Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1995-12-20
1997-07-01
Bond, Robert T.
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C07D47104, C07D48704, A61K 3147
Patent
active
056440553
DESCRIPTION:
BRIEF SUMMARY
SUMMARY OF THE INVENTION
The present invention is directed to novel tricyclic azepine derivatives described below which are useful as angiotensin converting enzyme (ACE) inhibitors and as neutral endopeptidase (NEP, EC 3.4.24.11) inhibitors. The compounds of the invention are particularly useful for the treatment of conditions which are responsive to ACE and NEP inhibition, particularly cardiovascular disorders, such as hypertension, renal insufficiency (including edema and salt reduction), pulmonary edema and congestive heart failure.
By virtue of their inhibition of neutral endopeptidase, the compounds of the invention may also be useful for the treatment of pain, depression, certain psychotic conditions, and cognitive disorders. Other potential indications include the treatment of angina, premenstrual syndrome, Meniere's disease, hyperaidosteronism, hypercalciuria, ascites, glaucoma, asthma and gastrointestinal disorders such as diarrhea, initable bowel syndrome and gastric hyperacidity.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the azepino[3,2,1-hi]indole and 1H-pyrido-[3,2,1-jk][1]benzazepine derivatives of the formula I ##STR2## wherein X represents oxo, one hydroxy or lower alkoxy and one hydrogen, or two hydrogens; alkoxy, nitro, amino or halogen; or R.sub.a and R.sub.b on adjacent carbons taken together represent lower alkylenedioxy; cycloalkyl, cycloalkyl-lower alkyl, biaryl, biaryl-lower alkyl or trifluoromethyl; with the carbon to which they are attached represent cycloalkylene or benzo-fused cycloalkylene; pharmaceutically acceptable ester; disulfide derivatives formed from said compounds wherein R is hydrogen;
The present invention is also directed to methods for preparation of said compounds; intermediates; methods of treating disorders in mammals which are responsive to ACE and NEP inhibition by administration of said compounds to mammals in need of such treatment; pharmaceutical compositions; and processes for the manufacture of pharmaceutical compositions.
Pharmaceutically acceptable esters are preferably prodrug ester derivatives, such being convertible by solvolysis or under physiological conditions to the free carboxylic acids of formula I.
Pharmaceutically acceptable prodrug esters are preferably e.g. lower alkyl esters, .alpha.-(lower alkanoyloxy)-lower alkyl esters, such as the methyl ester, pivaloyloxy-methyl ester, and .alpha.-(lower alkoxycarbonyl- or di-alkylamino carbonyl)-lower alkyl esters.
Pharmaceutically acceptable salts are salts derived from pharmaceutically acceptable bases for any acidic compounds of the invention, e.g. those wherein COOR.sub.3 represents carboxyl. Such are e.g. alkali metal salts (e.g. sodium, potassium salts), alkaline earth metal salts (e.g. magnesium, calcium salts), amine salts (e.g. tromethamine salts).
The definitions used herein, unless denoted otherwise, have the following meanings within the scope of the present invention.
Aryl represents carbocyclic or heterocyclic aryl.
Carbocyclic aryl represents preferably monocyclic carbocyclic aryl or optionally substituted naphthyl.
Monocyclic carbocyclic aryl represents optionally substituted phenyl, being preferably phenyl or phenyl substituted by one to three substituents, such being advantageously lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, halogen, cyano, trifluoromethyl, lower alkanoylamino, lower alkyl-(thio, sulfinyl or sulfonyl) or lower alkoxycarbonyl.
Optionally substituted naphthyl represents 1- or 2-naphthyl or 1- or 2-naphthyl preferably substituted by lower alkyl, lower alkoxy or halogen.
Heterocyclic aryl represents preferably monocyclic heterocyclic aryl such as optionally substituted thienyl, furanyl or pyridyl.
Optionally substituted furanyl represents 2- or 3-furanyl or 2- or 3-furanyl preferably substituted by lower alkyl.
Optionally substituted pyridyl represents 2-, 3- or 4-pyridyl or 2-, 3- or 4-pyridyl preferably substituted by lower alkyl, halogen or cyano.
Optionally substituted thienyl represents 2- or 3-thienyl or 2- or 3-thienyl
REFERENCES:
J. Med. Chem., vol. 27, pp. 816-818 (1984), Watthey et al.
Bond Robert T.
Ciba-Geigy Corporation
Gruenfeld Norbert
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