JPH0772171B2 - N-Substituted-arylalkyl- and -arylalkylene-aminoheterocycles as cardiovascular, antihistamine and antisecretory agents - Google Patents

Description

Description: FIELD OF THE INVENTION The present invention relates to novel N-substituted arylalkyl- and -aryl useful for treating cardiovascular dysfunction, suppressing histamine action in allergy, and suppressing gastric hypersecretion. It relates to alkylenepyrrolidine, piperidine, and homopiperidine.

(Prior Art) US Pat. No. 3,956,296 and its divisional application No. 4,0
32,642 discloses related compounds, some of which are included in the general formulas below.

In the above formula, Ar is a phenyl group, a p-fluorphenyl group or a m-trifluorophenyl group; R is a phenyl group,
is a p-fluorphenyl group or a cyclohexyl group; A is a hydrogen atom or a hydroxyl group, and these compounds are used as anti-inflammatory agents, sedatives and tranquilizers, and pharmaceutical compositions related thereto. Compounds having this structure are within the scope of the novel therapeutic methods of the invention,
It is excluded from the structural formulas representing new compounds.

U.S. Pat. No. 3,922,276 discloses compounds, including those within the general formula below.

In the formula, Ar is a phenyl group or a p-fluorphenyl group, R is a phenyl group, a p-fluorphenyl group, a m-trifluorophenyl group or a cyclohexyl group,
These compounds are used as anti-inflammatory and tranquilizers, and their related pharmaceutical compositions. Compounds of this structure are included within the scope of the novel therapeutic methods of the invention, but excluded from the formulas representing novel compounds.

U.S. Pat. No. 4,163,790 discloses compounds included in the structural formulas below.

In the formula, Ar and R are a phenyl group and a p-fluorophenyl group; Z is a hydrogen atom, an acetyl group, a p-fluorobenzoylpropyl group, a carbamoyl group, an N-methylcarbamoyl group, an N, N-dimethylcarbamoyl group. , A phenylcarbamoyl group, or N- (ω-morpholinoethyl)
A carbamoyl group; A is a hydrogen atom, a hydroxyl group,
Alternatively, it forms a double bond as indicated by the dotted line.
These compounds showed an effect of increasing coronary blood flow. But,
Although these compounds are substituted at the 4-position of piperidine and are also shown in the other above-mentioned specifications, the substitution at the 1-position of the piperidine group is essentially different in structure from the compound of the present invention, It is not included in the general or novel compounds of the present invention for use in various therapeutic methods.

The following formula 1-benzyl- (α, α-diphenyl) -4-benzilidinepiperidine is shown in German Patent Publication 2,800,919 as having anticonvulsant and vasodilatory effects. Similar formula 1-benzyl- (α, α-diphenyl) -4-benzilidine piperidines are shown in U.S. Pat. No. 4,035,372 as having a vasodilatory action. These compounds are excluded from the present invention by proviso.

General formula 1-benzyl- (α, α-diphenyl) -4-benzylpiperidines having antihistamine activity are shown in U.S. Pat. No. 3,965,257 as having antihistamine activity. These compounds are ketones and are different from the ethers used in the method of the invention.

General formula 4- (diphenylmethylene) 1-benzylpiperidines having hemodynamic, antiarrhythmic and antihistamine activity of are described in US Pat. No. 3,759,928. These are excluded from the invention by proviso.

U.S. Pat. No. 3,984,557 discloses compounds within the general formula:

In the formula, R is a lower alkyl group, a lower cycloalkyl group or a phenyl lower alkyl group, Y is a carbamoyl group,
It is a cyano group or a hydrogen atom, and these compounds are used as antiarrhythmic drugs. In the compounds of the invention:
The group at the 1-position of the cycloalkylamino moiety has an aryloxy group, an arylamino group or an aryl group (excluding phenyl group) on the alkyl chain.

Certain compounds of formula I, wherein (B) _z is limited to oxygen,
A is a hydrogen atom, a hydroxyl group, a cyano group, or forms a double bond).
It was made on December 20, 2013. The specification is incorporated herein by reference.

(Constitution of the Invention) The present invention relates to a novel compound which can be used for the treatment of cardiovascular disorders in animals and humans and can be used as an antihistamine and a gastric secretion inhibitor. The novel compound of the present invention has the following formula [In the Formula, p is 0, 1 or 2; A is a hydrogen atom, -OH, -C≡N or In it; m is Less than six; Q is -CH- or -CH ₂ -; d and n are selected from 0 or 1, the dotted line can be formed consistent with the valence of the carbon atoms Represents a volatile double bond; Ar and R are R may be a cycloalkyl group; D is selected from the group consisting of: Or selected from the group consisting of Ar (CH ₂ ) _1-4 −; X, Y and Z in Ar and R are a hydrogen atom, a lower alkyl group, a halogen atom, —NO ₂ , —O— (lower alkyl group), Selected from the group consisting of —CF ₃ or —C≡N; X, Y and Z in D are a hydrogen atom, a lower alkyl group,
Halogen ^{_{atom, -NO 2, -O-R 1}} , -CF _3, -C≡N, _{^{-N (R 1) 2, -C}} (O) OR 1, -SO 2 R 2, -SR 2, -S
(O) R ² , −CH ₂ COOM, Or B is O, S, (Wherein R ³ represents a hydrogen atom or a lower alkyl group); z is 1 or 0, provided that D is a phenyl group or a substituted phenyl group and at the same time one of the following occurs: That is, (A) _d is a hydrogen atom, or (A) _d
Is a cyano group, (A) _d is an aminocarbonyl group, or a double bond is formed between the α-carbon atom and the carbon atom of the central heterocyclic amine ring, z N is 0 and cannot be 0 at the same time; R ¹ is selected from a hydrogen atom, a lower alkyl group, a phenyl group or a phenyl lower alkyl group; R ² is a lower alkyl group, a phenyl group or a phenyl lower alkyl group Selected from a group; M is a pharmaceutically acceptable metal ion; provided that n is 0 and (A) _d is a hydrogen atom or a hydroxyl group, or d is 0 and α carbon atom (B) _z cannot represent an oxygen atom at the same time when D is a phenyl group or a substituted phenyl group when a double bond is formed with the carbon atom of the saturated central heterocyclic amine) Selected from the group Compound (where, alpha, in α- diphenyl-1-benzyl-4-piperidinemethanol, and the above equation, n is 0 or 1, Q is -CH- or -CH ₂ - and A, D is pyridyl (Excluding compounds), and pharmaceutically acceptable salts thereof, including their acid addition salts, quaternary salts, hydrates and alcoholates.

In the formulas and throughout the specification and claims, upon detailed definition of each symbol, each term has the following meaning.

The term "lower alkyl", as used herein, unless otherwise indicated, includes straight and branched chain groups of up to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, Examples thereof include t-butyl, amyl, isoamyl, hexyl, heptyl and octyl groups. The term "lower alkoxy" has the formula-
Having O-lower alkyl.

The term "cycloalkyl" as used herein primarily includes cyclic alkyl groups containing from 3 to 7 carbon atoms,
Examples include groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and methylcyclohexyl.

The term "halo" or "halogen" as used herein includes fluorine, chlorine, bromine and iodine unless otherwise indicated.

The term "central heterocyclic amine ring" refers to in formula I Means the portion represented by, where the dotted line may represent a double bond. The term "saturated central heterocyclic amine ring" means the above groups which do not contain double bonds.

The term "phenyl lower alkyl" includes a phenyl group having a hydrocarbon chain (eg, the lower alkyl groups above) attached thereto, wherein the phenyl group is a non-reactive or non-interfering group such as halogen, lower alkyl, It may be substituted with a group such as lower alkoxy.

The term "pharmaceutically acceptable salt" includes acid addition salts of compounds of formula I which are physiologically compatible in warm-blooded animals.
Includes hydrates, alcoholates and quaternary salts. Acid addition salts may be formed with either strong or weak acids. Representative examples of strong acids are hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. Typical examples of weak acids are fumaric acid, maleic acid, mandelic acid, tartaric acid, citric acid, oxalic acid, succinic acid, hexamic acid and the like. Suitable quaternary salts include alkyl halide salts and lower alkyl sulfate salts.

It has been found that the compounds of formula I are calcium antagonists and can be used as coronary vasodilators, antihypertensive agents, antiarrhythmic agents, antiallergic agents, antihistamines and antisecretory agents. As mentioned above, (B) _z is limited to oxygen and A is a hydrogen atom, a hydroxyl group, a cyano group, or a specific compound of formula I forming a double bond may be used as an antiallergic agent. The intended use was filed on December 20, 1985 (US Patent Application No. 811,799). The specification is incorporated herein by reference to show that these compounds can be used as antiallergic agents.

The pharmacological test method used for the screening which supports the therapeutic method of the present invention other than the antiallergic therapeutic method will be described later.

The compounds of formula I are described in U.S. Pat. Nos. 3,922,276 and 4,032,6.
No. 42, can be prepared according to the methods described in the respective specifications and according to the reaction schemes I, II, III, IV and V in the preparation of intermediates described below, and the description of Preparation Examples and Examples. One of the general methods used is shown schematically in the scheme of Reaction Scheme I. This reaction is carried out in an alcohol solvent (preferably refluxing butanol),
Alternatively, it can be carried out in dimethylformamide or dimethoxyethane in the presence of an acid acceptor (eg alkali metal carbonate), preferably with a potassium iodide catalyst. The reaction time is from several hours to 24 hours, depending on the reactivity of the halide and the temperature. The temperature is 80-125 ℃, the product is usually partitioned in solvent such as methylene chloride, chloroform, benzene and weak basic solution, washed, dried, concentrated the organic layer to free base, It is then isolated, if desired, by converting it into the acid addition salt by conventional methods.

Alternative B is shown by the formula in Reaction Scheme II. The reaction can be carried out at room temperature for several hours in a suitable solvent (eg tetrahydrofuran). A representative example of the preparation and isolation of the free base and salt is shown in Example 4.

Alternative C is shown by the formula in Reaction Scheme III. For example chloride
Mesylation or tosylation with mesyl or tosyl chloride
Is an acid acceptor such as a tertiary amine (eg triethyl
(Amine) with cooling. Mesyl compound
Or tosyl compound and DO M The final reaction with is suitable organic
It is carried out in a solvent, and the free base is washed with a conventional method, for example, by washing.
Purification, extraction with acid solutions and organic solvents, and solvent
Isolated by evaporation. The salt can be produced as described above.

Alternative D is shown in the formula in Reaction Scheme IV. Do the halo compound M
A suitable solvent for the reaction with compounds is dimethyl sulfoxide.
It is a side, and the optimum temperature is about 25 ° C. Halo compoundExcess when reacting with compoundsThe compound can be used as a solvent,
The temperature is appropriate.

Alternative Method E is shown by the formula in Reaction Scheme V. This method is limited to the preparation of certain derivatives (eg where D is a 2-pyridinyl group or a 2-quinolinyl group). Dimethyl sulfoxide is a suitable solvent and 60 ° C is a suitable temperature for the reaction.

To prepare acid addition salts, the free base is reacted with a calculated amount of an organic or inorganic acid in a water miscible solvent (eg ethanol or isopropanol) and isolated by concentration and / or cooling. Is reacted with an excess of acid in a water-immiscible solvent (eg diethyl ether or isopropyl ether) to directly separate the desired salt. Examples of this type of organic salt include oxalic acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, pamoic acid, succinic acid, methanesulfonic acid, acetic acid, propionic acid, tartaric acid, citric acid, lactic acid, It is formed using malic acid, citraconic acid, itaconic acid, hexamic acid, p-aminobenzoic acid, glutamic acid, stearic acid and the like. Examples of the above inorganic salts are formed using hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid.

If desired, the acid addition salt is partitioned between an organic solvent (eg methylene chloride) and a weakly basic aqueous solution (eg sodium bicarbonate), the methylene chloride layer is separated and this is evaporated to regenerate the free base. be able to.

The precursors (intermediate chemistries) used in the synthesis of compounds of Formula I are prepared by a variety of methods, as shown by the formulas 1-10 below. These are also applicable to pyrrolidinyl derivatives and homopiperidinyl derivatives. U.S. Patent No. 3,
See also 922,276 and 3,956,296.

A method for producing a specific starting material in which D is a phenyl group substituted with a hydroxyl group is represented by the following formula.

The preparation of other hydroxyphenyl intermediates and compounds is represented by the formula:

The preparation of a particular substituted phenolic starting material is shown by the formula:

Regarding the production of intermediate chemicals, the following Production Examples 1 to
Shown in 84. Examples 1-147 show synthetic methods for making compounds of Formula I. However, the scope of the present invention is not limited by the manufacturing method described here.

Preparation 1 4-Diphenylmethylenepiperidine A solution of 7.0 g of 1-acetyl-4-diphenylhydroxymethylpiperidine in 30 ml of anhydrous alcohol and 76 ml of concentrated hydrochloric acid is heated under reflux for 7 hours, cooled and cooled to 50% sodium hydroxide. Made basic. Extract the separated oil with benzene,
The extracts were combined and washed with water. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure. The residual oil crystallized on cooling and was recrystallized twice from petroleum ether to give 4.0 g (73.0%) of white crystals. Melting point 85-86 ° C.

Elemental analysis: Calculated value (C ₁₈ H ₁₉ N): C, 86.70; H, 7.68; N, 5.62 Measured value: C, 86.70; H, 7.83; N, 5.73 Production Example 2 [α, α-bis (p- Fluorophenyl)]-4-piperidinemethanol hydrochloride / hydrate [1: 1: 0.5] This compound (melting point 243 to 243.5 ° C.) is described in US Pat. No. 4,032,64
Prepared from the Grignard reagent formed from p-fluorobromobenzene and 1-acetyl-4- (p-fluorobenzoyl) piperidine by the method described in Preparation Example 1 of No. 2, followed by hydrolysis and salt formation. Was changed to.

Production Example 3 1- (Phenylmethyl) -4-piperidinecarboxylic acid ethyl ester hydrochloride [1: 1] 100 g ethyl isonipecotate in absolute ethanol 1
A mixture of (0.637 mol), benzyl chloride 80.64 g (0.64 mol) and sodium carbonate 67.84 g (0.64 mol) was refluxed for 8 hours and then stirred at room temperature for 10 hours. The solvent was removed in vacuo and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride phase was dried over magnesium sulfate and the solvent removed in vacuo to give the free base of the title compound as a liquid. The free base was converted to the hydrochloride salt and the salt was recrystallized from ethanol-ether to give 89.33 g (49.7%) of a white crystalline solid. Melting point 154-155 ° C.

Calcd _{(C 15 H 22 NO 2 Cl} ): C, 63.48; H, 7.81,; N, 4.94 Found: C, 63.07; H, 7.82 ; N, 4.91 Preparation 4 alpha, alpha-bis - (4-Fluorophenyl) -1- (phenylmethyl) -4-piperidinemethanol 6.08 g (0.25 mol) of magnesium turnings in 600 ml of dry tetrahydrofuran and 1 crystal of iodine under nitrogen atmosphere in p of 125 ml of tetrahydrofuran. A solution of bromfluorobenzene was added dropwise. The reaction temperature was kept below 10 ° C by cooling in an ice-methanol bath. The mixture was stirred at room temperature for 1.5 hours. A solution of 24.7 g (0.10 mol) of 1- (phenylmethyl) -4-piperidinecarboxylic acid ethyl ester hydrochloride in tetrahydrofuran was added and the mixture was stirred at room temperature for 17 hours. The reaction was poured into an aqueous solution of ammonium chloride in ice and the resulting solution was extracted with methylene chloride. The methylene chloride solution was extracted with dilute sodium hydroxide and magnesium sulfate. The solvent was removed in vacuo to give an oil. This was crystallized from ether-hexane to give 19.87 g (51%) of the title compound. Melting point 11
3 to 115 ° C.

Elemental analysis: Calculated value (C ₂₅ H ₂₅ NOF ₂ ): C, 76.31; H, 6.40; N, 3.56 Actual value: C, 76.24; H, 6.38; N, 3.50 Production Example 5 [α, α-bis (p -Fluorophenyl)]-4-piperidinemethanol A solution of 31.2 g (0.079 mol) of α, α-bis- (4-fluorphenyl) -1- (phenylmethyl) -4-piperidinemethanol in 400 ml of absolute ethanol was added to 50 psi. (3.5kg
/ cm ² ) and 70 ° C. with 5% palladium on carbon over the weekend. The mixture was passed and the liquid was concentrated under reduced pressure to give a gum as a residue. When methylene chloride was added to the residue, a gum crystallized. The mixture was diluted with petroleum ether, the solid was collected, washed with petroleum ether and dried to give a white solid 22g (92%). This was recrystallized from isopropyl ether-2-propanol. Melting point 159.5-160.5 ° C.

Elemental analysis: Calculated value (C ₁₈ H ₁₉ F ₂ NO): C, 71.27; H, 6.31; N, 4.62 Found: C, 70.93; H, 67.1; N, 4.38 Production Example 6 1- (phenylsulfonyl) -4-Piperidinecarboxylic acid ethyl ester 10.1 g of ethyl isonipecotic acid in 300 ml of pyridine (0.06
To a solution of 42 mol) (cooled in an ice bath) was added 13.2 g (0.075 mol) benzenesulfonyl chloride. Mix the mixture at room temperature 2
Stir for hours and remove the solvent in vacuo. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate and the solvent removed in vacuo to give a solid. This was recrystallized from ethanol-ether to obtain 4.59 g (24.1%) of a crystalline solid. Melting point 85
～86.5 ° C. Elemental analysis: Calculated _{(C 14 H 19 NO 4 S} ): C, 56.55; H, 6.44; N, 4.71 Found: C, 56.53; H, 6.55 ; N, in 4.67 other manufacturing, the double 100 g of ethyl pecotate (0.634
Mol) and 130.4 g (0.74 mol) of benzenesulfonyl chloride as described above. The reaction yielded the title product in 78.1% yield.

Production Example 7 α, α-bis (4-fluorphenyl) -1- (phenylsulfonyl) -4-piperidinemethanol Tetrahydrofuran (dried on Molecular Sieve 5A)
33.78 g (1.39 mol) of magnesium trimming pieces in 1
243.25 g of p-bromofluorbenzene in 150 ml of tetrahydrofuran in a suspension of (in an ice bath cooled under N ₂ atmosphere).
A solution of (1.39 mol) was added dropwise. After the addition was complete, the mixture was stirred for 2 hours. To this mixture was added 103 g of 1- (phenylsulfonyl) -4-piperidinecarboxylic acid ethyl ester.
(0.346 mol) was added as a solid and the solution was stirred at ambient temperature for 5 hours. The reaction was poured into an aqueous solution of ammonium chloride in ice. Each set was separated and the organic phase was freed from the solvent in vacuo. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate and concentrated in vacuo to a volume of 1. The title compound was obtained by adding hexane, cooling, recrystallizing the precipitate from ethyl acetate and hexane, and drying the solid in a high vacuum at 130 ° C. for 45 minutes. At this point the product had partially melted. Melting point 142.5-144 ° C.

Elemental analysis: Calculated value (C ₂₄ H ₂₃ NO ₃ SF ₂ ): C, 65.00; H, 5.23; N, 3.16 Found: C, 65.21; H, 5.30; N, 3.10 Production Example 8 4- [bis (4 -Fluorophenyl) methylene] -1-
(Phenylsulfonyl) piperidine α, α-bis (4-fluorphenyl) -1- (phenylsulfonyl) -4- in 100 ml acetic acid and 20 ml 2M sulfuric acid
A solution of 5.23 g (0.0118 mol) of piperidinemethanol Reflux, then pour onto ice. The mixture was basified with 50% sodium hydroxide and the basic mixture was extracted with methylene chloride. The methylene chloride solution was dried (anhydrous sodium sulfate) and the solvent removed in vacuo. The residue was recrystallized from ether-hexane to give 3.23 g of white crystalline solid (6
4.4%). Melting point 90-92.5 ° C.

Calcd _{(C 10 H 21 NO 2 SF} 2): C, 67.75; H, 4.98; N, 3.29 Found: C, 67.73; H, 5.00 ; N, 3.21 Preparation 9 4- [bis (4 -Fluorophenyl) methylene] piperidine hydrobromide [1: 1] 48% hydrobromic acid α, α- [bis (4-fluorophenyl)]-1- (phenylsulfonyl)-in 700 ml. A mixture of 164 g (0.342 mol) of 4-piperidinemethanol and 80 g (0.85 mol) of phenol was refluxed for 7 hours and then stirred at room temperature for 9 hours. The hydrobromic acid solution was decanted from the gum at the bottom of the reaction flask. The gum was triturated with about 1 ether to produce a tan solid. The solid was washed several times with ether and dried under high vacuum to give 9.13 g (73%) of slightly impure title product.
%) Was obtained. Melting point 211-215 [deg.] C. A small sample of this solid was recrystallized from methanol to give a pure crystalline solid by elemental analysis. Melting point 216-218 [deg.] C.

Elemental analysis: Calculated value (C ₁₈ H ₁₈ NBrF ₂ ): C, 59.03; H, 4.95; N, 3.82 Found: C, 58.96; H, 4.98; N, 3.76 Production Example 10 4- [Bis (4-ful Orphenyl) methyl] piperidine fumarate hydrate [1: 1: 0.5] 30.6 g phosphorus (0.99 mol) and iodine in 90 ml glacial acetic acid 15.
1 g (0.059 mol) of the mixture was stirred at room temperature for 20 minutes. Water 6
ml, methanesulfonic acid 70 ml, 4- [bis (4-fluorophenyl) methylene] piperidine 56.19 g (0.197 mol)
And 110 ml of glacial acetic acid were added and the mixture was refluxed for 7 hours. The solvent was removed in vacuo and the resulting viscous liquid was poured on ice. The ice mixture was made basic with 50% sodium hydroxide and the basic suspension was extracted with methylene chloride. The methylene chloride solution was extracted with aqueous sodium thiosulfate solution, dried over anhydrous sodium sulfate, and the solution was filtered through Celite. The solvent was removed in vacuo to give a rubber. This gum was dissolved in 400 ml hot methanol and 4.25 g of an unknown tan solid was taken from the warm solution.
Fumaric acid (22 g, 0.190 mol) was added to the methanol solution, followed by ether. A white precipitate was collected to give 22.55 g (32.3%) of a crystalline solid. Melting point 208-209 ° C.

Elemental analysis: Calculated value (C ₂₀ H ₂₂ NO _2.5 F ₂ ): C, 67.78; H, 6.26; N, 3.95 Found: C, 67.86; H, 6.12; N, 3.81 Production Example 11 4- [α- ( p-Fluorophenyl) -α-phenylmethyl] piperidine hydrochloride [1: 1] This compound is prepared by converting α- (p-fluorphenyl) benzilidinepiperidine over a palladium charcoal catalyst as described in US Pat. No. 4,032,642. It was prepared by hydrogenation. Melting point 81-82 ° C.

Calcd _{(C 18 H 21 ClFN):} C, 70.69; H, 6.92; N, 4.58 Found: C, 70.69; H, 6.93 ; N, 4.52 Preparation 12 1- [4- (3-chloro Propoxy) -3-methoxyphenyl] ethanone 1-bromo-3-chloropropane 15.15 kg (96.26 mol)
To a mixture of water and 25 l of water (heated to 86 ° C.) was added a solution of 3.93 kg (48.6 mol) of 50% sodium hydroxide and 8 kg (48.13 mol) of acetovanillone in 89 l of water over 2.5 hours. After the addition was complete, the mixture was heated to 80-85 ° C for 2-5 hours. The mixture was cooled and extracted twice with 49 kg each of toluene. The extracts were combined and washed once with 1.9 kg of 50% sodium hydroxide (diluted to 5 gallons (19 l)) and 5 gallons of water (1
9 l) washed once. The toluene layer was dried with 3 pounds (1.4 kg) of anhydrous sodium sulfate and diluted under reduced pressure. The residue was heated to reflux in 15 gallons (57 l) of diisopropyl ether, passed and the solution cooled. The title compound which crystallized was obtained by filtration and the liquor was collected at 25% of its original volume.
4.2kg including the compound obtained by concentrating to
(36%) 3.4 kg of recovered acetovanillone
It was. The product was recrystallized twice from cyclohexane and twice from ligroin. Melting point 57.8-58.5 ° C.

Elemental analysis: Calculated value (C ₁₂ H ₁₅ ClO ₃ ): C, 59.39; H, 6.23 Found value: C, 59.07; H, 6.22 Production Example 13 1- (3-phenoxypropyl) -4-piperidinecarboxylic acid Ethyl ester oxalate (1: 1) Ethyl isonipecotate (35.
5 g, 0.226 mol), 3-phenoxy-1-bromopropane (51.6 g, 0.24 mol) and sodium carbonate (25.4 g, 0.24 mol)
(Mol) was refluxed for 16 hours. The solvent was removed in vacuo and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The solution was dried over anhydrous sodium sulfate and the solvent removed in vacuo to give a liquid. This liquid was dissolved in absolute ethanol and a solution of oxalic acid (about 0.23 mol) in absolute ethanol was added. 73.43 g (87.7%) of product precipitated as a white crystalline solid. Melting point 180-181.5 ° C.

Elemental analysis: Calculated value (C ₁₉ H ₂₇ NO ₇ ): C, 59.83; H, 7.14; N, 3.67 Actual value: C, 59.76; H, 7.17; N, 3.64 Production Example 14 4- [Bis (4-ful Orthophenyl) methylene] -1-
(Phenylmethyl) -piperidine maleate [1: 1] α, α-bis (4-fluorphenyl) -1- (phenylmethyl) -4-piperidinemethanol (5.09 g, 0.013 mol) in 200 ml of acetic acid and 10 ml of 2M sulfuric acid. The mixture was refluxed for 2 hours. The solvent was removed in vacuo and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate and the solvent removed in vacuo to give the free base of the title compound as a solid. The free base was dissolved in methanol-diethyl ether and maleic acid (excess) was added. The product, 5.24 g (82.1%), precipitated as a white crystalline solid. Melting point 180-181.5 ° C.

Elemental analysis: Calculated value (C ₂₉ H ₂₇ NF ₂ O ₄ ): C, 70.86; H, 5.54; N, 2.85 Actual value: C, 70.80; H, 5.45; N, 2.79 Production Example 15 α, α-bis ( 4-Fluorophenyl) -4-pyridinemethanol 4-bromofluorobenzene (66.6 g, 0.381 mol) and magnesium (9.13 g, 0.381 mol) in tetrahydrofuran.
(Mole) to prepare a Grignard reagent (ice bath). This Grignard reagent at room temperature Stir and transfer to dropping funnel under N ₂ . This solution was added dropwise to a tetrahydrofuran solution of ethyl isonicotinate (25.0 g, 0.165 mol) (cooling with an ice bath). The reaction mixture was stirred at room temperature for 3 hours and poured onto ice containing ammonium chloride (28 g, 0.5 mol). The mixture was left overnight. The reaction mixture was diluted with water to 3 l and extracted with chloroform. The chloroform layer was back extracted with dilute sodium hydroxide. Chloroform was removed to give a gummy brown solid. The brown solid was triturated with methanol-diethyl ether (10-120 v / v) and placed in the refrigerator freezer. Separate solids and dry in vacuo at 80 ° C. overnight to give white crystalline product 1
Obtained 1.86 g (24%). Melting point 185-189 [deg.] C.

Calcd _{(C 18 H 13 NOF 2)} : C, 72.72; H, 4.41; N, 4.71 Found: C, 72.76; H, 4.39 ; N, 4.67 Preparation 16 4- [bis (4-full Orphenyl) methyl] -1-
(Phenylmethyl) piperidine fumarate [1: 1] 4.3 g (0.139 mol) phosphorus in 60 ml glacial acetic acid, 44 g (0.196 mol) 57% aqueous hydrogen iodide solution, and 4- [bis (4-fluorophenyl) methylene ] -1- (phenylmethyl)
A mixture of 4.15 g (0.0106 mol) piperidine was refluxed for 1 hour. The mixture was poured onto ice and made basic with 50% sodium hydroxide. The aqueous mixture was extracted with methylene chloride. The methylene chloride solution was extracted with aqueous sodium sulfite solution and dried over magnesium sulfate. The solvent was removed in vacuo to give 3.89 g (89%) of the free base of the title compound.
The free base was changed to the fumarate salt and the salt was recrystallized from methanol-ether to give a white solid 3.62 g (69.3%). Melting point 201-202 ° C.

Elemental analysis: Calculated value (C ₂₉ H ₂₉ NO ₄ F ₂ ): C, 70.57; H, 5.92; N, 2.84 Actual value: C, 70.69: H, 5.95; N, 2.81 Production Example 17 4- (2-chloro) Ethoxy) benzoic acid ethyl ester 71.7 g of 1-bromo-2-chloroethane in 200 ml of acetone
(0.5 mol), ethyl p-hydroxybenzoate 83.1 g (0.
A mixture of 5 mol) and 69.1 g (0.5 mol) of potassium carbonate was heated under reflux for 40 hours. The solid was removed and the liquid evaporated under reduced pressure leaving a semi-solid residue. The residue was triturated with 200 ml of 5% sodium hydroxide solution and passed. Wash overcake with water (100 ml), dry to solid 42.
4 g (37.2%) was obtained. A sample was recrystallized from benzene-petroleum ether (30-60 ° C) to give a white solid. Melting point 74
~ 76 ° C.

Elemental analysis: Calculated value (C ₁₁ H ₁₃ ClO ₃ ): C, 57.78; H, 5.73 Actual value: C, 57.87; H, 5.82 The pH of the solution was adjusted to 2 with concentrated hydrochloric acid. The resulting solid was collected, washed with water (100 ml) and dried to obtain 44.4 g of ethyl p-hydroxybenzoate.

Production Example 18 1- [4- (2-Chloroethoxy) -3-methoxyphenyl] ethanone To a solution of 12.7 g (0.55 mol) of sodium metal in 750 ml of anhydrous ethanol was added 83.1 g (0.5 mol) of acetovanillone to form a slurry. Got This slurry was then added to 107.6 g of 1-bromo-2-chloroethane (0.7
(5 mol) was added dropwise over 3 hours under reflux.
The slurry was rinsed into the reaction mixture with an additional 250 ml of ethanol. The mixture was heated at reflux overnight and then concentrated under reduced pressure to give a solid as a residue. The solid was partitioned between benzene 1 and water 1. Benzene water layer
Extract with 500 ml and combine the organic layers in turn with 200 ml of 5% sodium hydroxide solution three times, water once and brine once.
Washed twice. The benzene solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil. It gradually crystallized. This solid was triturated with petroleum ether, taken,
Recrystallized from 2-propanol to give an off-white solid 48.5 g (4
2%). An analytical sample was prepared from isopropyl ether. Melting point 69-71 ° C.

Elemental analysis: Calculated value (C ₁₁ H ₁₃ ClO ₃ ): C, 57.78; H, 5.73 Measured value: C, 57.55; H, 5.74 Production Example 19 1- [4- (4-Brombutoxy) -3-methoxyphen Enyl] ethanone To a warm solution of 12.7 g (0.55 mol) sodium metal in 500 ml absolute ethanol was added a slurry of 83.1 g (0.5 mol) acetovanillone in 250 ml absolute ethanol. All the solid dissolved and then the solid precipitated. The mixture was stirred at ambient temperature for 1 hour and then added over 3 hours under reflux to a solution of 177 g (0.82 mol) of 1,4-dibromobutane in 500 ml of absolute ethanol. After the addition was complete, the mixture was heated to reflux overnight. The mixture was concentrated under reduced pressure and the residue was benzene 1.
Partitioned between 5 1 and 1 water. The mixture was passed to remove undesired insoluble material. Separate each layer of liquid,
The organic layer is 4 times with 300 ml of 5% sodium hydroxide solution,
Wash once with water, once with brine, dry over anhydrous sodium sulfate and concentrate under reduced pressure to give 138 g of a gummy solid as a residue. This solid was purified by column chromatography on 1 kg of silica gel eluting with 2% ethyl acetate in benzene to give 69.6 g (46%) of the title compound as an off-white solid. The solid was recrystallized from isopropyl ether. Melting point 52-54 ° C.

Elemental analysis: Calculated value (C ₁₃ H ₁₇ BrO ₃ ): C, 51.84; H, 5.69 Measured value: C, 52.03; H, 5.76 Production Example 20 4- (diphenylmethyl) piperidine diphenyl-4-pyridylmethanol 99 g (0.379 mol) ), Concentrated hydrochloric acid 50 ml, 57% hydroiodic acid 200 ml, and glacial acetic acid 200 ml. After refluxing, the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured onto ice and made basic with 50% sodium hydroxide. Aqueous sodium thiosulfate solution was added and the mixture was extracted with methylene chloride. The methylene chloride solution was dried over magnesium sulfate and the solvent removed in vacuo. Methylene chloride
Recrystallize from a mixture of ether-hexane and collect a crystalline solid twice. 1st collection: 40.87g (44.0%),
Melting point 124-126 ° C; Second crop: 25.38 g (27.3%), melting point 123-125 ° C. The analysis of the mixture of the 1st and 2nd collections was as follows.

Calcd _{(C 18 H 15 N):} C, 88.13; H, 6.16; N, 5.71 Found: C, 87.67; H, 6.01 ; N, 5.56 Preparation 21 1- (3-chloro-propoxy) - A solution of 20.0 g (0.5 mol) of sodium hydroxide in 300 ml of 4-methoxybenzene water and 62.1 g (0.5 mol) of p-methoxyphenol in 300 ml of dioxane were stirred at room temperature for 1 hour. 472.35 g of 1-chloro-3-bromopropane in 100 ml of dioxane
(3.0 mol) was added and the reaction mixture was stirred overnight at 80 ° C. The lower layer was separated and the aqueous layer was extracted with hexane. The lower and hexane layers were combined and dried and the solvent removed in vacuo. The residue was dissolved in chloroform, extracted with 5% sodium hydroxide, chloroform was removed by evaporation,
A yellow oil was obtained. A 10 g sample of the oil was column chromatographed on silica gel using an eluent system consisting of hexane-methylene chloride-methanol. This gives 9.64g
A pure clear oil (79.3% based on the aliquot used) was obtained.

Calcd _{(C 10 H 13 O 2 Cl} ): C, 59.86 H, 6.53 Found: C, 59.39; H, 6.56 Preparation 22 1- [4- (3-chloro-propoxy) phenyl] ethanone in dioxane 200ml 68.08 g (0.5 mol) of p-hydroxyacetophenone and 20.0 g of sodium hydroxide in 400 ml of water
The sodium salt of p-hydroxyacetophenone was prepared from (0.5 mol). The reaction mixture was stirred at room temperature for 3/4 hours. Then chlorobromopropane 472.35g (3.0mol)
Was added with 200 ml dioxane and the mixture was heated at 80-90 ° C. with stirring overnight. The mixture was diluted with water to 41 and the aqueous phase was extracted with hexane and chloroform. These were combined and back-extracted with 5% sodium hydroxide. The solvent was removed by heating in vacuum. A 10 g sample of the oil was column chromatographed on silica gel with hexane-methylene chloride-methanol. Fractions showing similar TLC were combined and the solvent removed. The oil obtained from the column was not analyzed and was distilled (Chyotopass valve-
Bulb distillation). This gave 4.38 g (37.9%) of a clear oil.

Elemental analysis: Calculated value (C ₁₁ H ₁₃ O ₂ Cl): C, 62.12; H, 6.16 Found value: C, 61.70; H, 6.17 Preparation 23 4- (diphenylmethyl) piperidine hydrochloride [1: 1] diphenyl-4-pyridylmethane 62.69 in 300 ml glacial acetic acid.
g (0.256 mol) and 10% palladium on carbon 6.4 g (0.00
60 mol) of the mixture under an atmosphere of hydrogen (44 psi, about 3.1 kg /
cm ² ) Shaking at 85 ° C. for 4 days on a pal device. The reaction mixture was passed and the solvent was removed from the solution in vacuo.
The residue was partitioned between methylene chloride and dilute sodium hydroxide. Dry the methylene chloride solution over magnesium sulfate,
The solvent was removed in vacuo to give a solid. This was dissolved in a mixture of methanol and acetonitrile and excess ethereal hydrogen chloride was added. The precipitate was collected to give 59.13 g (80.3%) of the slightly impure title compound as a white crystalline solid. Melting point 273-274 ° C. A portion of this was recrystallized from methanol-ether to give an analytically pure sample. Melting point 275.5
~ 277 ° C.

Elemental analysis: Calculated value (C ₁₈ H ₂₂ NCl): C, 75.11; H, 7.70, N, 4.87 Found: C, 75.03; H, 7.73; N, 4.93 Production Example 24 α- (4-Fluorophenyl) -Α-phenyl-4-pyridinemethanol 18.5 g of magnesium chips in 800 ml of anhydrous diethyl ether
(0.761 mol) and a suspension of several crystals of iodine (cooled in an ice bath) under argon atmosphere 200 ml of diethyl ether
A solution of p-bromofluorobenzene in was added. The solution was stirred at 25 ° C for 2 hours, then 4-benzoylpyridine
97.02 g (0.530 mol) was added as a solid. 1 more
Anhydrous diethyl ether was added and the solution was stirred at 25 ° C. for 3 hours. The reaction mixture was poured into an ice solution of ammonium chloride. The mixture was left in the hood overnight and a white solid was collected. This solid was dissolved in a tamenol-methylene chloride mixture. The solution was passed and the solvent removed in vacuo. The residue was crystallized from chloroform-hexane to give 66.68 g (45%) of the title compound as a white crystalline solid. Melting point 189-192 [deg.] C. A part of this was recrystallized from methylene chloride-acetonitrile-hexane. Melting point 190-192 ° C.

Elemental analysis: Calculated value (C ₁₈ H ₁₄ NOF): C, 77.40; H, 5.05; N, 5.02 Actual value: C, 77.24; H, 5.03; N, 4.90 Production Example 25 α, α-bis (4-chlorophenyl) ) -1- (Phenylsulfonyl) -4-piperidinemethanol The title compound was prepared according to the method of Preparation 7, but using p-bromochlorobenzene instead of p-bromofluorobenzene.

Production Example 26 4- [bis (4-chlorophenyl) methylene] piperidine hydrobromide / hydrate [1: 1: 1] 48% α, α-bis (4-chlorophenyl)-in 400 ml of hydrobromic acid 1- (phenylsulfonyl) -4-piperidinemethanol 69.33 g (0.146 mol) and phenol 26 g
Reflux a mixture of (0.277 mol) for 6 hours, then at room temperature for 1 hour.
Stir for 0 hours. The reaction was decanted from the gum that formed at the bottom of the reaction flask. The gum was washed several times with water and then crystallized from ether to give a solid. This solid was recrystallized from a methanol-diethyl ether mixture to obtain 26.52 g (43.6%) of a white crystalline solid. Melting point 106-1
09 ℃.

Calcd _{(C 18 H 20 NBrCl 2 O} ): C, 51.83; H, 4.83; N, 3.36 Found: C, 52.13; H, 4.62 ; N, 3.38 Preparation 27 1-chloro-4- ( 3-Chloropropoxy) benzene p-Chlorophenol 77.2 g (0.60 mol), 1-bromo-3-chloropropane 189 g (1.2 mol), anhydrous potassium carbonate 249 g (1.8 mol) and acetone 600 ml vigorously under a nitrogen atmosphere. The mixture was stirred and refluxed for 16 hours. Potassium carbonate was removed by suction and acetone and excess bromochloropropane were removed by heating under reduced pressure. The residue was dissolved in petroleum ether and the resulting solution was cooled in an ice-inpropyl alcohol bath resulting in a white solid. The solid was taken and washed with cold petroleum ether. The liquid was concentrated and cooled to obtain two additional white crystals. The solids are combined and dried under vacuum at ambient temperature,
107 g (87%) of white flaky solid was obtained. Melting point 35-36
° C.

Elemental analysis: Calculated value (C ₉ H ₁₀ OCl ₂ ): C, 52.71; H, 4.92 Measured value: C, 52.99; H, 4.87 Production Example 28 4- (3-Chloropropoxy) benzoic acid methyl ester 4-hydroxybenzoic acid 83.1 g (0.50 mol) of ethyl acidate, 1
-Brom-3-chloropropane 107 ml (1.0 mol) and potassium carbonate (1.5 mol, 207.3 g) were mechanically stirred overnight under nitrogen in 600 ml of refluxing acetone. Potassium carbonate was removed, and the liquid was evaporated under reduced pressure to obtain a liquid (1.22 g). This liquid was dissolved in 250 ml of petroleum ether while cooling in an ice / 2-propanol bath with stirring. A white precipitate formed, which was collected and washed with cold petroleum ether to give 108 g of a solid.
Got An additional 6 g of product was obtained from the mother liquor. A small sample of this solid was dissolved in petroleum ether at room temperature. The solution was stirred and cooled in an ice bath. White crystals were collected, washed with cold petroleum ether and dried under vacuum at room temperature. Melting point 24
To 25 ° C. Elemental analysis: Calculated _{(C 12 H 15 O 3 Cl} ): C, 59.39; H, 6.23 Found: C, 59.69; H, 6.30 Preparation 29 1- (3-chloro propoxy-4-nitrobenzene acetone A mixture of 7.0 g (0.05 mol) of 4-nitrophenol, 15.7 g (0.1 mol) of 1-bromo-3-chloropropane, and 20.7 g (0.15 mol) of anhydrous potassium carbonate in 350 ml was heated under reflux for 17 hours. Cool, pass,
The liquid was concentrated to give an oil. It crystallized. The solid was taken, washed with petroleum ether and dried to give 10.1 g (94%) of the title compound. Analytical samples were prepared from ethyl ether-petroleum ether. Melting point 37-39 ° C. Elemental analysis: Calculated value (C ₉ H ₁₀ ClNO ₃ ): C, 50.13; H, 4.67; N, 6.50 Found: C, 49.95; H, 4.71; N, 6.51 Production Example 30 4- [ Bis (4-fluorphenyl) methyl] -1-piperidine propanol oxalate monohydrate 4- [bis (4-fluorphenyl) methyl] piperidine 10.67 g (0.0372 mol) in 400 ml of 1-butanol 3
A mixture of 5.42 g (0.039 mol) of brom-1-propanol and 8 g (0.095 mol) of sodium hydrogen carbonate was refluxed for 21 hours. The solvent was removed in vacuo and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate and the solvent removed in vacuo to give 8.88 g (67.3%) oil. This was the free base of the title compound. A small sample of this oil was converted to the oxalate salt and this salt was recrystallized from methanol-ether to give a white solid. Melting point 89-94 ° C. The total yield was calculated to be 75.1%.

