CH619924A5 - Process for the preparation of phenylalkylamines - Google Patents

Abstract

The compounds of formula I in which the symbols have the meaning given in Claim 1 are prepared by reaction of a compound containing a benzene ring drawn on the left in Figure 1 and substituted by a radical -CN, -CHO or -C(O)R3 with the corresponding lithiated aryl compound. The compounds can be converted to acid addition salts. They are useful as medicaments, in particular as antiinflammatory agents. <IMAGE>

Description

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

It is known that a very large 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 acid, for example a- (3-benzoyl- phenyl) propionic, generically called ketoprofen (British Patent No. 1164585 published Sept. 17, 1969). These acid agents are often irritants and, in some cases, ulcerogenic, vis-à-vis the gastric mucous membranes, when administered orally. There is therefore a great need for anti-inflammatory agents, for example compounds having a basic amine function, which one would expect that they will 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 N ° 3773944 patented on Nov. 20, 1973 (l- [3-aminopropal] -phthalanes); 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-anilino-1,3,5-triazines) and French patent No. 1549342 (4- [benzoylphenylmethyl] -morpholines)], none of these basic compounds is available in trade 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- [Ri- (phenyl) -C - (= X)] - phenyl (lower alkyl} amines,

which are useful as anti-inflammatory agents, of formula:

(I)

CHCH2-N = "B

(XXI)

followed by hydrolysis of the product formed, the compound obtained which corresponds to the formula Ioù> C = Xest> C = 0 is then reacted with hydroxylamine, and the oxime thus prepared is transformed into the amine defined above, with sodium in a lower alcohol, and, if desired, a free base obtained is converted into an acid addition salt.

-NH-

-at.

-N i in which R 1 represents a hydrogen atom or one or two identical or different groups chosen from the lower alkyl, hydroxy, lower alkoxy, trifluoromethyl, lower alkyl-mercapto, lower alkylsulfinyl, lower alkylsulfonyl so groups 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 55> c = 0,> C (R3) OH,> C (R3) H,> C = CH2,> C = NOH or> CHN (R'3) 2 (where R'3 is hydrogen and - N = B represents one of the groups

R3

1, - ”.

-NOT

I

CH.

I

R,

\

C6H5

CH-R,

1 ^

R,

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4

-NOT.

JV,

\

<CH2) n

■ Ch.

-NOT

R.

/ ~ r ~ \

M- /

and

-NHÇH (CH-) N T 2 n

T

\

where R3 represents a hydrogen atom or a lower alkyl group and has the same or different meanings when it appears more than once in the same group, R4 and R5 each represent a lower alkyl group; R6 and R7 each represent a hydrogen atom or a lower alkyl, cyclohexyl, cyclohexylmethyl, 2-cyclohexyl-ethyl, 3-cyclohexylpropyl or benzyl group; Z represents an atom O, S

20 or an N - R8 group; R8 represents a lower alkyl or cyclohexyl group, and n is one of the integers 1,2 or 3.

The preferred compounds of formula I are those in which R 1 represents a hydrogen atom or one or two identical or different groups: lower alkyl, lower alkoxy or 25 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

~ N

- <CH2> „

3

/AT

r-K 2

'M- /

or

-NHÇH (CH2) nN

T

Nt.

in which R6 represents a hydrogen atom or a lower alkyl, cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl 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 making

Ì1

R.

R.

Nj (CH2) n part of the field of the invention as described above are those in which Ri represents a hydrogen atom or one or two lower alkoxy groups or identical or different halogen atoms; R2 represents a hydrogen atom;

50> C = X represents a group> C = 0,> CHOH,> CH2,> C = NOH or> CHNH2, and N = B represents one of the groups

N Z

Z or

-NHCH (CH-) N 1 * n

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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 integer 1 or 2, and R3 and R4 have the meanings given above.

Used here, the terms lower alkyl and lower alkoxy denote monovalent and saturated aliphatic radicals, including branched chain radicals, having from one to four carbon atoms, for example methyl groups,

ethyl, propyl, isopropyl, butyl, s-butyl, isobutyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy and isobutoxy.

The compounds of formula I are prepared in which the group> C = X represents a group> C (Ra) OH in which R3 is a hydrogen atom or a lower alkyl group, after reaction of a lower 3-halophenylalkylamine of formula IX with a (lower alkyl) lithium in an aprotic organic solvent, for example diethyl ether, by reacting the aryl-lithium resulting from formula IXa directly with a Ri- (phenyl) -carboxaldehyde of formula XX (to prepare the compounds with R3 = H and, optionally, with> C = X => C = 0, as described below) or a Ri- (phenyl) carbonitrile of formula XXI (in which> C = X => C = 0, the compounds where> C = X => CHOH are prepared from the latter by reduction with an aluminum and alkali metal hydride, as described above) or with an Ri- (phenylXalkyl lower) ketone of formula XXII (to prepare the compounds where R3 is a lower alkyl group).

During the reaction of the aryllithium with an aldehyde, and for reasons which are not completely understood, a certain part of the alcohol product (C = X is a CHOH group) is oxidized to ketone and, in certain cases , it is necessary to reduce the crude product with an alkali metal borohydride as described below.

The lower 3-halophenylalkylamines of formula IX can in turn be prepared by one of two methods, depending on the identity of the group N = B in the final product. The compounds of formula IX, where N = B is a secondary amine group, can be prepared by reaction of the corresponding primary amine with a lower 3-halophenylalkanal of formula X, then reduction of the resulting Schiff base with a metal borohydride alkaline. The compounds of formula IX, where N = B is a tertiary amine group, can be prepared by reaction of a lower 3-halophenylalkanal of formula X with a secondary amine, transformation of the resulting 3-halophenylvinylamine of formula XI into the dominium salt of formula XII by reaction of the first with a mineral acid, and reduction of the iminium salt with an alkali metal borohydride. The condensation of the aldehyde with the amine in the latter procedure is preferably carried out in a water-immiscible solvent, for example benzene, toluene or xylene, at its reflux temperature, under a separator at water which is used to collect water as it is produced in the reaction. The reduction of the iminium salt can be carried out with an alkali metal borohydride in an inert organic solvent, for example a lower alkanol or dimethylformamide (DMF). The global method is represented by the following reactions:

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I (C = X is C = 0)) l (C = X is C (R) OH,

(N = B is a secondali amino radical ")

\ y

/NOT

^ R- is H)

I (C = X is C (R3) OHf R ^ is alkyl)

IXa

<r / o>

C-R.

XXI

XX.

XXII

Hai chch2-n = "b

<-

IXa

IX

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(N = B is a tertiary amino radical)

T ..

V ^

Vf Ns — CHCH-N-B XW

> ICr

R.

XI

XII

H-N = B

Hai

CHCHO

where Ri, R2, R3, N = B and Hai have the meanings given above, and X '~ J represents an anion of a mineral acid.

The methods described above are used to prepare the compounds of formula I where> C = X is an alcohol group> C (R3) OH where R3 is a hydrogen atom or a lower alkyl group. The compounds of formula I can be prepared where the group> C = X has the other meanings given above, by simple chemical transformations on the alcohol groups. Thus, one can prepare the compounds where the group> C = X represents a group> C (R3) H where R3 is a hydrogen atom or a lower alkyl group, by catalytic reduction of the corresponding alcohol> C (R3) OH, with hydrogen in the presence of perchloric acid. A preferred catalyst is palladium on carbon, and it is preferred to carry out the reaction in glacial acetic acid as a solvent. The reduction is carried out at a pressure between 2.7 and 6.8 atm.

