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US 9,067,935 B2Granted
Imidazo[1,2-α]pyridine sulfonamides as TRPM8 modulators
AssigneeJanssen Pharmaceutica NV
InventorsMark J Macielag, Mingde Xia, James J McNally, Jay M Matthews
Life of this patent
Estimating the term…
Abstract
Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds are represented by Formula I as follows: wherein Y, R1, R2, and are defined herein.
Claims6
A method for treating a disease, disorder, or condition that is affected by the modulation of TRPM8, comprising the step of administering to a mammal in need of such treatment a therapeutically effective amount of a TRPM8 antagonist of Formula (I)
- wherein
- Y is selected from the group consisting of hydrogen, bromo, chloro, C3-6 cycloalkyl, and C1-6 alkyl;
- R1 is
- i) C1-6alkyl wherein C1-6alkyl is unsubstituted or substituted with one substituent that is C3-6cycloalkyl or trifluoromethyl;
- or
- ii) phenylmethyl wherein the phenyl ring is unsubstituted or substituted with one to three substituents each of which is independently selected from the group consisting of chloro, fluoro, bromo, C1-4alkyl, C1-4alkoxy, trifluoromethoxy, C1-4alkoxycarbonyl, C1-3alkylthio, trifluoromethylthio, cyano, trifluoromethyl, C1-3 alkylsulfonyl, trifluoromethylsulfonyl, and C1-3 alkylcarbonyl;
- with the proviso that not more than two of the substituents are selected from the group consisting of C1-4alkoxy, trifluoromethoxy, C1-4 alkoxycarbonyl, C1-3alkylthio, trifluoromethylthio, cyano, trifluoromethyl, C1-3 alkylsulfonyl, trifluoromethylsulfonyl, and C1-3 alkylcarbonyl;
- R2 is one substituent selected from the group consisting of hydrogen, C1-4 alkyl, chloro, fluoro, and trifluoromethyl;
- with the proviso that R2 is other than 5-trifluoromethyl;
- R3 is
- i) C1-3alkyl wherein C1-3alkyl is unsubstituted or substituted with one substituent selected from the group consisting of carboxy, methoxycarbonyl, trifluoromethyl, and methoxy;
- ii) —(CH2)2NRARB wherein RA and RB are each independently C1-6alkyl;
- or, RA and RB are taken together with the nitrogen atom to which they are attached to form piperidin-1-yl;
- iii) phenyl substituted at the 4-position with pyrazolyl;
- wherein the point of attachment of the heteroaryl is through a nitrogen heteroatom;
- iv) phenyl wherein phenyl is unsubstituted or substituted with one or two substituents each of which is independently selected from the group consisting of chloro, fluoro, bromo, C1-4alkoxy, C1-4alkoxycarbonyl, carboxy, and C1-3 alkyl;
- or
- v) pyridin-3-yl substituted at the 6-position with morpholin-4-yl;
- provided that a compound of Formula (I) is other than
- the compound wherein Y is methyl, R1 is 4-trifluoromethoxyphenylmethyl, R2 is 7-trifluoromethyl, and R3 is phenyl;
- or the compound wherein Y is hydrogen, R1 is 4-trifluoromethoxyphenylmethyl, R2 is 6-chloro, and R3 is 4-carboxyphenyl;
- and enantiomers, diastereomers, and pharmaceutically acceptable salt forms thereof.
