WO2007120012A1 - Nouveaux composés, isomère de ceux-ci ou sels de ceux-ci acceptables d'un point de vue pharmaceutique utilisés comme antagoniste de récepteur vanilloïde et compositions pharmaceutiques contenant ceux-ci - Google Patents

Nouveaux composés, isomère de ceux-ci ou sels de ceux-ci acceptables d'un point de vue pharmaceutique utilisés comme antagoniste de récepteur vanilloïde et compositions pharmaceutiques contenant ceux-ci Download PDF

Info

Publication number
WO2007120012A1
WO2007120012A1 PCT/KR2007/001881 KR2007001881W WO2007120012A1 WO 2007120012 A1 WO2007120012 A1 WO 2007120012A1 KR 2007001881 W KR2007001881 W KR 2007001881W WO 2007120012 A1 WO2007120012 A1 WO 2007120012A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
fluoro
methyl
butyl
alkoxy
Prior art date
Application number
PCT/KR2007/001881
Other languages
English (en)
Inventor
Hee-Doo Kim
Young-Ger Suh
Hyeung-Geun Park
Uh Taek Oh
Seol Rin Park
Yeon Su Jeong
Song Seok Shin
Sun-Young Kim
Jin Kwan Kim
Ki-Wha Lee
Byoung Young Woo
Jin Kyu Choi
Young-Ho Park
Original Assignee
Amorepacific Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from EP06008140A external-priority patent/EP1857440A1/fr
Application filed by Amorepacific Corporation filed Critical Amorepacific Corporation
Publication of WO2007120012A1 publication Critical patent/WO2007120012A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/38—Amides of thiocarboxylic acids
    • C07C327/40—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C327/42—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • Novel compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist as vanilloid receptor antagonist ; and pharmaceutical compositions containing the same
  • the present invention relates to novel compounds, isomer thereof or
  • the vanilloid receptor-1 (VR1 , or transient receptor potential vanilloid-1 ,
  • TRPV1 is the receptor for capsaicin (8-methyl-N-vanil!yl-6 ⁇ nonenamide), a
  • TRPV1 is activated
  • stimuli such as capsaicin, resiniferatoxin, heat, acid,
  • TRPV1 is highly expressed in primary afferent sensory neurons, and also reportedly expressed in various organs and tissues such as bladder, kidney,
  • central nervous system including the
  • neuropeptides such as substance P, CGRP (Calcitonin Gene-Related Peptide)
  • TRPV1 knock-out mice showed normal responses in a wide range of
  • TRPV1 antagonists may be utilized for the prevention or treatment of various TRPV1 antagonists
  • TRPV1 antagonist also decreases hyperalgesia caused by physical stimuli in several models of inflammatory and neuropathic pain (Walker
  • the TRPV1 antagonist exerts defense
  • the TRPV1 is expressed on sensory neurons distributed in all
  • TRPV1 -expressing afferent nerves are abundantly distributed in airway mucosa, and bronchial hypersensitivity is very similar mechanism to
  • TRPV1 -/- mice are anatomically normal
  • TRPV1 is distributed in
  • dermatological diseases and disorders such as skin inflammation, due to
  • TRPV1 antagonist capsazepine inhibits inflammatory mediators in human skin
  • TRPV1 antagonists is under way, and some patents and patent applications
  • diseases such as neuropathies, HIV-related neuropathy, nerve injury,
  • GFD gastroesophageal reflux disease
  • pp13396-13401 neurotic/allergic/inflammatory skin diseases such as psoriasis
  • the present invention provides a novel compound of the following formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof;
  • X is O, S, or N-CN; Y is O or S; R 1 is hydrogen or C1-C5 alkyl;
  • R 2 , R 3 , R 4 , and R 5 are independently hydrogen, halogen, nitro, cyano, carboxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, halo (C1-C5) alkyl, C1-C5 alkylthio, C1-C5 alkoxy, or C1-C5 alkoxycarbonyl;
  • R 7 , R ⁇ , and Ri 0 are independently hydrogen, hydroxy, halogen, nitro, carboxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, halo (C1-C5) alkyl, halo (C1-C5) alkoxy, C1-C5 alkylthio, C1-C5 alkylsulfonyl, C1-C5 alkoxy, C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, C2-C5 alkenyloxy, (C1-C5)alkoxy(C1- C5)alkyl, (C1 -C5)alkoxycarbonyl(C1 -C5)alkyl, (C1 -C5)alkyIcarbonyloxy(C1 - C3)alkyl, (C1-C5)alkoxy(C1-C5)alkylamino, (C1-C5)alkoxy(C1
  • R 8 is halogen, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, halo (C1-C5) alkyl, halo (C1-C5) alkoxy, C1-C5 alkylthio, C1-C5 alkylsulfonyl, C1-C5 alkoxy,
  • (C3-C5)cycloalkyl(C1-C3)alkyl piperidinyl, morpholinyl, phenyl, pyridyl, or pyrimidinyl, wherein each (C3-C5)cycloalkyl may be unsubstituted or substituted with one or more methyl groups, and phenyl may be unsubstituted or substituted with one or more substituent selected from halogen, nitro, carboxy,
  • C1-C5 alkyl C2-C5 alkenyl, halo (C1-C5) alkyl, or C1-C5 alkoxy;
  • R 11 is C1-C5 alkyl or C2-C5 alkenyl; and R 12 and Ri 3 are hydrogen, halogen, or C1-C5 alkyl.
  • Another aspect of the present invention is a compound according to the above formula (I), an isomer and/or a pharmaceutically acceptable salt thereof; wherein,
  • X is O 1 S, or N-CN
  • Y is O or S
  • Ri is hydrogen or C1-C3 alky!
  • R 2 , R 3> R 4 , and R 5 are independently hydrogen, halogen, nitro, cyano, methyl, ethyl, ethenyl, ethynyl, trifluoromethyl, methoxy, ethoxy, or methoxycarbonyl;
  • R 7 , Rg, and R 10 are independently hydrogen, hydroxy, halogen, nitro, carboxy, C1-C5 alky], C2-C5 alkenyl, C2-C5 alkynyl, halo (C1-C5) alkyl, halo (C1-C5) alkoxy, C1-C5 alkylthio, C1-C5 alkylsulfonyl, C1-C5 alkoxy, C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, C2-C5alkenyloxy, (C1-C5)aikoxy(C1- C5)alkyl, (C1 -C5)alkoxycarbonyl(C1 -C5)alkyl, (C1 -C5)aIkylcarbonyloxy(C1 - C3)alkyl, (C1-C5)alkoxy(C1-C5)alkylamino, (C1-C5)alkoxy(C1-C
  • R 11 is C1-C3 alkyl or C2-C3 alkenyl
  • R-1 2 and R 13 are hydrogen, halogen, or C1-C3 alkyl.
  • the present invention also provides a novel compound of the formula (II), an isomer and/or a pharmaceutically acceptable salt thereof;
  • X is O 1 S, or N-CN
  • Ri is hydrogen or C1-C5 alkyl
  • R2, R3, R4. and R 5 are independently hydrogen, halogen, nitro, cyano, methyl, ethyl, ethenyl, ethynyl, trifluoromethyl, methoxy, ethoxy, or methoxycarbonyl;
  • RQ, R 7 , Rg, and R-io are independently hydrogen, hydroxy, halogen, nitro, carboxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, halo (C1-C5) alkyl, halo (C1-C5) alkoxy, C1-C5 alkylthio, C1-C5 alkylsulfonyl, C1-C5 alkoxy, C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, C2-C5alkenyloxy, (C1-C5)alkoxy(C1-
  • R 8 is halogen, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, halo (C1-C5) alkyl, halo (C1 -C5) alkoxy, C1-C5 alkoxy, C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, C2-C5alkenyloxy, (C1-C5)alkoxy(C1-C5)alkyl, (C1-
  • Rt 1 is C1-C5 alkyl or C2-C5 alkenyl; and Ri2 and R ⁇ are hydrogen, halogen, or C1-C5 alkyl.
  • One preferred aspect of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof; wherein, X is O, S, or N-CN;
  • Ri is hydrogen, methyl, or ethyl
  • R 2 , R3, R4, and R 5 are independently hydrogen, fluoro, chloro, bromo, nitro, cyano, methyl, ethyl, ethenyl, ethynyl, trifiuoro methyl, methoxy, ethoxy, or methoxycarbonyl;
  • R 6 , R 7 , R9, and Ri 0 are independently hydrogen, halogen, nitro, carboxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, ethenyl, propenyl, 2-propynyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, hexafluoropropyl, trifluoromethoxy, methylthio, methoxy, ethoxy, propoxy, allyloxy, acetyl, t-butoxy
  • R 8 is fluoro, chloro, bromo, iodo, C3-C5 alkyl, halo (C1-C5) alkyl, C2-C5 alkynyl, propenyl, butenyl, trifluoromethoxy, pentafluoroethoxy, ethoxy, propoxy, isopropoxy, acetyl, propionyl, allyloxy, methoxyethyl, C3-C6 cycloalkyl, mono- cyclopropylmethyl, di-cyclopropylmethyl, 2,2-dimethylcyclopropyl, 2,3- dimethylcyclopropyl, piperidinyl, or morpholinyl;
  • R 11 is C1-C3 alkyl or C2-C3 alkenyl
  • Ri 2 and Ri 3 are hydrogen, halogen, or C1-C3 alkyl.
  • One preferred aspect of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof; wherein,
  • X is O, S, or N-CN
  • Ri is hydrogen, methyl, or ethyl
  • R 3 and R 4 are independently hydrogen, fluoro, chloro, bromo, nitro, cyano, methyl, ethyl, ethenyl, ethynyl, trifluoromethyl, methoxy, ethoxy, or methoxycarbonyl;
  • R 2 , R 5 , and R 10 are hydrogen
  • R 6 , R 7 , and Rg are independently hydrogen, halogen, nitro, carboxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, ethenyl, propenyl, 2-propynyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, trifluoromethoxy, methylthio, methoxy, ethoxy, propoxy, allyloxy, acetyl, t- butoxycarbonylmethyl, ethoxycarbonylethyl, t-butylcarbonyloxymethyl, ethylcarbonyloxymethyl, isopropylcarbonyloxymethyl, methoxyethylamino, methoxyethoxy, cyclopropyl, cyclobutyl, piperidinyl, or morpholinyl;
  • R 8 is selected from C3-C5 alky], halo (C1-C5) alkyl, or C2-C5 alkynyl;
  • Rn is methyl
  • Ri 2 and Ri 3 are hydrogen, fluoro, chloro, methyl, or ethyl.
  • Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof; wherein, X is O, or N-CN;
  • Ri is hydrogen, methyl, or ethyl
  • R 3 and R 4 are independently hydrogen, fluoro, chloro, bromo, nitro, cyano, methyl, ethyl, ethenyl, ethynyl, trifluoromethyl, methoxy, ethoxy, or methoxycarbonyl;
  • R 2 , R 5 , and Ri O are hydrogen;
  • R ⁇ , R7, and Rg are independently hydrogen, halogen, nitro, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, ethenyl, propenyl, 2-propynyl, trifluoromethyl, pentafluoroethyl, trifluoromethoxy, methylthio, methoxy, ethoxy, propoxy, allyloxy, acetyl, t-butoxycarbonylmethyl, ethoxycarbonylethyl, t- butylcarbonyloxymethyl, ethylcarbonyloxymethyl, isopropylcarbonyloxymethyl, methoxyethylamino, methoxyethoxy, cyclopropyl, or morpholinyl;
  • Rs is isopropyl, sec-butyl, t-butyl, isobutyl, t-amyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, heptafluoro-iso-propyl, nonafluorobutyl, nonafluoro-t ⁇ butyl, 2-propynyl;
  • Rn is methyl
  • Ri 2 and Ri 3 are hydrogen, methyl, or ethyl.
  • Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof; wherein,
  • X is O or N-CN
  • Ri is hydrogen or methyl
  • R 3 and R 4 are independently hydrogen, fluoro, chloro, bromo, nitro, cyano, methyl, ethyl, ethenyl, ethynyl, or trifluoromethyl;
  • R 2 , R5, and R-io are hydrogen
  • R 7 , and Rg are independently hydrogen, halogen, nitro, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, ethenyl, propenyl, 2-propynyl, trifluoromethyl, pentafluoroethyl, trifluoromethoxy, methylthio, methoxy, ethoxy, propoxy, allyloxy, acetyl, t-butoxycarbonylmethyl, ethoxycarbonylethyl, t- butylcarbonyloxymethyl, ethylcarbonyloxymethyl, methoxyethylamino, methoxyethoxy, cyclopropyl, morpholinyl;
  • R 8 is isopropyl, sec-butyl, t-butyl, isobutyl, t-amyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, or 2-propynyl; Rn is methyl; and Ri 2 and Ri 3 are hydrogen or methyl.
  • Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof; wherein,
  • X is O or N-CN; Ri is hydrogen or methyl;
  • R 3 and R 4 are independently hydrogen, fluoro, chloro, bromo, nitro, cyano, methyl, ethyl, ethenyl, ethynyl, trifluoromethyl, methoxy, ethoxy, or methoxycarbonyl;
  • R 2 , Rs, and Ri O are hydrogen;
  • Re and Rg are independently hydrogen, halogen, nitro, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, ethenyl, propenyl, 2-propynyl, trifluoromethyl, pentafluoroethyl, trifluoromethoxy, methylthio, methoxy, ethoxy, propoxy, allyloxy, acetyl, t-butoxycarbonylmethyl, t-butylcarbonyloxymethyl, ethylcarbonyloxymethyl, methoxyethylamino, methoxyethoxy, cyclopropyl, or morpholinyl;
  • R 7 is hydrogen or halogen
  • R 8 is isopropyl, sec-butyl, t-butyl, isobutyl, pentafluoroethyl, or heptafluoropropyl;
  • Rn is methyl; and Ri 2 and Ri 3 are hydrogen or methyl.
  • Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof; wherein, X is O;
  • Ri is hydrogen or methyl
