NZ261331A - Heterocyclically-substituted 4-aminomethylpiperidines and pharmaceutical compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £61 331 New Zealand No. International No. 261331 Priority Date(s): Complete Specification Filed: isl.aj.9ft. 3lass: //.&). ^ia\Xk^U.ik^3, Publication Date: P.O. Journal No: NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Title of Invention: Novel heterocyclic aminomethyl-4 piperidine derivatives, their preparation and application in therapy Name, address and nationality of applicant(s) as in international application form: PIERRE FABRE MEDICAMENT, of 45 place Abel Gance, 92100 Boulogne, France 2b 1 5 3 1 -HT^ receptors, one of the sub-groups of serotoninergic receptor, play an important physiological role. Also, as can be seen in various chapters of the book "Brain 5-HTj^ Receptors: Behavioural and Neurochemical Pharmacology" (Editors C.T. Dourish, S. Ahlenins, P.H. Hutson, Ellis Horwood Ltd., Chichester," 1987) , 5-HT^ agonists may be useful for the treatment of anxiety, depression/ sleeping disorders, vascular and cardiovascular disorders and regularization of the taking of food. 5-HT^ agonists are also known to be inhibitors of gastric secretion (J.S. Gidda, J.M. Schaus, EP. 455,510 A2, 1991).

The subject of the present invention, performed * . at the Centre de Recherche Pierre Fabre, is new chemical compounds endowed with agonist activity towards 5-HT^ receptors, their preparation and their application in therapeutics.

The compounds of the invention correspond to the general formula 1: 1 in which: A represents an oxygen atom, a sulphur atom or a methylene radical; m may take the values 0 or 1; B represents a carbonyl function (CO) or a methylene (CH2) ; n may take the values 0 or 1; R represents a C3-C10 monocyclic or polycyclic 'cycloalkyl radical.

The invention also relates to the salts of the compounds of general formula 1, with pharmaceutically acceptable inorganic or organic acids. The acid employed may be, by way of example given with no limitation being implied, p-toluenesulphonic acid or fumaric acid. ~\ 26133 The present invention relates both to the racemic mixtures and to the various enantiomers of the compounds of general formula 1, and also to their mixtures in all proportions.

The compounds of general formula 1 where B represents a carbonyl radical may be prepared according to the reaction scheme: CCCr • 0 - CCCTXv A o^(CH,J„R o where - A, m, n, and R are defined as above, - X represents a nucleofugal group such as methyl-sulphonyloxy, benzene sulphonyl oxy or p-toluene-sulphonyloxy.

The starting amines 2 and the piperidines of formula 3. may be obtained according to standard methods.

The reaction between a compound of general formula 2 and a compound of general formula 3. is carried out either in the cibsence or in the presence of a solvent such as toluene, xylene, dime thyl forma, mi de or acetonitrile, preferably at a temperature between 50°C and 200°C, and optionally in the presence of an organic base such as a tertiary amine or a mineral base such as an alkali metal carbonate or hydrogen carbonate. A compound of general formula 4 is thus obtained which corresponds to the general formula 1 when B represents a carbonyl function.

The compounds of general formula 1 where B represents a methylene may. be prepared according to the reaction scheme: 261331 J Am \^^CH,(CH,)nR " 4 5 where A, m, n and R are defined as above.

Reduction of a compound of general formula 4., obtained according to the methods described above, is carried out by means of a boron or aluminium simple or complex hydride, for example lithium aluminium hydride, a diborane/ether complex or the diborane/methyl sulphide complex or any other equivalent means, in an inert Eiplvent such as diethyl ether or tetrahydrofuran.

The reduction may be carried out at room temperature or accelerated by heating to the reflux temperature of the solvent.

A compound of general formula 5. is thus obtained which corresponds to the general formula 1 when B represents a methylene.

The examples which follow illustrate the invention without, however, limiting its scope.

Elemental analyses and the IR and NMR spectra confirm the structure of the compounds obtained according to the invention. •g-ira-mpi e 1; 1- (1-Adamantanecarbonyl) -4- (1,4-.b°Ti3;.jdioxan-2-ylmethylaminomethyUpiperidine (Compound No 10; A = O, m = 1, B = CO, n= 0) .