Calcd _{(C 23 H 29 NO 6 F} 2): C, 60.92; H, 6.45; N, 3.09 Found: C, 61.49; H, 6.15 ; N, 3.03 Preparation 31 4- (3-chloro Propoxy) -3-methoxybenzoic acid methyl ester A mixture of 100 g (0.549 mol) of methyl vanillate, 172.8 g (1.1 mol) of 1-bromo-3-chloropropane and 228 g (1.65 mol) of anhydrous potassium carbonate in acetone 20 was added. Heated to reflux for hours. The mixture was cooled, passed and the liquid was concentrated to give a white solid as a residue. This solid was triturated with petroleum ether, taken and dried to give a white powder 13
7.8 g (97%) were obtained. This was recrystallized from isopropyl alcohol. Melting point 104-105 ° C.

Calcd _{(C 12 H 15 ClO 4)} : C, 55.71; H, 5.84 Found: C, 55.87; H, 5.94 Preparation 32 4- [bis (4-methoxyphenyl) methyl] pyridine anisole 108.13 g (1.0 mol) was cooled in an ice bath. Concentrated sulfuric acid 115.3 ml (2.0 mol) was added while the mixture was stirred in an ice bath. The temperature rose to 55 ° C. The reaction was then cooled in an ice bath. To this solution was added 53.5 g (0.5 mol) of 4-pyridinecarboxaldehyde. The temperature rose to 95 ° C. Further cooling and stirring will increase the temperature
The temperature was lowered to 20 ° C. The reaction mixture was heated to 70 ° C. for 3-1 / 2 hours. The red gel was made alkaline with 50% sodium hydroxide-ice mixture. The alkaline phase was extracted with toluene and the toluene was extracted with saturated sodium chloride solution. The product crystallized from a toluene solution while standing at room temperature. This white solid can be recrystallized from hot hexane-isopropyl alcohol.

A small 2.2 g sample of the product was added to methylene chloride-hexane (1:
9 v / v) and dried in vacuum at 80 ° C. overnight. This gave a white crystalline product in 49% yield. Mp 111.5 to 113.5 ° C. Elemental analysis: Calculated _{(C 20 H 19 NO 2)} : C, 78.66; H, 6.27; N, 4.59 Found: C, 78.14; H, 6.24 ; N, 4.54 Preparation 33 4- [ Bis (4-methoxyphenyl) methyl] piperidine hydrochloride / hydrate [1: 1: 1] precursor pyridine derivative 4- [bis-4-methoxyphenyl) methyl] pyridine as anisole in the presence of sulfuric acid Prepared by reaction of 4-pyridinecarboxaldehyde.

For the preparation of the title compound 4-acetic acid in 350 ml of acetic acid
[Bis-4-methoxyphenyl) methyl] pyridine 70.8
A solution of g (0.232 mol) was added to 5% palladium on carbon (7.08 mol).
g) was hydrogenated under heating for 5 hours. Hydrogenation was done overnight at room temperature. The reaction mixture was passed and rinsed with methanol. Remove the solvent from the liquid with a rotary evaporator,
The residue was partitioned between 5% sodium hydroxide and toluene. The aqueous layer was back extracted with toluene. The organic layer was dried over anhydrous sodium sulfate and passed. The solvent was removed by rotary evaporation to give 64 g (88.6%) of a white solid (free base). The free base was then converted to the hydrochloride salt by dissolving in methanol and treating with ethereal hydrogen chloride. Separate the white solid and dry overnight in vacuo at 80 ° C., 2.08
An amount of g (69.3%) was obtained. Melting point 132-135 [deg.] C.

Calcd _{(C 20 H 28 NO 3 Cl} ): C, 65.65; H, 7.71; N, 3.83 Found: 3,65.63; H, 7.53; N , 3.90 Preparation 34 4- [bis (4- Methylphenyl) methyl] piperidine hydrochloride [1: 1] 4-[(bis-4-methylphenyl) methyl] in acetic acid
The free base of the title compound was prepared by hydrogenation of piperidine using palladium on carbon as a catalyst and converted to the hydrochloride salt in methanol-diethyl ether.
The salt was recrystallized from methanol-diethyl ether and isopropyl alcohol-diethyl ether and in vacuo at 80 ° C.
Dried overnight at. A white solid was obtained in a yield of 46%. Melting point 232 [deg.] C.

Calcd _{(C 20 H 26 NCl):} C, 76.05; H, 8.30; N, 4.43 Found: C, 75.51; H, 8.33 ; N, 4.33 Preparation 35 N-[4- (3-chloro Propoxy) phenyl] acetamide 4-acetamidophenol A mixture of 182.2 g (1.2 mol), bromchloropropane 157.4 g (1.0 mol) and potassium carbonate 145.0 g (1.05 mol) was refluxed in 700 ml of acetone overnight. When the acetone solution was refrigerated overnight, white crystals were formed. This white solid was filtered and washed with acetone. The solution was stripped to dryness, the residue was dissolved in chloroform and extracted with 5% sodium hydroxide. Chloroform was removed to give an oil. The white solid was also dissolved in chloroform and extracted with 5% sodium hydroxide.
Chloroform was removed to give a white solid. The white solid and oil were combined and placed in acetone and placed in the refrigerator. White crystals were obtained. The white crystals were recrystallized twice from acetone. A 5 g sample of white crystals was recrystallized from acetone. This gave 1.76 g of a white crystalline product (80 ° C in vacuum).
(23%) was obtained after drying overnight. Melting point 125
~ 127 ° C.

Elemental analysis: Calculated value (C ₁₁ H ₁₄ NO ₂₇ Cl): C, 58.03; H, 6.20; N, 6.15 Found: C, 58.21; H, 6.28; N, 6.15 Preparation Example 36 1- (3-Chloropropoxy ) -3,5-Dimethoxidinezene 3,5-dimethoxyphenol 100.0 g (0.6486 mol), chlorobromopropane 148.0 g (0.96 mol), and potassium carbonate 89.6 g (0.96 mol) were gently refluxed in 600 ml of acetone. While heating overnight. The reaction mixture was cooled to room temperature, passed and stripped on a rotary evaporator,
Allowed to dryness. The oil obtained was dissolved in chloroform and the solution was extracted with 5% sodium hydroxide. Chloroform was removed to give a dark brown oil. A 5 g sample of oil was pumped at 80 ° C. in vacuum overnight. This gave a dark brown oil 3.23
g (53.2% yield based on aliquot used) were obtained.

H ¹ (CDCl ₃ ): δ2-2.4 (pentet, central methylene proton, 2H), 3.6-4.2 (m, aliphatic proton, 4H), 3.8
_{(S, OCH 3, 6H)} , 6.1 (s, aromatic protons, 3H).

Elemental analysis: Calculated value (C ₁₁ H ₁₅ O ₃ Cl): C, 57.27; H, 6.56 Found value: C, 56.96; H, 6.49 Production Example 37 4- (3-Chloropropoxy) benzonitrile 4-cyanophenol 125.0 g (1.05mol) Bromochloropropane 189.09g (1.2mol) and potassium carbonate 145.0g
(1.05 mol) was heated in 750 ml of acetone under reflux overnight. The reaction mixture was passed and stripped to dryness. The obtained residue was dissolved in chloroform and extracted with 5% sodium hydroxide. Chloroform was removed to give an oil. It crystallized to a white solid. A 5 g sample was recrystallized from isopropyl ether. This gave 1.22 g of a white solid (24.4% for a 5 g sample). Melting point 40
~ 44 ° C. It contained an impurity, a dimer.

Calcd _{(C 10 H 20 NOCl):} C, 61.39; H, 5.15; N, 7.16 Found: C, 61.57; H, 5.14 ; N, 7.20 Preparation 38 1- [4- (3-chloro Propoxy) -3-methylphenyl] ethanone 25 g (0.166 mol) of 4-hydroxy-3-methylacetophenone in 500 ml of acetone, 45.8 g (0.33 mol) of 1-bromo-3-chloropropane and anhydrous potassium carbonate 69.
A mixture of 1 g (0.5 mol) was heated to reflux for 20 hours. The mixture was cooled, passed and the liquor was concentrated under reduced pressure to give an oil as a residue. This oil was crystallized in petroleum. Take this solid, wash with petroleum ether, dry to an off-white powder 3
5.8 g (95%) was obtained. Analytical sample (melting point 41.5-42.5 ° C)
Was prepared from petroleum ether.

Calcd _{(C 12 H 15 ClO 2)} : C, 63.58; H, 6.67 Found: C, 63.40; H, 6.64 Preparation 39 4- (3-chloro-propoxy) -benzamide acetone 1 4-hydroxy Benzamide 50g (0.3
65 mol), 1-bromo-3-chloropropane 114.8 g (0.
A mixture of 729 g) and 151.3 g (1.1 mol) of anhydrous potassium carbonate was heated under reflux for 20 hours. The mixture was concentrated under reduced pressure and the residue was stirred with 1.2 l of water to remove inorganic solids.
The mixture was passed, the percake washed with water and petroleum ether and dried to give 75.5 g (97%) of a white solid.
The solid was recrystallized from ethyl acetate. Melting point 142-143
° C.

Calcd _{(C 10 H 12 ClNO 2)} : C, 56.22; H, 5.66; N, 6.56 Found: C, 55.92; H, 5.61 ; N, 6.56 Preparation 40 1- [4- (5- Chlorpentoxy) -3-methoxyphenyl] ethanone 59.7 g (0.36 mol) of acetovanillone in acetone 1
1-bromo-5-chloropentane 100 g (0.539 mol),
And a mixture of anhydrous potassium carbonate (138 g, 1 mol) was heated under reflux for 20 hours. The mixture was passed and the liquid was concentrated under reduced pressure to give an oil. It crystallized in petroleum ether (30
~ 60 ℃). Take this solid, wash with petroleum ether,
Upon drying, 81.4 g (84%) of a fluffy white solid was obtained.
The solid was recrystallized from isopropyl ether. Melting point
57-58 ° C.

Calcd _{(C 14 H 19 ClO 3)} : C, 62.11; H, 7.07 Found: C, 62.14; H, 7.10 Preparation 41 4- (3-chloro-propoxy) -3-methoxybenzene acetic acid ethyl ester A mixture of 50 g of ethyl homovanillate (0.238 mol), 75 g of 1-bromo-3-chloropropane (0.476 mol), and 98.7 g of anhydrous potassium carbonate (0.71 mol) in acetone 1 was heated to reflux for 24 hours. The mixture was passed and the liquid was concentrated under reduced pressure to give an oil. It gradually crystallized to a semi-solid. This solid was re-inclined from ethyl ether-petroleum ether (30-60 ° C) to give a white solid 44.4 g (65%).
Got Melting point 36-38 ° C.

Elemental analysis: Calculated value (C ₁₄ H ₁₉ ClO ₄ ): C, 58.64; H, 6.68 Found value: C, 58.74; H, 6.74 Preparation Example 42 1- (3-Chloropropoxy) -4- (methylsulfonyl) benzene 1- (3-chloropropoxy) in 100 ml of chloroform
To a solution of 21.7 g (0.1 mol) of 4- (methylthio) benzene was added 51.8 g of m-chloroperbenzoic acid in 450 ml of chloroform.
A slurry of (0.3 mol) was added carefully. The mixture was stirred at ambient temperature for 2 days then passed. The solution was washed 4 times with a solution of 110 ml saturated sodium hydrogen carbonate, 110 ml water and 30 ml 20% sodium hydroxide, once with brine, dried (sodium sulfate) and concentrated under reduced pressure.
A solid was obtained as a residue. This solid was triturated with petroleum ether, taken and air dried to give 24.3 g (98%) of a white solid. An analytical sample (melting point 84-86 ° C) was recrystallized from 2-propanol.

Calcd _{(C 10 H 13 ClO 3 S} ): C, 48.29; H, 5.27 Found C, 48.38; H, 5.30 Preparation 43 5-Oxo-1- (phenylmethyl) -3-pyrrolidinecarboxylic acid methyl Ester A solution of 158.2 g (1.0 mol) dimethyl itaconic acid and 107.2 g (1.0 mol) benzylamine in 750 ml methanol was left at ambient temperature over the weekend. Pass this solution,
The liquid was concentrated under reduced pressure to give an oil as a residue. The oil crystallized on trituration with petroleum ether (30-60 ° C). This solid is taken, dried and white powder 225.5g
(97%) was obtained. Analytical samples (mp 63-65 ° C) were prepared from diisopropyl ether.

Elemental analysis: Calculated value (C ₁₃ H ₁₅ NO ₃ ): C, 66.94; H, 6.48; N, 6.01 Found: C, 66.82; H, 6.48; N, 6.01 Production Example 44 1-benzyl-3-hydroxymethyl Pyrrolidine oxalate [1: 1] 5-oxo-1- (phenylmethyl) -3-pyrrolidinecarboxylic acid methyl ester 6 in dry dimethoxyethane 6
A solution of 0.0 g (0.2553 mol) was added to a mixture of dimethoxyethane and 47.0 g (1.23 mol) lithium aluminum hydride. The reaction mixture was stirred at room temperature for 2 hours and then heated at reflux for 2 hours. The mixture was then stirred overnight at room temperature before quenching the reaction by slowly adding ethyl acetate. The solid material was separated from the liquor by addition of ethyl acetate and the use of Celite. The solution was stripped, dried and dissolved in chloroform. The chloroform layer was extracted with 10% sodium hydroxide. The chloroform layer was dried, filtered and the solvent removed to give an oil. A portion of this oil was converted to oxalate. The salt was recrystallized from methanol-diethyl ether and the temperature was 80 ° C.
2.27 g of white crystalline solid, dried in vacuum overnight in
(39.4% of the aliquot used). Melting point 98-10
2 ° C.

Elemental analysis: Calculated value (C ₁₄ H ₁₉ NO ₅ ): C, 59.78; H, 6.81; N, 4.98 Found: C, 59.43; H, 6.79; N, 4.95 Production Example 45 1- [4- (6- Chlorhexyloxy) -3-methoxyphenyl] ethanone Acetylvanillone 41.6 g (0.25 mol), 1-bromo-6-chlorohexane 76 g (0.375 mol), and anhydrous potassium carbonate 103.7 g (0.75 mol) in 750 ml of acetone. The mixture was heated to reflux for 20 hours. Cool the mixture, pass,
The cake was washed with acetone. The combined liquids were concentrated under vacuum pump pressure at 90 ° C. to give an oil. It gradually crystallized. The residue was triturated with petroleum ether (30-60 ° C), taken and dried to give an off-white solid 59.6g (84%).
Got Analytical samples (mp 35-38 ° C) were prepared from isopropyl ether.

Elemental analysis: Calculated value (C ₁₅ H ₂₁ ClO ₃ ): C, 63.26; H, 7.43 Found value: C, 63.50; H, 7.60 Production Example 46 4- (3-chloropropoxy) benzenesulfonamide p in 500 ml of acetone -Hydroxybenzenesulfonamide 25 g (0.144 mol), 1-bromo-3-chloropropane 45.5 g (0.289 mol), and anhydrous potassium carbonate 59.7 g
A mixture of (0.432 mol) was heated to reflux for 24 hours. The mixture was cooled, passed and the liquor was concentrated under vacuum pump pressure at 90 ° C. to give 32.2 g of a tan gum as a residue. The rubbery substance was purified by column chromatography on 600 g of silica gel. Fractions containing the title compound eluted with 8% acetone in benzene were combined and concentrated under reduced pressure.
When recrystallized from propanol, 12.2 g (3
4%) was obtained. Melting point 106-107.5 ° C.

Elemental analysis: Calculated value (C ₉ H ₁₂ NO ₃ S): C, 43.29; H, 4.84; N, 5.61 Found: C, 43.48; H, 4.92; N, 5.62 Preparation 47 7- (3-Chloropropoxy ) -2H-1-benzopyran-2-one 16.8 g (0.10 g) of 7-hydroxycoumarin in 500 ml of acetone.
4 mol), 1-bromo-3-chloropropane 31.6 g (0.2
A mixture of 41.5 g (0.3 mol) of anhydrous potassium carbonate and refluxed for 24 hours. The mixture was passed (difficult) to give a milky white liquid. The liquor was treated with charcoal and filtered through Celite to give a clear liquor. The liquid was concentrated under reduced pressure to obtain a solid residue. This solid was converted to petroleum ether (30 ~
Triturated with 60 ° C.), taken and dried to give 19.1 g (77%) of a fluffy white solid. Analytical sample (melting point 100 to 10
2 ° C.) was obtained upon recrystallization from 2-propanol.

Calcd _{(C 12 H 11 ClO 3)} : C, 60.39; H, 4.65 Found; C, 60.35; H, 4.68 Preparation 48 7- (3-chloro-propoxy) -4-oxo-4H-1 −
Benzopyran-2-carboxylic acid ethyl ester 7-hydroxy-4-oxo-4H- in 500 ml acetone
1-benzopyran-2-carboxylic acid ethyl ester 23.4
g (0.1 mol), 1-bromo-3-chloropropane 31.6g
A mixture of (0.2 mol) and 41.5 g (0.3 mol) of anhydrous potassium carbonate was heated under reflux for 20 hours. Cool the mixture,
Passed by Celite. The liquid was concentrated under reduced pressure to obtain a solid residue. This solid was triturated with petroleum ether (30-60 ° C), taken and recrystallized from 2-propanol to give 22.5 g (73%) of a white solid. Mp 107-108 ° C. Elemental analysis: Calculated _{(C 15 H 15 ClO 5)} : C, 57.98; H, 4.87 Found: C, 58.21; H, 4.88 Preparation 49 1- [4- (3-chloro-propoxy) 2-Methoxyphenyl] ethanone 10.6 g (0.637 mol) of 1- (4-hydroxy-2-methoxyphenyl) ethanone, 20 g (0.127 mol) of 1-bromo-3-chloropropane, and anhydrous carbonic acid in 250 ml of acetone. A mixture of 26.4 g (0.19 mol) of potassium was heated to reflux for 20 hours. The mixture was cooled, passed and the liquor was concentrated at 90 ° C. under vacuum pump pressure to give an oil. It gradually crystallized. The solid was triturated with petroleum ether (30-60 ° C), taken, dried and recrystallized from isopropyl ether to give a white solid. Melting point 47-49 ° C.

Elemental analysis: Calculated value (C ₁₂ H ₁₅ ClO ₃ ): C, 59.39; H, 6.23 Measured value: C, 59.32; H, 6.26 Production Example 50 1- (3-Chloropropoxy) -4-sulfinylbenzene 1 The title compound was prepared by treating-(3-chloropropoxy) -4-methylthiobenzene with sodium perborate in glacial acetic acid.

Production Example 51 2- (3-Chloropropoxy) benzonitrile 2-Cyanophenol 50.0 g (0.42 mol), 1-bromo-3-chloropropane 67.7 g (0.43 mol), and a mixture of potassium carbonate 58.0 g (0.42 mol) Was heated overnight in 500 ml of acetone with gentle reflux. The reaction mixture was stripped to dryness and the residue was dissolved in chloroform. The chloroform layer was extracted several times with 5% sodium hydroxide. The chloroform layer was dried (anhydrous sodium sulfate), filtered and the solvent removed in vacuo to give a brown oil (80.0
9g) was obtained. 10 g of this oil on silica gel, 10%
Flash chromatography was performed using ethyl acetate-hexane and 20% ethyl acetate-hexane for elution. The fractions were combined and the solvent removed in vacuo. The clear oil obtained was dried under vacuum at room temperature for 18 hours and under vacuum at 80 ° C. for 8 hours. This gave 5.24 g of clear oil (yield 50.0
%, Based on the aliquot used). ¹ H NMR (CDCl ₃ ); δ2.1-2.5 (q, 2, -CH ₂ ), 3.8 (t, 2, -C
lCH ₂ ), 4.2 (t, 2, -OCH ₂ ), 6.9 (m, 2, aromatic proton,
Ortho and para to ether), 7.5 (m, 2, aromatic protons, ortho and para to CN group).

Calcd _{(C 10 H 10 NOCl):} C, 61.39; H, 5.15; N, 7.16 Found: C, 61.27; H, 5.15 ; N, 7.14 Preparation 52 1-phenylmethyl-3-pyrrolidinemethanol, A solution of 113.80 g (0.596 mol) of 1-benzyl-3-hydroxymethylpyrrolidine and 66.6 g (0.66 mol) of triethylamine in 600 ml of acetonitrile was prepared. The solution was cooled in an ice bath. A solution of 125.9 g (0.66 mol) of tosyl chloride in 300 ml of acetonitrile was added dropwise with stirring. The solution was stirred at room temperature overnight. A solid precipitated and passed the solution. The solution was removed by rotary evaporation and the residue was dissolved in chloroform. The chloroform layer was extracted with 5% sodium hydroxide and water. The chloroform layer was dried (anhydrous sodium sulfate), filtered and the solvent removed to give 232.9 g of a dark brown oil. The oil was converted to oxalate and recrystallized from methanol-diethyl ether. 80 in vacuum
After drying at ℃ overnight, white crystalline solid 181.63g
was gotten. A 5 g sample was recrystallized again from methanol-diethyl ether and dried in vacuum at 80 ° C. overnight. 1.41 g of a white crystalline solid (19.7% overall for the aliquot used) were obtained. Melting point 147-149 ° C.

Elemental analysis: Calculated value (C ₂₁ H ₂₅ NO ₇ S): C, 57.92; H, 5.79; N, 3.22 Found: C, 57.62; H, 5.82; N, 3.22 Production Example 53 α, α-diphenyl-3 -Pyrrolidineacetamide maleate [1: 1] A sample of 1-benzyl-α, α-diphenyl-3-pyrrolidineacetamide (1.13 g) dissolved in 50 ml of methanol at 75 ° C with 0.5 g of 10% palladium catalyst on charcoal at a pal hydrogenation system. Hydrogenated in overnight. After removing the catalyst, the liquid was concentrated to obtain 0.783 g (80%) of a light yellowish brown rubber substance. Mass spectrum and infrared spectrum were consistent with the structure. A sample of this free base in methanol was treated with 1 molar equivalent of a maleic acid solution in methanol. After removing the methanol, the residue was crystallized and recrystallized twice from isopropanol-ether. 110 ℃ /
It was dried at 0.1 mm for 3 hours. Melting point 110-145 ° C (softens,
And liquefied). This material appeared as an amorphous solid.

Elemental analysis: Calculated value (C ₂₂ H ₂₄ N ₂ O ₅ ): C, 66.65; H, 6.10; N, 7.07 Found value: C, 66.79; H, 6.05; N, 7.04 Production Example 54 α, α-diphenyl- 3-pyrrolidineacetamide ・ N
-Cyclohexyl sulfamate hydrate [1: 1: 1.5] α, α-diphenyl-3-pyrrolidineacetamide maleate was partitioned between chloroform and a basic aqueous solution, and the chloroform layer was evaporated to evaporate the above compound. A sample of 1.15 g of free base and 0.735 g of hexamic acid were dissolved in 10 ml of ethanol. The solvent was evaporated, the residue crystallized and then recrystallized from ethanol. Melting point 103-1
06 ° C.

Elemental analysis: Calculated value (C ₂₄ H ₃₃ N ₃ SO ₄ · 1.5H ₂ O): C, 59.24; H, 7.46; N, 8.64 Actual value: C, 58.97; H, 6.98; N, 8.51 Production example 55 1 Ester of 4- (phenylmethyl) -4-piperidinol and 4-methylbenzenesulfonic acid maleate [1:] N-benzyl-4-hydroxypiperidine 100 g (0.524 mol) and tosyl chloride 13 g (0.684) in 600 ml pyridine.
Solution) was stirred at room temperature overnight. Methylene chloride 1
And 500 ml of 0.5 M sodium hydroxide were added to the reaction mixture. The reaction mixture was stirred for 10 minutes and the phases were separated. The methylene chloride phase was extracted several times with dilute sodium hydroxide, dried over magnesium sulphate and evaporated in vacuo to give an oil (free base of the title compound). The free base was converted to the maleate salt, which was recrystallized from methylene chloride-diethyl ether to give a white solid. Melting point 159-160 ° C.

Calcd _{(C 23 H 27 NO 7 S} ): C, 59.86; H, 5.90; N, 3.04 Found: C, 59.79; H, 5.86 ; N, 2.95 Preparation 56 1- [2- (phenylthio ) Ethyl] -4-piperidinecarboxylic acid ethyl ester hydrochloride [1: 1] 2-chloroethylphenyl sulfide in absolute ethanol 1
69.3g (0.40mol), ethyl isonipecotate 61.65g
(0.393 mol), and 53 g of sodium carbonate (0.50 mol)
The mixture was refluxed for 30 hours in the presence of Molecular Sieve 3A. The reaction mixture was passed and the solution was freed from the solvent in vacuo. The residue was partitioned between methylene chloride and dilute sodium hydroxide and the methylene chloride solution was dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give the free base of the title compound as an oil. Convert the free base to the hydrochloride salt,
The salt was recrystallized from absolute ethanol-ether to give 38.62 g (29.8%) of white crystalline solid. Melting point 125-126 ° C.

Elemental analysis: Calculated value (C ₁₆ H ₂₄ NO ₂ SCl): C, 58.26; H, 7.33; N, 4.25 Found: C, 58.11; H, 7.32; N, 4.20 Production Example 57 1-[(4-methylphenyl ) Sulfonyl] -4-piperidinol and ester of 4-methylbenzenesulfonic acid 1.63 g (0.04) of 4-hydroxypiperidine in 80 ml of pyridine
A solution of 16 mol) and 13.9 g (0.0732 mol) tosyl chloride was stirred overnight at 25 ° C. The mixture was quenched in 200 ml water and the aqueous mixture was extracted several times with methylene chloride. The combined methylene chloride layers were extracted several times with 1M sulfuric acid, then 1M sodium hydroxide, and dried over magnesium sulfate. The solvent was removed in vacuo to give a solid. The solid was recrystallized from methylene chloride-diethyl ether to give 4.82 g (7
3.3%) was obtained. Melting point 140.5-141 ° C.

Elemental analysis: Calculated value (C ₁₉ H ₂₃ NO ₅ S ₂ ): C, 55.73; H, 5.66; N, 3.42 Actual value: C, 55.60; H, 5.64; N, 3.39 Production Example 58 1-[(4- Methylphenyl) sulfonyl] -α, α-
Diphenyl-4-piperidineacetonitrile The sodium salt of diphenylacetonitrile was prepared in toluene from 94.5 g (0.488 mol) diphenylacetonitrile and 19.6 g (0.488 mol) sodium hydride. The reaction mixture was heated to reflux for about 2 hours. A color change from green to brown was observed during the reaction. 1-[(4-Methylphenyl) sulfonyl] -4-piperidinol and the ester of methylbenzenesulfonic acid (200.0 g, 0.488 mol) were added portionwise as a solid while the reaction mixture was stirred under nitrogen at room temperature. The solution turned green. The solution / mixture was stirred at 100 ° C. overnight. The mixture was passed and the toluene was removed by rotary evaporation.

The residue obtained by removing the cake and toluene was combined and dissolved in chloroform. Chloroform was extracted several times with 5% sodium hydroxide and then with 1N sulfuric acid and sodium hydroxide. Chloroform was removed in vacuo to give a reddish brown oil.

A sample of this oil was crystallized from toluene and washed with isopropyl ether. The solid obtained was then recrystallized from methylene chloride-hexane and dried in vacuo at 80 ° C. overnight to give the title compound as a white solid in a yield of 26.7% based on the aliquot used. Melting point 183-184 ° C.

Calcd _{(C 26 H 26 N 2 O} 2 S): C, 72.53; H, 6.09; N, 6.51 Found: C, 72.11; H, 6.07 ; N, 6.45 Preparation Example 59 alpha, alpha-diphenyl -4-piperidineacetonitrile
Oxalate [2: 1] 48% hydrobromic acid 1-[(4-methylphenyl) sulfonyl] -α, α-diphenyl-4-piperidineacetonitrile (183.83 g, 0.428 mol) and phenol (150.0 g, 1.60) in 750 ml. Vigorously stir the solution of
The mixture was heated under reflux for / 2 hours. The reaction mixture was cooled and made alkaline with water / 50% sodium hydroxide. The reaction mixture was extracted with chloroform, and the chloroform layer was back-extracted with 5% sodium hydroxide. The chloroform layer was dried, passed over anhydrous sodium sulfate and the solvent was removed to give a red oil. This oil (free base of the title compound) was converted to the oxalate salt using a methanol-diethyl ether mixture. A sample of the oxalate salt was recrystallized from methanol-diethyl ether to give a white crystalline product in 17.9% yield. Melting point 275-276 ° C.

Calcd _{(C 20 H 21 N 2 O} 2): C, 74.74; H, 6.59; N, 8.72 Found: C, 74.51; H, 6.52 ; N, 8.60 Preparation Example 60 alpha, alpha-diphenyl - 4-piperidine acetamide fumarate [2: 3] α, α-diphenyl-4-piperidineacetonitrile ・
60.34 g (0.165 mol) of oxalate [2: 1] was converted to the free base by partitioning in 5% sodium hydroxide and chloroform. An oil was obtained by removing the chloroform from the chloroform layer. This is then concentrated sulfuric acid 280m
It was dissolved in a mixture of 1 and 30 ml of water. The solution was stirred at 90 ° C overnight. The reaction mixture was poured onto ice and carefully made alkaline with 50% sodium hydroxide. The aqueous layer was extracted several times with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed to give an oil. It crystallized. A 2 g sample of oil was concentrated to give the fumarate salt.
The salt was recrystallized from methanol-diethyl ether. A white solid was obtained (47.9 for the aliquot used).
% Yield), which was dried in vacuo at 80 ° C. overnight. Melting point 234-235 ° C.

Calcd _{(C 25 H 28 N 2 O} 7): C, 64.09; H, 6.02; N, 5.98 Found: C, 63.82; H, 6.14 ; N, 5.82 Preparation Example 61 1 - [(4- Methylphenyl) sulfonyl] -α, α-
Diphenyl-3-piperidine propane nitrile Sodium hydride (60
%, 39.0 g, 0.975 mol) and diphenylacetonitrile (188.90 g, 0.975 mol) to produce the sodium salt of diphenylacetonitrile. The resulting solution was stirred under nitrogen at room temperature for 1 hour. Of 3- (chloromethyl) -1-[(4-methylphenyl) sulfonyl] piperidine and 4-methylbenzenesulfonic acid 1-[(4-methylphenyl) sulfonyl] piperidin-3-yl-methyl ester dissolved in 400 ml of dimethyl sulfoxide. 221.42 g (0.975 mol) of the 90-10 mixture was added. The reaction mixture is 85
Heated to ℃ and stirred overnight at 73 ℃. Dimethyl sulfoxide was removed in vacuo and the resulting residue was dissolved in chloroform. The chloroform layer was extracted with 1N sulfuric acid. The chloroform layer was dried, filtered and chloroform was removed by rotary evaporation. A brown residue was obtained which was triturated with isopropyl ether to give a brown solid. A 5 g sample was recrystallized from ethyl acetate-isopropyl ether.
This gave 4 g of a white solid (56.8% of the aliquot used).
Yield). Melting point 136.5-137 ° C.

Elemental analysis: Calculated value (C ₂₇ H ₂₈ N ₂ O ₂ S): C, 72.94; H, 6.35; N, 6.30 Actual value: C, 72.82; H, 6.36; N, 6.28 Production Example 62 α, α-diphenyl -3-Piperidine propanenitrile fumarate [1: 1] 1-[(4-methylphenyl) sulfonyl] -α, α-
Diphenyl-3-piperidine propanenitrile 302.41g
A mixture of (0.68 mol), hydrogen bromide (48%, 750 ml), and 260 g (2.76 mol) of phenol was vigorously stirred while heating under reflux for 31/2 hours. The reaction mixture was cooled to room temperature and made alkaline with 50% sodium hydroxide-ice. The aqueous phase was extracted several times with chloroform and the chloroform layer was 5%
Back-extracted with sodium hydroxide. The chloroform layer was dried, filtered and the solvent was removed. About 80 according to NMR analysis
% Product was obtained, so the same reaction sequence was repeated.
The chloroform layer gave a brown oil which was converted to the oxalate salt. A portion of this oxalate salt was partitioned between chloroform and dilute sodium hydroxide, the chloroform layer was separated and converted to the free base by evaporation and converted to the fumarate salt. The salt was recrystallized from methanol-diethyl ether and dried in vacuum at 80 ° C. overnight to give 6.53 g of white crystalline product. Melting point 181-182 ° C. Elemental analysis: Calculated value (C ₂₄ H ₂₆ N ₂ O ₄ ): C, 70.92; H, 6.45; N, 6.89 Found: C, 70.46; H, 6.41; N, 6.86 Production Example 63 α , Α-diphenyl-3-piperidinepropanamide
Maleate [1: 1] A solution of 52.01 g (0.179 mol) of α, α-diphenyl-3-piperidinepropanenitrile in 280 ml of 90% sulfuric acid at 85 ° C.
Stir overnight. The reaction mixture was cooled to room temperature, then 50
Poured into a% sodium hydroxide / ice mixture. The basic layer was extracted with chloroform. The chloroform layer was dried, filtered and the solvent removed to give a fluffy solid (free base of the title compound). A portion of the free base, 3 g, was converted to the maleate salt and recrystallized from methanol-diethyl ether. The resulting salt was dried in vacuum at 80 ° C. overnight. This gave 2.15 g of a white crystalline product. Melting point 177
~ 179 ° C.

Elemental analysis: Calculated value (C ₂₄ H ₂₈ N ₂ O ₅ ): C, 67.91; H, 6.65; N, 6.60 Actual value: C, 67.85; H, 6.85; N, 6.55 Production Example 64 1-[(2- Chloroethyl) sulfonyl] -4-fluorobenzene A solution of 153 g (1.34 mol) of 30% hydrogen peroxide in 400 ml of glacial acetic acid was prepared. To this ice-cooled solution was added 70.11 g of 2-chloroethyl-p-fluorphenyl sulfide (200 ml) in 200 ml of glacial acetic acid.
369 mol) solution was added. The resulting solution is at room temperature 72
Stir for hours. The acetic acid volume was concentrated by rotary evaporation. The remaining material was dissolved in chloroform and extracted with a solution of sodium hydrogen carbonate and sodium sulfide. The chloroform layer was then dried, filtered and the solvent removed to give a white solid. A 5 g portion of this white solid was recrystallized from methylene chloride-isopropyl ether. The white solid was dried in vacuum at 80 ° C. overnight. This gave 1.84 g of a white crystalline solid (32.6% yield based on aliquot used). Melting point 72.5-74 ° C.

Elemental analysis: Calculated value (C ₈ H ₈ SO ₂ FCl): C, 43.15; H, 3.62 Measured value: C, 43.52; H, 3.66 Production Example 65 4-Fluoro-α- (4-fluorphenyl) benzeneacetonitrile 4-Fluorophenylacetonitrile (70.0g, 62.2m
1, d = 1.126, 0.518 mol) was heated to 120 ° C. Bromine (83.0 g, 26.6 ml, d = 3.119, 0.525 mol) was added dropwise over 1 hour while maintaining the temperature at 120 ° C. The solution was stirred at 120 ° C. for 1/2 hour and then flushed vigorously with nitrogen for 3/4 hour (Solution A).

Aluminum chloride (85.0 g, 0.644
Mol). Fluorobenzene (200g, 2.08mol,
(d = 1.024, 195.3 ml) was added dropwise over 1/2 hour with stirring while flushing with nitrogen (mixture B).

Solution A was added dropwise to mixture B starting from room temperature. temperature
Raised to 50 ° C. The reaction was stirred at this temperature for 1/3 hours. The temperature rose to 70 ° C and was held at this temperature for 1/3 hours. The reaction increased and some material was lost. The recovered mixture was added to 75 ml of ice / concentrated hydrochloric acid. The aqueous phase was extracted several times with chloroform. The solvent layer was dried, filtered and the solvent was removed to give a green solid. The solid was recrystallized from isopropanol, the solid was washed twice with cold isopropanol and dried in vacuo at 55 ° C overnight. This gave 29.72 g (25.1%) of a pale yellow solid. Melting point 62-6
3.5 ° C.

Elemental analysis: Calculated value (C ₁₄ H ₉ NF ₂ ): C, 73.36; H, 3.96; N, 6.11 Found: C, 73.55; H, 3.88; N, 6.10 Production Example 66 α, α-bis (4- Fluorphenyl) -1-[(4-
Methylphenyl) sulfonyl] -4-piperidineacetonitrile The sodium salt of 4-fluoro-α- (4-fluorphenyl) benzeneacetonitrile is taken up in dimethyl sulfoxide with 28.0 g (0.1223 mol) of its free base and 4.90 g of 60% sodium hydride. (0.1227 mol). The salt was stirred at room temperature for 1 hour. 1-[(4
-Methylphenyl) sulfonyl] -4-piperidinol and 4-methylbenzenesulfonic acid ester 50.0 g (0.1
223 mol) was added as a solid over 5 minutes under nitrogen with stirring. The resulting solution was stirred at 65 ° C. for 15 hours and then left at room temperature for 72 hours. The solution is stripped to dryness and the residue is dissolved in chloroform and
Extracted several times with% sodium hydroxide. The chloroform layer was dried (anhydrous sodium sulfate), filtered and the solvent was removed to give 111.36 g of a solid. The solid was triturated with isopropyl ether and placed in the freezer. After washing the solid several times with isopropyl ether, 55.41 g of a white solid was obtained. A 3 g sample was then triturated with 50-50 (v / v) hot isopropyl alcohol-methanol and placed in the freezer. The white solid collected was washed with isopropyl ether and dried in vacuum at 80 ° C. overnight. This gave 2.28 g of a white crystalline product. Melting point 190-191
° C.

Elemental analysis: Calculated value (C ₂₆ H ₂₄ N ₂ O ₂ SF ₂ ): C, 66.94; H, 5.18; N, 6.00 Actual value: C, 66.92; H, 5.17; N, 5.99 Production Example 67 α, α− Bis (4-fluorphenyl) -4-piperidineacetonitrile oxalate diethyl ether [1: 1: 0.5] 48% α, α-bis- (4-fluorphenyl) -1- in 200 ml of hydrobromic acid [(4-Methylphenyl) sulfonyl] -4-piperidine / acetonitrile 52.41 g (0.1125
3) with a solution of 50.0 g (0.53 mol) of phenol.
The mixture was heated under reflux for -1/2 hour. The reaction mixture was cooled to room temperature,
It was then made alkaline with an ice / 50% sodium hydroxide mixture. The alkaline phase was extracted several times with chloroform.
The chloroform layer was back extracted with 5% sodium hydroxide.
Dry the chloroform layer (anhydrous sodium sulfate),
The solvent was removed by filtration and 34.24 g of dark brown oil was obtained. The entire oil was converted to oxalate and recrystallized from methanol-diethyl ether. The resulting salt was dried in vacuum at 80 ° C. overnight to give 34.24 g (69.3%) of white crystalline solid. Melting point 124-127 ° C.

Calcd _{(C 23 H 25 N 2 F} 2 O 4.5): C, 62.86; H, 5.73; N, 6.37 Found: C, 62.30; H, 5.78 ; N, 6.17 Preparation 68 N-[3 -(3-Chloropropoxy) phenyl] urea 1- (3-hydroxyphenyl) urea 45.6 g (0.3 mol), 1-bromo-3-chloropropane 94.5 g (0.6 mol), anhydrous potassium carbonate 124.4 g (0.9 mol) ) And acetone 1 were heated to reflux with mechanical stirring for 20 hours. The mixture was concentrated and the residue was slurried with 1.5 l of water. The mixture was filtered and the cake was recrystallized from isopropanol to give 57.0 g (83%) of an off-white solid. Melting point 141-143 [deg.] C.

Calcd _{(C 10 H 13 ClN 2 O} 2): C, 52.52; H, 5.73; N, 12.25 Found: C, 52.37; H, 5.79 ; N, 12.17 Preparation 69 N-[4- ( 3-Chloropropoxy) phenyl] carbamic acid ethyl ester 4- (hydroxyphenyl) carbamic acid ethyl ester 6.6 g (0.036 mol), 1-bromo-3-chloropropane 11.5 g (0.072 mol), anhydrous potassium carbonate 13.8 g ( 0.10
Mol) and 150 ml of acetone was heated to reflux for 21 hours. The mixture was cooled and passed. The liquid was concentrated under reduced pressure to obtain a solid residue. This solid was converted to petroleum ether (30 ~
Triturated with 60 ° C.), taken and recrystallized from isopropanol to give a white solid, 7.7 g (83%). Melting point 91-93.

