JPS6412270B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel 1-(cyclohexyl)-4-aryl-4-piperidinecarboxylic acid derivatives. A number of 4-phenyl-4-piperidinecarboxylic acid derivatives have been described in J.Pharm.Pharmacol., 23 (11), 875-
876 (1971); J.Med.Chem., 19 , 16-19 (1976);
and J.Med.Chem., 19 , 1248-1250 (1976). formula These known piperidine derivatives which can be represented by have analgesic properties. In Japanese Patent Application Laid-open No. 53-53665, the formula A number of 1-(cyclohexyl) represented by
-4-phenylpiperidine derivatives are described. This latter compound is taught to be useful as a central nervous system depressant. The compounds according to the invention differ essentially from the above-mentioned conventional compounds in the nature of the specific substituents in the 4-position of the piperidine nucleus and/or in the 4-position of the cyclohexyl group. The present invention is based on the formula In the formula, R ¹ is a member selected from the group consisting of hydrogen and lower alkyl; R is hydroxy, lower alkyloxy, aryl lower alkyloxy, aryloxy lower alkyloxy, lower alkyloxy lower alkyloxy, amino lower alkyl Oxy, mono- and di(lower alkyl)amino lower alkyloxy, (1
-pyrrolidinyl)-, (1-piperidinyl)- and (4-morpholinyl)lower alkyloxy, amino, aryl lower alkylamino, mono- and di(lower alkyl)amino, 1-pyrrolidinyl, 1
- a member selected from the group consisting of piperidinyl and 4-morpholinyl; and Ar ¹ and Ar ² are each independently selected from the group consisting of aryl, thienyl and pyridinyl; herein the definitions of R, Ar ¹ and Ar ² The aryl used in is a member selected from the group consisting of phenyl and substituted phenyl, and the substituted phenyl is lower alkyl, lower alkyloxy, halo, nitro, amino, cyano, carboxyl, lower alkyloxycarbonyl, mono - and has 1 to 3 substituents each independently selected from the group consisting of di(lower alkyl)aminocarbonyl and trifluoromethyl, a series of novel 1-
(Cyclohexyl)-4-aryl-4-piperidinecarboxylic acid derivatives, pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof. The term "halo" used in the above definition is a generic term for fluorine, chlorine, bromine and iodine, and "lower alkyl" is a straight-chain and branched hydrocarbon group having 1 to 6 carbon atoms, such as It is meant to include methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, 2-methylpropyl, butyl, pentyl, hexyl, and the like. Compounds of formula () generally include a suitable 4-aryl-4-cyanocyclohexanone of formula (), where Ar ¹ is as defined above, and a compound of formula (), where R, R ¹ and Ar ² are as defined above. 4 with appropriate substitution of
-It can be produced by a reductive amination reaction with aryl-4-piperidinecarboxylic acid. This reductive amination reaction is advantageously carried out by catalytic hydrogenation of a stirred and heated mixture of the reactants in a suitable reaction-inert organic solvent, according to catalytic hydrogenation methods known in the art. It can be carried out. Suitable solvents are, for example, water; lower alkanols, such as methanol, 2-propanol, etc.; cyclic ethers, such as 1,4-dioxane;
halogenated hydrocarbons such as trichloromethane; dimethylformamide; dimethyl sulfoxide, etc. or mixtures of two or more such solvents. The term "catalytic hydrogenation methods known in the art" means that the reactants are carried out under an atmosphere of hydrogen in the presence of a suitable catalyst such as palladium on carbon, platinum on carbon, etc. . In order to prevent further undesired hydrogenation of certain functional groups in the reactants and reaction products, suitable catalyst poisons,
For example, it is advantageous to add thiophene and the like. In addition, the compound of formula () is a compound of formula () in which cyclohexanone of formula () is appropriately substituted with 4 of formula ().
- It can also be produced by reacting with a piperidine carboxylic acid derivative and then reducing the intermediate enamine of formula (). The enamine formation reaction is carried out in the presence of a catalytic amount of a relatively strong acid, such as 4-methylbenzenesulfonic acid, in a suitable reaction-inert organic solvent, such as an aliphatic, cycloaliphatic or aromatic hydrocarbon, such as n-hexane. , cyclohexane, methylbenzene, etc. by stirring the reactants together. In order to increase the reaction rate, it is appropriate to carry out the reaction at a slightly elevated temperature, preferably the reaction is carried out at the reflux temperature of the reaction mixture. Most preferably, the reaction is carried out with azeotropic removal of water formed during the course of the reaction. Reduction of the enamine of formula () can be carried out, for example, by stirring the enamine () in a suitable solvent in the presence of a suitable reducing agent, such as a complex metal hydride such as sodium borohydride. I can do it. Suitable solvents include, for example, alkanols such as methanol, 2-propanol, etc.; cyclic ethers such as tetrahydrofuran,
It is a mixture of 1,4-dioxane and the like, if necessary, with water. Elevated temperatures can be used to increase the reaction rate. In order to avoid undesired decomposition of the reducing agent, it may be advantageous to carry out the reaction in an alkaline medium such as sodium methylate in methanol, sodium hydride in water, etc. The compounds of formula () are new and, as useful as intermediates, they form part of the present invention. Compounds of formula () can also be prepared by converting an appropriately substituted aryl-cyano-cyclohexane of formula () into a suitable 4-piperidinecarboxylic acid derivative of formula () according to N-alkylation methods known in the art. It can be produced by reacting with. In formulas () and (), R, R ¹ ,
Ar ¹ and Ar ² are as defined above, and W
represents suitably a leaving group, such as halo, such as chloro, bromo or iodo, or a sulfonyloxy group, such as methylsulfonyloxy, 4-methylphenylsulfonyloxy and the like. The above N-alkylation reactions are preferably carried out using inert organic solvents, such as aromatic hydrocarbons such as benzene, methylbenzene, dimethylbenzene, etc.; lower alkanols such as methanol, ethanol,
-butanol etc.; ketones e.g. 4-methyl-2-
The reaction is carried out in pentanone, etc.; ethers such as 1,4-dioxane, 1,1'-oxybisethane, etc.; N,N-dimethylformamide; nitrobenzene, etc. In order to take up the acid formed in the course of the reaction, the addition of a suitable base, such as an alkali metal carbonate or alkali metal hydrogencarbonate, or an organic base, such as N,N-diethylethanamine, can be used. In some cases iodide salts, preferably alkali metal iodides, are suitable. Slightly elevated temperatures can be used to increase the reaction rate. Also, a compound of formula () in which R is hydroxy-
The compound is represented by formula (-a)-
can be derived by hydrolysis from a compound of formula () in which R is other than hydroxy, the latter R being represented by Ra, and the compound being of formula (-b) . Conversely, compounds of formula (-a) can be converted to the corresponding compounds of formula (-b) according to esterification or amination methods known in the art. where R ¹ , Ar ¹ and Ar ² are as defined above and R _a is as defined above except for hydroxy. The above hydrolysis reaction is generally carried out in an aqueous alkaline or acidic medium such as potassium hydroxide. This can be carried out by stirring the compound of formula (-b) in an aqueous solution or hydrochloric acid and heating if necessary. If Ra represents, for example, a phenylmethoxy group, the hydrolysis can be carried out by hydrogenolysis methods known in the art, for example in the presence of a suitable catalyst such as palladium on carbon, platinum on carbon, etc. , the starting compound (-b) can be catalytically hydrogenated. The esterification or amination reaction is carried out by reacting the starting acid (- a) can be carried out by stirring and heating with the appropriate alcohol or amine. Most preferably, the reaction is carried out at the reflux temperature of the reaction mixture, with azeotropic removal of water formed during the course of the reaction. In some cases it may be appropriate to previously convert the carboxylic acid function into the corresponding acid halide function and then react the acid halide thus obtained with a suitable alcohol or amine. Compounds of formula () can be converted to therapeutically active non-toxic acid addition salts by treatment with a suitable acid;
Examples of such acids are inorganic acids such as hydrohalic acids,
For example, hydrochloric acid, hydrobromic acid, etc., and sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids, such as acetic acid, propanoic acid, 2-hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, propanedioic acid, Butanedioic acid, (Z)-2-butenedioic acid, (E)-2-butenedioic acid, 2-hydroxybutanedioic acid, 2,3-dihydroxybutanedioic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid , benzoic acid, 3-phenyl-2-propanoic acid, α-hydroxybenzeneacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, An acid such as 4-amino-2-hydroxybenzoic acid. Conversely, the salt form can be converted to the free base form by treatment with alkali. It is clear from formula () that the compounds of the invention may exist in different stereochemically isomeric forms. Because of the substituents on the cyclohexyl ring, the compound has 2
Species may exist in different geometric isomeric forms, ie cis and trans forms. Furthermore, the piperidine moiety is
When R ¹ is lower alkyl, it exists in optical isomers and these optical isomers are usually referred to as "Ap (+)", "Ap
(-)", "Bp(+)" and "Bp(-)". Thus, for compound (), when R ¹ is hydrogen, there are only geometric isomers A and B, but when R ¹ is lower alkyl, there are 8 diastereoisomers. be. These isomers are referred to as "Ac-Ap(+)", "Ac-Ap(-)", "Ac-Bp"
(+)”, “(Ac−Bp(−)”, “Bc−Ap(+)”, “
Bc
−Ap(−)”, “Bc−Bp(+)” and “Bc−Bp
(-)". These isomers are called “Ac−Ap
(±)”, “Ac-Bp(±)”, “Bc-Ap(±)” and “Bc-Bp(±)”, it is clear that they occur as diastereomeric pairs or racemates. can be resolved into its enantiomers by methods known in the art.
