CS271341B2 - Method of n-/4-fluorphenyl/-1-methyl/ethyl-n-methyl-n-propinylamine production - Google Patents

Abstract

The compounds of the formula I in the form of race mate or optically active isomers, as well as its addition of salt with acids are prepared in such a way that the compound of the formula IX, where R<2> stands for fluorine, nitro group or amino group, R<4> stands for hydrogen or propynyl, and R<5> stands for hydrogen or methyl, in the form of race mate or optically active isomers, if R<2> has a different meaning than the atom of fluorine, R<2> is carried over into the atom of fluorine by the contingent reduction of nitro group to amino group, by diazotation to fluoroborate aggregation at presence of fluoroboric acid and by modification of diazonium fluoroborate by means of heating to a temperature of 70 to 90 degrees C to the atom of fluorine. As a consequence, if the substituents R<4> and/or R<5> mean the atom of hydrogen, the acquired compounds change by means of alkylation into the compound of the formula I and thus the acquired compound of the formula I contingently splits into optically active isomers or it can be carried over into the addition of salt with acid. The produced compounds are effective as selective inhibitors of monoamine oxidase-B and are used in pharmaceutics.<IMAGE>

Description

(57) Compounds of formula I in the form of a racemate or optically active isomers, as well as acid addition salts of a compound of formula I, are prepared by preparing a compound of formula IX in which R 2 is fluoro, nitro or amino; RP is hydrogen or methyl, in racemic form or in the form of optically active isomers when R ² is other than fluoro, converting R ^2, a fluorine atom optionally reducing the nitro group, diazotization to fluoroborate cluster in the presence of fluoroboric acid and converting diazoniumfluoroborátu heating to a temperature of 70 to 90 ° C to a fluorine atom, whereupon the compound thus obtained is isolated and optionally resolved into the optically active isomers, then optionally if the substituents r 4 and / or R 1 are hydrogen, by converting the obtained compounds by alkylation to a compound of formula I and the compound thus obtained is optionally it is resolved into the optically active isomers or is optionally converted into an acid addition salt. The compound produced serves as a selective monoamine oxidase-B inhibitor and is used as a medicament.

'0

The present invention relates to a process for the preparation of N - [2- (4'-fluorophenyl) -1-methyl] ethyl-N-methyl-N-propynylamine which is primarily active as a selective monoamine oxidase-B (MAO-B) inhibitor, it is therefore an inhibition of the uptake of biogenic amines and pyramines in the body.

U.S. Pat. Nos. 154,060 and 154,655 disclose processes for the preparation of phenyl8-propylamine derivatives and related optically active substances which, as disclosed in particular in U.S. Pat. soothing agents, pain threshold agents and weight loss aids, while U.S. Patent No. 154,655 describes the monoamine oxidase inhibitory activity of optically active agents of this type.

The present invention provides a process for the preparation of N- [2- (4-fluorophenyl) -1-methyl] ethyl-N-methyl-N-propynylamine (I).

CBL CH ₃ liters

CH ₂ - CH - X - - CH

?

in the form of the racemate or optically active isomers, and their acid addition salts, characterized in that the compound of the formula (IX)

in which

is fluorine, nitro or amino, is hydrogen or propynyl; and

is hydrogen or methyl, in racemic form or in the form of optically active isomers when R ² is other than a fluorine atom, converting R ^2, a fluorine atom optionally reducing the nitro group to aminoskuCS 271 341 B2 pin diazotisation on fluoroborate cluster in the presence of fluoroboric acid and converting the diazonium fluoroborate by heating to 70 to 90 ° C to a fluorine atom, whereupon the compound thus obtained is optionally isolated and optionally resolved into the optically active 45 isomers, then optionally, if the substituents R and / or R represent a hydrogen atom, the compound obtained by alkylation to a compound of formula I and the compound thus obtained is optionally resolved into the optically active isomers or is optionally converted into an acid addition salt.

In the case where an amine of the general formula IX in which:

4/5

R @ 1 and R @ 2 are as defined above and R @ 4 is hydrogen, the amine of formula IX is reacted with an inorganic acid or an organic sulfonic acid methyl ester or a mixture of formaldehyde and formic acid to introduce a methyl group.

Dimethyl sulphate, methyl halide, trimethyl phosphate or methylsulphuric acid is preferably used for methylation.

