US 5,478,946 AGranted

Guanidino compounds as regulators of nitric oxide synthase

AssigneeAbbott Laboratories

InventorsFerid Murad, James F. Kerwin, Lee D. Gorsky

Life of this patent

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Abstract

Compounds of the formula: ##STR1## useful as regulators of nitric oxide synthase that indirectly modulate cyclic guanosine monophosphate (cGMP), pharmaceutical compositions thereof, for treating disorders of vascular smooth muscles, macrophages, neurons, platelets, bronchial smooth muscles, optic muscles and gastrointestinal smooth muscles, sickle cell anemia and diabetes.

Claims8

Dependent claims

A compound of the formula:

##STR9## or a pharmaceutically-acceptable salt, ester, amide or prodrug thereof, wherein:
R.sup.1 is selected from the group consisting of:
(1) hydrogen;
(2) C.sub.1 -C.sub.6 -alkyl;
(3) C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.4 -alkyl;
(4) substituted C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.4 -alkyl;
(5) N-protecting group;
(6) --CO--C.sub.1 -C.sub.6 -alkyl;
(7) --CO--C.sub.6 -C.sub.12 -aryl;
(8) --CO--substituted C.sub.6 -C.sub.12 -aryl;
(9) --CO--(C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.4 -alkyl);
(10) --CO--(substituted C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.4 -alkyl);
and
(11) --CO-Het;
R.sup.2 is selected from the group consisting of:
(1) hydrogen;
(2) C.sub.1 -C.sub.6 -alkyl;
(3) C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.4 -alkyl;
and
(4) substituted C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.4 -alkyl;
R.sup.3 is selected from the group consisting of:
(1) hydrogen;
(2) C.sub.1 -C.sub.6 -alkyl;
(3) C.sub.2 -C.sub.6 -alkenyl;
(4) cyclo-C.sub.3 -C.sub.7 -alkyl;
(5) C.sub.6 -C.sub.12 -aryl;
and
(6) substituted C.sub.6 -C.sub.12 -aryl;
R.sup.4 is selected from the group consisting of:
(1) hydroxy;
(2) C.sub.1 -C.sub.6 -alkoxy;
(3) C.sub.6 -C.sub.12 -aryloxy;
(4) substituted C.sub.6 -C.sub.12 -aryloxy;
(5) --O--(C.sub.1 -C.sub.6 -alkyl-C.sub.6 -C.sub.12 -aryl);
(6) --O--(substituted C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.4 -alkyl);
and
(7) --NHR.sup.11, wherein R.sup.11 is hydrogen or C.sub.1 -C.sub.4 -alkyl;
or
R.sup.2 and R.sup.4 are linked together by a single bond to form a nitrogen-containing ring of the formula:
##STR10## wherein R.sup.1 and R.sup.3 are as defined above, R.sup.4 is O and R.sup.2 is --CR.sup.9 R.sup.10,
wherein R.sup.9 is selected from the group consisting of:
(1) hydrogen;
(2) C.sub.1 -C.sub.6 -alkyl;
(3) substituted C.sub.1 -C.sub.6 -alkyl;
(4) C.sub.6 -C.sub.12 -aryl;
(5) substituted C.sub.6 -C.sub.12 -aryl;
(6) C.sub.2 -C.sub.6 -alkenyl;
(7) carboxy;
(8) C.sub.1 -C.sub.4 -alkoxycarbonyl, as defined below;
(9) carboxamido;
and
(10) cyano;
R.sup.10 is hydrogen or C.sub.1 -C.sub.6 -alkyl;
and
R.sup.12 is hydrogen or C.sub.1 -C .sub.4 -alkyl;
R.sup.5 and R.sup.6 are independently selected from the group consisting of:
(1) hydrogen;
(2) C.sub.1 -C.sub.4 -alkyl;
(3) C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.6 -alkyl;
(4) substituted C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.6 -alkyl;
(5) halo-C.sub.1 -C.sub.2 -alkyl;
and
(6) halogen;
R.sup.7 is selected from the group consisting of:
(1) hydrogen;
(2) C.sub.1 -C.sub.3 -alkyl;
(3) cyano;
(4) nitro;
(5) hydroxy;
(6) amino;
and
(7) --OR.sup.15, wherein R.sup.15 is a hydroxy-protecting group;
R.sub.8 is hydrogen or C.sub.1 -C.sub.4 -alkyl;
and * may be a chiral center.

71 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/159,409Filed 30 Nov 1993 · continuation in part
Priority: 21 Jun 1989
Granted: 26 Dec 1995
Term ends: Not estimatedThe source records don’t support an estimate.

