NZ200178A

NZ200178A - Phenyl cyclobutyl alkylamines

Info

Publication number: NZ200178A
Application number: NZ200178A
Authority: NZ
Inventors: J E Jeffery; A Kozlik; E C Wilmshurst
Original assignee: Boots Co Plc Formerly The Boot
Priority date: 1981-04-06
Filing date: 1982-03-30
Publication date: 1985-07-31
Also published as: YU6385A; CA1248955A; FI77223B; LU84070A1; DK146482A; SU1482522A3; PT74580B; HK13888A; BG40652A3; ES511152A0; IE52768B1; RO89436A2; RO84802A; CS244672B2; GR76697B; FI821197A0; IE820481L; YU44336B; PL139120B1; PT74580A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £00178 % ■ / 2001 78 Priority Oate{£); /. Complete Specification .6-4- k~&i • • • • Class: MHioati .^7 Piled: -?P.73-e-3 DRAUTINBS new zealand patents act, 1953 No.: Date: GIWM. 8r &&Z e? tfEUttBT Ttre boors corv^^ complete specification THERAPEUTIC AGENTS xi/We, THE BOOTS COMPANY LIMITED, a British company of 1 Thane Road West, Nottingham, England, hereby declare the invention for which S / we pray that a patent may be granted to ®&/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - - 1 - (followed by page la 2001 7 Agent'a Ref. P/101' - 1&- The Boots Company Limited Therapeutic Agents This invention relates to compounds having useful therapeutic activity particularly hut not exclusively as antidepressants, to pharmaceutical compositions containing such compounds and to processes for the preparation of such compounds. The present invention provides compounds of formula I in which n = 0 or 1; in which, when n = 0, is a straight or branched chain alkyl group containing 1 to 6 carbon atoms, a cyclo-alkyl group containing 3 to 7 carbon atoms, a cycloalkylalkyl group in which the cycloalKyl group contains 3 to 6 carbon atoms and the alkyl group contains 1 to 3 carbon atoms, an. alkenyl group or an alkynyl group containing 2 to 6 carbon atoms or a group of formula II I II in which Rg and R^q, which are the same or different, are H, halo or an alkoxy group containing 1 to 3 carbon atcms; in which, when n = 1, R^ is H or an alkyl group containing 1 to 3 carbon atoms; in which R£ is H or an alkyl group containing 1 to 3 carbon atcms; in which R^ and R^ which are the same or different, are H, a straight or branched chain alkyl group containing 1 to 4 carbon atoms, an alkenyl group having 3 to 6 carbon a tans, an alkynyl group having 3 to 6 carbon atcins, a cycloalkyl group in which the ring contains 3 to 7 carbon atoms, -CHQ or R^ and together with the nitrogen atcm to which they are attached form (a) a heterocyclic ring containing one nitrogen atcm and 4 or 5 carbon atcms which is optionally substituted by one or more methyl groups (b) a heterocyclic ring containing a second nitrogen atcm vhich is optionally methylated and 3 or 4 carbon atcms or (c) a heterocyclic ring containing one nitrogen atcm and 3 or 4 carbon atoms and one or more double bonds: in which R,_ and R^, which are the same or different, are H, halo, trifluorcmethyl, an alkyl group containing 1 to 3 carbon atoms, an alkoxy or alkylthio group containing 1 to 3 carbon atcms, phenyl or R,- and R^, together with the carbon atcms to which they are attached, form a second benzene ring which may be substituted by one or more halo groups, an alkyl or alkoxy group containing 1 to 4 carbon atcms or the substituents of the second benzene ring together with the twD carbon atcms to which they are attached may form a further benzene ring; and in which R^ and Rg which may be the same or different are H or an alkyl group containing 1 to 3 carbon atcms; and their pharma-ceutically acceptable salts. In the formulae included in this specification the syntool represents a 1,1-disubstituted cyclcbutane group of formula "CH, CH2—CH2 - 3 - 2 C 0178 and -C^R^CCRyRgOnNR^R^ represents 'a group of formula h M /R3 — C J C 4— R2 \R8/n R4 In the preferred compounds of formula I in which n=0, R^ is a straight or branched chain alkyl group containing 1 to 4 carbon atoms, a cycloalkyl group containing 3 to 7 carbon atoms, a cycloalkylmethyl group i'n which the cycloalkyl' ring contains 3 to 6 carbon atoms or a group of formula II in which R^ and/or R^q are H, fluoro or methoxy and in which R£ is H or methyl. Examples of particularly preferred compounds of formula I are those in which when n = 0 and R2 is H, R-^ is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, eycloheptyl, cyclopropylmethyl, cvclobutyImethyl, cyclopentylmethyl, cyclohexyl-methyl and phenyl. In the preferred compounds of formula I In which n = 1, R-^ is H or methyl, and R^ is H. In particularly preferred compounds of formula I in which n = 1 both R-^ and R2 are H. In preferred compounds of formula I, R^ and/or R^ are hydrogen, methyl, ethyl or formyl. In particularly preferred compounds of formula I and/or are H, methyl, ethyl and formyl. In preferred compounds of formula I R^ and/or Rg are H, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy, phenyl or R^ and Rg together with the carbon atom to which they are attached form a second benzene ring which may optionally be substituted by one or more halo groups. \r .984, j & ■ A first group of preferred compounds Q.f formula I is represented by formula III * CR1R2(CR7R8)nliR3R4 R< III in >Ailch and Rg are as defined above. In preferred pounds of formula III R^ and Rg which may be the same or different, are H, fluoro, chloro, bromo, iodo, trifluoro-methyl, methyl, methoxy, phenyl or in which and Rg together with the carbon atoms to which they are attached form a second benzene ring which may optionally be substituted by a chloro group. In particularly preferred compounds of formula III R5 and/or Rg are H, fluoro, chloro, iodo, trifluoromethyl, methyl, phenyl or R^ and Rg together with the carbon atoms to which they are attached form a second benzene ring which may optionally be substituted by a chloro grouD. — A second group of preferred compounds of formula I is represented by formula IV in which R^ may be H, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy or phenyl and in which R^ is fluoro or methyl. In particular preferred compounds of formula IV R^ is H or chloro. In preferred compounds of formula I in which n = 1, Ry is H, methyl or ethyl and Rg is H and in particularly preferred compounds of formula I Ry is H or ethyl and Rg is H. Compounds of formula I may exist as salts with pharmaceut1c ally acceptable acids. Examples of such salts include hydrochlorides, maleates, acetates, citrates, fumarates, tartrates, succinates and salts with acidic amino acids such as aspartic and glutamic acids. R CR1R2(CFl7Ra)nNR3R4 IV Compounds of formula I which contain one or more asymmetric carbon atoms can exist in different optically active forms. When ^ and R2 are different or Ry and Rg are different, the compounds of formula I contain a chiral centre. Such compounds exist in two enantiomeric forms and the present invention includes both enantiomeric forms and mixtures thereof. When both R-^ and R2 are different and Ry and Rg are different, the compounds of formula I contain two chiral centres and the compounds exist in four diastereoisomeric forms. The present Invention includes each of these diastereoisomeric forms and mixtures thereof. The present invention also includes pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I together with a pharmaceutically acceptable diluent or carrier. In therapeutic use, the active compound may be administered orally, rectally, parenterally or topically, preferably orally. Thus the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for oral, rectal, parenteral or topical administration. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy. The compositions of the invention may contain 0.1-9096 by weight of active compound. The compositions of the invention are generally prepared in unit dosage form. Compositions for oral administration are the preferred compositions of the invention and these are the known pharmaceutical forms for such administration, for example tablets, capsules, syrups and aqueous or oily suspensions. The exclpients used in the preparation of these compositions are the exclpients known in the pharmacists' art. Tablets may be prepared by mixing the active compound with an inert diluent such as calcium phosphate in the presence of disintegrating agents, for example maize starch, and lubricating agents, for example magnesium stearate, and tableting the 2 0017 8 /■" — O - mixture by known methods. The tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention. Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate. Similarly, capsules, for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by conventional means and, if desired, provided with enteric coatings in a known manner. The tablets and capsules may conveniently each contain 1 to 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 present invention in a suitable vegetable oil, for example arachis oil. Compositions of the invention suitable for rectal administration are the knov.Ti pharmaceutical forms for such administration, for example suppositories with cocoa butter or polyethylene glycol bases. Compositions of the invention 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 comprise a matrix in which the pharmacologically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally. Alternatively the active compounds may be dispersed in a pharmaceutically acceptable cream or ointment base. In some formulations it may be beneficial to use the compounds of the present: invention in the form of particles of very small size, for example as obtained by fluid energy milling. - 7 - O n n 1 7 Q £_ \j L I / o In the compositions of the present invention the active cun.pound may, if desired, be associated with other comoatible pharmacologically active ingredients. The pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I may be used to treat depression in marrmals including human beings. In such treatment the amount of the compound of formula I administered per day is in the range 1 to 1000 mg preferably 5 to 500 mg. The substituents for the compounds of formulae Y-XJCV throughout the disclosure and claims of this specification are as defined for formula I unless otherwise indicated. Compounds of formula I in which is CHO may be prepared by the reductive amidation of ketones of formula V or of ketones or aldehydes of formula VI ^ . t; SCV 'ft R5 CF^RjCORy r6 /W/ LJ VI for example with formamide and formic acid or ammonium formate and formic acid to give compounds of formula I in which R» is CHO and R, is H or with formamides of formula KCONHR-^ 3 D in which R-, is an alkyl or cycloalkyl group and formic acid or amines of formula R-N^ in which R^ is an alkyl or cycloalkyl group and formic acid and R^ and R, are as defined above. f ■ . of -: Compounds of formula I in which R^ is CHO may be prepared by the formylation of compounds of Formula I in which R^ is H for example by reaction with methyl formate. ^ ■<" ' • Compounds of fonnula I in which R^ is other than H and is CHO may be prepared by reacting compounds of formula I in which R, is H and R^ is CHO with a conpound of formula R~X , where X is a leaving group such as a halo group in the presence of a base. - 8 - Compounds of formula I may be prepared by the reductive amination of ketones of formula V or of ketones or aldehydes of fonnula VI. Examples of suitable reductive amination processes are given below:- a) for compounds of formula I in which R^ and R^ are H, by reaction of 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 in which R3 is alkyl or cycloalkyl and is H by reaction of the ketone or aldehyde with an amine of formula and a reducing agent such as sodium cyanoborohydride, c) for compounds of formula I in which neither R^ nor is hydrogen or in which R^ and R^ together with the nitrogen atom form a heterocyclic ring, by reaction of the ketone or aldehyde with an amine of formula HNR^R^ and either formic acid or a reducing agent such as sodium cyanoborohydride, d) for compounds of formula I in which one or both of R* and R^ are H or an alkyl or a cycloalkyl group or in which and R^ together with the nitrogen atom form a heterocyclic ring, by catalytic hydrogenation at elevated temperature and pressure of a mixture of the ketone or aldehyde and jan amine of formula HNR^R4* Compounds of formula I in which and R^ are both alkyl groups may be prepared by reacting a ketone of formula V or a ketone or aldehyde of formula VI with a dialkyl formamide of formula HCONR^R^ for example in the presence of formic acid. Compounds of fonnula I may be prepared by the reduction of compounds of formula VII r5 z 200178 -9- in which a) Z is a group of formula - CR1=NOH or an ester or ether thereof to give compounds of formula I in which n = 0 and 1*2» R.J. and are H; b) Z is a group of formula - CR-^=NR^ r(where is other than H or CHO) togive compounds of formula I in which n = 0 and R£ and R^ are H; c) Z is a group of formula - CR^=NY in which Y represents a metal-containing moiety derived from an organometallic reagent to give compounds of formula I in which n = C and R2, R^ and R^ are H; d) Z is a group of formula - CR^R^CN to give compounds of formula I in which n = 1 and R^, R^, Ry and Rg are H; e) Z is a group of formula - CR^^CR^NOH or an ester or ether thereof to give compounds of formula I in which n = 1 and R^, R^ and Rg are H; f) Z is a group of formula - CR-^R^CR^NR^ (where i* other than H or CHO to give compounds of formula I in which n = 1 and R^ and Rg are H; g) Z is a group of formula - CR-jR^CRy =NY in which Y represents a metal-containing moiety derived from an organometallic reagent to give compounds cf formula I in which n = 1 and R^, R^ and Rg are H; h) Z is a group of formula - CR^^CONR^ to give compounds of formula I in which n = 1 and Ry and Rg are K. Suitable reducing agents for the above reactions include sodium borohydride, sodium cyanoborohydride, lithium aluminium hydride or borane-dimethylsulphide complex. In (c) and (g) above Y is preferably MgBr derived from a Grignard reagent or Li derived from an organolithium compound. ' <«* \v V.o\\ ;'e* V rw W ?C0173 - 10 - Compounds of formula I in which n = 0 may be prepared by the reaction of an organometallic reagent for example a Grignard reagent of formula R-jMgX where X is CI, Br or I or an organolithium compound of formula R-jLi with an imine of formula VIII CH=NR- VIII followed by hydrolysis to give a secondary amine of formula I. In a similar manner imines of formula IX may be converted to secondary amines of formula I in which n = 1 by reaction with an organometallic reagent, for example,a Grignard reagent of formula R-yMgBr or an organolithium compound of formula R7Li, followed by hydrolysis. CR-jR^Cf^NR^ IX Compounds of formula I in which and R^ are H may be prepared by the dscarboxylative rearrangement, for example using iodosobenzene-bistrifluoroacetate or by a Ho finann reaction using bromine in alkaline solution, of amides 01 formula X or amides of formula XI R, R/; Rc R, CR-jR^OM^ ^RgCRyRgCONHg XI followed by hydrolysis to give amines of formula 1 in which n = 0 and n = 1 respectively. 