When starting from an amine of formula (IX) in which R and R are as defined above and R1 is hydrogen, the amine of formula (IX) is reacted with propynyl halide, propynyl sulfonic acid ester or a mixture of formaldehyde and acetylene. The propylation is also preferably carried out via the corresponding halopropyl and halopropenyl derivatives.

Preferably, the process of the invention comprises reacting an amine of formula X

in which

R is as defined above, or an amine of formula XII CH ₃

CH.

I №

(XII) in which

As defined above, and a 1,2-dibromopropene derivative, the 2-bromopropenyl derivative obtained is converted by heating to 80-110 ° C or by treatment with a base to give the desired propynyl derivative of the formula I.

The compound of formula I and its optical isomers and salts are excellent monoamine oxidase inhibitors according to the results of various experiments. They selectively block MAO-B. They also have a long-lasting aphrodisiac effect. These substances also have very low toxicity. Significantly, in addition to these types of activity, these agents generally inhibit the uptake of biogenic amines as well as tyramine.

In view of the above properties, the compounds produced by the method of the invention are particularly suitable for the treatment of the elderly. In a more advanced age, administration of the compounds of formula I can improve general well-being, in particular mood, sexual activity, and motor system changes can be inhibited by continuous administration of these compounds to improve the general well-being of older people. These appear to be substances that counteract the decrease in dopamine concentration in the brain, which continues with age. It allows for better brain function without affecting the postsynaptic dopamine receptors, moreover, a substance of this type remains effective for many years of administration and has no or almost no adverse side effects.

Unless emphasized to be a particular isomer or salt, all isomers and salts of the compound of formula I are meant throughout the application.

The invention is based on the recognition that, in a group of compounds classified as N-alkyl-N-phenylakylamines, the position of the substituents on the phenyl moiety and the position of these substituents on the molecule affect the extent that efficacy cannot be generalized for the whole group.

Thus, the particular biological activity that could be demonstrated for the compounds produced by the process of the invention could not be ascribed or expected on the basis of the previously known compounds, since this is an effect that has been found only with some particular derivatives.

The process of the invention involves the preparation of a compound of formula I in both racemic and optically active form. Optically homogeneous antipodes can be prepared by resolution at any stage of the synthesis. The separation can be carried out at an early stage on the starting material. In this case, a left-handed or right-handed starting material is used for the synthesis.

Alternatively, the compound of formula I may be separated. The reaction may be carried out in a manner known per se by forming a diastereomeric salt pair using a suitable optically active acid, for example tartaric acid or dibenzoyltartaric acid.

The oily, fat-soluble compounds produced by the process of the present invention can be converted to water-soluble salts or the free material can be liberated from its salts. Salts with hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, formic, maleic, tartaric, lactic, 3,5-dinitrobenzoic, citric or oxalic acids can be prepared. Biologically inert or acceptable salts or free substances are suitable for use in medicine.

The compounds of formula (I) produced by the process of the present invention can be formulated into pharmaceutical compositions containing the active ingredients.

These pharmaceutical compositions may be prepared in a known manner such as tablets, dragees, suppositories, capsules, solutions, emulsions, injectables, together with conventional additives, carriers, glidants and fillers.

Some of the starting materials, in particular fluorinated derivatives, have not been known in the literature and therefore the preparation of these compounds will be described at least briefly in the example section of the application.

Pharmaceutical compositions containing the compounds of the present invention may be administered to geriatric initiators at a dose of 1-5 mg as an antidepressant at a dose of 20 to 50 mg, as an anti-Parkinson's drug at a dose of 5 to 10 mg per day.

The invention will be illustrated by the following examples:

Example 1

8.28 g (0.0495 mol) of (+) - N-methyl- [2- (4-fluorophenyl) -1-methyl] thylamine, prepared according to the method of J. Am. Chem. Soc. 68, 1009-1011 is dissolved in 45 ml of toluene. To this solution is added 0.078 g of benzyltriethylammonium chloride and, in parallel with 6.48 g (0.0545 mol) of propargyl bromide, a solution of 2.17 g (0.0543 mol) of sodium hydroxide in 7 ml. 5 ml of water dropwise with stirring over 5 minutes. The temperature of the reaction mixture rose from 23 to 26 ° C. The reaction mixture was stirred at 26 to 28 ° C for 20 hours. The two phases were separated, the toluene layer was dried over anhydrous sodium sulfate and then evaporated. The residue is distilled at 80-82 ° C and at a pressure of 13 Pa. This yields 5.05 of the resultant (+) - N-methyl-N-propynyl- [2- (4-fluorophenyl) -1-methyl] / ethylamine.

