HK1029042A - Ligands for sigma receptors and their therapeutical applications - Google Patents

Description

Field of invention.

The present invention relates to novel compounds derived from 2-arylalkenyl-azacycloalkanes ligands in vitro to sigma (σ) receptors, which may be useful in the treatment of gastrointestinal disorders and in the treatment of neurological dysfunctions and/or psychotic states.

The technical background of the invention.

Patent EP 362 001 describes N-cycloalkylalkylamines α,α disubstituted with specific affinity for sigma (σ) receptors, useful in the treatment of psychosis and gastrointestinal disorders, with formula in which: R1 and R5 are phenyl, R2 is alkyl, R3 is hydrogen or lower alkyl, R4 is cycloalkyl, m is 1 or 2.

Application EP 445 013 describes N-cycloalkylalkylamines with specific affinity for σ-receptors, useful for the treatment of psychosis and gastrointestinal disorders, with formula in which: R1 is a furyl or thienyl or phenyl radical provided that Q is cyclopropane 1,2-diyl, R2 is a lower alkyl, R3 is hydrogen or lower alkyl, m has a value of 1 or 2, R4 is cycloalkyl -CH(CH2)n with n from 2 to 5, R5 is phenyl or thienyl, Q is ethylene 1,2-diyl or cyclopropane 1,2-diyl.

Although they have a similar receptor affinity to the compounds of the present invention, these two documents have different amines in structure, which is that of amines in which the nitrogen atom is not included in a cycloalkane sequence.

Application WO 91/03243 describes 1-cycloalkyl piperidines with σ-receptor specific antagonist activity, useful for the treatment of psychosis and dyskinesia, with formula in which, preferably: X is C=O, CHOH or O; and/or m is O; and/or n and p are 1; and/or R3-R5 is H; and/or Ar is phenyl optionally substituted with halogens, OCH3, NH2, NO2 or another phenyl group, a and b otherwise representing single bonds or either double bond.

Application WO 93/09094 describes ethers derived from alkyl piperidines or pyrrolidines, which are antipsychotic agents with formula wherein, for preferred compounds: n and p are 1; and/or m is 1-3; and/or R is phenyl; and/or X is trans-CH=CH-; and/or Ar is phenyl, p-F-phenyl or p-CF3-phenyl; and/or the side chain is at position 4 of the piperidine cycle.

Among other differences, the compounds in claims WO 91/03243 and WO 93/09094 are formally distinguished from the compounds of the present invention by the presence in their intermediate chain of an oxygen function (C=O, CHOH) or an oxygen atom -O. It is also noteworthy that this chain is located or advertised as preferred to the carbon atom at position 4 (para) of the piperidine cycle, and in no case on the carbon atom at position 2 adjacent to the nitrogen atom.

Application WO 92/22527 describes calcium channel antagonists with formula in which, inter alia: R is C1-8 alkyl C3-8 cycloalkyl; p is 0 to 2; n is 0 to 6; A is -CH=CH-; Ar is aryl.

Application WO 93/15052 describes calcium channel antagonists with formula wherein, Ar being an optionally substituted aryl or heteroaryl, it is defined for the preferred compounds as: m is 0 to 3, R is C1-8 alkyl ((phenyle) p where p is 0 or 1, or R is C2-8 alkenyl ((phenyle) p where p is 1, A is oxygen or -CH=CH-, the chain length -CH2) nA-CH2) m being 2 to 6 atoms.

The latter two applications concern calcium channel antagonists, which are different from the compounds of the present invention by this application. Furthermore, contrary to what the advertised meanings for R, A, Ar, n and m suggest, none of the compounds mentioned in these papers impair the novelty of the 2-alkenyl-azacycloalkanes (I) objects of the present invention.

Summary of the invention.

The invention relates to new derivatives of 2-arylalkenyl-azacycloalkanes of formula (I) in which Ar is either aryl or heteroaryl optionally mono- to trisubstituted, The compounds of the invention show a particularly interesting affinity in vitro for σ receptors, which is significant for their usefulness in the prevention or treatment of neurological dysfunctions and/or psychotic states; and, in vivo, they show a particularly significant pharmacological usefulness in the treatment of gastrointestinal disorders.

The preferred compounds of the invention are those in which: Ar is an optionally substituted phenyl radical, n has values of 1 or 2,R is a cyclopropyl, cyclobutyl, or phenyl radical.

The present invention also describes the process of preparation of azacycloalkanes (I) and pharmaceutical compositions containing a compound (I) combined with pharmaceutically acceptable excipients, diluents or solvents.

Detailed description of the invention

For the compounds (I) of the present invention: In this case, the substituents, identical or different in case of multiple substitution, are chosen from the set comprising halogens, the nitro group, the lower alkyl, haloalkyl, alkoxy, haloalkoxy radicals, wherein below are the carbon chains comprising 1 to 4 sulphonyl atoms. Particularly the unsubstituted phenyl radical or heteroxy is preferred among the two higher sulphonyl atoms and the heterogeneous or heterogeneous radioactive radicals, such as sulphonyl or sulphonyl, especially the radioactive hydroxy, which are the monoxy or heteroxy.

As regards isomers, these include both geometric isomers resulting from the π-bonding of the aryl alkeneyl sequence and optical isomers resulting from the asymmetry of the carbon at position 2 of the azacycloalkane cycle and their mixtures, and in particular the racemic mixture.

For the addition salts of the compounds (I), pharmaceutically acceptable acids are those mineral or organic acids which have been shown to be athoxic at the usual therapeutic doses. These are, for example but not limited to, acetic, benzenesulfonic, camphosulfonic, citric, ethanesulfonic, bromide, lactic, maleic, malic, methanesulfonic, mucilage, nitric, pamoic, phosphoric, salicylic, stearic, succinic, sulfuric, tartaric acids, and hydrochloric acid which is preferred.

In another respect, the invention relates to a process for preparing the compounds (I), shown in Figure 1, from an azacycloalkane (III) where n and Ar are as defined for (I), which consists of: or to alkylate an intermediate (III) by an alkyl halides (IV) where m and R are as defined for (I), and Y is a halogen, preferably chlorine or bromine, or, preferably, to acylate the intermediate (III) by a reagent (IV) where m and R are as defined for (I), and X is -OH or a halogen such as chlorine or bromine, to obtain an intermediate carboxamide derivative (II) which is reduced by a metallic or organometallic hydride derived from boron or preferably aluminium.

The process of alkylation of the intermediate (III) by the halogenide (IV') which is preferably an alkyl chloride or alkyl bromide is carried out in an inert solvent such as toluene or acetonitrile. Alternatively, a basic agent, a mineral such as sodium carbonate, or an organic agent such as triethylamine is added to the reaction medium to promote the reaction. For 1 mol of intermediate (III) engaged, 0.5 to 1.5 mol of alkyl halogenide may be used, the reaction being carried out in 2 to 3 mol of the selected solvent.

The preferred method of preparation is to first obtain a carboxamide (II) from the intermediate (III) and then reduce it by a metal or organometallic hydride; where, in the reagent (IV), X is a halogen such as chlorine or bromine, the reaction, carried out in toluene or preferably dichloromethane, consists of adding 1 mol of an organic amine such as triethylamine, then the reagent (IV) in an equimolecular quantity to a solution containing between 1.0 and 1.5 mol of an organic amine such as triethylamine. The solution is then maintained at a temperature of 3 to 48 h at a temperature of 0 to 30 °C depending on the nature of the reagents.

When in the reagent (IV) X is -OH, an appropriate method is to prepare in situ an anhydride of the acid, possibly mixed, and then to acylate (III) by this anhydride. Favorably, one works in anhydrous apolar solvents of the ether oxide class such as tetrahydrofuran (THF) which is preferred. First the mixed anhydride is prepared at a temperature between - 40 and 0 °C by adding 1 mole of acid (IV), 1.0 to 1.5 mole of tertiary amine as N-methylmorpholine, leaving 0.9 to 1.2 mole of chloroformisate.

Alternative methods using dehydrating agents are listed in March, J. Advanced Organic Chemistry, 3rd ed., New York: Wiley-InterScience, 1985, p. 372; those using dicyclohexyl-carbodiimide or N-N'-carbonyl-diimidazole are particularly suitable.

The second step, reducing carboxamide (II), involves the use of boron or aluminium derived metallic or organometallic hydrides, of which borane (BH3) may be used as complexes and preferably aluminium derived hydrides, including simple hydrides such as AlH3 or Dibal [CH3) 2-CH-CH2]2AlH, mixed hydrides of aluminium and alkaline metals such as sodium or lithium, with aluminium hydride (AlLiH4 or LAH) and lithium hydride reducing AlH3 being the preferred agents.

The reactions are carried out in solvents of the ether-oxide class such as diethyl ether, 1,2-dimethoxyethane, and more particularly tetrahydrofuran (THF) which is particularly preferred for reductions by aluminium hydride, which is the favourably practised method for reducing carboxamides (II).