  • R 3 is hydrogen, fluoro, chloro, bromo, nitro, cyano, methyl, ethyl, ethenyl, ethynyl, or methoxy;
  • R 4 is hydrogen, fluoro, chloro, methyl or ethyl; R2, R5, R10. and R12 are hydrogen;
  • R 6 and R 9 are independently hydrogen, fluoro, chloro, bromo, iodo, nitro, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, ethenyl, propenyl, 2-propynyl, trifluoromethyl, pentafluoroethyl, trifluoromethoxy, methylthio, methoxy, ethoxy, propoxy, t-butylcarbonyloxymethyl, methoxyethylamino, methoxyethoxy, or morpholinyl;
  • R 7 is hydrogen or fluoro;
  • R 8 is isopropyl, sec-butyl, t-butyl, isobutyl, or pentafluoroethyl; R1 1 is methyl; and
  • Ri 3 is methyl or hydrogen.
  • Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof; wherein, X is O;
  • Ri is hydrogen or methyl
  • R 3 is hydrogen, fluoro, chloro, methyl, ethyl, ethenyl, or ethynyl
  • R 4 is hydrogen, fluoro, chloro, methyl or ethyl; R2, R5, R10, R12, and R13 are hydrogen;
  • R 6 and R 9 are independently hydrogen, fluoro, chloro, bromo, nitro, methyl, ethyl, ethenyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, methoxyethylamino, methoxyethoxy, or morpholinyl;
  • R 7 is hydrogen or fluoro;
  • Rs is t-butyl or isopropyl; and R 11 is methyl.
  • Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof as described further above; wherein Y is O.
  • Another preferred embodiment of the present invention is a compound
  • R1 is hydrogen or
  • Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically
  • R13 is hydrogen or methyl.
  • Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof as described further above; wherein, R 3 is nitro, cyano, C2-C5 alkenyl, C2-C5 alkynyl, or halo (C1-C5) alkyl.
  • Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof as described further above wherein, R 3 is cyano, ethenyl, ethynyl, or trifluoromethyl,
  • Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof as described further above; wherein, R 8 is C2-C5 alkenyl, C2-C5 alkynyl, C3-C6 cycloalkyl, or mono- or di- (C3-C5)cycloalkyl(C1-C3)alkyl, wherein each (C3-C5) cycloalkyl may be unsubstituted or substituted with one or more methyl groups.
  • Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof as described further above; wherein,
  • R 8 is C2-C5 alkynyl, propenyl, butenyl, cyclopropyl, cyclohexyl, mono- cyclopropylmethyl, di-cyclopropylmethyl, 2,2-dimethylcyclopropyl, or 2,3- dimethylcyclopropyl.
  • Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof as described further above; wherein, R 8 is methylcyclopropyl.
  • Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof as described further above; wherein, Rs is cyclobutyl, methylcyclobutyl, cyclopentyl, or methylcyclopentyl.
  • Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof as described further above; wherein, R 7 is C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, C2-C5 alkenyloxy,
  • Another preferred embodiment of the present invention is a compound according to the formula (I) and (II), an isomer and/or a pharmaceutically acceptable salt thereof as described further above; wherein,
  • R 7 is acetyl, t-butoxycarbonylmethyl, ethoxycarbonylethyl, methoxycarbonyimethyl, t-butylcarbonyloxymethyl, ethylcarbonyloxymethyl, isopropylcarbonyloxymethyl, piperidinyl, or morpholinyl.
  • Preferred examples of compounds according to the invention are selected from the group consisting of;
  • Particularly preferred compounds according to the present invention are 2-(4-tert-Butylphenoxy)-N-(4-methanesulfonylamino-3- vinylbenzyl)acetamide,
  • Preferred examples of compounds according to the invention are selected from the group consisting of;
  • the present invention also provides a novel compound of the following formula (III), an isomer, or a pharmaceutically acceptable salt thereof;
  • Ri is hydrogen or C1-C5 alky!
  • R2, R3, R4, and R 5 are independently hydrogen, halogen, nitro, cyano, carboxy, C1-C5 alkyl, halo (C1-C5) alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C1-C5 alkylthio, C1-C5 alkoxy, or C1-C5 alkoxycarbonyl;
  • Re, R7, R 9 , and Ri O are independently hydrogen, hydroxyl, halogen, C1-
  • R 8 is C1-C3 alkyldithiolanyl or C1-C3 alkyldithianyl
  • Rn is C1-C5 alkyl or C2-C5 alkenyl
  • R 12 and Ri 3 are independently hydrogen, halogen, or C1-C5 alkyl.
  • One preferred aspect of the present invention is a compound of above formula (III), an isomer, or a pharmaceutically acceptable salt thereof; wherein,
  • R 1 is hydrogen or C1-C5 alkyl
  • R2, R3, R4, and R5 are independently hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, trifluoromethyl, ethenyl, or ethynyl;
  • Re. R7. R9. and R 10 are independently hydrogen, hydroxy!, halogen, C1- C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C1-C5 alkyloxy, halo (C1-C5) alkyl, halo (C1-C5) alkoxy, C1-C5 alkylcarbonyloxy, C1-C5 alkoxycarbonyl, C2-C5 alkenyloxy, C1-C5 alkoxy (C1-C5) alkyl, C1-C5 alkoxycarbonyl (C1-C5) alkyl, C1-C5 alkoxycarbonyl (C1-C5) alkoxy, C1-C5 alkylcarbonyloxy (C1-C3) alkyl, phenylcarbonyloxy, C1-C5 alkoxy (C1-C5) alkoxy, C3-C5 cycloalkyl, C3-C5 cycloalkylmethyl
  • Rs is C1-C3 alkyldithiolanyl or C1-C3 alkyldithianyl
  • R 11 is C1-C5 alkyl or C2-C5 alkenyl
  • Ri 2 and R 13 are independently hydrogen, fluoro, or methyl.
  • Another preferred aspect of the present invention is a compound of above formula (III), an isomer, or a pharmaceutically acceptable salt thereof;
  • Ri is hydrogen;
  • R2 and R 5 are hydrogen;
  • R3 and R 4 are independently hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, trifluoromethyl, ethenyl, or ethynyl;
  • RQ and R 7 are independently hydrogen, hydroxyl, fluoro, chloro, methoxy, piperidinyl, or morpholinyl;
  • R 1 - I is methyl
  • R-12 and R13 are hydrogen.
  • Preferred examples of compounds according to the invention are selected from the group consisting of;
  • the present invention also provides a novel compound of the following formula (IV), an isomer, or a pharmaceutically acceptable salt thereof;
  • R 1 is hydrogen or C1-C5 alkyl
  • R2, R 3 . R4, and R 5 are independently hydrogen, halogen, nitro, cyano, carboxy, C1-C5 alkyl, halo (C1-C5) alkyl, C1-C5 alkylthio, C1-C5 alkoxy, or C1- C5 alkoxycarbonyl;
  • R 7 is C1-C5 alkylcarbonyloxy, C1-C5 alkoxycarbonyl (C1-C5) alkoxy, pyridylcarbonyloxy, phenylcarbonyloxy, or phenyl, wherein each phenyl or pyridyl may be unsubstituted or substituted with one or more substituents selected from halogen, C1-C5 alkyl, or halo (C1-5 alkyl);
  • R 8 is halogen, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, halo (C1-C5) alkyl, halo (C1-C5) alkoxy, C1-C5 alkoxy, C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, C2-C5 alkenyloxy, C1-C5 alkoxy (C1-C5) alkyl, C3-C6 cycloalkyl, mono- or di- (C3-C5) cycloalkyl (C1-C3) alkyl, C1-C3 alkyl dithiolanyl, C1-C3 alkyl dithianyl, piperidinyl, or morpholinyl, wherein each C3-C6 cycloalkyl may be unsubstituted or substituted with one or more methyl groups;
  • Rg and R 10 are independently hydrogen, hydroxy, halogen, nitro, carboxy, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, halo (C1-C5) alkyl, halo
  • C5)alkyl C1-C5 alkoxycarbonyl (C1-C5) alkyl, C1-C5 alkoxycarbonyl (C1-C5) alkoxy, C1-C5 alkylcarbonyioxy (C1-C3) alkyl, arylcarbonyloxy, C1-C5 alkoxy (C1-C5) alkylamino, C1-C5 alkoxy (C1-C5) alkoxy, C3-C5 cycloalkyl, C3-C5 cycloalkylmethyl, piperidinyl, or morpholinyl; and
  • Rn is C1-C5 alkyl.
  • One preferred aspect of the present invention is a compound of above formula (IV), an isomer, or a pharmaceutically acceptable salt thereof; wherein,
  • Ri is hydrogen or C1-C5 alkyl
  • R 2 , R 3 , R 4 , and R 5 are independently hydrogen, fluoro, chloro, bromo, nitro, cyano, methyl, trifluoromethyl, methoxy, or methoxycarbonyl;
  • R 6 is hydrogen, halogen, nitro, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, ethenyl, propenyl, 2-propynyl, trifluoromethyl, pentafluoroethyl, trifluoromethoxy, methylthio, methoxy, ethoxy, propoxy, allyloxy, acetyl, t-butoxycarbonylmethyl, ethoxycarbonylethyl, t- butylcarbonyloxymethyl, ethylcarbonyloxymethyl, isopropylcarbonyloxymethyl, methoxycarbonylmethoxy, phenylcarbonyloxy, methoxyethylamino, methoxyethoxy, cyclopropyl, or morpholinyl;
  • R 7 is C1-C5 alkylcarbonyioxy, C1-C5 alkoxycarbonyl (C1-C5) alkoxy, pyridylcarbonyloxy, or phenylcarbonyloxy, wherein phenyl or pyridyl may be unsubstituted or substituted with one or more substituents selected from fluoro, chloro, bromo, methyl, ethyl, propyl, and trifluoromethyl;
  • R 8 is isopropyl, sec-butyl, t-butyl, isobutyl, t-amyl, isopropenyl, trifluoromethyl, pentafluoroethyl, heptafluoropropyl, heptafluoro-iso-propyl, difluorobutyl, nonafluorobutyl, nonafluoro-t-butyl, 1-methylcyclopropyl, 2- methyl[1 ,3]dithiolan-2-yl, or 2-propynyl;
  • Rn is methyl
  • Another preferred aspect of the present invention is a compound of above formula (IV), an isomer, or a pharmaceutically acceptable salt thereof;
  • R 1 , R 2 , and R 5 are hydrogen;
  • R 3 and R 4 are independently hydrogen, fluoro, chloro, bromo, nitro, cyano, methyl, trifluoromethyl, methoxy, or methoxycarbonyl;
  • R 6 is hydrogen, fluoro, chloro, bromo, nitro, methyl, ethyl, ethenyl, trifluoromethyl, trifluoromethoxy, methoxy, ethoxy, methoxycarbonylmethoxy, phenylcarbonyloxy, methoxyethylamino, methoxyethoxy, or morpholinyl;
  • R 7 is methoxycarbonyimethyloxy, methylcarbonyloxy, phenylcarbonyloxy, or trifluoromethylpyridylcarbonyloxy,
  • Rs is t-butyl, isopropyl, 1-methylcyclopropyl, or 2-methyI[1 ,3]dithiolan-2-
  • Rg and R 10 are both hydrogen; and Rn is methyl.
  • Preferred examples of compounds according to the invention are selected from the group consisting of;
  • the Scheme 1 shows a proposed process for synthesizing the N- benzyl-2-phenoxyacetamide compound (3).
  • the 2-phenoxyacetic acid compound (2) is reacted with the benzylamine compound (1) and diethylphosphoryl cyanide (DEPC) to yield the N-benzyl-2-phenoxyacetamide compound (3).
  • DEPC diethylphosphoryl cyanide
  • the Scheme 2 shows another process for synthesizing the N-benzyl-2- phenoxyacetamide compound (5).
  • the benzylamine compound (4) is reacted with the 2-phenoxyacetic acid compound (2) and DMTMM ⁇ 4-(4,6-dimethoxy ⁇
  • the Scheme 3 shows a proposed process for synthesizing 2- phenoxyacetic acid compound (2) with various substituents.
  • Phenol compound (6) is reacted with alkyl 2-bromoacetate compound (7) to yield alkyl 2- phenoxyacetate compound (8).
  • the compound (8) is hydrolyzed with sodium hydroxide in methanol or lithium hydroxide in THF to yield 2-phenoxyacetic acid compound (2) with various substituents.
  • the Scheme 4 shows another process for synthesizing alkyl 2- phenoxyacetate compound (8).
  • Phenol compound (6) is reacted with alkyl 2- hydroxyacetate compound (9) under Mitsunobu reaction conditions (Synthesis, 1981, 1) to yield alkyl 2-phenoxyacetate compound (8).
  • the compound (8) is hydrolyzed using base in aqueous solvent according to the same procedure as described in scheme 3.
  • the Scheme 5 shows a proposed process for synthesizing the N-benzy- 2-phenylthioacetamide compound (13).
  • the thiophenol compound (10) is reacted with the alkyl ⁇ -bromoacetate compound (7) to yield the alkyl 2- phenylthioacetate compound (11).
  • the compound (11 ) is hydrolyzed to yield the phenylthioacetic acid compound (12).
  • the acid compound (12) is reacted with benzyl amine compound (1) to yield the N-benzy-2-phenyIthioacetamide compound (13).
  • the Scheme 6 shows a proposed process for synthesizing the N- benzyl-2-phenoxy-N'-cyanoacetamidine compound (16).
  • the compound (14) is reacted with Lawesson's reagent to yield the thioacetamide compound with phenoxy moiety (15).
  • the thioacetatmide compound (15) is reacted with cyanamide and HgCI 2 to yield the N-benzyl-2-phenoxy-N'- cyanoacetamidinecompound (16).
  • the Scheme 7 shows another proposed process for synthesizing the acetamide compound (22).