Пд ° = 1.5050.

The melting point of the hydrochloride is 132-133 ° C after recrystallization from ethanol and ether.

H, 7.09; N, 5.79; Cl, 13.66; F, 7.85. Found: C, 65.00; H, N, 5.95; Cl, 14.90; F, 8.01.

Example 2

3.38 g (0.022 mol) of (+) - N-methyl- [2- (4-fluorophenyl) -1-methyl] ethylamine are dissolved in 35 ml of acetone, then 19 g (0.14 mol) of potassium carbonate are added. and then dropwise 2.95 g (0.025 mol) of distilled propargyl bromide with stirring over 10 minutes. The temperature of the reaction mixture rose from 22 to 25 ° C. The reaction mixture was then heated at 55 ° C for 3.5 hours with stirring. Finally, the reaction mixture is left to stand overnight, filtered, washed three times with 25 ml of acetone and the filtrates of the acetone extracts are evaporated. The residue is distilled at a pressure of 266 Pa. In this way, the yield is

51.7% yields 2.28 g of (+) - N-methyl-N-propynyl / 2- (4-fluorophenyl) -1-methyl / ethylamine, b.p. 120-122 ° C at 1 mm Hg.

n * ⁰ = 1.5050.

Example 3

Dissolve 30.97 g (0.197 mol) of (+) - N-methyl- [2- (4-fluorophenyl) -1-methyl] ethylamine in 310 ml of acetone, then add 174.5 g (1.26 mol) potassium carbonate and a 68% solution of propargyl bromide toluene (39.7 g, 0.227 mol) dropwise from constant stirring over 20 minutes. The temperature of the reaction mixture rose from 26 to 40 ° C. The reaction mixture was stirred at 55 ° C for 6.5 hours, washed with acetone, and the acetone extract filtrate was evaporated. The residue was distilled at 1 mm Hg. 16.25 g of (+) - N-methyl-N-propynyl- [2- (4-fluorophenyl) -1-methyl] ethylamine (b.p. 90 DEG-92 DEG C.) are obtained in a yield of 41.2%.

Example 4

7.4 g (0.0443 mol) of (-) - N-methyl- [2- (4-fluorophenyl) -1-methyl] ethylamine and dissolved in ethanol with optical rotation (d) = -3.44 DEG in ethanol in 60 ml of acetone, ae 28.9 g (0.21 mol) of potassium carbonate and then a 60% solution of propargyl bromide in toluene (7.55 g, 0.045 mol) are added dropwise with stirring. The reaction mixture was stirred for 3 to 4 hours at 35-40 ° C, filtered, washed with acetone and the acetone extract filtrate was evaporated. The residue obtained is distilled at 1 mmHg. This way ве gains

3.3 g of (-) - N-methyl-N-propynyl- [2- (4-fluorophenyl) -1-methyl] ethylamine, b.p. The hydrochloride melts at 169-171 ° C. [.alpha.] _D @ ²⁰ = -6.2 DEG from ethanol, c = 2.4, [.alpha.] _D @ ²⁰ = -10.96 DEG from water, c = 2.9.

Example 5

An aqueous solution of 10 g (0.028 mol) of (-) - N-methyl- [2- (4-fluorophenyl) -1-methyl] ethylamine in the form of (+) - tartrate dihydrate, m.p. 88 DEG-91 DEG C. is applied by addition of 40%. aqueous sodium hydroxide solution to pH 12-13. The solution was then extracted with dichloromethane and the dichloromethane extract obtained was dried over sodium sulfate.

