CH618677A5 - Process for the preparation of phenylalkylamines - Google Patents

Abstract

The compounds of formula I ( &rdurule& C=X = &rdurule& C=O or &rdurule& CHOH); R1, R2 and -N=B see Claim 1) are prepared by selective reduction of a compound of formula V with a double hydride of aluminium and an alkali metal, protecting, if desired, the group &rdurule& C=X = &rdurule& C=O by intermediate acetalisation. Compounds of formula I where &rdurule& C=X will take the following meanings: (a) &rdurule& CHOH (reduction of the &rdurule& C=O group) (b) &rdurule& C=O (oxidation of the &rdurule& CHOH group) (c) &rdurule& CH2 (reduction of the &rdurule& CHOH group) (d) &rdurule& C=NOH ( &rdurule& C=O reacted with hydroxylamine) (e) &rdurule& CH-NH2 (reduction of the oxime) and (f) &rdurule& CH-N(CH3)2 (methylation of the amine e) are obtained via a number of additional reactions. All these compounds can be converted to acid addition salts. They are useful as medicaments, in particular as antiinflammatory agents. <IMAGE> <IMAGE>

Description

This invention relates to the preparation of phenyl (lower alkyl) amines useful as anti-inflammatory agents.

It is known that a very broad category of organic compounds having very diverse structural types are useful as anti-inflammatory agents, but that a large number of these anti-inflammatory agents are acidic, for example a- (3-benzoyl acid -phenyl) propionic acid, generically called Ketoprofen (British Patent No. 1164585 published Sept. 17, 1969). These acid agents are often irritants, and in some cases ulcerogenic,

618,677

vis the gastric mucosa when administered orally. There is therefore a great need for anti-inflammatory agents, for example of compounds having a basic amine function, which one would expect that they would not be irritating with respect to the gastric mucous membranes. Although the chemical literature describes many types of amino-substituted compounds, the anti-inflammatory activity of which is indicated [see, for example, the U.S. Patent. No. 3770748 patented Nov. 6, 1973 and the U.S. Patent N ° 3803127 patented on April 9, 1974 (N-phenylpolymethylene-imines); the U.S. patent No. 3772311 patented Nov. 13, 1973 and the U.S. Patent N ° 3773773 patented Nov. 20, 1973 (poly-methylene-imino (lower alkanoyl) pyrazoles); the U.S. patent No. 3773944 patented Nov. 20, 1973 (1- [3-aminopropyl] phthalans); the U.S. patent N ° 3801594 patented on April 2, 1974 (3-amino- (lower alkyl) indoles); the U.S. patent No. 3810985, patented on May 14, 1974 (4-anilo-l, 3,5-triazines) and French patent No. 1549342 (4- [benzoylphenylmethyl] morpholines)], none of these basic compounds is available in the to the knowledge of the licensee, and none is the subject of extensive research on the part of pharmacologists with a view to possible commercial development. The search for a non-acidic and effective anti-inflammatory agent enabling commercial development therefore continues.

The present invention relates to the preparation of N- {3- [R! - (phenyl) -C - (= X)] - phenyl (lower akyl)} amines, which are useful as anti-inflammatory agents, of formula:

chch2-n = * b

(IA)

r,

in which Rx represents a hydrogen atom or one or two identical or different groups chosen from lower alkyl, hydroxy, lower alkoxy, trifluoromethyl, lower alkyl-mercapto, lower alkylsulfinyl, lower alkylsulfonyl or halogen atoms groups chosen from fluorine , chlorine and bromine; R2 represents a hydrogen atom or an alkoxy or hydroxy group in position 4, or a lower alkyl group in position 2,4,5 or 6; R3 represents a hydrogen atom or a lower alkyl group; the group; C = X represents; C = 0,; C (HpH, 5 CH2,; C = NOH or; CHN (R'3) 2 (where the two R3 'are either hydrogen or a methyl group) and - N = B represents one of the groups

-NH - C - R.

-NOT-

r c

R.

-NOT

r ch-r4

\

CH-Ri

I <

r,

I

>

CIÎ2 R4

C6H5

r,

. (or) J n

R.

n ~ \

-NOT

and

V_ | _ /

-NHCH (CH-) M 2 n

1.

\

R,

R,

where R3 represents a hydrogen atom or a lower alkyl group and represents identical or different groups when it appears more than once in the same group, R4 and R5 each represent a lower alkyl group; R6 and R7 20 each represent a hydrogen atom or a lower alkyl, cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl or benzyl group; Z represents an O, S atom or an N — R8 group; R8 represents a lower alkyl or cyclohexyl group; and n is one of the integers 1,2 and 3. The preferred compounds of formula I are those in which Rt represents a hydrogen atom or one or two identical or different groups : lower alkyl, lower alkoxy or halogen atoms; R2 represents a hydrogen atom, or a lower alkoxy or hydroxy group in position 4; and N = B represents one of the groups r.

-NOT

V

R,

. (ch-)

' -NOT

2 n n ~ \

.-n z or

-NHCH (CH2) „N

nx in which R6 represents a hydrogen atom or a lower alkyl, cyclohexyl, cyclohexylmethyl, 2-cyclohexyl-50 ethyl or 3-cyclohexylpropyl group; R7 represents a hydrogen atom; Z represents an oxygen atom; and R3, R4 and n have the meanings given above.

The particularly preferred compounds of formula I forming part of the field of the invention as described above are those in which Rj represents a hydrogen atom or one or two lower alkoxy groups or identical or different halogen atoms; R2 represents a hydrogen atom; ; C = X represents a group 5 C = 0.5 CHOH,? CH2,? C = NOH or; CHNH2; and N = B represents one of the groupings

65

\

/ —V. .0 "

r,

<CH2 »n

618,677

4

/ ~ H

N Z

V7

Z or

-NHCH (CH-) N

/ R4

2 n

where R6 represents a hydrogen atom, a lower alkyl, cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl or 3-cyclohexylpropyl group; R7 represents a hydrogen atom; Z represents an oxygen atom; n represents the integers 1 or 2; and R3 and R4 have the meanings given above.

Used here, the terms lower alkyl and lower alkoxy denote saturated monovalent aliphatic radicals, including branched chain radicals, having from 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, s- butyl, isobutyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy and isobutoxy.

5

The compounds of formula I are prepared in which the group; C = X represents a group> C (H) OH after, for example, reaction with a suitable 3- [R1- (phenylX ^ O] -phenylalkanoyl lower halide formula III (prepared by reacting the corresponding acid of formula II with a thionyl halide) with an appropriate amine of formula IV H — N = B, according to the invention by reduction of 3- [R1- (phenyl) CO] phenyl-lower alkanoylamine resulting from formula V using a reagent capable of reducing amides to amines, namely an i5 hydride of aluminum and alkali metal. The process is represented by the following sequence of reactions:

tìiCO-

Hal

CHCO-N = B

where Rt, R2, R3 and N = B have the meanings given above, and Hai represents a halogen atom. The preparation of the acid halide can be carried out with or without a solvent, by heating the acid with a molar excess of the thionyl halide. The halide can be converted into the amide of formula V by reacting the halide with the amine in the presence of an acid acceptor, for example an alkali metal carbonate or bicarbonate, a lower trialkylamine or a excess of the amine H — N = B. The reaction is preferably carried out in an inert organic solvent, for example methylene dichloride, benzene, toluene or xylene. The reduction of the amide is preferably carried out with an aluminum and alkali metal hydride in an inert organic solvent, for example diethyl ether, tetrahydrofuran, dioxane or dibutyl ether.

As indicated by the previous reaction, the reduction of the lower 3- [Rr (phenyl) CO] phenylalkanoylamines of formula V also effects the reduction of the carbonyl group of the R1- (phenyl) CO part into an alcohol group? CHOH. This reduction can be avoided, if desired, by protecting the carbonyl group of the R1- (phenyl) CO part with an acetal group, for example the acetal formed with ethylene glycol. Acetals can be prepared by reacting the carbonyl compound with an alcohol in the presence of an acid catalyst under dehydrating conditions. The acetal group can then be eliminated by hydrolysis at a later stage, after reduction of the amide function. n / a Or, when the carbonyl group is reduced to an alcohol group, the alcohols can be reoxidized to ketones if compounds in which; C = X is a carbonyl group. The oxidizing agents preferred for this purpose are chromic acid or the nitric acid / perchloric acid mixture, and it is preferred to carry out the reaction in an inert organic solvent, for example benzene when the chromic acid is the oxidant, and 1,2-di-methoxyethane when the oxidant is the nitric acid / perchloric acid mixture.

