MXPA00004889A - Piperidinylaminomethyl trifluoromethyl cyclic ether compounds as substance p antagonists - Google Patents

Abstract

This invention provides a compound of formula (I) and its pharmaceutically acceptable salts, wherein R1 is C1-C6 alkyl;R2 is hydrogen, C1-C6 alkyl, halo C1-C6 alkyl or phenyl;R3 is hydrogen or halo;R4 and R5 are independently hydrogen, C1-C6 alkyl or halo C1-C6 alkyl;and n is one, two or three. These compounds are useful as analgesics or anti-inflammatory agents, or in the treatment of cardiovascular diseases, allergic disorders, angiogenesis, CNS disorders, emesis, gastrointestinal disorders, sunburn, urinary incontinence, or diseases, disorders or adverse conditions caused by i(Helicobacter pylori), or the like, in a mammalian subject, especially humans. Intermediates for preparation of the compounds of formula (I) are also disclosed.

Description

COMPOUNDS OF CYCLIC ETHERIES OF PIPERIDINH-AMINOMETHYL TRIFLUOROMETILO AS ANTAGONISTS OF THE SUBSTANCE P TECHNICAL FIELD This invention relates to novel cyclic ester compounds of piperidinylaminomethyl trifluoromethyl and their pharmaceutically acceptable salts, pharmaceutical compositions containing said compounds and to the use of said compounds as agonists of substance P.

PREVIOUS TECHNIQUE Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, so called for its rapid stimulatory action on smooth muscle tissue. More specifically, substance P is a pharmaceutically active neuropeptide that is produced in mammals (having been isolated at the beginning of the intestine) and possesses a characteristic amino acid sequence that is illustrated by D.F. Veber eí al. in U.S. Patent 4680283. The extensive implication of substance P and other tachykinins in the pathophysiology of numerous diseases has been amply demonstrated in the art. For example, it has been recently seen that substance P is involved in the transmission of pain or migraine, as well as in central nervous system disorders, such as anxiety and schizophrenia, in respiratory and inflammatory diseases, such as asthma. and rheumatoid arthritis, respectively, and in gastrointestinal disorders and diseases of the I Gl tract, such as ulcerative colitis, irritable bowel syndrome, Crohn's disease, etc. It has also been reported that tachykinin antagonists are useful for the treatment of cardiovascular diseases, allergic disorders, immunoregulation, vasodilation, bronchospasm, reflex or neuronal control of the viscera, senile dementia of the Alzheimer type, emesis, sunburn and infection with Helicobacter pylori. International Patent Publication No. WO 97/08144 discloses a wide variety of substituted piperidine compounds, including piperidine compounds having a substituent comprising a ring radical fused to an oxygen atom, as antagonists of substance P. Substance P antagonists have improved activity and fewer side effects.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides cyclic ether compounds of piperidinylaminomethyl trifluoromethyl with the following chemical formula (I): (1) and its pharmaceutically acceptable salts, wherein 1 is alkyl d-Ce; R 2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or phenyl; R3 is hydrogen or halogen; R 4 and R 5 are independently hydrogen, alkyl or C 1 -C 2 haloalkyl; and n is one, two or three. These compounds are useful as substance P antagonists and, therefore, are useful for the treatment of a disorder or disease selected from cardiovascular diseases, allergic disorders, angiogenesis, gastrointestinal disorders, central nervous system disorders, inflammatory diseases, emesis, incontinence. urinary, pain, migraine, severe anxiety disorders, stress disorders, anxiety, major depressive disorders, major depressive disorders with anxiety, depression, sunburn, sexual dysfunction, bipolar disorders, substance use disorders, schizophrenic disorders, movement disorders , cognitive disorders and diseases, disorders and adverse alterations caused by Helicobacter pylori, or similar, in a mammal, especially a human being. These compounds are especially useful as anti-inflammatory agents or anti-emetic agents or agents for the treatment of CNS disorders. Such CNS disorders include major depressive disorder, depression, major depressive disorder with anxiety, dystemia, manic depression (bipolar or cyclothymic disorder), anxiety disorder, obsessive-compulsive disorder (OCD), panic disorder, stress syndrome of post-traumatic phobias, neuralgia and cognitive disorders, such as dementia and amnestic disorder. These compounds are also useful for La Tourette syndrome, the akinetic rigidity syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia and other dyskinesias. These compounds are especially useful in the treatment of emesis, including acute, recall or anticipatory emesis, such as emesis or nausea induced by chemotherapy, radiation, surgery, pregnancy, movement, vestibular disorders, toxins, migraine and variations in the intracranial pressure. More specifically, these compounds are useful in the treatment of emesis induced by antineoplastic agents, including those used in anti-carcinogenic therapy and emesis induced by other pharmacological agents, such as rolipram or morphine. These compounds are also useful as antagonists of substance P with a lower susceptibility to metabolism in a mammal, especially a human. These compounds are also useful for chronic and acute pain, including hypertenal pain, neuropathic pain, post-operative pain and pain associated with nerve damage. The present invention also relates to a pharmaceutical composition for the treatment of a disorder or disease for which the antagonistic activity against substance P is required, in a mammal, which contains an amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, which is effective for the treatment of said disorder or disease and a pharmaceutically acceptable carrier The invention also relates to a method for the treatment of a disorder or disease for which antagonist activity against the substance is required P, in a mammal, comprising administering to a mammal in need of such treatment an amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, which is effective for the treatment of said disorder or disease. The invention also relates to a pharmaceutical composition for the treatment of a disorder selected from cardiovascular diseases, allergic disorders, angiogenesis, gastrointestinal disorders, central nervous system disorders, inflammatory diseases, emesis, urinary incontinence, pain, migraine; severe anxiety disorders, stress disorders, anxiety, major depressive disorders, major depressive disorders with anxiety, depression, sunburn, sexual dysfunction, bipolar disorders, substance use disorders, schizophrenic disorders, movement disorders, cognitive disorders and diseases, disorders and adverse alterations caused by Helicobacter pylori in a mammal, especially in a human being, comprising an amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof, which is effective in the prevention of said disorder or disease. The invention also relates to a method for the treatment of a disorder selected from cardiovascular diseases, allergic disorders, angiogenesis, gastrointestinal disorders, central nervous system disorders, inflammatory diseases, emesis, urinary incontinence, pain, migraine, severe anxiety disorders, disorders. of stress, anxiety, major depressive disorders, major depressive disorders with anxiety, depression, sunburn, sexual dysfunction, bipolar disorders, substance use disorders, schizophrenic disorders, movement disorders, cognitive disorders and diseases, disorders and alterations caused by Helicobacter pylori in a mammal, especially in a human being, comprising administering to a mammal that requires said treatment an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is effective in the prevention of attachment of said disorder or disease.

The term "treating", as used herein, refers to the regression, alleviation or inhibition of the progress of, or prevention of, the disorder or disease to which the term or one or more symptoms of said disorder or condition applies. disease. The term "treatment", as used herein, refers to the act of treating, being "treated" as defined immediately above.

DETAILED DESCRIPTION OF THE INVENTION In this specification, the term "halogen" means F, Cl, Br and I, preferably Cl or F. The term "alkyl" as used herein refers to straight or branched chain saturated radicals including, but not limited to methyl, ethyl, n-propyl, isopropyl and t-butyl. The term "haloalkyl C? -C6" is. used herein to denote a straight chain, branched or cyclic C 1 -C 7 alkyl substituted with one or more (preferably one to seven) halogens. These compounds include, but are not limited to, trifluoromethyl, difluoroethyl, trifluoroethyl, pentafluoroethyl, trifluoroisopropyl, tetrafluoroisopropyl, pentafluoroisopropyl, hexafluoroisopropyl and the like. The compounds of formula (I) contain at least two chiral centers and, therefore, there exist at least two diastereoisomeric pairs of optical isomers including the epimers. This invention initiates both individual isomers of the compounds of formula (I) together with mixtures thereof. A preferred group of compounds of formula (I) is wherein R 1 is C 1 -C 3 alkyl; R2 is hydrogen, C1-C3 alkyl, C1-C3 haloalkyl or phenyl; R3 is hydrogen or fluorine; R 4 and R 5 are independently hydrogen, C 1 -C 3 alkyl or C 1 -C 3 haloalkyl; and n is one or two. A more preferred group of compounds of formula (I) is that in which R1 is methyl; R2 is hydrogen, methyl, trifluoromethyl or phenyl; R3 is hydrogen and R4 and R5 are hydrogen. The compounds of formula (I) preferably have the (2S, 3S) configuration with the piperidine ring. The preferred individual compounds are: (2S, 3S) -3- (6-methoxy-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl) methylamino-2-phenylpiperidine or its salts; (2S, 3S) -3- (6-methoxy-1-methyl-1-trifluoromethyl-4-yichroman-7-yl) methylamino-2-phenylpiperidine or its salts; (2S, 3S) -3- (6-methoxy-3-methyl-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl) methylamino-2-phenylpiperidine or its salts; (2S, 3S) -3- (6-methoxy-3-phenyl-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl) methylamino-2-phenylpiperidine or its salts; and (2S, 3S) -3- [1 - (6-methoxy-3-methyl-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl) ethylamino] -2-phenylpiperidine or its salts. Particularly preferred individual compounds are (2S, 3S) -3 - [(1 R) - (6-methoxy-1-methyl-1-trifluoromethyl-isochroman-7-yl] methylamine-2-phenylpiperidine or its salts, and (2S, 3S) -3 - [(3R) - (6-methoxy-3-methyl-3-trifluoromethyl-1,3-dihydro-benzofuran-5-yl) methylamino-2-phenylpiperidine or its Also, the present invention provides a compound of formula (III): (lll) wherein W is hydrogen or Q (O =) C-, wherein Q is H, C-t-Cd alkyl or haloalkyl C-I-CT; R1 is C? -C? Alkyl (preferably methyl); R 2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or phenyl (preferably hydrogen, methyl, trifluoromethyl or phenyl) and n is one, two or three (preferably one or two). These compounds of formula (III) can be used as intermediates to prepare the compounds of formula (I). The compounds of formula (III) contain a chiral center. Accordingly, this invention also includes both individual isomers of the compounds of formula (lll) together with the mixture thereof. Preferred compounds of formula (III) include the enantiomeric pairs of 5-methoxy-1-trifluoromethyl-1,3-dihydroisobenzofuran; 6-methoxy-3-trifluoromethyl-1,3-dihydrobenzofuran-5-carbaldehyde; 5-methoxy-1,1-bistrifluoromethyl-1,3-dihydrobenzofuran; 6-methoxy-3,3-bis- (trifluoromethyl) -1,3-dihydroisobenzofuran-5-carbaldehyde; 6-methoxy-1-methyl-1-trifluoromethyl isochroman; 6-methoxy-1-methyl-1-trifluoromethyl-isochroman-7-carbaldehyde; 5-methoxy-1-methyl-1-trifluoromethyl-1,3-dihydroisobenzofuran; 6-methoxy-3-methyl-3-trifluoromethyl-1,3-dihydro-benzofuran-5-carbaldehyde; 1-trifluoromethyl-5-methoxy-1-phenyl-1,3-dihydroisobenzofuran; 3-trifluoromethyl-6-methoxy-3-phenyl-1,3-dihydroisobenzofuran-5-carbaldehyde; and 5-acetyl-3-methyl-6-methoxy-3-trifluoromethyl-1,3-dihydroisobenzofuran. Especially preferred compounds of formula (III) include: (1 R) -6-methoxy-1-methyl-1-trifluoromethyl isochroman; (1 R) -6-methoxy-1-methyl-1-trifluoromethyl-isochroman-7-carbaldehyde; (1 S) -6-methoxy-1-methyl-1-trifluoromethyl isochroman; (1 S) -6-methoxy-1-methyl-1-trifluoromethyl-isochroman-7-carbaldehyde; (1 R) -5-methoxy-1-methyl-1-trifluoromethyl-1,3-dihydroisobenzofuran; (1 R) -6-methoxy-3-methyl-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-carbaldehyde; (1 S) -5-methoxy-1-methyl-1-trifluoromethyl-1,3-dihydroisobenzofuran, and (1 S) -6-methoxy-3-methyl-trifluoromethyl-1,3-dihydroisobenzofuran-5-carbaldehyde.

