JPH07505648A - Azacyclic compounds - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Azacyclic compounds The present invention relates to certain azacyclic compounds useful as tachykinin antagonists. do. More specifically, the present invention provides arylmethyloxy or arylmethyloxy It consists of an azacyclic ring system substituted with a ruthio moiety.

Kukikinins are widely distributed throughout mammalian tissues, both within the central nervous system and in the peripheral nervous system. and a group of naturally occurring peptides also found in the circulatory system. three known mammals The structure of tachykinine is as follows: P substance: ^rg-Pro-Lys-Pro-Gl n-G 1 n-Phe-Phe-G ly-Leu-Me t-NH2 Neurokinin A: His-Lys-Thr-^sp-3er-Phe-Val-Gly-Leu- Met-Ni+.

221 Rokinine B: ^sp-Met-His-^sp-Phe-Phe-Val-Gly-Leu- The Met-NJP substance is a neurotransmitter of pain sensation [Tsuka et al., “Role of 5ubstance P as a 5ensory TransIlitt er in 5pinal Cord and Sympathetic Ga nglia” f1982 P-things in the nervous system0 Tsuka and Yana gisawaS”Does 5ubstance P Act as a Pa 1n Transmitter? ” TIPS (December 1987) 85 06-510], especially migraine (B, E, B, Sandberg et al., J IMed Chem, (1982) believed. These peptides are It has also been associated with diseases of the GI tract, such as intestinal (GI) disorders and inflammatory bowel disease. [Mantyh et al., Neuroscience (198g) 25 (3) 8 17-37 and Regoli-Trends in C1uster "l1eadache" (edited by Sicuteri et al., Elsevier 5cie ntific Publishers, Amsterdam (1987) 85 pages ji]. We also hypothesized that there is a neurogenic mechanism for arthritis that may involve substance P. [Kidd et al.”^ Neurogenic Mechanism f or Symmetrical Arthritis” (The Lance t, November 11, 1989) and GrQnblad et al. “Neuropep Tides in Synovium of Patients with R heumatoid＾rthritis and 0steoarthritis s” (J, Rheua+ato1. (198g)+5(12) 1807 ~10)]. Therefore, substance P is used in diseases such as rheumatoid arthritis and osteoarthritis. is believed to be involved in the inflammatory response [0'Byrne et al., Arthri et al. tis and Rheumatism (1990) 331023-8]. Taki Other disease areas where kinin antagonists may be useful include allergic conditions [H amelet dilatation, bronchial convulsion, visceral reflex regulation or neuronal regulation [Manty h et al., PNAS (1988) 853Z'35-9], and probably (Alz. In Heimer's senile dementia, Alzheimer's disease and Down syndrome, β-amylo Id-mediated neurodegenerative changes [Yankner et al., 5science (1990) 25 0.279-82] by preventing or retarding it.

Substance P is used in demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis [J, Lub Er-Narod et al., C,1,N,P, 10th Conference, June 28, 1992 - Poster presented on July 2nd] and bladder mechanisms such as bladder micturition hyperreflexia (The Lancet, May 16, 1992, 1239) .

Additionally, tachykinins have been suggested to be effective for the following disorders: In other words, Depression, dysthymia, chronic obstructive airway disease, irritability disorders such as sumac rash, angina Vascular attack diseases such as Leno's disease and Leno's disease, fibrotic diseases such as scleroderma and eosinophilic fluke disease syndrome and collagen disease, reflex sympathetic dystrophy such as shoulder-hand syndrome, and alcoholism. addictive disorders such as psychosis, stress-related physical disorders, neurological disorders, neuralgia, systemic Disorders of immune enhancement or suppression such as matosus (European Patent Application No. 04363) No. 34), eye diseases such as conjunctivitis, vernal keratitis, etc., as well as contact dermatitis, atopic Dermatitis, Zingma and Eczema dermatitis (European Patent Application No. 0394989) and vomiting (European Patent Application No. 0533280).

Peptide derivatives have limited utility as therapeutic agents due to lack of metabolic stability. It seems to be determined. It is for this reason that non-peptide tachykinin antagonists are preferred. Ru.

European patent application no. Disclosed are ring-membered azacyclic compounds. The compound is a tachykinin antagonist. It is said that

(In the formula, n is 1.2 or 3, and: X represents O or S; Y represents a hydrocarbon chain of 1, 2.3 or 4 carbon atoms which may be optionally substituted with oxo eagle, I: R1 is C1-6 alkyl, C2-. alkenyl, C2-, alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, -OR0, SR", SOR", SO, R', -NR"R"', -NR"C0Rb, -NR"COsR 1, 2 or 3 selected from ', -COIRl or -C0NR''Rb represents phenyl optionally substituted with a group; R2 is selected from phenyl and naphthyl; Selected aryls: indazolyl, chenyl, furyl, pyridyl, thiazolyl, heteroaryl selected from tetrazolyl and quinolyl; benzhydryl; represents benzyl and each aryl and heteroaryl moiety is cI-s alkyl , cI-6 may be substituted with alkoxy, halo or trifluoromethyl; R4 and and R8 may be located at any available carbon atom position in the azacyclic ring. Often and each independently H1 halo, C1,6 alkyl, oxo, CH, OR” , CO,R" or CONR"Rb; R8 represents an optionally substituted aromatic heterocycle; Ro and R1 are each independently , Hl trifluoromethyl, Cl-11 alkyl or optionally 01-, alkyl phenyl substituted with halo, halo or trifluoromethyl) A compound or a salt or prodrug thereof is provided.

Each expression definition used in this book appears more than once in any structure. In this case, it shall be unrelated to definitions elsewhere in the same structure.

The alkyl, alkenyl and alkynyl groups quoted with respect to the above formulas are straight chain, It may represent branched or cyclic groups or combinations thereof. Therefore, for example Suitable alkyl groups include methyl, ethyl, n- or iso-propyl, n-1 sec. -, iso- or tert-butyl, cyclopropyl, cyclobutyl, cyclopene cycloalkyl-methyl, such as methyl or cyclohexyl and cyclopropylmethyl. suitable alkenyl groups include vinyl and allyl; suitable alkenyl groups include vinyl and allyl; Alkynyl groups include propargyl.

The term "halo" as used herein refers to fluoro, chloro, bromo and iodo, In particular, it includes chloro and fluoro.

The present invention includes within its scope prodrugs of compounds of formula (1) above. in general Such prodrugs are capable of accommodating the required compound of formula (1) in vivo. It is a functional derivative of the compound of formula (1) which can be easily converted. suitable prodrug Conventional methods for selecting and preparing derivatives are described, for example in the “Designof Prodr. uggs”, edited by H. Bunffgaard, Elsevier, 1985. It is listed.

The compounds of the invention may exist as enantiomers or diastereoisomers.

In particular, the relative configuration of the 2- and 3-substituents on the azacyclic ring is can produce cis diastereoisomers, of which the cis diastereoisomer is preferred. stomach. It is understood that all such isomers and mixtures thereof are included within the scope of the present invention. I want to be understood.

Preferably, n is 2 or 3, more preferably 3.

Preferably, X represents O.

Y is CH,, C=O1CH(CH3), CHz (C=O) or (C=0) with 1 or 2 carbon atoms optionally substituted with oxo, such as CH, It is appropriate to represent a hydrocarbon chain. Y is CH, CH(CH3) or CH.

It is preferable to represent (C=O), and more preferably CH2 or CH(CHs). stomach. A particularly preferred subgroup of compounds of the invention are those of formula (I) in which Y is CH (CH3)).

Preferably R1 represents substituted phenyl. If R is substituted phenyl, appropriate Appropriate substituents include nitro: trifluoromethyl: trimethylsilyl; bromo ;chloro;fluoro;iodo:cyano;methyl, ethyl, i-propyl, i-butyl 01-6 alkyl such as methyl, t-butyl and cyclopropyl; such as vinyl C2-6 alkenyl; C1- such as methoxy, ethoxy and i-propoxy 6 alkoxy: phenoxy, amino; carboxamide and carbonylmethoxy is included. R1 is C1-4 alkyl such as methyl and t-butyl; selected from fluoromethyl and halo such as iodo, bromo, chloro and fluoro It is preferred to represent phenyl substituted with one or more groups.

R1 is monosubstituted phenyl, such as 3-substituted phenyl, or preferably 3.5-substituted phenyl It is appropriate to represent disubstituted phenyl, such as substituted phenyl. R1 took the lead in 3rd place. Substituted with a Cl-8 alkyl group such as trifluoromethyl or t-butyl phenyl, or the substituents independently trifluoromethyl, chloro, fluoro, methyl 3,5-disubstituted phenyl selected from and t-butyl. R Preferred examples for + include 3,5-bis(trifluoromethyl)phenyl, 3 , 5-dichlorophenyl, 3-t-butyl-5-methylphenyl, 3-chloro- 5-methylphenyl, 3-t-butyl-5-chlorophenyl, 3-trifluoro Includes methylphenyl and 3-t-butylphenyl. Particularly preferred is 3 ．． 5-bis(trifluoromethyl)phenyl.

R2 is benzhydryl or optionally substituted phenyl, such as fluoro or or phenyl optionally substituted, preferably in the 3-position, by halo such as chloro. It is appropriate to express R2 is unsubstituted phenyl or unsubstituted benzhydryl unsubstituted phenyl is preferred, and unsubstituted phenyl is even more preferred.

Suitable for R4 and RI+ are H, C, -, alkyl, especially methyl, hydrogen Includes droxymethyl and oxo. Substituents R4 and R5 are Any use of the azacyclic ring except for C=2 and C-3 when representing xo May be in any available carbon atom position. Small amounts of R4 and R5 (one of which represents H) is preferable. In one preferred group of compounds, R4 and R5 both represent H. represent. In a more preferred group of compounds, one of R4 and R6 is H, The other is methyl, preferably 2-methyl.

When R8 represents a substituted aromatic heterocycle, suitable substituents for the heterocycle include one or more Cl-6 alkyl, C1-6 alkoxo, phenyl, oxo, thioxo, halo , trifluoromethyl, NR'R', NR'C0R1', C0NR''Rb5Co , R", SR"5SO2R' and CH20R" (,:, this T, R' and Rb are already (as defined in ). Specific examples of suitable substituents include methyl , metquin, phenyl, oxo, thioxo, bromo, iodo, Nl2.5CH8 , CONH2 and cyano. Particularly preferred substituents include oxo and Nl 2 is included.

Examples of suitable R8 include chenyl, furyl, pyrrolyl, pyridyl, pyrazoli. triazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazinyl, pyrimidinyl, pyrimidinyl ridazinyl, triazinyl, oxacylyl, oxadiazolyl, thiadiazolyl , isoxazolyl-, quinolyl, isothiazolyl, imidazolyl, benzimida Zolyl, benzoxacylyl, benzothiophenyl, benzofuranyl and indo including lyle, any of which may be substituted.

Specifically, R8 is optionally substituted chenyl, furyl, pyridyl, triazoli tetrazolyl, thiazolyl, pyrazinyl, pyrimidinyl 3-pyridazinyl, Riazinyl, oxacylyl, oxadiazolyl, thiadiazolyl, imidazolyl , represents benzimidazolyl or benzoxacylyl.

In one group of compounds of the invention, R1+ is optionally substituted pyrrolyl, pyrrolyl Zolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, oxadia Zolyl, thiadiazolyl, imidazolyl, benzimidazolyl, benzoxasi Represents lyl, benzothiophenyl, benzofuranyl or indolyl.

R8 is, for example, oxasilyl, oxadiazolyl, tetrazolyl, thiazolyl , thiadiazolyl, triazolyl, pyrazinyl, pyridyl, pyrimidinyl, pyri Substituted or unsubstituted 5- or or a 6-membered nitrogen-containing aromatic heterocycle. R8 is optionally substituted Oxacylyl, oxadiazolyl, imidazolyl, thiadiazolyl, thoria zolyl, pyrazinyl, pyrimidinyl, pyridazinyl or triazinyl, or C+-S alkyl, preferably methyl-substituted tetrazolyl is preferred. More preferable.

In one preferred group of compounds of the invention, R8 is substituted or unsubstituted oxadiazole. zolyl, for example substituted with halo, amino, dialkylamino or methyl Represents oxadiazolyl. R8 represents 5-(3-aminooxadiazolyl) It is more preferable to

In a more preferred group of compounds of the present invention, Re is substituted or unsubstituted triazolyl for example, unsubstituted triazolyl or triazolyl substituted with oxo or thioxo. It represents azolyl, more preferably oxo-substituted triazolyl.

When the heterocyclic moiety R8 is substituted with an oxo or thioxo substituent, the substituent is Different to represent =0 or -OH, or =S or -SH, respectively. It will be understood that tautomeric forms may be taken. to avoid uncertainty Additionally, all such tautomeric forms are included in the present invention.

One subgroup of compounds of the invention comprises formula (IA) (IA) (In the formula, n is 1.2 or 3, (CHI), (7) each carbon atom is also R' may be substituted with 2 and/or Re3; X represents O or S; R'' is C1-6 alkyl, C triazinyl, c't-a+-quinyl, halo, Cyano, nitro, trifluoromethyl, trimethylsilyl, -〇R°, SRc, SOR”, S OtRe.

-N R'R', -NR"COR', -N R"CO, R', -CO.

optionally substituted with 1, 2 or 3 groups selected from R' or -CONR'R' represents phenyl; R is aryl selected from phenyl and naphthyl; imidazolyl, chenyl, furyl, pyridyl, thiazolyl, tetrazolyl and heteroaryl selected from noryl: benzhydryl; or represents benzyl; , where each aryl or heteroaryl moiety is C1-6 alkyl, cl-, a Substituted with alkoxy, halo or trifluoromethyl (; R+2 and Re3 each independently represent H1 halo, C troalkyl, oxo, C o2R' or C0NR''R'; R14 is an optionally substituted aromatic hetero Represents C1-4 alkyl substituted with a ring and optionally substituted with oxo; Re and R6 are each independently HSCl-6 alkyl, C.

phenyl or trifluoromethyl optionally substituted with -6 alkyl or halo ) and its salts or prodrugs.

Suitable heterocyclic moieties for R'' include chenyl, furyl, pyrrolyl, pyrrol. Zyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazinyl, pyrazolyl ridazinyl, oxacylyl, oxadiazolyl, thiadiazolyl, isoxazolyl quinolinopeisothiazine, imidazolyl, benzimidazolyl, benziolyl Includes xacylyl, benzothiophenyl, benzofuranyl and indolyl.

In one subclass of compounds of formula (IA), Re and R' are each independently represents H, C, -, alkyl, phenyl or trifluoromethyl.

Another subclass of compounds of formula (IA) are those in which n is 2 or 3: R12 and R1 3 are each independently H1 halo, C1-.

represents alkyl, C0tR' or C0NR'R'; R14 is optionally substituted C1-4 alkyl substituted with a 5- or 6-membered aromatic heterocycle, R" and R6 are each independently H, C,, alkyl, phenyl or trifluor Represented by a compound representing olomethyl. About this subclass of compounds Examples of suitable heterocyclic moieties for R are chenyl, furyl, pyrrolyl, Pyridyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxacylyl oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazinyl and Contains imidazolyl.

A preferred subclass of compounds of the invention has formula (IB): (fil) (wherein, X represents O or S, preferably 0; Y is as defined in formula (1) Thus, preferably CI4 alkyl optionally substituted with oxo, more preferably c H! or CH(CH3): R2 is phenyl or benzhydryl (any phenyl or benzhydryl moiety) (both phenyl rings may also be optionally substituted with halo or trifluoromethyl), preferably or unsubstituted phenyl: R8 is as defined in formula (1); R20 and R”It independent D, HSC+-s7 Luki JLy, Ct-s alkenyl , C2-6 alkynyl, bromo, chloro, fluoro, iodo, cyan, nitro, Trifluoromethyl, trimethylnoryl, OR", SR", SOR", 5o2R ’, N　R’Rb.

NR"COR", NR"CO,R', COR", CO,R" or C0NR'R' (where Ro and Rh are as defined above): Z is 1 or 2) or a salt or prodrug thereof.

Specific examples of R20 and R21 include I1, methyl, 1-butyl, methoxy , i-propoxy, chloro, fluoro, nitro, amino, carbonylmethoxy, Carboxamides and trifluoromethyl are mentioned. Which is R2o and R11? are also preferably other than H, and C1 located at the 3- and 5-positions of the phenyl ring −. Even more preferred are alkyl, halo or trifluoromethyl.

One subclass of compounds of the invention are those of formula (IB) (wherein R8 is optionally substituted). converted pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, Riazinyl, imidazolyl, benzimidazolyl, benzoxacylyl, benzo Thiophenyl, benzofuranyl, indolyl, thiadiazolyl or oxadiazole oxadiazolyl, more preferably oxadiazolyl.

Another subclass of compounds of the invention are compounds of formula (IB) (wherein R8 is optionally substituted) Oxadiazolyl, pyridinyl, benzimidazolyl, tetrazolyl, thiazolyl Azolyl, furyl, chenyl, triazolyl, thiadiazolyl, benzoxasi Lyle, oxacylyl, pyrazinyl, pyridazinyl, triazinyl, pyrimidinyl or imidazolyl).

A particularly preferred group of compounds of the present invention is the formula (Ia) (wherein R8 is optionally substituted). oxo-substituted triazole) It is a thing.

For use in medicine, the salts of the compounds of formula (1) will be pharmaceutically acceptable salts. However, other salts (such as dibenzoyl tartrate salts) may also be used with the compounds of the present invention or pharmaceutically acceptable salts. may be useful in the production of acceptable salts thereof. Appropriate pharmaceutical approval for compounds of the invention Examples of acceptable salts include, for example, adding a solution of a compound of the invention to hydrochloric acid, sulfuric acid, oxalic acid, fumaric acid, acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or p- Formed by mixing with a pharmaceutically acceptable acid solution such as toluenesulfonic acid Possible acid addition salts are included. Salts of amine groups also contain alkyl, alkyl, a quaternary group accompanied by a suitable organic group such as an alkenyl, alkynyl or aralkyl moiety. grade ammonium salts. Furthermore, if the compound of the invention has an acidic moiety, Suitable pharmaceutically acceptable salts include alkali salts such as sodium or potassium salts. metal salts, and alkaline earth metal salts, such as calcium or magnesium salts. may include metal salts such as metal salts.

Preferred salts of the compounds of the invention include salts of hydrochloric acid and p-toluenesulfonic acid. It will be done.

The invention further provides medicaments comprising one or more compounds of the invention together with a pharmaceutically acceptable carrier. A composition is provided. These compositions are suitable for oral, parenteral or rectal administration; tablets, gunpowders, capsules, powders, and granules for administration by inhalation or insufflation. , a solution or suspension, or a unit dosage form such as a suppository.

The present invention further provides a compound of formula (1) or a salt or prodrug thereof and a pharmaceutically acceptable provides a method for making a pharmaceutical composition comprising an acceptable carrier, the method comprising: a compound of formula (1); or a salt or prodrug thereof with a pharmaceutically acceptable carrier. Ru.

For preparing solid compositions such as tablets, the main active ingredient is combined with a pharmaceutical carrier, e.g. Starch, lactose, sucrose, sorbitol, talc, stearic acid , magnesium stearate, dicalcium phosphate or gummy, and other pharmaceutical diluents The compounds of the present invention or pharmaceutical forming a solid pre-formulated composition containing an acceptable, non-toxic homogeneous mixture of its salts; do. When these pre-formulated compositions are referred to as homogeneous, they are The active ingredient may be easily subdivided into equally effective unit dosage forms, such as capsules. It means that it is evenly distributed throughout the composition. Then this solid pre- The prepared formulation composition is prepared by adding the above-mentioned composition containing from 0.1 to about 500 mg of the active ingredient of the present invention. subdivide into unit dosage forms. Tablets or gunpowder of the new composition may be coated or unpacked. If not, it can be formulated to provide a dosage form that offers the advantage of prolonged action. It is. For example, a tablet or gunpowder consists of an internal drug component and an external drug component, and The drug component can be in the form of an envelope that covers the inner drug component. These two formations It serves to resist disintegration in the stomach and allows the internal components to pass through to the intestines intact. They can be separated by an enteric layer that allows for filtration or delayed release. That's it Various materials can be used for the enteric layer or skin; of polymeric acids, and polymeric acids and polymeric acids, cetyl alcohol and cellulose acetate. It includes mixtures of substances such as.

The novel compositions of the present invention are formulated into a miscible liquid dosage form for oral or injectable administration. may be used in aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and cottonseed oil, pepper elixirs and flavored emulsions containing edible oils such as hemp oil, coconut oil or peanut oil. and similar pharmaceutical vehicles. A suitable dispersing or suspending agent for aqueous suspensions. contains tragacanth, gum acacia, alginate, dextran, carboxyme Chylcellulose sodium, methylcellulose, polyvinylpyrrolidone or gelatin Includes synthetic and natural gums such as chin.

Compositions for inhalation or insufflation may contain pharmaceutically acceptable aqueous or organic solvents or mixtures, solutions and suspensions, and powders. liquid or solid compositions It may contain suitable pharmaceutically acceptable excipients as mentioned above. local or total It is preferred that the compositions be administered by the oral or nasal respiratory route to obtain a physiological effect. Yes. The composition, preferably in a sterile pharmaceutically acceptable solvent, is prepared using an inert gas. It is possible to formulate a spray formulation. Atomized formulations can be drawn directly from the nebulizer. You can also attach the nebulizer to a face mask, tent, or intermittent positive pressure breathing machine. It's okay. Solution, suspension or powder compositions may be prepared using a device for delivering the formulation in an appropriate manner. It can be administered preferably orally or nasally.

The compound of formula (1) has various properties characterized by an excess of action of tachykinins, especially substance P. It is of value in the treatment of clinical conditions. These clinical conditions include anxiety, depression, Disorders of the central nervous system such as psychosis, psychosis and schizophrenia: Alzheimer-type senile dementia Neurodegenerative disorders such as dementia, including dementia, Alzheimer's disease and Down syndrome: multiple Diseases such as sexual sclerosis (MS) and amyotrophic lateral sclerosis (ALS) patients with demyelinating diseases, as well as diabetic and chemotherapy-induced neuropathies and post-herpetic and other diseases. Other neuropathological disorders such as peripheral neuropathy, including chronic obstructive airway disease, Respiratory diseases such as bronchial pneumonia, bronchial lung disease and asthma; inflammatory bowel disease, psoriasis, and combination syndrome Inflammatory diseases such as rheumatoid arthritis, osteoarthritis and rheumatoid arthritis; eczema and rhinitis Allergies such as: hypersensitivity disorders such as sumac rash; conjunctivitis, vernal catarrh, etc. eye diseases such as contact dermatitis, atopic dermatitis, vulgaris and other eczema-like dermatitis. skin diseases such as; addictive disorders such as alcoholism; stress-related physical disorders: Reflex sympathetic dystrophy such as calendar syndrome: dysthymia disorder; rejection of transplanted tissue adverse immune reactions such as systemic lupus erythematosus, and immune enhancement or suppression such as systemic lupus erythematosus. Related disorders; such as gastrointestinal (Gl) disorders and disorders related to the control of visceral nervous tissue diseases of the Gl tract, such as ulcerative colitis, Crohn's disease and incontinence; for example, chemotherapy , induced by radiation, toxins, pregnancy, vestibular disorders, surgery, migraines and fluctuations in intracranial pressure. Vomiting, including acute, delayed, and preceding vomiting; bladder mechanisms such as bladder voiding hyperreflexia fibrotic and collagen diseases such as scleroderma and eosinophilic fluke disease; angina pectoris, unilateral Pain and Leno's disease-like vasodilation and blood nociception may be included. For example, the formula (1 ) compounds can be used to treat central nervous system disorders such as anxiety, psychosis and schizophrenia, and Alzheimer's disease. Neurodegenerative disorders such as Heimer's senile dementia, Alzheimer's disease and Down syndrome , especially chronic obstructive airway disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma. Respiratory diseases associated with excessive mucus secretion and bronchial congestion, such as inflammatory bowel disease, Inflammatory diseases such as osteoarthritis and rheumatoid arthritis, rejection of transplanted tissue such as adverse immune reactions, gastrointestinal (Gl) disorders and disorders associated with visceral nervous tissue regulation. Diseases of the urinary GI tract such as ulcerative colitis, Crohn's disease and incontinence, blood due to vasodilation Suitable for use in the treatment of flow disorders and, for example, of the above-mentioned conditions or of nociception. Ru.

