SE452611B - PHENYL SUBSTITUTED (CYCLOBUTYLALKYL) AMINES, PROCEDURE FOR PREPARING THESE AND A PHARMACEUTICAL COMPOSITION FOR TREATING DEPRESSION - Google Patents

Description

Wherein R 1 and R 2, which may be the same or different, are hydrogen, halo I or an alcohol group containing 1-3 carbon atoms: wherein, when n = 1, R 1 is hydrogen or an alkyl group containing 1-3 carbon atoms; wherein R 2 is hydrogen or an alkyl group containing 1-3 carbon atoms; wherein R 3 and R 3, which may be the same or different, are hydrogen, a straight or branched chain alkyl group containing 1-4 carbon atoms, an alkenyl group containing 3-6 carbon atoms, an alkynyl group containing 3-6 carbon atoms, a cycloalkyl group, wherein the ring contains 3 7 carbon atoms, a group of the formula R CO, wherein II R11 is hydrogen, or R and R together form the nitrogen atoms to which they are bonded eg pyrrolidinyl, piperidino, piperazinyl or tetrahydropyridyl ring, which is optionally substituted by a or more methyl groups: wherein R 5 and R 4, which may be the same or different, are hydrogen, halo, trifluoromethyl, an alkyl group containing 1-3 carbon atoms, an alkoxy or alkylthio group containing 1-3 carbon atoms or phenyl, or R 5 and R 6 form together with the carbon atoms to which they are attached a second benzene ring, which may be substituted by one or more halo groups, an alkyl or alkoxy group containing 1-4 carbon atoms, or also form the substituents in the second benzene ring together with the two carbon atoms to which they are attached an additional benzene ring: and wherein R 7 and R 8, which may be the same or different, are hydrogen or an alkyl group containing 1-3 carbon atoms: and their pharmaceutically acceptable salts.

In the formulas present in the present specification, the symbol 452 611 denotes a 1,1-disubstituted cyclobutane group having the formula and -CR 1 R 2. (CR 7 R 8.) NNR 3 R 4 represents a group having the formula f-21 'P 7 / R The preferred compounds of formula I, wherein n = 0, R 1 is a straight or branched chain alkyl group containing 1-4 carbon atoms, a cycloalkyl group containing 3-7 carbon atoms or a group of formula II , wherein R 9 and R 10 are hydrogen, fluoro or methoxy and wherein R 2 is hydrogen or methyl. Examples of particularly preferred compounds of formula I are those wherein, when n = 0 and R 2 is hydrogen, R 1 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or phenyl.

In the preferred compounds of formula I, wherein n = 1, R 1 is hydrogen or methyl and R 2 is hydrogen. In particularly preferred compounds of formula I, wherein n = 1, both R 1 and R 2 are hydrogen.

In preferred compounds of formula I, R 3 and R 4 are hydrogen, methyl, ethyl or formyl. In preferred compounds of formula I, R 5 and R 6 are hydrogen, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy or phenyl, or R 5 and R 6 together with the carbon atoms to which they are attached form a second benzene ring, which optionally substituted with halo.

A first group of preferred compounds of formula I is represented by the formula III m1R2 (° '' 7R8) nIlm3R4 H5 / in Rs wherein R1, R2, R3, R4, Rs, R6, R7, R8 and n have the meaning given above . In particularly preferred compounds of formula III, R 5 and R 6, which may be the same or different, are hydrogen, fluoro, chloro. bromo, iodo, trifluoromethyl, methyl or phenyl, or R 5 and R 6 together with the carbon atoms to which they are attached form a second benzene ring. which is optionally substituted with a chloro group.

A second group of preferred compounds of formula I is represented by the formula IV wherein R 1, R 2, R 3, R 4, R 5, R 7, R a and n have the meaning given above and wherein R 6 is fluoro or methyl. In particularly preferred compounds of formula IV, R 5 is hydrogen or chloro. In preferred compounds of formula I, wherein n = 1, R 7 is hydrogen, methyl or ethyl and R 8 is hydrogen and in particularly preferred compounds of formula I R 7 is hydrogen or ethyl and R 8 is hydrogen.

The compounds of formula I may exist as salts with pharmaceutically acceptable acids. Examples of such salts include hydrochlorides, maleate, acetate, citrate, fumarate, tartrate. succinates and salts with acidic amino acids such as aspartic acid and glutamic acid.

Compounds of formula I, which contain one or more asymmetric carbon atoms, may exist in various optically active forms.

When R1 and R2 are different or R7 and R8 are different, the compounds of formula I contain a chiral center. Such compounds exist in two enantiomeric forms and the present invention includes both enantiomeric forms and mixtures thereof.

When both R1 and R2 are different and R7 and R8 are different, the compounds of formula I contain two chiral centers and the compounds exist in four diastereoisomeric forms. The present invention encompasses each of these diastereoisomeric forms and mixtures thereof.

The present invention also encompasses pharmaceutical compositions for the treatment of depression which contain a therapeutically effective amount of a compound of formula I together with a pharmaceutically acceptable diluent or carrier.

For therapeutic use, the active compound may be administered orally, rectally, parenterally or topically, preferably orally.

Thus, the therapeutic compositions of the invention may be in the form of any known pharmaceutical composition for oral, rectal, parenteral or topical administration. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in pharmacology. The compositions of the invention may contain 0.1-90% by weight of the active compound. The compositions of the invention are generally prepared in unit dosage form. 452 511 = Compositions for oral administration constitute the preferred compositions according to the invention and these are present in the known pharmaceutical forms for such administration, for example in the form of tablets, capsules, syrups and suspensions in water or oils. The diluents used in the preparation of these compositions are those known in pharmacology.

Tablets may be prepared by mixing the active compound with an inert diluent such as calcium phosphate in the presence of disintegrants, for example corn starch, and lubricants, for example magnesium stearate, and tabletting the mixture according to known methods. The tablets may be formulated in a known manner to obtain a sustained release of the compounds of the invention. Such tablets may optionally be provided with an enteric coating according to known methods, for example using cellulose acetate phthalate. Similarly, capsules, for example hard or soft gelatin capsules containing the active compound with or without added diluent, may be prepared in a conventional manner and optionally provided with an enteric coating in a known manner. The tablets and capsules may conveniently each contain 1-500 mg of the active compound. Other compositions for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethylcellulose, and oily suspensions containing a compound of the invention in a suitable vegetable oil such as arachis oil. .

Compositions according to the invention which are suitable for rectal administration are the known pharmaceutical forms for such administration, e.g. suppositories based on cocoa butter or polyethylene glycol.

Compositions of the invention which are suitable for parenteral administration are the known pharmaceutical forms for such administration, for example sterile suspensions in aqueous and oily media or sterile solutions in a suitable solvent.

Compositions for topical administration may contain a matrix in which the pharmacologically active compounds of the invention are dispersed so that the compounds are kept in contact with the skin so that the compounds are administered transdermally. Alternatively, the active compounds may be dispersed in a pharmaceutically acceptable cream or linement base.

In certain compositions it may be of value to use the compounds of the invention in the form of particles of very small size, for example those obtained by grinding by means of liquid energy.

In the compositions of the invention, the active compound may optionally be present together with other combinable pharmacologically active components.

The pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I can be used to treat depression in human mammals. In such treatment, the amount of the compound of formula I administered per day is in the range of 1 to 1000 mg, preferably 5-500 mg.

Compounds of formula I, wherein R 4 is CHO, may be prepared by reductive amidation of ketones of formula V or of ketones or aldehydes of formula VI R COR1 VI for example with formamide and formic acid or ammonium formate and formic acid to give compounds of formula I, wherein R 4 is CHO and R 3 is hydrogen or with formamides of the formula HCONHR 3, wherein R 3 is an alkyl group or cycloalkyl group, and formic acid or amines of the formula R are NH, wherein R 3 is an alkyl group or a cycloalkyl group. and formic acid.

Compounds of formula I, wherein R 4 is CHO, can be prepared by formylation of compounds of formula I, wherein R 4 is hydrogen, for example by reaction with methyl formate.

Compounds of formula I, wherein R 3 is other than hydrogen and R 4 is CHO, can be prepared by reacting compounds of formula I, wherein R 3 is hydrogen and R 4 is CHO, with a compound of formula R 3 X, wherein X is a leaving group, for example a halo group, in the presence of a base.

Compounds of formula I may be prepared by reductive amination of ketones of formula V or of ketones or aldehydes of formula VI. Examples of suitable reductive amination procedures are given below: »MW _ ~ ._ .. ~ .__. \ .._.... ._... r ...... t. . v..,., _. 452 611 a) for compounds of formula I, wherein R 3 and R 4 are hydrogen, 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 I, wherein R 3 is alkyl or cycloalkyl and R 4 is hydrogen, by reacting the ketone or aldehyde with an amine having the formula R 3 NH 2 and a reducing agent such as sodium cyanoborohydride, c) for compounds of formula I, wherein neither R 3 nor R 4 is hydrogen or wherein R 3 and R 4 together with the nitrogen atom forms a heterocyclic ring, by reacting the ketone or aldehyde with an amine having the formula HNR 3 R 4 and either formic acid or a reducing agent such as sodium cyanoborohydride, d) for compounds of formula I, wherein one or both of R 3 and R 4 is hydrogen or an alkyl group or a cycloalkyl group or wherein R 3 and R 4 together with the nitrogen atom form a heterocyclic ring, by catalytic hydrogenation at elevated temperature and elevated pressure. a mixture of the ketone or aldehyde and an amine of the formula HNR3R4.

Compounds of formula I, wherein R 3 and R 4 are both alkyl groups can be prepared by reacting a ketone of formula V or a ketone or an aldehyde of formula VI with a dialkylformamide of formula HCONR 3 R 4, for example in the presence of formic acid.

Compounds of formula I may be prepared by reduction of compounds of formula VII wherein a) Z is a group having the formula -CR 1 = NOH or an ester or ether thereof to give compounds of formula I, wherein n = 0 and R 2, R 3 and R 4 are hydrogen; b) Z is a group having the formula -CR 1 = NR 3 (wherein R 3 than H or CHO) to give compounds of formula I, wherein otherwise n = 0 and R 2 and R 4 is hydrogen, c) Z is a group having the formula -CR 1 = NY, wherein Y represents a metal-containing group derived from an organometallic reagent to give compounds of formula I, wherein n = 0 and R 3 and R 4 are hydrogen d) Z is a group having the formula -CR 1 R 2 .CN to give compounds of formula I, wherein n '= 1 and R 3, R 4, R 7 and R 8 are hydrogen; e) Z is a group having the formula -CR 1 R 2. CR7 = NOH or an ester or an ether thereof to give compounds of formula I, wherein n = 1 and RR and R are hydrogen; f 'Z is a group having the formula -CR1R2.CR7 = NR3 (wherein R3 is something a than H or CHO) to give compounds of formula 1, wherein n = 1 and R 4 and R 8 are hydrogen; g) Z is a group having the formula -CR 1 R 2. CR 7 = NY, wherein Y represents a metal-containing group derived from an organometallic reagent to give compounds of formula I, wherein n = 1 and R R and R 3, 4 8 is hydrogen: h) Z is a group having the formula -CR 1 R 2. CONR 3 R 4 to give = 1 and R 7 and R are hydrogen. of compounds of formula I, wherein n 8 Suitable reducing agents for the above reactions include sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride or borane / dimethyl sulfide complexes. 452 611 II I (cl and (g) above, Y is preferably Mgßr derived from a Grignard reagent or Li derived from an organolithium compound.

Compounds of formula I, wherein n = 0, may be prepared by reacting an organometallic reagent, for example a Grignard reagent of formula R 1 MgX, wherein X is Cl, Br or J, or an organolithium compound of formula R 11 L 1 with an imine of formula VIII R C fl = NR3 "" VIII followed by hydrolysis to give a secondary amine having the formula I. Similarly, imines of the formula IX can be converted to secondary amines of the formula I, wherein n = l 5 \\ CR1RÅCH = UR3 "e IX Compounds of formula I, wherein R 3 and R 4 are hydrogen, can be prepared by decarboxylating regrouping, for example using iodosobenzene bistrifluoroacetate or according to a Hofmann reaction using bromine in alkaline solution, of amides having formula X or amides having formula XI RS \ “Riazwmz 452 611 12 5 \ I ONHZ to give amines of formula I, wherein n = 0 and n = 1, respectively.

Compounds of formula I, wherein R 3 and R 4 are hydrogen, can be prepared by decarboxylating regrouping of acyl azides according to the Curtius reaction. The acyl azides can be formed, for example, by reacting acid chlorides having the formula XII or acid chlorides having the formula XIII with sodium azide R 5 - a Schmidt reaction, wherein a carboxylic acid having the formula XIV or a carboxylic acid having the formula XV is reacted with hydrazo acid 452 611 13 R ca R coon 5 \ 1 2 36 _ 'xIv in H5 _ cnlazcngecoon - xv Compounds of formula I, wherein R 4 is hydrogen can be prepared by hydrolysis of compounds of formula I, wherein R 4 is CHO, for example by acid hydrolysis.

Compounds of formula I, wherein R 4 is methyl, can be prepared by reduction of compounds of formula I, wherein R 4 is CHO, for example by lithium aluminum hydride or sodium bis (2-methoxyethoxy) aluminum hydride.

