CS244672B2 - Production method of(1-arylcyclobutul)alkylamines - Google Patents

Abstract

Compounds of formula I <IMAGE> in which n=0 or 1; R1 is C1- alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, cycloalkylalkyl or optionally substituted phenyl when n=0 or R1 is H or C1-3 alkyl when n=1, R2 is H or C1-3 alkyl, R3 and/or R4 are H, formyl, C1-3 alkyl, C3-6 alkenyl, C3-6 alkynyl, C3-7 cycloalkyl or R3 and R4 together with the nitrogen atom form a heterocyclic ring system; R5 and/or R6 are H, halo, CF3, C1-3 alkyl, C1-3 alkoxy, C1-3 alkylthio or R5 and R6 together with the carbon atoms to which they are attached form a second benzene ring and R7 and/or R8 are H or C1-3 alkyl show therapeutic activity in the treatment of depression. Pharmaceutical compositions and processes for preparing compounds of formula I are disclosed.

Description

is 0 or 1, when n is 0, is a straight or branched (C 1 -C 6) alkyl, (C 3 -C 7) cycloalkyl, cyclohexylmethyl, phenyl or methoxyphenyl group; n is 1, R R is hydrogen, is hydrogen, methyl, ethyl or isopropyl,

R 6 represents a hydrogen atom or a methyl group and

R ₅ and R 8, which may be the same or different, each represent a hydrogen atom, a halogen atom, a trifluoromethyl group, a methyl group, a methoxy group or a phenyl group; and R 8 together with the carbon atom to which they are attached form a second benzene ring, which is optionally substituted with a chlorine atom.

The compounds of formula (I) may form salts with pharmaceutically acceptable acids. Examples of such salts include hydrochlorides, maleates, acetates, citrates, fumarates, tartrates, succinates and salts with acidic amino acids such as aspartic acid and glutamic acid.

The compounds of formula I contain an asymmetric carbon atom and exist in two enantiomeric forms. The invention encompasses both these enantiomeric forms and mixtures thereof.

The invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula I together with a pharmaceutically acceptable diluent or carrier.

For therapeutic use, the active compounds of the invention may be administered orally, rectally, parenterally or topically, preferably orally. Thus, the therapeutic compositions of the invention may be in any known pharmaceutical form suitable for oral, rectal, parenteral or topical administration.

Pharmaceutically acceptable carriers suitable for the preparation of such compositions are well known in the pharmaceutical art. The compositions according to the invention may contain from 0.1 to 90% by weight of active ingredient. The compositions of the invention are generally prepared in unit dosage form.

Preferred compositions of the invention are oral formulations known in the art for such administration, such as tablets, capsules, syrups and aqueous or oily suspensions. Conventional carriers and excipients are used to prepare these compositions. Tablets may be prepared by mixing the active ingredient with an inert diluent, such as calcium phosphate, in the presence of disintegrating agents, for example corn starch, and glidants, for example magnesium stearate, and processing the mixture thus obtained into known tablets.

Tablets may be prepared in a manner known per se to permit the sustained release of the compounds of the invention. Such tablets may optionally be coated in known manner to protect them from the gastrointestinal tract, for example using cellulose acetate phthalate.

Similarly, capsules, for example hard or soft gelatin capsules containing the active ingredient together with the excipients or the active ingredient alone, can be prepared in a conventional manner and, if necessary, provided with a coating known to protect them against the gastrointestinal tract.

The tablets and capsules may conveniently contain 1 to 500 mg of the active ingredient. Other compositions suitable for oral administration include, for example, aqueous suspensions containing the active ingredient in an aqueous medium in the presence of a non-toxic suspending agent, such as sodium carboxymethylcellulose, and oily suspensions containing a compound of the invention in a suitable vegetable oil, for example peanut oil.

Formulations of the invention suitable for rectal administration are known dosage forms for this mode of administration, for example suppositories with a base based on cocoa butter or polyethylene glycol.

Compositions of the invention suitable for parenteral administration are known dosage forms for this mode of administration, for example sterile suspensions in aqueous or oily media or sterile solutions in a suitable solvent.

Topical compositions may be formulated in which the pharmacologically active compound of the invention is dispersed by maintaining the compound in contact with the skin, thereby providing transdermal administration. Alternatively, the active ingredients may be dispersed in a pharmaceutically acceptable cream or mask base.

For some compositions, it may be advantageous to use the compounds of the invention in the form of particles of very small size, such as those obtained by fluid grinding.

The compositions of the invention may optionally be present in combination with other compatible pharmacologically active compounds.

Pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula I can be used to treat depression in mammals, including humans. In this treatment, a compound of formula I is administered in a daily dose ranging from 1 to 1000 mg, preferably from 5 to 500 mg.

The compounds of formula (I) are prepared in accordance with the invention by ketones of formula (Va)

(CHR ^ COR ')

(Va) undergoes reductive amidation by treatment with a formamide of the formula

HCONHR3 and formic acid to give compounds of formula IA

CHR (CHCH 3) N

3 n

(IA) the compounds of formula (IA) are then hydrolyzed to give the corresponding compounds of formula (I) in which Rr is hydrogen, and optionally those compounds of formula (I) in which R3 and R. are hydrogen are reacted with formaldehyde; formic acid to compounds of formula I wherein R 3 and R 3 are methyl.

In the above compounds, R 1, R 5, R 1, R 3 and n are as defined above.

In the ketones of formula Va, m is 0 or 1. If m is 0, then R 'is as defined above for R. and when m is 1, R' is methyl. Thus, suitable starting materials are ketones of formula V and ketones of formula VI

(VI) (VI)

The ketones of formula (V) may be prepared by hydrolysis of imines of formula (VII) in which:

(VII) means a metal-containing residue derived from an organometallic reagent.

Imines of formula VII may be prepared by reacting the above-mentioned organometallic reagent with a cyano compound of formula VIIT '

(VIII)

Suitable organometallic reagents include Grignard reagents of formula RMgX, wherein X is chlorine, bromine or iodine (Y = MgX) and organolithium compounds of formula RLi (Y = lithium).

The ketones of formula VI can be prepared by hydrolyzing imines of formula IX in which:

(IX) means a metal-containing residue derived from an organometallic reagent.