The process described above is used to prepare the compounds 60 of formula I where 5 C = X is a carbonyl group 5 C = 0, or an alcohol group; C (H) OH. The compounds of formula I are prepared, where the group; C = X has the other meanings given above, by simple chemical transformations on the carbonyl or alcohol groups. Thus, the compounds are prepared where the grouping; C = X represents a 2 C (H2) group by catalytic reduction of the corresponding alcohol 5 C (H) OH, with hydrogen in the presence of perchloric acid. A preferred catalyst is palladium on carbon, and it is preferred

5

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carry out the reaction in glacial acetic acid as solvent. The reduction is generally carried out at a pressure of between 2.7 and 6.8 atmospheres.

The compounds of formula I are prepared where> C = X is the group; C = NOH from the corresponding ketones (> C = X is a group; C = 0) by heating the latter with hydroxylamine in an inert organic solvent, for example a lower alkanol.

The compounds of formula I are prepared where C = X is the group CHNH2, by reducing the corresponding oximes (; C = X is a group; C = NOH) with sodium in a lower alkanol. The compounds of formula I where; C = X is a group; C = NOH, in addition to their utility as pharmaceutically active compounds as described below, are therefore also useful as intermediates for the preparation of compounds where> C = X is a group; CHNH2.

The compounds of formula I can be prepared in which; C = X represents a group? CHN (CH3) 2, from the corresponding primary amines by treatment of the latter with formaldehyde in the presence of formic acid.

The compounds of formula la are prepared in which the group C = X represents a group> CHNH2, from the corresponding compounds in which> C = X represents; C = 0, by transformation of the latter into oxime and reduction of the latter into amine as described above.

The amines of formula IV where - N = B is a group of formula:

R3

where n is the integer 1 and R7 is a hydrogen atom, by refluxing a mixture of the appropriate alkanedione, ammonium acetate and glacial acetic acid, and by catalytically reducing the platinum oxide 2-R3-5-R6-pyrrole resulting, according to the reaction sequence:

Ao oA

NH4OACJ

HOAC

*

H

R3 R3

I I

-nh-c-r ", -n-c-r5,

I I I r4 chr4

c6h5

ch-r4

-NOT

/

V

ch-r4 r3

Ri or - NHCH (CH2) nN

R *

/

\

Ri are known compounds.

The amines in which - N = B is the group:

rv>

R.

- <CH2> p

H

where R3 and R6 have the meanings given above.

Or, we prepare the amines in which - N = B is the group ^

35

-NOT

>

R.

<CH2) n where n is equal to 1 and R7 is a hydrogen atom, by reaction of a Grignard reagent R6MgHal with a 4-R3-halobutyronitrile of formula R3-CH— (Hai) - (CH2) 2— CN; direct cyclization of the resulting 1-amino-1-R6-4-R3-4-halobutene; and cata-45 lytic reduction of the resulting 2-R6-5-R3-4,5-dihydropyrrole as indicated by the reaction sequence:

not

J -Hai CN + V9Hal where n is equal to 2, are also known, and have been generally described in the US patent. No. 3238215. As described here, they are prepared by catalytic reduction on platinum oxide of the pyridines suitably substituted with groups R3, R6 or R7, which are commercially available.

We can prepare the amines in which - N = B is the group:

-NOT

\

R.

(CH2) „

^ / H, N \

618,677

6

where RS, R6 and Hai have the meanings given above.

The amines are advantageously prepared where - N = B is the group:

\ /

where Z is an atom O, according to the method described in British patent N ° 835717, which consists in passing a vaporized mixture of a glycolether of formula as well as the amines where - N = B is the group:

(0H2) n

OH OH

with ammonia and hydrogen on a nickel or cobalt-based hydrogenation / dehydrogenation catalyst, at a temperature of 150 to 250 ° C. A preferred catalyst is nickel on kieselguhr.

The amines of formula VI are preferably prepared in which —N = B is the group:

R_

where n is equal to 2, by catalytic reduction on platinum oxide of the corresponding 4-R6-pyridine.

We can prepare the amines where - N = B is the grouping:

20

-NOT

R.

-NOT

. (CH2) n

R,

R,

where Z is an atom S, by the methods described by Idson et al., "J. Am. Chem. Soc. ”, 76.2902 (1954), which include either the reaction of sodium sulfide with an appropriate bis-2-haloethylamine: -,

where R3 and R7 are hydrogen atoms, n is the integer 3 and R6 has the meaning given above, by Beckmann transposition of an appropriate R6-cyclohexanone oxime and reduction by double lithium hydride and aluminum of the resulting lactam, depending on the reaction:

H-N

\ -

Hai Hai r,

either the reaction of ammonia with an appropriate bis-2-haloethyl sulfide:

We can prepare the amines of formula VI where - N: group: r

Year

VlV

-NOT

R,

Hai Hai

6

where R3 and R6 have the meanings given above, and Hai represents a halogen atom.

The lower 3- [R1- (phenyl) CO] phenylalkanoic acids of formula II where R2 is a hydrogen atom or a lower alkyl group are generally known compounds which are prepared by the methods described in the British patent = B is No. 1164585. Although the compounds of formula II in which R2 is a hydroxy group can also be prepared by the methods used to prepare the compounds in which R2 is a hydrogen atom or an alkyl group lower and transform the compounds of formula II thus prepared, as described above, into final products of formula I, it is preferable to prepare the compounds of 65 formula I where R2 is a hydroxy group starting from an acid 4- (lower alkoxy ) lower phenylalkanoic by transformation of the latter into the corresponding acid halide; transformation of the latter into 4- (lower alkoxy) phenylalkanoyl-

corresponding lower amine by reaction of the acid halide with an amine H — N = B, and reduction of the resulting amide with a reagent capable of reducing amides to amines, for example an aluminum and alkali metal hydride; reaction of the resulting amine with an acid halide of formula Rt- (phenyl) - s where Ri, R3, R4, N = B and Hai have the meanings given above. The reaction conditions for the first four reactions in this sequence of reactions have been described above, and cleavage of the ether by hydrobromic acid is a conventional reaction well known to organic chemists.

The new compounds obtained according to the present invention are the compounds of formula I and IA and their acid addition salts. The free base form of the compounds obtained is transformed into the acid addition salt form by interaction of the base with an acid. Likewise, the free base can be regenerated from the acid addition salt in a conventional manner, i.e. by treating the salts with weak and cold aqueous bases, e.g. alkali metal carbonates and alkali metal bicarbonates. The bases thus regenerated can then be reacted with an identical or different acid to give the same or to obtain a different acid addition salt. Thus, the new bases and all of their acid addition salts are easily convertible into each other.

It will therefore be seen that the formulas not only represent the developed configuration of the bases, but also represent the structural entities which are common to all the compounds, either 55 in the form of the free base, or in the form of the acid addition salts from the base. It has been found that due to these common structural entities, bases and their acid addition salts have inherent pharmacological activity of a type which will be more fully described below. This inherent pharmacological activity can be taken advantage of in a form useful for pharmaceutical purposes by using the free bases themselves or the acid addition salts formed with pharmaceutically acceptable acids, i.e. say acids whose anions are harmless towards animal organisms, at effective doses 65 of the salts, so that the beneficial properties inherent in the common structural entity represented by the free bases are not modified by side effects attributable to anions.

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CO — Hai, under the conditions of the Friedel-Crafts reaction; and finally cutting the lower alkoxy group into a hydroxy group, using well known methods such as heating with hydrobromic acid. The process is represented by the following reactions:

CHCH2 ~ N = B

When using the pharmacological activity of the salts of the invention, it is obviously preferred to use pharmaceutically acceptable salts. Although insolubility in water, high toxicity or lack of crystallinity may make certain salt species less suitable or less suitable for use in this form in a given pharmaceutical application, the toxic or insoluble salts in l water can be converted to the corresponding pharmaceutically acceptable bases by decomposition of the salt using an aqueous base as explained above, or they can be transformed into any desired pharmaceutically acceptable acid addition salt, by double decomposition reactions concerning the anion, for example ion exchange procedures.

