US 6,632,836 B1Granted

Carbocyclic potassium channel inhibitors

AssigneeMerck & Co., Inc.

InventorsRobert K. Baker, Jianming Bao, Jennifer Chee, Maria L. Garcia, Gregory J. Kaczorowski, Frank Kayser, Andrew Kotliar, Chou Juitsai Liu, Shouwu Miao, William H. Parsons, Kathleen M. Rupprecht, William A. Schmalhofer, Christopher F. Claiborne, David A. Claremon, Nigel Liverton, Wayne J. Thompson

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Abstract

The present invention relates to a class of carbocyclic compounds of Formula I that are useful as potassium channel inhibitors to treat autoimmune disorders, cardiac arrhythmias, and the like.

Claims23

Dependent claims

A compound of structural Formula I:

or a pharmaceutically acceptable salt, crystal form, or hydrate, wherein:
n is:
0, 1, 2 or 3;
r is:
0 or 1;
s is:
0 or 1;
R6 and R7 are independently:
(1) halo, wherein halo is fluoro, chloro, bromo, or iodo,
(2) hydroxy,
(3) O[(C═O)Or]s(C1-C6)-alkyl,
(4) —(O)r(C0-C6)-alkyl-aryl, wherein aryl is phenyl or naphthyl unsubstituted or substituted with up to three substitutents selected from (C1-C3)alkyl, trifluoromethyl, and halo;
(5) NR8R9,
(6) hydrogen, or
(7) R6 and R7 can an be taken together when on adjacent carbons to form a fused benzo, dihydrofuranyl, furanyl, pyrrolidyl, dihydropyrrolidyl or 1,3-dioxolan group;
R3 and R4 are independently:
(1) halo, wherein halo is fluoro, chloro, bromo, or iodo,
(2) hydroxy,
(3) cyano,
(4) CO2(C1-C6)-alkyl,
(5) NR8R9,
(6) O(CO)NR8R9,
(7) NR8(CO)NR8R9,
(8) hydrogen,
(9) (C1-C10)-alkyl, wherein alkyl includes cyclic as well as acyclic groups and is unsubstituted or substituted with one or two of the substituents selected from the group consisting of:
(a) halo, wherein halo is fluoro, chloro, bromo, or iodo,
(b) hydroxy,
(c) O[(C═O)Or]s(C1-C6)-alkyl,
(d) aryl-(C1-C6)-alkyloxy,
(e) O(CO)NR8R9,
(f) CHO,
(g) CO2H,
(h) CO2(C1-C6)-alkyl, and
(i) CONR8R9,
(10) O[(C═O)Or]s(C1-C6)-alkyl, alkyl as defined above,
(11) O[(C═O)Or]s(C2-C6)-alkenyl, as defined above,
(12) O[(C═O)Or]saryl, aryl as defined above,
(13) O[(C═O)Or]sheteroaryl, heteroaryl as defined above, or
(14) O(CO)NH(CH2—CO—NR8R9);
R3 can also be any of the following when R4 is absent:
(15) oxo,
(16) ═CH2, or
R3 and R4 can be taken together to form a spiro-fused heterocyclyl group, wherein heterocyclyl is as defined above, or
R3 and R5 can be taken together to form a fused oxirane;
R5 is:
(1) hydrogen,
(2) halogen,
(3) (C2-C6)-alkenyl,
(4) hydroxy,
(5) O(CO)NR8R9,
(6) oxo, or
R5 and R3 can be taken together to form a fused oxirane;
and
R8 and R9 are independently selected from the group consisting of:
(1) hydrogen,
(2) [(C═O)Or]saryl, wherein aryl is as defined above,
(3) [(C═O)Or]s(C2-C8)-alkenyl, wherein alkenyl is as defined above,
(4) [(C═O)Or]s(C1-C8)-alkyl, wherein alkyl is as defined above,
(5) (C═O)rS(O)n(C1-C8)-alkyl, wherein alkyl is as defined above,
(6) (C═O)rS(O)naryl, wherein aryl is as defined above, and
(7) heterocyclyl, wherein heterocyclyl is defined above.

