CA1248955A - Therapeutic agents - Google Patents

Abstract

Abstract Compounds of formula I

Description

12~895S

This invention relates to compounds having useful therapeutic activity particularly but not exclusively as antidepressants, to pharmaceutical compositions containing such compounds and to proces~es for the preparation of such compounds.
The present invention pro~ldes compounds of formula I

R4 ~ ~ ~ R4 in which 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 cycloalkyalkyl ~roup 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 alXynyl group containing 2 to 6 carbon atoms or a group of formula II

" ~ II
: Rg in which Rg and Rlo, whlch may be the same or different, are H, halo or an alkoxy group contalning 1 to 3 carbon atoms;
in which R2 is H or an alkyl group containing 1 to 3 carbon atoms;

' ` ~:
,. ~ ..

:: :
'' ~ . .

~LZL~955 in which R3 and R4, which may be 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, a group of formula R1lCO where ~11 is H or R3 and R4 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring having 5 or 6 atoms in the ring which may contain further hetero atoms ln addltion to the nitrogen atom:
in which R~ and R6, which may be the same or dif~erent, 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 R5 and R~, together with the carbon atoms 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 atoms or the substituents of the second - benzene ring together with the two carbon atoms to which they are attached may form a further benzene ring;
and their pharmaceutically acceptable salts.
In the formulae included in this specification the symbol represent~ a 1,1-dl ub~tltuted ~yclobut~ yroup of ~ormula 1~4~5 In the preferred compounds of formula I, Rl 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 contalns 3 to 6 carbon atoms or a group of formula II in which Rg and/or Rlo ars H, fluoro or methoxy and in which R2 is H or methyl.
Examples of particularly preferred compounds of formula I are those in which R2 is H, Rl is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and phenyl.
In preferred compounds of I, R3 and/or R4 are hydrogen, methyl, ethyl or formyl or, when R3 and R4 together with the nitrogen atom to which they are attachsd form a heterocyclic ring, the preferred compounds of formula I contaln a heterocyclic group containing one nitrogen atom and 4 or 5 carbon atoms (e.g.
pyrrolidinyl, piperidino) which is optlonally substituted by one or more alkyl (e.g. methyl) groups (e.g. pyrrolidinyl substituted by two methyl groups), a heterocyclic group contalning a second nitrogen atom which is optionally alkylated (e.g. 4-methylpiperazinyl) or a heterocyclic group including one or more double bonds (e.~. 1,2,3,6-tetrahydropyridyl). In particularly preferred compound~ of formula I R3 and/or R4 are H, methyl, ethyl and ~ormyl.
In preferred compound~ of formula I R5 and/or R6 are ~, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy, phenyl or Rs and R6 together with the carbon atom to which they are attached form a second benzene ring whlch may optionally be substituted by halo.
A first group of preferred aompounds is repreaented by for~uls III

R5 ~ Trr y,f;~
C''~
'' ':

413~5~

in which R5 and R6 are as defined above. In preferred compounds of formula III Rs and R6 which may be the same or different, are H, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy, phenyl or R5 and ~6 together with the carbon atoms to which they are attached form a second benzene ring whlch may optlonally be substituted by a chloro group. In particularly prefsrred compounds o~ formula III R5 and/or R6 are H, fluoro, chloro, iodo, trifluoromethyl, methyl, phenyl or R5 and ~6 together with the carbon atoms to which they are attached form a second benzene ring which may optionally be substituted by a chloro group.
A second group of preferred compounds is represented by formula IV

in which R5 may be H, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy or phanyl and in which R6 ls fluoro or methyl. In particular preferred compound~ of formula IV R5 i~ H or chloro.
Compound~ of ~ormula I may exi3t a-~ salts wlth pharmaceutiaally acceptable acids. Examples o~ ~uch salt~
include hydrochloride~, maleates, acetates, citrate~, fumarates, tartrate~, succinates and salts with acidlc amino acids such as aspartlo and glutamic aclds.
Compounds o~ ~ormula I which contain one or more asymmetric carbon atoms can exist ln different optically active forms. When Rl and R2 are different, the compounds of formula I
contain a chiral centre. Such compound~ exi~t in two .~ .
,~, -~,, ' ~' ' 12~89,.:)5 enantiomeric forms and the present invention includes both enantiomeric forms and mixtures thereof.
The present invention also includes pharmaceutical compositions containing a therpeutically effective amount of a compound of formula I together with a pharmaceutically acceptable diluent or carrier.
In therapeutic use, the ac:tive compound may be administered orally, rectally, parenterally or topically, preferably orally. Thus th0 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 O.1-9O~ 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 inv~ntion and these are the known pharmaceutical forms for such administration, for example tablets, capsules, syrups and aqueous or oily suspensions. The excipients used in the preparation of these compositions are the excipients known in the pharmacists' art. Tablet~ 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 ~ i 9t~5 mixture by know~ me-tk.ods. The tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release o~ the compo~ds of the present invention.
Such tab]ets may, il 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 compaund w~ih or without added excipients, may be prepared by conven-tional means and, if desired, provided with enteric coatings in a know~ mar~ner. The tablets and capsulas may conveniantly each contain 1 to 500 mg of the active co~pound. Other compositions for oral administration include, for example, aqueous suspen- j sions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carbox~nethylcellulose, and oily suspensions con-taining a com~ound of the present imrention in a suitab~le vegetable oil, ~or example aracr.is oil.
Compositions of the ir.vention suitable ~or rectal administration are the known pharmaceutical forms for such administration, for example suppositories with cocoa butter or polyethylene glycol b~ses.
Compositions of the invention suitable for parentaral administration are the kncwn pharmaceutical forms for such administration, ~or example sterile suspensions in a~ueGus and oily med~a or sterile solutions in a suitable solvant.
Compositions for topical administration ~ay 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 dispersc-d in a pharmaceutically acceptable cream or ointment base.
In some formulations it may be bene~icial to use the compounds o~ the present invention in the ~orm of par-ticles o~ very small size, ~or example as obtained by ~luid energy milling~
:

12~9~S

In the compositions of the present invention the active compound may, if desired, be associated with other compatible pharmacologically active ingradients.

The pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I may be use~ to treat dspresslon in mammials includlng human beings.
In such treatment the amount of the compound of formula I
administered per day is in the ranye 1 to 1000 mg preferably 5 to 500 mg.

Compounds of formula I in which R4 iS CHO may be prepared by the redutive amidation of ketones of formula V

R~- ~

for example with formamide and formic acld or ammonlum formate and ~ormic acid to give compounds of ~ormula I in which R4 is CHO
and R3 ls H or with formamldes of ~ormula HCON~R3 in whlch R3 is an alkyl or cycloalkyl group and orm1c acid or amlne~ of formula R3NH2 in which R3 i8 an alkyl or cycloalkyl group and formic acld.
:
Compounds o~ formula I ln whloh R4 is CHO may be prepared by the formylation of compound~ of Formula I ln whlch R4 lq H for example by reaction with methyl formate.

Compounds of formula I ln which R3 is other than H and R4 is CHO may be prepared ~y reactlng compounds of formula I in which R3 is H and R4 is C~O with a compound of formula R3X where X is a leaving group suah as a halo group in the presence of a base.

'~

, :

8 lZ ~8~5 Compounds of formula I may be prepared by the reductive amination of ketones of formula V.

Examplas of suitable reductive amination processes are given below:
a) for compounds of formula I in which R3 and R4 are H, by reaction of the ketone wlth an ammonium salt for example ammonium acetate and a reducing agent such a sodium cyanoborohydride;
b) for compounds of formula I in which R3 is an alkyl or cycloalkyl and R4 is H by reaction of the ketone with an amine of formula R3NHz and a reducing agent such as ~odium cyanoborohydride;
c) for compounds of formula I in.which neither R3 nor R4 i9 hydrogen or in which R3 and R4 togethar with the nitrogen atom form a heterocyclic ring, by reaction of the ketone with an amine of formula HNR3R4 and either formic acid or a reducing agent such as sodium cyanoborohydride, d) for compounds of formula I in which ona or both of R3 and R4 are H or an alkyl or a cycloalkyl group or in which R3 and R4 together with the nitrogen atom form a heterocyclic ring, by catalytlc hydrogenation at elevated temperatur~ and pres urs o~ a mixture of the ketone and an amine of ormula HNR3R~.

Compounds of formula I in whlch R3 and R4 are both alkyl groups may be pr0pared by reacting a ketone of formula Y
with a dialkyl formamide o~ formula HCONR3R4 for example in the prssence of formic acid.

Compounds of formula I may be prepared by the rsduction of compound~ of formula V~I

, ~ ~

. .

lZ~9~5 g 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 R2, R3 and R4 are H;
b) Z is a group of formula - CR1=:NR3 (where R3 is other than H
or C~0) to give compoundY of formula I ln which R2 and R4 are H;
c) Z is a group of formula - CRl=NY in which Y represents a metal-containing molety derived frolm an organometallic reagent to give compounds of formula I in which R2, R3 and R4 are H.

Sultable reducing agents for the above reactions include sodium borohydride, sodlum.cyanoborohydride, lithium aluminium hydride.or borane-dimethylsulphide complexO

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

Compounds of formula I ln which n = 0 may be prepared by the raaction of an or~anometallic reagent for example a Grignard reagent of formula R~ MgX where X 18 Cl, Br or I or an organollthium oompo~nd o~ ~ormula R~Li with an imlne of formula VIII

~ VIII

followed by hydroly~is ~o giv~ a seoondary ~mlno o~ formula I.
:
Compounds of formula I in which R3 and R~ are ~ may be prepared by the decarboxylative rearrangement, for example using iodosobenzene-bist:rifluoroacetate or by a Hofmann reaction using bromine in alkaline solution, of amides of fo~mula X

~ ~, :

~ . ', - lo - lZ~5S

~ 2 X

to give amines of formula I.

Compounds of formula I in which R3 and R4 are H may be prepared by the decarboxylative rearrangement of acyl azides in the Curtiu~ reaction. The acyl azide may be formed for example by reaction of acid chlorid~ of formula XII ~ith sodium azide ~ , Compou~ds o~ ~on~ula I in wh b ~ an~ ~ are H ~ay be prepared by a Sohmidt reaction in which a carboxylic acid of formula XIV reacts with hydra~olc ac~d :

::
.;~,~7- : : :

, ,.

:: : : - ~
.

- 11 - 129~

Compounds of formula I in which R4 is H may be prepared by hydrolysis of compounds of formula I in which R4 is CHO, for example by acld hydrolysis.

Compounds of formula I in which R4 is methyl may be prepared by reduction of compounds of formula I in which R4 is CHO, for example by lithium aluminium hydride or by sodium bis(2-methoxyethoxy)aluminium hydride.

r .
....

:` ` :
~, .

