NO165724B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE ARYLYCYLOBUTYLYCAMLINES. - Google Patents

Description

The present invention relates to a method for the production of new therapeutic agents which are arylcyclobutylalkylamine derivatives and which are useful in the treatment of depression.

According to the invention, compounds of formula r are produced

and pharmaceutically acceptable salts thereof, wherein the group NR^R2 is selected from dimethylamino, diethylamino, tert-butylamino, N-butyl-N-methylamino, N-methyl-N-(2-morpholinoethyl)amino, N-methyl-N- (2-hydroxyethyl)amino, N-cyclohexyl-N-methylamino, piperidino, morpholino, 1,2,3,6-tetrahydropyridyl and 4-methylpiperidino; R 3 is phenyl, naphthyl or phenyl substituted with one or more fluoro, chloro, bromo, trifluoromethyl, methyl, methoxy, methylthio or phenyl groups, and R 4 is a group of formula IV

where R10 is a saturated or unsaturated aliphatic group containing 1 to 8 carbon atoms, optionally substituted with hydroxy,

methoxy or acetoxy, cyclohexyl or a cyclohexylmethyl group.

In preferred compounds of formula I, R 3 is phenyl, naphth-2-yl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-brotphenyl, 2-fluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-methylthiophenyl, 3-trifluoromethyl- phenyl, 3-chloro-5-methylphenyl, 3,5-dichloro-4-methoxyphenyl or 4-biphenylyl.

In preferred compounds of formula I, R 10 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 3-methylbutyl, pentyl, heptyl, octyl, 4-pentenyl, cyclohexyl or cyclohexylmethyl.

Compounds of formula I may exist as salts with pharmaceutically acceptable acids. Examples of such salts include hydrochlorides, hydrobromides, sulfates, nitrates, maleates, acetates, citrates, fumarates, tartrates, succinates, benzoates and salts with acidic amino acids such as glutamic acid. Such salts may exist in the form of solvates (e.g. hydrates).

Compounds according to formula I contain one or more asymmetric carbon atoms and exist in various optically active forms. When the compounds according to formula I contain one chiral center, the compounds exist in two enantiomeric forms, and the present invention includes the preparation of both enantiomeric forms and mixtures thereof. When the compounds according to formula I contain more than one chiral center, the compounds can exist in diastereoisomeric forms. The present invention includes the preparation of each of these diastereoisomeric forms and mixtures thereof.

Some compounds according to formula I can exist in the form of geometric isomers, and the present invention includes the preparation of all these geometric isomers and mixtures thereof.

Specific compounds according to formula I are: 1-[1-(3,4-dichlorophenyl)cyclobutyl]-1-d:methylamino-propan-2-one 1-dimethylamino-1-(1-phenylcyclobutyl)propane-2 -one 1-[1-(4-bromophenyl)cyclobutyl]-1-dimethylaminobutan-2-one 1-[1-(3-chloro-5-methylphenyl)cyclobutyl]-1-dimethylaminobutan-2-one 1- [1-(3,5-dichloro-4-methoxyphenyl)cyclobutyl]-1-dimethylamino-butan-2-one

1-[1-(4-Methoxyphenyl)cyclobutyl]-1-dimethylaminobutan-2-one 1-[1-(4-biphenylyl)cyclobutyl]-1-dimethylaminobutan-2-one 1-dimethylamino-l -[1-(3-trifluoromethylphenyl)-cyclobutyl]-butan-2-one 1-dimethylamino-1-[1-(2-naphthyl)cyclobutyl]butan-2-one 1-dimethylamino-1-[1-(4 -methylthiophenyl)cyclobutyl]-butan-2-one 1-[1-(4-chlorophenyl)cyclobutyl]-1-dimethylaminopentan-2-one 1-dimethylamino-1-[1-(3-trifluoromethylphenyl)cyclobutyl] -pentan-2-one

