MXPA99010525A - 4-[(aryl)(aryloxy)methyl]piperidine derivatives and their use as serotonin and/or noradrenaline reuptake inhibitors - Google Patents

Abstract

New 4-substituted piperidines of general formula (I) are describedáááin which groups R1 and R2 are non-substituted aryl radicals or aryl radicals mono- or poly-substituted with halogen (fluorine, chlorine, bromine, iodine), alkyl, alkoxy, cyano, trifluoromethoxy, trifluoromethyl, benzoyl, phenyl, nitro, amino, aminoalkyl, aminoaryl and carbonylamino. These compounds, and their pharmaceutically acceptable salts, inhibit serotonin and/or noradrenaline reuptake, and are useful as antidepressants. Other potential therapeutic applications of these compounds are treatment of nervous bulimia, obsessive-compulsive disorders, alcohol addiction, anxiety, panic, pain, pre-menstrual syndrome and social phobia, as well as migraine prophylaxis.

Description

New 4-substituted piperidines Introduction In recent years, selective serotonin reuptake inhibitors (SSRIs) have been introduced in the treatment of depression and other disorders of the central nervous system, including fluoxetine, citalopram, sertraline and paroxetine. All of them present different chemical structures, which helps explain their different metabolic and pharmacokinetic profiles. Their behavior as antidepressants is comparable to that of the classic tricyclic compounds but they have the advantage of being safer and better tolerated. The present invention relates to a series of new 4-substituted piperidines which possess the aryloxy functionality and which potently inhibit the reuptake of serotonin and / or noradrenaline, a consequence of their high affinity for the neuronal transporters thereof. This characteristic confers them a high antidepressant potential in human therapy. Other possible therapeutic applications of these compounds are the treatment of bulimia nervosa, alcohol addiction, anxiety, obsessive-compulsive disorders, panic, pain, premenstrual syndrome and social phobia, as well as the prophylaxis of migraine . Other derivatives of piperidine with aryloxy functionality are also described as potential antidepressants, although they are essentially different in nature from those claimed herein since piperidine is substituted in position 3. Thus, for example, compounds 3 - [( 2-methoxyphenoxy) phenyl] methyl-piperidine I (Melloni, P., Carniel, G., Della Torre, A., Bonsignari, A., Buonamici, M., Pozzi, O., Ricciardi, S., Rossi, AC Eur. J. Med. Chem. Chim. Ther. 1984, 3, 235-242; Melloni, P., Della Torre, A., De Munari, S., Meroni, M., Tonani, R. Gazzetta Chimica Italiana 1985 , 115, 159-163) and 3 - [(phenoxy) phenyl] methyl-piperidine 2 (FR 2,010,615 CA73; 66442J; GB 1,203,149 CA73: 120509b). In these compounds the replacement of the piperidine ring at position 3 gives rise to an additional chiral center. The presence of the two chiral centers causes diastereomeric mixtures, a form in which the preparation of these has been described compounds In no case is the preparation and / or isolation of the pure enantiomers described. In contrast, the compounds claimed herein possess a single chiral center since they have the piperidine ring substituted in position 4. They have been prepared as racemic mixtures and as pure enantiomers, following synthetic methods different from those used in the preparation of 1 and 2. On the other hand, other piperidine derivatives having aryloxy functionality and the piperidine ring substituted at position 4 (formulas 3 and 4) are also described as potential antidepressants. Thus, in the case of type 3 compounds (JP 96 40,999 CAÍ 24: 343333n), the aryloxy group is directly linked to the piperidine ring while in the type 4 compounds (JP 9640999 CA124: 343333n) said group is attached to the piperidine ring through a methylene group that has no further substitutions. The compounds described in the present invention differ greatly from them in that they have the aryloxy group attached to the piperidine ring through a methylene group where, in all cases, one of the hydrogens of the methylene group is substituted by an aryl group, substituted or not, as will be defined below. This means that these compounds are structurally different from type 3 and 4 and that the synthetic methodology used in their preparation is also radically different. Description The novel 4-substituted piperidines described in the present invention are represented by the general formula (I), wherein the groups R j and R 2 are unsubstituted aryl radicals or aryl radicals mono or poly-substituted with halogen (fluorine, chlorine, bromine, iodo), alkyl, alkoxy, cyano, trifluoromethoxyl trifluoromethyl-benzoyl, phenyl-nitro, amino, aminoalkyl, aminoaryl and carbonylamino.

(I) The compounds of general formula (I) have an asymmetric center and have been prepared as racemic mixtures and as pure enantiomers. The present invention includes all optical isomers of the compounds of general formula (I) and racemic mixtures thereof. Also included in the present invention are the pharmaceutically acceptable salts of these compounds with inorganic acids (for example: hydrochloric, hydrobromic, nitric, sulfuric and phosphoric) as well as with organic acids (for example: acetic, fumaric, tartaric, oxalic, citric, / 7-toluenesulfonic and methanesulfonic). The racemic compounds of general formula (I) were prepared following well-known synthetic methods from the compounds of general formula (II). The formation of the alkylaryl ether group was carried out using the Mitsunobu reaction (Mitsunobu, O. Synthesis 1981, 1; Hughes, D. L. Organic Rea'ctions 42, 335) with the phenols R2-OH where R2 is an aryl radical substituted or not as described for the general formula (I), and the compounds of the general formula (H) where R, is an aryl radical substituted or not as described for the general formula (I) and R3 is hydrogen or R4 which is an alkoxycarbonyl radical preferably ethoxycarbonyl and t-butoxycarbonyl.