Compounds of formula I, wherein one or both of R 3 and R 4 are other than hydrogen, may be prepared from compounds of formula I, wherein one or both of R 3 and R 4 is hydrogen, according to methods well known in the art for the conversion of primary amines to secondary or tertiary amines or for the conversion of secondary amines to tertiary amines. Examples of suitable processes are given below: a) by alkylation of primary amines having the formula I to form secondary amines having the formula I, for example by a process comprising the steps of protecting the primary "* r" "- * ï the amine having a protecting group such as trifluoroacetyl, alkylation with an alkyl halide and removal of the protecting group, for example by hydrolysis; b) by alkylation of primary amines having the formula I, for example with an alkyl halide to form tertiary amines having the formula I, wherein R 3 and R 4 are the same; c) by alkylation of secondary amines having formula I, for example with an alkyl halide to form tertiary amines having formula I, wherein R 3 and R 4 may be different: d) by reacting primary amines having formula I, with sodium borohydride and acetic acid to form secondary amines having the formula I, wherein R 3 is ethyl and R is hydrogen; E) by reacting primary amines having formula I, with formaldehyde and formic acid to form tertiary amines having formula I, wherein both R 3 and R 4 are methyl; f) by reacting secondary amines having the formula I, wherein R is hydrogen, with formaldehyde and formic acid to form 4 tertiary amines having the formula I, wherein R 3 is methyl; g) by formylation of primary amines having the formula I, for example by reaction with methyl formate and reduction of the formamides formed, for example with lithium aluminum hydride to form secondary amines having the formula I, wherein R 3 is methyl and R 4 is hydrogen; h) by formylation of secondary amines having formula I, for example by reaction with methyl formate and reduction of the formed formamides, for example with lithium aluminum hydride to form tertiary amines having formula I, wherein R 4 is methyl; i) by acylation of primary amines having the formula I. for example by reaction with an acyl chloride having the formula R 12 COCl 452 611 or an anhydride of the formula (R 12 CO) 20, wherein R 12 is alkyl, alkenyl or alkynyl and reduction of the obtained the amides, for example with lithium aluminum hydride to form secondary amines having the formula I, wherein R 3 is -CH 2 R 2 and R 4 is hydrogen; j) by acylation of secondary amines having the formula I, wherein R 4 is hydrogen, for example by reaction with an acyl chloride having the formula R 12 COOCl or an anhydride having the formula (R 12 CO) 2 O, wherein R 12 is alkyl, alkenyl or alkynyl and reduction of the resulting amides, for example with lithium aluminum hydride to give tertiary amines, wherein R 4 is CH 2 R 21; k) by reacting primary amines having formula I with an aldehyde having the formula R 13 CHO, wherein R 13 may be alkyl, alkenyl or alkynyl or a ketone having the formula R 14 COR 15, wherein R 14 and R 11, which may be the same or different, are alkyl, alkenyl, alkynyl or R 14 and R 11 together with the carbon atom to which they are attached may form an alicyclic ring and reduction of the resulting imines or enamines, for example with sodium cyanoborohydride or, when R 13, R 14 or R 15 is not alkenyl or alkynyl, by catalytic hydrogenation to give secondary amines having the formula I, wherein R 3 is R 13 CH 2 - or ? 15 R] 4-CH-; 1) by reacting primary amines having formula I with a non-geminally disubstituted alkane containing 2 or 3 carbon atoms between the carbon atoms having the substituents, which may be, for example, halo, preferably bnmh or p-toluesulfulfonyloxy to form compounds of formula I, wherein R 3 and R 4 together with the nitrogen atom to which they are attached form a heterocyclic ring containing no heteroatoms other than the nitrogen atom.

The ketones of formula V can be prepared by hydrolysis of imines having the formula XVI wherein Y represents a metal-containing group derived from an orcenometallic reagent. The imines of formula XVI can be prepared by reacting the organometallic reagent with a cyano compound having the formula CN. XVII Suitable organometallic reagents include Grignard reagents of formula R1MgX, wherein X is Cl, Br or J (Y = MgX) and organolithium compounds having the formula R1Li (Y = Li). The ketones of formula VI can be prepared by hydrolysis of imines having the formula XVIII R about nzmfm \ 1 XVIII Rs wherein Y represents a metal-containing group derived from an organometallic reagent. The imines of formula XVIII can be prepared by reacting the organometallic reagents with cyano compounds having the formula XIX RS CRIRZCN \ Rs - 452 611 17 Suitable organometallic reagents include Grignard reagents of formula R7HgX, wherein X is Cl, Br or J (Y = MgX) and organolithium compounds having the formula RILI (Y = Li).

Ketones of formula V 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 having the formula XX. R5 COC with a Grignard reagent having the formula Rlngx, wherein X is Cl, Br or J, at low temperature or by reacting a carboxylic acid having the formula XXI g COOH \ R -,, XII with an organometallic reagent , for example an organolithium compound of the formula R1IIi.

Ketones of formula VI 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 having formula XII with a Grignard reagent having the formula R 7 MgX, wherein X is Cl, Br or J, at low temperature or by reacting a carboxylic acid having the formula XIV with a metal-organic reagent such as an organolithium compound having the formula R7Li. Ketones of formula V, wherein R 1 is alkyl (eg methyl) and ketones of formula VI, wherein R 7 is alkyl (eg methyl) can be prepared by reacting a diazoalkane (eg diazomethane) with aldehydes having the formula XXII resp. WE.

R cao XXII Aldehydes of formula VI can be prepared according to methods well known in the art. The following are examples of suitable methods: a) by reduction of cyano compounds having the formula XIX, for example with di-tert-butylaluminum hydride or diisobutylaluminum hydride; b) by reduction of carboxylic acid derivatives such as: i) by reduction of compounds having formula VII, wherein Z is CR 1 R 2 CONR 3 R 4 and R 3 and R 4 are other than hydrogen, for example using lithium diethoxyaluminohydride; ii) by reducing amides formed by reacting ethyleneimine with an acid chloride having the formula XII, for example using lithium aluminum hydride as reducing agent; iii) by reduction of acid chlorides having the formula XII, for example with lithium tri-tert-butoxyaluminohydride; c) by reaction of alcohols (formed by reduction of carboxylic acids of formula XIV) with, for example, chromium trioxide-pyridine complex in dichloromethane under anhydrous conditions.

Compounds of formula VII, wherein Z is a group having the formula -CR 1 = NOH or -CR 1 R 2 .CR 7 = NOB or ethers or esters thereof can be prepared by reacting hydroxylamine or an ether or ester thereof with ketones having the formula V resp. ketones or aldehydes having the formula VI.

Compounds of formula VII, wherein Z is a group of the formula -CR 1 = NR 3 or -CR 1 R 2. CR 7 = NR 3 can be prepared by reacting amines having the formula NH 2 R 3, with ketones having the formula V and ketones or aldehydes having the formula VI.

The preparation of compounds of formula VII, wherein Z is a group having the formula -CR1 = NY or -CR1R2.CR7 = NY has been described above with respect to compounds having formula XVI resp. XVIII.

The preparation of compounds of formula VII, wherein Z is a group having the formula -CRIRZCN, is described below with reference to the cyano compounds of formula XIX.

Compounds of formula VII, wherein Z is a group having the formula - CR 1 R 2 CONR 3 R 4 can be prepared by reacting acid derivatives such as esters or acid halides (for example acid chlorides of formula XII) with amines having the formula HNR 3 R 4. Compounds of formula VII, wherein Z is CRIRZCONHZ can be prepared from cyano compounds of formula XIX for example by hydration with aqueous acids or collagenpm reaction with hydrogen peroxide in the presence of a base.

Imines of formula VIII and IX can be prepared by reacting amines having the formula R 3 NH 2 with aldehydes having the formulas XXII and WE.

Amides of formula X may be prepared by reacting ammonia with carboxylic acid derivatives, for example acid chlorides having the formula XII, or they may be prepared from cyano compounds of formula XIX, for example by hydration with aqueous acids or by reaction with hydrogen oxide in the presence of a base. Amides of formula XI may be prepared by reacting ammonia with carboxylic acid derivatives, for example acid chlorides of formula XIII or they may be prepared from cyano compounds of formula XXIII, for example by hydration with aqueous acids or by reaction with hydrogen peroxide in the presence of a bass.

RS \ Calaácpvñácr * \ I XXIII's Amides of formula X, wherein R1 and R2 are hydrogen, and amides of formula XI, wherein R? and R8 is hydrogen, can be prepared from acid chlorides of formulas XX and XII by reaction with diazomethane to give a diazoketone which is regrouped in the presence of ammonia and a catalyst such as silver to give the required amide.

Carboxylic acids of the formulas XIV, XV and XXI can be prepared by hydrolysis, for example basic hydrolysis, of cyano compounds of the formulas XIX, XXIII and XVII. Carboxylic acids of formulas XIV and XV can be prepared by reacting amides of formula X and XI with nitric acid. Carboxylic acids of formula XXI can be prepared by reacting nitric acidity with amides formed by reacting ammonia with carboxylic acid derivatives, for example acid chlorides of formula XX or by reacting cyano compounds of formula XVII, with the presence of hydrogen peroxide in the presence of a base.

Carboxylic acids of formula XIV, wherein R1 and R2 are hydrogen, and carboxylic acids of formula XV, wherein R7 and RB are hydrogen, can be prepared from acid chlorides of formulas XX and X2, respectively. XII by reaction with diazomethane to give diazoketones, which are regrouped in the presence of water and a catalyst such as silver to give the required acid. Cyano compounds of formula XVII can be prepared by reacting cyano compounds of formula XXIV CHQCN Rs XXIV with a 1,3-disubstituted propane, for example 1,3-dibromopropane, and a base such as sodium hydride.

Cyano compounds of formula XIX, wherein R 1 and R 2 are hydrogen, can be prepared from cyano compounds of formula XVII. for example by the following series of reactions: a) hydrolysis of the cyano group to form a carboxylic acid of formula XXI; b) reduction of the carboxylic acid, for example with lithium aluminum hydride or borane / dimethyl sulphide complex to form the corresponding alcohol; c) replacing the hydroxy group in the alcohol with a leaving group, for example a p-toluenesulfonyloxy group, and d) replacing the leaving group with a cyano group.

In a similar manner, cyano compounds having the formula XXIII can be prepared starting from cyano compounds having the formula XIX. Cyano compounds of formula XIX, wherein one or both of R 1 and R 2 is other than hydrogen, may be prepared from the corresponding cyano compounds of formula XIX, wherein R 1 and / or R 2 are hydrogen, for example by alkylation with an alkyl halide in the presence of a base such as lithium diisopropylamide. Cyano compounds having the formula XIX wherein R 2 is hydrogen can also be prepared by reacting ketones having the formula V or an aldehyde having the formula XXII with a reagent to introduce a cyano group such as p-toluenesulfonylmethyl isocyanide.

Similarly, cyano compounds of formula XXIII can be prepared starting from aldehydes or ketones of formula VI.

Acid chlorides of formulas XX, XII and XIII can be prepared by reacting 2 "carboxylic acids having the formula XXI, XIV and XV, respectively, with, for example, thionyl chloride.

Aldehydes having the formula XXII can be prepared according to methods well known in the art. The following are examples of suitable methods: a) by reduction of cyano compounds of formula XVII with, for example, di-tert-butylaluminum hydride or diisobutylaluminum hydride; b) by reduction of carboxylic acid derivatives, for example i) by reduction of tertiary amides formed by reaction of secondary amines with acid chlorides of formula XX for example when the secondary amine is a dialkylamine using lithium diethylaluminohydride as reducing agent or when the secondary amine is ethylene-imine with use of lithium aluminum hydride as reducing agent; ii) by reduction of acid chlorides having the formula XX, for example with lithium tri-tert-butoxyalinohydride; c) by oxidation of alcohols (prepared by reduction of carboxylic acids of formula XXI) with, for example, chromium trioxide / pyridine complex in dichloromethane under anhydrous conditions.

Ketones of formula V (except those wherein R 5 and R 6 are hydrogen and R 1 is methyl or ethyl), ketones of formula VI and aldehydes of formula VI (except those wherein R 1, R 2, R 5 and R 6 are hydrogen), compounds of the formula VII (except those in which f 452 611 23 Z = CRI = NY and R 5 and R 6 are hydrogen and R 1 is methyl and ethyl), the imines of formula VIII (except those in which R 5 and R 6 are hydrogen), IX, XVI (except those wherein R 5 and R 6 are hydrogen and R is methyl or ethyl) and XVIII, amides of formula X and XI, the carboxylic acids of formula XIV (except those wherein R 11 R 1 R 5 and R 6 are hydrogen) and XV, the cyano compounds of formula XIX2 and XXIII and the acid chlorides of formula XII (apart from those wherein R 1, R 2, R 5 and R 6 are hydrogen) and XIII, which are described herein as intermediates, are novel compounds.

Certain cyano compounds of formulas XVII and XXIV are new compounds. Such novel compounds constitute a further aspect of the present invention.

New formamides of the formula XXV R / 3 cnlnz; cR7R8JnN R cno \ - m 'Rs are described herein as intermediates in the preparation of compounds of formula I and such novel formamides constitute a further aspect of the invention.

The therapeutic activity of the compounds of formula I has been indicated by determining the ability of the compounds to reverse the hypothermic effects of reserpine 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 feed and water ad libitum. After 5 hours, the body temperature of each mouse was determined orally and the mice were injected intraperitoneally with reserpine (5 mg / kg) in solution in deionized water containing ascorbic acid (50 mg / ml). The amount of fluid injected was 10 ml / kg body weight. 9 hours after the start of the test, the feed was removed but water was still available ad libitum. 242 611 24 24 hours after the start of the test, the temperature of the mice was measured and the mice were given the test compound suspended in a 0.25% solution of hydroxyethylcellulose (sold under the trade name 'Cellosize QP 15000' by Union Carbide) in deionized water at a dose volume of 10 ml / kg body weight. 3 hours later, the temperature of all mice was determined again. The percentage reversal of the reserpine-induced decrease in body temperature was then calculated according to the formula: (Temperature after 27 hours - temperature after 24 hours) x 100 (Temperature after 5 hours - temperature after 24 hours) The mean value for each group of 5 mice was taken at a plurality of dosages to enable a value for the average dose that caused a 50% reversal (EDSO) would be obtained.

All compounds, which are end products in the embodiments given below, gave EDSO values of 30 mg / kg or less.

It is largely understood by a person skilled in the art that this test shows that the compounds have an anti-depressant activity in humans.

Table I lists the compounds of formula I which gave an ED 50 value in the above test of 10 mg / kg or less.