Elemental analysis: Calculated value (C ₁₂ H ₁₆ ClNO ₃ ): C, 55.93; H, 6.26; N, 5.43 Actual value: C, 55.93; H, 6.28; N, 5.46 Production Example 70 α- (4-Fluorophenyl) ) -2-Pyridineacetonitrile A sample of sodium hydride (60%, 1.60 g, 0.04 mol) was washed with dry hexane. After removing hexane, 100 ml of dimethyl sulfoxide was added. 4-into this mixture
Fluorophenylacetonitrile (5.41g, 0.04mol)
Solution was added. The mixture was stirred at room temperature for 3 hours under nitrogen. 2-Brompyridine (6.32 g, 0.04 mol) was added to the mixture and the reaction mixture was then stirred at 65 ° C overnight.
The reaction mixture was poured into 1.2 l of water and the aqueous phase was extracted several times with chloroform (chloroform layer was filtered through Celite). The chloroform layers were combined and extracted with water and 5% sodium hydroxide. The chloroform layer was dried over sodium sulfate, filtered, and the solvent was removed to give a red oil.
This oil was flash chromatographed on silica gel using 10% ethyl acetate / 90% hexane and 20% ethyl acetate / 80% hexane as the eluent. Fractions of similar purity were combined and the solvent removed in vacuo. The resulting oil was dried under vacuum at 80 ° C overnight to give 2.43 g (2
8.6%). ¹ H (CDCl ₃ ): δ8.5 (m, 1, proton adjacent to N of pyridine nucleus), 6.8-7.8 (m, 7, aromatic), 5.3 (s, 1, methine).

Elemental analysis: Calculated value (C ₁₃ H ₉ N ₂ F): C, 73.57; H, 4.27; N, 13.20 Measured value: C, 73.23; H, 4.23; N, 13.12 Production Example 71 α- (4-fluorf Enyl) -α- [1-[(4-methylphenyl) sulfonyl] -4-piperidinyl] -2
-Pyridineacetonitrile 1/2 hydrate α- (4-Fluorophenyl) -2-pyridineacetonitrile The sodium salt of the elution base is sodium hydride (60%, 5.16g, 0.129mol) in dimethylsulfoxide and α- Prepared from the eluting base of (4-fluorphenyl) -2-pyridineacetonitrile (27.36 g, 0.129 mol). This salt was added to dimethylsulfoxide at room temperature for 4
It was stirred for -1/2 hour. Then 4-methylphenylsulfonic acid and 1-[(4-methylbenzene) sulfonyl] -4
-The ester of piperidinol (52.8 g, 0.129 mol) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was stirred at 80 ° C. overnight. The solvent was removed in vacuo and the resulting residue was dissolved in chloroform. Chloroform was extracted with water and 5% sodium hydroxide. The chloroform layer was dried over sodium sulfate and passed. The solvent was removed to give a dark brown residue. This material was triturated with acetone to give 36.2 g of a white solid. 1 g was triturated with acetone and then recrystallized from methylene chloride-acetone.
The solid was dried in vacuum at 80 ° C. overnight to give 0.74 g of white crystals (62.4% based on aliquot used). Melting point 228-229 ° C.

Elemental analysis: Calculated value (C ₂₅ H ₂₅ N ₃ O _2.5 SF): C, 65.90; H, 5.49; N, 9.16 Measured value: C, 65.86; H, 5.27; N, 9.16 Production Example 72 α- (4- Fluorphenyl) -α- (4-piperidinyl) -2-pyridineacetonitrile oxalate [2:
3] α- (4-Fluorophenyl) -α- [1-[(4-methylphenyl) sulfonyl] -4-piperidinyl] -2-pyridineacetonitrile (30.86 g, 0.0687 mol) in 200 ml of 48% hydrobromic acid. ) And a solution of phenol (75 g, 0.8 mol) were heated to reflux for 3 hours. The mixture was cooled in ice and made alkaline with ice / 50% sodium hydroxide. The aqueous layer was extracted with chloroform, and the chloroform layer was extracted with 5% sodium hydroxide. The chloroform layer was dried over sodium sulfate, filtered and the solvent removed to give a dark brown oil. The entire oil was converted to the oxalate salt in methanol-diethyl ether. 1 g was taken, recrystallized from methanol-diethyl ether, and dried in vacuum at 80 ° C. overnight. This gave 0.90 g of white crystals (80.2% based on the aliquot used). Melting point 98 ° C (softens at 70 ° C).

Elemental analysis: Calculated value (C ₂₁ H ₂₁ N ₃ O ₆ F): C, 58.60; H, 4.92; N, 9.76 Found: 3,58.77; H, 5.01; N, 10.04 Preparation 73 3- (8- A solution of 8-hydroxyquinoline (36.0 g, 0.25 mol) and potassium t-butoxide (28.0 g, 0.25 mol) in 80 ml of quinolinyloxy) -1-propanol dimethylsulfoxide was stirred at room temperature for 1 hour. Three
-Chlor-1-propanol (24.0 g, 0.25 mol) was added and the solution was heated to 70 ° C overnight. This solution was poured into 500 ml of water. A brown solid / lump was obtained. The solid was washed several times with water and then triturated with acetone. The solid was filtered off and dried in vacuo at 80 ° C. overnight to give 35.67 g (70.3%) of a light brown solid. Melting point 126-127 ° C.

Elemental analysis: Calculated value (C ₁₂ H ₁₃ NO ₂ ): C, 70.92; H, 6.45; N, 6.89 Found: C, 70.94; H, 6.49; N, 6.87 Production Example 74 8- (3-Chloropropoxy) Quinoline Dried benzene (dried on 4A molecular sieve) 300ml
3- (8-quinolinyloxy) -1-propanol (32.0 g, 0.158 mol) and thionyl chloride (24.0 g, 0.203
Solution) was heated to reflux for 5 hours. The reaction mixture was cooled to room temperature then stripped to dryness. The residue was treated with potassium carbonate solution (30 g in 500 ml water). The gummy residue was dissolved in chloroform and the solution was extracted with potassium carbonate solution. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed to obtain a black lump.
It crystallized. This was treated with 500 ml boiling hexane. The hexane layer was decanted from the insoluble oil. When the hexane layer cooled, a white solid crystallized. This solid was dried under vacuum at room temperature overnight to yield 26.69 g of a white crystalline solid.
(76.2%) was obtained. Melting point 69-71 ° C.

Elemental analysis: Calculated value (C ₁₂ H ₁₂ NOCl): C, 65.02; H, 5.45; N, 6.32 Measured value: C, 65.19; H, 5.51; N, 6.27 Production Example 75 α, α-bis (4-ful Orphenyl) -1-[(4-
Methylphenyl) sulfonyl] -3-piperidineacetonitrile 4-fluoro-α- (4-fluorphenyl) benzene Sodium salt of acetonitrile is added to dimethyl sulfoxide.
Prepared from its free base (39.42 g, 0.172 mol) and sodium hydride (60%) (6.88 g, 0.172 mol) in 500 ml. The reaction mixture was stirred at room temperature for 1 hour. 1-[(4
-Methylphenyl) sulfonyl] -3-piperidinol-4-methylphenylsulfonic acid ester (70.4 g, 0.17
2 mol) was added and the solution was stirred at 65 ° C. overnight. The solution was stripped to dryness on a rotary evaporator.
The obtained residue was dissolved in chloroform, and the chloroform layer was extracted with 5% sodium hydroxide and water. Chloroform was removed to give a dark brown oil. 8 g of this oil was flash chromatographed on silica gel using 15% ethyl acetate-85% hexane as the eluent. Fractions of similar purity were combined and the solvent removed in vacuo. The residue was dried under vacuum at 80 ° C. overnight, 4.75 g of white amorphous material.
(45.9% of the aliquot used). ¹ H-NMR (CDCl ₃ ): 6.9-7.6δ (m, 12, aromatic), 3.7-4.0
(M, 2, proton adjacent to N of sulfonamide), 2.4
(S, 3, methyl), 1.3-2.9 (m, 7, aliphatic).

Elemental analysis: Calculated value (C ₂₆ H ₂₄ N ₂ O ₂ SF ₂ ): C, 66.93; H, 5.18; N, 6.00 Actual value: C, 66.62; H, 5.20; N, 5.89 Production Example 76 α, α− Bis (4-fluorphenyl) -3-piperidineacetonitrile maleate [1: 1] phenol (25.00 g, 0.2657 mol) in 48 ml of hydrobromic acid containing 48% α, α-bis (4-fluorophenyl) Enenyl) -1-[(4-methylphenyl) sulfonyl] -3
A solution of piperidineacetonitrile (25.00 g, 0.0536 mol) was heated to reflux for 31/2 hours. The solution was cooled to room temperature, diluted to 1 with ice and made alkaline with 50% sodium hydroxide. The purple aqueous phase was extracted 3 times with 300 ml of chloroform each. Chloroform layer 1N sodium hydroxide 15
Back-extract twice with 0 ml each. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed to obtain a light brown oil. The oil was converted to the maleate salt, which was recrystallized from methanol-diethyl ether. The precipitate was dried under vacuum at 80 ° C overnight to give 13.05g (56.8g) of white crystals.
%) Was obtained. Melting point 115-118 ° C.

Calcd _{(C 23 H 22 N 2 O} 4 F 2): C, 64.48; H, 5.18; N, 6.54 Found: C, 64.04; H, 5.15 ; N, 6.50 Preparation 77 4- [bis (4-Fluorophenyl) methyl] -1-
(3-Chloropropyl) piperidine 4- [bis (4-fluorophenyl) methyl] -1-piperidinepropanol (40.27) in 350 ml of chloroform.
g, 0.117 mol, free base) and thionyl chloride (17.90 g,
0.150 mol) was stirred at room temperature for 1/2 hour. 6 solution
Heat to reflux for hours, cool to room temperature, then strip to dryness. The obtained rubber substance was dissolved in chloroform and extracted with saturated sodium hydrogen carbonate. The chloroform layer was dried (anhydrous sodium sulfate), filtered and the solvent removed to give a reddish brown oil (42.11 g). An 8 g sample was flash chromatographed on silica gel using 50-50 (v / v) ethyl acetate-hexane for elution. The fractions were combined, the solvent was removed and the oil was dried in vacuum to give 6.84 g of a brown oil (yield 84.6%, based on aliquot).
Got

Elemental analysis: Calculated value (C ₂₁ H ₂₄ NOF ₂ Cl ₂ ): C, 69.32; H, 6.65; N, 3.85 Found: C, 69.09; H, 6.60; N, 3.84 Preparation 78 7-Hydroxy-4- Oxo-4H-1-benzopyran-
2-Carboxylic acid ethyl ester 30.4 g (0.2 mole ) And diethyl oxalate 58.5 g
A solution of (0.4 mol) was added dropwise over 30 minutes. The mixture is heated at reflux for 4 hours, then 200 ml of concentrated hydrochloric acid and 1.8 of water.
l of solution. The mixture was extracted twice with 500 ml of ethyl ether each time, the extracts were combined and concentrated under reduced pressure to give a solid residue.

This solid was dissolved in a mixture of 250 ml of ethanol and 3 ml of concentrated hydrochloric acid and heated under reflux for 2 hours. The mixture was concentrated under reduced pressure and the solid residue was triturated with ethyl ether, taken up,
Recrystallized from 95% ethanol and 28.1g (60g
%) Was obtained. 217-221 ° C.

Calcd _{(C 12 H 10 O 5)} : C, 61.54; H, 4.30 Found: C61.68; H, 4.34 Preparation 79 alpha, alpha-diphenyl-1- (phenylmethyl) -4-piperidine acetonitrile Hydrochloride [1: 1] 57% sodium hydride in 300 ml of dimethyl sulfoxide
32.80 g (0.17 mol) of diphenylacetonitrile was added to 8.00 g (0.19 mol) of slurry (which had been washed in advance). The solution was heated to 65 ° C for 1 hour. During that time the solution became deep red. Then 1- (phenylmethyl)
An ester of -4-piperidinol and benzenesulfonic acid (0.17 mol) (in 50 ml of dimethyl sulfoxide) was added and the solution was stirred at 60 ° C overnight. Cool the solution, water 1
Injected. This aqueous solution was extracted with toluene (3 x 15
0 ml). The toluene extract was treated with 500 ml of sulfuric acid, which caused a gummy residue to precipitate. The residue is methylene chloride and
Placed in a mixture of 10% sodium hydroxide. The layers were separated, the aqueous layer was extracted with methylene chloride, the extracts were combined and dried over magnesium sulfate. Concentrate to a tan solid 35.0
g (57%) was obtained. Melting point 138-142 ° C.

A small amount was changed to the hydrochloride salt, which was recrystallized from methanol / diethyl ether to give a white powder. Melting point> 250 ° C.

Elemental analysis: Calculated value (C ₂₆ H ₂₇ ClN ₂ ): C, 77.50; H, 6.75; N, 6.95 Found: C, 77.09; H, 6.76; N, 7.04 Production Example 80 α, α-diphenyl-1- (Phenylmethyl) -3-piperidinepropane nitrile hydrochloride [1: 1] α, α-diphenyl-3-piperidine propanenitrile
A mixture of 7.25 g (0.025 mol), benzyl bromide 4.28 g (0.025 mol), and potassium carbonate (5.53 g, 0.04 mol) was added to potassium iodide (0.3 g) in acetonitrile.
Stirred in 300 ml at room temperature overnight. The reaction mixture was stripped to dryness and the resulting residue was dissolved in chloroform. The chloroform layer was extracted several times with water, dried, filtered and the solvent removed to give an oil. The oil was converted to the hydrochloride salt with ethereal hydrogen chloride. The white solid was recrystallized from methanol-diethyl ether and in vacuo.
It was dried at 80 ° C. overnight. White solid 7.04 g (67.5
%)was gotten. Melting point 243-246 ° C (decomposition).

Elemental analysis: Calculated value (C ₂₇ H ₂₉ N ₂ Cl): C, 77.77; H, 7.01; N, 6.72 Found: C, 77.36; H, 6.97; N, 6.67 Production Example 81 α, α-diphenyl-1 -(Phenylmethyl) -4-piperidineacetamide fumarate [1: 1] A solution of 5.88 g (0.02 mol) of α, α-diphenyl-4-piperidineacetamide in acetonitrile was prepared by warming with a hair dryer. To this solution, benzyl bromide 3.42 g (0.02 mol) and potassium carbonate 6.91 g
(0.05 mol) was added. The mixture was stirred at room temperature overnight then heated at reflux for 5 hours. The reaction mixture was stripped to dryness and the resulting residue was partitioned between chloroform-water and chloroform-5% sodium hydroxide. Chloroform was removed to give an oil. This was subjected to column chromatography on silica gel using a mixture of ethyl acetate-dimethoxyethane for elution. Appropriate fractions were combined and converted to the fumarate salt. The salt was recrystallized from methanol-diethyl ether and dried in vacuum at 80 ° C overnight. 1.65 g (10%) of white crystalline material was obtained. Melting point 218-220 ° C.

Elemental analysis: Calculated value (C ₃₀ H ₃₂ N ₂ O ₅ ): C, 71.98; H, 6.44; N, 5.60 Actual value: C, 71.60; H, 6.47; N, 5.51 Production Example 82 α, α-diphenyl- 1- (phenylmethyl) -3-piperidinepropanamide hydrate [1: 0.5] α, α-diphenyl-3-piperidinepropanamide 7.
70 g (0.025 mol), benzyl bromide 4.28 g (0.025 mol),
And a mixture of 5.54 g (0.04 mol) of potassium carbonate, 300 ml of acetonitrile containing potassium iodide (0.3 g)
It was heated to reflux gently overnight. The reaction mixture was stripped to dryness and chloroform-water and chloroform-
Partitioned with 5% sodium hydroxide. Chloroform was removed to give an oil. The oil was column chromatographed on silica gel eluting with dimethoxyethane and ethyl acetate. Combine all column fractions at 80 ° C
After drying in vacuum overnight at., A yellow amorphous solid
3.34 g (32.8%) was obtained. ¹ H NMR (CDCl ₃ ) δ 7.1-7.6 (m, 15, aromatic), 5.5-6.0 (b
rs, 2, NH ₂ ), 3.4 (s, 2, CH ₂ ), 3.1 (s, 1,1 / 2H ₂ O), 1.0-
2.7 (m, 11, aliphatic) Calcd _{(C 27 H 31 N 2 O} 1.5): C, 79.57; H, 7.67; N, 6.87 Found: C, 79.65; H, 7.46 ; N, 6 , 88 Production Example 83 α, α-bis (4-fluorphenyl) -1- (phenylmethyl) -4-piperidineacetonitrile hydrochloride / hydrate [1: 1: 0.5] α, α-bis (4-fluorphenyl) (Enyl) -4-piperidineacetonitrile 6.05 g (0.019 mol), benzyl bromide 3.
A mixture of 32 g (0.019 mol) and 5.53 g potassium carbonate (0.04 mol) was gently heated overnight in 350 ml of acetonitrile containing potassium iodide. The reaction mixture was stripped to dryness and partitioned between chloroform and water. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed to obtain 7.55 g of a pale yellow oil.
The oil was converted to the hydrochloride salt with ethereal hydrogen chloride and the salt was recrystallized from methanol-diethyl ether.
The white solid obtained by filtration was washed with diethyl ether and dried in vacuo overnight at 80 ° C. White crystals 3.
Obtained 85 g (45.2%). Melting point 283 ° C (decomposition).

Elemental analysis: Calculated value (C ₂₆ H ₂₆ N ₂ O _0.5 F ₂ Cl): C, 69.71; H, 5.85; N, 6.25 Measured value: C, 70.07; H, 5.68; N, 6.25 Production Example 84 α, α -Bis (4-fluorophenyl) -1- (phenylmethyl) -3-pyrrolidinepropanenitrile hydrate [1: 0.5] 4-fluoro-α- (4-fluorphenyl) benzene Sodium salt of acetonitrile, dimethyl Prepared from 41.9 g (0.183 mol) of its free base and 7.32 g (0.183 mol) of 60% sodium hydride in sulfoxide. After stirring for 3 hours at room temperature, a solution of 63.18 g (0.183 mol) of 1-phenylmethyl-3-pyrrolidinemethanol methanesulfonate in dimethylsulfoxide was added. The resulting solution was stirred at 60 ° C overnight. The solvent was removed by rotary evaporation in vacuo. The oil obtained was dissolved in chloroform and extracted several times with 1N sulfuric acid. The chloroform layer was extracted with 5% sodium hydroxide, dried over anhydrous sodium sulfate, filtered and the solvent was removed to obtain 59.6 g of a dark brown oil. 10 g fractions were flash chromatographed on silica gel using 50-50 (v / v) ethyl acetate-hexane and 100% ethyl acetate as eluents. Fractions of similar purity were combined and the solvent removed in vacuo. A dark brown oil was obtained, which was dried at 80 ° C. in vacuum overnight.
4.13 g of a dark brown oil (33.5% based on the aliquot used) were obtained. ¹ H-NMR (CDCl ₃ ): δ6.8-7.4 (m, 13, aromatic), 3.5
(S, 2, 1.1-2.8 (m, 9, aliphatic).

Calcd _{(C 26 H 25 N 2 O} 0.5 F 2): C, 75.89; H, 6.12; N, 6.81 Found: C, 75.93; H, 6.00 ; N, 6.55 Example 1 4- (diphenyl Enenylmethylene-1- (3-phenoxypropyl) piperidine = oxalate [1: 1] 3-diphenylmethylenepiperidine 3.3 g (0.013 mol)
And (3-bromopropoxy) benzene 3.3 g (0.015 mol) and anhydrous sodium carbonate 5.3 g (0.05 mol) 1-
A mixture in 100 ml of butanol was heated under reflux for 20 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between water and benzene. The benzene layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the free base of the title compound as an oil as a residue. The free base was converted to oxalate and the solid was recrystallized from absolute ethanol to give 4.3 g (70%) of the title compound as a white powder.
Got Melting point 175-178 ° C.

Elemental analysis: Calculated value for C ₂₉ H ₃₁ NO ₅ : C, 73.55; H, 6.60; N, 2.96 Found: C, 73.59; H, 6.64; N, 2.83 Example 2 α, α-bis (4-fluoro) Phenyl) -1- (3-phenoxypropyl) -4-piperidinemethanol = oxalate = hydrate [1: 1: 0.5] α, α-bis (p-fluorophenyl)]-4-piperidinemethanol A mixture of 3.37 g (0.011 mol), (3-bromopropoxy) benzene 2.52 g (0.011 mol) and sodium bicarbonate 0.92 g (0.011 mol) in 200 ml of 1-butanol was heated under reflux overnight. . Butanol was removed by rotary evaporation and the residue was partitioned between chloroform and water. Removal of chloroform in vacuo yielded the free base of the title compound as a dark brown oil. Conversion of the free base to the oxalate salt and recrystallization of the salt from methanol-diethyl ether gave a white solid 1.41.
g (23.9%) was obtained. Melting point, 153 [deg.] C.

Elemental analysis: Calculated value for C ₂₉ H ₃₂ NO _6.5 F ₂ : C, 64.92; H, 6.01; N, 2.61 Found: C, 65.27; H, 5.87; N, 2.61 Example 3 4- [bis (4- Fluorophenyl) methylene] -1-
(3-Phenoxypropyl) piperidine = oxalate [1: 1] α, α-bis (4-fluorophenyl) -1- (3-phenoxypropyl) -4-piperidinemethanol 7.37 g
A solution of 100 ml of 6N hydrochloric acid (0.0168 mol) in 100 ml of methanol was gently refluxed for 4 hours. The reaction mixture was cooled, made alkaline with water / 50% sodium hydroxide and diluted to 1 liter with water. The aqueous layer was extracted with chloroform and the chloroform was removed to give an oil. The oil was converted to the oxalate salt and recrystallized from methanol-diethyl ether to give 3.45 g (40.3%) of a white solid.
Melting point, 190-192 ° C.

Elemental analysis: Calculated value for C ₂₉ H ₂₉ NO ₅ F ₂ : C, 68.36; H, 5.74; N, 2.75 Found: C, 68.43; H, 5.75; N, 2.69 Example 4 α, α-bis (4 -Fluorophenyl) -1- (3-phenoxypropyl) -4-piperidine Methanol oxalate [1: 1] Magnesium shavings 5.10 g (0.21 mol) and crystals of iodine, and (distilled from lithium aluminum hydride) In a mixture with 800 ml of tetrahydrofuran, 36.75 g (0.21 mol) of p-bromofluorobenzene was added to 10 ml of tetrahydrofuran.
What was dissolved in 0 ml was added. The reaction flask was cooled with an ice bath during this addition and the reaction mixture was placed under an atmosphere of nitrogen. The mixture was stirred at ambient temperature for 1 hour. Ethyl = N- (3-phenoxypropyl) isonicopecotate 20.17 g (0.0693 mol) in tetrahydrofuran 100 ml
Dissolved in and the solution was stirred at room temperature for 16 hours. The mixture was poured into an ice solution of ammonium chloride and the aqueous mixture was extracted with methylene chloride. The methylene chloride solution was extracted with dilute sodium hydroxide and dried over magnesium sulfate. The solvent was removed in vacuo to give a gummy residue.
The residue was treated with oxalic acid in methanol and the salt was recrystallized from methanol-ether to give 24.17 g (66.2%) of white crystalline solid. Melting point, 153-155
° C.

Elemental analysis: Calculated value for C ₂₉ H ₃₁ NO ₆ F ₂ : C, 66.02; H, 5.92; N, 2.66 Found: C, 65.78; H, 5.93; N, 2.63 Example 5 4- (diphenylmethyl) -1 -(4-Phenoxybutyl) piperidine = fumarate [1: 1] 4-diphenylmethylpiperidine 6.99 g (0.0278 mol)
Then, 6.64 g (0.029 mol) of (4-bromobutoxy) benzene and 5 g (0.060 mol) of sodium bicarbonate dissolved in 400 ml of 1-butanol were refluxed for 11 hours. The solvent was evaporated in vacuo and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate and the solvent removed in vacuo to give the free base of the title compound as an oil. The free base was dissolved in 500 ml ether and a small amount of solids was filtered from the solution. To the filtrate was added 3.2 g (0.0276 mol) of fumaric acid dissolved in 60 ml of methanol. The white precipitate is collected to give a white crystalline solid.
7.97 g (55.7%) was obtained. Melting point, 146-147 ° C.

Elemental analysis: Calculated value for C ₃₂ H ₃₇ NO ₅ : C, 74.54; H, 7.23; N, 2.72 Found: C, 74.68; H, 7.24; N, 2.68 Example 6 4- (diphenylmethyl) -1- ( 3-Phenoxypropyl) piperidine fumarate [1: 1] According to the procedure of Example 5, 4- (diphenylmethyl)
The free base of the title compound is formed by reacting piperidine with (3-bromopropoxy) benzene, which is reacted with fumaric acid in methanol to give white fumarate.
Obtained in% yield. Melting point, 171-172 ° C.

Elemental analysis: Calculated value for C ₃₁ H ₃₅ NO ₅ : C, 74.23; H, 7.03; N, 2.79 Found: C, 74.62; H, 7.03; N, 2.73 Example 7 4- [Bis (4-fluorophenyl) (Enyl) methyl] -1-
(3-Phenoxypropyl) piperidine = oxalate [1: 1] According to the treatment method of Example 2, 4- [bis (4-fluorophenyl) methyl] piperidine and (3-bromopropoxy) benzene were used. Was reacted to form the free base of the title compound, which was reacted with oxalic acid and recrystallized from meta-rail-diethyl ether to give a white oxalate salt in 60% yield. Melting point, 178-181 [deg.] C.

Elemental analysis: Calculated value for C ₂₉ H ₃₁ NO ₅ F ₂ : C, 69.09; H, 6.11; N, 2.74 Found: C, 68.37; H, 6.13; N, 2.76 Example 8 4- (diphenylmethyl) -1 -(2-Phenoxyethyl) piperidine = fumarate [1: 1] According to the procedure of Example 5, 4- (diphenylmethyl)
Reacting piperidine with (2-bromoethoxy) benzene to form the free base of the title compound, which is reacted with fumaric acid in an ether-methanol mixture to give a white fumarate in 85% yield. It was Melting point, 189-190 ° C.

Elemental analysis: Calculated value for C ₃₀ H ₃₃ NO ₅ : C, 73.90; H, 6.82; N, 2.87 Found: C, 74.07; H, 6.91; N, 2.85 Example 9 4- [Bis (4-fluorophenyl) (Enyl) methyl] -1-
(2-phenoxyethyl) piperidine oxalate [1: 1] 4- [bis (4-fluorophenyl) methyl] piperidine 5.83 g (0.02 mol) and (2-bromoethoxy) benzene 4.02 g (0.02 mol), 3.18 g of sodium carbonate (0.03
Mol) was gently heated to reflux in 300 ml of 1-butanol overnight. The reaction was filtered and the solvent removed in vacuo. The residue was dissolved in chloroform and extracted with water and 5% sodium hydroxide. Evaporation of chloroform gave an oil which was converted to the oxalate salt. The salt was recrystallized from methanol-diethyl ether to give 6.0 g (60.3%) of white crystalline product. Melting point, 180-182 ° C.

Elemental analysis: Calculated value for C ₂₈ H ₂₉ NO ₅ F ₂ : C, 67.60; H, 5.88; N, 2.82 Found: C, 67.68; H, 5.87; N, 2.81 Example 10 4- [bis (4- Fluorophenyl) methyl] -1-
(4-Phenoxybutyl) piperidine = oxalate [1: 1] According to the treatment method of Example 2, 4- [bis (4-fluorophenyl) methyl] piperidine was reacted with (4-bromopropoxy) benzene. Produces the free base of the title compound, which is reacted with oxalic acid to give a white oxalate salt (recrystallized from methanol-diethyl ether) 48%.
It was obtained in a yield of. Melting point, 206 ° C.

Elemental analysis: calculated for _{C 30 H 33 NO 5 F 2} : C, 68.56; H, 6.33; N, 2.67 Found: C, 68.79; H, 6.35 ; N, 2.67 Example 11 4 - [(4-fluoro (Phenyl) -phenylmethyl]-
1- (3-phenoxypropyl) piperidine = fumarate [1: 1] 4- [α- (p-fluorophenyl) -α-phenylmethyl] piperidine 5.4 g (0.02 mol) and (3-bromopropoxy) benzene A mixture of 4.5 g (0.021 mol), 8.0 g (0.075 mol) anhydrous sodium carbonate and acetonitrile (150 ml) was refluxed for about 20 hours and concentrated under reduced pressure to give a gummy residue. This residue was added to Florisil® 16
Purify by column chromatography on 0 g and elute the product with 2% acetone / benzene to give the free base of the title compound as an oil. When the free base is reacted with fumaric acid and the salt is recrystallized from isopropyl alcohol,
4.0 g (38%) of white crystals were obtained. Melting point, 169-171 [deg.] C.

Elemental analysis: Calculated value for C ₃₁ H ₃₄ FNO ₅ F: C, 71.66; H, 6.60; N, 2.70 Found: C, 71.37; H, 6.55; N, 2.66 Example 12 4- [bis (4-fluoro (Phenyl) methyl] -1-
[2- (2,6-Dichlorophenoxy) ethyl] piperidine 4- [bis (4-fluorophenyl) methyl] piperidine 6.13 g (0.021 mol) and 2- (2-bromoethoxy)-
A mixture with 5.38 g (0.03 mol) of 1,3-dichlorobenzene was gently heated to reflux overnight in 200 ml of 1-butanol. The reaction mixture was filtered, stripped to dryness. The residue was dissolved in chloroform and extracted with water and 5% sodium hydroxide solution. The obtained oil was chromatographed on 300 g of silica gel using hexane-ethyl acetate (50/50 v / v) as the eluent. The solvent was distilled off from the fractions containing the product to obtain an oil. The oil was dried under vacuum at 80 ° C overnight. This gave 5.99 g (59%) of product oil.

Elemental analysis: Calculated value for C ₂₆ H ₂₅ NOF ₂ Cl ₂ : C, 65.55; H, 5.29; N, 2.94 Found: C, 65.43; H, 5.34; N, 2.77 ¹ H NMR of this compound was determined by tetramethylsilane. Including CDCl ₃
This was in agreement with the structure of the title compound.

δ1.1-2.3 Aliphatic proton (cyclic) 7H δ2.8 or triple line N ₂ adjacent to N 2H δ2.8-3.1 N adjacent hydrogen 2H δ3.5, double line methine proton 1H δ6.8- 7.4 Aromatic Proton 11H Example 13 1- [3- (4-chlorophenoxy) propyl] -α,
α-bis (4-fluorophenyl) -4-piperidinemethanol [α, α-bis (p-fluorophenyl)]-4-piperidinemethanol 3.0 g (0.01 mol) and 1-chloro-4-
(3-chloropropoxy) benzene 2.0 g (0.01 mol)
Then, a mixture of anhydrous sodium carbonate 5.3 g (0.05 mol), potassium iodide 0.3 g and 1-butanol 100 ml was refluxed for 20 hours and treated in the same manner as in Example 1 (the free base was reconstituted from isopropyl alcohol). When crystallized), white crystals 1.
7 g (36%) was obtained. Melting point, 92-93 ° C.

Elemental analysis: Calculated value for C ₂₇ H ₂₈ ClF ₂ NO ₂ : C, 68.71; H, 5.98; N, 2.97 Found: C, 68.66; H, 5.99; N, 2.92 Example 14 4- [bis (4- Fluorophenyl) methyl] -1-
[3- (2-Fluorophenoxy) propyl] piperidine = oxalate [1: 1] 4- [bis (p-fluorophenyl) methyl] piperidine 5.85 g (0.02 mol) and 2- (3-chloropropoxy ) -1-Fluorobenzene 3.76 g (0.02 mol) and sodium carbonate 4.80 g (0.045 mol) potassium iodide 0.
A mixture of 3 g in 1-butanol (300 ml) was gently heated to reflux overnight. The reaction mixture was stripped to dryness and the resulting oil was partitioned between chloroform and 5% sodium hydroxide, then chloroform and water. Evaporation of chloroform gave an oil which was converted to the oxalate salt. Methanol with salt
Recrystallized from diethyl ether. The salt was then triturated with isopropanol and dried overnight at 80 ° C to give the product 5.82.
g (55%) was obtained. Melting point, 182-183 [deg.] C.

Elemental analysis: Calculated value for C ₂₉ H ₃₀ NO ₅ F ₃ : C, 65.78; H, 5.71; N, 2.65 Found: C, 66.05; H, 5.79; N, 2.59 Example 15 4- [bis (4- Fluorophenyl) methyl] -1-
[3- (3-Fluorophenoxy) propyl] piperidine = mandelate [1: 1] According to the treatment method of Example 14, 4- [bis (4-fluorophenyl) methyl] piperidine and 3- (3 -Chloropropoxy) -1-fluorobenzene was reacted to give the free base of the title compound, which was reacted with mandelic acid to give a white mandelate salt (recrystallized from isopropyl alcohol), melting point 145-147.5 ° C. (Yield 62%).

Elemental analysis: Calculated value for C ₃₅ H ₃₆ NO ₄ F ₃ : C, 71.05; H, 6.13; N, 2.37 Found: C, 71.10; H, 6.20; N, 2.36 Example 16 4- [bis (4- Fluorophenyl) methyl] -1-
[3- (4-Chlorophenoxy) propyl] piperidine = fumarate [1: 1] According to the treatment method of Example 14, 4- [bis (4-fluorophenyl) methyl] piperidine and 1- [4- Reaction with (3-chloropropoxy) -1-chlorobenzene gave the free base of the title compound. The free base was chromatographed on silica gel, eluted with hexane-ethyl acetate and reacted with fumaric acid to form the fumarate (methanol-
Recrystallized from diethyl ether) was obtained with a yield of 9%. Melting point, 169-170 ° C.

Elemental analysis: Calculated value for C ₃₁ H ₃₂ NO ₅ F ₂ Cl: C, 65.10; H, 5.64; N, 2.45 Found: C, 64.85; H, 5.63; N, 2.46 Example 17 4- [bis (4 -Fluorophenyl) methyl] -1-
[3- (4-Fluorophenyloxy) propyl] piperidine According to the treatment method combining Examples 14 and 16, 4- [bis (4-fluorophenyl) methyl] piperidine and 4-
Reacted with (3-chloropropoxy) -1-fluorobenzene, treated by chromatography in Example 16 and dried in vacuo at 80 ° C. overnight to give 53% yellow oil free base. Obtained in yield.

Elemental analysis: Calculated value for C ₂₇ H ₂₈ NOF ₃ : C, 73.78; H, 6.42; N, 3.19 Found: C, 73.64; H, 6.39; N, 3.14 Example 18 4- [bis (4-fluorophenyl) (Enyl) methyl] -1-
[3- (4-Methoxyphenoxy) propyl] piperidine = fumarate [1: 1] According to the treatment method of Example 14, 4- [bis (4-fluorophenyl) methyl] piperidine and 1- (3 -Chloropropoxy) -4-methoxybenzene to give the free base of the title compound, which is reacted with fumaric acid to give a white fumarate (recrystallized from methanol-diethyl ether) in 64% yield. Got with. Melting point, 172-173 ° C.

Elemental analysis: Calculated value for C ₃₂ H ₃₅ NO ₆ F ₂ : C, 67.71; H, 6.22; N, 2.47 Found: C, 67.89; H, 6.25; N, 2.39 Example 19 4- [bis (4- Fluorophenyl) methyl] -1-
[3- (2-Methoxyphenoxy) propyl] piperidine 4- [bis (4-fluorophenyl) methyl] piperidine 5.99 g (0.021 mol) and 2- (3-chloropropoxy) -1-methoxybenzene ether A mixture of 4.35 g (0.022 mol) and 3.18 g (0.03 mol) of sodium carbonate in 1-butanol was gently heated to reflux overnight. The reaction mixture was filtered off, stripped and dried. The residue was dissolved in chloroform and the solution was extracted with water and 5% sodium hydroxide. Evaporation of chloroform gave a dark brown oil. The oil was chromatographed on silica gel, eluting with acetone-ethyl acetate. The fractions were combined and the solvent was evaporated to give an oil. The oil was dried under vacuum at 80 ° C overnight. This gave 3.18 g (33.5%) of the title compound.

Elemental analysis: Calculated value for C ₂₈ H ₃₁ NO ₂ F ₂ : C, 74.48; H, 6.92; N, 3.12 Found: C, 74.42; H, 6.95; N, 3.00 ¹ H NMR of this compound was confirmed to be tetramethylsilane. Including CDCl ₃
This was in agreement with the structure of the title compound.

δ6.8 Proton on the ring containing a singlet or a methoxy group 4H δ6.8-7.3 Aromatic proton on the fluorophenyl ring 8H δ4.0 Triplet, CH ₂ —O 2H δ3.8 Singlet, O-CH ₃ 3H δ3.4 Doublet, methine proton 1H δ0.8-3.1 Multiplet 13H Example 20 α, α-bis (4-fluorophenyl) -1- [3-
(2-Methoxyphenoxy) propyl] -4-piperidinemethanol According to the procedure of Example 1, [α, α-bis (p-fluorophenyl)]-4-piperidinemethanol and 1
-Chloro-3- (2-methoxyphenoxy) propane was further reacted with a potassium iodide catalyst to obtain the title compound (recrystallized from isopropyl alcohol) in a yield of 66%. Melting point, 127-218 [deg.] C.

Elemental analysis: Calculated value for C ₂₈ H ₃₁ F ₂ NO ₃ : C, 71.93; H, 6.68; N, 3.00 Found: C, 71.88; H, 6.67; N, 2.98 Example 21 4- [bis (4- Fluorophenyl) methylene] -1-
[3- (2-Methoxyphenoxy) propyl] piperidine = oxalate [1: 1] According to the treatment method of Example 14, 4- [bis (4-fluorophenyl) methylene] piperidine and 2- (3 -Chloropropoxy) -1-methoxybenzene was further reacted with potassium iodide catalyst to give the free base of the title compound, which was reacted with oxalic acid to give white oxalate (methanol-diethyl ether). Was obtained in 73% yield. Melting point, 184-186 [deg.] C.

Elemental analysis: calculated for _{C 30 H 31 NO 6 F 2} : C, 66.78; H, 5.79; N, 2.60 Found: C, 66.74; H, 5.79 ; N, 2.61 Example 22 4- [bis (4- Fluorophenyl) methyl] -1-
[3- (3,4-Dimethoxy-phenoxy) propyl] piperidine = oxalate [1: 1] 4- [bis (4-fluorophenyl) methyl] piperidine 6.02 g (0.021 mol) and 4- (3-chloropropoxy )
A mixture of 4.83 g (0.021 mol) of 1,2-dimethoxybenzene and 5.52 g (0.04 mol) of potassium carbonate was refluxed overnight in 300 ml of 1-butanol containing 0.3 g of potassium iodide.
The reaction mixture was stripped to dryness and partitioned several times with chloroform and water. The chloroform layer was dried over anhydrous sodium sulfate and then passed through. Chloroform was removed on a rotary evaporator. The oil obtained was converted to a chiosalate salt and then recrystallized from methanol-diethyl ether and methanol isopropanol ether. 7.77 g (64.7%) of a white solid was obtained (melting point, 1
88 ° C).

Elemental analysis: Calculated value for C ₃₁ H ₃₅ NO ₇ F ₂ : C, 65.14; H, 6.17; N, 2.43 Found: C, 64.78; H, 6.14; N, 2.44 Example 23 4- [bis (4- Methylphenyl) methyl] -1- [3
-(2,6-Dimethoxyphenoxy) propyl] piperidine = fumarate [1: 1] Following the procedure of Example 22, 4- [bis (4-methylphenyl) methyl] piperidine and 2- (3-chloro) Propoxy) -1,3-dimethoxybenzene was reacted to give the free base of the title compound, which was reacted with fumaric acid to give a white fumarate salt (recrystallized from methanol-diethyl ether) in 66% yield. (mp 206-207 ° C.) elemental analysis: calculated for _{C 35 H 43 NO 7: C} , 71.29; H, 7.35; N, 2.38 Found: C, 71.24; H, 7.38 ; N, 2.36 example 24 4- [Bis (4-fluorophenyl) methylene] -1-
[3- (3,4-Dimethoxyphenoxy) propyl] piperidine = oxalate [1: 1] According to the treatment method of Example 22, 4- [bis (4-fluorophenyl) methylene] piperidine and 4- Reacting with (3-chloropropoxy) -1,2-dimethoxybenzene,
The free base of the title compound was obtained, which was reacted with oxalic acid to give a cream oxalate salt (recrystallized from methanol-diethyl ether) in 51% yield. Melting point, 173-1
76 ° C.

Elemental analysis: Calculated value for C ₃₁ H ₃₃ NO ₇ F ₂ : C, 65.37; H, 5.84; N, 2.46 Found: C, 65.02; H, 5.83; N, 2.50 Example 25 4- [bis (4- Fluorophenyl) methyl] -1-
[3- (2,6-Dimethoxyphenoxy) propyl] piperidine = oxalate = hydrate [1: 1: 1] Dimethoxyethane was used according to the procedure of Example 22 except that butanol was used. About 4- [bis (4-
Fluorophenyl) methyl] piperidine is reacted with 2- (3-chloropropoxy) -1,3-dimethoxybenzene to give the free base of the title compound, which is reacted with oxalic acid to give a white oxalate salt. (Recrystallized from methanol-diethyl ether) was obtained with a yield of 9%. Melting point, 132-1
34 ° C.