General Synthesis: The cyclic piperidinylaminomethyl trifluoromethyl ether compounds of formula (I) of this invention can be prepared as described in the following reaction schemes. Unless indicated otherwise, in the following reaction schemes R1, R2, R3, R4, R5, Q and n are as defined above and Z represent hydrogen or amino protecting group. Scheme 1 illustrates a method of preparing a compound of formula (la) by reductive alkylation of a compound (II) with a compound (III).

SCHEME 1 A compound of formula (la), wherein Z is hydrogen or an amino protecting group, can be synthesized by reductive alkylation of an amine compound of formula (II) with a compound of formula (III) according to known procedures which has been described in International Patent Publication No. WO 97/03066. The reaction can be carried out in the presence of an appropriate reducing reagent in a solvent inert to the reaction. Suitable reducing reagents are, for example, borohydrides, such as sodium triacetoxyborohydride (NaB- (OAc) H), sodium borohydride (NaBH4) and sodium cyanoborohydride (NaBH3CN), boranes, lithium aluminum hydride (LiAIH2) and trialkylsilanes. Suitable solvents include polar solvents, such as methanol, ethanol, methylene chloride, tetrahydrofuran (THF), dioxane, and ethyl ace. The reaction can be carried out from about -78 ° C to reflux temperature of the solvent, preferably from 0 to 25 ° C for 5 min to 48 hours, preferably 0.5 to 12 hours. Preferably, compounds in which Q is other than hydrogen can be obtained by reaction of the compound (II) with the compound (III) in which W is an acyl group. This reaction can be carried out in the presence of a reducing agent, such as NaBH3CN and a Lewis acid, such as tin (IV) chloride (TiCl) in a reaction-inert solvent, such as dichloromethane. { Tetrahedron Letter, Vol. 31, p. 5547, 1990). When Z is an amino protecting group, the amino protecting group can be removed after reductive alkylation using methods known to a person skilled in the art (see, for example, Protective Groups in Organic Synthesis, TW Greene, et al. , John Wiley &Sons, Inc., 1991) to obtain the compound of formula (I). Specifically, when Z is tert-butoxycarbonyl (abbreviated as "Boc"), Boc can be removed in the presence of an acid, such as HCl in a reaction-inert solvent, such as methanol, in an inert atmosphere (e.g. , nitrogen atmosphere). A starting material of the formula (II) can be prepared by protecting the nitrogen of a compound (2S, 3S) -3-amino-2-phenylpiperidine, which can be prepared by the known methods, as described, by example, in International Patent Publication No. WO 92/17449. The protection of the piperidine ring nitrogen from the compounds of the formula (II) can be carried out according to known procedures, as described for example in International Patent Publication No. WO 97/03066. Suitable protecting groups are, for example, Boc, benzyloxycarbonyl chloride (abbreviated as Cbz) or trifluoroacetyl. For example, protection of nitrogen with Boc can be carried out by treatment of the compound (2S, 3S) -3-amino-2-phenylpiperidine with (t-BuOCO) 2 in the presence of a base, such as sodium hydroxide, sodium bicarbonate or triethylamine. The compounds of formula (III) can be prepared by formylation or acylation of the compounds of formula (IV) as illustrated in scheme 2.

SCHEME 2 The known formylation or acylation methods can be used. For example, direct formylation can be performed by contacting the compound (IV) with an appropriate formulating agent in the presence of an appropriate catalyst. Suitable formilant / catalyst agent systems include methyl dichloromethyl ether / titanium (IV) chloride (CH2CHOCH3 / TiCl4), trifluoroacetic acid (CF3CO2H) / hexamethylenetetramine (modified Duff conditions) and phosphoryl trichloride (POCI3 / DMF) (Vilsmeier conditions) . More specifically, the formylation of the compound (IV) with CH 2 CHOHCH 3 / TiCl 4 can be carried out in an inert solvent for the reaction under a nitrogen atmosphere. Suitable solvents include dichloromethane and 1,2-dichloroethane from about -120 ° C to room temperature for about 1 minute to about 10 hours, preferably -78 ° C for 5 minutes to 4 hours. The Duff reaction can also be applied to the formylation according to the reaction conditions, described in the international patent publication WO 94/24081. Also, an appropriate indirect formylation method comprises (i) the halogenation of the compound (IV), (ii) the substitution of the halogen atom for a cyano group and then (iii) subjecting the substituted compound with resulting cyano to reduction, (i) ) Halogenation can be carried out according to known procedures such as that published by GA Olah et al. (J. Org. Chem., Vol. 58, pp. 3194-.1983). (I) Substitution of the halogen atom by a cyano group can be carried out according to known procedures as published by D.M. Tsachaem. et al, (Synth. Commun., Vol. 24, pp. 887-.1994) or K. Takagi et al, (Bull. Chem. Soc. Jpn., Vol. 64 pp. 1 18-1 19). (iii) The reduction, as used herein, can be carried out in the presence of diisopropylaluminum hydride (DIBAL-H) in dichloromethane or Ni Raney in formic acid. Acylation can be performed by the well known Friedel-Crafts acylation described, for example, in Advanced Organic Chemistry by Jerry March, John Wiley & Sons, fourth edition, 1992, p. 539, and the references cited therein. More specifically, the compound (IV) can react with an acylating agent in the presence of an acid catalyst to give the compound (III). Suitable acylating agents include acyl chloride, acyl fluoride and anhydrides, preferably acyl chloride. Suitable acidic catalysts include sulfuric acid and Lewis acid, such as aluminum chloride, preferably aluminum chloride. This reaction can be carried out typically at a temperature ranging from about -10 ° C to room temperature, for about 5 minutes to 2 hours, preferably at about 0 ° C for about 1 hour. A cyclic ether of formula (IV) can be prepared from a compound of formulas (Va) or (Vb) according to known procedures, as W.E. Parham went to. . { J. Org. Chem., Vol. 39, pgs. 2048, 1974) or the procedures illustrated in scheme 3.

SCHEME 3 In route A of scheme 3, a compound of formula (IV) can be synthesized from a compound of formula (Va), wherein Y 1 is Br, I or Cl (preferably Br) and Y 2 is hydrogen or a group hydroxy protector (appropriately tetrahydropyranyl, abbreviated as "THP"). The compound of formula (Va) can be metallized by treatment with an organometallic compound. The reaction mixture can be further treated with a carbonyl compound represented by CF3C (= O) R2 giving the diol (Ve). If necessary, the hydroxy protecting group Y2 can be removed from the diol (Ve). Next, the diol (Ve) can be cyclized to give the cyclic ether compound (IV). The metallization of the compound (Va) can be carried out in the presence of an organometallic compound, such as n-butyllithium, sec-butyllithium, or tert-butyllithium. The metallization and the subsequent reaction with CF3C (= O) R can be carried out in an inert solvent for the reaction, such as THF, ether and hexane, under an inert atmosphere, for example, in nitrogen, from about -150 °. C up to room temperature for 15 minutes up to 12 hours, preferably from -120 ° C to -30 ° C for 10 minutes up to 6 hours. The protection and deprotection of the hydroxy with protecting group Y2 can be carried out under appropriate conditions depending on the protecting group chosen according to the known methods (see for example Protective Groups in Organic Synthesis by T. W. Greene et al., Published by John Wiley & amp;; Sons, Inc.). Cyclization of the diol (Ve) can be carried out in the presence of an acid according to known methods published, for example, by W. E. Parham et al. . { Synthesis, pages. 16, 1976) or D. Seebach et al,. { Chem. Ber., Vol. 1 16, p. 8354-1994). Suitable acids are, for example, HCL, H2SO4 or p-toluenesulfonic acid, trifluoroacetic acid (abbreviated as TFA). The reaction can be carried out at from about room temperature to about 200 ° C for 10 minutes up to 12 hours, preferably at 60 ° C up to 150 ° C for 30 minutes up to 6 hours. Alternatively, the cyclization can be carried out according to known procedures such as the Mitsunobu reaction or the methods published by J. R. Falck et al. (J. Am. Chem. Soc, Vol, 116, pp. 8354-, 1994). For example, the Mitsunobu reaction can be carried out in the presence of triphenylphosphine / diethyl azodi-carboxylate in an appropriate solvent, such as dichloromethane under nitrogen at about 0 ° C for from about 5 minutes to 6 hours. In route B of scheme 3, a cyclic ether compound of formula (IV) can be synthesized by subjecting a compound of formula (Vb), in which Y3 is a leaving group, to a one-step cyclization with CF3C (= O) R2 in the presence of an appropriate base (see for example, J. Org. Chem., Vol. 41, pp. 1 184-1976). Suitable leaving groups include Cl, Br, tosylate, mesylate or triflate. Suitable bases include alkyl lithium, such as n-Bu-Li, sec-BuLi or t-BuLi. For example, the reaction can be carried out by first treating a compound of formula (Vb) with n-BuLi in a reaction-inert solvent, such as THF / hexane, in nitrogen from about -120 ° C to 0 ° C during the reaction. about 5 minutes to 12 hours, preferably from -100 ° C to -60 ° C for 10 minutes to 6 hours. Subsequently, the carbonyl compound CF3C (= O) R2 can be added to the reaction mixture and the temperature can be raised to about -50 ° C to room temperature. On the other hand, for example, a starting material of formulas (Va) and (Vb), in which R1 is methyl, can be prepared by bromination in the para position of a known or commercially available anisole according to known methods (for example, J. Org. Chem., Vol. 58 pp. 7507-, 1993 and J. Org. Chem., Vol. 46, pp. 1 18-, 1981).

