NO142907B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE PHENYLALKYLAMINES - Google Patents

Description

The present invention relates to the production of phenyl-lower-alkylamines which can be used as anti-inflammatory agents.

Many types of organic compounds can be used as anti-inflammatory agents, but many such agents are acidic,

this applies e.g. α-(3-benzoylphenyl)propionic acid, commonly known as ketoprofen (British Patent No. 1,164,585). Such acidic agents are often irritating, and they can in certain cases induce stomach ulcers when administered orally. There is thus a great need for anti-inflammatory agents which are not irritating to the mucous membranes of the stomach, e.g. compounds with a basic amine function. Although the chemical literature has described a number of amine-substituted compounds with anti-inflammatory activity (see, for example, US patents 3-770,748 and 3-803,127, (N-phenylpolymethylene imines); US patents 3-772,311 and 3 -773-772 (polymethyleneimino-lower-alkanoylpyrazoles), US-Patent 3-773-944 (1-/3-aminopropyl-7-phthalans), US-Patent 3,801,594 (3-amino-lower-alkylindoles), US-Patent 3,810. 985 (4-anilino-1,3,5-triazines)

and French Patent 1,549-342 (4-/benzoylphenylmethyl7-morpholines),

then, there are no such basic compounds commercially available, and none known to be investigated by pharmacologists for possible commercial development. There has therefore been a constant search for an effective non-acidic, anti-inflammatory agent that can be developed commercially.

The present invention relates to the production of N-3-/R-|_-(phenyl)-C-(=X)7-phenyl-lower-alkylamines which can be used as anti-inflammatory agents, and which have the following formula:

where R and R 1 represent hydrogen, lower alkyl, hydroxy, lower alkoxy, trifluoromethyl, lower alkyl mercapto, lower alkylsulfinyl, lower alkylsulfony1 or halogen such as fluorine, chlorine and bromine, R 2 represents hydrogen or lower alkoxy or hydroxy in 4 -position, or lower alkyl either in the 2-j 4-, 5- or 6-positions, represents hydrogen or lower alkyl, and the group ^:C=X represents >C=0, ^C(R3)OH, > C(R3)H, ^C=CH2, ^C=NOH or >CHN(R^)2 (where R^ is only hydrogen or methyl in the latter case), and N=B represents one of the groups where R, represents hydrogen or lower alkyl and are the same or different when they occur more than once, R^ and R^ represent lower alkyl, Rg and may each represent hydrogen, lower alkyl, cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl or benzyl, Z represents 0, S or N-Rg, where Rg represents lower-alkyl or cyclohexyl, and n represents one of the numbers 1, 2 and 3-Preferred compounds els of formula I are those in which R-^ represents hydrogen or one to two identical or different groups represented by lower-alkyl, lower-alkoxy. or halogen, R2 Represents hydrogen or lower alkoxy or hydroxy in the 4-position, and N=B represents one of the groups

where Rg represents hydrogen, lower alkyl, cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl or 3-cyclohexylpropyl, R^ represents hydrogen, Z represents oxygen and R^, R^ and n have the same meaning as stated above.

Particularly preferred compounds of formula I are those where R and R^ represent hydrogen, lower alkoxy or halogen, R 2 represents hydrogen, ^C=X represents ^C=O, ^CHOH, ^;CH 2 , ^C=NOH or ^CHNH 2 and N=B represents one of the groups where Rg represents hydrogen, lower-alkyl, cyclohexyl, cyclohexylmethyl, 2-cyclohexylat1 or 3-cyclohexylpropyl,

R^ represents hydrogen, Z represents oxygen, n represents 1 or 2 and R^ and R^ have the same meaning as stated above.

The terms lower-alkyl and lower-alkoxy mean saturated, monovalent, aliphatic radicals such as branched radicals with from 1-4 carbon atoms and e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy and isobutdoxy.

Compounds of formula I in which the group ^C=X represents ^C(R^)OH where R^ is hydrogen can be prepared by a reaction between an appropriate 3_/R^-(phenyl)-C07-phenyl-lower-alkanoyl halide of formula III (prepared by a reaction between the corresponding acid of formula II and a thionyl halide) is reacted with an appropriate amine of formula IV, H-N=B, after which the resulting 3-/R-^-(phenyl)-C07-f is reduced eny 1-lower-alkanoylamine of formula V with an agent which effectively reduces amides to amines, e.g. an alkali metal aluminum hydride, a trialkyl aluminum or dialkyl aluminum hydride. This procedure is indicated by the following reaction core:

where R, R^, R 2 and R^ and N=B have the same meaning as stated above, and Hal stands for halogen. The production of the acid halide is carried out with or without a solvent by heating the acid with a molar excess of thionyl halide. Conversion of the halide to the amide of formula V is carried out by reacting the halide with the amine in the presence of an acid acceptor, e.g. an alkali metal carbonate or bicarbonate, a tri-lower alkylamine or an excess of the amine H-N=B. The reaction is preferably carried out in an inert organic solvent, e.g. methylene dichloride, benzene, toluene or xylene. Reduction of the amine with an alkali metal aluminum hydride is carried out in an inert organic solvent, e.g. diethyl ether, tetrahydrofuran, dioxane or dibutyl ether.

As mentioned above, a reduction of 3-/RR-^-(phenyl)-CO/- phenyl-lower-alkanoylamines of formula V will also effect a reduction of the carbonyl group in the RR^-(phenyl)-CO group to the carbinol group, /CHOH. This reduction can be avoided if this is desired, by

to protect the carbonyl group of the RR^-(phenyl)-CO group with a ketal group, e.g. the ethylene glycol ketal. The ketals are prepared by reacting the carbonyl compound with an alcohol in the presence of an acid catalyst under dehydrating conditions. The ketal group

is removed by hydrolysis in a later step after the amide function has been reduced.

When e.g. the carbonyl group is alternatively reduced

to the carbinol group, the carbinols can be reoxidized to ketones if desired with compounds where ^C=X is a carbonyl group. Preferred oxidizing agents for this purpose are chromic acid or nitric/perchloric acid, and it is preferred to carry out the reaction in an inert organic solvent, e.g. benzene when chromic acid is the oxidizing agent, and 1,2-dimethoxyethane when nitric acid/perchloric acid is the oxidizing agent.

Another method for preparing compounds of formula I, where ^.C = X is a carbonyl group and is hydroxy or lower alkoxy in the 4-position, consists in acylating a phenyl lower alkylamine of formula VI with a benzoic acid halide with formula VII, F^-(pheny1)-CO-hal under Friedel-Crafts conditions which can be indicated by the following reaction:

where R, R^, Rg, R-j, N = B and hal have the same meaning as stated above. The reaction is carried out by adding the amine of formula VI to a stirred mixture of acid halide and a suitable Lewis acid acting as a Friedel-Crafts catalyst, e.g. an aluminum halide or ferric chloride. A preferred catalyst is aluminum halide.

Compounds of formula'I where the group ^C=X represents a carbonyl group can also be prepared by reacting a 3-benzoylphenyl-lower-alkyl p-toluenesulfonate of formula VIII with an amine, H-N=B in the presence of an acid acceptor, and this occurs by means of the following reaction:

where R, R^, R^, R^ and N=B have the same meaning as stated above, and Ts represents the p-toluenesulfonyl group. The reaction is preferably carried out by heating the reactants in an inert organic solvent, e.g. dimethylformamide or a lower alkanol. Suitable acid acceptors are alkali metal carbonates or bicarbonates or an excess of the amine H-N=B.

Tosylates of formula VIII can be prepared by a series of reactions which include reducing a 3-bromophenyl-lower-alkanaldehyde with an alkali metal borohydride to the corresponding 3-bromophenyl-lower-alkanol, after which a reaction is carried out between the latter and dihydropyran in the absence of a solvent and in the presence of a few drops of concentrated hydrochloric acid, whereby the corresponding 3-bromophenyl-lower-alkane tetrahydropyranyl ether is produced. A reaction between the latter compound and butyllithium followed by an appropriate R^-(phenyl)-nitrile and hydrolysis of the tetrahydropyranyl ether group affords a 3-benzoylphenyl lower alkanol which is then reacted with p-toluenesulfonyl chloride in the presence of pyridine. The procedure is indicated by the following reaction sequence:

where R, R^, Rg and R^ have the same meaning as stated above and Ts represents the p-toluenesulfonyl group.

Compounds of formula I where the group ^-C = X represents ^C(Rj)OH where R^ is hydrogen or lower alkyl can be prepared by reacting a 3-halophenyl-lower alkylamine of formula IX with a lower alkyllithium in an aprotic organic solvent, e.g. diethyl ether, and then react the resulting aryllithium of formula IXa either directly with a RR1~(phenyl)-carboxaldehyde of formula XX to produce compounds where R-j is hydrogen with the eventual production of compounds where ^C=X is ^C=0, which described below, or RR.^-(phenyl)-carbonitrile with formula XXI (by which the compound where^C=X is^C = 0 is produced, in that the compounds where^C=X is^C(H)OH are prepared the latter compound by reduction with an alkali metal aluminum hydride; as described above); or with a RR1~(phenyl) lower alkyl ketone of formula XXII (by which the compound is produced where R^ is lower alkyl), During the reaction between the aryllithium and the aldehyde, for reasons not fully understood, some of the carbinol product (C =X is CHOH) oxidized to the ketone, and in such cases it is necessary to reduce the crude product with an alkali metal borohydride as described earlier.

3-Halophenyl-lower alkylamines of formula IX can

then again produced by one of two methods depending on the identity of the group N=B in the final product. Compounds of formula IX where N=B is a secondary amino group can be prepared by reacting the corresponding primary amine with a 3-halophenyl lower alkane of formula X and then reducing the resulting Schiff base with an alkali metal borohydride. Compounds of formula IX where N=B is a tertiary amino group can be prepared by reacting a 3-[halophenyl-lower-alkanal with

in

formula X with a secondary amine, converting the resulting 3-halophenylvinylamine of formula XI into the iminium salt of formula XII by reacting the former with mineral acid, after which the iminium salt is reduced with an alkali metal borohydride. The condensation of the aldehyde with the amine in the latter method is preferably carried out in a water-immiscible solvent, e.g. benzene, toluene or xylene, by refluxing

by means of a water separator which is used to collect the water produced during the reaction. Reduction of the iminium salt with an alkali metal borohydride is carried out in an inert organic solvent, e.g. a lower alkanol or dimethylformamide (DMF). This procedure is indicated by the following reaction scheme:

11

where R, R1 > R2, R^, N=B and hal have the same meaning as stated above, and X represents an anion of a mineral acid.

The methods described above can be used to prepare compounds of formula I where ^C=X is either a carbonyl group, ^C = 0 or a carbinol group, ^-C(R^)OH,

where R 1 is either hydrogen or lower alkyl. Compounds of formula I where the group ^£=X has other meanings can be prepared by simple chemical transformations involving the carbonyl or carbinol groups. Thus, the connections where the group can

^>C=X represents ^C(R^)H, where is either hydrogen or lower alkyl, a catalytic reduction with hydrogen of a corresponding carbinol, ^C(R^)OH, is produced in the presence of perchloric acid. A preferred catalyst is palladium on charcoal, and it is preferred to carry out the reaction in glacial acetic acid as solvent. The reduction is carried out at a pressure varying from 3 to 7 kg/cm<2>.

Compounds of formula I where >C=X is the group >C = CH"2 are prepared by dehydrogenating the methylcarbinoles, where ^C=X is the group /CH3

C

OH

with concentrated sulfuric acid. The reaction is carried out by refluxing a solution of carbinol and sulfuric acid in a lower alkanol solvent.

Compounds of formula I where J>C=X is the group JiC=NOH are prepared from the corresponding ketones ( ^XC = X is ^.C = 0) by heating the latter compound with hydroxylamine in an inert organic solvent, e.g. a lower alkanol.