The compound of formula (1) may be used to treat pain or nociception and/or inflammation and related disorders such as diabetic neuropathy and chemotherapy-induced neuropathy pain, post-herpetic and other neuralgia, asthma, degenerative joint disease, rheumatoid arthritis, and especially It is particularly useful in treating migraines.

The invention further relates to the use of compounds of formula (I) in therapy.

According to a further or alternative aspect, the present invention provides a method for treating excess tachykinin, particularly substance P. Relating to the use of a compound of formula (I) in the manufacture of a medicament for the treatment of associated physiological disorders do.

The present invention further provides for the treatment of physiological disorders associated with excess tachykinins, particularly substance P; Related to preventive methods. The method provides tachykinin reduction in patients in need of such treatment. from administering an amount of a compound of formula (I) or a composition comprising a compound of formula (1). Become.

The compounds of this invention may be combined with other pharmacologically active agents in the treatment of specific conditions. It may be desirable to use them together. Treatment of breathing disorders such as asthma In this method, the compound of formula (1) is used as an R2-adrenergic receptor that acts at the NK-2 receptor. It may be used in conjunction with bronchodilators such as receptor antagonists or tachykinin antagonists. formula The compound (I) and the bronchodilator may be administered to the patient simultaneously, sequentially or in combination. good.

Accordingly, the present invention relates to a method of treating breathing disorders such as asthma; Administering an effective amount of the compound of formula (1) and an effective amount of a bronchodilator to a patient in need of treatment. It consists of things.

Furthermore, the present invention provides a compound of formula (1), a bronchodilator and a pharmaceutically acceptable carrier. A composition comprising:

Medicinal use of compounds of formula (1) suitable in the treatment of conditions associated with excess tachykinins The amount is about 0.001 to 50 mg/kg per day, especially about 0.01 to about 25 mg/kg, for example about 0.05 to about 10 mg/kg per day. example For example, when treating symptoms related to nerve transmission of pain, the appropriate dosage is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 1 per day 0 mg/kg, especially about 0.005 to 5 l11 g/kg per day. transformation The compound may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. stomach.

According to general method (A), the compounds of the invention have the formula (): (wherein R1, Rz, R4, R5, X and n are as defined in formula (1) above) A compound having the formula R8-Y-L (wherein L is chloro) is prepared in the presence of a base. , halo such as bromo or iodo, methylsulfonate or p-)rue sulfonates or suitable free radicals), e.g. or acyl halide, or the corresponding mezilad or toshisheet. can be produced by a method consisting of reacting with a suitable reagent for the introduction of the group Y-♂. It is Noh.

Suitable bases for use in the reaction include alkali metal carbonates, such as potassium carbonate. Examples include inorganic bases such as

The reaction is conveniently carried out in a suitable organic solvent such as dimethylformamide. .

According to the second method (B), formula (I) (wherein R8 represents 5-oxadiazolyl) The compound having the formula (■) is prepared by adding the compound of the formula (II) in the presence of a base to the compound having the formula (■): (wherein R1, R2, R4, R5, x, y and n are as defined in formula (I) , R3o represents an alkyl group, R'' is H or a suitable substituent, for example C3- 6 alkyl, C1-@alkoxy, ha0, NR"R"' or NR'C0Rb (this where R'' and R5 are as defined above) and the opposite. It can be manufactured by adapting the method.

Suitable bases for use in the reaction include, for example, alkali metals such as sodium, Examples include alkali metal hydrides such as sodium hydride.

The reaction is conveniently carried out in a suitable organic solvent. Choosing the right solvent depends on the salt used. Depends on the nature of the group. For example, when the base used is an alkali metal, suitable solvents include , for example, alcohols such as ethanol are included, and the base used is an alkali hydride. Suitable solvents include ethers such as tetrahydrofuran. .

Preferably, the reaction is carried out at elevated temperature, such as the reflux temperature of the chosen solvent.

According to another method (C), a compound having the formula (I), in which Ra represents tetrazolyl, The compound has the formula (■): (V) (In the formula, R1, R2, R4, R5, xSy and n are as defined in formula (1). ), the intermediate is treated with an alkali metal azide, such as sodium azide. It can be produced by processing.

The reaction is conveniently carried out in a high boiling organic solvent such as N-methylpyrrolidinone. It is advantageous.

According to yet another method (D), a compound of formula (I) in which R8 represents thiazolyl The compound has the formula (■): (vl) (In the formula, R1, R2, R4, R', X%Y and n are as defined in formula (1). from an intermediate of the formula Hal-CH2C(0)-ReO (where Ha l represents halo such as bromo, chloro or iodo, Rso is H or C1-6 prepared by reacting with a compound (representing a suitable substituent such as alkyl) It is possible.

The reaction may be performed using a ketone, such as acetone, or an alcohol, such as methanol, or in a suitable organic solvent such as a solvent mixture, preferably at the reflux temperature of the selected solvent. It is convenient to carry out the process at an elevated temperature, such as ℃.

According to yet another method (E), formula (■) (wherein R8 is thioxotriazolyl The compound of formula (■) (in which R1, R2, R4, R5, xSY and nlL, as defined in formula (1)) is an intermediate of formula R61NC3 (wherein R 61 represents a suitable substituent such as H or C1-6 alkyl) and a salt It can be prepared by reacting in the presence of a group.

Add a suitable base to be used in the reaction (for example, lf, 1,8-diazapinoclo[5 ,4,0]undec-7-ene (DBU). reaction( Well, it is convenient to carry out in a suitable organic solvent such as alcohol, for example butanol. be.

According to a further method (F), formula (I) (wherein R'l;! unsubstituted or substituted tri- Representing azolyl) compound (′!, formula % formula %) (In the formula, Y and Hal are as defined above, and R1@ is H or a triazole ring is suitable as a substituent for or convertible into such a group under the reaction conditions. It can be produced by reacting a compound (which is a group) in the presence of a base.

Suitable bases for use in the reaction include, for example, alkali carbonates such as potassium carbonate. Contains metal.

R11+ is H10CH3 (converted to an oxo substituent under the reaction conditions) or CO N.H. It is appropriate to express

The reaction is preferably carried out in an anhydrous organic solvent such as anhydrous dimethylformamide. Conveniently, this is carried out at an elevated temperature, such as about 140°C.

According to another method (G), formula (I) (wherein R8 is substituted or unsubstituted 1. 3.5-) Representing riazine) is a compound having the formula (IX) (1x) (wherein R1, R2, R4, R'SX, Y and n are as defined in formula (I) ) with a substituted or unsubstituted 1°3.5-triazine. It can be manufactured more easily.

The reaction is preferably carried out at 80-90°C in a suitable organic solvent such as acetonitrile. is conveniently carried out at an elevated temperature of about 82°C.

According to yet another method (H), formula (I) (wherein R8 is a substituted or unsubstituted 1. 2.5-1-Ryazine) The compound of formula (X) is a compound of formula (X[) : (wherein R1, R2, R4, R5, X1Y and n are as defined in formula (1) and R35 and R3g are each independently H or Cl-S alkyl, e.g. by reacting with a nocarbonyl compound (representing a suitable substituent such as til) It is easier to manufacture.

The reaction is conveniently carried out in a suitable organic solvent such as an ether, e.g. tetrahydrofuran. Generally, it is convenient to carry out the test at ambient temperature.

Suitable procedures are described in further detail in the accompanying examples.

The compound of formula (■) is described in J, Med, Chem, 27, (1984), 84 9.

Compounds of formula (1) can also be obtained from other compounds of formula (1) using appropriate interconversion procedures. Can be manufactured. For example, formula (1) (wherein Y is substituted with an aromatic heterocycle, Cl-4 represents alkyl) of the formula (■) (wherein Y is substituted with oxo and C1- (representing 4 alkyl) by reduction using, for example, borane. It is possible to build

Suitable interconversion procedures are described in the accompanying examples, but are not readily apparent to those skilled in the art. It should be obvious.

The intermediate of formula (m) is the intermediate of formula (n) with formula Ha 1-Y-CO2R30 (formula In, Hal represents halo such as oo, bromo or iodo, R311 and Y is as defined above) in the presence of a base. Manufacturable. Suitable bases include tertiary amines such as triethylamine. included. The reaction may be carried out in a suitable organic solvent such as an ether, e.g. tetrahydrofuran. It is convenient to carry out the reaction in a medium at an elevated temperature, such as the reflux temperature of the solvent.

Intermediates of formula (IV) are commercially available and can be obtained commercially using routine procedures well known to those skilled in the art. It may be manufactured from commercially available materials.

Intermediates of formula (II) are described in European Patent Application No. 0528495 It is possible to manufacture it as follows.

The intermediate of formula (V) is the intermediate of formula (II) with the formula Ha 1-Y-CN (wherein, Hal is halo such as bromo, chloro or iodo, and Y is as already defined. It can be produced by reacting with a certain compound).

Intermediates of formula (VI) are intermediates of formula (V) such as thioacetamide. It can be prepared by treatment with an alkylthioamide.

The intermediate of formula (■) is produced by treating the intermediate of formula (m) with hydrazine. It is possible. The reaction is carried out in a suitable organic solvent such as an alcohol, e.g. ethanol. , it is convenient to carry out at elevated temperature.

The intermediate of formula (IX) is the intermediate of formula (II) with the formula Ha I-Y-C(NH) By reacting with NH2 (where Hal and Y are already defined) Can be manufactured.

The intermediate of formula (X) is the intermediate of formula (n) with the formula Ha　-Y-C(NH)NH NH-Boc (where Hal and Y are as defined above, and Boc is t-butyl compound (which is a carbonyl compound) and then deprotected under acidic conditions It can be manufactured by

The compound of formula (X[) is commercially available, but it is possible to use a known compound It is also possible to manufacture by a method.

The above method for producing the compounds of the invention produces a stereoisomeric mixture. If desired, these isomers can be separated by conventional methods such as preparative chromatography. It can also be divided appropriately depending on the technology.

The novel compounds of the invention can be prepared in racemic form or the individual enantiomers can be combined into enantiomers. They can be produced either by thiospecific synthesis or resolution. for example Any suitable intermediate may include formation of diastereomeric esters or amides, and Such as subsequent separation by chromatographic separation or fractional crystallization and removal of chiral auxiliaries. The intermediate can be resolved into its component enantiomers by standard techniques. Then diastere The omer intermediate is used to prepare optically pure compounds of formula (1).

During any of the above synthetic chains, protect sensitive or reactive groups on the molecules involved. is necessary and/or desirable. This is Protective Groups i n Organic Chemistry, J, F, W.

Edited by McOa+ie, Plenum Press, 1973 and T, f, Gr. eene and P.

GoM, juts, Protective Groups in Orga nic 5 synthesis.

Conventions such as those described in John Filey & 5ons, 1991 This can be achieved using protective groups for Protecting groups are well known in the field. It may be removed in a suitable subsequent step using known methods.

The following examples illustrate the preparation of compounds of the invention.

This paper uses the human NKIR assay described in European Patent Application Publication No. 0528495. The antagonistic effect of Substance P described in was evaluated. The method primarily uses human NKI required to reduce the amount of radiolabeled P substance bound to R by 50%. quantitate the concentration of the test compound to be tested, thereby obtaining the IC6o value of the test compound. Including. For example, the compounds of Examples 1-10 have an IC of less than 500 nM. The value It was recognized that the company had

Production example Tosis-3-((3,5-bis(trifluoromethyl)phenyl)methyl oxy)-2-phenylpiperidine hydrochloride (a) 4-2 in acetic acid (39ml) containing ammonium acetate (12.12g) A solution of methyl trobutyrate (23 g) and benzaldehyde (16 ml) was added under nitrogen for 2 hours. The mixture was heated to reflux for an hour. When the reaction mixture was cooled to 5°C, a pale yellow solid crystallized. . This was isolated by filtration, then dissolved in dichloromethane and dissolved in saturated bicarbonate. slowly washed with aqueous MgSO4 solution (2x), then dried (MgSO4) and concentrated. , a yellow solid was obtained. Recrystallized from ethyl acetate to give 5-nitrate as a crystalline white solid. Lo-2-oxo-6-phenylpiperidine (12.5 g) was obtained.

IHNMR (CDCI3) δ7.46-7.26 (m), 6.0 (br) s), 5.24 (dd, J=1.4.7.0Hz), 4.70 (m), 2.70-2.50 (m), 2.38-2.24 (m).

(b) Mixture of dichloromethane:/ (50ml) and methanol (50ml) Potassium was added to the 5-nitro 2-oxo-6-phenylpiperidine (3 g) solution in t-Butoxide (1.68g) was added and the mixture was cooled to -78°C under nitrogen.

Ozone was bubbled into the solution for 3 hours. A yellow-green solution was obtained and by TLC the starting material It was shown that no quality remained. The reaction mixture was rinsed with oxygen for 5 min and filtered. Excess ozone was removed, then dimethyl sulfide (7+1) was added and the reaction mixture was warmed to 23°C. Remove the solvent under vacuum and partition the residue between dichloromethane and water. Ta. The layers were separated and the aqueous layer was extracted twice with dichloromethane. combined organic extract was washed with brine, then dried (K2CO3) and concentrated to give a yellow solid. this The composite material was suspended in dry tetrahydrofuran and lithium aluminum hydride ( IM in THF, 50+*l) and heated to reflux for 12 hours. Cooled to 23℃ After that, the reaction mixture was slowly added water (dropwise) and then 2M sodium hydroxide under nitrogen. was added to stop the reaction. Filter the mixture through a Hyfro pad and remove the filtrate. It was washed with brine, then dehydrated (K, C03), and concentrated to obtain a yellow solid product. Shirikage chromatography (CH2CI2/MeOH/NHs 97:3: 1, then purified by CH2CIt/MeOH95:5), respectively (C DCI3) 7.44-7.20 (m), 3.84 (2), 3.76 ( s), 3.54 (m), 3.4 (s), 3.3 (d, J=8Hz), 3.26 ( m), 3.04 (m), 2.78 (ddd, J=2.9. 11.9. 11゜9Hz), 2.70(ddd, J=2.9. 11.9. 11. old ( Z), 2゜18-1.78 (m), 1.48 (m), MS (EI) m /z 177 (M4).

(c) 3-hydroxy-2-phenylpipe in dichloromethane (8II+1) Di-t-butyl dicarbonate (1.36 g) was added to lysine (1 g) under nitrogen. Then, the mixture was stirred at 23°C for 3 hours. The solvent was removed under vacuum and the residue was washed with silica gel. Chromatography (CH2CIz/MeOH/NHs 97:3:0. 5) to produce cis- and trans-1-t-butylene as a clear viscous oil. Tyloxycarbonyl-3-hydroxy-2-phenylpiperidine (1,4g) I got it. 'HNMR (CDCI 3) 67.50-7.42 (m), 7. 40-7゜14 (m), 5.36 (d, J=5.6Hz), 4.50 ( m), 4.44 (m), 4.12-3.92 (m), 3.02 (d dd, J-3,0,12°5, 12.5Hz), 2.87 (d d d, J = 3.0.12.5.12.5Hz), 1.88-1.66 (m), 1.46 (s), 1.36 (s).

(d) 1-t-butyloxycarp in dry dimethylformamide (5l1l) Cooling of Bonyl-3-hydroxy-2-phenylpiperidine (1,4 g) (0 °C ) Sodium hydride (80% dispersion in mineral oil; 182++ g) was added to the solution.

The cold bath was removed and the reaction mixture was stirred at 23°C for 30 minutes. dry dimethyl formua 3,5-bis(trifluoromethyl)benzylbromide (1 ml) in 1 ml , 87g) solution and continued stirring at room temperature for 2 hours. Mixture with water (100 gardens) and extracted with ethyl acetate (3X 40ml). Salt the combined organic extracts Wash with water (IX 30ml), dehydrate (MgS O4), evaporate, A yellow oil was obtained. Gradient elution of hexane in ethyl acetate (9:1-4:1) Chromatograph on silica used Hz, CDC13) 67.77 (IH, s, Ar H), 7.71 (2H, s, ArH), 7.53-7.57 (2H, m, ArH ), 7.2-7.4 (3H, m, ArH), 5.70 (II (, brd.

H), 2.77 (IH, ddd, J=13.0.13.0, 3.0Hz.

H, m, CH2), 1.40 (9H, s, C(CHs)s).

(e) To the product (800 mg) of (d) above, add trifluoroacetic acid (3 ml). It was added under nitrogen and the resulting solution was stirred for 1 hour. Vacuum excess trifluoroacetic acid and the residue was partitioned between 2M sodium hydroxide and dichloromethane. organic The phase was washed with brine, dried (MgSO4) and evaporated to give a colorless oil. Siri (dichloromethane in methanol, 98:2-95:5). , the product cis-3-((3,5-bis(trifluoromethyl)phenyl) Methyloxy-2-phenylpiperidine (360 mg) was obtained as a colorless oil. Ta. 'HNMR (360M) Iz, CDCl5) 67.78 (IH,s, ArH ), 7.44 (2H, s, ArH), 7.18-7.38 (5H, s, ArH) , 4.52 (IH.

HPh), 3.68 (IH, d, J=15Hz), 3.28 (IH.

= 1.8-1.98 (2H, m, CH2), 1.64-1.78 (LH .

m/z404 ((M+1)", 90%).

The oil was dissolved in ether and excess ethereal hydrogen chloride was added. White when left alone A solid crystallized. The solid was filtered and recrystallized from ethyl acetate-methanol. The title compound was obtained as white crystals (melting point: 200-203°C). 'HNMR( 360MHz, DMSO) 67.95 (IH,s, ArH).

7.81(2H,s,ArH)"-17,37-7,47(5H,m,AHz , OCH dan), 3.96 (IH, s, NCHCHO), 3°CH2X2); M S (CI”) m/z 404 ((m+1)”, 90%); C2°H2°F Elemental analysis of sN OCI, 0.25Hto; Calculated value: C, 54,06; H , 4,65; N, 3.15%; Actual value: 54.08; H, 4,47: N, 3.13%.

3-((3,5-bis(trifluoromethyl)phenyl)methyloxy) -2-Phenylpiperidine hydrochloride (Production Example 1, Ig) was mixed with ethyl acetate and 2M water. It was liberated from the hydrochloride salt by partitioning into sodium oxide. organic phase continuously Washed with water, saturated brine, dried (MgSO4) and evaporated under vacuum. residual Triethylamine (0.4ml) was added to a solution of the oil in tetrahydrofuran (20ml). 1) and methyl bromoacetate (400 mg) were added, and the solution was heated under nitrogen atmosphere for 16 hours. The mixture was heated to reflux for a while. Add ethyl acetate and water to the cooled solution, and dilute the organic phase with more water. Washing and dehydration (MgSO<). After removing the solvent under vacuum, the residue is Chromatograph on glycerin gel eluting with ethyl acetate/petroleum ether (3:10) I put it on Laffey. The product was recrystallized from diethyl ether/petroleum ether. , the title compound was obtained (melting point: 81-83°C).

Elemental analysis of C23H23F 6N Os, 0.1 (H2O); Calculated value: C15 7,71: H, 4,86; N, 2.93%; Actual value: C, 57,35; H.

4.98; N, 2.84%. MS (C1”) m/z 476 (M+ H)”.

Production example 3: (+)-(2S,3S)-cis-3-((3゜5-bis(trif) fluoromethyl)phenyl)methyloxy)-2-phenylpiperidine hydrochloride (a) Cis and trans isomers of 3-hydroxy-2-phenylpiperidine ( Production Example 1, a mixture of (2b)) and 4-toluenesulfonic acid hydrate was dissolved in methanol. /Crystallized from ethyl acetate to give cis-3-hydroxy-2-phenylbiperidini Umutoshi sheet was obtained (melting point: 266-267°C).

(b) Toshisheet salt (preparation example 3 (a) above) was mixed with ethyl acetate while heating. % aqueous NaICog.

The organic phase was washed with saturated brine, dried (K*C05) and evaporated to give crystalline cis-3. -Hydroxy-2-phenylpiperidine was obtained (melting point: 110-110.5°C ).

(C) Cis-3-hydroxy-2-phenylpiperidine (Production Example 3b) and alcohol Dissolve (-) dibenzoyl tarte in methanol and add ethyl acetate to crystallize it. . The solid was recrystallized from warm methanol to give hemidipenzoyl tartrate (melting point : 223-224°C). This is released from the salt as described above to form a single enantiomer. (+)-cis-3-hydroxy-2-phenylpiperidine (melting point : 93-95°C). [α] 23o = +98.5' (c = 1, M e OH). The mother liquor was converted to the free base as described in Preparation Example 3b and tartaric acid (+ ) Crystallized using dibenzoyl in a similar manner to the above to obtain (-)-3-hydroxy C-2-phenylpiperidine was obtained (melting point: 93-95°C). [α] 23 ．． =-97,2° (c=1.MeOH).

(d) (+)-cis-3-hydroxy-2-phenylpiperidine Production Example 1c (+)-cis-3-((3,5- Bis(trifluoromethyl)phenyl)methyloxy-2-phenylpiperidine The hydrochloride salt was obtained as a crystalline solid (melting point: 215-216°C). [α] o=+ 87.3°C (c=1.MeOH). 'HNMR (360MHz, DMSO-d a) 67.95 (IH, s.

ArH), 7.81 (LH, s, ArH), 7.47 (2H, m.

ArH), 7.37 (3H, m, ArH), 4.78 (IH, d.

J=13. O)lz, QCdanH), 4.56 (IH,s, NCHPh) 2.00-1.64 (4H, m, CHzx2); MS (CI"") m /z 404 (M+1”, 90%); CzoH+5FaNO, HC] Elemental analysis: Calculated values: C, 54,62; H, 4,58; N, 3.18% .

Actual values: C, 54,52; H, 4,60, N, 3.11%.

Production example 4: (+)-(2S,3S)-3-((3,5-bis(trifluoro methyl)phenyl)methyloxy)-1-(carbomethoxy)methyl-2-phene Using the procedure described in Nilpiperidine Preparation Example 2, (+)-cis-3-( (3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-pheny The title compound was prepared from lupiperidine (Production Example 3) (melting point: 60-70°C) . [α], = 1132.3° (c = 1.MeOH), 'HNMR (360M HH), 2.04-2.17 (2H, m, CdanH, CHHN), 3.0 7-3.10 (LH, m, NCHC Dan 0), 3.20 (IH, d.

J=17.0Hz, NCHHCO2CH3), 3.31 (IH, d.

CH3), 3.93 (IH,s, NCHPh), 4.07 (IH.

d, J = 12.0Hz, 0CHH), 4.49 (LH, d, J = 12゜OHz, 0CHH), 7.28-7.34 (3H, m, ArH).

7.43-7.45 (2H, m, A rH), 7.54 (2H, s, ArH), 7°71 (IH, s, ArH). MS (CI”) m/z47 6 (M+1″″, 100%), elemental analysis of C23HxsF sN Os; total Calculated value 2C, 58,11; H, 4,88; N, 2.95%; Actual value: C15 8.31; H, 4,90; N, 2.94%.

Compound of Production Example 1 (5 g), potassium carbonate (1.7 g) and bromoacetonitrile (0.87 ml) was suspended in dimethylformamide (15 ml) and the mixture The mixture was stirred at 60° C. for 3 hours under nitrogen. Cool the mixture and dilute with water (200ml) , extracted with ethyl acetate (2X 50ml). The organic extract was washed with brine and dehydrated ( MgSO4) was evaporated to give a brown oil. This is used as an eluent in petroleum. of ethyl acetate (10%) to give the product as a colorless oil. I got it. The hydrochloride salt is prepared by dissolving in ethereal hydrogen chloride and the salt is dissolved in ether-hexylchloride. It was recrystallized from Sun (melting point: 133-134°C). iHNMR (360MH z, CDCI 3) d 1.75 (2H, mNCHHCN), 4.09 (I H, s, CHPh), 4.35 (1 = 13.0Hz, OCH), 7.4 (3 H, mc, ArH), 7°69-7.73 (5H, m, ArH); MS (CI ’) m/z 443 (M”+1,30%).C22H18F 6N 10.HC Elemental analysis of 1: Calculated value C, 55, 18, H, 4, 42: N, 5.85%; Actual values: C, 54,87; H, 4,30; N, 5.66%.