1-dimethylamino-1-[1-(2-fluorophenyl)cyclobutyl]-pentan-2-one 1-dimethylamino-1-[1-(2-naphthyl)cyclobutyl]pentan-2-one 1-dimethylamino-1- [1-(4-Methoxyphenyl)cyclobutyl]pentan-2-one 1-dimethylamino-1-[1-(4-tolyl)cyclobutyl]pentan-2-one 1-[1-(4-biphenylyl)cyclobutyl) -1-dimethylaminopentan-2-one 1-dimethylamino-1-(1-phenylcyclobutyl)pentan-2-one 1-[1-(4-chlorophenyl)cyclobutyl]-1-dimethylaminohexan-2-one 1-[1 -(3,4-dichlorophenyl)cyclobutyl]-1-dimethylaminohexan-2-one 1-[1-(3,4-dichlorophenyl)cyclobutyl]-1-dimethylamino-4-methylpentan-2-one

1-[1-(3,4-dichlorophenyl)cyclobutyl]-1-dimethylamino-5-methylhexan-2-one

1-[1-(3,4-dichlorophenyl)cyclobutyl]-1-dimethylamino-6-hepten-2-one 1-dimethylamino-1-(1-phenylcyclobutyl)-6-hepten-2-one 1 -[1-(4-chlorophenyl)cyclobutyl]-1-dimethylamino-6-hepten-2-one 1-[1-(3,4-dichlorophenyl)cyclobutyl]-1-dimethylaminooctan-2-one 1- [1-(4-chlorophenyl)cyclobutyl]-1-dimethylaminooctan-2-one 1-[1-(4-chlorophenyl)cyclobutyl]-1-dimethylaminononan-2-one 1-[1-(4-chlorophenyl) )cyclobutyl]-1-dimethylamino-9-deken-2-one 3-cyclohexyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]-1-dimethylaminopropan-2-one

1-[1-(4-chlorophenyl)cyclobutyl]-1-dimethylamino-5-methoxypentan-2-one

1-[1-(4-chlorophenyl)cyclobutyl]-1-dimethylamino-5-methoxy-hexan-2-one

1-[1-(3,4-dichlorophenyl)cyclobutyl]-1-dimethylamino-5-methoxyhexan-2-one

1-(N-tert-butylamino)-1-[1-(3,4-dichlorophenyl)-cyclobutyl]propan-2-one

1-(N-butyl-N-methylamino)-1-[1-(3,4-dichlorophenyl)-cyclobutyl]propan-2-one

1-[1-(3,4-dichlorophenyl)cyclobutyl]-1-morpholinopropan-2-one

1-[1-(3,4-dichlorophenyl)cyclobutyl]-1-(4-methyl-piperidino)-butan-2-one

1-[1-(3,4-dichlorophenyl)cyclobutyl]-1-(N-methyl-N-2-morpholinoethylamino)butan-2-one

1-[1-(3,4-dichlorophenyl)cyclobutyl]-1-[N-(2-hydroxyethyl)-N-methylamino]butan-2-one

1-[1-(3,4-dichlorophenyl)cyclobutyl]-1-(1,2,3,6-tetrahydro-1-pyridyl)butan-2-one

1-(N-cyclohexyl-N-methylamino)-1-[1-(3,4-dichlorophenyl)-cyclobutyl]butan-2-one

1-(N-methyl-N-2-morpholinoethylamino)-1-[1-(3-trifluoromethyl-phenyl)cyclobutyl]butan-2-one

1-[1-(3,4-dichlorophenyl)cyclobutyl]-1-piperidinobutan-2-one 1-[1-(4-chlorophenyl)cyclobutyl]-1-diethylami nobutan-2-one 1- [ 1-(3,4-Dichlorophenyl)cyclobutyl]-1-dimethylamino-'5-hydroxypentan-2-one

5-[ 1-(3,4-dichlorophenyl)cyclobutyl]-5-dimethylamino-4-oxopentylacetate

1-[1-(4-chlorophenyl)cyclobutyl]-1-dimethylaminopropan-2-one 1-[1-(4-chlorophenyl)cyclobutyl]-1-dimethylaminobutan-2-one 1-[1-(4-chlorophenyl) )cyclobutyl]-1-dimethylamino-3-methylbutan-2-one 1-[1-(3,4-dichlorophenyl)cyclobutyl]-1-dimethylaminobutan-2-one 1- [1- (4- chlorophenyl)cyclobutyl]-1-dimethylamithioheptan-2-one 1-cyclohexyl-2-[1-(3,4-dichlorophenyl)cyclobutyl]-2-dimethylaminoethanone and pharmaceutically acceptable salts thereof.

