Title of Invention	A PHARMACEUTICAL COMPOSITION INTENDED TO PREVENT THE PROLIFERATION OF TUMOUR CELLS
Abstract	A process for producing crystalline form I of cabergoline, which process comprises crystallization of the desired form from a toluene/diethyl ether mixture comprising raw cabergoline, followed by recovery and drying of the resulting crystals. A new solvate form V of cabergoline, useful as an intermediate, is also provided.

Full Text

The present invention relates to a novei use of ccmpounds having good affinity for the receptors ~c v;hich cis-M-cyclohexyl-N-ethyi [3- ( 3-chloro-4-cycio-hexylphenyl )allyl]amine binds, as well as to novel com¬pounds having the same properties. cis-N-Cyclohexyl-N-ethyl[3-(3-chlcro-4-cycIo-hexylphenyi) allyl]amine, also known under the code CM 31747 or SR 31747 and referred to hereinbelow as ^^SR 31747", is described in EP 376,350 which also dis¬cusses its immunosuppressant activity. It has been found that SR 31747 prevents cancer cells from prolif¬erating and that, consequently, it can exert antitumour activity. Furthermore/ it has been found that SR 31747 has receptor sites on these cells. Lastly, it has been found that any product capable of displacing tritiated SR 31747 from its receptors on tumour cells prevents cell proliferation. More particularly, it has been observed that' compounds capable of displacing tritiated SR 31747 (referred to hereinbelow as "3H-SR 31747") from its receptor sites have activity in preventing cell proliferation. Thus, according to .one of its aspects, the present invention relates ,to the use of compounds capable of displacing tritiated cis-N-cyclohexyl-N-ethyl[3-(3-chloro-4-cyclohexylphenyl)allyl]amine from its receptors for the preparation of pharmaceutical compositions intended to combat cell proliferation, The capacity of the compounds envisaged for the use accord¬ing to the present invention of displacing tritiated SR 31747 from its receptors may readily be determined biochemically using 3H-SR 31747 and binding it to the cells . This determination may be carried out with tumour cells chosen appropriately, preferably from cell lines which proliferate readily in vitro, for example human myeloma, kidney carcinoma or human lung cells or alternatively on mammary carcinoma cells. In the context of the present invention, in order to be able to carry out the determinations under: standardized conditions making it possible to obtain constant and reproducible results, a human mammary tumour cell line 'MCF-7" was chosen arbitrarily. Also, in the context of the present invention, -'H-SR 31747 was chosen arbitrarily, in which the trit¬ium is bound to the vinylene bond, but the SR 31747 may be labelled in any way at all since the labelling serves only to monitor the displacement of the product from its receptors. Determination of the capacity to displace ■"H-SR 31747 from its receptors present on cells, in particular cells of the MCF-7 cell line, was carried out by performing tests of total binding and of spe¬cific binding. According to the present invention, any product which, when subjected to the above preliminary opera¬tion, is capable of displacing 'H-SR 31747 from its receptors may be used for the preparation of pharmaceu¬tical compositions to combat cell proliferation, SR 31747 is, firstly, capable of displacing -"H-SR 31747 from its receptors and possesses powerful inhibitory activity on cell proliferation. More particularly, the subject of the present invention is the use of a com¬pound capable of displacing tritiated cis-N-cyclohexyl-N-ethyl [3- (3-chloro-4-cyclohexylphenyl) allyl]amine from its receptors, chosen from the group consisting of: a) amines of formula in which; - R1b represents a hydrogen atom or a halogen atom; - R2b represents a cyclohexyl group; - R3b represents a hydrogen atom or a C1-C3 alkyl group; - R4b represents a C1-C3 alkyl group which may be iden¬tical or different to the alkyl group in R3-; - R3b and R4b considered together may form, with the nitrogen atom to which they are attached, a 5- to 7-membered heterocyclic group chosen frcm piperidino> morpholino and pyrrolidine; - Ab represents a -CH2CH2- or -'CH=CH- group; f) the pharmaceutically acceptable addition salts with acids of the amines of formula (III). in which - A1 represents a phenyl, naphthyl, substituted phenyl or substituted naphthyl group, - n represents an integer between 1 and 4 inclusive, - RB represents an alkyl group and, in this case, A represents a single bond and RA and RC, which may be identical or different, represent, independently of each other, a hydrogen atom or a group chosen from halogen/ alkyl, alkyl substituted with one or more halogens, and alkoxy, - or RB and RC together form a bridge -{CH:)p- with p representing 0, 1 or 2 and, in this case, RA represents a hydroxy1 or alkoxy group in position 5 on the aro¬ matic ring which bears it or RA represents a hydrogen or halogen atom in any position on the aromatic ring, - or RB and RC together form a -CH= bridge, and the bond which links it to the aromatic ring is a single bond and, in this case, Ac represents a CH: group and RA represents a hydrogen atom or a hydroxyl or alkoxy group in position 5 on the aromatic ring which bears it, - or RB and RC together form a bond and Ac then repre¬ sents a group o the carbonyl being linked to the oxygen and the bond connecting Ac, to the carbon bearing the side chain is a double bond, and, in this case, RA represents a hydro¬gen atom or a hydroxyl or alkoxy group, - when RB represents an alkyl group, X and Y each rep¬ resent two hydrogen atoms or form, together with the carbon atom v;hich bears the:ri., a C=0 group, and ?/0 rep¬resents a hydrogen atom or an alkyl group, when RB and RC form a bridge, X and Y each representing two hydrogen atoms and RD, which exists only when all the bonds of the carbon which bears it are single bends, represents a hydrogen atom, it being understood that the terms 'alkyl" and "alkoxy" denote linear or branched saturated groups containing from 1 to 6 carbon atoms, - the term 'substituted' relating to the phenyl and naphthyi substituents means that these may be substi- tuted with 1 to 3 groups chosen from hydroxy!/ alkyl, alkyl substituted with one or more halogens, alkoxy and halogen, h) the pharmaceutically acceptable salts and solvates of the amines of formula (IV); I) amines of formula (V) in which: Ar2 and Ar3, which may be identical or different, rep¬resent, independently of each other, a phenyl group, or a naphthyi or phenyl group substituted with 1 to 3 groups chosen from hydroxyl, (C1-C6) alkyl, alkoxy, halogen and alkyl, and alkyl substituted with one or more halogens; - X' and y each represent two hydrogen atoms or together form an oxo group, " RE represents a (C1-C6)alkyl group, their isomers in pure form or in the form of a mixture, j) the pharmaceutically acceptable salts and solvates of the amines of formula (V) k) amines of formula (VI) - m" and n" represent 1 or 2, - Cy represents a (C3-C1)cycloalkyl, - Ar4 represents an aryl or a heteroaryl chosen from phenyl, naphthyl and thienyl, optionally mono- to trl- substituted with a halogen, a trifiuoromethyl, a (C1-C3) alkyl or a (C1-C3) alkoxy; n) the pharmaceutically acceptable addition salts with acids of the amines of formula (VII), 0) amines of formula (VIII) in which - Gi represents a (C1-C6)alkyl or a (C3-C7) cycloalkyl, G2 represents a (C1-C6) alkyl, a (C3-C6) cyclo-alkyl (C1-C3) alkyl, a (C3-C7) cycloalkyl, a phenyl/ benzyl or phenethyl group optionally substituted on the phenyl nucleus of the radical with a halogen or with a methoxy or nitro group, - or alternatively G1 and G2 form, together with the nitrogen atom to which they are attached, a