19 more elements
A method for treating a disease, disorder, or condition that is affected by the modulation of TRPM8, comprising the step of administering to a mammal in need of such treatment a therapeutically effective amount of a TRPM8 agonist of Formula (I)
- wherein
- Y is selected from the group consisting of hydrogen, bromo, chloro, C3-6 cycloalkyl, and C1-6 alkyl;
- R1 is
- i) C1-6alkyl wherein C1-6alkyl is unsubstituted or substituted with one substituent that is C3-6cycloalkyl or trifluoromethyl;
- or
- ii) phenylmethyl wherein the phenyl ring is unsubstituted or substituted with one to three substituents each of which is independently selected from the group consisting of chloro, fluoro, bromo, C1-4alkyl, C1-4alkoxy, trifluoromethoxy, C1-4alkoxycarbonyl, C1-3alkylthio, trifluoromethylthio, cyano, trifluoromethyl, C1-3 alkylsulfonyl, trifluoromethylsulfonyl, and C1-3 alkylcarbonyl;
- with the proviso that not more than two of the substituents are selected from the group consisting of C1-4alkoxy, trifluoromethoxy, C1-4 alkoxycarbonyl, C1-3alkylthio, trifluoromethylthio, cyano, trifluoromethyl, C1-3 alkylsulfonyl, trifluoromethylsulfonyl, and C1-3 alkylcarbonyl;
- R2 is one substituent selected from the group consisting of hydrogen, C1-4 alkyl, chloro, fluoro, and trifluoromethyl;
- with the proviso that R2 is other than 5-trifluoromethyl;
- R3 is
- i) C1-3alkyl wherein C1-3alkyl is unsubstituted or substituted with one substituent selected from the group consisting of carboxy, methoxycarbonyl, trifluoromethyl, and methoxy;
- ii) —(CH2)2NRARB wherein RA and RB are each independently C1-6alkyl;
- or, RA and RB are taken together with the nitrogen atom to which they are attached to form piperidin-1-yl;
- iii) phenyl substituted at the 4-position with pyrazolyl;
- wherein the point of attachment of the heteroaryl is through a nitrogen heteroatom;
- iv) phenyl wherein phenyl is unsubstituted or substituted with one or two substituents each of which is independently selected from the group consisting of chloro, fluoro, bromo, C1-4alkoxy, C1-4alkoxycarbonyl, carboxy, and C1-3 alkyl;
- or
- v) pyridin-3-yl substituted at the 6-position with morpholin-4-yl;
- provided that a compound of Formula (I) is other than
- the compound wherein Y is methyl, R1 is 4-trifluoromethoxyphenylmethyl, R2 is 7-trifluoromethyl, and R3 is phenyl;
- or the compound wherein Y is hydrogen, R1 is 4-trifluoromethoxyphenylmethyl, R2 is 6-chloro, and R3 is 4-carboxyphenyl;
- and enantiomers, diastereomers, and pharmaceutically acceptable salt forms thereof.
19 more elements
A method for treating neuropathic pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I)
- wherein
- Y is selected from the group consisting of hydrogen, bromo, chloro, C3-6 cycloalkyl, and C1-6 alkyl;
- R1 is
- i) C1-6alkyl wherein C1-6alkyl is unsubstituted or substituted with one substituent that is C3-6cycloalkyl or trifluoromethyl;
- or
- ii) phenylmethyl wherein the phenyl ring is unsubstituted or substituted with one to three substituents each of which is independently selected from the group consisting of chloro, fluoro, bromo, C1-4alkyl, C1-4alkoxy, trifluoromethoxy, C1-4alkoxycarbonyl, C1-3alkylthio, trifluoromethylthio, cyano, trifluoromethyl, C1-3 alkylsulfonyl, trifluoromethylsulfonyl, and C1-3 alkylcarbonyl;
- with the proviso that not more than two of the substituents are selected from the group consisting of C1-4alkoxy, trifluoromethoxy, C1-4 alkoxycarbonyl, C1-3alkylthio, trifluoromethylthio, cyano, trifluoromethyl, C1-3 alkylsulfonyl, trifluoromethylsulfonyl, and C1-3 alkylcarbonyl;
- R2 is one substituent selected from the group consisting of hydrogen, C1-4 alkyl, chloro, fluoro, and trifluoromethyl;
- with the proviso that R2 is other than 5-trifluoromethyl;
- R3 is
- i) C1-3alkyl wherein C1-3alkyl is unsubstituted or substituted with one substituent selected from the group consisting of carboxy, methoxycarbonyl, trifluoromethyl, and methoxy;
- ii) —(CH2)2NRARB wherein RA and RB are each independently C1-6alkyl;
- or, RA and RB are taken together with the nitrogen atom to which they are attached to form piperidin-1-yl;
- iii) phenyl substituted at the 4-position with pyrazolyl;
- wherein the point of attachment of the heteroaryl is through a nitrogen heteroatom;
- iv) phenyl wherein phenyl is unsubstituted or substituted with one or two substituents each of which is independently selected from the group consisting of chloro, fluoro, bromo, C1-4alkoxy, C1-4alkoxycarbonyl, carboxy, and C1-3 alkyl;
- or
- v) pyridin-3-yl substituted at the 6-position with morpholin-4-yl;
- provided that a compound of Formula (I) is other than
- the compound wherein Y is methyl, R1 is 4-trifluoromethoxyphenylmethyl, R2 is 7-trifluoromethyl, and R3 is phenyl;
- or the compound wherein Y is hydrogen, R1 is 4-trifluoromethoxyphenylmethyl, R2 is 6-chloro, and R3 is 4-carboxyphenyl;
- and enantiomers, diastereomers, and pharmaceutically acceptable salt forms thereof.
19 more elements
Dependencies are inferred from the claim text.