WO1994020466A1

WO1994020466A1 - Novel 2-phenoxy ethylamine derivatives, their preparation and their therapeutical use

Info

Publication number: WO1994020466A1
Application number: PCT/FR1994/000202
Authority: WO
Inventors: Bernard Bonnaud; Florence Castan; Dennis Bigg; Wouter Koek
Original assignee: Pierre Fabre Medicament
Priority date: 1993-03-04
Filing date: 1994-02-24
Publication date: 1994-09-15
Also published as: EP0687252A1; JPH08507302A; CA2152400A1; FR2702211A1; FR2702211B1; ZA941532B; AU6143594A

Abstract

2-phenoxy ethylamine derivatives of general formula (1) and therapeutically acceptable salts of such molecules are disclosed. The therapeutic use of the compounds of general formula (1) and methods for preparing same are also disclosed.

Description

New derivatives of 2-phenoxyethylamine, their preparation and their therapeutic use.

The _5-HT] ^ ^a subtypes of serotoninergic receptor, play an important physiological role. Also, as the various chapters of the book "Brain 5-HTJA Receptors: Behavioral and Neurochemical Pharmacology" show (Editors CT Dourish, S. Ahlenius, PH Hutson; Ellis Horwood Ltd., Chichester, 1987) 5-HTj ^ may be useful for the treatment of anxiety, depression, sleep disturbances, vascular and cardiovascular disorders, and the regulation of food intake. The 5-HTJ receptors also play a role in the regulation of gastric secretion (JS Gidda, JM Schaus, EP. 455.510 A2, 1991). The present invention, carried out at the Pierre Fabre Research Center, relates to new chemical compounds which show a high affinity for the 5-HTIA receptors, their preparation and their therapeutic application.

The compounds of the invention correspond to general formula 1:

or

- X represents one or more substituents chosen from a halogen atom, a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 alkoxy group:

- A represents a carbonyl function (CO), or a methylene:

- n can take the values of 0 or 1:

- R represents a C3-C10 cycloalkyl, monocyclic or polycyclic radical _. or a phenyl group substituted or not by one or more substituents chosen from a halogen atom, a C-- -C4 alkyl group, or a C1-C4 alkoxy group.

The invention also relates to the salts of the compounds of general formula 1 with pharmaceutically acceptable mineral or organic acids. The acid used can be, by way of nonlimiting example, hydrochloric acid, maleic acid, fumaric acid, or p-toluenesulfonic acid.

RECTIFIED SHEET (RULE 91) ISA / EP The present invention relates more particularly to the compounds of general formula 1, chosen from: Benzoyl-1 (2-phenoxy-ethylaminomethyl) -4 piperidine Benzyl-1 (2-phenoxy-ethylaminomethyl) -4 piperidine (3-methyl benzoyl) - 1 (phenoxy -2 ethylaminomethyl) -4 piperidine (3-methyl benzyl) -l (2-phenoxy ethylaminomethyl) -4 piperidine (3-methoxy benzoyl) - 1 (2-phenoxy ethylaminomethyl) -4 piperidine (3-methoxy benzyl) -l ( 2-phenoxyethylaminomethyl) -4 piperidine (3-Chloro benzoyl) - 1 (2-phenoxy ethylaminomethyl) -4 piperidine (3-Chloro benzyl) -l (2-phenoxy ethylaminomethyl) -4 piperidine Benzoyl- 1 [(2-methyl phenoxy) -2 ethylaminomethyl] -4 piperidine Benzyl-1 [(2-methyl phenoxy) -2 ethylaminomethyl] -4 piperidine Benzoyl- 1 [(3-fluoro phenoxy) -2 ethylaminomethyl] -4 piperidine Benzyl-1 [(fluoro- 3 phenoxy) -2 ethylaminomethyl] -4 piperidine Benzoyl- 1 [(4-chloro phenoxy) -2 ethylaminomethyl] -4 piperidine Benzyl-1 [(4-chloro phenoxy) -2 ethylaminomethyl] -4 piperidine Benzoyl- 1 [(2,6-dimethoxy phenoxy) -2 ethylaminomethyl] -4 piperidine Benzyl-1 [(2,6-dimethoxy phenoxy) -2 ethylaminomethylj-4 piperidine