However, apart from their usefulness in pharmaceutical applications, the salts are useful as characterization derivatives or the identification of free bases or in the procedures of separation or purification. Like all acid addition salts, these characterization or purification derivatives can, if desired, be used to regenerate the pharmaceutically acceptable free bases by reaction of the salts with an aqueous base, or they can be transformed into a pharmaceutically acceptable acid addition salt by ion exchange procedures, for example.

It will be seen from the above that all of the acid addition salts of the new bases are useful and important compounds, regardless of solubility, toxicity, physical condition, etc. considerations, and they do therefore part of the field of the present invention.

The new feature of the compounds obtained according to the invention then lies in the idea of the bases and cationic forms of the new N- {3- [R1- (phenyl) C (= X)] phenyl (lower alkyl)} amines and not in any particular acid or anionic acid group associated with the salt forms of the compounds; on the contrary, the acid groups or anions which can be associated with

R

HCO-Hal

CHCO-N = B

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8

Salt forms are in themselves neither new nor determinative, and they can be any acid anion or any other acidic substance which can form salts with bases. In fact, in aqueous solutions, the base form or the water-soluble acid addition salt form of the compounds of the invention both have a protonated cation or a common ammonium ion.

Thus, the appropriate acid addition salts are those derived from various acids such as formic acid, acetic acid, isobutyric acid, α-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, acid 1-naphthalenecarboxylic acid, cinnamic acid, cyclohexanecarboxylic acid, mandelic acid, tropic acid, crotonic acid, acetylenedicarboxylic acid, sorbic acid, 2-furanecarboxylic acid, cholic acid , pyrenecarboxylic acid, 2-pyridinecarboxylic acid, 3-indole-acetic acid, quinic acid, sulfamic acid, methane-sulfonic acid, isethionic acid, benzenesulfonic acid , p-toluenesulfonic acid, benzenesulfinic acid, butylaronic acid, diethylphosphonic acid, p-aminophenyl-arsinic acid, pheic acid nylstibnique, phenylphosphinous acid, methylphosphinic acid, phenylphosphinic acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, nitric acid, acid sulfuric, phosphoric acid, hydrocyanic acid, phosphotungs-tic acid, molybdic acid, phosphomolybdic acid, pyro-phosphoric acid, arsenic acid, picric acid, picrolo acid -nique, barbituric acid, boron trifluoride, etc.

The acid addition salts are prepared by reacting the free base and the acid in an organic solvent and separating the salt directly or by concentration of the solution.

Due to the presence of at least one asymmetric center, and at most four asymmetric centers, in the compounds of the invention, that is to say the carbon atom adjacent to the phenyl ring to which the R3 group is attached and the various asymmetric centers of the group - N = B to which the groups R3, R4, R5, R6 and R7 are fixed, the compounds of this invention can exist in stereochemically isomeric forms which are all considered to be part of the field of this invention. If desired, separation or production of a particular stereochemical form can be accomplished by application of general principles known in the art.

According to conventional pharmacological test procedures, it has been found that the compounds of formula I and IA have anti-inflammatory activity and are useful as anti-inflammatory agents. It has also been found that certain compounds of formula IA have antiviral activity and are therefore also useful as antiviral agents. The anti-inflammatory activity is determined by using: 1) the carrageenan-induced foot edema inhibition test essentially described by Van Arman et al, "J. Pharmacol. Exptl. Therap. ", 150, 328 (1965) as modified by Winter et al," Proc. Soc. Exp. Biol. and Med. ”, 111,544 (1962), and 2) a modification of the adjuvant-induced arthritis inhibition assay described by Pierson, J.,“ Chronic Diseases ”, 16, 863 (1963) and Glenn et al, "Am. J. Vet. Res. ”, 26.1180 (1965).

The antiviral activity of the compounds against the herpes simplex virus types 1 and 2 is demonstrated in vitro by addition of the compounds to tissue cultures infected with the herpes virus. Tissue culture monolayers (BSC, cell line, monkey kidney) are infected with one hundred DIJ0CT (infectious dose of tissue cultures) of infectious virus. After 1 h of virus absorption, a fresh maintenance medium containing various concentrations of the test compound is added to the monolayers. The cultures are then incubated at 36-37 ° C and, after 48 and 72 h, the cultures are examined under a microscope. In infected control tubes as well as in those containing inactive compounds, virus growth is indicated by the production of characteristic cytopathic effects with cell destruction. In the presence of an active compound, the cells normally grow in the same way as those contained in the control of tissue cultures. Simultaneously with the antiviral test, the toxicity of each compound is evaluated in separate cultures. Identical concentrations of the test compound are added to the tissue culture monolayers in the absence of virus. Concentrations of the compound that exhibit toxic effects on cells are not used in the antiviral assay. The activity of the compounds is expressed in minimum inhibitory concentration (MIC), the MIC being the lowest concentration of the test compound which completely inhibits the growth of the virus.

The formulations can be prepared for use by incorporating them into a dosage unit in the form of tablets or capsules for oral administration, either alone or in combination with suitable adjuvants such as calcium carbonate, starch, lactose, talc, magnesium stearate, gum arabic, etc. In addition, the compounds can be formulated for oral administration in aqueous alcohol, glycol or oily solutions or oil / water emulsions, in the same way as conventional medicinal substances are prepared.

The molecular structures of the compounds obtained according to the invention have been assigned on the basis of the study of their infrared, ultraviolet and NMR spectra and have been confirmed by the correspondence between the values calculated and found in the elementary analyzes of the elements.

The following examples will better illustrate the invention. The melting points are all uncorrected.

Preparation of amino intermediates Preparation I

In three separate tests, portions of 33.8 g (0.20 mole) of 2-benzylpyridine, each in a solution of about 225 ml of ethanol and 22 ml of concentrated hydrochloric acid, are reduced on portions 4.0 g of platinum oxide as catalyst, in about 3.7 atmospheres of hydrogen at a temperature of about 55-61 ° C. When the reduction is complete in each case, the catalyst is removed by filtration, it is washed with small portions of ethanol and the combined filtrates are evaporated to a volume of approximately 80 ml and diluted to approximately 500 ml with acetone at the boil. The solid which precipitates is collected, washed with acetone and dried, which gives a total yield of 124.8 g of 2-cyclohexylmethylpiperidine hydrochloride, m.p. 211-213 ° C. The free base is regenerated from the hydrochloride by neutralization of an aqueous solution of the latter using potassium carbonate, extraction of the oily base in benzene, evaporation of the benzene solution to dryness , and distillation of the residual oil under vacuum at 55-59 ° C / 0.27 mm. 89.4 g of 2-cyclohexylmethylpiperidine are thus obtained.

Preparation 2

The mixture is heated and stirred in a Parr hydrogenator under 3.75 atmospheres of hydrogen, at a temperature of approximately 60 ° C., a mixture of 15.52 g (0.10 mole) of 2-phenylpyridine, of 15 ml. concentrated hydrochloric acid and 2.0 g of platinum oxide in 185 ml of ethanol in a pressure bottle. When the reduction is complete in about 8 h, the catalyst is removed by filtration and the filtrate is concentrated to about 50 ml and diluted with 200 ml of acetone. The solid which separates is collected and dried, which gives 14.54 g of 2-cyclohexylpiperidine hydrochloride, m.p. 251-253 ° C.

Preparation 3

Heated and stirred in a Parr hydrogenator at about 3.75 atmospheres of hydrogen, at a temperature of about 60 ° C, a mixture of 9.1 g (0.05 mole) of 2-stilbazole (Shaw and al, "J. Chem. Soc.", 1933,77-79) and 1.0 g of platinum oxide in a solution of 240 ml of ethanol and 10 ml of hydrochloric acid

5

10

15

20

25

30

35

40

45

50

55

60

65

9

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concentrated in a pressure bottle. When the reduction is complete in approximately 8 h, the catalyst is filtered off, the filtrate is concentrated to a volume of approximately 50 ml and diluted with approximately 200 ml of acetone. The solid which separates is collected and dried, which gives 9.6 g of 2- (2-cyclo-hexylethyl) piperidine hydrochloride, m.p. 155-156 ° C.

