LU84070A1 - PHENYLCYCLOBUTYL DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION - Google Patents

Description

The present invention relates to compounds having interesting therapeutic activity, in particular - but not exclusively - as anti-depressants, to pharmaceutical compositions 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); r6 - in which n = 0 or 1; ~ in which, when n = 0, represents an alkyl group with a linear chain of the branched C1 to C6, a grou-15 cycloalkyl C3 to C7, a cycloalkoylalkoyl group in which the cycloalkyl 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): -GC = in which R ^ and R ^ q, which may be identical or different, each represent H , a halo radical, or a C1-C3 alkoxy group; wherein, when n = 1, R ^ = H or a C1-C3 alkyl group; R2 represents H or a C1 to C3 alkyl group; 5, R3 and R ^, which may be the same or different, each represents H, a straight chain or branched C1 to C4 alkyl group, a C3 to C6 alkenyl group, a = alkynyl group C3 to C5, a cycloalkyl group in which the nucleus contains from 3 to 7 carbon atoms, a group of formula R ^ CO in which R ^ = H; or, together and with the nitrogen atom to which they are attached, R ^ and R ^ form an optionally substituted heterocycle containing- / /

AT

L

2 nant 5 or 6 atoms in the nucleus which can contain other heterifroatomes in addition to the nitrogen atom;

Rg and Rg, which may be the same or different, each represents H, a halo group, a 5-trifluoro methyl group, a C1-C3 alkyl group, a C1-C3 alkoxy or alkylthio group, a phenyl group or, together and with the carbon atom to which they are attached, Rg and Rg form a second benzene ring which may be 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 to which they are attached, can form another benzene ring; R ^ and Rg, which may be the same or different, each represents 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 —ô ch 1 Γ 2 0 CHg —'cH2

and -CRj ^ R2 (CR ^ Rg) nRgR ^ represents a group corresponding to the formula: R./R.X

"" R4 In the preferred compounds of formula (I), in which n = O, R1 represents a straight or branched C1 to C4 alkyl group, a C3 to C7 cycloalkyl group, a cycloalkylmethyl group in which the cycloalkyl nucleus is C3 to C6 or a group of formula (II) in which R ^ and / or R ^ q = H, fluoro or methoxy and in which R2 = H or methyl. Examples of compounds - particularly preferable of formula (I) include those in which when n = 0 and Rj = H, R ^ represents a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyle, cyclopentyle, cyclohexyle, cyclcheptyle, cycloprroylmethylycyclobutylméthylf cyclor /! / ^

V

3 pentylmethyl, cyclohexylmethyl or phenyl.

In the preferable compounds of formula (I) in which n = 1, R ^ = H or methyl, and = H. In the particularly preferable compounds of formula (I) in which -5, which n = 1, = R2 = H.

In the preferable compounds of formula (I), and / or R ^ 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 nucleus heterocyclic, the preferable compounds of formula (I) contain a heterocyclic group containing a nitrogen atom and 4 or 5 carbon atoms (for example pyrrolidinyl piperidino) which is optionally substituted by one or more alkyl groups ( e.g. methyl) (e.g. pyrrolidinyl substituted by two methyl groups), a heterocyclic group containing a second nitrogen atom which is optionally alkylated (e.g. 4-methylpipetraazinyl) or a heterocyclic group comprising one or more double bonds (e.g. 1,2,3,6-tetrahy-20 dropyridinyl). In the particularly preferable compounds of formula (I) R ^ and / or R ^ each represent H or a methyl, ethyl or formyl group.

In the preferable compounds of formula (I), and / or Rg represent H, or a fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy, phenyl or group, together with the carbon atom on which they are attached, R, - and Rg form a second benzene ring which may optionally be substituted by a halo group.

A first group of preferred compounds of formula (I) 30 is represented by the formula (ni): έ CR ^ CR ^ g ^ RFy ^ - r5 ~ OHi 35 in which R ,. and Rg have the above definitions. In the preferred compounds of formula (III), Rg and Rg, which may be identical or different, each represent / fi 7 4 H or a fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy, phenyl or group, and with the carbon atoms on which they are attached, and Rg form a second benzene ring which may optionally be substituted by a chloro group. In the particularly preferred compounds of formula (III) R5 and / or Rg each represent H or a fluoro, chloro, iodo, trifluoromethyl, methyl, phenyl group or, together and with the carbon atoms to which they are attached, R ^ and 10 Rg form a second benzene ring which may optionally be substituted by a chloro group.

A second group of preferred compounds of formula (I) * is represented by the formula (XV) i "5 ^ cR ^ Cca ^ ® ^; Rb, wherein Rg may represent H, or a fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy or phenyl group and Rg represents a fluoro or methyl group. In the particularly preferred compounds of formula (IV) Rg = H or chloro.

In the preferred compounds of formula (I) in which n = 1, R ^ = H, methyl or ethyl and Rg * = H, and, in the particularly preferred compounds of formula (I), R ^ = H or ethyl and Rg = H.

The compounds of formula (I) can exist in the form of salts with pharmaceutically acceptable acids. Examples of these salts include chlorhy drates, maleates, acetates, citrates, fumarates, tartrates, 3 i 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 R ^ and Rg are different, the components

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5 of formula (I) contain a chiral center. These compounds exist in two enantiomeric forms and the present invention encompasses the two enantiomeric forms as well as their mixtures. When both R ^ and R £ are different and R ^ and Rg are different, the compounds of formula (I) contain two chiral centers and the compounds exist in four diastereoisomeric forms. The present invention encompasses each of these diastereoisomeric 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 administration by oral, rectal, parenteral or topical route. 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 forms known for this administration, for example * aqueous or oily tablets, capsules, syrups and suspensions. The excipients used in the preparation of T s 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 disintegrants such as, for example, corn starch, and lubricants such as magnesium stearate and into - h- 6 mant the mixture 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, may be provided with enteric coatings in known manner. The tablets and capsules may suitably contain from 1 to 500 mg of the active compound each. Other compositions which can be administered orally include, for example, aqueous suspensions containing the active compound in an aqueous 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 can 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. The active compounds 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 fluid energy milling.

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 a 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 R ^ = CHO can be prepared by reductive amidation of ketones of formula (V) or ketones or aldehydes of formula (VI) R5 λ CR1R2C0R7 25 X) r6 s \ = J - ! vi for example with formamide and formic acid or ammonium formate and formic acid, to obtain compounds of formula (I) in which = CHO and R3 = - 30 H, or with formamides of formula HCONHR ^ in which R ^ represents an alkyl or cycloalkyl group and; formic acid, or amines of formula R ^ N ^ in which * R ^ represents an alkyl or cycloalkyl group and formic acid.

35 The compounds of formula (I) in which R4 = CHO

can be prepared by formylation of compounds of formula (I) in which R ^ = H, for example by reaction 8 with methyl formate.

The compounds of formula (I) in which R * is not H and R ^ = CHO can be prepared by reacting compounds of formula (I) in which R ^ = H and R ^ = 5 CHO with a compound of formula R ^ X in which X is a labile group, such as 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 ceto-10 or of 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 R 1 and * R 4 = H, by reaction of the ketone or of the aldehyde with an ammonium salt (by example ammonium acetate) and a reducing agent such as sodium cyanoborohydride, b) for the compounds of formula (I) in which R- = bialkyl or cycloalcohol and R | = H, by reaction of the ketene ç > u of the aid-Jiyde with an amine of formula R.jNH2 and a reducing agent 'such as sodium cyanoborohydride, 20 c) for the compounds of formula (I) in which neither R ^ nor R ^ are of l hydrogen or in which R ^ and R ^, together and with the nitrogen atom, form a heterocycle, by reaction of the ketone or aldehyde with an amine of formula HNR ^ R ^ and either acid formic is a reducing agent such as sodium cyanoborohydride, d) for the compounds of formula (I) in which R ^ and / or R ^ represent H or an alkyl or cycloalkyl group or in which ls, together and with the nitrogen atom, R ^ and R ^ form a heterocycle, by catalytic hydrogenation at elevated temperature and pressure of a mixture of the ketone = or aldehyde and an amine of formula HNR ^ R ^.

The compounds of formula (I) in which R 1 and R v both represent alkyl groups can be prepared by reacting a ketone of formula (V) or a ketone or aldehyde of formula (VI) with a dialkyl formamide of formula HCONR ^ R ^ for example in the presence of formic acid.

Λα 9

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

R5 Z

£ Hi „r6 in which: a) Z is a group of formula -CR1 = NOH or one of its esters or ethers, in order to obtain compounds of formula 10 (I) in which n = 0 and R2, R ^ and R ^ = H; b) Z is a group of formula -CRj = NRg, in which R ^ is different from H or CHO, in order to obtain 'compounds of

V

formula (I) in which n = O and R2 and = H? c) Z is a group of formula -CRj = NY in which Y 15 represents a fragment containing a metal deriving from an organometallic reagent, in order to obtain compounds of h formula (I) in which n = 0 and R2, R ^ and R ^ = H; i d) Z is a group of formula -CR ^ R ^ N, in order to obtain compounds of formula (I) ‘in which n = 1 and R ^, R ^, 20 R? and Rg = H; e) Z is a group of formula -CR ^ RgCR- ^ NOH or one of its esters or ethers, in order to obtain compounds of formula (I) in which n = 1 and R ^, R ^ and Rg = H; f) Z is a group of formula -CR ^ R ^ CR ^ -NR ^ f in which Rg is different from H or CHO, in order to obtain compounds of • f formula (I) in which n = 1 and R ^ and Rg b H; g) Z is a group of formula.-CR ^ R ^ CR ^ 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 R ^, R ^ and Rg = H; h) Z is a group of formula -CR ^ R ^ CONRgR ^, in order to obtain compounds of formula (I) in which n = 1 and R ^ and Rg = H.

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

10

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 R ^ MgX in which X = Cl, Br or I, or of an organic lithium compound of formula R ^ Li with an imine of formula (VIII) - - -

RK __k CH = MU

10

R6 S * C = J _J VIII

V

followed by hydrolysis, in order to obtain a secondary amine of, formula (I). Similarly, the imines of formula (IX) can be converted into secondary amines b of formula (I) in which n = 1 L Rev. , __. CR, R’CH = NR2 R y \ = J _ ix 20 6

The compounds of formula (I) in which R ^ and R ^ = H, can be prepared by rearrangement by decarboxylation, for example using iodosobenzene-bistri-fluoroacetate or by a Hofmann reaction using bromine in alkaline solution, amides of formula (X) or amides of formula (XI) R5 ° hVam2 .jD-λ 30 o - in order to obtain amines of formula (I) in which n = 0 and n = 1, respectively.

"" 35 11

The compounds of formula (I) in which Rg and R ^ = H can be prepared by rearrangement by decarboxylation of acyl azides in the Ourtius reaction.

Acyl azides can be obtained, for example, by reaction of acid chlorides of formula (XII) or chloro. acid rures of formula (XIII) with sodium azide.

^ CR ^ o: i rÆ) i r6 - 10 R CWW001: —i

Ry \ = / _ xiii

. The compounds of formula (I) in which R ^ and R ^ = 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 acid

; hydrazooi · R- CR, IUC03H

20 y ^ C = J XXV

R6 -

R5 CR ^ CR ^ qCOOH

J & h.

25 R6

The compounds of formula (I) in which R ^ = 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 R ^ = 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 ) alu- w sodium minohydride.

The compounds of formula (I) in which R ^ and / or R ^ do not represent (s) hydrogen, can be prepared from compounds of formula (I) in which R ^ and / or R ^ = H, by methods well known in the art.

