NO780290L - AZACYCLOALKANS, AZACYCLOALKENES AND THEIR DERIVATIVES - Google Patents

Description

The invention relates to new azacycloalkanes, azacycloalkenes and derivatives thereof which are applicable as antidepressants, anticonvulsants, tranquilizers, analgesics and intermediates thereto, as well as methods for the production of these, as well as methods for treatment with pharmaceutically effective amounts thereof as well as pharmaceutical preparations containing such compounds as essentially active compounds.

Bauer et al., in US-PS No. 3 • 9 5 9 • ^ 7 5. mention substituted 1, 3-dihydrospiro (isobenzofuran) are with the formula: ••

wherein R means hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoromethyl, halogen, hydroxy or methylenedioxy, R-^means hydrogen, alkyl of 1-6 carbon atoms, cycloalkylalkyl of 4-8 carbon atoms , alkenyl with 3-6 carbon atoms, phenylalkyl with the formula -(CH„) -PhR, diphenylalkyl with the formula

-(CH2)m-CH(PhR)2, diphenylmethoxyalkyl with the formula -(CH2)m-

OCHPh2, alkanoyl with 2-6 carbon atoms, phenylalkanoyl with the formula

-CO(CH2) -PhR, benzoyl with the formula -COPhR, benzoylalkyl with the formula -(CH2)m-COPhR, phenylhydroxyalkyl1 with the formula _(CH2)m-CHOHPhR, alkoxycarbonyl1 with 2-6 carbon atoms, phenyloxycarbonyl1

or cycloalkylcarbonyl with 4-8 carbon atoms, R~ means alkyl with 1-6 carbon atoms or phenyl with the formula -PhR^, Y means hydrogen, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, hydroxy or phenyl with the formula PhR, Ph means phenyl m, n and n' are integers from 1 to 3 and x is an integer from 1 to 4 as well as optical antipodes and pharmaceutically acceptable acid addition salts thereof. In addition, the same patent mentions as intermediates o-hydroxyalkylphenylcycloazalkanols with the formula and o-hydroxyalkylphenylcycloazalkanols or their ethers with the formula

wherein R' means hydrogen, alkyl or tetrahydropyrany 1. These intermediates have not been found to have any biological activity.

Bauer et al., in US-PS 3-962,259 also mention as intermediates o-hydroxymethylphenylcycloazalkanols and their ethers with the formula

wherein R' means hydrogen or alkyl, R and R, m, n and n' have the above meanings. These intermediates do not structurally suggest the initially mentioned compounds and were found to have no biological activity. Biel et al., in US-PS 3-301,862 and 3-350,403 refer generally to intermediate compounds of formula 12 • wherein one or both of R and R may be benzyl. This, as will be seen below, is decisive for the compounds discussed in relation to the present invention are technically within the framework of this broad generic vision. However, Biel et al. does not or does not describe a single compound in which a benzyl group is attached to the 2- or ortho-strand of the phenyl ring, the only benzyl-containing intermediate specifically indicated is 4-(3-benzylphenyl)-4-hydroxypiperidine. It has been found that substitution of benzyl in this 2- or ortho-position is decisive for the biological, especially antidepressant effect. In addition, nothing is said about how the above-mentioned intermediate compounds are prepared and no reference is made to a compound within the above-mentioned generic formula in which the benzyl group is in this 2- or ortho-position. Likewise, Biel et al. in US-PS 3-221,017 and 3-221,018 generally to 1,2,5,6-tetrahydropyridines of formula 1 2 in which benzyl is included within the definition of R and R as intermediates in the preparation of 4-arylpyridines. These patents, like the above-mentioned US patents 3-301,862 and 3-350,403 mention a simple compound within the scope of the present invention, the only such intermediate identified in these patents is the 3-benzyl-substituted compound 4-(3-benzylphenyl)-1, 2,5,6-tetrahydropyridine. Beil et al. states nothing in these patents about any biological activity of these intermediates. It is clear from the disclosures of the Biel et al. patents, e.g. lines 14 to 18, column 5 of US-PS 3-221,018 that the starting materials used in the method of Biel et al. are compounds which are either commercially available, well-known or easily produced and do not relate to any of the compounds including the positional isomers which are covered by the present invention. The invention relates to azacycloalkanes, azacycloalkenes and derivatives thereof with formula

wherein X means C-R^ or C, Y is -(CH2)n- when X means CR^ and =(CH)-(CH2) when X is C, R means hydrogen, lower alkyl, phenyl lower alkyl of formula

hydroxy, benzoyl lavereal alkyl of formula

cycloalkyllower alkyl1 in which the cycloalkyl ring contains from 3-6 carbon atoms, alkoxy carbonyl with from 2-6 carbon atoms, phenyloxycarbonyl, benzoyl, benzoyloxy, or 12 3 R , R and R are the same or different and can each mean hydrogen, halogen, alkoxy with 1 or 2 carbon atoms, lower alkyl, hydroxy or trifluoro- 4 5 5

methyl, R means hydrogen or OR , R^ means hydrogen, lower alkyl, benzoyl or cycloalkanoyl in which the cycloalkyl ring contains from 3 to 6 carbon atoms, m is the whole number 1 or 2, n is the whole number 1, 2 or 3>sum of m and n is 3 or 4,' p is an integer 1, 2 3 or 4 as well as pharmaceutically acceptable addition salts thereof. In the above, the term "lower" means radicals containing from 1 to 5 carbon atoms.

Compounds preferred because of their biological activity are those where R is hydrogen, alkyl or hydroxy. Most preferred compounds within this group are those in which X is C-H.

Acids usable for the production of pharmaceutical tolerable acid addition salts according to the invention include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and perchloric acids as well as inorganic acids such as tartaric acid, citric acid, acetic acid, lactic acid, fumaric acid

and hydrochloric acids.

Some compounds within the scope of the invention have greater pharmaceutical activity than others. The latter are nevertheless desirable as intermediate products for the production of the more active compounds, as will be apparent from the following figures of several methods for the production.

Procedure A

2-Bromodiphenylmethane of formula

12 3 in which R , R and R^ with the exception of hydroxy have the above meaning are transferred into lithium derivatives by treatment with alkyl lithium at a reduced temperature of approx. -80 to -30°C in a solvent such as ether, hexane or tetrahydrofuran. The formed lithium derivative is reacted with a compound of formula where m and n and the sum of m and n are as mentioned above and R means lower alkyl, phenyl lower alkyl or cycloalkyl lower alkyl at a temperature from -80 to -20°C, preferably -60 to -30° C in a solvent such as ether, tetrahydrofuran or hexane to form the corresponding N-substituted azacycloalkanol,. a compound according to the invention with formula The starting 2-bromodiphenylmethane is prepared by reducing a corresponding 2-bromobenzophenone. A suitable method for carrying out this reduction is via Clemmensen reduction. Another very suitable method involves the use of hydroiodic acid and phosphorus under reflux conditions. A suitable way of preparing a 2-bromobenzophenone is by reacting a 2-bromobenzoyl chloride of formula with a benzene of formula

under Friedel-Crafts conditions.

Procedure B

An N-substituted azacycloalkanol mentioned under method A, in which R is benzyl, can be hydrogenated, e.g. with a palladium on carbon catalyst to form an N-unsubstituted azacycloalkanol.

Procedure C

An N-substituted azacycloalkanol mentioned under method A can be esterified by treatment with a suitable acid anhydride, acid or acid chloride to form an ester according to the invention in which -X means C-OR and R means lower acyl, benzoyl or cycloalkanoy1 in which the cycloalkyl ring contains from 3 to 6 carbon atoms. In some cases the yields can be improved by transferring the azacycloalkanol to the lithium derivative which is then esterified.

Procedure D

An N-unsubstituted azacycloalkanol mentioned under method B can be reacted in a known manner with benzoyl chloride to form the corresponding N-benzoyl azacycloalkanol.

Procedure E

An azacycloalkanol mentioned under method A or B is dehydrated to the corresponding azacycloalkene with formula

The dehydration can be carried out with one of several dehydration agents including trifluoroacetic acid, formic acid and a mixture of glacial acetic acid and concentrated hydrochloric acid and from ambient to reflux temperature of the reaction mixture.

Procedure F

An azacycloalkene prepared according to method E can be hydrogenated as described in method B to form the corresponding N-unsubstituted or substituted azacycloalkane, a compound according to the invention of formula

wherein R is benzyl.

Procedure G

An N-substituted cycloazalkane prepared according to method F in which R means alkyl can be treated with chloroformate, e.g. alkyl or phenyl chloroformate, at a temperature from 25 to 125°C in a solvent such as toluene, benzene or methylene chloride to form the corresponding N-Alkoxycarbonyl or N-phenyloxycarbonylcycloazalkane, a compound according to the invention.