  • the resorsinol compound (17) is reacted with the fe/f-butyl bromoacetate to give the phenol compound (18), which is reacted with acetic anhydride to yield the compound (19).
  • the ester compound (19) is hydrolyzed with trifluoroacetic acid to afford the acid compound (20), which is reacted with the benzyl amine salt (21) using the coupling agent DEPC finally to yield the acetamide compound (22).
  • the Scheme 8 shows another proposed process for synthesizing the acetamide compound (27).
  • the phenol compound (23) is reacted with 2-methyl-
  • the present invention also provides a novel compound according the above formula (I) or (II) for use as a medicament.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or (II), an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.
  • a compound of formula (I) or (II), an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient together with an pharmaceutically acceptable carrier is present in an effective amount for preventing or treating pain, acute pain, neuropathic pain, post-operative pain, migraine, arthralgia, neuropathies, nerve injury, diabetic neuropathy, neurodegeneration, stroke, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, urinary bladder hypersensitiveness, irritable bowel syndrome, fecal urgency, Crohn's disease, respiratory disorder such as asthma or chronic obstructive pulmonary disease, irritation of skin, eye or mucous membrane, stomach-duodenal ulcer, inflammatory bowel disease or inflammatory diseases.
  • the present invention also provides a pharmaceutical composition for preventing and treating a disease associated with the pathological stimulation and/or aberrant expression of vanilloid receptor, wherein said composition comprises a compound of formula (I) or (II), an isomer thereof or a pharmaceutically acceptable salt thereof; and pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition for preventing and treating a condition related to vanilloid receptor, where said composition comprises a compound of formula (I) or (II), an isomer thereof or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier.
  • said condition related to vanilloid receptor is 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, or heart disease.
  • said condition related to vanilloid receptor is acute pain, chronic pain, neuropathic pain, post-operative pain, rheumatic arthrodynia, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, HIV-related neuropathy, neurodegeneration, stroke, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, asthma, chronic obstructive pulmonary disease, urinary incontinence, inflammatory bowel disease, hyperacusis, tinnitus, vestibular hypersensitiveness, or inotropic ischemia.
  • the present invention provides a pharmaceutical composition for treating a condition selected from pain, inflammatory disease of the joints including inflammatory autoimmune diseases of the joints, urinary bladder hypersensitivity including urinary incontinence, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), neurotic/allergic/inflammatory skin disease, psoriasis, asthma, chronic obstructive pulmonary disease (COPD), pruritus, or prurigo comprising a compound, an isomer thereof or a pharmaceutically acceptable salt thereof according to anyone of formula (I) or (II), as defined further above.
  • the inventive compounds can be used in a pharmaceutical composition for treating pain, wherein the pain is -or is associated with- a condition selected from osteoarthritis ("OA"), rheumatoid arthritis ("RA”), Ankylosing Spondylitis (“AS”), diabetic neuropathic pain, postoperative pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine and other types of headaches.
  • OA osteoarthritis
  • RA rheumatoid arthritis
  • AS Ankylosing Spondylitis
  • diabetic neuropathic pain postoperative pain
  • non-inflammatory musculoskeletal pain including fibromyalgia, myofascial pain syndrome and back pain
  • migraine other types of headaches.
  • the compounds of the present invention are said to be useful to treat pain associated with osteoarthritis, it shall not be excluded that this also comprises the treatment of other signs and symptoms of osteoarthritis. Besides reducing the pain associated with osteoarthritis, the pharmacological intervention of osteoarthritis may be aimed at maintaining the mobility and minimizing the disability of the joints.
  • the term "inflammatory disease of the joints” includes diseases that involve to a more or less degree inflammatory processes in the joints, e.g. in knees, fingers, hips etc. An example for such a disease is osteoarthritis.
  • the term "inflammatory disease of the joints” does also include diseases or conditions which may involve autoimmune processes, such as e.g. rheumatoid arthrtitis or ankylosing spondylitis.
  • the inventive treatment of "inflammatory diseases of the joints” is primarily aimed at treating pain associated with these conditions but may also aim at improving the function of the affected joints, either directly or indirectly, e.g. by reducing the pain associated with the movement of said joints.
  • One outcome of the administration of the compounds of the present invention to patients suffering from an inflammatory disease of the joints may thus be reducing the pain experienced by the subject suffering from said disease relative to the pain experienced by the subject immediately before the administration of the compounds or combinations of the present invention.
  • Another outcome of said treatment may be preventing the re-occurence of pain which has previously been reduced as a result of pharmaco- or other therapy.
  • Another outcome of treatment may be decreasing the occurrence of and/or the severity of manifestations related to an inflammatory disease of the joints, including particularly osteoarthritis, rheumatoid arthritis ankylosing spondylitis.
  • the treatment may suitably result in an improved functionality of the joints, such as decreased stiffness, improved mobility.
  • OA osteoarthritis
  • OA osteoarthritis
  • idiopathic (primary) OA the most common form of the disease, no predisposing factor is apparent. Secondary OA is attributable to an underlying cause. Pain and joint dysfunction are the cardinal symptoms of OA.
  • the joint pain of OA is often described as a deep ache and is localized to the involved joint.
  • the pain of OA is aggravated by joint use and relieved by rest, but, as the disease progresses, it may become persistent. Nocturnal pain, interfering with sleep, is seen particularly in advance OA of the hip and may be enervating.
  • RA Rheumatoid Arthritis. RA is a chronic inflammatory autoimmune disease that causes the immune system to attack the joints, and particularly the synovium in the joint. The synovium becomes inflamed and causes swelling and pain. Cardinal symptoms of RA are joint pain and stiffness but additional symptoms include muscle aches, anemia and fever.
  • Diagnosis of RA can be confirmed by detecting an antibody in the blood called the "rheumatic (or “rheumatoid”) factor” and/or by a blood sedimentation test.
  • AS Ankylosing Spondylitis, which is a chronic, progressive autoimmune disease characterized by arthritis, inflammation and eventual immobility of the joints, particularly the spinal joints. It causes pain and stiffness in the back (often in the morning hours) as a result of ongoing swelling and irritation of the spinal joints (vertebrae). Inflammation of the tendons and ligaments that connect and provide support to the vertebrae can lead to pain and tenderness in the ribs, shoulder blades, hips, thighs, shins, heels and along the bony points of the spines.
  • the compounds according to the present invention are said to be of use in treating pain associated with an inflammatory autoimmune disease of the joints, this refers to the administration of the compounds or combinations of the compounds of the present invention to reduce at least one pain symptom experienced by a subject suffering from an inflammatory autoimmune disease of the joints including back pain, joint pain and muscle pain associated with RA or AS.
  • treatment of an inflammatory autoimmune disease of the joints may also include a decrease of the inflammation and/or swelling of the synovium and may help to improve the functionality (i.e. maintaining mobility, and minimizing disability) of the joints, in particular in patients suffering from RA or AS.
  • non-inflammatory musculoskeletal pain refers to the administration of the compounds or combinations of the compounds of the present invention to reduce the pain experienced by a subject suffering from non-inflammatory musculoskeletal pain including back pain, fibromyalgia, and myofascial pain syndrome.
  • One outcome of treatment may be reducing the pain experienced by the subject relative to the pain experienced by the subject immediately before the administration of the compounds or combinations of the present invention.
  • Another outcome of treatment may be preventing reoccurence of pain which has previously been reduced as a result of pharmacotherapy.
  • Another outcome of treatment may be decreasing the occurrence of and/or the severity of manifestations related to non-inflammatory musculoskeletal pain including back pain, fibromyalgia, and myofascial pain syndrome.
  • the treatment may suitably result in a reduction of increased muscle sensitivity characterized by pain evoked by a normally non-nociceptive stimulus (ailodynia) or increased pain intensity evoked by nociceptive stimuli (hyperalgesia).
  • ailodynia normally non-nociceptive stimulus
  • nociceptive stimuli hyperalgesia
  • the treatment of non-inflammatory musculoskeletal pain can also improve the associated symptoms of back pain, fibromyalgia, and myofascial pain syndrome.
  • fibromyalgia or "FMS” relates to a syndrome that causes widespread pain and stiffness throughout the tissue that supports and moves bones and joints. Fibromyalgia can be diagnosed by the presence of excessive tenderness on applying pressure to at least 11 of 18 specific muscle-tendon sites.
  • Myofascial pain syndrome is a chronic non-degenerative, non-inflammatory musculoskeletal pain condition. Distinct areas within muscles or their delicate connective tissue coverings (fascia) become abnormally thickened or tight. When the myofascial tissues tighten and lose their elasticity, neurotransmitter ability to send and receive messages between the brain and body is damaged. Symptoms include muscle stiffness and aching and sharp shooting pains or tingling and numbness in areas distant from the trigger point.
  • Back pain is a common non-inflammatory musculoskeletal pain condition that may be either acute or chronic. It may be caused by a variety of diseases and disorders that affect the lumbar spine. Low back pain is often accompanied by sciatica, which is pain that involves the sciatic nerve and is felt in the lower back, the buttocks, and the backs of the thighs.
  • the compounds of the present invention are also useful for treating signs and symptoms of an overactive bladder such as urinary incontinence, more specific urinary urge incontinence, urinary stress incontinence, urinary urgency, nocturia and/or urinary frequency.
  • an overactive bladder such as urinary incontinence, more specific urinary urge incontinence, urinary stress incontinence, urinary urgency, nocturia and/or urinary frequency.
  • compositions according to the present invention are preferably adapted for oral administration.
  • pharmaceutical composition containing the inventive compounds may be also formulated for topical or transcutaneous use.