Unless stated otherwise, the pressure of each of the above reactions is not critical. Generally, the reactions will be carried out at a pressure of about one to about three atmospheres, preferably at ambient pressure (about one atmosphere). The compounds of formula (I) and the intermediates shown in the above reaction schemes can be isolated and purified by conventional procedures, such as crystallization or chromatographic separation. Since the cyclic piperidinylamino-methyl trifluoromethyl ether compounds of this invention possess at least two asymmetric centers, they can exist in various stereoisomeric forms or configurations (e.g., diastereomers including epimers). Accordingly, the compounds can exist in separate optically active forms (-) and (+), as well as mixtures thereof. The present invention includes all these forms in its scope. All optical isomers and stereoisomers of the compounds of formula (I), (II) and mixtures thereof are considered to be within the scope of the invention. With respect to the compounds of formula (I) and (II), the invention includes the use of the recemate, one or more enantiomeric mixtures, one or more diastereomeric forms or mixtures thereof. The compounds of formula (I) and (II) may also exist as tautomers. This invention also relates to the use of said tautomers and mixtures thereof. The individual isomers can be obtained by known methods, such as optical resolution, fractional crystallization, chromatography or H.P.L.C. of a diastereomeric mixture of an intermediate, or a compound of formula (I) or an appropriate salt thereof. Also, individual stereoisomers can be synthesized from the appropriate optically active starting materials or intermediates using any of the general procedures described herein. Because the cyclic piperidinylaminomethyl trifluoromethyl ether compounds of this invention are basic compounds, they are all capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the basic compound of this invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert it into the free base compound by treatment with an alkaline reagent and then converting the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of this invention are readily prepared by treating the basic compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent or in an appropriate organic solvent, such as methanol or ethanol. By carefully evaporating the solvent, the desired solid salt is easily obtained. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned basic compounds of this invention are those which form non-toxic acid addition salts, ie, salts containing pharmaceutically acceptable anions, such as the salts hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate, or acid phosphate, acetate, lactate, citrate or citrate acid, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p toluenesulfonate and pamoate (ie 1,1'-methylene-bis- (2-hydroxy-3-naphthoate) The cyclic piperidinylaminomethyl trifluoromethyl ether compounds of the present invention exhibit significant receptor binding activity of the substance P and, therefore, have value for the treatment of a wide variety of clinical disorders that are characterized by p resence of an excess of said activity of the substance P. Such disorders include cardiovascular diseases, allergic disorders, angiogenesis, gastrointestinal disorders, central nervous system disorders, inflammatory diseases, emesis, urinary incontinence, pain, migraine; severe anxiety disorders, stress disorders, anxiety, major depressive disorders, major depressive disorders with anxiety, depression, sunburn, sexual dysfunction, bipolar disorders, substance use disorders, schizophrenic disorders, movement disorders, cognitive disorders and diseases, disorders and adverse alterations caused by Helicobacter pylori, or the like, in a mammal, especially a human. For the treatment of emesis, these compounds can be used frequently in combination with a 5HT3 receptor antagonist. The piperidinylaminomethyl trifluoromethyl cyclic ether compounds of formula (I) of this invention or their pharmaceutically acceptable salts can be administered orally or parenterally (for example, intravenously, intramuscularly or subcutaneously) or topically to mammals. In general, these compounds are most desirably administered in humans in doses ranging from about 0.3 mg to 750 mg per day, although variations will necessarily occur depending on the weight and condition of the subject to be treated and the particular route of administration chosen. However, a dosage level in the range of about 0.06 mg to about 6 mg per kg of body weight is more desirably employed. However, variations may occur depending on the species of animal to be treated and its individual response to said medicament, as well as the type of pharmaceutical formulation chosen and the period of time and interval with which said administration is carried out. In some cases, dosage levels below the lower limit of the aforementioned range may be adequate, while in other cases even higher doses may be employed without harmful side effects, provided that these higher dosage levels They are first divided into several smaller doses for administration throughout the day.

The piperidinylaminomethyl trifluoromethyl cyclic ether compounds of the present invention can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the previously mentioned routes, said administration being carried out in single or multiple doses. More especially, the novel therapeutic agents of the invention can be administered in a wide range of different dosage forms, i.e., they can be combined with various inert pharmaceutically acceptable carriers in the form of tablets, capsules, tablets, troches, hard candies, powders. , sprays, creams, ointments, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such vehicles include diluents or solid fillers, sterile aqueous media and various non-toxic organic solvents, etc. Also, oral pharmaceutical compositions can be sweetened and / or flavored. In general, the therapeutically effective compounds of this invention are present in said dosage forms at concentration levels ranging from about 5.0% to about 70% by weight. For oral administration, tablets containing various excipients may be used, such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine together with various disintegrants, such as starch (and preferably corn starch, potato or tapioca), acid alginic and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. Additionally, lubricating agents, such as magnesium stearate or sodium lauryl sulfate and talc are often very useful for the manufacture of tablets. Solid compositions of a similar type can also be used as fillers in gelatin capsules; Preferred materials in this regard also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When what is desired are aqueous suspensions and / or elixirs for oral administration, the active ingredient can be combined with various sweetening or flavoring agents, colorants or dyes, and if desired, also emulsifying and / or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and various similar combinations thereof. For parenteral administration, solutions of a compound of the present invention may be employed in sesame or peanut oil or in aqueous propylene glycol. The aqueous solutions should be buffered appropriately (preferably pH> 8) if necessary, making the liquid diluent first isotonic. These aqueous solutions are suitable for intravenous injections. Oily solutions are suitable for intra-articular, intra-muscular and subcutaneous injections. The preparation of all these solutions under sterile conditions is easily accomplished by the pharmaceutically standard techniques well known to those skilled in the art.

Additionally, it is also possible to administer the compounds of the present invention, topically for the treatment, for example, of inflammatory disorders of the skin, this being possible by means of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice. The activity of the compounds of the present invention, as antagonists of substance P, can be determined by their ability to inhibit the binding of substance P to their receptor sites in CHO cells, which express the NK1 receptor or cells IM-9 using radioactive agents. The antagonist activity of substance P of the cyclic ether compounds of piperidinylaminomethyl trifluoromethyl can be evaluated using the standard assay procedure described by D. G. Payan et al.,. { The Journal of Immunology, Vol. 133, p. 3260, 1984): This method essentially involves determining the concentration of the individual compound required to reduce by 50% the amount of radioactively labeled substance (SP) that reacts with its receptor sites in said isolated cow tissues or IM- cells. 9, obtaining characteristic Cl50 values for each compound tested. More specifically, the inhibition of the binding of [3H] Sp to human IM-9 cells by the compounds is determined in a test buffer (50 mM Tris-HCl, pH 7.4), 1 mM MnCl 2, bovine serum albumin 0.02%, bacitracin (40 μg / ml), leupeptin (4 μg / ml), chymostatin (2 μg / ml) and phosphoramidon (30 μg / ml). The reaction is initiated with the addition of cells to the assay buffer containing [H] SP 0.56 nM and various concentrations of compounds (total volume: 0.5 ml) and incubation for 120 minutes at 4 ° C. The incubation concludes by filtration in GF / B filters (previously impregnated in 0.1% polyethyleneimine for 2 hours). The non-specific binding is defined as the remaining radioactivity in the presence of 1 μM SP. The filters are placed in tubes and a count is made using a liquid scintillation counter. Alternatively, the anti-inflammatory activity of the compounds of this invention, in the periphery of a mammal, is demonstrated by a plasma extravasation assay induced by capsaicin, using the procedure described by A. Nagahisa et al.,. { European Journal of Pharmacology, Vol. 217 p. 191-195, 1992). In this assay, anti-inflammatory activity is determined by the percentage of inhibition of plasma protein extravasation in the ureter of a male Hartey guinea pig (300-350 g weight) anesthetized with pentobarbital (25 mg / kg i.p.). Extravasation of the plasma is induced by intraperitoneal injection of capsaicin (30 μM in BSA 0.1 containing buffer, 10 ml / animal) in the animals, which fasted overnight. The compounds of this invention were dissolved in 0.1% methylcellulose-water and administered orally 1 hour before stimulation with capsaicin. Evans blue dye (30 mg / kg) was administered intravenously 5 minutes before stimulation. The animals were sacrificed 10 minutes after the injection with capsaicin and the left and right ureters were removed. The content of the dyed fabric was quantified at 600 nm of absorbance after extraction with formamide overnight. The compound prepared in Example 3 of this invention showed a 98% inhibition with 0.03 mg / kg, while the structurally most related compound in Example 18 of WO 97/081 14 showed 72% with the same dosage. The adverse effect on the binding affinity to the Ca2 + channels is determined by studying the binding of varapamil in a rat heart membrane preparation. More specifically, binding to verapamil is performed as previously described by Reynolds et al.,. { J. Pharmacol. Exp. Ther. Vol. 237, p. 731, 1986). In summary, incubations are initiated with the addition of tissues to tubes containing [3H] desmetoxiverapamil 0.25 nM and various concentrations of compounds (total volume 1 ml). The non-specific binding is defined as the remaining binding to the radioactive ligand in the presence of 3-10 μM methoxiverapamil. The activity of the compounds of this invention against central nervous system disorders is determined in a paw test given with the legs induced by [Sar9, Met (O2) 11] substance P in gerbils, using a modification of the NMJ Rupniak method . { European Journal of Pharmacology, Vol. 265 p. 179-183, 1994) and L. J. Bristow. { European Journal of Pharmacology, Vol. 253 p. 245-252, 1994). More specifically, first a compound of this invention is subcutaneously administered to a gerbil. Second, gerbils are lightly anesthetized with ether and the cranial surface is exposed. In third place, is administered directly [Sar9, Met (O2) 11] substance P (5 μl) into the lateral ventricles by a 25 gauge needle inserted 3.5 mm below lambda. Next, the gerbils were placed individually in 1-liter beakers and the repetitive movement of beats with the claws of the legs was controlled. The anti-emetic activity of the compounds of this invention can be demonstrated in emesis assays induced by cisplatin in ferrets. A compound of this invention is administered subcutaneously to ferrets (males, p.c. = 13-1.6 kg) 30 minutes before injections with cisplatin. Cisplatin is injected intraperitoneally to ferrets, recording their emetic episodes (ie, retching, vomiting and nausea) by means of a video camera for 4 hours. The frequency of the episodes is counted. Some compounds of this invention exhibited a good anti-emetic activity in the assays (DE90 from 0.05 mg / kg to 0.1 mg / kg). The susceptibility of the compounds of this invention to be metabolized can be evaluated by an in vitro assay comprising (a) contacting a test compound with a reagent composition prepared by the addition of a cytochrome P-450 specific isoenzyme (eg, CYP2D6) isoenzyme for poor metabolizers (abbreviated as PM) hepatic microsomes (i.e. hepatic microsomes of an individual lacking said cytochrome P-450 specific isoenzyme) in a carrier material and (b) analysis of the substrate by a mass spectrometer attached to an HPLC (high performance liquid chromatography). More specifically, the substrate (1 μM) is incubated with human microsome PM (manufactured by Keystone Skin Bank) supplemented with a recombinant liver microsome expressing CYP2D6 (0-0.1 mg / ml) or microsomes in a control vector in the presence of NADP (nicotinamide-adenine dinucleotide-phosphate) 1.3 mM, NADH (reduced nicotinamide adenine dinucleotide phosphate) 0.9 mM, 3.3 mM MgCl2 and 8 units / ml G-6-PDH (glucose-6-phosphate dehydrogenase) respectively in a total volume of 1.2 ml of 100 mM potassium phosphate buffer. The pH of the solution is 7.4 and the temperature of the incubation is 37 ° C. At specific incubation times (0, 5, 10, 30 and 60 minutes), an aliquot of 100 μl of the reaction mixture is extracted and mixed with 1 ml of acetonitrile (ACN) containing 5 ng / ml of (2S , 3S) -3- (2-methoxybenzylammon) -2-diphenylmethyl-1-azabicyclo [2.2.2] octane as an internal standard (prepared according to the procedures described in WO / 05729). The protein is subsequently precipitated by centrifugation (1800 x g for 10 minutes) and the resulting supernatant is collected. The concentration of the substrates and products in the sample solutions is analyzed by a Sciex API-MI mass spectrometer coupled to an HPLC HP1090 system from Hewlett-Packard. The concentrations of the remaining substrates in each sample solution (% remaining) are plotted against the incubation times in a curve. The values of T -? / 2 are obtained in each graph. Calculate the quotients of the T z values of the compound tested (ie, quotient T1 2 = (T 2 per microsome with control vector) / (T? / 2 per microsome expressing CYP2D6 supplemented with human liver microsome PM)). Some compounds prepared in the following working examples had a lower susceptibility to be metabolized compared to the more structurally related compounds of the international patent publication WO 97/081144.