Compounds of formula I where ^;C=X is the group CHNH"2 are prepared by reducing the corresponding oximes ("^C=X is ^>C=NOH) with sodium in a lower alkanol. Compounds of formula I where >C=X is ^C=NOH apart from being used as pharmaceutically active compounds as described above, can also be used as intermediates for the preparation of compounds where >C = X is ^CHNH 2 .

Compounds of formula I where ^.C = X represents ^>CHN(CHj)2 are prepared from the corresponding primary amines by

treating the latter compound with formaldehyde in the presence of formic acid.

Amines of formula VI where -N=B is the group:

are known compounds.

The compounds of formula VI where -N=B is the group:

where n is 2 are also known and are described in US patent 3,238,215. As described in this patent, they can be prepared by a catalytic reduction over platinum oxide of an appropriate R 1 , R 2 , or R 2 -substituted pyridine, which are commercially available.

The compounds of formula VI where N=B is the group:

where n is 1 and Ry is hydrogen, can be prepared by refluxing a mixture of a suitable alkane ion, ammonium acetate and glacial acetic acid, and catalytic reduction over platinum oxide of the resulting 2-R^-5-Rg-pyrrole, which occurs by using the following reaction nucleus: where R^ and Rg have the same meaning as stated above. Alternatively, the compounds of formula VI where -N = B is the group where n is 1 and R^ is hydrogen can be prepared by reacting a Grignard reagent, RgMgHal, with a 4-R^-4-halobutyronitrile, R^-CH-( Hal)-(CH2)2_CN, direct cyclization of the resulting 1-amino-1-Rg-4-R^-i)-halobutene, and catalytic reduction of the resulting 2-Rg-5~R-j-4,5-dihydropyrrole , which can happen using the following reaction core:

where R^, Rg and Hal have the same meaning as stated above.

The compounds of formula VI where -N=B is the group:

can advantageously be prepared, in the same way as the amines where

-N=B is the group:

where n is 2, by a catalytic reduction over platinum oxide of the corresponding 4-Rg-pyridine.

The compounds of formula VI where -N=B is the group: where R, and Rj is hydrogen, n is 3 and Rg has the same meaning as stated above, can be prepared by Beckmann rearrangement, of a suitable Rg-substituted-cyclohexanone oxime and reduction with lithium aluminum hydride of the corresponding lactam, which takes place by means of the following reaction: The compounds of formula VI where -N=B is the group: where Z is 0, can be prepared by the method described in British patent 835,717, which includes carrying a vaporized mixture of a glycol ether of the formula: together with ammonia and hydrogen over a hydrogenation/dehydrogenation catalyst based either on nickel or cobalt, at a temperature from 150 to 250°C. A preferred catalyst is nickel on diatomaceous earth.

The compounds of formula VI where -N=B is the group:

where Z is S, is preferably prepared by the methods described in Idson et al., J. Am. Chem. Soc. 76, 2902 (1954), which either involves the reaction between a sodium sulphide and a suitable bis-2-halogenethylamine: or where one reacts ammonia with a suitable bis-2-halo-ethyl sulphide:

where R-j and Rg have the same meaning as stated above, and Hal represents halogen.

Said 3-[R^-(phenyl)-C07-phenyl-lower-alkanoic acid

with formula II where Rg is hydrogen or lower alkyl, are known compounds which can be prepared by the methods described in British patent 1,164,585. Although compounds of formula II where Rg is hydroxy can also be prepared by the methods used to prepare the compounds where Rg is hydrogen or lower alkyl and compounds of formula

II, as described above, to the end products of formula I, then it is preferred to prepare the compounds of formula I where Rg is hydroxy, from a 4-lower-alkoxy-phenyl-lower-alkanoic acid by converting the latter to the corresponding acid halide, converting this to the corresponding 4-lower-alkoxyphenyl-lower-alkanoylamine by reacting the acid halide with an amine H-N=B, after which reducing the resulting amine with a reagent that effectively reduces amides to amines, e.g. an alkali metal aluminum hydride, upon which the resulting amine of formula VI is reacted with an acid halide,

R-j^ -(phenyl)-CO-Hal with formula VII, using the Friedel-Crafts conditions, after which the mentioned lower alkoxy group is finally cleaved to the hydroxy group, using well-known methods, such as heating with hydrobromic acid. This procedure is indicated by the following reaction sequence:

where R1, Rj, R^, N=B and Hal have the same meaning as stated above. The reaction conditions for the first four reactions in this sequence have been described earlier, and the cleavage of the ether with hydrobromic acid is a common reaction that is well known. 3-Halophenyl-lower-alkanals of formula X can be prepared via Darzen's glycidine ester condensation by reaction with 3-halogen-lower-alkanophenone with a lower-alkyl haloacetate in the presence of an alkali metal alkoxide, after which the resulting glycidine ester is saponified and decarboxylated. This method can be used with the following reaction sequence:

The new compounds produced according to the present invention are the compounds of formula I, as well as their acid addition salts. Compounds of formula I in free base form can be converted to the acid addition salt form by reacting the base with an acid. In a similar way, the free base can be regenerated from the acid addition salt in the usual way, i.e. by treating the salts with a cold, weak aqueous base, e.g. alkali metal carbonates and alkali metal bicarbonates. The thus regenerated bases can again be reacted with the same or different acid, after which a different acid addition salt is obtained. All the new bases and all their acid addition salts are thus easily convertible into each other.

It is thus understood that the formulas I do not

only includes the bases themselves with said formulas, but also represents all compounds with said formulas whether in the form of a free base or in the form of an acid addition salt. Both the bases and their acid addition salts have been found to have the pharmacological activities described in more detail below. This activity can be used for pharmaceutical purposes either by

that one uses the free bases as such or their acid addition salts, i.e. using acids whose anions are harmless to animal organisms in effective doses so that the desired effects are achieved without said anions producing side effects.

When you want to utilize the pharmacological activities

in the present invention it is of course preferred to use pharmaceutically acceptable salts. Although water insolubility,

high toxicity and lack of crystalline character can do

some particular salt types unsuitable or less desirable for use in a given pharmaceutical case, then water-insoluble or toxic salts may be converted to the corresponding pharmaceutically acceptable bases by decomposing the salt with an aqueous base as explained above, or alternatively is converted to pharmaceutically acceptable acid addition salts by a double decomposition reaction involving the anion, e.g. by ion exchange.

Besides being used for pharmaceutical purposes, the salts can be used to characterize or identify derivatives of the free bases or to isolate or purify such bases. Like all other acid addition salts, such purification salt derivatives can, if desired, be used to regenerate the pharmaceutically acceptable free bases by reacting said salts with aqueous base or alternatively the base can be converted into pharmaceutically acceptable acid addition salts by ion exchange methods.

It appears from the foregoing that all acid addition salts of the new bases are usable and valuable compounds regardless of whether they are soluble, toxic, or have an unsuitable physical form for purely pharmaceutical purposes, and all compounds are thus included in the invention.

The basic properties of the compounds according to the present invention, whether they are in the form of bases or cationic forms, lie in the new N-{3-/R-^- (phenyl)-C (=X2/-phenyl-lower-alkyl} amines and not in a particular acid group or acid anion associated with the salt forms of these compounds, and these acid groups and anions are in themselves neither new nor critical and may therefore include any acid anion or acid-like substance capable of forming salts with In aqueous solutions, the base form or a water-soluble acid addition salt of compounds according to the present invention will thus both have an aqueous protonated cation or ammonium ion.

Suitable acid addition salts are thus those prepared from various acids, such as formic acid, acetic acid, isobutyric acid, alpha-mercaptopropionic acid, malic acid, fumaric acid, succinic acid, succinamic acid, tartaric acid, citric acid, lactic acid, benzoic acid, 4-methoxybenzoic acid, phthalic acid, anthranilic acid, 1-naphthalenecarboxylic acid , cinnamic acid, cyclohexanecarboxylic acid, mandelic acid, tropic acid, crotonic acid, acetylenedicarboxylic acid, sorbic acid, 2-furancarboxylic acid, cholic acid, pyrenecarboxylic acid, 2-pyridinecarboxylic acid, 3-indoleacetic acid, quinic acid, sulfamic acid, methanesulfonic acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzenesulfinic acid, butylarsonic acid, diethylphosphonic acid . , bortri- fluoride and the like.

The acid addition salts can be prepared by reacting the free base and the acid in an organic solvent, after which the salt is isolated directly or by concentrating the solution.

Due to the fact that there can be at least one and up to four asymmetric centers in the present compounds, i.e. the carbon atom next to the phenyl ring to which the R^ group is attached, as well as various asymmetric centers in the group -N=B

to which the groups R^, R^, R^, Rg and R^ are attached, compounds according to the present invention will exist in stereo-chemical isomeric forms, all of which are included in the present invention. If desired, a special stereochemical form can be isolated or produced, which can be done by using methods known per se.

In standard pharmacological tests, it has been found that compounds of formulas I and Ia have very valuable anti-inflammatory activity and can therefore be used as anti-inflammatory agents. Certain compounds of formula I have also been shown to have anti-viral activity, and can thus be used as an agent against viruses. The anti-inflammatory activity was determined using (1) the inhibition of the carrageenin-induced foot edema test essentially described by Van Arman et al.,

J. Pharmacol, Exptl. Therapy. 150, 328 (1965) modified by

Winter et al., Proe. Soc. Exp. Biol. and with. 111, 544 (1962)

and (2) a modification of the inhibition of adjuvant-induced arthritis test described by Pierson, J. Chronic Diseases 16, 863 (1963) and Glenn et al., Am. J. Vet. Res. 26. 1180 (1965).

The activity against viruses in vitro of compounds according to the present invention, i.e. a herpes simplex virus of types 1 and 2, was determined by adding the compounds to tissue cultures infected with herpes virus. Monolayers of the tissue cultures (BSC, cell line, monkey kidney) were infected with one hundred TCID^q (tissue-culture infectious dosec5nU) of infectious virus. After one hour of virus adsorption, fresh growth medium containing different concentrations of the test compound was added to said monolayer. The cultures were then incubated at 36-37°C, and after 48

and 72 hours the cultures were examined microscopically. In the infected control tubes as well as those containing inactive compounds, virus growth will be indicated by the production of characteristic cytopathic effects where the cells are destroyed. In the presence of an active compound, the cells will grow normally in the same way as it does in a tissue culture control. While assessing the activity against said virus, the toxicity of each compound was assessed in separate cultures. Identical concentrations of the test compound were added to tissue culture monolayers in the absence of virus. The concentrations of the compound that showed toxic effects on the cells were not used for evaluation of anti-viral activity. The activity of the compounds was expressed as a minimum inhibitory concentration (MIC), where the MIC described is the lowest concentration of the test compound that completely inhibits the growth of said virus.

Compounds according to the present invention can be prepared so that they can be processed into unit dosage forms for tablets or capsules for oral administration, either alone or in combination with suitable diluents such as calcium carbonate, starch, lactose, talc, magnesium stearate, gum acacia and the like. Furthermore, the compound can be prepared for oral administration in aqueous alcohol, glycol or oil solutions or in oil-water emulsions in the same way as is done in the normal pharmaceutical industry.

The molecular structure of the present compounds was determined

on the basis of studies of spectra in infrared, ultraviolet and nuclear magnetic spectra, and confirmed that there was an agreement between calculated and found values for the various elements in the compounds.

The following examples illustrate the invention. All melting points are uncorrected.

Preparation of amine intermediates

Production 1

In three separate experiments, 33.8 g (0.20 mol) portions of 2-benzylpyridine were each in a solution of approx. 225 ml ethanol and 22 ml concentrated hydrochloric acid, reduced over 4.0 g portions of platinum oxide catalyst under a pressure of approx. 3.8 kg/cm of hydrogen at a temperature of 55_6l°C. When the reduction was finished, the catalyst was filtered off, washed with a small amount of ethanol, and the combined filtrates evaporated to a volume of approx.