These racemates are sometimes called “Ac-Ap”, “Ac-
Bp,""Bc-Ap," and "Bc-Bp." Frame-pure stereochemical isomers of compound () can be obtained by applying methods known in the art. Geometric isomers and diastereomeric pairs can be separated from each other by physical separation methods, such as fractional crystallization and chromatographic methods, such as countercurrent partitioning, column chromatography, and the like. The frame-pure enantiomers are separated by resolution methods known in the art, such as frame-pure optically active reagents to form diastereomeric salts or other derivatives, and the diastereomeric salts and derivatives are separated by physical separation methods, such as fractional crystallization. and chromatography, and finally by methods known in the art to liberate the desired enantiomers. Also, frame-pure stereochemically isomeric forms can be derived from the corresponding frame-pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereochemically. Stereochemically isomeric forms of compounds of formula () are, of course, included within the scope of the present invention. A large number of the intermediates and starting materials in the above production methods are known compounds, all of which can be produced according to methods known in the art for producing similar compounds. A number of such manufacturing methods are discussed in more detail below. The intermediate of formula () is a suitable arylacetonitrile () and propenoic ester (propenoic acid ester).
It can be prepared by a Michael addition reaction with an acid ester) () followed by hydrolysis of the cyclic Michael addition reaction product thus obtained in an acidic medium. In the following reaction equation, R ²
represents an optionally substituted lower alkyl group. The Michael addition reaction described above is advantageously carried out in a suitable solvent such as an alkanol, such as ethanol, 1,
1-dimethylethanol etc.; in an aliphatic, cycloaliphatic or aromatic hydrocarbon such as n-hexane, cyclohexane, methylbenzene etc., depending on the solvent used, a suitable strong base such as sodium hydroxide, sodium methylate etc. This is done by stirring the reactants together and optionally heating in the presence of . Preferably the reaction is carried out at the reflux temperature of the reaction mixture. Hydrolysis is generally carried out by stirring and heating the Michael addition reaction product in an aqueous acidic medium such as hydrochloric acid. The arylacetonitrile () used as the starting material can be prepared by the following steps: (i) The appropriate arylmagnesium halide () is reacted with paraformaldehyde according to the Grignard reaction method known in the art. (ii) converting the arylmethyl alcohol () thus obtained into a suitable leaving group W; and (iii) replacing the group W of the intermediate () thus obtained with a cyano group. The Grignard reaction of a compound of formula () with paraformaldehyde is carried out in a suitable reaction-inert organic solvent, such as an ether such as tetrahydrofuran, 1,4-dioxane, etc., by stirring the reactants together and heating if necessary. be able to. Most preferably the reaction is conducted at the reflux temperature of the reaction mixture. Conversion of the hydroxy function into a leaving group can be carried out, for example, by subjecting the alcohol () to a suitable halogenating or sulfonylating agent, such as thionyl chloride, methanesulfonyl chloride, in an inert organic solvent such as methylbenzene. This can be done by stirring with etc. The leaving group W in formula () can be substituted with a cyano group by stirring the compound of formula () with an alkali metal cyanide, such as potassium cyanide, in a suitable solvent such as 2-propane. Intermediates of formula () can be prepared according to methods known in the art for converting nitriles to amides, carboxylic acids and esters. It can be derived from a suitably substituted 4-cyanopiperidine with where R ¹ and Ar ² are as described above and P represents a suitable protecting group. The method used and the reaction order may depend on the nature of P and R ¹ . For example, when P represents a 4-methylphenylsulfonyl group, the intermediate () is a compound of formula (XI) in the presence of a reagent of formula ROH, where R is as defined above. It can be produced by stirring in an acidic medium and heating if necessary. If ^Ar2 represents a trifluoromethylphenyl group, it may occur that the _CF3 group is converted into a -COOR group. Also intermediate ()
is obtained from cyanide (XI) by first hydrolyzing the cyanide functional group in an alkaline medium, converting the carboxylic acid thus obtained into the desired carboxylic ester when R is other than hydrogen, and then converting the protecting group to the desired carboxylic acid ester. according to methods known in the art, for example by stirring the intermediate in a suitable solvent in the presence of a suitable tetraalkylammonium halide or in the presence of a mixture of phenol and hydrogen bromide in acetic acid. It can be induced by removal. In some cases it may be advantageous to first remove P and then convert the CN- group to the desired ester or amide group. The intermediate of formula (XI) used as starting material in the above reaction is a suitable tertiary amine (XII), where P, R ¹ and W are as defined above, in an alkaline medium. It can be produced by reacting with arylacetonitrile (). The above reaction is advantageously carried out in the presence of a suitable base such as sodium hydride, potassium carbonate, etc., and a suitable inert organic solvent for the reaction, such as water; a cyclic ether such as tetrahydrofuran;
1,4-dioxane, etc.; or by stirring and heating the reactants together in a mixture of such solvents. The compounds of formula () and their pharmaceutically acceptable acid addition salts are effective antihistamines and can be used as such in the preparation of valuable medicaments for human and animal therapy. The useful antihistamine properties of compounds of formula () are demonstrated according to the following test method. Compound 48/80 - Protection of rats from induced lethality "Compound 48/80" is a mixture of oligomers (dimers, trimers) obtained by condensation of p-methoxy-N-methyl-phenylethylamine and formaldehyde. The trimer has the following structural formula. This “compound 48/80” is known as an effective histamine releaser [Int.Arch.Allergy, 13 ,
336 (1958)]. Compound 48/80--induced protection from lethal circulatory collapse appears to be a simple method to quantitatively assess the antihistamine activity of a test compound. Weight 240-260g
Inbred Wistar male rats were used in the experiments. After an overnight fast, rats were kept in a controlled laboratory room (temperature = 21 ± 1°C, relative humidity =
65±5%). The rats were administered subcutaneously or orally the test compound or vehicle (NaCl solution, 0.9
%). One hour after treatment, compound 48/80 freshly dissolved in water was injected intravenously at a dosage of 0.5 mg/Kg (0.2 ml/100 g body weight). In a symmetric experiment, 250 vehicle-treated animals received compound 4.
When the standard dose of 8/80 was injected, no more than 2.8% of the animals occurred after 4 hours. Therefore,
Survival after 4 hours is considered a safe criterion for the protective effect of drug administration. Tables 1 and 2 show oral dosages (mg/Kg body weight) at which rats are protected from compound 48/80-induced lethality for a number of compounds of formula (). The data shown in the table and in the table is for illustrative purposes only and is not intended to limit the scope of the invention.

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[Table] No fatal cases were observed for any of the compounds listed in Tables 1 and 2 above, even when administered orally to rats in an amount of 40 mg/Kg body weight. Therefore, the LD ₅₀ value of the compounds listed in Tables 1 and 2 is 40.
mg/Kg body weight or more (rat, oral). In view of its useful antihistamine activity, the present compounds can be formulated into various pharmaceutical forms for administration purposes. To prepare the pharmaceutical preparations of the present invention, an antihistaminetically effective amount of the specified compound in base or acid addition salt form as the active ingredient is brought into intimate admixture with a pharmaceutically acceptable carrier, the carrier being They can take a wide variety of forms depending on the form of preparation desired for administration.
The pharmaceutical preparation is preferably in a single dosage form suitable for oral, rectal or parenteral injection. For example, in preparing preparations in oral dosage forms, common pharmaceutical vehicles such as water, glycols, oils, alcohols, etc. are used in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions. ; In the case of powders, pills, capsules and tablets, solid carriers such as starch, sugar, kaolin, lubricants, binders, disintegrants, etc. can be used. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral administration, the carrier consists, at least in large part, of sterile water, although it may contain other ingredients, eg, to aid solubility. For example, injectable solutions can be prepared in a carrier consisting of a salt solution, a glucose solution or a mixture of salt and glucose solution. Injectable suspensions may also include a suitable liquid carrier,
It can be manufactured using a suspending agent or the like. The acid addition salts of formula () are clearly suitable for the production of aqueous preparations due to their increased solubility in water over the corresponding base forms. It is especially advantageous to formulate such pharmaceutical preparations in dosage unit form for ease of administration and uniformity of dosage. As used herein, dosage unit form refers to physically discrete units suitable as uniform dosages, each unit being calculated to produce the desired therapeutic effect in combination with the required pharmaceutical carrier. Contains a previously determined amount. Examples of such dosage unit forms are tablets (including cracked and coated tablets), capsules, pills,
powder sachets, wafers, injectable solutions or suspensions, teaspoonfuls, lablespoonfuls, etc., and separate compounds thereof. The following examples further illustrate the invention and are not intended to limit the scope of the invention. Unless otherwise specified, all parts are parts by weight. Preparation Example of Intermediate 1 1-Bromo-4 in 225 parts of tetrahydrofuran
8.4 parts of paraformaldehyde were added in portions to the stirred and refluxing Grignard complex previously prepared from 39.7 parts of fluoro-2-methylbenzene and 5.1 parts of magnesium. When added,
Stirring was continued under reflux for 1 hour. The reaction mixture was cooled and poured onto a mixture of crushed ice and acetic acid. The product was extracted with trichloromethane. Dry the extract,
filtered and evaporated. The residue was distilled and 4-
14 parts (47.6%) of fluoro-2-methylbenzene methanol were obtained; boiling point 110 DEG C. (under vacuum with a water pump). The following was also produced in the same manner as above: 4-chloro-3-(trifluoromethyl)benzene methanol; boiling point: 90°C/4mmHg. Example 2 To 14.3 parts of thionyl chloride, while cooling with ice water,
A solution of 14 parts of 4-fluoro-2-methylbenzene methanol and 0.9 parts of N,N-dimethylformamide in 45 parts of methylbenzene was added dropwise. Next, 135 parts of methylbenzene was added, and stirring was continued for 1 hour at room temperature. The reaction mixture was evaporated and the residue was 1-
17 parts (100%) of (chloromethyl)-4-fluoro-2-methylbenzene were obtained. The following was also produced in the same manner as above: 1-chloro-4-(chloromethyl)-2-(trifluoromethyl)benzene; boiling point: 100°C/100mm
Hg. Example 3 A mixture of 16 parts of 1-(chloromethyl)-4-fluoro-2-methylbenzene, 7.8 parts of potassium cyanide solution in a small amount of water, 0.1 part of potassium iodide and 240 parts of 2-propanone is stirred and refluxed for 22 hours. Ta.