Production Example 6: (2R zero, 3 zero)-3-((3,5-bis(trifluoromethyl)fluorocarbon) phenyl)methyloxy)-2-phenyl-1-(thiocarboxamitomethyl)pi The compound (1 g) of Peridine Production Example 5 was dissolved in dimethylformamide (anhydrous, 1 hl). and the solution was saturated with dry hydrogen chloride gas. The reaction mixture was heated under nitrogen for 100 min. It was heated to 0.degree. C. and thioacetamide (0.34 g) was added. This mixture was heated to 100°C. The mixture was stirred for 3 hours. Dimethylformamide was removed under vacuum. The residue was dissolved in ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate, brine, and dried (MgSO4). and concentrated under vacuum to give a brown oil. This is ethyl acetate (10- Purified on silica using a 50%) gradient elution. Ethyl acetate - recrystallized from petroleum The product was further purified by (melting point: 164-166°C) 'HNMR (360MHz, CDCl 3) δ 1.56-1.70 (2 H, m, CH2), 1.96-2゜10 (IH, m, Cdan H), 2.1 5-2.32 (2H, m, CI (IH, s, CHO), 3.60 (1) (, s , NCHPh).

7.75 (H, s, Ar-H), 7.61 (IH, bs, NHH).

8.99 (IH, bs, NHH); MS (CI”) m/z 477 (M’+1 ．． 15%); Elemental analysis of C2□H22F 6N 20 S; Calculated value C, 55, 46+ H, 4,65; N, 5.88%; Actual value: C155,09; H, 4,58; N, 5.97%.

Production Example 7: (2R*, 3g) -3-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-1-(carboxyhydrazidomethyl)-2-phenyl phenylpiperidinium hydrochloride Hydrogenated hydra was added to a solution of the compound of Production Example 2 (2.95 g) in ethanol (80 ml). Gin (3.0ml) was added. The solution was heated to reflux for 18 hours, then drained with ethanol under vacuum. removed. The residue was extracted into ethyl acetate, the organic layer was washed with brine and dried (M gS04) was reduced by 1 m to obtain the title compound (2.79 g). Add this to methanol ( 5 ml) and added methanolic hydrogen chloride solution. methanol under vacuum and the salt was recrystallized from diethyl ether to give the hydrochloride salt. IHNMR ( 360M Hz, D M S O) δ 1.77-1.93 (2H, m, 　CHz)　.

2.08-2.21 (IH, m, CHz), 2.22-2.35 ( LH.

7.36-7.46 (3H, m, ArH), 7.53-7.62 (2H.

b r s, ArH), 7.95 (2H, s, ArH), 7.97 (IH, s, A rH); MS (CI)” m/z 475° boxyhydrazide thyl)-2-phenylpiperidinium using the compound of Preparation Example 4 as the starting material The title compound was prepared by the procedure outlined in Preparation Example 7. 'HNMR (360MH z, DMSO) 61.77-1.93 (2H, m, CH2), 2.08- 2.21 (LH, m, CHI), 2.22-2.35 (IH.

7.36-7.46 (3H, m, ArH), 7.53-7.62 (2H.

b r s, ArH), 7.95 (2H, s, ArH), 7.97 (IH, s, ArH); MS (C1)” m/z 475° Procedure detailed in Preparation Example 5 The title compound was prepared by reacting bromoacetonitrile with the compound of Production Example 3. Manufactured. Chromatography on silica using 10% hexane in ethyl acetate Purification over time gave the product as a colorless oil. 'HNMR (360MHz , CDC11) δ1゜75 (2H, mc, CdanxcH1N), 2.14 ( 2H, me, CH2CdanzN), 2.63-2.74 (LH, m, CHHN), 2.97.4-7.48 (2H, m, ArH), 7.56 (2 H, m, ArH), 7.73 (IH, m, ArH).

Following the procedure described in Preparation Example 1cme, the compound of Preparation Example 3C and 3-t-butyl The title compound was prepared from -5-methylbenzyl bromide (melting point: 180-1 82℃). MS (CI”) m/z 338 (M”+1.100%), CzsHslNO.

! -(Elemental analysis of Cl; calculated value: C, 73, 87; H, 8, 62: N, 3°75%; Actual value: C,? 3.81; H, 8,63; N, 3.74% .

Following the procedure described in Preparation Example 1cme, the compound of Preparation Example 3C and 3,5-dichloro The title compound was prepared from lobenzyl chloride. IHNMR (CDC13) δ 1.49-1.53 (IH, m, CHH), 1.60-1.70 (I H, m, CHH), 1.82-1.95 (LH, m, CHH), 2. 14-2.18 (IH.

m, CHH), 2.79-2.87 (IH, m, NCHH), 3.27-3.3 1 (IH, m, NCHH), 3.60 (IH, s, CHO), 3.82 (IH , s, CHPh), 4.02-4.05 (IH.

d, J = 13Hz, 0CHH), 4.31-4.35 (IH, d.

J=13Hz, 0CHH), 6.80 (2H,'s, ArH), 7°15 (IH , s, ArH), 7.25-7.35 (5H, m, ArH). C+sH+eCI Elemental analysis of zNO, Hc I: Calculated value: C158,01; H,5,41: N, 3.76%: Actual value: C, 58, 24, H.

5.38; N, 3.91%.

Production example 12: (23,3S)-3-((3-chloro-5-methylphenyl) methyloxy)-2-phenylpiperidi compound and 3-chloro-5-methylben The title compound was prepared from zilpromide (melting point: 235-237°C). MS (C1”) m/z 316 (M’+H, 100%). CIIH! ICI No.

Elemental analysis of HCI; Calculated values: C, 64,78; H, 6,58; N, 3° 98%: Actual value: C, 64,68; H, 6,50, N, 3.98%.

(a) N-t-butyloxycarbonyl-(S)-diphenylalanal A solution of methyl sulfoxide (4.4 ml) in dichloromethane (13 ml) was added to dichloromethane (13 ml). Cooled (-78°C) solution of oxalyl chloride (411) in lolomethane (50ml) dripped into. After 15 minutes, N-t-butyloxycarbonyl-(S)-diphenyl A solution of alanol (10 g) in dichloromethane (150 ml) was added dropwise at -30°C. Ta. The solution was stirred for 30 minutes, triethylamine (17 L) was added and the solution was diluted to 11 L. Warmed to 0°C. Add ice water (200ml) to the solution, then add hexane (600ml) ) poured inside. Separate the organic layer and continuously add citric acid (200a+1), saturated Sodium carbonate aqueous solution (2X 150ml), salt water (IX 150ml) Washed with water, dried (MgSO4) and concentrated in vacuo to give a white crystalline solid. Yi HNMR (250MHz, CDCIs) δ 1.42 (9H, s.

C(CH3) 3), 4.48 (LH, d), 4.86 (LH, d).

5.10 (IH, t), 7°26 (IOH, m, A r H), 9.6 ( IH, s, CHO).

(b) N-t-butyloxycarbonyl-1-(diphenylmethyl)-2-hyperoxycarbonyl Droxibent-4-Uniru 1-2±2 N-t-butyloxycarbonyl-(S)-diphenylalanal (10,9g ) in tetrahydrofuran (60ml) was mixed with allyl magnesium chloride (tetrahydrofuran). 2M in hydrofuran, 36 Ill) solution at -10°C. After 30 minutes, mix The mixture was poured into a water-cooled saturated aqueous ammonium chloride solution and the resulting mixture was diluted with ethyl acetate (3 Extracted with X 150ml). The combined organic extracts were dissolved in brine (I ), dried (MgSO4) and concentrated under vacuum. The residue was extracted with acetic acid as eluent. Chromatography on silica gel using hexane in ethyl (gradient elution from 9.1 to 4.1) Purification by chromatography gave the compound as a white solid. 'HNMR( 360MHz, CD CI 3) 61.42 (9H, s, (CHx) s) , 2.22 (2H, m), 2.68 (3 fertilizer brs), 3.48 ( t), 3. ．． 57 (IH, m), 3.86 (IH, s), 4.07 (d , J=11Hz), 5.04 (IH, m).

5.71 (IH, m), 6.97-7.36 (IOH, m, ArH).

(c) 2-((3,5-bis(trifluoromethyl)phenyl)methyloxy c)-N-t-butyloxycarbonyl-i-<diphenylmethyl)-bent- 4-enyl-1-3.5-bis(trifluoromethyl)benzylbromide (5m l) and the compound (13b) above (5 g) in dimethylformamide (8 ml) To the was added sodium hydride (80% in oil, 0.53 g). After stirring for 1 hour , water (80ml) was added and the mixture was extracted with ethyl acetate (3X 100ml) . The combined organic extracts were washed with brine (IX 100a+1) and then dehydrated (M gsO4), concentrated to give an oil, and hexane in ethyl acetate (9 Purified on silica using gradient elution (7:3 to 4:1) as a colorless oil. The title compound was obtained. 'HNMR (360MHz, CD CI 3) δ 1.2 5(S).

1.30 (s), 2.35 (m), 3.31 (m), 3.40 (dd, J=5. 2.8.3Hz), 3.97 (d), 4.27 (d), 4.3 8 (m).

4.65 (m), 4.85 (d), 5.16-5.02 (m), 5.77 (m), 7.35-7.13 (m), 7.76 (s), 7.85 (s ).

(d) (2S,3S)-3-((3,5-bis(trifluoromethyl)phenylene ) Methyloxy-2-(diphenylmethyl)pyrrolidinium hydrochloride Compound (c) above in chloromethane (40ml) and methanol (40ml) (5.2 g) The solution was treated with a stream of ozone in oxygen for 1 hour at -78°C. methyl sulfide (3ml) was added and the mixture was warmed to 23°C and concentrated under vacuum. Chlorophorize the residue (50 ml) and added triethylsilane (5,6+nl), then A solution of trifluoroacetic acid (6.9ml) in chloroform (5l1l) was added dropwise. . After 1 hour, the solvent was removed under vacuum and trifluoroacetic acid (10ml) was added to the residue. I got it. After stirring for 30 minutes, the mixture was concentrated under vacuum and the residue was dissolved in dichloromethane. Partitioned between saturated aqueous sodium bicarbonate. The organic layer was dried (K, CO2) and concentrated. A brown oil was obtained. This was dissolved in dichloromethane/methanol (99:1). Purified by chromatography on silica gel and designated as free base. The compound was obtained and converted to the salt by treatment with methanolic hydrogen chloride (melting point: >230°C). [αko2”o=+46.6° (c=1, CHsOH).

Elemental analysis of C4Hz3FsNO, HC1,0,2H10; Calculated value: C,60, 11; H, 4,73; N, 2.70%: Actual value: C, 59,95; H , 4,74; N, 2.63%.

Production Example 14: (2R13S)-3-((3,5-bis(trifluoromethyl)fluorocarbon) (phenyl)methyloxy)-2-(diphenylmethyl)pyrrolidinium hydrochloride N-t-butyloxycarbo The title compound was prepared from nyl-(R)-diphenylalanol (melting point: >23 0℃). [α]238=+12.1° (c=1, CHs OH) .

Production Example 15・(2S,3S)-3-((3,5-dichlorophenyl)methylo (xy)-2-(diphenylmethyl)bi in a similar procedure to that described in Preparation Example 13c. Accordingly, the compound of Production Example 13b was added using 3,5°-dichlorobenzyl chloride. The title compound was obtained as an oil. 'HNMR (360MHz, CD CI3) δ 1.25 (9H, s).

2.41 -2.27 (2H, m), 3.32 (IH, m), 4.07 (IH, d, J = 11 Hz), 4.13 (IH, d, J = 12 Hz).

4.30 (IH, d, J = 12Hz), 4.65 (2H, m), 5.13 (2H , m), 5.76 (IH, m), 7.35 - 6.60 (13H.

m). MS (CM) m/z 526,528 (M”+1), 100%.

80%).

(b) (2S,3S)-3-((3,5-dichlorophenyl)methyloxy) -2-(diphenylmethyl)pyrrolidinium hydrochloride The compound of Preparation 15a above was prepared by a procedure similar to that described in Preparation Example 13d. , ozone and then triethylsilane-trifluoroacetic acid to give a white crystalline The title compound was obtained as a solid (melting point: >230°C). Cz4HzsCl　2NO .

Elemental analysis of HCI; Calculated values: C, 64, 23; H, 5, 39, N, 3゜1 2%: Actual value: C, 64, 52: H, 5, 34; N, 3.12%.

4-t-Butyl-2-chloroaniline (30g) was added to dichloromethane (1,21 ) and the solution was cooled to -5°C.

N-chlorosuccinimide (21.7 g) was added dropwise to the vigorously stirred solution. and continued stirring for 1 hour. Dimethyl sulfide (35 ml) was added to the solution (-5°C), Stirring was continued for an additional hour. The solution was then cooled to -65°C and diluted with triethylamine. (27 liters) was added. The solution was allowed to warm to room temperature overnight.

Evaporate the solution to half the volume and add successively sodium hydroxide (IN), water and Washed with brine. The organic solution was dehydrated and evaporated using hexane:hexane2 as the eluent. A three-dimensional product (31.2 g) was obtained. IH NMR (CDC I, 250 MH2) δ 1.27 (9H,s, (CHs)s), 1.99 (3H.s.

5CH3), 3.69 (2H1s, Cdan2sCHs), 4.38 (2゛H 1b r s. NH,), 6.92 (IH, d, J'=2.0Hz.ArH), 7.21 (IH, d, J=2.0Hz, ArH). MS(CI”)m /z 244 (M”+1,100%).

(b) 4-t-butyl-2-chloro-6-methylaniline 4-t-butyl- 2-chloro-6-(methylthiomethyl)aniline (1.3 g) was added to methanol-k (50m+1), t. t. C. (ether-hexane, 1 : 10) shows that all starting materials have reacted. Kel (prewarmed to pH 7) was added dropwise. filtered through celite The Raney nickel was removed by evaporation of the filtrate. Residue in ether The solution was dissolved in water, washed with brine, dehydrated (MgSO4), and evaporated. eluent and The residue was purified on silica using hexane-5% ether in hexane to give a yellow The product was obtained as a colored liquid. IH NMR (360MHz.CDC +3) δ 1.26 (9H, s, (CHs) s).

2, 19 (3H.s.C1(,), 3.97 (2H, s.NHz), 6.

97 (LH, d.J=2.0Hz, ArH), 7.14 (IH, d.

J = 2.0Hz, A rH).

(c) 3-t-butyl-5-chlorotoluene 4-t-butyl-2-chloro-6- Methylaniline (1.

97g) in ethanol (50ml), sulfuric acid (1.88a+1, concentrated was added dropwise, and the resulting blue solution was heated to reflux. Sodium nitrite (1. 72 g) was added dropwise over 30 minutes. The resulting mixture was heated to reflux for an additional 30 minutes. , then cooled, poured into ice water and extracted with ether (2×50 ml). A The extract was dehydrated (MgSO4), evaporated and hexane was used as eluent. Purification on silica gel using silica gel gave the product as a colorless oil. 'H NM R (360MH z, C D C I s) δ 1.29 (9H.

s. (CH3), 2.31 (3H.S, CHs), 6.9 8 (LH, brs, ArH), 7.05 (IH. brs, ArH) .

7, 15 (IH, b r s. ArH). MS (C I-) m/z 181 (M”-H, 100%).

(d) 3-t-butyl-5-chlorobenzylbromide 3-t-butyl-5-k Lorotoluene (5.7 g) was dissolved in carbon tetrachloride (80 ffil), and N- Bromosuccinimide (5.56g), then benzoyl peroxide (750g) mg) was added. This mixture was heated to reflux for 6 hours. Cool the mixture and sprinkle with celite The filtrate was concentrated under vacuum. Silica using hexane as eluent Purify the residue by chromatography above to give the title compound as a colorless liquid. Obtained. IH NMR (360MHz. CDC ls) δ 1, 31 (9H, s , (CH3) a), 4.42 (2H, s. CHI), 7.20 (IH, t.

J=1.5Hz, ArH), 7.26(1)1. t, J = 1.5Hz.

ArH), 7.28 (IH, t, J=1.5Hz, ArH).

(e) (23,3S)-1-t-butyloxycarbonyl-3-((3- t-Butyl-5-chlorophenyl)methyloxy)-2-phenylpiperidine By the procedure detailed in Preparation Example 1cmd, (+)-cis-3-hydroxo- 2-phenylpiperidine (Production Example 3c) was converted into 3-t-butyl-5-chlorobenzyl Reaction with bromide (preparation example 15d above) gave the title compound.

'HNMR (360MHz, CDC13) δ 1.27 (9H, s.

C(CH,) s>, 1.46 (9H, s, C(CHs) s), 1 ．． 52-1.66 (2H, m), 1.8-2.0 (2H, m), 2.69 (11 (, td, J=3.5Hz, 13.0Hz, NCCH), 3.81 (I H, q, J = 5Hz, NCH dan), 3.92 (I H, br d, CH O), 4.60 (2H, q, J = 12Hz, 0CHz), 5.70 (IH, brs, CHPh),? . 10 (IH, s, ArH), 7.18 (IH , s, ArH), 7.22 (2H, s, ArH), 7.43-7.47 (2 H, m, ArH), 7.57-7.59 (2H, m, ArH).

(f) Dissolve the compound of Preparation Example 15e above in methanolic hydrogen chloride overnight. I understand. The solution was then concentrated under vacuum and the residue was triturated with ether to give a white crystalline The title compound was obtained as a powder (melting point: 210-211°C). 'HNMR(36 0MHz, DMSOds) δ 1.21 (9H,s, C(CHs)3), 1 ．． 66-1.80 (2H, m, CHz), 1.86-1.93 (1s, ArH ), 7.00 (IH,s, ArH), 7.24 (IH.

t, J=1.8Hz, A rH), 7.3-7.5 (5H, m, ArH); MS (CI”) m/z 358 (M’+1.100%). Cm28 28CI N O, HCI (D elemental analysis: Total 1 Value: c, 67, oot H, 7,41; N, 3.55%; Actual value: C, 66,68; H, 7, 29; N, 3°40%.

Production Example 17: (2R*, 3H)-3-((3-carbomethoxyphenyl)methylene (2H, 3R*)-1-t-butyloxy)-2-phenylpiperidine (a) Tyloxycarbonyl-3-((3-cyanophenyl)methyloxy)-2-phenyl phenylpiperidine By the procedure described in Example 1d, 1-t-butyloxycarbonyl-3-hydro xy-2-phenylpiperidine (Production Example 1c) and α-bromo-m-tolnitri The title compound was prepared from the solution. 'HNMR (360MHz, CDC13) 61 ．． 49 (9H, s, (CHs)3), 1.6-1.72 (2H.

m), 1.87-1.99 (2H, m), 2.72 (IH, dt, Jri, 5.69 (LH, brs, CHPh), 7.1 - 7.5 (9H.

phenyl)methyloxy-2-phenylpiperidine The compound (a) above (1,5 g) was dissolved in methanol (15ml) and concentrated hydrochloric acid (aqueous, 10ml) was added. . The mixture was heated to reflux for 12 hours. Cool and evaporate the solution to obtain a brown oil. Ta. This was dissolved in methanolic hydrogen chloride, the resulting solution was stirred overnight and then evaporated. I let it emanate. The residue was purified by partitioning between water and ethyl acetate, and the organic layer was dehydrated (MgS 04), concentrated. Using a gradient elution of 2%-6% methanol in dichloromethane The residue was purified by chromatography on silica. first eluted The compound exhibited hydrochloride characteristics when dissolved in methanolic hydrogen chloride. Ethyl acetate The salt was recrystallized from lumethanol (melting point: 206-208°C).

(c) (2R*, 3R*)-3-((3-(carbomethquine)phenyl)methy 2-phenylpiperidine'HNMR (CD C1s) δ 1.45 -1.71 (2H, m.

44 (IH, bs, NH), 2.77 - 2.90 (IH, m, NC15H z, CHPh), 3.90 (3H, s, C00CHs), 4°15 (IH, d, J=12Hz, 0CHH), 4.39(IH, d.

J=12Hz, 0CHH), 7.09 (7H, m, ArH), 7°71 (IH, bs, ArH), 7.83-7.89 (IH, m, ArH); MS (C I’) m/z 326 (M’″+1,100%).

Elemental analysis of C2oH23N Oa, HC1; Calculated value: C, 66, 38; H, 6,69; N, 3.87%; Actual value: C, 66,31; H, 6,36; N, 3.80%.

The second compound to be eluted from the column described in 17b above is a colorless oil. isolated as. IHNMR (360MHz, CD CIs) 61.2 -2.2 (4H, m), 2°82 (IH, me), 3.27 (IH, mc) , 3.66 (IH, s), 3.82 (IH, s), 4.16 (IH, d, J=1 2Hz, QCHH), 4.48 (IH, d, J=12Hz, OCH), 5.5 3 (IH, brs, CONDanH), 6.18 (IH, brs, C0 NHH), 7.0-7.4 (9H, m, A r H).

Production example 19: (2R*, 3R*)-3-((2-methoxy-3-nitrophe methyloxy)-2-phenylpiperidinium hydrochloride Following the procedure described in Preparation Example 1 cme, the compound of IC described and 2-methoxy- The title compound was prepared from 5-nitrobenzyl bromide (melting point: 246-248 °C). MS (CF) m/z 343 (M”+1, 45%), C Elemental analysis of +eHz2NzO4, HC1, calculated value: C, 60, 24; old 6.1 2; N, 7.39%: Actual value: C, 60,52; H, 5,96; N, 7.45%.

Production Example 20 + (2R*, 3R-3-((5-amino-2 Compound of Production Example 19) (0,342 g) in methanol (20 ml) containing hydrochloric acid (1 ml, 2N) dissolved in. /< Ranrum charcoal (50 gg) was added and the mixture was heated under hydrogen atmosphere for 1 hour. It was left at room temperature for an hour. The solvent was removed under vacuum and the residue was dissolved in sodium hydroxide (2M). It was made basic. This solution was extracted with ethyl acetate, and the organic extract was dehydrated (MgS 04), concentrated to give a brown oil. Dichloromethane was used as the eluent. Purified by column chromatography on silica using 8% methanol in ethanol. Manufactured. The resulting oil was prepared by treatment with methanolic hydrogen chloride. (melting point = 241-243°C).

Using the appropriate benzyl halide, follow the procedure outlined in Preparation Examples 1 and 3. The following piperidine was prepared.

Production example 21: (2S, 3S)-2-phenyl-3-((3-(trifluoro Methyl)phenyl)methyloxy)piperidine’HNMR (CDCIg) δ1 ．． 4-2.2C4H.

m), 2.45 (LH, brs), 2.83 (IH, td, J=13Hz and 4 Hz), 3.3 (IH, m), 3.64 (IH, d.

J = 2Hz), 3.82 (IH, d, J = 2Hz), 4.13 (IH, d, J = 12Hz, QCHH), 4.42 (2H, J = 12Hz, 0CHH ), 7.75 (m, 9H, ArH).

Production example 22: (2S,3S)-3-((3,4-dichlorophenyl)methyl oxy)-2-phenylpiperi p, :lA'HNMR (DMSO-cig), 1.65-1.8 (2H, m), 1.8 (IH, m), 2.16 (IH, d, J = 12Hz), 3.05 (IH, m), 3.25 (IH, m), 3.83 (IH , s), 4°12 (11-L d, J = 12Hz), 4.5 (2H, m ), ’7.05 (IH, dd, J=7&2Hz), 7.28 (IH, d , J=2Hz), 7.35-7.5 (6H, m), 9.05 (IH, b r s), 9.8 (IH, b r s).

Ethyl acetate (10ml) was saturated with hydrogen chloride by passing HCI gas through for 5 minutes to form (2S , 3S)-1-t-butoxycarbonyl-3-((2,3-dimethylphenyl) methoxy)-2-phenylpiperidine (prepared according to Preparation Example 3d) (0,2 Add a solution of 54 g) in ethyl acetate (7+111). After stirring for 2 hours, the reaction The mixture was concentrated under vacuum. The remaining white solid was washed with ether, filtered, and dried. (23,3S)-3-((2,3-dimethylphenyl)methyloxy)-2-phenyl Phenylpiperidinium hydrochloride (0.23 g) was obtained.

