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US 7,253,205 B2Granted
Gem-disubstituted cyclohexane derivatives and their use as therapeutic agents
AssigneeMerck Sharp & Dohme Corp.
InventorsJose Luis Castro Pineiro, Kevin Dinnell, Jason Matthew Elliott, Gregory John Hollingworth, Duncan Edward Shaw, Christopher John Swain
Life of this patent
Estimating the term…
Abstract
The present invention relates compounds of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 represent a variety of substituents, ring A is a phenyl or pyridyl ring; d is zero, 1 or 2; and pharmaceutically acceptable salts and N-oxides thereof. The compounds are of particular use in the treatment or prevention of depression, anxiety, pain, inflammation, migraine, emesis or postherpetic neuralgia
Claims16
A compound of the formula (I):
- wherein:
- ring A is a phenyl or pyridyl ring;
- R1 represents hydroxy, C1-6alkyl, fluoroC1-6alkyl, C2-6alkenyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, C1-6alkoxy, fluoroC1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkoxyC1-4alkoxy, fluoroC1-6alkoxyC1-4alkyl, C2-6alkenyloxy, C3-7cycloalkoxy, C3-7cycloalkylC1-4alkoxy, phenoxy, cyano, halogen, NRaRb, SRa, SORa, SO2Ra, OSO2Ra, NRaCORc, CORa, CO2Ra or CONRaRb where Ra and Rb each independently represent hydrogen, C1-4alkyl, C3-5cycloalkyl, fluoroC1-4alkyl or CH2CO2C1-4alkyl, and Rc represents C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl or phenyl;
- R2 represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy;
- or when R2 is adjacent to R1, they may be joined together such that there is formed a 5- or 6-membered saturated or unsaturated ring containing one or two atoms selected from nitrogen, oxygen and sulphur, which ring is optionally substituted by a group selected from C1-4alkyl, CF3, ═O or ═S;
- R3 represents hydrogen, halogen, C1-6alkyl, fluoroC1-6alkyl, C1-6alkoxy, fluoroC1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, cyano, SRa, SORa, SO2Ra, NRaRb, NRaCORc, CORa, CO2Ra, CONRaRb or C1-4alkyl substituted by cyano, CO2Ra or CONRaRb where Ra, Rb and Rc are as previously defined;
- or R3 represents a 5- or 6-membered aromatic heterocyclic group containing 1, 2, 3 or 4 heteroatoms, selected from nitrogen, oxygen and sulphur, which group is optionally substituted by one or two groups selected from C1-6alkyl, C1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, trifluoromethyl, OCF3, NO2, CN, SRa, SORa, SO2Ra, CORa, CO2Ra, phenyl, —(CH2)rNRaRb, —(CH2)rNRaCORb, —(CH2)rCONRaRb, or CH2C(O)Ra, where Ra and Rb are as previously defined and r is zero, 1 or 2;
- R4 represents hydrogen, halogen, C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl, fluoroC1-6alkoxy, hydroxy, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or C1-4alkyl substituted by C1-4alkoxy, wherein Ra and Rb are as previously defined;
- R5 represents hydrogen, halogen, C1-6alkyl, fluoroC1-6alkyl or C1-6alkoxy substituted by C1-4alkoxy;
- R6 represents hydrogen, hydroxy or a C1-4alkyl group optionally substituted by a hydroxy group;
- R7 represents hydrogen, hydroxy, —(CH2)nNR11R12, —(CH2)nCO2Ra, carbocyclyl, C-linked heterocyclyl or heteroaryl, where Ra is as previously defined;
