IP Library › Granted Patent US 8,058,264

Granted Patent B2

US 8,058,264 · App. 11/257,056 · Granted Nov 15, 2011

Pharmaceutical compositions comprising CB1 cannabinoid receptor antagonists and potassium channel openers for the treatment of obesity and related conditions

Assignee: Abbott Products GmbH

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Quick Facts

Patent No.: US 8,058,264
App. No.: 11/257,056
Granted: Nov 15, 2011
Kind: B2

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Abstract

Described is a novel combination therapy for diabetes mellitus type I and/or for obesity and its concomitant and/or secondary diseases or conditions, in particular the metabolic syndrome and/or syndrome X, and/or diabetes mellitus type II, by administering a combination of at least one K ATP channel opener as a first active agent and at least one CB 1 cannabinoid receptor antagonist as a second active agent. The invention is further directed to such novel combination therapy wherein a dually acting compound with combined K ATP channel opening and CB 1 antagonistic properties is used. The invention also relates to novel pharmaceutical compositions comprising K ATP channel openers and CB 1 antagonists and the use of said pharmaceutical compositions in the treatment, delayed progression, delayed onset of and/or inhibition of diabetes mellitus type 1, and the prophylaxis and treatment, of obesity as well as the prophylaxis, treatment, delayed onset and/or inhbition of its concomitant and/or secondary diseases or conditions, in particular the metabolic syndrome and/or syndrome X, and/or diabetes mellitus type II, in mammals and humans. The invention is further directed to such novel pharmaceutical compositions comprising a dually acting compound with combined K ATP channel opening and CB 1 antagonistic properties.

Claims (219)

1. A method for treating type II diabetes and/or insulin resistance in a mammal or a human subject comprising:

administering to a subject in need thereof an effective amount of at least one K ATP channel opener in combination with at least one CB 1 antagonist

wherein the at least one K ATP channel opener is chosen from pinacidil; cromakalim; diazoxide; BPDZ 44; BPDZ 49; BPDZ 62; BPDZ 73; BPDZ 79; BPDZ 83; BPDZ 154; BPDZ 216 (=NNC 55-9216); NN414; NNC 55-0118; NNC 55-0462; MCC-134; SR 47063 and WAY 135201;

and wherein the at least one CB 1 antagonist is chosen from compounds of Formula I,

wherein:

R and R 1 are the same or different and are chosen from naphthyl, phenyl, thienyl and pyridyl groups, wherein the phenyl, thienyl and pyridyl groups may be substituted with 1, 2 or 3 substituents Y, which can each be the same or different;

R 2 is chosen from hydrogen, hydroxy, C 1-3 -alkoxy, acetyloxy and propionyloxy groups;

Y is chosen from C 1-3 -alkyl, C 1-3 -alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C 1-2 )-amino, mono- or dialkyl (C 1-2 )-amido, (C 1-3 )-alkyl sulfonyl, dimethylsulfamido, C 1-3 -alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl groups;

Aa is chosen from one of the groups (i), (ii), (iii), (iv) and (v),

wherein

R 4 is chosen from acetamido, dimethylamino, 2,2,2-trifluoroethyl, phenyl, and pyridyl groups; and

R 5 is hydrogen; or

R 4 and R 5 independently of each other are chosen from hydrogen, C 1-8 branched or unbranched alkyl, and C 3-8 cycloalkyl groups;

R 6 is chosen from hydrogen and C 1-3 unbranched alkyl groups;

Bb is chosen from sulfonyl and carbonyl groups;

R 3 is chosen from pyrrolidinyl, piperidinyl, morpholinyl, naphthyl, benzyl, phenyl, thienyl and pyridyl groups, wherein the benzyl, phenyl, thienyl and pyridyl groups may be substituted with 1, 2 or 3 substituents Y, which can be the same or different;

a prodrug thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 , wherein a subject without concomitant obesity is treated.

3. The method according to claim 1 , further comprising administering to the subject insulin substitution as needed.

4. The method according to claim 1 , wherein the at least one K ATP channel opener and the at least one CB 1 antagonist are administered simultaneously, stepwise, or in physical combination.

5. The method according to claim 1 , wherein the at least one K ATP channel opener and the at least one CB 1 antagonist are administered simultaneously in a fixed combination.

6. The method according to claim 1 , wherein the at least one CB 1 antagonist or the at least one K ATP channel opener is a dually acting compound comprising combined K ATP channel opening and CB 1 antagonistic properties.