Under the preferred conditions, the reduction in THF of a mole of carboxamide (II) consists first of generating in situ aluminium hydride by reaction of 0.75 to 2 mol of AlCl3 with 2.2 to 6 mol of LAH, these two reactants being in a stoichiometric ratio of 1 to 3, then of reducing (II) by addition at a temperature of - 10 to + 30 °C. The reaction is maintained for 1 to 24 h at the same temperature, then the resulting complexes are decomposed and the compounds of the invention (I) are isolated by the methods customary to man.

As described, the preparation of compounds (I) uses essential intermediate azacycloalkanes (III) which are prepared by methods described or adapted from the literature, from either 2- ((2-hydroxyethyl) azacycloalkanes (VIII) or N-nitroso-azacycloalkanes (X), as shown in Figure 2.

The process of preparing azacycloalkanes (III) from 2-(2-hydroxyethyl) -azacycloalkanes (VIII), which are commercially available or prepared by state-of-the-art processes, consists first of preparing an intermediate carbamate (VII), in which Z is an alkyl, aryl or polyalkylaryl, but the t-butyl radical is preferred in a protective N-t-butyloxycarbonyl (N-Boc) group. The implementation of these preparations requires conditions described in detail, e.g. by Geiger, R. and Koenig, W. Inigon, E. and Meienom, J. The New York-Academic Press: Peptides.

The reagent used for this purpose may be chosen from those described in March, J. Advanced Organic Chemistry. 3rd ed. p. 1057- 1060. The preferred reagent is pyridinium chlorchromate, which is used in ether medium, or in nitrobenzene, pyridine, or in a halogenated hydrocarbon such as dichloromethane, which is preferred.

This compound is then engaged in a Wittig reaction with a triphenylphosphonium halogenide of formula Ar-CH2-P ((C6H5) 3+ Hal-, in which Ar is as defined for (I) and Hal represents a halogen such as chlorine, bromine or iodine.Ethanol is preferred and close stoichiometric quantities are used for the triphenylphosphonium derivative and the alkaline agent, the reaction being carried out at a temperature of 10 to 50 °C, to obtain the intermediate N-carbamyl-2-arylalkenyl-azacycloalkane (V), which is subjected to an N-deprotection reaction by trifluoroacetic acid e.g. to obtain the intermediate essential azacycloalkane (III) in the form of a mixture of the isomers Z and E. These are separated by conventional techniques, including chromatography on silica, as well as by selective crystallization of the hydrochloride.In the case of the Hb-CHa-Cha-CHb- coupling constant, the coupling constant between Ha and Hb is typically 10 Hz if the molecule is Z, and approximately 17 Hz if it is E (Silverstein R.M. et al. Spectrometric identification of organic compounds, 4th ed., New York: Wiley, 1981, p. 235).

The alternative preparation process for compounds (III) should be used with caution, particularly for high volume operations, as it uses dangerous or advertised potentially carcinogenic reagents and intermediates. It consists of alkylating commercially available or prepared N-nitroso-azacycloalkanes (X) with an alkylating agent Ar-CH=CH-CH2-dialkylating agent, in which the halogen is chlorine or bromine, to an intermediate N-2-nitroso-arylalkene-azacycloalkan (IX), which is subjected to an N-denitrating reaction to obtain the essential intermediate (III). In the context of the description of the method, this method is used in low quantities, according to Seebach, Chem., D. 108, 1975, p. 1293-D, and Chem., D. 129, and Chem., D. 129.

To prepare an optically active (III) compound, one can: After deprotection, the resulting product is separated into its diasteroisomers by chromatography; by Edman degradation, two enantiomers of the amine (III) are then returned; or,solve a racemic compound (III) in an optically active acid solution, e.g. an enantiomer of the N-acetylphenylalanine enantiomer, and then for two salts of the diasteroisomers, by difference in solubility, selectively crystallize them to form a condensate in a solvent. The present invention is illustrated in a non-exhaustive manner by the following examples.The purity, physicochemical characteristics and structural identity of the products are determined and reported as follows:the products are purified by appropriate techniques, in particular column chromatography, for which the so-called chromato-flash technique on silica column is favourably used (Merck supplier, Kieselgel H 60, particle size 230 to 400 mesh).The purity of the products obtained is determined by the method of thin-film chromatography (CCM) of silica (Merck ready-to-use plates); the observed Rf and the elution solvents used are shown in the examples.The physical-chemical characteristics of the products, represented are: (a) by the melting point,(b) by infrared (IR) spectrography of the KBr compounds in capsules; the most intense absorptions are reported by the value of their wavelength in cm-1; (c) by the rotational power, determined at a temperature of about 20 °C on a Polartronic apparatus in a 10 cm long tank; the structural identity of the products is determined in accordance with: (a) the nuclear magnetic resonance of the proton (NMR) studied at 90 or 400 MHz, the products being soluble in deuterium chloride.(b) elementary centipede analysis, the results of which comply with accepted standards are not reported; however, these analyses are reported to be carried out by the representation of the dosed element; (c) high pressure liquid chromatography on alpha AGP (α-glyco-protein) chiral column, with UV detection at 220 nm, which allows the optical purity to be assessed.

Chemical experimental part Preparation 1 : E-2-cinnamylpyrrolidine (f. III; Ar = C6H5, n = 1) The substance is used as a solvent in the manufacture of other products.

Step a) In a one litre reactor, protected from moisture and under nitrogen atmosphere, 600 ml of dehydrated THF on molecular sieve and 25.3 g (35.0 ml - 0.25 mol) of diisopropylamine are introduced. The mixture is agitated at - 70 °C for 15 min. A solution of 25.0 g (0.25 mol) N-nitrosopyrrolidine (f.The orange solution is agitated for 10 min and then 49,3 g (0.25 mol) of cinnamyl bromide is added to the solution in 50 ml of anhydrous THF for 15 min at - 70 °C. - What? The reaction medium is maintained for 2 h at - 70 °C and then agitated for 16 h at - 20 / - 25 °C, after which 15.0 ml of pure acetic acid is introduced, which causes a yellowish insoluble to form.The aqueous phase is separated and extracted by 200 ml of dichloromethane, the organic phases are extracted by 200 ml of NaCl saturated solution and then dehydrated to Na2SO4. - What? After evaporation in a vacuum and in a water bath, the residual brown oil (60.0 g) is purified by silica column chromatography. The weight of the product is calculated as follows:2H) ; 3.30 - 3.90 (m, 2H) ; 4.25 - 4.70 (m, 1H) ; 6.00 - 6.60 (m, 2H) ; 7.10 - 7.50 (m, 5H).Stage b) In a moisture-protected reactor, 24.0 g (0.111 mol) of the N-nitroso derivative obtained in step a) above is introduced into solution in 1200 ml of anhydrous diethyl ether. Under agitation and maintaining a temperature of 25 ± 5 °C, the solution is saturated in approximately 1 h 30 min by distillation of hydrochloric acid gas. The solution is abandoned for 16 h at 15-20 °C, and the excess acid is removed by distillation of nitrogen.- What? The ether phase is extracted by 3 x 800 ml of water. The combined acidic aqueous phases are alkalized at a temperature below 10 °C by addition of sodium hydroxide solution to pH 12. The mixture is extracted by 3 x 750 ml of ether; the combined ether phases are washed by extractions with 3 x 400 ml of NaCl saturated aqueous solution, then dried to Na2SO4. After evaporation of the ether, the raw product (13.6 g) is purified by silica column chromatography. - What? The product obtained is purified as a pale yellow viscous oil by elusion with dichloromethane and then with a mixture of dichloromethane/ammonium methanol at 10 % 92/8 v/v.- What? The following is the list of active substances that are considered to be toxic if they are not classified as toxic: Dissolve 13,5 g (0,072 mmol) of (+/-) -E-2-cinnamylpyrrolidine obtained at step (a) above and 7,46 g (0,036 mmol) of N-acetylphenylalanine (L) in 250 ml of boiling acetone. After filtration on infusion soil, the insoluble precipitate which has cooled for 16 h at 20 ± 3 °C is filtered and recrystallized in the same manner twice.Alkaline treatment produces (-) -E-2-cinnamylpyrrolidine in the form of a pale yellow oil after ether extraction and evaporation. - What? The weight of the product is calculated as the sum of the weight of the products in the product and the weight of the products in the product. The substance is classified as a substance of very high concern. The filtrate obtained during the first filtration of the previous step (c) is treated in an alkaline medium; 9.5 g of an enantiomer (+) enriched base is obtained. As in the previous step, a diasteroisomer salt is prepared in acetone, this time with N-acetyl-phenylalanine (D). 2.6 g of (+) E-2-cinnamyl-pyrrolidine is obtained. [α]D = + 13.6 ° (c = 1,

Preparations 2 The following are the types of products: 1°) N-t-butyloxycarbonyl-2- ((2-acetaldehyde) -pipéridine (f. VI; n = 2)