80 ml, and then diluted with approx. 500 ml of boiling acetone.

The solid which precipitated was then collected, washed with acetone and dried, and a total yield of 124.8 g of 2-cyclohexylmethylpiperidine hydrochloride, m.p. 211-213°C. The free base was regenerated from the hydrochloride by neutralizing it with an aqueous solution of potassium carbonate, extracting the oily base into benzene, evaporating the benzene solution to dryness and distilling the remaining oil in vacuo at 55-59°C70.27 mm. 89.4 g of 2-cyclohexylmethylpiperidine were thus produced.

Manufacturing 2

A mixture of 15.52 g (0.10 mol) of 2-phenylpyridine in 15 ml of concentrated hydrochloric acid and 2.0 g of platinum oxide in 185 ml of ethanol in a pressure bottle was heated and shaken in a Parr hydrogenator under a pressure of approx. 4 kg/cm of hydrogen at a temperature of approx. 60°C. When the reduction was complete within 8 hours, the catalyst was removed by filtration, and the filtrate concentrated to 50 ml and diluted with 200 ml of acetone. The solid was collected and dried to give 14.54 g of 2-cyclohexylpiperidine hydrochloride, m.p. 251-253°C

Manufacturing 3

A mixture of 9.1 g (0.05 mol) of 2-stilbazole (Shaw et al., J. Chem. Soc. 1933, 11-19) and 1.0 g of platinum oxide in a solution of 240 ml of ethanol and 10 ml concentrated hydrochloric acid in a pressure bottle, was heated and shaken in a Parr hydrogenator under a hydrogen pressure of approx. 4 kg/cm<2> and at a temperature of approx. 60°C. When the reduction was finished within 8 hours, the catalyst was removed by filtration, the filtrate concentrated to a volume of approx. 50 ml and diluted with 200 ml of acetone. The solid was separated, dried and 9.6 g of 2-(2-cyclohexylethyl)-piperidine hydrochloride was obtained, m.p. 155-156°C.

Manufacturing 4

A solution of 78.1 g (0.84 mol) 4-methylpyridine and 89.0 g (0.84 mol) benzaldehyde in 103 g acetic anhydride was heated with stirring at reflux for 24 hours. The mixture was then concentrated to a thick oil in vacuo, and the residue dissolved in hot ethanol. The solid which separated was collected and recrystallized from ethanol, whereby 57.9 g of 4-styrylpyridine, m.p. 131.5-133°C

The latter compound (36.2 g, 0.2 mol) was dissolved in 220 ml of absolute ethanol and 30 ml of concentrated hydrochloric acid, was reduced over 3.0 g of platinum oxide under a hydrogen pressure of approx. 4 kg/cm. The product was worked up as described above during preparation no. 1 and isolated in the form of the hydrochloride salt, and 43.5 g of 4-(2-cyclohexylethyl)piperidine hydrochloride was obtained,

m.p. 246-248°C.

Manufacturing 5

15.5 g of 4-phenylpyridine (0.1 mol) was dissolved in 185 ml of absolute ethanol and 15 ml of concentrated hydrochloric acid and reduced with hydrogen over 2 g of platinum oxide under a hydrogen pressure of approx. 4 kg/cm 2. The product was worked up as described under preparation no. 1 and isolated in the form of the hydrochloride salt, and 15.3 g of 4-cyclohexylpiperidine hydrochloride was obtained (the free base has a m.p. of 106-109°C).

Production 6

A mixture of 8.6 g (0.36 mol) of magnesium shavings in 150 ml of dry ether was added in small portions while cooling and stirring to a solution of 45.0 g (0.36 mol) of benzyl chloride in 75 ml of anhydrous ether. After the addition was complete, the mixture was stirred for approx. 1 hour and then treated dropwise with a solution of 26.6 g of 4-chlorobutyronitrile in 95 ml of ether. After the addition was finished, the ether was gradually distilled off and replaced with an equivalent volume of toluene. The mixture was then heated under reflux (about 109°C) for about \ hour, cooled to 15°C, treated dropwise with 300 ml of a 10% aqueous ammonium chloride solution, filtered, after which the organic layer was separated. This was washed with 300 ml portions of dilute hydrochloric acid, and the combined acid extracts were acidified basic with solid potassium carbonate. The extraction of the mixture with ether and removal of the solvent from the combined organic extracts gave an oil which was distilled in vacuo and 13.05 g of 2-benzyl-4,5-dihydropyrrole was obtained, boiling point 123-125°C/13 mm, n2<5> = 1.5405.

The latter compound was dissolved in 210 ml of ethanol and

15 ml of concentrated hydrochloric acid, and then reduced with hydrogen over 2 g of platinum oxide at a hydrogen pressure of approx. 3.5 kg/cm 2. The mixture was worked up as described under preparation 1,

and the product was isolated in the form of the hydrochloric acid salt, so that 16.8 g of 2-cyclohexylmethylpyrrolidine hydrochloride was obtained, m.p. 130.5~ 131.5°C (from acetone).

Manufacturing 7

To a suspension of 11.2 g (1.6 mol) of lithium wire in 600 ml of anhydrous ether was added dropwise 125.6 g (0.8 mol) of bromobenzene. After the addition was finished, the mixture was stirred for approx. 5 hours and then treated dropwise first with a solution of 74.4 g (0.8 mol) of picoline in 100 ml of anhydrous ether, and then, after stirring for fifteen minutes, with a solution of 74.0 g (0.4 mol) 2-phenylethyl bromide in 100 ml of ether. The mixture was stirred at room temperature approx. 12 hours and then completely over for approx. 300 g of ice. When the excess of lithium had reacted, the layers were separated, and the aqueous layer was washed with further ether and the combined organic portions were washed with hydrochloric acid solution, dried and evaporated to dryness, whereby a residual oil was obtained which was distilled in vacuum, and a total of man 41.3 g 2-(3~phenyl-propyDpyridine, boiling point 76-78°C/0.05 mm, n<25> = 1.5592.

The latter compound (19.7 g, 0.1 mol) was dissolved in

235 ml of ethanol and 15 ml of concentrated hydrochloric acid, and was then reduced with hydrogen over 2 g of platinum oxide at a hydrogen pressure of approx. 4 kg/cm<2> at approx. 65°C.. The product was worked up as described under preparation 1 and isolated in the form of the hydrochloride salt, and 22.2 g of 2-(3-cyclohexylpropyl)piperidine hydrochloride was obtained,

m.p. 175-176.5°C (from ethyl acetate).

Manufacturing 8

Catalytic reduction of 3-benzylpyridine in glacial acetic acid over platinum oxide catalyst and isolation of the product as described above gave 3-benzylpiperidine.

Production of end products

Oak sample 1

To a solution of 25.4 g (0.1 mol) of α-(3-benzoylphenyl)-propionic acid in 40 ml of benzene was added 19.8 g (0.166 mol) of thionyl chloride, and the mixture was refluxed for 2 hours . The solvent was then removed in vacuo, and the resulting 28 g of an oil consisting of α-(3-benzoylphenyl)propionyl chloride was dissolved in 40 ml of diethyl ether and, with stirring during 30 minutes, added a solution of 2-cyclohexylmethylpiperidine in 80 ml of diethyl ether. The mixture was stirred for approx. 48 hours at room temperature, filtered, the filter washed with ether and the combined filtrate washed once with dilute acid, once with brine, once with aqueous potassium bicarbonate and evaporated to dryness to give 48.2 g of 2-cyclohexylmethyl-1- [α-(3-benzoylphenyl)propionyl7-piperidine.

35.5 g of the latter compound (0.085 mol) were dissolved

in 200 ml of diethyl ether, and the solution added dropwise with stirring to a mixture of 8.08 g (0.21 mol) of lithium aluminum hydride in 200 ml of ether while maintaining the temperature at 10-15°C. The reaction mixture was stirred at room temperature for approx. | hour, decomposed by the dropwise addition of 8.1 ml of water, after which 8.1 ml of 15% sodium hydroxide and a further 22.2 ml of water were added. The mixture was then stirred for 1 hour, filtered, after which the filtrate was evaporated to dryness, and 34.0 g of an oil was obtained, of which 10.5 g was chromatographed on 200 g of alumina and eluted with a solution of 60% hexane and 40 % ether. The first fractions were removed and evaporated to dryness, and 8.0 g of 2-cyclohexylmethyl-1-{2-[3-(α-hydroxybenzyl)phenyl]propyl)pyridine was obtained as a viscous oil.

Analysis:

Calculated for CggH^NO: C 82.91; H 9.69; N 3.45

Found : C 83.12; H 9.80; N 3.49-

Examples 1A-1D

By using the procedure described in

example 1, the following compounds of formula I were prepared: Example IA - 2-cyclohexylmethyl-1-{2-/3-(g-hydroxybenzyl)-phenyl7ethyl\piperidine, m.p. 122-124°C (5.8 g from benzene/hexane) prepared by reacting 42 g (0.16 mol) of 3-benzoylphenylacetyl chloride (German Patent Application 2,243,444, issued March 8, 1944) with 31.7 g (0.175 mol) of 2-cyclohexylmethylpiperidine in 150 ml of ether in the presence of 19.4 g (0.192 mol) of triethylamine and reducing the resulting 2-cyclohexylmethyl-1-(T3-benzoylphenyl)acetyl-7-piperidine (46 g) with 13 g (0.35 mol) of lithium aluminum hydride in 325 ml of ether.

Analysis:

Calculated for C^H^NO: C 82.81; H 9.52; N 3.58

Found : C 83.01; H 9.54; N 3.52.

Example IB - 2,6-Dimethyl-1-{2-[3-(q-hydroxybenzyl)phenyl7-ethyl]piperidine, m.p. 115-H7°C (9.53 g from benzene/hexane) prepared by reacting 42 g (0.16 mol) of 3-benzoylphenylacetyl chloride with 19.8 g (0.175 mol) of 2,6-dimethylpiperidine in 150 mL of ether in the presence of 19.4 g (0.092 mol) of triethylamine and reducing the resulting 2,6-dimethyl-1-(3-benzoylphenyl)acetyl-7piperidine (49 g) with 13.9 g (0.365 mol) of lithium aluminum hydride in 300 ml of ether.

Analysis:

Calculated for C22H"2gN0: C 81.69; H 9.04; N 4.33

Found : C 81.83; H 9.04; N 4.32.

Example 1C - 4-/2-(3-benzoylphenyl) ethyl 7-morpholine hydrochloride monohydrate, m.p. 177.5-180°C (29.0 g from acetone) prepared by a reaction between 46.5 g (0.18 mol) of 3-benzoylphenylacetyl chloride and 17.2 g (0.198 mol) of morpholine in 225 ml of methylene dichloride in the presence of 21.5 g (0.211 mol) of triethylamine, after which the resulting 49 g of 4-/(3-benzoylphenyl)acetyl-7-morpholine is converted into the corresponding ethylene glycol ketal by a reaction with the first-mentioned compound and 125 ml of ethylene glycol in 1250 ml of benzene in the presence of 2.5 g of p-toluenesulfonic acid, after which the resulting ketal (58.6 g) was reduced with 11.8 g (0.31 mol) of lithium aluminum hydride in 280 ml of ether, and then the ketal was hydrolyzed by stirring the product at 55-60 °C with 300 ml of 1.5N hydrochloric acid for 45 minutes.

Analysis:

Calculated for C-^H^NOg . HC1. HgO: C 65.23; H 6.91; Cl 10,13

Found : C 65.38; H 6.88; Cl 10,19.

