NL192201C - Phenylaminoalkylcyclobutane compounds which are pharmacologically active and preparations containing these compounds. - Google Patents

Description

1 192201

Pharmacologically active phenylaminoalkylcyclobutane compounds and preparations containing these compounds

The present invention relates to 1-phenyl-1-aminoalkylcyclobutane compounds having pharmacological action.

Such compounds are known from British Patent 973887. This reference discloses 1-phenyl-1-aminomethylcycloalkane compounds having a central analeptic action. In these compounds, the phenyl moiety may have one or two substituents which are arbitrarily selected from hydroxy, methyl or methoxy, or substituted with a methylenedioxy group, the cydoalkane ring contains from 3 to 5 carbon-10 atoms, such as the 2-position cydobutane ring. with an alkyl group of 1 to 3 carbon atoms, and the nitrogen atom may be substituted with one or two groups selected at random from saturated or unsaturated aliphatic hydrocarbon groups of up to 4 carbon atoms, or substituted with a cycloalkyl group of 4 to 6 carbon atoms, or the nitrogen atom moiety form a saturated ring that can contain another heteroatom.

No anti-depressant activity is reported for the compounds of this structure. New 1-phenyl-1-aminoalkylcydobutane compounds have now been found to exhibit an anti-depressant effect.

Therefore, the invention provides a fiber bond characterized by the formula 1 of the formula sheet, wherein n = 0 or 1, where, when n = 0, Rt is a straight or branched chain alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 -7 carbon atoms, cycloalkylalkyl group of which the cycloalkyl portion contains 3-6 carbon atoms and the alkyl portion contains 1-3 carbon atoms, an alkenyl group or an alkynyl group with 2-6 carbon atoms, or a group of formula 2, wherein R9 and R10, which may or may not equivalent, represents a hydrogen or halogen atom or an alkoxy group having 1-3 carbon atoms, wherein, if n = 1, R. represents a hydrogen atom or an alkyl group having 1-3 carbon atoms, R2 represents a hydrogen atom or an alkyl group having 1 -3 represents carbon atoms, R3 and R * which are the same or different, a hydrogen-25 atom, a straight or branched chain alkyl group with 1-4 carbon atoms, an alkenyl group with 3-6 carbon atoms, an alkynyl group with 3-6 carbon atoms , a cycloalkyl group, the ring of which contains 3-7 carbon atoms or a group of formula R ^ CO, wherein Rn is a hydrogen atom, or wherein R3 and R4 together with the nitrogen atoms to which they are attached are an optionally substituted 5- or 6-membered heterocyclic ring in the ring which, in addition to the nitrogen atom, further optionally contains hetero atoms, R 5 and R 6, which may or may not be the same, form a hydrogen or halogen atom, a trifluoromethyl group, an alkyl group with 1-3 carbon atoms, an alkoxy or alkylthio group with 1 -3 carbon atoms or a phenyl group, or wherein R5 and R6 together with the carbon atoms to which they are attached form a second benzene ring optionally substituted with one or more halogen atoms, an alkyl group or an alkoxy group of 1-4 carbon atoms or in which the substituents of the second benzene ring together with the two carbon atoms to which they are attached still form a benzene ring and R7 and R8, which may or may not may represent a hydrogen atom or an alkyl group of 1-3 carbon atoms, and by an antidepressant action as well as the pharmaceutically acceptable salts thereof.

In the formulas of this specification, the symbol of formula 1a represents a 1,1-disubstituted 40 cyclobutane group of formula 1b and a -Cr., R2 (CR7R8) nNR3R4 group represents a group of formula 1c.

In the recommended compounds of formula 1 wherein n = 0, R 1 is a straight or branched chain alkyl group of 1 to 4 carbon atoms, a cycloalkyl group of 3-7 carbon atoms, a cycloalkylmethyl group in which the cycloalkyl ring contains 3-6 carbon atoms or a group of formula 2 wherein R9 and / or R10 represent a hydrogen or fluorine atom or the methoxy group and wherein R2 is a hydrogen atom or the methyl-45 group. Examples of particularly recommended compounds of formula 1 are those in which if n = 0 and R2 represents a hydrogen atom R., the methyl, ethyl, propyl, isopropyl, butyl, sec.butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cydoheptyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl or phenyl group.

In the recommended compounds of formula 1 wherein n = 1, R1 represents a hydrogen atom or the methyl-50 group and R2 represents a hydrogen atom, in particular both substituents R1 and R2 are a hydrogen atom.

In recommended compounds of formula 1, R3 and / or R4 represent a hydrogen atom or a methyl, ethyl or formyl group, or, if R3 and R4 form a heterocyclic ring together with the nitrogen atom to which they are attached, the recommended compounds of formula 1 a heterocyclic group 55 containing one nitrogen atom and 4 or 5 carbon atoms which is optionally substituted by one or more alkyl groups, a heterocyclic group containing a second nitrogen atom optionally alkylated or a heterocyclic group containing one or more double bonds . In especially compounds of formula 1, 192201 2, R 3 and / or R 4 represent a hydrogen atom or a methyl, ethyl or formyl group.

Preferred compounds of formula 1 are represented by formulas 3 and 4, of formula 1 wherein Rs and R6, which may or may not be the same, are a hydrogen, fluorine, chlorine, bromine or 5 iodine atom or a trifluoromethyl- , methyl, methoxy or phenyl group or Rs and Re, together with the carbon atoms to which they are attached, form a second benzene ring which may be optionally substituted by chlorine. In especially recommended compounds of formula 3, R5 and / or R6 are a hydrogen, fluorine, chlorine or iodine atom or a trifluoromethyl, methyl or phenyl group or R5 and R6 together with the carbon atoms to which they are attached form a second benzene ring, which may be optionally substituted by chlorine and in formula 4, R 5 is a hydrogen, fluorine, chlorine, bromine or iodine atom or a trifluoromethyl, methyl, methoxy or phenyl group R 6 is a fluorine atom or a methyl group. In particular, R5 represents a hydrogen or chlorine atom in formula 4.

In recommended compounds of formula 1 wherein n = 1, R7 represents a hydrogen atom or a methyl or ethyl group and R8 represents a hydrogen atom, while in particularly recommended compounds of formula 1 R7 is a hydrogen atom or an ethyl group and R8 is a hydrogen atom.

The compounds of formula 1 can exist as salts with pharmaceutically acceptable acids. Examples of such salts are the hydrochlorides, maleates, acetates, citrates, fumarates, tartrates, succinates and salts with acidic amino acids, such as aspartic acid and glutamic acid.

Compounds of formula 1 containing one or more asymmetric carbon atoms can exist in different optically active forms. If R 1 and R 2 are different or R 7 and Re are different, the compounds of formula 1 have a chiral center. Such compounds can exist in two enantiomeric forms, and the present invention includes both enantiomeric forms and mixtures thereof. If both R1 and R2 and R7 and R8 are different, the compounds of formula I have two chiral centers and the compounds then exist in four diastereoisomeric forms.

The invention also relates to pharmaceutical preparations containing one or more compounds of formula 1, together with a pharmaceutically acceptable diluent and / or carrier.

For therapeutic use, the active compound can be administered orally, rectally, parenterally or topically, preferably orally. The therapeutic compositions of the invention may be in the form of any known pharmaceutical compositions for oral, rectal, parenteral or topical administration.

Pharmaceutically acceptable carriers suitable for inclusion in these preparations are known in the pharmaceutical field. The compositions of the invention may contain 0.1-90% by weight of active compound (s). The compositions of the invention are usually prepared or manufactured in unit dosage form.

The preparations for oral administration are the recommended preparations according to the invention and these are the known pharmaceutical forms for such administration.

The tablets and capsules may suitably each contain 1-500 mg of active compound.

For some preparations it may be advantageous to use the compounds according to the invention in the form of particles of a very small size, such as obtained for example by flow energy grinding.

In the compositions of the invention, the active compound (s) may be used together with other compatible pharmacologically active ingredients, if desired.

The pharmaceutical preparations containing a therapeutically effective amount of one or a number of compounds of the invention of the formula 1 can be used for the treatment of depression in mammals, including humans. For such treatment, the amount of the compound (s) of the invention of the formula 1 administered per day will be between 1 and 1,000 mg, preferably between 5 and 500 mg.

Compounds of formula 1 wherein R4 represents a -CHO group can be prepared by reductive amidation of ketones of formula 5 or of ketones or aldehydes of formula 6, for example with formamide and formic acid or ammonium formate and formic acid, to give compounds of formula 1 in which R4 represents a -CHO group and R3 is a hydrogen atom, or with formamides of formula HCONHR3, wherein R3 represents an alkyl or cycloalkyl group, and formic acid or amines of formula R3NH2, wherein R3 is an alkyl or cycloalkyl group, and formic acid

Compounds of formula 1 in which R4 represents a -CHO group can be obtained by formulating compounds of formula 1, in which R4 represents a hydrogen atom with, for example, 55 methyl foimate.

Compounds of formula 1, wherein R3 has a meaning other than hydrogen and R4 represents a -CHO group, may be prepared by reacting a compound of formula 1 wherein R3 is a hydrogen-192 192 atom and R4 represents a -CHO group, with a compound of formula R3X, wherein X = a cleavable group, such as halogen, in the presence of a base.

Compounds of formula 1 can be obtained by reductive amination of ketones of formula 5 or of ketones or aldehydes of formula 6. Examples of suitable reductive amination processes are given below.

a) for compounds of formula 1 wherein R3 and R4 represent a hydrogen atom, by reacting the ketone or aldehyde with an ammonium salt, for example ammonium acetate, and a reducing agent, such as sodium cyanoborohydride, b) for compounds of formula 1 wherein R3 is an alkyl or cycloalkyl group and R4 represents a hydrogen atom 10, by reacting the ketone or aldehyde with an amine of formula R3NH2 and a reducing agent, such as sodium cyanoborohydride, c) for compounds of formula 1 in which neither (noch. nor R4 represent a hydrogen atom or in which R3 and R4 together form a hetrocyclic ring with the nitrogen atom, by reacting the ketone or aldehyde with an amine of the formula HNR3R4 and either formic acid or a reducing agent, such as sodium cyanoborohydride, d) for compounds of formula 1 wherein one or both substituents R3 and R4 is a hydrogen atom or represent an alkyl or a cycloalkyl group or wherein R3 and R4 together with the nitrogen atom ee forming a hetrocyclic ring, by catalytic hydrogenation at an elevated temperature and pressure of a mixture of the ketone or aldehyde and an amine of the formula HNR3R4.

Compounds of formula 1 in which both R 3 and R 4 represent alkyl groups can be prepared by reacting a ketone of formula 5 or a ketone or aldehyde of formula 6 with a dialkyl formamide of formula HCONR3R4, for example in the presence of formic acid.

Compounds of formula 1 can be prepared by reduction of compounds of formula 7, wherein a) Z represents a group of formula -CR 1 NOH or an ester or ether thereof, to yield compounds of formula 1 wherein n = 0 and R2, R3 and R4 represent a hydrogen atom, b) Z represents a group of formula -CH1 = NR3, in which R3 has a different meaning than a hydrogen atom or a CHO group, whereby compounds of formula 1 are obtained in which n = 0 and R2 and R4 have a hydrogen atom, c) Z is a group of formula -CR ^ NY, wherein Y represents a metal-containing portion derived from an organometallic reagent, whereby compounds of formula 1 are obtained in which n = 0 and R2, R3 and R4 represent a hydrogen atom, d ) Z represents a group of formula -CR1R2CN to give compounds of formula 1 wherein n = 1 and R3, R4, R7 and R8 represent a hydrogen atom, e) Z a group of formula -CH1R2CR7 = NOH or an ester or ether thereof to give compounds of formula 1 wherein n = 1 and R3, R4 and R8 represent a hydrogen atom, f) Z is a group of formula -CR1R2CR7 = NR3, wherein R3 has a meaning other than hydrogen or a CHO group to yield compounds of formula 1 wherein n = 1 and R 4 and R 4 are hydrogen atom, g) Z represents a group of formula -CR 1 R 2 CR 7 = NY, wherein Y represents a metal-containing portion derived from 40 an organometallic reagent, whereby compounds of formula 1 in which n = 1 and R3, R4 and Re represent a hydrogen atom and h) Z represents a group of formula -CR1R2CONR3R4 to give compounds of formula 1 wherein n = 1 and R7 and R8 represent a hydrogen atom.

Suitable reducing agents for the above-described reactions are, for example, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, and the borane-dimethyl sulfide complex.

In (c) and (g) above, Y is preferably MgBr derived from a Grignard reagent or Li derived from an organolithium compound.

Compounds of formula 1 wherein n = 0 can be obtained by reaction of an organometallic reagent, for example a Grignard reagent of formula R, MgX, wherein X represents a chlorine, bromine or iodine 50 atom, or an organolithium compound of formula R. Li with an imine of formula 8 followed by hydrolysis to give a secondary amine of formula 1. Similarly, imines of formula 9 can be converted to secondary amines of formula 1, wherein n = 1.

Compounds of formula 1 in which R3 and R4 represent a hydrogen atom can be prepared by decarboxylating rearrangement, for example using iodoso-benzene bistrifluoroacetate or 55 according to a Hofmann reaction using bromine in an alkaline solution, of amides of the formula 10 or amides of formula 11, whereby amines of formula 1 wherein resp. n = 0 and n = 1 are obtained.

192201 4

Compounds of formula 1 in which R3 and R4 represent a hydrogen atom can be prepared by decatboxylating rearrangement of acyl azides in the Curtius reaction. The acyl azides can be formed, for example, by reaction of acid chlorides of formula 12 or acid chlorides of formula 13 with sodium azide.

Compounds of formula 1 wherein R3 and R4 represent a hydrogen atom can be prepared according to a Schmidt reaction, wherein a carboxylic acid of formula 14 or a carboxylic acid of formula 15 reacts with hydrogen azide.