  • the present invention relates to a method for inhibiting vanilloid ligand from binding to vanilloid receptor in a patient, comprising contacting cells expressing vanilloid receptor in the patient with a compound of formula (I) or (II), an isomer thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a method for preventing or treating a disease selected from pain, migraine, arthralgia, 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, which comprises administering to a mammal including a person in need thereof a therapeutically effective amount of a compound of formula (I) or (II), an isomer thereof, or a pharmaceutically acceptable salt thereof.
  • the disease is also selected from acute pain, chronic pain, neuropathic pain, post-operative pain, diabetic neuropathy, neurodegeneration, stroke, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, asthma, chronic obstructive pulmonary disease, urinary incontinence or inflammatory bowel disease.
  • the above method is treating pain that is or that is associated with a condition selected from osteoarthritis ("OA"), rheumatoid arthritis ("RA"), Ankylosing Spondylitis (“AS”), diabetic neuropathic pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), post-operative pain, migraine and other types of headache.
  • OA osteoarthritis
  • RA rheumatoid arthritis
  • AS Ankylosing Spondylitis
  • diabetic neuropathic pain including fibromyalgia, myofascial pain syndrome and back pain
  • post-operative pain migraine and other types of headache.
  • the present invention relates to the use of a compound of formula (I) or (II), an isomer thereof, or a pharmaceutically acceptable salt thereof as an antagonist of vanilloid receptor.
  • the present invention relates to the use of a compound of formula (I) or (II), an isomer thereof, or a pharmaceutically acceptable salt thereof for prevention or treatment of a condition related to vanilloid receptor, which is more specifically associated with the aberrant expression and/or aberrant activation of a vanilloid receptor.
  • the present invention relates to the use of a compound of formula (I) or (II), an isomer thereof, or a pharmaceutically acceptable salt thereof, in preparation of a medicament for prevention or treatment of a condition related to vanilloid receptor.
  • the present invention relates to the use of a compound of formula (I) or (II), an isomer thereof, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or the treatment of a condition that is selected from pain, inflammatory autoimmune disease of the joints, urinary bladder hypersensitivity including urinary incontinence, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), neurotic/allergic/inflammatory skin disease, psoriasis, asthma, chronic obstructive pulmonary disease (COPD), pruritus, or prurigo.
  • the present invention relates to the use of a compound for treating pain as described above, wherein the pain is or is associated with a condition that is selected from osteoarthritis ("OA"), rheumatoid arthritis ("RA"), Ankylosing Spondylitis (“AS”), diabetic neuropathic pain, post-operative pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine and other types of headaches.
  • OA osteoarthritis
  • RA rheumatoid arthritis
  • AS Ankylosing Spondylitis
  • diabetic neuropathic pain post-operative pain
  • non-inflammatory musculoskeletal pain including fibromyalgia, myofascial pain syndrome and back pain
  • migraine and other types of headaches include migraine and other types of headaches.
  • the present invention also provides a novel compound according the above formula (III) or (IV) for use as a medicament.
  • the present invention also provides a compound of formula (111), or (IV), an isomer thereof, or a pharmaceutically acceptable salt thereof for preventing and treating a condition associated with the pathological stimulation and/or aberrant expression of vanilloid receptors.
  • the present invention provides a compound of formula (I), (II), (III), or (IV), an isomer thereof, or a pharmaceutically acceptable salt thereof, for treating a condition selected from the group consisting of pain, inflammatory disease of the joints, neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration, stroke, urinary bladder hypersensitivity including urinary incontinence, cystitis, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), fecal urgency, gastro-esophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hyperacusis, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, hair growth-related disorders such as effluvium,
  • the present invention relates to a compound of formula (I), (II), (III), or (IV), an isomer thereof, or a pharmaceutically acceptable salt thereof for treating pain as described above, wherein the pain is or is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine and other types of headaches.
  • the present invention also provides a pharmaceutical composition comprising a compound of formula (I), (II), (III), or (IV), an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient together with a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition for preventing and treating a condition associated with the pathological stimulation and/or aberrant expression of vanilloid receptors, wherein said composition comprise a compound of formula (I), (II), (III), or (IV), an isomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier thereof.
  • the present invention provides a pharmaceutical composition comprising the compound of the present invention for treating a condition selected from the group consisting of pain, inflammatory disease of the joints, neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration, stroke, urinary bladder hypersensitivity including urinary incontinence, cystitis, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), fecal urgency, gastro-esophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hyperacusis, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, hair growth-related disorders such as effluvium, alopecia, rhinitis, and pancreatitis.
  • a condition selected from the group
  • the present invention relates to the pharmaceutical composition
  • the pharmaceutical composition comprising the compound of the present invention for treating pain as described above, wherein the pain is or is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine and other types of headaches.
  • a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine and other types of headaches.
  • the present invention also provides a pharmaceutical composition which is characterized in that it is adapted for oral administration.
  • the present invention relates to a method for inhibiting vanilloid ligand from binding to vanilloid receptor in a patient, comprising contacting cells expressing vanilloid receptor in the patient with the compound of formula (I), (II), (III), or (IV) 1 an isomer thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a method for preventing or treating a condition selected from the group consisting of pain, inflammatory disease of the joints, neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration, stroke, urinary bladder hypersensitivity including urinary incontinence, cystitis, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), fecal urgency, gastro-esophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hyperacusis, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, hair growth-related disorders such as effluvium, alopecia, rhinitis, and pancreatitis, which comprises administering to a mammal including
  • the present invention relates to the method of a compound of the present invention for treating pain as described above, wherein the pain is or is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine, and other types of headache.
  • a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine, and other types of headache.
  • the present invention relates to the use of a compound of formula (I), (II), (III), or (IV), an isomer thereof, or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention or treatment of a condition that is associated with the aberrant expression and/or aberrant activation of a vanilloid receptor.
  • the present invention relates to the use of a compound of formula (I), (II), (III), or (IV), an isomer thereof, or a pharmaceutically acceptable salt thereof, in preparation of a medicament for the prevention or treatment of a condition that is selected from the group consisting of pain, inflammatory disease of the joints, neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration, stroke, urinary bladder hypersensitivity including urinary incontinence, cystitis, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), fecal urgency, gastroesophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hyperacusis, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia
  • the present invention relates to the use of the compound of formula (I), (II), (III), or (IV) for preventing or treating pain as described above, wherein the condition is pain, which is or which is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post- operative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine, and other types of headaches.
  • a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post- operative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine, and other types of headaches.
  • a compound of formula (I), (II), (III), or (IV), an isomer thereof or a pharmaceutically acceptable salt thereof according to the present invention can be prepared as a pharmaceutical composition containing pharmaceutically acceptable carriers, adjuvants, diluents and the like.
  • the compounds of the present invention can be dissolved in oils, propylene glycol or other solvents which are commonly used to produce an injection. Suitable examples of the carriers include physiological saline, polyethylene glycol, ethanol, vegetable oils, isopropyl myristate, etc., but are not limited to them.
  • the compounds of the present invention can be formulated in the form of ointment or cream.
  • the compound according to the present invention may also be used in the forms of pharmaceutically acceptable salts thereof, and may be used either alone or in combination or in admixture with other pharmaceutically active compounds.
  • the compounds of the present invention may be formulated into injections by dissolving, suspending or emulsifying in water-soluble solvent such as saline and 5% dextrose, or in water-insoluble solvents such as vegetable oils, synthetic fatty acid glyceride, higher fatty acid esters and propylene glycol.
  • the formulations of the invention may include any of conventional additives such as dissolving agents, isotonic agents, suspending agents, emulsifiers, stabilizers and preservatives.
  • the preferable dose level of the compounds according to the present invention depends upon a variety of factors including the condition and body weight of the patient, severity of the particular disease, dosage form, and route and period of administration, but may appropriately be chosen by those skilled in the art.
  • the compounds of the present invention are preferably administered in an amount ranging from 0.001 to 100 mg/kg of body weight per day, and more preferably from 0.01 to 30 mg/kg of body weight per day. Doses may be administered once a day, or several times a day with each divided portions.
  • the compounds of the present invention are used in a pharmaceutical composition in an amount of 0.0001 — 10% by weight, and preferably 0.001 ⁇ 1 % by weight, based on the total amount of the composition.
  • the pharmaceutical composition of the present invention can be administered to a mammalian subject such as rat, mouse, domestic animals, human being and the like via various routes.
  • the methods of administration which may easily be expected include oral and rectal administration; intravenous, intramuscular, subcutaneous, intrauterine, duramatral and intracerebroventricular injections.
  • Alkyl includes monovalent saturated aliphatic hydrocarbyl groups.
