Hydroxyamidino derivatives useful as nitric oxide synthase inhibitors

A compound having the formula;

• ##STR117## and pharmaceutically acceptable salts, wherein:
• A is selected from O or S and may be taken together with R.sup.4 to form a heterocyclic ring;
• or
• A is N when R.sup.3 and R.sup.7 are taken together to form a heterocyclic ring;
• or R.sup.5 and A--R.sup.3 are taken together to form a covalent bond;
• or
• A is N--R.sup.3 provided R.sup.3 is not a heterocyclic radical;
• R.sup.1 is selected from the group consisting of hydrogen, hydroxyalkyls of from 1 to 4 carbon atoms, alkoxyalkyls of from 1 to 4 carbon atoms in each position, lower alkyls of from 1 to 8 carbon atoms and haloalkyls of from 1 to 4 carbon atoms;
• R.sup.2 is selected from the group consisting of straight and branched lower alkyls of from 1 to 4 carbon atoms, lower alkenyls and lower alkynyls of from 2 to 4 carbon atoms, cycloalkyls of from 1 to 4 carbon atoms, cycloalkenyls of from 3 to 8 carbon atoms, and haloalkyls of from 1 to 4 carbon atoms;
• R.sup.3 is selected from the group consisting of aryl, heteroaryl, alkylaryl, alkylheteroaryl, all optionally substituted by one or more of halogen, nitrile, carboxy, carboxyalkyl, carboxyalkylaryl;
• or
• R.sup.3 is also selected from the group consisting of H, alkyl of from 1 to 4 carbon atoms, alkenyl of from 2 to 4 carbon atoms, CH.sub.2 OC(.dbd.O)YR.sup.6, alkylhydroxy, alkylpolyhydroxy, alkyl(poly)oxyacyl, alkylcarboxy, optionally substituted by one or more of alkyl of from 1 to 4 carbon atoms, hydroxy, amino, carboxy, carboxyalkyl, alkylcarbonyl;
• R.sup.4 is selected from H, OH, SH, OR.sup.6, SR.sup.6, OC(.dbd.O)R.sup.6, SC(.dbd.O)R.sup.6, CH.sub.2 OC(.dbd.O)YR.sup.6, OC(.dbd.O)YR.sup.6, SC(.dbd.O)YR.sup.6 ;
• Y is independently selected from O, S, CH.sub.2, CHR.sup.6, C(R.sup.6).sub.2, NH, NR.sup.6 ;
• R.sup.5 is selected from H, OH, SH, OR.sup.6, SR.sup.6, OC(.dbd.O)R.sup.6, SC(.dbd.O)R.sup.6, CH.sub.2 OC(.dbd.O)YR.sup.6, OC(.dbd.O)YR.sup.6, SC(.dbd.O)YR.sup.6 ;
• provided that R.sup.4 and R.sup.5 are not simultaneously hydrogen or CH.sub.2 OC(.dbd.O)YR.sup.6 ;
• R.sup.6 is selected from hydrogen, alkyl of from 1 to 4 carbon atoms, alkenyl and alkynyl of from 2 to 4 carbon atoms, cycloalkyl of from 3 to 8 carbon atoms, heterocyclic of from 5 to 8 members, aryl, heteroaryl all optionally substituted by one or more alkyl of from 1 to 4 carbon atoms, alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, or amino groups;
• R.sup.7 is selected from H, S(O)R.sup.9, SO.sub.2 R.sup.9, CH.sub.2 OC(O)--R.sup.9, C(O)--R.sup.9 where C(O)--R.sup.9 can represent natural and synthetic amino acids or R.sup.9 can be defined as below, or R.sup.7 and R.sup.3 taken together comprise a 5- or 6- membered heterocyclic ring containing two or more heteroatoms, optionally substituted with alkyl of from 1 to 4 carbon atoms and/or oxygen functions including carbonyl, or taken together comprise a metal complex containing a divalent cation, or a boron complex;
• R.sup.8 is selected from H, acyl;
• R.sup.9 is selected from substituted dihydropyridyl, alkyl of from 1 to 4 carbon atoms, thioalkoxy, alkoxy, amino, cycloalkoxy, optionally substituted with one or more of amino, alkyl of from 2 to 4 carbon atoms, alkylaryl, heteroaryl, alkylheteroaryl, alkylmercaptoalkyl, which may optionally be substituted with one or more of hydroxy, amino, guanidino, iminoalkyl;
• X is selected from the group consisting of alkylenes, alkenylenes and alkynylenes having 2 to 6 carbon atoms and which may optionally be substituted by one or more alkyl groups;
• or
• X is selected from the group consisting of the formula --(CH.sub.2).sub.k Q(CH.sub.2).sub.t -- where k is 1, 2 or 3, t is 1, 2 or 3 and Q is O, Se, SiE.sub.2 where E is lower alkyl, aryl, S(O).sub.g where g is 0, 1 or 2, or NR where R is H or lower alkyl which may be optionally substituted with lower alkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, amino;
• or
• X is selected from the group consisting of the formula --(CH.sub.2).sub.m T(CH.sub.2).sub.n -- where m is 0, 1 or 2, n is 0, 1 or 2, T is a 3 to 6 membered carbocyclic or heterocyclic ring, aromatic ring or heteroaromatic ring which may optionally be substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halogen, nitro, cyano, trifluoroalkyl and amino.