Imines of formula IX can be prepared by reacting the above organometallic reagents with cyano compounds of formula X (X)

Suitable organometallic reagents include Grignard reagents of the formula CH3MgX, wherein X is chlorine, bromine or iodine (Y = MgX) and organolithium compounds of the formula CH3 Li (Y = lithium).

The ketones of formula (V) may be prepared by reacting carboxylic acid derivatives, such as amides or acid halides, with organometallic reagents, for example by reacting the acid chloride of formula (XI)

(XI) with a Grignard reagent of formula RMgX, wherein x is chlorine, bromine or iodine, at low temperature, or by reaction of a carboxylic acid of formula XII

(XII) with an organometallic reagent, for example an organolithium compound of formula R 1 Li

The 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 the acid chloride of formula XIII

CHgCOCI (XIII) with a Grignard reagent of the formula

CH 2 MgX where it represents chlorine, bromine or iodine, at low temperature, or by reaction of a carboxylic acid of formula XIV

CH ₂ COOH

(XIV) with an organometallic reagent, for example an organolithium compound of the formula CH 2 Li.

The ketones of formula (V) in which methyl is and the ketones of formula (VI) may be prepared by reaction of diazomethane with aldehydes of formula (XV).

CHO

(XV)

Cyano compounds of formula VIII can be prepared by reacting cyano compounds of formula XVI

(XVI) with 1,3-disubstituted propane hydride.

The cyano compound of formula X is the following sequence of reactions:

with 1,3-dibromopropane, and a base such as sodium may be prepared from cyano compounds of formula VIII, for example

a) hydrolysis of the cyano group to form the carboxylic acid of formula XII,

(b) reduction of the carboxylic acid with, for example, lithium aluminum hydride or borane -

- dimethylsulfide, to give the corresponding alcohol,

(c) replacing the hydroxy group in the alcohol with a leaving group, such as p-toluenesulfonyloxy; and

(d) replacement of the leaving group with a cyano group.

Acid chlorides of formula XI can be prepared by reacting carboxylic acids of formula XII with, for example, thionyl chloride.

The aldehydes of formula XV may be prepared by methods known per se. The following is an example of a suitable method.

Reduction of the cyano compounds of formula VIII with, for example, di-tert-butylaluminum hydride or diisobutylaluminum hydride. ,

The therapeutic efficacy of the compounds of this invention is determined by examining the ability of these compounds to reverse the hypothermic effects of reserpine, as follows. Male Charles River CD1 mice, weighing between 18 and 30 g, are divided into groups of five animals, and the animals are not restricted to food and water intake. After 5 hours, the body temperature of each mouse is orally determined and then mice are injected intraperitoneally with 5 mg / kg reserpine as a solution in deionized water containing 50 mg / ml ascorbic acid.

Injectable liquid is administered in an amount of 10 ml / kg body weight. Foods are taken 9 hours after the start of the test but are no longer restricted in water intake. 24 hours after the start of the test, the body temperature of each mouse is measured and the mice are dosed with a test compound suspended in a 0.25% solution of hydroxyethylcellulose in deionized water at a volume dose of 10 ml / kg body weight.

After 3 hours, the body temperature of each mouse is measured again. Using the following equation, the percent reversal of the reserpine-induced decrease in body temperature of the test animals is then calculated:

(temperature after 27 - temperature after 24 hours hoursh) x 100 (temperature after 5 - temperature after 24 hours hoursh)

For several different doses of the test compound, the average percentage is determined and the average dose causing 50% reversal of hypothermia ( ^ED 50 value) is calculated from the results. All compounds prepared in the following examples have ED 50 values of 30 mg / kg or less. It is generally known that this test is used to determine the antidepressant efficacy of substances in human medicine.

The invention is illustrated by the following non-limiting examples. All produced compounds were characterized by conventional analytical techniques and had satisfactory elemental analyzes.

Example 1

To a mixture of 7.5 g of sodium hydride dispersed in 7.5 g of mineral oil and 200 ml of dimethylsilyl du ^{LF-dioxide at} temperatures ^{of 30} and ³⁵ DEG C. ^EXAMPLES APE ^p from (TOS-em behind the ball ^hook the ^extensible mesh 25 ^{g 3,} 4-d ⁱ c ^hl orbenzylkyanidu and 15 ml of 1,3-dibromopropane in 150 ml of dry dimethylsulfoxide. the mixture was stirred for 2 hours at room temperature and then added dropwise 8 ml of 2-propanol then 110 mL of water.

The mixture was filtered through diatomaceous earth and the solid residue was washed with ether. Etheric. The layer was separated and evaporated, washed with water and dried. Distillation isolated 1- (3,4-dichlorophenyl) -1-bicyclo ^{b y} c ^l o utankarboni.tri te rt ^{pl of} boiling ¹⁰ and 8 ¹²⁰ ° ^{C / 20} mbar. The axis ^{T p} u ^p is also possible ^{to dif} AC ^and methods described by Butler et Pollatz in J. Org. Chem., Vol. 36, No. 9, 1971, p.

21.7 g of the above 1- (3,4-dichlorophen ^{yl) -1-cyclo-} klobutankarbonitrilu was dissolved in 50 ml of dry ether and this solution was added under nitrogen to the reaction product of gaseous methyl bromide with 3.9 g of magnesium turnings in 150 ml dry ether. The mixture was stirred at room temperature for 2 hours, then heated at reflux for 2 hours, then crushed ice was added followed by 100 mL of concentrated hydrochloric acid, and the resulting mixture was heated at reflux for 2 hours. The ether layer was separated, washed with water and aqueous sodium bicarbonate solution, dried and evaporated. 1-Acetyl-1- (3,4-dichlorophenyl) cyclobutane is isolated by distillation, boiling at 108-110 ° C / 27 Pa.

9.1 g of the above prepared 1-acetyl-2- (3,4-dichlorophenyl) cyclobutane, together with 6.5 ml of formamide and 3 ml of 98% formic acid, were heated at 180 ° C for 16 hours to give N-formyl-1- N - (3,4-dichlorophenyl) cyclobutyl] ethylamine.