Table I 1- [1- (3,4-Dichlorophenyl) -cyclobutyl] ethylamine hydrochloride; N-methyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride; N, N-dimethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride; 1- [1- (4-polyphenyl) cyclobutyl] ethylamine hyarokioria; N-methyl-1- [1- (4-iodophenyl) -cyclobutyl] -ethylamine hydrochloride; N, N-dimethyl-1- [1- (4-iodophenyl) cyclobutyl] -ethylamine hydrochloride; N-methyl-1- [1- (2-naphthyl) cyclobutyl] ethylamine hydrochloride; N, N-dimethyl-1- [1- (4-chloro-3-trifluoromethylphenyl) -cyclobutyl] -ethylamine hydrochloride; 1- [1- (4-Chlorophenyl) -cyclobutyl] -butylamine hydrochloride: N-methyl-1- [1- (4-chlorophenyl) -cyclobutyl] -butylamine hydrochloride; N, N-dimethyl-1- [1- (4-chlorophenyl) -cyclobutyl] -butylamine hydrochloride; _ ,, _ ,,, _. ,, ',. ,, _ ,. __.-. , _._, ...., _...... 452 611 25 1- [1- (3,4-Dichlorophenyl) -cyclobutyl] -butylamine hydrochloride; N-methyl-1- [1- (3,4-dichlorophenyl) -cycloputyl] butylamine hydrochloride; N, N-dimethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] -butylamine hydrochloride; 1- [1- (4-biphenylyl) cyclobutyl] -butylamine hydrochloride; N, N-dimethyl-1- [1- (4-biphenylyl) -cyclobutyl] butylamine hydrochloride; 1- [1- (4-chloro-3-fluorophenyl) cyclobutyl / butylamine hydrochloride; N-formyl-1- [1- (4-chloro-3-fluorophenyl) cyclobutyl] butylamine; 1- [1- (3-chloro-4-methylphenyl) cyclobutyl] -butylamine hydrochloride; N-formyl-1- [1-phenylcyclobutyl] -butylamine; 1- [1- (3-trifluoromethylphenyl) cyclobutyl] -butylamine hydrochloride; 1- [1- (naphth-2-yl) -cyclobutyl] -butylamine hydrochloride; 1- [1- (6-chloronaphth-2-yl) -cyclobutyl] -bucylamine; N-methyl-1- [1- (4-chlorophenyl) -cyclobutyl] -2-methylpropylamine hydrochloride; 1- [1- (4-chlorophenyl) -cycylbutyl] -pentylamine hydrochloride; N-methyl-1- [1- (4-chlorophenyl) cyclobutyl] -pentylamine hydrochloride; N, N-dimethyl-1- [1-phenylcyclobutyl] -3-methylbutylamine hydrochloride: 1- [1- (4-chlorophenyl) -cyclobutyl] -8-methylbutylamine hydrochloride; N-methyl-1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine hydrochloride: N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride: N-formyl -1- [1- (α-chlorophenyl) cyclobutyl] -3-methylbutylamine N, N-dimethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride; N-methyl-1- [1- (naphth-2-yl) -cyclobutyl] -3-methylbutylamine hydrochloride; 4 N-methyl-1- [1- (3,4-dimethylphenyl) cyclobutyl] -3-methylbutylamine hydrochloride; N- (4-chlorophenyl) cyclobutyl [N (cyclopropyl) -methylamine hydrochloride: N-methyl- [1- (4-chlorophenyl) cyclobutyl ]- (cyclopentyl) -methylamine hydrochloride; [1- (4-chlorophenyl) -cyclobutyl] - (cyclohexyl) -methylamine hydrochloride: 26 N-methyl- [1- (4-chlorophenyl) cyclobutyl] - (cyclohexyl) -methylamine hydrochloride; [1- (3,4-Dichlorophenyl) -cyclobutyl] - (cyclohexyl) -methylamine hydrochloride; 3 N-methyl- [1- (3,4-dichlorophenyl) -cyclobutyl] - (cyclohexyl) -methylamine hydrochloride; [1- (4-chlorophenyl) -cyclobutyl] - (cycloheptyl) -methylamine hydrochloride; 1- [1- (4-chlorophenyl) -cyclobutyl] -2-cyclopropylethylamine hydrochloride; N, N-dimethyl-1- [1- (4-chlorophenyl) -cyclobutyl] -2-cyclohexylethylamine hydrochloride; 0 (- [1- (4-chlorophenyl) -gyclobutyl] -benzylamine hydrochloride; N-methylx- [1- (4-chlorophenyl) -cyclobutyl] -benzylamine hydrochloride; 1- [1- (4-chloro-2-fluorophenyl) - cyclobutyl / butylamine; N, N-dimethyl-1- [1- (4-chloro-2-fluorophenyl) -cyclobutyl] -butylamine hydrochloride; 1- [1,1- (3,4-dichlorophenyl) -cyclobutyl] -methyl] -propylamine hydrochloride; N, N-dimethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] -methyl-propylamine hydrochloride; N, N-dimethyl-2- [1- (4-iodophenyl) - cyclobutyl] -ethylamine hydrochloride; N-ethyl-1- [1- (1,4-dichlorophenyl) cyclobutyl] -ethylamine hydrochloride; N, U-diethyl-1- [1- (3,4-dichlorophenyl) -cyclobul] / - The invention is further described by the following examples.

All compounds were characterized according to conventional analytical pre-techniques and gave satisfactory elemental analyzes. All melting points and boiling points are given in degrees Celsius. A solution of 3,4-dichlorobenzyl cyanide (25 g) and 1,3-dibromopropane (15 ml) in dry dimethyl sulfoxide (150 ml) was added dropwise under nitrogen to a stirred mixture of sodium hydride (45 g). 77, S g) dispersed in mineral oil (7.5 9) and dimethyl sulfoxide (200 ml) at a temperature in the range 30-350. The mixture was stirred at room temperature for 2 hours and propan-2-ol (8 ml) and then water (110 ml) were added dropwise. The mixture was filtered through diatomaceous earth sold under the trademark "CELITE" and the solid residue was washed with ether.

The ether layer was separated, washed with water, dried and evaporated. 1- (3,4-Dichlorophenyl) -1-cyclobutanecarbonitrile (boiling point 10 DEG-120 DEG C. at 0.1 mm mm) was isolated by distillation. This method is a modification of the method described by Butler and Pollatz (J. Org. Chem., Vol. 36, No. 9, 1971, page 1308).

The above prepared 1- (3,4-dichlorophenyl) -1-cyclobutanecarbonitrile (21.7 g) was dissolved in dry ether (SO ml) and the solution was added under nitrogen to the product of a reaction between gaseous methyl bromide and magnesium turnings ( 3.9 9) in dry ether (150 ml). The mixture was stirred at room temperature for 2 hours and then under reflux for 2 hours. Crushed ice and then concentrated hydrochloric acid (100 ml) added: and the mixture was heated under reflux for 2 hours. The ether layer was separated, washed with water and with aqueous sodium bicarbonate solution, dried and evaporated. 1-Acetyl-1- (3,4-dichlorophenyl) cyclobutane (b.p. 108 DEG-110 DEG C. at 0.2 mm Hg) was isolated by distillation. 1-Acetyl-1- (3,4-dichlorophenyl) -cyclobutane (9.1 g) prepared as above, formamide (6.5 ml) and 98% formic acid (3 ml) were heated at 180 ° for 16 hours to obtain N-formyl-1- [1- (3,4-dichlorophenyl) -cyclobutyl] -ethylamine. Concentrated hydrochloric acid (20 ml) was added and the mixture was heated under reflux for 3 hours. The solution was then cooled, washed with ether and sodium hydroxide solution was added. The product was extracted with ether and the ether extract was washed with water, dried and evaporated. 1- [1- (3,4-dichlorophenyl) cyclobucyl] ethylamine (b.p. 112-1180 at 0.2 mm Hg) was isolated by distillation.

The amine was dissolved in propan-2-ol and concentrated hydrochloric acid and the solution was evaporated to dryness to give 1- [1- (3,4-dichlorophenyl) -cyclobutyl-ethylamine hydrochloride (m.p. 185-19 °). (formula I n = 0; al = ne; R2, R and R = H; R = 4-cl; R4 - 3-Cl). Example 1a Preparation of N-formyl-1- [1- (3,4-dichlorophenyl) -cyclobutyl] -ethylamine (m.p. 124-125 ° C) (Example 1 (a) Formula I n = 0; R1 = Me : R 2 = H; R 3 = H; R 4 = CHO; R 5 = 4-Cl (OCh R 6 = 3-Cl) as described above were repeated and the product was isolated by cooling the reaction mixture and recovering the solid formed by filtration. The formamide was then hydrolyzed with concentrated hydrochloric acid in industrial spirit to give the hydrochloride salt of 1- [1- (3,4-dichlorophenyl) -cyclobutyl] -ethylamine.

In a similar manner to that described above in Example 1a, the following compounds were prepared. The conditions for the hydrolysis of the formamides isolated by suitable methods are given in the footnotes. \\ _: nnlNH¿.Hc1 “s Rs Example nl Å RS R6 cox point (free base) m.p. for No: HCl salt 1 (b) methyl cl n 1o7 ° / 1.2 mm ag A 1 (c) n -butyl c1 u 1: a-139 ° s 1 (a) mecyl JH 205-2o7 ° c 1 (e) methyl c1 CF3 216-211 ° o A. Aqueous HCl / industrial spirits B. l-valeryl-1- ( The 4-chlorophenyl) -cyclobutane was prepared in tetrahydrofuran. Hydrolysis was performed using concentrated HCl / industrial spirit C. Concentrated HCl / diethylene glycol dimethyl ether (similar to that described in Example 12).

D. Concentrated HCl / industrial spirit Example 2 The product from Example 1 (4.04 9), water (0.5 ml) and 93% formic acid (3.6 ml) were mixed under cooling. 37-40% aqueous formaldehyde (3.8 ml) was added and the solution was heated at 85-950 for 5 hours. The solution was evaporated to dryness and the residue was acidified with concentrated hydrochloric acid and water was removed by repeated addition of propan-2-ol followed by evaporation in vacuo. Crystals of N, N-dimethyl-1- [1- (3,4-dichlorophenyl) -cyclobutyl] -ethylamine hydrochloride (m.p. 211-213 °) (formula 1 n = o; ai = Me; R2 = H; R3, R4 = ne; ns = 4-: 1; R6 = 3-Cl) was isolated.

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

/ I \\ CHRlNe2.HCl “s.

Example Starting R1 Rs R6 M.p. for Boiling point for free material HCl salt base z (a) 1 (b) methyl c1 H se-100 ° / o, s mm Hg 2 (b) 1 (a) methyl J n zeo-2e1 ° Example 3 In a similar manner as described above in Examples 1 and 2, N, N-dimethyl-1- [1- (4-biphenylyl) -cyclobutyl] -ethylamine hydrochloride (m.p. 196-197 °) was prepared. (Formula I n = 0; R 1 = Me; R 2 = H; R 3, R 4 = Me; R 5 = 4-phenyl and R 6 = H). w -ç-f-mw. ~, -r: - »-.- n .--. ~» Mv- - .. »... I ~ a '4-c1 ørn R = 3-cl). 452 611 Example 4 4-Acetyl-1- (3,4-dichlorophenyl) -cyclobutane (15 g) prepared as described in Example 1, N-methylformamide (47.5 ml), 98% formic acid (10.3 ml) and a 25% aqueous solution of methylamine (1.5 ml) were mixed and heated with stirring at 170-180 ° for 8 hours. The mixture was cooled and extracted with ether. The ether extract was washed, dried and evaporated to give a light yellow oil, which was heated under reflux with concentrated hydrochloric acid (50 ml) for 2 hours. Industrial spirits (IMS) (50 ml) were added and the mixture was heated to reflux for 16 hours. The slurry was then cooled to 0 ° C and the white precipitate was collected by filtration, washed with acetone and dried. The product, N-methyl-1- [1- (3,4-dichlorophenyl) -cyclobutyl] -ethylamine hydrochloride had a melting point of 254- O = 0 = I 2 I 7. 0 = 0 = 256 (formula I n 0, R 1 Me, R 2 H, R 3 Me, R 4 H, R 5 In a manner similar to that described above, the following compounds of formula I were prepared: C1 / R 5 Example R 1 R 5 -R 6 Amine boiling point Mp for NO 4 HCl salt u (a) nr c1 n 98-1oo ° / 0.15 mn zuo-2a1 ° a (b) ne H ci 269-27z ° Mr) nr ar a 96-9a ° / 0.1 mm um) Me H ar 251-259 u (e) Me CF3 H 219-221: a (f) Me H- cr; 225-228 4 (¿) Me - (35 = cn) 2- 254-257 ° u (h) Me ci cr; 198-200: u (1) rst cl H 238-2ß0 a (3) Pr c1_ H 228-229 ° A a (x) nu c1 H 152-153 ° ^ uu) nr ~ I n ana-za? Q2) ¿O) I ° 31 Note A: The starting ketone was prepared in tetrahydrofuran as a reaction solvent instead of ether.

Example 5 A mixture of 70% aqueous ethylamine (50 ml) and water (100 ml) was gradually mixed with a mixture of 98% formic acid (50 ml) and water (100 ml) to obtain a neutral solution. , which was evaporated at 10006/100 mm Hg until 180 ml of water were recovered. The residue was heated to 1400 and 1-acetyl-1- (4-chlorophenyl) -cyclobutane (10.4 g) was prepared in a similar manner to that described in Example 1 for 1-acetyl-1- (3, 4-Dichlorophenyl) -cyclobutane and 98% formic acid (10 ml) were added. The mixture was heated on an oil bath at a temperature of 180-2000 for 16 hours. The mixture was distilled until an internal temperature of 1700 was reached and this temperature was maintained for 2 hours. Each volatile material was removed by distillation at 160 ° C / 20 mm and the residue was heated under reflux with concentrated hydrochloric acid (15 ml) and industrial spirit (IMS) (15 ml) for 3 hours. The IMS was evaporated on a rotary evaporator and the residue was washed with ether.

The aqueous phase was adjusted to pH 12 with sodium hydroxide and extracted with ether. The ether extract was dried and after evaporation a residue was obtained which was treated with aqueous hydrochloric acid to give N-ethyl-1- [1- (4-chlorophenyl] cyclobutyl] ethylamine hydrochloride (m.p. 203 DEG-20 DEG C.) (Form 1 n = o; nl = me; az = u; 113 = st; 1: 4 = H; Rs = 4-Cl; R6 = H).

Example 6 1- (4-Chlorophenyl) -1-cyclobutanecarbonitrile (159). prepared in a manner similar to that of 1- (3,4-dichlorophenyl) -cyclobutanecarbonitrile in Example 1, in dry ether (50 ml) was added to the product of a reaction between magnesium turnings (3,18) and propyl bromide. (1.59 g) in dry ether (50 ml). The ether was replaced with tetrahydrofuran and the mixture was heated with stirring and under reflux for 18 hours. The mixture was cooled and ice and then concentrated hydrochloric acid (52 ml) were added. The resulting mixture was stirred at reflux for 10 hours and extracted with ether. The ether extract gave a residue from which 1-butyryl-1- (4-chlorophenyl) -cyclobutane (b.p. 106-1080 / 0.3 m Hg) was distilled.

A mixture of the ketone described above (21 g) and 98% formic acid (6 ml) was added over a period of 1.5 hours to formamide (15 ml) at 160 ° C. After complete addition, the temperature was raised to 180-185 ° C and maintained at this interval for 5 hours. The mixture was cooled and extracted with chloroform to give a thick gummy substance which, after heating with petroleum ether (b.p. 60-80 °) gave a colorless solid which was recrystallized from petroleum ether (b.p. 60-800) to give N -formyl-1- [1- (4-chlorophenyl) -cyclobutyl] -butylamine (m.p. 97.5-98.5 ° C) (Formula I n = o; al = propyl; 122 = n; 113 = u; 1 : 4 = cno; Rs = 4-c1; 116 = u).

