Compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same
This present invention relates to novel compounds, isomer thereof or pharmaceutically acceptable salts thereof as vanilloid receptor (Vanilloid Receptor 1; VR1; TRPV1) antagonist; and a pharmaceutical composition containing the same. The present invention provides a pharmaceutical composition for preventing or treating a disease such as pain, migraine, arthralgia, neuralgia, neuropathies, nerve injury, skin disorder, urinary bladder hypersensitiveness, irritable bowel syndrome, fecal urgency, a respiratory disorder, irritation of skin, eye or mucous membrane, stomach-duodenal ulcer, inflammatory diseases, ear disease, and heart disease.
1. A compound of the formula (Ia), or an isomer or pharmaceutically acceptable salt thereof;
wherein,
X is CR 11 ═CR 12 , or C≡C, wherein, R 11 and R 12 are independently hydrogen, halogen, C1-C5 alkyl, or phenyl;
R 1 and R 2 are independently hydrogen, carboxy, C1-C5 alkyl, halogen, nitro, C1-C5 alkoxy, halo (C1-C5) alkyl, C1-C5 alkylcarbonyl, C1-C5 alkylcarbonylamino, C1-C5 alkylsulfonylamino, phenylsulfonylamino, C1-C5 alkylthio, C1-C5 alkylsulfonyl, or C1-C5 alkoxycarbonyl;
R 3 is hydrogen, C1-C5 alkyl, C1-C5 alkoxy, or halo (C1-5)alkyl;
R 4 , R 5 , R 6 , R 7 , and R 8 are independently hydrogen, carboxy, C1-C5 alkyl, nitro, C2-C5 alkenyl, C1-C5 alkoxy, C2-C5 alkynyl, halo (C1-C5) alkyl, C1-C5 alkylthio, C1-C5 alkylsulfonyl, C1-C5 alkyl carbonyl, C1-C5 alkoxycarbonyl, phenyl, or halogen, wherein, phenyl may be unsubstituted or substituted with one or more substituent selected from carboxy, C1-C5 alkyl, halogen, nitro, C2-C5 alkenyl, C1-C5 alkoxy, halo (C1-C5) alkyl, C1-C5 alkyl carbonyl, C1-C5 alkylthio, C1-C5 alkylsulfonyl, or C1-C5 alkoxy carbonyl;
R 9 is C1-C5 alkylsulfonyl or C2-C5 alkenylsulfonyl; and
R 10 is hydrogen;
provided that if R 3 is different from hydrogen, then R 11 and R 12 are not simultaneously hydrogen.
2. A compound according to claim 1 , or an isomer or pharmaceutically acceptable salt thereof;
wherein,
X is CR 11 ═CR 12 or C≡C, wherein, R 11 and R 12 are independently hydrogen, fluoro, bromo, chloro, iodo, methyl, ethyl, or propyl;
R 1 and R 2 are independently hydrogen, methyl, ethyl, propyl, fluoro, chloro, bromo, nitro, trifluoromethyl, methoxy, or ethoxy;
R 3 is hydrogen, methyl, ethyl, or methoxy;
R 4 , R 5 , R 6 , R 7 and R 8 are independently hydrogen, carboxy, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, nitro, ethenyl, propenyl, methoxy, ethoxy, propoxy, C2-C5 alkynyl, trifloromethyl, methylthio, acetyl, methoxycarbonyl, phenyl, bromo, chloro, or iodo, wherein, phenyl may be unsubstituted or substituted with one or more substituent selected from carboxy, C1-C5 alkyl, halogen, nitro, C2-C5 alkenyl, C1-C5 alkoxy, halo (C1-C5)alkyl, C1-C5 alkylcarbonyl, C1-C5 alkylthio, C1-C5 alkylsulfonyl, or C1-C5 alkoxycarbonyl;
R 9 is methanesulfonyl, ethanesulfonyl, or ethenylsulfonyl; and
R 10 is hydrogen;
provided that if R 3 is different from hydrogen, then R 11 and R 12 are not simultaneously hydrogen.
3. A compound according to claim 1 , or an isomer or pharmaceutically acceptable salt thereof;
wherein,
X is trans CR 11 ═CR 12 or C≡C, wherein, R 11 and R 12 are independently hydrogen or methyl;
R 1 is hydrogen, methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, nitro, methoxy, or ethoxy;
R 2 is hydrogen, methyl, fluoro, or chloro;
R 3 is hydrogen;
R 4 , R 5 , R 7 , and R 8 are independently hydrogen, carboxy, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, nitro, ethenyl, propenyl, methoxy, ethoxy, propoxy, ethynyl, propynyl, trifloromethyl, methylthio, acetyl, methoxycarbonyl, bromo, chloro, or iodo;
R 6 is halo (C1-C3) alkyl, isopropyl, or t-butyl;
R 9 is methanesulfonyl; and
R 10 is hydrogen.
4. A compound according to claim 1 , or an isomer or pharmaceutically acceptable salt thereof;
wherein, X is trans CR 11 ═CR 12 or C≡C, wherein, R 11 and R 12 are independently hydrogen or methyl;
R 1 is hydrogen, methyl, ethyl, propyl, fluoro, chloro, bromo, or iodo;
R 2 is hydrogen, methyl, fluoro, or chloro;
R 3 is hydrogen;
R 4 is hydrogen, carboxy, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, nitro, ethenyl, propenyl, methoxy, ethoxy, propoxy, ethynyl, propynyl, trifloromethyl, methylthio, acetyl, methoxycarbonyl, bromo, chloro, or iodo;
R 5 , R 7 and R 8 are all hydrogen;
R 6 is isopropyl or t-butyl;
R 9 is methanesulfonyl; and
R 10 is hydrogen.
