NZ521075A - Azetidine derivatives, preparation thereof and pharmaceutical compositions containing same - Google Patents

Azetidine derivatives, preparation thereof and pharmaceutical compositions containing same

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Publication number
NZ521075A
NZ521075A NZ521075A NZ52107501A NZ521075A NZ 521075 A NZ521075 A NZ 521075A NZ 521075 A NZ521075 A NZ 521075A NZ 52107501 A NZ52107501 A NZ 52107501A NZ 521075 A NZ521075 A NZ 521075A
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New Zealand
Prior art keywords
radical
methyl
chlorophenyl
formula
bis
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NZ521075A
Inventor
Daniel Achard
Herve Bouchard
Jean Bouquerel
Bruno Filoche
Serge Grisoni
Augustin Hittinger
Michael Myers
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Aventis Pharma S
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Publication of NZ521075A publication Critical patent/NZ521075A/en

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Abstract

Compounds of formula (I), wherein: R is CR1R2, C=C(R5)SO2R6 or C=C(R7)SO2alk, R3 and R4 are independently optionally substituted phenyl, pyridyl, pyrimidinyl, or thienyl. The compounds are used for the manufacture of medicaments for use as CB1 receptor antagonists.

Description

New Zealand Paient Spedficaiion for Paient Number 521 075 5210 75 AZETIDINE DERIVATIVES, PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME The present invention relates to a compound of formula in which N" (D -R R represents a radical CRxR2, C=C (R5) S02R6 or C=C(R7) S02alk, Ri represents a hydrogen atom and R2 represents a radical -C (R8) (R9) (Rio) , -C (R8) (Rn) (R12) , -CO-NR13Ri4, -CO-R6, -CO-cycloalkyl, -SO-Re, -S02-R6^ -C(OH) (R6) (alkyl) , -C (=NOalk) R6, -C (=NO-CH2-CH=CH2) R6, -CH2-C(=NOalk)R6, -CH(R6)NR31R32, -CH (R6) NHCONHalk or -CH (R6) NHCOalk, or Ri represents an alkyl, NH-r15, cyano, -S-alk-NRi6Ri7/ -CH2-NRi8Ri9, or -NR20R2i radical and R2 represents a radical -C (R8) (Rn) (Ri2) , R3 and R4, which are identical or different, represent either phenyl, being unsubstituted or substituted with one or more halogen atoms or alkyl, -alk-NR24R25 or CH2C1 radicals; or a heteroaromatic chosen from pyridyl, intellectual property of i\i.Z 17 DEC 2004 la (followed by page lb) pyrimidinyl and thienyl rings, being unsubstituted or substituted with one or more halogen atoms, R5 represents a hydrogen atom, R6 represents a radical Ar or Het, R7 represents a heterocyclenyl radical optionally substituted by a -CSO-phenyl radical, R8 represents a hydrogen atom, R9 represents a radical -CO-NR26R27, -COOH, -COOalk, -CH2OH, -NH-CO-NH-alk or -CH2-NHR28, Rio represents a radical Ar or Het, Rn represents a radical -S02-alk, -S02-Ar or -S02-Het, Ri2 represents a hydrogen atom or a radical Ar or Het, Ri3 represents a hydrogen atom or an alkyl radical, R14 represents a radical Ar, -alk-Ar or -alk-Het, Ris represents an alkyl, cycloalkyl or -alk-NR29R30 radical, r——_ I 'WTELLECTUAL PROPFRTV / OF 1V.7 " 17 DEC 2004 lb (followed by page lc) Ri6 and R17, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Ri6 and R17 together form with the nitrogen atom to which they are attached a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle optionally containing one or more other heteroatoms chosen from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl radicals, Ris represents a hydrogen atom or an alkyl radical, Rig represents a hydrogen atom or an alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -S02alk, -CO-NHalk or -COOalk radical, -NR20R21 represents a 3- to 8-membered saturated or unsaturated monocyclic heterocycle optionally containing another heteroatom chosen from oxygen, nitrogen and sulfur, R22 and R23, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R22 and R23 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono-or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals, 301328J.DOC INTELLECTUAL PROPERTY OFFICE] OF N.Z I 17 DEC 2004 RCrciiipft lc (followed by page Id) R24 and R25, which are identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or alternatively R24 and R25 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen 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 are identical or different, represent a hydrogen atom or an alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, -alk-COOalk, -alk-Ar, -alk-Het, Het or -alk-N(alk)2 radical, R26 and R27 may also form with the nitrogen atom to which they are attached a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle optionally containing one or more other heteroatoms chosen from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy radicals or halogen atoms, R2s represents a -CONHalk, -COalk or cycloalkylcarbonyl radical, n is equal to 1, 2 or 3, 301328 l.DOC fintellectual property office! i of n.z 1 17 DEC 2004 Id (followed by page le) R29 and R30, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R29 and R30 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono-or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals, R3i and R32, which are identical or different, represent a hydrogen atom or an alkyl, Ar or -alk-Ar radical or alternatively R31 and R32 together form with the nitrogen atom to which they are attached a heterocycle chosen from aziridinyl, azetidinyl, pyrrolidinyl and piperidinyl, alk represents an alkyl or alkylene radical, Ar represents a phenyl radical optionally substituted with one or more substituents chosen from a halogen atom or an 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 or SO2NH2 radical, 301328 1.DOC INTELLECTUAL PROPERTY OFFICE OF N.Z 17 DEC 2004 RECEIVED le (followed by page If) Het represents a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen and optionally substituted with one or more halogen atoms or alkyl, alkoxy, alkoxycarbonyl, —CONR22R23f hydroxyl, hydroxyalkyl, oxo or S02NH2 radicals, the alkyl and alkylene radicals and portions and the alkoxy radicals and portions 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.
Described are derivatives of formula: their salts, their preparation and the medicaments containing them.
(I) R INTELLECTUAL PROPERTY OFFICE OF N.Z 17 DEC 2004 301328 1.DOC DCPCn/r pi If (followed by page 2) In formula (I), F represents a radical CRXR2, C=C(R5)SC>2R6 or C=C (R7) S02alk, or Ri represents a hydrogen atom and R2 represents a radical -C(R8) (R9) (Rio) , -C (R8) (Ru) (Ri2) , -CO-NR13R14, -CH2—CO-NR13R14, -CH2-CO-R6, -co-Re, -CO-cycloalkyl, -SO-R6, -S02-R6, -C(OH) (Ri2) (R6) , -C (OH) (R6) (alkyl) , -C (=NOalk) R6, -C(=NO-CH2-CH=CH2)R6, -CH2-CH (R6) NR31R32, -CH2-C(=NOalk)R6, -CH(R6)NR3iR32/ -CH (R6) NHS02alk, -CH(R6)NHCONHalk or -CH (R6) NHCOalk, 2 or Ri represents an alkyl, NH-R15, cyano, -S-alk-NRi6Ri7, -CH2-NRi8Ri9, or -NR20R21 radical and R2 represents a radical -C(Ra) (Rn) (Ri2) , R3 and R4, which are identical or different, represent either an alkyl or cycloalkyl radical, or an aromatic chosen from phenyl, naphthyl or indenyl, these aromatics being unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, formyl, 10 hydroxyl, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR22R23, -CO-NH-NR24R25, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl or -alk-NR24R25 15 radicals; or a heteroaromatic chosen from the benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, 20 pyrimidinyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl, thiazolyl and thienyl rings, it being possible for these heteroaromatics to be unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, 25 cyano, -COOH, -COOalk, -CO-NH-NR24R25, -CONR22R23, -alk-NR24R25, alkylsulf anyl, alkylsulf inyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl or hydroxyalkyl radicals, 3 R5 represents a hydrogen atom or an alkyl radical, R6 represents a radical Ar or Het, R7 represents a cycloalkyl, heterocycloalkyl or heterocyclenyl radical optionally substituted by a -CSO-phenyl radical, Rg represents a hydrogen atom or an alkyl radical, R9 represents a radical -C0-NR26R27r -COOH, -COOalk, -CH2OH, -NH-CO-NH-alk, -CH2-NHR28 or -NHCOOalk, Rio represents a radical Ar or Het, Rn represents a radical -S02-alk, -S02-Ar or -S02-Het, Ri2 represents a hydrogen atom or a radical Ar or Het, R13 represents a hydrogen atom or an alkyl radical, Ri4 represents a radical Ar, Het, -alk-Ar or -alk-Het, R15 represents an alkyl, cycloalkyl or -alk-NR2gR30 25 radical, Rig and Riv, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Ri6 and R17 together form with the nitrogen atom to which 4 they are attached a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle optionally containing one or more other heteroatoms chosen from oxygen, sulfur and nitrogen and optionally substituted 5 with one or more alkyl radicals, Ris represents a hydrogen atom or an alkyl radical, Rig represents a hydrogen atom or an alkyl, cycloalkyl, 10 cycloalkylalkyl, cycloalkylcarbonyl, -SC>2alk, -CO-NHalk or -COOalk radical, or alternatively RX8 and Rig form with the nitrogen atom to which they are attached a 3- to 10-membered 15 unsaturated or saturated mono- or bicyclic heterocycle optionally containing one or more heteroatoms chosen 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 optionally containing another heteroatom chosen from oxygen, nitrogen and sulfur, R22 and R23, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R22 and R23 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono-or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals, R24 and R25, which are identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or alternatively R24 and R25 together form with the nitrogen atom to which they are attached a 3- to 10 10-membered saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl, 15 -alk-O-alk or -CO-NH2 radicals, R26 and R27, which are identical or different, represent a hydrogen atom or an alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, -alk-COOalk, -alk-Ar, -alk-Het, Het or 20 -alk-N(alk)2 radical, R26 and R27 may also form with the nitrogen atom to which they are attached a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle optionally containing one or more other heteroatoms chosen from oxygen, sulfur and nitrogen and 25 optionally substituted with one or more alkyl or alkoxy radicals or halogen atoms, 6 R28 represents a -CH2-alk, benzyl, -S02alk, -CONHalk, -COalk, cycloalkylalkylcarbonyl, cycloalkylcarbonyl or -CO-(CH2)nOH radical, n is equal to 1, 2 or 3, R2g and R30, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R2g and R30 together form with the nitrogen atom to which 10 they are attached a 3- to 10-membered saturated mono-or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals, R31 and R32, which are identical or different, represent a hydrogen atom or an alkyl, Ar or -alk-Ar radical or alternatively R31 and R32 together form with the nitrogen atom to which they are attached a heterocycle 20 chosen 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 chosen from a halogen atom or an alkyl, alkoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR22R23, -CO-NH-NR24R25, alkylsulf anyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, 7 alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl, -alk-NR24R25c -NR24R25 r alkylthioalkyl, formyl, hydroxyl, CF3, OCF3, Het, -O-alk-NH-cycloalkyl or SO2NH2 radical, Het represents a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen and optionally substituted with one or more halogen atoms or alkyl, alkoxy, alkoxycarbonyl, 10 -CONR22R23/ hydroxyl, hydroxyalkyl, oxo or S02NH2 radicals.
In the preceding definitions and in those which follow, unless otherwise stated, the alkyl and alkylene radicals and portions and the alkoxy radicals and 15 portions 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.
Among the alkyl radicals, there may be mentioned the methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl and hexyl radicals. Among the alkoxy radicals, there may be mentioned the methoxy, ethoxy, n-propoxy, iso-propoxy, 25 n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and pentyloxy radicals.
Among the cycloalkyl radicals, there may be mentioned the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals. 8 The heterocycloalkyl radicals are cycloalkyl radicals in which at least one of the carbon atoms is replaced with a heteroatom chosen from nitrogen, sulfur and oxygen. Among these, there may be mentioned the 5 pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl and morpholinyl rings.
The heterocyclenyl radicals are cycloalkyl radicals in which at least one carbon atom is replaced with a heteroatom chosen from oxygen, sulfur and 10 nitrogen and which contain at least one carbon-carbon or carbon-nitrogen double bond. Among the heterocyclenyl radicals, there may be mentioned the 1,2,3,4-tetrahydrohydropyridinyl, 3,6-dihydropyridyl, 1.2-dihydropyridyl, 1,4-dihydropyridyl, 15 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, 3,4-dihydro-2H-pyrane, dihydrofuranyl and fluorodihydrofuranyl rings. Those preferred are the 20 3,6-dihydropyridyl rings.
The term halogen comprises chlorine, fluorine, bromine and iodine.
Among the heterocycles representing Het, the following heterocycles may be mentioned: benzofuryl, 25 benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2.3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, indolinyl, indolyl, isochromanyl, isoquinolyl, piperidyl, pyrrolyl, pyridyl, pyrimidinyl, quinolyl, 9 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thiazolyl and thienyl.
When R3 and/or R4 represent independently a substituted phenyl, the latter is preferably mono-, di-5 or trisubstituted.
When Rig and Ri7 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, the latter is preferably an azetidinyl, pyrrolidinyl, 10 piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring.
When Rig and R19 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, 15 the latter is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring.
The heterocycle formed by NR20R21 is preferably azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 20 thiamorpholinyl, piperazinyl or imidazolyl.
When R22 and R23 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, the latter is preferably an azetidinyl, pyrrolidinyl, 25 piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring.
When R24 and R25 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, the latter is preferably an azetidinyl, pyrrolidinyl, piperidinyl,- morpholinyl, thiamorpholinyl or piperazinyl ring.
When R26 and R27 together form with the nitrogen 5 atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, the latter is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring.
When R29 and R30 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, the latter is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or 15 piperazinyl ring.
When R31 and R32 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, the latter is preferably an azetidinyl, pyrrolidinyl, 20 piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring.
Preferably, R represents a radical CR1R2, either Ri represents a hydrogen atom and R2 represents a radical -C(Rs) (R11) (R12) or C(R8) (R9) (Rio)/ 11 or Ri represents an alkyl radical and R2 represents a radical -C(R8) (R11) (R12) , R3 and R4> which are identical or different, represent 5 either a phenyl which is unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, trif luoromethyl, trif luoromethoxy, cyano, -CONR22R23, hydroxyalkyl or -alk-NR24R25 radicals; or a heteroaromatic chosen from the pyridyl, pyrimidinyl, 10 thiazolyl and thienyl rings, it being possible for these heteroaromatics to be unsubstituted or substituted with one or more halogen atoms or alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -CONR22R23/ -alk-NR24R25 or hydroxyalkyl radicals, R8 represents a hydrogen atom, Rg represents a -CO-NR26R27/ -COOalk, -CH2OH, -NH-CO-NH-alk, -CH2-NHR28 or -NHCOOalk radical, Rio represents a radical Ar or Het, Rn represents a radical -S02-alk, -S02-Ar or -S02-Het, R12 represents represents a hydrogen atom or a radical Ar or Het, R22 and R23, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R22 12 and R23 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono-or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and 5 being optionally substituted with one or more alkyl radicals, R24 and R25/ which are identical or different, represent a hydrogen atom or an alkyl, cycloalkyl, 10 alkylcycloalkyl or hydroxyalkyl radical or alternatively R24 and R25 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle optionally containing another heteroatom 15 chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo or -CO-NH2 radicals, Ar represents a phenyl or naphthyl radical optionally 20 substituted with 1 or 2 subtituents chosen from a halogen atom or an alkyl, alkoxy, -CO-alk, cyano, -COOalk, -CONR22R23/ alkylsulfonyl, hydroxyalkyl, -alk-NR24R25, -NR24R25, hydroxyl, CF3, OCF3, -O-alk-NH-cycloalkyl or S02NH2 radical, Het represents a benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, isoquinolyl, pyrrolyl, pyridyl, quinolyl, 13 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thiazolyl or thienyl ring.
The compounds of formula (I) may be provided in 5 the form of enantiomers and diastereoisomers. These optical isomers and mixtures thereof form part of the invention.
The compounds of formula (I) for which R represents a radical CR1R2, in which Ri represents a 10 hydrogen atom and R2 represents a radical C(Rs) (R11) (R12) in which R8 represents a hydrogen atom, Rn represents a radical -SC>2-Ar, -SC>2-Het or -S02alk and Ri2 represents a hydrogen atom or a radical Ar or Het, and the compounds of formula (I) for which R represents a radical 15 C=C(R5)S02R6 or C=C (r7) S02alk may be prepared according to the following reaction scheme: 14 R, Ra-S02CH2Rb + N- N- V Rc -S( Rb SOzRa Ra-S02-CH2-Si(CH3)3 + 3 N- \ ^-bU2 SO„-Ra lb XRt N- la X O0-Ra R3CH(Br)R4 HN- R_CH(Br)R.
\S02-Ra b HN- yOH "\T^S02-Ra rib COOCH=CH, CICOOCH=CH. \ 2 N- S02-Ra S02-Ra in these formulae, either Ra represents an alkyl, Het or Ar radical and Rb represents a hydrogen atom or a radical Ar or Het, or Ra represents a radical Ar or Het and Rb represents a hydrogen atom or an alkyl radical, or Ra represents an alkyl radical and Rb represents a cycloalkyl, heterocycloalkyl or heterocyclenyl radical optionally substituted with a radical -CSO-phenyl, Rc represents a hydrogen atom or an acetyl radical, R3, R4, Ar and Het have the same meanings as in formula (I).
Reactions d and e can only be used when Rb is a hydrogen atom.
The reaction is generally carried out in an inert solvent such as an ether (for example tetrahydrofuran), in the presence of a strong base such as tert-butyllithium, n-butyllithium, lithium diisopropylamide or potassium tert-butoxide, at a 10 temperature of between -70°C and -15°C.
The dehydration reaction b is generally carried out by any dehydration method known to a person skilled in the art which makes it possible to dehydrate an alcohol in order to obtain the corresponding alkene. 15 Preferably, the acetyloxy derivative is prepared by the action of acetyl chloride, in an inert solvent such as pyridine, tetrahydrofuran, dioxane, a chlorinated solvent (for example dichloromethane or chloroform), at a temperature of between 5°C and 20°C and then the 20 medium is treated with a base such as an alkali metal hydroxide (for example sodium hydroxide), an alkali metal carbonate (for example sodium or potassium carbonate), an amine such as a trialkylamine (for example triethylamine, 4-dimethylaminopyridine, 25 1,8-diazabicyclo[5.4.0]undec-7-ene, at a temperature of between 0°C and the boiling point of the reaction medium. The acetyloxy intermediate may be isolated or otherwise. The acetyloxy may also be prepared directly in the reaction medium of reaction a. 16 Reduction c is generally carried out in an inert solvent such as a (1-4C) aliphatic alcohol (for example methanol), a chlorinated solvent (for example chloroform or dichloromethane) or a mixture of these 5 solvents, in the presence of NaBH4, at a temperature of between 0°C and the boiling point of the reaction medium.
Reaction d is carried out by the action of trimethylsilyl chloride, in an inert solvent such as an 10 ether (for example tetrahydrofuran), in the presence of n-butyllithium, at a temperature of -70°C.
Reaction e is generally carried out in an inert solvent such as an ether (for example tetrahydrofuran), in the presence of a strong base such as 15 tert-butyllithium, n-butyllithium, lithium diisopropylamide or potassium tert-butoxide, at a temperature of between -70°C and -15°C.
Reaction f is generally carried out in a chlorinated solvent (for example dichloromethane or 20 chloroform), at a temperature of 0°C at the boiling point of the reaction medium.
The hydrolysis g is carried out in an inert solvent such as an ether (for example dioxane), by means of hydrochloric acid, at a temperature in the 25 region of 20°C.
The reactions h and j are preferably carried out in an inert solvent such as acetonitrile, in the presence of a base such as an alkali metal carbonate 17 (for example potassium carbonate), at the boiling point of the reaction medium.
Reaction i is carried out under a hydrogen atmosphere, in the presence of a catalyst such as 5 palladium or one of its derivatives, in an inert solvent such as methanol or ethanol, at a temperature of between 15°C and 60°C.
Reaction k is carried out in an inert solvent such as a chlorinated solvent (for example 10 dichloromethane or chloroform) at a temperature of between 0°C and the boiling point of the reaction mixture.
The derivatives R3CH(Br)R4 are commercially available or may be obtained by application or 15 adaptation of the method described by BACHMANN W.E., J. Am. Chem. Soc., 2135 (1933) . Generally, the corresponding alcohol R3CHOHR4 is brominated by means of hydrobromic acid, in acetic acid, at a temperature of between 0°C and the boiling point of the reaction 2 0 medium.
The corresponding alcohols R3CHOHR4 are commercially available or may be obtained by application or adaptation of the methods described by PLASZ A.C. et al., J. Chem. Soc. Chem. Comm., 527 25 (1972) .
The intermediates of formula 2 may be obtained by application or adaptation of the methods described in the examples. In particular, the procedure is 18 carried out according to the following reaction schemes: RaSNa Rb-CH2-Hal Ra-SO Rb-CH2-S-Ra oxidation Rb-CH2-S02-Ra RaSH RaNH„ isoamylnitrite MeSSMe d ICR, RaSCH, 1 nBuLi MeSS02Me RaSOgCHg RaHal in these formulae Hal represents a halogen atom and, preferably, chlorine, bromine or iodine, Ra and Rb have 10 the same meanings as previously mentioned for derivative 2.
Reaction a is generally carried out in an inert solvent such as dimethylformamide or a 1-4C aliphatic alcohol, at a temperature of between 20°C and 30°C. 15 Reactions b and e are carried out by any known method which makes it possible to oxidize a sulfur-containing derivative without affecting the rest of the molecule such as those described by M. HUDLICKY, Oxidations in Organic Chemistry, ACS Monograph, 186, 20 252-263 (1990). For example, the procedure is carried 19 out by the action of an organic peroxy acid or a salt of such a peroxy acid (peroxycarboxylic or peroxysulfonic acids, in particular peroxybenzoic acid, 3-chloroperoxybenzoic acid, 4-nitroperoxybenzoic acid, 5 peroxyacetic acid, trifluoroperoxyacetic acid, peroxyformic acid or monoperoxyphthalic acid) or inorganic peracids or a salt of such an acid (for example periodic or persulfuric acid), in an inert solvent such as a chlorinated solvent (for example 10 chloroform or dichloromethane), at a temperature of between 0 and 25°C. It is also possible to use hydrogen peroxide, optionally in the presence of a metal oxide (sodium tungstate) or a periodate (for example sodium periodate), in an inert solvent such as a 1-4C 15 aliphatic alcohol (for example methanol or ethanol), acetic acid, water or a mixture of these solvents, at a temperature of between 0 and 60°C. It is also possible to carry out the procedure by means of tert-butyl hydroperoxide in the presence of titanium 20 tetraisopropoxide in a 1-4C aliphatic alcohol (for example methanol or ethanol) or a water-alcohol mixture, at a temperature in the region of 25°C or by means of oxoneR (potassium peroxymonosulfate), in a 1-4C aliphatic alcohol (for example methanol or 25 ethanol), in the presence of water, acetic acid or sulfuric acid, at a temperature in the region of 20°C.
Reaction c is preferably carried out in an inert solvent such as a 1-4C aliphatic alcohol (for example methanol or ethanol), at a temperature of between 20°C and the boiling point of the reaction medium.
Reaction d is carried out under an inert atmosphere (argon), at a temperature of between 50°C 5 and the boiling point of the reaction medium.
Reaction f is generally carried out in an inert solvent such as tetrahydrofuran or an aliphatic ether (for example ethyl ether), at a temperature in the region of -70°C.
Reaction g is generally carried out in an inert solvent such as dimethylformamide, an aliphatic ether (for example ethyl ether) or a 1-4C aliphatic alcohol in the presence of a base (for example sodium hydride), at a temperature of between 0°C and 60°. 15 The derivatives of formula Rb-CH2-Hal are commercially available or may be obtained by application or adaptation of the methods described in the examples. In particular, the methylated derivative or the corresponding alcohol is halogenated using a 20 halogenating agent such as hydrobromic acid, in acetic acid, at a temperature close to 20°C or N-bromo- or N-chlorosuccinimide in the presence of benzoyl peroxide, in an inert solvent such as tetrachloromethane, at the boiling point of the 25 reaction medium. The methylated derivatives or the corresponding alcohols are commercially available or may be obtained according to the methods described by BRINE G.A. et al., J. Heterocyl. Chem, 26, 677 (1989) 21 and NAGARATHNAM D., Synthesis, 8, 743 (1992) and in the examples.
The azetidinones of formula 3 may be obtained by application or adaptation of the methods described by KATRITZKY A.R. et al., J. Heterocycl. Chem., 271 (1994), or DAVE P.R., J. Org. Chem., 61, 5453 (1996) and in the examples. The procedure is generally carried out according to the following reaction scheme: R O A R, HYDROXYLAMINE N R •OH R, B Br N *3 R4 X R A. 3 - M4 3 Nl-i Ro ^R4 O Z-V-Hal )H N R, In these formulae, R3 and R4 have the same meanings as in formula (I) and HAL represents a chlorine or bromine atom.
In step A, the procedure is preferably carried out in an inert solvent such as a 1-4C aliphatic 22 alcohol (ethanol or methanol for example), optionally in the presence of an alkali metal hydroxide, at the boiling point of the reaction medium.
In step B, the reduction is generally carried 5 out using lithium aluminum hydride, in tetrahydrofuran at the boiling point of the reaction medium.
In step C, the procedure is preferably carried out in an inert solvent such as a 1-4C aliphatic alcohol (ethanol or methanol for example) in the 10 presence of sodium hydrogen carbonate, at a temperature of between 20°C and the boiling point of the reaction medium.
In step D, the oxidation is preferably carried out in DMSO, using the sulfurtrioxide-pyridine complex, 15 at a temperature close to 20°C or using dimethyl sulfoxide, in the presence of oxalyl chloride and triethylamine, at a temperature of between -70 and -50°C.
In step E, the procedure is carried out 20 according to the method described by GRISAR M. et al., in J. Med. Chem., 885 (1973). The magnesium compound of the brominated derivative is formed and then the nitrile is reacted, in an ether such as ethyl ether, at a temperature of between 0°C and the boiling point of 25 the reaction medium. After hydrolysis with an alcohol, the intermediate imine is reduced in situ with sodium borohydride at a temperature of between 0°C and the boiling point of the reaction medium. 23 The R3-CO-R4 derivatives are commercially available or may be obtained by application or adaptation of the methods described by KUNDER N.G. et al. J. Chem. Soc. Perkin Trans 1, 2815 (1997); MORENO-MARRAS M., Eur. J. Med. Chem., 23 (5) 477 (1988); SKINNER et al., J. Med. Chem., 14 (6) 546 (1971); HURN N.K., Tet. Lett., 36 (52) 9453 (1995); MEDICI A. et al. , Tet. Lett., 2_4 (28) 2901 (1983); RIECKE R.D. et al., J. Org. Chem., 62 (20) 6921 (19 97); 10 KNABE J. et al., Arch. Pharm., 306 (9) 648 (1973); CONSONNI R. et al., J. Chem. Soc. Perkin Trans 1, 1809 (1996); FR-96-2481 and JP-94-261393.
The RsBr derivatives are commercially available or may be obtained by application or adaptation of the 15 methods described by BRANDSMA L. et al., Synth. Comm., 20 (11) 1697 and 3153 (1990); LEMAIRE M. et al., Synth. Comm., 2_4 (1) 95 (1994); GODA H. et al. , Synthesis, 9 849 (1992); BAEUERLE P. et al., J. Chem. Soc. Perkin Trans 2, 489 (1993) .
The R4CN derivatives are commercially available or may be obtained by application or adaptation of the methods described by BOUYSSOU P. et al., J. Het. Chem., 29 (4) 895 (1992); SUZUKI N. et al., J. Chem. Soc.
Chem. Comm., 1523 (1984); MARBURG S. et al., J. Het. 25 Chem., 17 1333 (1980); PERCC V. et al., J. Org. Chem., 60 (21) 6895 (1995) .
The compounds of formula (I) for which R represents a radical CR1R2 in which Ri represents a hydrogen atom and R2 represents a radical C(Rs) (R9) (Rio) 24 in which Rg represents a hydrogen atom, Rg represents a radical -CO-NR26R27, -COOH, -COOalk, -CH2OH, -NHCOOalk or -NH-CO-NH-alk and Rio represents a radical Ar or Het may be prepared according to the following reaction scheme: R, r3 N—, * CH — 4 rA COOalk N- V v OH COOalk R. '10 N- COOalk Ic R, R, R ch2oh Id Ric R.
HNR26R27 N- CONR2gR27 "10 R, R.-S N- ^-—COOalk 5 R,„ A N- le \ COOH R; N- N=C=0 '10 N- R r3 h HOalk NH-CO-NHalk N- lg R'° NH-COOalk R Ih in these formulae R3, R4, Ri0, R26 and R27 have the same meanings as in formula (I) and alk represents an alkyl radical.
The derivatives of formula 4 are commercially available or may be obtained by esterification of the 5 corresponding acids, optionally in an activated form such as the acid chloride. The acids are commercially available or may be obtained from the corresponding methylated derivatives according to the method described by JP. HANSEN et al., J. Heteocycl., 10, 711 10 (1973) .
Reaction a is generally carried out in an inert solvent such as an ether (for example tetrahydrofuran), in the presence of a strong base such as tert-butyllithium, n-butyllithium, lithium 15 diisopropylamide or potassium tert-butoxide, at a temperature of between -70°C and -15°C.
Reaction b is generally carried out by any dehydration method known to a person skilled in the art which makes it possible to dehydrate an alcohol in 20 order to obtain the corresponding alkene and in particular the methods previously described.
The reduction c is generally carried out in an inert solvent such as an aliphatic alcohol (1-4C) such as methanol, a chlorinated solvent such as chloroform, 25 dichloromethane or a mixture of these solvents, in the presence of NaBH4, at a temperature of between 0°C and the boiling point of the reaction medium.
Reaction d is carried out by any method known to a person skilled in the art which makes it possible 26 to pass from an ester to the corresponding acid without affecting the rest of the molecule. The procedure is preferably carried out in an inert solvent such as dioxane, in the presence of hydrochloric acid, at the 5 boiling point of the reaction medium.
Reaction e is carried out by any method known to a person skilled in the art which makes it possible to pass from an acid or a reactive derivative of this acid to a carboxamide without affecting the rest of the 10 molecule. Preferably, when the acid is used, the procedure is carried out in the presence of a condensing agent which is used in peptide chemistry such as a carbodiimide (for example N,N'-dicyclohexylcarbodiimide) or 15 N,N'-carbonyldiimidazole, in an inert solvent such as an ether (for example tetrahydrofuran or dioxane), an amide (dimethylformamide) or a chlorinated solvent (for example methylene chloride, 1,2-dichloroethane or chloroform) at a temperature of between 0°C and the 20 reflux temperature of the reaction mixture.. When a reactive derivative of the acid is used, it is possible to cause the anhydride, a mixed anhydride or an ester (which may be chosen from the activated or nonactivated esters of the acid) to react; the procedure is then 25 carried out either in an organic medium, optionally in the presence of an acid acceptor such as a nitrogen-containing organic base (for example trialkylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene or 1,5-diazabicyclo[4.3.0]non-5-ene), in a 27 solvent as cited above, or a mixture of these solvents, at a temperature of between 0°C and the reflux temperature of the reaction mixture, or in a biphasic aqueous-organic medium in the presence of an alkaline 5 or alkaline-earth base (sodium hydroxide or potassium hydroxide) or an alkali or alkaline-earth metal carbonate or bicarbonate at a temperature of between 0 and 40°C.
Reaction f is carried out by CURTIUS 10 arrangement, in the presence of diphenylphosphorazide azide and triethylamine, in toluene, at a temperature in the region of 50°C.
For reactions g and h, the procedure is carried out directly in the reaction medium of step g at a 15 temperature in the region of 20°C.
The compounds of formula (I) for which R represents a radical CR1R2 in which Ri is a hydrogen atom and R2 represents a radical -C(R8) (Rg) (Rio) for which Rg is a hydrogen atom, R9 is a radical -CH2-NHR28 20 and Rio represents a radical Ar or Het, may be prepared according to the following reaction scheme: 28 R n, A N- RdCHO n3 C)S02Re _ R4— HCH,Rd R,o li In these formulae, R3, R4 and Rio have the same meanings as in formula (I), Rd represents an alkyl or 5 phenyl radical, Re represents an alkyl radical, Rf represents an alkyl radical, Rg represents an alkyl, cycloalkylalkyl, cycloalkyl, -(CH2)nOH radical, n is equal to 1, 2 or 3.
Step a is generally carried out in an inert 10 solvent such as an aliphatic alcohol (1-4C) (for example methanol), in a chlorinated solvent (for example dichloromethane or dichloroethane) or tetrahydrofuran, in the presence of a base such as NaBH(OCOCH3) 3, at a temperature in the region of 20°C. 15 Step b is generally carried out in an inert solvent such as a halogenated solvent (for example dichloromethane), in the presence of an organic base such as triethylamine or dimethylaminopyridine, at a 29 temperature of between 0°C and the boiling point of the reaction medium. solvent such as tetrahydrofuran, dimethylformamide, a 5 chlorinated solvent (for example chloroform or 1,2-dichloroethane), an aromatic solvent (for example benzene or toluene), at a temperature of between 10°C and the boiling point of the reaction medium. person skilled in the art which makes it possible to pass from an acid or a reactive derivative of this acid to a carboxamide without affecting the rest of the molecule and in particular the preferred methods previously described.
The derivatives 6 may be obtained according to the following reaction scheme: Step c is generally carried out in an inert Step d is carried out by any method known to a MsCI N N a In these formulae, R3, R4 and Rio have the same meanings as in formula (I) and Ms is a methylsulfonyloxy radical.
Step a is generally carried out in an inert solvent such as tetrahydrofuran, in the presence of triethylamine, at a temperature of between 10 and 20°C, Step b is generally carried out with liquid aqueous ammonia in methanol, in an autoclave, at a temperature in the region of 60°C.
The compounds of formula (I) in which R represents a radical CRiR2 in which Rx is a hydrogen . atom and R2 is a radical -CONRi3Ri4 may be prepared according to the following reaction scheme: R.
N- MsCI \>H R n, A N- N- R, NaCN N OMs R,3R,4NH C0NHR.,R14 Im 13 14 N- -CN EtOCH2CH2OH COOH In these formulae, R3, R4, Ri3 and Ri4 have the same meanings as in formula (I), Ms represents a methylsulfonyloxy radical and Et represents ethyl.
Step a is carried out in the presence of triethylamine, in an inert solvent such as an ether 31 (for example tetrahydrofuran), at a temperature in the region of 0°C.
Step b is generally carried out in an inert solvent such as a mixture of water and 5 dimethylformamide, at a temperature of between 30 and 75 °C.
Step c is carried out by any method known to a person skilled in the art which makes it possible to pass from a cyanated compound to the corresponding acid 10 without affecting the rest of the molecule. Preferably, the procedure is carried out by means of potassium hydroxide in an aliphatic alcohol (1-4C) (for example ethanol) or in an aqueous medium, at the boiling point of the reaction medium.
Step d is carried out by any method known to a person skilled in the art which makes it possible to pass from an acid or a reactive derivative of this acid to a carboxamide without affecting the rest of the molecule molecule and in particular the preferred 20 methods previously described.
The compounds of formula (I) for which R represents a radical CRiR2 in which Ri is a hydrogen atom and R2 is a radical -CH2-CONRi3Ri4 may be prepared according to the following reaction scheme: 32 ,cooc2h5 '3 - N- R, r13r14nh n- \^,CONR„R14 d COOH In In these formulae, R3, R4, R13 and Ri4 have the same meanings as in formula (I) and Et represents an 5 ethyl radical.
Reaction a is generally carried out in an inert solvent such as tetrahydrofuran, in the presence of a base such as sodium hydride, or an alkali metal carbonate (for example potassium carbonate), at a 10 temperature of between 20°C and the boiling point of the reaction medium.
Reaction b is generally carried out by means of NaBH4, in ethanol, at a temperature in the region of 0°C.
Reaction c is carried out by any method known to a person skilled in the art which makes it possible to pass from an ester to the corresponding acid without affecting the rest of the molecule. The procedure is preferably carried out in an inert solvent such as 20 dioxane, in the presence of hydrochloric acid, at the boiling point of the reaction medium. 33 Reaction d is carried out by any method known to a person skilled in the art which makes it possible to pass from an acid or a reactive derivative of this acid to a carboxamide without affecting the rest of the 5 molecule molecule and in particular the preferred methods previously described.
The intermediates 7 may also be obtained by malonic synthesis according to the following reaction scheme: 0 R3 N N- R, b N OMs -COOC2H5 .COOH COOC2H5 In these formulae, Ms represents a methylsulfonyloxy radical, R3 and R4 have the same 15 meanings as in formula (I).
Reaction a is generally carried out by the action of diethyl malonate, in an inert solvent such as tetrahydrofuran, in the presence of freshly prepared sodium ethoxide, at the boiling point of the reaction 2 0 medium.
Reaction b is generally carried out in an aqueous solution of hydrochloric acid at the boiling point of the reaction medium.
The compounds In may also be obtained according 25 to the following reaction scheme: 34 PO(OC2H5)2-CH2COOH ^-4 PO{OC2Hg)2-CH2CONR13R14 In In these formulae, R3, R4, Ri3 and R14 have the same meanings as in formula (I).
Step a is carried out by any method known to a person skilled in the art which makes it possible to pass from an acid or a reactive derivative of this acid to a carboxamide without affecting the rest of the molecule molecule and in particular the preferred methods previously described.
Step b is generally carried out in an inert solvent such as tetrahydrofuran, in the presence of a base such as sodium hydride or potassium carbonate, at a temperature of between 20°C and the boiling point of the reaction medium.
The reduction of step c is generally carried out by means of NaBH4, in ethanol, at a temperature in the region of 20°C.
The compounds of formula (I) for which R represents a radical CR1R2 in which Ri is a hydrogen atom and R2 represents a radical -SORg or -SO2R6 may be prepared according to the following reaction scheme: In these formulae, R3, R4 and R6 have the same 5 meanings as in formula (I) and Ms is a methylsulfonyloxy radical.
Step a is generally carried out in an inert solvent such as tetrahydrofuran, in the presence of an inorganic base such as sodium hydride, at a temperature 10 of between 0°C and the boiling point of the reaction medium.
Step b is generally carried out by any method of persons skilled in the art for oxidizing a sulfur-containing derivative, such as those described 15 by M. HUDLICKY, Oxidations in Organic Chemistry, ACS Monograph, 186, 252-263 (1990). For example, the procedure is carried out by the action of an organic peroxy acid or a salt of such a peroxy acid (peroxycarboxylic or peroxysulfonic acids, in 20 particular peroxybenzoic acid, 3-chloroperoxybenzoic acid, 4-nitroperoxybenzoic acid, peroxyacetic acid, 36 trifluoroperoxyacetic acid, peroxyformic acid or monoperoxyphthalic acid) or inorganic peracids or a salt of such an acid (for example periodic or persulfuric acid), in an inert solvent such as a 5 chlorinated solvent (for example chloroform or dichloromethane), at a temperature of between 0 and 25°C or alternatively by means of oxone in a water-alcohol (methanol or ethanol) mixture.
Step c is generally carried out by any method 10 of persons skilled in the art for oxidizing a sulfinyl derivative. Preferably, the procedure is carried out by the action of an organic peroxy acid or a salt of such a peroxy acid (peroxycarboxylic or peroxysulfonic acids, in particular peroxybenzoic acid, 15 3-chloroperoxybenzoic acid, 4-nitroperoxybenzoic acid, peroxyacetic acid, trifluoroperoxyacetic acid, peroxyformic acid or monoperoxyphthalic acid) or alternatively by means of oxone, in a water-alcohol (methanol or ethanol) mixture. 2 0 The compounds of formula (I) for which R represents a radical CRiR2 in which Ri is a hydrogen atom and R2 represents a radical -COR6 or -CO-cycloalkyl may be prepared according to the following reaction scheme: 37 R, R, R, N- H3CHNOCH3 R, COOH N- CON(CH3)OCH3 b /RhMgBr R, R, N- iq CORh In these formulae, R3 and R4 have the same meanings as in formula (I) and Rh has the same meanings 5 as R6 or represents a cycloalkyl radical (3 to 10 carbon atoms).
Step a is carried out by any method known to a person skilled in the art which makes it possible to pass from an acid or a reactive derivative of this acid 10 to a carboxamide without affecting the rest of the molecule molecule and in particular the preferred methods previously described.
Step b is generally carried out in an inert solvent such as an ether such as tetrahydrofuran, at a 15 temperature in the region of 0°C. The organomagnesium compounds are prepared according to methods known to a person skilled in the art, such as those described in the examples. 38 The compounds of formula (I) for which Ri is a hydrogen atom and R2 is a radical -C(OH) (R6)Ri2)f -C (OH) (R6) (alkyl) , -C (=NO-CH2-CH=CH2) Re or -C(=NOalk)R6 may be prepared according to the following reaction scheme: R* N- Ir \^NORj Rc R.
RjONH, N- iq \ CORc RiMgBr R, N- Is Ri H Rc In these formulae, R3, R4 and R6 have the same meanings as in formula (I), Ri has the same meanings as R12 or represents an alkyl radical (1 to 6 straight- or 10 branched-chain carbon atoms) and Rj represents an alkyl radical (1 to 6 straight- or branched-chain carbon atoms) or -CH2-CH=CH2.
Step a is generally carried out in an inert solvent such as an aliphatic alcohol (for example 15 ethanol), in the presence of sodium acetate, at a temperature of between 20°C and the boiling point of the reaction medium. 39 Step b is generally carried out in an inert solvent such as an ether such as tetrahydrofuran, at a temperature in the region of 0°C. The organomagnesium compounds are prepared according to methods known to a 5 person skilled in the art such as those described in the examples.
The compounds of formula (I) for which R represents a radical CRiR2 in which Ri is a hydrogen atom and R2 represents a radical -CH (R6) NR31R32, in which 10 R31 and R32 are hydrogen atoms or radicals -CH (R6)NHS02alk, -CH (R6) NHCONHalk or -CH (R6) NHCOR31, may be prepared according to the following reaction scheme: 40 ru N- ru A.
N- iq CORfi OH MsCI R: N- OMs In these formulae, R3, R4, R6 and R31 have the same meanings as in formula (I), Ms represents a methylsulfonyloxy radical and alk represents an alkyl radical.
Reaction a is generally carried out by means c NaBH4 in ethanol, at a temperature in the region of 20 °C. 41 Step b is carried out in the presence of triethylamine, in an inert solvent such as an ether (for example tetrahydrofuran), at a temperature in the region of 0°C.
Step c is carried out by means of liquid aqueous ammonia in methanol, in an autoclave at a temperature in the region of 60°.
Step d is generally carried out in an inert solvent such as a halogenated solvent (for example 10 dichloromethane) or tetrahydrofuran, in the presence of an organic base such as triethylamine, dimethylaminopyridine, at a temperature in the region of 20°C.
Step e is carried out by any method known to a 15 person skilled in the art which makes it possible to pass from an acid or a reactive derivative of this acid to a carboxamide without affecting the rest of the molecule and in particular the preferred methods previously described.
Step f is generally carried out by means of an inert solvent such as tetrahydrofuran, dimethylformamide, a chlorinated solvent (for example chloroform or dichloroethane), an aromatic solvent (for example benzene or toluene), at a temperture of between 25 10°C and the boiling point of the reaction medium.
The compounds of formula (I) for which R represents a radical CRiR2 in which Ri is a hydrogen atom and R2 represents a radical -CH (Re) NR31R32, R31 is a hydrogen atom and R32 is an alkyl, Ar or -alk-Ar radical 42 may be prepared by the action of a halide HalR3i on a compound of formula (I) for which R represents a radical CR1R2 in which Ri is a hydrogen atom and R2 represents a radical -CH (R6) NR31R32, R3i and R32 are 5 hydrogen atoms.
This reaction is carried out in an inert polar solvent such as acetonitrile, tetrahydrofuran or dimethylformamide, in the presence of an organic or inorganic base (alkali metal (for example sodium or 10 potassium) carbonate, trialkylamine (for example triethylamine or dimethylaminopyridine)), at a temperature of between 0°C and the boiling point of the solvent, optionally in the presence of palladium or one of its salts or complexes.
The compounds of formula (I) for which R represents a radical CRiR2 in which Ri is a hydrogen atom and R2 represents a radical -CH (R6) NR3iR32, R31 is a hydrogen atom and R32 is an alkyl radical may also be prepared by the action of a corresponding compound of 20 formula (I) for which R represents a radical CRiR2 in which Ri is a hydrogen atom and R2 represents a radical -CO-R6 on an amine HNR31R32 for which R3i is a hydrogen atom and R32 is an alkyl radical.
This reaction is generally carried out in an 25 inert solvent such as a chlorinated solvent (for example dichloromethane or dichloroethane), in the presence of a reducing agent such as sodium triacetoxyborohydride, at a temperature of between 0°C and 7 0 0 C. 43 The compounds of formula (I) for which R represents a radical CRiR2 in which Ri is a hydrogen atom and R2 represents a radical -CH (R6) NR3iR32, R3i and R32 are alkyl, Ar or -alk-Ar radicals may be prepared by 5 the action of a halide HalR32 on a compound of formula (I) for which R represents a radical CRxR2 in which Rx is a hydrogen atom and R2 represents a radical -CH (R6) NR3iR32, R3i is a hydrogen atom and R32 is an alkyl, Ar or -alk-Ar radical.
This reaction is carried out in an inert polar solvent such as acetonitrile, tetrahydrofuran or dimethylformamide, in the presence of an organic or inorganic base (alkali metal (for example sodium or potassium) carbonate, trialkylamine (for example 15 triethylamine or dimethylaminopyridine)), at a temperature of between 0°C and the boiling point of the solvent, optionally in the presence of palladium or one of its salts or complexes.
The compounds of formula (I) for which R 20 represents a radical CRiR2 in which Rx is a hydrogen atom and R2 represents a radical -CH (Re) NR3iR32, R3i is a hydrogen atom and R32 is a (2-6C) alkyl or -(2-6C)alk-Ar radical may be prepared by the action of an aldehyde RaCHO for which Ra is an alkyl or -alk-Ar radical on a 25 compound of formula (I) for which R represents a radical CRiR2 in which Ri is a hydrogen atom and R2 represents a radical -CH (Re) NR3iR32, R3i and R32 are hydrogen atoms. 44 This reaction is carried out in an inert solvent such as dichloromethane, dichloroethane, toluene or tetrahydrofuran, at a temperature of between 0°C and 50°C in the presence of a reducing agent such 5 as sodium triacetoxyborohydride or sodium cyanoborohydride.
The compounds of formula (I) for which R represents a radical CRiR2 in which Ri is a hydrogen atom and R2 represents a radical -CH (R6) NR31R32, R31 is an 10 alkyl, Ar or -alk-Ar radical and R32 is a (2-6C) alkyl or -(2-6C)alk-Ar radical may be prepared by the action of an aldehyde RaCHO for which Ra is an alkyl or -alk-Ar radical on a compound of formula (I) for which R represents a radical CRiR2 in which Ri is a hydrogen 15 atom and R2 represents a radical -CH (Re) NR3iR32, R31 is a hydrogen atom and R32 is an alkyl, Ar or -alk-Ar radical.
This reaction is carried out in an inert solvent such as dichloromethane, dichloroethane, 20 toluene or tetrahydrofuran, at a temperature of between 0°C and 50°C in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride.
The compounds of formula (I) for which R 25 represents a radical CRiR2 in which Ri is a hydrogen atom and R2 represents a radical -CH (Re) NR3iR32, R3i and R32 form with the nitrogen atom to which they are attached a heterocycle chosen from aziridinyl, azetidinyl, pyrrolidinyl or piperidinyl may be prepared 45 by the action of a dihalide Hal-(2-5C)alk-Hal on a compound of formula (I) for which R represents a radical CR1R2 in which Ri is a hydrogen atom and R2 represents a radical -CH (Rg) NR3:LR32, R3i and R32 are 5 hydrogen atoms.
This reaction is carried out in an inert polar solvent such as acetonitrile, tetrahydrofuran or dimethylformamide, in the presence of an organic or inorganic base (alkali metal (for example sodium or 10 potassium) carbonate, trialkylamine (for example triethylamine or dimethylaminopyridine)), at a temperature of between 0°C and the boiling point of the solvent, optionally in the presence of palladium or one of its salts or complexes.
The compounds of formula (I) for which R represents a radical CRiR2 in which Ri is a hydrogen atom and R2 represents a radical -CH2-CORg, -CH2-CH (Rg) -NR3iR32 or -CH2-C (=NOalk) Rg may be prepared according to the following reaction scheme: 46 N- PO(OC2H5)2-CH2CON(CH3)OCH3 R 'o RJ N- OH N- H.CHNOCH, _ O 3 3 R R3 N- \^-CO-N(CH3)OCH3 \ CO-N(CH3)OCH3 R, R; I N- Iz alkONH, .NOalk R. d R, RgMgBr R N- lx R.
HNR31R32 Ro N- 3.1 o N 32 ly ° In these formulae, R3, R4, R6, R3i and R32 have the same meanings as in formula (I) and alk represents an alkyl radical.
Step a is generally carried out in a solvent such as tetrahydrofuran, at a temperature of between 20°C and the boiling point of the reaction medium.
Step b is generally carried out in an inert solvent such as an aliphatic alcohol (for example methanol), a chlorinated solvent (chloroform or 47 dichloromethane) or a mixture of these solvents, in the presence of a reducing agent such as NaBH4, at a temperature of between 0°C and the boiling point of the reaction medium.
Step c is carried out by any method known to a person skilled in the art which makes it possible to pass from an acid or a reactive derivative of this acid to a carboxamide without affecting the rest of the molecule and in particular the preferred methods 10 previously described.
Step d is generally carried out in an inert solvent such as an ether such as tetrahydrofuran, at a temperature in the region of 0°C. The organomagnesium compounds are prepared according to the m'yhodes known 15 to a person skilled in the art such as those described in the examples.
Step e is generally carried out in an inert solvent such as a 1-4C aliphatic alcohol such as methanol, in the presence of sodium acetate, at a 20 temperature of between 20°C and the boiling point of the reaction medium.
Step f is carried out in an inert solvent such as a chlorinated solvent (for example dichloromethane or dichloroethane), in the presence of a reducing agent 25 such as sodium triacetoxyborohydride, at a temperature of between 0°C and 70°C.
The compounds of formula (I) for which R represents a radical CR1R2 in which Ri represents a cyano, -S-alk-NRi6Ri7, -NHR15, alkyl or -NR20R21 radical 48 and R2 represents a radical -C(R8) (Rn) (R12) in which Rg is a hydrogen atom may be prepared according to the following reaction scheme: 12 alk-NR16R17 N- Ize N- 11 12 NR20R21 Izd 11 12 alk In these formulae, R3, R4, Ru, Ri2, R15, Ri6 and R17 have the same meanings as in formula (I), alk represents an alkyl radical, Hal represents a halogen atom and M represents a metal and preferably copper.
Step a is preferably carried out in a polar solvent such as dimethyl sulfoxide, at a temperature of between 20 and 50°C. 49 Step b is preferably carried out in an inert solvent such as dimethyl sulfoxide, tetrahydrofuran or acetonitrile, in the presence of a base such as an alkali metal carbonate (for example potassium 5 carbonate) or ammonium hydroxide, at a temperature of between 20°C and the boiling point of the reaction medium.
Step c is preferably carried out in an inert solvent such as dimethyl sulfoxide, tetrahydrofuran or 10 acetonitrile, in the presence of a base such as an alkali metal carbonate (for example potassium carbonate) or ammonium hydroxide, at a temperature of between 20°C and the boiling point of the reaction medium.
Step d is preferably carried out in an inert solvent such as an ether (ethyl ether) or tetrahydrofuran, at a temperature of between -78°C and 20 °C.
Step e is preferably carried out in an inert 20 solvent such as dimethyl sulfoxide, tetrahydrofuran, acetonitrile, dichloromethane or dichloroethane in the presence of a base such as an alkali metal carbonate (for example potassium carbonate) or ammonium hydroxide, at a temperature of between 20°C and the 25 boiling point of the reaction medium.
The compounds of formula (I) for which R represents a radical CRiR2 in which Ri represents a radical -alk-NRi8Ri9, Ris and Ri9 represent a hydrogen atom may be prepared by reducing the corresponding 50 compound of formula (I) for which R represents a radical CR1R2 in which Ri represents a cyano radical.
This reaction is generally carried out in an inert solvent such as tetrahydrofuran, ethyl ether or 5 toluene, at a temperature of between 0°C and the boiling point of the reaction medium, in the presence of a reducing agent such as aluminum hydride.
The compounds of formula (I) for which R represents a radical CRiR2 in which Ri represents a 10 radical -alk-NR18Ri9, Ri8 represents a hydrogen atom and R19 represents an alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -S02alk, -CO-NHalk or -COOalk radical may be prepared by the action of a halide HalRig, Hal represents a halogen, on a compound of 15 formula (I) for which R represents a radical CRiR2 in which Ri represents a radical -alk-NRi8Ri9, Ri8 and R19 represent a hydrogen atom.
This reaction is carried out in an inert polar solvent such as acetonitrile, tetrahydrofuran or 20 dimethylformamide, in the presence of an organic or inorganic base (alkali metal (for example sodium or potassium) carbonate, trialkylamine (for example triethylamine or dimethylaminopyridine)), at a temperature of between 0°C and the boiling point of the 25 solvent, optionally in the presence of palladium or one of its salts or complexes.