Example 7 A solution of 1- (3,4-dichlorophenyl) -1-cyclobutanecarbonitrile prepared as described in Example 1 (3S, 29) in ether (100 ml) was added to a solution of propylmagnesium bromide prepared by reaction of propyl bromide (32 g ) and magnesium turnings (6.36 g) in ether (100 ml). The ether was replaced with dry toluene and the mixture was heated under reflux for one hour. Water (200 ml) and then concentrated hydrochloric acid (120 ml) were added and the mixture was heated under reflux for one hour. The reaction mixture was extracted with ether and after washing and drying gave the extract a residue, from which 1-butyryl-1- (3,4-dichiorophenyl) -cyciobutane (b.p. ) desc111e- rades.

The ketone (37.0 g) and 98% formic acid (9 ml) prepared as above were added to formamide (23.5 ml) at 170 ° C and the temperature was maintained at 175-180 ° C for 5 hours. . An additional proportion of kidney acid (4.5 ml) was added to the mixture at 115 DEG-100 DEG C. for a further 15 hours. The mixture was extracted with ether which, after evaporation, gave a thick oil which was crystallized from petroleum ether (b.p. 60-80 ° C) to give N-formyl-1- [1- (3,4-dichlorophenyl) -cyclobutyl] -butylamine with a melting point 452 611 33 of 103-105 ° C (formula I n = O: R 1 = propyl; R 2 = H; R 3 = H; R 4 = CHO; R 5 = 4-Cl and R 6 = 3-Cl).

In a manner similar to that described above, the following compounds were prepared: czmlmac fl o Example B1 RS H6 $ mp_ (OC) 7 (a) isobutyl c1 H 11o-112 ° 7 (b) pmpyl c1 F 11s-116 ° 7 (c) phenyl cl H The product from Example 7 (4.0 g) in dry tetrahydrofuran (25 ml) was added rapidly to a stirred mixture of lithium aluminum hydride (1.4 g). in dry tetrahydrofuran (25 ml) under nitrogen.

The mixture was heated under reflux for 5 hours and then cooled. Water (15 ml) and then 10% sodium hydroxide solution (3 ml) were added and the mixture was filtered through diatomaceous earth sold under the trademark 'CELITE'. The product was extracted with ether, re-extracted to SN hydrochloric acid and the aqueous layer was made alkaline and extracted with ether. The ether extract gave an oil which was dissolved in propan-2-ol (5 ml) and concentrated hydrochloric acid was added to pH 2. Evaporation of the resulting solution gave a white solid which was collected, washed with acetone and dried.

The product was N-methyl-1- [1- (3,4-dichlorophenyl) -cyclobutyl] -butylamine amyarochioria and reached a melting point of 234-23 ° C (frame 1 n = 0; R1 = propyl; R2 = H; R = H; R4 = Me; Rs = 4-Cl and R3-Cl). 3 6 452 611 34 In a manner similar to that described above, the following compounds were prepared: CPIR1NHMe. HCl R / \ 5 R __.

°) Example R1 RS R6 mp '(C 3 (8) phenyl cl H 275_278: 3 (b) propyl Cl H 223-228 Example 9 The product from Example 7 (10 g) in solution in ether (50 ml) was added to a 70% toluene solution of sodium bis- (2-methoxyethoxy) aluminum hydride sold under the name 'Red-al' (40 ml) at a temperature in the range of 25-30 ° C. The mixture was stirred at this temperature for 4 hours. Water (25 ml) was added dropwise under cooling and the mixture was filtered through diatomaceous earth (CELITE), aqueous solution of NaOH was added and an ether extraction was performed, the ether extract was washed with water and re-extracted with SN hydrochloric acid A white solid (mp 232-235 ° C ) appeared at the interface and was recovered.Base was added to the aqueous phase and a further ether extraction was carried out Evaporation of the ether extract gave an oil which was dissolved in propan-2-ol (5 ml) and concentrated hydrochloric acid was added to pH 2 Evaporation to dryness gave a white solid (m.p. 236 ° C). The white solids were combined and recrystallized from propan-2-ol to give N-methyl-1- [1- (3,4-dichlorophenyl) -cyclobutyl] -butylamine hydrochloride (m.p. 236-237 ° C) (Formula I n = O; R1 = propyl; R2 = H; R3 = H; R4 = Me; Rs = 4-Cl and R6 = 3-Cl).

In a manner similar to that described above, the following compounds were prepared. When the formyl starting material was insoluble in ether, a solution of the reducing agent was added to a stirred suspension of the formyl compound. To the extent that the size of the group R1 increases 4552 1511, the hydrochloride salts of the desired compounds become less soluble in the aqueous phase and more soluble in the organic phase so that appropriate modifications to the isolation process are required, as will be apparent to those skilled in the art. cHnlNHMe.Hc1 Rs “Rs Example l H1 R5 R6 SNF - 9 (a) isopropyl Cl H 257-2590 9 (b) šggfburyi ci H zo9 ~ 212 ° 9 (r) isoburyi cl H 225-253 ° 9 (a) cyclopencyi c1 H 252-256 ° 9 (e) n-nexyi - c1 a 117-11a ° 9 (f) a-merorphenyl c1 H zsa-266 ° 9 (g) B-methoxy phenyl Cl H 2514-2559 9 (h) Z-methoxy phenyl Cl H 119-1550 9 (1) cycloneryl ci H 17ø-172 ° 9 (3) isobutyl - (ca = cH) 2- 56-2§9 ° 9 (k) cycloneryl c1 ci 225-22a ° 9 (1) isobutyl Me ne (1) 9 (m) 'propyl OMe H 173-175 ° 9 (n) methyl phenyl H 116-1180 (n xokpunkreni for the free base was> 100 ° C at 1.0 mm ng 611 36 Example 10 The product from Example 7 (49), diethylene glycol dimethyl ether (25 ml), water (10 ml) and concentrated hydrochloric acid (10 ml) were mixed and heated under reflux for 9 hours. The solution was washed with ether. and aqueous NaOH solution was added before an ether extraction was performed.The ether extract was washed with brine and water to give an oil after evaporation.The oil (3.19 g) was dissolved in a mixture of propan-2-ol (4 ml) and ether (20 ml) and concentrated hydrochloric acid (1.5 ml) was added. The solvent was evaporated in vacuo. Repeated dissolution in industrial spirits and evaporation in vacuo gave a gummy substance which solidified on heating in vacuo: The product was recrystallized from petroleum ether (boiling point 100-120 °) and had a melting point of 201-2039. The product was 1- [1- (3,4-dichlorophenyl) cyclobutyl] butylamine hydrochloride (Formula I n = O; R1 = propyl; R = H: RR = H; R = 4-Cl and R = 3-Cl) . In a manner similar to that described above, the following were prepared, the hydrochloride salts of the desired compounds became less soluble in those compounds. To the extent that the size of the group R in the aqueous phase and more soluble in the organic phase so that appropriate modifications of the isolation process were required as will be apparent to one skilled in the art.

CHR1NH2.HCl p '/ Example R1 RS H5 SNP- 0 10 (a) ISOPrOPYI Cl H 2 °°° 2 ° 2 ° 1Q (b) âgšfbutyl Cl H 178-179 1o (c) iaøbutyl c1 n 163-165 ° __ 10o (a) Cyclopentyl Cl H 185'21 °: (Éea11§fï_ 10 (e) phenyl Cl H 27l_276 ° 10 (f) 5-methoxyphenylyl Cl H Zla-2190 10 (g) cyclohexyl Cl H 206-2100 10 (h iscbutyl HH 210-2l2 ° 1 ° (i) cyßglgprgpyl Cl H 2ÛLl-2O6 ._ ... tm H. v. 452 611 31 'Example H1 Rs R6 M.p. 10 (j) propyl Ph H 235-2360 (x) propylene c1 zla-z17 ° 1ø (1) propyl - (cn = cH) 2- 157-159 ° 10o (m) in cyaloheptyl cl H 156-162 ° 10o (n) cycloneexyl cl c1 “215 ° 1ø (p) me: y1 c1 F 215-217 ° 10 (q) Q propyl 0Me H 178-1790 1o (r) propyl cl F 196-1es ° 1o (s) propyi c1 H 174-175 ° 1o (t) cyc1 ° nexymethyl c1 H las-15o ° 10 (u) burenyl _ c1 H 184-1a5 ° 1o (v) propyl -cn = cn-cc1 = cH- (a) 10o (w) propyl of CF3 126-12s ° 1o x) u-fluoro-phenyl 1 'C1 H 279 ° 10 (y) (b) methyl; p === c "m": H -en (a) the boiling point of the free base was 168 ° C / 0.05 mm Hg (b) diethylene glycol dimethyl ether was replaced with ethylene glycol dimethyl ether In a manner similar to that described above were prepared 1- [1- (4-chloro-2-fluorophenyl) cyclobutyl] butylamine (b.p. 99 ° C / 0.05 mm); (Formula I n = 0; R 1 = propyl; R 2, R 3 and R 4 = H; R 5 = 4-Cl; R 6 = 2-P); 1- [1- (2-fluorophenyl) -cyclobutyl] -butylamine hydrochloride (m.p. 175-177 ° C); (Formula I n = O; R 1 = propyl; R 2, R 3, R 3, R 5 = H and R 6 = 2-F): and 1- [1- (4-chloro-2-methyl) -cyclobutyl] -butylamine hydrochloride ( mp 188-190 ° C); O: RI = propyl; R 2, R 3 and R 4 = H; R5 = 4-Cl and R6 = 2-Me) as examples 10 (z), 10 (aa) and lob).

(Formula I n = Example 11 The product of Example 10 (c) (3.3 g) as the free base, formic acid (2.99 g) and water (1 ml) were mixed under cooling. aqueous solution of formaldehyde (3.93 ml) was added and the mixture was heated for 18 hours at a temperature of 85-9S ° C.

V 4.,.,., T,:.! ..;., W. ._. ,, ......_ '.., \ _ _ 452 611 ss An excess of dilute hydrochloric acid was added and the solution was evaporated to dryness. The residue was made alkaline with SN sodium hydroxide solution and the product was extracted with ether.

Evaporation of the ether gave a pale yellow oil which was dissolved in a mixture of propan-2-ol (4 ml) and ether (20 ml) and concentrated hydrochloric acid (2 ml) was added dropwise. The solution was evaporated and the residue was repeatedly dissolved in ethanol and evaporated in vacuo to give a gummy substance which was triturated with petroleum ether (b.p. 60-800) to give a yellow solid which was recrystallized from acetone. The product was N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride (m.p. 195-197 ° C). (Formula I n = O; R1 = iSObutyl; RZ = H; R3, R4 = Me; RS = 4-Cl; RG = H).

In a manner similar to that described above, the following compounds of formula I were prepared: cHnlNMe2.Hc1 R / Rs Example Starting R1 R5 R5 M.p. > material 11 (a) 10 (n) isobucyl HH 195 ~ 19s: s 11 (b) _10 (j) propyl Ph H 19A-1960 11 (c) 10 (n) cyclohxyl Cl Cl 227-2280 11 (d) 10 (q) propyl OMe H 187-1880 11 (e) 10o (s) propyl Cl H 19 "-196 _" kl hexyl- 0 11 (1) 10o (t) ° Y mgtyl. cl 134-196 11 (g) (U) butenyl Cl H 165-167 ° 11 (h) 10 (v) propyl -cn = cH-cc1 = cH- (a) '0 11 (1) isobutyl c1 c1 225-256 _11 (á) 1o ( x) 4-fluorophenyl / cl H 23A 1l (k) propyl isopropyl H 211-213 ° (a) the boiling point of the free base was <250 ° C / 0.05 mm Hg 452 611 39 Example gel ll (l) On a In a manner similar to that described above, N, N-dimethyl-1- [1- (4-chloro-2-fluorophenyl) -cyclobutyl] -butylamine hydrochloride (m.p. 1e3 ° C) was prepared. ; R = H; R3, R = Me; R = 4-Cl; R = 2-F) Example 4 The product from Example 7 (8.3 g), diethylene glycol dimethyl ether (SO ml), water (20 ml) and concentrated hydrochloric acid (20 ml) were mixed and heated under reflux for 16 hours The mixture was poured into water, aqueous NaOH was added and the product extracted s with ether. Evaporation gave a dark oil. A sample of this oil (7.99 g), water (0.7 ml) and formic acid (6.5 ml) were mixed and formaldehyde (6.5 ml) was added.

The mixture was heated under reflux for 3 hours and then concentrated hydrochloric acid (10 ml) and propan-2-ol (10 ml) were added. Evaporation to dryness gave N, N-dimethyl-1- [1- (3,4-dichlorophenyl) -cyclobutyl] -butylamine hydrochloride (m.p. 195-1960) as a white solid (formula I n = O; R1 = propyl; R 2 = H; R 3, R 4 = Me; R 5 = 4-Cl and R 6 = 3-Cl).

Example 13 - 1- (4-chlorophenyl) -1-cyclobutanecarbonitrile (37.6 g) prepared in a manner similar to that of 1- (3,4-dichlorophenyl) -1-cyclobutanecarbonitrile as described in Example 1 was added to a solution of potassium hydroxide (32.4 g) in diethylene glycol (370 ml) and the mixture was heated under reflux for 3.5 hours.

The reaction mixture was 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 concentrated hydrochloric acid (100 ml) and ice and the resulting precipitate of 1- (4-chlorophenyl) -1-cyclobutanecarboxylic acid (m.p. 86-88 ° C) was collected, washed with water and dried.

A solution of the acid (10.5 g) prepared as above in tetrahydrofuran (150 ml) was added dropwise under nitrogen to a stirred suspension of lithium aluminum hydride (2 g) in tetrahydrofuran (150 ml). The mixture was stirred at reflux for 2 hours and water was added. The mixture was filtered through diatomaceous earth (CELITE) and the product was extracted with ether.

After washing with water and drying, the ether was evaporated to give a residue, which was recrystallized from petroleum ether (b.p. 60-80 ° C). The product was 1- / 1- (4-chlorophenyl) -eyk1ebuey1 / -necyieikenei (cut point eo-e2 °).

A solution of the alcohol (60 g) prepared above in pyridine (52 ml) was added dropwise to a solution of p-toluenesulfonyl chloride (60 g) in pyridine (100 ml) cooled on ice. The temperature was allowed to rise to room temperature and remained there for 18 hours. 1- [1- (4-Chlorophenyl) -cyclobutyl] -methyl-p-toluenesulfonate (m.p. 99 DEG-100 DEG C.) The gene was precipitated by mixing the reaction mixture in a mixture of ice and concentrated hydrochloric acid (200 ml).