EXAMPLE The present invention is illustrated by the following examples. However, it should be understood that the invention is not limited to the specific details of these examples. The melting points were taken on a microscopic observation apparatus of Buchi melting points and are not corrected. The infrared absorption (IR) spectra were measured with a Shimadzu infrared spectrometer (IR-470). Nuclear magnetic resonance spectra of 1H (NMR) were measured in CDCI3 with a JEOL NMR spectrometer (JNM-GX270, 270 MHz for 1H) unless otherwise indicated and the positions of the peaks are expressed in parts per million (ppm) downfield of tetramethylsilane. The shapes of the peaks are the following: s, singlet; d, doublet; t, triplet; m, mutiplete.

EXAMPLE 1 Preparation of (2S, 3S) -3- (6-methoxy-3-trifluoromethyl-1, 3-dihydroisobenzon-5-yl) ritylamino-2-phenylpiperidine dihydrochloride (i) 2-Bromo-5-methoxybenzyl alcohol To a stirred suspension of lithium aluminum hydride (1.2 g, 30.6 mmol) in dry tetrahydron (40 ml) was added dropwise a solution of 2-bromo-5-methoxybenzoate of methyl (5.0 g, 20.4 mmol) in dry tetrahydron (80 ml) in nitrogen at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 hour. Sodium decahydrate sulfate and potassium fluoride were added to the reaction mixture. The resulting mixture was stirred at room temperature for 1 hour and filtered through a pad of celite. The filtrate was concentrated giving crude products as a white crystal. This was purified by column chromatography on silica gel eluted with a gradient of hexane and ethyl acetate (10: 1.8: 1.6: 1) to give the title compound as a white crystal (4.2 g, 94%). 1 H NMR (CDCl 3): 7.42 (d, J = 8.8 Hz, 1 H), 7.07 (d, J = 2.9 Hz, 1 H), 6.72 (dd, J = 8.8, 2.9 Hz, 1 H), 4.71 ( d: J = 6.2 Hz, 2H), 3.81 (s, 3H), 1.98 (t, J = 6.2 Hz, 1 H).

(I) 2- (2-Bromo-5-methoxybenzyloxytetrahydropyran) To a stirred mixture of 2-bromo-5-methoxybenzyl alcohol (3.91 g, 18.0 mmol) and dihydropyran (3.3 ml, 36.0 mmol) in dry dichloromethane (80 ml) camphorsulfonic acid (210 mg, 0.9 mmol) was added under nitrogen at 0 ° C. The reaction mixture was stirred at 0 ° C. for 1 hour.The reaction mixture was quenched with a saturated solution of aqueous sodium bicarbonate and stirred. The organic extracts were washed with brine, dried over magnesium sulfate and concentrated to give a crude product.This was purified by column chromatography on silica gel eluted with a solvent mixture of hexane and ethyl acetate. 1) giving the title compound as a colorless oil (5.68 g, quant.) 1 H NMR (CDCl 3): 7.40 (d, J = 8.8 Hz, 1 H), 7.10 (d, J = 3.3 Hz, 1 H), 6.69 (dd, J = 8.8, 3.3 Hz, 1 H), 4.80-4.76 (m, 2H), 4.53 (d, J = 13.6 Hz, 1 H), 3.97-3.88 (m, 1 H), 3.79 (s, 3H), 3.60-3.53 (m, 1 H), 1.93-1.54 (m, 6H). íip! 2,2,2-Trifluoro-1- (4-methoxy-2- (tetrahydropyran-2-loxymethyl) phenyl) ethanol To a stirred solution of 2- (2-bromo-5-methoxybenzyloxy) tetrahydropyran (1.0 g , 3.32 mmol) in dry tetrahydrofuran (20 ml) was added dropwise n-butyllithium (2.6 ml, 4.32 mmol) in nitrogen at -78 ° C. The reaction mixture was stirred at -40 ° C for 25 hours. To the reaction mixture was added dropwise a solution of trifluoromethylacetaldehyde (0.7 ml) in dry tetrahydrofuran (2 ml) at -78 ° C. After 2 hours at the same temperature, the reaction was quenched with a solution of saturated sodium bicarbonate, ammonium chloride and extracted with dichloromethane. The organic layers were dried over magnesium sulfate and concentrated to give crude products, which were purified by column chromatography on silica gel eluted with a gradient of hexane and ethyl acetate (30: 1, 20: 1 10: 1, 6: 1, 5: 1) to give the title compound as a colorless oil (390 mg, 36.7%). 1 H NMR (CDCl 3): 7.53 (d, J = 8.4 Hz, 1 H), 6.94 (d, J = 2.9 Hz, 1 H), 6.89 (dd, J = 8.4, 2.9 Hz, 1 H), 5.36- 5.25 (m, 1 H), 4.85 and 4.78 (each d, J = 12. 1 Hz, total 1 H), 4.69-4.63 (m, 1 H), 4.58 and 4.51 (each d, J = 12.1 Hz, total 1 H), 3.88-3.70 (m, 2H), 3.81 (s, 3H ), 3.56-3.51 (m, 1 H), 1.85-1.50 (m, 6H). (iv) 2,2,2, Trifluoro-1- (2-hydroxymethyl-4-methoxyphenyl) ethanol A mixture of 2,2,2-trifluoro-1- (4-methoxy-2- (tetrahydropyran-2-yloxymethyl) phenyl) ethanol (390 mg, 1.22 mmol) and a solvent mixture of acetic acid: tetrahydrofuran: water (4: 2, 1.24 ml) was stirred at room temperature for 2 hours. The reaction temperature was allowed to rise and was maintained at 40 ° C for 1.5 hours and then at 60 ° C for 2 hours. The solvent was removed and the residue was dried in vacuo to give the crude material of the title compound as a slightly yellow oil (410 mg). This material was used without further purification. (v) 5-Methoxy-1-trifluoromethyl-1,3-dihydroisobenzofuran To an ice-cooled solution of 2,2,2-trifluoro-1- (2-hydroxymethyl-4-methoxyphenyl) ethanol (160 mg, 0.54 mmol) and triphenylphosphine (312 mg, 1.19 mmol) in dry dichloromethane (6 ml) was added dropwise a solution of diethyl azodicarboxylate (0.255 ml, 1.62 mmol) in dry dichloromethane (2 ml) under nitrogen. The yellow reaction mixture was stirred at 0 ° C for 30 minutes and then at room temperature for 2 hours. Dichloromethane and water were added to the reaction mixture and the aqueous layer was extracted with dichloromethane. The extracts were combined and concentrated to give a crude product, which was purified by column chromatography on silica gel eluted with hexane: ethyl acetate (100: 1 to 20: 1) to give the title compound as a colorless oil ( 67 mg, 56.9%). 1 H NMR (CDCl 3): 7.29 (d, J = 8.4 Hz, 1 H), 6.88 (dd, J = 8.4.2.2 Hz, 1 H), 6.80 (sa, 1 H), 5.42-5.39 (m, 1 H ), 5.28-5.12 (m, 2H), 3.83 (s, 3H). (yjl 6-Methoxy-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-carbaldehyde To a stirred solution of 5-methoxy-1-trifluoromethyl-1,3-dihydroisobenzofuran (67 mg, 0.31 mmol) in dry dichloromethane (5 ml) was added titanium (IV) chloride (0.074 ml). , 0.68 mmole) in nitrogen at -78 ° C. After 15 minutes, a solution of methyl dichloromethyl ether (0.056 ml, 0.61 mmol) in dry dichloromethane (1 ml) was added to the yellow solution at the same temperature. The reaction mixture was stirred at -78 ° C for 1 hour, poured into ice water and stirred at room temperature for 30 minutes. The aqueous layer was extracted with methylene chloride. The extracts were washed with brine, dried over magnesium sulfate and concentrated to give a crude product. This was purified by column chromatography on silica gel eluted with a gradient of hexane and ethyl acetate (10: 1.8: 1.6: 1) to give the title compound as a white crystal (63 mg, 82.5%) 1 H NMR ( CDCI3): 10.45 (s, 1 H), 7.87 (s, 1 H), 6.92 (s, 1 H), 5.46-5.39 (m, 1 H), 5.30 (dd, J = 13.9, 2.2 Hz, 1 H), 5.19 (d, J = 13.9 Hz, 1 H)), 3.97 (s, 3H).

(Vii) -tert-butoxycarbonyl- 1 (2S, 3S) -3- (6-methoxy-3-trifluoromethyl-1.3-dihydro-isobenzofuran-5-yl) methylamino-2-phenylpiperidine To a stirred solution of 1 tert -butoxycarbonyl ( 2S, 3S) -3-amino-2-phenylpiperidine (71 mg, 0.26 mmol) which was prepared by a method described in international patent publication WO 97/03066 and 6-methoxy-3-trifluoromethyl-1, 3- Dihydroisobenzofuran-5-carbaldehyde (63 mg, 0.26 mmol) in dry dichloromethane (3 ml) was added portionwise to sodium triacetoxyborohydride (76 mg, 0.36 mmol) under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 5 h. The pH was adjusted to below 10 with a saturated solution of sodium bicarbonate, extracted with dichloromethane, dried over magnesium sulfate and concentrated to give a crude product. This was purified by column chromatography on silica gel eluted with a gradient of dichloromethane and methanol (50: 1, 25: 1, 20: 1) to give the title compound as a white amorphous solid (130 mg, 98.7%). 1 H NMR (CDCl 3): 7.60-7.54 (m, 2H), 7.35-7.22 (m, 4H), 6.70 (s, 1 H), 5.46 5.36 (m, 2H), 5.24 and 5.23 (each d, J = 12.1 Hz, total 1 H), 5.12 (d, J = 12.1 Hz, 1 H), 3.98-3.91 (m, 1 H), 3.88-3.80 (m, 2H), 3.72 (s, 3H), 3.05 - 2.96 (m, 2H), 1.82-1.61 (m, 4H), 1.50-1.36 (m, 1 H), 1.40 (s, 9H).