After the addition of 20 ml of concentrated hydrochloric acid, the resulting mixture was refluxed for 3 hours, then the reaction solution was cooled and, after washing with ether, sodium hydroxide solution was added thereto. The product was extracted with ether, the ether extract was washed with water and evaporated to dryness. 1- [1- (3,4-Dichloro-phenyl) -cyclobutyl] -ethylamine is isolated by distillation, boiling at 112-118 ° C / 27 Pa.

This amine was dissolved in 2-propanol and concentrated hydrochloric acid, and the solution was evaporated to dryness. 185 DEG-195 DEG C. 1-.beta .- (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride is obtained. The product is of formula I wherein n is 0, is methyl, R8 and R8 are hydrogen, Rg is chlorine at the 4-position, and Rg is chlorine at the 3-position.

Example 1a

The preparation of N-formyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine, m.p. 124 DEG-125 DEG C. [Example 1 (a)], a compound corresponding to the general formula (I) in which n is O, Rg is methyl, Rg is hydrogen, R6 is CHO, Rg is chlorine at 4 and Rg is chlorine at 3], the product isolated by cooling the reaction mixture and filtering off the solid. The formamide is then hydrolyzed with concentrated hydrochloric acid in denatured ethanol to give 1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine.

The following compounds were prepared in an analogous manner to that described in Example 1a above. The hydrolysis conditions of the formamides isolated by the appropriate methods are set out in the notes.

example ^R 1 ^R 5 CHR.NH _? . HCl 6 ^R 6 boiling point of the free base melting point hydrochloride note l (b) methyl Cl H 107 < ^D C / 160 Pa AND Kc) n-butyl Cl H 138-139 ° C В 1 (d) methyl AND H 205-207 ° C C l (e) methyl Cl ^CF 3 216-217 [deg.] C D

Notices:

A aqueous hydrochloric acid / denatured ethanol

N-Valeryl-1- (4-chlorophenyl) cyclobutane was prepared in tetrahydrofuran. The hydrolysis is carried out using a mixture of concentrated hydrochloric acid and denatured alcohol.

C concentrated hydrochloric acid / diethylene glycol dimethyl ether (operating in an analogous manner to that described in Example 12 below)

D concentrated hydrochloric acid / denatured ethanol.

Example 2

With cooling was mixed 4.04 g of product from Example 1, 0.5 ml water and 3.6 ml of 98% formic acid is added 3.8 ml 37 to 40% aqueous formaldehyde and the solution is heated for 5 hours at 85 to ⁹⁵ Deň: 32 ° C. Rea ^{at the} CN ^s maiden ^t o ^to the ^dp and ^{R to} Suc ^h at ^{zb y} te ^to the ^alkyl SEL ^{I to} oncen ^t routing ^alkyl Sehne ch ^ rovodíkovou and the water removed by repeated addition of 2-propanol followed each time by evaporation in vacuo . . .

^{September KA to} r ^y S ^{t where} c ^k y ^{n, N} - ^d ime ^thyl -l ^{- [1} ~ ^(3, 4-c ^{hl di} or ^phenoxy-yl) C ^yk lo ^b ut e ^{thy yl} lamin- ^hyd Roch ^l o ~ r ^ID of te ^pl OTE ^th her 2 ^{from 11} to ²¹³ ° C \ o ^dp s ^ID and ^d c ^d a ^b ECN ^é him formula I wherein nm ^and a value of 0, R |, and Rj represent methyl, Rg represents the chlorine atom at the 4-position and Rg represents the chlorine atom at the 3-position.

In an analogous manner to that described above, the compounds of Examples 1 (b) and 1 (d) were converted to the following compounds.

example starting material ^R 1 ^R 5 ^R 6 melting point hydrochloride boiling point of the free base 2 (a) l (b) methyl Cl H 98-100 ° C / 67 Pa 2 (b) l (d) methyl AND H Mp 260-261 ° C Ex lad 3

In an analogous manner as described in Examples 1 and 2 to prepare N, N-dimethyl-1- (l- (4- ^b Ifen ^{yl yl)} cylklobut Jethylai ^ n ^ ^^ ^ or ^ roc of ^T emperature ^of the T ^{and of 197} and ¹⁹⁶ ° ^{C, b} ecný of formula I wherein n is O, R, Rg and Rj are methyl groups, R g is 4-phenyl and R₈ is hydrogen.

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 ml of 98% formic acid and 1.5 ml of a 25% aqueous solution are mixed. ^{-Methyl amine} with the mixture ^{of H} nor behind the ball 8 ^h of ^di n for ^HRI VA ¹⁷⁰ and ^{Z 180} ° C ^for the PA oc ^h la ^di- and extracted with ether. The ethereal extract was washed and evaporated to dryness to give a slightly yellowish oily residue, which was refluxed with 50 ml of concentrated hydrochloric acid for 2 hours. After addition of 50 ml of denaturated ethanol the reaction mixture was heated 16 hours at reflux ^{d PE} sLex c ^ and n ^ ^p ^^ and ^^ och ^k to 0 ou 3 ^{-yl No.} Measured. ^{the white} precipitate was filtered off and washed with acetone and dried.

To give N-meth ^y l ll- ^ ^f ^ - ^(i3, 4- ^di c or ^{f hl} en ^yl) c of ^{YKL b} u ^t; yl] et ^hyl am ⁱ n ^- h ^yd ROC ^hl ori te ^d by ^P lot ^of point 254 ^{and 2} 56 ° C, from ^p OVI ^d ající ecnému of formula ^{b. And, in some} MŽ nm, ^{and h} o ^d u ^t O no, ^Rj and ^Rg represent: ⁱ methyl group, R₁ is hydrogen, R₂ is a chlorine atom in position 4 and Rg is a chlorine atom in position 3rd

The following compounds of formula I are prepared in an analogous manner to that described above.