Compounds of formula 1 in which R4 represents a hydrogen atom can be prepared by hydrolysis of compounds of formula 1 in which R4 represents an -CHO group, for example by acid hydrolysis.

Compounds of formula 1 in which R4 is a methyl group can be obtained by reduction of compounds of formula 1 in which R4 represents an -CHO group, for example with lithium aluminum hydride or sodium bis (2-methoxyethoxy) aluminum hydride.

Compounds of formula 1 in which one or both substituents R3 and R4 have a different meaning than hydrogen can be prepared from compounds of formula 1 in which one or both substituents Rg and R4 are hydrogen according to methods known in the art for conversion of primary to secondary or tertiary amines or for the conversion of secondary to tertiary amines. Examples of suitable processes are given below: a) alkylation of primary amines of formula 1 to secondary amines of formula 1, for example according to a process comprising the steps of protecting the primary amine with a protecting group, such as trifluoroacetyl, alkylation with a alkyl halide and removing the protecting group, for example by hydrolysis, comprises, b) alkylation of primary amines of formula 1, for example with an alkyl halide, to tertiary amines of formula 1 wherein R3 and R4 are equal, c) alkylation of secondary amines of formula 1, for example with an alkyl halide, to tertiary amines of formula 1 in which R3 and R4 may be different, d) reaction of primary amines of formula 1 with sodium borohydride and acetic acid to secondary amines of formula 1 in which R3 is an ethyl group and R4 is a hydrogen atom (e) reaction of primary amines of formula 1 with formaldehyde and formic acid to form tertiary am ines of formula 1, wherein both R 3 and R 4 represent a methyl group, f) reaction of secondary amines of formula 1, wherein R 4 represents a hydrogen atom, with formaldehyde and formic acid to tertiary amines of formula 1, in which R 4 represents a methyl group, g) formulation of primary amines of formula 1, for example by reaction with methyl formate, and reduction of the obtained formamides, for example with lithium aluminum hydride to secondary amines of formula 35, wherein R3 represents a methyl group and R4 represents hydrogen, h) formulation of secondary amines of formula 1 , for example, by reaction with methyl formate, and reduction of the obtained formamides, for example, with lithium aluminum hydride, to tertiary amines of formula 1, wherein R4 represents a methyl group, i) acylation of primary amines of formula 1, for example, by reaction with an acyl chloride of formula 40 R12COCI or an anhydride of formula (R12CO) 2O where R12 represents an alkyl, alkenyl or alkinyl group and reduction of the obtained amides, for example with lithium aluminum hydride, to secondary amines of formula 1 in which R3 represents a -CH2R12 group and R4 represents a hydrogen atom, j) acylation of secondary amines of formula 1, in which R4 represents a hydrogen atom, for example by reaction with an acyl chloride of formula R12COCI or an anhydride of formula (R12C0) 20, wherein R12 represents an alkyl, alkenyl or alkinyl group and reduction of the resulting amides with, for example, lithium aluminum hydride to tertiary amines, wherein R4 represents a CH2R12 group, k) reaction of primary amines of formula 1 with an aldehyde of formula R13CHO, wherein R13 represents an alkyl group, alkenyl group or alkinyl group or a ketone of formula R14COR15, wherein R14 and R1S, which may or may not be the same, represent an alkyl, alkenyl alkinyl group or wherein R14 and R1S together with the 50 carbon atom to which they are attached may form an alicyclic ring, and may reduce the ve Imines or enamines are obtained with, for example, sodium borohydride, or, if R13, R14 or R15 do not represent an alkenyl or alkinyl group, by catalytic hydrogenation to secondary amines of the formula 1, in which R3 and to represent a R 1 CH 2 and R 14 (R 15) CH group, 1) reaction of primary amines of formula 1 with a non-geminally disubstituted alkane having two or 55 three carbon atoms between the carbon atoms containing the substituents, e.g. halogen, preferably bromine, or p-toluenesulfonyloxy, to compounds of formula 1, wherein Rg and R4 together with the nitrogen atom to which they are attached form a hetrocyclic ring containing no heteroatoms other than the 192201 nitrogen atom.

The ketones of formula 5 can be prepared by hydrolysis of imines of formula 16, wherein Y represents a metal-containing portion derived from an organometallic reagent. The imines of formula 16 can be obtained by reacting this organometallic reagent with a cyano compound 5 of formula 17. Examples of suitable organometallic reagents are Grignard reagents of formula R., MgX, wherein X is a chlorine, bromine or iodine atom (Y = MgX ) represents an organolithium compound of formula R, Li (Y = Li).

The ketones of formula 6 can be prepared by hydrolysis of imines of formula 18, wherein Y represents a metal-containing portion derived from an organometallic reagent. The imines of formula 18 can be obtained by reacting these organometallic reagents with cyano compounds of formula 19. Suitable organometallic reagents are, for example, Grignard reagents of formula R7MgX, wherein X represents a chlorine, bromine or iodine (Y = MgX) atom and organolithium compounds of formula R1 (Y = Li).

Ketones of formula 5 can be obtained by reacting carboxylic acid derivatives, such as an amide 15 or acid halide, with an organometallic reagent, for example by reacting an acid chloride of formula 20 with a Grignard reagent of formula RtMgX, in which X is a chlorine, bromine or iodine atom, at a low temperature or by reacting a carboxylic acid of formula 21 with an organometallic reagent, for example, an organolithium compound of formula R1.

Ketones of formula 6 can be prepared by reacting carboxylic acid derivatives, such as an amide or acid halide, with an organometallic reagent, for example, by reacting an acid chloride of formula 12 with a Grignard reagent of formula R7MgX, wherein X is a chlorine, bromine or iodine atom, at a low temperature or by reacting a carboxylic acid of formula 14 with an organometallic reagent, for example an organolithium compound of formula R7Li.

Ketones of formula 5 wherein R 1 represents an alkyl group (e.g. a methyl group) and ketones of formula 6 wherein R 7 represents an alkyl group (e.g. a methyl group) may be prepared by reacting a diazoalkane (e.g. diazomethane) with aldehydes with resp. . formulas 22 and 6.

Aldehydes of formula 6 can be obtained by methods known in the art. Examples of suitable methods are given below: a) reduction of cyano compounds of formula 19 with, for example, d-tert.butylaium aluminum hydride or diisobutylaluminum hydride, b) reduction of carboxylic acid derivatives, for example: i) by reduction of compounds of formula 7, wherein Z is a CR1R2CONR3R4 group and R3 and R4 have a different meaning than hydrogen, for example with lithium diethoxyaluminum hydride, ii) by reduction of amides formed by reaction of ethyleneimine with an acid chloride of formula 12, for example with lithium aluminum hydride as reducing agent, iii) by reduction of sodium chloride of formula 12 , for example, with lithium tri-tert-butoxyaluminohydride, c) reaction of alcohols (formed by reduction of carboxylic acids of formula 14) with, for example, with chromium trioxide-pyridine complex in dichloromethane under anhydrous conditions.

Compounds of formula 7 wherein Z is a group of formula -CR 1 NOH or -CR 1 R 2 CR 7 = NOH or ethers 40 or esters thereof can be obtained by reacting hydroxylamine or an ether or ester thereof with, respectively. ketones of formula 5 or ketones or aldehydes of formula 6.

Compounds of formula 7 in which Z represents a group of formula -CR ^ NRg or -CR ^ gCR ^ NRg can be prepared by reacting amines of formula NH2R3 with. ketones of formula 5 and ketones or aldehydes of formula 6.

Preparation of compounds of formula 7 wherein Z is a group of formula -CRn = NY or -CRnY NY above with respect to compounds of resp. formulas 16 and 18.

The preparation of compounds of formula 7 wherein Z represents a group of formula -CR., R2CN will be described below with respect to the cyano compounds of formula 19.

Compounds of formula 7 wherein Z represents a group of formula -CR-CONRgR 4 can be obtained by reacting acid derivatives such as esters and acid halides (eg the acid chlorides of formula 12) with amines of formula HNR3R4. Compounds of formula 7 in which Z represents a CR1R2CONH2 group can be prepared from cyano compounds of formula 19, for example, by hydration, with aqueous acids or by reaction with hydrogen peroxide in the presence of a base.

Imines of formulas 8 and 9 can be obtained by reacting amines of formula RaNH2 55 with aldehydes with resp. formulas 22 and 6.

Amides of formula 10 can be obtained by reaction of ammonia with carboxylic acid derivatives, for example acid chlorides of formula 12, or from cyano compounds of formula 19, for example by 192201 6 hydration with aqueous acids or by reaction with hydrogen peroxide in the presence of a base.

Amides of formula 11 can be prepared by reacting ammonia with carboxylic acid derivatives, for example acid chlorides of formula 13, or can be obtained from cyano compounds of formula 23, for example, by hydration with aqueous acids or by reaction with hydrogen peroxide in the presence of a base.

Amides of formula 10 wherein R 1 and R 2 represent a hydrogen atom and amides of formula 11 wherein R 7 and R 8 are a hydrogen atom can be prepared from acid chlorides of formulas 20 and 12 by reaction with diazomethane to form a diazoketone which rearranges to the desired amide in the presence of ammonia and a catalyst, for example silver.

Carboxylic acids of formulas 14, 15 and 21 can be prepared by hydrolysis, for example basic hydrolysis, of cyano compounds with resp. formulas 19, 23 and 17. The carboxylic acids of formulas 14 and 15 can be prepared by reacting amides with resp. formulas 10 and 11 with nitrous acid. Carboxylic acids of formula 21 can be obtained by reacting nitrous acid with the amides formed by reaction of ammonia with carboxylic acid derivatives, for example acid chlorides of formula 20, or by reaction of cyano compounds of formula 17 with hydrogen peroxide in the presence of a base.

The carboxylic acids of formula 14 wherein R 1 and R 2 represent a hydrogen atom and carboxylic acids of formula 15 wherein R 7 and R 8 are a hydrogen atom can be prepared from acid chlorides of, respectively. formulas 20 and 12 by reaction with diazomethane to form diazoketones which rearrange to the desired acid in the presence of water and a catalyst, e.g. silver.

The cyano compounds of formula 17 can be obtained by reacting cyan compounds of formula 24 with a 1,3-disubstituted propane, for example 1,3-dibromopropane, and a base, such as sodium hydride.

Cyan compounds of formula 19, wherein R1 and R2 represent a hydrogen atom, may be prepared from cyan compounds of formula 17, for example according to the following series of reactions: a) hydrolysis of the cyano group to a carboxylic acid of formula 21, b) reaction of the carboxylic acid with, for example, lithium aluminum hydride or the borane-dimethyl sulfide complex to the corresponding alcohol, c) replacing the hydroxyl group of the alcohol with a cleavable group, for example, a p-toluenesulfonyloxy group, and d) replacing the cleavable group with a cyano group.

Similarly, cyano compounds of formula 23 can be obtained from cyan compounds of formula 19. Cyan compounds of formula 19 in which one or both substituents R 1 and R 2 have a meaning other than hydrogen can be obtained from the corresponding cyan compounds of formula 19, in which R 1 and / or R 2 represent a hydrogen atom, for example by alkylation with an alkyl halide in the presence of a base, such as lithium diisopropylamide.

Cyano compounds of formula 19 wherein R 2 represents a hydrogen atom can also be prepared by reacting ketones of formula 5 or an aldehyde of formula 22 with a reactant to introduce a cyano group, such as p-toluenesulfonylmethyl isocyanide. Likewise, cyano compounds of formula 23 can be obtained from aldehydes or ketones of formula 6.

Acid chlorides of formulas 20, 12 and 13 can be prepared by reacting carboxylic acids with resp. formulas 21, 14 and 15 with, for example, thionyl chloride.

Aldehydes of formula 22 can be obtained by methods known in the art. Examples of suitable methods are given below: a) reduction of cyano compounds of formula 17 with, for example, di-tert-butylaluminum hydride or diisobutylaluminum hydride, b) reduction of carboxylic acid derivatives, for example i) by reduction of tertiary amides formed by reaction of secondary amines with acid chlorides with formula 20, for example, if the secondary amine is a dialkylamine using lithium diethyoxyaluminohydide as the reducing agent or if the secondary amine is ethyleneimine using lithium aluminum hydride as the reducing agent, ii) by reducing acid chlorides of the formula 20 with, for example, lithium triester .butoxyaluminohydride.

c) oxidation of alcohols (prepared by reduction of carboxylic acids of formula 21) with, for example, the chromium trioxide-pyridine complex in dichloromethane under anhydrous conditions.

The therapeutic activity of the compounds of the formula I of the invention is indicated by the ability of these compounds to determine the hypothermic effects of reserpin in the following manner. Male mice (of the Charles River CDI strain) weighing between 18 and 30 g were divided into groups of 5 and provided with food and water ad libitum. After 5 days, the 7 192201 body temperature of each mouse was taken orally and the mice were injected intraperitoneally with reserpine (5mg / kg) dissolved in deionized water containing ascorbic acid (50mg / ml). The amount of liquid injected was 10 ml / kg body weight. The food was taken away 9 hours after the start of the experiment, but water was still available ad libitum. 24 hours after the start of the experiment, the temperatures of the mice were taken up again and the mice to be tested were suspended in a 0.25% solution of hydroxyethyl cellulose (under the trade name Cellosize QP 15 000 by Union Carbide in marketed) in deionized water at a dose of 10 ml / kg body weight. Three hours later, the temperatures of all mice were taken up again. The percentage reversal of the reserpine-induced loss of body temperature pasture is then calculated using the formula: (temperature after 27 hours - temperature after 24 hours) 1QQ (temperature after 5 hours - temperature after 24 hours) *

The mean value for each group of 5 mice was calculated at different dosages to allow to obtain a mean dose value causing a 50% bend (EDS0). All compounds, final products of the following examples, gave ED 2 values of 30 mg / kg or less. It will be apparent to those skilled in the art that these tests show that the compounds of the invention exert an antidepressant action in humans.