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

A solution of diisopropylamine (1G, 59) in dry tetrahydrofuran (50 ml) was stirred under nitrogen at a temperature of 0 DEG C. and a 1.6M solution of n-butyllithium in hexane (100 ml) was added dropwise. The reaction mixture was stirred for 30 minutes and then cooled to -7 ° C. a solution of z- [1- (4-chlorophenyl) -cyclobutyl] -acetonitrile (9.5 g) prepared as above in dry tetrahydrofuran (25 ml) was added dropwise. The temperature of the mixture was allowed to rise to 0 ° C and the mixture was stirred for 10 minutes before a solution of methyl iodide (10 ml) in tetrahydrofuran (10 ml) was added. Tetrahydrofuran (75 ml) was added to obtain a homogeneous solution and a further solution of methyl iodide (4 ml) in tetrahydrofuran (10 ml) was added.

The mixture was stirred at room temperature for 2 hours and then water (50 ml) was added. The aqueous phase was washed with ether and the ether was combined with the organic phase of the reaction mixture. k f »l fl gqhfaifJka-ši, .¿> _Å ____. The combined organic phases were washed three times with SN hydrochloric acid, three times with water, dried and evaporated to give an oil which solidified and recrystallized from industrial spirits to give 2- [1- (4-chlorophenyl) cyclobutyl]. / -2-methylpropionitrile (m.p. 73-75 ° C).

The nitrile prepared as above (4 g) was heated under reflux with potassium hydroxide (89) in diethylene glycol (40 ml) for 24 hours. The reaction mixture was cooled, added to water (50 ml) and the aqueous phase was washed twice with ether. The aqueous phase was acidified with SN hydrochloric acid and extracted with three portions of ether. The combined ether extracts were washed with water, dried and evaporated to give a white solid, which was recrystallized from petroleum ether (b.p. 60-800) to give 2- [1- (4-chlorophenyl) -cyclobutyl] -2-methylpropionic acid ( mp 95-110 ° C).

Oxalyl chloride (10 ml) was added to the acid prepared above (2 g) and after the initial foaming subsided, the mixture was heated under reflux for one hour. Excess oxalyl chloride was removed by distillation and the residual oil was added to concentrated aqueous ammonia (75 ml). An oily solid formed which was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to give 2- [1- (4-chlorophenyl) -cyclobutyl] -2-methylpropionamide. The amide (1.34 g) prepared above was dissolved in a mixture of acetonitrile (8 ml) and water (8 ml) and iodosobenzene bistrifluoroacetate (3.4 g) was added and the mixture was stirred at room temperature in 5.5 hours. Water (75 ml) and concentrated hydrochloric acid (8 ml) were added and the mixture was extracted with ether. The ether extract was washed with SN hydrochloric acid and the aqueous phase was made alkaline and extracted with additional portions of ether. which was dried and evaporated to give an oil. The oil was dissolved in petroleum ether (b.p. 80-1000) and dry hydrogen chloride gas was passed through the solution. 1- [1- (4-Chlorophenyl) -cyclobutyl] -1-methylethylamine hydrochloride (m.p. 255-259 ° C) was collected by filtration. (Formula I n = O; R1, R2 = Me: R3, R4 = H; RS = 4-Cl; R6 = H).

Example 14 The product from Example 4 (h) (3.4 g) was mixed with anhydrous sodium formate (0.72 g), 98% formic acid (10 ml) and 37-40% aqueous formaldehyde solution (5 ml) and the mixture was heated at a temperature of 85-95 ° C for 16 hours. The mixture was diluted with water (50 ml) and made alkaline to pH 10 with aqueous sodium hydroxide solution. The basic aqueous solution was extracted with ether, washed with water and dried over magnesium sulphate. Dry hydrogen chloride gas was bubbled through ether to give a white precipitate of N, N-dimethyl-1- [L-Å-chloro--3-trifluoromethylphenyl) -cyclobutyl] -ethylamine hydrochloride ', m.p. 246-247 ° C) (formula 1 n = o; nl = Me; R2 = H; na. R4 = Me; RS = 4-Cl and R6 = 3-CF3).

Example 15 Preparation of salts of the compounds of the invention is illustrated in 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 in a conventional manner.

M.p. for salt Eitmpel Bas Acid Solvent l5 (a) 10 (s) citric acid waterh. acetone 158-160 ° 1s (b) 1o (s) maleic acid ether iss-1s7 ° 1s (c) 1015) child sensitization: 152-1ss ° 1s (d) 2 L (+) tartaric acid inauscrisprit iso-153: l5 (e ) Note (a) citric acid ether / methanol 163-164 (β-hydro- (a) The base was 1- [1- (3,4-dimethylphenyl) -cyclobutyl] -3-methyl-butylamine prepared in a manner similar to that of according to Example 10 ... dn ... _ 4E52 61'1 43 Example 16 A solution of bromobenzene (1.5.7 g) in ether (SO ml) was added dropwise under cooling to magnesium turnings (2.4 g). A solution of 1- (4-chlorophenyl) -cyclobutanecarbonitrile (19.19) prepared in a manner similar to that of Example 1 for 1- (3,4-dichlorophenyl) cyclobutanecarbonitrile 1 ether (50 ml) under an atmosphere of nitrogen ) was added and the ether was replaced with dry toluene (130 ml) 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 sodium borohydride (19) in diethylene glycol dimethyl ether (60 ml) and the mixture was stirred for 1.5 hours, water (60 ml) was added slowly and the aqueous the whole layer was extracted with toluene.

The toluene extracts were washed with water, dried and evaporated to give a residue which was dissolved in methanol (50 ml). 6N Hydrochloric acid (5 ml) was added and the solution was filtered and evaporated. Trituration with dry acetone gave p <-J1- (4-chlorophenyl) -cyclobutyl / -benzylamine hydrochloride (m.p. 277-27900) (FormulaIn = O: R = Ph; R2 = H; RR = H; R = 4-C ] .: R = 1 3 '4 5 6 H) - Example 11 Methyl formate (62 ml) was added dropwise to isopropylamine (85.5 ml) while stirring at such a rate that a slight reflux occurred. Stirring was continued for two hours after the addition.

The methanol was distilled off at 100 ° C and N-isopropylformamide (b.p. 108-109 ° / 25 mm Hg) was obtained by distillation. 1-Acetyl-1- (4-chlorophenyl) -cyclobutane (10.4 g) prepared in a similar manner to Example 1 for 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane and 98% formic acid (5 ml) was added to N-isopropylformoma (43, sg) and the mixture was allowed to stand at 50 DEG C. for 4 hours. Excess starting material was distilled off under reduced pressure (20 m 2 Hg) leaving a viscous residue, which was heated under reflux with concentrated hydrochloric acid (30 ml) for 6 hours. The mixture was washed with ether until a colorless solution was obtained. The aqueous phase was made alkaline, extracted with ether, dried and evaporated to give an oil which was dissolved in SN hydrochloric acid. evaporation gave a yellow oil, which was triturated with petroleum ether (b.p. 62-68 ° C) to give N-isopropyl-1- [1- (4-chlorophenyl; cyclobutyl] ethylamine hydrochloride (m.p. 170 114 ° c) (formula 1 n = o; nl = me; n = a; R 2 R 4 = H; R 5 = 4-Cl: R 6 = H). 3 = isopropyl; Example 18 1-acetyl-1- ( 3,4-Dichlorophenyl) -cyclobutane (7.0 g) prepared as described in Example 1 was slowly added to a mixture of pyrrolidine (25 ml) and 98% formic acid (15 ml) was heated to 130-135 ° C for 5 hours. The mixture was stirred and heated at 160 DEG-165 DEG C. for 16 hours. After cooling, the mixture was poured into SN hydrochloric acid (200 ml), the solution was washed with ether, made alkaline with aqueous sodium hydroxide solution and extracted with ether. The ether extract was washed with water, dried and hydrogen chloride gas was introduced into the extract which was then evaporated to dryness The residue was triturated with dry ether to give a solid which was recrystallized from propan-2-ol to give of N-1- [1- (3,4-dichlorophenyl) -cyclobutyl] -ethylpyrrolidine hydrochloride (m.p. 233-235 ° C) (Formula I n = 0; R1 = Me; R2 = H; R 3 and R 4 together with the nitrogen atom to which they are attached to form a pyrrolidine ring; RS 4-Cl and R 6 = 3-Cl).

Example 19 1- (4-Chlorophenyl) -1-cyclobutanecarboxylic acid (10.5 g) prepared according to Example 13 was heated under reflux with thionyl chloride (20 ml) for 2.5 hours. excess thionyl chloride was evaporated and the acid chloride of the above acid was distilled (b.p. az-96 ° / o, 2 mm ng ;.

A solution of the acid chloride (23.0 g) in dry tetrahydrofuran (100 ml) was slowly added to the product of a reaction between magnesium turnings (3.0 g) and ethyl bromide (1.2.0 g) in dry tetrahydrofuran at a temperature of - 70 to -60 ° C. The temperature was maintained at -60 ° C for one hour and then allowed to rise to 0 ° C.

Water (50 ml) was added followed by SN hydrochloric acid (150 ml) while cooling. The reaction mixture was extracted with ether, washed with water, sodium bicarbonate solution and dried.

The solvent was removed by evaporation and 1-propionyl-1- (4-chlorophenyl) -cyclobutane was obtained by distillation (b.p. 96 DEG-140 DEG C./0.25 .mu.m).

The ketone prepared as above was converted to N, N-dimethyl-1- [1- (4-chlorophenyl) -cyclobutylpropylamine hydrochloride (m.p. 213-21 ° C) in a manner similar to that of Example 12. (Formula I n = 0: R = Et; R = H; R3, R4 = Me; R = 4-Cl; 2 R6 = H). Example 20 1-Acetyl-1- (4-chlorophenyl) -cyclobutane (61 g) prepared in a manner similar to that of Example 1 for 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane, platinum oxide (0.75 g), 33% solution of methylamine in ethanol (60 g) and ethanol (30 ml) were introduced into an autoclave. The autoclave was filled with hydrogen and kept at about 60 ° C and a pressure of 20 bar for 10 hours. The reaction mixture was filtered through charcoal and the solids were washed with absolute alcohol. The solvents were removed by evaporation and a sample of the residue (10 g) was shaken with 2M hydrochloric acid (50 ml) and ether (SO ml). The aqueous layer was made alkaline and extracted with ether. The ether extract gave a liquid on evaporation and was distilled (109 ° C / C, 3 mm Hg) to give N-methyl-1- [1- (4-chlorophenyl) cyclobutyl] ethylamine (Formula I n = 0; R1 = Me; R 2 = H; R 3 = Me; R = H; R 5 = 4-Cl and R 6 = H). Example 21 Sodium borohydride (2.09) was added to a solution of 1- [1- (3,4-dichlorophenyl) -cyclobutyl] -ethylamine (1.5 g prepared by treating the product of Example 1 with aqueous sodium hydroxide solution) in glacial acetic acid (30 ml). The mixture was heated at 95410000 for 16 hours and then cooled. Aqueous solution of sodium hydroxide was added and the reaction mixture was extracted with ether. The ether extract was shaken with SN hydrochloric acid and the aqueous layer was washed with ether, made alkaline and extracted with ether. Hydrogen chloride gas was passed through the ether extract, which was evaporated to dryness. Trituration with acetone gave N-ethyl-1- [1- (3,4-dichlorophenyl) -cyclobutyl] -ethylamine hydrochloride (m.p. 211-212 ° C). (Formula I n = 0; R1 = Me: R = H; R = Et: R = H; R = 4-Cl and R = 3-Cl). Example 22 A mixture of N-ethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine (0.5 g prepared by treating the product of Example 21 with aqueous sodium hydroxide solution) and acetic acid anhydride (1 ml) was heated at 40-45 ° C for 30 minutes. The reaction mixture was made alkaline and extracted with ether.

The ether extract was washed, dried and evaporated to give N-acetyl-N-ethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] -ethylamine as an oil.

This oil was dissolved in tetrahydrofuran (10 ml) and borane dimethyl sulfide complex (0.5 ml) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours and then heated to 35-40 ° C for 1 minute. after cooling, the reaction mixture was made alkaline and extracted with ether.

Hydrogen chloride gas was passed through the dried ether extract, which was evaporated to dryness. Trituration with ether gave N, N-diethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride (m.p. 199 DEG-210 DEG C.). (rermein 1 n = u; R L ne; R = H; RB. n 1 2 Et; Rs = 4-Cl Och R6 = 3-Cl). 4: Example 23 A mixture of 1-acetyl-1- (3,4-dichlorophenyl) -cyclobutane (2.2 g) prepared according to Example 1, ammonium acetate (7 g), sodium cyanoborohydride (0.4 g) and methanol (28 g ml) was stirred at room temperature for 4 days. 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, dried and the ether was removed to leave 1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine as an oil, which was identified by standard analytical procedures such as the compound of Example 1 in the form of its free base. Example 24, A mixture of 1-acetyl-1- (3,4-dichlorophenyl) -cyclobutane (4.86 g) prepared according to Example 1, hydroxylamine hydrochloride (1.6 g), sodium acetate trihydrate (3.3 g) , industrial spirit (15 ml) and water (2 ml) were heated under reflux for 20 hours.

The cooled reaction mixture was poured into water and the oil separating was cooled to give a solid, which was recrystallized from industrial spirits to give 1-acetyl-1- (3,4-dichlorophenyl) cyclobutanoxime (m.p. 120-121 ° C).

A solution of the oxime (4.0 g) prepared in ether (SO 4 ml) was slowly added to a stirred suspension of lithium aluminum hydride (0.9 g) in ether (50 ml) under nitrogen. The mixture was heated under reflux for one hour and after cooling water was added and then a 20% aqueous solution of Rochelle's salt (potassium sodium tartrate tetrahydrate) (27 ml) and a 10% aqueous solution of sodium hydroxide (6 ml). The reaction mixture was stirred for one hour and then extracted continuously with ether for 18 hours. The ether extract was dried and the ether was removed to give a solid from which 1- [1- (3,4-dichlorophenyl) cyclobyethyl] ethylamine was separated by high pressure liquid chromatography. The product was identified by standard analytical procedures as being the compound of Example 15; of its free base.

Example 25 A 1M solution of diisobutylaluminohydryl in hexane (200 ml) was added under nitrogen to a solution of 1-phenyl-1-cyclobutanecarbonitrile (31.4 g) in ether (100 ml) at a temperature below -30 ° C. The temperature was kept below 0 ° C for 30 minutes »two SN hydrochloric acid (200 ml) at a temperature of -10 ° C were added. The reaction mixture was washed with petroleum ether (b.p. 60-80 ° C) and then heated to 40 ° C. The reaction mixture was extracted with petroleum ether (b.p. 60-80) C) and the extract was dried and evaporated to give 1-phenyl-1-cyclobutanecarbaldehyde as an oil.