The compounds of formula (I) for which R represents a radical CRiR2 in which Ri represents a radical -alk-NRi8Ri9, Ri8 represents an alkyl radical and 51 Rig represents an alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -S02alk, -CO-NHalk or -COOalk radical may be prepared by the action of an alkyl halide on a compound of formula (I) for which R 5 represents a radical CRiR2 in which Ri represents a radical -alk-NRi8Ri9, Ris represents a hydrogen atom and Rig represents an alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -S02alk, -CO-NHalk or -COOalk radical.
This reaction is carried out in an inert polar solvent such as acetonitrile, tetrahydrofuran or dimethylformamide, in the presence of an organic or inorganic base (alkali metal (for example sodium or potassium) carbonate, trialkylamine (for example 15 triethylamine or dimethylaminopyridine)), at a temperature of between 0°C and the boiling point of the solvent, optionally in the presence of palladium or one of its salts or complexes.
The compounds of formula (I) for which R 20 represents a radical CRiR2 in which either Ri represents a hydrogen atom and R2 represents a radical —C (R8) (R9) (Rio) or -C(R8) (Rn) (Ri2) , or Ri represents an alkyl, NH-R15, cyano, -S-alk-NRi6Ri7, -alk-NRi8Ri9 or -NR2oR2i radical and R2 represents a radical 25 -C(Rg) (R11) (R12) and R8 represents an alkyl radical may be prepared by alkylation of a corresponding compound of formula (I) for which R8 is a hydrogen atom.
This reaction is preferably carried out by means of a base such as an alkali metal hydride (for 52 example sodium hydride), an alkali metal amide (for example sodium amide) or an organometallic derivative, in an inert solvent such as an aliphatic ether (ethyl ether) or tetrahydrofuran, at a temperature of between -78°C and 30°C, by means of an alkylating agent such as an alkyl halide or an alkyl sulfonate.
The compounds of formula (I) for which R represents a radical C=C(R7) S02alk may also be prepared according to the following reaction scheme: R7-CH2-P03Et2 a) n-BuLi b) S8 c) Hal-alk A r7 aik P03Et2 R, N- \_^S02alk *7 rA ^ — Salk r7 In these formulae, R3, R4 and R7 have the same meanings as in formula (I), alk represents an alkyl 15 radical and Hal represents a halogen atom.
Reaction A is generally carried out in an inert solvent such as an ether (for example ethyl ether), in the presence of a strong base such as tert-butyllithium 53 or n-butyllithium, at a temperature of between -7 0°C and -50°C, followed by the addition of sulfur and then an alkyl halide (for example iodide or bromide).
Reaction B is generally carried out in an inert 5 solvent such as an ether (for example tetrahydrofuran), in the presence of a strong base such as tert-butyllithium or n-butyllithium, at a temperature of between -70°C and -50°C, followed by the addition of azeditin-3-one, a return to room temperature and 10 hydrolysis.
Reaction C is carried out by any known method which makes it possible to oxidize a sulfur-containing derivative without affecting the rest of the molecule, such as those previously described.
It is understood for persons skilled in the art that, to carry out the processes according to the invention which are described above, it may be necessary to introduce groups protecting amino, hydroxyl and carboxyl functions in order to avoid side 20 reactions. These groups are those which allow removal without affecting the rest of the molecule. As examples of groups protecting the amino function, there may be mentioned tert-butyl or methyl carbamates which may be regenerated using iodotrimethylsilane or allyl using 25 palladium catalysts. As examples of groups protecting the hydroxyl function, there may be mentioned triethylsilyl and tert-butyldimethylsilyl which may be regenerated using tetrabutylammonium fluoride or alternatively asymmetric acetals (methoxymethyl or 54 tetrahydropyranyl for example) with regeneration using hydrochloric acid. As groups protecting carboxyl functions, there may be mentioned esters (allyl or benzyl for example), oxazoles and 2-alkyl-l,3-5 oxazolines. Other protecting groups which can be used are described by GREENE T.W. et al., Protecting Groups in Organic Synthesis, second edition, 1991, John Wiley & Sons.
The compounds of formula (I) may be purified by 10 the customary known methods, for example by crystallization, chromatography or extraction.
The enantiomers of the compounds of formula (I) may be obtained by resolution of the racemates for example by chromatography on a chiral column according 15 to PIRCKLE W.H. et al., Asymmetric synthesis, Vol. 1, Academic Press (1983) or by formation of salts or by synthesis from chiral precursors. The diastereoisomers may be prepared according to known conventional methods (crystallization, chromatography or from chiral 2 0 precursors) .
The compounds of formula (I) may be optionally converted to addition salts with an inorganic or organic acid by the action of such an acid in an organic solvent such as an alcohol, a ketone, an ether 25 or a chlorinated solvent. These salts also form part of the invention.
As examples of pharmaceutically acceptable salts, the following salts may be mentioned: benzenesulfonate, hydrobromide, hydrochloride, citrate, 55 ethanesulfonate, fumarate, gluconate, iodate, isethionate, maleate, methane sulfonate, methylene-bis-p-oxynaphthoate, nitrate, oxalate, pamoate, phosphate, salicylate, succinate, sulfate, 5 tartrate, theophyllineacetate and p-toluenesulfonate.
The compounds of formula (I) exhibit advantageous pharmacological properties. These compounds possess a high affinity for the cannabinoid receptors and particularly those of the CBl type. They 10 are CBl receptor antagonists and are therefore useful in the treatment and prevention of disorders affecting the central nervous system, the immune system, the cardiovascular or endocrine system, the respiratory system, the gastrointestinal apparatus and reproductive 15 disorders (Hollister, Pharm. Rev.; 38, 1986, 1-20, Reny and Sinha, Prog. Drug Res., 36, 71-114 (1991), Consroe and Sandyk, in Marijuana/Cannabinoids, Neurobiology and Neurophysiology, 459, Murphy L. and Barthe A. Eds, CRC Press, 1992).
Accordingly, these compounds may be used for the treatment or prevention of psychoses including schizophrenia, anxiety disorders, depression, epilepsy, neurodegeneration, cerebellar and spinocerebellar disorders, cognitive disorders, cranial trauma, panic 25 attacks, peripheral neuropathies, glaucomas, migraine, Parkinson's disease, Alzheimer's disease, Huntington's chorea, Raynaud's syndrome, tremor, obsessive-compulsive disorder, senile dementia, thymic disorders, Tourette's syndrome, tardive dyskinesia, 56 bipolar disorders, cancers, movement disorders induced by medicaments, dystonia, endotoxemic shocks, hemorrhagic shocks, hypotension, insomnia, immunological diseases, multiple sclerosis, vomiting, 5 asthma, appetite disorders (bulimia, anorexia), obesity, memory disorders, in weaning from chronic treatments and alcohol or drug abuse (opioids, barbiturates, cannabis, cocaine, amphetamine, phencyclide, hallucinogens, benzodiazepines for 10 example), as analgesics or potentiators of the analgesic activity of the narcotic and nonnarcotic drugs. They may also be used for the treatment or prevention of intestinal transit.
The affinity of the compounds of formula (I) 15 for the cannabis receptors has been determined according to the method described by KUSTER J.E., STEVENSON J.I., WARD S.J., D'AMBRA T.E., HAYCOCK D.A. in J. Pharmacol. Exp. Ther., 2 64 1352-1363 (1993) .
In this test, the IC50 of the compounds of 20 formula (I) is less than or equal to 1000 nM.
Their antagonist activity has been shown by means of the model of hypothermia induced by an agonist of the cannabis receptors (CP-55940) in mice, according to the method described by Pertwee R.G. in Marijuana, 25 Harvey D.J. eds, 84 Oxford IRL Press, 263-277 (1985) .
In this test, the DE50 of the compounds of formula (I) is less than or equal to 50 mg/kg. 57 The compounds of formula (I) exhibit low toxicity. Their LD50 is greater than 40 mg/kg by the subcutaneous route in mice.
The preferred compounds of formula (I) are the 5 following: (RS)-1-[bis(4-chlorophenyl)methyl)]-3-[(3,5-difluoro-phenyl)(methylsulfonyl)methyl]azetidine, (R)-1-[bis(4-chlorophenyl)methyl)]-3-[(3,5-difluoro-phenyl) (methylsulfonyl)methyl]azetidine, (S)-1-[bis(4-chlorophenyl)methyl)]-3-[(3,5-difluoro-phenyl) (methylsulfonyl)methyl]azetidine, (RS)-1-[bis(4-chlorophenyl)methyl)]— 3 —[(pyrid-3-yl)-(methylsulfonyl)methyl]azetidine, (R)-1-[bis(4-chlorophenyl)methyl)]-3-[(pyrid-3-yl)-20 (methylsulfonyl)methyl]azetidine, (S)-1-[bis(4-chlorophenyl)methyl)]-3-[(pyrid-3-yl)-(methylsulfonyl)methyl]azetidine, (RS)-1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluoro-phenyl)methylsulfonylmethyl]azetidine, (R)-1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluoro-phenyl)methylsulfonylmethyl]azetidine, 58 (S)-1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluoro-phenyl)methylsulfonylmethyl]azetidine, 1-[bis(4-chlorophenyl)methyl]-3-(RS)-{[3-azetidin-l-yl-phenyl]methylsulfonylmethyl}azetidine, 1-[bis(4-chlorophenyl)methyl]-3-(R)-{[3-azetidin-l-yl-phenyl]methylsulfonylmethyl}azetidine, 1-[bis(4-chlorophenyl)methyl]-3-(S)-{[3-azetidin-l-yl-phenyl]methylsulfonylmethyl}azetidine, (RS)-l-[3({l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-15 methylsulfonylmethyl)phenyl]pyrrolidine, (R)-1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-methylsulfonylmethyl)phenyl]pyrrolidine, (S)—1—[3—({1—[bis{4-chlorophenyl)methyl]azetidin-3-yl}-methylsulfonylmethyl)phenyl]pyrrolidine, (RS)-N-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonylmethyl)phenyl]-N-methylamine, (R)-N-[3-({l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-methylsulfonylmethyl)phenyl]-N-methylamine, (S)-N-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl} methylsulfonylmethyl)phenyl]-N-methylamine, (RS)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-bistri-fluoromethylphenyl)methylsulfonylmethyl]azetidine, (R)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-bistrifluoro methylphenyl)methylsulfonylmethyl]azetidine, (S)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-bistri-fluoromethylphenyl)methylsulfonylmethyl]azetidine, 1-[bis(4-chlorophenyl)methyl]-3-(phenylsulfonylmethyl) azetidine, (RS)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluoro-phenyl)methylsulfonylmethyl]-3-methylazetidine, (R)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluoro-phenyl)methylsulfonylmethyl]-3-methylazetidine, (S)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluoro-phenyl)methylsulfonylmethyl]-3-methyl-azetidine, (RS)-2-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclohexylacetamide, (R)—2—{1—[bis(4-chlorophenyl)methyl]azeditin-3-yl}-2-(3,5-difluorophenyl)-N-cyclohexylacetamide, 60 (S)—2—(1—[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclohexylacetamide, (RS)-2-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isobutylacetamide, (R)— 2 — {1—[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isobutylacetamide, (S)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isobutylacetamide, (RS)-2-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-15 (3,5-difluorophenyl)-N-cyclopropylmethylacetamide, (R)-2-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclopropylmethylacetamide, (S)-2-{1-bis(4-chlorophenyl)methyl]azetidin-3-yl} -2-(3,5-difluorophenyl)-N-cyclopropylmethylacetamide, (RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isopropylacetamide, (R)-2-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isopropylacetamide, (S)-2-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isopropylacetamide, (RS)-1-[bis(4-chlorophenyl)methyl]-3-[1-(3,5-difluorophenyl )-1-methylsulfonylethyl]azetidine, (R)-1-[bis(4-chlorophenyl)methyl]-3-[1-(3,5-difluoro-phenyl)-1-methylsulfonylethyl]azetidine, (S)-1-[bis(4-chlorophenyl)methyl]-3-[1-(3, 5-difluoro-phenyl)-1-methylsulfonylethyl]azetidine, (RS)-1-[bis(4-fluorophenyl)methyl]-3-[(3, 5-difluorophenyl) methylsulfonylmethyl]azetidine, (R)-1-[bis(4-fluorophenyl)methyl]-3-[(3,5-difluoro-phenyl)methylsulfonylmethyl]azetidine, (S)-1-[bis(4-fluorophenyl)methyl]-3-[(3,5-difluoro-phenyl)methylsulfonylmethyl]azetidine, (RS)-{1-[(3-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5— difluorophenyl)methylsulfonylmethyl]azetidine, (SS)-{1-[(3-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine, (RR)-{1-[(3-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine, 62 (SR)-{1-[(3-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine, (RS)-{1-[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine, (SS)-{1-[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine, (RR)-{1-[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine, (SR)-{1-[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5— 15 difluorophenyl)methylsulfonylmethyl]azetidine, (RS)-5-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)-methylsulfonylmethyl]azetidin-1-y1}methyl)pyrimidine, (SR)-5-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)- methylsulfonylmethyl]azetidin-1-y1}methyl)pyrimidine, (RR)-5-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)-methylsulfonylmethyl]azetidin-1-yl}methyl)pyrimidine, (SS)-5-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)-methylsulfonylmethyl]azetidin-l-yl}methyl)pyrimidine, 63 (SS)—{1—[(2-chloropyrid-5-yl)-(4-chlorophenyl)methyl] 3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine (RR)-{1-[(2-chloropyrid-5-yl)-(4-chlorophenyl)methyl] 5 3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine (RS)-{1-[(2-chloropyrid-5-yl)-(4-chlorophenyl)methyl] 3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine (SR)-{1-[(2-chloropyrid-5-yl)-(4-chlorophenyl)methyl] 3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine their optical isomers and their pharmaceutically acceptable salts.
The following examples illustrate the invention.
Example 1 (RS)-1-[Bis(4-chlorophenyl)methyl]-3-[(3,5-di 20 fluorophenyl)(methylsulfonylmethyl]azetidin may be prepared from 1.0 g of 1-[bis(4-chlorophenyl)methyl)] 3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine in 40 cm3 of methanol, 96 mg of sodium borohydride are added and the mixture is stirred for 25 3 hours at 20°C. After addition of 100 cm3 of dichloromethane, the reaction mixture is washed twice with 50 cm3 of water and dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The crude product is 64 chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 6 cm, diameter 3 cm), eluting under an argon pressure of 0.8 bar with dichloromethane and then the mixture dichloromethane + 1% methanol and 5 collecting 80-cm3 fractions. Fractions 13 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.55 g of a white solid is obtained which is taken up in 50 cm3 of diisopropyl ether, filtered and dried to give 0.47 g of (RS)-1-[bis(4-10 chlorophenyl)methyl)]-3-[(3,5-difluorophenyl)(methylsulf onyl ) methyl ] azetidine in the form of a white solid [ 1H NMR spectrum (400 MHz, (CD3)2SO d6 with addition of a few drops of CD3COOD d4, at a temperature of 353 K, 5 in ppm) : 2.4 6 (t, J = 7.5 Hz : 1H); 2.7 7 (s : 3H); 15 3.15 (mt : 2H); 3.40 (mt : 1H); 3.49 (broad t, J = 7.5 Hz : 1H); 4.46 (s : 1H); 4.81 (d, J = 9 Hz : 1H); from 7.05 to 7.20 (mt : 3H); from 7.15 to 7.45 (mt : 8H) ] . 1-[Bis(4-chlorophenyl)methyl)]— 3 —[(3,5-difluoro-20 phenyl)(methylsulfonyl)methylene]azetidine may be prepared according to two methods: Method 1 0.65 cm3 of methylsulfonyl chloride is added to a solution of 2.94 g of 1-[bis(4-chlorophenyl)methyl]-25 3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-azetidin-3-ol in 250 cm3 of dichloromethane at 22°C, followed, in small portions over 15 minutes by 2.42 g of 4-dimethylaminopyridine; the orange-colored solution is stirred for 2 hours at room temperature. The 65 reaction mixture is washed 3 times with 150 cm3 of distilled water and once with 150 cm3 of a saturated sodium chloride solution, then dried with magnesium sulfate, filtered and concentrated to dryness under 5 reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 5.5 cm, height 15 cm), under an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (1/9 by volume) as eluent and 10 collecting 70-cm3 fractions. Fractions 15 to 36 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 1.86 g of a white foam are obtained, which foam is crystallized from isopropyl ether to give a solid melting at 190°C. 15 Recrystallization from 45 cm3 of ethanol gives 1.08 g of 1-[Bis(4-chlorophenyl)methyl]-3-[(3,5-difluoro-phenyl)(methylsulfonyl)methylene]azetidine melting at 206°C [NMR spectrum in DMS0-d6, T=300K, 8 in ppm (300 MHz) : 3.00 (3H,s, SCH3) , 3.87 (2H, s, NCH2), 4.20 20 (2H, s, NCH2) , 4.75 (1H, s, NCH) , 7.15 (2H, d, J=8Hz, 2CH arom.), 7.30 (5H, m, 5CH arom.), 7.45 (4H, d, J=7Hz, 4CH arom.)]. 6.75 g of 3-[(3,5-difluorophenyl)(methylsulfonylmethyl- (RS) ] azetidin-3-ol hydrochloride are 25 added to a solution of 6.8 g of bis(4-chlorophenyl)-bromomethane in 300 cm3 of acetonitrile, followed by 2.97 g of potassium carbonate. The reaction mixture is heated for 1 hour under reflux, cooled to room temperature, filtered and concentrated to dryness under 66 reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 8.5 cm, height 22 cm), under an argon pressure of 0.5 bar with a mixture of ethyl 5 acetate and cyclohexane (25/75 by volume) as eluent and collecting 250-cm3 fractions. Fractions 11 to 48 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 5.3 g of 1-[bis(4-chlorophenyl)-methyl]-3-[(3,5-difluorophenyl)methylsulfonyl)methyl-10 (RS)]azetidin-3-ol are obtained. [1H NMR spectrum (300 MHz, (CD3)2SO d6, 5 in ppm) : 2.00 (s : 3H) ; 2.94 (s : 3H) ; 3.25 (mt : 2H); 3.48 (d, J = 9Hz : 1H); 3.80 (d, J = 9 Hz : 1H) ; 4.54 (s : 1H) ; 5.34 (s : 1H) ; 7.15 (d, J = 8.5 Hz : 2H); from 7.20 to 7.40 (mt : 8H); 7.50 15 (broad t, J = 9 Hz : 1H)].
Bis(4-chlorophenyl)bromomethane may be prepared according to the procedure described by BACHMANN W.E., J. Am. Chem. Soc., 2135 (1933). 3-[(3,5-Difluorophenyl)methylsulfonyl)methyl-20 (RS)]azetidin-3-ol hydrochloride may be obtained in the following manner: 160 cm3 of a 6.2 N hydrochloric acid solution in dioxane are added to a solution of 37 g of 3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-ol in 160 cm3 of dioxane. 25 After 16 hours at room temperature, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is taken up in 320 cm3 of ethanol, heated for 1 hour under reflux and cooled on an ice-cold bath. The solid which appears is 67 filtered, washed with ethyl ether and dried at 40°C under reduced pressure (2.7 kPa). 29.85 g of white crystals are obtained whose melting point is greater than 260°C. 3-[(3,5-Difluorophenyl)(methylsulfonyl)methyl- (RS)]-1-(vinyloxycarbonyl)azetidin-3-ol may be obtained in the following manner: a solution of 14 cm3 of vinyl chloroformate in 35 cm3 of dichloromethane is added at 5°C to a solution of 60.18 g of l-benzhydryl-3-[(3,5-10 difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol in 100 cm3 of dichloromethane. After 20 hours at room temperature, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel 15 column (particle size 0.04-0.06 mm, diameter 11 cm, height 32 cm), under an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (3/7 by volume) as eluent and collecting 1000-cm3 fractions. Fractions 8 to 18 are combined and then concentrated to 20 dryness under reduced pressure (2.7 kPa). 37 g of 3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-ol are obtained in the form of white crystals melting at 195°C. l-Benzhydryl-3-[(3,5-difluorophenyl)(methyl-25 sulfonyl)methyl-(RS)]azetidin-3-ol may be obtained in the following manner: 29.5 cm3 of 1.6 N n-butyllithium in solution in hexane are added to a solution of 6.73 cm3 of diisopropylamine in 110 cm3 of tetrahydrofuran, under an argon atmosphere, cooled to 68 -70°C. After 30 minutes, a mixture of 8.7 g of 3,5-difluorobenzyl methyl sulfone in 200 cm3 of tetrahydrofuran is then added and the stirring is maintained for 45 minutes at -70°C. 10 g of 5 l-benzhydrylazetidin-3-one dissolved in 60 cm3 of tetrahydrofuran are added and then the medium is stirred for 20 minutes while allowing the mixture to return to room temperature. The reaction mixture is hydrolyzed with 400 cm3 of a saturated ammonium 10 chloride solution, extracted with dichloromethane, washed 3 times with 500 cm3 of water and then a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure 15 (2.7 kPa). The residue (19 g) is taken up in isopropyl ether from which it crystallizes. After filtration and drying, 15.35 g of l-benzhydryl-3-[(3,5-difluorophenyl) (methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained in the form of white crystals. 20 l-Benzhydrylazetidin-3-one may be prepared according to the procedure described by KATRITZKY A.R. et al. in J. Heterocycl. Chem., 271 (1994). 3,5-Difluorobenzyl methyl sulfone may be prepared in the following manner: starting with 33.46 g 25 of 3,5-difluorobenzyl methyl sulfide in 318 cm3 of water, 318 cm3 of acetic acid and 318 cm3 of ethanol, 129.9 g of oxoneR are added at 5°C. After 16 hours at room temperature, the reaction mixture is diluted with dichloromethane, washed with water and with a saturated 69 sodium chloride solution, dried, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 35.57 g of 3,5-difluorobenzyl methyl sulfone are obtained in the form of white crystals, 5 m.p. = 135 °C. 3,5-Difluorobenzyl methyl sulfide may be prepared in the following manner: starting with 40 g of 3,5-difluorobenzyl bromide and 16.25 g of sodium methyl thiolate in DMF at 60°C, 33.46 g of 3,5-difluorobenzyl 10 methyl sulfide are obtained after treatment in the form of a yellow oil.
Method 2 0.80 g of crushed sodium hydroxide is added to a solution of 2.2 g of 3-acetoxy-l-[bis(4-chloro-15 phenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)-methyl-(RS)]azetidine in 25 cm3 of dioxane at room temperature. After 16 hours at room temperature, 50 cm3 of water and 100 cm3 of ethyl acetate are added. The mixture is separated after settling, the organic phase 20 washed again with 100 cm3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). A white foam is obtained which is crystallized from isopropyl ether to give 0.85 g of a solid melting at 190°C. 25 Crystallization from 20 cm3 of ethanol gives 0.70 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine melting at 205°C. 14 cm3 of a 1.6 N solution of n-butyllithium in hexane are added at -70°C to a solution of 4.77 g of 70 (3,5-difluorobenzyl)methyl sulfone in 70 cm3 of tetrahydrofuran under an argon atmosphere. After 1 hour at -70°C, a solution of 6.8 g of 1-[bis(4-chlorophenyl ) methyl ] azetidin-3-one in 30 cm3 of 5 tetrahydrofuran is added, followed 1 hour later by a solution of 2.34 cm3 of acetyl chloride in 20 cm3 of tetrahydrofuran and the temperature of the reaction mixture is increased to 20°C for 1 hour. 50 cm3 of water and 200 cm3 of ethyl acetate are added. The 10 mixture is separated after settling, the organic phase is washed with 100 cm3 of water, 100 cm3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) . 14.4 g of 3-acetoxy-l-[bis(4 -15 chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulf onyl ) methylsulf onylmethyl- (RS)]azetidine are obtained in the form of a yellow oil [1H NMR spectrum (400 MHz, CDCI3, 5 in ppm) : 2.79 (s : 3H); 3.04 (AB, J = 9 Hz : 2H); 3.27 (d, J = 9 Hz : 1H) 3.45 (s : 1H); 20 3.81 (d, J = 9 Hz : 1H); 4.32 (s : 1H); 4.49 (s : 1H); 6.88 (tt, J = 9 and 2.5 Hz); from 7.20 to 7.35 (mt : 10H)] . 1-[Bis(4-chlorophenyl)methyl]azetidin-3-one may be prepared according to the following procedure: a 25 solution of 8.1 cm3 dimethylsulfoxide in 17.6 cm3 of dichloromethane is added to a solution of 5.0 cm3 of oxalyl chloride in 73 cm3 of dichloromethane cooled to -78°C. After 0.5 hour at -78°C, a solution of 16.0 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ol dissolved in 71 50 cm3 of dichloromethane is poured in. After 5 hours at -78°C, 26.6 cm3 of triethylamine are added dropwise and the reaction mixture is allowed to return to room temperature. After 16 hours, the reaction mixture is 5 washed with 4 times 200 cm3 of water and then with 200 cm3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column 10 (particle size 0.04-0.06 mm, diameter 9.2 cm, height 21 cm), under an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (40/60 by volume) as eluent and collecting 200-cm3 fractions. Fractions 15 to 25 are combined and concentrated to 15 dryness under reduced pressure (2.7 kPa). 8.9 g of 1-bis(4-chlorophenyl)methyl]azetidin-3-one are obtained in the form of pale yellow crystals melting at 111°C. 1-[Bis(4-chlorophenyl)methyl]azetidin-3-ol may be prepared according to the procedure described by 20 KATRITZKY A.R. et al., J. Heterocycl. Chem., (1994), 271 starting with 35.5 g of [bis(4-chlorophenyl)-methyl]amine hydrochloride and 11.0 cm3 of epichlorohydrin. 9.0 g of 1-[bis(4-chlorophenyl)-methyl]azetidin-3-ol are isolated. 25 [Bis(4-chlorophenyl)methyl]amine hydrochloride may be prepared according to the method described by GRISAR M. et al., J. Med. Chem., 885 (1973).
Example 2 72 (-)-1-[Bis(4-chlorophenyl)methyl)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidine and (+)-1-[bis(4-chlorophenyl)methyl)]-3-[(3,5-difluoro-phenyl)(methylsulfonyl)methyl]azetidine may be prepared 5 by CLHP separation on a CHIRALPAK AS chiral column (particle size 20 |J,m, height 23 cm, diameter 6 cm) of 0.52 g of the racemate prepared in Example 1. By eluting with the heptane/ethanol (90/10) mixture at a flow rate of 80 cm3/min and after having concentrated 10 the collected fractions to dryness under reduced pressure (2.7 kPa), there are obtained 110 mg of (-)-1-[bis(4-chlorophenyl)methyl)]— 3 —[(3,5-difluoro-phenyl)(methylsulfonyl)methyl]azetidine [aD] = 6.3° (C = 0.5 M in methanol) in the form of a white solid 15 melting at 178°C and 134 mg of (+)-1-[bis(4-chlorophenyl ) methyl)]-3-[(3,5-difluorophenyl)(methylsulf onyl)methyl]azetidine [aD] = +5.8° (C = 0.5 M in methanol) in the form of a white solid melting at 17 8 °C. 2 0 Example 3 The mixture of the 2 A diastereoisomer forms 1—[4 —[ (R*)-(4-chlorophenyl)-{3-[3,5-difluorophenyl)-methylsulfonylmethyl-(R)]azetidin-l-yl}methyl]benzyl]-pyrrolidine and 1— [4 —[ (R*)-(4-chlorophenyl)-{3-[ (3,5 — 25 difluorophenyl)methylsulfonylmethyl-(S)]azetidin-l-yl }methyl]benzyl]pyrrolidone may be prepared by carrying out the procedure in the following manner: 20 mg of sodium borohydride are added to a solution of 60 mg of 1-(R*)-[4-(4-chlorophenyl)-{3-[(3,5-difluoro- 73 phenyl)methylsulfonylmethylene]azetidin-l-yl}methyl)-benzyl]pyrrolidone, A isomer form, in 2 cm3 of ethanol and 2 cm3 of dichloromethane. After stirring for 20 hours at 20°C, 0.25 cm3 of water and 20 cm3 of 5 dichloromethane are added and the mixture is stirred and dried over magnesium sulfate and then filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 7 cm, 10 diameter 1 cm), eluting under an argon pressure of 0.1 bar with dichloromethane and then with a mixture of dichloromethane and methanol (95/5 by volume) and collecting 5-cm3 fractions. Fractions 13 to 18 are combined and concentrated to dryness under reduced 15 pressure (2.7 kPa). 38 mg of the mixture of the 2 A diastereoisomer forms 1-[4-[(R*)-(4-chlorophenyl)-{3-[(3,5-difluorophenyl)methylsulfonylmethyl-(R)]azetidin-l-yl Jmethyl] benzyl] pyrrolidine and 1— [4—[(R*) — (4 — chlorophenyl)-{3-[(3,5-difluorophenyl)methylsulfonyl-20 methyl-(S)]azetidin-l-ylJmethyl]benzyl]pyrrolidine are obtained in the form of a white foam [1H NMR spectrum (400 MHz, CDC13, 8 in ppm) : 1.77 (mt : 4H) ; from 2.40 to 2.60 (mt :5H); 2.67 (s : 3H); from 3.10 to 3.25 (mt : 2H); 3.38 (mt : 1H); from 3.50 to 3.70 (mt : 3H) ; 25 4.24 (s : 1H); 4.25 (d, J = 11 Hz : 1H); 6.83 (broad t, J = 9 Hz : 1H); 6.94 (mt : 2H) from 7.10 to 7.35 (mt : 8H) ] . 1-(R*)-[4-(4-Chlorophenyl)-{3-[(3,5-difluorophenyl )methylsulfonylmethylene]azetidin-l-yl}methyl)- 74 benzyl]pyrrolidine, A isomer form, may be prepared by carrying out the procedure in the following manner: 50 mm3 of pyrrolidine are added to a solution of 0.32 g of 1—{(R*)—[4—(chloromethyl)phenyl]-(4-chlorophenyl)-5 methyl}-3-[(3,5-difluorophenyl)methylsulfonylmethylene] azetidine, A isomer form, and 5 mg of sodium iodide in 10 cm3 of dichloromethane. After stirring for 20 hours at 20°C, 50 mm3 of pyrrolidine are added to the mixture, the mixture is stirred for 8 hours and 10 then 50 mm3 of pyrrolidine are again added and the mixture is stirred for 20 hours at 20°C. The reaction mixture is washed with water and then the organic phase is dried over magnesium sulfate and concentrated to dryness under vacuum (2.7 kPa). The residue obtained is 15 chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 1.2 cm, height 30 cm), under an argon pressure of 0.1 bar, eluting with dichloromethane and then with a dichloromethane and methanol (97.5/2.5 by volume) mixture and collecting 3-cm3 fractions. 20 Fractions 12 to 40 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.18 g of 1-(R*)-[4-(4-Chlorophenyl)-{3-[(3,5-difluorophenyl)-methylsulfonylmethylene]azetidin-l-yl}methyl)benzyl]-pyrrolidine, A isomer form, is obtained in the form of 25 a white foam [a] 20365nm = -22.5° +/- 0.7 (c = 0.5%; dichloromethane) [1H NMR spectrum (300 MHz, CDCI3, 8 in ppm) : 1.78 (mt : 4H); 2.51 (mt : 4H); 2.81 (s : 3H) ; 3.58 (s : 2 H); 3.84 (mt : 2H); 4.33 (mt : 2H); 4.50 75 (2 : 1H) ; 6.84 (tt, J = 9 and 2.5 Hz : 1H) ; 6.98 (mt : 2H); from 7.20 to 7.40 (mt : 8H)]. 1-{(R*)-[(4-Chloromethyl)phenyl]-(4-chlorophenyl )methyl}-3-[(3,5-difluorophenyl)methylsulfonyl-5 methylene]azetidine, A isomer form, may be prepared by carrying out the procedure in the following manner: 12.4 cm3 of methylsulfonyl chloride are added to a solution of 28.0 g of the mixture of the 2 diastereoisomers (A forms) 1-{(R*)-[(4-chloromethyl)-10 phenyl]-(4-chlorophenyl)methyl}-3-[(R)-(3, 5-difluoro- phenyl)methylsulfonylmethyl)]azetidin-3-ol and 1—{(R*)— [(4-chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(S)-(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-3-ol and 32 g of 4-dimethylaminopyridine in 500 cm3 of 15 dichloromethane. After stirring for one hour at 10°C and then one hour at 20°C, the reaction mixture is washed with 500 cm3 of water, the organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue 20 is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 6 cm, height 30 cm), under an argon pressure of 0.2 bar, eluting with dichloromethane and collecting 250-cm3 fractions. Fractions 9 to 25 are combined and then concentrated to 25 dryness under reduced pressure (2.7 kPa). 6.3 g of 1- {(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)methylsulfonylmethylene]-azetidine, A isomer form, are obtained in the form of a white foam. 76 The mixture of the 2 diastereoisomers (A forms) 1-{(R*)-[4-chloromethyl)phenyl]-(4-chlorophenyl)-methyl}—3—[(R) — (3,5-difluorophenyl)methylsulfonylmethyl)] azetidin-3-ol and 1-{(R*)-[4-chloromethyl)-5 phenyl](4-chlorophenyl)methyl}-3-[(S)-(3,5- difluorophenyl)methylsulfonylmethyl)]azetidin-3-ol may be prepared by carrying out the procedure in the following manner: 6 cm3 of thionyl chloride are added to a solution of 0.20 g of the mixture of the 2 10 diastereoisomers (A forms) 1-{(R*)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(R)-(3,5-difluoro-phenyl)methylsulfonylmethyl)]azetidin-3-ol, and l-{(R*)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]-methyl}-3-[(S)-(3,5-difluorophenyl)methylsulfonyl-15 methyl)]azetidin-3-ol in 10 cm3 of dichloromethane. After stirring for 20 hours at 20°C, 5 cm3 of a saturated aqueous sodium hydrogencarbonate solution are added to the reaction mixture and then stirred for 15 minutes. The mixture is separated after settling, 20 the organic phase is washed with water, dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 1.0 cm, height 20 cm), under an 25 argon pressure of 0.2 bar, eluting with a cyclohexane and ethyl acetate (75/25 by volume) mixture and collecting 20-cm3 fractions. Fractions 4 to 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.17 g of the mixture of the 77 2 diastereoisomers (A forms) 1-{(R*)-[4-(chloromethyl)-phenyl]-(4-chlorophenyl)methyl}-3-[(R)-(3,5-difluoro-phenyl)methylsulfonylmethyl)]azetidin-3-ol and 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3- [(S)-(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-3-ol, are obtained in the form of a white foam.
The mixture of the 2 diastereoisomers (A forms) l-{(R*)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]-methyl}-3-[(R)-(3,5-difluorophenyl)methylsulfonyl-10 methyl)]azetidin-3-ol, and 1-{(R*)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(S)-(3,5-difluoro-phenyl)methylsulfonylmethyl)]azetidin-3-ol may be prepared by carrying out the procedure in the following manner: 1.6 cm3 of a 1.5 M solution of 15 diisobutylaluminum hydride in toluene are added to a solution, kept under argon and cooled to -30°C, of 0.58 g of the mixture of the 2 diastereoisomers (A forms) 3-acetoxy-l-{(R*)-(4-chlorophenyl)[4-(methoxy-carbonyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)-20 methylsulfonylmethyl)]azetidine and 3-acetoxy-l-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(S)-(3, 5-difluorophenyl)methylsulfonylmethyl)]-azetidine, in 10 cm3 of anhydrous toluene. After stirring for 15 minutes at -30°C, 1.0 cm3 of the same 25 hydride solution is again added and the mixture is allowed to return to 0°C. After stirring for 30 minutes, the stirred mixture is supplemented with 3 cm3 of water and 6 cm3 of 1 N sodium hydroxide and then extracted with 25 cm3 of dichloromethane. The 78 organic phase is washed with 5 cm3 of water, 5 cm3 of brine and then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica 5 gel column (particle size 0.06-0.200 mm, diameter 1.2 cm, height 30 cm), under an argon pressure of 0.1 bar, eluting with a cyclohexane and ethyl acetate (50/50 by volume) mixture and collecting 30-cm3 fractions. Fractions 4 to 12 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.42 g of the mixture of the 2 diastereoisomers (A forms) 1-{(R*)-(4-chlorophenyl)-[4-(hydroxymethyl)phenyl]methyl}-3-[(R)-(3,5-difluoro-phenyl)methylsulfonylmethyl)]azetidin-3-ol and 1-{(R*)~ 15 (4-chlorophenyl)[4-(hydroxymethylphenyl]methyl}-3-[(S)-(3,5-difluorophenyl)methylsulfonylmethyl)]azetidin-3- 01, are obtained in the form of a white lacquer.
The mixture of the 2 diastereoisomers (A forms) 3-acetoxy-l-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)-20 phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)methylsulf onylmethyl )] azetidine and 3-acetoxy-l-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(S)-(3,5-difluorophenyl)methylsulfonylmethyl)]azetidine may be prepared by carrying out the procedure in the 25 following manner: 3 cm3 of a 1.6 N solution of n-butyllithium in hexane are poured under argon over 5 minutes, into a solution, cooled to -60°C, of 1.0 g of (3,5-difluorobenzyl)methyl sulfone in 30 cm3 of tetrahydrofuran. After stirring for 1 hour at -60°C and 79 then for 30 minutes at -30°C, a solution, previously cooled to -60°C, of 1.45 g of 1-{(R*)-(4-chlorophenyl ) 14-(methoxycarbonyl)phenyl]methyl}azetidin-3-one, A isomer form, in 15 cm3 of tetrahydrofuran is 5 added dropwise to this mixture. After stirring for minutes at -60°C and then for 30 minutes at -30°C, 0.43 cm3 of acetyl chloride is added and the reaction mixture is allowed to return to 0°C. 40 cm3 of water and 4 0 cm3 of dichloromethane are then added to the 10 medium, with stirring, and then the medium is allowed to return to room temperature and it is separated after settling. The organic phase is washed with 20 cm3 of water and is then dried over magnesium sulfate, filtered and concentrated to dryness under reduced 15 pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.040-0.063 mm, diameter 3 cm, height 30 cm), eluting under an argon pressure of 0.5 bar with a cyclohexane and ethyl acetate (75/25 by volume) mixture and collecting 30-cm3 20 fractions. Fractions 21 to 35 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 1.28 g of the mixture of the 2 diasterisomers (A forms) 3-acetoxy-l-{(R*)-(4-chlorophenyl )[4-(methoxycarbonyl)phenyl]methyl}-3-[(R)-(3,5-25 difluorophenyl)methylsulfonylmethyl)]azetidine and 3-acetoxy-l-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)-phenyl]methyl}-3-[(S)—(3,5-difluorophenyl)methylsulf onylmethyl )] azetidine are obtained in the form of a cream-colored foam. 80 l-{(R*)-(4-Chlorophenyl)[4-methoxycarbonyl) -phenyl]methyl}azetidin-3-one, A isomer form, may be prepared by carrying out the procedure in the following manner: 0.90 cm3 of dimethyl sulfoxide is poured over 5 10 minutes into a solution, cooled to -60°C, of 0.55 cm3 of oxalyl chloride in 5 cm3 of dichloromethane. After stirring for 30 minutes at -60°C, a solution of 1.75 g of 1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)-phenyl]methyl}azetidin-3-ol, A isomer form, in 20 cm3 10 of dichloromethane is added to the mixture over 15 minutes. After stirring for 3 hours at -60°C, 2.7 cm3 of triethylamine are poured in and then the reaction medium is allowed to return to 0°C. 20 cm3 of water are then added, the mixture is stirred and then 15 separated after settling. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness at 50°C under reduced pressure (2.7 kPa) . The orange-colored oil obtained is chromatographed on a silica gel column (particle size 0.06-0.200 mm, 20 diameter 2 cm, height 30 cm), under an argon pressure of 0.5 bar, eluting with a cyclohexane and ethyl acetate (75/25 by volume) mixture and collecting 30-cm3 fractions. Fractions 2 to 15 are combined and then concentrated to dryness under reduced pressure 25 (2.7 kPa). 1.45 g of l-{(R*)-(4-chlorophenyl)[4- (methoxycarbonyl)phenyl]methyl}azetidin-3-one, A isomer form, are obtained in the form of a yellow foam. l-{(R*)-(4-Chlorophenyl)[4-methoxycarbonyl)-phenyl]methyl}azetidin-3-ol, A isomer form, may be 81 prepared by carrying out the procedure in the following manner: 0.605 g of sodium hydrogen carbonate is added to a suspension of 2.0 g of methyl (+)-4-[(R*)-amino-(4-chlorophenyl)methyl]benzoate in 30 cm3 of ethanol 5 followed by 0.60 cm3 of epibromohydrin. After stirring for 20 hours at 60°C, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 3 cm, 10 height 35 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (70/30 by volume for fractions 6 to 10 and then 60/40 for fractions 18 to 27, and then 50/50) and collecting 60-cm3 fractions. Fractions 15 to 40 are combined and 15 then concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 30 cm3 of ethanol and is then supplemented with 0.20 g of sodium hydrogen carbonate and 0.2 cm3 of epibromohydrin. After stirring for 48 hours at 20°C and then 24 hours at 35°C, the 20 mixture is filtered and the filtrate is concentrated to dryness at 60°C under reduced pressure (2.7 kPa) . 1.76 g of l-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)-phenyl]methyl}azetidin-3-ol, A isomer form, are obtained in the form of a pasty solid. 25 Methyl (+)-4-[(R*)-amino-(4-chlorophenyl)- methyl]benzoate may be prepared by carrying out the procedure in the following manner: 2.51 g of D-(-)-tartaric acid are added to a solution of 9.2 g of methyl 4-[(rs)-amino-(4-chlorophenyl)methyl]benzoate in 82 cm3 of methanol. The solution is concentrated to dryness under reduced pressure (2.7 kPa). The cream-colored foam obtained is dissolved in 50 cm3 of ethanol containing 5% of water and the resulting solution is 5 allowed to crystallize for 20 hours at 20°C. The crystals are filtered, washed with ethanol containing 5% of water, drained and then dried under reduced pressure (2.7 kPa). 3.4 g of white crystals are obtained, which crystals are named "A crystals" [and 10 which are stored for the subsequent preparation of the second enantiomer methyl (-)-4-[(R*)-amino-(4-chlorophenyl )methyl]benzoate)]. The mother liquors are concentrated to dryness and a white foam is obtained (8.1 g) which is dissolved in 100 cm3 of ethyl acetate. 15 The solution obtained is supplemented with 50 cm3 of 1 N sodium hydroxide, stirred and separated after settling. The organic phase is washed with 50 cm3 of water and then dried over magensium sulfate and concentrated to dryness under reduced pressure 20 (2.7 kPa). A yellow solid is obtained which is dissolved in 100 cm3 of methanol. The solution obtained is supplemented with 1.85 g of L-(+)-tartaric acid and the resulting solution is concentrated to dryness under reduced pressure (2.7 kPa). A cream-colored foam is 25 obtained which, once dissolved in 27 cm3 of ethanol containing 4% of water, is allowed to crystallize for 20 hours at 20°C. The crystals are filtered, washed with ethanol containing 4% of water, drained and then dried under reduced pressure (2.7 kPa). 3.4 g of 83 crystals of methyl (+)-4-[(R*)-amino-(4-chlorophenyl)-methyl]benzoate L-(+)-tartrate are obtained which are recrystallized from 60 cm3 of ethanol containing 5% of water. After draining and then drying, 2.78 g of white 5 crystals are obtained which are dissolved in 50 cm3 of ethyl acetate. The solution obtained is supplemented with 100 cm3 of 1 N sodium hydroxide, stirred and separated after settling. The organic phase is washed with 50 cm3 of water and then dried over magnesium 10 sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 2.1 g of methyl (+)-4-[(R*)-amino-(4-chlorophenyl)methyl]benzoate are obtained in the form of a white solid.
Methyl 4-[(RS)-amino-(4-chlorophenyl)methyl]-15 benzoate may be prepared by carrying out the procedure in the following manner: 3.9 cm3 of hydrazine hydrate are added to a suspension of 16.3 g of methyl 4-[(RS)~ phthalimido-(4-chlorophenyl)methyl]benzoate in 200 cm3 of methanol. After stirring for 5 hours at the reflux 20 temperature and then for 20 hours at 20°C, the reaction mixture is filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is taken up in a mixture of 200 cm3 of water and 200 cm3 of ethyl acetate. After stirring for 15 25 minutes, the resulting suspension is filtered, the filtrate separated after settling in a separating funnel and the organic phase is washed with 50 cm3 of water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 8.4 g of 84 methyl 4-[(RS)-amino-(4-chlorophenyl)methyl]benzoate are obtained in the form of a pale yellow oil.
Methyl 4-[(RS)-phthalimido-(4-chlorophenyl)-methyl]benzoate may be prepared by carrying out the 5 procedure in the following manner: 12.6 g of potassium phthalimide are added to a solution of 11.6 g of methyl 4-[(RS)-bromo-(4-chlorophenyl)methyl]benzoate in 70 cm3 of N,N-dimethylformamide. After stirring for 3 hours at the reflux temperature, the reaction mixture is cooled 10 to 20°C and then supplemented with 300 cm3 of ethyl acetate and 300 cm3 of water. After stirring, the mixture is separated after settling, the aqueous phase reextracted with twice 100 cm3 of ethyl acetate, the combined organic phases are washed with twice 400 cm3 15 of water and then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 16.3 g of methyl 4-[(RS)-phthalimido-(4-chlorophenyl)methyl]benzoate are obtained in the form of a pasty yellow solid.
Methyl 4-[(RS)-bromo-(4-chlorophenyl)methyl]- benzoate may be prepared by carrying out the procedure in the following manner: 10.18 g of N,N'-carbonyl-diimidazole and 54.3 cm3 of allyl bromide are added to a solution of 17.4 g of methyl 4-[(RS)-(4-chloro-25 phenyl)(hydroxy)methyl]benzoate in 200 cm3 of acetonitrile. After stirring for 30 minutes at 20°C, the reaction mixture is heated under reflux for 2 hours, stirred for 20 hours at 20°C and concentrated almost to dryness under reduced pressure (2.7 kPa). The 85 mixture, taken up in dichloromethane, is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 7 cm, height 30 cm), under an argon pressure of 0.5 bar, eluting with 5 dichloromethane, and collecting 500-cm3 fractions.
Fractions 3 to 6 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 11.6 g of methyl 4-[(RS)-bromo-(4-chlorophenyl)methyl]benzoate are obtained in the form of an oil which will be used 10 as it is in the next step.
Methyl 4-[(RS)-(4-chlorophenyl)(hydroxy)-methyl]benzoate may be prepared by carrying out the procedure in the following manner: 1.21 g of sodium borohydride are added slowly in small fractions (the 15 medium becomes slightly warm up to 50°C) to a suspension of 2.75 g of methyl 4 —(4 — chlorobenzoyl)benzoate in 200 cm3 of methanol at 20°C. After stirring for 20 hours at 20°C, the reaction mixture is concentrated to a reduced volume and then 20 supplemented with 150 cm3 of dichloromethane and, with stirring, with 100 cm3 of 0.5 N hydrochloric acid.
After decantation, the organic phase is dried over magensium sulfate, concentrated to dryness under reduced pressure (2.7 kPa). 2.5 g of methyl 4-[(RS)-(4-25 chlorophenyl)(hydroxy)methyl]benzoate are obtained in the form of a colorless oil which crystallizes slowly at 20°C and which will be used as it is in the next step. 86 Methyl 4-(4-chlorobenzoyl)benzoate may be prepared by carrying out the procedure in the following manner: 27.4 cm3 of tri-n-butylphosphine are added, under argon, to a solution, cooled to -22°C of 19.3 g 5 of terephthalic acid chloride monomethyl ester in 200 cm3 of tetrahydrofuran. After stirring for 20 minutes at -22°C, a solution of 4-chlorophenyl-magnesium bromide (prepared from 19.15 g of 4-bromochlorobenzene, 2.43 g of magnesium and one iodine 10 crystal in 100 cm3 of diethyl ether under reflux) is poured in while maintaining this temperature. After stirring for 30 minutes at -22°C, 150 cm3 of 1 N hydrochloric acid are added slowly, the mixture is allowed to return to 20°C and then the medium is 15 diluted with 200 cm3 of diethyl ether. The white suspension obtained is filtered, the solid is washed with twice 50 cm3 of water and then with twice 50 cm3 of diethyl ether. After draining and then drying under reduced pressure (2.7 kPa), 16.2 g of methyl 4-(4-20 chlorobenzoyl)benzoate are obtained in the.form of a white solid melting at 170°C.
Example 4 The mixture of the 2 B diastereoisomer forms 1-[4-[(R*)-(4-chlorophenyl)-{3-[(3,5-difluorophenyl)-25 methylsulfonylmethyl-(R)]azetidin-l-yl}methy1]benzyl]-pyrrolidine and 1-[4-[(R*)-(4-chlorophenyl)-{3-[(3,5-difluorophenyl)methylsulfonylmethyl-(S)]azetidin-l-yl }methyl ] benzylpyrrolidine may be prepared by carrying out the procedure as described in Example 3, starting 87 with 50 mg of (+)-1-[4-(R*)-(4-chlorophenyl)-{3-[(3,5-difluorophenyl)methylsulfonylmethylene]azetidin-l-yl}-methyl)benzyl]pyrrolidine, B isomer form, 1.5 cm3 of ethanol, 1.5 cm3 of dichloromethane and 18 mg of sodium 5 borohydride, with stirring for 8 hours at 50°C and then for 48 hours at 20°C. 50 mg of the mixture of the 2 B diastereoisomer forms 1-[4-[(R*)-(4-chlorophenyl)-{3-f(3,5-difluorophenyl)methylsulfonylmethyl-(R)]azetidin-l-yl }methyl]benzyl]pyrrolidine and 1-[4-[(R*)-(4-10 chlorophenyl)-{3-[(3,5-difluorophenyl)methylsulfonyl-methyl-(S)]azetidin-l-yl}methyl]benzylpyrrolidine are obtained in the form of a white foam tXH NMR spectrum (300 MHz, CDCI3, 8 in ppm) . A 60/40 mixture of diastereoisomers is observed, * 1.79 (mt: 4H); from 15 2.45 to 2.60 (mt: 5H); 2.67 (s : 3H); from 3.10 to 3.30 (mt : 2H); 3.40 (mt : 1H); 3.57 and 3.60 (2s : 2H in total); 3.65 (broad t, J = 7.5 Hz : 1H); 4.26 and 4.30 (2s : 2H in total); 6.84 (tt, J = 9 and 2 Hz : 1H); 6.9 6 (mt : 2H); from 7.25 to 7.40 (mt : 8H). 20 (+)-1-[4-(R*)-(4-Chlorophenyl)-{3-[(3,5- difluorophenyl)methylsulfonylmethylene]azetidin-l-yl Jmethyl)benzyl]pyrrolidine, B isomer form, may be prepared by carrying out the procedure as is described in Example 3, starting with 0.50 g of 1—{ (R*) — [4 — 25 (chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine, B isomer form, 5 mg of sodium iodide, 15 cm3 of dichloromethane and 0.190 g of pyrrolidine. The crude product is chromatographed on a silica gel column 88 (particle size 0.06-0.200 mm, diameter 1.5 cm, height 20 cm), under an argon pressure of 0.1 bar, eluting with dichloromethane and then with a dichloromethane and methanol (95/5 by volume) mixture and collecting 5 25-cm3 fractions. Fractions 20 to 40 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 0.28 g of (+)-1-[4-(R*)-(4-chlorophenyl)-{3-[(3,5-difluorophenyl)methylsulfonylmethylene]azetidin-l-yl }methyl) benzyl] pyrrolidine, B isomer form, is 10 obtained in the form of a white foam. [a]20365nm = +26.8 +/- 0.8 (c = 0.5%; dichloromethane) [_1H NMR spectrum (300 MHZ, CDC13, 8 in ppm) : 1.78 (mt : 4H) ; 2.50 (mt : 4 H); 2.8 0 (s : 3H); 3.57 (s : 2H); 3.8 4 (mt : 2H); 4.3 4 (mt : 2H); 4.50 (s : 1H); 6.84 (tt, J = 9 and 2.5 Hz : 15 1H); 6.98 (mt : 2H); from 7.20 to 7.40 (mt : 8H)]. 1-{ (R*)-[4 -(Chloromethyl)phenyl]-(4-chlorophenyl) methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]azetidine, B isomer form, may be prepared by carrying out the procedure as described in Example 3, 20 starting with 7.3 g of the mixture of the 2 B diastereoisomer forms 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(R)—(3,5-difluorophenyl)-(methylsulfonyl)methyl)]azetidin-3-ol and l-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(S)-25 (3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-ol, 8.2 g of 4-dimethylaminopyridine, 150 cm3 of dichloromethane and 3.2 cm3 of methylsulfonyl chloride. The crude product is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, 89 height 30 cm) under an argon pressure of 0.2 bar, eluting with dichloromethane and collecting 100-cm3 fractions. Fractions 15 to 30 are combined and then concentrated to dryness under reduced pressure 5 (2.7 kPa). 2.50 g of 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-dif1uorophenylmethy1-sulfonyl)methylene]azetidine, B isomer form, are obtained in the form of a white foam.
