CH652117A5 - COMPOUNDS HAVING THERAPEUTIC ACTIVITY, IN PARTICULAR AS ANTI-DEPRESSANTS, COMPOSITIONS CONTAINING THEM AND PROCESS FOR THEIR PREPARATION. - Google Patents

Description

The present invention relates to compounds having an interesting therapeutic activity, in particular - but not exclusively - as antidepressants, to a pharmaceutical composition containing these compounds as well as to a process for the preparation of these compounds.

The subject of the present invention is compounds corresponding to formula I:

in order to obtain a compound in which n = 0; R2 = H and Rls R5 and R6 are as defined in claim 1, or a ketone or an aldehyde of formula (VI):

% ^^ cr1r2cor7 (vi)

in order to obtain a compound in which n = 1; Rs = H and Rj, R2, Rs, R6 and R7 are as defined in claim 1.

17. Process for the preparation of compounds of formula (I) according to claim 1, comprising reducing a compound of formula (VII):

(VII)

CR1R2. (CR7Rs.) Nm5R4

(I)

where n = 0 or 1;

in which, when n = 0, Ri represents a straight chain or branched C1 to C6 alkyl group, a C3 to C7 cycloalkyl group, a cycloalkylalkyl group in which the cyclo-alkyl group is C3 to C6 and the group C1 to C3 alkyl, an alkenyl group or a C2 to C6 alkynyl group, or a group of formula II:

(II)

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in which R9 and Ri0, identical or different, each represent H, a halo radical, or a C1 to C3 alkoxy group;

wherein, when n = 1, Rx = H or a C1-C3 alkyl group;

R2 represents H or a C1 to C3 alkyl group;

R3 and R4, identical or different, each represent H, a straight chain or branched C1 to C4 alkyl group, a C3 to C6 alkenyl group, a C3 to C6 alkynyl group, a cycloalkyl group in which the nucleus contains 3 to 7 carbon atoms, a group of formula R ^ CO in which R: l = H; or, together and with the nitrogen atom to which they are attached, R3 and R4 form an optionally substituted heterocycle containing 5 or 6 atoms in the nucleus which may contain other heteroatoms in addition to the nitrogen atom; R5 and Re, identical or different, each represent H, a halo group, a trifluoromethyl group, a C1 to C3 alkyl group, a C1 to C3 alkoxy or alkylthio group, a phenyl group or, together and with the atom of carbon to which they are attached, R5 and R6 form a second benzene ring substituted or not substituted by one or more halo groups, a C1 to C4 alkyl or alkoxy group or the substituents of the second benzene ring, with the two carbon atoms on which they are fixed, can form another benzene nucleus; R7 and Rs, identical or different, each represent H or a C1 to C3 alkyl group; as well as their pharmaceutically acceptable salts.

In the formulas indicated here, the symbol represents a 1,1-disubstituted cyclobutane group corresponding to the formula i

-c ch „

Z 2

55 and - CRiR2 (CR7R8) nR3R4 represents a group corresponding to the formula:

»R-

-Cr-C — 1 N "

In the preferred compounds of formula I, in which n = 0, R 1 represents an alkyl group with a straight or branched chain from C 1 to C 4, a cycloalkyl group from C 3 to C 1, a cycloalkyl-methyl group in which the cycloalkyl nucleus is from C 3 to C6 or a 65 group of formula II in which R9 and / or R10 = H, fluoro or methoxy and in which R2 = H or methyl. As examples of particularly preferable compounds of formula I, mention will be made of those in which when n = 0 and R2 = H, Rj represents a group

652,117

4

methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl or phenyl.

In the preferable compounds of formula I in which n = 1, Rj = H or methyl, and R2 = H. In the particularly preferable compositions of formula I in which n = 1, Rj = R2 = H.

In the preferable compounds of formula I, R3 and / or R4 each represent H, a methyl, ethyl or formyl group, or when together and with the nitrogen atom to which they are attached R3 and R4 form a heterocyclic ring, the preferable compounds of formula I contain a heterocyclic group containing a nitrogen atom and 4 or 5 carbon atoms (for example pyrrolidinyl, pi-peridino) which is optionally substituted by one or more alkyl groups (for example methyl) (for example pyrrolidinyl substituted by two methyl groups), a heterocyclic group containing a second nitrogen atom which is optionally alkylated (for example 4-methylpiperazinyl) or a heterocyclic group comprising one or more double bonds (for example 1,2,3,6-tetrahydropyridinyl ). In the particularly preferable compounds of formula I, R3 and / or R4 each represent H or a methyl, ethyl or formyl group.

In the preferable compounds of formula I, R5 and / or R6 represent H, or a fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy, phenyl or group, together with the carbon atom to which they are attached , R5 and R6 form a second benzene ring optionally substituted by a halo group.

A first group of preferred compounds of formula I is represented by formula III:

(III)

in which R5 and R6 have the above definitions. In the preferred compounds of formula III, Rs and R6, identical or different, each represent H or a fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy, phenyl group or, together and with the carbon atoms on which they are fixed, R5 and R6 form a second benzene nucleus optionally substituted by a chloro group. In the particularly preferred compositions of formula III, R5 and / or Rq each represent H or a fluoro, chloro, iodo, trifluoromethyl, methyl, phenyl group or, together and with the carbon atoms to which they are attached, R5 and R6 form a second benzene nucleus optionally substituted by a chloro group.

A second group of preferred compounds of formula I is represented by formula IV:

wherein R5 represents H, or a fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy or phenyl group, and R6 represents a fluoro or methyl group. In the particularly preferred compounds of formula IV, R5 = H or chloro.

In the preferred compounds of formula I in which n = 1, R7 = H, methyl or ethyl and Rs = H, and in the particularly preferred compounds of formula I, R7 = H or ethyl and R8 = H.

The compounds of formula I can exist in the form of salts with pharmaceutically acceptable acids. As examples of these salts, mention will be made of hydrochlorides, maleates, acetates, citrates, fumarates, tartrates, succinates as well as salts with acidic amino acids such as aspartic and glutamic acids.

The compounds of formula I which contain one or more asymmetric carbon atoms can exist in different optically active forms. When R! and R2 are different or R7 and Rs are different, the compounds of formula I contain a chiral center. These compounds exist in two enantiomeric forms, and the present invention encompasses both enantiomeric forms and their mixtures. When both R! and R2 are different and R7 and Rs are different, the compounds of formula I contain two chiral centers and the compounds exist in four diastereomeric forms. The present invention encompasses each of these dias-tereoisomeric forms as well as their mixtures.

The present invention also relates to pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I as well as a pharmaceutically acceptable diluent or vehicle.

For therapeutic use, the active compound can be administered orally, rectally, parenterally or topically, preferably orally. Thus, the therapeutic compositions according to the present invention can take the form of any of the pharmaceutical compositions known for oral, rectal, parenteral or topical administration. The pharmaceutically acceptable vehicles usable in these compositions are well known in the pharmaceutical art. The compositions according to the invention can contain from 0.1 to 90% by weight of active compound. The compositions according to the invention are generally prepared in the form of unit doses.

The compositions which can be administered orally are the preferred compositions according to the invention, and are the known forms for this administration, for example tablets, capsules, syrups and aqueous or oily suspensions. The excipients used in the preparation of these compounds are the excipients well known in pharmaceutical technology. Tablets can be prepared by mixing the active compound with an inert diluent such as calcium phosphate in the presence of disintegrating agents such as, for example, corn starch, and lubricating agents such as magnesium stearate and transforming the mix into tablets by known procedures. The tablets can be prepared in a manner known to those skilled in the art, so as to provide a sustained release over time of the compounds according to the present invention. These tablets may optionally be provided with enteric coatings, by known procedures, for example using cellulose acetophthalate. Similarly, hard or soft gelatin capsules containing the active compound, with or without the addition of excipients, can be prepared in a conventional manner and optionally provide it with enteric coatings in a known manner. The tablets and capsules may suitably contain from 1 to 500 mg of the active compound each. As other compositions which can be administered orally, there may be mentioned, for example, aqueous suspensions containing the active compound in a medium in the presence of a non-toxic suspending agent such as sodium carboxymethylcellulose, and oily suspensions containing a compound according to the present invention in a suitable vegetable oil, for example peanut oil.

The compositions according to the invention which can be used for rectal administration are the pharmaceutical forms known for this administration, for example suppositories with bases of the cocoa butter or polyethylene glycol type.

The compositions according to the invention which can be used for parenteral administration are the pharmaceutical forms known for this administration, for example sterile suspensions in aqueous and oily media or sterile solutions in an appropriate solvent.

The compositions for topical administration may comprise a matrix in which the pharmacologically active compounds according to the present invention are dispersed so that the compounds are kept in contact with the skin in order to administer the compounds transdermally. Active compounds

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can also be dispersed in a pharmaceutically acceptable cream or ointment base.

In certain compositions, it may be beneficial to use the compounds according to the present invention in the form of very small particles, for example as obtained by grinding with fluid energy.

In the compositions according to the present invention, the active compound can optionally be combined with other compatible pharmacologically active ingredients.

Pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I can be used to treat depressive conditions in mammals, including humans. In such treatment, the amount of compound of formula I administered per day is from 1 to 1000 mg and, preferably, from 5 to 500 mg.

The compounds of formula I in which R4 = CHO can be prepared by reductive amidation of ketones of formula Y or of ketones or aldehydes of formula VI,

re çor-,

r5 cr-jrgcory for example with formamide and formic acid or ammonium formate and formic acid, to obtain compounds of formula I in which R4 = CHO and R3 = H, or with formamides of formula HCONHR3 in which R3 represents an alkyl or cycloalkyl group and formic acid, or amines of formula R3NH2 in which R3 represents an alkyl or cycloalkyl group and formic acid.

The compounds of formula I in which R4 = CHO can be prepared by formylation of compounds of formula I in which R4 = H, for example by reaction with methyl formate.

Compounds of formula I in which R3 is not H and R4 = CHO can be prepared by reacting compounds of formula I in which R3 = H and R4 = CHO with a compound of formula R3X in which X is a leaving group , like a halo group, in the presence of a base.

The compounds of formula I can be prepared by reductive amination of ketones of formula V or of ketones or aldehydes of formula VI. As examples of suitable reductive amination modes, mention will be made of:

a) for the compounds of formula I in which R3 and R4 = H, by reaction of the ketone or of the aldehyde with an ammonium salt (for example ammonium acetate) and a reducing agent such as cyanoborohydride of sodium,

b) for the compounds of formula I in which R3 = alkyl or cycloalkyl and R4 = H, by reaction of the ketone or aldehyde with an amine of formula R3NH2 and a reducing agent such as sodium cyanoborohydride,

c) for the compounds of formula I in which neither R3 nor R4 are hydrogen or in which R3 and R4, together and with the nitrogen atom, form a heterocycle, by reaction of the ketone or of the aldehyde with an amine of formula HNR3R4 and either formic acid or a reducing agent such as sodium cyanoborohydride,

d) for the compounds of formula I in which R3 and / or R4 represent H or an alkyl or cycloalkyl group or in which, together and with the nitrogen atom, R3 and R4 form a heterocycle, by catalytic hydrogenation at temperature and high pressure of a mixture of the ketone or aldehyde and an amine of formula HNR3R4.

The compounds of formula I in which R3 and R4 both represent alkyl groups can be prepared by reacting a ketone of formula V or a ketone or an aldehyde of formula VI with a dialkoyl formamide of formula HCONR3R4, for example in the presence of formic acid.

The compounds of formula I can be prepared by the reduction of compounds of formula VII

in which a) Z is a group of formula - CRj = NOH or one of its esters or ethers, in order to obtain compounds of formula I in which n = 0 and R2, R3 and R4 = H;

b) Z is a group of formula - CRX = NR3, in which R3 is different from H or CHO, in order to obtain compounds of formula I in which n = 0 and R2 and R4 = H;

c) Z is a group of formula - CR! = NY in which Y represents a fragment containing a metal deriving from an organometallic reagent, in order to obtain compounds of formula I in which n = 0 and R2, R3 and R4 = H;

d) Z is a group of formula - CRXR2 ■ CN, in order to obtain compounds of formula I in which n = 1 and R3, R4, R, and Rs =

H;

e) Z is a group of formula - CRi R2 • CR7 = NOH or one of its esters or ethers, in order to obtain compounds of formula I in which n = 1 and R3, R4 and R8 = H;

f) Z is a group of formula - CR ^ j • CR, = NR3, in which R3 is different from H or CHO, in order to obtain compounds of formula I in which n = 1 and R4 and R8 = H;

g) Z is a group of formula - CR ^ z • CR7 = NY in which Y represents a fragment containing a metal derived from an organometallic reagent, in order to obtain compounds of formula I in which n = 1 and R3, R4 and Rs = H;

h) Z is a group of formula - CR ^ j • CONR3R4, in order to obtain compounds of formula I in which n = 1 and R, and Rs = H.

Examples of suitable reducing agents for the above reactions include sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride or a borane-dimethyl sulfide complex.

In c and g above, Y preferably represents MgBr deriving from a Grignard reagent or Li deriving from an organic lithium compound.

The compounds of formula I in which n = 0 can be prepared by the reaction of an organometallic reagent, for example a Grignard reagent of formula RtMgX in which X = Cl, Br or I, or an organic compound of lithium of formula RjLi with an imine of formula VIII

ch = nr.

R,

"5

followed by hydrolysis, in order to obtain a secondary amine of formula I. In a similar manner, the imines of formula IX can be converted into secondary amines of formula I in which n = 1

cr, r „* ch = nr.

Compounds of formula I in which R3 and R4 = H can be prepared by rearrangement by decarboxylation, for example

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using iodosobenzenebistrifluorocetate or by a Hofmann reaction using bromine in alkaline solution, amides of formula X or amides of formula XI

Rc

CR ^ RgCOHHg

Rc

: R1R2CR7Rg: C0NH2

(XI)

in order to obtain amines of formula I in which n = 0 and n = 1, respectively.

The compounds of formula I in which R3 and R4 = H can be prepared by rearrangement by decarboxylation of acyl azides in the Curtius reaction. Acyl azides can be obtained, for example, by reacting acid chlorides of formula XII or acid chlorides of formula XIII with sodium azide. „

1. 2

cr1r2.cr7r8coci

(XIII)

The compounds of formula I in which R3 and R4 = H can be prepared by a Schmidt reaction in which a carboxylic acid of formula XIV or a carboxylic acid of formula XV reacts with hydrazoic acid qr1r2.cooh cr1r2.cr7r8cooh

The compounds of formula I in which R4 = H can be prepared by hydrolysis of compounds of formula I in which R4 = CHO, for example by acid hydrolysis.

The compounds of formula I in which R4 = methyl can be prepared by reduction of compounds of formula I in which R4 = CHO, for example using lithium aluminum hydride or bis (2-methoxyethoxy) aluminohydride sodium.