The following table lists compounds of the invention of formula 1 having ED50 values of 10 mg / kg or less in the test described above.

TABLE

Example 25 - I 1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride, IV N-methyl-1 - [1 - (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride, II N, N-dimethyl -1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride, 1 (d) 1 - [1 - (4-iodophenyl) cyclobutyl] ethylamine hydrochloride, 30 IV (1) N-methyl-1 - [1- (4-iodophenyl) cydobutyl] ethylamine.hydrochloride, 11 (b) Ν, Ν-dimethyM - [1 - (4-iodophenyl) cyclobutyl] ethylamine.hydrochloride, IV (g) N-methyl-1 - [1 - (2-naphthyl) cyclobutyl] ethylamine.hydrochloride, XIV Ν, Ν-dimethyM - [1 - (4-chloro-3-trifluoromethylphenyl) cyclobutyl] ethylamine.hydrochloride, X (s) 1 - [1 - (4- chlorophenyl) cyclobutyl] butylamine hydrochloride, 35 IV (j) N-methyl-1 - [1 - (4-chlorophenyl) cyclobutyl] butylamine hydrochloride,

X1 (e) N, N-dimethyl-1 - [1 - (4-chlorophenyl) cyclobutyl] butylamine hydrochloride, X 1 - [1 - (3,4-dichlorophenyl) cyclobutyl] butylamine hydrochloride, VIII N-methyl- 1 - [1 - (3,4-dichlorophenyl) cyclobutyl] butylamine hydrochloride, XII N, N-dimethyl-1 - [1 - (3,4-dichlorophenyl) cyclobutyl] butylamine hydrochloride, 40 X (j) 1- [1- (4-biphenylyl) cyclobutyl] butylamine hydrochloride,

X1 (e) Ν, Ν-dimethyM - [1- (4-biphenylyl) cyclobutyl] butylamine hydrochloride, X (r) 1 - [1 - (4-chloro-3-fluorophenyl) cyclobutyl] butylamine hydrochloride,

III (b) N-formyl-1 - [1 - (4-chloro-3-fluorophenyl) cyclobutyl] butylamine, X (k) 1 - [1 - (3-chloro-4-methylphenyl) cyclobutyl] butylamine, hydrochloride, 45 V11 (d) N-formyl-1- [1-phenylcyclobutyl] butylamine, X (w) 1 - [1 - (3-trifluoromethylphenyl) cyclobutyl] butylamine, hydrochloride, X (1) 1 - [naphth- 2-yl) cyclobutyl] butylamine hydrochloride, X (v) 1 - [1 - (6-chloomaphth-2-yl) cyclobutyl] butylamine, IX (a) N-methyl-1 - [1 - (4-chlorophenyl) cyclobutyl] -2methylpropylamine.hydrochloride, 50 l (c) 1- [1- (4-chlorophenyl) cyclobutyl] pentylamine.hydrochloride, IV (k) N-methyl-1 - [(4-chlorophenyl) cyclobutyl] pentylamine.hydrochloride,

X1 (a) Ν, Ν-dimethyM - [1-phenylcyclobutyl] -3-methylbutylamine.hydrochloride, X (c) 1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine.hydrochloride, IX (e) N-methyl-1 - [1 - (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride, 55 X N, N-dimethyl-1 - [1 - (4-chlorophenyl) cyclobutyl] -3-methyl-butylamine. hydrochloride,

III (a) N-formyl-1 - [1 - (4-chlorophenyl) cyclobutyl] -3-methylbutylamine, 192201 8 TABLE (continued)

Example 5 X1 (i) N, N-dimethyl-1 - [1 - (3,4-dichlorophenyl) cyclobutyl] -3-methyl-butylamine hydrochloride, IX (j) N-methyl-1 - [1 - (naphth -2-yl) cyclobutyl] -3-methylbutylamine.hydrochloride, IX (I) N-methyl-1 - [1 - (3,4-dimethylphenyl) cyclobutyl] -3-methyl-butylamine.hydrochloride, X (i) { 1- (4-chlorophenyl) cyclobutyl] (cyclopropyl) methylamine hydrochloride, IX (d) N-methyl- [1- (4-chlorophenyl) cyclobutyl] (cyclopentyl) methylamine hydrochloride, 10 X (g) {1 - ( 4-chlorophenyl) cyclobutyl] (cyclohexyl) methylamine hydrochloride, IX (i) N-methyl- [1- (4-chlorophenyl) cyclobutyl] (cyclohexyl) methylamine hydrochloride, X (n) {1- (3,4- dichlorophenyl) cyclobutyl] (cyclohexyl) methylamine hydrochloride, IX (k) N-methyl- [1- (3,4-dichlorophenyl) cyclobutyl] (cyclohexyl) methylamine hydrochloride, X (m) {1- (4- chlorophenyl) cyclobutyl] (cycloheptyl) methylamine hydrochloride, 15 X (h) 1 - [1 - (4-chlorophenyl) cyclobutyl] -2-cyclopropylethylamine hydrochloride,

X1 (f) N, N-dimethyl-1 - [1 - (4-chlorophenyl) cyclobutyl] -2-cyclohexyl-ethylamine.hydrochloride, X (e) a- [1- (4-chloro-phenyl) cyclobutyl] benzylamine.hydrochloride ,

III (a) N-methyl-a- [1 - (4-chlorophenyl) cyclobutyl] benzylamine hydrochloride, X (z) 1 - [1 - (4-chloro-2-fluorophenyl) cyclobutyl] butylamine, 20 Xl (1 ) N, N-dimethyl-1 - [1 - (4-chloro-2-fluorophenyl) cyclobutyl] butylamine hydrochloride, XLI 1 - [1 - (3,4-dichlorophenyl) cyclobutyl] methyl} propylamine, hydrochloride, XXXV ( a) N, N-dimethyl-1 - {{1 - (3,4-dichlorophenyl) cyclobutyl] methyl} propylamine hydrochloride, XXVII (b) N, N-dimethyl-2- [1- (4-iodophenyl) cyclobutyl ] ethylamine, hydrochloride, XXI N-ethyl-1 - [1 - (3,4-dichlorophenyl) cyclobutyl] ethylamine, hydrochloride and XXII N, N-diethyl-1 - [1 - (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride.

In the following examples, all compounds have been characterized by conventional analytical methods and satisfactory elemental analyzes have been obtained. All temperatures and boiling points are expressed in ° C, ether refers to diethyl ether.

Example I

A solution of 25 g of 3,4-dichlorobenzyl cyanide and 15 ml of 1,5-dibromopropane in 150 ml of dry dimethyl sulfoxide was added dropwise to a stirred mixture of 7.5 g of sodium hydride in 7.5 g of mineral oil in a nitrogen atmosphere and 200 ml of dimethyl sulfoxide at a temperature between 30 and 35 ° C. The mixture was stirred at room temperature for 2 hours and then 8 ml of propanol-2 and then 110 ml of water were added dropwise. The mixture was filtered through diatomaceous earth and the solid residue was washed with ether. The ethereal layer was separated, washed with water, dried and evaporated. 1- (3,4-Dichlorophenyl) -1-cyclobutanecarbonitrile (bp: 108-120 ° C at 0.15 mm Hg) 40 was recovered by distillation. This method is a modification of that described by Butler and Pollatz (J. Org. Chem., 36, (9, 1971), 1308-1309).

The 1- (3,4-dichlorophenyl) -1-cyclobutanecarbonitrile (21.7 g) prepared as described above was dissolved in 50 ml dry ether and this solution was added under nitrogen to the product of the reaction of gaseous methyl bromide with 3.9 g of magnesium shavings in 150 ml of dry ether. The mixture was then stirred at room temperature for 2 hours and then refluxed for 2 hours. Crushed ice and then 100 ml concentrated hydrochloric acid were then added and the mixture was refluxed for 2 hours. The ether layer was then separated, washed with water and aqueous sodium bicarbonate, dried and evaporated. 1-Acetyl-1- (3,4-dichlorophenyl) cyclobutane (boiling point: 108-110 ° C at 0.2 mm Hg) was separated by distillation.

50 1-Acetyl-1- (3,4-dichlorophenyl) cyclobutane (9.1 g), 6.5 ml formamide and 3 ml 98% formic acid prepared in the manner described above were heated at 180 ° C for 16 hours, to obtain N-formyl-1 - [- (3,4-dichlorophenyl) cyclobutyl] ethylamine. Then 20 ml of concentrated hydrochloric acid were added and the mixture was refluxed for 3 hours. The solution was then cooled with ether and cooled and a sodium hydroxide solution was added. The product was extracted with ether and the ether extract was washed with water, dried and evaporated. Distillation separated 1 - [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine (bp: 112-118 ° C at 0.2 mm Hg). The amine was dissolved in propanol-2 and concentrated hydrochloric acid and the resulting solution was evaporated to dryness, to give 1- (1- (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride (mp: 185-195 ° C), (formula 1, η = O; R., = Me; R2, R3 and R4 = H; R5 = 4-CI and R6 = 3-CI).

5 Example 1a

The previously described preparation of N-formyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine (melting point: 124-125 ° C) (example 1 (a), formula 1, η = 0; R1 = Me R2 = H; R3 = H; R4 = CHO; RS = 4-Cl and R6 = 3-Cl) was repeated and the product separated by cooling the reaction mixture and filtering the solid product formed. The formamide was then hydrolyzed with concentrated hydrochloric acid in 10 denatured alcohol to give the hydrochloride of 1 - [1 - (3,4-dichlorophenyl) cyclobutyl] ethylamine.

The following compounds were prepared in a manner similar to that described in Example 1a above. Conditions for the hydrolysis of the formamides separated by suitable methods are noted in the footnotes.

15

Compounds of formula 34

Example R., Rs R $ kpt. (free melt of note

base) the HCl

20 salt

l (b) methyl Cl Η 107 ° / 1.2 A.

mm Hg

1 (c) n-butyl Cl H 138-139 ° B

25 l (d) methyl 1 H 205-207 ° C

1 (e) methyl Cl CF 3 218-217 ° D

A. Aqueous HCl industrial denatured alcohol.

B. The 1-valeryl-1- (4-chlorophenyl) cyclobutane was prepared in tetrahydrofuran. The hydrolysis was performed with concentrated HCl industrial denatured alcohol.

C. Concentrated HCl diethylene glycol dimethyl ether (similarly as described below in Example XII).

D. Concentrated HCl industrial denatured alcohol.

35

Example II

4.04 g of the product of Example I, 0.5 ml of water and 3.6 ml of 98% formic acid were mixed with cooling. Then 3.8 ml of 37-50% aqueous formaldehyde was added and the solution was heated at a temperature between 85 and 95 ° C for 5 hours. The solution was then evaporated to dryness, the residue acidified to 40 with concentrated hydrochloric acid and the water removed by repeated addition of propanol-2 followed by evaporation under reduced pressure. The crystals of N, N-dimethyl-1- (1- (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride (m.p .: 211-213 ° C) (formula 1, n = 0; R, = Me; R2 = H; R3, R4 = Me; Rs = 4-CI; R6 = 3-CI) were separated.

In a manner similar to that described above, the compounds of Examples 1 (b) and 1 (d) were converted to the following compounds.

Compounds of formula 26

Example output RΛ Rs R 6 mp. From kpt. of the 50 material HCI free base salt 55 ll (b) l (d) methyl J H 260-261 ° ll (a) l (b) methyl Cl H 98-100 ° / 0.5 mm Hg 192201 10

Example III

Analogous to that described above in Examples I and II, N, N-dimethyl-1 - [1- (4-biphenylyl) cyclobutyl] ethylamine hydrochloride (mp: 196-197 ° C) was prepared (formula 1 n = O, R = Me; R2 = H; R3, R4 = Me; R5 = 4-phenyl and R6 = H).

5

Example IV

15 g of 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane prepared as described in Example I, 47.5 ml of N-methylformamide, 10.3 ml of 98% formic acid and 1.5 ml of a 25% The aqueous methylamine solutions were mixed and heated at a temperature between 170 and 180 ° C for 8 hours with stirring. Then the mixture was cooled and extracted with ether. The ether extract was washed, dried and evaporated to give a light yellow oil which was refluxed with 50 ml of concentrated hydrochloric acid for 2 hours. 50 ml of industrial denatured alcohol technical spirit were added; (IMS) and reflux the mixture for 16 hours. The mixture was then cooled to 0 ° C, the white precipitate was filtered off, washed with acetone and dried. The product obtained, N-methyl-1- [1-15 (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride, has a melting point of 254-256 ° C (formula 1 n = 0; R1 = Me; R2 = H; R3 = Me; R4 = H; Rs = 4-CI and R6 = 3-CI).

In an analogous manner as described above, the following compounds of formula 1 were prepared:

Compounds of formula 27 20 -

Example R1 R5 R6 kpt. from the smpt. of the amine HCl salt IV (a) Me Cl H 98-100 ° / 0.15 240-241 ° 25 mm Hg IV (b) Me H Cl 269-272 ° IV (c) Me Br H 96-98 ° / 0.1 mm Hg IV (d) Me H Br 251-255 ° 30 IV (e) Me CF3 H 219-221 ° IV (f) Me H CF3 225-228 ° IV (g) Me - (CH = CH) 2- 254-257 ° IV (h) Me Cl CF3 198-200 ° IV (i) Et Cl H 238-240 ° 35 IV (j) Pr Cl H 228-229 ° A) IV (k) Bu Cl H 152 -153 ° A) IV (I)) Me IH 242-243 °

Note A: The ketone starting material was run in tetrahydrofuran instead of ether as a solvent.