(II) The alkylaryl ether group was also prepared using an aromatic nucleophilic substitution reaction (Berglund, RA Org Proc. Res. Dev. 1997, 1, 328-330) with the compounds of general formula (II) defined above, and the derivatives fluorinated R2-F wherein R2 is a mono or poly substituted aryl radical with halogen (fluorine, chlorine, bromine, iodine), alkyl, alkoxy, cyano, trifluoromethoxy, trifluoromethyl, benzoyl, phenyl, nitro, amino, aminoalkyl, aminoaryl and carbonylamino. The compounds of general formula (H) were prepared, following conventional synthetic methods, from the compounds of general formula (III) (Duncan, RL, Helsley, G. C, Welstead, WJ, DaVanzo, JP, Funderburk, W. EL, Lunsford, CDJ Med. Chem. 1970, 13 (1), 1) where; is an acetyl, ethoxycarbonyl or t-butoxycarbonyl radical and Rs is cyano or carboxy.

The compounds of general formula (IH) defined above were transformed into the compounds of general formula (TV) where R is an aryl radical, whether or not substituted as described for (IV) compounds of general formula (I), and R7 is hydrogen, acetyl or R ^, which is an alkoxycarbonyl radical preferably ethoxycarbonyl and t-butoxycarbonyl. Said transformation was carried out using two types of reaction: a) a Friedel-Crafts reaction of the acid chlorides derived from the compounds of general formula (flT) where R; is acetyl or ethoxycarbonyl and Rg is carboxy (Duncan, RL, Helsley, G. C, Welstead, W. I, DaVanzo, JP, Funderburk, WH, Lunsford, CDJ Med. Chem. 1970, 13 (1), 1) with benzene or derivatives thereof conveniently functionalized or b) an addition reaction of Grignard reagents, prepared from conveniently functionalized aryl halides, to compounds of general formula (TU) wherein R 5 is acetyl, ethoxycarbonyl or t-butoxycarbonyl and R 5 is cyano (Duncan, RL, Helsley, G. C, Welstead, WJ, DaVanzo, JP, Funderburk, WH, Lunsford, CDJ Med. Chem. 1970, 13 (1), 1). The reduction of the compounds of general formula (IV) described provides the alcohols of general formula (II) defined above. The enantiomers that make up the racemic mixtures of general formula (I) were obtained by two different ways: a) resolution of the corresponding racemic mixture by fractional crystallization of the diastereomeric salts prepared with chiral acids (D or L-dibenzoyltartaric, D or L- tartaric, D or L-di-p-toluiltartaric and D or L-mandelic) and b) enantioselective synthesis. In the latter case, the enantiomers of general formula (T) were obtained by reaction of the phenols R, -OH or of the fluorinated aromatic derivatives R2-F defined above, with the enantiomers of the alcohols of general formula (II), as described for the racemic mixtures of general formula (I). In the enantiomers of the alcohols of the general formula (II), R is an aryl radical substituted or not, as defined for the compounds of the general formula (I), and R3 is hydrogen or R4, which is an alkoxycarbonyl radical, preferably ethoxycarbonyl and t-butoxycarbonyl. The enantiomers of the alcohols of the general formula (II) defined above were obtained by enantioselective reduction (Ramachandran, PV, Teodorovic, AV, Rangaishenvi, MV, Brown, HCJ Org. Chem. 1992, 57, 2379-2386) of the compounds of general formula (TV) (Duncan, RL, Helsley, G. C, Welstead, W. I, DaVanzo, J. P., Funderburk, WH, Lunsford, CDJ Med. Chem. 1970, 13 (1), 1), where x is an aryl radical substituted or not as defined for the compounds of general formula (I) and R-, is hydrogen or R 4, defined above. The pharmacological activity of the compounds of general formula (I) was determined using well established in vitro and in vivo pharmacological procedures. The affinity of the compounds for the serotonin reuptake receptors (5HT) was assessed in total rat brain cortex, using [3H] -paroxene as radioligand (Habert, E., Graham, D., Tahraoui, L., Claustre, Y., Langer, S. Z. Eur. J. Pharmacol. 