The compounds of formula I in which R3 and / or R4 do not represent hydrogen can be prepared from compounds of formula I in which R3 and / or R4 = H, by methods well known in the art of conversion from primary amines to secondary or tertiary amines or from the conversion of secondary amines to tertiary amines. Examples of suitable methods are given below:

a) by alkylation of primary amines of formula I to obtain secondary amines of formula I, for example by a process consisting in protecting the primary amine using a protective group (trifluoroacetyl for example), to alkylate to using an alkyl halide and removing the protective group, for example by hydrolysis;

b) by alkylation of primary amines of formula I, for example using an alkyl halide in order to obtain tertiary amines of formula I in which R3 and R4 are identical;

c) by alkylation of secondary amines of formula I, for example using an alkyl halide in order to obtain tertiary amines of formula I in which R3 and R4 may be different;

(X) 5 d) by reacting primary amines of formula I with sodium borohydride and acetic acid in order to obtain secondary amines of formula I in which R3 = ethyl and R4 = H;

e) reacting primary amines of formula I with formaldehyde and formic acid to obtain tertiary amines of formula I in which R3 and R4 are both methyl groups;

f) by reacting secondary amines of formula I in which R4 = H with formaldehyde and formic acid in order to obtain tertiary amines of formula I in which R4 = methyl;

g) by formylation of primary amines of formula I, for example by reaction with methyl formate, and reduction of the resulting form-amides, for example using lithium aluminum hydride in order to obtain secondary amines of formula I in which R3 = methyl and R4 = H;

h) by formylation of secondary amines of formula I, by (XII) for example by reaction with methyl formate, and reduction of the resulting formamides, for example using lithium aluminum hydride, in order to '' obtain tertiary amines of formula I in which R4 = methyl;

i) by acylation of primary amines of formula I, for example by reaction with an acyl chloride of formula RI2C0C1 or an anhydride of formula (Ri2C0) in which R12 represents a group

Alkyl, alkenyl or alkynyl, and reduction of the resulting amines, for example using lithium aluminum hydride in order to obtain secondary amines of formula I in which R3 =

—CH2R12 and R4 = H;

j) by acylation of secondary amines of formula I in which R4 = H, for example by reaction with an acyl chloride of formula R12CO6 or an anhydride of formula (R12CO) in which R12 represents an alkyl, alkenyl or alkynyl and reduction of the resulting amides, for example using lithium aluminum hydride in order to obtain tertiary amines in which R4 = CH2R12;

k) by reaction of primary amines of formula I with an aldehyde of formula R13CHO in which R12 may be an alkyl group, an alkenyl or alkynyl group or a ketone of formula R14C0Rls in which R14 and R15, which may be identical or different, each represents an alkyl group, an alkenyl group, an alkynyl group, or, together and with the carbon atom to which they are attached, R14 and R15 can form an alicyclic ring, and reduction of the resulting imines or enamines, for example to using sodium cyanoborohydride or, when R13, R14 or R15 do not represent an alkenyl or alkynyl group, by catalytic hydrogenation in order to obtain secondary amines of formula I in which R3 = respectively R ^ and R ^ -CH-;

* 15

55 1) by reaction of primary amines of formula I with a non-geminated di-substituted alkane containing 2 or 3 carbon atoms between the carbon atoms carrying the substituents which may be, for example, halo, preferably bromo, or p- toluenesulfonyloxy in order to obtain compounds of formula I in which R3 and R4, together and with the nitrogen atom to which they are attached, form a heterocycle containing no other heteroatoms than the atom nitrogen.

Ketones of formula V can be prepared by hydrolysis of imines of formula XVI

(XIV)

(XV)

45

çr1 = ny

(XVI)

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in which Y represents a fragment containing a metal derived from an organometallic reagent. The imines of formula XVI can be prepared by reacting said organometallic reagent with a compound of cyano type corresponding to formula XVII.

(XVII)

As examples of suitable organometallic reagents, Grignard reagents corresponding to the formula RjMgX in which X = Cl, Br or I (Y = MgX) and organic lithium compounds of formula RjLi (Y = Li) may be mentioned.

Ketones of formula VI can be prepared by hydrolysis of imines of formula XVIII

(XVIII)

in which Y represents a fragment containing a metal derived from an organometallic reagent. The imines of formula XVIII can be prepared by reacting said organometallic reagents with compounds of cyano type corresponding to formula XIX

CR, R ^ CN \ (XIX)

As examples of suitable organometallic reagents, Grignard reagents corresponding to the formula R7MgX in which X = Cl, Br or I (Y = MgX) and organic lithium compounds of formula RjLi (Y = Li) may be mentioned.

Ketones of formula V can be prepared by reacting carboxylic acid derivatives such as an amide or an acid halide with an organometallic reagent, for example by reacting an acid chloride of formula XX

COCl

(XX)

with a Grignard reagent of formula R ^ gX in which X = Cl, Br or I, at low temperature, or by reaction of a carboxylic acid of formula XXI

COOH

(XXI)

with an organometallic reagent, for example an organic lithium compound corresponding to the formula RjLi.

The ketones of formula VI can be prepared by reacting carboxylic acid derivatives such as an amide or an acid halide with an organometallic reagent, for example by reacting an acid chloride of formula XII with a Grignard reagent of formula R, MgX in which X = Cl, Br or I at low temperature, or by reaction of a carboxylic acid of formula XIV with an organometallic reagent, for example an organic lithium compound corresponding to the formula R7Li.

The ketones of formula V in which R 1 = alkyl (for example methyl) and the ketones of formula VI in which R 1 = alkyl (for example methyl) can be prepared by reactions of a diazoalkane (such as diazomethane) with aldehydes corresponding respectively in formulas XXII and VI.

(XXII)

The aldehydes of formula VI can be prepared by methods well known in the art. For example:

a) by reduction of cyano type compounds corresponding to formula XIX using, for example, ditert.-butyl-aluminum hydride or diisobutylaluminum hydride;

b) by reduction of carboxylic acid derivatives, for example:

i) by reduction of compounds of formula VII in which Z = CRiRjCONRaR. ^ and R3 and R4 do not represent hydrogen ^ for example using lithium diethoxyaluminohydride;

ii) by reduction of amides formed by reaction of ethylenimine with an acid chloride of formula XII, for example using lithium aluminum hydride as reducing agent;

iii) by reduction of acid chlorides of formula XII, for example using lithium tritert.-butoxyaluminohydride;

c) by reaction of alcohols (obtained by reduction of carboxylic acids of formula XIV using, for example, a chrompyridine tri-oxide complex in dichloromethane, in an anhydrous medium.

The compounds of formula VII in which Z represents a group of formula - CRt = NOH or - CRiR2 CR7 = NOH or their ethers or esters can be prepared by reaction of hydroxylamine or of a hydroxylamine ether or ester with, respectively, ketones of formula V and ketones or aldehydes of formula VI. The compounds of formula VII in which Z represents a group corresponding to the formula - CRj = NR3 or - CRjRj CR, = NR3 can be prepared by reaction of amines of formula NH2R3 with ketones of formula V and ketones or aldehydes of formula VI, respectively.

The preparation of the compounds of formula VII in which Z re-35 has a group corresponding to the formula - CRj = NY or

CR1R2-CR7 = NY has been described above with respect to the compounds of formulas XVI and XVIII, respectively.

The preparation of the compounds of formula VII in which Z represents a group corresponding to the formula - CRjR2CN will be described below with reference to the cyano-type compounds of formula XIX.

The compounds of formula VII in which Z represents a group - CRjRjCONRjR ^ can be prepared by reaction of acid derivatives such as esters or acid halides (for example acid chlorides of formula XII with amines of formula NHR3R4. The compounds of formula VII in which Z represents CRjRjCONHj can be prepared from cyano compounds of formula XIX, for example by hydration, using aqueous acids, or by reaction with hydrogen peroxide in the presence of a based.

The imines of formulas Vili and IX can be prepared by reaction of amines of formula R3NH2 with aldehydes corresponding to formulas XXII and VI respectively.

The amides of formula X can be prepared by reaction of ammonia with derivatives of carboxylic acids, for example 55 acid chlorides of formula XII, or can be prepared from cyano compounds of formula XIX, for example by hydration using aqueous acids or by reaction with hydrogen peroxide in the presence of a base.

The amides of formula XI can be prepared by reaction of ammonia with derivatives of carboxylic acids, for example acid chlorides of formula XIII, or can be prepared from cyano compounds of formula XXIII, for example by hydration using aqueous acids or by reaction with hydrogen peroxide in the presence of a base.

\

CR ^ CR ^ qCN

(XXIII)

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The amides of formula X in which Rt = R2 = H and the amides of formula XI in which R7 = Rs = H can be prepared from acid chlorides corresponding to formulas XX and XII respectively by reaction with diazomethane, in order to obtaining a diazoketone which undergoes rearrangement in the presence of ammonia and a catalyst, for example silver, by giving the required amide.

The carboxylic acids corresponding to formulas XIV, XV and XXI can be prepared, for example, by hydrolysis (for example basic hydrolysis) of cyano compounds corresponding respectively to formulas XIX, XXIII and XVII. The carboxylic acids of formula XIV and XV can be prepared by reaction of amides corresponding to formulas X and XI respectively with nitrous acid. The carboxylic acids of formula XXI can be prepared by reaction of nitrous acid on the amides obtained by reaction of ammonia with derivatives of carboxylic acids, for example acid chlorides of formula XX, or by reaction of cyano compounds of formula XVII on hydrogen peroxide in the presence of a base.

The carboxylic acids of formula XIV in which Ri = R2 = H and the carboxylic acids of formula XV in which R, = Rs = H can be prepared from acid chlorides corresponding to formulas XX and XII, respectively, by reaction on diazomethane, in order to obtain diazoketones which undergo by rearrangement in the presence of water and a catalyst, for example silver, giving the required acid.

Cyano compounds of formula XVII can be prepared by reaction of cyano compounds of formula XXIV

ch2cn

(XXIV)

for example, ditert.-butylaluminium hydride or diisobutylaluminium hydride;

b) by reduction of derivatives of carboxylic acids, for example: i) by reduction of tertiary amides formed by reaction of amines

5 condaires on acid chlorides of formula XX for example, when the secondary amine is a dialkoylamine using lithium diethoxyaluminohydride as reducing agent or, when the secondary amine is ethylenimine, using hy lithium and aluminum chloride as a reducing agent,

ii) by reduction of the acid chloride of formula XX, for example using lithium tritert.-butoxyaluminohydride,

c) by oxidation of alcohols (prepared by reduction of carboxylic acids of formula XXI using, for example, a chromium tri-oxide-pyridine complex in dichloromethane, in medium

15 anhydrous.

Ketones of formula V (except those in which R5 = R6 = H and R! = Methyl or ethyl), ketones of formula VI and aldehydes of formula VI (except those in which Z = CR! = NY and R5 = R6 = H and Ri = methyl or ethyl), the imines of formu-20 VIII (except those in which R5 = R6 = H), of formulas IX, XVI (except those in which Rs = R6 = H, and R! = methyl or ethyl) and of formula XVIII, the amides of formula X and XI, the carboxylic acids of formula XIV (except those in which Rls R2, R5 and Re = H) and XV, the cyano compounds of formulas XIX and 25 XXIII and the acid chlorides of formula XII (except those in which R1; R2, Rs and R <j = H) and XIII which are described here as intermediates are new compounds. Some of the cyano compounds of formulas XVII and XXIV are new compounds. These new compounds constitute one aspect of the present invention.

New formamides corresponding to formula XXV

\

with 1,3-disubstituted propane, for example 1,3-dibromo-propane and a base such as sodium hydride.

The cyano compounds of formula XIX in which Rj = R2 = H can be prepared from cyano compounds of formula XVII, for example by the following series of reactions:

a) hydrolysis of the cyano group in order to obtain a carboxylic acid of formula XXI;

b) reduction of the carboxylic acid, for example using lithium aluminum hydride or a borane-dimethyl sulfide complex, in order to obtain the corresponding alcohol;

c) replacement of the hydroxy group of the alcohol with a labile group, for example a p-toluenesulfonyloxy group, and d) replacement of the labile group with a cyano group.

Similarly, the cyano compounds of formula XXIII

can be prepared from cyano compounds of formula XIX. The cyano compounds of formula XIX in which one and / or the other of the radicals Rx and R2 do not represent hydrogen can be prepared from the corresponding cyano compounds of formula XIX in which R! and / or R2 = H, for example by alkylation using an alkyl halide in the presence of a base such as lithium diisopropylamide.

The cyano compounds of formula XIX in which R2 = H can also be prepared by reacting ketones of formula V or an aldehyde of formula XXII with a reagent making it possible to introduce a cyano group such as p-toluene-sulfonylmethyl isocyanide. Similarly, the cyano compounds of formula XXIII can be prepared from aldehydes or ketones of formula VI.

The acid chlorides of formulas XX, XII and XIII can be prepared by reacting carboxylic acids corresponding respectively to formulas XXI, XIV and XV with, for example, thionyl chloride.

The aldehydes of formula XXII can be prepared by methods well known to those skilled in the art, for example:

a) by reduction of cyano compounds of formula XVII using,

cwcïy ^ n1

CHO

(XXV)

are described herein as intermediates in the preparation of compounds of formula I, and these new formamides constitute yet another aspect of the present invention.

The therapeutic activity of the compounds of formula I was indicated by evaluating the power of the compounds to reverse the hypothermic effects of reserpine, as follows. 45 male Charles River CDI mice weighing between 18 and 30 g are separated into groups of 5 and receive food and water ad libitum. After 5 h, the temperature of each mouse is taken orally and the mice are injected, intraperitoneally, 5 mg / kg of reserpine in solution in deionized water containing 50 of ascorbic acid (50 mg / ml). The amount of liquid injected is 10 ml / kg of body weight. 9 h after the start of the test, the food is deleted but the mice still have water at will. 24 hours after the start of the test, the temperature of the mice is taken, and the test compound is administered to the mice, suspended in 55% solution at 0.25% of hydroxyethylcellulose (supplied under the trade name of Cellosize QP 15000 by Union Carbide) in deionized water, at a dose volume of 10 ml / kg of body weight. 3 h later, the temperature of all the mice is also taken. The percentage of reversal of the drop in body temperature due to reserpine is then calculated according to the formula:

End temperature Temperature after 27 h - 24 h x 100

Temperature after 5 h

Temperature after 24 h

The average value for each group of 5 mice is taken at various doses in order to obtain an average dose value causing an inversion of 50% (ED50). All the

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applied which are the final products of the examples below give ED50 values equal to or less than 30 mg / kg. It goes without saying for those skilled in the art that this test indicates compounds having antidepressant activity in humans.

Table I provides a list of compounds of formula I that provided an ED50 value of 10 mg / kg or less in the above test.

