US 2003/0195201 A1 · Vanilloid receptor ligands and their use in treatments

Abstract

Compounds having the general structure 1 and compositions containing them, for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritis, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.

A compound having the structure:

699
wherein:
R1 is
700
or a naphthyl or saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the naphthyl, heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R5, R6 and R7;
R2 is H, hydroxy, halo, C1-6alkyl substituted by 0, 1 or 2 substituents selected from R10,
701
or a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents independently selected from R5, R6 and R7;
or R1 and R2 together are
702
R3 is H or C1-4alkyl;
or R1 and R3 together are
703
R4 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the heterocycle and bridge are substituted by 0, 1, 2 or 3 substituents independently selected from C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, —ORa, —S(═O)nC1-6alkyl, —O—C1-4haloalkyl, —O—C1-6alkylNRaRa, —O—C1-6alkylORa, —O—C1-6alkylC(═O)ORa, —NRaRa, —NRa—C1-4haloalkyl, —NRa—C1-6alkylNRaRa, —NRa—C1-6alkylORa, —C(═O)C1-6alkyl, —C(═O)OC1-6alkyl, —OC(═O)C1-6alkyl, —C(═O)NRaC1-6alkyl and —NRaC(═O)C1-6alkyl;
or R4 is 10-membered bicyclic ring comprising fused 6-membered rings, containing 0, 1, 2, 3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6-membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, ORa, NRaRa, C1-6alkyl and C1-3haloalkyl;
and saturated carbon atoms may be additionally substituted by ═O;
except that when R1 is 4-chlorophenyl, 3-bromophenyl, 3-nitrophenyl, 2-nitro-3-chlorophenyl, 3,4-methylenedioxyphenyl, 3-methylthiophenyl or 2,3,4-methoxyphenyl, then R4 is not phenyl substituted by 1 or 2 substituents selected from halo and C1-4alkyl;
and R1 and R4 are not both 3,4-methylenedioxyphenyl;
and when R1 is 4-trifluoromethylphenyl, then R4 is not pyridinyl, 2-methyl-4-aminoquinolinyl or 3,3-dimethyl-1,3-dihydro-indol-2-on-6-yl;
R5 is independently, at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, —OC1-6alkyl, —O—C1-4haloalkyl, —O—C1-6alkylNRaRa, —O—C1-6alkylORa, —NRaRa, —NRa—C1-4haloalkyl, —NRa—C1-6alkylNRaRa or —NRa—C1-6alkylORa;
or R5 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O, N and S;
R6 is independently, at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, —OC1-6alkyl, —O—C1-4haloalkyl, —O—C1-6alkylNRaRa, —O—C1-6alkylORa, —NRaRa, —NRa—C1-4haloalkyl, —NRa—C1-6alkylNRaRa or —NRa—C1-6alkylORa;
or R5 and R6 together are a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the bridge are substituted by 0, 1, 2 or 3 substituents selected from halo, C1-6alkyl, (═O), —OC1-6alkyl, —NRaC1-6alkyl, —C1-6alkylORa and C1-6alkylNRaRa, and the available N atoms of the bridge are substituted by Ra, —C1-6alkylORa or C1-6alkylNRaRa;