200:73 - II - Compounds of formula I in which and R^ are H may be prepared by the decarboxylative rearrangement of acy.1 azides in the Curtius reaction. The acyl azides may be formed for example by reaction of acid chlorides of formula XII or acid chlorides of formula XIII with sodium azide CR^R^OCl XII CR-jR^RyRgCOCl XIII followed by hydrolysis to give amines of formula 1 in which n = 0 and n = 1 respectively. Compounds of formula I in which R5 and R4 are H may be prepared by a Schmidt reaction in which a carboxylic acid of formula XIV or a carboxylic acid of formula XV reacts with hydrazoic acid CR^COOH XIV o \.. RjRgpRyRgPOOH 27Fmm:;:i V : " XV followed by hydrolysis to give amines of formula I in which n = 0 and n = 1 respectively. Compounds of formula I in which R^ is H may be prepared by hydrolysis of compounds of formula I in which R^ is CHO, for example by acid hydrolysis. Compounds of formula I in which R^ is methyl may be prepared by reduction of compounds of formula I in which R^ is CHO, for example by lithium aluminium hydride or by sodium bis (2-rnethoxyethoxy )aluuiinium hydride. - 12 - 2001 7 8 Compounds of formula I in which one or both of and R^ is other than H may be prepared from compounds of formula I in which one or both of R^ and are hydrogen by methods which are well known in the art for the conversion of primary to secondary or tertiary amines or'for the conversion of secondary to tertiary amines. The following are given as examples of suitable processes a) by alkylating primary amines of formula I to give secondary amines of formula I for example by a process which includes the steps of protecting the primary amine with a protecting group such as trifluoroacetyl, alkylating with an alkyl halide and removing the protecting group for example by hydrolysis; b) by alkylating primary amines of formula I, for example, with an alkyl halide to give tertiary amines of formula I in which and are the same; c) by alkylating secondary amines of formula I, for example, with an alkyl halide to give tertiary amines of formula I in which R^ and R^ may be different; d) by reacting primary amines of formula I with sodium borohydride and acetic acid to give secondary amines of formula I in which R^ is ethyl and R^ is H; e) by reacting primary amines of formula I with formaldehyde and formic acid to give tertiary amines of formula I in which both R^ and R^ are methyl f) by reacting secondary amines of formula I in which R^ is H with formaldehyde and formic acid to give tertiary amines of formula I in which R^ is methyl g) by formylating primary amines of formula I, for example by reaction with methyl formate, and reducing the resulting formamides, for example with lithium aluminium hydride to give secondary amines of formula I in which R^ is methyl and R^ is H; X-o o \1% ■* t - 13 - h) by formylating secondary amines of fomrula I, for example by reaction with methyl formate, and reducing the resulting formamides, for example with lithium aluminium hydride to give tertiary amines of formula I in which R^ is methyl. i) by acylating primary amines of formula I, for example by reaction with an acyl chloride of fonnula R-^COCl or an anhydride of formula (R12C0)20 in which R12 is an alkyl, alkenyl or alkynyl group and reducing the resulting amides for example with lithium aluminium hydride to give secondary amines of formula I in which is -CH^R^ and is H. J) by acylating secondary amines of formula I in which R^ is H for example by reaction with an acyl chloride of formula R12C0C1 or an anhydride of formula (R^2C0)20 in which R^2 is an alkyl, alkenyl or alkynyl group and reducing the resulting amides for example with lithium aluminium hydride to give tertiary amines in which R^ is CH2R^2. k) by reacting primary amines of formula I with an aldehyde of formula R^CHO in which R-^ maY 2111 group, an alkenyl or alkynyl group or a ketone of formula R14C0R15 in which R14 and R^ which may be the same or different are an alkyl group, alkenyl group, alkynyl group or R^ and R^ together with carbon atom to which they are attached may form an alicyclic ring and reducing the resulting imines or enamines for example with sodium cyanoborohydride or, when R13' R14 or RI5 are noalkenyl or alkynyl, by catalytic hydrogenation to give secondary amines of formula I in which R15 rj is R^CHg- and r^^ —^H- respectively; 1) by reacting primary amines of formula I with a non-geminally disubstituted alkane containing 2 or 3 carbon atoms between the carbon atoms carrying the substitutents which may be for example halo preferably bromo,or jD-toluenesulphonyloxy to give compounds of formula I in which R^ and R^ together with the nitrogen to which they are attached form a heterocyclic ring containing no heteroatoms other than the nitrogen atom. 200178 - 14 - The ketones of formula V may be prepared by the hydrolysis of imines of formula XVI CJR-^NY XVI in which Y represents a metal-containing moiety derived from an organometallic reagent. The imines of formula XVI may be prepared by the reaction of said organometallic reagent with a cyano compound of formula XVII XVII Suitable organometallic reagents include Grignard reagents of formula R-^NgX where X is CI, Br or I (Y = MgX) and organolithium compounds of formula R-^Li (Y = Li). The ketones of formula VI may be prepared by the hydrolysis of imines of formula XVIII cr1r2/:r7=ny XVIII in which Y represents a metal-containing moiety derived from an organcnietallic reagent. The imines of formula XVIII may be prepared by the reaction of the said organometallic reagents with cyano compounds of formula XIX R, o cr1r2cn XIX 200178 - 15 - Suitable organometallic reagents include Grignard reagents of formula R^MgX where X is CI, Br or I (Y = MgX) and organolithium compounds of formula R-^Li (Y =Li). Ketones of formula V may be prepared by the reaction of acid halide with an organometallic reagent for example by the reaction of an acid chloride of formula XX with a Grignard reagent of formula R^MgX where X is CI, Br or I at low temperatures or by the reaction of a carboxylic acid of formula XXI with an organometallic reagent, for example an organolithium compound of formula R^Li. Ketones of formula VI may be prepared by the reaction of carboxylic acid derivatives such as an amide or acid halide with an organometallic reagent for example by the reaction of an acid chloride of formula XII with a Grignard reagent of formula RyMgX where X is CI, Br or I at low temperatures or by the reaction of a carboxylic acid of formula XIV with an organometallic reagent for example an organolithium compound of formula R^Li. Ketones of formula V in which R-^ is alkyl (e.g. methyl) and ketones of formula VI in which R^ is alkyl (e.g. methyl) may be prepared by the reaction of a diazoalkane (e.g. diazo-methane) with aldehydes of formula XXII and VI respectively. carboxylic acid derivatives such as an amide or XX XXI 2 001 7 - 16 R CHO XXII Aldehydes of formula VI may be prepared by methods well known in the art. The following are given as examples of suitable methods:- a) by reduction of cyano compounds of formula XIX with for example di-tert-butylaluminium hydride or di-isobutyl-aluminium hydride. b) by the reduction of carboxylic acid derivatives for example i) by reduction of compounds of formula VII in which Z is CR-^R^CONR^R^ and R^ and R^ are other than H for example by using lithium diethoxy-aluminohydride. - . ■ ii) by reduction of amides formed by the reaction of ethyleneimine with an acid chloride of formula XII for example using lithium aluminium hydride as the reducing agent. iii) by the reduction of acid chlorides of c) by the reaction of alcohols (formed by the reduction of carboxylic acids of formula XIV) with, for example, chromiun trioxide-pyridine complex in dichloromethane under anhydrous conditions. formula XII for example with lithium tri-tert-butoxyaluminohydride. 'I Xoon% - 17 - Compounds of formula VII in which Z is a group of formula -CRj=NOH or -CR^R^R^NOH or ethers or esters thereof may be prepared by the reaction of hydroxylamine or an ether or ester thereof with ketones of formula V and ketones or aldehydes of formula VI respectively. Compounds of formula VII in which Z is a group of formula -CR^=NR^ or -CR-jR^R^NR^ may be prepared by the reaction of amines of formula NH0R-, with ketones of formula V and ketones or aldehydes of formula VI respectively. The preparation of compounds of formula VII in which Z is a group of formula -CR-^-NY or -CR-jjR^R^NY has been described above in respect of compounds of formula XVI and XVIII respectively. The preparation of compounds of formula VII in which Z is a group of formula -CR-j^CN will be described hereinafter in respect of the cyano compounds of formula XIX. Compounds of formula VII in which Z is a group of formula -CR^RgCONR^R^ may be prepared by the reaction of acid derivatives such as esters or acid halides (for example acid chlorides of formula XII) with amines of formula HNRjR^. Compounds of fonnula VII in which Z is crq^conj^ may be prepared from cyano compounds of formula XIX for example by hydration, with aqueous acids or by reaction with hydrogen peroxide in the presence of a base. Imines of fonnula VIII and IX may be prepared by reaction of amines of formula R^NH2 with aldehydes of fonnula XXII and VI respectively. - 18 - 2 0 01 78 Amides of formula X may be prepared by the reaction of ammonia with carboxylic acid derivatives example acid chlorides of 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 peroxide in the presence of a base. Amides of formula XI may be prepared by the reaction of 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 base. Amides of formula X in which R-, and R~ are H and amides JL d of formula XI in which R^ and Rg are H may be prepared from acid chlorides of formula XX and XII respectively by reaction with diazcmethane to form a diazoketone which rearranges in the presence of ammonia and a catalyst for example silver to give the required amide. Carboxylic acids of formula XIV, XV and XXI may be prepared by the hydrolysis, for example basic hydrolysis, of cyano compounds of formula XIX, XXIII and XVII respectively. Carboxylic acids of formula XIV and XV may be prepared by the reaction of amides of formula X and XI respectively with nitrous acid. Carboxylic acids of formula XXI may be prepared by the reaction of nitrous acid with the amides formed by the reaction of ammonia with carboxylic acid derivatives for example acid chlorides of formula XX or by the reaction of cyano compounds of formula XVII with hydrogen peroxide in the presence of a base. 2001 7 - 13 - Carboxylic acids of formula XIV in which R-^ and R2 are H and carboxylic acids of formula XV in which Ry and Rq are H may be prepared from acid chlorides of formula XX and XII respectively by reaction with dia-zomethane to form diazoketones which rearranges in the presence of v/ater and a catalyst for example silver to give the required acid. Cyano compounds of formula XVII may be prepared by the reaction of cyano compounds of formula XXIV XXIV with a 1,3-disubstituted propane for example 1,3-dibromo— propane and a base such as sodium hydride. Cyano compounds of formula XIX in which R-^ and R2 are H may be prepared from cyano compounds of formula XVII by for example 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 aluminium hydride or borane-dimethylsulphide complex to form the corresponding alcohol; -20-- ■ 2 0 Q1 7 8 c) replacement of the hydroxy group of the alcohol by a leaving group for example a ^-toluene sulphonyloxy group and d)replacement of the leaving group with a cyano group. In a similar mariner cyano compounds of formula XXIII may be prepared from cyano compounds of formula XIX. Cyano compounds of formula XIX in which one or both of R-^ and R2 are other than H may be prepared from the corresponding cyano compounds of formula XIX in which R-^ and/or R2 are H, for example by. alkylation with an alkyl halide in the presence of a base such as lithium diisopropylamide. Cyano compounds of formula XIX in which R2 = H may also be prepared by reacting ketones of formula V or an aldehyde of formula XXII with a reagent for introducing a cyano group such as p-toluenesulphonylmethyl isocyanide. In a similar manner cyano compounds of formula XXIII may be prepared from aldehydes or ketones of formula VI. Acid chlorides of formula XX, XII and XIII may.be prepared by the reaction of carboxylic acids of formula XXI, XIV and XV respectively with for example thionyl chloride. Aldehydes of formula XXII may be prepared by methods well known to those skilled in the art. The following are given as examples of suitable methods a) by the reduction of cyano compounds of formula XVII with for example di-tert-butylaluminium hydride or di-isobutylaluminium hydride. b) by the reduction of carboxylic acid derivatives, for example i) by the reduction of tertiary amides formed by the reaction of secondary amines with acid chlorides of formula XX for example when the secondary amine is a dialkylamine using lithium diethoxyaluminohydride as reducing agent or when the secondary amine is ethyleneimine using lithium aluminium hydride as the reducing agent, ii) by the . reduction of acid chlorides of formula XX for example with lithium tri-tert-butoxyaluminohydride. 