To the above solution was added 22.5 g (0.16 mol) of potassium carbonate and then dropwise 5.96 g of propargyl bromide in toluene as a 60% solution. The reaction mixture was stirred at room temperature for 5 hours, filtered, and the filtrate was extracted four times with 25 ml of 20% acetic acid each and then four times with 25 ml of 10% hydrochloric acid each. The extracts obtained with aqueous hydrochloric acid are basified by addition of 40% sodium hydroxide solution and then extracted with dichloromethane. The dichloromethane solution was dried and then hydrogen chloride gas was introduced. Addition of petroleum ether gave 2.38 g of (-) - N-methyl-N-propynyl- [2- (4-fluorophenyl) -1-methyl] ethylamine hydrochloride, m.p. 168-170 ° C. Optical rotation / Л / р ⁰ = -10.89 ° from water, c = 2.5. Yield 47.1%.

Example 6

From 10 g (0.028 mol) of (-) - N-methyl- [2- (4-fluorophenyl) -1-methyl / ethylamine - (+) - cartrate dihydrate the base was released as in Example 5 and the dichloromethane solution was evaporated. The residue is dissolved in 60 ml of acetone, 22.5 g (0.16 mol) of potassium carbonate are added, followed by dropwise addition of a 60% toluene solution containing 5 > 96 g of propargyl bromide. The reaction mixture was stirred at room temperature for 3 hours and then filtered and evaporated. The residue was dissolved in toluene and then extracted with 10% hydrochloric acid. The acidic aqueous extract is basified by addition of 40% aqueous sodium hydroxide solution to pH 12-13 and then extracted with toluene. The toluene solution was dried and acidified to pH 3 with 31 Я ethanolic hydrogen chloride solution. The precipitated crystalline product was collected by filtration, washed with cold acetone and then dried. 2.05 g of product identical to that obtained in Example 5 were obtained. Yield 40.6

EXAMPLE 7 10 g (0.028 mol) of (-) - N-methyl- [2- (4-fluorophenyl) -1-methyl] ethylamine (+) tartrate dihydrate according to Example 5 is added a solution of 7.5 g of sodium hydroxide in 25 mol water and 17 ml of toluene. The mixture was stirred for 30 minutes. The two phases are separated and the aqueous phase is extracted three times with 6 ml of toluene each.

The toluene solution thus obtained was added to a solution of 1.37 g of sodium hydroxide, 0.04 g of benzyltriethylammonium chloride and 5 ml of water. 4.1 g of propargyl bromide are added dropwise thereto, and the reaction mixture is then stirred for 15 hours at room temperature. The phases are separated, the toluene layer is extracted twice with 7 ml of 5% acetic acid and then twice with 10 ml of 10% each. hydrochloric acid · The acidic aqueous extract is basified by addition of 40% aqueous sodium hydroxide solution and then extracted with toluene. The toluene solution was dried and then acidified to pH 3 by addition of 31% ethanolic hydrogen chloride solution. The crystalline product is collected by filtration, washed with cold acetone and dried. In this way, 2.72 g of a product identical to the final product prepared by the method of Example 5 are obtained.

Example 8

The base was released from 10 g (0.028 mol) of (-) - N-methyl- [2- (4-fluorophenyl) -1-methyl] -ethylamine (+) tartrate dihydrate as described in Example 7. 24 was added to the dried toluene solution. 7 g (0.17 mol) of potassium carbonate and then dropwise a 60% solution

3.66 g (0.03 mol) of propargyl bromide in toluene. The reaction mixture is stirred at room temperature and then filtered. The toluene filtrate is extracted twice with 7 ml of 5% acetic acid each and then twice with 10 ml of 10% hydrochloric acid each. The acidic aqueous extract was treated as described in Example 7 to give 2.6 g of the title product, which was identical to the compound prepared as in Example 5.

Example 9

To a solution of 8,3 g (0,05 mol) of (+) - N-methyl- [2- (4-fluorophenyl) -1-methyl] ethylamine,

5.4 g (0.1 mol) of propargylaldehyde are added in one portion, and then 100 ml of 96% ethanol and 3 g of aluminum foil, activated with tin (II) chloride at 20-30 ° C are added in portions. The reaction mixture was stirred at room temperature for 24 hours, then filtered and the filtrate was evaporated. Evaporate. Dissolve in 10% hydrochloric acid, extract with benzene, basify by adding 40% aqueous sodium hydroxide solution and then extract again with benzene. The benzene solution was dried and evaporated. The residue is distilled under vacuum at 1 mmHg. 5.6 g of (+) - N-methyl-N-propynyl- [2- (4-fluorophenyl) -1-methyl] -ethylamine are obtained, b.p. 120-123 [deg.] C. at a pressure of 266 Pa. Melting point of the hydrochloride is 130 to 132 ° C.