saturated, bridged or spiro heterocycle having only one endocyclic nitrogen atom and containing from 5 to 10 carbon atoms; a morpholino group; a piperazino group which is unsubstituted or substituted in position 4 with a (C1-C4) alkyl, with a phenyl, benzyl or phenethyl radical, the benzene group optionally being substituted with a halogen, or with a methoxy or nitro group; a group chosen from 4-phenyl-1, 2,3, 6-tetrahydropyrid-l-yl, 4-phenylpiperidino, 4-benzylpiperidino and 4-phenethylpiperidino radicals, it being possible for the phenyl group of the said radicals to oe unsubstituted or substituted with a halogen or with a methoxy group or a nitro group, (ii) a group of structure (2) in which - G3 represents hydrogen or a hydroxyl group; - GA represents hydrogen; - or alternatively G3 and G4 together constitute one or two bonds so as to form, with the carbon atoms to which they are attached, a vinylene group or an ethynylene group; - G5 represents a group chosen from phenyl, benzyl and phenethyl radicals, it being possible for the phenyl nucleus of the said radicals to be unsubstituted or substituted with a halogen, a methoxy group or a nitro group; - G6 represents a hydroxyl group or a hydrogen; - G7 and G7 represent hydrogen or may form a bond; or alternatively G5 and G6 together form an n-pentylene group; (iii) a group of structure (3) in which - G3 and G4 are as defined above; - Alk represents a (C1-C6)alkyl or a {C3-C6) alkenyl; - Gg represents a 1-adamantyl, a (C3-C7) cycloalkyl, a (C3-C7) cycloalkyl (C1-C3) alkyl or a group chosen from phenyl, benzyl and 2-phenethyl radicals, it being pos¬sible for the phenyl nucleus of the said radicals to be unsubstituted or substituted with a halogen, a methoxy group or a nitro group, - or alternatively Alk and G6, which may be identical or different, represent a (C4-C6)alkyl group; In particular, the amines of formula (I) and their pharmaceutically acceptable salts are described in EP 376,850; the said amines may be prepared as illustrated in that document and isolated in the form of base, salts and/or solvates. The amines of formula (II) and their pharmaceutically acceptable salts are described in EP 461,986; the said amines may be pre¬pared as illustrated in that document and isolated in the form of base, salts and/or solvates. The amines of formula (III) and their pharmaceutically acceptable salts are described in FR 2,249,659; the said amines may be prepared as illustrated in that document and isolated in the form of base, salts and/or solvates. The amines of formula (IV) and their pharmaceutically acceptable salts are described in EP 702,010; the said amines may be prepared as illustrated in that document and isolated in the form of base, salts and/or sol¬vates. The amines of formula (V) and their pharmaceuti¬cally acceptable salts are described in EP 707,004; the said amines may be prepared as illustrated in that document and isolated in the form of base, salts and/or solvates. The amines of formula (VI) and their pharma¬ceutically acceptable salts are described in EP 581,677; the said amines may be prepared as illus¬trated in that document and isolated in the form of base, salts and/or solvates. The amines of formula (VII) and their pharmaceutically acceptable salts are described in WO 95/1594 8; the said amines may be pre¬pared as illustrated in that document and isolated in the form of base, salts and/or solvates. or nitro group, - or alternatively G1 and G2 form, together with the nitrogen atom to which they are attached, a saturated, bridged or spiro heterocycle having only one endocyclic nitrogen atom and containing from 5 to 10 carbon atoms; a morpholino group; a piperazino group which is unsubstituted or substituted in position 4 with a (C1-C4) aikyl, with a phenyl, bentyl or phenocnyl radical, the phenyl nucleus optionally be ma substituted with a halogen, or with a methoxy or ni iro group; a group ,chosen from 4-phenyl-l, 2, 3, o'-tetrahydropyrid-l-yl, 4-phenylpiperidino, 4-benzyl-piperidino and 4-phenethylpiperidino radicals, it being possible for the phenyl group of the said radicals to be unsubstituted or substituted with a halogen or with a methoxy group or a nitro group, (ii) a group of structure (2) in which - G3 represents hydrogen or a hydroxyl group; - G4 represents hydrogen; - or alternatively G3 and G4 together constitute one or two bonds so as to form, with the carbon atoms to which they are attached/ a vinylene group or an ethynylene group; - G5 represents a group chosen from phenyl, benzyl and phenethyl radicals, it being possible for the phenyl nucleus of the said radicals to be unsubstituted or substituted with a halogen, a methoxy group or a nitro group; - Ge represents a hydroxyl group or a hydrogen; - G-5 and G-7 represent hydrogen or may form a bond; or alternatively G5 and Ge together form an n-pentylene group; - G6 being a hydroxyl group and it being possible for G1 and G7 to form a bond only when G5 is other than optionally substituted benzyl or phenethyl, (iii) a group of structure (3) in which - G3, and G. are as defined above; " Aik represents a (C1-C6)alkyl or a (C3C7) alkenyl ; - G9 represents a l-adamantyi, a (C3-C7) cycloalkyl, a (C5-C7) cycloalkyl (C1-C3) alkyl or a group chosen from phenyl, benzyl and 2-phenylethyl radicals, it being possible for the phenyl nucleus of the said radicals to be unsubstituted or substituted with a halogen, a methoxy group or a nitro group, - or alternatively Alk and G8 which may be identical or different, represent a (C4-C6)alkyl group; - GH not being a {C3-C6)cycloalkyl when L is hydrogen or a fluorine or chlorine atom, L' is hydrogen and Alk is a (C1-C6) alkyl; (B) the pharmaceutically acceptable salts and solvates of the compaund of formula (VIII), In these novel compounds of formula (VIIX), the halogen is preferably chlorine or fluorine, one of the groups h and L' being hydrogen and the other fluorine, chlorine or nitro or alternatively L and L', which are identical, being hydrogen or chlorine. These compounds are particularly advantageous. in which G3' and G/ are as defined above, Alk' is (C1-C6) alkyl, Ga" represents a 1 - adamantyl, phenyl, benzyl or 2-phenylethyl group or alternatively Alk' and G8, which are identical, each represent a (C—C. )alkyl group, and their pharmaceutically acceptable salts and solvates, are preferred. These novel compounds of formula (VIII) may be prepared by a process characterized in that: either, a functional derivative of cyclopropane-carboxylic acid of formula (IX) is then subjected to reduction in order to isolate the amines of formula (VIII), in which Z is a group of structure (1), in the form of their free bases or their pharmaceutically acceptable salts; - or, a compound of formula (XII) and the product thus obtained of f crmuia (VI11) in which Z has the structure (2) or (3) v/here G. and 3 together constitute two bonds so as to form, with the carbon atoms to which they are attached, an ethynylene group, is optionally subjected to hydrogenation with two or one mole of hydrogen so as to isolate the corresponding compound of formula (VIII) in which Z is a group of structure (2) or (3) where G3 and G. both respectively represent a hydrogen atom or, together, a bond which forms, with the two carbon atoms to which they are attached, a vinylene group; or the produce thus obtained of formula (VIII) in which Z has the structure (2) where G5 is phenyl, G3 is hydroxyl and G is hydrogen, is optionally subjected to dehydration m order to isolate a compound of formula (VIII) in which Z has the structure (2) where G5 is phenyl and G.: and G-together form a bond; it being possible for the said compounds to be isolated in the form of their free