Table I

1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride,

N-methyl-1- [1- (3,4-dichlorophenyl) -cyclobutyl] ethylamine hydrochloride,

N, N-dimethyl-1 - [- (3,4-dichlorophenyl) -cyclobutyl] ethylamine hydrochloride,

1- [1- (4-iodophenyl) cyclobutyl] ethylamine hydrochloride, N-methyl-1- [1- (4-iodophenyl) cyclobutyl] ethylamine hydrochloride,

N, N-dimethyl-1- [1- (4-iodophenyl) cyclo-butyl methylamine hydrochloride,

N-methyl-1- [1- (2-naphthyl) cyclobutyl] ethyl-amine hydrochloride,

N, N-dimethyl-1- [1- (4-chloro-3-trifluoro-methylphenyl) cyclobutyl] ethylamine hydrochloride,

l- [1- (4-chlorophenyl) cyclobutyl] butylamine hydrochloride, N-methyl-l - [- (4-chlorophenyl) cyclo-butyljbutylamine hydrochloride,

N, N-dimethyl-1- [1- (4-chlorophenyl) cyclo-butyl] butylamine hydrochloride,

1- [1- (3,4-dichlorophenyl) cyclobutyl] butylamine hydrochloride,

N-methyl-l- [1- (3,4-dichlorophenyl) cyclo-butyljbutylamine hydrochloride,

N, N-dimethyl-1- [1- (3,4-dichlorophenyl) -cyclobutyljbutylamine hydrochloride,

1- [1- (4-biphenylyl) cyclobutyl] butylamine hydrochloride, N, N-dimethyl-1- [1- (4-biphenylyl) cyclo-butyl] butylamine hydrochloride,

1- [1- (4-chloro-3-fluorophenyl) cyclo-butyljbutylamine hydrochloride,

N-formyl-1- [1- (4-chloro-3-fluorophenyl) cyclobutyl] butylamine,

1- [1- (3-chloro-4-methylphenyl) cyclo-butyljbutylamine hydrochloride,

N-formyl-1- [1-phenylcyclobutyl] butylamine,

1- [1- (3-trifluoromethylphenyl) cyclo-butyl] butylamine hydrochloride,

l- [l- (napht-2-yl) cyclobutyl] butylamine hydrochloride, l- [l- (6-chloronapht-2-yl) cyclobutyl] butylamine, N-methyl-l- [l- hydrochloride (4-chlorophenyl) cyclobutyl] -2-methylpropylamine,

1- [1- (4-chlorophenyl) cyclobutyI] pentyIamine hydrochloride, N-methyl-1- [1- (4-chlorophenyl) cyclobutyl] -pentylamine hydrochloride,

N, N-dimethyl-1- [1-phenylcyclobutyl] -3-methylbutylamine hydrochloride,

1- [1- (4-chlorophenyl) cyclobutyl] -3-methyl-butylamine hydrochloride,

N-methyl-1- [1- (4-chlorophenyl) cyclo-butyl] -3-methylbutylamine hydrochloride,

N, N-dimethyl-1- (1- (4-chlorophenyl) cyclo-butyl) -3-methylbutylamine hydrochloride,

N-formyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl-amine,

N, N-dimethyl-1- [1- (3,4-dichlorophenyl) cyclo-butyl] -3-methylbutylamine hydrochloride,

N-methyl-1- [1- (naphth-2-yl) cyclobutyl] -3-methylbutylamine hydrochloride,

N-methyl-1- [1- (3,4-dimethylphenyl) cyclo-butyl] -3-methylbutylamine hydrochloride,

[1- (4-chlorophenyl) cyclobutyl] (cyclopropyl) -methylamine hydrochloride,

N-methyl- [1- (4-chlorophenyl) cyclobutyl] - (cyclopently) methylamine hydrochloride,

[1- (4-chlorophenyl) cyclobutyl] (cyclohexyl) -methylamine hydrochloride,

N-methyl- [1- (4-chlorophenyl) cyclobutyl] - (cyclohexyl) methylamine hydrochloride,

[1- (3,4-dichlorophenyl) cyclobutyl] (cyclo-hexyl) methylamine hydrochloride,

N-methyl- [1- (3,4-dichlorophenyl) cyclo-butyl] (cyclohexyl) methylamine hydrochloride,

[1- (4-chlorophenyl) cyclobutyl] (cycloheptyl) -methylamine hydrochloride,

1- [1- (4-chlorophenyl) cyclobutyl] -2-cyclo-propylethylamine hydrochloride,

N, N-dimethyl-1- [1- (4-chlorophenyl) cyclo-butyl] -2-cyclohexylethylamine hydrochloride,

a- [1- (4-chlorophenyl) cyclobutyl] benzylamine hydrochloride, N-methyl-a- [1- (4-chlorophenyl) cyclobutyl] -benzylamine hydrochloride,

l- [l- (4-chloro-2-fluorophenyl) cyclobutyl] butylamine, N, N-dimethyl-l- [1- (4-chloro-2-fluorophenyl) -cyclobutyl] butylamine hydrochloride,

l - {[l- (3,4-dichlorophenyl) cyclobutyl] -methyl} propylamine hydrochloride,

N, N-dimethyl-1 - {[1- (3,4-dichlorophenyl) cy-clobutyl] methyl} propylamine hydrochloride,

N, N-dimethyl-2- [1- (4-iodophenyl) cyclo-butyl] ethylamine hydrochloride,

N-ethyl-1- [1- (3,4-dichlorophenyl) cyclo-butyl] ethylamine hydrochloride,

N, N-diethyl-1- [1- (3,4-dichlorophenyl) cyclo-butyl] ethylamine hydrochloride.

The following nonlimiting examples are given by way of illustration of the invention. All the compounds have been characterized by conventional analysis techniques and present satisfactory elementary analyzes.

Example 1:

A solution of 3,4-dichlorobenzyl cyanide (25 g) and 1,3-dibromopropane (15 ml) in dry dimethylsulfoxide (150 ml) is added dropwise under nitrogen to a stirred mixture of sodium hydride ( 7.5 g) dispersed in mineral oil (7.5 g) and dimethyl sulfoxide (200 ml) at a temperature of 30 to 35 ° C. The mixture is stirred at room temperature for 2 h, then added dropwise drop 8 ml of propan-2-ol followed by 110 ml of water. The mixture is filtered on diatomaceous earth supplied under the Celite trademark and the solid residue is washed with ether. The ethereal layer is separated and washed with water, dried and evaporated. 1- (3,4-Dichlorophenyl) -1-cyclobutanecarbonitrile is isolated (bp 108-120 ° C at 0.15 mmHg) by distillation. This procedure is a variant of that described by Butler and Pollatz ("J. Org. Chem.", Vol. 36, N ° 9, 1971, p. 1308).

The 1- (3,4-dichlorophenyl) -1-cyclobutanecarbonitrile prepared as described above (21.7 g) is dissolved in dry ether (50 ml) and the solution is added, under nitrogen, to the product of the reaction of methyl bromide gas on magnesium turnings (3.9 g) in dry ether (150 ml). The mixture is stirred at room temperature for 2 h, then at reflux for 2 h. Crushed ice is added, then 100 ml of concentrated hydrochloric acid, and the mixture is heated to reflux for 2 h. The ethereal layer is separated and washed with water and, using an aqueous solution of sodium bicarbonate, dried and evaporated. L-acetyl-1- (3,4-dichlorophenyl) cyclobutane (m.p. 108-110 ° C at 0.2 mmHg) is isolated by distillation.

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9.1 g of l-acetyl-1- (3,4-dichlorophenyl) cyc! Obutane prepared as described above, 6.5 ml of formamide and 3 ml of 98% formic acid are heated to 180 ° C. for 16 h, thereby obtaining N-formyl4- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine. 20 ml of concentrated hydrochloric acid are added and the mixture is heated to reflux for 3 h. Then the solution is cooled and washed with ether, and a solution of sodium hydroxide is added. The product is extracted with ether, and the ethereal extract is washed with water, dried and evaporated. 1- [1- (3,4-dichlorophenyl) cyclobutyl] ethyl-amine (m.p. 112-118 ° C at 0.02 mmHg) is isolated by distillation. The amine is dissolved in propan-2-ol and concentrated hydrochloric acid and the solution is evaporated to dryness, thus obtaining 1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride (F = 185-195 ° C). (Formula I: n = 0; R! = Me; R2, R3 and R4 = H; R5 = 4-C1; Rs = 3-C1.)

Example 1a:

The preparation of N-formyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine (Mp = 124-125 ° C) is repeated (example Ia: formula I: n = 0; R: = Me; R2 = H; R3 = H; R4 ('Il O: Rs = 4 — Cl and R6 = 3 —Cl) described above and the product is isolated by cooling the reaction mixture and recrystallizing the solid product by filtration. the formamide is hydrolyzed using concentrated hydrochloric acid in denatured alcohol, thus obtaining l- [l- (3,4-dichlorophenyl) cyclobutyl] ethyI ~ amine hydrochloride.

By operating as described in example la above, the following compounds are prepared. The hydrolysis conditions of the isolated formations by appropriate procedures are indicated in the notes.

Example

R!

R5

r6

Eb. (free base) (° C)

f hydrochloride (° C)

Note lb methyl

Cl

H

107 / 1.2 mmHg

138-139

AT

n-butyl

Cl

H

138-139

B

ld methyl i

H

205-207

VS

methyl

Cl cf3

216-217

D

A. Aqueous HCl / denatured alcohol.

B. L-Valeryl-1- (4-chlorophenyl) cyclobutane is prepared in tetrahydrofuran. The hydrolysis is carried out using concentrated HCl / denatured alcohol.

C. Concentrated HCl / diethylene glycol dimethyl ether (as described below in Example 12).

D. Concentrated HCl / denatured alcohol.

Example 2:

The product of Example 1 (4.04 g), water (0.5 ml) and 98% formic acid (3.6 ml) are mixed with cooling. 3.8 ml of aqueous formaldehyde solution are added at 37-40 ° C and the solution is heated to 85-95 ° C for 5 h. The solution is evaporated to dryness, the residue is acidified with concentrated hydrochloric acid and the water is eliminated by repeated addition of propan-2-ol followed by evaporation under vacuum. N, N-dimethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride crystals are isolated (Mp = 211-213 ° C). (Formula I: n = 0; R, = Me; R2 = H; R3, R4 = Me; Rs = 4-C1; R6 = 3-C1.)

By operating as described above, the compounds of Examples 1b and 1d are converted to the compounds indicated below.

Example

Starting substance

R.

R5

Ra

F hydrochloride (° C)

Eb. free base (° C)

2a 2b lb lb methyl methyl

Cl I

H H

260-261

98-100 / 0.5 mm

Example 3:

By operating as described above in Examples 1 and 2, N, N-dimethyl-l- [1- (4-biphenylyl) cyclo-butylethylamine hydrochloride (M = 196-197 ° C) is prepared. (Formula I: n = 0; Rj = Me; R2 = H; R3, R4 = Me; R5 = 4-phenyl and R6 = H.)

Example 4:

15 g of l-acetyl-1- (3,4-dichlorophenyl) cyclobutane prepared as described in Example 1, 47.5 ml of N-methylformamide, 10.3 ml of 98% formic acid and 1 , 5 ml of a 25% aqueous methylamine solution, and the mixture is heated with stirring at 170-180 ° C for 8 h. The mixture is cooled and extracted with ether. The ether extract is washed, dried and evaporated, thus obtaining a light yellow oil which is heated to reflux with 50 ml of concentrated hydrochloric acid for 2 h. 50 ml of denatured alcohol are added and the mixture is heated at reflux for 16 h. Then the mixture is cooled to 0 ° C., the white precipitate is collected by filtration, which is washed with acetone and dried. The product, N-methyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride, has a melting point of 254 to 256 ° C. (Formula I: n = 0; R! = Me ; R2 = H; R3 = Me; R4 = H; Rs = 4-CÎ and R6 = 3-CI.)

By operating as described above, the following compounds of formula I are prepared:

CHR-, KHMe. HCl

Example

R!

Rs r6

Eb. amine (° C)

F hydrochloride (° C)

Note

4a

Me

Cl

H

98-100 / 0.15mm

240-241

4b

Me

H

Cl

269-272

4c

Me

Br

H

96-98 / 0.1 mm

4d

Me

H

Br

251-255

4th

Cf3 me

H

219-221

4f

Me

H

cf3

225-228

4g

Me

- (CH = CH) 2-

254-257

4h

Me

C1

cf3

198-200

4i

And

Cl

H

238-240

4d

Pr

Cl

H

228-229

AT

4k

Drank

Cl

H

152-153

AT

41

Me i

H

242-243

Note A: The starting ketone is prepared using tetrahydrofuran as the reaction solvent instead of ether.

Example 5:

A mixture of 50 ml of 70% aqueous ethylamine solution and 100 ml of water is gradually mixed with a mixture of 98% formic acid (50 ml) and water (100 ml) in order to obtain a neutral solution which is evaporated at 100 ° C / 100 mmHg until 180 ml of water have been collected. The residue is brought to 140 ° C. and 10.4 g of l-acetyl-1- (4-chlorophenyl) cyclobutane, prepared in a similar manner to that described in Example 1 with respect to 1-acetyl-1, are added. - (3,4-dichlorophenyl) cyclobutane, as well as 10 ml of 98% formic acid. The mixture is heated on an oil bath at a temperature of 180 to 200 ° C for 16 h. The mixture is distilled until an internal temperature of 170 ° C. is obtained, and this temperature is maintained for 2 h. Any volatile substances are eliminated10

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ment present by distillation at 160 ° C / 20 mm and the residue is heated to reflux with 15 ml of concentrated hydrochloric acid and 15 ml of denatured alcohol for 3 h. The denatured alcohol is evaporated using a rotary evaporator and the residue is washed with ether. The aqueous phase is brought to pH 12 using sodium hydroxide, and extracted with ether. The ethereal extract is dried which, by evaporation, provides a residue which is treated with an aqueous hydrochloric acid solution, thus obtaining N-ethyl-l- [1- (4-chloro hydrochloride). -phenyl) cyclobutyl] ethylamine (mp 203-205 ° C). (Formula I: n = 0; R! = Me; R2 = H; R3 = Et; R4 = H; R5 = 4-C1; R6 = H.)

Example 6:

15 g of 1- (4-chlorophenyl) -1-cyclobutanecarbonitrile (prepared in a similar manner to 1- (3,4-dichlorophenyl) cyclo-butanecarbonitrile of Example 1) in 50 ml of dry ether are added. reaction product between 3.18 g of magnesium turnings and 15.99 g of propyl bromide in 50 ml of dry ether. The ether is replaced with tetrahydrofuran and the mixture is heated to reflux for 18 h, with stirring. The mixture is cooled and ice added, followed by concentrated hydrochloric acid (52 ml). The resulting mixture is stirred at reflux for 10 h, and extracted with ether. The ether extract provides a residue from which l-butyI-1- (4-chlorophenyl) cyclobutane is distilled (bp 106-108 ° C / 0.3 mmHg).