Example 10

To a solution of 6.0 g (0.036 mol) of (+) - N-methyl- [2- (4-fluorophenyl) -1-methyl] ethylamine and 60 ml of acetone was added 33.6 g (0.24 mol) of potassium carbonate and then 7.45 g (0.037 mole) of 2,3-dibromopropene dropwise at 25-30 ° C with stirring for 20-25 minutes. The reaction mixture is heated at reflux for 6 hours and then refluxed for 6 hours. filtered and evaporated. The residue is distilled under vacuum at a pressure of 520 to 650 Pa. This yields 6.52 g of (+) - N-methyl-N- (2-bromo-3-propenyl) - [2,4-fluorophenyl] -1- methyl / ethylamine, yield 63.3%. Boiling point 142-143 ° C, n * ° = 1.5234.

2.5 g of the above product are dissolved in 35 ml of ethanol and then 5 ml of 50% potassium hydroxide solution are added. The reaction mixture was heated at reflux for 16 hours and then evaporated. The residue was dissolved in water and the solution was extracted with benzene. The benzene solution is acidified with ethanolic hydrogen chloride solution. The precipitated product was collected by filtration and dried. 2.2 g of (+) N-methyl-N-propynyl / 2- (4-fluorophenyl) -1-methyl] ethylamine hydrochloride are obtained, m.p. 131 DEG-123 DEG.

271341 В2

Pharmacological tests

The following abbreviations will be used for active substances during the Individual Test:

IA =; +) - N-methyl-N - (2-propynyl) -2- (4-fluorophenyl) -1-methyl / ethylamine hydrochloride

IB = (-) - N-methyl-N - [(2-propynyl) -2- (4-fluorophenyl) -1-ethyl / ethylamine] hydrochloride pCIP = (+) - N-methyl-N - / (2-propynyl) ) -2- (4-Chlorophenyl) -1-methyl-ethylamine hydrochloride pBrP = (+) - N-methyl-N - / (2-propynyl) -2- (4-bromophenyl) -1-methyl / ethylamine hydrochloride

1. Monoaminooxydesis Inhibitory Activity (МАО)

1.1. In vitro experiments

1.1.1. Measurement on a Rat-Free, Nuclear-Free Rat Brain and Kidney Homogenate The Biochem method is used. Pharmacol. 1963, 12, 1417 and 1978, 27, 1939 Substrates;

MAO-B: CC-EA: 0.2 mM, specific activity 0.5 µCi / ml, MAO-A: С ⁴ С-5NT: 5.0 mM, specific activity 0.25 µCi / ml.

organ IB IA pClr pBrP T n ~ 50 brain 4.57x10 ⁸ 4.17x10 ” ⁸ 1,48x10 ”” 3.98x10 ” ⁷ MAO-B Liver l, 98xl0 ^-8 1, 19x10 ^S 1 x 10 ” ⁷ 1.64x10 ⁷ (M) selective index Liver 238.38 580.67 43.47 5.28

selective qMAO IC-A subscript "-------- IC _r MAO-B

Measurement on rat brain mitochondria

Method: Mitochrondria are prepared from the brains of male CFY rats weighing 200-250 6 as follows: After decapitation, tissue homogenate is prepared in 0.25M sucrose. The homogenate is centrifuged for 10 minutes at 1000 g and the supernatant is again centrifuged for 15 minutes at 9000 g, the sediment is mixed with 0.25M sucrose.

Substrates:

MAO-A: 6x10 ^{4 I} 5HT

MAO-B: 2x10 ⁵ M PEA

СЗ 271341 31

Results:

IC ^ q values for compound ХА

МАО-A 5хЮ ' ⁵

МАО-В: ЗхЮ ' ⁸

1.2. In vivo experiments using nuclear-free rat brain and rat liver homogenates

Method: Rats were dosed subcutaneously with a different dose of the test substance and the organs were removed four hours after administration, and the MAA activity was measured as described in paragraph 1.1.1.