  • the hydrocarbon chain may be either straight-chained or branched. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso- butyl, tert-butyl sec-butyl, tert-amyl.
  • Alkyldithiolanyl refers to the group , wherein R is “alkyl” described above.
  • Alkyldithianyl refers to the group S Q — / ' , wherein R is “alkyl” described above.
  • Alkoxy includes the group-OR where R is alkyl. Particular alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, tert-butoxy, iso-butoxy, sec-butoxy, n ⁇ pe ⁇ toxy, 1 ,2-dimethy!butoxy, and the like.
  • Alkoxyalkoxy refers to the group -OROR', wherein R and R' are the same or different "alkyl” groups as defined further above.
  • Alkoxyalkyl refers to the group -ROR', wherein R and R' are the same or different "alkyl" groups as defined further above
  • R' are the same or different "alkyl” groups as defined further above — N-R'-OR"
  • Alkoxyalkylamino refers to the group R , wherein R may be hydrogen or "alkyl", and R' and R" are both “alkyl” as defined further above.
  • a preferred "alkenyl” group is ethenyl (vinyl).
  • Alkenyloxy refers to the group -O-alkenyl, wherein “alkenyl” has the meaning as defined above.
  • Alkynyl includes acetylenically unsaturated hydrocarbyl groups being straight-chained or branched and having at least 1 triple bond.
  • a preferred alkynyl group is ethynyl (acetylene).
  • Alkylamino includes the group -NR'R", wherein R' is alkyl and R" is selected from hydrogen or alkyl
  • Alkylsulfonyl includes a radical-S(O) 2 R where R is an alkyl group as defined herein. Representative examples include, but are not limited to, methanesulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and the like.
  • Alkylthio includes a radical-S-R where R is an alkyl group as defined herein that may be optionally substituted as defined herein. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, and the like.
  • Cycloalkyl refers to cyclic saturated aliphatic hydrocarbyl groups.
  • the numbers of C-atoms referenced in connection with a given cycloalkyl group corresponds to the number of ring forming carbon atoms, e.g. "C3-C5 cycloalkyl” refers to a cycloalkyl with between three and five ring-forming C atoms.
  • Examples of “cycloalkyl” are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc. If indicated, a "cycloalkyl” group may be unsubstituted or substituted with one or more methyl groups. If a "cycloalkyl” carries more than one methyl substituent these substituents may be attached to the same or to different ring-forming carbon atoms.
  • Cycloalkyl refers to the group -CHs-cycloalkyl, wherein “cycloalkyl” is as defined further above
  • ⁇ thynyl refers to -C ⁇ CH.
  • Halo or halogen refers to fluoro, chloro, bromo and iodo. Preferred halo groups are either fluoro or chloro.
  • Haloalkyl includes an "alky! group as defined further above which is substituted with one or more halogens which may be the same, e.g. in trifluoromethyl, pentafluoroethyl, heptafluoropropyl, heptafluoro-isopropyl, or nonafluorobutyl, or which may be different.
  • Haloalkoxy includes an "alkoxy” group as defined further above which is substituted with one or more halogens which may be the same, e.g. in trifluoromethoxy, or which may be different.
  • Hydroxy refers to the radical-OH.
  • Niitro refers to the radical-NO 2 .
  • (C1-C5)alkoxy(C1-C5)alkyf includes the group-ROR where R is "alkyl” with up to five carbon atoms.
  • Particular alkoxyalkyi groups include, by way of example, methoxymethyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxyethyl, n-propoxymethyl, and the like.
  • Particular alkoxycarbonylalkyl groups include, by way of example, buthoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylmethyl, and the like.
  • (C1-C5)alkoxy(C1-C5)alkylamino includes the group RORNH- where R is “alkyl” with up to five carbon atoms.
  • Particular alkoxyalkylamino groups include, by way of example, methoxymethylamino, methoxyethylamino, ethoxymethylamino, and the like.
  • (C1-C5)alkoxy(C1-C5)alk ⁇ xy” includes the group RORO- where R is "alkyl” with up to five carbon atoms.
  • Particular alkoxyalkoxyl groups include, by way of example, methoxymethoxy, methoxyethoxy, methoxypropoxy, ethoxyethoxy, and the like.
  • Particular alkylcarbonyloxyalkyl groups include, by way of example, t-butylcarbonyloxymethyl, ethylcarbonyloxymethyl, isopropylcarbonyloxymethyl, and the like.
  • “Pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U. S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) salts formed when an acid is added to the parent compound, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2- ethane-disulfonic acid, 2-hydroxyethanes
  • “Pharmaceutically acceptable carrier” refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • Preventing refers to a reduction in risk of acquiring a disease or disorder (i. e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease).
  • Subject includes humans.
  • the terms “human,” “patient” and “subject” are used interchangeably herein.
  • “Therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • The”therapeutically effective amount can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
  • “Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i. e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • treating refers to modulating the disease or disorder, either physically, (e. g., stabilization of a discernible symptom), physiologically, (e. g., stabilization of a physical parameter), or both.
  • treating or “treatment” refers to delaying the onset of the disease or disorder.
  • a dried 25ml two-neck round bottom flask was filled with argon and (4- tert-butyl-phenoxy)-acetic acid (1.1eq, 0.11 mmol, 34.61mg) and N-(4- aminomethyl-2-fluoro-6-vinylphenyl)methanesulfonamide (1.Oeq, O.IOmmol, 35mg) were dissolved in DMF. To this solution were added DEPC (1.2eq, 0.12ITUTiOl, 18.21 ⁇ i) and TEA (2.0eq, 0.20mmol, 27.88 ⁇ ) and stirred for 12 hours.
  • Step 3 (R)-2-(4-ferf-Butylphenoxy)-/V-(3-fluoro-4- methanesulfonylaminobenzyl)propiffhide
  • Step 2 (S)-2-(4-fe/?-Butylphenoxy)propionic acid Small amount of water was added to a solution of (S)-2-(4-tert- butylphenoxy)propionic acid ethyl ester (1eq, 0.36mmol, 89.5mg) in MeOH followed by MeOH. After cooling to 0 0 C, NaOH (5eq, 1.79 mmol, 71.55 mg) was slowly added, and the reaction mixture was stirred for 5hrs. After completion of the reaction, the aqueous phase was washed with methylene chloride, acidified, and then extracted with ether (150 x 3). The ethereal phase was concentrated to give a pale yellow syrup 70.05 mg (87.6%).
  • Step 3 (SJ-2-(4-ferf-butylphenoxy)-/V-(3-fluoro-4- methanesulfonylaminobenzyl)propionamide
  • (S)-2-(4-tert-butyl-phenoxy)propionic acid 1.1 eq, 0.12mmol, 25.75mg
  • N-(4-aminomethyI-2-fluoro- phenyl)methanesulfonamide (1eq, 0.11 mmol, 35mg) in DMF under argon were added DEPC (1.2eq, 0.13mmol, 20.03 ⁇ ⁇ ) and TEA (2eq, 0.22mmol, 30.66M).
  • Step 1 (4-tert-Butyl-phenylsulfanyl)-acetic acid
  • the obtained liquid was dissolved in methylene chloride, added 3ml trifluoroacetic acid and stirred for 24 hours. After confirming the completion of the reaction with TLC, the reaction solution was extracted with methylene chloride, washed with 1N HCI and brine, dried over MgSO 4 , filtered and concentrated under reduced pressure to yield a liquid (1.3g, 73.0%).
  • Step 1 (4-Trifluoromethyl-phenoxy)-acetic acid
  • Step 2 N-(3-Fluoro-4 ⁇ methanesulfonylamino-benzyl)-2-(4- trifluoromethyl-phenoxy)-acetamide
  • Step 1 2-Bromo-N-(3-fluoro-4-methanesulfonylamino-benzyl)-acetannide
  • Step 2 2-(3,4-Dichloro-phenoxy)-N-(3-fluoro-4-methanesulfonylamino- benzyl)-acetamide
  • 2-Bromo-N-(3-fluoro-4-methanesulfonylamino-benzyl)-acetamicle 165 mg, 0.486 mmol
  • 3,4-dichlorophenol 96 mg, 0.59 mmol
  • sodium hydride 60 wt% 57 mg, 1.4 mmol
  • the reaction solvent was removed in vacuo.
  • the residue was extracted with methylene chloride (30 ml x 3) and H 2 O (30 ml).
  • the combined organic layer was dried with MgSO 4 and concentrated in vacuo.
  • the residue was purified with column chromatography to yield the title compound (14 mg).
  • Step 1 Synthesis of ethyl-(4-iodo-phenoxy)-acetate 4-lodophenol (327.7 mg, 1.48 mmol) and sodium hydride (60 wt%, 85 mg, 2.1 mmol ) were added in THF (20 ml). After the mixture was stirred for 20 min, ethyl 2-bromoacetate (0.2 ml, 1.8 mmol) was added into the mixture. The reaction mixture was stirred overnight. A reaction solvent was removed in vacuo. The residue was extracted with methylene chloride (30 ml x 2) and H 2 O (30 ml).
  • Step 3 N-(3-Fluoro-4-methanesulfonylamino-benzyl)-2-(4-iodo- phenoxy)-acetamide
  • Step 3 2-(2,6-Diiodo-4-trifluoromethyl-phenoxy)-N-(3-fluoro-4- methanesulfonylamino-benzyl)-acetamide
  • Step 4 (4-Amino-3-fluoro-5-iodobenzyl)carbamic acid t-butyl ester
  • a 25 ml two-neck round bottom flask was filled with argon gas and the solution of 4-aminomethyl-2-fluoro-6-iodophenylamine (31.9mg, 0.120mmol, 1 eg.) and triethylamine (18.4/ ⁇ , 0.132mmol, 1.1eg.) in methylene chloride was put into the flask and then cooled to 0 ° C .
  • Step 6 (3-Cyano-5-fluoro-4-methanesulfonylamino)carbamic acid t-butyl ester
  • Step 7 N-(4-Aminomethyl-2-cyano-6-fluorophenyl)methanesulfonamide (3-Cyano-5-fluoro-4-methanesulfonylamino)carbamic acid t-butyl ester (30mg, 0.12mmol) was put into 25ml round-bottom flask and then dissolved in methylene chloride(3ml). To the solution was added trifluoroacetic acid (0.5ml) and the reaction mixture was stirred for one night. After confirming the completion of the reaction with TLC, the reaction solution was concentrated under reduced pressure to yield a brown crude liquid (crude 100%).
  • Step 8 2-[4-(tert-Butyl)phenoxy]-/V-(3-cyano-5-fluoro-4-methanesulfonyl amino)benzylacetamide
  • N-(4-Aminomethyl-2-fluorophenyl)methanesulfonamide HCI salt 65.64mg, 0.32mmol
  • (4-tert-butylphenoxy)fluoroacetic acid 1.1 eq, 0.35mmol, 80.00mg
  • TEA 5eq, 1.60mmol, 222.00 ⁇ i
  • diethylcyanophosphonate 1.2eq, 0.38mmol, 58.OQpJL
  • Step 1 Synthesis of 4-isopropylphenoxyacetic acid To a solution of 4-isopropylphenol (0.38 g, 2.79 mmol) in acetonitrile (10 mL) were added cesium carbonate (1.37 g, 4.2 mmol) and ethyl bromoacetate (0.34 mL, 3.01 mmol). The resulting mixture was stirred for 1.5 hours at room temperature, concentrated under reduced pressure, and diluted with EtOAc and water. The organic layer was washed with brine and concentrated under reduced pressure. The crude residue was diluted with THF (7 mL) and 1 N LiOH (5 mL), and then stirred for 1 hour at room temperature.
  • Step 2 Synthesis of N-(3-fluoro-4-methanesulfonylaminobenzyl)-2-(4- isopropylphenoxy)acetamide
  • 3-fluoro-4-methanesulfonylaminobenzylamine hydrochloride 100 mg, 0.39 mmol
  • triethyiamine 82 ⁇ l_, 0.59 mmol
  • Step 2 Synthesis of N ⁇ (3-fluoro-4-methanesulfonylaminobenzyl)-2-(4-sec- butylphenoxy) acetamide
  • Step 1 Synthesis of indan-5-yloxyacetic acid To a solution of 5-indanol (0.38 g, 2.83 mmol) in acetonitrile (10 mL) were added cesium carbonate (1.37 g, 4.2 mmol) and ethyl bromoacetate (0.34 mL, 3.01 mmol). The resulting mixture was stirred for 1.5 hours at room temperature, concentrated under reduced pressure, and diluted with EtOAc and water. The organic layer was washed with brine and concentrated under reduced pressure. The crude residue was diluted with THF (7 mL) and 1 N LiOH (5 mL), and then stirred for 1 hour at room temperature.
  • Step 2 Synthesis of N-(3-fluoro-4-methanesulfonylaminobenzyl)-2-(indan-5- yloxy)acetamide
  • Step 3 (2-ButoxymethyI-4-trifluoromethyI-phenoxy)-acetic acid
  • Step 4 2-(2-ButoxymethyI-4-trifluoromethyl-phenoxy)-N-(3-fluoro-4- methanesulfonylamino-benzyl)-acetamide
  • Step 1 Synthesis of 4-cyclopentylphenoxyacetic acid
  • acetonitrile 10 ml_
  • cesium carbonate (1.37 g, 4.2 mmol)
  • ethyl bromoacetate (0.34 mL, 3.01 mmol).