7. A method for treating, delaying progression of, or delaying onset of diabetes mellitus in a subject comprising:

administering to a subject in need thereof an effective amount of at least one K ATP channel opener in combination with at least one CB 1 antagonist

and wherein the at least one CB 1 antagonist is chosen from compounds of Formula I,

wherein:

R 2 is chosen from hydrogen, hydroxy, C 1-3 -alkoxy, acetyloxy and propionyloxy groups;

Y is chosen from C 1-3 -alkyl, C 1-3 -alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C 1-2 )-amino, mono-or dialkyl (C 1-2 )-amido, (C 1-3 )-alkyl sulfonyl, dimethylsulfamido, C 1-3 -alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl groups;

Aa is chosen from one of the groups (i), (ii), (iii), (iv) and (v),

wherein

R 4 is chosen from acetamido, dimethylamino, 2,2,2-trifluoroethyl, phenyl, and pyridyl groups; and

R 5 is hydrogen; or

R 4 and R 5 independently of each other are chosen from hydrogen, C 1-8 branched or unbranched alkyl, and C 3-8 cycloalkyl groups;

R 6 is chosen from hydrogen and C 1-3 unbranched alkyl groups;

Bb is chosen from sulfonyl and carbonyl groups;

a prodrug thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof.

8. The method according to claim 7 , wherein the subject is further treated with insulin.

9. The method according to claim 7 , wherein obese or non-obese subjects with diabetes type I are treated weight-loss independently.

10. The method according to claim 8 , wherein obese or non-obese subjects with diabetes type I are treated weight-loss independently.

11. The method according to claim 7 , wherein obese or non-obese subjects with diabetes type II are treated weight-loss independently.

12. The method according to claim 8 , wherein obese or non-obese subjects with diabetes type II are treated weight-loss independently.

13. The method according to claim 7 , wherein the at least one K ATP channel opener and the at least one CB 1 antagonist are administered simultaneously, stepwise, or in physical combination.

14. The method according to claim 7 , wherein the at least one K ATP channel opener and the at least one CB 1 antagonist are administered simultaneously in a fixed combination.

15. The method according to claim 7 , wherein the at least one CB 1 antagonist or the at least one K ATP channel opener is a dually acting compound comprising combined K ATP channel opening and CB 1 antagonistic properties.

16. The method according to claim 1 , wherein R is 4-chlorophenyl, R 1 is phenyl, R 2 is hydrogen, Aa is the group (i) wherein R 4 is hydrogen and R 5 is methyl, Bb is sulfonyl, and R 3 is 4-chlorophenyl in the compound of Formula I, and salts thereof.

17. The method according to claim 1 , wherein the compound of Formula I is a levorotatory enantiomer.

18. The method according to claim 1 , wherein the compound of Formula I is chosen from

(S)-3-(4-chlorophenyl)-N-[(4-chlorophenyl)sulfonyl]-4,5-dihydro-N′-methyl-4-phenyl-1H-pyrazole-1-carboximidamide;

(−)-3-(4-chlorophenyl)-4,5-dihydro-N-methyl-4-phenyl-N′-(1-piperidinylsulfonyl)-1H-pyrazole-1-carboximidamide, and

(−)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-N-methyl-N′-[[4-(trifluoromethyl)-phenyl]sulfonyl]-1H-pyrazole-1-carboximidamide.

19. The method according to claim 6 , wherein the dually acting compound comprising combined K ATP channel opening and CB 1 antagonistic properties comprises at least one compound chosen from:

(4S)-3-(4-chlorophenyl)-N′-[(4-chlorophenyl)sulfonyl]-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidamide;

5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-piperidin-1-yl-1H-pyrazole-3-carboxamide;

5-(1,1-dimethylheptyl)-2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-phenol;

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-piperidin-1-yl-1H-pyrazole-3-carboxamide;

N′-(azepan-1-ylsulfonyl)-3-(4-chlorophenyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidamide;

(2S)-1-[3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl]-3-(3,4-dichloro-phenyl)-1-oxopropan-2-amine;

3-(4-chlorophenyl)-N′-[(4-chlorophenyl)sulfonyl]-4-phenyl-N-(pyridin-3-ylmethyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide;

(2S)-1-[3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl]-3-(1H-indol-3-yl)-N-methyl-1-oxopropan-2-amine;

2-[3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl]-5-ethyl-4,5-dihydro-1,3-oxazole;

3-(4-chlorophenyl)-N-[2-(diethylamino)ethyl]-N′-[(diethylamino)sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidamide;