1985, 118, 107-114) obtaining K values, between 0.5 and 400 nmol / L The affinity of the compounds for the noradrenaline reuptake receptors (NA) was evaluated in total rat brain cortex, using [ 3H] -nisoxetine as radioligand (Tejani-Butt, SM, J. Pharmacol, Exp. Ther, 1992, 260.1, 427-436) obtaining K values between 1 and 500 nmol ?. As predictive tests of antidepressant activity the following were used: suspension by the tail in mouse (Stéru, L., Chermat, R., Thierry, B., Mico, JA, Lenégre, A., Stéru, M., Simón, P ., Porsolt, RD Prog. Neuropsychopharmacol., Biol. Psychiat., 1987, 11, 659-671), desperate behavior in the rat or mouse (Porsolt, RD, Anton, G., Blavet, N., Jalfre, M. Eur. J. Pharmacol., 1978, 47, 379-394) and potentiation of the lethality induced by yohimbine in mouse (Quinten, R M. Brit. J. Pharmacol., 1963, 21, 51-66). The compounds with K, between 0.5 and 40 nmol / 1, for one of the transporters or for both, presented excellent antidepressant activity in the three models when they were administered in the range 1 to 30 mg / Kg orally, intraperitoneally or subcutaneous. The following examples illustrate the scope of the present invention without being limited by them in any way. Example 1 (+/-) - 4 - [(4-trifluoromethoxyphenoxy) -2- (4-fluorophenyl)] methyl-piperidine, fumarate A mixture of (+/-) - 4 - [(4-trifluoromethoxyphenyl) hiaroxy] acid] methyl-1-piperidinecarboxylic acid, 1,1-dimethyl-ethyl ester (2.25 g, 7.27 mmol), 2-pyridyl-diphenylphosphma (1.90 g, 7.27 mmol) and 1.3 g (7.4 g) mmol) of 4-trifluoromethoxyphenol in 40 mL of tetrahydrofuran (THF) was treated with a solution of diethyl aza-dicarboxylate (DEAD) (1.15 mL) in 10 mL of THF. The reaction mixture was stirred at 20 ° C for 4-6 h and concentrated. The residue was dissolved in ethyl ether, washed with aqueous HCl solution (10%) and aqueous NaOH solution (5%), dried (Na 2 SO 4), filtered and concentrated. 2.4 g (71%) of an oil was obtained which was dissolved in dichloromethane (50 mL) and treated with a solution of trifluoroacetic acid (2.1 mL) in 10 mL of dichloromethane. After 20 h at 20 ° C, it was washed with aqueous NaOH solution (5%) and saturated aqueous NaCl solution. Drying (Na2SO4), filtrate and concentrate provided 1.3 g (71%) of the product which was suspended in anhydrous ether (60 mL) and treated with fumaric acid (0.42 g) to obtain 1.0 g of fumarate. (60% yield) with a mp = 130-134 ° C. The H-NMR (DMSO-tf) shows a characteristic signal at 4.31 ppm (d, J = 5.9 Hz, 1H, CHOAr) and the 13C-NMR (DMSO-d6) presents at 74.9 ppm a signal corresponding to carbon CJHOAr. Example 2 (+/-) - 4 - [(4-fluorophenoxy) (4-fluorophenyl)] methyl-piperidine, hydrochloride A mixture of (+/-) - 4 - [(4-fluorophenyl) hydroxy] methyl-1 acid -piperidinecarboxylic acid, 1,1-dimethyl-ethyl ester (16.33 mmol) and 1.9 g of 4-fluorophenol in 50 mL of THF were treated with 5.0 g of triphenylphosphine and then a solution of DEAD (3%) was added. , 45 mL) in 10 mL of THF. After 3 h, the solvent was distilled and the resulting oil was treated with hexane to obtain a precipitate which was filtered. The filtrate was concentrated and the residue was dissolved in dichloromethane (100 mL) and treated with a solution of trifluoroacetic acid (8 L) in 30 mL of dichloromethane. After 15 h, the reaction was worked up in the usual way and the hydrochloride was prepared in THF, obtaining 3.6 g of it as a slightly hygroscopic amorphous pinkish solid (Yield: 70%) with a m.p. = 90 ° C (d). The NMR data of the hydrochloride shows an H-NMR (CDCLJ with a characteristic signal at 4.72 ppm (d, J = 5.8 Hz, CHOAr) and an NMR, 3C (CDC13) with a signal at 83, 1 ppm corresponding to carbon C_HOAr The following compounds were prepared analogously: (+/-) - 4 - [(4-fluorophenoxy) (4-chlorophenyl)] methyl-piperidine, hydrochloride (54% yield, hygroscopic), (+/-) - 4 - [(4-methoxyphenoxy) (4-fluorophenyl) methyl-piperidine, fumarate (60% yield, mp = 139-142 ° C), (+/-) - 4 - [(4 -trifluoromethylphenoxy) phenyl] methyl-piperidine, hydrochloride (36% yield, hygroscopic), (+/-) - 4- [phenoxy (4-chloropheni methyl-piperidine, hydrochloride (72% yield, mp = 80 ° C ( d)), (+/-) - 4 - [(4-benzoylphenoxy) phenyl] methyl-piperidine, hydrochloride (74% yield, mp = 70 ° C (d)) and (+ -) - 4 - [(4-trifluoromethoxy) phenyl] methyl-piperidine, fumarate (58% yield, mp = 76 ° C (d)). Example 3 (+/-) - 4- [(4-fluorophenoxy) phenyl] methyl-piperidine, sulfate A suspension of NaH (1.95 g, 60% mineral oil) in 20 mL of dimethyl sulfoxide (DMSO) was treated with a Solution of (+/-) - 4- (phenyl-idroxy) methyl-1-piperidinecarboxylic acid, 1,1-dimethyl-ethyl ester (13.8 g, 47 mmol) in 36 mL of DMSO. Potassium benzoate (7.5 g, 47 mmol) and 1,4-difluorobenzene (6.1 mL, 56 mmol) were added, and the reaction mixture was heated at 85 ° C until disappearance of the starting material. It was then treated with saturated aqueous NaCl solution and water, extracting with ethyl ether. The evaporation residue of the organic phase was treated with methanol (200 mL) and aqueous solution of HC1 (10%, 200 mL) and refluxed for one hour. The product was isolated following the usual methodology obtaining as an oil (9.6 g, 72% yield). The NMR data show in RMN-'H (CDC13) a signal at 4.70 ppm (d, J = 7.1 Hz, CHOAr) and at 3 C-NMR (CDC13) a signal at 85.0 ppm corresponding to the CHOAr carbon. The oil was treated with a solution of 1.85 mL of H2SO4 conc in 90 mL of water obtaining the sulfate as a solid with a p.f = 118-120 ° C (75% yield). Example 4 (+/-) - 4 - [(3-fluorophenoxy) phenyl] methyl-piperidine, sulfate A suspension of NaH (0.40 g, 60% mineral oil) in 6 mL of DMSO was treated with a solution of the acid (and -) - 4- (Phenimidroxy) meth-1-piperidinecarboxy, 1,1-dimethyl-ethyl ester (2.55 g, 8.75 mmol) in 6 mL of DMSO. Potassium benzoate (1.35 g, 8.43 mmol) and 1,3-difluorobenzene (1.05 mL, 10.6 mmol) were added and the reaction mixture was heated at 85 ° C until disappearance of the starting substance . It was then treated with saturated aqueous NaCl solution and water, extracting with ethyl ether. The evaporation residue of the organic phase was treated with methanol (30 mL) and aqueous HCl solution (10%, 30 mL) and refluxed for one hour. The usual procedure for making the reaction gave 2.16 g of an amber oil (88% yield) whose NMR data shows a signal at 4.78 ppm (d, J = 6, in H-NMR (CDC13)). 4 Hz, lH, CHOAr) and at 3 C-NMR (CDC13) a signal at 84.6 ppm corresponding to carbon CHOAr. The oil was treated with a solution of 0.20 mL of H2SO4 conc in 10 mL of water obtaining the sulfate as an almost white solid with a m.p. = 72-76 ° C. The following compounds were prepared analogously: (+/-) - 4- (phenoxyphenyl) methyl-piperidine, hydrochloride (73% yield, hygroscopic), (+/-) - 4 - [(4-cyanophenoxy) fenüjmeül- piperidine, fumarate (81% yield, mp = 76 ° C (d)), (+/-) - 4 - [(3-trifluorophenoxy) phenp] methyl-piperidine, hydrochloride (72% yield, mp = 58 ° C (d)), (+/-) - 4 - [(4-bromophenoxy ) phenyl] methyl-piperidine, sulfate (70% yield, mp = 99-103 ° C), (+/-) - N ^ -dimethyl-4 - [[(4-piperidinyl) phenyl] methyl] oxy-benzamide , hydrochloride (72% yield, mp = 45 ° C (deliquescent)), (-) - 4 - [(4-nitrophenyloxy) phenyl] methyl-piperidine, hydrochloride (80% yield, mp = 80 ° C (d )), (+/-) - 4 - [(4-cIorofenü) (l-nañnyloxy)] methyl-piperidine, sulfate (72% yield, mp = 186 ° C (d)), (+/-) - 4- [ (l-naphthyloxy) phenyl] methyl-piperidine, sulfate (70% yield, mp = 152 ° C (d)), (+/-) - 4 - [(2-fluorophenoxy) phenyl] methyl-piperidine, sulfate ( 72% yield, mp = 76 ° C (d)), (+/-) - 4 - [(3-cyanophenoxy) phenyl] methyl-piperidine, hydrochloride (80% yield, mp = 82 ° C (d) ), (+/-) - 4 - [(3-chlorophenoxy) phenyl] methyl-piperidine, sulfate (60% yield, mp = 101-104 ° C), (+/-) - 4 - [(2-trifluoromethylphenoxy) phen] merp-piperidine, sulfate (80% yield, mp = 10 ° C (d)), (+ / r) -4 - [(2- cyanophenoxy) phenyl] methyl-piperidine, oxalate (80% yield, mp = 105 ° C (d)), (+/-) - 4 - [[(2-biphenyl) oxy] phenyl] methyl-piperidine, hydrochloride ( 84% yield, mp = 84-87 ° C), (+/-) - 4 - [[(4-biphenyl) oxy] phenyl] methyl-piperidine, hydrochloride (82% yield, mp = 130 ° C ( d)), (+/-) - 4 - [(3-bromophenoxy) phenyl] methyl-piperidine, sulfate (75% yield, mp = 98 ° C (d)), (+/-) - 4 - [(4-iodophenoxy) phenyl] methyl-piperidine, sulfate (57% yield, mp = 105 ° C (d)), (+/-) - 4 - [(3-iodophenoxy) ) phenyl] methyl-piperidine, sulfate (37% yield, mp = 127 ° C (d)), (+/-) - 4 - [(3,5-difluorophenoxy) phenyl] methyl-piperidine, sulfate (86% yield, mp = 206-208 ° C), (+/-) - 4 - [(3-fluoro-2-methylphenoxy) phenyl] methyl-piperidine, sulfate (80% yield, mp = 125 ° C (d )), (and -) - 4 - [(3-chloro-4-cyanophenoxy) fenu] methyl-piperidine, hydrochloride (70% yield, mp = 125 ° C (d)), (+/-) - 4 - [(5-chloro-2-methyfenoxy) phenyl] methyl-piperidine, sulfate (75% yield, m.p. = 105 ° C (d)), (+/-) - 4 - [(3-chlorch2-methylphenoxy) fenu] methi-piperidine, sulfate (89% yield, mp = 130 ° C (d), (+/-) - 4 - [(3,4-dichlorophenoxy) phenyl] methyl-piperidine, sulfate (91% yield, mp = 108 ° C (d)), (+/-) - 4 - [(3-methoxy-5-fluorophenoxy) phen] me-piperidine, hydrochloride (65% yield, mp = 200-203 ° C) and (+/-) - 4 - [( 3-fluoro-5-cyanophenoxy) phenyl] methyl-piperidine, hydrochloride (76% yield, mp = 70 ° C (d)). Example 5, Resolution of (+/-) - 4 - [(3-fluorophenoxy) phenyl] methyl-piperidine About 7.1 g (25 mmol) of (+/-) - 4 - [(3-fluorophenoxy) phenyl] methyl-piperidine dissolved in 175 mL of ethanol (96%), 4.45 g of L - (-) - dibenzoyltartaric acid were added. A white solid was obtained (mp = 212 ° C (d)) which was treated with aqueous NaOH solution (5%) and extracted with chloroform, obtaining the levorotatory isomer (96% ee, mp = 59-62 ° C, [ x] 546 -11.4, c = 0.576, CHC13).

The obtained filtrate liquids were concentrated and the free base was extracted by treatment with aqueous NaOH solution (5%) and chloroform. The product obtained, dissolved in ethanol, was treated with D - (+) - dibenzoyltartaric acid following the above procedure. A white solid was obtained (mp = 208 ° C (d)) which was treated with aqueous NaOH solution (5%) and extracted with chloroform, obtaining the dextrorotatory isomer (98% ee, mp = 59-62 ° C, [ a] 546 + 11.4, c = 0.618, CHC13).

The following compounds were prepared analogously: (+) - 4 - [(4-fluorophenoxy) phenyl] methyl-piperidine, (96% ee, p.f = 100-102 ° C, [] 546 + 14, c = 0.259, CHCy, (-) - 4 - [(4-fluorophenoxy) phenyl] methyl-piperidine, (96% ee, m.p. = 100-102 ° C, [a] 546-14, c = 0.237, CHCl3), (+) '- 4 - [(4-trifluoromethylphenoxy) phenyl] methyl-piperidine, sulfate (96% ee, mp = 85 ° C (d), [] 365 + 17.8, c = 0.556, CHC13 ), (-) - 4 - [(4-trifluoromethylphenoxy) phenyl] methyl-piperidine, sulfate (96% ee, mp = 85 ° C (d), [a] 365-15.5, c = 0.508, CHCl3) , (+). 4 - [(4-bromophenoxy) phenyl] methyl-piperidine, (96% ee, mp = 129-131 ° C, [a] 436 + 54, c = l, 012, CHCl3), (.). 4 - [(4-bromophenoxy) phenyl] methyl-piperidine, (95% ee, m.p. = 129-131 ° C, [] 436-54.1, c = 1.048, CHCl3), (+) - 4 - [(3-chlorophenoxy) phenyl] methyl-piperidine, methanesulfonate (98% ee, p.f = 200-202 ° C (d), [a] 365 + 14.6, c = 0.646, CHC13), (-) - 4 - [(3-chlorophenoxy) phenyl] methyl-piperidine, methanesulfonate (99% ee, mp = 200-202 ° C (d) , [a] 365-13.6, c = 0.690, CHC13), (+) - 4 - [(3-cyanophenoxy) phenyl] methyl-piperidine, hydrochloride (95% ee, mp = 70 ° C (d), [ oc] 436 + 26.5, c = 0.600, CHCl3), (-) - 4 - [(3-cyanophenoxy) phenyl] methyl-piperidine, hydrochloride (98% ee, mp = 70 ° C (d), [a ] 365-27.1, c = 0.680, CHCl, (+) - 4 - [(3,5-difluorophenoxy) phenyl] methyl-piperidine, sulfate (96% ee, mp = 78 ° C (d), [a ] 436 + 19.4, c = 0.80, CHCl3), (-) - 4 - [(3,5-difluorophenoxy) phenyl] methyl-piperidine, sulfate (98% ee, mp = 78 ° C (d) , [a] 436-19.8, c = 0.724, CHC13), (+): 4 - [(3-fluorophenoxy) (3-fluorophenyl)] methyl-piperidine, hydrochloride (96% ee, mp = 75 ° C (d), [a] 546 + 15, c = 0.183, CHCl3) and (-) - 4 - [(3-fluorophenoxy) (3-fluorophenyl)] methyl-piperidine, hydrochloride (95.4% ee, pf = 78 ° C (d), [a] 546-16, c = 0.17, CHC13) Example 6 (+) - 4 - [(4-fluorophenoxy) phenyl] methy1-piperidine On a solution of 6.8 g of (+) - 5-chlorodiisopinocampheylborane ((+) - DIP-Cl) (21.25 mmol) in dichloromethane (20 mL, dry) cooled to 3-4 ° C was added 4-benzoyl-piperidine (2.0 g 10.6 mmol). After 72 h of