Patent EA-001574-B1 (EA)
Title: Spiro-piperidine derivatives and their use as therapeutic agents.
Inventor: BAKER RAYMOND
IPC: A61K31/395
Filed: 1997-06-17
Abstract: 1. A compound of the formula (I):   wherein R<1> represents hydrogen, hydroxy, C1-6-alkyl, C2-6-alkenyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-4-alkyl, C1-6-alkoxy, fluoro-C1-6-alkoxy, C1-6-alkoxy-C1-4-alkyl, C1-6-alkoxy-C1-4-alkoxy, fluoro-C1-6-alkoxy-C1-4-alkyl, C2-6-alkenyloxy, C3-7-cycloalkoxy, C3-7-cycloalkyl-C1-4-alkoxy, phenoxy, benzyloxy, cyano, halogen, NR<a>R<b>, SR<a>, SOR<a>, SO2R<a>, OSO2R<a>, NR<a>COR<14>, COR<a>, CO2R<a> or CONR<a>R<b> where R<a> and R<b> each independently represent hydrogen, C1-4-alkyl- or fluoro-C1-4-alkyl; R<2> represents hydrogen, halogen, C1-6-alkyl- or C1-6-alkoxy group; or when R<2> is adjacent to R<1>, 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 C1-4-alkyl, CF3, =O or =S; R<3> represents hydrogen, halogen, C1-6-alkyl, fluoro-C1-6-alkyl, C1-6-alkoxy, fluoro-C1-6-alkoxy, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-4-alkyl, cyano, SR<a>, SOR<a>, SO2R<a>, NR<a>R<b>, NR<a>COR<14>, COR<a>, CO2R<a>, CONR<a>R<b> or C1-4-alkyl group substituted by cyano, CO2R<a> or CONR<a>R<b> where R<a> and R<b> are as previously defined; R<4> represents hydrogen, halogen, C1-6-alkyl, C1-6-alkoxy, CF3, OCF3, NO2, CN, SR<a>, SOR<a>, SO2R<a>, CO2R<a>, CONR<a>R<b>, C2-6-alkenyl, C2-6-alkynyl- or C1-4-alkyl group substituted by C1-4-alkoxy group, where R<a> and R<b> are as previously defined; R<5> represents hydrogen, halogen, C1-6-alkyl, CF3 or C1-6-alkoxy substituted by C1-4-alkoxy group; R<6> represents hydrogen, COR<a>, CO2R<a>, COCONR<a>R<b>, COCO2R<a>, C1-6-alkyl optionally substituted by a group selected from (CO2R<a>, CONR<a>R<b>, hydroxy, CN, COR<a>, NR<a>R<b>, C(NOH)NR<a>R<b>, CONH-phenyl-(C1-4-alkyl-), COCO2R<a>, CONHNR<a>R<b>, C(S)NR<a>R<b>, CONR<a>C1-6-alkyl-R<12>, CONR<13>C2-6-alkenyl, CONR<13>C2-6-alkynyl, COCONR<a>R<b>, CONR<a>C(NR<b>)NR<a>R<b>, CONR<a>-heteroaryl, and phenyl optionally substituted by one, two or three substituents selected from C1-6-alkyl, C1-6-alkoxy, halogen and trifluoromethyl, wherein heteroaryl represents a group, selected from pyrrolyl, furanyl, thienyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, izoxazolyl, thiazolyl, izothiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, oxadiazolyl, thiadiazolyl, triazinyl, tetrazolyl; or R<6> represents a group of the formula -CH2C [triple bond] CCH2NR<7>R<8> where R<7> and R<8> are as defined below; or R<6> represents C1-6-alkyl, optionally substituted by oxo, substituted by heterocycle selected from the group consisting of:   wherein Z is C1-6-alkylene or C3-6-cycloalkyl; R<7> is hydrogen or C1-4-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-4-alkyl, or C2-4-alkyl substituted by C1-4-alkoxy or hydroxy; R<8> is hydrogen or C1-4-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-4-alkyl, or C2-4-alkyl substituted by C1-4-alkoxy, hydroxy or heteroaliphatic ring selected from the group containing pyrrolidino, piperidino, piperazino, morpholino and thiomorpholino; or R<7>, R<8> and the nitrogen atom to which they are attached form a heteroaliphatic ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidyl, morpholino, thiomorpholino, piperazino, and piperazino substituted on nitrogen atom by