Title of Invention

4- SUBSTITUTED PIPERIDINES

Abstract

New-4-substituted piperidines of general formula (I) are described in which R1 and R2 are aryl radicals, substituted or not which are obtained as racemic mixtures and as pure enantiomer. 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 nervous bulimia obsessive-compulsive disorders, alcohol addiction anxiety, panic, pain pre-menstrual syndrome and social phobia as well as migraine prophylaxis.

Full Text

FORM 2 THE PATENTS ACT 1970 [39 OF 1970] & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION [See Section 10; rule 13] "4-SUBSTITUTED PIPERIDINES" FAES, FABRICA ESPANOLA DE PRODUCTOS QUIMICOS Y FARMACEUTICOS, S.A., a Spanish company of Maximo Aguirre, No. 14, 48940-Lejona, Vizcaya, Spain, The following specification particularly describes the invention and the manner in which it is to be performed: Original 18 JUL 2007 18-07-2007 The present invention relates to 4-substituted piperidines. Introduction In recent years, selective serotonin reuptake inhibitors (SSRIs) have started to be used for treating 5 depression and other central nervous system disorders, noteworthy among which are fluoxetine, citalopram, sertraline and paroxetine. They all have different chemical structures, which helps to explain their different metabolic and pharmacokinetic profiles, their performance as antidepressants compares with rhar of classic tricyclic compounds, but their advantage is that they are safer and better tolerated. 10 The present invention relates to a number of new 4-substituted piperidines having an aryloxy functionality and potently inhibiting serotonin and/or noradrenaline reuptake, as a result :6f their " . high affinity for their neuronal transporters. This characteristic provides" them with an enhanced antidepressant potential in human therapy. Other potential dierapeutic applications of these compounds are treatment of nervous bulimia, alcohol addiction, anxiety, obsessive-compulsive 15 disorders, panic, pain, pre-menstrual syndrome and social phobia, as well as migraine prophylaxis. Bibliography also describes other piperidine derivatives with aryloxy functionality as potential antidepressants, albeit with a chemical nature differing essentially from those claimed"herein, since the piperidine is substituted at- the 3-position. That is for instance the case of such compounds as 3-[(2-merhoxyphenoxy)phenyl]methyl-piperidine I (Melloni, P., Carniel, G., Delia 20 Torre, A-, Bonsignalari. A.. Buonamici, M., Pozzi, O., Ricciardi, S., Rossi, A.C. Eur. J, Med Chem. Chim. Ther. 1984, 3, 235-242; Melloni, P., Delia Torre, A., De Munari, Si, Merohf, M, Tonani, R. Gazena Chimica Italiana 19S5, 115, 159-163) and 3-[(phenoxy)phenyl]methyl-piperidine 2 (FR 2,0I0,6"15 CA73; 66442J; GB 1,203,140 CA73: 120509b). In these compounds, the substitution of the piperidine ring at the 3-position results in an additional chiral centre. The 25 presence of the two chiral centres results in diastereomeric mixtures, which is the form in which the preparation of these compounds 50 has been described. The preparation and/or isolation of pure enantiomers is not described in any 35 case. However, the compounds claimed in the present specification possess a single chiral centre, 2 since they have the piperidine ring substituted at the 4-position, They have been prepared as racemic mixtures and as pure enantiomers, using synthetic methods differing from those used in preparing 1 and 2 Moreover, other piperidine derivatives having aryloxy functionality and the piperidine ring substituted at the 4-position have been described as potential antidepressants (formulae 3 and 4). Thus, in the case of 3 type compounds (JP 96 40,999 CA124: 343333n), the arytoxy group is directly joined ro die piperidine ring, whereas in the 4 type compounds (JP 96 40,999 CAI24: 343333nJ said group is joined to the piperidine ring trough a. methylene