IP Library › Granted Patent US 7,683,059

Granted Patent B2

US 7,683,059 · App. 10/587,846 · Granted Mar 23, 2010

Triazole compounds and uses related thereto

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 7,683,059
App. No.: 10/587,846
Granted: Mar 23, 2010
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention provides a triazole compound of the following formula: a prodrug thereof or a pharmaceutically acceptable salt thereof. The above-mentioned triazole compound is useful as a therapeutic drug for the treatment of diabetes, obesity or metabolic syndrome.

Claims (194)

1. A triazole compound represented by the following formula:

wherein

R 1 is an alkyl group or a cycloalkyl group

wherein the alkyl group and the cycloalkyl group are optionally substituted by 1 to 5 substituents each independently selected from a halogen atom, —CF 3 , —OH,

—NH 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —COOH, —CO—O-alkyl, —CO—N(R 7 )(R 8 ), —N(R 7 )—CO—R 8 , an aryl group and a heteroaryl group

wherein R 7 and R 8 are each independently a hydrogen atom or an alkyl group, and the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group,

—(CH 2 ) n —OH, —N(R 9 )(R 10 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 11 , an aryl group and a heteroaryl group

wherein n is 0-3, R 9 and R 10 are each independently a hydrogen atom, an alkyl group or —CO-alkyl, and R 11 is —OH, an alkoxy group, an alkyl group or

—N(R 12 )(R 13 ) wherein R 12 and R 13 are each independently a hydrogen atom or an alkyl group;

Y is a cycloalkyl group or a heterocycloalkyl group

wherein the cycloalkyl group and the heterocycloalkyl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group,

—(CH 2 ) n —OH, —N(R 9 )(R 10 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 11 , an aryl group and a heteroaryl group (n, R 9 , R 10 and R 11 are as defined above);

Ar 1 is an aryl group or a heteroaryl group;

R 2 and R 3

are each independently a hydrogen atom, a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) n —OH, —N(R 9 )(R 10 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 11 , an aryl group or a heteroaryl group

—N(R 9 )(R 10 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 11 , an aryl group and a heteroaryl group (n, R 9 ,R 10 and R 11 are as defined above);

Z is —(CH(R 14 )) p —,—(CH(R 14 )) p —N(R 16 )—CH(R 15 )) q — or

wherein Y 1 is a cycloalkyl group or a heterocycloalkyl group

wherein the cycloalkyl group and the heterocycloalkyl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) n —OH, —N(R 9 )(R 10 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 11 , an aryl group and a heteroaryl group (n, R 9 ,R 10 and R 11 are as defined above),

p is 0-3, q is 0-3, R 14 and R 15 are each independently a hydrogen atom, a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) n —OH, —N(R 9 )(R 10 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group,

—CO—R 11 , an aryl group or a heteroaryl group

—N(R 9 )(R 10 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 11 , an aryl group and a heteroaryl group (n, R 9 , R 10 and R 1 are as defined above), and

R 16 is a hydrogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) n —OH, —(CH 2 ) n —CO—R 11 , a cycloalkyl group, an alkenyl group, an aryl group or a heteroaryl group

—N(R 9 )(R 10 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 11 , an aryl group and a heteroaryl group (n, R 9 , R 10 and R 11 are as defined above);

Ar 2 is an aryl group or a heteroaryl group; or

wherein X 1 is —(CH 2 ) t — wherein t is 0-2, V 1 is ═CH—or ═N—, and W 1 is —C(R 17 )(R 18 )—, —O —, —S—, —SO 2 —, —SO—, —CO—or

—N(R 19 )—

wherein R 17 and R 18 are each independently a hydrogen atom, an alkyl group, an alkoxy group, a haloalkyl group, —(CH2) r —OH, —CO—R 20 , —N(R 21 )(R 22 ) or —L 1 —Ar 3

wherein r is 0-3, R 20 is —OH, an alkoxy group, an alkoxyalkyl group or —N(R 23 )(R 24 )

wherein R 23 and R 24 are each independently a hydrogen atom, an alkyl group, —(CH 2 ) s —OH, an alkoxyalkyl group, or in combination form

wherein s is 0-3, X 2 is —O—, —(CH 2 ) t — or —N(R 25 )—

wherein t is as defined above and R 25 is a hydrogen atom, —CO—R 26 , —SO 2 —R 26 or —(CH 2 ) u —Ar 4

wherein R 26 is an alkyl group, an alkoxy group, —NH-alkyl or —N(-alkyl) 2 , u is 0-3, and Ar 4 is an aryl group or a heteroaryl group wherein the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) n —OH,

