FI77223C - Process for the preparation of new compounds used in the management of depression. - Google Patents

Description

1 77223

A process for the preparation of new compounds useful in the treatment of depression

The present invention relates to a process for the preparation of new compounds of formula I useful in the treatment of dep-5 ression.

R5 \ /; - λ <fR1R2 (CR7R8) nNR3R4

10 R6 —J

wherein n is 0 or 1; when

when n is 0, is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a cycloalkylalkyl group in which the cycloalkyl group contains 3 to 6 carbon atoms and the alkyl group contains 1 to 3 carbon atoms, an alkenyl group having 2 to 6 carbon atoms or a group of formula II

20

-GC

R 9 wherein R 9 and R 10 are the same or different, represent hydrogen, halogen or an alkoxy group having 1 to 3 carbon atoms; and when n is 1, R 1 is hydrogen or an alkyl group having 1 to 3 carbon atoms; R 1 is hydrogen or an alkyl group having 1 to 3 carbon atoms; R 1 and R 2, which are the same or different, represent hydrogen, a straight-chain or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms or a formyl group, or R 3 and R 35 together with nitrogen atoms form an alkyl group optionally having 1 to 4 carbon atoms a substituted heterocyclic group which is a pyrrolidinyl, piperidin-2,7223 dinyl, tetrahydropyridyl or piperazinyl group; R 5 and R 8f, which are the same or different, represent hydrogen, halogen, trifluoromethyl, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or phenyl, or together with the carbon atoms to which they are attached form a second benzene ring, optionally substituted with one or more halogen groups, or the substituents on the second benzene ring together with the two 10 carbon atoms to which they are attached form a third benzene ring; and R 1 and R 8, which are the same or different, represent hydrogen or an alkyl group having 1 to 3 carbon atoms, and for the preparation of pharmaceutically acceptable salts thereof.

In the formulas of this publication, the term refers to the formula 20 t -C-CHO

I I

A 1,1-disubstituted cyclobutane group according to CH2-CH2 and -CR-ι R0 (CR-.R0) NR-, R. means 1 2 7 8 n 3 4 l1 f l Λ ^ r3

{vi J

30 R2 \ R8 '.

3 77223

Preferred compounds of formula I are those in which n is 0, a straight-chain or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a cycloalkylmethyl group in which the cycloalkyl group contains 3 to 6 carbon atoms or a group of formula II in which Rg and / or R 1 q represents hydrogen, fluorine or methoxy and R 2 is hydrogen or methyl. Examples of particularly preferred compounds of formula I are those wherein n is 0, R 2 is hydrogen and R 1 is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl or phenyl.

In preferred compounds of formula I, wherein 15 is n, R 1 is hydrogen or methyl and R 2 is hydrogen. In particularly preferred compounds of formula I wherein n is 1, both R 1 and R 2 are hydrogen.

In the preferred compounds of formula I, R 1 and / or R 2 are hydrogen, methyl, ethyl or formyl or, when R 1 and R 2 together with the nitrogen atom to which they are attached form a heterocyclic ring, the preferred compounds of formula I contain a nitrogen atom and A heterocyclic group having 4 or 5 carbon atoms (e.g. pyrrolidinyl, piperidinyl) optionally substituted with one or more alkyl (e.g. methyl) groups (e.g. pyrrolidinyl substituted with two methyl groups), a heterocyclic group containing another nitrogen atom which is optionally alkylated (e.g. 4-methylpiperazinyl) or a heterocyclic group containing one or more double bonds (e.g. 1,2,3,6-tetrahydropyridinyl). In particularly preferred compounds of the formula I, R 1 and / or R 4 denote hydrogen, methyl, ethyl and formyl.

In preferred compounds of formula I, R 1.

And / or R 1 is hydrogen, fluorine, chlorine, iodine, trifluoromethyl, methyl, methoxy or phenyl, or R 1. and Rg together with the carbon atoms to which they are attached form a second benzene ring optionally substituted with halogen.

4 77223

The first group of recommended compounds is described

formula III

_ ^ CR1R2 (CR7RQ) nNR3Rz + 5 * 5 ~ Υ _) - 1

10 wherein Rg and Rg have the same meaning as above. Formula III

Rg and Rg, which may be the same or different, are hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, methoxy or phenyl, or Rg and Rg together with the carbon atoms to which they are attached form another benzene ring which may be optionally substituted with chlorine. In particularly preferred compounds of the formula III, Rg and / or Rg are hydrogen, fluorine, chlorine, iodine, trifluoromethyl, methyl or phenyl.

Another group of preferred compounds is represented by Formula IV

CR 1 CR 2 NR 2 t> h 25 1 where 1 * 5 may be hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, methoxy or phenyl and R 8 is fluorine or methyl. In particularly preferred compounds of formula IV, R 9 is hydrogen or chlorine.

In preferred compounds of formula I wherein non 1, R? is hydrogen, methyl or ethyl and R 9 is hydrogen, and in particularly preferred compounds of formula I R 1 is hydrogen or ethyl and R 8 is hydrogen.

5 77223

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

The compounds of formula I containing one or more asymmetric carbon atoms may exist in various optically active forms. If and R 2 are different or R 7 and R 8 are different, the compounds of formula I contain a chiral center. These compounds exist in two enantiomeric forms, and the present invention encompasses the preparation of both enantiomeric forms and mixtures thereof. If both R 1 and R 2 are different and R 1 and R 8 are different, the compounds of formula I contain two chiral centers and the compounds exist in four diastereomeric forms. The present invention encompasses the preparation of all of these diastereomers and mixtures thereof.

For the process according to the invention a new formula I

for the preparation of the compounds according to the invention and their salts, it is characterized in that

A) Compounds of formula I wherein n is 0, R 1 is hydrogen and R 1, R 9 and R 8 are as defined in formula I are prepared by reacting ketones of formula V

and compounds of formula I wherein n is 1, R 1 is hydrogen and R 1, R 2, R 5, R 8 and R 8 are as defined in formula I are prepared by reacting ketones or aldehydes of formula VI

6 77223

Rr v / \ CR, R ^ COR ^

^ Vt-V

To react with a) formamide and formic acid to give compounds of formula I wherein R 1 is hydrogen and is CHO, b) formamides of formula IICONHR 4 wherein R 1 is alkyl or cycloalkyl, and with formic acid to give compounds of formula I wherein R 1 is CHO and R 2 is as defined above, c) with amines of formula R 3 NH 2 with alkyl or cycloalkyl and with formic acid to give compounds of formula I wherein R 1 is CHO and CHO and R 2 are as defined above, d) with an ammonium salt and a reducing agent to give compounds of formula I in which R 1 and R 2 are hydrogen, or e) with an amine of formula R 1 in NHR 4 in which R 1 and / or or R 1 represents hydrogen, alkyl or cycloalkyl or R 3 and R 4 form a heterocyclic group together with the nitrogen atom to which they are attached either i) by catalytic hydrogenation or ii) in the presence of formic acid to give compounds of formula I wherein R 1 and R 2 have the same meaning as above,

B) Compounds of formula I are prepared by reduction of compounds of formula VII

30 7 35 wherein 7 77223 a) Z is a group of formula -CR 2 = NOH or an ester or ether thereof, to give compounds of formula I wherein n is 0 and R 2, R 8 and R 2 are hydrogen; b) Z is a group of the formula -CR 2 = NY, wherein Y is a metal-containing moiety derived from an organometallic reagent such as MgBr or Li to give compounds of formula I wherein n is 0 and R 1, R 8 and R 2 are hydrogen ; c) Z is a group of formula -CR 9 R 2 CN to give compounds of formula I wherein n is 1 and R 9, R 6, R 6 and R 8 are hydrogen; d) Z is a group of the formula -CR 2 R 2 CR 4 = NOH or an ester or ether thereof to give compounds of formula I wherein n is 1 and R 9, R 6 and R 8 are hydrogen;

E) Z is a group of the formula -CR 1 R 2 CR 2 = NY, wherein Y

is a metal-containing moiety derived from an organometallic reagent such as MgBr or Li to give compounds of formula I wherein n is 1 and Rg, R1 and R8 are hydrogen; or f) Z is a group of formula -CRgR 1 ONRgR 4 to give compounds of formula I wherein n is 1 and R 1 and R 8 are hydrogen, the reductions being carried out using a reducing agent such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, boride dimethyl

C) Compounds of formula I are prepared by reacting an organometallic reagent which is a Grignard reagent of formula R 1 MgBr or an organolithium compound of formula R 1 Li with an imine of formula VIII

Rc \ / -v CH = NR ~ 35 R6 ~~ and the product obtained by hydrolysis to give compounds of formula I in which n is 0 and R1 is hydrogen, 77223 8 D) Compounds of formula I are prepared according to the formula X Rc CR, RoCONH_R6 by decarboxylating rearrangement of the amide to give amines-10 in which n is 0 and R 1 and R 2 are hydrogen, and after methods A to D, (i) possible hydrolysis of compounds of formula I wherein R 1 is CHO to give compounds of formula I , or hydrogen, or (ii) optionally reducing compounds of formula I wherein R 1 is CHO to give compounds of formula I wherein R 4 is methyl, and / or (iii) obtaining compounds of formula I wherein R 1 and and R 1 is hydrogen, optionally converted to compounds of formula I wherein R 1 and / or R 2 is other than hydrogen.

Compounds of formula I with hydrogen can be prepared by hydrolysis of compounds of formula I wherein R 1 is CHO, for example by acid hydrolysis.

Compounds of formula I wherein R 1 is methyl may be prepared by reduction of compounds of formula I wherein R 4 is CHO, for example with lithium aluminum hydride or sodium bis- (2-methoxyethoxy) aluminum hydride.

Compounds of formula I in which one or both of R 1 and R 2 are other than hydrogen may be prepared from compounds of formula I in which one or both of R 1 and R 2 are hydrogen by methods well known in the art for converting primary amines to secondary or to tertiary amines or to convert secondary amines to tertiary amines 77223 9. The following are examples of suitable methods: a) alkylation of primary amines of formula I to give secondary amines of formula I e.g.

5 a process comprising the steps of protecting a primary amine with a protecting group such as a trifluoroacetyl group, alkylating with an alkyl halide and deprotecting, for example, by hydrolysis; b) alkylating primary amines of formula I and, for example, an alkyl acid halide to give tertiary amines of formula I wherein and R 1 are the same; c) alkylating secondary amines of formula I, for example with an alkyl halide, to give tertiary amines of formula I, wherein R 1 and R 4 may be different; d) reacting the primary amines of formula I with sodium borohydride and acetic acid to give secondary amines of formula X wherein ethyl is hydrogen and R 1 is hydrogen; e) reacting the primary amines of formula I with formaldehyde and formic acid to give tertiary amines of formula I wherein R 1 and R 2 are both methyl; F) reacting secondary amines of formula I wherein R 1 is hydrogen with formaldehyde and formic acid to give tertiary amines of formula I wherein R 1 is methyl; g) formylating amines of the formula I, for example by reaction with methyl formate, and reducing the formamides obtained, for example with lithium aluminum hydride, to give secondary amines of the formula I in which R 1 is methyl and R 2 is hydrogen; h) formylating secondary amines of the formula I, for example by reaction with methyl formate, and reducing the resulting formamides, for example with lithium aluminum hydride, to give tertiary amines of the formula I in which R 1 is methyl; 77223 i) acylation of primary amines of the formula I, for example by reaction with an acyl chloride of the formula R 1 COCl or an anhydride of the formula (R 1 CO 2) 20 in which R 2 is an alkyl group, and reduction of the amides 5 obtained, for example with lithium aluminum chloride to obtain secondary amines according to which R 1 is -CH 2 R 12 and R 4 is hydrogen? j) acylation of secondary amines of the formula I in which R 1 is hydrogen, for example by reaction with an acyl chloride of the formula R 10 COCl or an anhydride of the formula (R 12 CO) 2 <O, wherein R 2 is an alkyl group and reduction of the amides obtained, for example with lithium aluminum hydride to obtain tertiary amines wherein R 4 is CH 2 R 12; K) reacting primary amines of formula I with an aldehyde of formula R 13 CHO, wherein R 3 may be an alkyl group, or with a ketone of formula R 14 COR 15, wherein R 4 and R 4 may be the same or different and represent alkyl groups, or 4 and R 1 together with the 20 carbon atoms to which they are attached may form an acyclic ring, and the resulting imines or enamines are reduced, for example by sodium cyanoborohydride or by catalytic hydrogenation, to give secondary amines of formula I wherein R 1 is R 13 CH 2 -R 15 or R 14, respectively. -CH- 1) reacting the primary amines of the formula I with a non-geminally disubstituted alkane containing 2 or 3 carbon atoms between the carbon atoms to which the substituents are attached, the substituents being, for example, halogen groups, preferably bromine groups, or p-toluenesulfonyloxy groups to give compounds of formula I wherein R 1 and R 4 together with the nitrogen atom to which they are attached form a heterocyclic ring containing no heteroatoms other than a nitrogen atom.

11 77223

Ketones of formula V can be prepared from formula XVI

5 r sK— / LI xvi by hydrolysis of imines according to K6, where Y represents a metal-containing moiety derived from an organometallic reagent. Imines of formula XVI can be prepared by reacting said organometallic reagent with a cyano compound of formula XVII.

"5 ^ y T

n - XVII

R6

Suitable organometallic reagents include Grignard reagents of formula R 1 MgX wherein X is Cl, Br or I (Y = MgX) and organolithium compounds of formula R 1 Li (Y = Li).

Ketones of formula VI can be prepared from formula XVIII

\ C ^ RgCR ^ .NY

jL / U XVIII

By hydrolysis of imines according to «6 30, wherein Y represents a metal-containing moiety derived from an organometallic reagent. The imines of formula XVIII can be prepared by reacting said organometallic reagents.

35 tion using formula XIX

12 77223 R5 X * - ^, “Λ ™ W) - 1

5 R6 - XIX

with cyano compounds according to

Suitable organometallic reagents include Grignard reagents of the formula R 1 MgX, wherein X is Cl, Br or J (Y = MgX) and organolithium compounds of the formula R 1 -Li (Y = Li).

Ketones of formula V can be prepared by the reaction of carboxylic acid derivatives such as an amide or acid halide with an organometallic reagent, for example of formula XX

By reaction of an acid chloride of formula Rc-COCl2 with a Grignard reagent of formula R-MgX, where X is Cl, Br or .1 at low temperatures, or by reaction of a carboxylic acid of formula XXI with an organometallic reagent, e.g. with an organolithium compound of formula R 1 Li.