Into a 250 ml round-bottomed flask over which is fitted a condenser are introduced 2.70 g (1.63 x 10~2 mol) of amine 2, (A = 0, m = 1) and 7.05 g (1.63 x 10"a mol) of tosylate 3_ (n = 0, R = 1-adamantyl, X = p-toluene-sulphonyloxy). The mixture is brought to 150°C for approximately 2 hours. This crude reaction product is subsequently dissolved in 50 ml of CHC1, and then treated with 50 ml of 10% NH40H and extracted. The aqueous phase is re-extracted with 50 ml of CHClj. The organic phases are combined and washed with 2 x 100 ml of -NaCl/HjO. After drying the organic phase over MgS04, filtration and purification by flash chromatography on silica gel 261331 (eluent: CEC13/CH30H = 90/10; Rf = 0.50) 2 .50 g (6.12 x 10"3 mol) of 1- (l-adamantanecarbonyl) -4-(1,4-benzodioxan-2-ylmethylaminome thy!) piperidine are recovered. To 1.00 g (2.35 x 10*1 mol) of this product dissolved in 30 ml of hot EtOH is added 0.27 g (2.33 x 10"3 mol) of fumaric acid. The solution is concentrated and the salt is precipitated by addition of EtOAc. After filtration, 2 washes with Et,0 and drying, 0.60 g of the hemifumarate of compound 10, is obtained in the form of a white powder. C3aH„N205 : 482.63 m.p. : 124 - 125°C IR (KBr) : 1623 cm"1 (CsO) *H NMR (CDClj) : 0.94-1.06 (m, CH3, 2H) ; 1.67-1.99 (m, CHj and CH, 18H) ; 2.51-2.87 (m, CH3, 6H) ; 3.93-4.37 (m, CH3 and CH, 5H); 4.50-6.50 (large s, OH and NH, 2H); 6.54 (a, -CH=, 1H); 6.83-6.85 (m, CH arom. , 4H) Elemental analysis :% Calc. C 69.68 H 7.94 N 5.80 % Pound C 68.23 H 8.10 N 5.68 % Water 1.38 % Cor. C 69.18 H 8.06 N 5.76 Example 2: l-Cyclohexylacetyl-4-(l,4-benzodioxan-2-ylmethylaminomethyl)piperidine (Compound No. 14: A = O, m = 1, B = CO, n = 1).

Into a 250 ml round-bottomed flask over which is fitted a condenser are introduced 4.06 g (2.46 x 10"a mol) of amine 2_ (A = O, m = 1) and 9.7 0 g (2.46 x 10"2 mol) of tosylate 3. (n = 1, R = cyclohexyl and X = p-toluene-sulphonyloxy). The mixture is brought to 180"C over approximately 12 hours. This crude reaction product is subsequently dissolved in 50 ml of CHC13 and then treated with 50 ml of 10% NH4OH and extracted. The organic phase is subsequently washed with 2 x 50 ml of 10% NH40H, then with 2 x 50 ml of NaCl/H20. After drying over MgS04, filtration and purification by flash chromatography on silica gel (eluent: CHClj/CHjOH = 90/10; Rf » 0.42) 3.40' g (8.80 x 10"s mol) of l-cyclohexylacetyl-4-(1,4-benzodi-oxan-2-ylmethylaminomethyl)piperidine are obtained. This product is dissolved in 10. ml of hot CH3OH. A methanolic 26133 solution of para- toluenesulphonic acid monohydrate (1.33 g; 7.00 x 10° mol) is added. The solution is concentrated and the salt is crystallized under cold conditions. After filtration, 2 washes with EtaO and drying, 3.20 g of the p-toluenesulphonate of compound 14 are obtained in the form of a white powder.