// y— 12 than the conversion of primary amines to secondary or tertiary amines or 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 method consisting in protecting the primary amine from using a protective group (trifluoroacetyl for example) to alkylate with an alkyl halide and to remove 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 R 1 and can be different; 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 R ^ = ethyl and R ^ = H; e) reacting primary amines of formula (I) with formaldehyde and formic acid to obtain tertiary amines of formula (I) in which R3 and R ^ are both methyl groups; f) reacting secondary amines of formula (I) in which R 4 = H with formaldehyde and formic acid in order to obtain tertiary amines of formula (I) in which R 4 = methyl; g) by formylation of primary amines of formula (I), for example by reaction with methyl formate, and reduction of the resulting formamides, for example using lithium aluminum hydride in order to obtain secondary amines of formula (I) in which = methyl and R4 = H; 13 h) by formylation of secondary amines of formula (I), for example by reaction with methyl formate, and f reduction of the resulting formamides, for example using lithium aluminum hydride, in order to d '' obtaining tertiary amines of formula (I) in which R ^ = methyl; i) by acylation of primary amines of formula (I), for example by reaction with an acyl chloride of formula R12CO6 or an anhydride of formula (R ^ CO ^ O in which R ^ 2 represents an alkyl, alkenyl group or alkynyl, and reduction of the resulting amides, for example using lithium aluminum hydride in order to obtain "secondary amines of formula. (I) in which = -CH-R, - and R. = H; 2 12 4 15 j) by acylation of secondary amines of formula (I) * in which R ^ = H, for example by reaction with a çT :. acyl chloride of formula R ^ COCl or an anhydride of formula (R12CO) 20 in which R12 represents an alkyl, alkenyl or alkynyl group and reduction of the resulting amides, for example using lithium hydride and aluminum in order to obtain tertiary amines in which R ^ = CH2R12; k) by reaction of primary amines of formula (I) with an aldehyde of formula R- ^ CHO in which R13 may be an alkyl group, an alkenyl or alkynyl group or a ketone of formula R14COR15 in which R14 and R15, which may be the same 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, R 4 and R 4 may form an alicyclic ring, and reduction of the resulting imines or enamines, for example using sodium cyanoborohydride or, when R13, Rl4 or R ^ j. do not represent an alkenyl or alkynyl group, by catalytic hydrogenation in order to obtain secondary amines of formula (I) in which R ^ = respectively R13CH2 ~ and R14 ~ CH-; Λ 14 1) by reaction with the primary amines of formula (I) with an alkane with non-gem-containing disubstitution containing 2 or 3 carbon atoms between the carbon atoms carrying the substituents which may, for example, be halo, preferably 5 bromo, or p-toluênesulfonyloxy in order to obtain compounds of formula (I) in which R ^ and R ^, together and with the nitrogen atom to which they are attached, form a heterocycle containing no other heteroatoms than the nitrogen atom.

The ketones of formula (V) can be prepared by hydrolysis of imines of formula (XVI)

Rs ^ A_f. = NY

R sK-J U ^ 15 R6 t wherein 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 the formula (XVII) R5 ^ Vh

P - XVII

R6 25 As examples of suitable organometallic reagents, Grignard reagents corresponding to the formula R ^ MgX in which X = Cl, Br or I (Y = MgX) and organic lithium compounds of formula R ^ Li (Y = Li will be cited) ).

The ketones of formula (VI) can be prepared by hydrolysis of imines of formula (XVIII) where J represents a fragment containing a metal derived from an organometallic reagent. The imines of formula (XVIII) can be prepared by reaction of said organometallic reagents with compounds of cyano type corresponding to formula (XIX)

R,. CR-. R_CN

r6 - XIX

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

The 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) R ^ \ r R6 20 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 (XXI) <Ό0Η 25 / r ^ n = / I— · xxi with an organometallic reagent, for example an organic lithium compound corresponding to the formula R ^ Li.

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 R ^ Li.

16

The ketones of formula (V) in which R ^ = aloqyle (for example methyl) and the ketones of formula (VI) in which R ^ = alkyl (for example methyl) can be prepared by reaction of a diazoalkane (such as diajço-5 methane) with aldehydes corresponding to formulas (XXII) and (VI) respectively.

r5 v ^ __ \ cho

Rr 'K = / _ XXII

10 6

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, di- * tert-butylaluminum hydride or diisobutylaluminum hydride; b) by reduction of carboxylic acid derivatives, for example: i) by reduction of compounds of formula (VII) in which Z = CR1R2CONR3R4 and R ^ and R ^ do not represent hydrogen, for example to using lithium diethoxyaluminohydride; ii) by reduction of amides formed by reaction of ethyleneimine on an acid chloride of formula (XII), | For example, using lithium hydride as a reducing agent; ! ! iii) by reduction of acid chlorides of formula (XII), for example using lithium tri-tert-butoxyalumino hydride.

C) by reaction of alcohols (obtained by reduction of carboxylic acids of formula (XIV) using, for example, a chromium trioxide-pyridine complex in dichlorome-thane, in an anhydrous medium.

The compounds of formula (VII) in which Z represents a group of formula -CR1 = NOH or -CR ^ R ^ R ^ NOH or their ethers or esters can be prepared by reaction of hydroxylamine or of aher or hydroxylamine ester on, 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 -CR ^ NR ^ or 5 -CR ^ R ^ CR ^ NR ^ can be prepared by reaction of amines of formula NI ^ R ^ with ketones of formula (V) and ketones or aldehydes of formula (VI) ”respectively.

The preparation of the compounds of formula (VII) in which Z represents a group corresponding to the formula 10 -CR ^ = NY or -CR ^ R ^ CR-y ^ NY has been described above in connection with, respectively, the compounds of formula (XVI) and (XVIII).

The preparation of the compounds of formula (VII) in which Z represents a group corresponding to the formula -CRj ^ CN will be described below in connection with the cyano-type compounds of formula (XIX).

The compounds of formula (VII) in which Z represents a group -CR1R2CONR3R ^ can be prepared by the reaction of acid derivatives such as esters or acid halides (for example acid chlorides of formula (20) XII) with amines of formula NHR3R ^. The compounds of formula (VII) in which Z represents CRiR2CONH2 can be prepared from cyano compounds of formula (XIX) for example by hydration, using acids aqueous, or by reaction with hydrogen peroxide in the presence of a base.

The imines of formula (VIII) and (IX) can be prepared by reaction of amines of formula R3NH2 on the aldehydes corresponding to the formulas (XXII) and (VI), respectively.

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

ί / \ t 18

The amides of formula (XI) can be prepared by reaction of ammonia with derivatives of carboxylic acids 1, for example acid chlorides of formula (XIII), or can be prepared from cyano compounds of formula 5 (XXIII), for example by hydration using aqueous acids or by reaction with hydrogen peroxide in the presence of a base.

1 ° R—

%. XXIII

The amides of formula (X) in which R ^, = R2 = H and the amides of formula (XI) in which R? = Rg = H; can be prepared from acid chlorides corresponding to formulas (XX) and (XII) respectively by reaction with diazomethane, in order to obtain a diazoketone which undergoes rearrangement in the presence of ammonia and a ca-- talyseur, for example money, 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 formulas (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 with the amides obtained by reaction of ammonia with derivatives ς. 30 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 R ^ = R £ = H and the carboxylic acids of formula (XV) in which R ^ = Rg = H can be prepared from acid chlorides corresponding respectively to l / \ 19 formulas (XX) and (XII), by reaction on diazomethane, in order to obtain diazoketones which undergo a rearrangement in the presence of water and a catalyst, for example silver, giving l acid required.

5 The cyano type compounds of formula (XVII) can

be prepared by reaction of cyano compounds of formula (XXIV) R

_ CH.jCÎ!

10 H '* “' - XXIV

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

The cyano compounds of formula (XIX) in which R ^ = 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 R 1 and R 2 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)

U

20 with a reagent for introducing a cyano group such as p-toluenesulfonylmethyl isocyanide. Similarly, the cyano compounds of formula (XXIII) i can be prepared from aldehydes or ketones of formula (VI).

The acid chlorides of formula (XX), (XII) and (XIII) can be prepared by reacting carboxylic acids corresponding to the formulas (XXI), (XIV) and (XV) respectively on, 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) to j - using, for example, di-tert-butylaluminum hydride j 15 or diisobutylaluminum hydride; | - b) by reduction of carboxylic acid derivatives, for example: ^ i) by reduction of tertiary amides formed by reaction of secondary amines on aci-20 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 ethyleneimine, using lithium hydride and aluminum hydride as reducing agent, | ii) by reduction of acid chlorides of formula (XX), j for example using lithium tri-tert-butoxyalumino hydride, c) by oxidation of alcohols (prepared by reduction of acid - Carboxylic acids of formula (XXI) using, for example, i a chromium trioxide-pyridine complex in dichloro-methane, in an anhydrous medium.

I Ketones of formula (V) (except those in which R 1 = Rg = H and = methyl or ethyl), ketones i of formula (VI) and aldehydes of formula (VI) (except those in which Z = CR, = KY and Rr = R, = H and R, = methyl 1 ob 1 or ethyl), the imines of formula (VIII) (except those in

U

/ 21 which Rg = Rg = H), of formula (IX), (XVI) (except those in which Rg = Rg = H, and Rj = methyl or ethyl) and of * formula (XVIII), the amides of formula ( X) and (XI), the carboxylic acids of formula (XIV) (except those in which R ^, R2 / Rg and Rg = H) and (XV), the cyano compounds of formula (XIX) and (XXIII) and the acid chlorides of formula (XII) (except those in which Rj, R2,

Rg and Rg = H) and (XIII) which are described here as intermediates are new compounds. Some of the cyano compounds of formula (XVII) and (XXIV) are new compounds. These new compounds constitute one of the aspects of the present invention.

New formamides corresponding to the formula (XXV) / "R3 15 r“ iV ^ yvvv ÿYy_ cho

r6 L 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. Male Charles strain mice

River CDI weighing between 18 and 30 g are separated into groups of 5 and receive unlimited food and water. After 5 hours, 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 ascorbic acid (50xtg / ml). The amount of liquid injected is 10 ml / kg of body weight. Nine hours after the start of the test, the food is removed, but the mice still have unlimited water. 24 hours after the start of the test, the temperature of the mice is taken, and the mice are administered the test compound, suspended in a 0.25% solution.

U

22 of hydroxyethyl cellulose (supplied under the trade name Cellosize QP 15000 by Union Carbide) in deionized water, at a dose volume of 10 ml / kg of body weight. Three hours later, the temperature of all the mice is also taken. The percentage of reversal of the drop in body temperature due to dreaming is then calculated according to the formula:

End temperature _ End temperature x 100 of 27 hours_ of 24 hours_ 10 End temperature _ Temperature after 5 hours of 24 hours

The average value for each group of five mice is taken at various doses in order to obtain an average dose value causing an inversion of 50%. 15 (ED50). All the compounds 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 an anti-depressive activity in humans.

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

TABLE I

1- / 1- (3,4-dichlorophenyl) cyelobutyl7-25 ethylamine hydrochloride. N-methyl-1- / 1- (3,4-dichlorophenyl) cyclo butyl7ethyl hydrochloride N, N-dimethyl hydrochloride -l- / l- (3,4-dichlorophenyl) -cyclobutyl / ethylamine 1- / 1- (4-iodophenyl) cyclobutyl / ethylamine hydrochloride N-methyl-l- / l- (4-iodophenyl hydrochloride ) cyclobutyl / ethylamine NfN-dimethyl-1 - /] .- (4-iodophenyl) cyclobutyl / ethylamine hydrochloride N-methyl-1- / 1- (2-naphthyl) cyclobutyl) -! 35 ethylamine N, N-dimethyl-1- / 1- (4-chloro-3-trifluoro-methylphenyl) cyclobutyl hydrochloride / ethylamine I /

I / V

23 1- / T- (4-chlorophenyl) cyclobutyl7 ~ butylamine hydrochloride; N-methyl-1- / T- (4-chlorophenyl) cyclo-butyl / butylamine hydrochloride; N, N-dimethyl-1- / 1- (4-chlorophenyl) -cyclobutyl / butylamine hydrochloride; 1- / T- (3,4-dichlorophenyl) cyclobutyl / “butylamine hydrochloride; N-methyl-1- / 1- (3,4-dichlorophenyl) -10 cyclobutyl / butylamine hydrochloride; N, N-dimethyl-1- / 1- (3,4-dichlorophenyl) -cyclobutyl / butylamine hydrochloride; 1- / 1- (4-biphënylyl) cyclobutyl / butylamine hydrochloride; N, N-dimethyl ~ 1- / 1- (4-biphënylyl) -c- cyclobutyl ^ / butylamine hydrochloride; 1- / T- (4-chloro-3-fluorophenyl) cyclo-butyl / butylamine hydrochloride; N-formyl-1- / T- (4-chloro-3-fluorophenyl) cyclobutyl / -t butylamine; 1- / 1- (3-chloro-4-methylphenyl) cyclo-butyl7butylamine hydrochloride; N-formyl-1- / 1-phenylcyclobutyl / butylamine; 1- / T- (3-trifluoromethylphenyl) cyclo-butyl / butyamine hydrochloride? 1- / 1- (naphth-2-yl) cyclobutyl / butylamine hydrochloride; 1- / T- (6-chloronapht-2-yl) cyclobutyl / butylamine; N-methyl-1- / 1- (4-chlorophenyl) cyclo-butyl / -2-methylpropylamine hydrochloride; 1- / 1- (4-chlorophenyl) cyclobutyl / -pentylamine hydrochloride;