(3-methyl benzoyl) - 1 [(2-methoxy phenoxy) -2 ethylaminomethyl] -4 piperidine (3-methyl benzyl) -l [(2-methoxy phenoxy) -2 ethylaminomethyl] -4 piperidine Cyclopentanecarbonyl-1 (phenoxy- 2 ethylaminomethyl) -4 piperidine Cyclopentylmethyl-1 (phenoxy-2 ethylaminomethyl) -4 piperidine Cycloheptanecarbonyl-1 (phenoxy-2 ethylaminomethyl) -4 piperidine Cycloheptylmethyl-1 (phenoxy-2 ethylaminomethyl) -4 piperidine (l-Adamantanecarbon 2-phenoxyethylaminomethyl) -4 piperidine (4-fluoro phenylacetyl) -l (2-phenoxyethylaminomethyl) -4 piperidine [(4-fluoro phenyl) - 2 ethyl] -l (2-phenoxy ethylaminomethyl) -4 piperidine Cyclohexylacetyl-1 (2-phenoxyethylaminomethyl) -4 piperidine

(Cyclohexyl- 2 ethyl) -l (2-phenoxyethylaminomethyl) -4 piperidine

The compounds of general formula i where A represents a carbonyl radical can be prepared according to the reaction scheme:

OR

SHEET OF E AP Âctf ^ NT (RULE 26) - X, n, and R are defined as above:

- Y represents a nucleofuge group such as methylsulfonyloxy, benzenesulfonyloxy, or p-toluenesulfonyloxy.

The starting amines 2 and the piperidines of formula 3 can be obtained according to conventional methods. The reaction between a compound of general formula 2 and a compound of general formula 3 is carried out either in the absence or in the presence of a solvent such as toluene, xylene, dimethylformamide, or acetonitrile, of preferably at a temperature between 50 ° C and 200 ° C, and optionally in the presence of an organic base such as a tertiary or mineral amine, such as an alkali carbonate or hydrogen carbonate. A compound of general formula 4 is thus obtained which corresponds to general formula 1 when A represents a carbonyl function.

The compounds of general formula X where A represents a methylene can be prepared according to the reaction scheme:

or - X, n and R are defined as above.

The reduction of a compound of general formula 4, obtained according to the methods described above, is carried out by means of a simple or complex hydride of boron or aluminum, for example, the double hydride of lithium and d aluminum, a diborane-ether complex, or the diborane-methyl sulfide complex, or any other equivalent means, in an inert solvent such as ethyl ether or tetrahydrofuran.

The reduction can 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 i when A represents methylene.

The following examples illustrate the invention without, however, limiting its scope. The centesimal analyzes as well as the IR and NMR spectra confirm the structure of the products obtained.

LOCATION SHEET (RULE 26) Example 1: (3-Methoxy benzoyl) - 1 (2-phenoxy-ethylaminomethyl) -4 piperidine (compound no. 5: X = H, A = CO, n = 0, R = 3-CH ₃ OC ₆ H ₄ ) A mixture of 3.9 g (9.66.10 "- * mole) of (3-methoxy benzoyl) -l (4-methyl benzenesulfonyloxymethyl) -4 piperidine and 1.35 g (9.84.10" - * mole) of phenoxy -2 ethylamine is maintained at 145 ° C - 5 with stirring for 3 hours. After returning to room temperature, the reaction crude obtained is taken up in chloroform (75 cm- *) and the solution is washed with 100 cm- * of 10% ammonia. The aqueous phase is reextracted with 50 cm 3 of chloroform and the combined organic phases are washed with water, dried over a2Sθ4, filtered and brought to dryness under vacuum. Recovering after purification by flash chromatography on silica gel (eluent: chloroform - methanol 95: 5) 1.8 g of (3-methoxy benzoyl) - 1 (2-phenoxy-ethylaminomethyl) -4 piperidine. To 0.6 g (1.63.10 "- * mole) of this product in solution in 3 cm- * of ethanol, 0J 8 g (1.55.10" - * mole) of maleic acid is added. The solution obtained is concentrated and the salt is crystallized by progressive addition of ethyl ether. After recrystallization from ethanol - ethyl acetate, 0.51 g of maleate of compound no. 5 in the form of white crystals.