C,oH42N2OsS : 558.74 m.p.: 216 - 217°C IR (KBr) : 1634 cm-1 (C=0) XH NMR (CDClj) : 0.76-2.09 (m, CH3, 16H) ; 2.27 (s, CH3, 3H); 2.37-4.74 (m, CH3 and CH, 13H) ; 6.78 (s, CH arom., 4H); 7.08 (d, CH arom., = 8.1 Hz, 2H) ; 7.64 (d, CH arom., = 8.1 Hz, 2H) ; 8.90-9.45 (large s, OH and NH, 2H) Elemental analysis: % Calc. C 64.49 H 7.58 N 5.01 S 5.74 % Found C 64.71 H 7.62 N 5.12 S 5.84 "grrample 3 : 1- (2-Cyclohexylethyl) -4- (l,4-benzodioxan-2-ylmethylaminomethyl)piperidine (Compound No. 15,; A = O, m = 1, B = CHj, n = 1) .

This reaction is carried out under an inert atmosphere. Into a 100 ml three-necked flask is introduced 0.29 g (7.63 x 10° mol) of LiAlH4 in 10 ml of anhydrous THF. 1.97 g (5.10 x 10°) of compound 14. dissolved in 15 ml of anhydrous THF are added dropwise and at 0°C. After 48 hours at room temperature the mixture is treated with 50 ml of EtOAc and 50 ml of 2N NaOH. The organic phase is extracted and then washed with 2 x 50 ml of NaCl/HjO. After drying the organic phase over MgS04, filtration and purification by flash chromatography on silica gel (eluent: CHCl3/CH3OH/NH4OH = 90/9/1; Rf = 0.26) 0.41 g (1.10 x 10"3 mol) of 1-(2-cyclohexylethyl)-4-(1,4-benzodioxan-2-ylnethylaminomethyl)piperidine is recovered. To this product, dissolved in 10 ml of hot CH}OH, is added a methanolic solution of fumaric acid (0.20 g; 1.72 x 10'3 mol). The solution is concentrated and the salt precipitates in the cold after addition of EtOAc. After filtration, 2 washes with EtaO and drying 0.45 g of the difumarate of compound 15. is obtained in the form of a white powder. 26133 C31H44N2O10: 604.70 m.p.: 214 - 215°C XH NMR (CDClj) : 0.85-1.85 (m, CH3, 18H) ; 2.50-4.35 (m, CH2 and CH, 13H) ; 6.53 (s, -CH=, 4H) ; 6.79-6.89 (m, CH arom., 4H); 7.50-10.50 (large s, mobile H, 4H) Elemental analysis: % Calc. C 61.57 H 7.33 N 4.63 % Found C 61.91 H 7.26 N 4.73 •g-ira-mpl e 4: l-Cyclohexylacetyl-4- [ (3,4-dihydro-2 [H] -1-benzopyran-2-yl)me thy1aminome thy1]piperidine (Compound No. 18; A = CH-,, m = 1, B = CO, n = 1) .

Into a 250 ml round-bottomed flask over which is fitted a condenser are introduced 5.34 g (3.27 x 10~J mol) of amine 2. (A = CHa, m = 1) and 10.15 g (2.58 x 10"3 mol) of tosylate 3. (n = 1, R = cyclohexyl and X = p-toluene-sulphonyioxy). The mixture is brought to 170°C for approximately 3 hours. This crude reaction product is then dissolved in 100 ml of CH2C12 and then treated with 3 x 100 ml of 10% NH4OH. The organic phase is then washed with 2 x 100 ml of NaCl/HjO, dried over MgS04, filtered, concentrated and purified by flash chromatography on silica gel (eluent: CH^Clj/CHjOH/NH^OH = 9 0/9/1; Rf = 0.45) . 4.41 g (1.1 x 102 mol) of compound 18. are recovered. To 0.51 g (1.33 x 10"3 mol) of this product dissolved in a mini mini of hot CH30H is added 0.23 g (1.21 x 10"3 mol) of para-toluenesulphonic acid dissolved in CH30H. The solvent is partially evaporated. The salt precipitates under cold conditions after addition of isopropyl ether. After filtration, 2 washes with Et30 and drying 0.42 g (7.54 x 10'4 mol) of the para-toluene-sulphonte of compound 18 is obtained in the form of a white powder.