, :

12~

Compounds sf formula I in which one or both of R3 and RL~ i5 OtheI' than ~ may be prepared from compounds o~ formula I in which one or ~voth of R3 and R4 are hydrogen by methods which are well kno~m in the art for the conversion of prim-ary to seccndary or tertiary amines or for the conversion of secondary to tertiary amines. The following are given as examples of suitahle processes:-a) by alkylating primary amines of formula I to giveseconJary aminQs ~f fcrmula I for example by a process wh~ch includes -the s-teps of protecting the primary amine with a protecting group such as tri*].uoroacetyl, alkylating with an ~lky' haliA.e and removing the protecting group for example by hydrolysis;
b) by alkylating primary amines of for3lula I, for example, with an alkyl haiide to give tertiary amines of formula I in which R3 and R4 are the same;
c) by alkylating secon~ary dmines of formula I, for example, with an alk~fl halide to giVQ tertiary amineS of formula I
in ~ich P3 anà R4 may be di~ferent;
d) by reacting primary amines of formula I with s~dium borohydride and acetic ac.id to give ~secondary amines of~
formula I in which R~ lS ethyl and P~4 is H;
e) by reacting primary amines of formula I wiih formalde-hyde and formic acid to give tertiary amines o~ formula I
in which both R3 and R4 are methyl f) by reacting secondary amines of Lormula I in which R4 is H with formaldehyde and formic acid to give tertiary amines of formula I in which R4 is methyl g) by formylating primary amines of formula I, for ~_ examp~e by reaction with methyl formate, and reducing the resulting formamides, for example with li~hium~aluminium hydride to give secondary amines o~ formula I in which R3 is methyl vnd R4 i~ H;

: ~ ' ~ : ;

.

1~ 9~

h~ by formylating ~econdary amines of formula I, for example by reaction with methyl formate, and reduclng the resulting formamides, for example with lithlum aluminium hydrlde to give tertiary amines of formula I in which R4 is methyl;
i) by acylating primary amlnes of formula I, for example by reaction with an acyl chloride of formula R12COC1 or an anhydride of formula (Rl2CO~20 in which R12 is an alkyl, alkenyl or alkynyl group and reducing the resulting ami.des for example with lithium aluminium hydride to give secondary amines of formula I in whlch R3 is -CH2R12 and R4 is H;
j) by acylating secondary amines of formula I in which R4 is H
for example by reaction with an acyl chloride o formula R12COCl or an anhydride of formula (R1 2 C )2 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 R4 is C~2 R1 2;
k) by reacting primary amines of formula I wlth an aldehyds of formula R13CHO in which R13 may be an alkyl group, an alkenyl or alkynyl group or a ketone of formula R1 4 CORl 5 in which R14 and Rl 5 which may be the same or different are an alkyl group, alkenyl group, alkynyl group or R14 and R1 5 together with carbon atom to which they are attached may form an alicycllc ring and reducing the resulting imine~ or anamines for example wlth sodium cyanoborohydride or, when R13, R1 4 or R1 5 are not alkenyl or alkynyl, by catalytic hydrogenation to give econdary amines of formula I in which Rl5 R3 is R13~H2- and R1 4 - CH- respectively;
l) by reacting primary amines of formula I with a non-geminally disubstltuted alkane containing 2 or 3 carbon atoms between the carbon atoms carrylng the -~ubstituents whlch may be for example halo preferably bromo, or p-toluenesulphonyloxy to give compounds of formula I ln which R3 and R4 together with the nitrogen to which they are attached form a heterocyclic ring containing no heteroatoms other than the nitrogen atom.

~Z4~3~SS

The ketones o~ formula V may be prepared by the hydrolysis of imlne~ o formula XVI

in which Y represent.q a metal-containing ~oloty dorlYed from an organometallic rsagent. The lmine~ of formula XVI may be prepared by the reaction of said organomatallic reagent with a cyano compound of formuls XVII

Suitable organometallic reagent~ Include ~rignara rsag~nts o~
formula RlMgX where X i9 Cl, Br or I (~ = MgX) and organolithium aompound~ of formula RlLi (Y - Li).
~: :

:

,: ~

~: i ` , , 12~ S

Ketones of formula V may be prepared by the reaction of carboxylic acid derivatives such a~ an amide or acid halide with an organometallic reagent for example by the reaction of an acid chloride of formula XX

~'~g with a Grignard reagent of formula R1MgX where X i9 Cl,-Br or I
at low temperatures or by the reaction of a oarboxylic acld of formula XXI

:: :

: ~

. ~ :

.... . .
- . -:
.

- 16 - ~Z~955 with an organometallic reagent, for example an organollthium compound of formula R1Li.

Ketones of formula V in which R1 is alkyl (e.g. methyl) may be prepared by the reaction of a dlazoalkane (e.g.
diazomethane) with aldehydes of formula XXII

~,~b Compounds of formula VII ~n which Z i~ a group of formula -CR1=NOH or ethers or esters thoreo~ may be prepared by the reaction of hydroxylamine or an ether or e~ter thereo wlth katones of formula V. :

:

: -.

- 17 _ 1 2 489 ~ ~

Compounds of formula VII iLn which Z i5 a ~roup of formula -CR1=NR3 may be prepared by the reaction of amines of formula NHiR3 with ketones of formula V.
, The preparation of compounds of formula VII in whlch Z
iLs a group o~ formula -CRl=NY has been described above in respect of compounds of formula XVI

' : ~.r : :

~ ~12'18~5 Imines of formula VIII may be prepared by reactlon of amines of formula R3 NH2 with aldehydes of formula XXII
respectively.

Amides of formula X may be prepared by the reaction of ammonia with carboxylic acid derivatives for 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 wlth hydrogen peroxide in the presence of a base.

Amlde~ of formula X in which Rl and R2 are H may be prepared from acld chlorldes of formula XX re~pectlvely by reactlon with dlazomethane to form a dlazoketone which rearranges ln the presence of ammonia and a catalyst for example silver ~to glve the required amide.

~, ..

~ ` ~

~124l~39S~

Carboxylic acids of formula XIV, and XXI may be prepared by the hydrolysis, for example basic hydrolyQis, of cyano compounds of formula XIX, and XVII respectively.
Carboxylic acids of formula XIV may be prepared by the reaction of amides of formula X w~th nitrous acid. Carboxylic acids of formula XXI may be prepared by the reaction of nitrou3 acid with the amides formed by the reaction oi ammonia with carboxylic acid derivatives for example acid chloricles of formula XX or by the reaction of cyano compounds of formula XVII wlth hydrogen peroxide in the presence of a base.

Carboxylic acids of formula XIV in whlch Rl and R2 are H may be prepared from acid chlorldes ffl formula XX respectlvely by reactlon with diazomathane to form dlazoketone~ which rearranges in the presence of water and a cataly~t for example silver to give the required acid.

Cyano compounds of formula XVII may be prepared by the reaction of cyano compound~ of formula XXIV

R6 : X~I

~12~55 with a 1,3-disubstituted propane for example 1,3-dibromopropane and a base such as sodium hydride.

Acid chlorides of formula XX, XII may be prepared by the reaction of carboxylic aclds of formula XXI, XIV 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 ars given as examples of suitable methods:

a) by the reduction of cyano compounds of formula XVII with for example di-tert-butylaluminium hydrids or di-isobutylaluminium hydride.
b) by the reduction of carboxylic acid derivative-~, for exampls i) by the reduction of tertlary amide~ fo~med by the reaction of secondary amlnes with acid chlorides of formula XX for exampls when the secondary amine is a dialkylamine using lithium d1ethoxyaluminohydr1de a~ reducing agent or when the secondary amine is ethyleneimlne using lithlum aluminium hydride a~
the reducing agent;

ii) by the reduction of acid chloride~ of formula XX
for example with lithium tri-tert~butoxyaluminohydride;

~, ..
" ~ , ~ . ., ' , , . , - . : . :
' ~ : ' ' '` ' - 21 - 'IX~89S~

c) by the oxldation of alcohols (prepared by the reduction of carboxylic acids of formula XXI) wi1;h, for example, chromium trioxide-pyridine complex in dichloromethane under anhydrous conditions.

~,... ~ . . ~, .

`

~3 ~z~s~

The therapeutic activity of the com~Qunds of formula I has been indicated by assessing the ability of the compounds to reverse the hypothermic effects of reser2ine in the following manner. Male mice cf the Charles Rive~ CDl strain weighin~ ~etween 18 and 30 grammes were separated into groups of five and were supplied with food and wa',er ad lib tum. 4fter five hours the body temperature OI each mouse was taken orally and the mice were in~'ected intra-peritotleally with reserpine (5 mg/kg) in solution in deionised water containing ascorbic acid t50 mg/ml). The ~mo~nl ^f liquid injected was 10 ml/Xg of body weight. Nine hours after the start of the'test food ~'2S with~2wn but wzter was still available ad libitum. Twenty-four hours alter the start of the iest the temperatures of the mice were ta~en and the mice were gi-~en the test compcund suspended in a il 0.25% solution of hydroxy ethyl cellulose (sold ~nder the trade name Cellosize QP 15000 by Union Carbide) in deionised water at a dose voll~e of lOml/kg OL bod~ weight. ~hr~e hours later ihe temperatures of,all ihe mice were again t~ken.
The percentage reversal of the reserpine-induced 1GSS OI body t.emperature is t~en calculated by the formula:
(Temperature alter 27 hrs - Temperature after 24 hours) X lOG
(Temperature after 5 hrs - Temperature after 24 hours) The mean value for each gro~lp of five mice was taken at several dose rates to enable a value o 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 tes-t is indicative of com~ounds having anti~ -depressant activity in humans.
Table I lists compounds of formula I which gave a value of ED50 in the above test of 10 mg/~g or less.
. . . .

' ''-' ~' .

Table I
1-[1-(3,4-dichlorophenyl)cyclobutyl~ethylamine hydrochloride N-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl~ethylamine hydrochloride N,N-dimethyl-l- Ll- (3,4-dichlorophenyl)cyclobutyl]ethyla~ine hydrochloride 1-[1-(4-iodophenyl)cyclobutyl]ethylamine hydrochloride N-methyl-1-[1-(4-iodophenyl)cyclobutyl]ethylamine hydro-chloride - `
N,N-dimethyl-1-[1-(4-iodophenyl)cyclobutyl]ethylamine hydrochloride N-methyl 1-[1-(2-naphthyl)cyclobutyl]ethylamine hydrochloride N,N-dimethyl-1-[1-(4-chloro-3-tri~luoromethylphenyl)cyclo-butyl~ethylamine hydrochloride 1-~1-(4-chlorophenyl)cyclobutyl~butylamine hydrochloride N-methyl-1-[1-(4-chlorophenyl)cyclobutyl~butylamine hydro-: chloride :
N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]butylamine:
hydrochloride 1-(3,4-dichlcrophenyl)cyclobutyl]butylamine hydrcchloride :: ~ :
-methyl-1-~1-(3,4-dichlorophenyl)cyclcbutyl3butylamine~
25 hydrochloride :
N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine hydrochloride [1-(4-biphenylyl)cyclobutyl]butylamine hydrochlorLde ~ 30 N,N-dimèthyl-1-{1-~4-biphenylyl)cyclobu~yl]butyIamine~
hydrochloride ~: : 1-[1-(4-chloro-3-fluorophenyl)cyclobutyl]butylamine hydro~
: ~ chloride ~ N-formyl-1-C1-(4-chloro-3-Pluorophenyl)cyclobutylJbutyl~
:~ 35 amine :: ~

.
` ~ : : :
.~.. :........................................... ' :

.