(Viii) (2S, 3S) -3- (6-Methoxy-3-trifluoromethyl-1, 3-dihydro-isobenzofuran-5-yl) methylamino-2-phenylpiperidine To a stirred solution of 1 -tert-butoxycarbonyl ( 2S, 3S) -3- (6-methoxy-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-yl) methylamino-2-phenylpiperidine (130 g, 0.26 mmol) in ethyl acetate (5 ml) was added drop drop a methanolic HCl solution (2.5 ml) under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 8 hours. The solvent was removed and recrystallized from ethanol to give the title compound as a white crystal (38 mg, 30.5%) mp = 180-187 ° C. 1 H NMR (free amine, CDCl 3): 7.28-7.25 (m, 5H), 7.01 -6.96 (each s, total 1 H), 6.57 and 6.55 (each s, total 1 H), 5.32-5.30 (m , 1 H), 5.24 5.07 (m, 2H), 3.89 (d, J = 2.2 Hz, 1 H), 3.70 and 3.64 (each d, J = 13 * 9 Hz, total 1 H), 3.51 -3.48 (each s, total 3H), 3.40 and 3.38 (each d, J = 13.9 Hz, total 1 H), 3.31 -3.25 (m, 1 H), 2.87-2.76 (m, 2H), 2.14-1.57 ( m, 3H), 1.46-1.41 (m, 1 H). The diastereomeric relationship between the epimers at position 3 in the dihydroisobenzofuran ring was determined by 1 H NMR as 5: 4 EXAMPLE 2 Preparation of (2S. 3S) -3- (6-Methoxy-3,3.- bis (trifluoromethyl-1, 3-dihydroisobenzofuran-5-ipmetilamino-2- feniSpiperidina Í 1.1.1.3.3,3, -Hexafluoro-2- (4-methoxy-2- (tetrahydropyran-2-yloxymethyl) -phenyl) propan-2-ol To a stirred solution of 2- (2-bromo- 5-methoxybenzyloxy) tetrahydropyran (1.0 g, 3.32 mmol) in dry tetrahydrofuran (20 ml) was added dropwise n-butyllithium (2.6 ml, 4.32 mmol) in nitrogen at -78 ° C. The reaction mixture was stirred at -40 ° C for 1.5 h. To the reaction mixture was added dropwise a solution of hexafluoroacetone (1 ml) in dry tetrahydrofuran (2 ml) at -78 ° C. The resulting mixture was left at 0 ° C for 3 hours. This was quenched with a saturated solution of ammonium chloride and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate and concentrated to give a crude product, which was purified by column chromatography on silica gel eluted with a gradient of hexane and ethyl acetate (30: 1, 25: 1, 20: 1 , 15: 1) to give the title compound (890 mg, 69.0%) 1 H NMR (CDCl 3): 7.68-7.25 (m, 1 H), 7.42 (s, 1 H), 6.95-6.90 (m, 2H) , 5.08 (d, J = 1 1.7 Hz, 1 H), 4.78-4.73 (m 1 H), 4.71 (d, J = 11 .7 Hz, 1 H), 3.83 (s, 3 H), 3.83-3.75 ( m, 1 H), 3.58-3.54 (m, 1 H), 1.79-1.52 (m, 6H). (ii) 1.1, 1,3,3,3-Hexafluoro-2- (2-hydroxymethyl-4-methoxyphenyl) propan-2-ol According to the procedure of the preparation of 2,2,2-trifluoro-1- (2 hydroxymethyl-4-methoxyphenyl) ethanol in example 1, 1, 1, 1, 3,3,3-hexafluoro-2- (4-methoxy-2- (tetrahydropyran-1 -iloximetil) fen¡l) propan 2-ol (350 mg, 0.90 mmol) was converted to the title compound (354 mg). This compound was used without further purification. (iii) 5-Methoxy-1,1-bistrifluoromethyl-1,3-dihydroisobenzofuran A mixture of 1,1,1,3,3-Hexafluoro-2- (2-hydroxymethyl-4-methoxyphenyl) ) propan-2-ol (300 mg) and concentrated hydrochloric acid (3 ml) was stirred at 120 ° C for 6 hours. After cooling, the reaction mixture was diluted with water, extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated to give the crude material of the title compound (258 mg). This was used without further purification. (iv) 6-Methoxy-3,3-bis (trifluoromethyl) -1,3-dihydroisobenzofuran-5-carbaldehyde According to the procedure of the preparation of 6-methoxy-3-trifluoromethyl-1,3-dihydroisobenzofuran-5- carbaldehyde in Example 1, 1,5-methoxy-1,1-bistrifluoromethyl-1,3-dihydroisobenzofuran (258 mg) was converted to the title compound (167 mg, 69.0% from 1, 1, 1, 3,3,3-hexafluoro-2- (2-hydroxymethyl-4-methoxyphenyl) propan-2-ol, 1 H NMR (CDCl 3): 10.44 (s, 1 H), 7.98 (s, 1 H), 6.98 ( s, 1 H), 5.36 (s, 2H), 4.00 (s, 3H). jV) 1-tert-Butoxycarbonyl- (2S-3S) -3- (6-methoxy-3,3-bis (tri-fluoromethyl) -1,3-dihydroisobenzofuran-5-yl) methylamino-2-phenylpiperidine According to the procedure of the preparation of 1-tert-butoxycarbonyl- (2S-3S) -3- (6-methoxy-3-trifluoromethyl-1,3-dihydro-benzofuran-5-yl) methylamino-2-phenylpiperidine in Example 1, 6-methoxy-3,3-bis (tri- fluoromethyl) -1,3-dihydrobenzofuran-5-carbaldehyde (191 mg, 0.61 mmol) was converted to the title compound (327 mg, 93.3%). 1 H NMR (CDCl 3): 7.57 - 7.54 (m, 2 H), 7.39 (s, 1 H), 7.35 - 7.23 (m, 3 H), 6.71 (s, 1 H), 5.43 (m, 1 H), 5.29 (s, 2H), 3.99 - 3.95 (m, 1 H), 3.84 (s, 2H), 3.75 (s, 3H), 3.07 - 2.99 (m, 2H), 1.87 - 1.33 (m, 5H), 1.39 ( s, 9H). (vi) (2S, 3S) -3- (6-Methoxy-3,3-bis (trifluoromethyl-1,3-dihydroisobenzofuran-5-yl) -methylamino-2-phenylpiperidine dihydrochloride) According to the preparation procedure of the (2S, 3S) -3- (6-methoxy-3-trifluoromethyl-1,3-dihydro-isobenzofuran-5-yl) methylamino-2-phenylpiperidine dihydrochloride in Example 1, 1-tert-butoxycarbonyl- ( 2S, 3S) -3- (6-methoxy-3,3- (bis) trifluoromethyl-1,3-dihydro-isobenzofuran-5-yl) methylamino-2-phenylpiperidine (327 mg, 0.57 mmol ) was converted to the title compound (226 mg, 72.4%) mp 180-187 ° C 1 H NMR (free amine, CDCl 3): 7.28 - 7.20 (m, 5H), 7.16 (s, 1 H) , 6.56 (s, 1 H), 5.27 (s, 2H), 3.89 (d, J = 2.6 Hz, 1 H), 3.69 (d, J = 13.9 Hz, 1 H), 3.52 (s, 3H), 3.35 (d, J = 13.9 Hz, 1 H), 3.28 - 3.25 (m, 1 H), 2.85 - 2.75 (m, 2H), 2.17 - 2.1 1 (m, 1 H), 2.04 - 1.85 (m, 1 H) ), 1 .68 - 1.57 (m, 1 H), 1.46 - 1.40 (m, 1 H).

EXAMPLE 3 Preparation of (2S, 3S) -3- (6-Methoxy-1-methyl-1-trifluoromethylsochroman-7-yl) methylamino-2-phenylpiperidine dihydrochloride (i) 2- (2-Bromo-5-methoxyphenyl) ethanol To a stirred solution of 3-methoxyphenethyl alcohol (1.18 g, 7.8 mmol) and pyridine (0.75 mL, 9.3 mmol) in dry dichloromethane (10 mL) was added dropwise. drop bromine (0.47 ml, 18.0 mmol) in nitrogen at 0 ° C. The orange solution was stirred at room temperature for 4 hours. The reaction mixture was quenched by the addition of an aqueous solution of 10% sodium bisulfite and extracted with dichloromethane. The organic extracts were washed with brine, dried over magnesium sulfate and concentrated to give crude products, which were purified by column chromatography on silica gel eluted with a gradient of hexane and ethyl acetate (10: 1, 8: 1, 5: 1) to give the title compound as a colorless oil (1.5 g, 83.2%). 1 H NMR (CDCl 3): 7.43 (d, J = 8.8 Hz, 1 H), 6.83 (d, J = 3.3 Hz, 1 H), 6.67 (dd, J = 8.8, 3.3 Hz, 1 H), 3.91 - 3.81 (m, 2H), 3.78 (s, H), 2.99 (t, J = 6.6 Hz, 2H). (ii) 2- (2- (2-Bromo-5-methoxyphenyl) ethoxy) tetrahydropyran According to the procedure of the preparation of 2- (2-bromo-5-methoxybenzyloxy) tetrahydropyran in Example 1, - (2-Bromo-5-methoxyphenyl) ethanol (1.5 g, 6.5 mmol) was converted to the title compound (2.05 g, quant.). 1 H NMR (CDCl 3): 7.40 (d, J = 8.8 Hz, 1 H), 6.86 (d, J = 2.9 Hz, 1 H), 6.65 (dd, J = 8.8, 2.9 Hz, 1 H), 4.63 - 4.60 (m, 1 H), 3.99 - 3.90 (m, 1 H), 3.82 - 3.74 (m, 1 H), 3.78 (s, 3 H), 3.68 - 3.59 (m, 1 H), 3.50 - 3.45 (m , 1 H), 3.02 (t, J = 7.0 Hz, 2H), 1.83-1.52 (m, 6H). 1, 1, 1-Trifluoro-2- (4-methoxy-2- (2-tetrahydropyran-2-loxy) ethyl) phen-P-propan-2-ol To a stirred solution of 2- (2- ( 2-bromo-5-methoxyphenyl) ethoxy) tetrahydropyran (1.0 g, 3.17 mmol) in dry tetrahydrofuran (20 ml) was added dropwise n-butyllithium (2.5 ml, 4.12 mmol) under nitrogen at -78 °. C. The reaction mixture was stirred at -40 ° C for 1 hour. To the reaction mixture was added dropwise a suspension of anhydrous cerium chloride (884 mg, 3.58 mmol) in dry tetrahydrofuran (15 ml) at -78 ° C and stirred for 1 hour. Trifluoroacetone (0.5 ml, 5.59 mmol) was added to the reaction mixture and the resulting mixture was stirred at -78 ° C for 1 hour. This was quenched by a saturated solution of ammonium chloride and extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated to give crude products, which were purified by column chromatography on silica gel eluted with a gradient of hexane and ethyl acetate (20: 1, 15: 1, 12). : 1, 10: 1) to give the title compound (555 mg, 50.3%). 1 H NMR (CDCl 3): 7.35, -7.31 (m, 1 H), 6.78 - 6.74 (m, 2 H), 5.70 and 5.62 (each s, total 1 H), 4.63 and 4.48 (each m, total 1 H), 4.18 - 4.1 1 and 3.99 - 3.92 (each m, total 1 H), 3.80 (s, 3H), 3.77 - 3.43 (m, 3H), 3.3 - 2.90 (m, 2H), 1.80 and 1.78 (each s, total 3H), 1.75 - 1.26 (m, 6H). (iv) 6-Methoxy-1-methyl-1-trifluoromethylsocroman A mixture of 1,1-trifluoro-2- (4-methoxy-2- (2-tetrahydropyran-2-yloxy) ethyl) phenyl) - propan-2-ol (470 mg, 1.35 mmol) and concentrated hydrochloric acid (4 ml) was stirred at 120 ° C for 3 hours. After cooling, the reaction mixture was diluted with water and the aqueous layer was extracted with dichloromethane. The organic extracts were dried over magnesium sulfate and concentrated to give the title compound as a brown oil (460 ml). This was used without further purification. (v) 6-Methoxy-1-methyl-1-trifluoromethyl-chromochanan-7-carbaldehyde According to the procedure of the preparation of 6-methoxy-3-trifluoromethyl-1,3-dihydro-benzofuran-5-carbaldehyde in Example 1 , 1-6-methoxy-1-methyl-1-trifluoromethyl-isochroman (460 mg) was converted to the title compound (179 mg, 48.3%) from 1,1,1-trifluoro-2- (4-methoxy). -2- (2-tetrahydropyran-2-yloxy) ethyl) phenyl) -propan-2-ol). 1 H NMR (CDCl 3): 10.41 (s, 1 H), 7.82 (s, 1 H), 6.78 (s, 1 H), 4.19 - 4.1 1 (m, 1 H), 3.94 (s, 3 H), 3.94 - 3.87 (m, 1 H), 2.91 (t, J = 4.4 Hz, 2H), 1.67 (s, 3H). iojl 1-tert-Butoxycarbonyl- (2S, 3S) -3- (6-Methoxy-1-methyl-1-trifluoromethyl-chromosan-7-yl) -methylamino-2-phenylpiperidine According to the procedure of the preparation of 1-ter -butoxycarbonyl- (2S, 3S) -3- (6-Methoxy-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl) methylamino-2-phenylpiperidine in Example 1, 6-methoxy-1-methyl -1-trifluoromethyl-isochroman-7-carbaldehyde (184 mg, 0.67 mmol) was converted to the title compound (330 mg, 91.8%). 1 H-NMR (CDCl 3): 7.59-7.55 (m, 2H), 7.34 - 7.17 (m, 4H), 6.56 (s, 1 H), 5.44 (m, 1 H), 4.16-4.08 (m, 1 H) , 3.99 -3.84 (m, 2H), 3.80 (m, 2H), 3.72 and 3.71 (each s, total 3H), 3.06 - 2.98 (m, 2H), 2.83 - 2.81 (m, 2H), 1.85 - 1.61 (m, 4H), 1.63 and 1.61 (each s, total 3H), 1.50 - 1.40 (m, 1 H), 1.39 (s, 9H). (vii) (2S. 3S) -3- (6-Methoxy-1-methyl-1-trifluoromethyl-7-yl) methylamino-2-phenylpiperidine dihydrochloride According to the process of preparing the (2S, 3S) -3- (6-methoxy-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl) methylamino-2-phenylpiperidine in Example 1, 1-tert-butoxycarbonyl- (2S, 3S) -3- (6-Methoxy-1-methyl-1-trifluoromethyl-chromocan-7-yl) methylamino-2-phenylpiperidine (325 mg, 0.61 mmol) was converted to the title compound (88 mg, 28.4% ) mp: 193-201 ° C. 1 H NMR (major isomer, free amine, CDCl 3): 7.33 - 7.20 (m, 5H), 6.95 (s, 1 H), 6.43 (s, 1 H), 4.13 - 4.09 (m, 1 H), 3.92 - 3.84 (m, 2H), 3.62 (d, J = 13.9 Hz, 1 H), 3.51 (s, 3H), 3.33 (d, J = 13.9 Hz, 1 H), 3.31 - 3.24 (m, 1 H), 2.84 - 2.74 (m, 4H), 2.12 - 2.07 (m, 1 H), 1.94 - 1.82 (m, 1 H), 1 .67 - 1.62 (m, 1 H ), 1.59 (s, 3H), 1.43-1.38 (m, 1 H). The diastereomeric ratio between the epimers at position 1 in the isocramano ring was determined by 1 H NMR as 5: 1 (1 R: 1 S). These isomers are (2S, 3S) -3 - [(1 R) -6-methoxy-1-methyl-1-trifluoromethyl-4-yichroman-7-yl] methylamino-2-phenylpiperidine and (2S, 3S) -3 - [(1 S) -6-methoxy-1-methyl-1-trifluoromethyl-5-chroman-7-yl] methylamino-2-phenylpiperidine. The most soluble epimer was recovered from the mother liquor. The diastereomeric ratio between the epimers at position 1 in the isochroman ring was determined by 1 H NMR as 1: 3 (1 R: 1 S). The absolute stereochemistry of the title compounds was determined by X-ray crystallography of the (3R) isomer after the subsequent purification by recrystallization. 1 H-NMR (major isomer, free amine, CDCl 3): 7.33-7.20 (m, 5H), 6.99 (s, 1 H), 6.40 (s, 1 H), 4.13-4.09 (m, 1 H), 3.92- 3.84 (m, 2H), 3.62 (d, J = 13.9 Hz, 1 H), 3.45 (s, 3H), 3.33 (d, J = 13.9 Hz, 1 H), 3.31-3.24 (m, 1 H), 2.84-2.74 (m, 4H), 2.12-2.07 (m, 1 H), 1.94-1.82 (m, 1 H), 1.67-1.62 (m, 1 H), 1.59 (s, 3H), 1.43-1.38 ( m, 1 H).

