US 6,645,968 B2Granted

Potassium channel openers

AssigneeAbbott Laboratories

InventorsRobert J. Altenbach, Hao Bai, Jorge D. Brioni, William A. Carroll, Murali Gopalakrishnan, Robert J. Gregg, Mark W. Holladay, Peggy P. Huang, John F. Kincaid, Michael E. Kort, Philip R. Kym, John K. Lynch, Arturo Perez-Medrano, Henry Q. Zhang

Life of this patent

Estimating the term…

Abstract

Compounds of formula I: are useful in treating diseases prevented by or ameliorated with potassium channel openers. Also disclosed are potassium channel opening compositions and a method of opening potassium channels in a mammal.

Claims78

Dependent claims

A compound having formula I:

or a pharmaceutically acceptable salt thereof wherein,
X is selected from the group consisting of O, S, CHCN, C(CN)2, CHNO2, and NR8;
R8 is selected from the group consisting of hydrogen, alkoxy, alkyl, alkylsulfonyl, arylalkoxy, aryloxy, arylsulfonyl, cyano, haloalkylsulfonyl, heterocyclealkoxy, heterocycleoxy, hydroxy, nitro, and sulfamyl;
R1 is selected from the group consisting of heterocycle, and heterocyclealkyl;
R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl(halo)alkyl, alkoxy(halo)alkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyl(halo)alkyl, alkylcarbonyloxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkylthioalkyl, alkynyl, amido, amidoalkyl, aryl, arylalkoxyalkyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylalkyl, arylcarbonyl, arylcarbonylalkyl, arylcarbonyloxyalkyl, aryl(halo)alkyl, aryloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylalkylthioalkyl, arylsulfonylalkyl, carboxy, carboxyalkyl, carboxy(halo)alkyl, cyanoalkyl, cyano(halo)alkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkoxyalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkyloxyalkyl, cycloalkylalkylthioalkyl, formyl, haloalkenyl, haloalkyl, haloalkylcarbonyl, haloalkynyl, heterocycle, heterocyclealkoxyalkyl, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocyclealkylthioalkyl, hydroxyalkyl, mercaptoalkyl, sulfamylalkyl, sulfamyl(halo)alkyl, and (NR9R10)alkyl wherein R9 and R10 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, formyl, and S(O)2R11, wherein R11 is selected from alkyl, aryl, and arylalkyl;
R3 is selected from the group consisting of alkyl, aryl, arylalkyl, heterocycle, and heterocyclealkyl;
R4 is hydrogen;
or
R4 and R1 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, indolinyl and isoindolinyl wherein benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, indolinyl and isoindolinyl are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfinyl, alkylsulfonyl, alkynyl, arylalkoxycarbonyl, cyano, halogen, haloalkyl, haloalkoxy, nitro, sulfamyl, and —NRARB wherein RA and RB are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl and formyl;
R5 is selected from the group consisting of hydrogen, alkyl and OR12;
R12 is selected from the group consisting of hydrogen, alkyl and arylalkyl;
or
R5 and R4 taken together form an alkylene bridge of 2-3 carbons;
R6 is hydrogen;
or
R6 and R5 taken together form an alkylene bridge of 2-3 carbons;
or
R6 taken together with the nitrogen atom to which it is attached and R3 taken together with the carbon atom to which it is attached, together form a heterocycle selected from the group consisting of 1-isoindolinonyl and 1-isoquinolinonyl wherein 1-isoindolinonyl and 1-isoquinolinonyl are optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfinyl, alkylsulfonyl, alkynyl, arylalkoxycarbonyl, cyano, halogen, haloalkyl, haloalkoxy, nitro, oxo, sulfamyl, and —NRARB wherein RA and RB are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl and formyl;
and
R7 is selected from the group consisting of hydrogen, haloalkyl, and lower alkyl;
or
R7 and R2 taken together with the carbon atom to which they are attached, together form a 5 or 6 membered carbocyclic ring wherein the 5 or 6 membered carbocyclic ring is optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkenyl, alkoxy, alkyl, alkynyl, halogen, haloalkoxy, and haloalkyl;
provided that when X is O;
R2 is —CCl3;
R3 is alkyl or phenyl;
and R4, R5, R6, and R7 are hydrogen;
then R1 is other than phenyl.