~Z~8'~55 1- Cl- (3-chloro-4-methylphenyl)cyclobutyl]butylamine hydro-chloride N-formyl-l-Cl-phenylcyclobutyl~butylamine 1-[1-(3-trifluoromethylphenyl)cyclobutylJbutylamine hydro-chloride l-[l-(naphth-2-yl)cyclobutyl]butylamine hydrochloride 1-[1-(6-chloronaphth-2-yl)cyclobutyl]butylamine N-methyl-1-[1-(4-chlorophenyl)c,yclobutyl]-2-met~ylpropylamine hydrochloride 1-[1-(4-chlorophenyl)cyclobutyl]pentylamine hydrochloride N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]pentylamine hydro-chloride E,N-dimethyl-l-[l-phenylcyclobutyl]-3-methylbutylamine hydrochloride 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl~mine hydro-chloride N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine hydrochloride N,E-dimethyl-1-~1-(4-chlorophenyl)cyclobutyl]-3-methyl- ;
butylamine hydrochloride N-formyl-1-[1-(4-chlorophenyl)cyclGbutyl~-3-methylbutylamine N,E-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-~-methyl-butylamine hydrochloride N-methyl-l-[l-(naphth-2-yl~cyclobutyl]-3-methylbu-tylamine hydrochloride : N-methyl-1-[1-(3,4-dimethylphenyl)cyclobutyl]-~-methyl-butylamine hydrochloride [1-(4-chlorophenyl)cyclobutyl](cyclopropyl)methylamine : hydrochloride ~ :
N-methyl-[1-(4-chlorophenyl)cyclobutyl~(cyclopentyl)methyl-amine hydrochlorlde : ~ :
~1-(4-chlorophenyl)cyclobuty ~ cyclohexyl)methylam~ne hydro-chloride :
:
~_ . . . . _ .

. .

N-methyl-[l-(4-chlorophenyl)clJclobutyl~c~cloheyyl)meth amine hydrochloride [1-(3,4-dichlorophenyl)cyclobutylXc~clohe-~l)methylamine 5 hydrochloride N-methyl-[1-(3,4-dichlorophenyl)cyclobuty~(c~clohexyl)methyl-~mine hydrochloride [1-(4-chlorophenyl)cyclobutyl~(cyclohe~ll)methyl~mine hydro-chlo-ide 1-[1-(4-chlorophenyl)cyc'^butyl~-2-cyclo~ro~ylethylamine 10 hydrochloride ~ , N.N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl~-2-cyclohexyl-ethylamine hydrochloride -[1-(4-chlorophenyl)cyclobutyl]benzyl~mine hydrochloride N-methyl-~-[1-(4-chlorophenyl)cyclobutyl]benzylamine hydro-chloride 1-[1-(4-chloro-2-fluorophenyl)cyclobutyl]butylamine N,N-dimethyl-1-[1-(4-chloro-2-fluoropherlyl)cyclobutyl]
butylamine hydrochloride 1-~[1-(3,4-dichlorophenyl)cyclobutyI]methyl~propylamine . hydrochloride N,N-dimethyl-1-~[1-(3,4-dichlorophenyl)cyclobutyl]methyl~
propylamine hydrochloride N-ethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine hydrochloride N,N-diethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]eth-;l~mine hydrochloride , , ~ :

:
`~ ':

.

-.

` ~ 2 The invention will now be illustrated by the ~ollow-ing Examples which are given by way of example only. All compounds were characterised by conventional analytical techniques and gave satisfactory elemental analyses. All melting and boiling points are expressed in degrees Celsius.

Example 1 A solution of 3,4-dichlorobenzyl cyanide (25 g) and 1,3-dibromopropane (15 ml) in dry dimethyl sulphoxide (150 ml) was added ~ropwise under nitrogen to a stirred mixture 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 35C. The mixture was stirred at room tempera-ture for two hours and propan-2-ol (8 ml) and then water ~110 ml) were added dropwise. The mixture was filtered 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. 1-(3,4-Dichlorophenyl)-l-cyclobutanecarbo-nitrile (b.po 108-1?0 C at 0.15 Hg) was isolated by distil-lation. This method is a modification o~ that described byButler and Pollatz (J.Org.Chem., Vol. 36, Nu. 9, 1971, p.l308).
The 1-(3,4-dichlorophenyl)-1-cyclobutanecarbonitrile prepared as above (2107 g) was dissolved in dry etner ~50 ml) and the solution was added under nitrogen to the product of the reaction of gaseous methy] bromide with magnesium tur-nings (3.9 g) in dry ether (150 ml). The mixture was stirred at room temperature for two hours and then under reflux for *wo hours. Crushed ice and then concentrated hydrochloric acid (100 ml) were added and the mixture heated under re~lux 30 for two hours. The ether layer was separated, washed with ~~
water and aqueous sodium bicarbonate~ dried and evaporated.
l-Acetyl-1-(3,4-dichlorophenyl)cyclobutane (b.p. 108-110 - at 0.2 mm Hg? was isolated by distillation.
l-Acetyl-1-(3,4-dichlorophenyl)cyclobutane (9.1 g) pre-pared as above, formamide (6.5 ml) and 98% formic acid t3 mlj were heated at 180C ~or sixteen hours to give N-formyl~
I
.

:: ~

- 27- lZ~95S

[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine. 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. 1-[1-(3,4-Dichloro-phe~yl)cycloDutyl~ethylamine (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 t~ dryness to give l-[l-(3,4-dichloro-phenyl)cyclobutyl]ethylamine hydrochlo~ide (m.p. 185-195GC).
(Formula I -Rl=Me; R2,R3 c~nd R4=H; R5=4-Cl; R6=3-Cl).
Ex2mple la The preparation of N-formyl-1-['-(3,4-dichlorophenyl)cyclo-butyl]ethylamine (m.p. 124-125C) (Example l(a) Formula I
Rl=Me; R2=H; R3=H; R4=CH0; R5=4-Cl and R6=3-Cl) described above was repeated and the product isolated by cooling the reaction mixtu.e ar.d 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 1-[1-(3,4-dichioro-phenyl)cyclobutyl]ethylamine.
In a similar manner to that described above in ExampleIa the following compounds were prepared. The conditions for the hydrolysis of the form~mides which were isolated by appropriate methods are shown in ~he footnotes.

R5 ~ MH2.HCl .

Example Rl R5 R6 b.p. ~free base) m p. of Note l(b) methyl Cl H 107/1.2 mm Hg A
l(c) n-butyl C1 H 138-139 B
l(d) methyl I H 205-207 C
l(e) methyl Cl CF3 216-217 D

~ . :

~Z~8~S~

A. aqueous HCljindustrial methylated spirit B. The l-valeryl-1-(4-chlorophenyl)cyclobutane was prepared in tetrahydrofuran. Hydrolysis was perfor~ed using concentrated HCl/industrial methylated spirit.
C. concentrated HCl/diethyleneglycoldimethyl ether (in a similar manner to that described later in Example 12).
D. concentrated HCl/industrial methylated spirit. --Example 2 The product of Example 1 (4.04 g), water (0.5 ml) and 98% formic acid (3.6 ml~ were mixed with coo~ing. 37-40/0 Aqueous formaldehyde (3.8 ml) was added and the solution was heated at 85-95C for five hours. The solution was evapo-rated to dryness and the residue acidified with concentrated nydrochloric acid ~nd the water removed by repeated addition of propan-2-ol followed by evaporation in vacuo. Crystals of N,N-dimethyl-1-[1-(~,4-dichloropheryl)cyclobutyl]ethyl-amine hydrochloride (m.~. 211-21~C) (~ormula I Rl=
Me; R2=H; R3,R4 = Me; R5=4-Cl; R6=3-Cl) were isolated.
In a similar way to thai described above the compounds of Example l(b) and l(d) were converted into the compounds listed below.

R5 ~ ~HRlh~e2.HCl Example Starting ~ R R R6 ~ P of b.p. of free Material 1 5 HCl salt base

2(a) l(b) methyl Cl H 98-100/0.5 mm 2(b) l(d) ~ methyl I H 260-261 ,:
Example In a similar manner to that described above in Examples 1 and 2 N,N-dimethyl-1-[1-(4-biphenylyl)cyclobutyI]ethylamine hydrochloride (m.p. 196-197C) was prepared. (Formula I
1 e; R2 H; R3~R4=Me; Rs=4-phenyl and R6=H).
~ : :

:: : : : :

, - . . , - . .
-. . . .
: : . : ~
- ., ~.

~ -~iL24~5 . .
Example 4 l~Acetyl-1-(3,4-dichlorophenyl)cyclobutane (15 g) pre-pared 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 0C and the white precipitate collected by filtration, washed with acetone and dried. The product, N-methyl-l-rl-(3,4-dichloro-phenyl)cyclobutyl]ethylamine hydrochloride, had a melting point of 254 to 256C (Formula I Rl = Me; R2 = H;

3 ; R4 H; R5 = 4-Cl and R6 = 3-Cl) In a similar manner to that described above the follow-ing compounds of formula I were prepared ~ ICHRlNHMn.HC

~ ' ~ ,, Exa~ple Rl R5 R6 b.p. of amine m.p. of Note . , HCl salt

4(a) Me Cl H 98-100/0.15 mm 240-241 4(b) Me - H Cl ~69-27~
4(c) Me Br H 96-98/0.1 mm 304(d) Me H Br 251-255 4(e) Me CF3 H 219-221 4(f) Me H CF3 225-228 4(g) Me --fCH = CH)2_ ~54-257 4(h) Me Cl CF3 198-200 4(i) Et Cl H 238-240 35 4(j) Pr Cl H 228-229 A :
4(k) Bu Cl H 152-153 A
4(1) Me I H 242-243 ..

,. . i ::

.

1~895 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 w:ith a mixture of 98% formic acid (50 ml) and water (100 ml) to give a neutral solution which was evaporated at 100C/100 mm Hg until 180 ml of water had been collected. The residue was heated to 140C
and l-acetyl-1-(4-chlorophenyl)cyclobutane (10.4 g) prepared in a similar manner to that described in Example 1 ~or l-acetyl-1-(3,4-dichlorophenyl)cyclobutane and 98%
formic acid (10 ml)were added. The mixture was heated on an oil bath at 2 temperature of 180-200C for sixteen hours.
me mixture was distilled until an internal temperature of 170C was ob~ained and this temperature was maintained for two hours. Any volatile material was removed by distillation at 160C/20 mm and the residue heated ur.der reflux with concen-trated hydrochloric acid (15 ml) and industrial methylated spirit (IMS) (15 ml) for three,hoursO The IMS was evaporated on a rotary evaporator and the residue washed with ether.
The aqueous phase was brought to pH 12 with sodil~lm kydroxide ~ 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-(4-chlorophenyl)-c~clobutyl]eth~lamine hydrochloride (m~p. 203-2C5CC~
(Formula I 1 ; 2 ; 3 ; 4 ; 5 4-Cl; R6 = H).

