HK1033313B

HK1033313B - Piperidinylaminomethyl trifluoromethyl cyclic ether compounds as substance p antagonists

Info

Publication number: HK1033313B
Application number: HK01103947.7A
Authority: HK
Inventors: 佐竹邦夫
Original assignee: 辉瑞大药厂
Priority date: 1997-11-19
Filing date: 1998-10-26
Publication date: 2005-04-08

Description

Piperidinylaminomethyltrifluoromethyl cyclic ether compounds as substance P antagonists

Technical Field

The present invention relates to novel piperidinylaminomethyltrifluoromethyl cyclic ether compounds and their pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds and the use of such compounds as substance P antagonists.

Background

Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, which are called tachykinins because of their rapid stimulatory action on smooth muscle tissue. More specifically, substance P is a pharmaceutically active neuropeptide produced in mammals (originally isolated from internal organs) and having a characteristic amino acid sequence, as described in U.S. patent 4680283 to d.f. veber et al. Substance P and other tachykinins are widely implicated in a variety of disease pathologies, as well established in the art. For example, substance P has recently been found to be involved in the transmission of pain or migraine; and central nervous system disorders such as anxiety and schizophrenia; related to respiratory and inflammatory diseases such as asthma and rheumatoid arthritis, respectively; and gastrointestinal disorders and diseases of the GI tract, such as ulcerative colitis, irritable bowel syndrome, Crohn's disease, etc. Tachykinin antagonists have also been reported for the treatment of cardiovascular disease, allergic indications, immunomodulation, vasodilation, bronchospasm, reflex and neuronal modulation of the gut, alzheimer's senile dementia, emesis, sunburn and helicobacter pylori infection.

International patent application WO 97/08144 discloses various substituted piperidine compounds, including piperidine compounds having substituents with oxygen atom containing fused ring moieties as substance P antagonists.

There remains a need for substance P antagonists with increased activity and reduced side effects.

Summary of The Invention

The present invention provides piperidinylaminomethyltrifluoromethyl cyclic ether compounds of the following formula (I):

wherein:

R¹is C₁-C₆An alkyl group;

R²is hydrogen, C₁-C₆Alkyl, halo C₁-C₆Alkyl or phenyl;

R³is hydrogen or halogen;

R⁴and R⁵Each independently is hydrogen, C₁-C₆Alkyl or halo C₁-C₆An alkyl group; and is

n is one, two or three.

These compounds are useful as substance P antagonists and thus in the treatment of conditions and indications selected from the group consisting of: cardiovascular diseases, allergic diseases, angiogenesis, gastrointestinal diseases, central nervous system diseases, inflammatory diseases, emesis, urinary incontinence, pain, migraine in mammals, especially humans; major anxiety disorder, stress disorder, anxiety, major depressive disorder with anxiety, depression, sunburn; bipolar affective disorders, substance use disorders (substance use disorders), schizophrenia, motility disorders, cognitive disorders, and diseases, disorders and adverse conditions caused by helicobacter pylori. These compounds are particularly useful as anti-inflammatory or anti-emetic agents, or as agents for treating CNS disorders. These CNS disorders include major depressive disorder, depression, major depressive disorder with anxiety, dysthymia (dyshemia), manic depression (bipolar psychosis with manic depression or bipolar cycling psychosis), anxiety, Obsessive Compulsive Disorder (OCD), panic disorder, post-terrorist stress syndrome, neuropathic pain, and cognitive disorders such as dementia and amnesia. These compounds are also useful in tourette's disease, akinesia, motor disorders associated with parkinson's disease, tardive dyskinesia and other dyskinesias. These compounds are particularly useful in the treatment of emesis, including acute, delayed and early emesis, such as nausea and vomiting due to chemotherapy, radiation therapy, surgery, pregnancy, motion, vestibular disorders, toxins, migraine and changes in intracranial pressure. More particularly, these compounds are useful in the treatment of emesis induced by antineoplastic agents, including those used in the treatment of cancer, and emesis induced by other drugs, such as ciclopirox and morphine. These compounds are also useful as substance P antagonists, and have reduced metabolic sensitivity in mammals, especially humans. These compounds are also useful for chronic and acute pain, including hyperalgesic pain, neuropathic pain, post-operative pain, and pain associated with nerve injury.

The invention is also directed to pharmaceutical compositions for treating a disease or condition in a mammal requiring treatment with substance P antagonist activity comprising an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof effective to treat such a disease or condition and a pharmaceutically acceptable carrier.

The invention also relates to a method of treating a disease or condition in a mammal requiring treatment with substance P antagonist activity, which method comprises administering to a mammal in need of such treatment an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof effective to treat such disease or condition.

The invention also relates to a pharmaceutical composition for treating a disease or condition in a mammal, particularly a human, comprising a disease or condition selected from the group consisting of cardiovascular disease, allergic disease, angiogenesis, gastrointestinal disease, central nervous system disease, inflammatory disease, emesis, urinary incontinence, pain, migraine; major anxiety disorder, stress disorder, anxiety, major depressive disorder with anxiety, depression, sunburn; sexual dysfunction, bipolar affective disorder with bipolar disorder, substance use disorders, schizophrenia, motility disorders, cognitive disorders, and diseases, disorders and adverse conditions caused by helicobacter pylori.

The present invention also relates to a method of treating a disease or condition selected from the group consisting of cardiovascular disease, allergic disease, angiogenesis, gastrointestinal disease, central nervous system disease, inflammatory disease, emesis, urinary incontinence, pain, migraine; major anxiety disorder, stress disorder, anxiety, major depressive disorder with anxiety, depression, sunburn; sexual dysfunction, bipolar affective disorder with bipolar disorder, substance use disorder, schizophrenia, motility disorder, cognitive disorder, and disease, disorder and adverse symptom caused by helicobacter pylori.

The term "treating" or "treatment" refers to reversing, alleviating, inhibiting the development of, or preventing the disease or condition to which the term applies, or one or more symptoms thereof. The term "treatment" refers to the action of "treatment" as defined above.

Detailed Description

In the present specification, the term "halo" refers to F, Cl, Br and I, preferably Cl or F.

The term "alkyl" refers to straight or branched chain saturated radicals including, but not limited to, methyl, ethyl, n-propyl, isopropyl, and isobutyl.

The term "halo C₁-C₆Alkyl "means substituted by one or more of (A), (B), (CPreferably one to seven) halogen-substituted straight, branched or cyclic C₁-C₆An alkyl group. These groups 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 centres and therefore exist as at least two pairs of diastereoisomeric optical isomers, including epimers. The present invention includes two individual isomers of the compounds of formula (I) and mixtures thereof.

Preferred compounds of formula (I) are those in which R is¹Is C₁-C₃An alkyl group; r²Is hydrogen, C₁-C₃Alkyl, halo C₁-C₃Alkyl or phenyl; r³Is hydrogen or fluorine; r⁴And R⁵Each independently is hydrogen, C₁-C₃Alkyl or halo C₁-C₃An alkyl group; and n is one or two.

More preferred compounds of formula (I) wherein R¹Is methyl; r²Is hydrogen, methyl, trifluoromethyl or phenyl; r³Is hydrogen; r⁴And R⁵Is hydrogen.

The compounds of formula (I) preferably carry a piperidine ring, having the (2S, 3S) configuration.

Preferred compounds are:

(2S, 3S) -3- (6-methoxy-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-yl) methylamino-2-phenylpiperidine or a salt thereof;

(2S, 3S) -3- (6-methoxy-1-methyl-1-trifluoromethyl isochroman-7-yl) methylamino-2-phenylpiperidine or a salt thereof;

(2S, 3S) -3- (6-methoxy-3-methyl-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-yl) methylamino-2-phenylpiperidine or a salt thereof;

(2S, 3S) -3- (6-methoxy-3-phenyl-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-yl) methylamino-2-phenylpiperidine or a salt thereof; and

(2S, 3S) -3- [1- (6-methoxy-3-methyl-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-yl) ethylamino ] -2-phenylpiperidine or a salt thereof.

Particularly preferred compounds are (2S, 3S) -3- [ (1R) - (6-methoxy-1-methyl-1-trifluoromethylisochroman-7-yl ] methylamino-2-phenylpiperidine or a salt thereof and (2S, 3S) -3- [ (3R) -6-methoxy-3-methyl-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-yl) methylamino-2-phenylpiperidine or a salt thereof.

In addition, the present invention provides compounds of formula (III):

wherein W is hydrogen or Q (O ═ C-, wherein Q is H, C₁-C₆Alkyl or halo C₁-C₆An alkyl group; r¹Is C₁-C₆Alkyl (preferably methyl); r²Is hydrogen, C₁-C₆Alkyl, halo C₁-C₆Alkyl or phenyl (preferably hydrogen, methyl, trifluoromethyl or phenyl); and n is one, two or three (preferably one or two).

These compounds of formula (III) are useful as intermediates in the preparation of compounds of formula (I). The compounds of formula (III) contain a chiral centre. Thus, the present invention also includes two separate isomers of the compound of formula (III) and mixtures thereof.

Preferred compounds of formula (III) include the enantiomeric pairs of the following compounds:

5-methoxy-1-trifluoromethyl-1, 3-dihydroisobenzofuran;

6-methoxy-3-trifluoromethyl-1, 3-dihydrobenzofuran-5-carbaldehyde (carbaldehyde);

5-methoxy-1, 1-bistrifluoromethyl-1, 3-dihydroisobenzofuran;

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-dihydroisobenzofuran-5-carbaldehyde;

1-trifluoromethyl-5-methoxy-1-phenyl-1, 3-dihydroisobenzofuran;

3-trifluoromethyl-6-methoxy-3-phenyl-13, -dihydroisobenzofuran-5-carbaldehyde; and

5-acetyl-3-methyl-6-methoxy-3-trifluoromethyl-1, 3-dihydroisobenzofuran.

Particularly preferred compounds of formula (III) include:

(1R) -6-methoxy-1-methyl-1-trifluoromethyl isochroman;

(1R) -6-methoxy-1-methyl-1-trifluoromethyl isochroman-7-carbaldehyde;

(1S) -6-methoxy-1-methyl-1-trifluoromethyl isochroman;

(1S) -6-methoxy-1-methyl-1-trifluoromethyl isochroman-7-carbaldehyde;

(1R) -5-methoxy-1-methyl-1-trifluoromethyl-1, 3-dihydroisobenzofuran;

(1R) -6-methoxy-3-methyl-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-carbaldehyde;

(1S) -5-methoxy-1-methyl-1-trifluoromethyl-1, 3-dihydroisobenzofuran; and

(1S) -6-methoxy-3-methyl-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-carbaldehyde.