24 more elements

A compound selected from the group consisting of

4-chloro-N-(1-{[(hydroxyimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-(1-{[(methoxyimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-(1-{[{[(4-fluorobenzyl)oxy]imino}(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-(2,2-dimethyl-1-{[[(methylsulfonyl)imino](3-pyridinylamino)methyl]amino}propyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(6-fluoro-1H-indol-1-yl)methyl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(6-fluoro-1H-benzimidazol-1-yl)methyl]amino}-2,2-dimethylpropyl)benzamide;
3-(4-chlorophenyl)-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)propanamide;
N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)-3-phenyipropanamide;
N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)-2-phenylacetamide;
N-[1-(5-chloro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)-2,2-dimethylpropyl]-N″-cyano-N′-(3-pyridinyl)guanidine;
4-(aminosulfonyl)-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)-2-fluorobenzamide;
4-chloro-N-[1-({(cyanoimino) [(4-ethyl-3-pyridinyl)amino]methyl}amino)-2,2-dimethylpropyl]benzamide;
N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylpropyl)-4-(trifluoromethoxy)benzamide;
4-chloro-N-[1-({(cyanoimino) [(4-ethyl-3-pyridinyl)amino]methyl}amino)-2,2-dimethylpropyl]-2-fluorobenzamide;
4-chloro-N-(1-{[(cyanoimino)(5-pyrimidinylamino)methyl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(5-pyrimidinylamino)methyl]amino}-2,2-dimethylpropyl)-2-fluorobenzamide;
N-(1-{[[(4-bromo-3-pyridinyl)amino](cyanoimino)methyl]amino}-2,2-dimethylpropyl)-4-chlorobenzamide;
4-chloro-2-fluoro-N-[2,2,2-trichloro-1-({(cyanoimino)[(4-ethyl-3-pyridinyl)amino]methyl}amino)ethyl]benzamide;
4-chloro-N-(2,2,2-trichloro-1-{[(cyanoimino)(5-pyrimidinylamino)methyl]amino}ethyl)benzamide;
4-chloro-2-fluoro-N-(2,2,2-trichloro-1-{[(cyanoimino)(5pyrimidinylamino)methyl]amino}ethyl)benzamide;
N-(1-{[[(4-bromo-3-pyridinyl)amino](cyanoimino)methyl]amino}-2,2,2-trichioroethyl)-4-chlorobenzamide;
N-(1-{[[(2-bromo-3-pyridinyl)amino](cyanoimino)methyl]amino}-2,2-dimethylpropyl)-4-chlorobenzamide;
4-chloro-N-[1-({(cyanoimino)[(2-ethyl-3-pyridinyl)amino]methyl}amino)-2,2-dimethylpropyl]benzamide;
N-(1-{[[(5-bromo-4-ethyl-3-pyridinyl)amino](cyanoimino)methyl]amino}-2,2-dimethylpropyl)-4-chlorobenzamide;
4-chloro-N-[1-({(cyanoimino) [(4,5-dibromo-3-pyridinyl)amino]methyl}amino)-2,2-dimethylpropyl]benzamide;
4-chloro-N-(1-{[[(5-chloro-3-pyridinyl)amino](cyanoimino)methyl]amino}-2,2-dimethylpropyl)benzamide;
N-(1-{[[(5-bromo-6-chloro-3-pyridinyl)amino](cyanoimino)methyl]amino}-2,2-dimethylpropyl)-4-chlorobenzamide;
N-(1-{[[(5-bromo-3-pyridinyl)amino](cyanoimino)methyl]amino}-2,2-dimethyipropyl)-4-chlorobenzamide;
N-(1-{[[(6-bromo-3-pyridinyl)amino](cyanoimino)methyl]amino}-2,2-dimethyipropyl)-4-chlorobenzamide;
