Pyrazole derivatives, compositions containing such compounds and methods of use
View Patent ↗Pyrazoles having a naphthyl group attached are disclosed. The compounds are useful for treating type 2 diabetes and related conditions. Pharmaceutical compositions and methods of treatment are also included.
1. A compound represented by formula I:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
each R 1 is H or is selected from the group consisting of:
(a) halo, OH, CO 2 R 4 , CN, SO p R 5 or NO 2 ,
(b) C 1-6 alkyl or OC 1-6 alkyl optionally substituted with: (1) 1-5 halo groups up to a perhaloalkyl group; (2) CO 2 R 4 ; (3) phenyl optionally substituted as follows: (i) 1-5 halo groups, (ii) 1 CO 2 R 4 , CN, S(O) p R 5 , NO 2 or C(O)NR 6 R 7 group, (iii) 1-2 C 1-10 alkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl, and 1-2 OH or CO 2 R 4 groups;
each R 2 is selected from R 1 as defined above, or 2 R 2 groups can be taken together to represent a fused 5-6 membered cyclic structure containing 1-2 oxygen atoms, and 1-2 carbon atoms each of which is optionally substituted with 1-2 F atoms;
R 3 is H or C 1-3 alkyl;
R 4 is H, C 1-6 alkyl, and
R 5 represents a member selected from the group consisting of: C 1-10 alkyl, Aryl or Ar—C 1-10 alkyl;
R 6 and R 7 each independently represent H or C 1-3 alkyl, and p is 0, 1 or 2 group.
2. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
one R 1 is H and the other is H or is selected from the group consisting of: (a) halo, OH, CO 2 R 4 ,CN, SO p R 5 or NO 2 , (b) C 1-6 alkyl or OC 1-6 alkyl optionally substituted with; (1) 1-5 halo groups up to a perhaloalkyl group; (2) CO 2 R 4 ; (3) phenyl optionally substituted a follows: (i) 1-5 halo groups, (ii) 1 CO 2 R 4 , CN, S(O) P R 5 ,NO 2 or C(O)NR 6 R 7 group, (iii) 1-2 C 1-10 alkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl, and 1-2 OH or CO 2 R 4 groups.
3. A compound in accordance with claim 2 , or a pharmaceutically acceptable salt thereof, wherein one R 1 is H and the other is H or is selected from the group consisting of: (a) halo or OH; and (b) C 1-4 alkyl or OC 1-4 alkyl, each optionally substituted with: 1-3 halo groups.
4. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 2 represents H or is selected from the group consisting of: (a) halo selected from Cl and F, (b) C 1-6 alkyl or OC 1-6 alkyl optionally substituted with 1-3 halo groups, or two R 2 groups taken together represent a fused 5-6 membered cyclic structure containing 1-2 oxygen atoms, and 1-2 carbon atoms, each of which are optionally substituted with 1-2 F atoms.
5. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein: R 3 represents H or methyl.
6. A compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
one R 1 is H and the other is H or is selected from the group consisting of:
(a) halo, OH, CO 2 R 4 , CN, SO P R 5 or NO 2 ,
(b) C 1-6 alkyl or OC 1-6 alkyl optionally substituted with: (1) 1-5 halo groups up to a perhaloalkyl group; (2) CO 2 R 4 ; (3) phenyl optionally substituted as follows: (i) 1-5 halo groups, (ii) 1 CO 2 R 4 , CN, S(O) P R 5 , NO 2 or C(O)NR 6 R 7 group, (iii) 1-2 C 1-10 alkyl or alkoxy groups, each optionally substituted with: 1-5 halo, up to perhaloalkyl, and 1-2 OH or CO 2 R 4 groups;
each R 2 represents H or is selected from the group consisting of: (a) halo selected from Cl and F, (b) C 1-6 alkyl or OC 1-6 alkyl optionally substituted with 1-3 halo groups, or two R 2 groups taken together represent a fused 5-6 membered cyclic structure containing 1-2 oxygen atoms, and 1-2 carbon atoms, each of which are optionally substituted with 1-2 F atoms; and
R 3 represents H or methyl;
R 4 is H or C 1-6 alkyl;
R 5 represents a member selected from the group consisting of: C 1-10 alkyl, Aryl or Ar—C 1-10 alkyl;
R 6 and R 7 each independently represent H or C 1-3 alkyl, and p is 0, 1 or 2.