A mixture of the ketone prepared as described above (21 g) and 98% formic acid (6 ml) is added over 1 hour to 15 ml of formamide at 160 ° C. When the addition is complete, the temperature is brought to a value of 180 to 185 ° C. and is kept between these limits for 5 h. The mixture is cooled and extracted with chloroform, which gives a thick gum which, when heated with petroleum ether (bp 60-68 ° C), gives a colorless solid product which, by recrystallization from petroleum ether (eb. 60-80 ° C), provides N-formyl-1- [1- (4-chlorophenyl) cyclobutyl] butylamine (F = from 97.5 to 98.5 ° C ). (Formula I: n = 0; Rj = propyl; R2 = H; R3 = H; R4 = CHO; R5 = 4-C1; R6 = H.)

Example 7:

A solution of 35.2 g of 1- (3,4-dichlorophenyl) -1-cyclo-butanecarbonitrile prepared as described in Example 1 in 100 ml of ether is added to a solution of propylmagnesium bromide prepared by reaction of 32 g of propyl bromide with 6.36 g of magnesium turnings in 100 ml of ether. The ether is replaced by dry toluene and the mixture is heated at reflux for 1 h. 200 ml of water are added, then 120 ml of concentrated hydrochloric acid, and the mixture is heated to reflux for 1 h. The reaction mixture is extracted with ether and, after washing and drying, the extract provides a residue from which l-butyryl-1- (3,4-dichlorophenyl) cyclobutane is obtained (bp 120-128 ° C 0.25 mm) by distillation.

37.0 g of the ketone prepared as described above and 9 ml of 98% formic acid are added to 23.5 ml of formamide at 170 ° C, and the temperature is maintained at 175-180 ° C for 5 h. A further 4.5 ml of formic acid is added and the mixture is kept at a temperature of 175 to 180 ° C for another 15 h. The mixture is extracted with ether and, after evaporation, a thick oil is obtained which, by crystallization from petroleum ether (bp 60-80 ° C),

gives N-formyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] butyl-amine having a melting point of 103 at 105 ° C. (Formula I: n = 0; R! = propyl; R2 = H; R3 = H; R4 = CHO; R5 = 4-C1 and R6 = 3-C1.)

By operating in a similar manner to that described above, the compounds appearing in the following table are prepared:

CHR .. NHCHO

R,

'5

Example

Ri

Rs

R6

F (° C) '

7a isobutyl

Cl

H

110-112

7b propyle

Cl

F

115-116

7c phenyl

Cl

H

94-96

7d propyle

H

H

98-102

Example 8:

The product of Example 7 (4.0 g) in dry tetrahydrofuran (25 ml) is rapidly added to a stirred mixture of 1.4 g of lithium aluminum hydride in 25 ml of dry tetrahydrofuran, under nitrogen. The mixture is heated at reflux for 5 h, then cooled. 15 ml of water are added, then 3 ml of a 10% sodium hydroxide solution and the mixture is filtered on diatomaceous earth (supplied under the registered trademark Celite). The product is extracted with ether, it is extracted back with 5N hydrochloric acid, the aqueous layer is basified and it is extracted with ether. The ethereal extract provides an oil which is dissolved in 5 ml of propan-2-ol and concentrated hydrochloric acid is added until pH 2. By evaporation of the resulting solution a white solid is obtained which is collect, wash with acetone and dry. The product is N-methyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] butylamine hydrochloride and has a melting point of 234-235 ° C. (Formula I: n = 0; Rt = propyl; R2 = H; R3 = H; R4 = Me; Rs = 4-C1 and R6 = 3-C1.)

By operating in a similar manner to that described above, the compounds appearing in the following table are prepared:

CHR.NHMe.HCl

Example ri rs r6

F. (° C)

8a phenyl

Cl

H

275-278

8b propyle

Cl

H

223-228

Example 9:

The product of Example 7 (10 g) in solution in ether (50 ml) is added to a 70% toluene solution of sodium bis- (2-methoxy-ethoxy) aluminohydride supplied under the trademark of Red-al (40 ml) at a temperature of 25 to 30 ° C. The mixture is stirred at this temperature for 4 h. Water (25 ml) is added dropwise while cooling and the mixture is filtered through diatomaceous earth (Celite). Add aqueous NaOH and extract with ether. The ether extract is washed with water and extracted in return using 5N hydrochloric acid. A white solid product (F = 232-235 ° C) appears at the interface that is collected. A base is added to the aqueous phase and extracted again. By evaporation of the ethereal extract an oil is obtained which is dissolved in 5 ml of propan-2-ol and added concentrated hydrochloric acid to pH 2. By dry evaporation, a white solid product is obtained (F = 233-236 ° C). White solid products are brought together; recrystallized from propan-2-ol, thus obtaining N-methyl-1- [l- (3,4-dichlorophen-yl) cyclobutyl] butylamine hydrochloride (mp = 236-237 ° C). (Formula I: n = 0; Rj = propyl; R2 = H; R3 = H; R4 = Me; Rs = 4-C1, and R6 = 3-C1).

By operating as described above, the following compounds are prepared. When the formylated starting material is insoluble in ether, a suspension of the reducing agent is added to a stirred suspension of the formylated compound. As the size of the group R! grows, the hydrochlorides of the compounds sought become less soluble in the aqueous phase and more soluble in the organic phase, so that the mode of isolation must be varied appropriately, as is obvious to those skilled in the art .

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12

CHR-jNHMe

.HCl

Example

Ri

Rs

R6

F. (° C)

9a isopropyl

Cl

H

257-259

9b sec-butyl

Cl

H

209-212

9c isobutyl

Cl

H

225-233

9d cyclopentyle

Cl

H

252-256

9th n-hexyl

Cl

H

117-118

9f

4-methoxyphenyl

Cl

H

264-266

9g

3-methoxyphenyl

Cl

H

254-255

9 a.m.

2-methoxyphenyl

Cl

H

149-153

9i cyclohexyl

Cl

H

170-172

9d isobutyle

- (CH =

CH) 2-

256-259

9k cyclohexyl

Cl

C1

223-224

91

isobutyle

Me

Me

(1)

9m propyle

OMe

H

173-175

9n methyl phenyl

H

116-118

(1) Free base boiling point> 150 ° C at 1.0 mmHg

Example lOn 10p lOq lOr 10s 10t lOu lOv lOw lOx lOyb

Ri cyclohexyl methyl propyl propyl propyl cyclohexylmethyl cyclopropylmethyl propyl propyl 4-fluorophenyl methyl

Cl Cl

OMe Cl Cl Cl Cl

—CH = CH H Cl

R "

Cl f H f H H H

-CCI

cf3

H

F. (° C)

-C = C-CH = CH-

db — CH

215 215-217 178-179 186-188 174-175 148-150 184-185 = CH— (a) 126-128

279 248-262

Example 10:

The product of Example 7 (4 g), dimethyl ether and diethylene glycol (25 ml), water (10 ml) and concentrated hydrochloric acid (10 ml) are mixed and heated at reflux for 9 h. The solution is washed with ether and an aqueous NaOH solution is added before extracting with ether. The ethereal extract is washed with brine and water, and an oil is obtained by evaporation. The oil (3.19 g) is dissolved in a mixture of propan-2-ol (4 ml) and ether (20 ml) and 1.5 ml of concentrated hydrochloric acid are added. The solvent is evaporated in vacuo. It is dissolved again in denatured alcohol and evaporated under vacuum, thus obtaining a gum which solidifies when heated under vacuum. The product is recrystallized from petroleum ether (eb. 100-120 ° C): it has a melting point of 201-203 ° C. The product is l- [l- (3,4-dichloro) hydrochloride -phenyl) cyclobutyl] butylamine. (Formula I: n = 0; Ri = propyl;

R2 = H; R3, R4 = H; R5

4-C1 and Rfi

3-C1.)

By operating as described above, the following compounds are prepared. As the size of the Rx group increases, the hydrochlorides of the sought compounds become less soluble in the aqueous phase and more soluble in the organic phase, so that appropriate modifications of the mode of isolation are required, as will of course for technical specialists.

chr1nh2.hci

Example

Ri

Rs

R6

F. (° C)

10a isopropyl

Cl

H

200-202

10b sec.butyle

Cl

H

178-179

10c isobutyl

Cl

H

163-165

lOd cyclopentyle

Cl

H

185-210 (dec.)

10th phenyl

Cl

H

271-276.

of

4-methoxyphenyl

Cl

H

214-21.9

10g cyclohexyl

Cl

H

206-210

oh isobutyl

H

H

210-212

cyclopropyl

Cl

H

204-206

lOj propyle

Ph

H

235-236

10k propyle

Me

Cl

214-217

(101

propyl

- (CH =

= CH) 2-

157-159

ÎOm cycloheptyle

Cl

H

156-162

a) boiling point of the free base: 168 ° C / 0.05 mmHg,

b) the dimethyl ether of diethylene glycol is replaced by dimethyl ether of ethylene glycol.

20

By operating as described above, 10a, 10aa and 10bb are prepared respectively, by way of examples:

l- [1- (4-chloro-2-fluorophenyl) cyclobutyl] butylamine (bp 99 ° C / 0.05 mm). (Formula I: n = 0; Rj = propyl; R2, R3 and R4 = 25 H; Rs = 4-C1; R6 = 2-F);

1- [1- (2-fluorophenyl) chlorophenyl) cyclobu-tyljbutylamine hydrochloride (mp 175-177 ° C). (Formula I: n = 0; Rj = propyl; R2, R3, R4, Rs = H and R6 = 2-F), and 1- [1- (4-chloro-2-methyl) cyclobutyl] butylamine hydrochloride 30 (mp 188-190 ° C). Formula I: n = 0; Rj = propyl; R2, R3 and R4 = H; Rs = 4-C1 and R6 = 2-Me.)

Example 11:

The product of Example 10c (3.3 g) in the form of a free base is mixed with cooling, formic acid (2.99 g) and water (1 ml). 3.93 ml of 37-40% aqueous formaldehyde solution is added and the mixture is heated for 18 h at a temperature of 85-95 ° C. An excess of dilute hydrochloric acid is added and the solution is evaporated to dryness . The residue is basified with a solution of 5N sodium hydroxide and the product is extracted with ether. By evaporation of the ether a pale yellow oil is obtained which is dissolved in a mixture of propan-2-ol (4 ml) and ether (20 ml), and 2 ml of hydrochloric acid are added dropwise concentrated. The solution is evaporated and the residue is dissolved several times in ethanol and evaporated to dryness, thus obtaining a gum which is triturated with petroleum ether (bp 60-80 ° C), which provides a solid yellow product which is recrystallized from acetone. The product is N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride (mp 195-197 ° C). (Formula I: n = 0; R, = so isobutyl; R2 = H; R3, R4 = Me; R5 = 4-C1; Rs = H.)

By operating as described above, the following compounds of formula I are prepared:

(Table at the top of the next page)

Example 11 (1):

By operating as described above, the hydrochloride of N, N-dimethyl-1- [1- (4-chloro-2-fluorophenyl) cyclobutyl] butylamine is prepared (mp = 183 ° C.). (Formula I: n = 0; Rj = propyl; R2 = H; R3, R4 = Me; R5 = 4-C1; R6 = 2-F.)

Example 12:

The product of Example 7 (8.3 g), dimethyl ether, diethylene glycol (50 ml), water (20 ml) and concentrated hydrochloric acid (20 ml) are mixed and heated. at reflux for 16 h. The mixture is poured onto water, an aqueous NaOH solution is added and the product is extracted with ether. By evaporation a dark oil is obtained. A sample of this oil (7.9 g), water (0.7 ml) and formic acid (6.5 ml) is mixed and 6.5 ml of

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Example

Starting substance

Ri

Rs

R6

F. (° C)

lia

10h isobutyle

H

H

195-198

11b

10d propyle

Ph

H

194-196

11c lOn cyclohexyle

Cl

Cl

227-228

1 ld lOq propyle

OMe

H

187-188

lie

10s propyle

Cl

H

194-196

llf

10t cyclohexyl

Cl

H

194-196

methyl

Hg or Cyclopropyl

Cl

H

165-167

methyl

llh lOv propyle

- CH = CH -

- CCI = CH -

(at)

Ili

isobutyle

THIS

Cl

225-226

Hj lOx

4-fluorophenyl

Cl

H

234

11k

''

isopropyl propyl

H

211-213

a) boiling point of the free base 250 ° C / 0.05 mmHg.

formaldehyde. The mixture is heated at reflux for 3 h, then concentrated hydrochloric acid (10 ml) and propan-2-ol (10 ml) are added. By dry evaporation, N, N-dimethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] butylamine hydrochloride (F = 195-196: C) is obtained in the form of a white solid product. . (Formula I: n = 0; R! = Propyl; R2 = H; R3, R4 = Me; Rs = 4-C1 and R6 = 3-C1.)

Example 13: 35

37.6 g of 1- (4-chlorophenyl) -1-cyclobutanecarbonitrile (prepared in the same manner as 1- (3,4-dichlorophenyl) -1-cyclo-butanecarbonitrile described in Example 1) are added to a solution of 32.4 g of potassium hydroxide in 370 ml of diethylene glycol, and the mixture is heated to reflux for 3 Yz h. The reaction mixture is poured onto a mixture of ice and water and the resulting solution is washed with ether. The aqueous layer is added to a mixture of concentrated hydrochloric acid (100 ml) and ice, the resulting precipitate is collected from 1- (4-chlorophenyl) -1-cyclobutane-carboxylic acid (mp 86-88 ° C ) which are washed with water and dried. 45

A solution of 10.5 g of the acid prepared as described above in 150 ml of tetrahydrofuran is added dropwise under nitrogen to a stirred suspension of lithium aluminum hydride (2 g) in tetrahydrofuran (150 ml). The mixture is stirred at reflux for 2 h and water is added. The mixture is filtered on 50 diatomaceous earth (Celite - RTM) and the product is extracted with ether. After washing with water and drying, the ether is evaporated, thus obtaining a residue which is recrystallized from petroleum ether (eb. 60-80 ° C). The product is 1- [1- (4- (chlorophenyl) cyclobutyl] methyl alcohol (M = 60-62 ° C).

A solution of the alcohol prepared as described above (60 g) in pyridine (52 ml) is added dropwise to a solution of p-toluenesulfonyl chloride (60 g) in pyridine (100 ml) cooled on ice. The temperature is allowed to rise to ambient temperature and to be maintained there for 18 h. A precipitate of 1- [1- (4-chlorophenyl) -cyclobutyl] methyl p-toluenesulfonate is obtained (Mp = 99-100 ° C.) by pouring the reaction mixture onto a mixture of ice and 200 ml of hydrochloric acid concentrated.

