Pharmacological uses of azetidine derivatives

A method of antagonizing the cannabinoid (CB1) receptor wherein a disease treatable by said antagonizing activity is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, and schizophrenia, this method comprising administering to a patient in need of said antagonization an effective amount of a compound of formula

• in which
• R represents a radical selected from CR1R2, C═C(R5)SO2R6 and C═C(R7)SO2alk, either R1 represents a hydrogen atom and R2 represents a radical selected from —C(R8)(R9)(R10), —C(R8)(R11)(R12), —CO—NR13R14, —CH2—CO—NR13R14, —CH2—CO—R6, —CO—R6, —CO-cycloalkyl, —SO—R6, —SO2—R6, —C(OH)(R12)(R6), —C(OH)(R6)(alkyl), —C(═NOalk)R6, —C(═NO—CH2—CHCH2)R6, —CH2—CH(R6)NR31R32, —CH2—C(═NOalk)R6, —CH(R6)NR31R32, —CH(R6)NHSO2alk, —CH(R6)NHCONHalk and —CH(R6)NHCOalk,
• or R1 represents an alkyl, NH—R15, cyano, —S-alk-NR16R17, —CH2—NR18R19, or —NR2OR21 radical and R2 represents a —C(R8)(R11)(R12) radical,
• R3 and R4, which may be identical or different, represent either an alkyl or cycloalkyl radical, or an
• aromatic radical selected from phenyl, naphthyl and indenyl, these aromatic radicals being unsubstituted or substituted with one or more radicals selected from halogen, alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoromethoxy, —CO-alk,
• cyano, —COGH, —COGalk, —CONR22R23, —CO—NH—NR24R25, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl and -alk-NR24R25 radicals;
• or a heteroaromatic radical selected from the benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidinyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, thiazolyl and thienyl rings, these heteroaromatic radicals being unsubstituted or substituted with one or more radicals selected from halogen, alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, —COGH, —COGalk, —CO—NH—NR24R25, —CONR22R23, -alk-NR24R25, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl and hydroxyalkyl radicals,
• R5 represents a hydrogen or alkyl radical,
• R6 represents an Ar or Het radical,
• R7 represents a cycloalkyl, heterocycloalkyl or heterocyclenyl radical, optionally substituted by a —CSO-phenyl radical,
• R8 represents a hydrogen or alkyl radical,
• R9 represents a radical selected
• from —CO—NR26R27, —COGH, —COGalk, —CH2OH, —NH—CO—NH-alk, —CH2—NHR28 and —NHCOOalk,
• R10 represents an Ar or Het radical,
• R11 represents a radical selected from —SO2-alk, —SO2—Ar and —SO2-Het,
• R12 represents a hydrogen, Ar or Het radical,
• R13 represents a hydrogen or alkyl radical,
• R14 represents an Ar, Het, -alk-Ar or -alk-Het radical,
• R15 represents an alkyl, cycloalkyl or -alk-NR29R30 radical,
• R16 and R17, which may be identical or different, represent a hydrogen or alkyl radical or, alternatively,
• R16 and R17, taken together with the nitrogen atom to which they are attached, form a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle ring, optionally containing one or more other heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl radicals,
• R18 represents a hydrogen or alkyl radical,
• R19 represents a hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, —SO2alk, —CO—NHalk or —COGalk radical,
• or, alternatively, R18 and R19, taken together with the nitrogen atom to which they are attached, form a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle ring, optionally containing one or more heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl radicals,
• —NR20R21 represents a 3- to 8-membered saturated or unsaturated monocyclic heterocycle ring, optionally containing another heteroatom selected from oxygen, nitrogen and sulfur,
• R22 and R23, which may be identical or different, represent a hydrogen or alkyl radical or,
• alternatively, R22 and R23, taken together with the nitrogen atom to which they are attached, form a 3- to 10-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals,
• R24 and R25, which may be identical or different, represent a hydrogen, alkyl, —COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or,
• alternatively, R24 and R25, taken together with the nitrogen atom to which they are attached, form a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, —COalk, —COOalk, —CO—NHalk, —CS—NHalk, oxo, hydroxyalkyl, -alk-O-alk or —CO—NH2 radicals,
• R26 and R27, which may be identical or different, represent a hydrogen, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, -alk-COOalk, -alk-Ar, -alk-Het, Het or -alk-N(alk)2 radical, or,
• alternatively, R26 and R27, taken together with the nitrogen atom to which they are attached, may form a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle, optionally containing one or more other heteroatoms selected from oxygen, sulfur and nitrogen, and optionally substituted with one or more halogen, alkyl or alkoxy radicals,
• R28 represents a —CH2-alk, benzyl, —SO2alk, —CONHalk, —COalk, cycloalkylalkylcarbonyl, cycloalkylcarbonyl or —CO—(CH2)nOH radical,
• n is equal to 1, 2 or 3,
• R29 and R30, which may be identical or different, represent a hydrogen or alkyl radical or,
• alternatively, R29 and R30, taken together with the nitrogen atom to which they are attached, form a 3- to 10-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen, and being optionally substituted with one or more alkyl radicals,
• R31 and R32, which may be identical or different, represent a hydrogen, alkyl, Ar or -alk-Ar radical or,
• alternatively, R31 and R32, taken together with the nitrogen atom to which they are attached, form a heterocycle selected from aziridinyl, azetidinyl, pyrrolidinyl and piperidinyl, alk represents an alkyl or alkylene radical,
• Ar represents a phenyl or naphthyl radical optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, —CO-alk, cyano, —COOH, —COOalk, —CONR22R23, —CO—NH—NR24R25, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl, -alk-NR24R25, —NR24R25, alkylthioalkyl, formyl, hydroxyl, CF3, OCF3, Het, —O-alk-NH-cycloalkyl and SO2NH2 radicals,
• Het represents a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle containing one or more heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more halogen, alkyl, alkoxy, alkoxycarbonyl, —CONR22R23, hydroxyl, hydroxyalkyl, oxo or SO2NH2 radicals,
• the alkyl, alkylene and alkoxy radicals are in the form of a straight or branched chain and contain 1 to 6 carbon atoms, the cycloalkyl radicals contain 3 to 10 carbon atoms and the heterocycloalkyl and heterocyclenyl radicals contain 3 to 10 carbon atoms,
• their optical isomers and their salts with an inorganic or organic acid.