General SynthesisMethod

The piperidine aminomethyl trifluoromethyl cyclic ether of formula (I) according to the present invention can be prepared as described in the following reaction scheme.

In the scheme, R is, unless otherwise indicated¹、R²、R³、R⁴、R⁵Q and n are as defined above and Z represents hydrogen or an amino protecting group.

Scheme 1 illustrates a process for the preparation of compounds of formula (Ia) by reductive alkylation of compounds of formula (II) with compounds of formula (III).

Route

Compounds of formula (Ia) wherein Z is hydrogen or an amino protecting group may be synthesized by reductive alkylation of an amine compound of formula (II) with a compound of formula (III) using known methods, for example as described in International patent application WO 97/03066. The reaction can be carried out in a reaction-inert solvent in the presence of a suitable reducing agent. Suitable reducing agents are, for example, borohydrides, such as sodium triacetoxyborohydride (NaB (OAc)₃H) Sodium borohydride (NaBH)₄) And sodium cyanoborohydride (NaBH)₃CN), borane, lithium aluminum hydride, and trialkylsilane. Suitable solvents include polar solvents such as methanol, ethanol, dichloromethane, Tetrahydrofuran (THF), dioxane and ethyl acetate. The reaction may be carried out at a temperature of about-78 deg.C to the reflux temperature of the solvent, preferably at 0-25 deg.C for 5 minutes to 48 hours, preferably 0.5-12 hours. Preferably, the compound (Ia) wherein Q is not hydrogen is obtainable by reacting a compound of formula (II) with a compound of formula (III) wherein W is acyl. The reaction can be carried out in a reducing agent, such as NaBH₃CN and Lewis acids, e.g. tin (IV) chloride (TiCl)₄) In the presence of a reaction-inert solvent, for example dichloromethane (tetrahedron letters, volume 31, page 5547, 1990). When Z is an amino protecting group, the amino protecting group may be protected byMethods known to those of ordinary skill in the art remove the protecting groups after reductive alkylation (see protective groups in Organic Synthesis, T.W.Greene et al, John Wieley)&Sons, inc., 1991) to obtain a compound of formula (I). Specifically, when Z is t-butyloxycarbonyl (abbreviated as "Boc"), Boc can be removed by reaction in the presence of an acid, e.g., hydrochloric acid, in a reaction-inert solvent, e.g., methanol, under an inert atmosphere, e.g., nitrogen.

The starting material of formula (II) may be prepared by a nitrogen-protected (2S, 3S) -3-amino-2-phenylpiperidine compound by a known method such as that described in International patent publication WO 92/17449. Nitrogen protection of the piperidine ring of the compound of formula (II) may be carried out, for example, according to the method described in International patent publication WO 97/03066. Suitable protecting groups are, for example, Boc, benzyloxycarbonyl chloride (abbreviated Cbz) or trifluoroacetyl. For example, nitrogen protection using Boc A (2S, 3S) -3-amino-2-phenylpiperidine compound can be used in the presence of a base such as sodium hydroxide, sodium bicarbonate or triethylamine (t-BuOCO)₂And performing O treatment.

The compounds of formula (III) can be prepared by formylation or acylation of compounds of formula (IV) as shown in scheme 2.

Route 2

Known formylation or acylation methods can be employed. For example, the formylation may be carried out directly by contacting a compound of formula (IV) with a suitable formylating agent in the presence of a suitable catalyst. Suitable formylation reagents/catalyst systems include dichloromethyl methyl ether/titanium (IV) Chloride (CH)₂CHOCH₃/TiCl₄) Trifluoroacetic acid (CF)₃CO₂H) Hexamethylenetetramine (modified Duff's conditions) and phosphorus oxychloride (POCl)₃) DMF (Vilsmeier conditions). More specifically, CH is used₂CHOCH₃/TiCl₄Formylating a Compound of formula (IV)The reaction of (3) can be carried out in a reaction-inert solvent under nitrogen atmosphere. Suitable solvents include dichloromethane and 1, 2-dichloroethane, and the reaction is carried out at about-120 ℃ to room temperature for about 1 minute to 10 hours, preferably at-78 ℃ for 5 minutes to 4 hours. The daff reaction can also be used for formylation according to the reaction conditions of International patent publication WO 94/24081.

In addition, suitable indirect formylation methods include (i) halogenation of the compound of formula (IV), (ii) replacement of the halogen atom with a cyano group, and (iii) reduction of the resulting cyano-substituted compound. (i) Halogenation reactions can be carried out according to known procedures reported in G.A.Olah et al (J.org.chem., vol.58, 3194-, 1983). (ii) Replacement of a halogen atom with a cyano group can be achieved, for example, according to the method reported by D.M.Tschaem et al (Synth.Commun., Vol.24, 887-, 1994) or by K.Takagi et al (Bull.chem.Soc.Jpn., Vol 64, pp.1118-, 1991). (iii) The reduction reaction used here can be carried out in dichloromethane or Raney Ni in formic acid in the presence of diisopropylaluminium hydride (DIBAL-H).

The acylation can be carried out by, for example, the well-known Friedel-Crafts acylation reaction described in advanced organic chemistry (Jerry March, John Wiely & Sons, 4 th edition, 1992, p539) and the literature therein. More specifically, compound (IV) can be reacted with an acylating agent in the presence of an acid catalyst to give compound (III). Suitable acylating agents include acid chlorides, acid fluorides and acid anhydrides, with acid chlorides being preferred. Suitable acid catalysts include sulfuric acid and lewis acids, such as aluminum chloride, preferably aluminum chloride. The reaction is generally carried out at about-10 ℃ to room temperature for about 5 minutes to about 2 hours, preferably about 0 ℃ for about 1 hour.

The cyclic ether of formula (IV) can be prepared from compound (Va) or (Vb) according to a known method as reported in w.e. parham et al (journal of organic chemistry, j.org.chem., Vol 39, 2048, 1974) or a method as shown in scheme 3.

Route 3

In route A of scheme 3, the compounds of formula (IV) may be prepared from compounds wherein Y¹Is Br, I or Cl (preferably Br) and Y²Synthesis of a compound of formula (Va) which is hydrogen or a hydroxy protecting group (suitably tetrahydropyranyl, abbreviated to "THP"). The compound of formula (Va) may be metallated by treatment with an organometallic compound. The reaction mixture may then be reacted with a compound of formula CF₃C(＝O)R²The carbonyl compound of (b) to give a diol (Vc). If desired, a hydroxyl-protecting group Y of the diol (Vc)²Can be removed. The diol (Vc) may then be cyclized to provide the cyclic ether of formula (IV).

The metal substitution of the compound of formula (Va) can be carried out in the presence of an organometallic compound, such as n-butyllithium, sec-butyllithium or tert-butyllithium. Metal substitution and subsequent reaction with CF₃C(＝O)R²The reaction of (a) may be carried out in a reaction-inert solvent such as THF, ether and hexane under an inert atmosphere, such as nitrogen, at about-150 ℃ to room temperature for 15 minutes to 12 hours, preferably at-120 ℃ to-30 ℃ for 10 minutes to 6 hours. Protection of hydroxyl groups and protecting groups Y²The removal of (A) can be carried out according to known methods under appropriate conditions depending on the protecting Group selected (protecting Group in Organic Synthesis), T.W.Greene, et al John Wiely&Sons, inc).

The cyclisation of the diol (Vc) can be carried out in the presence of an acid according to known methods reported, for example, by W.E.Parham et al (Synthesis, pp116-, 1976) or Seebach et al (chem.Ber., Vol.116, pp.8354-, 1994). Suitable acids are, for example, hydrochloric acid, sulfuric acid or p-toluenesulfonic acid, trifluoroacetic acid (abbreviated to TFA). The reaction may be carried out at about room temperature to about 200 ℃ for 10 minutes to 12 hours, preferably at 60 ℃ to 150 ℃ for 30 minutes to 6 hours.

Alternatively, cyclization can be carried out according to known methods, for example, Mitsunobu reaction or methods reported by J.R.falck et al (J.Am.chem.Soc.), Vol 116, pp8354-, 1994. For example, the Mitsunobu reaction may be carried out in the presence of triphenylphosphine/diethyl azodicarboxylate in a suitable solvent under a nitrogen atmosphere at about 0 ℃ for about 5 minutes to about 6 hours.

In route B of scheme 3, cyclic ether compounds of formula (IV) can be prepared by reacting a compound of formula (IV) wherein Y is³A compound of formula (Vb) which is a leaving group with CF₃C(＝O)R²The one-step cyclization is carried out in the presence of a suitable base (see, for example, journal of organic chemistry (J. org. chem.), Vol 41, pp.1184-, 1976). Suitable leaving groups include Cl, Br, tosylate, mesylate and triflate. Suitable bases include alkyl lithium such as n-butyl lithium, sec-butyl lithium and tert-butyl lithium. For example, the reaction may be carried out by first treating the compound of formula (Vb) with sec-butyllithium in a suitable reaction-inert solvent, such as THF/hexane, under a nitrogen atmosphere, at a temperature of about-120 deg.C to about 0 deg.C for a period of time of about 5 minutes to 12 hours, preferably at a temperature of-100 deg.C to-60 deg.C for a period of time of 10 minutes to 6 hours. Subsequently, a carbonyl compound CF may be added₃C(＝O)R²To the reaction mixture and the temperature is raised to about-50 ℃ to room temperature.

In another aspect, for example, where R¹The starting material of formula (Va), which is methyl, can be prepared according to known methods by bromination in the para-position of known or commercially available anisole compounds (e.g., J.org.chem., Vol.58, pp 7507-, 1993 and J.org.chem., Vol.46, pp 118-, 1981).

The pressure of the above reaction is not critical unless otherwise specified. Typically, the reaction is carried out at about one to three atmospheres, preferably at ambient pressure (about one atmosphere).

The compounds of formula (I) and intermediates shown in the above schemes may be isolated and purified by conventional methods, for example by recrystallization or chromatography.