Elemental analysis: Calculated value for C ₃₁ H ₃₇ NO ₈ F ₂ : C, 63.15; H, 6.32; N, 2.38 Found: C, 62.89; H, 5.98; N, 2.41 Example 26 4- [bis (4- Fluorophenyl) methyl] -1-
[3- (3,5-Dimethoxyphenoxy) propyl] piperidine 4- [bis (4-fluorophenyl) methyl] piperidine 5.51 g (0.019 mol) and 1- (3-chloropropoxy) -3,5 -Dimethoxybenzene 4.42g (0.019mol)
And 5.53 g (0.04 mol) of potassium carbonate were heated to reflux overnight in 350 ml of 1-butanol containing 0.3 g of potassium iodide. The reaction mixture was stripped to dryness and the residue was partitioned between chloroform-5% sodium hydroxide and chloroform-water. Evaporation of chloroform gave a brown oil. The oil was chromatographed on silica gel using a hexane-ethyl acetate and ethyl acetate-dimethoxyethane gradient elution system. The appropriate fractions eluting from the column were combined, the solvent was evaporated and the residual oil was dried in vacuo at 80 ° C overnight. This gave 2.61 g (28.5%) of a brown oil.

Elemental analysis: Calculated value for C ₂₉ H ₃₃ NO ₃ F ₂ : C, 72.33; H, 6.91; N, 2.91 Found: C, 71.62; H, 6.80; N, 2.98 ¹ H NMR of this compound was determined by tetramethylsilane. Including CDCl ₃
This was in agreement with the structure of the title compound.

δ7.0 multiplet, aromatic proton on fluorophenyl ring δ6.0 singlet, aromatic proton on methoxyphenyl ring 3H δ2.8 triplet, methylene proton adjacent to ether oxygen 2H δ3.75 singlet , OCH ₃ 6H δ3.4 doublet, methine 1H δ0.75-2.6 multiplet attached to two aromatic rings, residual aliphatic proton 13H Example 27 4- [bis (4-methoxyphenyl) ) Methyl] -1-
[3- (3,4-Dimethoxyphenoxy) propyl] piperidine 4- [bis (4-methoxyphenyl) methyl] piperidine 5.58 g (0.02 mol) and 4- (3-chloropropoxy) -1,2 -Dimethoxybenzene 4.83g (0.021mol)
And 5.52 g (0.04 mol) of potassium carbonate were heated to reflux overnight in 350 ml of 1-butanol containing 0.3 g of potassium iodide. The reaction mixture was stripped to dryness and the residue was partitioned between chloroform-5% sodium hydroxide and chloroform-water. Evaporation of chloroform gave a dark brown oil. The oil was chromatographed on silica gel with ethyl acetate-dimethoxyethane. This gives 4.72 g of dark brown oil (46.7 g
%) Was obtained.

Elemental analysis: Calculated value for C ₃₁ H ₃₉ NO ₅ : C, 73.64; H, 7.77; N, 2.77 Found: C, 72.38; H, 7.70; N, 2.72 ¹ H NMR of this compound includes tetramethylsilane CDCl ₃
This was in agreement with the structure of the title compound.

Example 28 4- [bis (4-methoxyphenyl) methyl] -1-
[3- (4-Methoxyphenoxy) propyl] piperidine = fumarate = hydrate [1: 1: 0.5] According to the treatment method of Example 22, 4- [bis (4-methoxyphenyl) methyl] Piperidine is reacted with 4- (3-chloropropoxy) -1-methoxybenzene to give the free base of the title compound, which is separated by extraction with sodium hydroxide-chloroform and reacted with fumaric acid. The title salt (recrystallized from methanol-diethyl ether several times and isopropanol) was obtained in 15% yield. Melting point, 163-165 ° C.

Elemental analysis: Calculated value for C ₃₄ H ₄₂ NO _8.5 : C, 67.98; H, 7.05; N, 2.33 Found: C, 68.16; H, 6.97; N, 2.34 Example 29 1- [4- [3- [ 4- [bis (4-fluorophenyl) methylene] -1-piperidine] propoxy] phenyl] ethanone oxalate [1: 1] Sodium carbonate was used instead of sodium bicarbonate according to the procedure of Example 2. To react 4- [bis (4-fluorophenyl) methylene] piperidine with 1- [4- (3-chloropropoxy) phenyl] ethanone to give the free base of the title compound, which is reacted with oxalic acid. Oxalate (recrystallized from methanol-diethyl ether)
Was obtained in a yield of 59%. Melting point, 196-198 ° C.

Elemental analysis: Calculated value for C ₃₁ H ₃₃ NO ₆ F ₂ : C, 67.26; H, 6.01; N, 2.53 Found: C, 66.94; H, 6.01; N, 2.40 Example 30 1- [4- [3 -[4- [Bis (4-fluorophenyl) methyl] -1-piperidinyl] propoxy] phenyl] ethanone oxalate [1: 1] According to the procedure of Example 2, sodium carbonate is used instead of sodium bicarbonate. With 4- [bis (4-fluorophenyl) methyl] piperidine and 1- [4- (3-chloropropoxy) phenyl] ethanone to give the free base of the title compound, which is reacted with oxalic acid. The oxalate salt (recrystallized from methanol-diethyl ether)
Obtained in% yield. Melting point, 141-143 [deg.] C.

Elemental analysis: Calculated value for C ₃₁ H ₃₃ NO ₆ F ₂ : C, 67.26; H, 6.01; N, 2.53 Found: C, 66.94; H, 6.01; N, 2.40 Example 31 1- [4- [3 -[4- [bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] phenyl] ethanone = 2-propanol [1: 1] According to the treatment method of Example 1, a potassium iodide catalyst was used. Using [α, α-bis (p-fluorophenyl)]-4-
Piperidine methanol was reacted with 1- [4- (3-chloropropoxy) phenyl] ethanone to give the free base of the title compound, which was recrystallized from isopropyl alcohol to give the white title compound in 71% yield. It was Melting point,
72 ~ 84 ℃.

Elemental analysis: Calculated value for C ₂₉ H ₃₁ F ₂ NO ₃ .C ₃ H ₈ O: C, 71.22; H, 7.28; N, 2.60 Found: C, 71.26; H, 7.34; N, 2.56 NMR It was shown that the solid contained 1 mol of 2-propanol as a solvate.

Example 32 1- [4- [3- [4- [bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] -3-methylphenyl] ethanone According to the procedure of Example 1, Using a potassium iodide catalyst, [α, α-bis (p-fluorophenyl)]-4-
Piperidine methanol was reacted with 1- [4- (3-chloropropoxy) -3-methylphenyl] ethanone to give the white title compound (recrystallized from isopropyl alcohol).
Was obtained in a yield of 76%. Melting point, 116-117 ° C.

Elemental analysis: Calculated value for C ₃₀ H ₃₃ F ₂ NO ₃ : C, 73.00; H, 6.74; N, 2.84 Found: C, 72.90; H, 6.80; N, 2.78 Example 33 4- [3- [4 -[Bis (4-fluorophenyl) hydroxymethyl] -1-piperidinine] propoxy] benzonitrile Following the procedure of Example 1, using potassium iodide as a catalyst, [α, α-bis (p- Fluorophenyl))
-4-Piperidinemethanol was reacted with 4- (3-chloropropoxy) benzonitrile to obtain a white title compound (recrystallized from isopropyl alcohol-isopropyl ether) in a yield of 30%. Melting point, 107-108 ° C.

Elemental analysis: Calculated value for C ₂₈ H ₂₈ F ₂ N ₂ O ₂ : C, 72,71; H, 6.10; N, 6.06 Found: C, 72.82; H, 6.11; Body, 6.05 Example 34 4- [ 3- [4- [bis (4-fluorophenyl) methyl] -1-piperidinyl] propoxy] benzonitrile fumarate [1: 1] According to the procedure of Example 22, using a potassium iodide catalyst, 4- [bis (4-fluorophenyl) methyl] piperidine is reacted with 4- (3-chloropropoxy) cyanobenzene to give the free base of the title compound, which is reacted with fumaric acid to form the fumarate (methanol -Recrystallized from diethyl ether) in a yield of 53%. Melting point, 167 [deg.] C.

Elemental analysis: Calculated value for C ₃₂ H ₃₂ N ₂ O ₅ F ₂ : C, 68.32; H, 5.73; N, 4.98 Found: C, 68.10; H, 5.70; N, 4.94 Example 35 4- [3- [4- [bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] benzoic acid ethyl ester = hydrochloric acid [1: 1] [α, α-bis (p-fluorophenyl)]-4- Piperidine methanol 6.0 g (0.02 mol) and 4- (3-chloropropoxy) benzoic acid methyl ester 5.0 g (0.02 mol)
A mixture of 0.4 g (0.07 mol) of anhydrous sodium carbonate, 0.3 g of 0.3 g of potassium iodide and 150 ml of dimethylformamide was heated on a steam bath for 20 hours and then poured into 1.5 liters of ice-water. A gum precipitated and the aqueous solution was decanted. The gum was dissolved in benzene and the solution was washed with water and dilute sodium hydroxide, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 9.2 g of gum as a residue. The gum was purified by column chromatography on 200 g Florisil® and the desired product was eluted with 20% acetone / benzene. Fractions containing the free base of the title compound were combined and concentrated under reduced pressure to give a gummy free base as a residue. Convert this free base to the hydrochloride salt,
When recrystallized from 2-propanol, 5.3 g of white powder (49
%) Was obtained. Melting point, 193.5-194.5 ° C.

Elemental analysis: C ₃₀ H ₃₄ ClF Calculated for _{2 NO 4: C, 65.99;} H, 6.28; N, 2.57 Found: C, 66.16; H, 6.32 ; N, 2.56 Example 36 4- [3- [4 -[Bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] benzoic acid = hydrochloric acid = hydrate [1: 1: 1] 4- [3- [4- [bis (4-fluorophenyl Ethenyl) hydroxymethyl] -1-piperidinyl] propoxy] benzoic acid ethyl ester 2.7 g (0.005 mol) and potassium hydroxide 1.2 g (0.022 mol) were added to ethanol 50 ml and water 20 ml.
What was melt | dissolved in was heated for 2 hours on the steam bath. Acetic acid
10 ml was added, the solution was poured into 500 ml ice water and the mixture was left at ambient temperature overnight. Sodium chloride was added to the mixture resulting in an agglomerated solid. The solid was filtered off and air dried. This solid was dissolved in 20 ml of isopropyl alcohol, and the solution was poured into 30 ml of ethereal hydrochloric acid. The slowly crystallizing salt was collected by filtration, washed with ethyl ether and dried, yielding 0.2 g (8%) of a white powder. Melting point, 148-1
58 ℃ (decomposition).

Elemental analysis: Calculated value for C ₁₉ H ₃₀ ClF ₂ NO ₄ .0.5H ₂ O: C, 63.82; H, 5.93; N, 2.66 Found: C, 63.97; H, 6.25; N, 2.51 Example 37 4- [3- [4- [bis (4-fluorophenyl) methyl] -1-piperidinyl] propoxy] benzoic acid ethyl ester = hydrogen bromide [1: 1] 4- [bis (4-fluorophenyl) methylene] 6.09 g (0.021 mol) of piperidine and 1- [4- (3-chloropropoxy) -phenyl: carbetoxybenzene 5.20 g
A mixture of (0.02 mol) and 4.30 g (0.04 mol) of sodium carbonate in 230 ml of 1-butanol containing 0.3 g of potassium iodide was gently heated to reflux overnight. The reaction mixture was stripped to dryness and partitioned between chloroform-water and chloroform-5% sodium hydroxide. Evaporation of chloroform produced an oil. This oil was converted to the hydrobromide salt with hydrogen bromide in glacial acetic acid. Acetic acid and excess hydrogen bromide were removed in vacuo. The salt was recrystallized from methanol-diethyl ether. The salt was washed with water to remove acetamide present as an impurity. The salt was washed with diethyl ether and dried in vacuo at 80 ° C overnight. A white solid was obtained in a yield of 6.81 g (59.5%). Melting point, 192-194 [deg.] C.

Elemental analysis: Calculated value for C ₃₀ H ₃₂ NO ₃ F ₂ Br: C, 62.94; H, 5.63; N, 2.45 Found: C, 62.83; H, 5.58; N, 2.45 Example 38 4- [3- [ 4- [bis (4-fluorophenyl) methyl] -1-piperidinyl] propoxy] benzoic acid ethyl ester = hydrogen bromide [1: 1] According to the procedure of Example 14, 4- [bis (4- Fluorophenyl) methyl] piperidine and 4- (3-chloropropoxy) benzoic acid ethyl ester were reacted using potassium iodide as a catalyst to obtain a free base, which was reacted with hydrogen bromide in glacial acetic acid. Let The oil was stripped to dryness and the solid obtained was recrystallized from isopropyl alcohol-diethyl ether to give a white salt.
Obtained in% yield. Melting point, 142-144 [deg.] C.

Elemental analysis: Calculated value for C ₃₀ H ₃₄ NO ₃ F ₂ Br: C, 62.72; H, 5.97; N, 2.44 Found: C, 62.66; H, 5.95; N, 2.45 Example 39 4- [3- [ 4- [bis (4-methoxyphenyl) methyl] -1-piperidinyl] propoxy] benzoic acid butyl ester 4- [bis (4-methoxyphenyl) methyl] -1-piperidine 6.22 g (0.02 mol) and 4 -(3-Chloropropoxy) benzoic acid ethyl ester 4.84 g (0.02 mol)
And potassium carbonate 5.60 g (0.04 mol) 1-butanol 3
The mixture in 50 ml was refluxed with potassium iodide overnight. The reaction mixture was stripped to dryness and the residue was partitioned between chloroform-5% sodium hydroxide and then chloroform-water. When chloroform is distilled off,
Produced oil. This oil was chromatographed on 200 g of silica gel column-packed with 50/50 (v / v) Hekin-ethyl acetate. This material was eluted with a hexane-ethyl acetate mixture and finally with 1% methanol-ethyl acetate. 5.09 g of oil (46.6
%) Was obtained.

Elemental analysis: Calculated value for C ₃₄ H ₄₃ NO ₅ : C, 74.83; H, 7.94; N, 2.57 Actual value: C, 74.19; H, 7.91; N, 2.53 ¹ H NMR spectrum was obtained with tetramethylsilane and described. Consistent with the structure of the compound.

[delta] 8.0 (CO ortho to ₂ protons, 2H) 6.8 (m, aromatic, 10H) 4.2 (m, CH 2 in α-position to O, 4H) 3.7 (s, OCH 3, 6H) 0.9-3.5 (m, aliphatic, 31H) Example 40 4- [3- [4- [bis (4-methoxyphenyl) methyl] -1-piperidinyl] propoxy] benzoic acid ethyl ester = fumarate = Hydrate [1: 1: 0.5] 4- [3- [4- [4- [3- [4-
[Bis (4-methoxyphenyl) methyl] piperidine is reacted with 4- (3-chloropropoxy) benzoic acid ethyl ester to produce the free base of the title compound, which is reacted with fumaric acid. White fumarate (recrystallized from methanol-diethyl ether) was obtained with a yield of 27%. Melting point, 147.5-148.5 ° C.

Elemental analysis: Calculated value for C ₃₆ H ₄₄ NO _9.5 : C, 67.27; H, 6.90; N, 2.18 Found: C, 62.26; H, 6.78; N, 2.19 Example 41 4- [3- [4- [ Bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] ethoxy] benzoic acid ethyl ester = hydrochloride According to the procedure of Example 35, α, α-bis (p-fluorophenyl) -4- Piperidine = Methanol and 4- (2
-Chloroethoxy) benzoic acid ethyl ester was reacted to prepare the hydrochloride salt.

Example 42 4- [3- [4- [bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] -3
-Methoxybenzeneacetic acid ethyl ester = hydrochloride According to the procedure of Example 35, [α, α-bis (p-fluorophenyl) -4-piperidine = methanol and 4-
Hydrochloride was prepared by reacting (3-chloropropoxy) -3-methoxybenzene acetic acid ethyl ester.

Example 43 4- [bis (4-fluorophenyl) methylene] -1-
[3- [4- (1,1-Dimethylethyl) phenoxy] propyl] piperidine fumarate [1: 1] According to the procedure of Example 9, 4- [bis (4-fluorophenyl) methylene ] Piperidine and 4- (3-chloropropoxy)-(1,1-dimethylethyl) benzene were reacted with potassium iodide catalyst to give an oil, which was dissolved in ethyl acetate and filtered through silica gel. , The free base of the title compound was obtained. The free base was reacted with fumaric acid to give a white fumarate salt (recrystallized from isopropyl ar-diethyl ether) in a yield of 40 ° C. Melting point, 208.5-209.5 ° C.

Elemental analysis: Calculated value for C ₃₅ H ₃₉ NO ₅ F ₂ : C, 71.05; H, 6.64; N, 2.37 Found: C, 70.91; H, 6.57; N, 2.38 Example 44 4- [bis (4- Fluorophenyl) methyl] -1-
[3- [4- (1,1-Dimethylethyl) phenoxy] propyl] piperidine = fumarate = hydrate [1: 1: 0.5] According to the treatment method of Example 9, 4- [bis (4 -Fluorophenyl) methyl] piperidine and 4- (3-chloropropoxy)-(1,1-dimethylethyl) benzene,
Reaction with a potassium iodide catalyst gave the free base of the title compound. Reacting this free base with fumaric acid,
White fumarate (recrystallized from methanol-diethyl ether and isopropyl alcohol-diethyl ether) was obtained in 55% yield. Melting point, 194-196 ° C (decomposition).

Elemental analysis: Calculated value for C ₃₅ H ₄₂ NO _5.5 F ₂ : C, 69.75; H, 7.02; N, 2.32 Found: C, 70.01; H, 6.89; N, 2.44 Example 45 4- [bis (4- Methoxyphenyl) methyl] -1-
[3- [4- (1,1-Dimethylethyl) phenoxy] propyl] piperidine = oxalate [1: 1] According to the treatment method of Example 22, 4- [bis (4-methoxyphenyl) methyl] piperidine And 4- (3-chloropropoxy)-(1,1-dimethylethyl) benzene,
Reaction with potassium iodide catalyst gave the free base. The free base was reacted with oxalic acid to give a white oxalate salt (recrystallized from methanol-diethyl ether).
Obtained in% yield. Melting point, 212 [deg.] C.

Elemental analysis: Calculated value for C ₃₅ H ₄₅ NO ₇ : C, 71.04; H, 7.67; N, 2.37 Found: C, 70.91; H, 7.70; N, 2.35 Example 46 1- [3- [4- ( 1,1-Dimethylphenyl) phenoxy] propyl] -α, α-bis (4-fluorophenyl) -4-piperidine = methanol According to the treatment method of Example 1, [α, α-bis (p- Fluorophenyl)]-4-piperidinemethanol and 4
-(3-Chloropropoxy)-(1,1-dimethylethyl) benzene was reacted with a potassium iodide catalyst to give a white powder (recrystallized from isopropyl alcohol).
Obtained in a yield of 41%. Melting point, 126-127 ° C.

Elemental analysis: Calculated value for C ₃₁ H ₃₇ F ₂ NO ₂ : C, 75.43; H, 7.56; N, 2.84 Found: C, 75.21; H, 7.58; N, 2.82 Example 47 4- [bis (4- Fluorophenyl) methyl] -1-
[3- [3- (Trifluoromethyl) phenoxy] propyl] piperidine = oxalate [1: 1] According to the treatment method of Example 9, 4- [bis (4-fluorophenyl) methyl] piperidine and 1- (3-Chloropropoxy) -3-trifluoromethylbenzene was reacted with potassium iodide catalyst to give the free base of the title compound. The free base was reacted with oxalic acid to give a white oxalate salt (recrystallized from methanol-diethyl ether) in 39% yield. Mp, one hundred and eighty-five to one hundred eighty-six ° C. Elemental analysis: calculated for _{C 30 H 30 NO 5 F 2} : C, 62.17; H, 5.22; N, 2.42 Found: C, 62.54; H, 5.27 ; N, 2.52 Example 48 N -[4- [3- [4- [bis (4-methylphenyl))
Methyl] -1-piperidinyl] propoxy] phenyl]
Acetamide = Fumarate = Hydrate [1: 1: 0.5] 4- [bis (4
-Methylphenyl) methyl] piperidine and N- [4-
(3-Chloropropoxy) phenyl] acetamide is reacted with a potassium iodide catalyst to produce a free base of the title compound, which is reacted with fumaric acid to give a white fumarate hydrate (methanol- Recrystallized from diethyl ether). Mp, 149-152 ° C. Elemental analysis: calculated for _{C 35 H 43 N 2 O 6.5} : C, 70.57; H, 7.28; N, 4.70 Found: C, 70.80; H, 7.28 ; N, 4.65 Example 49 N -[4- [3- [4- [Bis (4-fluorophenyl) methyl] -1-piperidinyl] propoxy] phenyl] acetamide = hydrobromide [1: 1] 4- [bis (4-fluoro) 25.68 g (0.089 mol) of phenyl) methyl] piperidine and 20.3 g (0.089 mol) of N- [4- (3-chloropropoxy) phenyl] acetamide
And 21.4 g (0.155 mol) of potassium carbonate were stirred in 350 ml of dimethylformamide at 70-80 ° C overnight. The reaction mixture was stripped to dryness and the residue was partitioned between chloroform-water. Evaporation of chloroform gave a dark red oil. This oil was dissolved in glacial acetic acid and hydrogen bromide in glacial acetic acid was used to generate the hydrobromide salt. The solvent was distilled off in vacuo and the residue was recrystallized from methanol-dimethyl ether. Light white solid, 2
Obtained in a yield of 1.68 g (43.5%). Melting point, 223-225 ° C.

Elemental analysis: Calculated value for C ₂₉ H ₃₃ N ₂ O ₂ F ₂ Br: C, 62.26; H, 5.95; N, 5.01 Found: C, 61.99; H, 5.94; N, 5.01 Example 50 4- [3 -[4- [Bis (4-fluorophenyl) methyl] -1-piperidinyl] propoxy] benzenamine = fumarate = hydrate [1: 1: 0.5] N- [4- [3- [4- 11.8 g (0.02709 mol) of [bis (4-fluorophenyl) methyl] -1-piperidinyl] propoxy] acetamide was gently heated to reflux for 4 hours in 500 ml of methanol containing 500 ml of 6N hydrochloric acid. The reaction was stopped and allowed to cool overnight. Evaporate reaction mixture to small volume on rotary evaporator, dilute with water, 5%
It was made alkaline with sodium hydroxide. The reaction mixture was then partitioned between the alkaline layer and chloroform. The chloroform layer was dried, filtered and the solvent evaporated to an oil. The oil was converted to the fumarate salt and this salt was recrystallized from methanol-diethyl ether. The white solid obtained was dried in vacuo at 80 ° C. overnight to give 8.49 g (71%) of white crystalline product. Melting point, 121.5-124
° C.

Elemental analysis: Calculated value for C ₃₁ H ₃₅ N ₂ O _5.5 F ₂ : C, 66.30; H, 6.28 N, 4.99 Found: C, 66.49; H, 6.13 N, 4.92 Example 51 N- [4- [3 -[4- [bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] phenylacetamide = hydrochloride hydrate [1: 1: 1] [α, α-bis (p-fluoro) (Phenyl)]-4-piperidinemethanol (3.0 g, 0.01 mol) and N- [4- (3
-Chloropropoxy) phenyl] acetamide 2.3 g (0.01
Mol), 5.3 g (0.05 mol) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 ml of 1-butanol gave a gum as a residue. The gum was purified by column chromatography on 80 g Florisil® and the product was eluted with 20% acetone / benzene. The combined fractions containing product were concentrated under reduced pressure to give a glass as a residue. The glass was dissolved in ethyl ether, filtered through cotton and the filtrate treated with ethereal hydrogen chloride. The resulting solid was collected by filtration, washed with ethyl ether and dried to give a white solid in 2.1 g (38%) yield. Melting point, 135-170 ° C
(Disassembly).

Elemental analysis: Calculated value for C ₂₉ H ₃₃ ClF ₂ N ₂ O ₃ .H ₂ O: C, 63.44; H, 6.43; N, 5.10 Found: C, 63.32; H, 6.56; N, 4.92 Example 52 α , Α-bis (4-fluorophenyl) -1- [3-
(4-Nitrophenoxy) propyl] -4-piperidinemethanol According to the treatment method of Example 1, using a potassium iodide catalyst, [α, α-bis (p-fluorophenyl)]-4-
Reaction of 9.1 g (0.03 mol) of piperidinemethanol with 6.7 g (0.03 mol) of 1- (3-chloropropoxy) -4-nitrobenzene produced 10.5 g of the title compound, which was recrystallized from isopropyl ether. Melting point, 93.5
~ 94.5 ° C.

Elemental analysis: Calculated value for C ₂₇ H ₂₈ F ₂ N ₂ O ₄ : C, 67.21; H, 5.85; N, 5.81 Found: C, 67.05; H, 5.83; N, 5.74 Example 53 4- [3- [4- [Bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] benzamide According to the treatment method of Example 1, using a potassium iodide catalyst, [α, α-bis (p-fluorophenyl) was used. 3.0 g (0.01 mol) of phenyl) -4-piperidinemethanol, 1 g (0.01 mol) of 4- (3-chloropropoxy) benzamide, and 6.9 g (0.05 mol) of anhydrous potassium carbonate were added to 100 m of 1-butanol.
When the mixture mixed in l was reacted, white powder 3.0 g (63
%). Melting point, 200-204 ° C. The recrystallization solvent used was absolute ethanol.

Elemental analysis: Calculated value for C ₂₈ H ₃₀ F ₂ N ₂ O ₃ .H ₂ O: C, 69.98; H, 6.29; N, 5.83 Found: C, 69.61; H, 6.49; N, 5.70 Example 544 -[Bis (4-fluorophenyl) methyl] -1-
[2- (1-naphthylenyloxy) ethyl] piperidine = hydrochloride [1: 1] 4- [α, α-bis (p-fluorophenyl) methyl]
Piperidine 2.84 g (0.0099 mol), 1- (2-bromoethoxy) -naphthalene 3.01 g (0.012 mol), sodium bicarbonate 5.0 g (0.060 g), 1-butanol 400 ml
The mixture in was refluxed for 16 hours. The solvent was evaporated in vacuo and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate and the solvent was evaporated in vacuo to give an oil. This was dissolved in a mixture of ether and methanol, excess ethereal hydrochloric acid was added, and a white precipitate was collected to give 3.13 g (64%) of a white crystalline solid. Melting point, 155-158 ° C.

Elemental analysis: Calculated value for C ₃₀ P ₃₀ MOF ₂ Cl: C, 72.94; H, 6.12; N, 2.84 Found: C, 73.20; H, 6.10; N, 2.78 Example 55 4- [bis (4-fluoro) (Phenyl) methyl] -1-
[2- (2-Naphthalenyloxy) ethyl] piperidine = oxalic acid salt [1: 1] According to the treatment method of Example 54, using 2- (2-bromoethoxy) naphthalene and oxalic acid instead of hydrochloric acid. The title compound was obtained as a white crystalline solid in 61.9% yield. Melting point, 168-171 ° C.

Elemental analysis: Calculated value for C ₃₂ H ₃₁ NO ₅ F ₂ : C, 70.19; H, 5.71; N, 2.56 Actual value: C, 70.26; H, 5.75; N, 2.63 Example 56 1- [4- [3 -[4-bis (4-fluorophenyl)
Methyl] -1-piperidinyl] propoxy] -3-methoxyphenyl] ethanone oxalate [1: 1] The title compound was prepared by the method described in U.S. Pat. See patent example 13): 4- [α, α-bis (p-fluorophenyl) methyl] piperidine 4.75 g (0.0165 mol) and 3- (p-acetyl-o-methoxyphen). Enoxy) propyl chloride 4.0 g (0.0165 mol) and sodium bicarbonate 1.4 g (0.0165 mol) were added to dimethylformamide.
The mixture in 60 ml was heated at 80 ° C. for about 2 hours. No product was observed at this time by thin layer chromatography (TLC). The temperature was raised to 100 ° C. for 1 hour, at which point TLC showed the reaction was complete. After cooling, the reaction mixture was filtered and dimethylformamide was distilled off under reduced pressure. The crude product was dissolved in chloroform, filtered, and the filtrate was concentrated under reduced pressure to give 7.7 g (94%).
The crude product of was obtained. The solid was dissolved in benzene and placed on Florisil®. Elution with an acetone-benzene gradient gave 5.5 g of product. The oxalate salt was prepared and recrystallized from isopropanol-methanol to yield 3.8 g of salt. Melting point, 164.5-166 ° C.

Elemental analysis: Calculated value for C ₃₂ H ₃₅ F ₂ NO ₇ : C, 65.86; H, 6.05; N, 2.40 Found: C, 66.11; H, 6.13; N, 2.39 Example 57 1- [4- [3 -[4-bis (4-fluorophenyl)
Methyl] -1-piperidinyl] propoxy] -3-methoxyphenyl] ethanol = fumarate [5: 6] 4- [bis (4-fluorophenyl) methyl) piperidine 58.26 g (0.203 mol) and 1- (Chloro-3- (4-
Acetyl-2-methoxyphenoxy) propane 54.5g
A mixture of (0.225 mol), 18.7 g (0.223 mol) of sodium bicarbonate and 1.2 g (0.0072 mol) of potassium iodide in 800 ml of 1-butanol was refluxed for 16 hours.
The hot reaction mixture was filtered and the solvent evaporated in vacuo from the filtrate. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate and the solvent was evaporated in vacuo to give an oil. The oil was dissolved in 600 ml of anhydrous ether and 4.91 g of solid was collected at room temperature. The ether solution was then treated with a solution of fumaric acid 30.2 g (0.26 mol) in methanol. Anhydrous ether was added to separate 99.88 g (77.7%) of the title compound. Melting point,
160-163 ° C. This was recrystallized from isopropanol-diethyl ether to give a second group of title compounds (additional 2.5 g (0.0216 g) fumaric acid). (First group, 44.1
5g, melting point, 163-1645 ° C; Group II, 38.75g, 161-163
C). From the initial ether-methanol filtrate, 10.00 g (8.786%) of the title compound was obtained, mp 159-162 ° C.

Elemental analysis: Calculated value for C _34.8 H _37.8 NO _7.8 F ₂ ^* : C, 66.05 ;; H, 6.02; N, 2.21 Found: C, 65.96 ;; H, 6.18; N, 2.16 ^* NMR shows that this salt is fumarine. It was shown to contain 1.2 equivalents of acid.

Example 58 1- [4- [3- [4-bis (4-fluorophenyl))
Methylene] -1-piperidinyl] propoxy] -3-methoxyphenyl] ethanone oxalate [1: 1] notation compound is described in US Pat. No. 3,922,276 (see Example 12 of the patent). Prepared as follows according to the method described. 4- [α, α-bis (p
-Fluorophenyl) methylene] piperidine 4.7 g (0.01
65 mol), 4.0 g (0.0165 mol) of 3- (p-acetyl-o-methoxyphenoxy) propyl chloride and 1.4 g of sodium bicarbonate in 60 ml of dimethylformamide are heated at 100 ° C overnight. did. After cooling, the reaction mixture was filtered and dimethylformamide was distilled off under reduced pressure. The residual oil was dissolved in benzene and placed on a Florisil® column.

Elution with an acetone-benzene gradient gave 5.7 g (70%) of a viscous brown oil. The free base was reacted with oxalic acid, recrystallized from isopropyl alcohol and dried in a nitrogen atmosphere to give the oxalate salt. Melting point, 169-1
70 ° C.

Elemental analysis: Calculated for C ₃₂ H ₃₃ F ₂ NO ₇ : C, 66.08; H, 5.72; N, 2.41 Found: C, 66.01; H, 5.67; N, 2.40 Example 59 1- [4- [3 -[4-[(4-Fluorophenyl) phenylmethylene] -1-piperidinyl] propoxy]-
3-Methoxyphenyl] ethanone = oxalate [1:
1] The title compound was prepared by the method described in US Pat. No. 3,922,276 (see Example 12 of the patent specification) as follows. 7.1 g of 4- [α- (p-fluorophenyl) -α-phenylmethylene] piperidine
(0.027 mol), 3- (p-acetyl-o-methoxyphenoxy) propyl chloride 6.5 g (0.027 mol),
A mixture of 2.3 g (0.027 mol) of sodium bicarbonate in 100 ml of dimethylformamide was stirred and heated at 100 ° C for about 8 hours. The mixture was filtered and dimethylformamide was evaporated under reduced pressure. Dissolve the residual oil in chloroform,
The mixture was filtered. The filtrate was concentrated in vacuo yielding 11.5 g (92%) of crude free base. The free base was reacted with oxalic acid and recrystallized from methyl isobutyl ketone to give the oxalate salt. Melting point, 143-145 ° C.

Elemental analysis: Calculated value for C ₃₂ H ₃₄ FNO ₇ : C, 68.19; H, 6.08; N, 2.49 Found: C, 68.14; H, 6.12; N, 2.54 Example 60 1- [3-methoxy-4- [3- [4- [phenyl [3
-(Trifluoromethyl) phenyl] methylene] -1-
The piperidinyl] propoxy] phenyl] ethanone oxalate [1: 1] notation compound was prepared by the method described in U.S. Pat. Prepared. 4- [α-phenyl-α
5.0 g (0.0157 mol) of-(m-trifluoromethylphenyl) methylene] piperidine and 3- (p-acetyl-o)
-Methoxyphenoxy) propyl chloride 3.82 g (0.015
7 mol) and 2.52 g (0.03 mol) of sodium bicarbonate 1-
While stirring the mixture in butanol 75 ml, 17-1
The mixture was heated under reflux for / 2 hours. The mixture was cooled, filtered and the filtrate evaporated under reduced pressure. The resulting glassy residue was 4.25 g (52
%), Dissolved in benzene and placed on a Florisil® column. The product was obtained as a glassy residue using an acetone-benzene gradient elution. The residue was dissolved in ether to give an oxalate salt. This salt is
It had a glassy appearance. Melting point, 120-125 ° C.

Elemental analysis: Calculated value for C ₃₃ H ₃₄ F ₃ NO ₇ : C, 64.59; H, 5.58; N, 2.28 Measured value: C, 64.34; H, 5.72; N, 2.04 Example 61 1- [4- [3 -[4- (Cyclohexylphenylmethylene) -1-piperidinyl] propoxy] -3-methoxyphenyl] ethanone oxalate [1: 1] The free base of the title compound is the same as in US Pat. No. 3,922,276, Example 1. Reaction of 4-[(α-cyclohexyl-α-phenyl) methylene] piperidine with 3- (p-acetyl-o-methoxyphenoxy) propyl chloride in a mixture of sodium bicarbonate and dimethylformamide. It was obtained by converting to the oxalate salt. Melting point, 184-185 ° C.

Elemental analysis: Calculated value for C ₃₂ H ₄₁ NO ₇ : C, 69.67; H, 7.49; N, 2.54 Actual value: C, 69.83; H, 7.58; N, 2.56 Example 62 1- [4- [3- [ 4- (cyclohexylphenylmethyl) -1-piperidinyl] propoxy] -3-methoxyphenyl] ethanone oxalate hydrate [1: 1: 1] 4-[(α-cyclohexyl-α-phenyl) methyl]
5.2 g (0.02 mol) of piperidine and 3- (p-acetyl-
o-Methoxyphenoxy) propyl chloride 4.9 g (0.02
Mol) and 1.7 g (0.02 mol) of sodium bicarbonate in 100 ml of dimethylformamide were stirred and heated to 100 ° C.
Heated for 4 hours. The reaction mixture was cooled and filtered, and dimethylformamide was distilled off under reduced pressure. The residual material was dissolved in benzene and placed on a Florisil® column. Elution with an acetone-benzene gradient gave 7.0 g (74.5%) of the free base of the title compound. The oxalate salt was prepared and recrystallized from isopropanol. Melting point, 15
5 to 160 ℃.

Elemental analysis: Calculated value for C ₆₄ H ₈₈ N ₂ O ₁₅ : C, 68.31; H, 7.88; N, 2.49 Found value: C, 68.60; H, 7.78; N, 2.42 The free base of the title compound is 4- [ Obtained by mixing (α-cyclohexyl-α-phenyl) methyl] piperidine and 3- (p-acetyl-o-methoxyphenoxy) propyl chloride with sodium bicarbonate, separated and separated with oxalic acid. Reacted with. The oxalate salt was recrystallized from isopropanol. Melting point, 155-160 ° C.

Example 63 4- [3- [4-bis (4-fluorophenyl) methylene] -1-piperidinyl] propoxy] -α-methylbenzenemethanol = oxalate [1: 1] 1- [4- [3- [ A solution of 3.56 g (0.0077 mol) of 4- [bis (4-fluorophenyl) methylene] -1-piperidinyl] propoxy] phenyl] ethanone and 1.51 g (0.04 mol) of sodium borohydride was stirred at room temperature for 6 hours. . The reaction mixture was stripped to dryness and partitioned between chloroform-water and chloroform-5% sodium hydroxide. Chloroform was distilled off to obtain oil,
This was converted to the oxalate salt. Recrystallization from methanol-diethyl ether gave 2.67 g of white crystalline product (62.
1%). Melting point, 142-145 [deg.] C.

Elemental analysis: Calculated value for C ₃₁ H ₃₃ NO ₆ F ₂ : C, 67.26; H, 6.01; N, 2.53 Found: C, 67.17; H, 5.92; N, 2.47 Example 64 4- [3- [4 -[Bis (4-fluorophenyl) methylene] -1-piperidinyl] propoxy] -3-methoxy-α-methylbenzenemethanol 3.0 g (0.079 mol) sodium borohydride was added to 250 ml 95% ethanol. 1- [3- (p
-Acetyl-o-methoxyphenoxy) propyl] -4
-[Α, α-bis (p-fluorophenyl) methyl] piperidine 4.40 g (0.00885 mol) in 95% ethanol 100 ml
What was melt | dissolved in was added. The resulting solution was stirred at room temperature for 2 1/2 hours. The reaction mixture was stripped to dryness and partitioned between chloroform and 5% sodium hydroxide. The organic layer was back extracted with 5% sodium hydroxide and water. Evaporation of chloroform produced an oil. The oil formed a white solid in diethyl ether. The white solid was filtered off and recrystallized from methylene chloride-diethyl ether. By this operation, white solid 2.16
g (49.2%) was obtained. Melting point, 132-135 [deg.] C.

Elemental analysis: Calculated value for C ₃₀ H ₃₅ NO ₃ F ₂ : C, 72.72; H, 7.12; N, 2.83 Found: C, 72.28; H, 7.21; N, 2.52 Example 65 1- [4- [3 5.0 g (0.02 mol) of 4-[(diphenylmethyl) -1-piperidinyl] propoxy] -3-methoxyphenyl] ethanone oxalate 4- (α-phenylbenzene) piperidine and 3- (p-acetyl-o) -Methoxyphenoxy) propyl chloride 4.85 g (0.02 mol), sodium bicarbonate 3.4 g (0.04 mol), dimethylformamide 10
A mixture of 0 ml was heated at 100 ° C. for about 3 hours. The reaction mixture was cooled, filtered and the filtrate concentrated under reduced pressure. The residual oil was dissolved in chloroform, and chloroform was filtered to remove insoluble materials. The filtrate was concentrated under reduced pressure to give 8.6 g (94.5%) of red oil. This oil was dissolved in a 4: 1 mixture of ether-isopropanol and treated with 2.3 g of oxalic acid dihydrate. If left alone, oxalate will precipitate,
Trituration in ether produced 8.4 g of salt. Melting point 149
~ 155 ° C. Recrystallization from isobutyl-methyl-ketone gave 7.0 g of salt. Melting point, 153-155 ° C. (U.S. Patent No. 3,
See Example 11 of 956,296).

Elemental analysis: Calculated value for C ₃₂ H ₃₇ NO ₇ : C, 70.18; H, 6.81; N, 2.56 Actual value: C, 70.00; H, 6.76; N, 2.56 Example 66 1- [4- [3- [ 4-bis (4-fluorophenyl)
Hydroxymethyl] -1-piperidinyl] propoxy]
-3-Methoxyphenyl] ethanone 5.0 g (0.0165 mol) of α, α-bis (p-fluorophenyl) -4-piperidinemethanol and 3- (p-acetyl-o-methoxyphenoxy) propyl chloride 4.0 g
(0.0165 mol) and 1.4 g (0.0165 mol) of sodium bicarbonate mixed with 60 ml of dimethylformamide,
The mixture was heated and stirred at 80 ° C for 2 hours. The temperature was raised to 100 ° C for 1 hour. After cooling, the reaction mixture was filtered and dimethylformamide was distilled off under reduced pressure. The residual oil crystallized on standing in ether, which was dissolved in benzene and placed on Florisil®. Elution with an acetone-benzene gradient produced 1.8 g (21.4%) of product from the column. Melting point, 141.5-143 ° C. (U.S. Patent No. 3,956,29
See Example 12 in No. 6).