—N(R 9 )(R 10 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 11 , an aryl group and a heteroaryl group (n, R 9 , R 10 and R 11 are as defined above),

L 1 is —(CH 2 ) v —, —O— or —CO—

wherein v is 0-3, and

Ar 3 is an aryl group or a heteroaryl group wherein the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) n —OH, —N(R 9 )(R 10 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group,

—CO—R 11 an aryl group and a heteroaryl group (n, R 9 , R 10 and R 11 are as defined above), and

R 21 and R 22 are each independently a hydrogen atom, an alkyl group, —CO-alkyl, —CO—O-alkyl or —L 1 ,—Ar 3 (L 1 and Ar 3 are as defined above), and

R 19 is a hydrogen atom, —Co—R 26 , —SO 2 —R 26 or —(CH 2 ) u —Ar 4 (R 26 , u and Ar 4 are as defined above); and

R 4 and R 5

are each independently a hydrogen atom, a halogen atom, —OH, —NO 2 , —CN, an alkyl group, an alkoxy group, —CO—R 27 , —SO 02 —R 27 , —CO—N(R 28 )(R 29 ) or —N(R 30 )(R 31 )

wherein the alkyl group and the alkoxy group are optionally substituted by 1 to 5 substituents each independently selected from a halogen atom, —CF 3 , —OH, an alkoxy group, a haloalkoxy group, —N(R 9 )(R 10 ), —CN, —NO 2 , a cycloalkyl group, an alkenyl group, —CO—R 11 , an aryl group and a heteroaryl group (R 9 , R 10 and R 11 are as defined above),

—N(R 9 )(R 10 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 11 , an aryl group and a heteroaryl group (n, R 9 , R 10 and R 11 are as defined above)

R 27 is —OH, an alkoxy group, an alkyl group, —NH 2 ,

—NH-alkyl or —N(-alkyl) 2 ,

R 28 and R 29 are each independently a hydrogen atom, an alkyl group or —(CH 2 ) w —R 32 ,

wherein w is 0-3 and R 32 is —OH, —CF 3 , an alkoxy group, —CONH 2 or —N(R 33 )(R 34 )

wherein R 33 and R 34 are each independently a hydrogen atom, an alkyl group, —CO-alkyl, or in combination form

(X 2 is as defined above)

or R 28 and R 29 in combination form

wherein X 3 is —CO—, —CH 2 —or —CH 2 —CH 2 —, X 4 is

—O—, —(CH 2 ) t—, —N(R 25 )—or

wherein Y 2 is cycloalkyl or heterocycloalkyl and t and R 25 are as defined above, and R 35 and R 36 are each independently a hydrogen atom, a halogen atom, an alkyl group optionally substituted by —OH, —OH, —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 37 , —N(R 38 )(R 39 )

wherein R 37 is —OH, an alkoxy group, —NH 2 ,

—NH-alkyl, —N(-alkyl) 2 or

(X 2 is as defined above)

wherein the alkyl group in —NH-alkyl and —N(-alkyl) 2 and the alkoxy group are optionally substituted by 1 to 5 substituents each independently selected from a halogen atom, —CF 3 , —OH, an alkoxy group, a haloalkoxy group,

—N(R 9 )(R 10 ), —CN, —NO 2 , a cycloalkyl group, an alkenyl group,

—CO—R 11 an aryl group and a heteroaryl group (R 9 , R 10 and R 11 are as defined above),

wherein the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) n —OH, —N(R 9 )(R 10 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 11 , an aryl group and a heteroaryl group (n, R 9 , R 10 and R 11 are as defined above), and

R 38 and R 39 are each independently a hydrogen atom, an alkyl group, —CO-alkyl or —CO—O—alkyl, and

R 30 and R 31 are each independently a hydrogen atom, an alkyl group optionally substituted by —OH, —SO 2 —R 40 , —(CH 2 ) x —CO—R 41 or

wherein x is 0-3, R 40 is an alkyl group or —NH 2 , R 41 is a hydrogen atom, an alkyl group optionally substituted by —OH, —OH, an alkoxy group, an alkoxyalkyl group or —(CH 2 ) s —N(R 42 )(R 43 )

wherein s is as defined above and R 42 and R 43 are each independently a hydrogen atom, an alkyl group, —OH, an alkoxy group, or in combination form