5. A compound according to claim 1 , or an isomer or pharmaceutically acceptable salt thereof;
wherein
X is CR 11 ═CH, CH═CR 12 , CR 11 ═CR 12 , or C≡C, wherein R 11 and R 12 are both methyl;
R 1 is hydrogen, methyl, ethyl, propyl, fluoro, chloro, bromo, iodo, nitro, methoxy or ethoxy;
R 2 is hydrogen, methyl, fluoro, or chloro;
R 3 is methyl;
R 4 , R 5 , R 7 and R 8 are independently hydrogen, carboxy, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, nitro, ethenyl, propenyl, methoxy, ethoxy, propoxy, ethynyl, propynyl, trifloromethyl, methylthio, acetyl, methoxycarbonyl, bromo, chloro, or iodo;
R 6 is halo (C1-C3) alkyl, isopropyl, or t-butyl;
R 9 is methanesulfonyl; and
R 10 is hydrogen.
6. A compound according to claim 1 , or an isomer or pharmaceutically acceptable salt thereof;
wherein X is CR 11 ═CH or C≡C, wherein R 11 is methyl;
R 1 is hydrogen, methyl, ethyl, propyl, fluoro, chloro, bromo, or iodo;
R 2 is hydrogen, methyl, fluoro, or chloro;
R 3 is methyl;
R 4 is hydrogen, carboxy, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, nitro, ethenyl, propenyl, methoxy, ethoxy, propoxy, ethynyl, propynyl, trifloromethyl, methylthio, acetyl, methoxycarbonyl, bromo, chloro, or iodo;
R 5 , R 7 and R 8 are all hydrogen;
R 6 is isopropyl or t-butyl;
R 9 is methanesulfonyl; and
R 10 is hydrogen.
7. A compound according to claim 1 , or an isomer or pharmaceutically acceptable salt thereof;
wherein R 1 is bound to the phenyl ring in the ortho position with respect to the sulfonyl amino group such that the compound has the formula (Ib)
8. A compound according to claim 1 , or an isomer or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of
3-(4-t-butyl-phenyl)-N-(4-methanesulfonylamino-benzyl)-2-methyl-acrylamide,
3-(4-t-butyl-phenyl)-N-(3-fluoro-5-iodo-4-methanesulfonylamino-benzyl) acrylamide,
3-(4-t-butyl-phenyl)-N-(4-methanesulfonylamino-benzyl)propiolicamide,
(E)-3-(4-t-butyl-phenyl)-N-(3-fluoro-4-methanesulfonylamino-benzyl)acrylamide,
3-(4-t-butyl-phenyl)-N-(3-chloro-4-methanesulfonylamino-benzyl)acrylamide,
3-(4-t-butyl-phenyl)-N-(3-methyl-4-methanesulfonylamino-benzyl)acrylamide,
3-(4-t-butyl-phenyl)-N-(3,5-difluoro-4-methanesulfonylamino-benzyl)acrylamide,
3-(4-t-butyl-phenyl)-N-(2,5-difluoro-4-methanesulfonylamino-benzyl)acrylamide,
3-(4-t-butyl-phenyl)-N-(3-chloro-5-iodo-4-methanesulfonylamino-benzyl)acrylamide,
3-(4-t-butyl-phenyl)-N-(3-chloro-4-methanesulfonylamino-5-methyl-benzyl)acrylamide,
3-(4-t-butyl-phenyl)-N-(3-fluoro-4-methanesulfonylamino-5-methyl-benzyl)acrylamide,
3-(4-t-butyl-phenyl)-N-(3-fluoro-4-methanesulfonylamino-benzyl)-2-methyl-acrylamide,
3-(4-t-butyl-phenyl)-but-2-enoic acid 3-fluoro-4-methanesulfonylamino-benzylamide,
3-(4-t-butyl-phenyl)-N-[1-(R)-(4-methanesulfonylaminophenyl)ethyl]propiolicamide,
3-(4-t-butylphenyl)-N-[1-(R)-(4-methanesulfonylaminophenyl)ethyl]-2-methylacrylamide, and
3-(4-t-butyl-phenyl)-N-[1-(3-fluoro-4-methanesulfonylaminophenyl)ethyl]-2-methyl-acrylamide.
9. A compound according to claim 1 , or an isomer or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of
3-(4-t-butyl-phenyl)-N-[1-(R)-(4-methanesulfonylaminophenyl)ethyl]-2-methylacrylamide,
3-(4-t-butyl-phenyl)-N-(3-fluoro-4-methanesulfonylamino-benzyl)-2-methyl-acrylamide,
3-(4-t-butyl-phenyl)-but-2-enoic acid 3-fluoro-4-methanesulfonylamino-benzylamide,
3-(4-t-butyl-phenyl)-N-[1-(R)-(4-methanesulfonylaminophenyl) ethyl]propiolicamide, and
3-(4-t-butyl-phenyl)-N-[1-(3-fluoro-4-methanesulfonylamino-phenyl)ethyl]-2-methyl-acrylamide.