Elemental analysis: calculated for _{C 30 H 33 F 2 O 4} : C, 70.71; H, 6.53; N, 2.75 Found: C, 70.49; H, 6.58 ; N, 2.59 Example 67 1- [4- [3 -[4-[(4-Fluorophenyl) hydroxyphenylmethyl] -1-piperidinyl] propoxy] -3-methoxyphenyl] ethanone α- (p-fluorophenyl) -α-phenyl-4-piperidinemethanol 6.5 g (0.023 mol) and 3- (p-
Acetyl-o-methoxyphenoxy) propyl chloride
5.5 g (0.023 mol) and sodium bicarbonate 1.92 g (0.023 mol)
Mol) was mixed with 80 ml of dimethylformamide and heated at 100 to 110 ° C. for 2 hours. The reaction mixture was cooled, filtered and the dimethylformamide was evaporated under reduced pressure.
The residual oil was dissolved in chloroform and filtered. Chloroform was distilled off under reduced pressure. The weight of the remaining solid residue is
8.6 g (77%) which was recrystallized from ethanol to give 3.1 g of material. Melting point, 147-148 [deg.] C. The sample was dried over refluxing toluene and submitted for analysis. (U.S. Patent No. 3,95
See Example 14 in 6,296.

Elemental analysis: Calculated value for C ₃₀ H ₃₄ NO ₄ F: C, 73.30; H, 6.97; N, 2.85 Found: C, 73.15; H, 7.05; N, 2.77 Example 68 1- [4- [3- [3- [4- (diphenylhydroxymethyl) -1-piperidinyl] propoxy] -3-methoxyphenyl] ethanone oxalate [1: 1] α, α-diphenyl-4-piperidinemethanol 5.2 g
(0.0194 mol), 3- (p-acetyl-o-methoxyphenoxy) propyl chloride 4.7 g (0.0194 mol),
A mixture of 1.6 g (0.0194 mol) of sodium bicarbonate in 60 ml of dimethylformamide was stirred at 100 ° C. for 3 hours. After cooling, the reaction mixture was filtered and dimethylformamide was distilled off under reduced pressure. The residual oil was 8.3 g (90%). Upon trituration in anhydrous ether some of the product crystallized and was collected by filtration. The filtrate was evaporated to dryness and the residue was dissolved in benzene-isooctane.
Upon cooling, a crystalline product was obtained. The total yield of solid product was 6.3%. The solid free base was converted to the oxalate salt. When recrystallized from isobutyl methyl ketone,
An off-white solid was obtained. Melting point, 174-176 ° C. (US Patent No.
See Example 15 in 3,956,296).

Elemental analysis: Calculated value for C ₃₂ H ₃₇ NO ₈ F: C, 68.19; H, 6.62; N, 2.49 Found value: C, 68.34; H, 6.75; N, 2.42 Example 69 1- [4- [3- [3- [4- [hydroxyphenyl [3-
(Trifluoromethyl) phenyl] methyl-1-piperidinyl] propoxy] -3-methoxyphenyl] ethanone = hydrochloric acid = hydrate [1: 1: 0.5] α-phenyl-α- (m-trifluoromethylphenyl) ) -4-piperidinemethanol 7.0 g (0.021 mol),
5.1 g (0.021 mol) of 3- (p-acetyl-o-methoxyphenoxy) propyl chloride and 3.0 of sodium bicarbonate
A mixture of g (0.036 mol) in 125 ml dry dimethylformamide was stirred and heated at 90-95 ° C for 5 hours.
The mixture was cooled and filtered. Excess water was added to the reaction mixture. The mixture was extracted several times with benzene and the combined extracts were dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude solid obtained was dissolved in benzene and placed on a Florisil® column. Elution with an acetone-benzene gradient gave a gummy solid. The gum was dissolved in ether to prepare the hydrochloride salt. The weight of the hydrochloride salt is 3.1g (25%),
It melted transparently at 95 ° C. (See Example 16 in US Pat. No. 3,956,296).

Elemental analysis: Calculated value for C ₆₂ H ₇₂ Cl ₂ F ₆ N ₂ O ₉ : C, 63.42; H, 6.18; N, 2.39 Found: C, 63.68; H, 6.03; N, 2.33 Example 70 1- [ 4- [3- [4- (cyclohexylhydroxyphenylmethyl) -1-piperidinyl] propoxy] -3
-Methoxyphenyl] ethanone = hydrochloric acid [1: 1] α-cyclohexyl-α-phenyl-4-piperidinemethanol 3.9 g (0.143 mol), 3- (p-acetyl-o)
-Methoxyphenoxy) propyl chloride 3.9 g (0.143
Mol) and 2.35 g (0.28 mol) of sodium bicarbonate in 100 ml of dimethylformamide were heated at 100 ° C. for 4 hours. After cooling, the reaction mixture was diluted with about 600 ml of water,
Extracted with benzene. The collected benzene extracts were washed with water and dried over anhydrous magnesium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting crude solid is
It was 5.1 g (74.5%). This solid was dissolved in ether and the ether solution was treated with excess ethereal hydrogen chloride. The obtained hydrochloride was recrystallized from isobutyl methyl ketone to obtain 4.0 g of salt. Melting point, 152-155 [deg.] C. (See US Pat. No. 3,956,296).

Elemental analysis: calculated for _{C 30 H 42 ClNO 4: C} , 69.82; H, 8.20; N, 2.71 Found: C, 69.50; H, 8.31 ; N, 2.62 Example 71 1- [4- [2- [ 4- [bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] ethoxy] -3-methoxyphenyl] ethanone According to the procedure of Example 1, using a potassium iodide catalyst, α, α -Bis (p-fluorophenyl) -4-piperidinemethanol 3.0 g (0.01 mol) and 1- [4- (2
-Chloroethoxy) -3-methoxyphenyl] ethanone
A mixture of 2.3 g (0.01 mol) and sodium carbonate in butanol was recrystallized from isopropyl alcohol, and then the title compound was prepared in a yield of 22%. Melting point, 131
~ 135 ° C.

Elemental analysis: Calculated value for C ₂₉ H ₃₁ F ₂ NO ₄ : C, 70.29; H, 6.31; N, 2.83 Found: C, 70.00; H, 6.39; N, 2.60 Example 72 1- [4- [4 -[4- [Bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] butoxy] -3-methoxyphenyl] ethanone This compound was prepared according to the procedure used to synthesize the compound of Example 35. It was prepared accordingly. 3.0 g (0.01 mol) of α, α-bis (p-fluorophenyl) -4-piperidinemethanol and 3.0 g (0.01 mol) of 1- [4- (4-bromobutoxy) -3-methoxyphenyl] ethanone And anhydrous sodium carbonate 5.3g (0.05mol) and potassium iodide 0.3g
Was mixed in 100 ml of dimethylformamide and purified by column chromatography (acetone-benzene) on Florisil® to give 0.8 g (15%) of an off-white powder. Melting point, 104-105 ° C (recrystallized from 2-propanol-isopropyl alcohol).

Elemental analysis: Calculated value for C ₃₁ H ₃₅ F ₂ NO: C, 71.11; H, 6.74; N, 2.68 Measured value: C, 70.84; H, 6.71; N, 2.65 Example 73 1- [4- [5- [4- [bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] pentoxy] -3-methoxyphenyl] ethanone According to the treatment method of Example 1, using a potassium iodide catalyst, α, 3.0 g (0.01 mol) of α-bis (p-fluorophenyl) -4-piperidinemethanol and 1- [4- (5
After mixing 2.7 g (0.01 mol) of -chloropentoxy) -3-methoxyphenyl] ethanone and sodium carbonate in butanol and recrystallizing from isopropyl alcohol, the title compound was obtained in a yield of 65%. Prepared. Melting point 11
7.5-118.5 ° C.

Elemental analysis: Calculated value for C ₃₂ H ₃₇ F ₂ NO ₄ : C, 71.49; H, 6.94; N, 2.61 Found: C, 71.51; H, 7.06; N, 2.50 Example 74 1- [4- [2 -[4- [Bis (4-fluorophenyl) methyl] -1-piperidinyl] ethoxy] -3-methoxyphenyl] ethanone 4- [bis (4-fluorophenyl) methyl] piperidine 4.88 g (0.017 mol) And 1- [4- (2-chloroethoxy) -3-methoxyphenyl] ethanone 3.86 g (0.017
Mol) and 5.53 g (0.04 mol) of sodium carbonate, 1-butanol 350 m containing potassium iodide (0.3 g)
Gently heated to reflux overnight in l. The reaction mixture was filtered, stripped to dryness. The dark brown oil obtained was dissolved in chloroform and extracted with 1N sulfuric acid and 5% sodium hydroxide. The chloroform layer was dried, filtered, and the solvent was evaporated. This treatment gave a brown oil which was subjected to flash chromatography on silica gel, eluting with hexane-ethyl acetate. The product-containing fractions were evaporated to give a white solid. The solid was extracted with diethyl ether and the mixture was placed in the freezer overnight. A white solid was obtained, which was dried in vacuum at 80 ° C. overnight. 2.2 g of white crystalline solid (27
%). Melting point, 129-131 [deg.] C.

Elemental analysis: Calculated value for C ₂₉ H ₃₁ NO ₃ F ₂ : C, 72.63; H, 6.52; N, 2.92 Found: C, 72.52; H, 6.45; N, 2.87 Example 75 1- [4- [3 -[4- [bis (4-chlorophenyl)]
Methylene] -1-piperidinyl] propoxy] -3-methoxyphenyl] ethanone 4- [bis (4-chlorophenyl) methylene] piperidine 3.96 g (0.01305 mol) and 1- [4- (3-chloropropoxy) -3. -Methoxyphenyl) ethanone 3.16 g
(0.013 mol) was mixed in 300 ml of 1-butanol containing 0.3 g of potassium iodide, and the mixture was gently heated to reflux overnight. The reaction mixture was stripped to dryness and partitioned between chloroform-water and chloroform-5% sodium hydroxide. Evaporation of the chloroform produced an oil, which was crystallized from isopropyl alcohol.
When the solid is recrystallized from isopropyl alcohol,
This gave 4.16 g (61%) of a light yellow solid. Melting point, 143-144
° C.

Elemental analysis: Calculated value for C ₃₀ H ₃₁ NO ₃ Cl ₂ : C, 68.70; H, 5.96; N, 2.67 Found: C, 69.11; H, 6.02; N, 2.55 Example 76 1- [4- [3 -[4-[(4-Fluorophenyl) phenylmethyl] -1-piperidinyl] propoxy] -3
-Methoxyphenyl] ethanone oxalate [1: 1] 4-[(4-fluorophenyl) phenylmethyl] piperidine 4.42 g (0.0164 mol) and 1- [4- (3-chloropropoxy) -3-methoxyphenyl Enil) Ethanone 4.11
A solution of g (0.0170 mol) and 0.01 g of potassium iodide in 1-butanol was refluxed for 18 hours. The solvent was evaporated in vacuo and the residue was partitioned between methylene chloride and dilute sodium hydroxide. Evaporation of the solvent in vacuo gave an oil. A solution of oil in methanol was treated with an equal number of oxalic acid, ethyl ether was added, and 6.39 g of white crystalline solid (6
8.9%). Melting point 161-163 [deg.] C.

Elemental analysis: Calculated value for C ₃₂ H ₃₆ NO ₇ F: C, 67.95; H, 6.42; N, 2.48 Found: C, 67.92; H, 6.42; N, 2.44 Example 77 1- [4- [3- [3- [4- [bis (4-methoxyphenyl) methyl] -1-piperidinyl] propoxy] -3-
Methoxyphenyl] ethanone oxalate [1: 1] 4- [bis (4-methoxyphenyl) methyl] piperidine 7.78 g (0.025 mol) and 1- [4- (3-chloropropoxy) -3-methoxyphenol (Enyl) ethanone 6.05 g (0.0
25 mol) and 1-butanol containing 0.3 g of potassium iodide
A mixture of 300 ml was refluxed overnight. The reaction mixture was stripped to dryness and the residue was partitioned between chloroform and water. The solvent was evaporated in vacuo to give a dark brown oil. The oil was column chromatographed on silica gel using a gradient elution consisting of methanol and ethyl acetate. The corresponding fractions were collected from the column and reacted with oxalic acid. The salt was recrystallized from methanol-diethyl ether to give 4.16 g (27.4%) of a white solid. Melting point, 163.5-165 ° C.

Elemental analysis: Calculated value for C ₃₄ H ₄₁ NO ₉ : C, 67.20; H, 6.80; N, 2.31 Found: C, 66.76; H, 6.84; N, 2.26 Example 78 1- [4- [3- [ 4- [bis (4-methylphenyl)
Methyl] -1-piperidinyl] propoxy] -3-methoxyphenyl] ethanone 4- [bis (4-methylphenyl) methyl] piperidine
5.10 g (0.018 mol) and 1- [4- (3-chloropropoxy) -3-methoxyphenyl] ethanone 4.42 g (0.018 mol)
A mixture of 350 ml of 1-butanol and 5.53 g (0.04 mol) of potassium carbonate and 0.3 g of potassium iodide was gently refluxed overnight. The reaction mixture was stripped to dryness and the resulting residue was partitioned between chloroform-5% sodium hydroxide and chloroform-water. Evaporation of chloroform gave a dark brown oil. The oil was column chromatographed on silica gel using a gradient elution consisting of hexane-ethyl acetate and ethyl acetate-dimethoxyethane. The appropriate fractions from the column were collected. It was dried in vacuo at 80 ° C. overnight to yield 2.60 g (29.7%) oil.

Elemental analysis: Calculated for C ₃₂ H ₃₉ NO ₃ : C, 79.14; H, 8.09; N, 2.88 Found: C, 78.70; H, 8.08; N, 2.80 ¹ 1H NMR (CDCl ₃ ): δ7.5 ( Multiplet line, aromatic proton adjacent to ketone, 2H) δ 6.7-7.6 (multiplet line, aromatic proton, 9H) 4.0 (triplet line, methylene adjacent to ether oxygen, 2H) 3.8 (singlet line, OCH ₃ , 3H) 3.3 (doublet, methine adjacent to the ring, 1H) 2.5 (singlet, methyl of ketone, 3H) 2.2 (singlet, methyl attached to the aromatic ring, 6
H) 1.0-3.0 (multiple lines, remaining aliphatic protons, 13
H) Example 79 1- [4- [4- [4- [bis (4-fluorophenyl) methyl] -1-piperidinyl] butoxy] -3-methoxyphenyl] ethanone 4- [bis (4-fluoro) 6.15 g (0.021 mol) of phenyl) methyl] piperidine and 6.45 g (0.02 mol) of 1- [4- (4-bromobutoxy) -3-methoxyphenyl] ethanone
Mol) in 350 ml of acetonitrile was stirred overnight at room temperature with 5.53 g (0.04 mol) of potassium carbonate and 0.3 g of potassium iodide. The mixture was then refluxed for 5 hours. The reaction mixture was stripped to dryness on a rotary evaporator and the residue was partitioned between chloroform-5% sodium hydroxide and chloroform-water. Evaporation of chloroform gave a dark brown oil. The oil was chromatographed on silica gel, eluting with a hexane-ethyl acetate-dimethoxyethane system. The fractions from the column were combined and the solvent was removed by aspirating in vacuo at 80 ° C. overnight. This gives a brown oil 3.
34 g (31.3%) was provided.

Elemental analysis: Calculated value for C ₃₁ H ₃₅ NO ₃ F ₂ : C, 73.35; H, 6.95; N, 2.76 Actual value: C, 72.34; H, 6.92; N, 2.70 NMR analysis results are as follows. It was ¹¹ H NMR (CDCl ₃ ): δ 6.8 to 7.6 (multiline, aromatic, 11H) 4.1 (triplet, methylene 2H adjacent to an ether bond) 3.4 to 3.6 (doublet, two fluorophenyl rings) Attached to methine, 1H) 3.8 (singlet, OCH ₃ , 3H) 2.5 (singlet, COCH ₃ , 3H) 1.1-3.0 Multiplex, residual aliphatic protons, 15
H) Example 80 4- [3- [4- [bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] -3
-Methoxybenzoic acid methyl ester According to the treatment method of Example 1, using a potassium iodide catalyst,
Using dimethylformamide instead of butanol,
4- (3-chloropropoxy) -3-methoxybenzoic acid methyl ester 5.4 g (0.021 mol), [α, α-bis (p-fluorophenyl)]-4-piperidinemethanol 6.9 g (0.02 mol) , Anhydrous sodium carbonate 7.4g (0.07
Mol) and 0.3 g of potassium iodide in 150 ml of dimethylformamide were reacted and recrystallized from isopropyl alcohol to give 5.7 g (53%) of a white solid.
Occurred. Melting point, 131-132.5 ° C.

Elemental analysis: Calculated value for C ₃₀ H ₃₃ F ₂ NO ₅ : C, 68.56; H, 6.33; N, 2.67 Actual value: C, 68.23; H, 6.35; N, 2.60 Example 81 α, α- [bis ( 4-fluorophenyl)]-1- [3
-[4- (Methylthio) phenoxy] propyl] -4-
Piperidinemethanol According to the treatment method of Example 1, [α, α-bis (p-fluorophenyl)]-4-piperidinemethanol 3.0 g (0.01
Mol), 2.2 g (0.01 mol) of 1-chloro-3- (4-methylthiophenoxy) propane, and anhydrous sodium carbonate
A mixture of 5.3 g (0.05 mol) and 0.3 g of potassium iodide in 100 ml of 1-butanol was reacted and recrystallized from isopropyl ether to give a white powder. Melting point, 113-115 [deg.] C.

Elemental analysis: Calculated value for C ₂₈ H ₃₁ F ₂ NO ₂ S: C, 69.54; H, 6.46; N, 2.90 Found: C, 69.57; H, 6.51; N, 2.85 Example 82 α, α- [bis (4-Fluorophenyl)]-1- [3
-[4- (methylsulfonyl) phenoxy] propyl]
-4-piperidinemethanol = fumarate [1: 1] According to the treatment method of Example 1, [α, α-bis (p-fluorophenyl)]-4-piperidinemethanol 3.0 g (0.01
Mol), 1- (3-chloropropoxy) -4- (methylsulfonyl) benzene 2.5 g (0.01 mol), anhydrous sodium carbonate 5.3 g (0.05 mol), and potassium iodide 0.3 g 1-butanol 100 ml Reaction of the mixture in produced a brown gum as a residue. React this gummy residue with fumaric acid. The resulting fumarate salt was recrystallized from acetonitrile to yield 3.0 g (48%) of a white solid. Melting point, 176-178 [deg.] C.

Elemental analysis: Calculated value for C ₃₂ H ₃₅ F ₂ NO ₈ S: C, 60.85; H, 5.59; N, 2.22 Actual value: C, 60.72; H, 5.54; N, 2.20 Example 83 4- [3- [ 4- [bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] -3
-Methoxybenzeneacetic acid = ethyl ester = hydrochloride According to the treatment method of Example 45, [α, α-bis (p-fluorophenyl)]-4-piperidinemethanol and 4-
Hydrochloride was prepared by reacting (3-chloropropoxy) -3-methoxybenzeneacetic acid = ethyl ester.

Example 84 4- [3- [4- [bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] ethoxy] benzoic acid ethyl ester = hydrochloride According to the treatment method of Example 45, α, α-bis (P-Fluorophenyl)]-4-piperidinemethanol and 4-
Hydrochloride was prepared by reacting (2-chloroethoxy) benzoic acid ethyl ester.

Example 85 4- [3- [4- [bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] -3
-Methoxybenzeneacetic acid sodium salt = hemihydrate This compound was prepared according to the procedure of Example 1.
[Α, α-bis (p-fluorophenyl)]-4-piperidinemethanol 3.0 g (0.01 mol) and 4- (3-chloropropoxy) -3- (methoxybenzeneacetic acid ethyl ester 2.9 g (0.01 mol) And anhydrous sodium carbonate 5.3g
A mixture of (0.05 mol) and 0.3 g of potassium iodide in 150 ml of acetonitrile was reacted to give a gum-like ester. The gum was converted to the hydrochloride salt with ethereal hydrogen chloride to give a white solid. The solid did not crystallize and was therefore partitioned between methylene chloride-5% sodium hydroxide solution. The emulsion formed was allowed to stand until the layers were separated. During this period solids precipitated. The mixture was filtered. The filter cake was recrystallized from ethyl acetate to give 0.7 g (13%) of a fluffy white solid.
Was generated. Melting point, 102-112 ° C Elemental analysis: Calculated value for C ₃₀ H ₃₂ F ₂ NNaO ₅・ 0.5H ₂ O: C, 64.74; H, 5.98; N, 2.52 Found: C, 64.50; H, 5.97; N, 2.39 Example 86 7- [3- [4- [bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] -2H
-1-Benzopyran-2-one This compound was prepared according to the procedure of Example 1.
[Α, α-bis (p-fluorophenyl)]-4-piperidinemethanol 3.0 g (0.01 mol) and 7- (3-chloropropoxy) -2H-1-benzopyran-2-one 2.4 g
(0.01 mol) and 5.3 g of anhydrous sodium carbonate (0.05 mol)
And 0.3 g of potassium iodide in 100 ml of 1-butanol produced 3.6 g (71%) of pale yellow crystals. Melting point, 99-120 ° C (decomposition). The recrystallization solvent used was 2-propanol.

Elemental analysis: Calculated value for C ₃₀ H ₂₉ F ₂ NO ₄ : C, 71.27; H, 5.78; N, 2.77 Found: C, 71.02; H, 5.89; N, 2.63 Example 87 2- [3- [4 -[Bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] benzoic acid ethyl ester = fumarate [4: 3] This compound was prepared according to the procedure of Example 1.
[Α, α-bis (p-fluorophenyl)]-4-piperidinemethanol 3.0 g (0.01 mol), 2- (3-chloropropoxy) benzoic acid ethyl ester 2.4 g (0.01 mol), anhydrous sodium carbonate Mixing 5.3 g (0.05 mol) with 0.3 g potassium iodide in 100 ml dimethylformamide produced 5.7 g of gum as a residue. The gum was purified by column chromatography on 100 g silica gel. Fractions eluted with 35% acetone / benzene were combined and concentrated to give a pale yellow gum as a residue. The gum was converted to the fumarate salt and the solid was recrystallized twice from 2-propanol to yield 2.0 g (32%) of a white solid. Melting point, 138-141 ° C.

Elemental analysis: Calculated value for C ₃₃ H ₃₆ F ₂ NO ₇ : C, 66.43; H, 6.08; N, 2.35 Found: C, 66.25; H, 6.08; N, 2.27 Example 88 2- [3- [4 -[Bis (4-fluorophenyl) methyl] -1-piperidinyl] propoxy] benzoic acid ethyl ester 4- [bis (4-fluorophenyl) methyl] piperidine 32.79 g (0.116 mol) and 2- (3- 27.04 g (0.114 mol) of chloropropoxy) benzoic acid ethyl ester,
A mixture with 19.40 g (0.140 mol) of potassium carbonate was heated to reflux overnight in 500 ml of diethoxyethane containing 0.4 g of potassium iodide. The reaction was filtered, stripped to dryness. The obtained residue was dissolved in chloroform and extracted with 5% sodium hydroxide, sodium sulfite and water.
The chloroform layer was dried (anhydrous sodium sulfate), filtered, and the solvent was evaporated to give 56.20 g of a dark brown oil. This oil was subjected to flash chromatography on a silica gel column 83.5 g and eluted with ethyl acetate. Fractions were pooled for similar purity. One sample 6.49g
(56.5%) was dried in vacuum at 80 ° C. overnight and analyzed. ¹ H NMR (CDCl ₃ ): δ7.8 (m, 1, aromatic protons ortho to ester); 7.0 (m, 11, aromatic); 4.3 (q, 2, C-
_{O-CH 2); 4.1 (} t, 2, -OCH 2); 3.5 (d, 1, methine); 1.3
_{(T, 3, CH 3)} ; 1.7~3.0 (m, 13, aliphatic protons).

Elemental analysis: Calculated value for C ₃₀ H ₃₃ NO ₃ F ₂ : C, 73.00; H, 6.74; N, 2.84 Found: C, 72.98; H, 6.70; N, 2.93 Example 89 1- [4- [5 -[4- [Bis (4-fluorophenyl) methyl] -1-piperidinyl] pentoxy] methoxyphenyl] ethanone hemihydrate 4- [bis (4-fluorophenyl) methyl] piperidine 6.03 g (0.021 Mol) and 5.69 g of 1- [4- (5-chloropentoxy) -3-methoxyphenyl] ethanone (0.0
21 mol) and 5.53 g (0.04 mol) of potassium carbonate, 350 ml of 1-butanol containing 0.2 g of potassium iodide
Heated to reflux gently overnight in. The reaction mixture was cooled to room temperature, filtered, stripped to dryness. The obtained residue was dissolved in chloroform and extracted with water several times. The chloroform layer was dried (sodium sulfate), filtered, and the solvent was evaporated to give a brown oil. The oil was flash chromatographed on a silica gel column, eluting with ethyl acetate and 2% methanol-ethyl acetate. Fractions of similar purity were combined and the solvent was evaporated. The sample was exposed to air for 24 hours and then dried at 70 ° C. overnight. 2.7 g (24.6%) of a brown oil was obtained. ¹ H NMR (CDCl ₃ ): δ6.8 to 7.6 (m, 11, aromatic); δ4.1
(T, 2, -OCH ₃ ); δ3.9 (s, 3, OCH ₃ ); δ3.4 to 3.6 (d, 1,
Methine of difluorophenyl group); δ2.5 (s, 3, δ1-3.0 (m, 18, aliphatic protons and 0.5 H ₂ O).

Elemental analysis: Calculated for C ₃₂ H ₃₈ NO _3.5 F ₂ : C, 72.43; H, 7.22; N, 2.64 Found: C, 72.75; H, 7.23; N, 2.57 Example 90 4- [3- [4 -[Bis (4-fluorophenyl) methyl] -1-piperidinyl] propoxy] benzamidophthalate [2: 3] 4- [bis (4-fluorophenyl) methyl] piperidine 6.10 g (0.02125 mol), 4- (3-chloropropoxy) benzamide 4.53 g (0.02125 mol), potassium carbonate 5.53 g (0.02125 mol) and potassium iodide 0.2 g
Heat gently to reflux in 350 ml butanol overnight. The reaction mixture was filtered, stripped to dryness. The obtained residue was dissolved in chloroform and extracted with water. The chloroform layer was dried, filtered and evaporated to yield an oil. The oil was converted to the fumarate salt and recrystallized from methanol-diethyl ether. The white crystalline solid obtained was dried in vacuo at 65 ° C. overnight. A white crystalline product was obtained in a yield of 5.47 g (40.3%). Melting point, 193-194 [deg.] C.

Elemental analysis: Calculated value for C ₃₄ H ₃₆ N ₂ O ₈ F ₂ : C, 63.94; H, 5.68; N, 4.39 Found: C64.03; H, 5.73; N, 4.37 Example 91 4- [bis ( 4-Fluorophenyl) methyl] -1-
[3- [4- (Methylsulfonyl) phenoxy] propyl] piperidine = oxalate [1: 1] 4- [bis (4-fluorophenyl) methyl] piperidine 6.02 g (0.021 mol) and 1- (3-chloro Propoxy) -4- (methylsulfonyl) benzene 5.22 g (0.021
(Mol) was gently heated to reflux overnight in 350 ml of 1-butanol containing 5.53 g (0.04 mol) of potassium carbonate and 0.2 g of potassium iodide. The reaction mixture was filtered, stripped to dryness. The obtained residue was dissolved in chloroform and extracted with water several times. The chloroform layer was dried, filtered and evaporated to yield an oil. The dark brown oil was converted to oxalate and recrystallized from methanol-diethyl ether to give a white solid. This material was dried in vacuo at 65 ° C. overnight. A white crystalline solid was obtained in a yield of 6.21 g (50.1%). Melting point, 202-204
° C.

Elemental analysis: Calculated value for C ₃₀ H ₃₃ NSO ₇ F ₂ : C, 61.11; H, 5.64; N, 2.38 Found: C, 60.99; H, 5.64; N, 2.36 Example 92 1- [4- [6 -[4- [bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] hexyloxy] -3-methoxyfuel] ethanone According to the treatment method of Example 1, using a potassium iodide catalyst, [α, α-bis (p-fluorophenyl)]-4-
The title compound was prepared from a mixture of piperidinemethanol, 1- [4- (6-chlorohexeoxy) -3-methoxyphenyl] ethanone and sodium carbonate in butanol.

Example 93 1- [4- [3- [4- [bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] -2-methoxyphenyl] ethanone Following the procedures of Examples 1 and 66. , [Α, α-bis (p
-Fluorophenyl)]-4-piperidinemethanol was reacted with 3- [p-acetyl-m-methoxyphenoxy) propyl chloride to prepare the title compound.

Example 94 α, α-bis (4-fluorophenyl) -1- [3-
(2-Hydroxyphenoxy) propyl] -4-piperidinemethanol According to the treatment method of Example 2, using a potassium iodide catalyst, [α, α-bis (p-fluorophenyl)]-4-
Piperidinemethanol and 2- (3chloropropoxy)
-1-Benzyloxybenzene gives 1- [3- (2-benzyloxyphenoxy) propyl] -α, α-bis (4-fluorophenyl) -4-piperidinemethanol, which is palladium / carbon. Reaction with hydrogen over the catalyst produced the title compound.

Example 95 α, α- [bis (4-fluorophenyl)]-1- [3
-(4-Methylsulfinyl) phenoxy] propyl]
-4-Piperidine Methanol Fumarate According to the treatment method of Examples 1 and 82, [α, α-bis (P
-Fluorophenyl)]-4-piperidinemethanol is reacted with 1- (3-chloropropoxy) -4- (methylsulfinyl) benzene to give the free base of the title compound, which is then fumaric acid. To give the title compound.

Example 96 4- [3- [4- [bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] benzenesulfonamide = hydrochloride [1: 1] This compound was treated as in Example 1. Prepared according to the method.
[Α, α-bis (p-fluorophenyl)]-4-piperidinemethanol 3.0 g (0.01 mol), 4- (3-chloropropoxy) benzenesulfonamide 2.5 g (0.01 mol), anhydrous sodium carbonate 5.3 Gum as a residue was obtained by mixing g (0.05 mol) and 0.3 g of potassium iodide in 100 ml of 1-butanol. The gum was converted to the hydrochloride salt with ethereal hydrogen chloride and the solid was recrystallized from absolute ethanol to give 3.5 g (64%) of a white solid.
Melting point, 152-175 ° C.

Elemental analysis: Calculated value for C ₂₇ H ₃₁ ClF ₂ N ₂ O ₄ S: C, 58.64; H, 5.65; N, 5.06 Found: C, 58.43; H, 5.68; N, 5.06 Example 97 N- [4 -[3- [4- [Bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] phenyl] methanesulfonamide According to the treatment method of Example 1, [α, α-bis (p- Fluorophenyl)]-4-piperidinemethanol and N-
[4- (3-Bromopropoxy) phenyl] methanesulfonamide was reacted to give the title compound.

Example 98 N- [4- [3- [4- [bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] phenyl-N′-methylurea Following the procedure of Example 1, [ α, α-bis (p-fluorophenyl)]-4-piperidinemethanol and N-
The title compound was obtained by reacting with [4- (3-bromopropoxy) phenyl] -N′-methylurea.

Example 99 [4- [3- [4- [bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] phenyl] carbamic acid ethyl ester According to the procedure of Example 1, [α, α-bis (p-fluorophenyl)]-4-piperidinemethanol, and [4
Reaction with-[3-bromopropoxy) phenyl] carbamic acid ethyl ester gave the title compound.

Example 100 N- [3- [3- [4- [bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] phenyl] urea According to the procedure of Example 1, [α, α] -Bis (p-fluorophenyl)]-4-piperidinemethanol and N-
The title compound was obtained by reacting with [3- (3-bromopropoxy) phenyl] urea.

Example 101 4- [3- [4- [bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] -3
-Methoxybenzoic acid sodium salt 4- (3-chloropropoxy) -in place of the corresponding 3-methoxy compound according to the procedure of Examples 1 and 85.
The title compound was obtained using 2-methoxybenzoic acid.

Example 102 1- [4- [3- [4- [bis (4-fluorophenyl) hydroxymethyl] -piperidinyl] propoxy]
2-Hydroxyphenyl] ethanone According to the procedure of Example 1, [α, α-bis (p-fluorophenyl)]-4-piperidinemethanol and 1-
[4- (3-Bromopropoxy) -2-hydroxyphenyl] ethanone was reacted to give the title compound.

Example 103 7- [3- [4- [bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] -4
-Oxo-4H-benzopyran-2-carboxylic acid = ethyl ester = hydrochloride [α, α-bis (p-fluorophenyl)]-4-piperidinemethanol (3.0 g, 0.01 mol) and 7- (3-chloro) Propoxy) -4-oxo-4H-1-benzopyran-
2-Carboxylic acid ethyl ester 3.1 g (0.01 mol), anhydrous sodium carbonate 5.3 g (0.05 mol), potassium iodide
A mixture of 0.3 g and 150 ml of acetonitrile was added to 48
Gum was obtained as a residue upon heating to reflux. The gum was purified by column chromatography on 120 g Florisil®. The desired fractions eluting with 10% acetone / benzene were collected and concentrated under reduced pressure to give a glass residue. The glass was dissolved in ether-isopropanol and treated with ethereal hydrogen chloride. The solid that precipitated was filtered off and recrystallized from absolute ethanol to give 1.9 g (31%) of a white solid. Melting point, 191 ° C
(Disassembly).

Elemental analysis: C ₃₃ H ₃₄ ClF Calculated for _{2 NO 6: C, 64.55;} H, 5.58; N, 2.28 Found: C, 64.41; H, 5.51 ; N, 2.26 Example 104 7- [3- [4 -[Bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] -2,
3-Dihydro-4H-1-benzopyran-4-one = hydrochloride According to the procedure of Example 103, [α, α-bis (p-fluorophenyl)]-4-piperidinemethanol and 7
-(3-Bromopropoxy) -2,3-dihydro-4H-1
Reaction with -benzopyran-4-one gave the title compound.

Example 105 1- [4- [3- [4- (diphenylmethylene) -1-
Piperidinyl] propoxy] -3-methoxyphenyl]
Ethanone oxalate hydrate [1: 1: 0.5] 4-diphenylmethylenepiperidine 7.5 g (0.030 mol)
A mixture of 6.3 g (0.032 mol) of 3- (p-acetyl-o-methoxyphenoxy) propyl 3-bromide, 25 g of potassium carbonate and 150 ml of toluene was heated under reflux for 16 hours, cooled, and filtered. Then, the solvent was distilled off under reduced pressure. The residual oil was taken up in benzene, washed with water, dried over magnesium sulphate and then the solvent was distilled off. Dissolve the free base in isopropanol to give 3.8 g of oxalic acid dihydrate.
(0.03 mol) was dissolved in dry ether and treated. The white salt that separated was separated from the isopropanol-methanol mixture. Product weight is 8.5g (54%)
It was. Melting point, 186-188 [deg.] C.

Elemental analysis: Calculated value for C ₃₂ H ₃₆ NO _7.5 : C, 69.29; H, 6.54; N, 2.53 Found value: C, 69.20; H, 6.49; N, 2.71 Example 106 1- [4- [3- [ 4- (cyclohexylphenylmethyl) -1,2,3,6-tetrahydropyridin-1-yl] propoxy] -3-methoxyphenyl] ethanone = oxalate = hydrate [1: 1: 0.5] of the title compound The free base was combined with 4- (α-cyclohexylphenylmethyl) -1,2,3,6-tetrahydropyridine and 3
Separated by reacting with-(p-acetyl-o-methoxyphenoxy) propyl chloride in a mixture of sodium bicarbonate in dimethylformamide and eluting with benzene on a Florisil ® column. I got it. The indicated salt was prepared. Melting point, 110 ° C.

Elemental analysis: Calculated value for C ₆₄ H ₈₄ N ₂ O ₁₅ : C, 68.55; H, 7.55; N, 2.50 Found: C, 68.79; H, 7.64; N, 2.47 Example 107 1- [4- [3 -[4-bis (4-fluorophenyl)
Hydroxymethyl] -1-piperidinyl] propoxy]
2-Methoxyphenyl] ethanone = hydrochloride [1: 1] This compound was prepared according to the procedure of Example 1.
3.0 g (0.01 mol) of [α, α-bis (p-fluorophenyl)]-4-piperidinemethanol and 1- [4- (3
-Chloropropoxy) -2-methoxyphenyl] ethanone 2.4 g (0.01 mol) and anhydrous sodium carbonate 5.3 g (0.05
Mol) and 0.3 g of potassium iodide to 100 m of 1-butanol.
Mixing in l gave the gum as a residue. The gum was purified by column chromatography on 80 g Florisil® and the fractions eluted with 20% acetone / benzene were collected and concentrated under reduced pressure to give a solid as a residue. The solid was converted to the hydrochloride salt and the solid was recrystallized from 2-propanol-isopropyl ether to give 2.2 g (40%) of white crystals. Melting point,
196-197 ° C.

Elemental analysis: calculated for _{C 30 H 34 ClF 2 NO 4} : C, 65.99; H, 6.28; N, 2.57 Found: C, 6587; H, 6.31 ; N, 2.54 Example 108 4- [bis (4- Fluorophenyl) methyl] -1-
[3- (2,6-Dichlorophenoxy) propyl] piperidine 4- [bis (4-fluorophenyl) methyl] piperidine (free base 6.90 g, 0.024 mol) and 1,3-dichloro-
A mixture of 5.72 g (0.024 mol) of 2- (3-chloropropoxy) benzene, 5.54 g of potassium carbonate and (0.04 mol) was gently heated overnight in 350 ml of 1-butanol containing 0.2 g of potassium iodide. Refluxed. The reaction was stripped to dryness. The residue was partitioned several times between chloroform and water. The chloroform layer was dried, filtered and evaporated to yield an oil. Oil, methanol 50
Place in refrigerator overnight in ml. A white solid was obtained which was dried in vacuo at 80 ° C overnight. The yield of white crystalline solid was 3.26 g (27.7%). Melting point, 101.5-103 ° C.

Elemental analysis: Calculated value for C ₂₇ H ₂₇ NOCl ₂ F ₂ : C, 66.13; H, 5.55; N, 2.85 Found value: C, 66.12; H, 5.56; N, 2.88 Example 109 4- [bis (4- Fluorophenyl) methyl] -1-
[3- (2,6-Dichlorophenoxy) propyl] piperidine oxalate [1: 1] The free base of Example 108 was converted to the oxalate salt, recrystallized from methanol-diethyl ether and dried in vacuo at 80
Dry overnight at ° C. Melting point, 158-161 [deg.] C.

Elemental _{analysis: C 29 H 29 NO 5 Cl} 2 F 2 Calculated for: C, 60.01; H, 5.04 ; N, 2.44 Found: C, 60.02; H, 5.07 ; N, 2.46 Example 110 2- [3- [4- [Bis (4-fluerophenyl) methyl] -1-piperidinyl] propoxy] benzonitrile 4- [bis (4-fluorophenyl) methyl] piperidine 7.41 g (0.025 mol) and 2- (3-chloropropoxy) ) Benzonitrile 4.90 g (0.025 mol) and potassium carbonate 5.54 g, (0.04 mol) mixture of potassium iodide
The mixture was heated to reflux overnight in 350 ml of 1-butanol containing 0.2 g. The reaction was stripped to dryness and the residue was partitioned between chloroform and water several times. The chloroform layer was dried (anhydrous sodium sulfate), filtered and the solvent was evaporated to give a brown oil. The oil was triturated in diethyl ether and placed in the freezer overnight. A white solid was obtained which was dried in vacuum at room temperature overnight. The yield of analytically pure material was 5.15 g (46.1%). Melting point, 8
8.5 ~ 90 ℃.

Elemental analysis: Calculated for C ₂₈ H ₂₈ N ₂ OF ₂ : C, 75.31; H, 6.32; N, 6.27 Found: C, 75.16; H, 6.34; N, 6.26 Example 111 α, α-bis (4 -Fluorophenyl) -1- [2-
(Phenylthio) ethyl] -4-piperidine Methanol = maleate [1: 1] Magnesium 5.81 g in tetrahydrofuran (ice bath)
(0.242 mol) and p-fluorobromobenzene 42.4 g (0.
242 mol) to prepare a Grignard solution. The Granoyard reagent was stirred in about 350 ml of tetrahydrofuran at room temperature for about 3 hours. The reaction mixture was then transferred (under nitrogen) to a 500 ml addition funnel. This solution was mixed with 29.10 g (0.1 mol) of 1- [2- (phenylthio) ethyl] -4-piperidinecarboxylic acid ethyl ester in about 2 parts of tetrahydrofuran.
It was added dropwise to a tetrahydrofuran solution dissolved in 00 ml. The solution was stirred at room temperature overnight and then poured into ice containing 35 g of ammonium chloride. The solution was extracted with chloroform and the chloroform was back extracted with 5% sodium hydroxide. Evaporation of chloroform gave a dark brown oil.
This oil was converted to maleate and recrystallized from methanol-diethyl ether to give 5.0 g of white crystalline product.
(56.5% yield for the collected sample) was obtained. Melting point, 171
~ 173 ° C.