Step 1: In a 2 l moisture-proof reactor, 40.0 g (0.309 mol) of 2- (f. VIII; n = 2) 2-hydroxyethyl) piperidine is introduced into 600 ml of dehydrated dichloromethane on molecular sieve. The solvent is removed by vacuum distillation and by water bath. The residual yellow oil is purified by silica column chromatography. The dilution by the dichloromethane/methanol mixture 95/5 v/v gives N-t-butyl-oxy-carbonyl-2-(2-hydroxyethyl) piperidine (f. VII; Z = t-butyl,n = 2. Weight :66.7 g Rdt: 94%- CCM:Rf = 0.70- 0.80 (ethyl acetate/hexane 90/10 v/v) - RMN :1,20- 2.20 (m, 18H) ; 2.50- 3.00 (m, 1H) ; 3.20- 3.80 (m, 2H) ; 3.80- 4.50 (m, 2H).Stage 2: In a 3 l moisture protected reactor, dissolve in 2.4 1 of the 66.0 g (0.287 mol) of the N-protected alcohol obtained in step a. The solution is further diluted with 125.0 g (0.58 mol) of pyridinium chlorchromate. The orange suspension which rapidly turns black is maintained at 16 ± 20 °C under agitation.- What? The emulsified mixture is filtered on a Buchner filled with infused earth. The filtrate is decanted, the aqueous phase is discarded. The organic phase is dehydrated to Na2SO4, then the solvent is removed by distillation. The black residue (35.0 g) is purified by chromatography on silica column. The following is the list of active substances which are to be used in the preparation of the product:The number of people who are in the study is estimated at between 35 and 35 (m, 3H); 3.80 to 4.20 (m, 1H); 4.70 to 5.00 (m, 1H); 9.70 to 9.80 (m, 1H).

The following shall be added to the list of substances which are to be authorised for use in the manufacture of the product:

Stage 1 is N-Boc-2-pyrrolidine methanol. The compound is prepared as described in paragraph 1 (a) above from 2-pyrrolidine ethanol with a yield of 100%. The test chemical is used to determine the concentration of the active substance in the test chemical. The compound is prepared from the N-protected alcohol obtained at the previous stage 1 according to the procedure described in paragraph 1 (b) of stage 2 with a yield of 68%. CCM: Rf = 0.85-0.95 (ethyl acetate/hexane 80/20 v/v) Stage 3 N-Boc-2-(2-methoxy-ethylene) -pyrrolidine In a moisture-protected reactor, 895 ml of absolute ethanol is introduced and 11,8 g (0.510 mol) of skimmed sodium is stirred.After dissolution, add 174.7 g of (methoxy-methyl) triphenyl-phosphonium chloride at 20-25 °C. Agitate the white suspension for 30 min at 20-25 °C. Then introduce a 71 g (0.356 mol) solution of the aldehyde obtained at the previous stage 2 into 199 ml of absolute ethanol. Boil the reaction medium for 2 h 30 min, then cool and evaporate under vacuum and on a water bath. The orange residue is then taken up into the filtered pentane. The wire is concentrated and chromatographed on silica by elevating by the 85/15th hexane/acetate mixture. Weight = 74 g Rdt: 60%.- What? CCM: Rf = 0.75-0.90 (hexane/ethyl acetate 70/30 v/v) Stage 4: 1 l of tetrahydrofuran and 102 g of the vinyl ether obtained at the previous stage are introduced into a reactor, followed by 150 ml of 10% (p/v) hydrochloric acid. The brown solution is kept agitated at 40 °C for 30 min, then cooled. 1 l of ether is added and the organic phase decanted which is washed with a saturated solution of NaCl, evaporated. The brown residue is purified by chromato-flash on silica by eluting with the hexane/acetate mixture of 75/25 v/v. Weight: 71.9 g Rdt: 75%

Preparation 2A: Z and E 2-cinnamyl piperidine (f. III; Ar = C6H5, n = 2)

Step a) In a moisture-protected reactor, 180 ml of absolute ethanol is introduced and 1.63 g (0.071 mol) of skimmed sodium is stirred. After dissolution, at 20-25 °C, 27.3 g (0.071 mol) of benzyl triphenylphosphonium chloride is added. The yellow suspension is stirred for 30 min at 20-25 °C and then a solution of approximately 16.0 g (0.070 mol) of the previously obtained acetaldehyde (f. VI n = 2) is introduced in 35 ml of absolute ethanol in 2 min. The white solution obtained is maintained for 30 min at 20-25 °C, the insolate is filtered on a bucket and discarded.The oil residue is concreted in 500 mi of n-pentane, this new insoluble is filtered and eliminated. The filtrate is concentrated. 19.0 g of crude N-t-butyloxycarbonyl-2-cinnamyl-pipperidine (f. V; Z = t-butyl, Ar = C6H5, n = 2) (Rdt = 90%) is obtained, which is started as in the next step.at a temperature below 5 °C, 190 ml of pure trifluoroacetic acid. The solution is maintained at this temperature for 30 min and then concentrated under vacuum and in a water bath. The residue is dissolved in 600 ml of ether, extracted by 200 ml of NaOH 1 N solution. The ether phase is washed with water and then dried on Na2SO4. The ether is evaporated, the crude product (12.0 g) is obtained as a clear brown oil which is dissolved in 120 ml of anhydrous dichloromethane. To this solution, 25 ml of 5 N hydrochloride ether is added and the solvents are evaporated by distillation. The residue is dissolved in 150 ml of isopropanol at boiling.The insoluble precipitated by cooling under agitation is filtered on buchner and then recrystallized in absolute ethanol. Weight :4,6 g Rdt: 30.7 % F: 225 °C- CCM:Rf = 0.30- 0.40 (dichloromethane/methanol ammoniacal at 10 % 90/10 v/v) C14 H20 Cl N): % C, H, Cl, N conform. By treatment in an alkaline medium of 4.0 g (16.8 mmol) of the hydrochloride, after extraction with ether and evaporation, 3.3 g of E-2-cinnamyl piperidine is obtained as a pale yellow viscous oil.The following are the main types of the test: - RMN :1,00- 1,90 (m, 6H) ; 1,95 (s, 1H ech. D2O) ; 2,10-2,40 (m, 2H) ; 2,40- 2,80 (m, 2H) ; 2,90- 3,20 (m, 1H) ; 6,00- 6,60 (m, 2H) ; 7,10- 7,45 (m, 5H). - What? The isopropanolic filtrate obtained is concentrated by distillation. The residue (9.0 g) is treated and extracted in an alkaline medium by ether. The ether is removed and the oily residue (6.4 g) is purified by chromatography on a silica column. Elution by the dichloromethane/ammonium methanol mixture at 10 % 95/5 v/v yields pure Z-2-cinnamyl piperidine (f. III-Z Ar = C6H5, n = 2) in the form of a highly viscous oil which solidifies slowly at cold temperatures.- What? The total number of samples of the test chemical is calculated by adding the following data: From (+/-) -E-2-cinnamyl-pipperidine obtained at the previous step, in a similar fashion to the preparation at step 1 (c) in which the final recrystallization is carried out in an aqueous medium, (-) -E-2-cinnamyl-pipperidine is obtained in the form of an oil with an efficiency of 33%. The following table shows the calculation of the maximum value of the product concerned:The substance is classified as a substance of very high concern in the Union for the purposes of the present Regulation. The process described in step 1 (d) of the preparation, by the last recrystallization in aqueous media, yields (+) -E-2-cinnamyl-pipperidine after return to the base, with a yield of 30%. The test chemical is a mixture of two or more of the following:

Preparation 2B: Z and E 2- ((p-fluoro-cinnamyl) -pipéridine (f. III; Ar = p-fluoro-phenyl, n = 2)

(a) Step a) According to the method of preparation 2A, step a) from p-fluoro-benzyl-triphenyl-phosphonium chloride, N-t-butyloxycarbonyl-2- ((p-fluoro-cinnamyl) piperidine is obtained with an efficiency of 96% as a yellow oil.State b) Deprotection by trifluoroacetic acid is carried out according to the method of preparation 2A, then step b). The product obtained as a crude orange yellow oil is a mixture of the isomers Z and E which is chromato-flashed on a silica column.The solution is then dissolved in isopropanol, and the residue is agitated by addition of ether to form a white precipitate of Z-2-(p-fluoro-cinnamyl) piperidine hydrochloride. By treatment in an alkaline medium, ether extraction and evaporation, Z-2- ((p-fluoro-cinnamyl) -pipéridine is obtained in the form of a yellow oil. - CCM:Rf = 0.70- 0.85 (dichloromethane/methanol ammonia at 10 % 80/20 v/v) - What? By a comparable treatment of the more polar fractions, E-2- ((p-fluoro-cinnamyl) -pipéridine hydrochloride is obtained as a white precipitate.- What? - What? The return to base provides E-2- ((p-fluoro-cinnamyl) -pipperidine with a yield of 25%.

Preparation 2C: E-2- ((p-chloro-cinnamyl) -pipéridine (f. III; Ar = p-chloro-phenyl, n = 2) is obtained by the addition of a solution of E-C2 to the preparation.