Suitable pharmaceutical preparations contain a therapeutically effective amount of a compound of formula I together with a pharmaceutically acceptable diluent or carrier.

In therapeutic use, the active compound can be administered orally, rectally, parenterally or topically, preferably orally. The therapeutic preparations can thus take the form of any of the known pharmaceutical preparations for oral, rectal, parenteral or topical administration. Pharmaceutically satisfactory carriers suitable for the use of such preparations are well known in pharmacy. The preparations can contain 0.1-90% by weight active compound.

Preparations for oral administration are the preferred preparations and these are the known pharmaceutical forms for such administration, e.g. tablets, capsules, syrups and aqueous or oily suspensions. The additives used in the production of these preparations are the additives known in pharmacy. Tablets can be prepared by mixing the active compound with an inert diluent such as calcium phosphate in the presence of solvents, e.g. corn starch, and lubricants, e.g. magnesium stearate, and make tablets of the mixture by known methods. The tablets can be designed in a manner known to those skilled in the art to achieve a sustained release of the compounds produced according to the present invention. Such tablets can, if desired, be supplied with an enteric coating using known methods, e.g. using cellulose acetate phthalate. Likewise, capsules, e.g. hard or soft gelatin capsules, containing the active compound with or without additives, are prepared in conventional ways and, if desired, provided with an enteric coating in a known manner. The tablets and capsules may suitably each contain 1-500 mg of the active compound. Other preparations for oral administration include e.g. aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethyl cellulose, and oil suspensions containing a compound produced according to the present invention in a suitable vegetable oil, e.g. arachi s oil.

Preparations suitable for rectal administration are the known pharmaceutical forms for such administration, e.g. suppositories based on cocoa butter or polyethylene glycol.

Preparations suitable for parenteral administration are the known pharmaceutical forms for such administration, e.g. sterile suspensions or sterile solutions in a suitable solvent.

Preparations for topical administration may comprise a matrix in which the pharmacologically active compounds produced according to the present invention are dispersed so that the compounds are kept in contact with the skin in order for the compounds to be administered transdermally. Alternatively, the active compounds may be dispersed in a pharmaceutically acceptable cream or ointment base.

In some embodiments, it may be advantageous to use the compounds produced according to the present invention in the form of particles of very small size, e.g. such as is achieved by fluid energy painting.

In the preparations, the active compound can, if desired, be combined with other compatible pharmacologically active components.

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

The methods for preparing the compounds according to formula I will now be described.

Compounds according to formula I where R 1 is a group according to formula -COR1Q can be prepared by thermal elimination of hydrogen cyanide from a compound according to formula VI where R 1 is a group according to formula -CH(OH)R 10 .

Compounds according to formula I where R4 is a group according to formula -COR1Q can be prepared by reacting an aminonitrile according to formula VII

with an organolithium reagent of formula R^gLi, followed by hydrolysis.

Compounds according to formula VI can be prepared by reacting a base such as a lithium diisopropylamine with a compound according to formula VII, followed by reaction with an aldehyde according to the formula R1QCHO, obtaining compounds according to formula VI where R11 is or a group according to the formula -CH(OH)R10.

Compounds according to formula VI where R 1 is a group according to the formula -CH(OH)R 10 can be prepared by reacting a base such as lithium diisopropylamide. with a compound of formula VII followed by reaction with an aldehyde of formula <R>10<C>HO.

Aminonitrile according to formula VII can be prepared by reacting an aldehyde according to formula XVIII

with an alkali metal cyanide (e.g. sodium cyanide} cg a salt of an amine according to the formula R^R^H.

Aminonitriles according to formula VII can also be prepared by reacting a cyanohydrin (formed by reacting an aldehyde according to formula XVIII with an alkali metal cyanide) with an amine according to the formula R1R2NH.

