NO324524B1 - Pharmaceutical preparations containing azetidine derivatives, the new azetidine derivatives and their preparation - Google Patents

Abstract

The invention concerns pharmaceutical compositions containing as active principle a compound of formula (I) wherein: R1 represents a -N(R4)R5, -N(R4)-CO-R5, -N(R4)-SO2R6 radical or one of its pharmaceutically acceptable salts, the novel derivatives of formula (I), their pharmaceutically acceptable salts and their preparation.

Description

The present invention relates to pharmaceutical preparations which, as active ingredient, contain at least one compound with the formula:

or a pharmaceutically acceptable salt thereof, the new derivatives of formula (I), their pharmaceutically acceptable salts as well as in their preparation. The compound of formula (I) where R 2 and R 3 mean phenyl residues, R 1 means a residue -N(R 4 )SO 2 R 6 , R 4 means a phenyl residue and R 6 means a methyl residue are described as synthesis intermediates in WO 99/01451. The other compounds and their pharmaceutically acceptable salts are novel per se and as such form part of the invention.

In formula (I) applies that:

Ri means a residue -N(R4)R5, -N(R4)-CO-R5, -N(R4)-SO2R6,

R 2 and R 3 are phenyl, optionally substituted with one or more halogen; or a heteroaromatic selected from pyridyl or pyrimidyl,

R4 means a residue -C(Rn)(Ri2)-Het, -Het, -(CRn)(Ri2)-Ar, Ar, cycloalkyl or norbornyl,

R5 means a hydrogen atom or alkyl,

Re means a residue alk-CONR7R8 or alkyl,

R 7 and R s , the same or different, mean a hydrogen atom or an alkyl residue,

Ri 1 means a hydrogen atom,

Ri 2 means a hydrogen atom,

Ar means a phenyl radical optionally substituted with one or more halogen, alkoxy, -COOalk, hydroxy or hydroxyalkyl,

Het means a heterocycle selected from pyridyl, quinolyl, isoquinolyl, pyrimidinyl, thiadiazolyl, thiazolyl, piperidyl or benzoisothiazolyl, where the heterocycle is optionally substituted with one or more alkyl, halogen or oxo,

alk means an alkyl or alkylene residue,

wherein alkyl and alkylene residues and parts and alkoxy acid residues and parts have a straight or branched chain containing 1 to 6 carbon atoms and cycloalkyl residues contain 3 to 10 carbon atoms,

their optical isomers and their salts with a pharmaceutically acceptable mineral or organic acid.

In the preceding and following definitions, unless otherwise stated, alkyl and alkylene residues and parts as well as alkoxy acid residues and parts contain 1 to 6 carbon atoms in a straight or branched chain, and the cycloalkyl residues contain 3 to 10 carbon atoms.

Among the alkyl radicals, mention may be made of the radicals methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl. Among the alkoxy radicals, the radicals methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentyloxy should be mentioned.

Among the cycloalkyl radicals, mention may be made of the radicals cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The term halogen includes chlorine, fluorine, bromine and iodine.

The compounds of formula (I) can exist in the form of enantiomers and diastereoisomers. These isomers and their mixtures also form part of the invention.

Preferably, the compounds of formula (I) are those in which:

that Het in formula (1) is selected from quinoline, pyridine, isoquinoline, pyrimidine, thiazole, thiadiazole, piperidine, these heterocycles being optionally substituted with one or more alkyl, halogen or oxo.

Even more particularly, the compounds of formula (I) are selected from among those compounds where:

Ri means a residue -N(R4)Rs, -N(R4)-SO2R6,

R2 means either a phenyl radical, optionally substituted with one or more halogens, or a heteroaromatic selected from pyridyl or pyrimidyl,

R3 means either phenyl which is optionally substituted with one or more halogen or a heteroaromatic selected from pyridyl or pyrimidyl,

R4 means a residue -C(Rn)(Ri2)-Het, -Het, -(CRu)(Ri2)-Ar, Ar or norbornyl,

R5 means a hydrogen atom or alkyl,

R6 means a residue -alk-CONR7R8 or alkyl,

R7 and Rg are the same or different and mean a hydrogen atom or an alkyl residue,

Rn means a hydrogen atom,

Ri2 means a hydrogen atom,

Ar means a phenyl radical optionally substituted with one or more halogen, alkoxy, hydroxy or hydroxyalkyl,

Het means a heterocycle selected from quinoline, pyridine, isoquinoline, pyrimidine, thiazole, thiadiazole, these heterocycles being optionally substituted with one or more alkyl, halogen or oxo,

their optical isomers and their salts with pharmaceutically acceptable mineral and organic acids.

Among the preferred compounds, one can choose the following compounds: N-{1-fris-(4-chlorophenyl)methyl]azeti N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-( 6-ethylpyrid-2-yl)-methylsulfonamide,

N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-^

N-{1-[bis-(4-Chlorophenyl)methyl]azeit(hn-3-yl}^^).

N-{1-phtis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-isoquinol-5-yl-methylsulfonamide,

N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-pyrid-3-yl-methylsulfonam N- {1 - [bis-(4-chlorophenyl)methyl]azetidin-3- yl}-N-(1-oxy-pyrid-3-yl)-methylsulfonamide,

N-(1R,2S,4S)-bicyclo[2,2,1]hept-2-yl-N-{1-[bis-(4-chlorophenyl)methyl]azeitdin-3-y^methylsulfonamide,

N-(1R,2R,4S)-bicyclo[2,2,1]hept-2-yl-N-{1-frees^^ methylsulfonamide,

N-{l-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)-methylsulfonarm N-{l-[bis-(4-chlorophenyl)methyl]azetidin- 3-yl}-N-(thiazol-2-yl)-methylsulfonamide,

N-{1-(^is-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3-methoxyphenyl)-methylsulfonamide,

N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3-hydroxyphenyl)methylsulfonamide,

N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3-hydroxymethyl-phenyl)-methylsulfonamide,

Ethyl-N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(methylsulfonyl)-3-aminobenzoate,

N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(1-isobutyl-piperid-4-yl)-methylsulfonamide,

N-benzyl-N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}amine,

N-{1-|^is-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorobenzyl)amine,

N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorobenzyl)-methylsulfonarm N- {1-[bis-(4-chlorophenyl) methyl]azetidin-3-yl}-N-(pyridin-3-yl-methyl)-methylsulfonamide,

N-{1-tris-(4-fluorophenyl)methyl]azetidem^

(RS)-N-{1-[(4-chlorophenyl)-pyridin-3-yl-methyl]azetidin-3-yl}-N-(3,5-difluorophenyl) sulfonamide,

(R)-N- {1-[(4-chlorophenyl)-pyrid-3-yl-methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)-methylsulfonamide,

(S)-N-{1-[(4-Chlorophenyl)-pyrid-3-yl-methyl]roxy sulfonamide,

(RS)-N-{1-[(4-chlorophenyl)-pyrid-4-yl-m^ sulfonamide,

(R)-N-{1-[(4-chlorophenyl)-pyrid-4-yl-methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)-methylsulfonamide,

(S)-N-{1-[(4-chlorophenyl)-pyrid-4-yl-methyl]azeti^ sulfonamide,

(RS)-N-{1-[(4-chlorophenyl)-pyrimidin-5-yl-methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)methylsulfonamide,

(R)-N-{1-[(4-Chlorophenyl)-pyriminium^^ methylsulfonamide,

(S)-N- {1-[(4-chlorophenyl)-pyrimidin-5-yl-methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)-methylsulfonamide,

N-{1-[(4-Chlorophenyl)-methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)-benzyl their optical isomers and their pharmaceutically acceptable salts.

The compounds of formula (I) where Ri means a residue -N(R4)Rs, R5 is a hydrogen atom,

-N(R4)-CO-R5, -N(R4)-SO2R6, R4 is a residue -C(Rn)(Ri2)-Ar or - C(Rn)(Ri2)-Het and R12 is a hydrogen atom is prepared in according to the following reaction scheme:

In these formulas, R2, R3, R$ and Rn have the same meaning as in formula (I), Rb means a residue Ar or Het, Ar and Het having the same meaning as in formula (I) and Hal means a halogen atom and preferably chlorine or bromine.

Step a is generally carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorinated solvent such as dichloromethane or chloroform, at a temperature between 15°C and 30°C and in the presence of a base, for example trialkylamine such as triethylamine or dipropylethylamine, or in pyridine, at a temperature between 0 and 30°C.

Step b is preferably carried out in methanol, in an autoclave and at a temperature between 50°C and 70°C.

Step c is generally carried out in an inert solvent, for example a chlorinated solvent such as dichloromethane, in the presence of sodium triacetoxyborohydride and acetic acid, at a temperature close to 20°C.

Steps d and e are generally carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorinated solvent such as dichloromethane or chloroform, in the presence of an amine, for example a trialkylamine such as triethylamine, at a temperature between 5°C and 20°C.

The Rb-CORn derivatives are commercial or can be obtained according to methods as described for example by R.C. Larock in "Comprehensive Organic Transformations", VCH publisher.

The Hal-SO 2 R 6 derivatives are commercial or can be obtained by halogenation of the corresponding sulphonic acids, particularly in situ in the presence of chlorosulphonyl isocyanate and alcohol, in a halogenated solvent such as dichloromethane or chloroform.

The Hal-CORs derivatives are commercial or can be prepared by halogenation of the corresponding carboxylic acids, particularly in situ in the presence of thionyl chloride in a halogenated solvent such as dichloromethane or chloroform.

The azetidinols 1 can be obtained using or adapting methods described by A.R. Katritzky et al. in "J. Heterocycl. Chem.", 271 (1994) or by P.R. Dave in "J. Org. Chem.", 61, 5453 (1996), and in the examples. One generally works according to the following reaction scheme:

where R2 and R3 have the same meanings as in formula (I) and Hal means a chlorine or bromine atom.

In step A, one preferably works in an inert solvent, for example an aliphatic Ci_4 alcohol such as ethanol or methanol, possibly in the presence of an alkali metal hydroxide and at the boiling temperature of the reaction medium.

In step B, the reduction is generally carried out using lithium aluminum hydride in tetrahydrofuran at the boiling temperature of the reaction medium.

In step C, one preferably works in an inert solvent, for example an aliphatic Ci-4 alcohol such as ethanol or methanol, in the presence of sodium bicarbonate and at a temperature between 20°C and the boiling temperature of the reaction medium.

In step D, one works according to the method described by M. Grisar et al. in "J. Med. Chem.", 885 (1973). The magnesium compound is formed from a bromine derivative and then the nitrile is converted into an ether such as ethyl ether at a temperature between 0°C and the boiling temperature of the reaction medium. After hydrolysis with an alcohol, the imide intermediate is reduced in situ with sodium borohydride at a temperature between 0°C and the boiling temperature of the reaction medium.

The R2-CO-R3 derivatives are commercial or can be obtained by applying or adapting the methods described by N.G. Customers et al. in "J. Chem. Soc. Perkin Trans", 1, 2815 (1997); by M. Moreno-Marras in "Eur. J. Med. Chem.", 23 (5) 477 (1988); by Skinner et al. in "J. Med. Chem.", 14 (6) 546 (1971); by N.K. Hurn in "Tet. Lett.", 36 (52) 9453 (1995); by A. Medici et al. in "Tet. Lett.", 24 (28) 2901 (1983); by R.D. Riecke et al. in "J. Org. Chem.", 62 (20) 6921 (1997); by J. Knabe et al. in "Arch. Pharm.", 306 (9) 648 (1973); by R. Consonni et al. in "J. Chem. Soc. Perkin Trans.", 1, 1809 (1996); as well as in FR-96-2481 and JP-94-261393.

The R3Br derivatives are commercial or can be obtained by using or adapting the methods described by L. Brandsma et al. in "Synth. Comm.", 20 (11) 1697 and 3153 (1990); by M. Lemaire et al. in "Synth. Comm.", 24 (1) 95 (1994); by H. Goda et al. in "Synthesis", 9, 849 (1992); and by P. Baeuerle et al. in "J. Chem. Soc. Perkin Trans.", 2, 489 (1993).

The R2CN derivatives are commercial or can be obtained using or adapting the methods described by P. Bouyssou et al. in "J. Het. Chem.", 29 (4) 895 (1992); by N. Suzuki et al. in "J. Chem. Soc. Chem. Comm.", 1523 (1984); by S. Marburg et al. in "J. Het. Chem.", 17 1333 (1980); and by V. Percec et al. in "J. Org. Chem.", 60 (21) 6895

(1995).

The compounds of formula (I) where Ri means a residue -N(R4)Rs can be prepared according to the following reaction scheme:

where R2, R3, R4 and R5 have the same meaning as in formula (I).

This reaction is generally carried out in an inert solvent, for example a chlorinated solvent such as dichloromethane, in the presence of sodium triacetoxyborohydride and acetic acid, at a temperature close to 20°C.

The compounds HN(R4)Rs are commercial or can be prepared according to classical methods as well known to those skilled in the art or by applying or adapting to methods as described by K.K. Park et al. in "J. Org. Chem.", 60 (19) 6202 (1995); by A. Kalir et al. in "J. Med. Chem.", 12 (3) 473 (1969); by R. Sarges in "J. Org. Chem.", 40 (9) 1216

(1975); H.E. Zaugg in "J. Org. Chem.", 33 (5) 2167 (1968); "Med. Chem.", 10,128

(1967); J. Am. Chem. Soc.", 2244 (1955); Chem. Ber., 106, 28990 (1973); "Chem. Pharm. Bull.", 16 (10) 1953 (1968); "Bull. Soc. Chim. Fr., 835 (1962).

The azetidinones 2 can be obtained by oxidation of the corresponding azetidinols, preferably in dimethylsulfoxide, with the help of sulphur-pyridine thyroxide complexes at a temperature close to 20°C or with the help of dimethylsulfoxide in the presence of oxalyl chloride and triethylamine at a temperature between -70°C and -50 °C.

The compounds of formula (I) where R1 means a residue -N(R4)COR5 or -N(R4)SO2R6 can be prepared according to the following reaction scheme:

In these formulas, R 2 , R 3 , R 4 , R 5 and R 5 have the same meaning as in formula (I) and Hal means a halogen atom and preferably chlorine.

Steps a and b are generally carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorinated solvent such as dichloromethane or chloroform, in the presence of an amine, for example a trialkylamine such as triethylamine, at a temperature between 5°C and 20°C.

The compounds of formula (I) where R 1 means a residue -N(R 4 )-SO 2 -R 6 , where R 4 is a residue Het or Ar, can be prepared according to the following reaction scheme:

where R2, R3 and R6 have the same meaning as in formula (I), Rd means a residue Ar or Het where Het and Ar have the same meanings as in formula (I) and Ms means a methylsulfonyloxy acid residue.

Step a is generally carried out in an inert solvent such as tetrahydrofuran in the presence of triphenylphosphine and diethyl azodicarboxylate at a temperature between 0°C and the boiling temperature of the reaction mixture.

Step b is generally carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorinated solvent such as dichloromethane or chloroform, at a temperature between 15°C and 30°C, in the presence of a base, for example a trialkylamine such as triethylamine or dipropylethylamine, or in pyridine, at a temperature between 0°C and 30°C.

Step c is generally carried out in an inert solvent such as dioxane in the presence of CSCO 3 at the reflux temperature of the reaction mixture.

The compounds where Rd means an N-oxidized nitrogen heterocycle can be obtained by reduction of non-oxidized compounds according to the method described by E. Sanghanel et al. in Synthesis, 1375 (1996).

The compounds Rd-NH-SCkRe can be obtained according to the following reaction scheme:

where Hal means a halogen atom and Rd a residue Het or Ar. The reaction takes place in an inert solvent such as tetrahydrofuran, dioxane, a chlorinated solvent such as dichloromethane or chloroform, at a temperature between 15°C and 30°C, in the presence of a base, for example trialkylamine such as triethylamine or dipropylethylamine, or in pyridine , at a temperature between 0°C and 30°C.

The compounds where Rd means an N-oxidized nitrogen heterocycle can be obtained according to the method described by R. Rhie in "Heterocycles", 41 (2) 323 (1995).

The compounds of formula (I) can also be prepared according to the following reaction scheme:

where the formulas Ri, R2 and R3 have the same meanings as in formula (I) and Ph means phenyl.

Step a is generally carried out in an alcohol such as methanol, in the presence of sodium borohydride at a temperature close to 20°C.

In step b, the magnesium compound is prepared from the bromine derivative and this is reacted in an inert solvent such as ethyl ether or tetrahydrofuran, at a temperature between 0°C and the boiling temperature of the reaction medium.