Methylamine was bubbled through a solution of the aldehyde (9.49) prepared as above in toluene (100 ml) while maintaining the temperature of the reaction mixture below 0 ° C. Magnesium sulfate (20 g), which was dried over a flame and then cooled under nitrogen, was added to the reaction mixture, which was allowed to stand for 16 hours at room temperature before being filtered. The toluene was then removed by evaporation and the residue was dissolved in ether (SO ml).

This solution was added to a solution of propyllithium prepared by slowly adding an excess of propyl bromide (22.89) to a suspension of lithium (1.269) in ether (50 ml).

The resulting mixture was allowed to stand for 16 hours at room temperature.

Traces of unreacted lithium were removed by filtration and the filter was washed with ether, water and then with SN hydrochloric acid. The filtrate and washings were heated on a steam bath for one hour. After cooling, the reaction mixture was washed with ether and the aqueous lard was made alkaline using aqueous sodium hydroxide solution. The reaction mixture was extracted with ether and the extract was dried and the ether was removed to give a residue in which N-methyl-1- (1-phenylcyclobutyl) butylamine was distilled (b.p. 80-86 ° / 0.1 mm Hg).

The amine (2.3 g) prepared as above was dissolved in ether (40 ml) and hydrogen chloride gas was passed through the solution to precipitate N-methyl-1- (1-phenylcyclobutyl) butylamine hydrochloride (m.p. 196-197 ° C). (Formula I n = O: R 1 = propyl; R 2 = H; R 3 = Me; R 4, R 5 and R 9 = n.) Example 26 A solution of 1- (3-chloro-5-methyl) -1-cyclobutanecarbonitrile (8 .0 g) in ether (40 ml) was added to a solution of propylmagnesium bromide / prepared by reacting 1-bromopropane (6.79) and magnesium (1.39) / in ether (80 ml) and the mixture was heated under reflux for 2.5 hours. 2/3 of the ether was evaporated and then, after cooling, a solution of sodium borohydride (3.5 g) in ethanol (iso ml) was added. The suspension was stirred at room temperature for 1 hour and water (50 ml) and then SN hydrochloric acid (50 ml) were added. The ether layer was separated, dried and evaporated to give a solid which was recrystallized from propan-2-ol to give 1- [1- (3-chloro-5-methyl) -cyclobutyl] -yl] 49-butylamine hydrochloride mp 145 -14 ° C).

The hydrochloride salt prepared as above was shaken with ether and SN sodium hydroxide solution and the ether layer was evaporated to give the primary amine which was converted to N, N-dimethyl-1- [1- (3-chloro-5-methyl) cyclobutyl / butylamine hydrochloride 2 = H, R3 and R = Me; R5 = 3-Cl and R6 = 5-Me) in a manner similar to that of Example 2. (Melting point 148 ° C) (Formula I n = 0; RI = propyl; R Example 27 1- (4-chlorophenyl) -1-Cyclobutanecarbonitrile (37.6 g) prepared in a manner similar to that of 1- (3,4-dichlorophenyl) -1-cyclobutanecarbonitrile according to Example 1 was added to a solution of potassium hydroxide (32.4 g) in diethylene glycol (370 ml) and the mixture was heated under reflux for 3.5 hours, the reaction mixture was 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 concentrated hydrochloric acid (100 ml) and ice and the precipitate formed of 1- (4-chlorophenyl) -1-cyclobutanecarboxylic acid (m.p. 86-88 ° C) was collected, washed with water and dried.

A solution of the acid prepared as above: (10.5 g) in tetrahydrofuran (150 ml) was added dropwise under nitrogen to a stirred suspension of lithium aluminum hydride (29) in tetrahydrofuran (150 ml). The mixture was stirred at reflux for 2 hours and water was added. The mixture was filtered through diatomaceous earth (CELITE) and the product was extracted with ether. After washing with water and drying, the ether was evaporated to give a residue, which was recrystallized from petroleum ether (b.p. 60-80 °). The product was 1- [1- (4-chlorophenyl) cyclobutyl] methylacionol (melting point so-s2 °).

A solution of the alcohol (60 g) in pyridine (S2 ml) prepared above was added dropwise to a solution of p-toluenesulfonyl chloride (60 g) in pyridine (100 ml) cooled on ice. The temperature was allowed to rise to room temperature and kept there for 18 hours. 452,611 SO 1- [1- (4-chlorophenyl) cyclobyethyl] methyl p-toluenesulfonate (m.p. 99 DEG-100 DEG C.) was precipitated by pouring the reaction mixture into a mixture of ice and concentrated hydrochloric acid (200 ml). .

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

The acetonitrile (20 g) prepared above was dissolved in ether (120 ml) and the solution was added dropwise under nitrogen to a stirred suspension of lithium aluminum hydride (5.84 g) in ether (80 ml).

The mixture was stirred at room temperature for 1.5 hours and then under reflux for a further 2 hours. Water was added dropwise and the resulting mixture was filtered through diatomaceous earth. The residue was washed with ether. The filtrate was extracted with ether and the combined portions were washed with water and extracted with SN hydrochloric acid. The acidic solution was washed with ether and aqueous NaOH was added. The product was extracted with ether and the extract was washed with water, dried and evaporated to give a residue which on distillation gave 2- [1- (4-chlorophenyl) -cyclobutyl] -ethylamine (b.p. mm Hg).

The ethylamine (6.9 g) prepared above contains 98% formic acid (6.6 ml). water (0.9 g) and 37-40% aqueous solution of formaldehyde (9 ml) were heated on a steam bath for 18 hours. The mixture was cooled and an excess of concentrated hydrochloric acid was added. A yellow solid was obtained on evaporation to dryness. The solid was partitioned between dichloromethane and SN sodium hydroxide solution and the aqueous layer was extracted with an additional portion of dichloromethane. The dichloromethane portions were combined, washed with water, dried and evaporated to a solid residue, which was dissolved in propan-2-ol (15 ml) and concentrated hydrochloric acid was added to pH 2.

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. chloride (m.p. 220-222 ° C) (Formula I n = 1; R1, R2 = H; In a manner similar to that described above, the following compounds were prepared: CH2CH2NMe2.HCl Rs .R5 Example RS R6 M.p. for HCl salt zvlal cl cl zla-22o ° 21 (b) J n 263-2es ° zvlcl -cn = cn - cn = cu- 234-23s ° 27 (d) In a similar manner N, N-dimethyl-2- / l- (4-chloro-2-fluorophenyl) cyclobutyl / ethylamine hydrochloride (m.p. 232-233 ° C (dec.)).

Example 28 2- [1- (4-Chlorophanyl) -cyclobycyl] -ethylanine 111 g) prepared according to Example 27, 1,4-dibromoburane (12.4 g) and anhydrous sodium luncarbonate (14.3 μl were mixed in nylane (loo nl ) and the mixture was heated under reflux and stirring for 16 hours The mixture was cooled, filtered and the xylene was removed by evaporation to give a residue which on distillation gave N-2- [1- (4-chlorophenyl) cyclobutyl]. -ethylpyrrolidine (kdkp. point 148-150 ° / 1.5 nn ng) (formula 1 n = 1; nl, R2 = H; R3 and R4 together with the nitrogen atom form a pyrrolidine ring; Rs = 4-Cl; R6, R7 and R8 = H).

In a manner similar to that described above, the following compounds were prepared and isolated in the form of their hydrochloride salts: 452 611 52 CH 2 CH 2 N .HCl R Example z RS R 6 M.p. for HCl salt 2a (a) c1 c1 z13 ° 28 (b) -cn = cn-ca = cu- 232-233 ° Example 29 A A solution of 2- [1- (4-chlorophenyl) -cyclobutyl / acetonitrile ( 9) prepared according to Example 27, in ether (100 ml) was added to the reaction product of methyl bromide gas and magnesium turnings (5.95 g) in ether (80 ml). The mixture is heated under reflux for 4 hours. Ice and then concentrated hydrochloric acid (105 ml) were added and the mixture was heated under reflux until all solids dissolved. The aqueous layer was washed with ether and the ether used for washing was combined with the ether phase from the reaction mixture. The combined ether extracts were washed with water, dried and evaporated to give a residue, which was distilled twice to give 1- [1- (4-chlorophenyl) -cyclobutyl] -propan-2-one (b.p. 1133-136 ° / 2.5 mm Hg).

The ketone prepared as above (5.4 g) was mixed with N-methylformamide (18 ml), 98% formic acid (4 ml) and 25% aqueous solution of methylamine (0.6 ml) and the mixture was heated under reflux in 16 hours. The mixture was poured into water and extracted with dichloromethane. The extract was washed, dried and evaporated to give a residue which was heated under reflux with concentrated hydrochloric acid (10 ml) for 6 hours. The mixture was evaporated to dryness and the residue was dried by repeated addition and evaporation of industrial spirit / toluene mixture. The solid residue was recrystallized from propan-2-ol to give N-methyl-2- [1- (4-chlorophenyl) -cyclobutyl] -1-methylethylamine hydrochloride (m.p. 193-194 ° C) (rormein 1 n = 1; nl, az = H; R3 = ne; R4 = n; Rs = 4-cl; R6 = H; R7 = ne; Rs = n).

Example 30 A mixture of 1- [1- (4-chlorophenyl) cyclobutyl] -propan-2-one prepared according to Example 29 (15 g) and 98% formic acid (4 ml) was added dropwise to formamide (12 ml) at 160 ° C. The temperature was raised to 180 ° C and maintained at this temperature for 10 hours. The mixture was cooled, diluted with water and extracted with chlorochomethane. The extract was washed, dried and evaporated to give a yellow oil which was hydrolyzed with concentrated hydrochloric acid under reflux. The resulting aqueous solution was washed after diluting with water with ether, aqueous NaOH was added and the aqueous solution was extracted with ether.

The extracts were washed, dried and evaporated to give a residue which, on distillation, gave 2- [1- (4-chlorophenyl) -cyclebucyl] -1-methylecylamine (b.p.

The amine (2.65 g) obtained as above was dissolved in propan-2-ol (15 ml) and concentrated hydrochloric acid was added dropwise until the pH was 2. Ether (110 ml) was added and colorless crystals of 2- [1- (4-chlorophenyl)) were added. -cyclobutyl / -1-methylethylamine hydrochloride (m.p. 184 DEG-85 DEG C.). (Formula I n = 1; P1, R2 = H; R3, R4 = H; RS = 4-Cl; R6 = H; R7 = Me and R8 = H.) Exemggl 3l 2- [1- (4-chlorophenyl) -cyclobutyl / -1-methylethylamine (3.94 g) prepared according to Example 30, 1,4-dibromobutane (3.82 g), anhydrous sodium carbonate (4.4 g) and xylene (30 ml) were mixed and heated under reflux for 16 hours. The mixture was cooled, filtered and evaporated to give a residue which was distilled twice (b.p. 130-1320 / 0.5 mm Hg). The product of the distillation was dissolved in propan-2-ol (5 ml) and ether (70 ml ) and concentrated hydrochloric acid was added to pH 2.

The solution was evaporated in vacuo and the residue was recrystallized from ethyl acetate to give N- {ε- [1- (4-chlorophenyl) cyclobutyl] -1-methylphethylpyrrolidine hydrochloride (m.p. 151-1520). 452 611 54 (Formula I 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 = H; R7 = Me; 118 = H.) Example 32 1- [1- (4-chlorophenyl) cyclobutyl] -propan-2-one prepared according to Example 29 (259) and 98% formic acid (10 ml) were added to formamide (22 ml) at 1600. The temperature was raised to 175 ° C and maintained at this temperature for 16 hours. The mixture was cooled, extracted with dichloromethane. The extract was washed with water and evaporated to give a gummy substance which was crystallized from petroleum ether (b.p. 40-60 ° C) to give N-formyl-2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine ( mp 71-73 ° C).

N-formyl-2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine (11.06 g) prepared as above was heated under reflux for 6 hours with a mixture of concentrated hydrochloric acid (34 ml), water (34 ml ) and diethylene glycol dimethyl ether (40 ml). The mixture was cooled, washed with ether and made alkaline with aqueous sodium hydroxide solution. The alkaline solution was extracted with ether, washed with water, dried, evaporated and distilled to give 2- [1- (4-chlorophenyl) -cyclobutyl] -1-mecylethynamine (kt-xpunyl 119-121 ° C via 0, 8 mm Hg). The amirene (mc: g) was dissolved in propan-2-ol (15 ml) and concentrated hydrochloric acid was added to pH 2. Ether (110 ml) was added and crystals of 2- [1- (4-chlorophenyl) cyclobutyl] -1 methylethylamine hydrochloride (melting point: 1s4-1ss ° c) was collected. (formula 1 n = 1; n ll Rz = H; R3, RÅ = H; Rs = 4-Cl; RS = H; R? = Me OCh Ra = H.) Example 33 2- [1- (4-chlorophenyl ) -cyclobutyl-1-methylethylamine (1.8 g) prepared according to Example 32 was mixed with formic acid (4.5 ml). 37-40% aqueous formaldehyde solution (6 ml) was added and the mixture was heated first at 45-SOOC for 30 minutes and then under reflux for 2 hours. The mixture was cooled, made alkaline with aqueous sodium hydroxide solution, extracted with ether, the ether extract washed with water and extracted with SN-hydrochloric acid. The acid extract was washed with ether, made alkaline with aqueous sodium hydroxide solution and extracted with ether. Hydrogen chloride gas was passed through the ether extract and a white solid formed. The solid was collected and recrystallized from ethyl acetate to give N, N-dimethyl-2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine hydrochloride (m.p. 108 DEG-110 DEG C.) (Formula I n = 1; RR = 1 '2 H: R3, R = Me: R = 4-Cl; R6 = H; R7 = Me; R = H). Example 34 A 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in toluene (sold under the trademark "Red-al") (35 ml) was added dropwise to a solution of N-formyl] -2- / 1- (4-Chlorophenyl) -cyclobutyl / -1-methylethylamine prepared according to Example 32 (5 g) in dry ether (110 ml) under cooling to maintain the temperature below 100 ° C. The temperature was allowed to rise to about ZSOC and then the mixture was heated under reflux for 2 hours. The reaction mixture was poured into a mixture of crushed ice and concentrated hydrochloric acid. The resulting mixture was washed with ether, made alkaline with an aqueous solution of sodium hydroxide and extracted with ether. The ether extract was washed with brine, dried and evaporated to give a liquid which was dissolved in petroleum ether (b.p. 40-60 ° C). Hydrogen chloride gas was bubbled through the solid precipitation solution, which was recrystallized from propan-2-ol to give N-methyl--2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine hydrochloride (formula I n = 1; al, R = 1n; 'R = u; R = Me; Rs = 4-c1; 2 3 4 ns = n, 1: 7 = ne and 1: 8 = m. melting point 192-194 ° c.