The therapeutic activity of the compounds according to formula I has been demonstrated by determining the ability of the compounds to reverse the hypothermic effects of reserpine in the following manner. Male Charles River CD1 mice weighing 18-30 g were separated into groups of five and given food and water ad libitum. After 5 hours, the body temperature of each mouse was measured orally and the mice were injected intraperitoneally with reserpine (5 mg/kg) dissolved in deionized water containing ascorbic acid (50 mg/ml). The amount of fluid injected was 10 ml/kg body weight. 9 hours after the start of the test, the food was taken away, but water was still available ad libitum. 24 hours after the test had started, the mice's temperature was measured and the mice were given the test compound orally with a dose volume of 10 mg/kg body weight. The compound is administered in one of the following ways: (a) in aqueous solution, (b) in solution with less than 1 vol% acetic acid, (c) in solution with less than 0.02N hydrochloric acid, (d) suspended in an acacia suspension which contained 100 mg of acacia in 5 ml of deionized water or (e) suspended in a 0.25% solution of hydroxyethyl cellulose (sold under the trade name "Cellosize QP" 15000 by Union Carbide) in deionized water. 3 hours later, the temperature of all the mice was measured again. The percentage reversal of the reserpine-induced loss of body temperature was then calculated according to the formula: (Temperature after 27 hours - temperature after 24 hours) xl00 (Temperature after 5 hours - temperature after 24 hours) The mean value for each group of five mice was calculated. All of the compounds which are the final products of the examples below gave at least 50% reversal when tested at 30 mg/kg. It is common knowledge among those skilled in the art that this test indicates compounds with antidepressant activity in humans.

The invention will now be illustrated by the following examples, which are given as examples only.- All compounds were characterized by conventional analytical techniques and gave satisfactory elemental analyses. All melting and boiling points are expressed in °C. Examples A-C describe the preparation of compounds according to formula VII which are used in the preparation of compounds according to formula I. In the description that follows, the term "fast chromatography" is used to describe the purification technique described by Still et al., [J. Org. Chem. 43, 2923-5 (1978)]. In this technique, a silica column is used and the elution medium is as described in the relevant example.

Example A

A 1M solution of diisobutylaluminum hydride in hexane (100 mL) was added dropwise to a stirred solution of 1-(4-chlorophenyl)cyclobutanecarbonitri 1 (19.1 g) in dry ether (50 mL) at -30°C under nitrogen . The mixture was allowed to warm to 0°C and was held at this temperature for 30 minutes. The mixture was cooled to -30°C and 5N hydrochloric acid (100 mL) was added dropwise with stirring. The mixture was filtered through a solid and the filtrate was extracted with ether. The solid was added to the ether extracts, which were washed with water and dried. Removal of the solvent gave 1-(4-chlorophenyl)cyclobutanecarbaldehyde as a yellow oil.

A mixture of 1-(4-chlorophenyl)cyclobutanecarbaldehyde (13.7 g), dry dimethylamine hydrochloride (6.6 g) and dry dimethyl sulfoxide (50 mL) was added dropwise to a stirred mixture of sodium cyanide (3.9 g) in dry dimethyl sulfoxide (100 ml). The mixture was stirred for 66 hours at ambient temperature and the reaction mixture was poured into water. The mixture was extracted with ether and the ether solution was then extracted with dilute hydrochloric acid. The aqueous phase was basified and extracted with ether. Removal of the ether gave 2-[ 1- [4-chlorophenyl) cyclobuty 1 ].-;.:; . 2-Dimethylaminoacetonitrile 1 (m.p. 90-91°C).

In a manner similar to that described in Example A above, the compounds of formula VII (where both P 1 and R 2 are methyl), listed in Table I, were prepared....

Notes to Table I

(1) The product was an oil whose boiling point was not determined.

(2) The acid back-extraction and the subsequent basification and ether extraction were not performed. (3) The product was obtained in the form of its hydrochloride monohydrate, which was converted to the free base and purified by distillation. (4) The reaction mixture was extracted with dichloromethane and the product was an oil which was triturated with petroleum ether (b.p. 60-80°C) to give a solid.