Step c is carried out using a halogenating agent such as hydrobromic acid, thionyl bromide, thionyl chloride, a mixture of triphenylphosine and carbon tetrabromo- or tetrachloride, in acetic acid or in an inert solvent such as dichloromethane, chloroform, carbon tetrachloride or toluene, at a temperature between 0°C and the boiling temperature of the reaction mixture.

Step d is carried out using hydrogen in the presence of palladium-treated carbon in an alcohol such as methanol, at a temperature close to 20°C.

Step c is carried out in an inert solvent such as acetonitrile, in the presence of an alkali metal carbonate such as potassium carbonate, and potassium iodide, at a temperature between 20°C and the boiling temperature of the reaction mixture.

The R 3 Br compounds and the R 2 -CHO compounds are commercial or can be obtained according to methods described for example by R.C. Larock in "Comprehensive Organic Transformations", VCH publisher.

The compounds of formula (I) where Ri means a residue -N(R4)-SO2-R6, where R4 is a piperid-4-yl residue, optionally substituted on the nitrogen atom by an alkyl residue, are likewise prepared according to the following reaction scheme:

where R 2 , R 3 and R 6 have the same meaning as in formula (I), alk means an alkyl residue and Re means a tert-butylcarbonateoxy acid residue.

Step a is carried out in an inert solvent, for example a chlorinated solvent such as dichloromethane, in the presence of a hydride such as sodium triacetoxyborohydride and acetic acid, at a temperature between 0°C and the boiling temperature of the reaction medium.

Step b is generally carried out in an inert solvent such as tetrahydrofuran, dioxane, a chlorinated solvent such as dichloromethane or chloroform, in the presence of an amine, for example a trialkylamine such as triethylamine, at a temperature between 5°C and 20°C.

Step c takes place using hydrochloric acid in dioxane at a temperature between 0°C and the boiling temperature of the reaction medium.

Step d is carried out in any manner known to those skilled in the art to alkylate an amine without affecting the rest of the molecule. You can, for example, use an alkyl halide in the presence of an organic base, for example triethylamine, an alkali metal hydroxide such as sodium or potassium hydroxide, optionally in the presence of tetrabutyl ammonium bromide, in an inert solvent such as dimethylsulfoxide, dimethylformamide or pyridine, by a temperature between 20°C and 50°C.

It is known to the person skilled in the art that in order to carry out the processes according to the invention as described above, it may be necessary to introduce protective groups for the amino, hydroxy and carboxy functions in order to avoid secondary reactions. These groups are such that can be removed later without affecting the rest of the molecule. As examples of protective groups for the amino function, tert-butyl or methyl carbamates can be mentioned which can be regenerated with the help of allyl or iodotrimethylsilane with the help of palladium catalysts. Examples of protective groups for the hydroxy function include triethylsilyl, tert-butyldimethylsilyl, which can be regenerated using tetrabutylammonium fluoride or also asymmetric acetals such as methoxymethyl or tetrahydropyranyl, with regeneration using hydrochloric acid. Mention may be made of esters such as allyl or benzyl, oxazoles and 2-alkyl-1,3-oxazolines as protective groups for the carboxy functions. Other useful protecting groups are described by T.W. Green et al. in "Protecting Groups in Organic Synthesis", 2nd edition, 1991, John Wiley & Sons.

The compounds of formula (I) can be purified by known, common methods such as crystallization, chromatography or extraction.

The enantiomers of the compounds of formula (I) can be obtained by resolution of the racemates, for example by column chromatography on chiral columns according to W.H. Pirkle et al. in "Asymmetric synthesis", vol. 1, Academic Press (1983), or by formation of salts or by synthesis from chiral precursors. The diastereoisomers can be prepared according to known, classical methods such as crystallization, chromatography or from chiral precursors.

The compounds of formula (I) can optionally be transferred to addition salts with mineral or organic acids by the action of such an acid in an organic solvent, for example an alcohol or a ketone, an ether or a chlorinated solvent. These salts also form part of the invention.

Examples of pharmaceutically acceptable salts include the following: benzenesulfonate, hydrobromide, hydrochloride, citrate, ethanesulfonate, fumarate, gluconate, iodate, isethionate, maleate, methanesulfonate, methylene-bis-b-oxynaphthoate, nitrate, oxalate, pamoate, phosphate , salicylate, succinate, sulfate, tartrate, theophylline acetate and p-toluenesulfonate.

The compounds of formula (I) exhibit interesting pharmacological properties. The compounds have a strong affinity for cannabioid receptors and especially those of the CB1 type. They are antagonists for receptor CB1 and are thus useful in the therapy and prevention of disorders affecting the central nervous system, the immune system, the cardiovascular or endocrine system, the respiratory system, the gastrointestinal tract and reproductive disorders, (see Hollister in "Pharm. Ree.", 38, 1986,1-20; Reny and Sinha in "Prog. Drug. Res.", 36,71-114 (1991); Consroe and Sandyk in "Marijuana/Cannabinoids, Neurobiology and Neurophysiology", 459, L. Murphy and A. Barthe, ed. CRC Press, 1992).

Thus, the compounds described here can be used for the therapy or prevention of psychoses, including schizophrenia, anxiety problems, depression, epilepsy, neurodegeneration, cerebellar and spinocerebellar disorders, cognitive disorders, cranial trauma, panic attacks, peripheral neuropathies, glaucoma, migraines, Parkinson's disease, Alzheimer's disease, Huntington's chorea, Raynaud's syndrome, tremors, compulsive-obsessional disorders, senile dementia, thymic disorders, Tourette's syndrome, tardive dyskinesia, bipolar disorders, cancers, movement disorders induced by drugs, dystonias, endotoxemic shocks, hemorrhagic shocks, hypertension, insomnia, immunological diseases, multiple sclerosis, vomiting, asthma, appetite problems such as bulemia and anorexia, obesity, memory difficulties, difficulties in connection with treatment after chronic use and abuse of alcohol or drugs such as opioids, bartiturates, cannabis, cocaine, amphetamine, phencyclide, hallucinogens, benzodiazepines and re, as analgesics or potentiators for the analgesic effect of narcotic and non-narcotic drugs. They can also be used for therapy or prevention of intestinal transit.

The affinity of the compounds of formula (I) for cannabis receptors is determined according to the method described by J.E. Kuster, J.I. Stevenson, S.J. Ward, T.E. D'Ambra as well as D.A. Haycock in "J. Pharmacol. Exp. Ther.", 264, 1352-1363 (1993).

In this test, the CI 50 value of the compounds of formula (I) is equal to or less than 1000 nM.

Their antagonistic activity has been demonstrated using a hypothermic model induced by an agonist of cannabis receptors (CP-55940) in mice, according to the method described by R.G. Pertwee in "Marijuana," D.J. Harvey, ed., 84 Oxford IRL Press, 263-277 (1985).

In this test, the DE 50 value for the compounds of formula (I) is equal to less than 50 mg/kg.

The compounds of formula (I) exhibit a low toxicity. Their DLso value is greater than 40 mg/kg subcutaneously in mice.

The following examples shall illustrate the invention.

Example 1

N-{l-[bis-(4-chlorophenyl)methyl]-azetidim-3-yl^ is prepared by working in the following manner: To a solution of 1.54 g of l-[bis-(4-chloro-phenyl) methyl]azetidin-3-ol and 1.22 g of N-(6-chloropyrid-2-yl)methylsulfonamide in 120 cm<3 >anhydrous tetrahydrofuran are placed, under argon, 2.4 cm<3> of diethyl azodicarboxylate and 1.44 g triphenylphosphine. After stirring for 20 hours at 20°C, concentrate to a dry state at 2.7 kPa. The residue is chromatographed on a silica gel column with granulometry 0.040-0.063 mm, height 30 cm and diameter 4.5 cm, eluting under an argon pressure of 0.5 bar with cyclohexamethyl acetate in a volume ratio of 80:20 and fractions of 60 cm<3 are recovered. >Fractions 6 to 9 are combined and concentrated to dryness at 2.7 kPa. 1.75 g of N-{1-1>is-(4-chlorophenyl)methyl]-azetimid-3-yl}-N-(6-chloropyrid-2-yl)-methylsulfonamide is obtained in the form of a white meringue mass.

<l>H-NMR (300 MHz, CDCl3.8 in ppm): from 2.85 to 3.00 (mt, 2H), 2.91 (s, 3H), 3.57 (t cleaved, J = 7 and 2 Hz, 2H), 4.25 (s, 1H), 4.64 (mt, 1H), from 7.20 to 7.35 (mt, 9H), 7.36 (dd, J = 8 and 1 Hz, 1H), 7.71 (t, J = 8 Hz, 1H). 1-[bis-(4-chlorophenyl)methyl]azetidin-3-ol can be prepared according to the method described by A.R. Katritzky et al. in "J. Heterocycl. Chem.", 271 (1994) starting from 35.5 g of [bis-(4-chlorophenyl)methyl}amine hydrochloride and 11.0 cm 3 of epichlorohydrin. 9.0 g of 1-[bis-(4-chlorophenyl)methyl]azetidin-3-ol are isolated.

|^is-(4-chlorophenyl)methyl}arnine hydrochloride can be prepared according to the method described by M. Grisar et al. in "J. Med. Chem.", 885 (1973).

N-(6-chloropyrid-2-yl)methylsulfonamide can be prepared by working as follows: To a solution cooled to +5°C of 2-amino-6-chloropyridine in 12.5 cm3 of pyridine, pour dropwise over 1 hour 7.8 cm<3> methylsulfonyl chloride. After returning to normal temperature and stirring for 20 hours, the black reaction mixture is added to 140 cm3 of water and extracted with 200 cm3 of dichloromethane. The organic phase is decanted, dried over magnesium sulphate, filtered and concentrated to dryness at 2.7 kPa. The oily residue obtained is chromatographed over a silica gel column with granulometry 0.063-0.200 mm, height 30 cm and diameter 4 cm, eluting under an argon pressure of 0.5 bar with cyclohexane:ethyl acetate in the volume ratio 70:30 and fractions of 60 cm<3. >Fractions 5 to 11 are combined and concentrated to dryness at 2.7 kPa. 17 g of N-(6-chloropyrid-2-yl)methylsulfonamide are obtained in the form of a yellow oil.

Example 2

N-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(t-ethylpyrid-2-yl)-methylsulfonamide can be prepared by working as described in Example 1, from 0, 61 g of 1-[bis-(4-chlorophenyl)-methyl]azetidin-3-ol, 0.40 g of N-(6-ethylpyrid-2-yl)methylsulfonamide, 50 cm3 of anhydrous tetrahydrofuran, 0.96 cm3 of diethyl azodicarboxylate and 0.577 g triphenylphosphine. The crude product is chromatographed over a silica gel column with granulometry 0.040-0.063 mm, height 20 cm, diameter 2 cm, eluting under an argon pressure of 0.5 bar with cyclohexane:ethyl acetate in the volume ratio 70:30 and fractions of 30 cm< 3>. Fractions 6 to 9 are combined and concentrated to dryness at 2.7 kPa. 0.3 g of an oil is obtained which is triturated in a mixture of 5 cm 3 of diethyl oxide and 5 cm 3 of diisopropyl oxide. The suspension is filtered, the solid is poured off, dried at 2.7 kPa. 0.11 g of N-{1-|>is-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(t-ethylpyrid-2-yl)-methylsulfonamide is obtained in the form of a white solid.

'H-NMR (300 MHz, CDCl3.8 in ppm): 1.26 (t, J = 7,5,3H), 2.76 (q, J = 7,5,2H), from 2.85 to 2.95 (mt, 2H), 2.90 (s, 3H), 3.53 (t split, J = 7 and 2 Hz, 2H), 4.22 (s, 1H), 4.69 (mt, 1H), 7.07 (d, J = 7.5 Hz, 1H), from 7.15 to 7.30 (mt, 9H), 7.64 (t, J = 7.5 Hz, 1H).

N-(6-ethylpyrid-2-yl)methylsulfonamide can be prepared by working as follows: To a solution cooled to +5°C of 2.50 g of 2-amino-6-ethylpyridine in 2.50 cm<3> pyridine is poured dropwise into 1.56 cm3 of methylsulfonyl chloride. After stirring for 20 hours at 20°C, 8 cm3 of water is added to the reaction mixture and filtered. The filtrate is concentrated to dryness at 50°C and 2.7 kPa. The residue is chromatographed on a silica gel column with granulometry 0.040-0.063 mm, height 30 cm and diameter 4 cm, eluting under an argon pressure of 0.5 bar with 1.5 liters of dichloromethane and then with dichloromethane:methanol in the volume ratio 98:2, fractions of 60 cm<3> are recovered. Fractions 8 to 12 are combined and concentrated to dryness at 2.7 kPa. 2.8 g of N-(6-ethylpyrid-2-yl)methylsulfonamide are obtained in the form of a yellow oil.

Example 3

N-{l-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-quinol-6-yl-methylsulfonamide can be prepared by working as follows: To a solution of 0.50 g of N -quinol-6-yl-methylsulfonamide in 50 cm3 of anhydrous tetrahydrofuran is placed under argon 0.70 g of 1-[bis-(4-chloro-phenyl)methyl]azetidin-3-ol, 0.597 g of triphenylphosphine and then poured into 0.40 cm<3> diethyl azodicarboxylate. After stirring for 20 hours at 20°C, the reaction mixture is heated to reflux for 4 hours and 2.98 g of triphenylphosphine and 2.0 cm3 of diethyl azodicarboxylate are added. After stirring for 48 hours at 20°C, the mixture is concentrated to a dry state at 2.7 kPa. The residue is taken up in 30 cm<3> of diethyl oxide, after which the resulting suspension is filtered and the filtrate is then concentrated to dryness. A fraction of 0.90 g of the obtained residue is purified on a Bond Elut column with SCX acid sulfonic acid cation exchange resin with granulometry 0.054 mm, height 4 cm and diameter 3 cm, eluting first with methanol and then with a 2 M ammonia solution in methanol to elute the expected product, recovering fractions of 5 cm<3>. Fractions 16 to 19 are combined and concentrated to dryness at 2.7 kPa. 0.33 g of an oil is obtained which is stirred in 10 cm<3> of diisopropyl oxide. The resulting suspension is filtered and the filtrate, filtered again, gives after 15 minutes a solid which dries at 50°C and 2.7 kPa. 83 mg of N-{1-|>is-(4-chlorophenyl)methyl]-azetito are obtained in the form of a white solid.

'H-NMR (300 MHz, CDCl3.8 in ppm): 2.87 (s, 3H), 2.89 (mt, 2H), 3.55 (t cleaved, J = 7

and 1 Hz, 2H), 4.18 (s, 1H), 4.69 (mt, 1H), from 7.15 to 7.30 (mt, 8H), 7.47 (dd, J = 8.5 and 4 Hz, 1H), 7.58 (dd, J = 9 and 2.5 Hz, 1H), 7.73 (d, J = 2.5 Hz, 1H), 8.10 to 8.20 (mt , 2H), 8.97 (dd, J = 4 and 1.5 Hz, 1H).

N-quinol-6-yl-methylsulfonamide can be prepared by working in the following way: To a solution cooled to +3°C of 1.98 g of 6-aminoquinoline in 1.75 cm3 of pyridine is poured dropwise over the course of 1 hour 1, 1 cm3 of methylsulfonyl chloride. After stirring for 20 hours at 20°C, 10 cm<3> of water and 50 cm3 of dichloromethane are added to the reaction mixture and filtered. The filtrate is decanted, the organic phase is dried over magnesium sulphate, filtered and concentrated to dryness at 2.7 kPa. 1.15 g of N-quinol-6-yl-methylsulfonamide is obtained in the form of a cream-coloured solid.

Example 4

N-{l-[^is-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-quinol-5-yl-methylsulfonamide can be prepared as follows: To a solution of 0.50 g of N-( quinol-5-yl)methylsulfonamide in 70 cm3 of anhydrous tetrahydrofuran is placed under argon 0.70 g of 1-[bis-(4-chlorophenyl)methyl]-azetidin-3-ol, 0.597 g of triphenylphosphine and then it is poured into 0.40 cm <3> diethyl azodicarboxylate and 0.45 g of 1,2-bis-(diphenylphosphine)ethane. After stirring for 20 hours at 20°C, the reaction mixture is concentrated to a dry state at 2.7 kPa. The residue is taken up in 70 cm<3> of ethyl acetate, after which the resulting solution is washed with 30 cm3 of brine, dried over magnesium sulfate, filtered and concentrated to dryness at 50°C and 2.7 kPa. The obtained violet oil is purified by chromatography on a silica gel column with granulometry 0.063-0.200 mm, height 35 cm and diameter 3.9, eluting under an argon pressure of 0.5 bar with cyclohexane:ethyl acetate in the volume ratio 40:60 -» 30: 70 -» 20:80 and as fractions of 50 cm<3> are recovered. Fractions 6 to 12 are combined and concentrated to dryness at 2.7 kPa. The residue is taken up in 15 cm3 of methanol and the resulting white suspension is filtered, the solid is poured off and dried at 50°C and 2.7 kPa. 0.35 g of N-{1-[is-(4-Morphenyl)methyl]-azetidin-3-yl}-N-quinol-5-yl-methylsulfonamide is obtained in the form of a white solid.

