Patent FR-2805818-A1 (FR)
Title: New 3-substituted 1-(di-((hetero)aryl)-methyl)-azetidine derivatives having cannabinoid CB1 receptor antagonist activity, useful e.g. for treating central nervous system, respiratory or gastrointestinal disorders
Inventor: ACHARD DANIEL
IPC: A61P23/00
Filed: 2000-03-03
Abstract: 3-Substituted or 3,3-disubstituted 1-(di-((hetero)aryl)-methyl)-azetidine derivatives (I) are new. Azetidine derivatives of formula (I), and their optical isomers and mineral or organic acid addition salts, are new. R  = CR1R2, C=C(R5)SO2R6 or C=C(R7)SO2-alk;  R1  = H; and  R2  = -CR8R9-R10, -CR8R11-R12, CONR13R14, CH2CONR13R14, CH2COR6, COR6, -CO-cycloalkyl, -SO-R6, SO2R6, C(OH)R6-R12, C(OH)R6-alkyl, -C(=NO-alk)R6, -C(=NO-CH2CH=CH2)R6, -CH2CHR6-NR31R32, -CH2-C(=NO-alk)R6, -CHR6-NR31R32, -CHR6-NHSO2-alk, -CHR6-NHCONH-alk or -CHR6-NHCO-alk; or  R1  = alkyl, NHR15, CN, -S-alk-NR16R17, -CH2-NR18R19 or NR20R21; and  R2  = -CR8R11-R12;  R3, R4  = alkyl or cycloalkyl, or phenyl, naphthyl or indenyl (all optionally substituted (os) by one or more of halo, alkyl, alkoxy, CHO, OH, CF3, OCF3, -CO-alk, CN, COOH, COO-alkyl, CONR22R23, CONHNR24R25, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NR24R25), benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, pyrimidinyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, thiazolyl or thienyl (all os by one or more of halo, alkyl, alkoxy, OH, CF3, OCF3, CN, COOH, COO-alk, CONR22R23, CONHNR24R25, -alk-NR24R25, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl);  R5, R8, R13  = H or alkyl;  R6, R10  = Ar or Het;  R7  = cycloalkyl, heterocycloalkyl or heterocyclenyl (all os by -CSO-phenyl);  R9  = -CONR26R27, COOH, COO-alk, CH2OH, NHCONH-alk, CH2NHR28 or NHCOO-alk;  R11  = SO2-alk, SO2Ar or SO2Het;  R12  = H, Ar or Het;  R14  = Ar, Het, -alk-Ar or -alk-Het;  R15  = alkyl, cycloalkyl or -alk-NR29R30;  R16 - R18  = H or alkyl;  R19  = H, alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, SO2-alk, -CONH-alk or -COO-alk; or NR16R17 or NR18R19  = 3-10 membered saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another O, S or N heteroatom and os by one or more alkyl;  NR20R21  = 3-8 membered saturated monocyclic heterocycle, optionally containing another O, S or N heteroatom;  R22, R23  = H or alkyl; or NR22R23  = 3-10 membered saturated mono- or bicyclic heterocycle, optionally containing another O, S or N heteroatom and os by one or more alkyl;  R24, R25 = H, alkyl, COO-alk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl; or NR24R25  = 3-10 membered saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another O, S or N heteroatom and os by one or more of alkyl, -CO-alk, -COO-alk, -CONH-alk, -CSNH-alk, oxo, hydroxyalkyl, -alk-O-alk or CONH2;  R26, R27  = H, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, -alk-COO-alk, -alk-Ar, -alk-Het, Het or -alk-N(alk)2; or NR26R27  = 3-10 membered saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another O, S or N heteroatom and os by one or more of alkyl, alkoxy or halo;  R28  = CH2-alk, benzyl, SO2-alk, CONH-alk, CO-alk, cycloalkylalkylcarbonyl or CO(CH2)nOH;  n  = 1-3; R29, R30  = H or alkyl; or NR29R30  = 3-10 membered saturated mono- or bicyclic heterocycle, optionally containing another O, S or N heteroatom and os by one or more alkyl;  R31, R32  = H or alkyl; or NR31R32  = aziridinyl, azetidinyl, pyrrolidinyl or piperidinyl;  alk = alkyl or alkylene;  Ar  = phenyl or naphthyl (both os by one or more of halo, alkyl, alkoxy, CN, -CO-alk, COOH, COO-alk, CONR22R23, CONHNR24R25, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl, -alk-NR24R25, NR24R25, alkylthioalkyl, CHO, OH, OCF3, CF3, Het, -O-alkyl-NH-cycloalkyl or SO2NH2); and Het  = 3-10 membered saturated or unsaturated mono- or bicyclic heterocycle, containing one or more O, S or N heteroatom(s) and os by one or more of halo, alkyl, alkoxy, alkoxycarbonyl, CONR22R23, OH, hydroxyalkyl, oxo or SO2NH2). Alkyl or alkylene moieties have 1-6C and cycloalkyl, heterocycloalkyl or heterocyclenyl moieties have 3-10C. Independent claims are included for the preparation of (I).