Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1996-11-27
1998-04-14
Shippen, Michael L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
558181, 560 38, 560190, 560211, 562 8, 562 15, A61K 3166
Patent
active
057391238
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to phosphinic acid derivatives and, more particularly, it relates to phosphinic acid derivatives useful in the treatment of cardiovascular diseases as metallopeptidase inhibitors.
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 and of heart failure in that they inhibit the formation of angiotensin II, a substance which increases the blood pressure.
Compounds with endothelin converting enzyme (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 enzyme is responsible for the inactivation, not only of endogenous enkephaline, but also of atrial natriuretic factor (ANF), a vasodilator hormone secreted by heart.
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, in the treatment of hypertension, renal failure and congestive heart failure.
In the U.S. Pat. No. 4,396,772 (Squibb & Sons, Inc.) some phosphinic acid derivatives and, more particularly, some phosphinyl alkanoyl amino acids are described as ACE-inhibitors.
As described by Brandley P. Morgan et al. in Journal of the American Chemical Society, 1991, 113, 297-307, some phosphinic acid derivatives and, particularly, the compound of formula ##STR2## wherein Ph is a phenyl group, resulted to be endowed with inhibitory activity towards thermolysin, an endopeptidase of bacterial origin. Successively, as described by Stephen R. Bertenshaw et al. in Journal of Medicinal Chemistry, 1993, 36, 173-176, some phosphinic acid derivatives having a dipeptide moiety analogous to that of phosphoramidon, a well-known molecule with ECE-inhibitory activity, resulted to be devoid of any significant ECE-inhibitory activity. Now we have found phosphinic acid derivatives which are endowed with angiotensin converting enzyme as well as neutral endopeptidase enzyme inhibitory activity (mixed ACE/NEP inhibitory activity) which renders them particularly useful in the cardiovascular therapy. Therefore, object of the present invention are the compounds of formula ##STR3## wherein
R is a biphenyl group optionally substituted by one or more substituents, the same or different, selected among halogen atoms, hydroxy groups, alkoxy, alkyl, thioalkyl or alkoxycarbonyl groups having from 1 to 6 carbon atoms in the alkyl moiety, C.sub.1 -C.sub.3 alkyl groups containing one or more fluorine atoms, carboxy groups, nitro groups, amino or aminocarbonyl groups, acylamino groups, aminosulphonyl groups, mono- or di-alkylamino groups having from 1 to 6 carbon atoms in the alkyl moiety, mono- or di-alkylaminocarbonyl groups having from 1 to 6 carbon atoms in the alkyl moiety;
R.sub.1 is a hydrogen atom, a straight or branched C.sub.1 -C.sub.6 alkyl group or an arylalkyl group having from 1 to 6 carbon atoms in the alkyl moiety wherein the aryl is a phenyl, a biphenyl, a naphthyl or a 5 or 6 membered aromatic heterocycle with one or two heteroatoms selected among nitrogen, oxygen and sulphur, optionally substituted with one or more substituents, the same or different, selected among halogen atoms, hydroxy groups, alkoxy, alkyl, thioalkyl or alkoxycarbonyl groups having from 1 to 6 carbon atoms in the alkyl moiety, C.sub.1 -C.sub.3 alkyl groups containing one or more fluorine atoms, carboxy groups, nitro groups, amino or aminocarbonyl groups, acylamino groups, aminosulphonyl groups, mono- or di-alkylamino groups having from 1 to 6 carbon atoms in the alkyl moiety, mono- or di-alky
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Botta Daniela
Morazzoni Gabriele
Norcini Gabriele
Santangelo Francesco
Shippen Michael L.
Zambon Group S.p.A.
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