<*>H-NMR (300 MHz, CDC13.8 in ppm): 2.60 (t, J = 7 Hz, 1H), 2.84 (t, J = 7 Hz, 1H), 2.99 (s , 3H), 3.36 (t slotted, J = 7 and 2.5 Hz, 1H), 3.56 (t slotted, J = 7 and 2.5 Hz, 1H), 4.01 (s, 1H) , 4.85 (mt, 1H), from 7.10 to 7.25 (mt, 8H), 7.40

(dd, J = 7.5 and 1 Hz, 1H), 7.54 (dd, J = 8.5 and 4 Hz, 1H), 7.74 (dd, J = 8 and 7.5 Hz, 1H) , 8.20 (d large, J = 8 Hz, 1H), 8.54 (d large, J = 9 Hz, 1H), 8.99 (dd, J = 4 and 1.5 Hz, 1H).

N-(ldnol-5-yl)methylsulfonamide can be prepared by working as described in Example 3 from 2.0 g of 5-aminoquinoline, 3.0 cm<3> pyridine, 1.1 cm<3> methylsulfonyl chloride. 2.47 g of N-(quinol-5-yl)methylsulfonamide is obtained in the form of a brown-yellow solid.

Example 5

N-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-isoquinol-5-yl-methylsulfonamide can be prepared by working as described in Example 4 from 0.497 g of N-(isoquinol- 5-yl)-methylsulfonamide, 70 cc of anhydrous tetrahydrofuran, 0.712 g of 1-[bis-(4-chlorophenyl)methyl]-azetidin-3-ol, 0.597 g of triphenylphosphine, 0.40 cc of diethyl azodicarboxylate and 0.45 g 1,2-(diphenylphosphine)ethane. The brown crude oil obtained is purified by chromatography on a silica gel column with granulometry 0.063-0.200 mm, height 38 and diameter 3 cm, eluting with cyclohexane:ethyl acetate in the volume ratio 30:70 and recovering fractions of 40 cm<3>. Fractions 8 to 23 are combined and concentrated to dryness at 2.7 kPa. The residue is stirred in 15 cm3 of diethyl oxide, after which the suspension is filtered and the insoluble is chromatographed on an SCX resin column with a height of 4 cm and a diameter of 3 cm, washing with methane/dichloromethane in the volume ratio 50:50 and then eluting with a 2 M ammonia solution in methanol and it is recovered fractions of 20 cm<3>. Fractions 1 to 6 are combined and the white insoluble material is filtered, the solid is poured off and dried at 50°C and 2.7 kPa. 0.169 g of N-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-isoquinol-5-yl-methylsulfonamide is obtained in the form of a white solid.

<!>H-NMR (300 MHz, CDCl 3 , 8 in ppm): 2.64 (t, J = 7 Hz, 1H), 2.81 (t, J = 7 Hz, 1H),

2.98 (s, 3H), 3.36 (t split, J = 7 and 2 Hz, 1H), 3.55 (t split, J = 7 and 2 Hz, 1H), 4.02 (s, 1H ), 4.86 (mt, 1H), from 7.10 to 7.25 (mt, 8H), 7.60 (dd, J = 8 and 1 Hz, 1H), 7.66 (t, J = 8 Hz, 1H), 7.93 (d large, J = 6 Hz, 1H), 8.06 (d large, J = 8 Hz, 1H), 8.66 (d, J = 6 Hz, 1H), 9 ,32 (s large, 1H).

N-(isoquinol-5-yl)-methylsulfonamide can be prepared by working as described in example 4 from 2.0 g of 5-aminoisoquinoline, 3.0 cm3 of pyridine and 1.1 cm3 of methylsulfonyl chloride. 2.3 g of N-(isoquinol-5-yl)-methylsulfonamide is obtained in the form of a beige solid.

Example 6

N-{l-|>is-(4-chlorophenyl)methyl]-azetdin-3-yl}-N-pyrid-3-yl-methylsulfo^ can be prepared by working in the following manner: To a solution of 0.144 g of N -{ 1-[bis-(4-chloro-phenyl)methyl]-azetidin-3-yl}-N-(1-oxide-pyrid-3-yl)-methylsulfonamide in 5 cm<3> chloroform, pour 0.042 cm <3> phosphorus trichloride and then the mixture is heated to reflux. After stirring for 1 hour and 30 minutes, the reaction mixture is allowed to return to normal temperature and 5 cm<3> of 0.1N hydrochloric acid is added, after which the whole is stirred and decanted. The organic phase is diluted with 20 cm<3> chloroform, dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The residue is chromatographed on a silica gel column with granulometry 0.063-0.200 mm, height 9 cm and diameter 1.8 cm, eluting under an argon pressure of 0.1 bar with dichloromethane:methanol in the volume ratio 95:5 and fractions of 15 cm< 3>. Fractions 2 to 4 are combined and concentrated to dryness at 2.7 kPa. The residue is stirred with 15 cm3 of diethyl oxide. The suspension is filtered and the solid is poured off and dried at 2.7 kPa. 35 mg of N-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-pyrid-3-yl-methylsulfonamide is obtained in the form of a cream-colored solid.

<*>H-NMR (300 MHz, CDCl 3 , 8 in ppm): from 2.80 to 2.95 (mt, 2H), 2.87 (s, 3H), 3.51 (t cleaved, J = 7 and 1.5 Hz, 2H), 4.18 (s, 1H), 4.65 (mt, 1H), from 7.15 to 7.35 (mt, 8H), 7.37 (dd large, J = 8 and 5 Hz, 1H), 7.64 (d demultiplied, J = 8 Hz, 1H), 8.52 (d large, J = 2 Hz, 1H), 8.61 (d large, J = 5 Hz, 1H).

Example 7

N-{l-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(1-oxide-pyrid-3-yl)-methylsulfonamide can be prepared by working as follows: To a solution of 0.265 g of 1-[bis-(4-chlorophenyl)methyl]azetidin-3-ol and 0.162 g of N-(1-oxide-pyrid-3-yl)methylsulfonamide in 25 cm3 of anhydrous tetrahydrofuran are placed under argon 0.16 cm< 3> diethyl azodicarboxylate and 0.226 g of triphenylphosphm. After stirring for 20 hours at 20°C and then 24 hours at reflux temperature, the reaction mixture is concentrated to dryness at 2.7 kPa. The residue is chromatographed on a silica gel column with granulometry 0.063-0.2 mm, height 20 cm and diameter 1.5 cm, eluting under an argon pressure of 0.5 bar with dichloromethane:methanol in the volume ratio 98:2 and recovering fractions of 40 cm<3>. Reactions 26 to 64 are combined and concentrated to dryness at 2.7 kPa. The residue is stirred in 10 cm<3> of diethyl oxide, after which the suspension is filtered and insoluble substances are poured off and dried at 2.7 kPa. 0.10 g of N-{1-[bis-(4-chlorophenyl)methyl]-azetdin-3-yl}-N-(1-oxide-pyrid-3-yl)-methylsulfonamide is obtained in the form of a white solid .

'H-NMR (400 MHz, (CD3)2SO d6.8 in ppm): 2.78 (t, J = 7 Hz, 2H), 3.06 (s, 3H), 3.37 (t,

J = 7 Hz, 2H), 4.45 (s, 1H), 4.71 (mt, 1H), from 7.30 to 7.50 (mt, 10H), 8.21 (d large, J = 6 .5 Hz, 1H), 8.27 (s large, 1H).

N-(1-oxide-pyrid-3-yl)methylsulfonamide can be prepared by working as follows: To a solution of 1.81 g of N-pyrid-3-yl-methylsulfonamide in 71 cm<3> N,N- dimethylformamide and 3 cm<3> of methanol are added portionwise to 7.1 g of 50-55% 3-chloroperoxybenzoic acid and then 0.56 cm<3> of 40% hydrofluoric acid. After stirring for 1 hour at 20°C, the reaction mixture is poured into 500 g of ice, stirred and filtered. The filtrate is concentrated to dryness at 60°C and 2.7 kPa. The residue is taken up in 50 cm<3> dichloromethane:methanol in the volume ratio 98:2 and filtered. The filtrate is chromatographed on a silica gel column with granulometry 0.063-0.2 mm, height 27 cm and diameter 4 cm, being eluted under an argon pressure of 0.5 bar with dichlorometammethanol in the volume ratio 98:2 -» 97:3 -> 50:50 and fractions of 60 cm<3> are recovered. Fraction 62 is concentrated to dryness at 2.7 kPa. 0.96 g of N-(1-oxide-pyrid-3-yl)methylsulfonamide is obtained in the form of a yellowish solid.

N-pyrid-3-yl-methylsulfonamide can be prepared by working as described in example 1 for 2 g of 3-aminopyridine, 5 cm<3> pyridine and 1.8 cm<3> methylsulfonyl chloride. The crude product obtained is stirred in 40 cm<3> of diethyl oxide, after which the suspension is filtered and the solid is poured off and dried at 2.7 kPa. 2.47 g of N-pyrid-3-yl-methylsulfonamide are obtained in the form of a pinkish solid.

Example 8

N-{l-(bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-cyclohexyl-methylsulfonamide can be prepared by working as follows: To a solution of 1.8 g of N-{l- [bis-(4-chloro-phenyl)methyl]-azetidin-3-yl}-N-cyclohexylamine, 0.7 cm<3> triethylamine and 20 mg of 4-dimethylaminopyridine in 25 cm<3> dichloromethane, are placed under stirring 0 .4 cm<3> of methylsulfonyl chloride. After stirring for 48 hours at 20°C, 20 cm<3> of dichloromethane, 20 cm<3> of water are added to the reaction mixture and the whole is stirred and decanted. The organic phase is dried over magnesium sulfate and concentrated at 50 °C and 2.7 kPa. The brown, oily residue is chromatographed on a silica gel column with granulometry 0.063-0.2 mm, height 30 cm and diameter 1.5 cm, eluting under an argon pressure of 0.1 bar with dichlorometammethanol in volume ratio 96:4 and fractions of 10 cm<3> are recovered. Fractions 2 to 4 and 5 to 10 are combined and concentrated to dryness at 2.7 kPa. The residue is chromatographed on a silica gel column with granulometry 0.063-0.2 mm, h diameter 30 cm and diameter 1.5 cm, as it is eluted under a pressure of 0.1 bar argon with cyclohexamethyl acetate in the volume ratio 70:30 and fractions of 5 cm<3 are recovered. >Fractions 7 to 10 are combined and concentrated to dryness at 2.7 kPa. 0.10 g of N-{1-|bis-(4-chlorophenyl)methyl]-azetid^n-3-yl}-N-cyclohexyl-methylsulfonar^ is obtained in the form of a cream-colored meringue mass.

<J>H-NMR (300 MHz, CDC13.8 in ppm): from 0.80 to 1.9 (mt, 10H), 2.82 (s, 3H), 3.36 (t large, J = 7 .5 Hz, 2H), 3.46 (t large, J = 7.5 Hz, 2H), 3.59 (mt, 1H), 4.08 (mt, 1H), 4.42 (s, 1H) , from 7.20 to 7.40 (mt, 8H).

N-{l-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-cyclohexylamine can be prepared by working as follows: To a solution of 1.5 g of l-[bis-(4 -chlorophenyl)methyl]azetidin-3-one in 25 cm<3>1,2-dichloroethane, add 0.5 g of cyclohexylamine, 1 g of sodium triacetoxyborohydride and 0.3 cm3 of 100% acetic acid. After stirring for 20 hours at 20°C, 20 cm<3> of dichloromethane and 10 cm<3> of water are added while stirring and the whole is then neutralized to pH 7 to 8 with a 1N aqueous sodium hydroxide solution. The mixture is decanted, the organic phase is decanted, dried over magnesium sulphate, filtered and concentrated to dryness at 50°C and 2.7 kPa. 1.8 g of N-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-cyclohexylamine is obtained in the form of a cream-colored paste which is used as such in the subsequent steps. l-[bis-(4-chlorophenyl)methyl]azetidin-3-one can be prepared as follows: To a solution of 5.0 cm<3> oxalyl chloride in 73 cm<3> dichloromethane cooled to -78°C, add a solution of 8.1 cm<3> of dimethylsulfoxide in 17.6 cm<3> of dichloromethane. After 0.5 hours at -78°C, it is poured into a solution of 16.0 g of 1-[bis-(4-chlorophenyl)methyl]azetidin-3-ol, dissolved in 50 cm<3> of dichloromethane. After 5 hours at -78°C, 26.6 cm<3> of triethylamine is added dropwise and the reaction mixture is allowed to return to ambient temperature. After 16 hours, the reaction mixture is washed with 4 x 200 cm<3> of water and then with 200 cm<3> of saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The obtained residue is chromatographed on a silica gel column with granulometry 0.04-0.06 mm, diameter 9.2 cm and height 21 under an argon pressure of 0.5 bar with ethyl acetate cyclohexane in the volume ratio 40:60 as eluents and fractions of 200 cm<3>. Fractions 15 to 25 are combined and concentrated to dryness at 2.7 kPa. 8.9 g of 1-[bis-(4-chlorophenyl)methyl]azetidin-3-one is obtained in the form of pale yellow crystals which melt at 1H°C.

Example 9

N-{l-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-cyclopropyl-methylsulfonamide can be prepared by working as described in Example 8 from 1.6 g of N-{l-[bis -(4-chlorophenyl)methyl]-azetidin-3-yl}-N-cyclopropylamine, 25 cm<3> dichloromethane, 0.7 cm<3> triethylamine, 20 mg 4-dimethylaminopyridine and 0.4 cm<3> methylsulfonyl chloride , stirring the mixture for 20 hours at 20°C. The crude product is chromatographed on a silica gel column with granulometry 0.063-0.2 mm, height 30 cm and diameter 2.0 cm, eluting under an argon pressure of 0.1 bar with dichlorometammethanol in the volume ratio 97:3 and fractions of 10 cm< 3>. Fractions 6 to 9 and 10 to 20 are combined and concentrated to dryness at 2.7 kPa. The residue obtained is chromatographed on a silica gel column with granulometry 0.063-0.2 mm, height 30 cm and diameter 2.0 cm, eluting under an argon pressure of 0.1 bar with cyclohexane:ethyl acetate in the volume ratio 70:30 and recovering fractions of 10 cm<3>. Fractions 6 to 11 are combined and concentrated to dryness at 2.7 kPa. 0.14 g of N-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-cyclopropyl-methylsulfonamide is obtained in the form of a cream-colored meringue mass.

1H-NMR (300 MHz, CDCl3.8 in ppm): 0.79 (mt, 2H), 0.95 (mt, 2H), 2.11 (mt, 1H), 2.84

(s, 3H), 3.17 (t large, J = 7 Hz, 2H), 3.50 (mt, 2H), 4.18 (mt, 1H), 4.29 (s, 1H), from 7 .20 to 7.40 (mt, 8H).

N-{l-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-cyclopropylamine can be prepared by working as described in Example 8 from 1.5 g of l-[bis-(4-chlorophenyl )methyl]azetidin-3-one, 25 cm<3>1,2-dichloroethane, 0.37 cm<3> cyclopropylamine, 1 g sodium triacetoxyborohydride and 0.3 cm<3> 100% acetic acid. 1.6 g of N-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-cyclopropylamine are obtained in the form of a brown oil which is used as such in the following step.

Example 10

N-(1R,2S,4S)-bicyclo[2,2,1]hept-2-yl-N-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-methylsulfonamide can be prepared by working as described in Example 8 from 2.0 g of N-(1R,2S,4S)-bicyclo[2,2,1]hept-2-yl-N-{1-[bis-(4-chlorophenyl) methyl]-azetidin-3-yl}amine, 25 cm<3> dichloromethane, 0.7 cm<3> triethylamine, 20 mg of 4-dimethylaminopyridine and 0.4 cm<3 >methylsulfonyl chloride while stirring for 20 hours. The brown, oily residue is chromatographed on a silica gel column with granulometry 0.063-0.2 mm, height 30 cm and diameter 2.0 cm, eluting under an argon pressure of 0.1 bar with dichlorometammethanol in the volume ratio 97:3 and fractions are recovered of 10 cm<3>. Fractions 6 to 18 are combined and concentrated to dryness at 2.7 kPa. The residue is chromatographed on a silica gel column with granulometry 0.063-0.2 mm, height 30 cm and diameter 2.0 cm, eluting under an argon pressure of 0.1 bar with cyclohexane:ethyl acetate in the volume ratio 70:30 and fractions of 10 cm are recovered <3>. Fractions 8 to 14 are combined and concentrated to dryness at 2.7 kPa. 0.70 g of N-(1R,2S,4S)-bicyclo-[2,2,1]hept-2-yl-N-{1-|^is-(4-chlorophenyl)methyl]-azetidin- 3-yl}-methylsulfonamide in the form of a cream-colored meringue mass.