EXAMPLE 4 Preparation of (2S, 3S) -3- (6-methoxy-3-methyl-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl) methylamino-2-phenylpiperidine (i) 2-Bromo-5-methoxybenzyl chloride To a stirred solution of 3-methoxybenzyl chloride (37.2 g, 0.238 mol) and pyridine (23.1 ml, 0.286 mol) dissolved in dry dichloromethane (400 ml) was added bromine (23 ml, 0.880 moles) at 0 ° C. The resulting mixture was stirred at 0 ° C for 1 hour, then at room temperature for 18 hours. This was diluted with a saturated aqueous solution of sodium thiosulfate and extracted with dichloromethane. The combined organic extracts were washed sequentially with a saturated aqueous solution of sodium thiosulfate, water, 2N HCl, water and brine. The extracts were dried over magnesium sulfate and concentrated to give a crude product as a slightly yellow crystal. This was dissolved with ethyl acetate and the precipitate was filtered. The filtrate was washed and concentrated to give a slightly yellow crystal, which was washed with hexane to give the title compound (43 g, 77%) as a solid crystal. 1 H NMR (CDCl 3): 7.44 (d, J = 8.8 Hz, 1 H), 7.02 (d, J = 3.3 Hz, 1 H), 6.74 (dd, J = 8.8, 3.3 Hz, 1 H), 4.64 ( s, 2H), 3.79 (s, 3H). (ii) 5-Methoxy-1-methyl-1-trifluoromethyl-1,3-dihydroisobenzo-furan To a stirred solution of 2-bromo-5-methoxybenzyl chloride (13.8 g, 0.059 mol) in a mixture of tetrahydrofuran Dry (330 mL) and hexane (10 mL) was added dropwise n-butyllithium (37.2 mL, 0.062 mole) in hexane for 30 minutes at -100 ° C under nitrogen, and the reaction mixture was stirred at room temperature. -100 ° C for 2.5 hours. Then, a solution of 1,1-trifluoroacetone (6.3 ml, 0.073 mol) dissolved in dry tetrahydrofuran (15 ml) and hexane (5 ml) at the same temperature was added dropwise to the mixture, and the mixture was added dropwise to the mixture. The resultant was allowed to increase to -30 ° C. This was quenched with water and the solvent was removed by evaporation. The residue was extracted with hexane. The combined organic extracts were dried over magnesium sulfate and concentrated to give crude products as a slightly yellow oil (13.6 g). The crude oil (13.6 g), glycine (575 mg 7.66 mmol) and potassium hydroxide (703 mg, 12.53 mmol) were dissolved in a mixture of ethanol (30 ml) and water (20 ml) and stirred under reflux for 2 hours. . After cooling, the reaction mixture was diluted with brine and extracted with hexane. The organic extracts were dried over magnesium sulfate and concentrated by evaporation to give a slightly yellow oil (12.6 g), which was purified by distillation (94 to 98 ° C / 1.5 mm Hg) to give the title compound as a colorless oil ( 10.8 g, 78.7%). 1 H NMR (CDCl 3): 7.20 (d, J = 8.4 Hz, 1 H), 6.87 (dd, J = 8.4, 2.6 Hz, 1 H), 6.76 (d, J = 2.6 Hz, 1 H), 5.21- 5.09 (m, 2H), 3.82 (s, 3H), 1.65 (d, J = 1 .1 Hz, 3H). (iii) 3-Methyl-3-trifluoromethyl-6-methoxy-1,3-dihydroisobenzofuran-5-carbaldehyde To a stirred solution of 5-methoxy-1-methyl-1-trifluoromethyl-1,3-dihydroisobenzofuran (10.8) g, 0.046 mol) in dry dichloromethane (280 ml) was added dropwise titanium (IV) chloride (1.2 ml, 0.102 mol) in nitrogen at -78 ° C and the resulting solution was stirred for 15 minutes. A solution of methyl dichloromethyl ether (8.4 ml, 0.903 mol) in dry dichloromethane (20 ml) was added to the resulting brown solution at -78 ° C and stirred for 1.5 hours. This mixture was poured into ice water and stirred at room temperature for 30 minutes. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated to give the title compound as a slightly yellow crystal (12.1 g, quant.). 1 H-NMR (CDCl 3): 10.45 (s, 1 H), 7.79 (s, 1 H), 6.88 (s, 1 H), 5.25-5.13 (m, 2 H), 3.97 (s, 3 H), 1.68 (m , 3H). ÍÍY) _ ZS ^ 3S) -3- (6-methoxy-3-methyl-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl) methylamino-2-phenylpiperidine To a stirred solution of (2S, 3S) -2-phenyl-3-aminopiperidine (4.1 g, 23.1 mmol), which was prepared by a method described in international patent publication WO 92/17499 and 3-methyl-3-trifluoromethyl-6-methoxy 1,3-dihydroisobenzofuran-5-carbaldehyde (6.1 g, 23.3 moles) in dry dichloromethane (200 ml) was added portionwise to sodium triacetoxyborohydride (7.8 g, 36.9 mmol) under nitrogen at room temperature and the resulting mixture was stirred thereto. temperature for 16 h. The pH was adjusted to below 10 with a saturated solution of aqueous sodium bicarbonate and extracted with dichloromethane. The extracts were dried over magnesium sulfate and concentrated to give a slightly yellow amorphous solid (10.1 g). A methanolic HCl solution was added to the crude products dissolved in ethyl acetate. The formed solids were collected by filtration, dried in vacuo and then purified by crystallization from methanol to give the title compound as a white crystal. mp: 200-207 ° C 1 H NMR (main isomer, free amine CDCl 3): 7.31 -7.21 (m, 5H), 6.89 (s, 1 H), 6.54 (s, 1 H), 5.16-5.04 (m, 2H), 3.90 (d, J = 2.3 Hz, 1 H), 3.68 (d, J = 14.3 Hz, 1 H), 3.52 (s, 3 H), 3.40 (d, J = 14.3 Hz, 1 H), 3.29-3.26 (m, 1 H), 2. 85-2.75 (m, 2H), 2.14-2.09 (m, 1 H), 1.95-1.76 (m, 1 H), 1.66-1.54 (m, 1 H), 1. 60 (s, 3H), 1.44-1.40 (m, 1 H). Analysis by 1 H NMR indicated the diastereomeric ratio at the 3-position of the dihydroisobenzofuran ring as 98: 2 (3R: 3S). These isomers are (2S, 3S) -3 - [(3R) -6-methoxy-3-methyl-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl] methylamino-2-phenylpiperidine and (2S) , 3S) -3 - [(3S) -6-methoxy-3-methyl-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl] methylamino-2-phenylpiperidine. From the residual mother liquors, the other epimer in position 3 in the dihydroisobenzofuran ring was recovered as a 9: 1 mixture (3S: 3R). The absolute stereochemistry of the title compounds was determined by X-ray crystallography of the (3R) isomer after purification by recrystallization. NMR of H (major isomer, free amine, CDCl 3): 7.31 -7.19 (m, 5H), 6.94 (s, 1 H), 6.51 (s, 1 H), 5.16-5.04 (m, 2H), 3.89 (d , J = 2.2 Hz, 1 H), 3.67 (d, J = 14.3 Hz, 1 H), 3.48 (s, 3 H), 3.37 (d, J = 14.3 Hz, 1 H), 3.28-3.24 (m, 1 H), 2.85-2.75 (m, 2H), 2.14-2.09 (m, 1 H), 1.97-1.86 (m, 1 H), 1.69-1.56 (m, 1 H), 1.59 (s, 3H), 1.45 -1.40 (m, 1 H).