Preparation 4

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

The latter is reduced (36.2 g, 0.2 mole), dissolved in 220 ml of absolute ethanol and 30 ml of concentrated hydrochloric acid, on 3.0 g of platinum oxide under hydrogen pressure d '' about 3.75 atmospheres. The product is treated as described above in Preparation 1 and is separated as the hydrochloride, and 43.5 g of 4- (2-cyclo-hexylethyl) piperidine hydrochloride, m.p. 246-248 ° C.

Preparation 5

Reduced with hydrogen over 2 g of platinum oxide under a hydrogen pressure of approximately 3.75 atmospheres 15.5 g (0.1 mole) of 4-phenylpyridine dissolved in 185 ml of absolute ethanol and 15 ml of concentrated hydrochloric acid. The product is treated as described above in Preparation 1 and separated as the hydrochloride to give 15.3 g of 4-cyclohexylpiperidine hydrochloride. (The free base melts at 106-109 ° C.)

Preparation 6

To a mixture of 8.6 g (0.36 mole) of magnesium turn in 150 ml of dry ether, a solution of 45.0 g (0.36 mole) of benzyl chloride in 75 ml of anhydrous ether. When the addition is complete, the mixture is stirred for approximately 1 h, then it is treated dropwise with a solution of 26.6 g of 4-chloro-butyronitrile in 95 ml of ether. Once the addition is complete, the ether is gradually distilled while replacing it with an equal volume of toluene. The mixture is heated under reflux (to approximately 109 ° C.) for approximately 30 min, it is cooled to approximately 15 ° C., it is treated dropwise with 300 ml of 10% aqueous ammonium chloride, it is filtered and the organic layer is separated. It is washed with three times 100 ml of dilute hydrochloric acid, and the combined acid extracts are made alkaline with solid potassium carbonate. Extraction of the mixture with ether and removal of the solvent from the combined organic extracts provides an oil which is distilled under vacuum, which gives 13.05 g of 2-benzyl-4,5-dihydropyrrole, eg 123 -125 ° C / 13 mm, n £ 5 = 1.5405.

The latter is reduced, dissolved in 210 ml of ethanol and 15 ml of concentrated hydrochloric acid, with hydrogen over 2 g of platinum oxide under a hydrogen pressure of approximately 3.4 atmospheres. The mixture is treated as described above in Preparation 1 and the product is isolated in the form of the hydrochloride, and 16.8 g of 2-cyclohexylmethylpyrro-lidin hydrochloride are obtained, m.p. 130.5-131.5 ° C (recrystallized from acetone).

Preparation 7

To a suspension of 11.2 g (1.6 mole) of lithium wire in 600 ml of anhydrous ether, 125.6 g (0.8 mole) of bromobenzene are added dropwise. Once the addition is complete, the mixture is stirred for approximately 1 h, then treated dropwise, first with a solution of 74.4 g (0.8 mole) of picoline in 100 ml of ether anhydrous, then, after having stirred for 15 min, with a solution of 74.0 g (0.4 mole) of 2-phenylethyl bromide in 100 ml of ether. The mixture is stirred at room temperature for about 12 h, then poured with stirring onto 300 g of ice. When all the excess lithium has reacted, the layers are separated, the aqueous layer is washed with additional ether, and the combined organic layers are washed with brine, dried and brought to dryness to obtain a residual oil which is distilled under vacuum, which gives 41.3 g of 2- (3-phenylpropyl) pyridine, mp 76-78 ° C / 0.05 mm, n £ 5 = 1.5592.

The latter is reduced (19.7 g, 0.1 mole) dissolved in 235 ml of ethanol and 15 ml of concentrated hydrochloric acid, with hydrogen over 2 g of platinum oxide under hydrogen pressure from about 3.75 atmospheres to about 65 ° C. The product is treated as described above in preparation 1 and separated in the form of the hydrochloride, and 22.2 g of the hydrochloride are obtained. 2- (3-cyclohexylpropyl) piperidine, mp 175-176.5 ° C (recrystallized from ethyl acetate).

Preparation 8

The catalytic reduction of 3-benzylpyridine in glacial acetic acid on a platinum oxide catalyst and the separation of the product using the procedure described above in preparation 1 provides 3-benzylpiperidine.

Preparation of final products Example 1

A. Add a solution of 25.4 g (0.1 mole) of α- (3-benzoylphenyl) propionic acid in 40 ml of benzene to 19.8 g (0.166 mole) of thionyl chloride and heat the solution

at reflux for 2'A h. Then the solvent is removed in vacuo and the resulting oil (28 g) consisting of a- (3-benzoylphenyl) propionyl chloride is dissolved in 40 ml of diethyl ether, and added with stirring over 30 min. a solution of 2-cyclohexylmethylpiperidine in 80 ml of diethyl ether. The mixture is stirred for about 48 h at room temperature, then it is filtered, the filter is washed with ether and the combined filtrates are 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-la- (3-benzoylphenyl) -propionylpiperidine.

B. The latter is dissolved (35.5 g, 0.085 mole) in 200 ml of diethyl ether and the solution is added dropwise with stirring to a mixture of 8.08 g (0.21 mole) of double hydride. of lithium aluminum in 200 ml of ether while maintaining the temperature at 10-15 ° C. The reaction mixture is stirred at room temperature for 3 h, it is decomposed by the dropwise addition of 8, 1 ml of water, then 8.1 ml of a 15% sodium hydroxide solution and an additional 22.2 ml of water. Then the mixture is stirred for 1 h, filtered and the filtrate is evaporated to dryness, which gives 34.0 g of an oil from which 10.5 g are chromatographed on 200 g of alumina which is eluted with a solution of 60% hexane and 40% ether. The first fractions are collected and evaporated to dryness, which gives 8.0 g of 2-cyclohexylmethyl-l- {2- [3- (a-hydroxybenzyl) phenyl] propyl} piperidine in the form of a viscous oil .

Analysis for ^ 28 ^ 39 ^ 0 *

Calculated: C 82.91 H 9.69 N3.45

Found: C 83.12 H 9.80 N3.49.

Examples 1A-1D

By following a procedure similar to that described in Example 1, the following compounds of formula I are prepared in the same way:

Example ÎA

2-Cyclohexylmethyl-l- {2- [3- (a-hydroxybenzyl) phenyl] -ethyljpiperidine, m.p. 122-124 ° C (5.8 g recrystallized from a benzene / hexane mixture), prepared by reaction of 42 g (0.16 mole) of 3-benzoylphenylacetyl chloride (German patent application

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No. 2243444, published March 8, 1974) with 31.7 g (0.175 mole) of

2-cyclohexylmethylpiperidine in 150 ml of ether, in the presence of 19.4 g (0.192 mol) of triethylamine, and reduction of the resulting 2-cyclo-hexylmethyl-1 - [(3-benzoylphenyl) acetyl] piperidine (46 g) with 13 g (0.35 mol) of double lithium aluminum hydride in 325 ml of ether.

Analysis for C27H37NO:

Calculated: C 82.81 H 9.52 N3.58

Found: C 83.01 H 9.54 N3.52.

Example 1B

2,6-Dimethyl-1- {2- [3- (a-hydroxybenzyl) phenyl] ethyl} -piperidine, m.p. 115-117 ° C (9.53 g recrystallized from a benzene / hexane mixture), prepared by reaction of 42 g (0.16 mole) of 3-benzoylphenylacetyl chloride with 19.8 g (0.175 mole) of 2.6 -dimethylpiperidine in 150 ml of ether, in the presence of 19.4 g (0.192 mole) of triethylamine and reduction of the resulting 2,6-dimethyl-1 - [(3-benzoylphenyl) acetyl] piperidine (49 g) with 13 , 9 g (0.365 mole) of double lithium aluminum hydride in 300 ml of ether.