N-methyl-1- / 1- (4-chlorophenyl) cyclo hydrochloride - "> M

butyl / pentylamine; N, N-dimethyl-1- / 1-phenylcyclobutyl / -3-35 methylbutylamine hydrochloride; 1- / 1- (4-chlorophenyl) cyclobutyl / -3-methylbutylamine hydrochloride; / 24 N-me thy1-1- / 1- (4-chlorophenyl) cyclo-butyl / -3-methylbutylamine hydrochloride; N / N-dimethyl-1- / 1 (4-ch.lorophenyl) -cyclobutyl7-3-methylbutylamine hydrochloride; N-formyl-1- / T- (4-chlorophenyl) cyclobutyl / -3-methyl-butylamine; NfN-dimöthyl-1-d / 1 ”(3,4-dichlorophenyl) -cyclobutyl / -3-methylbutylamine hydrochloride; N-methyl-1- / 1- (naphth-2-yl) cyclobutyl / -10 3-methylbutylamine hydrochloride; N-methyl-1- / 1- (3,4-dimethylphenyl) -cyclobutyl / -3-methylbutylamine hydrochloride; / 1- (4-chlorophenyl) cyclobutyl / (cyclo-i propy1) methylamine hydrochloride; N-methyl- / T- (4-chlorophenyl) cyclobutyl / - - (cyclopentyl) methylamine hydrochloride; / 1- (4-chlorophenyl) cyclobutyl / (cyclohexyl) methylamine hydrochloride; N-methyl- / T- (4-chlorophenyl) cyclobutyl / 20 - (cyclohexyl) methylamine hydrochloride; / 1- (3,4-dichlorophenyl) cyclobutyl / (cyclohexyl) methylamine hydrochloride; N-methyl- / T- (3,4-dichlorophenyl) cyclobutyl / (cyclohexyl) methylamine hydrochloride; / T- (4-chlorophenyl) cyclobutyl / (cyclo-heptyl) methylamine hydrochloride; 1- / 1- (4-chlorophenyl) cyclobutyl / -2-cyclopropylethylamine hydrochloride; N, N-dimethyl-1- / 1- (4-chlorophenyl) cyclo-butyl / -2-cyclohexylethylamine hydrochloride; ¢ (- / 1- (4-chlorophenyl) cyclobutyl / benzylamine hydrochloride; N-methyl-tfr / 1- (4-chlorophenyl) cyclobutyl / ben zyamine hydrochloride; 1- / T- ( 4-chloro-2-fluorophenyl) cyclobutyl / butylamine; N, N hydrochloride, dimethyl-1- / 1- (4-chloro-2-fluoro- // phenyl) cyclobutyl / butylamine; λ 25 hydrochloride 1 - ^ / 1- (3,4-dichlorophenyl) cyclobutyl / -methyl ^ -propylamine; N, N-dimethyl-1- (H) hydrochloride (3,4-dichlorophenyl) -cyclobutyl / methyl 1 ^ .- propylamine; N, N-dimethy1-2- / 1- (4-iodophenyl) cyclobuty1 / ethylamine hydrochloride; N-ethyl-1- (1- (3,4-dichlorophenyl) cyclobuty1 / ethylamine hydrochloride; N, N-diethyl-1- / T- (3,4-dichlorophenyl) -10 cyclobuty1 / 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.

15 All melting and boiling points are expressed.

= in degrees Celsius.

Example 1

A solution of 3,4-dichlorobenzyl cyanide (25 g) and 1,3-dibromopropane (15 ml) in dry dimethyl sulfoxy-20 (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 hours, then 8 ml of propan-2-ol are added dropwise, followed by 110 ml of water. The mixture is filtered through diatomaceous earth supplied under the registered trademark CELITE and wash the solid residue with ether. The ethereal layer is separated and washed with water, dried and evaporated. 1- (3,4-Dichlorophenyl) -1-30 cyclobutanecarbonitrile (m.p. 108-120 ° C at 0.15 mm Hg) is isolated by distillation. This procedure is a variant of - that described by Butler and Pollatz (J. Org. Chem., Vol. 36, n °?, 1971, p.1308).

1- (3,4-dichlorophenyl) -1-cyclobutane-35 carbonitrile prepared as described above (21.7 g) is dissolved in dry ether (50 ml) and the solution is added under nitrogen, to the reaction product of methyl bromide h 26 gas on magnesium turnings (3.9 g) in dry ether (150 ml). The mixture is stirred at room temperature for 2 hours, then at reflux for two hours. Crushed ice is added, followed by 100 ml of concentrated hydrochloric acid, and the mixture is heated at reflux for two hours. The ethereal layer is separated and washed with water and using an aqueous solution of sodium bicarbonate, dried and evaporated. 1-Acety1-1- (3,4-dichlorophenyl) cyclobutane (eb. 108-110 ° 10 to 0.2 mm Hg) is isolated by distillation.

9.1 g of 1-acetyl-1- (3,4-dichlorophenyl) -cyclobutane prepared as described above, 6.5 ml of formamide and 3 ml of 98% formic acid are heated to 180 °. C for 16 hours, thereby obtaining N-formyl-1- / T- (3,4-dichloro-phenyl) cyclobutyl / ethylamine. 20 ml of concentrated hydrochloric acid are added and the mixture is heated at reflux for 3 hours. 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 / ethylamine (bp 112-118 ° at 0.02 mm Hg) 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 chlor-hydrate (mp 185-195 ° C). (Formula (I): n = 0; R = Me; R2, R3 and R4 = H; R (. = 4-Cl; Rg = 3-C1).

Example the

The preparation of N-formyl-1- / 1- (3,4-dichlorophenyl) cyclobutyl / ethylamine (mp 124-125 ° C) is repeated (Example 1 (a) Formula (X): n = 0; = Me; R3 = H 'IR. = CHO; R, - = 4-C1 and R, - = 3-Cl) described above and L- 4 5 6 is isolated the product by cooling the reaction mixture and collecting the solid product by filtration. Then; 35 formamide is hydrolyzed using hydrochloric acid i concentrated in denatured alcohol, thereby obtaining 1- / ~ 1- (3,4-dichlorophenyl) cyclobutyl / -! / a 27 ethylamine.

By operating as described in example 1a above, the following compounds are prepared. The hydrolysis conditions of the formamides isolated by appropriate procedures are indicated in the notes.

r— ^ CHR-jNH2.HCl - —I 1 1-1 10 Example- R, Rc R <- eb (free base) F of Note pie 15 6 chlor_ _____ _ hydrate __

1 (b) methyl Cl H 107 ° / 1.2 min of Hg 138-139 ° A 1 (c) n-butyl Cl H '138-139 ° B

15 1 (d) methyl I H 205-207 ° C

1 (e) methyl Cl CF3 216-217 ° D

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

C. Concentrated HCl / dimethyl ether of diethylene glycol (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 37-40% aqueous formaldehyde solution are added and the solution is heated to 85-95 ° C for five hours. The solution is evaporated to dryness, the residue is acidified with concentrated hydrochloric acid and the water is removed by repeated addition of propan-2-ol followed by evaporation in vacuo. N, N-dimethyl-1- / T- (3,4-dichlo-rophenyl) cyclobutyl / ethylamine hydrochloride crystals are isolated (Mp = 211-213 ° C) (Formula (I) 35 n = 0; R1 = Me; R2 = H; R3, R4 = Me; R5 = 4-C1; Rß = 3-Cl).

By operating as described above, the compounds of Examples 1 (b) and 1 (d) are converted into the compounds indicated 28! below.

jj — λ CHR ^ NM ^ .HCl 'rS-Hl 1 5

Example Substance R. R- R ,. F. from eb. of the starting chlor- free base _ _ _ _ _ hydrate _ 2 (a) 1 (b) methyl Cl H 98-100 ° / 0.5 irm 10 2 (b) 1 (d) methyl I H 260-261 °

Example 3

By operating as described above in Examples - 1 and 2, N, N-dimethyl-1- / T- (4-biphenylyl) cyclobutyl / ethylamine hydrochloride is prepared (M = 196-197 ° C) ( Formula (I) sn - 0; R1 = Me; R2 = H; R3, R4 = Me;

Rg - 4-phenyl and Rg = H).

Example 4

15 g of 1-acetyl-1- (3,4-dichlorophenyl) -cyclobutane prepared as described in Example 1, 47.5 ml of 20 N-methylformamide, 10.3 ml of 98% formic acid are mixed. % and 1.5 d ml of a 25% aqueous methylamine solution, and the mixture is heated with stirring at 170-180 ° for eight hours. We cool! the mixture and extracted with ether. The ether extract is washed, dried and evaporated, thereby obtaining a light yellow oil which is heated to reflux with 50 ml of concentrated hydrochloric acid for two hours. 50 ml of denatured alcohol are added and the mixture is heated at reflux for sixteen hours. The mixture is then cooled to 0 ° C, the white precipitate is collected by filtration, washed with acetone and dried. The product, the

- N-methyl-l- / l- (3,4-dichlorophenyl) cyclo-butyl / ethylamine hydrochloride, has a melting point of 254 to 256 ° C

fi *** 1 * (Formula (I): n = 0; R ^ = Me; R2 = H; R ^ = Me; R ^ = H;

Rc = 4-C1 and Rr = 3-C1.

I b 6 I 35 Operating as described above, the following compounds of formula (I) are prepared: Îr \ CHR-.NHMe.HCl 29 \ v / r - 5 6

Example R. Rj- Rg boiling point melting point Note _ _ __ _ of the amine_ hydrochloride _ 4 (a) Me Cl H 98-100 '° / 0.15 mm 240-241 ° 4 (b) Ms H Cl 269-272 ° 10 4 (c) Ms Br H 96-98 ° / 0fl irm 4 (d) Me H Br 251-255 ° 4 (e) Ms CF3 H 219-221 ° 4 (f) Me H CF3 225-228 ° 4 (g) Me - (CH = Œ) 2- 254-257 ° 15 · 4 (h) Ife Cl CF3 198-200 ° 4 (i) Et Cl H 238-240 °

4 (j) Pr Cl H 228-229 ° A

4 (k) Bu Cl H 152-153 ° A

4 (1) Ms I H 242-243 ° 20 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 mm Hg until 180 ml of water have been collected.

The residue is brought to 140 ° C. and 10.4 g of 1-acetyl-30 1- (4-chlorophenyl) cyclobutane, prepared in a similar manner to that described in Example 1 for 1-acetyl, are added. -1- (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 180-200 ° C for 16 hours. The mixture is distilled until an internal temperature of 170 ° C is obtained, and this temperature is maintained for two hours. Volatile substances, if present, are removed 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 hours. 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 ether extract is dried which, by evaporation, gives a residue which is treated with an aqueous hydrochloric acid solution, thus obtaining N-ethyl-1- / l- hydrochloride (4- chlorophenyl) -cyclobutyl / -ethylamine (F = 203-205 ° C) (Formula (I): n = 0; R ^ = Me; R2 = H; R3 = Et; R4 = H; R5 = 4-Cl; Rg = H).

Example 6 <v

15 g of 1- (4-chlorophenyl) -1-cyclobutane-15 carbonitrile (prepared in a similar manner to 1- (3,4-I: dichlorophenyl) cyclobutanecarbonitrile of Example 1) are added to s! 50 ml of dry ether to the reaction product between 3.18 g i | „Of magnesium turnings and 15.99 g of propyl bromide in 5.0 ml of dry ether. The ether is replaced with tetra-hydrofuran and the mixture is heated at reflux for eighteen hours, with stirring. The mixture is cooled and ice added, followed by concentrated hydrochloric acid (52 ml). The resulting mixture is stirred at reflux for ten hours, and extracted with ether. The ethereal extract provides a residue from which 1-butyryl- 1- (4-chlorophenyl) cyclobutane (eg 106-108β / 0.3 mm Hg) is distilled.

A mixture of the ketone prepared as described above (21 g) and 98% formic acid (6 ml) is added over 1.5 hours to 15 ml of formamide at 160 ° C. Once the ad-. ~ 30 dition finished, the temperature is brought to a value of '180 to 185 ° C and maintained between these limits for 5 hours. The mixture is cooled and extracted with chlo-! form, which gives a thick gum which, when heated with petroleum ether (eb. 60-80 °), gives a colorless solid product which, on recrystallization from petroleum ether (eb 60-80 °) provides N-formyl-1- d / 1- (4-chlorophenyl) cyclobutyl / butylamine (F = from 97.5 to 1 / 6- 'd "31 98.5 ° C) ( Formula (I): n = 0; R ^ = propyl; R2 = H; R3 = H; R4 = CHO; R5 = 4-Cl; Rß = H).

