DK161770B - METHOD OF ANALOGUE FOR THE PREPARATION OF CYCLOBUTYLAMINE DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE SALTS THEREOF - Google Patents

Description

DK 161770 B

The present invention relates to an analogous process for the preparation of novel cyclobutylamine derivatives or pharmaceutically acceptable salts thereof, the compounds of which have the general formula 1 oo λ R * 7 ft 5 I shown in claim 11, wherein R 1, R R, R, R, R ° and n have the same meanings stated; the compounds have therapeutic effect, especially but not exclusively as antidepressants. The process of the invention is characterized by the characterizing part of claim 1, in the formulas of this specification, the symbol 15 represents a 1,1-disubstituted cyclobutane group of the formula # -C-CHO II 2 CH 2 -CH 2 20 and -CR 2 R 2 ( A group of the formula? VA ^ r3 25 IW- ^ n In the preferred compounds of formula I wherein n = 0, R 1 is a straight or branched alkyl group of 1-4 carbon atoms, a a cycloalkyl group having 3-7 carbon atoms, a cycloalkylmethyl group wherein the cycloalkyl ring contains 3-6 g of carbon atoms or a group of formula II wherein R and / or R R is O, H, fluorine or methoxy and where R R is H or methyl. Examples of particularly preferred compounds of formula I 2 are those wherein when n = 0 and R = H, R is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl , cyclobutylmethyl, 2!

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cyclopentylmethyl, cyclohexylmethyl or phenyl.

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

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

In particularly preferred compounds of formula I, R 3 and / or R 4 are H, methyl, ethyl or formyl.

In preferred compounds of formula I, R and / or g are R hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, methoxy or phenyl, or form R and R together with the carbon atom to which they are attached. benzene ring which may optionally be halogen substituted.

A first group of preferred compounds are those of the general formula III; , _. CR1R2 (CR2R3) nr3r4 R? ^ Ryj_ R4 30 1 ft where R -R and n have the meanings given above. In preferred 6 compounds of formula III, R and R which may be the same or different are hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, methoxy or phenyl, or together and together with the carbon atom to which they are linked another leg- ............

In particularly preferred compounds of formula III, R and / or 4-zene ring are optionally substituted with a chlorine atom.

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3 g of clay R are hydrogen, fluorine, chlorine, iodine, trifluoromethyl, methyl or phenyl.

Another class of preferred compounds are those of the general formula IV R 5. CR1R2 (CR7R8) NR3R4 _ R6

10 R

Wherein R -R and n have the indicated meanings and R in particular may be H, fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl,

C

methoxy or phenyl, and wherein R is fluorine or methyl. In particularly preferred compounds of formula IV, R is hydrogen or chlorine.

In preferred compounds of formula I wherein n = 1,7 8 is R hydrogen, methyl or ethyl and R hydrogen, and in particularly preferred such compounds of formula I, R 7 is the drug or ethyl and R hydrogen.

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

Compounds of general formula I which contain one or more asymmetric carbon atoms may exist in a variety of optically active forms. When R and R are different or R and R are different, the compounds of formula I contain a chiral center. Such compounds exist in two enantiomeric forms and the present invention is directed to the preparation of both the enantiomeric forms and mixtures thereof. When both R and R are different and 7 8 R and R are different, the compounds of formula I contain two chiral centers and the compound exists in four diastereoisomeric forms. The invention is directed to the preparation of all these diastereoisomeric forms and mixtures thereof.

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4

The present compounds can be worked up into pharmaceutical compositions containing a therapeutically effective amount of compound I together with a pharmaceutically acceptable diluent or carrier.

For therapeutic use, the active compound may be administered orally, rectally, parenterally or locally and preferably orally. Thus, pharmaceutical compositions of the subject compounds can be of any known pharmaceutical form for oral, rectal, parenteral or local administration. Pharmaceutically acceptable carriers suitable for such compositions are well known. The compositions may contain 0.1-90% by weight of the active substance. These preparations are generally prepared in dosage unit form.

Preferably, preparations for oral in-P5 venom are made in known pharmaceutical forms such as tablets, capsules, juice or aqueous or oily suspensions.

The pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I can be used to treat depression in mammals and humans.

In such a treatment, a compound of formula I per day is administered in an amount in the range of 1-1000 mg, preferably 5-500 mg.

For example, the reductive amidation according to reaction a) of ketones V or ketones or aldehydes VI may take place with formamide and formic acid or ammonium formate and formic acid, thereby forming a compound of formula I wherein R4 is CHO and R1 is H; or with formamides of the formula HCIHR 3 wherein R is an alkyl or cycloalkyl group as defined and formic acid; or amines of formula R NEL ·, wherein 3. R 'is an alkyl or cycloalkyl group as defined and formic acid.

Compounds of formula I wherein R 4 is CHO may be prepared by formylating compounds of formula I wherein R 4 is H, for example by reaction with methyl formate.

. 3

Compounds of formula I wherein R is different from 35 4 H and R is CHO may be prepared by reacting compounds 4 of formula I wherein R is H and R is CHO, with a compound 35

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the general formula R X, wherein X is a leaving group such as a halogen atom, in the presence of a base.

Compounds of formula I can be prepared by reductive amination of ketones of formula V or of ketones or aldehydes of formula VI. Examples of reductive amination processes are listed below: a) For the preparation of compounds of formula I wherein R 4 and R are H, reacting the ketone or aldehyde with an ammonium salt, eg ammonium acetate, and a reducing agent such as sodium cyanoborohydride, b) to preparing compounds of formula I wherein R 4 is alkyl and R is H, by reacting the ketone or aldehyde with an amine of formula R N 1 4 and a reducing agent such as sodium cyanoborohydride, c) to prepare compounds of formula I wherein 3 4 3 4 is neither R nor R is hydrogen, or wherein R and R together with the nitrogen atom form a heterocyclic ring, by reacting 3 4 of the ketone or aldehyde with a breast of the formula HNR R and either formic acid or a reducing agent such as sodium boron and d) for the preparation of compounds of formula I wherein 3/4 R and / or R is hydrogen or an alkyl or cycloalkyl group or where R and R together with the nitrogen atom form a hetero cyclic ring, catalytic hydrogenation at elevated temperature and pressure of a mixture of the ketone or aldehyde 34 and an amine of the general formula HNR R.

Compounds of formula I wherein both R 1 and R 2 are an alkyl group can be prepared by reacting a ketone of formula V or a ketone or an aldehyde of formula 3 4 30 VI with a dialkylformamide of formula HCONR R, for example in the presence of formic acid.

Suitable reducing agents for reducing a compound of formula VII according to reaction c) are in particular: sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride and borane dimethyl sulfide complex.

In the reactions mentioned in claims 1 under c (ii) and c (iv), Y is preferably MgBr derived from a Grignard reagent,

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6 or Li derived from an organolithium compound.

. 3 4

Compounds of formula I wherein R and R are hydrogen may, according to reaction d>, be prepared by a decarboxylative rearrangement, e.g., by iodosobenzene bistrifluoroacetate or by a Hofman reaction using bromine in alkaline solution, of amides of formula XI to produce amines of formula I wherein n is 0 or 1.

4

Compounds of formula I wherein R is hydrogen can, according to reaction e), be prepared by hydrolysis of compounds of formula I wherein R is CHO, for example by acid hydrolysis.

4

Compounds of formula I wherein R is methyl can, according to reaction f), be prepared by reducing compounds of formula I wherein R is CHO, for example with lithium aluminum hydride or with sodium bis- (2-methoxyethoxy) aluminum. Hydride.

Compounds of formula I wherein R 3 and / or R 4 are different from H may, according to reaction g), be prepared from compounds of formula I wherein R 3 and / or R 4 are hydrogen by methods known per se to convert 20 primary amines to secondary or tertiary amines or for the conversion of secondary to tertiary amines. The following are some examples of suitable processes: a) Alkylation of primary amines of formula I to form secondary amines of formula I, for example, by a process comprising the steps of protecting the primary amine with a protecting group such as trifluoroacetyl, alkylation with a alkyl halide and removal of the protecting group, for example, by hydrolysis; b) - alkylation of primary amines of formula I, for example with an alkyl halide to form a tertiary amine of formula 344 wherein R and R are the same; c) alkylation of secondary amines of formula I, e.g., with an alkyl halide to form tertiary amines of formula

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7 3 4 In which R and R may be different; d) reacting primary amines of formula I with sodium borohydride and acetic acid to form secondary amines 34 of formula I wherein R is ethyl and R is hydrogen; E) reacting primary amines of formula I with formaldehyde and formic acid to form tertiary amines of formula o in which both R and R are methyl; f) reacting secondary amines of formula I wherein 4 R is hydrogen with formaldehyde and formic acid to give 4 tertiary amines of formula I wherein R is methyl; g) formylation of primary amines of formula I, for example by reaction of methyl formate, and reduction of the resultant formamide, for example with lithium aluminum hydride to form secondary amines of formula I wherein R is methyl and R is hydrogen; H) formylation of secondary amines of formula I, for example by reaction with methyl formate, and reduction of the resulting formamide, eg with lithium aluminum hydride, to give 4 a tertiary amine of formula I wherein R is methyl; i) acylating primary amines of formula I, for example, by reacting with an acyl clone of formula R COC1 or a 12 12 anhydride of formula (R CO) 20 wherein R is an alkyl, alkenyl or alkynyl group, and reduction of the resulting amide, for example, with lithium aluminum hydride to form a secondary amine of formula I wherein R is -Cl 2 R and R is hydrogen; J) acylation of secondary amines of formula I wherein R 4 12 is H, for example by reaction with an acyl clone of formula R COC 12 12 or an anhydride of formula (R CO) 20 wherein R is an alkyl, alkenyl or alkynyl group and reducing the resulting amide with, for example, lithium aluminum hydride to form a tertiary amine wherein R is CH 2 R; k) reacting a primary amine of formula I with an aldehyde of formula R CHO wherein R is an alkyl, alkenyl 14 or alkynyl group, or a ketone of formula R COR, 14 15 wherein R and R can be the same or different and each is 14 15

An alkyl, alkenyl or alkynyl group or R and R

together with the carbon atom to which they are attached form an alicyclic ring, and reduction of the resulting imine or

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Is not alkenyl or alkynyl, by catalytic hydrogenation to form a secondary amine of formula I wherein R 2 is R 2 CH 2 and R 2, respectively. R ^ -CH-;

5 lS

1) by reacting a primary amine of formula I with a non-geminally disubstituted alkane containing 2 or 3 carbon atoms between the carbon atoms bearing the substituents which may be, for example, halogen and preferably bromine, or 10 p-toluenesulfonyloxy to form a compound of formula I wherein R and R together with the nitrogen atom to which they are attached form a heterocyclic ring containing no heteroatoms other than the nitrogen atom.

The ketones of formula V can be prepared by hydrolysis of imines of formula XVI

R 1 - CR 1 = NY

\ - XVI

r6-- 20

wherein Y is a metal-containing residue derived from an organometallic reagent. The imines of formula XVI can be prepared by reacting said organometallic reagent with a cyan compound of formula XVII

25

rIzt- ^ CN

^ - XVII

- 2Q Suitable organometallic reagents include Grignard reagents of formula R ^ MgX where X is Cl, Br or I (Y = MgX) and organolithium compounds of formula R ^ Li (Y = Li).

The ketones of formula VI can be prepared by hydrolysis of imines of formula XVIII

35

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9

d5 __. CR1R2CR7 = NY

^ \ __ XVIII

R6 -

5 where Y is a metal-containing residue derived from an organometallic reagent. The imines of formula XVIII can be prepared by reacting the organometal reagent with cyan compounds of formula XIX

10 5 ___ CR1R2CN

ψΛ In XIX

R6 -

Suitable organometallic reagents include Grignard reagents of formula R7MgX where X is Cl, Br or I (Y = MgX) and organolithium compounds of formula R ^ Li (Y = Li).

The ketones of formula V can be prepared by reacting carboxylic acid derivatives such as amides or acid halides with an organometal reagent, for example by reacting an acid chloride 20 of formula XX

5 - COC1 R6

with a Grignard reagent of formula R1MgX wherein X is Cl, Br or I at low temperature, or by reaction of a carboxylic acid of formula XXI

R 5, COOH

with an organometallic reagent such as an organolithium compound • 5C1 of formula R Li.

10

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Ketones of formula VI can be prepared by reacting carboxylic acid derivatives such as amides or acid halides with an organometallic reagent, for example by reacting an acid chloride 7 of formula XII with a Grignard reagent of formula R MgX 5 where X is Cl,. Br or I at low temperature, or at conversion. yielding a carboxylic acid of formula XIV with an organometallic reagent, for example an organolithium compound of formula R Li.