A solution of 97 g 65 of the sulfonate prepared as described above and 16.6 g of sodium cyanide in 370 ml of dimethyl sulfoxide is heated in the steam bath for 18 h. The mixture is poured onto water and extracted with ether. After washing and drying, the ether is evaporated, thus obtaining a solid residue of 2- [1- (4-chlorophen-yl) cyclobutyl] acetonitrile (mp 63-65 ° C).

A solution of diisopropylamine (16.5 g) in dry tetrahydrofuran (50 ml) is stirred, under nitrogen, at a temperature of 0 ° C., and a 1.6M solution of n-butyllithium in l is added dropwise. 'hexane (100 ml). The reaction mixture is stirred for 30 min, then cooled to -78 ° C. A solution of 2- [1- (4-chlorophenyl) cyclobutyl] acetonitrile (9.5 g) prepared as described above is added dropwise. above in dry tetrahydrofuran (25 ml). The temperature of the mixture is allowed to rise to 0 ° C, and the mixture is stirred for 10 min before adding a solution of methyl iodide (10 ml) in tetrahydrofuran (10 ml). 75 ml of tetrahydrofuran are added so as to obtain a homogeneous solution, and another solution of methyl iodide (4 ml) in tetrahydrofuran (10 ml) is added. The mixture is stirred at room temperature for 2 h, then 50 ml of water are added. The aqueous phase is washed with ether, and the ether is combined with the organic phase of the reaction mixture. The combined organic phases are washed 3 times with 5N hydrochloric acid, 3 times with water, dried and evaporated, which gives an oil which solidifies and which is recrystallized from denatured alcohol, thus obtaining 2- [1- (4-chlorophenyl) cyclo-butyl] -2-methylpropionitrile (mp 73-75 ° C).

The nitrile (4 g) prepared above is heated under reflux with 8 g of potassium hydroxide in 40 ml of diethylene glycol for 24 h. The reaction mixture is cooled, poured onto 50 ml of water and the aqueous phase is washed twice with ether. The aqueous phase is acidified with 5N hydrochloric acid and extracted with three aliquots of ether. The ethereal extracts are combined and washed with water, dried and evaporated, thus obtaining a white solid product which is recrystallized from petroleum ether (eb. 60-80: C), which provides 2- [1- (4-chlorophenyl) cyclobutyl] -2-methyl-propionitrile acid (F = 95-110 "C).

10 ml of oxalyl chloride are added to 2 g of the acid prepared as described above and, after the initial effervescence has subsided, the mixture is heated at reflux for 1 h. The excess oxalyl chloride is removed by distillation and the residual oil is added to 75 ml of concentrated ammonia. The resulting solid product is extracted with ethyl acetate. The extract is washed with water, dried and evaporated, thus obtaining 2- [1- (4-chlorophenyl) -cyclobutyl] -2-methylpropionamide.

The amide (1.34 g) prepared above is dissolved in a mixture of acetonitrile (8 ml) and water (8 ml), 3.4 g of bistrifluoro-

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iodosobenzene acetate and the mixture is stirred at room temperature for 5 h. 75 ml of water and 8 ml of concentrated hydrochloric acid are added and the mixture is extracted with ether. The ether extract is washed with 5N hydrochloric acid, the aqueous phase is basified and extracted with other aliquots of ether, dried and evaporated to provide an oil . The oil is dissolved in petroleum ether (bp 80-100 ° C) and dry hydrogen chloride gas is passed through the solution. 1- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine hydrochloride (Mp = 257-259 ° C) is collected by filtration. (Formula I: n = 0; Rj, R2 = Me; R3, R4 = H; R5 = 4-C1; Rô = H).

Example 14:

The product of Example 4h (3.4 g) is mixed with anhydrous sodium formate (0.72 g), 98% formic acid (10 ml) and an aqueous formaldehyde solution at 37-40 % (5 ml), and the mixture is heated to a temperature of 85-95 ° C for 16 h. The mixture is diluted with water (50 ml) and basified to pH 10 using an aqueous solution of sodium hydroxide. The basic aqueous solution is extracted with ether, washed with water and dried over magnesium sulphate, bubbled dry hydrogen chloride in the ethereal extract, which gives a white precipitate of N hydrochloride. , N-dimethyl-1- [1- (4-chloro-3-trifluoromethylphenyl) cyclobutyl] -ethylamine (mp 246-247 ° C). (Formula I: n = 0; Rj = Me; R2 = H; R3, R4 = Me; Rs = 4-C1 and R6 = 3-CF3.)

Example 15:

The preparation of salts of the compounds according to the invention is illustrated by the following examples in which equimolar proportions of the base and of the acid are taken up in a solvent. The salt is then obtained from the solution, by conventional techniques.

Example

Based

Acid

Solvent

F. salt (° C)

15a

10s citric aqueous acetone

158-160

15b

10s maleic

ether

155-157

15c

Succinic 10s

ether

152-155

15d

2

L (+) tartaric denatured alcohol

150-153

15th

Note (a)

citric

ether / methanol

163-164 (dec.)

a) The base is l- [l- (3,4-dimethylphenyl) cyclobutyl] -3-methyl-butylamine prepared in a similar manner to that described in Example 10.

Example 16:

A solution of bromobenzene (15.7 g) in ether (50 ml) is added dropwise, while cooling, to turnings of magnesium (2.4 g) under nitrogen. A solution of 1- (4-chlorophenyl) cyclo-butanecarbonitrile (19.1 g) prepared in a similar manner to that described in Example 1 for 1- (3,4-dichlorophenyl) cyclobutane-carbonitrile in 50 ml ether is added, and the ether is replaced with dry toluene (130 ml). The reaction mixture is heated on a steam bath for 1 h. 20 ml of the resulting solution are added to a solution of 1 g of sodium borohydride in 60 ml of diethylene glycol dimethyl ether and the mixture is stirred for 1 hr. 60 ml of water are slowly added and the aqueous layer is extracted with toluene. The toluene extracts are washed with water, dried and evaporated, thus obtaining a residue which is dissolved in 50 ml of methanol. 5 ml of 6N hydrochloric acid are added and the solution is filtered and evaporated. By trituration with acetone, α- [1- (4-chlorophenyl) cyclobutyl] benzylamine hydrochloride is obtained (mp = 277-279 ° C.). (Formula I; n = 0; Rj = Ph; R2 = H; R3, R4 = H; R5 = 4-C1; R6 = H.)

Example 17:

62 ml of methyl formate are added dropwise to 85.5 ml of isopropylamine, with stirring at a speed allowing gentle reflux to be maintained. Stirring is continued for 2 hours after the addition. Methanol is distilled at 100 ° C and N-isopropylform-amide is obtained (eb. 108-109 ° C / 25 mmHg) by distillation.

10.4 g of l-acetyl-1- (4-chlorophenyl) cyclobutane (prepared as described in Example 1 for l-acetyl-1- (3,4-dichlorophenyl) cyclobutane, and 5 ml are added. 98% formic acid at 43.5 g of N-isopropylformamide (43.5 g) and the mixture is heated at 180 ° C. for 4 h. The excess starting material is distilled under reduced pressure (20 mmHg), which leaves a viscous residue which is heated to reflux with 30 ml of concentrated hydrochloric acid for 6 h The reaction mixture is washed with ether until a colorless solution is obtained. aqueous, extracted with ether, dried and evaporated, which gives an oil which is dissolved in 5N hydrochloric acid. After evaporation, a yellow oil is obtained which is triturated with ether. petroleum (eb. 62-68 ° C), which gives N-isopropyl-l- [1- (4-chlorophenyl) cyclo-butylethylamine hydrochloride (M = 170-174 ° C). (Formula I: n = 0; Rj = Me; R2 = H; R3 = isopropyl; R4 = H; R5 = 4-C1; R6 = H.)

Example 18:

7.0 g of l-acetyl-1- (3,4-dichlorophenyl) -cyclobutane (prepared as described in Example 1) are slowly added to a mixture of 25 ml of Pyrrolidine and 15 ml of 98% formic acid. % brought to a temperature of 130 to 135 ° C, for 5 h. The mixture is stirred and heated to 160-165 ° C for 16 h. After cooling, the mixture is poured onto 200 ml of 5N hydrochloric acid. The solution is washed with ether, basified with an aqueous solution of sodium hydroxide and extracted with ether. The ether extract is washed with water, dried, and gaseous hydrogen chloride is passed through the extract which is then evaporated to dryness. The residue is triturated with dry ether; the resulting solid product is recrystallized from propan-2-ol, thus obtaining N-I- [I- (3,4-dichlorophenyl) cycobutyl] ethylpyrrolidine hydrochloride (mp 233-235 ° C). (Formula I: n = 0; Rx = Me; R2 - H; R3 and R4, together and with the nitrogen atom to which they are attached, form a Pyrrolidine ring; R5 = 4-C1 and R6 = 3- C1.)

Example 19:

10.5 g of 1- (4-chlorophenyl) -1-cyclobutane-carboxylic acid (prepared as described in Example 13) are heated to reflux with 20 ml of thionyl chloride for 2.5 h. The excess thionyl chloride is evaporated and the acid chloride of the above acid is distilled (eb. 82-96 ° C / 0.2 mmHg).

A solution of 23.0 g of acid chloride in 100 ml of dry tetrahydrofuran is slowly added to the reaction product of 3.0 g of magnesium turnings and 12.0 g of ethyl bromide in dry tetrahydrofuran, at a temperature of -70 to -60 ° C. The temperature is maintained at -60 ° C for 1 h, then it is allowed to come to 0 ° C. 50 ml of water are added followed by 150 ml of hydrochloric acid 5N, while cooling. The reaction mixture is extracted with ether, washed with water, using a solution of sodium bicarbonate and dried. The solvent is removed by evaporation and l-propionyl-1- (4-chlorophenyl) cyclobutane is obtained by distillation (eb. 96-104 ° C / 0.25 mmHg).

The ketone obtained above is converted into N, N-dimethyl-l- [1- (4-chlorophenyl) cyclobutyl] propylamine hydrochloride (mp 213-215 ° C.) by operating as described in Example 12. ( Formula I: n = 0; R, = Et; R2 = H; R3, R4 = Me; R5 = 4-C1; R6 = H.)

Example 20:

61 g of l-acetyl-1- (4-chloro-phenyl) cyclobutane (prepared as described in Example 1 for 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane) are introduced into an autoclave, 0.75 g of platinum oxide, 60 g of an ethanolic solution of methylamine at 33% and 30 ml of ethanol. The autoclave is filled with hydrogen and maintained at about 60 ° C and a pressure of 20 bar for 10 h. The reaction mixture is filtered over charcoal and the solids are washed with absolute alcohol. The solvents are removed by evaporation and

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10 g of the residue are shaken with 50 ml of 2N hydrochloric acid and 50 ml of ether. The aqueous layer is basified and extracted with ether. The ethereal extract provides a liquid by evaporation, a liquid which is distilled to obtain N-methyl-1- [1- (4-chlorophenyl) cyclo-butyl] ethylamine. (Formula I: n = 0; R, = Me; R2 = H; R3 = Me; R4 = H; Rs = 4-C1 and R6 = H.)

Example 21:

2.0 g of sodium borohydride are added to a solution of 1.5 g of 1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine (prepared by treating the product of Example 1 with an aqueous solution of sodium hydroxide) in 30 ml of glacial acetic acid. The mixture is heated to 95-100 ° C for 16 h, then cooled. An aqueous solution of sodium hydroxide is added and the reaction mixture is extracted with ether. The ethereal extract is shaken with 5N hydrochloric acid, the aqueous layer is washed with ether, basified and extracted with ether. Gaseous hydrogen chloride is passed through the ethereal extract which is evaporated to dryness. By trituration with acetone, N-ethyl-1 - [1 - (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride is obtained (mp = 211-212 ° C). (Formula I: n = 0; Ri = Me; R2 = H; R3 = Et; R4 = H; Rs = 4-C1 and R6 = 3-C1).

Example 22:

Heated to 40-45 ° C for 30 min, a mixture of 0.5 g of N-ethyl-1 - [1 - (3,4-dichlorophenyl) cyclobutyl] ethylamine (prepared by treating the product of the example 21 with an aqueous solution of sodium hydroxide) and 1 ml of acetic anhydride. The reaction mixture is basified and extracted with ether. The ether extract is washed, dried and evaporated, thereby obtaining N-acetyl-N-ethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine as an oil.

This oil is dissolved in 10 ml of tetrahydrofuran and 0.5 ml of borane / dimethyl sulfide complex is added dropwise. The reaction mixture is stirred at room temperature for 2 h, then brought to 35-40 ° C for 30 min. After cooling, the reaction mixture is basified and extracted with ether. Gaseous hydrogen chloride is passed through the dried ethereal extract which is evaporated to dryness. By trituration with ether, N, N-diethyl-l- [1- (3,4-dichlorophenyl) cyclo-butyl] ethylamine hydrochloride is obtained (mp = 199-201 ° C). (Formula I: n = 0; Ra = Me; R2 = H; R3, R4 = Et; Rs = 4-CI and R5 = 3-C1.)

Example 23:

A mixture of 2.2 g of l-acetyl-1- (3,4-dichlorophenyl)) cyclobutane (prepared as described in Example 1), 7 g of acetate is stirred at room temperature for 4 d. ammonium, 0.4 g of sodium cyanoborohydride and 28 ml of methanol. The reaction mixture is poured onto a mixture of ice and water and the resulting mixture is extracted with ether. The ether extract is washed with water, dried and the ether is removed, leaving l- [l- (3,4-dichlorophenyl) -cyclobutyl] ethylamine in the form of an oil which is identified by standard analytical techniques as the compound of Example 1 in its free base form.

Example 24:

A mixture of 4.86 g of 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane prepared as described in Example 1.1.6 g of hydroxylamine hydrochloride is heated at reflux for 20 h. 3.3 g of sodium acetate trihydrate, 15 ml of denatured alcohol and 2 ml of water. The cooled reaction mixture is poured into water and the oil which separates is cooled, which gives a solid product which is recrystallized from denatured alcohol, obtaining l-acetyl-l- (3,4- dichlorophenyl) cyclobutaneoxime (Mp = 120-121 ° C).

A solution of 4.0 g of the oxime prepared above in 50 ml of ether is slowly added to a stirred suspension of lithium aluminum hydride (0.9 g) in 50 ml of ether, under nitrogen. The mixture is heated at reflux for 1 h and, after cooling,

water is added, then an aqueous solution of Seignette salt (potassium tar-trate and sodium tetrahydrate) at 20% (27 ml) and an aqueous solution of sodium hydroxide at 10% (6 ml). The reaction mixture is stirred for 1 h, then extracted continuously with ether for 18 h. The ether extract is dried, dried, ether removed, leaving a solid product from which 1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine is separated by high pressure liquid chromatography. The product is identified by current techniques as being the compound of Example 1 in the form of its free base.