40

Preface V

A mixture of 50 ml of a 70% aqueous solution of ethyl amine and 100 ml of water was gradually mixed with a mixture of 50 ml of 98% formic acid and 100 ml of water to give a neutral solution which was at 100 ° C / 100 mm Hg was evaporated until 180 ml of water were collected. The residue 45 was heated to 140 ° C and 10.4 g of 1-acetyl-1 - [(4-chlorophenyl) cyclobutane, prepared in an analogous manner as described in Example I for 1-acetyM- (3,4-dichlorophenyl) cyclobutane , and 10 ml of 98% formic acid pastures are added. This mixture was heated in an oil bath at a temperature of 180-200 ° C for 16 hours. The mixture was then distilled until an internal temperature of 170 ° C was reached and the mixture was kept at this temperature for 2 hours. Any volatile material present was removed by distillation at 160 ° C / 20 mm Hg and the residue was refluxed for 3 hours with 15 ml concentrated hydrochloric acid and 15 ml industrial denatured alcohol (IMS). The IMS was evaporated on a rotary evaporator and the residue was washed with ether. The pH of the water phase was adjusted to 12 with sodium hydroxide and extracted with ether. The ethereal extract obtained was dried and a residue was obtained therefrom, which was treated with hydrochloric acid after evaporation. There was thus obtained 55 N-ethyl-1- [1- (4-chlorophenyl) -cyclobutyl] ethylamine hydrochloride (melting point: 203-205 ° C) (formula 1 n = O; R, = Me; R2 = H; R3 = Et; R4 = H; R5 = 4-CI; R6 = H).

11 192201

Example VI

15 g of 1- (4-Chlorophenyl) -1-cyclobutanecarbonitrile, prepared analogously to 1- (3,4-dichlorophenyl) -cyclobutanecarbonitrile in Example 1, in 50 ml dry ether were added to the product of the reaction of 3 , 18 g of magnesium shavings and 15.99 g of propyl bromide in 50 ml of dry ether. The ether was replaced with tetrahydrofuran and the mixture was refluxed with stirring for 18 hours. The mixture was cooled and ice and then 52 ml of concentrated hydrochloric acid were added. The resulting mixture was stirred at reflux for 10 hours and extracted with ether. A residue was obtained from the ether extracts, from which 1-butyryl-1- (4-chlorophenyl) cyclobutane (bp: 106-108 ° C / 0.3 mm Hg) was distilled.

A mixture of the ketone prepared in the manner described above (21 g) and 6 ml of 98% formic acid for 1.5 hours at 160 ° C was added to 15 ml of formamide. After the addition, the temperature was raised to 180-185 ° C and the reaction mixture was kept within this range for 5 hours. The mixture was cooled and extracted with chloroform to give a thick gum from which, by heating with petroleum ether (boiling point: 60-80 ° C), a colorless solid product was obtained which was obtained from petroleum ether (boiling point: 60-80 ° C) was recrystallized. There was thus obtained N-formyl-1 - (1- (4-chlorophenyl) cyclobutyl] butylamine (melting point: 97.5-98.5 ° C (formula 1 n = 0; R = propyl; R2 = H; R3 = H; R4 = CHO; R5 = 4-CI; R6 = H).

Example VII

A solution of 35.2 g of 1- (3,4-dichlorophenyl) -1-cyclobutanecarbonitrile, prepared as described in Example I, in 100 ml of ether was added to a solution of propyl magnesium bromide, which was prepared by reaction of 32 g of propyl bromide with 6.36 g of magnesium shavings in 100 ml of ether. The ether was replaced with dry toluene and the mixture was refluxed for 1 hour. Then 200 ml of water and then 120 ml of concentrated hydrochloric acid were added and the mixture was refluxed for 1 hour. The reaction mixture was extracted with ether and after washing and drying the extract a residue was obtained, from which 1-butyryl-1- (3,4-dichlorophenyl) cyclobutane (bp: 120-128 ° C at 0.25 mm Hg) was distilled.

37.0 g of the ketone prepared as described above and 9 ml of 98% formic acid were added to 23.5 ml of formamide at 170 ° C, and the temperature was held at 175-180 ° C for 5 hours. A further 4.5 ml portion of formic acid was added and the mixture was kept at a temperature between 175 and 180 ° C for an additional 15 hours. The mixture was extracted with ether, from which a thick oil was obtained by evaporation, which was crystallized from petroleum ether (bp: 60-80 ° C). There was thus obtained N-formyl-1 - {1- (3,4-dichlorophenyl) cyclobutyl] butylamine, m.p. 103-105 ° C (formula I, n = O; R1 = propyl; Ra = H; R3 = H ; R4 = CHO; Rs = 4-CI and R6 = 3-CI) 35 In an analogous manner as described above, the following compounds were prepared:

Compounds of Formula 28

Example Rt Rs Re smpt. (° C) 40 -

Vll (a) isobuty! Cl H 110-112 °

V11 (b) propyl Cl F 115-116 °

V11 (c) phenyl Cl H 94-96 ° 45 V11 (d) propyl Η H 98-102 °

Example VIII

4.0 g of the product of Example 7 in 25 ml of dry tetrahydrofuran in a nitrogen atmosphere was quickly added to a stirred mixture of 1.4 g of lithium aluminum hydride in 25 ml of dry tetrahydrofuran.

The mixture was then heated under reflux for 5 hours and then cooled. 15 ml of water and then 3 ml of a 10% strength sodium hydroxide solution were added and the mixture was filtered through diatomaceous earth. The product was extracted with ether, back extracted with 5N hydrochloric acid and the water layer was made alkaline and extracted with ether. An oil 55 was obtained from the ether extract, which was dissolved in 5 ml of propanol-2 and concentrated hydrochloric acid was added to pH 2. By evaporation of the resulting solution, a white product was obtained, which was collected, washed with acetone and dried. The product was N-methyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] buthylamine hydrochloride and had a 192201 12 melting point of 234-235 ° C. (formula 1 n = O; R- = propyl; R2 = H; R3 = H; R4 = Me; Rs = 4-Cl and R6 = 3-Cl). The following compounds were prepared in an analogous manner as described above:

Compounds of formula 27 5 -

Example R., Rs R6 m.p. (° C)

III (a) phenyl Cl H 275-278 °

Vlll (b) n-propyl Cl H 223-228 ° 10 -: -

Example IX

A solution of 10 g of the product of Example VII in 50 ml of ether was added to 40 ml of a 70% solution of sodium bis (2-methoxyethoxy) aluminum-15 hydride at a temperature between 25 and 30 ° C. in toluene. The mixture was then stirred at this temperature for 4 hours. 25 ml of water were then added dropwise with cooling and the mixture was filtered through diatomaceous earth. Aqueous sodium hydroxide was then added and extracted with ether. The ether extract was washed with water and back extracted with 5N hydrochloric acid. A white solid product (melting point: 232-235 ° C) separated on the interface and was collected. A base was added to the water phase, and the mixture was further extracted with ether. Evaporation of the ether extract gave an oil, which was dissolved in 5 ml of propanol-2 and concentrated hydrochloric acid was added to pH 2.

A white solid product was obtained by evaporation to dryness (melting point: 233-236 ° C). The white solid products were combined and recrystallized from propanol-2. There was thus obtained N-methyl-1 - (1- (3,4-dichlorophenyl) cyclobutyl] butylamine hydrochloride (melting point: 236-237 ° C) (formula 1n = O; R = propyl; R2 = 25 H; R3 = H; R4 = Me; Rs = 4-CI and Re = 3-CI).

The following compounds were prepared in an analogous manner as described above. If the formylite corridor material! insoluble in ether, a solution of the reducing agent was added to a stirred suspension of the formyl compound. As the size of the R group increased, the hydrochloride salts of the desired compounds became less soluble in the water phase and more soluble in the organic phase, necessitating appropriate modifications of the separation process, as will be apparent to those skilled in the art.

Compounds of Formula 27 Example R., R5 R6 m.p. (° C) IX (a) isopropyl Cl H 257-259 ° IX (b) sec.butyl Cl H 209-212 ° IX (c) isobutyl Cl H 225-233 ° 40 IX (d) cyclopentyl Cl H 252-256 ° IX (e) n-hexyl Cl H 117-118 ° IX (f) 4-methoxyphenyl Cl H 264-266 ° IX (g) 3-methoxyphenyl Cl H 254-255 ° IX (h) 2-methoxyphenyl Cl H 149 -153 ° 45 IX (i) cyciohexyl Cl H 170-172 ° IX (j) isobutyl - (CH = CH2) - 256-259 ° IX (k) cyciohexyl Cl Cl 223-224 ° IX (I) isobutyl Me Me ( 1) IX (m) n-propyl OMe H 173-175 ° 50 IX (n) methyl phenyl H 116-118 ° (1) free base boiling point> 150 ° at 1.0 mm Hg.

Example X.

55 4 g of the product of Example Fly, 25 ml of diethylene glycol diethyl ether, 10 ml of water and 10 ml of concentrated hydrochloric acid were mixed and this mixture was refluxed for 9 hours. The solution was then washed with ether and an aqueous sodium hydroxide solution was added before extracting 13 192201 with ether. The ether extract was washed with sodium chloride solution and water and an oil was obtained on evaporation. 3.19 g of this oil were dissolved in a mixture of 4 ml of propanol-2 and 20 ml of ether and 1.5 ml of concentrated hydrochloric acid were added. The solvent was evaporated under reduced pressure. By repeated dissolving in industrial denatured alcohol and evaporation under reduced pressure, a gum was obtained which solidified on heating under reduced pressure. The product was recrystallized from petroleum ether (boiling point: 100-120 ° C) and had a melting point of 201-203 ° C. The product was 1- [1- (3,4-dichlorophenyl) cyclobutyl] buthylamine hydrochloride (formula 1 n = 0; R. = propyl; R2 = H; R3, R4 = H; Rs = 4-Cl and R6 = 3-CI).

In an analogous manner as described above, the following compounds were prepared. As the size of the Rt group increased, the hydrochloride salts of the desired compounds became less soluble in the water phase and more soluble in the organic phase, necessitating appropriate modifications in the separation process.

Compounds of formula 34 15 -: -

Example R1 Rs R6 mp.

X (a) isopropyl Cl H 200-202 ° X (b) sec-butyl Cl H 178-179 ° 20 X (c) isobutyl Cl H 163-165 ° X (d) cyclopentyl Cl H 185-210 ° (dec. ) X (e) phenyl Cl H 271-276 ° X (f) 4-methoxyphenyl Cl H 214-219 ° X (g) cyclohexyl Cl H 206-210 ° 25 X (h) isobutyl Η H 210-212 ° X ( i) cyclopropyl Cl H 204-206 ° X (j) n-propyl Ph H 235-236 ° X (k) n-propyl Me Cl 214-217 ° X (l) n-propyl - (CH = CH) 2- 157-159 ° 30 X (m) cycloheptyl Cl H 156-162 ° X (n) cyclohexyl Cl Cl 215 ° X (p) methyl Cl F 215-217 ° X (q) n-propyl OMe H 178-179 ° X (r) n-propyl Cl F 186-188 ° 35 X (s) n-propyl Cl H 174-175 ° X (t) cyclohexylmethyl Cl H 148-150 ° X (u) cyclopropylmethyl Cl H 184-185 ° X ( v) n-propyl -CH = CH- CCI = CH- (a) X (w) n-propyl H CF3 126-128 ° 40 X (x) 4-fluorophenyl Cl H 279 ° X (y) methyl -C = C- 248-262 ° - C = C - CH = CH - / \

CH CH

\ /

j / - CH — CH

45 --——-- (a) boiling point of the free base 168 ° C / 0.05 mm Hg.

(b) replacing diethylene glycol dimethyl ether with ethylene glycol dimethyl ether.

In an analogous manner as described above, 1- [1- (4-chloro-2-fluorophenyl) cyclobutyl] butylamine (bp .: 50 99 ° C / 0.05 mm) (formula 1 n = 0; R = propyl; R2, R3 and R4 = H; R5 = 4-Cl; R6 = 2-F), 1- (1- (2-fluorophenyl) cyclobutyl] butylamine hydrochloride (melting point: 175-177 ° C). (Formula 1 n = 0; R = propyl; R2, R3, R4, R5 = H and R6 = 2-F) and 1- [1- (4-chloro-2-methyl) cyclobutyl] butylamine hydrochloride (m.p .: 188- 190 ° C) (formula 1 n = 0; R = propyl; R2, R3 and R4 = H; Rs = 4-Cl and Re = 2-Me) prepared as in examples X (z), X ( aa) and X (bb).

192201 14

Example XI

3.3 g of the product of Example X (c) in the form of the free base, 2.99 g of formic acid and 1 ml of water were mixed with cooling. 3.93 ml of 37-40% aqueous formaldehyde was then added and the mixture heated at a temperature between 85 and 95 ° C for 18 hours. An excess of dilute hydrochloric acid was added and the solution evaporated to dryness. The residue was made alkaline with a 5N sodium hydroxide solution and the product was extracted into ether. Evaporation of the ether gave a pale yellow oil, which was dissolved in a mixture of 4 ml of propanol-2 and 20 ml of ether, to which 2 ml of concentrated hydrochloric acid were added dropwise. The solution was evaporated and the residue was repeatedly dissolved in ether and evaporated to dryness under reduced pressure to obtain a gum which was treated with petroleum ether (bp: 60-80 ° C). A yellow solid product was obtained, which was recrystallized from acetone. This product was N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride (mp: 195-197 ° C). (Formula 1 n = 0; R = isobutyl; R2 = H; R3, R4 = Me; Rs = 4-CI and R6 = H).

The following compounds of formula 1 have been prepared in an analogous manner as described above.

15 Compounds of Formula 26

Example output R, Rs R6 mp.

material 20 Xl (a) X (h) isobutyl Η H 195-198 °

X1 (b) X (j) n -propyl Ph H 194-196 °

X1 (c) X (n) cyclohexyl Cl Cl 227-228 °

X1 (d) X (q) n -propyl OMe H 187-188 °

Xl (e) X (s) n-propyl Cl H 194-196 ° 25 Xl (f) X (t) cyclohexyl-Cl H 194-196 ° methyl

X1 (g) X (u) cyclopropyl-Cl H 165-167 ° methyl

X1 (h) X (v) n-propyl -CH = CH-CCI = CH- (a) 30 XI (i) - isobutyl Cl Cl 225-226 ° XI0) X (x) 4-fluorophenyl Cl H 234 °

X1 (k) - propyl isopropyl Η 211-213 ° (a) boiling point of the free base <250 ° C / 0.05 mm Hg.