Example 7 1

A solution of 35.2 g of 1- (3,4-dichlorophenyl) -1-5 cyclobutanecarbonitrile prepared as described in Example 1 in 100 ml of ether is added to a solution of propyl magnesium 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 with dry toluene and the mixture is heated under reflux for one hour.

200 ml of water are added, then 120 ml of concentrated hydrochloric acid, and the mixture is heated under reflux for one hour. The reaction mixture is extracted with ether and, after washing and drying, the extract provides a residue from which 1-butyryl-1- (3,4-dichlorophé-D nyl) cyclobutane is obtained (eb. 120 -128 ° C 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 20 for five hours. 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 fifteen hours. The mixture is extracted with ether and, after evaporation, a thick oil is obtained which, by crystallization. in petroleum ether (bp 60-80 ° C), gives N-foxmyl-1- / l- (3,4-dichlorophenyl) cyclobutyl / butylamine having a melting point of 103-105 ° C (Formula (I): n = 0; R. ^ = propyl; R2 = H; R ^ = H; R4 = CHO; R5 = 4-C1 and Rg = 3-CI).

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

AT

v

CHR ^ NHCHO

j I 32

Rs --1 1 5 · "6

Example R! H ^ 6 F <° C> 7 (a) isobutyl Cl H 110-112 ° 7 (b) propyl Cl F 115-116 ° 7 (c) phenyl Cl H 94-96 ° 10 7 (d) propyl HH 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. dry tetrahydrofuran, under nitrogen. The mixture is heated at reflux for five hours, then cooled. 15 ml of water are added, then 3 ml of 10% sodium hydroxide solution and the mixture is filtered on earth. diamines (supplied under the registered trademark CELITE) The product is extracted with ether, extracted in return with 5N hydrochloric acid, the aqueous layer is basified and extracted. The ethereal extract provides an oil which is dissolved in 5 ml of propan-2-ol and concentrated hydrochloric acid is added to pH 2. By evaporation of the resulting solution a white solid substance is obtained which is collected, washed with acetone and dried. The product is N-methyl-1- / T- (3,4-di-chlorophenyl) cyclobutyl / butylamine hydrochloride and has a point 234-235 ° C (Formula (I): n = 0; R = propyl; R £ = H; ύ 30 R3 = H; R4 = Me; Rg = 4-Cl and Rg = 3-C1).

By operating in a similar manner to that described above, the compounds appearing in the following table are prepared: jj ^ CHR-.NHMe.HCl 33 * 5-f> U | 1 * \ /! * - * 5 Example R ^ Rg melting point (° C) 8 (a) phenyl Cl H 275-278 ° 8 (b) propyl Cl H 223-228 °

Example 9

The product of Example 7 (10 g) in solution 10 in ether (50 ml) is added to a 70% toluene solution of sodium bis- (2-methoxyethoxy) aluminum hydride supplied under the trademark Red -al (40 ml) at a temperature of 25 to 30 ° C. The mixture is stirred at this temperature for four hours. 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 inter-face which 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 ( Mp 233-236 ° C). White solid products are brought together; recrystallized from propan-2-ol, thus obtaining N-methyl-1- / l- (3,4-di-chlorophenyl) cyclobutyl / butylamine hydrochloride (M = 236-237 ° C) (Formula (I) : n = 0; Rj * propyl; R2 = H; R ^ = H; R ^ = Me; R ^ = * 30 4-C1; and Rg = 3-Cl).

_: By operating as described above, the following i 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 formulated compound. As the size of the group R ^ increases, the hydrochlorides of the compounds sought become less / soluble in the aqueous phase and more soluble in the phase 34 organic phase, so that the mode must be varied appropriately. isolation, as is obvious for technical specialists.

r6

Example R ^ R ^ Rg Melting point

9 (a) isopropyl Cl H 257-259 ° C

10 9 (b) sec-butyl Cl H 209-212eC

9 (c) isobutyl Cl H 225-233 ° C

5 9 (d) cyclopentyle Cl H 252-256 ° C

=. 9 (e) n-hexyl Cl H 117-118 ° C

9 (f) 4-methoxyphenyl Cl H 264-266 ° C

15 9 (g) 3-Methoxyphenyl Cl H 254-255 ° C

9 (h) 2-methoxyphenyl ClH 149-153 ° C

9 (i) cyclohexyl Cl H 170-172 ° C

£ 9 (j) isobutyle “(CH = CH) - 256-259 ° C

9 (k) cyclohexyl Cl Cl 223-224 ° C

20 9 (1) isobutyle Me Me (1)

9 (m) propyle OMe H 173 “175 ° C

9 (n) methyl phenyl H 116-118 ° C

(1) Boiling point of the free base} 150 ° C at 1.0 min of Hg Example 10 The product of Example 7 (4 g) is mixed with dimethyl ether of ethylene glycol (25 ml ), water (10ml) and concentrated hydrochloric acid (10ml) and heated to reflux for nine hours. 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 chlorine acid are added! concentrated water. The solvent is evaporated in vacuo. It is again dissolved in denatured alcohol and evaporated in vacuo, thus obtaining a gum which solidifies when. heating 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 1- / 1- (3,4-dichlorophenyl-cyclobutyl / butylamine hydrochloride (Formula (I): n = O; R ^ = propyl; R2 = H; R ^, R ^ = H; R ^ - 4-Cl and Rg = 3-Cl). 5 Operating as described above, the following compounds are prepared: As the size of the group R ^ increases, the hydrochlorides of the compounds sought become less soluble in the aqueous phase and more soluble in the organic phase, so that appropriate modifications to the mode of isolation are required, as is evident to those skilled in the art.

, -y CHR1NH2.HC1; - ’pb

Example R1 R5 Rg Melting point (° C) * lû (a) isopropyl Cl H 200-202 10 (b) sec-butyl Cl H 178-179 20 10 (c) isobutyl Cl H 163-165 10 (d) cyclopentyl Cl H 185-210 (dec.) 10 (e) phenyl Cl H 271-276 10 (f). 4-methoxyphenyl Cl H 214-219 10 (g) cyclohexyl Cl H 206-210 25 10 (h) isobutyl HH 210-212 10 (i) cyclopropyl Cl H 204-206 10 (j) propyl Ph H 235-236 10 ( k) propyl Me Cl 214-217 10 (1) propyl - (CH = CH) 2- 157-159 * 30 10 (m) cycloheptyl Cl H 156-162 10 (n) cyclohexyl Cl Cl 215 t 10 (p) methyl Cl F 215-217 10 (q) propyle OMe H 178-179 10 (r) propyle Cl F 186-188 35 10 (s) propyle Cl H 174-175 10 (t) cyclohexylmethyl Cl H 148-150 / Λ 36

Example R ^ R ,. Rg Melting point (° C) 10 (u) cyc} .opropylmethyl Cl H 184-185 10 (v) propyl -CH = CH-CC1 = CH- (a) 10 (w) propyl H CF3 126-128 5 10 (x) 4-fluorophenyl Cl H 279 10 (y) (b) methyl -C = C-CH = CH- 248-262

HQ) CH

rib-ek (a) boiling point of the free base: 168 ° C / 0.05 mm of Hg (b) the dimethyl ether of diethylene glycol is replaced: with dimethyl ether of ethylene glycol.

j By operating as described above, respectively (10) (2), 10 (aa) and 10 (bb) are prepared as examples: 1- / Γ- (4-chloro-2-fluorophenyl-cyclobutyl / butylamine (eb. 99 ° C / 0.05 mm) (Formula (I—; n = 0; = propyl; ï R2, R3 and R4 = H; R5 = 4-Cl; Rß = 2-F) ; 1- / 1- (2-fluorophenyl) cyclobutyl / -0 butylamine hydrochloride (F = 175-177 ° C) (Formula (I): n = O; R ^ = propyl; R2, Rg t Rg = H and Rg = 2-F); and j 1- / T- (4-chloro-2-methyl) cyclo! butyl / butylamine hydrochloride (F = 188-190 ° C) (Formula (I): n = 0; j R ^ = propyl; R2, R ^ and R ^ = H; R5 = 4-Cl and Rg = 2-Me).

! Example 11 i · The product of Example 110 (c) (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 eighteen hours 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 5N sodium hydroxide solution and the product is extracted with ether. By evaporation of the ether an oil is obtained! pale yellow which is dissolved in a mixture of propan-2-ol (4 ml) and ether (20 ml), and 2 y ml of concentrated hydrochloric acid are added dropwise. The solution I is evaporated and the residue is dissolved several times in ethanol I and evaporated to dryness, thus obtaining a gum which is sorted! 37 ture with petroleum ether (eb. 60-80 °), which gives a yellow solid product which is recrystallized from acetone. The product is N, N-dimethyl- 1- / 1- (4-chlorophenyl) cyclobutyl / -3-methylbutylamine hydrochloride (M = 195-197 ° C) (Formula (I): n = 0; = isobutyl ; = H; R3, R4 = Me; R5 = 4-C1; Rg = H).

By operating as described above, the following compounds of formula (I) are prepared: 10 CHR ^ NMe ^ HCl

Example Substance Point de de R, Ej Rg fusion (° C) - _ start _ _ _ _ 11 (a) 10- (h) isobutyle HH 195-198 11 (b) 10 (j) propyle Ph H 194 -196 20 11 (c) 10 (n) cyclohexyl Cl Cl 227-228 11 (d) 10 (q) propyle OMe H 187-188 11 (e) 10 (s) propyle Cl H 194-196 11 (f) 10 (t) Methyl1 Cl H 194-196 11 (g) 10 (u) CyCmethyl1 C1 H 165-167 25 11 (h) 10 (v) propyl -CH = Œ-CC1 = CH- (a) 11 (i) - isobutyl Cl Cl 225-226 11 (j) 10 (x) 4-fluorophenyl Cl H 234 11 (k) - isopro propyl- H 211-213 pyle 30 (a) boiling point of free base 250 ° C / 0 , 05nmdeHg.

* Example 11 (1) = By operating as described above, the * hydrochloride of N, N-dimethyl-l- / l- (4-chloro-2-fluorophenyl) cyclobutyl / butylamine is prepared (F = 183 °) (Formula (I): n = 0; 35 R ^ = propyl; R2 = R3, R ^ = Me; R5 = 4-Cl; R ^ = 2-F).

Example 12

The product of Example 7 (8.3 g), dimethyl ether of diethylene glycol (50 ml), water (20 ml) / 38 and concentrated hydrochloric acid (20 ml) are mixed and heated at reflux for sixteen hours. 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 formaldehyde is added. We heat the mixture! reflux for three hours, then concentrated hydrochloric acid (10 ml) and propan-2-ol (10 ml) are added. By dry evaporation, N, N-dimethyl-l- / ï- (3,4-dichlorophenyl) cyclobutyl / butylamine hydrochloride (M = 195-196 °) is obtained in the form of a white solid product ( Formula (I) n = 0; R ^ = propyl; R2 = H; R ^, R ^ = Me; R5 = 4-Cl and R6 = 3-C1).

Example 13 * 37.6 g of 1- (4-chlorophenyl) -1-cyclobutane carbonitrile (prepared in the same manner as 1- (3,4-K dichlorophenyl) -1-cyclobutanecarbonitrile described in the example) are added. ple 1) to a solution of 32.4 g of potassium hydroxide I in 370 ml of diethylene glycol, and the mixture is heated at reflux for 3.5 hours. The reaction mixture is poured onto a mixture of ice and water and the resulting solution is washed with ether. The aqueous layer I is added to a mixture of concentrated hydrochloric acid (100 ml) and i! In ice, the resulting precipitate is collected from 1- (4- (chlorophenyl) -1-cyclobutanecarboxylic acid (mp 86-88 °) which 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 two hours and water is added. The mixture is filtered on diatomaceous earth (CELITE - RTM) and the product is extracted with ether, i. 35 After washing with water and drying, the ether is evaporated, thus obtaining a residue which is recrystallized in petroleum ether (eb. 60-80 °). The product is 1- / 1- (4- 39 (chlorophenyl) cyclobutyl / methyl alcohol (P = 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-toluenesulfor> yl chloride (60 g) in pyridine ( 100 ml) cooled on ice. The temperature is allowed to rise to ambient temperature and to remain there for eighteen hours. 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 concentrated hydrochloric acid .