The compounds of formula I can be prepared where> C = X is the group> C = CH2 by dehydration of the methyl substituted alcohols, where> C = X is the group

CH3

X

OH

with concentrated sulfuric acid. The reaction is usually carried out by refluxing a solution of the alcohol and sulfuric acid in a lower alkapol as a solvent.

The compounds of formula I can be 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 organic solvent inert, for example a lower alkanol.

The compounds of formula I can be 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 usefulness as pharmaceutically active compounds as described below, are therefore also useful as intermediates for preparing the compounds where> C = X is a grouping> CHNH2.

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

r3

I

-nh-c-r5, I

R *

r3

I

-N — C-Rs, I I chz r4 I

c6h5

-NOT'

/ X

r3

1

ch-r4

Œ-R4

1

r3

or -NHCH (CH2) „N

r3

/

\

are known compounds.

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

>

* 3 R7

. (CH2) P

where n is 2, are also known, and have been described generally in the U.S. Patent. N ° 3238215. As described here, they are prepared by catalytic reduction on oxide of

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platinum pyridines suitably substituted with R3, R6 or R7 groups, which are commercially available.

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

-NOT

V

- (CH2) n 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 catalytically reducing on platinum oxide the resulting 2-R3-5-R6-pyrrole, according to the reaction sequence:

To x

+ NH ^ OAc

HOAc

->

where R3 and Rg have the meanings given above.

Or, we can prepare the amines in which the group is

-N = B

where R3, Ré and Hai have the meanings given above.

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

as well as the amines where - N = B is the group:

not

-NOT

V

<CH2> n

R,

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

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

not

-NOT

. (CH2) n

R,

~ N

j-

<cVn

AT

1

Bal ™ + R6M9Ha1 '

3 Hai

R6 R3

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

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 catalytic reduction of the resulting 2-R6-5-R3-4,5-dihydropyrrole as indicated by the reaction sequence:

o

619924

We can prepare the amines of formula H —N = B where is the group:

/'AT

-N Z

Vj— /

-N = B where Z is an S atom, 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 Z is an O atom, according to the method described in British Patent No. 835717, which consists in passing a vaporized mixture of a glycolether of formula

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 H — N = B are preferably prepared in which —N = B is the group:

AT

-N Z

R,

H-N

'Hai Hai is the reaction of ammonia with a suitable bis-2-haloethyl sulfide:

Hai Hai where R.3 and R6 have the meanings given above, and Hai represents a halogen atom.

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The lower 3-halophenylalkanals of formula X can be prepared, via the condensation of Darzens' glycidic ester, by reaction of a 3-halo (lower alkano) phenone with a lower alkyl haloacetate in the presence of a metal alcoholate. alkaline, followed by saponi-40 formation and decarboxylation of the resulting glycidic ester. The process is represented by the following reactions:

9

619924

The new compounds obtained according to the present invention are the compounds of formula I and their acid addition salts. The free base form of the compounds of formula I can be transformed into the acid addition salt form by interaction of the base with an acid. Similarly, the free base can be regenerated from the acid addition salt in a conventional manner, that is to say by treating the salts with weak and cold aqueous bases, for example carbonates of alkali metals and bicarbonates of alkali metals. 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 one another.

It will therefore be seen that formula I not only represents the developed configuration of the bases of formula I, but also represents the structural entities which are common to all the compounds of formula I, either in the form of free base or in the form of the salts d addition of base acid. 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. acids whose anions are inolFensive to animal organisms, at effective doses of the salts, so that the beneficial properties inherent in the common structural entity represented by the free bases are not modified by attributable side effects to the anions.

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 derivatives for the characterization or 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 considerations of solubility, toxicity,

physical state, etc., and they therefore fall within the scope of the present invention.

The novel feature of the compounds of the invention then lies in the idea of the bases and cationic forms of the new N- {3- [Ri- (phenyl) -C (= X)] - phenyl (lower alkyl)} and not in any particular acid group or acid anion associated with the salt forms of the compounds; on the contrary, the acid groups or anions which can be associated with the salt forms are not in themselves new or determining and they can be any acid anion or any other substance of the acid type which can form salts with the 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, 1-naphthalenecarboxylic acid, cinnamic acid, l 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, methanesulfonic acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzenesulfinic acid , butyl arsonic acid, diethylphosphonic acid, p-amino-phenylarsinic acid, phenylstibnic acid, phenylphosphinous acid, methylphosphinic acid, phenylphosphinic acid, hydrofluoric acid , hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, nitric acid, sulfuric acid, acid phosphoric acid, cyanhydric acid, phosphotungstic acid, molybdic acid, phosphomolybdic acid, pyrophosphoric acid, arsenic acid, picric acid, picrolonic acid, 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 attached, 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 standard pharmacological test procedures, it has been found that the compounds of formula I have anti-inflammatory activity and are useful as anti-inflammatory agents. It has also been found that certain compounds of formula I 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. ", III, 544 (1962), and 2) a modification of the adjuvant-induced arthritis inhibition assay described by Pierson," J. Chronic Dieseases ", 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 100 di50ct (infectious dose of tissue culture) 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

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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 compounds of the invention 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 of the invention were assigned on the basis of the study of their infrared, ultraviolet and NMR spectra and were 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 without however limiting it. The melting points are all uncorrected.

Preparation of starting amines Preparation 1

In three separate tests, portions of 33.8 g (0.20 mol) 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 atm of hydrogen at a temperature of about 55-61CC. When the reduction is complete in each case, the catalyst is removed by filtration, washed with small vessels. 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 atm of hydrogen, at a temperature of approximately 60 ° C., a mixture of 15.52 g (0.10 mol) 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

The mixture is heated and stirred in a Parr hydrogenator under approximately 3.75 atm of hydrogen, at a temperature of approximately 60 ° C., a mixture of 9.1 g (0.05 mol) 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 concentrated hydrochloric acid in a pressure. 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-cyclohexylethyl) piperidine hydrochloride, m.p. 155-156 ° C.

Preparation 4

A solution of 78.1 g (0.84 mol) of 4-methylpyridine and 89.0 g (0.84 mol) 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 mol), 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 atm. The product is treated as described above in Preparation 1 and separated as the hydrochloride, and 43.5 g of 4- (2-cyclohexylethyl) 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 atm, 15.5 g (0.1 mol) 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-cyclo-hexylpiperidine hydrochloride. (The free base melts at 106-109 ° C.)

Preparation 6

To a mixture of 8.6 g (0.36 mol) of magnesium turn in 150 ml of dry ether, a solution of 45.0 g (0.36 mol) 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-chlorobutyronitrile 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 (at 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 separates the organic layer. 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,

në5 = 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 atm. 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-cyclohexylmethyl-pyrrolidine hydrochloride are obtained, m.p. 130.5-131.5 ° C (recrystallized from acetone).

Preparation 7

To a suspension of 11.2 g (1.6 mol) of lithium wire in 600 ml of anhydrous ether, 125.6 g (0.8 mol) of bromobenzene are added dropwise. Once the addition is complete, the mixture is stirred for approximately 4 h, then treated dropwise, first with a solution of 74.4 g (0.8 mol) of picoline in 100 ml of ether anhydrous, then, after having stirred for 15 min, with a solution of 74.0 g (0.4 mol) 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 everything

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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 an oil residual which is distilled under vacuum, which gives 41.3 g of 2- (3-phenylpropyl) pyridine, mp 76-78 ° C / 0.05 mm, në5 = 1.5592.

