Triazospiro compounds having nociceptin receptor affinity
AssigneeEuro-Celtique S.A.
InventorsDonald Kyle, R. Richard Goehring
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Abstract
Disclosed are compounds of the formula (I) 1 wherein A, R1, R2, R3, R4 and X1 are as disclosed herein. The compounds have affinity for the ORL1 receptor and are useful in the treatment of chronic and acute pain.
Claims32
A compound of the formula (I):
- 6
- wherein
- R2 is selected from the group consisting of hydrogen, C1-10 alkyl, C3-12 cycloalkyl and halogen, said alkyl optionally substituted with an oxo group;
- Z1 is selected from the group consisting of a C1-10 straight or branched alkyl substituted with an oxo or a carbonyl, said carbonyl optionally substituted on the carbon with halogen, C1-5alkyl, C3-5cycloalkyl, phenyl or phenyl-C1-3alkyl;
- alkenyl or alkenylene, wherein said substituted alkyl, alkenyl or alkenylene is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, C1-10 alkyoxy, phenyl, phenyl(C1-3)alkyl, said phenyl and phenylalkyl optionally substituted with 1-3 halogen or C1-10 alkyl;
- R1 is selected from the group consisting of hydrogen, C3-12 cycloalkyl, C3-12 cycloalkenyl, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a heteromonocyclic ring, and a bicyclic ring system of the formula (II)
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- wherein A is a saturated, unsaturated or partially unsaturated ring and X1 and X2 are independently selected from the group consisting of NH, O, S and CH2, wherein said C3-12 cycloalkyl, C3-12 cycloalkenyl, a monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, a heteromonocyclic ring, and a bicyclic ring system of the formula (II) optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-10 alkyl, nitro, trifluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy and benzyloxy are optionally substituted with 1-3 halogen or C1-10 alkyl;
- and pharmaceutically acceptable salts thereof.
A compound selected from the group consisting of
- 8-[4,4-Bis(p-fluorophenyl)butyl]-1-phenyl-1, 3, 8-triazospiro[4.5]decan-4-one;
- 8-[3,3-Bis(phenyl)propyl]-1-phenyl-1, 3, 8-triazospiro[4.5]decan-4-one;
- 8-[3,3-Bis(phenyl)-4-oxo-butyl]-1-phenyl -1-phenyl-1, 3, 8-triazospiro[4.5]decan-4-one;
- 8-[1, 2, 3, 4 tetrahydronaphthyl]-1-phenyl-1, 3, 8-triazospiro[4.5]decan-4-one;
- 8-propylcyclohexyl-1-phenyl-1, 3, 8-triazospiro[4.5]decan-4-one;
- 8-[1, 2, 3, 4 tetrahydronaphthyl]-3-[1-oxo-ethyl]-1-phenyl-1, 3, 8-triazospiro[4.5]decan-4-one;
- 8-fluorophenyloxypropyl-1-phenyl-1, 3, 8-triazospiro[4.5]decan-4-one;
- 8-benzodioxane-1-phenyl-1, 3, 8-triazospiro[4.5]decan-4-one;
- 8-quinoline-methyl-1-phenyl-1, 3, 8-triazospiro[4.5]decan-4-one;
- 8-dibenzocycloheptyl-1-phenyl-1, 3, 8-triazospiro[4.5]decan-4-one;
- 8-pyridyl-methyl-1-phenyl-1, 3, 8-triazospiro[4.5]decan-4-one;
- 8-phenyl-ethyl-1-phenyl-1, 3, 8-triazospiro[4.5]decan-4-one;
- 8-phenyl-benzyl-1-phenyl-1, 3, 8-triazospiro[4.5]decan-4-one;
- 8-benzyloxybenzyl-1-phenyl-1, 3, 8-triazospiro[4.5]decan-4-one;
- 8-naphthylmethyl-1-phenyl-1, 3, 8-triazospiro[4.5]decan-4-one;
- 8-trifluoromethylbenzyl-1-phenyl-1,3,8-triazospiro[4.5]decan-4-one;
- 8-benzylpiperadine-1-phenyl-1, 3, 8-triazospiro[4.5]decan-4-one;
- 8-[phenyl-1-oxo-ethyl]-1-phenyl-1, 3, 8-triazospiro[4.5]decan-4-one;
- 8-[4(p-fluorophenyl)-4-oxo-butyl]-1-phenyl-1, 3, 8-triazospiro[4.5]decan-4-one;
- 8-nitrofurfuryl-1-phenyl-1, 3, 8-triazospiro[4.5]decan-4-one;
- 8-dacalin-1-phenyl-1, 3, 8-triazospiro[4.5]decan-4-one;
- 8[1,4 dimethylpentyl]-1-phenyl-1, 3, 8-triazospiro[4.5]decan-4-one;
- 8[3-oxo-5-phenyl-1,2 cyclohexene]-1-phenyl-1, 3, 8-triazospiro[4.5]decan-4-one;
- 8-furfuryl-1-phenyl-1, 3, 8-triazospiro[4.5]decan-4-one and pharmaceutically acceptable salts thereof.
A method of modulating a response from opioid μ receptors comprising administering a compound having a binding affinity for the μ receptor of less than about 5.0 Ki (nM).
A method of reducing side effects associated with the administration of opioid analgesics in a human patient comprising administering to said human patient an analgesically effective amount of a non-opioid compound which exhibits a binding affinity for the μ receptor of less than about 5.0 Ki (nM).
A method of reducing side effects associated with the administration of opioid analgesics in a human patient comprising administering to said human patient an analgesically effective amount of a non-opioid compound which exhibits a binding affinity specificity for the μ receptor as compared to the +672 receptor (Ki (nM) at the +672 receptor/Ki (nM) at the μ receptor) of greater than about 10,000.
Dependencies are inferred from the claim text.