Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-11-13
1997-03-04
Haley, Jacqueline
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
548496, 548497, C07D20914
Patent
active
056080786
DESCRIPTION:
BRIEF SUMMARY
This is a National Stage Application of PCT/US 94/01716 filed Feb. 22, 1994, published as WO 94/22908 on Oct. 13, 1994.
FIELD OF THE INVENTION
This invention generally relates to dipeptides and analogs thereof having a phosphonomethyl moiety, pharmaceutical compositions comprising these compounds, processes for making such compounds, intermediates used in these processes, and methods for inhibiting the production of Endothelin. These compounds inhibit Endothelin Converting Enzyme and are thus useful in treating conditions responsive to inhibition of production of Endothelin.
BACKGROUND OF THE INVENTION
The peptide Big Endothelin, found in endothelium cells, is cleaved by the enzyme Endothelin Converting Enzyme (ECE) to produce the peptide Endothelin. Endothelin is a 21 amino acid vasoconstrictor and is produced by endothelium cells, mesangial, kidney and epithelial cells and by various human cancer cell lines and human macrophages.
Biologically, endothelin has effects on vascular smooth muscle, nonvascular smooth muscle, heart, nervous tissue, kidney and adrenal glands. Endothelin constricts arteries and veins, increases mean arterial blood pressure, decreases cardiac output, increases cardiac contractility in vitro, stimulates mitogenesis in vascular smooth muscle cells in vitro, contracts vascular smooth muscle including guinea pig trachea, human urinary bladder strips and rat uterus in vitro, increases airway resistance in vivo, induces formation of gastric ulcers, stimulates release of atrial natriuretic factor in vitro and in vivo, increases plasma levels of vasopressin, aldosterone and catecholamines, inhibits release of renin in vitro and stimulates release of gonadrotropin in vitro. See, for example, PCT patent application publication No. Wo 92/13545.
Possible indications for use of inhibitors of production of endothelin include treatment of cardiovascular diseases (e.g., myocardial ischemia, congestive heart failure, arrhythmia, unstable angina and hypertension); bronchoconstriction (pulmonary hypertension and asthma); neuronal action disorders (cerebral vasospasm and subarachnoid hemorrhage); endocrine disorders (pre-eclampsia); renal disease (acute/chronic renal failure); vascular disorders (atherosclerosis, Buergers disease, Takayasu's arteritis, Raynaud's phenomenon and complications in diabetes); cancer (especially pulmonary carcinoma; gastric mucosal damage (gastrointestinal disorders); and endotoxic shock and septicemia. See J. Med. Chem. 35(9): 1493-1508 (1992); Neurology 42:25-31 (1992); and Drug Development Research 26:361-387 (1992).
SUMMARY OF THE PRESENT INVENTION
A compound having the formula of: ##STR1## stereoisomers, hydrates, inner salts or pharmaceutically acceptable salts thereof, (CH.sub.2).sub.m -aryl, R.sub.4 --C(O)O--CH(R.sub.5)-- or nothing when the inner salt is formed, provided that when one of R.sub.1 or R.sub.2 is a hydrogen, C.sub.1-6 alkyl, or (CH.sub.2).sub.m -aryl, then the other is hydrogen or nothing when the inner salt is formed; (CH.sub.2).sub.m -aryl; (CH.sub.2).sub.m -aryl; forming the inner salt; R.sub.8 are H; treatment of conditions improved by the inhibition of Endothelin Converting Enzyme.
DETAILED DESCRIPTION OF THE PRESENT INVENTION
As used herein, certain terms have specific meanings such as those that follow.
"Cycloalkyl" means a saturated carbon atom ring having 3 to 8 carbon atoms including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl and the like. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from C.sub.1-6 alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialklyamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
"C.sub.1-6 alkyl" means straight or branched chain alkyl moieties containing from 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylproply, n-hexyl
REFERENCES:
patent: 5380921 (1995-01-01), Ishikawa et al.
J. Med. Chem. vol. 36, No. 1, pp. 173-176 (1993) S. R. Bertenshaw et al. "Phosphorus-containing inhibitors of endothelin converting enzyme: Effects of the electronic nature of phosphorus on inhibitor potency".
Biochem. and Biophysical Research Comm. vol. 186, No. 2, pp. 1146-1150 (1992) D. M. Pollock et al. "Rhamnose moiety of phosphoramidon is not required for in vivo inhibition of endothelin converting enzyme".
Chemical Abstracts vol. 119, No. 1, pp. 9174 (1993) Kimura Sadao et al. "Phosphonamides".
J. Med. Chem. vol. 33, No. 1, pp. 263-273 (1990) Z. P. Kortylewicz et al. "Phosphoramidate peptide inhibitors of human skin fibroblast collagenase".
Bioorganic & Medicinal Chemistry Letters vol. 4, No. 10, pp. 1257-1262 (1994) Takahiro Fukami et al. "Aminophosphonate endothelin converting enzyme inhibitors: potency-enhancing and selectivity-improving modifications of phosphoramidon".
Bigaud Marc
d'Orchymont Hugues
Haley Jacqueline
Merrell Pharmaceuticals Inc.
Moon Carolyn D.
Svoboda Craig G.
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