CHR1NHMe2. HCl

example ^R 1 ^R 5 ^R 6 the boiling point of the amine melting point hydrochloride note 4 (a) Me Cl H 98-100 ° C / 20 Pa 240-241 Noc: 2 ° C 4 (b) Me H Cl 269-272 Noc: 2 ° C 4 (0 Me Br H 96-98 ° C / 13 Pa 4 (d) Me H Br 251-255 Noc: 2 ° C 4 (e) Me CFg H 219-221 Noc: 2 ° C 4 (f) Me H ^CF 3 255-228 Noc: 2 ° C 4 (g) Me - (CH = CH) ₂ - 254-257 Noc: 2 ° C 4 (h) Me Cl CF3 189-200 Noc: 2 ° C 4 (i) Et Cl H 238-240 Noc: 2 ° C 4 (j) Ex Cl H 228-229 Noc: 2 ° C A ' 4 (k) Bu Cl H 152-153 Noc: 2 ° C AND 4 (2) Me AND H 242-243 Noc: 2 ° C Comment: AND default ketone is prepared in tetrahydrofuran as reaction solvent (instead of

ether).

In the preceding and following tables and formulas, Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl, Ph is phenyl.

Example 5

A mixture of 50 ml of 70% ethylamine in water 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 which was evaporated at 100 ° C under a pressure of ^about Pa 13'33 to remove ^and n ^s 1.80 m ^l of water.

Coll^ytek se zah^Řat 140 ° C and p^Řid^and se^to n^Ehim^{10.4 g} 1-acetyl-1- (⁴-ch^lsteed^Fenyl) c^yklo^butanu^[recraven analo^giC^toým^postu^pem, me^toý je^pO^pwith^andn v^exla^du 1^pro pHpravu¹-acetyl-1- (3^,4 -dichlorfen^yl) c^yklO^butanu^] and¹10 m^{l 9}8%^kyse^lin^y mravetáí.

After 16 h ^and n ^are heated ^and an oil bath temperature ^of 180 to ²⁰⁰ ° C, ^p and ^{k d} estiluje to achieve. HV ^and Tm ^s t.eplot ^{y 17} 0 C and ^{tet t} e rt ^{pl of} at ržuje ^{d 2 y D} in it. ^Vp ec ^h n ^y T ^e Kav ^{e p} from ⁱ l ^y a ^{dd il} est TO, THE ^{at 160} ° C for t ^ to ^{2666 P} AAZ ^would tek 3 ^h for ^d in ^y for ^gro IV ^{and the} reflux with 15 ml of concentrated hydrochloric acid and 15 ml of denatured ethanol.

The denatured ethanol was evaporated on a rotary evaporator and the residue was washed with ether. Aqueous phase of hydroxide; The mixture was basified to pH 12 with sodium hydroxide solution and extracted with ether. The ether extract was dried, evaporated. . ·. · And the residue is treatment with aqueous hydrochloric acid was converted to N-ethyl-1-F1- ^{(4-chloro-l-yl} or ^F en) ^yl Klot c> ut ^yl] eth ^ ^^ amine roc ^ or ^ o te ^{pl I th} for n ^{s 203} and ²⁰⁵ ° C, from ^{p-ovídající} general formula I wherein n is 0, R is methyl, R₁ and R₈ is hydrogen, R₂ is ethyl, and Rg represents chlorine in position 4.

Table 6.

g of 1- (4-chlorophenyl) -1-cyclobutanecarbonitrile prepared in an analogous manner as described in Example 1 for the preparation of 1- ^(3, 4-dichlorfdnyl) cyclobutane in 50 ml of dry ether was added to the reaction product of 3.18 g of magnesium shavings and 15.99 g propyl bromide in 50 ml dry ether.

The ether was replaced with tetrahydrofuran, the mixture was heated under reflux for 18 hours with stirring, then cooled, ice and 52 ml of concentrated hydrochloric acid were added. The resulting mixture was stirred at reflux for 10 hours and then extracted with ether. From the ethereal extract, after evaporation yielded a residue which is distilled to give 1-butyryl-l- (4-chloro- ^phenoxy-yl) C ^YKL an OBU ^{t BC s} boiling and ¹⁰⁶ and ^{of 108} ° C / 40 mbar.

К ¹⁵ ml of formamide at ⁶⁰ ° C for l added during 1.5 hours a mixture of ^{21 g} of the ketone obtained above and 6 ml of 98% formic acid. After complete addition the temperature was raised to ^180-185 ° C and this range is maintained for 5 ^s he ^di n.

The reaction mixture was cooled and, after extraction with chloroform, it gave a thick gummy ^residuals e ^k, wherein Z ^and hřevem with ^p etrolet ^h Erem (b.p. ^{60 and} 8 ⁰ C) ^p OSK ^y tne colorless ^p evný ^P ro ^d uct. . ^{p RX} EKR ^y s and ^t s ^{L s} of the ^p etrolet ^h interruption ^{(b.p. 60} to ⁸⁰ ° C) from ^{N-ka-form yl-1} '' - [l- ^{(4-chloro phenylpiperidine y1)} cy ^{b kl} of at ^{most l] b} ut ^ylamino te ^p lot ^of T ^and the ^97.5 and ^98.5 ° C, from ^p o ^{s classes} ajíc ^b ecnému of formula I in which n 0 represents a propyl group, R1 represents a hydrogen atom, R4 represents a methyl group. R 8 represents a chlorine atom in the 4-position and R 8 represents a hydrogen atom.

Example 7

A solution of 35.2 g of 1- (3,4-dichlorophenyl) -1-cyclobutanecarbonitrile, prepared as described in Example 1, in 100 ml of ether is added to a solution of propylmagnesium bromide prepared by reacting 32 g of propyl bromide with 6.36 g of magnesium shavings in 100 ml. of ether. The ether was replaced with dry toluene and the mixture was heated under reflux for 1 hour.

After adding 200 ml of water first and then 120 ml of concentrated hydrochloric acid, the mixture was heated under reflux for 1 hour, then extracted with ether. The extract is washed, dried and evaporated to a residue, from which was distilled to give 1-butyryl-1- ^{(3,4-dichloro phenoxy-yl)} C ^yk lo ^b utan boiling ^{even at 120} and ^{from 128} ° C ^{/ 33} and ^P .