The reaction mixture was cooled and filtered. The liquid was evaporated. The residue was taken up in water and the product was extracted with methylbenzene. Dry and strain the extract;
Evaporation gave 13 parts (87.2%) of 4-fluoro-2-methylbenzeneacetonitrile as a residue. The following was also produced in the same manner as above: 4-chloro-2-(trifluoromethyl)benzeneacetonitrile; boiling point: 83°C/0.2mmHg. Example 4 221 parts of 4-fluorobenzene acetonitrile,
A mixture of 700 parts of 30% sodium methylate solution and 900 parts of dimethylbenzene was stirred for 5 minutes. 309 parts of methyl 2-propanoate were added dropwise (exothermic reaction; temperature rose to 65°C). Upon addition, stirring was continued at reflux overnight. Methanol was distilled off until the internal temperature reached 110°C. After cooling, 6N hydrochloric acid
1000 parts were added dropwise and the whole was stirred and refluxed for 5 minutes. Upon cooling, the layers were separated. The organic phase was dried, filtered and evaporated. Add the residue to 500 parts of acetic acid and water.
The mixture was stirred and refluxed for 4 hours with 500 parts of hydrochloric acid solution and 500 parts of hydrochloric acid solution. After cooling, the product was extracted with trichloromethane. The extract was washed successively with water, dilute sodium hydroxide solution, water again until neutral, dried, filtered and evaporated. The residue was crystallized from 2-propanol to give 1-(4-fluorophenyl)
-4-oxocyclohexanecarbonitrile
134.5 parts were obtained; melting point 91.8°C. Following a similar method and using equivalents of the appropriate arylacetonitrile as starting material, the following were prepared:

Table Example 5 2-(chloromethyl)-4-fluoro-1-methylbenzene in 99 parts of ethanol is added to a stirred and refluxing mixture of 71 parts of sodium cyanide, 99 parts of ethanol, and 85 parts of water. 134 parts of the solution was added dropwise. Upon addition, stirring was continued first under reflux for 6 hours and then overnight at room temperature. The ethanol was evaporated and the residue was taken up in 4-methyl-2-pentanone and water. The layers were separated and the aqueous phase was extracted three times with 4-methyl-2-pentanone. The combined organic phase is diluted with water.
Washed twice, dried, filtered and evaporated.
The residue was distilled to obtain 98 parts of 5-fluoro-2-methylbenzeneacetonitrile; boiling point 124-128°C/
10mmHg. Example 6 N,N,N- in 90 parts of tetrahydrofuran is added to a stirred hot solution of 8.5 parts of N,N,N-triethylbenzene methanaminium chloride, 40 parts of sodium hydroxide and 360 parts of 50% sodium hydroxide solution.
A solution of 72.7 parts of bis(2-chloroethyl)-4-methylbenzenesulfonamide and 45.5 parts of 2,4-dichlorobenzeneacetonitrile was added dropwise. Upon addition, stirring was continued at 50° C. for 3 hours. The reaction mixture was cooled, 216 parts of methylbenzene and 480 parts of water were added, and the layers were separated. The organic phase was washed with water, dried, filtered and evaporated. The residue was crystallized from 2-propanol to give 28 parts (29%) of 4-(2,4-dichlorophenyl)-1-(4-methylphenylsulfonyl)-4-piperidinecarbonitrile.
with a melting point of 145°C. Following a similar method as above and using the appropriate amount of arylacetonitrile, the following was prepared: 4-(2-fluorophenyl)-1-(4-methylphenylsulfonyl)-4-piperidinecarbonitrile , as a residue; 4-(5-chloro-2-methoxyphenyl)-1
-(4-methylphenylsulfonyl)-4-piperidinecarbonitrile; 1-(4-methylphenylsulfonyl)-4-
[3-(trifluoromethyl)phenyl]-4-piperidinecarbonitrile; and 4-(2-methoxyphenyl)-1-(4-methylphenylsulfonyl)-4-piperidinecarbonitrile. Example 7 N,N-bis(2
A solution of 29.6 parts of -chloroethyl)-4-methylbenzenesulfonamide and 14.9 parts of 4-fluoro-2-methylbenzeneacetonitrile is added to a solution of 5.6 parts of lithium amide in 270 parts of methylbenzene at about 90°C.
It was dripped. Upon addition, the whole was heated to reflux and stirred at reflux overnight. The reaction mixture was cooled, poured into water and the layers were separated. dry the organic phase;
filtered and evaporated. The residue was crystallized from 2-propanol to give 4-(4-fluoro-2-
27 parts (72.6%) of methylphenyl)-1-(4-methylphenylsulfonyl)-4-piperidinecarbonitrile were obtained. Following a similar method as above and using equivalent amounts of the appropriate starting materials, the following was prepared: 4-(3-chloro-2-methylphenyl)-1-
(4-Methylphenylsulfonyl)-4-piperidinecarbonitrile; 4-(5-fluoro-2-methylphenyl)-1
-(4-Methylphenylsulfonyl)-4-piperidinecarbonitrile; melting point 168°C; (B)-4-(2-fluorophenyl)-3-methyl-1-(4-methylphenylsulfonyl)-4 -piperidinecarbonitrile; melting point 154°C; and (A)(+)-4-(2-fluorophenyl)-3-
Methyl-1-(4-methylphenylsulfonyl)-
4-piperidinecarbonitrile; melting point 135°C. Example 8 35.8 parts of 4-(2-fluorophenyl)-1-(4-methylphenylsulfonyl)-4-piperidinecarbonitrile and 50 parts of a 75% sulfuric acid solution were heated at about 150°C.
The mixture was stirred for 4 hours. 192 parts of ethanol was added dropwise.
Upon addition, stirring was continued at reflux temperature for 5 hours. The reaction mixture was cooled and poured onto crushed ice. The whole was made alkaline with ammonium hydroxide and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated leaving a residue of ethyl 4-(2
17.2 parts (68.4%) of -fluorophenyl)-4-piperidinecarboxylate were obtained. Following the hydrolysis method described above and starting from the corresponding carbonitrile, the following were prepared: Ethyl 4-(3-methylphenyl)-4-piperidinecarboxylate hydrochloride; and Ethyl 4-(2,4-dichloro phenyl)-4-
Piperidine carboxylate hydrochloride. Example 9 1-(4-methylphenylsulfonyl)-4-
16.32 parts of [3-(trifluoromethyl)phenyl]-4-piperidinecarbonitrile were added in portions to 35 parts of 75% sulfuric acid, and the mixture was stirred and heated at 155°C for 15 hours. Upon addition, stirring was continued under reflux overnight. The reaction mixture was cooled and poured into ice water. The whole was made alkaline with ammonium hydroxide and the product was extracted with dichloromethane. Dry the extract,
filtered and evaporated. The residue was converted to the hydrochloride salt in 2,2'-oxybispropane and 2-propanol. Separate the salt, dry, and add ethyl 4-
[3-(Ethoxycarbonyl)phenyl]-4-piperidinecarboxylate hydrochloride 6 parts (43.9%)
with a melting point of 121°C. Example 10 1-(4-methylphenylsulfonyl)-4-
[3-(trifluoromethyl)phenyl]-4-piperidinecarbonitrile 11.3 parts, potassium hydroxide
A mixture of 5.6 parts and 220 parts of 1,2-ethanediol was stirred and refluxed for 48 hours. The reaction mixture was cooled and poured onto ice-water, the whole was acidified with hydrochloric acid and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated leaving a residue of 1-(4-methylphenylsulfonyl)-4-[3
11.8 parts (100%) of -(trifluoromethyl)phenyl]-4-piperidinecarboxylic acid were obtained. Following the same hydrolysis method as above and starting from the corresponding carbonitrile, the following was prepared: 4-(5-chloro-2-methoxyphenyl)-1
-(4-methylphenylsulfonyl)-4-piperidinecarboxylic acid; 4-(2-methoxyphenyl)-1-(4-methylphenylsulfonyl)-4-piperidinecarboxylic acid as residue; 4-(4 -fluoro-2-methylphenyl)-1
-(4-methylphenylsulfonyl)-4-piperidinecarboxylic acid; 4-(3-chloro-2-methylphenyl)-1-
(4-Methylphenylsulfonyl)-4-piperidinecarboxylic acid; 4-(5-fluoro-2-methylphenyl)-1
-(4-methylphenylsulfonyl)-4-piperidinecarboxylic acid; melting point 157°C; (B)-4-(2-fluorophenyl)-3-methyl-1-(4-methylphenylsulfonyl)-4 -piperidinecarboxylic acid; melting point 186°C; and (A)-(±)-4-(2-fluorophenyl)-3-
Methyl-1-(4-methylphenylsulfonyl)-
4-piperidinecarboxylic acid as residue. Example 11 4-(5-chloro-2-methoxyphenyl)-1