Example 6 1-(4-Chlorophenyl)-l-cyclobutanecarbonitrile (15 g) prepared in a similar manner to the 1-(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.
'Themixturewas cooledandl'ce andthenconcentrated hydro~hloric :, :~
- ~ ", `,~.;. '` .. .
, 3lZ489~S

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 l-butyryl-1~(4-chloro-phenyl)cyclobutane (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 160C.
After completion of the addition the temperature was raised to 180 to 185C 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 sol,d which was recrys-tal-lised from petroleum ether (b.p. 60-~0) to yield N-formyl-l-[l-(4-chlorophenyl)c~rclobuty']butylamine (m.p.
97.5 to 98.5C) (Formula I Rl = propyl; R2 = H;
R~ = H; R4 = CHOi R5 = 4-C1; R6 = H)-Example 7 A solution of 1-(3,4-dichiorophenyl)-1-cyclobutane-carbonitrile prepared as described in Example 1 (35.2 g) in ether (100 ml) was added to a solution of propyl magne-sium 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 reac-tion 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. 120-128C
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) a~
170C and the temperature kept at 175-180C for five hours.
A further portion of formic acid (4.5 mI) was added and 35 the mixture was maintained at 175-180C for a further fifteen hours. The mixture was extracted with ether which ., ~
~" dL , A
: ~

. ' '~'` '' ' . ~ " ' ` ` " ~ ' ' ' ' ~' ' j :
, ~ ~ 8~S S

on evaporation gave a thick oil which was crystallised from petroleum ether (b.p. 60-80) to give N-formyl-l-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine having a melting point of 103-105C (Formula I Rl = propyl;
R2 = H; R3 = H; R4 = CH0; R5 = 4-Cl and R6 = 3-C1).
In a similar manner to that described above the following compounds were made ~=~ CHRlNHCHO

5 ~

Example Rl R5 R6 m.p. (C) 7(a) isobutyl Cl H 110-112 57(b) propyl Cl F 115-116 7(c) phenyl Cl H 94-96 ?(d) propyl H H 98-102 Example 8 The produci of Example 7 (4.0 g~ in dry tetrahydro-furan (25 ml) was added rapidly to a stirred mixture o~
lithium aluminium hydride (1.4 g) in dry tetræhydrofuran (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 extrac-ted in-to ether, back extracted in~o 5N hydrochloric acid and the aqueous layer was basified and extracted with 30 ether. The ether extract yielded an oil which was dissol-ved in propan-2-oi (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-l-[l-35 (3,4-dichlorophenyl)cyclobutyl]butylamine hydrochloride and " ' ':

.
. . . :~ -..

~ .

.

had a melting point of 234-2~5C (Formula I R1 =
propy~; R2 = H; R3 = H; R4 = Me; R5 = 4-C1 and R6 = 3-Cl) In a similar manner to that described above the following compounds were prepared 0 5~E~Me.HCl ExampleRl R5 R6 m.p. (C) 8(a)phenyl Cl H 275-278 8(b)propyl Cl H 223-228 Example 9 The product of Example 7 (10 g) in solution 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 30C~
m e mixture was stirred at this temperature for four hours.
Water (25 ml) was added dropwise with cooiing and t~le mix-ture filtered through diatomaceous earth (CELIlE). Aqueous NaOH was added and an ether extraction~eriormed. The ether extract was~washed with wa~er and back extracted with 5N
25 hydrochloric acid. A white solid (m.p. 2~2-235C) appeared at the interface which was collected. Base was added to the aqueous phase and~a further ether extraction performedO
Evaporation of the ether extract yielded an oil which ~as dissolved in propan-2-ol (5 ml3 and concentrated hydrochloric 30 acid added to pH 2. Evaporation to dryness gave a white solid (m.p. 233-236C). The white solids were combined and recrystallised from propan-2-ol to yield N-methyl-l-[l-(3,4-dichlorophenyl ~yclobutyl~butylam~ne hydrochloride (m.p. 236-237C) (Formula I Ri = propyl; Rz = H;
R3 = H; R4 = Me; R5 = 4-Cl and~R6 = ~-Cl).

.. ii :
:
. . .

, ' - . ' .
.: : . . ~. . .
: ' :" :'';. ' ~

:~Z4~ ;S

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 gr~p Rl 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.

~ CHRlNHMe.HCl 5 ~

Example Rl R5 R6 m.p.
9(a) isopropyl Cl H 257-259 15 9(b) sec-butyl Cl H 209-212 9(c) isobutyl Cl H 225-233 9(d) cyclopentyl Cl H 252-256 9(e) n-hexyl Cl H 117-118 9(f) 4-methoxyphenyl Cl H 264-266 20 9(g) 3-methoxyphenyl Cl H 254-255 9(h) 2-methoxyphenyl Cl H 149-15~
9(i) cyclohexyl Cl H 170-172 9(j) isobutyl -(CH = CH)2-256-259 9(k) cyclohexyl Cl Cl 223-224 9(1) isobutyl Me Me (1) 259(m) propyl OMe H 173-175 9(n) methyl phenyl H 116-118 (1) Boiling point of free base >150 ~tl.O mm Hg.

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 : `~
, ~ ', ' , .

:

-- :12'~8~.5 reflux for nine hours. The solutio~ 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 amixture of propan-2-ol (4 ml) and ether (20 ml) and concentr2ted hydrochloric acid (1.5 ml) added.
The solvent was evaporated n vacuo. Repeated dissolution in industrial methylated spirit and evaporation in vacuo gave a gum which solidified on warming in vacuo. The pro-duct was recrystallised from petroleum ether (b.p. 100-120C) and had a melting point of 201-203C. The product was 1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine hydro-chloride (Forlrula I Rl = propyl; R2 = H; R3, R4 = H;
R5 = 4-Cl and R6 = 3-Cl).
In a similar manner to that described above the following compounds were prepared. As the size of the group Rl 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 reGuired as will be apparent to those skilled in the art.

~ CHRlNH2.HCl 5 ~

Example Rl R5 R6 m.p.
lO(a) isopropyl Cl H 200-202 lO(b) sec-butyl Cl H 170-179 lO(c) i~obu;:-yl Cl H 163-165 lO(d) cyclopentyl Cl H 185-210(dec) lO(e) phenyl Cl H 271-276 10~f) 4-methoxyphenyl Cl H 214-219 lO(g) cyclohexyl Cl H 206-210 lO(h) isobutyl H H 210-212 35lO(i) cyc~opropyl Cl H 204-206 i~ :

~:

:

36 ` lZ48955 Example Rl R5 R6 m.p.
lO(j) propyl Ph H 235-236 lO(k) propyl Me Cl 214-217 10(1) propyl -(CH=CH)2- 157-159 lO(m) cycloheptyl Cl H 156-162 lO(n) cyclohexyl Cl Cl 215 lO(p) methyl Cl F 215-217 lO(q) propyl OMe H 178-179 lO(r) propyl C1 F 186-188 lO(s) propyl Cl H 174-175 lO(t~ cyclohexylmethyl Cl H 148-150 lO(u) cyclopropylmethyl Cl H 184-185 lO(v) propyl -CH=CH-CCl=CH- (a) lO(w) propyl ~I CF3 126-128b lO(x) 4-fluorophenyl Cl H 279 lO(y) (b) methyl /C = C\CH=CH- 248-262 C~ CH
. ~CH- CH
5a~ boiling point of free base 168 C/0.05 mm Hg.
~bJ diethyleneglycoldimethyl ether replaced b~J ethylene-glycoldimethyl ether.
In a similar manner to that described above, l-tl-(4-chloro-2-fluorophenyl)cyclobutyl]butylamine (b.p. 99C/0.05 mm).
(Formula I ; Rl = propyl; R2, R3 and R4 = H; R5 = 4-Cl;
R6 = 2-F), l-ll-(2-fluorophenyl)cyclo~utyl]butylamine hydrochloride (m.p. 175-177C). (Formula I ,Rl = propyI;
R2, R3, R4, R5 = H and R6 = 2-F) and ~1-[1-(4-chloro-2-methyl) cyclobutyl]butylamine hydrochloride (m.p. 188-190C) (Formula : 25 I ~Rl = propyl; R2, R~ and R4 = H; R5 = 4-Cl and R6 =
2-Me) were prepared as EXamples lO(z),lO(aa) and lO(bb~
Example 11 respectively.
The prod-~ct of Example lO(c) (3.3 g) in the form of the free base, formic acid (2.99 g) and water (1 ml) were mixed with cooling. 37-4~ Aqueous formaldehyde (3.93 ml) ~as added and the mixture heated for eighteen hours at a tempera-ture 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 : ~ .
,.

, ~ 5 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-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine hydrochloriàe (m.p. 195-197C~. (Formula I ; Rl = isobutyl; R2 = H; R3, R4 = Me; R5 = 4-Cl;
R6 = H).
In a similar manner to that described above the following compounds of Formula I were prepared CHRlNMe2. HCl R

5 ExampleStarting Rl R5 R6 m.p.

ll(a)lO(h) isobutyl H H 195-198 ll(b)lO(j) propyl Ph H 194-196 l](c)lO(n) cyclohe~yl Cl Cl 227-228 ll(d)lO(q3 propyl OMe H 187-188 ll(e)lO(s~ pro~yl Cl H 194-196 ll(f)lO(t~ methyl Cl H 194-196 ll(g)lO(u) methyl Cl H 165-167 ll(h) . lO~v) propyl -CH=CH-CCl=CH- (a) ~ ~ isobutyl Cl Cl 225-226 ll(j)lO~x) 4-fluorophenyl Cl H 234 ll(k)- propyl isoproprl H 211-213 (a) bo~ling point of free base <25~C/0.05 mm Hg.
Example 11(1) In a ~imilar manner to that described above N,N-dimethyl-l-[l--(4-chloro-2-fluorophenyl)cyclobutyl]
butylamine hyclrochloride (m.p. 183) was prepared.
(Formula I ~ i Rl = propyl; R2 = H; R3, R~ = Me;
Rs = 4-Cl; R6 = 2-F) .
~.~

.

~l~4~395S

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 concentra~ed hydrochloric acid (10 ml) and propan-2-ol (10 ml) were added. Evaporation to dryness gave W,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine hydrochlor de (m.p.
195-196) as a white solid (Formula I Rl = propyl;
R2 = H; R3, R4 = Me; R5 = 4-Cl and R6 = 3-Cl).

Example 1~
1-(4-Chlorophenyl)-l-cyclobutanecarbonitrile (37.6 g) prepared in a similar manner to the 1-(3,4-dichlorophenyl)-l-cycIobutanecarbonitrile described in Example 1 was added to a solution of potassium hydroxide (32.4 g) in diethyle-neglycol (370 ml) and the mixture hea-ced under refl~x fQr three and a half hours. The reaction mixture was poured into an ice~water mixture ~ld the resuiting solution was ~ ;
washed with ether. The aqueous layer was added to a mix-ture of concentrated hydrochloric acid (100 ml) and ice and the resulting precipitate of 1-(4-chlorophenylj~
cyclobutanecarbox~lic 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 dlatomaceous earth (CELITE - RTM) and the product extracted into ether. After washing with water and drying, the ether was evaporated to give a residue -__.. .~. . .

., . : ~

~Z9L89~S

.
which was recrystallised from petroleum ether (b.p. 60-80). The product was 1-[1-(4-chlorophenyl)cyclobutyl~-methyl alcohol (m.p. 60-62C).
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. 1-[1-(4-Chlorophenyl)cyclobutyl]methyl p-toluene sulphonate (m.p. 99-100C) was precipitated by pouring the reaction mixture into a mixture of ice and concentrated hydrochloris 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 ihe ether was evapo-rated to leave a solid residue of 2-[1-(4-chlorophenyl)-cyclobutyl~acetonitrile (m.p. 63-65C).
A solution of di-isopropylamine (16.5 g) in dry tetra-hydrofuran (50 ml) was stirred under nitrogen at a tempera-ture of 0C and a 1.6 M solution of n butyllithium in hexane (100 ml) added dropwise. The raaction mixture was ~-stirred for 30 minutes and then cooled to -78C. A solu-tion of 2-Ll~4-chlorophenyl)cyclobutyl]acetonitri-Le (9.5 g) prepared as described above in dry tetrahydrofuran (25 ml) was added dropwise. The t,emperature of the mixture was allowed to rise to 0C and the mixture was stirred for ten minutes be~ore a solution of methyl iodide (10 ml) in tetrahy~rofuran (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 organic phase of the reaction mixture. The combined organic .
.. .. , ....... .~ :

' ' S~
-- 40 -- `

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-[1-(4-chlorophenyl)cyclobutyl]-2-methylpropionitrile (m.p. 73-75C).
The nitrile p-epared 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-chloric acid and extracted with thrae 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. 60~0) to give 2-[1-(4-chlorophenyl)cyclobutyl]-2-methylpropionic acid (m.p. 95-110C).
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 residual oil added to concentrated aqueous ammonia (75 ml).
An oily solid formed which was extracted into ethyl ace-tate. The extract was washed with water, dried and e~apo-rated to give 2-[1-(4-chlorophenyl)cyclobutyl]-2-methyl propionamide.
The amide prepared as above (1.34 gj was dissolved in a mixtùre of acetonitrile (8 ml) and water (8 ml) and iodo-sobenzene bistrifluoroacetate (3.4 g) added and the mixture stirred at ambient temperature for ~ive and à half hours.
Water (75 ml) and concentrated hydrochloric acid (8 ml) 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 ~hich 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.