35 Example Xl (1)

In an analogous manner as described above, N, N-dimethyl-1- [1- (4-chloro-2-fluorophenyl) cyclobutyl] butylamine hydrochloride (mp .: 183 ° C) was prepared (formula 1 n = R = propyl; R2 = H; R3, R4 = Me; R5 = 4-Cl and R6 = 2-F).

40 Example XII

8.3g of the product of Example VII, 50ml of the dimethyl ether of diethylene glycol, 20ml of water and 20ml of concentrated hydrochloric acid were mixed and this mixture was refluxed for 16 hours. The mixture was then poured into water, an aqueous sodium hydroxide solution was added and the product was extracted into ether. A dark oil was obtained by evaporation. A sample of this oil 45 (7.9 g), 0.7 ml of water and 6.5 ml of formic acid were mixed and 6.5 ml of formaldehyde were added. This mixture was refluxed for 2 hours and then concentrated, then 10 ml of concentrated hydrochloric acid and 10 ml of propanol-2 were added. Evaporation to dryness gave N, N-dimethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl butylamine hydrochloride (melting point: 195-196 ° C) as a white solid product (formula 1 n = 0; R propyl; R2 = H; R3, R4 = Me; R5 = 4-Cl and R6 = 3-Cl).

50

Example XIII

37.6 g of 1- (4-chlorophenyl) -1-cyclobutanecarbonitrile, prepared analogously as 1- (3,4-dichlorophenyl) -1-cyclobutanecarbonitrile, described in Example 1, were added to a solution of 32.4 g potassium hydroxide in 370 ml diethylene glycol and this mixture was refluxed for 3.5 hours. The reaction mixture was then poured into a mixture of ice and water and the resulting solution was washed with ether. The aqueous layer was added to a mixture of 100 ml of concentrated hydrochloric acid and ice, and the resulting precipitate of 1- (4-chlorophenyl) -1-cyclobutanecarboxylic acid (mp: 86-88 ° C) was collected, washed with water and dried .

A solution of 10.5 g of the acid prepared as described above in 150 ml of tetrahydrofuran in a nitrogen atmosphere was added dropwise to a stirred suspension of 2 g of lithium aluminum hydride in 150 ml of tetrahydrofuran. The mixture was then stirred at reflux for 2 hours and water added. The mixture was filtered through diatomaceous earth and extracted into ether. After washing with water and drying and evaporating the ether, a residue was obtained which was recrystallized from petroleum ether (bp: 60-80 ° C). The product was 1- [1- (4-chlorophenyl) cyclobutyl] methyl alcohol (melting point: 60-62 ° C).

A solution of 60 g of the alcohol prepared in the manner described above was added dropwise in 52 ml of pyridine to a solution of 60 g of p-toluenesulfonyl chloride in 100 ml of pyridine, which was cooled with ice. The temperature was allowed to rise to room temperature and the reaction mixture was kept at this temperature for 18 hours. Pouring the reaction mixture into a mixture of ice and 200 ml of concentrated hydrochloric acid precipitated 1- [1- (4-chlorophenyl) cyclobutyl] methyl p-toluenesulfonate (mp: 99-100 ° C).

A solution of 97 g of the sulfonate compound prepared as described above and 16.6 g of sodium cyanide in 370 ml of dimethyl sulfoxide were heated on a steam bath for 18 hours. The mixture was then poured onto water and extracted with ether. After washing and drying, the ether was evaporated to leave a solid residue of 2- [1- (4-chlorophenyl) cyclobutyl] acetonitrile (mp: 63-65 ° C).

A solution of 16.5 g of di-isopropylamine in 50 ml of tetrahydrofuran in a nitrogen atmosphere was stirred at 0 ° C and 100 ml of a 1.6 M solution of n-butyl lithium in 100 ml of hexane was added. The reaction mixture was stirred for 30 minutes and then cooled to -78 ° C. A solution of 9.5 g of 2- [1- (4-dichlorophenyl) cyclobutyljacetonitrile, prepared as described above, was then added dropwise into 25 ml of dry tetrahydrofuran. The temperature of the reaction mixture was allowed to rise to 0 ° C and the mixture was then stirred for 10 min before adding a solution of 10 ml of methyl iodide in 10 ml of tetrahydrofuran. Then 75 ml of tetrahydrofuran were added to obtain a homogeneous solution, after which a solution of 4 ml of methyl iodide in 10 ml of tetrahydrofuran was added. The mixture was stirred at room temperature for 2 hours and then 50 ml of water were added. The aqueous phase was washed with ether and the ether was combined with the organic phase of the reaction mixture. The combined organic phases were washed three times with 5N hydrochloric acid, three times with water, dried and evaporated to give an oil which solidified and recrystallized from industrial denatured alcohol. There was thus obtained 2- [1- (4-dichlorophenyl) cyclobutyl] -2-methylpropionitrile (melting point: 73-75 ° C).

4 g of the nitrile prepared as described above were heated under reflux with 8 g of potassium hydroxide for 24 hours in 40 ml of diethylene glycol. The reaction mixture was then cooled, added to 50 ml of water and the aqueous phase was washed twice with ether. The water phase was acidified with 5N hydrochloric acid and extracted with three portions of ether. The combined ether extracts were washed with water, dried and evaporated, yielding a white solid, which was recrystallized from petroleum ether (bp: 60-80 ° C). There was thus obtained 2- [1 - (4-dichlorophenyl) -cyclobutyl] -2-methylpropionic acid (mp: 95-110 ° C).

40 ml of oxalyl chloride were added to 2 g of the acid prepared as described above. After the initial turbidity disappeared, the mixture was refluxed for 1 hour. The excess oxalyl chloride was distilled off and the residual oil was added to 75 ml of concentrated ammonia. An oily solid product formed, which was extracted into ethyl acetate. The extract was washed with water, dried and evaporated to give 2- [1- (4-45 chlorophenyl) cyclobutyl] -2-methyl propionamide.

1.34 g of the amide prepared as described above were dissolved in a mixture of 8 ml of acetonitrile and 8 ml of water, 3.4 g of iodozobenzene bis-trifluoroacetate were added and the mixture was stirred at room temperature for 5.5 hours. Then 75 ml of water and 8 ml of concentrated hydrochloric acid were added and the mixture was extracted with ether. The ether extract was washed with 5N hydrochloric acid and the aqueous phase was made alkaline and extracted with further portions of ether, which were dried and evaporated. There was thus obtained an oil, which was dissolved in petroleum ether (boiling point: 80-100 ° C), and dry hydrogen chloride gas was passed through the solution. Filtration gave 1- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine hydrochloride (mp: 257-259 ° C). (formula 1 n = 0; R1f R2 = Me; R3, R4 = H; R5 = 4-Cl and Re = H).

192201 16

Example XIV

3.4 g of the product of Example IV (h) were mixed with 0.72 anhydrous sodium formate, 10 ml of 98% formic acid and 5 ml of a 37-40% aqueous formaldehyde solution and heated for 16 hours at a temperature between 85 and 95 ° C. The mixture was then diluted with 50 ml of water and its pH adjusted to 10 with an aqueous sodium hydroxide solution. The basic aqueous solution was extracted with ether, washed with water and dried over magnesium sulfate. Dry hydrogen chloride gas was then bubbled through the ether extract to give a white precipitate of N, N-dimethyl-1- [1- (4-chloro-3-trifluoromethylphenyl) cyclobutyl] ethylamine hydrochloride (mp: 246-247 ° C) ( formula 1 n = 0; R1 = Me; R2 = H; R3, R4 = Me; Rs = 4-Cl and R6 = 3-CF3).

10

Example XV

The preparation of salts of the compounds of the invention is illustrated by the following examples, in which equimolar amounts of the base and the acid were taken up in a solvent. The salt was then obtained from the solution by conventional methods.

15

Example base acid solvent mp. of the salt XV (a) X (s) citric acid aqueous acetone 158-160 ° 20 XV (b) X (s) maleic ether ether 155-157 ° XV (c) X (s) tartaric acid ether 152-155 ° XV (d ) II L (+) tartaric acid technical spirit 150-153 ° XV (e) note (a)) citric acid ether-methanol 163-164 ° (dec.) 25 (a) The base was 1- [1- (3.4 dimethylphenyl) cyclobutyl] -3-methylbuthylamine prepared in a similar manner as described in Example X.

Example XVI

A solution of 15.7 g of bromobenzene in 50 ml of ether was added dropwise to 2.4 g of magnesium curls in a nitrogen atmosphere with cooling. Then, a solution of 19.1 g of 1- (1- (4-chlorophenyl) cyclobutanecarbonitrile, prepared in a similar manner as described in Example I for 1- (3,4-dichlorophenyl) cyclobutanecarbonitrile, in 50 ml of ether was added and the ether was replaced with 130 ml of dry toluene, then the reaction mixture was heated on a steam bath for one hour, a sample (20 ml) of the resulting solution was added to a solution of 1 g of sodium borohydride in 60 ml of the dimethyl ether of diethylene glycol and stirring the mixture was added for 1.5 hours, then 60 ml of water was slowly added and the aqueous layer was extracted with toluene. The toluene extracts were washed with water, dried and evaporated, yielding a residue, which was dissolved in 50 ml of methanol. ml of 6N hydrochloric acid, filtered, and evaporated, treatment by treatment with dry acetone 40 gave a- [1 - (4-chlorophenyl) cyclobutyl] benzylamine hydrochloride (melting point: 277-279 ° C) (formula 1 n = O, R = Ph; R2 = H; R3, R4 = H; Rs = 4-CI; R6 = H).

Example XVII

62 ml of methyl formate were added dropwise with stirring and at a rate of 85.5 ml of isopropyl-45 amine at such a rate that the reaction mixture continued to flow gently. After addition, stirring was continued for 2 hours. The methanol was distilled off at 100 ° C and N-isopropylformamide (boiling point: 108-109 ° C / 25 mm Hg) was obtained by distillation.

10.4 g of 1-acetyl-1- (4-chlorophenyl) cyclobutane, prepared in an analogous manner as described in Example 1 for 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane, and 5 ml of 98% strength were added. Add formic acid to 43.5 g of 50 N-isopropylformamide and heat the mixture at 180 ° C for 4 hours. The excess starting material was distilled off under reduced pressure (20 mm.Hg), leaving a viscous residue, which was heated under reflux for 6 hours with 30 ml of concentrated hydrochloric acid. The reaction mixture was then washed with ether until a colorless solution was obtained. The aqueous phase was made alkaline, extracted with ether, dried and evaporated, yielding an oil, which was dissolved in 5N hydrochloric acid. 55 A yellow oil was obtained by evaporation, which was treated with petroleum ether (boiling point: 62-68 ° C), yielding N-isopropyl-1- [1- (4-chlorophenyl) cyclobutyl] ethylamine hydrochloride (melting point: 170- 174 ° C) (Formula 1 n = 0; R 1 = Me; R 2 = H; R 3 = isopropyl; R 4 = H; R 5 = 4-CL and R 6 = H).

17 192201

Voonbee / c / XVIII

7.0 g of 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane, prepared as described in Example 1, were slowly added to a mixture of 25 ml of pyrrolidine and 15 ml of 98% formic acid, which was left to stand for 5 hours. 130-135 ° C was heated. The mixture was stirred and heated to 160-165 ° C for 16 hours. After cooling, the mixture was poured onto 5 200 ml of 5N hydrochloric acid. The solution was washed with ether, alkaline extracted with ether with an aqueous sodium hydroxide solution. The ether extract was washed with water, dried and hydrogen chloride gas was passed into the extract, which was then evaporated to dryness. The residue was treated with dry ether to give a solid product which was recrystallized from propanol-2.

There was thus obtained N-1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylpyrrolidine hydrochloride (melting point: 233-10 235 ° C) (formula 1 n = 0; R1 = Me; R2 = H; R3 and R4 together with a nitrogen atom to which they are attached form a pyrrolidine ring (Rs = 4-CI and R6 = 3-CI).

Example XIX

10.5 g of 1- (4-chlorophenyl) -1-cyclobutanecarboxylic acid, prepared as described in Example XIII, were refluxed in 20 ml of thionyl chloride for 2.5 hours. The excess thionyl chloride was distilled off and the acid chloride of the aforementioned acid was distilled (bp: 82-96 ° C at 0.2 mm Hg).

A solution of 23.0 g of the acid chloride in 100 ml of dry tetrahydrofuran was slowly added to the product of the reaction of 3.0 g of magnesium shavings and 12.0 g of ethyl bromide in dry tetrahydrofuran at a temperature of -70 to - 60 ° C. The reaction mixture was kept at -60 ° C for one hour, after which the temperature was allowed to rise to 0 ° C. Then 50 ml of water and then 150 ml of 5N hydrochloric acid were added with cooling. The reaction mixture was extracted with ether, washed with water and sodium bicarbonate solution and dried. The solvent was evaporated and 1-propionyl-1- (4-chlorophenyl) cyclobutane was distilled (bp: 96-104 ° C at 0.25 mm Hg).

The ketone obtained in the manner described above was converted into N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] propylamine hydrochloride (m.p .: 213-215 ° C) in an analogous manner as described in Example 25 XII. (formula 1 n = 0; P1 = Et; R2 = H; R3, R4 = Me; R5 = 4-Cl and R6 = H).