Because the piperidinylaminomethyltrifluoromethyl cyclic ether compounds of the invention have at least two asymmetric centers, they can be in various stereoisomeric forms or in various configurations (e.g., diastereomers including epimers). Thus, the compounds may exist in isolated (+) -and (-) -optically active forms and mixtures thereof. The present invention includes all of these forms. All optical isomers and stereoisomers of the formulae (I), (II) and mixtures thereof are considered to be within the scope of the present invention. With respect to the compounds of formula (I) and (II), the present invention includes the use of the racemates, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof. The compounds of formula (I) and (II) may exist in tautomeric forms. The present invention relates to the use of all such tautomers and mixtures thereof. The individual isomers may be obtained by known methods, for example by optical resolution, fractional crystallisation, chromatography or HPLC of the intermediate, or diastereomeric mixtures of compounds of formula (I) or a suitable salt thereof. The individual stereoisomers may be synthesized from the appropriate optically active starting materials or intermediates by any of the general methods described herein.

Since the piperidinylaminomethyltrifluoromethyl cyclic ethers of the invention are basic compounds, they can form many different salts with various inorganic and organic acids. Although such salts are intended to be useful for mobile administration, it is often necessary to first isolate the base compound of the invention as a non-pharmaceutically acceptable salt from the reaction mixture, then conveniently convert it to the free base by treatment with an alkaline reagent, and then convert the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of the present invention are conveniently prepared by treating the base compound with substantially equivalent amounts of the selected mineral or organic acid in an aqueous solvent and a suitable organic solvent, such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt is conveniently obtained. The acids used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of the invention described hereinbefore are those which form non-toxic acid addition salts, i.e. those containing a pharmaceutically acceptable anion salt, for example the hydrochloride, hydrobromide, hydroiodide, nitrate, sulphate or bisulphate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate (i.e. the 1, 1' -ethylene-bis- (2-hydroxy-3-naphthoic acid) salt).

The piperidinylaminomethyltrifluoromethyl cyclic ether compounds of the invention exhibit significant substance P receptor binding activity and are therefore of value in the treatment of a variety of clinical indications characterized by the presence of an excess of said substance P activity. Such indications include cardiovascular disease, allergic disease, angiogenesis, gastrointestinal disease, central nervous system disease, inflammatory disease, emesis, urinary incontinence, pain, migraine; major anxiety disorder, stress disorder, anxiety, major depressive disorder with anxiety, depression, sunburn; sexual dysfunction, bipolar affective disorder with bipolar disorder, substance use disorder, schizophrenia, motility disorder, cognitive disorder, and disease, disorder and adverse symptom caused by helicobacter pylori. For the treatment of emesis, such compounds are preferably used in combination with 5HT₃The receptor antagonists are used in combination.

The active piperidinylaminomethyltrifluoromethyl cyclic ether compounds of the formula (I) according to the invention or their pharmaceutically acceptable salts can be administered to mammals by oral, parenteral (e.g., intravenous, intramuscular or subcutaneous) or topical routes. Generally, the optimal dosage range for administration of these compounds to humans is from about 0.3mg to 750mg per day, although variations will be required depending on the weight and indication of the subject being treated and the route of administration chosen. However, the most desirable dosage level is from about 0.06mg to about 6mg per kg of body weight per day.

However, it will also vary with the species of animal being treated and its individual response to the drug, as well as the type of pharmaceutical formulation selected and the time period and interval at which administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, but in other cases, higher doses which do not produce deleterious side effects may be required, provided that such higher dosage levels should first be divided into several small doses for administration throughout the day.

The piperidinylaminomethyltrifluoromethyl cyclic ether compounds of this invention may be administered alone or in combination with a pharmaceutically acceptable carrier or diluent by any of the routes indicated above, in single or multiple doses. More particularly, the novel therapeutic agents of the present invention may be administered in a number of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers to form tablets, capsules, lozenges, troches, hard candies, powders, sprays, emulsions, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injections, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media, and various non-toxic organic solvents, and the like. Also, the oral pharmaceutical composition may be appropriately added with a sweetener and/or a flavoring agent. The therapeutically effective compounds of the present invention are present in such dosage forms at concentration levels of from about 5.0% to about 70% by weight.

For oral administration, tablets may be used, containing various excipients, such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycerol; and various disintegrating agents, such as starch (preferably corn, potato or tapioca starch), alginic acid and some complex silicates and granulation binders, such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, tableting is often performed using lubricants such as magnesium stearate, sodium lauryl sulfate, and talc. Solid ingredients of similar type may also be used as fillers in gelatin capsules; preferred materials for this conjugation also include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are used for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or coloring matter, and, if desired, emulsifying and/or suspending agents as well as diluents such as water, ethanol, propylene glycol, glycerin and various like combinations thereof.

Solutions of the compounds of the present invention in sesame or peanut oil or aqueous propylene glycol may be used for parenteral administration. If desired, the aqueous solution should be suitably buffered (preferably pH > 8) and the liquid diluent should first be made isotonic. These aqueous solutions are suitable for intravenous purposes. The oil solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. All of these solutions are readily prepared under sterile conditions by one of ordinary skill in the art using standard pharmaceutical techniques.

Furthermore, when treating, for example, skin inflammation, the compounds of the present invention may be administered topically, which may be in accordance with standard pharmaceutical practice, preferably with creams, jellies, gels, pastes, ointments and the like.

The activity of the compounds of the invention as substance P antagonists can be determined by their expression of NK by using radioactive agents₁The receptor is expressed in CHO cells or IM-9 cells with the ability to inhibit the binding of substance P at its receptor site. Substance P antagonist activity of The piperidinylaminomethyltrifluoromethyl cyclic ether compounds described herein can be assessed using standard assays described in D.G. Payan et al (journal of immunology, Vol. 133, P. 3260, 1984). The method essentially comprises determining the concentration of the individual compounds required to reduce the amount of radiolabeled Substance P (SP) agent at its receptor site to 50% in the isolated bovine tissue or IM-9 cells, thereby obtaining the IC characteristic of each test compound₅₀The value is obtained. More specifically, in assay buffer (50mM Tris-HCl (pH 7.4), 1mM MnCl₂0.02% bovine serum albumin, bacitracin (40. mu.g/ml), leupeptin (4. mu.g/ml), chymotrypsin inhibitor and phosphoramidon (30. mu.g/ml)), and the combination of the above-mentioned compounds [ p ], [2 ], [³H]Inhibition of SP binding to IM-9 cells. By adding the cells to a solution containing 0.56nM³H]SP and various concentrations of compounds in assay buffer (total volume: 0.5ml) initiated the reaction and incubated at 4 ℃ for 120 minutes. The culture was terminated by filtration on a GF/B filter (previously immersed in 0.1% polyethyleneimine for 2 hours). Non-specific binding was defined as the radioactivity remaining in the presence of 1 μ M SP. The filters were placed in tubes and counted with a liquid scintillation counter.

Alternatively, the anti-inflammatory activity of the compounds of the present invention in the mammal periphery was confirmed by capsaicin-induced plasma extravasation assay using the method described in A.Nagahisa et al (Journal of Pharmacology, European Pharmacology, Vol.217, pp.191-195, 1992). In this assay, anti-inflammatory activity was measured as the percent inhibition of plasma protein extravasation in pentobarbital anaesthetized male Hartey guinea pig ureters (300-350 g). Plasma extravasation was initiated by intraperitoneal injection of capsaicin (30 μ M in 0.1 BSA in buffer, 10ml per animal) into overnight fasted animals. The compounds of the invention were dissolved in 0.1% methylcellulose-water and administered orally 1 hour prior to capsaicin challenge. Evans blue (30mg/kg) was administered intravenously 5 minutes prior to stimulation. Animals were sacrificed 10 minutes after capsaicin challenge and the right and left ureters were removed.

The compound of example 3 of the invention showed 98% inhibition at a dose of 0.03mg/kg, whereas the compound of example 18 of WO 97/08114, structurally closest thereto, showed 72% inhibition at this same dose.

The side effects on calcium channel binding affinity were determined by verapamil binding studies in rat heart membrane preparations. More specifically, the verapamil binding assay was performed as previously described by Reynolds et al (Pharmacol. Exp. Ther. Vol.237, p.731, 1986). Briefly, a tissue is added to a solution containing 0.25nM [2 ]³H]The culture was started in tubes of desoxypregidine and various concentrations of compounds (total volume 1 ml). Non-specific binding is defined as residual radioligand binding in the presence of 3-10 μ M methoxy verapamil.

The improvement of the N.M.J. Rupniak method (J.Europan Journal of Pharmacology, Vol.265, pp.179-183, 1994) and the L.J. Bristow method (J.Europan Journal of Pharmacology, Vol.253, pp.245-252, 1994) was used in gerbils [ Sar ]⁹，Met(O)₂ ¹¹]The activity of the compounds of the invention against CNS disorders was determined in substance P-induced tapping assays. More specifically, the compound of the present invention is first administered subcutaneously to gerbils. Second, gerbils were lightly anesthetized with ether and left to expose the cranial surface. Third, the needle is inserted 3.5 mm below the point of the herringbone suture with a 25 gauge needle to directly couple [ Sar⁹，Met(O)₂ ¹¹]Substance P is injected into the lateral ventricle. Each gerbil was then placed in a 1-liter beaker and repetitive tapping of the hind paws was monitored.

The antiemetic activity of the compounds of the invention can be demonstrated by cisplatin-induced emesis in ferrets. The compounds of the invention were administered subcutaneously to ferrets (male, 1.3-1.6kg) 30 minutes prior to cisplatin injection. Ferrets are injected intraperitoneally with cisplatin and their emetic episodes (e.g. retching, vomiting and retching) are recorded with a video camera for 4 hours. The frequency of seizures is counted.

In the tests, some compounds of the invention showed good antiemetic action (ED)₉₀0.05 mg/kg-0.1 mg/kg).

The sensitivity of the compounds of the invention to metabolism can be assessed by an in vitro assay comprising (a) contacting the sample compound with a reagent composition prepared by adding specific cytochrome P-450 (e.g., CYP2D6) isozymes to poor metabolic initiators (abbreviated as PM) liver microsomes (human liver microsomes lacking said specific cytochrome P-450 isozymes) in a carrier material, and (b) analyzing the substrate by a mass spectrometer connected to HPLC (high pressure liquid chromatography). More specifically, 1.3mM NADP (nicotinamide adenine dinucleotide phosphate), 0.9mM NADH (reduced nicotinamide adenine dinucleotide), 3.3mM MgCl in a total volume of 1.2ml of 100mM potassium phosphate buffer₂And 8 units/ml of G-6-PDH (glucose-6-phosphate dehydrogenase), the substrate (1. mu.M) was cultured with PM human liver microsomes (manufactured by Keystone Skin Bank) or control vector microsomes to which recombinant CYP2D 6-expressing microsomes (0-0.1mg/ml) were added. The pH of the solution was 7.4 and the incubation temperature was 37 ℃. At the specified incubation time (0, 5, 10, 30 and 60 min), 100. mu.l of the reaction mixture was withdrawn and mixed with 1ml of 5ng/ml (2S, 3S) -3- (2-methoxybenzylamino) -2-diphenylmethyl-1-azabicyclo [2.2.2 ] containing as internal standard 5ng/ml]Octane (prepared according to the method disclosed in WO 90/05729) was mixed with acetonitrile (CAN). The concentrations of substrate and product in the sample solutions were analyzed by a Sciex API-III mass spectrometer connected to a Hewlett packard HP1090 HPLC system.The residual substrate concentration (% -residual) in each sample solution was plotted against the required incubation time. Obtaining T in each figure_1/2The value of (c). Calculating T of test Compound_1/2Ratio of values (i.e., T)_1/2Specific value (T obtained from control vector microsomes_1/2) /(T obtained by adding PM human liver microsomes expressing CYP2D 6-microsomes_1/2))

Certain of the compounds prepared in the examples below have a lower metabolic sensitivity than the most structurally similar compounds in International patent publication WO 97/08144.