(a) Step a) According to the method of preparation 2A, step a) from p-chloro-benzyl-triphenyl-phosphonium chloride, N-t-butyloxycarbonyl-2- ((p-chloro-cinnamyl) piperidine is obtained with an efficiency of 94% as a yellow oil.State b) Deprotection by trifluoroacetic acid is carried out according to the method of preparation 2A, stage b). The product obtained as a yellow oil is a mixture of isomers Z and E. By chromato-flash on silicon, the extraction by dichloromethane/ethanol mixture at 10/10 v/v of 90%, with a yield of 24%, of E-chloro-2-pyridine, allows the production of a yellow oil.

Preparation 2D: E-2- ((m-chloro-cinnamyl) -pipéridine (f. III; Ar = p-chloro-phenyl, n = 2) is obtained by the addition of a solution of E-Cinnamyl to the preparation.

Stage a) Following a similar procedure to preparation 2A, stage a) from m-chloro-benzyl-triphenyl-phosphonium chloride, N-t-butyloxycarbonyl-2- ((m-chloro-cinnamyl) piperidine is obtained with an efficiency of 99%. Stage b) Deprotection with trifluoroacetic acid is performed in the same procedure as preparation 2A, then stage b). The resulting product is a mixture of isomers Z and E. Chromato-flash on silica, the elusion by the dichloromethane/ammonium methanol mixture 10/10 v/v to 90%, yields E-dichloromethane in the interstitial fractions. The most polar fractions are treated in the second step to provide a 24%, as in the case of E-dichloromethane and E-dichloromethane, which is made in the same conditions as E-dichloromethane and E-dichloromethane.

Preparation 2E: E-2- (3,4-dichloro) -cinnamyl piperidine (f. III; Ar = 3,4-dichloro-phenyl, n = 2) The substance is used as a solvent in the manufacture of other products.

(a) According to step 2A, step (a), N-t-butyloxycarbonyl-2- ((3,4-dichloro) cinnamyl piperidine is obtained from 3,4 dichloro-benzyl triphenyl phosphonium chloride in the form of a yellow oil. - CCM:Rf = 0.60- 0.80 (dichloromethane) Stage b) Deprotection by trifluoroacetic acid and separation of the E isomer are carried out in the manner described in stage b) of preparation 2D. E-2-(3,4-dichloromethane) -cinnamyl piperidine, in the form of a yellow oil, is obtained with an efficiency of 18%. - CCM:Rf = 0.35- 0.55 (dichloromethane/MeOH ammonia at 10% 90/10 v/v)

Preparation 2F: E-2- ((p-methyl-cinnamyl) -pipéridine (f. III; Ar = p-toluyl, n = 2) is obtained by the addition of a solution of E-methyl to the preparation.

Step a) According to step a of the 2A process, N-t-butyloxycarbonyl-2- ((p-methyl-cinnamyl) piperidine (f. V; Ar = p-toluyl, n = 2) is obtained from p-methylbenzyl-triphenyl-phosphonium chloride in the form of an orange yellow oil. Rdt: 98 %- CCM:Rf = 0.25- 0.55 (dichloromethane) Stage b) The intermediate V of the previous stage is unprotected and the isomer E is separated according to the mode of operation of the preparation 2D, stage b. E-2- ((p-methyl-cinnamyl) -pipperidine, in the form of a yellow oil, is obtained at a yield of 14%. The corresponding hydrochloride is a white solid with a melting point of 178 °C (isopropanol).

Preparation 2G: E-2- ((p-trifluoromethyl-cinnamyl) -pipéridine (f. III; Ar = p-trifluoromethylphenyl, n = 2) is obtained by the addition of a solution of E-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p-p

Step (a) According to step (a) of the 2A process, N-Boc-2- (p-trifluoromethyl-cinnamyl) piperidine (f. V; Ar = p-trifluoromethylphenyl, n = 2) is obtained from p-trifluoromethylbenzyl-triphenyl-phosphonium chloride in the form of a yellow oil. Rdt:94 % Stage b) The intermediate V of the previous stage is unprotected and the isomer E is separated according to the method of preparation 2B stage b) applied to the isomer E. E-2- ((p-trifluoromethyl-cinnamyl) -pipéridine is obtained with a yield of 17%.

Preparation 2H: E-2- ((p-methoxy-cinnamyl) -pipéridine (f. III; Ar = p-methoxyphenyle, n = 2) The substance is used as a solvent in the manufacture of other products.

(a) Step (a) According to step 2A, step (a), from p-methoxybenzyl triphenyl phosphonium chloride, N-Boc-2- ((p-methoxy-cinnamyl) -pipéridine (f. V; Ar = p-methoxyphenyl, n = 2) is obtained as a yellow oil which is purified by silica column chromatography by elevating by a 98/2 v/v dichloromethane/acetone mixture. Rdt: 94%. - CCM:Rf = 0.55-0.75 (dichloromethane/acetone 98/2 v/v) Stage b) The intermediate V of the previous stage is unprotected and the isomer E is purified by the 2D process, stage b. E-2- ((p-methoxy-cinnamyl) -pipperidine is obtained as a yellow oil with a yield of 15%. - CCM:Rf = 0.45- 0.70 (dichloromethane/MeOH ammonia at 10 % 90/10 v/v) The concentration of the ammonia in the sample is calculated as follows:

Preparation 2I: E-2-(1-napht-1-yl-propene-3-yl) -pipéridine (f. III; Ar = napht-1-yl, n = 2) The preparation is made from a mixture of the following:

(a) Step a) According to step 2A, step a) from naphth-1-yl-methyl-triphenyl-phosphonium chloride, N-Boc-2-(1-napht-1-yl-propen-3-yl) -pipéridine (f. V; Ar = naphth-1-yl, n = 2) is obtained with a yield of 79%.

Preparation 2J: E-2-(1-thien-2-yl-propene-3-yl) -pipéridine (f. III; Ar = thien-2-yl, n = 2) The preparation is made from a mixture of the following:

Stage a) Following a similar procedure to preparation 2A, stage a) from thien-2-yl-methyl-triphenyl-phosphonium chloride, N-Boc-2-(1-thien-2-yl-propene-3-yl) -pipéridine is obtained with an efficiency of 91%.

Preparation 2K: Z-2-cinnamyl-pyrrolidine (f. III-Z; Ar = C6H5, n = 1) The substance is used as a solvent in the manufacture of other products.

Stage a) In a moisture-protected reactor, introduce 235 ml of absolute ethanol and then, under agitation, 2.16 g (0.094 mol) of skimmed sodium. After dissolution, at 20-25 °C, add 36.5 g (0.094 mol) of benzyl triphenylphosphonium chloride. The yellow solution is agitated for 30 min. Then, in 2 min, introduce a solution of about 20 g (0.094 g) of molybdenum acetate (f. VI; n = 1) obtained previously, into 47 ml of absolute ethanol. The white suspension is agitated for 45 min at 20-25 °C, then the solvent is filtered on a vacuum bath and discarded. The evaporated film is filtered underwater.The oily residue, taken from 300 ml of pentane, is maintained for 2 h at 0 °C under agitation, then filtered and concentrated. This last operation is repeated. 24.5 g (Rdt = 91%) of crude N-Boc-2-cinnamyl-pyrrolidine (f.V; Ar = C6H5, n = 1) is obtained in the form of a yellow oil, which is introduced as it is in the next stage. - CCM:Rf = 0.35-0,The test chemical is a mixture of ammonia and chlorine.

Preparation 2L: E-2- ((p-fluoro-cinnamyl) -pyrrolidine (f. III; Ar = p-fluoro-phenyl, n = 1) The substance is used in the manufacture of the preparation.

Step a) In a moisture-protected reactor, 42 g (0.103 mol) of p-fluorobenzyl triphenyl phosphonium chloride is introduced into 235 ml of toluene dehydrated on molecular sieve. 60 ml of 2.5 M n-butyl lithium solution is then introduced into the hexane in 10 min. The red suspension is agitated for 2 h at 20-25 °C, then a 20 g (0.094 ml) solution of molybdenum acetaldehyde (f. VI; n = 1) obtained previously is introduced in 42.2 ml of toluene in 5 min. The red suspension is agitated for 16 h, then 80 ml of a saturated ammonium chloride solution is introduced by cooling to 20 °C.The oil is then mixed with the oil and the oil is then mixed with the oil and the oil is then mixed with the oil and the oil is then mixed with the oil and the oil is then mixed with the oil and the oil is then mixed with the oil. The oil is then mixed with the oil and the oil is then mixed with the oil and the oil is then mixed with the oil.The hydrochloride of E-2- ((p-fluoro-cinnamyl) pyrrolidine is obtained as a white precipitate. The return to the base yields E-2- ((p-fluoro-cinnamyl) pyrrolidine with a yield of 19%. - CCM:Rf = 0.30- 0.50 (dichloromethane/MeOH ammonia at 10 % 90/10 v/v) The concentration of the ammonia in the sample is calculated as follows:

The following is the list of active substances which are to be used in the preparation of the additive:

Step a) In a moisture-protected reactor, introduce 4.5 g (0.024 mol) of E-2-cinnamylpyrrolidine (preparation 1, stage b) in solution into 100 ml of dehydrated dichloromethane on molecular sieve. Under agitation, add 2.5 g (3.5 ml - 0.025 mol) of triethylamine and then, at a temperature below 10 °C for about 10 min, 2.5 g (2.2 ml - 0.024 mol) of cyclopropane carboxylic acid chloride (f. IV; m = 1, R = cyclopropyl). 30 ml of 10% ammonia solution followed by 30 ml of water,30 ml of 10% HCl solution followed by 30 ml of water, 30 ml of saturated NaHCO3 solution followed by 30 ml of water. The organic phase is dehydrated to Na2SO4 and the solvent evaporated in vacuum and in a water bath. The oily residue (5.9 g) is purified by chromatography on a silica column. Elution by the dichloromethane/acetone mixture 95/5 v/v gives 2-cinnamyl-1-cyclopropane-carbonyl-pyrrolidine (f. II Ar = C6H5, m = 1, n = 1, R = cyclopropyl) pure, yellow oil. The following is the list of substances which are to be used in the preparation of the product:(b) In a nitrogen atmosphere, protected from moisture and not exceeding 0 °C, prepare a suspension of 1.9 g (0.049 mol) lithium aluminium hydride (LAH) in 25 ml of dehydrated THF on a molecular sieve and a solution of 2.15 g (0.016 mol) aluminium chloride in 25 ml of also dehydrated diethyl ether. After 30 min of contact for each preparation, the LAH/THF suspension is introduced into the etheric solution of AlCl3 for 10 min at 0 °C.then at this temperature and in 10 min a solution of 4.0 g (0.016 mol) of the amide (II) obtained at the previous stage is introduced into 16 ml of anhydrous THF. After 30 min at 0 °C the mixture is brought to the reflux for 10 min and then rapidly cooled to 0 °C. Then 2,9 ml of NaOH 15 % solution (p/v) is added carefully by drip and then 3,6 ml of water. After 30 min of contact the mixture is filtered on a buchner with a bed of infusions. The film is concentrated under vacuum and water treatment to obtain E-2-cinnamyl-N-cyclopropylmethylpyrrolidine,which is found to be pure by CCM. Weight: 3.2 g Rdt: 84.6% - CCM:Rf = 0.55-0.75 (dichloromethane/acetone 95/5 v/v) - RMN:0.00-0.30 (m, 2H) ; 0.40-0.70 (m, 2H) ; 0.80-1.20 (m, 1H) ; 1.40-3.00 (m, 10H) ; 3.20-3.50 (m, 1H) ; 6.00-6.60 (m, 2H) ; 7.10-7.55 (m, 5H).Chlorhydrate: The base is dissolved in 50 ml of dichloromethane, 5 ml of 5 N hydrochloride ether is added, and the solvents are removed by distillation. The solid residue is crystallized by dissolving in 50 ml of acetate. The white insoluble is filtered, dried to a constant weight.F = 163 °C The test chemical is used to determine the concentration of the active substance in the test chemical.

The compound is prepared as described in Example 1.1 above from (-) -E-2-cinnamylpyrrolidine (preparation 1, stage c). The substance is classified as a substance of very high concern for the protection of human health and the environment. Rdt :100 % [α]D = 24,5 ° (c = 1, dichloromethane) - CCM:Rf = 0,35- 0,50 (dichloromethane/acetone 95/5 v/v) Stage b) (+) -E-2-cinnamyl-1-cyclopropylmethylpyrrolidine is not included in the list of substances Rdt: 96 % [α]D = + 91.9 ° (c = 1, dichloromethane) - CCM:Rf = 0.45- 0.60 (dichloromethane/MeOH ammoniacal at 10% 95/5 v/v) - NMR:Identical with the racemic product (Ex. 1.1).Chlorohydrate: F = 196-198 °C (isopropanol). Analysis (C17 H21 Cl N) % C, H, N conforms to IR (KBr): Identical to the racemic product (Ex. 1.1).

The following is the list of active substances which are to be used in the preparation of the active substance:

The compound is prepared as described in Example 1.1 above from (+) -E-2-cinnamylpyrrolidine (preparation 1, stage d). The substance is classified as a substance of very high concern for the protection of human health and the environment. Rdt :100 % [α]D = - 20,8 ° (c = 1, dichloromethane) - CCM:Rf = 0,35- 0,50 (dichloromethane/acetone 95/5 v/v) Stage b) (-) - E-2-cinnamyl-1-cyclopropylmethylpyrrolidine Rdt: 94% [α]D = + 91.8 ° (c = 1, dichloromethane) - CCM:Rf = 0.45- 0.60 (dichloromethane/MeOH ammoniacal at 10 % 95/5 v/v) - NMR:Identical with the racemic product (Ex. 1.1).Chlorohydrate: F = 196-198 °C (isopropanol). Analysis (C17 H24 Cl N) : % C, H, N conform. IR: Identical with the racemic product (Ex. 1.1).

The following is the list of active substances in the active substance:

Stage a) Following the procedure in example 1.1, step a) from 2-cinnamyl-pyrrolidine and carboxylic acid cyclobutane chloride, 2-cinnamyl-1-cyclobutane-carbonylpyrrolidine (f. II; Ar = C6H5, m = 1, n = 1, R = cyclobutyl) is obtained at a 95% yield and introduced as in the following step. - CCM:Rf = 0.50- 0.60 (dichloromethane/MeOH ammoniacal at 10 % 95/5 v/v) - RMN :1,40- 3.20 (m, 18H) ; 5,95- 6,95 (m, 2H) ; 7,00- 7,45 (m, 5H).Chlorhydrate: Prepared as described in example 1.1, the product is crystallized in the dichloromethane/ethyl ether mixture. The test chemical is used to determine the concentration of the test chemical in the test medium.

The following is the list of active substances in the active substance:

Step a) In a moisture-protected reactor, 1 g (0.010 mol) of acetic cyclopropane acid, 2.34 g (0.012 mol) of E-2-cinnamylpyrrolidine in solution in 80 ml of dehydrated dichloromethane on molecular sieve and 2.9 g (0.015 mol) of 1-dimethylamypropyl-3-ethylcarbodiimide hydrochloride are introduced. The brown solution is maintained agitated 16-20 °C at 25 °C and the mixture is extracted successively by: 50 ml of HCl 1 N solution, then 2 x 50 ml of water,50 ml of saturated NaHCO3 solution, then 2 x 50 ml of water. The organic phase is dehydrated to Na2SO4, filtered, and then the solvent is evaporated under vacuum and in water bath.2-Cinnamyl-1-cyclopropane-acetylpyrrolidine (f. II; Ar = C6H5, m = 2, n = 1, R = cyclopropyl) is obtained as a brown oil. - CCM:Rf = 0.85-0.95 (dichloromethane/MeOH ammoniacal at 10 % 92/8 v/v) Stage b) Amide II of the previous stage is reduced in the manner described in example 1.1, stage b), followed by a chromatographic purification step on a silica column. The weight :1,7 g Rdt: 81 %- CCM:Rf = 0,The following is a list of the active substances that may be used in the preparation of the product: 85 - 1,00 (dichloromethane/ MeOH ammoniacal at 10 % 90/10 v/ v) - RMN: 0- 0,10 (m,2H) ; 0,40 - 0,50 (m,2H) ; 0,70 - 0,80 (m,1H); 1,30 - 1,90 (m,7H) ; 2,10 - 2,30 (m,2H) ; 2,30 - 2,40 (m,1H) ; 2,50 - 2,60 (m,1H) ; 2,90 - 3,00 (m,1H) ; 3,10 - 3,20 (m,1H) ; 6,10 - 6,20 (m,1H) 6,45 (d,1H) ; 7,10 - 7,40 (m,5H) Hydrochloride: F = 188 °C (isopropanol). The test chemical is used to determine the concentration of the test chemical in the test medium.

The following is the list of active substances in the active substance:

Stage a) Practice as in example 1.1, step a) from E-2-cinnamylpyrrolidine and phenylacetic acid chloride, with a yield of 97%, to obtain E-2-cinnamyl-1-phenylacetylpyrrolidine, which is used as in the next step. - CCM:Rf = 0.80- 0.95 (dichloromethane/MeOH ammonia at 10 % 90/10 v/v) - RMN :1,50- 2.00 (m,4H) ; 2.10- 2.30 (m,2H) ; 2.30- 2.60 (m,3H) ; 2.70- 2.90 (m,2H) ; 3.00- 3.20 (m,1H) ; 3.20- 3.30 (m,1H) ; 6.10- 6.20 (m,1H) ; 6.45 (d,1H) ; 7.10- 7.40 (m,10H) Hydrochloride: F = 120-122 °C (ethyl acetate/ethyl ether). The test chemical is a chemical which is used to determine the concentration of a substance in a solution.