group which has no further substitutions. The compounds described herein differ largely from those, since they have the aryloxy group joined to the piperidine ring through a methylene group wherein, in all cases, one of the methylene group"hydrogens is substituted by an aryl group, substituted or not, as defined hereinafter. These compounds arc therefore structurally different from the 3 and 4 rypes and the synthetic methodology used in preparing the same is"also absolutely different. The present invention is novel and inventive over Chemical Abstracts 106: 213767z and JP-A-61/227565. Description The new 4-substirude piperidines described in the present invention are represented by general formula (I), in which groups R, 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, a"minoalkyl, aminoaryl and carbonylamino. The compounds of genera] formula (I) have an .asymmetric centre and have been prepared as racemic mixtures and as pure enantiomers. The present invention includes all optical isomers of the compounds of general formula (J) and racemic mixtures thereof. The racemic compounds of general formula (7) were prepared using well-known synthetic methods starting with the compounds of general formula (II). 5 Formation of the alkylarylether group was carried out using the Mitsunobu reaction (Mitsunobu, 0. Synthesis 1981, 1; Hughes, D.L. Organic Reactions 42, 335) with phenols RrOH, in which R2 is an aryl radical, substituted or not, as described for general formula (I), and the compounds of general formula (II), in which R, is an aryl radical, substituted or not as described for general formuJa (I), and Rj is hydrogen or R,, which is an alkoxycarbonyl radical, preferably 10 ethoxycarbonyl and t-butoxycarbonyl. 15 The alkylarylether group was also prepared using an aromatic nucleophilic substitution reaction (Berglund, R.A. Org. Proc. Res. Dev. 1997 1, 32S-330) with the compounds of general formula (IT) defined above, arid the fluorinated derivatives Rj-F, in which R3 is an aryl radical mono- or poly-substituted with halogen (fluorine, chlorine, bromine, iodine), allcyl. alkoxy, cyano, 20 trifluoromethoxy, trifluoromefhyl, benzoyl, phenyl, nitro, amino, aminoalkyl, aminoaiyl and carbonylamino. The compounds of general formula (11) were prepared using conventional synthetic methods-, starring with the compounds of general formula (III) (Duncan,; R.L., Helsley, G.C.. Welstead, WJ, DaVanzo, J.P., Funderburk, W.H., Lunsford, CD. J. Med Chem. 1970, 15 (1), 1), in which R5 is an acetyl radical, ethoxycarbonyl and R (TO) The compounds of general formula (III) defined above were transformed into the compounds of 30 general formula (IV), in which R| is an aryl radical, substituted or not, * * J ■ as described for the compounds of general formula (I), and R1 is hydrogen, acetyl or R4, which is an alkoxycarbonyl radical, preferably ethoxycarbonyl and t-butoxycarbonyl. Such transformation was made using two reaction types: a) a Friedel-Crafts reaction of the acid chlorides derived from the compounds of general formula (HI), in which R5 is an acetyl or ethoxycarbonyl and R4 is 5 carboxy (Duncan, R.L., Helsley, G.C., Welstead, W.J., DaVanzo, J.P., Funderburk, W-H Lunsford, CD. J. Med. Chem. 1970, 13 (1), 1) with benzene or conveniently functionalised derivatives thereof; or b) a Grignard reactive addition reaction, prepared from conveniently funtiionansed ary\ halides, to compounds of general formla (III) in Which R1 is acetyl, ethoxycarbonyl or t-butoxycarbonyl and R« is cyano (Duncan, R.L., Helsley, G.C., Welstead, 10 W.J., DaVanzo, J.P., Funderburk, W.H., Lunsford, CD. J. Med. Chem. 1970, 13 (1), I). Reduction of the compounds of general formula (IV) described provides the general formula (IT) alcohols defined above. The enantiomers composing the racemic mixtures of general formula (I) were obtained using two different pathways: a) resolution of the corresponding