base or one of their pharmaceutically acceptable salts or solvates; where Alk" , G'5, G'6. G7 and G'8 are as defined above, is then subjected to reduction of the ketone so as to isolate the corresponding compound of formula (VIII) m which 2 is a group of structure (2) or (3) where G, is hydroxy1 and GA is hydrogen, after which the product thus obtained of formula (VIII), in which Z has the structure (2) where G5 is phenyl, G6 is hydroxy! and G-is hydrogen, is optionally subjected to dehydration in order to isolate a compound of formula (VIII) in which Z has the structure (2) where G5 is phenyl and G-- and G-. together form a bond; it being possible for the said compounds to be isolated in the form of their free base or one of their pharmaceuticaily acceptable salts; and the free bases of formula (VIII) are optionally converted into their pharmaceuticaily acceptable salts. Reaction of the functional derivative of the acid (IX) with the amine (X) takes place according to the standard procedures for the preparation of amides. As a functional derivative of the acid (IX), any common compound of peptide chemistry may be used, for example the chloride, the anhydride, a mixed anhydride, for example with carbonic acid monoethyl ester (obtained by reacting the acid (IX) with ethyl chloroformate), an activated ester or an activated amide. When, as a functional derivative, the chloride or the anhydride is used, it may be advantageous to work in the presence of a tertiary amine, for example triethylamine. The compound (XI) may also be reduced under the standard conditions for converting an amide into an amine, using a metal iodide such as lithium aluminium hydride or borane as reducing agent. The reaction between the acetylene derivatives (XII) or zhe acetophenones (XV) and the amines (XIII) and (XIV) in the presence of formaldehyde is carried out under the standard conditions of the Mannich reaction. Redactien cf the compounds of formula (.'/III, , m which Z has one of the structures (2) or (3; v;here Gi^ and G4 form two bonds, is carried out cy hydrogenation with one mole of hydrogen in order to obtain the compounds (VIII) (Z = structure 2 or 3 where G3 + G4 form a bond of cis configuration) or with two moles of hydrogen in order to obtain the saturated compounds, Reduction of the compound of formula (XVI) m order to obtain the compounds of formula {VIII) m which Z has one of the structures (2) or (3) where G; IS hydroxyl and G4 is hydrogen, is carried out according to the standard methods. When it is desired to obtain a hydroxy compound having a specific configuration on the chiral carbon atom, a stereospecific reducing agent may be used. When the hydroxyl at ed derivative musr then be dehydrated in order to obtain a compound of formula (VIII), in which Z has one of the structures (2) or (3) where G3 and G4 form a bond, the stereoconf iguration plays no role and the 'compound (XVI) may be reduced, for example, with sodium borohydride. The optional dehydration of the compound of formula (VIII), in which Z has one of the structures (2) or (3) where G3 is hydroxyl and G4 is hydrogen, is carried out by heating in the presence of agents or apparatus which promote the removal and/or uptake of water, for example using Dean-Stark apparatus. The configuration of the unsaturated compound (VIII) thus obtained is trans. This compound may m turn be hydrogenated in order to prepare an amine of formula (VIII) in which Z has one of the structures (2) or (3) where G3 and G4 are hydrogen. The starting acids of formula (IX) and their functional derivatives, as well as the amides of formula (XI), are novel products which may be prepared from a 4- ( 4"Cyclohexyl-3,5-L-L' -phenyl)-4-oxobutyric acid. More par~icularly, the acids of formula ax are obta ined DV reduction of the kezoPie r.o -4 - 4-cycIohexyl-3,5-L-L'-phenyl)-4-oxobutyric acid (L and L' being as defined above) m order to obtain 4 - 4 cyclohexyl-3,5-L-L'-phenyl)'4-hydroxybutyric acid whicn is converted into its lactone. This lactone is chlorinated and converted into 4-chloro-4-{4-cyclohexyl-3,S-L-L'-phenyl)butyric acid ester which m turn gives, on cyclization, the cyclopropanecarboxylic acid (IX). The 4- ( 4-cyclohexyl-3, S-L-L -phenyl) --4-oxo¬butyric acids (L and L' being as defined above) are prepared in the following way: • when L and L' represent H, according to N, P. Buu-Hoi et al,, Bull, Sec. Chim, France, 1944, 127; • when L represents H, L' represents CI according to F, Krausz et al. , Arzneim.-Forsh., 1974, 24, 1364-1367; BE 750,233; ■ when L represents H, L' represents NO: according to BE 750,233; • when L and L' represent CI, according to F. Krausz et al., Arzneim-Forsch., 1974, 24, 1364-1367; when L represents H, L' represents F by catalytic hydrogenation of 3- (4-cyclohexyl-3-fluoro)benzoyl-acrylic acid, which is itself described in JP 75770/71 and DE 2,103,749. in which Alk' is a (C1-C4) alkyl; - compound (XX) thus obtained is cyclized by heating in the presence of potassium t-butoxide and the cyclopropanecarboxylic acid of formula (IX) is isolated. The acids of formula (IX), their salts, their functional derivatives, in particular the chloride, the anhydride and the mixed anhydride with a mono™(C1-C4)alkyl ester of carbonic acid, as well as the amides of formula (XI), are novel products which constitute a further aspect of the present invention. Thus, the present invention also relates to a compound of formula (XXI) in which L and L' are as defined above and W is a hydroxyl group or a group of structure -NG1G1 where: - Gi represents a (C1-C6)) aikyl or a (C3-C7) cycloalkyl ; - G2 represents a (C1-C6)) alkyl, a (03-071 cycloalkyl, a (C3-C6) cycloalkyXd-Cs) alkyl; a phenyl, benzyl or phenethyl group optionally substituted on the benzene group of the radical with a halogen or with a methoxy or nitro group, - or alternatively Gi and G2 form, together with the nitrogen atom to which they are attached, a saturated, bridged or spire heterocycle having only one endocyclic nitrogen atom and containing from 5 to 10 carbon atoms; a morpholino group; a piperazino group which is unsubstituted or substituted in position 4 with a (C1-C6)) alkyl/ with a phenyl, benzyl or phenethyl radical, the phenyl nucleus optionally being substituted with a halogen or with a methoxy or nitro group; a group chosen from 4-phenyl-l,2,3,6-tetrahydropyrid-1-yl, 4-phenylpiperidino, 4-benzyl-piper idino and 4-phenethylpiperidino radicals, it being possible for the phenyl groups of the said radicals to be unsubstituted or substituted with a halogen or with a methoxy group or a nitro group; as well as the alkali metal salts and secondary and tertiary amine salts and the functional derivatives of the acid of formula (XXI) where W is a hydroxyl group. Among the alkali metal salts of the compounds of formula (XXI) where W is a hydroxyl group, the sodium salt, (W = ONa) is particularly advantageous, whereas among the salts with secondary or tertiary amines, those of trimethylamine (W = O-N(CH3)3] and of triethylamine [W = 0",N* (C:H5) 3I are particularly advantageous* Among the functional derivatives of the According to biochemical and pharmacological studies, exposure of the compounds used according to the invention to normal cells, under the same conditions as those which make it possible to obtain an antiproliferative activity on cancer cells, does not give rise to any detrimental effect on all the criteria examined, such as, for example, the integrity of the structures and of the cell functions or the maintenance of the viability. These products thus act with great specificity of action with respect to tumour cells* The antitumour activity was established on several human tumour lines in vitro