The present invention relates to a β 3 adrenergic receptor agonist of formula (I) or a pharmaceutical salt thereof; useful for treating Type II diabetes and/or obesity.
1. A compound of the formula:
wherein:
m is 1,2,3,4 or 5;
n is 0, 1 or 2;
A 1 , A 2 and A 3 are carbon;
Het is thien-2-yl optionally substituted with COCH 3 ;
R 1 and R 2 are H;
R 3 is H or C 1 –C 6 alkyl;
R 4 and R 5 are independently at each occurrence H or C 1 –C 6 alkyl; or R 4 and R 5 combine with the carbon to which they are both attached to form a C 3 –C 7 carbocyclic ring;
R 6 is independently at each occurrence halo, hydroxyl, cyano, C 1 –C 6 alkyl, C 1 –C 4 haloalkyl or C 1 –C 6 alkoxy;
R 7 is H, CO 2 R 8 , CONR 8 R 8 , CH═CHR 9 , CH 2 CH 2 R 9 , NR 8 R 8 , NR 8 SO 2 R 8 , O(CR 10 R 11 ) p R 12 , O(CR 10 R 11 ) q R 13 , SO 2 R 8 , SO 2 NR 8 R 8 , optionally substituted phenyl where when substituted has one to three groups independently selected from halo, hydroxy, oxo, cyano, nitro, phenyl, benzyl, C 1 –C 6 alkyl, C 1 –C 4 haloalkyl, C 1 –C 6 alkoxy, COR 17 , CONR 17 R 17 , CO 2 R 17 , NR 17 R 17 , NR 17 COR 18 , NR 17 SO 2 R 18 , OCOR 18 , OCO 2 R 17 , OCONR 17 R 17 , SR 17 , SOR 18 , SO 2 R 18 and SO 2 (NR 17 R 17 ), where R 17 is independently at each occurrence H, C 1 –C 6 alkyl, phenyl or benzyl and R 18 is independently at each occurrence C 1 –C 6 alkyl, phenyl or benzyl;
X is OCH 2 ;
p is 0, 1, 2 or 3;
q is 1, 2 or 3;
R 8 is independently at each occurrence H, C 1 –C 6 alkyl or phenyl;
R 9 is cyano, CO 2 R 14 , CONR 14 R 14 , CONR 14 SO 2 R 14 , SO 2 R 14 or optionally substituted phenyl where when substituted has one to three groups independently selected from halo, hydroxy, oxo, cyano, nitro, phenyl, benzyl, C 1 –C 6 alkyl, C 1 –C 4 haloalkyl, C 1 –C 6 alkoxy, COR 17 , CONR 17 R 17 , CO 2 R 17 , NR 17 R 17 , NR 17 COR 18 , NR 17 SO 2 R 18 , OCOR 18 , OCO 2 R 17 , OCONR 17 R 17 , SR 17 , SOR 18 , SO 2 R 18 and SO 2 (NR 17 R 17 ), where R 17 is independently at each occurrence H, C 1 –C 6 alkyl, phenyl or benzyl and R 18 is independently at each occurrence C 1 –C 6 alkyl, phenyl or benzyl;
R 10 and R 11 are independently at each occurrence H or C 1 –C 6 alkyl;
R 12 is hydrogen, CO 2 R 15 , CONR 15 R 15 , SO 2 R 15 , SO 2 NR 16 R 16 , pyridyl or optionally substituted phenyl where when substituted has one to three groups independently selected from halo, hydroxy, oxo, cyano, nitro, phenyl, benzyl, C 1 –C 6 alkyl, C 1 –C 4 haloalkyl, C 1 –C 6 alkoxy, COR 17 , CONR 17 R 17 , CO 2 R 17 , NR 17 R 17 , NR 17 COR 18 , NR 17 SO 2 R 18 , OCOR 18 , OCO 2 R 17 , OCONR 17 R 17 , SR 17 , SOR 18 , SO 2 R 18 and SO 2 (NR 17 R 17 ), where R 17 is independently at each occurrence H, C 1 –C 6 alkyl, phenyl or benzyl and R 18 is independently at each occurrence C 1 –C 6 alkyl, phenyl or benzyl;
R 13 is cyano, NR 16 R 16 , NR 16 SO 2 R 16 or OR 16 ;
R 14 , R 15 and R 16 are independently at each occurrence H, C 1 –C 6 alkyl or phenyl; or a pharmaceutical salt thereof.
2. The compound of claim 1 wherein:
m is 2;
n is 0 or 1;
A 1 , A 2 and A 3 are carbon;
Het is at the ortho-position relative to X and is thien-2-yl wherein said thien-2-yl moiety is optionally substituted with COCH 3 ;
R 1 , R 2 and R 3 are H;
R 4 and R 5 are independently H or methyl at each occurrence;
the 6,5 ring system is connected to the (CR 4 R 5 ) 2 moiety at the 3-position of the 6,5 ring system;
R 6 is independently at each occurrence methyl;
R 7 is at the 6- or 7-position of the 6,5 ring system to which it is attached and is O(CH 2 ) p R 12 ;
X is OCH 2 ;
p is 0 or 1; and
R 12 is CONH 2 , phenyl or pyridyl substituted once with CONH 2 ; or a pharmaceutical salt thereof.
3. The compound of claim 1 selected from:
or a pharmaceutical salt thereof.
4. The compound of claim 2 which is the hydrochloride salt.
5. A method of treating obesity comprising administering to a patient in need thereof an effective amount of a compound of claim 2 .