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

R 2, -, CHO

„£ H = i

R

Aldehydes of formula. VI can be prepared by well known methods. Some suitable examples are set forth below: a) Reduction of Cyan Compounds of Formula XIX by 20, for example, di-t-butylaluminum hydride or diisobutylaluminum hydride; b) reduction of carboxylic acid derivatives such as i) reduction of compounds of formula VII wherein Z is CR 2 R 2 CON 2 R 2 and R 2 and R 2 are different from hydrogen, for example by means of lithium diethoxyoxyaluminohydride; Ii) reduction of amides formed by reaction of ethylenimine with an acid chloride of formula XII · e cr1r2coci 30 ^ y <~ J xiif

JlV - '* eg using lithium aluminum hydride as reducing agent; iii) reduction of acid chlorides of formula XII, eg with lithium-tr i-t-butoxyaluminohydride; C) Reaction of alcohols (formed by reduction of carboxylic acids of formula XIV) 11 UK Ί bV / '/ Ub 5 cr1r2cooh>, £> h

R

with, for example, chromium trioxide-pyridine complex in dichloromethane under anhydrous conditions.

Compounds of Formula VII wherein Z is a group of formula -CR 2 = NOH or -CR 2 R 2CR 2 = NOH or ethers or esters thereof may be prepared by reaction of hydroxylamine or an ether or ester thereof with ketones of formula V and ketones, respectively. or aldehydes of formula VI.

Compounds of formula VII wherein Z is a group of formula -CR 2 = NR 2 or -CR 2 R 2CR 2 = NR 3 can be prepared by reacting amines of formula NE 1 R with ketones of formula V and ketones or aldehydes of formula WE.

Preparation of compounds of formula VII wherein 1 127 20 z is a group of formula -CR = NY or -CR R CR = NY is described above with respect to compounds of formula XVI and XVIII, respectively.

Preparation of Compounds of Formula VII wherein 1 2 Z is a group of formula -CR R CN will be described later on with respect to cyano compounds of formula XIX.

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

2

Amides of Formula XI, where n = 0 can be prepared by reacting ammonia with carboxylic acid derivatives, e.g., acid chlorides of formula XII, or they can be prepared from cyan compounds of formula XIX, e.g., by hydration with aqueous 12

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acid or by reaction with hydrogen peroxide in the presence of a base.

Amides of formula XI wherein n = 1 can be prepared by reacting ammonia with carboxylic acid derivatives, e.g., acid chlorides of formula XIII, or they can be prepared from cyan compounds of formula XXIII, e.g., by hydration with aqueous acid or by reaction with hydrogen peroxide in the presence of a base: r; *, -. cr1r2cr7r8cn

10 TI

in! Ί-- XXIII

- 1 2

Amides of formula XI wherein R and R are hydrogen can be prepared from acid chlorides of formula XX or XII by reaction with diazomethane to form a diazoketone which is rearranged in the presence of ammonia and a catalyst such as silver to form the desired amide .

Carboxylic acids of formulas XIV and XXI can be prepared by hydrolysis, e.g., basic hydrolysis, of cyan compounds of formulas XIX and XVII. Carboxylic acids of formula XIV can be prepared by reacting amides of formula X with nitric acid. Carboxylic acids of formula XXI can be prepared by reacting nitric acid with amides formed by reaction of ammonia with carboxylic acid derivatives such as acid chlorides of formula XX, or by reacting a cyan compound of formula XVII with hydrogen peroxide in the presence of a base.

1 2

Carboxylic acids of formula XIV wherein R and R are hydrogen can be prepared from acid chlorides of formula XX by reaction with diazomethane to form diazoketones which are rearranged in the presence of water and a catalyst such as silver to form the desired acid.

Cyan compounds of formula XVII can be prepared by reacting cyan compounds of formula XXIV 35 i-t I \ i υ i / v_ <u-> 13 with a 1,3-disubstituted propane such as 1,3-dibromopropane and a base such as sodium hydride.

1 2

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

Similarly, cyan compounds of formula XXIII can be prepared from cyan compounds of formula XIX.

Cyan compounds of formula XIX wherein R and / or R are different from hydrogen may be prepared from the corresponding 1 2 cyano compounds of formula XIX wherein R and / or R are hydrogen, for example, by alkylation with an alkyl halide in the presence of a base such as lithium diisopropylamide.

Cyan compounds of formula XIX wherein R = H can also be prepared by reacting a ketone of formula V or an aldehyde of formula XII with a reagent to introduce a cyano group such as p-toluenesulfonylmethyl isocyanide. Similarly, the cyan compound of formula XIII can be prepared from aldehydes or ketones of formula VI.

Acid chlorides of formula XX can be prepared by reacting carboxylic acids of formula XXI with, for example, trinyl chloride.

Aldehydes of formula XXII can be prepared by well known methods. The following are given as examples of suitable methods: 14

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a) reducing cyano compounds of formula XVII with, for example, di-t-butyl aluminum hydride or diisobutyl aluminum hydride; b) reduction of carboxylic acid derivatives, eg i) reduction of tertiary amides formed by reaction of secondary amines with acid chloride of formula XX, eg when the secondary amine is a dialkylamine using lithium diethoxy aluminum hydride as reducing agent or when the secondary amine is ethylene amine using lithium aluminum hydride as reducing agent; ii) reduction of acid chlorides of formula XX, eg with lithium tri-t-butoxyaluminohydride; c) oxidation of alcohols (prepared by reduction of carboxylic acids of formula XXI) with, for example, chromium trioxide-pyridine complex in dichloromethane under anhydrous conditions.

15. Ketones of Formula V (except those where and

6 X

R is hydrogen and R is methyl or ethyl), ketones of formula VI and aldehydes of formula VI (except those where R

R, R and R are hydrogen), the compounds of formula VII I

o X 5 6 (except those where Z = CR -NY and R and R are hydrogen 20 and R 1 is methyl and ethyl), the imines of formula XVI (except such 5 6 1 where R and R are hydrogen and R is methyl or ethyl) and XVIII,

amides of formula X and XI, carboxylic acids of formula XIV

o X 2 5 6 (except those where R, R, R and R are hydrogen), cyano compounds of formula XIX and XXIII and acid chlorides of formula XII (except those where Rx, R2, R ~ * and R ^ are hydrogen) and XIII described herein as intermediates are novel compounds. Some of the cyan compounds of formulas XVII and XXIV are novel compounds.

GB Patent No. 973887 discloses phenylcycloal-kanmethylamines which are stated to have central analgesic properties and have the general formula 35

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15 pa. Rd \ _C-ch9_n \ JW7 \ VRe '5 ch9 chrc \ 2 / CH2 wherein Ra and Rd are each hydrogen, hydroxy, methyl or methoxy or together methylenedioxy, R is hydrogen or β d.

alkyl and R and R each represent hydrogen, a saturated or unsaturated aliphatic hydrocarbon group or a cycloalkyl group, or together and with the N atom a saturated ring which may be interrupted by a further heteroatom.

A number of these compounds have been tested by the reser pin reversal test described later in this specification. The results are shown in Table I below, which shows that none of the compounds at a dose of 30 mg / kg resulted in a 50% or greater reversal of 50%. This means that ED 2 -g is above 30 mg / kg. It was not possible to calculate a value for ED 2g because the effect did not occur in many cases that could be dose related. It would be expected that the percent reversal would be greater when a dose of 25 60 mg / kg was administered than when a dose of 30 mg / kg was administered.

This could not be verified due to the toxicity of the compounds at the higher dose, as seen especially for compound C, where 2 of the 10 test animals died during the trial.

30 Based on these experimental results, it is not to be expected that the compounds known from GB 973887 have anti-depressant effect in humans. All of the compounds prepared by the following examples, as will be seen later in the specification, have an ED, g value of 30 mg / kg or less and many of them of 10 mg / kg or less, showing that they has antidepressant effect in humans.

16

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Table I CH2NRdRe.HX

5 R1 ^ -1

Ra Rd NRdRe X dose,% reverse gns.

- ____ mg / kg ring__ A H OMe NH 2 Cl 30 25.8.5 13 10 60 1.0 1 B H OMe Cl 10 2 2

N

30 46,41,37,24 37 60 27,15 21 15 Λ- CH OH 'Cl 30 22,15,17 18 60 1 D Η H NH 2 Cl 30 9,1 1, -7 4 20 60 12,22 17 E OMe OMe NH2 Cl 30 3.3.6 4 60 6.12 9 25 F OMe OMe NPr2 Cl 30 2.11 7 60 28.11 20 G OH OH NH2 Br 30 4.4 4 60 -3.2 -1 30 H OH OH NPr2 Br 30 6, -1 3 60 0.3 2 35

Toxic effects seen, leaving 2 out of 10 animals dead.

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17

From Israel J. Chem 5 (5), 223-229 (1967, hereinafter referred to as Dissertation I, cf. Chemical Abstracts Vol. 68, 19170 j), 1-phenylcycloalkylamine derivatives are known to have no pharmacological effect, but on the contrary, they must be tested for pharmacological action, of which nature is not stated, and thus no conclusion can be drawn from the antidepressant effect of the compounds of the present process.

That thesis was followed up by two later, the 10th one in J.Med.Chem. J_2, 473-477, 1969 (hereinafter referred to as Dissertation II), the second in the Israel Journal of Chemistry 13, No. 1, 125-136, 1975 (hereinafter referred to as Dissertation III).

As for dissertation II, it is difficult to understand the type of compounds it describes, since the tables are not provided with any formula to which the headings of the columns can be attributed. However, it has been concluded that the formulas for the compounds in the two tables must be 20 respectively

Ar ^ NR'R "Ar \ NR'R" 0 "6

Thus, cyclohexyl and cyclopentyl derivatives which are not closely related to the present compounds or to the compound II (n = 3) in thesis I.

Thesis III relates to phenylcyclidine analogues of the formula

Ar NR NR

(Οί,) η '2 n where n can be 3 (Compounds Nos. 3 and 4.) These compounds are clearly different from those prepared by the process of the invention (the cyclobutyl ring is directly linked to the amino group) and Compounds Nos. .

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18 34 and 35 are inactive in the pharmacological tests reported in Thesis III.

Thus, the compound known from the literature cited does not give rise to the presumption that the compounds prepared by the process according to the invention have antidepressant effect.

The therapeutic effect of the compounds of formula I is determined by assessing the ability of the compounds to reverse the hypothermic effects of reserpine in the following manner. Male mice of the Charles River CD1 strain weighing between 18 and 30 g were divided into groups of 5 and provided with food and water ad libitum. After 5 hours, all mice body temperatures were taken orally and the mice received intraperitoneal injections of reserpine (5 mg / kg) in solution in deionized water containing ascorbic acid (50 mg / ml). The amount of fluid injected was 10 ml / kg body weight. 9 Hours after the start of the experiment, the animals were cut off from food while water was still available ad libitum. Twenty-four hours after the start of the experiment, the mice temperature was again taken and the animals were suspended in a 0.25% solution of hydroxyethyl ethyl cellulose (which is traded under the trademark "Cellosize QP 15000" not registered in Denmark) in a deionized water. dose volume of 10 ml / kg body weight. Three hours later, all animals' temperature was resumed. The percent reversal of the 25 reserpine-induced decrease in body weight is then calculated according to the formula (temp, after 27 hours - temp, after 24 hours). 100 (temp, after 5 hours - temp, after 24 hours) 30

The average value for each group of 5 mice was determined at several different dose sizes to allow calculation of a value for the average dose causing a 50% reversal (ED ED q). All of the compounds which are final products of the examples set forth later in the specification give values for ED, -0 of 30 mg / kg or less. It is clear to the experts that this test indicates compounds with antide- 19

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depressive effect in humans.

Table II lists compounds of formula I which gave a value for ED5Q of the above test of 10 mg / kg or less.