Examples

The invention is illustrated by the following examples. It should be understood, however, that the invention is not limited to the specific details of these examples. Melting points were determined using a Buchi micro melting point apparatus, but were not calibrated. Infrared absorption Spectroscopy (IR) was measured using a Shimadzu Infrared spectrometer (IR-470).¹H-hydrogen nuclear magnetic resonance spectroscopy (NMR) in CDCl³Middle-used JEOL NMR spectrometer (JNM-GX270, pair)¹H270 MHz) unless otherwise noted. Peak position is expressed in parts per million (ppm) downfield from tetramethylsilane. The peak shape is represented as follows: s, singlet; d, double peak; t, triplet; m, multiplet.

Example 1

(2S, 3S) -3- (6-methoxy-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-yl) methylamino Preparation of (E) -2-phenylpiperidine dihydrochloride

(i) 2-bromo-5-methoxybenzyl alcohol

To a stirred suspension of lithium aluminium hydride (1.2g, 30.6mmol) in anhydrous tetrahydrofuran (40ml) was added dropwise a solution of methyl 2-bromo-5-methoxybenzoate (5.0g, 20.4mmol) in anhydrous tetrahydrofuran (80ml) at 0 ℃ under a nitrogen atmosphere. The reaction mixture was stirred at 0 ℃ for 1 hour. To the reaction mixture was added sodium sulfate dodecahydrate and potassium fluoride. The resulting mixture was stirred at room temperature for 1 hour and then filtered through a pad of celite. The filtrate was concentrated to give the crude product as white crystals. Purification by chromatography on silica gel eluting with a gradient of hexane and ethyl acetate (10: 1.8: 1.6: 1) afforded the title compound as white crystals (4.2g, 94.9%).

¹H-NMR(CDCl₃)：7.42(d，J＝8.8Hz，1H)，7.07(d，J＝2.9Hz，1H)，6.72(dd，J＝8.8，2.9Hz，1H)，4.71(d，J＝6.2Hz，2H)，3.81(s.3H)，1.98(t，J＝6.2Hz，1H)

(ii)2- (2-bromo-5-methoxybenzyloxy) tetrahydropyran

To a stirred mixture of 2-bromo-5-methoxybenzyl alcohol (3.91g, 18.0mmol) and dihydropyran (3.3ml, 36.0mmol) in dry dichloromethane (80ml) was added camphorsulfonic acid (210mg, 0.9mmol) under nitrogen at 0 ℃. The reaction was quenched with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic extracts were washed with brine, dried over magnesium sulfate and concentrated to give the crude product. Purification by chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (20: 1) gave the title compound as a colorless oil (5.68g, quantitative).

¹H-NMR(CDCl₃)：7.40(d，J＝8.8Hz，1H)，7.10(d，J＝3.3Hz，1H)，6.69(dd，J＝8.8，3.3Hz，1H)，4.80-4.76(m，2H)，4.53(d，J＝13.6Hz，1H)，3.97-3.88(m，1H)，3.79(s，3H)，3.60-3.53(m，1H)，1.93-1.54 (m，6H)

(iii)2, 2, 2-trifluoro-1- (4-methoxy-2- (tetrahydropyran-2-yloxymethyl) phenyl) ethanol

To a stirred solution of 2- (2-bromo-5-methoxybenzyloxy) tetrahydropyran (1.0g, 3.32mmol) in anhydrous tetrahydrofuran (20ml) was added n-butyllithium (2.6ml, 4.32mmol) dropwise under a nitrogen atmosphere at-78 ℃. The reaction mixture was stirred at-40 ℃ for 2.5 hours. To the reaction mixture was added dropwise a solution of trifluoromethylacetaldehyde (0.7ml) in anhydrous tetrahydrofuran (2ml) at-78 ℃. After stirring at the same temperature for 2 hours, the reaction was stopped with a saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated to give the crude product which was chromatographed on silica gel 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 (390mg, 36.7%).

¹H-NMR(CDCl₃): 7.53(d, J ═ 8.4Hz, 1H), 6.94(d, J ═ 2.9Hz, 1H), 6.89(dd, J ═ 8.4, 2.9Hz, 1H), 5.36-5.25(m, 1H), 4.85 and 4.78 (each d, J ═ 12.1Hz, total 1H), 4.69-4.63(m, 1H), 4.58 and 4.51 (each d, J ═ 12.1Hz, total 1H), 3.88-3.70(m, 2H), 3.81(s, 3H), 3.56-3.51(m, 1H), 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 (390mg, 1.22mmol) and a mixed solvent of acetic acid, tetrahydrofuran and water (4: 1, 24ml) was stirred at room temperature for 2 hours. The reaction temperature was raised and held at 40 ℃ for 1.5 hours and then at 60 ℃ for 2 hours. The solvent was removed and the residue was dried under vacuum to give the crude product (410mg) as a pale yellow title compound. The product was used without purification.

(v) 5-methoxy-1-trifluoromethyl-1, 3-dihydroisobenzofuran

To a stirred and ice-cooled solution of 2, 2, 2-trifluoro-1- (2-hydroxymethyl-4-methoxyphenyl) ethanol (160mg, 0.54mmol) and triphenylphosphine (312mg, 1.19mmol) in anhydrous dichloromethane (6ml) was added dropwise a solution of diethyl azido dicarboxylate (0.255ml, 1.62mmol) in anhydrous dichloromethane (2ml) under nitrogen. The yellow reaction mixture was stirred at 0 ℃ 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 the crude product, which was purified by silica gel column chromatography eluting with hexane: ethyl acetate (100: 1-20: 1) to give the title compound as a colorless oil (67mg, 56.9%).

¹H-NMR(CDCl₃)：7.29(d，J＝8.4Hz，1H)，6.88(dd，J＝8.4，2.2Hz，1H)，6.80(br.s，1H)，5.42-5.39(m，1H)，5.28-5.12(m，2H)，3.83(s，3H)

(vi) 6-methoxy-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-carbaldehyde

To a stirred solution of 5-methoxy-1-trifluoromethyl-1, 3-dihydroisobenzofuran (67g, 0.31mmol) in anhydrous dichloromethane (5ml) was added titanium tetrachloride (IV) (0.074ml, 0.68mmol) under a nitrogen atmosphere at-78 ℃. After 15 minutes, a solution of dichloromethyl ether (0.056ml, 0.61mmol) in dry dichloromethane (1ml) was added to the yellow solution at the same temperature. The reaction mixture was stirred at-78 ℃ for 1 hour, poured into ice water, and stirred at room temperature for 30 minutes. The aqueous layer was extracted with dichloromethane. The extract was washed with brine, dried over magnesium sulfate and concentrated to give the crude product. The product was purified by silica gel column chromatography eluting with hexane and ethyl acetate (10: 1, 8: 1, 6: 1) to give the title compound as white crystals (63mg, 82.5%).

¹H-NMR(CDCl₃)：10.45(s，1H)，7.87(s，1H)，6.92(s，1H)，5.46-5.39(m，1H)，5.30(dd，J＝13.9，2.2Hz，1H)，5.19(d，J＝13.9Hz，1H)，3.97(s，3H)

(vii) 1-Boc- (2S, 3S) -3- (6-methoxy-3-trifluoromethyl-1, 3-dihydroiso Benzofuran-5-yl) methylamino-2-phenylpiperidine

To a stirred solution of 1-tert-butoxycarbonyl- (2S, 3S) -3-amino-2-phenylpiperidine (71mg, 0.26mmol) (prepared by the method described in International patent application WO 97/03066) and 6-methoxy-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-carbaldehyde (63mg, 0.26mmol) in anhydrous dichloromethane (3ml) was added sodium triacetoxyborohydride (76mg, 0.36mmol) in portions under a nitrogen atmosphere at room temperature. The reaction mixture was stirred at room temperature for 5 hours. The pH was adjusted to below 10 with saturated sodium bicarbonate solution, extracted with dichloromethane, dried over magnesium sulfate and concentrated to give the crude product. The product was purified by column chromatography on silica gel eluting with methylene chloride and methanol (50: 1, 25: 1, 20: 1) to give the title compound as a white amorphous solid (130mg, 98.7%).

¹H-NMR(CDCl₃): 7.60-7.54(m, 2H), 7.35-7.22(m, 4H), 6.70(s, 1H), 5.46-5.36(m, 2H), 5.24 and 5.23 (each d, J ═ 12.1Hz, total 1H), 5.12(d, J ═ 12.1Hz, 1H), 3.98-3.91(m, 1H), 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, 1H), 1.40(s, 9H)

(viii) (2S, 3S) -3- (6-methoxy-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-yl) Methylamino-2-phenylpiperidine dihydrochloride

To a stirred solution of 1-tert-butoxycarbonyl- (2S, 3S) -3- (6-methoxy-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-yl) methylamino-2-phenylpiperidine (130mg, 0.26mmol) in ethyl acetate (5ml) under a nitrogen atmosphere at room temperature was added dropwise a solution of hydrochloric acid in methanol (2.5 ml). The reaction mixture was stirred at room temperature for 8 hours. The solvent was removed and recrystallized from ethanol to give the title compound (38mg, 30.5%) as white crystals.