:

~. .

~2~8~ s 1-[1-(4-Chlorophenyl)cyclobutyl]-l-methylethylamine hydro-chloride (m.p. 257-259C) was collected by filtration (Formula I Rl~ R2 = Me; R3, R4 = H; R5 = 4-Cl;
R6 = H).

Tpe product of Example 4(h) (3.4 g) was mixed with anhydrous sodium formate (0.72 g), 98% formic acid (10 ml) ~nd 37-40% aqueous formaldehyde solution (5 ml) and the mixture heated at a temperature of 85-95C for sixteen hours.
The mixture was diluted with water (50 ml) and basi~ied 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-[1-(4-chloro-3-tri~luoromethyl-phenyl)cyclobutyl]ethylamine hydrochloride (m.p. 246-247C) (Formula I Rl Me; R2 = H~ R3, R4 = Me; R5 = 4-Cl and R6 =3-CF3).

Example 15 The production of salts of the compour.ds 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 conventlonal techniques.
Example Base Acid Solvent m.p. of salt 15(a) 10(9)citric a~ueous acetone 158-160 15(b) lO(s)maleic ether 155-157 15(c) lO(s)succinic ether 152-I55~
15(d) 2L(*)tart~riG I.M.S. 150-153 15(e) Note (a) citric ether/methanol 163-164(dec) (a) The base was l-C1-(3,4-dimethylphenyl~cyclobutyl]-3-methylbutylamine prepared in a similar manner to that l ~ described in EXample 10.

,.,: ,~

- ,~ ,., ~ .
` .
.
: .

lZ~ 5 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 1-(4-chloro-phenyl)-cyclobutanecarbonitrile (19.1 g) prepared in a similar manner to that described in Example 1 for the 1-(3,4-dichloro-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.
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 clry acetone gave -[1-(4-chlorophenyl)cyclobutyl]benzylamine hydrochloride (m.p. 277-279C) (Formula I Rl=Ph; R2=
H; R3,R4=H; R5=4-Cl; R6 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 I00C and N-isopropylformamlde (b.p. 108-109C/25 ~ Hg) obtained by distillation.
l-~cety~-1-(4-chlorophenyl)cyclobutane (10.4 g~ prepared ,n a similar manner to that described in Example 1 for 1-acetyl-1-(3,4-dichlorophenyl)cyclobutane and 98% formic acid (5 ml)were added to N-isopropylformamide (43.5 g) and the 3G mixture heated at i80C for four hours. Excess starting material was clistilled off ~nder reduced pressure (20 mm Hg) to leave a viscous residue which was heated under reflux with concentrated hydrochloric acid (30 ml) for slx hours. The reaction mixture was washed with ether until a colourless solution was obtained. The aqueous phase was basi~ied,- extracted with ether, dried and evapo-` ''' lZ~ 5 .

rated to give an oil which was dissolved in 5N hydro-chloric acid. On evaporation a yellow oil was obtained which was triturated with petroleum ether (b.p. 62-68C) to give N-isopropyl-1-[1-(4-chlorophenyl)cyclobutyl]
ethy amine hydrochloride (m.p. 170-174PC) (Formula I
Rl = Me; R2 = H; R3 = isopropyl; R4=H; R5 =4-Cl;
R6 ~1 ) . . ..
Example 18 l-Acetyl-1-(3,4-dichlorophenyl)cyclobutane (7.0 g) prepared as described in Example 1 was slowly added to a mixture of pyrrolidine (25 ml) and 98% formic acid (15 ml) heated to 130-135C for fiva hours. The mixture was stirred and heated at 160-165C for sixteen hours. After cooling the mixture was poured into 5N hydrochloric acid (200 ml).
The solution was washed with ether, basified with aqueous 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 propan-2-ol to give N-1-[1-(3,4 dichlorophenyl)cyclobutyl]
ethyl pyrrolidine hydrochloride (m.p. 233-235C) (Formula I
Rl = Me; R2 = H; R3 and R4 together with the nitrogen to which they are attached form a pyrrolidine ring; R5 = 4-Cl and R6 = 3-Cl).
Example`l9 1-(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 chloride was evapora'ed off and the acid clloride of the above acid distilled tb.p. 82-96/0.2 mm Hg).
A solution of the acid chloride (23.0 g) in dry tetra-hydrofuran (100 ml)~was added slowly to ~he product of the reaction of magnesium turnings (3.0 g) and ethyl bromide (12.0 g) in dry tetrahydrofuran at a temperature of -70 to ,, : : ~

~ 2~ 5 -60C. The temperature was kept at -60C for an hour and was then allowed to rise to 0C. Water (50 ml) was added followed by 5N hydrochloric acid (150 ml) with cooling. The reaction mixture was extracted with ether, was~ed with water, sodium bicarbonate solution, dried~ The solvent was removed by evaporation and l-propionyl-1-(4-chlorophenyl)cyclobutane obtained by distillation (b.p. 96-104C/0.25 mm) The ketone produced above was converted to N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutylpropylamine hydrochloride (m.p. 213-215C) in a similar manner to that described in Example 12 (Formula I Rl = Et; R2 = H;
R~, R4 = Me; R5 = 4-Cl; R6 = H).

.
Example 20 1-Acetyl-1-(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), 33~0 solution of methylamine in ethanol (60 g) and ethanol (30 ml) were charged into an autoclave. The auto-20 clave was filled with hydrogen and maintained at about 60C and 20 bar pressure for ten hours. The reaction mixture was filtered through charcoal and the solids washed with abso-lute alcohol. The solvents were removed by evaporation and a sample of the residue (10 g) was shaken with ZM hydro-chloric 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 (109C/0.3 mm Hg) to give N-methyl-1-[1-(4-chlorophenyl`
cyclobutyl]ethylamine (Formula I Rl = Me, R2 = H;
R3 = Me; R4 = H; R5 = 4-Cl and R6 = H).

.

,~ .

lZ4~

Example 21 'Sodium borohydride (2.0 g) was added to solution o~
1~[1-(3,4-dichlorophenyl)cyclobutyl~ethylamine (1.5 g prepared by treating theproductofExample lwith aqueous sodium hydroxi~e) in glacial acetic acid (30 ml),. The mixture was heated at 95-100C 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. Trituration with acetone gave N-ethyl-l-[1-(3,4-dichlorophenyl)cyclobutylle~hylamine hydrochloride (m.p. 211-212C). (Formula I Rl = Me; R2 = H;
R3 = Et; R4 = H; R5 = 4-Cl and R6 = 3-Cl.) Example 22 A mixture of N-ethyl-1-[1-(3,4-dichlorophenyl) cyclobutyl]ethylamine (0.5 g prepared by treating the product of Example 21with aqueous sodium hydroxide) and acetic anhydride ~1 ml) was heated at 40-45C for thirty minutes. The reaction mixture was basified and extracted,with ether.
The ether extract was washed, dried and evaporat~d to give -N-acetyl-N-ethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]
ethylam,ine as an oil.
This oil was dissolved in tetrahydrofuran tlO ml) and borane-dimethylsulphide comple~ (0.5 ml) added dropwise.
The reaction mixture was stirred at room temperature for two hours and then heated to 35-40C 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-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine hydrochloride ' (m.p. 199-201C). (Formula I Rl = Me; R2 = H;
R3, R4 = Et; R5 = 4-Cl and R6 = 3-Cl.) ,.~,, , ..

;:
....

. ~ 2 ~9 S S

Example 2~

A mixture of l-acetyl-1-(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 ~or ~our days. The reaction mixture was poured into a mixture o~ 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) cyclobutyl]ethylamine as an oil which ~as identified by standard analytical techniques as the Gompound of Example 1 in the form of its free base.

Example 24 1~ - .
A mixture o~ l-acetyl-1-(3,4-dichlorophenyl)cyclobutane (4.86 g) prepared as described in Example 19 hydroxylamine hydrochloride (1.6 g), sodium acetate trihydrate (3.3 g), industrial methylated spirit (15 ml) and water (2 ml) was heated under refl~x 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 1-acetyl-1-(3,4-dichlorophenyl)cyclobutane oxime (m.p. 120-121C). ~`
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 ~or one hour and, after cooling, water and then a 20% aqueous solution of Rochelle's salt.(potassium ~odium tartrate tetrahydrate) (27 ml) ar a 10~ a~ueous 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 1-[1-(~,4-dichlorophenyl)cyclobutyl]
ethylamine was separated by high pressure li~uid chromatography. The product was identified by standard : ' . .
.

'~ ' '"' ' .-analytical techniques as the compound o~ Example 1 in the form of its free base.

Example 25 A lM solution of diisobutylaliminohydride in hexane (200 ml) was added under nitrogen to a solution of l-phenyl-l-cyclobutane carbonitrile (31.4 g) in ether (100 ml) at a temperature below -30C. The temperature was maintained below 0C ~or thirty minutes and 5N
hydrochloric acid (200 ml) at a temperature of -10C added.
m e reaction mixture was washed with petroleum ether (b.p. 60-80C) and then warmed to 40C. The reaction mixture was extracted with petroleum ether (b.p. 60-80C) and the extract dried and evaporated to yield l-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 o~ the reaction mixture was maintained below 0C. Magnesium sulphate (20 g) which had been dried over a flame andthencooled under nitrogen was added to the reaction mixture which was left for sixteen hours at room temperature be~ore being filtered. The toluene was then remov2d by evaporation~and the residue dissolved in ether (50 ml). ~his solution was added to a~
solution ofpropyll~hium prepared by slowly adding excess 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, ~ater and then 5N hydrochloric acid. The filtrate and washings were heated on a steam bath for one hour. After cooling the reaction mixture was washed wi~th ether and the aqueous layer was basified u3ing aqueous sodium hydroxide solution. The reaction mixture was extracted wit;h ether and the extract~dried and the ether ` 35 removed to give a residue~from which N-methyl~
phenylcyclobut~l)butylamine (b.p. 80-86/O.l~mm~Hg.)~
:
: ~ :

, , .

~Z485~3~;

was distilled.
The ~mine (2.3 g) prepared as described above was dissolved in ether (40 ml) and hydrogen chloride gas passed through the solution to precipi~ate N-methyl-l-(l-phenylcyclobutyl)butylamine hydrochloride (m.p. 196-197C).
(Formula I Rl = propyl; R2 = H; R3 = Me; ~4, R5 and R6 are H.) Example 26 A solution of 1-(3-chloro-5-metnylphenyl)-1-cyclobutane carbonitrile (8.0 g) in ether ~40 ml) was added to a solution of propyl mag~.esium bromide [prepared by the reaction of l-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 t a solution of sodium borohydride (3.5 g) in ethanol (150 ml) added. The mixture was maintained at 50C
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 ~rom propan-2-ol to give 1-[l-(3-chloro-s-methylphenyl)cyclobut butylamine hydrochloride (m`.p. 145-146C~.
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-dimethy~ (3-chloro-5-met~ly1phenyl~
cyclobutyl]butylamine hydrochloride (m.p. 148~C) (Formula I Rl = propyl; R2 = ~i R3 and R4 = Me; R5 = 3-Cl and R6 = 5-Me) in a similar manner to that described in ;~ Example 2.