Table II

1- [1- (3,4-Dichlorophenyl) -cyclobutyl] -ethylamine hydrochloride, N-methyl-1- [1- (3,4-dichlorophenyl) -cyclobutyl] -ethylamine hydrochloride, N, N-dimethyl -1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride, 1- [1- (4-iodophenyl) cyclobutyl] ethylamine hydrochloride, N-methyl-1- [1- (4 N-Dimethyl-1- [1- (4-iodophenyl) -cyclobutyl] -ethylamine hydrochloride, N-methyl-1- [1- (2-naphthyl) -hydroxyphenyl) -cyclobutyl] -ethylamine hydrochloride ) -cyclobutyl] -ethylamine hydrochloride, N, N-dimethyl-1- [1- (4-chloro-3-trifluoromethylphenyl) -cyclobutyl] -ethylamine hydrochloride, 1- [1- (4-chlorophenyl) -cyclobutyl] -butylamine hydrochloride, N-methyl-1- [1- (4-chlorophenyl) -cyclobutyl] -butylamine hydrochloride, N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -butylamine hydrochloride, 1- [1- (3,4-dichlorophenyl) -cyclobutyl] -butylamine hydrochloride, N-methyl-1- [1- (3,4-dichlorophenyl) -cyclobutyl] -butylamine hydrochloride, N, N -dimethyl-1- [1- (3,4-dichlorophenyl) -cyclobutyl] -butylamine hydrochloride, 1- [1- (4-biphenylyl) -cyclobutyl] -butylamine hydrochloride, N, N-dimethyl-1- [ 1- (4-biphenylyl) cyclobutyl] - butylamine hydrochloride, 1- [1- (4-chloro-3-fluorophenyl) -cyclobutyl] -butylamine hydrochloride, N-formyl-1- [1- (4-chloro-3-fluorophenyl) -cyclobutyl] -butylamine , 1- [1- (3-Chloro-4-methylphenyl) -cyclobutyl] -butylamine hydrochloride, N-formyl-1- [1-phenylcyclobutyl] -butylamine, 1- [1- (3-trifluoromethylphenyl) -cyclobutyl] -butylamine hydrochloride, 1- [1- (naphth-2-yl) -cyclobutyl] -butylamine hydrochloride, 1- [1- (6-chloro-naphth-2-yl) -cyclobutyl] -butylamine,

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N-methyl-1- [1- (4-chlorophenyl) -cyclobutyl] -2-methylpropylamine hydrochloride, 1- [1- (4-chlorophenyl) -cyclobutyl] -pentylamine hydrochloride, N-methyl-1 - [1- (4-chlorophenyl) -cyclobutyl] -pentylamine hydrochloride, 5 N, N-dimethyl-1- [1-phenylcyclobutyl] -3-methylbutylamine hydrochloride, 1- [1- (4-chlorophenyl) -cyclobutyl ] -3-methylbutylamine hydrochloride, N-methyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride, N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine hydrochloride, N-formyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine, N, N-dimethyl-1- [1- (3,4-dichlorophenyl) - cyclobutyl] -3-methylbutylamine hydrochloride, N-methyl-1- [1- (naphth-2-yl) -cyclobutyl] -3-methylbutylamine hydrochloride, N-methyl-1- [1- (3, 4-Dimethylphenyl) cyclobutyl] -3-methylbutulamine hydrochloride, [1- (4-chlorophenyl) cyclobutyl] - (cyclopropyl) methylamine hydrochloride, N-methyl- [1- (4-chlorophenyl) cyclobutyl] - (cyclopentyl) methylamine hydrochloride, [1- (4-chlorophenyl) cyclobutyl] - (cyclohexyl) methylamine hydrochloride, N-methyl- [1- (4-chlorophenyl) cyclobutyl] - ( cyclohex yl) methylamine hydrochloride, [1- (3,4-dichlorophenyl) cyclobutyl] - (cyclohexyl) methylamine hydrochloride, N-methyl- [1- (3,4-dichlorophenyl) cyclobutyl] - (cyclohexyl) methylamine hydrochloride, [1 "(4-chlorophenyl) cyclobutyl] - (cyclohexyl) methylamine hydrochloride, 1- [1- (4-chlorophenyl) cyclobutyl] -2-cyclopropylethylamine hydrochloride, N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -2-cyclohexylethyl-amine hydrochloride, α- [1- (4-chlorophenyl) cyclobutyl] benzylamine hydrochloride,

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21 N-methyl-α- [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} -propyl-amine hydrochloride, N, N-dimethyl-2- [1- (4-iodophenyl) -cyclobutyl] - ethylamine hydrochloride, N-ethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] -ethylamine hydrochloride, N, N-diethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] -ætylamin-hydro-chloride.

15

The method according to the invention will now be illustrated by some examples. All the compounds were characterized by conventional analytical technique and provided satisfactory elemental analysis.

20

Example 1

A solution of 25 g of 3,4-dichlorobenzyl cyanide and 15 ml of 1,3-dibromopropane in 150 ml of dry dimethyl sulfoxide was added dropwise under nitrogen to a stirred mixture of 7.5 g of sodium hydride dispersed in 7.5 g of mineral oil and 200 ml of dimethyl sulfoxide. at a temperature in the range of 30-35 ° C. The mixture was stirred at room temperature for 2 hours, then 8 ml of propan-2-one was added dropwise and then 110 ml of water. The mixture was filtered 2Q through diatomaceous earth, marketed under the name "Celite" ®, and the solid residue was washed with ether. The ether layer was separated, washed with water, dried and evaporated. 1- (3,4-Dichlorophenyl) -1-cyclobutanecarbonitrile (bp 108-120 ° C / 0.15 mm Hg) was isolated by distillation. This method is a modification of that described by Butler and Pollatz (J. Org. Chem., Vol. 36, No. 9, 1971, p. 1308).

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21.7 g of the 1- (3,4-dichlorophenyl) -1-cyclobutanecarbonitrile prepared in the manner described above were dissolved in 50 ml of dry ether and the solution was added under nitrogen to the product of reaction of gaseous methyl bromide with 3.9 g of magnesium -5 chips in 150 ml dry ether. The mixture was stirred at room temperature for 2 hours and then under reflux for 2 hours.

Crushed ice was added then 100 ml of concentrated hydrochloric acid and the mixture was heated under reflux for 2 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. 108-110uC / 0.2 mm Hg) was isolated by distillation.

9.1 g of 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane prepared as described above, 6.5 ml of formamide and 3 ml of 98% formic acid were heated to 180 ° C for 16 hours, N-Formyl-1- [1- (3,4-dichlorophenyl) -cyclobutyl] -ethylamine was obtained. 20 ml of concentrated hydrochloric acid was added and the mixture heated

under reflux for 3 hours. Then, the solution was cooled and washed with ether and sodium hydroxide solution was added.

The product was extracted with ether and the ether extract washed with water, dried and evaporated. 1- [1- (3,4-Dichlorophenyl) -cyclobutyl] -ethylamine (bp 112-118 ° C / 0.2 mm Hg) was isolated by distillation. The amine was dissolved in propan-2-one and concentrated hydrochloric acid and the solution evaporated to dryness to give 1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride, m.p. 185-195 ° C. (Formula I, n = 0; R3, = Me; R2 = R3 = R4 = H; R5 = 4-Cl; R6 = 3-Cl).

Example la 30

The above-described preparation of N-formyl-1- [1- (3,4-dichlorophenyl) -cyclobutyl] -ethylamine, m.p. 124-125 ° C (Example 1a, Formula I: n = 0; R1 = Me; R2 = H; R3 = H; R4 = CHO; R3 = 4-C1 and R3 = 3-C1) were repeated and the product isolated by cooling the reaction mixture and collecting the solid product by filtration. The formamide was then hydrolyzed with concentrated hydrochloric acid in industrial methylene.

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23 of ethanol and the hydrochloride salt of 1- [1- (3,4-dichlorophenyl) -cyclobutyl] -ethylamine was obtained.

In the same manner as described in Example 1a, the following compounds were prepared. The conditions for the hydrolysis 5 of the formamides isolated by appropriate methods are set out in footnotes.

__. CHR1NH0, HCl - l £ H = i

Example R R6 kp. (free base) HCl salt Note m.p.

1 (b) methyl Cl H 107 ° C / 1.2 mm Hg A

1 (c) n-butyl Cl H 138-139 ° C B

1 (d) methyl I H 205-207 ° C

1 (e) methyl Cl CP3 216-217 ° C D

2q A. Aqueous hydrochloric acid / industrial methylated ethanol.

B. 1-Valeryl-1- (4-chlorophenyl) cyclobutane was prepared in tetrahydrofuran; hydrolysis was performed with concentrated HCl / industrial or methylated ethanol.

C. Concentrated HCl / diethylene glycol dimethyl ether (similarly as described below in Example 12).

D. Concentrated HCl / industrial methylated ethanol.

Example 2 4.04 g of the product of Example 1, 0.5 ml of water and 3.6 ml of 98% formic acid were mixed with cooling. 3.8 ml of 37-40% aqueous formaldehyde was added and the solution was heated to 85-95 ° C for 5 hours. The solution was then evaporated to dryness and the residue was acidified with concentrated hydrochloric acid and the water removed by repeated addition of propan-2-ol followed by evaporation in vacuo. Crystals of N, N-dimethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride were isolated.

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chloride, m.p. 211-213 ° C. (Formula I: n = 0; R3 = Me; R2 = H; R3 = R4 = Me; R5 = 4-C1; R6 = 3-C1).

Similarly, the compounds of Examples 1 (b) and 1 (d) were converted to the compounds listed below.

5, _. CHR1NMe ^, HCl Π r6 >> - .......

10 15 6

Example Starting RRR HCl salt Free base bp., Material_mp., ° C ° C / mm · Hg_ 2 (a) 1 (b) methyl ClH 98-100 / 0.5 2 (b) 1 (d) methyl IH 260-261

Example 3 In a similar manner as described above in Examples 1 and 2, N, N-dimethyl-1- [1- (4-biphenylyl) -cyclobutyl] -ethylamine hydrochloride was prepared, m.p. 196-197 ° C. (Formula I, n = 20 O; R1 = Me; R2 = H; R3 = R4 = Me; R5 = 4-phenyl and R6 = H).

Example 4 15 g of 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane prepared as described in Example 1, 47.5 ml of N-methylformamide, 10.3 25 ml of 98% formic acid and 1.5 ml % aqueous methylamine solution was mixed 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 a pale yellow oil which was refluxed with 50 ml of concentrated hydrochloric acid for 2 hours. 50 ml of industrially methylated ethanol (IMS) was added and the mixture was heated under reflux for 16 hours. Then the mixture was cooled to 0 ° C and the white precipitate collected by filtration, washed with acetone and dried. The product, N-methyl-1- [1- (3,4-dichlorophenyl) -cyclobutyl] -ethylamine hydrochloride had m.p. 254-256 ° C (Formula 25)

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I: n = 0; R1 = Me; R2 = H; R3 = Me; = H; R5 = 4-C1 and R6 = 3-Cl).

Similarly, the following compounds of formula I were prepared: CHR NHMe, HCl 1 c c Example R R R amine bp. Note of HCl salt _______ m.p.

4 (a) Me Cl H 98-100 ° C / 0.15mm Hg 240-241 ° C

4 (b) Me H Cl 260-272 ° C

4 (c) Me Br H 96-98 ° C / 0.1 mm Hg

4 (d) Me H Br 251-255 ° C

4 (e) Me CF3 H 219-221 ° C

4 (f) Me H CF3 225-228 ° C

4 (g) Me - (CH = CH) 2- 254-257 ° C

4 (h) Me Cl CF3 198-200 ° C

4 (i) Et Cl H 238-240 ° C

4 (j) Pr Cl H 228-229 ° C A

4 (k) Bu Cl H 152-153 ° C A

4 (1) Me I H 242-243 ° C

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

30 35 26

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Example 5

A mixture of 50 ml of 70% aqueous ethylamine and 100 ml of water was gradually mixed with a mixture of 50 ml of 98% formic acid and 100 ml of water to give a neutral solution, evaporated at 100 ° C / 100 ml of Hg. until 180 ml of water was collected. The residue was heated to 140 ° C and 10.4 g of 1-acetyl-1- (4-chlorophenyl) cyclobutane (prepared in the same manner as described in Example 1 for 1-acetyl-1- (3,4-dichlorophenyl)) was added. -cyclobutane) and 10 ml of 98% formic acid. The mixture 10 was heated on an oil bath to the temperature 180-200 ° C for 16 hours. The mixture was distilled until an internal temperature of 170 ° C was obtained and this temperature was maintained for 2 hours.

All volatiles were removed by distillation at 160 ° C / 20 mm Hg and the residue was heated under reflux with 15 ml of concentrated hydrochloric acid and 15 ml of IMS for 3 hours. The industrially methylated ethanol was evaporated on a rotary vaporizer and the residue was washed with ether. The aqueous phase was brought to pH 12 with sodium hydroxide and extracted with ether. The ether extract was dried and, after evaporation, gave a residue 20 which was treated with aqueous hydrochloric acid to give N-ethyl-1- [1- (4-chlorophenyl) cyclobutyl] ethylamine hydrochloride with srnp. 203-205 ° C. (Formula I: n = 0? R "4 = Me; R ^ = H; R ^ =

One; R 4 = H; R5 = 4-Cl; R6 = H).

25 30 __________ 35

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27

Example 6 15 g of 1- (4-chlorophenyl) -1-cyclobutanecarbonitrile, prepared in a similar manner to 1- (3,4-dichlorophenyl) cyclobutanecarbonitrile in Example 1, in 50 ml of dry ether was added to the product 5 of the reaction between 3.18 g of magnesium chips and 15.99 g of propyl bromide in 50 ml of dry ether. The ether was replaced with tetrahydrofuran and the mixture heated under stirring and reflux for 18 hours. The mixture was cooled and ice and 52 ml of concentrated hydrochloric acid were added. The resulting mixture was stirred under reflux for 10 hours and extracted with ether. The ether extract gave a residue from which 1-butyryl-1- (4-chlorophenyl) cyclobutane was distilled with m.p. 106-108 ° C / 0.3 mm Hg.