^{The LF} formamide ^23.5 m on ^{t h} e ^p ture ^{of 170} ° C was ^{added 37.0 g} sliora ^{BC Star} Ready him ketone and ⁹ ml of ^{98% formic alkyl} petroleum jelly. The mixture ^of the 5 ^h after odi.n ^HRI VA ¹⁷⁵ and ^{Z 180} ° C, ^P and ^{K was added} to ^inferior C ^{4 h,} 5 mL of formic kyseMny ^C I a mixture can still be 15 ch ^LSI roll a heated I ⁷⁵ and ^Z 180 ^o C.

The reaction mixture was extracted. ether and the ether extract is evaporated to a thick oily unnecessary ^ ^kt projecting into the cavity of ^{the p} r ^y s ^t a ^{l i} z ^ ISATIO ro ^^ ERU ^{(b.p. 60} 0 ^{and 8} ° C) ^y tne ^p OSK N ^- formyl-L ^-f l- (3, ^{4-dichlorophenyl)} cyklot> ut ^yl.] but ^{yl amino} te rt ^{pl of} TONI 103 ^{and 1} 05 ° ^ ^í let ^s response ^generally had the formula I in which n = O, R ₃ is a propyl group, R ₃ is a hydrogen atom, R 4 is a CHO group, R 8 is a chlorine atom at the 4-position and R 8 is a chlorine atom at the 3-position.

The following compounds were prepared in an analogous manner to the above:

example ^R 1 ^R 5 ^R 6 temperature melting point (° C) 7 (a) isobutyl Cl H 110 - 112 7 (b) propyl Cl F 115 - 116 7 (c) phenyl Cl H 94 - 96 7 (d) propyl H H 98 - 102

Example 8

A mixture of 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 was heated under reflux for 9 hours. The resulting solution was washed with ether, an aqueous sodium hydroxide solution was added thereto, and the mixture was extracted with ether. The ethereal extract was washed with brine and water, and evaporated to an oily residue.

3.19 g of this oily residue are dissolved in a mixture of 4 ml of 2-propanol and 20 ml of ether, and 1.5 ml of concentrated hydrochloric acid are added thereto, and the solvent is evaporated off under vacuum. Recrystallization of the residue in denatured ethanol, followed by evaporation in vacuo, yielded a gummy residue which solidified upon heating in vacuo.

After ekrysta ^{EXAMPLE l} o ^ck of etro ^{p l} e ^th interruption (b.p. ^100-120 ° C) from ^ ^ka - ^{di chlorophenyl) yk} lo ^b c ut ^{yl] b} ut n ^y lam ^{i hyd} roc ^hl or ^ID of te lo ^{p I} T ^and the ²⁰¹ and ^{from 203} ° C,

1- (1- (3,4o ^dp s ^ID and ^I C ^s formula I wherein n is hydrogen, R₂ is a chlorine atom in

O, R ^ represents a propyl group, R a and R ^ represents the 4-position and R 8 represents the chlorine atom at the 3-position.

to prepare the following compounds. As the velise increases, the solubility of the hydrochlorides of these compounds in water decreases

By analogy to the above, the bones of the residue in the meaning of the symbol Rr are phase and their solubility in the organic phase is increased, so that the isolation procedure needs to be modified accordingly, which is not a problem for the person skilled in the art. CHRjNHj. HCl

example ^R 1 * ^{5 R} 6 melting point (° C) 8 (a) isopropyl Cl H 220-222 8 (b) sec-butyl Cl H 178-179 8 (c) isobutyl Cl H 163-165 8 (d) cyclopentyl Cl H 185-210 8 (e) phenyl Cl H (decomposition) 271-276 8 (f ^) 4-methoxyphenyl Cl H 214_- 219 8 (g) cyclohexyl Cl H 206-210 8 (h) isobutyl H H 210-212 8 (i) cyclopropyl Cl H 204-206 8 (j) propyl Ph H 235-236 8 (k) propyl Me Cl 214-217 8 mm (1) propyl - (CH = = CH) ₂ - 157-159 8 (m) cycloheptyl Cl H 156-162 8 (n) cyclohexyl Cl Cl 215 8 p methyl Cl F 215-217 8 (q) propyl About me H 178-179 8 (r) propyl Cl F 186-188 8 (s) propyl Cl H 174-175 8 (t) cyclohexylmethyl Cl H 148-150 8 (u) cyclopropylmethyl Cl H 184-185 8 (v) propyl ’ -CH = CH · -CCl = CH- (and) 8 (w) propyl H ^CF 3 126-128 8 (x) 4-fluorophenyl Cl H 279

Legend:

(a) (b) is 168 ° C / 6.7 mm Hg te ^pl OTA reflux in diethylene ^I don WZE replaced by ethylene glycol dimethyl ether.

In an analogous manner as above were also prepared 1- (1- (4-chloro-2-fluorfenyljcyklobutyl] butylamine ^by t ^e p ^lo thee boiling point of 99 ° C / ⁶ mbar f ^{7 the example,} 10 ^(a); ob ^{ecný formula} I, EMZ ^MV n ^is 0 h ^tillering herein, Rg is propyl, R and Rg are hydrogen, Rg represents a chlorine atom in position 4 and Rg is a fluorine atom in position 2.J R-RI ^{(2- fluorophenyl yl)} cy ^kl o ^b u ^t y ^{l] -Butyl l} AIM ^I NH ^y trihydrochloride of te ^p ture th ^{tup 175-177} DEG C. ^{[example 1} 0 ^{(aa) general} model ^{Orec I hv} EMZ n ^{has values} of 0, ^Rg is ^{and p} ro ^py hunting ^{ou s} to ^{p-well, R} 3 ^'R 4 ^{and R} 5 are hydrogen and R₆ is a fluorine atom in position 2] ¹ - ^[1 - ^{(4 l} or- CH ² -me ^thy l ) C ^yk lo ^b by ^those LJ ^b ut ^{s phenylamino} NH ^yd rochlor ^even the ^p ture mp 188-190 ° C / example 10 (bb); formula ^{I, in some} MŽ nm, ^{and h} o ^d note 0, R ^g represents ^{and pollen P} ro ^pi verifies SKU well, Rg and R ₄ each represent a hydrogen 'atom, R₂ represents a chlorine atom in position 4 and Rg is methyl Skupi position 2].