C26H32N2O7: 484.56

Mp: 85-87 ° C

IR (KBr): 1582 and 1623 cm " ¹ (C = O)

1 H NMR (D ₂ O): 1.18-1.44 (m, 2H); 1.74 (d, 1H); 1.95 (d, 1H); 2.14 (m, 1H); 2.87-3.20 (m, 4H); 3.51 (t, 2H); 3.73 (d, 1H); 3.83 (s, 3H); 4.32 (t, 2H); 4.51 (d, 1H); 6.26 (s, 2H); 6.97-7.13 (m, 6H); 7.34-7.47 (m, 3H).

Elementary analysis:% Cale. C 64.45 H 6.66 N 5.78

% Tr. C 63, 93 H 6.60 N 5.73

Example 2: (3-Methoxy benzyl) -1 (2-phenoxyethylaminomethyI) -4 piperidine. (Compound no. 6: X = H, A = CH2, n = 0, R = 3-CH ₃ O C6H4)

A solution of 1.15 g (3.12.10 "- * mole) of (3-methoxy-benzoyl) - 1 (2-phenoxy-ethylaminomethyl) -4 piperidine obtained according to the method described in Example 1 is added dropwise. , in 6 cm- * of tetrahydrofuran to a suspension of 0.18 g (4.74.10 "- * mole) of LiAlH4 in 10 cm- * of tetrahydrofuran with stirring, under nitrogen and cooling with an ice bath. After 16 hours of stirring at room temperature, the reaction mixture is hydrolyzed by addition of 2N sodium hydroxide. The suspension is filtered, the solvent is removed under vacuum and the aqueous phase is extracted with ethyl acetate. The extracts are washed with salt water, dried (Na2Sθ4) and filtered.

The oil obtained by evaporation of the solvent under vacuum is purified by flash chromatography on silica gel using chloroform containing 15% methanol as the eluting phase. 0.43 g of (3-methoxy-benzyl) -1 (2-phenoxyethylaminomethyl) -4 piperidine is obtained in the form of a pale yellow oil. To 0.4 g (1J3J0 "- * mole) of this product in solution in 3 cm- * of ethanol, 0.23 g (1.98J0" - * mole) is added

SUBSTITUTE SHEET (RULE 26) maleic acid. The solution obtained is concentrated and the salt crystallizes by progressive addition of ethyl ether. After recrystallization from isopropanol, 0.435 g of dimaleate of compound no.6 is obtained in the form of white crystals.

3H); 2.97 (m, 4H); 3.33 (m, 4H); 3.78 (s, 3H); (s, 2H); 6.97-7.05 (m, 6H); 7.30-7.42 (m, 3H);

Elementary analysis:% Cale. C 61.42 H 6.53 N 4.78

% Tr. C 61.23 H 6.48 N 4.80

Example 3: Cyclohexylacetyl-1 (2-phenoxyethylaminomethyl) -4 piperidine (Compound no. 26: X = H, A = CO, n ≈ 1, R = C ₆ H!)

