Patent ID: 6657063
Filing Date: 2003-12-02
Classification: C07D

Abstract:
A method for treating non-insulin dependent diabetes mellitus in a mammal comprising administering to said mammal a &bgr;3 adrenergic agonist and a growth hormone secretagogue for a time and under conditions effective to ameliorate said diabetes mellitus, wherein said &bgr;3 adrenergic agonist is a compound of formula I: wherein:R1g, R2g, R4g and R5g are independently hydrogen or (C1-C6)alkyl; R3g, R6g and R7g are independently hydrogen, halogen, (C1-C6)alkyl, nitro, cyano, trifluoromethyl, SO2R8g, SO2NR9gR10g, NR9gR10g, COR11g, CO2R9g, (C1-C6)alkoxy, NR9gSO2R8g, NR9gCOR11g, NR9gCO2R9g or OR9g; R8g is independently (C1-C6)alkyl or (C1-C6)alkoxy(C1-C6)alkyl; R9g and R10g are independently hydrogen, (C1-C6)alkyl, cycloalkyl(C3-C8), or (C1-C6)alkoxy(C1-C6)alkyl; R11g is independently hydrogen, (C1-C6)alkyl, NR9gR10g, (C3-C8)cycloalkyl, or (C1-C6)alkoxy(C1-C6)alkyl; W1 is N, CH, or, when R3g is bonded to W1, CR3g wherein R3g can be any of the values listed above for R3g in addition to H; W2 and W3 are independently a direct link, oxygen, sulfur, or NR1g wherein R1g is as defined above; W4 is (CH2)yOR9g, (CH2)zCO2 R11g, (CH2)zCOR11g, (CH2)zSO2NR9gR10g, (CH2)zâ€”NR9gSO2R8g, (CH2)zP(O)(OR1g)(OR2g), (CH2)zâ€”Oâ€”(CH2)yCO2R11g, (CH2)nâ€”Oâ€”(CH2)yCOR11g, (CH2)zâ€”Oâ€”(CH2)yP(O)(OR1g)(OR2g), (CH2)zâ€”Oâ€”(CH2)ySO2NR9gR10g, or (CH2)zâ€”Oâ€”(CH2)yâ€”NR9gSO2R8g; wherein R1g, R2g, R8g, R9g, R10g, and R11g are as defined above; y is 1 to 6; z is 0 to 6, provided that if Y is O or S, z is not 0; a pharmaceutically acceptable prodrug of said compounds; ora pharmaceutically acceptable salt of said compounds and said prodrugs;and further wherein said growth hormone secretagogue is a compound of the Formula IV: or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug,wherein:HET is a heterocyclic moiety selected from the group consisting of d is 0, 1 or 2; e is 1 or 2; f is 0 or 1; n and w are 0, 1 or 2, provided that n and w cannot both be 0 at the same time; y2 is oxygen or sulfur; A is a divalent radical, where the left hand side of the radical as shown below is connected to Câ€³ and the right hand side of the radical as shown below is connected to Câ€², selected from the group consisting of â€”NR2â€”C(O)â€”NR2â€”, â€”NR2â€”S(O)2â€”NR2â€”, â€”Oâ€”C(O)â€”NR2â€”, â€”NR2â€”C(O)â€”Oâ€”, â€”C(O)â€”NR2â€”C(O)â€”, â€”C(O)â€”NR2â€”C(R9R10)â€”, â€”C(R9R10)â€”NR2â€”C(O)â€”, â€”C(R9R10)â€”C(R9R10)â€”C(R9R10)â€”, â€”S(O)2â€”C(R9R10)â€”C(R9R10)â€”, â€”C(R9R10)â€”Oâ€”C(O)â€”, â€”C(R9R10)â€”Oâ€”C(R9R10)â€”, â€”NR2â€”C(O)â€”C(R9R10)â€”, â€”Oâ€”C(O)â€”C(R9R10)â€”, â€”C(R9R10)â€”C(O)â€”NR2â€”, â€”C(O)â€”NR2â€”C(O)â€”, â€”C(R9R10)â€”C(O)â€”Oâ€”, â€”C(O)â€”NR2â€”C(R9R10)â€”C(R9R10)â€”, â€”C(O)â€”Oâ€”C(R9R10)â€”, â€”C(R9R10)â€”C(R9R10)â€”C(R9R10