Aminoacid derivatives containing a disulfanyl group in the form of mixed disulfanyl and aminopeptidase n inhibitors

Abstract

The invention relates to novel compounds of formula (I): H2N-CH(R1)-CH2-S-S- CH2-CH(R2)-CONH-R5, wherein R1 is a hydrocarbon chain, phenyl or benzyl radical, methylene radical substituted by a 5 or 6 atom heterocycle; R2 is a phenyl or benzyl radical, a 5 or 6 atom aromatic heterocycle, methylene group substituted by a 5 or 6 atom heterocycle; R5 is a CH(R3)-COOR4 radical, wherein R3 is hydrogen, an OH or OR group, a saturated hydrocarbon group, a phenyl or benzyl radical and OR4 is hydrophile ester, or 5 or 6 membered heterocycle comprising several heteroatoms selected from a group consisting of nitrogen, sulphur and oxygen, with at least two nitrogene atoms, wherein said heterocycle is substitutable by an alkyl C1-C6, phenyl or benzyl radical.; The use of the inventive compounds in the form of drugs, a pharmaceutical composition comprising said compounds, a pharmaceutically acceptable excipient, the use in conjunction of at least one type of cannabinoid derivative for potentiating the analgesic and antidepressant effect of the novel compounds of formula (I) and / or morphine or the derivatives thereof are also disclosed.

Description

technical field [0001] The present invention relates to novel mixed inhibitors of neprilysin and aminopeptidase N. Background technique [0002] Naturally occurring opioid peptides or enkephalins—(Tyr-Gly-Gly-Phe-Met or Tyr-Gly-Gly-Phe-Leu)—are known to be degraded primarily by two zinc metallopeptidases that cleave Enkephalinase (EC 3.4.24.11) (Nature 276 (1978) 523) of the Gly3-Phe4 bond and aminopeptidase N (EC 3.4.11.2) (Eur.J.Pharmacol. 117 (1985) 233; reviewed in Pharmacological review., 1993, 45, 87-146). Mixed inhibitors of these two enzymes are known to completely protect endogenous enkephalins from enzymatic degradation, and they display the pharmacological activities of enkephalins, especially analgesic and antidepressant activities. Mixed inhibitors of these two enzyme activities described in the prior art are compounds with hydroxamate functional groups (FR 2 518 088 and FR 2 605 004), aminophosphinic acid compounds (FR 2 755 135 and FR 2 777 780) and amino a...

AI Technical Summary

Problems solved by technology

However, even if one of the compounds belonging to the amino acid derivative series was shown to be relatively water soluble (Pain, 73, (1997), 383-391), none of the previously disclosed molecules exhibited Solubility and sufficient bioavailability for oral administration and sufficiently low doses in animals to be adapted for humans provide a favorable analgesic response

Likewise, none of the previously described molecules can be administered intravenously because in animal testing they would need to be dissolved in mixtures incompatible with administration to humans by this route

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