Ketones of formula VI can be prepared by the reaction of carboxylic acid derivatives such as amide or acid halide with an organometallic reagent, for example 77223 13 with an organometallic reagent, for example by reaction of an acid chloride of formula XII with a Grignard reagent of formula R 1 MgX where X is Cl , Br or I, at low temperatures or by reaction of a carboxylic acid of formula XIV with an organometallic reagent, for example an organolithium compound of formula R 1 Li.

Ketones of formula V wherein R 1 is alkyl (e.g. methyl) and ketones of formula VI wherein R 1 is alkyl (e.g. methyl) can be prepared by reaction of a diazoalkane (e.g. diazomethane) with aldehydes of formula XXII and VI respectively.

R, CHO

5γΛΙ

a6 A = / U

Aldehydes of formula VI can be prepared by methods well known in the art. The following are examples of suitable processes: a) reduction of cyano compounds of formula XIX with, for example, di-tert-butylaluminum hydride or diisobutylaluminum hydride; b) reducing carboxylic acid derivatives, for example i) reducing compounds of formula VII wherein Z is CR 1 R 2 CONR 3 R 4 and both R 1 are other than hydrogen, using for example lithium diethoxyalumohydride; ii) reducing amides prepared by the reaction of ethyleneimine with an acid chloride of formula XII using, for example, lithium aluminum hydride as a reducing agent; iii) reduction of acid chlorides of formula XII with, for example, lithium tri-tert-butoxyaluminohydride; 77223 14 c) by reaction of alcohols (formed by reduction of carboxylic acids of formula XIV) with, for example, a chromium trioxide-pyridine complex in dichloromethane under anhydrous conditions.

Compounds of formula VII in which Z is a group of the formula -CR 2 = NOH or a group of the formula -CR 1 - CR 2 = NOH or their esters or ethers may be prepared by the reaction of hydroxylamine or an ester or ether thereof with ketones of formula V or with alde-10 hydes of formula VI, respectively.

The preparation of compounds of formula VII wherein Z is a group of formula -CR 1 R 2 = NY or a formula of formula -CR 1 R 2 CR 7 = NY is described above in connection with compounds of formulas XVI and XVIII, respectively.

The preparation of compounds of formula VII wherein Z is a group of formula -CR 2 R 2 CN is described below for cyano compounds of formula XIX.

Compounds of formula VII in which Z is a group of formula -CR 2 R 6 CONR 4 R 4 may be prepared by the reaction of acid derivatives such as esters or acid halides (e.g. acid chlorides of formula XII) with amines of formula HNR 1 R 4. Compounds of formula VII in which Z is CR-CON 2 may be prepared from cyano compounds of formula XIX, for example by hydration with aqueous acids or by reaction with hydrogen peroxide in the presence of a base.

Imines of formula VIII can be prepared by reacting amines of formula R 1 N 2 with aldehydes of formula XXII.

Amides of formula X can be prepared from ammonia

reaction of carboxylic acid derivatives, for example of formula XII

CR, R-COCl

R5 \ / —Λ 1 XII

With acid chlorides of formula R6-77223 or can be prepared from cyano compounds of formula XIX, for example by hydration with aqueous acids or by reaction with hydrogen peroxide in the presence of a base.

Amides of formula X wherein R 1 and R 2 are hydrogen can be prepared from acid chlorides of formula XX by reaction with diazomethane to produce diazoketones which are resolved in the presence of ammonia as a catalyst, for example using silver to give the desired amides.

Carboxylic acids of formula XXI can be prepared by hydrolysis, for example by basic hydrolysis of cyano compounds of formula XIX. Carboxylic acids of formula XXI can be prepared by the reaction of nitric acid with amides prepared by the reaction of ammonia with carboxylic acid derivatives, for example acid chlorides of formula XX or by reaction of cyano compounds of formula XVII with hydrogen peroxide in the presence of a base.

Cyano compounds of formula XVII can be prepared from formula XXIV

R5 ^ 25 y-ch2cn xxiv by reaction of cyano compounds according to R6 with 1,3-disubstituted propane, for example 1,3-dibromopropane and a base such as sodium hydride.

Cyano compounds of formula XIX wherein R 1 and R 2 are hydrogen can be prepared from cyano compounds of formula XVII by, for example, the following series of reactions: a) hydrolysis of a cyano group to form a carboxylic acid of formula XXI, b) reduction of the carboxylic acid with to form the corresponding alcohol, 16 77223 c) replacement of the hydroxy group of the alcohol with, for example, a leaving group of the p-toluenesulfonyloxy group, and d) replacement of the leaving group with a cyano group.

Cyano compounds of formula XIX in which one or both of the groups and R 2 are other than hydrogen may be prepared from the corresponding cyano compounds of formula XIX in which R 1 and / or R 2 are hydrogen, for example by alkylation with an alkyl halide of a base such as lithium diisopropylamide. acid.

Cyano compounds of formula XIX wherein R 2 is hydrogen may also be prepared by reacting ketones of formula V or aldehydes of formula XXII with a reagent to add a cyano group such as p-toluenesulfonylmethyl isocyanide.

Acid chlorides of formulas XX and XII may be

prepares formulas XXI and XIV, respectively

CR1R2COOH

20 ^ __ XIV

6 by reaction of carboxylic acids with, for example, thionyl chloride.

Aldehydes of formula XXII can be prepared by methods well known to those skilled in the art. The following are examples of suitable processes: a) Reduction of cyano compounds of formula XVII with, for example, di-tert-butylaluminum hydride or diisobutylaluminum hydride, b) reduction of carboxylic acid derivatives, for example i) reduction of tertiary amides with secondary amines acid chlorides, for example, when the secondary amine is a dialkylamine, using lithium diethoxyalumohydride as a reducing agent, or when the secondary amine is ethyleneimine, using lithium aluminum hydride as a reducing agent, 17 77223 ii) c) oxidation of alcohols (prepared by reduction of carboxylic acids of formula XXI with, for example, a chromium trioxide-pyridine complex in dichloromethane under anhydrous conditions.

Compounds of formula V (except those in which R 9 and R 8 are hydrogen and R 6 is methyl or ethyl), ketones of formula VI and aldehydes of formula VI (except those in which R 1, R 2, R 8 and R 8 are hydrogen), compounds of formula VII (except those in which Z is -CR 2 = NY and R 9 and R 8 are hydrogen and R 2 is methyl or ethyl), imines of formula VIII (except those in which R 8 and R 8 are hydrogen) and compounds of formula XVI imines (except those in which Rg and Rg15 are hydrogen and R1 is methyl or ethyl) and of formula XVIII

imines of formula X, amides of formula X, carboxylic acids of formula XIV (except those in which R 1, R 2, R 9 and R 8 are hydrogen), cyano compounds of formula XIX and acid chlorides of formula XII (except those in which R 1, R 2, R 8 and R 8 are and Rg are hydrogen), which are listed above as intermediates, are novel compounds. Some of formulas XVII and XXIV

cyano compounds are novel compounds.

The therapeutic effect of the compounds of formula I has been demonstrated by noting the ability of the compounds to reverse the hypothermic effects of reser-25 in the following manner. Male Charles River CDI mice weighing between 18 and 30 grams were separated into groups of five individuals and given food and water ad libitum. After 5 hours, the body temperature of each mouse was measured orally and the mice were injected intraperitoneally with reserpine (5 mg / kg) dissolved in deionized water containing ascorbic acid (50 mg / ml). The amount of solution injected was 10 ml / kg body weight. Nine hours after the start of the test, feeding was stopped, but water 35 was still available ad libitum. Mice were measured 24 hours after the start of the assay and given test compound suspended in 0.25% hydroxyethylcellulose solution (sold by Union Carbide under the trade name 77223 18

Cellosize 15000) in deionized water at a dose of 10 ml / kg body weight. After three hours, the temperatures of all mice were measured again. The percentage inhibition of reserpine-induced decrease in body temperature was then calculated from the equation: (Temperature after 27 hours - temperature after 24 hours) x 100 (Temperature after 5 hours - temperature after 24 hours) 10 The mean of each group of five mice was determined at several dose levels. to determine the average dose that gives a 50% inhibitory effect (ED ^ g value). All compounds which are the final products of the following examples gave an ED 50 value of 30 mg / kg or less. It is generally known to those skilled in the art that this test detects compounds that have anti-depressant effects in humans.

Table I lists the compounds of formula I having an ED5g value of 10 mg / kg or less in the above test.

Table I

1- [T- (3,4-dichlorophenyl) cyclobutyl / ethylamine hydrochloride, N-methyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] ethyl] amine hydrochloride, N, N-dimethyl-1- 1- (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride, 1- [1- (4-iodophenyl) cyclobutylethylamine hydrochloride, N-methyl-1- [1- (4-iodophenyl) cyclobutyl] ethylamine hydrochloride, N, N-dimethylamine 1- [1- (4-iodophenyl) cyclobutyl] ethylamine hydrochloride, N-methyl-1- [N- (2-naphthyl) cyclobutyl] ethylamine hydrochloride, 35 N, N-dimethyl-1- [1- -chloro-3-trifluoromethylphenyl) cyclobutyl / ethylamine hydrochloride, 1- {1- (4-chlorophenyl) cyclobutyl / butylamine hydrochloride, N-methyl-1- [1- (4-chlorophenyl) cyclobutyl] butylamine hydrochloride, 77223 N, -dimethyl-1- [1H - (4-chlorophenyl) cyclobutyl / butylamine hydrochloride, 1- [1- (3,4-dichlorophenyl) cyclobutyl] butylamine hydrochloride, 5N-methyl-1- [1- (3 (4-dichlorophenyl) cyclobutyl tert-butylamine hydrochloride, Ν, Ν-dimethyl-1- [1- (3,4-di chlorophenyl) cyclobutyl / butylamine hydrochloride, v.

1- / 1- (4-biphenyl) cyclobutyl / butylamine hydrochloride, 10 N, N-dimethyl-1- [1- (4-biphenylyl) cyclobutyl] butylamine hydrochloride, 1- [1- (4-chloro-3-fluorophenyl) ) cyclobutyl / butylamine hydrochloride, N-formyl-1- [1- (4-chloro-3-fluorophenyl) cyclobutyl] -butyl] amine, 1- [1- (3-chloro-4-methylphenyl) cyclobutyr / butylamine hydrochloride, N-formyl-1-Z1-phenylcyclobutyl-butylamine, 1- [N- (3-trifluoromethylphenyl) cyclobutyl] butyl-20-amine hydrochloride, 1- [1- (naphth-2-yl) cyclobutyl] butylamine hydrochloride, 1- N- (6-chloronaphth-2-yl) cyclobutyl] -butylamine, N-methyl-1- [1- (4-chlorophenyl) cyclobutyl] -2-methylpropylamine hydrochloride, 25- [1- 4-chlorophenyl) cyclobutyl / 4-pentylamine hydrochloride, N-methyl- [1- (4-chlorophenyl) cyclobutyl] pentylamine hydrochloride, N, N-dimethyl-1- (1-phenylcyclobutyl) -r-3-methylbutylamine , 1- [1- (4-chlorophenyl) cyclobutyl] [3-methylbutylamine hydrochloride, N -methyl-1- [N- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride, 35β, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -5-methylbutylamine hydrochloride, N -formyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine, 77223 20 N, N-dimethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride, N-methyl-1- [1- (naphth-2-yl) cyclobutyl] -3-methylbutylamine hydrochloride, N-methyl-1- [1- (3,4-dimethylphenyl) cyclobutyl] -3-methyl libutylamine hydrochloride, [1- (4-chlorophenyl) cyclobutyl] (cyclopropyl) methylamine hydrochloride, N-methyl- [1- (4-chlorophenyl) cyclobutyl] (cyclopentyl-10-yl) methylamine hydrochloride, N, 1- (4-chloro) cyclobutyl / (cyclohexyl) methylamine hydrochloride, N-methyl- (1- (4-chlorophenyl) cyclobutyl] (cyclohexyl) methylamine hydrochloride, [1- (3,4-dichlorophenyl) cyclobutyl] (cyclohexyl) hydrochloride methyl / L- (3,4-dichlorophenyl) cyclobutyl / (cyclohexyl i) methylamine hydrochloride, [1- (4-chlorophenyl) cyclobutyl] (cyclohexyl) methyl-20-amine hydrochloride, 1- [1- (4-chlorophenyl) cyclobutyl] -N-cyclopropylethylamine hydrochloride, N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -2-cyclohexylethylamine hydrochloride, [1- (1- (4-chlorophenyl) cyclobutyl] benzylamine hydrochloride, N-methyl-Cf- [1- (4-chlorophenyl) cyclobutyl] benzylamine hydrochloride, 1- [1- (4-chloro-2-fluorophenyl) cyclobutyl] butylamine, N, N-dimethyl-1- [1- (4-chloro-2-fluorophenyl) cyclobutyl] '- butylamine hydrochloride, 1- [1- (3,4-dichlorophenyl) cyclobutyl / methyl] propylamine hydrochloride, N, N-dimethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] methyl] propylamine hydrochloride, N , N-dimethyl-2- [1- (4-iodophenyl) cyclobutyl] ethylamine hydrochloride, 2i 77223 / Ns N-ethyl-1- [2- (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride, and Ν, Ν-diethyl-l-Zi- (3,4-dichlorophenyl) syklobutyyli7etyyli-amiinihydrok chloride.

The compounds of formula I provide pharmaceutical preparations comprising a therapeutically effective amount of a compound of formula I in association with a pharmaceutically acceptable diluent or carrier.

When used therapeutically, the active compound may be administered orally, rectally, parenterally or topically, preferably orally.

The pharmaceutical is well known for pharmaceutically acceptable carriers suitable for use in pharmaceutical preparations. These preparations may contain from 0.1 to 15% by weight of active compound, and are usually prepared in unit dosage form.