)â€”C(R9R10)â€”, â€”S(O)2â€”NR2â€”C(R9R10)â€”C(R9R10)â€”, â€”C(R9R10)â€”C(R9R10)â€”NR2â€”C(O)â€”, â€”C(R9R10)â€”C(R9R10)â€”Oâ€”C(O)â€”, â€”NR2â€”C(O)â€”C(R9R10)â€”C(R9R10)â€”, â€”NR2â€”S(O)2â€”C(R9R10)â€”C(R9R10)â€”, â€”Oâ€”C(O)â€”C(R9R10)â€”C(R9R10)â€”, â€”C(R9R10)â€”C(R9R10)â€”C(O)â€”NR2â€”, â€”C(R9R10)â€”C(R9R10)â€”C(O)â€”, â€”C(R9R10)â€”NR2â€”C(O)â€”Oâ€”, â€”C(R9R10)â€”Oâ€”C(O)â€”NR2â€”, â€”C(R9R10)â€”NR2â€”C(O)â€”NR2â€”, â€”NR2â€”C(O)â€”Oâ€”C(R9R10)â€”, â€”NR2â€”C(O)â€”NR2â€”C(R9R10)â€”, â€”NR2â€”S(O)2â€”NR2â€”C(R9R10)â€”, â€”Oâ€”C(O)â€”NR2â€”C(R9R10)â€”, â€”C(O)â€”N&boxH;C(R11)â€”NR2â€”, â€”C(O)â€”NR2â€”C(R11)&boxH;Nâ€”, â€”C(R9R10)â€”NR12â€”C(R9R10)â€”, â€”NR12â€”C(R9R10)â€”, â€”NR12â€”C(R9R10)â€”C(R9R10)â€”, â€”C(O)â€”Oâ€”C(R9R10)â€”C(R9R10)â€”, â€”NR2â€”C(R11)&boxH;Nâ€”C(O)â€”, â€”C(R9R10)â€”C(R9R10)â€”N(R12)â€”, â€”C(R9R10)â€”NR12â€”, â€”N&boxH;C(R11)â€”NR2â€”C(O)â€”, â€”C(R9R10)â€”C(R9R10)â€”NR2â€”S(O)2â€”, â€”C(R9R10)â€”C(R9R10)â€”S(O)2â€”NR2â€”, â€”C(R9R10)â€”C(R9R10)â€”C(O)â€”Oâ€”, â€”C(R9R10)â€”S(O)2â€”C(R9R10)â€”, â€”C(R9R10)â€”C(R9R10)â€”S(O)2â€”, â€”Oâ€”C(R9R10)â€”C(R9R10)â€”, â€”C(R9R10)â€”C(R9R10)â€”Oâ€”, â€”C(R9R10)â€”C(R9R10)â€”, â€”C(O)â€”C(R9R10)â€”C(R9R10)â€” and â€”C(R9R10)â€”NR2â€”S(O)2â€”NR2â€”; Q is a covalent bond or CH2; W is CH or N; X is CR9R10, C&boxH;CH2 or C&boxH;O; Y is CR9R10, O or NR2; Z is C&boxH;O, C&boxH;S or S(O)2; G1 is hydrogen, halo, hydroxy, nitro, amino, cyano, phenyl, carboxyl, â€”CONH2, â€”C1-C4)alkyl optionally independently substituted with one or more phenyl, one or more halogens or one or more hydroxy groups, â€”(C1-C4)alkoxy optionally independently substituted with one or more phenyl, one or more halogens or one or more hydroxy groups, â€”(C1-C4)alkylthio, phenoxy, â€”COO(C1-C4)alkyl, N,N-di-(C1-C4)alkylamino, â€”(C2-C6)alkenyl optionally independently substituted with one or more phenyl, one or more halogens or one or more hydroxy groups, â€”(C2-C6)alkynyl optionally independently substituted with one or more phenyl, one or more halogens or one or more hydroxy groups, â€”(C3-C6)cycloalkyl optionally independently substituted with one or more (C1-C4)alkyl groups, one or more halogens or one or more hydroxy groups, â€”(C1-C4)alkylamino carbonyl or di-(C1-C4)alkylamino carbonyl; G2 and G3 are each independently selected from the group consisting of hydrogen, halo, hydroxy, â€”(C1-C4)alkyl optionally independently substituted with one to three halo groups and â€”(C1-C4)alkoxy optionally independently substituted with one to three halo groups; R1 is