<!>H-NMR (300 MHz, CDC13.8 in ppm): from 1.20 to 1.75 (mt, 7H), 1.84 (t large, J = 12.5

Hz, 1H), 2.29 (mt, 1H), 2.35 (mt, 1H), 2.82 (s, 3H), from 3.35 to 3.55 (mt,

3H), 3.66 (mt, 1H), from 3.90 to 4.05 (mt, 2H), 4.51 (s, 1H), from 7.20 to 7.45 (mt, 8H).

NKlR,2S,4S)-bicyclo[2,2,1]hept-2-yl-N-{l-[bis-(4-chlorophenyl)methyl]-azetimn-3-yl}amine can be prepared by working as described in Example 8 from 1.5 g of 1-[bis-(4-chlorophenyl)-methyl]azetidin-3-one, 25 cm<3> 1,2-dichloroethane, 1.5 gN-(1R,2S,4S )-bicyclo[2,2,1]hept-2-amine, 1 g of sodium triacetoxyborohydride and 0.3 cm<3>100% acetic acid. 2 g of N-(1R,2S,4S)-bicyclo[2,2,1]hept-2-yl-N-{1-|>is-(4-chlorophenyl)methyl]-azetimn-3-yl are obtained }amine in the form of a brown oil which is used as such in the subsequent step.

Example 11

N-(1R,2R,4S)-bicyclo[2,2,1]hept-2-yl-N-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-methylsulfonamide can be prepared by working as described in Example 8 from 1.8 g of N-(1R,2R,4S)-bicyclo[2,2,1]hept-2-yl-N-{1-[bis-(4-chlorophenyl) methyl]-azetdin-3-yl}-amine, 25 cm3 of dichloromethane, 0.7 cm<3> triethylamine and 20 mg of 4-dimethylaminopyridine and 0.4 cm3 of methylsulfonyl chloride, stirring for 20 hours. The brown oil residue is chromatographed on a silica gel column with granulometry 0.063-0.2 mm, height 30 cm and diameter 2.0 cm, eluting under an argon pressure of 0.1 bar with cyclohexamethyl acetate in the volume ratio 60:40, recovering fractions of 10 cm<3>. Fractions 3 to 12 are combined and concentrated to dryness at 2.7 kPa. The residue is chromatographed on a silica gel column with granulometry 0.063-0.2 mm, height 30 cm and diameter 2.0 cm, eluting under an argon pressure of 0.1 bar with cyclohexane:ethyl acetate in the volume ratio 70:30 and fractions of 10 cm<3>. Fractions 4 to 10 are combined and concentrated to dryness at 2.7 kPa. 0.10 g of N-(1R,2R,4S)-bicyclo-[2,2,1]hept-2-yl-N-{1-[bis-(4-chlorophenyl)methyl]-azetidine-3 -yl}-methylsulfonamide in the form of a yellow meringue mass.

<!>H-NMR (300 MHz, CDC13.8 in ppm): from 1.00 to 1.85 (mt, 8H), 2.14 (mt, 1H), 2.33

(mt, 1H), 2.82 (s, 3H), from 3.40 to 3.60 (mt, 4H), 3.71 (dd large, J = 8 and 6 Hz, 1H), 4.10 ( mt, 1H), 4.47 (s, 1H), from 7.20 to 7.40 (mt, 8H).

N-(1R,2R,4S)-bicyclo[2,2,1]hept-2-yl-N-{l-^amine can be prepared by working as described in Example 8 from 1.5 g of l-[bis -(4-chloro-phenyl)methyl]azetidin-3-one, 25 cm<3>1,2-dichloroethane, 0.6 g (1R,2R,4S)bicyclo[2,2,1]hept-2- amine, 1.0 g sodium triacetoxyborohydride and 0.3 cm<3>100% acetic acid. 1.8 g of N-(1R,2R,4S)-bicyclo[2,2,1]hept-2-yl-N-{1-[bis-(4-chlorophenyl)methyl]-azetidine-3- yl}-amine in the form of a cream-coloured paste which is used as such in the subsequent step.

Example 12

N-[(1-benzhydryl)azetidin-3-yl]-N-phenyl-methylsulfonamide can be prepared as follows: To a solution of 2 g of 1-benzhydryl-3-anilino-azetidine in 40 cm<3> of dichloromethane is poured 0 .7 cm3 of methylsulfonyl chloride and then 1.34 cm<3> of triethylamine is added. After 4 hours and 15 minutes of stirring at 20°C, the reaction mixture is washed with 2 x 20 cm<3> of water, after which the organic phase is dried over magnesium sulfate and concentrated to dryness at 50°C and 2.7 kPa. The meringue colored oil is obtained and chromatographed on a silica gel column with granulometry 0.063-0.2 mm, height 26 cm and diameter 3.6 cm, eluting under an argon pressure of 0.5 bar with cyclohexane:ethyl acetate in the volume ratio 70:30 and recovered fractions of 50 cm<3>. Fractions 10 to 15 are combined and concentrated to dryness at 2.7 kPa and the residue triturated in diethyl oxide, the suspension filtered, the solid poured off and then dried at 2.7 kPa. 35 mg of N-[(1-benz-hydryl)azetidin-3-yl]-N-phenyl-methylsulfonamide is obtained in the form of a white solid.

<!>H-NMR (300 MHz, (CD3)2SO d6 with a few drops of CD3COOD d4, 8 in ppm): 2.72 (mt,

2H), 2.92 (s, 3H), 3.36 (mt, 2H), 4.32 (s, 1H), 4.73 (mt, 1H), from 7.10 to 7.45 (mt, 15H). l-benzhydryl-3-anilino-azetidine can be prepared by working as described in Example 8 from 5 g of l-benzhydryl-azetidin-3-one, 1.92 cm3 aniline, 74 cm<3>1,2-dichloroethane, 6 .3 g sodium triacetoxyborohydride and 1.2 cm<3>100% acetic acid. 8.81 g of 1-benzhydryl-3-anilino-azetidine is obtained in the form of a meringue-coloured gum which is used as such in the subsequent steps.

Example 13

N-{1-[bis-(4-chlorophenyl)methyl]-azetdin-3-yl^ is prepared in the following way: To a mixture of 1.23 g of 1-[bis-(4-chlorophenyl)methyl]-azetidine- 3-yl-methylsulfonate and 0.66 g of N-3,5-difluorophenyl)methylsulfonamide in 25 cm<3>dioxane, 1.0 g of cesium carbonate is added. After stirring for 5 hours at reflux temperature and then 20 hours at 20°C, 50 cm<3> of diethyl oxide and 30 cm3 of salt solution are added to the reaction mixture, which is then stirred and decanted. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness at 50°C and 2.7 kPa. The orange colored oil obtained is chromatographed over a silica gel column with granulometry 0.040-0.063 mm, height 25 cm and diameter 2.0 cm, eluting under an argon pressure of 0.5 bar with cyclohexamethyl acetate in a volume ratio of 65:35, and fractions of 10 cm<3>. Fractions 6 to 10 are combined and concentrated to dryness at 2.7 kPa. The residue is chromatographed on a silica gel column with granulometry 0.040-0.063 mm, height 15 cm and diameter 1.0 cm, eluting under an argon pressure of 0.5 bar with cyclohexane:ethyl acetate in the volume ratio 65:35 and fractions of 5 cm<3>. Fraction 7 is concentrated to a dry state at 2.7 kPa. 0.11 g of N-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(3,5-difluorophenyl)-methylsulfonamide is obtained in the form of a white powder.

<*>H-NMR (300 MHz, CDC13.8 in ppm): 2.82 (s, 3H), 2.85 (mt, 2H), 3.52 (t cleaved, J = 7 and 2 Hz, 2H ), 4.22 (s, 1H), 4.47 (mt, 1H), from 6.75 to 6.90 (mt, 3H), from 7.20 to 7.35 (mt, 8H).

Method 2

To a solution of 1.41 g of 1-[bis-(4-chlorophenyl)methyl]azetidin-3-ol and 0.95 g of N-(3,5-difluorophenyl)methylsulfonamide in 100 cm3 of anhydrous tetrahydrofuran is placed under argon 0, 78 cm 3 of diethyl azodicarboxylate and 1.31 g of triphenylphosphine. After stirring for 16 hours at 20°C, 300 cm3 of ethyl acetate is added, after which the reaction mixture is washed with 2 x 100 cm3 of water, dried over magnesium sulfate and concentrated to dryness at 2.7 kPa. The residue is chromatographed on a silica gel column with granulometry 0.20-0.063 mm, height 50 cm and diameter 4 cm, eluting under an argon pressure of 0.6 bar with cyclohexane:ethyl acetate in the volume ratio 75:25 and fractions of 125 cm< 3>. Fractions 6 to 12 are combined and concentrated to dryness at 2.7 kPa. 1.8 g of a solid is obtained which is dissolved hot in ethyl acetate:diisopropyl ether in the volume ratio 15:2, cooled, diluted with 100 cm3 of pentane to promote crystallization. After filtration and drying, 1.0 g of N-{l-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(3,5-difluorophenyl)-methylsulfonamide are obtained in the form of white crystals which melt at 154°C.

N-(3,5-difluorophenyl)methylsulfonamide can be prepared by working as follows: To a solution of 3.5 g of 3,5-difluoroaniline in 75 cm<3> of dichloromethane is slowly added 2.0 cm<3>methylsulfonyl chloride, 3.8 cm<3> triethylamine and 20 mg 4-dimethylaminopyridine. After stirring for 20 hours at 20°C, 20 cm3 of dichloromethane and 20 cm3 of water are added to the reaction mixture, stirred and decanted. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The residue is chromatographed on a silica gel column with granulometry 0.063-0.200 mm, height 20 cm and diameter 2.0 cm, and it is eluted under an argon pressure of 0.1 bar with dichloromethane and fractions of 25 cm<3> are recovered. Fractions 14 to 20 are combined and concentrated to dryness at 2.7 kPa. 0.66 g of N-(3,5-difluorophenyl)methylsulfonamide is obtained in the form of a white powder. l-[bis-(4-chlorophenyl)methyl]azetidin-3-yl-methylsulfonate can be prepared as follows: To a solution of 12 g of l-[bis-(4-chlorophenyl)methyl]azetidin-3-ol in 200 cm<3> of dichloromethane is placed under argon and, over the course of 10 minutes, 3.5 cm<3> of methylsulfonyl chloride, after which it is cooled to +5°C and over the course of 10 minutes, poured into 3.8 cm<3> of pyridine. After stirring for 30 minutes at +5°C and then 20 hours at 20°C, the reaction mixture is diluted with 100 cm<3> of water and 100 cm<3> of dichloromethane. The mixture is filtered and decanted. The organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The obtained oil is chromatographed on a silica gel column with granulometry 0.063-0.200 mm, height 40 cm and diameter 3.0 cm, eluting under an argon pressure of 0.5 bar with cyclohexamethyl acetate in the volume ratio 70:30 and recovering fractions of 100 cm<3 >. Fractions 4 to 15 are combined and concentrated to dryness at 2.7 kPa. 6.8 g of 1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl-methyl-sulfonate are obtained in the form of a yellow oil. 1-[bis-(4-chlorophenyl)methyl]azetidin-3-ol can be prepared according to the procedure described by A.R. Katritzky et al. in "J. Heterocycl. Chem.", 271 (1994), starting from 35.5 g of [bis-(4-chlorophenyl)methyl]amine hydrochloride and 11.0 cm<3> of epichlorohydrin. 9.0 g of 1-[bis-(4-chlorophenyl)methyl]azetidin-3-ol are isolated. 1-[2-is-(4-chlorophenyl)methyl]amine hydrochloride can be prepared according to the method described by M. Grisar et al. in "J. Med. Chem.", 885 (1973).

Example 14

N-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(4,6-dimethylpyrimid-2-yl)-methylsulfonamide can be prepared by working as described in Example 13, Method 2, from 0.20 g of N-(4,6-dimethylpyrimid-2-yl)-methylsulfonamide and 0.308 g of 1-[bis-(4-chlorophenyl)methyl]-azetidin-3-ol. After chromatography on a silica gel column with granulometry 0.06-0.04 mm, height 50 cm and diameter 2 cm, and elution under an argon pressure of 0.6 bar with dichloromethane and then dichloromethane +1% methanol and then dichloromethane + 2% methanol and fractions of 2 cm<3> are recovered, after which fractions 4 to 7 are combined and concentrated to dryness at 2.7 kPa. After crystallization from diisopropyl ether, filtration and drying, 0.20 g of N-{1-|>is-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(4,6-dimethylpyrrinid-2-yl) are obtained -methylsulfonamide in the form of a white solid.

<!>H-NMR (300 MHz, CDC13.8 in ppm): 2.39 (s, 6H), 2.89 (t large, J = 7.5 Hz, 2H), 3.51 (s,

3H), 3.77 (mt, 2H), 4.27 (s, 1H), 4.77 (mt, 1H), 6.73 (s, 1H), from 7.20 to 7.35 (mt, 8H).

N-(4,6-d^methylpyrimid-2-yl)-methylsulfonamide can be prepared by working as follows: To a solution of 1.23 g of 2-amino-4,5-dimethylpyrimidine, 0.77 cm3 of methylsulfonyl chloride and 50 mg of 4-dimethylaminopyridine dissolved in 50 cm<3> of dichloromethane, add 1.4 cm<3> of triethylamine at 0°C. After 16 hours at ambient temperature, the reaction mixture is washed with 2 x 100 cm 3 of water, dried over magnesium sulfate, filtered and evaporated to dryness at 2.7 kPa. 1.0 g of a yellow powder is obtained which is treated with 15 cm<3> of 10% sodium hydroxide at 100°C for 1 hour. After cooling, the reaction mixture is extracted with 2 x 50 cm<3> of dichloromethane. The aqueous phase is acidified to a pH equal to 1 with 5 cm<3>10N hydrochloric acid and extracted with 2 x 50 cm3 of dichloromethane. The organic phases obtained are combined, washed with 50 cm3 of water, dried over magnesium sulfate, filtered and concentrated. 0.20 g of N-(4,6-dimethylpyrimid-2-yl)-methylsulfonamide is obtained in the form of a yellow powder.

Example 15

N-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(1,3,4-thiadiazol-2-yl)-methylsulfonamide can be prepared by working as described in Example 13 , method 2, from 0.10 g of N-(1,3,4-thiadiazol-2-yl)-methylsulfonamide and 0.215 g of 1-[bis-(4-chlorophenyl)methyl]azetidin-3-ol. After chromatography on a silica gel column with granulometry 0.06-0.04 mm, height 25 cm and diameter 1 cm, and elution under an argon pressure of 0.5 bar with ethyl-acetafccyclohexane in the volume ratio 20:80 and then 40:60 and recovery of fractions of 60 cm<3>, fractions 26 to 31 are combined and concentrated to dryness at 2.7 kPa. After crystallization from diisopropyl ether, filtration and drying, 40 mg of N-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(1,3,4-thiadiazol-2-yl) are obtained -methylsulfonamide in the form of a white solid.

<!>H-NMR (300 MHz, CDC13.8 in ppm): 3.01 (s, 3H), 3.09 (t cleaved, J = 7 and 1.5 Hz, 2H),

3.70 (t slotted, J = 7 and 1.5 Hz, 2H), 4.28 (s, 1H), 4.76 (mt, 1H), from 7.20 to 7.35 (mt, 8H) , 9.01 (p, 1H).

N-(1,3,4-itadiazol-2-yl)-methylsulfonamide can be prepared by working as follows: To a mixture of 2.02 g of 2-amino-1,3,4,-thiadiazole in 10 cm< 3> pyridine is added to 1.5 cm<3 >methylsulfonyl chloride. After 2 hours at ambient temperature, 60 cm<3> of water are added, after which the reaction mixture is filtered. The aqueous phase is recovered and acidified to pH equal to 2 with 1N hydrochloric acid, extracted with 2 x 50 cm<3> ethyl acetate and the organic phase is washed with 2 x 50 cm<3> water, dried over magnesium sulfate, filtered and evaporated to dryness at 2.7 kPa. 0.1 g of a yellow powder is obtained.