Procedure H

An N-Alkoxycarbonyl or N-Phenyloxycarbonylcycloazalkane prepared according to method G is treated with a base such as sodium or potassium hydroxide using a solvent such as water or ethanol or with an acid such as hydrogen bromide in acetic acid at a temperature from ambient to 125°C to form the corresponding N-unsubstituted azacycloalkane, a compound according to the invention.

Procedure I

An N-unsubstituted compound prepared by methods B, C, E, F or H can be transferred to a corresponding N-benzoyloxy compound, a compound according to the invention by adding a cooled solution of benzoyl peroxide in a suitable organic solvent such as benzene.

Procedure J

An N-benzoyloxy compound prepared according to method I is transferred to the corresponding N-hydroxy compound, a compound according to the invention by a method known per se. One such method is cleavage of benzoyloxy groups by treatment with aqueous potassium or sodium hydroxide in ethanol and allowing the mixture to react at the reflux temperature of the reaction mixture.

Procedure K

An ester produced by process C can be hydrogenated all the way to the corresponding azacycloalkane by a process known per se. Such a method includes the use of

. palladium on carbon catalyst.

Procedure L

An N-unsubstituted compound prepared by method BjC, E, F or H can be reacted with a compound of formula

wherein p and R<1> have the previously indicated meaning to form a corresponding compound. This reaction can be carried out in the presence of an organic solvent such as n-butanol and an acid scavenger at ambient temperature to the reflux temperature of the reaction mixture.

Procedure M

A compound prepared according to method L can be subjected to hydrolysis by a method known per se to form an N-benzoylalkyl compound, a compound according to the invention. Such a method is carried out with a refluxed mixture of methanol and concentrated hydrochloric acid.

Procedure N

An aldehyde-containing compound in which an aldehyde group is placed in a phenyl ring can be dealkylated by a method known per se to form a corresponding phenolic compound. A preferred method is dealkylation by refluxing hydrobromic acid under an inert atmosphere such as nitrogen.

The compounds of the invention are useful in the treatment of depression in mammals, as shown by their ability to prevent tetrabenazine-induced ptosis in mice (International Journal of Neuropharmacology, 8, 73 (1969))" a standard method for

assess antidepressant properties. Thus, e.g. the intra-

peritoneal dose where the following compounds (ED^Q) effect a 50% inhibition of tetrabenazine-induced ptosis in mice:

Similarly, a 25 mg/kg intraperitoneal dose of 4-acetoxy-1-methyl-4-Z2-(a-phenyltolyl)piperidine hydrochloride exerts a 40% inhibition of tetrabenazine-induced ptosis. These data show that compounds according to the invention are useful in the treatment of depression when they are administered in an amount from 0.1 to 50 mg/kg.

Compounds of the invention are useful as analgesic agents due to their ability to relieve pain in mammals. The analgesic ability of the compounds according to the invention shows in the 2-phenyl-1,4-quinone-induced pain phenomenon in mice, a standard method of analgesia (Proe. Soc. Exptl. Biol. Med., 95, 729 (1957)) - Thus, for example, a 50% inhibition of the pain works by oral administration of 28.4 mg/kg of body weight of 4-acetoxy-1-methyl-4-£2-(a-phenyltolyl)7piperidir hydrochloride. Other representative compounds according to the invention and their respective ability to prevent said pain is shown below in Table II.

These data show that the compounds according to the invention

are useful as analgesic substances in a dose of 0.1 to 50 mg/kg body weight. In comparison, aspirin and propoxyphene hydrochloride, known analgesic substances, will cause a 34% and 50% inhibition of the pain, respectively a dose of 60 mg/kg po.

The compounds of the invention are further useful as anticonvulsants for mammals as shown by the method of Woodbury, L.A. and Davenport, V.D., in Arch. Int. Pharmacodynam, Vol. 92, (1952) pp. 97-107. For example, an intraperitoneal dose of 17.6 mg/kg body weight of 1-methyl-4-{2-Za-(4-fluorophenyl)tolyl?}-1,2,3,6-tetrahydropyridine hydrobromide provides 8% protection from the effect of supra maximal electroshock (SES). Intraperitoneal doses of other representative compounds of the invention and their ability to protect against the effects of SES are shown in Table III.

These data show the applicability of the compounds

according to the invention for the treatment of convulsions in mammals when administered in amounts from approx. 1 to 50 mg/kg body weight per day.

The compounds according to the invention are further useful

as tranquilizers due to their ability to reverse amphetamine toxicity as measured by amphetamine aggregation.

Toxicity Reversal Assay (Chance, M.R.A., J. Pharmacol. Exper. Therap. 87, pp. 214-219 (1946) and Proctor, C.D., Putts, J.T., Lundy, R.O., and Greenfield, E.J., Arch. Int. Pharmacodynam., 163, (1) pp. 79-86 (1966)). In the article "aggregated mice" 5 mice per group placed in such a way as to provide 20 cm 2 of floor space per mouse. The animals are aggregated immediately after injection with amphetamine sulfate and examined for survival up to 3 hours. For example, under these conditions, an oral dose of 20 mg/kg body weight of Cb~(4-fluorobenzoyl)propyl7_4-£2-(a-phenyl-tolylDpiperidine) produces a 60% protection against an intraperitoneal dose of 15 mg per kg of amphetamine sulfate. figures show that the compounds of the invention are useful as tranquilizers when administered in amounts up to 0.1 to 50 mg/kg.

Effective amounts of the compounds according to the invention can be administered to a patient by one or another of different methods, for example orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions and in some cases intravenously in the form of sterile solutions. The final free base product which is effective in itself can be formulated and administered in the form of their pharmaceutically acceptable acid addition salts for post-crystallization stability purposes, increased solubility and the like.

The active compounds according to the invention can be administered orally, for example with an inert diluent or by a digestible carrier or they can be enclosed in gelatin capsules or they can be compressed into tablets. For the purpose of oral therapeutic administration, the active compound according to the invention can be incorporated with auxiliaries and used in the form of tablets, dragees, capsule elixirs, suspensions, syrups, biscuits, chewing gum and the like. These preparations should contain at least 0.5% active substance, but can vary depending on the particular form and can usually lie between k% to approx. 70$ of the unit's weight. The amount of active compound in such compositions is such that a suitable dose is obtained. Preferred compositions and preparations according to the invention are prepared in such a way that an oral dose unit form contains between 1.0 and 300 mg of active substance.

Tablets, pills, capsules, dragees and the like may also contain the following substances: A binding agent such as microcrystalline cellulose, gum tragacanth or gelatin, an auxiliary agent that is placed under lactose a disintegrant such as alginic acid, Primogel, granulated starch and the like, lubricant such as magnesium stearate or "Sterotex" , a lubricant such as colloidal silicon dioxide, a sweetener such as sucrose or saccharin can be added or a flavoring such as peppermint, methyl salicylate or orange flavour. When the dosage unit form is a capsule, the contents may, in addition to materials of the above type, be a liquid carrier such as a fatty oil. Other dosage unit forms may contain other different materials that modify the physical form of the dosage unit, for example as a coating. Thus, tablets or pills can be coated with sugar, shellac or other enteric coating substances. A syrup can contain, in addition to the active compounds sucrose, as a sweetener and certain preservatives, colors and dyes and flavourings. Materials used for the production of these different compositions should be pharmaceutically pure and non-toxic in the quantities used.

In case of parenteral therapeutic administration, the active compounds according to the invention can be incorporated into a solution or suspension. These preparations should contain at least 0.1% active compound, but can vary between 0.5 and approx.

50% by weight. The amount of active compounds in such preparations is

so that a is obtained. appropriate dose. Preferred compositions and preparations according to the invention are prepared so that a parenteral dose unit contains between 0.5 and 100 mg of active compound.

The solutions or suspensions may also include the following components: A sterile diluent such as water for injection, saline solution, solid oils, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents, antibacterial substances such as benzyl alcohol or methyl paraben, antioxidants such as ascorbic acid or sodium bisulphide, gelling substances such as ethylenediaminetetraacetic acid, buffers such as acetates, citrates or phosphates and substances to adjust osmotic pressure such as sodium chloride or dextrose. The parenteral preparations can be enclosed in ampoules, disposable syringes or multi-dose vials made of glass or plastic. The invention is illustrated by the following examples: 1-methyl-4-^2-(a-phenyl-3-trifluoromethyltolyl)7-4-piperidinol 1-n-butyl-4-i^2-(a-phenyl-4-chlorotolylX7-3- pyrr,olidinol, 4-£2-(a-phenyl-4-hydroxytolylX7-1,2,3,6-tetrahydropyridine, 3-acetoxy-1-(3-phenylpropyl)-3-£2-(a-phenyl- 4-ethoxytolyl7 pyrrolidine,

1-(3-phenethyl)-4-Z!2-(a-phenyl)tolyl 17-1,2,3,6-tetrahydropyridine and

4- £2-(a-phenyl-4-t"butyltolyl)-1-phenoxycarbonylpiperidine. The invention will be explained in more detail with the help of some examples and their preparation.