Formulations for oral administration are preferred and include known pharmaceutical forms for such administration, for example, tablets, capsules, syrups, and aqueous or oily suspensions. The additives used in the preparation of these compositions are pharmaceutically known 1 excipients. Tablets may be prepared by mixing the active compound with an inert diluent such as calcium phosphate, disintegrating agents, for example, corn starch, and lubricating agents, for example, magnesium stearate, and tabletting the mixture by known methods. Tablets may be prepared in a manner known to those skilled in the art to provide a sustained release of the compounds of formula I. If desired, these tablets may be provided with an enteric coating by known methods using, for example, cellulose acetate phthalate. Correspondingly, capsules, for example hard or soft gelatine capsules, can be prepared by conventional methods and provided with an enteric shell in a known manner. Tablets and capsules may each contain from 1 to 500 mg of active compound. Other compositions for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium together with a non-toxic suspending agent such as sodium carboxymethylcellulose and oily suspensions containing the compound of this invention in a suitable vegetable oil, for example vegetable oil.

Preparations suitable for rectal administration are known pharmaceutical preparations for this administration, for example suppositories together with coconut butter or polyethylene glycol base.

Preparations suitable for parenteral administration are known pharmaceutical preparations for this administration, for example, sterile suspensions in aqueous medium or sterile solutions in a suitable solvent.

Formulations suitable for topical administration may comprise a matrix in which the pharmacologically active compounds of formula I are dispersed so that the compounds remain in contact with the skin for transdermal administration of the compounds. Alternatively, the active compounds may be dispersed in a pharmaceutically acceptable ointment or salve.

In some compositions it may be advantageous to use compounds of the formula I in very finely divided form, for example in liquid energy milling.

In the above preparations, the active compound of formula I may, if desired, be used in combination with other compatible pharmaceutically active ingredients.

Pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I may be used to treat depressive conditions in a mammal, including a human. In this treatment, the daily amount of the compound of formula I administered is in the range of 1 to 1000 mg, preferably 5 to 500 mg.

The invention is illustrated by the following examples. All compounds were identified by standard analytical methods and obtained satisfactory elemental analyzes. All melting and boiling points are given in degrees Celsius.

23 77223

Example 1

A solution of 3,4-dichlorobenzyl cyanide (25 g) and 1,3-dibromopropane (15 ml) in dry dimethyl sulfoxide (150 ml) was added dropwise under nitrogen to a stirred mixture of sodium hydride (7.5 g). 5 dispersed in mineral oil (7.5 g) and dimethyl sulfoxide (200 ml), at a temperature in the range of 30-35 ° C.

The mixture was stirred at room temperature for two hours and then propan-2-ol (8 ml) was added dropwise followed by water (110 ml). The mixture was filtered through diatomaceous earth, sold under the tradename CELITE, and the solid residue was washed with ether. The ether layer was separated, washed with water, dried and concentrated. 1- (3,4-Dichlorophenyl) -1-cyclobutanecarbonitrile (b.p. 108-120 ° C at 0.15 mm Hg) was isolated by distillation. This method is a modification of the method proposed by Butler and Pollatz (J.Org.Chem.,

Col. 36, no. 9, 1971, page 1308).

1- (3,4-Dichlorophenyl) -1-cyclobutanecarbonitrile (21.7 g) prepared as described above was dissolved in dry ether (50 ml) and the solution was added under nitrogen to the reaction product obtained from gaseous methyl bromide on magnesium turnings (3, 9 g) in dry ether (150 ml). The mixture was stirred at room temperature for two hours and then refluxed for two hours with stirring. Crushed ice and then concentrated hydrochloric acid (100 ml) were added and the mixture was refluxed for two hours. The ether layer was separated, washed with water and aqueous sodium bicarbonate, dried and evaporated. 1-Acetyl-1- (3,4-dichlorophenyl) cyclobutane (b.p. 108-110 ° C, 0.2 mmHg) was isolated by distillation.

1-Acetyl-1- (3,4-dichlorophenyl) -cyclobutane (9.1 g) prepared as described above in formamide (6.5 ml) and 98% formic acid (3 ml) were heated at 180 ° C for 16 hours under N -formyl-1- [1- (3,4-dichloro-phenyl) -cyclobutyl] -ethylamine. 35 Concentrated hydrochloric acid (20 ml) was added and the mixture was refluxed for 3 hours. The solution was then cooled, washed with ether and sodium hydroxide solution was added. The product was extracted with ether and the ether extract was washed with water, dried and evaporated to dryness. By distillation, 1- ^ 1- (3,4-

Q

dichlorophenyl) -cyclobutyl / ethylamine (b.p. 112-118 ° C, pressure 0.2 mm Hg). The amine was dissolved in propan-2-ol and concentrated hydrochloric acid and the solution was evaporated to dryness to give 1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride (m.p. 185-195 ° C) (Formula I n = O; R 1 = Me; R 2, R 4 = H; R 5 = 4-Cl; R 8 = 3-Cl).

Example la

The above preparation of N-formyl-1- {1- (3,4-dichlorophenyl) cyclobutyl-ethylamine was repeated (m.p.

= 124-125 ° C) (Example 1 (a) Formula I n = O; R 2 = Me; R 2 = H; R 2 = H; = CHO; R 8 = 4-Cl and R 9 = 3-Cl) and the product was isolated by cooling the reaction mixture and collecting the solid by filtration. The formamide was then hydrolyzed with concentrated hydrochloric acid in a methylated industrial spirit to give the hydrochloride salt of 1- [1- (3,4-dichlorophenyl) -cyclobutyl-K] ethylamine.

The following compounds were prepared as described in Example Ia. The hydrolysis conditions of the formamides isolated by suitable methods are given in the notes.

Λ- ^ CHR1NH2.HCl

K _> - I

I-1

Example R ^ Rg Rg kp. (free HCl salt- Note base) lan m.p. tuksia

30 1 (b) methyl Cl H 107 ° C / 1.2 Å

mmHg

1 (c) n-butyl Cl H 138-139 ° C B

1 (d) methyl H 205-207 ° C

1 (e) methyl Cl CF 3 216-217 ° C D

35 A = aqueous HCl / methylated industrial spirit 25 77223 B = 1-valeryl-1- (4-chlorophenyl) cyclobutane was prepared in tetrahydrofuran. Hydrolysis was performed using concentrated hydrochloric acid / methylated industrial spirit.

5 C = Concentrated HCl / diethylene glycol methyl ether mixture (in the same manner as described later in Example 12).

D = concentrated hydrochloric acid / methylated industrial spirit.

Example 2

The product of Example 1 (4.04 g), water (0.5 ml) and 98% formic acid (3.6 ml) were stirred under cooling. A 37-40% aqueous formaldehyde solution (3.3 ml) was added and the solution was heated at 35-95 ° C for five hours. The solution was evaporated to dryness and the residue was acidified with concentrated hydrochloric acid and the water was removed by repeated addition of propan-2-ol, then evaporated to dryness in vacuo. Crystals of N, N-dimethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride (m.p. 211-213 ° C) were isolated (Formula I, 20 n = O; = Me; R 2 - H; R3, R4 = Me; R5 = 4-Cl; R8 = 3-Cl).

As described above, the compounds of Examples 1 (b) and 1 (d) were converted to the following compounds r,-, CHR-jNMe ^ HCl 30 Eg Starting R ^ R ^ Rg The free base of the HCl salt of the HCl salt at its boiling point _________point_ 2 (a) 1 (b) methyl Cl H 98-10 ° C / 0.5 mmHg

2 (b) 1 (d) methyl 1H 260-261 ° C

35 26 77223

Example 3

N, N-Dimethyl-1- [1- (4-biphenylyl) cyclobutyl] ethylamine hydrochloride (mp 196-197 ° C) was prepared as described in Examples 1 and 2 above (Formula I, n = 0; 5 = Me; R 2 = R 3 »R 4 = Me» R 5 = 4-phenyl and R 8 = H).

Example 4

1-Acetyl-1- (3,4-dichlorophenyl) cyclobutane (15 g), N-methylformamide (47.5 ml), 98% formic acid (10.3 ml) prepared as in Example 1 and a 25% aqueous solution of methylamine (1.5 ml) was stirred together and heated with stirring at 170-180 ° C for 8 hours. The mixture was cooled and extracted with ether. The ether extract was washed, dried and evaporated to give a pale yellow oil which was boiled with concentrated hydrochloric acid (50 ml) for 2 hours. Methylated industrial alcohol (IMS) (50 mL) was added and the mixture was refluxed for 16 hours. The mixture was then cooled to 0 ° C and the white precipitate was collected by filtration, washed with acetone and dried. The product, N-20 methyl-1- / 1- (3,4-dichlorophenyl) cyclobutyl / ethylamine hydrochloride, had a melting point of 254-256 ° C (formula I, n = O;

R 1 = Me; R2 = H; R3 = Me; R4 = H, R5 = 4-Cl and = 3-Cl).

The following compounds of formula I were prepared as described above.

25 27 7 7 2 2 3 CHR, NHMe.HCl S R5 ^) r6 -

Eg R R_ R., Amine kp. HCl salt Note.

_1 5 O ___ sp._ 4 (a) Me Cl H 98-100 ° / 0.15 "” «9 240-241 ° 10 4 (b) Me H Cl 269-272 ° 4 (c) Me Br H 96-98 ° / 0.1 n ^ g 4 (d) Me H Br 251-255 ° 4 (e) Me H CF 3 H 219-221 ° 4 (f) Me H CF 3 225-228 ° 15 4 (g) Me - (CH = CH) 2 - 254-257 ° 4 (h) Me Cl CF? 198-200 ° 4 (i) Et Cl H 238-240 °

4 (j) Pr Cl. H 228-229 ° A

4 (k) Bu Cl H 152-153 ° A

20 4 (1) Me I H 242-243 ° 25 Note. A The starting ketone was prepared using tetrahydrofuran as the reaction solvent instead of ether.

Example 5

A mixture of 70% aqueous ethyleneamine (50 ml) and water (100 ml) was slowly stirred with a mixture of 98% formic acid (50 ml) and water (100 ml) to give a neutral solution. evaporated at 100 ° C / 100 mmHg until 180 ml of water was collected. The residue was heated to 140 ° C and 1-acetyl-1- (4-chloro-35-phenyl) cyclobutane (10.4 g) prepared in Example 11 was added to 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane 28 77223 and 98% formic acid (10 mL). The mixture was heated in an oil bath at 180-200 ° C for 16 hours. The mixture was distilled until an internal temperature of 170 ° C was reached and this temperature was maintained for 2 hours.

All volatiles were removed by distillation at 160 ° C / 20 mmHg and the residue was refluxed with concentrated hydrochloric acid (15 mL) and methylated industrial alcohol (IMS) (15 mL) for 3 hours. The IMS was removed by evaporation on a vortex evaporator and the residue was washed with ether.

The pH of the aqueous phase was adjusted to 12 with sodium hydroxide and extracted with ether. The ether extract was dried and evaporated to give a residue which was treated with aqueous hydrochloric acid to give N-ethyl-1- [E- (4-chlorophenyl) -cyclobutyl] -N-ethylamine hydrochloride (m.p. 203-205 ° C) (formula I, m.p. = O; R 1 = Me; R 2 = H; R 2 = Et; R 2 = H; R 5 = 4-Cl; R 8 = H).

Example 6 1- (4-Chlorophenyl) -1-cyclobutanecarbonitrile (15 g) prepared in the same manner as 1- (3,4-dichlorophenyl) cyclobutanecarbonitrile shown in Example 1 was added to the reaction product in dry ether (50 ml). obtained by the reaction of magnesium turnings (3.18 g) and propyl bromide (15.99 g) in dry ether (50 ml). The ether was replaced with tetrahydrofuran and the mixture was heated at reflux for 18 hours. The mixture was cooled with ice and then concentrated hydrochloric acid (53 ml) was added. The resulting mixture was refluxed with stirring for 10 hours and then extracted with ether. The ether extract gave a residue from which 1-butyryl-1- (4-chlorophenyl) -30 cyclobutane (b.p. 106-108 ° C, 0.3 mmHg) was isolated by distillation.

A mixture of the ketone (21 g) prepared as described above and 98% formic acid (6 ml) was added to formamide (15 ml) at 160 ° C over 1 1/2 hours. At the end of the addition, the temperature was raised to 180-185 ° C and maintained in this range for 5 hours. The mixture was cooled and extracted with chloroform to give a thick gum which, when heated with petroleum ether (b.p. 60-80 ° C), gave a colorless solid which was recrystallized from petroleum ether (b.p. 60-80 ° C). to give N-formyl-1- [1- (4-chlorophenyl) cyclobutyl] butylamine (m.p.

97.5-98.5 ° C) (formula I, n = 0; R 1 = propyl; R 2 = H; R 1 = H; R 4 = CHO; R 5 = 4-Cl; R 8 = H).

Example 7

A solution of 1- (3,4-dichlorophenyl) -1-cyclobutanecarbonitrile (35.2 g) prepared in Example 1 in ether 10 (100 ml) was added to a solution of propylmagnesium bromide prepared by the reaction of propyl bromide (32 g) with magnesium turnings (6, 36 g) in ether (100 ml). The ether was replaced with dry toluene and the mixture was refluxed for one hour. Water (200 ml) was added followed by concentrated hydrochloric acid (120 ml) and the mixture was refluxed for one hour. The reaction mixture was extracted with ether, and after washing and drying, a residue was obtained from the extract, which was separated by distillation of 1-butyryl-1- (3,4-dichlorophenyl) cyclobutane (b.p. 120-128 ° C, pressure 0.25 mmHg).

The ketone (37.0 g) prepared as described above and 98% formic acid (9 ml) were added to formamide (23.5 ml) at 170 ° C and maintained at 175-180 ° C for 5 hours. The next portion of formic acid (4.5 mL) was added and the mixture was maintained at 175-180 ° C for an additional 15 hours. The mixture was extracted with ether to give a thick oil which on crystallization from petroleum ether (b.p. 60-80 ° C) gave N-formyl-1- {1- (3,4-dichlorophenyl) cyclobutyl] -butylamine, m.p. 103-105 ° C (formula I, n = O; R 1 = propyl; R 2 = H; R 3 = H; R 4 = CHO; R 5 = 4-Cl and R 8 = 3-Cl).