The mixture of the 2 B diastereoisomer forms 1-10 {(R*)-[4-(chloromethyl)phenyl[4-chlorophenyl)methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]-azetidin-3-ol and 1-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(S)-(3,5-difluorophenyl)-(methylsulfonyl)methyl)]azetidin-3-ol may be prepared 15 by carrying out the procedure as described in Example 3, starting with 11.0 g of the mixture of the 2 B diastereoisomer forms l-{(R*)-4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(R)-(3,5-difluoro-phenyl)(methylsulfonyl)methyl)]azetidin-3-ol and 1-2 0 { (R*)- (4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]-azetidin-3-ol, 250 cm3 of dichloromethane and 3.1 cm3 of thionyl chloride. The crude product is chromatographed on a silica gel column (particle size 0.04-0.06 mm, 25 diameter 3 cm, height 30 cm), under an argon pressure of 0.2 bar, eluting with a cyclohexane and ethyl acetate (70/30 by volume) mixture and collecting 50-cm3 fractions. Fractions 9 to 25 are combined and then concentrated to dryness under reduced pressure 90 (2.7 kPa). 7.3 g of the mixture of the 2 B diastereoisomer forms 1-{(R*)-[4-(chloromethyl)phenyl]• (4-chlorophenyl)methyl}-3-[(R) -(3,5-difluorophenyl)-(methylsulfonyl)methyl)]azetidin-3-ol and l-{(R*)-[4-5 (chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-ol are obtained in the form of a white foam.
The mixture of the 2 B diastereoisomer forms 1-{(R*)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-10 3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]- azetidin-3-ol and 1-{(R*)-[4-(chlorophenyl)[4-(hydroxymethyl )phenyl]methyl}-3-[(R)-3,5-difluorophenyl)-(methylsulfonyl)methyl)]azetidin-3-ol may be prepared by carrying out the procedure as described in Example 15 3, starting with 18.0 g of the mixture of the 2 B diastereoisomer forms 3-acetoxy-l-{(R*)-(4-chlorophenyl )[4-(methoxycarbonyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidine and 3-acetoxy-l-{ (R*)-(4-chlorophenyl) [4 -(methyloxycarbonyl)-20 phenyl]methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulf onyl ) methyl ] azetidine , 150 cm3 of anhydrous toluene and 100 cm3 of a 20% solution of diisobutylaluminum hydride in toluene. The crude product is chromatographed on a silica gel column (particle size 25 0.06-0.200 mm, diameter 3 cm, height 30 cm), under an argon pressure of 0.1 bar, eluting with a cyclohexane and ethyl acetate (50/50 by volume) mixture and collecting 50-cm3 fractions. Fractions 15 to 30 are combined and concentrated to dryness under reduced 91 pressure (2.7 kPa). 11.0 g of the mixture of the 2 B diastereoisomer forms 1-{(R*)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl) (methylsulfonyl)methyl]azetidin-3-ol and 1-5 {(R*)-[(4-chlorophenyl)[4-(hydroxymethyl)phenyl]-methyl}-3-[(S)-3,5-difluorophenyl)(methylsulfonyl)-methyl]azetidin-3-ol are obtained in the form of a white foam.
The mixture of the 2 B diastereoisomer forms 3-10 acetoxy-1-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)-phenyl]methyl}—3—[(R) — (3,5-difluorophenyl) (methylsulf onyl)methyl]azetidine and 3-acetoxy-l-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(S)-(3,5-difluorophenyl)methylsulfonyl)methyl]azetidine may 15 be prepared by carrying out the procedure as described in Example 3, starting with 11.2 g of (3,5-difluorobenzyl ) methyl sulfone, 350 cm3 of tetrahydrofuran, 34 cm3 of a 1.6 N solution of n-butyllithium in hexane, 11.2 g of 1-{ (R*)-(4-chlorophenyl)[4-(methoxycarbonyl)-20 phenyl]methyl}azetidin-3-one, B isomer form, and 5.5 cm3 of acetyl chloride. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 4 cm, height 40 cm), eluting with a cyclohexane and ethyl acetate (70/30 by volume) 25 mixture and collecting 100-cm3 fractions. Fractions 10 to 30 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 21 g of a still impure cream-colored foam are obtained, which foam is chromatographed on a silica gel column (particle size 92 0.06-0.200 mm, diameter 4 cm, height 40 cm), eluting with dichloromethane and collecting 100-cm3 fractions. Fractions 11 to 30 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 20.0 g of 5 the mixture of the 2 B diastereoisomer forms 3-acetoxy-l-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]-methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)-methyl]azetidine and 3-acetoxy-{(R*)-(4-chlorophenyl)-[4 -(methoxycarbonyl)phenyl]methyl}—3—[(S) — (3,5 — 10 difluorophenyl)(methylsulfonyl)methyl]azetidine are obtained in the form of a white foam. l-{(R*)-(4-Chlorophenyl)[4-methoxycarbonyl)-phenyl]methyl}azetidin-3-one, B isomer form, may be prepared by carrying out the procedure as described in 15 Example 3, starting with 8.7 cm3 of oxalyl chloride, 350 cm3 of dichloromethane, 14.2 cm3 of dimethyl sulfoxide, 29.0 g of l-{(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azeditin-3-ol, B isomer form, and 43 cm3 of triethylamine. The crude product is 20 chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 4 cm, height 40 cm), eluting with dichloromethane and collecting 250-cm3 fractions. Fractions 7 to 25 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 15.5 g of 1-25 {(R*)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]- methyl}azetidin-3-one, B isomer form, are obtained in the form of an orange-colored oil. l-{(R*) -(4-Chlorophenyl)[4-(methoxycarbonyl)-phenyl]methyl}azeditin-3-ol, B isomer form, may be 93 prepared as described in Example 3, starting with 25.5 g of methyl (-)-4-[1-(R*)-amino-1-(4-chlorophenyl)methyl]benzoate, 250 cm3 of ethanol, 7.9 g of sodium hydrogen carbonate and 7.7 cm3 of 5 epibromohydrin. 29 g of 1-{(R*)-(4-chlorophenyl)[4- (methoxycarbonyl)phenyl]methyl}azeditin-3-ol, B isomer form, are obtained in the form of a yellow oil.
Methyl (-)-4-[(R*)-amino-(4-chlorophenyl)-methyl]benzoate may be prepared by carrying out two 10 successive recrystallizations of the white crystals (3.4 g) named "A crystals" of Example 3, from 68 cm3 of ethanol containing 5% of water under reflux. The crystals obtained are filtered, drained and then dried under reduced pressure (2.7 kPa). 2.2 g of methyl (-)-15 4-[1-(R*)-amino-(4-chlorophenyl)methyl]benzoate D-(-)-tartrate are obtained in the form of white crystals which are dissolved in 50 cm3 of ethyl acetate. The solution obtained is supplemented with 50 cm3 of 1 N sodium hydroxide, stirred and then separated after 20 settling. The organic phase is washed with 50 cm3 of water and then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 1.9 g of methyl (-)-4-[(R*)-amino-(4-chlorophenyl)methyl]benzoate are obtained in the form 25 of a white solid. [a]20°C, 365 nm = -58.1° +/- 1 (c = 0.5%) Example 5 1-[Bis(thien-2-yl)methyl]-3-[(RS)-(3,5-difluorophenyl)methylsulfonylmethyl]azetidine may be 94 prepared by carrying out the procedure as described in Example 3, starting with 0.10 g of 1-[bis(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethylene] azetidine, 2 cm3 of methanol, 2 cm3 of 5 dichloromethane and 25 mg of sodium borohydride, with stirring for 3 hours at 20°C. The crude product is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 7 cm, diameter 1 cm) eluting under an argon pressure of 0.1 bar with dichloromethane 10 and collecting 4-cm3 fractions. Fractions 2 to 5 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 83 mg of 1-[bis(thien-2-yl)methyl]-3-[(RS)-(3,5-difluorophenyl)methylsulfonylmethyl]-azetidine are obtained in the form of a white solid [1H 15 NMR spectrum (400 MHz, CDCI3, 8 in ppm) : from 2.60 to 2.70 (mt : 1H); 2.66 (s : 3H); 3.31 (mt : 2H); 3.40 (mt : 1H); 3.73 (broad t, J = 7.5 Hz : 1H) ; 4.27 (d, J = 11 Hz : 1H); 4.92 (s : 1H); 6.83 (tt, J = 9 and 2.5 Hz); from 6.85 to 7.00 (mt : 6H); 7.21 (mt : 2H)]. 20 l-[Bis(thien-2-yl)methyl]-3-[(3,5-difluoro- phenyl)methylsulfonylmethylene]azetidine may be prepared by carrying out the operation according to the procedure described in Example 6, starting with 2.2 g of l-[bis(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)-25 methylsulfonylmethyl-(RS)]azetidin-3-ol, 0.64 cm3 of methylsulfonyl chloride, 2.3 g of 4-dimethylamino-pyridine and 75 cm3 of dichloromethane; after purification by chromatography and crystallization from diisopropyl ether, 1.3 g of 1-[bis(thien-2-yl)methyl]- 95 3-[(3,5-difluorophenyl)methylsulfonylmethylene]-azetidine are obtained in the form of white crystals melting at 165°C. 1-[Bis(thien-2-yl)methyl]-3-[(3,5-5 difluorophenyl)methylsulfonylmethyl-(RS)]azetidin-3-ol may be prepared by carrying out the procedure in the following manner: 4 cm3 of 1.6 N n-butyllithium in hexane are added, under argon over 10 minutes, to a solution, cooled to -60°C, of 1.3 g of (3,5-difluoro-10 benzyl)methyl sulfone in 20 cm3 of tetrahydrofuran.
After stirring for 45 minutes at -70°C, a solution of 1.5 g of 1-[bis(thien-2-yl)methyl]azetidin-3-one in 20 cm3 of tetrahydrofuran is poured in over 10 minutes. After stirring for 3 hours at -70°C, the reaction 15 mixture is allowed to return to room temperature and then is supplemented with 10 cm3 of a saturated aqueous ammonium chloride solution. The mixture is separated after settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated to 20 dryness under reduced pressure (2.7 kPa). The residue is taken up in 20 cm3 of a mixture of cyclohexane and ethyl acetate (60/40 by volume) the suspension obtained is filtered, the solid is drained and then air-dried. 2.2 g of 1-[bis(thien-2-yl)methyl]-3-[(3,5-difluoro-25 phenyl)methylsulfonylmethyl-(RS)]azetidin-3-ol are obtained in the form of white crystals melting at 14 5 ° C. 1-[Bis(thien-2-yl)methyl]azetidin-3-one may be prepared by carrying out the procedure as described in 96 Example 1 (method 2) starting with 4 g of 1-[bis(thien- 2-yl)methyl]azetidin-3-ol, 2.6 cm3 of dimethyl sulfoxide, 7.7 cm3 of triethylamine, 7.7 cm3 of oxalyl chloride and 100 cm3 of dichloromethane. The residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm) with, as eluent, a cyclohexane and ethyl acetate (1/1 by volume mixture). The fractions obtained are evaporated to dryness under reduced pressure 10 (2.7 kPa). 3.2 g of 1-[bis(thien-2-yl)methyl]azetidin- 3-one are obtained in the form of cream-colored crystals melting at 70°C. 1-[Bis(thien-2-yl)methyl]azetidin-3-ol may be prepared by carrying out the procedure as described in 15 Example 3, starting with 6 g of 1-[bis(thien-2- yl)methyl]amine, 2.5 cm3 of epibromohydrin, 2.6 g of sodium bicarbonate and 50 cm3 of ethanol. 4 g of 1-[bis(thien-2-yl)methyl]azetidin-3-ol are obtained in the form of beige crystals melting at 115°C. 20 1-[Bis(thien-2-yl)methyl]amine may be prepared in the following manner: a solution of 5 cm3 of 2-thiopheninecarbonitrile in 50 cm3 of diethyl ether is poured, dropwise, into a solution, cooled under argon to 10°C, of thien-2-ylmagnesium bromide (prepared from 25 1.29 g of magnesium and 3.22 cm3 of 2-bromothiophene in 75 cm3 of diethyl ether). After refluxing for 1 hour and 30 minutes, the reaction medium is cooled to 5°C and then twice 20 cm3 of methanol are poured in dropwise, the suspension is filtered and the solid is 97 washed with methanol. The filtrate obtained [lacuna] a brown solution. 2.45 g of sodium borohydride are added to this solution in several portions, under argon. The mixture is stirred at room temperature for 16 hours and 5 is then diluted with ethyl acetate and slowly supplemented with water. The organic phase is extracted, washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure (2.5 kPa) at 55°C. A brown oil is obtained 10 which is chromatographed on a silica gel column (particle size 0.2-0.063 mm, diameter 8 cm, height 23 cm) and eluted with a cyclohexane and ethyl acetate (90/10 and then 85/15 by volume) mixture. Fractions 21 to 30 are combined and evaporated to dryness under 15 reduced pressure (2.7 kPa). 11 g of 1-[bis(thien-2-yl)methyl]amine are obtained in the form of a crystallized solid.
Example 6 1-[Bis(p-tolyl)methyl]-3-[(RS)methylsulfonyl-20 phenylmethyl]azetidine may be prepared by carrying out the procedure as described in Example 3, starting with 0.10 g of 1-[bis(p-tolyl)methyl]-3-(methylsulfonyl-phenylmethylene)azetidine, 2 cm3 of methanol, 2 cm3 of dichloromethane and 25 mg of sodium borohydride. The 25 crude product is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 7 cm, diameter 1 cm), eluting under an argon pressure of 0.1 bar with dichloromethane and collecting 4-cm3 fractions.
Fractions 5 to 10 are combined and concentrated to 98 dryness under reduced pressure (2.7 kPa). 35 mg of 1-[bis(p-tolyl)methyl]-3-[(RS)methylsulfonylpheny1-methyl]azetidine are obtained in the form of a white solid [XH NMR spectrum (300 MHz, CDC13, 5 in ppm) : 2.24 5 (s : 3H); 2.27 (s : 3H); 2.53 (t,J = 7.5 Hz : 1H); 2.58 (s : 3H); 3.19 (mt : 2H); 3.49 (mt : 1H); 3.69 (broad t, J = 7.5 Hz : 1H); 4.22 (s : 1H); 4.28 (d, J = 11.5 Hz : 1H); from 6.95 to 7.45 (mts : 13H)]. 1-[Bis(p-tolyl)methyl]-3-(methylsulfonylphenyl-10 methylene)azetidine may be prepared by carrying out the procedure in the following manner: 0.125 cm3 of methylsulfonyl chloride is added to a solution of 0.48 g of 1-[bis(p-tolyl)methyl]-3-[methylsulfonyl-phenylmethyl-(RS)]azetidin-3-ol in 25 cm3 of anhydrous 15 dichloromethane followed in small fractions by 0.4 65 g of 4-dimethylaminopyridine. After stirring for 20 hours at 20°C, the reaction mixture is washed with twice 80 cm3 of water, with 80 cm3 of brine, dried over magnesium sulfate and then concentrated to dryness 20 under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.040-0.063 mm, height 17 cm, diameter 3.2 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and 25 collecting 40-cm3 fractions. Fractions 5 to 8 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is stirred with diisopropyl ether, the solid is filtered, drained and then dried under reduced pressure (2.7 kPa). 0.25 g of 99 1-[bis(p-tolyl)methyl]-3-(methylsulfonylphenyl-methylene)azetidine is obtained in the form of a white solid [NMR spectrum in DMS0-d6, T=300K, 5 in ppm (250 MHz) : 2.23 (6H, s, 2Ph-CH3) , 2.98 (3H, s, SCH3) , 5 3.76 (2H, s, NCH2) , 4.20 (2H, s, NCH2) , 5.55 (1H, s, NCH), 7.10 (4H, d, J=7Hz, 4 CH arom.), 7.32 (4H, d, J=7Hz, 4CH arom.), 7.43 (5H, s, phenyl)]. 1-[Bis(p-tolyl)methyl]-3-[(methylsulfonyl)-phenylmethyl-(RS)]azetidin-3-ol may be prepared by 10 carrying out the procedure in the following manner: 0.6 g of 3-[(methylsulfonyl)(phenyl)methyl-(RS)]-azetidin-3-ol hydrochloride is added to a solution of 0.59 g of bromo(bis-p-tolyl)methane in 20 cm3 of acetonitrile followed by 0.3 g of potassium carbonate. 15 After heating for 1 hour and 15 minutes at the reflux temperature, the reaction mixture is cooled to 20°C and filtered. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is chromatographed on a silica gel column (particle size 20 0.04-0.06 mm, diameter 4 cm, height 16 cm), eluting with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and collecting 50-cm3 fractions. Fractions 8 to 13 are concentrated to dryness under reduced pressure (2.7 kPa). 0.48 g of 1-[bis(p-tolyl)methyl]-3-25 [(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol is obtained in the form of a white solid.
Bromo(bis-p-tolyl)methane may be prepared according to the procedure described by BACHMANN W.E., J.Am.Chem.Soc., 2135, (1933). 100 3-[(Methylsulfonyl)phenylmethyl-(RS)]azeditin-3-ol hydrochloride may be prepared by carrying out the procedure in the following manner: 12.6 cm3 of a 6.2 N hydrochloric acid solution in dioxane are added to a 5 solution of 2.62 g of 3-[(methylsulfonyl)(phenyl)-methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-ol in 12.6 cm3 of dioxane. After stirring for 20 hours at 20°C, the mixture is concentrated to dryness at 50°C under reduced pressure (2.7 kPa). The residue is taken 10 up in 25 cm3 of ethanol, heated under reflux for 1 hour and then allowed to return to 20°C and filtered. The solid is rinsed with diethyl ether and then drained and dried under reduced pressure (2.7 kPa). 1.89 g of 3-[(methylsulfonyl)phenylmethyl-(RS)]azeditin-3-ol 15 hydrochloride are obtained in the form of white crystals. 3-[(Methylsulfonyl)(phenyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-ol may be prepared by carrying out the procedure in the following manner: a 20 solution of 0.99 cm3 of vinyl chloroformate in 4 cm3 of anhydrous dichloromethane is poured dropwise into a mixture, cooled to +5°C, of 3.92 g of l-benzhydryl-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol in 500 cm3 of anhydrous dichloromethane. After stirring 25 for 48 hours at 20°C, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 5.6 cm, height 15.5 cm), eluting with a mixture of 101 cyclohexane and ethyl acetate (70/30 by volume) and collecting 50-cm3 fractions. Fractions 17 to 36 are concentrated to dryness under reduced pressure (2.7 kPa). 0.9 g of 3-[(methylsulfonyl)(phenyl)methyl-5 (RS)]-1-(vinyloxycarbonyl)azetidin-3-ol is obtained in the form of a white solid. l-Benzhydryl-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol may be prepared by carrying out the procedure as described in Example 1 (method 1), 10 starting with 47 cm3 of diisopropylamine, 205.6 cm3 of a 1.6 M solution of n-butyllithium in hexane, 2.2 litres of tetrahydrofuran, 50 g of benzylmethyl sulfone and 69.6 g of l-benzhydrylazetidin-3-one. 94.3 g of 1-benzhydryl-3-[(methylsulfonyl)(phenyl)methyl-15 (RS)]azetidin-3-ol are obtained in the form of white crystals.
Example 7 1-[Bis(3-fluorophenyl)methyl]-3-(RS)-[(3,5— difluorophenyl)methylsulfonylmethyl]azetidine may be 20 prepared by carrying out the procedure as described in Example 3, starting with 0.10 g of l-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethylene] azetidine, 2 cm3 of methanol, 2 cm3 of dichloromethane and 20 mg of sodium borohydride, with 25 stirring for 48 hours at 20°C. The crude product is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 7 cm, diameter 1 cm), eluting under an argon pressure of 0.1 bar with dichloromethane and collecting 4-cm3 fractions. Fractions 3 to 7 are 102 combined and concentrated to dryness under reduced pressure (2.7 kPa). 95 mg of 1-[bis(3-fluorophenyl)-methyl]-3-(RS)-[(3,5-difluorophenyl)methylsulfonylmethyl] azetidine are obtained in the form of white 5 crystals NMR spectrum (300 MHz, CDC13, 6 in ppm) : 2.57 (t, J = 7.5 Hz : 1H); 2.66 (s : 3H); from 3.15 to 3.30 (mt : 2H); from 3.30 to 3.50 (mt : 1H); 3.66 (broad t, J = 7.5 Hz : 1H); 4.27 (d, J = 11.5 Hz : 1H); 4.28 (s : 1H); from 6.75 to 7.35 (mt : 11H)]. 10 1- [Bis(3-fluorophenyl)methyl]-3-[(3,5- difluorophenyl)methylsulfonylmethylene]azetidine may be prepared by carrying out the procedure as described in Example 6, starting with 1.15 g of 1-[bis (3-fluorophenyl) methyl]-3-[ (3,5-difluorophenyl)(methylsulfonyl)-15 methyl-(RS)]azetidin-3-ol, 30 cm3 of dichloromethane, 0.264 cm3 of methylsulfonyl chloride and 0.98 g of 4-dimethylaminopyridine. After chromatography on a silica gel column (particle size 0.06-0.200 mm, diameter 2.8 cm, height 25 cm), under an argon pressure of 1 bar with a 20 mixture of ethyl acetate and cyclohexane (15/85 by volume) as eluent and collecting 60-cm3 fractions, 0.55 g of 1-[bis(3-fluorophenyl)methyl]-3-[(3,5— difluorophenyl)(methylsulfonyl)methylene]azetidine is obtained in the form of a white solid melting at 178°C. 25 1-[Bis(3-fluorophenyl)methyl]-3-[(3,5- difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol may be prepared according to the following procedure: 3.65 cm3 of a 1.6 M solution of n-butyllithium in hexane are poured over 10 minutes into 103 a mixture, cooled to -60°C, of diisopropylamine and 10 cm3 of tetrahydrofuran, the mixture is stirred for 10 minutes at -30°C and then cooled to -70°C. A solution of 1.2 g of (3,5-difluorobenzyl)methyl sulfone 5 in 30 cm3 of tetrahydrofuran is then added over minutes. After stirring for 30 minutes at -70°C, the mixture is supplemented over 30 minutes with a solution of 1.5 g of 1-[bis(3-fluorophenyl)methyl]azetidin-3-one in 10 cm3 of tetrahydrofuran. After stirring for 10 2 hours at -70°C, the reaction mixture is brought to room temperature and then supplemented with 20 cm3 of a saturated aqueous ammonium chloride solution and 100 cm3 of dichloromethane. The mixture is separated after settling, the organic phase is washed with water 15 and then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) . The residue is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 3.2 cm, height 30 cm), eluting under an argon pressure 20 of 1 bar with a mixture of ethyl acetate and cyclohexane (20/80 by volume) and collecting 60-cm3 fractions. Fractions 9 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 1.95 g of 1-[bis(3-fluorophenyl)methyl]-3-25 [(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]- azetidin-3-ol are obtained in the form of a white solid melting at 170°C (decomposition). 1-[Bis(3-fluorophenyl)methyl]azetidin-3-one may be prepared by carrying out the procedure as described 104 in Example 1 (method 2) starting with 0.7 cm3 of oxalyl chloride, 16 cm3 of dichloromethane, 1.12 cm3 of dimethylsulfoxide, 2 g of 1-[bis(3-fluorophenyl)-methyl]azetidin-3-ol and 3.7 cm3 of triethylamine. 1.55 g of 1-[bis(3-fluorophenyl)methyl]azetidin-3-one are obtained in the form of an oil which crystallizes at 20°C. 1-[Bis(3-fluorophenyl)methyl]azetidin-3-ol may be prepared by carrying out the procedure as described 10 by KATRITSKY A.R. in J. Heterocycl. Chem, 31, 271 (1994) starting with 4.9 g of [bis(3-fluorophenyl)-methyl]amine and 1.7 8 cm3 of epichlorohydrin.
[Bis(3-fluorophenyl)methyl]amine may be prepared in the following manner: a solution of 5.17 g 15 of 3,3'-difluorobenzophenone oxime in 30 cm3 of tetrahydrofuran is poured, under an argon atmosphere over 30 minutes, into a suspension of 1.27 g of lithium aluminum hydride in 80 cm3 of tetrahydrofuran. After stirring for 5 hours under reflux, 1.3 cm3 of water, 2 0 1.3 cm3 of 4 N sodium hydroxide, 2.6 cm3 of water and then 50 cm3 of ethyl acetate are added successively. After drying over magnesium sulfate and concentrating to dryness under reduced pressure (2.7 kPa), 4.9 g of [bis(3-fluorophenyl)methyl]amine are obtained in the 25 form of a yellow oil. 3,3'-Difluorobenzophenone oxime may be prepared according to the following procedure: a solution of 1.6 g of hydroxylamine hydrochloride in 8 cm3 of water is poured dropwise into a solution of 5.0 g of 105 3.3'-difluorobenzophenone in 10 cm3 of ethanol and then 1.2 g of sodium hydroxide pellets are added in small fractions. The reaction mixture, heated under reflux for 10 minutes, is cooled to 20°C and then acidified 5 with 7.5 cm3 of 4 N hydrochloric acid. The oily precipitate obtained, once it has been triturated, becomes a white solid which is filtered, washed with water and then dried at 35°C under reduced pressure (2.7 kPa). 5.17 g of 3,3'-difluorobenzophenone oxime 10 are obtained in the form of a white solid.
Example 8 1-[Bis(4-chlorophenyl)methyl]-3-(RS)-{[3-azetidin-l-yl-phenyl]methylsulfonylmethyl}azetidine may be prepared by carrying out the procedure as described 15 in Example 3, starting with 0.10 g of 1-[bis(4-chlorophenyl ) methyl ] -3-[(azetidin-l-yl-phenyl)methylsulfonylmethylene] azetidine, 2 cm3 of methanol, 2 cm3 of dichloromethane and 30 mg of sodium borohydride, stirring for 24 hours at 20°C. The crude product is 20 chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 7 cm, diameter 1 cm), eluting under an argon pressure of 0.1 bar with dichloromethane and collecting 4-cm3 fractions. Fractions 5 to 10 are combined and concentrated to dryness under reduced 25 pressure (2.7 kPa). 20 mg of 1-[bis(4-chlorophenyl)- methyl]-3-(RS)-{[3-azetidin-l-yl-phenyl]methylsulfonylmethyl } azetidine are obtained in the form of an off-white lacquer [1H NMR spectrum (300 MHz, CDCI3, 5 in ppm) : 2.39 (mt : 2H); from 2.50 to 2.65 (mt : 1H); 106 2.60 (s : 3H); 3.20 (mt : 2H); 3.47 (mt : 1H); 3.66 (broad t, J = 7 Hz : 1H); 3.89 (broad t, J = 7.5 Hz : 4H); 4.20 (d, J = 11 Hz : 1H); 4.26 (s : 1H); from 6.35 to 6.50 (mt : 2H); 6.67 (broad d, J = 7.5 Hz : 1H); from 7.10 to 7.40 (mt : 9H)]. 1-[Bis(4-chlorophenyl)methyl]-3-[(azetidin-1-yl-phenyl)methylsulfonylmethylene]azetidine may be prepared by carrying out the procedure by carrying out the procedure as described in Example 6, starting with 10 0.83 g of 1-[bis(4-chlorophenyl)methyl]-3-[(azetidin-1-yl-phenyl)methylsulfonylmethyl-(RS)]azetidin-3-ol, 20 cm3 of dichloromethane, 0.18 cm3 of methylsulfonyl chloride and 0.75 g of 4-dimethylaminopyridine. 0.40 g of 1-[bis(4-chlorophenyl)methyl]-3-[(azetidin-l-yl-15 phenyl)methylsulfonylmethylene]azetidine is obtained in the form of a white foam. 1-[Bis(4-chlorophenyl)methyl]-3-[(azetidin-l-yl -phenyl )methylsulfonylmethyl-(RS)]azetidin-3-ol may be prepared by carrying out the procedure as described 20 in Example 5, starting with 1.55 g of l-(3-methyl-sulfonylmethylphenyl)azetidine, 5.2 cm3 of a 1.6 M solution of n-butyllithium in hexane, 30 cm3 of tetrahydrofuran and 2.11 g of 1-[bis(4-chlorophenyl)-methyl]azetidin-3-one. 0.83 g of 1-[bis(4-chloro-25 phenyl)methyl]-3-[(azetidin-l-yl-phenyl)methylsulfonyl-methyl-(RS)]azetidin-3-ol is obtained in the form of an ochre-colored solid melting at 172°C. 1-(3-Methylsulfonylmethylphenyl)azetidine may be prepared by carrying out the procedure in the 107 following manner: a solution of 1.9 g of l-(3-methylsulfanylmethylphenyl)azetidine in 10 cm3 of ethanol is added to a mixture, cooled to 0°C, of 10 cm3 of water, 5 cm3 of acetic acid, 1.5 cm3 of 36 N sulfuric 5 acid and 6.15 g of oxone. After stirring for 20 hours at 20°C, the reaction mixture is supplemented with 100 cm3 of water, 100 cm3 of ethyl acetate and is then neutralized by stirring with sodium hydrogen carbonate. The mixture obtained is separated after settling, the 10 organic phase is dried over magensium sulfate and then filtered and concentrated to dryness under reduced pressure (2.7 kPa). 1.55 g of 1-(3-methylsulfonylmethylphenyl )azetidine are obtained in the form of a light brown gum. 15 1-[3-(Methylsulfonylmethyl)phenyl]azetidine may be prepared by carrying out a procedure in the following manner: 2.57 g of potassium tert-butoxide, 0.64 g of 1,1'-bis(diphenylphosphino)ferrocenyl-palladium chloride, 1.49 g of 1,1'-bis(diphenyl-20 phosphino)ferrocene, 0.12 g of copper iodide and 2.0 g of azetidine are added, under argon, to a solution of 4.6 g of l-iodo-3-(methylsulfanylmethyl)benzene in 60 cm3 of tetrahydrofuran. After heating for 3 hours at the reflux temperature, the reaction mixture is cooled 25 to room temperature and filtered on celite and then washing the latter with 150 cm3 of ethyl acetate. The combined filtrate and washings is acidified with 120 cm3 of 1 N hydrochloric acid and then separated after settling. The aqueous phase is supplemented with 108 60 cm3 of ethyl acetate and is then alkalinized with sodium hydrogen carbonate and the mixture is separated after settling. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness 5 under reduced pressure (2.7 kPa). The residue is is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 3.5 cm, height 50 cm), eluting under an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (20/80 by volume) and 10 collecting 100-cm3 fractions. Fractions 1 to 3 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 1.9 g of 1-[3-(methylsulfonylmethyl )phenyl]azetidine are obtained in the form of an oil. 1,1'-Bis(diphenylphosphino)ferrocenylpalladium chloride may be prepared by carrying out the procedure according to Hayashi T. et al., in J. Am. Chem. Soc, 106, 158 (1984) . l-Iodo-3-(methylsulfanylmethyl)benzene may be 20 prepared by carrying out the procedure in the following manner: 6.4 g of sodium methylthiolate are added to a solution of 25 g of 3-iodobenzyl bromide in 80 cm3 of N,N-dimethylformamide. After stirring for 20 hours at 20°C, the reaction mixture is supplemented with 250 cm3 25 of water, 200 cm3 of ethyl acetate and is stirred and then separated after settling. The organic phase is washed with four times 200 cm3 of water, dried over magnesium sulfate, filtered and then concentrated to dryness at 50°C under reduced pressure (2.7 kPa). 22 g 109 of l-iodo-3-(methylsulfanylmethyl)benzene are obtained in the form of a gum.
Example 9 The mixture of the 2 A form diastereoisomers 1-5 (R*)-{4-[(4-chlorophenyl)-{3-[(3,5-difluorophenyl)-methylsulfonylmethyl-(R)]-3-imidazolyl-azetidin-l-yl}methyl]benzyl}-IH-imidazole and l-(R*)-{4(4-chlorophenyl)-{3-[(3,5-difluorophenyl)methylsulfonylmethyl- (S))}-3-imidazolyl-azetidin-l-yl}methyl]benzyl]-10 IH-imidazole may be prepared by carrying out the procedure in the following manner: 13.6 mg of imidazole are added to a solution of 50 mg of l-{(R*)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}—3 —[(3,5-difluorophenyl)methylsulfonylmethylene]azetidine, A 15 isomer form, in 1 cm3 of dichloromethane. After stirring for 20 hours at 20°C, the reaction mixture is directly chromatographed on a silica gel column: (particle size 0.063-0.200 mm, height 7 cm, diameter 1 cm), eluting under an argon pressure of 0.1 bar with 20 a mixture of dichloromethane and methanol (98/2 by volume) and collecting 4-cm3 fractions. Fractions 4 to 9 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 20 mg of the mixture of the 2 A form diastereoisomers 1-(R*)-{4-[(4-chlorophenyl)-25 {3-[(3,5-difluorophenyl)methylsulfonylmethyl-(R)]-3- imidazolyl-azetidin-1-yl}methyl]benzyl}-1H-imidazole and 1-(R*)-{4-[(4-chlorophenyl)—{3—[3—[(3,5— difluorophenyl)methylsulfonylmethyl-(S)]}-3-imidazolyl-azetidin-l-yl }methyl] benzyl] -IH-imidazole are obtained 110 in the form of a white lacquer [1H NMR spectrum (300 MHz, CDCI3, 8 in ppm) : a mixture of diastoero-isomers is observed, *2.64 (s : 3H); 3.42 (d, J = 8 Hz : 1H); 3.50 (d, J = 8 Hz : 1H); 3.75 (mt : 1H); 4.31 5 (broad d, J = 8 Hz : 1H); 4.40 (s : 1H); 4.54 and 4.55 (2s : 2H in total); 4.72 (s : 1H); 6.84 (mt : 2H); 6.87 (s : 1H); 6.95 (mt : 1H); 7.11 (s : 1H); from 7.20 to 7.40 (mt 12)].
Example 10 (l-Benzhydrylazetidin-3-yl)phenylmethanone O-methyloxime, a mixture of the 2 isomers Z and E, may be prepared by carrying out the procedure in the following manner: 0.28 6 g of O-methylhydroxylamine and 0.32 g of sodium acetate are added to a suspension of 15 0.80 g of l-benzhydryl-3-benzoylazetidine in 30 cm3 of ethanol. After stirring for 24 hours at reflux temperature, the reaction mixture is allowed to cool at room temperature and filtered. The filtrate is concentrated to dryness at 50°C under reduced pressure 20 (2.7 kPa). The residue is taken up in 100 cm3 of dichloromethane and the solution is supplemented with 20 cm3 of water and 1 N hydrochloric acid, stirring until an acidic pH is obtained. The organic phase is separated after settling, dried over magnesium sulfate 25 and then filtered and concentrated to dryness under reduced pressure (2.7 kPa).
The residue is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 36 cm, diameter 3.8 cm), eluting under an argon pressure of Ill 0.5 bar with a mixture of cyclohexane and ethyl acetate (95/5, 92/8 and then 80/20 by volume) and collecting 30-cm3 fractions. Fractions 8 to 14 are combined and concentrated to dryness under reduced pressure 5 (2.7 kPa). 0.20 g of (l-benzhydrylazetidin-3-yl)phenyl-methanone O-methyloxime, a mixture of the 2 isomers Z and E, is obtained in the form of a white solid [1H NMR spectrum (250 MHz, (CD3)2SO d6, d in ppm) . A 65/35 mixture of isomers is observed, * 2.68-3.02 and from 10 3.25 to 3.90 (mts : 5H in total); 3.76 and 3.80 (2s :3H in total); 4.26 and 4.38 (2s : 1H in total); from 7.10 to 7.50 (mt : 15H)]. l-Benzhydryl-3-benzoylazetidine may be prepared by carrying out the procedure in the following manner: 15 112 cm3 of a 1 M solution of phenylmagnesium bromide in tetrahydrofuran are poured dropwise, under argon, into a solution, cooled to 0°C, of 11.5 g of (1-benzhydrylazetidin-3-yl)carboxylic-N-methoxy-N-methylamide acid in 350 cm3 of tetrahydrofuran, and 20 then the mixture is allowed to return to room temperature. After stirring for 20 hours at 20°C, the reaction mixture is supplemented with 400 cm3 of a saturated ammonium chloride solution and then with 250 cm3 of ethyl acetate. After stirring, the mixture 25 is separated after settling, the aqueous phase reextracted with 250 cm3 of ethyl acetate and the combined two organic phases are washed with twice 250 cm3 of water, dried over magnesium sulfate, filtered and concentrated to dryness at 50°C under 112 reduced pressure (2.7 kPa). The residue is stirred with 50 cm3 of diisopropyl ether, the suspension is filtered, the solid is drained and then dried under reduced pressure (2.7 kPa). l-benzhydryl-3-5 benzoylazetidine are obtained in the form of a cream-colored solid. (l-Benzhydrylazetidin-3-yl)carboxylic-N-methoxy-N-methylamide may be prepared by carrying out the procedure in the following manner: 13.35 g of (1-10 benzhydrylazetidin-3-yl)carboxylic acid and 1.0 g of hydroxybenzotriazole hydrate are added, with stirring, to a suspension of 4.0 g of N,O-dimethylhydroxylamine hydrochloride in 250 cm3 of dichloromethane. 6.92 g of 1-(3-dimethylaminopropyl)3-ethylcarbodiimide 15 hydrochloride and 8.8 cm3 of N,N-diisopropylethylamine are added to this mixture, placed under argon and cooled to +5°C. After stirring for 3 hours at +5°C and then for 20 hours at 20°C, the reaction mixture is supplemented with 200 cm3 of water and then separated 20 after settling. The organic phase is washed with 300 cm3 of water, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is stirred with 100 cm3 of diisopropyl ether, the suspension is filtered and 25 the solid is drained and then dried under reduced pressure (2.7 kPa). 10.76 g of (l-benzhydrylazetidin-3-yl)carboxylic-N-methoxy-N-methylamide are obtained in the form of a cream-colored solid. 113 (l-Benzhydrylazetidin-3-yl)carboxylic acid may be prepared by carrying out the procedure in the following manner: a solution of 11 g of potassium hydroxide in 9 cm3 of water is added dropwise to a 5 suspension, cooled to +5°C, of 14 g of (1-benzhydryl-azetidin-3-yl)carbonitrile in 140 cm3 of 2-ethoxy-ethanol and then the mixture is heated to 95°C. After stirring for 16 hours at this temperature, the reaction mixture is poured slowly, with stirring, over ice and 10 left at 0°C for 68 hours and then concentrated to dryness to dryness at 50°C under reduced pressure (2.7 kPa). The residue is taken up in 400 cm3 of water, the solution is acidified to pH 4 with 6 N hydrochloric acid and then supplemented with 400 cm3 of ethyl 15 acetate. The resulting suspension is filtered, the solid is drained and then dried at 50°C under reduced pressure (2.7 kPa). 13.55 g of (l-benzhydrylazetidin-3-yl)carboxylic acid are obtained in the form of a cream-colored solid. (l-Benzhydrylazetidin-3-yl)carbonitrile may be prepared by carrying out the procedure in the following manner: a solution of 18.54 g of sodium cyanide in 25 cm3 of water is added dropwise to a solution of 40 g of l-benzhydrylazetidine-3-yl methylsulfonate in 25 350 cm3 of N,N-dimethylformamide. After stirring for 24 hours at 65°C, the reaction mixture, allowed to return to room temperature, is then poured, with stirring, into a mixture of 550 cm3 of water and 300 g of ice. The suspension obtained is filtered, the solid 114 is washed with three times 110 cm3 of water and then dissolved in 350 cm3 of dichloromethane. The solution is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure 5 (2.7 kPa). The residue is stirred with 200 cm3 of diisopropyl ether, the suspension filtered, the solid drained and then dried under reduced pressure (2.7 kPa). 28.4 g of (l-benzhydrylazetidin-3-yl)-carbonitrile are obtained in the form of a pinkish 10 cream-colored solid. l-Benzhydrylazetidin-3-yl methylsulfonate may be prepared by carrying out the procedure starting with 100 g of l-benzhydrylazetidin-3-ol, 800 cm3 of dichloromethane, 31 cm3 of methylsulfonyl chloride and 15 35 cm3 of pyridine. The crude product obtained is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 50 cm, diameter 11 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (80/20, 75/25, and then 20 70/30 and 60/40 by volume) and collecting 1-litre fractions. Fractions 12 to 31 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 66 g of l-benzhydrylazetidine-3-yl methylsulfonate are obtained in the form of a yellowish 25 white solid. l-Benzhydrylazetidin-3-ol may be prepared by carrying out the procedure as described by Alan R. KATRITZKY et al., in J. Heterocyclic Chem.; 31, 271 (1994). 115 Example 11 (RS)-1-[3-({1-Bis(4-chlorophenyl)methyl]-azetidin-3-yl}methylsulfonylmethyl)phenyl]pyrrolidine may be prepared by carrying out the procedure as 5 described in Example 3, starting with 0.10 g of 1—[3 — ({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-methylsulfonylmethylene)phenyl]pyrrolidine, 1.5 cm3 of anhydrous methanol, 1.5 cm3 of anhydrous dichloromethane, and 30 mg of sodium borohydride, 10 stirring for 3 hours at 20°C and then 8 hours at 50°C. The crude product is chromatographed on a silica gel column (particle size 0.040-0.063 mm, height 8 cm, diameter 1 cm), eluting under an argon pressure of 0.8 bar with a mixture of cyclohexane and ethyl acetate 15 (80/20 by volume) and collecting 5-cm3 fractions.
Fractions 22 to 28 are combined and concentrated to dryness under reduced pressure (2.7 kPa), the residue is stirred with 5 cm3 of pentane, the solid is filtered, drained and dried. 18 mg of (RS)-1-[3-({1-2 0 [bis(4-chlorophenyl)methyl]azetidin-3-yl}methyl- sulfonylmethyl)phenyl]pyrrolidine are obtained in the form of white powder [1H NMR spectrum (300 MHz, CDC13, 5 in ppm) : 2.01 (mt : 4H); 2.59 (mt : 1H); 2.61 (s : 3H); from 3.10 to 3.25 (mt : 2H); 3.27 (mt : 4H); from 25 3.40 to 3.55 (mt : 1H); 3.66 (mt : 1H); 4.20 (d, J = 12 Hz : 1H); 4.25 (s : 1H); from 6.45 to 6.65 (mt : 3H); from 7.10 to 7.35 (mt : 9H) ] . l-[3-({l-[Bis(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonylmethylene)phenyl]pyrrolidine may be 116 prepared by carrying out the procedure as described in Example 6, starting with 0.6 g of l-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(3-pyrrolidinylphenyl)methyl-(RS)]azetidin-3-ol, 0.1 cm3 5 of methylsulfonyl chloride and 0.5 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm) under an argon pressure of 0.5 bar with a 10 dichloromethane and ethanol mixture as eluent (98.5/1.5 by volume) and collecting 10-cm3 fractions. Fraction 4 is concentrated to dryness under reduced pressure (2.7 kPa). After recrystallization from 5 cm3 of diethyl ether, 0.5 g of 1-[3-({1-[bis(4-chlorophenyl)-15 methyl]azetidin-3-yl}methylsulfonylmethylene)phenyl]-pyrrolidine is obtained in the form of a solid melting at 133 °C. 1-[Bis(4-chlorophenyl)methyl]-3-[(methylsulf onyl )(3-pyrrolidinylphenyl)methyl-(RS)]azetidin-3-20 ol may be obtained by carrying out the operation according to the procedure of Example 5, starting with 0.5 g of 1-[3-(methylsulfonylmethyl)phenyl]pyrrolidine, 0.6 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one, 15 cm3 of tetrahydrofuran and 1.4 cm3 of a 1.6 N 25 solution of n-butyllithium in hexane. 0.6 g of 1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(3-pyrrolidinylphenyl)methyl-(RS)]azetidin-3-ol is obtained in the form of a cream-colored solid. 117 1-[3-(Methylsulfonylmethyl)phenyl]pyrrolidine may be prepared by carrying out the procedure described in Example 8, starting with 6 cm3 of water, 6 cm3 of 100% acetic acid, 3.5 cm3 of 36 N sulfuric acid, 3.11 g 5 of oxone, 0.96 g of 1-[3-(methylsulfanylmethyl)phenyl]-pyrrolidine and 6 cm3 of ethanol. 0.478 g of 1—[3 — (methylsulfonylmethyl)phenyl]pyrrolidine is obtained in the form of a light brown gum. 1-[3-(Methylsulfanylmethyl)phenyl]pyrrolidine 10 may be prepared by carrying out the procedure as described in Example 8, starting with 4.0 g of 1-iodo-3-(methylsulfanylmethyl)benzene, 120 cm3 of tetrahydrofuran, 2.2 g of sodium tert-butoxide, 0.556 g of 1,1'-bis(diphenylphosphino)ferrocenylpalladium 15 chloride, 1.26 g of 1,1'-bis(diphenylphosphino)- ferrocene and 2.6 g of pyrrolidine. 1.9 g of 1—[3 — (methylsulfanylmethyl)phenyl]pyrrolidine are obtained in the form of an oil.
Example 12 N-(RS)-[3-({l-[Bis(4-chlorophenyl)methyl]- azetidin-3-yl}methylsulfonylmethyl)phenyl]-N-methyl-carbamic acid tert-butyl ester may be prepared by carrying out the procedure as described in Example 3, starting with 0.10 g of N-[3-({1-[bis(4-chlorophenyl)-2 5 methyl]azetidin-3-yl}methylsulfonylmethylene)phenyl]-N-methylcarbamic acid tert-butyl ester, 1.5 cm3 of anhydrous methanol, 1.5 cm3 of anhydrous dichloromethane and 30 mg of sodium borohydride, with stirring for 3 hours at 20°C. The crude product is 118 stirred with 10 cm3 of diisopropyl ether, the solid is filtered, drained and then dried under reduced pressure (2.7 kPa). 94 mg of N-(RS)-[3-({1-[bis(4-chlorophenyl)-methyl]azetidin-3-yl}methylsulfonylmethyl)phenyl]-N-5 methylcarbamic acid tert-butyl ester are obtained in the form of a white powder [1H NMR spectrum (300 MHz, (CD3)2SO d6, 8 in ppm) : 1.36 (s : 9H) ; 2.46 (t, J = 7.5 Hz : 1H); 2.75 (s : 3H); from 3.00 to 3.55 (mt : 4H); 3.17 (s : 3H); 4.45 (s : 1H); 4.78 (d, J = 11 Hz : 10 1H); from 7.20 to 7.50 (mt : 12H)].
N-[3-({1-[Bis(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonylmethylene)phenyl]-N-methylcarbamic acid tert-butyl ester may be prepared by carrying out the procedure as described in Example 6, starting with 15 5.6 g of 1-[bis(4-chlorophenyl)methyl]-3-{[3-(N-tert-butyloxycarbonyl-N-methylamino)phenyl]methylsulfonylmethyl- (RS )} azetidin-3-ol , 100 cm3 of dichloromethane, 1.59 g of methylsulfonyl chloride and 4.5 g of 4-dimethylaminopyridine. The crude product obtained is 20 purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm and weight of silica 250 g), eluting under a nitrogen pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (30/70 by volume) and collecting 100-cm3 fractions. 25 Fractions 12 to 18 are combined, concentrated to dryness under reduced pressure (2.7 kPa). 3.2 g of N-[3—({1—[bis(4-chlorophenyl)methyl]azetidin-3-ylJmethylsulfonylmethylene)phenyl]-N-methylcarbamic 119 acid tert-butyl ester are obtained in the form of a white foam. 1-[Bis(4-chlorophenyl)methyl]-3-{[3-(N-tert-butyloxycarbonyl-N-methylamino)phenyl]methylsulfonyl-5 methyl-(RS)}azetidin-3-ol, may be prepared by carrying out the procedure as described in Example 5, starting with 3.8 g of N-[3-(methylsulfonylmethyl)phenyl]-N-methylcarbamic acid tert-butyl ester, 50 cm3 of tetrahydrofuran, 9.5 cm3 of a 1.6 N solution of n-10 butyllithium in hexane, and 3.82 g of l-[bis(4- chlorophenyl)methyl]azetidin-3-one. The crude product is purified by chromotography on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, weight of silica 250 g), eluting under a nitrogen pressure of 15 0.5 bar with dichloromethane and then with a dichloromethane and ethanol (99/1 by volume) mixture and collecting 500-cm3 fractions. Fractions 10 to 16 are combined, concentrated to dryness under reduced pressure (2.7 kPa). 5.6 g of 1-[bis(4-chlorophenyl)-20 methyl]-3-{[3-(N-tert-butyloxycarbonyl-N-methylamino)-phenyl]methylsulfonylmethyl-(RS)}azetidin-3-ol are obtained in the form of a foam.
N-[3-(Methylsulfonylmethyl)phenyl]-N-methylcarbamic acid tert-butyl ester may be prepared by 25 carrying out the procedure in the following manner: 3.7 g of di-tert-butyl dicarbonate are added to a solution of 3 g of N-[3-(methylsulfonylmethyl)phenyl]N-methylamine in 8 0 cm3 of dichloromethane. After stirring for 20 hours at 20°C, the reaction mixture is 120 supplemented with 100 cm3 of water and then separated after settling. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue 5 is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm and weight of silica 300 g), eluting under a nitrogen pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (45/55 by volume) and collecting 100-cm3 fractions. Fractions 10 11 to 16 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 3.8 g of N-[3-(methylsulf onylmethyl ) phenyl ] -N-methylcarbamic acid tert-butyl ester are obtained in the form of a gum which crystallizes.
N-[3-(Methylsulfonylmethyl)phenyl]N-methylamine may be obtained by carrying out the procedure in the following manner: a mixture of 9.65 cm3 of formic acid and 19.63 cm3 of acetic anhydride is heated at 50°C for 3 hours under argon, and then the solution obtained is 20 allowed to return to room temperature. 40 cm3 of tetrahydrofuran are poured in and the medium is cooled to -20°C. After stirring for 2 hours at -20°C, a solution of 14.8 g of 3-(methylsulfonylmethyl)phenyl-amine is poured in while the temperature is maintained. 25 After stirring for 2 hours at -20°C, and then for 48 hours at 20°C, the mixture is filtered, the solid is drained and then washed with three times 50 cm3 of diisopropyl ether and dried under reduced pressure (2.7 kPa). A solid A is obtained. The filtrate is 121 concentrated to half the volume, the resulting suspension is filtered, the solid is drained, washed with diisopropyl ether and dried. A solid B is obtained. The two solids A and B are combined and taken 5 up in 375 cm3 of tetrahydrofuran and the mixture, cooled to 0°C, is supplemented, over 20 minutes, with 80 cm3 of a 2 M solution of borane-dimethyl sulfide complex in tetrahydrofuran and then heated at reflux temperature for 3 hours. The reaction mixture, cooled 10 to +5°C, is supplemented over 20 minutes with 60 cm3 of methanol, stirred for 1 hour at room temperature and then supplemented with gaseous hydrochloric acid to a pH of 1. The mixture is heated under reflux for one hour and then supplemented with 300 cm3 of water and 15 with a 3 N solution of sodium hydroxide to pH 8. The resulting mixture is extracted with 500 cm3 of ethyl acetate, the organic phase is washed successively with a saturated aqueous sodium hydrogen carbonate solution, and with brine, and is then dried over magnesium 20 sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 100 cm3 of 4 N sulfuric acid, the solution obtained is washed with 100 cm3 of ethyl acetate, then alkalinized to pH 8 with 3 N sodium hydroxide and with a saturated aqueous 25 sodium carbonate solution and is then extracted with twice 75 cm3 of ethyl acetate. The combined extracts are dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 8.98 g of N- 122 [3-(methylsulfonylmethyl)phenyl]N-methylamine are obtained in the form of a pink solid. 3-(Methylsulfonylmethyl)phenylamine may be prepared by carrying out the procedure in the following 5 manner: a suspension of 23.7 g of 1-(methylsulfonylmethyl ) -3-nitrobenzene in 150 cm3 of methanol and 65 cm3 of 36% hydrochloric acid is heated to reflux temperature and then 18.5 g of iron are carefully added over 10 minutes, in small fractions. After heating 10 under reflux for 4 hours and then stirring at room temperature for 20 hours, the reaction mixture is supplemented with 5 g of iron and then again heated under reflux for one hour and then at room temperature for 20 hours. The mixture is then alkalinized to pH 9 15 with aqueous ammonia and with sodium hydrogen carbonate, and then extracted with 3 times 250 cm3 of ethyl acetate, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). 14.9 g of 3-(methylsulfonylmethyl)phenyl-20 amine are obtained in the form of a beige powder. 1-(Methylsulfonylmethyl)-3-nitrobenzene may be prepared by heating under reflux 23.8 g of 3-nitro-benzyl chloride, 20 g of sodium methyl sulfinate and 250 cm3 of absolute ethanol. 23.74 g of 1-(methyl-25 sulfonylmethyl)-3-nitrobenzene are obtained in the form of a white powder.
Example 13 (RS)-N-[3-({1-[Bis(4-chlorophenyl)methyl]-azetidin-3-yl}methylsulfonylmethyl)phenyl]-N- 123 methylamine may be prepared by carrying out the procedure as described in Example 3 starting with 0.10 g of N-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonylmethylene)phenyl]-N-methylamine, 5 1.5 cm3 of anhydrous methanol, 1.5 cm3 of anhydrous dichloromethane and 45 mg of sodium borohydride, with stirring for 20 hours at 20°C and then for 5 hours at 50°C. The crude product is chromatographed on a silica gel column (particle size 0.040-0.063 mm, height 10 cm, 10 diameter 1 cm), eluting under an argon pressure of 0.8 bar with a mixture of cyclohexane and ethyl acetate (80/20, and then 60/40 by volume) and collecting 5-cm3 fractions. Fractions 20 to 26 are combined and concentrated to dryness under reduced pressure 15 (2.7 kPa), the residue is stirred with 5 cm3 of pentane, the solid is filtered, drained and dried. 20 mg of (RS)-N-[3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-yl}methylsulfonylmethyl)phenyl]-N-methylamine are obtained in the form of a white powder 20 [1H NMR spectrum (300 MHz, CDC13, 8 in ppm) : from 2.50 to 2.65 (mt : 1H); 2.60 (s : 3H); 2.82 (d, J = 5 Hz : 3H); 3.18 (mt : 2H); from 3.35 to 3.50 (mt : 1H); 3.64 (broad t, J = 7.5 Hz : 1H); 3.80 (mt : 1H); 4.18 (d, J = 11.5 Hz : 1H); 4.24 (s : 1H); from 6.50 to 6.70 (mt : 25 3H); from 7.10 to 7.35 (mt : 9H].
