroxyl or methoxy radical and R'" represents a hydrogen, chlorine, bromine or iodine atom or a nitro radical, with a derivative of formula: norbornylacetyl, norbornylphenoxycarbonyl, benzoyl, nicotinoyl, 4-phenylbenzoyl, 4-tert-butylbenzoyl or 2-pyrrolidinecarbonyl radical or a protective group for an amine functional group and R.sub.2, R.sub.3, R.sub.4, n, m and p have the same meanings as in the formula (I), the sum m+n+p being equal to at least 1, optionally followed by deprotection of the end amine functional group in order to obtain the compounds in which R.sub.1 represents a hydrogen atom and/or optionally, when R represents an alkyloxy or phenylalkyloxy radical, by deprotection of the carboxyl functional group in order to obtain the compounds in which R represents a hydroxyl radical.
Coupling of the derivatives of formulae (II) and (III) is carried out by any method known to a person skilled in the art for coupling an amino derivative and a peptide.
It is particularly advantageous to use the derivative of formula (III) in the activated form. Mention may be made, as activated form, of the reaction product of the derivative of formula (III) with N-hydroxysuccinimide, N-hydroxybenzotriazole or hexafluoromethylphosphate, which can be prepared in an inert solvent, such as an amide such as dimethylformamide or N-methyl-2-pyrrolidone, a chlorinated solvent such as chloroform or methylene chloride, an ether such as tetrahydrofuran or a mixture of these solvents, at a temperature of between 15.degree. and 60.degree. C., in the presence of 4 .ANG. molecular sieve or of a coupling agent such as dicyclohexylcarbodiimide or alternatively a pentafluorophenyl ester which can be prepared according to the method described by L. Kisfaludy et al., Synthesis, 325-327 (1983).
The condensation of the product of formula (II) with the activated product of formula (III) is generally carried out under the same temperature and reaction mixture conditions as those described above for the preparation of the activated form of the derivative of formula (III), optionally in the presence of pyridine or of an amine such as diisopropylethylamine. These reactions can be carried out without isolating the activated prod

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Rioux et al., European Journal of Pharmacology 66(4): 273-9, Sep. 1980.
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J. H. Walsdorff(ed.), Cittilin, Report of Scientific Results 1991, p. 68.
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A. G. Brown et al., Synthesis of Analogues of the Biphenomycin Antibiotics, Tetrahedron Letters, 31(45), 1990, pp. 6581-6584.

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