Example 25:

200 ml of a 1M solution of diisobutyl aluminohydride in hexane, under nitrogen, are added to a solution of 31.4 g of 1-phenyl-1-cyclobutanecarbonitrile in 100 ml of ether, at a temperature below -30 ° C. The temperature is kept below 0 ° C for 30 min and 200 ml of 5N hydrochloric acid are added at a temperature of -10 "C. The reaction mixture is washed with ether. petroleum (eb. 60-80 ° C), then it is brought to 40 ° C. The reaction mixture is extracted with petroleum ether (eb. 60-80 ° C), the extract is dried and evaporated, obtaining thus 1-phenyl-1-cyclobutanecarbaldé-hyde in the form of an oil.

Methylamine is bubbled through a solution of 9.4 g of the aldehyde prepared as described above in 100 ml of toluene, while keeping the temperature of the reaction mixture below 0 ° C. 20 g are added of magnesium sulfate (dried over a flame, then cooled under nitrogen) to the reaction mixture which is left at room temperature for 16 h before being filtered. The toluene is then removed by evaporation and the residue is dissolved in 50 ml of ether. This solution is added to a propyllithium solution prepared by slowly adding an excess of propyl bromide (12.8 g) to a suspension of 1.26 g of lithium in 50 ml of ether. The resulting mixture is left for 16 h at room temperature. Traces of unreacted lithium are removed by filtration and the filter is washed with ether, with water, then with 5N hydrochloric acid. The filtrate is heated and the washes on a steam bath for 1 h. After cooling, the reaction mixture is washed with ether and the aqueous layer is basified with an aqueous solution of sodium hydroxide. The reaction mixture is extracted with ether, the extract is dried and the ether is removed, thus obtaining a residue from which N-methyl-1- (1-phenylcyclobutyl) butylamine is distilled (eb. 80- 86 ° C / 0.1 mmHg).

2.3 g of the amine prepared as described above are dissolved in 40 ml of ether and hydrogen chloride gas is passed into the solution, thus obtaining a precipitate of N-meth-yl-1 hydrochloride - (1-phenylcyclobutyl) butylamine (mp 196-197 ° C). (Formula I: n = 0; Rj = propyl; R2 = H; R3 = Me; R4, R5 and R6 = H.)

Example 26:

A solution of 8.0 g of 1- (3-chloro-5-methyl) -1-cyclobutanecarbonitrile in 40 ml of ether is added to a solution of propylmagnesium bromide (prepared by reacting 6.7 g of 1- bromopropane and 1.3 g magnesium) in 80 ml ether, and the mixture is heated to reflux for 2.5 h. Two-thirds of the ether is evaporated off and, after cooling, a solution of 3.5 g of sodium borohydride in 150 ml of ethanol is added. The mixture is kept at 50 ° C. for 1 h, and 50 ml of water are added, then 50 ml of 5N hydrochloric acid. The ethereal layer is separated, dried and evaporated, which gives a solid product which, by recrystallization from propan-2-ol, gives 1- [1- (3-chloro-5-methyl) cyclobutyl hydrochloride] butylamine (mp 145-146 ° C).

The hydrochloride prepared as described above is shaken with ether and a 5N sodium hydroxide solution, and the ethereal layer is evaporated, giving the primary amine which is converted into N, N- hydrochloride dimethyl-1- [1- (3-chloro-5-methyl) cyclobutyl] -butylamine (mp = 148 ° C). (Formula I: n = 0; R! = Propyl; R2 = H; R3 and R4 = Me; Rs = 3-C1 and R6 = 5-Me), operating as described in Example 2.

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Example 27:

37.6 g of 1- (4-chlorophenyl) -1-cyclobutanecarbonitrile (prepared as 1- (3,4-dichlorophenyl) -1-cyclobutanecarbonitrile described in Example 1) are added to a solution of 32.4 g of potassium hydroxide in 370 ml of diethylene glycol, and the mixture is heated to reflux for 3.5 h. The reaction mixture is poured onto a mixture of ice and water and the resulting solution is washed with ether. The aqueous layer is added to a mixture of concentrated hydrochloric acid (100 ml) and ice, the resulting precipitate is collected from 1- (4-chlorophenyl) -1-cyclobutanecarboxylic acid (mp 86-88 ° C), it is washed with water and dried.

A solution of 10.5 g of the acid prepared as described above in 150 ml of tetrahydrofuran is added dropwise under nitrogen to a stirred suspension of lithium aluminum hydride (2 g) in tetrahydrofuran (150 ml). The mixture is stirred at reflux for 2 h and water is added. The mixture is filtered on earth with diatoms (Celite - RTM) and the product is extracted with ether. After washing with water and drying, the ether is evaporated, which gives a residue which is recrystallized from petroleum ether (bp 60-80 ° C). The product is l- [1- (4-chlorophenyl) cyclobutyl] methyl alcohol (mp = 60-62 ° C).

A solution of 60 g of the alcohol prepared as described above in 52 ml of pyridine is added dropwise to a solution of 60 g of p-toluenesulfonyl chloride in 100 ml of ice-cold pyridine. The temperature is allowed to rise to ambient temperature and to be maintained there for 18 h. A precipitate of 1- [1- (4-chlorophenyl) -cyclobutylmethyl (p = toluenesulfonate) is obtained by pouring the reaction mixture onto a mixture of ice and concentrated hydrochloric acid (200 ml) .

A solution of 97 g of the sulfonate prepared as described above and 16.6 g of sodium cyanide in 370 ml of dimethyl sulfoxide is heated on a steam bath for 18 h. The mixture is poured onto water and extracted with ether. After washing and drying, the ether is evaporated, which leaves a solid residue of 2- [1- (4-chloro-phenyl) cyclobutyl] acetonitrile (mp 63-65 ° C).

20 g of the acetonitrile prepared above are dissolved in 120 ml of ether and the solution is added dropwise, under nitrogen, to a stirred suspension of lithium aluminum hydride (5.84 g) in ether (80 ml). The mixture is stirred at room temperature for 1.5 h, then at reflux for a further 2 h. Water is added dropwise and the resulting mixture is filtered through diatomaceous earth. The residue is washed with ether. The filtrate is extracted with ether, after which the combined ethereal solutions are washed with water and extracted with 5N hydrochloric acid. The acid solution is washed with ether and an aqueous NaOH solution is added. The product is extracted with ether and the extract is washed with water, dried and evaporated, which leaves a residue which, by distillation, gives 2- [1- (4-chlorophenyl) cyclo-butyl methylamine (eb 119-121 ° C / 1.5 mmHg).

Heated on a steam bath, for 18 h, 6.9 g of ethylamine prepared as described above, 6.6 ml of 98% formic acid, 0.9 g of water and 9 ml of 37-40% aqueous formaldehyde solution. The mixture is cooled and an excess of concentrated hydrochloric acid is added. A yellow solid residue is obtained, after evaporation to dryness. The solid product is partitioned between dichloromethane and a 5N sodium hydroxide solution and the aqueous layer is extracted by further adding dichloromethane. The dichloromethane solutions are combined and washed with water, dried and evaporated, obtaining a solid residue which is dissolved in 15 ml of propan-2-ol, and concentrated hydrochloric acid is added until pH 2. The mixture is evaporated to dryness and the residue is recrystallized from ethyl acetate, thus obtaining colorless crystals of N, N-dimethyl-2- [1- (4-chlorophenyl) cyclobutyl] ethylamine hydrochloride ( Mp 220-222 ° C). (Formula I: n = 1; Rlt R2 = H; R3, R4 = Me; Rs = 4-C1; R6, R, and Rs = H.)

By operating in a similar manner to that described above, the following compounds are prepared:

R,

L5

Example

Rs

Ra

F hydrochloride (° C)

27a

Cl

Cl

218-220

27b

I

H

263-265

27c

- CH = CH-

- CH = CH -

234-236

The hydrochloride is prepared in a similar way

27d of N, N-dimethyl-2- [1 - (4-chloro-2-fluorophenyl) -

cyclobutyljethylamine (F

■

= 232-233 ° C (dec)).

Example 28:

12.4 g of 2- [1- (4-chlorophenyl) -cyclobutylethylamine prepared as described in Example 27 are mixed in 100 ml of xylene, 12.4 g of 1,4-dibromobutane and 14.3 g of sodium carbonate anhydrous and the mixture is heated to reflux, with stirring, for 16 h. The mixture is cooled, filtered and the xylene is removed by evaporation, which gives a residue which, by distillation, gives N-2- [1- (4-chlorophenyl) cyclobutyl] ethylpyrrolidine (eb. 148-150 ° C / 1.5 mmHg). (Formula I: n = 1; Rj, R2 = H; R3 and R4, together and with the nitrogen atom to which they are attached forming a Pyrrolidine ring; R5 = 4-C1; R6, R7 and Rs = H .)

In a similar manner to that described above, the following compounds are prepared, which are isolated in the form of hydrochlorides.

.HCl

Example

Rs

R6

F hydrochloride (° C)

28a 28b

Cl

—CH = CH-

Cl

-CH = CH—

213 232-233

Example 29:

A solution of 30 g of 2- [1- (4-chlorophenyl) cyclo-butyl] acetonitrile (prepared as described in Example 27) in 100 ml of ether is added to the reaction product of methyl bromide gas and of magnesium turnings (5.95 g) in 80 ml of ether. The mixture is heated at reflux for 4 h. Ice is added, then 105 ml of concentrated hydrochloric acid and the mixture is heated to reflux until all the solid product has dissolved. The aqueous layer is washed with ether and the ether used for washing is combined with the ethereal phase of the reaction mixture. The combined ethereal extracts are washed with water, dried and evaporated to give a residue which is distilled twice, thus obtaining l- [1- (4-chlorophenyl) cyclobutyl] propane-2-one (eb. 133- 136 ° C / 2.5 mmHg).

The ketone prepared as described above (5.4 g) is mixed with 18 ml of N-methylformamide, 4 ml of 98% formic acid and 0.6 ml of a 25% aqueous methylamine solution, and the mixture is heated at reflux for 16 h. The mixture is poured onto water and extracted with dichloromethane. The extract is washed, dried and evaporated, which gives a residue which is heated to reflux with 10 ml of dilute hydrochloric acid for 6 h. The mixture is evaporated to dryness and the residue is dried by adding and evaporating under vacuum, several times, a denatured alcohol / toluene mixture. The solid residue is recrystallized from propan-2-ol, thus obtaining N-methyl-2- [1- (4-chlorophenyl) cyclobutyl] -1-methyl-ethylamine hydrochloride (mp 193-194 ° C). (Formula I: n = 1; Rx, R2 = H; R3 = Me; R4 = H; R5 = 4-C1; R6 = H; R7 = Me; R8 = H.)

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Example 30:

A mixture of 15 g of 1- [1- (4-chlorophenyl) cyclobutyl] propan-2-one prepared as described in Example 29 and 4 ml of 98% formic acid is added dropwise to 12 ml of formamide at 160 ° C. The temperature is brought to 180 ° C. and maintained at this level for 10 h. The mixture is cooled and diluted with water and extracted with dichloromethane. The extract is washed, dried and evaporated, giving a yellow oil which is hydrolyzed using concentrated hydrochloric acid at reflux. After dilution with water, the resulting aqueous solution is washed with ether, added with an aqueous NaOH solution and extracted with ether. The extracts are washed, dried and evaporated, which gives a residue which, by distillation, provides 2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine (eb. 105-107 ° C / 0 , 7 mmHg).

The amine obtained above (2.65 g) is dissolved in propan-2-ol (15 ml) and concentrated hydrochloric acid is added dropwise until a pH of 2 is obtained. Add 110 ml of ether and collect colorless crystals of 2- [1- (4-chloro-phenyl) cyclobutyl] -1-methylethylamine hydrochloride (mp = 184-185 ° C). (Formula I: n = 1; Rt, R2 = H; R3, R4 = H; Rs = 4-C1; R6 = H; R7 = Me and R8 = H.)

Example 31:

3.94 g of 2- [1- (4-chlorophenyl) cyclobutyl] -1-methyl-ethylamine prepared as described in Example 30, 3.82 g of 1,4-dibromobutane, 4.4 g of anhydrous sodium carbonate and 30 ml of xylene, and the mixture is refluxed for 16 h. The mixture is cooled, filtered and evaporated, a residue is obtained which is distilled twice (eb. 130-132 ° C / 0.5 mmHg). The distillation product is dissolved in 5 ml of propan-2-ol and 70 ml of ether and concentrated hydrochloric acid is added until pH 2. The solution is evaporated in vacuo and the residue is recrystallized from l ethyl acetate, thus obtaining N- {2- [1- (4-chlorophenyl) cyclobutyl] -1-methyl} -ethylpyrrolidine hydrochloride (mp 151-152 ° C). (FormulaI: n = 1; R1; R2 = H ;. R3 and R4, together and with the nitrogen atom to which they are attached, form a Pyrrolidine ring; Rs = 4-C1; R6 = H; R7 = Me; Rs = H.)

Example 32:

To 22 ml of formamide, at 160 ° C., 25 g of 1- [1- (4-chlorophenyl) cyclobutyl] propan-2-one prepared as described in Example 29 and 10 ml of 98% formic acid are added. %. The temperature is brought to 175 ° C. and maintained at this level for 16 h. The mixture is cooled and extracted with dichloromethane. The extract is washed with water and evaporated, which gives a gum which is crystallized from petroleum ether (eb. 40-60 ° C), thus obtaining N-formyl-2- [1 - (4-chlorophenyl) cyclobutyl] -1-methylethylamine (mp 71-73 ° C).

11.06 g of N-formyl-2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine prepared as described above are heated at reflux for 6 h with a mixture of concentrated hydrochloric acid ( 34 ml), water (34 ml) and diethylene glycol dimethyl ether (40 ml). The mixture is cooled and washed with ether and basified with an aqueous solution of sodium hydroxide. The basified solution is extracted with ether, washed with water, dried, evaporated and distilled, and 2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine (eb. 119-121) is obtained ° C / 0.8 mmHg). The amine (2.65 g) is dissolved in 15 ml of propan-2-ol and concentrated hydrochloric acid is added until pH 2. 110 ml of ether are added and the crystals of hydrochloride are collected. 2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine (F = 184-185 = C.) (Formula I: n = 1; R!, R2 = H; R3, R4 = H; Rs = 4-C1; R6 = H; Rv = Me and R8 = H.)