'HNMR (DMSO-d,) δ 1.6-1.9 (3H, m).

1.75 (3H, s), 2.15 (3H, s), 2.2 (IH, m).

3.05 (IH, m), 3.25 (IH, m), 3.84 (IH, s).

4.05 (IH, d, J = 14Hz), 4.45 (IH, d, J = 14Hz), 4.48 (IH, s), 6.95-7.5 (8H, m), 8°'H NMR (36 0MI (z, CDCI 3) 61.21 (9H.

s, C (CH3) 3), 1.45 (3H, s), 1.52-1.67 =13Hz, 0CHH), 6.87-6.89 (IH, m+ ArH), 7.0 5 (IH, s, ArH), 7.11-7.15 (IH, m.

ArH), 7.20-744 (4H, m, ArH), 7.55-7゜ 58 (2H, m, ArH). MS (CI”) m/z 323 (M’+l, 1 00%).

Production Example 25: (2H units, 3R units)-3-((3,5-dimethylphenyl)methyl oxy)-2-phenylpiperidinium hydrochloride 'HNM R (360MHz, CD CIs) δ 1.48 (m).

1.62 (m), 1.86 (m), 2.20 (s), 2.82 (ddd, J=3 ．． 0. 3.0. 12.6Hz), 3.26 (dt, J = 2.15. 2.15゜12.5Hz), 3.63(s), 3.78(s), 4. IQ (d, J=12°0Hz), 4.33 (d, J=12.0Hz), 6. 31 (s), 7.2-7.4 (m), MS (CI”) m/z 29 6 (M”+1).

Production Example 26: (2R*, 3R*)-3-((3,5-bis(trifluoromethane) methyl)phenyl)methyloxy)-2-(3-chlorophenyl)piperidine (a) Methyl-4-nitrobutyrate in a similar manner to that described in Preparation Example 1a. and 3-chlorobenzaldehyde to form 2-(3-chlorophenyl)-3 -Nitro 6-oxtubiveridine was obtained (melting point: 131-133°C). IHN MR (360MHz, CDC13) 62.26-2.36 (IH.

m), 2.50-2.72 (3H, m), 4.66-4.71 (IH, m), 5.24-5.28 (IH, d), 6.57 (IH, s), 7.17 -7.40 (4H, m).

(b) treating the product of part (a) in a manner analogous to that described in Preparation Example 1b; 2-(3-chlorophenyl)-3゜6-thioxobiperidine was obtained (melting point: 144-147°C). IHNMR (360MHz, CDCIs) δ 2.8 (4H, m).

5.0 (IH, d), 6.4 (IH, s), 7.22-7.42 ( 48゜m).

(C) by a method similar to that described in Preparation Examples 1c and 3a (melting point: >250°C) ,'HNMR (360MHz, CDCl3) 61.6'0-2.07 (4H, m ), 2.28 (3H, s), 3.00-3.11 (IH, m), 4.02 (IH, s), 4.62-4.66 (IH, d), 5.96 (IH , s), 7.10-7.20 (2H, d).

7.41-7.59 (6H, m).

(d) treating the product of part (C) in a manner similar to that described in Preparation Example IC; Cis-1-t-butyloxycarbonyl-2-(3-k) as a clear viscous oil. lorophenyl)-3-hydroxypiperidine was obtained. IHNMR (360MHz , CDCl5) δ 1.4Q (9H,s), 1.61 - 1.90 (4 H, m), 2.88-3.01 (IH, ddd), 3.93-3°99 (IH, dd), 4.03-4.10 (11-1, m), 5.33 (IH, d), 7.20-7.26 (2H, m), 7.34-7.38 (IH.

m), 7.47-7.52 (LH, m), m/z (CI-) 310.312 ;m/z　(CI　　)　312.　314゜(e)　Described in Production Example 1d The product of part (d) and 3,5-bis(tri1+leolomethyl ) benzyl bromide to give 3-((3,5-bis(trifluoromethane) methyl)phenyl)methyloxy)-1-t-butyloxycarbonyl-2-(3 -chlorophenyl)piperidine was obtained. 'HNMR (250MHz, CDCIs ) δ 1.24-1.30 (IH, m), 1.47 (9H, s), 1. 60-2.00 (3H, m), 2.67-2.80 (IH, ddd), 3.81-4.01 (2H, m), 4.8 (2H, s), 5.61- 5.67 (IH, d), 7.23-7.27 (2H, m), 7.39- 7.44 (IH, m), 7.6 (IH, s), 7.78 (2H, s), 7.8 ( IH,s).

(f) part (e) of fluoromethyl)phene in a similar manner to that described in Preparation Example IC methyloxy)-2-(3-chlorophenyl)piperidine hydrochloride was obtained ( Melting point: 158°C). 'HNMR (360MHz, DMSOds) δ1.70-1 ゜96 (4H, m), 2.19-2.28 (IH, m), 3.02-3 ．． 13 (IH, m), 3.84 (IH, s), 4.35-4.39 (2H .

d), 4.60 (IH, s), 4.79-4.85 (2H, d), 7.39-7.44 (3H, m), 7.58 (IH, s), 7.84 (2H.

s), 7.97 (IH, s), 9.2 (brs), 10.05 (brs). C2 ゜H,, Elemental analysis of CI F, NO, HCI; Calculated value: C150,65; H, 4,04; N, 2.95%: Actual value: C, 50,44; H.

4.13: N, 3.01%. m/z (CI”), 438.440 °Melting point: 219-221°C. 'HNMR (360MHz, CDCl5) δ 1. 50-1.68 (2H, m), 2.11-2.15 (IH.

m), 2.20 (3H, s, CH3), 2.31-2.35 (IH, m) HO) , 4.15-4.18 (IH, m, CHPh), 4.18 (1H , d, J=13Hz, 0CHH), 4.33(IH, d, J=13H z, 0CHH), 6.47 (LH, d, ArH), 6.59 (IH, s, ArH ), 6.66 (IH, d, ArH), 7.26-7.37 (3H, m, ArH) , 7.52-7.54 (2H, m.

ArH), MS (C1') m/z 300 (M''+1,100%).

Production Example 28: (3R*)-3-((3,5-bis(trifluoromethyl)fluoride) phenyl)methyloxy)-2-methyl-2-(2R*)-2-phenylpiperidi (a) 3,6-thioxo-2-phenylpiperidine (Production Example 1b) (5 g) Dissolved in dimethylformamide (25ml) at 0°C. Sodium hydride (8 73 mg (80% dispersion in oil) was added dropwise and the mixture was stirred for 15 minutes. Methi-iodide (1,8n+1) and the mixture was stirred for 12 hours. Add the mixture to water (250 ml) and extracted with ethyl acetate (3x). Combined organic extracts with brine Washed, dried (MgSO4) and concentrated to give a solid 3,6-thioxo-2-methyl- 2-phenylpiperidine was obtained.

(b) Suspend the ketone (3.2 g) from (a) above in methanol under nitrogen and heat it. The temperature was ~40°C. Sodium borohydroxide (0.3 g) was added dropwise and the mixture was Stirred for 0 min, then concentrated under vacuum while azeotroping with tetrahydrofuran. Mullet Tetrahydrofuran chain (64 11 liters in tetrahydrofuran).

OM) was added and the mixture was heated to reflux overnight. Cool the mixture and rinse with methanol. The mixture was then concentrated under vacuum. The resulting residue was evaporated into ethanol. (100 ml), added potassium carbonate (4.2 g) and stirred the mixture for 12 hours. The mixture was heated to reflux. The mixture was cooled, evaporated and the residue extracted with ethyl acetate and water.

The organic extract was washed with salt water, dehydrated (MgR (360 MHz, CD Cl s ) δ7.79 (2H, d, ArH), 7.40 (2H, t, ArH), 7.15 -7.19 (IH, m.

ArH), 3.89 (IH, me), 2.89-3.01 (2H, m), 1. 67-1.91 (4H, m), 1.39 (3H, s, CHs).

(C) Dissolve the alcohol (3g) in (b) above in dichloromethane (50i1) , di-t-butyl dicarbonate (3,48 g) was added and the solution was stirred for 12 hours. Ta. The solution was concentrated in vacuo and the residue was purified with ethyl acetate (20: Purification by chromatography on silica using 80) yields a clear oil. as N-t-butyloxycarbonyl-2-hydroxy-2-methyl-2-phenyl Phenylpiperidine was obtained.

'1-I NMR (250MHz, CDCIs) 6 1.08 (9H, s.

(CHs) s), 1.80 (3H, S, CHs), 1.6 - 2.0 (4H, m), 3.6-3.74 (2H, m), 3.8-3.92 (I H.

m, CHO), 7.2-7.36 (5H, m, A rH).

(d) The alcohol (2.2 g) of the above (C) was mixed with dry dimethylformamide (1 2 ml). Add sodium hydride (0°36g, 60% dispersion in oil) dropwise. and the mixture was stirred at room temperature for 30 minutes. 3.5-bis(trifluoromethyl)base Dilbromide (3.5 g) was added dropwise and the mixture was stirred for 5 hours. aqueous mixture Diluted with ammonium chloride, extracted with ethyl acetate, washed the organic extract with brine, and dried. (MgSO4) was evaporated under vacuum. 100% petroleum as eluent, vinegar in petroleum Column chromatography on silica using a gradient elution of 10% ethyl acid The residue was purified to obtain the product 3-((3゜5-bis(trifluoromethyl) phenyl)methyloxy-1-t-butyloxycarbonyl-2-methyl-2- Phenylpiperidine was obtained as a colorless oil. 'HNMR (360MHz Hz) , CD Cl s) δ 1.13 (9H, S (CHs) 3), 1.85 (3 H, s, CH3), 1.85-1.99 (4H, m, C82CH2), 3.48 (IH, b r s, NCHH), 3.68-3゜75 (IH, m, NCHH ), 3.80-3.85 (IH, m, CH, m, ArH), 7.42 (2 H, s, ArH), 7.71 (IH, s, ArH).

(e) Add the compound (2.1 g) of (d) above to trifluoroacetic acid (30i1) at 1 Dissolved for 0 minutes and then evaporated under vacuum. Dissolve the residue in dichloromethane, hydrate Sodium chloride (2M), washed with water and brine, then dehydrated (MgSO4) under vacuum. Concentrated into Methanolic hydrogen chloride was added to the residue, and after dissolution, the solvent was evaporated.

The residue was triturated with ether to obtain a white powder. c)-2-methyl(2R*)-2-phenylpiperidine was obtained. If-I NM R (360MHz, DMSO) δ 1.67 (3H, s, CHs), 1.70 (IH, m), 1.84-1.91 (IH, m), 1.99-2.06 (2H, m), 3.16 (IH, m), 3.33 (IH, m).

7.33 (IH, m, ArH), 7.37-7.41 (3H, m, ArH), 7 ．． 54 (2H, s, ArH), 7.56 (IH, brs.

ArH), 7.89 (IH, s, ArH) o Cz+H! +Elemental analysis of FsNO : Calculated value: C, 55,58; H, 4,89; N, 3.09%; Actual value: C, 55,38; H, 4,92; N, 3.08%.

'HNMR (CDCIg) 61.4-1.9 (3H, m).

2.11 (3H, s), 2.17 (3H, s), 2.1-2.3 (IH.

m), 2.78 (IH, m), 3.25 (LH, m), 3.60 (LH.

s), 3.76 (LH, s), 4.08 (if-1, d, J = 12) 1z).

4.27 (IH, d, J = 12Hz), 6.7 (2H, m), 6.92 (IH, d, J=9Hz), 7.2-7.5 (5H, m).

(3H, m), 1.97 (IH, d, J=7Hz), 2.16 (IH, m), 3 ．． 05 (IH, m), 3.3 (IH, m), 3.84 (IH, s), 4.09 ( IH, d, J = 12Hz), 4.41 (IH, d, J = 12Hz), 4.44 ( IH, m), 4.5 (IH.

s), 6.6 (2H, m), 6.72 (IH, m), 7.09 (IH.

t, J=8Hz), 7.3-7.5 (5H, m).

Production example 31: (2S, 3S)-3-((3,5-bis(trifluoromethyl ) phenyl) methyloxy) -2-(3-fluorophenyl) piperidine 'HNMR (360MHz, CD CI x) δ 1.66-1.9 (3H, m), 2.2-2.3 (LH, m), 2.43-2.5 (IH, m), 3.0-3.2 (IH, m), 3.98 (LH, s), 4°37 (IH, d, J = 12Hz), 4.62 (IH, s), 4.79 (IH, d, J = 12Hz), 7.04-7.46 (4H, m, ArH), 7.80 (2H, s, ArH), 7 ．． 96 (IH, s, ArH).

Example 1 Hydroxyguanidine sulfate hydrate (2.3 g) was dissolved in water and lyophilized overnight. . Solid hydroxyguanidine with ethanol (35ml) and powdered molecular Sieves (1 g) were added and the suspension was stirred under nitrogen for 1 hour. sodium in the mixture (670+ag) was added and stirred until all the sodium had reacted. this stage The orange-colored suspension was then placed in an ultrasound bath for 15 minutes. Production example 2 S Teru (1.4 g) was added to the mixture and then heated to reflux for 2 hours. The reaction mixture is Cool and filter through Celite. The ethanol was removed under vacuum and the residue was dissolved in acetic acid. Extracted into chill and washed with water and brine. The organic layer was dried (MgSO<) and evaporated. and the residue was purified on silica using 25% ethyl acetate in petroleum as eluent. The product (800 mg) was obtained as a solid and recrystallized from ether/hexane to free A colored prism was obtained (melting point: 160-161°C). 'HNMR (360MHz , DMSO δ6) δ1.47-1°54 (2H, m, CH2), 1-. 85- 1.9 (I H, m, CHH) H2), 7.23-7.31 (3H, m, Ar H), 7.42-7.44 (2H, m, ArH), 7.69 (2H, s, ArH ), 7.93 (IH, s, ArH); MS (CI”) m/z 501 ((M+ 1)’, 75%). Elemental analysis of C23H2□F aN 40m: Calculated value: C , 55, 20; H, 4, 43; N, 11.2%; Actual value: C, 54, 8 1, H, 4,47; N, 11.2%.

Acetamide oxime (117 g) and powdered molecular sieves were dissolved in dry tetamide. It was suspended in lahydrofuran (10ml) and stirred for 1 hour under nitrogen. Hydrogenated sodium (63 mg, 60% suspension in oil) and stirred the mixture until all the hydrogen had evolved. The mixture was heated to 50°C. The ester (500+g) of Production Example 2 was added to tetrahydrofura (2 ml) and added to the above mixture. The mixture was heated to reflux for 2 hours and cooled. , filtered through Celite and evaporated under vacuum. Dissolve the residue in ethyl acetate, water, It was then washed with brine. The organic layer was dried (MgSO4) and evaporated under vacuum. melt Medium pressure chromatography using 25% ethyl acetate in petroleum as a release agent (Loba The residue was purified by subjecting to r) to obtain the product as a crystalline solid (melting point: 85-8 6℃). 'HNMR (360MHz, DMSOds) δ 1.47-1.54 (2H, m, CH2), 1.85-1.89 (LH, m.

CH Dan), 7.25-7.31 (3H, m, ArH), 7.43-7 ゜45 (2H, m, ArH), 7.70 (2H, s, ArH), 7゜93 (IH , s, ArH); MS (E I) m/z 500 ((M+l)", 100% ), Elemental analysis of Cz<HzsF eN 3oz; Calculated value: C, 57, 7 2; H, 4,64; N, 8.41%: Actual value: C, 57°94; H, 4 , 79; N, 8.23%.

Example 3 (+)-3-amino-5-[IC28,3S)-3-((3,5-bis(trif fluoromethyl)phenyl)methyloxy)-2-phenylpiperidino 1 methyl] -1,Z-.

The title compound was prepared from the ester of Preparation 4 using the procedure described in Example 1 ( Melting point: 13g -139°C). [α]23°=+147.7° (c=1 ．． MeOH), 'HNMR (360MHz, CDCl5) δ 1.47-1.5 0 (2H, m, CH,).

H, d, J=15.0Hz, NCHH-het), 4.05 (IH.

31 (3H, m, ArH), 7.42 - 7.44 (2H, m, ArH), 7 ．． 69 (2H, s, ArH), 7.93 (IH, s, ArH): MS (C M) m/z 501 (M+1”, 75%), C23HzF 8N 40 Elemental analysis of 2: Calculated values: C, 54,98; H, 4,54, N, 11.30% ; Actual value: C, 54,81; H, 4,47; N, 11.2%.

Compound of Production Example 1 (410 mg), 3-picolyl chloride (167 mg) and Potassium carbonate was suspended in dimethylformamide (3o+1) and the mixture was heated at 60°C. Heated for 12 hours. The mixture was cooled, diluted with water (50 ml) and diluted with ethyl acetate (2X 1 hl).

The organic layer was washed with brine, dried (MgSO4) and evaporated.

The residue was purified on silica using a gradient elution of 25-50% ethyl acetate in petroleum.

Dissolve the product in ethereal hydrogen chloride to form the hydrochloride salt and recrystallize from benzene. (melting point = 198-200°C). 'HNMR (360MHz, DMSOd s.

353K) 61.68-1.82 (2H, m, CH2), 2.09-2 ．． ICCO2,4,16 (IH, brd, NC 1-pyridine), 7.3 7-7.41 (3H, m, ArH), 7.60-7.64 (IH.

m, ArH), 7.71-7.72 (2H, m, ArH), 7.86 (IH, s , ArH), 7.89 (2H, s, ArH), 8.08 (IH, d, J=8.0 Hz, ArH), 8.64 (IH, s.

ArH), 8.68 (LH, d, J=5.0Hz, ArH); MS (CI)" ) m/z 495 (M”+1.60%): CzsHt4FsN20. Elemental analysis of 2HC1,1,5H20; Calculated value: C, 52, 54: H, 4, 9 2; N, 4゜71%; Actual value, C, 52,45; H, 4,90, N, 4 ．． 52%.

(lifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methy ] Pyridinium Hydrochloride Preparation Example Compound 1 was reacted with 2-picolyl chloride (melting point: 175-180°C).

'HNMR (360MHz, DM S O-ds) δ 1.65-1.8 3 (2H, m, CHz), 2.08-2.15 (2H, m, CHz).

7.24 (IH, d, J = 7.5Hz, ArH), 7.36-7.4 (3H, m , ArH), 7.47-7.51 (IH, m, ArH), 7.62 (2H, mc , ArH), 7.85 (IH, dt, J=7.5, 2.0Hz, ArH), 7. 94 (2H, s, ArH), 7°97 (IH, s, ArH), 8.65 (IH, d, J = 7.5Hz.

ArH); MS (CM) m/z 495 ((m+1)', 100%). C26 824F6N20.2HC], HzO elemental analysis; Calculated value: C, 53, 30; H, 4,82, N, 4.78%; Actual value: C, 53°01; H, 4,79 ; N, 4.69%.

Example 6 2-[12R*,3R*)-3-((3,5-bis(trifluoromethyl)ph) phenyl)methyloxy)-2-phenylpiperidino)methyl]benzimidazole Following the procedure described in Example 4, the compound of Preparation Example 1 was prepared using 2-(chloromethyl)benzene. Melting point: 152-153℃), 'HNMR (360MHz, DMSO (2 fertilizers, NCH Danju CHHCH2N), 2 ．． 86-2.89NCHCdan0), 3.63(IH,s,NCdanCHO), 3.807.07-7.15 (2H, m, ArH), 7.24-7.34 (3H.

m, ArH), 7.43-7.52 (2H, m, A'rH), 7.60-7. 62 (2H, m, ArH), 7.67 (2H, s, ArH).

7.94 (IH, s, ArH), 12.10 (IH, s, NH); MS (C I”) m/z 534 ((M+1)”, 100%).

The compound of Production Example 5 (1.0 g), triethylamine hydrochloride (467 mg) and a Sodium dilide (441 mg) was dissolved in 1-methyl-2-pyrrolidinone (5 ml). The reaction mixture was heated to reflux under nitrogen for 2 hours. Then cool the mixture in ice/water The mixture was diluted with (80 g/l) and acidified to pH=2 using methanolic hydrogen chloride. child The product, which precipitated as a white solid, was diluted with methanol (0%) in dichloromethane. -5%) on silica using gradient elution and recrystallized from ether/hexane. (melting point: 114-115℃), 'HNMR (360MHz, DM SOdo) δ 1.59-1.65 (2H, m, NCH2CHHz5.5Hz , NCHH-tetrazole), 4.05-4.10 (IH.

NH), 7.30-7.35 (3H, m, ArH), 7.45-7.47 ( 2f(,m,ArH), 7.51(2H,s,ArH), 7.74(IH,s, ArH); MS (CI") m/z 486 (M" 11.85%). Cz2H Elemental analysis of 2+FaNsO, 0,5HzO; Calculated values: C, 53, 44; H, 4,48; N, 14.16%; Actual value: c.

53.14; H, 4,58; N, 13.96%.

Example 8 2-[((2R*,3R*)-3-((3,5-bis(triacetone anhydrous (2m l), methanol (2m+1) and tetrabutylammonium perbromide (ll1m g) was stirred under nitrogen to form a bromoacetone solution in situ. to the mixture The compound of Production Example 6 (150 mg) was added, and the resulting solution was stirred for 2 hours. Second An equivalent amount of bromoacetone was added and the mixture was stirred for a further 2 hours. True volatile solvent Removed in vacuo and the residue partitioned between aqueous potassium carbonate and ethyl acetate. Brine the organic layer Washed with water, dried (MgSO4) and concentrated in vacuo to give a brown oil. this , purified on silica using a gradient elution of ethyl acetate (10-30%) in petroleum, The product was obtained as a clear oil. 'HNMR (360MHz, CD C 15) bs, Cdan 0), 3.58 (H, bs, CHPh), 3.94 (1 (3H , m, Ar-H), 7.52-7.54 (2H, m, Ar-)-1), 7. 58 (2H, s, A r-H), 7.72 (IH, s, Ar-H); M S (CI") m/z 515 (M"+1.too%).

Elemental analysis of C2SH24F 6N 2o S; calculated values: C, 58, 36, H.

4.70; N, 5.44%; Actual value: C, 58,59; H, 4,88; N, 5°48%.

Example 9 (2R*, 3R*)-3-((3,5-bis(trifluoromethyl)phenyl) Methyloxy)-1-(2-furoyl)-2-phenylpiperidine The compound of Production Example 1 (400w1g) and triethylamine (300mg) were diluted. Dissolved in lolomethane and stirred the mixture for 10 minutes at 0°C. Add 2-fluoride chloride to the solution. Royle (155 g) was added and the reaction mixture was stirred for 15 minutes. Then the mixture Washed with brine, the organic layer was separated, dried (MgSO4) and concentrated under vacuum.

The residue was chromatographed on silica using 20% ethyl acetate in petroleum. was purified to give a clear oil. l) 1NMR (360MHz, DMSO-d ll) δ 1.6-1.8 (2H.

m, CHI), 1.9-2.1 (2H, m, CHz), 2.99 (IH, mc, C Dan HN), 4.02 (IH, Q, J=5.0Hz, -=13.0Hz, OC Hdan), 5.95 (IH,s, CHPh).

6.62 (LH, s, furan-H), 6.99 (IH, s, furan-H), 7.25-7.36 (3H, m, ArH), 7.51-7.54 (2H , m, Ar, H), 7.83 (LH, s, furan-H), 7°90 (2H, s , ArH), 7.99 (IH, s, ArH); MS (CI"") m/z 4 98 (M”+1, 20%).

Example 10 2-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-2-phenylpiperidino)methyl]furan The compound of Example 9 (34011 g) was dissolved in tetrahydrofuran. This melt Add poran-dimethyl sulfide complex (0,181111, 10M solution) to the solution to obtain The resulting solution was heated to reflux for 8 hours. Cool the mixture and remove the excess by adding methanol. The solution was quenched and the solvent was removed under vacuum. Dissolve the residue in methanol (10ml) Then, potassium carbonate (238,111 g) was added. This mixture was heated to reflux for 1 hour. , methanol was removed under vacuum and the residue was partitioned between ethyl acetate and brine. Ethyl acetate The layers were dried (MgSO4) and evaporated. The residue was purified using 10% ethyl acetate in petroleum. The product was recrystallized from ether-hexane (melting point: 103-104°C). 'HNMRN), 3.11-3.15 (IH, d, J = 15.0Hz, NCHH-(IH,s, NCHCHo), 4.02-4. 06 (IH, d.

