Hydroxyamidino derivatives useful as nitric oxide synthase inhibitors

A compound having the formula;

• and pharmaceutically acceptable salts, wherein:
• A is a heterocyclic ring;
• R1 is selected from the group consisting of H, hydroxyalkyl of from 1 to 4 carbon atoms, alkoxyalkyl of from 1 to 4 carbon atoms in each position, alkyl of from 1 to 8 carbon atoms and haloalkyl of from 1 to 4 carbon atoms;
• R2 is selected from the group consisting of straight and branched alkyl of from 1 to 4 carbon atoms, alkenyl and alkynyl of from 2 to 4 carbon atoms, cycloalkyl of from 1 to 4 carbon atoms, cycloalkenyl of from 3 to 8 carbon atoms, and haloalkyl of from 1 to 4 carbon atoms;
• all optionally substituted by one or more of alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, or amino groups;
• R3 is selected from the group consisting of H, alkyl of from 1 to 4 carbon atoms, alkenyl of from 2 to 4 carbon atoms, CH2OC(═O)YR6, alkylhydroxy, alkylpolyhydroxy, alkyl(poly)oxyacyl, alkylcarboxy, amino, hydroxy, optionally substituted by one or more of alkyl of from 1 to 4 carbon atoms, hydroxy, amino, carboxy, carboxyalkyl, alkylcarbonyl;
• R4 is selected from the group consisting of H, OH, SH, OR6, SR6, OC(═O)R6, SC(═O)R6, CH2OC(═O)YR6, OC(═O)YR6, SC(═O)YR6;
• Y is independently selected from O, S, CH2, CHR6, C(R6)2, NH, NR6;
• R5 is selected from the group consisting of H, OH, SH, OR6, SR6, OC(═O)R6, SC(═O)R6, CH2OC(═O)YR6, OC(═O)YR6, SC(═O)YR6;
• R6 is selected from the group consisting of H, 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;
• R7 is selected from the group consisting of H, S(O)R9, SO2R9, CH2OC(O)—R9, C(O)—R9 where C(O)—R9 is represented by natural and synthetic amino acids or R9 is defined as below;
• R8 is selected from the group consisting of H and acyl;
• provided that R4, R5, R7 and R8 are not simultaneously hydrogen, except when Q is SiE2;
• R9 is selected from the group consisting of 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 alkylene, alkenylene and alkynylene 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 —(CH2)kQ(CH2)t— where k is 1, 2 or 3, t is 1, 2 or 3 and Q is O (oxygen), Se, SiE2 where E is alkyl, aryl and NR where R is H or alkyl which may be optionally substituted with alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, amino;
• or
• X is selected from the group consisting of the formula —(CH2)mT(CH2)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 alkyl, alkoxy, hydroxy, halogen, nitro, cyano, trifluoroalkyl and amino.