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 in a steam bath for eighteen hours. The mixture is poured into water "and extracted with ether. After washing and drying, the ether is evaporated, obtaining a solid residue of 2- / 1- (4- ^ chlorophenyl) cyclobutyl / acetonitrile (Mp 63-65 ° C).

A solution of di-isopropylamine (16.5 g) in dry tetrahydrofuran (50 ml) is stirred under nitrogen at a temperature of 0 ° C, and a 1.6 M solution of n-butyllithium in hexane (100 ml). We . stir the reaction mixture for 30 minutes, then cool to -78 ° C. A solution of 2- / 1- (4-chlorophenyl) cyclobutyl / acetonitrile (9.5 g) prepared as described above is added dropwise in dry tetrahydrofuran (25 ml). The temperature of the mixture is allowed to rise to 0 ° C, and the mixture is stirred for ten minutes before adding a solution of methyl iodide (10 ml) in 30 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 hours, then 50 ml of water is 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, three times with 5N hydrochloric acid, three times with water, dried and evaporated, which gives an oil which solidifies and which is recrystallized from denatured alcohol, thus obtaining 2- / T- (4-ch1orophény1) cyclobutyl / -2-methylpropionitrile 5 (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 hours. The reaction mixture is cooled, poured into 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 ether 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 °), which provides c 2- / T- (4-chlorophenyl) cyclobutyl7-2-methylpropionic acid (mp 95-110 ° C).

; 10 ml of oxalyl chloride are added to 2 g of the acid prepared as described above and, after the initial effervescen-20 has subsided, the mixture is heated at reflux for one hour. The excess oxal 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- / Γ- ί (4-chloropheny1) cyclobutyl / -2-methylpropionamide.

] I The amide (1.34 g) prepared above is dissolved in a mixture of acetonitrile (8 ml) and water (8 ml), 3.4 g of iodosobenzene bistrifluoroacetate are added and the mixture is stirred _ '30 the mixture at room temperature for 5.5 hours.

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 it is extracted with other ali-35 quotes portions of ether, dried and evaporated, which provides an oil. The oil is dissolved in petroleum ether at (eb. 80-100 °) and dry hydrogen chloride 41 is passed through the solution. 1- / T- (4-chlorophenyl) cyclobutyl / -1-inethylethylamine hydrochloride (M = 257-259 °) is collected by filtration (Formula (I): n = 0; R ^, 1 * 2 = Me; R3, R4 = H; R5 = 4-Cl; Rg = H).

5 Example 14

The product of Example 4 (h) (3.4 g) is mixed with anhydrous sodium formate (0.72 g), 98% formic acid (10 ml) and an aqueous formaldehyde solution to 37-40% (5 ml), and the mixture is heated to a temperature of 85-95 ° C for sixteen hours. 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 sulfate. Chlor-15 ride dry hydrogen gas is bubbled into the ethereal extract, which * · gives a white precipitate of N, N-dimethyl-1- / 1- (4-chloro-3-trifluoromethylphenyl) hydrochloride. cyclobutyl / ethyl-i amine (F = 246-247 ° C) (Formula (I): n = 0; R1 = Me; R2 = H; R-, R. = Me; Rc = 4-Cl and R, = 3-CF-).

3 4 5 6 3 20 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 Solvent Acid Base Melting Point

____ salt, ° C

15 (a) 10 (s) citric aqueous acetone 158-160 15 (b) 10 (s) maleic ether 155-157 30 15 (c) 10 (s) succinic ether 152-155 15 (d) 2 L (+) tartaric denatured alcohol 150-153 15 (e) Note (a) citric ether / methanol 163-164 (dec) (a) The base is 1- / T- (3,4-dimethylphenyl) cyclobutyl / -3- methylbutylamine prepared in a similar way to that s.

35 described in Example 10.

Example 16 A solution of bromobenzene (15.7 g) in ether l · 42 (50 ml) is added dropwise, while cooling, to turnings of magnesium (2.4 g) under nitrogen. A solution of 1- (4-chlorophenyl) -cyclobutanecarbonitrile (19.1 g) prepared in a similar manner to that described in Example 5 1 for 1- (3,4-dichlorophenyl) cyclobutane carbonitrile in 50 ml of ether is added, and the ether is replaced with dry toluene (130 ml). The reaction mixture is heated on a steam bath for one hour. 20 ml of the resulting solution are added to a solution of 1 g of sodium borohydride in 60 ml of ethylene glycol dimethyl ether and the mixture is stirred for 1.5 hours.

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, thereby 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 is obtained; . ^ - / 1- (4-chlorophenyl) cyclobutyl / benzylamine hydrochloride (P = 277-279 ° C) (Formula (I): n = 0; = Ph, - R2 = H; 20 R3, R4 = H ; R5 = 4-C1; Rß = H).

Example 17 I 62 ml of methyl formate i are added dropwise to 85.5 ml of isopropylamine, with stirring at a speed which makes it possible to maintain a gentle reflux. Stirring is continued for two hours after the addition. Methanol is distilled at 100 ° C and N-isopropylformamide (eb 108-109 ° C / 25 mm Hg) is obtained by distillation.

10.4 g of 1-acetyl-1- (4-chlorophenyl) cyclobutane (prepared as described in Example 1 for 1-acetyl-1-1 (3,4-dichlorophenyl) cyclobutane) are added and 5 ml 98% formic acid at 43.5 g of N-isopropylformamide (43.5 g) and the mixture is heated at 180 ° C for 4 hours. The excess starting material is distilled under reduced pressure (20 mm Hg), which leaves a viscous residue which is heated to reflux with 30 ml of concentrated hydrochloric acid for six hours. The reaction mixture is washed with ether until a colorless solution is obtained. The aqueous phase is basified, 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 petroleum ether (bp 62-68 ° C), which gives N-isopropyl- 1- / 1- (4-chlorophenyl) hydrochloride cyclobutyl / ethylamine (P = 170-174 ° C) (Formula (X): n = 0; R ^ = Me; R2 = H; R ^ = isopropyl; R4 = H; R5 = 4-C1; Rg = H) .

Example 18 7.0 g of 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane (prepared as described in Example 1) is added slowly 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

* five hours. The mixture is stirred and heated to 160-165 ° C

15 for sixteen hours. After cooling, the mixture is poured into 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 ethereal extract is washed with water, dried, and hydrogen chloride gas 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 Nl- / l- (3, 4-dichlorophenyl) cyclobutyl / ethyl pyrrolidine hydrochloride (F = 233-25 235 ° C) (Formula (I) ; n = 0; = Me; .R2 = H; R3 and R4, apparently and with the nitrogen atom to which they are attached, form a pyrrolidine nucleus; R ^ = 4-C1 and Rg = 3-C1 ). Example 19

10.5 g of 1- (4-chlorophenyl) -1-cyclo-butane carboxylic acid (prepared as described in Example 13) are heated to reflux with 20 ml of thionyl chloride for 2.5 hours. . The excess thionyl chloride is evaporated and the acid chloride of the above acid is distilled (bp = 82-96 ° / 0.2 mm Hg).

A solution of 23.0 g of the 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 · 44 of ethyl bromide in dry tetrahydrofuran, at a temperature of -70 to -60 ° C. The temperature is maintained at -60 ° C for one hour, then allowed to come to 0 ° C. 50 ml of water are added, followed by 150 ml of 5N hydrochloric acid, 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 1-propionyl-1- (4-chlorophenyl) cyclobutane is obtained by distillation (eb. 96-104 ° C / 0.25 mm). The ketone obtained above is converted into N, N-dimethyl-l- / T- (4-chlorophenyl) cyclobutyl / pro! pylamine (F = 213-215 ° C) by operating as described in example-! pie 12 (Formula (I): n = 0; - And; R2 = H; R3, = Me; R5 = 4-C1; Rg = H).

Example 20 i 61 g of 1-acetyl-1- (4-chlorophenyl) cyclobutane (prepared as described in Example 1) for 1-acetyl-1- (3,4-) are introduced into an autoclave. dichlorophenyl) cyclobutane), 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 bars for ten hours. The reaction mixture is filtered over charcoal and the solids are washed with absolute alcohol. Solvants are removed by evaporation and 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- / ï- (4-chlorophenyl) -, 5 30 cyclobutyl / ethylamine (Formula (I): n = 0 ; R ^ = Me; R2 = H; R3 = Me; R4 = H; R5 = 4-C1 and Rg = 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 / ethyl I amine (prepared by treating the product of Example 1 with I an aqueous solution of sodium hydroxide) in 30 ml of glacial acetic acid. The mixture is heated to f 45 95-100 ° C for sixteen hours, then cooled. An aqueous solution of sodium hydroxide is added and the reaction mixture is extracted with ether. The ether-extract is shaken with 5N hydrochloric acid, the aqueous layer 5 is washed with ether, basified and extracted with ether. Gaseous hydrogen chloride is passed through the ether extract which is evaporated to dryness. By trituration with acetone, N-ethyl-1- / T- (3,4-dichlorophenyl) cyclobutyl / ethylamine hydrochloride is obtained (P = 211-212eC) (For-10 mule (I): n = 0; R = Me; R- = H; R = Et; R. = H; R ^ =; 4-Cl and Rß = 3-C1) „

Example 22

Heated to 40-45 ° C, for 30 minutes, a mixture of 0.5 g of N-ethyl.li- / Î- (3f 4-dichlorophenyl) cyclobutyl / -15 ethylamine (prepared by treating the product of 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-20 ethyl-1- / l- (3,4-diohlorophenyl) cyclobutyl / ethylamine in the form of an oil .

This oil is dissolved in 10 ml of tetrahydrofuran and ne 0.5 ml of borane-dimethyl sulfide complex is added dropwise. The reaction mixture is stirred at room temperature for two hours, then brought to 35-40 ° C for 30 minutes. 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 î. 30 ether, N, N-diethyl-1- / T- (3,4-dichloropheny I) cyclobutyl / ethylamine hydrochloride is obtained (F = 199-201 ° C) (Formula (I) .: n - - 0; R ^ = Me; R2 = H; R3, R4 = Et; R5 = 4-Cl and R5 = 3-C1).

Example 23 A mixture of 2.2 g of 1-acetyl-1- (3,4-dichlorophenyl) cyclo- / 46 butane (prepared as described in Example 1) is stirred at room temperature for 4 days. 7 g of ammonium acetate, 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 ethereal extract is washed with water, dried and the ether is eliminated, this mistletoe leaves 1- / I- (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 hydrochloride is heated at reflux for 20 hours. hydroxylamine, 3.3 g of sodium acetate trihydrate, 15 Ä ml of denatured alcohol and 2 ml of water. The cooled reaction mixture is poured onto water and the oil is cooled. which separates, which gives a solid product guron re crystallizes from denatured alcohol, obtaining 1-acetyl-20 1- (3,4-dichlorophenyl) cyclobutane oxime (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 hydride and aluminum (0.9 g) in 50 ml of ether, under nitrogen. The mixture is heated at reflux for one hour and, after cooling, water is added, then an aqueous solution of potassium salt and sodium carbonate (20% tetrahydrate) (27 ml) and an aqueous solution 10% sodium hydroxide (6 ml). The reaction mixture is stirred for one hour, then extracted continuously with ether for eighteen hours. The ether extract is dried, dried, and the ether is 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 standard techniques as the compound of Example 1 in the form of its free base.

1 flr- 47

Example 25

200 ml of an IM solution of diisobutyl aluminum hydride in hexane, under nitrogen, are added to a solution of 31.4 g of 1-phenyl-1-cyclobutane carbonitrile in 100 5 ml of ether, at a temperature below -30 ° C. The temperature is kept below 0 ^ C for 30 minutes and 200 ml of 5N hydrochloric acid are added at a temperature of -10 ° C. The reaction mixture is washed with petroleum ether (bp 60-80 ° C), then it is brought to 40 ° C. The reaction mixture is extracted with petroleum ether (bp 60-80 ° C), the extract is dried and evaporated, thus obtaining 1-phenyl-1-cyclobutane-carbaldehyde 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 ε are added. of magnesium sulfate (dried over a flame, then cooled under nitrogen) to the reaction mixture which is left at room temperature for sixteen hours before being filtered. The toluene is then removed by evaporation and the residue is dissolved in 50 ml of ether. This solution was 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 hours 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 washings on a steam bath for one hour. After cooling, the reaction mixture is washed with ether and the aqueous layer is basified using an aqueous solution of sodium hydroxide. The reaction mixture is extracted with ether, the extract is dried and the ether is removed, thereby obtaining a residue from which N-methyl-1- (1-phenylcyclobutyl) butylamine is distilled (eb. 80 -86 ° / 0.1 mm Hg).