J=13.0Hz, QCCI-), 4.59-4.62 (IH, d, J = 13.0Hz, OCH dan-), 6.08-6.09 (IH, m, flat (once), 6.35-6.36 (-18, scolded franc once), 7.24- 7.32 (3H, m, ArH), 7.46-7.48 (2H, m, ArH), 7 ．． 55 (IH,s, furan-H), 7.68 (2H,s.

ArH), 7.93 (IH, s, ArH); MS (CI”) m/z 485 (M”+1, 100%), C2sHtsN F 60 (D elemental analysis: total Calculated value: C, 62,27; H, 4,83, N, 2.96%; Actual value: C, 62,11; H, 4,80; N, 2.90%.

Example of preparing diisopropylethylamine (220 μm) in dry acetonitrile Compound 1 (20hg) and 5-promo-3-(chloromethyl)-1,2,4- Oxadiazole (99mg) (J, Heterocyclic Chew , 1989.26.23). The resulting solution was heated at room temperature for 48 hours. Stir for hours.

After this time, the solvent was removed under reduced pressure and the residual oil was purified with ethyl acetate (2 Purified by column chromatography on silica using 0% A solid was obtained. An ethereal solution of this solid is treated with ethereal hydrogen chloride to produce a white A precipitate was obtained. Recrystallization from ether gives the title compound as an amorphous white solid. (Melting point: 100-102°C).

'HNMR (360MHz, DMSO-d,) δ 1.67-1.70 sol), 4.73 (IH, d, J=11.0Hz, QCHH-Ar), 7.3 4-7.42 (5H, m, A r H), 7.68 (2H, s, ArH ), 7.73 (IH, s, ArH); MS (CI”) m/z 564 ( (M+1)”, 20%). CIIH! @N10, F, Br, HCI source Elementary analysis; calculated value: C, 45, 98; H.

3.52; N, 6.99%: Actual value: C, 45,64; H, 3,63; N, 6゜5-[((2R*, 3R*)-3-((3,5-bis(triflu) (oromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl 1- 3-dimethylamino-1,2゜4-oxadiazole hydrochloride Compound of Example 11- (169 mg) in dimethylamine (33% in ethanol) ) was heated to 40°C for 30 minutes. Remove the solvent under reduced pressure and use hexane as eluent. Column chromatography on silica using ethyl acetate (20%) in The residue was purified. The compound is dissolved in ether and treated with excess ethereal hydrogen chloride. A white precipitate was obtained. Recrystallization from ether gave the product (11 0g) was obtained (melting point + 179-180°C), 'HNMR (360MHz, D MSO-, 3,60 (IH, b r s, CH-0-CHz), 3.70 (IH .

(3H, m, ArH), 7.4 (2H, m, ArH), 7.49 (2H, s, A rH), 7.64 (IH, s, ArH); MS (CI　’) m/　z　(M 4+ 1) 529゜CtsHtsN 40tF　s, HCl, H2O element content Analysis; Total 11: C, 51,51; H, 5,01; N, 9.61%; Actual value : C, 51,87; H, 4,93; N, 9.62%.

The compound of Preparation Example 1 was converted to 2-thiophenecarbonylchloride as outlined in Example 9. I made it react. After treatment an oil was obtained, the solvent was removed and the residue was dissolved in petroleum ether. Purified by chromatography on silica eluting with 10% ethyl acetate in The pure product was obtained as a clear oil. 1HNMR (250MHz, CD Cis) 61.6-1.8 (2H.

m, CHg), 2.1-2.2 (2H, m, CHz), 3.0 (IH.

J=7Hz, CHAr), 4.8(LH,d, J=7Hz.

-7,44 (4H, m, Ar-H), 7.5 (IH, dd, J=1.3Hz, Chi Offen-H), 7.6-7.92 (5H, m.

Reacting the compound of Example 13 with dimethylborane sulfide as described in Example 10 Ta. The free base was recrystallized from ether and hexane as a white crystalline solid. The product was obtained. 'HNMR (250MHz, CD CI g) δ 1.44- 1.64 (2H, m, CHz), 1.9-2.2 (2H, m, CHt).

J=7Hz, CHN), 3.4 (IH, s, CH0), 3.567 en), 4.88 (LH, d, J=10Hz, CH-tit7゜J=IHz, thiophene- H), 6.9 (H, dd, J = 2Hz, 3Hz, Thiophen H), 7.2 (I H, d, J = 3 Hz, thio7xn-H), 7.28 (4H, m, Ar-H).

7.5 (3H, m, Ar-H), 7.68 (IH, s, Ar-H), MS　m/　z　500　(M”, 100%).

Compound of Preparation 7 (0.50 g) and methyl iso in 1-butanol (1 hL) The thiocyanate (0,09i1) suspension was heated to reflux for 10 minutes. 1.8-dia Add zabicyclo[5,4,0]undec-7-ene (0.1ml) and mix the reaction mixture. The mixture was heated to reflux for 2.5 hours. Remove the solvent under vacuum and take the residue in water and ethyl acetate. distributed. The organic layer was dried (MgSOi) and evaporated. Dichloromethane as eluent Purification on silica using 795% methanol gave the title compound. product ( 47 o g) exhibited the characteristics of a hydrochloride salt. 'HNMR (360MHz.

DMSO-ds) 61.77-1.93 (2H, m, CHt), 2゜2 ．． 0Hz, NCl-1CHHz), 3.97 (IH, b r s, CH-0 ), 4.24 (IH, d, J = 15.5 Hz, N-CHl-1-he t).

4.32 (IH, d, J=15.5Hz, N-CH dan-het).

4.33 (LH, d, J=12.5Hz, O-CHl), 4.76 ( IH, brs, ArH), 7.85 (2H, s, ArH), 7.89 (IH, s , ArH), 9.15 (LH, brs, NH): MS (FAB) m/z 53 0 ((M+1)”, 13%).

Example 16 3-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-2-phenylpiperidino)methyl]-1.2.4- Compound of triazole production example 1 (1.0 g), anhydrous potassium carbonate (0.94 g ) and N-formyl-2-chloroacetamidohydrazone (0.46g) (Y anagisawa, I, J, Med, Chew, 1984.27 ．． 849) in anhydrous dimethylene, reformamide at 60°C for 3 hours. , and then heated at 130° C. for 12 hours. The reaction mixture was cooled and diluted with ethyl acetate (100 diluted with water (3×20 ml) and washed with water (3×20 ml). The ethyl acetate layer was dehydrated (MgS 04), filtered and evaporated to give a brown oil. This is used as an eluent in petroleum. Purified on silica using ethyl acetate (70:30) to yield as a white solid. I got something. 'HNMR (250MHz.

CDCl5) δ 1.6 (2H, m, CH2), 1.95-2.24 (2 H, m, CH2), 2.34 (LH, m, NCCHl, 3.06 (1 Old scolding NCH), 3.44 (IH, d, NCl-triazole), 3. 5 (IH, bs, CH0), 3.6 (IH.

bs, NCHPh), 3.8 (IH, d, N-CHl-triazole), 4.0 4 (LH, d, QCCHlA r), 4.50 (IH, d, 0CHHAr ), 7.3 (3H, m, ArH).

7.44 (2H, m, ArH), 7.5 (2H, s, ArH), 7°7 (IH, s, ArH), 7.9 (IH, s, triazole-H). MS　(CI”)m /z　485(M”+1.35%).

Example 17 5-　[[(2R*,3R*)-3-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihy Dro-(4H)um (0.45g) and concentrated hydrochloric acid (2.3ml) were heated under reflux for 2 hours. Ta.

After cooling, solid sodium hydroxide was added until the pH was 8, and the aqueous layer was diluted with acetic acid. Extracted with chill. The organic layer was dehydrated (MgSO4), filtered, and evaporated to yield crude semicarba. The dido was obtained and heated to reflux in 2N sodium hydroxide solution (1011) for 2 hours.

After cooling, the solution was acidified to pH 5-6 and the product was extracted into ethyl acetate. organic The layers were dried (M g S O4), filtered and evaporated. 40% crude triazole Chromatog on silica eluting with ethyl acetate/60-80 petroleum ether Ruffy gave the title compound as a white solid. 'HNMR (250MH z, CDCIs) δ 1.6 (2H, m, CHt), 1.9-2.3 (3H, m, CH, +NCHH), 2.95 (LH.

bd, NCHH), 3.16 (IH, d, NC H-Het), 3.20 (I H, bs, CHO), 3.6 (IH, bs, NCAr), 7.32 (5H, m, ArH), 7.5 (2H, s, Ar-H), 7.78 (IH, s, ArH), M S (FAB) m/z 517 (M”+1.80%).

Example 18 5-[1(2R*,3R*)-3-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-2-phenylpiperidino)methyl]-2-methylte Torazol Compound of Example 7 (500 mg)'jr: Water (4 ml) i: 11i11. , sodium hydroxide (44 mg) was added. This is done at an external temperature of 96℃. and dimethyl sulfate (65+ag) was added. The reaction mixture was heated under nitrogen at 96°C. Stirring was continued at 5°C for 1 hour and then 24 hours at 5°C. The product is then diluted Extracted into chloromethane and washed with water and brine. Dehydrate the organic layer (MgS04) , evaporated. The residue was purified on silica using medium pressure chromatography (Lobar). was purified and eluted with 25% ethyl acetate in petroleum. Isolate the first compound to be eluted The product (50 g) was obtained as a crystalline solid and recrystallized from ether/hexane. white crystals were obtained (melting point: 139-141°C). 'HNMR (360MH z, DMSO) δ 1.44-1.51 (2H, m, CH, s, NCHCHO ), 3.58 (IH, s, NCHCHO) (3H, s, CHs), 4.60 (I H, d, J = 13Hz, OCCH), 7.23-7.33 (3H, m, A rH), 7.49-7゜51 (2H, m, ArH), 7.68 (2H, s, ArH), 7°93 (IH, s, ArH); MS (CI”) m/z 500 ( -(M+1)’″, 100%). Elemental analysis of CisHzsN go F m; total Calculated value: C, 55,31, H, 4,64; N, 14.02%; Actual value; C1 55,56; H, 4,76; N, 14.20%.

Nylpiperidino)methyl]-1-methyltetrazole As described in Example 18 The title compound was prepared.

During purification, the second compound to be eluted is isolated to give the product (12 %g) and recrystallized from ether/hexane to give yellow crystals (melting point: 7 5-77°C). IHNMR (360MHz, DMSO) 61.51-1.55 (2H.

84 (3H, s, CH3), 4.14 (IH, d, J=13Hz.

0CHH), 4.85 (IH, d, J=13Hz, 0CHH).

7.26-7.32 (3H, m, ArH), 7°45-7.48 (2H.

m, ArH), 7.74 (2H, s, ArH), 7.94 (IH.

s, A rH); MS (CM) m/z 500 ((M+1)”.

methane of (lifluoromethyl)phenyl)methyloxy)-2-phedimethylamine 5-chloro-3-(chloromethyl) solution (0.5 ml x 33%) -1,2,4-thiadiazole (540 mg) (J, Goerdeler, Chew, Ber, 1957+9 (Lp182 or ICI EP 00 06679) and potassium carbonate (1.0 g) in methanol.

The solution was stirred at room temperature for 3 hours, then the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate. (4 hl) and washed with water (2 hl) and brine (20 l). organic The layers were dried (MgSO4), filtered and the solvent removed to give a yellow gum. elution Flash chromatography using 10% ethyl acetate in hexane as agent The product (3301 mg) was obtained as a yellow oil. 1HNMR (36 0MHz, CD C1s) δ3.15 (6H,s, N(CHs) 2), 4.51 (2H, s, CI CH,), MS (C1″″) m/z 1 78 ((M+1)”, 95%).

(b) Compound of Production Example 1 (223o+g), 5-dimethylamino-3-(k) lolomethyl)-1,2,4-thiadiazole (100 mg) and diisopropyl A solution of ethylamine (0,2■1) was heated to reflux in dry acetonitrile for 3 hours. Ta. The reaction mixture was then cooled to room temperature and the solvent was removed under reduced pressure. Flush the residue Purified by chromatography (40% EtOAc/n1lex) to give a yellow color. A colored gum was obtained. Recrystallized from n-hexane to yield yellow platelets. A product was obtained (melting point: 144-145°C). 'HNMR (360MHz, C DCI 5) 51 (2H, s, ArH), 7.53 (2H, m, ArH), 7 ゜69 (IH, s, ArH); MS (CI") m/z 545 ((M+1)" , 60%). Elemental analysis of CzsHzoFaN4So; calculated value: C,55,1 4, H, 4,81, N, 10.30%; Actual value: C955, 12; H, 4, 75; N, 10.38%.

(lifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methy ]-4,7-dimethylbenzoxazole 2-(chloromethyl)-4,7-cymethylene in dry acetonitrile (10+*l) A solution of rubenzoxazole (285 mg) was added to diisopropylethylamine (0 , 4+1) in addition to a dry acetonitrile (lhl) solution of the compound of Preparation Example 1 containing Ta. The resulting mixture was heated to reflux for 3 hours, cooled to room temperature, and eluted with 20% acetic acid. Flash chromatography on silica using ethyl/n-hexane The residue was purified. The isolated material was recrystallized from n-hexane to give white needles. The product was obtained as a solid (melting point: 109-110°C). 'HNMR (CDC13 ) 1.49-1.53 (2H, m, CHI), 1.56-HN), 3.5 9 (LH, m, CHOCH2), 3.67 (IH.

s, ArH), 7.32 (3H, m, ArH), 7.54 (2H.

s, ArH), 7.57 (2H, m, ArH), 7.71 (IH.

s, ArH); MS (CI") m/z 563 ((M+1)".

70%), Elemental analysis of CC50828N202F; Calculated value: C, 64°05 ; H, 5,01; N, 5.00%; Actual value: C, 64,09; H, 5 ,04; N, 5.12%.

(lifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methy 2-(chloromethyl)benzoxa as an alkylating agent This compound was prepared according to the procedure described in Example 21 using Sol (melting point : 95-97°C). 'HNMR (CDC13) 61.47-1.60 (2H , m, CH2), 2.06-2.1J=6.0, 4.0Hz, NCHH), 3.26 (IH, dd, J = Sol), 3.66 (IH, d, J = 2.0Hz, CHPh), 4゜02 (LH, d, J = 15.0Hz, CHtan-Benzoxazo -/shi), 4.04 (IH, d, J=12.0)lz, 0CHH), 4 ．． 48 (IH, d, J=12.OHi, OCH), 7.26-7.67 (12H, m, ArH); MS (C1”) m/z 535 ((M+1), 6 5%). C2@H24F 8N zOL’/4H! Elemental analysis of O; calculated value: C, 62,39, H, 4,58, N, 5.20%; Actual value: C162,36; H, 4,67, N, 5.27%.

fluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl] Oxazole By J. Hodges, F. Patt and C. Connolly. According to the procedure described in J, OrL Box 1991.56.449-452 1.3-oxazole-4-carboxaldehyde was prepared.

(a) 4-(hydroxymethyl)-1,3-oxazole-1,3-oxazole- 4-Carboxaldehyde (0.38 g) was dissolved in anhydrous methanol and stirred under nitrogen. Stir and slowly add sodium borohydroxide (0,074 g). After 1 hour, elute TLC using 50% ethyl acetate in hexane as agent revealed no starting material. It was confirmed that there was no such thing. In a rotary evaporator (water bath temperature: 40℃) methanol was removed. Cylinder on silica eluting with 100% diethyl ether. The residue was purified by chromatography to give the alcohol (0,27 g) was obtained. IHNMRδ (360 (IH,s, oxazole-H).

4-(hydroxymethyl)-1,3-oxazole (0,13 g) was dissolved in anhydrous dichloromethane (4 ml). Triethylamine in the reaction mixture (0.1 hl) and p-toluenesulfonyl chloride (0.13 g), Stirred at room temperature for 1 hour. Add another portion of p-toluenesulfonyl to the reaction mixture. Chloride (0.13 g) and a catalytic amount of dimethylaminopyridine were added. Manufacturing example Compound 3 (1.2 g, free base) was dissolved in dimethylformamide (5 ml). to the reaction mixture followed by triethylamine (0.19ml). mixture The mixture was heated at 60°C for 2 hours, the resulting mixture was diluted with water (50ml) and dichloromethane was added. Extracted with methane (3X 20ml).

The combined organic layers were dried (MgSO4) and concentrated under vacuum to give a yellow oil.

The oil was purified using a gradient of 30-60% ether in hexanes to give a white solid. The title compound was obtained and recrystallized from ether/hexane (melting point: 102- 104℃). 'HNMR (360MHz, CDC1s) δl, 46r), 4 ．． 46 (IH, d, J=11.5Hz, 0CHHAr).

7.24-7.58 (8H, m, ArH), 7.70 (11 (, s, ArH), 7.80 (IH, s, ArH); MS (CI”) 485 (M”+1,100 %).

fluoromethyl)phenyl)methyloxy)-2-phenyl2-methylpyrazine ( 1 g) was dissolved in carbon tetrachloride (50 ml) under nitrogen. N-chlorosuccinimide (1,42 g) and benzoyl peroxide (1 g) and the mixture was stirred for 24 hours. The mixture was heated to reflux for a while. Cool the reaction mixture, filter through Celite, and remove the filtrate under vacuum. Concentrated. The resulting oil was purified on silica using 30% ethyl acetate in petroleum. did. II NMR (360MH2, CDC13) 64.72 (2H, s, CH 2CI), 8°56 (2H, s, ArH), 8.76 (IH, s, ArH).

2-(chloromethyl)pyrazine (0.17g), potassium carbonate (0.6g) and The compound of Preparation Example 3 (0.35 g) was suspended in dimethylformamide (311). Ta. The reaction mixture was heated at 60°C for 12 hours. Cool the mixture and add water (30ml) Diluted and extracted with ethyl acetate (2X 20ml). Wash the combined organic layers with brine. , dried (MgSO4) and concentrated under vacuum to give a brown oil. 1 in hexane Column chromatography on silica with gradient elution of 5-35% ethyl acetate The product was purified as a white solid and recrystallized from pentane. Colorless crystals were obtained (melting point: 108-110°C). IHNM　R(360MH z, DM S Od s) δ1.42-1.60 (2H.

J = 13.0Hz, 0CHHA r), 7.20-7.33 (3H, m.

ArH), 7.49-7.56 (2H, m, ArH), 7.71 (2H, s, A rH), 7.93 (IH, s, ArH), 8.48-8°63 (3H, m, Ar H); MS (CI") 496 (M"+1°60%). C211H23F 6 Elemental analysis of N sO: Calculated values: C, 60, 6o; H, 4, 68, N, 8. 48%; Actual value: C, 60,90; H, 4,86: N, 8.48%.

To a suspension of the compound of Production Example 3 and potassium carbonate in dimethylformamide (5 ml), 4-(chloromethyl)-2-methylthiazole hydrochloride (83 mg) was added. I got it. The resulting mixture was heated at 60°C for 18 hours, cooled to room temperature, and poured with water (50 ml). diluted with This solution was extracted with ethyl acetate (2X 25ml) and the combined organic The extract was washed with water (2X 20ml), brine (20ml) and dehydrated (MgSO4 ), filtered. The resulting solution was evaporated under reduced pressure to give a yellow oil. hexane The oil was purified by medium pressure liquid chromatography using 50% ethyl acetate. The product was prepared as a white solid, treated with ethereal hydrogen chloride, and treated with methyl-t-butylene. Recrystallization from thyl ether gave the title compound (melting point: 58-60°C).

IHNMR (360MHz, DMSO-da) δ 1.71 (2H, m, CH , 2゜11 (2H, mc, CHz), 2.49 (IH, m, CdanHN) .

2.69 (3H, s, Ar-CHz), 3.15 (LH, m, CH N), 3.54 (IH, m, CH0), 4.12 (2H, m, C H2-thiazole), 4.16 (LH, d, J = 10.0 Hz, 03 (5H, m , ArH), 7.64 (IH, brs, ArHΣ.

7.92 (2H, s, ArH), 7.97 (IH, s, ArH); MS (CI ”) m/z 515 (M”+1) o CzsH*aFsNxO3,2H,0 element Elementary analysis: Calculated values: C, 48,16; H, 4,85; N.

4.49%; Actual value: C, 48,17; H, 4,76; N, 4.52% .

Example 26 3-[+(2S,3S)-3-((3,5-bis(triff potassium carbonate) To the stirred suspension was added 3-(chloromethyl)-1,2,4-oxadiazole (270 mg) was added. The reaction mixture was heated at 60°C for 4 hours, cooled to room temperature and diluted with water (50+ 11). Extract the aqueous solution with ethyl acetate (3X 50ml) and extract the organic extract. Combine, wash with water (3 x 5 hl) and salt water (50 ml), and dehydrate (Mg). SO4) was filtered. The resulting solution was concentrated under reduced pressure and hexane was used as the eluent. Column chromatography on silica gel using 20% ethyl acetate in and purified. The resulting oil was treated with ethereal hydrogen chloride to give a white powder. The title compound was obtained (melting point: 74-75°C). 'HNMR (360MHz, D MSOds) δ 1.62 (2H, m, CH2), 1.97-2.1 (2 H, m, CH2), 2.505 (2H, m, ArH), 7.78 (3H, m , ArH), 7.94 (IH,s, ArH).

3-[1(2S,3S)-3-((3,5-bis(triphthyl'I-1,2, 4-thiadiazole (3.0 g) (J, Goerdeler, Chew, Ber, 1957.90.182) with sodium iodide (excess ) was added. The resulting solution was heated to reflux for 4 hours, cooled to room temperature, and filtered. filtrate Diluted with water (20ml) and extracted with ethyl acetate (50ml). Remove the ethyl acetate layer. water (MgS04), filtered and concentrated under vacuum to give a red oil that could be further purified. Instead, it was used in the next reaction.

(b) 3-[+(2S,3S)-3-((3,5-bis(trifluoromethyl ) phenyl)methyloxy)-2-phenylpiperidino)methyl]-5-iodo -1,2,4-thiadiazole 5-Iodo-3-(iodomethyl)-1 in dry acetonitrile (10ml), 2,4-thiadiazole (160++g) and the compound of Production Example 3 (200mg) Diisopropylethylamine (116 mg) was added to the stirred solution. The obtained solution The solution was stirred at room temperature for 18 hours. Filter the reaction mixture and remove the solvent under vacuum to obtain a red color. An oil was obtained. This was carried out using 20% ethyl acetate in hexane as the eluent. Purified by column chromatography on silica gel to obtain the product as a powder. Melting point: 98-101℃), 'HNMR (360M) (z, CDCl 5) δ 1.55 (3H, m, NCH2CH2CH1+NCH2CdanH), 2.13 (I H, m, NCH2CH dan + NC dan H), 2゜42 (1, H , m, CHHN), 3.21 (IH, m, CHO).

3.69 (2H,m,Cdanph+cdanH-thiadiazole).

4.02 (2H, m, CHH-thiadiazole 10 CHH).

4.48 (IH, d, J=8.0Hz, 0CHH), 7.32 (5H.

m, ArH), 7.51 (2H, s, ArH), 7.70 (IH.

fluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl] -1.2.4-thiadiazole human Example 27 in dry methanol (25 μl) A stirring solution of compound (50 (lsg)) and palladium chloride (n) (280 mg) Sodium borohydride (28 grams) was added to the solution. The resulting mixture was heated for 30 minutes. Stirred, then filtered through Celite, and concentrated the filtrate under vacuum. in this way The solid residue obtained was dissolved in ethyl acetate, and the solution was washed with water (10 ml). The extract was dried (MgSO<), filtered and concentrated in vacuo to give a yellow oil. child Treatment of the oil with ethereal hydrogen chloride gave the title compound as a white powder ( Melting point: 89-90°C). 1HNMR (360MHz, DMSO-do) δ 1 ．． 79 (2H, -m, CH2), 1.9-2.20 (3H, m, CHH N+N　CHzCdanz), 2.6 (IH, m, CHHN), 3.8 (IH, bm .

CH0), 3.89 (IH, b r s, CHPh), 4.2-4. 3 (3H, m, Cdan, -thiadiazole + OCdanH), 4.76 (IH, d , J=9.0Hz, 0CHH), 7.39 (3H, m.