and in vivo in mice- The cells used were all obtained from the ATCC international collection. MCF'7 cells were used to perform the binding studies, The membranes were prepared as follows: 10 MCF-7 cells are homogenized for 10 seconds on a Polytron*' in 10 ml of Hepes^ buffer pH = 7.4 containing: 210 mM D-mannitol, 70 mM sucrose, 1 mM EDTA, 0.3 mM PMSF. The homogenate is centrifuged at 650 xg for 15 minutes and the supernatant is then taken up and centrifuged for 1 hour at 100,000 xg. The pellet is ' human myelomas U266 and RPMI 8226 • human kidney carcinoma 293 • human lung carcinoma A54 9 • human mammary carcinoma MCF-7 ' HCF-1 human lymphocyte leukaemia The antitumour activity is measured according to the colorimetry method using MTT, 3-(4,5-dimethylthiazole-2,5-diphenyltetrazolium) bromide as described by Mosmann T., Journ. of Imm. Methods; 1983, 65, 55, This colorimetrie assay makes it possible to measure quantitatively the antitumour activity of a solution containing a compound used according to the invention. According to the procedure used, the suspended cells (such as the myeloma cells) are inoculated at 2xl03 cells/mi in 1 mi welis ^ m defined medium. 7n^ adherent ceils (such as the MCr-7 ceiis) are mocuiatec at 5x104 cells/ml m 1 ml wells in RPMI medium +0.5"; FCS overnight. The next day, the cell carpet is washed twice and replaced by the defined medium. The defined m.edium corresponds to: RPMI + 10 ug/ml insulin + 10 ug/ml human transferrin. In order to carry out this test, cells are maintained in the presence of the solution containing a compound used according to the invention for 5 days, and the MTT is then added to the culture medium. The 5 day period which was selected corresponds to the optimum time for the activity. After culturing for 5 days, the proliferation of the cells is measured by the test described above. The optical density at 570 nm is measured. A blue coloration develops in the wells where the cells are still alive. The intensity of the coloration is proportional to the quantity of live cells . The results obtained are described in Table A below. growth and that this effect is obtained on ail "ne turriOur ceils examined. The effect observed in vivo of inhibition of an MCF-7 cell line was studied m vivo in 'nude' mice/ intraperitoneally at doses of between 3 and 10 0 mg/kg in a model according to Neri C, et al.; Cancer Research, 1990, 50; 58 92-5897 and according to Berebbi M., et al.; Oncogene, 1990, 5; 505-509. Another study was also performed in order to determine the effect of SR 31747 on the in vitro and in vi^^o growth of mammary and prostate epithelial tumour cells - The study consisted in evaluating the potential antitumour activity of SR 31747 on the growth of a variety of cancerous breast epithelial lines. The study is carried out in vitro on cell cultures, as well as m vivo after inoculation of tumoral mammary lines in 'nude*' athymic mice. The cell lines which were used are as follows: The hormone-sensitive MCF-7 line originates from a pleural effusion of a breast adenocarcinoma. The antioestrogen-resistant MCF-7LY2 cells were obtained from the MCF-7 line by selective pressure in the presence of a high-affinity antioestrogen. The MCF-7LCC1 and MCF-7LCC2 lines were developed in nude mice, after inoculation of the MCF-7 cells. The two lines are oestrogen-independent. The MCF-7LCC2 cells are also antioestrogen-resistant. The MCF-7AZTD5 line is derived from the MCF-7 line after stable transfeetion with the H-ras oncogene. The MCF-7AZTD5 cells are antioestrogen-resistant in vitro. All of these lines are maintained on DMEM/F12 (1/1, vol/vol) containing 10% decomplemented foetal calf serum and 16 ng/ml of human insulin. The MCF-7LCC2 line is cultured in the permanent presence of 10' M hydroxytamoxifen. The MDA'MB231 tumoral mammary epithelial cells are oestrogen- and antioestrogen-insensitive. They are cultured in L15 medium suppiemented with 10% FCS, 1% essential aip.ino acids and 10 µg/ml of human insulin. The InCaP, PC3 and DU145 epithelial lines are derived from prostate adenocarcinomas. Only the LnCa? cells are hormone-sensitive. The three lines are cultured in RPMI supplemented with 10% FC3. All the lines are maintained at 37°^0 m a humid air/CO; (95%/5%) atmosphere, except for the MDA-MB251 cells which are cultured in the absence of CO.. The cell lines are checked regularly free of mycoplasms. The inoculation and treatment of the animals were carried out as follows: The animals used are "nude" female athymic mice, which may or may not have been ovariectomized, obtained at 4 weeks old (R. Janvier) . Before inoculating the hormone-sensitive mammary cells (MCF-7, MCF-'7AZTD5) , the animals receive 10 µl of ethanolic 10-5 M ©estradiol solution applied percutaneously. The treatment is repeated three times over one week. One million cells suspended in 100 ul of PBS/Ca' are inoculated subcutaneously above each of the hips. The following day, the animals receive 200 ul of injection solution (ethanol/Tween 80/physiological saline, 1/1/18, vol/vol) containing the various reactants at the predefined concentrations. The injections are made intraperitoneally and are repeated every day. RESULTS In vitro activity of SR 31747 on the proliferation of various tumoral breast epithelial lines The results relating to the effect of SR 31747 on the proliferation of mammary epithelial cells in culture are given in Table 3. The activity of SR 31747 was evaluated in the presence of various concentrations of saline. In the presence of reduced concentrations of saline, SR 31747 exerts an inhibitory action on the proliferation of all the tumoral epithelial lines tested. Larger amounts of saline in the culture media partially or totally antagonize the inhibitory activity of SR 31747 on the cell growth. For a given serai concentration^ zhe capacity of SR 31747 to inhibit the proi if eration aiso varies according to the line considered. In the presence ot 0.1% FCS, which makes it possible both to maintain a minimum cell proliferation and to observe a consequeni activity of SR 31747, the IC50 determined for the hormone-sensitive MCF-7 lines (MCF-7, MCF-7AZ, MCF-7 22HTB) ranges from 2x10-9 M to 7x10" M. Similar IC-values are also obtained for the MDA-MB231 and MCF-7LCC cells. On the other hand, the MCF-7AZTD5 and MCF-7LY2 lines show greater sensitivities to the inhibitory action of SR 31747 since the ICsc- values determined are 2x10"'"' to 5x10-11 M respectively. In all cases, the virtually total inhibitions of the cell proliferation observed m the presence of 10-6 M and occasionally 10"' M SR 31747 are, from all evidence, cytotoxic effects. The results obtained also indicate that SR 31747 is incapable of reversing the stimulatory action of oestradiol on the hormone-sensitive MCF-7 line, Table B - Effect of SR 31747 on the proliferation of mammary epithelial cells. Determination of the ICj- after 6 days of treatment - medium changed every 48 hours In vivo effect of SR 31747 on the frequency and size of tumours developed after inoculation of tumoral mammary epithelial lines in "nude" mice Figures 1 and 2 indicate the effect of SR 31747 on tumours developed in ovariectomized 'nude' mice from MDA-MB231 cells. Each mouse receives 5x10' MDA'MB231 cells above each hip (i.e. 2 points of inoculation per mouse). The animals are then treated daily via the intraperitoneal route and receive 500 ug SR 31747 - D,003 u--^ Z2 (20 m,ice). The control batch receives 0.003 ua Z2 (20 mice). The amount (as a percentage of inoculated turriours) and size of the tumours developed are deter^ mined at different times in the course of the treat¬ment. At the end of the treatment (day 92), the animals are sacrificed and