The latter is reduced (19.7 g, 0.1 mol) dissolved in 235 ml of ethanol and 15 ml of concentrated hydrochloric acid, with hydrogen over 2 g of platinum oxide under hydrogen pressure about 3.75 atm at 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

To 220 g (1.65 mol) of aluminum chloride, 81 g (0.67 mol) of acetophenone are added with vigorous stirring over 20 min. The resulting mixture is treated dropwise with stirring, in 40 min, with 120 g (0.8 mol) of bromine. Once the addition is complete, the mixture is stirred for an additional 15 min, then it is extracted with four times 150 ml of ether. The combined ethereal extracts are washed once with water, once with 10% potassium bicarbonate, once with saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness, to give 141 g of an oil which is distilled under vacuum, which gives 108.7 g of 3-bromoaceto-acetophenone, mp 71.5-76 ° C / 0.5 mm.

To 2200 ml of isopropanol in a round bottom flask with three tubes purged with nitrogen, 60 g (2.6 mol) of sodium are added in pieces. When all the sodium has dissolved, the mixture is cooled to about 7-8 ° C and treated in 30 min with a solution of 318 g (1.6 mole) of 3-bromoacetophenone and 352 g (2, 88 mol) of ethyl chloro-acetate. The mixture is stirred at 7-8 ° C for 5 h, then at room temperature for about 48 h, heated to reflux for 1 h, distilled to remove about 11 of isopropanol, and the residue is diluted with 1900 ml of water and 1200 ml of toluene and stirred. The layers are separated, the aqueous phase is extracted with additional toluene, and the combined toluene extracts are washed with saturated brine, dried and evaporated to dryness, which gives 558.8 g of a brown liquid. combined with a solution of 70 g of sodium hydroxide in 225 ml of water and 1200 ml of absolute ethanol and which is heated to reflux for approximately 12 h. The mixture is then brought to dryness under vacuum, which gives 575.6 g of a solid which is dissolved in water, acidified with dilute hydrochloric acid, and the mixture is extracted with benzene. The benzene extracts are brought to dryness, which gives 485.4 g of substance which is entrained in water vapor, which gives 272.5 g of a- (3-bromophenyl) propionaldehyde.

Is heated to reflux using a Dean-Stark trap, for about 12 h, a solution of the latter with 465 g (2.6 mol) of 2-cyclohexylmethylpiperidine in 61 of benzene. The solvent is removed in vacuo, which gives 712.1 g of an oil which is distilled in vacuo to remove impurities of lower boiling point. 357.2 g of 2-cyclohexylmethyl-1- [2- (3-bromophenyl) -1-propenyl] piperidine are thus obtained in the form of a residue with a higher boiling point.

The latter is dissolved (0.95 mol) in 3 l of hexane, and the solution is cooled in an ice bath and treated with 220 ml (1.20 mol) of 4.9N ethereal hydrochloric acid. The separating white gummy solid which is formed from iminium hydrochloride is collected, filtered, washed with fresh hexane, dissolved

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in 3.5 l of dimethylformamide and the solution is treated with 72 g (1.9 mol) of sodium borohydride added in small quantities over 10 min. The mixture is then stirred at room temperature for approximately 1 hour, treated with 11 10% sodium hydroxide and 61% water, then extracted with hexane. The combined extracts of hexane provide 305.4 g of a yellow oil which is distilled under vacuum, which gives 189.6 g of substance, e.g. 143-161 ° C / 0.06 mm, which is redistillates to 0.5 mm (pe 167-187 ° C) to obtain 158.5 g of 2-cyclo-hexylmethyl-1 - [2- (3-bromophenyl) propyl] piperidine.

Analysis for C2iH32BrN:

Calculated: C 66.66 H 8.52 Br 21.12

Found: C 66.71 H 8.36 Br 21.20.

A solution of the latter product (37.8 g, 0.1 mol) dissolved in 80 ml of diethyl ether is treated dropwise with 165 ml (0.18 mol) of a 1.08M solution of n -butyllithium in diethyl ether while maintaining the temperature in the vicinity of 10 ° C. Once the addition is complete, the mixture is stirred for 30 min at about 10 ° C, then at room temperature for 1 h, it is heated to reflux for approximately 30 min, once 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 around 15-20 ° C. Then the mixture is heated to reflux for 20 min, it is cooled, it is made alkaline by the addition of 110 ml of 10% sodium hydroxide and it is stirred for 10 min. Then the mixture is filtered, the organic layer is separated and the aqueous layer is extracted with additional diethyl ether. The combined organic extracts are washed with saturated brine, dried over sodium sulfate and evaporated to dryness, which gives 55 g of an oil which is dissolved in 150 ml of absolute methanol. The solution is carefully treated with 7 g of sodium borohydride, stirred at 15 ° C for 20 min, carefully acidified by the addition of 150 ml of sulfuric acid and extracted three times with hexane. The aqueous solution is made alkaline with 150 ml of 10% sodium hydroxide, diluted with water and extracted four times with hexane. The combined hexane extracts provide 32 g of an oil which is chromatographed on 500 g of alumina using as eluent 1.5% of isopropylamine in hexane. The first three liters of eluate are collected and separated, and the next 3.7 liters are collected and evaporated to dryness, which gives 20.4 g of 2-cyclohexylmethyl-1- [ 2- [3- (oc-hydroxy-4-methoxy-benzyl) phenyl] propyl} piperidine in the form of a yellow oil.

Analysis for C29H41NO2:

Calculated: C 79.95 H 9.49 N 3.22

Found: C 78.88 H 9.43 N3.07.

Examples 1A-1H

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

Example 1A

2-Cyclohexylmethyl-l- {2- [3- (a-hydroxy-3-chlorobenzyl) -phenyl] propyl | piperidine (26.8 g as a yellow oil), prepared by reacting 37.8 g (0.1 mol) of 2-cyclohexylmethyl-l- [2- (3-bromophenyl) propyl] piperidine with 0 , 19 mol of n-butyllithium and reaction of the resulting lithiated derivative with 28.0 g (0.2 mol) of 3-chlorobenzaldehyde in approximately 250 ml of diethyl ether.

Analysis for C28H38CINO:

Calculated: C 76.42 H 8.70 N 3.18

Found: C 76.64 H 8.98 N 3.16.

Example 1B

2-Cyclohexylmethyl-l- {2- [3- (a-hydroxybenzyl) phenyl] -propyl} pyrrolidine (5.3 g as a yellow-brown viscous oil), prepared by reaction of 10.8 g ( 0.03 mol) of 2-cyclohexyl-methyl-1- [2- (3-bromophenyl) propyl] pyrrolidine with 0.06 mol of

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n-butyllithium and reaction of the resulting lithiated derivative with 7.0 g (0.066 mol) of benzaldehyde.

Analysis for c37h37no:

Calculated: C 82.81 H 9.52 N 3.58

Found: C 82.29 H 10.03 N 3.51.

Example 1C

2-Cyclohexylmethyl-l- {2- [3- (oc-hydroxy-3,4-dichlorobenzyl) -phenyl] propyl} piperidine (12.3 g as an oil), prepared by reaction of 37.8 g (0.1 mol) of 2-cyclohexylmethyl-1- [2- (3-bromophenyl) propyl] piperidine with 0.19 mole of n-butyllithium and reaction of the resulting lithiated derivative with 35.1 g (0.2 mol ) of 3,4-dichlorobenzaldehyde in diethyl ether.

