Hydroxyamidino derivatives useful as nitric oxide synthase inhibitors

A compound having the formula;

• and pharmaceutically acceptable salts, wherein:
• A is O;
• R1 is selected from the group consisting of hydrogen, 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 hydrogen, alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, or amino groups;
• R3 is selected from the group consisting of aryl, alkylaryl, all optionally substituted by one or more of halogen, nitrile, carboxy, carboxyalkyl, carboxyalkylaryl;
• or
• R3 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, 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 H, OH, SH, OR6, SR6, OC(═O)R6, CH2OC(═O)YR6, and OC(═O)YR6;
• Y is independently selected from O, S, CH2, CHR6, C(R6)2, NH, NR6;
• R5 is selected from H, OH, SH, OR6, SR6, OC(═O)R6, CH2OC(═O)YR6, OC(═O)YR6;
• R6 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, and aryl 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 H, CH2OC(O)—R9, C(O)—R9 where C(O)—R9 can represent natural and synthetic amino acids or R9 can be defined as below;
• R8 is selected from H, acyl;
• provided that R4, R5, R7 and R8 are not simultaneously hydrogen;
• R9 is selected from substituted 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, 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 or 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 ring or a aromatic 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.