Example 1

To a stirred solution at -40°C and 18.5 g of 2-bromodiphenylmethane, 70 ml of tetrahydrofuran and 18 ml of anhydrous hexane are added over the course of 20 minutes. 38 ml of a 2.2 M solution of n-butyllithium in hexane. After complete addition, stirring is continued for 50 min. after which 8.84 g of 1-methyl-4-piperidone in 25 ml of tetrahydrofuran are added with stirring during 25 min. while maintaining the low temperature. After complete addition, the solution is stirred at this same temperature for 1 1/2 tin and then warmed to 0°C. The reaction solution is hydrolysed with 25 ml of water with ice water cooling. The resulting suspension is diluted by adding 200 ml of water and 500 ml of hexane. The suspension is shaken vigorously, an aqueous phase is separated and the organic phase is washed with 200 ml of water. The organic phase is filtered and the filter cake is washed well with hexane and dried. Recrystallization of the dried filter cake from toluene gives colorless crystals, mp 163-165°C of 1-methyl-4-Z2-(a-phenyltolyl)7-4-piperidinol.

Analysis:

Calculated for C^H^NO: 81.08*0, 8.25#H, 4.98#N.

Found: 80.91*C, 8.10JÉH, 4.90JÉN.

Example 2-6

By following the procedure indicated above in Example 1, reaction of 2-grom-4'-methoxydiphenylmethane and 1-methyl-4-piperidone, 2-bromo-4'-fluorodiphenylmethane and 1-methyl-4-piperidine, 2-bromo -2'-fluoro-4'-methyldiphenylmethane and 1-methyl-4-piperidone, 2-bromodiphenylmethane and 1-(2-phenethyl)-4-piperidone; and 2'-bromo-2,5-difluorodiphenylmethane and 1-methyl-4-piperidone to give 1-methyl-4-{ 2- £a-(4-methoxyphenyl) tolyl7 } 4-piperidinol, 1-methyl-4- { 2- Ca-(4-fluorophenyl)-tolyl7}-4-piperidinol, l-methyl-4-{ 2- Ca-(2-fluoro-4-methylphenyl)toly]J}-4-piperidinol, l-( 2-phenethyl-)-4-Z2-(a-phenyl)tolyl7-4-piperidinol and 1-methyl-4-{2-^a-(2,5-difluoro-phenyl)tolyl7}-4-piperidinol respectively as indicated in Table I

again as example 2-6.

Example 7

To a solution of 5.0 g of 2-bromo-2'-fluoro-4'-methyldiphenylmethane in 50 ml of tetrahydrofuran at -60°C was added dropwise 9 ml (2.4 m) of n-butyllithium. After complete addition, the solution is stirred for 30 min. and then a solution of 3.41 g of 1-benzyl-4-piperidone in 10 ml of tetrahydrofuran is added dropwise while maintaining the reaction temperature at -60°C. The reaction mixture is kept at this temperature for 30 min. and then poured into 400 ml of ice-cooled water. The resulting mixture is extracted with ether and the ether extract is dried, concentrated and the hydrochloride salt is prepared. The salt is collected by filtration and dissolved in chloroform. The chloroform solution is washed with water, dried, filtered and the chloroform evaporated leaving a white solid. The substance is recrystallized from a methanol-acetone-ether mixture for. to give the salt with m.p. 216-218°C of 1-benzyl-4-{2-£^-(2-fluoro-4-methylphenyl)tolyam}-4-piperidinol hydrochloride.

Analysis:

Calculated for C26H2gPNO-HC1: 73.31#C, 6.86#H, 3.29#H.

Found: 73.12*0,. 6.93*H, 3.06*H.

Example 8

To a solution of 5.6 g of 2'-bromo-2,5-difluorodiphenylmethane in 18 ml of tetrahydrofuran at -50°C, 14 ml of n-butyllithium is added dropwise while maintaining the temperature below -50°C. After total addition, the reaction mixture is stirred at a temperature of -60 to -70°C for 30 min. A solution of 3.5 g of 1-benzyl-3-pyrrolidone in 5 ml of tetrahydrofuran is added dropwise, the reaction mixture is stirred at this temperature for 30 min. after which ice is added and the resulting mixture is extracted twice with 200 ml portions of ether. The combined ether extracts are shaken with 120 ml of 1N hydrochloric acid which forms an oily residue. The ether and aqueous layer are carefully separated and the oily residue is made alkaline with dilute ammonium hydroxide. The basic solution is extracted with ether and the ether extract is dried. The ether solution is treated with ethereal hydrogen bromide to form a crystalline salt which is recrystallized from a methanol-ether mixture to give crystals of m.p. 203-205°C of 1-benzyl-3-{2-Za-(2,5-difluorophenyl)-tolyl 7}-3-pyrrolidinol hydrobromide. Analysis:

Calculated for C2i|H23F2NO • HBr: 62.59*0, 5.25*H, 3.04*N.

Found: 62.51*0, 5.39*H, 3.05*N.

Example 9

By following the procedure indicated in Example 8 and replacing l-benzyl-4-piperidone with l-benzyl-3-pyrrolidone,

is formed 1-benzyl-4-{ 2- Co.-( 23 5-diflyorphenyDtolylJ}-4-piperidinol • hydrobromide with m.p. 143-146°C.

Analysis:

Calculated for C25H25<F>2<N>O'HBr: 63.30*0, 5.52*H, 2.95*N, 16.84*Br. Found: 63.28*0, 5.64*H, 3.01*N, l6.82*Br. Example 10..

To a solution at -50°C of 5.6 g of 2-bromo-2'-fluoro-4'-methyldiphenylmethane in 15 ml of tetrahydrofuran, 11 ml of 2.2 M butyllithium is added dropwise while maintaining the reaction temperature below -50°C. After total addition, stirring is continued at -60 to -70°C for 30 min. and then a solution of 3.5 g of 1-benzyl-3-pyrrolidone in 5 ml of tetrahydrofuran is added over the course of 5 minutes. After total addition, stirring is continued at this low temperature for 30 min., ice is added and then the organic material is extracted twice with 200 ml portions of ether. The combined ether extracts are shaken vigorously with an excess of 1N hydrochloric acid which forms an oily residue which slowly solidifies on standing. The solid is recrystallized from a methanol-acetone-ether mixture to

give white prisms, m.p. 292-294°C of 1-benzyl-3-{2-[ct-(2-fluoro-4-methylphenyl)tolyl 17}-3-pyrrolidinol hydrochloride.

Analysis:

Calculated for C25H26FN0'HC1: 72.90*0, 6.60*H, 3.40*N, 8.60*01. Found: 72.64*0, 6.77*H, 3.35*N, 8.44*01.

Example 11

By following the procedure indicated in example 10 and replacing l-(2-phenethyl)-4-piperidone with l-benzyl-3-pyrrolidone, a white powder is formed, m.p. 262-263°C of 4-{2-Zo-(2-fluoro-4-methylphenyl)tolyl7}-1-phenethyl-4-piperidinol hydrochloride.

Analysis:

Calculated for <C>^HjgFNO-HCl: 73.70*0," 7.10*H, 3.18*N, 8.06*01. Found: 73.49*0, 7.21*H, 3 .00*N, 8.15*01.

Example 12

To a stirred solution at -50°C of 18.5 g of 2-bromodiphenylmethane, 70 ml of tetrahydrofuran and 18 ml of hexane are added over the course of 30 minutes. 40 ml of 2.2 M hexane solution of n-butyllithium. After the addition, the solution is stirred at -50°C for 30 min. and then a solution of 14.8 g of 1-benzyl-4-piperidone in 40 ml of tetrahydrofuran is added over the course of 30 minutes. After total addition, the solution is stirred at -50°C for 60 min., heated to -30°C and then mixed with 40 ml of water. The reaction mixture is diluted with 400 ml of water and 500 ml of hexane. The organic phases are separated and the organic phase is collected and washed with water. The washed organic phase is evaporated leaving an oil which is azotropically dried benzene. The oil is diluted with an equivalent volume of hexane and the hexane mixture is left at 5°C for 2 hours. The upper phase is decanted off and the hexane is washed, repeating this twice. The first lower phase is diluted with 50 ml of tetrahydrofuran, acidified with a 5* hydrochloric acid solution which forms a dark oil which separates as the upper phase. The biphasic mixture is extracted twice with 75 ml portions of chloroform and the combined extracts are washed with water and then a 5% sodium hydroxide solution. The organic solution is dried, filtered and the filtrate is evaporated to an oil which dissolves in ether and precipitates as a hydrogen chloride salt. The salt is dried in vacuum at ambient temperature and then recrystallized from acetonitrile to form slightly brown crystals, m.p. 190-191°C of 1-benzyl-4-Z2-(o-phenyltolyl)7-4-piperidinol hydrochloride.

