Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-06-23
2000-12-26
Aulakh, C. S.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546335, 546337, 548203, 548204, 548205, 549 77, 514365, 514438, A61K 3144, A61K 31426, C07D21304
Patent
active
061660515
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to thiol derivatives with metallopeptidase inhibitory activity and, more particularly, it relates to N-mercaptoacyl alanine derivatives useful in the treatment of cardiovascular diseases.
The pharmacologic interest towards the study of metallopeptidase inhibitory molecules derives from the role that said enzymes exert on the level of the cardiocirculatory system.
It is well-known in fact that compounds with angiotensin converting enzyme (ACE) inhibitory activity are mainly useful in the treatment of hypertension. heart failure and post-infarct in that they inhibit the formation of angiotensin II, a substance which comprises several effects among which the increase of the blood pressure.
Compounds with endothelin converting enzvme (ECE) inhibitory activity are useful as anti-vasoconstrictors in that they inhibit the formation of endothelin, a 21 amino acid peptide with vasoconstrictor activity.
Instead, compounds with inhibitory activity of the neutral endopeptidase enzyme (NEP), also called enkephalinase. are useful as vasodilators in that the NEP enzvme is responsible for the inactivation, not only of endogenous enkephaline, but also of some natriuretic factors among which, for instance. the atrial factor (ANF), a hormone secreted by heart which increases the vasodilation and, on the renal level increases diuresis and natriuresis.
Therefore, even exerting their action on the cardiovascular system with different mechanisms of action, the compounds with metallopeptidase inhibitory activity are generally used, alone or in combination among them, in the treatment of hypertension, renal failure, congestive heart failure and ischemic cardiopathies.
Among the thiol derivatives inhibitors of metallopeptidases, Thiorphan [(DL-(3-mer-capto-2-benzylpropanoyl)glycine], described for the first time by Roques et al. in Nature, Vol. 288, pages 286-288, (1980), and Captopril (The Merck Index, XI ed., No. 1773, page 267) are considered the parent compounds for NEP-inhibitors and ACE-inhibitors, respectively.
Other molecules having a thiol structure endowed with metallopeptidase inhibitory activity were described in the literature.
N-mercaptoacyl dipeptides endowed with ECE-inhibitory activity and, more particularly, N-mercaptoacyl derivatives of triptophan were described by S. R. Bertenshaw et al. in Bioorganic & Medicinal Chemistry Letters, 10, 1953-1958, 1993.
U.S. Pat. No. 4,401,677 (E.R. Squibb & Sons, Inc.) describes mercaptoalkanoyl amino acids endowed with enkephalinase inhibitory activity.
U.S. Pat. No. 4,199,512 (E.R. Squibb & Sons. Inc.) describes mercaptoalkanoyl amino acids endowed with ACE-inhibitory activity.
The European patent application No. 0566157 (Schering Corporation) describes N-mercaptoacyl derivatives of alanine endowed with NEP-inhibitory activity.
The European patent application No. 0449523 (E.R. Squibb & Sons, Inc.) describes mercapto or acylthio trifluoromethylamides with NEP-inhibitory activity.
The European patent application No. 0524553 [Institut National de la Sante et de la Recherche Medicale (INSERM)] describes acylmercaptoalkanoyldipeptides endowed with neutral endopeptidase and peptidylpeptidase A inhibitory activity.
The international patent application No. WO 93/08162 [Rhone-Poulenc Rorer S.A.--Institut National de la Sante et de la Recherche Medicale (INSERM)] describes .beta.,.beta.-disubstituted .alpha.-mercaptomethylpropionylamides endowed with mixed ACE/NEP inhibitory activity.
The European patent application No. 0419327 (Societe Civile Bioproject) describes amino acid derivatives such as, for instance, N-mercaptoacyl derivatives of phenylalanine, stydine and triptophan, endowed with enkephalinase and ACE inhibitory activity.
.alpha.-Mercaptoacyl dipeptides endowed with ACE-inhibitory and NEP-inhibitory activity were also described by S. S. Bhagwat et al. in Bioorganic & Medicinal Chemistry Letters, 7, 735-738, 1995.
In this last work the authors conclude that, while the presence of a biphenylmethyl group confers an interesting mixed ACE/NEP-inhibito
REFERENCES:
patent: 5414013 (1995-05-01), Delaney et al.
Norcini Gabriele
Pellacini Franco
Romagnano Stefano
Santangelo Francesco
Semeraro Claudio
Aulakh C. S.
Zambon Group S.p.A.
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