Elemental analysis: Calculated value for C ₃₀ H ₃₁ NO ₅ SF ₂ : C, 64.85; H, 5.62; N, 2.52 Found value: C, 64.80; H, 5.62; N, 2.45 Example 112 4- [bis (4- Fluorophenyl) methylene] -1-
[2- (phenylthio) ethyl] piperidine α, α-bis (4-fluorophenyl) -1- [2-
(Phenylthio) ethyl] -4-piperidinemethanol = maleate 26.13 g (0.047 mol) was partitioned between methylene chloride and weak base solution and converted to the free base by evaporating the organic layer to give an oil. It was 6N of this oil
It was dissolved in 150 ml of methanol containing 100 ml of hydrochloric acid, and this solution was gently heated to reflux for 4.5 hours. The reaction mixture was cooled to room temperature, made alkaline with ice-50% sodium hydroxide mixture and extracted with chloroform. Evaporation of the chloroform layer produced an oil which crystallized.
The solid was triturated in methanol, stored in the refrigerator and filtered to give the title compound in 60% yield.
Melting point, 101.5-103.5 ° C.

Elemental analysis: Calculated for C ₂₆ H ₂₅ NSF ₂ : C, 74.08; H, 5.98; N, 3.32 Found: C, 74.12; H, 5.96; N, 3.25 Example 113 α, α-bis (4-fluoro) (Phenyl) -1- [2-
[(4-Chlorophenyl) sulfonyl] ethyl] -4-
Piperidinemethanol α, α-bis (4-fluorophenyl) -4-piperidinemethanoe 5.85 g (0.0193 mol), 2-chloroethyl-p-chlorophenylsulfone 4.76 g (0.020 mol),
Sodium carbonate 4.90 g (0.0462 mol) in acetonitrile 6
The mixture in 00 ml was heated at 65 ° C. for 18 hours. The solvent was evaporated in vacuo and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over sodium sulphate and the solvent evaporated in vacuo to give a solid. The solid was recrystallized from a mixture of methylene chloride (400 ml), methanol (50 ml) and hexane (200 ml) to give 6.99 g (71.7%) of a white solid. Melting point, 211-212 ° C.

Elemental analysis: Calculated value for C ₂₆ H ₂₆ NO ₃ SF ₂ Cl: C, 61.72; H, 5.18; N, 2.77 Actual value: C, 61.51; H, 5.16; N, 2.81 Example 114 1- [2- [ (4-Chlorophenyl) sulfonyl] ethyl] -4- [bis (4-fluorophenyl) methylene]
Piperidine α, α-bis (4-fluorophenyl) -1- [2-
[(4-Chlorophenyl) sulfonyl] ethyl] -4-
Piperidine methanol 2.74 g (0.0054 mol) was added to glacial acetic acid 100.
A mixture of 1 ml and 40 ml of 2 molar sulfuric acid was refluxed for 6 hours. The solvent was evaporated in vacuo and the resulting solid was recrystallized from methylene chloride-hexane to give 1.95 g (74%) of white crystalline solid. Melting point, 152-153 [deg.] C.

Elemental analysis: Calculated for C ₂₆ H ₂₄ NO ₂ SClF ₂ : C, 63.99; H, 4.96; N, 2.87 Found: C, 64.24; H, 4.95; N, 2.84 Example 115 4- [bis (4- Fluorophenyl) methyl] -1-
5.74 g (0.02 mol) of [3 (phenylsulfonyl) propyl] piperidine = fumarate [1: 1.5] 4- [bis (4-fluorophenyl) methyl] piperidine and 4.36 g (0.02 mol) of 3-chloropropylphenyl sulfone Mol) and 3.18 g of sodium carbonate
A mixture of (0.03 mol) and 0.3 g of potassium iodide in 300 ml of n-butanol was refluxed overnight. The reaction mixture was stripped to dryness and the residue was chloroform-5.
Partitioned between% sodium hydroxide and then chloroform-water. Evaporation of chloroform produced an oil which was converted to the fumarate salt. Recrystallisation from isopropyl alcohol-diethyl ether yielded 3.31 g (25.7%) of a white solid. Melting point, 172-173
° C.

Elemental analysis: Calculated for C ₂₂ H ₃₅ NO ₈ F ₂ S: C, 61.58; H, 6.48; N, 2.18 Found: C, 61.69; H, 5.54; N, 2.14 Example 116 4- [bis (4 -Fluorophenyl) methyl] -1-
[2-[(4-chlorophenyl) sulfonyl] ethyl]
Piperidine = maleate [1: 1] 4- [bis (4-fluorophenyl) methyl] piperidine 4.22 g (0.0147 mol), 2-chloroethyl-p-chlorophenyl sulfone 3.363 g (0.0152 mol) and sodium carbonate 4.1 A mixture of g (0.039 mol) and 400 ml of acetonitrile was refluxed for 22 hours. The solvent was evaporated in vacuo and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried (magnesium sulfate) and the solvent evaporated in vacuo to give an oil. This was converted to the maleate salt and this salt was recrystallized from methanol-diethyl ether to give a white crystalline solid 6.84.
yielded g (76.9%). Melting point, 185-186 [deg.] C.

Elemental analysis C ₃₀ H ₃₀ NO ₆ SF ₂ Calculated for Cl: C, 59.45; H, 4.99; N, 2.31 Found: C, 59.57; H, 4.99 ; N, 2.32 Example 117 4- [bis (4- Fluorophenyl) methyl] -1-
[2- (phenylsulfonyl) ethyl] piperidine maleate [1: 1] 4- [bis (4-fluorophenyl) methyl] piperidine 5.20 g (0.016 mol) and 2-chloroethylphenyl sulfone 3.32 g ( 0.0162 mol) and 500 g of potassium carbonate (0.0
(362 mol) in 500 ml of acetonitrile and refluxed for 19 hours. The solvent was evaporated in vacuo and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The organic solution was dried (magnesium sulfate) and the solvent evaporated in vacuo to give an oil. This was converted to the maleate salt and this salt was recrystallized from methanol-ether to give 4.82 g (52.4%) of a white crystalline solid. Melting point, 183.5-184.5 ° C.

Elemental analysis: Calculated for C ₃₀ H ₃₁ NO ₆ F ₂ S: C, 63.04; H, 5.47; N, 2.45 Found: C, 62.88; H, 5.40; N, 2.45 Example 118 1- (2,3 -Dihydro-1,4-benzodioxan-2-ylmethyl) -α, α-diphenyl-4-piperidineacetonitrile 2- (bromomethyl) -1,4-benzodioxane 6.24 g
(0.027 mol), α, α-diphenyl-4-piperidineacetonitrile 0.027 mol, and potassium carbonate 6.91 g (0.
(05 mol) and stirred at room temperature overnight. The reaction mixture was refluxed for 5 hours and then stirred at room temperature overnight. The reaction mixture was stripped to dryness. The residue was dissolved in chloroform and the solution was extracted with water and 5% sodium hydroxide. Evaporation of chloroform produced an oil. NM
According to R, the product to starting material ratio was 2/1. The reaction mixture was then refluxed overnight in 350 ml of 1-butanol containing 0.3 g of potassium iodide and 6.91 g (0.05 mol) of potassium carbonate. Strip the reaction mixture to dryness,
The resulting residue is chloroform-water and chloroform-
Partitioned with 5% sodium hydroxide. Evaporation of chloroform gave an oil, which was crystallized from methanol and dried in vacuo at 80 ° C overnight. White crystalline product,
Obtained in a yield of 7.18 g (62.6%). Melting point, 130-131.5 ° C.

Elemental analysis: Calculated value for C ₂₈ H ₂₈ N ₂ O ₂ : C, 79.22; H, 6.65; N, 6.60 Measured value: C, 78.88; H, 6.62; N, 6.56 Example 119 1- [3- (4 -Acetyl-2-methoxyphenoxy)
Propyl] -α, α-diphenyl-4-piperidineacetonitrile = oxalate [1: 1] 1- [4- (3-chloropropoxy) -3-methoxyphenyl] ethanone 6.78 g (0.05 mol) and α, α A mixture of -diphenyl-4-piperidineacetonitrile 7.72 g (0.028 mol) was heated to reflux overnight in 350 ml 1-butanol containing 0.4 g potassium iodide. The reaction mixture was stripped to dryness and the residue was dissolved in chloroform. The chloroform layer was extracted with 1N sulfuric acid and then 5% sodium hydroxide. When chloroform was distilled off in a vacuum,
This gave a brown oil. The oil was converted to the oxalate salt and the salt was recrystallized from methanol. Vacuum the salt 80
Dry overnight at ° C. A white solid was obtained in a yield of 8.36 g (52.2%). Melting point, 226-227 ° C (decomposition).

Elemental analysis: Calculated value for C ₃₃ H ₃₆ N ₂ O ₇ : C, 69.21; H, 6.34; N, 4.89 Found value: C, 68.78; H, 6.32; N, 4.84 Example 120 1- [3- (4 -Acetyl-2-methoxyphenoxy)
Propyl] -α, α-diphenyl-3-piperidinepropanenitrile α, α-diphenyl-3-piperidinepropanenitrile
5.80 g (0.02 mol) and 1- [4- (3-chloropropoxy) -3-methoxyphenyl] ethanone 4.84 g (0.02 mol)
Mol) and 5.60 g (0.04 mol) of potassium carbonate, dimethylformamide 40 containing 0.3 g of potassium iodide.
Heated at 68 ° C. in 0 ml overnight. The reaction mixture was stripped to dryness, chloroform-water and chloroform-5.
Partitioned between% sodium hydroxide. The chloroform layer was dried, filtered and evaporated to yield an oil. This oil was subjected to column chromatography on a silica gel column and eluted with ethyl acetate. Fractions containing product were collected and transferred to a brown glass bottle with acetone. The oil was triturated with diethyl ether and dried in vacuo at 80 ° C overnight. An oil was obtained with a yield of 2.37 g (23.9%).

Elemental analysis: Calculated value for C ₃₂ H ₃₆ N ₂ O ₃ : C, 77.39; H, 7.31; N, 5.64 Actual value: C, 77.00; H, 7.35; N, 5.63 Example 121 1- [4- (4 -Acetyl-2-methoxyphenoxy)
Butyl] -α, α-diphenyl-3-piperidinepropanenitrile α, α-diphenyl-3-piperidinepropanenitrile
A mixture of 5.80 g (0.02 mol), 1- [4- (4-bromobutoxy) -3-methoxyphenyl] ethanone 6.02 g (0.02 mol) and potassium carbonate 5.60 g (0.04 mol) was iodinated. Heated at room temperature overnight in 400 ml of acetonitrile containing 0.3 g of potassium. The mixture was then stirred under reflux overnight, then stripped to dryness and the resulting residue partitioned between chloroform-water and chloroform-5% sodium hydroxide. The chloroform layer was dried, filtered and evaporated to yield a dark yellow oil. This oil was subjected to silica gel column chromatography and eluted with ethyl acetate. Pure fractions were collected and the oil was triturated with diethyl ether. The oil was dried in vacuum at 80 ° C. overnight. A pale yellow oil was obtained in a yield of 5.96 g (58.4%). ¹ H NMR (CDCl ₃ ) δ 7.2 to 7.8 (m, 12, aromatic), 6.9 (d,
1, aromatic), 4.1 (t, 2, CH ₂ O), 3.9 (s, 3, -OCH ₃ ),
2.5 (s, 3, C- CH 3), 1.1~2.4 (m, 17, aliphatic).

Elemental analysis: Calculated value for C ₃₃ H ₃₈ N ₂ O ₃ : C, 77.61; H, 7.50; N, 5.48 Measured value: C, 76.96; H, 7.55; N, 5.35 Example 122 1- [3- (4 -Acetyl-2-methoxyphenoxy)
Propyl] -α, α-diphenyl-3-pyrrolidine acetamide α, α-diphenyl-3-pyrrolidine acetamide 5.00 g
(0.018 mol), 3-chloro-1-[(4-acetyl-2-methoxy) phenoxy] propane 4.14 g (0.018 mol) and sodium carbonate 1.91 g (0.018 mol) were mixed in 1-butanol 100 ml. This was refluxed for 18 hours.
The solution was cooled and concentrated in vacuo. Methylene chloride residue
Absorb in 300 ml, wash with 100 ml of dilute sodium hydroxide, 100 ml of dilute hydrochloric acid and 100 ml of dilute sodium hydroxide, dry over magnesium sulfate and concentrate to give 7.70 g (88%) of a yellow glass. . The glass was crystallized from methylene chloride / diethyl ether to give 5.70 g (67%) of a fine tan powder containing ether. Recrystallization of this powder from ethyl acetate and acetonitrile yielded an off-white powder. Melting point, 143.5-148.5 ° C.

Elemental analysis: calculated for _{C 30 H 34 N 2 O 4} : C, 74.05; H, 7.04; N, 5.76 Found: C, 73.80; H, 7.01 ; N, 5.80 Example 123 1- [3- (4 -Acetyl-2-methoxyphenoxy)
Propyl] -α, α-diphenyl-4-piperidine acetamide = fumarate = hydrate [1: 0.5: 1] α, α-diphenyl-4-piperidine acetamide 5.88 g
(0.02 mol) and 1- [4- (3-chloropropoxy)
-3-Methoxyphenyl] ethanone 4.84 g (0.02 mol)
And 6.91 g (0.05 mol) of potassium carbonate were heated to reflux overnight in 350 ml of 1-butanol containing 0.3 g of potassium iodide. The reaction mixture was stripped to dryness.
The resulting residue was partitioned between chloroform-water and chloroform-5% sodium hydroxide layer. The chloroform layer was dried, filtered and the solvent was evaporated on a rotary evaporator. The resulting residue was converted to the fumarate salt.
The salt was recrystallized from methanol-diethyl ether. The resulting white solid was dried in vacuum at 80 ° C. overnight. A white solid was obtained in a yield of 3.71 g (32.2%). Melting point, 211-213 ° C.

Elemental analysis: Calculated value for C ₃₄ H ₄₀ N ₂ O ₇ : C, 68.73; H, 6.99; N, 4.86 Measured value: C, 68.56; H, 6.72; N, 4.60 Example 124 1- [4- (4 -Acetyl-2-methoxyphenoxy)
Butyl] -α, α-diphenyl-4-piperidine acetamide = fumarate hydrate [1: 0.5: 1] α, α-diphenyl-4-piperidine acetamide 6.0 g
(0.02 mol) and 1- [4- (4-bromobutoxy)-
3-methoxyphenyl] ethanone 6.02 g (0.02 mol)
And 5.60 g (0.04 mol) of potassium carbonate were stirred overnight at room temperature in 30 ml of acetonitrile containing 0.2 g of iodine. The mixture was then gently heated to reflux overnight. The reaction mixture was stripped to dryness and the resulting residue was partitioned between chloroform and water. The chloroform layer was dried, filtered and the solvent was evaporated to give a gummy residue. This material was converted to the fumarate salt. Methanol-
Recrystallization from diethyl ether and drying in vacuo at 80 ° C. overnight gave a white solid in a yield of 5.91 g (50.0%). Melting point, 169-171 [deg.] C.

Elemental analysis: Calculated for C ₃₄ H ₄₂ N ₂ O ₇ : C, 69.13; H, 7.17; N, 4.74 Found: C, 69.22; H, 6.89; N, 4.44 Example 125 1- [3- (4 -Acetyl-2-methoxyphenoxy)
Propyl] -α, α-diphenyl-3-piperidinepropanamide hydrate [1: 0.5: 1] α, α-diphenyl-3-piperidinepropanamide 7.
00 g (0.0227 mol) and 1- [4- (3-chloropropoxy) -3-methoxyphenyl] ethanone 5.50 g (0.022
27 mol) and 11.2 g (0.08 mol) of potassium carbonate, 350 ml of 1-butanol containing 0.3 g of potassium iodide
Heated to reflux overnight in. The reaction mixture was stripped to dryness. The resulting residue was partitioned between chloroform-water and chloroform-5% sodium hydroxide layer. The chloroform layer was dried, filtered and evaporated to yield an oil. This oil was subjected to column chromatography on silica gel and eluted with dimethoxyethane-ethyl acetate. Fractions of pure material were collected and dried in vacuo at 80 ° C overnight. 3.75 g (31.5%) of pale yellow amorphous solid
Was obtained in a yield of. ¹ H NMR (CDCl ₃ ): δ7.7 (m, 12, aromatic), 6.9 (d, 1, aromatic), 5.8 to 6.4 (broad s, 2, NH ₂ ), 5.1 (broad s,
1.5, H ₂ O), 3.9 (t, 2, CH ₂ O), 3.9 (s, 3, OCH ₃ ), 2.5
(S, 3, C-CH 3), 1.1~2.4 (m, 15, aliphatic).

Elemental analysis: Calculated for C ₃₂ H ₃₉ N ₂ O _4.5 : C, 73.40; H, 7.51; N, 5.35 Found: C, 73.42; H, 7.47; N, 5.22 Example 126 4- [bis (4- Fluorophenyl) methyl] -1-
[(2,3-dihydro-1,4-benzodioxan-2-yl) methyl] piperidine oxalate [1: 1] 4- [bis (4-fluorophenyl) methyl] piperidine 5.53 g (0.019 mol) , 2- (bromomethyl) -2,3
A mixture of 4.39 g (0.019 mol) of dihydro-1,4-benzodioxane and 7.80 g (0.056 mol) of potassium carbonate was stirred overnight at room temperature in 250 ml of acetonitrile. The reaction mixture was stripped to dryness and partitioned between chloroform and water. Evaporation of chloroform yielded a tan oil which was converted to the oxalate salt. The salt was recrystallized from methanol-diethyl ether. A white solid was obtained in a yield of 3.63 g (36.3%). Melting point, 142-145
° C.

Elemental analysis: Calculated value for C ₂₉ H ₂₉ NO ₆ F ₂ : C, 66.28; H, 5.56; N, 2.61 Actual value: C, 66.06; H, 5.50; N, 2.61 Example 127 1- [2- (2 , 6-Dichlorophenoxy) ethyl]-
α, α-diphenyl-3-piperidinepropanenitrile α, α-diphenyl-3-piperidinepropanenitrile
6.09 g (0.021 mol) and 2- (2-bromoethoxy)-
5.53 g of potassium carbonate was obtained by mixing 5.63 g (0.021 mol) of 1,3-dichlorobenzene with 350 ml of acetonitrile.
(0.04 mol) and 0.2 g potassium iodide at room temperature overnight. The mixture was then gently heated to reflux overnight. The mixture was then stripped to dryness. The obtained residue was dissolved in chloroform. Chloroform
It was extracted with 5% sodium hydroxide and water. The chloroform layer was then dried, filtered and evaporated to yield 12.2 g of oil. 20% of this oil on silica gel
Flash chromatography was performed using ethyl acetate-hexane and 50% ethyl acetate-hexane as eluents. Fractions of pure material were collected and the solvent removed in vacuo. The brown oil was dried in vacuum at 80 ° C. overnight. A brown oil was obtained in a yield of 5.49 g (54.5%). ¹ H NMR (CDCl ₃ ): δ6.8 to 7.4 (m, 13, aromatic), 4.1
_{(T, 2, -OCH 2)} , 0.7~2.9 (m, 13, remaining aliphatic).

Elemental analysis: Calculated value for C ₂₈ H ₂₈ N ₂ OCl ₂ : C, 70.14; H, 5.89; N, 5.84 Found: C, 70.08; H, 5.88; N, 5.76 Example 128 1- [5- (4 -Acetyl-2-methoxyphenoxy)
Pentyl] -α, α-diphenyl-3-piperidinepropanenitrile = hydrate [1: 0.5] α, α-diphenyl-3-piperidinepropanenitrile
5.80 g (0.02 mol) and 1- [4- (5-chloropentoxy) -3-methoxypentyl] ethanone 5.42 g (0.02 mol)
Mol) and 5.53 g (0.04 mol) of potassium carbonate were gently heated to reflux overnight in 350 ml of 1-butanol containing 0.3 g of potassium iodide. The reaction mixture was stripped to dryness and the residue was dissolved in chloroform. The chloroform layer was extracted with water and dried over anhydrous sodium sulfate. Chloroform was distilled off on a rotary evaporator and then filtered. The oil obtained when chloroform was distilled off was subjected to column chromatography (flash chromatography) on silica gel and eluted with methanol-ethyl acetate (4:96 v / v). Similar fractions were collected and the solvent was removed in vacuo to give a brown oil. The oil was dried under vacuum at 80 ° C overnight. The oil was triturated with diethyl ether and dried again in vacuo at 80 ° C overnight. A clear brown oil was obtained in a yield of 6.37 g (59.6%). ¹ H NMR (CDCl ₃ ): δ7.2 to 7.8 (m, 12, aromatic), 6.9
(D, 1, aromaticity), 4.1 (t, 2, CH ₂ O), 3.9 (s, 3, OC
H ₃ ), 2.5 (s, 3, 1.1-2.4 (m, 19, aliphatic).

Elemental analysis: Calculated value for C ₃₄ H ₄₁ N ₂ O _3.5 : C, 76.52; H, 7.74; N, 5.25 Measured value: C, 76.37; H, 7.65; N, 5.19 Example 129 1- [3- (4 -Acetyl-2-methoxyphenoxy)
Propyl] -α, α-bis (4-fluorophenyl)-
4-piperidineacetonitrile = maleate [1: 1] α, α-bis (4-fluorophenyl) -4-piperidineacetonitrile 6.45 g (0.021 mol) and 1- [4-
(3-Chloropropoxy) -3-methoxyphenyl] ethanone 5.00 g (0.021 mol) and potassium carbonate 5.53 g (0.0
4 mol) was gently heated to reflux overnight in 350 ml of 1-butanol containing 0.2 g of potassium iodide. The reaction mixture was stripped to dryness and then partitioned several times between chloroform and water. The chloroform layer was dried, filtered and evaporated to give a dark brown oil. This oil was converted to the maleate salt. The salt was recrystallized from methanol-diethyl ether and dried in vacuo at 80 ° C overnight. White crystals were obtained in a yield of 6.80 g (51.8%). Melting point, 1
58 ~ 160 ℃.

Elemental analysis: Calculated value for C ₃₅ H ₃₆ N ₂ O ₇ F ₂ : C, 66.24; H, 5.72; N, 4.14 Found value: C, 66.13; H, 5.69; N, 4.41 Example 130 1- [3- (2,6-Dichlorophenoxy) propyl]-
α, α-bis (4-fluorophenyl) -4-acetonitrile = maleate [1: 1] α, α-bis (4-fluorophenyl) -4-piperidineacetonitrile oxalate 5.99 g (0.0192 mol)
And 1,3-dichloro-2- (3-chloropropoxy)-
A mixture of 4.76 g (0.02 mol) of benzene, 5.53 g (0.04 mol) of potassium carbonate and 0.2 g of potassium iodide.
Heated to reflux in 350 ml butanol overnight. The reaction mixture was stripped to dryness and the resulting residue was partitioned between chloroform and water several times. The chloroform layer was dried (anhydrous sodium sulfate), filtered and the solvent was evaporated to give a light brown oil. All of this oil was converted to the maleate salt. The salt was recrystallized from methanol-diethyl ether and dried in vacuo at 80 ° C overnight. 4.55 white crystals
Obtained in a yield of g (37.5%). Melting point, 162-163 [deg.] C.

Elemental analysis: Calculated value for C ₃₂ H ₃₀ N ₂ O ₅ F ₂ Cl ₂ : C, 60.83; H, 4.79; N, 4.14 Found value: C, 60.89; H, 4.82; N, 4.44 Example 131 1- [ 3- (2,6-dichlorophenoxy) propyl]-
α, α-diphenyl-3-piperidinepropanenitrile = oxalate [1: 1] α, α-diphenyl-3-piperidinepropanenitrile
5.80 g (0.02 mol) and 1,3-dichloro-2- (3-chloropropoxy) -benzene 4.76 g (0.02 mol) 1-
Mix in 350 ml butanol and add 5.5% potassium carbonate.
The mixture was heated under reflux with 4 g (0.04 mol) and 0.2 g of potassium iodide overnight. The reaction mixture was stripped to dryness and the residue was partitioned between water and chloroform several times. The chloroform layer was dried (anhydrous sodium sulfate), filtered, and the solvent was evaporated to give an oil. All of this oil was converted to oxalate. The salt was recrystallized from methanol-diethyl ether and dried in vacuo at 80 ° C overnight. 7.23 g (6
2%) yield. Melting point, 159-161 [deg.] C.

Elemental analysis: Calculated value for C ₃₁ H ₃₂ N ₂ O ₅ Cl ₂ : C, 63.81; H, 5.53; N, 4.80 Found: C, 64.02; H, 5.61; N, 4.86 Example 132 1- [4- (4-acetyl-2-methoxyphenoxy)
Butyl] -α, α-bis (4-fluorophenyl) -4
-Piperidineacetonitrile = fumarate [1: 1] α, α-bis (4-fluorophenyl) -4-piperidineacetonitrile 5.38 g (0.0172 mol) and 1- [4-
A mixture with (4-bromobutoxy) -3-methoxyphenyl] ethanone (5.20 g, 0.0172 mol) was added to potassium carbonate.
The mixture was heated under reflux overnight in 350 ml of acetonitrile containing 5.53 g (0.04 mol) and 0.2 g of potassium iodide. The reaction mixture was slit to dryness and the resulting residue was partitioned between chloroform and water several times. The chloroform layer was dried (anhydrous sodium sulfate), filtered, and the solvent was evaporated to give an oil. This oil was converted to the fumarate salt. The salt was recrystallized from methanol-diethyl ether and vacuumed to 80
Dry overnight at ° C. White crystals were obtained in a yield of 5.78 g (51.7%). Melting point, 181.5-182 ° C.

Elemental analysis: Calculated value for C ₃₆ H ₃₈ N ₂ O ₇ F ₂ : C, 66.66; H, 5.90; N, 4.32 Found: C, 66.56; H, 5.92; N, 4.28 Example 133 1- [2- (2,6-Dichlorophenoxy) ethyl]-
α, α-Diphenyl-3-piperidinepropanamide α, α-diphenyl-3-piperidinepropanenitrile
7.65 g (0.025 mol) and 2- (2-bromoethoxy)-
A mixture of 6.70 g (0.025 mol) of 1,3-dichlorobenzene and 5.54 g (0.04 mol) of potassium carbonate was heated to reflux overnight in 350 ml of acetonitrile containing 0.2 g of potassium iodide. The reaction mixture was stripped to dryness and the residue was partitioned between water and chloroform several times. Chloroform layer,
Dry (anhydrous sodium sulfate), filter and evaporate the solvent to give 12.91 g of a brown oil. All this oil
Subject to flash chromatography on silica gel,
Eluted with 75-25 v / v ethyl acetate-hexane and 100% ethyl acetate. Similar fractions were collected and the solvent was evaporated. The resulting oil was dried under vacuum at 65 ° C overnight. A clear oil was obtained in a yield of 6.98 g (56.1%). ¹ H NMR (CDCl ₃ ): δ6.9 to 7.5 (m, 13, aromatic), 6.0 (wide 2, NH ₂ ), 4.0 (t, 2, O-CH ₃ ), 2.7 (t, 2, N -CH ₂ ), 1.0
~ 2.3 (m, 11, aliphatic).

Elemental analysis: Calculated for C ₂₈ H ₃₀ N ₂ O ₂ Cl ₂ : C, 67.61; H, 6.08; N, 5.63 Found: C, 67.52; H, 6.08; N, 5.63 Example 134 α- [1- [3- (4-acetyl-2-methoxyphenoxy) propyl] -4-piperidinyl-α- (4-fluorophenyl) -2-pyridineacetonitrile = fumarate [1: 1] α- (4-fluorophenyl Enyl) -α- (4-piperidinyl) -3-pyridineacetonitrile 7.18 g (0.024 mol)
And 1- [4- (3-chloropropoxy) -3-methoxyphenyl] ethanone 5.89 g (0.024 mol) and potassium carbonate 5.54 g (0.04 mol) were mixed with potassium iodide.
Heat overnight in 350 ml of 1-butanol containing 0.15 g. The reaction mixture was stripped to dryness and the resulting residue was partitioned between chloroform and water. The chloroform layer was extracted with 1N sulfuric acid, 5% sodium hydroxide and water. The chloroform layer was dried over sodium sulfate, filtered and evaporated to give an oil. The oil was converted to the fumarate salt and recrystallized from methanol-diethyl ether. A white solid was obtained and dried in vacuo at 80 ° C. overnight to give white crystals in a yield of 9.43 g (62.7%). Melting point, 166-167 ° C.

Elemental analysis: Calculated value for C ₂₄ H ₃₆ N ₃ O ₇ F: C, 66.11; H, 5.87; N, 6.80 Actual value: C, 65.57; H, 5.89; N, 6.70 Example 135 α- [1- [ 3- (4-acetyl-2-methoxyphenoxy) propyl] -4-piperidinyl] -α- (4-fluorophenyl) -2-pyridineacetonitrile = fumarate = hydrate [1: 1] Example 134 A part of the compound prepared in 1. was exposed to air for 3 days. Melting point, 166-167 ° C.

Elemental analysis: Calculated for C ₂₄ H ₃₈ N ₃ O ₈ F: C, 64.24; H, 6.02; N, 6.61 Found: C, 64.07; H, 5.82; N, 6.58 Example 136 α, α-diphenyl- 1- [3- (8-quinolinyloxy) propyl] -3-piperidinepropanenitrile hydrate [1: 0.5] α, α-diphenyl-3-piperidinepropanenitrile
8.12 g (0.028 mol) and 8- (3-chloropropoxy)
Quinoline 6.18g (0.028mol) and potassium carbonate 5.53g
A mixture with (0.04 mol) was heated to reflux overnight in 350 ml of 1-butanol containing 0.3 g of potassium iodide. The reaction mixture was filtered, stripped and dried on a rotary evaporator. The obtained residue was dissolved in chloroform and extracted with 5% sodium hydroxide and water. The clohaform layer was dried over anhydrous sodium sulfate, filtered and evaporated to give a dark red material. This material was flash chromatographed on silica gel, eluting with 10% methanol-ethyl acetate, 20% methanol-ethyl acetate and 50% methanol-ethyl acetate. Fractions of similar purity were collected and the solvent was evaporated on a rotary evaporator. The resulting residue was dried in vacuo at 80 ° C. overnight to give a dark brown residue in a yield of 5.29 g (39%). ¹ H NMR (CDCl ₃ ): δ8.9 (m, 1, proton in ortho position relative to N in the ring), 7.9 to 8.1 (m, 1, proton in para position relative to N in the ring), 6.9 to 7.6 (m, 14, aromatic), 4.2 (t, 2,
Methylene adjacent to an oxygen atom), 1.1~2.7 (m, 16, aliphatic protons and 0.5H ₂ IH from O) Elemental analysis: calculated for _{C 32 H 33 N 3 O 1.5} : C, 79.31; H, 7.07 N, 8.67 Found: C, 79.47; H, 7.19; N, 8.69 Example 137 8- [3- [4- [bis (4-fluorophenyl) methyl] -1-piperidinylpropoxy] quinoline = Hydrate [1: 0.5] 4- (α-p-fluorophenyl) -p-fluorobenzylpiperidine 8.03 g (0.028 mol), 8- (3-chloropropoxy) quinoline 6.18 g (0.028 mol), A mixture with 5.53 g (0.04 mol) of potassium carbonate was heated to reflux overnight in 350 ml of 1-butanol containing 0.3 g of potassium iodide. The reaction mixture was filtered through activated charcoal and the solvent was distilled off on a rotary evaporator. The residue was dissolved in chloroform and extracted with 5% sodium hydroxide and water. The chloroform layer was dried over anhydrous sodium sulfate,
Filtration and evaporation of the solvent gave a dark red substance. This material was flash chromatographed on silica gel, eluting with 10,20 and 50% methanol / ethyl acetate. Fractions of the same purity were collected and the solvent was evaporated. The residue was dried in vacuo at 80 ° C overnight to yield 3.74 g (2
8%). ¹¹ H NMR (CDCl ₃ ): δ8.9 (m, 1, proton in ortho position relative to N in ring), 7.9 to 8.1 (m, 1, proton in para position relative to N in ring), 6.8 to 7.4 (m, 12, aromatic), 4.2 (t, 2,
CH ₂ attached to O), 3.5 (d, methine attached to 1,2 aromatic rings), 1.0 to 3.2 (m, 14, aliphatic protons and 0.5H ₂
O IH from) Elemental _{analysis: C 30 H 30.50 N 2 O} 7.5 F 2 Calculated for: C, 75.53; H, 6.44 ; N, 5.87 Found: C, 75.66; H, 6.56 ; N, 5.86 Example 138 2- [3- [4- [bis (4-fluorophenyl) methyl] -1-piperidinyl] propoxy] benzoic acid hydrate [1: 0.5] 2- [3- [4- [bis (4- Fluorophenyl) methyl] -1 piperidinyl] propoxy] benzoic acid ethyl ester 25.3 g (0.051 mol) was added to potassium hydroxide (16.8
What was dissolved in 400 ml of 200 ethanol containing g, 0.30 mol) was heated under reflux for 4 hours. The reaction mixture was concentrated to a volume of about 200 ml. The reaction mixture was acidified with 1N hydrochloric acid. The acidic layer was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to give a gummy residue. This material was subjected to flash chromatography, 20% methanol-80% ethyl acetate,
And eluted with 50% methanol-50% ethyl acetate. Fractions of similar purity were collected. The solvent was removed in vacuo and the residue dried in vacuo at 80 ° C overnight to give 5.72g (23.6g).
%) Material was obtained. ¹ H NMR (CDCl ₃ ): δ 9.2 (wide 2, COOH and 0.5 H ₂ O), 7.
8 (H adjacent to m, 1, COOH), 6.7 to 7.3 (m, 11, aromatic), 4.1 (CH ₂ bonded to m, 2,0), 1.5 to 3.66 (m, 14,
Aliphatic) Elemental analysis: Calculated for C ₂₈ H ₃₀ NO _3.5 F ₂ : C, 70.87; H, 6.37; N, 2.95 Found: C, 71.42; H, 6.31; N, 3.01 Example 139 4- [bis (4-Fluorophenyl) methyl] -N-phenyl-1-piperidinepropanamine = maleate [1: 2] 4- [bis (4-fluorophenyl) methyl] -1-
A solution of 35.27 g (0.097 mol) of (3-chloropropyl) piperidine in 200 ml of aniline (204.4, 2.2 mol) was stirred overnight at 100 ° C. The solution was cooled to room temperature and then extracted several times with 1N sulfuric acid. The chloroform layer was extracted with 5% sodium hydroxide and then dried over anhydrous sodium sulfate. The solution was filtered and the solvent was evaporated in vacuo,
This gave a dark brown oil. The oil was converted to the maleate salt, which was recrystallized from methanol-diethyl ether. The resulting solid was dried at 80 ° C. under vacuum overnight to give 29.84 g (47.1%) of a light brown solid. Melting point 153-1
54 ° C.

Elemental analysis: Calculated value for C ₂₇ H ₃₀ NO ₂ OF ₂ : C, 64.41; H, 5.87; N, 4.29 Found value: C, 64.36; H, 5.87; N, 4.39 Example 140 N- [3- [4 -[Bis (4-fluorophenyl) methyl] -1-piperidinyl] propyl] -N-methylbenzenamine 4- [bis (4-fluorophenyl) methyl] -1-
(3-chloropropyl) piperidine 8.43 g (0.023 mol)
Was dissolved in 100 ml of N-methylaniline at 100 ° C.
It was stirred for 30 hours. The reaction mixture was cooled to room temperature and diluted with 300 ml of chloroform. Chloroform layer 100 ml of 1N sulfuric acid
Each was extracted three times (each neutral to litmus paper). 10 ml of 1N sulfuric acid used for the fourth extraction was strongly acidic on litmus paper. This fourth fraction was made alkaline with ice and 50% sodium hydroxide and extracted with chloroform. The chloroform layer was back extracted with 5% sodium hydroxide and dried over anhydrous sodium sulfate. Chloroform was evaporated on a rotary evaporator to produce a reddish brown oil. This oil was flash chromatographed on silica gel, eluting with ethyl acetate. Fractions of the same purity were collected and the solvent was evaporated. Get residue and vacuum 80
Drying overnight at C gave 4.41 g (44.1%) of a brown oil. ¹ NMR (CDCl ₃ ): δ6.6 to 7.2 (m, 13, aromatic), 3.5 (d,
1, methine bound to aromatic nucleus), 3.3 (t, 2, aromatic N
Bound to methylene), 2.9 (s, 3, N-CH ₃ ), 1.1 to 2.7
(M, 13, aliphatic) Elemental _{analysis: C 28 H 32 N 2 F} 2 Calculated for: C, 77.39; H, 7.42 ; N, 6.45 Found: C, 77.44; H, 7.44 ; N, 6.42 carried Example 141 1- [3- (4-acetyl-2-methoxyphenoxy)
Propyl] -α, α-bis (4-fluorophenyl)-
3-piperidineacetonitrile = oxalate = hydrate [1: 1: 1] α, α-bis (4-fluorophenyl) piperidineacetonitrile 6.55 g (0.02 mol) and 1- [4- (3-chloropropoxy) -3-Methoxyphenyl] ethanone 5.
1-Butanol containing a mixture of 08 g (0.02 mol) and 5.53 g (0.04 mol) of potassium carbonate, 0.2 g of potassium iodide
Gently heated to reflux overnight in 350 ml. The reaction mixture was stripped to dryness and the resulting residue was dissolved in chloroform. Chloroform was extracted with water and 5% sodium hydroxide. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to give a dark brown oil. The oil was converted to the oxalate salt which was recrystallized twice from methanol-diethyl ether. The salt was dried under vacuum at 80 ° C. overnight to yield a white crystalline solid.
Obtained in a yield of 2.28 g (17.4%). Melting point, 108-109 ° C.

Elemental analysis: Calculated for C ₃₃ H ₃₆ N ₂ O ₃ F ₂ : C, 63.25; H, 5.79; N, 4.47 Found: C, 63.08; H, 5.48; N, 4.39 Example 142 1- [3- (4-Cyanophenoxy) propyl] -α,
α-bis (4-fluorophenyl) -3-piperidineacetonitrile 4- (3-chloropropoxybenzonitrile 6.39 g (0.0
327 mol) and α, α-bis (4-fluorophenyl)
A mixture of 10.22 g (0.0327 mol) of piperidineacetonitrile and 5.54 g (0.04 mol) of potassium carbonate was heated to reflux overnight in 350 ml of 1-butanol containing 0.2 g of potassium iodide. The reaction mixture was stripped to dryness and the resulting residue was partitioned between chloroform and water. The chloroform layer was back extracted with water. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to give an oil. This oil was chromatographed on 300 g of silica gel with 50% hexane-50% ethyl acetate and 75% hexane.
Elution with% ethyl acetate-25% hexane. Fractions of the same purity were combined and the resulting oil was dried in vacuo at 80 ° C overnight. This material crystallized during overnight drying. The solid obtained was recrystallized from an equal volume of isopropanol and low boiling petroleum ether. The solid obtained is vacuumed to 80
After drying overnight at ℃ 5.85 g (37.9
%). Melting point, 132-133 [deg.] C.

Elemental analysis: Calculated for C ₂₉ H ₂₇ N ₃ OF ₂ : C, 73.87; H, 5.77; N, 8.91 Found: C, 73.56; H, 5.75; N, 8.85 Example 143 4- [3- [4 -Bis (4-fluorophenyl) methyl] -1-piperidinyl] propoxy] -3-methoxybenzonitrile The sodium salt of 4-hydroxy-3-methoxybenzonitrile is sodium hydride (60%, 0.8 g, 0.02 mol). )
And 4-hydroxy-3-methoxybenzonitrile (3.
00g, 0.02 mol) and 250 ml of dry dimethylsulfoxide. At the beginning, the solution was cloudy white, but a little (10 minutes) after stirring,
The solution turned clear brown. The reaction mixture was stirred at room temperature for 30 minutes. 4- [bis (4-fluorophenyl) methyl] -1- (3-chloropropyl) piperidine (7.26 g,
0.02 mol) of dimethylsulfoxide solution was added and the resulting solution was stirred at 50 ° C. overnight. Dimethyl sulfoxide was distilled off under vacuum, and the obtained residue was dissolved in chloroform. The organic layer was extracted with 5% sodium hydroxide and water.
The chloroform layer was dried over sodium sulfate, filtered,
Evaporation of the solvent produced a dark brown oil. This oil was flash chromatographed on silica gel, eluting with ethyl acetate and 2% methanol-ethyl acetate. Fractions of similar purity were collected, the solvent was removed in vacuo and the residue dried in vacuo at 80 ° C. overnight to give 4.40 g (46.2%) of a brown oil. ¹¹ H NMR (CDCl ₃ ): δ 6.8 to 7.3 (m, 11, aromatic), 4.1
(T, 2, _{3.8 (s, 3, -OCH 3} ), 3.4~3.6 (d, methine bonded to the carbon having one or two of fluoro-phenylalanine group), 1.2~3.0 (m,
13, aliphatic).

Elemental analysis: Calculated for C ₂₉ H ₃₀ N ₂ O ₂ F ₂ : C, 73.09; H, 6.34; N, 5.88 Found: C, 72.38; H, 6.34; N, 5.78 * NMR is 1 / 4H ₂ O And traces of ethyl acetate.

Example 144 4- [bis (4-fluorophenyl) methyl] -1-
(2-Natafurenyloxy) propyl] piperidine] hydrobromide hydrate [1: 1: 0.5] The sodium salt of α-naphthol is α-naphthol (2.59 g, 0.018 mol) in 300 ml of dimethyl sulfoxide. ) And sodium hydride (60%, 0.72 g, 0.018 mol). The sodium salt was stirred at room temperature for 2.5 hours. 4- [bis (4-fluorophenyl) methyl] -1- (3-chloropropyl) piperidine (6.52 g, free base 0.018 mol)
Was added to 100 ml of dimethylsulfoxide and the resulting solution was stirred at 65 ° C. overnight. The solvent was removed in vacuo,
The resulting residue was partitioned between chloroform-water, chloroform-1N sulfuric acid, and chloroform-5% sodium hydroxide. The chloroform layer was dried over sodium sulfate, filtered and evaporated to give a green oil.
The oil was converted to the hydrobromide salt and recrystallized from methanol-diethyl ether. The white salt obtained was dried in vacuo at 80 ° C. overnight. By exposing the crystalline solid to air overnight, 1.88 g (18.6 g) of a white crystalline solid was obtained.
%). Melting point, 220-223 ° C.