Example ID - N-(2-(3-benzoylphenyl)ethyl7-N-(3-dimethylamino-propyl)amine dihydrochloride hemihydrate, m.p. 194-197°C (11.1 g of the free base obtained as a dark oil, a small amount converted to the dihydrochloride) prepared by reacting 46.3 g (0.167 mol) of 3-benzoylphenylacetyl chloride with 30.2 g (0. 3 mol) of 3-dimethylaminopropylamine in 200 ml of methylene dichloride in the presence of 20.1 g (0.2 mol) of triethylamine, converting the resulting 9 g of N-(3-benzoylphenyl)acetyl7-N-(3-dimethylaminopropyl)amine to

the corresponding ethylene glycol ketal by a reaction between 15 g of the former and 37.5 ml of ethylene glycol in the presence of 9.75 g of p-toluenesulfonic acid in 395 ml of benzene, and reducing the resulting ketal (15.6 g) by 3.2 g (0.084 mol) of lithium aluminum hydride in a solution of 50 ml of dioxane and 50 ml of di-n-butyl ether and hydrolyze the ketal by heating it for 1 hour in 200 ml of dilute hydrochloric acid at 55°C.

Analysis :

Calculated for C^H<g>gN<g>O. 2HC1.1/2HgO: C 61.22; H 7.43; Cl 18.01

Found : C 61.97; H 7.48; Cl 17.70.

Example 2

Using a procedure similar to that described in Example 1, 2,6-dimethyl-1-[α-(3-benzoylphenyl)-propionyl]piperidine (14.3 g as an oil) was prepared from 12.7 g of a -(3-benzoylphenyl)propionic acid, 10 g (0.084 mol) thionyl chloride, 6.22 g (0.055 mol) 2,6-dimethylpiperidine and 6.05 g (0.06 mol) triethylamine, and the resulting amide (14.3 g) reduced with 3.9 g (0.103 mol) of lithium aluminum hydride in diethyl ether, and this gave 13.2 g of 2,6-dimethyl-1-{2-[3-(α-hydroxybenzyl)phenyl-7-propyl]-piperidine as a yellow oil.

Analysis:

Calculated for C^H^NO: C 82.34; H 8.71; N 4.18

Found : C 82.22; H 8.82; N 4.15.

Examples 2A-D

Using the same procedure as described in example 1, the following compounds of formula I were prepared: Example 2A - N-t-butyl-N-{ 2-/ 3~( q-hydroxy-4-methyl-2-chlorobenzyI)- phenyl7propyj\ amine prepared by reacting α-/3-(4-methyl-2-chlorobenzoyl)phenyl7propionyl chloride with t-butylamine and reducing with lithium aluminum hydride the resulting N-t-butyl-N-{q<->/3-(4- methy1-2-chlorobenzoyl)phenyl7propionyl^ amine.

Example 2B - N-benzyl-N-t-butyl-N-f2-/3-(q-hydroxy-3-trifluoromethylbenzyl)phenyl7propyl\amine prepared by reacting O1-/3-(3-trifluoromethylbenzoyl)phenyl7propionyl chloride with N -benzyl-N-t-butylamine and reducing with lithium aluminum hydride the resulting N-benzyl-N-t-butyl-N-{et-[3-(3-trifluoromethylbenzoyl)phenyl7-propionyl}amine.

Example 2C - N,N-di-isobuty1-N-| 2-/3~(q-hydroxy-2,4-dichloro-benzyl)phenyl7propyl"y amine prepared by reacting q<->/3~(2,4-dichlorobenzoyl)phenyl7propionyl chloride with N,N-di-isobutylamine and reduce with lithium aluminum hydride the resulting N,N-di-isobutyl-N-{q-[3-(2,4-dichlorobenzoyl)phenyl7propionyl}amine.

Example 2D - 4-(2-Cyclohexylethyl)-1-{2-/3-(q-Hydroxy-2-bromo-benzyl)-4-methylphenyl7-propyph\piperidine prepared by reacting q<->/3-(2- bromobenzoyl)-4-methylphenyl7propionyl chloride with 4-(2-cyclohexylethyl)piperidine and reducing with lithium aluminum hydride the resulting 4-(2-cyclohexylethyl)-1-£q<->/3~(2-bromobenzoyl)-4-methylphenyl7propionyl)piperidine .

Example 3

220 g (1.65 mol) of aluminum chloride were by vigorous stirring

in the course of 20 minutes added 8l g (0.67 mol) of acetophenone. The resulting mixture was treated dropwise with stirring over 40 minutes with 120 g (0.8 mol) of bromine. The mixture was then stirred for another quarter of an hour and then extracted with 150 ml portions of ether. The combined ether extracts were washed once with water, once with 10% potassium bicarbonate, once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness to give 141 g of an oil which was distilled in vacuo to give 108 .7 g of 3-bromo-acetophenone, boiling point 71.5-76°C/0.5 mm.

To 2,200 ml of isopropanol in a three-necked flask purged with nitrogen was added 60 g (2.6 mol) of sodium in small pieces. When all the sodium had dissolved, the mixture was cooled to 7-8°C

and in the course of 30 minutes treated with a solution of 3J8 g (1.6 mol) of 3-bromoacetophenone and 352 g (2.88 mol) of ethyl chloroacetate. The mixture was stirred at 7-8°C for 5 hours and then at room temperature

for about. 48 hours, boiled under reflux for 1 hour, distilled to remove approx. 1 liter of isopropanol after which the residue was diluted with 1900 ml of water and 1200 ml of toluene and then stirred. The layers were separated, the aqueous layer extracted with additional toluene and the combined toluene extracts were washed with a saturated sodium chloride solution, dried and evaporated to dryness to give 558.8 g of a brown liquid which was combined with a soln. of 70 g of sodium hydroxide in 225 ml of water and 1200 ml of absolute ethanol, and this mixture was refluxed for approx. 12 hours. The mixture was then evaporated to dryness in vacuo, and 575.6 g was obtained which was dissolved in water, acidified with dilute hydrochloric acid, after which the mixture was extracted with benzene. The benzene extracts were evaporated to dryness and 485.4 g of a substance was obtained which was steam distilled and this gave 272.5 g of α-(3-bromophenyl)propionaldehyde.

A solution of the latter with 465 g (2.6 mol) of 2-cyclohexylmethylpiperidine in 6 liters of benzene was refluxed using a Dean-Stark trap over 12 hours. The solvent was removed in vacuo and 712.1 g of an oil was obtained which was distilled in vacuo to remove lower boiling impurities.

A higher-boiling product of 357.2 g of 2-cyclohexylmethyl-1-(2-(3-bromophenyl)-1-propenyl-7-piperidine was thus obtained.

The latter compound (0.95 mol) was dissolved in 3 liters of hexane, and the solution was cooled in an ice bath and treated with 220 ml (1.20 mol) of 4.9N ethereal hydrogen chloride. A white gummy substance consisting of iminium hydrochloride was separated, this was collected, filtered and washed with fresh hexane, dissolved in 3.5 liters of dimethylformamide, after which the solution was treated with 72 g (1.9 mol) of sodium borohydride added in small amounts during of 10 minutes. The mixture was stirred at room temperature for approx. lg hour, treated with 1 liter 10%. sodium hydroxide and 6 liters of water and then extracted with hexane. The combined hexane extracts gave 305.4 g of a yellow oil which was distilled in vacuo to give 189.6 g of a substance which had a boiling point of 143-161°C/0.06 mm and this was redistilled at 0 .5 mm (boiling point 167-187°C), and 158.5 g of 2-cyclohexylmethyl-1-(2-(3-bromophenyl)propyl-7-piperidine were obtained.

Analysis:

Calculated for C^H^BrN: C 66.66; H 8.52; Bro. 21.12

Found: C 66.71; H 8.36; Br 21,20

A solution of the latter compound 37.8 g (0.1 mol) dissolved in 80 ml of diethyl ether was treated dropwise with 165 ml (0.18 mol) of a 1.08 molar solution of n-butyllithium in diethyl ether while keeping the temperature around 10° C. When the addition was finished, the mixture was stirred for approx. 30 minutes at approx. 10°C, then at room temperature for 1 hour, boiled under reflux for approx. 30 minutes, again cooled to 10°C and treated with a solution of 25.8 g (0.19 mol) of 4-methoxybenzaldehyde in 50 ml of ether while maintaining the temperature at 15-20°C. The mixture was refluxed for 20 minutes, cooled, basified by adding 110 ml of 10% sodium hydroxide and then stirred for 10 minutes. The mixture was then filtered, the organic layer separated and the aqueous layer extracted with additional diethyl ether. The combined organic extracts were washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness, and 55 g of an oil was obtained which was dissolved in 150 ml of absolute methanol. The solution was treated with 7 g of sodium borohydride, stirred for 20 minutes at 15°C and then gently acidified by adding 150 ml of sulfuric acid and then extracted three times with hexane. The aqueous solution was basified with 150 ml of 10%. sodium hydroxide, diluted with water and extracted four times with hexane. The combined hexane extracts gave 32 g of an oil which was chromatographed on 500 g of alumina using 1.5% isopropylamine in hexane as eluent. The first 3 liters of the eluate were collected and set aside, while the next 3.7 liters were collected and evaporated to dryness, yielding 20.4 g of 2-cyclohexylmethyl-1-in 2-(3-(α-hydroxy -4-Methoxybenzyl)phenyl7propyl}piperidine as a yellow oil.

Analysis:

Calculated for C^H^NOg-. C 79.95; H 9.49; N 3.22

Found : C 78.88; H 9.43; N 3.07.

Examples 3A-3H

Using the same procedure as described in

example 3, the following compounds of formula I were prepared: Example 3A - 2-cyclohexylmethyl-1-{2-/3-(q-hydroxy-3-chlorobenzyl)-phenyl7-propyl\piperidine (26.8 g as a yellow oil) prepared by reacting 37.8 g (0.1 mol) of 2-cyclohexylmethyl-1-(2-(3-bromophenyl)-propyl-7-piperidine with 0.19 mol of n-butyllithium and reacting the resulting lithium derivative with 28.0 g (0 .2 mol) 3-chlorobenzaldehyde in approx. 250 ml of diethyl ether.

Analysis :

Calculated for CggH^gClNO: C 76.42; H 8.70; N 3.18

Found : C 76.64; H 8.98; N 3.16.

Example 3B - 2-cyclohexylmethyl-1-f2-/3-(q-hydroxybenzyl)phenyl7-propylpyrrolidine (5.3 g as a pale brown viscous oil) prepared by reacting 10.8 g (0.03 mol) 2 -cyclohexylmethyl-1-12-(3-bromophenyl)propyl7pyrrolidine with 0.06 mol of n-butyllithium and react the resulting lithium derivative with 7.0 g (0.066 mol) of benzaldehyde. Analysis:

Calculated for C^H^<N>O: C 82.8l; H 9.52; N 3.58

Found : C 82.29; H 10.03; N 3.51.

Example 3C - 2-cyclohexylmethyl-1-/2-/3-(q-hydroxy-3,4-dichloro-benzyl)phenyl7propyl' 1) piperidine (12.3 g as an oil) prepared by reacting 37.8 g (0.1 mol) of 2-cyclohexylmethyl-1-(3-bromophenyl)-propyl-7-piperidine with 0.19 mol of n-butyllithium and reacting the resulting lithium derivative with 35.1 g (0.2 mol) of 3.4 -dichlorobenzaldehyde in diethyl ether.

Example 3D - 2-cyclohexylmethyl-1-(2-/3-(q-hydroxy-2-chlorobenzyl)-phenyl7-propyl\piperidine (30.7 g as an oil) prepared by reacting 37.8 g (0.1 mol ) 2-cyclohexylmethyl-1-(3-bromophenyl)-propyl7-piperidine with 0.19 mol of n-butyllithium and react the resulting lithium derivative with 28.0 g (0.2 mol) of 2-chlorobenzaldehyde in diethyl ether.