A mixture of 21 g of the ketone prepared in the manner described above and 6 ml of 98% formic acid was added to 15 ml of formamide at 160 ° C over a period of 1 1/2 hours.

Upon completion of the addition, the temperature was raised to 180-185 ° C and kept here for 5 hours. The mixture was cooled and extracted with chloroform to give a thick gum which upon heating with petroleum ether (bp 60-80 ° C) afforded a colorless dissolved solid which was recrystallized from petroleum ether (bp 60-80 ° C) to produce of N-formyl-1- [1- (4-chlorophenyl) -cyclobutyl] -butylamine, m.p. 97.5-98 ° C (formula I: n = 0; R1 = propyl; R2 = R3 = H; R4 = CHO; R5 = 4-C1; R6 = H).

Example 7

A solution of 35.2 g of 1- (3,4-dichlorophenyl) -1-cyclobutane carbonitrile, prepared as described in Example 1, in 100 ml of ether was added to a solution of propyl magnesium bromide prepared by reaction of 32 g of propyl bromide with 6.36 g of magnesium chips in 100 ml ether. The ether was replaced with dry toluene and the mixture heated under reflux for 1 hour. 200 ml of ether were added and then 120 ml of concentrated hydrochloric acid and the mixture was heated at reflux for 1 hour. The reaction mixture was extracted with ether and after washing and drying the extract gave a residue from which 1-butyryl-1- (3,4-dichlorophenyl) cyclobutane was distilled with m.p. 120-128 ° C / 0.25 mm Hg.

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28 37.0 g of the ketone prepared in the manner described above and 9 ml of 98% formic acid were added to 23.5 ml of formamide at 170 ° C and the temperature maintained at 175-180 ° C for 5 hours.

An additional portion of 4.5 ml of formic acid was added and the mixture maintained at 175-180 ° C for another 15 hours. The mixture was extracted with ether which after evaporation afforded a thick oil which crystallized from petroleum ether (bp 60-80 ° C) to give N-formyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] -butylamine, m.p. . 103-105 ° C (formula I: n = 0; = propyl; R2 = R3 = H; R4 = CHO; R5 = 4-C1 and R6 = 3-C1).

In the same manner as just described, the following compounds were prepared:

_____ CHR1NHCHO

Example R 2 R 3 R 3 m.p. (° C) 20 7 (a) Isobutyl Cl H 110-112 7 (b) Propyl Cl F 115-116 7 (c) Phenyl Cl H 94-96 7 (d) Propyl Η H 98-102 Example 8 4.0 g of the product of Example 7 in 25 ml of dry tetrahydrofuran was rapidly added to a stirred mixture of 1.4 g of lithium aluminum hydride in 25 ml of dry tetrahydrofuran under nitrogen.

The mixture was heated under reflux for 5 hours and then cooled. 15 ml of water and then 3 ml of 10% sodium hydroxide solution were added and the mixture was filtered through diatomaceous earth ("Celite" ®). The product was extracted into ether and back extracted with 5N hydrochloric acid, then the aqueous layer was basified and extracted with ether. The phytite extract gave an oil which was dissolved in 5 ml of propan-2-ol and hydrochloric acid was added to pH 2. Evaporation of the resulting solution gave a white solid which was collected, washed with acetone and dried. The product was N-methyl-1- [1- (3,4-dichlorophenyl) -

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29 cyclobutyl] -butylamine hydrochloride and had m.p. 234-235 ° C (formula I: n = 0; R R = propyl; R ^ = R R = H; R ^ = Me; R R = 4-Cl and R R = 3-C1).

Similarly, the following compounds were prepared: 5. CHR ^ NHMe, HCl »5 ΓΛ | - 1 °

Example Rx R3 R ° Mp. (° C) 8 (a) phenyl Cl H 275-278 8 (b) propyl Cl H 223-228 Example 9 10 g of the product of Example 7 in solution in 50 ml ether was added to 40 ml 70% sodium toluene solution -bis- (2-methoxyethoxy) aluminum hydride traded under the trademark "Red-al" not registered in 2Q Denmark, at a temperature in the range 25-30 ° C. The mixture was stirred at this temperature for 4 hours. 25 ml of water was added dropwise and, under cooling, and the mixture was filtered through diatomaceous earth ("Ce-lite" ®). Aqueous NaOH was added and extracted with ether. The ether extract was washed with water and back-extracted with 5N hydrochloric acid. A white solid with m.p. 232-235 ° C and it was collected. Base was added to the aqueous phase and extracted again with ether. Evaporation of the ether extract gave an oil which was dissolved in 5 ml of propan-2-ol 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) cyclobutyl] -butylamine hydrochloride, m.p. 236-237 ° C (Formula I: n = 0; R = = propyl; R ^ = R = = H; 4,5 6 R = Me; R = 4-C1 and R = 3-C1.

In the same way as described above, the following compounds were prepared. Where the formyl starting material was unopened

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After dissolving in ether, a solution of the reducing agent was added to a stirred suspension of the formyl compound. As the size of the group increases, the hydrochloride salts of the desired compounds become less soluble in the aqueous phase and more soluble in the organic phase, so that appropriate modifications are needed in the isolation process as will be apparent to those skilled in the art.

........ CHR1 2 3 4NHMe, HC1 “* 5-Ofi

Example R (° C) 9 (a) isopropyl Cl H 275-259 9 (b) s-Butyl Cl H 209-212 9 (c) Isobutyl Cl H 225-233 9 (d) Cyclopentyl Cl H 252-256 9 (e) (f) 4-methoxyphenyl Cl H 264-266 9 (g) 3-methoxyphenyl Cl H 254-255 9 (h) 2-methoxyphenyl Cl H 149-153

9 (i) cyclohexyl Cl H 170-172 I

9 (j) isobutyl - (CH = CH) + 256-259 9 (k) cyclohexyl Cl Cl 223-224 25 9 (i) isobutyl Me Me (1) 9 (m) propyl OMe H 173-175 9 (n) methyl phenyl H 116-118

Boiling point above 150 ° C / 1.0 mm Hg for the free base.

2 3 ° 3

Example 10 4 4 g of the product of Example 7, 25 ml of diethylene glycol dimethyl ether, 10 ml of water and 10 ml of concentrated hydrochloric acid were mixed and heated under reflux for 9 hours. The solution was washed with ether and aqueous NaOH was added before extraction with ether. The ether extract was washed with brine and evaporated to give an oil. 3.19 g of the oil

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31 was dissolved in a mixture of 4 ml of propan-2-ol and 20 ml of ether and 1.5 ml of concentrated hydrochloric acid was added. The solvent was evaporated in vacuo. Repeated solution in industrial methylated ethanol 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 m.p. 201-203 ° C. The product was 1- [1- (3,4-dichlorophenyl) -cyclobutyl] -butylamine hydrochloride (Formula I: n = 0; R 2 = propyl; = H; = 4-Cl and R 6 = 3-Cl) .

In the same manner as just described, the following compounds were prepared. As the size of the R group increases, the hydrochloride salts of the desired compounds become less soluble in the aqueous phase and more soluble in the organic phase, so that appropriate modifications of the isolation process are needed, which modifications will be apparent to those skilled in the art.

- απΑϊΗ ,, ΗΟΙ R6 ^ -

Example R1 R5 R6 m.p. (° C) 10 (a) isopropyl Cl H 200-202 (b) s-Butyl Cl H 178-179 (c) Isobutyl Cl H 163-165 (d) Cyclopentyl Cl H 185-210 10 (e) (f) 4-methoxyphenyl Cl H 214-219 10 (g) cyclohexyl Cl H 206-210 10 (h) isobutyl Η H 210-212 10 (i) cyclopropyl Cl H 204-206 10 (j) propyl Ph H 235-236 (k) propyl Me Cl 214-217 (1) propyl - (CH = CH) 2 ~ 157-159 (m) cycloheptyl Cl H 156-162 10 (n) cyclohexyl Cl Cl 215 10 (p) methyl Cl F 215-217

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32 (q) propyl OMe H 178-179 10 (r) propyl Cl F 186-188 10 (s) propyl Cl H 174-175 10 (t) cyclohexylmethyl Cl H 148-150 5 (u) butenyl Cl H 184 -185, 10 (v) propyl -CH = CH-CC1-CH- (a) 10 (w) propyl H CF ^ 126-128 (x) 4-fluorophenyl Cl H 279 10 (y) (b) methyl - C-C-CH = CH-248-262

10 CH CH

\ //

CH-CH

(a) Boiling point of the free base 168 ° C / 0.05 mm Hg.

(b) Diethylene glycol dimethyl ether replaced by ethylene glycol dimethyl. r tyleat.

1b In a similar manner as described above, 1- [1- (4-chloro-2-fluorophenyl) -cyclobutyl] -butylamine was prepared with b.p. 99 ° C / 0.05 mm Hg (Formula I: n = 0; R 2 = propyl; R 2 = R 2 = R 4 = H; R 2 = 4-C 1; R 2 = 2-F), 1- [1- (2-fluorophenyl) -cyclobutyl] -butyl-ZU τ: amine hydrochloride, m.p. 175-177 ° C (formula I: n = 0; Rx = propyl; R2 = R3 = R4 = R5 = H; R6 = 2-F) and 1- [1- (4-chloro-2-

methyl) cyclobutyl] -butylamine hydrochloride, m.p. 188-190 ° C

(Formula I: n = 0; R 1 = propyl; R 2 = R 2 = R 4 = H; R 2 - 4-C 1; R 6 = 2-Me) as Examples 10 (z), 10 (aa) and 10 (bb) * 25

Example 11 3.3 g of the product of Example 10 (c) in the form of the free base, 2.99 g of formic acid and 1 ml of water were mixed with cooling. 3.93 ml of 37-40% aqueous formaldehyde 0 * 0 was added and the mixture was heated for 18 hours at a temperature of 85 ° C.

.. N

95 ° C. Excess dilute hydrochloric acid was added and the solution evaporated to dryness. The residue was basified with 5N sodium hydroxide solution and the product extracted with ether. Evaporation of the ether gave a pale yellow oil which was dissolved in a mixture of 4 ml of propan-2-ol and 20 ml of ether, and 2 ml of concentrated hydrochloric acid was added dropwise. The solution evaporates

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33 pedes and the residue was dissolved repeatedly in ethanol and evaporated in vacuo to give a gum triturated with petroleum ether (bp 60-80 ° C) to give a yellow solid which was recrystallized from acetone. The product was N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride, m.p. 195-197 ° C (formula I: n = 0; R "+" = isobutyl; R2 = H; R3 = R4 = Me; R5 = 4-C1; R6 = H).

In a similar manner as described above, the following compounds of formula I were prepared: 10 CHR-1-NMe 2 HCl - Pfi R 6

Example Initial R ^ R ^ R ^ Mp (° C) material 11 (a) 10 (h) isobutyl Η H 195-198 11 (b) 10 (j) propyl Ph H 194-196 20 11 (c) 10 (n) cyclohexyl Cl Cl 227-228 11 (d) 10 (q) propyl OMe H 187-188 11 (e) 10 (s) propyl Cl H 194-196 11 (f) 10 (t) cyclohexyl Cl H 194 -196 methyl 11 (g) 10 (u) butane Cl H 165-167 nyl 11 (h) 10 (v) propyl -CH = CH-CC1 = CH- (a) 11 (i) - isobutyl Cl Cl 225 -226 11 (j) 10 (x) 4-fluorophenyl Cl H 234 11 (k) - propyl isopropyl Η 211-213 30 (a) The free base boiling point below 250 ° C / 0.05 mm Hg.

Example 11 (1) In a similar manner as described above, N, N-dimethyl-1- [1- (4-chloro-2-fluorophenyl) -cyclobutyl] -butylamine hydrochloride was prepared, m.p. 183 ° C (formula I: n = 0; R3 "= propyl; R2 = H; R3 = R4 = Me; R5 = 4-C1; R6 = 2-F).

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34

Example 12 8.3 g of the product of Example 7, 50 ml of dimethylene glycol dimethyl ether, 20 ml of water and 20 ml of concentrated hydrochloric acid were mixed and heated under reflux for 16 hours. The mixture was poured into water, which was added aqueous NaOH and the product. extracted with ether. Evaporation gave a dark oil.

A sample of 7.9 g of this oil, 0.7 ml of water and 6.5 ml of formic acid was mixed and 6.5 ml of formaldehyde was added. The mixture was heated under reflux for 3 hours and then 10 ml of concentrated hydrochloric acid and 10 ml of propan-2-ol were added. Evaporation to dryness gave N, N-dimethyl-1- [1- (3,4-dichloroacetic acid)

phenyl) -cyclobutyl] -butylamine hydrochloride, m.p. 195-196 ° C

1 2 as a white solid (formula I: n = 0; R = propyl; R = H; R3 = R4 = Me; R5 = 4-C1; R6 = 3-C1).