Example 16

N-{l-| N-(thiazol-2-yl)-methylsulfonamide and 0.5 g of 1-[bis-(4-chlorophenyl)methyl]azetidin-3-ol. After chromatography on a silica gel column with granulometry 0.06-0.04 mm, height 60 cm and diameter 2 cm, elution under an argon pressure of 0.9 bar with ethyl acetate:cyclohexane in the volume ratio 20:40 and then 40:60 and recovery of fractions of 30 cm<3>, combine fractions 9 to 12 and concentrate to dryness at 2.7 kPa. After crystallization from diisopropyl ether, filtration and drying, 0.21 g of N-{1-[bis-(4-chlorophenyl)methyl]-azetidir-3-yl}-N-(thiazol-2-yl)-methylsulfonamide is obtained in the form of a white solid.

^-NMR (300 MHz, CDCl3.8 in ppm): from 2.95 to 3.10 (mt, 2H), 3.00 (s, 3H), 3.59 (mt,

2H), 4.22 (s large, 1H), 4.69 (mt, 1H), from 7.20 to 7.35 (mt, 9H, 7.60 (mt, 1H).

N-(thiazol-2-yl)-methylsulfonamide can be prepared by working in the following way: 1.15 g of methylsulfonyl chloride is added to a mixture of 1.0 g of 2-aminothiazole in 5 cm3 of pyridine. After 2 hours at ambient temperature, 20 cm<3> of water are added, after which the reaction mixture

filtered and the solid recovered (0.35 g). The recovered aqueous phase is acidified to pH equal to 2 with 1N hydrochloric acid, extracted with 2 x 40 cm<3> ethyl acetate and the organic phase

washed with 2 x 30 cm<3> of water, dried over magnesium sulfate, filtered and evaporated to dryness at 2.7 kPa. 0.15 g of a white solid with spectral characteristics close to the filtered solid corresponding to a mixture of N-(thiazol-2-yl)-methylsulfonamide and N-(thiazol-2-yl)-di(methylsulfonyl)imide is obtained which is used as such in the following step.

Example 17

N- {1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(3-hydroxyphenyl)-methylsulfonamide can be prepared by working as follows: To a mixture of 0.5 g of N -{ l-[bis-(4-chloro-phenyl)methyl]-azetidUn-3-yl}-N-(3-methoxyphenyl)-methylsulfone in 20 cm<3> dichloromethane is added dropwise at 2°C 7.63 cm <3> IM boron tribromide solution. After 20 hours at ambient temperature, the reaction mixture is poured into ice and extracted with 60 cm<3> of dichloromethane. The organic phase is washed with 3 x 80 cm<3> of water and then with 2 x 80 cm<3> of saturated, aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to dryness at 2.7 kPa. 0.33 g of a white meringue mass is obtained, which is taken up in acetonitrile, filtered and dried to obtain 0.20 g of a white solid.

'H-NMR (300 MHz, CDCl3.8 in ppm): 2.81 (s, 3H), 2.86 (t large, J = 7.5 Hz, 2H), 3.50 (t large, J = 7.5 Hz, 2H), 4.20 (s, 1H), 4.53 (mt, 1H), 5.36 (mf, 1H), from 6.70 to 6.85 (mt, 3H), from 7.15 to 7.35 (mt, 9H).

Example 18

N-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(3-methoxyphenyl)-methylsulfonamide can be prepared by working as described in Example 15 from 1.58 g of N-( 3-methoxyphenyl)-methylsulfonamide and 2.0 g of 1-[bis-(4-chlorophenyl)methyl]azetidin-3-ol. After chromatography on a silica gel column with granulometry 0.06-0.04 mm, height 24 cm and diameter 7.8 cm, and elution under an argon pressure of 0.7 bar with ethyl acetate:cyclohexane in the volume ratio 50:50 and then 40:60 and recovering 100 cm<3> fractions, pool fractions 7 through 10 and concentrate to dryness at 2.7 kPa (2.05 g). After crystallization from diisopropyl ether, filtration and drying, 0.21 g of N-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(3-methoxyphenyl)-methylsulfonamide is obtained.

N-(3-Methoxyphenyl)-methylsulfonamide can be prepared by working as follows: To a mixture of 5.0 g of 3-methoxyaniline in 150 cm<3> pyridine, put at 3°C, 3.14 cm<3>

methylsulfonyl chloride. After 20 hours at ambient temperature, 200 cm<3> of water and 400 cm<3> of ethyl acetate are added and the reaction mixture is decanted. The organic phase is washed with 2 x 400 cm<3> of water and 400 cm<3> of saturated, aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to dryness at 2.7 kPa. After chromatography on a silica gel column with granulometry 0.06-0.04 mm, height 23 cm and diameter 7.8 cm, and elution under an argon pressure of 0.7 bar with ethyl acetate:cyclohexane in the volume ratio 25:75 and recovery of fractions of 100 cm<3>, fractions 24 to 36 are combined and concentrated to dryness at 2.7 kPa and 6.21 g of N-(3-methoxyphenyl)-methylsulfonamide is recovered in the form of an orange colored oil.

Example 19

N-{1-|>is-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(3-hydroxymethylphenyl)methylsulfonamide can be prepared by working as follows: To a mixture of 0.5 g ethyl-N-{ 1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(methylsulfonyl)-3-aminobenzoate in 20 cm<3 >toluene is added dropwise and at -50°C, 1.46 cm<3> 20% toluene solution of diisopropyl aluminum hydride. After 1.5 hours at 0°C and 1.5 hours at 10°C, the reaction mixture is cooled to 0°C and 20 cm 3 of water is slowly added. After filtering the precipitate and extracting with ethyl acetate, the organic phase is washed with 2 x 80 cm<3> of water and then 80 cm3 of saturated, aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to dryness at 2.7 kPa. 0.46 g of oil is obtained which is chromatographed on a silica gel column with granulometry 0.06-0.042 mm, height 16 cm and diameter 4 cm, eluting under an argon pressure of 0.7 bar with ethyl acetate:cyclohexane in the volume ratio 40:60 and fractions of 20 cm<3> are recovered. Fractions 72 to 76 are combined and concentrated to dryness at 2.7 kPa. 0.20 g of N-{1-[bis-(4-chlorophenyl)-methyl]-azetidin-3-yl}-N-(3-hydroxymethylphenyl)-methylsulfonamide is obtained in the form of a white solid.

1H NMR (300 MHz, CDCl 3 , 8 in ppm): 1.80 (mt, 1H), 2.83 (s, 3H), 2.87 (mt, 2H), 3.52

(mt, 2H), 4.21 (s large, 1H), 4.60 (mt, 1H), 4.74 (d large, J = 4 Hz, 2H), from 7.10 to 7.45 (mt , 12H).

Example 20

Ethyl-N-{1-[bis-(4-chlorophenyl)methyl]-azetdin-3-yl}-N-(methylsulfonyl)-3-aminobenzoate can be prepared by working as described in Example 15, from 1.58 g ethyl N-(methyl-sulfonyl)-3-aminobenzoate and 2.0 g of 1-[bis-(4-chlorophenyl)methyl]azetdin-3-ol. After chromatography on a silica gel column with granulometry 0.06-0.04 mm, height 24 cm and diameter 7.8 cm, and elution under an argon pressure of 0.7 bar with ethyl acetate:cyclohexane in the volume ratio 50:50 and then 40:60 and recovering fractions of 100 cm<3>, fractions 7 to 10 are combined and concentrated to dryness at 2.7 kPa to obtain 2.0 g of a yellow oil.

Ethyl-N-(methylsulfonyl)-3-aminobenzoate can be prepared by working in the following way: To a mixture of 5.0 g of ethyl-3-aminobenzoate in 150 cm<3> pyridine is added at 3°C 2.35 cm< 3 >methylsulfonyl chloride. After 20 hours at ambient temperature, 200 cm 3 of water and 400 cm 3 of ethyl acetate are added and the reaction mixture is decanted. The organic phase is washed with 3 x 400 cm3 of water and 400 cm3 of saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to dryness at 2.7 kPa. After chromatography on a silica gel column with granulometry 0.06-0.04 mm, height 25 cm and diameter 7.8 cm, and elution under an argon pressure of 0.7 bar with ethyl acetate:cyclohexane in the volume ratio 25:75 and recovery of fractions of 100 cm<3>, fractions 27 to 36 are combined and concentrated to dryness at 2.7 kPa, whereby 5.24 g of ethyl-N-(methylsulfonyl)-3-aminobenzoate is obtained in the form of an orange colored oil.

Example 21

N-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(1-isobutyl-pipeird-4-yl)methylsulfonamide can be prepared by working as follows: To a solution of 0.47 g of N-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(piperid-4-yl)-methylsulfonamide in 20 cm<3 >dichloromethane is placed 0.11 cm3 isobutyraldehyde, 0.057 cm<3> 100% acetic acid and 320 mg sodium triacetoxyborohydride. After stirring for 20 hours at 20°C, 50 cm<3> of a saturated, aqueous sodium bicarbonate solution is added to the reaction mixture and decanted. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The residue is purified by chromatography on a silica gel column with granulometry 0.063-0.200 mm, height 20 cm and diameter 2 cm, and it is eluted under an argon pressure of 0.5 bar with cyclohexane-ethyl acetate in the volume ratio 40:60 and fractions of 30 cm are recovered <3>. Fractions 3 to 15 are combined and concentrated to dryness at 2.7 kPa. 0.22 g of N-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(1-isobutyl-piperid-4-yl)methylsulfonamide is obtained in the form of a white meringue mass.

*H-NMR (300 MHz, CDC13.6 in ppm): 0.87 (d, J = 7 Hz, 6H), from 1.60 to 1.90 (mt, 5H), 1.93 (t large, J = 11.5 Hz, 2H), 2.03 (d, J = 7.5 Hz, 2H), 2.84 (s, 3H), 2.89 (d large, J = 11.5 Hz, 2H ), 3.38 (t large, J = 7 Hz, 2H), 3.47 (t large, J = 7 Hz, 2H), 3.62 (mt, 1H), 4.08 (mt, 1H), 4.43 (s, 1H), from 7.20 to 7.40 (mt, 8H).

N-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(piperid-4-yl)-methylsulfonamide can be prepared as follows: To a solution of 19 g of N-{ l -[bis-(4-chlorophenyl)methyl]-azeti(iin-3-yl}-N-(l-tert-butoxycarbonatyl-piperid-4-yl)-methylsulfonamide in 100 cm<3>dioxane is slowly added to 50 cm3 6N hydrochloric acid solution in dioxane. After stirring for 20 hours at 20°C, the reaction mixture is concentrated at 50°C and 2.7 kPa. The residue is taken up in 200 cm<3> of ethyl acetate and 200 cm<3> of water. The aqueous phase is made alkaline with a 4N aqueous sodium hydroxide solution and then extracted with 200 cm<3> ethyl acetate. This organic phase is dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. 15.5 g of N-{ l-[bis-(4 -chlorophenyl)methyl]-azetidin-3-yl}-N-(piperid-4-yl)-methylsulfonamide in the form of a cream colored meringue mass. N- {1 -|>is-(4-chlorophenyl)methyl]-azetidin- 3-yl}-N-(1-tert-butoxycarbonatyl-piperid-4-yl)-methylsulfonamide can be prepared as follows: To a solution of 14.7 g 4-{ 1-[bis-(4-chlorophenyl)methyl] azetidin-3-ylamino}-(1-tert-butoxycarbonyl)-piperidine in 150 cm<3> dichloromethane is slowly added 4.60 cm<3> methylsulfonyl chloride and then 4.60 cm<3> of triethylamine and 100 mg of 4-dimethylaminopyridine. After stirring for 20 hours at 20°C, 200 cm<3> of a saturated aqueous sodium bicarbonate solution is added to the reaction mixture and then stirred for 30 minutes and decanted. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The resulting meringue mass is taken up in 250 cm<3> of dichloromethane, 4.60 cm<3> of methylsulfonyl chloride and then 4.60 cm<3> of triethylamine and 100 mg of 4-dimethylaminopyridine are again slowly added. After stirring for 20 hours at 20°C, 200 cm<3> of a saturated, aqueous sodium hydrogen carbonate solution is added to the reaction mixture, stirred for a further 30 minutes and decanted. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The residue is purified by chromatography on a silica gel column with granulometry 0.063-0.200 mm, height 35 cm and diameter 5 cm, and is eluted under an argon pressure of 0.5 bar with cyclohexane-ethyl acetate in the volume ratio 70:30, whereby fractions of 250 cm are recovered <3>. Fractions 4 to 18 are combined and concentrated to dryness at 2.7 kPa. 19 g of N-{l-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(l-tert-butoxycarbonatyl-piperid-4-yl)-methylsulfonamide are obtained in the form of a cream-colored meringue mass which is used as such in the following step.

4-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylamino}-(1-tert-butoxycarbonyl)-piperidine can be prepared by working as follows: To a solution of 9.22 g l- 6.58 g of 1-tert-butoxy-carbonylpiperidin-4-one are added to [bis-(4-chlorophenyl)methyl]azetidin-3-ylamine in 300 cm<3> of dichloromethane. To the mixture, cooled to +5°C, 9.54 g of sodium triacetoxyborohydride are added in two portions, after which it is poured into 1.72 cm<3> of 100% acetic acid. After stirring for 20 hours at 20°C, the reaction mixture is slowly added to 500 cm<3> of a saturated, aqueous sodium bicarbonate solution, stirred and decanted. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness at 50°C and 2.7 kPa. 15 g of 4-{l-[bis-(4-chlorophenyl)methyl]azetidin-3-ylamino}(l-tert-butoxycarbonyl)-piperidine are obtained in the form of a cream-colored meringue mass which is used as such in the following step.

Example 22

N-benzyl-N-{ l-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}amine: To a solution of 369 mg of l-[bis-(4-chlorophenyl)methyl]azetidin-3- ylamine in 15 cm<3> dichloromethane is placed at ambient temperature and under an argon atmosphere, 0.134 cm<3> benzaldehyde. The mixture is cooled to 0°C before 382 mg of sodium triacetoxyborohydride and then 70 mm 3 of acetic acid are progressively added. After stirring for 16 hours at ambient temperature, the mixture is poured into 50 cm 3 of a saturated aqueous sodium bicarbonate solution and then extracted with 2 x 25 cm<3> of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The obtained residue is purified by flash chromatography on silica gel with dichloromethane:methanol in the volume ratio 95:5 as eluent. 0.29 g of N-benzyl-N-{1-[bis-(4-chloro-phenyl)methyl]-azetidin-3-yl}amine is obtained in the form of a colorless oil.

<X>H-NMR (300 MHz, CDC13.8 in ppm): 2.71 (t large, J = 7 Hz, 2H), 3.42 (mt, 2H), 3.49

(mt, 1H), 3.70 (s, 2H), 4.25 (s, 1H), from 7.20 to 7.40 (mt, 13H). 1-I>is-(4-chlorophenyl)methyl]azetidin-3-yl-amine can be prepared as follows: To 27 g of 1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylmethylsulfonate contained in an autoclave , previously cooled down to -60°C, add 400 cm<3> of methane-liquid ammonia in the volume ratio 50:50. The reaction medium is then stirred at 60°C for 24 hours and exposed to open air to allow evaporation of the ammonia and then concentrated at 2.7 kPa. The residue is taken up in 500 cm3 of a 0.37N aqueous sodium hydroxide solution and extracted with 4 x 500 cm3 of ethyl ether. The combined organic phases are washed successively with 200 cm 3 of distilled water and 100 cm 3 of saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness at 2.7 kPa. The obtained residue is purified by flash chromatography on silica gel and eluted with dichloromethane:methanol in the volume ratio 95:5. 14.2 g of 1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl-amine are obtained in the form of an oil which solidifies to a cream-colored solid.

Example 23

N-benzyl-N-{l-(>is-(4-chlorophenyl)methyl]-azetidin-3-yl}-methylsulfonamide: To a solution of 120 mg of N-benzyl-N-{l-[bis- (4-Chlorophenyl)methyl]-azetidin-3-yl}-amine in 5 cm<3>dichloromethane is placed at ambient temperature and under argon, 104 mm3 of triethylamine.The mixture is cooled down to 0°C before adding 46.4 mm3 of methylsulfonyl chloride, after which the whole is stirred at ambient temperature for 16 hours. The reaction mixture is diluted with 20 cm<3> of dichloromethane and then washed with 2x15 cm3 of distilled water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa and a varnish which is brought to crystallization by trituration in methanol. In this way, 42 mg of N-benzyl-N-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-methylsulfonamide is obtained in the form of a cream-colored powder which melts at 171°C.

Example 24

N-{l-[bis-(4-chlorophenyl)methyl]-azeti can be prepared as in example 22, but by using 188 mg of 3,5-difluorobenzaldehyde and 369 mg of l-[bis-(4-chlorophenyl)methyl] azetidin-3-yl-amine and 382 mg of sodium triacetoxyborohydride, without purification by flash chromatography. 0.48 g of N-{1-[bis-(4-chlorophenyl)methyl]-azeti(Un-3-yl}-N-(3,5-difluorobenzyl)arnine is obtained in the form of a colorless oil.

