Patent EA-002778-B1 (EA)
Title: SELECTIVE beta3 ADRENERGIC AGONISTS
Inventor: BELL MICHAEL G
IPC: A61K31/4192
Filed: 1996-09-20
Abstract: 1. A compound of the Formula I:   wherein: X1 is -O-, -OCH2-, R2 is H, (C1-C4)alkyl, or phenyl; R3 is H; R4 is an optionally substituted heterocycle or a moiety selected from the group consisting of:   X2 is a bond, or a 1 to 5 carbon straight or branched alkylene; R5 is H, or (C1-C4)alkyl; R6 is H, or (C1-C4)alkyl; or R5 and R6 combine with the carbon to which each is attached to form a (C3-C6)-cycloalkyl; or R6 combines with to X2 and the carbon to which X2 is attached to form a (C3-C8)-cycloalkyl; or R6 combines with X2, the carbon to which both X2 are attached, and R6 and with R4 form:   provided that R5 is H; R7 is H; R8 is independently H, halo or (C1-C4)-alkyl; R9 is halo, CN, OR10, (C1-C4)-alkyl, (C1-C4)-haloalkyl, CO2R2, CONR11R12, CONH((C1-C4)-alkyl) or CONH(C1-C4alkoxy), SR2, CSNR2, CSNR11R12, SO2R2, SO2NR11R12, SOR2, NR11R12, phenyl optionally substituted with -CONR11R12, optionally substituted 5-6 membered heterocycle, comprising 1 to 4 nitrogen atoms or (C2-C4) alkenyl substituted with CN, CO2R2 or CONR11R12; R10 is (C1-C4)alkyl, (C1-C4)haloalkyl, (CH2)n (C3-C8)cycloalkyl, (CH2)nphenyl, optionally substituted CN, CONR11R12 or CONH(C1-C4alkoxy), (CH2)n optionally substituted 5-6 membered heterocycle, comprising 1 to 4 nitrogen atoms optionally substituted with one or two substituents, selected from CN, CONR11R12 or (C1-C4) alkoxy; R11 and R12 are independently H, (C1-C4)-alkyl, or combined with the nitrogen to which each is bound form morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl; A1 and A2 are independently O, S, NH, CH2, NCH3, or NCH2CH3; m is 0 or 1; n is 0, 1, 2, or 3; or a pharmaceutically acceptable salt thereof with proviso that when R4 is   then neither R5 nor R6 are not hydrogen. 2. A compound of Claim 1 wherein: R1 is phenyl or pyridyl; said phenyl or pyridyl are substituted with -CONR11R12. 3. A compound of the Formula II:   wherein: X1 is -O-, -OCH2-; The bond between A3 and A4 is either a single or double bond; A3 and A4 are independently carbon or nitrogen; R2 is H, (C1-C4) alkyl, or phenyl; R3 is hydrogen; R4 is an optionally substituted heterocycle or a moiety selected from the group consisting of:   X2 is a bond, or a 1 to 5 carbon straight or branched alkylene; R5 is C1-C4alkyl; R6 is C1-C4alkyl; R7 is hydrogen; R8 is independently H, halo or (C1-C4)-alkyl; R9 is OR10, or CONR11R12; R10 is (CH2)nphenyl, optionally substituted CN, CONR11R12, CO2R2 or CONH(C1-C4alkoxy), (CH2)n- optionally substituted 5-6 membered heterocycle, comprising 1 to 4 nitrogen atoms optionally substituted with one or two substituents, selected from CN, CONR11R12 or (C1-C4) alkoxy; R11 and R12 are independently H, (C1-C4)-alkyl, (CH2)nphenyl,or combined with the nitrogen to which each is bound form morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl; m is 0 or 1; n is 0, 1, 2, or 3; or a pharmaceutically acceptable salt thereof. 4. A compound of Claim 3 of the formula:   wherein: A5 is CH or N; R7 is H; X1 is -OCH2-; and X2 is methylene or ethylene. 