Analysis for C22H29NO:

Calculated: C 81.69 H 9.04 N4.33

Found: C 81.83 H 9.04 N 4.32.

Example 1C

4- [2- (3-Benzoylphenyl) ethyl] morpholine hydrochloride monohydrate, m.p. 177.5-180 ° C (29.0 g recrystallized from acetone), prepared by reaction of 46.5 g (0.18 mole) of chloride

3-benzoylphenylacetyl with 17.2 g (0.198 mole) of morpholine in 225 ml of methylene dichloride, in the presence of 21.5 g

(0.211 mole) of triethylamine; transformation of the 49 g resulting from 4 - [(3-benzoylphenyl) acetyl] morpholine into corresponding ethylene glycol acetal by reaction of the latter with 125 ml of ethylene glycol in 1250 ml of benzene, in the presence of 2.5 g of p-toluenesulfonic acid; and reduction of the resulting acetal (58.6 g) with 11.8 g (0.31 mole) of lithium aluminum hydride in 280 ml of ether, followed by hydrolysis of the acetal by stirring the product at 55-60 ° C with 300 ml of 1.5N hydrochloric acid for 45 min.

Analysis for C19H21N02, HC1, H20:

Calculated: C 65.23 H 6.91 Cl 10.13 Found: C 65.38 H 6.88 Cl 10.19.

Example 1D

N- [2- (3-benzoylphenyl) ethyl] dihydrochloride -N- (3-dimethylaminopropyl) amine hemihydrate, m.p. 194-197 ° C (11.1 g of the free base obtained in the form of a dark oil, a small amount of which is transformed into dihydrochloride), prepared by reaction of 46.3 g (0.167 mole) of 3-benzoylphenylacetyl chloride with 30.2 g (0.3 mole) of 3-dimethylaminopropylamine in 200 ml of methylene dichloride, in the presence of 20.1 g (0.2 mole) of triethylamine; transformation of the resulting 9 g of N - [(3-benzoylphenyl) acetyl] -N- (3-dimethylaminopropyl) amine into the corresponding ethylene glycol acetal by reaction of 15 g of the amine with 37.5 ml of ethylene glycol, in the presence 9.75 g of p-toluenesulfonic acid, in 395 ml of benzene, and reduction of the resulting acetal (15.6 g) with 3.2 g (0.084 mol) of double lithium aluminum hydride in a solution of 50 ml of dioxane and 50 ml of di-n-butyl ether, followed by the hydrolysis of the acetal by heating this acetal for 1 h in 200 ml of hydrochloric acid diluted at 55 ° C.

Analysis for C20H26N2O, 2HCl, '/ 2H2O:

Calculated: C 61.22 H 7.43 Cl 18.01 Found: C 61.97 H 7.48 Cl 17.70.

Example 2

Following a procedure similar to that described in Example 1, 2,6-dimethyl-1- [a- (3-benzoylphenyl) -propionyl] piperidine is prepared (14.3 g in the form of an oil ) from 5 12.7 g of a- (3-benzoylphenyl) propionic acid, 10 g (0.084 mole) of thionyl chloride, 6.22 g (0.055 mole) of 2,6-dimethylpiperidine and 6.05 g (0.06 mole) of triethylamine, and the resulting amide is reduced (14.3 g) with 3.9 g (0.103 mole) of lithium aluminum hydride in diethyl ether, which gives 13.2 g of 2,6-dimethyl-1- {2- [3- (a-hydroxybenzyl) phenyl] propyl] piperidine as a yellow oil.

Analysis for C23H31NO:

Calculated: C 82.34 H 8.71 N 4.18 15 Found: C 82.22 H 8.82 N 4.15.

Examples 2A-D

By following a procedure similar to that described in Example 1, the following compounds of formula I are prepared in the same way:

Example 2 A

Nt-Butyl-N- {2- [3- (a-hydroxy-4-methyl-2-chlorobenzyl) -phenyl] propyl} amine, prepared by reaction of a- [3- (4-methyl- 2-chlorobenzoyl) pheny] propionyl with t-butylamine and reduction, by double lithium aluminum hydride, of Nt-butyl-N- {a- [3- (4-methyl-2-chloro- resulting benzoyl) phenyl] propionyl} amine.

30 Example 2B

N-Benzyl-Nt-butyl-N- {2- [3- (a-hydroxy-3-trifluoromethyl-benzyl) phenyl] propyl} amine, prepared by reaction of a- [3- (3-trifluoromethylbenzoyl) chloride phenyl] propionyl with N-benzyl-Nt-butylamine and reduction, by double lithium aluminum hydride, of N-benzyl-Nt-butyl-N- {a- [3- (3-tri -fluoromethylbenzoyl) phenyl] propionyl} amine resulting.

Example 2C

40 N, N-Diisobutyl-N- {2- [3- (a-hydroxy-2,4-dichlorobenzyl) -phenyl] propyl} amine, prepared by reaction of oc- [3- (2,4- dichlorobenzoyl) phenyl] propionyl with N, N-di-isobutylamine and reduction, by double lithium aluminum hydride, of N, N-diisobutyl-N- {a- [3- (2,4- 4-dichloro benzoyl) phenyl] propionyl} amine resulting, and

2D example

4- (2-Cyclohexylethyl) -1- {2- [3- (a-hydroxy-2-bromo-benzyl) -4-methylphenyl] propyl} piperidine, prepared by the reaction of a- [3- ( 2-bromobenzoyl) -4-methylphenyl] propionyl with 4- (2-cyclohexylethyl) piperidine and reduction, by double lithium aluminum hydride, of 4- (2-cyclohexylethyl) -l- {a- [3- (2-bromobenzoyl) -4-methylphenyl] propionyl} -piperidine resulting.

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Example 3

A solution of 13.0 g (0.032 mole) of 2-cyclohexylmethyl-1- {2- [3- (a-hydroxybenzyl) -phenyl] propyl} piperidine is described in a Parr hydrogenator (described above in Example 1) in 60,167 ml of glacial acetic acid and 33 ml of perchloric acid, and reduced to 3.5 g of 10% palladium on charcoal, at room temperature, under a hydrogen pressure of 3, 7 atmospheres. When the reduction is complete, the catalyst is removed for filtration, the filtrate is brought to dryness, and the residue is made alkaline with 65% sodium hydroxide and extracted four times with hexane . The combined hexane extracts are dried, brought to dryness, and the residue is chromatographed on 220 g of alumina and eluted with a mixture of 10% ether, 89% hexane and 1% iso -

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propylamine. The first 350 milliliters of eluate when brought to dryness provides 10.6 g of 2-cyclohexylmethyl-1- [2- {3-ben2ylphenyl) propyl] piperidine as a yellow oil.

Analysis for C28H39N:

Calculated: C 86.32 H 10.09 N3.59

Found: C 86.18 H 10.34 N3.51.

Example 4

Vigorously stirred and cooled to 16 ° C a solution of 26.8 g (0.066 mole) of 2-cyclohexylmethyl-1- (2- [3- (a-hydroxy-benzyl) phenyl] propyl} piperidine (described below) above in Example 1) in 140 ml of benzene, then it is treated dropwise, in 10 min, with 58 ml of a solution prepared by dissolving 26.7 g of chromic anhydride in 23 ml of sulfuric acid concentrated and diluting with water to 100 ml. The mixture is stirred with cooling for 1V * h, the benzene layer is removed, and the aqueous layer is made alkaline by the addition of 120 ml of 10% sodium hydroxide and extracted with benzene. The organic extracts, by washing once with a dilute base, once with brine and evaporation to dryness, provide 21.8 g of an oil which is chromatographed on 300 g of alumina using 3% isopropylamine in hexane as eluent. The first 600 milliliters of eluate are collected and brought to dryness, which gives 16.2 g of 2-cyclohexylmethyl-l- [2- (3-benzoylphenyl) -propyljpiperidine in the form of a pale yellow viscous oil .

Analysis for C28H37NO:

Calculated: C 83.33 H 9.23 N3.47

Found: C 83.30 H 9.33 N3.45.