48

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-methyl-1- hydrochloride ( 1-phenylcyclo-5 butyl) butylamine (mp 196-197 ° C) (Formula (I): n = 0;

Rj = propyl; R2 = H; = Me; R4, R ,, and Rß = H).

Example 26

A solution of 8.0 g of 1- (3-chloro-5-methyl) -1-cyclobutane-carbonitrile in 40 ml of ether is added to a solution of propyl magnesium bromide / prepared by reacting 6.7 g of 1-bromopropane and 1.3 g of magnesium / in 80 ml of ether, and the mixture is heated at reflux for 2.5 hours. 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 one hour, 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- hydrochloride (3-chloro-5-methyl ) cyclobutyl7butylamine (mp 145-146 ° C).

The hydrochloride prepared as described above is shaken with ether and 5N sodium hydroxide solution, and the ethereal layer is evaporated to give the primary amine which is converted to N, N hydrochloride -dimethyl-1- / T- (3-chloro-5-methyl) cyclobutyl / butylamine (F = 148 ° C) (Formula (I): n = 0; = propyl; R2 = H; R3 and R ^ = Me ; Re- = 3-CL and R ^ = 5-Me), operating as described in Example 2.

30 Example 27

37.6 g of 1- (4-chlorophenyl) -1-cyclobutane carbonitrile (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 at reflux for 3.5 hours. The reaction mixture is poured onto a mixture of ice and water and the resulting solution L · 49 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 1- (4-chlorophenyl) -1-cyclo-butanecarboxylic acid (M = 86-88 ° C ), 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 tetra-10 hydrofuran (150 ml). The mixture is stirred at reflux for two hours and water is added. The mixture is filtered on diatomaceous earth (CELITE - RTM) and the product is extracted with ether. After washing with water and drying,. evaporate the ether, which gives a residue which is recrystallized from petroleum ether (bp 60-80 °). The product is * 1- / T- (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 pyri-20 dine is added dropwise to a solution of 60 g of p-toluenesulfonyl chloride in 100 ml of pyridine cooled on ice. The temperature is allowed to rise to ambient temperature and to be maintained there for 18 hours. A precipitate of 1- / T- (4-chlorophenyl) -25 cyclobutyl7 methyl p-toluenesulfonate (F = 99-100 ° C) 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 hours. 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-chlorophenyl) cyclobutyl / acetonitrile (m = 63-65 ° C).

20 g of the acetonitrile prepared above are dissolved in 120 ml of ether and the glutte 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 15 hours, then at reflux for a further 2 hours. 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, leaving a residue which, by distillation, gives 2- / 1- (4-chlorophenyl) cyclobutyl / ethyl-? amine (bp 119-121 ° C / 1.5 mm Hg).

6.9 g of ethylamine prepared as described above, 6.6 ml of 98% formic acid, 0.9 g of water and 9 ml are heated on a steam bath for 18 hours. 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 dichlorome-thane and a 5N sodium hydroxide solution and the aqueous layer is extracted by further adding dichlorome-thane. 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 'at 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- / T- (4-chlorophenyl) "cyclobutyl7ethylamine hydrochloride (F = 220 -222 ° C) (Formula (I): n = 1; R ^, R £ = H; R ^, R ^ = Me; R ^ = 4-Cl; Rg, R ^ and Rg = H). l By operating in a similar manner to that described above, the following compounds are prepared: h

U

f 51

AT

__v CH, CHJIMe5.HCl v-Of, r6 5 Example R Rfi Melting point of _ _ _ hydrochloride (° C) 27 (a) Cl Cl 218-220 27 (b) IH 263-265 27 (c) -CH = CH - CH = CH- 234-236 10 27 (d) N, N-dimethy 1-2- / 1- (4-chloro-2-fluorophenyl) cy- * clobutyl hydrochloride is prepared in a similar manner / ethylamine (mp 232-233 ° C (dec)).

? Example 28

In 12 ml of xylene, 12 g of 2- / 1- (4-chlorophenyl) cyclobutyl / ethylamine prepared as described in Example 27 are mixed, 12.4 g of 1,4-dibromobutane and 14.3 g of carbonate anhydrous sodium and the mixture is heated to.

reflux, with shaking, for sixteen hours. The mixture is cooled, filtered and the xylene is removed by evaporation. This mistletoe provides a residue which, by distillation, gives N-2- / T- (4-chlorophenyl) cyclobutyl / ethylpyrrolidine (eb.

148-150 ° / 1.5 mm Hg) (Formula (I): n = 1: R ^, R2 = H; R ^ and. R ^, together and with the nitrogen atom on which they are fixed forming a pyrrolidine nucleus; R ^ = 4-C1; Rg, • 25 R? and Rg = H).

In a similar manner to that described above, the following compounds are prepared which are isolated in the form of hydrochlorides. (i, _v CH „CH-N J .HCl;” °

Example Rc R, Melting point of the hydrochloride (° C) _ d b __ 28 (a) Cl Cl 213 35 28 (b) -CH = CH-CH = CH- 232-233

Example 29 / A solution of 30 g of 2- / l- (4-chlorophenyl) -52 cyclobutyl / acetonitrile (prepared as described in Example 27) in 100 ml of ether is added to the bromide reaction product. methyl gas and magnesium turnings (5.95 g) in 80 ml of ether. The mixture is heated at reflux for four hours. 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 10 combined ether extracts are washed with water, dried and evaporated to give a residue which is distilled twice, thus obtaining 1- / Ï- (4-chlorophenyl) cyclobuty3./-propane-2- : one (eb. 133-136 ° / 2.5 mm Hg).

* 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 an aqueous methyl amine solution at 25%, and the mixture is heated at reflux for 16 ^ hours. The mixture is poured onto water and extracted with dichloromethane. The extract is washed, dried and evaporated to give a residue which is heated to reflux with 10 ml of dilute hydrochloric acid for 6 hours. The mixture is evaporated to dryness and the residue is dried by adding and evaporating under vacuum several times a mixture of denatured alcohol / toluene. The solid residue is recrystallized from propan-2-ol, thus obtaining N-methyl-1-2- / 1- (4-chlorophenyl) cyclobutyl / - 1-methylethylamine hydrochloride (mp 193-194 ° C) (Formula (I): n = 1?

Rj, R2 * H; R3 = Me; R4 = H; R5 = 4-C1; Rg = H; R? = Me; , R8 = H) · f 30 Example 30

A mixture of 15 g of 1- / 1-l (4-chlorophenyl) cyclobuty ^ / propan-2-one prepared as described in Example 29 and 4 ml of 98% formic acid is added dropwise. ml of formamide at 160 ° C. The temperature is brought to 180 ° C and maintained at this level for ten hours. The mixture is cooled and diluted with water and extracted with dichloromethane. The extract is washed, dried and evaporated, which gives 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, gives 2- / T- (4-chlorophenyl) cyclobutyl / -l-methylethylamine (mp 105-107 ° C / 0 , 7 mm Hg).

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. 110 ml of ether are added and colorless crystals of 2- / 1- (4-chlorophenyl) cyclobutyV, -1-methylethylamine hydrochloride (M = 184-185 ° C) are collected (Formula (I): n = 1; 15 Rx, R2 = H; R3, R4 = H; R & = 4-C1; Rg = H; R? = Me and - R8 = H).

Example 31 c. 3.94 g of 2- / T- (4-chlorophenyl) cyclobutyl / -1-methylethylamine, prepared as described in Example 30, are mixed. 3.82 g of 1,4-dibromobutane, 4.4 g of carbonate anhydrous sodium and 30 ml of xylene, and heated to reflux for 16 hours. The mixture is cooled, filtered and evaporated, a residue is obtained which is distilled twice (eb. 130-132 ° / 0.5 mm Hg). The product of distillation 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 product is recrystallized. residue in ethyl acetate, thus obtaining N- ^ 2- / l- (4-chlorophenyl) cyclobutyl / -1-methyl ^ ethylpyrroli-dine hydrochloride (mp = 15-152 ° C). (Formula (I): n = 1; R ^, R2 = H; R ^ and R ^, together and with the nitrogen atom to which they are attached form a pyrrolidine ring; R, - = 4-Cl; R g = H; R? = Me; Rg = H).

Example 32 To 22 ml of formamide, at 160 ° C., 25 g of 1- / T- (4-chlorophenyl) cyclobutyl / propan-2-one prepared as described in Example 29 and 10 ml of acid are added. 98% formic.

/ to '54

The temperature is brought to 175 ° C and maintained at this level for sixteen hours. 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 (m.b. 40-60 ° C), thus obtaining N-formy 1-2- / 1- (4-chlorophenyl) cyclobutyjL / - 1-methylethyl-amine (mp 71-73 ° C).

11.06 g of N-formy1-2- / 1- (4-chlorophenyl) cyclobutyl / -1-methylethyl-Ι amine prepared as described above, with a mixture of acid, are heated at reflux for six hours. 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,. evaporates and distills, and 2- / T- (4-chlorophenyl) cyclobutyl7-1-methylethyl thylamine (mp 119-121 ° C at 0.8 mm Hg) is obtained. The amine (2.65 g) is dissolved in 15 ml of propan-2-ol and concentrated hydrochloric acid is added to pH 2. 110 ml of ether are added and the 2- / 1- (4-chlorophenyl) cyclo-butyl / -1-methylethylamine hydrochloride crystals (F = 184-185 ° C) (Formula (I) ï n = 1; R, R2 = H; R3, R ^ = H; R5 = 4-Cl; Rg = H; R? = Me and Rg = H).

25 Example 33

1.8 g of 2- / T- (4-chlorophenyl) cyclobutyl / -1-methylethylamine prepared as described in Example 32 are mixed with 4.5 ml of formic acid. 6 ml of a 37-40% aqueous formaldehyde solution are added and the mixture is heated ~ 30 first at 45-50 ° C for 30 minutes and then at reflux for two hours. 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! S / 55 and a white solid product is formed which is collected and recrystallized from ethyl acetate, thereby obtaining N, N- hydrochloride dimethyl-2- / l- (4-chlorophenyl) cyclo-butyl7 “1-methylethylamine (M = 108-110 ° C) (Formula (I): 5 n = 1; Rlf R2 = H; R3, R4 = Me; Rg = 4-Cl; Rß = H; R? = Me and Rg = H).

Example 34

35 ml of a 70% toluene solution of sodium bis (2-methoxyethoxy) aluminum hydride (supplied under the trade name Red-al) are added dropwise to a solution of 5 g of N-formy1-2- / 1- (4-chlorophenyl) cyclobutyl / -1-methyl-. ethylamine (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 is allowed to reach about 25 ° C, then the mixture is heated to reflux for two hours. 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 through the solution which precipitates a solid product which is recrystallized from propan-2-ol, thereby obtaining N-methyl-1-2- / 1- hydrochloride (4- chlorophenyl) -cyclobutyl / -l-methylethylamine (Formula (I): n = 1; Rlf R2 = H; R3 = H; R4 = Me; R5 = 4-Cl; Rg * = H; R? = Me and R8 = H) (mp 192-194 ° C).

30 Example 35

A solution in ether (80 ml) of 2- / T- (3,4-dichlorophenyl) cyclobutyl / acetonitrile (23 g), prepared in a similar manner to that described in Example 27 for 2, is added. - / 1- (4-chlorophenyl) cyclobutyl / acetonitrile 35 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.

56

The ether is removed and replaced with toluene, and the mixture is heated under reflux for one hour. 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 one hour and filtered through diatomaceous earth supplied under the registered trademark CELITE. The filtrate is extracted with dichloromethane and the extract is washed with water and using a solution of sodium bicarbonate and dried. The solvent is removed by evaporation and the residue is distilled, thus obtaining 1- / T- (3,4-dichloro-phenyl) cyclobutyl / butane-2-one (eb. 149-150 ° / 1.1 mm of Hg). - The ketone prepared above is converted into 1 - ^ / ï- (3,4-dichlorophenyl) cyclobutyl / methyl ^ -pro- »pylamine chlorhy drate (F = 225-2260C) (Formula (I): n = 1; R ^, R2, Rg, 15 R4 = H; R5 = 4-C1; Rg = 3-Cl; R? = Et; Rg = H) in a similar manner to that described in the example 32.