weighed. The tumours are removed and weighed. The figures show that SR 31747 has a tendency to reduce the size, weight and frequency of tum.ours developed in ovariectomized nude mice from MDA-M32 31 cells. However, the differences in the size and weight of the tumours between control groups and SR 31747 do not appear to be significant, due to the large vari¬ability observed in each group. Thus, in vitro SR 31747 has antiproliferative activity on the proliferation of all of the mamm.ary tumoral epithelial cells studied. This activity 15 especially apparent in the presence of reduced concen¬trations of seruiu, and varies as a function of the lines considered. Although, in most cases, the IC: values measured in 0.1% FCS vary between 2x10-2 M and 2x10-8 M, an extreme sensitivity of the MCF-7LY2 cells to SR 31747 is, however, observed, A general tendency of SR 31747 to reduce, at the same time, the size, weight and frequency of tumours developed from MDA-MB2 31 cells is observed. The present invention also relates to a technique of in vivo imaging of tumours which uses as target, for the compounds used according to the invention radio-labelled, for example, with 123I, 23F, 11C or 23N, the receptors to which the ■'H SR 31747 binds, The reason for this is that the high density of these receptors in tumour cells has suggested that they may advantageously be used to bind the radioligands using the PET (positron emission tomography) and SPECT (single photon emission tomography) techniques. The present invention thus relates also to the use of compounds radiolabelled with isotopes that are well known to those skilled in the art as imaging agents for radiolabelling. Moreover, other imaging techniques involving an antigen-radiolabelled antibody complex may be used. Such methods include, but are not limited to, the SPECT technique or the technique known as PET. The use of the compounds according to the invention also comprises the preparation of medicinal products intended for therapy involving the targeting of radiolabelled products as radiation-releasing agents close to or in the tumour itself/ using the said com¬pounds to target radiolabelled products onto the tumour or into its immediate environment in order to subject the tumour ceils to the radiation emitted by the said radiolabelled products. The use of the compounds according to the invention may also comprise a step of radiotherapy in which the cells in contact with the compounds undergo the effect of ionizing radiation including, for exam¬ple, gamma-rays, beta-rays, X-rays or alpha particles which may be delivered by an external source as for the X-rays or gamma-rays, or by radionucleides which are administered directly to the patient as described, for example, in Principles of Radiation Therapy in Cancer, Principles and Practice of Oncology, Devita, V.T. et ai. eds, 4th ed. J.B. Lippincott Co. Philadelphia, 1993, 15, 248-275. These compounds may also be administered in combination with other anticancer active principles which are well known to those skilled in the art. According to the biochemical and pharmacological studies illustrated above, the best activity was shown by the following compounds: N-benzyl-N^methyl[3-(3-chloro-4-cyclohexylphenyl)-propyl]amine 1-(3-nitro-4-cyclohexylphenyl)-3-(4-phenylpiperidino)-propan-2-ol trans-3-[3-(3-nitro'4-cyclohexylphenyl)allyl]-4-phenylpiperidine I- [3- (3-chioro-4--cyclohexylphenyl) prop-2-ynyl ] -4- phenylpiperidine 1-[3-(3'Chloro-4-cyclohexyiphenyl)propyl]- 4-phenyl- 1,2,3,6-tetrahydropyridine 1-[3-{4-cyclohexylphenyl)propyl]-4-phenylpiperidine cis-3-[3-(3-chloro-4-cyclohexylphenyl)allyl]-3-aza- spiro[5.5]undecane 3-[3-(3-chloro-4-cyclohexylphenyl)propyl]-3- azaspiro[5.5]undecane cis-N-'adamantan-l-yi-N-ethyl [3- (3-chloro-4-cyclohexyl- phenyi)allyl]amine 4-benzy1-1- [3- {3-chloro-4-cyclohexylphenyl)propyl]- piperidine 1-(3-chloro^4-cyclohexylphenyl)-3-(4-phenylpiperidine) ■ propan-l-ol N-cyclohexyl-N-ethyl[3-(4-cyclohexylphenyl)propyl]amint cis-N-ethyl-N-phenyl(3-(3-chlbro-4-cyclohexylphenyl)-allyl]amine N-benzyl-N-methyl(3-(3-chloro-4-cyclohexylphenyl)-propyl]amine N-phenethyl-N-methyl-1-[3-(3-chloro-4-cyclohexyl-phenyl)propyl)amine cis-N-cyclohexyl-N-ethyl[3-(4-cyclohexylphenyl)allyl]-amine N-cyclohexyl-N-ethyl[3-(3/5-dichloro-4-cyclohexyl-phenyl)allyl]amine trans-N/N-dihexyl [3- {3-chloro-4--cyclohexylphenyl) -allyl]amine cis-N-cyclohexyi-N-ethyl[3-(3-chloro-4-cyclohexyl-phenyl)allyl]amine trans-N-cyclohexyl-N-ethyi[3-(3-chloro-4-cyclohexyl-phenyl)allyl]amine N-cyclohexyl-N-ethyl[3-O-chloro-A-cyclohexyl-phenyl)propyl]amine 1-[3-(3-chloro-4-cyclohexylphenyl)allyl]azepane trans-N,N-dicyclohexyl-3-[(3-chloro-4-cyclohexyl¬phenyl) allyl]amine N-cyclohexyl-N-ethyl [3- (3-chloiro-4-cyclohexylphenyl) -prop-2-ynyl]amine The compounds capable of displacing -'H-SR 31747 from its receptors may be used in therapy in any patho¬logical process which involves the proliferation of tumour cells. This cell proliferation may be either hormone-sensitive or hormone-insensitive . More precisely, clinical applications for which the use of these compounds may be envisaged comprise diseases resulting from cell proliferation, in particular glioblastomas, neuroblastomas, lymphomas, myelomas, leukaemia and colon, colorectal, epithelial, hepatic, pulmonary, mammary, ovarian, pancreatic or prostate carcinomas. For these purposes, the compounds capable of displacing 3H-SR 31747 from its receptors, in particular the compounds of formulae (I) to (VIII) and their pharmaceutically acceptable salts, may be used for the preparation of oral, parenteral, sublingual, transdermal or topical pharmaceutical compositions. These pharmaceutical compositions contain at least one of the above products, in combination with a pharmaceutically inert vehicle . More particularly, the present invention relates, according to another of its aspects, to pharmaceutical compositions containing, as active principle, a compound of formula (VIII) or one of its pharmaceutically acceptable salts. Acids, both organic and inorganic, may be used to form addition salts with acids of the amines of formula (VIII) which are n on-toxic and pharmaceutically acceptable, in particular sulphuric acid, nitric acid, phosphoric acid, hydrochloric acid, citric acid, acetic acid, lactic acid, tartaric acid, pamoic acid, ethanedisulphonic acid, methanesulphonic acid, succinic acid, cyclohexylsulphonic acid, fumaric acid, maleic acid and benzoic acid. As regards oral or sublingual administration, simple or sugar-coated tablets, gelatin capsules, granules which may have a delayed-release action, drops or liposomes are used in particular. As regards intravenous, subcutaneous or intramuscular administration, use is made of sterile or sterilizable solutions, in particular for venous infusion, whereas conventional patches may be produced for transdermal administration. For topical use, creams or lotions to be spread on the skin may be used. The pharmaceutical compositions according to the present invention may be prepared according to usual methods that are well known in the pharmaceutical technical field, The active principle may be incorporated into the excipients usually used in these pharmaceutical compositions, such as talc, gum arable, lactose, starch, magnesium stearate, aqueous or non-aqueous vehicles, fatty substances of animal or plant origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preserving agents, etc. The pharmaceutical compositions of the invention may advantageously contain a compound of formula (VIII) or one of its pharmaceutically acceptable addition salts in combination with one or more other medicinal products known and commonly used for the same therapeutic indications. The amount of active principle to be administered per day, according to the method of the present invention, depends on the specific nature of the therapeutic indication, the seriousness of rhe For topical administration, the pharmaceuticai compositions generally contain from 0,0001 to 10% of active principle and preferably from 0.01 to 5%. The examples which follow illustrate the invention without, however, limiting it. In these examples, Y means 'yield" and m,p. means "melting point", determined on a Koffler heating block. Preparation of the acetylene derivatives for the 73.6 g (0.66 mol) of semicarbazide hydrochloride and' 54.2 g (0,66 mol) of sodium acetate are dissolved in 600 ml of distilled water and the mixture is then stirred vigorously and 142, 1 g (0 . 