Example 5

Following a procedure similar to that described in Example 4, 15.2 g (0.39 mole) of 2,6-dimethyl-l- {2- [3- (a-hydroxybenzyl) phenyl] propyl are oxidized. } piperidine (described above in Example 2) with 34 ml of a solution prepared by dissolving 13.4 g of chromic anhydride in 11.5 ml of concentrated sulfuric acid and diluting with water to 50 ml. The product is purified in the form of the free base, it is chromatographed on alumina using a mixture of 10% ether, 3% isopropylamine and 87% hexane as eluent. 4.8 g of 2,6-dimethyl-1- [2- (3-benzoylphenyl) propyl] piperidine are thus obtained in the form of a colorless viscous oil.

Analysis for C23H29NO:

Calculated: C 82.34 H 8.71 N4.18

Found: C 82.23 H 8.82 N4.15.

Examples 5A-5G

By proceeding in a similar manner to that described in Examples 1 and 4, the following compounds of formula I are obtained:

Example 5 A

2-Methyl-1- [2- (3-benzoylphenyl) propyl] hexamethyleneimine, prepared by reacting a- (3-benzoylphenyl) -propionyl chloride with 2-methylhexamethyleneimine [Mueller et al., « Monatsch. ”, 61,212-218 (1932)]; reduction with the resulting lithium aluminum hydride of 2-methyl-1- [a- (3-benzoylphenyl) -propionyl] hexamethylene-imine, and oxidation by chromic anhydride of 2-methyl-1 - {2- [3- (a-hydroxybenzyl) phenyl] -propyl} hexamethyleneimine.

Example 5B

4-Cyclohexyl-1- [2- (3-benzoylphenyl) propyl] piperidine, prepared by reaction of a- (3-benzoylphenyl) propionyl chloride with 4-cyclohexylpiperidine; reduction by lithium aluminum hydride of 4-cyclohexyl-1- [a- (3-benzoyl-

phenyl) propionyl] piperidine, and chromic anhydride oxidation of 4-cyclohexyl-1- (2- [3- (oc-hydroxybenzyl) phenyl] -propyl} piperidine.

Example 5C

3-Butyl-4- [2- (3-benzoylphenyl) propyl] morpholine,

prepared by reacting a- (3-benzoylphenyl) propionyl chloride with 3-butylmorpholine; reduction by the lithium aluminum hydride of 3-butyl-4- [a- (3-benzoylphenyl) -propionyl] morpholine resulting, and oxidation by chromic acid of 3-butyl-4- { 2- [3- (a-hydroxybenzyl) phenyl] propyl} -morpholine.

Example 5D

3-Ethyl-4- [2- (3-benzoylphenyl) propyl] thiomorpholine, prepared by reaction of a- (3-benzoylphenyl) -propionyl chloride with 3-ethylthiomorpholine; transformation of the

3-ethyl-4- [a- (3-benzoylphenyl) propionyl] thiomorpholine resulting in the corresponding ethylene glycol acetal; reduction by the double lithium aluminum hydride of the resulting acetal, and hydrolysis by a dilute mineral acid of the ethylene glycol acetal of 3-ethyl-4- [2- (3-benzoylphenyl) propyl] resulting thiomorpholine.

Example 5 E

4-Methyl- 1- [2- (3-benzoylphenyl) propyl] piperazine, prepared by reacting a- (3-benzoylphenyl) propionyl chloride with 1-methylpiperazine; reduction with 4-methyl-1- [oc- (3-benzoylphenyl) -propionyl] piperazine lithium aluminum hydride, and oxidation by chromic acid of

Resulting 4-methyl-1- {2- [3- (a-hydroxybenzyl) phenyl] propyl} -piperazine.

Example 5 F

3-Benzyl-1- [2- (3-benzoylphenyl) propylpiperidine, prepared by reaction of oc- (3-benzoylphenyl) propionyl chloride with 3-benzylpiperidine; reduction by lithium aluminum hydride of 3-benzyl-1- [a- (3-benzoylphenyl) propionyl] -piperidine; and chromic acid oxidation of 3-benzyl-1- {2- [3- (a-hydroxybenzyl) phenyl] propyl} piperidine.

Example 5 G

N- [5- (N ', N'-Dimethylamino) -2-pentyl] -N- [2- (3-benzoyl-phenyl) propyl] amine, prepared by reaction of a- (3-benzoylphenyl) chloride propionyl with 5- (N ', N'-dimethylamino) -2-pentylamine; reduction by the double lithium aluminum hydride of N- [5- (N ', N'-dimethylamino) -2-pentyl] -N- [a- (3-benzoylphenyl) propionyl] amine, and oxidation by the chromic acid of the resulting N- [5- (N ', N'-dimethylamino) -2-pentyl] -N- {2- [3- (a-hydroxybenzyl) phenyl] propyl} amine.

Example 6

A mixture of 37.5 g (0.093 mole) of 2-cyclohexylmethyl-l- [2- (3-benzoylphenyl) propyl] piperidine (described in Example 4 above) and 10.0 g is treated with stirring. (0.14 mole) of hydroxylamine in 125 ml of 95% ethanol and 25 ml of water, with 19.4 g of sodium hydroxide powder and the mixture is heated to reflux for 1 h. Then the mixture is cooled, diluted with hexane, the aqueous layer is separated and, after drying, the organic layer is evaporated to dryness, which gives 41.6 g of a yellow oil which is chromatographed on alumina with a 30:70 mixture of diethyl ether and hexane, which gives 37.3 g of 2-cyclohexylmethyl-l- [2- (3-benzoylphenyl) propyl] -piperidine-oxime in the form of an oil.

Analysis for C28H38N20:

Calculated: C 80.33 H 9.15 N 6.69

Found: C 80.03 H 9.42 N6.44.

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Examples 6A and 6B

By following a procedure similar to that described in Example 6, the following compounds of formula I are prepared in the same way:

Example 6A

4- [2- (3-Benzoylphenyl) ethyl] morpholine-oxime (mp 117-134 ° C, recrystallized from a benzene / hexane mixture), prepared by reacting 18.15 g (0.05 mole) of hydrochloride 4 - [2- (3-benzoylphenyl) ethyl] morpholine with 5.6 g (0.08 mole) of hydroxylamine hydrochloride, in the presence of 12.5 g (0.31 mole) of sodium hydroxide in 70 ml ethanol and 18.5 ml of water, to obtain 14.06 g of product.

Analysis for Q9H22N2O2:

Calculated: C 73.52 H 7.14 N9.03

Found: C 73.79 H 7.26 N8.72.

Example 6B

4- [2- (3-benzoylphenyl) propyl] morpholine-oxime (mp 117-130 ° C), recrystallized from isopropanol), prepared by reaction of 27 g (0.078 mole) of 4- [2- ( 3-benzoylphenyl) -propyl] morpholine with 8.2 g (0.117 mole) of hydroxylamine hydrochloride, in the presence of 18.8 g (0.47 mole) of sodium hydroxide, in 115 ml of ethanol and 27 ml of water, which gives 3.2 g of product.

Example 7

A solution of 17 g (0.041 mol) of 2-cyclo-hexylmethyl-1 -2- (3-benzoylphenyl) propylpiperidine-oxime described above in example 6 is brought to reflux in 110 ml of ethanol and the treated with 10 g (0.043 mole) of metallic sodium, added in small pieces. Heating is continued at reflux until all the sodium has dissolved, then the solution is cooled, diluted with 140 ml of water, evaporated to a volume of approximately 150 ml under vacuum, then it is extracted with three portions of benzene. Evaporation of the benzene extracts to dryness provides 14.2 g of an oil which is transformed into acetate by dissolution in chloroform, addition of glacial acetic acid and evaporation to dryness. The acetate is redissolved in chloroform and chromatographed on alumina, eluting with chloroform. The acetate hydrolyzes on the column, and the free base obtained from the eluate is dissolved in ethanol and the solution is acidified with ethereal hydrochloric acid and evaporated to dryness. which gives 6.38 g of 2-cyclohexylmethyl-1- {2- [3- (a-amino-benzyl) phenyl] propyl} piperidine dihydrochloride, mp 167-195 ° C.

Analysis for CjgH ^ Nj ^ HCl:

Calculated: N5.87 Cl 14.85

Found: N5.61 Cl 14.66.