reaction, 2.0 mL of acetaldehyde (35.46 mmol) was added and stirred at room temperature for 3 h. 24 mL of an aqueous solution of NaOH (6N) was added, dichloromethane and saturated aqueous NaCl solution. The phases were separated and the usual treatment of the organic phase gave (+) - α-phenyl-4-piperidinemethanol as a white solid of m.p. = 64-66 ° C in a yield of 90% (84% ee). L8 g of the aminoalcohol (+) - a-phenyl-4-piperidinemethanol (9.6 mmol) were dissolved in methanol (10 mL). The solution was cooled to 0 ° C and a solution of diterbutyl dicarbonate ((Boc) 20) (2.5 g, 11.27 mmol) in 10 mL of methanol was dropped. The mixture was stirred for 24 h at room temperature, the methanol was concentrated, water was added and extracted with dichloromethane. The usual treatment of the organic phase gave the desired alcohol as a lightly colored oil in 93% yield. On a suspension of NaH (60%, 0.6 g) in DMSO (5 mL), the alcohol prepared above (2.7 g, 9.3 mmol) dissolved in DMSO (25 mL) was added. Potassium benzoate (1.53 g, 9.63 mmol) and 1,4-difluorobenzene (1.3 mL, 11.9 mmol) were added and the mixture was heated (70-75 ° C) until the substance disappeared. of departure. The reaction mixture was poured into water and saturated aqueous NaCl solution extracting with ether. The oil obtained was treated with a methanol mixture (40 mL) and an aqueous solution of hydrochloric acid (40 mL) for 1 h at reflux. Isolation of the product following the usual methodology provided (+) - 4 - [(4-fluorophenoxy) phenyl] methyl-piperidine as an oil in 54% yield. Treatment of 0.5 g (1.75 mmol) of this oil with D-dibenzoyltartaric acid in ethanol (96%, 30 mL) gave a precipitate that was filtered (mp = 198-199 ° C). The arninoether was released resulting in a white solid with 98.6% ee, p.f = 102-104 ° C, and [a] 546 +15 (c = 0.105, CHC13). The following compounds were prepared analogously: (+) - 4 - [(4-nitrophenoxy) phenyl] methyl-piperidine, hydrochloride (96% ee, mp = 55 ° C (d), [a] 436 + 36, c = 0.045, Ethanol), (-) - 4 - [(l-naMoxi) fenu] methyl-piperidine. hydrochloride (98% ee, p.f. = 65 ° C (d), [a] 546-180, c = 0.080, CHCl3) and (+) - 4 - [(2-fluorophenoxy) phenyl] methyl-piperidine, sulfate (97.6% ee, mp = 105 ° C (d), [] S46 +31, c = 0.081, CHCl3) . Example 7 (-) - 4 - [(4-fluorophenoxy) phenyl] methyl-piperidine On a solution of 25 g of (-) - DIP-Cl (78.125 mmol) in dichloromethane (75 mL, dry) cooled to 0-2 ° C was added 4-benzoyl-piperidine (7.35 g, 39.05 mmol). After 72 h of reaction, 5.2 mL of acetaldehyde (92.2 mmol) was added and stirred at room temperature for 3 h. 71 mL of an aqueous solution of NaOH (6N), dichloromethane and saturated aqueous NaCl solution were added. The phases were separated and the usual treatment of the organic phase provided (-) - α-phenyl-4-piperidinemethanol as a white solid of p. F. = 48-50 ° C in 85% yield (86% ee). 2 g of the aminoalcohol (-) - cc-phenyl-4-piperidinemethane I (10.67 mmol) were dissolved in methanol (10 mL). The solution was cooled to 0 ° C and a solution of (Boc) 20 (2.6 g, 11.73 mmol) in 7 mL of methanol was dropped. The mixture was stirred for 20 h at room temperature, the methanol was concentrated, water was added and extracted with dichloromethane. The usual treatment of the organic phase gave the expected alcohol as a slightly colored oil in 90% yield. On a suspension of NaH (60%, 210 mg) in DMSO (5 mL), the alcohol prepared above (1.3 g, 4.5 mmol) dissolved in DMSO (10 mL) was added. Potassium benzoate (715 mg, 4.5 mmol) and 1,4-difluorobenzene (0.75 mL, 6.86 mmol) were added, and the mixture was heated (70-75 ° C) until disappearance of the starting material . The reaction mixture was poured into water and saturated aqueous NaCl solution extracting with ether. The oil obtained was treated with a mixture of methanol (17 mL) and an aqueous solution of hydrochloric acid (17 mL) for 1 h at reflux. The usual working-up of the reaction gave (-) - 4 - [(4-fluorophenoxy) phenyl] methyl-piperidine as an oil in 64% yield. The treatment of this oil with L-dibenzoyltartaric