6 mol) of 3-chloro-4-cyclohexylacetophenone dissolved in 600 ml of ethanol are added rapidly at room temperature. The reaction mixture is then heated at 50°C for 2 hours and stirred at room temperature overnight, then the crystals formed are drained, washed with water, with acetone and with diethyl ether, dried and concentrated under vacuum in order to obtain 169.5 g of white crystals, Y = 96%. I- (3-Nitro-4-cyclohexylphenyl) -3- (4-phenylpxper±dlno) -propanone 12 . 3 g of 3-nitro-4'-cyciohexylacetophenone, 9.85 g of 4-phenylpiperidine, 7.5 g of paraformaldehyde and 1.5 ml of concentrated hydrochloric acid are dissolved in 100 ml of 1,2-dimethoxyethane and the reaction mixture is then heated at reflux with stirring for 5 hours. The reaction mixture is then left overnight at room temperature/ after which a precipitate is separated out by filtration and washed successively with ethyl acetate and then wirh diethyl ether in order to give 17 g of the expected compound. Example 1 3~ [3- {3-'Chloro-4-cyclohexylphenyl)prop-2-ynyl] -3~ azaspiro[5,5]undecane hydrochlorxde 4,85 g (0.022 moi) of the compound obtained m Preparation 2 and 0.5 g of CuCi: are dissolved in 25 rr.i of 1, 2-dimethoxyethane, A solution of 2.7 g of 35' formaldehyde and 3.14 g of 3-azaspiro [ 5 . 5] undecane ir. 20 ml of 1,2-dimethoxyethane is then added dropwise. After addition, the reaction mixture is heated at iQ^c for 30 minutes, the solvent is removed under vacuum and uhe residue is then, successively, taken up in diethyl ether, washed with aqueous 5% sodium hydroxide solution, with saturated sodium chloride solution and dried over magnesium sulphate. The hydrochloride is crystallized from ethyl acetate to give 7.6 g of the expected product; m.p. = 241°C. Example 2 c±s-3- [3- (3'ChlorO-4-cyclohexylphenyl) allyl] -3- azasplro [5. 5] undecaiXQ hydrochloride 3 g of the hydrochloride of the acetylenic compound obtained in Example 1 above are liberated by aqueous 10% sodium hydroxide solution. The oil obtained after extraction with diethyl ether is washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under vacuum* The residue thus obtained is taken up in 100 ml of ethyl acetate, 5 ml of methanol are added, followed by 0.2 g of Pd/BaS04 and the reaction mixture is hydrogenated at room temperature and at atmospheric pressure. The catalyst is separated out by filtration through silica, the filtrate is concentrated under vacuum and the residual oil is then chromatographed on a column of silica gel; eluent: 98/2 (v/v) dichloro-methane/methanol. Concentration of the pure fractions gives the hydrochloride, which is recrystallized from ethyl acetate; Y = 44%; m.p. = 238°C. - N-ethyl-N-phenyl-B-(3-chloro-4-cyclohexylphenyl)prop-2-ynylainine hydrochloride (Example 5) ; - N-(1-adamantyl)-N-ethyl-3-(3-chloro-4-cyclohexyi- phenyl)prop-2-ynylamine hydrochloride (Example 6); - N^benzyl-N-methyi-3-{3^chloro-4-cyclohexyi- phenyl) prop-2-*ynylamine hydrochloride (Example 7) ; - N-methyl-N-(2-phenylethyl)-3-(3-chloro-4-cyclohexyl- phenyl)prop-2-ynylamine hydrochloride (Example 8); - 4-benzyl-1- [3- (3-'ChlorO-4-cyclohexylphenyl) prop-2- ynyl]piperidine hydrochloride (Example 9); and - 4-hydroxy'-4-phenyl-l- [3- (3-chloro-4-cyclohexyl- phenyl)prop-2-ynyl]piperidine hydrochloride (Example 10) . Examples 11 and 12 Working as described in Example 1, by reacting 4-cyclohexyl-l-ethynylbenzene with, respectively, eyelohexylethylamine and 4-phenylpiperidine in the presence of formaldehyde, the following are obtained: - x-cyclohexyl-N-ethyl- 5-- ( 4-cyclohexylphenyi ) prop-2-ynylamine hydrochloride. - 4-phenyi-l- [ 5- (4-'cyclohexyLpheny.l) prop-2--ynyi 1 -piperidme hydrochloride (Example 12) . Examples 13 to 16 Working as described in Example 2, by hydrogenation of the acetylene derivatives obtained according to Examples 4 to 6 and 11, the cis-propenamines of Table I are obtained. Example 17 1- (3-Nitro-4--cyclohGxylphenyl) -3-(4-phenyl- piperidino)propanol 13.8 g of the ketone obtained in Preparation 3 are suspended in 300 ml of methanol. The mixture is cooled to 10°C, 8.42 g of sodium borohydride are then added and the reaction mixture is left at -10°C for 10 minutes and is then allowed to warm to room temperature. The precipitate formed is separated out by filtration and washed with methanol to give 9,5 g of the expected product; m.p. = 148-150°C, Example 18 trans-1-[3-[3 10.5 g of the alcohol prepared in Example 17 and 10.4 g of para-toluenesulphonic acid are dissolved m 3 00 ml of xylene and the reaction mixture 15 i:nen heated at reflux for 6 hours with stirring using Dean Stark apparatus to collect the water formed. The solvent is evaporated off under vacuum and the resicual oil is then, successively/ taken up in ethyl acetate, washed with aqueous 0. 5N sodium hydroxide solution, dried over magnesium sulphate and concentrated under vacuum to 50 ml of solvent, into which hydrogen chloride gas is then bubbled. The mixture is concentrated under vacuum and the precipitate is rinsed with diethyl ether in order to obtain 8 g of the expected hydrochloride; m.p, - 225-233°C. Example 19 3"(N"Ethyl-N-phenyl)amino-1-(3-chloro-4-cyclo-hexyl)phenylpropanol hydrochloride a) Working as described in Preparation 3, starting with 3-chloro-4-"cyclohexylacetophenone, by reacting with phenylethylamine, 1- (3-chloro-4-cyclohexylphenyl)-3-(N- ethyl-N-phenylamino)propanone is obtained. b) Working as described in Example 17, by reduction of the ketone obtained in step (a) with sodium borohydride, the expected product is obtained in the form of the hydrochloride; m.p. = 219*C. Example 20 3-[3-(3-Chloro-4-cyclohexylphenyl)propyl]-3- azaspiro[5-5]undecane hydrochloride 3 g of the hydrochloride of the acetylene compound obtained in Example 1 are liberated with aqueous 10% sodium hydroxide solution. The oil obtained after extraction with diethyl ether is washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under vacuum. The residual oil is then taken up in 100 ml of ethyl acetate, after which 5 ml of methanol are added, followed by 0.2 g of Pd/BaS04, and the reaction mixture is hydrogenated at room temperature and at atmospheric pressure. The catalyst is separated out by filtration vacuum. The residue obtained is taken up in the minium amount of methanol in the presence of 50 ml of 3 a hydrochloric acid and is then successively extracted with dichioromethane, washed with 2N hydrochloric acid solution, with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under vacuum in order to obtain 2g of the expected hydrochloride; m,p, = 266°C. Examples 21 to 26 Working as described in Example 20, by hydrogenation, respectively, of the acetylene derivatives prepared in Examples 11, 1, 8, 9, 12 and 10, the corresponding saturated derivatives of Table II are respectively obtained. Example 27 1-[3-(3-Chloro-4-cyclohexylphenYl)propyl]-4-phenyl- 1,2,3,6-tetrahydropyridinG hydrochloride 1 g of the compound of Example 26 and 0,51 g of para-toluenesulphonic acid are dissolved in 25 ml of xylene. The reaction mixture is heated at reflux for 2 hours and then concentrated under vacuum. The residue is taken up in 10% sodium hydroxide solution and then, successively, extracted with dichloromethane, washed with water, with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under borohydride are then added and the mixture is left overnight at room temperature. This reaction mixture is poured into 3 1 of water and 85 ml of concentrated hydrochloric acid are then added in order to obtain the expected hydroxy derivative. b) 5- (3-Chloro-4-cyclohexylphenyl)dihydrofuran-2-one » The compound obtained in (a) is dissolved in 300 ml of toluene and the reaction mixture is heated at reflux in the presence of Dean-Stark apparatus in order to remove the water. The solvent is then concentrated under vacuum in order to obtain the expected lactone; m = 16 g; m.p. = 60°C. c) Methyl 4-chloro-4-(3-chiorO-4-cyclohexylphenyl)- butyrate. 