36 parts of thionyl chloride were added dropwise to a stirred and refluxing mixture of 21 parts of -(4-methylphenylsulfonyl)-4-piperidinecarboxylic acid and 270 parts of benzene. Upon addition, the whole was stirred and refluxed for 4 hours. The reaction mixture was evaporated and the residue was washed twice with methylbenzene and 22 parts of 4-(5-chloro-2-methoxyphenyl)-1-(4-methylphenylsulfonyl)-4-piperidinecarbonyl chloride ( 100%). In addition, in the same manner as above, the following was produced; 4-(2-methoxyphenyl)-1-(4-methylphenylsulfonyl)-4-piperidine carbonyl chloride, as a residue; 1-(4- methylphenylsulfonyl)-4-
[3-(trifluoromethyl)phenyl]-4-piperidinecarbonyl chloride, as residue; 4-(4-fluoro-2-methylphenyl)-1
-(4-methylphenylsulfonyl)-4-piperidinecarbonyl chloride, as residue; 4-(3-chloro-2-methylphenyl)-1-
(4-Methoxyphenylsulfonyl)-4-piperidinecarbonyl chloride, as residue; 4-(5-fluoro-2-methylphenyl)-1
-(4-methylphenylsulfonyl)-4-piperidinecarbonyl chloride, as residue; (A)-3-methyl-1-(4-methylphenylsulfonyl)-4-phenyl-4-piperidinecarbonyl chloride; (B )-4-(2-fluorophenyl)-3-methyl-1-(4-methylphenylsulfonyl)-4-piperidinecarbonyl chloride; (A)-(±)-4-(2-fluorophenyl) -3-
Methyl-1-(4-methylphenylsulfonyl)-
4-piperidinecarbonyl chloride, as a residue; (B)-(-)-3-methyl-1-(4-methylphenylsulfonyl)-4-phenyl-4-piperidinecarbonyl chloride; and (B)-(+) -3-Methyl-1-(4-methylphenylsulfonyl)-4-phenyl-4-piperidinecarbonyl chloride, as residue Example 12 4-(3-chloro-2-methylphenyl)-1-
(4-Methylphenylsulfonyl)-4-piperidinecarbonyl chloride 36.5 parts and ethanol
240 parts of the mixture was stirred and refluxed overnight. The reaction mixture was treated with hot activated carbon. This was separated and allowed to cool to room temperature to crystallize the product from the liquid. The product was separated, dried and ethyl 4-(3-chloro-2-methylphenyl)-1-
Obtained 33 parts (89.1%) of (4-methylphenylsulfonyl)-4-piperidinecarboxylate; melting point
134℃. Following an esterification procedure similar to that described above, the following was prepared by reacting the corresponding acid chloride with the appropriate alcohol: Ethyl 4-(5-chloro-2-methoxyphenyl)-1-(4-methylphenyl) enylsulfonyl)-
4-piperidinecarboxylate; ethyl 4-(2-methoxyphenyl)-1-
(4-methylphenylsulfonyl-4-piperidinecarboxylate; ethyl 1-(4-methylphenylsulfonyl)
-4-[3-(trifluoromethyl)phenyl]-
4-Piperidinecarboxylate; Ethyl 4-(4-fluoro-2-methylphenyl)-1-(4-methylphenylsulfonyl)-
4-piperidinecarboxylate; melting point 151°C; ethyl 4-(5-fluoro-2-methylphenyl)-1-(4-methoxyphenylsulfonyl)
-4-piperidinecarboxylate; melting point 94°C; (A)-(phenylmethyl)3-methyl-1-(4-
methylphenylsulfonyl)-4-phenyl-4
-piperidinecarboxylate; (B)-(phenylmethyl)4-(2-fluorophenyl)-3-methyl-1-(4-methylphenylsulfonyl)-4-piperidinecarboxylate;
Melting point 110°C; (A)-(±)-(phenylmethyl)4-(2-fluorophenyl)-3-methyl-1-(4-methylphenylsulfonyl)-4-piperidinecarboxylate; (B)- (±)-phenylmethyl 3-methyl-1-
(4-Methylphenylsulfonyl)-4-phenyl-4-piperidinecarboxylate; (B)-(-)-phenylmethyl 3-methyl-1-
(4-Methylphenylsulfonyl)-4-phenyl-4-piperidinecarboxylate; and (B)-phenylmethyl 3-methyl-1-(4-
methylphenylsulfonyl)-4-phenyl-4
-Piperidine carboxylate. Example 13 Ethyl 4-(5-chloro-2-methoxyphenyl)-1-(4-methoxyphenylsulfonyl)
A mixture of 17 parts of -4-piperidine carboxylate, 7.5 parts of phenol and 135 parts of a solution of hydrobromic acid in acetic acid was stirred at room temperature overnight. The reaction mixture was poured into water and the whole was washed with 2,2'-oxybispropane. The aqueous phase was made alkaline with sodium hydroxide while cooling. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was converted to the hydrochloride salt in 2-propanol and 2,2'-oxybispropane to give 7 parts (55%) of ethyl 4-(5-chloro-2-methoxyphenyl)-4-piperidinecarboxylate hydrochloride. I got it. Example 14 a (B)-(±)-3- in 3200 parts of 2-propanol
Methyl-1-(4-methylphenylsulfonyl)
-4-phenyl-4-piperidinecarboxylic acid 73
of the stirred and boiling solution (-)-
A solution of 24 parts of α-methylbenzenemethanamine was added. This solution crystallized. Separate the products and add 2-propanol 4800, 4000 and 2-propanol, respectively.
Recrystallized three times from 3200 parts to obtain (B)-(-)-3-methyl-1-(4-methylphenylsulfonyl)-4-phenyl-4-piperidinecarboxylic acid α-methylbenzenemethanamine (1: 1) Obtained 27 copies (27%). (B)-(-)-3-Methyl-1-(4-methylphenylsulfonyl)-4-phenyl-4-piperidinecarboxylic acid α-methylbenzenemethanamine (1:1) 27 parts, concentrated hydrochloric acid 60 parts and 1000 parts of water was stirred for a while and brought to a boil. The precipitated product was separated, washed with water and boiled in water. The product was separated and dissolved in trichloromethane. This was dried, filtered and evaporated. The residue was stirred in 2,2'-oxybispropane to give (B)-(-)-3-methyl-1-
(4-Methylphenylsulfonyl)-4-phenyl-4-piperidinecarboxylic acid 18.4 parts (94%)
I got it. b (B)-(-)-3- in 1600 parts of 2-propanol
Methyl-1-(4-methylphenylsulfonyl)
-4-phenyl-4-piperidinecarboxylic acid
To 100 parts of a stirred and refluxing solution are added 2
A solution of 32.5 parts of (+)-α-methylbenzenemethanamine in 400 parts of -propanol was added. This reaction mixture was crystallized. Separate the product
It was recrystallized four times from 6400, 5600, 4800 and 3200 parts of 2-propanol, respectively. The product was separated and recrystallized from 2400 parts of 2-propanol. This was separated again to obtain 22 parts of product. Product obtained by evaporating the liquid and crystallizing the residue
In addition to 22 parts, (B)-(+)-3-methyl-1-(4
-methylphenylsulfonyl)-4-phenyl-4-piperidinecarboxylic acid α-methylbenzenemethanamine (1:1) 28 parts (21%) were obtained. (B)-(+)-3-Methyl-1-(4-methylphenylsulfonyl)-4-phenyl-4-piperidinecarboxylic acid α-methylbenzenemethanamine (1:1) 28 parts, concentrated hydrochloric acid 60 parts and 1000 parts of water was boiled for a while. The reaction mixture was filtered. The filter cake was washed with water and stirred in boiling water. The product was separated and dissolved in trichloromethane. This was dried, filtered and evaporated. The residue was boiled in 2,2'-oxybispropane to give (B)-(+)-3-methyl-1-(4-methylphenylsulfonyl)-
4-phenyl-4-piperidinecarboxylic acid 19.7
(93%). Example 15 Suspension of 11 parts of ethyl 1-(4-methylphenylsulfonyl)-4-[3-(trifluoromethyl)phenyl]-4-piperidinecarboxylate and 8 parts of tetraethylammonium bromide in 200 parts of ethanol. Hg −2.15V using a mixture of Ag and AgCl as cathode and reference electrode
It was electrolytically detosylated. The ethanol solution was discarded and the solvent was evaporated. The residue was taken up in dichloromethane. This was washed three times with water, dried and evaporated. The residue was converted to the hydrochloride salt in 2-propanol and 2,2'-oxybispropane. This salt was separated to obtain 6.9 parts (85.2%) of ethyl 4-[3-(trifluoromethyl)phenyl]-4-piperidinecarboxylate hydrochloride. In a similar manner as above, the following were prepared: Ethyl 4-(2-methoxyphenyl)-4-piperidinecarboxylate hydrochloride; Ethyl 4-(4-fluoro-2-methylphenyl)-4-piperidinecarboxylate as a residue; ethyl 4-(3-chloro-2-methylphenyl)-4-piperidinecarboxylate; as a residue; (B)-phenylmethyl 3-methyl-4-phenyl-4-piperidinecarboxylate ethanedioate (1 :1); (A)-Phenylmethyl 3-methyl-4-phenyl-4-piperidinecarboxylate, as residue; Ethyl 4-(5-fluoro-2-methylphenyl)-4-piperidinecarboxylate hydrochloride; melting point 198.8°C ; (B)-Phenylmethyl 4-(2-fluorophenyl)-3-methyl-4-piperidinecarboxylate hydrochloride; melting point 220°C; (A)-(±)-phenylmethyl 4-(2-fluorophenyl) -3-Methyl-4-piperidinecarboxylate ethanedioate (1:1); melting point
170℃; (B)-(-)-phenylmethyl 3-methyl-4-
Phenyl-4-piperidinecarboxylate hydrochloride; and (B)-(+)-phenylmethyl 3-methyl-4-
