US 8,273,749 B2 · N-substituted oxindoline derivatives as calcium channel blockers

Abstract

A series of N-substituted oxindole derivatives represented by Formula I, or pharmaceutically acceptable salts thereof. Pharmaceutical compositions comprise an effective amount of the instant compounds, either alone, or in combination with one or more other therapeutically active compounds, and a pharmaceutically acceptable carrier. Methods of treating conditions associated with, or caused by, calcium channel activity, including, for example, acute pain, chronic pain, visceral pain, inflammatory pain, neuropathic pain, urinary incontinence, itchiness, allergic dermatitis, epilepsy, diabetic neuropathy, irritable bowel syndrome, depression, anxiety, multiple sclerosis, sleep disorder, bipolar disorder and stroke, comprise administering an effective amount of the present compounds, either alone, or in combination with one or more other therapeutically active compounds.

Claims15

Dependent claims

A compound of structural formula I:

or pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof:
wherein:
R1=aryl or heteroaryl, optionally substituted with 1-3 substituents consisting of:
C1-6 alkyl, C1-4-fluoroalkyl, C6-10-aryl, or C6-10heteroaryl, F, Cl, Br, CN, OR5, NR5R6, SO2R5, SO2NR5R6, NR5SO2R6, CO2R5, CONR5R6;
R2=C1-6 alkyl, C1-6 fluoroalkyl;
R3=(CH2)naryl or (CH2)nheteroaryl, wherein each aryl or heteroaryl is optionally substituted with 1-3 substituents consisting of:
C1-6 alkyl, C1-4-fluoroalkyl, C6-10-aryl, C6-10heteroaryl, F, Cl, Br, CN, OR5, NR5R6, SO2R5, SO2NR5R6, NR5SO2R6, CO2R5, CONR5R6;
each R4 is independently selected from H, C1-6 alkyl, C1-4-fluoroalkyl, aryl, heteroaryl, F, Cl, Br, CN, OR5, NR5R6, SO2R5, SO2NR5R6, NR5SO2R6, CO2R5, and CONR5R6;
R5 and R6 are each independently selected from H, C1-6 alkyl, C1-4-fluoroalkyl, C3-7-cycloalkyl, C6-10-aryl, and C6-10heteroaryl or R5 and R6 join to form a 3-7 member carbocyclic or heterocyclic ring and
n=0-6.

7 more elements

A compound which is:

3-methyl-1-pyridin-2-yl-3-(pyrimidin-5-ylmethyl)-5-[3-(trifluoromethyl)phenyl]-1,3-dihydro-2H-indol-2-one,
5-(4-fluorophenyl)-3-methyl-1-pyridin-2-yl-3-(pyrimidin-5-ylmethyl)-1,3-dihydro-2H-indol-2-one,
1-(6-aminopyrazin-2-yl)-5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1,3-dihydro-2H-indol-2-one,
3-methyl-1-pyrazin-2-yl-3-(pyrimidin-5-ylmethyl)-5-[3-(trifluoromethyl)phenyl]-1,3-dihydro-2H-indol-2-one,
1-(5-aminopyrazin-2-yl)-5-(3-chlorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1,3-dihydro-2H-indol-2-one,
5-(3-chloro-4-fluorophenyl)-3-methyl-1-pyrimidin-2-yl-3-(pyrimidin-5-ylmethyl)-1,3-dihydro-2H-indol-2-one,
5-(3-chloro-4-fluorophenyl)-3-methyl-1-pyridin-4-yl-3-(pyrimidin-5-ylmethyl)-1,3-dihydro-2H-indol-2-one,
1-(5-aminopyrazin-2-yl)-5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1,3-dihydro-2H-indol-2-one,
5-(3-chloro-4-fluorophenyl)-1-(1H-imidazol-4-yl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1,3-dihydro-2H-indol-2-one,
5-(3-chloro-4-fluorophenyl)-3-methyl-1-pyridin-3-yl-3-(pyrimidin-5-ylmethyl)-1,3-dihydro-2H-indol-2-one,
3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1H-1,2,4-triazol-3-yl)-5-[3-(2,2,2-trifluoroethoxy)-phenyl]-1,3-dihydro-2H-indol-2-one,
5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1H-1,2,4-triazol-3-yl)-1,3-dihydro-2H-indol-2-one,
5-(3,4-difluorophenyl)-3-methyl-1-pyrimidin-2-yl-3-(pyrimidin-5-ylmethyl)-1,3-dihydro-2H-indol-2-one,
5-(4-fluorophenyl)-3-methyl-1-pyrimidin-2-yl-3-(pyrimidin-5-ylmethyl)-1,3-dihydro-2H-indol-2-one,
3-(3,5-difluorobenzyl)-5-[4-fluoro-3-(trifluoromethyl)phenyl]-3-methyl-1-pyrimidin-2-yl-1,3-dihydro-2H-indol-2-one,
3-(3,5-difluorobenzyl)-5-[4-fluoro-3-(trifluoromethyl)phenyl]-3-methyl-1-pyridin-2-yl-1,3-dihydro-2H-indol-2-one,
3-(3,5-difluorobenzyl)-5-[2-fluoro-5-(trifluoromethyl)phenyl]-3-methyl-1-pyrimidin-2-yl-1,3-dihydro-2H-indol-2-one,
3-(3,5-difluorobenzyl)-3-methyl-1-pyridin-2-yl-5-[3-(trifluoromethyl)phenyl]-1,3-dihydro-2H-indol-2-one,
3-(3,5-difluorobenzyl)-3-methyl-1-pyrimidin-2-yl-5-[3-(trifluoromethyl)phenyl]-1,3-dihydro-2H-indol-2-one,
5-(3-chloro-4-fluorophenyl)-3-(3,5-difluorobenzyl)-3-methyl-1-pyrimidin-2-yl-1,3-dihydro-2H-indol-2-one,
5-(3-chloro-4-fluorophenyl)-3-(3,5-difluorobenzyl)-3-methyl-1-pyridin-2-yl-1,3-dihydro-2H-indol-2-one,
5-(3-chlorophenyl)-3-(3,5-difluorobenzyl)-3-methyl-1-pyrimidin-2-yl-1,3-dihydro-2H-indol-2-one,
5-(3-chlorophenyl)-3-(3,5-difluorobenzyl)-1,3-dimethyl-1,3-dihydro-2H-indol-2-one,
3-(3,5-difluorobenzyl)-3-methyl-1-pyrazin-2-yl-5-[3-(trifluoromethyl)phenyl]-1,3-dihydro-2H-indol-2-one,
3-(3,5-difluorobenzyl)-1,3-dimethyl-5-[3-(trifluoromethyl)phenyl]-1,3-dihydro-2H-indol-2one,
1-(6-aminopyridin-2-yl)-5-(3-chlorophenyl)-3-(3,5-difluorobenzyl)-3-methyl-1,3-dihydro-2H-indol-2-one,
1-(5-aminopyrazin-2-yl)-5-(3-chlorophenyl)-3-(3,5-difluorobenzyl)-3-methyl-1,3-dihydro-2H-indol-2-one,
5-(3-chlorophenyl)-3-(3,5-difluorobenzyl)-3-methyl-1-pyridin-2-yl-1,3-dihydro-2H-indol-2-one,
5-(3-chlorophenyl)-3-(3,5-difluorobenzyl)-3-methyl-1-pyrimidin-2-yl-1,3-dihydro-2H-indol-2-one,
5-(3-chlorophenyl)-3-(3,5-difluorobenzyl)-3-methyl-1-pyrazin-2-yl-1,3-dihydro-2H-indol-2-one,