The following compounds were prepared as described above: 77223

CHR1NHCHO

R5v_ / ~ h 5% '-'

Eg R ± R5 R6 sP- (° C) 7 (a) Isobutyl Cl H 110-112 ° 7 (b) Propyl Cl F 115-116 ° 10 7 (c) Phenyl Cl H 94-96 ° 7 (d) Propyl HH 98-102 °

Example 8 The product of Example 7 (4.0 g) in dry tetrahydrofuran (25 ml) was added rapidly to a stirred mixture of lithium aluminum hydride (1.4 g) in dry tetrahydrofuran (25 ml) under nitrogen. The mixture was refluxed for 5 hours and then cooled. Water (15 mL) was added followed by 10% sodium hydroxide solution (3 mL) and the mixture was filtered through diatomaceous earth sold under the tradename CELITE. The product was extracted into ether, back-extracted with 5N hydrochloric acid and the aqueous layer was basified and extracted with ether. An oil was obtained from the extract, which was taken up in propan-2-ol (5 ml) and concentrated hydrochloric acid was added to pH 2. Evaporation to dryness gave a white solid which was separated, washed with acetone and dried. The product was N-methyl-1 H- (3,4-dichlorophenyl) cyclobutyl / butylamine hydrochloride and had a melting point of 234-235 ° C (formula I, n = 0; = propyl; R 2 = H; R 3 = H; R4 = Me; R5 = 4-Cl and R8 = 3-Cl).

The following compounds were prepared as described above: 35 31 milli CHR.NHMe.HCl, 'Pb

Eg SP (C) 8 (a) Phenyl Cl H 275-278 ° 8 (b) Propyl Cl H 223-228 ° 10

Example 9

The product of Example 7 (10 g) dissolved in ether (50 ml) was added to a 70% toluene solution (40 ml) of bis- (2-methoxyethoxy) aluminum hydride-15 sold under the tradename Redal at a temperature in the range of 25-30 ° C. The mixture was stirred at this temperature for 4 hours. Water (25 ml) was added dropwise with cooling and the mixture was filtered through diatomaceous earth (CELITE). NaOH-water-20 solution was added and extraction with ether was performed. The ether extract was washed with water and back-extracted with 5N hydrochloric acid. A white solid formed (m.p. 232-235 ° C) on the interface, which was collected. Base was added to the aqueous phase and ether extraction was performed again. Evaporation of the ether extract gave 25 oils which were dissolved in propan-2-ol (5 ml) and concentrated hydrochloric acid was added to pH 2. Evaporation to dryness gave a white solid (m.p. 233-236 ° C). The white solids were combined and recrystallized from propan-2-ol to give N-methyl-1- {1- (3,4-dichlorophenyl-3H-ethylamine hydrochloride (m.p. 236-237 ° C) (Formula I, n = O; R 1 = propyl; R 2 = H; = H; R 2 = Me; R 5 = 4-Cl and R 8 = 3-Cl).

The following compounds were prepared as described above. When the formyl starting material was insoluble in ether, a solution of the reducing agent was added to the stirred suspension of the formyl compound. As the size of the group R 1 increases, the solubility of the hydrochloride salts of the desired compounds in the aqueous phase decreases and the solubility in the organic phase increases, so that suitable changes in the isolation procedure are required, as known to those skilled in the art.

5 CHR-. NHMe .HCl R5_Ofn r6 ^

Eg ___ R ^ __ R ^ Sp. (° C) 9 (a) Isopropyl Cl H 257-259 ° 15 g (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 ci H 264-266 ° 20 9 (g) 3-methoxyphenyl C1 H 254-255 ° 9 (h) 2-methoxyphenyl ci H 149-153 ° 9 (i) Cyclohexyl C1 H 170-172 ° 9 (J) Isobutyl - (CH = CH) 2-256-259 ° 9 (k) Cyclohexyl C1 C1 223-224 ° 25 9 (1) Isobutyl Me Me (χ) 9 (m) Propyl OMe H 173-175 ° 9 (n) Methyl Phenyl H 116-118 30 (1) boiling point free base> 150 ° C / 1.0 mmHg Example 10

The product of Example 7 (4 g), diethylene glycol-35-dimethyl ether (25 ml), water (10 ml) and concentrated hydrochloric acid (10 ml) were mixed and the mixture was refluxed for 9 hours. The solution was washed with ether and aqueous NaOH was added before ether extraction. The ether extract was washed with brine and water and evaporated to give an oil. The oil (3.19 g) was dissolved in a mixture of propan-2-5 ol (4 ml) and ether (20 ml) and concentrated hydrochloric acid (1.5 ml) was added. The solvent was removed by evaporation in vacuo. Repeated dissolution in methylated industrial alcohol and evaporation in vacuo gave a gum which solidified on heating in vacuo. The product was recrystallized from petroleum ether (b.p. = 100-120 ° C) and had a melting point of 201-203 ° C. The product was 1- {1- (3,4-dichlorophenyl) -cyclobutyl] -butylamine hydrochloride (of formula I, n = O; R 2 = propyl; R 2 = H; R 2, R 2 = H; R 2 = 4-Cl and Rg = 3-Cl).

The following compounds were prepared as described above. As the size of the R 1 group increases, the solubility of the hydrochloride salts of the desired compounds in the aqueous phase decreases and increases in the organic phase, so that appropriate changes in the separation procedures are required, as known to those skilled in the art.

20, - CHR1NH2.HC1 R? v_ / H 1-1 25 n

For example, Rej .___ _% _ Sp. (C) 10 (a) Isopropyl Cl H 200-202 10 (b) Sec-butyl Cl H 178-179 10 (c) Isobutyl Cl H 163-165 2q 10 (d) Cyclopentyl Cl H (dec) 185-210 10 (e) Phenyl Cl H 271-276 10 (f) 4-methoxyphenyl Cl H 214-219 ° 10 (g) Cyclohexyl Cl H 206-210 ° 10 (h) Isobutyl HH 210-212 ° 35 10 (i) Cyclopropyl Cl H 204-206 ° 77223 34 ESlm- R5 R6 M.p. (° C> 10 (j) Propyl Ph H 235-236 ° 10 (k) Propyl Me Cl 214-217 ° 10 (1) Propyl - (CH = CH ) 2- 157-159 ° 5 10 (m) Cycloheptyl Cl H 156-162 ° 10 (n) Cyclohexyl Cl Cl 215 ° 10 (p) Methyl Cl F 215-217 ° 10 (q) Propyl OMe H 178-179 ° 10 (r) Propyl Cl F 186-188 ° 10 10 (s) Propyl Cl H 174-175 ° 10 (t) Cyclohexylmethyl Cl H 148-150 ° 10 (u) 3-Butenyl Cl H 184-185 ° 10 (v) ) Propyl -CH = CH-CC1 = CH- (a) 10 (w) Propyl H CF3 126-128 ° 15 10 (x) 4-fluorophenyl Cl H 279 ° 10 (y) <b> Methyl -C — C- CH = CH- 248-262 ° / \

CH CH

W //

CH-CH

20 (a) boiling point of the free base 168 ° C / 0.05 mmHg (b) diethylene glycol dimethyl ether replaced by ethylene glycol dimethyl ether

As described above, 1- [1- (4-chloro-2R-2-fluorophenyl) -cyclobutyl] -butylamine (b.p. 99 ° C / 0.05 mmHg) was prepared. (Formula I, n = O; = propyl; R 2, R 3 and R 4 = H; R 1 = 4-Cl; R 6 = 2-F), 1- {1- (2-fluorophenyl) cyclobutyl-7-butylamine hydrochloride (m.p. 179 -180 ° C). (Formula I, n = O; R 3 = propyl; R 2, R 3, R 4, R 5 = H and R 8 = 2-F) and 1- {1- (4-chloro-2-methylphenyl) cyclobutyl] butylamine hydrochloride (m.p. 188-190 ° C) (formula I, n = O; R 1 = propyl; R 2, R 3 and R 4 = H; R 1 = 4-Cl and R 8 = 2-Me) as examples 10 (z), 10 (aa ) and 10 (bb), respectively.

35 35 7 7 2 2 3

Example 11

The product of Example 10 (c) (3.3 g) as the free base, formic acid (2.99 g) and water (1 ml) were stirred under cooling. A 40% aqueous solution of formaldehyde 37-5 (3.93 ml) was added and the mixture was heated at 85-95 ° C for 18 hours. Excess dilute hydrochloric acid was added and the solution was evaporated to dryness. The residue was basified with 5N sodium hydroxide solution and the product was extracted with ether. Removal of the ether by evaporation gave a pale yellow oil which was dissolved in a mixture of propan-2-ol (4 ml) and ether (20 ml) and concentrated hydrochloric acid (2 ml) was added dropwise. The solution was evaporated to dryness and the residue was repeatedly dissolved in ethanol and evaporated in vacuo to give a gum which was triturated with petroleum ether (b.p. 60-80 ° C) to give a yellow solid which was recrystallised from acetone.

The product was N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride (m.p. 195-197 ° C). (Formula I, n = 0; R 2 = isobutyl; 1 * 2 = H; R 2, R 2 = Me; R 2 = 4-Cl and R 8 = H). The following compounds of formula I were prepared as described above.

36 77223 CHR.NMe, .HCl 1-1

Eg Starting material R 1 R 2 R 2 Mp (° C) 10Q 11 (a) 10 (h) iscutyl HH 195-198 ° 11 (b) 10 (j) Propyl Ph H 194-196 ° 11 (c) 10 (n) Cyclohexyl Cl Cl 227-228 ° 11 (d) 10 (q) Propyl OMe H 187-188 ° 11 (e) 10 (s) Propyl Cl H 194-196 ° is 11 (f) 10 (t) iÄT '11' Cl H 194-196 ° 11 (g) 10 (u) 3-Butenyl Cl H 165-167 ° 11 (h) 10 (v) Propyl -CH = CH-CC1 = CH- (a) 11 (i) ) - Xsobutyl Cl Cl 225-226 20 11 (d) 10 (x) 4-fluorophenyl Cl H 234 ° 11 (k) - ““ 1 Propyl Isopropyl H 211-213 ° (a) Boiling point 250 ° C of free base .05 mmHg 25 Example 11 (1)

As described above, N, N-dimethyl-1- [1- (4-chloro-2-fluorophenyl) cyclobutyl] butylamine hydrochloride (m.p. 183 ° C) was prepared. (Formula I, n = 0; R 1 = propyl; R 2 = H; R 3, R 4 = Me; R 5 - 4-Cl; R 8 = 2-F).

30 Example 12

The product of Example 7 (8.3 g), diethylene glycol dimethyl ether (50 ml), water (20 ml) and concentrated hydrochloric acid (20 ml) were mixed and the mixture was refluxed for 16 hours. The mixture was poured into water, aqueous NaOH was added and the product was extracted into ether. Evaporation gave a dark oil. A sample of this oil (7.9 g), water 37 7 7 2 2 3 (0.7 ml) and formic acid (6.5 ml) were mixed together and the mixture was refluxed for three hours and then concentrated hydrochloric acid (10 ml) and propane were added. -2-ol (10 mL). Evaporation to dryness gave N, N-dimethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] t-butylamine hydrochloride (m.p. 195-196 ° C) as a white solid (formula I, n = O; R 2 = propyl; R 6 = H; R 2 = R 2 = Me; R 2 = 4-Cl and R 8 = 3-Cl).

Example 13 1- (4-Chlorophenyl) -1-cyclobutanecarbonitrile 10 (37.6 g) prepared in the same manner as in Example 1 1- (3,4-dichlorophenyl) -1-cyclobutanecarbonitrile was added to potassium hydroxide (32.4 g). to a solution in dimethylene glycol (370 mL) and the mixture was refluxed for 3 1/2 hours. The reaction mixture was poured into ice / water and the resulting solution was washed with ether. The aqueous layer was added to a mixture of concentrated hydrochloric acid (100 ml) and ice, and the formed 1- (4-chlorophenyl) -1-cyclobutanecarboxylic acid precipitate (m.p. 86-88 ° C) was collected, washed with water and dried.

A solution of the acid (10.5 g) prepared as described above in tetrahydrofuran (150 ml) was added dropwise under nitrogen to a stirred suspension of lithium aluminum hydride (2 g) in tetrahydrofuran (150 ml). The mixture was refluxed for two hours and water was added. The mixture was filtered through diatomaceous earth (CELITE - RTM) and the product was extracted into ether. After washing with water and drying, the ether was removed by evaporation to give a residue which was recrystallized from petroleum ether (b.p. 60-80 ° C). The product was 1- [1- (4-chlorophenyl) cyclobutyl] methyl alcohol (m.p. 60-62 ° C).

A solution of the alcohol (60 g) prepared as described above in pyridine (52 ml) was added dropwise to an ice-cooled solution of p-toluenesulfonyl chloride (60 g) in pyridine (10 ml). The temperature was allowed to rise to room temperature and held for 18 hours. Pouring the reaction mixture into a mixture of ice and concentrated hydrochloric acid (200 ml) gave 1- [1- (4-chlorophenyl) cyclobutyl] methyl] -1-p-toluenesulfonate (m.p. 99-100 ° C).

38 7 7 2 2 3

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

A solution of diisopropylamine (16.5 g) in dry tetrahydrofuran (50 ml) was stirred at 0 ° C under nitrogen and a 1.6 M solution of n-butyllithium in hexane (100 ml) was added dropwise. The reaction mixture was stirred for 30 minutes and then cooled to -78 ° C. A solution of 2-N- (4-chlorophenyl) -cyclobutyl / acetonitrile (9.5 g) prepared as described above in dry tetra-15 hydrofuran (25 ml) was added dropwise. The temperature of the mixture was allowed to rise to 0 ° C and the mixture was stirred for 10 minutes before a solution of methyl iodide (10 ml) in tetrahydrofuran (10 ml) was added. Tetrahydrofuran (75 ml) was added to obtain a homogeneous solution, and a further solution of methyl iodide (4 ml) in tetrahydrofuran (10 ml) was added. The mixture was stirred at room temperature for two hours and then water (50 ml) was added. The aqueous phase was washed with ether and the ether contained in the organic phase of the reaction mixture. The combined organic phases were washed three times with 5N hydrochloric acid, three times with water, dried and evaporated to give an oil which solidified and recrystallized from methylated industrial alcohol to give 2- [5Γ- (4-chlorophenyl) cyclobutyl] -2-methylpropionitrile (sp. 73-75 ° C).

The nitrile prepared above (4 g) was boiled with potassium hydroxide (8 g) in diethylene glycol (40 ml) for 24 hours. The reaction mixture was cooled, added to water (50 ml) and the aqueous phase was washed twice with ether. The aqueous phase was acidified with 5N hydrochloric acid and extracted with three portions of ether. The combined ether extracts 39 77223 were washed with water, dried and evaporated to give a white solid which was recrystallised from petroleum ether (b.p. 60-80 ° C) to give 2- [L- (4-chlorophenyl) cyclobutyl] -2-methylpropionic acid ( mp.