(5) The product was recrystallized from petroleum ether (bp. 40-60°C).

Example B

A solution of sodium cyanide (19.5 g) in water (50 mL) was added dropwise over a period of 30 minutes to a solution of 1-(3,4-dichlorophenyl)cyclobutanecarbaldehyde [(62.16 g) prepared on a manner similar to that described in

e.g. A for 1-(4-chlorophenyl)-cyclobutanecarbaldehyde] in methanol (70 mL) while maintaining the temperature at 20°C upon cooling.

A saturated aqueous solution of sodium metabisulphite (81 ml) was added over a period of 20 minutes at 20°C and the mixture was stirred for 16 hours and then poured into a mixture of ice and water. The resulting mixture was extracted with ether and the extracts were washed and dried. Evaporation of the solvent gave 2-[1-(3,4-dichlorophenyl)cyclobutyl]-2-hydroxyacetonitrile as a yellow oil, which was used without further purification.

4-Methylpiperidine (4.8g) was added to a solution of 2-[1-3,4-dichlorophenyl)cyclobutyl]-2-hydroxyacetonitrile 1 (12g) in toluene (50ml). The reaction mixture was stirred and heated at 100-105°C for 2 hours, cooled and diluted with water (100 mL) and ether (60 mL). The organic layer was separated, washed with water and dried. Evaporation of the solvents gave an oil which solidified on standing, giving a solid which was triturated with petroleum ether (b.p. 60-80°C), giving 2-[1-(3,4-dichlorophenyl)cyclobutyl ]-2-(4-methyl-piperidino)acetonitrile 1 (m.p. 76-78°C).

In a manner similar to that described above, the compounds of formula VII [wherein R^ is 3,4-dichlorophenyl for Examples B(a)-B(h), 4-chlorophenyl for Example B(i) and 3-tri -fluoromethylphenyl for example B(j)] listed in Table II prepared.

Notes to Table II

(1) An excess of the amine of the formula R^R^H and 2-hydroxyacetonitrile were heated together without any solvent present. (2) The product was an oil whose boiling point was not determined. (3) After the amine of formula R^F^NH and 2-hydroxyacetone had been heated for 4 hours, excess amine was removed by evaporation and the crude product converted to a hydrochloride salt. When the salt was made basic, the free base was obtained, which was extracted with ether. (4) The amine according to formula R^^NH and 2-hydroxyacetonitrile was dissolved in ether and the solution heated to 40 C for 30 min. The ether was removed by distillation and the residue heated at 90-95°C for 1.5 hours-(5) The amine according to formula R-^NH and 2-hydroxyacetonitrile was dissolved in dichloromethane and heated with stirring at 90-95°C for 2 hours. (6) An excess of the amine of formula R-j^NH and 2-hydroxyacetonitrile was easily dissolved: toluene containing MgSO^ and heated at 45°C for 5 days.

(7) The amine according to formula R^R2NH and 2-hydroxyacetonitrile was heated: toiuen at 110°C for 1 hour.

Examples 1-44

The compounds according to formula I where R. is a group according to formula IV (listed in table III!) have been prepared from amino groups according to formula VII by the following general reaction scheme.

A solution of an organolithium compound according to formula LiR^q : a solvent A (1 = ether, 2 = hexane, 3 = pentane) is added dropwise at ambient temperature under nitrogen or argon to a solution of aminoni trilet prepared as described in the example listed in the column with the superscript SM in solvent B (1 = toluene, 2 = ether, 3 = pentane/toluene). The mixture was then stirred for a period of C hours and the resulting intermediate was hydrolyzed with aqueous hydrochloric acid. The desired product was isolated from the reaction mixture and purified as indicated by the notes in the column headed PM, which have the following meanings: (1) by distillation - the boiling point range of the product given in the last column (2) by distillation : an apparatus of the type " Buchi Kugelrohr"