a C1-4-alkyl group or C2-4-alkyl group, substituted by hydroxy- or C1-2-alkoxy group wherein said heteroaliphatic ring is optionally substituted by one or two groups selected from hydroxy or C1-4-alkoxy optionally substituted by C1-4-alkoxy- or hydroxy group; or R<7>, R<8> and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system, selected from 5-azabicyclo[2.1.1]hexyl, 5-azabicyclo[2.2.1]heptyl, 6-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.2]octyl, 6-azabicyclo[3.2.2]nonyl, 6-azabicyclo[3.3.1]nonyl, 6-azabicyclo[3.2.2]decyl, 7-azabicyclo[4.3.1]decyl, 7-azabicyclo[4.4.1]undecyl, and 8-azabicyclo[5.4.1]dodecyl; or Z, R<7> and the nitrogen atom to which they are attached form a heteroaliphatic ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidyl and morpholino; R<9> and R<10> each independently represent hydrogen, halogen, C1-6-alkyl, CH2OR<e>, oxo, CO2R<a> or CONR<a>R<b> where R<a> and R<b> are as previously defined and R<e> represents hydrogen, C1-6-alkyl or phenyl; R<12> represents OR<a>, CONR<a>R<b> or heteroaryl; wherein heteroaryl is previously defined; R<13> represents hydrogen or C1-6-alkyl; R<14> represents C1-6-alkyl, C1-6-alkoxy, fluoro-C1-6-alkyl or phenyl; X is an oxygen atom or two hydrogen atoms; and the broken line represents an optional double bond; or a pharmaceutically acceptable salt thereof. 2. A compound as claimed in Claim 1 wherein R<1> is hydroxy, C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, fluoro-C1-6-alkoxy, C2-6-alkenyloxy, C3-7-cycloalkoxy, C3-7-cycloalkyl-C1-4-alkoxy, cyano, NR<a>R<b>, SR<a>, OSO2R<a>, or R<1> together with the group R<2> form a 5-membered saturated ring containing one oxygen atom. 3. A compound as claimed in Claim 1 or 2 wherein R<2> is a hydrogen, fluorine or chlorine atom. 4. A compound as claimed in any of Claims 1-3 wherein R<3> is hydrogen, halogen, fluoro-C1-6-alkyl, fluoro-C1-6-alkoxy, cyano, NR<a>R<b>, or NR<a>COR<14>. 5. A compound as claimed in any of Claims 1-4 wherein R<4> is a hydrogen atom or a fluorine atom. 6. A compound as claimed in any of Claims 1-5 wherein R<5> is a hydrogen atom. 7. A compound as claimed in any of Claims 1-6 wherein R<6> is a hydrogen atom or a C1-6-alkyl group substituted by a 5-membered heterocycle containing 2 or 3 nitrogen atoms as defined in Claim 1. 8. A compound as claimed in any of Claims 1-7 wherein one of R<9> and R<10> is hydrogen. 9. A compound as claimed in any of Claims 1-8 wherein X represents two hydrogen atoms. 10. A compound as claimed in any of Claims 1-9 wherein the double bond represented by the broken line is absent. 11. A compound of Claim 1 having the formula (Ia):   wherein R<1>, R<2>, R<3>, R<4> and the broken line are as defined in Claim 1 or a pharmaceutically acceptable salt thereof. 12. A compound as claimed in Claim 1 wherein R<1> represents hydrogen, hydroxy, C1-6-alkyl, C2-6-alkenyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-4-alkyl, C1-6-alkoxy, fluoro-C1-6-alkoxy, C1-6-alkoxyC1-4-alkyl, C1-6-alkoxy-C1-4-alkoxy, fluoro-C1-6-alkoxy-C1-4-alkyl, C2-6-alkenyloxy, C3-7-cycloalkoxy, C3-7-cycloalkyl-C1-4-alkoxy, phenoxy, benzyloxy, cyano, halogen, NR<a>R<b>, SR<a>, SOR<a>, SO2R<a>, OSO2R<a>, NR<a>COR<14>, COR<a>, CO2R<a> or CONR<a>R<b> where R<a> and R<b> each independently represent hydrogen, C1-4-alkyl or fluoro-C1-4-alkyl; R<2> represents