Example 9

3.3 g of the product of Example 8 (c) as the free base, 2.99 g of formic acid and 1 ml of water are mixed under cooling, 3.93 ml of 37-40% aqueous formaldehyde are added and the mixture is heated at room temperature for 18 hours. 85-95 ° C. After addition of excess dilute hydrochloric acid, the reaction solution was evaporated to dryness, the residue basified with 5N sodium hydroxide solution and the product was extracted with ether.

Evaporation of the ether yielded a pale yellow oily material which was dissolved in a mixture of 4 ml of 2-propanol and 20 ml of ether, and 2 ml of concentrated hydrochloric acid was added dropwise. The resulting solution was evaporated and the residue was redissolved in ethanol, followed by evaporation in vacuo. Give a gum which was triturated with petroleum ^e ther ^em (warm-those boiling ^at 60-80 ° C) ^Ex converted to the yellow ^p evný ^P ro ^d uct, which, ^{Pla to} trait ^T & ^L CVAN ^{s from} AC ^E t ^{one p} OSK ^y tne N, N-dimethyl ll- ^y / l- (4-chloro- ^phenoxy-yl) c c ^b u ^{YKL-cyclopentyl]} -3-me ^th yl ^lb u ^t y ^l am ⁱ n hy ^d RCCH ^l chloride ^for t ^ep l ^of I th ^tup 195-197 ° C from ^ sponding of ^b ECN ^é he formula ^{I, in some} meters ^from nM ^{s h} o ^d no ^t u 0, R₂ is isobutyl, R g is hydrogen hydrogen, R4 and Rg are methyl groups and R g ^{P h} pose a C atom in position Loru '.

The following compounds of formula I are prepared in an analogous manner as above:

Example starting material (example #)

Rg melting point (° C)

9 (a) 8 (h) isobutyl H H 195 - 198 9 (b) 8 <j) propyl Ph H 194 - 196 9 (c) ‘ 8 (n) cyclohexyl Cl Cl 227 - 228 9 (d) 8 (q) propyl About me H 187 - 188 9 (e) 8 (s) propyl Cl H 194 - 196 9 (f) 8 (t) cyclohexylmethyl Cl H 194 - 196 9 (g) 8 (u) cyclopropylmethyl Cl H 165 - 167 9 (h) 8 (v) propyl -CH = CH-CCl = = CH- (and) 9 i - isobutyl Cl NO. 1 225 - 226 9 (j) 8 (x) 4-fluorophenyl Cl H 234 9 (k) - propyl isopropyl H 211 - 213

Legend:

(a) in the ^BA-L of the ^p boils ^{above 250} ° ^{C / 6.7} mbar.

Example 9 (1)

In an analogous manner as above to prepare N, N-dimethyl-l- [l- (4-chloro-2-fluorophenyl) cyclobutyl] ^b ut ^yl am ^{i n-hydroxy-droc hectoliters} or ^even to heat ^{thee t} U ^{s 183} ° C by ^p Daj s ^{s s s} c a ^b ecnému formula ^I I in which n is 0, R is a propyl group, Rg and R ^ are methyl, R₆ represents a chlorine atom in position 4 and Rg is a fluorine atom in position the second

Example 10

A mixture of 8.3 g of the product of Example 7, 50 ml of diethylene glycol dimethyl ether, 20 ml of water and 20 ml of concentrated hydrochloric acid was heated under reflux for 16 hours. The reaction mixture was poured into water, aqueous sodium hydroxide solution was added, and the product was extracted with ether. Evaporation of the extract gave a dark colored oily residue.

7.9 g of this oily material are mixed with 0.7 ml of water and 6.5 ml of formic acid, and 6.5 ml of formaldehyde are added.

The mixture was heated at reflux for 3 hours, then 10 ml of concentrated hydrochloric acid and 10 ml of 2-propanol were added. Evaporation to dryness gave N, N-dimethyl-1-1H-1'-dichlorophenylcyclobutyl-butylamine hydrochloride. ^white solid ^e l ^beginnings of te ^p ture point ¹⁹⁵ and ^{from 196} ° C [Formula I, ^{in some} M ^F nm ^and a ^h odnotu 0, R ^G represents ^and prop ^ verifies ^Sapin, Rg and R ₄ represent a methyl group, R₆ represents a hydrogen chlorine at the 4-position and Rg represents a chlorine atom at the 3-position].

Example 11 ‘

The preparation of salts of the compounds of the invention is illustrated by the following examples in which equimolar amounts of base and acid are contacted in a suitable solvent. The resulting salt is then recovered from the solution in a conventional manner. The prepared salts are summarized as follows:

base example acid (example number)

solvent melting point sdi ( ^O C)

11 (a) 8 (s) lemon aqueous acetone 158 - 160 11 (b) 8 (s) maleic ether 155 - 157 ll (c) 8 (s) amber ether 152 - 155 11 (d) 2 L (+) - guilty denatured ethanol 150 - 153 11 (e) note (a) lemon ether / methanol 163 - 164

(decomposition)

Legend:

(a) ^{to the BA} of the ^p ou ^Gd weighing ^{1- [1} - ^(3,4 dřmethyl ^{phenyl l)} cy of ^{KL b ut-yl] -} 3 ^- meth ^{ut? lb? lb} utylamin prepared analogously as described in Example 8.

Example 12

To 85.5 ml of isopropylamine was added dropwise with stirring 62 ml of methyl formate at such a rate that the mixture was constantly refluxing gently. After completion of the addition ^stirring okra ^CU is still ^{of two hours} at the ^C EZ methylenedi oddestduje ^at temperatures of ¹⁰⁰ ° C. Destilado ^the residual U was obtained ^and N ⁱ with ^p ro ^py l ^{id f} ORMA boiling ^{at 108-109} ° C ^{/ 3.33 kP} a.

To 43.5 g of N-isopropylformamidu were added 10.4 g of 1-acetyl ^gamma ll- (4-chlorophenyl) ^cyclo- klobutanu [prepared by a procedure analogous to that described in Example 1 for the preparation of l-acetyl-l - [(3 , 4-dichlorophenyl ^^^ íbutanuQ and ⁵ m ^{l of 98%} sel ^{alkyl and} n ^y formic acid.