- the dr:ft temperature is shown in the last column

(3) by high-performance liquid chromatography ("high performance liquid chromatography") - the boiling point of the product was not determined (4) by hydrochloride salt formation - the melting point of the salt is listed in the sixth column (4a) by hydrochloride salt formation, obtaining a hygroscopic solid whose melting point could not be determined (5) by maleate salt formation - the salt's melting point is listed in the last column (6) by oxalate salt formation - the salt's melting point is listed in the last column column (7) by maleate salt formation, obtaining a gum, followed by flash chromatography using a mixture of petroleum ether (b.p. 40-60°C) and ether (7a) in the ratio 80:20 or using of a mixture of petroleum ether (b.p. 40-60°C) and ether (7b) in the ratio 87.5:12.5, yielding an oil - the boiling point of the product was not determined (8) the free base was obtained as a solid - the melting point is listed in the last column (9) the product was isolated as an oil which was not further purified - the boiling point was not determined (10) by flash chromatography using ethyl acetate (10a), a mixture of petroleum ether (b.p. 40-60 °C) and ether (10b) in the ratio 95:5 or a mixture of petroleum ether (bp. 40-60°C) and ether (10 c) in the ratio 90:10 as eluent - the boiling point of the product was not determined (11) by distillation in a "Buchi Kugelrohr" type apparatus (190°C/0.5 mm Hg) followed by maleate salt formation and then high-performance - liquid chromatography, obtaining an oil - the boiling point was not determined.

Example 45

A portion (70 mL) of a 0.305 M solution of 3-(1-ethoxyethoxy)propyllithium [prepared from l-bromo-3-(1-ethoxyethoxy)propane (21.8 g) and lithium wire (2.07 g) in ether (80 ml)] was added under argon to a stirred solution of the product according to example A(c) (5 g) in toluene (50 ml) at 20-25°C. The mixture was stirred at ambient temperature for 16 hours.

Water (40 ml) and then 5N hydrochloric acid (50 ml) were added with cooling so that the temperature was kept below 25°C. The resulting mixture was poured into water (200 mL), and the aqueous phase was basified and extracted with ether. The extract was dried, filtered and evaporated to give 1-[1-(3,4-dichlorophenyl)cyclobutyl]-1-dimethylamino-5-hydroxypentan-2-one, which was purified by flash chromatography using a mixture of petroleum ether (bp. 40-60°C) and ether in the ratio 75:25 as eluent, obtaining an oil whose boiling point was not determined.

Example 46

Triethylamine and then a solution of acetyl chloride in ether was added dropwise to a solution of the product of Example 45 in ether, and the mixture was heated under reflux for 90 minutes, cooled and filtered. The filtrate was diluted with water and extracted with ether. The extract was washed,

dried and evaporated, yielding an oil which was distilled on a "Buchi Kugelrohr" type apparatus (200°/0.5 mm), yielding 5-[1-(3,4-dichlorophenyl)cyclobutyl.] -5-dimethylamino-4-oxopentyl acetate.

Example 47

A 1.55M solution of n-butyl Hium in hexane (129 mL) was added to a stirred solution of diisopropylamine (22.3 g) in dry tetrahydrofuran (90 mL), and the resulting mixture was stirred in 30 minutes at 0°C. The mixture was then cooled to -70°C in an acetone/dry ice bath and a solution of 2-[1-4-chlorophenyl)-cyclobutyl]-2-dimethylaminoacetonitrile 1 (30 g prepared as described in Ex. A) in dry tetrahydrofuran (100 mL) was added to the reaction mixture under nitrogen over 50 minutes at -70°C and then stirred for 1.5 hours at a temperature below 5°C. The mixture was then cooled to

-70°C and treated with a solution of acetaldehyde (13.6 g)

in dry tetrahydrofuran (40 mL). After the mixture was stirred for 1 hour at -70°C under nitrogen, the mixture was heated with excess saturated ammonium chloride solution and allowed to warm to 0°C. The aqueous phase was then separated and extracted with ether. The extract was mixed with the organic phase of the reaction mixture, dried and the solvents removed by evaporation to give an oil which was distilled (while eliminating hydrogen cyanide) (154-160°C/-5 mm Hg, giving 1- [1-(4-Chlorophenyl)cyclobutyl]-1-dimethylaminopropan-2-one.