Example XX

61 g of 1-acetyl-1- (4-chlorophenyl) cyclobutane (prepared in a similar manner as described in Example 1 for 1-acetyl-1- (3,4-dichlorophenyl) cydobutane), 0.75 was placed in an autoclave. g of platinum oxide, 60 g of a 33% solution of methylamine in ethanol and 30 ml of ethanol. The autoclave was filled with hydrogen and kept at 60 ° C and a pressure of 20 bar for 10 hours. The reaction mixture was then filtered through charcoal and water to solids with absolute alcohol. The solvents were then evaporated and a sample of the residue (10 g) was shaken with 50 ml of 2M hydrochloric acid and 50 ml of ether. The water layer was made alkaline and extracted with ether. A liquid was obtained from the ether extracts on evaporation, which was distilled at 109 ° C and 0.3 mm Hg. There was thus obtained N-methyl-1 - (1- (4-chlorophenyl) cyclobutyl] ethylamine (formula 1 n = 0; R, = Me; R2 = H; R3 = Me; R4 = H; R5 = 4-CI and R6 = H).

Example XXI

40 2.0 g of sodium borohydride were added to a solution of 1.5 g of 1- [1- (3,4-dichlorophenyl) cyclobutyl ethyiamine (prepared by treating the product of Example I with aqueous sodium hydroxide) in 30 ml glacial acetic acid . The mixture was then heated at a temperature between 95 and 100 ° C for 16 hours and then cooled. A solution of aqueous sodium hydroxide was added and the reaction mixture was extracted with ether. The ether extract was shaken with 5N hydrochloric acid, the aqueous layer was washed with ether, made alkaline and extracted with ether. Hydrogen chloride gas was then introduced into the ether extract, which was then evaporated to dryness. Treatment with acetone gave N-ethyl-1- (1- (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride (mp: 211-212 ° C). (Formula 1n = 0; Rj = Me; R2 = H ; R3 = Et; R4 = H; R5 = 4-CI and Rg = 3-CI).

50 Example XXII

A mixture of 0.5 g of N-ethyl-1- [1-3,4-dichlorophenyl) cyclobutyl] ethylamine (prepared by treating the product of Example XXI with an aqueous solution of sodium hydroxide) and 1 ml of acetic anhydride was stirred for 30 min. heated at a temperature between 40 and 45 ° C. The reaction mixture was then made alkaline and extracted with ether. The ether extract was washed, dried and evaporated to give 55 N-acetyl-N-ethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine as an oil.

This oil was dissolved in 10 ml of tetrahydrofuran and 0.5 ml of the borane-dimethyl sulfoxide complex was added dropwise thereto. The reaction mixture was then stirred at room temperature for 2 hours and then 192201 18 and then heated at a temperature between 35 and 40 ° C for 30 min. After cooling, the reaction mixture was made alkaline and extracted with ether. Hydrogen chloride gas was passed through the dried ether extract, which was then evaporated to dryness. Treatment with ether gave N, N-diethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride, mp: 119-201 ° C. (formula 1 n = 0; R1 = Me; R2 = H; 5 R3, R4 = Et; Rs = 4-Cl and R6 = 3-Cl).

Example XXIII

A mixture of 2.2 g of 1-acetyl-1- [1- (3,4-dichlorophenyl) cyclobutane (prepared as described in Example 1), 7 g of ammonium acetate, 0.4 g of sodium cyanoborohydride and 28 ml of methanol was added Stirred at room temperature for 4 days. Then the reaction mixture was poured into a mixture of ice and water and the resulting mixture was extracted with ether. The ether extract was washed with water and dried and the ether was removed to give 1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine as an oil. It was identified in the free base form by standard analytical methods as the compound of Example I.

15

Example XXIV

A mixture of 4.86 g of 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane prepared as described in Example 1 was heated, 1.6 g of hydroxylamine hydrochloride, 3.3 g of sodium acetate trihydrate, 15 ml of industrial denatured alcohol and 2 ml of water under reflux for 20 hours. The cooled reaction mixture was then poured into water and the separated oil was cooled to obtain a solid product which was recrystallized from industrial denatured alcohol. There was thus obtained 1-acetyl-1- (3,4-dichlorophenyl) -cyclobutanoxime (mp: 120-121 ° C).

A solution of the oxime (4.0 g) prepared in 50 ml of ether in a nitrogen atmosphere as described above was slowly added to a stirred suspension of 0.9 g of lithium aluminum hydride in 50 ml of ether. This mixture was then heated under reflux for one hour and, after cooling, first added water and then 27 ml of a 20% solution of Rochelle's salt (potassium sodium tartrate tetrahydrate) in water and 6 ml of a 10% solution of sodium hydroxide in water. The reaction mixture was then stirred for 1 hour and then extracted continuously with ether for 18 hours. The ether extract was dried and the ether was removed, leaving a solid product from which 1- [1- (3,4-dichloro-30-phenyl) cyclobutyl] ethylamine was separated by high pressure liquid chromatography.

This product was identified as the free base compound of Example 1 by standard analytical methods.

Example XXV

A 1M solution of diisobutylaluminohydride in 200 ml of hexane in a nitrogen atmosphere and at a temperature below -30 ° C was added to a solution of 31.4 g of 1-phenyl-1-cyclobutanecarbonitrile in 100 ml of ether. The temperature was kept at 0 ° C for 30 min and 200 ml of 5N hydrochloric acid was added at a temperature of -10 ° C. The reaction mixture was then washed with petroleum ether (boiling point: 60-80 ° C) and then heated to 40 ° C. The reaction mixture was extracted with petroleum ether (bp: 60-80 ° C), the extract was dried and evaporated to give 1-phenyl-1-cyclobutane-carbaldehyde as an oil.

Methylamine was bubbled through a solution of 9.4 g of the aldehyde prepared in 100 ml of toluene as described above, while keeping the temperature of the reaction mixture below 0 ° C. Then 20 g of magnesium sulfate, which had been dried over a flame and then cooled in a nitrogen atmosphere, were added to the reaction mixture, which was kept at room temperature for 16 hours before being filtered. The toluene was then removed by evaporation and the residue was dissolved in 50 ml of ether. This solution was added to a solution of propyl lithium prepared by slowly adding an excess (12.8 g) of propyl bromide to a suspension of 1.26 g of lithium in 50 ml of ether. The resulting solution was allowed to stand at room temperature for 16 hours. A trace of 50 unreacted lithium was filtered off and the filter was washed with ether, water and then with 5N hydrochloric acid. The filtrate and washings were heated on a steam bath for 1 hour. After cooling, the reaction mixture was washed with ether and the water layer was made alkaline with an aqueous sodium hydroxide solution. The reaction mixture was extracted with ether and the extract was dried and the ether was removed. There was thus obtained a residue from which N-methyl-1- [1- (1-phenylcyclobutyl) butylamine, bp: 55 80-86 ° C at 0.1 mm Hg, was distilled. The amine (2.3 g) prepared as described above was dissolved in 40 ml ether and hydrogen chloride gas was passed through this solution. Thus, N-methyl-1- (1-phenylcyclobutyl) butylamine, hydrochloride, m.p. 196-197 ° C, precipitated. (formula 1 19 192201 η = 0; R = propyl; Ra = H; R3 = Me; R4, Rs are H).

Example XXVI

A solution of 8.0 g of 1- (3-chloro-5-methyl) -1-cyclobutanecarbonitrile in 40 ml of ether was added to a solution of propyl magnesium bromide [prepared by reaction of 6.7 g of 1-bromopropane and 1, 3 g magnesium] in 80 ml ether and reflux this mixture for 2.5 hours. Two thirds of the ether were distilled off and then, after cooling, a solution of 3.5 g of sodium borohydride in 150 ml of ethanol was added. The mixture was kept at 50 ° C for 1 hour and first 50 ml of water and then 50 ml of 5N hydrochloric acid were added. The ether layer was separated, dried and evaporated to give a solid product, which was recrystallized from propanol-2. There was thus obtained 1- [1- (3-chloro-5-methyl) cyclobutyl] butylamine hydrochloride, m.p. 145-146 ° C.

The hydrochloride salt prepared in the manner described above was shaken with ether and a 5N sodium hydroxide solution and the ether layer was evaporated to yield the primary amine, which was in N, N-dimethyl-1- [1- (3-chloro-5- methyl) cyclobutyl] butylamine hydrochloride, m.p. 148 ° C, was reacted (formula 1 n = 0; R 1 = propyl; R 2 = H; R 3 and R 4 = Me; R 5 = 3-Cl and R 6 = 5-Me) , in an analogous manner as described in Example II.

Example XXVII

37.6 g of 1- (4-chlorophenyl) -1-cyclobutanecarbonitrile, prepared analogously as 1- (3,4-dichlorophenyl) -1-20 cyclobutanecarbonitrile described in Example I, was added to a solution of 32.4 g potassium hydroxide in 370 ml diethylene glycol and this mixture was refluxed for 30 min. The reaction mixture was then poured into a mixture of water and ice and the resulting solution was washed with ether.

The aqueous layer was added to a mixture of 100 ml of concentrated hydrochloric acid and ice and the resulting precipitate of 1- (4-chlorophenyl) -1-cyclobutanecarboxylic acid, mp 86-88 ° C, was washed with water and dried.

A solution of 10.5 g of the above acid in 150 ml of tetrahydrofuran was added dropwise to a stirred suspension of 2 g of lithium aluminum hydride in 150 ml of tetrahydrofuran in a nitrogen atmosphere. The mixture was then stirred at reflux for 2 hours and water added. The mixture was filtered through diatomaceous earth and the product extracted into ether. After washing with water and drying, the ether was evaporated to give a residue which was recrystallized from petroleum ether, bp 60-80 ° C. The product obtained is 1- [1- (4-chlorophenyl) cyclobutyl] methyl alcohol, mp 60-62 ° C.

A solution of 60 g of the above alcohol in 52 ml of pyridine was added dropwise to a solution of 60 g of p-toluenesulfonyl chloride in 100 ml of pyridine, which was cooled in ice. The temperature was then allowed to rise to room temperature and the reaction mixture was held for 18 hours. Pouring the reaction mixture into a mixture of ice and 200 ml of concentrated hydrochloric acid precipitated 1- [1- (4-chlorophenyl) -cyclobutylmethyl p-toluenesulfonate, mp: 99-100 ° C.

A solution of 97 g of the above-described sulfonate compound and 16.6 g of sodium cyanide in 370 ml of dimethyl sulfoxide was heated on a steam bath for 18 hours. The mixture was then poured onto 40 water and extracted with ether. After washing and drying, the ether was evaporated to leave a solid residue of 2- [1 - (4-chlorophenyl) cyclobutyl] acetonitrile, mp 63-65 ° C. 20 g of the aforementioned acetonitrile were dissolved in 120 ml of ether and the resulting solution was added dropwise to a stirred suspension of 5.84 g of lithium aluminum hydride in 80 ml of ether in a nitrogen atmosphere. The mixture was then stirred at room temperature for 1.5 hours and then refluxed for an additional 2 hours. Water was then added dropwise and the resulting mixture was filtered through diatomaceous earth. The residue was washed with ether. The filtrate was extracted with ether, the combined ether portions were washed with water and extracted with 5N hydrochloric acid. The acidic solution was washed with ether and an aqueous sodium hydroxide solution was added. The product was then extracted into ether, the extract was washed with water, dried and evaporated, yielding a residue, from which 2- [1- (4-chlorophenyl) cyclobutyl] ethylamine, bp: 119-121 °, was obtained by distillation. C at 1.5 mm Hg was obtained.

6.9 g of the ethylamine prepared in the manner described above, 6.6 ml of 98% formic acid, 09 g of water and 9 ml of a 37-40% solution of formaldehyde in water were heated on a steam bath for 18 hours. . The mixture was then cooled and an excess of concentrated hydrochloric acid was added. A yellow solid residue was obtained by drying 55 vapors. This solid product was partitioned between dichloromethane and a 5N sodium hydroxide solution and the aqueous layer extracted with an additional portion of dichloromethane. The dichloromethane portions were combined, washed with water, dried and evaporated, 192201 to give a solid residue which was dissolved in 15 ml of propanol-2 and to which concentrated hydrochloric acid was added to pH 2. Finally, the mixture was evaporated to dryness and the residue was recrystallized. from ethyl acetate to give colorless crystals of N, N-dimethyl-2 - [- 1 - (4-chlorophenyl) cyclobutyl ethylamine hydrochloride, m.p. 220-222 ° C (formula 1 n = 1; R ,, R2 = H; Ra, R4 = 5 Me; R5 = 4-CI and R6, R7 and R8 = H).

The following compounds were prepared in an analogous manner as described above:

Compounds of Formula 29 10 Example R5 Re m.p. of the HCl salt XXVII (a) Cl Cl 218-220 ° XXVII (b) IH 263-265 ° XXVII (c) -CH = CH-CH = CH- 234-236 ° 15 XXVII (d) Similarly, N N-dimethyl-2- [1- (4-chloro-2-fluorophenyl) cyclobutyl] ethylamine hydrochloride (mp 232-233 ° dec).

Example XXVIII

12 g of 2- [1- (4-chlorophenyl) cyclobutyi] ethylamine prepared according to Example XXVII were mixed, 12.4 g 1,4-dibromobutane and 14.3 g anhydrous sodium carbonate in 100 ml xylene and heated for 16 hours under reflux and with stirring. The mixture was then cooled, filtered and the xylene evaporated to give a residue from which N-2 [1- (4-chlorophenyl) cyclobutyl] ethylpyrrolidine was distilled, bp: 148-150 ° C at 1.5 mm Hg. , separated, (formula 1 n = 1; R 1 (R 2 = H; R 3 and R 4 together with the nitrogen atom form a pyrrolidine ring, R 5 = 4-Cl; R 6, R 7 and R 8 = H).

In a manner similar to that described above, the following compounds were prepared and separated as their hydrochloride salts.