Classification4 codes

C07C 279/12
Having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton: being further substituted by nitrogen atoms not…
C07C 279/36
N-nitroguanidines: substituted N-nitroguanidines
C07C 281/16
Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these…:…
C07C
Acyclic or carbocyclic compounds

Family

Serial369,364Parent of this continuation-in-part · filed 21 Jun 1989
Serial755,398Parent of this continuation-in-part · filed 5 Sep 1991
5288897Parent of this continuation-in-part
US 5,478,946 AThis patent

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Abstract

A compound of the formula:

##STR9## or a pharmaceutically-acceptable salt, ester, amide or prodrug thereof, wherein:
R.sup.1 is selected from the group consisting of:
(1) hydrogen;
(2) C.sub.1 -C.sub.6 -alkyl;
(3) C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.4 -alkyl;
(4) substituted C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.4 -alkyl;
(5) N-protecting group;
(6) --CO--C.sub.1 -C.sub.6 -alkyl;
(7) --CO--C.sub.6 -C.sub.12 -aryl;
(8) --CO--substituted C.sub.6 -C.sub.12 -aryl;
(9) --CO--(C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.4 -alkyl);
(10) --CO--(substituted C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.4 -alkyl);
and
(11) --CO-Het;
R.sup.2 is selected from the group consisting of:
(1) hydrogen;
(2) C.sub.1 -C.sub.6 -alkyl;
(3) C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.4 -alkyl;
and
(4) substituted C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.4 -alkyl;
R.sup.3 is selected from the group consisting of:
(1) hydrogen;
(2) C.sub.1 -C.sub.6 -alkyl;
(3) C.sub.2 -C.sub.6 -alkenyl;
(4) cyclo-C.sub.3 -C.sub.7 -alkyl;
(5) C.sub.6 -C.sub.12 -aryl;
and
(6) substituted C.sub.6 -C.sub.12 -aryl;
R.sup.4 is selected from the group consisting of:
(1) hydroxy;
(2) C.sub.1 -C.sub.6 -alkoxy;
(3) C.sub.6 -C.sub.12 -aryloxy;
(4) substituted C.sub.6 -C.sub.12 -aryloxy;
(5) --O--(C.sub.1 -C.sub.6 -alkyl-C.sub.6 -C.sub.12 -aryl);
(6) --O--(substituted C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.4 -alkyl);
and
(7) --NHR.sup.11, wherein R.sup.11 is hydrogen or C.sub.1 -C.sub.4 -alkyl;
or
R.sup.2 and R.sup.4 are linked together by a single bond to form a nitrogen-containing ring of the formula:
##STR10## wherein R.sup.1 and R.sup.3 are as defined above, R.sup.4 is O and R.sup.2 is --CR.sup.9 R.sup.10,
wherein R.sup.9 is selected from the group consisting of:
(1) hydrogen;
(2) C.sub.1 -C.sub.6 -alkyl;
(3) substituted C.sub.1 -C.sub.6 -alkyl;
(4) C.sub.6 -C.sub.12 -aryl;
(5) substituted C.sub.6 -C.sub.12 -aryl;
(6) C.sub.2 -C.sub.6 -alkenyl;
(7) carboxy;
(8) C.sub.1 -C.sub.4 -alkoxycarbonyl, as defined below;
(9) carboxamido;
and
(10) cyano;
R.sup.10 is hydrogen or C.sub.1 -C.sub.6 -alkyl;
and
R.sup.12 is hydrogen or C.sub.1 -C .sub.4 -alkyl;
R.sup.5 and R.sup.6 are independently selected from the group consisting of:
(1) hydrogen;
(2) C.sub.1 -C.sub.4 -alkyl;
(3) C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.6 -alkyl;
(4) substituted C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.6 -alkyl;
(5) halo-C.sub.1 -C.sub.2 -alkyl;
and
(6) halogen;
R.sup.7 is selected from the group consisting of:
(1) hydrogen;
(2) C.sub.1 -C.sub.3 -alkyl;
(3) cyano;
(4) nitro;
(5) hydroxy;
(6) amino;
and
(7) --OR.sup.15, wherein R.sup.15 is a hydroxy-protecting group;
R.sub.8 is hydrogen or C.sub.1 -C.sub.4 -alkyl;
and * may be a chiral center.

71 more elements

Facts

Application

08/159,409Filed 30 Nov 1993 · continuation in part

Priority

21 Jun 1989

Granted

26 Dec 1995

Term ends

Not estimatedThe source records don’t support an estimate.

Classification4 codes

C07C 279/12
Having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton: being further substituted by nitrogen atoms not…
C07C 279/36
N-nitroguanidines: substituted N-nitroguanidines
C07C 281/16
Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these…:…
C07C
Acyclic or carbocyclic compounds