Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus acids or salts thereof
Patent
1996-09-13
1998-06-02
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus acids or salts thereof
514110, C07F 922, A01N 5736
Patent
active
057602859
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to some phosphonic acid derivatives useful in the treatment of cardiovascular diseases and, more particularly, it relates to some phosphonic 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 as anti-hypertensives 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 endowed with metallopeptidase inhibitory activity are generally used, alone or in combination, in the treatment of hypertension, renal failure and congestive heart failure.
The U.S. Pat. No. 4,432,972 (E. R. Squibb & Sons, Inc.) describes phosphonamidates which possess ACE-inhibitory activity and enkephalinase inhibitory activity useful as hypotensive and analgesic agents.
The European patent application No. 0518299 (Takeda Chemical Industries, Ltd.) describes compounds endowed with ECE-inhibitory activity useful in the treatment of hypertension, of cardiac or cerebral circulatory diseases and of renal diseases, having the general formula: ##STR2## wherein R.sub.1, R.sub.2 and R.sub.3 represent each a hydrocarbon radical which can be substituted, with the exception of the cases wherein (1) R.sub.2 is an unsubstituted methyl, (2) R.sub.3 is an unsubstituted hydrocarbon radical having from 1 to 3 carbon atoms, and (3) R.sub.1 is benzyloxycarbonylaminomethyl, R.sub.2 is isobutyl and R.sub.3 is isobutyl or phenylmethyl.
Within the scope of the aforementioned patent application, the definition of optionally substituted hydrocarbon radical is extremely broad in that it comprises any radical formed from at least one to an infinite number of carbon atoms and optionally substituted by any other chemically compatible organic or inorganic group.
Among the meanings of optionally substituted hydrocarbon radical, alkyl, cycloalkyl and arylalkyl groups are specifically indicated. As a preferred arylalkyl group, in particular, an alkyl group having from 1 to 5 carbon atoms substituted by an aromatic hydrocarbon having from 6 to 12 carbon atoms, is intended; as a still more preferred arylalkyl group, a phenylmethyl group optionally substituted by lower alkyl or cycloalkyl groups, halogens, optionally protected hydroxy and alkoxy groups, is intended.
Now we have found that some of the compounds, which could be apparently considered comprised among the innumerable meanings for the substituents in the general formula I, but which were not specifically indicated in the combination of the meanings for R.sub.1, R.sub.2 and R.sub.3, least of all exemplified in the European patent application No. 0518299, are endowed with a pharmacologic activity different from that described in the aforementioned European patent application and, in particular, are endowed with a mixed ACE-inhibitory and NEP-inhibitory activity.
This mixed inhibitory activity renders the compounds 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 h
REFERENCES:
patent: 4379146 (1983-04-01), Karanewsky et al.
patent: 4432972 (1984-02-01), Greenlee et al.
patent: 5151414 (1992-09-01), Casagrande et al.
patent: 5451608 (1995-09-01), Santangelo et al.
Merz et al., "Free Energy Perturbation Simulations of the Inhibition of Thermolysin: Prediction of the Free Energy of Binding of a New Inhibitor", J. Am. Chem. Soc., vol. 111, No. 15 (1989), pp. 5649-5658.
Mookhtiar, K.A. et al., "Phosphonamidate Inhibitors of Human Neutrophil Collagenase". Biochemistry, vol. 26, No. 7 (1987), pp. 1962-1965.
McMahon et al., "Phosphoramidon Blocks the Pressor Activity of Porcine Big Endothelin-1-(1-39) In Vivo and Conversion of Big Endothelin-1-(1-39), 2 Endothelin-1-(1-21) In Vitro", Proceedings National Academy of Science, vol. 88 (Feb. 1991), pp. 703-707.
Fukuroda, T. et al., "Inhibition of Biological Action of Big Endothelin-1 by Phosphoramidon", Biochemical and Biophysical Research Communication, vol. 172, No. 2 (Oct. 30, 1990), pp. 390-395.
Rich, H. David, "Peptidase Inhibitors" in Comprehensive Medicinal Chemistry: The Rational Design, Mechanistic Study & Therapeutic Application of Chemical Compounds, vol. 2 (Pergamon Press PLC), pp. 391-496 (not continuous), 1990.
Kam, C.M. et al., "Inhibition of Thermolysin and Carboxy Peptidase A Biphosphoramides", Biochemistry, vol. 18, No. 14 (1979), pp. 3032-3038.
Carey et al., "Reactions and Synthesis": Chapter 11 entitled Multistep Synthesis at pp. 539, 553, Advanced Organic Chemistry, Second Ed., Part B (New York Plenum Press), 1983.
Morazzoni Gabriele
Norcini Gabriele
Santangelo Francesco
Killos Paul J.
Zambon Group S.p.A.
LandOfFree
Phosphonyldipeptides useful in the treatment of cardiovascular d does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Phosphonyldipeptides useful in the treatment of cardiovascular d, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Phosphonyldipeptides useful in the treatment of cardiovascular d will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1461861