Example 1D

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 mol) of 2-cyclohexylmethyl-

1- [2- (3-bromophenyl) propyl] piperidine with 0.19 mol of n-butyllithium and reaction of the resulting lithiated derivative with 28.0 g (0.2 mole) of 2-chlorobenzaldehyde in diethyl ether.

Example 1E

2- (3-Cyclohexylpropyl) -l- {2- [3- (oc-hydroxybenzyl) phenyl] -propyljpiperidine (5.4 g in the form of a viscous oil), prepared by reaction of 12.2 g (0 , 03 mol) of 2- (3-cyclohexylpropyl) -1- [2- (3-bromophenyl) propyl] piperidine with 0.68 mol of n-butyl lithium and reaction of the resulting lithiated derivative with 7.0 g (0 0.06 mol) of benzaldehyde in diethyl ether.

Analysis for c3oh43no:

Calculated C 83.09 H 9.99 N3.23

Found: C 82.92 H 10.26 N3.19.

Example 1F

2-Cyclohexylmethyl-l- {2- [3- (a-hydroxy-4-methylmercapto-benzyl) phenyl] propyl} piperidine, prepared by reaction of

2-cyclohexylmethyl-1- [2- (3-bromophenyl) propyl] piperidine with n-butyllithium and reaction of the resulting lithiated derivative with 4-methyl-mercaptobenzaldehyde.

Example 1G

2-Cyclohexylmethyl-l- {2- [3- (a-hydroxy-4-methylsulfinyl-benzyl) phenyl] propyl} piperidine, prepared by reaction of 2-cyclohexylmethyl-l- [2- [3- (a-hydroxy -4-methyImercapto-benzyl) phenyl] propyl} piperidine, with a molar equivalent of hydrogen peroxide in fornic acid.

Example 1H

2-Cyclohexylmethyl-1 - {2- [3- (a-hydroxy-4-methylsulfonyl-benzyl) phenyl] propyl} piperidine, prepared by reaction of 2-cyclohexylmethyl-1 - {2- [3- (a-hydroxy -4-methylmercapto-benzyl) phenyl] propyl} piperidine, with two molar equivalents of hydrogen peroxide in formic acid.

Example 2

Following a procedure similar to that described in Example 1, 18.9 g (0.05 mol) of 2-cyclohexylmethyl-l- [2- (3-bromophenyl) propyl] piperidine are reacted with 0.1 mol of n-butyl lithium in diethyl ether and the resulting lithiated derivative is reacted directly with 12.3 g (0.103 mol) of 4-methylbenzal-dehyde, which gives 16.9 g of 2-cyclohexylmethyl-1 - {2- [3- (a-hydroxy-4-methylbenzyl) phenyl] propyl} piperidine in the form of a yellow oil.

Analysis for C2oH41NO:

Calculated: C 83.00 H 9.85 N 3.34 Found: C 83.04 H 10.01 N 3.31.

Example 3

By following a procedure similar to that described in Example 1 above, 18.9 g (0.05 mol) of 2-cyclo-hexylmethyl-1- [2- (3-bromophenyl) propyl] are reacted. piperidine with 0.1 mol of n-butyllithium in diethyl ether and the resulting lithiated derivative is reacted directly with 15.5 g (0.11 mol) of 4-chlorobenzaldehyde. The crude product is reduced with 4.5 g (0.12 mol) of sodium borohydride in methanol, giving 16.6 g of 2-cyclohexylmethyl-1- (2- [3- (a-hydroxy-4 -chloro-benzyl) phenyl] propyl} piperidine in the form of an oil.

Analysis for C28H38ClNO:

Calculated: C 76.42 H 8.70 Cl 8.06

Found: C 76.82 H 8.76 Cl 8.14.

By following a procedure similar to that described in Example 3, the following compound of formula I is prepared in the same way,

Example 3A

2-Cyclohexylmethyl-l- {2- [3- (a-hydroxy-2,6-dichloro-benzyl) phenyl] propyl} piperidine (yellow oil), prepared by reaction of 18.9 g (0.5 mol) of 2-cyclohexylmethyl-1- [2- (3-bromo-phenyl) propyl] piperidine with 0.1 mol of butyllithium in diethyl ether, then with 19.2 g (0.1 l mol) of 2,6-dichlorobenzaldehyde, which gives 19.3 g of product.

Analysis for C28H37CI2NO:

Calculated: C 70.87 H 7.86 CI 14.94

Found: C 71.06 H 8.08 Cl 14.81.

Example 4

Following a procedure similar to that described in Example 1, 37.8 g (0.1 mol) of 2-cyclohexylmethyl-l- [2- (3-bromophenyl) propyl] piperidine are reacted with 0.18 mol of n-butyl lithium in diethyl ether and the resulting lithiated derivative is reacted directly with 27 g (0.23 mol) of acetophenone, which gives 11.8 g of 2-cyclohexylmethyl-1 - {2 - [3- (a-hydroxy-a-methylbenzyl) phenyl] propyl} piperidine in the form of a yellow oil.

Analysis for c29h41no:

Calculated: C 83.00 H 9.85 N3.34

Found: C 83.34 H 9.97 N 3.23.

Example 5

A solution of 0.15 mol of n-butyllithium in 90 ml of diethyl ether is 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 volume of the solution is added to give 0.093 mol to a solution of 19.4 g (0.051 mol) of 2-cyclohexylmethyl-1- [2- (3-bromo-phenyl) propyl] piperidine in 100 ml of ether. The mixture is stirred for 30 min while maintaining the temperature below 10 ° C., the mixture is heated at reflux for 30 min, it is cooled once again below 10 ° C., it is treated in 10 min with a solution of 13, 3 g (0.10 mol) of 4-methoxybenzonitrile in 80 ml of ether, the mixture is stirred for an additional hour at a temperature below 10 ° C., then it is 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 is heated to reflux for 2 h, it is cooled, it is made alkaline with 100 ml of 10% sodium hydroxide, the layers are separated and the aqueous layer is extracted with ether. The ethereal extracts are washed with brine, dried and brought to dryness, which gives 32.6 g of substance which is dissolved in hexane and which is extracted with a solution of 8 ml of concentrated sulfuric acid, 136 ml of water and 144 ml of methanol. The extracts are made alkaline with 10% sodium hydroxide, the mixture is extracted once again with hexane and the extracts are washed in hexane with a

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brine, dried and brought to dryness, which gives 28.1 g of substance which is chromatographed on 400 g of alumina and which is eluted with a mixture of 50% benzene / 50% hexane. The first 1750 ml of eluate are brought to dryness, the residue is heated under vacuum to 0.1 mm / 220 ° C. (bath temperature) to remove the 4-methoxy-benzonitrile, and the mixture is chromatographed once again. residue on alumina (250 g) using a mixture of 15% ether and 85% hexane. The first 400 ml of eluate are discarded and the following 1200 ml, by evaporation to dryness, provide 7.1 g of 2-cyclohexylmethyl-1 - {2- [3- (4-methoxy benzoy l) pheny l] propyl} -piperidine in the form of a yellow oil.

Analysis for C29H39NO2:

Calculated: C 80.33 H 9.07 N3.23 Found: C 80.50 H 9.17 N3.14.