R7 is independently, at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, —OC1-6alkyl, —O—C1-4haloalkyl, —O—C1-6alkylNRaRa, —O—C1-6alkylORa, —NRaRa, —NRa—C1-4haloalkyl, —NRa—C1-6alkylNRaRa or —NRa—C1-6alkylORa;
R8 is independently, at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, —OC1-6alkyl, —O—C1-4haloalkyl, —O—C1-6alkylNRaRa, —O—C1-6alkylORa, —NRaRa, —NRa—C1-4haloalkyl, —NRa—C1-6alkylNRaRa or —NRa—C1-6alkylORa;
or R7 and R8 together are a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the bridge are substituted by 0, 1, 2 or 3 substituents selected from halo, C1-6alkyl, (═O), —O—C1-6alkyl, —NRaC1-6alkyl, —C1-6alkylORa and C1-6alkylNRaRa, and the available N atoms of the bridge are substituted by Ra, —C1-6alkylORa or C1-6alkylNRaRa;
R9 is independently, at each instance, H, C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, —OC1-6alkyl, —O—C1-4haloalkyl, —O—C1-6alkylNRaRa, —O—C1-6alkylORa, —NRaRa, —NRa—C1-4haloalkyl, —NRa—C1-6alkylNRaRa or —NRa—C1-6alkylORa;
R10 is independently, at each instance, H, C1-9alkyl, —C1-3alkylORa, C1-4haloalkyl, halo, nitro, cyano, —ORa, —S(═O)nC1-6alkyl, —O—C1-4haloalkyl, —O—C1-6alkylNRaRa, —O—C1-6alkylORa, —O—C1-6alkylC(═O)ORa, —NRaRa, —NRa—C1-4haloalkyl, —NRa—C1-6alkylNRaRa, —NRa—C1-6alkylORa, —C(═O)C1-6alkyl, —C(═O)OC1-6alkyl, —OC(═O)C1-6alkyl, —C(═O)NRaC1-6alkyl or —NRaC(═O)C1-6alkyl;
R11 is independently, at each instance, H, C1-9alkyl, —C1-3alkylORa, C1-4haloalkyl, halo, nitro, cyano, —ORa, —S(═O)nC1-6alkyl, —O—C1-4haloalkyl, —O—C1-6alkylNRaRa, —O—C1-6alkylRc, —O—C1-6alkylORa, —O—C1-6alkylC(═O)ORa, —NRaRa, —NRa—C1-4haloalkyl, —NRa—C1-6alkylNRaRa, —NRa—C1-6alkylORa, —C(═O)C1-6alkyl, —C(═O)OC1-6alkyl, —OC(═O)C1-6alkyl, —C(═O)NRaC1-6alkyl or —NRaC(═O)C1-6alkyl;
or R10 and R11 together are a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, ═O, —ORa, —C1-6alkylORa, —C1-6alkyl, —NRaRa, —C1-6alkylNRaRa, —C(═O)ORa, —C(═O)NRaRa, —C1-3alkylC(═O)ORa, —C1-3alkylC(═O)NRaRa, —OC(═O)C1-6alkyl, —NRaC(═O)C1-6alkyl, —C1-3alkylOC(═O)C1-6alkyl or —C1-3alkylNRaC(═O)C1-6alkyl, and any nitrogen atoms in the bridge are substituted by H, —C1-6alkylORa, —C1-6alkyl, —C1-6alkylNRaRa, —C1-3alkylC(═O)ORa, —C1-3alkylC(═O)NRaRa, —C1-3alkylOC(═O)C1-6alkyl, —C1-3alkylNRaC(═O)C1-6alkyl, —C(═O)Rc or —C1-3alkylRc;
wherein if R10, R12, R13 and R14 are all H, then R11 is not —O—C1-6alkylNRaRa or —O—C1-6alkylORa;
R12 is independently, at each instance, H, C1-9alkyl, —C1-3alkylORa, C1-4haloalkyl, halo, nitro, cyano, —ORa, —S(═O)nC1-6alkyl, —O—C1-4haloalkyl, —O—C1-6alkylNRaRa, —O—C1-6alkylORa, —O—C1-6alkylC(═O)ORa, —NRaRa, —NRa—C1-4haloalkyl, —NRa—C1-6alkylNRaRa, —NRa—C1-6alkylORa, —C(═O)C1-6alkyl, —C(═O)OC1-6alkyl, —OC(═O)C1-6alkyl, —C(═O)NRaC1-6alkyl or —NRaC(═O)C1-6alkyl;