5-(3-chlorophenyl)-3-(3,5-difluorobenzyl)-1-(6-methoxypyridin-2-yl)-3-methyl-1,3-dihydro-2H-indol-2-one,
5-(3-chlorophenyl)-3-(3,5-difluorobenzyl)-1-(1H-imidazol-4-yl)-3-methyl-1,3-dihydro-2H-indol-2-one,
5-(3-chloro-4-fluorophenyl)-3-(3,5-difluorobenzyl)-3-methyl-1-pyridin-2-yl-1,3-dihydro-2H-indol-2-one,
5-(3-chloro-4-fluorophenyl)-3-(3,5-difluorobenzyl)-3-methyl-1-pyrimidin-2-yl-1,3-dihydro-2H-indol-2-one,
3-(3,5-difluorobenzyl)-3-methyl-1-(1H-1,2,4-triazol-5-yl)-5-[3-(trifluoromethyl)phenyl]-1,3-dihydro-2H-indol-2-one,
3-(3,5-difluorobenzyl)-3-methyl-1-pyridin-3-yl-5-[3-(trifluoromethyl)phenyl]-1,3-dihydro-2H-indol-2-one,
3-(3,5-difluorobenzyl)-3-methyl-1-pyrimidin-5-yl-5-[3-(trifluoromethyl)phenyl]-1,3-dihydro-2H-indol-2-one,
1-(5-aminopyridin-2-yl)-3-(3,5-difluorobenzyl)-3-methyl-5-[3-(trifluoromethyl)phenyl]-1,3-dihydro-2H-indol-2-one,
3-(3,5-difluorobenzyl)-3-methyl-1-pyridin-4-yl-5-[3-(trifluoromethyl)phenyl]-1,3-dihydro-2H-indol-2-one,
1-(6-aminopyrazin-2-yl)-3-(3,5-difluorobenzyl)-3-methyl-5-[3-(trifluoromethyl)phenyl]-1,3-dihydro-2H-indol-2-one,
1-(6-aminopyridin-2-yl)-5-(3-chlorophenyl)-3-(3,5-difluorobenzyl)-3-methyl-1,3-dihydro-2H-indol-2-one,
1-(6-aminopyrazin-2-yl)-5-(3-chlorophenyl)-3-(3,5-difluorobenzyl)-3-methyl-1,3-dihydro-2H-indol-2-one,
1-(5-aminopyrazin-2-yl)-5-(3-chlorophenyl)-3-(3,5-difluorobenzyl)-3-methyl-1,3-dihydro-2H-indol-2-one,
3-(3,5-difluorobenzyl)-5-(4-fluorophenyl)-3-methyl-1-pyrimidin-2-yl-1,3-dihydro-2H-indol-2-one,
1-(6-aminopyrazin-2-yl)-3-(3,5-difluorobenzyl)-5-(4-fluorophenyl)-3-methyl-1,3-dihydro-2H-indol-2-one,
3-(3,5-difluorobenzyl)-5-(3,4-difluorophenyl)-3-methyl-1-pyrimidin-2-yl-1,3-dihydro-2H-indol-2-one,
1-(5-aminopyrazin-2-yl)-5-(3-chloro-4-fluorophenyl)-3-(3,5-difluorobenzyl)-3-methyl-1,3-dihydro-2H-indol-2-one,
5-(3-chloro-4-fluorophenyl)-3-(3,5-difluorobenzyl)-1-(1H-imidazol-4-yl)-3-methyl-1,3-dihydro-2H-indol-2-one,
5-(3-chloro-4-fluorophenyl)-3-(3,5-difluorobenzyl)-3-methyl-1-pyridin-4-yl-1,3-dihydro-2H-indol-2-one,
3-(3,5-difluorobenzyl)-5-(3,4-difluorophenyl)-3-methyl-1-pyrimidin-2-yl-1,3-dihydro-2H-indol-2-one,
3-methyl-3-pyrimidin-5-ylmethyl-1-(1H-[1,2,4]triazol-3-yl)-5-(3-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one,
3-methyl-1-(1-methyl-1H-imidazol-4-yl)-3-pyrimidin-5-ylmethyl-5-(3-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one,
5-(3,4-difluoro-phenyl)-3-methyl-1-(1-methyl-1H-imidazol-4-yl)-3-pyrimidin-5-ylmethyl-1,3-dihydro-indol-2-one,
5-(3,4-difluoro-phenyl)-3-methyl-3-pyrimidin-5-ylmethyl-1-(1H-1,2,4-triazol-3-yl)-1,3-dihydro-indol-2-one,
3-methyl-3-pyrimidin-5-ylmethyl-1-(1H-1,2,4-triazol-3-yl)-5-[3-(2,2,2-trifluoro-ethoxy)-phenyl]-1,3-dihydro-indol-2-one,
3-methyl-1-(1-methyl-1H-imidazol-4-yl)-3-pyrimidin-5-ylmethyl-5-[3-(2,2,2-trifluoro-ethoxy)-phenyl]-1,3-dihydro-indol-2-one,
or
pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

55 more elements

Dependencies are inferred from the claim text.

N-substituted oxindoline derivatives as calcium channel blockers

Life of this patent

N-substituted oxindoline derivatives as calcium channel blockers

Life of this patent

Abstract

Claims15