4-chloro-N-(1-{[(cyanoimino)({5-[(4-fluorophenyl)sulfonyl]-3-pyridinyl}amino)methyl]amino}-2,2-dimethylpropyl)benzamide;
N-(1-{[({5-[(aminoperoxy)sulfanyl]-3-pyridinyl}amino)(cyanoimino)methyl]amino}-2,2-dimethylpropyl)-4-chlorobenzamide;
N-(1-{[[(6-bromo-4-fluoro-3-pyridinyl)amino](cyanoimino)methyl]amino}-2,2-dimethylpropyl)-4-chlorobenzamide;
4-chloro-N-[1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}cyclopentyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}cyclohexyl)benzamide;
4-chloro-N-[{[(cyanoimino)(3-pyridinylamino)methyl]amino}(2,6-dimethylphenyl)methyl]benzamide;
4-chloro-N-[{[(cyanoimino)(3-pyridinylamino)methyl]amino}(3-pyridinyl)methyl]benzamide;
4-chloro-N-[{[(cyanoimino)(3-pyridinylamino)methyl]amino}(2-pyridinyl)methyl]benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2-methyl-2-phenylpropyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-3,3-dimethyl-2-oxobutyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-3,3,3-trifluoro-2-oxopropyl)benzamide;
4-chloro-N-[1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-3,3,3-trifluoro-2-methyl-2-(trifluoromethyl)propyl]benzamide;
methyl 4-[(4-chlorobenzoyl)amino]-4-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-3,3-dimethylbutanoate;
4-chloro-N-[1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-4-(dimethylamino)-2,2-dimethylbutyl]benzamide;
4-chloro-N-(4-cyano-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylbutyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-4-methoxy-2,2-dimethylbutyl)benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-4-hydroxy-2,2-dimethylbutyl)benzamide;
N-(4-(aminosulfonyl)-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethylbutyl)-4-chlorobenzamide;
4-chloro-N-[1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-dimethyl-4-(phenylsulfonyl)butyl]benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-3-hydroxy-2,2-dimethylpropyl)benzamide;
4-chloro-N-{2,2,2-trichloro-1-[2-(cyanoimino)-3-(3-pyridinyl)imidazolidinyl]ethyl}benzamide;
4-chloro-N-{1-[2-(cyanoimino)-3-(3-pyridinyl)imidazolidinyl]-2,2-dimethyipropyl}benzamide;
2-tert-butyl-3-(4-chlorobenzoyl)-N′-cyano-N-(3-pyridinyl)-1-imidazolidinecarboximidamide;
N-(4-(aminosulfonyl)-2,2-dichloro-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}butyl)-4-chlorobenzamide;
4-chloro-N-[4-cyano-1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-bis(trifluoromethyl)butyl]benzamide;
4-chloro-N-(1-{[(cyanoimino)(3-pyridinylamino)methyl]amino}-2,2-difluoro-4-oxopentyl)benzamide;
4-chloro-N-(1-{[2-cyano-1-(3-pyridinylamino)ethenyl]amino}-2,2-dimethylpropyl)benzamide;
4-chloro-N-{1-[[(cyanoimino)(3-pyridinylamino)methyl](hydroxy)amino]-2,2-dimethyipropyl}benzamide;
4-chloro-N-(2,2,2-trichloro-1-{[2-nitro-1-(3-pyridinylamino)ethenyl]amino}ethyl)benzamide;
and
4-chloro-N-(2,2,2-trichloro-1-{[2-cyano-1-(3-pyridinylamino)ethenyl]amino}ethyl)benzamide.

