VANILLOID RECEPTOR LIGANDS AND THEIR USE IN TREATMENTS
First Claim
Patent Images
1. A compound having the structure:
-
wherein;
R1 isor 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;
R4 isR5 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 Rs 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, R11, 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 R1 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;
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;
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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Abstract
Compounds having the general structure
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.
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Citations
9 Claims
-
1. A compound having the structure:
-
wherein; R1 is 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; R4 is 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 Rs 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, R11, 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 R1 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;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;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.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9)
Rb is H, C1-6alkyl, —
C(═
O)C1-6alkyl, C1-6alkyl-O—
Ra; andY2 is —
NRa—
or —
O—
.
-
-
4. A compound according to Claim 2, wherein:
-
R4 is L3 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 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)Ro or —
C1-3alkylRc;Rb is H, C1-6alkyl, —
C(═
O)C1-6alkyl, C1-6alkyl-O—
Ra; andY2 is —
NRb—
or —
O—
.
-
-
5. A compound according to Claim 2, wherein:
-
R4 is 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;Rb is H, C1-6alkyl, —
C(═
O)C1-6alkyl, C1-6alkyl-O—
Ra; andY2 is —
NRb—
or —
O—
.
-
-
6. A compound according to Claim 2, wherein:
-
R4 is 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;Rb is H, C1-6alkyl, —
C(═
O)C1-6alkyl, C1-6alkyl-O—
Ra; andY2 is —
NRb—
or —
O—
.
-
-
7. A compound according to Claim 2, wherein:
-
R4 is Rb is H, C1-6alkyl, —
C(═
O)C1-6alkyl, C1-6alkyl-O—
Ra; andY2 is —
NRa—
or —
O—
.
-
-
8. A compound according to Claim 2, wherein:
-
R4 is R10 is independently, at each instance, H, C1-9alkyl, —
C1-3alkylORa, C1-4haloalkyl, halo, nitro, cyano, —
ORn, —
S(═
O)C1-6alkyl, —
O—
C1-4haloalkyl, —
O—
C1-6alkylNRaRa, —
O—
C1-6alkylORa, —
O—
C1-6alkyl, —
O—
C1-4haloalkyl, —
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)C1-6alkyl, —
O—
C1-4haloalkyl, —
O—
C1-6alkylNRaRa, —
O—
C1-6alkylRo, —
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;C1-6alkylNRaRa; R12 is independently, at each instance, H, C1-9alkyl, —
C1-3alkylORa, C1-4haloalkyl, halo, nitro, cyano, —
ORa, —
S(═
O)C1-6alkyl, —
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;R13 is independently, at each instance, H, C1-9alkyl, —
C1-3alkylORa, C1-4haloalkyl, halo, nitro, cyano, —
ORa, —
S(═
O)C1-6alkyl, —
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; andR14 is independently, at each instance, H, C1-9alkyl, —
C1-3alkylORa, C1-4haloalkyl, halo, nitro, cyano, —
ORa, —
S(═
O)C1-6alkyl, —
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;
wherein one of R10 and R12 is not H.
-
-
9. A pharmaceutical composition comprising a compound according to Claim 1 and a pharmaceutically-acceptable diluent or carrier.
Specification
-
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Current AssigneeAmgen Inc.
-
Original AssigneeAmgen Inc.
-
InventorsChen, Ning, Kelly, Michael G., Wang, Xianghong, Zhu, Jiawang, Bo, Yunxin Y., Liu, Qingyian, Han, Nianhe, Fotsch, Christopher H., Doherty, Elizabeth M., Ognyanov, Vassil I., Chakrabarti, Partha P., Norman, Mark Henry
-
Application NumberUS12/492,376Publication NumberTime in Patent OfficeDaysField of SearchUS Class Current514/230.500CPC Class CodesA61P 1/00 Drugs for disorders of the ...A61P 1/04 for ulcers, gastritis or re...A61P 1/12 AntidiarrhoealsA61P 11/00 Drugs for disorders of the ...A61P 11/02 Nasal agents, e.g. deconges...A61P 11/06 AntiasthmaticsA61P 13/00 Drugs for disorders of the ...A61P 13/10 of the bladderA61P 17/00 Drugs for dermatological di...A61P 17/02 for treating wounds, ulcers...A61P 17/04 AntipruriticsA61P 17/06 AntipsoriaticsA61P 17/14 for baldness or alopeciaA61P 19/02 for joint disorders, e.g. a...A61P 25/00 Drugs for disorders of the ...A61P 25/02 for peripheral neuropathiesA61P 25/04 Centrally acting analgesics...A61P 25/06 Antimigraine agentsA61P 27/02 Ophthalmic agentsA61P 29/00 Non-central analgesic, anti...View All