A mixture of 6.30 g (1.60J0 ^-2 mole) of cyclohexylacetyl-1 (4-methyl benzenesulfonyloxymethyl) -4 piperidine and 2J7 g (1.58J0 " ² mole) of 2-phenoxyethylamine is maintained at 130 ° - 140 ° C. for 3 hours After returning to ambient temperature, the crude reaction product obtained is taken up in dichloromethane (100 cm ³ ) and the solution is washed with 100 cm- * of 10% ammonia The organic phase is washed with a saturated aqueous solution of NaCl, dried over MgSθ4, filtered and brought to dry The oil thus obtained is purified by flash chromatography on silica gel (eluent: dichloromethane / methanol / 32% ammonia = 90/8/2). 1.71 g (4.77 × 10 ⁻³ mol) of cyclohexylacetyl-1 (2-phenoxyethylaminomethyl) -4 piperidine are recovered. To 0.58 g (1.63% " ³ mol) of this product in solution in 5 cm 3 of methanol, 0.77 g (1.46% ³ mol) of maleic acid added in solution in 3 ml of methanol is added. The solution is concentrated and the salt is crystallized by progressive addition of isopropyl ether. After recrystallization from methanol, filtration, washing with ether and drying in an oven, 0.58 g (1.22% - * mol) of maleate of compound No. 26 is obtained in the form of white crystals.

C26H38N2O6 MP: 139-140 ° C

IR (KBr): 1653 cm " ¹ (C = O)

1 H NMR (CD ₃ OD): δ 0.98-1.33 (m, 7H); 1.70-2.07 (m, 9H); 2.28 (d, 2H); 2.64 (m, 2H); 3.04 (m, 2H); 3.12 (m, 1H); 3.49 (t, 2H); 4.05 (d, 1H); 4.30 (t, 2H); 4.59 (d, 1H); 6.25 (s, 2H); 6.96-7.03 (m, 3H); 7.28-7.36 (m, 2H).

Elementary analysis:% Cale. C 65.80 H 8.07 N 5.90

% Tr. C 65.72 H 8.03 N 5.88

Example 4: (2-Cyclohexyl ethyl) -1 (2-phenoxyethylaminomethyl) -4 piperidine (Compound no. 27, X = H, A = CH ₂ , n = 1, R = C ₆ H! J).

REF SHEET /. PLACENT (RULE 26) A solution of 1J2 g (3J2J0 " ³ mole) of cyclohexylacetyl-1 (2-phenoxy-2 ethylaminomethyl) -4 piperidine obtained according to the method described in Example 3 in 15 cm ³ of tetrahydrofuran is added dropwise. 0.20 g (5.26.10 ^" ³ mole) of LiAlH4 in 10 cm ³ of tetrahydrofuran, with stirring, under nitrogen and cooling with an ice bath. After 48 hours of stirring, at room temperature, the reaction mixture is hydrolyzed by the addition of 20 cm ³ of ethyl acetate, then with a 2N aqueous sodium hydroxide solution.

The suspension is filtered, the solvent is removed under vacuum and the aqueous phase is extracted with ethyl acetate. The extracts are washed with salt water, dried over MgSO4 and filtered. The oil obtained by evaporation of the solvent under vacuum is purified by flash chromatography on silica gel (eluent: dichloromethane / methanol = 90/10). 0.39 g (1.13 × 10 ⁻³ mole) of (cyclohexyl-2-ethyl) -1 (2-phenoxyethylaminomethyl) -4 piperidine is recovered. 0.38 g of this product (1.10 × 10 mole) ) in solution in 5 ml of methanol, 0.23 g (2J0 ~ ³ mole) of maleic acid is added in solution in 5 ml of methanol. The solution is concentrated and the salt precipitates by addition of ethyl ether. After filtration and drying in an oven, 0.48 g (8.32.10 "mol) of dimaleate of compound No. 27 is obtained in the form of white crystals. C30H44N2O9 MP: 189 - 191 ° C

^Ï NMR (CD3OD): δ 0.97 to 2.15 (m, 14H); 3.01-4.90 (m, 16H); 6.25 (s, 4H); 6.95- 7.02 (m, 3H); 7.27-7.35 (m, 2H). Elementary analysis:% Cale. C 62.48 H 7.69 N 4.86

% Tr. C 62.67 H 7.75 N 4.85

Table 1 below summarizes the main synthesized products.