- or R6 and R7 together represent ═O, ═CHCO2Raor —O(CH2)mO—, where Ra is as previously defined;
- R8 represents hydrogen, hydroxy, C1-6alkyl, C1-6alkoxy, hydroxyC1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4alkyl substituted by C1-4alkoxy or C1-6alkoxy substituted by C1-4alkoxy;
- R9 represents hydrogen, halogen or hydroxy and R10 represents hydrogen;
- or R9 and R10 both represent fluorine or together represent oxo (═O);
- R11 and R12 each independently represent hydrogen, C1-6alkyl, C2-6alkenyl, hydroxyC1-6alkyl, (CH2)qC3-7cycloalkyl, (CH2)qaryl, (CH2)qheterocyclyl, CHO, C(O)C1-6alkyl, C(O)(CH2)qC3-7cycloalkyl, C(O)(CH2)qaryl, C(O)(CH2)qheterocyclyl, C(O)(CH2)pNRaRb, (CH2)qCO2C1-6alkyl, CO2(CH2)qC3-7cycloalkyl, CO2(CH2)qaryl, CO2(CH2)qheterocyclyl, CO2(CH2)qNRaRb, (CH2)pNRaCORb, (CH2)pNRaCO2Rb, (CH2)qCONRaaryl or (CH2)qCONRaheterocyclyl where Ra and Rb are as previously defined;
- or R11 and R12, together with the nitrogen atom to which they are attached, represent a ring selected from the group consisting of:
- R13 and R14 each independently represent hydrogen, halogen, hydroxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, hydroxyC1-6alkyl, fluoroC1-6alkyl, C1-6alkoxy, (CH2)qC3-7cycloalkyl, (CH2)qaryl, (C2-6alkenyl)aryl, (C2-6alkynyl)aryl, (CH2)qheterocyclyl, (CH2)qNRaRb, O(CH2)qC3-7cycloalkyl, O(CH2)qaryl, O(CH2)qheterocyclyl, O(CH2)pNRaRb, OC(O)C1-6alkyl, C(O)C1-6alkyl, C(O)(CH2)qaryl, C(O)(CH2)qheterocyclyl, C(O)(CH2)qNRaRb, CO2H, CO2C1-6alkyl, CO2(CH2)qC3-7cycloalkyl, CO2(CH2)qaryl, CO2(CH2)qheterocyclyl or CO2(CH2)pNRaRb, where Ra and Ra are as previously defined;
- or, when they are attached to the same carbon atom, R13 and R14 may together represent ═O, ═CHCO2Ra, —O(CH2)mO—, —CH2O(CH2)s—, —CH2OCH2C(O)—, —CH2OCH2CH(OH)—, —CH2OCH2C(CH3)2—, —CH2OC(CH3)2CH2—, —C(CH3)2OCH2CH2—, —CH2C(O)OCH2—, —OC(O)CH2CH2—, —C(O)OCH2CH2—, —C(O)OC(CH3)2CH2—, —C(O)OCH2C(CH3)2—, —OCH2(CH2)s—, —OC(CH3)2CH2CH2—, —OCH2C(CH3)2CH2—, —OCH2CH2C(CH3)2—, —OCH2CH═CHCH2—, —OCH2CH(OH)CH2CH2—, —OCH2CH2CH(OH)CH2—, —OCH2C(O)CH2CH2—, —OCH2CH2C(O)CH2—, or a group of the formula
- or, where they are attached to adjacent carbon atoms, R13 and R14 may together represent —OCH2CH2— or —OCH2CH(OH)—, or R13 and R14 may together form a fused benzene ring;
- or, R13 and R14 together form a C1-2alkylene bridge across the pyrrolidine, piperidine or hexamethyleneimine ring to which they are attached;
- R15 represents hydrogen, C1-6alkyl, (CH2)qC3-7cycloalkyl, (CH2)qaryl, (CH2)qheterocyclyl, CHO, C(O)C1-6alkyl, C(O)(CH2)qC3-7cycloalkyl, C(O)(CH2)qaryl, C(O)(CH2)qheterocyclyl, CO2C1-6alkyl, CO2(CH2)qC3-7cycloalkyl, CO2(CH2)qaryl, CO2(CH2)qheterocyclyl or CO2(CH2)pNRaRb, where Ra and Rb are as previously defined;
- or, where they are attached to adjacent carbon atoms, R15 and R16 may together form a fused imidazolyl or triazolyl ring;
- R16 and R17 each independently represent hydrogen, halogen, hydroxy, C1-6alkyl or oxo (═O);
- R18 represents hydrogen, halogen, hydroxy, C1-4alkyl, hydroxyC1-4alkyl or fluoroC1-4alkyl;
- d is 1;
- n is zero, 1 or 2;
- m is 1 or 2;
- p is 1, 2, 3 or 4;
- q is zero, 1, 2, 3 or 4;
- and
- s is 1, 2 or 3;
- or a pharmaceutically acceptable salt or N-oxide thereof.