21 - ?0C1 7 c) by the oxidation of alcohols (prepared by the 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 in which and Rg are H and R^ is methyl or ethyl), ketones of formula VI and aldehydes of formula VI (except those in which R^, R2> R^ and Rg = H), the compounds of formula VII (except those in which Z = CR-^ = NY and and Rg are H and R-^ is methyl and ethyl), the imines of formula VIII (except those in which R^ and Rg are H), IX, XVI (except those in which R^ and Rg are H and R^ is methyl or ethyl) and XVIII, the amides of formula X and XI, the carboxylic acids of formula XIV (except those in which R^, R2, R^ and Rg are H) and XV, the cyano compounds of formula XIX and XXIII and the acid chlorides of formula XII (except those in which R^ R2, R^ and Rg are H) and XIII which are described herein as intermediates are novel compounds. Some of cyano compounds of formula XVII and XXIV are novel compounds. Such novel compounds form a further aspect of the present invention. Novel formamides of formula XXV R CHO XXV are described herein as intermediates, in the preparation of 2 C 01 7 3 - 22 - compounds of formula I and such novel formamides form a further aspect of the present invention. The therapeutic activity of the compo.unds of formula I has been indicated by assessing the ability of the compounds to reverse the hypothermic effects of reserpine in the following manner. Male mice of the Charles River CD1 strain weighing between 18 and 30 grammes were separated into groups of five and were supplied with food and water ad libitum. After five hours the body temperature of each mouse was taken orally and the mice were injected intra-peritoneally with reserpine (5 mg/kg) in solution in deionised water containing ascorbic acid (50 mg/ml). The amount of liquid injected was 10 ml/kg of body weight. Nine hours after the start of the test food was withdrawn but water was still available ad libitum. Twenty-four hours after the start of the test the temperatures of the mice were taken ana the mice were given the test compound suspended in a 0.25% solution of hydroxy ethyl cellulose (sold under the trade name Cellosize OP 15000 by Union Carbide) in deicnised water at a dose volume of 10ml/kg of body weight. Three hours later the temperatures of all the mice were again taken. The percentage reversal of the reserpine-induced loss of body temperature is then calculated by the formula: (Temperature after 27 hrs - Temperature after 24 hours) X 100 (Temperature after 5 hrs - Temperature after 24 hours) The mean value for each group of five mice was taken at several dose rates to enable a value of the mean dose which causes a 50% reversal (ED50) to be obtained. All the compounds which are the final products of the Examples hereinafter gave values of ED50 of 30 mg/kg or less. It is widely understood by those skilled in the art that this test is indicative of compounds having antidepressant activity in humans. Table I lists compounds of formula I which gave a value of ED50 in the above test of 10 mg/kg or less. - 23 - 2001 7 Table I 1-[l-(3,4-dichlorophenyl)cyclobutyl]ethylamine hydrochloride N-methyl-1-[l-(3,4-dichlorophenyl)cyclobutylJethylamine hydrochloride N,N-dimethyl-1-[l-(3,4-dichlorophenyl)cyclobutyl]ethylamine hydrochloride 1-[l-(4-iodophenyl)cyclobutylJethylamine hydrochloride N-methyl-1-[l-(4-iodophenyl)cyclobutylJethylamine hydrochloride N,N-dimethyl-1-[l-(4-iodophenyl)cyclobutylJethylamine hydrochloride N-methyl-1-[l-(2-naphthyl)cyclobutylJethylamine hydrochloride N,N-dimethyl-1-[l-(4-chloro-3-trifluoromethylphenyl)cyclobutyl Jethylamine hydrochloride 1-[l-(4-chlorophenyl)cyclobutylJbutylamine hydrochloride N-methyl-1-[l-(4-chlorophenyl)cyclobutylJbutylamine hydrochloride N,N-dimethyl-1-[l-(4-chlorophenyl)cyclobutylJbutylamine hydrochloride 1-[l-(3,4-dichlorophenyl)cyclobutylJbutylamine hydrochloride N-methyl-1-[l-(3,4-dichlorophenyl)cyclobutylJbutylamine hydrochloride N,N-dimethyl-1-[l-(3,4-dichlorophenyl)cyclobutylJbutylamine hydrochloride l-[l-(4-biphenylyl)cyclobutylJbutylamine hydrochloride N,N-dimethyl-1-[l-(4-biphenylyl)cyclobutylJbutylamine hydrochloride 1-[l-(4-chloro-3-fluorophenyl)cyclobutylJbutylamine hydrochloride N-formyl-1-[l-(4-chloro-3-fluorophenyl)cyclobutylJbutylamine . 1-[l-(3-chloro-4-methylphenyl)cyclobutylJbutylamine hydrochloride N-formyl-1-[l-phenylcyclobutylJbutylamine 1-[l-(3-trifluoromethylphenyl)cyclobutylJbutylamine hydrochloride 1- Cl-(naphth-2-yl) cyclobutyl Jbutylamine hydrochloride 1-[l-(6-chloronaphth-2-yl)cyclobutylJbutylamine N-methyl-1-[l-(4-chlorophenyl)cyclobutylJ-2-methylpropylamine hydrochloride 1-[l-(4-chlorophenyl)cyclobutylJpentylamine hydrochloride N-methyl-1-[l-(4-chlorophenyl)cyclobutylJpentylamine hydrochloride N,N-dimethyl-1-[l-phenylcyclobutylJ-3-methylbutylamine hydrochloride 1-[l-(4-chlorophenyl)cyclobutylJ-3-methylbutylamine hydrochloride N-methyl-1-[l-(4-chlorophenyl)cyclobutylJ-3-methylbutylamine hydrochloride N,N-dimethyI-l-[l-(4-chlorophenyl)cyclobutylJ-3-methyl-butylamine hydrochloride N-formyl-1-[l-(4-chlorophenyl)cyclobutylJ-3-methylbutylamine N,N-dimethyl-1-[l-(3»4-dichlorophenyl)cyclobutylJ-3-methyl-butylam'ine hydrochloride N-methyl-1- [l-(naphth-2-yl)cyclobutyl J-3-methylbutylamine hydrochloride N-methyl-1-[l-(3,4-dimethylphenyl)cyclobutylJ-3-methyl-butylamine hydrochloride [l- (4-chlorophenyl )cyclo butyl J(cyclopropyl )methylamine hydrochloride N-methyl-[l-(4-chlorophenyl)cyclobutylJ(cyclopentyljethylamine hydrochloride [l-(4-chlorophenyl)cyclobutylicyclohexyl)methylamine hydrochloride 10 - 25 - N-methyl- El-(4-chlorophenyl )cyclobutyl ipyclohexyl )methyl-amine hydrochloride [l-( 3,4-dichlorophenyl) cyclobutyl Jcyclohexyl )methylamine hydrochloride N-methyl- [l- (3,4-dichlorophenyl )cyclobutyll (cyclohexyl )methyl-amine hydrochloride [l-(4-chlorophenyl )cyclobutyl ]( cycloheptyl )methylamine hydrochloride 1- [l-( 4-chlorophenyl )cyclobutyl ]-2-cyclopropylethylamine hydrochloride N,N-dimethyl-1- [l- (4-chlorophenyl )cyclobutyl J-2-cyclohexyl-ethylamine hydrochloride a- [l-(4-chlorophenyl )cyclobutyl ]benzylamine hydrochloride N-methyl-a- [l- (4-chlorophenyl )cyclobutyl Jbenzyl amine hydrochloride 1- [l-(4-chloro-2-fluorophenyl )cyclobutyl jbutylamine N, N-dimethyl-1- [l- (4-chloro-2-f luorophenyl )cyclobutyl ] butylamine hydrochloride 1-^ [l- (3,4-dichlorophenyl )cyclobutyl ]me thy 1^ propylamine hydrochloride N,N-dimethyl-1- £[l- (3,4-dichlorophenyl )cyclobutyl Jmethyl^-propylamine hydrochloride N,N-dimethyl-2- tl- ( 4-iodophenyl )cyclobutyl Jethylamine hydrocljloride N-ethyl-1- [ 1- (3»4-dichlorophenyl )cyclobutyl ] ethylamine hydrochloride N,N-di ethyl-l-[l-( 3»4-dichlorophenyl )cyclobutyl Jethylamine hydrochloride 15 20 25 - 26 - 2 001 The invention will now be illustrated by the following Examples which are given by way of example only. All compounds were characterised by conventional analytical techniques and gave satisfactory elemental analyses. All 5 melting and boiling points are expressed in degrees Celsius. Example 1 A solution of 3,4-dichlorobenzyl cyanide (25 g) and 1,3-dibromopropane (15 ml) in dry dimethyl sulphoxide (150 ml) was added dropwise under nitrogen to a stirred mixture 10 of sodium hydride (7.5 g) dispersed in mineral oil (7-5 g) and dimethylsulphoxide (200 ml) at a temperature in the range 30 to 35°C. The mixture was stirred at room temperature for two hours and propan-2-ol (8 ml) and then water (110 ml) were added dropwise. The mixture was filtered 15 through a diatomaceous earth sold under the Registered Trade Mark CELITE and the solid residue washed with ether. The ether layer was separated, washed with water, dried and evaporated. l-(3i4-Dichlorophenyl)-l-cyclobutanecarbo-nitrile (b.p. 108-120°C at 0.15 Hg) was isolated by distil-20 lation. This method is a modification of that described by / Butler and Pollatz (J.Org.Chem., Vol. 36, No. 9, 1971, p.1308). The l-(3»4-dichlorophenyl)-l-cyclobutanecarbonitrile prepared as above (21.7 g) was dissolved in dry ether (50 ml) and the solution was added under nitrogen to the product of 25 the reaction of gaseous methyl bromide with magnesium turnings (3*9 g) in dry ether (150 ml). The mixture was stirred at room temperature for two hours and then under reflux for two hours. Crushed ice and then concentrated hydrochloric acid (100 ml) were added and the mixture heated under reflux 30 for two hours. The ether layer was separated, washed with water and aqueous sodium bicarbonate> dried and evaporated. l-Acetyl-l-(3,4-dichlorophenyl)cyclobutane (b.p. 108-110 at 0.2 mm Hg) was isolated by distillation. l-Acetyl-l-(3,4-dichlorophenyl)cyclobutane (9.1 g) pre-35 pared as above, formamide (6.5 ml) and 98% formic acid (3 ml) were" heated at 180°C for sixteen hours to give N-formyl-1- - 27 - ft 10 [l-(3,4-dichlorophenyl)cyclobutylJethylamine. Concentrated hydrochloric acid (20 ml) was added and the mixture heated under reflux for three hours. The solution was then cooled, washed with ether and sodium hydroxide solution added. The product was extracted with ether, and the ether extract washed with water, dried and evaporated. l-[l-(3,4-Dich!oro-phenyl)cyclobutylJethylamine (b.p. 112-118° at 0.2 mm Hg) was isolated by distillation. The amine was dissolved in propan-2-ol and concentrated hydrochloric acid and the solution evaporated to dryness to give l-[l-(3,4-dichlorophenyl) cyclobutylJethylamine hydrochloride (m.p. 185-195°C). (Formula I n = 0; R^=Me; R^=H; R^=4-C1; Rg=3-Cl). Example la The preparation of N-formyl-l-[l-(3,4-dichlorophenyl)cyclo-butylJethylamine (m.p. 124-125°C) (Example 1(a) Formula I n = 0; R1=Me; R£=H; R3=H; R4=CH0; R5=4-C1 and Rg=3-Cl) described above was repeated and the product isolated by cooling the reaction mixture and collecting the solid produced by filtration. The formamide was then hydrolysed by concentrated hydrochloric acid in industrial methylated spirit to give the hydrochloride salt of I-[l-(3,4-dichloro-20 phenyl)cyclobutylJethylamine. In a similar manner to that described above in Example la the following compounds were prepared. The conditions for the hydrolysis of the formamides which were isolated by appropriate methods are shown in the footnotes. 15 25 SHR^NH^HCl 30 35 Example Kb) 1(c) 1(d) 1(e) R-, Rime thy1 CI n-butyl CI methyl I methyl CI Rg b.p. (free base) H 107°/1.2 mm Hg H H CF- m.p. of HC1 salt 138-139° 205-207° 216-217° Note A B C D - 28 - 2 0 7 ^ ^ u 10 15 20 25 50 A. B. C. aqueous HCl/industrial methylated spirit The 1-valeryl-l-(4-chlorophenyl)cyclobutane was prepared in tetrahydrofuran. Hydrolysis was performed using concentrated HCl/industrial methylated spirit, concentrated HCl/diethyleneglycoldimethyl ether (in a similar manner to that described later in Example 12). concentrated HCl/industrial methylated spirit. D. Example 2 The product of Example 1 (4.04 g), water (0.5 ml) and 98% formic acid (3.6 ml) were mixed with cooling. 37-40% Aqueous formaldehyde (3.8 ml) was added and the solution was heated at 85-95°C for five hours. The solution was evaporated to dryness and the residue acidified with concentrated hydrochloric acid and the water removed by repeated addition of propan-2-ol followed by evaporation in vacuo♦ Crystals of N,N-dimethyl-1-[l-(3,4-dichlorophenyl)cyclobutylJethylamine hydrochloride (m.p. 211-213°C) (Formula I n=0; R^= Me; R2=H; = Me; R^=4-C1; Rg=3-Cl) were isolated. In a similar way to that described above the compounds of Example 1(b) and 1(d) were converted into the compounds listed below. CHR-jNMe^HCl Example Starting Material R1 R5 R6 m.p. HC1 of salt b.p. of free base 2(a) Kb) methyl CI H 98-100°/0.5 mm 2(b) Kd) methyl I H 260- ■261° Example 1i In a similar manner to that described above in Examples 1 and 2 N,N-dimethyl-1-[l-(4-biphenylyl)cyclobutylJethylamine hydrochloride (m.p. 196-197°C) was prepared. (Formula I n=0; R-^=Me; R2=H; R^,R^=Me; R^=4-phenyl and Rg=H). - 29 - 2 0 01 7 Example 4 10 15 20 30 35 l-Acetyl-l-(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 eight hours. The mixture was cooled and extracted with ether. The ether extract was washed, dried and evaporated to yield a light yellow oil which was heated under reflux with concentrated hydrochloric acid (50 ml) for two hours. Industrial methylated spirit (IMS) (50 ml) was added and the mixture heated under reflux for sixteen hours. The mixture was then cooled to 0°C and the white precipitate collected by filtration, washed with acetone and dried. The product, N-methyl-1-[l-(3>4-dichloro-phenyl)cyclobutyljethylamine hydrochloride, had a melting point of 254 to 256°C (Formula I n = 0; ^ = Me; R2 = H; R3 = Me; R4 = H; R^ = 4-C1 and Rg = 3-C1). In a similar manner to that described above the following compounds of formula I were prepared CHR-jNHMe.HCl Example R1 R5 R6 b.p. of amine m.p. of Note HC1 salt 4(a) Me CI H 98-100°/0.15 mm 240-241° 4(b) Me H CI 269-272° 4(c) Me Br H 96-98°/0.1 mm 4(d) Me H Br 251-255° 4(e) Me CF3 H (-(CH = H 219-221° 4(f) 4(g) Me Me cf3 "car?