5. A compound of Claim 3 selected from the group consisting of:   or pharmaceutically acceptable salts thereof; or   or   6. A compound of Claim 3 wherein: A4 is N; and A3 is CH or N. 7. A compound of Claim 6 of the formula:   wherein: A5 is CH or N. 8.A compound of Claim 7 wherein R7 is H; X1 is -OCH2-; X2 is methylene or ethylene, and R10 is phenyl or pyridyl said phenyl or pyridyl being substituted with CONR11R12, CO2R2, CN. 9. A compound of Claim 8 selected from the group consisting of:     or pharmaceutically acceptable salts thereof. 10. A compound of any of Claims 1 through 9 for use as a pharmaceutical. 11. A compound of any of Claims 1 through 9 for use in treating Type II diabetes. 12. A compound of any of Claims 1 through 9 for use in treating obesity. 13. A compound of any of Claims 1 through 9 for use in agonizing the β3 receptor. 14. A pharmaceutical formulation comprising as an active ingredient a compound of any one of Claims 1 through 9, associated with one or more pharmaceutically acceptable carriers, excipients or diluents. 15.A compound of the Formula III:   wherein: A5 is CH or N; X2 is a bond or a 1 to 5 carbon straight or branched alkylene. R5 is H, (C1-C4)-alkyl; R6 is H, (C1-C4)-alkyl; or R5 and R6 combine with the carbon to which each is attached to form a (C3-C6) cycloalkyl; or R6 combines with X2 and the carbon to which X2 is attached to form a (C3-C8) cycloalkyl; R14 is (C1-C4)-alkyl, (C1-C4)-haloalkyl, hydroxy, carboxy, tetrazolyl, acyl, COOR2, CONR11R12, CONH((C1-C4)-alkoxy), cyano, (C1-C4)-alkoxy, (C1-C4)-alkyl, phenyl, nitro, NR11R12, NHCO ((C1-C4)-alkyl), NHCO(benzyl), NHCO(phenyl), SR2, S((C1-C4)-alkyl), OCO((C1-C4)-alkyl), SO2(NR11R12), SO2((C1-C4)-alkyl), or SO2(phenyl); or pharmaceutically acceptable salts thereof. 16. A process of preparing a compound of Claim 1 of the formula IA   wherein: A5 is CH or N; which comprises: in step 1, hydrolysis of a compound of the formula IB:   and in step 2, reacting the product of step 1 to form an acid addition salt. 17. A process of preparing a compound of Claim 1, which comprises: in step 1 reacting an epoxide of the formula (XI):   with an amine of formula (B):   and in step 2 reacting the product of step 1 to form an acid addition salt. 18.A compound of the Formula I:   wherein X1 is -OCH2-, -SCH2- or a bond; R2 and R3 are independently H, C1-C4alkyl, or aryl; R3 is H; R4 is an optionally substituted heterocycle or a moiety selected from the group consisting of:   X2 is a bond, or a 1 to 5 carbon straight or branched alkylene; R5 is C1-C4alkyl; R6 is C1-C4alkyl; R7 is H, halo, hydroxy, C1-C4-alkyl, C1-C4-haloalkyl, aryl, CN, COOR2, CONHR2, NHCOR2, OR2, NHR2, SR2, SO2R2, SO2NHR2 or SOR2; R8 is H, halo, or C1-C4-alkyl; R9 is CN, OR10, CONR11R12; R10 is (CH2)nphenyl, optionally substituted CN, CONR11R12, CO2R2 or CONH(C1-C4alkoxy), (CH2)n optionally substituted 5-6 membered heterocycle, comprising 1 to 4 nitrogen atoms optionally substituted with one or two substituents, selected from CN, CONR11R12 or (C1-C4) alkoxy; R11 and R12 are independently H, (C1-C4)-alkyl, or combined with the nitrogen to which each is bound form morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl; A1 and A2 are independently O, S, NH, CH2, NCH3, or NCH2CH3; m is 0 or 1; n is 0, 1, 2, or 3; or a pharmaceutically acceptable salt thereof. 19. A compound of Claim 18, wherein R5 and R6 are methyl; R7 is H, halo, hydroxy, (C1-C4)alkyl, (C1-C4)alkoxy, NH2, SR2, SO2R2 or SOR2; A1 and A2 are NH; and R4 is