30 more elements
A compound which is selected from the group consisting of
- (RS)-3-[3,5-bis(trifluoromethyl)phenyl]-1-(1,4-dioxa-8-phenylspiro[4.5]decan-8-yl)-2-pyrrolidinone;
- (RS)-3-hydroxy-[3,5-bis(trifluoromethyl)phenyl]-1-(1,4-dioxa-8-phenylspiro[4.5]decan-8-yl)-2-pyrrolidinone;
- (RS)-3-methyl-[3,5-bis(trifluoromethyl)phenyl]-1-(1,4-dioxa-8-phenylspiro-[4.5]decan-8-yl)-2-pyrrolidinone;
- (RS)-3-[3,5-bis(trifluoromethyl)phenyl]-1-(4-oxo-1-phenylcyclohexyl)-2-pyrrolidinone;
- (RS)-3-hydroxy-3-[3,5-bis(trifluoromethyl)phenyl]-1-(4-oxo-1-phenylcyclohexyl)-2-pyrrolidinone;
- (RS)-3-methyl-3-[3,5-bis(trifluoromethyl)phenyl]-1-(1,4-dioxa-8-phenylspiro[4.5]decan-8-yl)-2-pyrrolidinone;
- trans-(RS)-3-[3,5-bis(trifluoromethyl)phenyl]-1-(4-dimethylamino-1-phenylcyclohexyl)-2-pyrrolidinone;
- and pharmaceutically acceptable salts and N-oxides thereof.
5 more elements
A compound of the formula (I):
- wherein:
- ring A is a phenyl ring;
- R1 represents hydroxy, C1-6alkyl, fluoroC1-6alkyl, C2-6alkenyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, C1-6alkoxy, fluoroC1-6alkoxy, C1-6alkoxyC1-4alkyl, C1-6alkoxyC1-4alkoxy, fluoroC1-6alkoxyC1-4alkyl, C2-6alkenyloxy, C3-7cycloalkoxy, C3-7cycloalkylC1-4alkoxy, phenoxy, cyano, halogen, NRaRb, SRa, SORa, SO2Ra, OSO2Ra, NRaCORc, CORa, CO2Raor CONRaRb where Raand Rb each independently represent hydrogen, C1-4alkyl, C3-5cycloalkyl, fluoroC1-4alkyl or CH2CO2C1-4alkyl, and Rc represents C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl or phenyl;
- R2 represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy;
- or when R2 is adjacent to R1, they may be joined together such that there is formed a 5-or 6-membered saturated or unsaturated ring containing one or two atoms selected from nitrogen, oxygen and sulphur, which ring is optionally substituted by a group selected from C1-4alkyl, CF3, ═O or ═S;
- R3 represents hydrogen, halogen, C1-6alkyl, fluoroC1-6alkyl, C1-6alkoxy, fluoroC1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, cyano, SRa, SORa, SO2Ra, NRaRb, NRaCORc, CORa, CO2Ra, CONRaRb or C1-4alkyl substituted by cyano, CO2Ra or CONRaRb where Ra, Rb and Rc are as previously defined;
- or R3 represents a 5- or 6-membered aromatic heterocyclic group containing 1, 2, 3 or 4 heteroatoms, selected from nitrogen, oxygen and sulphur, which group is optionally substituted by one or two groups selected from C1-6alkyl, C1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, trifluoromethyl, OCF3, NO2, CN, SRa, SORa, SO2Ra, CORa, CO2Ra, phenyl, —(CH2)rNRaRb, —(CH2)rNRaCORb, —(CH2)rCONRaRb, or CH2C(O)Ra, where Raand Rb are as previously defined and r is zero, 1 or 2;
- R4 represents hydrogen, halogen, C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl, fluoroC1-6alkoxy, hydroxy, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or C1-4alkyl substituted by C1-4alkoxy, wherein Raand Rb are as previously defined;
- R5 represents hydrogen, halogen, C1-6alkyl, fluoroC1-6alkyl or C1-6alkoxy substituted by C1-4alkoxy;
- R6 represents hydrogen, hydroxy or a C1-4alkyl group optionally substituted by a hydroxy group;
- R7 represents hydrogen, hydroxy, —(CH2)nNR11R12, —(CH2)nCO2Ra, carbocyclyl, C-linked heterocyclyl or heteroaryl, where Ra is as previously defined;