* ) 225-228° 254-257° 4(h) Me '"cr-^ cf3~" H 198-200° 4(i) Et CI 238-240° 4(j) Pr CI • H 228-229° a 4(k) Bu CI H 152-153° a 4(1) Me i H 242-243° - 30 - 20C178 Note A The starting ketone was prepared in tetrahydro-furan as reaction solvent in place 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 give a neutral solution which was evaporated at 100°C/100 mm Hg until 180 ml of water had been collected. The residue was heated to 140°C and l-acetyl-l-(4-chlorophenyl)cyclobutane (10.4 g) prepared in a similar manner to that described in Example 1 for 1-acetyl-l-(3,4-dichlorophenyl)cyclobutane and 98% 10 formic acid (10 ml) were added. The mixture was heated on an oil bath at a temperature of 180-200°C for sixteen hours. The mixture was distilled until an internal temperature of 170°C was obtained and this temperature was maintained for two hours. Any volatile material was removed by distillation 15 at l60°C/20 mm and the residue heated under reflux with concentrated hydrochloric acid (15 ml) and industrial methylated spirit (IMS) (15 ml) for three hours. The IMS was evaporated on a rotary evaporator and the residue washed with ether. The aqueous phase was brought to pH 12 with sodium hydroxide 20 and extracted with ether. The ether extract was dried and on evaporation yielded a residue which was treated with aqueous hydrochloric acid to give N-ethyl-1-[l-(4-chlorophenyl)-cyclobutyljethylamine hydrochloride (m.p. 203-205°C) (Formula I n = 0; = Me; R2 =H; R^ = Et; R^ = H; R^ = 25 4-C1; R6 = H). J Example 6 l-(4-Chlorophenyl)-l-cyclobutanecarbonitrile (15 g) 30 prepared in a similar manner to the l-(3,4-dichlorophenyl)-cyclobutanecarbonitrile of Example 1 in dry ether (50 ml) was added to the product of the reaction between magnesium turnings (3.18 g) and propyl bromide (15.99 g) in dry ether (50 ml). The ether was replaced by tetrahydrofuran and the mixture heated with stirring under reflux for eighteen hours. The mixture was cooled and ice and then concentrated. hydrochloric 2001 7 - 31 - acid (52 ml) added. The resulting mixture was stirred under reflux for ten hours and extracted with ether. The ether extract yielded a residue from which i-butyryl-1-(4-chlorophenyl) eyelobutane (b.p. 106-108^0.3 mm Hg) was distilled. A mixture of the ketone produced as described above (21 g) and 98% formic acid (6 ml) was added over a period of one and a half hours to formamide (15 ml) at 160°C. After completion of the addition the temperature was raised to 180 to 185°C and maintained in this range for five hours. The mixture was cooled and extracted with chloroform to yield a thick gum which on heating with petroleum ether (b.p. 60-80°) gave a colourless solid which was recrystal-lised from petroleum ether (b.p. 60-80°) to yield N-formyl-1-[l-(4-chlorophenyl)cyclobutyljbutylamine (m.p» 97.5 to 98.5°C) (Formula I n = 0; R-^ = propyl; R2 = H; R3 = H; R^ = CHO; R5 = 4-C1; Rg = H). Example 7 A solution of l-(3,4-dichlorophenyl)-l-cyclobutane-carbonitrile prepared as described in Example 1 (35.2 g) in ether (100 ml) was added to a solution of propyl magnesium bromide prepared by the reaction of propyl bromide (32 g) with magnesium turnings (6.36 g) in ether (100 ml). The ether was replaced by dry toluene and the mixture heated under reflux for one hour. Water (200 ml) and then concentrated hydrochloric acid (120 ml) were added and the mixture heated under reflux for one hour. The reaction mixture was extracted with ether and after washing and drying the extract yielded a residue from which 1-butyryl-1-(3>4-dichlorophenyl)cyclobutane (b.p. 120-128°C at 0.25 mm) was distilled. The ketone produced as described above (37.0 g) and 98% formic acid (9 ml) were added to formamide (23.5 ml) at 170°C and the temperature kept at 175-180°C for five hours. A further portion of formic acid (4.5 ml) was added and the mixture was maintained at 175-180°C for a further fifteen hours. The 'mixture was extracted with ether which - 32 - 1 / dn evaporation gave a thick oil which was crystallised from petroleum ether (b.p. 60-80°) to give N-formyl-1-[l-(3,4-dichlorophenyl)cyclobutyljbutylamine having a melting point of 103-105°C (Formula I n = 0; R-^ = propyl; R2 = H; R^ = H; R^ = CHO; R$ = 4-C1 and Rg = 3-C1). In a similar manner to that described above the following compounds were made 10 Example 7(a) 15 7(b) 7(c) 7(d) CHR1NHCH0 Ri isobutyl propyl phenyl propyl 5 CI CI CI H R6 H F H H m.p. (°C) 110-112 115-116° 94-96° 98-102° Example 8 ^ The product of Example 7 (4.0 g) in dry tetrahydro- furan (25 ml) was added rapidly to a stirred mixture of lithium aluminium hydride (1.4 g) in dry tetrahydrofuran (25 ml) under nitrogen. The mixture was heated under reflux for five hours and then cooled. Water (15 ml) and 25 then 10% sodium hydroxide solution (3 ml) were added and the mixture filtered through diatomaceous earth sold under the Registered Trade Mark CELITE. The product was extracted into ether, back extracted into 5N hydrochloric acid and the aqueous layer was basified and extracted with 30 ether. The ether extract yielded 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-[l-(3,4-dichlorophenyl)cyclobutylJbutylamine hydrochloride and 10 01 - 33 - had a melting point of 234-235°C (Formula I n = 0; R^ = propyl; R2 = H; R^ = H; R^ = Me; R^ = 4-C1 and Rg = 3-Cl) In a similar manner to that described above the following compounds were prepared CHR-j^NHMe.HCl Example R1 R5 R6 B V • o o v—> 8(a) phenyl CI H 275-278° 8(b) propyl. CI H 223-228° 20 15 Example 9 The product of Example 7 (10 g) in solution in ether (50 ml) was added to a 70% toluene solution of sodium bis-(2-methoxyethoxy)aluminium hydride sold under the trade markRed-al(40 ml) at a temperature in the range 25 to 30°C. The mixture was stirred at this temperature for four hours. Water (25 ml) was added dropwise with cooling and the mixture filtered through diatomaceous earth (CELITE). Aqueous NaOH was added and an ether extraction performed. The ether extract was washed with water and back extracted with 5N hydrochloric acid. A white solid (m.p. 232-235°C) appeared at the interface which was collected. Base was added to the aqueous phase and a further ether extraction performed. Evaporation of the ether extract yielded an oil which was dissolved in propan-2-ol (5 ml) and concentrated hydrochloric 30 acid added to pH 2. Evaporation to dryness gave a white solid (m.p. 233-236°C). The white solids were combined and recrystallised from propan-2-ol to yield N-methyl-1-[l-(3*4-dichlorophenyl )cyclobutylJbutylamine hydrochloride (m.p. 236-237°C) (Formula I n = 0; R^ = propyl; R2 = H; 55 R3 = H; R^ = Me; R5 = 4-C1 and Rg = 3-Cl). 25 - 34 - * "7 In a similar manner to that described above the following compounds were prepared. Where the formyl starting material was insoluble in ether, a solution of the reducing agent was added to a stirred suspension of the formyl compound. As the size of the group. R-j_ is increased 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 in the isolation procedure are required as will be apparent to those skilled in the art. 10 15 20 : 25 30 CHR-^NHMe. HC1 Example R1 R5 R6 m.p. 9(a) isopropyl CI H 257-259° 9(b) sec-butyl CI H 209-212° 9(c) isobutyl CI H 225-233° 9(d) cyclopentyl CI H 252-256° 9(e) n-hexyl CI H 117-118° 9(f) 4-methoxyphenyl CI H 264-266° 9(g) 3-methoxyphenyl CI H 254-255° 9(h) 2-methoxyphenyl CI H 149-153° 9(i) cyclohexyl CI 170-172° 9(d) isobutyl 256-259° 9(k) cyclohexyl CI W_L ei 223-224° 9(1) : isobutyl Me Me (1) 9(m) propyl OMe H 173-175° 9(n) methyl phenyl H 116-118° (1) Boiling point of free base >150° at1.0 mm Hg. 35 Example 10 The product of Example 7 (4 g), diethyleneglycol-dimethyl ether (25.ml), water (10 ml) and concentrated hydrochloric acid (10 ml) were mixed and heated under - 35 - 2 0017 3 reflux for nine hours. The solution was washed with ether and aqueous NaOH added before an ether extraction was performed. The ether extract was washed with brine and water and yielded an oil on 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) added. The solvent was evaporated in vacuo. Repeated dissolution in industrial methylated spirit and evaporation in vacuo gave a gum which solidified on warming in vacuo. The product was recrystallised from petroleum ether (b.p. 100-10 120°C) and had a melting point of 201-203°C. The product was l-[l-(3,4-dichlorophenyl)cyclobutylJbutylamine hydrochloride (Formula I n = 0; R1 = propyl; R2 = H; R^, R^ -■ H; R5 = 4-C1 and Rg = 3-Cl). In a similar manner to that described above the following compounds were prepared. As the size of the group R-^ is increased 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 in the isolation procedure are required as will be apparent to those skilled in the art. 15 20 25 CHR1NH2.HC1 30 35 Example R1 R5 R6 m.p. 10(a) isopropyl CI H 200-202° 10(b) sec-butyl CI H 178-179° 10(c) isobutyl CI H 163-165° 10(d) cyclopentyl CI H 185-210°(dec) 10(e) phenyl CI H 271-276° 10(f) 4-me thoxypheny1 CI H 214-219° 10(g) cyclohexyl CI H 206-210° 10(h) isobutyl H H 210-212° 10(i) cyclopropyl CI H 204-206° t m 10 15 20 25 : • : ' J & <■' * • • 1 £ >1; ii i.J 30 35 , - 36 - Example R1 R5 R6 10(d) propyl Ph H 10(k) propyl Me ci 10(1) propyl -(ch= =ch)2- 10(m) cycloheptyl ci h 10(n) cyclohexyl ci ci 10(p) methyl ci F 10(q) propyl OMe H 10(r) propyl ci F 10(a) propyl ci H 10(t) cyclohexylmethyl ci H 10(u) cyclopropylmethyl ci H 10(v 10(w 10(x 10(y (b) propyl propyl 4-fluorophenyl methyl -CH=CH-CC1=CH-H CF-. CI H 3 /C= :c-ch=ch-ch m «p • 235-236° 214-217° 157-159° 156-162° 215° 215-217° 178-179° 186-188° 174-175° 148-150° 184-185° (a) 126-128° 279° 248-262° fe) V* boiling point of free base 168 C/0.05 mm Hg. diethyleneglycoldimethyl ether replaced by ethylene-glycoldimethyl ether. In a similar manner to that described above, l-[l-(4- chloro-2-fluorophenyl )cyclobutylJbutylamine (b.p. 99°C/0.05'mm), (Formula I n = 0; = propyl; R2, R^ and R^ = H; R^ = 4-C1; Rg = 2-F), 1-[l-(2-f luorophenyl )cyclobutyl Jbutylamine hydrochloride (m.p. 175-177°C). (Formula I n = 0; R^ = propyl; R2, R3, R^, R^ = H and Rg = 2-F) and l-[l-(4-chloro-2-methyl) cyclobutylJbutylamine hydrochloride (m.p. 188-190°C) (Formula I n=P; R^ = propyl; R2, R^ and R^ = H; = 4-C1; and Rg = 2-Me) were prepared as Examples 10(z),10(aa) and 10(bb) n respectively. The product of Example 10(c) (3.3 g) in the form of the free base, formic acid (2.99 g) and water (1 ml) were mixed with cooling. 37-40% Aqueous formaldehyde (3.93 ml) was added and the mixture heated for eighteen hours at a temperature of 85-95°C. Excess dilute hydrochloric acid was added and the solution evaporated to dryness. The residue was basified with 5N sodium hydroxide solution and the product was extracted into ether. Evaporation of the ether yielded 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 dissolved repeatedly in ethanol and evaporated in vacuo to give a gum which was triturated with petroleum ether (b.p. 60-80°) to yield a yellow solid which was recrystallised from acetone. The , product was N,N-dimethyl-1-Cl-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine hydrochloride (m.p. 195-197°C). (Formula I n = 0; = isobutyl; = H; R^, R^ = Me; R^ = 4-C1; r6 = h). In a similar manner to that described above the following compounds of Formula I were prepared 10 CHR-LNMe2.HCl 20 25 30 35 Example Starting Material R1 R5 R6 m.p. 11(a) 10(h) isobutyl H H 195-198° 11(b) 10(d) propyl Ph H 194-196° 11(c) 10(n) cyclohexyl Cl Cl 227-228° 11(d) 10(q) propyl OMe H 187-188° 11(e) 10(s) propyl Cl H 194-196° 11(f) io(t) cyclohexyl methyl Cl H 194-196° 11(g) 10 (u) cyclopropyl methyl Cl H 165-167° 11(h) 10(v) propyl <QH=CH- -CC1=CH^ (a) ll(i n(d 11 (k isobutyl Cl Cl 10(x) 4-fluorophenyl Cl H propyl isopropyl H 234° 211-213C (a) boiling point of free base <250°C/0.05 mm Hg. Example 11(1) In a similar manner to that described above N,N-dimethyl-l-[l-(4-chloro-2-fluorophenyl )cyclobutyl] butylamine hydrochloride (m.p. 183°) was prepared. (Formula I n = 0; R^ = propyl; R^ = H; R^, R^ = Me; R5 = 4-C1; R* = 2-F) " A "7 : *• - 38 - Example 12 The product of Example 7 (8.3 g), diethyleneglycol-dimethyl ether (50 ml), water (20 ml) and concentrated hydrochloric acid (20 ml) were mixed and heated under reflux for sixteen hours. The mixture was poured into water, aqueous NaOH was added and the product extracted into ether. Evaporation gave a dark oil. A sample of this oil (7.9 g), water (0.7 ml) and formic acid (6.5 ml) were mixed and formaldehyde (6.5 ml) added. The mixture was heated under reflux for three hours and then concentrated hydrochloric acid (10 ml) and propan-2-ol (10 ml) were added. Evaporation to dryness gave N,N-dimethyl-1-[l-(3,4-dichlorophenyl)cyclobutylJbutylamine hydrochloride (m.p. 195-196°) as a white solid (Formula I n = 0; = propyl; R2 = H; R3, R4 = Me; R5 = 4-C1 and Rg = 3-Cl). Example 13 l-(4-Chlorophenyl)-l-cyclobutanecarbonitrile (37.6 g) prepared in a similar manner to the 1-(3,4-dichlorophenyl)-1-cyclobutanecarbonitrile described in Example 1 was added to a solution of potassium hydroxide (32.4 g) in diethyle-neglycol (370 ml) and the mixture heated under reflux for three and a half hours. The reaction mixture was poured into an ice/water mixture 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)-l-cyclobutanecarboxylic acid (m.p. 86-88°) 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 aluminium hydride (2 g) in tetrahydrofuran (150 ml). The mixture was stirred under reflux for two hours and water added. The mixture was filtered through diatomaceous earth (CELITE - RTM) and the product extracted into ether. After washing with water and drying, the ether was evaporated to give a residue - 39 - 2 001 "7 o * o 15 which was recrystallised from petroleum ether (b.p. 60-80°). The product was 1-[l-(4-chlorophenyl)cyclobutyl]-methyl alcohol (m.p. 60-62°C). ^ A solution of the alcohol prepared as described above (60 g) in pyridine (52 ml) was added dropwise to a solution of p-toluenesulphonylchloride (60 g) in pyridine (100 ml) cooled in ice. The temperature was allowed to rise to room temperature and remain there for eighteen hours. l-[l-(4-Chlorophenyl)cyclobutyl]methyl p-toluene sulphonate (m.p. 99-100°C) was precipitated by pouring the reaction mixture into a mixture of ice and concentrated hydrochloric acid (200 ml). A solution of the sulphonate compound (97 g) prepared as described above and sodium cyanide (16.6 g) in dimethyl sulphoxide (370 ml) was heated on a steam bath for eighteen hours. The mixture was poured into water and extracted with ether. After washing and drying the ether was evaporated to leave a solid residue of 2-[l-(4-chlorophenyl)-cyclobutylJacetonitrile (m.p. 63-65°C). 20 A solution of di-isopropylamine (16.5 g) in dry tetra hydrofuran (50 ml) was stirred under nitrogen at a temperature of 0°C and a 1.6 M solution of n-butyllithium in hexane (100 ml) added dropwise. The reaction mixture was stirred for 30 minutes and then cooled to -78°C. A solution of 2-[l-(4-chlorophenyl)cyclobutyl]acetonitrile (9.5 g) prepared as described 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 ten minutes before a solution of methyl iodide (10 ml) in-tetrahydrofuran (10 ml) was added. Tetrahydrofuran (75 ml) was added to give a homogeneous solution and a further solution of methyl iodide (4 ml) in tetrahydrofuran (10 ml) added. The mixture was stirred at ambient temperature for two hours and then water (50 ml) added. The aqueous phase was washed with ether and the ether combined with the 35 organic phase of the reaction mixture. The combined organic 25 30 - 40 - 7 H f) 1 1 Q ; w 'u 2 * -{ j phases were washed three times with 5N hydrochloric acid, three times with water, dried and evaporated to yield an oil which solidified and was recrystal-lised from industrial methylated spirit to give 2-[l-(4-5 chlorophenyl)cyclobutyl]-2-methylpropionitrile (m.p. 73-75°C). The nitrile prepared above (4 g) was heated under reflux with potassium hydroxide (8 g) in diethyleneglycol (40 ml) for 24 hours. The reaction mixture was cooled, added to water (50 ml) and the aqueous phase washed twice with ether. The aqueous phase was acidified with 5N hydro-10 chloric 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 recrystal-lised from petroleum ether (b.p. 60-80°) to give 2-[l-(4-chlorophenyl)cyclobutyl]-2-methylpropionic acid (m.p. 95-15 110°C). Oxalyl chloride (10 ml) was added to the acid (2 g) prepared as above and after the initial effervesence had subsided the mixture was heated under reflux for one hour. Excess oxalyl chloride was removed by distillation and the 20 residual oil added to concentrated aqueous ammonia (75 ml). An oily solid formed which was extracted into ethyl acetate. The extract was washed with water, dried and evaporated to give 2-[l-(4-chlorophenyl)cyclobutyl]-2-methyl propionamide. 