~0 ~.

:
:: :

. . .
- ; , , . . .
: " ,.

. .~
:~ :

Examplc 27 solution of isobutylmagnesium bromide was ~repared by the addition under nitrogen of isobutyl bromide ~9 g) in ether (150 ml) to a stirred mixture S of ma~nesium turnings (18 g) and ether over a period of one and three auarter hours. The mixture was heated under reflux for 30 minutes. The ether was replaced by toluene (300 ~L) and a solution of 1-(4-chlorophenyl)1-cyclobutanecarbonitrile (97.2 g prepared as described in Example 1) in ~oluene (60 ml) ~ras added to the solution of isobutyl nagnesium bromide prepared as described above over a period of 30 minutes. The reaction mixture was he2ted at around 90C or 19 hours and then cooled. A suspension of sodium borohydride (30 g) in ethanol (750 ml) was added dropwise over a period of one and three quarter hours. The reaction ~ixture was maintained at iOC for two hours and then ethanol (580 ml) was removed by evaporation. Water (70 ml) was added and 16 hours later concentrated hydrochloric acid (200 ml~ was added dropwise. The toluene phase of the reaction mixture was washed, dried and the solvent removed to leave a residue which was stirred with a mixture of e~her and petroleum e~her (b.p. 40-60C) and 16M aqueous sodium hydroxide solution. The organic layer was washed, dried and evaporat~d to leave 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine (b.p. 124-128C/0.2 mm Hg) as a brown oil (Formula I n = 0; R1 - isobutyl; R2, R3 and R4 = H; R5 - 4-Cl and R6 = H).

The primary amine (1n2.7 g) and 98% formic acid (310 ml) were mîxed with ice cooling and 37-40% aqueous formaldehyde (123 ml) was added. The mixture was heated at 90-100C fo~ 16 hours and ~Jas then cooled and poured into a mixture of ice (500 g) and 16~1 aqueous sodium hydroxide solution (250 ml). Thc produc~ s ~ ~`

- , ,:

1291~9 j5 extracted with ether and the extracts wera washed, drled and evaporated to leave N,N-dimethyl-1-~1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamlne (m.p.53-55C) (Formula I n = O; R1 = isobutyl; R2 = H~ R3 and R4 Me; Rs = 4-C1 and R6 = H ) .

Example 28 Pharmaceutical compositions containing any one of the compound~ of formula I disclosed in Examples 1 to 27 are prepared in the following manner.

.
' .
.. -.

~L~489~5 Example 28(a) Tablets are prepared from the following ingredients:

Parts by ~ t 5 Active Ingredient 50.0 Lactose 78.5 Polyvinylpyrrolidone 5.0 Maize Starch 15.0 Magnesium Stearate 1.5 The active ingredient, the lactose and some of the starch are mixed and grar.ulated with a solution of the ~olyvinylpyrro idone in ethanol. The granulate is mixed with the stearic acid and the rest of the starch and the mixture is compressed in a tabletting machine to give ablets containing 50.0 mg. of the active ingredient.

Example 28tb) Capsules are prepared in the following way. A mixture o~ the active ingredient (45 parts by weight) and lactose 20 powder (205 parts by weight) is filled into hard gelatin !
ca~sules, eac~ capsule containing 45 mg. of the active irgredient.
I
Exam~le 28(c) ;~
:~ , In the preparation of enteric coated tablets, the tablets described in Example t28a) ~re gi~en a thin coat of shellac vPrnish, followed by 20 coats of cellulose acetate phthalate in a manner well known in the art. In a similar m~ner the capsules of Examp le t28b) may be provided with an enteric coating.

Example 28~d) Vials containing a solution of water_soluble compounds o~ the present invention suitable for injection are prepa-red from the fol~owing ingredients~
:: :

12~ 55 Active Ingrcdient 1100 ga Mannitol 1100 g.
Water, fr~shly distilled to 11 litres The active ingredient and mannitol are dissolved insome 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 con-taining 1.65 ml. of solution.

Example 28~e) 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 100 mg. of the active ingredient.
In the preceding Examples novel ketones of formula ~
have been disclosed in which Rl, R5 and R6 have the meaning given in Examples 1, l(a) to l~e), 3, 4, 4(a~ to 4(~), 6, 7, 7(a) to 7(d) 9, 9(a) to 9(n), 10, lO(a) ~o lO(z), lO(aa), lO(bb), ll(i), ll(k) and 11(1). These novel ketones of formula V are prepared by hydrolysis of novel imines of iormula XVI in which Y = MgBr and Rl, R5 and R6 have the meanlng given in the Examoles specifiod above.

: ::
~ :
In the preceding `Examples novel cyano compound~ of iormula XVII are disclosed in whlch R5 and R6 have the meaning given in Examples l, l(d), l(e), 4(g), 9(e), 9(m), lO(k), lO(e)~ lO(p), lO(r), lO(v), lO~y), lO(z), lO(aa)~
lO(bb), ll(k), 11(1) and 26.

. , .. ~ , : , :

, ~ . ., 1248~3S5i In the preceding Examples novel formamides of rormula XXVTII are disclosed in which Rl, R3, R5, R6, R7, R8 and n have the meaning given in Exa~ples 1, l(a) to l(e), 3, 4, 4(a) to 4(e), 6, 7, 7(a) to 7(d), 9, 9(a) to 9(n), 10, lO(a) to lO(z), lO(aa), lO(bb), ll(i), ll(k), 11(1).

.:

:

Claims (172)

WE CLAIM:

1. A process for preparing compounds of formula I:

I

in which, 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:
II

in which R9 and R10, which are the same or different, are H, halo or an alkoxy group containing 1 to 3 carbon atoms;
in which R2 is H or an alkyl group containing 1 to 3 carbon atoms;

in which R3 and R4, 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, a group of formula R11CO where R11 is H or R3 and R4 together with the nitrogen atoms to which they are attached form a heterocyclic ring which (a) contains 4 or 5 carbon atoms in addition to the nitrogen atom and is unsubstituted or substituted, by one or more lower alkyl groups or (b) contains a second nitrogen atom which is unsubstituted or substituted by a lower alkyl group; and in which R5 and R6 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 R5 and R6, 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 substituents of the second benzene ring together with the two carbon atoms to which they are attached form a further benzene ring;
and their pharmaceutically acceptable salts; said process being selected from:
(i) the reductive amidation of ketones of formula V:

V

to give compounds in which R2= H, R4= CHO and R1, R5 and R6 are as defined above;
(ii) reductive amination of ketones of formula V:

V
to give compounds in which R2 = H and R1, R5 and R6 are as defined above;
(iii) the reduction of compounds of formula VII:

VII
in which:
a) Z is a group of formula -CR=NOH or an ester or ether thereof to give compounds of formula I in which R2, R3 and R4 are H;
b) Z is a group of formula -CR1=NR3 to give compounds of formula I in which R2 and R4 are H;
c) Z is a group of formula -CR1= NY in which Y represents a metal-containing moiety derived from an organometallic reagent to give compounds of formula I in which R2, R3 and R4 are H;
(iv) the reaction of an organometallic reagent with an imine of formula VIII:

VIII
followed by the hydrolysis of the resulting product to give compounds of formula I;

(V) the decarboxylative rearrangement of (a) an amide of formula X

or (b) an acyl azide formed by reaction of sodium azide with an acid chloride of formula XII:
XII

to give amines (vi) the reaction of hydrazoic acid with a carboxylic acid of formula XIV
XIV
to give amines;

(vii) in the case where R4 is H, the hydrolysis of compounds of formula I in which R4 is CHO;
(viii) in the case where R4 is methyl, the reduction of compounds of formula I in which R4 is CHO; and, (ix) in the case where one or both of R3 and R4 is other than H, the conversion of a compound of formula I in which one or both of R3 and R4 are hydrogen to the required compound.

2. Compounds of formula I as given in claim 1 and pharmaceutically acceptable salts thereof, whenever prepared by a process according to claim 1 or an obvious chemical equivalent thereof.

3. A process for the preparation of compounds of formula I as given in claim 1 comprising the reductive amination of ketones of formula V
V
to give compounds of said formula I in which R2 = H, R4 -CHO
and R1, R3, R5 and R6 are as defined in claim 1.

4. Compounds of formula I as given in claim 1 wherein R4 =
CHO, R2 = H and R1, R3, R5 and R6 are as defined in claim 1, and pharmaceutically acceptable salts thereof, whenever prepared by a process according to claim 3 or an obvious chemical equivalent thereof.

5. A proces for the preparation of compounds of formula I as defined in claim 1 comprising reductive amination of ketones of formula V:
V
to give compounds of said formula I in which R2 = H and R1, R3, R4, R5 and R6 are as defined in claim 1.

6. Compounds of formula I as given in claim 1, wherein R2 = H
and R1, R3, R4, R5, R6 are as defined in claim 1, and pharmaceutically acceptable salts thereof, whenever prepared by a process according to claim 5 or an obvious chemical equivalent thereof.

7. A process for preparing 1-[1-(4-chlorophenyl) cyclobutyl]
butylamine of formula:

and pharmaceutically acceptable salts thereof comprising the reductive amination of a compound of formula:

8. 1-[1-(4-chlorophenyl) cyclobutyl]butylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 7 or an obvious chemical equivalent thereof

9. A process for preparing 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine of formula:
and pharmaceutically acceptable salts thereof comprising the reductive amination of a compound of formula:

10. 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 9 or an obvious chemical equivalent thereof

11. A process for preparing .alpha.-[1-(4-chlorophenyl)cyclobutyl]benzylamine of formula:

and pharmaceutically acceptable salts thereof comprising the reductive amination of a compound of formula:

12. .alpha.-[1-(4-chlorophenyl)cyclobutyl]benzylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 11 or an obvious chemical equivalent thereof

13. A process for preparing N-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine of formula:

and pharmaceutically acceptable salts thereof comprising the reductive amination of a compound of formula:

14. N-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 13 or an obvious chemical equivalent thereof.

15. A process for preparing N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of formula:
and pharmaceutically acceptable salts thereof comprising the reductive amination of a compound of formula:

16. N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 15 or an obvious chemical equivalent thereof.

17. A process for preparing N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]butylamine of formula:
and pharmaceutically acceptable salts thereof comprising the reductive amination of a compound of formula:

18. N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]butylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 17 or an obvious chemical equivalent thereof

19. A process for preparing N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine of formula:

and pharmaceutically acceptable salts thereof comprising the reductive amination of a compound of formula:

20. N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]
butylamine and a pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 19 or an obvious chemical equivalent thereof.

21. A process for preparing N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of formula:
and pharmaceutically acceptable salts thereof comprising the reductive amination of a compound of formula:

22. N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylhutylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 21 or an obvious chemical equivalent thereof.

23. A process for preparing N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-3-methylbutylamine of formula:

and pharmaceutically acceptable salts thereof comprising the reductive amination of a compound of formula:

24. N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-3-methylbutylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 23 or an obvious chemical equivalent thereof.

25. A process for preparing N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine of formula:
and pharmaceutically acceptable salts thereof comprising the reductive amination of a compound of formula:

26. N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]
ethylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 25 or an obvious chemical equivalent thereof.