5 95-110 ° C).

To the acid prepared as described above (2 g) was added oxalyl chloride (10 ml), and after the initial effervescence ceased, the mixture was refluxed for one hour. Excess oxalyl chloride was removed by distillation and the residual oil was added to concentrated aqueous ammonia (75 mL). The resulting oily solid was extracted into ethyl acetate. The extract was washed with water, dried and evaporated to give 2- [1- (4-chlorophenyl) cyclobutyl] -2-methylpropionamide.

The amide (1.34 g) prepared as described above was dissolved in a mixture of acetonitrile (8 ml) and water (8 ml), and iodobenzene bistrifluoroacetate (3.4 g) was added, and the mixture was stirred at room temperature for 5 1/2 hours. Water (75 ml) and concentrated hydrochloric acid (8 ml) were added and the mixture was extracted with ether. The ether extract was washed with 5N brine and the aqueous phase was basified and evaporated to give an oil. the oil was dissolved in petroleum ether (b.p. 80-100 ° C) and dry hydrogen chloride gas was passed through the solution. Filtration afforded N- [1- (4-chlorophenyl) -cyclobutyl] -1-methylethylamine hydrochloride (m.p. 257-259 ° C) (Formula I, n = 0; R 1, R 2 = Me; = H; R 1 - = 4-Cl; R 6 - H) ·

Example 14

The product of Example 4 (h) (3.4 g) was mixed with anhydrous sodium formate (0.72 g), 98% formic acid (10 ml) and 37-40% aqueous formaldehyde (5 ml) and the mixture heated at 85-95 ° C for 16 hours. The mixture was diluted with water (50 mL) and basified to pH 10 with aqueous sodium hydroxide solution. The basic aqueous solution was extracted with ether, washed with water and dried over magnesium sulfate. Dry hydrogen chloride gas was bubbled through an ether extract to give a white precipitate of N, N-dimethyl-1- [1- (4-chloro-3-trifluoromethylphenyl) cyclobutyl] ethylamine hydrochloride (m.p. 246-247 ° C) (Formula I). , n = 0; R 1 = Me; R 2 = H; R 3, R 4 = Me; R 5 = 4-Cl and R 8 = 3-CF 3).

5 Example 15

The preparation of salts of the compounds of the invention is illustrated by the following examples in which equimolar amounts of base and acid were added to a solvent. The salt was separated from the solution by conventional methods.

10

Eg Base Acid_Solvent_Salt m.p. (° C)

15 (a) 10 (s) Citric acid Aqueous 158-160 ° C

acetone

15 (b) 10 (s) Maleic acid Ether 155-157 ° C

^ 15 (c) 10 (s) Succinic acid Ether 152-155 ° C

15 (d) (2) L (+) - tartaric acid I.M.S. 150-153 ° C

Note 15 (e) (a) Citric acid Ether / meta- 163-164 ° C (dec.) Nol (a) The base was 1- [1- (3,4-dimethylphenyl) cyclobutyl] -3-methylamine prepared according to the procedure described in Example 10. ^ way.

Example 16

To a solution of bromobenzene (15.7 g) in ether (50 ml) was added dropwise and cooled magnesium turnings (2.4 g) under a nitrogen atom. A solution of 1- (3,4-dichlorophenyl) cyclobutanecarbonitrile (19.1 g) prepared as described in Example 1 with respect to 1- (3,4-dichlorophenyl) cyclobutanecarbonitrile (50 ml) was added and ether was added. replaced with dry toluene (130 mL). The reaction mixture was heated on a steam bath for one hour.

A sample (20 ml) of the resulting solution was added to a solution of sodium borohydride (1 g) in diethylene glycol dimethyl ether (60 ml), and the mixture was stirred for 1 1/2 hours. Water (60 ml) was added slowly and the aqueous layer was extracted with toluene. The toluene extracts were washed with water, dried and evaporated to give a residue which was dissolved in methanol (50 ml).

4i 77223

6N Hydrochloric acid (5 ml) was added and the solution was filtered and evaporated. Trituration with dry acetone gave N, N-L- (4-chlorophenyl) cyclobutyl / benzylamine hydrochloride (m.p. 277-279 ° C). (Formula I, n = O; R 2 = Ph; R 2 = H; R 5, R 4 = H; R 5 = 4-Cl; R 8 = H).

Example 17

Methyl formate (62 mL) was added dropwise with stirring to isopropylamine (85.5 mL) at a rate to maintain poor reflux conditions. Stirring was continued for 2 hours after the addition. The methanol was removed by distillation at 100 ° C to give N-isopropylformamide (b.p. 108-110 ° C / mmHg).

1-acetyl-1-, (4-chlorophenyl) cyclobutane (10.4 g) prepared in the same manner as in Example 1 1-15 acetyl-1- (3,4-dichlorophenyl) cyclobutane and 98% formic acid (5 ml) was added to N-isopropylformamide (43.5 g) and the mixture was heated at 180 ° C for 4 hours. Excess starting material was removed by distillation under reduced pressure (20 mmHg) to give a viscous residue which was boiled under reflux with concentrated hydrochloric acid (30 ml) for 6 hours. The reaction mixture was washed with ether until a colorless solution was obtained. The aqueous phase was basified, extracted with water, dried and evaporated to give an oil which was dissolved in 5N hydrochloric acid. Evaporation gave a yellow oil which was triturated with petroleum ether (b.p. 62-68 ° C) to give N-isopropyl-1- [1- (4-chlorophenyl) cyclobutyl / ethylamine hydrochloride (m.p. 170-174 ° C). ) (formula I, n = 0; R 1 = Me; R 2 = H; R 3 = isopropyl; R 4 = H; R 4 = 4-Cl; R 8 = H).

30 Example 18

1-Acetyl- (3,4-dichlorophenyl) cyclobutane (7.0 g) prepared as in Example 1 was slowly added to a mixture of pyrrolidine (25 ml) and 98% formic acid (15 ml) which was heated to 13 ° C to 135 ° C. heat-35 mode for 5 hours. The mixture was stirred and heated at 160-165 ° C for 16 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 introduced into the extract, which was then evaporated to dryness. The residue was triturated with dry ether to give a solid which was recrystallized from propan-2-ol to give N-1- [1- (3,4-dichlorophenyl) cyclobutyl / ethylpyrrolidine hydrochloride (m.p. 233-235 ° C). (Formula I, n = O; R 1 = Me; R 2 = 10 H; R 3 and R 4 together with the nitrogen atom to which they are attached form a pyrrolidine ring; R 1 = 4-Cl and R 8 = 3-Cl).

Example 19

1- (4-15 Chlorophenyl) -1-cyclobutanecarboxylic acid (10.5 g) prepared as in Example 13 was refluxed with thionyl chloride (20 mL) for 2 1/2 hours. Excess thionyl chloride was removed by evaporation and the acid chloride of the above acid was separated by distillation (b.p. 82-96 ° C / 0.2 mmHg).

A solution of the acid chloride (23.0) in dry tetrahydrofuran (100 ml) was slowly added to the reaction product of magnesium turnings (3.0 g) and ethyl bromide (12.0 g) in dry tetrahydrofuran at a temperature between -70 ° C and -60 ° C. . The temperature was maintained at -60 ° C for one hour and then allowed to rise to 0 ° C. Water (50 ml) was added followed by 5N hydrochloric acid (150 ml) under cooling. The reaction product was extracted with ether, washed with water and sodium bicarbonate solution, and dried. The solvent was removed by evaporation and distillation gave 1-propionyl-1- (4-30 chlorophenyl) cyclobutane (b.p. 96-104 ° C / 0.25 mmHg).

The ketone prepared as described above was converted to N, N-dimethyl-1- / T- (4-chlorophenyl) cyclobutyl / propylamine hydrochloride (m.p. 213-215 ° C) as described in Example 12. (Formula I, n = O; R 2 = Et; R 2 = H; R 2, R 2 = 35 Me; R 5 = 4-Cl; R 8 = H).

43 77223

Example 20

A mixture of 1-acetyl-1- (4-chlorophenyl) cyclobutane (61 g) prepared in the same manner as in Example 1 1-acetyl-1- (3,4-dichlorophenyl) cyc-5 lobutane, platinum oxide (0, 75 g), a 33% solution of methylamine in ethanol (60 g) and ethanol (30 ml) were placed in an autoclave. The autoclave was filled with hydrogen and kept at a temperature of about 60 ° C and a pressure of 20 bar for 10 hours. The reaction mixture was filtered through activated carbon and the solids were washed with absolute alcohol. The solvents were removed by evaporation and a sample of the residue (10 g) was shaken with 2M hydrochloric acid (50 ml) and ether (50 ml). The aqueous layer was basified and extracted with ether. Evaporation of the ether extract gave a liquid which was distilled (109 ° C / 0.3 mmHg) to give N-methyl-1- [α- (4-chlorophenyl) cyclobutyl] ethylamine (Formula I, n = O; RL = Me; R 2). = H; R3 = Me; R4 = H; R5 = 4-Cl and R8 = H).

Example 21

Sodium borohydride (2.0 g) was added to a solution of (3,4-dichlorophenyl) cyclobutyl / ethylamine (1.5 g prepared by treating the product of Example 1 with aqueous sodium hydroxide) in glacial acetic acid (30 ml). The mixture was heated at 95-10 ° C for 16 hours and then cooled. Aqueous sodium hydroxide solution was added and the reaction mixture was 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 introduced into the ether extract which was evaporated to dryness. Trituration with acetone gave N-ethyl-1- [1- (3,4-30 dichlorophenyl) cyclobutyl / ethylamine hydrochloride (m.p.

211-212 ° C). (Formula I, n = 0; = Me; R 2 = H; R 1 = Et; R 4 = H; R 5 = 4-Cl and R 8 = 3-Cl).

Example 22

A mixture of N-ethyl-1- [1- (3,4-dichlorophenyl) cyclobutylethylamine (0.5 g prepared by treating the product of Example 21 with an aqueous solution of sodium hydroxide 44 7722 3) and acetic anhydride (1 ml ) was heated at 40-45 ° C for 30 minutes. The reaction mixture was basified and extracted with ether. The ether extract was washed, dried and evaporated to give N-acetyl-N-ethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine as an oil.

This oil was dissolved in tetrahydrofuran (10 ml) and borane dimethyl sulfide complex (0.5 ml) was added dropwise. The reaction mixture was stirred at room temperature for two 10 hours and then heated to 35-40 ° C for 30 minutes. After cooling, the reaction mixture was basified and extracted with ether. Hydrogen chloride gas was passed to a dried ether extract which was evaporated to dryness. Trituration with ether gave N, N-diethyl-1- [1- (3,4-dichloro-15-phenyl) -cyclobutyl] -ethylamine hydrochloride (m.p. 199-201 ° C). (Formula I, n = O; R1 = Me; R2 = H; R-j, R4 = Et; Rg = 4-Cl; Rg = 3-Cl).

Example 23

A mixture of 1-acetyl-1- (3,4-dichlorophenyl-20) cyclobutane (2.2 g) prepared as in Example 1, ammonium acetate (7 g), sodium cyanoborohydride (0.4 g) and methanol (28 ml) was stirred at room temperature for four days. The reaction mixture was poured into a mixture of ice and water, and the resulting mixture was extracted with ether.

The ether extract was washed with water, dried and the ether removed to give 1- {1- (3,4-dichlorophenyl) cyclobutyl] ethylamine as an oil which was identified by standard analytical methods as the compound of Example 1 in the form of its free base.

30 Example 24

A mixture of 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane (4.86 g) prepared as in Example 1, hydroxylamine hydrochloride (1.6 g), sodium acetate trihydrate (3.3 g), methylated industrial -35 alcohol (15 ml) and water (2 ml) were refluxed for 20 hours. The cooled reaction mixture was poured into water and the separated oil was cooled to give a solid which was recrystallized from methylated industrial alcohol to give 1-acetyl-1- (3,4-dichlorophenyl) -cyclobutane oxime (m.p. 12-121 ° C).

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

20 Example 25

A 1M solution of diisobutylaluminum hydride (200 ml) was added under nitrogen to a solution of 1-phenyl-1-cyclobutanecarbonitrile (31.4 g) in ether (100 ml) at a temperature below -30 ° C. The temperature was then maintained below 0 ° C for 30 minutes and 5N hydrochloric acid (200 ml) was added at -10 ° C. The reaction mixture was washed with petroleum ether (b.p. 60-80 ° C) and then warmed to 40 ° C. The reaction mixture was extracted with petroleum ether (b.p. 60-8 ° C) and the extract was dried and evaporated to give 1-phenyl-1-30 cyclobutanecarbaldehyde as an oil.

Methylamine was bubbled through a solution of the aldehyde (9.4 g) prepared as described above in toluene (100 ml) and the temperature of the mixture was kept below 0 ° C. Magnesium sulfate (20 g), dried over 35 flames and then cooled under nitrogen, was added to the reaction mixture, which was then kept at room temperature for 16 hours before being filtered. The toluene was then removed by evaporation and the residue was dissolved in ether (50 ml). This solution was added to a solution of propyllithium prepared by slowly adding an excess of propyl bromide (12.8 g) to a suspension of lithium (1.26 g) in ether (50 ml). The resulting mixture was kept at room temperature for 16 hours. Residues of unreacted lithium were removed by filtration and the filtrate was washed with ether, water and then 5N hydrochloric acid. The filtrate and washings were heated in a steam bath for one hour. After cooling, the reaction mixture was washed with ether and the aqueous layer was basified with aqueous sodium hydroxide solution. The reaction mixture was extracted with ether, and the extract was dried and the ether was removed, whereby N-methyl-1- (1-phenylcyclobutyl) butylamine (b.p. 80-86 ° C / 0.1 mmHg) was separated from the resulting residue by distillation.

The amine prepared as described above (2.3 g) was dissolved in ether (40 ml) and hydrogen chloride gas was passed through the solution to precipitate N-methyl-1- (1-phenylcyclobutyl) butyl-20 amine hydrochloride (m.p. 196-197 ° C). (Formula I, n = O; R 1 = propyl; R 2 = H; R 3 = Me; R 4, R 1 -, R 8 = H).