The following is the list of active substances which are to be used in the preparation of the active substance:

Step a) Step a) is applied as in example 1.1 from E-2-cinnamyl piperidine (preparation 2A, stage b) and cyclopropane carboxylic acid chloride to obtain E-2-cinnamyl-1-cyclopropane-carbonyl piperidine (f. II; Ar = C6H5, m = 1, n = 2, R = cyclopropyl). - CCM:Rf = 0.80- 0.90 (ethyl acetate) - RMN:0.50- 1.10 (m, 5H) ; 1.30- 1.90 (m, 8H) ; 4.00- 5.00 (m, 1H) ; 5.90- 6.60 (m, 2H) ; 7.10-7.40 (m, 5H).State b) The amide (II) of the previous stage is reduced as described in example 1.1, stage b) to obtain E-2-cinnamyl-1-cycloproprane-carbonyl-pipéridine. Rdt: 86 % - CCM:Rf is 0,The product is prepared in the conditions described in Example 1.1 by crystallization in ethyl acetate at boiling. F = 152°C. The following data are available for the analysis of the following substances:- Two feet.

The following is added to the list of active substances:

The compound is prepared as described in Example 2A.1 above from (-) -E-2-cinnamyl-pipperidine (preparation 2A, stage c). The test chemical is a cyclopropyl (C6H5) with a pH of -10 ± 5 °C. - CCM:Rf = 0.60- 0.75 (dichloromethane/acetone 95/5 v/v) Stage b) (+) -E-2-cinnamyl-1-cyclopropylmethyl-pipéridine Rdt: 95% [α]D = + 27.7 ° (c = 1, dichloromethane) - CCM: 0.60- 0.75 (dichloromethane/acetone 95/5 v/v) - NMR: identical to the racemic product (Ex. 2A.1) Chlorohydrate: F = 153 °C (ethyl acetate). Analysis (C18 H26 Cl N): % C, H, Cl, N conform; IR (KBr) : Identical with the racemic product (Ex. 2A.1)

The following is added to the list of active substances:

The compound is prepared as described in Example 2A.1 above from (+) -E-2-cinnamyl-pipperidine (preparation 2A, stage d). The test chemical is used to determine the concentration of cyclopropyl in the test chemical. - CCM:Rf = 0.60- 0.75 (dichloromethane/acetone 95/5 v/v) Stage b) (-) - E-2-cinnamyl-1-cyclopropylmethyl-pipéridine Rdt: 94% [α]D = - 28.5 ° (c = 1, dichloromethane) The concentration of the active substance in the sample is calculated as follows: - CCM:Rf = 0.45- 0.65 (dichloromethane/MeOH ammoniacal at 10 % 95/5 v/v) - RMN:Identical with the racemic product (Ex.2A.1). Analysis (C18 H26 Cl N): % C, H, Cl, N conform.IR: identical to the racemic product (Ex.2A.1).

The following is the list of active substances which are to be classified in the Annex to this Regulation:

Step a) Proceed as in example 1.1 step a) from E-2-cinnamyl piperidine and carboxylic acid cyclobutane chloride to obtain E-2-cinnamyl-1-cyclobutane-carbonyl piperidine (f. II; Ar = C6H5, m = 1, n = 2, R = cyclobutyl). Rdt: 99%. - CCM:Rf = 0.40-0.55 (dichloromethane/acetone 95/5 v/v) Stage b) The intermediate of the previous stage is reduced under the conditions described in example 1.1, stage b) to obtain E-2-cinnamyl-1-cyclobutane-carbonyl-pipéridine. - CCM:Rf = 0.65- 0.90 (dichloromethane/MeOH ammoniacal at 10 % 95/5 v/v) - RMN: 1.20- 2.60 (m, 18H) ; 2.70- 2.80 (m, 2H) ; 6.10- 6.20 (m, 1H) ; 6.40 (d, 1H) ; 7.10- 7.40 (m, 5H).Chloride: F = 163 °C (ethyl acetate) The test chemical is a chemical that is used to determine the concentration of a substance in a solution.

The following is the list of active substances which are to be classified in the Annex to this Regulation:

The compound is prepared as described in Example 1.6 above from E-2-cinnamyl piperidine and phenylacetic acid chloride. The test chemical is used to determine the concentration of E-Cinnamyl-1-phenyl acetyl piperidine in the test chemical. - CCM:Rf = 0.50- 0.60 (dichloromethane/acetone 95/5 v/v) Stage b) E-2-cinnamyl-1-phenethyl-pipperidine Rdt: 73% The concentration of the active substance in the product is calculated as follows: - CCM:Rf = 0.60- 0.80 (dichloromethane/MeOH ammonium at 10 % 98/2 v/v) - RMN :1,30- 1.80 (m, 6H) ; 2.30- 2.60 (m, 4H) ; 2.80- 3.00 (m, 5H) ; 6.10- 6.20 (m, 1H) ; 6.40 (d, 1H) ; 7.10-7.40 (m, 10H) Hydrochloride: Hygroscopic product F = 95-100 °C (ethyl ether/isopropanol) The test chemical is used to determine the concentration of the test chemical in the test medium.

The following is the list of active substances which are to be classified in the Annex to this Regulation:

The compound is prepared as described in Example 2A.1 above from Z-2-cinnamyl piperidine (preparation 2A, stage b). The test chemical is a chemical that is used to produce a specific chemical. - CCM:Rf = 0.75- 0.80 (ethyl acetate) - RMN: 0.60- 0.85 (m, 2H) ; 0.85- 1.10 (m, 2H) ; 1.10- 1.90 (m, 9H) ; 2.40- 3.00 (m, 2H) ; 3.80- 5.00 (m, 1H) ; 5.45- 5.85 (m, 1H) ; 6.40- 6.70 (m, 1H) ; 7.10- 7.50 (m, 5H). - CCM:Rf = 0.50- 0.70 (dichloromethane/MeOH ammonia at 10 % 95/5 v/v) - RMN: 0.00- 0.10 (m, 2H) ; 0.30- 0.60 (m, 2H) ; 0.60- 1.00 (m, 1H) ; 1.10- 1.80 (m, 6H) ; 2.00- 2.65 (m, 6H) ; 2.90- 3.20 (m, 1H) ; 5.45- 5.90 (m, 1H) ; 6.35- 6.60 (m, 1H) ; 7.10- 7.50 (m, 5H).Chlorhydrate: Fthy = 112 °C (etheric). The test chemical is used to determine the concentration of the test chemical in the test medium.

The following is the list of active substances which are to be used in the preparation of the active substance:

In a moisture-protected reactor, 2.3 g (0.010 mol) of E-2-(p-fluoro-cinnamyl) -pipéridine (preparation 2B) is introduced in solution in 25.2 ml of acetonitrile, followed by 1.56 g (1.1 ml - 0.012 mol) of bromethylcyclopropane in 2 min. The medium is kept agitated at room temperature for 1 h 30 min, raised to 60 °C for 4 h, then reduced to 20 ± 3 °C for 16 h. The solvent is evaporated under vacuum and in a water bath. The oily residue is taken up in water, acidified and extracted with ether. After extraction, the cooling phase is decomposed by welding, etherisation and washing with a solution of NaCl saturated aqueous.The organic phase is dehydrated to Na2SO4, then the solvent is removed by distillation. The residue is purified by chromato-flash by eluting with the dichloromethane/ammonium methanol mixture at 10 % 90/10 v/v, and subjected to a second acid-alkaline treatment. E-2-(p-fluoro-cinnamyl)-1-cyclopropylmethyl-pyrrolidine is obtained as a yellow oil. Weight: 0.9 g Rdt: 31% - CCM:Rf = 0.35- 0.60 (dichloromethane/MeOH ammonia at 10 % 90/10 v/v) - RMN: 0.00- 0.20 (m, 2H) ; 0.40- 0.60 (m, 2H) ; 0.70- 1.00 (m, 1H) ; 1.10- 1.90 (m, 6H) - 2.00- 2.70 (m, 6H) ; 2.8-3,20 (m, 1H) ; 5.90- 6.50 (m, 2H) 6,I'm not sure.

Hydrochloride: F = 135 °C (ethyl acetate) is obtained by the reaction of hydrochloric acid with hydrochloric acid. The test chemical is used to determine the concentration of the test chemical in the test medium.

The following is the list of active substances which are to be classified in the Annex to this Regulation:

The compound is prepared as described in Example 2B.1 above from Z-2- ((p-fluoro-cinnamyl) -pipéridine (preparation 2B) with a yield of 43%. - CCM:Rf = 0.35- 0.60 (dichloromethane/MeOH ammonia at 10 % 90/10 v/v) - RMN: 0.00- 0.10 (m, 2H) ; 0.20- 0.60 (m, 2H) ; 0.60- 1.00 (m, 1H) ; 1.10- 1.80 (m, 6H) ; 2.00- 2.60 (m, 6H) ; 2.80- 3.20 (m, 1H) ; 5.50- 5.90 (m, 1H) ; 6.30- 6.60 (m, 1H) 6.90- 7.30 (m,4H).

The hydrochloride: F = 102 °C (ethyl acetate). The test chemical is used to determine the concentration of the test chemical in the test medium.

The following is the list of active substances in the active substance:

The compound is prepared as described in Example 2B.1 above from E-2- ((p-chloro-cinnamyl) -pipéridine (2C preparation with a yield of 44%). - RMN: 0.00- 0.20 (m, 2H) ; 0.40- 0.60 (m, 2H) ; 0.60- 1.00 (m, 1H) ; 1.10- 1.80 (m, 6H) ; 2.10- 2.80 (m, 6H) ; 2.90- 3.20 (m, 1H) ; 5.90- 6.70 (m, 2H) ; 7.30 (m, 4H).