Example 33:

1.8 g of 2- [1- (4-chlorophenyl) cyclobutyl] -1-methyl-ethylamine prepared as described in Example 32 are mixed with 4.5 ml of formic acid. 6 ml of an aqueous formaldehyde solution are added to

37-40% and the mixture is heated first at 45-50 ° C for 30 min and then at reflux for 2 h. The mixture is cooled, basified with an aqueous sodium hydroxide solution, extracted with ether, the ether extract is washed with water and extracted with 5N hydrochloric acid. The acid extract is washed with ether, basified with an aqueous solution of sodium hydroxide and extracted with ether. Hydrogen chloride gas is passed through the ethereal extract and a white solid product is formed which is collected and recrystallized from ethyl acetate, thereby obtaining N, N-dimethyl hydrochloride

2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine (mp 108-110 ° C). (Formula I: n = 1; R15 R2 = H; R3, R4 = Me; R5 = 4-Cl; R6 = H; R7 = Me and R8 = H.)

Example 34:

35 ml of a 70% toluene solution of sodium bis- (2-methoxyethoxy) aluminohydride (supplied under the trade name Red-al) are added dropwise to a solution of 5 g of N-formyl-2- [ l- (4-chlorophenyl) cyclobutyl] -1-methylethylamine (prepared as described in Example 32) in 100 ml of dry ether, while cooling in order to maintain the temperature below 10 ° C. the temperature reach approximately 25 ° C., then the mixture is heated at reflux for 2 h. The reaction mixture is poured onto a mixture of crushed ice and concentrated hydrochloric acid. The resulting mixture is washed with ether, basified with an aqueous solution of sodium hydroxide and extracted with ether. The ethereal extract is washed with brine, dried and evaporated, which gives a liquid which is dissolved in petroleum ether (bp 40-60 ° C). Hydrogen chloride gas is bubbled into the solution, which precipitates a solid product which is recrystallized from propa-ne-2-ol, thus obtaining N-methyl-2- hydrochloride [1- (4 -chlorophenyl) cyclobutyl] -1-methylethylamine (mp 192-194 ° C). (Formula I: n = 1; Rj, R2 = H; R3 = H; R4 = Me; Rs = 4-Cl; R6 = H; R7 = Me and R8 = H.) (F = 192-194 ° C. )

Example 35:

A solution of ether (80 ml) of 2- [1- (3,4-dichlorophenyl) cycobutyl] acetonitrile (23 g) prepared in a similar manner to that described in Example 27 for the 2- [1- (4-chlorophenyl) cyclo-butyl] acetonitrile to the reaction product between 3.53 g of magnesium turnings and 10.8 ml of ethyl bromide in 80 ml of dry ether, while stirring and heating on a steam bath. The ether is removed and replaced with toluene, and the mixture is heated to reflux for 1 h. Water is added and the mixture is added to a mixture of ice and concentrated hydrochloric acid. The mixture is heated on a steam bath for 1 h and filtered through diatomaceous earth provided under the Celite registered trademark. The filtrate is extracted with dichloromethane and the extract is washed with water and using a sodium bicarbonate solution and dried. The solvent is removed by evaporation and the residue is distilled, thus obtaining l- [l- (3,4-di-chlorophenyl) cyclobutyl] butane-2-one (eb. 149-150 "C / l, 1 mmHg) .

The ketone prepared above is converted into 1 - {[1- (3,4-dichlorophenyl) cyclobutyl] methyl} propylamine hydrochloride (mp = 225-226 ° C). (Formula I: n = 1; Rlf R2, R3, R4 = H; Rs = 4-C1; R6 =

3-C1; R7 = And; Rs = H) in a similar manner to that described in Example 32.

Operating in a similar manner to that described above, 2- [1- (3,4-dichlorophenyl) cyclo-butyl] -1-methylethylamine hydrochloride (F = 179 "C) is prepared (Example 35a ; formula I: n = 1; Rj, R2, R3 and R4 = H; Rs = 4-C1; R6 = 3-C1; R7 = Me and R8 = H.)

Example 36:

By operating in a manner similar to that described in Example 33, compounds prepared in a similar manner to that described in Example 35 are converted into the corresponding N, N-dimethyl compounds.

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18

CH-CHR-NMe „.HCl

Example

Starting substance r5

r6

r7

FCC)

36a 36b

35 35a

Cl Cl

Cl Cl

And me

177-178 204-205

Example 37:

By operating in a similar manner to that described in Example 34, N-formylated compounds prepared as described in Example 32 are converted from ketones prepared as in Example 35 into the corresponding N-methylated compounds. .

CH0CHR „NHMe.HCl

R.

l5

Example

Rs

Ra

R7

F (° C)

37a

Cl

H

And

170-172

37b

Cl

Cl

And

193-194

Example 38:

A mixture of 10.1 g of 2- [1- (4-chlorophenyl) cyclo-butyl] acetonitrile (prepared as described in Example 27), 8.1 g of potassium hydroxide and 92 ml of diethylene glycol are heated. at reflux, for 2.5 h. The mixture is poured onto a mixture of water and ice and the resulting solution is washed three times with ether, and added to a mixture of ice and concentrated hydrochloric acid. A solid product separates during cooling: it is recrystallized from petroleum ether (bp 62-68 ° C) using charcoal. The recrystallized product is 2- [1- (4-chlorophenyl) cyclobutyl] acetic acid (mp 83-84 ° C).

5 g of the acid prepared as described above are added to 20 ml of thionyl chloride and the mixture is heated at reflux for 1 h. The excess thionyl chloride is removed and the residue is poured into a solution of piperidine (3.8 g) and ether (20 ml). The mixture is stirred for 30 min, then water is added to dissolve the piperidine hydrochloride. The ethereal layer is separated and the aqueous layer is washed with ether. The ethereal phases are combined and washed with water, dried and evaporated, which gives a brown oil which is purified by distillation (eb. 168 ° C / l mmHg) and crystallization from petroleum ether (eb 40-60 ° C). The solid product is N-2- [1- (4-chlorophenyl) cyclobutyl] acetylpiperidine (mp 66-68 ° C).

A solution of 2.7 g of the compound prepared as described above in 20 ml of ether is added dropwise to a stirred mixture of lithium aluminum hydride (0.7 g) and ether, under nitrogen. Stirring is continued for 1 h at room temperature then with reflux for 2 h. After cooling on ice, the excess lithium aluminum hydride is decomposed by adding water. The mixture is filtered on diatomaceous earth (Celite). The aqueous part of the filtrate is washed with a portion of ether and this portion is combined with the portions of ether used to wash the solid residue. All the ethereal portions are washed with water, dried and evaporated. The residue is purified by distillation. The product is N-2- [1- (4-chlorophenyl) cyclobutyl] ethylpiperidine (bp 152-156 ° C / 1.5mmHg). (FormulaI: n = 1; Rj, R2 = H; R3etR4, together and with the nitrogen atom, form a piperidine ring; Rs = 4-C1; R6, R7 and R8 = H.)

By operating in a similar manner to that described above, the following compounds are prepared, which are isolated in the form of hydrochlorides by bubbling dry hydrogen chloride gas into a solution of the base in petroleum ether (eb. 62-68 ° C).

Example

Rs

R6

nr3r4

F (° C)

Me jl

38a

Cl

H

167-169

38b

Cl

H

-.oï-Me \ /

281-283 (dec.)

38c

Cl

H

-o

246-248

Example 39:

A mixture of 9 g of sodium hydride, 9 g of mineral oil and 150 ml of dry dimethylformamide under nitrogen at 0 ° C. is stirred. A solution of p-toluenesulfonyl methyl isocyamere is added over 20 minutes sold under the trade name TosMIC (24.6 g) in dimethylformamide (50 ml). The mixture of 18 g of absolute alcohol is then added, at 0 ° C, over 1 hour. 24 g of l-acetyl-1- (4-chlorophenyl) cyclobutane (prepared in a similar manner to that described in Example 1 for l-acetyl-1- (3,4-dichlorophenyl) cyclo-butane are added. ) dissolved in 20 ml of dry dimethylformamide, and the mixture is stirred for 16 h during which the temperature rises to room temperature. The mixture becomes viscous and 25 ml of petroleum ether (bp 80-100 ° C) are added. The mixture is poured onto water and the pH is brought to 6 by the addition of 5N hydrochloric acid. The resulting mixture is extracted with ether and the ethereal extract is washed with water, dried and partially evaporated. A brown solid product separates: it is removed by filtration and the filtrate is evaporated, then the 2- [l- (4-chlorophenyl) cyclobutyl] propio-nitrile is collected (bp 128-136 ° C / 0.6 mmHg ) by distillation.

A solution of 3.5 g of propionitrile (prepared as described above) in 20 ml of dry ether is added dropwise to a stirred mixture of 0.9 g of lithium aluminum hydride in 20 ml ether, at a temperature of 15 to 20 ° C. The mixture is stirred at room temperature for 2 h, then with reflux for a further 3 h. 20 ml of a 5N sodium hydroxide solution and 50 ml of water are added, and the mixture is filtered on diatomaceous earth (Celite). The filtration medium is washed with ether and the ether washes are combined with the reaction mixture. All the extracts are extracted with 5N hydrochloric acid. A solid product is formed at the interface which is collected by filtration, washed with acetone and dried. The solid product is 2- [1- (4-chlorophenyl) cyclo-butyl] propylamine chlorhyrate (mp 210-230 ° C).

1 g of the hydrochloride prepared above is dissolved in water, a 5N aqueous solution of sodium hydroxide is added and the solution is extracted with ether. The extract is dried and evaporated until an oil is obtained which is heated under reflux for 6 h with 0.82 g of 1,4-dibromobutane, 0.96 g of anhydrous sodium carbonate and 6 , 5 ml of xylene. The mixture is cooled, filtered through diatomaceous earth (Celite) and evaporated to dryness. The residue is dissolved in 10 ml of propan-2-ol and 5 ml of hydrochloric acid are added. concentrated. The mixture is evaporated to dryness and the residue is collected which is washed with ether and dried. The product is N-2- [1- (4-chlorophenyl) cyclobutyl] propylpyrrolidine hydrochloride (mp 238-248 ° C). (Formula I: n = 1; Rj = Me; R2 = H; R3 and R4, together and with

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652117

the nitrogen atom on which they are fixed, form a Pyrrolidine nucleus: R5 = 4-C1; R6, R7 and R8 = H.)

Example 40:

A solution of 70 g of 1- (3,4-dichlorophenyl) -1-cyclobutanecarbonitrile (prepared in a similar manner to that described in Example 1) in 200 ml of denatured alcohol is mixed with a solution of 3, 7 g of sodium hydroxide in 5 ml of water and a 30% solution of hydrogen peroxide is added dropwise. The mixture is heated at 50 ° C for 1 h and stirred with 10% palladium on carbon (0.5 g) for 1 h. The mixture is filtered and evaporated to dryness, thus obtaining 1- (3,4-dichlorophenyl) -1-cyclo-butanecarboxamide.

The carboxamide prepared above is dissolved in 500 ml of dioxane and 100 ml of concentrated hydrochloric acid, then a solution of 35 g of sodium nitrite in 80 ml of water is added dropwise. The mixture is heated to a temperature of 85 to 95: C for 16 h, then poured onto water. The mixture is extracted with ether and the extract is extracted, in return, using an aqueous solution of potassium carbonate. The basic extract is washed with ether and acidified with concentrated hydrochloric acid, thus obtaining l- (3,4-dichlorophenyl) -l-cyclobutanecarboxylic acid (M = 120-121 ° C) .

The acid prepared above is converted to the compound of Example 27a in a manner similar to that described in Example 27, and to the compound of Example 28a in a manner similar to that described in l 'example 28.

Example 41:

A solution of 23 g of 2- [1- (3,4-dichlorophenyl) cyclo-butyl] acetonitrile (prepared in a similar manner to the 2- [1- (4-chlorophenyl) cyclobutyl] acetonitrile described in Example 27) in 50 ml of dry ether to a solution of ethylmagnesium bromide prepared by dropwise addition of 15.83 g of ethyl bromide in 80 ml of dry ether to a stirred mixture of 3, 53 g of magnesium turnings and 80 ml of ether. The mixture is heated at reflux for 30 min, and stirred without further heating for 16 h, then at reflux for another 2 h. 1- [1- (3,4-dichlorophenyl) cyclobutyl] -2-butaniminyl magnesium bromide is collected by filtration, and a sample of the solid product (about 1 g) is added to a solution of 3 g of sodium borohydride in 30 ml of ethylene glycol diethyl ether. The mixture is stirred at 45 ° C for 90 min. The reaction mixture is extracted with 5N hydrochloric acid. The aqueous phase is basified with an aqueous sodium hydroxide solution and extracted with ether. The ether extract is dried and hydrogen chloride gas is passed through the extract to obtain a precipitate of l - {[l- (3,4-di-chlorophenyl) cyclobutyl] methyl} propylamine ( Mp = 223-224 ° C). (Formula I: n = 1; Rl5 R2, R3 and R4 = H; Rs = 4-C1; R6 = 3-C1; R, = Et; R8 = H.)

Example 42:

7 ml of formic acid are added dropwise to 15 ml of Pyrrolidine, at a temperature of 135 to 140 ° C. 3 g of l- [l- (3,4-dichlorophenyl) cyclobutyl] butane are added dropwise -2-one (prepared as described in Example 35) and the mixture is heated to 140 ° C for 1 h. The temperature is brought to 185-190 ° C for 16 h. The reaction mixture is cooled and poured onto 5N hydrochloric acid. The solution is washed with ether; basified and extracted with ether. The ether extract is dried and hydrogen chloride gas is passed through the extract. By dry evaporation a solid product is obtained which is triturated with dry ether and recrystallized from a mixture of petroleum ether and propan-2-ol, thus obtaining Nl - {[l- (3 , 4-dichlorophenyl) cyclobutyl] methyl} -propylpyrrolidine (F = 157-160 "C). (Formula I: n = 1; R1} R2 = H: R3 and R4, together and with the nitrogen atom on which they are fixed, form a Pyrrolidine nucleus; R5 = 4-C1; R6 = 3-C1; R7 = Et and R8 = H.)

Example 43:

25 g of 1- [1- (3,4-dichlorophenyl) cyclobutyl] -2-buta-niminyl magnesium bromide (prepared as described in Example 41) are heated at 90-95 ° C for 2 h with a mixture of 20 ml of concentrated hydrochloric acid and 30 ml of water. The reaction mixture is extracted with ether, then the ethereal extract is dried and evaporated to dryness. The 1- [1- (3,4-dichlorophenyl) cyclobutyl] -butane-2-one (dist. 122-124 ° C / 0.1 mmHg) is obtained by distillation.

A mixture of 4.3 g of 1- [1- (3,4-dichlorophenyl) cyclobutyl] butane-2-one (prepared as described above), 2.65 g, is stirred at room temperature for 16 h. hydroxylamine sulfate, 4.0 g sodium acetate, 56 ml denatured alcohol and 23 ml water. The reaction mixture is extracted with ether. The ether extract is washed with water, dried and evaporated, which gives a solid product which is recrystallized from petroleum ether (eb. 80-100 ° C), thus obtaining l- [l- (3,4-dichlorophenyl) cyclobutyl] butane-2-oneoxime (mp 106-110 ° C).