Examples 5A-5L

By following a procedure similar to that described in Examples 1,2 and 3, the following compounds of formula I are prepared in the same way:

Example 5A

2-Cyclohexylmethyl-1- [2- (3-benzoylphenyl) propyl] pyrroli-dine (viscous amber liquid), prepared by reaction of 21.3 g (0.1 mol) of a- (3-bromophenyl) propionaldehyde with 31.4 g (0.2 mol) of 2-cyclohexylmethylpiperidine in benzene; transformation of the resulting 33.7 g of 1- [2- (3-bromophenyl) -1-propenyl] -pyrrolidine into iminium chloride using ethereal hydrochloric acid; reduction of iminium chloride (34.0 g) with 6.4 g (0.17 mol) of sodium borohydride in dimethylformamide; reaction of 9.8 g (0.027 mol) of 2-cyclohexylmethyl-1- [2- (3-bromophenyl) -propyl] resulting pyrrolidine (18.8 g) (e.g. 135-136 ° C / 0.02 mm) with 0.05 mol of butyllithium, then with 6.2 g (0.06 mole) of benzo-nitrile in diethyl ether and decomposition of the product with a solution of 4 ml of concentrated sulfuric acid in 20 ml of water and 50 ml of dioxane to obtain 5.1 g of product.

Analysis for c27h35no:

Calculated: C 83.24 H 9.06 N3.60

Found: C 82.77 H 9.05 N3.64.

Example 5B

2-Cyclohexylmethyl-l- {2- [3- (4-fluorobenzoyl) phenyl] -propyl} piperidine (yellow oil), prepared by reaction of 18.9 g (0.05 mole) of 2-cyclohexylmethyl-l- [ 2- (3-bromophenyl) propyl] -piperidine with 0.1 mole of butyllithium in diethyl ether, then with 12.8 g (0.11 mole) of 4-fluorobenzonitrile and decomposition of the product with a solution of 3, 8 ml of concentrated sulfuric acid in 19 ml of water and 45 ml of dioxane, to obtain 6.5 g of product.

Analysis for C28H36FNO:

Calculated: C 79.77 H 8.61 N3.32 Found: C 79.60 H 8.76 N3.51.

Example 5C

2-Cyclohexylmethyl-1- {2- [3- (4-methylbenzoyl) phenyl] -propyl} piperidine (9.7 g as a yellow oil), prepared by reaction of 18.9 g (0.05 mol ) of 2-cyclohexylmethyl-1- [2- (3-bromo-phenyl) propyl] piperidine with 0.1 mole of butyllithium in diethyl ether, then with 12.4 g (0.11 mol) of 4-methylbenzo -nitrile and decomposition of the product with a solution of 3.8 ml of concentrated sulfuric acid in 19 ml of water and 45 ml of dioxane, which gives 9.7 g of product.

Analysis for c29h39no:

Calculated: C 83.40 H 9.41 N3.35

Found: C 83.34 H 9.61 N3.30.

Example 5D

2- (3-Cyclohexylpropyl) -l- [2- (3-benzoylphenyl) propyl] -piperidine (yellow oil), prepared by reaction of 12.2 g (0.03 mol) of 2- (3-cyclohexylpropyl) - l- [2- (3-bromophenyl) propyl] -piperidine with 0.06 mol of butyllithium in diethyl ether, then with 7.2 g (0.07 mol) of benzonitrile and decomposition of the product with a solution of 8 , 3 ml of concentrated sulfuric acid in 42 ml of water and 100 ml of dioxane, which gives 6.2 g of product.

Analysis for C30H4XNO:

Calculated: C 83.47 H 9.57 N 3.24

Found: C 83.28 H 9.77 N3.05.

Example 5E

2-Cyclohexyl-1 - [2- (3-benzoylphenyl) propyl] piperidine (light yellow-brown oil), prepared by reaction of 12.7 g (0.035 mol) of 2-cyclohexyl-l- [2- (3- bromophenyl) propyl] piperidine with 0.07 mol of butyllithium in diethyl ether, then with 8.9 g (0.077 mol) of benzonitrile, and decomposition of the product by a solution of 9 ml of concentrated sulfuric acid in 45 ml d water and 100 ml of dioxane, which gives 6.1 g of product.

Analysis for c27h35no:

Calculated: C 83.24 H 9.06 N 3.60

Found: C 83.16 'H 9.16 N 3.44.

Example 5F

2- (2-Cyclohexylethyl) -1- [2- (3-benzoylphenyl) propyl] -piperidine (pale yellow-brown liquid), prepared by reaction of 13.7 g (0.035 mol) of 2- (2-cyclohexylethyl) -l- [2- (3-bromophenyl) -propyl] piperidine with 0.07 mol of butyllithium in diethyl ether, then with 8.9 g (0.077 mol) of benzonitrile, and decomposition of the product by a solution of 9 ml of concentrated sulfuric acid in 45 ml of water and 100 ml of dioxane, which gives 8.9 g of product.

Analysis for c29h39no:

Calculated: C 83.40 H 9.41 N 3.35

Found: C 83.57 H 9.40 N 3.35.

Example 5 G

8- [2- (3-Benzoylphenyl) propyl] -1,4-dioxa-8-azaspiro- [4,5] -decane (pale yellow oil), prepared by reaction of 10.6 g (0.05 mol) of a- (3-bromophenyl) propionaldehyde with 14.3 g (0.1 mol) of 1,4-dioxa-8-azaspiro- [4,5] -decane in benzene; transformation of the resulting 15.7 g of 8- [2- (3-bromophenyl) -1-propenyl] -1,4-dioxa-8-azaspiro- [4,5] -decane into iminium chloride using ethereal hydrochloric acid; reduction of iminium chloride with 3.8 g (0.08 mol) of sodium borohydride in dimethylformamide; reaction of the resulting 17.5 g (0.05 mol) of 8- [2- (3-bromophenyl) propyl] -1,4-dioxa-8-azaspiro- [4,5] -decane with 0.1 mol of butyllithium, then with 15.5 g (0.15 mol) of benzonitrile in diethyl ether, and decomposition of the product with a solution of 6 ml of concentrated sulfuric acid in 30 ml of water and 72 ml of dioxane, this which gives 5.1 g of product.

Analysis for C23H27N03:

Calculated: C 75.58 H 7.45 N 3.83 Found: C 75.60 H 7.69 N 3.87.

Example 5H

4- [2- (3-Benzoylphenyl) propyl] morpholine (pale yellow oil), prepared by reacting 21.3 g (0.1 mol) of a- (3-bromophenyl) -propionaldehyde with 17.4 g ( 0.2 mol) of morpholine in benzene; transformation of the resulting 27.3 g of 4- [2- (3-bromo-phenyl) -1-propenyl] morpholine into iminium chloride using ethereal hydrochloric acid; reduction of iminium chloride by s

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7.6 g (0.2 mol) of sodium borohydride in dimethylformamide; reaction of the 19 g resulting from 4- [2- (3-bromophenyl) -propyljmorpholine (eg 99-120 ° C / 0.09 mm, nè4 = 1.5477) with 0.1 mol of butyllithium, then with 15.5 g (0.15 mol) of benzonitrile in diethyl ether, and decomposition of 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, to obtain 7.5 g of product.

Analysis for C20H23NO2:

Calculated; C 77.64 H 7.49 N 4.53

Found: C 77.62 H 7.37 N4.71.