Phenyl-4-piperidinecarboxylate hydrochloride. Example 16 6.9 parts of 1-piperidine propanol were added dropwise to a stirred and refluxing mixture of 14 parts of 4-phenyl-4-piperidinecarbonyl chloride hydrochloride and 130 parts of methylbenzene. Upon addition, stirring was continued at reflux overnight. The methylbenzene phase was decanted and the remaining oil was boiled in a mixture of 2,2'-oxybispropane and ethanol. The precipitated product was separated, dried and 3-
(1-piperidinyl)propyl 4-phenyl-
14 parts of 4-piperidinecarboxylate dihydrochloride monohydrate were obtained; melting point 176.1°C. Following a method similar to that described above and using equivalent amounts of the appropriate starting materials, the following was prepared: 2-(dimethylamino)ethyl 4-phenyl-4-piperidinecarboxylate dihydrochloride; mp 230°C; 3- (dimethylamino)propyl 4-phenyl-4-piperidinecarboxylate dihydrochloride;
Melting point: 150°C; 2-(1-pyrrolidinyl)ethyl 4-phenyl-4-piperidinecarboxylate dihydrochloride;
Melting point 185°C; and 2-(4-morpholinyl)ethyl 4-phenyl-4-piperidinecarboxylate ethanedioate (1:1); melting point 210°C. Example 17 4-oxo-1-(2-pyridinyl)cyclohexanecarbonitrile 4.5 parts, ethyl, 4-phenyl-4-piperidine carboxylate 5.2 parts,
A mixture of 1 part 4-methylbenzenesulfonic acid and 225 parts methylbenzene was stirred and refluxed overnight using a water separator. The reaction mixture was evaporated and the residue was crystallized from 2-propanol and ethyl 1-[4-cyano-4-(2-pyridinyl)
-1-cyclohexenyl]-4-phenyl-4-
4.5 parts (45%) of piperidine carboxylate were obtained; melting point 160°C. Following a similar method as above, using equivalents of appropriately substituted cyclohexanone and piperidine,
The following was prepared: Ethyl 1-[4-cyano-4-(4-fluorophenyl)-1-cyclohexen-1-yl]-4
- phenyl-4-piperidine carboxylate,
As a residue; ethyl 1-(4-cyano-4-phenyl-1
-cyclohexen-1-yl)-4-phenyl-
4-piperidinecarboxylate, as residue; ethyl 1-[4-cyano-4-(4-methoxyphenyl)-1-cyclohexen-1-yl]-4
- phenyl-4-piperidine carboxylate,
As a residue; ethyl 1-[4-(4-chlorophenyl)-4
-cyano-1-cyclohexen-1-yl]-4
- phenyl-4-piperidine carboxylate,
as a residue; and 1-[1-(4-cyano-4-phenyl-1-cyclohexen-1-yl)-4-phenyl-4-
Piperidinylcarbonyl]piperidine, as a residue. Preparation Example 18 of Final Compound Ethyl 1-[4-cyano-4-(2-pyridinyl)-1-cyclohexenyl]-4-phenyl-4
- To a stirred mixture of 4.5 parts of piperidine carboxylate and 80 parts of ethanol was added portionwise 0.4 part of sodium borohydride. Upon addition, stirring was continued initially at room temperature overnight and under reflux for an additional 30 minutes.
The reaction mixture was cooled and poured into water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 2-propanol and ethyl 1-[4-cyano-4
-(2-pyridinyl)cyclohexyl]-4-phenyl-4-piperidinecarboxylate 2 parts (35
%); melting point 157.1°C. Following a similar method as above, the following was prepared: Ethyl 1-(4-cyano-4-phenylcyclohexyl)-4-phenyl-4-piperidinecarboxylate; mp 130.5°C; Ethyl 1-[4-cyano -4-(4-methoxyphenyl)cyclohexyl]-4-phenyl-4
-piperidine carboxylate; melting point 122°C; ethyl 1-[4-(4-chlorophenyl)-4
-cyanocyclohexyl]-4-phenyl-4-
piperidine carboxylate; melting point 155°C; and 1-phenyl-4-[4-phenyl-4-(1-
piperidinylcarbonyl)-1-piperidinyl]
Cyclohexanecarbonitrile hydrochloride; melting point
283.2℃. Example 19 To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol is added 1-(4-fluoro-2-methylphenyl)-
4-Oxo-cyclohexanecarbonitrile 4.7
1 part, 5.4 parts of ethyl 4-phenyl-4-piperidinecarboxylate hydrochloride, 2 parts of sodium acetate, and 120 parts of ethanol were added. The whole was hydrogenated at atmospheric pressure and room temperature over a 10% palladium on carbon catalyst. After absorbing the calculated amount of hydrogen, the catalyst was separated on a Hyflo and the liquid was evaporated. The free base was liberated from the residue in the usual manner with ammonium hydroxide and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified with trichloromethane and ethanol (98.5:
1 volume part) of the mixture was purified by column chromatography on silica gel. The pure fraction was collected and the eluent was evaporated. The residue was crystallized from ethanol and ethyl 1-[4-
3 parts (33.4%) of cyano-4-(4-fluoro-2-methylphenyl)cyclohexyl]-4-phenyl-4-piperidinecarboxylate were obtained;
Melting point: 135.2℃. Following a method similar to that described above and using equivalent amounts of the appropriate starting materials, the following were prepared:

【table】

【table】

[Table] Example 20 Ethyl 1-[4-cyano-4-(4-fluorophenyl)-1-cyclohexen-1-yl]-4-
Phenyl-4-piperidine carboxylate 11.7
1 part of 30% sodium methylate solution and 320 parts of methanol was added in portions to 1 part of sodium borohydride. Upon addition, stirring was continued at room temperature. The reaction mixture was poured into ice water and the product was extracted with trichloromethane.
The extract was dried, filtered and evaporated. The residue was crystallized from ethanol and (B)-ethyl 1-
[4-cyano-4-(4-fluorophenyl)-1
5.9 parts of -cyclohexyl]-4-phenyl-4-piperidinecarboxylate were obtained; melting point 145.8
℃. 2 parts of a solution of 2 parts of thiophene in 40 parts of ethanol, 27 parts of 1-(4-fluorophenyl)-4-oxocyclohexanecarbonitrile, ethyl 4-phenyl-4-piperidinecarboxylate hydrochloride.
34 parts, 15 parts of residual sodium vinegar, and 400 parts of ethanol were added. The whole was hydrogenated at atmospheric pressure and room temperature over a 10% palladium on carbon catalyst.
After absorbing the calculated amount of hydrogen, the catalyst was separated on a Hyflo and the liquid was evaporated. The free base was liberated from the residue in the usual manner with ammonium hydroxide and extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified using a mixture of trichloromethane and methanol (99:1 parts by volume) as eluent.
Part (9.6 parts) was purified by column chromatography on silica gel. A pure fraction was collected and the eluent was evaporated. The residue was converted to the hydrochloride salt in 2-propanol. The impure fractions were separated and the liquid was treated with activated carbon. Separate this, evaporate the liquid, and (A)-ethyl 1-
4.8 parts of [4-cyano-4-(4-fluorophenyl)cyclohexyl]-4-phenyl-4-piperidinecarboxylate hydrochloride hydrate were obtained;
Melting point: 210.7℃. Example 21 To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol is added 1-(5-chloro-2-methoxyphenyl)-
5.3 parts of 4-oxocyclohexane carbonitrile,
5.4 parts of ethyl 4-phenyl-4-piperidinecarboxylate hydrochloride, 3 parts of sodium acetate and 200 parts of ethanol were added. 10% supported on carbon
The whole was hydrogenated at normal pressure and 50° C. over 2 parts of platinum catalyst. After absorbing the calculated amount of hydrogen, the catalyst was separated and washed with a mixture of acetic acid and ethanol. The liquid was evaporated and water was added to the residue. The whole was made alkaline with sodium hydroxide and the product was extracted with trichloromethane. The extract was washed with water, filtered and evaporated. The residue was purified with trichloromethane and methanol (99:1) as eluent.
(parts by volume) was purified by column chromatography on silica gel. The first fraction (A-isomer) was collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane to give (A)-ethyl 1-[4-(5-chloro-2-methoxyphenyl)-4-cyanocyclohexyl]-4-phenyl-4-piperidine. Obtained 0.8 parts (8%) of carboxylate; melting point 165.5
℃. The second fraction (B-isomer) was collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane to give (B)-ethyl 1-
[4-(5-chloro-2-methoxyphenyl)-4
-cyanocyclohexyl]-4-phenyl-4-
1.2 parts (12%) of piperidine carboxylate were obtained; melting point 131.8°C. Example 22 To 2 parts of a solution of 2 parts of thiophene in 40 parts of ethanol, 4.4 parts of 1-(4-fluorophenyl)-4-oxocyclohexanecarbonyltolyl, (B)-ethyl 3-methyl-4-phenyl-4 - 5 parts of piperidine carboxylate, 3 parts of sodium acetate and 160 parts of ethanol were added. 10% supported on carbon
The whole was brought to normal pressure and 50°C by using 2 parts of palladium catalyst.
