Substituted azepinone dual inhibitors of angiotensin converting enzyme and neutral exdopeptidase

A compound of the formula:

• ##STR61## including a pharmaceutically acceptable salt thereof wherein:
• R.sub.1 is hydrogen or ##STR62## R.sub.2 is hydrogen, alkyl, cycloalkyl-(CH.sub.2).sub.m --, substituted alkyl, aryl-(CH.sub.2).sub.m --, substituted aryl-(CH.sub.2).sub.m --, or heteroaryl-(CH.sub.2).sub.p --;
• n is zero or one;
• m is zero or an integer from 1 to 6;
• p is an integer from 1 to 6;
• R.sub.3 is alkyl, substituted alkyl, cycloalkyl-(CH.sub.2).sub.m --, aryl-(CH.sub.2).sub.m --, substituted aryl-(CH.sub.2).sub.m --, or heteroaryl-(CH.sub.2).sub.m --;
• X.sub.1 is ##STR63## R.sub.4 and R.sub.6 are both hydrogen, or one is hydrogen and the other is alkyl, substituted alkyl, cycloalkyl-(CH.sub.2).sub.m --, aryl-(CH.sub.2).sub.m --, substituted aryl-(CH.sub.2).sub.m --, or heteroaryl-(CH.sub.2).sub.m --;
• R.sub.10 is hydrogen, alkyl, substituted alkyl, aryl-(CH.sub.2).sub.p --, or substituted aryl-(CH.sub.2).sub.p --;
• R.sub.12 is hydrogen, alkyl, substituted alkyl, aryl-(CH.sub.2).sub.m --, or substituted aryl-(CH.sub.2).sub.m --;
• the term "alkyl" refers to straight and branched chain radicals having one to seven carbon atoms;
• the term "cycloalkyl" refers to saturated rings of 4 to 7 carbon atoms;
• the term "substituted alkyl" refers to such straight and branched chain radicals having to 1 to 7 carbon atoms wherein one or more hydrogens have been replaced by a hydroxy, amino, halo, trifluoromethyl, --NH(lower alkyl of 1 to 4 carbons), --N(lower alkyl of 1 to 4 carbons).sub.2, lower alkoxy of 1 to 4 carbons, or lower alkylthio of 1 to 4 carbons;
• 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 of 1 to 4 carbons, lower alkoxy of 1 to 4 carbons, lower alkylthio of 1 to 4 carbons, halo, hydroxy, trifluoromethyl, amino, --NH(lower alkyl of 1 to 4 carbons), and --N(lower alkyl of 1 to 4 carbons).sub.2, and di- and tri- substituted phenyl, 1-naphthyl, and 2-naphthyl wherein said substituents are selected from methyl, methoxy, methylthio, halo, hydroxy, and amino;
• and
• the term "heteroaryl" refers to unsaturated monocyclic rings of 5 of 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 a 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.

A compound of the formula ##STR64## and pharmaceutically acceptable salts thereof wherein:

• R.sub.1 is hydrogen, ##STR65## or R.sub.18 --S--;
• R.sub.2 and R.sub.19 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl-(CH.sub.2).sub.m --, substituted alkyl, aryl-(CH.sub.2).sub.m --, substituted aryl-(CH.sub.2).sub.m --, and heteroaryl-(CH.sub.2).sub.m --;
• n is zero or one provided that n must be zero when R.sub.2 and R.sub.19 are both other than hydrogen;
• m is zero or an integer from 1 to 6;
• R.sub.3 is alkyl, substituted alkyl, cycloalkyl-(CH.sub.2).sub.m --, aryl-(CH.sub.2).sub.m --, substituted aryl-(CH.sub.2).sub.m --, or heteroaryl-(CH.sub.2).sub.m --;
• R.sub.18 is alkyl, substituted alkyl, cycloalkyl-(CH.sub.2).sub.m --, aryl-(CH.sub.2).sub.m --, substituted aryl-(CH.sub.2).sub.m --, or --S--R.sub.18 completes a symmetrical disulfide wherein R.sub.18 is of the formula ##STR66## X.sub.1 is of the formula ##STR67## R.sub.4 and R.sub.5 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl-(CH.sub.2).sub.m --, aryl-(CH.sub.2).sub.m --, substituted aryl-(CH.sub.2).sub.m --, and heteroaryl-(CH.sub.2).sub.m --, or one of R.sub.4 and R.sub.5 is hydrogen and the other is hydroxy, or R.sub.4 and R.sub.5 together with the carbon to which they are attached complete a keto substituent;
• R.sub.6 and R.sub.10 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl-(CH.sub.2).sub.m --, aryl-(CH.sub.2).sub.m --, substituted aryl-(CH.sub.2).sub.m --, and heteroaryl-(CH.sub.2).sub.m --;
• R.sub.7 and R.sub.11 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl -(CH.sub.2).sub.m --, aryl-(CH.sub.2).sub.m, substituted aryl -(CH.sub.2).sub.m --, and heteroaryl-(CH.sub.2).sub.m --;
• b is zero or one;
• R.sub.12 is hydrogen, alkyl, substituted alkyl, aryl-(CH.sub.2).sub.m --, substituted aryl-(CH.sub.2).sub.m --, heteroaryl-(CH.sub.2).sub.m --, or ##STR68## R.sub.14 is hydrogen, lower alkyl, cycloalkyl, or phenyl;
• R.sub.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, amine, halo, trifluoromethyl, cyano, --NH(lower alkyl), --N(lower alkyl).sub.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, amine, halo, trifluoromethyl, cyano, --NH(lower alkyl), --N(lower alkyl).sub.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, amine, --NH(lower alkyl), and --N(lower alkyl).sub.2, di- and tri-substituted phenyl, 1-naphthyl, or 2-naphthyl wherein said substituents are selected from methyl, methoxy, methylthio, hale hydroxy, and amine;
• 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).sub.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.

A compound of the formula ##STR69## and pharmaceutically acceptable salts thereof wherein:

• R.sub.1 is hydrogen or H.sub.3 C--C(O)--;
• R.sub.2 is benzyl, (2-thienyl)methyl, or straight or branched chain alkyl of 1 to 5 carbons;
• R.sub.6 and R.sub.7 are both methyl;
• and
• R.sub.10 and R.sub.11 are both hydrogen or one is hydrogen and the other is methyl.