3-(4-chlorophenyl)-N-[(4-chlorophenyl)sulfonyl]-N′-(3-hydroxy-2,2-dimethylpropyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidamide;

3-(4-chlorophenyl)-N-[2-(dimethylamino)ethyl]-4-phenyl-N′-(piperidin-1-ylsulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide;

3-(4-chlorophenyl)-N′-[(4-chlorophenyl)sulfonyl]-N-[(1-methylpyrrolidin-3-yl)methyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidamide;

3-(4-chlorophenyl)-N-{[isopropyl(methyl)amino]sulfonyl}-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbothioamide;

5-(4-bromophenyl)-N-[(4-chlorophenyl)sulfonyl]-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxamide;

5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazole-3-carbonitrile;

8-chloro-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetrahydrobenzo[6,7]cyclo-hepta[1,2-c]pyrazole-3-carboxamide;

3-(4-chlorophenyl)-N′-[(diethylamino)sulfonyl]-4-hydroxy-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidamide;

methyl 3-(4-chlorophenyl)-N-[(diethylamino)sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbimidothioate;

1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine;

5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-3-[(Z)-2-(3,5-difluorophenyl)-2-(methyl-sulfonyl)vinyl]-4-methyl-1H-pyrazole;

4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-N-piperidin-1-yl-1,3-thiazole-2-carboxamide;

2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-1,2-benzisothiazol-3(2H)-one 1,1-dioxide;

5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-N-piperidin-1-yl-1,3-thiazole-2-carboxamide;

1-(4-bromophenyl)-N-cyclohexyl-2-(2,4-dichlorophenyl)-5-ethyl-1H-imidazole-4-carboxamide;

1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-5-ethyl-N-pentyl-1H-imidazole-4-carboxamide;

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-pyrrolidin-1-yl-1H-1,2,4-triazole-3-carboxamide;

3-(4-chlorophenyl)-N′-[(4-hydroxypiperidin-1-yl)sulfonyl]-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidamide;

3-(4-chlorophenyl)-N′-[(dimethylamino)sulfonyl]-N-(2-fluoroethyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidamide;

1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-N-piperidin-1-yl-1H-1,2,4-triazole-3-carboxamide;

1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-N-morpholin-4-yl-1H-1,2,4-triazole-3-carboxamide;

3-(4-chlorophenyl)-4-(3-fluorophenyl)-N-methyl-N′-(piperidin-1-ylsulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide;

3-(4-chlorophenyl)-N-methyl-N′-(morpholin-4-ylsulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidamide;

4-(4-chlorophenyl)-N-cyclohexyl-5-(2,4-dichlorophenyl)-1-methyl-1H-imidazole-2-carboxamide;

5-(4-chlorophenyl)-N-cyclohexyl-4-(2,4-dichlorophenyl)-1-methyl-1H-imidazole-2-carboxamide;

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N,N-diethyl-1H-imidazole-4-carboxamide;

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-4,5-dihydro-1H-pyrazole-3-carboxamide;

3-(4-chlorophenyl)-N′-[(4-chlorophenyl)sulfonyl]-N-methyl-4-pyridin-3-yl-4,5-dihydro-1H-pyrazole-1-carboximidamide;

1-(4-chlorophenyl)-5-phenyl-N-piperidin-1-yl-4,5-dihydro-1 H-pyrazole-3-carboxamide;

1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboximidamide;

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-(4-hydroxycyclohexyl)-5-methyl-1H-imidazole-4-carboxamide;

N-azepan-1-yl-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxamide;

2-(2,5-dichlorophenyl)-5-ethyl-1-phenyl-N-piperidin-1-yl-1H-imidazole-4-carboxamide;

N-cyclohexyl-2-(1,5-dimethyl-1H-pyrrol-2-yl)-5-ethyl-1-phenyl-1H-imidazole-4-carboxamide;

1-(4-chlorophenyl)-N-methyl-5-phenyl-N′-(piperidin-1-ylsulfonyl)-4,5-dihydro-1H-pyrazole-3-carboximidamide;

1-(4-chlorophenyl)-N-cyclohexyl-5-ethyl-2-(3-methylpyridin-2-yl)-1H-imidazole-4-carboxamide;

1-(4-chlorophenyl)-5-ethyl-2-(3-methylpyridin-2-yl)-N-piperidin-1-yl-1H-imidazole-4-carboxamide;

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-[4-(trifluoromethyl)benzyl]-1H-imidazole-4-carboxamide;

