DERIVATIVES OF AZA ADAMANTANE AND USES THEREOF

摘要

The present invention relates to certain amide derivatives that have the ability to inhibit 11-β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) and which are therefore useful in the treatment of certain disorders that can be prevented or treated by inhibition of this enzyme. In addition the invention relates to the compounds, methods for their preparation, pharmaceutical compositions containing the compounds and the uses of these compounds in the treatment of certain disorders. It is expected that the compounds of the invention will find application in the treatment of conditions such as non-insulin dependent type 2 diabetes mellitus (NIDDM), insulin resistance, obesity, impaired fasting glucose, impaired glucose tolerance, lipid disorders such as dyslipidemia, hypertension and as well as other diseases and conditions.

主权项

1. A compound of formula (I): wherein: each R1, R1α and R2 is independently selected from the group consisting of H, halogen, OH, NO, CN, SH, NH2, CF3, OCF3, OCH3, CH2OH, CH2CO2H, CH2CH2CO2H, CH2NH2, optionally substituted C1-C12alkyl, optionally substituted C1-C12haloalkyl optionally substituted C2-C12alkenyl, optionally substituted C2-C12alkynyl, optionally substituted C2-C12heteroalkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C3-C12cycloalkenyl, optionally substituted C2-C12heterocycloalkyl, optionally substituted C2-C12heterocycloalkenyl, optionally substituted C6-C18aryl, optionally substituted C1-C18heteroaryl, optionally substituted C1-C12alkyloxy, optionally substituted C2-C12alkenyloxy, optionally substituted C2-C12alkynyloxy, optionally substituted C2-C10heteroalkyloxy, optionally substituted C3-C12cycloalkyloxy, optionally substituted C3-C12cycloalkenyloxy, optionally substituted C2-C12heterocycloalkyloxy, optionally substituted C2-C12 heterocycloalkenyloxy, optionally substituted C6-C18aryloxy, optionally substituted C1-C18heteroaryloxy, optionally substituted C1-C12alkylanmino, SR3, SO3H, SO2NR3R4, SO2R3, SONR3R1, SOR3, COR3, COOH, COOR3, CONR3R4, NR3COR4, NR3COOR4, NR3SO2R4, NR3CONR3R4, and NR3R4; Ar is an optionally substituted C1-C18heteroaryl group or an optionally substituted C2-C12heterocycloalkyl group; A is selected from the group consisting of S, SO, SO2, O, and —CRaRb—; B is a group of the formula —(CRcRd)n—; wherein each Ra, Rb, Rc and Rd is independently selected from the group consisting of H, halogen, OH, NO2, CN, SH, NH2, CF3, OCF3, optionally substituted C1-C12alkyl, optionally substituted C2-C10heteroalkyl, optionally substituted C1-C12haloalkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C6-C18aryl, optionally substituted C1-C18heteroaryl; SR3, SO3H, SO2NR4, SO2R3, SONR3R4, SOR3, COR3, COOH, COOR3, CONR3R4, NR3COR43, NR3COOR4, NR3SO2R4, NR3CONR3R4, NR3R4; or any two Ra, Rb, Rc and Rd on the same carbon atom when taken together may form a substituent of the formula: wherein each R3 and R4 is independently selected from the group consisting of H, optionally substituted C1-C12alkyl, optionally substituted C2-C10heteroalkyl, optionally substituted C1-C12haloalkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C6-C18aryl, and optionally substituted C1-C18heteroaryl; R5 is selected from the group consisting of O, S, and NR; R6 is selected from the group consisting of H, OR7, optionally substituted C1-C12alkyl, optionally substituted C1-C12haloalkyl optionally substituted C2-C12alkenyl, optionally substituted C1-C12alkynyl, optionally substituted C1-C12alkyloxy, optionally substituted C1-C12haloalkyloxy, optionally substituted C2-C10heteroalkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C3-C12cycloalkenyl, optionally substituted C2-C12 heterocycloalkyl, optionally substituted C2-C12 heterocycloalkenyl, optionally substituted C6-C18aryl, and optionally substituted C1C18heteroaryl; R7 is selected from the group consisting of H, optionally substituted C1-C12alkyl, optionally substituted C2-C10heteroalkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C6-C18aryl, and optionally substituted C1-C18heteroaryl; or any two or more Ra, Rb, Rc and Rd may join together to form a multiple bond between adjacent carbon atoms such as a double or triple bond, or a cyclic moiety connecting the carbon atoms to which they are attached; n is an integer selected from the group consisting of 0, 1, 2, 3, and 4; a is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; or a pharmaceutically acceptable salt, N-oxide, or prodrug thereof.