N-[3-({1-[Bis(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonylmethylene)phenyl]-N-methylamine may be prepared by carrying out the procedure in the following manner: 2.7 g of 1-[bis(4-chlorophenyl)methyl]-3-{[3- 124 (N-tertbutyloxycarbonyl-N-methylamino)phenyl]methylsulf onylmethylene } azetidine in 30 cm3 of dioxane and 30 cm3 of a 4.7 N solution of hydrochloric dioxane are stirred for 20 hours. The reaction medium is evaporated 5 to dryness under reduced pressure (2.7 kPa), taken up in 50 cm3 of water and 50 cm3 of ethyl acetate, stirred and cautiously neutralized with a saturated aqueous sodium bicarbonate solution. The organic phase is separated, dried over magnesium sulfate, treated with 10 animal charcoal and then concentrated under reduced pressure (2.7 kPa) to a volume of about 25 cm3, then filtered and concentrated to dryness under reduced pressure. 1.3 g of N-[3-({1-[bis(4-chlorophenyl)-methyl]azetidin-3-yl}methylsulfonylmethylene)phenyl]-N-15 methylamine are obtained in the form of white crystals melting at 228°C.
Example 14 (RS)-1-[Bis(4-chlorophenyl)methyl]-3-[(3,5-bis-trif luoromethylphenyl )methylsulfonylmethyl]azetidine 20 may be prepared by carrying out the procedure as described in Example 3, starting with 0.10 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-bis-trifluoro-methylphenyl)methylsulfonylmethylene]azetidine, 1.5 cm3 of anhydrous methanol, 1.5 cm3 of anhydrous 25 dichloromethane and 15 mg of sodium borohydride, with stirring for 3 hours at 20°C. The crude product is stirred with 5 cm3 of pentane, the solid is filtered, drained and dried. 82 mg of (RS)-1-[bis(4-chlorophenyl ) methyl ] -3-[(3,5-bis-trifluoromethylphenyl)- 125 methylsulfonylmethyl]azetidine are obtained in the form of a white powder [1H NMR spectrum (400 MHz, (CD3)2SO d6, 5 in ppm) : 2.84 (s : 3H); 3.08 (mt : 2H); from 3.25 to 3.40 (mt : 1H); from 3.45 to 3.65 (mt : 2H); 4.45 (s : 1H); 5.13 (d, J = 10.5 Hz : 1H); from 7.25 to 7.50 (mt : 8H); 8.11 (broad s : 2H)? 8.15 (broad s : 1H) ] . 1-[Bis(4-chlorophenyl)methyl]-3-[(3,5-bis-trif luoromethylphenyl )methylsulfonylmethylene]azetidine 10 may be prepared by carrying out the procedure in the following manner: 0.96 g of crushed sodium hydroxide is added in fractions to a solution of 3.16 g of 3-acetoxy-1-[bis(4-chlorophenyl)methyl]-3-{[3,5— bis(trifluoromethyl)phenyl]methylsulfonylmethyl-(RS)}-15 azetidine in 40 cm3 of dioxane. After stirring for 1 hour at room temperature, the reaction mixture is supplemented with 200 cm3 of ethyl acetate, 200 cm3 of water and is then separated after settling. The organic phase is washed with twice 80 cm3 of water, then with 20 80 cm3 of brine, dried over magnesium sulfate, then filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.040-0.063 mm, height 14.5 cm, diameter 4.8 cm), eluting under an argon 25 pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (85/15 by volume) and collecting 40-cm3 fractions. Fractions 8 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa), 1.49 g of 1-[bis(4-chlorophenyl)methyl]-3- 126 {[(3,5-bis-trifluoromethylphenyl]methylsulfonylmethylene } azetidine are obtained in the form of a white foam. 3-Acetoxy-l-[bis(4-chlorophenyl)methyl]-3-5 {[3,5-bis(trifluoromethyl)phenyl]methylsulfonylmethy1-(RS)}-azetidine may be prepared by carrying out the procedure in the following manner: 4.1 cm3 of a 1.6 N solution of n-butyllithium in hexane are poured dropwise, under argon, into a solution, cooled to 10 -78°C, of 2.0 g of [3,5-bis(trifluoromethyl)benzyl]-methyl sulfone in 35 cm3 of tetrahydrofuran. After stirring for one hour at -70°C, a solution of 2.0 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one in 35 cm3 of tetrahydrofuran is added dropwise. After stirring 15 for 2 hours at -78°C, a solution of 0.7 cm3 of acetyl chloride in 5 cm3 of anhydrous dietheyl ether is poured in and then the mixture is allowed to return to room temperature. After stirring for 2 hours and 30 minutes, the reaction mixture is supplemented with 100 cm3 of 20 water and separated after settling. The organic phase is washed with 100 cm3 of water, then with 100 cm3 of brine and is then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica 25 gel column (particle size 0.04-0.06 mm, diameter .6 cm, height 16 cm), eluting under an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (10/90 and then 40/60 by volume) and collecting 100-cm3 fractions. Fractions 37 to 52 are 127 combined and concentrated to dryness under reduced pressure (2.7 kPa). 3.56 g of 3-acetoxy-l-[bis(4-chlorophenyl)methyl]-3-{[3,5-bis(trifluoromethyl)-phenyl]methylsulfonylmethyl-(RS)}-azetidine are 5 obtained in the form of a white foam. [3,5-Bis(trifluoromethyl)benzyl]methyl sulfone may be prepared by heating under reflux 1.8 g of 3,5-bis(trifluoromethyl)benzyl chloride, 50 cm3 of absolute ethanol and 1.22 g of sodium methyl sulfinate. 10 1.86 g of [3,5-bis(trifluoromethyl)benzyl]methyl sulfone are obtained in the form of a white solid. Example 15 N- [ 4 - ( ( 4-Chlorophenyl)-{3-[ (3,5-difluorophenyl)methylsulfonylmethyl-(RS)]azetidin-1-15 ylJmethyl-(RS))benzyl]-N,N-dimethylamine, a mixture of two diastereoisomers, may be prepared by carrying out the procedure as described in Example 3, starting with 0.10 g of N-[4-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)methylsulfonylmethylene]azetidin-1-20 yl}methyl-(RS)-benzyl]-N,N-dimethylamine, 1.5 cm3 of anhydrous methanol, 1.5 cm3 of anhydrous dichloromethane and 45 mg of sodium borohydride, with stirring for 16 hours at 20°C and then for 16 hours at 50°C. The crude product is chromatographed on a silica 25 gel column (particle size 0.040-0.063 mm, height 22 cm, diameter 1 cm), eluting under an argon pressure of 0.8 bar with a mixture of ethyl acetate and methanol (97/3 by volume) and collecting 20-cm3 fractions. Fractions 17 to 25 are combined and concentrated to 128 dryness under reduced pressure (2.7 kPa), the residue is stirred with 5 cm3 of pentane, the solid is filtered, drained and dried. 6 mg of N-[4-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)methylsulfonyl-5 methyl-(RS)]azetidin-l-yl}methyl-(RS))benzyl]-N,N- dimethylamine, a mixture of two diastereoisomers, are obtained in the form of a white powder [1H NMR spectrum (300 MHz, CDCI3, 5 in ppm) : 2.20 (s : 6H); 2.53 (t, J = 7 Hz : 1H) ; 2.65 (s : 3H); from 3.10 to 3.25 (mt : 2H) ; 10 from 3.30 to 3.45 (mt : 1H); 3.35 (broad s : 2H); 3.63 (broad t, J = 7 Hz : 1H); 4.24 (s : 1H); 4.25 (d, J = 11 Hz : 1H); 6.82 (tt, J = 9 and 2 Hz : 1H); 6.94 (mt : 2H); from 7.15 to 7.35 (mt : 8H)].
N-[4-((4-Chlorophenyl)-{3-[(3,5-difluoro-15 phenyl)methylsulfonylmethylene]azetidin-l-yl}methyl-(RS))benzyl]-N,N-dimethylamine may be prepared by carrying out the procedure in the following manner: 1.0 g of (RS)-4-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)methylsulfonylmethylene]azetidin-1-20 yl}methyl)benzaldehyde is added, under argon, to a solution of 0.93 cm3 of a 2 M solution of dimethylamine in methanol in 30 cm3 of anhydrous 1,2-dichloroethane. After stirring for 30 minutes at room temperature, 0.9 g of sodium triacetoxyborohydride is added in small 25 fractions. After stirring for 48 hours, the reaction mixture is supplemented with 2.65 cm3 of 1 N sodium hydroxide, 100 cm3 of water and 100 cm3 of dichloromethane and is then separated after settling. The organic phase is washed with twice 80 cm3 of water 129 and with 80 cm3 of brine and is then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 5 0.04-0.06 mm, diameter 4 cm, height 17.5 cm), eluting under an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (30/70 by volume) and collecting 40-cm3 fractions. Fractions 48 to 53 are combined and concentrated to dryness under reduced 10 pressure (2.7 kPa). 0.46 g of N-[4-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)methylsulfonylmethylene]-azetidin-l-yl}methyl-(RS))benzyl]-N,N-dimethylamine is obtained in the form of a white solid.
(RS)-4-((4-Chlorophenyl)-{3-[(3,5-difluoro-15 phenyl)methylsulfonylmethylene]azetidin-l-yl}methyl)-benzaldehyde may be prepared by carrying out the procedure in the following manner: 75.6 cm3 of 5 N hydrochloric acid are added to a solution of 18.9 g of 1-[(4-chlorophenyl)-(4 -[1,3]dioxolan-2-ylphenyl)-20 methyl]-(RS)-3-[(3,5-difluorophenyl)methylsulfonylmethylene] azetidine in 80 cm3 of tetrahydrofuran. After 3 hours at room temperature, the mixture is taken up in dichloromethane and distilled water and then brought to pH 14 by addition of 30% sodium hydroxide and separated 25 after settling. The organic phase is washed twice with 100 m3 of water and then 100 cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 16 g of (RS)-4-((4-chlorophenyl)- 130 {3-[(3,5-difluorophenyl)methylsulfonylmethylene]-azetidin-l-ylJmethyl)benzaldehyde are obtained in the form of a white foam. 1-[(4-Chlorophenyl)-(4-[1,3]dioxolan-2-5 ylphenyl)methyl]-(RS)-3-[(3,5-difluorophenyl)methylsulf onylmethylene] azetidine may be prepared according to the following method: 13.0 cm3 of 1,8-diazabicyclo-[5-4-0]undec-7-ene are added dropwise to a solution of 34.45 g of the mixture of the two diastereoisomers of 10 1-[(4-chlorophenyl)-(4-[1,3]dioxolan-2-ylphenyl)methyl-(RS)]-3-[(3,5-difluorophenyl)methylsulfonylmethy1-(RS)]azetidin-3-yl acetate in 400 cm3 of tetrahydrofuran under argon at 0°C, and after the usual treatment, the product is chromatographed on a silica 15 gel column (particle size 0.04-0.06 mm, diameter .2 cm, height 23 cm), eluting under an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (20/80 by volume) and collecting 250-cm3 fractions; 16.6 g of 1-[(4-chlorophenyl)-(4-2 0 [1,3]dioxolan-2-ylphenyl)methyl]-(RS)-3-[(3,5- difluorophenyl)methylsulfonylmethylene]azetidine are obtained in the form of a white solid.
The mixture of the two diastereoisomers 1—[ (4 — chlorophenyl)-(4-[1,3]dioxolan-2-ylphenyl)methyl-(RS)]-25 3-[(3,5-difluorophenyl)methylsulfonylmethyl- (RS)]azetidin-3-yl acetate diastereoisomers may be obtained in the following manner: by carrying out the procedure according to Example 1 (method 2), starting with 11.6 g of (3,5-difluorobenzyl)methyl sulfone, 131 .1 cm3 of a 1.6 N solution of n-butyllithium in hexane, 19.3 g of 1-{(4-chlorophenyl)[4-([1,3]dioxolan-2-yl)phenyl]methyl-(RS)}azetidin-3-one and 8.8 cm3 of acetyl chloride in 500 cm3 of tetrahydrofuran, 37.8 g 5 of the mixture of the two 1-[(4-chlorophenyl)-(4-[1,3]dioxolan-2-ylphenyl)methyl-(RS)]-3-[(3,5-difluorophenyl)methylsulfonylmethyl-(RS)]azetidin-3-yl acetate diastereoisomers are obtained in the form of a white foam. l-{(4-Chlorophenyl)[4-([1,3]dioxolan-2-yl)- phenyl]methyl-(RS)}azetidin-3-one may be prepared in the following manner: 4 6 cm3 of triethylamine are added, at room temperature, to a solution of 28.32 g of 1-{(4-chlorophenyl)[4-([1,3]dioxolan-2-yl)phenyl]-15 methyl-(RS)}azetidin-3-ol in 200 cm3 of dimethyl sulfoxide, followed by the dropwise addition of a solution of 34 g of sulfur trioxide-pyridine complex in 100 cm3 of dimethyl sulfoxide. After 0.25 hour at room temperature, the reaction mixture is poured over ice, 20 extracted with ethyl acetate, washed with 3 times 400 cm3 of water and then with 400 cm3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is 25 chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 9.2 cm, height 21 cm) under an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (20/80 by volume) as eluent and collecting 250-cm3 fractions. Fractions 9 to 18 are 132 combined and then concentrated to dryness under reduced pressure (2.7 kPa). 20.4 g of l-{(4-chlorophenyl)[4-([1,3]dioxolan-2-yl)phenyl]methyl-(RS)}azetidin-3-one are obtained in the form of a yellow oil. 1-{(4-Chlorophenyl)[4-([1,3]dioxolan-2- yl)phenyl]methyl-(RS)}azetidin-3-ol may be prepared as described in Example 3, starting with 35.0 g of {(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}amine, 8.3 g of epibromohydrin, 5.1 g of sodium hydrogen 10 carbonate and 400 cm3 of ethanol. 30.3 g of 1—{ (4 — chlorophenyl)[4-([1,3]dioxolan-2-yl)phenyl]methyl-(RS)}azetidin-3-ol are isolated. {(4-Chlorophenyl)[4-([1,3]-dioxolan-2-yl)phenyl]methyl-(RS)}amine hydrochloride may be 15 prepared according to the method described by GRISAR M. et al., J. Med Chem., 885 (1973) starting with 67.2 g of 4-([1,3]-dioxolan-2-yl)benzonitrile, 88.2 g of l-bromo-4-chlorobenzene, 11 g of magnesium and 600 cm3 of ethyl ether. 42.3 g of {(4-chlorophenyl)[4-([1,3]-20 dioxolan-2-yl)phenyl]methyl-(RS)}amine are obtained in the form of a yellow oil.
Example 16 1-[(4-Chlorophenyl)(thien-2-yl)methyl-(RS)]-3-[(3,5-difluorophenyl)methylsulfonylmethyl-25 (RS)]azetidine, a mixture of two diastereoisomers, may be prepared by carrying out the procedure as described in Example 3, starting with 0.10 g of 1—[ (4 — chlorophenyl)(thien-2-yl)methyl-(RS)]-3-[(3,5— difluorophenyl)methylsulfonylmethylene]azetidine, 133 1.5 cm3 of anhydrous methanol, 1.5 cm3 of anhydrous dichloromethane and 45 mg of sodium borohydride, with stirring for 16 hours at 20°C and then for 16 hours at 50°C. The crude product is chromatographed on a silica 5 gel column (particle size 0.040-0.063 mm, height 25 cm, diameter 1 cm), eluting under an argon pressure of 1 bar with a mixture of cyclohexane and ethyl acetate (90/10 by volume), and collecting 20-cm3 fractions. Fractions 37 to 42 are combined and concentrated to 10 dryness under reduced pressure (2.7 kPa), the residue is stirred with 5 cm3 of pentane, the solid is filtered, drained and dried. 8 mg of 1-[(4-chloro-phenyl)(thien-2-yl)methyl-(RS)]-3-[(3,5-difluoro-phenyl)methylsulfonylmethyl-(RS)]azetidine, a mixture 15 of two diastereoisomers, are obtained in the form of a white powder [1H NMR spectrum (300 MHz, CDC13, 8 in ppm). A mixture of diastereoisomers is observed, from 2.50 to 2.70 (mt : 1H); 2.66 and 2.68 (2s : 3H in total); from 3.15 to 3.80 (mt : 4H); from 4.20 to 4.30 20 (mt : 1H); 4.31 and 4.57 (2s : 1H in total); from 6.80 to 7.00 and from 7.10 to 7.40 (mts : 10H in total)]. 1-[(4-Chlorophenyl)(thien-2-yl)methyl-(RS)]-3-[(3,5-difluorophenyl)methylsulfonylmethylene]azetidine may be prepared by carrying out the procedure as 25 described in Example 6, starting with 0.52 g of a mixture of the two 1-[(4-chlorophenyl)(thien-2-yl)-methyl-(RS)]-3-[(3,5-difluorophenyl)methylsulfonylmethyl- (RS) ] azetidin-3-ol diastereoisomers, 0.14 cm3 of methylsulfonyl chloride and 0.49 g of 4-dimethylamino- 134 pyridine. After chromatography on a silica gel column (particle size 0.06-0.200 mm, diameter 2.4 cm, height 20 cm), eluting under an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (20/80 by 5 volume) and collecting 30-cm3 fractions, 0.32 g of (RS)-1-[(4-chlorophenyl(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethylene]azetidine is obtained in the form of a white solid melting at 176°C.
The mixture of the two 1-[(4-chlorophenyl)-10 (thien-2-yl)methyl-(RS)]-3-[(3,5-difluorophenyl)methylsulf onylmethyl-(RS)]azetidin-3-ol diastereoisomers may be prepared by carrying out the procedure as described in Example 0, starting with 1.60 cm3 of 1.6 N n-butyllithium in solution in hexane, 0.83 g of (3,5-15 difluorobenzyl)methyl sulfone and 1.06 g of l-[(4- chlorophenyl)(thien-2-yl)methyl-(RS)]azetidin-3-one. After purification on a silica gel column (particle size 0.06-0.200 mm, diameter 2.8 cm, height 30 cm), eluting under an argon pressure of 0.5 bar with a 20 mixture of ethyl acetate and cyclohexane (25/75 by volume) and collecting 40-cm3 fractions, 0.55 g of the mixture of the 1-[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]-3-[(3,5-difluorophenyl)methylsulfonylmethyl-(RS)]azetidin-3-ol diastereoisomers is obtained in the 25 form of an off-white solid. 1-[(4-Chlorophenyl)(thien-2-yl)methyl-(RS)]azetidin-3-one may be prepared by carrying out the procedure as described in Example 1 (method 2), starting with 1.83 cm3 of oxalyl chloride, 20 cm3 of 135 dichloromethane, 3.04 cm3 of dimethyl sulfoxide, 5.2 g of 1-[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]azetidin-3-ol, 80 cm3 of dichloromethane and 9.12 cm3 of triethylamine. 3.3 g of 1-[(4-chlorophenyl)(thien-2-5 yl)methyl-(RS)]azetidin-3-one are obtained in the form of a yellow oil which crystallizes at room temperature. 1-[(4-Chlorophenyl)(thien-2-yl)methyl-(RS)]azetidin-3-ol may be prepared by carrying out a procedure in the following manner: 4.12 g of sodium 10 bicarbonate are added to a solution of 11.0 g of [(4- chlorophenyl)(thien-2-yl)methyl-(RS)]amine in 80 cm3 of ethanol. The mixture, heated to 65°C, is supplemented with 4.03 cm3 of epibromohydrin. After stirring for 20 hours at 65°C, the crude mixture is filtered and the 15 filtrate concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 3.6 cm, height 32 cm), eluting under an argon pressure of 0.5 bar with a mixture of ethyl acetate and 20 cyclohexane (25/75 by volume) and collecting 60-cm3 fractions. 6.3 g of 1-[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]azetidin-3-ol are obtained in the form of a pale yellow oil. [(4-Chlorophenyl)(thien-2-yl)methyl-(RS)]amine 25 may be prepared in the following manner: a solution of 10.92 g of 2-thiophenecarbonitrile in 80 cm3 of diethyl ether is poured slowly into a suspension, cooled to 10°C of 4-chlorophenylmagnesium bromide (prepared from 19.15 g of 4-bromochlorobenzene and 2.43 g of 136 magnesium) in 120 cm3 of anhydrous ethyl ether. After refluxing for one hour, the mixture is cooled to 10°C, supplemented slowly with 40 cm3 of methanol and then filtered on supercel. 4.54 g of sodium borohydride are 5 added under argon and in small fractions over minutes and then the reaction medium is stirred for 20 hours at 20°C. The mixture obtained is diluted with ethyl acetate and then washed with water. The organic phase is dried over magnesium sulfate, concentrated to 10 dryness at 50°C under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 5 cm, height 42 cm), eluting under an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (4/6 by 15 volume) and collecting 100-cm3 fractions. Fractions 6 to 12, concentrated to dryness, correspond to 13 g of imine in the form of a yellow oil which is taken up in 100 cm3 of methanol. The solution obtained is supplemented with 2.4 g of sodium borohydride and 20 stirred for one hour at 5°C. The mixture obtained is diluted with ethyl acetate and then washed with water. The organic phase is dried over magnesium sulfate, concentrated to dryness at 50°C under reduced pressure (2.7 kPa). The residue is chromatographed on a silica 25 gel column (particle size 0.06-0.200 mm, diameter 3.2 cm, height 40 cm), eluting under an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (4/6 by volume) and collecting 60-cm3 fractions. 11.0 g of [(4-chlorophenyl)(thien-2- 137 yl)methyl-(RS)]amine are obtained in the form of a yellow oil.
Example 17 (RS)-[3-({l-[Bis(4-chlorophenyl)methyl]-5 azetidin-3-yl}methylsulfonylmethyl)phenyl]methanol may be prepared by carrying out the procedure as described in Example 3, starting with 0.050 g of [3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonylmethylene ) phenyl ] methanol , 1.0 cm3 of anhydrous 10 methanol, 1.0 cm3 of anhydrous dichloromethane and mg of sodium borohydride, with stirring for 3 hours at 20°C. The crude product is chromatographed on a silica gel column (particle size 0.040-0.063 mm, height 20 cm, diameter 1 cm), eluting under an argon pressure 15 of 0.8 bar with a mixture of cyclohexane and ethyl acetate (90/10 by volume) and collecting 10-cm3 fractions. Fractions 30 to 38 are combined and concentrated to dryness under reduced pressure (2.7 kPa), the residue is stirred with 5 cm3 of 20 pentane, the solid is filtered, drained and dried. 13 mg of (RS)-[3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-yl}methylsulfonylmethyl)phenyl]methanol are obtained in the form of a white powder [1H NMR spectrum (300 MHz, CDCI3, 5 in ppm) : 1.75 (t, J = 6 Hz : 1H); 25 2.52 (t, J = 7.5 Hz : 1H); 2.59 (s : 3H); 3.17 (broad t, J = 7.5 Hz : 2H); 3.4 8 (mt : 1H); 3.65 (mt : 1H); 4.23 (s : 1H); 4.28 (d, J = 11.5 Hz : 1H); 4.70 (d, J = 6 Hz : 2H); from 7.15 to 7.40 (mt : 12H)]. 138 [3-({1-[Bis(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonylmethylene)phenyl]methanol may be prepared by carrying out the procedure in the following manner: 17 cm3 of a 1 M solution of tetrabutylammonium 5 fluoride in tetrahydrofuran are poured into a solution, cooled to +5°C, of 5.1 g of 1-[bis(4-chlorophenyl)-methyl]-3-{[3-(tertbutyldimethylsilyloxymethyl)phenyl]-methylsulfonyl-methylene}azetidine in 51 cm3 of tetrahydrofuran. After stirring for 20 minutes at 10 cooled temperature and then for 3 hours at 20°C, the reaction mixture is poured into a mixture of 200 cm3 of water and 100 cm3 of ethyl acetate and then separated after settling. The organic phase is washed with water, dried over magnesium sulfate and then filtered and 15 concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm), eluting under a nitrogen pressure of 0.5 bar with a 20 dichloromethane and ethanol (97/3 by volume) mixture and collecting 100-cm3 fractions. Fractions 10 to 14 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The yellow solid obtained is taken up in 2 cm3 of dichloromethane and 10 cm3 of ethyl 25 acetate and then filtered on sintered glass and washed with 2 cm3 of ethyl acetate. 1.6 g of [3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonylmethylene ) phenyl ] methanol are obtained in the form of a white solid melting at 214°C. 139 1-[Bis(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl]methylsulfonylmethylene } azetidine may be prepared by carrying out the operation according to the procedure of Example 1, 5 starting with 10.8 g of 1-[bis(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl]-methylsulfonylmethyl-(RS)}azetidin-3-ol, 2 cm3 of methylsulfonyl chloride and 8.5 g of 4-dimethylamino-pyridine, the residue obtained is purified by 10 chromotography on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, height 40 cm) under a nitrogen pressure of 0.5 bar with dichloromethane as eluent and collecting 100-cm3 fractions. Fractions 12 to 29 are combined and concentrated to dryness under 15 reduced pressure (2.7 kPa). 5.2 g of 1-[bis(4-chlorophenyl) methyl]-3-{[3-(tert-butyldimethylsilyloxy-methyl)phenyl]methylsulfonyl-methylene}azetidine are obtained in the form of a gum. 1-[Bis(4-chlorophenyl)methyl]-3-{ [3 - (tert-20 butyldimethylsilyloxymethyl)phenyl]methylsulfonyl- methyl-(RS)}azetidin-3-ol may be prepared by carrying out the operation according to the procedure of Example 5, starting with 5.8 g of tert-butyl-(3-methylsulfonyl-methylbenzyloxy)dimethylsilane and 5.6 g of l-[bis(4-25 chlorophenyl)methyl]azetidin-3-one, 10.8 g of l-[bis(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxy-methyl)phenyl]methylsulfonylmethyl-(RS)}azetidin-3-ol are obtained in the form of a gum. 140 tert-Butyl-(3-methylsulfonylmethylbenzyloxy)-dimethylsilane may be prepared by carrying out the procedure in the following manner: 4.87 g of imidazole are added to a solution of 5.73 g of (3-methylsulfonyl-5 methylphenyl)methanol in 50 cm3 of N,N-dimethylform-amide, followed by 10.3 cm3 of tert-butylchlorodi-methylsilane. After stirring for 20 hours at room temperature, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue 10 is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 3.5 cm, weight of silica 100 g), eluting under a nitrogen pressure of 0.5 bar with dichloromethane, and collecting 100-cm3 fractions. Fractions 2 to 7 are combined, concentrated to dryness 15 under reduced pressure (2.7 kPa). 5.8 g of an oil are obtained, which oil crystallizes at room temperature (m.p. = 7 5 ° C.) (3-Methylsulfonylmethylphenyl)methanol may be prepared by carrying out the procedure in the following 20 manner: a mixture of 26 g of 3-(methylsulfonylmethyl)-benzoic acid and 4.6 g of lithium aluminum hydride in 600 cm3 of tetrahydrofuran is stirred for 18 hours at a temperature close to 20°C. The solution is cooled to 0°C and then 15 cm3 of ethyl acetate, 30 cm3 of water, 25 5 cm3 of a 15% aqueous solution of sodium hydroxide and finally 30 cm3 of water are added successively. The mixture is filtered on celite and the filtrate taken up in 600 cm3 of ethyl acetate. The organic phase is taken up in 500 cm3 of water and then 200 cm3 of a saturated 141 aqueous sodium chloride solution, separated after settling, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 10.4 g of (3-methylsulfonyl-5 methylphenyl)methanol are obtained in the form of a gum. 3-(Methylsulfonylmethyl)benzoic acid may be prepared in the following manner: by carrying out the operation according to the procedure of Example 14, 10 starting with 23.3 g of 3-chloromethylbenzoic acid. 23.3 g of sodium methane sulfinate,26 g of 3-(methylsulfonylmethyl) benzoic acid are obtained in the form of a white solid melting at 210°C.
Example 18 1-[Bis(4-chlorophenyl)methyl]-3- (phenylsulfonylmethyl)azetidine may be prepared by carrying out the procedure in the following manner: 13 mg of sodium borohydride are added, under argon, to a solution of 0.15 g of 1-[bis(4-chlorophenyl)methyl)]-20 3-(phenylsulfonylmethylene)azetidine in 3 cm3 of anhydrous ethanol and 3.5 cm3 of anhydrous dichloromethane. After stirring for 1 hour and 45 minutes, 14 mg of sodium borohydride are again added and then the mixture is kept stirring for 20 hours at 25 20°C. The reaction mixture is then heated to 50°C, supplemented with 9.5 mg of sodium borohydride and kept stirred for 2 hours and 30 minutes at 50°C and then cooled to room temperature. 0.5 cm3 of water, 10 cm3 of dichloromethane and then 50 mg of magnesium sulfate are 142 then added to the mixture, filtered and then evaporated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 15 cm, diameter 5 1 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 5-cm3 fractions. Fractions 12 to 19 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 29 mg of l-[bis(4-10 chlorophenyl)methyl)]-3-(phenylsulfonylmethyl)azetidine are obtained in the form of a white solid [1H NMR spectrum (300 MHz, CDCI3, 8 in ppm) : from 2.75 to 8.90 (mt : 3H); 3.32 (mt : 2H); 3.37 (d, J = 7 Hz : 2H) ; 4.22 (s : 1H) ; from 7.20 to 7.30 (mt : 8H) ; 7.57 (broad 15 t, J = 7.5 Hz : 2H); 7.67 (tt, J = 7.5 and 1.5 Hz : 1H); 7.88 (broad d, J = 7.5 Hz : 2H)].
Example 19 1-[Bis(4-chlorophenyl)methyl)]-3-(phenylsulfonylmethylene)azetidine may be prepared by 20 carrying out the procedure in the following manner: 12 cm3 of a 1.6 M solution of n-butyllithium in hexane are poured, over 5 minutes, into a solution, cooled to -70°C, under argon, of 4.34 g of (phenylsulfonylmethyl) trimethylsilane in 40 cm3 of dimethyl ether. 25 After stirring the mixture for 30 minutes at -60°C, a solution of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one in 30 cm3 of dimethyl ether [produced in the form of a base prepared by treating 7.35 g of 1-[bis(4-chlorophenyl ) methyl] azetidin-3-one hydrobromide dissolved in 143 cm3 of water, with 25 cm3 of 1 N sodium hydroxide and extracting the base obtained with 30 cm3 of diethyl ether, then drying and concentrating to dryness under reduced pressure (2.7 kPa)] is poured in over 5 10 minutes. After stirring for 45 minutes at -70°C and then for 2 hours at 20°C, the reaction mixture is supplemented with 12 cm3 of a saturated aqueous ammonium chloride solution, 20 cm3 of water and then extracted with 12 40 cm3 of ethyl acetate. The combined 10 organic phases are [lacuna] with 40 cm3 of water, dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 40 cm, diameter 5 cm), eluting 15 under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (90/10 and then 85/15 by volume) and collecting 100-cm3 fractions. Fractions 10 to 16 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is 20 triturated in 10 cm3 of diethyl ether, the suspension filtered and the solid dried. 1.17 g of l-[bis(4-chlorophenyl)methyl)]-3-(phenylsulfonylmethylene)-azetidine are obtained in the form of a white solid [1H NMR spectrum (300 MHz, CDCI3 d in ppm) : 3.88 25 (mt : 2H); 4.29 (mt : 2H); 4.50 (s : 1H); 6.17 (mt : 1H); from 7.20 to 7.40 (mt : 8H); 7.56 (broad t, J = 7.5 Hz : 2H); 7.64 (tt, J = 7.5 and 1.5 Hz : 1H); 7.87 (broad d, J = 7.5 Hz : 2H)]. 144 (Phenylsulfonylmethyl)trimethylsilane may be prepared by carrying out the procedure in the following manner: 13 cm3 of a 1.6 M solution of n-butyllithium in hexane are poured, with stirring under argon over 20 5 minutes, into a solution, cooled to -70°C, of 3 g of methyl phenyl sulfone in 40 cm3 of anhydrous tetrahydrofuran. After stirring for 30 minutes at -70°C, 2.66 cm3 of trimethylchlorosilane are added to the mixture, and the heating is stopped. After stirring 10 for 4 hours at room temperature, the reaction mixture is supplemented with 30 cm3 of water and extracted with 30 cm3 of ethyl acetate. The organic phase is washed with 30 cm3 of water, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced 15 pressure (2.7 kPa). 4.34 g of (phenylsulfonylmethyl)-trimethylsilane are obtained in the form of a yellow liquid.
Example 2 0 2-{1-[Bis(4-chlorophenyl)methyl]azetidin-3-20 ylmethylsulfonyl}pyridine may be prepared by carrying out the procedure in the following manner: 0.125 g of sodium borohydride is added to a solution of 0.25 g of 2 — {1—[bis(4-chlorophenyl)methyl)]azetidin-3-ylidenemethylsulfonyl}pyridine in 20 cm3 of a 50/50 25 mixture of dichloromethane and ethanol. After stirring for 1 hour at 50°C, the reaction mixture is cooled to 20°C, supplemented with 20 cm3 of dichloromethane, 1 cm3 of water and 0.1 g of magnesium sulfate. The mixture is filtered and the filtrate is concentrated at 50°C under 145 reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.040-0.063 mm, height 15 cm, diameter 1 cm), eluting under an argon pressure of 0.5 bar with a mixture of 5 cyclohexane and ethyl acetate (40/60 by volume) and collecting 10-cm3 fractions. Fractions 5 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.18 g of 2-{l-[bis(4-chlorophenyl)methyl]azetidin-3-ylmethylsulfonyl}-10 pyridine is obtained in the form of a white powder (1H NMR spectrum (300 MHz, CDCI3, 8 in ppm) : from 2.80 to 3.00 (mt : 3H); 3.34 (mt : 2H); 3.7 0 (d, J = 7 Hz : 2H); 4.25 (s : 1H); from 7.20 to 7.40 (mt : 8H); 7.57 (ddd, J = 8-5 and 1 Hz : 1H); 7.97 (split t, J = 8 and 15 1.5 Hz : 1H); 8.07 (broad d, J = 8 Hz : 1H); 8.75 (broad d, J = 5 Hz : 1H)]. 2-{1-[Bis(4-chlorophenyl)methyl)]azetidin-3-ylidenemethylsulfonyl}pyridine may be prepared by carrying out the procedure in the following manner: 20 0.25 cm3 of methylsulfonyl chloride is added to a solution of 0.9 g of 1-[bis(4-chlorophenyl)methyl)]-3-(pyrid-2-ylsulfonylmethyl)azetidin-3-ol in 50 cm3 of dichloromethane, the mixture is stirred for 15 minutes and 0.9 g of 4-dimethylaminopyridine is added. After 25 stirring for 3 hours at 20°C, 30 cm3 of water and 30 cm3 of dichloromethane are added to the mixture and then the organic phase is separated after settling, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue 146 is chromatographed on a silica gel column (particle size 0.04-0.063 mm, height 25 cm, diameter 2 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (40/60 by 5 volume) and collecting 20-cm3 fractions. Fractions 4 to 8 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.50 g of 2—{1—[bis(4— chlorophenyl)methyl)]azetidin-3-ylidenemethylsulfonyl}-pyridine is obtained in the form of a yellow powder. 10 1-[Bis(4-chlorophenyl)methyl)]-3-(pyrid-2- ylsulfonylmethyl)azetidin-3-ol may be prepared by carrying out the procedure in the following manner: 2.13 g of potassium tert-butoxide are added to a solution, cooled to -78°C under argon, of 2.92 g of 1-15 [bis(4-chlorophenyl)methyl)]azetidin-3-one and 3 g of 2-methylsulfonylpyridine in 50 cm3 of tetrahydrofuran. After stirring for 3 hours at -78°C, the reaction mixture is allowed to return to 0°C and then 50 cm3 of diethyl ether, 10 cm3 of water and 10 cm3 of a saturated 20 aqueous ammonium chloride solution are added. The organic phase is separated after settling, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 25 0.063-0.200 mm, height 30 cm, diameter 3 cm), eluting under an argon pressure of 0.5 bar, first with dichloromethane and then with a mixture of dichloromethane and methanol (97/3 by volume) and collecting 20-cm3 fractions. Fractions 8 to 15 are 147 combined and concentrated to dryness under reduced pressure (2.7 kPa). A still impure brown oil is obtained which is chromatographed on a silica gel column (particle size 0.04-0.063 mm, height 20 cm, 5 diameter 2 cm), eluting under an argon pressure of 0.5 bar, first with dichloromethane and then with a mixture of dichloromethane and methanol (97/3 by volume) and collecting 20-cm3 fractions. Fractions 5 to 25 are combined and concentrated to dryness and the 10 residue obtained is again chromatographed on the same column and under the same conditions but eluting with dichloromethane. Fractions 12 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.3 g of 1-[bis(4-chlorophenyl)methyl)]-3-15 (pyrid-2-ylsulfonylmethyl)azetidin-3-ol is obtained in the form of a white foam. 2-Methylsulfonylpyridine may be prepared by carrying out the procedure in the following manner: 0.25 cm3 of 100% acetic acid is added, with stirring 20 under argon, to a solution of 20 g of sodium tungstate dihydrate in 10 cm3 of water, followed by 7.0 g of 2-methylsulfanylpyridine. This mixture is heated to 65°C, 10 cm3 of 30% hydrogen peroxide are slowly poured in over 15 minutes, then the mixture is stirred at 85°C 25 for 30 minutes and then cooled to +10°C. 1.0 cm3 of 32% aqueous ammonia and 5.0 cm3 of a 37.5% aqueous solution of sodium hydrogen sulfite are added to the medium, followed by 10 cm3 of water and 50 cm3 of dichloromethane. The mixture is separated after 148 settling, the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The colorless oil obtained is disintegrated with 50 cm3 of petroleum ether and the 5 insoluble gum is filtered and taken up in 30 cm3 of dichloromethane. The solution obtained is concentrated to dryness at 50°C under reduced pressure (2.7 kPa) . 3.5 g of 2-methylsulfonylpyridine are obtained in the form of a colorless oil. 2-Methylsulfanylpyridine may be prepared by carrying out the procedure in the following manner: 6.2 cm3 of methyl iodide are slowly added to a solution of 11.0 g of 2-mercaptopyridine in 105 cm3 of 1 N sodium hydroxide. The reaction mixture, whose temperature has risen to 30°C, is cooled to room temperature. After stirring for 2 hours, the mixture is extracted with 100 cm3 of dichloromethane, the organic phase is dried over magnesium sulfate and concentrated to dryness at 50°C under reduced pressure (2.7 kPa).
The oil obtained is purified by distillation under reduced pressure. 9.0 g of 2-methylsulfanylpyridine are obtained in the form of a colorless liquid, b.p. = 84 °C/45 mmHg.
Example 21 3 —{1—[Bis(4-chlorophenyl)methyl]azetidin-3- ylmethylsulfonyl}pyridine may be prepared by carrying out the procedure as described in Example 20, starting with 0.15 g of 3-{1-[bis(4-chlorophenyl)methyl)]-azetidin-3-ylidenemethylsulfonyl}pyridine, 20 cm3 of a 149 50/50 mixture of dichloromethane and ethanol, and 80 mg of sodium borohydride. 0.11 g of 3-{1-[bis(4-chlorophenyl )methyl]azetidin-3-ylmethylsulfonyl}pyridine is obtained in the form of a white powder [1H NMR spectrum 5 (300 MHz, CDC13, 5 in ppm) : from 2.75 to 2.95 (mt : 3H); 3.35 (mt : 2H); 3.43 (d, J = 6.5 Hz ; 2H) ; 4.25 (s : 1H); from 7.20 to 7.40 (mt : 8H); 7.54 (ddd, J = 8-5 and 1 Hz : 1H); 8.18 (ddd, J = 8-2.5 and 1.5 Hz : 1H); 8.90 (dd, J = 5 and 1.5 Hz : 1H); 9.11 10 (dd, J = 2.5 and 1 Hz : 1H)]. 3-{1-[Bis(4-chlorophenyl)methyl)]azetidin-3-ylidenemethylsulfonyl}pyridine may be prepared by carrying out the procedure as described in Example 20, starting with 0.8 g of 1-[bis(4-chlorophenyl)methyl)]-15 3-(pyrid-3-ylsulfonylmethyl)azetidin-3-ol, 50 cm3 of dichloromethane, 0.22 cm3 of methylsulfonyl chloride and 0.8 g of 4-dimethylaminopyridine. 0.50 g of 3 —{1 — [bis(4-chlorophenyl)methyl)]azetidin-3- ylidenemethylsulfonyljpyridine is obtained in the form 20 of a cream-colored powder. 1-[Bis(4-chlorophenyl)methyl)]-3-(pyrid-3-ylsulfonylmethyl)azetidin-3-ol may be prepared by carrying out the procedure as described in Example 20, starting with 3.3 g of 1-[bis(4-chlorophenyl)methyl)]-25 azetidin-3-one, 50 cm3 of tetrahydrofuran, 3.5 g of 3-methylsulfonylpyridine and 2.4 g of potassium tert-butoxide. 1.4 g of 1-[bis(4-chlorophenyl)methyl)]-3-(pyrid-3-ylsulfonylmethyl)azetidin-3-ol are obtained in the form of a white powder. 150 3-Methylsulfonylpyridine may be prepared by carrying out the procedure as described in Example 20, starting with 33 g of sodium tungstate, 10 cm3 of water, 0.25 cm3 of 100% acetic acid, 9.5 g of 3-5 methylsulfanylpyridine, 15 cm3 of 30% hydrogen peroxide and then 2 cm3 of 32% aqueous ammonia and 2 cm3 of a 37.5% aqueous solution of sodium hydrogen sulfite. The crude oil obtained is crystallized with 20 cm3 of diisopropyl ether, the crystals are filtered, drained 10 and dried under reduced pressure (2.7 kPa). 4.5 g of 3-methylsulfonylpyridine are obtained in the form of white crystals (m.p. = 58°C.) 3-Methylsulfanylpyridine may be prepared by carrying out the procedure in the following manner: 20 cm3 of isoamyl nitrite are added to a mixture, heated to 80°C under argon, of 9.4 g of 3-aminopyridine and 100 cm3 of dimethyl disulfide. After stirring for 2 hours at 90°C, the reaction mixture is cooled to 20°C and then purified by fractional distillation under 20 reduced pressure. 8.4 g of 3-methylsulfanylpyridine are obtained in the form of a pale yellow liquid, b.p. = 90°C/30 mm of mercury.
Example 22 4-{1-[Bis(4-chlorophenyl)methyl]azetidin-3-25 ylmethylsulfonyl}pyridine may be prepared by carrying out the procedure as described in Example 20, starting with 0.15 g of 4-{1-[bis(4-chlorophenyl)methyl)]-azetidin-3-ylidenemethylsulfonyl}pyridine, 20 cm3 of a 50/50 mixture of dichloromethane and ethanol, and 80 mg 151 of sodium borohydride. 0.13 g of 4-{1-[bis(4-chlorophenyl )methyl]azetidin-3-ylmethylsulfonyl}pyridine is obtained in the form of a white powder [XH NMR spectrum (300 MHz, CDC13, 8 in ppm) : from 2.75 to 2.90 (mt : 5 1H); 2.88 (t, J = 7 Hz : 2H); 3.36 (t, J = 7 Hz : 2H); 3.42 (d, J = 7 Hz : 2H); 4.25 (s : 1H); from 7.20 to 7.35 (mt : 8H); 7.75 (broad d, J = 6 Hz : 2H); 8.93 (broad d, J = 6 Hz : 2H)]. 4-{1-[Bis(4-chlorophenyl)methyl)]azetidin-3-10 ylidenemethylsulfonyl}pyridine may be prepared by carrying out the procedure as described in Example 20, starting with 0.8 g of 1-[bis(4-chlorophenyl)methyl)]-3-(pyrid-4-ylsulfonylmethyl)azetidin-3-ol, 50 cm3 of dichloromethane, 0.22 cm3 of methylsulfonyl chloride 15 and 0.8 g of 4-dimethylaminopyridine. The crude product is purified by chromatography on a silica gel column (particle size 0.04-0.063 mm, height 20 cm, diameter 2 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (40/60 by 20 volume) and collecting 20-cm3 fractions. Fractions 5 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.42 g of 4-{l-[bis(4-chlorophenyl)methyl)]azetidin-3-ylidenemethylsulfonyl}-pyridine is obtained in the form of a white crystalline 25 powder. 1-[Bis(4-chlorophenyl)methyl)]-3-(pyrid-4-ylsulfonylmethyl)azetidin-3-ol may be prepared by carrying out the procedure as described in Example 20, starting with 2.5 g of 1-[bis(4-chlorophenyl)methyl)]- 152 azetidin-3-one, 50 cm3 of tetrahydrofuran, 2.6 g of 4-methylsulfonylpyridine and 1.8 g of potassium tert-butoxide. The crude product obtained is purified by chromatography on a silica gel column (particle size 5 0.04-0.063 mm, height 30 cm, diameter 3 cm), eluting under an argon pressure of 0.5 bar with dichloromethane and then with a mixture of dichloromethane and methanol (98/2 by volume) and collecting 20-cm3 fractions. Fractions 8 to 27 are combined and concentrated to 10 dryness under reduced pressure (2.7 kPa). A cream- colored powder is obtained which is recrystallized from 5 cm3 of acetonitrile. The crystals are filtered, drained and dried under reduced pressure (2.7 kPa). 1.4 g of 1-[bis(4-chlorophenyl)methyl)]-3-(pyrid-4-15 ylsulfonylmethyl)azetidin-3-ol are obtained in the form of white crystals, m.p. = 130°C. 4-Methylsulfonylpyridine may be prepared by carrying out the procedure as described in Example 20, starting with 14 g of sodium tungstate, 4 cm3 of water, 20 0.05 cm3 of 100% acetic acid, 3.3 g of 4-methyl- sulfanylpyridine, 6.5 cm3 of 30% hydrogen peroxide and then 0.25 cm3 of 32% aqueous ammonia and 1 cm3 of 37.5% aqueous solution of sodium hydrogen sulfite. The crude oil obtained is crystallized with 10 cm3 of diisopropyl 25 ether, the crystals are filtered, drained and dried under reduced pressure (2.7 kPa). 2.6 g of 4-methyl-sulfonylpyridine are obtained in the form of white crystals. 153 4-Methylsulfanylpyridine may be prepared by carrying out the procedure as described in Example 20, starting with 11.0 g of 4-mercaptopyridine, 105 cm3 of 1 N sodium hydroxide and 6.2 cm3 of methyl iodide. The 5 crude oil obtained is purified by distillation under reduced pressure. 4.0 g of 4-methylsulfanylpyridine are obtained in the form of a white paste, b.p. = 120°C/45 mm of mercury.
Example 23 1-[Bis(4-chlorophenyl)methyl]-3-[(3, 5- difluorophenyl)sulfonylmethyl]azetidine may be prepared by carrying out the procedure in the following manner: 78 mg of sodium borohydride are added, under argon, to a solution of 0.50 g of 1-[bis(4-chlorophenyl)methyl]-15 3-[(3,5-difluorophenyl)sulfonylmethylene]azetidine dissolved in 25 cm3 of anhydrous methanol and 25 cm3 of anhydrous dichloromethane. After stirring for 24 hours, 80 cm3 of water and 50 cm3 of dichloromethane are added, the mixture is separated after settling, washed with 20 80 cm3 of water and then 80 cm3 of a saturated aqueous sodium chloride solution. The organic phase is dried with magnesium sulfate, filtered and then evaporated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle 25 size 0.02-0.04 mm, height 20 cm, diameter 14 cm), eluting under an argon pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (90/10 by volume) and collecting 5-cm3 fractions. Fractions 60 to 82 are combined and concentrated to dryness under 154 reduced pressure (2.7 kPa). 0.29 g of l-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)sulfonylmethyl] azetidine is obtained in the form of a white solid [1H NMR spectrum (300 MHz, CDCI3, 6 in ppm) : from 5 2.75 to 2.95 (mt : 1H); 2.88 (t, J = 7 Hz : 2H); 3.36 (t, J = Hz : 2H); 3.41 (d, J = 7 Hz : 2H); 4.26 (s : 1H); 7.13 (tt, J = 9 and 2.5 Hz : 1H); from 7.20 to 7.35 (mt : 8H); 7.44 (mt : 2H)].
Example 24 1-[Bis(4-chlorophenyl)methyl]-3-[(3,5- difluorophenyl)sulfonylmethylene]azetidine may be prepared by carrying out the procedure in the following manner: 4.3 cm3 of methylsulfonyl chloride are added to 18.8 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-15 difluorophenyl)sulfonylmethyl]azetidin-3-ol dissolved in 800 cm3 of dichloromethane at room temperature, followed, in small portions, by 16 g of 4-dimethylamino pyridine. After 22 hours, the reaction mixture is washed with 3 times 700 cm3 of water and then 700 cm3 of 20 a saturated aqueous sodium chloride solution. The organic phase is dried with magnesium sulfate, filtered and then evaporated to dryness under reduced pressure (2.7 kPa) . The residue (25 g) is chromatographed on a silica gel column (particle size 0.02-0.04 mm, height 25 36 cm, diameter 8.5 cm) eluting under an argon pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (90/10 by volume) and collecting 250-cm3 fractions. Fractions 2 to 148 are combined and concentrated to dryness under reduced pressure (2.7 155 kPa). 2.79 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)sulfonylmethylene]azetidine are obtained in the form of a white solid [1H NMR spectrum (300 MHz, CDC13, 5 in ppm) : 3.91 (mt : 2H); 4.28 (mt : 2H) ; 4.51 5 (s : 1H); 6.15 (mt : 1H); 7.08 (tt, J = 9 and 2.5 Hz : 1H); from 7.25 to 7.40 (mt : 8H); 7.40 (mt : 2H)]. 1-[Bis(4-chlorophenyl)methyl]-3-[(3,5-difluoro-phenyl)sulfonylmethyl]azetidin-3-ol may be prepared by carrying out the procedure in the following manner: 10 42.9 cm3 of 1.6 M butyllithium in hexane are added dropwise to a solution of 13.2 g of (3,5-difluorophenyl ) methyl sulfone in 800 cm3 of tetrahydrofuran. After 0.5 hour at -70°C and 0.5 hour at -30°C, 14 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one dissolved 15 in 150 cm3 of tetrahydrofuran are added dropwise at -70°C. After 3 hours at -70°C, the reaction mixture is poured into a saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed twice with 400 cm3 of water and then 400 cm3 of a 20 saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and then evaporated to dryness under reduced pressure (2.7 kPa). The residue (25.14 g) is chromatographed on a silica gel column (particle size 0.06-0.04 mm, height 31 cm, diameter 25 7.5 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (85/15 by volume) and collecting 200-cm3 fractions. Fractions 13 to 16 are combined and concentrated to dryness under reduced pressure (2.7 kPa). After crystallization from 156 ethyl ether, filtration and drying, 4.5 g of l-[bis(4-chlorophenyl)methyl]-3-[(3,5— difluorophenyl)sulfonylmethyl]azetidin-3-ol are obtained in the form of a white solid. (3,5-Difluorophenyl)methyl sulfone may be prepared by carrying out the procedure in the following manner: 225 cm3 of water and, in small quantities at 5°C, 56.3 g of oxoneR are added to a solution of 13.3 g of (3,5-difluorophenyl)methylsulfide dissolved in 450 cm3 of methanol. After 20 hours at room temperature, the reaction mixture is diluted with dichloromethane and water and separated after settling. The organic phase is washed twice with 700 cm3 of water and then 700 cm3 of a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and then evaporated to dryness under reduced pressure (2.7 kPa). 13.2 g of (3,5-difluorophenyl)methyl sulfone are obtained in the form of a white solid. (3,5-Difluorophenyl)methylsulfide may be prepared by carrying out the procedure in the following manner: 64 cm3 of 1.6 M n-butyllithium in hexane are added dropwise at -70°C to 11.8 cm3 of l-bromo-3,5-difluorobenzene diluted in 200 cm3 of ethyl ether.