15 I

Example 13! 37.6 g of 1- (4-chlorophenyl) -1-cyclobutanecarbonitrile prepared in a similar manner as described for 1- (3,4-dichlorophenyl) -2Q1-cyclobutanecarbonitrile in Example 1 were added to a solution of 32.4 g. potassium hydroxide in 370 ml of diethylene glycol and the mixture heated under reflux for 3 1/2 hours. The reaction mixture was poured into a mixture of ice and water and the resulting solution washed with ether. The aqueous layer was added to a mixture of 100 ml of concentrated hydrochloric acid and ice and the resulting precipitate of 1- (4-chlorophenyl) -1-cyclobutanecarboxylic acid (mp 86-88 ° C) was collected, washed with water and dried.

A solution of 10.5 g of the acid prepared in the manner described above in 150 ml of tetrahydrofuran was added dropwise under nitrogen to a stirred suspension of 2 g of lithium aluminum hydride in 150 ml of tetrahydrofuran. The mixture was heated under reflux for 2 hours and water was added. The mixture was filtered through diatomaceous earth ("Celite" ®) and the product extracted with ether. After washing with water and drying, the ether was evaporated and a residue was obtained which was recrystallized from petroleum ether (b.p. 60-80 ° C). The product was 1- [1- (4-chloro-phenyl) -cyclobutyl] -methyl alcohol with mp. 60-62 ° C.

DK 161770 B

35

A solution of 60 g of the alcohol prepared in the manner described above in 52 ml of pyridine was added dropwise to a solution of 60 g of p-toluenesulfonyl chloride in 100 ml of pyridine, cooled in ice. The temperature was allowed to rise to room temperature and stayed there for 18 hours. 1- [1- (4-chlorophenyl) -cyclobutyl] -methyl-p-toluenesulfonate, m.p. 99-100 ° C was precipitated by pouring the reaction mixture into a mixture of ice and concentrated hydrochloric acid (200 ml). A solution of 97 g of the sulfonate compound prepared in the manner described above and 16.6 10 g of sodium cyanide in 370 ml of dimethyl sulfoxide were heated on a steam bath for 18 hours. The mixture was poured into water and extracted with ether. After washing and drying, the ether was evaporated leaving a solid residue of 2- [1- (4-chlorophenyl) cyclobutyl] acetonitrile with m.p. 63-65 ° C.

A solution of 16.5 g of diisopropylamine in 50 ml of dry tetrahydrofuran was stirred under nitrogen at a temperature of 0 ° C and a 1.6M solution of n-butyl lithium in 100 ml of hexane was added dropwise. The reaction mixture was stirred for 30 minutes and then cooled to -78 ° C. A solution of 9.5 g of (2- [1- (4-chlorophenyl) -cyclobutyl] -acetonitrile), prepared in the manner described above, was added dropwise in 25 ml of dry tetrahydrofuran dropwise. 0 ° C and the mixture was stirred for 10 minutes before adding a solution of 10 ml of methyl iodide in 10 ml of tetrahydrofuran.

25 ml of tetrahydrofuran was added to give a homogeneous solution and further a solution of 4 ml of methyl iodide in 10 ml of tetrahydrofuran was added. The mixture was stirred at ambient temperature for 2 hours and then 50 ml of water was added. The aqueous phase is washed with ether and the ether is added with the organic phase of the reaction mixture. The combined organic phases were washed three times with 5N hydrochloric acid and three times with water, dried and evaporated to give an oil which solidified and recrystallized from IMS to give 2- [1- (4-chlorophenyl) cyclobutyl] -2-methylpropio -35 nitrile with m.p. 73-75 ° C.

4 g of the nitrile prepared in the manner described above was heated under reflux with 8 g of potassium hydroxide in 40 ml of diethylene glycol for 24 hours. The reaction mixture cools.

DK 161770 B

36 dec and added to 50 ml of water and the aqueous phase washed twice with ether. The aqueous phase was acidified with 5N hydrochloric acid and extracted with 3 portions of ether. The combined ether extracts were washed with water, dried and evaporated to give a white solid which was recrystallized from petroleum ether (bp 60-80 ° C) to give 2- [1- (4-chlorophenyl) cyclobutyl] -2- methylpropionic acid, m.p. 95-110 ° C.

10 ml of oxalyl chloride was added to 2 g of the acid prepared in the manner described above, and after the initial effervescence had ceased, the mixture was heated under reflux for 1 hour. Excess oxalyl chloride was removed by distillation and the residual oil was added to 75 ml of concentrated ammonia water. An oily solid formed which was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to give! 2- [L- (4-chlorophenyl) cyclobutyl] -2-metylpropionamid. 1.34 g of the amide thus prepared was dissolved in a mixture of 8 ml of acetonitrile and 8 ml of water, and 3.4 g of iodosobenzene-bistrifluoroacetate was added and the mixture was stirred at room temperature for 5 1/2 hours. . 75 ml of water and 8 ml of concentrated hydrochloric acid were added and the mixture was extracted with ether. The ether extract was washed with 5N hydrochloric acid and the aqueous phase was basified and extracted with additional portions of ether which were dried and evaporated to give an oil. The oil was dissolved in petroleum ether (bp 80-100 ° C) and dry hydrogen chloride gas was passed through the solution. 1- [1- (4-Chlorophenyl) -cyclobutyl] -1-methylethylamine hydrochloride, m.p. 257-259 ° C were collected by filtration (formula I: n = 0; R1 = R2 = Me; R3 = R4 = H; R5 = 4-C1; R6 = H).

30

Example 14 3.4 g of the product of Example 4 (h) was mixed with 0.72 g of anhydrous sodium formate, 10 ml of 98% formic acid and 5 ml of 37-40% aqueous formaldehyde solution, and the mixture was heated to a temperature of 85 -95 C for 16 hours. The mixture was diluted with 50 ml of water and basified to pH 10 with aqueous sodium hydroxide solution. The basic aqueous solution is extra-

DK 161770 B

37 was cured with ether, washed with water and dried with magnesium sulfate. Dry hydrogen chloride was bubbled through the 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; = R2 = R4 = Me; R2 = H; R5 = 4-Cl and R6 = 3-CF3).

Example 15

Preparation of salts of the compound of formula I is illustrated by the following examples in which equimolar amounts of the base and acid were taken up in a solvent. The salt was then extracted from the solution in a conventional manner.

Solution Mp. of the salt

Example Base Acid Agent (° C) 15. ...................... - 15 (a) 10 (s) lemon aqueous acetone 158-160 15 (b) 10 (s) maleic ether 155 -157 15 (c) 10 (s) amber 152-155 15 (d) 2 L (+) wine- IMS 150-153 20 15 (e) Note (a) lemon-ether / methanol 163-164 (probes) (a) The base was 1- [1- (3,4-dimethylphenyl) -cyclobutyl] -3-methylbutylamine, prepared in a similar manner as described in Example 10.

25

Example 16

A solution of 15.7 g of bromobenzene in 50 ml of ether was added dropwise while cooling to 2.4 g of magnesium chips under an atmosphere of nitrogen. A solution of 19.1 g of 1- (4-chlorophenyl) -cyclobutanecarbonitrile, prepared in a similar manner as described in Example 1 for 1- (3,4-dichlorophenyl) -cyclobutanecarbonitrile, was added in 50 ml of ether and the ether was replaced by 130 ml. ml of dry toluene. The reaction mixture was heated on a steam bath for 35 hours. A sample of 20 ml of the resulting solution was added to a solution of 1 g of sodium borohydride in 60 ml of diethylene glycol dimethyl ester and the mixture was stirred for 1 1/2 hours. 60 ml of water were slowly added and the aqueous layer DK 161770 B! j 38 j was extracted with toluene. The toluene extracts were washed with water, dried and evaporated to give a residue which was dissolved in 50 ml of methanol. 5 ml of 6N hydrochloric acid was added and the solution filtered and evaporated. Dry acetone trituration gave 5? - [1- (4-chlorophenyl) cyclobutyl] benzylamine hydrochloride, m.p. 277-279 ° C (formula I: n = 0; R1 = Ph; R2 = R3 = R4 = H; R5 = 4-Cl; R6 = H).

Example 17 10: 62 ml of methyl formate was added dropwise to 85.5 ml of isopropylamine with stirring at a rate which ensured the maintenance of gentle reflux conditions. Stirring was continued for 2 hours after addition. The methanol is distilled off! was prepared at 100 ° C and N-isopropylformamide was obtained with b.p. ! 108-109 ° C / 25 mm Hg) by distillation.

10.4 g of 1-acetyl-1- (4-chlorophenyl) cyclobutane prepared in the same manner as described in Example 1 for 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane were added and 5 ml of 98 % formic acid j to 43.5 g of N-isopropylformamide, and the mixture was heated to U U18 ° C for 4 hours. Excess starting material was distilled off under reduced pressure (20 mm Hg) leaving a viscous residue which was heated under reflux with 30 ml of concentrated hydrochloric acid for 6 hours. The reaction mixture was washed with ether until a colorless solution was obtained. The aqueous phase was made basic, extracted with ether, dried and evaporated to 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; R1 = Me; R2 = R4 = H; R3 = isopropyl; R5 = 4-C1; R6 = H).

Example 18 7.0 g of 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane, prepared as described in Example 1, was slowly added to a mixture of 25 ml of pyrrolidine and 15 ml of 98% formic acid heated to 130-135 ° C for 5 hours. The mixture was stirred and heated to 39

DK 161770 B

160-165 ° C for 16 hours. After cooling, the mixture was poured into 200 ml of 5N hydrochloric acid. The solution was washed with ether, basified with aqueous sodium hydroxide solution and extracted with ether. The ether extract was washed with water and 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 = 0; R "= Me; R 2 = 3 4, 10 H; R plus R together with the associated nitrogen atom 5 6 forms a pyrrolidine ring; R = 4-C1; R = 3 -C 1).

Example 19 10.5 g of 1- (4-chlorophenyl) -1-cyclobutanecarboxylic acid, prepared as described in Example 13, was heated under reflux with 20 ml of thionyl chloride for 2 1/2 hours. Excess thionyl chloride was evaporated and the acid chloride of the above acid distilled (bp 82-96 ° C / 0.2 mm Hg).

A solution of 23.0 g of the acid chloride in 100 ml of dry tetrahydrofuran was slowly added to the reaction product of 3.0 g of magnesium shavings and 12.0 g of ethyl bromide in dry tetrahydrofuran at a temperature of -70 to -60 ° C. The temperature was kept at -60 ° C for 1 hour and then allowed to rise to 0 ° C.

2 ^. 50 ml of water was added followed by 150 ml of 5N hydrochloric acid under cooling. The reaction mixture was extracted with ether, washed with water and sodium bicarbonate solution and dried. The solvent was removed by evaporation and 1-propionyl-1- (4-chlorophenyl) cyclobutane was obtained by distillation and had b.p. 96-104 ° C / 0.25 mm Hg.

30

The ketone prepared according to the foregoing was converted to N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutylpropylamine hydrochloride, m.p. 213-215 ° C in a similar manner to that described in Example 12 (formula I: n = 0; R 2 = Et; R 2 = H; R 3 = R 4 = Me; R 5 = 4-C 1; R 6 = H).

Example 20 61 g of 1-acetyl-1- (4-chlorophenyl) cyclobutane, prepared in 40

DK 161770 B

in a similar manner as described in Example 1 for 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane, 0.75 g of platinum oxide, 60 g of 33% solution of methylamine in ethanol and 30 ml of ethanol were charged into an autoclave. The autoclave was filled with hydrogen and held at approx. 60 C and a pressure of 20 bar for 10 hours. The reaction mixture was filtered through charcoal and the solids washed with absolute alcohol. The solvents were removed by evaporation and a 10 g sample of the residue was shaken with 50 ml of 2M hydrochloric acid and 50 ml of ether. The aqueous layer was made basic and extracted with ether. The ether extract gave by evaporation a liquid distilled at 109 ° C / 0.3 mm Hg to give N-methyl-1- [1- (4-chlorophenyl) cyclobutyl] ethylamine (Formula I: n = 0; R1 = R3 = Me; R2 = R4 = H; R5 = 4-C1; R6 = H).

Example 21 i

2.0 g of sodium borohydride was added to a solution of 1.5 l

in g of 1- [1- (3,4-dichlorophenyl) -cyclobutyl] -ethylamine (prepared by treating the product of Example 1 with aqueous sodium-2g hydroxide) in 30 ml of glacial acetic acid. The mixture was heated to 95-100 ° 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 evaporated to dryness. Trituration with acetone gave N-ethyl-1- [1- (3,4-dichlorophenyl] -cyclobutyl] -ethylamine hydrochloride, mp 211-212 ° C (formula I: n = 0; R 2 = Me; R 2 = r 4 = H; R3 - Et; R5 = 4-Cl; R6 = 3-C1).