¹H-NMR (free amine, CDCl)₃): 7.28-7.25(m, 5H), 7.01 and 6.96 (each s, total 1H), 6.57 and 6.55 (each s, total 1H), 5.32-5.30(m, 1H), 5.24-5.07(m, 2H), 3.89(d, J ═ 2.2Hz, 1H), 3.70 and 3.64 (each d, J ═ 13.9Hz. total 1H), 3.51-3.48 (each s, total 3H), 3.40 and 3.38 (each d, J ═ 13.9Hz, total 1H), 3.31-3.25(m, 1H), 2.87-2.76(m, 2H), 2.14-1.57(m, 3H), 1.46-1.41(m, 1H)

Warp beam¹H-NMR measurement showed that the diastereomer ratio of the epimer at position 3 of the dihydroisobenzofuran ring was 5: 4.

Example 2

(2S, 3S) -3- (6-methoxy-3, 3-bis (trifluoromethyl) -1, 3-dihydroisobenzofuran-5-yl) Preparation of methylamino-2-phenylpiperidine dihydrochloride

(i)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 (1.0g, 3.32mmol) in anhydrous tetrahydrofuran (20ml) was added n-butyllithium (2.6ml, 4.32mmol) dropwise under a nitrogen atmosphere at-78 ℃. The reaction mixture was stirred at-40 ℃ for 2.5 hours. To the reaction mixture was added dropwise a solution of hexafluoroacetone (1ml) in anhydrous tetrahydrofuran (2ml) at-78 ℃. The resulting mixture was stirred at 0 ℃ for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated to give the crude product which was chromatographed on silica gel with a gradient of hexane and ethyl acetate (30: 1, 25: 1, 20: 1, 15: 1) to give the title compound (890mg, 69.0%).

¹H-NMR(CDCl₃)：7.68-7.25(m，1H)，7.42(s，1H)，6.95-6.90(m，2H)，5.08(d，J＝11.7Hz，1H)，4.78-4.73(m，1H)，4.71(d，J＝11.7Hz，1H)，3.83(s，3H)，3.83-3.75(m，1H)，3.58-3.54(m，1H)，1.79-1.52(m，6H)

(ii)1, 1, 1, 3, 3, 3-hexafluoro-2- (2-hydroxymethyl-4-methoxyphenyl) propan-2-ol

1, 1, 1, 3, 3, 3-hexafluoro-2- (4-methoxy-2- (tetrahydropyran-2-yloxymethyl) phenyl) propan-2-ol (350mg, 0.90mmol) was converted to the title compound (354mg) according to the procedure for the preparation of 2, 2, 2-trifluoro-1- (4-methoxy-2- (tetrahydropyran-2-yloxymethyl) phenyl) ethanol in example 1. The product was used without purification.

(iii) 5-methoxy-1, 1-bistrifluoromethyl-1, 3-dihydroisobenzofuran

A mixture of 1, 1, 1, 3, 3, 3-hexafluoro-2- (4-methoxy-2- (tetrahydropyran-2-yloxymethyl) phenyl) propan-2-ol (300mg) and concentrated hydrochloric acid was stirred at 120 ℃ for 6 hours. After cooling, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated to give the title compound as a crude product (258 mg). The product was used without purification.

(iv) 6-methoxy-3, 3-bis (trifluoromethyl) -1, 3-dihydroisobenzofuran-5-carbaldehyde

5-methoxy-1, 1-ditrifluoromethyl-1, 3-dihydroisobenzofuran (258g) was converted to the title compound (167mg, 69.0% yield with respect to 1, 1, 1, 3, 3, 3-hexafluoro-2- (2-hydroxymethyl-4-methoxyphenyl) propan-2-ol) according to the method for preparing 6-methoxy-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-carbaldehyde in example 1.

¹H-NMR(CDCl₃)：10.44(s，1H)，7.98(s，1H)，6.98(s，1H)，5.36(s，2H)，4.00(s，3H)

(v) 1-Boc- (2S, 3S) -3- (6-methoxy-3, 3-bis (trifluoromethyl) -1, 3-bis Hydroisobenzofuran-5-yl) methylamino-2-phenylpiperidine

6-methoxy-3, 3-bis (trifluoromethyl) -1, 3-dihydroisobenzofuran-5-carbaldehyde (191mg, 0.61mmol) was converted to the title compound (327mg, 93.3%) according to the procedure for preparing 1-tert-butoxycarbonyl- (2S, 3S) -3- (6-methoxy-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-yl) methylamino-2-phenylpiperidine in example 1.

¹H-NMR(CDCl₃)：7.57-7.54(m，2H)，7.39(s，1H)，7.35-7.23(m，3H)，6.71(s，1H)，5.43(m，1H)，5.29(s，2H)，3.99-3.95(m，1H)，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

Following the procedure for the preparation of (2S, 3S) -3- (6-methoxy-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-yl) methylamino-2-phenylpiperidine dihydrochloride as in example 1, 1-tert-butoxycarbonyl- (2S, 3S) -3- (6-methoxy-3, 3-bis (trifluoromethyl) -1, 3-dihydroisobenzofuran-5-yl) methylamino-2-phenylpiperidine (327mg, 0.57mmol) was converted into the title compound (226mg, 72.4%).

Melting point: 180 ℃ and 187 DEG C

¹H-NMR (free amine, CDCl)₃)：7.28-7.20(m，5H)，7.16(s，1H)，6.56(s，1H)，5.27(s，2H)，3.89(d，J＝2.6Hz，1H)，3.69(d，J＝13.9Hz，1H)，3.52(s，3H)，3.35(d，J＝13.9Hz，1H)，3.28-3.25(m，1H)，2.85-2.75(m，2H)，2.17-2.11(m，1H)，2.04-1.85(m，1H)，1.68-1.57(m，1H)，1.46-1.40(m，1H)

Example 3

(2S, 3S) -3- (6-methoxy-1-methyl-1-trifluoromethyl isochroman-7-yl) methylamino-2-benzene Preparation of phenylpiperidine dihydrochloride

(i)2- (2-bromo-5-methoxyphenyl) ethanol

To a stirred mixture of 3-methoxyphenethanol (1.18g, 7.8mmol) and pyridine (0.75ml, 9.3mmol) in dry dichloromethane (10ml) was added dropwise bromine at 0 ℃ under nitrogen. The orange solution was stirred at room temperature for 4 hours. The reaction was stopped by adding 10% aqueous sodium hydrogen sulfite solution, and extracted with dichloromethane. The organic extracts were washed with brine, dried over magnesium sulfate and concentrated to give the crude product, which was subjected to silica gel column chromatography eluting with hexane and ethyl acetate (10: 1, 8: 1, 5: 1) to give the title compound as a colorless oil (1.5g, 83.2%).

¹H-NMR(CDCl₃)：7.43(d，J＝8.8Hz，1H)，6.83(d，J＝3.3Hz，1H)，6.67(dd，J＝8.8，3.3Hz，1H)，3.91-3.81(m，2H)，3.78(s，3H)，2.99(t，J＝6.6Hz，2H)

(ii)2- (2- (2-bromo-5-methoxyphenyl) ethoxy) tetrahydropyran

2- (2-bromo-5-methoxyphenyl) ethanol (1.5g, 6.5mmol) was converted to the title compound (2.05g, quant.) according to the procedure for the preparation of 2- (2-bromo-5-methoxybenzyloxy) tetrahydrofuran in example 1.

¹H-NMR(CDCl₃)：7.40(d，J＝8.8Hz，1H)，6.86(d，J＝2.9Hz，1H)，6.65(dd，J＝8.8，2.9Hz，1H)，4.63-4.60(m，1H)，3.99-3.90(m，1H)，3.82-3.74(m，1H)，3.78(s，3H)，3.68-3.59(m，1H)，3.50-3.45(m，1H)，3.02(t，J＝7.0Hz，2H)，1.83-1.52(m，6H)

(iii)1, 1, 1-trifluoro-2- (4-methoxy-2- (2- (tetrahydropyran-2-yloxy) ethyl) phenyl) Propan-2-ol

To a stirred solution of 2- (2- (2-bromo-5-methoxyphenyl) ethoxy) tetrahydropyran (1.0g, 3.17mmol) in anhydrous tetrahydrofuran (20ml) was added n-butyllithium (2.5ml, 4.12mmol) dropwise under a nitrogen atmosphere at-78 ℃. The reaction mixture was stirred at-40 ℃ for 1 hour. To the reaction mixture was added dropwise a solution of anhydrous cerium chloride (884mg, 3.58mmol) in anhydrous tetrahydrofuran (15ml) at-78 ℃. The resulting mixture was stirred at-78 ℃ for 1 hour. To the reaction mixture was added trifluoroacetone (0.5ml, 5.59mmol), and the resulting mixture was stirred at-78 ℃ for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated to give the crude product which was chromatographed on silica gel with a gradient of hexane and ethyl acetate (20: 1, 15: 1, 12: 1, 10: 1) to give the title compound (555mg, 50.3%).¹H-NMR(CDCl₃): 7.35-7.31(m, 1H), 6.78-6.74(m, 2H), 5.70 and 5.62 (each s, total 1H), 4.63 and 4.48 (each m, total 1H), 4.18-4.11 and 3.99-3.92 (each m, total 1H), 3.80(s, 3H), 3.77-3.43(m, 3H), 3.33-2.90(m, 2H), 1.80 and 1.78 (each s, total 3H), 1.75-1.26(m, 6H)

(iv) 6-methoxy-1-methyl-1-trifluoromethyl isochroman

A mixture of 1, 1, 1-trifluoro-2- (4-methoxy-2- (2- (tetrahydropyran-2-yloxy) ethyl) phenyl) propan-2-ol (470mg, 1.35mmol) and concentrated hydrochloric acid (4ml) was stirred at 120 ℃ for 3 hours. After cooling, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated to give the title compound (460mg) as a brown oil. The product was used without purification.

(v) 6-methoxy-1-methyl-1-trifluoromethyl isochroman-7-carbaldehyde

6-methoxy-1-methyl-1-trifluoromethyl isochroman (460mg) was converted to the title compound (179mg, 48.3% yield relative to 1, 1, 1-trifluoro-2- (4-methoxy-2- (2- (tetrahydrofuran-2-yloxy) ethyl) phenyl) propan-2-ol) according to the procedure for preparing 6-methoxy-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-carbaldehyde in example 1.

¹H-NMR(CDCl₃)：10.41(s，1H)，7.82(s，1H)，6.78(s，1H)，4.19-4.11(m，1H)，3.94(s，3H)，3.94-3.87(m，1H)，2.91(t，J＝4.4Hz，2H)，1.67(s，3H)

(vi) 1-tert-butyloxycarbonyl- (2S, 3S) -3- (6-methylhydroxy-1-methyl-1-trifluoromethyl isochroman -7-yl) methylamino-2-phenylpiperidine

6-methoxy-1-methyl-1-trifluoromethylisochroman-7-carbaldehyde (184mg, 0.67mmol) was converted to the title compound (330mg, 91.8%) according to the procedure for preparing 1-tert-butoxycarbonyl- (2S, 3S) -3- (6-methoxy-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-yl) methylamino-2-phenylpiperidine in example 1.