racemic mixture by split crystallisation of 15 the diaslereomeric salts prepared with chiral acids (D or L-dibenzoyltartaric, D or L-tartaric, D or L-di- p-toluyltartaric and D or L-mandclic) and b) enantioselective synthesis. In the latter case, the enantiomers of general formula (I) were obtained by reacting phenols R2-OH or the fluorinated aromatic derivatives R2-F defined above, with the enantiomers of the general formula (II) alcohols, as described for the racemic mixtures of general formula (I). In the enantiomers of the 20 general formula (II) alcohols, R1 is an aryl radical, substituted or not, as defined for the compounds of general formula (I), and R3 is hydrogen or R4, which is an alkoxycarbonyl radical, preferably ethoxycarbonyl and t-butoxycarbonyl. The enantiomers of the general formula (II) alcohols defined above were obtained by enantioselective reduction (Ramachandran, P.V., Teodorovic, A.V., Rangaishenvi, M.V., Brown, H.C. J. Org. Chem. 1992, 57, 2379-2386) of the 25 compounds of general formula (fV) (Duncan, R.L., Helsley, G.C., Welstead, W.J., DaVanzo. J.P., Funderburk, W.H., Lunsford, CD- J- Med. Chem. 19707 13(1), 1), in which R1 is an aryl radical, substituted or not as defined for-the compounds of general formula (I), and R1 is hydrogen or R4, defined above. The pharmacological activity of the compounds of general formula (I) was determined using well- 30 established in vitro and in vivo pharmacological processes. The affinity of the compounds for the serotonin reuptake receptors (SHT) was evaluated in full rat cerebral cortex, using [3H]-paroxetine as radioligand (Habert, E., Graham, D., Tahraoui, L., Claustre, Y., Langcr, S.Z. Eur J. Pharmacol. 1985, 118, 107-114) yielding Ki values ranging between 0.5 and 500 nmol/1. The affinity of the compounds for noradrenaline (NA) reuptake receptors was evaluated in full rat cerebral cortex, 35 using [H]-nisoxetine as radioligand (Tejani-Butt, S.M, J. Pharmacol. Exp. Ther. 1992, 260, 1, 29-oct-1999 22:08 +34 915566SS7 98% P. 427-436), yielding Ki values ranging between 1 and 500 nmol/1. The following were used as assays predicting antidepressant activity: mouse tail suspension (Stem, L., Chermat, R., Thierry, B., Mico, J.A., Lenegre, A., Steru, M., Simon, P., Porsolt, R.D. Prog. Neurophsychopharmacol. Biol Psychiat, 1987, 11, 659-671), rat or mouse desperate behaviour (Porsolt, R.D., Anton, G., Blavet, N., Jalfre, M. Eur. J. Pharmacol. 1978, 48, 379-394) and enhancing rat yohimbine induced lethality (Quinton, R.M., Brit J. Pharacol. 1963, 21, 51-66). The compounds with Ki ranging between 0.5 and 40 nmol/1, for one of the transporters or for both, displayed an excellent antidepressant activity in the three models when administered within the 1 to 30 mg/Kg range orally, intraperitoneally or subcutaneously. Accordingly, there is provided 4-substituted piperidines, of general formula (I), in which Ri 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, and their pharmaceutically acceptable salts with inorganic acids and organic acids of the kind such as herein described. Accordingly, there is also provided pharmaceutical compositions containing a therapeutically effective quantity of a compound of general formula (I) comprised between lmg and 200 mg, mixed with pharmaceutically acceptable excipients, to be orally, parenterally and topically administered. -6- 10 The following examples illustrate the scope of the present invention, which is not howsoever limited to such examples. Example J . (+/-)-[(4-trifluoromechoxy phe"naxy-2-4-fluorophcny]methyI-piperidine]fumarate A mixture of (+/-)-4-[(4-trifluoromethoxyphenyl)hydroxy]methyI-l-piperidinecarboxyI,ic acid, 15 1,1-dimethyl-cihyIester (2.25 g, 7.27 mmol), 2-pyridyI-diphenyIphosphine (1.90 g, 7.27 mmol) and 1J g (7.4 mmol) of 4-trifluoromethoxyphenoJ in 40 mL of retrahydrofurane (THF) was treated with a solution of diethyl-aza-dicarboxylate (DEAD) (1.15 mL) in 10 mL of THF. The reaction mixture was stirred at20°C for 4-6 h and concentrated. The residue was dissolved in ediyl ether, washed with an aqueous HC! (10%) solution and an aqueous NaOH (5%) solution, dried 20 (anh. Na2SO4), filtered and concentrated. 