Substituted azepinone dual inhibitors of angiotensin converting enzyme and neutral exdopeptidase

Claim 1

A compound of the formula ##STR54## and pharmaceutically acceptable salts thereof wherein: R 1 is hydrogen, ##STR55## or R 18 --S--; R 2 and R 19 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl--(CH 2 ) m --, substituted alkyl, aryl-(CH 2 ) m --, substituted aryl-(CH 2 ) m --, and heteroaryl-(CH 2 ) m -- or R 2 and R 19 taken together with the carbon atom to which they are attached complete a cycloalkyl ring or a benzofused cycloalkyl ring; n is zero or one; m is zero or an integer from 1 to 6; R 3 is alkyl, substituted alkyl, cycloalkyl-(CH 2 ) m --, aryl-(CH 2 ) m --, substituted aryl-(CH 2 ) m --, or heteroaryl-(CH 2 ) m --; R 18 is alkyl, substituted alkyl, cycloalkyl-(CH 2 ) m --, aryl-(CH 2 ) m --, substituted aryl-(CH 2 ) m --, or --S--R 18 completes a symmetrical disulfide wherein R 18 is of the formula ##STR56## X 1 is of the formula ##STR57## R 4 and R 5 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl-(CH 2 ) m --, aryl-(CH 2 ) m --, substituted aryl-(CH 2 ) m --, and heteroaryl-(CH 2 ) m --, or one of R 4 and R 5 is hydrogen and the other is hydroxy, or R 4 and R 5 together with the carbon to which they are attached complete a keto substituent; R 6 and R 10 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl --(CH 2 ) m --, aryl-(CH 2 ) m --, substituted aryl-(CH 2 ) m --, and heteroaryl-(CH 2 ) m --; R 7 and R 11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl --(CH 2 ) m --, aryl-(CH 2 ) m --, substituted aryl-(CH 2 ) m -- and heteroaryl-(CH 2 ) m --; b is zero or one; R 12 is hydrogen, alkyl, substituted alkyl, aryl-(CH 2 ) m --, substituted aryl-(CH 2 ) m --, heteroaryl-(CH 2 ) m --, or ##STR58## R 14 is hydrogen, lower alkyl, cycloalkyl, or phenyl; R 15 is hydrogen, lower alkyl, lower alkoxy, or phenyl; the term "alkyl" refers to straight and branched chain radicals having one to seven carbon atoms; the term "substituted alkyl" refers to such straight or branched chain radicals of 1 to 7 carbons wherein one or more hydrogens have been replaced by a hydroxy, amino, halo, trifluoromethyl, cyano, --NH(lower alkyl), --N(lower alkyl) 2 , lower alkoxy, lower alkylthio or carboxy; the term "alkenyl" refers to straight or branched chain radicals of 3 to 7 carbon atoms having one or two double bonds; the term "substituted alkenyl" refers to such straight or branched radicals of 3 to 7 carbons having one or two double bonds wherein a hydrogen has been replaced by a hydroxy, amino, halo, trifluoromethyl, cyano, --NH(lower alkyl), --N(lower alkyl) 2 , lower alkoxy, lower alkylthio, or carboxy; the term "cycloalkyl" refers to saturated rings of 3 to 7 carbon atoms; the term "aryl" refers to phenyl, 1-naphthyl, and 2-naphthyl; the term "substituted aryl" refers to phenyl, 1-naphthyl; and 2-naphthyl having a substituent selected from lower alkyl, lower alkoxy, lower alkylthio, halo, hydroxy, trifluoromethyl, amino, --NH(lower alkyl), and --N(lower alkyl) 2 , di- and tri-substituted phenyl, 1-naphthyl, or 2-naphthyl wherein said substituents are selected from methyl, methoxy, methylthio, halo, hydroxy, and amino; the term "heteroaryl" refers to unsaturated monocyclic rings of 5 or 6 atoms containing one or two O and S atoms and/or one to four N atoms provided that the only other atoms in said monocyclic ring are C atoms and that the total number of O,S and N atoms is four or less and bicyclic rings wherein the five or six membered ring as defined above is fused to a phenyl or pyridyl ring, said heteroaryl ring is attached by way of an available carbon or nitrogen atom; and said monocyclic or bicyclic ring can be substituted at an available carbon atom by lower alkyl of 1 to 4 carbons, halo, hydroxy, benzyl, or cyclohexylmethyl, or can be substituted at an available nitrogen atom by benzyloxymethyl, p-toluene sulfonyl, 2,4-dinitrophenyl, lower alkyl of 1 to 4 carbons, benzyl or benzhydryl; the term "lower alkyl" refers to straight or branched chain radicals having one to four carbons; the term "substituted lower alkyl" refers to such straight or branched chain radicals having one to four carbons wherein one hydrogen has been replaced by a hydroxy, amino, halo, trifluoromethyl, cyano, --NH(lower alkyl), --N(lower alkyl) 2 , lower alkoxy, lower alkylthio, or carboxy; the terms "lower alkoxy" and "lower alkylthio" refer to such lower alkyl groups as defined above attached to an oxygen or sulfur; and the term "halo" refers to chloro, bromo, fluoro, and iodo.