2-(2,4-dichlorophenyl)-5-methyl-N-piperidin-1-yl-1-pyridin-2-yl-1H-imidazole-4-carboxamide;

1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-5-ethyl-N-piperidin-1-yl-1H-imidazole-4-carboxamide;

1-(2,4-dichlorophenyl)-N-methyl-N′-(morpholin-4-ylsulfonyl)-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboximidamide;

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-ethyl-N-piperidin-1-yl-1H-imidazole-4-carboxamide;

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-(fluoromethyl)-N-piperidin-1-yl-1H-imidazole-4-carboxamide;

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-(hydroxymethyl)-N-piperidin-1-yl-1H-imidazole-4-carboxamide;

3-(4-chlorophenyl)-N′-[(4-chlorophenyl)sulfonyl]-N-(2-fluoroethyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidamide;

1-(4-chlorophenyl)-N-cyclohexyl-2-(2,4-dichlorophenyl)-5-(methylthio)-1H-imidazole-4-carboxamide;

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-(methylsulfonyl)-N-piperidin-1-yl-1H-imidazole-4-carboxamide;

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-(methylsulfinyl)-N-piperidin-1-yl-1H-imidazole-4-carboxamide;

3-(4-chlorophenyl)-N-methyl-4-pyridin-3-yl-N′-{[4-(trifluoromethyl)phenyl]sulfonyl}-4,5-dihydro-1H-pyrazole-1-carboximidamide;

5-(4-chlorophenyl)-4-(2,5-dichlorophenyl)-1-methyl-N-piperidin-1-yl-1H-imidazole-2-carboxamide;

2-(2-chlorophenyl)-1-(5-chloropyridin-2-yl)-5-ethyl-N-piperidin-1-yl-1H-imidazole-4-carboxamide;

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-piperidin-1-yl-5-(2,2,2-trifluoroethyl)-1H-imidazole-4-carboxamide;

1-(5-chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-ethyl-N-piperidin-1-yl-1H-imidazole-4-carboxamide;

N-[1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-yl]benzamide;

3-(4-chlorophenyl)-N′-[(dimethylamino)sulfonyl]-4-(3-fluorophenyl)-N-methyl-4,5-dihydro-1H-pyrazole-1-carboximidamide;

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-piperidin-1-yl-5-(pyrrolidin-1-ylmethyl)-1H-imidazole-4-carboxamide;

(4S)-3-(4-chlorophenyl)-N′-[(4-chlorophenyl)sulfonyl]-4-(3-fluorophenyl)-N-methoxy-4,5-dihydro-1H-pyrazole-1-carboximidamide;

N-[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]piperidine-1-carboxamide;

1-(4-bromophenyl)-5-chloro-2-(2,4-dichlorophenyl)-N-piperidin-1-yl-1H-imidazole-4-carboxamide;

2[1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-yl]hexan-2-ol;

(4S)-3-(4-chlorophenyl)-N-methyl-4-phenyl-N′-(piperidin-1-ylsulfonyl)-4,5-dihydro-1H-pyrazole-1-carboximidamide;

N-1-adamantyl-5-pentyl-4-phenyl-1,3-thiazole-2-carboxamide;

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-piperidin-1-yl-1H-imidazole-4-carboxamide;

N-1-adamantyl-4-pentyl-5-phenyl-1,3-thiazole-2-carboxamide;

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-4-pentyl-1H-imidazole;

3-(4-chlorophenyl)-N′-[(4-chlorophenyl)sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidamide;

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-(ethylthio)-N-piperidin-1-yl-1H-imidazole-4-carboxamide; and

(4S)-3-(4-chlorophenyl)-N′-[(4-chlorophenyl)sulfonyl]-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidamide.

20. The method according to claim 19 , wherein the dually acting compound comprising combined K ATP channel opening and CB 1 antagonistic properties is (4S)-3-(4-chlorophenyl)-N′-[(4-chlorophenyl)sulfonyl]-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidamide.

21. The method according to claim 7 , wherein R is 4-chlorophenyl, R 1 is phenyl, R 2 is hydrogen, Aa is the group (i) wherein R 4 is hydrogen and R 5 is methyl, Bb is sulfonyl, and R 3 is 4-chlorophenyl in the compound of Formula I, and salts thereof.

22. The method according to claim 7 , wherein the compound of Formula I is a levorotatory enantiomer.

23. The method according to claim 7 , wherein the compound of Formula I is chosen from