25 The amide prepared as above (1.34 g) was dissolved in a mixture of acetonitrile (8 ml) and water (8 ml) and iodo-sobenzene bistrifluoroacetate (3.4 g) added and the mixture stirred at ambient temperature for five and & half hours. Water (75 ml) and concentrated hydrochloric acid (8 ml) 30 were added and the mixture extracted with ether. The ether extract was washed with 5N hydrochloric acid and the aqueous phase basified and extracted with further portions of ether which were dried and evaporated to give an oil. The oil was dissolved in petroleum ether (b.p. 80-100°) and dry hydrogen chloride gas passed through the solution. - 41 - 2 001/8 l-[l-(4-Chlorophenyl)cyclobutyl]-l-methylethylamine hydro- • chloride (m.p. 257-259°C) was collected by filtration (Formula I n = 0;. R^, = Me; R^, R^ = H; R^ = 4-C1; Example 14 The product of 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 heated at a temperature of 85-95°C for sixteen hours. The mixture was diluted with water (50 ml) and basified to pH 10 with aqueous sodium hydroxide solution. The basic aqueous solution was extracted with ether, washed with water and dried with magnesium sulphate. Dry hydrogen chloride gas was bubbled through the ether extract to give a white precipitate of N,N-dimethyl-1-[l-(4-chloro-3-trifluoromethyl-phenyl)cyclobutylJethylamine hydrochloride (m.p. 246-247°C) (Formula I n=0; R^ = Me; R2 = H; R^, R^ = Me; R^ = 4-C1 and Rg ^3-CF^). Example 15 The production of salts of the compounds of the invention is illustrated by the following Examples in which equimolar amounts of the base and the acid were taken up in a solvent. The salt was then obtained from the solution by ^ conventional techniques. Example Base Acid Solvent m.p. of salt 15(a) 10(a ) citric aqueous acetone 158-160° 15(b) 10(s ) maleic ether 155-157° 15(c) 10 (s ) succinic ether 152-155° 15(d) 2 L( + )tartaric I.M.S. 150-153° 15(e) Note (a) citric ether/methanol 163-164°(dec) The base was 1-[l-(3,4-dimethylphenyl)cyclobutyl]-3-methylbutylamine prepared in a similar manner to that described in Example 10. (a) 35 - 42 - 2 001 7 Example 16 A solution of bromobenzene (15.7 g) in ether (50 ml) was added dropwise with cooling to magnesium turning (2.4 g) under an atmosphere of nitrogen. A solution of l-(4-chloro-phenyl)-cyclobutanecarbonitrile (19.1 g) prepared in a similar manner to that described in Example 1 for the l-(3,4-dichloro-5 phenyl)cyclobutane carbonitrile in ether (50 ml) was added and the ether replaced by 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 (1 g) in diethyleneglycoldimethyl ether (60 ml) and the mixture was stirred for one and a half hours. 10 Water (60 ml) was added slowly and the aqueous layer 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 filtered and evaporated. Trituration with 15 dry acetone gave a-[l-(4-chlorophenyl)cyclobutyl]benzylamine hydrochloride (m.p. 277-279°C) (Formula I n=0; R^=Ph; R2= H; R3,R4=H; R5=4-C1; R6=H). 20 25 Example 17 Methyl formate (62 ml) was added dropwise to isopropyl-amine (85.5 ml) with stirring at a rate which maintained gentle reflux conditions. Stirring was continued for two hours after the addition. Methanol was distilled off at 100°C and N-isopropylformamide (b.p. 108-109°C/25 mm Hg) obtained by distillation. l-A'cety!J.-l-(4-chlorophenyl)cyclobutane (10.4 g) prepared in a similar manner to that described in Example 1 for 1-acety1-1-(3,4-dichlorophenyl)cyclobutane and 98% formic acid (5 ml) were added to N-isopropylformamide (43.5 g) and the mixture heated at 180°C for four hours. Excess starting ^ material was distilled off under reduced pressure (20 mm Hg) to leave a viscous residue which was heated under reflux with concentrated hydrochloric acid (30 ml) for six hours. The reaction mixture was washed with ether until a colourless solution was obtained. The aqueous 35 phase was basified,• extracted with ether, dried and evapo- - 43 - 2 001 7\ rated to give an oil which was dissolved in 5N hydrochloric acid. On evaporation a yellow oil was obtained which was triturated with petroleum ether (b.p. 62-68°C) to give N-isopropyl-l-[l-(4-chlorophenyl)cyclobutyl] 5 ethylamine hydrochloride (m.p. 170-174°C) (Formula I n = 0; R-^ = Me; R2 = H; R^ = isopropyl; R4=H; R^ =4-Cl; rg=h). Example 18 l-Acetyl-l-(3,4-dichlorophenyl)cyclobutane (7.0 g) prepared as described in Example 1 was slowly added to a 10 mixture of pyrrolidine (25 ml) and 98% formic acid (15 ml) heated to 130-135°C for five hours. The mixture was stirred and heated at 160-165°C for sixteen hours. After cooling the mixture was poured into 5N hydrochloric acid (200 ml). The solution was washed with ether, basifiea with aqueous 15 sodium hydroxide solution and extracted with ether. The ether extract was washed with water, dried and hydrogen chloride gas was passed into the extract which was then evaporated to dryness. The residue was triturated with dry ether to give a solid which was recrystallised from 20 propan-2-ol to give N-l-[l-(3,4-dichlorophenyl)cyclobutyl] ethyl pyrrolidine hydrochloride (m.p. 233-235°C) (Formula I n = 0; R1 = Me; R2 = H; R^ and R^ together with the nitrogen to which they are attached form a pyrrolidine ring; R^ = 4-C1 and Rg = 3-Cl). 25 Example 19 l-(4-Chlorophenyl)-l-cyclobutane carboxylic acid (10.5 g) prepared as described in Example 13 was heated under reflux with thionyl chloride (20 ml)for 2% hours. Excess thionyl 30 chloride was evaporated off and the acid chloride of the above acid distilled (b.p. 82-96°/0.2 mm Hg). A solution of the acid chloride (23.0 g) in dry tetrahydrofuran (100 ml) was added slowly to the product of the reaction of magnesium turnings (3-0 g) and ethyl bromide 35 (12.0 g) in dry tetrahydrofuran at a temperature of -70 to - 44 - 2001 7 -60°C. The temperature was kept at -60°C for an hour and was then allowed to rise to 0°C. Water (50 ml) was added followed by 5N hydrochloric acid (150 ml) with cooling. The reaction mixture was extracted with ether, washed with water, sodium bicarbonate solution, dried. The solvent was removed by evaporation and 1-propionyl-l-(4-chlorophenyl)cyclobutane obtained by distillation (b.p. 96-104°C/0.25 mm) The ketone produced above was converted to N,N-dimethyl-1-[l-(4-chlorophenyl)cyclobutylpropylamine hydrochloride (m.p. 213-215°C) in a similar manner to that described in Example 12 (Formula I n = 0; R-j_ = Et; R2 = H; R3, R4 = Me; R5 = 4-C1; Rg = H). Example 20 l-Acetyl-l-(4-chlorophenyl)cyclobutane (61 g prepared in a similar manner to that described in Example 1 for 1-acetyl-l-(3,4-dichlorophenyl)cyclobutane., platinum oxide (0.75g), 33% solution of methylamine in ethanol (60 g) and ethanol (30 ml) were charged into an autoclave. The autoclave was filled with hydrogen and maintained at about 60°C and 20 bar pressure for ten hours. . The reaction mixture was filtered through charcoal and the solids 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 (50 ml). The aqueous layer was basified and extracted with ether. The ether extract yielded a liquid on evaporation which was distilled (109°C/0.3 mm Hg) to give N-methyl-1-[l-(4-chlorophenyl) cyclobutyljethylamine (Formula I n=0; R^ = Me; R2 = H; R3 = Me; R4 = H; R^ = 4-C1 and Rg = H). - 45 - *7 ^ / O / C'J;1 Example 21 Sodium borohydride (2.0 g) was added to solution of 1-[l-(3,4-dichlorophenyl )cyclobutylJethylamine (1.5 g prepared by treating the product of Example 1 with aqueous sodium hydroxide) in glacial acetic acid (30 ml). The mixture was heated at 95-100°C for sixteen hours and then cooled. Aqueous sodium hydroxide solution was added and the reaction mixture extracted with ether. The ether extract was shaken with 5N hydrochloric acid and the aqueous layer was washed with ether, basified and extracted with ether. Hydrogen chloride gas was passed into the ether extract which was evaporated to dryness. Trititration with acetone gave N-ethyl-1-[l-(3,4-dichlorophenyl)cyclobutylJethylamine hydrochloride (m.p. 211-212°C). (Formula I n = 0; R-^ = Me; R2 = H; R3 = Et; R^ = H; R5 = 4-C1 and Rg = 3-Cl. ) Example 22 A mixture of N-ethyl-l-[l-(3,4-dichlorophenyl) cyclobutylJethylamine (0.5 g prepared by treating the product of Example. 21 with aqueous sodium hydroxide) and acetic anhydride (1 ml) was heated at 40-45°C for thirty minutes. The reaction mixture was basified and extracted with ether. The ether extract was washed, dried and evaporated to give N-acetyl-N-ethyl-l-[1-(3»4-dichlorophenyl)cyclobutyl] ethylamine as an oil. This oil was dissolved in tetrahydrofuran (10 ml) and borane-dimethylsulphide complex (0.5 ml) added dropwise. The reaction mixture was stirred at room temperature for two hours and then heated to 35-40°C for thirty minutes. After cooling the reaction mixture was basified and extracted with ether. Hydrogen chloride gas was passed into the dried ether extract which was evaporated to dryness. Trituration with ether gave N,N-diethyl-l-[l-(3,4-dichlorophenyl )cyclobutylJethylamine hydrochloride (m.p. 199-201°C). (Formula I n = 0; = Me; R£ = H; R3, R^ = Et; R5 = 4-C1 and Rg = 3-Cl.) 2 0017n Example 23 A mixture of l-acetyl-l-(3,4-dichlorophenyl) cyclobutane (2.2 g) prepared as described in Example 1, ammonium acetate (7 g), sodium cyanoborohydride (0.4 g) and methanol (28 ml) was stirred at room temperature for four days. The reaction mixture was poured into a mixture of ice and water and the resulting mixture extracted with ether. The ether, extract was washed with water, dried and the ether removed to leave 1-[1-(3»4-dichlorophenyl) cyclobutylJethylamine as an oil which was identified by standard analytical techniques as the compound of Example 1 in the form of its free base. Example 24 A mixture of l-acetyl-l-(3♦4-dichlorophenyl)cyclobutane (4.86 g) prepared as described in Example 1, hydroxylamine hydrochloride (1.6 g), sodium acetate trihydrate (3.3 g), industrial methylated spirit (15 ml) and water (2 ml) was heated under reflux for twenty hours. The cooled reaction mixture was poured into water and the oil which separated was cooled to give a solid which was recrystallised from industrial methylated spirit to give l-acetyl-l-(3,4-dichlorophenyl)cyclobutane oxime (m.p. 120-121°C). A solution of the oxime prepared above (4.0 g) in ether (50 ml)-was added slowly to a stirred suspension of lithium aluminium hydride (0.9 g) in ether (50 ml) under nitrogen. The mixture was heated under reflux for one hour and, after cooling, water 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) added. The reaction mixture was stirred for one hour and then continuously extracted with ether during eighteen hours. The ether extract was dried and the ether removed to leave a solid from which l-[l-(3»4-dichlorophenyl)cyclobutyl] ethylamine was separated by high pressure liquid chromatography. The product was identified by standard ' 2 0017p analytical techniques as the compound of Example 1 in the form of its free base. Example 25 5 A 1M solution of diisobutylaliminohydride in hexane (200 ml) was added under nitrogen to a solution of 1-phenyl-l-cyclobutane carbonitrile (31.4 g) in ether (100 ml) at a temperature below -30°C. The temperature was- maintained below 0°C for thirty minutes and 5N 10 hydrochloric acid (200 ml) at a temperature of -10°C added. The reaction mixture was washed with petroleum ether (b.p. 60-80°C) and then warmed to 40°C. The reaction mixture was extracted with petroleum ether (b.p. 60-80°C) and the extract dried and evaporated to yield 15 1-phenyl-l-cyclobutane-carbaldehyde as an oil. Methylamine was bubbled through a solution of the aldehyde (9.4 g) prepared as above in toluene (100 ml) whilst the temperature of the reaction mixture was maintained below 0°C. Magnesium sulphate (20 g) which had 20 been dried over a flame and then cooled under nitrogen was ■ added to the reaction mixture which was left for sixteen hours at room temperature before being filtered. The toluene was then removed by evaporation and the residue dissolved in ether (50 ml). This solution was added to a solution of propyllithium prepared by slowly adding excess 25 propyl bromide (12.8 g) to a suspension of lithium (1.26 g) in ether (50 ml). The resulting mixture was left for sixteen hours at room temperature. A trace of unreacted lithium was removed by filtration and the filter washed with ether, water and then 5N hydrochloric acid. The 30 filtrate and washings were heated on a steam bath for one hour. After cooling the reaction mixture was washed with ether and the aqueous layer was basified using aqueous sodium hydroxide solution. The reaction mixture was extracted with ether and the extract dried and the ether 35 removed to give a residue from which N-methyl-1-(1-phenylcyclobutyl)butylamine (b.p. 80-86°/0.1 mm Hg.) - 48 - was distilled. The amine (2.3 g) prepared as described above was dissolved in ether (40 ml) and hydrogen chloride gas passed through the solution to precipitate N-methyl-1-(1-phenylcyclobutylJbutylamine hydrochloride (m.p. 196-197°C). (Formula I n = 0; Rx = propyl; R2 = H; R? = Me; R4, R5 and Rg are H. ) Example 26 A solution of 1~( 3-chloro-5-methylphenyl) -1-cyclobutane-carbonitrile (8.0 g) in ether (40 ml) was added to a solution of propyl magnesium bromide [prepared by the reaction of 1-bromopropane (6.7 g) and magnesium (1.3 g)] in ether (80 ml) and the mixture heated under reflux for two and a half hours. Two thirds of the ether was evaporated off and then, after cooling, a solution of sodium borohydride (3.5 g) in ethanol (150 ml) added. The mixture was maintained at 50°C for one hour and water (50 ml) and then 5N hydrochloric acid (50 ml) added. The ether layer was separated, dried and evaporated to yield a solid which was recrystallised from propan-2-ol to give 1- [ 1- ( 3-chloro-5-me thy lphenyl) cyclobutyl) butylamine hydrochloride (m.p. 145-146°C). The hydrochloride salt prepared as above was shaken with ether and 5N sodium hydroxide solution and the ether layer evaporated to give the primary amine which