Example 35 A solution in ether (80 ml) of 2- [1- (3,4-dichlorophenyl) cyclobutyl] -acetonitrile (23 g) prepared in a manner similar to that of Example 27 for 2- / 1- ( 4-Chlorophenyl) cyclobutyl / acetonitrile was added to the product of the reaction between magnesium turnings (3, 3 g) and ethyl bromide (10, 8 ml) in dry ether (80 ml) with stirring and heating on a steam bath. The ether was removed and replaced with toluene and the mixture was heated under reflux for one hour. Water was added and the mixture was added to a mixture- -h-è f; 4 2 61'1 S6 ice and concentrated hydrochloric acid. The mixture was heated on a steam bath for one hour and filtered through a diatomaceous earth product sold under the trademark 'CELITE'.

The filtrate was extracted with dichloromethane and the extract was washed with water and sodium bicarbonate solution and dried.

The solvent was removed by evaporation and the residue was distilled to give 1- [1- (3,4-dichlorophenyl) -cyclobutyl] -bucan-2-one (coke punk 149-150 ° / 1.1 mm ng).

The ketone prepared above was converted to 1- [1- (3,4-dichlorophenyl) cyclobutyl] -methyl-propylamine hydrochloride (m.p. 225 DEG-226 DEG)) (the formula 1 n = 1; nl, az, R3, R4 = n ; RS = 4-Cl; R = 3-Cl; R7 = Et; R8 = H) in a manner similar to that described in Example 32.

In a manner similar to that described above, 2- [1- (3,4-dichlorophenyl) cyclobutyl] -1-methylethylamine hydrochloride (m.p. 1790) was prepared (Example 35a Formula I n = 1; R1, R2, R3 and R4 = H; RS = 4-Cl; R6 = 3-Cl; R7 = Me and R8 = H).

Example 36 In a manner similar to that of Example 35, compounds prepared in a manner similar to that of Example 33 were converted to the corresponding N, N-dimethyl compounds I / \ CH2CH7NMe2.Hc1 Starting R R M.p.

Example material 5 6 ~ R7 3e (a) 35 c1 cl nu 111-11a ° 36th) ssta) c1 cl -ne 204-2os °. : x-m. '=. Example 37 In a manner similar to that described in Example 34, N-formyl compounds prepared according to Example 32 were converted from ketones prepared as in Example 35 to the corresponding N-methyl compounds. cH2cHR7NHMe.Hc1 Re Example Rs R6 R7 M.p. 31 (a) c1 n at 110-11z ° 37 (b) cl cl st 193-194 ° Example 38 A mixture of 2- [1- (4-chlorophenyl) cyclobutyl] -acetonitrile (10, 1g) prepared according to Example 27 , potassium hydroxide (8.1 g) and diethylene glycol (92 ml) were heated under reflux for 3.5 hours. The mixture was poured into a mixture of ice and water and 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 (b.p. 62-680) using charcoal.

The recrystallized product was 2- [1- (4-chlorophenyl) -cyclobutyl] acetic acid (m.p. 83-84 ° C).

The acid (5 g), prepared as above, was added to thionyl chloride (20 ml) and heated under reflux for one hour. excess thionyl chloride was then removed and the residue was poured into a solution of piperidine (3.89 g) in ether (20 ml).

The mixture was stirred for 30 minutes 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 4552 6 '1 S8 aostiliation (xok point 1es ° / 1 mm ng) and crystallization of petroleum ether (boiling point 40-60 ° C). The solid product was N-2- [1- (4-chlorophenyl) -cyclobutyl] -acetylpiperidine (m.p. 66-67 ° C).

A solution of the above compound (2.7 g) in ether (20 ml) was added dropwise to a stirred mixture of lithium aluminum hydride (0.7 g) and ether under a nitrogen atmosphere.

Stirring was continued for one hour at room temperature and then under heating at reflux for 2 hours. After cooling in ice, excess lithium aluminum hydride was decomposed by adding water. The mixture was filtered through diatomaceous earth ("CELITE"). The aqueous portion of the filtrate was washed with a portion of ether and this was combined with ether portions used to wash the solid residue. The combined ether portions were washed with water, dried and evaporated. The residue was purified by distillation. The product was N-2- [1- (4-chlorophenyl] cyclobutyl] ethylpiperidine (b.p. 152-1ss ° / 1.5 mm H9) (formula 1 m = 1; nl, R2 = H; RB and R4 together with the nitrogen atom form a piperidine ring; RS = 4-Cl: R6, R7 and R8 = H.) In a manner similar to that described above, the following compounds were prepared and isolated in the form of their hydrochloride salts by bubbling dry hydrogen chloride gas through a solution of the base in petroleum ether ( boiling point 62-68 ° C).

CH2CH2NR3Rb.HCl R i / \ Rs ° c Example R5 R6 NR5R4 mp '() Me W e 452 611 59 3a (b) c1' H -Û-Me 2a1-2a3 ° (decomposition) 58 (e) b c1 a - Example 39 A mixture of sodium hydride (9 g), mineral oil (9 g) and dry dimethylformamide (150 ml) was stirred under nitrogen at 0 ° C.

A solution of p-toluenesulfonylmethyl isocyanide sold under the tradename "TosMIC" (24.6 g) in dimethylformamide (50 ml) was added over 20 minutes. Absolute alcohol (18 g) was then added to the mixture at 0 ° C for a period of one hour. 1-Acetyl-1- (4-chlorophenyl) -cyclobutane (24 g), prepared in a manner similar to that of Example 1 for 1-acetyl-1- (3,4-dichlorophenyl) -cyclobutane, dissolved in Dry dimethylformamide (20 ml) was added and the mixture was stirred for 16 hours during which time the temperature rose to room temperature. The mixture became viscous and petroleum ether (b.p. 80-100 ° C) (25 ml) was added. The mixture was poured into water and the pH was adjusted to 6 by the addition of SN hydrochloric acid. The resulting mixture was extracted with ether and the ether extract was washed with water, dried and partially evaporated. A brown solid separated and was filtered off and the filtrate was evaporated and 2- [1- (4-chlorophenyl) cyclobutyl] -propionitrile (b.p. 128-136 ° / 0.6 mm) was recovered by distillation.

A solution of the propionitrile (3.59) described above in dry ether (20 ml) was added dropwise to a stirred mixture of lithium aluminum hydride (0.9 g) in dry ether (20 ml) at a temperature in the range 1-5 ° C. The mixture was stirred at room temperature for 2 hours and then heated under reflux for a further 3 hours. SN sodium hydroxide solution (20 ml) and water (50 ml) were added and the mixture was filtered through diatomaceous earth ("CELITE"). The filter medium was washed with ether and the washings were combined with the ether from the reaction mixture.

The combined extracts were extracted with SN hydrochloric acid. A solid formed at the separation surface, which was collected by filtration, washed with acetone and dried. The solid was 2- [1- (4-chlorophenyl) -cyclobutyl] -propylamine hydrochloride (m.p. 210-230 ° C).

The hydrochloride salt (1.0 g) as above was dissolved in water, SN aqueous solution of sodium hydroxide was added and the solution was extracted with ether. The ether extract was dried and evaporated to give an oil which was heated under reflux for 6 hours with 1,4-dibromobutane (0.82 g), anhydrous sodium carbonate (0.96 g) and xylene (6.5 ml). The mixture was cooled, filtered through diatomaceous earth ("CELITE") and evaporated to dryness, the residue was dissolved in propan-2-ol (10 ml) and concentrated hydrochloric acid (5 ml) was added, the mixture was evaporated to dryness and the residue was washed. with ether and dried The product was N-2- [1- (4-chlorophenyl) -cyclobutyl] -propylpyrrolidine hydrochloride (m.p. 238-248 ° C) (Formula I n = 1; R = Me; R2 = H; R3 and R 4 together with the nitrogen atom to which they are attached form a pyrrolidine ring; RS = 4-Cl; Re, R., and Ra = a.) Example gel 40 A solution of 1- (3,4-dichlorophenyl) -1-cyclobutanecarbonitrile (70 g) prepared in a manner similar to that of Example 1 in industrial spirit (200 ml) was mixed with a solution of sodium hydroxide (3.7 g) in water (5 ml) and 30% hydrogen peroxide solution was added dropwise. 5000 for one hour and then stirred with 10% palladium on carbon (0.5 g) for one hour. The mixture was filtered and evaporated to dryness to give 1- (3,4-dichlorophenyl) -1-cyclobutanecarboxamide.

The carboxamide prepared above was dissolved in dioxane (500 ml) and concentrated hydrochloric acid (100 ml) and then a solution of sodium nitrite (35 g) in water (80 ml) was added dropwise.

The mixture was heated at 85-95 ° C for 16 hours and then poured into water. The mixture was extracted with ether and the extract was re-extracted with an aqueous solution of potassium carbonate. The basic extract was washed with ether and acidified with concentrated hydrochloric acid to give 1- (3,4-dichlorophenyl) -1-cyclobutanecarboxylic acid (m.p. 120-121 ° C).

The acid described above was converted to the compound of Example 27 (a) in a manner similar to that described in Example 27 and to the compound described in Example 28 (a) in a manner similar to that described in Example 28.

Example 41 A solution of 2- [1- (3,4-dichlorophenyl) cyclobutyl] acetonitrile (23 g) prepared in a manner similar to that of 2- [1- (4-chlorophenyl) cyclobutyl / acetonitrile described in Example 27, in dry ether (50 ml) was added to a solution of ethyl magnesium bromide prepared by dropwise addition of ethyl bromide (1.53 g) in dry ether (80 ml) to a stirred mixture of magnesium turnings (3.53 g) and ether (80 ml). ml). The mixture was heated under reflux for 30 minutes and stirred without further heating for 16 hours and then under reflux for another 2 hours. 1- [1- (3,4-Dichlorophenyl) -cyclobutyl] -2-butaniminylmagnesium bromide was collected by filtration and a sample of the solid (about 1 g) was added to a solution of sodium borohydride (3 g) in diethylene glycol dimethyl ether ( 30 ml). The mixture was stirred at 45 ° C for 90 minutes. The reaction mixture was extracted with SN 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 introduced into the extract to precipitate 1- [1- (3,4-dichlorophenyl) -cyclobutyl / methyl-propylamine hydrochloride (m.p. 223-224 ° C).

(Formula I n = 1; R 1, R 2, R 3 and R 4 = H; R 5 = 4-Cl; R 6 = 3-Cl: R 7 = Et: R 8 = B).

Example 42 Formic acid (7 ml) was added dropwise to pyrrolidine (15 ml) at a temperature in the range 135-340 ° C. 1- [1- (3,4-Dichlorophenyl) -cyclobutyl / butan-2-one (3 g) prepared according to Example 35 was added dropwise and the mixture was heated at 140 ° C for one hour. The temperature was raised to 185-190 ° C for 16 hours. 452N611 62 The reaction mixture was cooled and poured into SN hydrochloric acid.

The solution was washed with ether, made alkaline and extracted with ether. The ether extract was dried and hydrogen chloride gas was introduced into the extract. Evaporation to dryness gave a solid which was triturated with dry ether and recrystallized from a mixture of petroleum ether and propan-2-ol to give N 151-100 ° C) (formula 1 m = 1; nl, az = n; R3 and R4 together with the nitrogen atom form a pyrrolidine ring; R5 = 4-Cl; R = 3-Cl; R7 = Et and R = H Example 43 - 1- [1- (3,4-Dichlorophenyl) -cyclobutyl] -2-butaniminylmagnesium bromide (25 g) prepared according to Example 41, heated at 90-95 ° C for two hours with a mixture of concentrated hydrochloric acid (20 ml) and water (30 ml). The reaction mixture was extracted with ether and the ether extract was dried and evaporated to dryness. 1- [1- (3,4-Dichlorophenyl) cyclobutyl / butan-2-one (boiling point: 122-1z4 ° at 0.1 mm ng) is distilled.

A mixture of 1- [1- (3,4-dichlorophenyl) cyclobutyl] -butan-2-one (4.3 g) prepared as above, hydroxylamine sulphate (2.65 g), sodium acetate (4.0 g), industrial spirits (56 ml) and water (23 ml) were dissolved at room temperature for 10 hours. The reaction mixture was extracted with ether. The ether extract was washed with water, dried and evaporated to give a solid which was recrystallized from petroleum ether (b.p. 80 DEG-10 DEG C.) to give 1- [1- (3,4-dichlorophenyl) cyclobutyl] -butan-2-one oxime (melt pump los-110 ° C).

A solution of trifluoroacetic acid (2.33 ml) in tetrahydrofuran (5 ml) was added to a stirred suspension of sodium borohydride (1.3 g) in tetrahydrofuran (30 ml) over a period of 5 minutes. A solution of the oxime (1.7 g), prepared as above, in tetrahydrofuran (25 ml) was added dropwise and the mixture was heated under reflux for 6 hours. The mixture was cooled and water (25 ml) and then SN sodium hydroxide solution (25 ml) were added. The mixture was extracted with ether and 63 .mu.l; .ß- .n; ,, - -A ___._ The ether extract was washed with water, dried and evaporated to give a residue, which was dissolved in petroleum ether \; _ * .., -, -.; - :, «.« (25 ml). Dry hydrogen chloride gas was passed through the ether solution to give 1 - [[1- (3,4-dichlorophenyl) cyclobutyl] methylpropylamine amylaxyl chloride (m.p. 222-224 ° C). (Formula 1 n = 1 R 1, R 2, R 4 and R 4 = H; R 5 = 4-Cl; R = 3-Cl; R 6 = Et and R 8 = 36 H).

Example 44 A solution of 1- [1- (3,4-dichlorophenyl) cyclobutyl] -butan-2-one (5.0 g), prepared according to Example 43, and methoxyamine hydrochloride (1.63 g) in a mixture of pyridine (60 ml) and ethanol (60 ml) were heated under reflux for 72 hours. The reaction mixture was 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-chloro-phenyl) -cyclobuyl] -ruan-2-anoxime-0-methyl ether.

The oximeter (15 g) prepared above was then reduced to the product of Example 43 using sodium borohydride (0.95 g) in a manner similar to that of Example 43.

Example 45 Sodium cyanoborohydride (0.49) was added to a solution of 1- [1- (3,4-dichlorophenyl) cyclobutyl / butan-2-one (2.4S g) prepared according to Example 42, and ammonium acetate (7 g ) in methanol (28 ml) and the mixture was stirred at room temperature for 4 days. Water (25 ml) was added dropwise under cooling. The aqueous mixture was extracted with ether and the ether layer was washed with water and SN hydrochloric acid (50 ml). The compound of Example 43 was precipitated as a white solid.