Hydrogenated at °C. After absorbing the calculated amount of hydrogen,
The catalyst was separated and the liquid was evaporated. The residue was purified with trichloromethane and methanol (98:
A mixture of 2 parts by volume) was purified by column chromatography on silica gel. A pure fraction was collected and the eluent was evaporated.
The residue was crystallized from 2,2'-oxybispropane to give (Bc-Bp)-ethyl 1-[4-cyano-4-
(4-fluorophenyl)cyclohexyl]-3-
3.3 parts (37%) of methyl-4-piperidinecarboxylate were obtained; melting point 133.3°C. To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol, 4.4 parts of 1-(4-fluorophenyl)-4-oxocyclohexanecarbonitrile, (A)-ethyl 3-methyl-4-phenyl-4-piperidine carboxy 5 parts of alcohol and 160 parts of ethanol were added.
By two parts of 10% palladium supported on carbon,
The whole was hydrogenated at normal pressure and 50°C. After absorbing the calculated amount of hydrogen, the catalyst was separated and the liquid was evaporated. The residue was crystallized from acetonitrile to give (Bc-
Ap)-ethyl 1-[4-cyano-4-(4-fluorophenyl)cyclohexyl]-3-methyl-4
-Phenyl-4-piperidinecarboxylate
2.6 parts (28%) were obtained; melting point 125.9°C. Example 23 To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol is 4.4 parts of 1-(4-fluorophenyl)-4-oxocyclohexanecarbonitrile, 4 parts of 4-phenyl-4-piperidinecarboxamide and 120 parts of methanol. Added a section. 10% supported on carbon
The whole was brought to normal pressure and 50°C by using 2 parts of palladium catalyst.
Hydrogenated at °C. After absorbing the calculated amount of hydrogen,
The catalyst was separated and the liquid was evaporated. The residue was purified by column chromatography on silica gel. Trichloromethane and methanol (99:1
Elution with a mixture of (parts by volume) gave the A-isomer, which was crystallized from 2,2'-oxybispropane. The product was separated, recrystallized from ethanol, and 0.5 part (6
%); melting point 171.4°C. Elution with a mixture of trichloromethane and methanol (97:3 parts by volume) gave the B-isomer, which was crystallized from 2,2'-oxybispropane. The product was separated and recrystallized from ethanol to yield (B)-1-[4-
1 part (12%) of cyano-4-(4-fluorophenyl)cyclohexyl]-4-phenyl-4-piperidinecarboxamide was obtained; melting point 243.1°C. Example 24 A mixture of 4.3 parts of 1-(4-fluorophenyl)-4-oxocyclohexanecarbonitrile, 5.3 parts of 4-(4-chlorophenyl)-N,N-dimethyl-4-piperidinecarboxamide and 200 parts of methanol was , hydrogenated over two parts of a 10% platinum catalyst on carbon at normal pressure and 50°C. After absorbing the calculated amount of hydrogen, the catalyst was separated and the liquid was evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (99:1 parts by volume) as eluent. Collect pure fraction,
The eluent was evaporated. The residue was crystallized from a mixture of 2-propanol and 2,2'-oxybispropane. Separate the product (reserving the mother liquor);
Dry, (A+B)-4-(4-chlorophenyl)-
1-[4-cyano-4-(4-fluorophenyl)
2 parts of [cyclohexyl]-N,N-dimethyl-4-piperidinecarboxamide were obtained; melting point 184.4
℃. From the above mother liquor, another fraction was crystallized and (A)-4-(4-chlorophenyl)-1-[4
1.5 parts of -cyano-4-(4-fluorophenyl)cyclohexyl]-N,N-dimethyl-4-piperidinecarboxamide was obtained; melting point 212.2°C. Example 25 To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol is 1.2 parts of 1-(4-fluorophenyl)-4-oxocyclohexanecarbonitrile, (A)-ethyl 3-methyl-4-(4- methoxyphenyl)-4-
Two parts of piperidine carboxylate ethanedioate (1:1), two parts of sodium acetate and 120 parts of ethanol were added. The whole was hydrogenated over two parts of 10% palladium on carbon catalyst at normal pressure and room temperature. After absorbing the calculated amount of hydrogen, the catalyst was separated on Hyflo and washed with acetic acid. The liquid was evaporated. From the residue, the free base was liberated in the usual manner with ammonium hydroxide and extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and ethanol (98:2 parts by volume) as eluent. A pure fraction was collected and the eluent was evaporated. The residue was converted to the hydrochloride salt in ethanol and 2-propanol. Separate this salt, dry it, and (Bc-Ap)-ethyl 1-[4
-cyano-4-(4-fluorophenyl)cyclohexyl]-4-(4-methoxyphenyl)-3-
0.6 part (21.6%) of methyl-4-piperidinecarboxylate monohydrochloride was obtained; melting point 240.9°C. To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol, 13 parts of 1-(4-fluorophenyl)-4-oxocyclohexanecarbonitrile, (A)-phenylmethyl 3-methyl-4-phenyl-4-piperidine carboxy rate 18.4 parts and 2-propanol
Added 200 copies. The whole was hydrogenated with two parts of 5% platinum on carbon catalyst at normal pressure and 50°C. After absorbing the calculated amount of hydrogen, separate the catalyst and
The liquid was evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (98:2 parts by volume) as eluent. The first fraction was collected and the eluent was evaporated. From the residue, Ac
- Hexane, trichloromethane and methanol (100:100:0.5) using Ap fraction as eluent
Parts by volume) of the mixture were separated by HPLC. The pure fraction was collected, the eluent was evaporated, and (Ac-Ap)-(phenylmethyl)1-[4
1.5% (5%) of -cyano-4-(4-fluorophenyl)cyclohexyl]-3-methyl-4-phenyl-4-piperidinecarboxylate was obtained. To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol, 3.5 parts of 1-(4-fluorophenyl)-4-oxocyclohexanecarbonitrile, (B)-(phenylmethyl)4-(2-fluorophenyl)- 3-Methyl-4-piperidinecarboxylate hydrochloride 6
parts, potassium acetate 4 parts and 2-propanol 160 parts
Added a section. The whole was hydrogenated with two parts of 5% platinum on carbon catalyst at normal pressure and 50°C.
After absorbing the calculated amount of hydrogen, the catalyst was separated and the liquid was evaporated. The residue was taken up in trichloromethane. This was washed with water to remove inorganic materials. The organic phase was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (98:2 parts by weight) as eluent. Collect pure fraction,
The eluent was evaporated. HPLC the Bc-Bp-fraction using a mixture of trichloromethane, hexane and methanol (100:100:5 parts by volume).
Separated by A pure fraction was collected and the eluent was evaporated. The residue was converted to the hydrochloride salt in 2-propanol. The salt was separated, dried and (Bc-Bp)-phenylmethyl)1-[4-cyano-4-(4-fluorophenyl)cyclohexyl]-4-(2-fluorophenyl)-3-methyl- 4-Piperidinecarboxylate monohydrochloride
4.4 parts were obtained; melting point 239.4°C. In 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol, 13 parts of 1-(4-fluorophenyl)-4-oxocyclohexanecarbonyl, (A)-phenylmethyl 3-methyl-4-phenyl-4-piperidinecarboxylate. 18.4 parts and 2-propanol 160
Added a section. The whole was hydrogenated with 2 parts of 5% platinum on carbon at normal pressure and 50°C. After absorbing the calculated amount of hydrogen, the catalyst was separated and the liquid was evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (98:2 parts by volume) as eluent. The pure Bc-Ap fraction was collected and the eluent was evaporated. The residue was converted to the hydrochloride salt in 2-propanol. The salt was separated, dried and (Bc-Ap)-phenylmethyl 1-[4-cyano-4-(4-fluorophenyl)cyclohexyl]-3-methyl-4-phenyl-4-piperidinecarboxylate monohydrochloride. Obtained 8.4 parts of salt; melting point
223.6℃. To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol, 6.6 parts of 1-(4-fluorophenyl)-4-oxocyclohexanecarbonitrile, (B)-phenylmethyl 3-methyl-4-phenyl-4-piperidine carboxy 10.5 parts of lattate hydrochloride, 6 parts of potassium acetate and 200 parts of 2-propanol were added. The whole was hydrogenated with 4 parts of 5% platinum on carbon at normal pressure and 50°C. After absorbing the calculated amount of hydrogen, the catalyst was separated and washed with acetic acid. The liquid was evaporated and the residue was taken up in water. The whole was made alkaline with sodium hydroxide and the product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (98:2 parts by volume) as eluent. A pure fraction was collected and the eluent was evaporated. From the residue
Ac-Bp praction was carried out using hexane, trichloromethane and methanol (100:
A mixture of 100:0.5 parts by volume) was used for separation by HPLC. The pure fraction was collected, the eluent was evaporated, and (Ac-Bp)-phenylmethyl 1-[4
0.8 part (5%) of -cyano-4-(4-fluorophenyl)cyclohexyl]-3-methyl-4-phenyl-4-piperidinecarboxylate was obtained. In a similar manner as above, the following was prepared: (Bc-Bp)-phenylmethyl 1-[4-cyano-4-(4-fluorophenyl)cyclohexyl]
-3-Methyl-4-phenyl-4-piperidinecarboxylate; melting point 131°C; (Ac-Bp)-phenylmethyl 1-[4-cyano-4-(4-fluorophenyl)cyclohexyl]
-4-(2-fluorophenyl)-3-methyl-4
-piperidine carboxylate; (Bc-Ap) (±)-phenylmethyl 1-[4-
Cyano-4-(4-fluorophenyl)cyclohexyl]-4-(2-fluorophenyl)-3-methyl-4-piperidinecarboxylate monohydrochloride; melting point 213.1°C; (Ac-Ap) (±)- Phenylmethyl 1-[4-
Cyano-4-(4-fluorophenyl)cyclohexyl]-4-(2-fluorophenyl)-3-methyl-4-piperidinecarboxylate; (Bc-Bp)(+)-phenylmethyl 1-[4-
cyano-4-(4-fluorophenyl)cyclohexyl]-3-methyl-4-phenyl-4-piperidinecarboxylate; and (Bc-Bp)(-)-phenylmethyl 1-[4-
Cyano-4-(4-fluorophenyl)cyclohexyl]-3-methyl-4-phenyl-4-piperidinecarboxylate. Example 26 Ethyl 1-[4-cyano-4-(4-fluorophenyl)-1-cyclohexyl]-4-phenyl-
10.9 parts of 4-piperidine carboxylate, 11.2 parts of potassium hydroxide, 50 parts of water, and 96 parts of 2-propanol.