was • -converted into N, N-dimethyl-1-[l-(3-chloro-5-methylphenyl) cyclobutylJbutylamine hydrochloride (m.p. 148°C) (Formula I n = 0; R]_ = propyl; R2 = H; R^ and R^ = Me; R^ = 3-Cl and Rg - 5-Me) in a similar manner to that described in Example 2. - 49 - 2 001 7 Example 27 l-(4-Chlorophenyl)-l-cyclobutanecarbonitrile (37.6 g) prepared in a similar manner to the l-(3,4-dichlorophenyl)-1-cyclobutanecarbonitrile described in Example 1 was added to a solution of potassium hydroxide (32.4 g) in diethyle-neglycol(370 ml) and the mixture, heated under reflux for three and a half hours. The reaction mixture was poured into an ice/water mixture 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)-l-cyclobutanecarboxylic acid (m.p. 86° - 88°C) 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 aluminium hydride (2 g) in tetrahydrofuran (150 ml). The mixture was stirred under reflux for two hours and water added. The mixture was filtered through diatomaceous earth (CELITE - RTM) and the product extracted into ether. After washing with water and.drying, the ether was evaporated to give a residue which was recrystallised from petroleum ether (b.p. 60 -80°). The product was l-[l-(4-chlorophenyl)cyclobutyl]-methyl alcohol (m.p. 60 - 62°C). A solution of the alcohol prepared as described above (60 g) in pyridine (52 ml) was added dropwise to a solution of p-toluenesulphonylchloride (60 g) in pyridine (100 ml) cooled in ice. The temperature was allowed to rise to room temperature and remain there for eighteen hours. l-[l-(4-Chlorophenyl)cyclobutyl]methyl p-toluene sulphonate (m.p. 99 - 100°C) was precipitated by pouring the reaction mixture into a mixture of ice and concentrated hydrochloric acid (200 ml). - 50 - 2001 10 15 a solution of the sulphonate compound (97 g) prepared as described above and sodium cyanide (16.6 g) in dimethyl sulphoxide (370 ml) was heated on a steam bath for eighteen hours. The mixture was poured into water and extracted with ether. After washing and drying the ether was evaporated to leave a solid residue of 2-[l-(4-chlorophenyl)-cyclobutylJacetonitrile (m.p. 63 - 65°C). The acetonitrile prepared above (20 g) was dissolved in ether (120 ml) and the solution added dropwise under nitrogen to a stirred suspension of lithium aluminium hydride (5.84 g) in ether (80 ml). The mixture was stirred at ambient temperature for one and a half hours and then under reflux for a further two hours. Water was added dropwise and the resulting mixture filtered through diatomaceous earth. The residue was washed with ether. The filtrate was extracted with ether and the combined ether portions were washed with water and extracted with 5N hydrochloric acid. The acid solution was washed with ether and aqueous NaOH was added. The product was extracted into ether and the extract washed with water, dried and evaporated to give a residue which on distillation gave 2-[l-(4-chlorophenyl)cyclobutylJethylamine (b.p. 119 -121°/l.5 mm Hg). The ethylamine prepared as described above (6.9 g), 98% formic acid (6.6 ml), water (0.9 g) and 37 to 40% aqueous formaldehyde solution (9 ml) were heated on a steam bath f.or eighteen hours. The mixture was cooled and excess concentrated hydrochloric acid added. a yellow solid residue was obtained on evaporation to dryness. The solid was partitioned with dichloromethane and 5N sodium hydroxide solution and the aqueous layer extracted with a further 30 portion of dichloromethane. The dichloromethane portions were combined, washed with water, dried and evaporated to yield 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 recry-35 stallised from ethyl acetate to give colourless crystals of N,N-dimethyl-2-[l-(4-chlorophenyl)cyclobutylJethylamine 20 25 - 51 - 200! hydrochloride (m.p. 220-222°C) (Formula 1 n = 1; R2 = H; R^, R^ = Me; R^ = 4-C1; Rg, Ry and Rg = H). In a similar manner to that described above the following compounds were made 10 15 20 25 30 CH2CH2HMe2.HCl Example 27(a) 27(b) 27(c) R5 Cl i "6 Cl H m.p. of HC1 salt 218-220° 263-265° 234-236° -CH=CH - CH^CH^i —_ - 27(d) In a similar manner N,N-dimethyl-2-[l-(4-chloro-2-fluorophenyl)cyclobutyl]ethylamine hydrochloride (m.p. 232-233°C (dec)) was prepared. Example 28 2-[l-(4-Chlorophenyl)cyclobutylJethylamine (12 g) prepared as described in Example 27, 1,4-dibromobutane (12.4 g) and anhydrous sodium carbonate (14.3 g) were mixed in xylene (100 ml) and the mixture heated under reflux with stirring for sixteen hours. The mixture was cooled, filtered and the xylene removed by evaporation to give a residue which on distillation gave N-2-Ll-(4-chlorophenyl )cyclobutylJethylpyrrolidine (b.p. 148-150°/1.5 mm Hg)' (Formula 1 n = 1; Rl»R2 — H; R^ and R^ together with the nitrogen atom forming a pyrrolidine ring; R^ = 4-C1; Rg, Ry and Rg = H). In a similar manner to that described above the following compounds were made and isolated as their hydrochloride salts. ch2ch2n 35 .HC1 - 52 - f*\ 4 *■? ' -J v./ £ * Example 28 (a) 28(b) R R, 5 1V6 Cl Cl V-CM=CH-CH=CH-J \ m.p. of HC1 salt 213° 232-233° Example 29 A solution of 2-[l-(4-chlorophenyl)cyclobutyl]aceto-nitrile (30 g) prepared as described in Example 27 in ether 10 (100 ml) was added to the reaction product of methyl bromide gas and magnesium turnings (5.95 g) in ether (80 ml). The mixture was heated under reflux for four hours. Ice and then concentrated hydrochloric acid (105 ml) were added and the mixture heated under reflux until all solid material had 15 dissolved. The aqueous layer was washed with ether and the ether used for washing was combined with the ether phase of the reaction mixture. The combined ether extracts were washed with water, dried and evaporated to yield a residue which was distilled twice to yield l-[l-(4-chloro-20 phenyl)eyelobutyl]propan-2-one (b.p. 133-136°/2.5 mm Hg). The ketone prepared as described above (5.4 g) was mixed with N-methylformamide (18 ml), 98% formic acid (4 ml) and 25% aqueous methylamine (0.6 ml) and the mixture heated under reflux for sixteen hours. The mixture was 25 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 six hours. The mixture was evaporated to dryness and the residue dried by repeated addition and 3q vacuum evaporation of an industrial methylated spirit/ toluene mixture. The solid residue was recrystallised from propan-2-ol to give N-methyl-2-[l-(4-chlorophenyl)-cyclobutyl]-l-methylethylamine hydrochloride (m.p. 193-194°C) (Formula I n = 1 R1, R2 = H; = Me; R^ = H; R5 = 4-C1; R6 = H; R? = Me; RQ = H). - 53 - "'17 s 10 15 Example 30 A mixture of l-[l-(4-chlorophenyl)cyclobutyl]propan-2-one prepared as described in 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 ten hours. The mixture was cooled, diluted with water and extracted with dichloromethane. The extract was washed, dried and evaporated to yield a yellow oil which was hydrolysed with concentrated hydrochloric acid under reflux. The resulting aqueous solution after dilution with water was washed with ether, aqueous NaOH was added and the aqueous solution extracted with ether. The extracts were washed, dried and evaporated to yield a residue which on distillation gave 2-[l-(4-chlorophenyl )cyclobutyl]-l-methylethylamine (b.p. 105-107°/0.7 mm Hg). The amine obtained above (2.65 g) was dissolved in propan-2-ol (15 ml) and concentrated hydrochloric acid added dropwise until the pH was 2. Ether (110 ml) was added and colourless crystals of 2-[l-(4-chlorophenyl)-20 cyclobutyl]-l-methylethylamine hydrochloride (m.p. 184-185°C) were collected. (Formula I n = 1; R^, R2 = H; R^, R^ = H; R^ = 4-C1; Rg = H; Ry = Me and Rg = H). Example 31 25 2-[l-(4-Chlorophenyl)cyclobutyl]-l-methylethylamine (3.94 g) prepared as described in Example 30, 1,4-dibromo-butane (3.82 g), anhydrous sodium carbonate (4.4 g) and xylene (30 ml) were mixed and heated under reflux for sixteen hours. The mixture was cooled, filtered and evaporated to yield a residue which was distilled twice (b.p. 130-132°/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 added to pH 2. The solution was evaporated in vacuo and the residue recrystallised from ethyl acetate to give N-^2-[l-(4-chlorophenyl)cyclobutyl]-^ 1-methyl^ethylpyrrolidine hydrochloride (m.p. 151-152°C) 30 2C01 78 - 54 - 10 15 20 25 30 (Formula I n=l; R-^F^K; R^ and R^ together with the nitrogen atom forming a pyrrolidine ring; R^ = 4-C1; R6 = H; Ry = Me; RQ = H). Example 32 1- [l-(4-Chlorophenyl )cyclobutyl]propan-2-one prepared as described in Example 29 (25 g) and 98% formic acid (10 ml) were added to formamide (22 ml) at 160°C. The temperature was raised to 175°C and maintained at this temperature for sixteen hours. The mixture was cooled, extracted with dichloromethane. The extract was washed with water and evaporated to give a gum which was crystallised from petroleum ether (b.p. 40-60°C) to give N-formyl-2-[l-(4-chlorophenyl)cyclobutyl]-l-methylethylamine (m.p. 71-73°C). N-Formyl-2- Cl- (4-chlorophenyl )cyclobutyl ]-l-methyl~ ethylamine (11.06 g) prepared as described above was heated under reflux for six hours with a mixture of concentrated hydrochloric acid (34 ml), water (34 ml) and diethylene-glycoldimethyl ether (40 ml). The mixture was cooled, washed with ether and basified with aqueous sodium hydroxide. The basified solution was extracted into ether, washed v/ith water, dried, evaporated and distilled to give 2—[l—(4— chlorophenyl)cyclobutyl3-1-methylethylamine (b.p. 119-121°C at 0.8 mm Hg).The amine (2.65 g) was dissolved in propan-2-ol (15 ml) and concentrated hydrochloric acid added to pH 2. Ether (110 ml) was added and crystals of 2-[l-(4-chlorophenyl) cyclobutyl]-l-methylethylamine hydrochloride (m.p. 184-185°C) were collected. (Formula I n = 1; R-. R5 = 4-C1; R6 = H; Ry = Me and Rg = H. ) R2 = H; R 3' 4 R. = K; Example 33 2- [l- (4-Chlorophenyl )cyclobutyl ]-l-methylethyl amine (1.8 g) prepared as described in Example 32 was mixed with formic acid (4.5 ml). 37 to 40% Aqueous formaldehyde solution (6 ,ml) was added and the mixture heated first at 45-50°C for 30 minutes and then under reflux for two hours. The mixture was cooled, basified with aqueous ^odium hydroxide, extracted with ether, the ether extract as washed with water and extracted with 5N hydrochloric acid. The acid extract was washed with ether, basified 10 15 20 - 55 - ; '! i with aqueous sodium hydroxide, and extracted with ether. Hydrogen-chloride gas was passed through the ether extract and a white solid was formed. The solid was collected and recrystallised from ethyl acetate to give N,N-dimethyl-2-[l-(4-chlorophenyl)cyclobutyl]-l-methylethylamine hydrochloride (m.p. l08-110°C) (Formula I n = 1; R^, = H; L3, R4 = Me; R5 = 4-C1; Rg = H; Ry = Me; Rg = H). R Example 34 A 70% solution of sodium bis(2-methoxyethoxy) aluminium hydride' in toluene (sold under the trade mark Red-al)(35 mi) was added dropwise to a solution of n-formyl-2-[l-(4-chlorophenyl)cyclobutyl]-l-methylethylamine prepared as described in Example 32 (5 g) in dry ether (110 ml) with cooling to maintain the temperature at less than 10°C. The temperature was allowed to rise to about 25°C and then the mixture was heated under reflux for two hours. The reaction mixture was poured into a mixture of crushed ice and concentrated hydrochloric acid. The resulting mixture was washed with ether, basified with aqueous 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 solution to precipitate a solid which was recrystallised from propan-2-ol to give N-methyl-2-[l-(4-chlorophenyl)cyclobutyl]-l-methylethylamine hydrochloride (Formula I n = 1; R^, R2 = H; R^ = H; R^ = Me; 25 R5 = 4-C1; Rg = H; Ry = Me and RQ = H) (m.p. 192-194°C). Example 35 A solution in ether (80 ml) of 2-[l-(3,4-dichloro- . phenyl)cyclobutyl]acetonitrile (23 g) prepared in a similar manner to that described in Example 27 for 2-[l-(4-chlorophenyl )cyclobutyl]acetonitrile was added to the product of the reaction between magnesium turnings (3.53 g) and ethyl bromide (10.8 ml) in dry ether (80 ml) with stirring whilst heating on a steam bath. The ether was removed and replaced 35 with toluene and the' mixture heated under reflux ^ * T - 56 - for one hour. Water was added and the mixture added to a mixture of ice and concentrated hydrochloric acid. The mixture was heated on a steam bath for one hour and filtered through a diatomaceous earth sold under the ^ Registered Trade Mark CELITE. The filtrate was extracted with dichloromethane and the extract washed with water and sodium bicarbonate solution and dried. The solvent was removed by evaporation and the residue distilled to give l-[l-(3,4-dichlorophenyl )cyclobutyl]butan-2-one (b.p. 149-150°/1.1 mm Hg). The ketone prepared as above was converted into l-^[ 1-(3»4-dichlorophenyl )cyclobutyl]methyl^propylamine hydrochloride (m.p. 225-226°C) (Formula I n = 1; R^, R2, R3,.R4 = H; R5 = 4-C1; Rg = 3-Cl; R? = Et; RQ = H) in a similar manner to that described in Example 32. 15 In a similar manner to that described above 2-[l-(3>4- dichlorophenyl)cyclobutyl]-l-methylethylamine hydrochloride (m.p. 179°C) (Example 35a Formula I n = 1; R^, R2, R^ and R^ = H; R^ = 4-C1; Rg = 3-Cl; FU, = Me and RQ = H) was prepared. 20 Example 36 In a similar manner to that described in Example 33 compounds prepared in a similar manner to that described in Example 35 were converted into the corresponding N,N-dimethyl compounds. 25 35 • - 57 - 2 00 Example Starting Material R5 R6 a? m.p. • .36(a) ■35 Cl Cl Et 177-178° 36(b) 35Jt a) Cl Cl Me 204-205° 10 Example .37 In a similar manner to that described in Example 34, N-formyl compounds prepared as described in Example 32 from ketones prepared as in Example 35 were converted into the corresponding N-methyl compounds. 15 20 CH2CHR7NHMe.HCl Example R5 R6 Ry m.p. 37(a) Cl H Et 170-172° 37 (b) Cl Cl Et 193-194° 25 30 35 Example 38 A mixture of 2-[1—(4-chlorophenyl )cyclobutyl]aceto-nitrile (10.1 g) prepared as described in Example 27 » potassium hydroxide (8.1 g) and diethyleneglycol (92 ml) was heated under reflux for three and a half hours. The mixture was poured into an ice/water mixture and the resulting solution washed three times with ether and added to a mixture of ice and concentrated hydrochloric acid. On cooling a solid product separated which was recrystallised from petroleum ether (b.p. 62-68°C) with the use of charcoal. The recrystallised product was 2-[l-(4-chlorophenyl)-cyclobutyl]acetic acid (m.p. 83-84°C). 