(X 3 , X 4 , R 35 and R 36 are as defined above),

V 2 is ═CH—or ═N— and W 2 is —C(R 44 )(R 45 )—, —O—or —N(R 46 )—

wherein R 44 and R 45 are each independently a hydrogen atom, an alkyl group, an alkoxy group, a haloalkyl group, —(CH 2 ) r —OH, —CO—R 47 or —N(R 48 )(R 49 )

wherein r is as defined above, R 47 is —OH, an alkoxy group, an alkoxyalkyl group,

—N(R 50 )(R 51 )

wherein R 50 and R 51 are each independently a hydrogen atom, an alkyl group, —(CH 2 ) s —OH (s is as defined above) or an alkoxyalkyl group, and

R 48 and R 49 are each independently a hydrogen atom, an alkyl group, —CO-alkyl or —CO—O—alkyl, and

R 46 is a hydrogen atom, —CO—R 52 or —SO 2 —R 52

wherein R 52 is an alkyl group, an alkoxy group, —NH-alkyl or —N(-alkyl) 2 or

R 30 and R 31 in combination form

(X 3 , X 4 , R 35 and R 36 are as defined above), or

R 4 and R 5 in combination may form —O-alkylene-O—,

a prodrug thereof or a pharmaceutically acceptable salt thereof.

2. The triazole compound of claim 1 , wherein Z is —(CH(R 14 )) p —and p is 0, a prodrug thereof or a pharmaceutically acceptable salt thereof.

3. The triazole compound of claim 2 , wherein Y is a C 3-8 cycloalkyl group, a prodrug thereof or a pharmaceutically acceptable salt thereof.

4. The triazole compound of claim 3 , wherein Ar 1 is a phenyl group, a prodrug thereof or a pharmaceutically acceptable salt thereof.

5. The triazole compound of claim 4 , wherein R 2 and R 3 are each independently a halogen atom or a hydrogen atom, a prodrug thereof or a pharmaceutically acceptable salt thereof.

6. The triazole compound of claim 1 , wherein Ar 2 is a phenyl group, R 4 is a hydrogen atom and R 5 is —CO—N(R 28 )(R 29 ), a prodrug thereof or a pharmaceutically acceptable salt thereof.

7. The triazole compound of claim 6 , wherein R 28 and R 29 are each independently a hydrogen atom or an alkyl group, a prodrug thereof or a pharmaceutically acceptable salt thereof.

8. The triazole compound of claim 1 , wherein Ar 2 is a phenyl group, R 4 is a hydrogen atom and R 5 is —N(R 30 )(R 31 ) wherein R 30 is a hydrogen atom and R 31 is —(CH 2 ) X—CO—R 41 , a prodrug thereof or a pharmaceutically acceptable salt thereof.

9. The triazole compound of claim 8 , wherein X is 0 and R 41 is an alkoxy group, a prodrug thereof or a pharmaceutically acceptable salt thereof.

10. The triazole compound of claim 8 , wherein X is 0 and R 41 is —(CH 2 ) s —N(R 42 )(R 43 ), a prodrug thereof or a pharmaceutically acceptable salt thereof.

11. The triazole compound of claim 10 , wherein s is 0, R 42 is a hydrogen atom and R 43 is an alkoxy group, a prodrug thereof or a pharmaceutically acceptable salt thereof.

12. The triazole compound of claim 1 , wherein Ar 2 is a phenyl group, R 4 is a hydrogen atom and R 5 is —N(R 30 )(R 31 ) wherein R 30 and R 31 are joined to form

and X 3 is —CO—, a prodrug thereof or a pharmaceutically acceptable salt thereof.

13. The triazole compound of claim 12 , wherein X 4 is —O—, a prodrug thereof or a pharmaceutically acceptable salt thereof.