1H-NMR (300 MHz, CDCl3.8 in ppm): 2.73 (mt, 2H), from 3.40 to 3.55 (mt, 3H), 3.70 (s,

2H), 4.26 (s, 1H), 6.69 (tt, J = 9 and 2 Hz, 1H), 6.83 (mt, 2H), from 7.20 to 7.35 (mt, 8H) .

Example 25

N-{l-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(3,5-difluorobenzyl)methylsulfonamide: To a solution of 433 mg of N-{l-[>is-( 4-chlorophenyl)methyl]-azetidin-3-yl}-N-(3,5-difluoro-benzyl)amine in 30 cm<3> of dichloromethane is placed, at ambient temperature and under argon, 347 mm 3 of triethylamine. The reaction mixture is cooled down to 0°C, before a solution of 46.4 mm<3> of methylsulfonyl chloride in 5 cm<3> of dichloromethane is added, after which the whole is then stirred at ambient temperature for 1 hour. The reaction mixture is diluted with 20 cm<3> of dichloromethane and then washed with 2 x 20 cm<3> of distilled water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The residue is introduced into solution in methanol in a Bond Elut® SCX column (10 g) and eluted successively with methanol and with an IM ammoniacal methanol solution. The ammoniacal fractions are combined and concentrated to dryness at 2.7 kPa. 0.44 g of N-{1-|is-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(3,5-difluorobenzyl)methylsulfonamide is obtained in this way in the form of a cream-colored meringue mass.

<!>H-NMR (300 MHz, CDC13.8 in ppm): 2.81 (s, 3H), 3.02 (t large, J = 7.5 Hz, 2H), 3.38 (t large, J = 7.5 Hz, 2H), 4.23 (s, 1H), 4.40 (mt, 1H), 4.54 (s, 2H), 6.75 (tt, J = 9 and 2 Hz, 1H), 6.95 (mt, 2H), 7.25 (mt, 8H).

Example 26

N-{1-[bis-(4-chlorophenyl)methyl]-azetid-4n-3-yl}-N-(3,5-difluorobenzyl)acetamide: To a solution of 2 g of N-{1-[bis-(4 -chlorophenyl)methyl]-azetidin-3-yl}-N-(3,5-difluorobenzyl)-amine in 75 cm3 of dichloromethane is added, at ambient temperature and under argon, 1.6 cm<3 >triethylamine. The mixture is cooled to down to 0°C before 0.66 cm<3 >acetyl chloride is added dropwise and the whole is then stirred at ambient temperature for 16 hours. The reaction mixture is diluted with 50 cm3 of dichloromethane and then washed with 2 x 20 cm3 of distilled water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The residue obtained is purified by flash chromatography on silica gel and eluted with dichloromethane in the volume ratio 98:2. 1.2 g of N-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(3,5-difluorobenzyl)acetamide are obtained in the form of a colorless oil.

3-NMR (300 MHz, CDCl3.8 in ppm). A mixture of rotamers is observed. <*> 2.06

and 2.14 (2s, 3H combined), 2.97 (mt, 2H), 3.43 (mt, 2H), 4.20 and 4.25 (2s, 1H combined), 4.54 and from 4.75 to 4.80 (mt, 1H together), 4.68 and 4.78 (2s large, 2H together), 6.70 (mt, 3H), 7.24 (s large, 8H).

Example 27

N-{l-|>is-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(pyrid-4-yl-methyl)-methylsulfonarm To a solution of 398 mg of N-{l-[bis -(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(pyrid-4-ylmethyl)amine in 8 cm<3> dichloromethane is placed, at ambient temperature and under argon, 346 mm<3> triethylamine. The mixture is cooled to down to 0°C before 155 mm<3> methylsulfonyl chloride is added and the whole is then stirred at ambient temperature for 3 hours. The reaction mixture is diluted with 35 cm<3> of dichloromethane and then washed with 2 x 20 cm<3> of distilled water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The obtained residue is purified by flash chromatography on silica gel and eluted with dichloromethane:methanol in the volume ratio 97:3. 288 mg of N-{1-|>is-(4-chlorophenyl)methyl]-azetdin-3-yl}-N-(pyrid-4-yl-methyl)-methylsulfonamide is obtained in the form of a cream-colored meringue mass.

<*>H-NMR (300 MHz, CDCl 3 , 8 in ppm): 2.83 (s, 3H), 3.02 (t large, J = 7.5 Hz, 2H), 3.40 (t large, J = 7.5 Hz, 2H), 4.23 (s, 1H), 4.43 (mt, 1H), 4.57 (s, 2H), from 7.20 to 7.35 (mt, 8H) , 7.32 (d large, J = 5.5 Hz, 2H), 8.60 (d large, J = 5.5 Hz, 2H).

Example 28

N-{1-|>is-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(pyrid-4-yl-methyl)amine can be prepared in the following manner. To a solution of 369 mg of 1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl-amine in 15 cm<3> dichloromethane is added, at ambient temperature and under argon, 0.126 cm<3 >pyrid-4-yl -carboxaldehyde. The mixture is cooled to down to 0°C before 382 mg of sodium triacetoxyborohydride and then 70 mm<3> of acetic acid are progressively added. After stirring for 72 hours at ambient temperature, the mixture is poured into 100 cm<3> of a saturated, aqueous sodium bicarbonate solution and then extracted with 2 x 100 cm<3> of dichloromethane. The organic phases are combined and washed with 50 cm<3> of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness at 2.7 kPa. The residue is dissolved in 5 cm<3> methanol on a Bond Elut® SCX column (10 g) and eluted successively with 50 cm<3> methanol and 60 cm<3> 1M ammonia solution in methanol. The ammoniacal fractions are combined and concentrated to dryness at 2.7 kPa. 0.48 g of N-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(pyrid-4-yl-methyl)amine is obtained in this way in the form of a colorless oil .

Example 29

N-{1-(^is-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(pyrid-3-yl-methyl)-methylsulfonamide: By working as in Example 27, but by going from 380 mg of N-{l-[bis-(4-chlorophenyl)-methyl]-azetidin-3-yl}-N-(pyrid-3-yl-methyl)amine, 319 mg of N-{l-[ bis-(4-chloro-phenyl)methyl]-azetdin-3-yl}-N-(pyrid-3-yl-methyl)-methylsulfonamide in the form of a cream-colored meringue mass.

<*>H-NMR (300 MHz, CDC13.8 in ppm): 2.80 (s, 3H), 3.02 (t cleaved, J = 7 and 1.5 Hz, 2H), 4.22 (s , 1H), 4.35 (mt, 1H), 4.56 (s, 2H), 7.23 (s large, 8H), 7.31 (dd, J = 8

and 5 Hz, 1H), 7.80 (d large, J = 8 Hz, 1H), 8.57 (dd, J = 5 and 1.5 Hz, 1H), 8.63 (d large, J = 1 .5 Hz, 1H).

Example 30

N-{l-[>is-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(pyrid-3-yl-methyl)amine can be prepared as in example 28, but starting from 0.124 cm<3> pyrid-3-yl-carboxaldehyde, 0.36 g of 1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl-amine and 0.38 g of sodium triacetoxyborohydride. 0.44 g of N-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(pyrid-3-yl-methyl)amine is obtained in this way in the form of a colorless oil .

Example 31

N- {1 - [bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(1,1-dioxo-1H-1A,6-benzo[d]isothiazol-3-yl)- amine: 182 mg of 1,2-benzoisothiazol-3-amine is added to 386 mg of 1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylmethylsulfonate in solution in 10 cm<3> of dimethylformamide, l-dioxide and 326 mg of cesium carbonate. The reaction medium is then stirred at 100°C for 9 hours and then concentrated at 2.7 kPa. The residue is washed with 4x5 cm<3> of boiling, distilled water, disaggregated by stirring for 5 cm<3> distilled at ambient temperature and recovered by filtration and purification by flash chromatography on silica gel by elution with dichloromethane:methanol in the volume ratio 98:2. 53 mg of N-{1-[bis-(4-chlorophenyl)-methyl]-azetidin-3-yl}-N-(1,1-dioxo-1H-1X,<6->benzo[d]isothiazole is obtained -3-yl)-amine in the form of a pasty product.

<!>H-NMR (300 MHz, CDC13.8 in ppm): 3.17 (mt, 2H), 3.61 (t large, J = 7.5 Hz, 2H), 4.37

(s, 1H), 4.75 (mt, 1H), from 6.30 to 6.40 (mf, 1H), from 7.20 to 7.35 (mt, 8H), 7.62 (d large, J = 7.5 Hz, 1H), 7.69 (t large, J = 7.5 Hz, 1H), 7.76 (t large, J = 7.5 Hz, 1H), 7.93 (d large , J = 7.5 Hz, 1H).

1,2-benzisothiazol-3-amine.1,1-dioxide can be prepared according to the method described by P. Stoss et al. in "Chem. Ber." (1975), 108(12), 3855-63.

Example 32

N-{1-[bis-(4-chlorophenyl)methyl]-azetidn-3-yl}-N-(3,5-difluorophenyl)-N'-tert-butyloxy-carbonylsulfamide can be prepared as follows: To a solution of 0.095 cm3 of tert-butyl alcohol in 2 cm3 of anhydrous dichloromethane, 0.048 cm<3> of chlorosulfonyl isocyanate is added and after stirring for 2 minutes, 0.21 g of N-{1-[bis-(4-chlorophenyl)-methyl]-azetidine- 3-yl}-N-(3,5-difluorophenyl)-amine in 1.25 cc of anhydrous dichloromethane and then 0.084 cc of triethylamine. After stirring for 1 hour at a temperature close to 20°C, 2 cm3 of a saturated sodium bicarbonate solution is added with vigorous stirring. The reaction medium is decanted, dried over magnesium sulphate, filtered and concentrated to dryness at 2.7 kPa. The obtained residue is chromatographed on a 6 cm. The residue obtained is chromatographed on a 6 cm Varian column equipped with 3 g of fine silica (0.040-0.063 mm), conditioned and then eluted with petroleum ethylene ethyl acetate using a Duramat pump, recovering fractions of 2 cm<3>. Fractions 6 to 17 are combined and concentrated to dryness at 2.7 kPa and 40°C for 2 hours. In this way, 61 mg of N-{1-[bis-(4-fluorophenyl)methyl]-azetidin-3-yl}-N-(3,5-difluorophenyl)-N,-tert-butyloxy-carbonylsulfamide are obtained in the form of a white meringue mass.

<J>H-NMR (400 MHz, CDC13.8 in ppm): 1.47 (s, 9H), 2.77 (t large, J = 8 Hz, 2H), 3.52 (mt,

2H), 4.19 (s, 1H), 5.06 (mt, 1H), from 6.75 to 6.90 (mt, 3H), from 7.15 to 7.35 (mt, 8H).

Example 33

(RS)-N-{1-tris-(4-chlorophenyl)-pyridin-3-yl^methylsulfonamide can be obtained in the following manner: To a mixture of 0.2 g of 3-[bromo-(4-chlorophenyl)-methyl ]-pyridine and 0.22 g of N-azetidin-3-yl-N-(3,5-difluorophenyl)-methylsulfonamide hydrochloride in 10 cm3 of acetonitrile, 0.2 g of potassium carbonate and 23 mg of potassium iodide are added, after which the mixture is heated to reflux in 3 hours. After adding 0.2 g of potassium carbonate, the whole is heated to reflux for a further 5 hours. After cooling to 21°C

the insoluble substances are removed by filtration and then the whole is concentrated to a dry state at 40°C under 2.7 kPa. 170 mg of a colorless varnish is obtained which is purified by chromatography on a silica column (reference SIL-020-005, FlashPack, Jones Chromatography Limited, New Road, Hengoed, Mid Glamorgan, CF82 8AU, Royaume Uni) and it is eluted with cyclohexamethyl acetate 1: 1 at a rate of 6 cm3/min. and it is all captured in fractions of 5 cm<3>. The fractions Rf=5/57 (cyclohexamethylacetate 1:1, silicon dioxide plate, Merck reference 1.05719, Merck KGaA, 6427 Darmstadt, BRD) are combined and concentrated under 2.7 kPa and 40°C and 100 mg of (RS)-N-{ 1-[bis-(4-chlorophenyl)-pyridin-3-yl-methyl]azetic^^ which melts at 110°C.

<!>H-NMR (300 MHz, (CD3)2SO d6, 8 in ppm): 2.77 (mt, 2H), 2.98 (s, 3H), 3.38 (mt, 2H),

4.50 (s, 1H), 4.70 (mt, 1H), 7.11 (mt, 2H), from 7.20 to 7.40 (mt, 2H), 7.34 (d, J = 8 Hz, 2H), 7.41 (d, J = 8 Hz, 2H), 7.72 (d large, J = 8 Hz, 1H), 8.40 (dd, J = 5 and 1.5 Hz, 1H ), 8.58 (d, J = 1.5 Hz, 1H).

The two isomers of (RS)-N-{1-[bis-(4-chlorophenyl)-pyridin-3-yl-methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)-methylsulfonamide can be separated on stationary chiral CHIRACEL OD phase.

First isomer: 1H-NMR (300 MHz, CDCl3.8 in ppm): 2.82 (s, 3H), 2.87 (mt, 2H), 3.53

(mt, 2H), 4.29 (s, 1H), 4.47 (mt, 1H), 6.80 (mt, 3H), 7.19 (dd, J = 8 and 5 Hz, 1H), from 7.20 to 7.35 (mt, 4H), 7.62 (d large, J = 8 Hz, 1H), 8.45 (d large, J = 5 Hz, 1H), 8.59 (s large, 1H).

Second isomer: 1H-NMR (300 MHz, CDCl 3.8 in ppm): 2.82 (s, 3H), 2.87 (mt, 2H), 3.54

(mt, 2H), 4.29 (s, 1H), 4.48 (mt, 1H), 6.80 (mt, 3H), 7.19 (dd large, J = 8 and 5 Hz, 1H), from 7.25 to 7.35 (mt, 4H), 7.62 (dt, J = 8 and 2 Hz, 1H), 8.46 (dd, J = 5 and 2 Hz, 1H), 8.59 ( d large, J = 2 Hz, 1H).

N-azetidin-3-yl-N-(3,5-difluorophenyl)-methylsulfonamide hydrochloride is obtained in the following way: In a hydrogenator of 500 cm<3>, a solution of 1 g of N-(1-benz-hydryl- azetidin-3-yl)-N-(3,5-difluorophenyl)-methylsulfonamide in a mixture of 2.5 cm<3 >IM hydrochloric acid and 0.41 cm<3> acetic acid in the presence of 0.161 g of palladium hydroxide under a hydrogen pressure of 30 bar for 4 hours. The catalyst is removed by filtration on a pad of Celite, after which the filtrate is concentrated to dryness at 40°C under 2.7 kPa to give 630 mg of N-azetidin-3-yl-N-(3,5-difluorophenyl)-methylsulfonamide as melts at 216°C. N-(l-benzhydiyl-azetidin^ can be obtained by working as in example 13, method 2, in the following way: To a solution of 2 g of l-benzhydryl-azetidin-3-ol in 100 cm<3> tetrahyck-ofuran successively add 0.86 g of N-(3,5-difluorophenyl)-methylsulfonamide, 3.28 g of triphenylphosphine and then 2 ml of diethyl azodicarboxylate. An increase in the temperature which goes from 22°C to 29°C and the formation of a precipitate at the end of the addition of diethyl azodicarboxylate. After 20 hours at 22°C the precipitate is removed by filtration and then the filtrate is concentrated to dryness at 40°C under 2.7 kPa. The residue is triturated with 5 cm<3> methanol for 20 minutes at 21 °C, giving 1.07 g of N-(1-benzhydryl-azetidin-3-yl)-N-(3,5-difluorophenyl)-methylsulfonamide as a white, amorphous solid. 3-ol can be prepared according to the procedure described by A. R. Katritzky et al. in "J. Heterocycl. Chem.", 271 (1994).

3-[bromo-(4-chlorophenyl)-methyl]-pyridine is obtained in the following way: To 1.5 g of (4-chlorophenyl)-pyridin-3-yl-methanol add 3.5 cm3 of a 48% hydrobromic acid solution in acetic acid and 1 cm<3> acetyl bromide. The amber mixture thus obtained is heated to reflux for 4 hours and then cooled to 20°C, concentrated to dryness at 40°C under 2.7 kPa, leading to 1.53 g of 3-[bromo-( 4-chlorophenyl)-methyl]-pyridine (Rf=75/90, 254 nm, silicon dioxide plates, reference 1.05719, Merck, KGaA, 64271 Darmstadt,

BRD).