  • the resulting mixture was stirred overnight at room temperature, concentrated under reduced pressure, and diluted with EtOAc and water.
  • the organic layer was washed with brine and concentrated under reduced pressure.
  • the crude residue was diluted with THF (7 mL) and 1 N LiOH (5 mL), and then stirred for 1 hour at room temperature.
  • Step 1 2-(2-ChIoro-4-trifluoromethyl-phenoxy)-tetrahydro-pyran
  • Step 4 2-(2-Chloro-4-trifluoromethyl-phenoxy)-N-(3-fluoro-4- methanesulfonylamino-benzyl)-acetamide 3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (50 mg, 0.196 mmol) was suspended in THF and treated with triethylamine (21.8 mg, 0.216 mmol) and then the resulting mixture was stirred for lOmins. (2-Chloro-4- trifluoromethyl-phenoxy)-acetic acid (50 mg, 0.196 mmol) was added to the reaction mixture followed by DMTMM (59.7 mg, 0.216 mmol) after 10 mins.
  • Step 1 [4-(1-Hydroxy-1-methyl-ethyl)-phenoxy]-acetic acid ethyl ester
  • Step 3 N-(3-Fluoro-4-methanesulfonylamino-benzyl)-2-(4-isopropenyl- phenoxy)-acetamide
  • N-(4-Aminomethyl-3-fluoro-phenyl)-methanesulfonamide HCI salt 131 mg, 0.515 mmol
  • NMP (0.15 ml)
  • DMTMM 135 mg, 0.487 mmol
  • (4-tert-butyl-2-fluoro- phenoxy)-acetic acid 109 mg, 0.481 mmol
  • the reaction mixture was stirred overnight.
  • the reaction solvent was removed in vacuo.
  • the residue was extracted with methylene choride (30 ml x 3) and H 2 O (30 ml).
  • N-(4-Aminomethyl-3-fluoro-phenyl)-methanesulfonamide HCI salt (127mg, 0.499) and NMP (0.15 ml) were added in 10 ml THF. The mixture was stirred for 10 mins. DMTMM (135 mg, 0.487 mmol) and (4-tert-butyl-2-chloro-phenoxy)- acetic acid (112 mg, 0.463 mmol) were added into the mixture. The reaction mixture was stirred overnight. The reaction solvent was removed in vacuo. The residue was extracted with methylene chloride (30 ml x 3) and H 2 O (30 ml). The combined organic layer was washed with sat.
  • Step 2 (2-Bromo-4-tert-butyl-phenoxy)-acetic acid ethyl ester
  • 2-bromo-4-tert-butyl-phenol (1900 mg, 8.29 mmol) and bromoethyl acetate (1662 mg, 9.95 mmol) in CH 3 CN (20 ml) was added Cs 2 CO 3 (4.53 mg, 12.44 mmol).
  • Cs 2 CO 3 (4.53 mg, 12.44 mmol)
  • the mixture was stirred for overnight at room temperature.
  • the reaction mixture was diluted with EtOAc and then washed three times with H 2 Oand brine, dried over MgSO 4 , filtered, and concentrated under reduced pressure.
  • the obtained residue was column chromatographed to yield the (2 ⁇ bromo-4-tert-butyl-phenoxy)-acetic acid ethyl ester (2.5 g, 96 %).
  • Step 4 2-(2-Bromo-4-tert-butyl-phenoxy) ⁇ N-(3-fluoro-4-methanesulfonylamino- benzyl)-acetamide 3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (369mg, 1.44 mmol) was suspended in THF and treated with triethylamine (161.2 mg, 0.093 mmol), and then the resulting mixture was stirred for 10mins. (2-Bromo-4-tert- butyl-phenoxy)-acetic acid (417 mg, 1.44 mmol) was added to the reaction mixture followed by DMTMM (440.9 mg, 1.59 mmol) after 10 mins.
  • N-(4-Aminomethyl-3-fluoro-phenyl)-methanesulfonamide HCI salt (133mg, 0.522) and NMP (0.2 ml) were added in 10 ml THF. The mixture was stirred for 10 mins. DMTMM (153 mg, 0.550 mmol) and (2-tert-butyl-4-methyl-phenoxy)- acetic acid (116 mg, 0.521 mmol) were added into the mixture. The reaction mixture was stirred overnight. The reaction solvent was removed in vacuo. The residue was extracted with methylene chloride (30 ml x 3) and H 2 O (30 ml). A combined organic layer was washed with sat. NaHCOs (30ml) and washed with brine (30 ml), dried with MgSO 4 , and concentrated in vacuo. The residue was purified with column chromatography to yield white solid (132 mg).
  • Step 2 (4-tert-Butyl-2-trifluoromethyl-phenoxy)-acetic acid ethyl ester
  • N-(3-Fluoro-4-methanesulfonylamino-benzyl)-2-[3-fluoro-4-(2-isopropyl- [1 ,3]dithiolan-2-yl)-phenoxy]-acetamide (81.5 mg, 0.163 mmol), NIS (84 mg, 0.373 mmol) and TBAH2 (176 mg, 0.583 mmol) were added in 10 ml CH 2 CI 2 at -78 0 C. The mixture was stirred for 2 hrs. The reaction solvent was removed in vacuo. The residue was extracted with methylene chloride (30 ml x 3) and H 2 O (30 ml). A combined organic layer was washed with sat.
  • Step 1 (4-tert-Butyl-3-methyl-phenoxy)-acetic acid ethyl ester
  • Step 2 (4-tert-Butyl-3-methyl-phenoxy)-acetic acid
  • Step 3 2-(4-tert-Butyl-3-methyl-phenoxy)-N-(3-fluoro-4-methanesulfonylamino- benzyl)-acetamide 3-Fluoro-4-methanesulfonylaminobenzylamine hydrochloride (68.7mg, 0.27 mmol) was suspended in THF and treated with triethylamine (27.3 mg, 0.27 mmol) and then the resulting mixture was stirred for 10mins. (4-tert-Butyl-3- methyl-phenoxy)-acetic acid (50 mg, 0.22 mmol) was added to the reaction mixture followed by DMTMM (74.7 mg, 0.27 mmol) after 10 mins.
  • Step 1 (2-Bromo-4-tert-butyl-5-fluoro-phenoxy)-acetic acid ethyl ester
  • 2-bromo-4-tert-butyl ⁇ 5-fluoro-phenol (424 mg, 1.716 mmol) and bromoethyl acetate (429 mg, 2.57 mmol) in CH 3 CN was added C-S 2 CO 3 (838 mg, 2.57 mmol).
  • the mixture was stirred for overnight at room temperature.
  • the reaction mixture was diluted with EtOAc and then washed three times with H 2 O and brine, dried over MgSO 4 , filtered, and concentrated under reduced pressure.
  • the obtained residue was column-chromatographed to yield the (2-bromo-4-tert-butyl-5-fluoro-phenoxy)-acetic acid ethyl ester (527 mg, 92 %).
  • Step 2 (2-Bromo-4-tert-butyl-5-fluoro-phenoxy)-acetic acid (2-Bromo-4-tert-butyl-5-fluoro-phenoxy)-acetic acid ethyl ester (120 mg, 0.36 mmol) in THF was added a solution of 0.5 N-LiOH (2 eq) and the mixture was stirred for 1.5 hrs at room temperature. The resulting residue was dissolved in H 2 O and then washed three times with Et 2 O, acidified with 1 N HCI to pH 1-2. . The solution was extracted three times with methylene chloride and then dried over anhyd. Na 2 SO 4 and concentrated in vacuo to give (2-bromo-4-tert-butyl-5- fluoro-phenoxy)-acetic acid (61 mg, 55 %).
  • Step 3 2-(2-Bromo-4-tert ⁇ butyl-5-fluoro-phenoxy)-N-(3-fluoro-4- methanesulfonylarnino-benzyl)-acetamide
  • Step 1 (4-tert-Butyl-2,6-difluoro-phenoxy)-acetic acid ethyl ester
  • Step 2 (4-tert-Butyl-2,6-difluoro-phenoxy)-acetic acid
  • Step 3 2-(4-tert-Butyl-2,6-difluoro-phenoxy)-N-(3-fluoro-4- methanesulfonylamino-benzyl)-acetamide
  • Step 3 2-(4-tert-Butyl-3-fluoro-phenoxy)-N-(3-ethynyl-5-fluoro-4- methanesulfony!amino-benzyl)-acetamide N-(4-Aminomethyl-2-ethynyI-6-fluoro-phenyl)-methanesulfonamide HCI salt
  • N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide HCI salt 113 mg, 0.407 mmol
  • NMP 0.1 ml
  • DMTMM 123 mg, 0.444 mmol
  • (4-tert-butyl-2- f!uoro-phenoxy)-acetic acid 90.7 mg, 0.481 mmol
  • Step 1 2-Fluoro-4-iodo-6-trifluoromethylphenylamine
  • 2-Fluoro-6-trifluoromethylphenylamine 600.1 mg, 3.35mmol, 1.0eq
  • Iodine monochloride 1.1 eq, 3.68mmol, 598.2mg
  • the reaction mixture was extracted with methylene chloride, washed with H2O and brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 3 (4-Amino-3-fluoro-5 -trifluoromethylbenzyl)-carbamic acid terf-butylester Lithum aluminumhydride (465.72mg, 12.27mmol, 3eq) was suspended in THF at a two-neck round bottom flask. To this suspension was added slowly 4- amino-3-fluoro-5-trifluorobenzonitrile (204.12mg, 2.45mmol, 1 eq) and refluxed at 7O 0 C for one hour. After confirming the completion of the reaction with TLC, to this reaction mixture were added 0.8ml H2O and 0.4ml 5N NaOH, and the resulting mixture was stirred for 30 minutes.
  • Step 4 (3-Fluoro-4-methanesulfonylamino-5-trifluoromethylbenzyl) carbamic acid tert-butyl ester.
  • (4-Amino-3-fluoro-5-trifluoromethylbenzyl)carbamic acid ferf-butyl ester (293.2mg, LUmmol, 1.0eq) was dissolved in pyridine in a dried 50ml two-neck round bottom flask filled with argon.
  • Step 5 ⁇ /-(4-Ethyl-2-fluoro-6-trifluoromethylphenyl)methansylfonamide
  • a solution of (3-fluoro-4-methanesulfonylamino-5- trifluoromethy!benzy])carbamic acid fe/f-butylester (143.6mg, 0.47mmol, 1eq) in methylene chloride was added 1.0ml trifluoroacetic acid. The resulting solution was stirred for 8 hours. After confirming the completion of the reaction, to the reaction was added toluene. The resulting mixture was stirred for 10 minutes, and concentrated under reduced pressure to give a brown syrup (222.2mg, 100.9%).
  • Step 6 2-(4 ⁇ fe/t-Butylphenoxy)-/V-(3-fluoro-4-methanesuifonylamino-5- trifluoromethyl benzyl) acetamide
  • step 1 ethyl 2-[4-(fert-butyl)phenoxy]-2,2-difIuoroacetate
  • step 2 2-[4-(terf-butyI)phenoxy]-2,2-difluoroacetic acid
  • step 3 2-[4-(fe/t-butyl)phenoxy3-2,2-difIuoro- ⁇ /-3-fluoro-4-
  • Example 42 ⁇ /-(3-fluoro-4-methylsulfonylam ⁇ no-benzyI)-2-[4-(1- methylcyclopropyl)phenoxy]acetamide
  • step 1 1-[4-(methoxymethoxy)phenyl]-1-ethanone
  • step 2 1 ⁇ isopropenyl-4-(methoxymethoxy)benzene
  • step 3 1-(methoxymethoxy)-4-(1-methylcyclopropyl)benzene
  • step 4 ethyl 2-[4-(1-methylcyclopropyl)phenoxy]acetate
  • step 6 /V-(3-fluoro-4-methylsulfonylaminobenzyl)-2-[4-(1- methylcyclopropyl)phenoxy]acetamide
  • IR(KBr pellet, cnT 1 ) 2954, 1667, 1586, 1514, 1469, 1365, 1310, 1155, 971 , 817, 756
  • step 1 4-amino-3-fluorobenzenecarbonitrile
  • step 2 4-amino-3-fluoro-5-iodobenzenecarbonitrile 4-amino-3-fluorobenzenecarbonitrile (4.06g, 29.9mmol) and ICI (1.0M in methylene chloride, 40.0 ml, 40.0mmol) were added to methylene chloride (100ml). A reaction mixture was stirred for 20hrs. A reaction was quenched by adding sodium thiosulfate solution. An aqueous solution was extracted with MC. A combined organic solution was washed with H 2 O and brine, dried with Na 2 SOz J , concentrated in vacuo.
  • step 3 4-aminomethyl-2-fluoro-6-iodophenylamine
  • 4-amino-3-fluoro-5-iodo-benzonitrile 84.4 mg, 0.322mmol, l eg.
  • Borane-THF complex solution 1.0M solution in THF, 0.64ml, 0.644mmol, 2eg.
  • the temperature of reaction mixture was raised to room temperature, heated, and refluxed.
  • 5% HCI solution was added into the reaction mixture.
  • the mixture was stirred for 20 minutes.
  • the resulting solution was basified using 1 N KOH, extracted with ether, washed with brine and dried over Na 2 SO 4 .
  • the obtained liquid was concentrated under reduced pressure to yield a pale yellow solid (78.4mg, 80.5%).
  • step 4 (4-amino-3-fluoro-5-iodobenzyl)carbamic acid t-butyl ester
  • a 25 ml two-neck round bottom flask was filled with argon gas and the solution of 4-aminomethyl-2-fluoro-6-iodophenylamine (31.9mg, 0.120mmol, 1 eg.) and triethylamine (18.4/ ⁇ , 0.132mmol, 1.1 eg.) in methylenechloride were put into the flask and then cooled to 0 ° C.
  • step 5 (3-fluoro-5-iodo-4-methanesulfonylamino)carbamic acid t-butyl ester
  • step 6 (3-cyano-5-fluoro-4-methanesulfonylamino)carbamic acid t-butyl ester
  • step 7 N-(4-aminomethyl-2-cyano-6-fluorophenyl)methanesulfonamide (3-cyano-5-fluoro-4-methanesulfonylamino)carbamic acid t-butyl ester (30mg, 0.12mmol) was put into 25ml round-bottom flask and dissolved in methylenechloride(3ml). To the solution was added trifluoroacetic acid (0.5ml) and stirred for one night. After confirming the completion of the reaction with TLC, the reaction solution was concentrated under reduced pressure to yield a brown crude liquid (crude 100%).
  • step 8 2-[4-(te/f-butyl)phenoxy]- ⁇ /-(3-cyano-5-fluoro-4-methylsulfonyl aminobenzyl)acetamide
  • step 9 2-[4-(te/f-butyl)phenoxy]- ⁇ /-(3-cyano-5-fluoro-4- methylsulfonylaminobenzyl)-thioacetamide
  • Step 1 Ethyl 4-acetyl-3-fluoro-phenoxy acetate 3-F!uoro-4-acetyl-phenol (797.7 mg, 5.17 mmol), ethyl bromoacetate (0.61 ml, 5.5 mmol) and cesium carbonate (1.667 g, 5.12 mmol) were added in 70 ml of acetonitrile. The reaction mixture was stirred overnight. The reaction solvent was removed in vacuo. The residue was washed saturated with NaHCO 3 and brine. The residue was dried and then concentrated in vacuo.