hydrogen, â€”CN, â€”(CH2)qN(X6)C(O)X6, â€”(CH2)qN(X6)C(O)(CH2)tâ€”A1, â€”(CH2)qN(X6)S(O)2(CH2)tâ€”A1, â€”(CH2)qN(X6)S(O)2X6, â€”(CH2)qN)C(O)N(X6)(CH2)tâ€”A1, â€”(CH2)qN(X6)C(O)N(X6)(X6), â€”(CH2)qC(O)N(X6)(X6), â€”(CH2)qC(O)N(X6(CH2)tâ€”A1, â€”(CH2)qC(O)OX6, â€”(CH2)qC(O)O(CH2)tâ€”A1, â€”(CH2)qOX6, â€”(CH2)qOC(O)X6, â€”(CH2)qOC(O)(CH2)tâ€”A1, â€”(CH2)qOC(O)N(X6)(CH2)tâ€”A1, â€”(CH2)qOC(O)N(X6)(X6), â€”(CH2)qC(O)X6, â€”(CH2)qC(O)CH2)tâ€”A1, â€”(CH2)qN(X6)C(O)OX6, â€”(CH2)qN(X6)S(O)2N(X6)(X6), â€”(CH2)qS(O)mX6, â€”(CH2)qS(O)m(CH2)tâ€”A1, â€”(C1-C10)alkyl, â€”(CH2)tâ€”A1, â€”(CH2)qâ€”(C3-C7)cycloalkyl, â€”(CH2)qâ€”Y1â€”(C1-C6)alkyl, â€”(CH2)qâ€”Y1â€”(CH2)tâ€”A1 or â€”(CH2)qâ€”Y1â€”(CH2)tâ€”(C3-C7)cycloalkyl; where the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted with (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, â€”CONH2, â€”S(O)m(C1-C6)alkyl, â€”CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups; Y1 is O, S(O)m, â€”C(O)NX6â€”, â€”CH&boxH;CHâ€”, â€”Câ‰¡Câ€”, â€”N(X6)C(O)â€”, â€”C(O)NX6â€”, â€”C(O)Oâ€”, â€”OC(O)N(X6)â€” or â€”OC(O)â€”; q is 0, 1, 2, 3 or 4; t is 0, 1, 2 or 3; said â€”(CH2)q group and (CH2)t group in the definition of R1 are optionally independently substituted with hydroxy, (C1-C4)alkoxy, carboxyl, â€”CONH2, â€”S(O)m(C1-C6)alkyl, â€”CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro groups or 1 or 2 (C1-C4)alkyl groups; R1A is selected from the group consisting of hydrogen, F, Cl, Br, I, (C1-C6)alkyl, phenyl(C1-C3)alkyl, pyridyl(C1-C3)alkyl, thiaolyl(C1-C3)alkyl and thienyl(C1-C3)alkyl, provided that R1A is not F, Cl, Br or I when a heteroatom is vicinal to Câ€³; R2 is hydrogen, (C1-C8)alkyl, â€”(C0-C3)alkyl-(C3-C8)cycloalkyl, â€”(C1-C4)alkyl-A1 or A1; where the alkyl groups and the cycloalkyl groups in the definition of R2 are optionally substituted with hydroxy, â€”C(O)OX6, â€”C(O)N(X6)(X6), â€”N(X6)(X6), â€”S(O)m(C1-C6)alkyl, â€”C(O)A1, â€”C(O)(X6), CF3, CN or 1, 2 or 3 independently selected halo groups; R3 is selected from the group consisting of A1, (C1-C10)alkyl, â€”(C1-C6)alkyl-A1, â€”(C1-C6)alkyl-(C3-C7)cycloalkyl, â€”(C1-C5)alkyl-X1â€”(C1-C5)alkyl, â€”(C1-C5)alkyl-X1â€”(C0-C5)alkyl-A1 and â€”(C1-C5)alkyl-X1â€”(C1-C5)alkyl-(C3-C7)cycloalkyl; where the alkyl groups in the definition of R3 are optionally substituted with â€”S(O)m(C1-C6)alkyl, â€”C(O)OX3, 1, 2, 3, 4 or 5 independently selected halo groups or 1, 2 or 3 independently selected â€”OX3 groups; X1 is O, S(O)m, â€”N(X2)C(O)â€”, â€”C(O)N(X2)â€”, â€”OC(O)â€”, â€”C(O)Oâ€”, â€”CX2&boxH;CX2â€”, â€”N(X2)C(O)Oâ€”, â€”OC(O)N(X2)â€” or â€”Câ‰¡Câ€”; R4 is hydrogen, (C1-C6)alkyl or (C3-C7)cycloalkyl, or R4 is taken together with R3 and the carbon atom to which they are attached and form (C5-C7)cycloalkyl, (C5-C7)cycloalkenyl, a partially saturated or fully saturated 4- to 8-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or is a bicyclic ring system consisting of a partially saturated or fully saturated 5- or 6-membered ring, fused to a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; X4 is hydrogen or (C1-C6)alkyl or X4 is taken together with R4 and