Acetamidine derivatives and their use as inhibitors for the nitric oxide synthase

A compound of formula (1B):

• ##STR29## wherein R.sup.1 is hydrogen,
• a C.sub.1-6 hydrocarbyl group optionally substituted by halo,
• halo,
• nitro,
• cyano or
• a group XR.sup.3 wherein X is oxygen, C(O).sub.m wherein m is 1 or 2, S(O).sub.n wherein n is 0, 1 or 2, or a group NR.sup.4 wherein R.sup.4 is hydrogen or C.sub.1-6 alkyl;
• and R.sup.3 is hydrogen, C.sub.1-6 alkyl, or a group NR.sup.5 R.sup.6 wherein R.sup.5 and R.sup.6 are independently hydrogen or C.sub.1-6 alkyl, provided that R.sup.3 is not NR.sup.5 R.sup.6 when X is oxygen or S(O).sub.n ;
• R.sup.1a and R.sup.1b are independently selected from hydrogen and halo, and R.sup.14 represents one or two substituents on the phenyl ring independently selected from halo, ZR.sup.7 or a group:
• ##STR30## wherein Z is oxygen, C(O).sub.m wherein m is 1 or 2, S(O).sub.n wherein n is 0, 1 or 2, or a group NR.sup.8 wherein R.sup.8 is hydrogen or C.sub.1-6 alkyl, R.sup.7 is hydrogen, C.sub.1-6 alkyl, or a group NR.sup.9 R.sup.10 wherein R.sup.9 and R.sup.10 are independently hydrogen or C.sub.1-6 alkyl, and R.sup.11 has a definition the same as for R.sup.1, or R.sup.14 is a C.sub.1-6 hydrocarbyl group optionally substituted by one or two groups which may be the same or different, and are selected from halo, ZR.sup.7 or a group:
• ##STR31##

A compound of formula 1C:

• ##STR32## wherein R.sup.1 is hydrogen,
• a C.sub.1-6 hydrocarbyl group optionally substituted by halo,
• halo,
• nitro,
• cyano or
• a group XR.sup.3 wherein X is oxygen, C(O).sub.m wherein m is 1 or 2, S(O).sub.n wherein n is 0, 1 or 2, or a group NR.sup.4 wherein R.sup.4 is hydrogen or C.sub.1-6 alkyl;
• and R.sup.3 is hydrogen, C.sub.1-6 alkyl, or a group NR.sup.5 R.sup.6 wherein R.sup.5 and R.sup.6 are independently hydrogen or C.sub.1-6 alkyl, provided that R.sup.3 is not NR.sup.5 R.sup.6 when X is oxygen or S(O).sub.n ;
• R.sup.1a and R.sup.1b are independently selected from hydrogen and halo;
• R.sup.15 is a bond or CH.sub.2 ;
• and
• Y is selected from the group consisting of optionally substituted phenyl and indanyl;
• wherein Y is optionally substituted by one or more groups independently selected from the group consisting of halo, amino, cyano, nitro, hydroxy, and C.sub.1-6 hydrocarbyl optionally substituted by hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 thioalkyl, CF.sub.3, N.sup.3, a group:
• ##STR33## wherein n is 0, 1 or 2, C(O).sub.m B' or S(O).sub.n B' wherein m is 1 or 2, n is 0, 1 or 2 and B' is amino or C.sub.1-6 alkyl,
• a group:
• ##STR34## wherein n is 0, 1 or 2 and D and E are independently selected from the group consisting of hydrogen, hydroxy, amino, C.sub.1-6 alkyl, --CNHCH.sub.3, --CO.sub.2.sup.t Bu,
• a group:
• --(CH.sub.2).sub.n --NH--(CH.sub.2).sub.n --A
• wherein n is 0, 1 or 2, n' is 0, 1 or 2, and A is phenyl.

A process for the preparation of a compound of formula (I) ##STR35## or a salt thereof, wherein R.sup.1 is

• hydrogen,
• a C.sub.1-6 hydrocarbyl group optionally substituted by halo,
• halo,
• nitro,
• cyano or
• a group XR.sup.3 wherein X is oxygen, C(O).sub.m wherein m is 1 or 2, S(O).sub.n wherein n is 0, 1 or 2, or a group NR.sup.4 wherein R.sup.4 is hydrogen or C.sub.1-6 alkyl;
• and R.sup.3 is hydrogen, C.sub.1-6 alkyl, or a group NR.sup.5 R.sup.6 wherein R.sup.5 and R.sup.6 are independently hydrogen or C.sub.1-6 alkyl, provided that R.sup.3 is not NR.sup.5 R.sup.6 when X is oxygen or S(O).sub.n ;
• R.sup.1a and R.sup.1b are independently selected from hydrogen and halo;
• R.sup.2 is a C.sub.1-14 hydrocarbyl group the group R.sup.2 being optionally substituted by one or more groups independently selected from halo;
• N.sub.3 ;
• nitro;
• CF.sub.3 ;
• ZR.sup.7 wherein Z is oxygen, C(O).sub.m wherein m is 1 or 2, S(O).sub.n wherein n is 0, 1 or 2, or a group NR.sup.8 wherein R.sup.8 is hydrogen or C.sub.1-6 alkyl and R.sup.7 is hydrogen, C.sub.1-6 alkyl or a group NR.sup.9 R.sup.10 wherein R.sup.9 and R.sup.10 are independently hydrogen or C.sub.1-6 alkyl;
• or R.sup.2 is substituted by a group ##STR36## wherein R.sup.11 has a definition the same as R.sup.1 ;
• with the proviso that when R.sup.1 is a C.sub.1-6 alkyl group and R.sup.2 is a C.sub.1-14 hydrocarbyl substituted by two groups ZR.sup.7 wherein one group ZR.sup.7 is CO.sub.2 H, the other group ZR.sup.7 is not NH.sub.2 ;
• said process comprising the reaction of an amine of formula (II):
• H.sub.2 N--R.sup.2
• or a protected derivative thereof;
• with a 1-benzylthioethaniminium derivative of formula (III):
• ##STR37## followed by deprotection if necessary.