ArH), 7.55 (2H, m, ArH), 7.89 (2H, s.

ArH), 8J2 (IH, s, Arc), 10.32 (IH, s.

N-Cdan-3); MS (CI”) m/z 502 (M”+1) .

Elemental analysis of CxsH21F eN3o S, HC1,1,25HzO; calculated value : C, 49,48; H, 4,37; N, 7.52%; Actual value: C, 49 °31; f(,4,09; N, 7.18%.

fluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl Co-5-methoxy-1,2,4-thiadiazole hydrochloride To a stirred solution of the compound of Example 27 (20 h+g) in methanol (5 ml) was added Thorium methoxide (34 mg) was added.

The solution was heated to reflux for 2 hours, cooled to room temperature, and the solvent was removed under reduced pressure to yield a solid residue. . Dissolve the solid in ethyl acetate (15ml) and wash the organic layer with water (20+nl) , separation, dehydration (MgSO4) and removal of solvent under reduced pressure. Ether the remaining solids The resulting solid was recrystallized from ethyl acetate to give white needles. The product was obtained as (melting point: 74-75°C). 'HNMR(36(1MHz , DMSOdo) δ 1.55 dan-thiadiazole), 3.75 (IH, m, CH H-thian 4.14 (38, s, QC) (s), 4.45 (LH, d, J=lO , OHz, OCH dan), 7.30 (3H, m, ArH), 7.51 ( 4H, brs, ArH), 7.54 (IH, s, ArH); MS (CI　’)m / Z 532 (M”+ 1) o Cz4HxsFaNHO1S.

Elemental analysis of HCl, 0.5) 1.0: Calculated value I C, 49,96; H, 4° 37; N, 7.28%; Actual value: C, 49,89; H, 4,10, N, The title compound was prepared by the procedure described in 7.4. Etherify the free base with water chloride Treatment with crude oil gave the product as a white crystalline solid. Melting point (free base): 2 09-210℃. CzsH! ! Elemental analysis of F5N40.2HCl; Calculated value: C, 49,56; I(, 4,34; N, 10.05%; Actual value: C, 49 , 36; H, 4, 57; N, 10.05%.

Example 31 Using the compound of Preparation Example 8 as the starting material and following the procedure described in Example 17, the title The compound was prepared and the product was obtained as a white solid and treated with ethereal hydrogen chloride to give the product. Obtained crystalline hydrochloride (melting point + 154-157°C), Cx5HzxFsN40 ．． HC1゜2H20(') Elemental analysis; Calculated value: C, 46,90; H, 4, 62; N, 9°51; CI, 6.02%; Actual value: C, 46,59; H, 4,52, N, 9°26; CI, 5.84%.

fluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl ]-1-(p-toluenesulfonyl)imidazole-2-carboxaldehyde ( 1.92 g) were suspended in dichloromethane (20 ml). Add p-tol to the mixture Ensulfonyl chloride (3.8 g) and triethylamine (2°8 Ill) were added. The mixture was stirred at room temperature for 12 hours. Dilute the resulting slurry with water and wash the organic layer with salt water. Cleaned, dried (MgSO4) and filtered. Concentrate the dichloromethane layer under vacuum, eluent Column chromatography using 50% ethyl acetate in hexane as The residue was purified to give the product as a yellow oil which was allowed to crystallize. 'HNM R (360MHz, CDCl5) 62.44 (3H, s, A r CH r , 7.31 (IH.

d, J=1.5Hz, imidazole-H), 7.37 (2H, a.

J=8.0Hz, ArH), 7.83(IH,d, J=1.5Hz.

Imidazole-H), 8.00 (2H, d, J=8.0Hz, ArH) , 9.78 (IH, s, CHO), MS (CI') m/z 251 (M'+1).

The above aldehyde (a) (3 g) was dissolved in methanol (15 proof) and borohydride was added. Sodium (114 mg) was added dropwise. This solution was stirred for 10 minutes. under vacuum The methanol was removed (MgS04), filtered and the solvent was removed under vacuum to give crystallinity. A solid was obtained. 'HNMR (250MHz, CDC13) δ2゜42 (3H, s, ArCHs), 4.84 (2H,s, CHzO).

7.00 (IH, d, J = 1.5Hz, imidazole-〇), 7.36 (2H, d, J=8.0Hz, ArH), 7.40 (IH, d.

J = 1.5Hz, imidazole-H), 7.84 (2H, d, J = 8.0H z, ArH).

(c) ((N-p-toluenesulfonyl)imidazol-2-yl)methyl Methanesulfonate The alcohol described in (b) above (12,6+++g) is diluted with Dissolved in lolomethane (2,5ml) and triethylamine (0,07i1) . The solution was cooled to 0°C and methanesulfonyl chloride (0.04ml) was added dropwise. . After stirring for 10 min, the solution was diluted with water, the organic layer was separated and dried (MgSO4). , filtered and removed the solvent under vacuum to obtain a white solid, which was followed without further purification. used in the reaction. 'HNMR (250MHz, CDC1,) 62.44 (3H, s, ArH), 2.94 (3H, s, 502CH3), 5.51 (2H, S, CHzSOz), 7.08 (IH.

d, J=1.5Hz, imidazole-H), 7.40 (2H, d.

J=8.0l-1z, ArH), 7.49(IH,d, J=1.5Hz.

imidazole-H), 7.92 (2H, d, J=8.0Hz, ArH).

(d) Compound of Preparation Example 3 (2,4 7 g) and potassium carbonate (801 g), ((N-p-)-toluene Sulfonyl)imidazol-2-yl)methylmethanesulfonate t-(1,6g ) was added, the resulting output was combined, washed with salt water, dehydrated (MgSO4), and vacuum Concentration to the bottom gave a colorless oil. using 25-30% ethyl acetate in hexane It is purified by column chromatography on silica and produced as a white crystalline solid. The product was obtained and recrystallized from dichloromethane/petroleum (melting point: 125-126°C ). 'HNMR (360MHz, DMSO-ds) δ1.4-1゜2.35 ( 3H, s, CH3), 2.4 (IH, mc, NCCH).

s, CHO), 3.76 (LH, d, J=1.5Hz, CHPh)=1.0Hz , imidazole-H), 7.12 (21-1, d, J = 8° 5Hz, ArH ), 7.2-7.3 (3H, m, ArH), 7.34 (IH, d, J = 1.0H z, imidazole-H), 7.46-7.58 (2H, m, ArH), 7. 60 (2H, s, ArH).

7.71 (IH, A rH), 7.79 (2H, d, J = 8.5Hz.

A rH): MS (CI”) m/z 638 (M”+1), Cs+Hz Elemental analysis of eFsNsoss; Calculated values: C, 58, 39; H, 4, 58, N , 6.59: s, 5.03%: Actual value: C, 58,48; H, 4,7 g, N, 6.72; s, 4.81%.

The compound of Example 32 was dissolved in dichloromethane and ethereal hydrogen chloride was added.

The resulting solution was stirred for 30 minutes and the title compound crystallized from the solution. filter this and recrystallized from ethyl acetate/methanol as a white crystalline compound. The title compound was obtained. 'HNMR (360MHz.

D20) 61.61-1.74 (IH, m, CHH), 1.76-1°8 8 (IH, m, CHH), 2.04-2.21 (2H, m, CHI), 3 ．． 07-3.23 (IH, m, NCCHH, 3,41-3,51 (IH, m, NCHH), 3.66 (IH, s, CHO), 4.09 (IH, d, J=13.0Hz, QCCHH, 4,25 (IH, d.

J=15.5Hz, CHH-imidazole), 4.30 (IH, s.

, 7.1-7.2 (3H, m, ArH), 7.2-7.3 (2H, m.

A rH), 7.38 (2H, s, imidazole-H), 7.48 (2H, s, ArH), 7.51 (IH, s, ArH); MS (CI”) m/z 484 (M”+1, 25%).C24H!IF aN-sO, 2HCl , Hzo elemental analysis; Calculated value, C, 50, 18; H, 4°74; N, 7.32; CI, 12.34%, Actual value: C, 50,32; H.

4.92; N, 7.23; CI, 12.58%.

Example 34 4-[+(2S,3S)-3-((3,5-bis(trifuberidino)methyl Coimidazole dihydrochloride The compound of Preparation Example 3 and 4-(hydrochloride) were used as starting materials. (roxymethyl)imidazole according to the procedure described in Example 33 to produce white crystals. The title compound was obtained as a crystalline compound (melting point = 206-210°C). 'HNMR( 360MHz, DzO) δ 1.73 (IH, NCH2CH2CHH), 1.94-2.06 (IH.

0), 4.30 (IH, d, J=12.5Hz, 0CHH), 4.4 2 (2H, s, NCH2-imidazole), 4.50 (IH, s.

NCHPh), 4.75 (1) T, d, J = 12.5 Hz, OCH Ph), 7.4 8 (6H, brs, ArH + imidazole-H), 7°74 (2H, s, ArH ), 7.95 (IH, s, ArH), 8° 80 (LH, s, imidazole-H) ;MS (CI") m/z484 (M"+1). Cz4HxsF++NsO , 2HC1, HzO; Calculated values: C, 50,18; H, 4,74; N, 7.32: Cl.

12, 34%: Actual value: C, 50, 22; Fertilization 4.82; N, 7.18: C1゜12.49%.

Example 35 5-[((2R*, 3R*)-3-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihy Dro-(4H)-3-oxo-1,2,4-triazole hydrochloride ■l) To the solution was added sodium methoxide (0,032g) at 0°C. reaction mixture Stirred at room temperature for 30 minutes, then neutralized with acetic acid (0,034a+1). methyl Hydrorazinocarboxylate (1,79 g) was added and the reaction mixture was stirred at room temperature for 30 min. Stir for a minute. The solution was concentrated under vacuum to give the title compound as an orange solid. Obtained. MS (CI)” m/z 166° (b) Compound of Production Example 1 ( 0.50 g) of N-carbomethoxy- 2-chloroacetamithracine (0.19 g) and potassium carbonate (0.47 g) The mixture was stirred at 70° C. for 18 hours. The reaction mixture was then stirred at 140°C for 1 hour. After cooling, the material was partitioned between ethyl acetate and methanol. Wash the organic layer with water and remove Water (MgSO4), filtered and evaporated. Ethyl acetate 95% methanol as eluent The residue was purified by chromatography on silica using ethyl acetate/ Recrystallization from petroleum gave the title compound as a white crystalline solid (melting point: 16 8-172°C). The compound exhibited hydrochloride characteristics. MS (CI) m/ z 500 ((M+1)”, 18%).C23H24N 4016F gCI Elemental analysis; Calculated values: C, 50,60; H, 4,43; N, 10.26; C1,6゜49%, actual value: C,50,65; H,4,43; N, 1 0.22; CI.

Suspension of N,N-dimethylurea (25.0 g) in acetonitrile (200111) Add a solution of chlorocarbonylsulfenyl chloride (11.5 g) in acetonitrile to Added over 20 minutes. The reaction mixture was stirred at 23° C. for 1 hour and then filtered. Mail Add tanol (20+al) to the filtrate and remove excess chlorocarbonylsulfenyl chloride. I disassembled the file. Remove the solvent under vacuum and dichloromethane in hexane (3:1). ) to give a yellow oil. The product was obtained as 'HNMR (250MHz, CDCl5) 63.04 ( 6H.

s, (CH3) z); MS (CI”) m/z 164 (M”+ Chloroacetonitrile (1,3 ml) in NH dimethylformamide (1 ml) was heated to 150-155°C and 5-(N,N-di-methylamino)-1,3 , 4-oxathiazolin-2-one (1.0 g) was added portionwise. After 5 minutes, The reaction mixture was cooled and concentrated under vacuum. Hexane/ethyl acetate (9: Purify the residue by chromatography on silica using 1) to obtain a white crystal. The product was obtained as a crystalline solid.

'HNMR (250MHz, CD C1*) δ3.19 (6H, s.

(CH3) 2), 4.82 (2H, s, CH2); MS (CI◆) 2-Fe Nylpiperidino)methyl]-3-(N,N-dime(chloromethyl)-3-( N,N-dimethylamino)thiadiazole to give the title compound as a white solid. A product was obtained (melting point: 160-161°C), 'HNMR (360MHz, D MSO-d, +TFA) δ 1.69-1.87 (2H, m, CH2), 2.01-2.26 (2H, m, CHt), 3.10 (6H, s.

4.26-4.34 (2H, m, CHz), 4.61 (IH, d, J =7(21-(,s,ArH), 7.99(IH,s,ArH).

Example 37 5-[+(2S,3S)-3-((3,5-bis(triph) prepared as starting material The title compound was prepared using the compound of Preparation Example 9 according to the procedure described in Example 7 (melting Point: 179-181℃), MS (C1″″) m/z 486 (MH”, 35%), Cm! Elemental analysis of H21F6N50; Calculated value: C, 54, 43, H , 4,36; N, 14.43%; Actual value: C, 54,61; H, 4,53 ; N, 14.37%.

This was prepared by the procedure described in Example 18 using the compound of Example 37 as the starting material. The compound was prepared and the title compound was obtained as a white crystalline material (melting point: 158-1 59℃). MS (CI") m/z 500 (MH", 70%). C zsHssF　sN　s.

Elemental analysis; Calculated values: C, 55,31; H, 4,64; N, 14.03 %: Actual value: C, 55,84; H, 4,66; N, 14.13%.

Example 39 5-[+(2S,3S)-3-((3,5-bis(trifluoromethyl)ph) phenyl)methyloxy)-2-phenylpiperidino)methyl]-1-methyltet The procedure described in Example 19 using the compound of Example 37 as the lazole starting material This compound was prepared from the following to give the title compound as a clear oil. MS (Cl ”) 500 (MH”, 40%). C23H23F IIN 80 elements Analysis; Calculated value: C, 55, 31: H.

4.64: N, 14.02%; Actual value: C, 55,27; H, 4,69 ;N.

13.67%.

Example 40 3- [+ (2S, 3S)-3-((3,5-bis(trif 1,2-pyridadi ion-3-carboxaldehyde (0,89 g) (G, Helnisch, E, Lu 5zczak and M, Pa1ler, Mh, Chew 104, 1372 (1973)) in water, and slowly added sodium borohydroxide (0,081 g). I added it. After 1 hour, using 10% methanol in dichloromethane as eluent. TLC confirmed the absence of any starting material. Moisture under vacuum It was removed to obtain a rubbery material. Extract the rubbery substance with dichloromethane and combine the organic substances. was dehydrated (MgSO4) and concentrated under vacuum to obtain the alcohol as a solid, and further It was used in the next experiment without purification. 'HNMR (360MHz, CD Cls) ridazine-I), 7.65 (IH, dd, pyridazine-H).

9.17 (IH, dd, pyridazine-H).

(b) 3-[[(23,3S)-3-((3,5-bis(trifluoromethyl) phenyl)methyloxy)-2=phenylpiperidino)methyl]pyridazine 3-(Hydroxymethyl)-1,2-pyridazine was dissolved in anhydrous dichloro under nitrogen atmosphere. Dissolved in methane and cooled in an ice/water bath. Triethylamine (0,68+1) and and methanesulfonyl chloride (0,378a+1) were added and the reaction mixture was stirred for 1 hour. did.

The starting material was determined by °TLC using 920012295% methanol as eluent. It was confirmed that there was no quality. Removal of the solvent under vacuum gave a solid. Manufacturing example Dissolve compound 3 (free base, 0.48 g) in dimethylformamide (5 ml) and added to the solid followed by potassium carbonate (0.85 g). - 60% of the mixture ℃ for 12 hours, then poured into water (75i1) and diluted with ethyl acetate (3X 40 a+1), dried (MgSO4) and concentrated to give a brown oil, which was Chromatography on silica gel with gradient elution of 10-30% ethyl acetate in petroleum It was purified by applying a fee. Medium pressure chroma eluting with ethyl acetate/petroleum 50/50 Further purification by chromatography afforded the title compound as a white solid (melting point + 111-113℃). IHNMR (360MHz, DMSOdi) δ 1.4 3-1.66r), 7.23-7.35 (3H, m, Ar-) (), 7.50-7.56 (2H, m, ArH), 7.66 (2H, s, pyridazine- H) (M”+1), 30%).

The compound of Production Example 3 (2 g), chloroacetamidine hydrochloride (1.17 g) and dichloroacetamidine Isopropylethylamine (3.17ml) was dissolved in acetonitrile (lhl). The resulting mixture was stirred at 60° C. for 12 hours under nitrogen. the resulting mixture Evaporated and the residue was partitioned between ethyl acetate and water. The aqueous layer was dissolved in ethyl acetate (2X 50 m1) and dichloromethane (2X 50ml).

The combined organic portions were washed with brine, dried (MgSC) 4) and evaporated. 9200 12295% methanol and 10% methanol in dichloromethane, -1% aqueous solution Purify the residue by chromatography on silica using ammonia gradient elution. The intermediate amidine was obtained as a semi-solid material without further purification.

Intermediate amidine (2 g) and 1,3.5-triazine (0.35 g) were dissolved in acetonitrile. It was dissolved in tolyl (7 ml) and heated under reflux for 12 hours. Cool the solution, evaporate it, The residue was chromatographed on silica using 50% petroleum in ethyl acetate as eluent. Purification by heating to give the product as a crystalline solid, which was recrystallized from hexane. (Melting point: 117-119°C). IHNMR (360MHz, DMSOds ) δ 1.41-1.60 (2H.

m, CHH), 3.26-3.30 (IH, J = 15.0Hz, N C0CHHA r), 7.18-7.29 (3H, m, ArH), 7.48- 7.52 (2H, m, ArH), 7.68 (2H, s, ArH), 7.13 (L H,s, ArH), 9.20 (2H,s, triazine-H). MS (CI” ) m/z 497 (M”+1.100%).

The compound of Preparation 10 was reacted with the procedure described in Example 35 to form a crystalline solid. The title compound was obtained (melting point: 185-187°C). 'HNMR (360MHz , CDCl, ) δ 1°d, J=15. OHz, NCHH-triazole') , 2.96-3°z, NCHH-1 riazole), 4.13 (IH, d, J= 12°0Hz, QC Dan HAr), 4.28 (LH, d, J = 12.0Hz.

0CHHAr), 6.53 (IH,s, ArH), 6.89 (IH.

s, ArH), 7.00 (IH, s, ArH), 7.26-7.38 (3H, m , ArH), 7.45-7.50 (2H, m, ArH), MS (CI”) Elemental analysis of m/z 435 (M”+1.60%), C11H34N402: Calculated value: C, 71,86, H, 7,89; l'lJ, -12,89%; Actual measurement Values: C, 72,10; H, 7,94; N, 13.05%.

The compound of Preparation 11 was reacted according to the procedure described in Examples 32/33 to give the title A compound was obtained (melting point: 129-131°C). 'HNMR (360MHz, DM SOd6) δ 1.84 NCR, CHH), 3.09-3.20 (IH , m, NCCHH.

midazole), 7.16-7.48 (101-1, m, A rH), 7.84 (IH, bs, NH). MS (C!’″) m/z 415 (M+1”, 70%).C2□H23C1□Ns0.2HCl　, 2HzO element Elementary analysis: Calculated value: C, 50,30; H, 5,56; N, 7.99%; Actual Measured values: C, 50,71; H, 5,28, N, 8.05%.

[chill]-2,3-dihydro-3-oxo-1,2,4-triazole The compound of Preparation Example 12 was reacted according to the procedure described in Example 35 to give a white crystalline The title compound was obtained as a solid (melting point: 227-228°C). 'HNMR(36 0M) (z, DMSO-d6) δ 1. ．． 35-1.55 (2H, m, NC0 CHHA Dan, ).

1.78-1.88 (IH, m, NCH, CHH), 2.06-2.1 3-3.39 (IH, m, CHO), 3.42 (LH, d, J=14°s, A rH), 6.79 (IH, s, ArH), 7.07 (IH.

s, ArH), 7.25 - 7.34 (3H, m, ArH), 7.51 - 7 ．． 53 (2H, m, ArH), MS (CM) m/z 412 (M++1.20 %). Elemental analysis of C2□H25CI　N40□; Calculated value: C, 63,99; H, 6, 10; N, 13.57%; Actual value: C964, 30; H, 6, 13; N, 13.67%.

The compound of Preparation 13 was converted to N-carbomethoxy-2 by the procedure described in Example 35. - Reacted with chloroacetamithracine to obtain the product as a white crystalline solid. . IHNMR (250MHz, CDCI3) δ 1.92 (2H, m), 2.62 (IH, m), 2.90 (IH, d, J = 15Hz), 3.14 (2H , m), 3.78 (2H, m), 4.08 (IH, rn), 4°28 (2H, m), 7.1 - 7.4 (10 summer (, m, A rH), 7.48 (2 H, s, ArH), 7.77 (IH, s, ArH), MS (CI”) m/ z　577　(M"+　1　, 100%).

Example 46 5-[+(2R,3S)-3-((3,5-bis(trifluoromethylphenylene) methyloxy)2-(diphenylmethyl)pyrrolidino)methyl]-2.3 -dihydro-3-oxo-1,2,4-triazole The compound of Preparation 14 was converted to N-carbomethoxy-2 by the procedure described in Example 35. -The title compound is obtained as a white crystalline solid by reaction with chloroacetamithracine. Obtained. 1HNMR (360MHz, CDCIs) δ2.00 (2H, m) .

2.69 (LH, m), 3.03 (IH, t, J=7.5Hz), 3.26 ( 11-1, d, J = 14.5Hz), 3.32 (IH, d, J = 14°5 Hz), 3.68 (2H, s), 3.76 (IH, d, J=3.5Hz), 4. 31 (LH, d, J=12.5Hz), 4.42 (LH, d.

J = 12.5Hz), 7.40-7.19 (IOH, m, A rH), 7 ．． 64 (2H, s, ArH), 7.76 (IH, s, ArH), MS (CM) m/z 577 (M”+1.100%).

Example 47 3-[+(2S,3S)-3-((3,5-dichlorophenyl)methyloxy c)2-(diphenylmethyl)pyrrolidino)methyl]-1.2.4-triazo The compound of Preparation Example 15 was prepared using the procedure described in Example 16. Reaction with loroacetamithracine gave the title compound as a crystalline solid ( Melting point: 128-129°C). 'HNMR (360MHz, DMSOds) δ 1.65 (IH, b r s), 1.76 (IH, b r s), 3.10 (2 H.

m), 3.61 (IH, d, J=12.0Hz), 3.92 (IH, brs), 4.01 (IH, brs), 4.22 (2H, m), 7.02 (2H, d, J= 1.8Hz, ArH), 7.10 (IH, m.

ArH), 7.14(3)1. m, ArH), 7.22 (2H, t.

ArH), 7.39 (2H, d, ArH), 7.46 (3H, m.

ArH), MS (CI") m/z 493 (M"+1.60%).

Elemental analysis of C2□H2, C1□N40: Calculated values: C, 65, 72; H.

5.31: N, 11.35%; Actual value: C, 65,95; H, 5,22 ;N.

5-[+(2S,3S)-3-<(3-t-butyl-5-chlorophenyl ) methyloxy)-2-phenylpiperidino) methyl]-2,3-dihydro 3-oxo-1,2゜4-triazole The compound of Preparation 16 was converted to N-carbomethoxy-2 by the procedure described in Example 35. -The title compound is obtained as a white crystalline solid by reaction with chloroacetamithracine. (Melting point: 1.81-182°C). MS (CI”) m/z 455 ( M"+1.100%). Elemental analysis of CIHs+C]N40; Calculated value: C , 66° 47; H, 6,91; N, 12.45%; Actual value: C, 65 , 99; H, 6° 87: N, 12.31%.

Example 49 5-[+(28,3S)-3-((3-bis(trifluoromethyl)phenylene) methyloxy-2-phenylpiperidino)methyl]-2,3-dihydro3 -oxo-1,2゜4-triazole hydrochloride Labeled according to the procedure described in Example 35 using the compound of Preparation Example 3 as the starting material A compound was prepared. Recrystallization of hydrochloride from ethyl acetate/methanol gives white crystalline A solid was obtained (melting point: 265-266°C). 'HNMR (360MHz, DM So-d, 10TFA) δ 1.75-1.95 (2H, m, CH,).