58 more elements

The compound of structural formula I

wherein:
R6 and R7 are independently:
(1) halo, wherein halo is fluoro, chloro, bromo, or iodo,
(2) hydroxy,
(3) (C1-C6)-alkyloxy, wherein the alkyl is cyclic or straight-chained,
(4) acetoxy,
(5) NR8R9,
(6) —(O)r(C0-C3)-aryl, wherein aryl is phenyl or naphthyl unsubstituted or substituted with up to three substitutents selected from (C1-C3)alkyl, trifluoromethyl, and halo,
(7) hydrogen, or
(8) R6 and R7 can an be taken together to form a fused benzo, dihydrofuranyl, furanyl, pyrrolidyl, dihydropyrrolidyl or 1,3-dioxolan group;
R3 and R4 are independently:
(1) halo, wherein halo is fluoro, chloro, bromo, or iodo,
(2) hydroxy,
(3) (C═O)O(C1-C6)-alkyl,
(4) CH2CO2—(C1-C6)-alkyl,
(5) cyano,
(6) benzyloxy,
(7) CH2OAc,
(8) OAc,
(9) (C1-C6)-alkyl, wherein alkyl can be unsubstituted or substituted with bromide
(10) NR8R9,
(11) O(CO)NR8R9,
(12) NR8(CO)NR8R9,
(13) hydrogen,
(14) CH2OH,
(15) CH2O(C═O)phenyl, wherein phenyl is unsubstituted or monosubstituted with methoxy,
(16) O(C═O)-phenyl, wherein phenyl is unsubstituted or monosubstituted with bromide,
(17) O(C═O)O-phenyl, wherein phenyl is unsubstituted or monosubstituted with nitro,
(18) CH2(CO)NR8R9,
(19) O(C═O)O—(C2-C6)-alkenyl,
(20) O(C═O)—(C1-C3)-alkyl, wherein the alkyl can be unsubstituted or substituted with bromide or —CO2CH3,
(21) O(C1-C6)-alkyl, wherein alkyl can be unsubstituted or substituted with phenyl,
(22) O(C═O)O—(C1-C6)-alkyl,
(23) CH2O(CO)NR8R9, or
(24) CH2(C═O)O—(C1-C6)-alkyl,
R3 can also be any of the following when R4 is absent:
(25) oxo,
(26) ═CH2,
(27) ═CH—CO2—(C1-C6)-alkyl,
(28) ═CH—(CO)—NR8R9, or
(29) ═CH—CO2H, or
R3 and R4 can be taken together to form a spiro-fused heterocyclyl group, wherein heterocyclyl is defined as:
(30) oxirane,
(31) 1,3-dioxolan,
(32) 2,2-dimethyl-1,3-dioxolan, or
(33) glycol sulfite, or
R3 and R5 can be taken together to form a fused oxirane;
R5 is:
(1) hydrogen,
(2) halogen,
(3) (C2-C6)-alkenyl,
(4) hydroxy,
(5) O(CO)NR8R9,
(6) oxo, or
R5 and R3 can be taken together to form a fused oxirane;
R8 and R9 are independently selected from the group consisting of:
(1) hydrogen,
(2) (C═O)O(C1-C6)-alkyl, wherein alkyl is optionally substituted with phenyl or methoxy,
(3) (C═O)phenyl, wherein phenyl is optionally substituted with bromide or methoxy,
(4) (C1-C6)-alkyl, wherein alkyl is optionally substituted with phenyl, methoxy, hydroxy, OCH2OCH3, benzylSO3, phenylSO3, or carboxymethyl,
(5) (C2-C6)-alkenyl,
(6) (C═O)O-phenyl, wherein phenyl is optionally substituted with nitro,
(7) (C═O)O(C2-C6)-alkenyl,
(8) (C═O)(C1-C3)-alkyl, wherein alkyl is optionally substituted with phenyl,
(9) (C═O)(C2-C4)-alkenyl,
(10) phenyl,
(11) SO2-phenyl,
(12) SO2-benzyl,
(13) CH2(CO)CH3,
(14) CH2(CO)NH-benzyl,
(15) CH2(CO)NH-allyl,
(16) CH2(CO)N(CH3)2,
(17) CH2(CO)NH(CH3),
(24) CH2CH2NHCO2(C1-C3)alkyl,
(25) CH2CH2O(CO)NHCH3,
(26) CH2CH2O(CO)NH-allyl,
(27) CH2CH2NH(SO2)CH3,
(28) CH2CH2NH2,
(29) CH2CH2NH(CO)CH2CH3, and
(30) benzyl.

77 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/422,143Filed 21 Oct 1999 · us provisional application
Priority: 30 Oct 1998
Granted: 14 Oct 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification64 codes

C07D 207/08
Having no double bonds between ring members or between ring members and non-ring members: with hydrocarbon radicals, substituted by hetero atoms,…
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/02
Drugs for disorders of the alimentary tract or the digestive system: stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…