(4-Chlorophenyl)-pyridin-3-yl-methanol is obtained in the following way: To a solution of 3 g of pyridine-3-carboxaldehyde in tetrahydrofuran, at 5°C, 20 cm<3> of a molar solution of magnesium 4-chlorophenyl bromide in ethyl ether. After reheating to 20°C, the whole is allowed to react for 15 hours with stirring. 20 cm<3> of a saturated ammonium chloride solution and 20 cm<3> of ethyl acetate are then added. The mixture is decanted and the organic phases are extracted with 20 cm<3> additional ethyl acetate. The organic extracts are combined, dried over magnesium sulfate and concentrated to dryness at 40°C and 2.7 kPa. the residue obtained is chromatographed on silica (Amicon, 20-45 nm, 500 g silica, column diameter 5 cm), eluting with cyclohexamethyl acetate 80:20 to 50:50 under an argon pressure of 0.4 bar. The fractions containing the compound Rf=13/53

(silica sheets, reference 1.05719, Merck, KGaA, 64271 Darmstadt, BRD)

combine and evaporate to dryness at 40°C under 2.7 kPa to give 2.53 g of (4-chloro-phenyl)-pyridin-3-yl-methanol.

Example 34

N-{1 - [>is-(4-chlorphrenyl)methyl]-az^^ is obtained in the following way: To a mixture of 0.2 g of 4,4'-difluorobenzhydryl chloride and 0.26 g of N-azetidine-3- yl-N-(3,5-difluorophenyl)-methylsulfonamide hydrochloride in 10 cm3 of acetonitrile, 36 g of potassium carbonate and 27 mg of potassium iodide are added, after which the whole is heated to reflux for 3 hours. After cooling to 21°C, the insoluble substances are removed by filtration and then the whole is concentrated to a dry state at 40°C and 2.7 kPa. The residue is triturated with 30 cm3 of ethyl acetate and the solid is then removed by filtration. The filtrate is concentrated to dryness at 40°C under 2.7 kPa and 90 mg of pale yellow solid is obtained which is purified by chromatography on a BondElut SCX column containing 2 g of grafted silica reference 1225-6019, Varian Associates, Inc., 24201 Frampton Avenue , Harbor City, CA 90710, USA) and it is eluted with a 2M methanolic ammonia solution. The fraction Rf=16/82 (cyclohexamethylacetate 7:3, silica plates, reference 1.05719, Merck, KGaA, 64271 Darmstadt, BRD) is combined and concentrated at 2.7 kPa and 40°C, and 243 mg of N-{ l-[ bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(3,5-difluorophenyl)methylsulfonamide melting at 98°C.

'H-NMR (300 MHz, (CD3)2SO d6, 6 in ppm): 2.74 (t large, J = 7 Hz, 2H), 3.00 (s, 3H),

3.37 (t large, J = 7 Hz, 2H), 4.43 (s, 1H), 4.69 (mt, 1H), from 7.05 to 7.20 (mt, 6H), 7.28 (tt, J = 9 and 2.5 Hz, 1H), 7.40 (mt, 4H).

Example 35

(RS)-N-{1-[(4-chlorophenyl)-pyrimn-4-yl-methyl]-azetimn-3-yl}-N-(3,5-difluorophenyl)-methylsulfonamide can be obtained in the following way: A mixture of about 100 mg of (4-pyridyl)-(4-chlorophenyl)-chloromethane, 143 mg of N-azetidin-3-yl-N-(3,5-difluorophenyl)-methylsulfonamide hydrochloride, 17 mg of potassium iodide and 200 mg of potassium carbonate in 5 cm<3 >acetonitrile is stirred for around 18 hours at a temperature close to 20°C. The reaction mixture

is then brought to reflux for 3 hours, 17 mg of potassium iodide is added and refluxed for 2 more hours. After cooling to a temperature close to 20°C, the reaction medium is filtered on a glass frit. The solid is rinsed with acetonitrile and then 2 x 3 cm3 of ethyl acetate. The filtrates are concentrated to dryness under reduced pressure. 230 mg of a pale yellow paste is obtained which is purified by preparative thin-layer chromatography on silicon dioxide (4 preparative Merck Kieselgel 60F254 plates; 20 cm x 20 cm; thickness 0.5 mm), and eluting with methane/dichloromethane in a volume ratio of 5:95. After elution of the zone corresponding to the desired product and filtration on a glass frit with subsequent evaporation of the solvents under reduced pressure at a temperature of 40°C, 12 mg of (RS)-N-

{1-[(4-Chlorophenyl)-pyridine-4-^ amide.

<*>H-NMR (300 MHz, CDCl 3 , 8 in ppm): 2.82 (s, 3H), 2.96 (mf, 2H), from 3.50 to 3.80 (mt, 2H), 4 .33 (mf, 1H), 4.54 (mt, 1H), 6.82 (mt, 3H), from 7.20 to 7.45 (mt, 6H), 8.53 (d large, J = 5 .5 Hz, 2H).

The two isomers of (RS)-N-{1-[(4-chlorophenyl)-pyridin-4-yl-methyl]-azetidin-3-yl}-N-(3,5-chfluorophenyl)-methylsulfonamide can be separated on chiral stationary phase CHIRACEL OJ.

First isomer: <*>H-NMR (300 MHz, CDCl3.8 in ppm): 2.83 (s, 3H), 2.87 (t large, J = 7.5

Hz, 2H), 3.51 (mt, 1H), 3.60 (mt, 1H), 4.24 (s, 1H), 4.50 (mt, 1H), 6.82 (mt, 3H), from 7.20 to 7.35 (mt, 6H), 8.50 (d large, J = 5.5 Hz, 2H).

Second isomer: <!>H-NMR (300 MHz, CDCl 3.8 in ppm): 2.83 (s, 3H), 2.88 (t, J = 7.5 Hz,

2H), 3.51 (mt, 1H), 3.61 (mt, 1H), 4.25 (s, 1H), 4.51 (mt, 1H), 6.81 (mt, 3H), from 7 .20 to 7.35 (mt, 6H), 8.50 (d large, J = 5.5 Hz, 2H).

(4-pyridyl)-(4-chlorophenyl)-chloromethane can be prepared as follows: To a suspension of 100 mg of (4-pyridyl)-(4-chlorophenyl)-methanol in 2 cm3 of toluene, cooled to a temperature close to 0° C, add 0.0598 cm3 of thionyl chloride. After 2 hours at a temperature close to 0°C and 1 hour at a temperature close to 20°C, the reaction medium is concentrated under reduced pressure. Around 100 mg of (4-pyridyl)-(4-chlorophenyl)-chloromethane is obtained in the form of a white solid.

(4-pyridyl)-(4-chlorophenyl)-methanol can be prepared in the following way: To a solution of 2 g of 4-(4-chlorobenzoyl)-pyridine in 160 cm<3> ethanol is added, at a temperature close to 20°C , 348 mg sodium tetrahydroboride. After stirring for 2 hours at a temperature close to 20°C, 90 mg of sodium tetrahydroboride is added. After approx. W2 hours at the same temperature, the reaction medium is diluted with 200 cm<3> of dichloromethane and 200 cm3 of water. The pH value in the aqueous phase is adjusted to around 5 by adding around 13 cm<3> IN aqueous hydrochloric acid solution. After decantation, the aqueous phase is extracted with 3 x 100 cm3 of dichloromethane. The organic phases are combined and dried over magnesium sulfate, filtered and concentrated under reduced pressure. In this way, 2 g of (4-pyridyl)-(4-chloro-phenyl)-methanol is obtained in the form of a white powder.

Example 36

To a solution of 330 mg of {1-|^is-(4-chlorophenyl)methyl]-azetidin-3-yl}(3,5-difluoro-benzyl)amine in 25 cm<3> of tetrahydrofuran is added at ambient temperature and under argon, 24.4 mg of a 75% sodium hydride dispersion in mineral oil. The mixture is stirred at ambient temperature for 1 hour before adding 59 mm<3> methyl chloroformate, after which stirring is continued for 18 hours under the same conditions. 0.3 cm3 of distilled water is added to the reaction mixture and the tetrahydrofuran is driven off with a rotary evaporator. The residue obtained is extracted into dichloromethane, after which the organic phase is dried over magnesium sulphate, filtered and concentrated to a dry state at 2.7 kPa. The obtained residue is purified by flash chromatography on silica gel and eluted with dichloromethane:methanol in the volume ratio 97.5:2.5. 328 mg of {1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}(3,5-difluorobenzyl)carbamate is obtained in the form of a colorless oil.

<*>H-NMR (300 MHz, CDC13.8 in ppm): 2.97 (mt, 2H), 3.39 (mt, 2H), 3.71 (s, 3H), 4.24 (s large , 1H), 4.45 (mf, 1H), 4.57 (s, 2H), from 6.65 to 6.80 (mt, 3H), from 7.15 to 7.30 (mt, 8H).

Example 37

(RS)-N-{l-|l)is-(4-Chlorophen<y>l)-pyrinu^n-5-yl-methyl]-azetdin-3-yl}-N-(3 ,5-difluorophenyl)-methylsulfonamide can be obtained by working as in Example 33 from 0.16 g of (RS)-5-[bromo-(4-chlorophenyl)-methyl]-pyrimidine, 0.131 g of N-azetidin-3-yl -N-(3,5-difluorophenyl)-methanesulfonamide hydrochloride in 5 cm<3> acetonitrile, 303 mg of potassium carbonate and 95 mg of potassium iodide, in this way 26 mg of (RS)-N-{ l-[bis- (4-Chlorophenyl)-pyrimidin-5-yl-methyl]-azetidin-3-yl}-N-(3,5-difluorophenyl)-methylsulfonamide in the form of a yellow meringue mass.

<!>H-NMR (300 MHz, CDCl 3 , 8 in ppm): 2.83 (s, 3H), 2.91 (mt, 2H), 3.57 (mt, 2H), 4.31

(s, 1H), 4.50 (mt, 1H), from 6.75 to 6.90 (mt, 3H), 7.29 (s, 4H), 8.71 (s, 2H), 9.08 (p, 1H).

The medicaments according to the invention consist of at least one compound of formula (I) or an isomer or a salt of such a compound, in its pure state or in the form of a mixture in which it is associated with any other compatible pharmaceutical product, whether inert or physiologically active. The medicines according to the invention can be used orally, parenterally, rectally or topically.

Tablets, pills, powders (gelatin capsules, cachets) or granules can be used as solid preparations for oral administration. In these mixtures, the active ingredient according to the invention is mixed with one or more inert diluents such as starch, cellulose, sucrose, lactose or silicon dioxide, under argon. The mixtures may also include substances other than the diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragés) or a varnish.

As liquid preparations for oral administration, one can use pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil. The mixtures may include substances other than the diluents, for example wetting agents, flavourings, thickeners, aroma substances or stabilisers.

Sterile preparations for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions. Water, propylene glycol, a polyethylene glycol, vegetable oils, and especially olive oil, injectable organic esters such as ethyl oleate or other suitable organic solvents can be used as solvent or carrier. These preparations may also contain adjuvants and especially wetting agents, isotonizing agents, emulsifiers, dispersants and stabilisers. Sterilization can take place in many ways, for example by aseptic filtration, by incorporating sterilizing agents into the mixture, by irradiation or heating. The mixtures can also be prepared in the form of solid, sterile preparations which can be dissolved at the time of use in sterile water or any other injectable, sterile medium.

The preparations for rectal administration are rectal suppositories or capsules which, in addition to the active ingredient, contain emollients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

The preparations for topical administration can be, for example, creams, lotions, eye drops, colloquials, nasal drops or aerosols.

In the human therapeutic area, the compounds according to the invention are particularly suitable for the therapy and/or prevention of psychoses, including schizophrenia, anxiety problems, depression, epilepsy, neurodegeneration, cerebellar and spinocerebellar disorders, cognitive disorders, cranial trauma, panic attacks, peripheral neuropathies, glaucoma, migraines, Parkinson's disease, Alzheimer's disease, Huntington's chorea, Raynaud's syndrome, tremors, compulsive-obsessional disorders, senile dementia, thymic disorders, Tourette's syndrome, tardive dyskinesia, bipolar disorders, cancer, movement disorders induced by drugs, dystonias, endotoxemic shocks, hemorrhagic shocks, hypertension , insomnia, immunological diseases, plaque sclerosis, vomiting, asthma, appetite problems such as bulemia and anorexia, obesity, memory difficulties, difficulties in connection with treatment after chronic use and abuse of alcohol or drugs such as opioids, bartiturates, cannabis, cocaine, amphetamine, phencyclide, hallucinogens nogenes, benzodiazepines and others, as analgesics or potentiators for the analgesic effect of narcotic and non-narcotic drugs. They can also be used for therapy or prevention of intestinal transit.

The doses depend on the intended effect, the duration of the treatment and the administration mode used, but are generally between 5 mg and 1000 mg per day orally for an adult with unit doses from 1 mg to 250 mg of active ingredient.

In general, it is the doctor who determines the appropriate dosage as a function of age, weight and all other factors in the individual to be treated.

The following examples shall illustrate the preparations of the invention:

EXAMPLE A

Gel pills dosed to 50 mg of active ingredient and with the following composition are produced in a manner known per se:

EXAMPLE B

Tablets are produced in a manner known per se, dosed to 50 mg of active ingredient and with the following composition:

EXAMPLE C

An injectable solution is prepared containing 10 mg of active ingredient and with the following composition:

Claims (20)