2.04-2.30 (2H, m, CH2), 3.20-3J2 (LH.

m, NCHH), 3.58-3.69 (IH, m, NCHH), 3°90 (IH , d, J = 15.0 mouth z, NCHH-triazole).

3.93 (IH, s, CHO), 3.94 (IH, d, J=15.0Hbrs, ArH), 7.56 (2H, brs, ArH), 7.89 (2H, s, ArH) ,? . 95 (IH, s, ArH). M-3 (CI’) m/z 501 (M”+1.60%). Elemental analysis of C23H22F aN 40.8C1; Calculated values: C, 51,45; H, 4,32; N.

10.44, CI, 6.60%; Actual value: C, 51,41; H, 4 ,15,N.

10.58; C1, 6,46%.

piperidino)methyl]-1-methyl-1,2,4-triazole hydrochloride The compound of Example 30 (0.5 g) was dissolved in methanol in a test tube. Natoriu (0,03 g) and iodomethane (0,075 ml) were added, and the container was sealed. . The resulting solution was heated at 65° C. for 1 hour, cooled, and evaporated. Dilute the residue with water and ethyl acetate distributed to The organic layer was dehydrated (MgS O4), filtered, and the solvent was removed under vacuum. I left. Chromatography on silica using ethyl acetate as eluent The residue was purified to give the product as a colorless oil, which was salted by adding ethereal hydrogen chloride. Converted to acid salt. The salt was recrystallized from ether/petroleum. 'HNMR (360M Hz, DMSOdo) δ 1.70-1.84 (2H.

m, CHz), 2.12-2.51 (2H, m, CH2), 3.3 6s, ArH), 7.60 (2H, b r s, ArH), 7.93 (2H, s , ArH), 7.96 (IH, s, ArH), 8.05 (1H, s, C = NH () Riazol)); MS (C1”) m/z 499 (M”+1, 85%).

Example 51 3-[1(2S,3S)-3-((3,5-bis(trifluoromethyl)fer) methyloxy)-2-phenylpiperidino)methyl]-5-phenyl-1 ,2,4-oxadiazole hydrochloride The compound of Preparation 3 was prepared by the procedure described in Example 26. phenyl-1,2,4-oxadiazole. The product is its hydrochloride (Melting point: 88-90℃), HNMR (360MHz .

CDCl,, free base) δ 1.50-1.64 (2H, m, CHz), 2.06-2.22 (2H, m, CH2), 2.44-2.56 (L H.

m, CHHN), 3.18-3.28 (IH, m, CHHN), -3°60 (LH, s, CHO), 3.66-3.74 (IH, d, J=15 ．． 0 Hz, NCHH-oxadiazole), 3.78 (IH.

s, CHPh), 3.88-3.98 (LH, d, J=15.0I (z.

ArH), 7.68 (IH, s, ArH), 8.08-8.18 (2H, m, A rH); MS (CI") m/z 562 (M"+1).

Example 52 3-[1(2R*,3R*)-3-((3,5-bis(trifluoromethyl)ph) Ethanol (5 ml) of the compound of Example 17 To the solution, add sodium metquinde (0,001 g) and heat the mixture for 10 minutes. It refluxed. Addition of methyl iodide (0,012 ml) in ethanol (Il 1 l) The mixture was then heated under reflux for 3 hours. The solvent was then removed under vacuum and the residue was dissolved in acetic acid. Partitioned between chill and water. The organic layer was dried (MgSO4) and concentrated under vacuum. eluent Chromatography on silica using 50% ethyl acetate in petroleum as The residue was purified. Compounds by treating the free base with methanolic hydrogen chloride was isolated as the hydrochloride salt (melting point: 105-107°C). 'HNMR (360M Hz.

D M S Od s 10 T F A) δ 1.73-1.91 (2H, m, C (IH, m, CH dan), 2.63 (3H, s, CHs), 3.2 8 (IH, m, NCHHCHz), 3.73 (IH, m, NCHHCH z), 3.92 (IH, brs, CHO), 4.10 (2H.

dd, J=20Hz, 14.5Hz, NCH2), 4.29 (IH.

d, J=13Hz, 0CHH), 4.68 (IH, s, CHPh), 4.79 (IH, d, J = 13Hz, 0CHH), 7.42-7.48 (3H , m, ArH), -7,57(2H, brs, ArH).

7.88 (2H, s, ArH), 7.95 (LH, s, ArH).

MS (C1"") m/z 531 (M"+1, 44%).Cz* Elemental analysis of HzaF6N40S, HCI; Calculated value: C, 50, 84; H, 4 °44; N, 9.88; CI, 6.25%; Actual value: C, 51 , 29; H, 4°62; N, 9.79 + CI, 6.06%.

methyloxy)-2-phenylpiperidino)methyl] described in Example 35. According to the procedure, the compound of Preparation Example 11 was reacted to give the title compound, and warm dimethylform was added to give the title compound. Recrystallized from Muamide (melting point: >220°C). IHNMR (360MHz) , D M S O-d,, 353K) δ 1.45-1.58 (2H, m .

NCHH), 2.94 (IH,brd,NCHCHHz), 3.40(IH , d, J=14.5Hz, NCHH), 3.45 (IH.

d, CHO), 3.52 (IH, d, CHPh), 3.91 (IH.

7.47-7.55 (3H, m, A r H).

The compound of Preparation 17 was reacted with 4-picolyl chloride by the procedure described in Example 4. The title compound was obtained. IHNMR (250MHz, CDCl3) 61.42- 1.61 (2H, m.

3.54 (IH, m, NCHPh), 3.86 (IH, d, J=14Hz, NC HH-pyridine), 3.93 (3H, s, 0CHz), 4.06 (IH, d, J = 11Hz, 0CHHAr), 4.30 (IH, d, J = 11Hz, 0CHHA r), 7.12 (IH.

m, ArH), 7.22 - 7.39 (6H, m, ArH), 7 ．． 45-7.56 (2H, d d, pyridine-H), 7.77 (IH, bs.

ArH), 7.85 - 7.92 (IH, ArH), 8.46 - 8.55 (2H, dd, Piriji:/-H), MS (C!”) m/Z 417 (M′″+1.50%).CzsH[N 10s, 2)I Elemental content of C1 Analysis; Calculated value: C, 63,80; H, 6,18; N, 5.72%; Actual value 1C, 64,10; H, 6,06; N, 5.62%.

Example 55 4-　[[(2R*,3R*)-3-((3-carboxamidophenyl)methyl oxy)-2-phenylpiperidino)″methylcopyridine The compound of Preparation 18 was reacted with 4-picolyl chloride according to the procedure described in Example 4. The title compound was obtained. IHNM R (360 MHz, CD C] s) δ 1.43-1.56 (2H, m.

r), 3.35 (IH, m, CHO), 3.54 (IH, bs, CrH), 8. 48 (2H, d, J=4Hz, pyridine-H).

MS (CI’) m/z 40.2 (M”+1.20%).

According to the procedure described in Example 2, the compound of Preparation Example 19 was reacted to form the compound I got it. 'HNMR (360MHz, CHs), 3.91 (LH, d, J =16Hz, NCHH-het)d, J=9Hz, H), 7.22-7.37 (3H, m, ArH).

7.48-7.54 (2H, bd, Ardan), 8.09-8.14 (I H.

dd, J = 9Hz, J = 3Hz, ArH), 8.15-8.18 (IH, d, J =3Hz, -A rH), MS (CI") m/z439 (M"+1, 100%).

According to the procedure described in Example 1, the compound of Preparation Example 20 was reacted with the following compound: I got it. 'HNMR (360MHz, C3.61 (3H,s, QC times), 3.82 (IH, d, J = 16HArH), 6.43-6.48 (I H, m, ArH), 6.54-6°58 (IH, d, J=8.5Hz, ArH) , 7.26-7.58 (3H, m, ArH), 7.48-7.54 (2H, m, ArH).

The compound of Preparation Example 3 was converted into 6-(chloromethyl)uracil under the conditions described in Example 4. The title compound was obtained.

'HNMR (360MHz, CDC) 3) 1.52-1.71 (2H.

Uracil), 2.92-3.01 (IH, m, CdanH), 3.38 -OCH Dan A r), 5.41 (IH, s, HA), 7.32-7.40 (5H, m, ArH), 7.50 (2H, s, H), 7.56 (IH, s, H) , 8.64 - 9.04 (2H, bs, NH+NH).

MS (CI”) m/z 528 (M+1”, 100%), C*5HssN 3 Elemental analysis of 03F@, calculated values: C, 56,93; H, 4,40; N.

7.97%; Actual value: C, 57,16; H, 4,03; N, 7.88% .

Example 59 3-[f (2R*, 3R*)-3-((3,5-bis(trifluoromethyl ) Phenyl)methyloxy)-2-phe 1 was reacted with 2-chloro-N-carboxamide acetamide hydrazone. The title compound was obtained as a white solid (melting point = 195°C. v**t (KB) r) 1680c++-'; Elemental analysis of C24HzsFsNsOz: Calculated value: C, 54,65; H, 4,40; N, 13.27%; Actual value: C, 5 5,14; H, 4,58; N, 12.82%.

(lifluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methy ]-5-cyano-1,2,4-triazole The compound of Example 59 (0.61 g) was dissolved in chloroform (10o+1), and the obtained The resulting solution was cooled to 0°C in a water bath. Triethylamine (2 ml), then Phosphorous oxychloride (1, bl) was added dropwise. The solution was stirred at room temperature for 1 hour. under vacuum The solvent was removed and the residue was partitioned between chloroform and sodium bicarbonate. organic layer Washed with brine, dried (MgSO4), filtered and concentrated in vacuo. eluent Column chromatography on silica using 30% petroleum in ethyl acetate as The residue was purified using ethereal hydrogen chloride to obtain the product as the hydrochloride salt ( Melting point: 81°C), MS (CI”) m/z 510 (M4-Ziku lorophenyl)methyloxy)-2-phenylpiperidino)ethyl]-1.2. 4-triazole 2-chloropropionitrile in anhydrous methanol (150ml) Sodium methoxide (0,162 g) was added to a solution of 10,5 g at 0°C. Ta. The reaction mixture was stirred at room temperature for 1 h and then neutralized with acetic acid (0.18 ml). . N-formylhydrazine (7.04 g) was added and the mixture was stirred overnight. Obtained The pink solution was concentrated under vacuum to give the title compound as a pink solid. Ta.

(b) The compound of Production Example 11 (5.9 g) was mixed with dimethylformamide (46n+1 ) dissolved in N-formyl-2-chloropropionamide hydrazone (3.5 g) Then, potassium carbonate (5.7 g) was added. The mixture was stirred at room temperature for 2 hours, The mixture was then diluted with xylene (150ml) and heated under reflux for 2 hours. After cooling, the mixture Filtration and concentration under vacuum gave a brown residue. IHNMR of the crude product showed a ratio of 3:1. It was shown that a mixture of diastereoisomers in proportions was present. Diku as eluent Medium pressure chromatography on silica using 4% methanol in lolomethane (Lo The residue was purified over 10 minutes at bar). The first product eluted, isomer 1, bubbles It was isolated as a solid and recrystallized from ether-hexane (melting point: 105-1 07℃). IHN~IR (360MHz, CD CI 3) 61.31 (3H.

d, J = 7.0Hz, -CHCHs), 1.52-1.59 (2H , m.

J=2.0Hz, ArH), 7.21(IH,t, J=2.0Hz.

ArH), 7.3-7.4 (3H, m, ArH), 7.40-7.47 (2H, m, ArH), 7.89 (IH, s, triazole-2H), MS (C1'') m/z.

Example 62 3-[(IR)-1-+ (2S, 38)-3-((3,5-dichlorophenylon methyloxy)-2-phenylpiperidino)ethyl]-1,2,4-1- The second product isolated from the column described in Riazole Example 61 was dissolved in ether. The title compound was obtained by recrystallization (melting point: 132-134'C), and its stereochemistry 'HNMRn, 0. e. Proved by experiment. 'HNMR (360MHz, DM SO-d6) 61.06-1.15 (IH, m, NCH, CH, CHH) , 1° (IH, m, NCR, CHH), 1.66-1.85 (2H, m.

NCCHCHH), 1.98-2.02 (IH,m, NCHzCHI CI Dan), 3.01-3.03 (IH, d, J = 10.5Hz, NC CHH, 3,39 (IH, s, CHO), 3.86 (IH, d, J=1 3.0Hz, 0CHH), 3.98 (IH, Q, J=7Hz.

CHCHs), 4.33 (LH, d, J = 13.0Hz, 0CHH), 6.92 (IH, d, J=2.0Hz, ArH), 7.26-7.46 (6H, m, Ar H).

Example 63 Kageji U Nagiyu and Ze crying Nyunie■L ``Niemushi IA mi phantom'' ``Manyuki and two legs 1,2,4-triazole According to the method described in Example 16, the compound of Production Example 23 (100+ag) was The title compound was obtained by reacting with lumyl-2-chloroacetamide hydrazone (69 mg). I got something. 'HNMR (CDCIs) δ 1.50 (2H, m), 1.94 (3 H, s), 2.0-2.35 (3H, m), 2.2 (3H, s), 3.02 (I H, m), 3.45 (2H, m), 3.57 (IH, s), 3.95 (IH, b rs), 3.95 (IH, d, J=11Hz), 4.26 (IH, d, J= 11Hz), 6.86 (IH, d, J = 7Hz), 7.06 (IH, d, J = 7 Hz), 7.2-'7.5 (6H, m).

7.7 (IH, brs).

The following compounds were prepared by the procedure described in Example 35.

Example 64 5-[+(2S,3S)-3-((2,3-dimethylphenyl)methyloxy -2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3 -oxo-1,2,4-triazole The compound of Production Example 23 was used as a starting material. IHNMR (CDCl2) δ 1 ．． 4-1.55 (2H, m), 1.89 (3H, s), 1.9-2.2 (3H, m), 2.15 (3H, s), 2°91 (IH, d, J=15Hz) , 2.95 (IH, m), 3.28 (IH, s), 3.50 (IH, s), 3. 66 (IH, d, J=15Hz), 4.06 (IH, d, J=12Hz), 4. 29 (IH.

d, J = 12Hz), 6.77 (IH, d, J = 7Hz), 6.9 (IH, t, J=7Hz), 6.97 (IH, d, J=7Hz).

7.2-7.45 (5H, m).

5-　[[(2S,33)-2-phenyl-3-((3-(trifluoromethyl )phenyl)methyloxy)piperidino)methyl]-3-oxo-1,2,4- The compound of Preparation Example 21 was used as the triazole starting material. IHNMR (CDC 13) δ 1.5 (2H, m), 1.9-2.2 (3H.

m), 2.91 (IH, d, J=15Hz), 3.0 (IH, m).

3.3 (IH, s), 3.5 (fH, s), 3.64 (IH, d, J=15Hz ), 4.12 (IH, d, J=12Hz), 4.41 (IH.

d, J=12Hz), 7.0-7.46 (9H, m), 9.9 (2H.

The compound of Preparation Example 22 was used as the starting material. IHNMR (CDCl5)61. 5 (2H, m), 1.85-2.2 (3H, m), 2.88 (IH, d , J=15Hz), 3.0 (IH.

m), 3.27 (IH, s), 3.48 (IH, s), 3.67 (IH.

d, J=15Hz), 4.05 (IH, d, J=12Hz), 4.35 (IH, d, J=12Hz), 6.7 (IH, brd, J-7Hz), 6.95 (IH, b r s), 7.16 (IH, d, J=7Hz), 7.2-7.45 (5H, m), 9.8 (IH, brs), 10.5 (IH, brs).

Example 67 k))ftL--ixy)-2-phenylpiperidino)methyl]-3-oxo- The compound of Preparation Example 24 was used as the 1,2,4-triazole starting material. 'HN MR (CDCl3) 61.23 (9H,s, C(CHa)s).

1.40-1.51 (2H, m, CHz), 1.82-1.85 (IH .

Zolone), 2.88 (LH, m, NCHI-1), 3.38 (LH, d.

J = 14Hz, NCH triazolone), 3.40 (IH, m.

NCHCHO), 3.51 (IH, s, NCHCHO), 3.85 (IH, d, J=12Hz, QCCHH,4,23(LH,d.

J=12Hz, OCH), 6.80-6.82 (IH, m, ArH) , 7.06-7.34 (6H, m, ArH), 7.53-7.55 (2 H, m, ArH), 11.16 (IH, s, NH), 11.24 ( IH, s, NH); MS (CI”) m/z 420 (M’″+1°10%) . Elemental analysis of CzsH32N 4o: Calculated value: C,? 1.40:H, 7, 67; N, 13.32%; Actual value: C,? 1.51; H, 7, 51; N, 13.08%.

Example 68 5-[((2R*, 3R*)-3-((35-dimethylphenyl)methyloxy cy)-2-phenylpiperidino)methyl]-3-oxo1,2,4-triazo The compound of Preparation Example 25 was used as a starting material. 'HNMR (360MHz, DMSO-ds) 6 1.41 - 1.47 (2H.

m, CH2), 1.81-1.85 (IH, m, CHH), 2. 05-2.11 (2H, m, CHH and NCCHH, 2,15 (6H.

36 (1, H, d, J = 2.5 Hz, CHO), 3.40 (IH, d.

J = 14Hz, NCH Dan-Triazolone), 3.44 (IH, b (2 fertilizers , A rH), 6.79 (II-(,s, A rH), 7.25 -7.33 (3H, m, ArH), 7.51-7.53 (2H, m.

A rH), 11.16 (IH, s, NH), ], 1.25 (L H,s.

(2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyl hydroxy)-2-phenyl-1-1-hydroxybenzotriazole hydrate (3 08mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide Lochloride (436mg), triethylamine (0,3i1) and 1,2.4 -triazole-3-carboxylic acid (12% g) in dimethylformamide 'C5m 1) and the resulting mixture was stirred for 15 minutes. Compound of Production Example 3 (0,5 g) was added and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water (10 The product was extracted into ethyl acetate (3x50ml). organic The parts were washed successively with citric acid (aqueous), water, potassium carbonate and brine, then Dehydrated (M g S O4), filtered and concentrated. 70% vinegar in hexane as eluent The residue was purified by column chromatography on silica using ethyl acid; Recrystallization from ethyl acetate/petroleum gave a crystalline white solid (melting point +77-7 9℃). MS (CI-) m/z478 ((M-HF)-+ioo%) .

pyrid-4-yl)ethyl-2-phenylpiperidinium hydrochloride Following the procedure outlined in Example 69, the compound of Preparation 3 was added to 4-pyridyl vinegar. Reaction with acid gives a colorless oil, which is treated with ethereal hydrogen chloride to give a solid was recrystallized from benzene/hexane. MS (CI”) m/z 52 3 (M”+1.100%).C2?H24F sN to!, Original of 2H20 Elementary analysis two calculated values: C, 54,50; H, 4,91; N, 4.70; C ], 5.96%; Actual value: C, 54, 67;) (, 4, 86, N, 4 ．． 66, C1, 6°3-(bromoacetyl)pyridinium hydropromide (3 36 mg) in dimethylformamide (3 ml), and to this solution, Production Example 3 (440 mg) and then potassium carbonate (550 mg) were added. mixture The material was stirred at room temperature for 2 hours, diluted with water and extracted into ethyl acetate. Organic layer with brine Washed, dried (MgSO4) and evaporated. 70% ether in hexane as eluent The residue was purified by chromatography on silica using Medium pressure chromatography using ethyl acetate (60:40) in hexane (Lo Further purification was carried out at bar). 'HNMR (250MHz, DMS O -d s) δ 1.4-1.6 (2) 1. m), 1.8-1.98 ( IH, m, C Dan H), 2.06-2.2 (IH, m, CH Dan), 2゜5 -2.6 (IH, m), 2.9-3.0 (IH, m), 3.54 (IH, d, N CHHCO), 3.62 (IH, brs, CHO).

3.74 (IH, d, CHPh), 3.84 (IH, d, 0CHH), 7.2- 7.3 (2H, m, ArH), 7.38-7.5 (3H, -m, ArH), 7. 5 (IH, dd, Dy　r-H), 7.85 (2H, s, ArH), 7.92 ( LH, s, ArH), 8.14 (IH, dt, pyr-H), 8.62 (IH, dd, pyr-H), 8.94 (IH, d, pyr-H).

Example 72 3-[(Is)-1-[(2S,3S)-3-((3,5-bis(trifluoro) Preparation Example 3 according to the procedure described in Example 61 from the compound and N-formyl-2-chloropropionamide hydrazone A compound was prepared. Column (3% methane in dichloromethane as eluent on silica) When the first compound to be eluted was isolated from (Melting point: 66-68℃), MS (CM) m/z 499 ( (M+1)”, 100%).

-2-phenylpiperidino)ethyl]-1,2,4-triazole The second product isolated from the column described in Example 72 was purified using ethyl acetate/hexane. The title compound was obtained by recrystallization from water (melting point: 108-111°C), MS (CI") m/z 499 ((M+1)", 100%).

The compound of Preparation Example 3 and N-carbomethoxy-2-chloropropio as starting materials Amidohydrazone (CI CH(CHs)C(=NH)NHNHCOOCHs ) using the procedure described in Example 35 to prepare the title compound. Iris HNMR (CDC13) 60.94 (3H, d, J=7Hz), 1.4-1.58 (2H , m), 1.8 (IH, mc), 2.06-.

2.2 (IH, m), 2.26'2.4 (IH, m), 3.3 (IH.

me), 3.52 (IH, s), 3.64-3.72 (2H, m), 4゜06 ( LH, d, J = 12Hz), 4.64 (LH, d, J = 12Hz), 7.2-7 ．． 38 (3H, m), 7.6-7.7 (2H, m).

7.74 (2H, s), 7.94 (IH, s). MS (CI”) m/z 5 15 ((M+1)', 23%).

The title compound was prepared from the compound of Preparation 11 by the procedure described in Example 16. (Melting point: 208-212°C). MS (CI”) m/z 417 ((M +1)”, 100%).

5-Cf (2R*, 3R*)-3-((3,5-bis(t) described in Example 35 The title compound was prepared from the compound of Production Example 26 according to the procedure (melting point: 125 -127°C). 'HNMR (360MHz, DMSO) 61.46-1.52 (2H, m), 1.9-1.95 (IH, m), 2.0-2.2 (2H, m), 2.92 (LH, d, J = 15Hz, NCHH-) rear zone on), 2゜98 (I H, mc), 3.35 (IH, s, CHO), 3.44 (IH, d, J = 15 Hz, NCHH-triacylon), 3.50 (LH, brs, CHPh), 3 ．． 96 (IH, d, J = 12Hz, QC DanH), 4.43 (IH, d, J = 12 Hz, OCH Dan), 7.15-7.22 (2H, m, ArH), 7.3 7-7.41 (2H.

m, ArH), 7.48 (2H, s, ArH), 7.65 (IH.

s, A rH). MS (CI”) m/z 535.537 (M”+1° 100, 30%).

Example 77 5-[f (2S, 3S)-3-((3,4-dimethylphenyl)methyloxy 2-phenylpiperidino)methyl]=2.3-dihydro-(4H)-3- Oxo-1,2,4-triazole Using the compound of Preparation Example 29 as the starting material, the standard was prepared by the procedure described in Example 35. The following compound was prepared. IHNMR (CDC13) δ 1.37-1.55 (2 H, m), 1.9-2.2 (3H, m), 2゜1 (3H, s), 2.15 ( 3H, s), 2.85 (LH, d, J=15Hz), 2.97 (LH, m), 3 ．． 26 (IH, s), 3.51 (IH, s), 3.65 (IH, d, J = 15H z), 4.06 (IH, d, J=11Hz), 4.26 (IH.

d, J = 11Hz), 6.65 (2H, m), 6.9 (IH, d, -J = 8Hz ), 7.2-7.45 (5H, m), 9.5 (IH, b as starting material Preparation Example 3 The title compound was prepared by the procedure described in Example 35 using compound 0. I HNMR (CDCIs) δ1,25 (6H, d, J=6Hz), 1.35-1 ．． 55 (2H, m), 1.9 -2.2 (3H, m), 2.89 (IH, d, J = 15Hz), 2.99 (IH, d, J = 10Hz).

3.27 (IH, s), 3.51 (IH, s), 3.66 (IH, d.