Operating in a similar manner to that described above, 2- / 1- (3,4-dichlorophenyl) cyclobutyl / -1-methylethylamine hydrochloride (M = 179 ° C) is prepared (Example 35a; Formula (I): n = 1; R ^, R2, Rg and R ^ = H; R5 = 4-C1; Rß = 3-Cl; R? = Me and Rg = 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 Ν, Ν-dimethyl compounds.

CH2CHR7NMe2.HCl. ·, R6

Example Substance Rj. Rc R_ Melting point _ starting point _ _ _ _ (° C) _ 36 (a) 35 Cl Cl Et 177-178 35 36 (b) 35 (a) Cl Cl Me 204-205

Example 37

By operating in a similar manner to that described in Example 34, N-formylated compounds prepared L ·, 57 as described in Example 32 are converted from ketones prepared as in Example 35, into the compounds Corresponding N-methylated.

CH2CHR7NHMe.HCl s R6

Example R ^ Rg R ^ Melting point (° C) 37 (a) Cl H Et 170-172 10 37 (b) Cl Cl Et 193-194

Example 38> A mixture of 10.1 g of 2- / T- (4-chloro-: phenyl) cyclobutyl / acetonitrile (prepared as described in Example 27), 8.1 g of potassium hydroxide and 92 ml of ethylene glycol at reflux for 3.5 hours. 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 "upon cooling: it is recrystallized from petroleum ether (bp 62-68 ° C) using charcoal. The recrystallized product is 2- / T- (4-chlorophenyl acid) ) cyclobutyl / acetate (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 one hour. 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 minutes, 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 ° / 1 mm Hg) and crystallization from petroleum ether ( bp 40-60 ° C). The solid product is N-2- / 1- (4-35 chlorophenyl) cyclobutyl7acetylpiperidine (mp 66-68 ° C).

A solution of 2.7 g of the compound prepared as described above in 20 ml of ether 58 is added dropwise to a stirred mixture of lithium aluminum hydride (0.7 g) and ether , under nitrogen. Stirring is continued for one hour at room temperature then with reflux for two hours. 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 residue from the solid. All the ethereal portions are washed with water, dried and evaporated. The residue is purified by distillation. The product is N-2- / T- (4-chlorophenyl) cyclo-butyl / ethylpiperidine (eb. 152-156 ° / 1.5 mm of Hg) (Formula (I): n = 1; R, R2 = H; R3 and R4, together and with the nitrogen atom form a piperidine ring; R ^ = 4-Cl; Rg, R ^ and s 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 ether of petroleum (eb. 62-68 ° C).

, __ CH5CH5NR, R..HC1 'vf) -A.

25 L

Example R5 Rg NR3R4 F (° C)

Me 38 (a) Cl H _ifS 167-169

Me 38 (b) Cl H -lOi-Me '281-283 (dec) = V— / 38 (c) Cl H -iQ 246-248 ° 30 Example 39

A mixture of 9 g of sodium hydride, 9 g of mineral oil and 150 ml of dry dimethylformamide is stirred under 59

P

nitrogen at 0 ° C. A solution of p-toluenesulfonylmethyl isocyanide sold under the trade name TosMIC (24.6 g) in dimethylformamide (50 ml) is added over twenty minutes. The mixture of 18 g of absolute alcohol is then added, at 0 ° C., over one hour. 24 g of 1-acetyl- 1- (4-chlorophenyl) cyclobutane (prepared in a similar manner to that described in Example 1 for 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane) are added. in 20 ml of dry dimethylformamide, and the mixture is stirred for 16 hours 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- / T- (4-chlorophenyl) cyclobutyl / propionitrile (bp 128-136 ° / 0.6 mm) is collected 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 of ether, at a temperature of 15 to 20 ° C. The mixture was stirred at room temperature for two hours, then heated to reflux for another three hours. 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 of the reaction mixture are combined. 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) cyclobutyl / propylamine hydrochloride (F = 210-230¾). 35 g of the hydrochloride prepared above are dissolved in water, a 5N aqueous solution is added. of sodium hydroxide and the solution is extracted with ether. We dry the ex-

L

60 lines and evaporated until an oil which is heated at reflux for 6 hours 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 concentrated hydrochloric acid are added. The mixture is evaporated to dryness and the residue is collected, which is washed with ether and dried. The product is Ν-2- / Γ- (4-chloro-10 phenyl) cyclobutyl / propylpyrrolidine hydrochloride (F = 238-248 ° C) (formula (I): n = 1; = Me; = H; R ^ et R ^, together and with j the nitrogen atom on which they are fixed form a pyrrolidine nucleus; R ^ = 4-C1; R ^, R ^ and Rg = H).

* Example 40 A solution of 70 g of 1- (3,4-dichlorophenyl) -1-cyclobutane carbonitrile (prepared in a manner similar to that described in Example 1) is mixed in 200 ml of denatured alcohol with a solution of 3.7 g of sodium hydroxide in 5 ml of water and a solution of 30% hydrogen peroxide is added dropwise. The mixture is heated at 50 ° C for one hour and stirred with 10% palladium on carbon (0.5 g) for one hour. The mixture is filtered and evaporated to dryness, thus obtaining 1- (3,4-dichlorophenyl) -1-cyclobutane-carboxamide.

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 85 to 95 ° C for 16 hours, 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 1- (3,4-dichlorophé-35 nyl) -1-cyclobutane carboxylic acid (F = 120- 121 ° C).

The acid prepared above is converted to the compound of Example 27 (a) in a similar manner to that described f; 61 / in Example 27, and in the compound of Example 28 (a) in a similar manner to that described in Example 28.

Example 41

A solution of 23 g of 2- / 1- (3,4-dichloro-5 phenyl) cyclobutyl / acetonitrile (prepared in a similar manner to the 2- / T- (4-chlorophenyl) cyclobutyl / acetonitrile described in 1) is added. Example 27) in 50 ml of dry ether to a solution of ethyl magnesium 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 minutes, and stirred without continuing to heat for 16 hours, then at reflux for another 2 hours. 1- / 1- (3,4-Dichlorophenyl) cyclo-butyl7-2-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 diethylene glycol dimethyl ether. The mixture is stirred at 45 ° C for 90 minutes. 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 ethereal extract is dried and hydrogen chloride gas is passed through the extract to obtain a precipitate of 1- (3-dichlorophenyl) cyclobutyl / methyl ^ -propylamine hydrochloride (F = 223-224 ° C) (Formula (I): n = 1; R ^ R2, R3 and R4 = H? R5 = 4-Cl; Rg = 3-Cl; R? = Et; Rg = H) .

Example 42

7 ml of formic acid are added dropwise to 30 ml of pyrrolidine, at a temperature of 135 to 140 ° C. 3 g of l- / l- (3,4-dichlorophenyl) - cyclobutyl7butane-2-one (prepared as described in Example 35) are added dropwise and the mixture is heated at 140 ° C for one hour. The temperature is brought to 185-190 ° C for sixteen hours. 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 L · 62 gaseous hydrogen chloride 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 - ^ / 1- hydrochloride ( 3,4-dichlorophenyl) cyclo butyl / methyl ^ -propylpyrrolidine (F = 157-160 ° F) (Formula (I): n = 1; R ^, R2 = H; R3 and R ^, together, and with the nitrogen atom on which they are fixed, form a pyrrolidine nucleus; R ^ = 4-C1; Rg = 3-C1; = Et and Rg = H).

Example 43 25 g of 1- / 1- (3,4-dichlorophenyl) cyclo-butyl7-2-butaniminyl magnesium bromide (prepared as described in Example 41) are heated at 90-95 ° C for 2 hours * with a mixture of 20 ml of concentrated hydrochloric acid 15 and 30 ml of water. The reaction mixture is extracted with ether, then the ether extract is dried and evaporated to dryness. 1- / Γ- (3,4-Dichlorophenyl) -cyclobutyl / butane-2-one (dist. 122-124 ° at 0.1 mm 'Hg) is obtained by distillation.

A mixture of 4.3 g of 1- / T- (3,4-dichlorophenyl) cyclobutyl ./- butane-2-one (prepared as described above) is stirred at room temperature for 16 hours, 2 , 65 g of hydroxylamine sulfate, 4.0 g of sodium acetate, 56 ml of denatured alcohol and 23 ml of 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 (b. 80-100 ° C), thus obtaining the 1- / T - (3,4-dichlorophenyl) cyclobutyl / -butane-2-one oxime (mp 106-110 ° C).

A solution of 2.33 ml of trifluoracetic 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 five minutes. A solution of 1.7 g of oxime (prepared as described above) in 25 ml of tetrahydrofuran is added dropwise, and the mixture is heated at reflux for six hours. The mixture is cooled and 25 ml of water are added, followed by 25 ml of a 5N sodium hydroxide solution. Extract the mixture Î t 63

AT

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, thus obtaining 5 - chlorhy-drate of 1 - ^ / 1- (3,4-dichlorophenyl) cyclobutyl / methyl ^ - propylamine (mp 222-224 ° C ) (Formula (I): n = 1; 1 * 2 'R2f ^ 3 and R4 = H; R5 = 4-Cl; Rß = 3-C1; R? = Et and Rg = H).

Example 44

A solution of 5.0 g of 1- / 1- (3,4-dichlorophenyl) cyclobutyl / - butane-2-one (prepared as described in example) is reacted at reflux for 72 hours. 43) 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 1- / 1- (3,4-dichlorophenyl) O-methyl ether cyclobutyl / butane-2-one oxime.

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 similar manner 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- / Î- (3,4-dichlorophenyl) cyclobutylT-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 days. 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 4 6 2- / 1- (4-Chlorophenyl) cyclobytyl / acetic acid (1.5 g; prepared as described in Example 38) is heated under reflux with thionyl chloride. We eliminate the excess

U

AT

64 of thionyl chloride 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 thirty minutes. Water is added and the aqueous phase 5 is extracted with ether. The ether extract is dried and the ether is removed, thereby obtaining 2 - /, 1- (4-chlorophenyl) cyclobutyl / -N-cyclopropylacetamide.

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 one hour, then heated to reflux for another two hours. 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 minutes. 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-cyclopropy1-2- / 1- (4-chlorophenyl) cyclo-butyl / 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 '' 37-40% aqueous formaldehyde solution. The reaction mixture is cooled and extracted with ether. The ether extract is washed with water, dried and filtered. Gaseous hydrogen chloride is passed through the filtrate which is heated, which gives a solid product: chlorhy-v 30 drate of N-cyclopropy lN-methyl-2- / T- (4-chlorophenyl) cyclo- butyl / ethylamine (M = 149-153 ° C) (Formula (X): n = 1; ^ and R2 = H; R3 = cyclopropyl; R ^ = Me; R ^ = 4-Cl; R ^, R? and Rg = H).

Example 47 Pharmaceutical compositions containing any of the compounds of formula (I) described in Examples 1 to 46 are prepared as follows.

/ „

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65

Example 47 (a)

Tablets are prepared from the following ingredients:

Parts by weight 5 Active ingredient 50.0

Lactose 78.5

Polyvinylpyrrolidone 5.0

Corn starch 15.0

Magnesium stearate 1.5 10 The active ingredient, lactose and a little starch are mixed and made 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 compression apparatus so as to obtain tablets containing * 50.0 mg of the active ingredient.

. Example 47 (b)

We prepare capsules of. the following way. A mixture of the active ingredient (45 parts by weight and powdered lactose (205 parts by weight) is introduced into hard gelatin capsules, each capsule containing 45 mg of the active ingredient.

Example 47 (c)

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

30 Example 47 (d)

Vials containing a solution of water-soluble compounds according to the present invention which can be used in injections are prepared, using the following ingredients: Active ingredient 1100 g

Mannitol 1100 g

Water, freshly distilled to make 11 liters.

L ·

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66

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

Example 47 (e)

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 R, and Rg have the meanings given in Examples 1, 1 (a) to 1 (e), 15 3, 4, 4 (a) to 4 (e), 6, 7, 7 (a) to 7 (d), 9, 9 (a) to 9 (n), 10, 10 (a) to 10 (z), 10 (aa), 10 (bb ), 11 (i), 11 (k) and 11 (1). These new ketones of formula (V) are prepared by hydrolysis of new imines of formula (XVI) in which Y = MgBr and R ^, R ^ and Rg have the meanings given in the above examples.

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

In the previous examples, new cyano-type compounds of the formula (XVII) have been described in which Rj. and Rg have the meanings given in Examples 1, 1 (d), 1 (e), 4 (g), 9 (e), 9 (m), 10 (k), 10 (e), 10 (p), 10 (r), 10 (v), 10 (y), 10 (z), 10 (aa), 10 (bb), 11 (k), 11 (11) and 26.