A small amount of the free base is transformed into the hydrochloride to obtain the hydrochloride monohydrate of 4- [2- (3-benzoylphenyl) propyl] morpholine, m.p. 151-155 ° C.

Analysis for C2oH23N02, HCl, H20:

Calculated: C 66.02 H 7.20 Cl 9.74

Found: C 66.37 H 7.24 Cl 9.59.

Example 5J

2,6-dimethyl-4- [2- (3-benzoyl-phenyl) propyl] morpholine cyclohexanesulfamate, prepared by reaction of 21.3 g (0.1 mol) of a- (3-bromophenyI) propionaldehyde with 23 g (0.2 mol) of 2,6-dimethylmorpholine in benzene; transformation of the resulting 28.4 g of 2,6-dimethyl-4- [2- (3-bromophenyl) -1-propenylmorpholine into iminium chloride using ethereal hydrochloric acid; reduction of iminium chloride with 10 g (0.26 mol) of sodium borohydride in dimethylformamide; reaction of the resulting 15.5 g of 2,6-dimethyl-4- [2- (3-bromo-phenyl) propyl] morpholine (pe 125-129 ° C / 0.01 mm, no4 = 1.5294) with 0 , 1 mol of butyllithium, then with 11 g (0.11 mol) of benzonitrile in diethyl ether, and decomposition of the product with 150 ml of a solution prepared by dissolving 45 g of concentrated sulfuric acid in 225 ml of water and 540 ml of dioxane. The product is converted into cyclohexanesulfamate which is recrystallized from acetone, which gives 7.7 g of product, m.p. 156-158 ° C.

Analysis for C22H27N02, C6Hi3N03S:

Calculated: C 65.08 H 7.80 S 6.20

Found: C 64.86 H 7.72 S 6.22.

Example 5K

2-Cyclohexylmethyl-l- [2- (3-benzoyl-2-methylphenyl) -ethyl] piperidine prepared by reaction of 2-bromo-6-bromo-methyltoluene [described by Lindsay et al, "J. Am. Chem. Soc. ”, 83, 943-949 (1961)] with potassium cyanide in ethanol at reflux; reduction of (3-bromo-2-methylphenyl) acetonitrile resulting from diisobutylaluminum hydride; reaction of the resulting (3-bromo-2-methyl-phenyl) acetaldehyde with 2-cyclohexylmethylpiperidine in benzene at reflux using a Dean-Stark trap; reduction with sodium borohydride of iminium hydrochloride of 2-cyclohexylmethyl-l- [2- (3-bromo-2-methylphenyl) -l-ethenyl] piperidine, and reaction of 2-cyclohexylmethyl-1- [ 2- (3-bromo-2-methylphenyl) ethyl] resulting piperidine with n-butyllithium in diethyl ether followed by reaction of the resulting lithiated derivative with benzonitrile.

Example 5L

4- [2- (3-Benzoyl-2-methylphenyl) ethyl] morpholine, prepared by reacting (3-bromo-2-methylphenyl) acetaldehyde with morpholine in benzene at reflux using a Dean-Stark trap; reduction by sodium borohydride of iminium hydrochloride of 4- [2- (3-bromo-2-methylphenyl) -l-ethenyl] -morpholine, and reaction of 4- [2- (3-bromo- 2-methyl-phenyl) ethyl] resulting morpholine with n-butyllithium in diethyl ether followed by reaction of the resulting lithiated derivative with benzonitrile.

Example 6

Following a procedure similar to that described in Example 5, 18.9 g (0.05 mol) of 2-cyclohexylmethyl-1 - [2- (3-bromophenyl) propyl] piperidine are reacted with 0.095 mol of n-butyllithium in diethyl ether and the resulting lithiated derivative is reacted directly with 12.4 g (0.106 mol) of 2-methylbenzo-nitrile, which gives 4.85 g of 2-cyclohexylmethyl-1- { 2- [3- (2-methylbenzoyl) phenyl] propyl | piperidine in the form of a yellow oil.

Analysis for c29h39no:

Calculated: C 83.40 H 9.41 N 3.35

Found: C 83.14 H 9.54 N3.67.

Example 7

Following a procedure similar to that described in Example 5, 18.9 g (0.05 mol) of 2-cyclohexylmethyl-

1- [2- (3-bromophenyl) propyl] piperidine with 0.095 mol of n-butyllithium in diethyl ether and the resulting lithiated derivative is reacted directly with 12.4 g (0.106 mol) of 3-methylbenzo- nitrile, which gives 10.7 g of 2-cyclohexylmethyl-1 - [2- [3- (3-methyl-benzoyl) phenyl] propylj piperidine in the form of a yellow oil.

Analysis for C29H39NO:

Calculated: C 83.40 H 9.41 N 3.35

Found: C 83.06 H 9.38 N3.48.

Example 8

A solution of 13.0 g (0.032 mol) of 2-cyclohexylmethyl-1- {2- [3- (a-hydroxybenzyl) -phenyl] propyl! Piperidine in 167 ml of glacial acetic acid is placed in a Parr hydrogenator. and 33 ml of perchloric acid, and reduced to 3.5 g of 10% palladium on carbon, at room temperature, under a hydrogen pressure of 3.7 atm. When the reduction is complete, the catalyst is removed for filtration, the filtrate is brought to dryness, and the residue is basified with 10% 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% isopropylamine . The first 350 milliliters of eluate, when brought to dryness, provides 10.6 g of

2-cyclohexyImethyl-1- [2- (3-benzylphenyl) propyl] piperidine in the form of 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 9

Following a procedure similar to that described in Example 8, 11.1 g (0.027 mol) of 2-cyclohexylmethyl-1 - {2- [3- (ot-hy droxy-a-methylbenzy l) phenyl are reduced ] propyl} piperidine (described in Example 4) dissolved in 180 ml of glacial acetic acid and 20 ml of 72% perchloric acid, with hydrogen over 0.8 g of palladium on carbon, which gives 10.3 g of 2-cyclohexylmethyl-1- (2- [3- (a-methylbenzyl) phenyl] propyl] -piperidine in the form of a yellow oil.

Analysis for C29H41N:

Calculated: C 86.29 H 10.24 N 3.47

Found: C 86.04 H 10.21 N3.70.

Example 10

Vigorously stirred and cool to 16 ° C a solution of 26.8 g (0.066 mol) of 2-cycohexylmethyl-1- (2- [3- (a-hydroxy-benzyl) phenyl] propyl} piperidine 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.

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35

40

45

5 "

55

60

65

619924

concentrated risk and diluting with water to 100 ml. The mixture is stirred with cooling for 13 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-benzoyl-phenyl) propyl] piperidine in the form of an oil. pale yellow viscous.

Analysis for C28H37NO:

Calculated: C 83.33 H 9.23 N 3.47

Found: C 83.30 H 9.33 N 3.45.

Example 11

Following a procedure similar to that described in Example 5, 5.0 g (13.2 mol) of 2-cyclohexylmethyl-1- [2- (3-bromophenyl) propyl] piperidine is reacted with 0.026 mol of n-butyllithium in diethyl ether and the resulting lithiated derivative is reacted directly with benzonitrile, which gives 4.0 g of 2-cyclohexylmethyl-l- [2- (3-benzoylphenyl) propyl] piperidine, identical to substance described in Example 10.