acid in ethanol (96 %, 35 mL) provided a precipitate that was filtered (m.p. = 193-194 ° C). The amino ether was released resulting in a white solid with 98% ee, m.p. = 100-102 ° C, and [a] 546-14 (c = 0.2, CHC13). The following compounds were prepared analogously: (.) - 4 - [(4-atropofenoxy) phenyl] methyl-piperidine, hydrochloride (98.7% ee, mp = 59 ° C (d), [a] 436-31) , c = 0.042, Ethanol), (+) - 4 - [(l-naphthyloxy) phenyl] methyl-piperidine, hydrochloride (94% ee, mp = 115 ° C (d), [] 546 + 156, c = 0.128 , CHCl3) and (-) - 4 - [(2-fluorophenoxy) phenyl] methyl-piperidine, sulfate (97.6% ee, mp = 90 ° C (d), [a] 546-31, c = 0.140, CHC13). Example 8 (+/-) - 4 - [(3-fluorophenoxy) (3-fluorophenyl)] methyl-piperidine, sulfate A mixture of 4-cyanopiperidine (5 g, 40.92 mmol), (Boc) 20 (11, 7 g, 53.7 mmol), sodium bicarbonate (11.7 g, 139.3 mmol) and water (117 mL) was stirred at room temperature for 17 h. It was extracted with dichloromethane and the organic phase was dried (NajSO, anh.), Filtered and concentrated. The resulting oil was purified by flash column chromatography (Still, W.C., Kahn, M., Mitra, A. 'J.

Org. Chem. 1978, 43, 2923), 4-cyano-1-piperidinecarboxylic acid, 1, 1-dimethyl-ethylester being obtained as a yellow oil in 43% yield. A suspension of Mg (0, 5 g) in ether (dry, 22 mL) was treated with a few milliliters (about 1/4 of the total) of a solution of l-bromo-3-fluorobenzene (2.15 mL, 19.4 mmol) in ether. (dry, 16 mL) and an iodine crystal. It was heated until a smooth reflux and disappearance of the color was observed. The remainder of the solution was then added, dripping, keeping the reflux smooth. At the end of the addition, it was refluxed for 1 h 30 min and allowed to cool to room temperature. A solution of 4-cyano-1-piperidmecarboxylic acid, 1,1-dimethyi-ethyl ester (2.7 g, 12.84 mmol) in dry ether (27 mL) was dropped and the resulting mixture was refluxed for 3 h. A saturated aqueous solution of NH 4 Cl (50 mL) was added and extracted with ether. The usual treatment of the organic phase gave an oil which was purified by flash column chromatography (Still, W. C, Kahn, M., Mitra, AJ Org Chem. 1978, 43, 2923) obtaining 2.4 g. (61% yield) of 4- (3-fluorobenzoyl) -l-piperidmecarboxylic acid, 1,1-dimethyl-ethyl ester as a yellowish oil. The product obtained above (2.4 g, 7.8 mmol) was dissolved in methanol (30 mL) and NaBH4 (0.2 g) dissolved in 3.5 mL of water was added. The mixture was heated for 2 h in an oil bath (50-60 ° C) and the product was isolated in the usual way obtaining (+/-) - 4 - [(3-fluorophenone) Mdroxy] meru-1-piperid carboxypic, 1, 1-dimethyl-ethyl ester as a very dense yellowish oil in quantitative yield. A solution of the racemic alcohol prepared above (2.4 g, 7.8 mmol) in DMSO (25 mL) was dripped onto a suspension of NaH (60%) (0.62 g) in DMSO (15 mL). Potassium benzoate (1.53 g, 9.55 mmol) and 1,3-difiuorobenzene (1.2 mL, 11.9 mmol) were added, and the mixture was heated in an oil bath (65-70 ° C) until disappearance of the starting substance. It was then poured into a mixture of saturated NaCl solution (50 mL) and water (39 mL). It was extracted with ether and the usual treatment of the ether phase gave an oil which was treated with a mixture of methanol (40 mL) and aqueous HCl solution (10%, 40 mL) under reflux for 1 h 30 min. The desired product (+/-) - 4 - [(3-fluorophenoxy) (3-fluorophenyl)] methyl-piperidine was isolated as an amber oil in 50% yield. The NMR data of this product show at NMR-H (CDC13) a signal at 4.55 ppm (d, J = 6.1 Hz, CHOAr) and at 13 C-NMR (CDC13) a signal at 83.9 ppm corresponding to carbon CJFíOAr. The oil prepared above was treated with a 0.22 mL solution of H2SO4 conc. in 16.5 mL of water, the sulfate being obtained as a lightly colored solid (m.p. = 158 ° C (d)). The following compounds were prepared analogously: (+/-) - 4 - [(2-fluorophenoxy) (3-fluorophenyl)] methyl-piperidine, hydrochloride (62% yield, mp = 90 ° C) and (+ / -) - 4 - [(4-fluorophenoxy) (3-fluorophenyl)] methyl-piperidine, hydrochloride (30% yield, mp = 65 ° C).