30

Example 22

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

DK 161770 B

41

This oil was dissolved in 10 ml of tetrahydrofuran and 0.5 ml of borane-dimethyl sulfide complex was added dropwise. The reaction mixture was stirred at room temperature for 2 hours and then heated to 35-40 ° C for 30 minutes. After cooling 5, the reaction mixture was basified and extracted with aster. Hydrogen gas was introduced into the dried ether extract which evaporated to dryness. Trituration with ether gave N, N-diethyl-1- [1- (3,4-dichlorophenyl) -cyclobutyl] -ethylamine hydrochloride, m.p. 199-201 ° C (formula I: n = 0; R1 = Me; R2 = H; R4 = R4 = 10 Et; R5 = 4-Cl; R6 = 3-C1).

Example 23

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

Example 24 λ 3 ___________

A mixture of 4.86 g of 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane prepared as described in Example 1, 1.6 g of hydroxylamine hydrochloride, 3.3 g of sodium acetate trihydrate, 15 ml of industrial methylated ethanol and 2 ml of water were heated under 0 η, υ reflux for 20 hours. The cooled reaction mixture was poured into water and the oil which separated cooled to give a solid which was recrystallized from industrial methylated ethanol to give 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane oxime, m.p. 120-121 ° C.

A solution of 4.0 g of the oxime prepared as described above in 50 ml of ether was slowly added to a stirred suspension of 0.9 g of lithium aluminum hydride in 50 ml of ether under nitrogen. The mixture was heated at reflux for 1 hour

DK 161770 B

After cooling, water and then 27 ml of a 20% aqueous solution of Rochelle's salt (potassium sodium tartrate tetrahydrate) and 6 ml of a 10% aqueous solution of sodium hydroxide were added. The reaction mixture was stirred for 1 hour and then extracted continuously with ether for 18 hours. The ether extract was dried and the ether removed, leaving a solid from which 1- [1- (3,4-dichlorophenyl) -cyclobutyl] -ethylamine was separated by high-pressure liquid chromatography. The product was identified by standard analysis technique as the compound of Example 1 in the form of the free base.

Example 25 200 ml of a 1M solution of diisobutyl aluminum hydride in hexane was added under nitrogen to a solution of 31.4 g of 1-

phenyl-1-cyclobutanecarbonitrile in 100 ml ether at a temperature I

below -30 ° C. The temperature was kept below 0 ° C for 30 minutes and 200 ml of 5N hydrochloric acid was added at a temperature of -10 ° C. The reaction mixture was washed with petroleum ether (b.p.

60-80 ° C) and then heated to 40 ° C. The reaction mixture was extracted with petroleum ether (same boiling range) and the extract dried and evaporated to give 1- phenyl-1-cyclobutane-carbaldehyde as an oil.

Methylamine was bubbled through a solution of 9.4 g of the aldehyde 25 prepared in the manner described above in 100 ml of toluene while maintaining the temperature of the reaction mixture below 0 ° C. 20 g of magnesium sulfate, which had been dried over a flame and then cooled under nitrogen, was added to the reaction mixture which was left for 16 hours at room temperature before being filtered. The toluene was then removed by evaporation and the residue dissolved in ether (50 ml). This solution was added to a solution of propyllithium prepared by slowly adding excess propyl bromide (12.8 g) to a suspension of 1.26 g of lithium in 50 ml of ether. The resulting mixture was left at room temperature for 16 hours. Traces of unreacted lithium were removed by filtration and the filter washed with ether, water and then 5N hydrochloric acid. The filtrate and washings were heated in a steam bath for 1 hour. After cooling, the reaction mixture was washed with ether and the aqueous layer was basified

DK 161770 B

43 using an aqueous sodium hydroxide solution. The reaction mixture was extracted with ether and the extract dried and the ether removed to give a residue from which N-methyl-1- [1-phenylcyclobutyl) -butylamine with b.p. 80-86 ° C / 0.1 mm Hg was distilled.

2.3 g of the amine prepared in the manner described above was dissolved in 40 ml of ether and hydrogen chloride gas was passed through the solution to precipitate N-methyl-1- (1-phenylcyclobutyl) -butylamine hydrochloride with m.p. 196-197 ° C (formula I: n = 0; Rx = propyl; R2 = R4 = R5 = R6 = H; R3 = Me).

Example 26

A solution of 8.0 g of 1- (3-chloro-5-methylphenyl) -1-cyclobutane-carbonitrile in 40 ml of ether was added to a solution of propylmagnonium bromide (prepared by reaction of 6.7 g of 1-bromopropane and 1.3 g of magnesium) in 80 ml of ether and the mixture was heated under reflux for 2 1/2 hours. 2/3 of the ether was evaporated and after cooling a solution of 3.5 g of sodium boro-2Q hydride in 150 ml of ethanol was then added. The mixture was kept at 50 ° C for 1 hour and 50 ml of water and then 50 ml of 5N hydrochloric acid were added. The ether layer was separated, dried and evaporated to give a solid which was recrystallized from propan-2-ol to give 1- [1- (3-chloro-5-methylphenyl) -cyclobutyl] -butylamine hydrochloride, m.p. 145-146 ° C.

The hydrochloride salt prepared in the manner described above was shaken with ether and 5N sodium hydroxide solution and the ether layer was evaporated to give the primary amine converted to N, N-dimethyl-1- [1- (3-chloro-5-methylphenyl) - cyclobut-2-methyl-butylamine hydrochloride, m.p. 148 ° C in a similar manner as described in Example 2 (formula I: n = 0; R3- = propyl; R2 = H; R3 = R4 = Me; R5 = 3-C1; R6 = 5-Me).

Example 27 37.6 g of 1- (4-chlorophenyl) -1-cyclobutanecarbonitrile (prepared in a similar manner to 1- (3,4-dichlorophenyl) -1-cyclobutane carbonitrile described in Example 1) were added to a solution of 32 4 g of potassium hydroxide in 370 ml of diethylene glycol, and mix 44 '-

DK 161770 B

>

the gene was heated at reflux for 3 1/2 hours. The reaction mixture was poured into a mixture of ice and water and the resulting solution washed with ether. The aqueous layer sat- I

to a mixture of 100 ml of concentrated hydrochloric acid and ice and the resulting precipitate of 1- (4-chlorophenyl) -1-cyclobutane-carboxylic acid, m.p. 86-88 ° C were collected, washed with water and dried. A solution of 10.5 g of the acid prepared in the above described manner in 150 ml of tetrahydrofuran was added dropwise under nitrogen to a stirred suspension of 10 2 g of lithium aluminum hydride in 150 ml of tetrahydrofuran. The mixture was stirred under reflux for 2 hours and added in S) in water. The mixture was filtered through diatomaceous earth ("Celite" w) and the product extracted with ether. After washing with water and drying, the ether was evaporated to give a residue which was recrystallized from petroleum ether (bp 60-80 ° C). The product was ΙΕ 1- (4-chloro-phenyl-1-cyclobutyl] -methyl alcohol, m.p. 60-62 ° C. j

A solution of 60 g of the alcohol prepared in the manner described above in 52 ml of pyridine was added dropwise to a solution of 60 g of p-toluenesulfonyl chloride in 100 ml of pyridine cooled in ice. The temperature was allowed to rise to room temperature and remain there for 18 hours. 1- [1- [(4-chlorophenyl) -cyclobutyl] -methyl-p-toluenesulfonate precipitated with m.p. at 99-100 ° C by pouring the reaction mixture into a mixture of ice and concentrated hydrochloric acid (200 ml). i! A solution of 97 g of the sulfonate compound was readily prepared as above and 16.6 g of sodium cyanide in 370 ml of dimethyl sulfoxide were heated on a steam bath for 18 hours. The mixture was poured into water and extracted with ether. After washing and drying, the ether was evaporated leaving a solid residue of 2- [1- (4-chlorophenyl) cyclobutyl] acetonitrile, m.p. 63-65 ° C.

20 g of the acetonitrile thus prepared were dissolved in 120 ml of ether and the solution was added dropwise under nitrogen to a stirred suspension of 5.84 g of lithium aluminum hydride in 80 ml of ether. The mixture was stirred at ambient temperature for 35 1/2 hours and then refluxed for another 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.

DK 161770 B

45 extracts were washed with water and extracted with 5N hydrochloric acid.

The acidic solution was washed with ether and aqueous NaOH was added. The product was extracted with ether and the extract was washed with water, dried and evaporated to give a residue which gave, by distillation, 2- [1- (4-chlorophenyl) cyclobutyl] ethylamine with b.p. 119-121 ° C / 1.5 mm Hg.

6.9 g of the ethylamine thus prepared, 6.6 ml of 98% s formic acid, 0.9 g of water and 9 ml of 37-40% s aqueous formaldehyde solution were heated in 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 with dichloromethane and 5N sodium hydroxide solution and the aqueous extracted with a further portion of dichloromethane. The dichloromethane phases were combined, washed with water, dried and evaporated to give a solid residue which was dissolved in 15 ml of propan-2-ol, then concentrated hydrochloric acid was added to pH 2. The mixture was evaporated to dryness and the residue was recrystallized from ethyl acetate to give colorless crystals of N N-dimethyl-2- [1- (4-chlorophenyl) -cyclobutyl] -20-ethylamine hydrochloride, m.p. 220-222 ° C (formula I: n = 1; R3, = R2 = R6 = R7 = R8 = H; R3 = R4 = Me? R5 = 4-C1).

In the same manner as just described, the following compounds were prepared: 25, -. CH ~ CH0NMe0, HCl »s ΓΛ i 2 2 R6 Example R5 R8 m.p. of the HCl salt (° C) 27 (a) Cl Cl 218-220 27 (b) 1H 263-265 27 (c) -CH = CH-CH = CH-234-236 27 (d) Similarly, N N-Dimethyl-2- [1- (4-chloro-2-fluorophenyl) -cyclobutyl] -ethylamine hydrochloride, m.p. 232-233 ° C with decomposition.

46

DK 161770 B

Example 28 12 g of 2- [1- (4-chlorophenyl) -cyclobutyl] -ethylamine, prepared as described in Example 27, 12.4 g of 1,4-dibromobutane and 14.3 g of anhydrous sodium carbonate were mixed in 100 ml of xylene and The mixture was heated under reflux and stirring for 16 hours. The mixture was cooled and filtered and the xylene removed by evaporation to give a residue which, by distillation, gave N-2- [1- (4-chlorophenyl) cyclobutyl] ethylpyrrolidine with b.p. 148-150 ° C / 1.5 mm Hg (Formula I: n = 1; = R2 = R 2 = 7 8 3 4 10 R = R = H; R plus R plus the nitrogen atom and pyrrolidine ring; R5 = 4- C1).

Similarly, the following compounds were prepared which were isolated as their hydrochloride salts:

/ N

rlT \ P 2 vJ L — I

Example R5 R6 m.p. of the HCl salt (° C) 20 - 28 (a) Cl Cl 213 28 (b) -CH = CH-CH = CH-232-233

Example 29 A solution of 30 g of 2- [1- (4-chlorophenyl) cyclobutyl] acetonitrile, prepared as described in Example 27, in 100 ml of ether was added to the reaction product of methyl bromide gas and 5.95 g of magnesium chips in 80 ml of ether . The mixture was heated at reflux for 4 hours. Ice was added and then 105 ml o of concentrated hydrochloric acid and the mixture was heated under reflux until all the solid was dissolved. The aqueous layer was washed with ether and the ether used for the wash was combined with the ether phase of the reaction mixture. The combined ether extracts were washed with water, dried and evaporated to give a rema-3 · 4 which was distilled twice to give 1- [1- (4-chlorophenyl) cyclobutyl] -propan-2-cn with b.p. 133-136 ° C / 2.5 mm Hg.

DK 161770 B

47 5.4 g of the ketone thus prepared were mixed with 18 ml of N-methylformamide, 4 ml of 98% s formic acid and 0.6 ml of 25% s aqueous methylamine and the mixture was heated under reflux for 16 hours. The mixture was poured into water and extracted with dichloromethane. The extract was washed, dried and evaporated to give a residue which was heated under reflux with 10 ml of concentrated hydrochloric acid for 6 hours. The mixture was evaporated to dryness and the residue dried by repeated addition and vacuum evaporation of a mixture of IMS and toluene. The solid residue was recrystallized from propan-2-ol to give N-methyl-2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine hydrochloride, m.p. 193-194 ° C (formula I: n = 1; R3 = R2 = R4 = R4 = R8 = H; R3 = R7 = Me; R5 = 4-C1).