- or R6 and R7 together represent ═O, ═CHCO2Ra or —O(CH2)mO—, where Ra is as previously defined;
- R8 represents hydrogen, hydroxy, C1-6alkyl, C1-6alkoxy, hydroxyC1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4alkyl substituted by C1-4alkoxy or C1-6alkoxy substituted by C1-4alkoxy;
- R9 represents hydrogen, halogen or hydroxy and R10 represents hydrogen;
- or R9 and R10 both represent fluorine or together represent oxo (═O);
- R11 and R12 each independently represent hydrogen, C1-6alkyl, C2-6alkenyl, hydroxyC1-6alkyl, (CH2)qC3-7cycloalkyl, (CH2)qaryl, (CH2)qheterocyclyl, CHO, C(O)C1-6alkyl, C(O)(CH2)qC3-7cycloalkyl, C(O)(CH2)qaryl, C(O)(CH2)qheterocyclyl, C(O)(CH2)pNRaRb, (CH2)qCO2C1-6alkyl, CO2(CH2)qC3-7cycloalkyl, CO2(CH2)qaryl, CO2(CH2)qheterocyclyl, CO2(CH2)pNRaRb, (CH2)pNRaCORb, (CH2)pNRaCO2Rb, (CH2)qCONRaaryl or (CH2)qCONRaheterocyclyl where Ra and Rb are as previously defined;
- or R11 and R12, together with the nitrogen atom to which they are attached, represent a ring selected from the group consisting of:
- R13 and R14 each independently represent hydrogen, halogen, hydroxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, hydroxyC1-6alkyl, fluoroC1-6alkyl, C1-6alkoxy, (CH2)qC3-7cycloalkyl, (CH2)qaryl, (C2-6alkenyl)aryl, (C2-6alkynyl)aryl, (CH2)qheterocyclyl, (CH2)qNRaRb, O(CH2)qC3-7cycloalkyl, O(CH2)qaryl, O(CH2)qheterocyclyl, O(CH2)pNRaRb, OC(O)C1-6alkyl, C(O)C1-6alkyl, C(O)(CH2)qaryl, C(O)(CH2)qheterocyclyl, C(O)(CH2)qNRaRb, CO2H, CO2C1-6alkyl, CO2(CH2)qC3-7cycloalkyl, CO2(CH2)qaryl, CO2(CH2)qheterocyclyl or CO2(CH2)pNRaRb, where Ra and Rb are as previously defined;
- or, when they are attached to the same carbon atom, R13 and R14 may together represent ═O, ═CHCO2Ra, —O(CH2)mO—, —CH2O(CH2)s—, —CH2OCH2C(O)—, —CH2OCH2CH(OH)—, —CH2OCH2C(CH3)2—, —CH2OC(CH3)2CH2—, —C(CH3)2OCH2CH2—, —CH2C(O)OCH2—, —OC(O)CH2CH2—, —C(O)OCH2CH2—, —C(O)OC(CH3)2CH2—, —C(O)OCH2C(CH3)2—, —OCH2(CH2)s—, —OC(CH3)2CH2CH2—, —OCH2C(CH3)2CH2—, —OCH2CH2C(CH3)2—, —OCH2CH═CHCH2—, —OCH2CH(OH)CH2CH2—, —OCH2CH2CH(OH)CH2—, —OCH2C(O)CH2CH2—, —OCH2CH2C(O)CH2—, or a group of the formula
- or, where they are attached to adjacent carbon atoms, R13 and R14 may together represent —OCH2CH2— or —OCH2CH(OH)—, or R13 and R14 may together form a fused benzene ring;
- or, R13 and R14 together form a C1-2alkylene bridge across the pyrrolidine, piperidine or hexamethyleneimine ring to which they are attached;
- R15 represents hydrogen, C1-6alkyl, (CH2)qC3-7cycloalkyl, (CH2)qaryl, (CH2)qheterocyclyl, CHO, C(O)C1-6alkyl, C(O)(CH2)qC3-7cycloalkyl, C(O)(CH2)qaryl, C(O)(CH2)qheterocyclyl, CO2C1-6alkyl, CO2(CH2)qC3-7cycloalkyl, CO2(CH2)qaryl, CO2(CH2)qheterocyclyl or CO2(CH2)pNRaRb, where Ra and Rb are as previously defined;
- or, where they are attached to adjacent carbon atoms, R15 and R16 may together form a fused imidazolyl or triazolyl ring;
- R16 and R17 each independently represent hydrogen, halogen, hydroxy, C1-6alkyl or oxo (═O);
- R18 represents hydrogen, halogen, hydroxy, C1-4alkyl, hydroxyC1-4alkyl or fluoroC1-4alkyl;
- d is 1;
- n is 1;
- m is 1 or 2;
- p is 1, 2, 3 or 4;
- q is zero, 1, 2, 3 or 4;
- and
- s is 1, 2 or 3;
- or a pharmaceutically acceptable salt or N-oxide thereof.
30 more elements
Dependencies are inferred from the claim text.