58 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/777,217Filed 5 Feb 2001 · continuation in part
Priority: 3 Aug 1999
Published: US 2002/0028836 A17 Mar 2002
Granted: 11 Nov 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification52 codes

C07D 213/40
Radicals substituted by singly-bound nitrogen atoms: acylated substituent nitrogen atom
A61K 31/17
Amides, e.g. hydroxamic acids: having the group >N—C—N< or >N—C—N<, e.g. urea, thiourea, carmustine
A61K 31/275
Medicinal preparations containing organic active ingredients: nitriles; Isonitriles
A61K 31/4406
Non condensed pyridines; Hydrogenated derivatives thereof: only substituted in position 3, e.g. zimeldine

Family

Application60/146,967Us provisional application · filed 3 Aug 1999
Application09/621,154Parent of this continuation-in-part · filed 21 Jul 2000
US 2002/0028836 A1Pre-grant publication · published 7 Mar 2002
US 6,645,968 B2This patent

From the US filing history. Foreign family members aren’t listed.

Timeline

Citations

Open elsewhere

patentgrep

Loading patent…

Potassium channel openers

AssigneeAbbott Laboratories

Life of this patent

Estimating the term…

Abstract

A compound having formula I:

or a pharmaceutically acceptable salt thereof wherein,
X is selected from the group consisting of O, S, CHCN, C(CN)2, CHNO2, and NR8;
R8 is selected from the group consisting of hydrogen, alkoxy, alkyl, alkylsulfonyl, arylalkoxy, aryloxy, arylsulfonyl, cyano, haloalkylsulfonyl, heterocyclealkoxy, heterocycleoxy, hydroxy, nitro, and sulfamyl;
R1 is selected from the group consisting of heterocycle, and heterocyclealkyl;
R2 is selected from hydrogen, alkenyl, alkenyloxyalkyl, alkenyloxy(alkenyloxy)alkyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl(halo)alkyl, alkoxy(halo)alkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyl(halo)alkyl, alkylcarbonyloxyalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, alkylthioalkyl, alkynyl, amido, amidoalkyl, aryl, arylalkoxyalkyl, arylalkoxycarbonyl, arylalkoxycarbonylalkyl, arylalkyl, arylcarbonyl, arylcarbonylalkyl, arylcarbonyloxyalkyl, aryl(halo)alkyl, aryloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, arylalkylthioalkyl, arylsulfonylalkyl, carboxy, carboxyalkyl, carboxy(halo)alkyl, cyanoalkyl, cyano(halo)alkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkoxyalkyl, cycloalkylalkyl, cycloalkylcarbonyl, cycloalkyloxyalkyl, cycloalkylalkylthioalkyl, formyl, haloalkenyl, haloalkyl, haloalkylcarbonyl, haloalkynyl, heterocycle, heterocyclealkoxyalkyl, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxyalkyl, heterocyclealkylthioalkyl, hydroxyalkyl, mercaptoalkyl, sulfamylalkyl, sulfamyl(halo)alkyl, and (NR9R10)alkyl wherein R9 and R10 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, formyl, and S(O)2R11, wherein R11 is selected from alkyl, aryl, and arylalkyl;
R3 is selected from the group consisting of alkyl, aryl, arylalkyl, heterocycle, and heterocyclealkyl;
R4 is hydrogen;
or
R4 and R1 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, indolinyl and isoindolinyl wherein benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, indolinyl and isoindolinyl are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfinyl, alkylsulfonyl, alkynyl, arylalkoxycarbonyl, cyano, halogen, haloalkyl, haloalkoxy, nitro, sulfamyl, and —NRARB wherein RA and RB are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl and formyl;
R5 is selected from the group consisting of hydrogen, alkyl and OR12;
R12 is selected from the group consisting of hydrogen, alkyl and arylalkyl;
or
R5 and R4 taken together form an alkylene bridge of 2-3 carbons;
R6 is hydrogen;
or
R6 and R5 taken together form an alkylene bridge of 2-3 carbons;
or
R6 taken together with the nitrogen atom to which it is attached and R3 taken together with the carbon atom to which it is attached, together form a heterocycle selected from the group consisting of 1-isoindolinonyl and 1-isoquinolinonyl wherein 1-isoindolinonyl and 1-isoquinolinonyl are optionally substituted with 1, 2, or 3 substituents selected from the group consisting of alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfinyl, alkylsulfonyl, alkynyl, arylalkoxycarbonyl, cyano, halogen, haloalkyl, haloalkoxy, nitro, oxo, sulfamyl, and —NRARB wherein RA and RB are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl and formyl;
and
R7 is selected from the group consisting of hydrogen, haloalkyl, and lower alkyl;
or
R7 and R2 taken together with the carbon atom to which they are attached, together form a 5 or 6 membered carbocyclic ring wherein the 5 or 6 membered carbocyclic ring is optionally substituted with 1 or 2 substituents independently selected from the group consisting of alkenyl, alkoxy, alkyl, alkynyl, halogen, haloalkoxy, and haloalkyl;
provided that when X is O;
R2 is —CCl3;
R3 is alkyl or phenyl;
and R4, R5, R6, and R7 are hydrogen;
then R1 is other than phenyl.

24 more elements

Facts

Application

09/777,217Filed 5 Feb 2001 · continuation in part

Priority

3 Aug 1999

Published

US 2002/0028836 A17 Mar 2002

Granted

11 Nov 2003

Term ends

Not estimatedThe source records don’t support an estimate.

Classification52 codes

C07D 213/40
Radicals substituted by singly-bound nitrogen atoms: acylated substituent nitrogen atom
A61K 31/17
Amides, e.g. hydroxamic acids: having the group >N—C—N< or >N—C—N<, e.g. urea, thiourea, carmustine
A61K 31/275
Medicinal preparations containing organic active ingredients: nitriles; Isonitriles
A61K 31/4406
Non condensed pyridines; Hydrogenated derivatives thereof: only substituted in position 3, e.g. zimeldine

Family

Application60/146,967Us provisional application · filed 3 Aug 1999

Application09/621,154Parent of this continuation-in-part · filed 21 Jul 2000

US 2002/0028836 A1Pre-grant publication · published 7 Mar 2002

US 6,645,968 B2This patent

From the US filing history. Foreign family members aren’t listed.