  • Step 2 [3-Fluoro-4-(2-methyl-[1 ,3]dithiolan-2-yI)-phenoxy]-acetic acid ethyl ester Ethyl 4-acetyl-3-fluoro-phenoxy acetate (917.6 mg, 3.82 mmol), ethyldithiol
  • Step 3 [3-Fluoro-4-(2-methyl-[1 ,3]dithiolan-2-yI)-phenoxy]-acetic acid [3-Fluoro-4-(2-methyl-[1 ,3]dithiolan-2-yl)-phenoxy]-acetic acid ethyl ester (790 mg) and aqueous 1 M KOH solution (5 ml, 5 mmOI) were added in 50 ml of methanol. The reaction mixtue was stirred for 1.5 hrs. The reaction solvent was removed in vacuo. The residue was neutralized with 1 N HCI solution. An aqueous solution was extracted with EtOAc (30 ml x 3). The combined organic layer was dried with MgSO 4 .
  • Step 4 N-(3-Ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-2-[3-fluoro-4-(2- methyl-[1 ,3]dithiolan-2-yl)-phenoxy]-acetamide
  • N-(4-Aminomethyl-2-ethynyI-6-fluoro-phenyl)-methanesulfonamide HCI salt (205 mg, 0.407 mmol) and NMP (0.3 ml) were added in 10 ml THF. The mixture was stirred for 10 mins. DMTMM (213 mg) and [3-fluoro-4-(2-methyl- [1 ,3]dithiolan-2-yl)-phenoxy]-acetic acid (202 mg, 0.700 mmol) were added into the mixture. The reaction mixture was stirred overnight. The reaction solvent was removed in vacuo. The residue was extracted with MC (30 ml x 3) and H 2 O (30 ml).
  • N-(4-Aminomethyl-3-fluoro-phenyl)-methanesulfonamide HCI salt (153 mg, 0.600 mmol) and NMP (0.2 ml) were added in 10 ml THF. The mixture was stirred for 10 mins. DMTMM (153 mg) and [3-Fluoro-4-(2-methyl-[1,3]dithiolan- 2-yl)-phenoxy]-acetic acid (153 mg, 0.530 mmol) were added into the mixture. The reaction mixture was stirred overnight. The reaction solvent was removed in vacuo. The residue was extracted with MC (30 ml x 3) and H 2 O (30 ml). A combined organic layer was washed with sat. NaHCO 3 (30ml) and washed with brine (30 ml), dried with MgSO 4 , and concentrated in vacuo. The residue was purified with column chromatography to yield white solid (210 mg).
  • N-(4-Aminomethyl-3-fluoro-phenyl)-methanesulfonamide HCI salt 190 mg, 0.746 mmol
  • NMP 0.2 ml
  • DMTMM 181 mg, 0.654 mmol
  • [3-fluoro-4-(2-isopropyl- [1 ,3]dithiolan-2-yl)-phenoxy]-acetic acid (193 mg, 0.645 mmol) were added into the mixture.
  • the reaction mixture was stirred overnight.
  • the reaction solvent was removed in vacuo.
  • the residue was extracted with MC (30 ml x 3) and H 2 O (30 ml).
  • Step 1 (4-tert-Butyl-3-methoxycarbonylmethoxyphenoxy)acetic acid tert-butyl ester
  • Step 3 ⁇ 2-tert-Butyl-5-[(3-fluoro-4- methanesulfonylaminobenzylcarbamoyl)methoxy] phenoxy ⁇ acetic acid methyl ester
  • Example 48 Benzoic acid 2-tert-butyI-5-[(3-fluoro-4- methanesulfonylaminobenzylcarbamoyl)methoxy]phenyl ester
  • Step 1 Benzoic acid ⁇ -tert-butoxycarbonylmethoxy ⁇ -tert-butylphenyl ester
  • Step 2 Benzoic acid 2-tert ⁇ butyl-5-carboxymethoxyphenyI ester To a dried 100ml two neck round bottom flask were added benzoic acid 5-tert- butoxycarbonylmethoxy-2-tert-butylphenyl ester (0.17mmol, 65mg) and CF 3 COOH 0.8ml and the mixture was dissolved in methylene chloride, stirred at room temperature for 4 hours. After confirming the completion of the reaction, the reaction mixture was concentrated under reduced pressure at low temperature, added anh. benzene, and reconcentrated under reduced pressure to yield a white solid (55.4mg.
  • Step 3 Benzoic acid 2-tert-butyl-5-[(3-fluoro-4- methanesulfonylaminobenzylcarbamoyl)methoxy]phenyl ester A dried 100ml two neck round bottom flask was filled with Ar gas and to this flask were added 4-aminomethyl-2-fluorophenylamine (36.18mg, 0.18mmol) and benzoic acid 2-tert-butyl-5-carboxymethoxyphenyl ester (1.1 eq, 0.19mmol, 64mg), and dissolved in DMF.
  • Step 1 6-Trifluoromethylnicotinic acid 5-tert-butoxycarbonylmethoxy-2-tert- butylphenyl ester
  • 6-trifluoromethylnicotinic acid 5-tert-butoxycarbonylmethoxy-2-tert-butylphenyl ester (1.30mmol, 591.3mg) and CF 3 COOH 1.5ml were added in methylene chloride.
  • the reaction mixture was stirred at room temperature for 5 hours. After confirming the completion of the reaction, the reaction mixture was concentrated under reduced pressure at low temperature. To the resulting liquid was added anh.toluene, reconcentrated under reduced pressure to yield a gray syrup (518.1 mg, 100%).
  • Step 3 6-TrifluoromethyInicotinic acid 2-tert-butyl-5-[(3-fluoro-4- methanesulfonylamino benzylcarbamoyl)methoxy]phenyl ester 4-Aminomethyl-2-fluoropheny!amine (54.11mg, 0.27mmol) and 6- trifluoromethylnicotinic acid 2-tert-butyl-5-carboxymethoxy-phenyl ester (1.1 eq, 0.29mmol, 115mg) were added in DMF.
  • Example 50 Acetic acid 2-tert-butyl ⁇ 5-[(3-fluoro-4- methanesulfonylaminobenzylcarbamoyl) methoxy]phenyl ester
  • Step 1 (4-tert-Butyl-3-hydroxyphenoxy)acetic acid tert-butyl ester A dried 100ml two neck round bottom flask was filled with Ar gas and to this flask anh.K 2 CO 3 (3.0 ⁇ q, 1.80mmol, 234.38mmol), 4-tert ⁇ Butylbenzene-1 ,3- diol(100mg, 0.60mmol), and bromoacetic acid tert-butyl ester (1.2eq, 0.72mmol, 106.32 ⁇ ) were added in acetonitrile. The mixture was stirred at -10 ° C for overnight.
  • Step 2 (3-Acetoxy-4-tert-butylphenoxy)acetic acid tert-butyl ester Acetic anhydride(5.0eq, 1.67mmol, 150.96/ ⁇ ), (4-tert-Butyl-3-hydroxyphenoxy)- acetic acid tert-butyl ester (90mg, 0.32mmol) and anh. triethylamine(3eq, 0.96mmol, 134.20/ ⁇ ) were added in anh. methylene chloride. The reaction mixture was stirred at room temperature for overnight. After confirming the completion of the reaction, the mixture was quenched with 5% HCI sol'n and washed with H 2 O and brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 4 Acetic acid 2-tert-butyl ⁇ 5-[(3-fluoro-4- methanesulfonylaminobenzylcarbamoyl) methoxy]phenyl ester 4-Aminomethyl-2-fluorophenylamine (14.94mg, 0.07mmol) and (3-acetoxy-4- tert-butylphenoxy)acetic acid(1.1eq, O.O ⁇ mmol, 20mg) were added in DMF, Triethylamine(5eq, 0.35mmol, 48.73 ⁇ i) and diethylcyanophosphonate(1.2eq, 0.82mmol, 12.43 ⁇ £) were added into the mixture. The reaction mixture was stirred for 12 hours at room temperature.
  • Neonatal (2-3 day old or younger than 2-3 day old) SD rats were put in ice for 5 minutes to anesthetize and disinfected with 70% ethanol.
  • DRG of all part of spinal cord were dissected (Wood et al., 1988, J. Neurosci. 8, pp3208- 3220) and collected in DME/F12 medium to which 1.2g/l sodium bicarbonate, 50mg/l gentamycin were added. The DRG were incubated sequentially at 37 0 C for 30 mins in 200 U/ml collagenase and 2.5mg/ml trypsin, separately.
  • the ganglia were washed twice with DME/F12 medium supplemented with 10% horse serum, triturated through a fire-polished Pasteur pipette, filtered through Nitex 80 membrane to obtain single cell suspension and the suspension was washed once more. This was subjected to centrifugation, then resuspended in cell culture medium at certain level of cell density.
  • DME/F12 medium supplemented with 10% horse serum was diluted with identical medium conditioned by C6 glioma cells 2 days on a confluent monolayer (1 :1), and NGF (Nerve Growth Factor) was added to adjust 200ng/ml as final concentration.
  • cytosine arabinoside Ara-C, 100 ⁇ M
  • medium was changed to one without Ara-C.
  • the resuspended cells were plated at a density of 1500-2000 neurons/well onto Terasaki plates previously coated with 10 ⁇ g/ml poly-D-ornithine.
  • DRG nerve cells from the primary culture of 2 days were equilibrated by washing 4 times with HEPES (1OmM, pH 7.4)-buffered Ca 2+ , Mg 2+ -free HBSS (H-HBSS).
  • H-HBSS HEPES (1OmM, pH 7.4)-buffered Ca 2+ , Mg 2+ -free HBSS
  • the solution in each well was removed from the individual well.
  • Medium containing the test compound plus capsaicin (final concentration 0.5 ⁇ M) and 45 Ca (final concentration 10 ⁇ Ci/ml) in H-HBSS was added to each well and incubated at room temperature for 10 mins. Terasaki plates were washed five times with H-HBSS and dried at room temperature. To each well, 0.3% SDS (10 ⁇ l) was added to elute 45 Ca.
  • Analgesic activity test Mouse writhing test by inducing with phenyl-p-quinone Male ICR mice (mean body weight 25g) were maintained in a controlled lighting environment (12 h on/ 12 h off) for experiment. Animals received an intraperitoneal injection of 0.3ml of the chemical irritant phenyl-p-quinone (dissolved in saline containing 5% ethanol to be a dose of 4.5mg/kg) and 6 mins later, the number of abdominal constrictions was counted in the subsequent 6 mins period.
  • C and T represent the number of writhes in control and compound-treated group, respectively.
  • the compound according to the present invention is useful to prevent or to treat pain, inflammatory disease of the joints, neuropathies, HIV-related neuropathy, nerve injury, neurodegeneration, stroke, urinary bladder hypersensitivity including urinary incontinence, cystitis, stomach duodenal ulcer, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), fecal urgency, gastro-esophageal reflux disease (GERD), Crohn's disease, asthma, chronic obstructive pulmonary disease, cough, neurotic/allergic/inflammatory skin disease, psoriasis, pruritus, prurigo, irritation of skin, eye or mucous membrane, hyperacusis, tinnitus, vestibular hypersensitivity, episodic vertigo, cardiac diseases such as myocardial ischemia, hair growth-related disorders such as effluvium, alopecia, rhinitis, and pancreatitis.
  • cardiac diseases such as myocardial ischemia, hair growth-related disorders such as effl
  • the compound according to the present invention is useful to preventing and treating of pain, which is or which is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine, and other types of headaches.
  • pain which is or which is associated with a condition selected from the group consisting of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, diabetic neuropathic pain, post-operative pain, dental pain, non-inflammatory musculoskeletal pain (including fibromyalgia, myofascial pain syndrome and back pain), migraine, and other types of headaches.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne de nouveaux composés, un isomère de ceux-ci ou des sels de ceux-ci acceptables d'un point de vue pharmaceutique qui sont utilisés comme antagonistes de récepteur vanilloïde (récepteur vanilloïde 1, VR1, TRPV1), ainsi qu'une composition pharmaceutique contenant ceux-ci. Cette invention concerne une composition pharmaceutique permettant de prévenir ou de traiter une maladie telle que la douleur, une maladie inflammatoire des articulations, des neuropathies, une neuropathie liée au VIH, une lésion nerveuse, une neurodégénération, un accident vasculaire cérébral, une hypersensibilité de la vessie y compris une incontinence urinaire, une cystite, un ulcère gastro-duodénal, le syndrome du côlon irritable, une affection abdominale inflammatoire, une défécation impérieuse, un reflux gastro-oesophagien pathologique (GERD), la maladie de Crohn, l'asthme, une bronchopneumopathie chronique obstructive, une toux, une maladie cutanée névrotique/allergique/inflammatoire, un psoriasis, un prurit, un prurigo, une irritation de la peau, de l'oeil ou des muqueuses, une hyperacousie, des acouphènes, une hypersensibilité vestibulaire, un vertige épisodique, des maladies cardiaques telles qu'une ischémie myocardique, des troubles liés à la pousse des cheveux tels qu'un effluvium, une alopécie, une rhinite et une pancréatite.
PCT/KR2007/001881 2006-04-19 2007-04-18 Nouveaux composés, isomère de ceux-ci ou sels de ceux-ci acceptables d'un point de vue pharmaceutique utilisés comme antagoniste de récepteur vanilloïde et compositions pharmaceutiques contenant ceux-ci WO2007120012A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP06008140.3 2006-04-19
EP06008140A EP1857440A1 (fr) 2006-04-19 2006-04-19 Composés, leurs isomères, ou leurs sels pharmaceutiquement acceptables comme antagonistes des récepteurs vanilloides; leurs compositions pharmaceutiques
EP06015725 2006-07-27
EP06015725.2 2006-07-27