After 0.5 hour at -70°C, 14.2 g of S-methyl methylthiosulfonate dissolved in 60 cm3 of tetrahydrofuran are added dropwise at -70°C. After 3 hours at -70°C and then 18 hours at room temperature, the reaction mixture is poured into a saturated ammonium chloride solution and extracted with ethyl 157 acetate. The organic phase is washed twice with 200 cm3 of water and then 300 cm3 of a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and then evaporated to dryness under reduced 5 pressure (2.7 kPa). 13.3 g of (3,5-difluorophenyl)- methylsulfide are obtained in the form of a yellow oil. Example 25 0.25 g of meta-chloroperbenzoic acid is added at room temperature to a solution of 0.40 g of 1-10 [bis(4-chlorophenyl)methyl]-3-(phenylsulfanyl)azetidine in 20 cm3 of dichloromethane. After stirring for 3 hours at room temperature, the reaction mixture is washed with 30 cm3 of a saturated sodium hydrogen carbonate solution, dried over magnesium sulfate, 15 filtered and concentrated to dryness under reduced pressure (2.7 kPa). After chromatography on a silica gel column (particle size 0.06-0.200 mm, height 25 cm, diameter 2 cm), eluting under an argon pressure of 0.8 bar with an ethyl acetate/cyclohexane 20/80 by 20 volume mixture and collecting 60-cm3 fractions, fractions 9 to 16 are combined and concentrated to dryness under reduced pressure (2.7 kPa), taken up in heptane in order to isolate 100 mg of 1-[bis(4-chlorophenyl) methyl]-3-[(RS)-phenylsulfinyl]azetidine in the 25 form of a white solid [XH NMR spectrum (300 MHz, CDCI3, 5 in ppm) : 3.01 (broad t, J = 7.5 Hz : 1H) ; 3.32 (broad t, J = 7.5 Hz : 1H); 3.45 (broad t, J = 7.5 Hz : 2H); 3.59 (mt : 1H); 4.45 (broad s, : 1H); from 7.15 to 7.65 (mts : 13H)]. 158 Example 26 1.2 g of oxoneR are added in several portions to a solution of 0.80 g of l-[bis(4-chlorophenyl)methyl]-3-(phenylsulfanyl)azetidine in 5 3.4 cm3 of water, 3.4 cm3 of acetic acid, 3.4 cm3 of ethanol and 1.7 cm3 of sulfuric acid. After stirring for 20 hours at room temperature, the reaction mixture is diluted with 100 cm3 of dichloromethane, washed with 3 times 100 cm3 of water, dried over magnesium sulfate, 10 filtered and concentrated to dryness under reduced pressure (2.7 kPa). After chromatography on a silica gel column (particle size 0.06-0.200 mm, height 40 cm, diameter 2 cm), eluting under an argon pressure of 0.8 bar with an ethyl acetate/cyclohexane (20/80 by 15 volume) mixture and collecting 60-cm3 fractions, fractions 9 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa), taken up in heptane, the solid filtered and dried in order to isolate 0.23 g of 1-[bis(4-chlorophenyl)methyl]-3-20 (phenylsulfonyl)azetidine in the form of a white solid [XH NMR spectrum (300 MHz, CDCI3, 8 in ppm) : from 3.35 to 3.50 (mt : 4H); 3.96 (mt : 1H); 4.44 (s : 1H); from 7.20 to 7.35 (mt : 8H); 7.57 (broad t, J = 7.5 Hz : 2H); 7.68 (tt, J = 7.5 and 1.5 Hz : 1H); 7.88 (broad d, 25 J = 7.5 Hz : 2H)].
Example 27 43.5 mg of sodium borohydride are added to a solution of 0.6 g of methyl 5-({1-[bis(4-chlorophenyl)-methyl]azetidin-3-ylidene}methylsulfonylmethyl)thien-2- 159 ylcarboxylate in 70 cm3 of methanol cooled to around 0°C. The reaction medium is stirred for 15 minutes at this temperature, and then for 5 hours at 20°C before again being cooled to around 0°C and supplemented with 8.7 mg of sodium borohydride. After 18 hours at room temperature, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is supplemented with 100 cm3 of dichloromethane and 20 cm3 of distilled water. The mixture is separated after settling, the organic phase washed with twice 20 cm3 of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluent: cyclohexane/ethyl acetate (70/30 by volume)]. 0.18 g of methyl (RS)-5-({1-[bis(4-chlorophenyl)-methyl]azetidin-3-yl}methylsulfonylmethyl)thien-2-ylcarboxylate is obtained in the form of a white powder [■"■H NMR spectrum (400 MHz, (CD3)2SO d6, 8 in ppm) : 2.60 (t, J = 7.5 Hz : 1H); 2.86 (s : 3H); 3.14 (mt : 2H); from 3.20 to 3.35 (mt : 1H)/ 3.45 (broad t, J = 7.5 Hz : 1H); 3.82 (s : 3H); 4.47 (s : 1H) ; 5.27 (d, J = 11 Hz : 1H); 7.28 (d, J = 4 Hz : 1H); from 7.30 to 7.50 (mt : 8H); 7.72 (d, J = 4 Hz : 1H)]. 160 Methyl 5-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-y1idene}methylsulfonylmethyl)thien-2-ylcarboxylate may be obtained in the following manner: 5.15 g of methyl 5-(methylsulfonylmethyl)thien-2-5 ylcarboxylate are added, at room temperature under an argon atmosphere, to a solution of 6.12 g of l-[bis(4-chlorophenyl)methyl]azetidin-3-one in 200 cm3 of tetrahydrofuran and then the suspension obtained is cooled to -70°C. There are successively added 2.47 g of 10 potassium tert-butoxide, and then after 1 hour 30 min at this temperature a solution of 1.7 cm3 of methylsulfonylchloride in 8 cm3 of ethyl ether over 2 minutes. The reaction medium is maintained for 1 hour at -70°C and then the temperature is allowed to rise to 15 around 20°C before pouring in 80 cm3 of distilled water. The tetrahydrofuran is expelled under reduced pressure and the aqueous residue obtained is extracted with 500 cm3 of dichloromethane. The mixture is separated after settling, the organic phase is washed with 3 20 times 80 cm3 of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography on silica gel [eluent: cyclohexane/ethyl acetate (70/30 by volume)]. 1.6 g of 25 methyl 5-({1-[bis(4-chlorophenyl)methyl]azetidin-3- ylidene}methylsulfonylmethyl)thien-2-ylcarboxylate are obtained in the form of a cream-colored foam. 161 Methyl 5-(methylsulfonylmethyl)thien-2-ylcarboxylate may be obtained in the following manner: 31.7 g of sodium methyl sulfinate are added to a solution of 73 g of methyl 5-(bromomethyl)thien-2-5 ylcarboxylate in 150 cm3 of ethanol and the suspension obtained is heated under reflux for 7 hours. The reaction medium is then concentrated to dryness under reduced pressure (2.7 kPa). The residue is extracted with four times 500 cm3 of ethyl acetate, the combined 10 organic phases are washed successively with 250 cm3 of distilled water and 250 cm3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and incompletely concentrated under reduced pressure. The solid which appears is isolated by 15 filtration, rinsed with three times 25 cm3 of ice-cold ethyl acetate and provides 21.4 g of methyl 5-(methylsulfonylmethyl)thien-2-ylcarboxylate in the form of a cream-colored powder.
Methyl 5-(bromomethyl)thien-2-ylcarboxylate 20 may be prepared according to the method described by Wityak J. et al., Bioorg. Med. Chem. Lett. (1995), 5(18), 2097-100.
Example 28 (RS)-1-[Bis(4-chlorophenyl)methyl]-3-[(3,5-25 difluorophenyl)methylsulfonylmethyl]azetidin-3- ylcyclopropylamine may be prepared in the following manner: 2.52 cm3 of cyclopropylamine are added to a solution of 3 g of 1-[bis(4-chlorophenyl)methyl)]-3- 162 [(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine in 30 cm3 of dichloromethane, at a temperature in the region of 24°C, under an inert argon atmosphere. After 39 hours at a temperature in the region of 24°C, 5 the reaction medium is concentrated under reduced pressure (3 mbar) at a temperature in the region of 40°C. 3.26 g of a pale yellow foam are thus obtained, which foam is taken up in 30 cm3 of dichloromethane and 2.52 cm3 of cyclopropylamine. The solution obtained is 10 stirred at a temperature in the region of 21°C, under an inert argon atmosphere, for 87 hours and then concentrated under 3 mbar at a temperature in the region of 40°C. 3.64 g of (RS)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-15 methylsulfonylmethyl]azetidin-3-ylcyclopropylamine are thus obtained in the form of a pale yellow foam. [1H NMR spectrum (300 MHz, CDCI3, 5 in ppm) : 0.29 (mt : 1H); from 0.4 0 to 0.7 5 (mt : 3H); 2.50 (mt : 1H); 2.7 3 (s : 3H); 2.90 (unresolved complex : 1H); from 3.45 to 3.70 20 (mt : 3H); 4.36 (broad s : 1H); from 4.60 to 4.80 (broad unresolved complex : 1H); 6.87 (tt, J = 9 and 2.5 Hz : 1H); from 7.20 to 7.40 (mt : 10H)].
Example 2 9 (RS)-{l-[Bis(4-chlorophenyl)methyl]-3-[(3,5-25 difluorophenyl)methylsulfonylmethyl]azetidin-3-yl}-(2-pyrrolidin-l-ylethyl)amine may be prepared in the following manner: 0.076 cm3 of 1-(2-aminoethyl)-pyrrolidine is added to a solution of 50 mg of 1- 163 [bis(4-chlorophenyl)methyl)]-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine in 0.5 cm3 of dichloromethane, at a temperature in the region of 21°C, under an inert argon atmosphere. The solution 5 obtained is stirred at a temperature in the region of 21°C, under an argon atmosphere, for 22 hours, concentrated under an air stream at a temperature in the region of 42°C and then the crude residue obtained is dried under reduced pressure (about 3 mbar) at a 10 temperature in the region of 40°C. (RS)-{1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulf onylmethyl ] azetidin-3-yl}-(2-pyrrolidin-1-yl-ethyl)amine is obtained in the form of an ochre-colored foam. [1H NMR spectrum (300 MHz, CDC13, 8 in ppm) ; from 15 1.75 to 1.95 (mt : 4H); from 2.55 to 2.85 (mt : 6H); 2.79 (s : 3H); 2.91 (t, J = 6.5 Hz : 2H); 3.06 (d, J = 8.5 Hz : 1H); 3.17 (d, J = 8.5 Hz : 1H); 3.32 (d, J = 8.5 Hz : 1H); 3.41 (d, J = 8.5 Hz : 1H); 4.31 (s : 1H); 4.56 (s : 1H); 6.88 (tt, J = 8.5 and 2.5 Hz : 1H); 7.22 20 (s : 4H); 7.25 (s : 4H; 7.34 (mt : 2H)].
Example 30 (RS)-{1-[Bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methanesulfonylmethyl]azetidin-3-yl}methylamine may be prepared according to Example 29, 25 starting with 50 mg of 1-[bis(4-chorophenyl)methyl)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine, 0.5 cm of dichloromethane and 0.3 cm of a solution of methylamine in tetrahydrofuran (2 M 164 solution). (RS)-{1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-3-yl}methylamine is obtained in the form of a yellow gum. [ 1H NMR spectrum (400 MHz, CDC13 8 in ppm) : from 2.00 5 to 2.20 (broad unresolved complex : 1H); 2.62 (s : 3H) ; 2.76 (s : 3H); 3.04 (d, J = 9 Hz : 1H); 3.18 (d, J = 9 Hz : 1H); 3.37 (AB, J = 9 Hz : 2H); 4.31 (s : 1H); 4.55 (s : 1H); 6.89 (tt, J = 9 and 2.5 Hz : 1H); 7.22 (s : 4H); 7.24 (s : 4H); 7.32 (mt : 2H)].
Example 31 (RS)-{1-[Bis(4-chlorophenyl)methyl]-3-[(3,5— difluorophenyl)methylsulfonylmethyl]azetidin-3-yl}isobutylamine may be prepared according to Example 29, starting with 50 mg of 1-[bis(4-chlorophenyl)-15 methyl)]-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]azetidine, 0.5 cm3 of dichloromethane and 0.0596 cm3 of isobutylamine. (RS)-{1-[bis(4-chlorophenyl )methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl ] azetidin-3-yl } isobutylamine is obtained in the 20 form of a white foam [1H NMR spectrum (300 MHz, CDCI3 8 in ppm) : 1.01 (2d, J = 7 Hz : 6 H); from 1.7 0 to 2.15 (broad unresolved complex : 1H); 1.7 6 (mt : 1H); 2.51 (dd, J = 10.5 and 7 Hz : 1H); 2.76 (s : 3H); 2.80 (dd, J = 10.5 and 6 Hz : 1H); 3.01 (d, J = 8.5 Hz : 1H); 25 3.14 (d, J = 8.5 Hz : 1H); 3.32 (d, J = 8.5 Hz : 1H); 3.44 (d, J = 8.5 Hz : 1H)/ 4.31 (s : 1H); 4.58 (s : 1H); 6.88 (tt, J = 8.5 and 2.5 Hz : 1H); from 7.15 to 7.30 (mt : 8 H); 7.35 (mt : 2H)] . 165 Example 32 (RS)-{1-[Bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-3-yl}ethylamine may be prepared according to Example 2 9 5 starting with 50 mg of 1-[bis(4-chlorophenyl)methyl)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine, 0.5 cm3 of dichloromethane and 0.3 cm3 of a solution of ethylamine in tetrahydrofuran (2 M solution). (RS)-{1-[bis(4-chlorophenyl)methyl]-3-[(3,5 10 difluorophenyl)methylsulfonylmethyl]azetidin-3- yl}ethylamine is obtained in the form of a yellow gum [XH NMR spectrum(300 MHz, CDC13 8 in ppm) : 1.22 (t, J 7 Hz : 3 H); from 2.70 to 2.85 (mt : 2H); 2.77 (s : 3H); from 2.95 to 3.10 (unresolved complex : 1H); 3.05 15 (d, J = 8.5 Hz : 1H); 3.17 (d, J = 8.5 Hz : 1H); 3.33 (d, J = 8.5 Hz : 1H); 3.40 (d, J = 8.5 Hz : 1H); 4.30 (s : 1H); 4.54 (s : 1H); 6.89 (tt, J = 9 and 2.5 Hz : 1H); from 7.15 to 7.30 (mt : 8H); 7.34 (mt : 2H)]. Example 33 (RS)-N-{1-[Bis(4-chlorophenyl)methyl]-3- [(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-3-yl}-N',N'-dimethylethane-1,2-diamine may be prepared according to Example 29, starting with 50 mg of 1-[bis(4-chlorophenyl)methyl)]-3-[(3,5-difluorophenyl)-25 (methylsulfonyl)methylene]azetidine, 0.5 cm3 of dichloromethane and 0.0659 cm3 of N,N-dimethylethylene-diamine. (RS)-N-{l-bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-3-yl}- 166 N' , N'-dimethylethane-1,2-diamine is obtained in the form of a white foam [NMR spectrum (300 MHz, CDC13 8 in ppm) : 2.32 (s : 6H)/ 2.53 (t, J = 6 Hz : 2H); 2.79 (s : 3H); 2.94 (t, J = 6 Hz : 2H); 3.06 (d, J = 5 8.5 Hz : 1H); 3.16 (d, J = 8.5 Hz : 1H); 3.30 (d, J = 8.5 Hz : 1H); 3.41 (d, J = 8.5 Hz : 1H); 4.30 (s : 1H); 4.55 (s : 1H); 6.88 (tt, J = 9 and 2.5 Hz : 1H); 7.21 (s : 4H); 7.24 (s : 4H); 7.34 (mt : 2H)].
Example 34 (RS)-1-[Bis(4-chlorophenyl)methyl]-3-[(3,5- difluorophenyl)methanesulfonylmethyl]-3-methylazetidine may be prepared in the following manner: a few drops of pure methyl iodide are added, under an argon atmosphere at a temperature in the region of 24°C, to a suspension 15 of 400 mg of magnesium turnings in 2.5 cm3 of anhydrous diethyl ether, followed by 1 cm3 of methyl iodide in solution in 22.5 cm3 of diethyl ether. The suspension obtained is stirred for 30 minutes at a temperature in the region of 24°C and then cooled to a temperature in 20 the region of 0°C with an ice + water mixture. 1.65 g of CuBr.Me2S complex, are added, at a temperature in the region of 0°C, and then the reaction mixture is stirred for 15 minutes at a temperature in the region of 0°C. The yellow suspension obtained is added, at a 25 temperature in the region of 0°C, to a solution of 0.5 g of 1-[Bis(4-chlorophenyl)methyl)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine in a mixture of 1 cm3 of tetrahydrofuran and 167 1 cm3 of diethyl ether. The suspension obtained is stirred for 4 hours at a temperature in the region of 0°C and then at a temperature in the region of 25°C for 16 hours. The black suspension obtained is diluted with 5 100 cm3 of ethyl acetate and 15 cm3 of saturated aqueous ammonium chloride solution. The reaction mixture is filtered on sintered glass covered with Celite, the solid residue is rinsed with ethyl acetate and then with water. After decantation of the filtrate, the 10 organic phase is separated, washed with 10 cm3 of water, 10 cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered on sintered glass and concentrated under reduced pressure (20 mbar) at a temperature in the region of 43°C. 550 mg of an 15 orange-colored foam are thus obtained, which foam is purified by preparative thin-layer chromatography on silica [14 preparative Merck Kieselgel 60F254 plates; 20x20 cm; thickness 0.5 mm; deposition in solution in dichloromethane], eluting with a methanol-20 dichloromethane mixture (0.5-99.5 by volume). After elution of the zone corresponding to the desired product with a methanol-dichloromethane (15-85 by volume) mixture, filtration on sintered glass and then evaporation of the solvents under reduced pressure at a 25 temperature in the region of 40°C, 290 mg of a white foam are obtained, which foam is dissolved in 15 cm3 of anhydrous dichloromethane and reacted with 500 mg of thiophenol resin (supplier Argonaut, 1.45 mMol/g) and 168 1 g of ethylenediamine resin (0.8 mMol/g) for 38 hours at a temperature in the region of 20°C. The suspension is filtered on sintered glass, the resins are rinsed with dichloromethane and the filtrate is concentrated 5 under reduced pressure (5 mbar) at a temperature in the region of 43°C. 272.8 mg of a white foam are obtained, which foam is dissolved in 2 cm3 of dichloromethane and reacted with 1 cm3 of ethylenediamine for 72 hours at a temperature in the region of 24°C. The crude residue 10 obtained is taken up in 50 cm3 of ethyl acetate and cm3 of water. After decantation, the organic phase is washed with 10 cm3 of a 1 N aqueous hydrochloric acid solution, 10 cm3 of a saturated aqueous sodium hydrogen carbonate solution, 10 cm3 of water, 10 cm3 of a 15 saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered on sintered glass and concentrated under reduced pressure (8 mbar) at a temperature in the region of 42°C. 263.4 mg of a pale yellow foam are obtained, which foam is purified by 20 preparative thin-layer chromatography on silica [7 preparative Merck Kieselgel 60F254 plates; 20x20 cm; thickness 0.5 mm; deposition in solution in dichloromethane], eluting with a methanol-dichloromethane mixture (0.5-99.5 by volume). After 25 elution of the zone corresponding to the desired product with a methanol-dichloromethane (15-85 by volume) mixture, filtration on sintered glass and then evaporation of the solvents under reduced pressure at a 169 temperature in the region of 40°C, 191.4 mg of (RS)-l-[bis(4-chlorophenyl)methyl]-3-[([3,5- difluorophenyl)methylsulfonylmethyl]-3-methylazetidine are obtained in the form of a white foam [1H NMR 5 spectrum (300 MHz, CDCI3, 5 in ppm): 1.75 (s : 3H); 2.67 (s : 3H); 2.74 (broad d, J = 7.5 Hz : 1H); 2.93 (d, J = 7.5 Hz : 1H); 3.21 (broad d, J = 7.5 Hz : 1H); 3.46 (d, J = 7.5 Hz : 1H); 4.33 (broad s : 2H); 6.87 (tt, J = 9 and 2.5 Hz : 1H); 7.12 (mt : 2H) from 7.15 10 to 7.35 (mt : 8H].
Example 35 (RS)-1-(2-{1-[Bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-3-ylsulfanyl}ethyl)-4-methylpiperazine may be prepared in 15 the following manner: 128 mg of 1-(ethanethiol-2-yl)-4-methylpiperazine are added to a solution of 99 mg of 1-[bis(4-chlorophenyl)methyl)]-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]-azetidine in 2 cm3 of dichloromethane, at a temperature in the region of 20 20°C. After stirring overnight at a temperature in the region of 20°C, 706 mg of Merrifield resin (1.7 mMol/g) are added. After stirring overnight at a temperature in the region of 20°C, the suspension is filtered and the resin is rinsed with twice 1 cm3 of dichloromethane. The 25 filtrate is concentrated under reduced pressure. 125 mg of a white oil are thus obtained, which oil is purified by chromatography on silica (13 cm3 of 0.06-0.2 mm silica), eluting with a methanol-dichloromethane (0-100 170 and then 5-95 by volume) mixture. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure. 62 mg of (RS)-l-(2-{l-[bis(4-chlorophenyl)methyl]-5 3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-3-ylsulfanyl}ethyl)-4-methylpiperazine are thus obtained in the form of white crystals [1H NMR spectrum (300 MHz, (CD3)2SO d6, 8 in ppm): 2.15 (s : 3H) ; 2.30 and 2.41 (2mfs : 8H); 2.55 (mt : 2H); 2.85 (s : 3H); 3.02 (mt : 10 2H); 3.09 (d, J = 8.5 Hz : 1H); 3.38 (d, J = 8.5 Hz : 1H); 3.42 (d, J = 8.5 Hz : 1H); 3.79 (d, J = 8.5 Hz : 1H); 4.68 (s : 1H); 5.37 (s : 1H); from 7.30 to 7.50 (mt : 11H)].
Example 36 (RS)-(2-{l-[Bis(4-chlorophenyl)methyl]- 3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-3-ylsulfanyl}ethyl)dimethylamine may be prepared by carrying out the procedure as in Example 35, starting with 99 mg of 1-[bis(4-chlorophenyl)methyl)]-3-20 [(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine, 2 cm3 of dichloromethane, 84 mg of 2-(dimethylamino)ethanethiol and 706 mg of Merrifield resin (1.7 mMol/g). 36 mg of (RS)-(2-{l-[bis(4-chlorophenyl)methyl]— 3 —[(3,5-difluorophenyl)-25 methylsulfonylmethyl]azetidin-3-ylsulfanyl}ethyl)- dimethylamine are thus obtained in the form of an off-white powder. 171 Example 37 (RS)-{l-[[4-(Chloromethyl)phenyl]-(4-chlorophenyl ) methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl ] azetidin-3-yl } ethylamine may be prepared in the 5 following manner: A solution of 40 mg of (RS)—{1—[[4— (chloromethyl)phenyl]-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethylene]azetidine in 0.1125 cm3 of ethylamine (2 M solution in tetrahydrofuran), containing a grain of sodium iodide, 10 is stirred at a temperature in the region of 20°C for 2 hours and then diluted with 20 cm3 of ethyl acetate and 5 cm3 of a saturated aqueous sodium hydrogen carbonate solution. The separated organic phase is washed with 5 cm3 of water, 5 cm3 of a saturated aqueous 15 sodium chloride solution, dried over magnesium sulfate, filtered on sintered glass and concentrated under reduced pressure (15 mbar) at a temperature in the region of 40°C. The yellow oil obtained is purified by preparative thin-layer chromatography on silica [2 20 preparative Merck Kieselgel 60F254 plates; 20x20 cm; thickness 0.5 mm; deposition in solution in dichloromethane], eluting with a methanol-dichloromethane mixture (3-97 by volume). After elution of the zone corresponding to the desired product with a 25 methanol-dichloromethane (15-85 by volume) mixture, filtration on sintered glass and then evaporation of the solvents under reduced pressure at a temperature in the region of 40°C, 17 mg of (RS)-{1-[[4- 172 (chloromethyl)phenyl]-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-3-yl}ethylamine are obtained in the form of a white solid [ 1H NMR spectrum (400 MHz, (CD3)2SO d6, 5 in ppm) : 1.11 5 (t, J = 7 Hz : 3H); from 2.10 to 3.55 (mt : 8H); 2.95 (s : 3H); 4.44 (s : 1H); 5.09 (s : 1H); from 7.10 to 7.55 (mt : 11H)].
(RS)-{1-[[4-(Chloromethyl)phenyl]-(4-chlorophenyl ) methyl ] -3-[(3,5-difluorophenyl)methylsulfonyl-10 methylene]azetidin may be prepared in the following manner: 0.525 cm3 of N,N-diisopropylethylamine is added, at a temperature in the region of 21°C, to a solution of 590 mg of (RS)-[4-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)methylsulfonylmethylene]azetidin-1-15 yl}methyl)phenyl]methanol in 5 cm3 of anhydrous dichloromethane, followed by 0.19 cm3 of methanesulfonyl chloride. After 1 hour at a temperature in the region of 21°C, 2 cm3 of a methanol/dichloromethane (2.5/97.5 by volume) mixture are added and then after 20 5 minutes the reaction mixture is concentrated under reduced pressure (20 mbar) at a temperature in the region of 40°C. The yellow foam obtained is purified by chromatography on silica (50 g of 0.06-0.2 mm silica contained in a column 3 cm in diameter), eluting with a 25 methanol/dichloromethane (0/100 and then 1/99 by volume) mixture, collecting 10-cm3 fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced 173 pressure. 421.2 mg of (RS)-{1-[[4-(chloromethyl)-phenyl]-(4-chlorophenyl)methyl]-3-[(3,5-difluoro-phenyl)methylsulfonylmethylene]azetidine are thus obtained in the form of a yellow foam.
(RS)-[4-((4-Chlorophenyl)-{3-[(3,5-difluoro phenyl )methylsulfonylmethylene]azetidin-l-yl}methyl)-phenyl]methanol may be prepared in the following manner: 4 9 mg of sodium tetraborohydride are added portionwise to a solution of 420 mg of (RS)—[4—((4— 10 chlorophenyl)-{3-[(3,5-difluorophenyl)methylsulfonylmethylene] azetidin-l-yl}methyl)benzaldehyde in 7 cm3 of methanol, cooled to a temperature in the region of 0°C (ice + water). After 2 hours at a temperature in the region of 0°C, the reaction medium is concentrated 15 under reduced pressure (15 mbar) at a temperature in the region of 35°C. The residue obtained is purified by chromatography on silica (40 g of 0.06-0.2 mm silica contained in a column 3 cm in diameter), eluting with a methanol/dichloromethane (1/99 and then 2.5/97.5 by 20 volume) mixture, collecting 10-cm3 fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure. 418 mg of (RS)-[4-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)methylsulfonylmethylene]azetidin-25 1-ylJmethyl)phenyl]methanol are thus obtained in the form of a white foam. 174 Example 38 (RS)-{1-[Bis(4-chlorophenyl)methyl]-3-[(3,5-bistrifluoromethylphenyl)methylsulfonylmethyl]azetidin-3-yl}isobutylamine may be prepared according to Example 5 29 starting with 50 mg of l-[bis(4-chlorophenyl)methyl)]-3-[(3,5-bistrifluoromethylphenyl)(methylsulfonylmethylene] azetidine, 0.5 cm3 of dichloromethane and 0.05 cm3 of isobutylamine. 57 mg of (RS)-{1-10 [bis(4-chlorophenyl)methyl]—3—[(3,5 — bistrifluoromethylphenyl)methylsulfonylmethyl]azetidin-3-yl}isobutylamine are obtained in the form of a pale yellow foam [ 1H NMR spectrum (300 MHz, CDC13, 5 in ppm) : 1.01 (d, J = 7.5 Hz : 6H); 1.76 (mt : 1H); 2.47 (dd, 15 J = 10.5 and 7.5 Hz : 1H); from 2.75 to 2.85 (mt : 1H); 2.79 (s : 3H); 2.82 (dd, J = 10.5 and 5.5 Hz : 1H); 3.00 (d, J = 9 Hz : 1H); 3.10 (d, J = 9 Hz : 1H); 3.31 (d, J = 9 Hz : 1H); 3.40 (d, J = 9 Hz : 1H); 4.30 (s : 1H); 4.74 (s : 1H); 7.13 (d, J = 8.5 Hz : 2H) ; 20 from 7.15 to 7.25 (mt : 6H); 7.96 (broad s : 1H); 8.31 (broad s : 2H)].
Example 39 (RS)-1-[Bis(4-chlorophenyl)methyl]-3-cyano-3-[(3,5-difluorophenylmethylsulfonylmethyl]azetidine may 25 be prepared in the following manner: 17 mg of potassium cyanide are added to a solution of 99 mg of l-[bis(4-chlorophenyl)methyl)]-3-[(3,5-difluorophenyl)(methylsulf onyl ) methylene] azetidine in 2.5 cm3 of dimethyl 175 sulfoxide, at a temperature in the region of 20°C. The yellow and then brown solution obtained is heated for 15 minutes at a temperature in the region of 40°C and then cooled to a temperature in the region of 20°C. The 5 reaction medium is concentrated under reduced pressure and then taken up in 10 cm3 of dichloromethane, washed with three times 5 cm3 of water. The organic phase obtained is dried over magnesium sulfate, filtered and concentrated under reduced pressure. 100 mg of a yellow 10 paste are thus obtained, which paste is purified by chromatography on silica (10 cm3 of 0.06-0.2 mm silica contained in a column 1 cm in diameter), eluting with dichloromethane. The fractions containing only the desired product are combined and concentrated to 15 dryness under reduced pressure. 60 mg of (RS)-1-[bis(4-chlorophenyl)methyl]-3-cyano-3-[(3,5-difluorophenyl-methylsulfonylmethyl]azetidine are thus obtained in the form of a yellow paste [ 1H NMR spectrum (300 MHz, (CD3)2SO, d6, 5 in ppm): 2.94 (s : 3H) ; 3.07 (d, 20 J = 7.5 Hz : 1H); from 3.20 to 3.40 (mt : 1H); 3.61 (broad d, J = 7.5 Hz : 1H); 3.68 (broad d, J = 7.5 Hz : 1H); 4.64 (s : 1H); 5.51 (s : 1H); from 7.25 to 7.50 (mt : 11H)].
Example 40 (RS)-{1-[Bis(4-chlorophenyl)methyl]-3-[(3,5- difluorophenyl)methylsulfonylmethyl]azetidin-3-ylmethyl}-(1-cyclopropylethyl)amine may be prepared in the following manner: 0.03 cm3 of cyclopropyl methyl 176 ketone, 0.006 cm3 of acetic acid and then 32 mg of sodium triacetoxyborohydride are successively added to a solution of 53 mg of (RS)-C-{1-[bis(4-chlorophenyl)-methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]-5 azetidin-3-yl}methylamine in 2 cm3 of 1, 2-dichloroethane at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 20°C for 18 hours and then 2 cm3 of a saturated aqueous sodium hydrogen carbonate solution are added. After 10 decantation, the organic phase is concentrated under reduced pressure. 60 mg of a viscous yellow oil are thus obtained, which oil is triturated with isopropyl ether and petroleum ether. After drying under 0.1 mbar, 55 mg of a residue are obtained which is purified by 15 chromatography on silica (4 cm3 of 0.06-0.2 mm silica contained in a column 1.2 cm in diameter), eluting with a methanol/dichloromethane (0/100 and then 5/95 by volume) mixture. The fractions containing only the desired product are combined, concentrated to dryness 20 under reduced pressure and repurified by chromatography on silica (4 cm3 of 0.04-0.063 mm silica contained in a column 1.2 cm in diameter), eluting with a methanol/dichloromethane (0/100 and then 1/99 by volume) mixture. The fractions containing only the 25 desired product are combined and concentrated to dryness. 20 mg of (RS)-{1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-3-ylmethyl}-(1-cyclopropylethyl)amine are thus obtained 177 [■""H NMR spectrum (300 MHz, CDC13, 5 in ppm) : a mixture of diastereoisomers is observed, from 0.00 to 0.30 and from 0.40 to 0.80 (mts : 5H); 1.09 and 1.17 (2d, J = 6.5 Hz : 3H in total); 1.87 (mt : 1H); from 2.55 to 5 2.75-from 2.75 to 2.95 and from 3.25 to 3.55 (mts : 4H); 2.68 (s : 3H); 3.12 (d, J = 8.5 Hz : 1H); from 3.80 to 3.90 (mt : 1H); 4.42 and 4.43 (2s : 1H in total); 4.79 and 4.84 (2s : 1H in total); 6.89 (tt, J = 9 and 2.5 Hz : 1H); 7.16 (mt : 2H); from 7.15 to 10 7.35 (mt : 8H]).
(RS)-C-{l-[Bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-3-ylJmethylamine may be prepared in the following manner: 1.27 cm3 of a 1.5 M solution of diisobutylaluminum 15 hydride in tetrahydrofuran are added dropwise to a solution of 250 mg of (RS)-1-[bis(4-chlorophenyl)-methyl]-3-cyano-3-[(3,5-difluorophenyl)methylsulfonylmethyl] azetidine in 10 cm3 of anhydrous tetrahydrofuran, cooled to a temperature in the region of 0°C. After 20 30 minutes at a temperature in the region of 0°C and then 4 hours at a temperature in the region of 20°C, the solution is again cooled to a temperature of 0°C. 6.35 cm3 of water and then 1.06 cm3 of aqueous hydrochloric acid (12 N) are added successively. After 25 decantation, the aqueous phase is extracted with three times 10 cm3 of ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. 0.42 g of a dark 178 yellow oil is thus obtained which is purified by chromatography on silica (40 cm3 of 0.063-0.2 mm silica contained in a column 2.7 cm in diameter), eluting with a methanol/dichloromethane (0/100 and then 5/95 by 5 volume) mixture. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure. 110 mg of (RS)-C-{1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl )methylsulfonylmethyl]azetidin-3-yl}methylamine 10 are thus obtained.
Example 41 (RS)-N-{1-[Bis(4-chlorophenyl)methyl]- 3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-3-ylmethyl}isobutyramide may be prepared in the following manner: 0.0187 cm3 of isobutyric acid, 0.032 cm3 of 1,3-diisopropylcarbodiimide and 2.5 mg of 4-dimethylaminopyridine are successively added to a solution of 53 mg of (RS)-C-{1-[bis(4-chlorophenyl)-methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]- azetidin-3-yl}methylamine in 2 cm3 of anhydrous dichloromethane at a temperature in the region of 20°C. After stirring for 72 hours at a temperature in the region of 20°C, 2 cm3 of water are added, the mixture is separated after settling and then the organic phase is 25 dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude residue obtained is purified by preparative thin-layer chromatography on silica [1 preparative Merck Kieselgel 179 60F254 plate; 20x20 cm; thickness 1 mm], eluting with an ethyl acetate-dichloromethane (5-95 by volume) mixture. After elution of the zone corresponding to the desired product, filtration on sintered glass and then 5 evaporation of the solvent under reduced pressure at a temperature in the region of 40°C, 16 mg of (RS)-N-{1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonylmethyl]azetidin-3-ylmethyl}isobutyramide are obtained in the form of a pale yellow powder [1H NMR 10 spectrum (300 MHz, CDCI3, 8 in ppm): 1.22 (d, J = 7 Hz : 6H); 2.46 (mt : 1H); 2.69 (s : 3H); 2.99 (d, J = 8.5 Hz : 1H) ; 3.23 (AB, J = 8.5 Hz : 2H) ; 3.40 (d, J = 8.5 Hz : 1H); 3.57 (dd, J = 14 and 4.5 Hz : 1H); 4.09 (dd, J = 14 and 7.5 Hz : 1H); 4.34 (s : 1H) ; 4.35 15 (s : 1H); 6.71 (dd, J = 7.5 and 4.5 Hz : 1H); 6.95 (tt, J = 9 and 2.5 Hz : 1H); from 7.10 to 7.35 (mt : 10H)]. Example 42 (RS)-N-{1-[Bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-3-20 ylmethyl}cyclopropanecarboxamide may be prepared in a manner similar to Example 39, starting with 53 mg of (RS)-C-{1-[bis(4-chlorophenyl)methyl]-3-[(3 , 5-difluorophenyl) methanesulfonylmethyl]azetidin-3-yl}methylamine, 2 cm3 of anhydrous dichloromethane, 0.0167 cm3 of 25 cyclopropanecarboxylic acid, 0.032 cm3 of 1,3-diisopropylcarbodiimide and 2.5 mg of 4-dimethylaminopyridine. 28 mg of (RS)-N-(l-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)- 180 methylsulfonylmethyl]azetidin-3-ylmethyl}-cyclopropanecarboxamide are obtained in the form of a beige powder [XH NMR spectrum (300 MHz, CDC13, 5 in ppm): 0.81 (mt : 2H); 1.01 (mt : 2H); from 1.35 to 1.55 5 (mt : 1H); 2.7 0 (s : 3H); 3.02 (d, J = 8.5 Hz : 1H); 3.21 (limiting AB, J = 8 Hz : 2H); 3.45 (d, J = 8.5 Hz : 1H); 3.62 (dd, J = 14 and 4.5 Hz : 1H); 4.10 (dd, J = 14 and 7.5 Hz); 4.31 (s : 1H); 4.36 (s : 1H); 6.75 (dd, J = 7.5 and 4.5 Hz : 1H); 6.95 (tt, J = 9 and 10 2 Hz : 1H); from 7.15 to 7.35 (mt : 10H)].
Example 43 (RS)-{1-[Bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-3-ylmethyl}diethylamine may be prepared in a manner 15 similar to Example 40, starting with 53 mg of (RS)-C-{l-[bis(4-chlorophenyl)methyl]-3-[(3, 5-difluorophenyl )methylsulfonylmethyl]azetidin-3-yl}methylamine, 2 cm3 of 1,2-dichloroethane, 0.017 cm3 of acetaldehyde, 0.006 cm3 of acetic acid and 32 mg of sodium 20 triacetoxyborohydride. 12 mg of (RS)-{1-[bis(4-chlorophenyl) methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl ] azetidin-3-ylmethyl } diethylamine are thus obtained in the form of an off-white powder [1H NMR spectrum (300 MHz, CDCI3, 5 in ppm) : 1.00 (t, J = 7 Hz : 25 6H); 2.49 (q, J = 7 Hz : 4H); 2.54 (d, J = 13.5 Hz : 1H); 2.69 (s : 3H); 2.76 (broad d, J = 7.5 Hz : 1H); 3.07 (broad d, J = 7.5 Hz : 1H); 3.15 (d, J = 13.5 Hz : 1H); 3.24 (broad d, J = 7.5 Hz : 1H); 4.06 (broad d, 181 J = 7.5 Hz : 1H): 4.35 (s : 1H); 5.02 (s : 1H); 6.91 (mt : 1H); from 7.15 to 7.40 (mt : 10H)].
Example 44 (RS)-N-{1-[Bis(4-chlorophenyl)methyl]-5 3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-3-ylmethyl}methanesulfonamide may be prepared in the following manner: 150 mg of anhydrous IRA-68 resin are added to a solution of 53 mg of (RS)-C-{1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-10 methylsulfonylmethyl]azetidin-3-yl}methylamine in 2 cm3 of ethyl acetate, at a temperature in the region of 20°C, followed by 0.012 cm3 of methylsulfonyl chloride. After stirring overnight at a temperature in the region of. 20°C, 0.001 cm3 of water and then 150 mg of anhydrous 15 IRA-68 resin are added. After stirring for 1 hour at a temperature in the region of 20°C, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. 81 mg of a yellow paste are thus obtained, which paste is purified by preparative thin-20 layer chromatography on silica [1 preparative Merck Kieselgel 60F254 plate; 20x20 cm; thickness 1 mm] , eluting with an ethyl acetate-dichloromethane (5-95 by volume) mixture. After elution of the zone corresponding to the desired product, filtration on 25 sintered glass and evaporation of the solvents under reduced pressure at a temperature in the region of 40°C, 25 mg of (RS)-N-{1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-3- 182 ylmethylJmethanesulfonamide are obtained in the form of a pale yellow powder [1H NMR spectrum (300 MHz, CDC13, 8 in ppm): 2.70 (s : 3H); from 2.95 to 3.10 (mt : 2H); 3.05 (s : 3H); 3.22 (broad d, J = 8 Hz : 1H); 3.52 (d, 5 J = 8 Hz : 1H); 3.74 (dd, J = 13.5 and 8 Hz : 1H); 3.90 (dd, J = 13.5 and 5.5 Hz : 1H); 4.23 (s : 1H); 4.4 6 (s : 1H); 5.54 (mt : 1H); 7.00 (tt, J = 9 and 2 Hz : 1H); from 7.05 to 7.35 (mt : 10H)].
Example 45 (RS)-l-{l-[Bis(4-chlorophenyl)methyl]-3- [(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-3-ylmethyl}-3-isopropylurea may be prepared in the following manner: 0.0197 cm3 of isopropyl isocyanate is added to a solution of 53 mg of 15 (RS)-C-{l-[bis(4-chlorophenyl)methyl]- 3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-3-yl}methylamine in 2 cm3 of dichloromethane, at a temperature in the region of 20°C. After stirring overnight at a temperature in the region of 20°C, 20 0.05 cm3 of water is added and then after stirring for 15 minutes at a temperature in the region of 20°C, the reaction mixture is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained (75 mg) is purified by preparative 25 thin-layer chromatography on silica [1 preparative Merck Kieselgel 60F254 plate; 20x20 cm; thickness 1 mm], eluting with an ethyl acetate-dichloromethane (5-95 by volume) mixture. After elution of the zone 183 corresponding to the desired product, filtration on sintered glass and then evaporation of the solvent under reduced pressure at a temperature in the region of 40°C, 16 mg of (RS)-1-{1-[bis(4-chlorophenyl)-5 methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]-azetidin-3-ylmethyl}-3-isopropylurea are obtained in the form of a pale yellow powder [1H NMR spectrum (300 MHz, CDC13, 5 in ppm) : 1.17 (d, J = 7 Hz : 6H) ; 2.68 (s : 3H); 3.00 (broad d, J = 8.5 Hz : 1H); 3.11 10 (d, J = 8.5 Hz : 1H); 3.17 (d, J = 8.5 Hz : 1H); 3.46 (broad d, J = 8.5 Hz : 1H); 3.64 (dd, J = 14 and 5 Hz : 1H); 3.86 (mt : 1H); 3.96 (dd, J = 14 and 7.5 Hz : 1H); 4.15 (d, J = 8 Hz : 1H); 4.29 (s : 1H); 4.43 (s : 1H); 5.11 (mt : 1H); 6.94 (tt, J = 9 and 15 2 Hz : 1H); from 7.10 to 7.30 (mt : 10H)].
Example 46 (RS)-{1-[Bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-3-ylmethyl}carbamic acid isobutyl ester may be prepared 20 in the following manner: 0.016 cm3 of isobutyl chloroformate is added to a solution of 53 mg of (RS)-C-{1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenylmethylsulf onylmethyl] azetidin-3-yl}methylamine in 2 cm3 of pyridine, at a temperature in the region of 25 20°C. After stirring overnight at a temperature in the region of 20°C, the reaction mixture is concentrated under reduced pressure. 68 mg of a yellow paste are obtained, which paste is purified by preparative thin- 184 layer chromatography on silica gel [1 preparative Merck Kieselgel 60F254 plate; 20x20 cm; thickness 1 mm] , eluting with an ethyl acetate-dichloromethane (5-95 by volume) mixture. After elution of the zone 5 corresponding to the desired product, filtration on sintered glass and then evaporation of the solvents under reduced pressure at a temperature in the region of 40°C, 14 mg of (RS)-{1-[bis(4-chlorophenyl)methyl]-3-[(3, 5-difluorophenyl)methylsulfonylmethyl]azetidin-3-10 ylmethyl}carbamic acid isobutyl ester are obtained in the form of an off-white powder [1H NMR spectrum (300 MHz, CDC13, 5 in ppm): 0.96 (d, J = 7 Hz : 6H) ; 1.95 (mt : 1H); 2.68 (s : 3H); 3.04 (d, J = 8.5 Hz : 1H); 3.19 (s : 2H); 3.51 (d, J = 8 Hz : 1H); 3.75 (dd, 15 J = 14 and 5 Hz : 1H); from 3.80 to 4.00 (mt : 3H); 4.30 (s : 1H); 4.34 (s : 1H); 5.63 (unresolved complex: 1H); 6.95 (tt, J = 9 and 2 Hz : 1H); from 7.10 to 7.30 (mt : 10H) ] .
Example 4 7 (RS)-{1-[Bis(4-chlorophenyl)methyl]- 3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-3-ylmethyl}dimethylamine may be prepared in the following manner: 138 mg of potassium carbonate are added, at a temperature in the region of 20°C, to a solution of 25 52 mg of (RS)-C-{1-[bis(4-chlorophenyl)methyl]-3- [(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-3-yl}methylamine in 2 cm3 of acetonitrile, followed by 0.0075 cm3 of methyl iodide. After stirring overnight at 185 temperature in the region of 20°C, the reaction medium is filtered on sintered glass, the solid is rinsed with dichloromethane and the filtrate is concentrated under reduced pressure. The crude residue obtained (90 mg) is 5 purified by preparative thin-layer chromatography on silica [1 preparative Merck Kieselgel 60F254 plate; 20x20 cm; thickness 1 mm], eluting with an ethyl acetate-dichloromethane (5-95 by volume) mixture. After elution of the zone corresponding to the desired 10 product, filtration on sintered glass and then evaporation of the solvents under reduced pressure at a temperature in the region of 40°C, 11 mg of (RS)-{1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-methylsulfonylmethyl]azetidin-3-ylmethyl}dimethylamine 15 are obtained [1H NMR spectrum (300 MHz, CDC13, 8 in ppm): 2.18 (s : 6H); 2.30 (d, J = 13 Hz : 1H); from 4.65 to 4.78 (mt : 1H); 2.70 (s : 3H); 2.98 (d, J = 13 Hz : 1H); 3.09 (d, J = 8 Hz : 1H); 3.32 (d, J = 7.5 Hz : 1H); 4.11 (d, J = 8 Hz : 1H); 4.35 (s : 20 1H); 4.94 (s : 1H); 6.92 (mt : 1H); from 7.10 to 7.40 (mt : 10H)].
Example 48 (RS)-1-[Bis(4-chlorophenyl)methyl]-3-[(4-methoxyphenyl)methylsulfonylmethyl]azetidine may 25 be prepared in the following manner: 25.5 mg of sodium tetraborohydride are added to a solution of 400 mg of 1-[bis(4-chlorophenyl)methyl]-3-[(4-methoxyphenyl)-methylsulfonylmethylene]azetidine in 4.5 cm3 of ethanol, 186 under an argon atmosphere, at a temperature in the region of 20°C. After stirring for 16 hours at a temperature in the region of 20°C, 26 mg of sodium tetraborohydride are added. The reaction medium is 5 stirred at a temperature in the region of 20°C for 4.5 hours and then at a temperature in the region of 50°C for 3 hours. After cooling to a temperature in the region of 20°C, the reaction medium is concentrated under reduced pressure. The white deposit obtained is 10 taken up in 2 cm3 of water and 2 cm3 of dichloromethane. After decantation, the organic phase is concentrated under reduced pressure and the yellow foam obtained is purified by preparative thin-layer chromatography on silica [2 preparative Merck Kieselgel 60F254 plates, 15 20x20 cm; thickness 0.5 mm], eluting with a methanol-dichloromethane (1-99 by volume) mixture. After elution of the zone corresponding to the desired product with a methanol-dichloromethane (10-90 by volume) mixture, filtration on sintered glass and then evaporation of 20 the solvents under reduced pressure at a temperature in the region of 40°C, 14 mg of (RS)-1-[bis(4-chlorophenyl) methyl]-3-[(4-methoxyphenyl)methylsulfonylmethyl ] azetidine are obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDC13, 8 in ppm) : 2.56 25 (mt : 1H); 2.58 (s : 3H); 3.20 (mt : 2H); from 3.35 to 3.55 (mt : 1H); 3.66 (broad t, J = 7.5 Hz : 1H); 3.81 (s : 3H); 4.21 (d, J = 4.5 Hz : 1H); 4.26 (broad s : 187 1H); 6.90 (d, J = 8.5 Hz : 2H); from 7.15 to 7.40 (mt : 10H)]. 1-[Bis(4-chlorophenyl)methyl]-3-[(4-methoxyphenyl)methylsulfonylmethylene]azetidine 5 may be prepared by carrying out the procedure as described in Example 1, starting with 1 g of (RS)-1-[bis(4-chlorophenyl)methyl]-3-[methylsulfonyl-(4-methoxyphenyl)methyl]azetidin-3-ol, 20 cm3 of dichloromethane, 0.229 cm3 of methylsulfonyl chloride 10 and 722 mg of 4-dimethylaminopyridine. After purification by chromatography on silica at atmospheric pressure (100 g of silica, particle size 0.063-0.2 mm contained in a column 3 cm in diameter), eluting with dichloromethane), the fractions containing only the 15 desired product are combined and concentrated to dryness under reduced pressure. 650 mg of l-[bis(4-chlorophenyl)methyl]-3-[(4-methoxyphenyl)methylsulfonylmethylene] azetidine are thus obtained in the form of a yellow gum. 20 (RS)-1-[Bis(4-chlorophenyl)methyl]- 3-[methylsulfonyl-(4-methoxyphenyl)methyl]azetidin-3-ol may be prepared by carrying out the procedure as described in Example 1, starting with 19.6 cm3 of 1.6 N n-butyllithium in solution in hexane, 5.7 g of 25 4-methoxybenzyl methyl sulfone and 8.71 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one in 450 cm3 of tetrahydrofuran. 8.3 g of (RS)-1-[bis(4-chlorophenyl ) methyl ] -3-[methylsulfonyl-(4-methoxyphenyl)- 188 methyl]azetidin-3-ol are thus obtained in the form of a beige solid. 4-Methoxybenzyl methyl sulfone may be prepared by carrying out the procedure as described in 5 Example 27, starting with 13.6 cm3 of 4-methoxybenzyl chloride, 30 mg of sodium iodide, 14.4 g of sodium methyl sulfinate in 125 cm3 of ethanol. 5.75 g of 4-methoxybenzyl methyl sulfone are thus obtained in the form of a white powder.
Example 4 9 (RS)-2-{l-[Bis(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-acetyl-morpholine may be prepared in the following manner: 252 mg of supported EDCI (2.3 equivalents, the 15 supported EDCI reagent is commercially available, and may also be prepared according to the following reference: M. Desai, L. Stramiello, Tetrahedron Letters, 34, 48, 7685-7688 (1993)), 2 cm3 of anhydrous dichloromethane, 0.006 cm3 or morpholine and then 20 0.010 cm3 of triethylamine are successively added, at a temperature in the region of 20°C, to 37 mg of (RS-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorophenyl)acetic acid hydrochloride. After stirring for 12 hours at a temperature in the region of 25 20°C, the reaction mixture is filtered on sintered glass. The filtrate is washed with 2 cm3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at a 189 temperature in the region of 20°C. 15 mg of (RS)— 2 —{1 — [bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-acetylmorpholine are thus obtained in the form of a beige foam [XH NMR spectrum (300 MHz, 5 CDC13, 8 in ppm): from 2.60 to 3.80 (mt : 13H); 3.93 (d, J = 10 Hz : 1H); 4.27 (s : 1H) from 6.65 to 6.85 (mt : 3H) from 7.20 to 7.40 (mt : 8H)].
Example 50 (RS)-2-{1-[Bis(4-chlorophenyl)methyl]-10 azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclohexylacetamide may be prepared in the following manner: 0.070 cm3 of cyclohexylamine, 144 mg of 1—(3 — dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.141 cm3 of triethylamine and then 4 mg of 15 hydroxybenzotriazole hydrate are successively added to a solution of 250 mg of (RS)-{1-[bis(4-chlorophenyl)-methyl]azetidin-3-yl}-(3,5-difluorophenyl)acetic acid hydrochloride in 10 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution 20 obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction medium is deposited on a Varian cartridge (25 cm3) filled with 12 g of fine silica (0.040-0.063 mm), conditioned and then eluted with a dichloromethane-petroleum ether 25 (80-20 by volume) mixture with the aid of a Duramat pump, collecting 1.5-cm3 fractions. Fractions 11 to 17 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 169 mg of (RS)-2-{1-[bis(4- 190 chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl ) -N-cyclohexylacetamide are thus obtained in the form of a white foam [XH NMR spectrum (300 MHz, CDC13, 5 in ppm): from 0.90 to 1.45 (mt : 6H); from 1.50 to 1.90 5 (mt : 4H); 2.66 (mt : 1H); 2.90 (mt : 1H) from 3.00 to 3.15 (mt ': 2H) ; 3.42 (broad t, J = 7.5 Hz : 1H) ; 3.52 (d, J = 10.5 Hz : 1H); from 3.60 to 3.80 (mt : 1H); 4.27 (s : 1H); 5.25 (broad d, J = 8 Hz : 1H); 6.90 (tt, J = 9 and 2.5 Hz : 1H); 6.82 (mt : 2H); from 7.20 to 10 7.35 (mt : 8H].
Example 51 (RS)-2-{1-[Bis(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-acetyl-piperidine may be prepared in the following manner: 15 0.012 cm3 of piperidine, 29 mg of 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS)-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-20 3,5-difluorophenyl)acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction medium is deposited on a Varian cartridge 25 (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm), eluting with dichloromethane with the aid of a Duramat pump. The fractions between 8 and 15 cm3 are combined and concentrated to dryness under reduced pressure 191 (2.7 kPa) at 40°C. 14 mg of (RS)-2-{1-[bis(4-chlorophenyl ) methyl ] azetidin-3-yl}-2-(3,5-difluorophenyl)-N-acetylpiperidine are thus obtained in the form of a white crystalline powder [1H NMR spectrum (300 MHz, 5 CDC13, 5 in ppm): from 0.95 to 1.15 and from 1.30 to 1.50 (2mts : 6H in total); 2.74 (mt : 2H); from 3.00 to 3.15 (mt : 2H) from 3.30 to 3.45 (mt : 4H); from 3.55 to 3.70 (mt : 1H); 3.95 (d, J = 10 Hz : 1H); 4.26 (s : 1H) ; 6.68 (tt, J = 9 and 2.5 Hz : 1H) ; 6.80 (mt : 2H) ; 10 from 7.20 to 7.35 (mt : SH)] .