The mixture is heated at 180 DEG C. for 4 hours and the excess starting material is distilled off at a pressure of 2.7 kPa. The viscous residue was refluxed 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 basified, extracted with ether, dried and evaporated to an oily residue which was dissolved in 5N hydrochloric acid.

Evaporation gave a yellow oil which, after trituration with petroleum ether (b.p. 62-68 ° C), gave N-isopropyl-1- [1- (4-chlorophenyl) cyclobutyl] ethylamine hydrochloride, m.p. 170-174 ° C. in which n is 0, R ₁ is methyl, and R g is hydrogen, R g is isopropyl, and R g is chloro in the 4-position.

Example 13

37.6 g of 1- (4-chlorophenyl) -1-cyclobutanecarbonitrile f prepared in a manner analogous to that described in Example 1 for the preparation of 1- (3,4-dichlorophenyl) -1-cyclobutanecarbonitrile] was added to a solution of 32.4 g of hydroxide Potassium chloride in 370 ml diethylene glycol was added and the mixture was heated under reflux for 3.5 hours.

The reaction mixture was poured into ice-water, the solution was washed with ether and the aqueous layer was added to a mixture of 100 ml of concentrated hydrochloric acid and ice. The precipitated 1- (4-chlorophenyl) -1-cyclobutanecarboxylic acid is filtered off and dried after washing with water. The product melts at 86-88 ° C.

A solution of 10.5 g of the above acid in 150 ml of tetrahydrofuran was added dropwise to a stirred suspension of 2 g of lithium aluminum hydride in 150 ml of tetrahydrofuran under nitrogen. After stirring at reflux for 2 hours, water was added, the resulting mixture was filtered through diatomaceous earth and the product was extracted with ether.

After washing with water and drying, the ether is evaporated and the residue is recrystallized from petroleum ether (b.p. 60-80 ° C). 1- [1- (4-chlorophenyl) cyclobutyl] methyl alcohol, m.p. 60-62 ° C.

A solution of 60 g of the above alcohol in 52 ml of pyridine is added dropwise to a solution of 60 g of p-toluenesulfonyl chloride in 100 ml of ice-cooled pyridine. The mixture was allowed to warm to room temperature and maintained at this temperature for 18 hours. The reaction mixture was poured over a mixture of ice and 200 ml of concentrated hydrochloric acid to precipitate 1- [1- (4-chlorophenyl) cyclobutyl] methyl p-toluenesulfonate, m.p. 99-100 ° C.

A solution of 97 g of the above sulfonate and 16.6 g of sodium cyanide in 370 ml of dimethyl sulfoxide was heated on a steam bath for 18 hours. The mixture was poured into water and extracted with ether. The extract was washed, dried and the ether was evaporated. 2- [1- (4-Chloro-phenyl) -cyclobutyl] -acetonitrile, m.p. 63-65 ° C, was obtained as a solid residue.

A solution of 30 g of 2-L1- (4-chlorophenyl) cyclobutyl] acetonitrile, prepared as described above, in 100 ml of ether is 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 to reflux for 4 hours, then ice and 105 ml of concentrated hydrochloric acid were added thereto, and the resulting mixture was heated to reflux until all solid material had dissolved.

The aqueous layer was washed with ether and the ether used for washing was combined with the ether phase of the reaction mixture. The combined ether phases were washed with water and evaporated to dryness. The residue gave 1- [1- (4-chlorophenyl) cyclobutyl] propan-2-one by distillation, b.p.

5.4 g of the above ketone are mixed with 18 ml of N-methylformamide, 4 ml of 98% formic acid and 0.6 ml of 25% aqueous methylamine, and the mixture is heated under reflux for 16 hours. The resulting mixture was poured into water and drawn with dichloromethane. The extract was washed, dried and evaporated. ,

The residue is refluxed for 6 hours with 10 ml of concentrated hydrochloric acid, the mixture is evaporated to dryness and the residue is dried by repeatedly adding a mixture of denatured ethanol and toluene, followed by evaporation under vacuum. The solid residue was recrystallised from propan-2-ol N-methyl-2- [l- (4-chlorophenyl) -1-cyklobutylj methylethylamťn hydrochloride qt l _ep I _{of n} th s 193,194 ^t e ^pl OTE ^{th nus 193} up to ¹⁹⁴ ° C,

R 8 represents hydrogen atoms, R 8 represents a methyl group at the 4-position.

corresponding to the general formula. And, ^{in some} MŽ ^n, m ^{and h} o ^d note 1, R and ^R 4 represents chlorine Rg XAMPLES 14

To 12 ml of formamide at 160 ° C was added dropwise a mixture of 15 ^p -propan-2-one, prepared as described in Example 13 and ^T e ^pl of ^T is ^increased, Even at ¹⁸⁰ ° C and ^tet him ^d No ^Te is u ^d R ^z u is ¹⁰ hocUn. The reaction mixture was cooled ^, diluted with water and extracted with dichloromethane.

1 ^{- [1-} (4-c ^h lorfen ^yl) C ^YKL OBu ^yl] ml of 98% formic acid.

The extract was washed, dried and evaporated to a yellow oily residue which was hydrolyzed under reflux with concentrated hydrochloric acid. After diluting with water, the solution was washed with ether, aqueous sodium hydroxide solution was added thereto, and the aqueous mixture was extracted with ether. The extracts were washed and evaporated to dryness. The residue 2- ^F l- ^{(4-chloro- phenyl l)} cyclohexyl ^l of ^{Butyl j-} l ^- ylethyl ^{h meth} y ^l am ⁱ n, boiling ^{at 05} to I I0 distilled to ⁷ ° C / 93 mbar.

2.65 g of the above amine are dissolved in 15 ml of 2-propanol and concentrated hydrochloric acid is added to the solution until pH 2. After addition of 110 ml of ether, crystalline 2- [1- (4-chloroethyl) cyclobutyl] -1- methy1eth amin-h ^y 1 ^y 1 droch1orid a temperature ^{from 184} to ¹⁸⁵ ° C by ^dp mar gin o ^{s s} o ^b ecnému ^Formula II, ^{in some} MŽ nM ^{and h} odnotu Rg, ^{Rg, R4} and Rg are hydrogen and R4 is a chlorine atom in the 4-position.