Example 12

A mixture of 37.5 g (0.093 mol) of 2-cyclo-hexylmethyl-1- [2- (3-benzoylphenyl) propyl] piperidine (described in Examples 10 and 11 above) and 10 is treated with stirring. , 0 g (0.14 mol) of hydroxylamine in 125 ml of 95% ethanol and 25 ml of water, per 19.4 g of sodium hydroxide powder and the mixture is heated to reflux for 'A 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 C28H38N2O:

Calculated: C 80.33 H 9.15 N 6.69

Found: C 80.03 H 9.42 N6.44.

Examples 12A-12B

By following a procedure similar to that described in Example 12, the following compounds of formula I are prepared in the same way

Example 12 A

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 mol) of hydrochloride 4 - [2- (3-benzoylphenyl) ethyl] morpholine 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 ethanol and 18.5 ml of water, to obtain 14.06 g of product.

Analysis for C19H22N2O2:

Calculated: C 73.52 H 7.14 N 9.03

Found: C 73.79 H 7.26 N 8.72.

Example 12B

4- [2- (3-Benzoylphenyl) propyl] morpholine-oxime (mp 117-130 ° C, recrystallized from isopropanol), prepared by reaction of 27 g (0.078 mol) of 4-2- hydrochloride (3- benzoyl-phenyl) propylmorpholine 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, which gives 3.2 g of product.

Example 13

A solution of 17 g (0.041 mol) of 2-cyclohexylmethyl-l-2- (3-benzoylphenyl) propylpiperidine-oxime described above in example 12 is brought to reflux in 110 ml of ethanol and treated with 10 g (0.043 mol) 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- (oc-aminobenzyl) -phenyl] propylj piperidine dichlorohydrate, pf 167-195 ° C.

Analysis for C2sH4iN2,2HCl:

Calculated: N 5.87 Cl 14.85

Found: N 5.61 Cl 14.66.

Examples 13A-13B

By following a procedure similar to that of Example 13, the following compounds of formula I are prepared in the same way.

Example 13 A

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

Analysis for C19H24N20,2HC1:

Calculated: C 61.79 H 7.10 Cl 19.20

Found: C 61.88 H 6.90 Cl 19.16.

Example 13B

4- {2- [3- (a-aminobenzyl) phenyl] propyll-morpholine dihydrochloride (mp 255-265 ° C), (9.5 g, crystallized from methanol / diethyl ether), prepared by reduction of 10 .0 g (0.03 mol) of 4- [2- (3-benzoylphenyl) propyl] morpholine-oxime with 7.1 g (0.31 mol) of sodium in 65 ml of absolute ethanol.

Analysis for C2oH26N20,2HC1:

Calculated: C 62.66 H 7.36 Cl 18.50

Found: C 61.78 H 7.17 Cl 18.01.

Example 14

Stirred and heated under reflux for 45 min a solution of 13.0 g (0.031 mol) of 2-cyclohexylmethyl-1- (2- [3- (a-hydroxy-a-methylbenzyl) phenyl) propyl | piperidine in 130 ml of methanol and 3 ml of concentrated sulfuric acid, then cooled, diluted with 100 ml of water, made alkaline with 5 ml of 35% sodium hydroxide and extracted with hexane. The combined hexane extracts, by washing with brine, drying and evaporating to dryness, give 14.2 g of an oil which is chromatographed on 260 g of alumina in an 8:92 mixture of diethyl ether and of hexane. 9.8 g of 2-cyclohexylmethyl-1- [2- [3- (1-phenyl-1-vinyl) phenyl] propyl] piperidine are thus obtained in the form of an oil.

5

H)

15

20

25

30

35

40

45

50

55

60

65

619924

16

Analysis for c29h39n:

Calculated: C 86.72 H 9.79 N3.49

Found: C 86.79 H 9.76 N3.28.

Example 15

Heated and stirred at 50 ° C for about 12 h a mixture of 45 g (0.13 mol) of 2,6-dimethyl-1- [2- (3-benzoyl-4-methoxy-phenyl) ethyl] piperidine and 34.9 g (0.26 mol) 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 'is heated once again 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.

Analysis for C22H27N02.HC1:

Calculated: C 70.67 H 7.55 N 3.75 Found: C 70.87 H 7.58 N 3.73.

Example 16

A solution of 13.2 g (0.03 mol) of 2-cyclohexylmethyl-l- {2- [3- (a-hydroxy-4-chloro-benzyl) phenyl] propyl} piperidine is heated under reflux for 1 hour * (described above in Example 3), 16 ml of concentrated nitric acid and 32 ml of 50% perchloric acid in 160 ml of 1,2-dimethoxyethane, then cooled, diluted with 50 ml of water, it is 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 a 10:90 mixture of ether and hexane as the eluent. The first 75 milliliters of eluate are discarded and the next 600 ml is brought to dryness, which gives 9.2 g of 2-cyclohexylmethyl-1- (2- [3- (4-chlorobenzoyl) phenyl] propyl} piperidine).

Analysis for C28H36ClNO:

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

Examples 16A-16D

By following a procedure similar to that described in Example 16, the following compounds of formula I are prepared in the same way:

Example 16A

2-Cyclohexymethyl-l- [2- (3-benzoylphenyl) ethyl] -piperidine (yellow oil), prepared by oxidation of 14.0 g (0.03 mol) of 2-cyclohexylmethyl-l- {2- [3- (a-hydroxybenzyl) phenyl] 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.

Analysis for c27h35no:

Calculated: C 83.24 H 9.06 N 3.60

Found: C 83.46 H 9.26 N3.75.

Example 16B

2-Cyclohexylmethyl-l- {2- [3- (3-chlorobenzoyl) phenyl] -propyl} piperidine (yellow oil), prepared by oxidation of 17.0 g (0.039 mol) of 2-cyclohexylmethyl-l- {2- [3- (a-hydroxy-3-chloro-benzyl) phenyl] propyl} piperidine (described above in Example 1A) 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 C28H36CINO:

Calculated: C 76.77 H 8.28 N3.20

Found: C 76.86 H 8.36 N 3.13.

Example 16C

2-Cyclohexylmethyl-l- {2- [3- (3,4-dichlorobenzoyl) -phenyl] propyl} piperidine (yellow oil), prepared by oxidation of 11.9 g (0.25 mol) of 2-cyclohexylmethyl-l - {2- [3- (a-hydroxy-3,4-dichlorobenzyl) phenyl] propyl} piperidine (described above in Example 1C) in 156 ml of a solution prepared by dissolving 24 ml of perchloric acid at 50% and 12 ml of concentrated nitric acid in 120 ml of 1,2-dimethoxyethane. 5.2 g of product are thus obtained.

Analysis for C28H35CI2NO:

Calculated: C 71.18 H 7.47 N2.96

Found: C 71.47 H 7.82 N2.96.

Example 16D

2-Cyclohexylmethyl-l- {2- [3- (2-chlorobenzoyl) phenyl] -propyljpiperidine (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 (described above in Example 1D) in 225 ml of a solution prepared by dissolving 48 ml of 50% perchloric acid and 24ml d nitric acid concentrated 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 N 3.20

Found: C 76.47 H 8.58 N 3.09.

Example 17

The reaction of 2-cyclohexylmethyl-1- {2- [3- (4-methoxy-benzoyl) phenyl] propyl} piperidine described above in Example 5 with hydrobromic acid in glacial acetic acid, and separation of the product in a neutral medium, provide 2-cyclohexylmethyl-1- {2- [3- (4-hydroxybenzoyl) phenyl] -propyl} piperidine.