C31H44N305S: 556.77 m.p.: 160 - 162°C IR (KBr) : 1645 cm"1 (C=0) XH NMR (CDC13) : 0.85-1.37 (m, CH3, 7H) ; 1.54-2.15 (m, C^, 14H) ; 2.35 (s, CH3, 3H) ; 2.42-4.60 (m, CH2 and CH, 10H) ; 6.78-7.05 (m, CH arom. , 4H) ; 7.13 (d, = 8.0 Hz, CH arom., 2H) ; 7.71 (d, a 8.0 Hz, CH arom., 2H) ; 8.50 2613 3 (laxge s, mobile H, 2H) .

Elemental analysis: % Calc. C 66.87 H 7.96 N 5.03 S 5.76 % Found C 67.21 H 8.02 N 5.07 S 5.75 Kyarrmle 5: l-Cyclohexylacetyl-4- (1,4-benzoxathian-2-ylmethylaminomethyl) piperidine (Compound No. 20, A = S, m = 1, B - CO/ n = 1) - In a 250 ml round-bottomed flask over which is fitted a condenser are introduced 5.73 g (3.16 x 10a mol) of amine 2 (A = S, m = 1) and 9.3 g (2.3 6 x 10"J mol) of tosylate 3_ (n = 1, R = cyclohexyl and X = p-toluene-sulphonyloxy) . The mixture is brought to 180°C for approximately 3 hours u^This „crude reaction product is subsequently dissolved in 150 ml of CH3C13 and then treated with 3 x 100 ml of 10% NHAOH. The organic phase is then washed with 2 x 100 ml of NaCl/H30, dried over MgS04# filtered/ concentrated and purified by flash chromatography on silica gel (eluent: CH3Cl3/CH3OH/NH4OH = 90/9/1; Rf = 0.45). 3.04 g of compound 2_0 are recovered. To 0.96 g (2.33 x 10° mol) of this product dissolved in a minimum of hot CH30H is added 0.40 g (2.10 x 10° mol) of para-toluenesulphonic acid dissolved in CH3OH. The solvent is partially evaporated. The salt precipitates under cold conditions after addition of isopropyl ether. After filtration, 2 washes with EtsO and drying 1.10 g (1.91 x 10° mol) of the para-toluenesulphonate of compound 20 are obtained in the form of a white powder. C30H43N3O5S3: 574.81 m.p.: 149 - 151°C IR (KBr) : 1642 cm"1 (C=0) aH NMR (CDClj) : 0.45-1.36 (m, CH3, 8H) ; 1.68-2.23 (m, CH3, 12H); 2.36 (s, CH3, 3H); 2.77-4.83 (m, CH2 and CH, 9H) ; 6.84-7.06 (m, CH arom., 4H) ; 7.16 (d, Jm = 8.0 Hz, CH arom., 2H) ; 7.70 (d, = 8.0 Hz, CH arom., 2H) ; 9.04 (s, mobile H, 2H).

Elemental analysis: % Calc. C 62.69 H 7.3 6 N 4.87 S 11.16 % Found C 62.66 H 7.42 N 4.91 S 11.20 26133 SyaTrmie 6: l-Cyclohexylacetyl-4- [(2,3-dihydrobenzofuran-2-yl)methylaminomethyl] piperidine (Compound No. 24: A = CHa, m = 0, B = CO, n = 1) .

Into a 250 ml round-bottomed flask over which, is fitted a condenser are introduced 1-24 g (8.31 x 10"3 mol) of amine 2 (A = CH2, m = 0) and 3.26 g (8.28 x 10"3 mol) of tosylate 3. (n = 1, R = cyclohexyl and X = p-toluene-sulphonyloxy) . The mixture is dissolved in 10 ml of 1,2-dichloroethane and then brought to 90°-100°C for 5 hours. This crude reaction product is subsequently dissolved in 100 ml of CHjClj and then treated with 3 x 100 ml of 10% NH40H. The organic phase is then washed with 2 x 100 ml of NaCl/HjO, dried over MgS04,, filtered,'concentrated and purified by flash chromatography on silica gel (eluent: CHjCl2/CHjOH/NH^OH = 90/9/1; Rf = 0.35). 0.89 g (2.40 x 103 mol) of compound 24 is recovered. This product is dissolved in a minimum of hot CH30H and 0.41 g (2.15 x 10*3 mol) of para-toluenesulphonic acid dissolved in CH3OH is added. The solvent is partially evaporated. The salt precipitates under cold conditions after addition of isopropyl ether. After filtration, 2 washes with Et30 and drying 0.71 g (1.31 x 10"3 mol) of the para-toluene-sulphonate of compound 24 is obtained in the form of a white powder.