Table 1

Compound X A n R Salt PF (° C) no.

1 H CO 0 phenyl hemifumarate 172-174

2 H CH ₂ 0 phenyl difumarate 160-162

3 H CO 0 3-methylphenyl hydrochloride 184-186

4 H CH ₂ 0 3-methylphenyl dihydrochloride> 260

5 H CO 0 3-methoxyphenyl maleate 85-87

6 H CH ₂ 0 3-methoxyphenyl dimaleate 190-192

7 H CO 0 3-chloro-phenyl maleate 175-177

8 H CH ₂ 0 3-chloro-phenyl dimaleate 178-180

9 2-CH ₃ CO 0 phenyl fumarate 153-155

10 2-CH3 CH ₂ 0 phenyl difumarate 170-172

11 3-F CO 0 phenyl fumarate 165-167

12 3-F CH ₂ 0 phenyl dimaleate 139-141

13 4-C1 CO 0 phenyl maleate 156-158

14 4-C1 CH ₂ 0 phenyl dimaleate 194-196

15 2.6 di.CH ₃ 0 CO 0 phenyl fumarate 176-178

16 2.6 di.CR.3O CH ₂ 0 phenyl dimaleate 169-171

17 2-CH3O CO 0 3-methylphenyl maleate 140-142

18 2-CH3O CH ₂ 0 3-methylphenyl dimaleate 178-180

19 H CO 0 cyclopentyle fumarate 143-145

20 H CH ₂ 0 cyclopentyle difumarate 182-184

21 H CO 0 cycloheptyle fumarate 153-155

22 H CH ₂ 0 cycloheptyle difumarate 205-207

23 H CO 0 1-adamantyle maleate 149-151

24 H CO 1 fluoro-4 phenyle fumarate 190-192

25 H CH ₂ 1 fluoro-4 phenyl difumarate 181-183

26 H CO 1 cyclohexyl maleate 139-140

27:00 CH _? 1 cyclohexyl dimaleate 189-191

The compounds of the invention have been subjected to pharmacological tests which have demonstrated their interest as substances with therapeutic activity.

Thus, they were the subject of a study on their affinity for serotonergic receptors of the 5-HTJA type *

The study of the binding to the 5-HTJA receptor is carried out as described by Sleight and Peroutka (Nauyn-Schmiedeberg Arch. Pharmacol .. 343. 106-116, 1991). For these experiments, rat cerebral cortices are used. The brain is dissected and the cortex is homogenized in 20 volumes of Tris-HCl buffer (50 mM, pH 7, 4 at 25 ° C) maintained at 4 ° C. The homogenate is centrifuged at 39,000 xg for 10 minutes, the centrifuge pellet is suspended in the same volume of buffer and centrifuged again. After resuspension under the same conditions, the homogenate is incubated for 10 minutes at 37 ° C and then centrifuged again. The final pellet is suspended in 80 volumes of reaction buffer containing: pargyline (10 ^"5 M), CaCl (4 mM) and ascorbic acid (0.1%) in Tris-HCl (50

SUBSTITUTE SHEET (RULE 26) M, 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 0J ml of different concentrations of [ ³ H] 8-OH-DPAT (between 0.06 and 8 nM), 0J ml of reaction buffer or 5-HT (ÎO ^" - ^{* 5} M, to determine non-specific binding) and 0.8 ml of tissue.