J = 15Hz), 4.1 (4H, d, J = 12Hz), 4.38 (1f-1, m ), 6.48 (IH, d, J=7Hz), 6.57 (IH.

s), 6.66 (IH, d, J=7Hz), 7.2-7.5 (5H.

By the procedure outlined in Example 35, the compound of Preparation 27 was reacted to give the standard The following compound was prepared (melting point: 228-229°C). 'HNMR (360MHz , DMSO) 61.4-1.55 (2H, m, CHz), 1.8-1.9 (LH, m, CH2), 2.02-2.18 (2H, m, CHz and NCHH), 2.21 (3H, s, CH3), 2.73 (LH, d, NCHH-het, J=14Hz), 2.87-2.90 (IH, d, NC H13, 41 (IH, d, NCHH-h et, J = 14Hz), 3 ．． 46r, J=12.5Hz), 6.50-6.55 (2H, m, ArH).

6.80-6.83 (IH, m, ArH), 7.29-7.31 (3H.

m, ArH), 7.51-7.53 (2H, m, ArH), 11.18 (IH, s, NH), 11. '28 (IH, s, NH), MS (CI"") m/z 397 (M″″+1.10%).

The title compound is prepared from the compound of Preparation 28 by the procedure outlined in Example 35. Prepared. IHNMR (360MHz, MeOD) 61.43 (3H,s, CH s), 1.46 (LH.

m), 1.91 (3H, m), 2.57 (2H, m), 2.98 (IH.

Ron), 3.72 (IH, d, J=12Hz, 0CHH), 4.36ArH), 7.25 (2H, t, ArH), 7.37 (2H, s.

ArH), 7.53 (IH, -s, ArH), 7.56 (IH, s.

ArH), 7.71 (IH, s, ArH).

'HNMR (CDCIs) δ 1.42-1.62 (2H, m).

1.84 - 2.2 (3H, m), 2.86 - 3.1 (2H, m), 3. 38-3.58 (3H, m), 4.08 (IH, d, J=12Hz, OCH Dan) , 4.54 (IH, d, J=12Hz, 0CHH), 6°92-7. 04 (IH, m, ArH), 7.16-7.32 (3H, m.

ArH), 7.54 (2H, s, ArH), 7.76 (IH, s.

3-[+(2S,3S)-3-((3,5-bis(trifluoromethyl)fluorocarbon) phenyl)methyloxy)-2-phenylpiperidino)methyl]-1,2,4-t Riazine (a) Compound (1 g) of Production Example 3 was added to dimethylformamide (8 ml) Dissolved in N-t-butyloxycarbonyl-2-chloroacetamitracine ( 0.6 g) and then potassium carbonate (0.9 g). Mixture overnight at room temperature Stirred. The mixture was diluted with water, extracted with ethyl acetate, and the organic layer was washed with brine and dried. (MgS04), evaporated. Color on silica using ethyl acetate as eluent The residue was purified by mucochromatography to obtain the compound as a white solid, which was Recrystallized from tel/hexane. 'HNMR (360MHz, C-DC13 ) 61.40 (9H, s, CHs) s), 1.42-1.6 (3H , m), 2.13-2.2 (2H, m), 2.62 (IH, d, J=15Hz, NC DanHC=NH), 3.07-3.10 (IH, m.

C Dan HN), 3.36 (IH, d, J=15Hz, NCH Dan C; NH), 3.3 8 (LH, s, CHO), 3.57 (IH, brs.

(5H, m, ArH), 7.53 (2H, s, ArH), 7.73 (IH, s, ArH).

(b) Dissolve Boc-protected amithracine (1 g) in methanolic hydrogen chloride and add 1 Stirred for 2 hours. Evaporate the solvent and proceed to the next reaction without further purification of the crude product. used for.

(c) Add amithracine hydrochloride (200 mg) from (b) above to ethanol (2+al ) dissolved in Add magnesium sulfate (100 mg) and stir the mixture for 30 minutes. did. Triethylamine (0.06ml), then glyoxal (9hg, triethylamine) mer dihydrate) was added. This mixture was stirred for 12 hours. Remove solvent under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was dried (MgSO4) and concentrated. , yielding a brown oil, coloring on silica using hexane (95%) in ethyl acetate. Purification by mucochromatography gave the title compound. IHNMR (36 0MHz, CDCI3) δ 1.53-1.72 (2H, m.

CHz), 1.98-2.22 (2H, m, CHri, 2.42-2. 537.48-7.6 (4H, m, ArH), 7.70 (IH, s, ArH), 8.6 (IH, s, ArH), MS (C1◆) m/z497 (M’+ 1) , 100%).

The examples below demonstrate pharmaceutical compositions of the invention.

Compound of formula (1) 1.0 2.0 25.0 Microcrystalline cellulose 20.0 2 0.0 20.0 Corn starch for prepared foods 20.0 20.0 20.0 la Cutose 58.5 57.5 34.5 Magnesium stearate 0.5 0.5 0.5 Compound of formula (1) 26.0 50.0 100.0 Microcrystalline cell Loin 80.0 80.0 80.0 Corn starch for prepared foods 80.0 80.0 80.0 Lactose 213.5 189.5 139.5 Steary Magnesium phosphate 0.5 0.5 0.5 Compound of formula (I), cellulose, laminated Mix cutose and some cornstarch and make 10% cornstarch paste. and granulate. The resulting granules were sieved, dried, and the remaining corn starch and starch Mix with magnesium phosphate.

Then, the obtained granules were added at a rate of 1. hg, 2.0mg, 25.0mg, 2 Compressed into tablets containing 6°0mg, 50.0mg and 100a+g of active compound Rib Compounds of formula (I) 1-1oolIg Citric acid hydrate Q, 75mg Sodium phosphate 4.5 parts g Sodium chloride 91g Water for injection up to b+1 Dissolve sodium phosphate, citric acid-hydrate and sodium chloride in one part water.

The compound of formula (1) is dissolved or suspended in the solution to adjust the volume.

Compound of formula (1) 1-10g Emulsifying wax 30g Liquid paraffin 20g White soft paraffin up to ioo g Heat white soft paraffin until melted. Mixing liquid paraffin and emulsifying wax Stir until combined and dissolved. Add the compound of formula (1) and stir until dispersed Continue.

The mixture is then cooled to a solid.

Copy and translation of written amendment) submission address (Article 184-8 of the Patent Law) October 1994 13th

Claims (23)

[Claims] 1. Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, n is 1, 2 or 3; X represents O or S; Y represents a hydrocarbon chain of 1, 2, 3 or 4 carbon atoms which may be optionally substituted with oxo eagle, I; R1 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo, Cyano, nitro, trifluoromethyl, trimethylsilyl, -OR■, SR■, SOR■, SO2R■, -NRaRb, -NR■CORb, -NR■CO2Rb , -CO2R■ or -CONR■Rb with 1, 2 or 3 groups selected from represents optionally substituted phenyl; R2 is selected from phenyl and naphthyl; Aryl; imidazolyl, thienyl, furyl, pyridyl, thiazolyl, tet Heteroaryl selected from lazolyl and quinolyl; benzhydryl; and each aryl and heteroaryl moiety is C1-6 alkyl, C may be substituted with 1-6 alkoxy, halo or trifluoromethyl; R4 and R 5 may be at any available carbon atom position in the azacyclic ring. , and each independently H, halo, C1-6 alkyl, oxo, CH2OR■, C Represents O2R■ or CONRaRb; R6 represents an optionally substituted aromatic heterocycle; Ra and Rb are each independently , H, trifluoromethyl, C1-6 alkyl or optionally C1-6 alkyl, phenyl substituted with halo or trifluoromethyl) substance or its salt or prodrug. 2. Formula (IA): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IA) [where n is 1, 2 or 3, Any carbon atom of (CH2)■ may be substituted with R12 and/or R13; X represents O or S; R10 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo , cyano, nitro, trifluoromethyl, trimethylsilyl, -ORc, SRc , SORc, SO2Rc, -NRcRd, -NRcCORd, -NRcCO2R d, -CO2Rc or -CONRcRd. represents optionally substituted phenyl; R11 is selected from phenyl and naphthyl; aryl imidazolyl, thienyl, furyl, pyridyl, thiazolyl, tetra Heteroaryl selected from zolyl and quinolyl; benzhydryl; or ben where each aryl or heteroaryl moiety is C1-6 alkyl , C1-6 alkoxy, halo or trifluoromethyl; R12 and R13 each independently represent H, halo, C1-6 alkyl, oxo, C represents O2Rc or CONRcRd; R14 is an optionally substituted aromatic hetero Represents C1-4 alkyl substituted with a ring and optionally substituted with oxo; Rc and Rd are each independently H, C1-6 alkyl, C1-6 alkyl or Represents phenyl or trifluoromethyl optionally substituted with halo] The compound according to claim 1, or a salt or prodrug thereof. 3. n is 2 or 3; R12 and R13 are each independently H, halo, C1 -6 alkyl, CO2Rc or CONRcRd; R14 is optionally substituted; represents C1-4 alkyl substituted with a 5- or 6-membered aromatic heterocycle; Rc and Rd are each independently H, C1-6 alkyl, phenyl or trifluor 3. A compound according to claim 2 representing olomethyl. 4. 1 in which R1 is selected from C1-4 alkyl, trifluoromethyl and halo; Claims 1 to 3 represent phenyl substituted with more than one group. compound. 5. Claim 1 wherein R2 represents benzhydryl or optionally substituted phenyl. 4. The compound according to any one of et al. 6. R6 is optionally substituted thienyl, furyl, pyridyl, triazolyl, te Torazolyl, thiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl Nil, oxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, ben Any one of claims 1 to 5 representing zoimidazolyl or benzoxazolyl. Compounds described in. 7. R8 represents a substituted or unsubstituted 5- or 6-membered nitrogen-containing aromatic heterocycle; 6. A compound according to any one of claims 1 to 5. 8. R8 is optionally substituted oxazolyl, oxadiazolyl, imidazolyl , thiadiazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl or triazinyl, or C1-6-substituted tetrazolyl. Compounds described in. 9. R8 is unsubstituted triazolyl or triazolyl substituted with oxo or thioxo 9. A compound according to claim 8 representing azolyl. 10. 10. A compound according to any one of claims 1 to 9, wherein n is 3. 11.3-amino-5-[((2R*,3R*)-3-((3,5-bis(tri fluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl ]-1,2,4-oxadiazole: 5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)ph) phenyl)methyloxy)-2-phenylpiperidino)methyl]-3-methyl-1 ,2,4-oxadiazole; (+)-amino-5-[((2S,3S)-3-((3,5-bis(trifluoro) methyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]-1 ,2,4-oxadiazole; 3-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)ph) 2-[phenyl)methyloxy)-2-phenylpiperidino)methyl]pyridine; ((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl ) methyloxy)-2-phenylpiperidino)methyl]pyridine; 2-[((2 R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)methy 5-[( (2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]tetrazole; 2-[(( 2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)methane methyloxy)-2-phenylpiperidino)methyl]-4-methyl-1,3-thia Zor: (2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-1-(2-furoyl)-2-phenylpiperidine; 2-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)ph) 5-[( (2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenylpiperidino)methyl]-3-promo-1,2,4 -oxadiazole; 5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)ph) phenyl)methyloxy)-2-phenylpiberidino)methyl]-3-dimethyla Mino-1,2,4-oxadiazole; (2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenyl-1-(2-thienoyl)piperidine; (2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-phenyl-1-(2-thienyl)methylpiperidine; 5- [((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenylene) methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro- 4-Methyl-3-thioxo-1,2,4-triazole; 3-[((2R*,3 R*)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy )-2-phenylpiperidino)methyl]-1,2,4-triazole; 5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)ph) phenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-dihyde rho-(4H)-3-thioxo-1,2,4-triazole; 5-[((2R*, 3R*)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy c)-2-phenylpiperidino)methyl]-2-methyltetrazole; 5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)ph) phenyl)methyloxy)-2-phenylpiperidino)methyl]-1-methyltet Razol 3-[((2R*,3R*)-3-((3,5-bis(trifluoromethane) methyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]-5-di Methylamino-1,2,4-thiadiazole; 2-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)ph) phenyl)methyloxy)-2-phenylpiveridino)methyl]-4,7-dimethy Rubenzoxazole; 2-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)ph) phenyl)methyloxy)-2-phenylpiperidino)methyl]benzoxazole 4-[((2S,3S)-3-((3,5-bis(trifluoromethyl)fluorocarbon) phenyl)methyloxy)-2-phenylpiperidino)methyl]oxazole; 2 -[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl ) methyloxy)-2-phenylpiperidino)methyl]pyrazine; 4-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenylene) methyloxy)-2-phenylpiperidino)methyl]-2-methyl-1,3 -thiazole; 3-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenylene) methyloxy)-2-phenylpiperidino)methyl]-1,2,4-oxa Diazole; 3-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenylene) methyloxy)-2-phenylpiperidino)methyl]-5-iodo-1,2 ,4-thiadiazole; 3-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenylene) methyloxy)-2-phenylpiperidino)methyl]-1,2,4-thiazidi Azole: 3-[((2S,3S)-3-((3,5-bis(trifluoromethi) phenyl)methyloxy)-2-phenylpiperidino)methyl]-5-meth xy-1,2,4-thiadiazole; 3-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenylene) methyloxy)-2-phenylpiperidino)methyl]-1,2,4-tria 5-[((2S,3S)-3-((3,5-bis(trifluoromethyl ) phenyl)methyloxy)-2-phenylpiperidino)methyl]-2,3-di Hydro-(4H)-3-thioxo-1,2,4-triazole; 2-[((2S ,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy -2-phenylpiperidino)methyl]-1-(p-toluenesulfonyl)yl midazole; 2-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenylene) methyloxy)-2-phenylpiperidino)methyl]imidazole; 4-[ ((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyl 5-[((2 R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl)methy (2-phenylpiperidino)methyl]-2,3-dihydro(4H) -3-oxo-1,2,4-triazole; 5-[((2R*,3R*)-3- ((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylene Nylpiperidino)methyl]-3-(N,N-dimethylamino)-1,2,4-thi Diazole; 5-[((2S,3S)-3-((3,5-bis(trifluoro) methyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]tetra 5-[((2S,3S)-3-((3,5-bis(trifluoromethyl ) phenyl)methyloxy)-2-phenylpiperidino)methyl]-2-methyl Tetrazole; 5-[((2S,3S)-3-((3,5-bis(trifluoro methyl)phenyl)methyloxy)-2-phenylpiperidino)methyl]-1- Methyltetrazole; 3-[((2S,3S)-3-((3,5-bis(trif) fluoromethyl)phenyl)methyloxy)-2-phenylpiperidino)methyl] Pyridazine; 2-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenylene) methyloxy)-2-phenylpiperidino)methyl]-1,3,5-tria 5-[((2S,3S)-3-((3-t-butyl-5-methylphenyl ) methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro-( 4H)-3-oxo-1,2,4-triazole; 2-[((2S,3S)-3-((3,5-dichlorophenyl)methyloxy) -2-phenylpiperidino)methyl]imidazole; 5-[((2S,3S)-3-((3-chloro-5-methylphenyl)methylo xy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3 -oxo-1,2,4-triazole; 5-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenylene) methyloxy)-2-diphenylmethyl)pyrrolidino)methyl]-2,3- Dihydro-(4H)-3-oxo-1,2,4-triazole; 5-[((2R ,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy -2-diphenylmethyl)pyrrolidino)methyl]-2,3-dihydro-(4 H)-3-oxo-1,2,4-triazole; 3-[((2S,3S)-3- ((3,5-dichlorophenyl)methyloxy)-2-diphenylmethyl)pyro lysino)methyl]-1,2,4-triazole; 5-[((2S,3S)-3- ((3-t-butyl-5-chlorophenyl)methyloxy)-2-phenylpipe lysino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4-to Riazole; 5-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenylene) methyloxy)-2-phenylpiperidino)methyl]-2,3-dihydro- (4H)-3-oxo-1,2,4-triazole; 3-[((2S,3S)- 3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2- phenylpiperidino)methyl]-1-methyl-1,2,4-driazole; 3-[((2S,3S)-3-((3,5-bis(trifluoronutyl)phenylene) methyloxy)-2-phenylpiperidino)methyl]-5-phenyl-1, 2,4-oxadiazole; 3-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)ph) phenyl)methyloxy)-2-phenylpiperidino)methyl]-5-thiomethyl -1,2,4-triazole; 5-[((2S,3S)-3-((3,5-dichlorophenyl)methyloxy) -2-phenylpiperidino)methyl-2,3-dihydro-(4H)-3-oxo -1,2,4-triazole; 4-[((2R*,3R*)-3-((3-carbomethoxyphenyl)methylo xy)-2-phenylpiperidino)methyl]pyridine; 4-[((2R*,3R*)-3-((3-carboxamidophenyl)methylo xy)-2-phenylpiperidino)methyl]pyridine; 5-[((2R*,3R*)-3-((2-methoxy-3-nitrophenyl)methyl methyloxy)-2-phenylpiperidino)methyl]-3-methyl-1,2,4- Oxadiazole; 3-amino-5-[((2R*,3R*)-3-((5-amino-2-methoxy phenyl)methyloxy)-2-phenylpiperidino)methyl]-1,2,4- Oxadiazole; 6-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenylene) methyloxy)-2-phenylpiperidino)methyl]uracil; 3-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)ph) phenyl)methyloxy)-2-phenylpiperidino)methyl]-5-carboxa mido-1,2,4-triazole; 3-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)ph) phenyl)methyloxy)-2-phenylpiperidino)methyl]-5-cyano-1 ,2,4-triazole; 3-[((1S)-1-((2S,3S)-3-((3,5-dichlorophenyl ) methyloxy)-2-phenylpiperidino)ethyl]-1,2,4-triazo 3-[(1R)-1-((2S,3S)-3-((3,5-dichlorophene) methyloxy)-2-phenylpiperidino)ethyl]-1,2,4-tri Azole; 3-[((2S,3S)-3-((2,3-dimethylphenyl)methyl (2-phenylpiperidino)methyl]-1,2,4-triazole; 5-[((2S,3S)-3-((2,3-dimethylphenyl)methyloxy) -2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-ox So-1,2,4-triazole; 5-[((2S,3S)-2-phenyl-3-((3-trifluoromethyl)phenyl) phenyl)methyloxy)piperidino)methyl]-2,3-dihydro-(4H)- 3-oxo-1,2,4-triazole; 5-[((2S,3S)-3-((3,4-dichlorophenyl)methyloxy) -2-phenylpiberidino)methyl]-2,3,-dihydro-(4H)-3-o xo-1,2,4-triazole; 5-[((2S,3S)-3-((3-t-butylphenyl)methyloxy)- 2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo -1,2,4-triazole; 5-[((2R*,3R*)-3-((3,5-dimethylphenyl)methyloxy -2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3- Oxo-1,2,4-triazole; (2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyl (oxy)-2-phenyl-1-(3-(1,2,4-triazolyl))piperi (2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl ) methyloxy)-1-(1-oxo-2-pyrid-4-yl)ethyl-2-ph Phenylpiperidine; (2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl)methyl (oxy)-1-(2-oxo-2-pyrid-3-yl)ethyl-2-phenyl piperidine; 3-(1S)-1-((2S,3S)-3-((3,5-bis(trifluoromethane) thyl)phenyl)methyloxy)-2-phenylpiperidino)ethyl]-1,2 ,4-triazole; 3-(1R)-1-((2S,3S)-3-((3,5-bis(trifluoromethane) thyl)phenyl)methyloxy)-2-phecolpiperidino)ethyl]-1,2 ,4-triazole; 5-(1S)-1-((2S,3S)-3-((3,5-bis(trifluoromethane) thyl)phenyl)methyloxy)-2-phenylpiperidino)ethyl]-2,3 -dihydro-(4H)-3-oxo-1,2,4-triazole; 3-[((2 S,3S)-3-((3,5-dichlorophenyl)methyloxy)-2-pheny lupiperidino)methyl]-1,2,4-triazole; 5-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl)ph) phenyl)methyloxy)-2-(3-chlorophenyl)piperidino)methyl]- 2,3-dihydro-(4H)-3-oxo-1,2,4-triazole; 5-[((2S,3S)-3-((3,4-dimethylphenyl)methyloxy) -2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-ox So-1,2,4-triazole; 5-[((2S,3S)-3-((3-i-propoxyphenyl)methyloxy )-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-o xo-1,2,4-triazole; 5-[((2S,3S)-3-((3-fluoro-5-methylphenyl)methyl oxy)-2-phenylpiperidino)methyl]-2,3-dihydro-(4H)- 3-oxo-1,2,4-triazole; 5-[(3-(3R*)-((3,5-bis(trifluoromethyl)phenyl) methyloxy)-2-methyl-2-(2R*)-phenylpiperidino)methyl] -2,3-dihydro-(4H)-3-oxo-1,2,4-triazole; 5-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenylene) methyloxy)-2-(3-fluorophenyl)piperidino)methyl]-2 ,3-dihydro-(4H)-3-oxo-1,2,4-triazole; 3-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenylene) methyloxy)-2-phenylpiperidino)methyl]-1,2,4-tria 2. The compound according to claim 1, and its salts and prodrugs, selected from: 12. A method for producing the compound according to claim 1, comprising: (A) formula (II) ▲Numerical formula, There are scientific formulas, tables, etc. ▼ (II) (In the formula, R1, R2, R4, R5, X and n are As defined in formula (I)), a compound having React with drugs or (B) Compound of formula (III), formula (IV): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼(III) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV) (In the formula, R1, R2, R4, R5, X, Y and n are as defined in formula (I), and R30 is alkyl R31 represents H or an appropriate substituent) and a base. react in the presence of (C) Formula (V): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) (In the formula, R1, R2, R4, R5, X, Y and n are as defined in formula (I)) React with remetal or (D) Formula (VI): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VI) (In the formula, R1, R2, R4, R5, X, Y and n are as defined in formula (I)), a compound having the formula Ha1-C H2C(=O)R60 (where Ha1 represents halo and R60 is H or a suitable (representing a substituent), or (E) Formula (VII): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VII) (In the formula, R1, R2, R4, R5 , X, Y and n are as defined in formula (I)), a compound having the formula R61N A compound having CS (where R61 is H or an appropriate substituent) and a base. react in the presence of (F) The compound of the already defined formula (II), formula (VIII): ▲ mathematical formula, chemical formula, There are tables etc. ▼ (VIII) (In the formula, Y and Hal are already as defined, R18 is H, or is suitable as a substituent of the triazole ring, or is (a group that can be converted into such a group depending on the situation) and the presence of a base. (G) Formula (IX): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IX) (In the formula, R1, R2, R4, R5, X, Y and n are as defined in formula (I)), substituted or unsubstituted or (H) A compound having formula (X) is expressed as formula (XI): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼(X)▲There are mathematical formulas, chemical formulas, tables, etc.▼(XI) (In the formula, R1, R2, R 4, R5, X, Y and n are as defined in formula (I), and R35 and R36 are as defined in formula (I). (each independently represents H or an appropriate substituent) How to be different. 13. Claim 12 In the case of (A) or (F), the base is an alkali metal carbonate. The method described in. 14. In case (A), the suitable reagent for introducing the group Y-R8 is R8-Y-L (where and L is chloro, promo, iodo, methylsulfonate or p-toluenesulfonate. 14. The method according to claim 12 or 13. 15. In case (B), the base must be an alkali metal or an alkali metal hydride. The method according to claim 12. 16. In the case of (C), the alkali metal azide is sodium azide, and the reaction The process according to claim 12, wherein is carried out in N-methylpyrrolidinone as solvent. . 17. In the case of (D), R60 is H or C1-8 alkyl, according to claim 12. Method described. 18. In the case of (E), the base is 1,8-diazabicyclo[5,4,0]unde 13. The method according to claim 12, wherein 7-ene is used. 19. 13. The method according to claim 12, wherein in the case of (F), R18 is methoxy. 20. In the case of (G), the method according to claim 12, wherein the reaction temperature is 80-90°C. Law. 21. In the case of (H), claim 12 in which R35 and R36 each represent H Method described. 22. according to any one of claims 1 to 11 in combination with a pharmaceutically acceptable carrier. Tachykinin antagonist compositions comprising the described compounds. 23. 23. The tachykinin antagonist composition of claim 22, further comprising a bronchodilator.