14. The triazole compound of claim 1 , which is

3—chloro—4-[4-methyl-5-(1-phenyl-cyclopropyl)-4H-[1,2,4]triazol-3-yl]-benzamide,

{3-chloro-4-[4-methyl-5-(1-phenylcyclopropyl)-4H-[1,2,4]triazol-3-yl]benzoyl}morpholine hydrochloride,

3-chloro-N-methyl-4-[4-methyl-5-(1-phenylcyclopropyl)-4H-[1,2,4]triazol-3-yl]benzamide hydrochloride,

3-chloro-N,N-dimethyl-4-[4-methyl-5-(1-phenylcyclopropyl)-4H-[1,2,4]triazol-3yl]benzamide hydrochloride,

3-chloro-N-(2-hydroxy-ethyl)-4-[4-methyl-5-(1-phenylcyclopropyl)-4H-[1,2,4]triazol-3-yl]benzamide,

3-chloro-N-isopropyl-4-[4-methyl-5-(1-phenylcyclopropyl)4H-[1,2,4]triazol-3-yl]benzamide,

{3-chloro-4-[4-methyl-5-(1-phenyl-cyclopropyl)-4H[1,2,4]triazol-3-yl]benzoyl}piperidine hydrochloride,

{3-chloro-4-[4-methyl-5-(1-phenylcyclopropyl)-4H[1,2,4]triazol-3-yl]benzoyl}-(4-hydroxy)piperidine,

N-carbamoylmethyl-3-chloro-4-[4-methyl-5-(1-phenylcyclopropyl)-4H-[1,2,4]triazol-3-yl]benzamide,

3-chloro-4-[4-methyl-5-(1-phenylcyclopropyl)-4H-[1,2,4]triazol-3-yl]-N-(2,2,2-trifluoro -ethyl)-benzamide hydrochloride,

N-(2-acetylamino)ethyl-3-chloro-4-[4-methyl-5-(1-phenylcyclopropyl)-4H-[1,2,4]triazol-3-yl]benzamide hydrochloride,

3-chloro-N-(2-methoxy)ethyl-4-[4-methyl-5-(1-phenylcyclopropyl)-4H-[1,2,4]triazol-3-yl]benzamide hydrochloride,

1-acetyl-(4-{3-Chloro-4-[4-methyl-5-(1-phenylcyclopropyl)-4H-[1,2,4]triazol-3-yl]benzoyl}piperazine hydrochloride,

3-chloro-N-(2-dimethylamino)ethyl-4-[4-methyl-5-(1-phenylcyclopropyl)-4H-[1,2,4]triazol-3-yl]benzamide,

3-chloro-4-[4-methyl-5-(1-phenylcyclopropyl)-4H-[1,2,4]triazol-3-yl]-N-(2-morpholin-4-yl)ethylbenzamide,

4-[4-methyl-5-(1-phenylcyclopropyl)-4H-[1,2,4]triazol-3-yl]-3-methoxybenzamide,

3-chloro-4-{4-methyl-5-[1-(4-fluorophenyl)cyclopropyl]-4H-[1,2,4]triazol-3-yl}benzamide,

3-chloro-N-methyl-4-{4-methyl-5-[1-(4-fluoro-phenyl)cyclopropyl]-4H-[1,2,4]triazol-3-yl}benzamide,

4-[4-isopropyl-5-(1-phenylcyclopropyl)-4H-[1,2,4]triazol-3-yl]benzamide,

3-chloro-4-[4-methyl-5-(1-thiophen-2-yl)cyclopropyl-4H-[1,2,4]triazol-3-yl]benzamide,

4-{5-[1-(4-fluorophenyl)cyclopropyl]-4-isopropyl-4H-[1,2,4]triazol-3-yl}benzamide,

4-chloro-3-{5-[1-(4-fluorophenyl)cyclopropyl]-4-methyl-4H-[1,2,4]triazol-3-yl}benzamide,

4-chloro-3-{5-[1-phenylcyclopropyl]-4-methyl-4H-[1,2,4]triazol-3-yl}benzamide,

3-chloro-4-[4-ethyl-5-(1-phenylcyclopropyl)-4H-[1,2,4]triazol-3-yl]benzamide,

3-chloro-4-{4-ethyl-5-[1-(4-fluorophenyl)cyclopropyl]-4H-[1,2,4]triazol-3-yl}benzamide,

3-[4-isopropyl-5-(1-phenylcyclopropyl)-4H-[1,2,4]triazol-3-yl]benzamide,

3-{5-[1-(4-fluoro-phenyl)cyclopropyl]-4-isopropyl-4H-[1,2,4]triazol-3-yl}benzamide,