The displacement experiments are carried out as described by Sleight and Peroutka fNauvn-Schmiedebere Arch. Pharmaco 343. 106-116, 1991). All the dilutions of the products to be studied are made in the reaction buffer. The reaction tubes contain 0J ml of [ ³ H] 8-OH-DPAT (0.2 nM), 0J ml of product to be tested 6-7 concentrations (successive dilutions to 1/10) and 0.8 ml of tissue. If the alleged affinity of the products is in the nanomolar range, the lowest concentration tested is 10 ^" * M, if the product has a presumed low affinity, the highest concentration tested is ÎO ^" ^ M. The reaction tubes are incubated at 23 ° C for 30 minutes then quickly filtered under vacuum on Whatman GF / B filters, 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 analyzed in liquid scintillation by adding 4 ml of scintillating liquid (Emulsifier Safe, Packard). All the experiments are carried out in triplicate and repeated at least 3 times.

The dissociation constant (K - ₎ ) and the maximum number of binding sites (Bmax) for the radioligand are estimated from the saturation experiments using the non-linear regression program EBDA / LIGAND (Biosoft) (Munson and Rodbard , Anal. Biochem. 107, 220-239, 1980). The affinity constants (Ki) of the reference products are estimated from the displacement experiments using the non-linear regression program EBDA / LIGAND. This method admits that the value of the Hill coefficient is not different from unity. The data from the displacement experiences are analyzed with the one site and two site models, respectively, and the calculated F 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 as an average of 3 to 5 experiments.

Table 2 gives, by way of example,

certain derivatives of the invention, compared to Buspirone which is used in cn that.

Table 2: affinity for the 5-HTJA receptor

Compound no. pki

3 8.97

4 8.47

17 9.37

18 9.50

19 8.53

Buspirone 7.95

SUBSTITUTE SHEET (RULE 26) The results of the tests show that the compounds of the invention have a high affinity for serotonergic receptors of the 5-HTJA type. Also, the compounds of the invention can be useful for the treatment of anxiety, depression, disorders. sleep, for the regulation of food intake, for the regulation of gastric secretion, and for the treatment of vascular, cardiovascular and cerebrovascular disorders such as hypertention or migraine. Pharmaceutical preparations containing these active ingredients can be shaped for oral, rectal or parenteral administration, for example in the form of capsules, tablets, granules, capsules, liquid solutions, syrups or oral suspensions, and contain the suitable excipients. It is also possible to combine it with other active pharmaceutical and therapeutically acceptable ingredients.

LOCATION SHEET (TEGLE 26)

Claims

1) 2-Phenoxyethylamine derivatives corresponding to the general formula i:

or - X represents one or more substituents chosen from a halogen atom, a hydrogen atom, a C1-C4 alkyl group, or a C1-C4 alkoxy group:

- A represents a carbonyl function (CO), or a methylene: - n can take the values of 0 and 1:

- R represents a cycloalkyl, monocyclic or polycyclic radical in C ₃ -Cιo _> or a phenyl group substituted or not by one or more substituents chosen from a halogen atom, a C1-C4 alkyl group, or a C1 alkoxy group -C4: as well as their salts with therapeutically acceptable mineral or organic acids.

2) Compounds of general formula i, according to claim 1, characterized in that they are chosen from:

Benzoyl- 1 (2-phenoxyethylaminomethyl) -4 piperidine

Benzyl-1 (2-phenoxyethylaminomethyl) -4 piperidine

(3-methylbenzoyl) - 1 (2-phenoxyethylaminomethyl) -4 piperidine (3-methylbenzyl) -l (2-phenoxyethylaminomethyl) -4 piperidine

(3-methoxy benzoyl) - 1 (2-phenoxyethylaminomethyl) -4 piperidine (3-methoxy benzyl) -l (2-phenoxy ethylaminomethyl) -4 piperidine (3-chloro benzoyl) - 1 (2-phenoxyethylaminomethyl) -4 piperidine (3-Chloro benzyl) -l (2-phenoxy-ethylaminomethyl) -4 piperidine Benzoyl- 1 [(2-methylphenoxy) -2 ethylaminomethyl] -4 piperidine Benzyl-1 [(2-methylphenoxy) -2 ethylaminomethyl] - 4 piperidine Benzoyl- 1 [(3-fluoro-phenoxy) -2 ethylaminomethyl] -4 piperidine Benzyl-1 [(3-fluoro-phenoxy) -2 ethylaminomethyl] -4 piperidine Benzoyl- 1 [(4-chloro-phenoxy) -2 ethylaminomethyl] -4 piperidine