The results are shown in the following table:

organ IB XA pBrP ^ID 50 brain 0.104 0,076 5.61 MAO-B liver 0,772 0.292 8.85 (mg / kg? selective index liver 148.8 168.6 13.33

selective ΙΌ МАО-A index ~ ---- ТП

After administration for 21 days at a daily dose of 0.2p mg / kg of compound Ia, the inhibition of MAO-B 9 was 2 to 94% expressed in control and the inhibition of MAO-A was 0

2. Inhibitory activity on tyramine uptake in the pulmonary artery of a rabbit of both sexes weighing 2-4 kg was sacrificed by a blow to the neck and immediately thereafter the heart was removed and placed in an oxygen-supplied Krebs solution. The composition of the Krebe solution was as follows (mmol / liter): sodium chloride 111, potassium chloride 4.7, calcium chloride 2.52, magnesium sulfate 1.64, sodium bicarbonate 25, potassium dihydrogen carbonate 1.2 glucose 11. The vessel was cleaned of connective tissue tissue and a 1.5 mm spiral was excised. The vessel segment thus obtained was placed in a 5 ml organ bath containing Krebs solution, a gas mixture of 95% oxygen and 5% carbon dioxide was bubbled through the bath, maintaining the bath temperature at 37 ° C. Activity was recorded by a semi-isometric compensator using a 1 g bias.

Tyramine uptake was inhibited on the above formulation by Compound 1B in a dose-dependent manner. IC ^ q = 5.4 x 10 &quot; M.

3. Biogenic amino acid uptake (method: J. Pharm. Exp. Ther. (1969) 165, 78-36)

1 and tka concentration weighing substances (M) region IA IC. _A FIRST 9 O · EA 5xl0 ⁸ hypothalarnus Bx10 ⁶ 5HT 1x10 ^-7 hypocampus 6; <1C * ⁴ BYE 1x10 ^-7 atriatum 2xl0 ⁷

NA: 1H-noradrenaline

5HT: 1H-5-hydroxytryptamine

DA: 1H-dopamine

4. Stimulation of in vivo activity of external phenethylamine (PEA) (MAO-B)

4.1. Stimulating efficacy on membrane nictitating? on an anesthetized cat

The nictitating membrane contracts after intravenous administration in dependence of aa PEA. The dose-response curves of PEA are shifted to the left after intravenous administration of compound IA at a dose of 0.1 or 0.25 tng / kg.

4.2. Increase in stereotyped behavior induced by PEA

Method: Arzneimittel Porsch. (Drug Research) 22, 1178 (1972).

The results are shown in the following table:

compound mg / kg max.acore total acore control - 0.5 + 0.22 1, 1710, 54 IA 0.25 2.17 + 0.31 8.17 + 0.87 0.1 1.67 + 0.21 5.67 + 0.49 0.05 1.0 + 0.37 2.83 ^ 1.01

The efficacy of PEA at a dose of 40 mg / kg is potentiated by Compound IA in a 0.05 to 60 mg bridge

0.25 µg / kg subcutaneously depending on dose height.

5. Experiments with the central nervous system

5.1. Modified plate test

Compound IA did not inhibit the defense reflexes in the rat at a dose of 15 mg / kg (Knoll 1963 method).

5.2. Metabolic test

Compound IA at 5 mg / kg did not increase rat metabolism (Issekutz method 1942).

5.3. Effectiveness on food intake

The experiment was performed after 96 hours of fasting on groups of 10 to 13 rats. Compound IA, when administered subcutaneously at a dose of 5 mgAg, reduced food intake statistically significantly predominantly in the first hour after dosing, and at higher doses of 10 to 15 mg / kg subcutaneously, there was a statistically significant decrease in food intake.

5.4. Effect on catalepsy

Catatonia induced by a dose of 3 mg / kg tetrabenzine was inhibited in a dose-dependent manner by compounds IA and IB.

^ed 5o ' ^{ia = 2} > ^{* * 5 6}

ED-q-IB = 2.9 mg / kg.

СЗ 271341 Б2

6, Effect on sexual activity in male rats

In male rats, compound IA was a potent, long-lasting stimulant. After a single dose of 0.1 mg / kg and 0.25 mg / kg, the compound significantly increased ejaculation at 24 hours, 2-3 weeks and 4 weeks post-dosing compared to control animals. . Thus, the aphrodisiac effect of this compound has been demonstrated in the method described in Medical Science 33, 179-180 (1982).