Elemental analysis: Calculated value for C ₃₁ H ₃₃ NO _1.5 F ₂ Br: C, 66.31; H, 5.92; N, 2.49 Found value: C, 66.46; H, 5.84; N, 2.49 Example 145 2- [3- [ 4- [bis (4-fluorophenyl) methyl] -1-piperidinyl] propoxy] quinoline hydrate [1: 0.5] 4- [bis (4-fluorophenyl) methyl] -1-piperidine propanol sodium The salt consists of its free base (6.90g, 0.02mol) and sodium hydride (60%, 0.8g, 0.
02 mol) in 300 ml of dimethylsulfoxide. 2-chloroquinoline (3.26 g, 0.02 mol) was added,
The reaction mixture was heated at 60 ° C. for 1 week. The reaction mixture was stripped to dryness and the resulting residue was dissolved in chloroform. The chloroform layer was extracted with water and 5% sodium hydroxide. The chloroform layer was dried over sodium sulfate, filtered and evaporated to give an oil. The oil was flash chromatographed on silica gel and extracted with ethyl acetate. Fractions of similar purity were collected and the solvent was evaporated. The residue was dried in vacuo at 80 ° C. overnight to give 5.16 g (53.6%) of a clear brown oil. ¹¹ H NMR (CDCl ₃ ): δ 6.8 to 7.9 (m, 14, aromatic), 4.5
_{(T, 2, -OCH 2)} , 3.4 and 3.6 (d, methine bonded to one or two aromatic rings), 1.2~3.1 (m, 13, remaining aliphatic).

Elemental analysis: Calculated value for C ₃₀ H ₃₁ N ₂ O _1.5 F ₂ : C, 74.82; H, 6.49; N, 5.82 Found: C, 74.56; H, 6.36; N, 5.69 Example 146 4- [bis ( 4-Fluorophenyl) methyl] -1-
[3- (2-Naphthalenyloxy) propyl] piperidine] hydrate [1: 0.5] The sodium salt of 2-naphthol was hydrogenated with 2-naphthol (3,00 g, 0.0208 mol) in 300 ml of dimethyl sulfoxide. Formed with sodium (60%, 0.83 g, 0.0208 mol). The solution was stirred at room temperature for 1 hour and became a clear brown color. 4- [bis (4-fluorophenyl)
Methyl] -1- (3-chloropropyl) piperidine (7.
55 g, 0.0208 mol) in 100 ml of dimethylsulfoxide was added. The resulting solution was stirred at 60 ° C overnight. The solvent was evaporated in vacuo and the resulting residue was partitioned between chloroform-water and chloroform-5% sodium hydroxide.
The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to give a brown oil. This oil (free base) was flash chromatographed on silica gel using 50-50 ethyl acetate-hexane and 7
Elution was performed with 5-25 ethyl acetate-hexane. Fractions of similar purity were collected and evaporated to an oil.
The oil was dried in vacuo at 80 ° C. overnight and exposed to laboratory air overnight to give 2.97 g (32.3 g of dark brown glass).
%). ¹ H NMR (CDCl ₃ ): δ 6.8 to 7.8 (m, 15, aromatic), 4 to 4.
_{3 (t, 2, -OCH 2} ), 3.4~3.6 (d, methine bonded to one or two of fluoro-phenylalanine group), 1.1~3.0 (m, 13, aliphatic).

Elemental analysis: Calculated value for C ₃₀ H ₃₁ NOF ₂ : C, 77.48; H, 6.71; N, 2.91 Found: C, 77.86; H, 6.65; N, 2.94 Example 147 3- [3- [4- [ Bis (4-fluorophenyl) methyl] -1-piperidinyl] propoxy] benzonitrile hydrate [1: 0.5] 4- [bis (4-fluorophenyl) methyl] piperidine (7.85 g, 0.027 mol) , 3- (3-chloropropoxy) -1-benzonitrile (5.33 g, 0.027 mol) and potassium carbonate (5.84 g, 0.027 mol) in 350 ml of 1-butanol containing potassium iodide (0.2 g). Heated to reflux overnight. The reaction mixture was filtered, stripped to dryness. The obtained residue was dissolved in chloroform and extracted with water and 5% sodium hydroxide. The chloroform layer was dried over sodium sulfate, filtered and evaporated to give a brown oil. This oil was flash chromatographed on silica gel using ethyl acetate-
Elute with hexane. Fractions of similar purity were collected and the solvent was evaporated. The residue was dried in vacuo at 80 ° C. overnight to yield 5.65 g (45.9%) of a dark brown oil. ¹ H NMR (CDCl ₃ 9: δ 6.7 to 7.3 (m, 12, aromatic), 3.8 to
4.1 (t, 2, methylene adjacent to oxygen atom), 3.4 to 3.6
(Methine attached to d, 1,2 phenyl groups), 1.1-3.0
(M, 13, remaining aliphatic protons).

Elemental analysis: Calculated for C ₂₈ H ₂₉ N ₂ O _1.5 F ₂ : C, 73.83; H, 6.42; N, 6.15 Found: C, 74.05; H, 6.27; N, 6.09 Example 148 α, α-bis (4-Fluorophenyl) -1- [3-
(4-Methoxyphenoxy) propyl] -4-piperidinemethanol This compound was prepared according to the method used for the synthesis of the compound of Example 1. α, α-bis (p-fluorophenyl)
3.0 g (0.01 mol) of 4-piperidinemethanol, 1-
Chloro-3- (4-methoxyphenoxy) propane 2.0 g
(0.01 mol), anhydrous sodium carbonate 5.3 g (0.035 mol), and potassium iodide 0.3 g 1-butanol 100 ml
2.3 g (49%) of the title compound as a white solid.
% Yield). Melting point, 107-108 ° C.

Elemental analysis: C₂₈H₃₁F₂NO₃Calculated for: C, 71.93; H, 6.68; N, 3.00 Found: C, 71.90; H, 6.70; N, 2.99 Example 149 α, α-bis (4-fluorophenyl) -1- [3-
(4-Methylphenoxy) propyl] -4-piperidine
Methanol = fumarate [1: 1] This compound was prepared according to the method used for the synthesis of the compound of Example 1.
Was manufactured. α, α-bis (p-fluorophenyl)
3.0 g (0.01 mol) of 4-piperidinemethanol, 1-
Chloro-3- (4-methylphenoxy) propane 1.8 g
(0.01 mol) and 5.3 g of anhydrous sodium carbonate (0.035 mol)
) And 0.3 g of potassium iodide, 1-butanol 100 m
Mixing in 1 gave a gum as a residue. Gum
100 g of Florisil ) Column chromatography
Purified by mattografie. 10% acetone / ben
Collecting and concentrating the fraction eluted with Zen, the gum becomes
occured. The gum is converted to the fumarate salt and the solid is dried over anhydrous ethanol.
Recrystallization from tanol yielded 3.2 g (56%) of the title compound.
Obtained as a white solid. Melting point, 193-194 ° C (decomposition).

Elemental analysis: C₃₂H₃₅F₂NO₆Calculated for: C, 67.71; H, 6.22; N, 2.47 Found: C, 67.93; H, 6.25; N, 2.53 Example 150 1- [3- (4-Fluorophenoxy) propyl]-
α, α-bis (4-fluorophenyl) -4-piperidi
Methanol = fumarate = hydrate [1: 1: 1] This compound was prepared according to the method used for the synthesis of the compound of Example 1.
Was manufactured. α, α-bis (p-fluorophenyl)
3.0 g (0.01 mol) of 4-piperidinemethanol, 1-
Chloro-3- (4-fluorophenoxy) prone 1.9 g
(0.01 mol) and 5.3 g of anhydrous sodium carbonate (0.035 mol)
100 ml of 1-butanol with 0.3 g of potassium iodide
Mixing in gave a solid as a residue. Solid
Full lysyl By 60g column chromatography
Further purified. Elute with 2-10% acetone / benzene
The collected fractions were concentrated to give a solid residue.
The solid is converted to the fumarate salt and the solid is converted to isopropanol
2.2 g (39%) of the title compound as a white solid.
Obtained as a body. Melting point, 155-157 ° C.

Elemental analysis: Calculated value for C ₃₁ H ₃₄ F ₃ NO ₇ : C, 63.14; H, 5.81; N, 2.38 Found: C, 62.99; H, 5.64; N, 2.28 Example 151 1- [3- (4 -Ethyl-2-methoxyphenoxy) propyl] -α, α-bis (4-fluorophenyl) -4
-Piperidinemethanol This compound was prepared according to the method used for the synthesis of the compound of Example 1. α, α-bis (p-fluorophenyl)
3.0 g (0.01 mol) of 4-piperidinemethanol, 3-
2.3 g (0.01 mol) of (4-ethyl-2-methoxyphenoxy) propyl chloride and 5.3 g of anhydrous sodium carbonate (0.
05 mol) and 0.3 g of potassium iodide and 1-butanol 10
3.7 g of the title compound as a white solid, mixed in 0 ml.
(74%). Melting point, 118-120 ° C.

Elemental analysis: calculated for _{C 30 H 35 F 2 NO 3} : C, 72.70; H, 7.12; N, 2.83 Found: C, 72.72; H, 7.43 ; N, 2.81 Example 152 1- (3-Fuenoki Cypropyl) -α, α-diphenyl-4-piperidinemethanol This compound was prepared according to the method used for the synthesis of Example 1. α, α-diphenyl-4-piperidinemethanol
4.0 g (0.015 mol), 1-bromo-3-phenoxypropane 3.2 g (0.015 mol), anhydrous sodium carbonate 5.3 g
(0.05 mol) and 0.4 g of potassium iodide in 100 ml of 1-butanol gave the title compound as a white solid.
This yielded 3.2 g (53%). Melting point, 87-88 ° C.

Elemental analysis: C₂₇H₃₁NO₂Calculated for: C, 80.76; H, 7.78; N, 3.49 Found: C, 80.82; H, 7.79; N, 3.52 Example 153 α, α-bis (4-fluorophenyl) -1- [3-
[4- (methylsulfinyl) phenoxy] propyl]
-4-piperidinemethanol = oxalate = hydrate
The compound of (1: 1: 1.5) and 2-propanol (1: 0.5)
It was α, α-bis (p-fluorophenyl) -4-pipet
Lysine methanol 3.0 g (0.01 mol) and 1- (3-chloro)
Ropropyl) -4-methylsulfinyl) benzene 2.3 g
(0.01 mol) and 5.3 g of anhydrous sodium carbonate (0.05 mol)
And 0.3 g of potassium iodide in 100 ml of 1-butanol
The mixture produced a gum as a residue. Full of gum
Lycile Purified by 120g column chromatography
did. Fluxe eluted with 15-25% acetone / benzene
Yong was collected and concentrated to give the purified base as an oil. Oil
Converted to oxalate and recrystallized solid from 2-propanol
Crystallization yielded 2.6 g (40%) of the title compound as a white solid.
It was Melting point, 75-105 ° C.

Elemental analysis: Calculated value for C ₃₀ H ₃₆ F ₂ NO _8.5 S ・ 0.5 (C ₃ H ₈ O): C, 58.50; H, 6.23; N, 2.17 Found: C, 58.32; H, 5.99; N, 2.05 Example 154 α, α-bis (4-fluorophenyl) -1- [3-
[4- (1-methylethyl) phenoxy] propyl]-
4-Piperidinemethanol = oxalate [1: 1] This compound was prepared according to the method used for the synthesis of Example 1. α, α-bis (p-fluorophenyl) -4-piperidinemethanol 4.6 g (0.015 mol) and 1-chloro-3- (4-isopropylphenoxy) propane 3.2 g
(0.015 mol), anhydrous sodium carbonate 5.3 g (0.05 mol), and potassium iodide 0.4 g, 1-butanol 100 ml
Mixing in gave a solid as a residue. The solid was converted to the oxalate salt and the solid was recrystallized from ethyl acetate to give 4.6 g (54% yield) of the title compound as a white solid. Melting point, 105-109 ° C (decomposition).

Elemental analysis: Calculated value for C ₃₂ H ₃₇ F ₂ NO ₆ : C, 67.47; H, 6.55; N, 2.46 Measured value: C, 66.92; H, 6.61; N, 2.52 Example 155 3- [3- [4 -[Bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] benzoic acid ethyl ester = fumarate [1: 1] This compound was prepared according to the method used to synthesize the compound of Example 1. . α, α-bis (p-fluorophenyl)
-4-piperidinemethanol 3.0 g (0.01 mol), anhydrous sodium carbonate 2.4 g (0.01 mol), and potassium iodide 0.
Mixing 4 g with 100 ml dimethylformamide yielded a gum as a residue. The title compound was obtained when the gum was converted to fumarate and the solid was recrystallized from acetonitrile.
4.2 g (67%) were obtained as a fluffy white solid. Melting point,
123-131 ° C.

Elemental analysis: calculated for _{C 34 H 37 F 2 NO 8} : C, 65.27; H, 5.96; N, 2.24 Found: C, 65.09; H, 5.95 ; M, 2.25 Example 156 1- [4- [3 -[4- [bis (4-methylphenyl)]
Methylene] -1-piperidinyl] propoxy] -3-methoxyphenyl] ethanone This compound was prepared according to the method used for the synthesis of the compound of Example 1. α, α-bis (4-methylphenyl)-
4.6 g (0.015 mol) of 4-piperidinemethanol and 1-
[4- (3-chloropropoxy) -3-methoxyphenyl] ethanone 3.6 g (0.015 mol), anhydrous sodium carbonate 5.3 g (0.05 mol) and potassium iodide 0.4 g were mixed in 1-butanol 100 ml. Yielded a brown gum as a residue. The gum was dissolved in ethyl ether and filtered to remove insoluble material. The liquid is treated with ethereal hydrochloric acid,
The solid crystallized gently. An attempt to recrystallize from solid isopropanol failed. The solid was partitioned between methylene chloride and sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a brown gum. The gum was converted to the fumarate salt. The solid was recrystallized twice from 2-propanol but no satisfactory combustion analysis was obtained. The salt was partitioned between methylene chloride and sodium bicarbonate as above to give a gum as a residue. After standing for several days, the gum was recrystallized. The solid was triturated with petroleum ether, collected over and recrystallized from 2-propanol to give 2.2 g (46%) of the title compound as an off-white solid. Melting point, 92-95 ° C (decomposition).

Elemental analysis: Calculated value for C ₃₂ H ₃₇ NO ₃ : C, 79.47; H, 7.71; N, 2.90 Found: C, 79.18; H, 7.88; N, 2.88 Example 157 1- [4- [3- [ 4- [bis (4-methylphenyl)
Hydroxymethyl] -1-piperidinyl] propoxy]
-3-Methoxyphenyl] ethanone = oxalate = hydrate [1: 1: 1] This compound was produced according to the method for synthesizing the compound of Example 1. 4.6 g (0.015 mol) of α, α-bis (4-methylphenyl) -4-piperidinemethanol and 1- [4- (3
3.6 g (0.015 mol) of -chloropropoxy) -3-methoxyphenyl] ethinone and 5.3 g of anhydrous sodium carbonate (0.0
5 mol) and 0.4 g of sodium iodide, 1-butanol 1
Mixing in 00 ml gave a brown gum as a residue. The gum was converted to the oxalate salt and the solid was recrystallized from absolute ethanol to give 5.3 g (58%) of the title compound as a gray solid. Melting point, 92-95 ° C (decomposition).

Elemental analysis: Calculated value for C ₃₄ H ₄₃ NO ₉ : C, 66.97; H, 7.11; N, 2.30 Found: C, 66.61; H, 6.79; N, 2.29 Example 158 4- [3- [4- [ Bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] benzoic acid methyl ester = fumarate [1: 1] α, α-bis (p-fluorophenyl) -4-piperidinemethanol 9.1 g (0.03 Mol) and 4- (3-chloropropoxy) benzoic acid methyl ester 6.7 g (0.3 mol)
A mixture of 10.6 g (0.1 mol) of anhydrous sodium carbonate and 0.6 g of potassium iodide in 125 ml of dimethylformamide was heated in a steam bath for 25 hours, and the reaction mixture was mixed with ice water 1.
Pour into 5 liters. Collect the resulting solids by filtration,
It was washed with water and dried. The solid was converted to the fumarate salt to give 12.5 g (68%) of the title compound as a white solid.
Melting point, 140-174 ° C (decomposition).

Elemental analysis: Calculated value for C ₃₃ H ₃₅ F ₂ NO ₈ : C, 64.80; H, 5.77; N, 2.29 Found value: C, 64.67; H, 5.80; N, 2.34 Example 159 1- [3- (4 -Aminophenoxy) propyl] -α,
α-bis (4-fluorophenyl) -4-piperidinemethanol = oxalate [1: 2] α, α-bis (4-fluorophenyl) -1- [3-
2.6 g (0.0054 mol) of (4-nitrophenoxy) propyl] -4-piperidinemethanol in tetrahydrofuran 50
What was dissolved in ml was hydrogenated at 40 psi in the presence of 5% palladium / carbon catalyst at ambient temperature. Have a mixture,
The liquor was concentrated to give a gum as a residue. The gum was converted to the heavy oxalate salt and the solid was recrystallized from 95% ethanol to give 2.1 g (62%) of the title compound as an off-white solid. Melting point, 136-139 ° C (decomposition).

Elemental analysis: Calculated value for C ₃₁ H ₃₄ F ₂ N ₂ O ₁₀ : C, 58.86; H, 5.42; N, 4.43 Found: C, 58.73; H, 5.48; N, 4.43 Example 160 1- [4- [3- [4- [bis (4-fluorophenyl) methyl] -1-piperidinyl] propoxy] -2-
Methoxyphenyl] ethanone oxalate [1: 1] 4- [bis (4-fluorophenyl) methyl] piperidine (5.74 g, 0.02 mol) and 1- [4- (3-chloropropoxy) -2-methoxy Phenyl] ethanone (4.85
g, 0.02 mol) and potassium iodide (5.54 g, 0.04 mol)
A mixture of and contains potassium iodide (0.2g) 1
Heated at reflux in butanol (350 ml) overnight. The reaction mixture was evaporated to dryness and the resulting residue was partitioned between chloroform and water. The chloroform layer was extracted with water, dried over sodium sulfate, filtered, and the solvent was removed to give a brown oil. The oil was converted to the oxalate salt. The oxalate salt was recrystallized from methanol-diethyl ether. A white solid was obtained and dried under vacuum at 80 ° C. overnight to yield 7.04 g (60.3% yield) of white crystalline product. Melting point, 190.5-191
° C.

Elemental analysis: Calculated value for C ₃₂ H ₃₅ NO ₇ F ₂ : C, 65.86; H, 6.05; N, 2.40 Actual value: C, 65.73; H, 6.05; N, 2.45 Example 161 4- [bis (4- Fluorophenyl) methyl] -1-
[3- (4-Ethyl-2-methoxyphenoxy) propyl] piperidine = oxalate [1: 1] 4- [bis (4-fluorophenyl) methyl] piperidine (5.74 g, 0.024 mol) and 1- [4- (3-chloropropoxy) -2-methoxyphenyl] ethanone (5.57
g, 0.024 mol) and potassium carbonate (5.54 g, 0.04 mol)
A mixture of and contains potassium iodide (0.2g) 1
Heated gently in 350 ml butanol at reflux overnight. The reaction mixture was evaporated to dryness and the residue was partitioned several times between chloroform and water. The chloroform layer was back extracted with water and 5% sodium hydroxide. The chloroform layer was dried over sodium sulfate, filtered, and the solvent was removed to give an oil.
The oil was converted to the oxalate salt and recrystallized from methanol diethyl ether. A white solid was obtained, overnight under vacuum at 80 ° C.
When dried at 10.04g of white crystalline product (73.4% yield)
Occurred. Melting point, 185-186 [deg.] C.

Elemental analysis: Calculated value for C ₃₂ H ₃₇ NO ₆ F ₂ : C, 67.47; H, 6.55; N, 2.46 Found value: C, 67.41; H, 6.53; N, 2.50 Example 162 1- [4- [3 -[4- [bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] phenyl] -1-propanone and 2-propanol compound (1: 1) This compound is the compound of Example 1. Prepared according to the synthetic method. 3.0 g (0.01 mol) of α, α-bis (p-fluorophenyl) -4-piperidinemethanol and 1- [4- (3
-Chloropropoxy) phenyl] -1-propanone 2.3 g
(0.01 mol), anhydrous sodium carbonate 3.7 g (0.035 mol), and potassium iodide 0.4 g, 1-butanol 100 ml
3.7 g (76%) of the title compound as a white solid.
%). Melting point, 57-62 ° C.

Elemental analysis: C₃₀H₃₃F₂NO₃・ C₃H₈Calculated for O: C, 71.59; H, 7.46; N, 2.53 Found: C, 71.42; H, 7.29; N, 2.63 Example 163 1- [4- [3- [4- [bis (4-methoxyphenyl)
) Hydroxymethyl] -1-piperidinyl] -propo
[Xy] -3-methoxyphenyl] ethanone = oxalate
[1: 1] This compound was prepared according to the synthetic method of the compound of Example 1.
It was α, α-bis (4-methoxyphenyl) -4-pipet
3.2 g (0.01 mol) of lysine methanol and 1- [4- (3
-Chloropropoxy) -3-methoxyphenyl] ethano
2.4 g (0.01 mol) and 3.7 g of anhydrous sodium carbonate (0.03
5 mol) and 0.4 g of potassium iodide to 1-butanol 100
Mixing in ml yielded gum as a residue. Gum
Florisil By 100 g column chromatography
Refined. Elute with 5-40% acetone in benzene
Fractions are collected and concentrated under reduced pressure to leave a residue.
Resulted in a brown glass. Converts glass to oxalate
The solid was recrystallized from absolute ethanol to give the title compound.
3.3 g (53%) was obtained as a white solid. Melting point, 139-1
42 ° C (decomposition).

Elemental analysis: C₃₄H₄₁NO_TenCalculated for: C, 65.48; H, 6.63; N, 2.25 Found: C, 65.38; H, 6.70; N, 2.38 Example 164 1- [4- [6-4- [bis (4-fluorophenyl) )
Hydroxymethyl] -1-piperidinyl] hexyloxy
Si] -3-methoxyphenyl] ethanone hydrochloride [1: 1] This compound was prepared according to the synthetic method of the compound of Example 1.
It was α, α-bis (p-fluorophenyl) -4-pipet
3.0 g (0.01 mol) of radine methanol and 1- [4- (4
-Chlorohexyloxy) -3-methoxyphenyl] e
Tanone 2.8g (0.01mol) and anhydrous sodium carbonate 5.3g
(0.05 mol) and potassium iodide 0.3 g
Mixture in 100 ml of gum yields gum as a residue
It was Florisil gum 80g column chromatography
It was purified by With 2-5% acetone in benzene
Collect the eluted fractions and concentrate to a residue.
Resulted in glass. Dissolve glass in anhydrous ethyl ether
It was thawed, filtered and the solution was treated with ethereal hydrochloric acid. Adhesive
Some solids precipitated. Viscous until a fine white solid is obtained.
The sticky solid was triturated with fresh ethyl ether. Solid
1.0 g (17%) of the title compound when collected by filtration and dried.
Was obtained as a white solid. Melting point, 182-186 ° C (min
Solution).

Elemental analysis: Calculated value for C ₃₃ H ₄₀ ClF ₂ NO ₄ : C, 67.37; H, 6.86; N, 2.38 Found: C, 67.17; H, 6.94; N, 2.37 Found 165 1- [4- [3 -[4- [bis (4-chlorophenyl)]
Methyl] -1-piperidinyl] propoxy] -3-methoxyphenyl] ethanone = oxalate = hydrate [1: 1:
0.5] 4- [bis (4-chlorophenyl) methyl] piperidine (11.39 g, 0.0357 mol) and 1- [4- (3-chloropropoxy) -3-methoxyphenyl] ethanone (8.64
g, 0.0357 mol) and potassium carbonate (5.54 g, 0.04 mol)
Containing a mixture of and potassium iodide (0.2g) 1-
Heated to reflux in 300 ml butanol overnight. The reaction mixture was evaporated to dryness and the resulting residue was partitioned between chloroform and water for several times. The chloroform layer was dried over sodium sulfate, filtered, and the solvent removed to give a dark brown oil. The oil was converted to the oxalate salt and the salt was recrystallized from methanol-diethyl ether. A yellow solid was isolated and dried under vacuum overnight at 80 ° C. The yellow solid was then exposed to air for 24 hours and analyzed. This method produced 6.65 g (30% yield) of a pale yellow solid. Melting point, 169-171
° C.

Elemental analysis: Calculated value for C ₃₂ H ₃₆ NO _7.5 Cl ₂ : C, 61.44; H, 5.80; N, 2.24 Found value: C, 61.40; H, 5.71; N, 2.24 Example 166 1- [4- [3 -[4- [bis (4-chlorophenyl)]
Hydroxymethyl] -1-piperidinyl] propoxy]
-3-Methoxyphenyl] ethanone = oxalate [1:
1.5] This compound was produced according to the method for synthesizing the compound of Example 1. 2.5 g (0.0075 mol) of α, α-bis (4-chlorophenyl) -4-piperidinemethanol and 1- [4- (3
-Chloropropoxy) -3-methoxyphenyl] ethane
1.8 g (0.0075 mol) and anhydrous sodium carbonate 3.7 g (0.035 mol)
Mol) and 0.4 g of potassium iodide 1-butanol 100 m
Mixing into 1 gave a sticky solid as a residue. This solid was converted to the oxalate salt and the solid was recrystallized from absolute ethanol to give 1.4 g (30%) of the title compound as a pale yellow solid. Melting point, 89-113 ° C (decomposition).

Elemental analysis: Calculated value for C ₃₃ H ₃₆ C ₁₂ NO ₁₂ : C, 58.50; H, 5.36; N, 2.07 Found value: C, 58.22; H, 5.32; N, 2.07 Example 167 4- [3- [4 -[Bis (4-fluorophenyl) methyl] -1-piperidinyl] propoxy] -3-methoxybenzoic acid methyl ester The sodium salt of methyl vanillate is in 30 ml of dimethyl sulfoxide (dried with 4A molecular sieves). Formed from methyl vanillate (11.26 g, 0.062 mol) and sodium hydroxide (2.47 g, 60%, 0.062 mol). During the formation of this sodium salt, the dimethyl sulfoxide solution turned light green. The salt was stirred for 0.5 hours at room temperature in the presence of a nitrogen atmosphere. Next, 4- [bis (4-fluorophenyl)
Methyl] -1- (3-chloropropyl) piperidine (2
1.32 g, 0.062 mol) / 100 ml of dimethylsulfoxide were added dropwise. The resulting solution was stirred overnight at 60 ° C. The warm reaction mixture was rotary evaporated until dry. The residue was dissolved in chloroform and extracted several times with water. The chloroform layer was dried over sodium sulfate, filtered and the solvent removed to give a dark brown oil (31.35g). Dissolve the oil in ethyl acetate and silica gel (800 g)
The column was loaded. The column was eluted with ethyl acetate. Fractions of equal purity were collected and dried under vacuum at 80 ° C. overnight to yield 22.70 g (71.9% yield) of brown oil. ¹ H NMR (CDCl ₃ ): δ6.7-7.7 (m, 11, aromatic), 4.0-4.3
(T, 2, -OCH ₂ ), 3.9 (s, 6, OC of esters and ethers
H ₃ ), 3.5 (d, 2, a methine group in contact with two fluorophenyl groups), 1.3-3.0 (m, 12, remaining aliphatic).

Elemental analysis: calculated for _{C 30 H 33 NO 4 F 2} : C, 70.71; H, 6.53; N, 2.75 Found: C, 70.48; H, 6.60 ; N, 2.71 Example 168 1- [4- [3 -[4- [Bis (3-fluorophenyl) methyl] -1-piperidinyl] propoxy] -3-
Methoxyphenyl] ethanone fumarate [1: 1] 4- [bis (3-fluorophenyl) methyl] piperidine 5.32 g (0.019 mol) and 3- (4-acetyl-2-methoxyphenoxy) -1 -Chloropropane 4.80 g (0.020
Mol), sodium bicarbonate 2.4 g (0.029 mol) and potassium iodide 0.20 g (0.0012 mol) 1-butanol 4
The mixture in 00 ml was heated at reflux for 23 hours. The solvent was removed under vacuum and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate and the solvent removed in vacuo to give an oil.
This was dissolved in methanol and the solution treated with excess fumaric acid. Ether was added to form a gum. The gum was triturated with acetonitrile to give 1.75 g of the title compound (15.1 g
%) As a white crystalline solid. Melting point 180-181 ° C.

Elemental analysis: Calculated value for C ₃₄ H ₃₇ NO ₇ F ₂ : C, 66.98; H, 6.12; N, 2.30 Found: C, 66.70; H, 6.11; N, 2.32 Was recrystallized from a methanol-ether-acetonitrile mixture to give 2.83 g (24.4%) of the title compound. Melting point, 181-182 ° C.

Elemental analysis: Calculated value for C ₃₄ H ₃₇ NO ₇ F ₂ : C, 66.98; H, 6.12; N, 2.30 Found: C, 66.95; H, 6.09; N, 2.28 Example 169 4- [3- [4 -[Hydroxy (diphenyl) methyl]
-1-Piperidinyl] propoxybenzoic acid methyl ester This compound was produced according to the synthetic method of the compound of Example 1. α, α-diphenyl-4-piperidinemethanol 5.
3 g (0.02 mol), 4- (3-chloropropoxy) benzoic acid methyl ester 4.6 g (0.02 mol), anhydrous sodium carbonate 7.4 g (0.07 mol) and potassium iodide 0.5 g in 100 ml of dimethylformamide. The mixture yielded 6.8 g (74%) of the title compound as a fluffy white solid. Melting point,
146-147 ° C.

Elemental analysis: Calculated value for C ₂₉ H ₃₃ NO ₄ : C, 75.79; H, 7.24; N, 3.05 Found: C, 75.68; H, 7.22; N, 3.11 Example 170 1- [4- [6-[ 4- [bis (4-fluorophenyl) methyl] -1-piperidinyl] hexyloxy]-
3-Methoxyphenyl] ethanone.

4- [bis (4-fluorophenyl) methyl] piperidine (7.90 g, 0.0275 mol) and 1- [4- (6-chlorohexyloxy) -3-methoxyphenyl] ethanone (7.82 g, 0.025 mol) And potassium carbonate (5.54g, 0.04
The mixture was heated at reflux overnight in 400 ml of 1-butanol containing potassium iodide (0.2 g). The mixture was cooled to room temperature and passed. Butanol was removed on a rotary evaporator. The obtained brown oil was dissolved in chloroform, and the dissolved product was extracted several times with water. The chloroform layer was dried over sodium sulfate, filtered and the solvent removed to give a brown oil. This oil was dissolved in ethyl acetate and flash chromatographed on silica gel eluting with ethyl acetate and 5% methanol-ethyl acetate. Fractions of the same purity were collected and the solvent was removed to give an oil. The oil was dried under vacuum at 80 ° C. overnight to yield 7.28 g (54.4% yield) of the title compound as a light brown oil. ¹ H NMR (CDCl ₃ ): δ6.7-7.5 (m, 11, aromatic), 4-4.2
(M, 2, -OCH ₂ ), 3.9 (s, 3, -OCH ₃ ), 3.4-3.6 (d, carbon methine in contact with 1,2 fluorophenyl groups), 2.6 (s,
3, 1.5-3.0 (m, 13, remaining aliphatic).

Elemental analysis: calculated for _{C 33 H 39 NO 3 F 2} : C, 73.99; H, 7.34; N, 2.61 Found: C, 73.92; H, 7.54 ; N, 2.62 Example 171 4- [3- [4 -[Bis (4-fluorophenyl) methyl] -1-piperidinyl] propoxy] -3-methoxybenzoic acid hydrate [1: 0.5] 4- [3- [4- [bis (4-fluorophenyl) ) Methyl] -1-piperidinyl] propoxy] -3-methoxybenzoic acid methyl ester (18.58 g, 0.0365 mol) dissolved in 400 ml of ethanol was refluxed with potassium hydroxide (16.8 g) in 50 ml of water for 6 hours. Heated. Ethanol was removed on a rotary evaporator. Next, 1N sulfuric acid (~
200 ml) was added. The aqueous layer was made neutral with litmus paper by the addition of 5% sodium hydroxide. The neutral aqueous layer was extracted several times with chloroform. The chloroform layer was dried over sodium sulfate, filtered, and the solvent was removed to yield a white solid. The white solid was triturated with dimethyl ether and cooled to about 0 ° C. The solution was then removed by passing a white solid, followed by vacuum drying overnight at 8 ° C. to give a white crystalline product, 11.38 g (61.8% yield) of the title compound. Melting point, 123-126
° C.

Elemental analysis: Calculated value for C ₂₉ H ₃₂ NO _4.5 F ₂ : C, 69.03; H, 6.39; N, 2.78 Found: C, 69.18; H, 6.32; N, 2.78 Example 172 4- [bis (4- Fluorophenyl) methyl] -1-
The sodium salt of [3- (3-methoxyphenoxy) propyl] piperidine hydrate [1: 0.5] m -methoxyphenol is sodium hydroxide (60%, 1.10 g, 0.027%) in dimethyl sulfoxide.
Mol) and m -methoxyphenol (3.36 g, 0.027 mol)
Manufactured from. The salt was stirred for 0.75 hours at room temperature to give a clear brown solution. Next, 4- [bis (4-fluorophenyl)]
Methyl] -1- (3-chloropropyl) piperidine (9.
34 g, 0.027 mol) / 100 ml of dimethylsulfoxide were added. The resulting solution was stirred overnight at 55 ° C. The solvent was removed in vacuo and the resulting oil was flash chromatographed on silica gel, eluting with 50% hexane-ethyl acetate. Fractions of similar purity were collected and the solvent was removed. A brown oil was obtained which was dried in vacuo overnight at 80 ° C. yielding 3.96 g (31.8%) of a brown oil. ¹ H NMR (CDCl ₃ ): δ 6.3-7.3 (m, 12, aromatic), 3.8-4.1
(M, 2, -OCH ₂ ), 3.7 (s, 3, -OCH ₃ ), 3.4-3.6 (d, methine in contact with 1,2 fluorophenyl rings), 1.2-3.0 (m, 1
3, remaining aliphatic protons) Elemental analysis: Calculated value for C ₂₈ H ₃₂ NO _2.5 F ₂ : C, 73.02; H, 7.00; N, 3.04 Found: C, 72.66; H, 6.89; N, 3.06 Example 173 1- [4- [3- [4- [cyclohexyl (4-fluorophenyl) methyl] -1-piperidinyl] propoxy] -3-methoxyphenyl] ethanone 4- [cyclohexyl (4-fluorophenyl) methyl ] Piperidine (5.71 g, 0.0207 mol) and 1- [4-
(3-chloropropoxy) -3-methoxyphenyl] ethanone (5.03 g, 0.0207 mol) and potassium carbonate (5.53 g
g, 0.04 mol) was heated under reflux overnight in 350 ml of 1-butanol containing potassium iodide (0.2 g). The reaction mixture was cooled to room temperature and passed. Removal of 1-butanol by rotary evaporation yielded a brown oil. This oil was dissolved in chloroform and the chloroform layer was extracted with 5% sodium hydroxide and water. The chloroform layer was dried over sodium sulfate and the solvent removed to give a brown oil. The oil was flash chromatographed on silica gel. Elution was performed with ethyl acetate, 5% methanol-ethyl acetate, and 10% methanol-ethyl acetate. Isolation fractions of equal purity were collected and the solvent was removed to yield a yellow oil. The oil was dried under vacuum overnight at 80 ° C. to give 7.36 g (73.
8%) occurred. ¹ H NMR (CDCl ₃ ): δ6.7-7.5 (m, 7, aromatic), 4.0 (m, 2,-
OCH ₂ ), 3.9 (s, 3, -OCH ₃ ), 2.5 (s, 3, 1.0-3.0 (m, 25, remaining aliphatic).

Elemental analysis: Calculated value for C ₃₀ H ₄₀ NO ₃ F: C, 74.81; H, 8.37; N, 2.91 Found: C, 74.39; H, 8.36; N, 2.81 Example 174 4- [bis (4-fluoro (Phenyl) methyl] -1-
[3- (phenylthio) propyl] piperidine citrate [1: 1] 4- [bis (4-fluorophenyl) methyl] piperidine 19.23 g (0.067 mol) and 3-thiophenoxy-1-
A mixture of 16.0 g (0.069 mol) of bromopropane and 6.72 g (0.080 mol) of sodium bicarbonate in 400 ml of 1-butanol was heated under reflux for 25 hours. Remove the solvent in vacuo,
The residue was partitioned between methylene chloride and dilute sodium hydroxide solution. The methylene chloride solution was dried over magnesium sulfate and the solvent removed in vacuo to give the title compound in non-salt form as an oil. This was converted to the citrate salt and the salt recrystallized from methanol-ether to give 33.05 g of the title compound.
(78.3%) occurred as a white crystalline solid. Melting point, 149.5
~ 151 ° C.

Elemental analysis: Calculated value for C ₃₃ H ₃₇ NO ₇ SF ₂ : C, 62.94; H, 5.92; N, 2.22 Actual value: C, 63.08; H, 5.94; N, 2.23 Example 175 4- [bis (4- Fluorophenyl) methyl] -1-
[3- (phenylsulfinyl) propyl] piperidine = oxalate [1: 1] 4- [bis (4-fluorophenyl) methyl] -1-
[3- (phenylthio) propyl] piperidine 4.33 g
(0.0099 mol) and 7.70 g (0.050 mol) of sodium perborate tetrahydrate dissolved in a mixture of 150 ml of methanol and 100 ml of 30% sulfuric acid solution were stirred at room temperature for 2 hours. Pour the reaction mixture onto ice and mix the mixture 50%.
It was made basic with sodium hydroxide solution and extracted with methylene chloride. The extracts were dried over magnesium sulphate and the solvent removed in vacuo to give the title compound in non-salt form as an oil. This was converted to the oxalate salt and the oxalate salt was recrystallized from methanol-ether to give 4.38 g (8
1.4%) as a white crystalline solid. Melting point, 173.5-17
4 ° C (decomposition).

Elemental analysis: Calculated value for C ₂₉ H ₃₁ NO ₅ SF ₂ : C, 64.07; H, 5.75; N, 2.58 Found: C, 63.91; H, 5.74; M, 2.57 By the same method, obtain 3.46 g of the title compound. It was Melting point 169-170.5
° C.

Elemental analysis: Calculated value for C ₂₉ H ₃₁ NO ₅ SF ₂ : C, 64.07; H, 5.75; N, 2.58 Measured value: C, 63.80; H, 5.75; N, 2.61 Example 176 1- [3- (4 -Acetyl-2-methoxyphenoxy)
Propyl] -α, α-bis (4-fluorophenyl)-
3-pyrrolidineacetonitrile α, α-bis (4-fluorophenyl) -3-pyrrolidineacetonitrile (5.13 g, 0.0172 mol) and 1- [4
-(3-Chloropropoxy) -3-methoxyphenyl]
Ethanone (4.17 g, 0.0172 mol) and potassium carbonate (5.5
A mixture of 3 g and 0.04 mol) was heated under reflux overnight in 350 ml of 1-butanol containing potassium iodide (0.2 g). Butanol was removed on a rotary evaporator. The residue obtained was dissolved in chloroform and extracted several times with water. The chloroform layer was dried over sodium sulfate, filtered, and the solvent removed in vacuo to give a dark brown oil.
The oil was flash chromatographed on silica gel, eluting with ethyl acetate and 25% ethanol-75% ethyl acetate. Fractions of the same purity were collected and the solvent was removed. A dark brown oil was obtained and dried in vacuo at 80 ° C. for 2 days to give 5.85 g (57.5% yield) of the title compound as a dark brown gum. ¹ H NMR (CDCl ₃ ): δ6.8-7.6 (m, 11, aromatic), 4.3 (t, 2,
-OCH _2- ), 3.9 (s, 3, -OCH ₃ ), 2.6 (s, 3, -COCH _3- ), 1.
3-3.8 (m, 11, aliphatic).

Elemental analysis: Calculated value for C ₃₀ H ₃₀ N ₂ O ₃ F ₂ : C, 71.41; H, 5.99; N, 5.55 Found: C, 70.94; H, 5.99; N, 5.51 Example 177 1- [3- (4-acetyl-2-methoxyphenoxy)
Propyl] -α, α-bis (3-fluorophenyl)-
4-Piperidinemethanol This compound was produced according to the synthetic method of the compound of Example 1. 3.0 g (0.01 mol) of 4- [α, α, bis (4-fluorophenyl) hydroxymethyl] piperazine and 1-
2.4-g (0.01 mol) of [4- (3-chloropropoxy) -3-methoxyphenyl] ethanone and anhydrous sodium carbonate
A mixture of 3.7 g (0.035 mol) and 0.4 g potassium iodide in 100 ml 1-butanol yielded 3.6 g (71%) of the title compound as an off-white solid. Melting point, 149-151 ° C (absolute ethanol).