EXAMPLE 5 Preparation of (2S, 3S) -3- (6-methoxy-3-phenyl-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-H) methyl-amino-2-phenylpiperidine dihydrochloride (i) 1-Trifluoromethyl-5-methoxy-1-phenyl-1,3-dihydroisobenzofuran To a stirred solution of 2-bromo-5-methoxybenzyl chloride (3.0 g, 12.7 mmol) in a dry tetrahydrofuran mixture (60 ml ) and hexane (20 ml) was added dropwise n-butyllithium (8.4 ml, 13.4 mmol) in hexane for 15 minutes at -85 ° C under nitrogen, and the reaction mixture was stirred at -85 ° C for 2 hours. Then, to the mixture was added dropwise a solution of 2,2,2-trifluoroacetophenone (2.70 g, 15.3 mmol) dissolved in dry tetrahydrofuran (20 ml) at the same temperature, and the resulting mixture was allowed to rise to a temperature ambient. This was quenched with water and the solvent was removed by evaporation. The residue was extracted with dichloromethane. The organic extracts were dried over magnesium sulfate and concentrated to give crude products as a dark yellow oil. The crude oil was purified by the method of using glycine described for the synthesis of 5-methoxy-1-methyl-1-trifluoromethyl-1,3-dihydroisobenzofuran in Example 4 and by gel column chromatography. silica (20 g) with hexane-ethyl acetate (20: 1) to give the title compound as a slightly yellow oil (760 mg, 20.3%). 1 H NMR (CDCl 3): 7.74-7.66 (m, 2H), 7.52-7.28 (m, 4H), 6.90 (dd, J = 8.6, 2.5 Hz, 1 H), 6.80-6.76 (m, 1 H), 5.33 (d, J = 12.2 Hz, 1 H), 5.23 (d, J = 12.2 Hz, 1 H), 3.82 (s, 3H). (ii) 3-Trifluoromethyl-6-methoxy-3-phenyl-1,3-dihydro-benzofuran-5-carbaldehyde According to the procedure of the preparation of 6-methoxy-3-trifluoromethyl-1,3-dihydroisobenzofuran-5 -carbaldehyde in Example 1, 1-trifluoro-methyl-5-methoxy-1-phenyl-1,3-dihydroisobenzofuran was converted and the crude product was purified by silica gel column chromatography (70 g) with hexane- ethyl acetate (5: 1) to give the title compound as a yellow viscous oil (507 mg, 61.7%). 1 H NMR (CDCl 3): 10.45 (s, 1 H), 8.06 (s, 1 H), 7.75-7.66 (m, 2 H), 7.44-7.30 (m, 3 H), 6.90 (s, 1 H), 5.38 (d, J = 13.4 Hz, 1 H), 5.27 (d, J = 13.4 Hz, 1 H), 3.96 (s, 3H). 1D-1-tert-butoxycarbonyl- (2S, 3S) -3- (6-methoxy-3-phenyl-3-trifluoromethyl-1,3-dihydro-5-benzofuran-5-yl) methylamino-2-phenylpiperidine according to the process of the preparation of 1-tert-butoxycarbonyl- (2S, 3S) -3- (6-methoxy-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl) methylamino-2-phenylpiperidine in the Example 1, 3-trifluoromethyl-6-methoxy-3-phenyl-1,3-dihydro-benzofuran-carbaldehyde (453 mg, 1.41 mmol) was converted and the crude product was purified by column chromatography on silica gel (40 g. g) with dichloromethane-methanol (80: 1) to give the title compound (657 mg) as a pale yellow oil. This was used for the next step without further purification.

M. (2S, 3S) -3- (6-methoxy-3-phenyl-3-trifluoromethyl-1,3-dihydro-benzofuran-5-yl) methylamino-2-phenylpiperidine To a stirred solution of 1-tert-butoxycarbonyl - (2S, 3S) -3- (6-methoxy-3-phenyl-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-yl) methylamino-2-phenylpiperidine (657 mg) in ethyl acetate (25 ml) added concentrated hydrochloric acid (3 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 1.5 hours. The pH of the mixture was adjusted to below 10 with 2N sodium hydroxide under cooling with ice. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate and concentrated to give the crude products (559 mg) as a yellow oil. The crude products were purified by silica gel column chromatography (18 g) with dichloromethane-methanol (40: 1 to 10: 1) to give the title compound as a yellow viscous oil (497 mg, 87.9%).

(V) (2S, 3S) -3- (6-methoxy-3-phenyl-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-¡l) methylamino-2-phenylpiperidine (2S, 3S) -3 - (3-trifluoromethyl-6-methoxy-3-phenyl-1,3-dihydroisobenzofuran-5-yl) methylamino-2-phenylepidine (497 mg, 1.03 mmol) was treated with a solution of 10% hydrogen-methanol (20 ml). After removing the solvent in vacuo, the residue was washed with hot ethanol to give the title compound as a white solid, mp 203-204 ° C. The diastereomeric ratio between the epimers at the 3-position on the dihydroisobenzofuran ring was determined by H NMR as 6.5: 1. 1 H NMR (major isomer, free amine, CDCl 3): 7.71-7.62 (m, 2H), 7.45-7.17 (m, 9H), 6.55 (s, 1 H), 5.29 (d, J = 12.2 Hz, 1 H), 5.19 (d, J = 12. 2 Hz, 1 H), 3.88 (d, J = 2.1 Hz, 1 H), 3.67 (d, J = 14.3 Hz), 3.51 (s, 3H), 3.42 (d, J = 14.3 Hz, 1 H), 3.35-3.23 (m, 1 H), 2.89-2.73 (m, 2H), 2.20-1.78 (m, 4H), 1.70-1.35 (m, 2H). A more soluble epimer was recovered from the mother liquor as a 2: 1 mixture. 1 H NMR (major isomer, free amine, CDCl 3): 7.70-7.60 (m, 2H), 7.45-7.15 (m, 9H), 6.52 (s, 1 H), 5.29 (d, J = 12.2 Hz, 1 H), 5.19 (d, J = 12.2 Hz, 1 H), 3.90 (d, J = 2.5 Hz, 1 H), 3.72 (d, J = 14.0 Hz, 1 H), 3.47 (s, 3H), 3. 33 (d, J = 14.0 Hz, 1 H), 3.33-3.21 (m, 1 H), 2.88-2.72 (m, 2H), 2.18-1.78 (m, 4H), 1.72-1.35 (m, 2H).

EXAMPLE 6 Preparation of (2S, 3S) -3-p - (6-methoxy-3-metH-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl) eti! -amino1-2-phenylpiperidine dihydrochloride íi? 5-Acetyl-3-methyl-6-methoxy-3-trifluoromethyl-1,3-dihydroisobenzofuran To a solution of aluminum chloride (689 mg, 5.17 mmol) in dry dichloromethane (10 ml) was added acetyl chloride (0.37 ml, 5.17 mmol) at 0 ° C and stirred for 10 minutes. A solution of 5-methoxy-1-methyl-1-trifluoromethyl-1, 3-dihydroisobenzofuran (1.00 g, 4.31 mmol) in dry dichloromethane (10 ml) to the mixture at 0 ° C and the resulting solution was added dropwise was stirred at the same temperature for 1 hour. This mixture was poured into a mixture of ice-cold hydrochloric acid (1 N) and the organic layer was separated. The aqueous layer was extracted with dichloromethane and the organic fractions were combined. The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with hexane and ethyl acetate (8: 1) to give the title compound as a white crystal (1.10 g, 93%). 1 H NMR (CDCl 3): 7.69 (s, 1 H), 6.86 (s, 1 H), 5.21 (d, J = 13.2 Hz, 1 H), 5.14 (d, J = 13.2 Hz, 1 H), 3.94 (s, 3H), 2.62 (s, 3H), 1.67 (s, 3H). (2S, 3S) -3-p - (6-methoxy-3-methyl-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl) ethylamino-2-phenylpiperidine To a stirred mixture of (2S, 3S) -2 -phenyl-3-aminopiperidine (350 mg, 1.99 mmol), 5-acetyl-3-methyl-6-methoxy-3-trifluoromethyl-1,3-dihydroisobenzofuran (545 mg, 1.99 mmol) and triethylamine (0.83) ml, 5.96 mmoles) in dry dichloromethane (20 ml) was added dropwise titanium tetrachloride (0.1 ml), 0.99 mmol) at 0 ° C. The mixture was stirred at room temperature for 1 hour and then cooled to 0 ° C. Sodium cyanoborohydride (374 mg, 5.96 mmol) in methanol (5 ml) was added at the same temperature and the mixture was allowed to warm to room temperature and stirred for 30 minutes. Hydrochloric acid (1 N, 15 ml) was added and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (80 ml) was added to the resulting mixture and the mixture was extracted with hydrochloric acid (1 N, 60 ml, x 3). The combined aqueous organic extracts were washed with ethyl acetate (60 ml x 2) and the pH was adjusted to pH 9 with saturated aqueous potassium carbonate. The aqueous layer was extracted with ethyl acetate (60 ml x 3) and the combined organic fractions were washed with a saturated solution of sodium bicarbonate (60 ml). The organic solution was dried over sodium sulfate and evaporated in vacuo to give a crude product. This was purified by column chromatography on silica gel eluted with hexane: ethyl acetate (10: 1) to give the title compound as a colorless foam (145 mg, 17%). The 1 H NMR analysis showed that it consisted of a 5: 5: 2: 2 mixture of four diastereomers based on the C-3 of the dihydroisobenzofuran and on the C1 of the ethylamino part. 1 H NMR (C6D6, partial data): 1.70, 1.59, 1.56, and 1.52 (four singlets, total 3H). The ratio was 5: 5: 2: 2 respectively). (iii) (2S, 3S) -3-p- (6-methoxy-3-methyl-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-y!) ethylaminol-2-phenylpiperidine dihydrochloride To a stirred solution of the (2S, 3S) -3- [1- (6-methoxy-3-methyl-3-trifluoromethyl-1,3-dihydro-p-benzofuran-5-yl) ethylamino] -2-phenylpiperidine (106 mg, 0.24 mmol) ) in methanol (1 ml) was added 10% methanolic hydrogen chloride followed by stirring at room temperature for 30 minutes. The mixture was concentrated in vacuo and the residue crystallized from methanol and diethyl ether to give a white solid (45 mg, 36%). The diastereomeric ratio of this solid was determined by 1 H NMR analysis as 20: 30: 1: 3. 1 H NMR (free base, C6D6, partial data): 6.06 (s, 1 H), 5.00 (d, J = 12.0 Hz, 1 H), 4.83 (d, J = 12.0 Hz, 1 H), 3.59-3.36 (m, 2H), 3.18, 3.17 and 3.13 (3s, total 3H), 3.07-3.01 (m, 1 H) , 2.68-2.63 (m, 1 H), 2.49-2.37 (m, 1 H), 1 .73, 1.62, 1.56 and 1.53 (four singles, total 3 H. The ratio was 20: 30: 1: 3 respectively), 1.31, 1.28, 1.07 and 1.01 (four doublets, J = 5.6, 5.6, 6.3 and 6.6 Hz respectively, total 3H). The mother liquor was evaporated under reduced pressure. The residual solid was washed with diethyl ether and dried to give a slightly yellow solid (39 mg, 32%).

The 1H NMR analysis of this solid showed the ratio of diastereomers as 5: 1: 5: 4. 1 H NMR (free base, C6D6, partial data): 6.06 (s, 1 H), 5.03-4.96 (m, 1 H), 4.85-4.77 (m, 1 H), 3.18, 3.17 and 3.13 (3s, total 3H), 1.71, 1.58, 1.53 and 1.52 (four singlets, total 3H). The ratio was 5: 1: 5: 4 respectively), 1.29, 1.26, 1.05, 1.00 (four doublets, J = 4.5, 4.5, 6.3 and 6.6 Hz respectively, total 3H).