7. Toxicity

The tests were performed on both white male and female CPI rats weighing

100-120 g. The compounds were administered intravenously, the animals were observed for 48 hours.

The results are shown in the following table.

IA IB pCIP

LD ₅₀ 60 64 35 mg / kg

Pharmaceutical preparations

Example A

The following ingredients are mixed:

g (+) - N-methyl-N-propargyl- [2- (4-fluorophenyl) -1-methyl] ethylamine hydrochloride g talc g magnesium stearate g polyvinylpyrrolidone g corn starch

170 g lactose

The ingredients are homogenized and 1000 tablets are compressed from the mixture obtained.

Example В

The following ingredients are mixed:

110 g of (-) - N-methyl-N-propargyl- [2- (4-fluorophenyl) -1-methyl) ethylamine hydrochloride g talc g magnesium stearate g polyvinylpyrrolidone

100 g potato starch

150 g lactose

All ingredients are mixed thoroughly and the mixture is compressed to 1000 tablets.

The invention will be further elucidated by further examples of the manufacture of active ingredients.

Example 11

16.7 g of (+) - N-methyl- (2- (4-fluorophenyl) -1-methyl) ethylamine are dissolved in 150 ml of acetone and 69.2 g of sodium carbonate are added with stirring. Then add yet

13.3 g of allyl bromide are added and the reaction mixture is refluxed for 8 hours and then filtered. The filtrate was evaporated and allowed to distill under vacuum. 15.2 g of (+) - N-methyl-N- (2-propenyl) - [2- (4-fluorophenyl) -1-methyl] ethylamine are obtained. This product was dissolved in 100 mL of carbon tetrachloride and 11.8 g of bromine was added dropwise. After stirring for an additional 8 hours, the solution was evaporated and the residue was dissolved in 400 ml of ethanol. 100 ml of 50% strength aqueous sodium hydroxide solution were added and the reaction mixture was heated under reflux for 20 hours. After the ethanol was evaporated, water was added and the mixture was extracted with benzene. The benzene solution was extracted with 2N hydrochloric acid and, after addition of sodium hydroxide and benzene extraction, repeated. The benzene extract was dried over sodium sulfate, filtered and evaporated. The residue was distilled under vacuum to give 5.6 g of (+) - N-methyl-N- (2-propynyl) - [2- (4-fluorophenyl) -1-methyl] ethylamine. Boiling point 90-93 ° C at 80 Pa.

Example 12

A solution of 8.2 g (0.05 mol) of (+) - N-methyl-2- (4-aminophenyl) -1-methylethylamine (Hungarian Patent Specification 154 060) to 30 ml of 56% fluoroboric acid and 3.5 g (0.051 mol) of sodium nitrite in 25 ml of water is simultaneously added dropwise to 100 ml of 56% fluoroboric acid while stirring and cooling to -5 to -7 ° C so that a small excess of the nitrile solution is always present in the reaction mixture during the addition. The mixture is then stirred for an additional 30 minutes at -5 to -7 ° C, while 2.5 g of freshly prepared cuprous chloride is added in small portions. The mixture was stirred at room temperature for 2 hours and then at 80-90 ° C for a further 2 hours. The mixture was cooled, extracted with ether and the acidic aqueous layer was basified by addition of concentrated ammonium hydroxide and then extracted with benzene. After drying, the benzene extract was evaporated and the residue was extracted at 1330 Pa. 5.6 g of (+) - N-methyl-2- (4-fluorophenyl) -1-methylethylamine having a boiling point of 87-90 [deg.] C., at a pressure of 1330 Pa are obtained as the main fraction. This compound is reacted with propargyl bromide as described in Example 2, and the resulting reaction mixture is further treated as in Example 2. 3.8 g of (+) - N-methyl-N-propynyl-2- are obtained. (4-fluorophenyl) -1-methylethylamine, b.p. 120-123 ° C at 1 mm Hg. · N £ ^u = 1.5054.