Example 30

A mixture of 15 g of 1- [1- (4-chlorophenyl) -cyclobutyl] -propan-2-one, prepared as described in Example 29, and 4 ml of 98% formic acid were added dropwise to 12 ml of formamide at 160 ° C. The temperature was raised to 180 ° C and maintained at this temperature

u V

for 10 hours. The mixture was cooled, diluted with water and extracted with dichloromethane. The extract was washed, dried and evaporated to a yellow oil which was hydrolyzed with concentrated hydrochloric acid under reflux. The resulting aqueous solution after dilution with water was washed with ether, aqueous NaOH was added and the aqueous solution extracted with ether. The extract was washed, dried and evaporated to give a residue which gave, by distillation, 2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine with b.p. 105-107 ° C / 0.7 mm Hg.

2.65 g of the amine obtained according to the foregoing was dissolved in 15 ml of propan-2-ol and dropwise concentrated hydrochloric acid was added to the pH was 2. 110 ml of ether was added and colorless crystals of 2- [1- (4) were added. -chlorophenyl) -cyclobutyl] -1-methylethylamine hydrochloride, m.p. 184-185 ° C (formula I: n = 1; R1 = R2 = R3 = R4 = R6 = R8 = H; R5 = 4-C1; R7 = Me).

Example 31 3.94 g of 2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine,

DK 161770B

48 prepared as described in Example 30, 3.82 g of 1,4-dibromobutane, 4.4 g of anhydrous sodium carbonate and 30 ml of xylene were mixed and heated under reflux for 16 hours. The mixture was cooled, filtered and evaporated to give a residue which was distilled twice and then had b.p. 130-132 ° C / 0.5 mm Hg. The distillation product was dissolved in 5 ml of propan-2-ol and 70 ml of ether 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-if 2 - [1- (4-chlorophenyl) cyclobutyl] - Ι-ΙΟ methyljethylpyrrolidine hydrochloride, m.p. 151-152 ° C (formula I: n = 1; R R = R = = R R = R8 = H; R8 plus R ^ plus nitrogen atom with 7 and pyrrolidation; R = 4-Cl; R = Me) .

Example 32 25 g of 1- [1- (4-chlorophenyl) cyclobutyl] propan-2-one, prepared as described in Example 29, and 10 ml of 98% formic acid were added to 22 ml of formamide at 160 ° C. The temperature was raised to 175 ° C and kept at this temperature for 16 hours. The mixture was cooled and extracted with dichloromethane. The extract was washed with water and evaporated to a gum which crystallized from petroleum ether (bp 40-60 ° C) to give N-formyl-2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine, m.p. 71-73 ° C.

11.06 g of N-formyl-2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine, prepared as described above, were refluxed for 6 hours with a mixture of 34 ml of concentrated hydrochloric acid, 34 ml of water and 40 ml of diethylene glycol dimethyl ether. The mixture was cooled, washed with ether and basified with aqueous sodium hydroxide. The base solution was extracted-2Q with ether, washed with water, dried, evaporated and distilled to give 2- [1- (4-chlorophenyl) cyclobutyl] -1-methyl-ethylamine with b.p. 119-121 ° C / 0.8 mm Hg. 2.65 g of the amine was dissolved in 15 ml of propan-2-ol and concentrated hydrochloric acid was added to pH 2. 110 ml of ether was added and crystals of 2- [1- (4-chlorophenyl) cyclobutyl] -1 were added. -methylethylamine hydrochloride, m.p. 184-185 ° C (formula I: n = 1; R R = R = = R R = R R = R6 = R8 = H; R5 = 4-Cl; R7 = Me).

DK 161770B

49

Example 33 1.8 g of 2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine, prepared as described in Example 32, were mixed with 4.5 ml of formic acid. 6 ml of 37-40% aqueous formaldehyde solution was added and the mixture was first heated to 45-50 ° C for 30 minutes and then refluxed for 2 hours. The mixture was cooled, basified with aqueous sodium hydroxide and extracted with ether, then the ether extract was washed with water and extracted with 5N hydrochloric acid. The acidic extract was washed with ether, basified with aqueous sodium hydroxide and extracted with ether.

Hydrogen chloride gas was passed through the ether extract and a white solid formed. The solid was collected and recrystallized from ethyl acetate to give N, N-dimethyl-2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine hydrochloride, m.p. 108-110 ° C (formula I: n = 1; = R2 = R8 = R8 = H; R3 = R4 = R7 = Me; R5 = 4-C1).

Example 34 35 ml of a 70% solution of sodium bis- (2-methoxy-α-ethyloxy) aluminum hydride in toluene ("Red-al") was added dropwise to a solution of 5 g of N-formyl-2- [ 1- (4-Chlorophenyl) -cyclobutyl] -1-methylethylamine, prepared as described in Example 32, in 110 ml of dry ether under cooling to maintain a temperature below 10 ° C. The temperature was allowed to rise to approx. 25 ° C and then the mixture was heated under reflux for 2 hours. The reaction mixture was poured into a mixture of crushed ice and concentrated hydrochloric acid. The resulting mixture was washed with ether, basified with aqueous sodium hydroxide 2Q and extracted with ether. The ether extract was washed with brine, dried and evaporated to give a liquid which was dissolved in petroleum ether (bp 40-60 ° C). Hydrogen chloride gas was bubbled through the solution to precipitate a solid which was recrystallized from propan-2-ol to give N-methyl-2- [1- (4-chlorophenyl) -cyclobutyl] -1-methylethylamine hydrochloride (Formula I: n = 1; R ^ = R2 = R3 = R6 = R8 = H; R4 = R7 = Me; R5 = 4-C1) with m.p. 192-194 ° C.

Example 35 50

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A solution in 80 ml of ether of 23 g of 2- [1- (3,4-dichlorophenyl) -cyclobutyl] -acetonitrile (prepared in a similar manner as described in Example 27 for 2- [1- (4-chlorophenyl) - cyclobutyl] -5 'acetonitrile) was added to the product of the reaction between 3.53 g of magnesium chips and 10.8 ml of ethyl bromide in 80 ml of dry ether with stirring and heating on a steam bath. The ether was removed and replaced with toluene and the mixture heated under reflux for 1 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 1 hour and filtered through diatomaceous earth ("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 with b.p. 149-150 ° C / l, .1 mm Hg.

The ketone thus prepared was converted to 1- [1- (3,4-dichlorophenyl) cyclobutyl] methyl} propylamine hydrochloride, m.p. 225-2260C in the same manner as described in Example 20 32 (formula I: n = 1; R1 »R2 = R3 = R4 = H; R5 = 4-C1; R6 = 3-Cl; R7 = Et; R8 = H) .

In a similar manner as described above, 2- [1- (3,4-dichlorophenyl) cyclobutyl] -1-methylethylamine hydrochloride was prepared with m.p. 179 ° C (Example 35a, Formula I: n = 1; R1 = R = 25 R3 = R4 = H; R5 = 4-C1; R6 = 3-C1; R7 = Me; R8 = H).

Example 36 In a similar manner as described in Example 33, 2Q compounds prepared in a similar manner as described in Example 35 were converted to the corresponding Ν, Ν-dimethyl compounds.

__. CH "CHR7NMe0, HCl

RIllll 2 35 R6

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51

Example Starting R7 Mp, (° C) Material 36 (a) 35 Cl Cl Et 177-178 36 (b) 35 (a) Cl Cl Me 204-205 5

Example 37 In a similar manner as described in Example 34, N-formyl compounds prepared as described in Example 32 from ketones prepared in Example 35 were converted to the corresponding N-methyl compounds.

-. CHOCHR7NHMe, HCl 15 r6 ^ ~ I-1

Example r5 r® r7 Mp, (° C) 37 (a) Cl H Et 170-172 2Q 37 (b) Cl Cl Et 193-194

Example 38

A mixture of 10.1 g of 2- [1- (4-chlorophenyl) cyclobutyl] -

acetonitrile, prepared as described in Example 27, 8.1 9 S

g of potassium hydroxide and 92 ml of diethylene glycol were refluxed for 3 1/2 hours. The mixture was poured into a mixture of ice and water and the resulting solution was washed three times with ether and added to ice and concentrated hydrochloric acid. On cooling, a solid product separated out which was recrystallized from petroleum ether (bp 62-68 ° C) using charcoal. The recrystallized product was 2- [1- (4-chlorophenyl) -cyclobutyl] -acetic acid, m.p. 83-84 ° C.

5 g of the acid thus prepared was added to 20 ml of thionyl chloride and heated under reflux for 1 hour.

Then, excess thionyl chloride was removed and the residue was poured into a solution of 3.8 g of piperidine in 20 ml of ether. The mixture was stirred for 30 minutes and then water was added to dissolve the piperidine hydrochloride. The ether layer was separated and - 52. ! UK TbT / '/ U-b in the aqueous layer was washed with ether. The combined ether phases were washed with water, dried and evaporated to give a brown oil which was purified by distillation (bp 168 ° C / 1 mm Hg) and recrystallization from petroleum ether (bp 40-60 ° C). The solid product was N-2- [1- (4-chlorophenyl) -cyclobutyl] -acetylpiperidine, m.p. 66-67 ° C. in

A solution of 2.7 g of the thus-prepared yeast

compound in 20 ml ether was added dropwise to a stirred mixture I

of 0.7 g of lithium aluminum hydride and ether under a nitrogen atmosphere.

Stirring was continued for 1 hour at room temperature and then! under reflux for 2 hours. After cooling in ice, excess lithium aluminum hydride was degraded by addition of water. The mixture was filtered through diatomaceous earth ("Celite" ®). The aqueous portion of the filtrate was washed with a portion of 15 ether and this portion was combined with the ether portions used to wash the solid residue. The combined ether portions were washed with water, dried and evaporated.

The residue was purified by distillation. The product was W-2- [1- (4-chlorophenyl) -cyclobutyl] -ethyl piperidine with b.p. 152-156 ° C / 1.5 20 mm Hg (formula Is n = 1; R1 = R2 = R6 = R7 = R8 = H; R3 plus in 45 in R plus nitrogen atom forms a piperidine ring; R = 4-C1) . In a similar manner as described above, the following compounds were prepared and isolated as their hydrochloride salts by bubbling dry hydrogen chloride gas through a solution 25 of the base in petroleum ether (bp 62-68 ° C).

OCHOCHONR3R4, HCl - li - R6

Example R5 R6 NR3R4 Mp. (° C)

Me 38 (a) Cl H -lf] 167-169

V

35 Me 38 (b) Cl H -N * VN -Me 281-283 (shredder / split)

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53 38 (c) Cl H -O 246-248

Example 39 A mixture of 9 g of sodium hydride, 9 g of mineral oil and 150 ml of dry dimethylformamide was stirred under nitrogen at 0 ° C. Within 20 minutes, a solution of 24.6 g of p-toluenesulfonylmethyl isocyanide (traded under the trade name TosMIC not registered in Denmark) was added in 50 ml of 10 dimethylformamide. Then, 18 g of absolute alcohol was added to the mixture at 0 ° C over 1 hour. 24 g of 1-acetyl-1- (4-chlorophenyl) cyclobutane (prepared in a similar manner as described in Example 1 for 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane) dissolved in 20 ml was added. dimethylformamide and the mixture was stirred for 16 hours during which time the temperature rose to ambient. The mixture was viscous and 25 ml of petroleum ether (bp 80-100 ° C) was added. The mixture was poured into water and the pH was adjusted to 6 by the addition of 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 removed by filtration and the filtrate was evaporated and 2- [1- (4-chlorophenyl) -cyclobutyl] -propionitrile with b.p. 128-136 ° C / 0.6 mm Hg was collected by distillation.

A solution of 3.5 g of the propionitrile prepared in the manner described above in 20 ml of dry ether was added dropwise to a stirred mixture of 0.9 g of lithium aluminum hydride in 20 ml of dry ether at a temperature in the range 15-20 ° C. The mixture was stirred at ambient temperature for 2 hours and then heated and refluxed for an additional 3 hours.

20 ml of 5N sodium hydroxide solution and 50 ml of water were added and the mixture was filtered through diatomaceous earth ("Celite" ®). The filter medium was washed with ether and the washings were combined with the ether of the reaction mixture. The combined extracts were extracted with 5N hydrochloric acid. A solid formed in the contact surface and it was collected by filtration, washed with acetone and dried. The solid was 2- [1- (4-chlorophenyl) -cyclobutyl] -propylamine hydrochloride, m.p. 210-230 ° C.

DK 161770 B

54 g of the hydrochloride salt prepared as described above was dissolved in water, to which 5N aqueous sodium hydroxide solution was added and the solution extracted with ether. The ether extract was dried and evaporated to give an oil which was refluxed for 6 hours with 0.82 g of 1,4-dibromobutane, 0.96 g of anhydrous sodium carbonate and 6.5 ml of xylene. The mixture was cooled, filtered through diatomaceous earth ("Celite" ®) and evaporated to dryness. The residue was dissolved in 10 ml of propan-2-ol and 5 ml of concentrated hydrochloric acid was added. The mixture 10 was evaporated to dryness and the residue collected, 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; R1 = Me? R2 = R6 = R7 = R8 = H? R3 plus R4 plus the nitrogen atom forms a pyrrolidine ring; R = 4-C1).