EXAMPLE 7 Preparation of (2S, 3S) -3-LY1 dihydrochloride RM6-methoxy-1-methyl-1-trifluoromethyl-isochroman-7-p-methylamine-2-phenylepyridine (i) 6-Hydroxy-1-methyl-1-trifluoromethyl isochroman To a stirred solution of 6-methoxy-1-methyl-1-trifluoromethyl isochroman (71 g, 0.29 mmol) in AcOH (600 mL) was added 48% aqueous HBr ( 300 ml) and the mixture was stirred at 130 ° C for 13 hours. After removing the AcOH in vacuo, the reaction mixture was treated with aqueous NaOH (8 M) until the pH was 5-6. The resulting solution was extracted with AcOEt (400 ml x 2) and the combined AcOEt extracts were washed with brine (100 ml), dried over MgSO and concentrated in vacuo. Flash chromatography (silica gel, 15 x 20 cm, AcOEt-hexane 17%) gave 6-hydroxy-1-methyl-1-trifluoromethyl isochroman (67 g, 100%) as a colorless oil. 1 H NMR (CDCl 3): 7.22 (d, J = 9.1 Hz, 1 H), 6.73 (dd, J = 9.1, 2.6 Hz, 1 H), 6.63 (d, J = 2.6 Hz, 1 H), 5.00 (s, 1 H), 4.17-4.07 (m, 1 H), 3.90 (dt, J = 1 1, 5.8 Hz, 1 H), 2.84-2.78 (m, 2H), 1.64 (s, 3H). (ii) 6-Acetoxy-1-methyl-1-trifluoromethyl isochroman To a stirred solution of 6-hydroxy-1-methyl-1-trifluoromethyl isochroman (79 g, 0.34 mmol) and triethylamine (120 mL, 0.88 mol) in THF ( 680 ml) was added acetyl chloride (31 ml, 0.44 mol) at 0 ° C and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding aqueous 1 N HCl (400 mL) and extracted with AcOEt (500 mL). The extracts were washed with saturated aqueous NaHC 3 (100 ml) and brine (100 ml), dried over MgSO and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 15 x 20 cm, AcOEt-hexane 6%) to give 6-acetoxy-1-methyl-1-trifluoromethyl isochroman (83 g, 89%) as a colorless oil. 1 H NMR (CDCl 3): 7.36 (d, J = 7.2 Hz, 1 H), 6.98 (dd, J = 7.2, 2.5 Hz, 1 H), 6.91 (d, J = 2.5 Hz, 1 H), 4.18- 4.08 (m, 1 H), 3.92 (dt, J = 1 1, 5.4 Hz, 1 H), 2.86 (t, J = 5.4 Hz, 2H), 2.30 (s, 1 H), 1 .66 ( s, 3H). (iii) (1 R) -6-Acetoxy-1-methyl-1-trifluoromethyl-isochroman and (1 S) -6-hydroxy-1-methyl-1-trifluoromethyl-isochroman A mixture of 6-acetoxy-1-methyl Racemic 1 -trifluoromethyl isochroman (38.4 g, 0.140 mol), 10% secbutanol solution in hexane (1.3 I) and PS lipase (35 g) was stirred vigorously at room temperature for 23 hours. After the filtration, the filtrate was concentrated under reduced pressure to give a mixture. This was purified by column chromatography on silica gel eluted with a gradient of hexane and ethyl acetate (15: 1, 5: 1, 2: 1) giving first (1 R) -6-Acetoxy-1 - methyl-1-trifluoromethyl isochroman as a colorless oil (17.3 g, 45%, 94%). The 1 H NMR spectrum of this compound was identical to that of the racemate. The second fraction gave (1 S) -6-hydroxy-1-methyl-1-trifluoromethyl-isochroman as crystals (16.9 g, 52%, 83%). The 1 H NMR spectrum of this material was identical to that of the racemate. - (iv) (1 R) -6-Hydroxy-1-methyl-1-trifluoromethyl-isochroman To a stirred solution of (1 R) -6-acetoxy-1-methyl-trifluoromethyl-isochroman (35.5 g, 0.129 mol) , methanol (860 ml) and water (340) were added potassium carbonate (35.7 g, 0.258 mol) at 0 ° C, then the mixture was stirred at room temperature for 1 hour. The resulting mixture was acidified with 2N hydrochloric acid (pH 3) and evaporated in vacuo to remove the methanol. The residue was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give the title compound as a colorless oil (28.0 g, 93%). This was used without further purification. The 1 H NMR spectrum of this compound was identical to that of the racemate. (v) (R) -6-methoxy-1-methyl-1-trifluoromethyl-isochroman To a stirred solution of sodium hydride (3.47 g, 0.145 mmol) in DMF (50 ml) was added a solution of (1 R) - 6-hydroxy-1-methyl-1-trifluoromethyl isochroman (28.0 g, 0.121 mol) in DMF (370 ml) at 0 ° C, then the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water and diluted with saturated aqueous ammonium chloride. This was extracted with ethyl acetate-toluene (4: 1). The organic fraction was washed with water and brine and dried over magnesium sulfate. The solvent was removed in vacuo, the residue was purified by column chromatography on silica gel eluted with hexane and ethyl acetate (40: 1) to give the title compound as a colorless oil (29.1 g, 98%). The H NMR spectrum of this material was identical to that of the racemate. (vi) (2S, 3S) -3- (1 R) - (6-methoxy-1-methyl-1-trifluoromethyl-chromocan-7-illmethylamino-2-phenylpiperidine) hydrochloride The above (1 R) - (6-methoxy) -1-methyl-1-trifluoromethyl-isochroman was subsequently converted to the title compound following the method of the preparation of Example 3 to give the title compound in a single diastereomeric form Optical rotation: [a] 27D = + 75.44 ° ( c = 0.424, MeOH) The chemical structures of the compounds of formula (I) prepared in Examples 1 to 7 are summarized in the following table. (0 PICTURE

Claims (11)

NOVELTY OF THE INVENTION CLAIMS

1 .- A compound of the formula (I) (I) and its pharmaceutically acceptable salts, wherein R 1 is C 1 -C 6 alkyl; R 2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or phenyl; R3 is hydrogen or halogen; R 4 and R 5 are independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; and n is one, two or three.

2. A compound according to claim 1, wherein R is C1-C3 alkyl; R2 is hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, or phenyl; R3 is hydrogen or fluorine; R4 and R5 are independently hydrogen, C1-C3 alkyl or C1-C3 haloalkyl; and n is one or two.

3. A compound according to claim 2, wherein R1 is methyl; R 2 is hydrogen, methyl, trifluoromethyl or phenyl: R 3 is hydrogen; and R4 and R5 are hydrogen.

4. A compound according to claim 3 selected from (2S, 3S) -3- (6-methoxy-3-trifluoromethyl-1,3-dihydroiso-benzofuran-5-yl) methylamino-2-phenylpiperidine or its salts; (2S, 3S) -3- (6-methoxy-1-methyl-1-tr-fluoro-methyl-chromosan-7-yl) -methylamino-2-phenylpiperidine or its salts; (2S, 3S) -3- (6-methoxy-3-methyl-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl) methylamino-2-phenylpiperidine or its salts; (2S, 3S) -3- (6-methoxy-3-phenyl-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl) methylamino-2-phenylpiperidine or its salts; and (2S, 3S) -3- [1- (6-methoxy-3-methyl-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl) ethylamino] -2-phenylpiperidine or its salts.

5. A compound according to claim 4, said compound being (2S, 3S) -3 - [(1 R) - (6-methoxy-1-methyl-1-trifluoromethyl-isochroman-7-yl] methylamino-2 phenylpiperidine or its salts, or (2S, 3S) -3 - [(3R) - (6-methoxy-3-methyl-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl) methyl-amino-2- phenylpiperidine or its salts

6. A compound of formula (III) (III) wherein W is hydrogen or Q (O =) C-, wherein Q is H, C -? - C6 alkyl or C? -C6 haloalkyl; R1 is C -? - C6 alkyl; R 2 is hydrogen, C 1 -C 6 alkyl, C 1 β haloalkyl or phenyl and n is one, two or three.

7. A compound according to claim 6, wherein said compound is selected from: 5-methoxy-1-trifluoromethyl-1,3-dihydroisobenzofuran; 6-methoxy-3-trifluoromethyl-1,3-dihydrobenzofuran-5-carbaldehyde; 5-methoxy-1,1-bistrifluoromethyl-1,3-dihydrobenzofuran; 6-methoxy-3,3-bis- (trifluoromethyl) -1,3-dihydroisobenzofuran-5-carba Idehyde; 6-methoxy-1-methyl-1-trifluoromethyl isochroman; 6-methoxy-1-methyl-1-trifluoromethyl-isochroman-7-carbaldehyde; 5-methoxy-1-methyl-1-trifluoromethyl-1,3-dihydroisobenzofuran; 6-methoxy-3-methyl-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-carbaldehyde; 1-trifluoromethyl-5-methoxy-1-phenyl-1,3-dihydroisobenzofuran; 3-trifluoromethyl-6-methoxy-3-phenyl-1,3-dihydroisobenzofuran-5-carbaldehyde; and 5-acetyl-3-methyl-6-methoxy-3-trifluoromethyl-1,3-dihydroisobenzofuran. (1 R) -6-methoxy-1-methyl-1-trifluoromethyl isochroman; (1 R) -6-methoxy-1-methyl-1-trifluoromethyl-chromocan-7-carbaldehyde; (1 S) -6-methoxy-1-methyl-1-trifluoromethyl isochroman; (1 S) -6-methoxy-1-methyl-1-trifluoromethyl-isochroman-7-carbaldehyde; (1 R) -5-methoxy-1-methyl-1-trifluoromethyl-1,3-dihydroisobenzofuran; (1 R) -6-methoxy-3-methyl-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-carbaldehyde; (1 S) -5-methoxy-1-methyl-1-trifluoromethyl-1,3-dihydroisobenzofuran; and (1 S) -6-methoxy-3-methyl-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-carbaldehyde.

8. A pharmaceutical composition for the treatment of a disorder or disease, for which an antagonistic activity against the substance P in a mammal is required, which contains an amount of a compound of claim 1, or a pharmaceutically acceptable salt of the same, which is effective for the treatment of said disorder or disease and a pharmaceutically acceptable vehicle.

9. A composition for the treatment of a disorder or disease selected from cardiovascular diseases, allergic disorders, angiogenesis, gastrointestinal disorders, central nervous system disorders, inflammatory diseases, emesis, urinary incontinence, pain, migraine, severe anxiety disorders, stress disorders, anxiety, major depressive disorders, depressive disorders with anxiety, depression, sunburn, sexual dysfunction, bipolar disorders, substance use disorders, schizophrenic disorders, disorders of movement, cognitive disorders and diseases, disorders and adverse alterations caused by Helicobacter pylori, or the like, in a mammal, containing an amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, which is effective for the treatment of said disorder or disease and a pharmaceutically acceptable vehicle.

10. A method for the treatment of a disorder or disease, for which an antagonistic activity against the substance P in a mammal is required, which comprises the administration to a mammal in need of said prevention or treatment of an amount of a The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is effective for the treatment of said disorder or disease.

11. A method for the treatment of a disorder or disease selected from cardiovascular diseases, allergic disorders, angiogenesis, gastrointestinal disorders, central nervous system disorders, inflammatory diseases, emesis, urinary incontinence, pain, migraine, severe anxiety disorders, stress, anxiety, major depressive disorders, major depressive disorders with anxiety, depression, sunburn, sexual dysfunction, bipolar disorders, substance use disorders, schizophrenic disorders, movement disorders, cognitive disorders and diseases, disorders and adverse alterations caused by Helicobacter pylori, or the like, in a mammal, comprising administration to a mammal in need of such prevention or treatment of an amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, which is effective for the treatment of said tra storno or disease.