Bridged and fused antidiabetic compounds
View Patent ↗This invention provides for certain bridged and fused compounds of the formula G-L-A I or a pharmaceutically acceptable salt, ester of solvate thereof wherein: A is and the other variables are defined herein; the inventive compounds are agonists of the G-protein coupled receptor 40 (GPR40, also known as free fatty acid receptor FFAR). This invention further relates to pharmaceutical compositions containing these compounds, and the use of these compounds to regulate insulin levels in a mammal. The compounds may be used, for example in the prevention and treatment of Type 2 diabetes mellitus and in the prevention and treatment of conditions related to Type 2 diabetes mellitus, such as insulin resistance, obesity and lipid disorders.
1. A compound which is represented by the structural formula
or a pharmaceutically acceptable salt thereof wherein
G is aryl, aryl alkyl, heteroaryl, or heteroarylalkyl, which is optionally substituted by at least one R 2 ;
L is —O—, —C(O)—, —S(O) q —, or —N(R 3 )—;
W is —C— or —N—;
Y is a bond, -[C(R a )(R b )] n —O—[C(R a )(R b )] n , -[C(R a )(R b )] n —C(O)-[C(R a )(R b )] n , -[C(R a )(R b )] n —S(O) q -[C(R a )(R b )] n , -[C(R a )(R b )] m - or —N(R 8 )—;
R is a group selected from the group consisting of
and
(v) tetrazolyl,
wherein
Q is —CH— or —N—, and
J is —S—, —CH 2 —, —O— or —N(R 8 )—;
R a is independently selected from the group consisting of H, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl;
R b is independently selected from the group consisting of H, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl;
R 1 is independently selected from the group consisting of H, halogen, —SF 5 , —S(O) q -alkyl, —CN, —NO 2 , —N(R 6 )(R 7 ), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy wherein said alkyl, alkoxy, cycloalkl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy are optionally substituted with one or more groups selected from the group consisting of —OH, halo, —S(O) q -alkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl;
R 2 is independently selected from the group consisting of halogen, —SF 5 , —CN, —NO 2 , —N(R 6 )(R 7 ), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl and —S(O) q -alkyl, wherein said alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, aryl, arylalkyl, heteroaryl, and heteroarylalkyl are optionally substituted with one or more groups selected from the group consisting of —OH, halo, alkyl, —S(O) q -alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl;
R 3 is independently selected from the group consisting of H, alkyl, haloalkyl;
R 4 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;
R 5 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;
R 6 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl;
R 7 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;
or R 6 and R 7 together form a 4- to 7-membered heterocycloalkyl or a 5- or 5-membered heteroaryl ring optionally having, in addition to the N atom, 1 or 2 heteroatoms selected from the group consisting of O, N(R 8 ), N or S, wherein said rings are optionally substituted by one or more R 12 moieties;
R 8 is independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R 5 , —C(O)O—R 5 , —C(O)N(R 6 )(R 7 ), —C(O)-alkylene-OR 4 , —C(O)— alkylene-N(R 6 )(R 7 ), —C(O)-alkylene-S(O) q —R 5 , —S(O) q —R 5 , —S(O) q -alkylene-OR 4 , —S(O) q -alkylene-N(R 6 )(R 7 ), -alkylene-OR 4 , -alkylene-S(O) q —R 5 , -alkylene-N(R 6 )(R 7 ), and —S(O) 2 N(R 6 )(R 7 ) wherein said alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and alkylene are optionally substituted with one or more groups selected from the group consisting of —OH, halo, alkyl, haloalkyl, alkoxy, haloalkoxy and cycloalkyl;
R 9 is independently selected from the group consisting of H, alkyl, haloalkyl;
R 10 is independently selected from the group consisting of H, —OH, alkyl, alkyl, cycloalkyl or alkoxy wherein said alkyl, alkyl, cycloalkyl or alkoxy groups are optionally substituted with at least one substituent selected from the group consisting of halo and —OR 5 ;
R 11 is independently selected from the group consisting of H, alkyl, and haloalkyl;
wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl groups in R 4 , R 5 , R 6 , and R 7 are independently unsubstituted or substituted by one or more R 12 groups, where
R 12 is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR 4 , —C(O)—R 5 , —C(O)O—R 5 , —S(O) q —R 5 , —C(O)N(R 6 )(R 7 ), and —S(O) 2 N(R 6 )(R 7 ), —NO 2 , —SF 5 , —CN, —N(R 6 )(R 7 ) and halo and wherein each alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl group in R 12 is independently unsubstituted or substituted by one or more R 13 groups, where
R 13 is independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR 4 , —C(O)—R 5 , —C(O)O—R 5 , —S(O) q —R 5 , —C(O)N(R 6 )(R 7 ), and —S(O) 2 N(R 6 )(R 7 ), —NO 2 , —SF 5 , —CN, and halo;
m is independently 1, 2, or 3;
n is independently 0, 1 or 2;
q is independently 0, 1, or 2; and
p is 0, 1,2,or 3.
2. The compound according to claim 1 which is a compound selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1 wherein W is —CH—; or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 3 wherein R is
and R 8 is H or —(C 1 -C 4 )alkyl; or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 4 , wherein Y is —CH 2 —; or a pharmaceutically acceptable salt thereof.
6. The compound which is:
or a pharmaceutically acceptable salt thereof.
7. The compound which is:
8. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
9. A method for controlling insulin levels in a mammal in need thereof which comprises administering an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof to said mammal.
10. A method for the treatment of Type-2 diabetes mellitus in a mammal in need thereof which comprises administering an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof to said mammal.