Hydrochloride: F = 173 °C (ethyl acetate) is obtained by the reaction of hydrochloric acid with hydrochloric acid. The test chemical is used to determine the concentration of the test chemical in the test medium.

The following is the list of substances that are to be used in the preparation of the test chemical:

The compound is prepared as described in Example 1.1 from E-2- ((m-chloro-cinnamyl) -pipéridine (preparation 2D). The following is the list of active substances which are to be classified in the additive: - CMM:Rf = 0.7 (dichloromethane/MeOH ammonia at 10 % 90/10 v/v).- RMN:0.00- 0.30 (m, 2H) ; 0.60- 0.70 (m, 2H) ; 0.90- 1.10 (m, 1H) ; 1.30- 1.90 (m, 6H) ; 2.30- 2.80 (m, 6H) ; 3.10- 3.20 (m, 1H) ; 6.30- 6.50 (m, 2H) ; 7.20- 7.50 (m, 4H).Chlorhydrate: F = 129 °C (ethyl acetate). The test chemical is used to determine the concentration of the test chemical in the test medium.

The following is the list of active substances which are to be used in the preparation of the additive:

The compound is prepared as described in Example 1.1 from E-2-(3,4-dichloro-cinnamyl) -pipéridine (preparation 2E). The test chemical is a cyclopropane-carbonyl-pipperidine (f. II; Ar = 3,4-dichlorophenyl, m = 1, n = 2, R = cyclopropyl). - CMM:Rf = 0.90- 1.00 (dichloromethane/MeOH ammoniacal at 10 % 90/10 v/v).Stage b) E-2-(3,4-dichloro-cinnamyl)-1-cyclopropyl methyl piperidine. Rdt: 79%. - CMM:Rf = 0.65- 0.80 (dichloromethane/MeOH ammonia at 10 % 90/10 v/v).- RMN:0.00- 0.20 (m, 2H) ; 0.40- 0.70 (m, 2H) ; 0.70- 1.10 (m, 1H) ; 1.10- 1.80 (m, 6H) ; 2.10- 2.80 (m, 6H) ; 2.90- 3.20 (m, 1H) ; 6.20- 6.40 (m, 2H) ; 7.10- 7.50 (m, 3H).Chlorhydrate: F = 153 °C (ethyl acetate). The test chemical is used to determine the concentration of the test chemical in the test medium.

The following is the list of active substances in the active substance:

The compound is prepared as described in Example 1.1 from E-2- ((p-methyl-cinnamyl) -pipéridine (preparation 2F). The following is the list of active substances which are to be classified in the additive: - RMN: 0.00- 0.20 (m, 2H) ; 0.40- 0.60 (m, 2H) ; 0.70- 1.10 (m, 1H) ; 1.10- 1.90 (m, 6H) ; 2.35 (s, 3H) ; 2.10-2.80 (m, 6H) ; 2.80- 3.20 (m, 1H) ; 5.90- 6.50 (m, 2H) ; 6.90- 7.30 (m,4H).Chlorhydrate: F = 152 °C (ethyl acetate). The test chemical is a chemical that is used to determine the concentration of a substance in a solution.

The following is the list of active substances in the active substance:

The compound is prepared as described in Example 1.1 from E-2- ((p-trifluoromethyl-cinnamyl) -pipéridine (preparation 2G). The following is the list of active substances which are to be classified in the additive: - CCM:Rf = 0.6 (dichloromethane/MeOH ammonia at 10 % 90/10 v/v) - RMN: 0.00- 0.20 (m, 2H) ; 0.40- 0.60 (m, 2H) ; 0.80- 1.00 (m, 1H) ; 1.20- 1.80 (m, 6H) ; 2.30- 2.70 (m, 6H) ; 3.00- 3.10 (m, 1H) 6.20- 6.40 (m, 1H) 6.45 (d, 1H) ; 7.30- 7.70 (m,4H). The test chemical is used to determine the concentration of the test chemical in the test medium.

The following is the list of active substances in the active substance:

The compound is prepared as described in Example 1.1 from E-2- ((p-methoxy-cinnamyl) -pipéridine (preparation 2H). The test chemical is a chemical that is used to produce a substance that is a mixture of two or more substances. - CCM:Rf = 0.90- 1.00 (dichloromethane/MeOH ammoniacal at 10 % 90/10 v/v.Stade b) E-2- ((p-methoxy-cinnamyl)-1-cyclopropyl methyl piperidine. Rdt: 72% The concentration of the ammoniacal in the sample is approximately the same as that in the sample. - CMM:Rf = 0.80­1.00 (dichloromethane/MeOH ammoniacal at 10 % 90/10 v/v. A final chromato-flash purification step is introduced on a silica column by elevating the dichloromethane mixture. Ammonium methanol at 10 per cent 95/5 v/v. - RMN: 0.10- 0.30 (m, 2H) ; 0.40- 0.70 (m, 2H) ; 0.70- 1.10 (m, 1H); 1.20- 2.00 (m, 6H) ; 2.00- 2.80 (m, 6H) ; 2.80- 3.20 (m, 1H) ; 3.75 (s, 3H) ; 5.90- 6.50 (m, 2H) ; 6.70- 7.00 (m, 2H) ; 7.20- 7.40 (m, 2H). Analysis (C19 H27 N O): % C, H, N, O are in accordance with The following is the total number of samples of the product:

The following is the list of substances that are to be used in the preparation of the test chemical:

The compound is prepared as described in Example 1.1 from E-2-(1-napht-1-yl-propene-3-yl) -pipéridine (preparation 2I). The test chemical is a chemical that is used to produce a specific chemical in a particular chemical compound. - CCM:Rf = 0,75 (dichloromethane/MeOH ammonia at 10 % 90/10 v/v) - RMN: 0,00- 0,20 (m, 2H) ; 0,40- 0,60 (m, 2H) ; 0,80- 1,00 (m, 1H); 1,10-1,40 (m, 1H) ; 1,40-1,90 (m, 5H) ; 2,30-2,80 (m, 6H) ; 3,00- 3,20 (m, 1H) ; 6,10-6,30 (m, 1H) ; 7,10 (d, 1H) ; 7,30-7,60 (m,4H); 7,70-7,90 (m, 2H) 8,10 (d,1H).Chlorhydrate: F = 118 °C (ethyl acetate). The test chemical is a chemical that is used to determine the concentration of a substance in a solution.

The following is the list of substances that are to be used in the preparation of the test chemical:

The compound is prepared as described in Example 1.1 from E-2-(1-thien-2-yl-propene-3-yl) -pipéridine (preparation 2J). The following is the list of active substances which are to be classified in the additive: - CCM:Rf = 0.8 (dichloromethane/MeOH ammonia at 10 % 90/10 v/v) A chromato-flash purification step is introduced on a silica column by elevating the dichloromethane/ammonium methanol mixture at 10 % 95/5 v/v. - RMN: 0.00- 0.20 (m, 2H) ; 0.50- 0.60 (m, 2H) ; 0.80- 0.90 (m, 1H); 1.20- 1.80 (m, 6H) ; 2.20- 2.60 (m, 6H) ; 3.00- 3.10 (m, 1H) ; 6.00- 6.10 (m, 1H) ; 6.50 (d, 1H) ; 6.80- 7.00 (m, 2H); 7.10 (d, 1H).Chlorhydrate: F = 175 to 177 °C (ethyl acetate). The test chemical is a chemical which is used to determine the concentration of a substance in a solution.

The following is the list of active substances in the active substance:

The compound is prepared as described in Example 1.1 from Z-2-cinnamyl-pyrrolidine (preparation 2K). The test chemical is a Z-2-cinnamyl-1-cyclopropane-carbonyl-pyrrolidine (f. II; Ar = phenyl, m = 1, n = 1, R = cyclopropyl). - CCM:Rf = 0.35- 0.55 (dichloromethane/acetone 95/5 v/v) Stage b) Z-2cinnamyl-1cyclopropylmethylpyrrolidine. Rdt: 97% The concentration of the active substance in the product is calculated as follows: A chromato-flash purification step is introduced on a silica column by elevating with the dichloromethane/ammonium methanol mixture at 10 per cent 96/4 v/v. The following is the list of substances which are considered to be toxic if they are used in the manufacture of the product: - Rf = 0.50- 0.80 (dichloromethane/methanol ammoniacal at 10 % 98/2 v/v) - RMN: 0.00- 0.20 (m, 2H) ; - 0.40- 0.60 (m, 2H) ; - 0.80- 0.90 (m, 1H); - 1.50- 2.00 (m, 5H); - 2.10- 2.20 (m, 1H) ; - 2.30- 2.40 (m, 2H) - 2.60- 2.80 (m, 2H) ; - 3.80- 3.90 (m, 1H) ; - 5.60- 5.70 (m, 1H) ; - 6.50 (m, 1H); - 7.10-30 (m, 5H). - Chlorohydrate: F = 129 °C (ethyl ether/isopropanol). The test chemical is a chemical that is used to determine the concentration of a substance in a solution.