Elemental analysis: calculated for _{C 30 H 35 F 2 NO 4} : C, 70.71; H, 6.53; N, 2.75 Found: C, 70.66; H, 6.53 ; N, 2.79 Example 178 alpha, alpha-bis (4 -Fluorophenyl) -1- [3-
(2-Methoxy-4-methylphenoxy) propyl]-
4-Piperidinemethanol This compound was produced according to the synthetic method of the compound of Example 1. [Α, α-bis (4-fluorophenyl)]-4-
4.5 g (0.015 mol) of piperidine methanol, 3.2 g (0.015 mol) of 1-chloro-3- (2-methoxy-4-methylphenoxy) propane, and 5.3 g of anhydrous sodium carbonate
(0.05 mol) and 0.4 g of potassium iodide as 1-butanol
Mixing in 100 ml gives the title compound as a white solid.
This yielded 5.4 g (75%). Melting point, 121-122 ° C (2-propanol).

Elemental analysis: Calculated value for C ₂₉ H ₃₃ F ₂ NO ₃ : C, 72.33; H, 6.91; N, 2.91 Found: C, 72.34; H, 6.95; N, 2.90 Example 179 1- [2- [3 -[4-bis (4-fluorophenyl)
Humanroxymethyl] -1-piperidinyl] propoxy]
Phenyl] ethanone This compound was produced according to the synthetic method of the compound of Example 1. [Α, α-bis (4-fluorophenyl)]-4-
3.0 g (0.01 mol) of piperidinemethanol and 2 '-(3
-Chloropropoxy) acetophenone 2.1 g (0.01 mol)
, 3.7 g (0.035 mol) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol yielded 3.4 g (71%) of the title compound as a white solid. Melting point 113-114 [deg.] C.

Elemental analysis: Calculated value for C ₂₉ H ₃₁ F ₂ NO ₃ : C, 72.63; H, 6.52; N, 2.92 Found: C, 72.54; H, 6.56; N, 2.94 Example 180 1- [3- [3 -[4- [bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] phenyl] ethanone = oxalate = hydrate [1: 1:
1] This compound was produced according to the method for synthesizing the compound of Example 1. [Α, α-bis (4-fluorophenyl)]-4-
3.0 g (0.01 mol) of piperidinemethanol and 3 '-(3
-Chloropropoxy) acetophenone 2.1 g (0.01 mol)
, 13.7 g (0.035 mol) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave a gum as a residue. The gum was converted to the oxalate salt and the solid was recrystallized from 2-propanol to give 4.4 g (75%) of the title compound as a tan solid. Melting point, 95-100 ° C.

Elemental analysis: Calculated value for C ₃₁ H ₃₅ F ₂ NO ₈ : C, 63.36; H, 6.00; N, 2.38 Found: C, 62.94; H, 6.02; N, 2.20 Example 181 α, α-bis (4 -Fluorophenyl) -1- [3-
(3-Methoxyphenoxy) propyl] -4-piperidinemethanol This compound was produced according to the synthetic method of the compound of Example 1. [Α, α-bis (4-fluorophenyl)]-4-
3.0 g of piperidine methanol (0.01 mol) and 2.0 g of 1-chloro-3- (3-methoxyphenoxy) propane (0.01 mol)
Mol) and 3.7 g (0.035 mol) of anhydrous sodium carbonate,
Mixing with 0.4 g potassium iodide in 100 ml 1-butanol yielded 3.1 g (65%) of the title compound as a white solid. Melting point, 107-108 ° C (2-propanol).

Elemental analysis: Calculated value for C ₂₈ H ₃₁ F ₂ NO ₃ : C, 71.93; H, 6.68; N, 3.00 Found: C, 71.90; H, 6.70; N, 3.01 Example 182 1- [3- (4 -Ethylphenoxy) propyl) -α,
α-Bis (4-fluorophenyl) -4-piperidinemethanol = oxalate [1: 1] This compound was produced according to the method of synthesizing the compound of Example 1. [Α, α-bis (4-fluorophenyl)] piperidinemethanol 30 g (0.01 mol) and 1-chloro-3-
(4-Ethylphenoxy) propane 2.0 g (0.01 mol)
And 3.7 g (0.035 mol) of anhydrous sodium carbonate mixed with 0.4 g of potassium iodide in 100 ml of 1-butanol gave a solid as a residue. The solid was converted to the oxalate salt and the oxalate salt was recrystallized from 2-propanol to give 3.0 g (54%) of the title compound as a white solid. Melting point, 132-135 ° C.

Elemental analysis: Calculated value for C ₃₁ H ₃₅ F ₂ NO ₆ : C, 67.01; H, 6.35; N, 2.52 Found: C, 66.60; H, 6.32; N, 2.31 Example 183 1- [3- (2 -Ethoxyphenoxy) propyl]-
α, α-Bis (4-fluorophenyl) -4-piperidinemethanol This compound was produced according to the synthetic method of the compound of Example 1. [Α, α-bis (4-fluorophenyl)]-4-
3.0 g of piperazine methanol (0.01 mol) and 2.1 g of 1-chloro-3- (2-ethoxyphenoxy) propane (0.01 mol)
Mol) and 3.7 g (0.035 mol) of anhydrous sodium carbonate,
Mixing 0.4 g potassium iodide in 100 ml 1-butanol yielded 3.6 g (75%) of the title compound as an off-white solid. Melting point 89-91 ° C (petroleum ether, 60-110 ° C).

Elemental analysis: Calculated value for C ₂₉ H ₃₃ F ₂ NO ₃ : C, 72.33; H, 6.91; N, 2.91 Found: C, 72.39; H, 6.90; N, 2.96 Example 184 α, α-bis (4 -Fluorophenol) -1- [3-
(2-Methylphenoxy) propyl] -4-piperidinemethanol This compound was produced according to the synthetic method of the compound of Example 1. [Α, α-bis (4-fluorophenyl)]-4-
3.0 g (0.01 mol) of piperidine methanol, 1.8 g (0.01 mol) of 1-chloro-3- (2-methylphenoxy) propane, 3.7 g (0.035 mol) of anhydrous sodium carbonate and 0.4 g of potassium iodide were added to 1-butanol. Mixing in 100 ml gave 2.5 g (56%) of the title compound as a white solid. Melting point, 108.5-109 ° C (petroleum ether, 60-110 ° C).

Elemental analysis: Calculated value for C ₂₈ H ₃₁ F ₂ NO ₂ : C, 74.48; H, 6.92; N, 3.10 Found: C, 74.57; H, 6.92; N, 3.11 Example 185 α, α-bis (4 -Fluorophenyl) -1- [3-
(3-Methylphenoxy) propyl] -4-piperidinemethanol This compound was produced according to the synthetic method of the compound of Example 1. 3.0 g (0.01 mol) of α, α-bis (4-fluorophenyl)]-4-piperidinemethanol and 1-chloro-
A mixture of 1.8 g (0.01 mol) of 3- (3-methylphenoxy) propane, 3.7 g (0.035 mol) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol was 2.8 g of the title compound (62 %) As a white solid. Melting point, 112.5-114 [deg.] C (2-propanol).

Elemental analysis: Calculated value for C ₂₈ H ₃₁ F ₂ NO ₂ : C, 74.48; H, 6.92; N, 3.10 Found: C, 74.44; H, 6.95; N, 3.15 Example 186 α, α-bis (4 -Fluorophenyl) -1- [3-
[2- (1-methylethoxy) phenoxy] propyl]
-4-Piperidinemethanol This compound was produced according to the synthetic method of the compound of Example 1. [Α, α-bis (4-fluorophenyl)]-4-
Piperidine methanol 3.0 g (0.01 mol), 1-chloro-3- [2- (1-methylethoxy) phenoxy] propane 2.3 g (0.01 mol), and anhydrous sodium carbonate 3.7 g (0.
035 mol) and 0.4 g of potassium iodide to 1-butanol 1
Mixing in 00 ml gave 2.9 g (58%) of the title compound as a fluffy white solid. Melting point, 74-79 [deg.] C (2-propyl ether).

Elemental analysis: C₃₀H₃₅F₂NO₃Calculated for: C, 72.70; H, 7.12; N, 2.83 Found: C, 72.65; H, 7.47; N, 2.69 Example 187 4- [3- [4- [bis (4-fluorophenyl) hydrido]
Roxymethyl] -1-piperidinyl] propoxy] ben
Zenacetic acid ethyl ester = oxalate [1: 1] = ethi
This compound was prepared according to the synthetic method of the compound of Example 1.
It was [Α, α-bis (4-fluorophenyl)]-4-
Piperidine methanol 7.6g (0.025mol) and 4- (3
-Chloropropoxy) benzeneacetic acid methyl ester 6.1 g
(0.025 mol) and anhydrous sodium carbonate 9.5 g (0.09 mol)
) And 0.4 g of potassium iodide in dimethylformamide
Mixing in 150 ml yields gum as a residue
It was Florisil gum 250 g column chromatography
It was purified by With 5-25% acetone in benzene
Collect the eluted fractions and concentrate them to obtain a residue.
Produced a gum. Convert gum to oxalate and sterilize the solid
Recrystallisation from ethyl acid gave 7.0 g (43%) of the title compound.
Obtained as a white solid. Melting point, 93-98 ° C (decomposition).

Elemental analysis: Calculated value for C ₃₂ H ₃₅ F ₂ NO ₈・ 0.5C ₄ H ₈ O ₂ : C, 63.44; H, 6.10; N, 2.18 Actual value: C, 63.00; H, 5.99; N, 2.23 Example 188 1- [3- (2,6-dimethoxyphenoxy) propyl]
-Α, α-Bis (4-fluorophenyl) -4-piperidinemethanol This compound was produced according to the synthetic method of the compound of Example 1. [Α, α-bis (4-fluorophenyl)]-4-
3.0 g (0.01 mol) of piperidinemethanol and 1- (3-
Chloropropoxy) -2,6-dimethoxybenzene 2.3 g
(0.01 mol), anhydrous sodium carbonate 3.7 g (0.035 mol), and potassium iodide 0.4 g, 1-butanol 100 ml
Mixing in gave 2.0 g (40%) of the title compound as a white solid. Melting point, 136-137 [deg.] C (2-propyl ether / 2-propanol).

Elemental analysis: Calculated value for C ₂₉ H ₃₃ F ₂ NO ₄ : C, 70.00; H, 6.68; N, 2.81 Actual value: C, 70.15; H, 6.78; N, 2.85 Example 189 4- [3- [4 -[Bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] benzeneacetic acid = hydrate [1: 0.5] 4- [3- [4- [bis (4-fluorophenyl) hydroxymethyl] ] -1-Piperidinyl] propoxy] benzeneacetic acid ethyl ester = 3.7 g (0.0073 mol) of free base of oxalate [1: 1] and 0.8 g of potassium hydroxide (0.01
45 mol), 100 ml of water, and 50 ml of 95% ethanol were mixed and heated under reflux in a nitrogen atmosphere for 1.5 hours. The solution was poured into a mixture of glacial acetic acid 1.3 g (0.022 mol) in ice water 500 ml and left overnight in ambient air. The precipitated solid was collected by filtration, washed with water, air dried and recrystallized from 2-propanol to give the title compound 2.
9 g (78%) was obtained as a white solid. Melting point, 113-121
° C (decomposition).

Elemental analysis: Calculated value for C ₂₉ H ₃₂ F ₂ NO _4.5 : C, 69.03; H, 6.39; N, 2.78 Found value: C, 69.35; H, 6.43; N, 2.74 Example 190 1- [4- [3 -[3- [Bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] -3-methoxyphenyl] ethanone This compound was prepared according to the synthetic method of the compound of Example 1. 3.0 g (0.01 mol) of α, α-bis (4-fluorophenyl) -3-piperidinemethanol and 1- [4- (3
-Chloropropoxy) -3-methoxyphenyl] ethanone 2.4 g (0.01 mol) and anhydrous sodium carbonate 3.7 g (0.03
5 mol) and 0.4 g of potassium iodide to 1-butanol 100
Mixing in ml gave 4.0 g (78%) of the title compound as an off-white solid. Melting point, 100-105 <0> C (2-propanol).

Elemental analysis: C₃₀H₃₃F₂NO₂Calculated for: C, 70.71; H, 6.53; N, 2.75 Found: C, 70.62; H, 6.61; N, 2.77 Example 191 1- [4- [3- [3- [bis (4-fluorophenyl)
) Hydroxymethyl] -1-piperidinyl] propoxy
Ci] -3-Methoxyphenyl] ethanone α, α-bis (4-fluorophenyl) -3-piperidi
2.9 g (0.01 mol) of methanol and 1- [4- (3-
Lolopropoxy) -3-methoxyphenylethanone 2.4 g
(0.01 mol) and 1- [4- (3-chloropropoxy)
2.4 g (0.01 mol) of 3-methoxyphenylethanone,
5.3 g (0.05 mol) of anhydrous sodium carbonate and potassium iodide
0.3 g (0.002 mol) of aluminum in 100 ml of 1-butanol
The mixture was heated under reflux for 24 hours. The mixture is concentrated under reduced pressure.
Shrink and partition the residue between 100 ml of benzene and 100 ml of water.
It was Rinse the benzene layer with water and saline and wash with sodium sulfate.
Dried and concentrated under reduced pressure to give a brown gum.
The gum is Florisil 80g column chromatography
A 0-10% acetone / benzene gradient elution system
It was purified using Fraction containing the desired purified product
Were collected and concentrated under reduced pressure to yield 3.2 g of brown gum.
It was Furthermore, this gum was applied to high pressure liquid chromatography
Otter's Society Preparations LC / C
Stem 500A (Waters Associates Prep LC / System500
A); Preppac 500 silica; 1% methanol
/ Methylene chloride; flow rate 150 ml / min]. Place
Collect the fractions containing the desired product and concentrate under reduced pressure.
Yielded 1.7 g (34% yield) of the title compound as a pale yellow glass.
Obtained as a solid. Melting point, 44-46 ° C.

Elemental analysis: Calculated value for C ₂₉ H ₃₁ F ₂ NO ₄ : C, 70.29; H, 6.31; N, 2.83 Found: C, 69.60; H, 6.26; N, 2.86 Screening Method for Calcium Channel Blocking in Isolated Rabbit Aorta Rabbits that were not fasted were killed by cervical dislocation.
The spiral arterial strip is removed from the thoracic aorta by the methods of Furchgott (RF) and Bhadrakom (S.) (Jeanal of Pharmacology and
EXPERIMENTAL THERAPY (J.PHARMACOL.EXP.THE
R.), 108, 129-43 (1953)). Replace this strip with a 10 ml water jacket.
Suspended in an organ bath maintained at 0 ° C and aerated with a mixture of 95% oxygen and 5% carbon dioxide. Isometric tissue responses were recorded on a glass force-transition transducer (FT03C model) and a glass polygraph. The load tension on the strip is about 1 g. Maximum relaxation occurs at 90 minutes and the bath is changed every 15 to 20 minutes during this period. This bath is a physiological solution prepared using glass distilled water and adjusted to pH 7.4 (hereinafter,
(Referred to as a specified bath solution). The composition of the solution in millimoles per liter is as follows.

Sodium Chloride 120 Potassium Chloride 5.6 Calcium Chloride 2.6 Magnesium Chloride Hexahydrate 1.2 Sodium Dihydrogen Phosphate Hydrate 1.5 Sodium Bicarbonate 25.0 Glucose 9.1 Strips should be norepinephrine at a first bath concentration of 10 ^-5 mol. After checking the vitality based on the response to, wash with standard bath solution until the remaining tension returns to baseline. After this, the defined bath solution is designated as a calcium-free bath solution and is replaced with a physiological solution having the same pH and composition as the defined bath solution except that it does not contain calcium. The strips are then incubated in this calcium free solution for 10 minutes. During this period, the solution was changed three times with fresh physiological (calcium-free) solution.

The strips are tested for calcium depletion integrity by incubating for 15 minutes in a calcium depolarizing solution. The composition of the depolarizing solution in millimoles per liter is as follows.

Sodium chloride 32.2 Potassium chloride 100.0 Magnesium chloride hexahydrate 1.2 Trihydroxymethyl hydrochloric acid 12 Glucose 9.1 This solution is prepared using glass distilled water and adjusted to pH 7.4. If the strip is contracting, wash it with a physiological solution and then incubate again in the depolarizing solution. If desired, the process is repeated until the strip is less sensitive and thus calcium depleted. Alternatively, the strips may be rewashed with a depolarizing solution until they are calcium depleted.

Cumulative concentration response curve (control)
ssum, JM) method (ARCH.INT.PHARMACODYN., Volume 143,
299-330, 1963), using calcium chloride as an agonist. The final bath concentration of calcium chloride is
0.1 mmol, 0.3 mmol and 1.0 mmol.
(Godfraind, T) and hippopotamus (Kaba, A)
BRIT.J.PHARMACOL., Vol. 36, 549-60, 1969). The response is allowed to reach a plateau before adding the next increment of calcium chloride.

After obtaining a control response, the strip is treated with the test drug (formula I) at 10 ^-7.
Rinse with a defined bath solution containing a molar concentration at intervals of 15-20 minutes for about 1 hour. (See Broekaert, A and Godfraind, T. (1979).) During this time, the tissue returns to resting tension.

The strips are then incubated with physiological solution (calcium free) for 10 minutes and finally with a depolarizing solution for 15 minutes, both of which solutions now contain the test drug of formula I. If the strip is contracting in the depolarizing solution, wash until insensitive as described above.
A cumulative concentration response to calcium chloride is then generated over the range of concentrations used for control measurements.

As a final test measuring the selectivity and whether there is α-blocking activity, the strips are washed with a defined bath solution containing the compound under study until resting tension is again at baseline. The strips are then retested for response to norepinephrine at a final bath concentration of 10 ^-5 molar.

In the above primary screen, a minimum of two strips are used to test each drug at 10 ^-7 moles. Compounds that constantly inhibit at least 20% of calcium-induced contraction are further tested. PA ₂ values can be obtained for those test medications that give interesting positive results. Van
See Van Rossum, 1963, ibid. The control product used for comparison is lidofrazine, diltiazem, verapamil, nifedipine or other suitable drug. In this test, Examples 56,57
Highly active compounds, such as Compounds 60 and 60, caused a 100% change (reduction) in the contraction caused by 1 mM calcium at 10 ^-7 molar of these drugs. These compounds have been found to be superior compared to the control calcium channel blockers.

Test Method for Antihypertensive Effect of Orally Administered Drugs on Unanesthetized Spontaneous Hypertensive Rats Surgical Preparation of Rats Charles River spontaneously hypertensive rats are anesthetized with pentobarbital sodium (50 mg / kg, ip).
Shave and clean the abdomen and crown. A midline incision is made in the skin on the lateral surface of the neck of the animal about 5 mm long. A 22 cm long brass tube with a slight bend at the end was passed through the incision under the skin just below the rat's back and obliquely to the right of the lower abdomen. The animal is then fixed to the table in a supine position.
A midline incision about 4 cm long is made on the skin with scissors and, on the other hand, through the muscle wall of the abdomen. With a small hemostat,
The skin is separated from the abdominal muscles at the midline to expose the tip of the brass tube. With the forceps tip of the hemostat, make a small opening through the abdominal muscle at an appropriate angle.

The tip of a modified Weak cannula is inserted into the abdominal cavity and the other end is screwed into a brass tube until it emerges at the base of the neck of the animal. The brass tube is removed and the cannula 7 mm cured polyethylene chips are lined up and placed for insertion into the abdominal aorta. The placed cannula is filled with isotonic saline.

Gently pull aside the internal organs to expose the aorta at the carina. Remove the aorta and use 1-1.5c with 2 ligatures
Tie at m intervals. The ligature is used to occlude blood flow easily and gently. The abdominal aorta was punctured to the tracheal bifurcation with the tip of a No. 23 hypodermic needle. The needle is removed and the tip of the cannula is inserted through this opening into the heart. Care must be taken that this tip is vertically aligned with the aorta.
Backflow the blood through the cannula to ensure proper insertion. From Kanyure, isotonic salt water 0.4c
Flow c to drop blood. Stability of the cannula in the artery is ensured by suturing a ligature tied around the cannula to the dorsal muscular layer immediately to the aorta. The cannula is also sutured to the abdominal wall at the exit site. The viscera is returned to its original position and the abdominal wall and skin are sewn on separate layers with a blanket bent over. Animals are dosed with 0.2 ml of Combiotic (Procaine penicillin G and dihydrostreptomycin sulfate).

The distal end of the cannula protruding at the base of the neck is closed and threaded into an L-shaped piece of aluminum tubing that is secured to the skull by screws and dental cement. [Purdy and Ashbrooke, 1978
Year, Journal of Pharmacy and Pharmacology (J.PHARM.PHARMACOLOGY), Volume 30, 436-4
Page 1] In order to protect and attach the cannula to the cage, the cannula is a flexible metal spring of a certain length, which is an aluminum tube and part of the universal bearing that allows the animal to move around the cage with relative freedom. It is inserted in a spring that is attached to something that allows it to move. During recovery, each rat was given a bottle of Terramycin containing 5% dextrose for drinking. (1 tsp. Fiber / teramycin soluble powder / 5% dextrose 1 liter).

Blood Pressure Recording The day after surgery, the closed cannula was reopened and attached to the universal bearing device. One end of a length of saline filled polyethylene 50 tubing was attached to a free bearing and the other to a Statham pressure transducer (P231D type) to form a continuous saline-arterial communication. Continuous recording from direct aortic blood pressure is a glass polygraph (type 7)
Recorded in. Heart rate was measured from blood pressure pulses. The electrical output of the blood pressure signal from the polygraph was measured using a Baxco Channeler Cardiovascular analyzer (Bu
Send to xco Channel Cardiovascular eanalyzer (type 12). The blood pressure is measured as an average value for one minute of the signal, and the measurement of the blood pressure and the heart rate is printed on the Texas Instruments Data Terminal (700ASR type).

Maintenance of rat In order to maintain the openness of the cannula and to allow the animal to be used for as long as possible, a sterile saline solution of heparin (2 mg / ml) is continuously applied to the animal at a rate of 0.05 to 0.06 ml / hour. Inject. Purina Mouse Chiyo (Pu
rina Mouse Chow) and water ad libitum. A solution containing 5% dextrose and teramycin is administered once a week. Surgically prepared rats can be used more than once during the study period. A minimum of 3 days must elapse before the rat can be used again. One rat is
It is used only once in one dose group.

Experimental Method Each surgically prepared rat is placed in a separate cage, one at a time. A rat number and a rat number are consecutively attached to each cage. A single dose of 10, 20 and 30 mg / kg of the test drug calculated by free base content was administered with a syringe and 16
Oral administration using a No. 1 tube. The control product is PEG-300-saline (1: 1). Reference products are verapamil and nifedipine. PEG-300 carrier of compound of formula I with verapamil
Saline (1: 1), ethanol for nifedipine. The test and control product dose volume is 1 ml / kg body weight. For each rat, before drug administration, and 3
Arterial blood pressure and heart rate are measured at 0, 60, 90, 120, 180, 240, 300, 360 minutes and 24 hours later.

Highly active compounds, such as the compounds of Examples 56 and 57, have a modest reduction in blood pressure of hypertensive rats, but a long duration of action, as compared to nifedipine.

Method for Measuring the Effect of Compounds on Coronary Blood Flow The method used to measure the effect of the above compounds on coronary blood flow is explained as follows.

Male and female crossbreed dogs were treated with sodium phenobarbital (100 mg / kg) and sodium pentobarbital (100 m
(g total dose) The trachea was surgically exposed, the tracheal tube was inserted, and the dog was artificially ventilated with room air using a Harvard 613 respirator. The heart was exposed at the fourth intercostal space by a left thoracic incision. Left anterior descending coronary, exposing approximately 1.5 cm of artery,
am) An electromagnetic blood flow probe was implanted around the blood vessel. The blood flow probe cable was connected to a Starsum 2201 blood flow meter. Carotid blood pressure and coronary blood flow were continuously recorded using a glass type 5 polygraph.

The compound was administered via the femoral artery. The magnitude of change in coronary blood flow from the level before drug administration and the change over time were measured.
Generally, multiple doses of test compound were administered to the same dog. At appropriate intervals for administration, blood flow was allowed to recover to the control level.

For example, the compounds of Examples 56,57,61,62,69,74,76,89,105,106 and 128 increased the coronary blood flow to about 75-120 ml / min at a compound dose of 0.5 mg / kg. .

Screening method for antihistamine action The compounds of the present invention show antihistamine action in guinea pigs. The test method is Tozzi etc. [Agents and Actions, No. 4 /
Vol. 4, pp. 264-270, 1974]. Guinea pigs are fasted in individual cages for 18-24 hours. Give water freely. On the day of the test, animals divided into 3 groups are injected intraperitoneally with 30 mg / kg of the test compound prepared in the appropriate vehicle. After 30 minutes, the histamine dose of 1.2 mg / kg (= 2
X LD ₉₉ ) and inject it into the ear vein. If the guinea pig survives for 24 hours, it is considered to have a positive antihistamine effect. If the vehicle used for the test compound is something other than water, the effect is confirmed by testing the same amount of vehicle alone as a control. From the dose-response curves, the 50% protection from animal death (PD ₅₀ ) can be determined. Compounds like Examples 58 and 105 have at least 3
It was active even at doses as low as mg / kg.

Screening method for gastric anti-secretory activity with pylorus ligation rats Female Sprague-Dawley rats weighing 130-180 g were fasted singly for 24 hours in a wire bottom cage with water ad libitum. Animals were divided into groups of 9 treated animals and 8 control rats. Each group was injected with the test drug at a dose of 25.0 mg / kg (0.2 ml / 100 g body weight) into the duodenum at the time of pylorus ligation. A rat to which deionized water (2 ml / kg) was administered was used as a control rat. The rat was killed 4 hours after the ligation, the stomach was taken out, and the gastric juice was collected and the amount thereof was measured.
Total hydrochloric acid secretion was measured by potentiometric titration up to the end point of pH 7.0 using a Radiometer TTA-61 automatic titrator. Statistical analysis was performed using the "Student's t test" significance method. For example, at a dose of 25 mg / kg, a significant reduction in secretion of about 85% in gastric fluid and 98% in acid was obtained for the compound of Example 58. Similarly, the reductions obtained for the compound of Example 105 were about 65% for both gastric juice volume and acid.

Toxicity Test When the compounds of Example 36 and Example 66 among the compounds of the present invention were subjected to toxicity test, the following results were obtained.

(Regarding the toxicity of the compound of Example 36) As a result of the acute and subacute (13-week) toxicity test by administration of the compound of Example 36 to mice, rats, dogs and rabbits, it was revealed that the toxicity was relatively low. It was
Oral administration to dogs for 13 weeks had no effect at doses of 10 mg / kg / day or less, and decreased serum cholesterol levels at doses of 30-60 mg / kg / day. The compound of Example 36 is not teratogenic.

Regarding the toxicity of the compound of Example 66 The rats orally administered with the compound of Example 66 at a rate of 12 mg / kg / day for 13 weeks showed no significant effect. In rats, the lethal dose was 30 mg / kg / day. Dogs given orally at a dose of 5 mg / kg / day for 13 weeks showed no meaningful effect. Furthermore, dogs dosed at 15 mg / kg / day for 8 weeks showed no changes. The lethal dose was 25 mg / kg / day. Reproductive /
In a perinatal or postnatal toxicity study from a teratological perspective, fertility (fer
tility) was not affected, but females had a longer gestation period and delivery at a dose of 4 mg / kg / day, and further increased doses reduced litter size and litter survival. did. There was no evidence of possible malformation. The mutagenicity test was negative.

Pharmaceutical Compositions and Administration Compositions for administration to living animals will have at least one compound of Formula I according to the methods of treatment of this invention in association with a pharmaceutical carrier or excipient. An effective amount of this compound may be given by various routes, such as orally as elixirs, capsules, tablets or coated tablets, parenterally in the form of sterile solutions, suspensions, in some cases intravenously in the form of sterile solutions. It can be administered intranasally in the form of drops, gargles, syrups, powders, etc. and into the throat or bronchi, or subcutaneously. Suitable tableting excipients include lactose, potato and corn starch, talc, gelatin, stearic acid and silicic acid, magnesium stearate and polyvinylpyrrolidone.

For parenteral administration, the carrier or excipient may comprise a sterile parenterally acceptable liquid such as water or peanut oil in ampoules.

The compositions are conveniently formulated as dosage units, so that each unit is sufficient to provide a constant dose of the active ingredient. Tablets, coated tablets, capsules, ampoules, sprays and suppositories are examples of preferred dosage forms. It is only necessary for the active ingredient to constitute an effective amount, such that a suitable effective dosage will be employed, and in combination with a dosage form which may be more than once if desired. The exact individual dose, as well as the daily dose, will, of course, be determined according to standard medical principles under the guidance of a physician or veterinarian. Generally, the following guidelines, which focus on oral administration to humans, describe the activity of known agents in the field of animal screening tests and the activity obtained in the same animal screening test for various information in the method of the invention. Guided by knowledge. However, the amount of active compound administered is not limited by these data, as there is uncertainty when transferring comparative animal data to human therapy.

The oral dose for adult hypertension is 40-30 daily.
The dose is about 0 mg, which is administered in 2 to 3 divided doses. For example, 2 capsules containing 10-50 mg of the active agent of formula I
It can be given three times to lower blood pressure.

Oral doses used to treat adult angina range from 60-
The dose is 400 mg / day, and it is administered in 2 or 3 divided doses. For example, 2 capsules containing 10-30 mg of active compound of formula I can be administered 2-5 times daily to increase coronary blood flow.

The oral dose used as an adult antihistamine is
The dose is about 10 to 120 mg / day, which is given in 2 or 3 divided doses. For example, 1 or 2 capsules containing 10-40 mg of the active compound of the formula I may be administered in an amount of 2 to 2 times daily to temporarily relieve the cough due to irritation of the throat and bronchi caused by a common cold or inhaled irritants. It can be administered three times each.

The oral dose when used as an adult antisecretory agent is
The dose is 4 to 150 mg / day, and it is administered in 2 or 3 divided doses.
For example, one containing 0.5 to 50 mg of the active compound of formula I may be administered a few times a day to temporarily quench the excess acid release in the stomach.

Other routes of administration, such as subcutaneous, intraperitoneal, intravenous, etc., are possible, as will be apparent to those skilled in the art, with dosage forms adapted to the circumstances.

Various modifications and alterations will be apparent to those skilled in the art and can be made in the compounds, processing methods and compositions of the present invention without departing from the spirit or scope of the invention and, therefore, the invention is claimed. It should be understood that the scope is limited only.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location C07D 401/06 211 401/12 211 405/12 211 409/12 211 // A61K 31/445 ABF ABS ABU ACL AEM

Claims (41)

[Claims] 1. The following formula: [In the Formula, p is 0, 1 or 2; A is a hydrogen atom, -OH, -C≡N or In it; m is Less than six; Q is -CH- or -CH ₂ -; d and n are selected from 0 or 1, the dotted line can be formed consistent with the valence of the carbon atoms Represents a volatile double bond; Ar and R are R may be a cycloalkyl group; D is selected from the group consisting of: Or selected from the group consisting of Ar (CH ₂ ) _1-4 −; X, Y and Z in Ar and R are a hydrogen atom, a lower alkyl group, a halogen atom, —NO ₂ , —O— (lower alkyl group), Selected from the group consisting of —CF ₃ or —C≡N; X, Y and Z in D are a hydrogen atom, a lower alkyl group,
Halogen ^{_{atom, -NO 2, -O-R 1}} , -CF _3, -C≡N, _{^{-N (R 1) 2, -C}} (O) OR 1, -SO 2 R 2, -SR 2, -S
(O) R ² , −CH ₂ COOM, Or B is O, S, (Wherein R ³ represents a hydrogen atom or a lower alkyl group); z is 1 or 0, provided that D is a phenyl group or a substituted phenyl group and at the same time one of the following occurs: That is, (A) _d is a hydrogen atom, or (A) _d
Is a cyano group, (A) _d is an aminocarbonyl group, or a double bond is formed between the α-carbon atom and the carbon atom of the central heterocyclic amine ring, z N is 0 and cannot be 0 at the same time; R ¹ is selected from a hydrogen atom, a lower alkyl group, a phenyl group or a phenyl lower alkyl group; R ² is a lower alkyl group, a phenyl group or a phenyl lower alkyl group Selected from a group; M is a pharmaceutically acceptable metal ion; provided that n is 0 and (A) _d is a hydrogen atom or a hydroxyl group, or d is 0 and α carbon atom (B) _z cannot represent an oxygen atom at the same time when D is a phenyl group or a substituted phenyl group when a double bond is formed with the carbon atom of the saturated central heterocyclic amine) Selected from the group Compounds (however, α, α-diphenyl-1-benzyl-4-piperidinemethanol, and in the above formula, n is 0 or 1, Q is -CH- or -CH
_2- , except for compounds where D is pyridyl), and pharmaceutically acceptable salts thereof, including their acid addition salts, quaternary salts, hydrates and alcoholates. 2. 7- [3- [4- [bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] -2H-1-benzopyran-2-one or its pharmaceutically acceptable A compound according to claim 1 which is a salt. 3. 7- [3- [4- [bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] -4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester or The compound according to claim 1, which is a pharmaceutically acceptable salt thereof. 4. 7- [3- [4- [Bis (4-fluorophenyl) hydroxymethyl] -1-piperidinyl] propoxy] -2,3-dihydro-4H-1-benzopyran-4
-A compound according to claim 1 which is one or a pharmaceutically acceptable salt thereof. 5. α, α-bis (4-fluorophenyl)-
1- [2- (phenylthio) ethyl] -4-piperidinemethanol or a pharmaceutically acceptable salt thereof,
The compound according to claim 1. 6. The method according to claim 1, which is 4- [bis (4-fluorophenyl) methylene] -1- [2- (phenylthio) ethyl] piperidine or a pharmaceutically acceptable salt thereof. The described compound. 7. α, α-Bis (4-fluorophenyl)-
The compound according to claim 1, which is 1- [2-[(4-chlorophenyl) sulfonyl] ethyl] -4-piperidinemethanol or a pharmaceutically acceptable salt thereof. 8. 1- [2-[(4-chlorophenyl) sulfonyl] ethyl] -4- [bis (4-fluorophenyl) methylene] piperidine or a pharmaceutically acceptable salt thereof. The compound according to item 1 of the above. 9. The method according to claim 1, which is 4- [bis (4-fluorophenyl) methyl] -1- [3- (phenylsulfonyl) propyl] piperidine or a pharmaceutically acceptable salt thereof. The compound according to. 10. A 4- [bis (4-fluorophenyl) methyl] -1- [2-[(4-chlorophenyl) sulfonyl] ethyl] piperidine or a pharmaceutically acceptable salt thereof. The compound according to item 1 of the above. 11. A method according to claim 1, which is 4- [bis (4-fluorophenyl) methyl] -1- [2- (phenylsulfonyl) ethyl] piperidine or a pharmaceutically acceptable salt thereof. The compound according to. 12. 1- (2,3-dihydro-1,4-benzoxan-2-ylmethyl) -α, α-diphenyl-4-piperidineacetonitrile or a pharmaceutically acceptable salt thereof. A compound according to the first section. 13. 1- [3- (4-Acetyl-2-methoxyphenoxy) propyl] -α, α-diphenyl-4-
The compound according to claim 1, which is piperidine acetonitrile or a pharmaceutically acceptable salt. 14. 1- [3- (4-Acetyl-2-methoxyphenoxy) propyl] -α, α-diphenyl-3-
The compound according to claim 1, which is piperidine propane nitrile or a pharmaceutically acceptable salt thereof. 15. A method according to claim 1, which is 1- [4- (4-acetyl-2-methoxyphenoxy) butyl] -α, α-diphenyl-3-piperidinepropanenitrile or a pharmaceutically acceptable salt thereof. The compound according to item 1. 16. 1- [3- (4-Acetyl-2-methoxyphenoxy) propyl] -α, α-diphenyl-3-
The compound according to claim 1, which is pyrrolidineacetamide or a pharmaceutically acceptable salt thereof. 17. 1- [3- (4-Acetyl-2-methoxyphenoxy) propyl] -α, α-diphenyl-4-
The compound according to claim 1, which is piperidine acetamide or a pharmaceutically acceptable salt thereof. 18. A compound according to claim 1, which is 1- [4- (4-acetyl-2-methoxyphenoxy) butyl] -α, α-diphenyl-4-piperidineacetamide or a pharmaceutically acceptable salt thereof. The compound according to item 1. 19. 1- [3- (4-Acetyl-2-methoxyphenoxy) propyl] -α, α-diphenyl-3-
The compound according to claim 1, which is piperidine propanamide or a pharmaceutically acceptable salt thereof. 20. 4- [bis (4-fluorophenyl) methyl] -1-[(2,3-dihydro-1,4-benzodioxan-2-yl) methyl] piperidine or its pharmaceutically acceptable A compound as claimed in claim 1 which is a possible salt. 21. 1- [2- (2,6-Dichlorophenoxy) ethyl] -α, α-diphenyl-3-piperidinepropanenitrile or a pharmaceutically acceptable salt thereof. The compound according to item 1. 22. 1- [5- (4-acetyl-2-methoxyphenoxy) pentyl] -α, α-diphenyl-3-
The compound according to claim 1, which is piperidine propane nitrile or a pharmaceutically acceptable salt thereof. 23. 1- [3- (4-Acetyl-2-methoxyphenoxy) propyl] -α, α-bis (4-fluorphenyl) -4-piperidineacetonitrile or a pharmaceutically acceptable salt thereof. Yes, Claim 1
The compound according to the item. 24. 1- [3- (2,6-dichlorophenoxy) propyl] -α, α-bis (4-fluorophenyl) -4-piperidineacetonitrile or a pharmaceutically acceptable salt thereof. The compound according to claim 1. 25. 1- [3- (2,6-Dichlorophenoxy) propyl] -α, α-diphenyl-3-piperidinepropanenitrile or a pharmaceutically acceptable salt thereof. The compound according to item 1. 26. 1- [4- (4-acetyl-2-methoxyphenoxy) butyl] -α, α-bis (4-fluorophenyl) -4-piperidineacetonitrile or a pharmaceutically acceptable salt thereof. A compound as claimed in claim 1. 27. 1- [2- (2,6-Dichlorophenoxy) ethyl] -α, α-diphenyl-3-piperidinepropanamide or a pharmaceutically acceptable salt thereof. The compound according to item 1. 28. α- [1- [3- (4-acetyl-2-
Methoxyphenoxy) propyl] -4-piperidinyl]
The compound according to claim 1, which is -α- (4-fluorophenyl) -2-pyridineacetonitrile or a pharmaceutically acceptable salt thereof. 29. α- [1- [3- (4-acetyl-2-
Methoxyphenoxy) propyl] -4-piperidinyl]
The compound according to claim 1, which is -α- (4-fluorophenyl) -2-pyridineacetonitrile or a pharmaceutically acceptable salt thereof. 30. α, α-Diphenyl-1- [3- (8-
Quinolinyloxy) propyl] -3-piperidinepropanenitrile or a pharmaceutically acceptable salt thereof,
The compound according to claim 1. 31. 8- [3- [4- [bis (4-fluorophenyl) methyl] -1-piperidinyl] propoxy]
The compound according to claim 1, which is quinoline or a pharmaceutically acceptable salt thereof. 32. The method according to claim 1, which is 4- [bis (4-fluorophenyl) methyl] -N-phenyl-1-piperidinepropanamine or a pharmaceutically acceptable salt thereof. Compound. 33. N- [3- [4- [bis (4-fluorophenyl) methyl] -1-piperidinyl] propyl]-
The compound according to claim 1, which is N-methylbenzenamine or a pharmaceutically acceptable salt thereof. 34. 1- [3- (4-Acetyl-2-methoxyphenoxy) propyl] -α, α-bis (4-fluorphenyl) -3-piperidineacetonitrile or a pharmaceutically acceptable salt thereof. Yes, Claim 1
The compound according to the item. 35. 1- [3- (4-Cyanophenoxy) propyl] -α, α-bis (4-fluorphenyl) -3
-A compound according to claim 1 which is piperidine acetonitrile or a pharmaceutically acceptable salt thereof. 36. 4- [Bis (4-fluorophenyl) methyl] -1- [3- (1-naphthylenyloxy) propyl] piperidine or a pharmaceutically acceptable salt thereof. A compound according to the first section. 37. 2- [3- [4- [bis (4-fluorophenyl) methyl] -1-piperidinyl] propoxy]
The compound according to claim 1, which is quinoline or a pharmaceutically acceptable salt thereof. 38. 4- [Bis (4-fluorophenyl) methyl] -1- [3- (2-naphthalenyloxy) propyl] piperidine or a pharmaceutically acceptable salt thereof. A compound according to the first section. 39. The method according to claim 1, which is 4- [bis (4-fluorophenyl) methyl] -1- [3- (phenylthio) propyl] piperidine or a pharmaceutically acceptable salt thereof. Compound of. 40. A compound according to claim 1, which is 4- [bis (4-fluorophenyl) methyl] -1- [3- (phenylsulfinyl) propyl] piperidine or a pharmaceutically acceptable salt thereof. The described compound. 41. 1- [3- (4-Acetyl-2-methoxyphenoxy) propyl] -α, α-bis (4-fluorophenyl) -3-pyrrolidineacetonitrile or a pharmaceutically acceptable salt thereof. The compound according to claim 1.