Example 4 8

In a way similar to that described in ex. 47 1-11-4-chlorophenyl)cyclobutyl]-1-dimethylaminobutan-2-one was prepared. The fractions collected in the boiling point range 136-140°C/2 mm Hg were purified by high-performance liquid chromatography on a silica column followed by flash chromatography using a mixture of equal parts of ethyl acetate and petroleum ether (b.p. 60-80 °C) as eluent. The product was then dissolved in propan-2-ol and excess concentrated hydrochloric acid was added. The solvents were removed by evaporation and the residue dried by azeotropic distillation with propan-2-ol, giving a solid which was recrystallized from propan-2-ol, giving 1-[1-(4-chlorophenyl)cyclobutyl]- 1-dimethylaminobutan-2-one hydrochloride (m.p. 174-176°C).

Example 49

1-[1-(4-chlorophenyl)cyclobutyl]-1-dimethylamino-3-methyl-butan-2-one (1 g prepared in a manner similar to that described in Ex. 47, and with a boiling point range of 144- 148°C/2 mmHg)

was heated under reflux for 20 minutes with a mixture of 30% aqueous oxalic acid solution (9 mL) and methanol (90 mL). The reaction mixture was poured into water and the aqueous mixture

was washed with ether, basified and extracted with ether. The solvent was removed from the dried ether extract and the residue was treated with a mixture of excess concentrated hydrochloric acid and propan-2-ol. Removal of the solvents gave a residue which was dried by azeotropic distillation with propan-2-ol. The residue was then triturated with acetone to give a solid, which was recrystallized twice from propan-2-ol to give 1-[1-(4-chlorophenyl)cyclobutyl]-1-dimethylamino-3-methylbutan-2 -one hydrochloride (m.p. 202-204°C).

Example 50

A solution of 2-[1-(3,4-dichlorophenyl)cyclobutyl]-2-dimethylaminoacetonitrile 1 (28.3 g, prepared as described in ex. A(c) in dry tetrahydrofuran (150 ml) was added with stirring to a solution of lithium diisopropylamide [prepared by adding a 1.6M solution of butyllithium in hexane (100 ml) to a solution of diisopropylamine (22.4 ml) in ether (200 ml) followed by removal of the solvents at 80°C and dissolving the residue in tetrahydrofuran (100 mL)] at -20° C. The temperature of the solution was maintained at -12° C. for 30 minutes. The mixture was then cooled to -40° C. and propionaldehyde (20 mL) was added. The temperature was allowed to rise to -10°C and an excess of aqueous ammonium chloride solution was added at the same temperature. The aqueous phase was separated and extracted with ether, and the extract was mixed with the organic phase from the reaction mixture. The resulting organic phase was dried and the solvents removed. The residue was distilled (while eliminating hydrog encyanide) (154°C/6 mm Hg) - 180°C/1.2 mm Hg), giving an oil which was dissolved in petroleum ether (40-60°C). A solid separated from the solution was collected by filtration and discarded, and the filtrate was evaporated. The residue was dissolved in methanol, oxalic acid (20 g) was added and the mixture was heated at 90-95°C for 40 minutes. The solution was poured into water (about 1.5 liters) and the resulting mixture was washed with ether, basified and extracted with ether. The extract gave an oil which was distilled in a "Buchi Kugelrohr" type apparatus (175°C/0.9 mm Hg), giving 1-[1-(3,4-dichlorophenyl)cyclobutyl]-1- dimethylaminobutan-2-one.