¹H-NMR(CDCl₃): 7.59-7.55(m, 2H), 7.34-7.17(m, 4H), 6.56(s, 1H), 5.44(m, 1H), 4.16-4.08(m, 1H), 3.99-3.84(m, 2H), 3.80(m, 2H), 3.72 and 3.71 (s, 3H in total), 3.06-2.98(m, 2H), 2.83-2.81(m, 2H), 1.85-1.61(m, 4H), 1.63 and 1.61 (s, 3H in total), 1.50-1.40(m, 1H), 1.39(s, 9H)

(vii) (2S, 3S) -3- (6-methoxy-1-methyl-1-trifluoromethyl isochroman-7-yl) methylamino -2-phenylpiperidine dihydrochloride

Following the procedure for the preparation of (2S, 3S) -3- (6-methoxy-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-yl) methylamino-2-phenylpiperidine dihydrochloride as in example 1, 1-tert-butoxycarbonyl- (2S, 3S) -3- (6-methoxy-1-methyl-1-trifluoromethylisochroman-7-yl) methylamino-2-phenylpiperidine (325mg, 0.61mmol) was converted into the title compound (88mg, 28.4%).

Melting point: 193 ℃ C. -

¹H-NMR (main isomer, free amine, CDCl)₃): 7.33-7.20(m, 5H), 6.95(s, 1H), 6.43(s, 1H), 4.13-4.09(m, 1H), 3.92-3.84(m, 2H), 3.62(d, J ═ 13.9Hz, 1H), 3.51(s, 3H), 3.33(d, J ═ 13.9Hz, 1H), 3.31-3.24(m, 1H), 2.84-2.74(m, 4H), 2.12-2.07(m, 1H), 1.94-1.82(m, 1H), 1.67-1.62(m, 1H), 1.59(s, 3H), 1.43-1.38(m, 1H) were passed through¹H-NMR measurement showed that the diastereomer ratio of the epimer at position 1 of the isochroman ring was 5: 1 (1R: 1S). These isomers are (2S, 3S) -3- [ (1R) - (6-methoxy-1-methyl-1-trifluoromethyl-isochroman-7-yl)]Methylamino-2-phenylpiperidine and (2S, 3S) -3- [ (1S) - (6-methoxy-1-methyl-1-trifluoromethyl-isochroman-7-yl)]Methylamino-2-phenylpiperidine. Recovering the more soluble epimer from the mother liquor. By passing¹H-NMR measurement showed that the diastereomer ratio of the epimer at position 1 of the isochroman ring was 1: 3 (1R: 1S).

The absolute stereochemistry of the title compound was determined by X-ray crystallography of the (3R) isomer after purification by recrystallization.

¹H-NMR (main isomer, free amine, CDCl)₃)：7.33-7.20(m，5H)，6.99(s，1H)，6.40(s，1H)，4.13-4.09(m，1H)，3.92-3.84(m，2H)，3.62(d，J＝13.9Hz，1H)，3.45(s，3H)，3.33(d，J＝13.9Hz，1H)，3.31-3.24(m，1H)，2.84-2.74(m，4H)，2.12-2.07(m，1H)，1.94-1.82(m，1H)，1.67-1.62(m，1H)，1.59(s，3H)，1.43-1.38(m，1H)

Example 4

(2S, 3S) -3- (6-methoxy-3-methyl-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-yl) Preparation of methoxy-2-phenylpiperidine

(i) 2-bromo-5-methoxybenzyl chloride

To a stirred solution of 3-methoxybenzyl chloride (37.2g, 0.238mol) and pyridine (23.1ml, 0.286mol) in anhydrous dichloromethane (400ml) was added bromine (23ml, 0.880mol) at 0 ℃. The resulting mixture was stirred at 0 ℃ for 1 hour, and then at room temperature for 18 hours. The mixture was diluted with saturated aqueous sodium thiosulfate solution and extracted with dichloromethane. The combined extracts were washed sequentially with saturated aqueous sodium thiosulfate solution, water, 2N hydrochloric acid, water, and brine. The extracts were dried over magnesium sulfate and concentrated to give a pale yellow crystalline crude product. The product was dissolved in ethyl acetate and the precipitate was filtered. The filtrate was washed and concentrated to give pale yellow crystals, which were washed with hexane to give the title compound (43g, 77%) as white crystals.

¹H-NMR(CDCl₃)：7.44(d，J＝8.8Hz，1H)，7.02(d，J＝3.3Hz，1H)，6.74(dd，J＝8.8，3.3Hz，1H)，4.64(s，2H)，3.79(s，3H)

(ii) 5-methylhydro-1-methyl-1-trifluoromethyl-1, 3-dihydroisobenzofuran

To a solution of 2-bromo-5-methoxybenzyl chloride (13.8g, 0.059mol) in a mixture of anhydrous tetrahydrofuran (330ml) and hexane (110ml) was added dropwise a solution of n-butyllithium (37.2ml, 0.062mol) in hexane (15ml) at-100 ℃ under a nitrogen atmosphere over a period of 30 minutes, and the reaction mixture was stirred at-100 ℃ for 2.5 hours. Then, 1, 1, 1-trifluoroacetone (6.3ml, 0.071mol) dissolved in anhydrous tetrahydrofuran (5ml) and hexane (5ml) was added to the mixture, and the resulting mixture was warmed to-30 ℃. The reaction was stopped with water and the solvent was removed by evaporation. The residue was extracted with hexane. The organic extracts were dried over magnesium sulfate and concentrated to give a pale yellow crude product (13.6 g). The crude oil (13.6g), glycerol (575mg, 7.66mmol) and potassium hydroxide (703mg, 12.53mmol) were dissolved in a mixture of ethanol (30ml) and water (20ml) 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 pale yellow oil (12.6g) which was purified by distillation (94-98 deg.C/1.5 mmHg) to give the title compound as a colourless oil (10.8g, 78.7%)

¹H-NMR(CDCl₃)：7.20(d，J＝8.4Hz，1H)，6.87(dd，J＝8.4，2.6Hz，1H)，6.76(d，J＝2.6Hz，1H)，5.21-5.09(m，2H)，3.82(s，3H)，1.65(d，J＝1.1Hz，3H)

(iii) 3-methyl-3-trifluoromethyl-6-methoxy-1, 3-dihydroisobenzofuran-5-carbaldehyde

Titanium tetrachloride (IV) (11.2ml, 0.102mol) was added to a stirred solution of 5-methoxy-1-methyl-1-trifluoromethyl-1, 3-dihydroisobenzofuran (10.8g, 0.046mol) in anhydrous dichloromethane (280ml) under a nitrogen atmosphere at-78 ℃ and the resulting solution was stirred for 15 minutes. To the resulting brown solution was added a solution of dichloromethyl ether (0.4ml, 0.093mol) in dry dichloromethane (20m) at-78 ℃ and stirred for 1.5 hours. The 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 pale yellow crystals (12.1g, quantitative).

¹H-NMR(CDCl₃)：10.45(s，1H)，7.79(s，1H)， 6.88(s，1H)，5.25-5.13(m，2H)，3.97(s，3H)，1.68(m，3H)

(iv) (2S, 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 (4.1g, 23.1mmol) and 3-methyl-3-trifluoromethyl-6-methoxy-1, 3-dihydroisobenzofuran-5-carbaldehyde (6.1g, 23.3mmol) prepared by the method described in International patent publication WO 92/17449 (200ml) was added sodium triacetoxyborohydride (7.8g, 36.9mmol) in portions at room temperature under a nitrogen atmosphere, and the resulting mixture was stirred at the same temperature for 16 hours. After adjusting the pH to 10 or less with a saturated aqueous sodium bicarbonate solution, the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated to give a pale yellow amorphous solid (10.1 g). A solution of hydrochloric acid in methanol was added to the crude product dissolved in ethyl acetate. The solid formed was collected by filtration, dried under vacuum and then purified by crystallization from methanol to give the title compound as white crystals.

Melting point: 200 ℃ and 207 DEG C

¹H-NMR (main isomer, free amine, CDCl)₃): 7.31-7.21(m, 5H), 6.89(s, 1H), 6.54(s, 1H), 5.16-5.04(m, 2H), 3.90(d, J ═ 2.3Hz, 1H), 3.68(d, J ═ 14.3Hz, 1H), 3.52(s, 3H), 3.40(d, J ═ 14.3Hz, 1H), 3.29-3.26(m, 1H), 2.85-2.75(m, 2H), 2.14-2.09(m, 1H), 1.95-1.76(m, 1H), 1.66-1.54(m, 1H), 1.60(s, 3H), 1.44-1.40(m, 1H) are passed through¹H-NMR analysis showed that the ratio of the diastereomers at the 3-position of the dihydroisobenzofuran ring was 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.

In the remaining mother liquor, the other epimers at position 3 of the dihydroisobenzofuran ring of the 9: 1 (3R: 3S) mixture are recovered.

1H-NMR (main isomer, free amine, CDCl 3): 7.31-7.19(m, 5H), 6.94(s, 1H), 6.51(s, 1H), 5.16-5.04(m, 2H), 3.89(d, J ═ 2.2Hz, 1H), 3.67(d, J ═ 14.3Hz, 1H), 3.48(s, 3H), 3.37(d, J ═ 14.3Hz, 1H), 3.28-3.24(m, 1H), 2.85-2.75(m, 2H), 2.14-2.09(m, 1H), 1.97-1.86(m, 1H), 1.69-1.56(m, 1H), 1.59(s, 3H), 1.45-1.40(m, 1H)

Example 5

(2S, 3S) -3- (6-methoxy-3-phenyl-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-yl) Preparation of methylamino-2-phenylpiperidine dihydrochloride

(i) 1-trifluoromethyl-5-methoxy-1-phenyl-1, 3-dihydroisobenzofuran

To a stirred solution of 2-bromo-5-methoxybenzyl chloride (3.0g, 12.7mmol) in a mixture of anhydrous tetrahydrofuran (60ml) and hexane (20ml) was added dropwise n-butyllithium (8.4ml, 13.4mmol) over 15 minutes at-85 ℃ under a nitrogen atmosphere, and the reaction mixture was stirred at-85 ℃ for 2 hours. Then, 2, 2, 2-trifluoroacetone (2.70g, 15.3mmol) in anhydrous tetrahydrofuran (20ml) was added to the mixture at the same temperature, and the resulting mixture was allowed to warm to room temperature. The reaction was stopped 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 the crude product as a dark yellow oil. The crude oil was purified by the method using glycerol described in the synthesis of 5-methoxy-1-methyl-1-trifluoromethyl-1, 3-dihydroisobenzofuran in example 4, and column chromatography on silica gel (20g) eluting with hexane-ethyl acetate (20: 1) to give the title compound (760mg, 20.3%) as a pale yellow oil.