30 Compounds of Formula 30

Example Rs R6 mp. of the HCl salt XXVIII (a) Cl Cl 213 ° 35 XXVIII (b) -CH-CH-CH = Ch- 232-233 °

Example XXIX

A solution of 30 g of N-2- [1- (4-chlorophenyl) cyclobutyl] acetone tril, prepared as described in Example XXVII, in 100 ml of ether was added to the reaction product of methyl bromide and 5.95 g of magnesium shavings in 80 ml of ether. The mixture was then heated under reflux for 4 hours. Ice and then 105 ml of concentrated hydrochloric acid were then added and the mixture was refluxed until all the solid had dissolved. The aqueous layer was washed with ether and the ether used for washing with the ether phase of the reaction mixture was combined. The combined ether extracts 45 were washed with water, dried and evaporated to leave a residue which was distilled twice. There was thus obtained 1 - [- 1- (4-chlorophenyl) cyclobutyl] propan-2-one (bp: 133-136 ° C at 2.5 mm Hg).

The ketone (5.4 g) prepared as described above was mixed with 18 ml of N-methylformide, 4 ml of 98% formic acid and 0.6 ml of 25% aqueous methylamine and refluxed for 16 hours. 50 The mixture was then poured into water and extracted with dichloromethane. The extract was washed, dried and evaporated to give a residue which was refluxed with 10 ml of concentrated hydrochloric acid for 6 hours. The mixture was evaporated to dryness and the residue was tolerated by repeated addition and evaporation under reduced pressure of a mixture of industrial denatured alcohol and toluene. The solid residue was recrystallized from propanol-2 to give 55 N-methyl-2 - [- 1 - (4-chlorophenyl) cyclobutyl] -1-methylamine hydrochloride, mp 193-194 ° C, (Formula 1 n = 1; R1, R2 = H; R3 = Me; R4 = H; Rs = 4-Cl; R6 = H; R7 = Me and R8 = H).

21 192201

Example XXX

A mixture of 15 g of 1 - [- 1- (4-chlorophenyl) cyclobutyl] propan-2-one prepared in the manner described in Example XXIX and 4 ml of 98% formic acid at 160 ° C was added dropwise to 12 ml formamide. The temperature was raised to 180 ° C and held at this temperature for 10 hours. The mixture was then cooled, diluted with water and extracted with dichloromethane. The extract was washed, dried and evaporated to give a yellow oil, which was hydrolyzed with reflux concentrated hydrochloric acid. The aqueous solution obtained after dilution with water was washed with ether, aqueous sodium hydroxide was added and the aqueous solution was extracted with ether. The extracts were washed, dried and evaporated to give a residue, from which 2 - [- 1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine, boiling point: 105-107 ° C at 0.7 mm, was distilled by 10 Hg, isolated.

The amine (2.65 g) obtained above was dissolved in 15 ml of propanol-2 and concentrated hydrochloric acid was added dropwise until the pH was 2. Then 110 ml of ether were added and the colorless crystals were isolated with 2- [1 - (4- chlorophenyl) -cyclobutyl] -1-methylethylamine hydrochloride, m.p. 184 DEG-185 DEG C. (formula 1 n = 1; R 1, fl 2 = H; R 3, R 4 = H; R 5 = 4-C 1; R 6 = H; R7 = Me and R8 = H).

Voonbee / d XXXI

3.94 g of 2- [1- (4-chlorophenyl) cydobutyl] -1-methylethylamine, prepared as described in Example XXX, 3.82 g of 1,4-dibromutane, 4.4 g of anhydrous sodium carbonate and 30 ml of xylene and reflux this mixture for 16 hours. The mixture was cooled, filtered and evaporated to give a residue which was distilled twice (bp: 130-132 ° C at 0.5 mm Hg). The distillation product was dissolved in 5 ml of propanol-2 and 70 ml of ether and concentrated hydrochloric acid was added to pH 2. The solution was evaporated under reduced pressure and the residue was recrystallized from ethyl acetate to give N- {2- [1 - (4-chlorophenyl) -cyclobutyl] -1-methyl} ethylpyrrolidine.hydrochloride having a melting point of 151-152 ° C, (formula 1 n = 1; R1 (R2 = H; R3 and R4 form together with the nitrogen atom) a pyrrolidine ring; Rs = 4-Cl; Re = H; R7 = Me and Re = H).

Example XXXII

25 g of 1- [1- (4-chlorophenyl) -cyclobutyl] propan-2-one prepared as described in Example XXIX and 10 ml of 98% formic acid were added to 22 ml of formamide at 160 ° C. The temperature was then raised to 175 ° C and the mixture held at this temperature for 16 hours. The mixture was then cooled and extracted with dichloromethane. The extract was washed with water and evaporated to give a gum which was crystallized from petroleum ether (bp: 40-60 ° C). There was thus obtained N-formyl-2- [1- (4-chlorophenyl) -cyclobutyl] -1-methylethylamine, m.p. 71-73 ° C. 11.06 g of N-2- [1- (4-chlorophenyl) -cyclobutyl] -1-methylethylamine, prepared as described above, were heated under reflux for 6 hours with a mixture of 34 ml of concentrated hydrochloric acid, 34 ml of water and 40 ml of the dimethyl ether of diethylene glycol. The mixture was cooled, washed with water and made alkaline with aqueous sodium hydroxide. The alkaline solution was extracted into ether, washed with water, dried, evaporated and distilled to give 2- [1- (4-chlororenyl) -40 cyclobutyl] -1-methyl ethyl amine boiling at 119-121 ° C at 0. Obtained 8 mm Hg. The amine (2.65g) was dissolved in 15 ml of propanol-2 and concentrated hydrochloric acid was added to pH 2. Then 110 ml of ether were added and the crystals of 2- [1 - (4-chlorophenyl) cyclobutyl] - were isolated. 1-methyl ethyl amine hydrochloride, m.p. 184-185 ° C. (formula 1 n = 1; R 'Ra = H; R3, R4 = H; Rs = 4-CI; R6 = H; R7 = Me and Ra = H).

45

Example XXXIII

1.8 g of 2- [1- (4-chlorophenyl) -cyclobutyl] -1-methylethylamine, prepared as described in Example XXXII, were mixed with 4.5 ml of formic acid. Then 6 ml of a 37-40% solution of formaldehyde in water was added and the mixture was first heated at 45-50 ° C for 30 min and then refluxed 2 onions. The mixture was cooled, made alkaline with aqueous sodium hydroxide and extracted with ether, and the ether extract was washed with water and extracted with 5N hydrochloric acid. The acidic extract was washed with ether, made alkaline with aqueous sodium hydroxide, and extracted with ether. Hydrogen chloride gas was passed through the ether extract to form a white solid product. The solid product was separated and recrystallized from ethyl acetate to give N, N-dimetheyl * 2-55 [1- (4-chlorophenyl) -cyclobutyl] -1-methylethylamine hydrochloride, m.p. 108-110 ° C (formula 1 n = 1; R 1, R 2 = H; R 3, R 4 = Me; R 5 = 4-CI; R 6 = H; R 7 = Me and R 8 = H).

192201 22

Example XXXIV

35 ml of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in toluene were added dropwise to a solution of 5 g of N-formyl-2- [1- (4-chlorophenyl) -cyclobutyl] -1-methylethylamine prepared in the manner described in Example XXXII in 110 ml of dry ether, the temperature being kept below 10 ° C by cooling. The temperature was then allowed to rise to about 25 ° C and the mixture was refluxed for 2 hours. The reaction mixture was poured onto a mixture of whipped ice and concentrated hydrochloric acid. The resulting mixture was washed with ether, made alkaline with aqueous sodium hydroxide and extracted with ether. The ether extract was washed with sodium chloride solution, dried and evaporated to give a liquid which was dissolved in petroleum ether (bp: 40-60 ° C). Hydrogen chloride gas was bubbled through the solution to precipitate a solid product which was recrystallized from propanol-2. There was thus obtained N-methyl-2- [1- (4-chlorophenyl) -cyclobutyl] -1-methylethylamine hydrochloride (formula 1 n = 1; R2 = H; R3 = H; R4 = Me; R5 = 4-CI R6 = H; R7 = Me and R8 = H) (melting point: 192-194 ° C).

Example XXXV

A solution of 23 g of 2- [1- (3,4-dichlorophenyl) -cyclobutyl] acetonitrile, prepared in a similar manner as described in Example XXVII for 2- [1- (4-chlorophenyl) -cyclobutyl] acetonitrile, was added in Add 80 ml of ether with stirring to the product of the reaction of 3.53 g of magnesium shavings and 10.8 ml of ethyl bromide in 80 ml of water while heating on a steam bath. The ether was removed and replaced with toluene, and the mixture was refluxed for 1 hour. Water was then added and the mixture added to a mixture of ice and concentrated hydrochloric acid. The mixture was heated on a steam bath for 1 hour and filtered through diatomaceous earth. The filtrate was extracted with dichloromethane and the extract was washed with water and sodium bicarbonate solution and dried. The solvent was evaporated and the residue was distilled to give 1- [1- (3,4-dichlorophenyl) -cyclobutyl] butan-2-one having a boiling point at 149-150 ° C at 1.1 mm Hg.

The ketone expanded as described above was converted to 1 - {[1- (3,4-dichlorophenyl) -cyclobutyl] methylethylamine} propylamine hydrochloride, m.p. 225-226 ° C, in an analogous manner as described in Example XXXII. (formula 1 n = 1; R1; R2, R3, R4 = H; Rs = 4-Cl; R6 = 3CI; R7 = Et and Re = H).

In an analogous manner as described above, 2- [1- (3,4-dichlorophenyl) -cyclobutyl] -1-30 methylethylamine hydrochloride, m.p. 179 ° C, was prepared (Example XXXVa, formula 1 n = 1;

R2 R2, R3 and R4 = H; Rs = 4-CI; R6 = 3-CI; R7 = Me and R8 = H).

Example XXXVI

Analogously as described in Example XXXIII, compounds analogously prepared as described in Example XXXV were converted to the corresponding N, N-dimethyl compounds.

Compounds of formula 31

Example output R5 R6 R7 mp.

40 material XXX (a) XXXV Cl Cl Et 177-178 ° XXXVI (b) XXXV (a) Cl Cl Me 204-205 ° 45

Example XXXVII

In an analogous manner as described in Example XXXIV, N-formyl compounds prepared in the manner described in Example XXXII were prepared from ketones prepared as described in Example XXXV into the corresponding N-methyl compounds.

50

Compounds of formula 32

Example R5 R6 R7 mp.

55 XXXVII (a) Cl H Et 170-172 ° XXXVII (b) Cl Cl Et 193-194 ° 23 192201

Example XXXVIII

A mixture of 10.1 g of 2- [1- (4-chlorophenyl) -cyclobutyl] acetonitrile prepared in the manner described in Example XXVII, 8.1 g of potassium hydroxide and 92 ml of diethylene glycol was heated for 3.5 hours. flow. The mixture was then poured onto a mixture of ice and water, the resulting solution was washed three times with ether and added to a mixture of ice and concentrated hydrochloric acid. On cooling, a solid product separated, which was recrystallized from petroleum ether (bp: 62-68 ° C) using charcoal. The recrystallized product was 2- [1- (4-chlorophenyl) -cyclobutyl] acetic acid, m.p. 83-84 ° C.

The acid (5 g) prepared as described above was added to 20 ml of thionyl chloride and heated under reflux for 10 hours. The excess thionyl chloride was removed and the residue was poured into a solution of 3.8 g piperidine in 20 ml ether. The mixture was stirred for 30 min and then water was added to dissolve the piperidine hydrochloride. The ether layer was separated and the aqueous layer was washed with ether. The combined ether portions were washed with water, dried and evaporated to give a brown oil which was purified by distillation (bp: 168 ° C at 1 mm Hg) and crystallization from petroleum ether (bp: 40-60 ° C). The solid product was 2- [1- (4-chlorophenyl) -cyclobutyl] acetylpiperidine, mp 66-67 ° C.

A solution of the previously prepared compound (2.7 g) in 20 ml of ether was added dropwise to a stirred mixture of 0.7 g of lithium aluminum hydride and ether in a nitrogen atmosphere. Stirring was continued for 1 hour at room temperature and then refluxed for 2 hours. After cooling in ice, the excess lithium aluminum hydride was decomposed by adding water. The mixture was filtered through diatomaceous earth. The aqueous portion of the filtrate was washed with a portion of ether and this portion was combined with the ether portions used to wash the solid residue. The combined ether protions were washed with water, dried and evaporated. The residue was purified by distillation. There was thus obtained N-2- [1 - (4-chlorophenyl) -cyclobutyl] ethylpiperidine, boiling point 152-156 ° C at 1.5 mm Hg (formula 1 n = 1; R1 (R2 = H; R3 and R4 together with a nitrogen atom form a piperidine ring (Rs = 4-Cl; R6, R7 and R8 = H).

In an analogous manner as described above, the following compounds were prepared and isolated as their hydrochloride salts by passing dry hydrogen chloride gas through a solution of the base in petroleum ether (bp: 62-68 ° C).

30

Compounds of formula 33

Example Rs R6 NR3R4 mp. (° C) 35 Μβ XXXVIII (a) Cl H 167-169 °

Me 40 / - \ XXXVIII (b) Cl H -N ^ N-Me 281-283 ° (dec.) XXXVIII (c) Cl H -N0 246-248 °

50 Example XXXIX

A mixture of 9 g of sodium hydride, 9 g of mineral oil and 150 ml of dry dimethylformamide was stirred in a nitrogen atmosphere at 0 ° C. A solution of 24.6 g of p-toluenesulfonylmethyl isocyanide in 50 ml of dimethylformamide was then added over a period of 30 minutes. Then 18g of absolute alcohol was added to the mixture at 0 ° C. Then 24 g of 1-acetyl-1 - (- 4-55 chlorophenyl) cyclobutane, prepared in an analogous manner as described in Example 1 for 1-acetyl-1 - (3,4-dichlorophenyl) cyclobutane, dissolved in 20 ml dry dimethylformamide and stir the mixture for 16 hours, the temperature rising to room temperature. The mixture became viscous and 24192201 of 24 ml of petroleum ether (bp: 80-100 ° C) was added. The mixture was then poured into water and the pH adjusted to 6 by adding 5N hydrochloric acid. The resulting mixture was extracted with ether and the ether extract was washed with water, dried and partially evaporated. A brown solid product separated, which was filtered off and the filtrate was evaporated, from which 2- [1- (4-chlorophenyl) -5 cyclobutylpropionitrile boiling at 128-136 ° C at 0.6 mm was distilled. parted.