Example 26

A solution of 1- (3-chloro-5-methylphenyl) -1-cyclobutanecarbonitrile (8.0 g) in ether (40 ml) was added with propylmagnesium bromide (prepared from 1-bromopropane (6.7 g) and magnesium ( 1.3 g) in ether (80 ml) and the mixture was refluxed for 2 1/2 hours. Two-thirds of the ether was removed by evaporation and then, after cooling, a solution of sodium borohydride (3.5 g) in ethanol (150 ml) was added. The mixture was kept at 50 ° C for one hour and then water (50 ml) and 5N hydrochloric acid (50 ml) were added. The ether layer was separated, dried and evaporated to give a solid which on recrystallization from propan-2-ol gave 1- [1- (3-chloro-5-methylphenyl) cyclobutyl] -butylamine hydrochloride (m.p. 145-146 ° C). ).

47 77223

The hydrochloride salt prepared as above was shaken with ether and 5N sodium hydroxide solution and the ether layer removed by evaporation to give the primary amine which was converted as described in Example 2 to N, N-dimethyl- [1- (3-chloro-5-methylphenyl) cyclobutyl] butyl] butyl (m.p. 148 ° C) (formula I, n = 0; R 1 = propyl; R 2 = H;, R 2 = Me; R 8 = 3-Cl and R 9 = 5-Me).

Example 27 1 “(4-Chlorophenyl) -1-cyclobutanecarbonitrile (37.6 g) prepared in the same manner as 1- (3,4-dichlorophenyl) -1-cyclobutanecarbonitrile in Example 1 was added to a solution of potassium hydroxide (32.4 g). in diethylene glycol (370 ml) and the mixture was refluxed for 3 1/2 hours. The reaction mixture was poured into ice / water and the resulting solution was washed with ether. The aqueous layer was added to a mixture of concentrated hydrochloric acid (100 ml) and ice, and the resulting precipitate of 1- (4-chlorophenyl) -1-cyclobutanecarboxylic acid (m.p. 86-88 ° C) was collected, washed with water and dried.

A solution of the acid prepared as described above (10.5 g) in tetrahydrofuran (150 ml) was added dropwise under nitrogen to a stirred suspension of lithium aluminum hydride (2 g) in tetrahydrofuran (150 ml). The mixture was refluxed and stirred for 2 hours and then water was added. The mixture was filtered through diatomaceous earth (CELITE ®) and the product was extracted into ether. After washing with water and drying, the ether was removed by evaporation to give a residue which was recrystallized from petroleum ether (b.p. 60-80 ° C). The product was 1- [1- (4-chlorophenyl) cyclobutyl] methyl alcohol (m.p. 60-62 ° C).

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

48 7 7 2 2 3

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

Acetonitrile (20 g) prepared as described above was dissolved in ether (120 ml) and the solution was added dropwise under nitrogen to a stirred suspension of lithium aluminum hydride (5.84 g) in ether (80 ml). The mixture was stirred at room temperature for 1 1/2 hours and then refluxed for a further 2 hours. Water was added dropwise and the resulting mixture was filtered through diatomaceous earth. The residue was washed with ether. The filtrate was extracted with ether and the combined ether portions were washed with water and extracted with 5N hydrochloric acid. The acid solution was washed with ether and aqueous NaOH was added. The product was extracted into ether and the extract was washed with water, dried and evaporated to give a residue which on distillation gave 2- (1- (4-chlorophenyl) cyclobutyl) ethylamine (b.p. 119-121 ° C / 1). .5 mmHg).

Ethylamine (6.9 g) prepared as described above, 98% formic acid (6.6 ml), water (0.9 g) and 37-40% aqueous formaldehyde solution (9 ml) were heated on a steam bath for 18 hours. The mixture was cooled and excess concentrated hydrochloric acid was added. Evaporation to dryness gave a yellow solid residue. The solid was partitioned between dichloromethane and 5N sodium hydroxide solution and the aqueous layer was extracted with another portion of dichloromethane. The dichloromethane portions were combined, washed with water, dried and evaporated to a solid residue which was dissolved in propan-2-ol (15 ml) and concentrated hydrochloric acid was added to pH 2.

The mixture was evaporated to dryness and the residue was recrystallized from ethyl acetate to give colorless crystals of N, N-dimethyl-2- [1- (4-4977223 chlorophenyl) cyclobutyl] ethylamine hydrochloride (m.p. 220-222 ° C) (formula I, n = 1; R 1, R 2 = H; R 3, R 4 = Me; R 5 = 4-Cl; R 8, R 7, R 8 = H).

The following 5 compounds were prepared as described above:. CH2CH2NMe2.HCl 10 R6 -

Eg Rc R-HCl salt —__ 5_6_sp, (° c) 27 (a) Cl Cl 218-220 ° 2? (B) 1H 263-265 ° 15 27 (c) -CH = CH - CH = CH- 234 -236 ° 27 (d) In a similar manner, N, N-dimethyl-2- [1- (4-chloro-2-fluorophenyl) cyclobutyl / ethyl-2Q amine hydrochloride (m.p. 232-233 ° C, dec.) Was prepared.

Example 28

2- [1- (4-chlorophenyl) cyclobutyl] ethylamine (12 g), 1,4-dibromobutane (12.4 g) and anhydrous sodium carbonate (14.3 g) prepared according to Example 27 were mixed with xylene ( 100 ml) and the mixture was refluxed and stirred for 16 hours. The mixture was cooled, filtered and the xylene removed by evaporation to give a residue which on distillation gave Ν-2- [1- (4-chlorophenyl) cyclobutyl] / ethylpyrrolidine (b.p. 148-30,150 ° C / 1.5 mmHg) (Formula I , n = 1; R 1, R 2 = H; R 1 and R 2 together with the nitrogen atom form a pyrrolidine ring; R 8 = 4 -Cl; R 8, R 1, R 8 = H).

The following compounds were prepared as described above and isolated as their hydrochloride salts.

35 50 77223 • - ^ b0

Eg Rj. Rg HCl salt m.p. (° C) 28 (a) Cl Cl 213 10 28 (b) -CH = CH-CH = CH- 232-233

Example 29

A solution of 2- [1- (4-chlorophenyl) cyclobutyl] acetonitrile (30 g) prepared according to Example 27 in ether (100 ml) was added to the reaction product of methyl bromide gas and magnesium turnings (5.95 g) in ether (80 ml). The mixture was refluxed for 4 hours. Ice and then concentrated hydrochloric acid (105 mL) were added and the mixture was refluxed until all material was dissolved. The aqueous layer was washed with ether and the ether used for washing was combined with the ether phase of the reaction mixture. The combined ether extracts were washed with water, dried and evaporated to a residue which was distilled twice to give 1- [1- (4-chlorophenyl) cyclobutyl] -propan-2-ol (b.p. 133-136 ° C / 2.5 mmHg).

The ketone (5.4 g) prepared as above was mixed with N-methylformamide (18 ml), 98% formic acid (4 ml) and 25% aqueous methylamine (0.6 ml) and the mixture was refluxed for 16 hours. . The mixture was poured into water and extracted with dichloromethane. The extract was washed, dried and evaporated to a residue which was boiled under reflux with concentrated hydrochloric acid (10 ml) for 6 hours. The mixture was evaporated to dryness and the residue was dried by repeatedly adding and evaporating in vacuo a mixture of methylated industrial alcohol and toluene. The solid residue was recrystallized from pro-77,7233 pan-2-ol to give N-methyl-2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine hydrochloride (m.p. 193-194 ° C) (formula I, n = 1; 1 ^, R2 = H; Rg = Me; R4 = H; R5 = 4-Cl; Rg = H; R2 = Me; Rg = H).

5 Example 30

A mixture of 1- [1- (4-chlorophenyl) cyclobutyl] propan-2-one prepared according to Example 29 (15 g) and 98% formic acid (4 ml) was added dropwise to formamide (12 ml) at 160 ° C. The temperature was raised to 180 ° C and this temperature was maintained for 10 hours. The mixture was cooled, diluted with water and extracted with dichloromethane. The extract was washed, dried and evaporated to give a yellow oil which was hydrolysed with concentrated hydrochloric acid using reflux. After dilution with water, the resulting aqueous solution was washed with ether, aqueous NaOH was added, and the aqueous solution was extracted with ether. The extracts were washed, dried and evaporated to a residue which distilled to give 2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine (b.p. 105-107 ° C / 0.7 mmHg).

The above amine (2.65 g) was dissolved in propan-2-ol (15 ml) and concentrated hydrochloric acid was added dropwise until the pH was 2. Ether (110 ml) and 2- / Γ- (4- colorless crystals of chlorophenyl) cyclobutyl-1-methylethylamine hydrochloride were collected (m.p. 184-255 ° C). (Formula I, n = 1; R 1, R 2 = H; R 8, R 2 = H; R 8, R 2 = H; R 5 = 4-Cl; R 8 = H; R 2 = Me; R 9 = H).

Example 31

2- [1- (4-Chlorophenyl) cyclobutyl] -1-methylethylamine (3.94 g), 1,4-di-bromobutane (3.82 g), anhydrous sodium carbonate (4.4 g) prepared according to Example 30 and xylene (30 mL) was mixed and refluxed for 16 hours. The mixture was cooled, filtered and evaporated to a residue which was distilled twice (b.p. 130-132 ° C / Q, 5 mmHg). The distillation product was dissolved in propan-2-ol 35 (5 ml) and ether (70 ml) and concentrated hydrochloric acid were added to pH 2. The solution was evaporated in vacuo and the residue was recrystallized from ethyl acetate to give N- 2- {1- (4-chlorophenyl) cyclobutyl] -N-methyl-ethyl-pyrrolidine hydrochloride (m.p. 151-152 ° C) (formula I, n = 1;

Rr R2 = H; R 9 and R 6 together with the nitrogen atom form a pyrrolidine ring; Rg = 4-Cl; Rg = H; = Me; Rg = H).

Example 32

1- [1- (4-Chlorophenyl) cyclobutyl] cyclopan-2-one (25 g) and formic acid (98%, 10 mL) prepared as described in Example 29 were added to formamide 10 (22 mL) at 160 ° C. The temperature was raised to 175 ° C and this temperature was maintained for 16 hours. The mixture was cooled, extracted with dichloromethane. The extract was washed with water and evaporated to a gum which was crystallized from petroleum ether (b.p. 40-60 ° C) to give N-formyl-2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine (m.p. 71-73 C).

N-Formyl-2- [1- (4-chlorophenyl) -cyclobutyl] -1-methylethylamine (11.06 g) prepared as described above was boiled under reflux for 6 hours with a mixture of concentrated hydrochloric acid (34 ml), water (34 ml) and diethylene glycol dimethyl ether (40 ml). The mixture was cooled, washed with ether and basified with aqueous sodium hydroxide solution. The basic solution was extracted with ether, washed with water, dried, evaporated and distilled to give 2- [1- (4-chlorophenyl) cyclobutyl] 1-25 methylethylamine (b.p. 119-121 ° C / 0.8 mmHg). The amine was dissolved in propan-2-ol (15 ml) and concentrated hydrochloric acid was added to pH 2. Ether was added and crystals of 2- [N- (4-chlorophenyl) cyclobutyl] -1-methylethylamine hydrochloride were collected (m.p. 184-185 ° C). ) (formula I, n = 1; R 2, R 2 = H; R 3, R 4 = H; R 5 = 4-Cl; R 8 = H; R 2 = Me and R 8 = H).

Example 33

2- [1- (4-Chlorophenyl) cyclobutyl] -1-methylethylamine (1.8 g) prepared as in Example 32 was mixed with formic acid (4.5 ml). A 37-40% aqueous solution of form-35 aldehyde (6 ml) was added and the mixture was first heated at 45-50 ° C for 30 minutes and then refluxed for 2 hours. The mixture was cooled, basified with aqueous sodium hydroxide solution, extracted with ether, the ether extract washed with water and then extracted with 5N hydrochloric acid. The acidic extract was washed with ether, basified with aqueous sodium hydroxide solution and extracted with ether. Hydrogen chloride gas was passed through ether extraction to give a white solid. The solid was collected and recrystallized from ethyl acetate to give N, N-dimethyl-2- [1- (4-chlorophenyl-10-yl) cyclobutyl] -1-methylethylamine hydrochloride (m.p. 108-110 ° C) (Formula I, m.p. = 1; R1 # R2 = H; R3, R4 = Me; Rg = 4-Cl; Rg = H2R2 = Me; Rg = H).

Example 34

A 70% to 15% solution of sodium bis- (2-methoxyethoxy) aluminum hydride in toluene (35 ml) (sold under the tradename Red-ali) was added dropwise to the N-formyl-2H- (4-chlorophenyl) prepared as described in Example 32. -cyclobutyl-1-methylethylamine (5 g) in dry ether (110 ml) with cooling keeping the temperature below 20 ° C. The temperature was allowed to rise to about 25 ° C and the mixture was then refluxed for 2 hours. The reaction mixture was poured into a mixture of crushed ice and concentrated hydrochloric acid. The resulting mixture was washed with ether, basified with aqueous sodium hydroxide solution and extracted with ether.

The ether extract was washed with brine, dried and evaporated to give a liquid which was dissolved in petroleum ether (b.p. 40-60 ° C). Hydrogen chloride gas was bubbled through the solution to precipitate a solid which was recrystallized from propan-2-ol to give N-methyl-2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine hydrochloride (Formula I, n = 1). R 1 = R 2 = H; R 2 = H; R 4 = Me; R 5 = 4-Cl; R 8 = H; R 2 = Me and R 9 = H) (m.p. 192-194 ° C).

Example 35 35 2- [1- (3,4-Dichlorophenyl) cyclobutyl] acetonitrile (23 g) prepared in the same manner as 2- [1- (4- 54 7 7 2 2 3 chlorophenyl) cyclobutyl] acetonitrile in Example 27 , a solution in ether (80 ml) was added to the reaction product of magnesium turnings (3.53 g) and ethyl bromide (10.8 ml) in dry ether (80 ml) with stirring under heating in a steam bath. The ether was removed and replaced with toluene and the mixture was refluxed for one hour. Water was added and the mixture was added to a mixture of ice and concentrated hydrochloric acid. The mixture was heated on a steam bath for one hour and filtered through diatomaceous earth sold under the tradename CELITE. The filtrate was extracted with dichloromethane and the extract was washed with water and sodium bicarbonate solution and dried. The solvent was removed by evaporation and the residue was distilled to give 1- {1- (3,4-dichlorophenyl) -cyclobutyl] -butan-2-one (b.p. 149-150 ° C / 1.1 mmHg).