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/

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67

In the previous examples, new formamides of formula (XVIII) are described in which R ^ f R ^, Rg,

Rg r Ry, Rg and n have the meanings given in Examples 1, 1 (a) to 1 (e), 3, 4, 4 (a) to 4 (e), 6, 7, 7 (a) to 7. (d), 5 9, 9 (a) to 9 (n), 10, 10 (a) to 10 (z), 10 (aa), 10 (bb), 11 (i), 11 (k), 11 (1), 29, 32, 35 and 36.

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/

Claims (34)

1. An r \ -GC; in which and R ^ q, which may be the same or different, each represents H, a halo radical, or a C1-C3 alkoxy group; in which, when n - 1, R ^ = H or a C1 to C3 alkyl group; R2 represents H or a C1 to C3 alkyl group; and R ^, which may be the same or different, each has H, a straight chain alkyl group. or branched from C1 to C4, a C3 to C6 alkenyl group, a C3 to C6 alkynyl group, a cycloalkyl group in which the nucleus contains from 3 to 7 carbon atoms, a group of formula R ^ CO ^ and which R · ^ = H; or, together and with the nitrogen atom to which they are attached, R3 and R ^ form an optionally substituted heterocycle containing 69 having 5 or 6 atoms in the nucleus and optionally containing other hetero atoms in more than the nitrogen atom; Rj. and Rg, which may be the same or different, each represents H, a halo group, a 5-trifluoro-methyl group, a C1-C3 alkyl group, a C1-C3 alkoxy or alkylthio group, a phenyl group or, together and with the carbon atom to which they are attached, R5 and Rg form a second benzene kingdom which can be substituted by one or more halo groups, a C1-C4 alkyl or alkoxy group or the substituents of the second benzene ring, with the two carbon atoms to which they are attached can form another benzene ring; R_ and R0, which may be the same or different, each represents H or a C1 to C3 alkyl group; As well as their pharmaceutically acceptable salts. - 2. Compounds of formula (X) according to claim 1, characterized in that n = 0; R ^ represents a linear or branched C1 to C4 alkyl group, a C3-C7 cycloalkyl group, a cycloalkylmethyl group in which the cycloalkyl group is C3 to C6, or a group of formula (II) in which R ^ and R ^ q = H, fluoro or methoxy, and R3 = H or methyl; 1. Compounds corresponding to formula (I): R5 CR1R2 (CR7R8) nNR3R4.) 0-h R6 in which n = 0 or 1; in which, when n = 0, R ^ represents a branched C1 to C6 straight chain alkyl group, a group C3 to C7 to C7 cycloalkyl a cycloalkoylalkyl group in which the cycloalkyl group is to C3 to C6 and the C1 to C3 alkyl group, an alkenyl group or a C2 to C6 alkynyl group, or a group of formula (II): 3. Compounds of formula (I) according to claim 2, characterized in that R ^ represents a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl group , cyclobutylmethyl, eyclopentylmethyl, cyclohexylmethyl or phenyl. 4. Compounds of formula (I) according to claim 30 1, characterized in that n = 1, R ^ = H or methyl and R3 = H. 5. VI in which t r ^, r ^., R ^. and R ^ have the above meanings. 5. Compounds of formula (I) according to any one of the preceding claims, characterized in that R ^ and R ^ = H, methyl, ethyl or formula. 6. Compounds of formula (I) according to any one of claims 1 to 4, characterized in that, together and with the nitrogen atom to which they are attached, R3 and R4 LA 70 form a heterocyde containing a nitrogen atom and 4 or 5 carbon atoms which is optionally substituted by one or more alkyl groups, or a heterocyde containing a second nitrogen atom which is optionally alkyl or a heterocyde containing one or more double bonds. 7. Compounds of formula (I) characterized in that R ,. and Rg = H or a fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy, phenyl group or, together and with the carbon atoms to which they are attached R ^ and Rg form a second optionally substituted benzene ring by a halo group. - 8. Compounds of formula (I) according to any one of claims 1, 4, 5, 6 and 7, characterized in that 15 R ^ = H, methyl or ethyl and Rg = H. 9. Compounds according to claim 1, corresponding to formula (III)>. CRLR2 (CR7R8) nSR3R4 20 5 \ / □ III in which R ^, R2 * Rg "^ 4r ** 5 'Rg" ** 7' e * "- its ^ as defined in claim 1. 10. Compounds according to claim 9, characterized in that R, - and Rg '' which may be the same or different, represent H or a fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy, phenyl or group. and with the carbon atoms to which they are attached, R 1 and R 6 form a second benzene ring optionally substituted by a chloro group. 11. Compounds according to claim 1, corresponding to formula (IV): ”" '^ 2 (^ 8 ^ 3¾ 35 - ^ _ IV R6 / _ ”71 in which R ^, R2, Rg, R ^, Rg, R ^, Rg and n are as defined in claim 1 and Rg represents a fluoro or methyl group. 12. Compounds of formula (IV) according to claim 5 11, characterized in that R ^ = H or a fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy or phenyl group and Rg represents a fluoro or methyl group. 13. Compounds of formula (I) which are: 1- / 1- (4-chlorcphenyl) cyclobutyl / butylamine, N, N-dimethyl-1- / 1- (4-chlorophenyl) cyclobutyl / buT-tylamine, "N-methyl ^ l- / l- (3,4Tdichlorophenyl) cyclobutyl / bu ·:;. tylamine, N, N- dimé thy 1-r lr / l- C3y 4 -r di ch lorophenyl) cyclobutyl / 15 butylamine, - H-methyl-i- / l- (4-chlorophenyl) cyclobutyl / -3-methyl-butylamine, N, N- dimé thy 1-1- / 1- (4-ch lorophenyl) cyclobutyl / w3 -2q methylbutylamine, N, N-dimethyl 1-1- / 1 t ·· (3,4 -rdichlorophenyl) cyclobuty l / 'r- 3-me thy lbuty lamine, 1- / 1- (3,4- di chlorophenyl) cyclobutyl7ë thy lamine f 25 N, N-dimethyl-l ^ / lr (3,4-d ± chlorophenyl) cyclobutyl / · ethylamine, c (/ 1- C4-ch lorophenyl) cyclobutyl / benzy lamine, and s their pharmaceutically acceptable salts, if h A 72 14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (X) according to any one of the preceding claims. 15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (III) according to claim 9 or 10. 16. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (IV) according to claim 11 or 12. 17. Pharmaceutical composition according to any one of claims 14, 15 or 16, in the form of doses - unit. vs. - 18. Pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 13. 19. A process for the preparation of compounds of formula (I) according to claim 1, comprising subjecting to a reductive amidation pne ketone of formula (V): R6 in order to obtain a compound in which n "0? R7 = H; R4 = CHO and Ri, Rg and Rg are as defined in the claim. 25 tion 1, or a ketone or an aldehyde of formula (VI): R5 CR ^ CQRy, HsCJ Π VI - -30 in order to obtain a compound in which n = 1; R ^ = CHO, Rg = H and R ^ R2, R5, Rg and R? are as defined in claim - 1. A. = CHO. 4 20. A process for the preparation of compounds of formula (I) according to claim 1, comprising subjecting to a reductive amination a ketone of formula (V): L 73 r6 lj v 5 in order to obtain a compound in which n = 0 ; R2 = H and R, Rg and Rg are as defined in claim 1, or a ketone or an aldehyde of formula (VI): R5 CR- ^ COFL, 10 ~~ Ί VI R6 '"in order to obtain a compound where n = 1; Rg = H and R ^, s - R2 / Rj, Rg and are as defined in claim 1. 21. Process for the preparation of compounds of formula (I) according to claim 1, consisting in reducing a compound of formula (VII): t. R5 z. 20 / - Ί 1 r6 ^ C = / U vil in which: a) z represents a group of formula -CR = NOH or one of its esters or ethers, in order to obtain a compound of formula 25 (I) in which n = 0 and R2, R3 and R ^ = H; b) Z represents a group of formula -CR ^ NR ^ in order to obtain a compound of formula (I) in which n = 0 and R ^ and R4 = H; c) z represents a group of formula -CRj = NY in which * 30 Y represents a fragment containing a metal derived from an organometallic reagent, in order to obtain a compound of ^ formula (I). in which n = 0 and R2 , R ^ and R ^ = H; d) Z represents a group of formula -CR ^^ CN, in order to obtain a compound of formula (I) in which n = 1 and R ^, 35 R4, R? and Rg = H; e) Z represents a group of formula -CRjR2CR7 = NOH or one of its esters or ethers, in order to obtain a compound of formula 74 in which n = 1 and Rg, R ^ and Rg = H; f) Z represents a group of formula -CRjRgCR- ^ NRg r in order to obtain a compound of formula (I) in which n = 1 and R4 and Rg = H; 5 g) Z represents a group of formula -CR ^ RgCR ^ 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 Rg, R ^ and Rg = H; h) Z represents a group of formula -CR ^ RgCONRgR ^, 10 in order to obtain a compound of formula (I) in which n = 1 and R ^ and Rg - H. 22. Method according to claim 21, characterized in that Y represents MgBr or Li. 23. Process for the preparation of compounds of formula (I) according to claim 1, comprising (a) reacting E an organometallic reagent with an imine of formula (VIII): r • · -s 5ΝΓΛ .'CH: bNR3, Wh 20 o and (b) to hydrolyze the resulting product, in order to obtain a compound of formula (I) in which n = 0. 24. The method of claim 23, characterized in that the organometallic reagent is a reagent of 25. A process for preparing compounds of formula (I) according to claim 1, comprising (a) reacting an organometallic reagent with an imine of formula (IX) - 30. - R5 * £> -b 35 and (b) to hydrolyze the resulting product, in order to obtain a compound of formula (I) in which n = 1. / L · "75 A 25 Grignard with the formula R ^ MgBr or an organic lithium compound with the formula R ^ Li. 26. The method of claim 25, characterized in that the organometallic reagent is a Grignard reagent having the formula R ^ MgBr or an organic lithium compound having the formula R ^ Li. 27. A process for the preparation of compounds of formula (I) according to claim 1, comprising carrying out the rearrangement by decarboxylation of (a) -an amide of formula (X): R5 CR, R5CONHo ". I 2 I HXJ'U ε in order to obtain an amine in which n = 0; (b) an amide of formula (XI): 15 r. b. (^ i ^ 2 ^ R7 ^ C0NH2 I v ^ ô-b. in order to obtain an amine in which n = 1; 20 (c) an acyl azide obtained by reaction of sodium azide azide with a chloride d acid of formula (XII): ^ S) £ s * \: R1R2C0C1 j 25 * 6 U XU in order to obtain an amine in which n = 0; (d) an acyl azide obtained by reaction of sodium azide on an acid chloride of formula (XIII): ~ 30 I * 5 CRlR2CR ^ gCOCl p) - I / W = / · _ mi r6 35 in order to obtain an amine in which n = 1. fi 76 * 28. A method of preparing compounds of formula (I) according to claim 1, comprising reacting azothydrigue acid on (a) a carboxylic acid of formula (XIV): 5 ΒΝ <ΓΛ “Λ0000 □ =” in order to 'obtain an amine in laguelle n = 0 10 or (b) a carboxylic acid of formula (XV) * "' Vt, crir2cW00H 'jÉ> -b, r6 15 w in order to obtain an amine in laguelle n = 1. : 29. Process for the preparation of compounds of formula (I) according to claim 1 in lesguels R ^ - H, consisting in hydrolyzing a compound of formula (I) in which 30. A process for preparing compounds of formula (I) according to claim 1, in lesguels R ^ = methyl, consisting in reducing a compound of formula (I) in which R „= CHO. 4 31. Process for the preparation of compounds of formula (I). according to claim 1 in which R ^ and / or R ^ do not represent hydrogen, consisting in converting a compound of formula (I) in which R ^ and / or R ^ = H into the desired compound. l 30 32. Compounds of formula (V) r C0Rl v £> h 35 in which Rx, R5 and Rg have the abovementioned meanings provided that when R1 = methyl or ethyl R ^ does not represent a hydrogen atom. / _ 77 33. ComjJHhftfe of formula (VI): R1R2 ^ .0R7, 34. Compt »tof ^ corresponding to the formula (XXV): ίο t; · 1λ »ααΌ '· IL \ = y' V _ xxv in which Ηχ, R. ,, R ^ 'R,., Rg, R ?, Rg and n have the meanings defined in claim 1. Î.VàAAha- 5S