Claims (5)

Claims 1.- 4-substituted piperidines of general formula (I), wherein R, and R2 are unsubstituted aryl radicals or mono- or poly-substituted aryl radicals with halogen (fluorine, chlorine, bromine, iodine), alkyl, alkoxy, cyano, trifluoromethoxy, trifluoromethyl, benzoyl, phenyl, nitro, amino, aminoalkyl, aminoaryl and carbonilarnino, as well as their pharmaceutically acceptable salts with inorganic acids and organic acids. ,
1. (I)
2. 2. - According to claim 1, the 4-substituted piperidines of general formula (I) obtained as racemic mixtures and as pure enantiomers.
3. 3. According to claims 1 and 2, the 4-substituted piperidines of the general formula (I) listed below, obtained as racemic mixtures and as pure enantiomers, as well as their pharmaceutically acceptable salts: 4- (phenoxyphenyl) methyl-piperidine. 4 - [(4-fluorophenoxy) phenyl] meul-piperidine, 4 - [(4-methoxyphenoxy) (4-fluorofeml)] methyl-piperidine, 4 - [(4-fluorophenoxy) (4-fluorophenyl)] methyl-piperidine, 4 - [(4-fluorophenoxy) (4-chlorophenyl)] methyl-piperidine, 4 - [(4-trifluoromethylphenoxy) phenyl] methyl-piperidine, 4 - [(4-trifluoromethoxyphenoxy) (4-fluorophenyl)] methyl-piperidine, 4- [Phenoxy (4-chlorophenyl)] methyl-piperidine, 4- [(4-benzoyl-phenoxy) -phenyl] -methyl-piperidine, 4 - [(4-trifluoromethoxyphenoxy) phenyl] methyl-piperidine, 4 - [(4-cyanophenoxy)) fenü] methyl-piperidine, 4 - [(3-trifluorophenoxy) phenyl] methyl-piperidine, 4- [(3-fluorophenoxy) phenyl] mea -piperidine, 4 - [(4-bromophenoxy) phenyl] methyl-piperidine, NjV- dimethyl-4 - [[(4-pipericylinyl) phenyl] methyl] oxy-benzamide, 4 - [(4-nitrophenyloxy) phenyl] methyl-piperidine, 4 - [(4-chlorophenyl) (1-naphthyloxy)] methyl-piperidine , 4 - [(1-naphthyloxy) phenyl] methyl-piperidine, 4 - [(2-fluorophenoxy) phenyl] methyl-piperidine, 4 - [(3-cyanophenoxy) phenyl] methyl-piperidine, 4 - [(3-chlorophenoxy) ) phenyl] methyl-piperidine, 4 - [(2-trifluoromethylphenoxy) phenyl] til-piperidine. 4 - [(2-cyanophenoxy) phenyl] methyl-piperidine, 4 - [[(2-biphenyl) oxy] phenyl] methyl-piperidine, 4 - [(3-fluorophenoxy) (3-fluorophenyl)] methyl-piperidine,, 4 - [(2-fluorophenoxy) (3-fluorophenyl)] methyl-piperidine, 4 - [(4-fluorophenoxy) (3-fluorophenyl)] methyl-piperidine, 4 - [[(4-biphenyl) oxy] phenyl] methyl -piperidine, 4 - [(3-bromophenoxy) phenyl] methyl-piperidine, 4 - [(4-iodophenoxy) phenyl] methyl-piperidine, 4 - [(3-iodophenoxy) phenyl] methyl-piperidine, 4- [(3 , 5-difluorophenoxy) phenyl] methyl-piperidine, 4 - [(3-fluoro-2-methylphenoxy) phenyl] methyl-piperidine, 4 - [(3-chloro-4-cyanophenoxy) phenyl] methyl-piperidine, 4- [ (5-chloro-2-methylphenoxy) phenyl] methyl-piperidine, 4 - [(3-chloro-2-methylphenoxy) phenyl] methyl-piperidine, 4 - [(3,4-dichlorophenoxy) phenyl] methyl-piperidine, - [(3-methoxy-5-fluorophenoxy) phenyl] methyl-piperidine and 4 - [(3-fluoro-5-cyanophenoxy) phenyl] methyl-piperidine.
4. 4. Pharmaceutical compositions containing a therapeutically effective amount of a compound of general formula (I) according to the preceding claims, mixed with pharmaceutically acceptable excipients, for oral, parenteral and topical administration.
5. 5. A method of treatment of disorders of the central nervous system in humans, in particular depression, bulimia nervosa, obsessive-compulsive disorders, alcohol addiction, anxiety, panic, pain, premenstrual syndrome, social phobia and the prophylaxis of migraine, consisting in the administration of a therapeutically effective amount of a compound of general formula (I) according to the preceding claims.