C30H43NaOsSj: 0.28 ^O: 547.7 8 m.p.: 158 - 160°C IR (XBr) : 1645 cm"1 (C=0) 3H NMR (CDClj) : 0.90-2.14 (m, CH2, 18H) ; 2.37 (s, CH3, 3H) ; 2.40-5.31 (m, CHa and CH, 9H) ; 6.77-6.91 (m, CH arom., 2H); 7.08-7.27 (m, CH arom., 4H); 7.19 (d, CH arom., Jffl = 8.06 Hz, 2H) ; 7.75 (d, CH arom., Jm = 8.06 Hz, 2H) ; 9.01 (large s, NH and OH, 2H).

Elemental analysis: % Calc. C 66.39 H 7.80 N 5.16 S 5.91 % Found C 65.75 H 7.84 N 5.12 S 5.99 % Water 0.93 % Cor. C 66.37 H 7.81 N 5.17 S 6.05 261331 T*Vil f 1 below summarizes the main products synthesized which illustrate the invention without, however, limiting its scope.

Table 1 Compound No.

A m B n R Salt MPt{°C) 1 0 1 CO 0 cyclopropyl p-toluene sulphonate 194-195 2 O 1 CH, 0 cyclopropyl difumarate 169-170 3 o 1 CO 0 cyclobutyl p-toluene sulphonate 153-155 4 0 1 CO 0 cyclopentyl p-toluenesulphonate 181-183 o 1 CH, 0 cyclopentyl di fumarate 202-204 6 • 0 1 CO 0 cyclohexyl p- toluenesulphonate 211-213 7 0 1 CH, 0 cyclohexyl difumarate 215-216 8 0 1 CO 0 cycloheptyl p-toluenesulphonate 220-222 9 0 1 CH, 0 cycloheptyl difumarate 195-197 0 1 CO 0 1-admnnntyl hemi fumarate 124-125 11 0 1 CH, 0 1-adnmnntyl difumarate 218-219 12 0 1 CO 1 cyclopentyl p-toluenesulphonate 194-196 13 0 1 CH, 1 cyclopentyl difumarate 186-188 14 0 1 CO 1 cyclohexyl p- toluenesulphonate 216-217 0 1 CH, 1 cyclohexyl difumarate 214-215 16 0 1 CO 1 1-adnmnntyl p-toluenesulphonate 246-248 17 0 1 CH, 1 1-adamantyl difumarate 218-220 18 CH, 1 CO 1 cyclohexyl p-toluenesulphonate 160-iSl ■ 19 CH, 1 CH, 1 cyclohexyl difumarate 224-226 s 1 CO 1 cyclohexyl p-toluenesulphona te 149-151 21 s 1 CH, 1 cyclohexyl difumarate 208-210 22 0 1 CO 0 3-noradnmnntyl p- toluene sulphonate 217-219 23 0 1 CH, 0 3-noradnjnnntyl difumarate 199-201 24 CH, 0 CO 1 cyclohexyl p-toluene sulphonate 158-160 The compounds of the invention were subjected to pharmacological tests which have demonstrated their value as substances having therapeutic activity.

They have thus been the subject of a study 5 bearing on their affinity for serotoninergic receptors of the 5-HT^ type.