Analysis:

Calculated for C^H^NO-HOI: 76.21*0, 7.18*H, 3.56*N, 9.00*01. Found: 76.22*0, 7.24*H, 3.47*N, 8.82*01.

Example 13

By following the procedure indicated in example 12 and using 1-benzyl-3-pyrrolidone for 1-benzyl-4-piperidone, 1-benzyl-3-[2-(a-phenyltolyl)]-3-pyrrolidinol hydrochloride is formed.

Analysis:

-Calculated for C21|H25N0«HCl: 75.86*0, 6.91*H, 3.69*N, 9.33*01. Found: 75.62*0, 6.96*H, 3.69*N, 9.15*C1.

Example 14

To a 500 ml Parr hydrogenation vessel filled with 1.0 g of a 10* palladium on charcoal catalyst and 30 ml of isopropyl alcohol under a nitrogen atmosphere is added a mixture of 5.0 g of 1-benzyl-3-£2-(α-phenyltolyl7-3 -pyrrolidinol hydrochloride, example 13, and 70 ml of isopropyl alcohol. The reaction mixture is hydrogenated at 3.5 atmospheres while heating and shaking for 30 min. After hydrogenation, the mixture is cooled to room temperature and filtered under suction. The filter cake is washed well with methanol and the methanol wash is combined with the isopropyl alcohol filtrate. combined methanol wash and the filtrate is evaporated leaving a solid which is recrystallized from isopropyl alcohol to give colorless crystals mp 211-211.5°C with cleavage of 3-Z2-(α-phenyltolyl7-3-pyrrolidinol hydrochloride).

Analysis:

Calcd for C17H^N0«HC1: 70.44*0, 6.97*H, 4.83*N, 12.23*01. Found: . ;..70.64*0, 7.09*H, 4.79*N, 12.27*01.

Example 15

Following the procedure outlined in Example 14, hydrogenation of 1-benzyl-4-Z2-(α-phenyltolyl7-4-piperidinol hydrochloride, Example 12) will give 4-β2-(α-phenyltolyl)7-4-piperidinol hydrochloride which is recrystallized from isopropyl alcohol on cooling to give the salt as colorless crystals, mp 226-227°C with cleavage.

Analysis:

Calculated for C2H2NO-HCl: 71.15*0, 7.31*H, 4.6l*N, 11.67*01. Found: 71.24*0, 7.43*H, 4.42*N, 11.53*01. Example 16. To a solution of 2.0 g of 1-(2-phenethyl)-4-£2-(a-phenyl-tolyl)7-4-piperidinol, Example 5, in 30 ml of tetrahydrofuran at -60°C is added dropwise a solution of 2.8 ml of 2.4 mol n-butyllithium in hexane. After addition, the reaction mixture is stirred for 15 min. while maintaining the reduced temperature and then 1 ml of benzoyl chloride is added dropwise. The reaction mixture is stirred at ambient temperature for 16 hours and then diluted with 40 ml of tetrahydrofuran and 10 ml of water. The biphasic mixture is separated and the organic phase is washed successively with 10 ml of 5* sodium hydroxide solution and 10 ml of water, treated with a small excess of ethereal hydrogen chloride and then the solvent is evaporated. The oily residue is azeotropically dried with benzene and the solid is triturated with cold acetone, dissolved in chloroform and precipitated by gradual dilution with ether. The precipitate is dried to a colorless solid, m.p. 198-203°C of 4-benzoyloxy-1-(2-phenethyl)-4-Z"2-(α-phenyltolyl)7-piperidine hydrochloride.

Analysis:

Calculated for C^H^NO^HCl: 77.38#C, 6.71*H, 2.74#N.

Found: 77.39#C, 6.90#H, 2.62#N.

Example 17

A solution of 10.3 g of 1-benzyl-4-£2-(α-phenyltolyl)7-4-piperidinol hydrochloride, Example 112, in 70 ml of chloroform is washed twice with 50 ml portions of 5% sodium hydroxide solution, dried and the chloroform is evaporated to give the free base as an oil. The oil is dissolved in 10 ml of ether and treated carefully with 30 ml of acetyl chloride. The resulting suspension is diluted with 30 ml of ether and stirred for 16 hours at ambient temperature. The precipitate is collected by filtration and washed well with ether and dried and then recrystallized from isopropyl alcohol to give colorless crystals, m.p. 193-194°C of 4-acetoxy-1-benzyl-4-[2-(a-phenyltolyl)piperidine hydrochloride.

Analysis:

Calculated for C^H^NOg-HCl: 74.3#C, 6.95f»H, 3.21*N, 8.13*01. Found: 74.19#C, 6.99$H, 3.14#N, 8.28*C1. Example 18

1.41 g of 1-methyl-4-£2-(α-phenyltolyl7-4-piperidinol, Example 1) is treated with 4.0 ml of acetyl chloride with cooling and stirring. The resulting suspension is stirred at room temperature under nitrogen for 1 hour and allowed to stand then for 94 hours.The mixture is diluted with 10 ml of ether and filtered.

The filter cake is washed with ether and then recrystallized from absolute ethanol to give colorless crystals, m.p. 205-206°C of 4-acetoxy-1-methyl-4-[2-(a-phenyltolyl)]piperidine hydrochloride. Example 19

2.0 g of 1-methyl-4-Z<*>2-(α-phenyltolyl)J-4-piperidinol, free base according to example 1, is treated with 8.15 ml of cyclopropanecarboxylic acid chloride while stirring and cooling. The resulting suspension is stirred for 16 hours at room temperature and then diluted with 25 ml of ether and allowed to stand for 144 hours. The precipitate is collected by filtration under suction and the filter cake is washed with ether, dried in vacuum at 40°C for 16 hours leaving colorless crystals which are recrystallized twice from isopropyl alcohol to give colorless crystals of m.p. 198-200°C of 4-cyclopropylcarbonyloxy-1-methyl-4-[2-(a-phenyltolyl]piperidine hydrochloride).

Analysis:

Calculated for C^H^NO^HCl: 71.57#C,'7.33#H, 3.63#N, 9.18*Cl. Found: 71.3W, 7.50$H, 3.43#N, 9.02*C1. Example 20 2.0 g of 1-methyl-4-[2-(a-phenyltolyl)]-4-piperidinol, Example 1, is treated with 10 ml of benzoyl chloride while stirring and cooling. The reaction solution is diluted with 20 ml of ether and stirred for 2 hours and the resulting precipitate is collected by filtration under suction. The filter cake is washed well with ether and dried in vacuum at 40°C over sodium hydroxide pellets. The dried filter cake is recrystallized twice from a chloroform-ether mixture to give colorless crystals, m.p. 197-198°C of 4-benzoyloxy-1-methyl-4-[2-(a-phenyltolyl)]-piperidine hydrochloride. Analysis: Calculated for C2gH27N02•HC1: 74.00$C, 6.70$H, 3.32*N, 8.40$C1. Found: 74.04$C,• 6.76ZH,.3.36$N, 8.66$C1.

Example 21

2.0 g of 1-methyl-4-r2-(α-phenyltolyl)7-4-piperidinol, Example 1, is treated with 10 g of cyclobutanecarbonyl chloride while stirring and cooling. The reaction mixture is stirred for 48 hours at room temperature, diluted with 15 ml of ether and then stirred for 2 hours. The resulting precipitate is collected by filtration under suction, the filter cake is washed well with ether and dried in a vacuum over sodium hydroxide pellets. The filter cake is recrystallized twice from an acetone-ether mixture to give colorless crystals, m.p. 194.5-195°C of 4-cyclobutylcarbonyloxy-1-methyl-h-2-(α-phenyltolyl-7piperidine hydrochloride).

Analysis:

Calculated for C211H2gN02•HC1: 72.24#C, 7.34#H, 3.51*H, 8, 885ÉC1. Found: 72.02#C, 7.57#H, 3.4l#H, 8.83*C1. Example 22

1.41 g of 1-methyl-4-£2-(α-phenyltolyl)7-4-piperidinol, Example 1, is treated with 5.0 ml of propionyl chloride while stirring and cooling. The reaction mixture, at room temperature, is stirred for 30 min. and then left for 137 hours under nitrogen. The mixture is diluted with 5.0 ml of ether, stirred for 5 min. and the resulting precipitate is collected by filtration under suction. The filter cake is washed well with ether and recrystallized twice from isopropyl alcohol to give colorless crystals, m.p. 191-193C

of 1-methyl-4-£2-(α-phenyltolyl)7-4-propionyloxypiperidine hydrochloride.

