Guanidino compounds as regulators of nitric oxide synthase
First Claim
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1. A compound of the formula:
- ##STR9## or a pharmaceutically-acceptable salt, ester, amide or prodrug thereof, wherein;
R1 is selected from the group consisting of;
(1) hydrogen;
(2) C1 -C6 -alkyl;
(3) C6 -C12 -aryl-C1 -C4 -alkyl;
(4) substituted C6 -C12 -aryl-C1 -C4 -alkyl;
(5) N-protecting group;
(6) --CO--C1 -C6 -alkyl;
(7) --CO--C6 -C12 -aryl;
(8) --CO--substituted C6 -C12 -aryl;
(9) --CO--(C6 -C12 -aryl-C1 -C4 -alkyl);
(10) --CO--(substituted C6 -C12 -aryl-C1 -C4 -alkyl); and
(11) --CO-Het;
R2 is selected from the group consisting of;
(1) hydrogen;
(2) C1 -C6 -alkyl;
(3) C6 -C12 -aryl-C1 -C4 -alkyl; and
(4) substituted C6 -C12 -aryl-C1 -C4 -alkyl;
R3 is selected from the group consisting of;
(1) hydrogen;
(2) C1 -C6 -alkyl;
(3) C2 -C6 -alkenyl;
(4) cyclo-C3 -C7 -alkyl;
(5) C6 -C12 -aryl; and
(6) substituted C6 -C12 -aryl;
R4 is selected from the group consisting of;
(1) hydroxy;
(2) C1 -C6 -alkoxy;
(3) C6 -C12 -aryloxy;
(4) substituted C6 -C12 -aryloxy;
(5) --O--(C1 -C6 -alkyl-C6 -C12 -aryl);
(6) --O--(substituted C6 -C12 -aryl-C1 -C4 -alkyl); and
(7) --NHR11, wherein R11 is hydrogen or C1 -C4 -alkyl;
orR2 and R4 are linked together by a single bond to form a nitrogen-containing ring of the formula;
##STR10## wherein R1 and R3 are as defined above, R4 is O and R2 is --CR9 R10,wherein R9 is selected from the group consisting of;
(1) hydrogen;
(2) C1 -C6 -alkyl;
(3) substituted C1 -C6 -alkyl;
(4) C6 -C12 -aryl;
(5) substituted C6 -C12 -aryl;
(6) C2 -C6 -alkenyl;
(7) carboxy;
(8) C1 -C4 -alkoxycarbonyl, as defined below;
(9) carboxamido; and
(10) cyano;
R10 is hydrogen or C1 -C6 -alkyl; and
R12 is hydrogen or C1 -C 4 -alkyl;
R5 and R6 are independently selected from the group consisting of;
(1) hydrogen;
(2) C1 -C4 -alkyl;
(3) C6 -C12 -aryl-C1 -C6 -alkyl;
(4) substituted C6 -C12 -aryl-C1 -C6 -alkyl;
(5) halo-C1 -C2 -alkyl; and
(6) halogen;
R7 is selected from the group consisting of;
(1) hydrogen;
(2) C1 -C3 -alkyl;
(3) cyano;
(4) nitro;
(5) hydroxy;
(6) amino; and
(7) --OR15, wherein R15 is a hydroxy-protecting group;
R8 is hydrogen or C1 -C4 -alkyl; and
* may be a chiral center.
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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.
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Citations
8 Claims
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1. A compound of the formula:
- ##STR9## or a pharmaceutically-acceptable salt, ester, amide or prodrug thereof, wherein;
R1 is selected from the group consisting of; (1) hydrogen; (2) C1 -C6 -alkyl; (3) C6 -C12 -aryl-C1 -C4 -alkyl; (4) substituted C6 -C12 -aryl-C1 -C4 -alkyl; (5) N-protecting group; (6) --CO--C1 -C6 -alkyl; (7) --CO--C6 -C12 -aryl; (8) --CO--substituted C6 -C12 -aryl; (9) --CO--(C6 -C12 -aryl-C1 -C4 -alkyl); (10) --CO--(substituted C6 -C12 -aryl-C1 -C4 -alkyl); and (11) --CO-Het; R2 is selected from the group consisting of; (1) hydrogen; (2) C1 -C6 -alkyl; (3) C6 -C12 -aryl-C1 -C4 -alkyl; and (4) substituted C6 -C12 -aryl-C1 -C4 -alkyl; R3 is selected from the group consisting of; (1) hydrogen; (2) C1 -C6 -alkyl; (3) C2 -C6 -alkenyl; (4) cyclo-C3 -C7 -alkyl; (5) C6 -C12 -aryl; and (6) substituted C6 -C12 -aryl; R4 is selected from the group consisting of; (1) hydroxy; (2) C1 -C6 -alkoxy; (3) C6 -C12 -aryloxy; (4) substituted C6 -C12 -aryloxy; (5) --O--(C1 -C6 -alkyl-C6 -C12 -aryl); (6) --O--(substituted C6 -C12 -aryl-C1 -C4 -alkyl); and (7) --NHR11, wherein R11 is hydrogen or C1 -C4 -alkyl;
orR2 and R4 are linked together by a single bond to form a nitrogen-containing ring of the formula;
##STR10## wherein R1 and R3 are as defined above, R4 is O and R2 is --CR9 R10,wherein R9 is selected from the group consisting of; (1) hydrogen; (2) C1 -C6 -alkyl; (3) substituted C1 -C6 -alkyl; (4) C6 -C12 -aryl; (5) substituted C6 -C12 -aryl; (6) C2 -C6 -alkenyl; (7) carboxy; (8) C1 -C4 -alkoxycarbonyl, as defined below; (9) carboxamido; and (10) cyano; R10 is hydrogen or C1 -C6 -alkyl; and R12 is hydrogen or C1 -C 4 -alkyl; R5 and R6 are independently selected from the group consisting of; (1) hydrogen; (2) C1 -C4 -alkyl; (3) C6 -C12 -aryl-C1 -C6 -alkyl; (4) substituted C6 -C12 -aryl-C1 -C6 -alkyl; (5) halo-C1 -C2 -alkyl; and (6) halogen; R7 is selected from the group consisting of; (1) hydrogen; (2) C1 -C3 -alkyl; (3) cyano; (4) nitro; (5) hydroxy; (6) amino; and (7) --OR15, wherein R15 is a hydroxy-protecting group; R8 is hydrogen or C1 -C4 -alkyl; and
* may be a chiral center. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8)
- ##STR9## or a pharmaceutically-acceptable salt, ester, amide or prodrug thereof, wherein;
Specification
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Current AssigneeAbbott Laboratories Patent and Trademark Department
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Original AssigneeAbbott Laboratories
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InventorsMurad, Ferid, Kerwin, James F., Gorsky, Lee D.
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Primary Examiner(s)Killos, Paul J.
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Application NumberUS08/159,409Time in Patent Office756 DaysField of Search548/215, 548/567, 560/34, 564/108, 564/104, 564/226, 564/227US Class Current548/215CPC Class CodesC07C 279/12 being further substituted b...C07C 279/36 Substituted N-nitroguanidinesC07C 281/16 Compounds containing any of...