Example 13

To 7.65 g (0.05 mol) of (+) - 2- (4-fluorophenyl) -1-methylethylamine (Belgian patent 609 630) in 25 ml of benzene, 5.3 g (0.05 mol) were added. of distilled benzaldehyde and the solution obtained ee is left to stand overnight and then dried. 6.3 g (0.05 mol) of dimethyl sulphate are added to the dried solution, after which the mixture is refluxed for 3 hours, cooled with stirring, and then a solution of 2 ml of concentrated hydrochloric acid in 50 ml of water is added. The mixture was stirred for an hour, then the two layers were separated, the acidic aqueous layer was basified by addition of sodium hydroxide and then extracted with benzene. The benzene solution was dried and evaporated and the residue was distilled in vacuo. 4.15 g of b.p. 87 DEG-90 DEG C. at 1 mmHg are obtained. This was dissolved in 40 ml of toluene, 23.5 g (0.17 mol) of potassium carbonate was added, and then a solution of 3.65 g (0.031 mol) of propargyl bromide in 60% toluene was added dropwise and the mixture was stirred at room temperature for 14 hours. rooms. The mixture was filtered and the filtrate was acidified to pH 3 with ethanol containing 31% hydrochloric acid. The crystalline product was collected by filtration and recrystallized from ethanol-ether. 2.1 g of (+) - N-methyl-N-propynyl-2- (4-fluorophenyl) -1-methyl-1-ethylamine hydrochloride of melting point 130 DEG-132 DEG C. are obtained.

CS 271341 B2

Example 14 g (0.018 mol) of N-methyl-N-propynyl- [2- (4-nitrophenyl-1-methyl) ethylamine hydrochloride (m.p. 164-167 ° C) (prepared as described in Example 8 of U.S. Pat. No. 271342) was dissolved in a mixture of 10 ml of water and 3 ml of concentrated hydrochloric acid, and 4.7 g of zinc powder was added thereto, and the reaction mixture was stirred at 75 DEG C. for 2 hours. The organic layer was dried, filtered and evaporated to give 5 g of crude (+) - N-methyl-N-propynyl- [2- (4-aminophenyl) -1-methyl] ethylamine which diazotized in the environment fluoroboric acid, the diazonium fluoroborate thus obtained is quenched by the addition of cuprous chloride at 80 ° C (described in more detail in Example 12) to give (+) - N-methyl-N-propynyl / 2- (4-fluorophenyl) -1 The mixture was basified and extracted with benzene, and the organic layer was dried, filtered. The residue was distilled under reduced pressure to give 1.7 g of (+) - N -methyl-N-propynyl- [2- (4-fluorophenyl) -1-methyl] -ethylamine, b.p. 120-122. Deň: 32 ° C. n /> = 1.5054.

Claims (6)

A process for the preparation of N- (2- (4-fluorophenyl) -1-methyl) ethyl-N-methyl-N-propynylamine of formula I CH 2 CH ₃ in the form of the racemate or optically active isomers, as well as its acid addition salts, characterized in that in a compound of the general formula (IX): R ² is fluorine, nitro or amino, r 4 is hydrogen or propynyl and R1 represents a hydrogen atom or a methyl group, in the form of a racemate or in the form of optically active isomers; a temperature of 70 to 90 ° C per fluorine, whereupon the compound thus obtained is isolated and optionally resolved into optically active isomers, then optionally, if the substituents and / or are hydrogen, the obtained compounds are alkylated to the compound of formula I and the compound thus obtained is optionally resolved into the optically active isomers or optionally converted to an acid addition salt. 2. The process of claim 1 wherein the amine of formula (IX): Wherein R and H are as defined in 1, and R ^y is hydrogen, reacted with an inorganic acid or an organic sulfonic acid methyl ester or formaldehyde and formic acid. 3. A process according to claim 2, wherein the methylation of the compound is carried out The formula (4) of formula (IX) in which R1 and R2 are as defined in (1) and R1 is hydrogen is carried out by treatment with dimethyl sulphate, methyl halide, trimethyl phosphate or methylsulphuric acid. 4. The process of claim 1 wherein the amine of formula (IX): Wherein R and R are as defined in 1 and R is hydrogen, reacted with propynyl halide, propynyl sulfonic acid ester or formaldehyde and acetylene. 5. Process according to claim 1, characterized in that the propynylation is carried out successively over the corresponding halopropyl and halopropenyl derivatives. 6. The process of claim 5, wherein the amine of formula (X) is reacted in which R is as defined in point 1, or an amine of formula XII (XII) wherein: R is as defined in point 1,