Example 52 (RS)-2-{1-[Bis(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-acetyl-pyrrolidine may be prepared in the following manner: 15 0.010 cm3 of pyrrolidine and 0.023 cm3 of diisopropylcarbodiimide, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS)-{1-[bis(4-chlorophenyl )methyl]azetidin-3-yl}-(3,5-difluorophenyl)acetic 20 acid hydrochloride in 2 cm3 of anhydrous dichloromethane at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction medium is deposited on a Varian cartridge (6 cm3) filled with 3 g 25 of fine silica (0.040-0.063 mm), eluting with dichloromethane with the aid of a Duramat pump. The fractions between 11 and 19 cm3 are combined and concentrated to dryness under reduced pressure 192 (2.7 kPa) at 40°C. 29 mg of (RS)-2-{1-[bis(4-chlorophenyl )methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-acetylpyrrolidine are thus obtained in the form of a white foam [1HNMR spectrum (300 MHz, CDCI3, 5 in ppm) : 5 from 1.7 5 to 2.00 (mt : 4H); 2.7 4 (mt : 2H); from 3.0 0 to 3.30 (mt : 3H); from 3.35 to 3.60 (mt : 4H); 3.80 (d, J = 10.5 Hz : 1H); 4.25 (s : 1H); 6.68 (tt, J = 9 and 2.5 Hz : 1H); 6.84 (mt : 2H); from 7.20 to 7.40 (mt : 8H) ] .
Example 53 (RS)-2-{l-[Bis(4-chlorophenyl)methyl] -azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclopropyl-acetamide may be prepared in the following manner: 0.009 cm3 of cyclopropylamine, 29 mg of 1-(3-dimethyl-15 aminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS)-{1-[bis(4-chlorophenyl)-methyl]azetidin-3-yl}-(3,5-difluorophenyl)acetic acid 20 hydrochloride in 2 cm3 of anhydrous dichloromethane at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction medium is deposited on a Varian cartridge (6 cm3) filled with 3 g 25 of fine silica (0.040-0.063 mm), conditioned and then eluted with dichloromethane with the aid of a Duramat pump, collecting 2-cm3 fractions. Fractions 2 to 6 are combined and concentrated to dryness under reduced 193 pressure (2.7 kPa) at 40°C. 29 mg of (RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluoro-phenyl)-N-cyclopropylacetamide are thus obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDC13, 5 5 in ppm): 0.40 (mt : 2H); 0.74 (mt : 2H); 2.64 (mt : 2H); 2.89 (dd, J = 7.5 and 5 Hz : 1H); 3.08 (mt : 2H) ; 3.42 (broad t, J = 7.5 Hz : 1H); 3.51 (d, J = 10.5 Hz : 1H); 4.25 (s : 1H); 5.50 (unresolved complex : 1H); 6.70 (tt, J = 9 and 2.5 Hz : 1H); 6.81 (mt : 2H) from 10 7.15 to 7.35 (mt : 8H)].
Example 54 (RS)-2-{1-[Bis(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclohexyl-N-methylacetamide may be prepared in the following 15 manner: 0.016 cm3 of N-methylcyclohexylamine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS)-{1-[bis(4-chlorophenyl)-20 methyl]azetidin-3-yl}-(3,5-difluorophenyl)acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction medium is 25 deposited on a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm), conditioned and eluted with dichloromethane with the aid of a Duramat pump, collecting 2-cm3 fractions. Fractions 4 to 6 are 194 combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 17 mg of (RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclohexyl-N-methylacetamide 5 are thus obtained in the form of a white foam [1H NMR spectrum (250 MHz, (CD3)2SO d6, at a temperature of 373K, 5 in ppm): from 0.98 to 1.85 (mt : 10H); from 2.60 to 3.05 (mt : 8H); (broad t, J = 7.5 Hz : 1H); 4.25 (broad d, J = 9 Hz : 1H); 4.45 (s : 1H); 7.00 (mt : 10 3H); from 7.25 to 7.45 (mt : 8H)].
Example 55 (RS)-2-{l-[Bis(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(tetrahydro-furan-2-ylmethyl)acetamide may be prepared in the 15 following manner: 0.013 cm3 of tetrahydrofurylamine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS)-{1-bis(4-chlorophenyl)-20 methyl]azetidin-3-yl]-(3,5-difluorophenyl)acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction medium is 25 deposited on a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm), conditioned and then eluted with dichloromethane with the aid of a Duramat pump, collecting 2-cm3 fractions. Fractions 3 to 8 are 195 combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 27 mg of 2(RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3, 5-difluorophenyl) -N-(tetrahydrofuran-2-ylmethyl)acetamide are 5 thus obtained in the form of a white solid [1H NMR spectrum (300 MHz, CDC13, 8 in ppm): from 1.65 to 1.95 (mt : 4H); 2.64 (mt : 1H); 2.89 (dd, J = 7.5 and 5.5 Hz : 1H); from 3.00 to 3.20 (mt : 3H); from 3.30 to 3.60 (mt : 2H); 3.58 (d, J = 10.5 Hz : 1H); from 3.65 10 to 3.95 (mt : 3H); 4.25 (s : 1H); 5.81 (mt : 1H); 6.68 (tt, J = 9 and 2.5 Hz : 1H); 6.82 (mt : 2H); from 7.15 to 7.35 (mt : 8H)].
Example 56 (RS)-2-{1-[Bis(4-chlorophenyl)methyl]-15 azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(2-morpholin-4-ylethyl)acetamide may be prepared in the following manner: 0.016 cm3 of aminoethylmorpholine, 2 9 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of 20 hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS)-{1-[bis(4-chlorophenyl)-methyl]azetidin-3-yl}-(3,5-difluorophenyl)acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution 25 obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction medium is deposited on a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm), conditioned with 196 dichloromethane with the aid of a Duramat pump, eluted successively with a dichloromethane-ethyl acetate (70-30 by volume) mixture, collecting 2-cm3 fractions for fractions 1 to 12, and then with a dichloromethane-5 methanol (98-2 by volume) mixture, collecting 2-cm3 fractions for fractions 12 to 27. Fractions 13 to 27 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 34 mg of (RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl]-2-(3, 5-difluoro-10 phenyl)-N-(2-morpholin-4-ylethyl)acetamide are thus obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDC13, 8 in ppm): 2.33 (broad t, J = 5 Hz : 4H); 2.38 (t, J = 7 Hz : 2H); 2.65 (mt : 1H); from 2.85 to 3.20 (mt : 3H); 3.25 (broad q, J = 7 Hz : 2H); 3.43 15 (mt : 1H); 3.57 (t, J = 5 Hz : 4H); 3.61 (d, J = .5 Hz : 1H); 4.26 (s : 1H); 5.98 (unresolved complex: 1H); 6.70 (tt, J = 9 and 2.5 Hz : 1H); 6.83 (mt : 2H); from 7.15 to 7.35 (mt : 8H)].
Example 57 (RS)-2-{l-[Bis(4-chlorophenyl)methyl]- azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(1-ethyl-pyrrolidin-2-ylmethyl)acetamide may be prepared in the following manner: 0.018 cm3 of aminomethylethyl-pyrrolidine, 29 mg of 1-(3-dimethylaminopropyl)-3-25 ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS)-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- 197 (3,5-difluorophenyl)acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours.
The reaction medium is deposited on a Varian cartridge (of 12 mm in diameter) filled with 4 cm3 of silica (0.060-0.200 mm), conditioned with dichloromethane with the aid of a vacuum apparatus, eluting with dichloromethane between 0 and 6 cm3 and then with a 10 dichloromethane-methanol (95-5 by volume) mixture. The fractions containing the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C for 2 hours. The yellow paste thus obtained is taken up in 2 cm3 of ethyl acetate and then 15 with 2 cm3 of distilled water. After stirring, the mixture is frozen, the organic phase is concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. The residue obtained is taken up in 2 cm3 of diisopropyl ether and is then concentrated to dryness under reduced 20 pressure (2.7 kPa) at 40°C. 38 mg of (RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(l-ethylpyrrolidin-2-ylmethyl)acetamide are thus obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDC13 with 25 addition of a few drops of CD3C00D d4, 8 in ppm) : 0.96 and 1.17 (2t, J = 7.5 Hz : 3H in total); from 1.60 to 2.00 (mt : 4H); from 2.50 to 2.95-from 3.10 to 3.85 (mts : 11H); from 3.95 to 4.10 (mt : 1H); 4.10 and 4.14 198 (2d, J = 10.5 Hz : 1H in total); 5.18 and 5.25 (2 broad s : 1H in total); 6.66 (mt : 1H); from 6.80 to 7.00 (mt : 2H); from 7.15 to 7.45 (mt : 8H)].
Example 58 (RS)-2-{l-[Bis(4-chlorophenyl)methyl]- azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isobutylacetamide may be prepared in the following manner: 0.012 cm3 of isobutylamine, 29 mg of 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS)-{1-[bis(4-chlorophenyl) methyl] azetidin-3-yl}-(3,5-difluorophenyl)acetic acid hydrochloride in 2 cm3 of anhydrous 15 dichloromethane, at a temperature in the region of °C. The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction medium is deposited on a Varian cartridge (of 12 mm in diameter) filled with 5 cm3 of silica (0.060-0.200 mm), 20 conditioned in dichloromethane with the aid of a vacuum apparatus, eluting with dichloromethane between 0 and 6 cm3 and then with a dichloromethane-ethyl acetate (95-5 by volume) mixture. The fractions containing only the desired product are combined and concentrated to 25 dryness under reduced pressure (2.7 kPa) at 40°C. 40 mg of (RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isobutylacetamid^ are thus obtained in the form of a white foam [1H NMR spectrum 199 (300 MHz, (CD3)2SO d6 5 in ppm): 0.75 (d, J = 7.5 Hz : 6H); 1.62 (mt : 1H); 2.61 (mt : 1H); from 2.70 to 2.95 (mt : 3H); 3.03 (mt : 2H); 3.22 (broad t, J = 7 Hz : 1H); 3.83 (d, J = 10.5 Hz : 1H); 4.45 (s : 1H); 7.00 5 (mt : 2H); 7.08 (tt, J = 9 and 2.5 Hz : 1H); from 7.25 to 7.45 (mt : 8H) ; 8.11 (t, J = 6 Hz : 1H)] .
Example 59 (RS)-2-{l-[Bis(4-chlorophenyl)-methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N,N-10 dimethylacetamide may be prepared in the following manner: 0.06 cm3 of dimethylamine in 2 M solution in tetrahydrofuran, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole 15 hydrate are successively added to a solution of 50 mg of (RS)-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorophenyl)acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution obtained is stirred at a 20 temperature in the region of 20°C for about 12 hours. The reaction medium is deposited on a Varian cartridge (of 12 mm in diameter) filled with 4.4 cm3 of silica (0.060-0.200 mm), conditioned in dichloromethane with the aid of a vacuum apparatus, eluting with 25 dichloromethane between 0 and 6 cm3 and then with a dichloromethane-ethyl acetate (95-5 by volume) mixture. The fractions containing only the desired product are combined and concentrated to dryness under reduced 200 pressure (2.7 kPa) at 40°C. 13 mg of (RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluoro-phenyl)-N,N-dimethylacetamide are thus obtained in the form of a white powder [■''H NMR spectrum (300 MHz, CDC13, 5 5 in ppm): from 2.70 to 2.80 (mt : 2H); 2.92 (s : 3H); 2.95 (s : 3H); from 3.00 to 3.15 (mt : 2H); 3.38 (broad t, J = 7.5 Hz : 1H); 3.96 (d, J = 10 Hz : 1H); 4.26 (s : 1H); 6.69 (tt, J = 9 and 2.5 Hz : 1H); 6.81 (mt : 2H); from 7.20 to 7.35 (mt : 8H)].
Example 60 (RS)-2-{l-[Bis(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-benzylacetamide may be prepared in the following manner: 0.013 cm3 of benzylamine, 29 mg of 1-(3-dimethylaminopropyl-15 3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS)-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorophenyl)acetic acid hydrochloride in 2 cm3 20 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction mixture is deposited on a Varian cartridge (of 12 mm in diameter) filled with 4.4 cm3 of silica 25 (0.060-0.200 mm) conditioned in dichloromethane with the aid of a vacuum apparatus, eluting with dichloromethane between 0 and 6 cm3 and then with a dichloromethane-ethyl acetate (95-5 by volume) mixture. 201 The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 37 mg of (RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-5 (3,5-difluorophenyl)-N-benzylacetamide are thus obtained in the form of white crystals [1H NMR spectrum (300 MHz, CDC13, 5 in ppm): 2.67 (mt : 1H); 2.93 (mt : 1H) : 3.11 (mt : 2H); 3.43 (broad t, J = 7.5 Hz : 1H); 3.62 (d, J = 10.5 Hz : 1H); 4.26 (s : 1H); 4.38 (mt : 10 2H); 5.71 (mt : 1H); 6.71 (broad t, J = 9 Hz : 1H); 6.83 (mt : 2H) ; from 7.10 to 7.40 (mt : 13H)] .
Example 61 (RS)— 2 —{1—[Bis(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclohexyl-15 methylacetamide may be prepared in the following manner: 0.016 cm3 of aminomethylcyclohexane, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to 20 a solution of 50 mg of {1-[bis(4-chlorophenyl)methyl]-azetidin-3-yl}-(3,5-difluorophenyl)acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 25 20°C for about 12 hours. The reaction medium is deposited on a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm), conditioned and then eluted with dichloromethane with the aid of a Duramat 202 pump, collecting 2-cm3 fractions. Fractions 2 to 3 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 49 mg of (RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluoro-5 phenyl)-N-cyclohexylmethylacetamide are thus obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDC13, 8 in ppm): from 0.75 to 1.75 (mt : 11H); 2.65 (mt : 1H); from 2.85 to 3.15 (mt : 5H); 3.42 (broad t, J = 7.5 Hz : 1H); 3.57 (d, J = 10.5 Hz : 1H); 4.27 (s : 10 1H); 5.40 (mt : 1H); 6.71 (broad t, J = 9 Hz : 1H); 6.83 (mt : 2H); from 7.15 to 7.40 (mt : 8H)].
Example 62 (RS)-2-{l-[Bis(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-[3-(2-15 oxopyrrolidin-l-yl)propyl]acetamide may be prepared in the following manner: 0.017 cm3 of aminopropyl-pyrrolidinone, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole 20 hydrate are successively added to a solution of 50 mg of (RS)-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorophenyl)acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution obtained is stirred at a 25 temperature in the region of 20°C for about 12 hours. The reaction medium is deposited on a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm), conditioned and then eluted with dichloromethane with 203 the aid of a Duramat pump, collecting 2-cm3 fractions. Fractions 4 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 35 mg of (RS)-2-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-5 2-(3,5-difluorophenyl)-N-[3-(2-oxopyrrolidin-l- yl)propyl]acetamide are thus obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDC13, 5 in ppm) : from 1.50 to 1.65 (mt : 2H); 2.04 (mt : 2H); 2.43 (t, J = 8 Hz : 2H); 2.64 (mt : 1H); 2.88 (dd, J = 7.5 and 10 5.5 Hz : 1H); from 3.00 to 3.30 (mt : 6H); from 3.30 to 3.45 (mt : 3H); 3.64 (d, J = 10.5 Hz : 1H); 4.27 (s : 1H); 6.67 (tt, J = 9 and 2.5 Hz : 1H); 6.90 (mt : 2H) ; 7.15 (t, J = 6 Hz : 1H); from 7.20 to 7.35 (mt : 8H)]. Example 63 (RS)-2-{l-[Bis(4-chlorophenyl)methyl]- azetidin-3-yl}-2-(3,5-difluorophenyl)-N-acetyl(4-methylpiperazine) may be prepared in the following manner: 0.013 cm3 of N-methylpiperazine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 20 hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS)-{1-[bis(4-chlorophenyl)-methyl]azetidin-3-yl}-(3,5-difluorophenyl)acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at 25 a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction medium is deposited on a Varian cartridge (6 cm3) filled with 3 g 204 of fine silica (0.040-0.063 mm), conditioned with dichloromethane with the aid of a Duramat pump, eluted with a dichloromethane-ethanol (98-02 by volume) mixture, collecting 2-cm3 fractions. Fractions 10 to 24 5 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 39 mg of (RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- 2-(3,5-difluorophenyl)-N-acetyl(4-methylpiperazine) are thus obtained in the form of a white foam [1H NMR 10 spectrum (300 MHz, CDCI3, 5 in ppm) : 1.83 (mt : 1H) ; from 2.10 to 2.4 5 (mt : 3H); 2.21 (s : 3H); 2.7 4 (mt : 2H); from 2.95 to 3.15 (mt : 2H); from 3.30 to 3.55 (mt : 4H); 3.73 (mt : 1H); 3.93 (d, J = 10 Hz : 1H) ; 4.25 (s : 1H); 6.69 (tt, J = 9 and 2.5 Hz : 1H); 6.78 15 (mt : 2H); from 7.15 to 7.35 (mt : 8H)].
Example 64 (RS)-2-{l-[Bis(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(2,2-dimethyl-propyl)acetamide may be prepared in the following 20 manner: 0.014 cm3 of neopentylamine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS)-{1-[bis(4-chlorophenyl)-25 methyl]azetidin-3-yl}-(3,5-difluorophenyl)acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 205 °C for about 12 hours. The reaction medium is deposited on a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm), conditioned with dichloromethane with the aid of a Duramat pump, eluted 5 with a dichloromethane-petroleum ether (80-20 by volume) mixture, collecting 1.5-cm3 fractions. Fractions 4 to 8 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 40 mg of (RS)-2-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-10 2-(3,5-difluorophenyl)-N-(2,2-dimethylpropyl)acetamide are thus obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDC13, 8 in ppm): 0.81 (s : 9H) ; 2.66 (mt : 1H); from 2.90 to 3.20 (mt : 5H); 3.44 (broad t, J = 7.5 Hz : 1H); 3.61 (d, J = 10.5 Hz : 1H) : 4.28 15 (s : 1H); 5.40 (mt : 1H); 6.72 (tt, J = 9 and 2.5 Hz : 1H); 6.85 (mt : 2H); from 7.20 to 7.35 (mt : 8H)]. Example 65 (RS)-2-{1-[Bis(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(2-pyrrolidin-20 1-ylethyl)acetamide may be prepared in the following manner: 0.015 cm3 of aminoethylpyrrolidine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to 25 a solution of 50 mg of (RS)-{1-[bis(4-chlorophenyl)-methyl]azetidin-3-yl}-(3,5-difluorophenyl)acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution 206 obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction medium is deposited on a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm), conditioned with 5 dichloromethane with the aid of a Duramat pump, eluted with a dichloromethane-ethanol (98-04 by volume) mixture, collecting 1.5-cm3 fractions. Fractions 13 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 33 mg of (RS)-2-{l-10 [bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(2-pyrrolidin-1-ylethyl)acetamide are thus obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDC13, 8 in ppm) : 1.78 (mt : 4H); from 2.50 to 2.70 (mt : 3H); 2.54 (mt : 15 4H); 2.91 (dd, J = 7.5 and 5 Hz : 1H); 3.10 (mt : 2H); from 3.20 to 3.45 (mt : 3H); 3.64 (d, J = 10.5 Hz : 1H); 4.27 (s : 1H); 6.67 (tt, J = 9 and 2.5 Hz : 1H); 6.86 (mt : 2H); from 7.15 to 7.35 (mt : 8H)].
Example 66 (RS)-2-{l-[Bis(4-chlorophenyl)methyl]- azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclopropylmethylacetamide may be prepared in the following manner: 0.011 cm3 of cyclopropanemethylamine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 25 hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS)-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- 207 (3,5-difluorophenyl)acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours.
The reaction medium is deposited on a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm), conditioned and then eluted with a dichloromethane-petroleum ether (80-20 by volume) mixture with the aid of a Duramat pump, collecting 1.5-cm3 fractions. 10 Fractions 3 to 8 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 37 mg of (RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclopropylmethylacetamide are thus obtained in the form of a white foam [1H NMR 15 spectrum (300 MHz, CDCI3, 8 in ppm): 0.13 (mt : 2H) : 0.45 (mt : 2H); 0.86 (mt : 1H); 2.65 (mt : 1H); 2.91 (dd, J = 7.5 and 5 Hz : 1H); from 3.00 to 3.15 (mt : 4H); 3.41 (broad t, J = 7.5 Hz : 1H); 3.57 (d, J = 10.5 Hz : 1H); 4.25 (s : 1H); 5.50 (mt : 1H); 6.70 (tt, 2 0 J = 9 and 2.5 Hz : 1H); 6.84 (mt : 2H); from 7.15 to 7.35 (mt : 8H)].
Example 67 (RS)-2-{l-[Bis(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-propylacetamide 25 may be prepared in the following manner: 0.015 cm3 of propylamine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole 208 hydrate are successively added to a solution of 50 mg of (RS)-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorophenyl)acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the 5 region of 20°C. The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction medium is deposited on a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm), conditioned and eluted with dichloromethane with the 10 aid of a Duramat pump. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 21 mg of (RS)-2-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-propylacetamide are thus 15 obtained in the form of a white solid [1H NMR spectrum (300 MHz, CDCI3, 5 in ppm): 0.84 (t, J = 7.5 Hz : 3H) ; 1.45 (mt : 2H); 2.65 (mt : 1H); 2.92 (dd, J = 7.5 and 5.5 Hz : 1H); from 3.00 to 3.20 (mt : 2H); 3.15 (q, J = 7 Hz : 2H); 4.43 (broad t, J = 7.5 Hz : 1H); 3.56 (d, 2 0 J = 10.5 Hz : 1H); 4.2 6 (s : 1H); 5.3 9 (mt : 1H); 6.7 0 (tt, J = 9 and 2.5 Hz : 1H); 6.83 (mt : 2H); from 7.15 to 7.35 (mt : 8H].
Example 68 (RS)-2-{l-[Bis(4-chlorophenyl)methyl]-25 azetidin-3-yl}-2-(3,5-difluorophenyl)-N-propylacetamide may be prepared in the following manner: 0.050 cm3 of a 2 M solution of methylamine in tetrahydrofuran, 2 9 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 209 hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS)-{1-[bis(4-chlorophenyl)-methyl]azetidin-3-yl}-(3,5-difluorophenyl)acetic acid 5 hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction medium is deposited on a Varian cartridge (6 cm3) filled with 3 g 10 of fine silica (0.040-0.063 mm) conditioned and eluted with dichloromethane with the aid of a Duramat pump. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 19 mg of (RS)—2 — {1 — 15 [bis(4-chlorophenyl)methyl]azetidin-3-yl}- 2-(3,5-difluorophenyl)-N-methylacetamide are thus obtained in the form of a white solid [1H NMR spectrum (300 MHz, CDC13, 5 in ppm): 2.66 (mt : 1H); 2.76 (d, J = 5 Hz : 3H); 2.93 (mt : 1H); 3.10 (mt : 2H); 3.44 (broad 20 t, J = 7.5 Hz : 1H); 3.59 (d, J = 10.5 Hz : 1H); 4.28 (s : 1H); 5.41 (unresolved complex : 1H); 6.71 (tt, J = 9 and 2.5 Hz : 1H); 6.83 (mt : 2H); from 7.20 to 7.35 (mt : 8H)].
Example 69 (RS)-2-{1-[Bis(4-chlorophenyl)methyl]- azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isopropylacetamide may be prepared in the following manner: 0.011 cm3 of isopropylamine, 29 mg of 210 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS)-{1- [bis(4-chlorophenyl)methyl]azetidin-3-yl}- (3,5-difluorophenyl)acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours. 10 The reaction medium is deposited on a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm) conditioned and then eluted with dichloromethane with the aid of a Duramat pump, collecting 1.5-cm3 fractions. Fractions 6 to 14 are combined and concentrated to 15 dryness under reduced pressure (2.7 kPa) at 40°C. 21 mg of (RS)-2-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}~ 2-(3,5-difluorophenyl)-N-isopropylacetamide are thus obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDCI3, 8 in ppm) : 1.05 (d, J = 7 Hz : 3H) ; 1.10 (d, J = 7 Hz : 3H); 2.65 (mt : 1H); 2.90 (dd, J = 7.5 and 5.5 Hz : 1H); from 3.00 to 3.15 (mt : 2H); 3.42 (broad t, J = 7.5 Hz : 1H); 3.51 (d, J = 10.5 Hz : 1H); 4.00 (mt : 1H); 4.26 (s : 1H); 5.19 (broad d, J = 7.5 Hz : 1H); 6.70 (tt, J = 9 and 2.5 Hz : 1H); 6.82 25 (mt : 2H) : from 7.20 to 7.40 (mt : 8H)].
Example 70 (RS)-2-{1-[Bis(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-piperidin-1- 211 ylacetamide may be prepared in the following manner: 0.013 cm3 of aminopiperidine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of 5 hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS)-{1-[bis(4-chlorophenyl)-methyl]azetidin-3-yl}-(3,5-difluorophenyl)acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution 10 obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction medium is deposited on a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm) conditioned with dichloromethane with the aid of a Duramat pump, eluted 15 with a dichloromethane-ethanol (98-02 by volume) mixture, collecting 2-cm3 fractions. Fractions 7 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 33 mg of (RS)-2-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-20 2-(3,5-difluorophenyl)-N-piperidin-l-ylacetamide are thus obtained in the form of a white solid [XH NMR spectrum (300 MHz, CDCI3, 5 in ppm): from 0.95 to 1.85-2.05 and 2.29 (mts : 10H); from 2.60 to 2.80 (mt : 2H); from 3.00 to 3.20 (mt : 2H); 3.39 (broad t, J = 25 7.5 Hz : 1H); 4.26 (s : 1H); 4.32 (d, J = 10.5 Hz : 1H); 6.00 (s : 1H); 6.65 (tt, J = 9 and 2.5 Hz : 1H); 6.85 (mt : 2H); from 7.15 to 7.35 (mt : 8H)] . 212 Example 71 (RS)— 2 —{1—[Bis(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cycloheptylacetamide may be prepared in the following 5 manner: 0.015 cm3 of cycloheptylamine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS)—{1— [bis(4-chlorophenyl)methyl]azetidin-3-yl}- (3,5-difluorophenyl)acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours.
The reaction medium is deposited on a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm) conditioned and then eluted with dichloromethane with the aid of a Duramat pump, collecting 2-cm3 fractions. Fractions 3 to 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 24 mg of (RS)-2-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- 2-(3,5-difluorophenyl)-N-cycloheptylacetamide are thus obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDCI3, 8 in ppm): from 1.20 to 1.95 (mt : 12H); 2.65 (mt : 1H); 2.90 (dd, J = 7.5 and 5.5 Hz : 1H); from 3.00 to 3.15 (mt : 2H); 3.42 (broad t, J = 7.5 Hz : 1H); 3.52 (d, J = 10.5 Hz : 1H); 3.86 (mt : 1H); 4.26 (s : 1H); 5.31 (broad d, J = 7.5 Hz : 1H); 213 6.70 (tt, J = 9 and 2.5 Hz : 1H); 6.82 (mt : 2H); from 7.20 to 7.35 (mt : 8H)].
Example 72 (RS)-2-{1-[Bis(4-chlorophenyl)methyl]-5 azetidin-3-yl}-2-(3,5-difluorophenyl)acetamide may be prepared in the following manner: 60 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 3 mg of hydroxybenzotriazol hydrate are successively added to a solution of 98 mg of (RS)- {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- (3,5-difluorophenyl)acetic acid hydrochloride in 4 cm3 of anhydrous dichloroethane, at a temperature in the region of 20°C, ammonia is bubbled through for 2 hours, with stirring at a temperature in the region of 20°C.
The reaction medium is washed with water and is then deposited on a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm) conditioned and eluted with a dichloromethane-ethyl acetate (9-1 by volume) mixture with the aid of a Duramat pump. The fractions between 36 and 80 ml are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 32 mg of (RS)-2-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- 2-(3,5-difluorophenyl)acetamide are thus obtained in the form of an amorphous powder [1H NMR spectrum (300 MHz, CDC13, 5 in ppm): 2.66 (mt : 1H); 2.95 (dd, J = 7 and 5 Hz : 1H); from 2.95 to 3.15 (mt : 2H); 3.45 (broad t, J = 7 Hz : 1H); 3.67 (d, J = 10.5 Hz : 1H); 4.27 (s : 1H); from 5.20 to 5.40 (unresolved complex : 214 2H); 6.72 (tt, J = 9 and 2.5 Hz : 1H); 6.84 (mt : 2H) ; from 7.20 to 7.35 (mt : 8H)].
Example 73 Methyl (RS)-2-{l-[Bis(4-chlorophenyl)methyl]-5 azetidin-3-yl}-2-(3,5-difluorophenyl)-N-acetylamino acetate may be prepared in the following manner: 100 mg of glycine methyl ester hydrochloride, 115 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 6 mg of hydroxybenzotriazol hydrate are successively added to a solution of 200 mg of (RS)-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorophenyl)acetic acid hydrochloride in 8 cm3 of dichloroethane, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature 15 in the region of 20°C for about 12 hours. The reaction medium is washed with water, dried, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. The residue thus obtained is taken up in 1 cm3 of dichloromethane and then deposited on an 20 1ST FlashPack cartridge with the reference SIL-020-005 conditioned and eluted with a dichloromethane-ethyl acetate (95-05 by volume) mixture with the aid of a Duramat pump. The fractions between 18 and 42 ml are combined and concentrated to dryness under reduced 25 pressure (2.7 kPa) at 40°C. 68 mg of methyl (RS)-2-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- 2-(3,5-difluorophenyl)-N-acetylamino acetate are thus obtained in the form of white cottony crystals ["""H NMR 215 spectrum (300 MHz, CDC13, 5 in ppm): 2.67 (mt : 1H); 2.93 (broad dd, J = 7.5 and 5 Hz : 1H); from 3.00 to 3.15 (mt : 2H); 3.41 (broad t, J = 7.5 Hz : 1H) ; 3.68 (d, J = 10.5 Hz : 1H); 3.74 (s : 3H); 3.93 (dd, J = 18 5 and 5 Hz : 1H); 4.03 (dd, J = 18 and 5 Hz : 1H) ; 4.27 (s : 1H); 5.96 (mt : 1H); 6.71 (tt, J = 9 and 2 Hz : 1H); 6.85 (mt : 2H); from 7.20 to 7.35 (mt : 8H)]. Example 74 (RS)— 2 —{1—[Bis(4-chlorophenyl)methyl]-10 azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(3-dimethyl-aminopropyl)acetamide may be prepared in the following manner: 0.015 cm3 of N,N-dimethylpropane-1,3-diamine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of 15 hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS)-{1-[bis(4-chlorophenyl)-methyl]azetidin-3-yl}-(3,5-difluorophenyl)acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution 20 obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction medium is deposited on a Varian cartridge (of 12 mm in diameter) filled with 4 cm3 of silica (0.060-0.200 mm) conditioned with dichloromethane with the aid of a vacuum 25 apparatus, eluting with dichloromethane between 0 and 6 cm3 and then with a dichloromethane-methanol (95-5 by volume) mixture. The fractions containing only the desired product are combined and concentrated to 216 dryness under reduced pressure (2.7 kPa) at 40°C. 33 mg [lacuna] (RS)-2-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(3-dimethylamino-propyl)acetamide are thus obtained in the form of white 5 crystals [1H NMR spectrum (300 MHz, CDC13, with addition of a few drops of CD3COOD d4, 6 in ppm) : 1.91 (mt : 2H) ; 2.71 (s : 6H); 2.95 (mt : 2H); from 3.15 to 3.40 (mt : 2H); from 3.40 to 3.60 (mt : 1H); from 3.60 to 3.80 (mt : 2H); 4.00 (mt : 2H); 4.28 (d, J = 10.5 Hz : 1H) ; 10 5.22 (s : 1H); 6.68 (tt, J = 9 and 2.5 Hz : 1H); 6.90 (mt : 2H); 7.33 (mt : 4H); 7.46 (d, J = 8 Hz : 4H)]. Example 75 (RS)— 2 —{1—[Bis(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(2-15 hydroxyethyl)acetamide may be prepared in the following manner: 0.024 cm3 of ethanolamine, 29 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to 20 a solution of 50 mg of (RS)-{1-[bis(4-chlorophenyl)-methyl]azetidin-3-yl}-(3,5-difluorophenyl)acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 25 20°C. The reaction medium is washed with 2 cm3 of a saturated sodium bicarbonate solution, dried over magnesium sulfate and is then deposited on an 1ST FlashPack cartridge with the reference SIL-016-002 217 conditioned with dichloromethane and eluted with a dichloromethane-ethyl acetate (95-05 by volume) mixture with the aid of a Duramat pump. The fractions between 25 and 60 cm3 are combined and concentrated to dryness 5 under reduced pressure (2.7 kPa) at 40°C. The residue obtained is again chromatographed on an 1ST FlashPack cartridge with the reference SIL-016-002 conditioned with dichloromethane and eluted with a dichloromethane-ethyl acetate (95-05 by volume) mixture with the aid of 10 a Duramat pump. The fractions between 25 and 35 cm3 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 14 mg of (RS)-2-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-(2-hydroxyethyl)acetamide are 15 thus obtained in the form of a white solid [XH NMR spectrum (300 MHz, CDCI3, 8 in ppm): 2.65 (mt : 1H) ; 2.91 (mt : 1H); from 3.00 to 3.15 (mt : 2H); from 3.30 to 3.50 (mt : 3H) ; 3.60 (d, J = 10.5 Hz : 1H) ; 3.66 (t, J = 5.5 Hz : 2H); 4.2 6 (s : 1H); 5.8 8 (mt : 1H); 6.71 20 (tt, J = 9 and 2 Hz : 1H); 6.84 (mt : 2H); from 7.20 to 7.35 (mt : 8H)].
Example 7 6 (RS)-1-[{1-[Bis(4-chlorophenyl)methyl]-azetidin-3-yl}-(3,5-difluorophenyl)methyl]-3-propylurea 25 may be prepared in the following manner: 0.056 cm3 of triethylamine and 0.064 cm3 of diphenylphosphonoazide are successively added to a solution of 50 mg of (RS)-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- 218 (3,5-difluorophenyl)acetic acid hydrochloride in 3 cm3 of anhydrous toluene, under an inert argon atmosphere, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 5 50°C for about 1 hour. 0.016 cm3 of propylamine is added, the stirring is maintained at a temperature in the region of 20°C for about 12 hours. The reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 10 40°C. The residue is taken up in 1 cm3 of dichloromethane and then deposited on a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm) conditioned and eluted with a dichloromethane-ethyl acetate (95-5 by volume) mixture 15 with the aid of a Duramat pump. The fractions between 12 and 16 cm3 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 13 mg of (RS)-1-[{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2(3,5-difluorophenyl)methyl]-3-propylurea are thus 20 obtained in the form of a beige solid [1H NMR spectrum (400 MHz, CDC13, 8 in ppm): 0.92 (t, J = 7.5 Hz : 3H); 1.53 (mt : 2H); from 2.55 to 2.75 (mt : 1H); from 2.80 to 3.25 (mt : 6H); 4.26 (t, J = 5.5 Hz : 1H); 4.29 (s 1H); 4.92 (t, J = 7 Hz : 1H); 5.31 (d, J = 5.5 Hz : 25 1H); 6.66 (tt, J = 9 and 2.5 Hz : 1H); 6.79 (mt : 2H); from 7.15 to 7.40 (mt : 8H)]. 219 Example 77 (RS)-{l-[Bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorophenyl)acetic acid hydrochloride may be prepared in the following manner: 3 cm3 of 6 N 5 hydrochloric acid are added to a solution of 0.44 g of (RS)-{l-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorophenyl)acetic acid ethyl ester in 7 cm3 of dioxane. The solution obtained is stirred under reflux for about 2 hours and then left at a temperature in the 10 region of 20°C for about 12 hours. The precipitate formed is filtered on No. 3 sintered glass, washed with 10 cm3 of diisopropyl ether and then dried under reduced pressure (0.27 kPa) at a temperature in the region of 40°C. 0.185 g of (RS)-{1-[bis(4-chlorophenyl)methyl]-15 azetidin-3-yl}-(3,5-difluorophenyl)acetic acid hydrochloride is thus obtained in the form of a white powder [1H NMR spectrum (400 MHz, (CD3)2SO d6, at a temperature of 363K, 8 in ppm): 2.87 (dd, J = 14 and 4 Hz : 1H); 2.95 (mt : 1H); 3.18 (mt : 1H); 3.96 (d, 20 J = 10.5 Hz : 1H); 4.18 (t, J = 9 Hz : 1H); 4.72 (t, J = 9 Hz : 1H); 5.26 (unresolved complex : 1H); 7.00 (mt : 2H); 7.06 (tt, J = 9.5 and 2.5 Hz : 1H); from 7.30 to 7.60 (mt : 8H)].
Example 78 (RS){1-[Bis(4-chlorophenyl)methyl]azetidin-3- yl}-(3,5-difluorophenyl)acetic acid ethyl ester may be prepared in the following manner: 121 mg of sodium borohydride are added, at a temperature in the region 220 of 0°C, to a suspension of 0.78 g of (RS)-{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene]-(3,5-difluorophenyl)acetic acid ethyl ester in 20 cm3 of ethanol. The suspension obtained is stirred at a 5 temperature in the region of 20°C for about 12 hours. The reaction medium is poured into 200 cm3 of distilled water and then extracted with three times 40 cm3 of ethyl acetate. The organic phase is successively washed with 3 times 40 cm3 of distilled water and then with 10 40 cm3 of a saturated sodium chloride solution. After decantation, the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40°C. The residue obtained is chromatographed 15 on a column filled with 75 cm3 of fine silica (0.040-0.063 mm) under a pressure of 0.7 bar with a dichloromethane-ethyl acetate mixture (the percentage of ethyl acetate varying from 0 to 10%), collecting 15-cm3 fractions. Fractions 4 to 11 are combined and 20 concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 0.46 g of (RS)-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorophenyl)acetic acid ethyl ester is thus obtained in the form of a yellow lacquer [1H NMR spectrum 25 (300 MHz, CDC13, 5 in ppm): 1.19 (t, J = 7 Hz : 3H) ; 2.62 (broad t, J = 6 Hz : 1H); 2.87 (dd, J = 7.5 and 6 Hz : 1H); from 2.95 to 3.15 (mt : 2H); 3.39 (broad t, J = 7.5 Hz : 1H); 3.78 (d, J = 10.5 Hz : 1H); 4.10 221 (mt : 2H); 4.25 (s : 1H); 6.69 (tt, J = 9 and 2.5 Hz : 1H); 6.80 (mt : 2H); from 7.20 to 7.35 (mt : 8H)].
Fractions 16 to 26 from the preceding chromatography are combined and concentrated to dryness 5 under reduced pressure (2.7 kPa) at 40°C. 0.24 g of (RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)ethanol is thus obtained in the form of a yellow foam [1H NMR spectrum (300 MHz, CDC13, 8 in ppm): 1.98 (unresolved complex : 1H); 2.69 (mt : 10 1H); from 2.70 to 2.85 (mt : 1H); from 2.90 to 3.10 (mt : 2H); 3.18 (mt : 1H); 3.44 (mt : 1H); from 3.65 to 3.85 (mt : 2H); 4.28 (s : 1H); from 6.60 to 6.80 (mt : 3H); from 7.20 to 7.35 (mt : 8H)]. {1-[Bis(4-chlorophenyl)methyl]azetidin-15 3-ylidene}-(3,5-difluorophenyl)acetic acid ethyl ester may be prepared in the following manner: 6.6 g of 4-dimethylaminopyridine and 2.1 cm3 of methylsulfonyl chloride are added to a solution of 9.1 g of {1-[bis-4-chlorophenyl)methyl]-3-hydroxyazetidin-3-yl}-20 (3,5-difluorophenyl)acetic acid ethyl ester in 200 cm3 of dichloromethane. The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction mixture is washed three times with 250 cm3 of distilled water and then dried with magnesium 25 sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40°C. The residue obtained is taken up hot with 50 cm3 of isopropyl ether and then left at a 222 temperature in the region of 20°C for about 12 hours. The white suspension obtained is filtered on sintered glass, washed with 20 cm3 of petroleum ether and then dried under vacuum under reduced pressure (0.27 kPa) at 5 a temperature in the region of 40°C for 2 hours. 7.9 g of {1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-(3,5-difluorophenyl)acetic acid ethyl ester are thus obtained in the form of a cream-colored powder [1H NMR spectrum (300 MHz, CDC13, 5 in ppm) : 1.25 (t, J = 7 Hz : 10 3H); 3.85 (mt : 2H); 4.12 (AB, J = 7.5 Hz : 2H); 4.23 (mt : 2H); 4.51 (s : 1H); from 6.65 to 6.80 (mt : 3H); from 7.20 to 7.40 (mt : 8H)]. {1-[Bis(4-chlorophenyl)methyl]-3-hydroxyazetidin-3-yl}-(3,5-difluorophenyl)acetic acid 15 ethyl ester may be prepared in the following manner: 34.54 cm3 of a 1.6 M butyllithium solution in hexane are added dropwise over 15 minutes to a solution of 7.73 cm3 of diisopropylamine in 125 cm3 of anhydrous tetrahydrofuran under an inert nitrogen atmosphere at a 20 temperature in the region of -70°C, the stirring is maintained at this temperature for 45 minutes, a solution of 11.01 g of ethyl 3,5-difluorophenylacetate in 85 cm3 of anhydrous tetrahydrofuran are added over 15 minutes, the stirring is continued for 1 hour at 25 -78°C, 16.84 g of 1-[bis(4-chlorophenyl)methyl]- azetidin-3-one in 90 cm3 of anhydrous tetrahydrofuran are added, the stirring is continued for 1 hour at -70°C, 300 cm3 of a saturated ammonium chloride solution 223 are added over 30 minutes at 0°C with vigorous stirring, the reaction mixture is separated after settling after 12 hours, the organic phase is washed 3 times with a saturated sodium bicarbonate solution, 5 dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a column 70 mn in diameter filled with 2000 cm3 of fine silica (0.040-0.063 mm) under a pressure of 0.7 bar 10 with a dichloromethane-ethyl acetate (99-01 by volume) mixture. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C for 2 hours. 9.1 g of {1-[bis(4-chlorophenyl)methyl]-3-hydroxyazetidin-3-15 yl}-(3,5-difluorophenyl)acetic acid ethyl ester are thus obtained in the form of a cream-colored solid [1H NMR spectrum (300 MHz, CDCI3, 5 in ppm): 1.25 (t, J = 7 Hz : 3H); 2.87 (d, J = 8 Hz : 1H); 3.07 (d, J = 8 Hz : 1H); (broad d, J = 8 Hz : 1H); 3.28 (broad d, J = 2 0 8 Hz : 1H); 4.12 (s : 2H); 4.21 (mt : 2H); 4.3 6 (s : 1H); 6.78 (tt, J = 9 and 2.5 Hz : 1H); 6.98 (mt : 2H) ; from 7.20 to 7.40 (mt : 8H)].
Ethyl 3,5-difluorophenylacetate may be prepared in the following manner: 20.4 cm of 25 triethylamine and then 27.6 g of 3,5-difluorophenylacetic acid chloride in solution in 60 cm3 of dichloromethane are successively added to a solution of 12 cm3 of ethanol in 300 cm3 of anhydrous 224 dichloromethane at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction mixture is successively washed with twice 150 cm3 of a 5 decinormal solution of hydrochloric acid and then with twice 150 cm3 of a saturated sodium bicarbonate solution. The organic phase is dried with magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the 10 region of 40°C. 29 g of ethyl 3,5-difluorophenyl acetate are thus obtained in the form of a yellow oil. 3,5-Difluorophenylacetic acid chloride may be prepared in the following manner: 19.3 cm3 of oxalyl chloride and then a few drops of dimethylformamide are 15 successively added to a solution of 25 g of 3,5-difluorophenylacetic acid in 350 cm3 of 1,2-dichloroethane at a temperature in the region of 20°C, after stirring for 3 hours at a temperature in the region of 20°C, 30 cm3 of oxalyl chloride and a then 20 few drops of dimethylformamide are again successively added. The reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40°C. 27.6 g of 3,5-difluorophenylacetic acid chloride are thus obtained in the form of a yellow 25 oil.
Example 7 9 (RS)-1-[Bis(4-chlorophenyl)methyl]—3—[1—(3,5 — difluorophenyl)-1-methylsulfonylethyl]azetidine is 225 obtained in the following manner: 0.5 cm3 of a 2 M solution of lithium diisopropylamide is added to a solution of 0.5 g of (RS)-1-[bis(4-chlorophenyl)-methyl)]-3-[(3,5-difluorophenyl)(methylsulfonyl)-5 methyl]azetidine in 10 cm3 of tetrahydrofuran cooled to -78°C and maintained under an inert atmosphere. The temperature is allowed to rise to -20°C and then 0.06 cm3 of iodomethane is added. The temperature is allowed to rise to 0°C over a period of 2 hours and 10 then 20 cm3 of a saturated aqueous ammonium chloride solution are added. The reaction medium is separated after settling and the aqueous phases are extracted with twice 20 cm3 of ethyl acetate. The organic extracts are combined, dried over magnesium sulfate and 15 evaporated to dryness at 40°C under 2.7 kPa, providing 550 mg of cream-colored residue. The residue is chromatographed on a silica column (Dynamax, reference 83-121-C, size 21.4 mm x 250 mm, precolumn 21.4 mm x 50 mm, reference R00083121G, 8 p silica, porosity 20 60 Angstroem; Rainin Instrument Co. Inc., Mac Road, Woburn, MA 01801, USA), eluting with a heptane: isopropanol (99:1 by volume) mixture at 15 cm3 per minute (detection 254 nm, 10-cm3 fractions). The fractions containing the compound with an Rf=32/77 25 (cyclohexane:ethyl acetate 70:30, 254 nm, silica plates reference 1.05719, Merck KGaA, 64271 Darmstadt, Germany) are combined and evaporated at 40°C under 2.7 kPa, providing 80 mg of 1-[bis(4-chlorophenyl)- 226 methyl]-3-f1-(3,5-difluorophenyl)-1-methylsulfonylethyl ] azetidine in the form of a white amorphous powder [1H NMR spectrum (300 MHz, CDCI3, 8 in ppm) : 2.05 (s : 3H); 2.54 (s : 3H); 2.63 (t, J = 7.5 Hz : 1H); 3.17 5 (broad t, J = 8 Hz : 1H); 3.32 (mt : 1H); 3.44 (broad t, J = 8 Hz : 1H); 3.71 (mt : 1H); 4.27 (s : 1H) ; 6.83 (tt, J = 9 and 2.5 Hz : 1H); 7.15 (mt : 2H); from 7.20 to 7.40 (mt : 8H)].
Example 80 (RS)-1-[Bis(4-fluorophenyl)methyl]- 3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine may be prepared in the following manner: a few granules of potassium iodide are added to a suspension of 0.191 cm3 of bis(4-fluorophenyl)chloromethane, 300 mg of 15 (RS)-3-[(3,5-difluorophenyl)methylsulfonylmethyl]- azetidine and 167 mg of potassium carbonate in 5 cm3 of acetonitrile, at a temperature in the region of 20°C. After 48 hours at a temperature in the region of 20°C, the reaction medium is filtered on sintered glass, the 20 solid is rinsed with acetonitrile and the filtrate is purified by preparative thin-layer chromatography on silica [3 preparative Merck Kieselgel 60F254 plates, 20x20 cm; thickness 1 mm], eluting with a methanol-dichloromethane (1-99 by volume) mixture. After elution 25 of the zone corresponding to the desired product with a methanol-dichloromethane (10-90 by volume) mixture, filtration on sintered glass and then evaporation of the solvents under reduced pressure at a temperature in 227 the region of 40°C, 39 mg of (RS)-1-[bis(4-fluorophenyl )methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl ] azetidine are obtained in the form of a yellow foam [1H NMR spectrum (300 MHz, CDC13, 5 in ppm): 2.54 5 (broad t, J = 7 Hz : 1H) ; 2.66 (s : 3H) ; 3.18 (mt : 2H); from 3.20 to 3.45 (mt : 1H); 3.63 (broad t, J = 7 Hz : 1H); 4.27 (s : 1H); 4.28 (d, J = 11 Hz : 1H); 6.83 (tt, J = 9 and 2 Hz : 1H); from 6.90 to 7.05 (mt : 6H); from 7.25 to 7.40 (mt : 4H)]. 10 (RS)-3-[(3,5-Difluorophenyl)methylsulfonyl methyl ] azetidine hydrochloride may be prepared may be prepared in the following manner: a suspension of 8.5 g of l-benzhydryl-3-[(3,5-difluorophenyl)(methylsulfonyl methylene]azetidine and 1.3 g of palladium hydroxide 15 (20% by weight of palladium), in 600 cm3 of methanol, 20 cm3 of 1 N hydrochloric acid and 4 cm3 of acetic acid, is stirred at a temperature in the region of 20°C under a hydrogen atmosphere (1.5 bar) until complete absorption of a volume of 2.1 liters of hydrogen is 20 obtained. The reaction medium is then filtered on sintered glass covered with charcoal. The filtrate is concentrated to dryness under reduced pressure and then the residue obtained is taken up in ethanol. The crystallized white product is filtered and dried. 5.4 g 25 of (RS)-3-[(3,5-difluorophenyl)methylsulfonylmethyl] azetidine hydrochloride are thus obtained in the form of white crystals. 228 l-Benzhydryl-3-[(3,5-difluorophenyl)(methylsulf onyl ) methylene] azetidine may be prepared may be prepared in the following manner: a mixture of 18.8 g of 3-acetoxy-l-benzhydryl-3-[(3,5-difluorophenyl)-5 (methylsulfonyl)methyl]azetidine and 3.9 g of lithium hydroxide monohydrate in 120 cm3 of acetonitrile is heated at a temperature in the region of 70°C for 3 hours. After cooling to a temperature in the region of 2°C, 120 cm3 of tert-butyl and methyl ether and 10 80 cm3 of distilled water are successively added followed, slowly, by 5 cm3 of acetic acid. After decantation, the organic phase is washed with 80 cm3 of a saturated aqueous sodium hydrogen carbonate solution, 80 cm3 of distilled water, 80 cm3 of a saturated aqueous 15 sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue obtained is taken up in ethanol. After leaving overnight at a temperature in the region of 20°C, the mixture obtained is filtered on sintered 20 glass, the white crystals obtained are rinsed with ethanol, diisopropyl ether and dried under reduced pressure at a temperature in the region of 45°C. 14.6 g of l-benzhydryl-3-[(3,5-difluorophenyl)(methylsulf onyl ) methylene] azetidine are thus obtained in the 25 form of white crystals. 3-Acetoxy-l-benzhydryl-3-[(3,5-difluorophenyl ) methylsulf onyl ) methyl ] azetidine may be prepared may be prepared in the following manner: 47.1 cm3 of 229 I.6 N n-butyllithium in solution in hexane are added dropwise over approximately 25 minutes to a suspension of 12.37 g of 3,5-difluorobenzyl methyl sulfone in 200 cm3 of tetrahydrofuran, under an inert nitrogen atmosphere at a temperature in the region of -30°C. The cloudy yellow solution is stirred at a temperature in the region of -30°C for 2 hours and then a solution of II.87 g of l-benzhydrylazetidin-3-one in 75 cm3 of dichloromethane is added dropwise. The reaction mixture is stirred for 1.5 hours at a temperature in the region of -30°C and then 6.07 cm3 of acetyl chloride are added and the temperature of the medium is allowed to return to a temperature in the region of -10°C over about 30 minutes. 200 cm3 of water and 100 cm3 of 15 dichloromethane are added. After stirring vigorously for 30 minutes and decantation, the organic phase is washed with 3 times 150 cm3 of a saturated aqueous sodium hydrogen carbonate solution, 150 cm3 of a saturated aqueous sodium chloride solution, dried over 20 magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crystalline residue obtained is taken up in 50 cm3 of boiling ethanol. The white suspension obtained is allowed to stand overnight at a temperature in the region of 20°C and then the 25 solid obtained is drained over sintered glass, rinsed with diisopropyl ether and dried under reduced pressure at a temperature in the region of 50°C. 19.5 g of 3-acetoxy-l-benzhydryl-3-[(3,5-difluorophenyl)(methyl- 230 sulfonyl)methyl]azetidine are thus obtained in the form of white crystals. l-Benzhydrylazetidin-3-one may be prepared according to the procedure described by KATRITZKY A.R. et al. in J. Heterocycl. Chem., 271 (1994). 3,5-Difluorobenzyl methyl sulfone may be prepared may be prepared in the following manner: a mixture of 66.69 cm3 of 3,5-difluorobenzyl bromide, 71.97 g of the sodium salt of methanesulfinic acid and 10 150 mg of sodium iodide in 625 cm3 of ethanol is heated under reflux, under an argon atmosphere, for about 16 hours. After cooling to a temperature in the region of 20°C, the reaction medium is diluted with 3 liters of ethyl acetate, washed with 500 cm3 of water, 500 cm3 15 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (50 mbar) at a temperature in the region of 40°C. The residue obtained is taken up in 300 cm3 of ethyl ether, and the solid is filtered on 20 sintered glass, rinsed with 200 cm3 of ethyl ether, dried under reduced pressure at a temperature in the region of 20°C. 86 g of 3,5-difluorobenzyl methyl sulfone are thus obtained in the form of a white powder. 2 5 Example 81 (RS)-{1-[(3-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine may be prepared in the following manner: a mixture of 231 47 mg of 3-(pyridyl)-(4-chlorophenyl)bromomethane, 50 mg of (RS)-3-[(3,5-difluorophenyl)methylsulfonylmethyl ] azetidine hydrochloride and 58 mg of potassium carbonate in 2 cm3 of acetonitrile, is stirred for about 5 3 hours at a temperature in the region of 20°C, for 2 hours at the reflux temperature of the solvent, for about 16 hours at a temperature in the region of 20°C and then for 1.5 hours at the reflux temperature of the solvent. A few granules of potassium iodide are then 10 added and the reaction mixture is maintained for about 2 hours at the reflux temperature of the solvent. After cooling to a temperature in the region of 20°C, the reaction medium is purified by preparative thin-layer chromatography on silica [2 preparative Merck Kieselgel 15 60F254 plates; 20x20 cm; thickness 0.5 mm], eluting with a methanol-dichloromethane (2.5-97.5 by volume) mixture. After elution of the zone corresponding to the desired product with a methanol-dichloromethane (10-90 by volume) mixture, filtration on sintered glass 20 and then evaporation of the solvents under reduced pressure at a temperature in the region of 40°C, 11 mg of (RS)-{1-[(3-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine are obtained in the form of a colorless lacquer [1H NMR 25 spectrum (300 MHz, CDC13, 5 in ppm): 2.59 (mt : 1H); 2.66 (s : 3H); 3.21 (mt : 2H); from 3.30 to 3.50 (mt : 1H); 3.67 (mt : 1H); 4.28 (broad d, J = 11 Hz : 1H); 4.32 (broad s : 1H); 6.84 (tt, J = 9 and 2 Hz : 1H); 232 6.95 (mt : 2H); 7.19 (broad dd, J = 8 and 5 Hz : 1H); from 7.20 to 7.40 (mt : 4H); 7.64 (broad d, J = 8 Hz : 1H); 8.45 (mt : 1H); 8.59 (very broad s : 1H]. (3-Pyridyl)-(4-chlorophenyl)bromomethane may 5 be prepared in the following manner: a mixture of 150 mg of (3-pyridyl)-(4-chlorophenyl)methanol in 0.356 cm3 of hydrobromic acid (at 33% in acetic acid) and 0.101 cm3 of acetyl bromide is heated under reflux for 1 hour and then left at a temperature in the region 10 of 20°C for 2 hours, before being concentrated under reduced pressure and coevaporated with a few cm3 of toluene. 234 mg of (3-pyridyl)-(4-chlorophenyl)-bromomethane are thus obtained in the form of a gummy beige solid. (3-Pyridyl)-(4-chlorophenyl)methanol may be prepared in the following manner: 0.5 cm3 of 3-pyridinecarboxaldehyde is slowly added to a solution of 5.83 cm3 of 4-chlorophenylmagnesium bromide (1 M solution in ethyl ether) in 5 cm3 of tetrahydrofuran, 20 under an inert argon atmosphere. After about 3 hours, 3 cm3 of a saturated aqueous ammonium chloride solution and 10 cm3 of water are added to the reaction medium. After stirring for 5 minutes at a temperature in the region of 20°C, the reaction medium is acidified to a 25 pH of about 2 with a 1 N aqueous hydrochloric acid solution. The aqueous phase is extracted with 3 times 15 cm3 of dichloromethane. The remaining aqueous phase is treated with 10 cm3 of a 1 N aqueous sodium hydroxide 233 solution and reextracted with 3 times 15 cm3 of ethyl acetate. The organic phases containing the ethyl acetate are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. 466 mg of (3-pyridyl)-(4-chlorophenyl)methanol are thus obtained in the form of a bright yellow solid.
