IP Library › Granted Patent US 7,279,490

Granted Patent B2

US 7,279,490 · App. 10/515,127 · Granted Oct 9, 2007

Ophthalmic compositions for treating ocular hypertension

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Quick Facts

Patent No.: US 7,279,490
App. No.: 10/515,127
Granted: Oct 9, 2007
Kind: B2

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Abstract

This invention relates to selective m1 muscarinic agonist, their use or a formulation thereof in the treatment of glaucoma and/or other conditions which are related to elevated intraocular pressure in the eye of a patient. This invention also relates to the use of such compounds to provide a neuroprotective effect to the eye of mammalian species, particularly humans. In addition, the present invention relates to the use of the compounds in the treatment of dementia such as Alzheimer's disease and vascular dementia, depression, attention deficit disorder, sleep disorder, schizophrenia, pain, ischemia, atrophic gastritis, and atony of gastrointestinal tract.

Claims (125)

1. A compound of structural formula I:

or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof:

wherein,

R 1 represents R 8 , (CH 2 ) n OR 8 , COOR,COOR 8 , (CH 2 ) n N(R)(R 8 ), (CH 2 ) n N + (R) 3 , (CH 2 ) n NRCOR, (CH 2 ) n N(R 8 )CO 2 R, (CH 2 ) n N(R 8 )COR, (CH 2 ) n NRCO 2 R, SO 2 R, SO 2 N(R) 2 , (CH 2 ) n CON(R) 2 , CONRR 8 , CONHC(R) 3 ,COR, COR 8 , CON(R 8 ) 2 , nitro, or cyano;

Z represents CH 2 , CO, CHCO 2 R, or SO 2 ;

Ar represents (CH 2 ) n 5-11 heterocyclyl, (CH 2 ) n C 5-10 heteroaryl, or (CH 2 ) n C 6-10 aryl, said heterocycle, aryl or heteroaryl optionally substituted with 1-3 groups of R a ;

R a represents C 1 -C 6 alkyl optionally substituted with fluoro, C 2-6 alkenyl, C 2-6 alkynyl, F, Cl, I, Br, (CH 2 ) n NR 2 , (CH 2 ) n NRR 8 , NO 2 , CN, —CF 3 , —COR, —COR 8 , —CONRR 8 , —CONR 2 , —(CH 2 ) n COOR, —(CH 2 ) n NHCOR, —(CH 2 ) n NHCOR 8 , —(CH 2 ) n NHCOOR, —SO 2 NR 2 , —SiR 3 , —(CH 2 ) n OR, —(CH 2 ) n OR 8 , —O(CH 2 ) n OR, —(CH 2 ) n O(CH 2 ) n OR, —S(O) m R, —S(O) m R 8 , —C(NH)NH 2 , R 8

R represents hydrogen, C 1-6 alkyl optionally substituted with fluoro, C 2-6 alkenyl, or C 2-6 alkynyl;

R 8 represents (CH 2 ) n C 3-8 cycloalkyl, (CH 2 ) n C 5-11 heterocycle, (CH 2 ) n C 5-10 heteroaryl, (CH 2 ) n C 6-10 aryl, said heterocycle, aryl or heteroaryl optionally substituted with 1-3 groups of R b ;

R b represents F, Cl, I, Br, or C 1-6 alkyl

n is 0-3

m is 0-2.

2. A compound according to claim 1 wherein Z is CH 2 .

3. A compound according to claim 1 wherein Z is CO.

4. A compound according to claim 1 wherein Ar is (CH 2 ) n C 6-10 aryl.

5. A compound according to claim 4 wherein Ar is optionally

substituted with 1-2 groups of R a , Z is CO or CH 2 and n=0.

6. A compound according to claim 1 wherein Ar is (CH 2 ) n C 5-10 heteroaryl, and all other variables are as originally described.

7. A compound according to claim 6 wherein Ar is optionally substituted with 1-2 groups of R a , Z is CO or CH 2 and n=0.

8. A compound which is:

1-[1-[1-(3-Thienoyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(2-Methoxynicotinoyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[2-(Methoxycarbonyl)benzoyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(4-Methoxy-3-thienoyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[(1-Methyl-2-pyrrolyl)carbonyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[(3-Indolyl)carbonyl]piperidin-4-yl]piperidin-4yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(2-Methylbenzoyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[2-(Methylthio)nicotinoyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[2-(Methylthio)benzoyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[(1,2-Dihydro-1-benzofuran-7-yl)carbonyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(3Chloro-2-thienoyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(2-Ethylbenzoyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[2-(Phenoxymethyl)benzoyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(3-Ethoxy-2-thienoyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(3-Methoxy-2-thienoyl)piperidin-4-yl]piperidin-4yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(2-Methylbenzyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(2,6-Dimethylbenzyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(2-Chlorobenzyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[2-(Trifluoromethyl)benzyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(2-Thienylmethyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[2-(Methylthio)benzyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(2-Bromobenzyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(2-Hydroxybenzyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(2-Iodobenzyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[(3-Methyl-2-thienyl)methyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[(5-Methyl-2-thienyl)methyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[(3-Bromo-2-thienyl)methyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[2-(Methoxycarbonyl)benzyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[(Thieno[2,3-b]thien-2-yl)methyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[(3-Chloro-2-thienyl)methyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(2-Ethylbenzyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(3-Methyl-2-furoyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(3-Methylfurfuryl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(Thiazol-5-ylmethyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[(1-Methyl-1H-imidazol-4-yl)methyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[(5-Methyl-3-methylthio-isothiazol4-yl)methyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[(4Methyl-1,2,3-thiadiazol-5-yl)methyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[(Isoxazol-5-yl)methyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[(Thiazol-2-yl)methyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(2-Methylbenzyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