2.4 g (71%) were obtained of an oil 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, this was washed with an aqueous NaOH (5%) solution and saturated aqueous NaCI solution. Drying (anh. NASO4), filtering and concentration provided 1.3 g (71%) of the product, which was suspended in anhydrous ether (60 mL) and treated with 25 fumaric acid (0.42 g), yielding 1.0 g of the fumarate (60% yield) with am.p. = 130^134°C. The RMN-"H (DMSO-d4) displayed a characteristic signal at 4-31 ppm (d, /= 5.9 Hz, IH, CHOAr) __■ and RMN-3C (DMSO-d6)displayed_at_74.9 ppm a signal corresponding to CHOAr carbon. Exam ple2 (+/-)-4-[(4-fluorophenoxy)(4-fluorophenyI)]methyl|piperidine, hydrochloride 30 A mixture of (+/-)-4-[(4-fluorophenyl)hydroxy]mediyI-I-pipcridinecarboxylic acid, 1,1-dtmechyl-ethykster (16.33 mmol) and 1.9 g of 4-fluorophenol in 50 mL of THF was treated with 5.0 g of triphenylphosphine and a DEAD solution (3.45 mL) in 10 mL of THF was then added. After 3 h, the solvent was distilled and the resultanc oil was treated with hexane, yielding a precipitate which was filtered. The filtrate was concentrated and the residue dissolved in dichloromethane (100 mL) 35 and treated with a trifluoroacetic acid solution (8 mL) in 30 mL of dichloromethane. After 15 h, the reaction was worked as usual and the hydrochloride was prepared in THE, yielding 3.6 " thereof as an amorphous and slightly hygroscopic rose-coloured solid (Yield: 70%) with a m.p. = 90°C (d). RMN-"H (CDCIJ) of the hydrochloride displayed a characteristic signal at 4.72 ppm (d, J ~ 5.8 Hz, CHOAr) and RMM-13C (CDCI3) a signal at 83.1 ppm corresponding to CHOAr 5 carbon. The following compounds were analogously prepared: (+-/-)-4-[(4-fluorophenoxy)4-chloropheny1]methy"]piperidine, hydrochloride (54% yield, hygroscopic), (+/-)-4-[(4-methoxyphenoxy)(4-fluorophenyl)]methyl/piperidine, fu"marate (60% yield, m.p. = 10 139-142°C), (+/-)-4-[(4-trifluoromethylphenoxy)(pheny1)methyl(-piperidine, hydrochloride (36% yield, hygroscopic), (+/-)-4-rphenoxy)(4-chlorophenyl)]methylkiperidine, hydrochloride (72% yield, m.p. = 80°C (d)), (+/-)-4-[(4-benzoylphenoxy](phenyr)meihyf|piperidine, hydrochloride (74% yield, m.p. 70°C (d)), 15 and (+/-4-[(4-trifluoromethoxy)(pheny1)methylJpiperidine, fumarate (58% yield, m.p. = 76°C (d))-Example 3 (+/-)-4-[(4-fluorophenoxy)(pheny1)methy1)piperidine, sulfate An NaH (1.95 g, 60% mineral water) suspension in 20 mL of dimethylsulfoxide (DMSO) was 20 treated with a solution of (+/-)-4-(phenyIhydroxy)rnethyl-I-piperidinecarboxylic acid, 1.1-dimethyl-ethylester (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 to 85°C until the starting substance disappeared. This was then treated with saturated aqueous NaCI and water solution, and extracted with ethyl ester. The organic phase evaporation residue was 25 treated with methanol (200 mL) and aqueous HCI (10%, 200 mL) solution and refluxed for an hour. The product was isolated with the usual methodology, yielding an oil (9.6 g, 72% yield). RMN-"H (CDCI3) displayed a signal at 4.70 ppm (d, J= 7.1 Hz, CHOAr) and RMN-IJC (CDCIj) a signal at 85.0 ppm corresponding to CHOAr carbon. The oil was treated with a 1.85 mL cone. H1SO.4 solution in 90 mL of water, yielding the sulfate as a solid with a m.p. = 118-120°C (75% 30 yield). Example 4 (+/)-4-[(3-fluorophenoxy)(pheny1)methyl]pipcridine) sulfate An NaH (0.40 g, 60% mineral water) suspension in 6 mL DMSO was treated with a solution of (+/-)-4-(phenylhydroxy)methyl-l-piperidiriecarboxylic acid, 1,1-dimethyl-ethylester (2.55 g, 8.75 35 mmol) in 6 mL of DMSO. Potassium benzoatc (1.35 g, 8.43 mmol) and 1 3-difluorobenzene (1.05 -8 29-0CT-1999 22:09 +34 915566567 97% P-09 mL, 10.6 mmof) were added, and the reaction mixture was heated to 85"C until the starting substance disappeared. It was then treated with saturated aqueous NaCl and water solution, and extracted with ethyl ester. The organic phase evaporation residue was treated with methanol (30 mL) and aqueous HCI (10%, 30 mL) solution and refluxed for an hour. The usual reaction 5 working process yielded 2.16 g of an amber oil (88% yield). RMN-"H (CDClj) displayed a signal at 4.78 ppm (d, J = 6.4 Hz, 1H, CHOAr) and RMN-I3C (CDCI3) a signal at 84.6 ppm corresponding to CHOAr carbon. The oil was treated with a 0.20 mL cone. H2SO4 solution in 10 mL of water, yielding the sulfate as a solid widi a m.p. = 72-76°C. The following compounds were analogously prepared: 10 (+/-)-4-(phenoxyphenyl)methyI-piperidine, hydrochloride (73% yield, hygroscopic), (+/-)4-[(4-cyanophenoxy)|(pneny1)methylf-piperidine, fumarate (81% yield, m.p. - 76°C (d)), (+/-)4-[(3-trifluorophenoxy)(6heny1)methyl|piperidine, hydrochloride (72% yield, m.p. - 58°C (d)), (+A)-4-[(4-bromophenoxy)6henyl)methyl|piperidine1 sulfate (70% yield, m.p. = 99-103°C), 15 (+/-)-N"-N--dimerhy-4-[[(4-piperidinyl)phenyl]methyl]oxy-benzamidc, hydrochloride (72% yield, m.p. = 45°C (deliquescent)), (+-1)-4-[("4-nitorophenyloxy)(pheny1)mediyl)piperidine, hydrochloride (80% yield, m.p. = 80°C (d)), (+/-4-[(4-chlorophenylX]-naphthyloxy)]methyl-piperidine, sulfate (72% yield, m.p. = 186°C (d)), 20 (+/-H-K1 -naphthyloxy)(phenylmerhy]piperidine, sulfate (70% yield, m.p. = 152°C (d)), (+/.)-4-.[(2.fluorophenoxy)pheny1)methy]piperidine, sulfate (72% yield, m.p. = 76°C (d)), (+/-4-[(3-cyanophenoxy)pheny1)methy1-)piperidine, hydrochloride (80% yield, m.p. = 82°C (d)), (+A)-4-[(3-chlorophenoxypheny])methyi|piperidine, sulfate (60% yield, m.p, = 101-104°C), (+/-)-4-[(2-rifluoromethylpherioxy)(pheriy1)methylJpiperidine, sulfate (80% yield, m.p. = 110°C 25 (d)), . (+/-)-4-[(2-cyanophenoxy)6heny1)methyl|piperid(ne, oxalate (80% yield, m.p. = 105DC (d)), (+/-H-[[(2-biphenyl)oxy]phenypmethyi|piperidine, hydrochloride (84% yield, m.p. = 84-87DC), (+/-)-4-[[(4-biphenyl)oxyphenyj)methylJpiperidine> hydrochloride (82% yield, m.p. = 130°C (d)), (+/.)-4-f(3-bromophenoxy)pheny])methyl]piperid!ne, sulfate (75% yield, m.p. = 9S°C (d)), 30 (+/-4-[(4-iodophenoxy)pheny1)methy1] piperidine, sulfate (57% yield, m.p. = 105°C (d)), (+/-4-[(3-iodophenoxy)pheny1)methy]piperidine, sulfate (37% yield, m.p. = 127°C (d)), (+/-)4-[(3,5-difluorophenoxypheny])methyljpiperidine, sulfate (86% yield, m.p. = 206-20S°C), (+/-)-4-[(3-fluoro-2-methylphenoxy)^heny])methyllpiperidine, sulfate (80% yield, m.p. = 125°C (d) 29-0CT-1999 22:10 +34 915566567 97% P-10 (+/.)4[(3-chloro-4-cyanophenoxy]pheny]}rnethyl|piperidine, hydrochloride (70% yield, m.p, = 125°C (d)), (+/-)-4-[(5-chloro-2-methylphenoxy)phertyI)methyllpiperidine, sulfate (75% yield, m.p. = I05°C (d)), 5 (+/-[(3-chloro-2-methylphenoxy]pheny1])metliy1]piperidine1 sulfate (89% yield, m.p. = 130aC (d)), (+/-)-4-[(3,4-dichlorophenoxy^henyj)methyl|piperidine, sulfate (91% yield, m.p. = 108°C (d)), (+/-)-4-[(3-methoxy-5-fluorophenoxy](pheny]methy1]piperid ine, hydrochloride (65% yield, rn.p. — 200-203°C (d)), and 10 (+/-H-[(3-fluoro-5-cyanophenoxy)|pheny1)methyl|piperidine, hydrochloride (76% yield, m.p. = 70C (d)). Example 5 Resolution of(+/-)-4-[(3-fIuorophcnoxy)pheny1)methyl|piperidine 4.45 g of L-(-)-dibenzoylrartaric acid were added over 7.1 g (25 mmol) of (-+-/-)-4-[3-15 fluorophenoxy)phenyl]methyl-piperidine dissolved in 175 mL of ethanol (96%). A white solid was obtained (m.p. = 212°C (d)) which was treated with aqueous NaOH (5%) solution and extracted with chloroform, yielding the levorotary isomer (96% ee. m.p, = 59-62°C, [a]-346 - 11.4, c = 0.576. CHC13). The filtrate liquids obtained were concentrated and the free base was extracted by treatment with 20 aqueous NaOH (5%) solution and chloroform. The product obtained, dissolved in ethanol, was treated with D-(+)-dibenzoyltartaric acid using the preceding process. A white solid was obtained (m.p. = 208°C (d)) which was treated with aqueous NaOH (5%) solution and extracted wiih chloroform, yielding the dextrorotary isomer (98% ee, m.p. = 59^62°C, [a]546 + 11.4, c = 0.618, CHCI3). 