Example 3E - 2-(3-Cyclohexylpropyl)-1-/2-/5-(q-hydroxybenzyl)-phenyl7propyl\piperidine (5.4 g as a viscous oil) prepared by reacting 12.2 g (0.03 mol) 2-(3-cyclohexylpropyl)-1-(2-(3-bromophenyl)propyl)piperidine with 0.68 mol of n-butyllithium and react the resulting lithium derivative with 7.0 g (0.06 mol) of benzaldehyde in diethyl ether.

Analysis :

Calculated for C^qH^NO: C 83.09; H 9.99; N 3.23

Found : C 82.92; H 10.26; N 3.19-

Example 3F - 2-cyclohexylmethyl-1-{2-/3-(ct-hydroxy-4-methyl-mercaptobenzyl)phenyl/propyl)piperidine prepared by reacting 2-cyclohexylmethyl-1-(2-(3-bromophenyl)propyl7piperidine with n-butyllithium and react the resulting lithium derivative with 4-methyl-mercaptobenzaldehyde.

Example 3G - 2-cyclohexylmethyl-1-f2-/3-(ct-hydroxy-4-methyl-sulfinylbenzyl)phenyl7propyl' 1;piperidine prepared by reacting 2-cyclohexylmethyl-1-{2-/3-(ct-hydroxy -4-methylmercaptobenzyl)-phenyl7-propyl}piperidine described in Example 3F with a molar equivalent amount of hydrogen peroxide in formic acid.

Example 3H - 2-cyclohexylmethyl-1-f2-/3-(ct-hydroxy-4-methyl-sulfonylbenzyl)phenyl7propyl\piperidine prepared by reacting 2-cyclohexylmethyl-1-{2-/3-(ct-h<y >hydroxy-4-methylmercaptobenzyl)-phenyl/propyl}piperidine described in Example 3F with two molar equivalents of hydrogen peroxide in formic acid.

Example 4

Using the same procedure as in Example 3, 18.9 g (0.05 mol) of 2-cyclohexylmethyl-1-(2-(3-bromophenyl)propyl7-piperidine was reacted with 0.1 mol of n-butyllithium in diethyl ether, and the resulting lithium derivative was reacted directly with 12.3 g (0.103 mol) of 4-methylbenzaldehyde, and 16.9 g of 2-cyclohexylmethyl-1-{2-(3-(a-hydroxy-4-methylbenzyl)phenyl-7-propyl-piperidine) was obtained as a yellow oil.

Analysis:

Calculated for C^ E^ NO: C 83.00; H 9.85; N 3.34

Found : C 83.04; H 10.01; N 3.31.

Example 5

Using the same procedure as in Example 3, 18.9 g (0.05 mol) of 2-cyclohexylmethyl-1-(2-(3-bromophenyl)propyl7-piperidine was reacted with 0.1 mol of n-butyllithium in diethyl ether, and the resulting lithium derivative reacted directly with 15.5 g

(0.11 mol) of 4-chlorobenzaldehyde. The raw product was reduced by

4.5 g (0.12 mol) of sodium borohydride in methanol, and 16.6 g were obtained

2-Cyclohexy Ime ty 2-(α-Hydroxy-4-chlorobenzyl)phenyl7-propyl)piperidine as an oil.

Analysis:

Calculated for CggH^gClNO: C 76.42; H 8.70; Cl 8.06

Found : C 76.82; H 8.76; Cl 8,14.

Using the same procedure as described in Example 5, the following compound of formula I was prepared: Example 5A - 2-cyclohexylmethyl-1-/2-/3-(q-hydroxy-2,6-dichloro-benzyl)phenyl-7-propyl-piperidine (yellow oil) prepared by

react 18.9 g (0.05 mol) of 2-cyclohexylmethyl-1-(2-(3-bromophenyl)-propyl-7-piperidine with 0.1 mol of butyllithium in diethyl ether followed by 19.2 g (0.11 mol) of 2,6-dichlorobenzaldehyde , whereby 19.3 g of the product was obtained.

Analysis:

Calculated for CggH^ClgNO: C 70.87; H 7.86; Cl 14.94

Found : C 71.06; H 8.08; Cl l4.8l.

Example 6

Using the same procedure as described in

example 3, 37.8 g (0.1 mol) of 2-cyclohexylmethyl-1-(2-(3-bromophenyl)propyl-7-piperidine was reacted with 0.18 mol of n-butyllithium in diethyl ether, and the resulting lithium derivative reacted directly with 27 g (0.23 mol) of acetophenone, and 11.8 g of 2-cyclohexylmethyl-1-{'2-/3-(q-hydroxy-q-methylbenzyl)phenyl7propyl}piperidine were obtained as a yellow oil.

Analysis:

Calculated for C^H^NO: C 83.00; H 9.85; N 3.34

Found : C 83.34; H 9.97; N 3.23.

Example 7

A solution of 0.15 mol of n-butyl lithium in 90 ml of diethyl ether was prepared by adding 20.5 g of n-butyl bromide in 30 ml of ether to 2.58 g (0.375 mol) of lithium. Sufficient of the solution to obtain 0.093 mol was added to a solution of 19.4 g (0.051 mol) of 2-cyclohexylmethyl-1-(2-(3-bromophenyl)propyl-7-piperidine (described above in Example 3) in 100 ml of ether. The mixture was stirred for 1 hour while maintaining the temperature below 10°C, refluxed for 30 minutes and again cooled to below 10°C, treated over 10 minutes with a solution of 13.3 g

(0.10 mol) of 4-methoxybenzonitrile in 80 ml of ether, stirred for a further 1 hour below 10°C, then stirred overnight at room temperature and treated with 110 ml of a solution prepared by dissolving 9 ml of concentrated sulfuric acid in 45 ml of water and 108 ml of dioxane. The solution was refluxed for 2 hours, cooled,

basified with 100 ml of 10% sodium hydroxide, after which the layers were separated and the aqueous layer extracted with ether. The ether extracts were washed with sodium chloride solution, dried and evaporated to dryness to give 32.6 g of a material which was dissolved in hexane and extracted with a solution of 8 ml of concentrated sulfuric acid, 136 ml of water and 144 ml of methanol. The extracts were basified with 10% sodium hydroxide, the mixture again extracted with hexane, after which the hexane extracts were washed with sodium chloride solution, dried and evaporated to dryness,

and 28.1 g of a material was obtained which was chromatographed on

400 g of alumina and eluted with 50% benzene/50% hexane. The first 1750 ml of the eluate was evaporated to dryness, the residue heated in vacuo at 0.1 mm/220°C (bath temperature) to drive off some 4-methoxybenzonitrile, and the residue again chromatographed on 250 g of alumina, using 15 % ether/85% hexane.

The first 400 ml of the eluate was discarded, while the next 1200 ml

was evaporated to dryness to give 7.1 g of 2-cyclohexylmethyl-1-[2-(3-(4-methoxybenzoyl)phenyl-7-propyl)] piperidine as a yellow oil. Analysis :

Calculated for C2gH3gN02: C 80.33; H 9.07; N 3.23

Found : C 80.50; H 9.17; N 3.14.

Example 7A-7L

Using the procedure described in Examples 3, 4 and 5, the following compounds of formula I were prepared: Example 7A - 2-cyclohexylmethyl-1-/2-(3-benzoylphenyl)propyl7-pyrrolidine (viscous amber liquid) was prepared by reacting 21.3 g (0.1 mol) of α-(3-bromophenyl)propionaldehyde with 31.4 g (0.2

mol) of 2-cyclohexylmethylpiperidine in benzene, convert the resulting 33.7 g of 1-(3-bromophenyl)-1-propenyl-7-pyrrolidine into the iminium chloride with hydrogen chloride-containing ether, reduce the iminium chloride (34.0 g) by 6.4 g (0 .17 mol) sodium borohydride in dimethylformamide, react 9.8 g (0.027 mol) of the resulting (18.8 g) 2-cyclohexylmethyl-

1-/2-(3-bromophenyl)propyl7pyrrolidine (boiling point 135-136°C70.02 mm) with 0.05 mol of butyllithium followed by 6.2 g (0.06 mol) of benzonitrile in diethyl ether and decomposing the product with a solution of 4 ml of concentrated sulfuric acid in 20 ml of water and 50 ml of dioxane, which gave 5.1 g of the product.

Analysis:

Calculated for C^H^NO: C 83.24; H 9.06; N 3.60

Found : C 82.77; H 9.05; N 3.64.

Example 7B - 2-cyclohexylmethyl-1-f 2-/3-(4-fluorobenzoyl)phenyl7-propyl\piperidine (yellow oil) prepared by reacting 18.9 g (0.05 mol) of 2-cyclohexylmethyl-1- /2-(3-bromophenyl)propyl7piperidine with 0.1 mol of butyllithium in diethyl ether followed by 12.8 g (0.11 mol) of 4-fluorobenzonitrile and decomposing the product with a solution of 3.8 ml of concentrated sulfuric acid in 19 ml of water and 45 ml of dioxane, which gave 6.5 g of the product.

Analysis :

Calculated for CggH^FNO: C 79.77; H 8.61; N 3.32

Found : C 79.60; H 8.76; N 3.51.

Example 7C - 2-cyclohexylmethyl-1-(2-/3-(4-methylbenzoyl)phenyl7-propyl)piperidine (9.7 g as a yellow oil) prepared by reacting 18.9 g (0.05 mol) 2 -cyclohexylmethyl-1-(2-(3-bromophenyl)propyl7-piperidine with 0.1 mol of butyllithium in diethyl ether followed by 12.4 g (0.11 mol) of 4-methylbenzonitrile and decomposing the product with a solution of 3.8 ml concentrated sulfuric acid in 19 ml of water and 45 ml of dioxane, yielding 9.7 g of the product.

Analysis:

Calculated for C2gH3gNO: C 83.40; H 9.4l; N 3.35

Found : C 83.34; H 9.61; N 3.30.

Example 7D - 2-(3-cyclohexylpropyl)-1-12-(3-benzoylphenyl)-propyl-7piperidine (yellow oil) prepared by reacting 12.2 g (0.03 mol) of 2-(3-cyclohexylpropyl)-1 -/2-(3-bromophenyl)propyl7-piperidine with 0.06 mol of butyllithium in diethyl ether followed by 7.2 g (0.07 mol) of benzonitrile and decomposing the product with a solution of 8.3 ml of concentrated sulfuric acid in 42 ml of water and 100 ml of dioxane, yielding 6.2 g of the product.

Analysis:

Calculated for C^H^NO: C 83.47; H 9.57; N 3.24

Found : C 83.28; H 9.77; N 3.05-

Example 7E - 2-cyclohexyl-1-/2-(3-benzoylphenyl)propyl/piperidine (light brown oil) prepared by reacting 12.7 g (0.035 mol) of 2-cyclohexyl-1-/2-(3- bromophenyl)propyl7piperidine with 0.07 mol of butyllithium in diethyl ether followed by 8.9 g (0.077 mol) of benzonitrile and decomposing the product with a solution of 9 ml of concentrated sulfuric acid in 45 ml of water and 100 ml of dioxane which gave 6.1 g of the product.

Analysis:

Calculated for C^H^NO: C 83.24; H 9.06; N 3.60

Found : C 83.16; H 9.16; N 3.44.

Example 7F - 2-(2-cyclohexylethyl)-1-12-(3-benzoylphenyl)propyl7-piperidine (pale brown liquid) prepared by reacting 13.7 g (0.035 mol) of 2-(2-cyclohexylethyl)-1- /2-(3-bromophenyl)propyl7-piperidine with 0.07 mol of butyllithium in diethyl ether followed by 8.9 g (0.077 mol) of benzonitrile and decomposing the product with a solution of 9 ml of concentrated sulfuric acid in 45 ml of water and 100 ml dioxane, giving 8.9 g of the product.

Analysis:

Calculated for C^H^NO: C 83.40; H 9.41; N 3.35

Found : C 83.57; H 9.40; N 3.35.