or R11 and R12 together are a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the each of the carbon atoms in the bridge is substituted by H, ═O, —ORa, —C1-6alkylORa, —C1-6alkyl, —NRaRa, —C1-6alkylNRaRa, —C(═O)ORa, —C(═O)NRaRa, —C1-3alkylC(═O)ORa, —C1-3alkylC(═O)NRaRa, —OC(═O)C1-6alkyl, —NRaC(═O)C1-6alkyl, —C1-3alkylOC(═O)C1-6alkyl or —C1-3alkylNRaC(═O)C1-6alkyl, and any nitrogen atoms in the bridge are substituted by H, —C1-6alkylORa, —C1-6alkyl, —C1-6alkylNRaRa, —C1-3alkylC(═O)ORa, —C1-3alkylC(═O)NRaRa, —C1-3alkylOC(═O)C1-6alkyl, —C1-3alkylNRaC(═O)C1-6alkyl, —C(═O)Rc or —C1-3alkylRc;
when R1 is 4-C1-6alkylphenyl or 2,4-dimethylphenyl, then R11 is C1-9alkyl, C1-4haloalkyl, halo, nitro, cyano, —ORa, —S(═O)nC1-6alkyl, —O—C1-4haloalkyl, —O—C1-6alkylNRaRa, —O—C1-6alkylRc, —O—C1-6alkylORa, —O—C1-6alkylC(═O)ORa, —NRaRa, —NRa—C1-4haloalkyl, —NRa—C1-6alkylNRaRa, —NRa—C1-6alkylORa, —C(═O)C1-6alkyl, —C(═O)OC1-6alkyl, —OC(═O)C1-6alkyl, —C(═O)NRaC1-6alkyl or —NRaC(═O)C1-6alkyl;
or R10 and R11 together are —L3—NRa—, respectively, or —L4—O—, respectively;
or R11 and R12 are —NRa—L3—, —L3—NRa—, —O—L4— or —L4—O—;
or R12 is —NRaRb;
or R4 is 10-membered bicyclic ring comprising fused 6-membered rings, containing 0, 1, 2, 3 or 4 N atoms with the remainder being carbon atoms, with at least one of the 6-membered rings being aromatic, wherein the carbon atoms are substituted by H, halo, ORa, NRaRa, C1-6alkyl and C1-3haloalkyl;
and saturated carbon atoms may be additionally substituted by ═O;
or R4 is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 atoms selected from O, N and S that is optionally vicinally fused with a saturated or unsaturated 3- or 4-atom bridge containing 0, 1, 2 or 3 atoms selected from O, N and S with the remaining atoms being carbon, so long as the combination of O and S atoms is not greater than 2, wherein the carbon atoms of the heterocycle and bridge are substituted by 1, 2 or 3 substituents independently selected from C2-9alkyl, C1-4haloalkyl, halo, nitro, cyano, —ORa, —S(═O)nC1-6alkyl, —O—C1-4haloalkyl, —O—C1-6alkylNRaRa, —O—C1-6alkylORa, —O—C1-6alkylC(═O)ORa, —NRaRa, —NRa—C1-4haloalkyl, —NRa—C1-6alkylNRaRa, —NRa—C1-6alkylORa, —C(═O)C1-6alkyl, —C(═O)OC1-6alkyl, —OC(═O)C1-6alkyl, —C(═O)NRaC1-6alkyl and —NRaC(═O)C1-6alkyl;
R13 is independently, at each instance, H, C1-9alkyl, —C1-3alkylORa, C1-4haloalkyl, halo, nitro, cyano, —ORa, —S(═O)nC1-6alkyl, —O—C1-4haloalkyl, —O—C1-6alkylNRaRa, —O—C1-6alkylORa, —O—C1-6alkylC(═O)ORa, —NRaRa, —NRa—C1-4haloalkyl, —NRa—C1-6alkylNRaRa, —NRa—C1-6alkylORa, —C(═O)C1-6alkyl, —C(═O)OC1-6alkyl, —OC(═O)C1-6alkyl, —C(═O)NRaC1-6alkyl or —NRaC(═O)C1-6alkyl;