25 The following compounds were analogously prepared: (-r)-4-[(4-fluorophenoxy)|phenyl)methynpiperidine (96% ee, m.p. = 100-102°C, [a]546+ 14, c = 0.259, CHCI3) (-H-[(4-fluorophenoxy)]pheny)methy1][piperidine (96% ee, m.p. = 100-102°C, [a]546 - 14, c = 0.237, CHCI3) 30 (+H-[(4-trifluoromemylphenoxy]|phenyT)methyllpiperidine, sulfate (96% ee, m.p. = 85°C (d), [a]365 + 17.S,c = 0.556, CHCI3) (.)-4-[(4-trifIuoromerhylphenoxy)pheny1)methylipiperidine, sulfate (96% ee, m.p. = 85°C (d), [a] 365-15.5, c = 0.508, CHClj) (+)_4-[(4-bromophenoxy(pheny1)methyi|piperidine (96% ee, m.p. = 129-13 TC (d), [a]436 + 54, c 35 = 1.012, CHC13) (.)-4[(4-bromophenoxy)(phenyl)methyflpiperidine (95% ee, m.p. = 129-131 °C (d), [a]436 - 54.1, c = 1.048, CHC13) (+4--[(3-chlorophenoxy)phenjn)methyl|piperidine, methanosulfare (98% ee, m.p. = 200-202DC (d), [a-kis + 14.6, c = 0.646, CHCI3) 5 (-H-[(3-chJorophenoxy)^henyI)methyUpiperidine, methanosulfate (99% ee. m.p. = 200-202°C (d), [a]J65 -13.6, c = 0.690, CHC|3) (+)-4-[(3-cyanophenoxy^henyl)merhyIJpiperidine, hydrochloride (95% ee, m.p. = 70°C (d). [a]^4 +26.5, c = 0.600, CHC13) (-)-4-f(3-cyanophenoxy^henyT)methyllpiperid ine, hydrochloride (98% ee, m.p. = 70°C (d); [ajj^j 10 -27.1, c = 0.680, CHCI3) (+)^-[(3i5^if]uoropheno.xy^henyT)methyiJ-piperidihe, sulfate (96% ee, m.p. = 7S°C (d), [a JIM + 19.4, c = 0.80, CHC13) (-H-[(3,5-dirluorophenoxy]^henyTjmethyljpiperidine, sulfate (98% ee, m.p. = 78°C (d), [a]J34 -19.8, o = 0.724, CHCIj) 15 (+-)-4-[(3-fluorophenoxy)(3-fluorophenyl)]methyl|piperidine, hydrochloride (96% ee, m.p. = 75eC (d), [ajsjs + 15, c = 0.183, CHCIj) and (-)-4-[(3-fluorophenoxy)(3-fluorophenyl)]metliyl|piperidine, hydrochloride (95.4% ee. m.p. = 7S8C (d), [a]^ - 16, c = 0.17, CHClj) Example 6 20 (+)-4-[(4-fluorophenoxy)(phenyT)methyljpiperidine 4-benzoyl-piperidine (2,0 g, 10.6 mmol) was added over a solution of 6.H g of (+)-#-chlorodifsopinocanfeilboran ((+)-DIP-CI) (21.25 mmol) in dichloromethane (20 mL, dry) cooled down to 3-4°C. After reacting for 72 h, 2.0 mL of aceraldehyde (35^46 mmol) were added and stirred at room temperature for 3 h. 24 mL of an aqueous NaOH (6N) solution, dichloromethane 25 and saturated aqueous NaCI solution were added. The phases were separated and the usual treatment of the organic phase provided (+)-a-phenyM-piperidinemethanoI as a white solid with a m.p. = 64-66°C in a 90% yield (84% ee). 1.8 g of aminoalcohol (+)-a-phenyl-4-piperidinemeihanol (9.6 mmol) were dissolved in methanol (10 mL). The solution was cooled down to 0eC and a diterburyl dicarbonate ((Boc)20) (2.5 g, 30 11.27 mmol) solution was added dropwiseto 10 mL of methanol. 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 provided the desired alcohol as a slightly coloured oil in a 93% yield. The alcohol prepared above (2.7 g, 9.3 mmol) dissolved In DMSO (25 mL) was added over an 35 NaH (60%, 0.6 g) suspension in DMSO (5 mL). Potassium benzoate (1.53 g, 9.63 mmol) and 1,4- 29-6-OCT-1999: 22:10 +34 915S66567 98% P.12 difluorobenzene (1.3 mL, 11.9 mmol) were added and the mixture was heated (70-75°C) until the starting substance disappeared. The reaction mixture was poured into water and saturated aqueous NaC1 solution, and extracted with ether. The oil obtained was refluxed with a mixture of methanol (40 mL) and an aqueous hydrochloric acid (40 mL) solution for lh. Isolation of the product using 5 the customary methodology provided (+)-4-[(4-fluorophenoxy)(pheny1)methy1)piperidine as an oil in a 54% yield. Treatment of 0.5 g (1.75 mmol) of this oil with D-dibenzoyltartaric acid in ethanol (96%, 30 mL) provided a precipitate which was filtered (m.p. = 198-199°C). The aminoether was released yielding a white solid with a 96% ee, m.p. = 102-104°C, and [a]5J6 + 15, c = 0.105, CHC13). 