A solution of the propionitrile prepared in the manner described above (3.5 g) in 20 ml of dry ether was added dropwise to a stirred mixture of 0.9 g of lithium aluminum hydride in 20 ml of dry water at a temperature between 15 and 20 ° C. ether. This mixture was stirred at room temperature for 2 hours and then refluxed for an additional 3 hours. Then 20 ml of a 5N sodium hydroxide solution and 50 ml of water were added and the mixture was filtered through diatomaceous earth. The filter mass was washed with ether and the washings were combined with the ether of the reaction mixture. The combined extracts were extracted with 5N hydrochloric acid. A solid product formed on the boundary layer, which was filtered off, washed with acetone and dried. The solid product was 2- [1- (4-chlorophenyl) -cyclobutyl] propylamine hydrochloride, mp 210-230 ° C.

1.0 g of the hydrochloride salt prepared as described above were dissolved in water, a 5N aqueous sodium hydroxide solution was added and the solution was extracted with ether. The ether extract was dried and evaporated to give an oil, which was refluxed for 6 hours with 0.82 g 1,4-dibromobutane, 0.96 anhydrous sodium carbonate and 6.5 ml xylene. The mixture was cooled, filtered through diatomaceous earth and evaporated to dryness. The residue was dissolved in 10 ml of propanol-2 and 5 ml of concentrated hydrochloric acid were added. The mixture was evaporated to dryness and the residue was isolated, washed with ether and dried. The product was N-2- [1- (4-chlorophenyl) cyclobutylpropylpyrrolidine hydrochloride, mp 238-248 ° C. (formula 1 n = 1; R. = Me; R2 = H; R3 and R4 together with the nitrogen atom to which they are attached form a pyrrolidine ring; R5 = 4-Cl; Re, R7 and R8 = H).

25

Example XL

A solution of 70 g of 1- (3,4-dichlorophenyl) -cyclobutanecarbonitrile, prepared in an analogous manner as described in Example 1, was mixed in 200 ml of industrial denatured alcohol with a solution of 3.7 g of sodium hydroxide in 5 ml of water and a 30% hydrogen peroxide solution was added thereto. The mixture was then heated at 50 ° C for 1 hour and then stirred for 1 hour with 0.5 g of 10% palladium on charcoal. The mixture was then filtered and evaporated to dryness to give 1- (3,4-dichlorophenyl) -1-cyclobutanecarboxamide.

The carboxamide prepared above was dissolved in 500 ml of dioxane and 100 ml of concentrated hydrochloric acid and a solution of 35 g of sodium nitrite in 80 ml of water were added thereto. The mixture was then heated at a temperature between 85 and 95 ° C for 16 hours and then poured into water. The mixture was extracted with ether and the extract was back extracted with aqueous potassium carbonate. The basic extract was washed with ether and acidified with concentrated hydrochloric acid to give 1- (3,4-dichlorophenyl) -1-cyclobutanoic acid with a melting point of 120-121 ° C.

The acid prepared above was converted to the compound of Example XXVII (a) in an analogous manner as described in Example XXVII and converted to the compound of Example XXVIII (a) in an analogous manner as described in Example XXVIII.

Example XLI

A solution of 23 g of 2- [1- (3,4-dichlorophenyl) -1-cyclobutyl] -acetonitrile (prepared analogously as 45 2- [1- (4-chlorophenyl) cyclobutyl] -acetonitrile described in Example XXVII) in 50 ml dry ether was added to a solution of ethylmagnesium bromide prepared by dripping 15.83 g ethyl bromide in 80 ml dry ether to a stirred mixture of 3.53 g magnesium curls and 80 ml ether. The mixture was refluxed for 30 minutes and stirred without further heating for 16 hours, then refluxed for 2 hours. Filtering gave 1- [1- (3,4-dichlorophenyl) cyclobutyl] -2-50 butaniminyl magnesium bromide and a sample of about 1 g of this solid product was added to a solution of 3 g of sodium borohydride in 30 ml of the dimethyl ether of diethylene glycol. The mixture was stirred at 45 ° C for 90 min. Then the reaction mixture was extracted with 5N hydrochloric acid. The aqueous phase was made alkaline with an aqueous solution of sodium hydroxide and extracted with ether. The ether extract was dried and hydrogen chloride gas was passed through the 55 extract to precipitate 1 - {[1- (3,4-dichlorophenyl) cyclobutyl] methyl} -propylamine hydrochloride, mp 223-224 ° C (formula 1n = 1; R1, R2, R3 and R4 = H; R5 = 4-Cl; R6 = 3-Cl; R7 = Et; R8 = H).

25 192201

Example XLII

7 ml of formic acid were added to 15 ml of pyrrolidine at a temperature between 135 and 140 ° C. Then 3 g of 1 - [1- (3,4-dichlorophenyl) cyclobutyl] butan-2-one, prepared as described in Example XXXV, were added dropwise and the mixture was heated at 140 ° C for 1 hour. The temperature was then raised to 185-190 ° C for 16 hours. The reaction mixture was then cooled and poured into 5N hydrochloric acid. The solution was washed with ether, made alkaline and extracted with ether. The ether extract was dried and hydrogen chloride gas was passed through the extract. Evaporation to dryness gave a solid product, which was treated with dry ether and recrystallized from a mixture of petroleum ether and propan-2-ol. There was thus obtained N-1- {[1- (3,4-10 dichlorophenyl) cyclobutyl] methyl} propylpyrrolidine hydrochloride, m.p. 157-160 ° C (formula 1 n = 1; Rv R2 = H; R3 and R4 together with the nitrogen atom form a pyrrolidine ring; Rs = 4-CI; R6 = 3-CI; R7 Et and R8 = H).

Example XLIII

25 g of 1- [1- (3,4-dichlorophenyl) cyclobutyl] -2-butaniminyl magnesium bromide, prepared as described in Example XLI, were heated at a temperature of 90 to 95 ° C for 2 hours with a mixture of 20 ml of concentrated hydrochloric acid and 30 ml of water. The reactant was extracted with ether and the ether extract was dried and evaporated to dryness. The 1- [1- (3,4-dichlorophenyl) cyclobutyl] butan-2-one with a boiling point of 122-124 ° C at 0.1 mm Hg was distilled.

A mixture of 4.3 g of 1- [1- (3,4-dichlorophenyl) cyclobutyl] butan-2-one prepared in the manner described above was stirred, 2.65 g of hydroxylamine sulfate, 4.0 g of sodium acetate, 56 ml of industrial denatured alcohol and 23 ml of water at room temperature for 16 hours. The reaction mixture was then extracted with ether. The ether extract was washed with water, dried and evaporated to dryness, yielding a solid product, which was recrystallized from petroleum ether (bp: 80-100 ° C). There was thus obtained 25 1 - [1 - (3,4-dichlorophenyl) cyclobutyl] butan-2-one oxime, m.p. 106-110 ° C.

A solution of 2.33 ml of trifuloroacetic acid in 5 ml of tetrahydrofuran was added over 5 minutes to a stirred suspension of 1.13 g of sodium borohydride in 30 ml of tetrahydrofuran. A solution of 1.7 g of the oxime prepared as described above was then added dropwise into 25 ml of tetrhydrofuran and the mixture was refluxed for 6 hours. The mixture was then cooled and 25 ml of water and then 25 ml of a 5N sodium hydroxide solution were added first. The mixture was extracted with ether and the extract was washed with water, dried and evaporated to give a residue which was dissolved in 25 ml of petroleum ether. The introduction of dry hydrogen chloride gas through the ether solution gave 1 - {[1- (3,4-dichlorophenyl) cyclobutyl] methyl} propylamine.hydrocWoride, mp 222-224 ° C (formula 1 n = 1; R1, R2, R3 and R4 = H; R5 = 4-Cl; R6 = 3-Cl; R7 = 35 Et and R8 = H).

Example XUV

A solution of 5.0 g of 1- [1- (3,4-dichlorophenyl) cyclobutyl] butan-2-one, prepared as described in Example XLIII, and 1.63 g of methoxyamine hydrochloride in a mixture was heated of 60 ml pyridine and 40 60 ml ethanol under reflux for 72 hours. The reaction mixture was then evaporated to dryness and a mixture of water and ether was added to the residue. The ether layer was washed with sodium bicarbonate solution and water, dried and evaporated to give 1- [1- (3,4-dichlorophenyl) cyclobutyl] butan-2-one oxime O-methyl ether.

The oxime ether (15 g) prepared as described above was then reduced in an analogous manner as described in Example XLIII with 0.95 g of sodium borohydride to a product of Example XLIII.

Example XLV

0.4 g of sodium cyanoborohydride was added to a solution of 2.45 g of 1- [1- (3,4-50 dichlorophenyl) cyclobutyl] butan-2-one, prepared as described in Example XLII and 7 g of ammonium acetate in 28 ml of methanol and stirring this mixture at room temperature for 4 days. 25 ml of water were then added dropwise with cooling. The aqueous mixture was extracted with ether and the ether layer was washed with water and 50 ml of 5N hydrochloric acid. The compound of Example XLIII precipitated as a white solid product.

Claims (2)

192201 26 Example XLVI 1.5 g of 2- [1- (4-chlorophenyl) cyclobutyl] acetic acid, prepared as described in Example XXXVIII, were heated under reflux with thionyl chloride. The excess thionyl chloride was then removed under reduced pressure and the residue was added dropwise to a solution of 0.94 g of cyclopropylamine in 10 ml of ether and this mixture was stirred for 30 min. Then water was added and the aqueous phase was extracted with ether. The ether extract was dried and the ether was removed to give 2- [1 - (4-chlorophenyl) cyclobutyl] -N-cyclopropylacetamide. A solution of 1.45 g of the amide prepared in the above-described manner in 15 ml of ether in a nitrogen atmosphere was added dropwise to a stirred suspension of 0.42 g of lithium aluminum hydride in 7.5 ml of ether. The mixture was then stirred for 1 hour at room temperature and then refluxed for an additional 2 hours. After cooling, 0.45 ml of water, then 0.45 ml of a 15% sodium hydroxide solution and finally 1.35 ml of water were added and the mixture was stirred for 15 min. The mixture was filtered and extracted with ether. The ether extract was washed with N-hydrochloric acid to form a solid product in the aqueous layer. This product was N-cyclopropyl-2- [1- (4-15 chlorophenyl) cyclobutyl] ethylamine hydrochloride, m.p. 166-170 ° C. A mixture of 0.41 g of the hydrochloride salt prepared as described above, 0.1 g of sodium formate, 1 ml of 98% formic acid and 0.5 ml of a 37-40% aqueous formaldehyde is heated. solution for 18 hours at a temperature between 85 and 90 ° C. The reaction mixture was then cooled and extracted with ether. The ether extract was washed with water, dried and filtered. By passing hydrogen chloride gas through the filtrate which was then heated, a solid product was obtained, which was N-cyclopropyl-N-methyl-2- [1- (4-chlorophenyl) cyclobutyl] ethylamine hydrochloride, melting point 149- 153 ° C. (formula 1 n = 1; R1 and R2 = H; R3 = cyclopropyl; R4 = Me; Rs = 4-Cl; R6, R7 and Re = H). Claims 1. 1-Phenyl-1-aminoalkylcyciobutane compound having a pharmacological action, characterized in that it has an anti-depressant effect and satisfies the formula 1 on the formula sheet, wherein n = 0 or 1, where, if n = 0 , R, a straight or branched chain alkyl group of 1 to 6 carbon atoms, a cycloalkyl group of 3 to 7 carbon atoms, a cycloalkylalkyl group of which the cycloalkyl portion contains 3-6 carbon atoms and the alkyl portion contains 1 to 3 carbon atoms, an alkynyl group or an alkynyl group having 2-6 carbon atoms or a group of formula 2 wherein R9 and R10, which are the same or different, represent a hydrogen or halogen atom or an alkoxy group having 1-3 carbon atoms, where, if n = 1, R, represents a hydrogen atom or an alkyl group with 1-3 carbon atoms, R2 represents a hydrogen atom or an alkyl group with 1-3 carbon atoms, R3 and R4, which may or may not be equal, a hydrogen atom, a straight or branched chain alkyl group and 1-4 charcoal of atoms, an alkenyl group of 3-6 carbon atoms, an alkynyl group of 3-6 carbon atoms, a cycloalkyl group the ring of which contains 3-7 carbon atoms or a group of formula R ^ CO wherein R ^ is a hydrogen atom, or wherein R3 and R4 together with the nitrogen atoms to which they are attached form an optionally substituted heterocyclic ring with 5 or 6 40 atoms in the ring which, in addition to the nitrogen atom, further optionally contains hetero atoms, R 5 and R 6, which may or may not be the same, a hydrogen or halogen atom, a trifluoromethyl group, an alkyl group of 1-3 carbon atoms, an alkoxy or alkylthio group of 1-3 carbon atoms or a phenyl group, or wherein R5 and R6 together with the carbon atoms to which they are attached form a second benzene ring which is optionally substituted having one or more halogen atoms, an alkyl group or an alkoxy group having 1 to 4 carbon atoms or in which the substituents of the second benzene ring together with the two carbon Substance atoms to which they are attached still form a benzene ring and R7 and R8, which may or may not be the same, represent a hydrogen atom or an alkyl group of 1-3 carbon atoms, as well as the pharmaceutically acceptable salts thereof. 2. An anti-depressant whey pharmaceutical composition, characterized in that it contains a therapeutically effective amount of a compound of formula 1 according to claim 1 and a pharmaceutically acceptable carrier or a pharmaceutically acceptable diluent. Hereby 2 sheets drawing