RECTIFIED SHEET (RULE 91) tSΛ / EP Benzyl-1 [(4-chloro-phenoxy) -2 ethylaminomethyl] -4 piperidine Benzoyl- 1 [(2,6-dimethoxy phenoxy) -2 ethylaminomethyl] -4 piperidine Benzyl-1 [(2,6-dimethoxy phenoxy) -2 ethylaminomethyl] -4 piperidine (3-methyl-benzoyl) - 1 [(2-methoxy-phenoxy) -2 ethylaminomethyl] -4 piperidine (3-methyl-benzyl) -l [(2-methoxy-phenoxy) -2 ethylaminomethyl] -4 piperidine Cyclopentanecarbonyl-1 (phenoxy -2 ethylaminomethyl) -4 piperidine Cyclopentylmethyl-1 (phenoxy-2 ethylaminomethyl) -4 piperidine Cycloheptanecarbonyl-1 (phenoxy-2 ethylaminomethyl) -4 piperidine Cycloheptylmethyl-1 (phenoxy-2 ethylaminomethyl) -4 piperidine (l-Adamantanecarbon) (2-phenoxyethylaminomethyl) -4 piperidine (4-fluoro phenylacetyl) -l (2-phenoxy ethylaminomethyl) -4 piperidine [(4-fluoro phenyl) - 2 ethylj-1 (2-phenoxy ethylaminomethyl) -4 piperidine Cyclohexylacetyl-1 (2-phenoxyethylaminomethyl) -4 piperidine (2-cyclohexyl-ethyl) -l (2-phenoxyethylaminomethyl) -4 piped ridicule

3) Process for the preparation of compounds according to claims 1 and 2, where A represents a carbonyl function, characterized in that an amine of general formula 2 is reacted with a compound of general formula 3 according to the scheme:

or - X, n and R are defined as above:

- Y represents a nucleofuge group such as methylsulfonyloxy, benzenesulfonyloxy, or p-toluenesulfonyloxy: - the compounds of general formula 4_ correspond to the compounds of general formula i when A represents a carbonyl function.

4) 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 such as toluene, xylene, dimethylformamide or acetonitrile, preferably at a temperature between 50 and 200 ° C, and optionally in the presence of an organic base such as a tertiary or mineral amine, such as an alkali carbonate or hydrogen carbonate.

SHEET OF P _v PLACE ÏHT (RULE 26) 5) Process for the preparation of compounds according to Claims 1 and 2, where A represents a methylene, characterized in that a compound of general formula 4 is reduced according to the scheme:

or

• X, n and R are defined as above:

the compounds of general formula 5 correspond to the compounds of general formula i when A represents a methylene.

6) 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 simple or complex hydride of boron or aluminum, for example, double lithium aluminum hydride, a diborane / ether complex or the diborane / methyl sulfide complex, or any other equivalent means, in an inert solvent such as ethyl ether or tetrahydrofuran at a temperature between the ambient temperature and that of reflux of the solvent. 7) As new drugs, the compounds defined according to one of claims 1 and 2.

8) Medicines according to claim 7, useful in particular for the treatment of anxiety, depression, sleep disorders, for the regulation of food intake, for the regulation of gastric secretion, and for the treatment of vascular, cardiovascular disorders such as hypertension or migraine.

9) Pharmaceutical composition characterized in that it contains a compound defined according to one of claims 1 and 2.

SUBSTITUTE SHEET (RULE 26)