The following is the list of active substances in the active substance:

The compound is prepared as described in Example 1.1 from E-2- ((p-fluoro-cinnamyl) -pyrrolidine (preparation 2L). The test chemical is a single active substance, which is a mixture of two or more substances. - CCM:Rf = 0.40- 0.55 (dichloromethane/acetone 95/5 v/v) Stage b) E-2- ((p-fluoro-cinnamyl)-1-cyclopropyl methyl pyrrolidine. Rdt: 84% The concentration of the active substance in the product is approximately the same as in the active substance. The pH of the solution is approximately the same as that of the solvent, and the pH of the solution is approximately the same as that of the solvent. The test chemical is a chemical that is used to produce a substance.

Pharmacological studies

The compounds of the invention (I) and their salts show their ability to interact with sigma receptors in binding experiments performed in vitro in the presence of a specific signaling ligand of the sigma receptors, (+) [3H]-SKF 10.047.

In addition, in vivo, the ability of the compounds of the invention (I) to inhibit gastric duodenal ulcers caused by cystheamine administration has been demonstrated very favorably by comparison with hygemesin hydrochloride (DCI proposed) or (+) -N-(cyclopropyl-methyl)-1-ethyl-N-methyl-1,4-diphenylbut-3-en-1-ylamine hydrochloride, the preferred compound of EP 362 001.

The protection conferred by the products of the invention against experimentally induced diarrhoea by a bacterial endotoxin, salmonella lipopolysaccharide, has also been demonstrated in mice.

In vitro study

Sigma and PCP receptor binding experiments are performed with the ligands (+) [3H]-SKF 10.047 and [3H]-TCP respectively, using the technique described by Largent, B.L. et al. in J. Pharmacol. Exp. Ther., 1986, vol. 238, p. 739-748.

The technique consists in incubating a rat brain membrane preparation, pre-charged with the specific labelled ligand of the test receptor, in solutions of variable concentration of the test product.

The results are expressed as CI50 of the test product, which is the concentration at which tritiate ligand can be moved from 50% of its binding sites in the membrane preparation used. The CI50 is therefore lower as the product has a high affinity for the receptor. The values obtained are given in Table 1 below. Haloperidol (DCI), known for its affinity for σ receptors among other properties, is given as a reference. - What? Tableau 1

Récepteurs Produits à l'essai	Sigma	PCP
Exemple 1.1	34,25	>10.000
Exemple 1.4	4,52	>10.000
Exemple 2A.6	34,3	>10.000
Halopéridol	8,95	1.268

These results show that the products (I) of the invention have a high affinity for the sign receptor, particularly for the compound in Example 1.4.

In a second series of experiments, CI50 versus [3H]-SKF 10.047 on rat brain membranes was measured for other products of the invention and compared with CI50 for haloperidol by the CI50 ratio of haloperidol to CI50 of the test product. The results are given in Table 2. - What? Tableau 2

Produits testés		Produits testés
Ex.1.3	1,6	Ex.2A.5	1,0
Ex.1.5	0,8	Ex.2B.2	1,6
Ex.1.6	1,3	Ex.2G	0,8
Ex.2A.3	1,4	Ex.2K	4,3
Ex.2A.4	2,3	Ex.2L	1,1

These results confirm that the products (I) of the invention have a high affinity for the sigma receptors characterised by [3H]-SKF 10.047, greater or equivalent to that of haloperidol, and in a number of cases about 2-4 times stronger.

In conclusion, these results are evidence of a high affinity of the products of the invention for sigma receptors.

In addition, this affinity is accompanied by a remarkable specificity since, unlike haloperidol, there is no interference with the PCP receptors.

In vivo study: gastric duodenal ulcer caused by cysteamine

The activity of the compounds of the invention on the gastrointestinal tract has been demonstrated in rats by their ability to inhibit gastric duodenal ulcers caused by the administration of cystheamine. In practice, the study is performed according to the method described by Robert A. et al., Digestion, 1974, vol. 11, p. 199-214, on batches of male Sprague-Dawley rats of an average weight of 200 g to which a solution of cystheamine hydrochloride at 400 mg/kg is administered by subcutaneous injection. The test products are administered to the animals before the ulcer agent, respectively 1 or 30 min, depending on whether the oral or intravenous route of administration is used.Eighteen hours later, the rats are killed by elongation; their stomach and duodenum are removed, rinsed with physiological solvent, and pinned onto a cardboard board. The presence of anthro-pyloroduodenal ulcers is sought, and their area, expressed in mm2, is assessed by multiplying the two main perpendicular axes of the lesion. Statistical analysis of the results is performed by a Student test of ulcer surfaces, compared to a control batch. The results obtained after intra-perioral administration are presented in Table 3, and expressed in DE50 which is the effective dose (mg/kg) of product to inhibit 50% of ulcers caused by cystamine.Hygmésine is presented for comparison. Tableau 3

Produits testés		Produits testés
Exemple 1.1	0,185	Exemple 2A.1	0,100
Exemple 1.2	< 0,100	Exemple 2A.2	< 0,100
Exemple 1.3	< 0,100	Exemple 2A.6	< 0,100
Exemple 1.4	0,137	Igmésine	5,950

Evidently, the compounds of the invention are about 30 to more than 60 times more active than the compound of the previous art with which they are compared.

Diarrhoea caused by the lipopolysaccharide of salmonella.

The activity of the products of the invention in a model of diarrhoea induced by Salmonella enteritidis lipopolysaccharide (LPS) was studied in accordance with a protocol inspired by Ciancio M.J. et al. Gastroenterology, 1992, vol. 103, pp. 1437- 1443. Male dBA2 mice weighing 20-25 g, placed in individual cages with a grill, were given the test product orally for 1 h with an injection of LPS from S. enteridis (reference L6761 Signa) at a dose of 15 mg/kg i.v. The feces were removed in 2 h.50 by placing them under a filter paper, which reduced the calcium intake by 50% compared to the control batch receiving Lotoxine DEPS.

In this model, the products (I) of the invention tested showed particularly interesting activity, with DE50s generally below 100 μg/kg.

These results indicate the possible use of the products of the invention for the symptomatic treatment of diarrhoea with a secretory component and of various etiologies: toxic, infectious including viral, inflammatory, post-antibiotic, and diarrhoea following organic mucosal damage.

The acute toxicity of the products of the invention was investigated after oral administration in rats, which allowed an approximate value of their LD50 to be determined, which is the lethal dose for 50% of the animals under the experimental conditions.

Forms of expression

As described, these pharmacological properties, combined with the low toxicity of the compounds of the invention, suggest a potential use as drugs for the prevention or treatment of (i) neurological dysfunctions, including psychotic states, depressive states, memory and behavioural disorders, stress and anxiety, and (ii) gastrointestinal tract dysfunctions, such as certain forms of gastro-oduodenal ulcers, or diarrhoea, including secretory component.

The dose range is usually between 0.1 and 1000 mg, and more particularly between 1 and 500 mg of the product, depending on the nature and severity of the condition to be treated. These daily therapeutic doses may be divided into several doses. Generally, a daily dose of 5 to 250 mg of the product, divided into two to four doses, leads to a satisfactory therapeutic result.

The products of the invention are administered to patients to be treated in the form of medicinal products of a nature appropriate to the condition to be treated.

Depending on the case, the medicinal preparations will be, as examples but not limited to, tablets, dressing, capsules, powders, solutions, suspensions, gels or suppositories.

Generally, in solid forms of medicinal products, the active substance accounts for 2 to 50% by weight of the total finished form, while excipients account for 98 to 50%; for liquid forms, or those which can be considered as such, the amount of active substance is between 0.1 and 10% by weight of the finished form, while excipients may account for 99.9 to 90% by weight of this form.

For illustration, the formula and preparation of tablets and isotonic solution with the compound in Example 1.4 is described.

Other The formula is:

- principe actif (composé de l'exemple 1.4)	5,0 à 25,0 mg
- polyvinylpyrrolidone	20,0 mg
- carboxyméthylamidon	8,0 mg
- stéarate de magnésium
- silice colloïdale	0,4 mg
- lactose en quantité suffisante pour	200,0 mg

Preparation of the product:

The active substance in hydro-alcoholic solution is mixed with lactose, then granulated with polyvinylpyrrolidone also in solution. The grains are dried and sifted on a 1 mm opening grid. Carboxymethylamidone is mixed with colloidal silica, then added to the granules. It is then mixed closely with magnesium stearate, then compressed at 200.0 mg per tablet.

Isotonic solutes for injection The formula is:

- substance active (I), chlorhydrate de l'Ex. 1.4	10,0 mg
- chlorure de sodium	9,0 mg
- eau distillée en quantité suffisante pour	1,0 ml

Preparation of the product:

The isotonic solute is divided into ampoules of appropriate volume which are, after sealing, sterilised by the usual thermal means; or else the solute is sterilised by filtration, divided into ampoules which are then sealed, all of these operations being carried out under sterile atmosphere.

Claims (1)

1. Use of a sigma receptor ligand compound for the preparation of a medicinal product for the prevention and treatment of diarrhoea.