A solution of 2.33 ml of trifluoroacetic acid in 5 ml of tetrahydrofuran is added to a stirred suspension of 1.13 g of sodium borohydride in 30 ml of tetrahydrofuran, over 5 min. A solution of 1.7 g of the oxime (prepared as described above) in 25 ml of tetrahydrofuran is added dropwise, and the mixture is heated to reflux for 6 h. The mixture is cooled and 25 ml of water are added, followed by 25 ml of a 5N sodium hydroxide solution. The mixture is extracted with ether, the extract is washed with water, dried and evaporated, and the resulting residue is dissolved in 25 ml of petroleum ether. Dry hydrogen chloride gas is passed through the ethereal solution, thereby obtaining 1 - {[1- (3,4-dichlorophenyl) cyclobutyl] methyl} propylamine hydrochloride (mp 222-224 ° C). (Formula I: n = 1; R2, R3 and R4 = H; Rs = 4-C1; Rs = 3-C1; R7 = Et and R8 = H.)

Example 44:

A solution of 5.0 g of 1- [1- (3,4-dichlorophenyl) cyclobutyl] butane-2-one (prepared as described in Example 43) is reacted at reflux for 72 h and 1, 63 g of methoxyamine hydrochloride in a mixture of 60 ml of pyridine and 60 ml of ethanol. The reaction mixture is evaporated to dryness and the residue is added to a mixture of water and ether. The ethereal layer is washed with a sodium bicarbonate solution and with water, dried and evaporated, thus obtaining the O- methyl ether of 1- [1- (3,4-dichlorophenyl) -cyclobutyl] butane-2-oneoxime.

The oxime ether prepared as described above (15 g) is then reduced to the product of Example 43 using sodium borohydride (0.95 g), operating in a manner similar to that described. in example 43.

Example 45:

0.4 g of sodium cyanoborohydride is added to a solution of 2.45 g of 1- [1- (3,4-dichlorophenyl) cyclobutyl] butane-2-one (prepared as described in Example 42) and 7 g of ammonium acetate in 28 ml of methanol, and the mixture is stirred at room temperature for 4 d. 25 ml of water are added dropwise, while cooling. The aqueous mixture is extracted with ether, the ethereal layer is washed with water and 5N hydrochloric acid (50 ml). The compound of Example 43 precipitates in the form of a white solid product.

Example 46:

2- [1- (4-chlorophenyl) cyclobutyl] acetic acid (1.5 g; prepared as described in Example 38) is heated to reflux with thionyl chloride. The excess thionyl chloride is removed in vacuo and the residue is added dropwise to a solution of 0.94 g of cyclopropylamine in 10 ml of ether and the mixture is stirred for 30 min. Water is added and the aqueous phase is extracted with ether. The ether extract is dried and the ether is removed, thereby obtaining 2- [1- (4-chlorophenyl) cyclobutyl] -N-cyclopropylacetamide.

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A solution of 1.45 g of the amide prepared above in 15 ml of ether is added dropwise to a stirred suspension of 0.42 g of lithium aluminum hydride in 7.5 ml of ether under nitrogen. The mixture is stirred at room temperature for 1 h, then heated to reflux for a further 2 h. After cooling, 0.45 ml of water is added, then 0.45 ml of a 15% sodium hydroxide solution, then finally 1.35 ml of water, and the mixture is stirred for 15 min. The mixture is filtered and extracted with ether. The ether extract is shaken with N hydrochloric acid and a solid product is formed in the aqueous layer. The solid product is N-cyclopropyl-2- [1- (4-chlorophenyl) cyclobutyl] ethylamine hydrochloride (mp 166-170 ° C).

A mixture of 0.41 g of the hydrochloride prepared as described above, 0.1 g of sodium formate and 0.5 ml of an aqueous solution is heated at a temperature of 85 to 90 ° C. for 18 h. 37-40% formaldehyde. The reaction mixture is cooled and extracted with ether. The ethereal extract is washed with water, dried and filtered. Gaseous hydrogen chloride is passed through the filtrate which is heated, which gives a solid product: N-cyclo-propyl-N-methyl-2- [1- (4-chlorophenyl) cyclobutyl] ethylamine hydrochloride (Mp 149-153 ° C). (Formula I: n = 1; Ri and R2 = H; R3 = cyclopropyl; R4 = Me; R5 = 4-C1; R6, R7 and Ra = H.)

Example 47:

Pharmaceutical compositions containing one of the compounds of formula I described in Examples 1 to 46 are prepared as follows.

Example 47a:

Tablets are prepared from the following ingredients:

Parts by weight

Active ingredient 50.0

Lactose 78.5

Polyvinylpyrrolidone 5.0

Corn starch 15.0

Magnesium stearate 1.5

The active ingredient, lactose and a little starch are mixed and transformed into granules using an ethanolic solution of polyvinylpyrrolidone. The granular product is mixed with the stearic acid and the rest of the starch and the mixture is compressed in a tabletting apparatus so as to obtain tablets containing 50.0 mg of the active ingredient.

Example 47b:

The capsules are prepared as follows. A mixture of the active ingredient (45 parts by weight) and of powdered lactose (205 parts by weight) is introduced into hard gelatin capsules,

each capsule containing 45 mg of the active ingredient.

Example 47c:

To prepare enteric coated tablets, a thin coating of shellac followed by 20 layers of cellulose acetophthalate is applied to the tablets described in Example 47a, in a manner well known in the art. Similarly, an enteric coating can be applied to the capsules of Example 47b.

Example 47d:

Vials are prepared containing a solution of water-soluble compounds according to the present invention which can be used in injections, using the following ingredients:

Active ingredient 1100g

Mannitol 1100g

Water, freshly distilled to make 111

The active ingredient and the mannitol are dissolved in part of the water and the volume of the solution is brought to 11 1. The resulting solution is sterilized by filtration and introduced into sterile vials each containing 1.65 ml of solution.

Example 47e:

To prepare suppositories, 100 parts by weight of the finely ground active ingredient are incorporated into 1214 parts by weight of base for triglyceride suppositories, and the mixture is put into the form of suppositories each containing 100 mg of the active ingredient.

In the previous examples, new ketones of formula V have been described in which R15 R5 and R6 have the meanings given in examples 1, la to le, 3, 4,4a to 4e, 6, 7, 7a to 7d, 9, 9a at 9n, 10.10a to 10z, IOaa, lObb, 1 li, 1 lk and 11 (1). These new ketones of formula V are prepared by hydrolysis of new imines of formula XVI in which Y = MgBr and R15 R5 and R6 have the meanings given in the above examples.

In the previous examples, new ketones of formula VI have been described in which Rx, R2, R5, R6 and R, have the meanings given in examples 29, 35, 36 and 43. These new ketones of formula VI were prepared by hydrolysis new imines of formula XVIII in which Y = MgBr and Rx, R2, R5, R6 and R, have the meanings given in Examples 29, 35, 36 and 43.

In the previous examples, new cyano-type compounds of formula XVII have been described in which Rs and R6 have the meanings given in Examples 1, ld, le, 4g, 9e, 9m, 10k, 10e, 10p, lOr, lOv, lOy , 10z, lOaa, lObb, 11k, 11 (11) and 26.

In the previous examples are described new formamides of formula XVIII in which Rj, R3, R5, R6, R7, Rs and n have the meanings given in Examples 1, la to le, 3, 4,4a to 4e, 6, 7 , 7a to 7d, 9, 9a to 9n, 10, 10a to lOz, IOaa, lObb, Ili, 11k, 11 (1), 29, 32, 35 and 36.

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R

Claims (16)

652117 2 1. Compounds corresponding to formula (I): CR1R2 (CR7R8) nNR3R4 Rc in which n = 0 or 1; in which, when n = 0, Rj represents a C1 to C6 straight or branched chain alkyl group, a C3 to C1 cycloalkyl group, a cycloalkoylalkoyl group in which the cycloalkyl group is in C3 to C6 and the alkyl group is in C1 to C3, an alkenyl group or a C2 to C6 alkynyl group, or a group of formula (II): (II) in which R9 and R10, identical or different, each represent H, a halo radical, or a C1 to C3 alkoxy group; in which, when n = 1, Rj = H or a C1 to C3 alkyl group; R represents H or a C1 to C3 alkyl group; R3 and R4, identical or different, each represent H, a straight chain or branched C1 to C4 alkyl group, a C3 to C6 alkenyl group, a C3 to C6 alkynyl group, a cycloalkyl group in which the nucleus contains 3 to 7 carbon atoms, a group of formula RnCO in which Ru = H; or, together and with the nitrogen atom to which they are attached, R3 and R4 form an optionally substituted heterocycle containing 5 or 6 atoms in the nucleus and optionally containing other hetero atoms in addition to the atom nitrogen; R5 and R6, identical or different, each represent H, a halo group, a trifluoromethyl group, a C1 to C3 alkyl group, a C1 to C3 alkoxy or alkylthio group, a phenyl group or, together and with the atom of carbon to which they are attached, R5 and R6 form a second benzene ring substituted or not substituted by one or more halo groups, a C1 to C4 alkyl or alkoxy group or the substituents of the second benzene ring, with the two carbon atoms on which they are fixed, form another benzene nucleus; R7 and Rs, identical or different, each represent H or a C1 to C3 alkyl group; as well as their pharmaceutically acceptable salts. 2. Compounds of formula (I) according to claim 1, characterized in that n = 0; R! represents a linear or branched C1-C4 alkyl group, a C3-C7 cycloalkyl group, a cycloalkylmethyl group in which the cycloalkyl group is C3-C6, or a group of formula (II) in which R9 and R10 = H, fluoro or methoxy, and R2 = H or methyl. 3. Compounds of formula (I) according to claim 2, characterized in that Rj represents a methyl, ethyl, propyl, isor propyl, butyl, isobutyl, sec.-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl , cyclo-butylmethyl, cyclopentylmethyl, cyclohexylmethyl or phenyl. 4. Compounds of formula (I) according to claim 1, characterized in that n = 1, Rj = Hou methyl and R2 = H. 5. Compounds of formula (I) according to one of the preceding claims, characterized in that R3 and R4 = H, methyl, ethyl or formyl. 6. Compounds of formula (I) according to one of claims 1 to 4, characterized in that, together and with the nitrogen atom to which they are attached, R3 and R4 form a heterocycle containing a nitrogen atom and 4 or 5 carbon atoms which is optionally substituted by one or more alkyl groups, or a heterocycle containing a second nitrogen atom which is optionally alkylated or a heterocycle containing one or more double bonds. 7. Compounds of formula (I) according to claim 1, characterized in that Rs and R6 = H or a fluoro, chloro, bromo group, (I) 5 iodo, trifluoromethyl, methyl, methoxy, phenyl, or, together and with the carbon atoms to which they are attached, R5 and R6 form a second benzene ring optionally substituted by a halo group. 8. Compounds of formula (I) according to one of claims 1, 4, io 5, 6 and 7, characterized in that R, = H, methyl or ethyl and Rs = H. 9. Compounds according to claim 1, corresponding to formula (III): CR1R2 (CR7R8) nNR3R4 N / -h in which Rls R2, R3, R4, R5, R6, R7, Rs and n are as defined in claim 1. 10. "Compounds according to claim 9, characterized in that R5 and R6, which may be identical or different, represent H or a fluoro, chloro, bromo, iodo, trifluoromethyl group, methyl, methoxy, phenyl or, together and with the atoms of 25 carbon on which they are fixed, R5 and R6 form a second benzene nucleus optionally substituted by a chloro group. 11. Compounds according to claim 1, corresponding to formula (IV): 30 CR1R2 (CR7Ra) nIIR3R4 (IV) in which R1; R2, R3, R4, R5, R7, Rg and n are as defined in claim 1, and R6 represents a fluoro or methyl group. 12. Compounds of formula (IV) according to claim 11, characterized in that R5 = H or a fluoro, chloro, bromo, 40 iodo, trifluoromethyl, methoxy or phenyl, and R6 represents a fluoro or methyl group. 13. Compounds of formula (I) according to claim 1, which are l- [1- (4-chlorophenyl) cyclobutyl] butylamine, N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] butylamine, 45 N-methyl-1 - [1 - (3,4-dichlorophenyl) cyclobutyl] butylamine, N, N-dimethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] butylamine, N-methyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine, N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbu-50 tylamine, N, N-dimethyl-l- [1- (3,4-dichlorophenyl) cyclobutyl] -3-methyl-butylamine, l- [l- (3,4-dichlorophenyl) cyclobutyl] ethylamine, N, N-dimethyl-l- [l- (3,4-dichlorophenyl) cyclobutyl] ethylamine, 55 la a- [l- (4- chlorophenyl) cyclobutyl] benzylamine, and their pharmaceutically acceptable salts. 14. Pharmaceutical composition comprising a tea-therapeutically effective amount of a compound of formula (I) according to one of the preceding claims. 15. Process for the preparation of compounds of formula (I) according to claim 1, consisting in subjecting to a reductive amidation a ketone of formula (V): (V) in order to obtain a compound in which n = 0; R2 = H; R4 = CHO, 652,117 and R], Rs and R6 are as defined in claim 1, or a ketone or an aldehyde of formula (VI): cr1r2cor7 (VI) in order to obtain a compound in which n = 1; R4 = CHO, R8 = H, and Ri, R2, Rs, R6 and R7 are as defined in claim 1. 16. Process for the preparation of compounds of formula (I) according to claim 1, comprising subjecting to a reductive amination a ketone of formula (V): (V) in which: a) Z represents a group of formula - CRj = NOH or one of its esters or ethers, in order to obtain a compound of formula (I) in which n = 0 and R2, R3 and R4 = H; b) Z represents a group of formula —CR! = NR3, in order to obtain a compound of formula (I) in which n = 0 and R2 and R4 = H; c) Z represents a group of formula - CR! = NY in which Y represents a fragment containing a metal derived from a gold-ganometallic reagent, in order to obtain a compound of formula (I) in which n = 0 and R2, R3 and R4 = H; d) Z represents a group of formula - CRjR2CN, in order to obtain a compound of formula (I) in which n = 1 and R3, R4, R7 and Rs = H; e) Z represents a group of formula - CR ^^ R, = NOH or one of its esters or ethers, in order to obtain a compound of formula (I) in which n = 1 and R3, R4 and Rs = H; 0 Z represents a group of formula - CR! R2CR7 = NR3, in order to obtain a compound of formula (I) in which n = 1 and R4 and Rs = H; g) Z represents a group of formula —CRjR2CR7 = NY in which Y represents a fragment containing a metal derived from an organometallic reagent, in order to obtain a compound of formula (I) in which n = 1 and R3, R4 and Rs = H; h) Z represents a group of formula - CR! R2CONR3R4, in order to obtain a compound of formula (I) in which n = 1 and R7 and Rr = H.