¹H-NMR(CDCl₃)：7.74-7.66(m，2H)，7.52-7.28(m，4H)，6.90(dd，J＝8.6，2.5Hz，1H)，6.80-6.76(m，1H)，5.33(d，J＝12.2Hz，1H)，5.23(d，J＝12.2Hz，1H)，3.82(s，3H).

(ii) 3-trifluoromethyl-6-methoxy-3-phenyl-1, 3-dihydroisobenzofuran-5-carbaldehyde

Following the procedure for the preparation of 6-methoxy-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-carbaldehyde in example 1, 1-trifluoromethyl-5-methoxy-1-phenyl-1, 3-dihydroisobenzofuran was converted and purified by column chromatography on silica gel (70g) eluting with hexane-ethyl acetate (5: 1) to give the title compound as a yellow viscous oil (507mg, 61.7%).

¹H-NMR(CDCl₃)：10.45(s，1H)，8.06(s，1H)，7.75-7.66(m，2H)， 7.44-7.30(m，3H)，6.90(s，1H)，5.38(d，J＝13.4Hz，1H)，5.27(d，J＝13.4Hz，1H)，3.96(s，3H)，

(iii) 1-tert-Butoxycarbonyl- (2S, 3S) -3- (6-methoxy-3-phenyl-3-trifluoromethyl-1, 3-) Dihydroiso-benzofuran-5-yl) methylamino-2-phenylpiperidine

Following the procedure for the preparation of 1-tert-butoxycarbonyl- (2S, 3S) -3- (6-methoxy-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-yl) methylamino-2-phenylpiperidine in example 1, 3-trifluoromethyl-6-methoxy-3-phenyl-1, 3-dihydroisobenzofuran-5-carbaldehyde (453mg, 1.41mmol) was converted and the crude product was purified by column chromatography on silica gel (40g) eluting with dichloromethane-methanol (80: 1) to give the title compound as a pale yellow oil (657 mg). The product was used in the next reaction without purification.

(iv) (2S, 3S) -3- (6-methoxy-3-phenyl-3-trifluoromethyl-1,3-dihydroisobenzofurans -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 (657mg) in ethyl acetate (25ml) were added concentrated hydrochloric acid (3ml) under ice-cooling. The reaction mixture was stirred at room temperature for 1.5 hours. The pH of the mixture was adjusted to 10 or less with 2N sodium hydroxide under ice cooling. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and concentrated to give the crude product as a yellow oil (559 mg). The crude product was purified by column chromatography on silica gel (18g) eluting with dichloromethane-methanol (40: 1-10: 1) to give the title compound as a yellow viscous oil (497mg, 87.9%).

(v) (2S, 3S) -3- (6-methoxy-3-phenyl-3-trifluoromethyl-1, 3-dihydroisobenzofuran -5-yl) methylamino-2-phenylpiperidine dihydrochloride

(2S, 3S) -3- (6-methoxy-3-phenyl-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-yl) methylamino-2-phenylpiperidine (497mg, 1.03mmol) was treated with 10% methanolic hydrochloric acid (20 ml). After removal of the solvent in vacuo, the residue was washed with hot ethanol to give the title compound as a white solid.

Melting point: 203 ℃ to 204 DEG C

By passing¹The ratio of the diastereomers at the 3-position of the dihydroisobenzofuran ring, determined by H-NMR, was 6.5: 1.

¹H-NMR (main isomer, free amine, CDCl)₃)：7.71-7.62(m，2H)，7.45-7.17(m，9H)，6.55(s，1H)，5.29(d，J＝12.2Hz，1H)，5.19(d，J＝12.2Hz，1H)，3.88(d，J＝2.1Hz，1H)，3.67(d，J＝14.3Hz，1H)，3.51(s，3H)，3.42(d，J＝14.3Hz，1H)，3.35-3.23(m，1H)，2.89-2.73(m，2H)，2.20-1.78(m，4H)，1.70-1.35(m，2H).

In the mother liquor, recoveringTo the more soluble epimer of the 2: 1 mixture.¹H-NMR (main isomer, free amine, CDCl)₃)：7.70-7.60(m，2H)，7.45-7.15(m，9H)，6.52(s，1H)，5.29(d，J＝12.2Hz，1H)，5.19(d，J＝12.2Hz，1H)，3.90(d，J＝2.5Hz，1H)，3.72(d，J＝14.0Hz，1H)，3.47(s，3H)，3.33(d，J＝14.0Hz，1H)，3.33-3.21(m，1H)，2.88-2.72(m，2H)，2.18-1.78(m，4H)，1.72-1.35(m，2H).

Example 6

(2S, 3S) -3- [ (1- (6-methoxy-3-methyl-3-trifluoromethyl-1, 3-dihydroisobenzofuran) -5-yl) ethylamino]Preparation of (E) -2-phenylpiperidine dihydrochloride

(i) 5-acetyl-3-methyl-6-methoxy-3-trifluoromethyl-1, 3-dihydroisobenzofuran

To a solution of aluminum chloride (689mg, 5.17mmol) in dry dichloromethane (10ml) was added acetyl chloride (0.37ml, 5.17mmol) at 0 deg.C and stirred for 10 min. A solution of 5-methoxy-1-methyl-1-trifluoromethyl-1, 3-dihydroisobenzofuran (1.00g, 4.31mmol) in dry dichloromethane (10mL) was added dropwise to the mixture at 0 deg.C, and the resulting solution was stirred at the same temperature for 1 hour. The mixture was poured into a mixture of ice-hydrochloric acid (1N), and the organic layer was separated. The aqueous layer was extracted with dichloromethane and the organic portions were combined. The organic extracts were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluting with hexane and ethyl acetate (8: 1), to give the title compound (1.10g, 93%) as white crystals.

¹H-NMR(CDCl₃)：7.69(s，1H)，6.86(s，1H)，5.21(d，J＝13.2Hz，1H)，5.14(d，J＝13.2Hz，1H)，3.94(s，3H)，2.62(s，3H)，1.67(s，3H)

(ii) (2S, 3S) -3- [1- (6-methoxy-3-methyl-3-trifluoromethyl-1, 3-dihydroisobenzoyl Furan-5-yl) ethylamino]-2-phenylpiperidine

To a stirred solution of (2S, 3S) -2-phenyl-3-aminopiperidine (350mg, 1.99mmol), 5-acetyl-3-methyl-6-methoxy-3-trifluoromethyl-1, 3-dihydroisobenzofuran (545mg, 1.99mmol) and triethylamine (0.83ml, 5.96mmol) in anhydrous dichloromethane (20ml) was added dropwise titanium tetrachloride (0.11ml, 0.99mmol) at 0 ℃. The mixture was stirred at room temperature for 1 hour and then cooled to 0 ℃. After addition of a solution of sodium cyanoborohydride (374mg, 5.96mmol) in methanol (5ml) at the same temperature, the mixture was allowed to warm to room temperature and stirred for 30 minutes. After addition of hydrochloric acid (1N, 15ml), the mixture was stirred at room temperature for 1 hour. Ethyl acetate (80ml) was added to the resulting mixture, and the mixture was extracted with hydrochloric acid (1N, 60 ml. times.3). The combined aqueous extracts were washed with ethyl acetate and the pH adjusted to 9 with saturated aqueous potassium carbonate. The aqueous layer was extracted with ethyl acetate (60 ml. times.3), and the combined organic portions were washed with saturated aqueous sodium bicarbonate (60 ml). The organic solution was dried over sodium sulfate and evaporated in vacuo to give the crude product. The crude product was purified by column chromatography on silica gel eluting with hexane: ethyl acetate (10: 1) to give the title compound as a colorless foam (145, g, 17%).

¹H-NMR analysis showed a composition of 5: 2 based on the four diastereomers at the 3-position of the dihydroisobenzofuran and the C1-position of the ethylamino moiety.

¹H-NMR(C₆D₆Partial data): 1.70, 1.59, 1.56 and 1.52 (four single peaks, 3H in total, ratio 5: 2, respectively).

(iii) (2S, 3S) -3- [1- (6-methoxy-3-methyl-3-trifluoromethyl-1, 3-dihydroisobenzoyl Furan-5-yl) ethylamino]-2-phenylpiperidine dihydrochloride

To a stirred solution of (2S, 3S) -3- [1- (6-methoxy-3-methyl-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-yl) ethylamino ] -2-phenylpiperidine (106mg, 0.24mmol) in methanol (1ml) was added a 10% methanol hydrochloride solution (10ml), followed by stirring at room temperature for 30 minutes. The mixture was concentrated in vacuo and the residue was purified by crystallization from methanol and ether to give a white solid (45mg, 36%).

By passing¹The ratio of diastereomers in this solid was 20: 30: 1: 3, as determined by H-NMR.¹H-NMR (free base, C)₆D₆Partial data): 6.06(S, 1H), 5.00(d, J ═ 12.0Hz, 1H), 4.83(d, J ═ 12.0Hz, 1H), 3.59-3.36(m, 2H), 3.18, 3.17 and 3.13(3S, total 3H), 3.07-3.01(m, 1H, 2.68-2.63(m, 1H), 2.49-2.37(m, 1H), 1.73, 1.62, 1.56 and 1.53 (four singlet, total 3H, ratio 20: 30: 1: 3, respectively), 1.31, 1.28, 1.07 and 1.01 (four doublets, J5.6, 5.6, 6.3 and 6.6Hz, respectively, total 3H).

The mother liquor was evaporated under reduced pressure. The residual solid was washed with ether and dried to give a pale yellow solid (39mg, 32%).

¹H-NMR analysis showed the ratio of diastereomers in this solid to be 5: 1: 5: 4.

¹H-NMR (free base, C)₆D₆Partial data): 6.06(s, 1H), 5.03-4.96(m, 1H), 4.85-4.77(m, 1H), 3.18, 3.17 and 3.13(3s, total 3H), 1.71, 1.58, 1.53 and 1.52 (four single peaks, total 3H, ratio 5: 1: 5: 4, respectively), 1.29, 1.26, 1.05 and 1.00 (four twin bees, J4.5, 4.5, 6.3 and 6.6Hz, respectively, total 3H).