Analysis:

Calculated for C22H27N02'HC1::-70, 65*C,: 7.56*H, 3.75#N, 9.48*01. Found: 70.55*C, 7.65*H, 3.74*N, 9.57*01.

Example 23

A solution of 1.49 g of 1-methyl-4-Z2-(ct-phenyltolyl)7-4-piperidinol, 4.5 ml of valeryl chloride and 30 ml of chloroform is stirred for 16 hours at room temperature. The solution is made basic with a 5* sodium hydroxide solution and the basic solution is stirred overnight at room temperature. The biphasic mixture is separated and the organic part is washed with water, dried and the solvent is evaporated leaving an oil. The oil is dissolved in absolute ethanol and transferred to an oxalate salt. The solvent is evaporated, the residue is dried in vacuum for 7 days at 40°C. The dried product is recrystallized from absolute ethanol to give colorless crystals, m.p. 194-196°C of 1-methyl-4-Z2-(α-phenyltolyl)7-4-valeryloxypiperidine oxalate.

Analysis:

Calculated for C24H31N02 * C2H2°4: 68»55*C, 7.30*H, 3.08*N.

Found: 68.29*0, 7.16*H, 3.07*N. Example 24

1.5 g of 1-methyl-4-{2-Za-(2-fluoro-4-methylphenyl)tolyl7}-4-piperidinol, Example 4, is carefully treated with 7 ml of benzoyl chloride while stirring and cooling. The reaction mixture is stirred for 16 hours at room temperature and then diluted with 15 ml of ether. The formed precipitate is filtered, washed with ether

and transferred to free base which is column chromatographed on aluminum oxide using ether as eluent. The free base is transferred to the hydrogen chloride salt which is recrystallized from a methanol-acetone-ether mixture to give a white powder, m.p. 218-219°C of 4-benzoyloxy-4-{2-phy-(2-fluoro-4-methylphenyl)tolyl 7}-1-methylpiperidine hydrochloride. Analysis:.

Calcd for'C^HggFNO^HCl:' 71.WC, 6.44*H, 3.09*.N.... Found: 71.08*0, 6.55*H, 2.88*N.

Example 25

By following the procedure according to example 24, 1.97 g of 1-methyl-4-{2-(3-(2-fluoro-4-methylphenyl)tolyl 7}-4-piperidinol, example 4, is treated with 6, 3 ml of propionyl chloride to form 4-{2-fix-(2-fluoro-4-methylphenyl)tolyl7}-4-propionyloxy-1-methylpiperidine hydrochloride which is recrystallized from an acetone-ether mixture to form a product which has a melting point of 183-186°C.

Analysis:

Calculated for C23H2gFN02•HC1: 68.04*0, 7.20*H, 3.45*N, 8.74*01. Found: 67.89*0, 7.27*H, 3.42*N, 8.87*01.

Example 26

A suspension of 5.0 g of 3-£2-(α-phenyltolyl17-3-pyrrolidinol hydrochloride, Example 14) in 40 ml of methanol is diluted with water until a solution is formed. The solution is treated with an excess of a 5* sodium hydroxide solution and then methanol is removed on a rotary evaporator leaving a suspension. The suspension is diluted with 50 ml of water and extracted successively with 100 ml and 20 ml portions of chloroform. The combined chloroform extracts are washed once with 50 ml of

a 5* sodium hydroxide solution and twice with 50 ml portions of water and dried and the chloroform removed. The residue is subjected to azeotropic distillation with benzene and then dried in vacuum at 40°C for 2 hours before being suspended in 30 ml of heated chloroform containing 2.2 g of triethylamine. 2.60 g of benzoyl chloride are added dropwise to this suspension. After total addition, the solution is stirred for 2 hours and then allowed to stand for 48 hours. The solution is diluted with 30 ml of chloroform, washed successively with 50 ml of water and an equal amount of a 5* sodium hydroxide and dried and the solution is removed leaving a tenacious foam. The foam is dissolved in 60 ml of ether (heating may be necessary) and the solution is filtered through glass wool. A precipitate forms as is collected by filtration under suction and dried in vacuum at room temperature and leaves a colorless solid, m.p. 113-116°C of 1-benzoyl-3-β2-(α-phenyltolyl)7-3-pyrrolidinol.

Analysis:

Calculated for C2i|H2 N0'2 : ■ 80, 63*0, 6, 50*H, 3.92*N.

Found: 80.51*0, 6.62*H, 3.80*N.

Example 27

A solution of 8.0 g of 1-methyl-4-£2-(α-phenyltolyl7-4-piperidinol, example 1) in 100 ml of 97% formic acid is refluxed with stirring for 16 hours. The solution is poured into 300 ml of water which is made strongly basic with 50* sodium hydroxide solution and the basic mixture is extracted three times with 100 ml portions of chloroform. The combined chloroform extracts are dried and the chloroform removed leaving an oil. The oil is dissolved in 20 ml of dimethylsulfoxide. The solution is diluted with 250 ml of water leaving a cream solid which is recrystallized from dimethylsulfoxide to give colorless crystals, mp 55-57°C of 1-methyl-4-[2-(a-phenyltolyl)J-1,2,3,6-tetrahydropyridine.

Analysis:

Calculated for C^H^N: 86, 63*0, 8.05*H.

Found: 86.75*0, 8.29*H.

Example 28

A suspension of 3.0 g of 4-Z2-(α-phenyltolyl)7-4-piperidinol hydrochloride, example 15 in 25 ml of glacial acetic acid and 5 ml of concentrated hydrochloric acid is refluxed with stirring for 60 min. The solution is cooled and then diluted with 100 ml of water and made basic with 50* sodium hydroxide solution. The alkaline solution is extracted 3 times with 30 ml portions of chloroform and the combined chloroform extracts are dried and the chloroform is removed leaving an oil which crystallizes on standing. The crystals are recrystallized from hexane leaving a cream colored crystal with m.p. 73-75°C of 4-Z2-(α-phenyltolyl)7-1,-2,3,6-tetrahydropyridine.

Analysis:

Calculated for Cl8H19N: 86.69*0, 7.70*H.

Found: 86.72*0, 7.85*H.

Example 29

Following the procedure set forth in Example 28, 2.86 g of 1-(2-phenethyl)-4-£2-(α-phenyltolyl)7-4-piperidinol, Example 5, is dehydrated and treated to obtain colorless crystals of m.p. . 98-100°C of 1-(2-phenethyl)-4-Z"2-(a-phenyl-tolyl)7-1,2,3,6-tetrahydropyridine.

Analysis:

Calculated for C^H^N:' 88, 32*0, 7.71*H, 3.96*N.

Found: 88.55*0, 7.79*H, 3.93*N.

Example 30

A mixture of 5.0 g of 1-methyl-4-{2-Co.-(4-methoxyphenyl tolyl)J7_4-piperidinol, Example 2, 30 ml of glacial acetic acid and 6 ml of concentrated hydrochloric acid is refluxed with stirring for 2 hours and then set aside 48 hours at room temperature. The reaction mixture is poured into ice water and then made basic with 50* sodium hydroxide solution. The basic solution is extracted twice with 200 ml of chloroform each time and the combined chloroform extracts are dried, filtered and the chloroform removed under partial vacuum leaving an oil. The oil is dissolved in ether and the hydrogen bromide salt is precipitated. The precipitate is collected by filtration under suction and dried in a vacuum at 40°C. The dried precipitate is recrystallized from isopropyl alcohol to give colorless crystals, m.p. 149-152°C of 1-methyl-4-{2-Ca-(4-methoxyphenyl)tolyl 7}-1,2,3,6-tetrahydropyridine hydrobromide.

Analysis:

Calculated for O^qH^NO ' HBr: 64.17*0, 6.46*H, 21.35*Br.

Found: 64.09*0, 6.51*H, 20.98*Br.

Example 31 & 32

By following the procedure indicated in Example 30, 2.30 g of 4-{2-Æ-(4-fluorophenyl)tolyl}-1-methyl-4-piperidinol, Example 3 and 3.5 g of 1-benzyl-4- 2-(α-phenyltolyl)-7-4-piperidinol hydrochloride, Example 12, dehydrated and treated to give 4-{2-Æ-(4-fluorophenyl)tolyl)}-1-methyl-1,2,3,6- tetrahydropyridine hydrobromide and 1-benzyl-4-Cl-(α-phenylethyl 1 )J-1,2,3j6-tetrahydropyridine hydrochloride respectively as indicated in Table 2 indicated as examples 31 and 32.