Study of the binding to the 5-HTj^ receptor is carried out as described by Sleight and Peroutka, (Naunvn-Schneideberg Arch. Pharmacol.. 343, 106-116, 1991). Rat 10 cerebral cortex is used for these experiments. The brain 2613 3 is dissected and the cortex is homogenized in 20 volumes of TriB-HCl buffer (50 nH, pH 7.4 at 25°C) maintained at 4°C. The homogenate is centrifuged at 39,000 x g for 10 minutes and the centrifugation pellet is suspended in the 5 same volume of buffer and recentrifuged. After resuspension under the same conditions the homogenate is incubated for 10 minutes at 37°C and then recentrifuged. The final pellet is suspended in 80 volumes of reaction buffer containing: pargyline (10"s M) , CaClj (4 mM) and 10 < ascorbic acid (0.1%) in Tris-HCl (50 mM, pH 7.4 at 25°C). The final tissue concentration in the incubation medium is 10 mg/tube.

In the saturation experiments the reaction tubes contain 0.1 ml of various concentrations of [3H] 8-OH-DPAT 15 (between 0.06 and 8 nM) , 0.1 ml of reaction buffer or -HT (10"s M, in order to determine the nonspecific binding) and 0.8 ml of tissue.

The displacement experiments are carried out as described by Sleight and Peroutka (Naunvn-Schneiderbera 20 Arch. Pharmacol., 343, 106-116, 1991). All dilutions of the products to be studied are carried out in the reaction buffer. The reaction tubes contain 0.1 ml of [3H] 8-OH-DPAT (0.2 nM) , 0.1 ml of product to be tested in 6-7 concentrations (successive dilutions by 1/10) and 25 0.8 ml of tissue. If the presumed affinity of the products is situated in the nanomolar region the weakest concentration tested is 10*11 M, if the product has a weak presumed affinity the strongest concentration tested is lO"4 M. The reaction tubes are incubated at 23 °C for 3 0 3 0 minutes and then rapidly filtered under vacuum through Whatman 6F/B filters and the tubes are rinsed with 2 x 5 ml of Tris-HCl buffer (50 mM, pH 7.4 at 25°C). The radioactivity collected on the filter is analysed by liquid scintillation, by adding 4 ml of scintillation 35 liquid (Emulsifier Safe, Packard). All the experiments are carried out in triplicate and repeated at least" 3 times.

The dissociation constant (Kg) and the maximum number of binding sites (Bmax) for the radioligand are - 11 26133 estimated from saturation experiments using the EBDA/LIGAND nonlinear regression program (Biosoft) (Munson and Rodbard, Anal. Biochem., 107, 220-239, 1980) . The affinity constants (K±) of the reference products are estimated from displacement experiments using the EBDA/LIGAND nonlinear regression program. This method assumes that the value of the Hill coefficient is not different from unity. The data from the displacement experiments are respectively analysed with the one site and two site models, and the F calculated makes it possible to determine whether the two site model is more representative of the data obtained than the one site model. The pKi values are given in the form of an average ± SEM of 3 to 5 experiments.

By way of example, Table 2 gives the 5-HT^ pKi's for some derivatives of the invention, relative to Buspirone which is used clinically.

TahlAffinity for the 5-HT^ receptor — 25 Compound No. pKi 3 8.64 7 8.67 8 9.26 11 8.49 14 9.25 18 8.93 8.94 Buspirone 7.95 The test results show that the. compounds of 30 general formula 1 possess a high affinity for serotoninergic receptors of 5-HT^ type.

The central activity of the compounds of the invention was evaluated by their capacity to induce 5-HT syndrome, which is characterized by alternate flexion and 35 extension of the fore-paws (reciprocal fore-paw treading: 2613 FPT) , lower-lip retraction. (LLR) and by a posture in which the ventral surface of the animal is in contact with the floor of the cage, with the hindlegs extended (flat body posture: FBP).

The experiments for the evaluation of 5-HT syndrome are carried out in male rats (Sprague Dawley) according to the method described by F. C, Colpaert et al-, (Drug Dev. Res., 26. 21-48; 1992).

By way of example, Table 3 gives the effective 10 doses (EDS0) for some derivatives of the invention relative to a reference product, Buspirone.