2*78 g of lactone obtained in (b) are dissolved in 30 ml of benzene, 2,2 ml of thionyl chloride are then added dropwise and the reaction mixture is heated at reflux for 3 hours. This reaction mixture is then added to a cooled solution of hydrogen chloride gas m methanol and this mixture is stirred overnight at room temperature and then concentrated under vacuum in order to obtain 3.5 g of the expected chloro derivative. d) 2-(3-Chloro-4-cyclohexylphenyl)cyclopropane- carboxylic acid. 3 g of the ester obtained in (c) are dissolved in 10 ml of t-butanol, 1.5 g of potassium tert-butoxide are then added and this mixture is heated at reflux for 4 hours. Patter cooling, 50 ml of water are then added and the Tiixture is extracted with diethyl ether. After concentration of the solvent, saponification is then carried out by dissolving the residue in 20 ml of ethanol and 10 ml of water in the presence of 0.3 g of potassium hydroxide, and this reaction aiixture is -hen heated at reflux for 2 hours. After cooling the solution, water is added, the mixture is acidified by addition of 6N hydrochloric acid and is extracted with diethyl ether, dried and concentrated under vacuum m order to obtain 1,4 g of the expected acid. Examples 29 to 32 a) Working as described in Example 28 (a), starting with 4-(4-cyclohexylphenyl)-4-oxobutyric acid, 4- (4- cyclohexyl-3,5-dichlorophenyl)-4-oxobutryic acid, 4-(4- cyclohexyl-3-fluorophenyl)-4-oxobutryic acid and, respectively, 4-(4-cyclohexyl-3'nitrophenyl)-4- oxobutyric acid, by reduction with sodium borohydride, the following are obtained; - 4-(4-cyclohexylphenyl)-4-hydroxybutyric acid (Example 29a) ; - 4-(4-cyciohexyl-3,S-dichlorophenyl)-4-hydroxybutyric acid (Example 30a); - 4-(4-cyclohexyl-3-fluorophenyl)-4-hydroxybutyric acid (Example 31a); and, respectively, - 4-(4-cyclohexyl-3'nitrophenyl)-4-hydroxybutyric acid (Example 32a) b) Working as described in Example 28 (b) , starting with the hydroxybutyric acids obtained in Examples 29a to 32a above, by heating or reflux in toluene in the presence of Dean-Stark apparatus, the following are obtained: - 5-(4-cyclohexylphenyl)dihydrofuran-2-one (Example 29b) - 5-(4-cyclohexyl-3,5-dichlorophenyl)dihydrofuran-2-one (Example 30b) - 5- (4-cyclohexyl-3--fluorophenyl) dihydrofuran-2-one (Example 31b) and, respectively, - 5-(4-cyciohexyl-3'nitrcphenyl)dihydrofuran-2-Gne (Example 32b) c ) Working as described m Example 2 3 (c) , by reaction of the lactones obtained m Examples 29 fb) and 32 ' b) above with thionyl chloride and then with HCl in methanol, the following are obtained: - methyl «^-chloro-4- ( 4-cyclohexylphenyl) butyrate (Example 29c); - rue thy 1 4-chloro-'4- ( 4-cyclohexyl--3, 5-dichlorophenyl) -butyrate (Example 30c) ; - methyl 4~-chloro-4- ( 4-cyclohexyl-3-f luorophenyl) -butyrate (Example 31c); and, respectively, - methyl 4-chloro-4-(4-cyclohexyl-3-nitrophenyl)-butyrate (Example 31d)- d) Working as described in Example 28 (d), by heating the esters obtained in Examples 29 (c) to 32 (c) above in t-butanol in the presence of potassiuin t-butoxide, the following are obtained: - 2-(4-cyclohexylphenyl)cyclopropanecarboxylic acid (Example 29d); - 2-(4-cyclohexyl-3, 5-dichlorophenyl) cyclopropane¬carboxylic acid (Example 30d); - 2-(4'Cyclohexyl'3-fluorophenyl)cyclopropanecarboxylic acid (Example Bid) and, respectively, -2-(4-cyclohexyl-3-nitrophenyl)cyclopropanecarboxylic acid (Example 32d). Example 33 a) 2-(3-Chloro^4*cyclohexYlphenyl)cyclopropane¬ carboxylic acid chloride. 4 g of the acid obtained in Example 2 8 and 3,7 ml of thionyl chloride are dissolved in 50 ml of carbon tetrachloride. The reaction mixture is heated at reflux for 3 hours and is then concentrated under vacuum in order to obtain 5.9 g of the expected acid chloride in the. form of an oil, b) N-cycXohexyl-Nr-ethyl-2- (3-chloro-4-cyclohexyi- phenyl)cyclopropanecarboxamide ' - 2-(4-cyclohexylphenyl)cyclopropanecarboxyiic acid chloride (Example 34a); - 2-(4-cyclohexyl-3,5-dichlorophenyl)cyclopropane¬ carboxyiic acid chloride (Example 35a); - 2-(4-cyclohexyl-3-fluorophenyl)cyclopropanecarboxyiic acid chloride (Example 3 6a) and, respectively, - 2-(4-cyclohexyl-3-nitrophenyl)cyclopropanecarboxyiic acid chloride (Example 37a). b) Working as described in Example 33 (b) , by reaction of the acid chlorides obtained in Examples 34 (a) to 37 (a) above with cyclohexylethylamine, the following are obtained: - N-cyclohexyl-N-ethyl-2-(4-cyclohexylphenyl)cyclo- propanecarboxamide (Example 34b) - N-cyclohexyl-N-ethyl-2- (4-cyclohexyl'-3, 5-dichloro¬phenyl) cyclopropanecarboxamide (Example 3 5b) - N-cyclohexyl-N-ethyl-2- (4-cyclohexyl-3-f luoro-phenyl)cyclopropanecarboxamide (Example 36b) - N-cyclohexyl"N-ethyl-2-' (4-cyclohexyl-3-nitrophenyl) - cyclopropanecarboxamide (Example 37b) Example 38 [2- (3-Chloro-4--cYclohexylphenyl) cyclopropylmethyl ] - cyclohexylethylamine hydrochloride 5.1 g of the amide obtained in Example 33 are dissolved in 50 ml of diethyl ether, a suspension of 0.99 g of lithium aluminium hydride in diethyl ether is then added and che reaction mixture 15 stirred for 3 hours at room remperature and then poured into aquecus 53 sodium hydroxide solution. The reaction mixture is -hen extracted v/ith ether and then, successively, the organic phase is separated out by setrling, dried over magnesium sulphate and hydrogen chloride gas is bubbled through the solution in order to obtain 3,54 g of the expected hydrochloride; m.p, = 202°C, Example 39 a) Working as described in Preparation 3, starting with 3-chloro-4^cyclohexylacetophenone, by reaction with di-n-hexylamine and formaldehyde, 1-(3-chloro-4-cyclohexylphenyl)-3-dihexylaminopropanone is obtained, b) Working as described in Example 17, by reduction of the ketone obtained in step (a) with sodium borohydride^ 3-dihexylamino-l(3-chloro-4-cyclohexyl-phenyl)propanol is obtained* c) Working as described in Example 18, by dehydration of the alcohol obtained in step (b), N-trans- [3- (3-chloro'4-cyclohexylphenyl)allyl]dihexylamine is obtained; m.p. = 128°C. Examples 40 to 52 Starting with 2- (3-chloro-4-cyclohexylphenyl)- cyclopropanecarboxylic acid chloride, obtained as described in Example 33 (a), by reaction, respectively, with diethylamine, dihexylamine, (1-adamantyl)ethyl- amine, ethylphenylamine, benzylmethylamine, methyl{2- phenylethyl)amine^ morpholine, piperidine, 4-phenyl- 1,2,3,e^tetrahydropyridine, 4-phenylpiperidine, 4-ben2ylpiperidine, 4- (2-phenylethyl)piperidine, 3-azaspiro[5.5]undecane, and working according to the indications of Example 33 (b) , the following are obtained: - N,N-diethyl-2-(3-chloro-4-cyclohexylphenyl)cyclo-propanecarboxamide (Example 40) ; - N, N-dihexyl-2- ( 3-chloro-4^cyclohexylphenyl) cyclo-propanecarboxamide (Example 41); - 1- (2- (3-chloro--4-cyclohexylphenyl) cyclopropyl] -carbonyl-4-phenylpiperidine (Example 49); - 1-[2- (3-chloro-4-cyclohexylphenyl) cyclopropyl]-carbonyl-4-benzylpiperidine (Example 50); - 1'[2- (3-chloro-4-cyclohexylphenyl) cyclopropyl]- carbonyl'4-(2-phenylethyl)piperidine (Example 51); - 3-[2-(3-chloro-4-cyclohexylphenyl)cyclopropyl]- carbonyl-3-azaspiro[5.5]undecane (Example 52); Examples 53 to 65 WorJcing as described in Example 38, by reduction of the amides obtained in Examples 40 to 52, the following are obtained: - N, N-'diethyl-2- ( 3-chloro-4-cyclohexylphenyl) cyclo- propylmethanamine (Example 53) ; - N,N-dihexyl-2-(3~chloro-4-cyclohexylphenyl)cyclo- propylmethanamine (Example 54) ; - N-(1-adamantyl)-N-ethyl-2-(3^chloro-4-cyclohexyl- phenyl)cyclopropylmethanamine (Example 55); - N-ethyl-N'phenyl-2-(3-chloro-4™cyclohexylphenyl)- cyclopropylmethanamine (Example 56); - N-benzyl-N-methyl-2-(3-chloro-4-cyclohexyiphenyl)™ cyclopropylmethanamine (Example 57); N-CYclohexYl-N-Qthyl-2-(3-chloro-4-GYClohexYlphenyl) -cyclopropaneca rboxami de a) 1.34 g (12,3 mmol) of ethyl chloroformate are added to a solution of 3.4 g (12.2 mmol) of 2~(3-chloro-4-cyciohexylphenyl)cyclopropanecarboxylic acid and 1,25 g (12,3 rrunol) of triethylamine in 50 ml of dioxane, cooled to *5°C. This internal temperature is maintained for 20 minutes with stirring, the mixture is then allowed to warm to room temperature, the triethylamine hydrochloride is filtered off and the solution of the mixed anhydride of 2- (3-chloro-4-cyclohexylphenyl) -cyclopropanecarboxylic acid and of monoethyl ester of the carbonic acid thus obtained is used. A solution of 1-56 g of cyclohexylethylamine in 30 ml of tetrahydrofuran is added to the solution of the mixed anhydride thus obtained and the reaction mixture is stirred for 8 hours at room temperature. The solution is then washed with water and dried and the solvent is evaporated off, N-Cyclohexyi-N-N-ethyl-2- (3-chloro^4-cyciohexylphenyl)cyciopropanecarboxamide is thus obtained. WE CLAIM: 1. A Pharmaceutical composition containing, as active principle, an amine of formula Vlll in which - G1 represents a (C1-C6)alkyl or a (C3-CO cycloalkyl, G7 represents a (C1-C6) alkyl, a (C3-C6) cycloal-kyl (C1-C3) alkyl, a [C3-C7) cycloalkyl, a phenyl, benzyl or phenethyl group optionally substituted on the phenyl nucleus of the radical with a halogen or with a methoxy or nitro group, - or alternatively G1 and G2 form, together with the nitrogen atom to which they are attached, a saturated, bridged or spiro heterecycle having only one endocyclic nitrogen atom and containing from 5 to 10 carbon atoms; a morpholino group; a piperazino group which is unsubstituted or substituted in position 4 with a (C1-C4) alkyl, with a phenyl, benzyl or phenethyl radical, the phenyl nucleus optionally being substitnteci with a halogen, or with a methoxy or nitro group; a group chosen frorr. 4-phenyl'-l, 2,3, 6-tetrahydropyrid-l-yl, 4-pheRyipiperidino, 4-benzyl-piperidino and 4-phenethylpiperidino radicals, it being possible for the phenyl group of the said radicals to be unsubstituted or substituted with a halogen or with a methoxy group or a nitro group/ (ii) a group of structure (2) in which - G3 represents hydrogen or a hydroxyl group; - G4 represents hydrogen; - or alternatively G3 and G4 together constitute one or two bonds so as to form, with the carbon atoms to which they are attached, a vinylene group or an ethynylene group; - G5 represents a group chosen from phenyl, benzyl and phenethyl radicals, it being possible for the phenyl nucleus of the said radicals to be unsubstituted or substituted with a halogen, a methoxy group or a nitro group; ~ G6 represents a hydroxyl group or a hydrogen; ~ G6 and G7 represent hydrogen or may form a bond; or alternatively G5 and G6 together form an n-pentylene group; - G6 being hydroxyl and it being possible for G5 and G7 to form a bond only when G5 is other than optionally substituted benzyl or phenetyl, (iii) a group of structure (3) in which - G3 and G4 are as defined above; - Alk represents a (C1-C6) alkyl or a (C3-C6) alkenyl; - G8 represents a 1-adamantyl, a (c3-C7)cycloalkyl, a (C3-C7) cycloalkyl (C1-C3) alkyi or a group chosen from phenyl, benzyl and 2-phenylethyl radicals, it being possible for the phenyl nucleus of the said radicals to be unsubstituted or substituted with a halogen, a methoxy group or a nitro group, - or alternatively Alk and GR, which may be identical or different, represent a (C4-C6)alkyl group; - G^ not being a (C3-C6) cycloalkyl when L is hydrogen or a fluorine or chlorine atom, L' is hydrogen and Alk is a (C1-C6) alkyl; (B) the pharmaceutically acceptable salts and solvates of the compound of formula (VIII). 2. The amine as claimed in claim 1 of formula (VIII) in which the halogen is chlorine or fluorine, one of the groups L and L' being hydrogen and the other fluorine, chlorine or nitro, or alternatively L and L\ which are identical, being hydrogen or chlorine. - G1' representis d iC —C.) alkyl or a C3-C7) cycloai kyi ; G2' represents a {C1-C6) alkyl, a ( C3-C7) cycloalkyi (C1-C5) aikyi, a (C3-C7) cycloalkyi or a qroup chosen from phenyl, benzyl and 2'-phenylethyl radicals, it being possible for the phenyl nucleus of the said radicals to be unsubstituted or substituted with a halogen or with a methoxy or nitro group, - or alternatively G1 and G2 form, together with the nitrogen atom to which they are attached, a morpholino, pyrrolidine, piperidino or hexahydroazepino group or a group chosen from 4-phenyl-l, 2,3, 6-tetrahydropyrid-l- yl, 4-phenylpiperidino, 4-benzylpiperidino and 4-phenethylpiperidino radicals, it being possible for the phenyl group of the said radicals to be unsubsti- tuted or substituted with a halogen or with a methoxy group or a nitro group, (ii') a group of structure (2') group and its pharmaceurically acceptable sai- s a no. solvates. 4. The amine as claimed m claim 3 chosen Iron Lhe group consisting of; N'-benzyi-N-methyl [3- (3-chloro-4-cyclohexylphenyl) -propyllamine 1- ( 3-nitro-4'-cyclohexylphenyl) -3- { 4-phenylpiperidino) -propanol trans-3- [3- (3-nitro-4-cyclohexylphenyi)allyl]-4-phenylpiperidine 1-[3-(3-chloro-4-cyclohexylphenyl)prop-2-ynyl]-4-phenyipiperidine 1'[3-(3-chloro-4-cyciohexylphenyl)propyl]- 4-phenyl-1,2,3, 6--tetrahydropyridine 1-[3-(4-cyclohexylphenyl)propyl] -4-phenylpiperidine ci5-3-[3- (3-chicro~4-cyclohexylphenyl)allyl]-3-aza-spiro[5.5]undecane 3-[3-(3-chloro-4-cyclohexylphenyl)propyl]-3-azaspiro[5.5]undecane cis-N-adamantan-l-yl-N-ethyl[3-(3-chloro-4-cyclohexyl¬phenyl) allyl]amine 4-benzyl-1- [3- (3-chloro-4-cyclohexylphenyl)propyl]-piperidine 1-(3-chloro-4-cyclohexylphenyl) -3-(4-phenylpiperidin-l-yl )propan-1-ol cis-N-ethyl-N-phenyl[3-(3-chloro-4-cyclohexylphenyl)-allyl]amine N-phenethyl-N'-methyl^l'- [3- (3-chloro-4^cyclohGxyl-phenyl)propyl]amine N-cyclohexyl-N-ethyl-l-[3-(3, 5-dichloro-4-cyclohexyl-phenyl)allyl]amine trans-N, N-dihexyl [3- (3'chloro-'4-cyclohexylphenyl) -allyl]amine and their pharmaceutically acceptable salts and solvates. 5. The pharmaceutical composition as claimed in claim 1, wherein it is in unit dosage form. 6. The pharmaceutical composition as claimed in claims 1 and 5, containing from 0.0001 to 10% of active principle.

Documents:

1648-mas-1997-abstract.pdf

1648-mas-1997-claims filed.pdf

1648-mas-1997-claims granted.pdf

1648-mas-1997-correspondnece-others.pdf

1648-mas-1997-correspondnece-po.pdf

1648-mas-1997-description(complete)filed.pdf

1648-mas-1997-description(complete)granted.pdf

1648-mas-1997-drawings.pdf

1648-mas-1997-form 1.pdf

1648-mas-1997-form 26.pdf

1648-mas-1997-form 3.pdf

1648-mas-1997-form 5.pdf

1648-mas-1997-other documents.pdf