27. A process for preparing 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of formula:

and pharmaceutically acceptable salts thereof comprising the reductive amination of a compound of formula:

28. 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 27 or an obvious chemical equivalent thereof.

29. A process for the preparation of compounds of formula I
comprising the reduction of compounds of formula VII:
VII

in which a) Z is a group of formula CR1=NOH or an ester or ether thereof to give compounds of said formula I in which R2, R3 and R4 are H;
b) Z is a group of formula -CR1=NR3 to give compounds of said formula I in which R2 and R4 ace H; or c) Z is a group of formula -CR1=NY in which Y represents a metal-containing moiety derived from an organometallic reagent to give compounds of said formula I in which R2, R3 and R are H:

30. A process as claimed in claim 29 in which Y is MgBr or Li.

31. Compounds of formula I
as given in claim 1 and pharmaceutically acceptable salts thereof, whenever prepared by a process according to claim 29 or claim 30 or an obvious chemical equivalent thereof.

32. A process for preparing 1-[1-(4-chlorophenyl)cyclobutyl]butylamine of formula:
and pharmaceutically acceptable salts thereof comprising the reduction of a compound of formula:
or an ester or ether thereof

33. 1-[1-(4-chlorophenyl)cyclobutyl]butylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 32 or an obvious chemical equivalent thereof.

34. A process for preparing 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine of formula:
and pharmaceutically acceptable salts thereof comprising the reduction of a compound of formula:

or an ester or ether thereof

35. 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 34 or an obvious chemical equivalent thereof.

36. A process for preparing .alpha.-[1-(4-dichlorophenyl)cyclobutyl]benzylamine of formula:
and pharmaceutically acceptable salts thereof comprising the reduction of a compound of formula:
or an ester or ether thereof.

37. .alpha.-[1-(4-dichlorophenyl)cyclobutyl]benzylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 36 or an obvious chemical equivalent thereof.

38. A process for preparing 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of formula:
and pharmaceutically acceptable salts thereof comprising the 70 reduction of a compound of formula:
or an ester or ether thereof.

39. 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 38 or an obvious chemical equivalent thereof.

40. A process according to claim 29 wherein a compound of formula in which Y represents a metal containing moiety derived from an organo-metallic agent, is reduced to give a compound of formula I as defined in claim 1 and in which R2, R3 and R4 are H; and R1, R5 and R6 are as defined in claim 1.

41. The process of claim 40 wherein Y is MgBr or Li.

42. Compounds of formula 1 as given in claim 1, in which R2, R3 and R4 are H; whenever prepared by a process according to claim 40 or claim 41 or an obvious chemical equivalent thereof.

43. A process for preparing 1-[1-(4-chlorophenyl)cyclobutyl]butylamine of formula:
and pharmaceutically acceptable salts thereof comprising the reduction of a compound of formula:
wherein Y represents a metal-containing moiety derived from an organometallic agent.

44. The process of claim 43 wherein Y is MgBr or Li.

45. 1-[1-(4-chlorophenyl)cyclobutyl]butylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 43 or claim 44 or an obvious chemical equivalent thereof.

46. A process for preparing 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine of formula:
and pharmaceutically acceptable salts thereof comprising the reduction of a compound of formula:
wherein Y represents a metal-containing moiety derived from an organometallic agent.

47. The process of claim 46 wherein Y is MgBr or Li.

48. 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 46 or claim 47 or an obvious chemical equivalent thereof.

49. A process for preparing 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of formula:
and pharmaceutically acceptable salts thereof comprising the reduction of a compound of formula:
wherein Y represents a metal-containing moiety derived from an organometallic agent.

50. The process of claim 49 wherein Y is MgBr of Li.

51. 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 49 or claim 50 or an obvious chemical equivalent thereof.

52. A process for preparing .alpha.-(1-(4-chlorophenyl)cyclobutyl]benzylamine of formula:
and pharmaceutically acceptable salts thereof, comprising the reduction of a compound of the general formula:
wherein Y is a metal-containing moiety derived from an organometallic agent.

53. The process of claim 52 wherein Y is MgBr or Li.

54. .alpha.-[1-(4-chlorophenyl)cyclobutyl]benzylamine and its pharmaceutically acceptable salts whenever prepared by a process according to claim 52 or claim 53 or an obvious chemical equivalent thereof.

55. A process for the preparation of compounds of formula I
as given in claim 1 comprising the reduction of compounds of formula VII b:
VIIb to give compounds of said formula I in which R2 and R4 are hydrogen, and R1, R3, R5 and R6 are as defined in claim 1.

56. Compounds of formula I as given in claim 1 in which R2 and R4 ace hydrogen, and R1, R3, R5 and R6 ace as defined in claim 1, whenever prepared by a process according to claim 55, or an obvious chemical equivalent thereof.

57. A process for preparing N-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine of formula:

and pharmaceutically acceptable salts thereof comprising the reduction of a compound of formula:

58. N-methyL-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 57 or an obvious chemical equivalent thereof.

59. A process for preparing N-methyl-1-[1-(4-chlorophenyl)cyclobutyl)-3-methylbutylamine of formula:
and pharmaceutically acceptable salts thereof comprising the reduction of a compound of formula:

60. N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 59 or an obvious chemical equivalent thereof.

61. A process for the preparation of compounds of formula I
as given in claim 1 comprising (a) the reaction of an organometallic reagent with an imine of formula VIII:
VIII
and (b) the hydrolysis of the resulting product to give compounds of said formula I,

62. A process as claimed in claim 61 in which the organometallic reagent is a Grignard reagent of formula R1MgBr or an organolithium compound of formula R1Li.

63. Compounds of formula I as given in claim 1 and pharmaceutically acceptable salts thereof, whenever prepared by a process according to claim 61 or claim 62 or an obvious chemical equivalent thereof.

64. A process for preparing N-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine of formula:
and pharmaceutically acceptable salts thereof comprising a first step in which an organometallic reagent of formula CH3CH2CH2 W wherein W represents a metal-containing group, is reacted with an imine of formula followed by a second step wherein the resultant product is hydrolysed.

65. The process according to claim 64 wherein said organometallic reagent is a Grignard reagent of formula CH3CH2CH2MgBr or an organolithium compound of formula CH3CH2CH2Li.

66. N-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 64 or claim 65 or an obvious chemical equivalent thereof.

67. A process for preparing N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of formula:
and pharmaceutically acceptable salts thereof comprising a first step in which an organometallic reagent of formula (CH3)2CHCH2W in which W represents a metal-containing group, is reacted with an imine of formula:

followed by a second step wherein the resultant product is hydrolysed.

68. The process according to claim 67 wherein said organometallic reagent is a Grignard reagent of formula (CH3)2CHCH2MgBr or an organolithium compound of formula (CH3)2CHCH2Li.

69. N-methyl-1-[1-(4-chlorophenyl)chclobutyl]-3-methylbutylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 67 or claim 68 or an obvious chemical equivalent thereof.

70. A process for the preparation of compounds of formula I
wherein R3 and R4 are H comprising the decarboxylative rearrangement of (a) an amide of formula X
X

to give amines of said formula I, or (b) an acyl azide formed by reaction of sodium azide with an acid chloride of formula XII
XII

to give amines of said formula I.

71. Compounds of formula I as given in claim 1 and pharmaceutically acceptable salts thereof, whenever prepared by a process according to claim 70 or an obvious chemical equivalent thereof.

72. A process for preparing 1-[1-(4-chlorophenyl)cyclobutyl]butylamine of formula:

and pharmaceutically acceptable salts thereof comprising decarboxylative rearrangement of an amide of formula:

73. 1-[1-(4-chlorophenyl)cyclobutyl]butylamine and pharmaceutical acceptable salts thereof whenever prepared by a process according to claim 72 or an obvious chemical equivalent thereof.

74. A process for preparing 1-[1-(4-chlorophenyl)cyclobutyl]butylamine of formula:
and pharmaceutically acceptable salts thereof comprising decarboxylative rearrangement of an acyl azide first formed by reaction of sodium azide with an acyl chloride of formula:

75. 1-(1-(4-chlorophenyl)cyclobutyl]butylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 74 or an obvious chemical equivalent thereof.

76. A process for preparing 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine of formula:
and pharmaceutically acceptable salts thereof comprising decarboxylative rearrangement of an amide of formula:

77. 1-[1-(3,4-dichlocophenyl)cyclobutyl]ethylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 76 or an obvious chemical equivalent thereof.

78. A process for preparing -[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine of formula:
and pharmaceutically acceptable salts thereof comprising decarboxylative rearrangement of an acyl azide first formed by reaction of sodium azide with an acyl chloride of formula:

79. ?1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 78 or an obvious chemical equivalent thereof.

80. A process for preparing ?-[1-(4-chlorophenyl)cyclobutyl]benzylamine of formula:
and pharmaceutically acceptable salts thereof comprising decarboxylative rearrangement of an amide of formula: :

81. .alpha.-[1-(4-chlorophenyl)cyclobutyl]benzylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 80.

82. A process for preparing .alpha.-[1-(1-(4-chlorophenyl)cyclobutyl]benzylamine of formula:
and pharmaceutically acceptable salts thereof comprising decarboxylative rearrangement of an acyl azide first formed by reaction of sodium azide within an acyl chloride of formula:

83. .alpha.-[1-(4-chlorophenyl)cyclobutyl]benzylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 82 or an obvious chemical equivalent thereof.

84. A process for preparing 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of formula:

and pharmaceutically acceptable salts thereof comprising the decarboxylative rearrangement of an amide of formula:

85. 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 84 or an obvious chemical equivalent thereof.

86. A process for preparing 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of formula and pharmaceutically acceptable salts thereof comprising decarboxylative rearrangement of an acyl azide first formed by reaction of sodium azide with an acyl chloride of formula

87. 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 86 or an obvious chemical equivalent thereof.

88. A process for preparing compounds of formula I as defined in claim 1 in which R3 and R4 are H comprising the reaction of hydrazoic acid with (a) a carboxylic acid of formula XIV
XIV
to give amines of said formula I.

89. Compounds of formula I as given in claim 1 and pharmaceutically acceptable salts thereof, whenever prepared by a process according to claim 88 or an obvious chemical equivalent thereof.

90. A process for preparing 1-[1-(4-chlorophenyl)cyclobutyl]butylamine of formula:
and pharmaceutically acceptable salts thereof comprising reacting hydrazoic acid with a carboxylic acid of formula:

91. 1-[1-(4-chlorophenyl)cyclobutyl]butylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 90 or an obvious chemical equivalent thereof.

92. A process for preparing 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine of formula:
and pharmaceutically acceptable salts thereof comprising reacting hydrazoic acid with a carboxylic acid of formula:

93. 1-[1-(3-4-dichlorophenyl)cyclobutyl]ethylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 92 or an obvious chemical equivalent thereof.

94. A process for preparing ?-[1-(4-chlorophenyl)cyclobutyl]benzylamine of formula:

and pharmaceutically acceptable salts thereof comprising reacting hydrazoic acid with a carboxylic acid of formula:

95. ?-[1-(4-chlorophenyl)cyclobutyl]benzylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 94 of an obvious chemical equivalent thereof.

96. A process for preparing 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of formula and pharmaceutically acceptable salts thereof comprising reacting hydrazoic acid with a carboxylic acid of formula

97. 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 96 or an obvious chemical equivalent thereof.

98. A process for the preparation of compounds of formula I
as given in claim 1 in which R4 is H comprising the hydrolysis of compounds of formula I in which R4 is CHO.