Example 46 2- [1- (4-Chlorophenyl) cyclobutyl / acetic acid (1.59 prepared according to Example 38) was heated under reflux with thionyl chloride. Excess thionyl chloride was removed in vacuo and the residue 40 DEG-64 DEG C. was added dropwise to a solution of cyclopropylamine (0.94 g) in ether (10 ml) and the mixture was stirred for 30 minutes. 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 the amide (1.45 g) prepared in ether (15 ml) prepared above was added dropwise to a stirred suspension of lithium aluminum hydride (0.42 g) in ether (7.5 ml) under nitrogen.

The mixture was stirred at room temperature for one hour and then heated under reflux for a further 2 hours. After cooling, water (0.4S ml) was added, then 15% sodium hydroxide solution (0.45 ml) and then water (1.3S ml) and the mixture was stirred for 15 minutes. The mixture was filtered and extracted with ether. The ether extract was shaken with N hydrochloric acid and a solid formed in the aqueous layer.

The solid was N-cyclopropyl-2- [1- (4-chlorophenyl) -cyclobutyl] -amino] -maryochlorine melting point 166 DEG-110 DEG C.).

A mixture of the hydrochloride salt prepared above (0.4 g), sodium formate (0.19). 98% formic acid (1 ml) and a 37-40% aqueous solution of formaldehyde (0.5 ml) were heated at 85-90 ° C for 18 hours. The reaction mixture was cooled and extracted with ether. The ether extract was washed with water, dried and filtered. Hydrogen chloride gas was passed through the filtrate, which was then heated to give a solid consisting of N-cyclopropyl-N-methyl-2- [1- (4-chlorophenyl) cyclobutyl] ethylamine hydrochloride (m.p. 149-13 ° C). (formula I n = 1; R and az = H; R = cyclopropyl; R4 = Me; Rs = 4-Cl; R6, R7 and Ra = H.) Example 47 Pharmaceutical compositions containing any of the compounds of formula I, which are given in Examples 1-46, were prepared as follows: ** y 452 611 65 Example 47 (a) Tablets were prepared from the following components:, parts by weight Active component _ 50.0 Lactose 78.5 Polyvinylpyrrolidone 5.0 Maize starch 15.0 Magnesium stearate 1.5 The active component, the lactose and part of the starch were mixed and granulated with a solution of the polyvinylpyrrolidone in ethanol. The granulate was mixed with the stearic acid and the rest of the starch and the mixture was compressed in a tablet machine to obtain tablets containing 50.0 mg of the active ingredient.

Example 47 (b) Capsules were prepared as follows. A mixture of the active ingredient (45 parts by weight) and lactose powder (205 parts by weight) was filled into hard gelatin capsules, each capsule containing 45 mg of the active ingredient.

Example 47 (c) In the preparation of enteric coated tablets, the tablets described in Example 47 (a) were provided with a thin coating of shellac varnish, followed by coatings of cellulose acetate phthalate in a known manner. In a similar manner, the jaws of Example 47 (b) could be provided with an enteric coating.

Example 47 (d) Glass vessels containing a solution of water-soluble compounds according to the invention suitable for injection are prepared from the following components: Active component 1100 g Mannitol '1100 9 Water, freshly distilled to 11 liters The active component and mannitol are dissolved in a part of the water "YJL Wool ä? : much '66 and the volume of the solution is set to 11 liters. The resulting solution is sterilized by filtration and filled into sterile glass vessels, each containing 1.65 ml of solution.

Example 47 (e) In the preparation of suppositories, 100 parts by weight of the atomized active component were incorporated with 1214 parts by weight of triglyceride suppository base and the mixture was formed into a few suppositories each containing 100 mg of the active component.

In the preceding examples, new ketones of formula V have been indicated, wherein R 1, R 5 and R 6 have the meaning given in Examples 1, 1 (a) to 1 (e), 3, 4, 4 (a) to 4 (e), 6, 7, 7 (a) to 7 (d), 9, 9 (a) to 9 (n), 10, 10 (a) to 10 (z), 10 (aa), 10 (bb), 11 ( i), ll (k) and ll (l). These novel ketones of formula V are prepared by hydrolysis of novel imines of formula XVI, wherein Y = MgBr and R1, RS and R6 have the meaning given in the examples given above.

In the preceding examples, new ketones of formula VI have been given, wherein R 1, R 2, R 5, R 6 and R 7 have the meaning given in Examples 29, 35, 36 and 43. These new ketones of formula VI were prepared by hydrolysis of new imines of formalin III, wherein Y = MgBr and R 1, R 2, R 5, R 6 and R 7 have the meaning given in Examples 29, 35, 36 and 43.

In the preceding examples, new cyano compounds of formula XVII have been indicated, wherein R 5 and R 6 have it in Examples 1, 1 (d), 1 (e), 4 (9). 9 (e), 9 (m), 10 (k), 10 (e), 10 (P), 10 (r), 10 (V), 10 (Y), 10 (z), 10 (aa), l0 (bb), ll (k), ll (l) and 26 given meaning.

The foregoing examples set forth novel formamides of formula XXVIII wherein R 1, R 3, R 5, R 6, R 7, R 8 and n have it in Examples 1, 1 (a) (e), 6, 7, 7 (a) to 7 (d), 9, 9 (a) 1 to 9 (n), 10, 10 (a) to 10 (z), 10 (aa), 10 ( bb), ll (i), ll (k), I ll (l). 29, 32, 35 and 36.

Claims (14)

'fUL Uli 67 PATENTKRAV Compounds having the general formula I 5 in ca1R _, _ (cP.7R8) nNR3n _, * I Rs wherein n = 0 or 1; wherein, when n = 0, R 1 is a straight or branched chain alkyl group containing 1-6 carbon atoms, a cycloalkyl group containing 3-7 carbon atoms, a cycloalkylalkyl group wherein the cycloalkyl group contains 3-6 carbon atoms and the alkyl group contains 1-3 carbon atoms , an alkenyl group or an alkynyl group containing 2-6 carbon atoms or a group having the formula II R 10 n wherein R 9 and R 10, which may be the same or different, are hydrogen, halo or an alkoxy group containing 1-3 carbon atoms; Å wherein, when n = 1, R 1 is hydrogen or an alkyl group containing 1-3 carbon atoms; wherein R 2 is hydrogen or an alkyl group containing 1-3 carbon atoms; wherein R 3 and R 3, which may be the same or different, are hydrogen, a straight or branched chain alkyl group containing 1-4 carbon atoms, an alkenyl group containing 3-6 carbon atoms, an alkynyl group containing 3-6 carbon atoms, a cycloalkyl group wherein the ring contains 3-7 carbonates, a group of the radical Rum, wherein Ru is hydrogen or R 4 and R 4 together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidino, piperazinyl or tetrahydropyridyl ring, which is optionally substituted with one or more methyl groups; wherein R 5 and R 6, which may be the same or different, are hydrogen, halo, trifluoromethyl, an alkyl group containing 1-3 carbon atoms, an alkoxy or alkylthio group containing 1-3 carbon atoms, phenyl or R 5 and R 6 together with the carbon atom to which they are bonded form a second benzene ring which is optionally substituted with one or more halo groups, an alkyl or alkoxy group containing 1-4 carbon atoms or wherein the substituents in the second benzene ring together with the two carbon atoms to which they are attached form an additional benzene ring; and wherein R 7 and R a, which may be the same or different, represent hydrogen or alkyl containing 1-3 carbon atoms; and their pharmaceutically acceptable salts. Compounds of formula I according to claim 1, characterized in that n = 0, R 1 is a straight or branched chain alkyl group containing 1-4 carbon atoms, a cycloalkyl group containing 3-7 carbon atoms or a group having the formula II, wherein R 9 and R 10 are hydrogen, fluoro or methoxy and wherein R 2 is hydrogen or methyl. Compounds of formula I according to claim 2, characterized in that R 1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, cyclopropyl, cyclopentyl. cyclohexyl, cycloheptyl or phenyl. Compounds of formula I according to claim 1, characterized in that n = 1, R 1 is hydrogen or methyl and R 2 is hydrogen. Compounds of formula I according to any one of the preceding claims, characterized in that R 3 and R 4 are hydrogen, methyl, ethyl or formyl. 452 611 69 Compounds of formula I, characterized in that R 5 and R 6 are hydrogen, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy, phenyl or R 5 and R 6 together with the carbon atoms to which they are attached form a other benzene ring optionally substituted with halo. Compounds of formula I according to any one of claims 1, 4, S or 6, characterized in that R 7 is hydrogen, methyl or ethyl and R 8 is hydrogen. Compounds according to claim 1 of the formula III CR1 §2 (CP "7R8 excipient * R \ / 111 Re wherein R1, R2, R3, R4, RS, R6, R7, R8 and n have the meaning given in claim l. . Compounds according to claim 8, characterized in that R 5 and R 6 which are the same or different are hydrogen, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy, phenyl or wherein R 5 and R 6 together with the carbon atoms were to which they are attached form a second benzene ring which is optionally substituted by a chloro group. Compounds according to claim 1 of the formula IV wherein R 1, R 2, R 3, R 4, R 5, R 7, R 7 and R 6 have the meaning given in claim 1 and R 6 is fluoro or methyl . 11. ll. Compounds of formula IV according to claim 10, characterized in that R 5 is hydrogen or chloro and R 6 is fluoro or methyl. Compounds of formula I in the form of: 1- [1- (4-chlorophenyl) cyclobutyl] butylamine and its pharmaceutically acceptable salts: n, -alkylethyl] 1- [1- <4-chlorophenyl] cyclobutyl] butylamine and its pharmaceutically acceptable salts; N-methyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] butylamine and its pharmaceutically acceptable salts; N, N-dimethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] butylamine and its pharmaceutically acceptable salts; N-methyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine and its pharmaceutically acceptable salts; N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine and its pharmaceutically acceptable salts; N, N-dimethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] -3-methylbutylamine and its pharmaceutically acceptable salts; 1- [1- (3,4-dichlorophenyl) cyclobutyl / ethylamine and its pharmaceutically acceptable salts; N, N-dimethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine and its pharmaceutically acceptable salts: - [1- (4-chlorophenyl) cyclobutyl] benzylamine and its pharmaceutically acceptable salts. A pharmaceutical composition for the treatment of depression containing a therapeutically effective amount of a compound of: formula I in claim 1 according to any one of the preceding claims. 14. A process for the preparation of compounds of formula I, characterized in that it comprises reductive amidation of ketones having the formula V i: m Kyl __- ': year 452 611 71 Rs * m1 to form compounds wherein n = 0; R 2 = H, R 4 = CHO and R 1, R 5 and R 6 are as defined above, or of ketones or aldehydes of the formula VI H 5 CR 1 R 2 COR 7 VI R 5 __ to form compounds wherein n = 1; R 4 = CHO, R 8 = H and R 1, R 2, R 5, R 6 and R 7 have the meaning given above; that it comprises reductive: reduction of ketones having the formula V H5 coal __ - v “s to form compounds wherein n = 0: R2 = H and R, R or of ketones or aldehydes of the formula VI CR R2COR7 Rs | 1 vi ßš-f R 5 452 611 72 to form compounds wherein n = 1: R 8 = H and R 1, R 2, 5, R 6 and R 7 have the meaning given above; that it comprises reducing compounds having the formula VII wherein R) wherein a) Z is a group of the formula -CR = NOH or an ester or an ether thereof to form compounds of formula I, wherein n = 0 and R2 , R 3 and R 4 are hydrogen; b) -Z is a group of the formula -CR 1 = NR 3 to form compounds of formula I, wherein n = 0 and R 2 and R 4 are hydrogen; c) Z is a group having the formula -CR 1 = NY, wherein Y represents a metal-containing group derived from an organometallic reagent to form compounds of formula I, wherein n = 0 and R 2, R 3 and R 4 are hydrogen: d) Z is a group having the formula -CRIFZCN to form compounds of formula I, wherein n = 1 and R 3, R 4, R 7 and R 8 are hydrogen: e) Z is a group having the formula -CR 1 R 2 CR 7 = NOH or an ester or ether thereof to form compounds of formula I, wherein n = 1 and R 3, R 4 and R 8 are hydrogen: f) Z is a group of the formula -CR R CR = NR 3 to form compounds of formula I, wherein n = 1 and R 4 and R 8 are hydrogen: g) Z is a group of the formula -CR 1 R 2 CR 7 = NY, wherein Y represents a metal-containing group derived from an organometallic reagent to form compounds of formula I, wherein n = 1 and R 3 , R 1 and R 2 are hydrogen: h) Z is a group of the formula -CR 1 R 2 CONR 3 R 4 to form compounds of formula I, wherein n = 1 and R and RB is hydrogen: wherein Y may be Mgßr or Li; That it comprises (a) reacting an organometallic reagent with an imine having the formula VIII Rs cn = ua3 \ VIII and (b) hydrolyzing the obtained product to give compounds of formula I, wherein n = 0; wherein the organometallic reagent may be a Grignard reagent of the formula R1MgBr or an organolithium compound of the formula R Li; In that it comprises (a) reacting an organometallic reagent with an imine having the formula IX, the hydrolysis of the obtained product to give compounds of formula I, wherein n =: wherein the organometallic reagent may be a Grignard reagent having the formula R7MgBr or an organolithium compound of the formula R7Li; that it comprises decarboxylating regrouping of (a) amides having the formula X R; calnzcoxmz \ .__ X Rs _ aèë 452 i611 74 to form amines, wherein n = 0: (b) amides of the formula XI ßßwm fl ç '5 .__ ¶R1R2 ° R7R8 °° NH2 to form amines, wherein n = 1: (C) acylazides formed by reacting sodium azide with acid chlorides having the formula XII - "xxx to form amines wherein n = 0; (d) acyl azides formed by reacting sodium azide with acid chlorides having the formula XIII R5. CR1R ¿CR7R8coc1 \ XIII Rs to form amines wherein n = 1: or in that it comprises reaction of a hydrazo acid with (al carboxylic acids having the formula XIV www r '~ r # 1; 4! 52 61'1 ~ v, v. 75 Q ü g so Rs CRIRZCOOH gi XIV Rs to form amines wherein n = 0: _or (b) carboxylic acids of the formula XV R5 coon \\ ° R1R2 ° R7Re6 .. XV Re to form amines, wherein n = 1; or "to prepare compounds of formula I, wherein R4 is hydrogen, hydrolysis of compounds of formula I, wherein R is CHO; or 4 for the preparation of compounds of formula I, wherein R 4 is methyl, performing reduction of compounds of formula I, wherein R is CHO; or 4 that for the preparation of compounds of formula I, wherein one or both of R 3 and R 4 is other than hydrogen, a compound of formula I, wherein one or both of R 3 and R 3 is hydrogen, is converted to the desired compound.