Example 70 - 8-/2-(3-benzoylphenyl)propyl7-1,4-dioxa-8-azaspiro-1\,5/decane (pale yellow oil) prepared by reacting 10.6 g (0.05 mol) α-(3-bromophenyl)propionaldehyde with 14.3 g (0.1 mol) of 1,4-dioxa-8-azaspiro/4,5-7decane in benzene, converting the resulting 15.7 g of 8-/2-( 3-bromophenyl)-1-propenyl7-1,4-dioxa-8-azaspiro-/5,7decane to the iminium chloride with ether containing hydrogen chloride, reduce the iminium chloride with 3.8 g (0.08 mole) of sodium borohydride in dimethylformamide, react the resulting 17.5 g (0.05 mol) 8-(2-(3-bromophenyl)propyl7-1,4-dioxa-8-azaspiro/4,5_7decane with 0.1 mol butyllithium followed by 15.5 g (0, 15 mol) of benzonitrile in diethyl ether and decompose the product with a solution of 6 ml of concentrated sulfuric acid in 30 ml of water and 72 ml of dioxane, whereby 5.1 g of the product was obtained.

Analysis:

Calculated for C^H^NCy C 75.58 ; H 7.45; N 3.83

Found : C 75.60; F 7.69; N 3.87.

Example 7H - 4-/2-(3-benzoylphenyl)propyl-7-morpholine (pale yellow oil) prepared by reacting 21.3 g (0.1 mol) of α-(3-bromophenyl)propionaldehyde with 17.4 g (0 .2 mol) of morpholine in benzene, convert the resulting 27.3 g of 4-(3-bromophenyl)-1-propenyl7morpholine to the iminium chloride with hydrogen-containing ether, reduce the iminium chloride with 7.6 g (0.2 mol) of sodium borohydride in dimethylformamide, react the resulting 19 g of 4-(2-(3-bromophenyl)propyl7morpholine (boiling point 99-120°C70.09 mm, n^ A I, = 1.5477) with 0.1 mol of butyllithium followed by 15.5 g (0 .15 mol) of benzonitrile in diethyl ether and decompose the product with 150 ml of a solution prepared by dissolving 6 ml of concentrated sulfuric acid in 30 ml of water and 72 ml of dioxane, which gave 7.5 g of the product.

Analysis :

Calculated for C^H^NCy C 77.64; H 7.49; N 4.53

Found : C 77.62; H 7.37; N 4.71.

A small amount of the free base was converted to the hydrochloride salt and 4-(2-(3-benzoylphenyl)propyl7-morpholine hydrochloride monohydrate was obtained, m.p. 151-155°C.

Analysis:

Calculated for C^H^NC^ . HC1. HgO: C 66.02; H 7.20; Cl 9.74

Found : C 66.37; H 7.24; Cl 9,59-Example 7J - 2, 6- dimethyl- 4-/ 2-( 3- benzoylphenyl) propyl 7-morpholine cyclohexanesulfamate prepared by reacting 21.3 g (0.1 mol) of α-(3-bromophenyl)propionaldehyde with 23 g (0.2 mol) of 2,6-dimethyl-morpholine in benzene, converting the resulting 28.4 g of 2,6-dimethyl-4-(5-(3-bromophenyl)-1-propenyl-7-morpholine into the iminium chloride with ether containing hydrogen chloride, reduce iminium chloride with 10 g (0.26 mol) of sodium borohydride in dimethylformamide, react the resulting 15.5 g of 2,6-dimethyl-4- 12-(3-bromophenyl)propyl7-morpholine (boiling point 125-129 n C/0 .01 mm~ , n^ ?4 - 1.5294) with 0.1

mol of butyllithium followed by 11 g (0.11 mol) of benzonitrile in diethyl ether and decomposing the product with 150 ml of a solution prepared by dissolving 45 ml of concentrated sulfuric acid in 225 ml of water and 540 ml of dioxane. The product was converted to the cyclohexane-sulfamate salt which was recrystallized from acetone and 7.7 g of the product was obtained, m.p. 156-158°C.

Analysis:

Calculated for C22H"27N02 . CgH-^NC^S : C 65.08; H 7.80; S 6.20

Found : C 64.86; H 7.72; S 6.22.

Example 7K - 2-cyclohexylmethyl-1-12-(3-benzoyl-2-methylphenyl)-ethyl-7-piperidine prepared by reacting 2-bromo-6-bromomethyltoluene (described by Lindsay et al., J. Am. Chem. Soc. 83 , 943-949 (I96D) with potassium cyanide in boiling ethanol, reduce the resulting (3-bromo-2-methylphenyl)acetonitrile with diisobutylaluminum hydride; react the resulting (3-bromo-2-methylphenyl)acetaldehyde with 2-cyclohexylmethylpiperidine in boiling benzene under a Dean-strong trap, reduce with sodium borohydride the iminium hydrochloride of the resulting 2-cyclohexylmethyl-1-(2-(3-bromo-2-methylphenyl)-1-ethenyl7piperidine, and react the resulting 2-cyclohexylmethyl-1- [ 2 -(3-bromo-2-methylphenyl)ethyl7piperidine with n-butyllithium in diethyl ether followed by a reaction between the lithium derivative and benzonitrile.

Example 7L - 4-/ 2-(3-benzoyl-2-methylphenyl)ethyl7morphoTine prepared by reacting (3-bromo-2-methylphenyl)acetaldehyde with morpholine in boiling benzene under a Dean-Stark trap, reducing with sodium borohydride the iminium hydrochloride of the resulting 4-(3-bromo-2-methylphenyl)-1-ethenyl-7-morpholine, and reacting the resulting 4-(3-bromo-2-methylphenyl)ethyl-7-morpholine with n-butyllithium in diethyl ether followed by a reaction between the lithium derivative and benzonitrile.

Example 8

Using the procedure described in Example

7, 18.9 g (0.05 mol) of 2-cyclohexylmethyl-1-(2-(3-bromophenyl)-propyl-7-piperidine was reacted with 0.095 mol of n-butyllithium in diethyl ether, and the resulting lithium derivative was directly reacted with 12.4 g (0.106 mol) of 2-methylbenzonitrile, and 4.85 g of 2-cyclohexylmethyl-1-{2-(3-(2-methylbenzoyl)phenyl-7-propyl-piperidine) were obtained as a yellow oil.

Analysis:

Calculated for C"2gH3gNO: C 83.40; H 9.4l; N 3.35

Found : C 8 3.14; H 9.54; N 3.67.

Example 9

Using the same procedure as described in Example 7, 18.9 g (0.05 mol) of 2-cyclohexylmethyl-1-(2-(3-bromophenyl)-propyl-7-piperidine was reacted with 0.095 mol of n-butyllithium in diethyl ether, and the resulting lithium derivative reacted directly with 12.4 g

(0.106 mol) of 3-methylbenzonitrile and 10.7 g of 2-cyclohexy1-methyl-1-{2-(3-(3-methylbenzoyl)phenyl7propyl)piperidine were obtained as a yellow oil.

Analysis:

Calculated for C^H^NO: C 83.40; H 9, hl; N 3.35

Found : C 83.06; H 9.38; N 3.48.

Example 10

A solution of 13.0 g (0.032 mol) of 2-cyclohexylmethyl-1-{2-/3-(α-hydroxybenzyl)phenyl7propyl} piperidine (described in Example 1) in 167 ml of glacial acetic acid and 33 ml of perchloric acid was placed in a Parr hydrogenation apparatus 'and reduced over 3.5 g of 10% in palladium-on-charcoal at room temperature and at a hydrogen pressure of approx. 4 kg/cm. The catalyst was then removed by filtration, the filtrate evaporated to dryness and the residue basified with 10% sodium hydroxide and extracted four times with hexane. The combined hexane extracts were dried, evaporated to dryness and the residue chromatographed on 220 g alumina, eluted with 10% ether/89% hexane/1% isopropylamine. The first 350 mL of the eluate was evaporated to dryness, yielding 10.6 g of 2-cyclohexylmethyl-1-(2-(3-benzylphenyl)propyl)piperidine as a yellow oil.

Analysis:

Calculated for CggH^gN: C 86.32; H 10.09; N 3.59

Found : C 85.18; H 10.34; N 3.51.

Example 11

Using the same procedure as described in Example 10, 11.1 g (0.027 mol) of 2-cyclohexylmethyl-1-(2-[3-(ct-hydroxy-α-methylbenzyl)-phenyl-17-propyl)-piperidine (described in example 6) dissolved in 180 ml of glacial acetic acid and 20 ml of 72% perchloric acid reduced with hydrogen over 0.8 g of palladium-on-charcoal, and 10.3 g of 2-cyclohexylmethyl-1-{2-/3-(a- methylbenzyl)phenyl7propyl} piperidine as a yellow oil.

Analysis:

Calculated for C^H^N: C 86.29; H 10.24; N 3.47

Found : C 86.04; H 10.21; N 3.70.

Example 12

A solution of 26.8 g (0.066 mol) of 2-cyclohexylmethyl-1-[2-[3-(α-hydroxybenzy1)phenyl7propyl}piperidine (described in Example 1) in 140 ml of benzene was vigorously stirred and cooled to 16°C and then treated dropwise over 10 minutes with 58 ml of a solution prepared by dissolving 26.7 g of chromium trioxide in 23 ml of concentrated sulfuric acid and diluting with water to 100 ml. The mixture was stirred with cooling for approx. 1 hour 45 minutes, the benzene layer removed and the aqueous layer made basic by adding 120 ml of 10% sodium hydroxide, after which the whole was extracted with benzene. The organic extracts were washed once with dilute alkali, once with sodium chloride solution and then evaporated to dryness to give 21.8 g of an oil which was chromatographed over 300 g of alumina, using 3% isopropylamine in hexane as eluent. The first 600 mL of the eluate was collected and evaporated to dryness, yielding 16.2 g of 2-cyclohexylmethyl-1-(2-(3-benzoylphenyl)propyl)piperidine as a pale yellow viscous oil.

Analysis:

Calculated for CggH^NO: C 83.33; H 9.23; N 3.47

Found : C 83.30; H 9.33; N 3.45.

Example 13

Using the same procedure as in Example 12,

15.2 g (0.39 mol) of 2,6-dimethyl-1-{2-(α-hydroxybenzyl)-phenyl-7-propyl} piperidine (described above in Example 2) was oxidized with 34 ml of a solution prepared by to dissolve 13.4 g of chromium trioxide in 11.5 ml of concentrated sulfuric acid and dilute this with water to 50 ml. The product in the form of the free base was purified

by chromatography on alumina using 10% ether/3% isopropylamine/87% hexane as eluent. 4.8 g of 2,6-dimethyl-1-(2-(3-benzoylphenyl)propyl-7-piperidine was thus produced as a colorless viscous oil.

Analysis:

Calculated for C23H2gNO: C 82.34; H 8.71; N 4.18

Found : C 82.23; H 8.82; N 4.15-

Examples 13A-13G

Using the same procedure as described in Examples 1 and 12, the following compounds of formula I were prepared: Example I3A - 2-methyl-1-/2-(3-benzoylphenyl)propyl7hexamethyleneimine prepared by reacting α-(3-benzoylphenyl) propionyl chloride with 2-methylhexamethyleneimine (mueller et al., Monatsh. 61, 212-218

(1932). .

Example 13B - 4-cyclohexy1-1-12-(3-benzoylphenyl)propyl7piperidine prepared by reacting α-(3-benzoylphenyl)propionyl chloride with 4-cyclohexylpiperidine, reducing with lithium aluminum hydride the resulting 4-cyclohexy1-1-/et-( 3-benzoylphenyl)propionyl-7-piperidine, after which a chromic acid oxidation of the resulting 4-cyclohexyl-1-(2-(3-(a-hydroxybenzyl)phenyl-7-propyl)piperidine was carried out.

