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US 7,115,628 B2Granted
Bridged piperidine derivatives as melanocortin receptor agonists
AssigneeMerck & Co., Inc.
InventorsZhixiong Ye, Khaled J. Barakat, Liangqin Guo, Ravi P. Nargund, Iyassu K. Sebhat
Life of this patent
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Abstract
Certain novel bridged piperidine derivatives are agonists of the human melanocortin receptor(s) and, in particular, are selective agonists of the human melanocortin-4 receptor (MC-4R). They are therefore useful for the treatment, control, or prevention of diseases and disorders responsive to the activation of MC-4R, such as obesity, diabetes, sexual dysfunction, including erectile dysfunction and female sexual dysfunction.
Claims19
A compound of structural formula I:
- or a pharmaceutically acceptable salt thereof;
- wherein m is 1 or 2;
- each n is independently 0, 1, or 2;
- each p is independently 0, 1 or 2;
- q is 1 or 2;
- R1 is selected from the group consisting of
- hydrogen,
- C1-8 alkyl,
- (CHR7)n—C3-6 cycloalkyl,
- (CHR7)q—O(CHR7)aryl,
- (CHR7)n-aryl, and
- (CHR7)n-heteroaryl;
- wherein aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R6;
- and alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R6 and oxo;
- R2 is selected from the group consisting of
- hydrogen,
- C1-8 alkyl,
- (CH2)nC3-6 cycloalkyl, and
- (CH2)n-aryl;
- R3 and R4 are each independently selected from the group consisting of
- hydrogen,
- C1-8 alkyl,
- (CH2)nC3-6 cycloalkyl,
- (CH2)n-aryl,
- hydroxy,
- halogen, and
- amino;
- R5 is selected from the group consisting of
- hydrogen,
- C1-8 alkyl,
- (CH2)n-aryl,
- (CH2)nC3-6 cycloalkyl,
- (CH2)n-heteroaryl,
- (CH2)n-heterocyclyl,
- COC(R7)2NH2,
- COR7,
- (CH2)nOR7,
- (CH2)nCO2R7,
- (CH2)nCONR7R7,
- CH2C≡CH,
- CO2R7,
- CH2CHF2,
- CONR7R7, and
- SO2R7;
- wherein aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R6;
- and alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R6 and oxo;
- each R6 is independently selected from the group consisting of
- hydrogen,
- C1-6 alkyl,
- (CH2)n-phenyl,
- (CH2)n-naphthyl,
- (CH2)n-heteroaryl,
- (CH2)n-heterocyclyl,
- (CH2)nC3-7 cycloalkyl,
- halogen,
- OR7,
- (CH2)nN(R7)2,
- (CH2)nC≡N,
- (CH2)nCO2R7,
- NO2,
- (CH2)nNR7SO2R7,
- (CH2)nSO2N(R7)2,
- (CH2)nS(O)pR7,
- (CH2)nNR7C(O)N(R7)2,
- (CH2)nC(O)N(R7)2,
- (CH2)nNR7C(O)R7,
- (CH2)nNR7CO2R7,
- O(CH2)nC(O)N(R7)2,
- CF3,
- CH2CF3,
- OCF3, and
- OCH2CF3;
- wherein phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C1-4 alkyl, trifluoromethyl, and C1-4 alkoxy;
- and wherein any methylene (CH2) carbon atom in R6 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1-4 alkyl;
- or two substituents when on the same methylene (CH2) carbon atom are taken together with the carbon atom to which they are attached to form a cyclopropyl group;
- each R7 is independently selected from the group consisting of
- hydrogen,
- C1-8 alkyl,
- (CH2)n-phenyl,
- (CH2)n-naphthyl,
- (CH2)n-heteroaryl, and
- (CH2)nC3-7 cycloalkyl;
- wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R6;
- alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R6 and oxo;
- and wherein any methylene (CH2) carbon atom in R7 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1-4 alkyl;
- or two R7 groups together with the atom to which they are attached form a 5- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC1-4 alkyl;
- each R8 is independently selected from the group consisting of
- hydrogen,
- (CH2)nC1-7 alkyl,
- (CH2)n-aryl,
- (CH2)n-heteroaryl,
- (CH2)n-heterocyclyl, and
- (CH2)nC3-7 cycloalkyl;
- wherein aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R6;
- and alkyl, cycloalkyl, heterocyclyl, and (CH2)n are unsubstituted or substituted with one to three groups independently selected from R6 and oxo;
- or two substituents when on the same methylene (CH2) carbon atom are taken together with the carbon atom to which they are attached to form a cyclopropyl group;
- or two R8 groups together with the atoms to which they are attached form a 5- to 8-membered mono- or bi-cyclic ring system optionally containing an additional heteroatom selected from O, S, NR7, NBoc, and NCbz;
- X is selected from the group consisting of
- C1-8 alkyl,
- (CH2)nC3-8 cycloalkyl,
- (CH2)n-phenyl,
- (CH2)n-naphthyl,
- (CH2)n-heteroaryl,
- (CH2)nheterocyclyl,
- (CH2)nC≡N,
- (CH2)nCON(R8R8),
- (CH2)nCO2R8,
- (CH2)nCOR8,
- (CH2)nNR8C(O)R8,
- (CH2)nNR8CO2R8,
- (CH2)nNR8C(O)N(R8)2,
- (CH2)nNR8SO2R8,
- (CH2)nS(O)pR8,
- (CH2)nSO2N(R8)(R8),
- (CH2)nOR8,
- (CH2)nOC(O)R8,
- (CH2)nOC(O)OR8,
- (CH2)nOC(O)N(R8)2,
- (CH2)nN(R8)(R8), and
- (CH2)nNR8SO2N(R8)(R8);
- wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R6;
- alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R6 and oxo;
- and
- wherein any methylene (CH2) carbon atom in X is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1-4 alkyl;
- and
- Y is selected from the group consisting of
- hydrogen,
- C1-8 alkyl,
- C2-6 alkenyl,
- (CH2)nC3-8 cycloalkyl,
- (CH2)n-phenyl,
- (CH2)n-naphthyl,
- (CH2)n-heteroaryl, and
- (CH2)n-heterocyclyl;
- wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R6;
- alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one to three groups independently selected from R6 and oxo;
- and wherein any methylene (CH2) carbon atom in Y is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1-4 alkyl.
134 more elements
Dependencies are inferred from the claim text.