Table 3: 5-ET Syndrome - 12 The test results show that the compounds of general formula 1 possess a high in vitro affinity for serotoninergic receptors of 5-HTu type. In vivo thev show an agonist activity with regard to these receptors. 25 The compounds, of the invention may therefore be useful for the treatment of anxiety, depression, sleeping disorders, for the regularization of the taking of food, for regulation of gastric secretion and for the treatment of vascular, cardiovascular and cerebrovascular disorders 30 such as hypertension or migraine.

The pharmaceutical preparations containing these active principles may be formulated for oral, rectal or parenteral administration, for example in the form of wafer capsules, tablets, granules, gelatin capsules, 35 solutions, syrups or drinkable suspensions, and may Compound No.

ED50 : mg/kg ip FBP LLR FPT 3 1.25 <0.63 2.5 4 0.31 0.31 0.63 6 0.31 0.31 0.63 12 0.31 <0.16 0.63 14 0.31 0.31 0.31 Buspirone .0 1.25 >40

Claims (20)

contain suitable excipients. It is also possible for other pharmaceutically and therapeutically acceptable active principles to be combined therewith. - 14 - 26 13 3 1 Claims

1. Heterocyclic derivatives of 4-aminomethyl- piperidine corresponding to the general formula 1: in which: A represents an oxygen atom, a sulphur atom or a methylene radical; m may take the values 0 or 1; B represents a carbonyl function (CO) or a methylene (CH3) ; n may take the values 0 or 1; R represents a C3-C10 monocyclic or polycyclic cyclo-alkyl radical, and their salts with therapeutically acceptable inorganic or organic acids and the racemic mixtures, as well as the various enantiomers of the compounds and their mixtures in all proportions.

2. Compounds of general formula 1 according to Claim 1, characterized in that they are chosen from: - l-Cyclopropanecarbonyl-4- (1, 4-benzodioxan-2-ylmethyl-aminomethyl) piperidine - l-Cyclopropylmethyl-4- (1,4-benzodioxan-2-ylmethylamino-methyl) piperidine - l-Cyclobutanecarbonyl-4-(1,4-benzodioxan-2-ylmethyl-aminomethyl) piperidine - l-Cyclopentanecarbonyl-4- (1,4-benzodioxan-2-ylmethyl-aminomethyl) piperidine - 1 -Cyc 1 opentylmethy 1 -4- (1,4-benzodioxan-2-ylmethylamino-methyl)piperidine - l-Cyclohexanecarbonyl-4-(1,4-benzodioxan-2-ylmethyl-aminomethyl) piperidine - l-Cyclohexylmethyl-4- (1,4-benzodioxan-2-ylmetiiylamino-methyl)piperidine - i-Cycloheptanecarbonyl-4- (1, 4-benzodioxan-2 -ylmethyl- 261331 ami nomethy1)piperidine - 1 -Cy c 1 oheptylmethy 1 - 4 - (1,4-benzodioxan-2-ylmethylamino-methyl} piperidine - 1- (1-Adamantanecarbonyl) -4- (1,4-benzodioxan-2-ylmethyl-ami nnmethyl)piperidine - 1- (1-Adamantylmethyl) -4-(1,4-benzodioxan-2-ylmethyl-aminomethyl) piperidine - l-Cyclopentylacetyl-4- (1,4-benzodioxan-2 -ylxse thy lamino-methyl) piperidine - 1-(2-tCyclopentylethyl)-4-(l/4-benzodioxan-2-ylmethyl-aminomethyl) piperidine - l-Cyclohexylacetyl-4- (1, 4-benzodioxan-2-ylmethylamino-methyl) piperidine - 1-(2-Cyclohexylethyl) -4- (1,4-benzodioxan-2-ylmethyl-aminomethyl)piperidine - 1- (1-Adamantylacetyl) -4- (1,4-benzodioxan-2-ylmethyl-ami nomethyl)piperidine - 1- [2- (l-Adamantyl) ethyl] -4- (1,4-benzodioxan-2-ylmethyl-aminomethyl)piperidine - l-Cyclohexylacetyl-4-[ (3,4-dihydro-2 [H]-l-benzopyran-2-yl) me thylaminome thyl] piperidine - 1-(2^Cyclohexylethyl) -4- [ (3 , 4-dihydro-2 [H]-1-benzc -pyran-2-yl)methylaminomethyl] piperidine - 1-Cyc1ohexylacetyl- 4 - (1,4-benzoxathian-2-ylme thyl-ami nomethyl)piperidine - 1- (2-Cyclohexylethyl) -4-(l,4-benzoxathian-2-ylmethyl-ami nomethyl)piperidine - 1-(3-Noradamantanecarbonyl)-4-(1,4-benzodioxan-2-ylme thylaminome thyl) piperidine - - 1- (3-Noradamantylmethyl)-4-(1,4-benzodibxan-2-yl-methylami nomethyl) piperidine - l-Cyclohexylacetyl-4- [ (2,3-dihydrobenzofuran-2-yl) -methyl aminomethyl]piperidine.