The above ketone was converted to 1- (N - (- 3,4-dichlorophenyl) cyclobutyl) methyl] propylamine hydrochloride (m.p. 225-226 ° C) as described in Example 32 (Formula I, n = 1; R 1, R 2 , R3, R4 = H; R5 = 4-Cl; R3 = 3-Cl; R2 = Et; R8 = H).

As described above, 2- [1- (3,4-dichlorophenyl) cyclobutyl] -1-methylethylamine hydrochloride (m.p. 179 ° C) was prepared (Example 35a, formula I, n = 1; R 1, R 2, R 3, R4 = H; R5 = 4-Cl; R8 = 3-Cl; R2 = Me; RQ = H).

Example 36 The following compounds were prepared as described in Example 33 and converted to the corresponding Ν, Ν-dimethyl compounds as described in Example 35: CH2CHR7NMe2.HCl 30 R5_Γ \ -I—, r6

For example, the starting material Rg Ry Sp. (C) 35 36 (a) 35 Cl Cl Et 177-178 ° 36 (t) 35 (a) Cl Cl Me 204-205 ° 55 77223

Example 37

In the same manner as in Example 34, the N-formyl ketones prepared according to Example 32 obtained according to Example 35 were converted to the corresponding corresponding N-methyl compounds.

CH2CHR7NHMe.HCl1J = ^ h 1Q ^ - R6

Example R5 Rg Ry Sp. (° C) 37 (a) Cl H Et 170-172 ° 37 (b) Cl Cl Et 193-194 °

Example 38

A mixture of 2- [1- (4-chlorophenyl) cyclobutyl] acetonitrile (10.1 g) prepared as described in Example 20 27, potassium hydroxide (8.1 g) and diethylene glycol (92 ml) was boiled under reflux. 3 1/2 hours. The mixture was poured into ice / water and the resulting solution was washed three times with ether and added to a mixture of ice and concentrated hydrochloric acid. Upon cooling, a solid product separated which was recrystallized from petroleum ether (b.p. 62-68 ° C) using activated carbon. The recrystallized product was 2- [1- (4-chlorophenyl) -cyclobutyl] -acetic acid (m.p. 83-84 ° C).

The acid prepared as above (5 g) was added to thionyl chloride (20 ml) and the mixture was refluxed for one hour. Excess thionyl chloride was removed and the residue was poured into a solution of piperidine (3.8 g) in ether (20 ml). The mixture was stirred for 30 minutes and then water was added to dissolve the piperidine hydrochloride. The ether layer was separated and the aqueous layer was washed with ether.

The combined ether portions were washed with water, dried and evaporated to a brown oil which was purified by distillation (b.p. 168 ° C / 1 mmHg) and crystallized from petroleum ether (b.p. 40-60 ° C). Solid product oil N-2- [1- (4-chlorophenyl) cyclobutyl] -acetylpiperidine (m.p. 66-67 ° C).

A solution of compound 5 (2.7 g) prepared as described above in ether (20 ml) was added dropwise to a stirred mixture of lithium aluminum hydride (0.7 g) and ether under a nitrogen atmosphere. Stirring was continued for one hour at room temperature and then by heating to reflux for two hours. After cooling with ice, the excess lithium aluminum hydride was decomposed by adding water. The mixture was filtered through diatomaceous earth (CELITE). The aqueous portion of the filtrate was washed with a portion of ether and this portion was combined with the amounts of ether used to wash the solid residue. The combined ether portions were washed with water, dried and evaporated. The residue was purified by distillation. The product was N-2- [1- (4-chlorophenyl) cyclobutyl] ethylpiperidine (b.p. 152-156 ° C / 1.5 mmHg) (formula n = 1; R 1, R 2 = H; R 2 and R 1 together with the nitrogen atom form a piperidine ring; R 1 - = 4-Cl; R 8, R 2 and R 8 = H). The following compounds were prepared as described above and separated as their hydrochloride salts by passing bubbles of dry hydrogen chloride gas through a solution of the base in petroleum ether (b.p. 62-68 ° C).

__k CH CH ^ NR.R, .HCl, ηΓ ^ Ι17 R6 ^ I-- ^ Ex._ Rg_Rg NR ^ R ^ Sp. . (° C)

Me 38 (a) Cl. H -Nj 167-169 °

Me 35 38 (b) Cl H -iTVMe 281-283 ° w (dec.) 38 (c) Cl H -φ 246-248 ° 77223 57

Example 39

A mixture of sodium hydride (9 g), mineral oil (9 g) and dry dimethylformamide (150 ml) was stirred under nitrogen at 0 ° C. A solution of p-toluenesulfonylmethyl isocyanide sold under the tradename TosMIC (24.6 g) in dimethylformamide (50 ml) was added over 20 minutes. Absolute alcohol (18 g) was then added to the mixture at 0 ° C over 1 hour. 1-Acetyl-1- (4-chlorophenyl) cyclobutane 10 (24 g) prepared in the same manner as 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane dissolved in Example 1 in dimethylformamide (20 ml) was added and the mixture was stirred for 16 hours. , during which the temperature rose to room temperature. The mixture became viscous and petroleum ether (b.p.

80-100 ° C) (25 ml). The mixture was poured into water and the pH was adjusted to 6 by adding 5N hydrochloric acid. The resulting mixture was extracted with ether and the ether extract was washed with water, dried and partially evaporated. A brown solid separated and was filtered off and the filtrate was evaporated and 2- [1- (4-chlorophenyl) cyclobutyl] propionitrile (b.p. 128-136 ° C / 0.6 mmHg) was recovered by distillation.

A solution of the propionitrile (3.5 g) prepared as described above in dry ether (20 ml) was added dropwise to a stirred mixture of lithium aluminum hydride (0.9 g) in dry ether (20 ml) at 15-20 ° C. The mixture was stirred at room temperature for 2 hours and then during reflux for a further 3 hours. 5N Sodium hydroxide solution (20 ml) and water (50 ml) were added and the mixture was filtered through diatomaceous earth (CELITE). The filtration medium 30 was washed with ether and the washings were combined with the ether of the reaction mixture. The combined extracts were extracted with 5N hydrochloric acid. A solid formed on the interface which was collected by filtration, washed with acetone and dried. The solid was 2- {1- (4-chlorophenyl) -cyclobut-35-propylamine hydrochloride (m.p. 210-230 ° C).

77223 58

The hydrochloride salt (1.0 g) prepared as described above was dissolved in water, 5N aqueous sodium hydroxide solution was added, and the solution was extracted with ether. The ether extract was dried and evaporated to an oil which was refluxed for 6 hours with a mixture of 1,4-dibromobutane (0.82 g), anhydrous sodium carbonate (0.96 g) and xylene (6.5 ml). The mixture was cooled, filtered through diatomaceous earth (CELITE) and evaporated to dryness. The residue was dissolved in propan-2-ol (10 mL) and concentrated hydrochloric acid (5 mL) was added. The mixture was evaporated to dryness and the residue was taken up, washed with ether and dried. The product was N-2- [1- (4-chlorophenyl) -cyclobutyl] -propylpyrrolidine hydrochloride (m.p. 238-248 ° C) (formula I, n = 1; R 2 = Me; R 2 = H; R 8 and R together with the nitrogen atom to which they are attached form a pyrrolidine ring; Rg = 4-Cl; Rg, R1, Rg = H).

Example 40

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

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

The acid prepared as described above was converted to the compound of Example 27 (a) and the compound of Example 5 28 (a) as described in Example 28.

Example 41

A solution of 2- [1- (3,4-dichlorophenyl) cyclobutyl] -acetonitrile (23 g prepared in the same manner as in Example 27 2- (N- (4-chlorophenyl) cyclobutyl) acetonitrile) in a dry in ether (50 ml) was added to a solution of ethyl magnesium bromide prepared by adding ethyl bromide (15.83 g) dropwise in dry ether (80 ml) to a stirred mixture of magnesium turnings (3.53 g) and ether (80 ml). The mixture was refluxed for 30 minutes and stirred without heating for 16 hours and then refluxed for a further 2 hours. 1- (1- (3,4-Dichlorophenyl) cyclobutyl} -2-butaniminylmagnesium bromide was collected by filtration and a sample of the solid (ca. 1 g) was added to a solution of sodium borohydride (3 g) in diethylene glycol dimethyl ether (30 ml). . The mixture was stirred at 45 ° C for 90 minutes. The reaction mixture was extracted with 5N hydrochloric acid. The aqueous phase was basified with aqueous sodium hydroxide solution and extracted with ether. The ether-25 extract was dried and hydrogen chloride gas was introduced into the extract to precipitate 1- [1- (3,4-dichlorophenyl) cyclobutyl] methyl] propylamine hydrochloride (m.p. 223-224 ° C) (formula I, n = 1; R 1, R 2, R3 and R4 = H, R5 = 4-Clj, R8 = 3-Cl, R2 = Et;

Rg = H).

30 Example 42

Formic acid (7 ml) was added dropwise at a temperature in the range 135-140 ° C of pyrrolidine (15 ml). 1- [1- (3,4-Dichlorophenyl) cyclobutyl] butan-2-one (3 g) prepared according to Example 35 was added dropwise, and the mixture was heated at 140 ° C for one hour. The temperature of 77223 60 was raised to 185-190 ° C for 16 hours. The reaction mixture was cooled and poured into 5N hydrochloric acid. The solution was washed with ether, basified and extracted with ether. The ether extract was dried and hydrogen chloride gas was bubbled into the extract. Evaporation to dryness gave a solid which was triturated with dry ether and then recrystallized from a mixture of petroleum ether and propan-2-ol to give N1- [N- (3,4-dichlorophenyl) -cyclobutyl] methyl] propylpyrrolidone hydrochloride (m.p. 157). ° C) (formula I, N = 1; R 1, R 6 = H; R 8 and R 2 together with the nitrogen atom form a pyrrolidine ring; R 5 = 4-Cl; R 6 = 3-Cl; R 2 = Et; R 8 = H) .

Example 43

1- [T-15 (3,4-dichlorophenyl) -cyclobutyl] -2-butaniminylmagnesium bromide (25 g) prepared as in Example 41 was heated at 90-95 ° C for two hours with concentrated hydrochloric acid (20 ml) and water. (30 ml) with the mixture. The reaction mixture was extracted with ether and the ether extract was dried and evaporated to dryness. Distillation gave 1- [N- (3,4-dichlorophenyl) cyclobutyl] butan-2-one (b.p. 122-124 ° C / 0.1 mmHg).

A mixture of 1- [1- (3,4-dichlorophenyl) cyclobutyl} 'butan-2-one (4.3 g) prepared as described above, hydroxylamine sulfate (2.65 g), sodium acetate (4.0 g g), methylated industrial alcohol (56 ml) and water (23 ml) were stirred at room temperature for 16 hours. The ether extract was washed with water, dried and evaporated to a solid which was recrystallized from petroleum ether (b.p. 80-100 ° C) to give 1- [N- (3,4-di-30-chlorophenyl) cyclobutyl] butan-2-one oxime (mp 106-110 ° C).

A solution of trifluoroacetic acid (2.33 ml) in tetrahydrofuran (5 ml) was added to a stirred suspension of sodium borohydride (1.13 g) in tetrahydrofuran (30 ml) over 5 minutes. A solution of the oxime (1.6 g) prepared as described above in tetrahydrofuran (25 ml) was added dropwise and the mixture was refluxed for 6 hours. The mixture was cooled and water (25 ml) was added followed by 5N aqueous sodium hydroxide solution (25 ml). The mixture was extracted with ether and the extract was washed with water, dried and evaporated and the residue obtained was dissolved in petroleum ether (25 ml). Dry hydrogen chloride gas was bubbled through an ether solution to give 1 - (£ 3 - 1- (3,4-dichlorophenyl) cyclobutyl) -methyl} propylamine hydrochloride (m.p. 222-224 ° C).

(Formula I, n = 1; 1 ^, 1 ^, Rg = Hj R5 = 4-Cl; Rg = 3-Cl; R? = 10 Et and Rg = H).

Example 44

A solution of 1- [1- (3,4-dichlorophenyl) cyclobutyl] butan-2-one (5.0 g) and methoxyamine hydrochloride (1.63 g) prepared according to Example 43 in pyridine (60 ml) and ethanol (60 ml) was prepared. ) in the mixture, refluxed for 72 hours. The reaction mixture was evaporated to dryness and a mixture of water and ether was added to the residue. The ether layer was washed with sodium bicarbonate solution and water, dried and evaporated to give 1- [1- (3,4-dichloro-phenyl) -cyclobutyl] -butan-2-one oxime O-methyl ether. The oxime (15 g) prepared as described above was then reduced to the product of Example 43 using sodium borohydride (0.95 g) as described in Example 43.

25 Example 45

Sodium cyanoborohydride (0.4 g) was added to a solution of 1- (N- (3,4-dichlorophenyl) cyclobutyl) butan-2-one (2.45 g) prepared according to Example 42 and then ammonium acetate (7 g) in methanol (28 ml). ) and the mixture se-30 was stirred at room temperature for four days. Water (25 ml) was added dropwise with cooling. The aqueous mixture was extracted with ether and the ether layer was washed with water and 5N hydrochloric acid (50 ml). The compound of Example 4 3 precipitated as a white solid.

35 Example 46

2- [1- (4-Chlorophenyl-62,77223) cyclobutyl] acetic acid (1.5 g) prepared according to Example 38 was boiled under reflux with thionyl chloride. Excess thionyl chloride was removed in vacuo and the residue was added dropwise to a solution of cyclopropylamine (0.94 g) in ether (10 ml) and the mixture was stirred for 30 minutes. Water was added and the aqueous phase was extracted with ether. The ether extract was dried and the ether was removed to give 2- [1- (4-chlorophenyl) cyclobutyl] -N-cyclopropylacetamide.

A solution of the amide (1.45 g) prepared as described above in ether (15 ml) was added dropwise to a stirred suspension of lithium aluminum hydride (0.42 g) in ether (7.5 ml) under nitrogen. The mixture was stirred at room temperature for one hour and then boiled under reflux for a further two hours. After cooling, water (0.45 ml) was added, then 15% aqueous sodium hydroxide solution (0.45 ml) and water (1.35 ml) were added, and the mixture was stirred for 15 minutes. The mixture was filtered and extracted with ether. The ether extract was shaken with 5N hydrochloric acid and a solid formed in the aqueous layer. The solid was N-cyclopropyl-2- [1- (4-chlorophenyl) cyclobutyl] ethylamine hydrochloride (m.p. 166-170 ° C).