Example 33

A suspension of 0.70 g of platinum oxide (Adam's catalyst) in 50 ml of 95* ethanol is hydrogenated on a Parr shaker at 3.5 atmospheres for 3 hours at room temperature. To this hydrogenated suspension is added a solution of 2.4 g of 1-methyl-

4-£2-(α-phenyltolyl)-7-lj 2, 3, 6-tetrahydropyridine, Example 27,

in 50 ml of 95* ethanol and the resulting mixture is similarly hydrogenated overnight. The mixture is filtered and the filtrate is evaporated to a colorless oil which is taken up in ether. The ethereal solution is filtered, the filtrate is treated with ethereal hydrogen chloride which causes a hydrogen chloride salt to precipitate. The salt is collected by filtration under suction and recrystallized twice from isopropyl alcohol to give colorless crystals, m.p. 220.5-222.5°C of 1-methyl-4-[2-(a-phenyl-tolylpiperidine hydrochloride).

Analysis:

Calculated for C-^Hg-jN-HOI: 75.59*0, 8.03*H, 11.74*01.

Found: 75.40*0, 8.08*H, 11.57*01.

Example 34

A suspension of 0.3 g of platinum oxide and 10 ml of absolute ethanol is hydrogenated in a Parr apparatus at room temperature at a pressure of 1.5 atmospheres for 15 min. A solution of 3.1 g of 1-phenethyl-4-[2-(a-phenyl-tolyl)-1,2,3,6-tetrahydropyridine, example 29, in 100 ml of absolute ethanol is added to the hydrogenated suspension. The reaction suspension is hydrogenated in a similar manner for 48 hours. The suspension is filtered and the filtrate is treated with anhydrous hydrogen bromide. The filtrate is concentrated on a rotary evaporator and leaves an oil which becomes solid on standing. The solid is recrystallized from 150 ml of hot absolute ethanol followed by gradual dilution with 350 ml of ether to give colorless crystals, m.p. 220-225°C of 1-phenethyl-4-(α-phenyltolyl)β-piperidine hydrobromide.

Analysis:

Calculated for C^gH^N • HBr: 71, 55*0, 6, 93*H, 3.21*N.

Found: 71.54*0, 7.H*H, 3.12*N..

Example 35

A suspension of 0.5 g of platinum oxide and 25 ml of 95* ethanol is hydrogenated at 2.8 atmospheres for 30 min. at room temperature. To the hydrogenated suspension is added a solution of 2.5 g of 4/~2-(α-phenyltolyl).7-1,2,3,6-tetrahydropyridine, example 28, in 25 ml of 95% ethanol and the reaction suspension is hydrogenated in a similar manner for 24 hours." The hydrogenated suspension is filtered under suction and the filtrate is evaporated to a colorless oil. Hydrogenation is repeated on this oil. The oil formed after another hydrogenation is transferred to the hydrochloride salt. The salt is subjected to hydrogenation using 400 mg of platinum oxide at 3 .5 atmosphere. The salt was then recrystallized from 30 mL of isopropyl alcohol leaving colorless crystals mp 207.5-209.5°C of 4-Z~2-(α-phenyltolyl)7-piperidine hydrochloride.

Analysis:

Calculated for C<l8>H21N-HCl: 75.10*0, 7.72*H, 4.87*N.

Found: 75.13*0, 7.71*H, 4.80*N.

Example 36

A mixture of 36.6 g of 4-{2-α-(4-methoxyphenyl)tolyl 7 }-1-methyl-1,2,3,6-tetrahydropyridine hydrobromide, Example 30,

153 ml of absolute methanol and 1.5 g of platinum oxide are hydrogenated at 3.5 atmospheres at room temperature for 48 hours. The suspension is filtered under suction, while it is still warm, through a sintered glass Biachner funnel and the filter cake is washed with several portions of hot chloroform. The filtrate and washing liquid combine

res and then the solvent is removed leaving a solid which is dried in vacuo at 40°C for 16 hours. The solid is recrystallized from chloroform and the first five bodies are dried in an Abderhalden gun over xylene for 32 hours, leaving colorless crystals, m.p. 182-185°C of 4-{2-Ex-4-methoxyphenyl)-tolyl 7}-1-methylpiperidine hydrobromide.

Analysis:

Calculated for C^H^NO • HBr: 63.83*0, 6.96*H, 3.72*N.

Found: 63.97*0, 7.06*H, 3.87*N.

Example 37

A solution of 24.9 g of 1-methyl-4-Z~2-(α-phenyltolyl)7 piperidine hydrochloride, Example 33, in 100 ml of methylene chloride is washed twice with 50 ml portions of a 5% sodium hydroxide solution. The methylene chloride solution is dried and filtered and then a solution of 14.1 g of phenylchloroformate X 100 ml of methylene chloride is added dropwise with stirring over the course of 40 minutes. The solution is stirred for 16 hours and then the solvent is evaporated leaving a solid residue. The residue is suspended in ether and combined by filtration under suction. The filter cake is washed with ether and dried in vacuum at 40°C over sodium hydroxide pellets. The dried filter cake is recrystallized from isopropyl alcohol, leaving colorless crystals, m.p. 120-122°'

of 4-/f2- (a-f enyltolyl ) J-l-f enoxycarbonyl lpiperldine.

Analysis:

Calculated for C^H^NCy 80.82*C, 6.80*H, 3.77*N.

Found: 80.99*0, 6.80*H, 3.69*N.

Example 38

A mixture of 36.6 g of 4-{2-[α-(4-methoxyphenyl)tolyl}-1-methyl-1,2,3,6-tetrahydropyridine hydrobromide, Example 30,

153 ml of absolute methanol and 1.5 g of platinum oxide are hydrogenated

at 3.5 atmospheres at room temperature for 48 hours. The suspension is filtered under suction hot through a sintered glass Buchner funnel and the filter cake is washed with several portions of hot chloroform. The filtrate and washing liquid are combined and concentrated

raised to dryness leaving a solid which is vacuum dried at 40°C for 16 hours. The solid is recrystallized from 450 ml of chloroform. The first 5 parts are combined and dried in an Abderhalden gun over xylene for 32 hours leaving colorless crystals, m.p. 182-185°C of 4-{2-alpha-(4-methoxyphenyl)tolyl)}-1-methylpiperidine hydrobromide.

Analysis:

Calculated for C2QH25NO•HBr: 63.83*C, 6.96*H, 3.72*N.

Found: 63.97*C, 7.06*H, 3.87*N.

Example 39

A mixture of 6.89 g of 4-{2-α-(4-methoxyphenyl)7-tolyl}-1-methylpiperidine, free base from Example 38, 85 ml of methylene chloride and 4.0 g of phenylchloroformate is stirred for 16 hours. The solvent is then removed on a rotary evaporator and the residue is azeotropically distilled with benzene. The solid residue is dried in vacuum at 40°C and recrystallized from absolute ethanol, leaving colorless crystals with m.p. 116-118°C of 4-{2-α-(4-methoxyphenyl)-tolyl 7}-1-phenoxy-carbonylpiperidine.

Analysis:

Calculated for C^H^NCy 77.77*C, 6.79*H, 3.49*N.

Found: 77.85*C, 6.83*H, 3.46*N.

Example 40

A stirred suspension of 4.0 g of 4-{2-Ca-(4-methoxyphenyl)-tolyl7}-1-phenoxycarbonylpiperidine, Example 39, 110 ml of ethylene glycol and 14 ml of a solution prepared from 20 g of potassium hydroxide pellets in 22 ml water is heated to reflux and then cooled to room temperature followed by ice bath cooling to form a precipitate. The precipitate is collected by filtration and dissolved in 100 ml of chloroform. The solution is washed with water, dried and filtered and the filtrate is treated with an excess of hydrogen chloride gas. The solvent is removed on a rotary evaporator and the residue is dried in vacuo at 40°C leaving a solid which is recrystallized from ethanol to give colorless crystals of m.p. 246-248°C of 4-{2-[alpha-(f-methoxyphenyl)tolyl)}piperidine

hydrochloride.

Analysis:

Calculated for C^H^NO • HC1: 71.79*0, 7.6l*H, 4.4l*N.

Found: 72.00*0, 7.75*H, 4.51*N.

Example 4l

A solution of 5.37 g of 4-[2-(α-phenyltolyl)-7-piperidine hydrochloride, Example 35, in 50 ml of chloroform is washed with an excess of 5* sodium hydroxide solution and dried and the solvent removed leaving a viscous oil. The oil is dissolved in 10 ml of benzene and added dropwise while stirring in an ice water bath to a solution of 2.28 g of benzoyl peroxide in 75 ml of benzene. After complete addition, the reaction solution is stirred with ice water cooling for 10 min. and 2.5 hours at room temperature. The solution is concentrated on a rotary evaporator at 40°C, leaving an oil which is dissolved in 95% ethanol. The ethanolic solution is maintained at 5°C for 48 hours with stirring. After this time, a crystalline precipitate appears which is collected by filtration under suction, washed with 95% ethanol and dried in a vacuum at 40°C. The dried product is recrystallized from 95% ethanol, leaving cream-colored crystals with m.p. 102-103°C of 1-benzoyloxy-4-Z2-(α-phenyltolyl)J7piperidine.