Examples TA and 7B

By following a procedure similar to that of Example 7, the following compounds of formula I are prepared in the same way:

TA example

4- {2- [3- (a-aminobenzyl) phenyl] -ethyljmorpholine dihydrochloride, m.p. 260-263 ° C (15.42 g crystallized from methanol / diethyl ether), prepared by reducing 14.55 g (0.047 mole) of 4- [2- (3-benzoylphenyl) ethyl] morpholine-oxime with 11, 5 g (0.50 mole) of sodium in 100 ml of absolute ethanol.

Analysis for C! 9H24N20,2HC1:

Calculated: C 61.79 H 7.10 Cl 19.20

Found: C 61.88 H 6.90 Cl 19.16.

Example 7B

4- {2 '- [3- (a-aminobenzyl) phenyl] propyl} dihydrochloride -

morpholine (mp 255-265 ° C), (9.5 g, crystallized from a methanol / diethyl ether mixture), prepared by reduction of 10.0 g (0.03 mole) of 4- [2- (3-benzoylphenyl ) propyl] morpholine-oxime with 7.1 g (0.31 mole) of sodium in 65 ml of absolute ethanol.

5 Analysis for C20H26N2O, 2HCl:

Calculated: C 62.66 H 7.36 Cl 18.50 Found: C 61.78 H 7.17 Cl 18.01.

10 Example 7C

Heated and stirred at 50 ° C for about 12 h a mixture of 45 g (0.13 mole) of 2,6-dimethyl-1- [2- (3-benzoyl-4-methoxy-phenyl) ethyl] piperidine and 34.9 g (0.26 mole) of aluminum chloride in tetrachloroethane, then poured into a solution of 30 ml of concentrated hydrochloric acid and 30 ml of ice water. The mixture is made alkaline with sodium carbonate, extracted 4 times with chloroform, and the chloroform extracts are washed with saturated brine, dried and evaporated to dryness to obtain a crude product which l the mixture is heated once more for 12 h at 50 ° C. with 30 g of aluminum chloride and 30 ml of tetrachloroethane. By treating it as above, we obtain 8 g of crude substance which is dissolved in chloroform. The organic solution is washed 5 times with 10% sodium carbonate, once with brine, then dried and brought to dryness. The residue is dissolved in acetone, and the solution is treated with ethereal hydrochloric acid to obtain a solid which is recrystallized from isopropanol. 5.8 g of 2,6-dimethyl-1- [2- (3-benzoyl-4-hydroxyphenyl) ethyl] piperidine hydrochloride are thus obtained, m.p. 217-219 ° C.

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Analysis for C22H27NO2, HCl:

Calculated: C 70.67 H 7.55 N3.75 Found: C 70.87 H 7.58 N3.75.

35 Example 8

A solution of 13.2 g (0.03 mole) of 2-cyclohexylmethyl-l- {2- [3- (a-hydroxy-4-chloro-benzyl) phenyl] propyl} piperidine is heated under reflux for 1 hour * , 16 ml of concentrated nitric acid 40 and 32 ml of 50% perchloric acid in 160 ml of 1,2-dimethoxyethane, then cooled, diluted with 50 ml of water, made alkaline with 150 ml of 10% sodium hydroxide and extracted with hexane. The hexane extracts are washed once with water, once with brine, dried and evaporated to dryness to give 12 g of crude product which is chromatographed on 200 g of alumina using as eluent a 10:90 mixture of ether and hexane. The first 75 milliliters of eluate are discarded and the next 600ml is brought to dryness, which gives 9.2 g of 2-cyclo-hexylmethyl-1- (2- [3- (4-chlorobenzoyl) phenyl] propyl} - 50 piperidine.

Analysis for C28H36ClNO:

Calculated: C 76.77 H 8.28 Cl 8.09 Found: C 76.85 H 8.35 Cl 8.27.

55 Examples 8A to 8D

By following a procedure similar to that described in Example 8, the following compounds of formula I are prepared in the same way:

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Example 8A

2-Cyclohexymethyl-1- [2- (3-benzoylphenyl) ethyl] piperidine (yellow oil), prepared by oxidation of 14.0 g (0.03 mole) of 2-cyclohexylmethyl-l- {2- [3- ( a-hydroxybenzyl) phenyl] -65 ethyl} piperidine in 227 ml of a solution prepared by dissolving 44.5 ml of 72% perchloric acid, 20 ml of water and 32 ml of concentrated nitric acid in 320 ml of 1,2-dimethoxyethane. 8.74 g of product are thus obtained.

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Analysis for C27H35NO:

Calculated: C 83.24 H 9.06 N3.60 Found: C 83.46 H 9.26 N3.75.

Example 8B

2-Cyclohexylmethyl-l- {2- [3- (a-hydroxy-3-chlorobenzyl) -phenyl] propyl} piperidine (26.8 g as a yellow oil), is prepared by reaction of 37.8 g (0.1 mole) of 2-cyclohexylmethyl-1- [2- (3-bromophenyl) propyl] piperidine with 0.19 mole of n-butyl lithium and reaction of the resulting lithiated derivative with 28.0 g (0.2 mole) of 3-chlorobenzaldehyde in about 250 ml of diethyl ether.

Analysis for C28H3gClNO:

Calculated: C 76.42 H 8.70 N 3.18 Found: C 76.64 H 8.98 N 3.16.

2-Cyclohexylmethyl-l- {2- [3- (3-chlorobenzoyl) phenyl] -propyljpiperidine (yellow oil), prepared by oxidation of 17.0 g (0.039 mole) of 2-cyclohexylmethyl-l- {2- [3 - (a-hydroxy-3-chloro-benzyl) phenyl] propyl} piperidine 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 product are thus obtained.

Analysis for C2gH36ClNO:

Calculated: C 76.77 H 8.28 N3.20 Found: C 76.86 H 8.36 N3.13.

Example 8C

2-Cyclohexylmethyl-l- {2- [3- (a-hydroxy-3,4-dichloro-benzyl) phenyl] propyl} piperidine (12.3 g in the form of an oil), prepared by reaction of 37, 8 g (0.1 mole) of 2-cyclohexylmethyl-1- [2- (3-bromophenyl) propyl] piperidine with 0.19 mole of n-butyl lithium and reaction of the resulting lithiated derivative with 35.1 g (0 , 2 moles) of 3,4-dichlorobenzaldehyde in diethyl ether.

2-Cyclohexylmethyl-l- {2- [3- (3,4-dichlorobenzoyl) phenyl] -propyl} piperidine (yellow oil), prepared by oxidation of 11.9 g (0.25 mole) of 2-cyclohexylmethyl-l - {2- [3- (a-hydroxy-3,4-dichlorobenzyl) phenyl] propyl} piperidine 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 of 1,2-dimethoxyethane. 5.2 g of product are thus obtained.

Analysis for C28H35Cl2NO:

Calculated: C 71.18 H 7.47 N 2.96 Found: C 71.47 H 7.82 N 2.96.

Example 8D

2-Cyclohexylmethyl-l- {2- [3- (a-hydroxy-2-chlorobenzyl) -phenyl] propyl} piperidine (30.7 g as an oil), prepared by reaction of 37.8 g (0 , 1 mole) of 2-cyclohexylmethyl-1- [2- (3-bromophenyl) propyl] piperidine with 0.19 mole of n-butyllithium and reaction of the resulting lithiated derivative with 28.0 g (0.2 mole) of 2 -chlorobenzaldehyde in diethyl ether.

2-Cycoohexylmethyl-l- {2- [3- (2-chlorobenzoyl) phenyl] -propyl} piperidine (yellow oil), prepared by oxidation of 15.7 g (0.036 mol) of 2-cyclohexylmethyl-l- {2- [3- (a-hydroxy-2-chloro-benzyl) phenyl] propyl} piperidine 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 are thus obtained.

Analysis for C28N36ClNO:

Calculated: C 76.77 H 8.28 N3.20 Found: C 76.47 H 8.58 N3.09.