Example 82 (RS)-{1-[(4-Pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine 10 may be prepared in the following manner: a mixture of 160 mg of (4-(pyridyl)-(4-chlorophenyl)bromomethane, 169 mg of (RS)-3-[(3,5-difluorophenyl)methylsulfonylmethyl ] azetidine hydrochloride and 94 mg of potassium carbonate in 5 cm3 of acetonitrile, is stirred for about 15 17 hours at a temperature in the region of 20°C. A few granules of sodium iodide are then added and after stirring for 2 hours at a temperature in the region of 20°C, the reaction mixture is maintained for about 1.5 hours at the reflux temperature of the solvent. 20 After cooling to a temperature in the region of 20°C, the reaction medium is purified by preparative thin-layer chromatography on silica [4 preparative Merck Kieselgel 60F254 plates; 20x20 cm; thickness 0.5 mm], eluting with a methanol-dichloromethane (2.5-97.5 by 25 volume) mixture. After elution of the zone corresponding to the desired products with a methanol-dichloromethane (10-90 by volume) mixture, filtration on sintered glass and then evaporation of the solvents 234 under reduced pressure at a temperature in the region of 40°C, there are obtained a first mixture of diastereoisomers, that is to say 24 mg of (RS)—{1— [(4-pyridyl)-(4-chlorophenyl)methyl]-5 3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine in the form of a yellow lacquer, and a second mixture of diastereoisomers, that is to say 31 mg of (RS)-{1-[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine in 10 the form of a yellow foam. The first mixture of diastereoisomers has the characteristics are the following [XH NMR spectrum (300 MHz, CDCI3, 5 in ppm) : 2.62 (t, J = 7 Hz : 1H); 2.67 (s : 3H); 3.21 (broad t, J = 7 Hz : 2H); 3.42 (mt : 1H); 3.70 (broad t, 15 J = 7 Hz : 1H); 4.28 (s : 1H); 4.28 (d, J = 11 Hz : 1H); 6.85 (tt, J = 9 and 2.5 Hz : 1H); 6.97 (mt : 2H) ; from 7.20 to 7.35 (mt : 6H); 8.52 (dd, J = 4.5 and 1.5 Hz : 2H) .
The second mixture of diastereoisomers has 20 the characteristics are the following [1H NMR spectrum (300 MHz, CDCI3, 8 in ppm) : 2.59 (t, J = 7 Hz : 1H) ; 2.67 (s : 3H); 3.26 (mt : 2H); from 3.35 to 3.50 (mt : 1H); 3.63 (broad t, J = 7 Hz : 1H); 4.28 (s : 1H); 4.28 (d, J = 11 Hz : 1H); 6.85 (tt, J = 9 and 2 Hz : 1H); 25 6.97 (mt : 2H); from 7.20 to 7.40 (mt : 6H); 8.50 (dd, J = 4.5 and 1.5 Hz : 2H). (4-Pyridyl)-(4-chlorophenyl)bromomethane may be prepared in the following manner: a solution of 235 100 mg of (4-pyridyl)-(4-chlorophenyl)methanol in 0.24 cm3 of hydrobromic acid (at 33% in acetic acid) is heated under reflux for 1 hour and then allowed to return to a temperature in the region of 20°C. 0.675 cm3 5 of acetyl bromide is then added and the reaction mixture is heated under reflux for 1.5 hours and then allowed to return to a temperature in the region of 20°C before being concentrated under reduced pressure. 163 mg of (4-pyridyl)-(4-chlorophenyl)bromomethane are 10 thus obtained in the form of a beige foam-gum. (4-Pyridyl)-(4-chlorophenyl)methanol may be prepared in the following manner: 348 mg of sodium tetraborohydride are added, at a temperature in the region of 20°C, to a solution of 2 g of 15 4-(4-chlorobenzoyl)pyridine in 160 cm3 of ethanol. After stirring for 2 hours at a temperature in the region of 20°C, 90 mg of sodium tetraborohydride are added. After about 1.5 hours at the same temperature, the reaction medium is diluted with 200 cm3 of dichloromethane and 20 200 cm3 of water. The pH of the aqueous phase is adjusted to a value of about 5 by addition of about 13 cm3 of an aqueous 1 N hydrochloric acid solution. After decantation, the aqueous phase is extracted with 3 times 100 cm3 of dichloromethane. The organic phases 25 are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. 2 g of (4-pyridyl)-(4-chlorophenyl)methanol are thus obtained in the form of a white powder. 236 Example 83 (RS)-{1-[(2-Chloropyrid-5-yl)-(4-chlorophenyl )methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl ] azetidine may be prepared in the following manner: a mixture of 300 mg of (2-chloropyrid-5-yl)-(4-chlorophenyl)bromomethane, 225 mg of (RS)-3-[(3,5-difluorophenyl)methylsulfonylmethyl]-azetidine hydrochloride, 125 mg of potassium iodide and 521 mg of potassium carbonate in 5 cm3 of acetonitrile, 10 is heated for about 2 hours at the reflux temperature of the solvent. After cooling to a temperature in the region of 20°C, the reaction medium is filtered on sintered glass. The solid residue is rinsed with dichloromethane and the filtrates are evaporated under 15 reduced pressure. 402 mg of a chocolate foam are thus obtained, which foam is purified by preparative thin-layer chromatography on silica [4 preparative Merck Kieselgel 60F254 plates; 20x20 cm; thickness 0.5 mm], eluting with a methanol-dichloromethane (2.5-97.5 by 20 volume) mixture. After elution of the zone corresponding to the desired product with a methanol-dichloromethane (10-90 by volume) mixture, filtration on sintered glass and then evaporation of the solvents under reduced pressure at a temperature in the region 25 of 40°C, there are obtained a first mixture of diastereoisomers, that is to say 14 mg of (RS)-{l-[(2- chloropyrid-5-yl)-(4-chlorophenyl)methyl]- 3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine 237 in the form of a brown foam, and a second mixture of diastereoisomers, that is to say 10 mg of (RS)-{1-[(2-chloropyrid-5-yl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine 5 in the form of a beige foam.
The first mixture of diastereoisomers has the characteristics are the following: [1H NMR spectrum (300 MHz, CDC13, 5 in ppm): 2.57 (t, J = 7.5 Hz : 1H) ; 2.65 (s : 3H); from 3.15 to 3.30 (mt : 2H); 3.40 (mt : 1H); 10 3.63 (broad t, J = 7.5 Hz : 1H); 4.27 (d, J = 11 Hz : 1H) ; 4.31 (s : 1H) ; 6.8 4 (tt, J = 9 and 2 Hz : 1H) ; 6.95 (mt : 2H); from 7.20 to 7.35 (mt : 5H); 7.63 (dd, J = 8 and 2.5 Hz : 1H); 8.38 (d, J = 2.5 Hz : 1H).
The second mixture of diastereoisomers has 15 the characteristics are the following: [1H NMR spectrum (300 MHz, CDCI3, 5 in ppm): 2.57 (t, J = 7.5 Hz : 1H) ; 2.64 (s : 3H); 3.18 (broad t, J = 7.5 Hz : 2H); 3.38 (mt : 1H); 3.63 (broad t, J = 7.5 Hz : 1H); 4.24 (d, J = 11.5 Hz : 1H); 4.29 (s : 1H); 6.83 (tt, J = 9 and 20 2 Hz : 1H); 6.94 (mt : 2H); 7.20 (d, J = 8 Hz : 1H) ; from 7.20 to 7.35 (mt : 4H); 7.59 (dd, J = 8 and 2.5 Hz : 1H); 8.34 (d, J = 2.5 Hz : 1H). 2-(Chloropyrid-5-yl)-(4-chlorophenyl)bromomethane may be prepared in the following manner: 25 0.153 cm3 of thionyl bromide is added to a solution of 100 mg of (2-chloropyrid-5-yl)-(4-chlorophenyl)methanol in 2 cm3 of carbontetrachloride, under an inert argon atmosphere, at a temperature in the region of 0°C. 238 After 3.5 hours at a temperature in the region of 0°C, the reaction medium is concentrated under reduced pressure and coevaporated with a few cm3 of toluene. 1.3 g of a brown liquid are thus obtained, which liquid 5 is taken up in dichloromethane and supplemented with water and sodium dithionite. After decantation, the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. 0.33 g of 2-(chloropyrid-5-yl)-(4-chlorophenyl)bromo-10 methane is thus obtained in the form of a brown oil. 2-(Chloropyrid-5-yl)-(4-chlorophenyl)bromomethane may be prepared by carrying out the procedure in a manner similar to Example 84, starting with 22.5 cm3 of 4-chlorophenylmagnesium bromide (1 M 15 solution in ethyl ether) in 30 cm3 of tetrahydrofuran, under an inert argon atmosphere, and 2.9 g of 2-chloropyridine-5-carboxaldehyde in 30 cm3 of tetrahydrofuran. 3.42 g of 2-(chloropyrid-5-yl)-(4-chlorophenyl)methanol are thus obtained in the form 20 of a pale green powder. 2-Chloropyridine-5-carboxaldehyde may be prepared according to the following reference: G. Pandey, T.D. Bagul, A.K. Sahoo, J. Org. Chem., 1998, 63, 760-768. 2 5 Example 84 (RS)-5-((4-chlorophenyl)-{3-[(3,5-difluorophenyl) methylsulfonylmethyl] azetidin-l-yl }methyl ) pyrimidine may be prepared in the following 239 manner: a mixture of 50 mg of 5-[bromo-(4-chlorophenyl)methyl]pyrimidine, 52.6 mg of (RS)-3-[(3,5-difluorophenyl)methylsulfonylmethyl]-azetidine hydrochloride, 44 mg of potassium iodide and 5 73 mg of potassium carbonate in 2 cm3 of acetonitrile, is heated for about 5 hours at the reflux temperature of the solvent. After cooling to a temperature in the region of 20°C, the reaction medium is purified by direct deposition on preparative thin-layer 10 chromatography on silica [2 preparative Merck Kieselgel 60F254 plates; 20x20 cm; thickness 0.5 mm], eluting with a methanol-dichloromethane (2.5-97.5 by volume) mixture. After elution of the zone corresponding to the desired product with a methanol-dichloromethane 15 (10-90 by volume) mixture, filtration on sintered glass and then evaporation of the solvents under reduced pressure at a temperature in the region of 40°C, there are obtained a first mixture of diastereoisomers, that is to say 8 mg of (RS)-5-((4-chlorophenyl)-{3-20 [(3,5-difluorophenyl)methylsulfonylmethyl]azetidin-l-yl }methyl)pyrimidine in the form of a yellow foam, and a second mixture of diastereoisomers, that is to say 6 mg of (RS)-5-((4-chlorophenyl)-{3-[(3,5-difluorophenyl )methylsulfonylmethyl]azetidin-l-yl}methyl)-25 pyrimidine in the form of a yellow foam.
The first mixture of diastereoisomers has the characteristics are the following: [ 1H NMR spectrum (300 MHz, CDCI3, 8 in ppm): 2.60 (broad t, J = 7 Hz : 240 1H); 2.66 (s : 3H); 3.24 (broad t, J = 7 Hz : 2H); 3.41 (mt : 1H); 3.66 (broad t, J = 7 Hz : 1H); 4.28 (d, J = 11.5 Hz : 1H); 4.33 (broad s : 1H); 6.84 (broad t, J = 9 Hz : 1H); 6.95 (mt : 2H); from 7.25 to 7.35 (mt : 5 4H); 8.71 (broad s : 2H); 9.08 (broad s : 1H).
The second mixture of diastereoisomers has the characteristics are the following: [1H NMR spectrum (300 MHz, CDCI3, 5 in ppm): 2.61 (t, J = 7 Hz : 1H); 2.66 (s : 3H); 3.24 (broad t, J = 7 Hz : 2H); 3.43 10 (mt : 1H); 3.65 (broad t, J = 7 Hz : 1H) ; 4.28 (d, J = 11.5 Hz : 1H); 4.33 (s : 1H); 6.85 (tt, J = 9 and 2 Hz : 1H); 6.96 (mt : 2H); from 7.25 to 7.35 (mt : 4H); 8.69 (s : 2H); 9.06 (s : 1H).
-[Bromo-(4-chlorophenyl)methyl]pyrimidine 15 may be prepared in the following manner: 0.36 cm3 of thionyl bromide is added to a solution of 205 mg of (4-chlorophenyl)pyrimidin-5-ylmethanol in 1 cm3 of carbontetrachloride, and 1 cm3 of dichloromethane, under an inert argon atmosphere, at a temperature in the 20 region of 0°C. After 2.5 hours at a temperature in the region of 0°C, the reaction medium is brought to a temperature in the region of 20°C, concentrated under reduced pressure and coevaporated with a few cm3 of toluene. The brown liquid obtained is taken up in 10 cm3 25 of dichloromethane, washed with 5 cm3 of a saturated aqueous sodium dithionite solution and then with water. After decantation, the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness 241 under reduced pressure. 227 mg of a beige viscous liquid are thus obtained, which liquid is taken up in a minimum quantity of dichloromethane and purified by preparative thin-layer chromatography on silica [2 5 preparative Merck Kieselgel 60F254 plates; 20x20 cm, thickness 0.5 mm], eluting with a methanol-dichloromethane (2.5-97.5 by volume) mixture. After elution of the zone corresponding to the desired product with a methanol-dichloromethane (10-90 by 10 volume) mixture, filtration on sintered glass and then evaporation of the solvents under reduced pressure at a temperature in the region of 40°C, 51 mg of 5-[bromo-(4-chlorophenyl)methyl]pyrimidine are obtained in the form of a yellow foam. 15 4-(Chlorophenyl)pyrimidin-5-ylmethanol may be prepared by carrying out the procedure in a manner similar to Example 83, 2.5 cm3 of n-butyllithium (1.6 M solution in hexane) are added dropwise to a solution of 636 mg of 5-bromopyrimidine in 10 cm3 of 20 tetrahydrofuran, under an inert argon atmosphere, at a temperature in the region of -78°C. After 10 minutes at a temperature in the region of -78°C, a solution of 562 mg of 4-chlorobenzaldehyde in 1 cm3 of tetrahydrofuran is added dropwise. After stirring for 25 30 minutes at a temperature in the region of -78°C, the temperature of the reaction medium is allowed to rise slowly to a temperature in the region of 20°C, and 15 cm3 of a saturated aqueous ammonium chloride 242 solution, 60 cm3 of ethyl acetate and 10 cm3 of water are added successively. The aqueous phase is extracted with 15 cm3 of ethyl acetate, the organic phases are combined, dried over magnesium sulfate, filtered on 5 sintered glass and concentrated under reduced pressure (20 mbar) at a temperature in the region of 44°C. The bulk of the orange-colored oil obtained (1.09 g) is purified by chromatography on a column 30 mn in diameter filled with 60 g of medium silica 10 (0.063-0.200 mm) at atmospheric pressure, eluting with a methanol/dichloromethane (0/100 to 7/93 by volume) gradient. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure. 293 mg of 4-(chlorophenyl)pyrimidin-15 5-yl)methanol are thus obtained in the form of a yellow oil.
Example 85 The phenolic ester of 4-({1-[bis(4-chlorophenyl ) methyl]azetidin-3-ylidene}methylsulfonylmethyl) -20 3,6-dihydro-2H-pyridine-l-carbothioic acid may be prepared in the following manner: 0.140 g of 4-dimethylaminopyridine and then 0.042 cm3 of methanesulfonyl chloride are added to a solution of 0.23 g of the phenolic ester of 4-({1-bis(4-chloro-25 phenyl)methyl]-3-hydroxyazetidin-3-yl}methylsulfonylmethyl )-3,6-dihydro-2H-pyridine-l-carbothioic acid in 5 cm3 of dichloromethane. The reaction mixture is stirred for 20 hours at 20°C and then diluted with 243 cm3 of water. After decantation, the organic phase is successively washed with 100 cm3 of water and 100 cm3 of a saturated NaCl solution, dried over magnesium sulfate and then concentrated to dryness at 40°C under 2.7 kPa.
The oil obtained is triturated for 45 minutes in 50 cmJ of diisopropyl ether. The solid formed is filtered, providing 120 mg of the phenolic ester of 4-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methylsulfonylmethyl)-3,6-dihydro-2H-pyridine-10 1-carbothioic acid in the form of a beige solid melting at 184°C [1H NMR spectrum (400 MHz, CDCI3, 5 in ppm) : 2.53 (unresolved complex: 2H); 2.95 (s : 3H); 3.90 (unresolved complex: 2H); 4.04 (t, J = 5.5 Hz : 1H); 4.24 (mt : 3H); 4.49 (unresolved complex: 2H); 4.60 15 (mt : 1H); 5.90 (unresolved complex: 1H); from 7.05 to 7.50 (mt : 13H)].
The phenolic ester of 4-({1-[bis(4-chlorophenyl )methyl]-3-hydroxyazetidin-3-yl}methyl-sulfonylmethyl)-3,6-dihydro-2H-pyridine-l-carbothioic 20 acid is prepared in the following manner: 0.52 g of potassium tert-butoxide is added to a mixture of 0.72 g of the phenolic ester of 4-methylsulfonylmethyl-3,6-dihydro-2H-pyridine-l-carbothioic acid and 0.708 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one in 15 cm3 25 of dry tetrahydrofuran cooled under an inert atmosphere to -78°C. The reaction mixture is stirred at -78°C for 4 hours and then 0.354 g of 1-[bis(4-chlorophenyl)-methyl]azetidin-3-one are added. After two hours at 244 -78°C, the temperature is allowed to return to 20°C. The reaction mixture is diluted in 100 cm3 of water and then the tetrahydrofuran is evaporated off under 2.7 kPa at 40°C. The aqueous phase is extracted with 5 twice 100 cm3 of ethyl acetate. The organic extracts are combined and dried over magnesium sulfate, concentrated under 2.7 kPa at 40°C. The residue obtained is chromatographed on silica (200 g of silica, Amicon, 20-45 (J.m, porosity 60Angstroem, column 5 cm in 10 diameter), eluting with a cyclohexane:ethyl acetate (6:4 by volume) mixture. The fractions with an Rf=ll/64 (cyclohexane:ethyl acetate 6:4, silica plate, Merck reference 1.05719, Merck KGaA, 64721 Darmstatd, Germany) are combined and concentrated under 2.7 kPa at 15 40°C to give 240 mg of the phenolic ester of 4-({1-[bis(4-chlorophenyl)methyl]-3-hydroxyazetidin-3-ylJmethylsulfonylmethyl)-3,6-dihydro-2H-pyridine-l-carbothioic acid.
The phenolic ester of 4-methylsulfonylmethyl-20 3,6-dihydro-2H-pyridine-l-carbothioic acid may be prepared in the following manner: 0.77 8 cm3 of phenyl thiochloroformate is added to a solution of 1 g of l-benzyl-4-methylsulfonylmethyl-l,2,3,6- tetrahydropyridine in 10 cm3 of dichloromethane under an 25 argon atmosphere. The solution instantly acquires a very dark amber color. The reaction mixture is stirred for 4 hours at 21°C and then diluted in 100 cm3 of dichloromethane. The organic medium is washed with 245 twice 50 cm3 of water, dried over magnesium sulfate and evaporated to dryness at 40°C under 2.7 kPa. The residue obtained is purified by chromatography on a silica cartridge (reference SIL-020-005, FlashPack, 5 Jones Chromatography Limited, New Road, Hengoed, Mid Glamorgan, CF82 8AU, Great Britain), eluting with a cyclohexane:ethyl acetate 6:4 mixture (10 cm3/min, 5-cm3 fractions). The fractions with an Rf=12/74 (cyclohexane:ethyl acetate 1:1, silica plate, Merck 10 reference 1.05719, Merck KGaA, 64271 Darmstatd, Germany) are combined and concentrated under 2.7 kPa at 40°C to give 700 mg of the phenolic ester of 4-methylsulfonylmethyl-3,6-dihydro-2H-pyridine-l-carbothioic acid. 15 1-Benzy1-4-methylsulfonylmethyl-1,2,3,6- tetrahydropyridine may be prepared in the following manner: a solution of 5.14 g of sodium borohydride and 25 g of sodium carbonate in 700 cm3 of water is added dropwise over one hour, without exceeding a temperature 20 of 5°C in the reaction medium, to a solution of 17.6 g of l-benzyl-4-methylsulfonylmethylpyridinium bromide in 700 cm3 of water cooled to 5°C. The reaction medium is stirred for four hours at 0°C and then the temperature is allowed to return to room temperature overnight. The 25 yellow solid formed is isolated by filtration and dried under 2.7 kPa, giving 9.6 g of l-benzyl-4-methylsulfonylmethyl-1,2,3,6-tetrahydropyridine having an Rf of 44/81 (dichloromethane:methanol, 95:5 by 246 volume, silica plate, Merck reference 1.05719, Merck KGaA, 64271 Darmstatd, Germany). 1-Benzyl-4-methylsulfonylmethylpyridinium bromide may be prepared in the following manner: 14 cm3 5 of benzyl bromide are added to a solution of 10 g of 4-methylsulfonylmethylpyridine in 200 cm3 of acetonitrile and then the mixture is heated under reflux for 3 hours and is then allowed to return to room temperature overnight. The solid formed is 10 filtered, dried under vacuum at 2.7 kPa, giving 17.6 g of l-benzyl-4-methylsulfonylmethylpyridinium bromide. 4-Methylsulfonylmethylpyridine may be prepared in the following manner: 14 g of sodium hydroxide pellets and then 35.7 g of sodium 15 methanesulfinate are slowly added to a solution of 57.4 g of 4-chloromethylpyridine hydrochloride in 700 cm3 of ethanol. After addition, the temperature is 28°C. The reaction mixture is heated under reflux for two hours and then allowed to return to room 20 temperature overnight. The reaction medium is heated to 50°C and then filtered hot on paper. The filtrate is evaporated to dryness at 40°C under 2.7 kPa. The residue is recrystallized from 300 cm3 of isopropanol, giving 29.6 g of 4-methylsulfonylmethylpyridine. 2 5 Example 86 (RS)-l-[2-{l-[Bis(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)ethyl]-3-propylurea may be prepared by carrying out the 247 procedure in the following manner: 0.052 cm3 of n-propyl isocyanate is added to a solution of 90 mg of (RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)ethylamine in 5 cm3 of 5 tetrahydroduran. After stirring for about 72 hours at a temperature in the region of 20°C, the reaction mixture is filtered, concentrated to dryness under reduced pressure, and taken up in diisopropyl ether. The mixture obtained is filtered and concentrated to 10 dryness under reduced pressure. 80 mg of a pale yellow solid are thus obtained, which solid is dissolved in 5 cm3 of tetrahydrofuran, and to which 80 mg of scavenger resin are added. After stirring for about 18 hours at a temperature in the region of 20°C, the 15 reaction mixture is filtered and then concentrated to dryness under reduced pressure. 36 mg of a pasty solid are thus obtained, which solid is purified by chromatography under pressure on a silica cartridge, eluting with a mixture of cyclohexane and ethyl acetate 20 (50/50 by volume). Fractions 16 to 20 are combined and concentrated to dryness under reduced pressure. 6 mg of (RS)-1-[2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)ethyl]-3-propylurea are obtained in the form of an oil [1H NMR spectrum (300 MHz, CDC13, 25 8 in ppm): 0.88 (t, J = 7.5 Hz : 3H); from 1.35 to 1.60 (mt : 2H); from 2.25 to 2.55 and from 2.65 to 3.05 (2 series of mts : 6H in total); 3.04 (mt : 2H); 3.22 (mt : 1H); 3.38 (mt : 1H); 4.07 (mt: 1H); from 4.10 to 248 4.20 (mt : 1H); 4.17 (s : 1H); 6.62 (tt, J = 9 and 2.5 Hz : 1H); 6.82 (mt : 2H); from 7.20 to 7.45 (mt : 8H] .
(RS)— 2 —{1—[Bis(4-chlorophenyl)methyl]-5 azetidin-3-yl}-2-(3,5-difluorophenyl)ethylamine may be prepared by carrying out the procedure in the following manner: 1.2 g of (RS)-2-{1-[bis(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(3,5-difluorophenyl)methanesulfonic acid ethyl ester in solution in 10 cm3 of methanol and 10 then a solution of 30 cm3 of ammonia in 30 cm3 of methanol are introduced into an autoclave cooled by a bath of acetone and dry ice. The closed autoclave is shaken and heated to a temperature in the region of 60°C for 24 hours. After cooling to a temperature in 15 the region of 20°C, the ammonia is allowed to evaporate in the air, at a tempeature in the region of 20°C, and then the remaining solution is concentrated to dryness under reduced pressure. A gum is thus obtained which is triturated with ethyl ether, at a temperature in the 20 region of 20°C for about 16 hours. The insoluble matter obtained is filtered and dried in a desiccator for 3 hours. 830 mg of (RS)-2-{1-[bis(4-chlorophenyl)-methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)ethylamine are thus obtained in the form of a whitish solid. 25 (RS)-2-{l-[Bis(4-chlorophenyl)methyl]- azetidin-3-yl}-2-(3,5-difluorophenyl)methanesulfonic acid ethyl ester may be prepared by carrying out the procedure in the following manner: 0.34 cm3 of 249 methanesulfonyl chloride is added to a solution of 1.9 g of (RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)ethanol in 20 cm3 of dichloromethane, at a temperature in the region of 5 20°C. After cooling of the reaction mixture to a temperature in the region of 10°C, 0.89 cm3 of triethylamine is added. After stirring the solution for 20 hours at a temperature in the region of 20°C, 100 cm3 of water are added dropwise followed by 150 cm3 of 10 dichloromethane. The organic phase separated after settling out is washed with twice 50 cm3 of water, 50 cm3 of a saturated aqueous sodium chloride solution, 50 cm3 of water, and then dried over magnesium sulfate, filtered and evaporated to dryness under reduced 15 pressure. The yellow foam thus obtained (2 g) is purified on a silica column (particle size 0.020 -0.045 mm), at a pressure of 0.4 bar, eluting with a mixture of cyclohexane and ethyl acetate (80/20 by volume). Fractions 49 to 111 are combined and 20 concentrated to dryness under reduced pressure. 1.2 g of (RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)methanesulfonic acid ethyl ester are obtained in the form of a white foam.
Example 8 7 (RS)-N-[2-{1-[Bis(4-chlorophenyl)methyl]- azetidin-3-yl}-2-(3,5-difluorophenyl)ethyl]cyclo-propanecarboxamide may be prepared by carrying out the procedure in the following manner: 0.018 cm of 250 diisopropylcarbodiimide, 10 mg of cyclopropanecarboxylic acid, 16 mg of hydroxybenzotriazole hydrate and then 0.4 g of morpholine supported on polystyrene are added 5 successively to a solution of 90 mg of (RS)-2-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)ethylamine in 5 cm3 of tetrahydrofuran, at a temperature in the region of 20°C. The suspension obtained is stirred at a 10 temperature in the region of 20°C for 20 hours. The reaction medium is filtered and concentrated to dryness under reduced pressure. 80 mg of a pasty product are thus obtained, which product is purified by passage over an SPE cartridge (SCX phase, 1 g of phase). 76 mg 15 of a residue are thus obtained, which residue is purified by chromatography under pressure on a silica cartridge, eluting with a mixture of cyclohexane and ethyl acetate (70/30 by volume). Fractions 9 to 19 are combined and concentrated to dryness under reduced 20 pressure. 12 mg of (RS)-N-[2-{1-[bis(4-chlorophenyl)-methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)ethyl]-cyclopropanecarboxamide are obtained in the form of a colorless oil [ 1H NMR spectrum (300 MHz, CDCI3, 5 in ppm): 0.7 0 (mt : 1H); from 0.80 to 1.00 (mt : 2H); from 25 1.15 to 1.35 (mt : 1H); from 2.35 to 2.55 and from 2.70 to 3.10 (2 series of mts : 7H in total); 3.26 (mt : 1H); 3.47 (mt : 1H); 4.19 (s : 1H); 5.63 (mt : 1H); 251 6.62 (tt, J = 9 and 2.5 Hz : 1H); 6.81 (mt : 2H); from 7.20 to 7.45 (mt : 8H)].
Example 88 (RS)-N-[2-{l~[Bis(4-chlorophenyl)methyl]-5 azetidin-3-yl}-2-(3,5-difluorophenyl)ethyl]- 3-methylbutyramide may be prepared by carrying out the procedure in the following manner: 114 mg of HATU, 30.6 mg of isovaleric acid and then 0.2 g of morpholine supported on polystyrene are added to a solution of 10 45 mg of (RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)ethylamine in 5 cm3 of tetrahydrofuran, at a temperature in the region of 20°C. The suspension obtained is stirred at a temperature in the region of 20°C for 20 hours. The 15 reaction medium is filtered and concentrated to dryness under reduced pressure. 46 mg of an orange-colored oil are thus obtained, which oil is purified by chromatography under pressure on a cartridge of 5 g of silica, eluting with a mixture of cyclohexane and ethyl 20 acetate (70/30 by volume). The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure. 6 mg of (RS)-N-[2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)ethyl]-3-methylbutyramide are 25 obtained in the form of a colorless oil [1H NMR spectrum (400 MHz, CDCI3, 5 in ppm) : 0.88 (d, J = 6.5 Hz : 3H) ; 0.91 (d, J = 6.5 Hz : 3H); from 1.85 to 2.10 (mt : 3H) ; from 2.30 to 2.55 and from 2.70 to 3.10 (2 series of 252 mts : 6H in total); 3.37 (mt : 2H); 4.19 (s : 1H); 5.45 (mt : 1H); 6.65 (tt, J = 9 and 2.5 Hz : 1H); 6.82 (mt : 2H) ; from 7.20 to 7.45 (mt : 8H)] .
Example 89 (RS)-N-[2-{l-[Bis(4-chlorophenyl)methyl- azetidin-3-yl}-2-(3,5-difluorophenyl)ethyl]iso-butyramide may be prepared by carrying out the procedure in the manner similar to Example 3 above: starting with 45 mg of (RS)-2-{1-[bis(4-chlorophenyl)-10 methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)ethylamine, 5 cm3 of tetrahydrofuran, 114 mg of HATU, 26 mg of isobutyric acid and 0.2 g of morpholine supported on polystyrene, 10 mg of (RS)-N-[2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-15 (3,5-difluorophenyl)ethyl]isobutyramide are obtained in the form of an opaque oil [1H NMR spectrum (400 MHz, (CD3)2SO d6, 5 in ppm): 0.87 (d, J = 7 Hz : 3H); 0.93 (d, J = 7 Hz : 3H); from 2.15 to 2.85 (mt : 7H); from 3.00 to 3.25 (mt : 2H); 4.40 (s : 1H); from 7.00 to 20 7.20 (mt : 3H); 7.38 (mt : 4H); 7.52 (mt : 4H); 7.77 (mt : 1H)].
Example 90 {1-[Bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3,4-difluorophenyl)methanone may be prepared by 25 carrying out the procedure in the following manner: 3 cm3 of a 0.5 N solution of 3,4-difluorophenylmagnesium bromide in tetrahydrofuran are added to a solution of 128 mg of 1-[bis(4-chlorophenyl)methyl]azetidine- 253 3-carboxylic acid N-methoxy-N-methylamide in 3 cm3 of tetrahydrofuran, cooled in a bath of acetone and dry ice. After stirring for 20 hours at a temperature in the region of 0°C, 10 cm3 of water are added and then 5 the reaction medium is stirred for 1 hour at a temperature in the region of 20°C. The aqueous phase separated by settling is extracted with 20 cm3 of ethyl acetate. The combined organic phases are washed with twice 15 cm3 of water, dried over magnesium sulfate and 10 concentrated to dryness under reduced pressure. 123 mg of a residue are thus obtained, which residue is purified by chromatography under pressure on a cartridge of 20 g of silica, eluting with dichloromethane (stabilized on amylene). 47 mg of 15 {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- 3,4-difluorophenyl)methanone are thus obtained in the form of a white powder [ 1H NMR spectrum (300 MHz, CDC13, 5 in ppm): 3.34 (t, J = 7.5 Hz : 2H); 3.56 (t, J = 8 Hz : 2H); 4.05 (mt : 1H); 4.35 (s : 1H); from 7.15 to 7.40 20 (mt : 9H); 7.58 (dmt, J = 9 Hz : 1H); 7.70 (ddd, J = 9/7.5 and 2.5 Hz : 1H]. 1-[Bis (4-chlorophenyl)methyl]azetidine-3-carboxylic acid N-methoxy-N-methylamide may be prepared by carrying out the procedure in the following manner: 25 2.65 cm3 of 1-methylpiperidine are added to a suspension of 2.03 g of N,O-dimethylhydroxylamine hydrochloride in 40 cm3 of dichloromethane, cooled to a temperature in the region of 0°C by an ice cold water bath. The yellow 254 solution obtained (solution A) is stored at a temperature in the region of 0°C. 2.65 cm3 of 1-methylpiperidine and then 1.6 cm3 of methyl chloroformate are added successively to a suspension of 5 7 g of 1-[bis(4-chlorophenyl)methyl]azetidine- 3-carboxylic acid in 300 cm3 of dichloromethane and 40 cm3 of tetrahydrofuran, cooled to a temperature in the region of -8°C by an ice and isopropanol bath.
After stirring for about 5 minutes at a temperature in 10 the region of -8°C, solution A prepared above is added dropwise. After stirring for 10 minutes at a temperature in the region of -8°C, the cooling bath is removed, and the reaction mixture is stirred at a temperature in the region of 20°C for about 20 hours, 15 and then washed with 3 times 150 cm3 of water, and concentrated to dryness under reduced pressure. 8.19 g of a residue are thus obtained, which residue is purified under pressure on 500 g of Amicon silica (diameter of the particles: 20 - 45 ?m), eluting with 20 an ethyl acetate/dichloromethane (8 - 92 by volume) mixture. 6.6 g of 1-[bis(4-chlorophenyl)methyl]-azetidine-3-carboxylic acid N-methoxy-N-methylamide are thus obtained in the form of a pale yellow oil. 1-[Bis(4-chlorophenyl)methyl]azetidine-25 3-carboxylic acid may be prepared in a manner similar to that described by ANDERSON A.G. and LOK R. J. Org. Chem., 37, 3953-3955 (1972) from 1-benzhydrylazetidin- 255 3-ol, using, as raw material, 1-[bis(4-chlorophenyl)-methyl]azetidin-3-ol.
Example 91 {1-[Bis(4-chlorophenyl)methyl]azetidin-3-yl}-5 (3,5-difluorophenyl)methanone may be prepared by carrying out the procedure as for {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3,4-difluorophenyl)methanone, starting with 1.1 g of 1-[bis(4-chlorophenyl)methyl]azetidine-3-carboxylic 10 acid N-methoxy-N-methylamide, 1.5 cm3 of 1-bromo- 3,5-difluorobenzene, and 316 mg of magnesium turnings. 880 mg of {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorophenyl)methanone are thus obtained in the form of a pale yellow viscous oil [ 1H NMR spectrum 15 (300 MHz, CDCI3, 8 in ppm): 3.34 (t, J = 7.5 Hz : 2H) ; 3.55 (t, J = 8 Hz : 2H); 4.03 (mt : 1H); 4.44 (s : 1H); 7.01 (tt, J = 9 and 2.5 Hz : 1H); from 7.20 to 7.4 0 (mt : 10H)].
Example 92 {1-[Bis(4-chlorophenyl)methyl]azetidin-3-yl}- cyclohexylmethanone may be prepared by carrying out the procedure as for {1-[bis(4-chlorophenyl)methyl]-azetidin-3-yl}-(3,4-difluorophenyl)methanone, starting with 284 mg of 1-[bis(4-chlorophenyl)methyl]azetidine-25 3-carboxylic acid N-methoxy-N-methylamide and 1.68 cm3 of 2 N cyclohexylmagnesium chloride in THF. 116 mg of {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-cyclohexylmethanone are thus obtained in the form of a 256 yellow viscous oil [XH NMR spectrum (400 MHz, CDCI3, 5 in ppm) : from 1.10 to 1.35 and from 1.55 to 1.85 (2 series of mt : 10H in total); 2.30 (mt : 1H); 3.14 (t, J = 8 Hz : 2H); 3.36 (t, J = 8 Hz : 2H); 3.56 (mt : 5 1H); 4.31 (s : 1H); from 7.20 to 7.35 (mt : 8H)]. Example 93 {1-[Bis(4-chlorophenyl)methyl]azetidin-3-yl}-phenylmethanone may be prepared by carrying out the procedure as for {1-[bis(4-chlorophenyl)methyl]-10 azetidin-3-yl}-(3,4-difluorophenyl)methanone, starting with 258 mg of 1-[bis(4-chlorophenyl)methyl]azetidine-3-carboxylic N-methoxy-N-methylamide and 1.02 cm3 of 3 N phenylmagnesium bromide in THF. 208 mg of {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-15 phenylmethanone are thus obtained in the form of a yellow viscous oil [1H NMR spectrum (300 MHz, CDC13, 6 in ppm): 3.35 (t, J = 8 Hz : 2H); 3.57 (t, J = 8 Hz : 2H); 4.13 (mt : 1H); 4.35 (s : 1H); 7.25 (dmt, J = 8 Hz : 4H); 7.34 (dmt, J = 8 Hz : 4H); 7.45 (broad t, J = 8 20 Hz : 2H); 7.56 (tt, J = 8 and 1.5 Hz : 1H); 7.84 (dmt, J = 8 Hz : 2H)].
Example 94 (RS)—1—{1—[Bis(4-chlorophenyl)methyl]-azetidin-3-yl}-1-(3,5-difluorophenyl)ethanol may be 25 prepared by carrying out the procedure in the following manner: 0.167 cm3 of a 3 N methylmagnesium bromide solution is added to a solution of 100 mg of {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- 257 (3,5-difluorophenyl)methanone in 4 cm3 of tetrahydrofuran, cooled to a temperature of less than -40°C. After stirring for 20 hours at a temperature in the region of 0°C, 5 cm3 of water are added and then the 5 aqueous phase separated by settling is extracted with 5 cm3 of ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated to dryness under reduced pressure. 91 mg of a residue are thus obtained, which residue is purified by 10 chromatography under pressure on a cartridge of 10 g of silica, eluting with an ethyl acetate/cyclohexane (1/9 by volume) mixture. 74 mg of (RS)-1-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-1-(3,5-difluorophenyl)ethanol are thus obtained in the 15 form of a colorless oil [1H NMR spectrum (300 MHz, CDC13, 5 in ppm): 1.46 (s : 3H); 2.71 (mt : 1H); 2.82 (mt : 1H); 2.98 (t, J = 7.5 Hz : 1H); 3.24 (t, J = 7.5 Hz : 1H); 3.34 (mt : 1H); 4.31 (s : 1H); 4.33 (mf : 1H); 6.67 (tt, J = 9 and 2.5 Hz : 1H); 6.98 (mt : 2H) ; 20 from 7.25 to 7.35 (mt : 8H)].
Example 95 {1-[Bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorophenyl)methanone O-allyloxime may be prepared by carrying out the procedure in the following 25 manner: a solution of 100 mg of {1-[bis(4-chlorophenyl) methyl] azetidin-3-yl}-(3,5-difluorophenyl)-methanone and 101 mg of O-allylhydroxylamine hydrochloride in 5 cm3 of pyridine is stirred at a 258 temperature in the region of 20°C for 20 hours. 5 cm3 of water are then added and the reaction mixture is extracted with twice 5 cm3 of ethyl acetate. The combined organic phases are dried over magnesium 5 sulfate and then concentrated to dryness under reduced pressure. Ill mg of a yellow oil are thus obtained, which oil is purified by chromatography under pressure on a cartridge of 20 g of silica (diameter of the particles from 0.04 to 0.063 mm), eluting with an ethyl 10 acetate/cyclohexane (2/98 by volume) mixture. 68 mg of {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorophenyl)methanone O-allyloxime are thus obtained in the form of a colorless viscous oil [aH NMR spectrum (300 MHz, CDC13, 5 in ppm). A mixture of the 2 15 Z and E isomers is observed in the approximate proportions 65/35 or conversely; 2.84 and 3.11 (2 broad t, respectively J = 8 Hz and J = 7.5 Hz : 2H in total); 3.44 and 3.66 (2 broad t, respectively J = 7.5 Hz and J = 8 Hz : 2H in total); 3.58 and 3.81 (2 mts : 1H 20 total); 4.16 and 4.30 (2s : 1H in total); 4.59 (mt : 2H); 5.22 (dmt, J = 11 Hz : 1H); 5.27 (dmt, J = 18 Hz : 1H); 5.96 (mt : 1H); 6.80 (tt, J = 9 and 2.5 Hz : 1H); 6.91 (mt : 2H); from 7.20 to 7.35 (mt : 8H].
Example 96 {1-[Bis(4-chlorophenyl)methyl]azetidin-3-yl}- (3,5-difluorophenyl)methanone O-ethyloxime may be prepared by carrying out the procedure as described for the preparation of {1-[bis(4-chlorophenyl)methyl]- 259 azetidin-3-yl}-(3,5-difluorophenyl)methanone O-allyloxime: starting with 100 mg of {1-[bis(4-chlorophenyl )methyl]azetidin-3-yl}-(3,5-difluorophenyl)-methanone and 90 mg of O-ethylhydroxylamine 5 hydrochloride, 83 mg of {1-[bis(4-chlorophenyl)methyl]-azetidin-3-yl}-(3,5-difluorophenyl)methanone O-ethyloxime are thus obtained in the form of a colorless viscous oil [1H NMR spectrum (300 MHz, CDC13, 5 in ppm). A mixture of the 2 Z and E isomers is 10 observed in the approximate proportions 65/35 or conversely; 1.25 and 1.27 (2 t, J = 7 Hz : 3H in total); 2.82 and 3.12 (2 broad t, respectively J = 8 Hz and J = 7.5 Hz : 2H in total); 3.45 and 3.66 (2 broad t, respectively J = 7.5 Hz and J = 8 Hz : 2H in total); 15 3.58 and 3.78 (2 mts : 1H total); from 4.05 to 4.20 (mt : 2H); 4.16 and 4.30 (2 s : 1H in total); 6.80 (tt, J = 9 and 2.5 Hz : 1H); 6.91 (mt : 2H); from 7.20 to 7.35 (mt : 8H)].
Example 97 (RS)-l-[{l-[Bis(4-chlorophenyl)methyl]- azetidin-3-yl}-(3,5-difluorophenyl)methyl]-3-methylurea may be prepared in the following manner: 0.336 cm3 of triethylamine and 0.384 cm3 of diphenylphosphonoazide are added successively to a solution of 300 mg of 2 5 {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- (3,5-difluorophenyl)acetic acid hydrochloride in 15 cm3 anhydrous toluene, under an inert nitrogen atmosphere, at a temperature in the region of 20°C. The solution 260 obtained is stirred at a temperature in the region of 60°C for about 90 minutes. 2.6 cm3 of a 2 M methylamine solution in tetrahydrofuran are added, the stirring is maintained at a temperature in the region of 20°C for 5 about 12 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40°C. The residue is taken up in 1 cm3 of methanol and then deposited on a BOND-ELUT SCX VARIAN 5 g cartridge with the reference 10 1225-6027 conditioned with methanol. The cartridge is washed with methanol and eluted with 2 N ammoniacal methanol. The ammoniacal fractions are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40°C. 15 250 mg of a light oil are thus obtained, which oil is taken up in 1 cm3 of dichloromethane and then deposited on a cartridge 16 mn in diameter, filled with 5 g of silica of particle size 0.015-0.035 mm, conditioned and eluted with dichloromethane between 0 and 40 cm3 and 20 then eluted with a dichloromethane-ethyl acetate (80-20 by volume) mixture with the aid of a pumping system. The fractions between 50 and 80 cm3 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 140 mg of (RS)-1-[{1-25 [bis(4-chlorophenyl)methyl]azetidin-3-yl}- (3,5-difluorophenyl)methyl]-3-methylurea are thus obtained in the form of a foam NMR spectrum (400 MHz, CDCI3, 5 in ppm): 2.66 (mt : 1H); 2.82 (d, J = 5 Hz 261 : 3H); 2.95 (mt : 1H); 3.03 (mt : 1H); 3.18 (mt : 2H); 4.24 (mt : 1H); 4.30 (s : 1H); 4.92 (t, J = 7 Hz : 1H); 5.36 (broad d, J = 7 Hz : 1H); 6.67 (tt, J = 9 and 2.5 Hz : 1H); 6.80 (mt : 2H); from 7.20 to 7.30 (mt : 8H)].
The preparation of {1-[bis (4-chlorophenyl)- methyl]azetidin-3-yl}-(3,5-difluorophenyl)acetic acid hydrochloride has been described in the patent "carbon-containing derivatives", example 77.
Example 98 (RS)-l-[{l-[Bis(4-chlorophenyl)methyl]- azetidin-3-yl}-(3,5-difluorophenyl)methyl]-3-isopropylurea may be prepared in the following manner: 3 cm3, that is 0.1 mM of a freshly prepared solution of (RS)-1-[bis(4-chlorophenyl)methyl]-3-15 [(3,5-difluorophenyl)isocyanatomethyl]azetidine are added to a solution of 17 yl of isopropylamine in 1 cm3 of anhydrous toluene, under an inert nitrogen atmosphere, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the 20 region of 20°C for about 12 hours. The reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40°C. The solid residue is taken up in 1 cm3 of methanol and then deposited on a BOND-ELUT SCX VARIAN 500 mg cartridge 25 with the reference 1210-2040, conditioned with methanol. The cartridge is washed with methanol and then eluted with 2 N ammoniacal methanol. The ammoniacal fractions are combined and concentrated to 262 dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40°C. The solid residue thus obtained is taken up in 1 cm3 of dichloromethane and then deposited on an 1ST FlashPack cartridge with 5 the reference SIL 016-002, filled with 2 g of silica (0.065-0.090 mm), conditioned with dichloromethane and eluted with a dichloromethane-ethyl acetate (90-10 by volume) mixture with the aid of a pumping system. The fractions between 20 and 38 cm3 are combined and 10 concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 14 mg of (RS)-1-[{1-[bis(4-chlorophenyl) methyl] azetidin-3-yl}-(3,5-difluorophenyl)-methyl]-3-isopropylurea are thus obtained in the form of a white foam ['''H NMR spectrum (400 MHz, CDC13, 5 in 15 ppm): 1.14 (d, J = 6.5 Hz : 3H); 1.15 (d, J = 6.5 Hz : 3H); 2.66 (mt : 1H); 2.92 (broad dd, J = 8 and 5.5 Hz : 1H); 3.01 (broad dd, J = 8 and 5.5 Hz : 1H); 3.16 (t, J = 8 Hz : 1H); 3.20 (t, J = 8 Hz : 1H); 3.85 (mt : 1H); 4.06 (d, J = 8 Hz : 1H); 4.29 (s : 1H); 4.91 (t, J = 7 20 Hz : 1H); 5.17 (d, J - 6.5 Hz : 1H); 6.66 (tt, J = 9 and 2 Hz : 1H); 6.78 (mt : 2H); from 7.20 to 7.35 (mt : 8H) ] .
(RS)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)isocyanatomethyl]azetidine may be 25 prepared in the following manner: 0.126 cm3 of triethylamine and 0.195 cm3 of diphenylphosphonoazide are added successively to a solution of 150 mg of {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- 263 (3,5-difluorophenyl)acetic acid hydrochloride in 9 cm3 of anhydrous toluene, under an inert nitrogen atmosphere, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the 5 region of 50°C for about 1 hour. The mixture is allowed to cool and (RS)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)isocyanatomethyl]azetidine is thus obtained in solution in toluene and will be subsequently used in this form.
Example 99 (RS)-l-[{l-[Bis(4-chlorophenyl)methyl]-azetidin-3-yl}-(3,5-difluorophenyl)methyl]-3-isobutylurea may be prepared in the following manner: 3 cm3, that is 0.1 mM of a freshly prepared solution of 15 (RS)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl ) isocyanatomethyl ] azetidine are added to a solution of 20 yil of isobutylamine in 1 cm3 of anhydrous toluene, under an inert nitrogen atmosphere, at a temperature in the region of 20°C. The solution 20 obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40°C. The solid residue is taken up in 1 cm3 of methanol and then 25 deposited on a BOND-ELUT SCX VARIAN 500 mg cartridge with the reference 1210-2040 conditioned with methanol. The cartridge is washed with methanol and then eluted with 2 N ammoniacal methanol. The ammoniacal fractions 264 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40°C. The residue thus obtained is taken up in 1 cm3 of dichloromethane and then deposited on an 1ST FlashPack 5 cartridge with the reference SIL 016-002 filled with 2 g of silica (0.065-0.090 mm), conditioned with dichloromethane and eluted with a dichloromethane-ethyl acetate (90-10 by volume) mixture with the aid of a pumping system. The fractions between 0 and 15 cm3 are 10 combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 14 mg of (RS)-1-[{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorophenyl)methyl]-3-isobutylurea are thus obtained in the form of a white foam [1H NMR spectrum 15 (400 MHz, CDC13, 6 in ppm): 0.89 (d, J = 6.5 Hz : 3H) ; 0.90 (d, J = 6.5 Hz : 3H); 1.74 (mt : 1H); 2.66 (mt : 1H); from 2.90 to 3.25 (mt : 6H); 4.29 (s and mt : 2H in total); 4.90 (t, J = 7 Hz : 1H); 5.34 (broad d, J = 6.5 Hz : 1H); 6.66 (tt, J = 9 and 2 Hz : 1H); 6.80 (mt 20 : 2H); from 7.20 to 7.35 (mt : 8H)].