N-{3-chloro-4-[4-methyl-5-(1-phenylcycloproppyl)-4H-[1,2,4]triazol-3-yl]phenyl}-1-morpholinecarboxamide,

3-{3-chloro-4-[4-methyl-5-(1-phenylcyclopropyl)-4H-[1,2,4]triazol-3-yl]-phenyl}-1,1-dimethylurea,

{3-chloro-4-[4-methyl-5-(1-phenylcyclopropyl)-4H-[1,2,4]triazol-3-yl]-phenyl}urea,

ethyl N-{3-Chloro-4-[4-methyl-5-(1-phenyl-cyclopropyl)-4H-[1,2,4]triazol-3-yl]-phenyl}-carbamate,

N-{3-chloro-4-[4-methyl-5-(1-phenylcycloproppyl)-4H-[1,2,4]triazol-3-yl]phenyl}-1-(4-methoxypiperidine)carboxamide,

N-{3-chloro-4-[4-methyl-5-(1-phenylcycloproppyl)-4H-[1,2,4]triazol-3-yl]phenyl}-1-(3-hydroxypiperidine)carboxamide,

N-{3-chloro-4-[4-methyl-5-(1-phenylcycloproppyl)-4H-[1,2,4]triazol-3-yl]phenyl}-1-(4-hydroxypiperidine)carboxamide,

1-{3-chloro-4-[4-methyl-5-(1-phenylcyclopropyl)-4H-[1,2,4]triazol-3-yl]-phenyl}-3-methoxyurea,

1-{3-chloro-4-[4-methyl-5-(1-phenylcyclopropyl)-4H-[1,2,4]triazol-3-yl]phenyl}-3-hydroxy -3-methylurea,

1-(3-chloro-4-{5-[1-(4-fluorophenyl)cyclopropyl]-4-methyl-4H-[1,2,4]triazol-3-yl}phenyl)-3-methoxyurea,

1-(4-{5-[1-(4-fluorophenyl)cyclopropyl]-4-isopropyl-4H-[1,2,4]triazol-3-yl}phenyl)-3-methoxyurea,

1-(3-{5-[1-(4-fluorophenyl)cyclopropyl]-4-isopropyl-4H-[1,2,4]triazol-3-yl}phenyl)-3-methoxyurea,

3-{3-chloro-4-[4-methyl-5-(1-phenylcyclopropyl)-4H-[1,2,4]triazol-3-yl]-phenyl}oxazolidin -2-one,

1-{3-chloro-4-[4-methyl-5-(1-phenylcyclopropyl)-4H-[1,2,4]triazol-3-yl]phenyl}imidazolidin-2-one,

3-(3-chloro-4-{5-[1-(4-fluoro-phenyl)cyclopropyl]-4-methyl-4H-[1,2,4]triazol-3-yl}phenyl)oxazolidin-2-one,

3-(4-{5-[1-(4-fluorophenyl)cyclopropyl]-4-isopropyl-4H-[1,2,4]triazol-3-yl}phenyl)oxazolidin-2-one,

3-(4-chloro-3-{5-[1-(4-fluorophenyl)cyclopropyl]-4-methyl-4H-[1,2,4]triazol-3-yl}phenyl)oxazolidin-2-one,

3-(3-{5-[1-(4-fluorophenyl)cyclopropyl]-4-isopropyl-4H-[1,2,4]triazol-3-yl}phenyl)oxazolidin-2-one,

methyl N-(4-chloro-3-{5-[1-(4-fluorophenyl)cyclopropyl]-4-methyl-4H-[1,2,4]triazol-3-yl}phenyl)carbamate,

a prodrug thereof or a pharmaceutically acceptable salt thereof.

15. The triazole compound of claim 1 , which is 3-chloro-4-[4-methyl-5-(1-phenyl-cyclopropyl)-4H-[1,2,4]triazol-3-yl]-benzamide,

{3-chloro-4-[4-methyl-5-(1-phenylcyclopropyl)-4H-[1,2,4]triazol-3-yl]benzoyl}morpholine hydrochloride,

3-chloro-N-methyl-4-[4-methyl-5-(1-phenylcyclopropyl)-4H-[1,2,4]triazol-3-yl]benzamide hydrochloride,

3-chloro-N,N-dimethyl-4-[4-methyl-5-(1-phenylcyclopropyl)-4H-[1,2,4]triazol-3-yl]benzamide hydrochloride,