Example 13c - 3-butyl-4-/2-(3-benzoylphenyl)propyl7-morpholine prepared by reacting α-(3-benzoylphenyl)propionyl chloride with 3-butylmorpholine, reducing with lithium aluminum hydride the resulting 3-butyl-4-/α-( 3-benzoylphenyl)propionyl7morpholine and chromic acid oxidize the resulting 3-butyl-4-jJ2-[3-(a-hydroxybenzyl)phenyl7propyl}morpholine.

Example 13D - 3-ethyl-4-/2-(3-benzoylphenyl)propyl7-thiomorpholine prepared by reacting α-(3-benzoylphenyl)propionyl chloride with 3-ethylthionorpholine, converting the resulting 3-ethyl 1-4-/α-(3 ~ benzoylphenyl)propionyl7thiomorpholine to the corresponding ethylene glycol ketal, reduce this with lithium aluminum hydride and carry out a hydrolysis with dilute mineral acid on the resulting 3-ethyl1-4-/2-(3-benzoylphenyl)propyl7thiomorpholineethyleneglycol ketal.

Example I3E - 4-methyl-1-12-(3-benzoylphenyl)propyl7piperazine prepared by reacting α-(3-benzoylphenyl)propionyl chloride with 1-methylpiperazine, reducing with lithium aluminum hydride the resulting 4-methyl-1-(α-(3 -benzoylphenyl)propionyl7piperazine, after which a chromic acid oxidation was carried out on the resulting 4-methyl-1-{_2-/3-(α-hydroxybenzy 1)pheny17propyl\piperazine.

Example 13F - 3-benzyl-l-/2-(3-benzoylphenyl)propyl-7piperidine prepared by reacting α-(3-benzoylphenyl)propionyl chloride with 3-benzylpiperidine, reducing with lithium aluminum hydride the resulting 3-benzyl-l-/α-( 3-benzoylphenyl)propionyl7piperidine, after which a chromic acid oxidation was carried out on the resulting 3-benzyl-1-{2-(3-(a-hydroxybenzyl)phenyl7propyl}piperidine.

Example 13G - N-/5~(N',N'-dimethylamino)-2-pentyl7-N-/2-(3~benzoylphenyl)propyl7amine prepared by reacting α-(3-benzoylphenyl)propionyl chloride with 5-(N ',N'-dimethylamino)-2-pentylamine, reducing with lithium aluminum hydride the resulting N-(N',N'-dimethylamino)-2-pentyl7-N-(3-benzoylphenyl)propionyl7amine, after which performed a chromic acid oxidation on the resulting N-(N',N'-dimethylamino)-2-pentyl7-N-{2-(3-(α-hydroxybenzyl)-phenyl7propyl}amine.

Example 14

Using the same procedure as described in Example 7, 5.0 g (13.2 mol) of 2-cyclohexylmethyl-1-(2-(3-bromophenyl)-propyl-7-piperidine was reacted with 0.026 mol of n-butyllithium in diethyl ether, and the resulting lithium derivative was reacted directly with benzonitrile, whereby 4.0 g of 2-cyclohexylmethyl-1-(2-(3-benzoylphenyl)propyl7piperidine identical to the compound described in example 12 was obtained.

Example 15

A mixture of 37.5 g (0.093 mol) of 2-cyclohexylmethyl-1-(2-(3-benzoylphenyl)propyl-7-piperidine (described in Examples 12

and 14 above) and 10.0 g (0.14 mol) of hydroxylamine in 125 ml of 95% ethanol and 25 ml of water were treated with stirring with 19.4 g of powdered sodium hydroxide and the mixture was refluxed for 1 hour. The mixture was then cooled, diluted with hexane, the aqueous layer separated, after which the organic layer after drying was evaporated to dryness and 41.6 g of a yellow oil was obtained which was chromatographed on alumina in 30:70 diethyl ether/hexane, whereby gave 37.3 g of 2-cyclohexylmethyl-1-(2-(3-benzoylphenyl)propyl-7-piperidinoxime as an oil).

Analysis:

Calcd for CggH^gNgO: C 80.33; H 9.15; N 6.69

Found : C 80.03; H 9.42; N 6.44.

Examples I5A-15C

Using the same procedure as described in example 15, the following compounds were prepared: Example 15A - 4-12-(3-benzoylphenyl)ethyl7morpholinoxime (m.p. 117-134°C from benzene/hexane) prepared by reacting 18.15 g (0, 05 mol) 4-(2-(3-benzoylphenyl)ethyl 7-morpholine hydrochloride with 5.6 g (0.08 mol) of hydroxylamine hydrochloride in the presence of 12.5 g (0.31 mol) of sodium hydroxide in 70 ml of ethanol and 18.5 ml of water, and this gave 14.06 g of the product.

Analysis:

Calculated for <C>19<H>22N2°2: C 75'52' H 7^ > N 9'°3

Found : C 73.79; H 7.26; N 8.72.

Example 15B - 4-(3-benzoylphenyl)methylmorpholine oxime (m.p. 145-167°C) prepared by reacting 28.62 g (0.09 mol) of 4-(3-benzoylphenyl)methylmorpholine hydrochloride with 9.63 g (0 .14 mol) of hydroxylamine hydrochloride in the presence of 21.68 g (0.54 mol) of sodium hydroxide in 35 ml of ethanol and 27 ml of water to give 13.9 g of the product.

Example 15c - 4-/2-(3-benzoylphenyl)propyl-7-morpholine oxime (m.p. 117-130°C from isopropanol) prepared by reacting 27 g (0.078 mol) of 4-/2-(3-benzoylphenyl)propyl-7-morpholine hydrochloride with 8.2 g (0.117 mol) of hydroxylamine hydrochloride in the presence of 18.8 g (0.47 mol) of sodium hydroxide in 115 ml of ethanol and 27 ml of water, yielding 3.2 g of product.

Example 16

A solution of 17 g (0.041 mol) of 2-cyclohexylmethyl-1-(2-(3-benzoylphenyl)propyl-7-piperidinoxime (described in Example 15) in 110 ml of ethanol was refluxed and then treated with 10 g (0.043 mol ) sodium metal added in small pieces. Refluxing was continued until all the sodium had dissolved, the solution was then cooled, diluted with 140 ml of water and then evaporated to a volume of about 150 ml in vacuo and then extracted with three portions of benzene. A evaporation of the benzene extracts to dryness gave 14.2 g of an oil which was converted to the acetate salt by dissolving in chloroform, adding glacial acetic acid and evaporating the whole to dryness. The acetate salt was again dissolved in chloroform and chromatographed on alumina eluting with chloroform. The acetate was hydrolyzed on the column, and the free base was obtained from the eluate and then dissolved in ethanol, after which the solution was acidified with hydrogen chloride-containing ether and then evaporated to dryness, this gave 6.38 g of 2-cyclohexylmethyl-1-'1.2-/3 - (α-aminoben zyl)phenyl7propyl^ piperidine dihydrochloride, m.p. 167-195°C.

Analysis:

Calculated for C28Hi|lN2 ' 2HC1: N 5>87> C1 14 >85

Found : N 5, Sl; Cl 14.66.

Examples I6A-I6C

By using the same method as described in example 16, the following compounds with the formulas I and Ia were prepared: Example 16A - 4-/2-/3~(α-aminobenzyl)phenyl7ethyl\morpholine dihydrochloride, m.p. 260-263°C (15.42 g from methanol/diethyl ether) prepared by reducing 14.55 g (0.047 mol) of 4-(2-(3-benzoylphenyl)ethyl-7-morpholinoxime with 11.5 g (0.50 mol) of sodium in 100 ml of absolute ethanol.

Analysis:

Calculated for C^H^NgO. 2HCl: C 61.79; H 7.10; Cl 19,20

Found : C 61.88; H 6.90; Cl 19,16.

Example 16B - 4-/"/ J> - (q-aminobenzyl)phenyl7methyl\morpholini hydrochloride monohydrate, m.p. 270-274°C (8.3 g from methanol/ether) prepared by reducing 8.12 g ( 0.027 mol) of 4-1\3-benzoylphenyl)-methyl-7-morpholino oxime with 6.45 g (0.28 mol) of sodium in absolute ethanol.

Analysis:

Calculated for Cl8H22N20.2HC1.HgO: C 60.84; H 6.81; Cl 19.96

Found : C 60.68; H 6.83; Cl 20,27.

Example 16C - 4-^2-/3-(α-aminobenzyl)phenyl7propyl"j;morpholindi hydrochloride, m.p. 255-265°C (9.5 g from methanol/diethyl ether) prepared by reducing 10.0 g (0.03 mol) 4-(2-(3-benzoylphenyl)propyl7morpholinoxime with 7.1 g (0.31 mol) sodium in 65

ml absolute ethanol.

Analysis:

Calculated for C2Q<H>26<N>2<0>.2HC1: C 62.66; H 7.36; Cl 18.50

Found : C 61.78; H 7.17; Cl 18.01.

Example 17

A solution of 13.0 g (0.031 mol) of 2-cyclohexylmethyl-1-{2-[3-(ct-hydroxy-ct-methylbenzyl)phenyl-7-propyl} piperidine (described in Example 6) in 130 ml of methanol and 3 ml of concentrated sulfuric acid was stirred and refluxed for three quarters of an hour, then cooled, diluted with 100 mL of water, basified with 5 mL of 35% sodium hydroxide, and then extracted with hexane. The combined hexane extracts were washed with sodium chloride solution, dried and evaporated to give 14.2 g of an oil which was chromatographed on 260 g of alumina in 8:92 diethyl ether/hexane. 9.8 g of 2-cyclohexylmethyl-1-{2-[3-(1-phenyl-1-vinyl)-phenyl-7-propyl}piperidine were prepared as an oil.

Analysis:

Calculated for C^H<->^N: C 86.72; H 9.79; N 3.49

Found : C 86.79; H 9.76; N 3.28.

Example 18

4-Methoxyphenylacetic acid (41.5 g, 0.25 mol) was converted to the corresponding acid chloride with 47.7 g (0.4 mol) of thionyl chloride in benzene using the procedure of Example 1. The prepared acid chloride (36, 8 g, 0.2 mol) was reacted with 24.1 g

(0.21 mol) of 2,6-dimethylpiperidine in ether in the presence of 24.2 g (0.24 mol) of triethylamine using the procedure of Example 1. The resulting 38'.8 g (0.15 mol) of 2, 6-dimethyl-l-/"(4-methoxy-phenyl)acetyl-7-piperidine was reduced with lithium aluminum hydride and the product isolated in the form of the hydrochloride salt, and 15.32 g of 2,6-dimethyl-l-/2-(4-methoxyphenyl) were obtained )ethyl 7-piperidine hydrochloride, mp 195-200°C.

The latter compound (1.0 g, 0.004 mol) in the form of

the free base was added in small portions to a stirred mixture of 1.21 g (0.009 mol) aluminum chloride and 1.28 g (0.009 mol) benzoyl chloride. The resulting viscous mixture was stirred for approx. 12 hours at room temperature and then mixed with ice, 2 ml of concentrated hydrochloric acid and 2 ml of water. The resulting mixture was extracted with chloroform and the chloroform extracts washed with sodium chloride solution, dried and evaporated to dryness to give 2,6-dimethyl-1-(2-(3-benzoyl-4-methoxyphenyl)-ethyl-7-piperidine as a yellow oil.