7. A compound in accordance with claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein one R 1 represents H and the other is selected from Cl, F, CF 3 or OC 1-3 alkyl;
R 2 represents halo, CF 3 , OC 1-3 alkyl or OCF 3 , and
R 3 is H or methyl.
8. A compound in accordance with claim 1 selected from the following tables:
TABLE 1
Ar
R
3,5-diCF 3 Ph
H
3,5-diClPh
MeO
4-CF 3 , 2-PrOPh
H
3,5-diClPh
CF 3 O
4-CF 3 , 2-PrOPh
CF 3 O
4-Cl, 3-FPh
MeO
2-CF 3 OPh
MeO
2-F, 5-CF 3 Ph
MeO
3,5-diClPh
H
4-CF 3 OPh
MeO
4-CF 3 ,2-PrOPh
MeO
4-CF 3 OPh
CF 3 O
3-Cl, 2-EtOPh
MeO
2,4-diFPh
MeO
2-EtOPh
MeO
4-Cl, 2-EtOPh
MeO
TABLE 2
Ar
Ar 1
3,5-diClPh
4-CF 3 ,
2-PrOPh
3,5-diClPh
4-CF 3 OPh
3,5-diClPh
TABLE 3
Ar
R
4-Cl, 2-PrOPh
CF 3 O
5-Cl, 2-CF 3 OPh
CF 3 O
3,5-diClPh
EtO
3,5-diClPh
CF 3
5-Cl, 2-CF 3 OPh
CF 3
3,4-diClPh
MeO
4-Cl, 2-CF 3 OPh
MeO
3,4,5-triFPh
MeO
3-CF 3 OPh
MeO
3-Cl, 4-FPh
MeO
2-F, 4-CF 3 Ph
MeO
2-F, 4-CF 3 Ph
EtO
3-Cl, 4-FPh
CF 3
3,4,5-triFPh
CF 3
3,4-diClPh
CF 3
2-F, 5-CF 3 Ph
CF 3 O
4-CF 3 , 2-cPrCH 2 OPh
MeO
4-CF 3 , 2-cPentOPh
MeO
3-Cl, 4-FPh
Cl
3,4,5-triFPh
Cl
4-Cl, 2-CF 3 OPh
Cl
3,4-diFPh
MeO
5-Cl, 2-FPh
CF 3 O
3-Cl, 4-EtOPh
MeO
3-Cl, 4-cPrCH 2 OPh
MeO
5-Cl, 2-MeOPh
MeO
5-Cl, 2-PrOPh
MeO
5-Cl, 2-cPentOPh
MeO
2,3,5-triClPh
MeO
3-Cl, 4-EtOPh
Cl
3-Cl, 4-cPrCH,OPh
Cl
3-CF 3 Ph
Cl
2,5-diFPh
CF 3 O
2,4,5-triFPh
CF 3 O
4-Cl, 2-MeOPh
MeO
4-Cl, 2-cPentOPh
MeO
4-Cl, 2-PrOPh
Cl
4-Cl, 2-PrOPh
MeO
5-Cl, 2-CF 3 OPh
MeO
4-CF 3 OPh
MeO
3,5-diClPh
Cl
5-Cl, 2-CF 3 OPh
Cl
3,4-diClPh
CF 3 O
4-Cl, 2-CF 3 OPh
CF 3 O
3,4,5-triFPh
CF 3 O
3-CF 3 OPh
CF 3 O
3-Cl, 4-FPh
CF 3 O
2-F, 4-CF 3 Ph
CF 3 O
3-Cl, 4-FPh
EtO
2-F, 4-CF 3 Ph
CF 3
3-CF 3 OPh
CF 3
2-F, 5-CF 3 Ph
EtO
3,5-diClPh
OH
4-CF 3 , 2-EtOPh
MeO
4-Cl, 2-CF 3 OPh
CF 3
2-F, 4-CF 3 Ph
Cl
3-CF 3 OPh
Cl
3,4-diClPh
Cl
5-Cl, 2-FPh
MeO
3-Cl, 4-MeOPh
MeO
3-Cl, 4-PrOPh
MeO
3-Cl, 4-cPentOPh
MeO
5-Cl, 2-EtOPh
MeO
5-Cl, 2-cPrCH 2 OPh
MeO
2,5-diClPh
MeO
3-Cl, 4-MeOPh
Cl
3-Cl, 4-PrOPh
Cl
3-Cl, 4-cPentOPh
Cl
2,5-diFPh
MeO
2,4,5-triFPh
MeO
2-F, 5-CF 3 Ph
Cl
4-Cl, 2-EtOPh
MeO
4-Cl, 2-cPrCH 2 OPh
MeO
TABLE 4
Ar
R
4-Cl, 2-PrOPh
CF 3 O
5-Cl, 2-CF 3 OPh
CF 3 O
3,5-diClPh
MeO
2,5-diClPh
MeO
4-Cl, 2-PrOPh
MeO
5-Cl, 2-CF 3 OPh
MeO
3,5-diClPh
CF 3
2,3,5-diClPh
MeO
TABLE 5
Ar
R
3,5-diClPh
CF 3 O
4-Cl, 2-PrOPh
CF 3 O
3,5-diClPh
CF 3
5-Cl, 2-CF 3 OPh
CF 3 O
3,5-diClPh
CF 3 O
4-Cl, 2-PrOPh
CF 3 O
5-Cl, 2-CF 3 OPh
CF 3
TABLE 6
Ar
R
3,5-diClPh
H
4-CF 3 OPh
EtO
5-Cl, 2-CF 3 OPh
H
MeO
MeO
CF 3 O
4- t BuPh
MeO
3-F, 4-CF 3 OPh
MeO
4-FPh
MeO
3-Me, 4-FPh
MeO
MeO
2-i-PrOPh
MeO
3-ClPh
MeO
4-Cl, 3-FPh
MeO
2-FPh
MeO