1. Pharmaceutical preparation, characterized in that it contains as active ingredient at least one compound of formula (I): there Ri means a residue -NCRORs, -N(R4)-CO-R5, -N(R4)-SO2Re, R 2 and R 3 are phenyl, optionally substituted with one or more halogen; or a heteroaromatic selected from pyridyl or pyrimidyl, R4 means a residue -C(Rn)(Ri2)-Het, -Het, -(CRn)(Ri2)-Ar, Ar, cycloalkyl or norbornyl, R5 means a hydrogen atom or alkyl, Re means a residue -alk-CONR7R8 or alkyl, R7 and R», the same or different, mean a hydrogen atom or an alkyl residue, Rn means a hydrogen atom, Ri2 means a hydrogen atom, Ar means a phenyl radical optionally substituted with one or more halogen, alkoxy, -COOalk, hydroxy or hydroxyalkyl, Het means a heterocycle selected from pyridyl, quinolyl, isoquinolyl, pyrimidinyl, thiadiazolyl, thiazolyl, piperidyl or benzoisothiazolyl, where the heterocycle is optionally substituted with one or more alkyl, halogen or oxo, alk means an alkyl or alkylene residue, wherein alkyl and alkylene residues and parts and alkoxy acid residues and parts have a straight or branched chain containing 1 to 6 carbon atoms and cycloalkyl residues contain 3 to 10 carbon atoms, their optical isomers and their salts with a pharmaceutically acceptable mineral or organic acid. 2. Pharmaceutical preparation according to claim 1, characterized in that Het in formula (I) is selected from quinoline, pyridine, isoquinoline, pyrimidine, thiazole, thiadiazole, piperidine, these heterocycles being optionally substituted with one or more alkyl, halogen or oxo. 3. Pharmaceutical preparation according to claim 1, characterized in that Ri means a residue -N(R4)R5, -N(R4)-SO2R6, R2 means either a phenyl radical, optionally substituted with one or more halogens, or a heteroaromatic selected from pyridyl or pyrimidyl, R3 means either phenyl which is optionally substituted with one or more halogen or a heteroaromatic selected from pyridyl or pyrimidyl, R4 means a residue -C(Rn)(Ri2)-Het, -Het, -(CRn)(Ri2)-Ar, Ar or norbornyl, R5 means a hydrogen atom or alkyl, Re means a residue -alk-CONR7R8 or alkyl, R 7 and R s are the same or different and mean a hydrogen atom or an alkyl residue, Rn means a hydrogen atom, R12 means a hydrogen atom, Ar means a phenyl radical optionally substituted with one or more halogen, alkoxy, hydroxy or hydroxyalkyl, Het means a heterocycle selected from quinoline, pyridine, isoquinoline, pyrimidine, thiazole, thiadiazole, these heterocycles being optionally substituted with one or more alkyl, halogen or oxo, their optical isomers and their salts with pharmaceutically acceptable mineral and organic acids. 4. Pharmaceutical preparation according to claim 1, characterized in that R 1 means a residue -N(R 4 )-SO 2 R 6 , R 2 means either phenyl which is optionally substituted with one or more halogen; or a heteroaromatic selected from pyridyl or pyrimidyl, R 3 means either phenyl which is optionally substituted with one or more halogen; or a heteroaromatic selected from pyridyl or pyrimidyl, R 4 means -Het or Ar, R6 means an alkyl residue, R7 and R% are the same or different and mean a hydrogen atom or an alkyl residue, Ar means a phenyl radical optionally substituted with one or more halogen, alkoxy, hydroxy or hydroxyalkyl, Het means a heterocycle selected from quinoline, pyridine, isoquinoline, pyrimidine, thiazole, thiadiazole, these heterocycles being optionally substituted with one or more alkyl, halogen, or oxo, hydroxy, their optical isomers and their salts with a pharmaceutically acceptable mineral or organic acid. 5. Preparation according to claim 1, characterized in that the compound of formula (I) is selected from among the following compounds: ■> N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(6-chloropyrid-2-yl)-methylsulfonamide, N-{1-phtis-(4-chlorophenyl)methyl] azetidine-3^ N- {1 -[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-quinol-6-yl-methylsulfonamide, N-{l-|>is-(4-chlorophenyl) methyl]azetidin-3-yl}-N-quinol-5-yl-methylsulfonamide, N-{l-|>is-(4-chlorophenyl)methyl]azetidin-3-yl}-N-isoquinol-5-yl- methylsulfonamide, N-{l-[bis-(4-chlorophenyl)methyl]azetidUn-3-yl}-N-pyrid-3-yl-methylsulfonamide, N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(1-oxide-pyrid-3-yl)-methylsulfonamide, N-(1R,2S,4S)-bicyclo[ 2,2,1]hept-2-yl-N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-methylsulfonamide, N-(1R,2R,4S)-bicyclo[2,2,1]hept-2-yl-N-{1-|^is-(4-chlorophenyl)methyl]azetidin-3-yl}-methylsulfonamide, N-{1-|>is-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)-methylsulfonamide, N- {1 -[bis-(4-chlorophenyl)methyl] azetidin-3-yl}-N-(thiazol-2-yl)-methylsulfonamide, N-{l-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3-methoxyphenyl)-methylsulfonamide , N-{1-[bis-(4-chlorophenyl)methyl]azeti(Un-3-yl}-N-(3-hydroxyphe N- {1 -[bis-(4-chlorophenyl)methyl]azetidine-3- yl}-N-(3-hydroxymethyl-phenyl)-methylsulfonamide, Ethyl-N-{l-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(methylsulfonyl)-3-am N- {1-[bis-(4-chlorophenyl)methyl]azetidine- 3-yl}-N-(1-isobutyl-piperid-4-yl)-methylsulfonamide, N-benzyl-N- {1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}amine, N- {1-rbis-(4-chlorophenyl)methyl]azetidin-3-yl}-N- (3,5-difluorobenzyl)amine, N-{l-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorobenzyl)-methylsulfonane^ N-{l-|> is-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(pyrid-3-yl-methyl)-methylsulfonanu N-{ l-|>is-(4-fluorophenyl)methyl]^ (RS)- N-{1-[(4-chlorophenyl)-pyrid-3-yl-methyl]azetimn-3-yl}-N-(3,5-difluorophenyl) sulfonamide, (R)-N-{1-[(4-chlorophenyl)-pyrid-3-yl-methyl]azeti(in-3-yl}-N-(3,5-diphenyl) sulfonamide, (S)-N-{1-[(4-chlorophenyl)-pyrid-3-yl-m^ sulfonamide, (RS)-N-{l-[(4-chlorophrenyl)-pyrid-4-yl-methyl]azetdin-3-yl}-N-(3,5-difluorophenyl sulfonamide, (R)-N-{ l- [(4-Chlorophenyl)-pyride-^ sulfonamide, (S)-N-{1-[(4-chlorophenyl)-pyrid-4-yl-methyl]azetimn-3-yl}-N-(3,5-difluorophenyl^ sulfonamide, (RS)-N- {1 -[(4-chlorophenyl)-pyrim(Un-5-yl-methyl]azeti}-N-(3,5-difluorophenyl)-methylsulfonamide, (R)-N- {1 - [(4-chlorophenyl)-pyrirmcun-5-yl-methyl]azeud^n methylsulfonamide, (S)-N- {1 -[(4-chlorophenyl)-pyrimidin-5-yl-methyl]azetidin-3-yl} -N-(3,5-difluorophenyl)-methylsulfonamide, N-{1-[(4-chlorophenyl)-methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)-benzylsulfonamide, their optical isomers and their salts with a pharmaceutically acceptable mineral or organic acid. 6. Compound, characterized by the formula: there Ri means a residue -N(R4)R5, -N(R4)-CO-R5, -N(R4)-SO2R6, R 2 and R 3 are phenyl, optionally substituted with one or more halogen; or a heteroaromatic selected from pyridyl or pyrimidyl, R4 means a residue -C(Rn)(Ri2)-Het, -Het, -(CRn)(Ri2)-Ar, Ar, cycloalkyl or norbornyl, R5 means a hydrogen atom or alkyl, Re means a residue -alk-CONR7R8 or alkyl, R7 and Rs. same or different, means a hydrogen atom or an alkyl residue, Rn means a hydrogen atom, R12 means a hydrogen atom, Ar means a phenyl radical optionally substituted with one or more halogen, alkoxy, -COOalk, hydroxy or hydroxyalkyl, Het means a heterocycle selected from pyridyl, quinolyl, isoquinolyl, pyrimidinyl, thiadiazolyl, thiazolyl, piperidyl or benzoisothiazolyl, where the heterocycle is optionally substituted with one or more alkyl, halogen or oxo, alk means an alkyl or alkylene residue, wherein alkyl and alkylene residues and parts and alkoxy acid residues and parts have a straight or branched chain containing 1 to 6 carbon atoms and cycloalkyl residues contain 3 to 10 carbon atoms, their optical isomers and their salts with a pharmaceutically acceptable mineral or organic acid, except for the compound where R 2 and R 3 are phenyl radicals, R 1 is a radical -N(R 4 )SO 2 R 6 , where R 4 is a phenyl radical and R 6 is a methyl radical. 7. Compound with formula (I) according to claim 1, characterized in that Het is selected from quinoline, pyridine, isoquinoline, pyrimidine, thiazole, thiadiazole, piperidine, these heterocycles being optionally substituted with one or more alkyl, halogen or oxo. 8. Compound with formula (I) according to claim 6, characterized by Ri means a residue -N(R4)R5, -N(R4)-SO2R6, R2 means either a phenyl radical, optionally substituted with one or more halogens, or a heteroaromatic selected from pyridyl or pyrimidyl, R3 means either phenyl which is optionally substituted with one or more halogen or a heteroaromatic selected from pyridyl or pyrimidyl, R4 means a residue -C(Rn)(Ri2)-Het, -Het, -(CRn)(Ri2)-Ar, Ar or norbornyl, R5 means a hydrogen atom or alkyl, Re means a residue -alk-CONR7R8 or alkyl, R7 and Rg are the same or different and mean a hydrogen atom or an alkyl residue, Rn means a hydrogen atom, Ri2 means a hydrogen atom, Ar means a phenyl radical optionally substituted with one or more halogen, alkoxy, hydroxy or hydroxyalkyl, Het means a heterocycle selected from quinoline, pyridine, isoquinoline, pyrimidine, thiazole, thiadiazole, these heterocycles being optionally substituted with one or more alkyl, halogen or oxo, their optical isomers and their salts with pharmaceutically acceptable mineral and organic acids, except for the compound where R 2 and R 3 mean a phenyl residue, R 1 means a residue -N(R 4 )SO 2 R 6 , where R 4 means a phenyl residue and R 6 means a methyl residue. 9. Compound with formula (I) according to claim 6, characterized by R 1 means a residue -N(R 4 )-SO 2 R 6 , R 2 means either phenyl which is optionally substituted with one or more halogen; or a heteroaromatic selected from pyridyl or pyrimidyl, R 3 means either phenyl which is optionally substituted with one or more halogen; or a heteroaromatic selected from pyridyl or pyrimidyl, R 4 means -Het or Ar, R6 means an alkyl residue, R 7 and R s are the same or different and mean a hydrogen atom or an alkyl residue, Ar means a phenyl radical optionally substituted with one or more halogen, alkoxy, hydroxy or hydroxyalkyl, Het means a heterocycle selected from quinoline, pyridine, isoquinoline, pyrimidine, thiazole, thiadiazole, these heterocycles being optionally substituted with one or more alkyl, halogen, or oxo, hydroxy, their optical isomers and their salts with a pharmaceutically acceptable mineral or organic acid, except for the compound where R 2 and R 3 mean a phenyl radical, R 1 means a radical -N(R 4 )SO 2 R 6 , where R 4 means a phenyl radical and Ré means a methyl radical. 10. Compound with formula (I) according to claim 6, characterized in that it is selected from the following compounds: N-{1-[bis-(4-chlorophenyl)methyl]azeti(U^-3-yl}-N-(6- chloropyrid-2-yl)-methylsulfonamide, N-{1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(6-ethylpyrid-2-yl)-methylsulfonamide, N- {1 - tois-(4-Morphenyl)methyl]azetidin-3-yl}-N-quinol-6-yl-methylsulfonamide, N-{l-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N- kmol-5-yl-methylsulfonamide, N- {1-[>is-(4-chlorophenyl)methyl]azetidin-3-yl}-N-isoxmol-5-yl-methylsulfonamide, N-{l-[>is- (4-chlorophenyl)methyl]azetidin-3-yl}-N-pyrid-3-yl-methyl^ N- {1 - [bis-(4-chlorophenyl)methyl] azetidin-3-yl} -N-( 1 -oxide-pyrid-3-yl)-methylsulfonamide, N-(1R,2S,4S)-bicyclo[2,2,1]hept-2-yl-N-{1-[bis^ methylsulfonamide, N-(1R ,2R,4S)-bicyclo[2,2,1]hept-2-yl-N-{l-[bis-(4-chlorophenyl)methyl]azetdin-3-yl}-methylsulfonamide, N-{l-| >is-(4-ldorphenyl)methyl]azeti(un-3-yl}-N-(3,5-difluorophenyl)-methylsulfo^ N- {1 -[bis-(4-chlorophenyl)methyl]azetidin-3- yl}-N-(thiazol-2-yl)-methylsulfonamide, N-{1-I>is-(4-chlorophenyl)methyl l]azetidin-3-yl}-N-(3-methoxyphenyl)-methylsulfonamide, N- {1-[bis-(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3-hydroxyphenyl)-methylsulfonamide , N-{l-[bis-(4-chlorophenyl)methyl]azetidin-3-y^^ amide, Ethyl-N- {1 -|>is-(4-chlorophenyl)methyl]azetidin-3-yl} - N-(methylsulfonyl)-3-aminobenzoate, N-{1-[bis-(4-chlorophenyl)methyl]azetid4n-3-yl}-N-(1-isobutyl-piperid^-yl)-methylsulfonamide, N-benzyl -N- {1 - [bis-(4-chlorophenyl)methyl] azetidin-3-yl} amine, N-{ l -|^is-(4-Worphenyl) me<y>tl]azetidin-3-yl} -N-(3,5-difluorobenzyl)amine, N-{l-|>is-(4-chlorophenyl)methyl]azeudmO^ N-{1-phtis-(4-chlorophenyl)methyl]azetimn-^^ N- { l-[Ms-(4-fluorophenyl)meth^ (RS)-N-{ l-[(4-chlorophenyl)-py^ sulfonamide, (R)-N- {1-[(4-chlorophenyl)-pyride -3-yl-methyl]azetidin-3-yl}-N-(3,5-difluorophenyl)-methylsulfonamide, (S)-N-{1-[(4-chlorophenyl)-pyrid-3-yl-methyl] azetimn-3-yl}-N-(3,5-difluorophenyl sulfonamide, (RS)-N- {1 -[(4-chlorophenyl)-pyrid-4-yl-methyl]azetidin-3-yl} -N- (3,5-difluorophenyl)-methylsulfonamide, (R)-N-{l-[(4-chlorophenyl)-pyrid-4-yl-methyl]α^ sulfonamide, (S)-N-{l-[(4 -claw rphenyl)-pyrid-4-yl-methyl]azetimn-3-yl}-N-(3,5-difluorophenyl)-methyl^ sulfonamide, (RS)-N-{l-[(4-chlorphrenyl)-pyrimin- 5-yl-methyl]azetidin-3-yl}-N-(3,5-difl^^ methylsulfonamide, (R)-N-{1-[(4-chlorophenyl)-pyrimin-5-yl-methyl]azetidine -3-yl}-N-(3,5-difl^methylsulfonamide, (S)-N- {1 -[(4-chlorophenyl)-pyrimidin-5-yl-methyl]azetidin-3-yl} -N- (3,5-difluorophenyl)-methylsulfonamide, N-{l-[(4-chlorophenyl)-methyl]azetidin-3-yl}-^^ their optical isomers and their salts with a pharmaceutically acceptable mineral or organic acid. 11. N-{1-[bis-(4-chlorophenyl)methyl]-azetidin-3-yl}-N-(3,5-difluorophenyl)-methylsulfonamide, its optical isomers and its pharmaceutically acceptable salts with a mineral or organic acid. 12. Process for the preparation of compounds of formula (I) according to claim 6, where Ri means a residue -N(R4)Rs, where R5 is a hydrogen atom, R4 is a residue -CRnRi2-Ar or -CRnRi2-Het and R12 is a hydrogen atom , characterized by reacting a compound Rb-CORn, where Rn has the same meaning as in claim 6, with a compound of the formula: where Rb means a residue Ar or Het, R2, R3, Ri, Ar and Het have the same meaning as in claim 6, isolates the product and optionally converts it into a pharmaceutically acceptable salt. 13. Process for the preparation of compounds of formula (I) according to claim 6, where Ri means a residue -N(R4)-CO-R5, where R4 is a residue -C(R2n)(Ri2)-Het or -C(Rn) (Ri2)-Ar and R12 is a hydrogen atom, characterized by reacting a compound Hal-CORs with a compound of the formula: where Hal means a halogen atom, Rb means a residue Ar or Het and R2, R3, R5, Rn, Ar and Het have the same meaning as in claim 6, isolates the product and optionally converts it into a pharmaceutically acceptable salt. 14. Process for the preparation of compounds of formula (I) according to claim 6, where Ri means a residue -NCRO-SC^, where R4 is a residue -C(Rn)(Ri2)-Het or -C(Rn)(Ri2)- Ar and R12 is a hydrogen atom, characterized by reacting a compound Hal-SC^Ré with a compound of the formula: where R2, R3, Rn and R5 have the same meaning as in claim 6, Hal means a halogen atom and Rb means a residue Ar or Het, isolates the product and optionally converts it into a pharmaceutically acceptable salt. 15. Process for the preparation of compounds of formula (I) according to claim 6, where Ri means a residue -NCRORs, characterized by reacting a compound Rs(R4)NH with a compound of the formula: where R2, R3, R4 and R5 have the same meaning as in claim 6, isolates the product and optionally converts it into a pharmaceutically acceptable salt. 16. Process for the preparation of compounds of formula (I) according to claim 6, where Ri means a residue-N(R4)SO2R6, characterized by reacting a compound Hal-SO2R6 with a compound of the formula: where R2, R3, R4 and Ré have the same meaning as in claim 6 and Hal means a halogen atom, isolates the product and optionally converts it into a pharmaceutically acceptable salt. 17. Process for the preparation of compounds of formula (I) according to claim 6, where Ri means a residue-N(R4)COR5, characterized by reacting a compound Hal-COR^ with a compound of the formula: where R2, R3, R4 and R5 have the same meaning as in claim 6 and Hal means a halogen atom, isolates the product and optionally converts it into a pharmaceutically acceptable salt. 18. Process for the preparation of compounds of formula (I) according to claim 6, where Ri means a residue N(R4)-SO2-R6, where R4 is a residue Het or Ar, characterized in that a compound Rd-NH-SO6 is reacted -R6 with a compound of the formula: where Rd means a residue Ar or Het, R2, R3 and Ré have the same meaning as in claim 6 and Ms means a methylsulfonyloxy acid residue, isolates the product and optionally converts it into a pharmaceutically acceptable salt. 19. Process for the preparation of compounds of formula (I) according to claim 6, characterized in that a compound R2-CHBr-R3 is reacted with a compound of the formula: where Ri, R2 and R3 have the same meaning as in claim 6, isolates the product and optionally converts it into a pharmaceutically acceptable salt. 20. Process for the preparation of compounds of formula (I) according to claim 6, where Ri means a residue -N(R4)-SO2-R6, where R4 is a piperid-4-yl residue substituted on the nitrogen with an alkyl residue, characterized in that one alkylates a corresponding compound of formula (I), where Ri means a residue -N(R4>-SO2-R6 where R4 is a piperid-4-yl residue), isolates the product and optionally converts it into a pharmaceutically acceptable salt.