Example 7

(2S, 3S) -3- [ (1R) - (6-methoxy-1-methyl-1-trifluoromethyl-isochroman-7-yl) methylamino Preparation of (E) -2-phenylpiperidine dihydrochloride

(i) 6-hydroxy-1-methyl-1-trifluoromethyl isochroman

To a stirred solution of 6-methoxy-1-methyl-1-trifluoromethyl isochroman (71g, 0.29mol) in acetic acid (600ml) was added 48% aqueous HBr (300ml) and the mixture was stirred at 130 ℃ for 13 h. After removal of the acetic acid in vacuo, the reaction mixture was treated with aqueous sodium hydroxide (8M) until pH 5-6. The resulting solution was extracted with ethyl acetate (400 ml. times.2), and the combined ethyl acetate extracts were washed with brine (100ml), dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography (silica gel, 15X 20cm, 17% ethyl acetate-hexanes) gave 6-hydroxy-1-methyl-1-trifluoromethyl isochroman (67g, 100%) as a colorless oil.

¹H-NMR(CDCl₃)：7.22(d，J＝9.1Hz，1H)，6.73(dd，J＝9.1，2.6Hz，1H)，6.63(d，J＝2.6Hz，1H)，5.00(s，1H)，4.17-4.07(m，1H)，3.90(dt，J＝11，5.8Hz，1H)，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 (79g, 0.34mol) and triethylamine (120ml, 0.88mol) in THF (680ml) was added acetyl chloride (31ml, 0.44mol) at 0 deg.C and the mixture was stirred at room temperature for 1 hour. 1N aqueous hydrochloric acid (400ml) was added to stop the reaction, and the mixture was extracted with ethyl acetate (500 ml). The extract was washed with saturated aqueous sodium bicarbonate (100ml) and brine (100ml), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 15X 20cm, 17% ethyl acetate-hexanes) to give 6-acetoxy-1-methyl-1-trifluoromethyl isochroman (83g, 89%).

¹H-NMR(CDCl₃)：7.36(d，J＝7.2Hz，1H)，6.98(dd，J＝7.2 ，2.5Hz，1H)，6.91(d，J＝2.5Hz，1H)，4.18-4.08(m，1H)，3.92(dt，J＝11，5.4Hz，1H)，2.86(t，J＝5.4Hz，2H)，2.30(s，1H)，1.66(s，3H).

(iii) (1R) -6-acetoxy-1-methyl-1-trifluoromethyl isochroman and (1S) -6-hydroxy-1- Methyl-1-trifluoromethyl isochroman

Racemic 6-acetoxy-1-methyl-1-trifluoromethyl isochroman (38.4g, 0.140mol), 10% sec-butylA mixture of butanol in hexane (1.3L) and lipase PS (35g) was stirred vigorously at room temperature for 23 hours. After filtration, the filtrate was concentrated under reduced pressure to give a mixture. The mixture was subjected to silica gel column chromatography, eluting with a gradient of hexane and ethyl acetate (15: 1, 5: 1, 2: 1), to give first (1R) -6-acetoxy-1-methyl-1-trifluoromethyl isochroman (17.3g, 45%, 94% ee) as a colorless oil. Of the compound¹H-NMR was the same as for its racemate. The second fraction yielded crystalline (1S) -6-hydroxy-1-methyl-1-trifluoromethyl isochroman (16.9g, 52%, 83% ee). Of the compound¹The H-NMR spectrum was identical to that of the racemate.

(iv) (1R) -6-hydroxy-1-methyl-1-trifluoromethyl isochroman

To a stirred mixture of (1R) -6-acetoxy-1-methyl-1-trifluoromethyl isochroman (35.5g, 0.129mol), methanol (860ml) and water (340ml) was added potassium carbonate (35.7g, 0.258mol) at 0 ℃ and the mixture was stirred at room temperature for 1 hour. The resulting mixture was acidified (pH 3) with 2N hydrochloric acid and the methanol was evaporated in vacuo. 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 (28.0g, 93%) as a colorless oil. The compound was used without purification. Of the compound¹The H-NMR spectrum was identical to that of the racemate.

(v) (1R) -6-methoxy-1-methyl-1-trifluoromethyl isochroman

To a stirred mixture of sodium hydride (3.47g, 0.145moL) in DMF (50ml) was added a solution of (1R) -6-hydroxy-1-methyl-1-trifluoromethyl isochroman (28.0g, 0.121moL) in DMF (370ml) at 0 ℃ and then stirred at room temperature for 1 hour. After the reaction mixture was quenched with water, it was diluted with a saturated aqueous ammonium chloride solution. Extraction was performed with ethyl acetate-toluene (4: 1). The organic portion was washed with water and brine and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel eluting with hexane and ethyl acetate (40: 1) to give the title compound as a colorless oil (29.1 g.98%). Of the compound¹The H-NMR spectrum was identical to that of the racemate.

(vi) (2S, 3S) -3- [ (1R) -6-methoxy-1-methyl-1-trifluoromethyl isochroman-7-yl]First of all Amino-2-phenylpiperidine dihydrochloride

The procedure of example 3 was followed to convert the above (1R) -6-methoxy-1-methyl-1-trifluoromethyl isochroman further to the title compound to give the title compound as a single diastereomer.

Optical rotation: [ alpha ] to]²⁷ _D＝+75.44°(c＝0.424，MeOH)

The chemical structures of the compounds of formula (I) prepared in examples 1-7 are summarized in the following table.

Watch (A)

Example No. 2	R¹	R²	R³	R⁴	R⁵	n	RS-configuration of the piperidine ring
Example No. 2	R¹	R²	R³	R⁴	R⁵	n	RS-configuration of the piperidine ring	1	CH₃	H	H	H	H	1	(2S，3S)
2	CH₃	CF₃	H	H	H	1	(2S，3S)	1	CH₃	H	H	H	H	1	(2S，3S)
2	CH₃	CF₃	H	H	H	1	(2S，3S)	3	CH₃	CH₃	H	H	H	2	(2S，3S)
4	CH₃	CH₃	H	H	H	1	(2S，3S)	3	CH₃	CH₃	H	H	H	2	(2S，3S)
4	CH₃	CH₃	H	H	H	1	(2S，3S)	5	CH₃	C₆H₅	H	H	H	1	(2S，3S)
6	CH₃	CH₃	H	CH₃	H	1	(2S，3S)	5	CH₃	C₆H₅	H	H	H	1	(2S，3S)
6	CH₃	CH₃	H	CH₃	H	1	(2S，3S)	7	CH₃	CH₃	H	H	H	2	(2S，3S)

Claims

1. A compound of formula (I):

wherein: r¹Is C₁-C₆An alkyl group; r²Is hydrogen, C₁-C₆Alkyl, halo C₁-C₆Alkyl or phenyl; r³Is hydrogen; r⁴And R⁵Each independently is hydrogen or C₁-C₆An alkyl group; and n is 1 or 2.

2. A compound according to claim 1, wherein R¹Is C₁-C₃An alkyl group; r²Is hydrogen, C₁-C₃Alkyl, halo C₁-C₃Alkyl or phenyl; r³Is hydrogen; r⁴And R⁵Each independently is hydrogen or C₁-C₃An alkyl group; and n is 1 or 2.

3. A compound according to claim 2, wherein R¹Is methyl; r²Is hydrogen, methyl, trifluoromethyl or phenyl; r³Is hydrogen; r⁴And R⁵Is hydrogen.

4. A compound according to claim 3, selected from:

5. The compound according to claim 4, wherein said compound is

(2S, 3S) -3- [ (1R) - (6-methoxy-1-methyl-1-trifluoromethyl-isochroman-7-yl ] methylamino-2-phenylpiperidine or a salt thereof, or

(2S, 3S) -3- [ (3R) - (6-methoxy-3-methyl-3-trifluoromethyl-1, 3-dihydroisobenzofuran-5-yl) ] methylamino-2-phenylpiperidine or a salt thereof.

6. A compound of formula (III):

wherein W is hydrogen or Q (O ═ C-, wherein Q is H or C₁-C₆An alkyl group; r¹Is C₁-C₆An alkyl group; r²Is hydrogen, C₁-C₆Alkyl, halo C₁-C₆Alkyl or phenyl; and n is 1, 2 or 3.

7. The compound according to claim 6, wherein said compound is selected from the group consisting of:

5-methoxy-1-trifluoromethyl-1, 3-dihydroisobenzofuran;

6-methoxy-3-trifluoromethyl-1, 3-dihydrobenzofuran-5-carbaldehyde;

5-methoxy-1, 1-bis (trifluoromethyl) -1, 3-dihydroisobenzofuran;

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-dihydroisobenzofuran-5-carbaldehyde;

1-trifluoromethyl-5-methoxy-1-phenyl-1, 3-dihydroisobenzofuran;

3-trifluoromethyl-6-methoxy-3-phenyl-1, 3-dihydroisobenzofuran-5-carbaldehyde;

5-acetyl-3-methyl-6-methoxy-3-trifluoromethyl-1, 3-dihydroisobenzofuran;

(1R) -6-methoxy-1-methyl-1-trifluoromethyl isochroman.

8. A pharmaceutical composition for treating a disease or condition in a mammal requiring substance P antagonist activity comprising an amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, effective to treat such disease or condition and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition according to claim 8, wherein the disease or indication for which the composition is indicated is selected from the group consisting of cardiovascular diseases, allergic diseases, angiogenesis, gastrointestinal diseases, central nervous system diseases, inflammatory diseases, urinary incontinence, pain, migraine; major anxiety disorder, stress disorder, anxiety, major depressive disorder with anxiety, depression, sunburn; bipolar affective disorder, substance use disorder, schizophrenia, motility disorder, cognitive disorder, and disease, disorder and adverse symptom caused by helicobacter pylori.

10. The use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or condition in a mammal requiring antagonist activity of substance P.

11. The use according to claim 10, wherein the disease or indication for which the medicament is indicated is selected from cardiovascular diseases, allergic diseases, angiogenesis, gastrointestinal diseases, central nervous system diseases, inflammatory diseases, emesis, urinary incontinence, pain, migraine; major anxiety disorder, depression, stress disorder, anxiety, major depressive disorder with anxiety, depression, sunburn; bipolar affective disorder, substance use disorder, schizophrenia, motility disorder, cognitive disorder, and disease, disorder and adverse symptom caused by helicobacter pylori.