Analysis:

Calculated for C25_25N02: 8o>82^c>6.80*H, 3.77*N.

Found: 80.74*0, 6.86*H, 3.75*N.

Example 42

A suspension of 2.63 g of 1-benzoyloxy-4-[2-(a-phenyl-tolyl)-7-piperidine, 25 ml of absolute ethanol and 20 ml of a 10% sodium hydroxide solution is heated on a water bath at 100°C

for 40 min. After this time, the suspension is cooled to room temperature, stirred at room temperature for 1.5 hours and then concentrated on a rotary evaporator to 1/3 of the

original volume. The reaction solution is diluted with 50 ml of water and the pH is adjusted to 6.0 with 5* hydrochloric acid, leaving a suspension which is extracted twice, each time with 50 ml of chloroform. The combined extracts are dried and the solvent removed leaving a solid residue which is recrystallized from 95% ethanol to leave colorless crystals, m.p. 142-147°C of 1-hydroxy-4-Z"2-(a-phenyltolyl)7piperidine. Analysis:

Calculated for Cl8H21NO: 80.85*0, 7.93*H, 5.24*N.

80, 79350', 8.04*H, 5.07*N.

Example 43

A stirred mixture of 6 g of 1-methyl-4-{ 2-Ca-(4-methoxyphenyl)tolyl \~ J } piperidine hydrobromide, Example 38, and 9.6 ml of 48* hydrobromide solution is immersed in an oil bath (140°C ) for 30 min. The hot solution is poured into cold water and 174 ml of concentrated ammonium hydroxide is added to form a precipitate. The precipitate is collected by filtration and the filter cake is dried overnight in vacuum at room temperature. The dried precipitate is recrystallized from absolute ethanol to leave a bright red crystalline solid with m.p. 229-232°C of 4-{2-Ca-(4-hydroxy-■phenyl)tolyl}-1-methylpiperidine.

Analysis:

Calculated for C-^H^NO: 81.11*0, 8.31*H, 4.95*N, 5.4l*0. Found: 81.10*0, 8.24*H, 4.98*N, 5.69*0.

Example 4 4

To a stirred refluxing suspension of 5.76 g of 4-Z2-(α-phenyl)-tolyl-7-piperidine hydrochloride, Example 35,

18.0 g of potassium carbonate and 70 ml of n-butyl alcohol are added dropwise to 8.70 g of 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane. After total addition, the reaction mixture is refluxed with stirring for 16 hours, filtered and then the filtrate is concentrated to dryness leaving an oil which is dissolved in 75 ml of ether. The ether solution is filtered and the filtrate is treated with ethereal hydrogen chloride. An oil separates out as the lower phase, which is washed twice with portions of ether and then dissolved in chloroform. The chloroform solution is evaporated to dryness and leaves a tough foam which is again dissolved in 15 ml of chloroform and this solution is diluted to the point of clarity with ether. The mixture is stirred until a thick suspension is formed which

dilute with 20 ml of ether. A precipitate appears which is collected by filtration under suction. The filter cake is washed well with ether followed by recrystallization from isopropyl alcohol which gives colorless crystals of m.p. 185-187°C of 1-Z3~(4-fluorobenzoyl)propyl7-4-£2-(a-phenyltolyl_7piperidine ethylene ketal hydrochloride .-

Analysis:

Calculated for C^H^FNC^ • HC1: 72.63*0, 7.13*H, 2.82*N.

Found: 72.62*0, 7.20*H, 2.79*N.

Example 45

A stirred solution of 330 g of 1-C$-(4-fluorobenzoyl)propyl 17-4-£2-(α-phenyltolyl)Jpiperidine ethylene ketal hydrochloride, Example 44, 100 ml of methanol and 50 ml of concentrated hydrochloric acid is refluxed for 2 hours. The hot solution is poured onto ice and the reaction mixture is made alkaline with 50% sodium hydroxide solution and the basic mixture is extracted three times, each time with 100 ml of chloroform. The combined extracts are dried, the solvent evaporated leaving an oil. The oil is taken up in 5 ml of hexane and stirring the hexane solution causes a thick suspension of crystalline solid which is collected by filtration. The solid is recrystallized from acetonitrile to give colorless crystals, m.p. 100-101.5°C of 1-β3-(4-fluorobenzoyl)propyl 17-4-β2-(α-phenyltolyl)-7piperidine.

Analysis:

Calculated for C^H-^FNO: 80.92*0, 7329*H, 4.57*F, 3.37*N. Found: 8l.07*C, 7.37*H, 4.72*F, 3>32*N.

Example 46

A solution of 1.4 g of 4-{-2-[ct-(2-fluoro-4-methylphenyl)tolyl-7-phenyl}-1-phenethyl-4-piperidinol, Example 11, in 30 ml of tetrahydrofuran is cooled to -60°C . 1.5 ml of n-butyllithium is added to the cooled solution and the resulting solution is stirred for 15 min. 0.3 ml of propionyl chloride is added dropwise to this solution at this low temperature and after the addition the solution is allowed to reach room temperature. The solution is stirred at room temperature for 24 hours. The solution is diluted with water and extracted with chloroform. The chloroform extract is dried and filtered and the chloroform is evaporated leaving a white powder. The powder is recrystallized from a methanol-acetone-ether mixture to give the product with m.p. 195-197°C of 4-{2-Ca-(2-fluoro-4-methylphenyl)tolyl}-4-propionyloxy-1-phenethylpiperidine hydrochloride.

Analysis:

Calculated for C^qH-^FNC^ • HC1: . 72, 63*C, 7.H*H, 2.82*N.

Found: 73.08*C, 7.35*H, 2.65*N.

Example 47

A mixture of 3 g of 4-{2-£a-(4-methoxyphenyl)tolyl7}piperidine hydrochloride, example 40, and 48 ml of 48* HBr is refluxed on an oil bath (157°C) with stirring for 32 min, of - cooled and then poured into 48 ml of chilled water. The resulting suspension is mixed with 48 ml of concentrated ammonium hydroxide and stirred and the solid is collected by filtration under suction. The filter cake is dried in a vacuum at 40°C over sodium hydroxide pellets and then dissolved in 500 ml of hot absolute ethanol. 32 ml of triethylamine is added to the hot ethanolic solution. The warm solution is diluted with chloroform and then washed twice with water. The organic phase is collected, dried and filtered and then the solvent is evaporated leaving a solid product which is recrystallized from absolute ethanol in the presence of activated charcoal to give yellowish crystals of m.p. 217-221°C of 4-{2-[alpha]-(4-hydroxyphenyl)tolyl 7 }piperidine. Analysis:

Calculated for C^gH^NO: 80, 86*C, 7.92*H, 5.24*N.

Found: 80.75*C, 7.89*H, 4.10*N.

Example 48

A mixture of 4 g of 4-{2-ZTa-(4-fluorophenyl)tolyl7}-1-methyl-1,2,3,6-tetrahydropyridine hydrobromide, Example 31,

0.3 g of platinum oxide and 150 ml of methanol are hydrogenated at 3.5 atmospheres at room temperature for 48 hours. The suspension is then filtered under suction and the filtrate is evaporated under reduced pressure. The solid residue is collected and vacuum dried at 40°C and then recrystallized from isopropanol to give colorless crystals, m.p. 183-186°C of 4-{2-Ca-(4-fluorophenyl)tolyl 7}-1-methylpiperidine hydrobromide.

Analysis:

Calculated for'Cl9H22FN•HBr: 62.66*C, 6.36*H, 3.85*N, 5.22*F. Found: 62.8l*C, 6.39*H, 3.94*N, 5.06*F.

Example 49

A mixture of 28.6 g of 4-{2-Zo-(4-fluorophenyl)tolyl}-1-methylpiperidine, free base from Example 48, 85 ml of methylene chloride and 1732 g of phenylchloroformate is stirred for 16 hours at room temperature followed by distillation of the solvent on

rotary evaporator and azeotropic distillation of the residue with

benzene. The resulting oil solidified by trituration with ether. The solid is recrystallized from absolute ethanol to give colorless crystals, m.p. 107-H0°C of 4-{2-α-(4-fluorophenyl)tolyl}-1-phenoxycarbonylpiperidine.

Analysis:

Calculated for C^H^FNO: 77.10*0, 6.21*H, 3.60*N.

Found: 77.00*0, 6.18*H, 3.59*N.