Example 19

A mixture of 45 g (0.13 mol) of 2,6-dimethyl-1-(2-(3-benzoyl-4-methoxyphenyl)ethyl-7-piperidine (described in Example 18) and 34.9 g (0.26 mol) of aluminum chloride in tetrachloroethane was heated and stirred at 50°C for approx. 12 hours and then completely poured into a solution of 30 ml of concentrated hydrochloric acid and 30 ml of ice water. The mixture was made basic with sodium carbonate, extracted four times with chloroform, after which the chloroform extracts were washed with a saturated sodium chloride solution, dried and evaporated to dryness, thereby obtaining a crude product which was again heated for 12 hours to _50°C with 30 g of aluminum chloride and 30 ml tetrachloroethane. By working up as described above, 8 g of crude product was obtained which was dissolved in chloroform. The organic solution was washed five times with 10% sodium carbonate, once with sodium chloride solution and then dried and evaporated to dryness. The residue was dissolved in acetone, after which the solution was treated with ether containing hydrogen chloride and a solid was obtained which was recrystallized from isopropanol. 5.8 g of 2,6-dimethyl-1-(2-(3-benzoyl-4-hydroxyphenyl)ethylpiperidine hydrochloride was obtained, m.p. 217-219°C Analysis :

Calcd for C22H27N02.HC1: C 70.67; H 7.55; N 3.75

Found : C 70.87; H 7.58; N 3.73-Example 20

A solution of 13.2 g (0.03 mol) of 2-cyclohexylmethyl-1-(2-/3-(α-hydroxy-4-chlorobenzyl)phenyl-7-propyl) piperidine (described above in Example 5), 16 ml of concentrated nitric acid and 32 ml of 50% perchloric acid in 160 ml of 1,2-dimethoxyethane was heated at reflux for 1 hour, then cooled, diluted with 50 ml of water, basified with 150 ml of 10% sodium hydroxide and then extracted with hexane. The hexane extracts were washed once with water, once with sodium chloride solution, dried and evaporated to dryness to give 12 g of a crude product which was chromatographed on 200 g of alumina using 10:90 ether/hexane as eluent. The first 75 ml of the eluate was discarded, while the next 600 ml were evaporated to dryness and 9.2 g of 2-cyclohexylmethyl-1-[2-(3-(4-chloro-benzoyl)phenyl-7-propyl)piperidine was obtained.

Analysis:

Calculated for C^H^gClNO: C 76.77; H 8.28; Cl 8.09

Found : C 76.85; H 8.35; Cl 8.27.

Examples 20A-20D

Using the same procedure as described in Example 20, the following compounds were prepared: Example 20A - 2-cyclohexylmethyl-1-/2-(3-benzoylphenyl)ethyl7-piperidine (yellow oil) prepared by oxidizing 14.0 g (0, 03 mol) 2-cyclohexylmethyl-1-(2-/3~(α-hydroxybenzyl)phenyl7ethyl)piperidine (described above in Example IA) in 227 ml of a solution prepared by dissolving 44.5 ml of 72% perchloric acid, 20 ml water and 32 ml of concentrated nitric acid in 320 ml of 1,2-dimethoxyethane.

8.74 g of the product was produced.

Analysis:

Calculated for C^H^NO: C 83.24; H 9.06; N 3.60

Found : C 83.46; H 9.26; N 3.75.

Example 20B - 2-cyclohexylmethyl-1-f2-/3~(3-chlorobenzoyl)-phenyl-7-propyl-piperidine (yellow oil) prepared by oxidizing 17.0 g (0.039 mol) of 2-cyclohexylmethyl-1-(2-/3 -(α-hydroxy-3-chlorobenzyl)phenyl7propyl}piperidine (described above in Example 3A) in 244 ml of a solution prepared by dissolving 48 ml of 50% perchloric acid and 24 ml of concentrated nitric acid in 240 ml of 1,2-dimethoxyethane. 9.65 g of the product was produced.Analysis:

Calculated for C^H^gClNO: C 76.77; H 8.28; N 3.20

Found : C 76.86; H 8.36; N 3.13.

Example 20C - 2-Cyclohexylmethyl-1-f2-(3,4-dichlorobenzoyl)-phenyl-7-propylpiperidine (yellow oil) prepared by oxidizing II, 9 g (0.25 mol) of 2-cyclohexylmethyl-1-{ 2-(α-Hydroxy-3,4-dichlorobenzyl)phenyl7propyl^piperidine (described above in Example 3C) in 156 ml of a solution prepared by dissolving 24 ml of 50% perchloric acid and 12 ml of concentrated nitric acid in 120 ml 1,2-Dimethoxyethane. 5.2 g of the product was produced. Analysis :

Calculated for <C>2<gH>55<C>12NO: C 71.18; H 7.47; N 2.96

Found : C 71.47; H 7.82; N 2.96.

Example 20D - 2-cyclohexylmethyl-1-{2-/3-(2-chlorobenzoyl)-phenyl7propyl\piperidine (yellow oil) prepared by oxidizing 15.7 g (0.036 mol) of 2-cyclohexylmethyl-1-{2- /3-(a-hydroxy-2-chlorobenzyl)phenyl/propyl^piperidine (described above in Example 3D) in 225 ml of a solution prepared by dissolving 48 ml of 50% perchloric acid and 24 ml of concentrated nitric acid in 240 ml of 1,2 -dimethoxyethane. 6.4 g of product was produced.

Analysis:

Calculated for C₂N₂ClNO: C 76.77; K 8.28; N 3.20

Found : C 76.47; H 8.58; N 3.09.

Example 21

A solution of 11.0 g (0.126 mol) of morpholine in 24 ml of dimethylformamide was stirred with external cooling in a water bath and treated during 10 minutes with a solution of 17.35 g (0.06 mol) 1 -(3-benzoylphenyl)-1-bromoethane in 24 ml of dimethylformamide. After the addition was complete, the mixture was stirred for an additional 1 hour at room temperature. It was then filtered, the filter washed with ether and the filtrate poured into 125 ml of water and the mixture extracted twice with ether. Isolation of the product in the form of a free base from the ether extracts in the usual manner gave 14.8 g of an oily product which was chromatographed on alumina using a 1:1 ether/hexane solution as eluent, and this gave 12 g of 4- /l-(3~ benzoylphenyl)ethyl7morpholine as a pale yellow oil.

Analysis:

Calculated for CigH21N<0>2<:> C 77.26; H 7.17; N 4.74

Found : C 76.95; H 7.11; N 4.6l.

Example 22

4-{2-/3~(α-aminobenzyl)phenyl7ethyl}morpholine (15.6 g, 0.05 mol, described in Example 16A) was mixed with 13.8 g (0.30 mol) of 97% formic acid and 9 .4 g (0.11 mol) 35% formaldehyde solution. The mixture was heated to 95°C to obtain complete dissolution of the gummy base, heating was continued for 10 hours, after which the solution was cooled and poured into a dilute mixture of sodium hydroxide and ice. Isolation of the organic material in the usual manner by extraction with ether gave 15.6 g of an oil which was chromatographed on 400 g of alumina using 1.5:98.5 isopropylamine:hexane as eluent. The first ten

fractions of 75 ml each were collected and set aside, while the next ten fractions, each from 75-100 ml, were combined and evaporated to dryness, giving a total of 10.6 g of 4-{2-/3_( a-dimethylaminobenzyl)phenyl-7-ethyl^morpholine as an oil which crystallized on standing, m.p. 60-63°C.

Analysis:

Calculated for <C>21H2gN2<0:> C 77.74; H 8.70; N 8.63

Found : C 77.20; H 8.60; N 8.48.

Example 23

If one reacts 2-cyclohexylmethyl-1-£2-/3~(4-methoxybenzoyl)phenyl7propyl^ piperidine described above in example 7, with hydrobromic acid in glacial acetic acid and isolates the product from a neutral medium, 2-cyclohexylmethyl-1 is produced -{2-[3-(4-hydroxybenzoyl)phenyl-7-propyl}piperidine.

Example 24

Reduction of α-(3-bromophenyl)propionaldehyde with sodium borohydride using the procedure of Example 3, and then reacting the resulting 2-(3-bromophenyl)propanol with an excess of dihydropyran at room temperature in the presence of a few drops of concentrated hydrochloric acid, then 2-(3-bromophenyl)propane tetrahydropyranyl ether is produced. The latter compound can be reacted in diethyl ether with n-butyllithium followed by a reaction of the resulting lithium derivative with benzonitrile using the method from example 7, and 2-(3-benzoylphenyl)propanol is produced which can be reacted with p-toluenesulfonic acid in the presence of pyridine, and this gives 2-(3-benzoylphenyl)propanol p-toluenesulfonate. A reaction between the latter compound and 1-cyclohexylpiperazine in DMF in the presence of anhydrous potassium carbonate,

gives 1-(2-(3-benzoylphenyl)propyl7-4-cyclohexylpiperazine).

Biological test results

Said N-{3~/R-^-(phenyl)-C (=X)7-phenyl-lower-alkyl)-amines with the formulas I and Ia according to the present invention have been tested in the known carrageenan tumors (CE) and adjuvant arthritis (AA) samples and were found to have anti-inflammatory activity. The results obtained expressed as percent inhibition at a dose expressed in millimoles (µM)/kg body weight are shown in Table A below. For comparative purposes, data obtained in a carrageenan edema sample with a reference compound (indicated "Ref."), i.e. 4-([3-benzoylphenyl)methyl/morpholine, described in French patent 1,549,342, have also been given. All data were obtained by oral administration.

x Statistically different from controls p< 0.05

xx Statistically different from controls ps 0.01

Certain N-{3-/R-L-(phenyl)-C(=X}7-phenyl-lower-alkyl^y amines of formula I were tested for anti-viral activity against herpes simplex virus types 1 and 2, and found to have anti-viral activity.They obtained data expressed as minimum inhibitory concentration (meg./ml) given in Table B below.

Claims (1)

Analogous method for the preparation of therapeutically active compounds with the general formula: where R and is hydrogen, lower alkyl, hydroxy, lower alkoxy, trifluoromethyl, lower alkyl mercapto, lower alkylsulfinyl, lower alkylsulfonyl or halogen selected from fluorine, chlorine and bromine; R? is hydrogen, or lower alkoxy or hydroxy in the 4-position, or lower alkyl either in the 2-, 4-, 5- or 6-position; R 1 is hydrogen or lower alkyl; the group ^C=X represents ^C = 0, ;?C(R3)OH, ^C(R3)H, ^C = CH2, ^C=NOH or ^ Cm( R^) 2 (where R-j is only hydrogen or methyl in the latter case); and N=B is one of the groups wherein R-j is hydrogen or lower alkyl and are the same or different when they occur more than once; R 1 and R 2 are each lower alkyl; R 8 and R 8 are each hydrogen, lower alkyl, cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl or benzyl; Z is 0, S or N-Rg, wherein Rg is lower alkyl or cyclohexyl; and n is an integer of 1, 2 or 3; as well as acid addition salts thereof, characterized in that (a) a compound is prepared where ^C=X is ^CR^OH and R^ is H, by reduction using an alkali metal aluminum hydride, of a corresponding compound with the formula: or prepares a compound where ^C=X is~>C=0 by ketalization of the ^C=0 group in the RR^-(phenyl)-CO part in the compound of formula V before the reduction step and then carrying out a deketalization sering after the reduction step; or (b) prepares a compound wherein ^C=X is ^C = 0 and R 2 is hydroxy or lower alkoxy in the 4-position by reaction in the presence of a Lewis acid, of a compound of the formula: with a compound of the formula: where Hal is halogen and, if desired, cleavage of an obtained compound I where R,, is lower alkoxy to form the corresponding end compound where R 1 is hydroxy; or (c) produces a compound where >C=X is^C=0 by reacting a compound of the formula: with an amine of the formula H-N=B in the presence of an acid acceptor; or (d) prepares a compound where ^C=X is ^C(R3)OH or ^C=0 by reacting a compound of the formula: with a compound of the formula: wherein a compound of formula I, where ^C=X is ^C(H)OH from (XX), ^C = 0 (from XXI), or >C (R^ )OH (where R^ is only lower-alkyl in XXII) are produced respectively; and, if desired, oxidizes a compound thus obtained where ^C = X is ^C(H)OH to obtain the corresponding compound where ^C=X is ^C = 0; and, if desired, reducing an obtained compound where >C=X is ^C=0 to obtain the corresponding compound where ^C=X