Example 9

4- {2- [3- (a-aminobenzyl) phenyl] ethyl} -

morpholine (15.6 g, 0.05 mole), described in Example 8A with 13.8 g (0.30 mole) 97% formic acid and 9.4 g (0.11 mole) of 35% formaldehyde solution. The mixture is heated to 95 ° C. to effect complete dissolution of the gummy base, it is continued to heat for 10 h, and the solution is cooled and poured into a dilute mixture of sodium hydroxide and ice. Separation of the organic substance, in the usual manner by extraction with ether, provides 15.6 g of an oil which is chromatographed on 400 g of alumina using a 1.5: 98 mixture as eluent, 5 isopropylamine and hexane. The first ten fractions, each of 75 ml, are collected and set aside, and the next ten fractions, 75-100 ml each are combined, and brought to dryness, giving 10.6 g of 4- { 2- [3- (a-dimethylaminobenzyl) -phenyl] ethyl} morpholine in the form of an oil which crystallizes at rest, mp 60-63 ° C.

Analysis for C21H28N20:

Calculated: C 77.74 H 8.70 N 8.63

Found: C 77.20 H 8.60 N 8.48.

Example 10

The reaction of 2-cyclohexylmethyl-l- {2- [3- (4-methoxy-benzoyl) phenyl] propyl} piperidine with hydrobromic acid in glacial acetic acid, and the separation of the product in a neutral medium, provide 2-cyclohexylmethyl- {2- [3- (4-hydroxybenzoyl) phenyl] propyl} piperidine.

Bioassay results

We tried the N- {3- [R! - (phenyl) -C (= X)] phenyl (lower alkyl)} amines of formulas I in the tests on edema induced by carrageenan (OC) and adjuvant-induced arthritis (AA) and has been found to have anti-inflammatory activity. The data thus obtained, indicated in percentages of inhibition at a dose expressed in millimoles (nM) / kg, are given in Table A. For reasons of comparison, the data obtained in the edema test are also given. induced by the carrageenan of the reference compound (designated Ref.), the 4 - [(3-benzoyl-phenyl) methyl] morpholine described in French patent No. 1549342. All the data are obtained by oral administration.

Table A

Example

Dose

OC

AA

1

0.005

13

56 **

0.02

23

73 **

0.08

60 **

0.324

73 **

-

IA

0.004

0

-

0.02

0

0.08

51 **

0.324

62 **

-

1B

0.004

0

_

0.02

0

-

0.08

13

-

0.324

Toxic

-

1 C

0.08

40 *

0.324

77 * #

-

1D

0.08

36 *

-

0.324

65 **

-

X *)

0.004

0

_

0.02

0

-

0.08

34 **

_

0.324

75 **

-

0.004

14

-

0.005

-

54 **

5

10

15

20

25

30

35

40

45

50

55

60

65

618,677

14

Table A (continued)

Example

Dose

OC

AA

Y *)

'0.02

41 *

70 **

0.08

-

88 **

3

0.005

7

25

0.02

26 *

63 *

0.08

60 **

91 **

4

0.004

0

-

0.02

15

-

0.08

29 *

-

0.324

64 **

-

4

0.005

21

69 **

0.02

41 **

81 **

0.08

51 **

87 **

0.324

69 **

-

5

0.004

0

37 **

0.015

15

52 **

0.06

37 *

78 **

0.08

54 **

-

0.324

56 **

-

6

0.004

16

-

0.02

43 **

92 **

0.08

91 **

6A

0.08

27

-

0.324

29

-

7

0.004

16

-

0.005

-

80 **

0.02

31 *

89 **

0.08

-

108 **

7A

0.08

27

-

0.324

39 *

-

0.08

49 **

7B

0.324

84 **

8

0.004

16

-

0.005

-

63 **

0.02

52 **

90 **

0.08

-

Toxic

8A

0.004

9

-

0.02

25

-

0.08

46 **

-

0.324

70 **

-

30

Table A (continued)

Example

Dose

OC

AA

8B

0.004

14

0.02

0

-

0.08

22 *

-

0.324

65 **

-

8C

0.004

17 *

-

0.02

15

-

0.08

19 *

-

0.324

51 **

-

8D

0.004

0

-

0.005

-

35 *

0.02

36 **

54 *

0.08

-

79 # *

9

0.08

29

-

0.324

63 **

-

Ref.

0.08

0

-

0.324

23 *

-

*) X = 2-Cyclohexylmethyl-1- [2- (3- [a-hydroxy-3-chlorobenzyl] -25 phenyl) propyl] piperidine.

*) Y = 2-Cyclohexylmethyl-l- [2- (3- [ot-hydroxy-4-chlorobenzyl] -

phenyl) propyl] piperidiiie.

* Statistically different from witnesses p. <0.05. ** Statistically different from the witnesses p. S 0.01.

Some of the N- {3- [Ri- (phenyl) -C (= X)] phenyl (lower alkyl)} amines of formula I have been tested to determine their antiviral activity against herpes simplex virus types 1 and 2 and have been found to have antiviral activity. The data thus obtained, expressed in minimum inhibitory concentrations (| xg / ml), are given in Table B.

Table B

Example

CIM

1B

50 ng / ml

Y *)

6ng / ml

3

6 ng / ml

5

6 (ig / ml

*) See table A there.

R

Claims (6)

618,677 2 1. Process for the preparation of a compound of formula X R3 _ <^ H-CH -N = B (I) hexylethyl, 3-cyclohexylpropyl or benzyl; Z represents = 0, = S or = N — Rg where R8 is a lower alkyl or cyclohexyl radical; and n is the integer 1,2 or 3; and their acid addition salts, characterized in that reduced by a double aluminum hydride and from which: Rj represents hydrogen or one or two substituents, identical or not, chosen from lower alkyl, hydroxy, lower alkoxy, - CF3, lower alkylmercapto, lower alkylsulfinyl, lower alkylsulfonyl, fluorine, chlorine and bromine; R2 is hydrogen or a lower alkoxy or hydroxy radical in position 4, or a lower alkyl radical in position 2,4,5 or 6; R3 is hydrogen or a lower alkyl radical; X O H OH \ / ^ Çrepresents ^ .C ^ or; —N = B represents one of the groupings 20 25 r -NH - C - R5, R / -NOT Rn I3 CH- R, CH-R4 3 1 -O- w R / R- -o î3 8 , CH -C-N = B (V) X H OH I! \ / which gives a compound of formula I where C = C, / \ / \ X II and, if we want this group not to be reduced to > CHOH, it is protected by acetalization before reduction and it is deacetal after reduction, and, if desired, a free base obtained is converted into one of its acid addition salts. 2. Method according to claim 1, characterized in that one oxidizes a compound obtained in which> C = X is> C (HXOH), to obtain the corresponding compound where; C = X is> C = 0. 3. Method according to claim 1, characterized in that a compound obtained is reduced in which 5 C = X is; C = 0, to obtain the corresponding compound where> C = X is; C (H) (OH). 4. Process for the preparation of a compound of formula I in X II which C is a CH2 radical, characterized in that / V prepares a compound of formula I where; C = X is a group > CHOH by the process according to claim 1, and then this compound obtained by hydrogen is reduced on a catalyst in the presence of perchloric acid, and, if desired, a free base obtained is converted into one of its acid addition salts. 5. Process for the preparation of a compound of formula I in which ~ C = X is a radical; C = NOH, characterized in that a compound of formula I is prepared where; C = X is; C = 0 by the process according to claim 1, and which this compound obtained is then reacted with hydroxylamine, and, if desired, a free base obtained is converted into one of its addition salts acid. 6. Use of a compound of formula I, where; C = X is; C = 0, obtained by the process according to claim 1, to prepare a corresponding compound where 5 C = X is a group > CHNH-j, characterized in that this ketone compound is reacted with hydroxylamine, and the oxime is reduced with sodium in a lower alcohol, and, if desired, a free base is transformed obtained in one of its acid addition salts. 55 and -NHÇH1CH) nN L where R3 represents hydrogen or a lower alkyl radical and represents identical or different groups when it appears more than once, R4 and R5 each represent a lower alkyl radical; R6 and R7 each represent hydrogen or a lower alkyl, cyclohexyl, cyclohexylmethyl, 2-cyclo radical