10 The following compounds were analogously prepared: (+)-4-[(4-nitrophenoxy)pheny])methyl|piperidine) hydrochloride (96% ee, m.p. = 55°C (d), [a]436 +■ 36, c = 0.045, Ethanol) (-)-4-[(|-naphthyloxy](pheny])methyljpiperidine, hydrochloride (98% ee, m.p. = 65°C (d), [a]436 - ISO, c = 0.030, CHC13) and 15 (+)-4-[(2-fluorophenoxy)phenyl]methyl-piperidine, sulfate (97,6% ec, m.p. = I05°C (d), [a.]546 + 31, c ="0.081, CHCI3). Example 7 (-)-4-[(4-fluorophenoxy)pheny1}methyI-piperidine 4-benzoyl-piperidine (7.35 g, 39.05 mmol) was added over a solution of 25 g of (-J-DIP-C1 20 (78.125 mmol) in dichloromethane (75 mL, dry) cooled down to 0-2°C. After reacting for 72 h, 5.2 mL of acetaldehyde (92.2 mmol) were added and stirred at room temperature for 3 h. 71 mL of an aqueous NaOH (6N) solution, dichloromediane and saturated aqueous NaCl solution were added. The phases were separated and the usual treatment of the organic phase provided (-)~CL-phenyl-4-piperidinemerhanoI as a white solid with a m.p. = 48-50°C in a 85% yield (86% ee). 25 2 g of aminoalcohol (-)-a-phenyl-4-piperidinemethanol (10.7 mmol) were dissolved in methanol (10 mL). The solution was cooled down to 0°C and a (Boc)20 (2,6 g, 11.73 mmol) solution was added dropwjse to 7 mL of methanol. The mixture was stirred for 20 h at room temperature, die methanol was concentrated, water was added and extracted with dichloromediane. The usual treatment of the organic phase provided the desired alcohol as a slightly coloured oil in a 90% 30 yield. The alcohol prepared above (1.3 g, 4.5 mmol) dissolved in DMSO (10 mL) was added over an NaH (60%, 210 g) suspension in DMSO (5 mL). Potassium benzoate (715 g, 4.5 mmol) and 1,4-difluorobenzene (0.75 mL, 6.86 mmol) were added and the mixture heated (70-75°C) until the starting substance disappeared. The reaction mixture was poured into water and saturated aqueous 35 NaC1 solution, and extracted with ether. The oil obtained was refluxed with a mixture of methanol 12 29-0CT-1999 22:11 +34 91556656? 975 P. 13 (17 mL) and an aqueous hydrochloric acid (17 mL) solution for Ih. The usual working of the reaction provided (-)4-[(4-fluarophenoxy)pheny])methyijpiperidine as an oil in a 64% yield-Treatment of this oil with L-dibenzoyltartaric acid in ethanol (96%, 35 mL) provided a precipitate which was filtered (m.p. = 193-194°C). The aminoether was released yielding a white solid with a 5 98% ee, m.p. = 100-I02°C, and [a]546 - 14, c = 0,2, CHC13). The following compounds were analogously prepared: (-)-4-[(4-niirophenoxy]pheny])methyl]piperidine, hydrochloride (98.7% ee, m.p. =59°C (d), [a].Q6 - 3 Lc = 0.042, Ethanol) " (+)-4-(l-naphrhyloxy](pheny1]methy1]piperidine, hydrochloride (94% ee, m.p. = 115BC (d), [a]M 10 -+156, c = 0.128, CHCl3)and (-)-4-[(2-fluorophenoxy)phenypmethyltpiperidine, sulfate (97.6% ee, m.p. = 90°C (d), [a]546 -31, c = 0.140, CHCl3). Examples (+/-)-4-[(3-fluorophendxy)(3-fluorophenyI)]methylpiperidine, sulfate 15 a mixrure of 4-cyanopiperidine (5 g, 40.92 mmol), (Boc)iO (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. this was extracted with dichloromethane and the organic phase dried (anh. NajSO A Mg (0-5 g) suspension in ether (dry, 22mL) was treated with some millilitres (approximately "/4 of the total) of a I-bromo-3-fluorobcnzene (2.15 mL, 19.4 mmol) solution in ether (dry, 16 mL) and an iodine crystal. This was heated until a smooth reflux was observed and the colour disappeared. The rest of the solution was then added dropwise maintaining a mild reflux. With the 25 addition at an end, this was refluxed for 1 h 30 min and allowed to cool down to room temperature. A 4-cyano-l-piperidinecarboxyIic acid ,1,1-dimethyl-ethylester (2.7 g, 12.S4 mmol) solution was added dropwise to dry ether (27 mL) and the resultant mixture refluxed for 3 h. A saturated aqueous NR|C! (50 mL) solution was added and extracted with ether. The usual trearmenr of the organic phase provided an oil which was purified by flash chromatography (Still, 30 W.C., Kahn, M., Mitra, A. J. Org. Chem, 1978, 43, 2923) yielding 2.4 g (61% yield) of 4-(3-fluorobenzoyD-l-piperidinecarboxylicacid, 1,1-dimethy-cthyIesteras a yellowish oil. The product obtained above (2.4 g, 7:8 mmol) was dissolved in methanol (30 mL) and NaBR, (0.2 g) dissolved in 3.5 mL water was added. The mixrure was heated for 2 h in an oil bath (50-60°C) and the product isolated in the usual manner, yielding (+/-)4-(3-fluoropheny|)hydroxy]methyl-l- 13 29-OCT-l999 22:11 +34 915566567 98% P14 -12- piperidinecarboxylic acid, 1,1-dimethyl-ethylester 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 added dropwise to an NaH (60%) (0.62 g) suspension in DMSO (15 mL). Potassium benzoate (1.53 g, 5 9.55 mmol) and 1,3-difItuorobenzene (12 mL, 11.9 mmol) were added and the mixture was heated in an oil bam (65-70°C) until the starting substance disappeared. This was then poured into a mixture of saturated NaC1 (50 mL) solution and warer (39 mL). This was extracted with ether and the usual treatment of the ethereal phase provided an oil which was refluxed with a mixture of methanol (40 mL) and aqueous HCI (10 %, 40 mL) solution for 1 h 30 min. The desired product 10 (+/-)-4-[(3-fluorophenoxy)(3-fluorophenyl)Jmechyl|piperidine was obtained as an amber oil in a 50% yield. RMN-"H (CDCl3) of this.product displayed a signal at 4,55 ppm (d. J = 6.1 Hz, CHOAr) and RMN-l3C (CDC13) a, signal at 83.9 ppm corresponding to CHOAr carbon. The oil prepared above was treated with a 0.22 mL cone. H2SO1 solution in 16.5 mL of water, yielding the sulfate as a slightly coloured solid (m.p. = 158°C (d)). 15 The following compounds were analogously prepared: (+/-)-4-[(2-fluorophenoxy)(3-fluon3phenyl)]rnethyl|piper dine, hydrochloride (62% yield, m.p. = 90°C) and (+A)-+-f(4-fluorophcnoxy)(3-fIuor)phenyl)]mediyl|piperidine, hydrochloride (30% yield, m.p. = 65°C). 14 29-0CT-1999 22:12 +34 91S5665S7 98% P-15 WE CLAIM: 1. 4-substituted piperidines, of general formula (I), in which 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, and their pharmaceutically acceptable salts with inorganic acids and organic acids of the kind such as herein described. 2. The 4-substituted piperidines of general formula (I) as claimed in claim 1, obtained as racemic mixtures or as pure enantiomers. 3. The 4-substituted piperidines of general formula (I) as claimed in claim 1 and 2 as listed below, obtained as racemic mixtures or pure enantiomers and their pharmaceutically acceptable salts: 4-[(phenoxyphenyl)methyl]piperidine, 4- [(4-fluorophenoxy) (phenyl) -methyl] -piperidine 4-[(4-methoxyphenoxy)(4-fluorophenyl)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-benzoylphenoxy)(phenyl)methyl]-piperidine 4-[(4-trifluoromethoxyphenoxy)(phenyl)methyl]-piperidine 15 4-[(4-cyaxiophenoxy)(phenyl)methyl]-piperidine 4-[(3-trifluorophenoxy)(phenyl)methyl]-piperidine 4-[(3-fluorophenoxy)(phenyl)methyl]-piperidine 4-[(4-bromophenoxy)(phenyl)methyl]-piperidine 4-[(4-nitrophenyloxy)(phenyl)methyl]-piperidine 4-[(4-chlorophenyl) (1 -naphthyloxy)methyl]-piperidine 4-[(l-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)methyl]-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 4-[(3-methoxy-5-fluorophenoxy)(phenyl)methyl]-piperidine, and 4-[(3-fluoro-5-cyanophenoxy)(phenyl)methyl]-piperidine. 16 4. 4-substituted piperidines substantially as herein described with reference to the foregoing examples. 5. Pharmaceutical compositions substantially as herein described with reference to the foregoing examples. Dated this 15th day of November, 1999

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