Example 100 N-Methyl-N-phenyl-1-[bis(4-chlorophenyl)-methyl]azetidine-3-carboxamide may be prepared in the following manner: 0.039 cm3 of N-methylaniline, 87 mg of 25 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.063 cm3 of triethylamine and then 4 mg of hydroxybenzotriazol hydrate are added successively to a solution of 100 mg of 1-[bis(4-chlorophenyl)- 265 methyl]azetidine-3-carboxylic acid in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction 5 medium is deposited on an 1ST FlashPack cartridge with the reference SIL 016-005 filled with 5 g of silica (0.065-0.090 mm), conditioned with dichloromethane and eluted with a gradient of dichloromethane-ethyl acetate mixture (the percentage of ethyl acetate varying from 0 10 to 5 by volume) with the aid of a pumping system, collecting 1.5 cm3 fractions. Fractions 3 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 50°C. 95 mg of 1-[bis(4-chlorophenyl )methyl]azetidine-N-methyl-N-phenyl-3-carboxamide 15 are thus obtained in the form of a cream-colored foam NMR spectrum (400 MHz, CDCI3, 5 in ppm) : 3.08 (mt : 2H); 3.21 (mt : 3H); 3.27 (s : 3H); 4.35 (s : 1H) ; 7.06 (d, J = 7.5 Hz : 2H); from 7.15 to 7.45 (mt : 11H)]. Example 101 1-[Bis(4-chlorophenyl)methyl]azetidine- N-benzyl-N-methyl-3-carboxamide may be prepared in the following manner: 0.0213 cm3 of N-benzylmethylamine is added to a suspension of 150 mg of 1-[bis(4-chlorophenyl) methyl] azetidine-3-carboxylic acid activated on 25 TFP resin (165 yiM) in 2 cm3 of dichloromethane. The suspension is stirred at a temperature in the region of 20°C for 22 hours and then filtered on sintered glass. The solid residue is washed again with twice 1 cm3 of 266 dichloromethane. The filtrates are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40°C. 38 mg of 1-[bis(4-chlorophenyl)methyl]azetidine-N-benzyl-5 N-methyl-3-carboxamide are thus obtained in the form of a colorless gum [1H NMR spectrum (300 MHz, CDC13, 8 in ppm): 2.78 (s : 3H); from 3.25 to 3.55 (mt : 5H); 4.38 (mt : 2H); 4.57 (s : 1H); from 7.15 to 7.40 (mt : 13H]. 1-[Bis(4-chlorophenyl)methyl]azetidine-10 3-carboxylic acid activated on TFP resin may be prepared in the following manner: 2 g of 1-[bis(4-chlorophenyl)methyl]azetidine-3-carboxylic acid, 73 mg of 4-dimethylaminopyridine, 0.927 cm3 of 1,3-diisopropylcarbodiimide are added to a suspension 15 of 2.7 g of TFP resin (free phenol functional group, 1.1 mmol/g, that is 2.975 mM) in 40 cm3 of anhydrous dimethylformamide. After stirring for 19 hours at a temperature in the region of 20°C, the suspension is filtered, the resin is washed with 40 cm3 of 20 dimethylformamide, 40 cm3 of tetrahydrofuran, 40 cm3 of dichloromethane and then dried under vacuum to a constant weight. 3.6 g of 1-[bis(4-chlorophenyl)-methyl]azetidine-3-carboxylic acid activated on TFP resin are thus obtained. 25 1-[Bis(4-chlorophenyl)methyl]azetidine- 3-carboxylic acid may be prepared in a manner similar to that described by ANDERSON A.G. and LOK R., J. Org. Chem., 37, 3953-3955 (1972) from 1-benzhydrylazetidin- 267 3-ol, using, as raw material, 1-[bis(4-chlorophenyl)-methyl]azetidin-3-ol.
The TFP resin (free phenol functional group) may be prepared according to the procedure described in 5 patent W09967228.
Example 102 (RS)-[{1-[Bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorophenyl)methyl]methylamine may be prepared in the following manner: 0.099 cm3 of 10 methylamine is added to a solution of 108 mg of {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorophenyl)methanone in 2 cm3 of anhydrous 1,2-dichloroethane, followed successively by 84 mg of sodium triacetoxyborohydride and 0.014 cm3 of acetic 15 acid. After stirring for 12 hours at a temperature in the region of 20°C, 0.992 cm3 of methylamine, 85 mg of sodium triacetoxyborohydride and then 0.143 cm3 of acetic acid are again added successively. The solution obtained is stirred at a temperature in the region of 20 20°C for about 24 hours and then washed with 4 cm3 of a saturated sodium bicarbonate solution. The organic phase is separated by settling and then dried over magnesium sulfate, filtered and then concentrated under reduced pressure (2.7 kPa). The residue thus obtained 25 is purified on an 1ST FlashPack cartridge with the reference SIL 016-002 filled with 2 g of silica (0.065-0.090 mm) conditioned with dichloromethane and eluted with a gradient of dichloromethane-methanol 268 mixture (the percentage of methanol varying from 0 to 6 by volume) with the aid of a pumping system, collecting 1 cm3 fractions. Fractions 8 to 18 are combined and concentrated to dryness under reduced pressure 5 (2.7 kPa) at 50°C. 66 mg of [{1-[bis(4-chlorophenyl)-methyl]azetidin-3-yl}-(3,5-difluorophenyl)methyl]-methylamine are thus obtained in the form of a colorless honey [XH NMR spectrum (300 MHz, CDC13, 5 in ppm): 2.25 (s : 3H); 2.60 (mt : 1H); 2.68 (t, J = 7 Hz 10 : 1H); 2.94 (t, J = 7 Hz : 1H); 3.02 (broad t, J = 7 Hz : 1H); 3.34 (broad t, J = 7 Hz : 1H); 3.58 (d, J = 9 Hz : 1H); 4.25 (s : 1H); 6.67 (tt, J = 9 and 2.5 Hz : 1H); 6.80 (mt : 2H)/ from 7.20 to 7.35 (mt : 8H)].
Example 103 (RS)-[{l-[Bis(4-chlorophenyl)methyl]azetidin- 3-yl}-(3,5-difluorophenyl)methyl]isobutylamine may be prepared in the following manner: 0.028 cm3 of isobuthylamine is added to a solution of 109 mg of {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-20 (3,5-difluorophenyl)methanone in 2 cm3 of anhydrous 1,2-dichloroethane, followed successively by 85 mg of sodium triacetoxyborohydride and 0.015 cm3 of acetic acid. The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction 25 medium is deposited on a cartridge filled with 5 g of silica, conditioned with dichloromethane and eluted with a gradient of dichloromethane-ethyl acetate mixture (the percentage of ethyl acetate varying from 0 269 to 10 by volume) with the aid of a pumping system. The fractions containing the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 8 mg of (RS)-[{1-[bis (4-chloro-5 phenyl)methyl]azetidin-3-yl}-(3,5-difluorophenyl)- methyl]isobutylamine are thus obtained [1H NMR spectrum (300 MHz, CDCI3, 5 in ppm): 0.85 (d, J = 7 Hz : 3H) ; 0.87 (d, J = 7 Hz : 3H); 1.63 (mt : 1H); 2.15 (dd, J = 11 and 7.5 Hz : 1H); 2.25 (dd, J = 11 and 7 Hz : 1H); 10 2.57 (mt : 1H); 2.70 (t, J = 7 Hz : 1H); 2.92 (t, J = 7 Hz : 1H); 3.01 (broad t, J = 7.5 Hz : 1H); 3.33 (broad t, J = 7.5 Hz : 1H); 3.66 (d, J = 9 Hz : 1H) ; 4.25 (s : 1H); 6.66 (tt, J = 9 and 2.5 Hz : 1H); 6.81 (mt : 2H); from 7.20 to 7.35 (mt : 8H)].
Example 104 (RS)-[{1-[Bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorophenyl)methyl]butylamine may be prepared in the following manner: 0.02 65 cm3 of n-butylamine is added to a solution of 108 mg of 20 {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- (3,5-difluorophenyl)methanone in 2 cm3 of anhydrous 1,2-dichloroethane, followed successively by 95 mg of sodium triacetoxyborohydride and 0.0143 cm3 of acetic acid. After stirring for about 16 hours at a 25 temperature in the region of 20°C, 0.0265 cm3 of n-butylamine, 85 mg of sodium triacetoxyborohydride and then 0.143 cm3 of acetic acid are again successively added. The solution obtained is stirred at a 270 temperature in the region of 20°C for about 24 hours and then washed with 4 cm3 of a saturated sodium bicarbonate solution. The organic phase is separated by settling and then dried over magnesium sulfate, 5 filtered and then concentrated under reduced pressure (2.7 kPa). The residue thus obtained is purified on an 1ST FlashPack cartridge with the reference SIL 016-002 filled with 2 g of silica (0.065-0.090 mm), conditioned with dichloromethane and eluted with a gradient of 10 dichloromethane-methanol mixture (the percentage of methanol varying from 0 to 6 by volume) with the aid of a pumping system, collecting 1 cm3 fractions. Fractions 25 to 30 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 50°C. 37 mg of 15 RS)-[{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}- (3,5-difluorophenyl)methyl]butylamine are thus obtained in the form of a colorless honey [1H NMR spectrum (300 MHz, CDC13, 5 in ppm): 0.85 (t, J = 7.5 Hz : 3H); from 1.20 to 1.50 (mt : 4H); 2.37 (broad t, J = 7 Hz : 20 2H); 2.56 (mt : 1H); 2.67 (t, J = 7 Hz : 1H) ; 2.89 (t, J = 7 Hz : 1H); 2.99 (broad t, J = 7 Hz : 1H); 3.32 (broad t, J = 7 Hz : 1H); 3.67 (d, J = 9 Hz : 1H); 4.24 (s : 1H); 6.65 (tt, J = 9 and 2.5 Hz : 1H); 6.80 (mt : 2H); from 7.20 to 7.35 (mt : 8H].
Example 105 (RS)-N-[{1-[Bis(4-chlorophenyl)methyl]-azetidin-3-yl}-(3,5-difluorophenyl)methyl]-3-methylbutyramide may be prepared in the following 271 manner: 0.025 cm3 of N,N'-diisopropylcarbodiimide, 10 mg of hydroxybenzotriazole hydrate, 30 mg of (RS)-C-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-C-(3,5-difluorophenyl)methylamine are added 5 successively to a solution of 0.017 cm3 of isovaleric acid in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction medium is 10 deposited on a BOND-ELUT SCX VARIAN 500 mg cartridge with the reference 1210-2040, conditioned with methanol. The cartridge is washed with methanol and then eluted with 2N ammoniacal methanol. The ammoniacal fractions are combined and concentrated to dryness 15 under reduced pressure (2.7 kPa) at a temperature in the region of 40°C. 35 mg of (RS)-N-[{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorophenyl)methyl]-3-methylbutyramide are thus obtained in the form of a yellow honey [1H NMR spectrum 20 (300 MHz, CDC13, 5 in ppm) : 0.98 (d, J = 5 Hz : 6H) ; from 2.05 to 2.25 (mt : 3H); 2.71 (mt : 1H); 2.90 (mt : 1H); 3.00 (mt : 1H); 3.20 (mt : 2H); 4.30 (s : 1H); 5.14 (t, J = 7.5 Hz : 1H); 6.48 (broad d, J = 7.5 Hz : 1H); 6.67 (tt, J = 9 and 2.5 Hz : 1H); 6.75 (mt : 2H) ; 25 from 7.20 to 7.40 (mt : 8H)].
(RS)-C-{1-[Bis(4-chlorophenyl)-methyl]azetidin-3-yl}-C-(3,5-difluorophenyl)methylamine may be prepared in the following manner: to a solution 272 of 216 mg of (RS)-{1-[bis(4-chlorophenyl)methyl]-azetidin-3-yl}-(3,5-difluorophenyl)methanone in 10 cm3 of methanol, followed successively by 385 mg of ammonium acetate and 2 9 mg of sodium cyanoborohydride.
The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours and then made lukewarm at 45°C for 6 h. 29 mg of sodium cyanoborohydride are added to this solution. The stirring is continued at a temperature in the region of 10 20°C for 72 hours. The reaction medium is poured into a mixture of 30 cm3 of ice-cold water with 5 cm3 of a 4 N aqueous sodium hydroxide solution, and then extracted with twice 30 cm3 of ethyl acetate, the organic phase is extracted with twice 30 cm3 of N hydrochloric acid, the 15 aqueous phase thus obtained is alkalinized with a normal aqueous sodium hydroxide solution and then extracted with three times 20 cm3 of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and then concentrated to dryness 20 under reduced pressure (2.7 kPa) at 40°C. 35 mg of (RS)-C-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-C-(3,5-difluorophenyl)methylamine are thus obtained in the form of a yellow honey.
The medicaments according to the invention 25 consist of a compound of formula (I) or an isomer or a salt of such a compound, in the pure state or in the form of a composition in which it is combined with any other pharmaceutically compatible product which may be 273 inert or physiologically active. The medicaments according to the invention may be used orally, parenterally, rectally or topically.
As solid compositions for oral 5 administration, tablets, pills, powders (gelatine capsules, sachets) or granules may be used. In these compositions, the active ingredient according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, 10 under an argon stream. These compositions may also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a coloring, a coating (sugar-coated tablets) or a glaze.
As liquid compositions for oral administration, there may be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil. 20 These compositions may comprise substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.
Sterile compositions for parenteral administration may be preferably solutions which are 25 aqueous or nonaqueous, suspensions or emulsions. As solvent or vehicle, there may be used water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for 274 example ethyl oleate or other suitable organic solvents. These compositions may also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents.
Sterilization may be carried out in several ways, for example by asepticizing filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They may also be prepared in the form of sterile solid compositions which may be dissolved at 10 the time of use in sterile water or any other injectable sterile medium.
Compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as 15 cocoa butter, semisynthetic glycerides or polyethylene glycols.
Compositions for topical administration may be, for example, creams, lotions, collyria, collutoria, nasal drops or aerosols.
In human therapy, the compounds according to the invention are particularly useful for the treatment and/or prevention of psychoses including schizophrenia, anxiety disorders, depression, epilepsy, neurodegeneration, cerebellar and spinocerebellar 25 disorders, cognitive disorders, cranial trauma, panic attacks, peripheral neuropathies, glaucomas, migraine, Parkinson's disease, Alzheimer's disease, Huntington's chorea, Raynaud's syndrome, tremor, obsessive- 275 compulsive disorder, senile dementia, thymic disorders, Tourette1s syndrome, tardive dyskinesia, bipolar disorders, cancers, movement disorders induced by medicaments, dystonia, endotoxemic shocks, hemorrhagic shocks, hypotension, insomnia, immunological diseases, multiple sclerosis, vomiting, asthma, appetite disorders (bulimia, anorexia), obesity, memory disorders, intestinal transit disorders, in weaning from chronic treatments and alcohol or drug abuse (opioids, barbiturates, cannabis, cocaine, amphetamine, phencyclide, hallucinogens, benzodiazepines for example), as analgesics or potentiators of the analgesic activity of the narcotic and nonnarcotic drugs.
The doses depend on the desired effect, the duration of the treatment and the route of administration used; they are generally between 5 mg and 1000 mg per day orally for an adult with unit doses ranging from 1 mg to 250 mg of active substance.
In general, the doctor will determine the appropriate dosage depending on the age, weight and any other factors specific to the subject to be treated.
The following examples illustrate the compositions according to the invention: 276 EXAMPLE A Gelatin capsules containing a dose of 50 mg of active product and having the following composition are prepared according to the usual technique: - Compound of formula (I) 50 mg - Cellulose 18 mg - Lactose 55 mg - Colloidal silica 1 mg - Sodium carboxymethylstarch 10 mg - Talc 10 mg - Magnesium stearate 1 mg EXAMPLE B Tablets containing a dose of 50 mg of active 15 product and having the following composition are prepared according to the usual technique: - Compound of formula (I) 50 mg - Lactose 104 mg - Cellulose 40 mg - Polyvidone 10 mg - Sodium carboxymethylstarch 22 mg - Talc 10 mg - Magnesium stearate 2 mg - Colloidal silica 2 mg - Mixture of hydroxymethylcellulose, glycerin, titanium oxide (72-3.5-24.5) qs 1 finished film-coated tablet containing 245 mg

Claims (54)

277 EXAMPLE C An injectable solution containing 10 mg of active product having the following composition is prepared: 5 - Compound of formula (I) 10 mg - Benzoic acid 80 mg - Benzyl alcohol 0.06 ml - Sodium benzoate 80 mg - Ethanol, 95% 0.4 ml 10 - Sodium hydroxide 24 mg - Propylene glycol 1.6 ml - Water qs 4 ml 278 CLAIMS
1. Compound of formula R 5 in which R represents a radical CRiR2, C=C(R5)S02R6 or C=C (R7) S02alk, 10 Ri represents a hydrogen atom and R2 represents a radical -C(R8) (R9) (Rio) , -C (R8) (Ru) (R12) , -CO-NR13Ri4, -CO-R6, -CO-cycloalkyl, -SO-R6, -S02-R6, -C (OH) (R6) (alkyl) , -C (=NOalk) R6, -C (=NO-CH2-CH=CH2) R6, -CH2-C (=NOalk) R6, -CH (R6) NR3iR32/ -CH (R6) NHCONHalk or 15 -CH(R6)NHCOalk, or Ri represents an alkyl, NH-R15, cyano, -S-alk-NRi6Ri7, -CH2-NRi8Ri9, or -NR20R2i radical and R2 represents a radical -C(R8) (Ru) (Ri2) , 20 R3 and R4, which are identical or different, represent either phenyl, being unsubstituted or substituted with one or more halogen atoms or alkyl, -alk-NR24R25 or CH2C1 radicals; or a heteroaromatic chosen from pyridyl, INTELLECTUAL PROPFRTvl)FiCE OF M.7 17 dec 200*1 279 pyrimidinyl and thienyl rings, being unsubstituted or substituted with one or more halogen atoms, R5 represents a hydrogen atom, 5 Re represents a radical Ar or Het, R7 represents a heterocyclenyl radical optionally substituted by a -CSO-phenyl radical, 10 R8 represents a hydrogen atom, Rg represents a radical -CO-NR26R27, -COOH, -COOalk, -CH2OH, -NH-CO-NH-alk or -CH2-NHR28, 15 Rio represents a radical Ar or Het, R11 represents a radical -S02-alk, -S02-Ar or -S02~Het, 20 R12 represents a hydrogen atom or a radical Ar or Het, R13 represents a hydrogen atom or an alkyl radical, R14 represents a radical Ar, -alk-Ar or -alk-Het, 25 R15 represents an alkyl, cycloalkyl or -alk-NR2gR3o radical, intellectual property office of n.z 17 dec 2m n r r> r n/ r n 280 Ri6 and Rn, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively Ri6 and R17 together form with the nitrogen atom to which they are attached a 3- to 10-membered unsaturated or 5 saturated mono- or bicyclic heterocycle optionally containing one or more other heteroatoms chosen from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl radicals, 10 Rie represents a hydrogen atom or an alkyl radical, Rig represents a hydrogen atom or an alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -S02alk, -CO-NHalk or -COOalk radical, 15 -NR20R21 represents a 3- to 8-membered saturated or unsaturated monocyclic heterocycle optionally containing another heteroatom chosen from oxygen, nitrogen and sulfur, 20 R22 and R23, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R22 and R23 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono- 25 or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals, intellectual property office of n.z 17 dec 2004 281 R24 and R25, which are identical or different, represent a hydrogen atom or an alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or alternatively R24 and R25 together form with the nitrogen 5 atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, -COalk, -COOalk, 10 -CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl, -alk-O-alk or -CO-NH2 radicals, R26 and R27, which are identical or different, represent a hydrogen atom or an alkyl, hydroxyalkyl, cycloalkyl, 15 cycloalkylalkyl, -alk-COOalk, -alk-Ar, -alk-Het, Het or -alk-N(alk)2 radical, R26 and R27 may also form with the nitrogen atom to which they are attached a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle optionally containing one or more other 20 heteroatoms chosen from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy radicals or halogen atoms, R28 represents a -CONHalk, -COalk or cycloalkylcarbonyl 25 radical, n is equal to 1, 2 or 3, 282 R29 and R3o, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R29 and R30 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono-5 or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals, 10 R31 and R32, which are identical or different, represent a hydrogen atom or an alkyl, Ar or -alk-Ar radical or alternatively R31 and R32 together form with the nitrogen atom to which they are attached a heterocycle chosen from aziridinyl, azetidinyl, pyrrolidinyl and 15 piperidinyl, alk represents an alkyl or alkylene radical, Ar represents a phenyl radical optionally substituted 20 with one or more substituents chosen from a halogen atom or an alkyl, alkoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR22R23, -CO-NH-NR24R25, alkylsulf anyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl, 25 -alk-NR24R25, ~NR24R25f alkylthioalkyl, formyl, hydroxyl, CF3, OCF3, Het, -O-alk-NH-cycloalkyl or S02NH2 radical, intellectual property office of N.Z 17 DEC 2004 received 283 Het represents a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle containing one or more heteroatoms chosen from oxygen, sulfur and nitrogen and optionally substituted with one or more 5 halogen atoms or alkyl, alkoxy, alkoxycarbonyl, -CONR22R23, hydroxyl, hydroxyalkyl, oxo or SO2NH2 radicals, the alkyl and alkylene radicals and portions and the 10 alkoxy radicals and portions 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, 15 their optical isomers and their salts with an inorganic or organic acid.
2. Compound according to claim 1, for which Het is chosen from pyridyl, pyrimidinyl and thienyl.
3. Compound of formula (I) according to 20 claim 1, for which when Ri6 and R17 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, the latter is a piperazinyl ring.
4. Compound of formula (I) according to 25 claim 1, for which the heterocycle formed by NR20R21 is an imidazolyl ring.
5. Compound of formula (I) according to claim 1, for which when R24 and R2s together form with intellectual propertv office OF N7 17 dec 2004 284 the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, the latter is an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or 5 piperazinyl ring.
6. Compound of formula (I) according to claim 1, for which when R26 and R27 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic 10 heterocycle, the latter is an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring.
7. Compound of formula (I) according to claim 1, for which when R29 and R30 together form with 15 the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, the latter is an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring. 20
8. Compound of formula (I) according to claim 1, for which: R represents a radical CR1R2, 25 either Ri represents a hydrogen atom and R2 represents a radical -C(R8) (Ru) (R12) or C(R8) (R9) (R10) , Intellectual propertv office of iM.7 17 dec 20m j 285 or Ri represents an alkyl radical and R2 represents a radical -C(R8) (Ru) (R12) , R3 and R4, which are identical or different, represent 5 either a phenyl which is unsubstituted or substituted with one or more halogen atoms or alkyl, -alk-NR24R25 or CH2C1 radicals; or a heteroaromatic chosen from the pyridyl, pyrimidinyl and thienyl rings, being unsubstituted or substituted with one or more halogen 10 atoms, R8 represents a hydrogen atom, R9 represents -CO-NR26R27,- -COOalk, -CH2OH, -NH-CO-NH-alk 15 or -CH2-NHR28, Rio represents a radical Ar or Het, Ru represents a radical -S02-alk, -S02-Ar or -S02-Het, 20 R12 represents a hydrogen atom or a radical Ar or Het, R22 and R23, which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R22 25 and R23 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mono-or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and 286 being optionally substituted with one or more alkyl radicals, R24 and R25, which are identical or different, represent 5 a hydrogen atom or an alkyl, cycloalkyl, alkylcycloalkyl or hydroxyalkyl radical or alternatively R24 and R25 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle 10 optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo or -CO-NH2 radicals, 15 Ar represents a phenyl radical optionally substituted with 1 or 2 subtituents chosen from a halogen atom or an alkyl, alkoxy, -CO-alk, cyano, -COOalk, -CONR22R23r alkylsulfonyl, hydroxyalkyl, -alk-NR24R2s, -NR24R25/ hydroxyl, CF3, OCF3, -O-alk-NH-cycloalkyl or SO2NH2 20 radical, Het represents a benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, isoquinolyl, pyrrolyl, pyridyl, quinolyl, 25 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thiazolyl or thienyl ring, INTELLECTUAL PROPERTY QFFir OF l\!J7 ur 11 1 7 DEC 2004 RE C EIV F n 287 their optical isomers and their salts with an inorganic or organic acid.
9. Compound chosen from the following compounds: 5 (RS)-1-[bis(4-chlorophenyl)methyl)]-3-[(3,5-difluoro-phenyl)(methylsulfonyl)methyl]azetidine, 10 (R)-1-[bis(4-chlorophenyl)methyl)]-3-[(3,5-difluorophenyl) (methylsulfonyl)methyl]azetidine, (S)-1-[bis(4-chlorophenyl)methyl)]-3-[(3,5-difluoro-phenyl)(methylsulfonyl)methyl]azetidine, (RS)-1-[bis(4-chlorophenyl)methyl)]-3-[(pyrid-3-yl) 15 (methylsulfonyl)methyl]azetidine, (R)-1-[bis(4-chlorophenyl)methyl)]-3-[(pyrid-3-yl) (methylsulfonyl)methyl]azetidine, 20 (S)-1-[bis(4-chlorophenyl)methyl)]-3-[(pyrid-3-yl) (methylsulfonyl)methyl]azetidine, (RS)-1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluoro-phenyl)methylsulfonylmethyl]azetidine, 25 (R)-1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, intellectual propertv office) OF N7 1 7 DEC 2004 received 288 (S)-1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, 1-[bis(4-chlorophenyl)methyl]-3-(RS)-{[3-azetidin-l-yl-5 phenyl]methylsulfonylmethyl}azetidine, 1-[bis(4-chlorophenyl)methyl]-3-(R)-{[3-azetidin-l-yl-phenyl]methylsulfonylmethyl}azetidine, 1-[bis(4-chlorophenyl)methyl]-3-(S)-{[3-azetidin-l-yl-phenyl]methylsulfonylmethyl}azetidine, (RS)-1-[3({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-methylsulfonylmethyl)phenyl]pyrrolidine, (R)-1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-methylsulfonylmethyl)phenyl]pyrrolidine, (S)-1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonylmethyl)phenyl]pyrrolidine, (RS)-N-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonylmethyl)phenyl]-N-methylamine, 25 (R)-N-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-methylsulfonylmethyl)phenyl]-N-methylamine, 15 20 INTELLECTUAL PROPERTY OFFICE OF H.7. 1 7 dec 2004 -jlelceived 289 (S)-N-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-methylsulfonylmethyl)phenyl]-N-methylamine, (RS)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-bistri-5 fluoromethylphenyl)methylsulfonylmethyl]azetidine, (R)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-bistri-fluoromethylphenyl)methylsulfonylmethyl]azetidine, (S)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-bistri-fluoromethylphenyl)methylsulfonylmethyl]azetidine, 1-[bis(4-chlorophenyl)methyl]-3-(phenylsulfonyl-methyl)azetidine, (RS)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluoro-phenyl)methylsulfonylmethyl]-3-methylazetidine, (R)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl) methylsulfonylmethyl] -3-methylazetidine, (S)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl) methylsulfonylmethyl] -3-methylazetidine, 25 (RS)-2-{l-[bis(4-chlorophenyl)methyl]azetidin- 3 yl} 2 (3,5-difluorophenyl)-N-cyclohexylacetamide, intellectual property office of n.z 17 dec 2004 DCOCu/i—«-* 15 20 290 (R)-2-{1-[bis(4-chlorophenyl)methyl]azeditin-3-yl}-2-(3,5-difluorophenyl)-N-cyclohexylacetamide, (S)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-5 3-yl}-2-(3,5-difluorophenyl)-N-cyclohexylacetamide, (RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isobutylacetamide, (R)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isobutylacetamide, (S)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isobutylacetamide, (RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclopropylmethylacetamide, (R)—2—{1—[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclopropylmethylacetamide, (S)-2-{1-bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclopropylmethylacetamide, 25 (RS)—2—{1—[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isopropylacetamide, Intellectual property office of 1 7 dec 2004 15 20 291 (R)—2 — {1—[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isopropylacetamide, (S)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-5 2-(3,5-difluorophenyl)-N-isopropylacetamide, (RS)-1-[bis(4-chlorophenyl)methyl]-3-[1-(3,5-difluorophenyl) -1-methylsulfonylethyl]azetidine, 10 (R)-1-[bis(4-chlorophenyl)methyl]-3-[1-(3,5-difluoro-phenyl)-1-methylsulfonylethyl]azetidine, (S)-1-[bis(4-chlorophenyl)methyl]-3-[1-(3,5-difluorophenyl) -1-methylsulfonylethyl]azetidine, 15 (RS)-1-[bis(4-fluorophenyl)methyl]-3-[(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, (R)-1-[bis(4-fluorophenyl)methyl]-3-[(3,5-difluoro-20 phenyl)methylsulfonylmethyl]azetidine, (S)-1-[bis(4-fluorophenyl)methyl]-3-[(3,5-difluorophenyl) methylsulfonylmethyl] azetidine, 25 (RS)-{1-[(3-pyridyl)-(4-chlorophenyl)methyl]- 3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine, intellectual propfrtv QFHCEl OF i\S7 I 17 DEC 2004 D l~ r- i « . ~ — 292 (SS)-{1-[(3-pyridyl)-(4-chlorophenyl)methyl]- 3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine, (RR)-{1-[(3-pyridyl)-(4-chlorophenyl)methyl]-5 3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine, (SR)-{1-[(3-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5— difluorophenyl)methylsulfonylmethyl]azetidine, (RS)-{1-[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine, (SS)-{1-[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5— difluorophenyl)methylsulfonylmethyl]azetidine, (RR)-{1-[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5— difluorophenyl)methylsulfonylmethyl]azetidine, (SR)-{1-[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine, (RS)-5-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)-methylsulfonylmethyl]azetidin-l-ylJmethyl)pyrimidine, 25 (SR)-5-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)- methylsulfonylmethyl]azetidin-l-yl}methyl)pyrimidine, 15 20 intellectual PROPERTY office OF W.7 17 DEC 2004 RECEIVED 293 (RR)-5-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)-methylsulfonylmethyl]azetidin-l-yl}methyl)pyrimidine, (SS)-5-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)-5 methylsulfonylmethyl]azetidin-l-yl}methyl)pyrimidine, (SS)-{1-[(2-chloropyrid-5-yl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine, 10 (RR)-{1-[(2-chloropyrid-5-yl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine, (RS)-{1-[(2-chloropyrid-5-yl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine, 15 (SR)-{1-t(2-chloropyrid-5-yl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]azetidine, their optical isomers and their pharmaceutically 20 acceptable salts with an inorganic or organic acid.
10. Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical CRj.R2, in which Rx represents a hydrogen atom and R2 represents a radical C(R8) (Ru) (R12) in which Rs 25 represents a hydrogen atom, Ru represents a radical -S02-Ar, -S02-Het or -S02alk and Ri2 represents a hydrogen atom or a radical Ar or Het, characterized in that a derivative of formula: intellectual PROPFRTv office OF iM.Z 17 dec 2004 orr>pn»rr\ in which Ra represents an alkyl, Het or Ar radical and Rb represents a hydrogen atom or an Ar, Het or alkyl 5 radical, Ar and Het having the same meanings as in claim 1, is reduced, the product isolated and optionally converted to a salt with an inorganic or organic acid.
11. Process for preparing the compounds of 10 formula (I) according to claim 1 for which R represents a radical CRiR2, in which Ri represents a hydrogen atom and R2 represents a radical C(R8) (Ru) (Ri2) in which R8 represents a hydrogen atom, Ru represents a radical -S02-Ar, -S02-Het or -S02alk and Ri2 represents a 15 hydrogen atom or a radical Ar or Het, characterized in that a derivative R3CH(Br)R4 is reacted with a derivative of formula: HN- X SCX-Ra 20 in which Ra represents an alkyl, Het or Ar radical and Rb represents a hydrogen atom or an Ar, Het or alkyl INTELLECTUAL PROPERTY OFFICE! OF HZ 1 17 dec 2004 n r <s ^ 295 radical, Ar and Het having the same meanings as in claim 1, the product isolated and optionally converted to a salt with an inorganic or organic acid.
12. Process for preparing the compounds of 5 formula (I) according to claim 1 for which R represents a radical C=C(R5)S02R6 or C=C (R7) S02alk, characterized in that a derivative of formula: 10 in which either Ra represents a radical Ar or Het and Rb represents a hydrogen atom or an alkyl radical, or Ra represents an alkyl radical and Rb represents a cycloalkyl, heterocycloalkyl or heterocyclenyl radical 15 optionally substituted with a radical -CSO-phenyl, Rc represents a hydrogen atom or an acetyl radical, R3, R4, Ar and Het having the same meanings as in claim 1, is dehydrated, the product isolated and optionally converted to a salt with an inorganic or organic acid. 20
13. Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical C=C(R5)S02R6 or C=C (R7) S02alk, characterized in that R3CH(Br)R4 is reacted with a derivative of formula: intellectual property office i OF INJ.Z 17 dec 2004 296 HN i {/" X S02-Ra b in which either Ra represents a radical Ar or Het and Rb represents a hydrogen atom or an alkyl radical, or 5 Ra represents an alkyl radical and Rb represents a cycloalkyl, heterocycloalkyl or heterocyclenyl radical optionally substituted with a radical -CSO-phenyl, Rc represents a hydrogen atom or an acetyl radial, r3, R4, Ar and Het having the same meanings as in claim 1, the 10 product isolated and optionally converted to a salt with an inorganic or organic acid. formula (I) according to claim 1 for which R represents a radical CRiR2 in which Ri represents a hydrogen atom 15 and R2 represents a radical C(R8) (Rg) (Rio) in which R8 represents a hydrogen atom, Rg represents a radical -CO-NR26R27 and Ri0 represents a radical Ar or Het, characterized in that an amine HNR26R27 in which R26 and R27 have the same meanings as in claim 1, is reacted 20 with an acid of formula:
14. Process for preparing the compounds of intellectual property office of n.z 17 dec 2004 DCPCl\/r-i-> 297 in which R3, R4 and Rio have the same meanings as in claim 1, the product isolated and optionally converted to a salt with an inorganic or organic acid. 5 15. Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical CR1R2 in which Ri represents a hydrogen atom and R2 represents a radical C(R8) (R9) (Rio) in which R8 represents a hydrogen atom, Rg represents a radical 10 -COOH and Rio represents a radical Ar or Het, characterized in that the corresponding ester of formula: Ra-\ N- R COOalk 10
15 in which R3, R4 and Rio have the same meanings as in claim 1 and alk represents an alkyl radical (1-6C in the form of a straight or branched chain), is hydrolyzed, the product isolated and optionally converted to a salt with an inorganic or organic acid. 20
16. Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical CR1R2 in which Ri represents a hydrogen atom and R2 represents a radical C(R8) (R9) (Rio) in which R8 represents a hydrogen atom, Rg represents a radical INTELLECTUAL PROPERTY OFFICE OF i\I.Z 17 dec 2004 v—» 1 11 r Pv 298 -COOalk or -ch2oh and Rio represents a radical Ar or Het, characterized in that a compound of formula: R. N- Y-COOalk Rio 5 in which r3, R4 and Rio have the same meanings as in claim 1 and alk represents an alkyl radical (1-6C in the form of a straight or branched chain, is reduced, the product isolated and optionally converted to a salt 10 with an inorganic or organic acid.
17. Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical CRiR2 in which Rx represents a hydrogen atom and R2 represents a radical C(Rg) (Rg) (Rio) in which R8 15 represents a hydrogen atom, Rg represents a radical -NH-CO-NH-alk and Rio represents a radical Ar or Het, characterized in that ah amine alkNH2 for which alk represents an alkyl radical (1-6C in the form of a straight or branched chain) is reacted with a 20 derivative of formula: INTEt.ilPTIjAt TWicf; or 1 17 DEC 2004 ! i RECElVPf) 299 \^/N=C=0 Rio in which R3, R4 and Rio have the same meanings as in formula (I), the product isolated and optionally converted to a salt with an inorganic or organic acid. 5
18. Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical CR1R2 in which Rx is a hydrogen atom and R2 represents a radical -C(R8) (R9) (Rio), Rs is a hydrogen atom, Rg is a radical -CH2-NHR28, R28 represents a 10 radical -CO-NHalk and Rio represents a radical Ar or Het, characterized in that a derivative of formula: r3 in which R3, R4 and Rio have the same meanings as in 15 claim 1, is reacted with a derivative RfNCO for which Rf represents an alkyl radical (1-6C in the form of a straight or branched chain), the product isolated and optionally converted to a salt with an inorganic or organic acid. INTELLECTUAL PROPFRTV OFFICE OF N.Z 1 7 DEC 2004 300
19. Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical CR1R2 in which Rx is a hydrogen atom and R2 represents a radical -C(R8) (R9) (Rio) r Rs is a hydrogen 5 atom, Rg is a radical -CH2-NHR28, R28 represents a -COalk or cycloalkylcarbonyl radical and Rio represents a radical Ar or Het, characterized in that a derivative of formula: FL N in which R3, R4 and Rio have the same meanings as in claim 1, is reacted with an acid HOOCRg for which Rg represents an alkyl (1-6C in the form of a straight or branched chain), cycloalkyl(3-10C)alkyl(1-6C in the 15 form of a straight or branched chain), cycloalkyl(3-10C) or -(CH2)nOH radical and n is equal to 1, 2 or 3, the product isolated and optionally converted to a salt with an inorganic or organic acid.
20. Process for preparing the compounds of 20 formula (I) according to claim 1 for which R represents a radical CRiR2 in which Ri is a hydrogen atom and R2 is a radical -CONR13R14, characterized in that an amine INTELLECTUAL PROPFRTV OFFICE OF iM.7 1 7 DEC 2004 RFrciucn 301 HNR13R14 in which R13 and Ru have the same meanings as in claim 1, is reacted with a derivative of formula: N COOH 5 in which R3 and R4 have the same meanings as in formula (I), the product isolated and optionally converted to a salt with an inorganic or organic acid.
21. Process for preparing the compounds of formula (I) according to claim 1 for which R represents 10 a radical CRiR2 in which Ri is a hydrogen atom and R2 represents a radical -S0R6, characterized in that a derivative of formula: FL R4A N SR6 in which R3, R4 and R6 have the same meanings as in 15 claim 1, is oxidized, the product isolated and optionally converted to a salt with an inorganic or organic acid.
22. Process for preparing the compounds of formula (I) according to claim 1 for which R represents 20 a radical CRiR2 in which Ri is a hydrogen atom and R2 INTELLECTUAL PROPERTY OFICE OF M7 17 DEC 2004 RECEIVED 302 represents a radical -S02R6/ characterized in that a derivative of formula: R. N \ sor„ 5 in which R3, R4 and R6 have the same meanings as in claim 1, is oxidized, the product isolated and optionally converted to a salt with an inorganic or organic acid. 10 formula (I) according to claim 1 for which R represents a radical CRiR2 in which Ri is a hydrogen atom and R2 represents a radical -COR6 or -CO-cycloalkyl, characterized in that a derivative of formula: 15 in which R3 and R4 have the same meanings as in claim 1, is reacted with a derivative RhMgBr for which Rh has the same meanings as R6 in claim 1 or else represents a radical cycloalkyl(3-10C), the product isolated and optionally converted to a salt with an inorganic or 20 organic acid.
23. Process for preparing compounds of N \ CON{CH3)OCH3 INTELLECTUAL propfrtv OFFICE OF iM.7 17 DEC 2004 RPf!Fi\/cn 303
24. Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical CRiR2 in which Rx is a hydrogen atom and R2 represents a radical -C(=N0alk)R6 or 5 -C(=N0-CH2-CH=CH2) R6, characterized in that a derivative of formula: Ra R, , n- ru •A \ cor6 in which R3, R4 and R6 have the same meanings as in 10 claim 1, is reacted with a derivative RjONH2 for which Rj represents an alkyl radical (1-6C in the form of a straight or branched chain) or -CH2-CH=CH2, the product isolated and optionally converted to a salt with an inorganic or organic acid. 15
25. Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical CRiR2 in which Ri is a hydrogen atom and R2 represents a radical -CH (R6) NR3iR32, R3X and R32 represent hydrogen atoms, characterized in that aqueous ammonia 20 is reacted with a derivative of formula: OROPFRTV OFFICE op N-7- 17 dec 2004 received. 304 y^OMs Ra in which R3, R4 and R6 have the same meanings as in claim 1 and Ms represents a methylsulfonyloxy radical, the product isolated and optionally converted to a salt 5 with an inorganic or organic acid.
26. Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical CR1R2 in which Ri is a hydrogen atom and R2 represents a radical -CH (Rg) NR3iR32, R3i is a hydrogen 10 atom and R32 is an alkyl, Ar or -alk-Ar radical, characterized in that a halide HalR3i is reacted with a corresponding compound of formula (I) for which R represents a radical CRiR2 in which Ri is a hydrogen atom and R2 represents a radical -CH (R6) NR3XR32, R3i and 15 R32 are hydrogen atoms, the product isolated and optionally converted to a salt with an inorganic or organic acid.
27. Process for preparing the compounds of formula (I) according to claim 1 for which R represents 20 a radical CRiR2 in which Ri is a hydrogen atom and R2 represents a radical -CH (R6) NR3iR32, R31 and R32 are alkyl, Ar or -alk-Ar radicals, characterized in that a halide HalR32 is reacted with a corresponding compound of formula (I) for which R represents a radical CR1R2 in Intellectual property office of n.z 17 DEC 200*1 305 which Ri is a hydrogen atom and R2 represents a radical -CH (R6) NR31R32, R31 is a hydrogen atom and R32 is an alkyl, Ar or -alk-Ar radical), the product isolated and optionally converted to a salt with an inorganic or 5 organic acid.
28. Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical CR1R2 in which Ri is a hydrogen atom and R2 represents a radical -CH (R6) NR3iR32, R31 is a hydrogen 10 atom and R32 is a (2-6C) alkyl or - (2-6C) alk-Ar radical, characterized in that an aldehyde RaCHO for which Ra is an alkyl or -alk-Ar radical is reacted with a corresponding compound of formula (I) for which R represents a radical CR1R2 in which Ri is a hydrogen 15 atom and R2 represents a radical -CH (R6) NR3iR32, R31 and R32 are hydrogen atoms, the product isolated and optionally converted to a salt with an inorganic or organic acid.
29. Process for preparing the compounds of 20 formula (I) according to claim 1 for which R represents a radical CRiR2 in which Ri is a hydrogen atom and R2 represents a radical -CH (R6) NR3iR32, R31 is an alkyl, Ar or -alk-Ar radical and R32 is a (2-6C) alkyl or -(2-6C)alk-Ar radical, characterized in that an 25 aldehyde RaCHO for which Ra is an alkyl or -alk-Ar radical is reacted with a corresponding compound of formula (I) for which R represents a radical CRiR2 in which Ri is a hydrogen atom and R2 represents a radical of n.7. \ 7 dec 2004 306
-CH (Re) NR31R32, R31 is a hydrogen atom and R32 is an alkyl, Ar or -alk-Ar radical, the product isolated and optionally converted to a salt with an inorganic or organic acid. 5 30. Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical CR1R2 in which Ri is a hydrogen atom and R2 represents a radical -CH (Rg) NR3iR32, R31 and R32 form with the nitrogen atom to which they are attached a 10 heterocycle chosen from aziridinyl, azetidinyl, pyrrolidinyl and piperidinyl, characterized in that a dihalide Hal-(2-5C)alk-Hal is reacted with a corresponding compound of formula (I) for which R represents a radical CRiR2 in which Ri is a hydrogen 15 atom and R2 represents a radical -CH (R6) NR31R32, R31 and R32 are hydrogen atoms, the product isolated and optionally converted to a salt with an inorganic or organic acid.
31. Process for preparing the compounds of 20 formula (I) according to claim 1 for which R represents a radical CR1R2 in which Ri is a hydrogen atom and R2 represents a radical -CH (R6) NHCONHalk, characterized in that a derivative of formula: INTELLECTUAL PROPF.RTV OFFICES OF N.7 1 \ 7 DEC 2004 307 nh2 r, '6 in which R3, R4 and Re have the same meanings as in claim 1, is reacted with a derivative alkNCO for which alk represents an alkyl radical (1-6C in the form of a 5 straight or branched chain), the product isolated and optionally converted to a salt with an inorganic or organic acid. formula (I) according to claim 1 for which R represents 10 a radical CRiR2 in which Ri is a hydrogen atom and R2 represents a radical or -CH (Re)NHCOalk, characterized in that a derivative of formula: 15 in which R3, R4 and R6 have the same meanings as in claim lr is reacted with a derivative alkCOOH, the product isolated and optionally converted to a salt with an inorganic or organic acid.
32. Process for preparing the compounds of nhz INTELLECTUAL PROPERTV OFFICE OF IM.7 \ 7 dec 2004 received 308
33. Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical CR1R2 in which Ri is a hydrogen atom and R2 represents a radical -CH2-C(=N0alk)R6, characterized in 5 that a derivative of formula: in which R3 and R4 have the same meanings as in claim 1, is reacted with a derivative of formula alkONH2 for 10 which alk represents an alkyl radical (1-6C in the form of a straight or branched chain), the product isolated and optionally converted to a salt with an inorganic or organic acid. 15 formula (I) according to claim 1 for which R represents a radical CRXR2 in which Ri represents a cyano radical and R2 represents a radical -C(R8) (Ru) (R12) in which R8 is a hydrogen atom, characterized in that a derivative of formula:
34. Process for preparing the compounds of V 20 intellectual property office of m.7 17 DEC 2004 RECEIVED 309 in which R3, R4, Ru and Ri2 have the same meanings as in claim 1, is reacted with sodium cyanide, the product isolated and optionally converted to a salt with an inorganic or organic acid. 5 35. Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical CR1R2 in which Ri represents a radical -S-alk-NRi6Ri7 and R2 represents a radical -C(R8) (Ru) (R12) in which R8 is a hydrogen atom, characterized in that a 10 derivative of formula: R3
A in which R3, R4, Ru and Ri2 have the same meanings as in 15 claim 1, is reacted with a derivative HS-alk-NRi6Ri7 for which alk represents an alk radical represents an alkyl radical (1-6C in the form of a straight or branched chain) and Ri6 and R17 have the same meanings as in claim 1, the product isolated and optionally converted to a 20 salt with an inorganic or organic acid.
36. Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical CRiR2 in which Ri represents a radical -NHR15 INTELLECTUAL PROPERTY OFFICE OF n.z 17 DEC 2004 310 and R2 represents a radical -C(R8) (Ru) (R12) in which R8 is a hydrogen atom, characterized in that a derivative of formula: 5 in which R3, R4, Ru and R12 have the same meanings as in claim 1, is reacted with a derivative H2NRi5 for which Ri5 has the same meanings as in claim 1, the product isolated and optionally converted to a salt with an inorganic or organic acid. 10
37. Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical CRiR2 in which Ri represents an alkyl radical and R2 represents a radical -C(R8) (Ru) (Ri2) in which R8 is a hydrogen atom, characterized in that a derivative 15 of formula: in which R3, R4, Ru and Ri2 have the same meanings as in claim 1, is reacted with a derivative alkMHal for which n r INTELLECTUAL PROPERTY OFFICE OF N.Z 17 DEC 2004 311 alk represents an alkyl radical (1-6C in the form of a straight or branched chain) and M represents a metal, the product isolated and optionally converted to a salt with an inorganic or organic acid. 5
38. Process for preparing the compounds of formula (I) according to claim 1, for which R represents a radical CR3.R2 in which Ri represents a radical -NR20R21 and R2 represents a radical -C(R8) (Ru) (R12) in which R8 is a hydrogen atom, 10 characterized in that a derivative of formula: Ra hA N- \ R 11 ' '12 in which R3, R4, Ru and R12 have the same meanings as in claim 1, is reacted with a derivative HNR20R21 for which 15 NR20R21 has the same meanings as in claim 1, the product isolated and optionally converted to a salt with an inorganic or organic acid
39. Process for preparing the compounds of formula (I) according to claim 1 for which R represents 20 a radical CRiR2 in which Ri represents a radical -CH2-NRi8Ri9, Ris and R19 represent hydrogen atoms, characterized in that a corresponding compound of formula (I) for which Ri represents a cyano radical is INTELLECTUAL PROPFRTV OFFICE OF iM.7 17 DEC 2094 RECEIVED 312 reduced, the product isolated and optionally converted to a salt with an inorganic or organic acid.
40. Process for preparing the compounds of formula (I) according to claim 1 for which R represents 5 a radical CR1R2 in which Ri represents a radical -CH2-NR18R19, Ri8 represents a hydrogen atom and Rig represents an alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -SC>2alk, -CO-NHalk or -COOalk radical, characterized in that a halide HalRig, Hal 10 represents a halogen, is reacted with a corresponding compound of formula (I) for which R represents a radical CRiR2 in which Ri represents a radical -alk-NRieRig, Ris and Rig represent a hydrogen atom, the product isolated and optionally converted to a salt with an inorganic or 15 organic acid.
41. Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical CRiR2 in which Ri represents a radical -alk-NRisRig, Ris represents an alkyl radical and Rig 20 represents an alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -S02alk, -CO-NHalk or -COOalk radical, characterized in that an alkylhalide is reacted with a corresponding compound of formula (I) for which R represents a radical CRiR2 in which Ri 25 represents a radical -alk-NRisRig, Ris represents a hydrogen atom, and R19 represents an alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -S02alk, -CO-NHalk intellectual propfrtv office OF >\].7 1 7 DEC 2004 313 or -COOalk radical, the product isolated and optionally converted to a salt with an inorganic or organic acid. formula (I) according to claim 1 for which R represents 5 a radical C=C (R7) S02alk, characterized in that a derivative of formula: in which R3, R4 and R7 have the same meanings as in claim 1 and alk represents an alkyl radical (1-6C in 10 the form of a straight or branched chain), is oxidized, the product isolated and optionally converted to a salt with an inorganic or organic acid. formula (I) according to claim 1 for which R represents 15 a radical CR1R2 in which Rx is a hydrogen atom and R2 represents a radical -CH (Re) NR3iR32, R3i is a hydrogen atom and R32 is an alkyl radical, characterized in that a corresponding compound of formula (I) for which R represents a radical CRiR2 in which Ri is a hydrogen 20 atom and R2 represents a radical -CO-R6, is reacted with an amine HNR3iR32 for which R3i is a hydrogen atom and R32 is an alkyl radical, the product isolated and
42. Process for preparing the compounds of N
43. Process for preparing the compounds of intellectual property office OF i\!.Z 1 7 DEC 2004 RECFi VFn 314 optionally converted to a salt with an inorganic or organic acid.
44. Pharmaceutical composition for use as a CBl receptor antagonist, comprising a pharmaceutically 5 acceptable carrier or diluent and, as an active ingredient, at least one compound of formula (I) according to one of claims 1 to 9.
45. A.pharmaceutical composition according to claim 44 for use in the treatment or prevention of a 10 disorder affecting the central nervous system, the immune system, the cardiovascular or endocrine system, the respiratory system or the gastrointestinal system, or a reproductive disorder.
46. A pharmaceutical composition according 15 to claim 44 for the treatment or prevention of psychoses including schizophrenia, anxiety disorders, depression, epilepsy, neurodegeneration, cerebellar and spinal cerebellar disorders, cognitive diseases, cranial trauma, panic attacks, peripheral neuropathies, 20 glaucomas, migraine, Parkinson's disease, Alzheimer's disease, Huntingdon's chorea, Raynaud's syndrome, tremor, obsessive-compulsive disorder, senile dementia, thymic disorders, Tourette's syndrome, tardive dyskinesia, bipolar disorders, cancer, movement 25 disorders induced by medicaments, dystonia, endotexemic shocks, haemorragic shocks, hypotension, insomnia, immunological disease, multiple sclerosis, vomiting, asthma, appetite disorders, obesity, memory disorders, intellectual property office i of n.z 17 DEC 2004 315 withdrawal from chronic treatments or from alcohol or drug abuse, or as analgesics or potentiators of the analgesic activity of narcotic or non-narcotic drugs, or in the prevention of intestinal transit. 5
47. A compound according to claim 1 and specifically hereinbefore mentioned.
48. A process according to any one of claims 10 to 43 and substantially as hereinbefore described.
49. A compound, or a pharmaceutically 10 acceptable salt thereof, when produced by a process as claimed in any one of claims 10 to 41.
50. A pharmaceutical composition according to claim 44 and substantially as hereinbefore described. INTELLECTUAL PROPERTY OFFICE OF N.7. 17 dec w received 316
51. Use of a compound according to any one of claims 1 to 9 in the preparation of a medicament for treating a disorder affecting the central nervous system, the immune system, the cardiovascular or endocrine system, the respiratory system or the gastrointestinal system, or a reproductive disorder.
52. Use of a compound according to any one of claims 1 to 9 in the preparation of a medicament for treating or preventing psychoses including schizophrenia, anxiety disorders, depression, epilepsy, neurodegeneration, cerebellar and spinal cerebellar disorders, cognitive disorder, cranial trauma, panic attacks, peripheral neuropathies, glaucomas, migraine, Parkinson's disease, Alzheimer's disease, Huntington's chorea, Raynaud's syndrome, tremor, obsessive-compulsive disorder, senile dementia, thymic disorders, Tourette's syndrome, tardive dyskinesia, bipolar disorders, cancer, movement disorders induced by medicaments, dystonia, endotoxemic shocks, haemorragic shocks, hypotension, insomnia, immunological disease, multiple sclerosis, vomiting, asthma, appetite disorders, obesity, memory disorders, withdrawal from chronic treatments or from alcohol or drug abuse, or as analgesics or potentiators of the analgesic activity of narcotic or nonnarcotic drugs or in the prevention of intestinal transit.
53. A use according to any one of claims 51 or 52 substantially as herein described with reference to any example thereof.
54. A compound of formula (I) when prepared by a process according to any one of claims 10 to 43 and 48. intellectual "ropertv office OF i\|.7 1 7 DEC 2004 received
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