2 001 10 30 - 58 - £UU f / The acid (5 g) prepared as described above was added to thionyl chloride (20 ml) and heated under reflux for one hour. Excess thionyl chloride was then removed and the residue poured into a solution of piperidine (3.8 g) in ether (20 ml). The mixture was stirred for thirty minutes and then water was added to dissolve piperidine hydrochloride. The ether layer was separated and the aqueous layer washed with ether. The combined ether portions were washed with water, dried and evaporated to yield a brown oil which was purified by distillation (b.p. 168°/1 mm Hg) and crystallisation from petroleum ether (b.p. 40-60°C). The solid product was N~2-[l-(4-chlorophenyl)cyclobutyl]-acetylpiperidine (m.p. 66-67°C). a solution of the compound prepared as described above (2.7 g) in ether (20 ml) was added dropwise to a stirred mixture of lithium aluminium hydride (0.7 g)and ether under a nitrogen atmosphere. Stirring was continued for one hour at room temperature and then during heating under reflux for two hours. After cooling in ice, excess lithium aluminium hydride was decomposed by the addition of water. 2q The mixture was filtered through diatomaceous earth (CELITE). The aqueous portion of the filtrate was washed with a portion of ether and this portion was combined with ether portions which had been used to wash the solid residue. The combined ether portions were washed with water, dried and evaporated. The residue was purified by distillation. The 25 product was N-2-[l-(4-chlorophenyl)cyclobutyl]ethy3piperi-dine (b.p. 152-156°/1.5 mm Hg) (Formula n = 1; R^, R2 = H; R^ and R^ together with the nitrogen atom forming a piperidine ring; R^ = 4-C1; Rg, Ry and Rg = H). In a similar manner to that described above the following compounds were made and isolated as their hydrochloride salts by bubbling dry hydrogen chloride gas through a solution of the base in petroleum ether (b.p. 62-68°C). - 59 - 200178 10 15 20 25 30 CH2CH2NR3R4.HC1 Example 38 (a) 38(b) 38(c) Rr Cl Cl Cl R, H H H nr3r4 -lOj-Me \—I -O m.p.(°C) 167-169° 281-283° (dec) 246-248° 35 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 jD-toluenesulphonylmethyl iso-cyanide which is sold under the trade name TosMIC (24.6 g) in dimethylformamide (50 ml) was added over twenty minutes. Absolute alcohol (18 g) was then added to the mixture at 0°C over a period of one hour. 1-Acetyl-l-(4-chlorophenyl)-cyclobutane (24 g) prepared in a similar manner to that described in Example 1 for 1-acetyl-l-(3,4-dichlorophenyl)-cyclobutane dissolved in dry dimethylformamide (20 ml) was added and the mixture was stirred for sixteen hours during which the temperature rose to ambient 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 adjusted to 6 by the addition of 5N hydrochloric acid. The resulting mixture was extracted with ether and the ether extract washed with water, dried and partially evaporated. A brown solid separated and was removed by filtration and the filtrate was evaporated and 2-[l-(4-chlorophenyl)cyclobutyl]propionitrile (b.p. 128-136°/0.6 mm) collected by distillation. 10 20017£ - 60 - a solution of the propionitrile prepared as described above (3.5 g) in dry ether (20 ml) was added dropwise to a stirred mixture of lithium aluminium hydride (0.9 g) in dry ether (20 ml) at a temperature in the range 15 to 20°C. The mixture was stirred at ambient temperature for two hours and then during heating under reflux for a further three hours. 5N Sodium hydroxide solution (20 ml) and water (50 ml) were added and the mixture filtered through diatomaceous earth (CELITE). The filter medium was washed with ether and the washings combined with the ether of the reaction mixture. The combined extracts were extracted with 5N hydrochloric acid. A solid formed at the interface which was collected by filtration, washed with acetone and dried. The solid was 2-[l-(4-chlorophenyl)cyclobutyl]-propylamine hydrochloride (m.p. 210-230°C). ^ The hydrochloride salt (1.0 g) prepared as above was dissolved in water, 5N aqueous sodium hydroxide solution was added and the solution extracted with ether. The ether extract was dried and evaporated to yield an oil which was heated under reflux for six hours with 1,4-dibro-2q mobutane (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) added. The mixture was evaporated to dryness and the residue collected, washed with 25 ether and dried. The product was N-2-[l-(4-chlorophenyl)-cyclobutylJpropylpyrrolidine hydrochloride (m.p. 238-248°C) (Formula I n = 1; R-^ = Me; R2 = H; R^ and R^ together with the nitrogen to which they are attached forming a pyrrolidine ring; R^ = 4-C1; Rg, R„ and RQ = H). 30 2 o f a 35 - 61 - 2001 7 8 Example 40 A solution of l-(3>4-dichlorophenyl)-l-cyclobutane carbonitrile (70 g) prepared in a similar manner to that 5 described in Example 1 in industrial methylated spirit (200 ml) was mixed with a solution of sodium hydroxide (3.7 g) in water (5 ml) and 30% hydrogen peroxide solution added dropwise. The mixture was heated at 50°C for one hour and then stirred with 10% palladium on charcoal (0.5 g) for one hour. The mixture was filtered and evaporated to 20 dryness to give 1-(3,4-dichlorophenyl)-l-cyclobutane-carboxamide. 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) 15 were added dropwise. The mixture was heated at 85 to 95°C for sixteen hours and then poured into water. The mixture was extracted with ether and the extract back-extracted with aqueous -potassium carbonate. The basic extract was washed with ether and acidified with concentrated 20 hydrochloric acid to give 1-(3,4-dichlorophenyl)-l-cyclobutanecarboxylic acid (m.p. 120-121°C). The acid prepared as above was converted into the compound of Example 27(a) in a similar manner to that described in Example 27 and to the compound of Example 28(a) in a similar manner to that described in Example 28. 25 Example 41 A solution of 2-[l-(3,4-dichlorophenyl)cyclobutyl]-acetonitrile (23 g prepared in a similar manner to 2-3q [l-(4-chlorophenyl)cyclobutyl]acetonitrile described in Example27)in dry ether (50 ml) was added to a solution of ethyl magnesium bromide prepared by the dropwise addition of ethyl bromide (15.83 g) in dry ether (80 ml) to a stirred mixture of magnesium turnings (3.53 g) and ether (80 ml). The mixture was heated under reflux for ^ 30 minutes and stirred without further heating for 16 hours and then under reflux for a further two hours. 10 25 200178 - .62 - 1-[l-(3,4-Dichlorophenyl )cyclobutyl ]-2-butaniminyl magnesium 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 diethyleneglycoldimethyl ether (30 ml). The mixture was stirred at 45°C for 90 minutes. The reaction mixture was extracted with 5N hydrochloric acid. The aqueous phase was basified with aqueous sodium hydroxide solution and extracted with ether. The ether extract was dried and hydrogen chloride gas passed into the extract to precipitate 1-^[l-(3» 4-dichlorophenyl)cyclobutyl]methylj -propylamine hydrochloride (m.p. 223-224°C) (Formula I n = 1; R1, R2, R3 and R4 = H; R^ = 4-C1; Rg = 3-Cl; R? = Et; RQ = H). Example 42 Formic acid (7 ml) was added dropwise to pyrrolidine 15 (15 ml) at a temperature in the range 135-140°C. l-[l-(3,4-Dichlorophenyl)cyclobutyl]butan-2-one (3 g) prepared as described in Example 35 was added dropwise and the mixture heated at 140°C for one hour. The temperature was raised to 185-190°C for sixteen hours. The reaction mixture was 20 cooled and poured into 5N hydrochloric acid. The solution was washed with ether, basified and extracted with ether. The ether extract was dried and hydrogen chloride gas passed into the extract. Evaporation to dryness gave a solid which was triturated with dry ether and recrystallised from a mixture of petroleum ether and propan-2-ol to give N-l-|^[l-(3,4-dichlorophenyl )cyclobutyl Jmethyl^propylpyrrolidine hydrochloride (m.p. 157-160°C) (Formula I n = 1; R^f R2 = H;. R^ and R^ together with the nitrogen atom forming a pyrrolidine ring; R5 = 4-C1; Rg = 3-Cl; Ry = Et and RQ = H). 30 - 63 - 2 C 0 1 7 3 Example 43 1- tl- (3 ,4-D ichlorophenyl )cyclobutyl ]-2-butani-minyl magnesium bromide (25 g) prepared as described in Example 41 was 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 dried and evaporated to dryness. l-[l-(3,4- Dichlorophenyl)cyclobutyl]butan-2-one (b.p. 122-124° at 0.1 mm Hg) was distilled. 10 A mixture of 1-[l-(3,4-dichlorophenyl)cyclobutyl]butan- 2-one (4.3 g) prepared as described above, hydroxylamine sulphate (2.65 g), sodium acetate (4.0 g), industrial methylated spirit (56 ml) and water (23 ml) was stirred at ambient temperature for sixteen hours. The reaction mixture was 15 extracted with ether. The ether extract'was washed with water, dried and evaporated to give a solid which was recrystallised from petroleum ether (b.p. 80-100°C) to give 1-[l-(3,4-dichlorophenyl)cyclobutyl]butan-2-one oxime (m.p. 106-110°C). 20 , A solution of trifluoroacetic acid (2.33 ml) in tetrahydrofuran (5 ml) was added to a stirred suspension of sodium borohydride (1.13 g) in tetrahydrofuran (30 ml) over a period of five minutes. A solution of the oxime (1.7 g) prepared as described above in tetrahydrofuran (25 ml) was added dropwise and the mixture heated under reflux for six hours. The mixture was cooled and water (25 ml) ana then 5N sodium hydroxide solution (25 ml)vere added. The mixture was extracted with ether and the extract washed with water, dried and evaporated to give a residue which was dissolved in 30 petroleum ether (25 ml). Dry hydrogen chloride gas was passed through the ether solution to give 1- 4-dichlorophenyl) cyclobutylImethyl^propylamine hydrochloride (m.p. 222-224°C). (Formula I n = 1; R-^, &2> ^3 ^4 = R5 = 4-C1; Rg = 3-Cl; R^ = Et and R„ = H). 35 - 64 - Vv > ^ a J i 7 10 Example 44 A solution of l-[l-(3,4-dichlorophenyl )cyclobutyl] butan-2-one (5.0 g) prepared as described in Example 43 and methoxy-amine hydrochloride (l.63.g) in a mixture of pyridine (60 ml) and ethanol (60 ml) was heated under reflux for 72 hours. The reaction mixture was evaporated to dryness and a mixture of water and ether added to the residue. The ether layer was washed with sodium bicarbonate solution and water, dried and evaporated to give l-[l-(3>4-dichlorophenyl)cyclobutyl]butan-2-one oxime 0-methyl ether. The oxime ether prepared as described above (15 g) was then reduced to the product of Example 43 using sodium borohydride (0.95 g) in a similar manner to that described in Example 43* 15 Example 45 Sodium cyanoborohydride (0.4 g) was added to a solution of l-[l-(3,4-dichlorophenyl )cyclobutyl]butan-2-one (2.45 g) prepared as described in Example 42. and ammonium acetate (7 g) in methanol (28 ml) and the mixture stirred at room temperature for four days. Water (25 ml) was added dropwise with cooling. The aqueous mixture was extracted with ether and the ether layer washed with water and 5N hydrochloric acid (50 ml). The compound of Example 43 precipitated as a white solid. ^ Example 46 2-[l-(4-Chlorophenyl)cyclobutyl]acetic acid (1.5 g prepared as described in Example 38 ) was heated under reflux with thionyl chloride. Excess thionyl chloride was removed in vacuo and the residue added dropwise to a solution of cyclopropylamine (0.94 g) in ether (10 ml) and the mixture stirred for thirty minutes. Water was added and the aqueous phase extracted with ether. The ether extract was dried and the ether removed to give 2-[l-(4-chlorophenyl)cyclobutyl]-N-cyclopropylacetamide. 35 20 30 2G01 - 65 - A solution of the amide prepared as above (1.45 g) in ether (15 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (0.42 g) in ether (7.5 ml) under nitrogen. The mixture was stirred at ambient temperature for one hour and then heated under reflux for a further two hours. After cooling, water (0.45 ml), then 15% sodium hydroxide solution (0.45 ml) and then water (1.35 ml) were added and the mixture stirred for fifteen 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-[l-(4-chlorophenyl)cyclobutylJethylamine hydrochloride (m.p. 166-170°C). A mixture of the hydrochloride salt (0.41 g) prepared as described above, sodium formate (0.1 g), 98% formic acid (l ml) and 37-40% aqueous formaldehyde solution (0.5 ml) was . heated at 85-90°C for eighteen 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 warmed to give a solid which was N-cyclopropyl-N-methyl-2-[1-(4-chlorophenyl)cyclobutyl]ethylamine hydrochloride (m.p. 149-153°C). (Formula I n = 1; and R2 = H; = cyclopropyl; R^ = Me; R^ = 4-C1; Rg, Ry and Rg = H). Example 47 Pharmaceutical compositions containing any one of the compounds of formula I disclosed in Examples 1 to 46 are prepared in the following manner. - 66 - Example '^7 (a ) Tablets are prepared from the following ingredients: - Parts by Weight 5 Active Ingredient 50.0 Lactose 78.5 Polyvinylpyrrolidone 5.0 Maize Starch 15.0 Magnesium Stearate 1.5 10 The active ingredient, the lactose and some of the starch are mixed and granulated with a solution of the polyvinylpyrrolidone in ethanol. The granulate is mixed with the magnesium stearate and the rest of the starch and the mixture is compressed in a tabletting machine to give 15 tablets containing 50.0 mg. of the active ingredient. Example ^(b) Capsules are prepared in the following way. A mixture of the active ingredient (45 parts by weight) and lactose powder (205 parts by weight) is 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) are given a thin coat of shellac varnish, followed by 20 coats of cellulose acetate phthalate in a manner well known in the art. In a similar manner the capsules of Example 47-(b) may be 30 provided with an enteric coating. Example 47(d) Vials containing a solution of water—soluble compounds of the present invention suitable for injection are prepa-35 red from the following ingredients: 20 1AR1934 2001 7 O - 67 - Active Ingredient 1100 g. Mannitol 1100 g. Water, freshly distilled to 11 litres 5 The active ingredient and mannitol are dissolved in some of the water and the volume of the solution is adjusted to 11 litres. The resulting solution is sterilised by filtration and filled into sterile vials each containing 1.65 ml. of solution. Example 47 Ce) In the preparation of suppositories, 100 parts by weight of the finely ground active ingredient is incorporated in 1214 parts by weight of triglyceride suppository base and the mixture is formed into suppositories each containing 15 100 mg. of the active ingredient. In the preceding Examples novel ketones of formula V have been disclosed in which R^, R^ and Rg 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), 20 10(bb), ll(i), ll(k) and 11(1). These novel ketones of formula V are prepared by hydrolysis of novel imines of formula XVI in which Y = MgBr and R^, R^ and Rg have the meaning given in the Examples specified above. In the preceding Examples novel ketones of formula VI 25 have been disclosed in which R^, R2, R^, Rg and Ry have the meaning given in Examples 29, 35, 36 and 43. These • novel ketones of formula VI were prepared by hydrolysis of novel imines of formula XVIII in which Y = MgBr and Rl* R2* R5' R6 ^7 kave the meaning given in Examples 30 29, 35, 36 and 43. In the preceding Examples novel cyano compounds of formula XVII are disclosed in which R^ and Rg have the meaning given in Examples 1, 1(d), 1(e), 4(g), 9(e), 9(m), 10(k), 10(e), 10(p), 10(r), 10(v), 10(y), 10(z), 10(aa), 35 10(bb), ll(k), 11(1) and 26. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> - 68 - In the preceding Examples novel formamides of formula XXV are disclosed in which R^, R^, R^, Rg, Ry, RQ and n 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), ll(i), ll(k), 11(1), 29, 32, 35 and 36. 69 2 C 0 1 7 3 WHAT WE CLAIM IS: 1) A compound of formula I R, '5 CR1R2(CR7R8)nNR3R4 I in which n = 0 or 1; in which, when n = 0, R1 is a straight or branched chain alkyl group containing 1 to 6 carbon atoms, a cycloalkyl group containing 3 to 7 carbon atoms, a cycloalkylalkyl group in which the cycloalkyl group contains 3 to 6 carbons and the alkyl group contains 1 to 3 carbon atoms, an alkenyl group or an alkynyl group containing 2 to 6 carbon atoms or a group of formula II H, halo or an alkoxy group containing 1 to 3 carbon atoms; in which, when n = 1, R-^ is H or an alkyl group containing 1 to 3 carbon atoms; in which R2 is H or an alkyl group containing 1 to 3 carbon atoms; in which R^ and R^, which are the same or different, are H, a straight or branched chain alkyl group containing 1 to 4 carbon atoms, an alkenyl group having 3 to 6 carbon atoms, an alkynyl group having 3 to 6 carbon atoms, a cycloalkyl group in which the ring contains 3 to 7 carbon atoms, -CHO or and together with the nitrogen atoms to which they are attached form (a) a heterocyclic ring containing one nitrogen atom and 4 or 5 carbon atoms which is optionally substituted by one or more methyl groups (b) a heterocyclic ring containing a second nitrogen atom which is optionally methylated and 3 or 4 carbon atoms or (c) a heterocyclic ring containing one nitrogen atom and 3 or 4 carbon atoms and one or more double bonds,- II in which Rg and R10» which are the same or different, are 10 30 200178 - 70 - in which and Rg» which are the same or different, are H, halo, trifluoromethyl, an alkyl group containing 1 to 3 carbon atoms, an alkoxy or alkylthio group containing 1 to 3 carbon atoms, phenyl or R^ and Rg, together with the carbon atoms to which they are attached, form a second benzene ring optionally substituted by one or more halo groups, an alkyl or alkoxy group containing 1 to 4 carbon atoms or the substi-tuents of the second benzene ring together with the two carbon atoms to which they are attached form a further benzene ring; and in which Ry and Rg which are the same or different are H or an alkyl group containing 1 to 3 carbon atoms; and their pharmaceutically acceptable salts. 2) a compound of formula I as claimed in claim 1 in which n = 0, R^ is a straight or branched chain alkyl group containing 1 to 4 carbon atoms, a cycloalkyl group containing 3 to 7 carbon atoms, a cycloalkylmethyl group in which the cycloalkyl ring contains 3Ato 6 carbon, atoms or a group of formula II ijp which and R^q which are the same or different are H, fluoro or methoxy and in which R^- *s H .or methyl. 3) A compound of formula I as.claimed in claim 2 in which R^ is methyl, ethyl, propyl, isopropyl. "butyl, isobutyl, secondary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, eycloheptyl, cyclopropylmethyl, cyclobutylmethyl, 25 cyclopentylmethyl, cyclohexylmethyl or phenyl. *0 A compound formula I as claimed in claim 1 in which n = 1, R^ is H or methyl and R2 is H. 5) A compound of formula I as claimed in any one of the preceding claims in which R^ and R^ are H, methyl, ethyl or formyl. 35 200173 - 71 - 6) A compound of formula I as claimed in claim 1 in which Rc- and Rg are H, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy, phenyl or R,. and R^ together with the carbon atoms to which they are attached form a second benzene ring optionally substituted by one or more halo groups. 7) A compound of formula I as claimed in any one of claims 1, 4, 5 or 6 in which R_ is H, methyl or ethyl and Rfi is H. 8 ) a compound as claimed in claim 1 of formula III defined "in claim 1. 9) A compound as claimed in claim 8 in which and Rg, which are "the same or different, are H, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy, phenyl or R^ and Rg together with the carbon atoms to which they are attached form a second benzene ring optionally substituted by a chloro group. 10 15 20 25 200178 - 72. - 10-) a compound as claimed in claim 1 of formula IV CR1R2 (CR7R8 ^^^4 IV in which R-^, R^, R^, R^, R^, Ry, Rg and n are as defined in claim 1 and Rg is fluoro or methyl. ll) a compound of formula IV as claimed in claim 10 in which R^ is H, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy or phenyl and in which Rg is fluoro or methyl. 12 ) a compound formula I named in Table I herein. 13 ) A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I claimed in any one of the preceding claims. 14 ) a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula III claimed in claim 8 or claim 9. 15) A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula IV claimed in claim 10 or claim H- 30 16) a pharmaceutical composition as claimed in any one of claims 13, 14 or 15 in unit dosage form. 17) A pharmaceutical composition comprising a therapeutically active amount of a compound claimed in claim 12. 35 . . V" 200178 - 73 - 18) A process for the preparation of compounds of formula I as claimed in claim 1 comprising the reductive amidatlon of ketones of formula V cor, Rs by reaction with ammonium formate and formic acid or with an amide of formula HNR3R4 wherein R3 is H, alkyl or cycloalkyl and R4 is CHO and formic acid to give compounds In which n = 0; R2 =H; R3 is H, alkyl or cycloalkyl; R4 = CHO and R-|, R5 and Rg are as defined in claim 1 or of ketones or aldehydes of formula VI cr1r2cor7 71 by reaction with ammonium formate and formic acid or with an amide of formula HNR3R4 wherein R3 is H, alkyl or cycloalkyl and R4 is CHO and formic acid to give compounds in which n =1; R3 is H, alkyl or cycloalkyl; R4 = CHO, Rg = H and R], R2, R5, Rg and R7 are as defined in claim 1. 19) A process for the preparation of compounds of formula I as claimed in claim 1 comprising reductive amination of ketones of formula V by reaction with an amine of formula HN(R3>-R4 wherein R3 and R4 are as defined in claim 1 excluding CHO and a reducing agent to give compounds In which n = 0; R2 = H and R1, R5 and Rg are as defined in claim 1 or of ketones or aldehydes of formula VI cr1r2cor7 VI by reaction with an amine of formula HN(R3)-R4 wherein R3 and R4 are as defYned in claim 1 excluding CHO and a reducing agent to give compounds in which n = 1; Rg = H and R^, R2, R5, Rg and R7 are as defined In claim 1, provided that In the compounds of formula I produced by reductive amination, R3 and R4 cannot be CHO. - 74 - 200178 20) A process for the preparation of compounds of formula I as claimed in claim 1 comprising the reduction of compounds of formula VII In wh ich a) Z is a group of formula -CR-|=N0H or an ester or ether thereof to give compounds of formula I In which n = 0 and R2, R3 and R4 are H; b) Z is a group of formula -CR-|=NR3 (where R3 is other than H or CHO) to give compounds of formula I In which n = 0 and R2 and R4 are H; c) Z Is a group of formula -CR-|=NY In which Y represents a metal-containing moiety derived from an organometallic reagent to give compounds of formula I in which n = 0 and R2, R3 and R4 are H; d) Z is a group of formula —CR-j R2CN to give compounds of formula I in which n = 1 and R3, R4, R7 and Rg are H; e) Z is a group of formula -CR1 R2CRy=N0H or an ester or ether thereof to give compounds of formula I in which n = 1 and R3, R4 and Rg are H; f) Z Is a group of formula -CR-] R2CRy=NR3 (where R3 is other than H or CHO) to give compounds of formula I in which n = 1 and R4 and Rg are H; g) Z is a group of formula -CR-]R2CR7=NY In which Y represents a metal-contain i ng moiety derived from an organorneta! I ic reagent to give compounds of formula I in which n = 1 and R3, R4 and Rg are H; h) Z Is a group of formula -CR-|R2CONR3R4 to give compounds of formula I In which n = 1 and R7 and Rg are H. 21) A process as claimed In claim 20 in which Y is MgBr or Li. 22) A process for the preparation of compounds of formula I as claimed in claim 1 where R2 and R4 are H comprising: (a) the reaction of an organometallic reagent containing a group R^ which VII Is def Ined in claim 1 with an Imine of formul a VI I I R, 3 VIII in which R3, R5 and Rg are as defined In claim 1, and (b) the hydrolysis of the resulting product to give compounds of formula I In whIch n = 0. 2G0178 - 75 23) A process as claimed in claim 22 to give compounds of formula I in which n = 0 in which the organometallic reagent Is a Grignard reagent of formlua R^MgBr or an organolithium compound of formula R-j L i, in which is as defIned In claim 1. 24) A process for the preparation of compounds of formula I as claimed in claim 1 where R4 and Rg are H comprising: (a) the reaction of an organometallic reagent containing a group R7 which Is as defined in claim 1 with an Imlne of formula IX In which Rj, R2, R3, R5 and Rg are as defined In claim 1, and (b) the hydrolysis of the resulting product to give compounds of formula I in whIch n = 1. 25) A process as claimed in claim 24 In which the organometallic reagent Is a Grignard reagent of formula RyMgBr or an organolithium compound of formula R7U, in which R7 is as defined in claim 1. 26) A process for the preparation of compounds of formula I as claimed In claim 1 where R3 and R4 are H comprising the decarboxylatlve rearrangement of (a) amides of formula X R, I In which R-], R2, R5 and Rg are as defined in claim 1, followed by hydrolysis to give amines in which n = 0 (b) | am Ides of formula XI 1 R. XI In which R1, R2, R5, R6» R7 and Rg are as defined In claim 1, followed by hycfro'f'ysls to give amines In which n = 1 200173 - 76 - (c) acyl azides formed by reaction of sodium azide with acid chlorides of formula XII 10 15 25 30 «6 CR^COCl XII in which Rlf R2, R5 and R6 are as defined in claim 1, followed by hydrolysis to give amines in which n = O, or (d) acyl azides formed by reacting sodium azide with acid chlorides of formula XIII /' u « .. XIII in which R^, R2, R5, Rq, R7 and Rg are as defined in claim 1, followed by hydrolysis to give amines in which n = 1. 27) A process for the preparation of compounds of formula I as claimed in claim 1 where R3 and R4 are H comprising the reaction of hydrazoic acid with (a) carboxylic acids of formula XIV CR^COOH XIV in which Rlr R2, R5 and Rg are as defined in claim 1, followed by hydrolysis to give amines in which n = O or (b) carboxylic acids of formula XV CR^CR^gCOOH XV in which Rlf R2, R5, Rg<• R7 and Rg are as defined in claim 1, followed by hydrolysis to give amines in which n = 1. 28) A process for the preparation of canpounds of forma la I as claimed in claim 1 in vfoich R4 is H comprising the hydrolysis of canpounds of formal I in which is CHO. and R^ is other than CHO. la - 77 - 200173 29) A process for the preparation of compounds of formula I as claimed in claim 1 in which is methyl comprising the reduction of compounds of formula I in which R^ is CHD.and R^ is other than CHO. 30) A process far the preparation of compounds of formula I as claimed in claim 1 in which one or both of R^ and R^ is other than H comprising the conversion of a primary amine of formula I in viiich both of R^ and R^ are hydrogen to a secondary or tertiary amine, or the conversion of a secondary amine of formula I in vvhich one of R3 and R4 are hydrogen to a tertiary amine. 31) A compound of formula I as claimed in claim 1 whenever made by a 33) A compound of formula I as claimed in claim 1 substantially as described herein with reference to any one of the examples. 34) A compound of formula III as claimed in claim 8 substantially as described herein with reference to any one of the examples. 35) A compound of formula IV as claimed in claim 10 substantially as described herein with reference to any one of the examples. 36) A compound of formula XXV as claimed in claim 32 substantially as described herein with reference to any one of the examples. 37) A pharmaceutical composition conprising a therapeutically active amount of a conpound as claimed in any one of claims 33, 34 or 35. 38) A process for preparing compounds of formula I as claimed in claim 1 substantially as hereinbefore described with reference to any one of the examples 1 to 46. 32) A compound of formula XXV in which R^, R^, Rg, R7, Rg and n are as defined in claim 1. 200178 t 78 - 39). l-[l-(4-cblorophenyl )cyclobutyl jbutylamine and its pharmaceutically acceptable salts. 40) N,N- Dimethyl-l-[l-(4-chlorophenyl )cyclobutyl jbutylamine and its pharmaceutically acceptable salts. , 41) N- tfethyl-l~[l-(5,4-dichlorophenyl )cyclot>utyl jbutylamine and its pharmaceutically acceptable salts. 42) N, N-fiimethyl-l-[l-(3,4-dichlorophenyl )cyclo butyl jbutylamine and its pharmaceutically acceptable salts. 43) N-Methyl-l-[l-(4-chlorophenyl )cyclobutyl j-3-methylbutylamine and its pharmaceutically acceptable salts. 44) N,N-£>imethyl-l-[l-(4-chlorophenyl )cycloburtyl j-3-methylbutylamine and its pharmaceutically acceptable salts. '45) N, N- Bimethyl-l-[l-(3,4-dichlorophenyl )cyclobutyl j-3-methylbutylamine and its pharmaceutically acceptable salts. 46) l-[l-(3,4-Dichlorophenyl )cyclobutyljethylamine and its pharmaceutically acceptable salts. 47i) N ,N-Dicnethyl-l-[l-(3,4-dichlorophenyl )cyclobutyl jethylamine and its pharmaceutically acceptable salts. 48) a-[l-(4-ehlorophenyl )cyclobutyl jbenzylamine and its pharmaceutically acceptable salts. . • . f. la"**' ByHteTTheir Authorised Agents, A. J. PARK & SON Per, </div>