Example 50

A mixture of 500 ml of ethylene glycol, a solution of 60 g of potassium hydroxide in 66 ml of water and 16.6. g 4-{ 2-Zot-(4-fluorophenyl)-tolyl }-1-phenoxycarbonylpiperidine, example 49, Heat gradually to 200°C with constant stirring and reflux. The mixture is then cooled, filled with nitrogen and allowed to stand in 48 hours. The mixture is filtered under suction and the filter cake is dissolved in chloroform. Water is added to the chloroform solution and extracted with ether. The combined extracts are dried, filtered and then treated with gaseous hydrobromic acid. The solution is evaporated under reduced pressure to give a solid which is recrystallized twice from isopropanol to give colorless crystals of m.p. 227-231°C of 4-{2-Zct-(4-fluorophenyl)tolyl7}piperidine hydrobromide.

Analysis:

Calculated for Cl8H20FN•HBr: 6l.72*C, 6.04*H, 4.00*N, 5.42*F. Found: 6l.95*C, 53 88*H, 3>99*N, 5.43f»F.

Claims (26)

1. Compound of formula I Wherein X is C-R <4> or C, Y is ~ (CH2 ) - when X is CR <4> and =CH-(CH ) - when X is C, R is hydrogen, lower alkyl, - phenyl-. lower alkyl with formula hydroxy, benzoyl lower alkyl of formula cycloalkyl lower alkyl cycloalkyl lower alkyl in which the cycloalkyl part contains from 2 to 6 carbon atoms, alkoxycarbonyl with from 2 to 6 carbon atoms, phenyloxycarbonyl, benzoyl, benzoyloxy or R , R and R are the same or different and can be hydrogen, halogen, alkoxy with from 1 to 2 carbon atoms, lower alkyl, hydroxy or trifluoromethyl, R l) is hydrogen or OR , R is hydrogen, lower alkyl, benzoyl or cycloalkanoyl in which the cycloalkyl ring contains from 3 to 6 carbon atoms, m means an integer 1 or 2, n means an integer 1, 2 or 33 the sum of m and n is 3 or 4, p is an integer 1, 2, 3 or 4 and pharmaceutically acceptable acid addition salts thereof . 2. Compound according to claim 1, characterized in that it is 1-methyl-4-α2-(α-phenyltolyl)7-4-piperidinol and a pharmaceutically acceptable acid addition salt thereof. 3. Compound according to claim 1, characterized in that it is 3-2-(α-phenyltoyl)7-3-pyrrolidinol and a pharmaceutically acceptable acid addition salt thereof. 4. Compound according to claim 1, characterized in that it is 4-[2-(a-phenyltolyl)]7-4-piperidinol and a pharmaceutically acceptable acid addition salt thereof. 5. Compound according to claim 1, characterized in that it is 4-acetoxy-1-methyl-4-[2-(a-phenyltolyl)]piperidine hydrochloride and a pharmaceutically acceptable acid addition salt thereof. 6. Compound according to claim 1, characterized in that it is 1-methyl-4-β2-(α-phenyltolyl X7-4-propionyl-oxypiperidine and a pharmaceutically acceptable acid addition salt thereof). 7. Compound according to claim 1, characterized in that it is 4-{2-Ca-(2-fluoro-4-methylphenyl)tolyl 17 }-4-propionyloxy-1-methylpiperidine and a pharmaceutically acceptable acid addition salt thereof. 8. Compound according to claim 1, characterized in that it is 1-methyl-4-α2-(α-phenyltolyl)7-1,2,3,6-tetrahydropyridine and a pharmaceutically acceptable acid addition salt thereof. 9. Compound according to claim 1, characterized in that it is 1-methyl 1-4-{-2-Ca-(4-methoxy eny 1) toly 17 }-4-piperidinol and a pharmaceutically acceptable acid addition salt thereof. 10. Compound according to claim 1, characterized in that it is 1-methyl-4-{2-Ca-(4-fluorophenyl)tolyl7}-4-piperidinol and a pharmaceutically acceptable acid addition salt thereof. 11. A compound according to claim 1, characterized in that it is 1-methyl-4-{2-Ca-(2-fluoro-4-methylphenyl)tolyl}-4-piperidinol and a pharmaceutically acceptable acid addition salt thereof. 12. Compound according to claim 1, characterized in that it is 1-methyl-4-{2-Ca-(2,5-difluorophenyl)tolyl7}-4-piperidinol and a pharmaceutically acceptable acid addition salt thereof. 13. Compound according to claim 1, characterized in that it is 4-α2-(α-phenyltolyl)7-1,2,3,6-tetrahydropyridine and a pharmaceutically acceptable acid addition salt thereof. 14. Compound according to claim 1, characterized in that it is 4-{2-Ca-(4-fluorophenyl)tolyl7}-1-methyl-1,2,3,6-tetrahydropyridine and a pharmaceutically acceptable acid addition salt thereof. 15. Compound according to claim 1, characterized in that it is 1-methyl-4-[2-(a-phenyltolyl)]-piperidine and a pharmaceutically acceptable acid addition salt thereof. 16. A compound according to claim 1, characterized in that it is 4-β2-(α-phenyltolyl)β-piperidine and a pharmaceutically acceptable acid addition salt thereof. 17. Compound according to claim 1, characterized in that it is 4-{2-α-(4-methoxyphenyl)tolyl 7}-1-methylpiperidine and a pharmaceutically acceptable acid addition salt thereof. 18. Compound according to claim 1, characterized in that it is 4-{2-Za-.(4-methoxyphenyl)tolyl7}piperidine and a pharmaceutically acceptable acid addition salt thereof. 19. Compound according to claim 1, characterized in that it is 1-hydroxy-4-β2-(α-phenyltolyl.17piperidine) and a pharmaceutically acceptable acid addition salt thereof. 20. Compound according to claim 1, character e,rise r.t in that it is 4-{2-α-(4-hydroxyphenyl)tolyl7}piperidine and a pharmaceutically acceptable acid addition salt thereof. 21. Compound according to claim 1, characterized in that it is 1-(3-(4-fluorobenzoyl)propyl)-4-(2-(a-phenyl-tolyl))piperidine ethylene ketal and a pharmaceutically acceptable acid addition salt thereof. 22. Compound according to claim 1, characterized in that it is 1-[3-(4-fluorobenzoyl)propyl]-4-[2-(a-phenyl-tolyl]-piperidine and a pharmaceutically acceptable acid addition salt thereof). 23. Treatment method, characterized in that a pharmaceutically effective amount of a compound specified in claim 1 is administered to a patient. 24. Pharmaceutical composition, characterized in that it comprises a compound as stated in claim 1 and a pharmaceutically acceptable carrier thereof. 25. Procedure for. preparation of a compound according to claim 1, characterized by the transfer of a 2-bromodiphenylmethane of formula to the lithium derivative and reaction of the lithium derivative with a bond with formula To give a compound of formula I according to claim 1, in which X means COH, or optionally hydrogenation of a compound of formula I, in which R means benzyl, to form a compound of formula I in which R means hydrogen or optionally esterification optionally after transfer to a lithium derivative of a compound of formula I in which X means COH or to form a compound of formula I in which X means COR in which R^ has the meaning stated in claim 1, but does not mean hydrogen or possibly transfer of a compound with formula I in which X means COR^ with a compound of this formula in which X means C and Y means =CH-^CH2^n-l~' eHere optionally hydrogenating this compound to form a compound of formula I in which X means CH and Y means -(CH^ ^-, or optionally setting up a compound of formula I in which R means lower alkyl or hydrogen, an alkyl or phenylchloroformate to form a compound of formula I wherein R is alkoxycarbonyl or phenoxycarbonyl or optionally hydrolyzing this compound to form a compound of formula I wherein R is hydrogen or optionally treating the compound with benzoyl peroxide to form a compound of formula I in which R means benzoyloxy or optionally hydrolyzing the compound to give a compound of formula I in which R means hydroxy or optionally hydrogenating the compound of formula I in which R^ means lower acyl, benzoyl or cycloalkanoy1 wherein cycloalky1 contains from 3 to 6 carbon atoms to form a compound of formula I in which R means hydrogen, or optionally reacting a compound of formula I in which R means hydrogen with a bond with formula ( to form a compound of formula I wherein R is or optionally hydrolyzing this compound to form a compound in which R means -(C^)' - COCVH,- and optionally dealkylating a compound of formula I • 12 3 where at least one of the radicals Rf, R or R is alkoxy to form a compound of formula I in which R 1 , R 2 and/or R 3 is hydroxy and possibly forming a pharmaceutically acceptable acid addition salt. 26. Process for the production of a drug, characterized in that a compound of formula I according to claim 1, optionally in mixture or compound with a pharmaceutically acceptable carrier and/or stabilizer, is brought into a form suitable for therapeutic use.