99. Compounds of formula I as given in claim 1 in which R4 is H and pharmaceutically acceptable salts thereof, whenever prepared by a process according to claim 98 or an obvious chemical equivalent thereof.

100. A process of preparing 1-[1-(4-chlorophenyl)cyclobutyl]butylamine of formula and pharmaceutically acceptable salts thereof, which comprises the hydrolysis of an N-formyl compound of formula:

101. 1-[1-(4-chlorophenyl)cyclobutyl]butylamine and its pharmaceutically acceptable salts whenever prepared by a process according to claim 100 or an obvious chemical equivalent thereof.

102. A process for preparing 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine of formula and pharmaceutically acceptable salts thereof, comprising the hydrolysis of an N-formyl compound, of formula:

103. 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine and its pharmaceutically acceptable salts whenever prepared by a process according to claim 102 or an obvious chemical equivalent thereof.

104. A process for preparing 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of formula

105. 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 104 or an obvious chemical equivalent thereof.

106. A process for preparing N-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine of formula and pharmaceutically acceptable salts thereof which comprises reducing the corresponding N-formyl compound, of formula:

107. N-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 106 or an obvious chemical equivalent thereof.

108. A process for preparing N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of formula:

and pharmaceutically acceptable salts thereof comprising the reduction of a compound of formula:

109. N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 108 or an obvious chemical equivalent thereof.

110. A process for preparing N, N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]butylamine of formula:
and pharmaceutically acceptable salts thereof comprising the reduction of a compound of formula:

111. N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-butylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 110 or an obvious chemical equivalent thereof.

112. A process for preparing N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine of formula:

and pharmaceutically acceptable salts thereof comprising the reduction of a compound of formula:

113. N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-butylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 112 or an obvious chemical equivalent thereof.

114. A process for preparing N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of formula:

and pharmaceutically acceptable salts thereof comprising the reduction of a compound of formula:

115. N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methyl-butylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 114 or an obvious chemical equivalent thereof.

116. A process for preparing N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-3-methyl-butylamine of formula and pharmaceutically acceptable salts thereof comprising the reduction of a compound of formula

117. N,N-dimethyl-1-[1-(3,4-dichlocophenyl)cyclobutyl]-3-methylbutylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 116 or an obvious chemical equivalent thereof.

118. A process for preparing N,N-dimethyl-1-[3,4-dichlorophenyl)cyclobutyl]ethylamine of formula:

and pharmaceutically acceptable salts thereof comprising the reduction of a compound of formula:

119. N,N-dimethyl-1-[1-(3,4-dichlocophenyl)cyclobutyl]-ethylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 118 or an obvious chemical equivalent thereof.

120. A process as claimed in claim 1 part (IX)thereof for the preparation of compounds of formula I as given in claim 1 in which one or both of R3 and R4 is other tnan H comprising the conversion of a compound of said formula I in which one or both of R3 and 24 is or are hydrogen to the required compound.

121. Compounds of formula I as given in claim 1 in which one or both of R3 and R4 is other than H and pharmaceutically acceptable salts thereof, whenever prepared by a process according to claim 120.

122. A process for preparing N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]butylamine of formula and pharmaceutically acceptable salts thereof, comprising the methylation of the corresponding primary amine compound, of formula:

123. N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]butylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 122 or an obvious chemical equivalent thereof.

124. A process for preparing N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine of formula:

and pharmaceutically acceptable salts thereof comprising the methylation of a compound of formula:

125. N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]
butylamine and its pharmaceutically acceptable salts whenever prepared by a process according to claim 124 or an obvious chemical equivalent thereof.

126. A process for preparing N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of formula and phacmaceutically acceptable salts theceof compcising the methylation of a compound of formula:

127. N,N-dimethyl-1-(4-chlorophenyl)cyclobutyl]-3 methyl butylamine and pharmaceutically acceptable salts whenever prepared by a process according to claim 126 or an obvious chemical equivalent thereof.

128. A process for preparing N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-3-methyl butylamine of formula:

and pharmaceutically acceptable salts thereof comprising the methylation of an amine of formula:

129. N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]
-3-methylbutylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim or an obvious chemical equivalent thereof.

130. A process for preparing N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine formula:

and pharmaceutically acceptable salts thereof comprising the methylation of an amine of formula:

131. N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]
ethylamine and its pharmaceutically acceptable salts whenever prepared by a process according to claim 130 or an obvious chemical equivalent thereof.

132. A process for preparing N-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine of formula:

and pharmaceutically acceptable salts thereof comprising the reaction of the corresponding primary amine of formula:

(a) with a methyl halide after suitably protecting the primary amine with an appropriate protecting group whereafter the protecting group is removed by a known method; or (b) with methyl formate followed by reduction of the resultant formamide.

133. N-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 132 or an obvious chemical equivalent thereof.

134. A process for preparing N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of formula:

and pharmaceutically acceptable salts thereof comprising the reaction of the corresponding primary amine of formula:

(a) with a methyl halide after suitably protecting the primary amine with an appropriate protecting group whereafter the protecting group is removed by a known method; or (b) with methyl formate followed by reduction of the resultant formamide.

135. N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methyl-butylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 134 or an obvious chemical equivalent thereof.

136. A process for preparing N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]butylamine of formula:

and pharmaceutically acceptable salts thereof comprising either I) the reaction of the corresponding primary amine of formula:

(a) with methyl halide; or (b) with formaldehyde and formic acid;
or II) the reaction of the corresponding secondary amine of formula:

(a) with methyl halide; or (b) with formaldehyde and formic acid; or (c) with methyl formate followed by reduction or the resultant formamide.

137. N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]butylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 136 or an obvious chemical equivalent thereof.

138. A process for preparing N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]butylamine of formula and pharmaceutically acceptable salts thereof comprising either I) the reaction of the corresponding primary amine of formula:

a) with methyl halide or b) with formaldehyde and formic acid or II) the reaction of the corresponding secondary amine of formula:

a) with methyl halide, or b) with formaldehyde and formic acid, or e) with methyl formate followed by reduction of the resultant formamide.

139. N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]
butylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 138 or an obvious chemical equivalent thereof.

140. A process for preparing N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of formula and pharmaceutically acceptable salts thereof comprising either I) the reaction of the corresponding primary amine of formula:

a) with methyl halide, or b) with formaldehyde and formic acid or II) the reaction of the corresponding secondary amine of formula:

a) with methyl halide, or b) with formaldehyde and formic acid, or c) with methyl formate followed by reduction of the resultant formamide

141. N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 140 or an obvious chemical equivalent thereof.

142. A process for preparing N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-3-methylbutylamine of formula:

and pharmaceutically acceptable salts thereof comprising either I) the reaction of the corresponding primary amine of formula:

a) with methyl halide, or b) with formaldehyde and formic acid or II) the reaction of the corresponding secondary amine of formula:

a) with methyl halide, or b) with formaldehyde and formic acid, or c) with methyl formate followed by reduction of the resultant formamide

143. N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-3-methylbutylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 142 or an obvious chemical equivalent thereof.

144. A process for preparing N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine of formula:

and pharmaceutically acceptable salts thereof comprising either I) the reaction of the corresponding primary amine of formula:

a) with methyl halide, or b) with formaldehyde and formic acid or II) the reaction of the corresponding secondary amine of formula:

a) with methyl halide, or b) with formaldehyde and formic acid, or c) with methyl formate followed by reduction of the resultant formamide

145. N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]
ethylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 144 or an obvious chemical equivalent thereof.

146. A process for preparing N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine of formula:

and pharmaceutically acceptable salts thereof comprising hydrolysis of the N-formyl compound of formula:

followed by methylation of the resultant primary amine of formula:

147. N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and pharmaceutically acceptable salts thereof whenever prepared by a process according to claim 146 or an obvious chemical equivalent thereof.

148. Compounds of formula I:

(I) in which 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

(II) in which R9 and R10, which are the same or different, are H, halo or an alkoxy group containing 1 to 3 carbon atoms;
in which R2 is H or an alkyl group containing 1 to 3 carbon atoms;
in which R3 and R4, 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, a group of formula R11CO where R11 is H or R3 and R4 together with the nitrogen atoms to which they are attached form a heterocyclic ring which a) contains 4 or 5 carbon atoms in addition to the nitrogen atom and is unsubstituted or substituted by one or more alkyl groups or b) contains a second nitrogen atom which is unsubstituted or substituted by an alkyl group;
in which R5 and R6 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 R5 and R6, together with the carbon atoms to which they are attached, form a second benzene ring which is unsubstituted or substituted by one or more halo groups, an alkyl or alkoxy group containing 1 to 4 carbon atoms or the substituents of the second benzene ring together with the two carbon atoms to which they are attached form a further benzene ring; and their pharmaceutically acceptable salts.

149. Compounds of formula I as claimed in claim 148 in which R1 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 3 to 6 carbon atoms or a group of formula II in which R9 and R10 are H, fluoro or methoxy and in which R2 is H or methyl.

150. Compounds of formula I as claimed in claim 149 in which R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl or phenyl.

151. Compounds of formula I as claimed in claim 148, 149 or 150 in which R3 and R4 are H, methyl, ethyl or formyl.

152. Compounds of formula I as claimed in claim 148, 149 or 150 in which R5 and R6 are H, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy, phenyl, or R5 and R6 together with the carbon atoms to which they are attached form a second benzene ring optionally substituted by halo.

153. Compounds as claimed in claim 148 of formula III

(III) in which R1, R2, R3, R4, R5 and R6 are as defined in claim 148.

154. Compounds as claimed in claim 153 in which R5 and R6, which are the same or different, are H, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy, phenyl or R5 and R6 together with the carbon atoms to which they are attached form a second benzene ring optionally substituted by a chloro group.

155. Compounds as claimed in claim 148 of formula IV

(IV) in which R1, R2, R3, R4 and R5 are as defined in claim 148 and R6 is fluoro or methyl.

156. Compounds of formula IV as claimed in claim 155 in which R5 is H, fluoro, chloro, bromo, iodo, trifluoromethyl, methyl, methoxy or phenyl and in which R6 is fluoro or methyl.

157. Compounds of formula I named in Table I herein.

158. 1-[1-(4-chlorophenyl)cyclobutyl]butylamine and its pharmaceutically acceptable salts.

159. N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-butylamine and its pharmaceutically acceptable salts.

160. N-methyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-butylamine and its pharmaceutically acceptable salts.

161. N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-butylamine and its pharmaceutically acceptable salts.

162. N-methyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and its pharmaceutically acceptable salts.

163. N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine and its pharmaceutically acceptable salts.

164. N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-3-methylbutylamine and its pharmaceutically acceptable salts.

165. 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine and its pharmaceutically acceptable salts.

166. N,N-dimethyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-ethylamine and its pharmaceutically acceptable salts.

167. .alpha.-[1-(4-chlorophenyl)cyclobutyl]benzylamine and its pharmaceutically acceptable salts.

168. 1-{[1-(3,4-dichlorophenyl)cyclobutyl]methyl}-propylamine and its pharmaceutically acceptable salts.

169. N,N-dimethyl-1-{[1-(3,4-dichlorophenyl)cyclobutyl]-methyl}propylamine and its pharmaceutically acceptable salts.

170. N,N-dimethyl-2-[1-(4-iodophenyl)cyclobutyl]ethylamine and its pharmaceutically acceptable salts.

171. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 148 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable excipient.

172. A pharmaceutical composition as claimed in claim 171 in unit dosage form.