A mixture of the hydrochloride salt prepared as described above (0.41 g), sodium formate (0.1 g), 98% formic acid (1 ml) and a 37-40% aqueous solution of formaldehyde (0.5 ml) was heated to 85- At 90 ° C for 18 hours. The reaction mixture was cooled and extracted with ether. The ether extract was washed with water, dried and filtered. Hydrogen chloride gas was passed through the filtrate, which was then heated to give 30 solids which were N-cyclopropyl-N-methyl-2-Z1- (4-chlorophenyl) cyclobutyl] ethylamine hydrochloride (m.p. 149-153 ° C). (Formula I, n = 1; R 1 and R 2 = H; R 8 = cyclopropyl; R 4 = Me; R 5 = 4-Cl; R 9, R 7 and R 8 = H).

Example 47 A solution of 1.3 M sec-butyllithium in cyclohexane (34 ml) was added dropwise under an argon atmosphere to petroleum ether (b.p. 80-100 ° C; 100 ml) at -65-60 ° C. Mixture 63 77223 was cooled to -70 ° C and a solution of cyclopropylmethyl iodide (7.5 g) in dry ether (10 ml) was added over two minutes while maintaining the temperature at -70 to -65 ° C and the resulting mixture was stirred for a further 5 minutes at this temperature. . A solution of 1- (4-chlorophenyl) -1-cyclobutanecarbonyl chloride (5 g) in ether (10 ml) was cooled to -70 ° C and added dropwise to the mixture over two minutes while maintaining the temperature in the range of -70 to -60 ° C. The temperature was maintained in this range for 10 hours and then allowed to rise to ambient temperature within one hour. The reaction mixture was cooled to -60 ° C and water (30 mL) was added. When the mixture reached ambient temperature, it was extracted with ether. The ether extracts were washed, dried and the solvent removed to give an oil which was distilled. Fractions distilling at 160-180 ° C at 0.15 mmHg and 200-220 ° C at 0.15 mmHg were collected and pooled. The combined distillates were purified by preparative gas-liquid chromatography to obtain a fraction containing 47% of 1-20 (4-chlorophenyl) cyclobutylcyclopropylmethyl ketone and no allylic protons based on proton magnetic resonance analysis. A mixture of this crude ketone (0.47 g) and ammonium acetate (1.8 g) in methanol (10 ml) was stirred and sodium cyanoborohydride (0.1 g) was added thereto, followed by stirring for 10 days. . The mixture was heated to reflux for 2 hours and then cooled to 0 ° C. Water (5 ml) was added to the mixture, and the aqueous mixture was first acidified and then basified and extracted with ether. The ether extract was evaporated to give an oil which was dissolved in ether (10 ml). A solution of maleic acid (0.2 g) in ether (20 ml) was added to give a solid which was stirred in ethyl acetate (10 ml), collected and dried to give 35 1 - [1- (4-chlorophenyl) cyclobutyl] -2-cyclopropylethyl amine maleate (m.p. 143-145 ° C) is of 0, is cyclopropylmethyl, R 2 and R 2 are hydrogen, is 4-Cl and R 8 is hydrogen.

Claims (9)

77223 64 A process for the preparation of novel compounds useful in the treatment of depression of formula I 5 -Λ? R1R2 (CR7R8) nNR3R4 R6 wherein n is 0 or 1; wherein when n is 0, it is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a cycloalkylalkyl group in which the cycloalkyl group contains 3 to 6 carbon atoms and the alkyl group contains 1 to 3 carbon atoms, 2 to 6 carbon atoms an alkenyl group or a group of formula II -GC R9 wherein R8 and R10 'which are the same or different represent hydrogen, halogen or an alkoxy group having 1 to 3 carbon atoms; and when n is 1, R 1 is hydrogen or an alkyl group having 1 to 3 carbon atoms; R2 is hydrogen or an alkyl group having 1 to 3 carbon atoms; R 1 and R 2, which are the same or different, represent hydrogen, a straight-chain or branched alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms or a formyl group, or R 1 and R 3 together with nitrogen atoms optionally form 1 to 4 carbon atoms a heterocyclic group substituted with an alkyl group which is a pyrrolidinyl, piperidin-7722365 dinyl, tetrahydropyridyl or piperazinyl group; R 5 and which are the same or different, represent hydrogen, halogen, trifluoromethyl, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or phenyl, or R 1. and R 9 together with the carbon atoms to which they are attached form a second benzene ring optionally substituted with one or more halogen groups, or the substituents of the second benzene ring together with the two carbon atoms to which they are attached form a third benzene ring; and R? and R 9, which are the same or different, represent hydrogen or an alkyl group having 1 to 3 carbon atoms, and for the preparation of their pharmaceutically acceptable salts, characterized in that A) compounds of the formula I in which n is 0, R 4 is hydrogen and R 1, R 8 and R 8 are as defined in formula I, are prepared by reacting ketones of formula V R 6 and compounds of formula I wherein n is 1, R 1 is hydrogen and R 1, R 6, R 5, R 8 and R 8 are as defined as in formula I is prepared by reacting ketones or aldehydes of formula VI CR1RjCOR, R635 to react with a) formamide and formic acid to give compounds of formula I wherein R1 is hydrogen and R1 is CHO, b) formamides of formula HCONHR4 wherein R1 is alkyl or cycloalkyl, and with formic acid to give compounds of formula I wherein R 1 is CHO and R 2 is as defined above, c) with amines of formula R 1 N 1 · 4 wherein R 3 is alkyl or cycloalkyl and with formic acid to give compounds of formula I wherein R 1 is CHO and R 2 is as defined above, d) with an ammonium salt and a reducing agent to give compounds of formula I wherein R 1 and R 2 are hydrogen, or e) with an amine of formula R 1 NHR wherein R 1 and / or R 2 represent hydrogen, alkyl or cycloalkyl or R 1 and R 2 form a heterocyclic group together with the nitrogen atom to which they are attached either by i) catalytic hydrogenation or ii) in the presence of formic acid, of formula I according to combine to obtain compounds in which R 1 and R 2 are as defined above, B) the compounds of the formula I are prepared by reducing the compounds of the formula VII in which a) Z is a group of the formula -CR 3 = NOH or an ester or ether thereof, to give compounds of formula I wherein n is 0 and R 1, R 2 and R 2 are hydrogen; b) Z is a group of the formula -CR 2 = NY, wherein Y is a metal-containing moiety derived from an organometallic reagent such as MgBr or Li to give compounds of formula I wherein n is 0 and R 2, R 1 and R 2 are hydrogen. 35 ice; 67 77223 c) Z is a group of the formula -CR 2 I 2 CN to give compounds of formula I wherein n is 1 and R 1, R 4, Ry and R 8 are hydrogen; d) Z is a group of the formula -CR 2, CR 2 NOH or an ester or ether thereof to give compounds of formula I wherein n is 1 and R 1, R 2 and R 8 are hydrogen; e) Z is a group of the formula -CR-j-CR-^ NY, wherein Y is a metal-containing moiety derived from an organometallic reagent such as MgBr or Li to give compounds of formula I wherein n is 1 and R R 1 and R 8 are hydrogen; or f) Z is a group of formula -CR 2 R 2 CONR 8 R 2 to give compounds of formula I wherein n is 1 and R 1 and R 8 are hydrogen, which reductions are carried out using a reducing agent such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, borane dimethyl or borane dimethyl ) Compounds of formula I are prepared by reacting an organometallic reagent which is a Grignard reagent of formula R 1 MgBr or an organolithium compound of formula R 1 Li with an imine of formula VIII Rc. -. CH = NR0 25 R6 - and the product obtained by hydrolysis to give compounds of formula I in which n is 0 and R1 is hydrogen, D) compounds of formula I are prepared by decarboxylating an amide of formula X Rc - CR .. RoCO0Ho R6 77223 68 by rearrangement to give amines in which n is 0 and and are hydrogen, and after methods A to D, (i) optionally hydrolysing compounds of formula I wherein R 1 is CHO to give compounds of formula I wherein R 1 is hydrogen is performed, or (ii) optional reduction of compounds of formula I wherein R 1 is CHO to give compounds of formula I wherein R 1 is methyl and / or (iii) obtaining compounds of formula I wherein R 1 and / or R 2 is CHO. is hydrogen, optionally converted to compounds of formula I in which R 1 and / or R 2 are other than hydrogen. Process according to Claim 1, characterized in that a compound of the formula III '---- CR is prepared. R0NR0R. / T \ 1234 R, - ('Λ-- III' 20 5 \ / R6 wherein R1 is a straight-chain or branched alkyl group having 1 to 4 carbon atoms, R2 is hydrogen, R1 is hydrogen, methyl or ethyl, R 4 is hydrogen or methyl and R 9 and R 8, which are the same or different, represent hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, methoxy or phenyl, or R 9 and R 8 together with the carbon atoms to which they are attached associated, a second benzene ring optionally substituted with chlorine. Process according to Claim 2, characterized in that a compound is prepared in which isobutyl, R 1 is hydrogen or methyl, R 1 is hydrogen or methyl, 35 Rg is chlorine and Rg is hydrogen. 69 Patent Krav 77223 A process for the preparation of a compound having a depression according to the formula I or R 5 R 2: R 1 R 2 (CR 7 R 8) n NR 3 R 4 10 color n is 0 or 1; varvid di n är 0, är en rakkedjad eller förgrenad alkylgrupp med 1-6 cholatomer, en cycloalkylgroup med 3-7 kol-atomer, en cycloalkylalkylgryg, color cycloalkylgroup 15 innehciller 3-6 kolatomer och alkylgroupen innehiller 1-1 2-6 cholaters or groups of formula II oC color Rg and R 2g, a single ring or an oil, a hydrogen group of 25, halogen or an alkoxy group of 1-3 cholaters; and is 1, R 1 is an alkyl group having 1-3 cholatomers; R 2 is selected from the group consisting of 1-3 colatomers; R ^ och R ^, vilka är lika eller olika, betecknar väte, en 30 rakkedjad eller förgrenad alkylgrupp med 1-4 cholatomer, en cycloalkylgrupp med 3-7 kolatomer, eller en formyl-grupp, eller R ^ och R4 tillsammans med kväveatomen bildar optionally with an alkyl group having 1-4 cholatomic substituents, heterocyclic groups, such as pyrrolidinyl, piperidinyl, tetrahydropyridinyl and piperazinyl; R5 and R8, a single ring or an alkyl group, halogen, trifluoromethyl, an alkyl group having 1-3 cholatomers, an alkoxy group having 1-3 cholatomers or a phenyl group, or R1 and R8 are a same group as the cholatomic moiety, 70 77223 bundna, bildar en andra bensenring, vilken eventuellt substituerats med en eller flera halogengrupper, eller substituenterna head and andra bensenringen bildar tillsam-Mans med de tvä colatomerna, vid vilka de är bundna, en 5 tredje bensenring; and Rj and Rg, vilka är lika or olika, betecknar väte eller en alkylgupp med 1-3 kolatomer; and the pharmaceutical composition of the formulation of the formulation of the formulation, Fig. 10 A) the formulation of the formulation I, the color is 0, the amount of the formulation of formulation I, the formulation of the formulation ketone or the formulation V d, _k COR R6 and derivatives of formula I, color n is 1, R ^ is a value of 20 and Rg, R2, Rg, Rg and Rg are the same as in formula I, the genome being a ketone or an aldehyde of formula VI cr, r_cor7 0 a) with formamide and myrrh, for a mixture of 30 with formula I, color Rg with the formula and R4 with CHO, b) with formamide with formula HCONHRg, color Rg with alkyl or cycloalkyl, with myrrh for hydrogen with formula I, color R ^ är CHO and Rg betecknar samma som ovan, 35 c) with an amine with formula RgNH2, color Rg är alkyl or cycloalkyl, och med myrsyra, förhalhur av föreningar med formuleln I, color R ^ är CHO och Rg betecknar samma som ovan, 71 77223 (d) in the case of airanoniumsalt and to reduction agents, for the purpose of ngar med formula I, color R3 and R ^ betecknar väte, eller e) med en Amin med formuleln R ^ NHR ^, vari R ^ och / 5 ell4 R4 betecknar väte, alkyl or cycloalkyl or R3 and R ^ tillsammans med den kväveatomen vid (i) the genome of a catalytic hydrolysis or (ii) a myrrh of a myrrh, a mixture of the compounds of formula I, or R3 10 and the same mixture as in formula B, In the genome reductive formulation with the formulation VII Z 15 5 _, VII R6 ^ = / L vari a) Z with the group formulation -CR ^ = NOH or es-20 or with the ether form, for the addition of the formulation Formula I, vari n is 0 and R 2, R 3 and R 2; b) Z is a group of formula -CR 2 = NY, vari Y is a metal halide, preferably a derivative of an organometallic reagent, wherein MgBr or Li, is used for a mixture of 25 with formula I, vari is 0 and R2, R3 and R6; c) a group selected from the group consisting of -CR 2 R 2 CN, derived from the group consisting of Formula I, variant 1 and R 3, R 2, Ry and R 8; d) A group selected from the group consisting of -CR3R2CRy = NOH or an ester or an ether derived from the group consisting of a compound of formula I, a mixture of 1 or Rg, R1 and R8; e) Z is a group of formula -CR 2 R 2 CRy = NY, or Y is a metal halide, which is a derivative of an organometallic reagent such as MgBr or Li, for which a mixture of formula I is used, R3, R2 and R8; or 72 7 7 2 2 3 f) The group consisting of the formula -CR ^ I ^ CONR ^ R ^> for the formulation of the formulation I, color n is 1 and R7 and Rg is the value of the other genome that a reduction medium with sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride or a borane dimethyl sulfide complex, , which is imin with the formula VIII _ CH = NR.j 5 ^ Λ V \ - VIII r 15 and the genomic hydrolysis of the product, for the product of formula I, color n is 0 and R is the value, D ) framställer föreningar med formeln I, genom decarboxylativom omgrupperande av en amide med formuleln X 20 D CRtR ^ CONH »W] R6 D i) and optionally hydrolysis of the compounds of formula I, color R4 and CHO, for different in the case of a mixture of formula I, color R 1 or methyl, or 30 ii.) and eventual reduction of the formulation of formula I, color R 4 and CHO, for a mixture of formulations I, color R 4 and methyl, and / or iii) en eventual use of the formulation with the formulation I, color R ^ och / or R4 is the same, 35 accounts for the formulation I, color R ^ och / or R4 with the formulation.