15

Example 40

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

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

The mixture was heated to 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. The basic extract was washed with ether and acidified with concentrated hydrochloric acid to give 1- (3,4-dichlorophenyl) -1-cyclobutanecarboxylic acid, m.p. 120-121 ° C.

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

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Example 41 55

A solution of 23 g of 2- [1- (3,4-dichlorophenyl) -cyclobutyl] -acetonitrile (prepared in a similar manner to Example 27 for 2- [1- (4-chlorophenyl) -cyclobutyl] -acetonitrile) in 50 ml of dry ether was added to a solution of ethyl magnesium bromide prepared by dropwise addition of 15.83 g of ethyl bromide in 80 ml of dry ether to a stirred mixture of 3.53 g of magnesium chips and 80 ml of ether. The mixture was heated under reflux for 30 minutes and stirred without further heating for 16 hours and then under reflux for another 2 hours. 1- [1- (3,4-Dichlorophenyl) -cyclobutyl] -2-butaniminyl-magnium bromide was collected by filtration, and a sample of ca. 1 g of the solid was added to a solution of 3 g of sodium borohydride in 30 ml of diethylene glycol dimethyl ether. The mixture was stirred at 45 ° C for 90 minutes. The reaction mixture was extracted with 5N hydrochloric acid. The aqueous phase was basified with aqueous sodium hydroxide solution and extracted with ether. The ether extract was dried and hydrogen chloride gas was passed through the extract to precipitate 1 - {[1- (3,4-dichlorophenyl) cyclobutyl] methyl) -propylamine hydrochloride, m.p. 223-224 ° C (formula I: n = 1; R1 = R2 = R3 = R4 = R8 = H; R5 = 4-C1; R6 = 3-C1; R7 = Et).

Example 42 7 ml of formic acid was added dropwise to 15 ml of pyrrolidine at a temperature in the range 135-140 C. 3 g of 1- [1- (3,4-dichlorophenyl) -cyclobutyl] -butan-2-one were added dropwise as prepared. described in Example 35, and the mixture was heated to 140 ° C for 1 hour. The temperature 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, made basic and extracted with ether. The ether extract was dried and hydrogen chloride gas was introduced into the extract. Evaporation to dryness gave a solid which was triturated with dry ether and recrystallized from a mixture of petroleum ether and propan-2-ol to give N1- [1- (3,4-dichlorophenyl) cyclobutyl] methyl} propyl pyrrolidine hydrochloride, m.p. 157-160 ° C (Formula I: n = 1; R1 = R2 = R8 = H; R3 plus R4 plus the nitrogen atom forms a pyr

DK 161779B

rolidinring; R4 = 4-C1; R ° = 3-Cl; R7 = Et).

Example 43 25 g of 1- [1- (3,4-dichlorophenyl) cyclobutyl] -2-butaniminyl magnesium bromide, prepared as described in Example 41, were heated to 90-95 ° C for 2 hours with a mixture of 20 ml concentrated hydrochloric acid and 30 ml of water. The reaction mixture was extracted with ether and the ether extract dried and evaporated to dryness. 1- [1- (3,4-Dichlorophenyl) -cyclobutyl] -butan-2-one was distilled off with b.p. 122-124 ° C / 0.1 mm Hg.

A mixture of 4.3 g of 1- [1- (3,4-dichlorophenyl) -cyclobutyl] -butan-2-one, prepared as described above, 2.65 g of hydroxylamine sulfate, 4.0 g of sodium acetate, 56 ml industrial methylated 15 ethanol and 23 ml of water were stirred at ambient temperature for 16 hours. The reaction mixture was extracted with ether. The ether extract was washed with water, dried and evaporated to give a solid which was recrystallized from petroleum ether (bp 80-100 ° C) to give 1- [1- (3,4-dichlorophenyl) cyclobutyl] -butane] 2-on oxime with m.p. 106-110 ° C.

A solution of 2.33 ml of trifluoroacetic acid in 5 ml of tetrahydrofuran was added to a stirred suspension of 1.13 g of sodium borohydride in 30 ml of tetrahydrofuran over a period of 5 minutes. A solution of 1.7 g of the 25 oxime prepared as described above in 25 ml of tetrahydrofuran was added dropwise and the mixture was heated under reflux for 6 hours. The mixture was cooled and 25 ml of water and then 25 ml of 5N sodium hydroxide solution were added. The mixture was extracted with ether and the extract was washed with water, dried and evaporated to give a residue which was dissolved in 25 ml of petroleum ether.

Dry hydrogen chloride gas was passed through the ether solution to give 1- {[1- (3,4-dichlorophenyl) -cyclobutyl] -methyl} -propylamine hydrochloride, m.p. 222-224 ° C (formula I: n = 1; R1 = R2 = R3 = R4 = R8 = H; R5 = 4-C1; R6 = 3-Cl; R7 = Et).

35

Example 44

A solution of 5.0 g of 1- (1- (3,4-dichlorophenyl) -cyclobutyl] -butan-2-one, prepared as described in Example 43, and 1.63

DK 161770 B

57 g of methoxyamine hydrochloride in a mixture of 60 ml of pyridine and 60 ml of ethanol were heated under reflux for 72 hours. The reaction mixture was evaporated to dryness and a mixture of water and ether was added to the residue. The ether layer was washed with 5 sodium bicarbonate solution and water, dried and evaporated to give 1- [1- (3,4-dichlorophenyl) cyclobutyl] -butan-2-one oxime-O-methyl ether.

15 g of the oxime ether thus produced was then reduced to the product of Example 43 by 0.95 10 g of sodium borohydride in a similar manner as described in Example 43.

Example 45 0.4 g of sodium cyanoborohydride was added to a solution of 2.45 g of 1- [1- (3,4-dichlorophenyl) cyclobutyl] -butan-2-one, prepared as described in Example 42, and 7 g ammonium acetate in 28 ml of ethanol and the mixture was stirred at room temperature for 4 days. 25 ml of water were added dropwise and with cooling.

The aqueous mixture was extracted with ether and the ether layer was

V

spoon with water and 50 ml of 5N hydrochloric acid. The compound of Example 43 precipitated as a white solid.

Example 46 1.5 g of 2- [1- (4-chlorophenyl) -cyclobutyl] -acetic acid, prepared as described in Example 38, was heated under reflux with thionyl chloride. Excess thionyl chloride was removed in vacuo and the residue was added dropwise to a solution of 0.94 g of cyclopropylamine in 10 ml of ether and the mixture was stirred for 5 minutes for 30 minutes. Water was added and the aqueous phase extracted with ether. The ether extract was dried and the ether removed to give 2- [1- (4-chlorophenyl) -cyclobutyl] -N-cyclopropyl-acetamide.

A solution of 1.45 g of the thus obtained 55 amide in 15 ml of ether was added dropwise to a stirred suspension of 0.42 g of lithium aluminum hydride in 7.5 ml of ether under nitrogen. The mixture was stirred at room temperature for 1 hour and then refluxed for a further 2 hours. After 58

DK 161770 B

After cooling, 0.45 ml of water was added, then 0.45 ml of 15% sodium hydroxide solution and then 1.35 ml of water, and the mixture was stirred for 15 minutes. The mixture was filtered and extracted with ether. The ether extract was shaken with N-hydrochloric acid and a solid formed in the aqueous layer. The solid was N-cyclopropyl-2- [1- (4-chlorophenyl) -cyclobutyl] -ethylamine hydrochloride, m.p. 166-170 ° C.

A mixture of 0.41 g of the hydrochloride salt thus prepared, 0.1 g of sodium formate, 1 ml of 98% s formic acid and 0.5 10 ml of 37-40% s aqueous formaldehyde solution was heated to 85-90 ° C for 18 hours. . The reaction mixture was cooled and extracted with ether. The ether extract was washed with water, dried and filtered. Hydrogen chloride gas was passed through the filtrate which was then heated to give a solid which was N-cyclopropyl-15 N-methyl-2- [1- (4-chlorophenyl) cyclobutyl] ethylamine hydrochloride with m.p. 149-153 ° C (formula I: n = 1; R1 = R2 = R6 = R7 = R8 = H; R3 = cyclopropyl; R4 = Me; R5 = 4-C1).

20 25 30 35

Claims (2)

An analogous process for the preparation of cyclobutylamine derivatives of the general formula I wherein R is 0 or 1 and 10 where, if n = 0, R1 "is a straight or branched alkyl a group of 1-6 carbon atoms, a cycloalkyl group of 3-7 carbon atoms, a cycloalkylalkyl group whose cycloalkyl moiety contains 3-6 carbon atoms and the alkyl moiety 1-3 carbon atoms, an alkenyl group of 2-6 carbon atoms or a group of formula II, - R10 -GC, 20 9 10 wherein R and R, being the same or different, each represent hydrogen, halogen or an alkoxy group having 1-3 carbon atoms and where, if n = 1, R1 is hydrogen or an alkyl group having 1-3 carbon atoms Is hydrogen or an alkyl group having 1-3 carbon atoms, 4 R and R being the same or different, each being hydrogen, a straight or branched alkyl group having 1-4 carbon atoms, 2 an alkenyl or alkynyl group having 3- 6 carbon atoms, a cycloalkyl group whose ring contains are 3-7 carbon atoms, or a group CHO, or 34 where R and R together and together with the nitrogen atom form an optionally substituted heterocyclic ring of 5 or 6 atoms in the ring which may contain additional heteroatoms besides the nitrogen atom, 35. and R are the same or different, each being hydrogen, halogen, trifluoromethyl, an alkyl group having 1-3 carbon atoms, an alkoxy or alkylthio group having 1-3 carbon atoms, or 60 | DK 161770 B j C g a phenyl group or where R and R together and together with the carbon atom to which they are attached form an additional benzene ring which may be optionally substituted with one or more halogen atoms or an alkyl or alkoxy group having from 5 to 4 carbon atoms. or wherein the substituents on the additional benzene ring together with the two carbon atoms to which they are attached form another benzene ring, 7 and wherein R and R which are the same or different each are hydrogen or an alkyl group having 1-3 carbon atoms, Or pharmaceutically acceptable salts thereof, characterized in that a) reductively amidates a ketone of the general formula V, 5 --- COR1 in ice · in R6 - I2 i to form a compound of formula I wherein n = 0 , R = H, R4 = CHO and R 1, R 2 and R 2 have the above meanings, or a ketone or an aldehyde of the general formula VI R 5 ___ CR 1 R 2 COR 7 I 25, 4 to form a compound of the formula In which n = 1, R = 8 1 2 5 6 7 CHO, R = H and R, R, R, R and R have the above meanings, or b) reductively amine a ketone of the general formula V. 2 to form a compound of formula I wherein n = 0, R = 15 6 H and R, R and R have the meanings given above, or -one ketone or an aldehyde of the general formula VI to form a compound - compound of formula I wherein n = 1, R = H and R, R, R, R and 7 R have the above meanings, or c) reduces a compound of the general formula VII R5 - 1 Z i - VII DK 161770 B 61 wherein i) Z is a group of formula -CRUNCH or an ester or ether thereof to form a compound of formula I wherein n = 0 and R 2, R 3 and R 4 are hydrogen, or 5 ii Z is a group of formula -CR1 = NY, where Y is a metal-containing residue derived from an organometallic reagent to form a compound of formula I where n = 0 and where 2 3 4 R, R and R are hydrogen, or 12 7 iii) Z is a group of formula -CR R CR = NOH or an ester 10 or ether thereof to form a compound of formula 4 wherein n = 1 and R, R and R are hydrogen, or 12 7 iv ) Z e r is a group of formula -CR R CR = NY, where Y is a metal-containing residue derived from an organometallic reagent, to form a compound of formula I wherein n = 1 3 4 8 15 and R, R and R are hydrogen, or v ) Z is a group of formula -CR1R2CONR3R4 to form 7 a compound of formula I wherein n = 1 and R and g R are hydrogen, or 1 2 vi) Z is a group of formula -CR R CN to form 3 4 A compound of formula I wherein n = 1 and R, R, 7 8 R and R are hydrogen, or d) performs decarboxylative rearrangement of an amide of the general formula XI 25. cr1h2 (ce7r ''] conh n r6-A_ Wherein R 1, R 2, R 5, R 6, R 7, R 8 and n have the above meanings to form an amine of formula I wherein R = R = H, or 4 e) hydrolyzes a compound of formula I wherein R is CHO to form a compound of formula I wherein R4 is K, or DK f) reduces a compound of formula I wherein R4 is CHO to form a compound of formula I n in which R 4 is a methyl group, or g) converts a compound of general formula I wherein 3 5 and / or R is hydrogen to form a compound 3 λ of formula I wherein R and / or R different from hydrogen, and, if desired, converting the compound obtained by any one of the processes a) to f into a pharmaceutically acceptable salt thereof. Process according to claim 1 (c), characterized in that Y is MgBr or Li. j! 1