Example 15 l mp adds colorless ⁶⁰ ° ^{C was added 25} gl ^- [l- ^{(4-c hl} or ^F et ^yl) c ^b u ^{y k} lo ^the l] ^p ro ^p anv Example 13 and 10 ml of 98% formic acid. Temperature

¹ to ²² п Forman-ai ^at rt ^{t h} e ^{pl of}

-2-one prepared as described ^and the mixture is increased to ¹⁷⁵ ° C and ^tet on you ^do is ^f U is kept to him ^di n. ^D reaction with ^j ^ EC was cooled and extracted with dichloromethane, the extract was washed with water and evaporated to gum, ^the esters of ^{p to} r ^y s ^t, and ^{if i} zac etro from ^{p l} e ^t heru (te ^pl OTA boiling point ^40-60 ° C), ^P os tne ^alkyl ^^^^ - 2 - ^ .- (4o ^pl te ^s counting on ^{you 71} and ^{from 73} ° C.

11.06 g of N-formyl-2-FL- (4-chlorophenyl) c klobutyl ^yl] -1-methylethylamine prepared above reflux with a mixture of 34 ml koncentrodiethylenglykoldimethyletheru.

as above, heated to boiling under ml of water for 6 hours, washed with ether and extracted with ether (40 ml), washed with water, dried

The reaction mixture was cooled, sodium. Made alkaline solution and ^dp Ari. Zb ^yt e ^Kp axis ^alkyl no ^{d il} est AC ^{and 2} - ^[l- (4-chloro- ^phenoxy-yl) cyJklobutylT-L-Thy rnethy ^ ^ ^ lai boiling n ^{s at 119} 1 ² 1 ° ^{C /} 1 ° ⁷ and ^{p. 2.65} g of this ^{t h} a ^p AMM extended breath ^{as well as} in 15 п ^{1 2-p} ro ^p yes u ^{l to the} solution was added concentrated hydrochloric acid until - 2 pH.

and basified with aqueous hydroxide

After the ^{plated at} d ^{1 110} m of ether ZIS ^{ka k} r ^y hundred ^if c ^{is c 2} - [l- ^(4-ethyl-1 or ^{F 1)} c ^YK1 OBu ^y 1] - ^{1 -methyl-1} ^^ e am ^ -h ^ ^ Roch TAD q ^{t pl} e of th ^{e I t 184} to ¹⁸⁵ ° C by ^p s ^i, and ^ID and the formula 'I wherein n is 1, R4, Rg, R4 and Rg each represent a hydrogen and R4 represents a chlorine atom at the 4-position.

Example 16 ^1.8 g (4-chlorfenyIJcyklobutylJ L-methylethylarninu, prepared according to Example 15 were mixed with 4.5 ml of formic acid, 6 ml of 37-40% vrdnéhr frztrku fofma ^ Formaldehyde and the mixture was ^HRI in ^{best P} PVP ³⁰ m ^and the nut ⁴ to 5 to 50 ° C and then for 2 proud ^NY VA ^FU fart reflux.

The resulting mixture was cooled, basified with a heartbreak of potassium hydroxide, extracted with ether, the ethereal extract was washed with water, and extracted with 5N HCl. The acidic extract was washed with ether, basified with aqueous hydroxide solution and extracted with ether.

Hydrogen chloride gas was introduced into the ether, and the precipitated solid material was filtered off and recrystallized from ethyl acetate. To give N-cdimethylc-cLl- cchlrrfenylCcyklrc ^{-but-l-yl c c} Me et ^{hyl methyl} am ⁱ n ^chyd Foch ^{Rf even} the ^PL CT ^of T ^ck l ⁰ И0 to 8 ° C, rd ^P r ^{í í} Daj c ^{í é} rbecn him vzcrci I wherein n is 1, R and R are hydrogen, R and R are methyl groups and R represents a chlorine atom in position 4th

Claims (2)

A process for the preparation of (1-arylcyclobutylCalkylamines of Formula I wherein: CHR ₁ (CHCH p _n NR ₃ R 4 (I) is 0 or 1, ^R 1 when n is 0 is straight or branched (C 1 -C 6) alkyl, (C 3 -C 7) cycloalkyl, or ^R @ 3 is hydrogen, methyl, ethyl or isopropyl ether, ^R @ 4 is hydrogen or methyl ^R @ 5 ^{and R} @ 3 is hydrogen, methyl, ethyl, phenyl, phenyl and phenyl ^; 6 ', which may be the same or different, each represent a hydrogen atom, a halogen atom, a trifluoromethyl group, a methyl group, a methoxy group or a phenyl group, or R 8 and R 8 together with the carbon atom to which they are attached form a second benzene ring optionally substituted by a chlorine atom, characterized in that it is subjected to reductive amidation by treatment with an amide of the formula HCQNHRj where Rr is as defined above, and formic ketones of the formula Va (CHR 1) COR 'm (Va) wherein ^R 1' Rg and Rg are as defined above, and either m is 0 and R 'is as defined above for Rg, to give the compounds of formula O below, and R1, Rg, Rg and Rg are as defined above. of which IA wherein n case has a value or m has a value of 1 and R 'is a methyl group, in which case compounds of formula I are formed in which: Rj. and R 8 are as defined above. n is 1, and Rg, Rg, to form compounds of formula IA ^R 3 CHR, (CHCHJ N 3 n CHO (IA) of the corresponding compounds: ₄ represents a hydrogen atom, whereupon optionally those compounds of formula (g) and (Rg) to form compounds of formula (IA) are then hydrolyzed to give formula (I) wherein R is in which R is a form. are converted by reaction with formaldehyde and acidic formula I, in which Rg and Rg are methyl 1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine, in which m has the value 0, R R is an isobutyl group, R $ represents a chlorine atom in the 4-position and Rg represents a hydrogen atom, reacted with formamide and with formic acid to form a compound of formula IA wherein n is 0 and R = isobutyl, Rg is hydrogen, Rg and Rg are as defined above, and the compound of formula IA is then hydrolyzed with acid. 2. uso ^{P b} wherein