3. Process for the preparation of compounds accord ing to Claims 1 and 2 where B represents a carbonyl function, characterized in that am amine of general formula 2 is reacted with a compound of general formula 261331 16 - (frV^ where: N.Z. Pr~ ' 1 6 FEB &™ - A, xaff n and R are defined as above, I RECEIVED i —-T | - X represents a nucleofugal group, - the compounds of general formula 4 correspond to the compounds of general formula 1 when B represents a carbonyl function.

4. Process for the preparation of compounds according to claim 3 characterised in that X is methylsulphonyloxy, benzenesulphonyloxy or p-toluenesulphonyloxy.

5. Process for the preparation of compounds according to Claim 3, characterized in that the reaction of an amine of general formula 2 with a compound of general formula 3. is carried out either in the absence or in the presence of a solvent.

6. Process for the preparation of compounds according to claim 5 characterised in that the solvent is toluene, xylene, dimethylformamide or acetonitrile.

7. Process for the preparation of compounds according to claim 5 characterised in that the reaction is carried out at a temperature between SO and 200°C.

8. Process for the preparation of compounds according to claim 5 characterised in that the reaction is carried out in the presence of an organic base or an inorganic base.

9. Process for the preparation of compounds according to claim 8 characterised in that the organic base is a tertiary amine and the inorganic base is an alkali metal carbonate or hydrogen carbonate. 261331 - 17 -

10. Process for the preparation of compounds accord ing to Claims 1 and 2 where B represents a methylene, characterized in that a compound of general formula 4 is reduced according to the scheme: N.Z. PATENT OFF!CE 1 6 FEB 1936 where: RECEIVED - A, m, n and R are defined as above, ' - the compounds of general formula 5. correspond to the compounds of general formula 1. when B represents a methylene. I

ll Process for the preparation of compounds according to Claim 5, characterized in that the reduction of a compound of general formula 4 is carried out by means of a boron or aluminium simple or complex hydride, a diborane/ether complex or the diborane/methyl sulphide complex in an inert solvent at a temperature between room temperature and that of reflux of the solvent.

12. Process for the preparation of compounds according to claim 11 characterised in that the box*on or aluminium simple or complex hydride is lithium aluminium hydride.

13. Process for the preparation of compounds according to claim 11 characterised in that the inert solvent is diethyl ether or tetrahydrofuran.

14. The compounds defined according to either of Claims 1 and 2 as useful new medicaments. 261331 ~ 18 "

15. The compounds of claim 14 characterized in that the new medicaments are for the treatment of anxiety, depression, sleeping disorders, for regularization of the taking of food, for regularization of gastric secretion and for the treatment of vascular, cardiovascular and cerebrovascular disorders.

16. The compounds of claim 15 characterized in that the cerebrovascular disorders are hypertension or migraane.

17. Pharmaceutical composition characterized in that it contains a compound defined according to either of Claims 1 and 2. I

18. Heterocyclic derivatives of 4-aminomethyl-piperidine of claim 1 as specifically set forth herein.

19. The process of any one of claims 3 to 13 substantially as herein described with reference to the Examples.

20. A pharmaceutical composition of claim 17 substantially as herein described.