R14 is independently, at each instance, H, C1-9alkyl, —C1-3alkylORa, C1-4haloalkyl, halo, nitro, cyano, —ORa, —S(═O)nC1-6alkyl, —O—C1-4haloalkyl, —O—C1-6alkylNRaRa, —O—C1-6alkylORa, —O—C1-6alkylC(═O)ORa, —NRaRa, —NRa—C1-4haloalkyl, —NRa—C1-6alkylNRaRa, —NRa—C1-6alkylORa, —C(═O)C1-6alkyl, —C(═O)OC1-6alkyl, —OC(═O)C1-6alkyl, —C(═O)NRaC1-6alkyl or —NRaC(═O)C1-6alkyl;
Ra is independently, at each instance, H, phenyl, benzyl or C1-6alkyl;
Rb is H, C1-6alkyl, —C(═O)C1-6alkyl, C1-6alkyl-O—Ra;
Rc is phenyl substituted by 0, 1 or 2 groups selected from halo, C1-3haloalkyl, —ORa and —NRaRa;
or Rc is a saturated or unsaturated 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein no more than 2 of the ring members are O or S, wherein the heterocycle is optionally fused with a phenyl ring, and the carbon atoms of the heterocycle are substituted by 0, 1 or 2 oxo groups, wherein the heterocycle or fused phenyl ring is substituted by 0, 1, 2 or 3 substituents selected from halo, C1-3haloalkyl, —ORa and —NRaRa;
L1 is a bond, —CH2CH2— or —CH═CH—;
L2 is NRa, O, S(═O)n, —N═CH—, —CH2NRa—, —CH═N— or —NRaCH2—;
L3 is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and 0, 1 or 2 atoms independently selected from O, N and S, wherein the each of the carbon atoms in the bridge is substituted by H, ═O, —ORa, —C1-6alkylORa, —C1-6alkyl, —NRaRa, —C1-6alkylNRaRa, —C(═O)ORa, —C(═O)NRaRa, —C1-3alkylC(═O)ORa, —C1-3alkylC(═O)NRaRa, —OC(═O)C1-6alkyl, —NRaC(═O)C1-6alkyl, —C1-3alkylOC(═O)C1-6alkyl or —C1-3alkylNRaC(═O)C1-6alkyl, and any nitrogen atoms in the bridge are substituted by H, —C1-6alkylORa, —C1-6alkyl, —C1-6alkylNRaRa, —C1-3alkylC(═O)ORa, —C1-3alkylC(═O)NRaRa, —C1-3alkylOC(═O)C1-6alkyl, —C1-3alkylNRaC(═O)C1-6alkyl, —C(═O)Rc or —C1-3alkylRc;
L4 is a 2- or 3-atom, saturated or unsaturated, bridge containing 1, 2 or 3 carbon atoms and 0 or 1 atoms independently selected from O, N and S, wherein at least one of the carbon atoms in the bridge is substituted by ═O, —ORa, —C1-6alkylORa, —C1-6alkyl, —NRaRa, —C1-6alkylNRaRa, —C(═O)OC1-6alkyl, —C(═O)NRaRa, —C1-3alkylC(═O)ORa, —C1-3alkylC(═O)NRaC1-6alkyl, —OC(═O)C1-6alkyl, —NRaC(═O)C1-6alkyl, —C1-3alkylOC(═O)C1-6alkyl or —C1-3alkylNRaC(═O)C1-6alkyl, and any nitrogen atoms in the bridge are substituted by H, —C1-6alkylORa, —C1-6alkyl, —C1-6alkylNRaRa, —C1-3alkylC(═O)ORa, —C1-3alkylC(═O)NRaRa, —C1-3alkylOC(═O)C1-6alkyl, —C1-3alkylNRaC(═O)C1-6alkyl, —C(═O)Rc or —C1-3alkylRc;
X is O, S or NRa;
or X and R2 together are ═N—CH═CH—, ═C—O—, ═C—S—, or ═C—NRa—;
Y is NH or O;
and
n is independently, at each instance, 0, 1 or 2;
with the proviso that when R1 is 4-chlorophenyl, then R4 is not 3-methoxyphenyl.

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Vanilloid receptor ligands and their use in treatments

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Vanilloid receptor ligands and their use in treatments

Life of this patent

Abstract

Claims201