3-MePh
MeO
4-Me, 2-MeOPh
MeO
2,4-diClPh
MeO
4-CF 3 OPh
H
4-Cl, 2-PrOPh
H
CF 3 O
H
H
4-ClPh
MeO
3-F, 4-EtOPh
MeO
3,5-diFPh
MeO
3-EtOPh
MeO
3-F, 4-MeO
MeO
MeO
2-MeO, 4-FPh
MeO
2,4-diFPh
MeO
2-CF 3 OPh
MeO
3-Cl, 4-CF 3 Ph
MeO
3-Cl, 4-CF 3 OPh
MeO
5-F, 2-MeO
MeO
or a pharmaceutically acceptable salt thereof.
9. A compound in accordance with claim 1 selected from the following table:
or a pharmaceutically acceptable salt thereof.
10. A compound in accordance with claim 1 represented by the structure:
or a pharmaceutically acceptable salt thereof.
11. A compound in accordance with claim 1 represented by the structure:
or a pharmaceutically acceptable salt thereof.
12. A compound in accordance with claim 1 represented by the structure
or a pharmaceutically acceptable salt thereof.
13. A compound in accordance with claim 1 represented by the structure
or a pharmaceutically acceptable salt thereof.
14. A compound in accordance with claim 1 represented by the structure:
or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising a compound in accordance with claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
16. A method of treating type 2 diabetes mellitus in a mammalian patient in need of such treatment comprising administering to said patient a compound in accordance with claim 1 in an amount that is effective to treat said type 2 diabetes mellitus.
17. A method of delaying the onset of type 2 diabetes mellitus in a mammalian patient in need thereof, comprising administering to the patient a compound in accordance with claim 1 in an amount that is effective to delay the onset of said type 2 diabetes mellitus.
18. A method of treating hyperglycemia, diabetes or insulin resistance in a mammalian patient in need of such treatment which comprises administering to said patient an effective amount of a compound in accordance with claim 1 .
19. A method of treating non-insulin dependent diabetes mellitus in a mammalian patient in need of such treatment comprising administering to the patient an anti-diabetic effective amount of a compound in accordance with claim 1 .
20. A compound in accordance with claim 13 represented by the structure:
21. A pharmaceutical composition comprising a compound in accordance with claim 10 in combination with a pharmaceutically acceptable carrier.
22. A pharmaceutical composition in accordance with claim 20 in combination with a pharmaceutically acceptable carrier.
23. A compound in accordance with claim 13 of the structural formula:
or a pharmaceutically acceptable salt thereof.