5-Bromo-1-[1-[1-(2-methylbenzyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one; or

5-Bromo-1-[1-[1-[(3-methyl-2-thienyl)methyl]piperidin-4-yl]piperdin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one,

or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof.

9. A method for treating ocular hypertension or glaucoma comprising administration to a patient in need of such treatment a therapeutically effective amount of a compound of structural formula I:

or a pharmaceutically acceptable salt, enantiomer, diastereomer or mixture thereof:

wherein,

R 1 represents R, R 8 , (CH 2 ) n OR, (CH 2 ) n OR 8 , COOR, COOR 8 , (CH 2 ) n N(R) 2 , (CH 2 ) n N(R)(R 8 ), (CH 2 ) n N + (R) 3 , (CH 2 ) n NRCOR, (CH 2 ) n N(R 8 )CO 2 R, (CH 2 ) n N(R 8 )COR, (CH 2 ) n NRCO 2 R, SO 2 R, SO 2 N(R) 2 , (CH 2 ) n CON(R) 2 , CONRR 8 , CONHC(R) 3 , COR, COR 8 , CON(R 8 ) 2 , nitro, cyano, or halogen, alkyl or alkoxy optionally substituted with 1-3 groups of R a ;

Z represents CH 2 , CO, CHCO 2 R, or SO 2 ;

Ar represents (CH 2 ) n 5-11 heterocyclyl, (CH 2 ) n C 5-10 heteroaryl, or (CH 2 ) n C 6-10 arly, said heterocycle, aryl or heteroaryl optionally substituted with 1-3 groups of R a ;

R a represents C 1 -C 6 alkyl optionally substituted with fluoro, C 2-6 alkenyl, C 2-6 alkynyl, F, Cl, L Br, (CH 2 ) n NR 2 , (CH 2 ) n NRR 8 , NO 2 , CN, —CF 3 , —COR, —COR 8 , —CONRR 8 , —CONR 2 , —(CH 2 ) n COOR, —(CH 2 ) n NHCOR, —(CH 2 ) n NHCOR 8 , —(CH 2 ) n NHCOOR, —SO 2 NR 2 , —SiR 3 , —(CH 2 ) n OR, —(CH 2 ) n OR 8 , —O(CH 2 ) n OR, —(CH 2 ) n O(CH 2 ) n OR, —S(O) m R, —S(O) m R 8 , —C(NH)NH 2 , R 8 ;

R represents hydrogen, C 1-6 alkyl optionally substituted with fluoro, C 2-6 alkenyl, or C 2-6 alkynyl;

R 8 represents (CH 2 ) n C 3-8 cycloalkyl, (CH 2 ) n C 5-11 heterocyclyl, (CH 2 ) n C 5-10 heteroaryl, (CH 2 ) n C 6-10 aryl, said heterocyclyl, aryl or heteroaryl optionally substituted with 1-3 groups of R b ;

R b represents F, Cl, I, Br, or C 1-6 alkyl;

n is 0-3 and

m is 0-2.

10. The method according to claim 9 wherein the compound of formula I is applied as a topical formulation in a solution or suspension.

11. The method according to claim 9 wherein the compound is:

1-[1-[1-(3-Thienoyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(2-Methoxynicotinoyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[2-(Methoxycarbonyl)benzoyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(2-Methoxybenzoyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(4-Methoxy-3-thenoyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[(1-Methyl-2-pyrrolyl)carbonyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[(3-Indolyl)carbonyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(2-Methylbenzoyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[2-(Methylthio)nicotinoyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[2-(Methylthio)benzoyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[(1,2-Dihydro-1-benzofuran-7-yl)carbonyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(3-Chloro-2-thenoyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(2-Ethylbenzoyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[2-(Phenoxymethyl)benzoyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(3-Ethoxy-2-thenoyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(3-Methoxy-2-thenoyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(2-Methylbenzyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(2,6-Dimethylbenzyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(2-Chlorobenzyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[2-(Trifluoromethyl)benzyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[-(2-Thienylmethyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-[2-(Methylthio)benzyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(2-Bromobenzyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(2-Hydroxybenzyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(2-Iodobenzyl)piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one;

1-[1-[1-(3-Methyl-2-thienyl)methyl]piperidin-4-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidiazol-2-one;