Publications (1)

Publication Number Publication Date
WO2007120012A1 true WO2007120012A1 (fr) 2007-10-25

Family

ID=38609733

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2007/001881 WO2007120012A1 (fr) 2006-04-19 2007-04-18 Nouveaux composés, isomère de ceux-ci ou sels de ceux-ci acceptables d'un point de vue pharmaceutique utilisés comme antagoniste de récepteur vanilloïde et compositions pharmaceutiques contenant ceux-ci

Country Status (1)

Country Link
WO (1) WO2007120012A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018185559A1 (fr) * 2017-04-04 2018-10-11 Adama Makhteshim Ltd. Séparation d'isomère de phénol
CN110621654A (zh) * 2017-05-11 2019-12-27 安塔尔遗传学公司 Trpv1调节剂化合物
CN113692276A (zh) * 2019-02-19 2021-11-23 加利福尼亚大学董事会 Nurr1受体调节剂

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002016318A1 (fr) * 2000-08-21 2002-02-28 Pacific Corporation Nouveaux derives de thiourea et compositions pharmaceutiques renfermant ceux-ci
WO2004035533A1 (fr) * 2002-10-17 2004-04-29 Digital Biotech Co., Ltd. Nouveaux composes de n-hydroxythiouree, d'uree et amides et les compositions pharmaceutiques les renfermant
US20060205980A1 (en) * 2005-03-10 2006-09-14 Pfizer, Inc. Substituted N-sulfonylaminophenylethyl-2-phenoxyacetamide compounds as VR1 receptor antagonists

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002016318A1 (fr) * 2000-08-21 2002-02-28 Pacific Corporation Nouveaux derives de thiourea et compositions pharmaceutiques renfermant ceux-ci
WO2004035533A1 (fr) * 2002-10-17 2004-04-29 Digital Biotech Co., Ltd. Nouveaux composes de n-hydroxythiouree, d'uree et amides et les compositions pharmaceutiques les renfermant
US20060205980A1 (en) * 2005-03-10 2006-09-14 Pfizer, Inc. Substituted N-sulfonylaminophenylethyl-2-phenoxyacetamide compounds as VR1 receptor antagonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PARK N.-S. ET AL.: "Bioisosterixm: Interchange of 4-OH to 4-NH2 in Vanillin or Homovanillin Ring of Capsaicinoids", ARCH. PHARM. RES., vol. 22, no. 2, 1999, pages 184 - 188 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018185559A1 (fr) * 2017-04-04 2018-10-11 Adama Makhteshim Ltd. Séparation d'isomère de phénol
CN110573483A (zh) * 2017-04-04 2019-12-13 安道麦阿甘有限公司 苯酚异构体的分离
US11203562B2 (en) 2017-04-04 2021-12-21 Adama Agan Ltd. Separation of phenol isomer
CN110573483B (zh) * 2017-04-04 2023-12-29 安道麦阿甘有限公司 苯酚异构体的分离
CN110621654A (zh) * 2017-05-11 2019-12-27 安塔尔遗传学公司 Trpv1调节剂化合物
CN113692276A (zh) * 2019-02-19 2021-11-23 加利福尼亚大学董事会 Nurr1受体调节剂
EP3927330A4 (fr) * 2019-02-19 2022-11-30 The Regents of the University of California Modulateurs du récepteur nurr1

Similar Documents

Publication Publication Date Title
US7960584B2 (en) Compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same
CA2658925C (fr) Nouveaux derives de sulfonylamino acrylamide, isomeres de ceux-ci, ou sels acceptables sur le plan pharmaceutique de ceux-ci utilises en tant qu'antagonistes du recepteur vanilloide, et compositions pharmaceutiquesles contenant
JP4422034B2 (ja) テトラヒドロ−ナフタレン誘導体
KR101619341B1 (ko) 바닐로이드 수용체 길항체로서의 신규 화합물, 이의 이성질체 또는 약제학적으로 허용가능한 염, 및 이를 함유하는 약학 조성물
EP1882687A1 (fr) Composés hétérocycliques, leur utilisation comme antagonistes du récepteur vanilloide et les compositions pharmaceutiques qui les contiennent
JP4440113B2 (ja) バニロイド受容体アンタゴニストとしてのテトラヒドロ−ナフタレン誘導体
WO2007120012A1 (fr) Nouveaux composés, isomère de ceux-ci ou sels de ceux-ci acceptables d'un point de vue pharmaceutique utilisés comme antagoniste de récepteur vanilloïde et compositions pharmaceutiques contenant ceux-ci
KR20170012152A (ko) Blt 저해 활성을 갖는 신규 화합물 및 이를 유효성분으로 포함하는 염증성 질환 예방 또는 치료용 조성물
WO2006098554A1 (fr) Nouveaux composes, isomere de ceux-ci ou sels pharmaceutiquement acceptables de ceux-ci en tant qu’antagonistes du recepteur vanilloide ; et composition pharmaceutique contenant ceux-ci
KR102221928B1 (ko) 아미노사이클로부탄 유도체들, 이들을 제조하는 방법 및 약물들로서 그들의 용도
JP2003192660A (ja) 尿素誘導体
JP4621654B2 (ja) ヒドロキシ−テトラヒドロ−ナフタレニル尿素誘導体
EP1857440A1 (fr) Composés, leurs isomères, ou leurs sels pharmaceutiquement acceptables comme antagonistes des récepteurs vanilloides; leurs compositions pharmaceutiques
RU2448108C2 (ru) Новые соединения, их изомер или их фармацевтически приемлемые соли в качестве антагониста ванилоидного рецептора и содержащая их фармацевтическая композиция
WO2007142426A1 (fr) Nouveaux composés, leurs isomères ou leurs sels pharmaceutiquement acceptables en tant qu'antagonistes du récepteur vanilloïde et composition pharmaceutique les contenant
DK2054411T3 (en) HIS UNKNOWN RELATIONS, ISOMS THEREOF, OR PHARMACEUTICAL ACCEPTABLE SALTS THEREOF, AS VANILLOID RECEPTOR ANTAGONIST AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07746044

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07746044

Country of ref document: EP

Kind code of ref document: A1