Example 51

A solution of 2-[1-(4-chlorophenyl)cyclobutyl]-2-dimethylaminoacetonitrile 1 (15 g prepared as described in ex. A) in dry tetrahydrofuran (50 ml) was added with stirring at -70°C during a period of 35 minutes to a solution of lithium diisopropylamide [prepared by adding a 2.7M solution of butyllithium in hexane (37 ml) to a solution of diisopropylamine (15 ml) in dry tetrahydrofuran (45 ml) at 5 °C] followed by stirring for 1 hour at a temperature below 5 °C. A portion (about 100 ml) of the above solution was cooled to -70°C. A solution of hexanal (12 mL) in dry tetrahydrofuran (20 mL) was added over 10 minutes and the mixture was stirred for 1 hour at -70°C. The temperature was maintained at -70°C while excess saturated ammonium chloride solution was added, and the mixture was then allowed to warm to ambient temperature. The mixture was extracted with ether and the dried extract evaporated to give an oil, which was distilled (160-170°C/-1 mm Hg) while eliminating hydrogen cyanide. The distillate was dissolved in an excess of 2N hydrochloric acid, obtaining an aqueous solution, which was washed with ether, made basic and extracted with ether. The extract was dried and the solvent removed by evaporation, yielding an oil which was distilled in a "Buchi Kugelrohr" type apparatus (250°/l mm), yielding 1-[1-(4-chlorophenyl)cyclobutyl]- 1-dimethylaminoheptan-2-one.

Example 52

A solution of 2-[1-(3,4-dichlorophenyl)cyclobutyl]-2-dimethylaminoacetonitrile 1 (11.3 g prepared as described in ex. A(c) in tetrahydrofuran (20 ml) was, over a period of 10 minutes added to a solution of lithium diisopropylamide at -50°C [prepared by adding a 2.7M solution of butyllithium in hexane (24.7 ml) to a solution of diisopropylamine (10.25 ml) in dry tetrahydrofuran (30 mL) at 10-15° C. under argon], and the mixture was allowed to warm to 3° C. and held at 3° C. for 30 min. The mixture was cooled to -70° C. and cyclohexanecarbaldehyde (11.5 g ) was added with stirring over a period of 20 minutes. Stirring was continued at this temperature for another 40 minutes, and then saturated aqueous ammonium chloride solution (100 mL) was slowly added at -70° C. The mixture was allowed to warm to 20-25 °C and the aqueous phase was separated and extracted with ether.The ether extracts were mixed with the organic phase from the reaction mixture, dried and evaporated , giving an oil which was heated (while eliminating hydrogen cyanide) at 90-95°C for 3 hours and then cooled and dissolved in methanol (100 ml). Oxalic acid (10 g) was added and the mixture heated at 90-95°C for 1 hour. The mixture was cooled, basified and extracted with ether. The ether extract was dried and evaporated to give an oil, which was purified by flash chromatography using a 95:5 mixture of petroleum ether and ether as eluent. The resulting oil solidified on standing and was recrystallized from petroleum ether (b.p. 60-80°C) to give 1-cyclohexyl-2-[1-(3,4-dichlorophenyl)cyclobutyl]-2-dimethylaminoethanone (m.p. 79 -80°C).

Claims (2)

1. Analogy method for the preparation of therapeutically active compounds of formula I and pharmaceutically acceptable salts thereof, wherein the group NR 1 R 2 is selected from dimethylamino, diethylamino, tert-butylamino, N-butyl-1-N-methylamino, N-methyl-N-(2-morpholinoethyl)amino, N-methyl-N-(2 -hydroxyethyl)amino, N-cyclohexyl-N-methylamino, piperidino, morpholino, 1,2,3,6-tetrahydropyridyl and 4-methylpiperidino; R3 is phenyl, naphthyl or phenyl substituted with one or more fluoro, chloro, bromo, trifluoromethyl, methyl, methoxy, methylthio or phenyl groups, and R 4 is a group of formula IV where R10 is a saturated or unsaturated aliphatic group containing 1-8 carbon atoms, optionally substituted with hydroxy, methoxy or acetoxy, cyclohexyl or a cyclohexylmethyl group, characterized by) reaction of aminonitriles with formula VII with an organolithium reagent of formula R^qLI» followed by hydrolysis, or b) thermal elimination of hydrogen cyanide from a compound of formula VI where Rn is a group of the formula CH(OH)Ri0. 2. Process according to claim 1 for the production of 1-[1-(4-chlorophenyl)-cyclobutyl]-1-dimethylaminobutan-2-one or a pharmaceutically acceptable salt thereof, characterized in that corresponding starting materials are used.