The mixture was stirred and refluxed for 4 hours. The reaction mixture was filtered over Hyflo while hot, and the liquid was diluted with water.
Pour over 300 copies. The whole was neutralized with acetic acid to a pH value of 6-7. The precipitated product was separated, washed three times with water and converted to the hydrochloride salt in ethanol and 2-propanol. The salt was separated and suspended in a solution of 1.4 parts of potassium hydroxide in 150 parts of water. The free base was extracted four times with 70 parts of 1,1-oxybisethane. The aqueous phase was separated and the whole was stirred in a rotary evaporator to remove all 1,1'-oxybisethane.
The clear aqueous phase was acidified to a pH value of 6 with 10% acetic acid solution. The precipitated product was separated, washed with water and dried overnight at about 105°C to give 1-[4-cyano-4-(4-
5.4 parts (66.4%) of fluorophenyl)cyclohexyl]-4-phenyl-4-piperidinecarboxylic acid
obtained; melting point 281.1°C. Following the same method as above, the following were produced;

[Table] Example 27 (B)-Phenylmethyl 1-[4-cyano-4-(4-fluorophenyl) in 80 parts of 2-propanol
cyclohexyl]-3-methyl-4-phenyl-
A mixture of 1.2 parts of 4-piperidine carboxylate was hydrogenated over 1 part of 10% palladium on carbon catalyst at atmospheric pressure and room temperature. After absorbing the calculated amount of hydrogen, potassium hydroxide was added until the precipitated product went into solution. Separate the catalyst, 2
- The propanol was evaporated. The aqueous phase was washed with 2,2'-oxybispropane and neutralized with 10% acetic acid solution. The precipitated product was separated and converted to the hydrochloride salt in 2-pronol. The crude salt was crystallized from ethanol to yield (Bc-Bp)-1-[4-cyano-
4-(4-fluorophenyl)cyclohexyl]-
0.8 part (73%) of 3-methyl-4-phenyl-4-piperidinecarboxylic acid monohydrochloride was obtained: melting point +300
℃. (Ac-Bp)-phenylmethyl 1-[4-cyano-4-(4-fluorophenyl)cyclohexyl]
-3-Methyl-4-phenyl-4-piperidinecarboxylate 0.8 part and tetrahydrofuran 90
The mixture was hydrogenated over 1 part of 10% palladium on carbon catalyst at normal pressure and room temperature.
After absorbing the calculated amount of hydrogen, the catalyst was separated and the liquid was evaporated. The residue was converted to the hydrochloride salt in ethanol and 2,2'-oxybispropane. The salt was separated, dried and (Ac-Bp)-1-[4-cyano-4-(4-fluorophenyl)cyclohexyl]-3-methyl-4-phenyl-4-piperidinecarboxylic acid monohydrochloride. 0.5 parts (68%) were obtained; melting point 209.2°C. (Bc-Bp)-phenylmethyl)1-[4-cyano-4-(4-fluorophenyl)cyclohexyl]-4-(2-fluorophenyl)-3-methyl-4-piperidinecarboxylate 3.4 parts and tetrahydrofuran 135 parts of the mixture was hydrogenated over 2 parts of 10% palladium on carbon catalyst at atmospheric pressure and room temperature. After absorbing the calculated amount of hydrogen, the catalyst was separated and washed with ammonia-saturated methanol. The liquid was evaporated and the residue was taken up in a mixture of potassium hydroxide and water. The whole was washed with trichloromethane. 10% alkaline aqueous phase
Neutralized with acetic acid solution. Separate the precipitated product,
Washed with water, dried and converted to the hydrochloride salt in methanol. Separate this salt, dry it, and (Bc−Bp)−
1-[4-cyano-4-(4-fluorophenyl)
cyclohexyl]-4-(2-fluorophenyl)
2 parts (66%) of -3-methyl-4-piperidinecarboxylic acid monohydrochloride were obtained; melting point 300.6°C. (Bc-Ap)-phenylmethyl 1-[4-cyano-4-(4-fluorophenyl)cyclohexyl]
7 parts of -3-methyl-4-phenyl-4-piperidinecarboxylate and 270 parts of tetrahydrofuran
The mixture was hydrogenated over 2 parts of 10% palladium on carbon catalyst at normal pressure and room temperature.
After absorbing the calculated amount of hydrogen, the catalyst was separated and the liquid was evaporated. The residue was converted to the hydrochloride salt in methanol and 2,2'-oxybispropane. The salt was separated, dried and (Bc-Ap)-1-[4-cyano-4-(4-fluorophenyl)cyclohexyl]-3-methyl-4-phenyl-4-piperidinecarboxylic acid monohydrochloride. One part (16%) of the monohydrate was obtained; melting point 291.8°C. A mixture of 1.5 parts of (Ac-Ap)-(phenylmethyl)1-[4-cyano-4-(4-fluorophenyl)cyclohexyl]-3-methyl-4-phenyl-4-piperidinecarboxylate and 90 parts of tetrahydrofuran was added. Hydrogenation was carried out over 1 part of 10% palladium on carbon catalyst at normal pressure and room temperature. After absorbing the calculated amount of hydrogen, the catalyst was separated and the liquid was evaporated. The residue was taken up in water and potassium hydroxide. The whole was washed with trichloromethane. The alkaline aqueous phase was neutralized with 10% acetic acid solution. The precipitated product was separated, washed with water, dried and converted to the hydrochloride salt in methanol and 2,2'-oxybispropane to give (Ac-Ap)-1-[4-cyano-4-( 4-fluorophenyl)cyclohexyl]-3-methyl-4-phenyl-4-piperidinecarboxylic acid monohydrochloride monohydrate 0.6 parts (42%)
obtained; melting point 261.6°C. (Ac-Bp)-phenylmethyl 1-[4-cyano-4-(4-fluorophenyl)cyclohexyl]
-4-(2-fluorophenyl)-3-methyl-4
- a mixture of 0.9 parts of piperidine carboxylate and 90 parts of tetrahydrofuran supported on carbon 10
% palladium catalyst at normal pressure and room temperature. After absorbing the calculated amount of hydrogen, the catalyst was separated and washed with ammonia-saturated methanol. The liquid was evaporated and the residue was taken up in a mixture of water and potassium hydroxide. The whole was washed with trichloromethane. The alkaline aqueous phase was neutralized with 10% acetic acid solution. The precipitated product was separated and converted to the hydrochloride salt in methanol and 2,2'-oxybispropane. Separate this salt, dry it, and (Ac−Bp)
-1-[4-cyano-4-(4-fluorophenyl)cyclohexyl]-4-(2-fluorophenyl)-3-methyl-4-piperidinecarboxylic acid monohydrochloride monohydrate 0.3 parts (37 %); melting point 242.2
~244.4℃. Example 28 (Ac-Ap)-(±)-phenylmethyl 1-[4-
10% palladium supported on carbon in a mixture of 0.7 parts of cyano-4-(4-fluorophenyl)cyclohexyl]-4-(2-fluorophenyl)-3-methyl-4-piperidinecarboxylate and 90 parts of tetrahydrofuran. Hydrogenation was carried out over 1 part of catalyst at normal pressure and room temperature. After absorbing the calculated amount of hydrogen, the catalyst was separated. The filter cake was washed with ammonia-saturated methanol and the liquid was evaporated. The residue was taken up in water and potassium hydroxide. The whole was washed with trichloromethane. The alkaline aqueous phase was neutralized with 10% acetic acid solution. The precipitated product was separated, washed with water, dried and converted to the hydrochloride salt in methanol and 2,2'-oxybispropane. Separate this salt, dry it, and (Ac−Ap)−
(±)-1-[4-cyano-4-4-(4-fluorophenyl)cyclohexyl]-4-(2-fluorophenyl)-3-methyl-4-piperidinecarboxylic acid monohydrochloride 0.3 part ( 49%); melting point 282.7
℃. In a similar manner as above, the following was prepared: (Bc-Ap)(±)-1-[4-cyano-4-(4
-fluorophenyl)cyclohexyl]-4-(2
-fluorophenyl)-3-methyl-4-piperidinecarboxylic acid monohydrochloride; melting point 288.8°C. Example 29 (Bc-Bp)-(-)-phenylmethyl 1-[4-
A mixture of 4 parts of cyano-4-(4-fluorophenyl)cyclohexyl]-3-methyl-4-phenyl-4-piperidinecarboxylate and 225 parts of tetrahydrofuran was prepared with 2 parts of 10% palladium on carbon. Hydrogenation was carried out at normal pressure and room temperature. After absorbing the calculated amount of hydrogen, separate the catalyst and
Washed with ammonia saturated methanol. The liquid was evaporated. The residue was converted to the hydrochloride salt in methanol. Separate this salt, dry it, and (Bc−Bp)−(−)
-1-[4-cyano-4-(4-fluorophenyl)cyclohexyl]-3-methyl-4-phenyl-4-piperidinecarboxylic acid monohydrochloride 3 parts (82
%); melting point 298.1°C. The following was produced in the same manner as above; (Bc-Bp)-(+)-1-[4-cyano-4-
(4-fluorophenyl)cyclohexyl]-3-
Methyl-4-phenyl-4-piperidinecarboxylic acid monohydrochloride; melting point 298.9°C.