Bioassay results

The N- {3- [Ri- (phenyl) -C (= X)] - phenyl (lower alkyl)} amines of formula I of the invention were tested in the tests on carrageenan-induced edema (OC ) and adjuvant-induced arthritis (AA) and have 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-benzoylphenyl) methyl] morpholine described in French patent No. 1549342. All the data are obtained by oral administration.

5

10

15

20

25

30

35

40

45

50

55

60

65

Table A

17

Table A (continued)

619,924

Example

Dose

OC

AA

1

0.005

0

0

0.02

3

2

0.08

35 *

30

1A

0.004

0

-

0.02

0

-

0.08

34 **

-

0.324

75 **

-

1B

0.08

19

-

0.16

-

91 **

0.324

63 **

-

1E

0.004

14

-

0.02

34 **

-

2

0.004

0

-

0.02

1

-

0.08

18

-

0.324

72 **

-

3

0.004

14

-

0.005

-

64 **

0.02

41 *

70 **

.

0.08

-

88 **

3A

0.004

0

-

0.02

0

-

0.08

58 **

-

0.324

68 **

-

4

0.004

14

-

0.02

5

-

0.08

28 *

-

0.324

55 **

-

5

0.004

0

-

0.02

22

-

0.08

-

63 **

5A

0.08

45 **

-

0.16

-

90 **

0.324

60 **

-

5B

0.004

3

-

0.005

-

61 **

0.02

38 *

55 *

0.08

-

85 **

5 C

0.004

0

-

0.02

10

-

0.08

58 **

-

0.324

75 **

-

5D

0.08

37 **

-

0.16

-

100 **

0.324

49 **

-

5E

0.08

33 *

92 **

0.324

58 **

5F

0.08

33 **

9 d **

0.16

-

Toxiqi

0.324

2] **

-

5G

0.004

33 **

-

0.02

42 **

-

0.08

-

76 **

5H (base)

0.004

29 *

-

0.02

44 **

-

0.08

-

81 **

5H (HCl)

0.08

68 **

-

0.324

73 **

-

5d

0.08

62 **

-

0.324

66 **

-

Example

Dose

OC

AA

5 6

0.004

2

_

0.02

21

-

0.08

33 **

-

0.324

68 **

-

io 7

0.004

0

_

0.02

0

-

0.08

21

-

0.324

47 **

-

15 8

0.005

7

25

0.02

26 *

63 *

0.08

60 **

91 **

9

0.004

0

-

0.02

15

-

20

0.08

29 *

-

0.324

64 **

-

10.11

0.005

21

69 **

0.02

41 **

81 **

25

0.08

• 51 **

87 **

0.324

69 **

-

12

0.004

16

-

0.02

43 **

92 **

0.08

91 **

30

12A

0.08

-

0.324

29

-

13

0.004

16

-

0.005

-

80 **

35

0.02

31 *

89 **

0.08

-

108 **

13A

0.08

27

-

0.324

39 *

-

4o 13B

0.08

49 **

-

0.324

84 **

-

14

0.004

9

-

0.02

16

-

0.08

47 **

-

45

0.324

67 **

-

15

0.02

5

_

0.08

0

-

0.16

-

1

50

0.324

23 *

-

16

0.004

16

-

0.005

-

63 **

0.02

52 **

90 **

55

0.08

-

Toxiqi

16A

0.004

9

-

0.02

25

-

0.08

46 **

-

0.324

70 **

-

60

16B

0.004

14

-

0.02

0

-

0.08

22 *

-

0.324

65 **

-

"16C

0.004

17 *

-

0.02

15

-

0.08

19 *

-

0.324

51 **

-

619,924

Table A (continued)

Example Dose OC AA

16D 0.004 0

0.005 - 35 *

0.02 36 ** 54 *

0.08 - 79 **

Ref. 0.08 0

0.324 23 *

* Statistically different from controls p <0.05.

** Statistically different from controls p <0.01.

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

Table B

Example

CIM

3

6 (ig / ml

8

6 ng / ml

10.11

6 ng / ml r

Claims (10)

619,924 2. Process for the preparation of a compound of formula I in which> C = X is a radical> C = 0, characterized in that 2 CLAIMS 1. Process for the preparation of a compound of formula X R (I) in which: R 1 represents hydrogen or one or two substituents, identical or not, chosen from the lower alkyl, hydroxy, lower alkoxy, - cf3, lower alkyl mercapto, lower alkylsulfinyl, lower alkylsulfonyl, fluorine, chlorine and bromine radicals; R2 is hydrogen or a lower alkoxy or hydroxy radical P C H - Ç H - ÏJ = B at P08'1'011or a lower alkyl radical in position 2,4,5 or 6; R3 is hydrogen or a lower alkyl radical; X R3 11 \ / C represents \ —N = B represents one of the groupings r -NH - C R, 3. Process for the preparation of a compound of formula I in which> C = X is a radical> CHR, characterized in that the process of claim 1 is carried out and that hydrogen is reduced on a catalyst in presence of perchloric acid the product obtained where> C = X is a residue> C (R) OH. 3 619,924 carry out the process of claim 1 and oxidize the compound obtained in which> C = X is a radical> CHOH. »3 where R3 represents hydrogen or a lower alkyl radical and has the same or different meanings when it appears more than once, R4. and R5 each represents a lower alkyl group; Rö and R7 each represent hydrogen or a lower alkyl, cyclohexyl, cyclohexylmethyl, 2-cyclohexylethyl, 3-cyclohexylpropyl or benzyl radical; Z represents = 0, = S or = N — Rg; R8 is a lower alkyl or cyclohexyl radical, and n is the whole 1,2 or 3, and their acid addition salts, characterized in that a compound of formula is reacted CHCH2-N = with a compound of formula \ v or (XX) (IXa) (XXII) and that the product obtained is subjected to hydrolysis, which gives a compound of formula I where> C = X is> CHOH from com-65 posed XX and> C (R) OH from compound XXII, R being a lower alkyl group. 3 -N - C - 4. Process for the preparation of a compound of formula I in which> C = X is a radical> C = CHi, characterized in that the process of claim 1 is carried out and that a compound obtained where> C is dehydrated = X is the remainder> C (CH3) OH. 5. Process for the preparation of the compounds of formula I in which> C = X is the radical> C = 0, and of their acid addition salts, characterized in that a compound of formula IXa is reacted with a nitrile of formula (XXI) followed by hydrolysis of the product obtained. 5 ' -NOT Ro î 'CH-3 R, CH-R4 AT * CK2) n v_ / k3 V ± y and R -WJICH (CH0) nN I 2 ^ * 4 * 5 / 6. Process for the preparation of a compound of formula I in which> C = X is the residue> CHOH, characterized in that the process according to claim 5 is carried out and that the product obtained is reduced where> C = X is the oxo radical. 7. Process for the preparation of a compound of formula I in which> C = X is the residue> C = NOH, characterized in that the process according to claim 5 is carried out and the product obtained is reacted where> C = X is the oxo radical, with hydroxylamine. 8. Method according to one of claims 1 to 4, characterized in that a base obtained is transformed into one of its acid addition salts. 9. Method according to one of claims 5 to 7, characterized in that a base obtained is transformed into one of its acid addition salts. 10. Process for the preparation of a compound of formula I in which> C = X is a group> CHNH2 characterized in that a compound of formula IXa is reacted with a nitrile of formula