hydrogen or halogen; or when R<2> is adjacent to R<1>, they may be joined together such that there is formed a 5-membered unsaturated ring containing an oxygen atom; R<3> represents hydrogen, halogen, C1-6-alkyl, fluoro-C1-6-alkyl, C1-6-alkoxy, fluoro-C1-6-alkoxy, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-4-alkyl, cyano, SR<a>, SOR<a>, SO2R<a>, NR<a>R<b>, NR<a>COR<14>, COR<a>, CO2R<a>, CONR<a>R<b> or C1-4-alkyl substituted by cyano group, CO2R<a> or CONR<a>R<b> where R<a> and R<b> are as previously defined; R<4> represents hydrogen or halogen; R<5> represents hydrogen; R<6> represents hydrogen, or R<6> represents C1-6-alkyl, substituted by heterocycle selected from the group consisting of:   R<7> is hydrogen or C1-4-alkyl; R<8> is hydrogen or C1-4-alkyl; R<9> and R<10> each independently represent hydrogen; R<14> represents C1-6-alkyl, C1-6-alkoxy, fluoro-C1-6-alkyl or phenyl; X is an oxygen atom or two hydrogen atoms; Z is C1-6-alkylene; and the broken line represents an optional double bond; or a pharmaceutically acceptable salt thereof. 13. A compound according Claim 1 selected from: (5R,6S)-3-(2-methoxy-5-trifluoromethoxyphenyl)-6-phenyl-1-oxa-7-azaspiro[4.5]dec-3-ene; (3S,5R,6S)-3-(2-methoxy-5-trifluoromethoxyphenyl)-6-phenyl-1-oxa-7-azaspiro[4.5]decane; (3S,5R,6S)-3-(2-methoxy-5-trifluoromethoxyphenyl)-6-phenyl-7-(1,2,4-tri-azolyl-3-methylene)-1-oxa-7-azaspiro[4.5]decane; (5R,6S)-3-(2-isopropoxy-5-trifluoromethoxyphenyl)-6-phenyl-1-oxa-7-azaspiro[4.5]dec-3-ene; (5R,6S)-3-(2-allyloxy-5-trifluoromethoxyphenyl)-6-phenyl-1-oxa-7-azaspiro[4.5]dec-3-ene; (5R,6S)-3-(5-trifluoromethoxy-2,3-dihydrobenzofuran-7-yl)-6-phenyl-1-oxa-7-azaspiro[4.5]dec-3-ene; (5R,6S)-3-(2-methoxy-5-(2,2,2-trifluoroethoxy)phenyl)-6-phenyl-1-oxa-7-azaspiro[4.5]dec-3-ene; (5R,6S)-3-(2,5-bis(2,2,2-trifluoroethoxy)phenyl)-6-phenyl-1-oxa-7-azaspiro[4.5]dec-3-ene; (5R,6S)-3-(2-difluoromethoxy-5-trifluoromethoxyphenyl)-6-phenyl-1-oxa-7-azaspiro[4.5]dec-3-ene; (5R,6S)-3-(2-(2,2,2-trifluoroethoxy)-5-trifluoromethoxyphenyl)-6-phenyl-1-oxa-7-azaspiro[4.5]dec-3-ene; (3S,5R,6S)-3-(2-isopropoxy-5-trifluoromethoxyphenyl)-6-phenyl-1-oxa-7-azaspiro[4.5]decane; (3S,5R,6S)-3-(5-trifluoromethoxy-2,3-dihydrobenzofuran-7-yl)-6-phenyl-1-oxa-7-azaspiro[4.5]decane; (3S,5R,6S)-3-(2-methoxy-5-(2,2,2-trifluoroethoxy)phenyl)-6-phenyl-1-oxa-7-azaspiro[4.5]decane; (3S,5R,6S)-3-(2,5-bis(2,2,2-trifluoroethoxy)phenyl)-6-phenyl-1-oxa-7-azaspiro[4.5]decane; (3S,5R,6S)-3-(2-difluoromethoxy-5-trifluoromethoxyphenyl)-6-phenyl-1-oxa-7-azaspiro[4.5]decane; (3S,5R,6S)-3-(2-(2,2,2-trifluoroethoxy)-5-trifluoromethoxyphenyl)-6-phenyl-1-oxa-7-azaspiro[4.5]decane; (3S,5R,6S)-3-(2-(2,2,2-trifluoroethoxy)-5-fluorophenyl)-6-phenyl-1-oxa-7-azaspiro[4.5]decane; (5R,6S)-3-(5-methanesulfonyl-2-methoxyphenyl)-6-phenyl-1-oxa-7-azaspiro[4.5]dec-3-ene; (3S,5R,6S)-3-(5-methanesulfonyl-2-methoxyphenyl)-6-phenyl-1-oxa-7-azaspiro[4.5]decane; (5R,6S)-3-[2-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-azaspiro[4.5]dec-3-ene; (3S,5R,6S)-3-[2-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-azaspiro[4.5]decane; (5R,6S)-3-[2-cyclobutoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-azaspiro[4.5]dec-3-ene; (3S,5R,6S)-3-[2-cyclobutoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-7-azaspiro[4.5]decane; (5R,6S)-3-(2-(2-fluoroethoxy)-5-(trifluoromethoxy)phenyl)-