the nitrogen atom to which X4 is attached and the carbon atom to which R4 is attached and form a five to seven membered ring; R6 is a bond or is where a and b are each independently 0, 1, 2 or 3; X5 and X5a each independently selected from the group consisting of hydrogen, CF3, A1 and optionally substituted (C1-C6)alkyl; the optionally substituted (C1-C6)alkyl in the definition of X5 and X5a is optionally substituted with a substituent selected from the group consisting of A1, OX2, â€”S(O)m(C1-C6)alkyl, â€”C(O)OX2, (C3-C7)cycloalkyl, â€”N(X2)(X2) and â€”C(O)N(X2)(X2); or the carbon bearing X5 or X5a forms one or two alkylene bridges with the nitrogen atom bearing R7 and R8 wherein each alkylene bridge contains 1 to 5 carbon atoms, provided that when one alkylene bridge is formed then only one of X5 or X5a is on the carbon atom and only one of R7 or R8 is on the nitrogen atom and further provided that when two alkylene bridges are formed then X5 and X5a cannot be on the carbon atom and R7 and R8 cannot be on the nitrogen atom; or X5 is taken together with X5a and the carbon atom to which they are attached and form a partially saturated or fully saturated 3- to 7-membered ring, or a partially saturated or fully saturated 4- to 8-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen; or X5 is taken together with X5a and the carbon atom to which they are attached and form a bicyclic ring system consisting of a partially saturated or fully saturated 5- or 6-membered ring, optionally having 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; Z1 is a bond, O or Nâ€”X2, provided that when a and b are both 0 then Z1 is not Nâ€”X2 or O; R7 and R8 are each independently hydrogen or optionally substituted (C1-6)alkyl; where the optionally substituted (C1-C6)alkyl in the definition of R7 and R8 is optionally independently substituted with A1, â€”C(O)Oâ€”(C1-C6)alkyl, â€”S(O)m(C1-C6)alkyl, 1 to 5 halo groups, 1 to 3 hydroxy groups, 1 to 3 â€”Oâ€”C(O)(C1-C10)alkyl groups or 1 to 3 (C1-C6)alkoxy groups; or R7 and R8 can be taken together to form â€”(CH2)râ€”Lâ€”(CH2)râ€”; where L is C(X2)(X2), S(O)m or N(X2); R9 and R10 are each independently selected from the group consisting of hydrogen, fluoro, hydroxy and (C1-C5)alkyl optionally independently substituted with 1-5 halo groups; R11 is selected from the group consisting of (C1-C5)alkyl and phenyl optionally substituted with 1-3 substitutents each independently selected from the group consisting of (C1-C5)alkyl, halo and (C1-C5)alkoxy; R12 is selected from the group consisting of (C1-C5)alkylsulfonyl, (C1-C5)alkanoyl and (C1-C5)alkyl where the alkyl portion is optionally independently substituted by 1-5 halo groups; A1 for each occurrence is independently selected from the group consisting of (C5-C7)cycloalkenyl, phenyl, a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen and a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen; A1 for each occurrence is independently optionally substituted, on one or optionally both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF3, OCF2H, CF3, CH3, OCH3, â€”OX6, â€”C(O)N(X6)(X6), â€”C(O)OX6, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, â€”S(O)m(C1-C6)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, â€”N(X6)(X6), â€”N(X6)C(O)(X6), â€”S(O)2N(X6)(X6), â€”N(X6)S(O)2-phenyl, â€”N(X6)S(O)2X6, â€”CONX11X12, â€”S(O)2NX11X12, â€”NX6S(O)2X12, â€”NX6CONX11X12, â€”NX6S(O)2NX11X12, â€”NX6C(O)X12, imidazolyl, thiazolyl and tetrazolyl, provided that if A1 is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy; where X11 is hydrogen or optionally substituted (C1-C6)alkyl; â€ƒthe optionally substituted (C1-C6)alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, (C1-C6)alkoxycarbonyl, â€”S(O)m(C1-C6)alkyl, 1 to 5 halo groups, 1 to 3 hydroxy groups, 1 to 3 (C1-C10)alkanoyloxy groups or 1 to 3 (C1-C6)alkoxy groups; X12 is hydrogen, (C1-C6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X12 is not hydrogen, the X12 group is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH3, OCH3, OCF3 and CF3; or X11 and X12 are taken together to form â€”(CH2)râ€”L1â€”(CH2)râ€”; â€ƒL1 is C(X2)(X2), O, S(O)m or N(X2); r for each occurrence is independently 1, 2 or 3; X2 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl or optionally substituted (C3-C7)cycloalkyl, where the optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X2 are optionally independently substituted with â€”S(O)m(C1-C6)alkyl, â€”C(O)OX3, 1 to 5 halo groups or 1-3 OX3 groups; X3 for each occurrence is independently hydrogen or (C1-C6)alkyl; X6 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl, (C2-C6)halogenated alkyl, optionally substituted (C3-C7)cycloalkyl, (C3-C7)-halogenated cycloalkyl, where optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X6 is optionally independently mono- or di-substituted with (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, CONH2, â€”S(O)m(C1-C6)alkyl, carboxylate (C1-C4)alkyl ester or 1H-tetrazol-5-yl; or when there are two X6 groups on one atom and both X6 are independently (C1-C6)alkyl, the two (C1-C6)alkyl groups may be optionally joined and, together with the atom to which the two X6 groups are attached, form a 4- to 9-membered ring optionally having oxygen, sulfur or X7 as a ring member; X7 is hydrogen or (C1-C6)alkyl optionally substituted with hydroxy; m for each occurrence is independently 0, 1 or 2; with the proviso that: X6 and X12 cannot be hydrogen when attached to C(O) or S(O)2 in the form C(O)X6, C(O)X12, S(O)2X6 or S(O)2X12; and when R6 is a bond then L is N(X2) and each r in the definition â€”(CH2)râ€”Lâ€”(CH2)râ€” is independently 2 or 3.