Claims (1)

[Claims] 1 formula In the formula, R ¹ is a member selected from the group consisting of hydrogen and lower alkyl; R is hydroxy, lower alkyloxy, aryl lower alkyloxy, aryloxy lower alkyloxy, lower alkyloxy lower alkyloxy, amino lower alkyl Oxy, mono- and di(lower alkyl)amino lower alkyloxy, (1
-pyrrolidinyl) lower alkyloxy, (1-piperidinyl) lower alkyloxy, (4-morpholinyl) lower alkyloxy, amino, aryl lower alkylamino, mono- and di(lower alkyl) amino, 1-pyrrolidinyl, 1-piperidinyl and a member selected from the group consisting of 4-morpholinyl; and Ar ¹ and Ar ² are each independently selected from the group consisting of aryl, ^thienyl and ^pyridinyl ; is a member selected from the group consisting of phenyl and substituted phenyl, and the substituted phenyl is lower alkyl, lower alkyloxy,
halo, nitro, amino, cyano, carboxyl,
A compound having 1 to 3 substituents each independently selected from the group consisting of lower alkyloxycarbonyl, mono- and di(lower alkyl)aminocarbonyl, and trifluoromethyl, and a pharmaceutically acceptable acid thereof Addition salts and stereochemically isomeric forms. 2 1-[4-cyano-4-(4-fluorophenyl)cyclohexyl]-3-methyl-4-phenyl-4-piperidylcarboxylic acid, its pharmaceutically acceptable acid addition salts and stereochemical isomerism The compound according to claim 1, which is a compound selected from the group consisting of body type. 3 formulas In the formula, R ¹ is a member selected from the group consisting of hydrogen and lower alkyl; R is hydroxy, lower alkyloxy, aryl lower alkyloxy, aryloxy lower alkyloxy, lower alkyloxy lower alkyloxy, amino lower alkyl Oxy, mono- and di(lower alkyl)amino lower alkyloxy, (1
-pyrrolidinyl) lower alkyloxy, (1-piperidinyl) lower alkyloxy, (4-morpholinyl) lower alkyloxy, amino, aryl lower alkylamino, mono- and di(lower alkyl) amino, 1-pyrrolidinyl, 1-piperidinyl and a member selected from the group consisting of 4-morpholinyl; and Ar ¹ and Ar ² are each independently selected from the group consisting of aryl, ^thienyl and ^pyridinyl ; is a member selected from the group consisting of phenyl and substituted phenyl, and the substituted phenyl is lower alkyl, lower alkyloxy,
halo, nitro, amino, cyano, carboxyl,
1-(cyclohexyl)-4-aryl- having 1 to 3 substituents each independently selected from the group consisting of lower alkyloxycarbonyl, mono- and di(lower alkyl)aminocarbonyl, and trifluoromethyl.
1. An antihistamine agent comprising, as an active ingredient, a compound selected from the group consisting of 4-piperidinecarboxylic acid derivatives, pharmaceutically acceptable acid addition salts, and stereochemically isomeric forms thereof. 4 1[4-cyano-4-(4-fluorophenyl)cyclohexyl]-3-methyl-4-phenyl-4-piperidinecarboxylic acid, pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof The antihistamine agent according to claim 3, which contains a compound selected from the group consisting of as an active ingredient. 5 formula In the formula, R ¹ is a member selected from the group consisting of hydrogen and lower alkyl; R is hydroxy, lower alkyloxy, aryl lower alkyloxy, aryloxy lower alkyloxy, lower alkyloxy lower alkyloxy, amino lower alkyl Oxy, mono- and di(lower alkyl)amino lower alkyloxy, (1
-pyrrolidinyl) lower alkyloxy, (1-piperidinyl) lower alkyloxy, (4-morpholinyl) lower alkyloxy, amino, aryl lower alkylamino, mono- and di(lower alkyl) amino, 1-pyrrolidinyl, 1-piperidinyl and a member selected from the group consisting of 4-morpholinyl; and Ar ¹ and Ar ² are each independently selected from the group consisting of aryl, ^thienyl and ^pyridinyl ; is a member selected from the group consisting of phenyl and substituted phenyl, and the substituted phenyl is lower alkyl, lower alkyloxy,
halo, nitro, amino, cyano, carboxyl,
A pharmaceutically acceptable compound having 1 to 3 substituents each independently selected from the group consisting of lower alkyloxycarbonyl, mono- and di(lower alkyl)aminocarbonyl, and trifluoromethyl; In preparing acid addition salts and stereochemically isomeric forms, the formula Where Ar ¹ is as defined above, a compound of the formula wherein R, R ¹ and Ar ² are as defined above. by catalytic hydrogenation of a stirred and heated mixture under an atmosphere of hydrogen and, if necessary, treatment of the compound of formula () with a suitable acid to form the therapeutically active non-toxic acid addition salt form. and further optionally to prepare stereochemically isomeric forms of compound (), pharmaceutically acceptable acid addition salts thereof and stereochemically isomeric forms thereof. Methods for producing isomeric forms. 6 formula where R ₁ is a member selected from the group consisting of hydrogen and lower alkyl; and Ar ¹ and Ar ² are each independently selected from the group consisting of aryl, thienyl and pyridinyl; where Ar ¹ and Ar ² Aryl used in the definition is a member selected from the group consisting of phenyl and substituted phenyl, and the substituted phenyl is lower alkyl, lower alkyloxy, halo, nitro, amino, cyano, carboxyl, lower alkyloxycarbonyl. , mono- and di(lower alkyl)aminocarbonyl, and trifluoromethyl.
In the preparation of compounds of the formula, pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof, having three substituents, where R ¹ , Ar ¹ and Ar ² are as defined above; and Ra is lower alkyloxy, aryl lower alkyloxy, aryloxy lower alkyloxy, lower alkyloxy lower alkyloxy, amino lower alkyloxy, mono - and di(lower alkyl)amino lower alkyloxy, (1-pyrrolidinyl) lower alkyloxy, (1-piperidinyl) lower alkyloxy, (4-morpholinyl)
Lower alkyloxy, amino, aryl lower alkyloxy, mono- and di(lower alkyl)amino, 1-pyrrolidinyl, 1-piperidinyl and 4
- a member selected from the group consisting of morpholinyl; wherein aryl is a member selected from the group consisting of phenyl and substituted phenyl, where the substituted phenyl is lower alkyl, lower alkyloxy, halo, nitro; , amino, cyano, carboxyl, lower alkyloxycarbonyl, mono-
and having 1 to 3 substituents each independently selected from the group consisting of di(lower alkyl)aminocarbonyl and trifluoromethyl, is hydrolyzed in an aqueous alkaline or acidic medium, and optionally Converting a compound of formula (-a) to a therapeutically active non-toxic acid addition salt form by treatment with a suitable acid and further optionally preparing stereochemical isomers of compound (-a). A method for producing the compound of formula (-a), its pharmaceutically acceptable acid addition salts and stereochemically isomeric forms, characterized in that: 7 formula where R ¹ is a member selected from the group consisting of hydrogen and lower alkyl; and Ar ¹ and Ar ² are each independently selected from the group consisting of aryl, thienyl and pyridinyl; where Ar ¹ and Ar ² Aryl used in the definition is a member selected from the group consisting of phenyl and substituted phenyl, and the substituted phenyl is lower alkyl, lower alkyloxy, halo, nitro, amino, cyano, carboxyl, lower alkyloxycarbonyl. , mono- and di(lower alkyl)aminocarbonyl, and trifluoromethyl.
For the preparation of compounds of the formula, pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof, having 3 substituents, wherein R ¹ , Ar ¹ and Ar ² are as defined above; and R'a represents a phenylmethoxy group, and optionally the compound of formula (-a) is said compound is converted into a therapeutically active non-toxic acid addition salt form by treatment with a suitable acid and further optionally produces stereochemical isomers of compound (-a). Expression (−
A process for producing the compound of a), its pharmaceutically acceptable acid addition salts and stereochemically isomeric forms. 8 Phenylmethyl 1-[4-cyano-4-(4-
Fluorophenyl)cyclohexyl]-4-phenyl-3-methyl-4-piperidinecarboxylate is hydrogenated in the presence of a palladium-on-carbon catalyst and, if desired, the product is 1-, consisting of conversion into an acceptable acid addition salt or stereochemically isomeric form.
[4-cyano-4-(4-fluorophenyl)cyclohexyl]-3-methyl-4-phenyl-4-
Claim 7 for producing a compound selected from the group consisting of piperidylcarboxylic acid, its pharmaceutically acceptable acid addition salts and stereochemically isomeric forms.
Manufacturing method described in section.