FI63227B - PROCEDURE FOR THE FRAMEWORK OF THERAPEUTIC NUTRITIONAL N- (2- (2-FURYL) -ETHYL) -AMINDERIVAT - Google Patents

Description

ΓΒ1 m, ADVERTISEMENT,? 9 9 n KU LbJ (11) UTLÄCCNINGSSKRIFT OOZZf 5¾¾ CM »Patent granted 10 05 1983 ^ Patent neddelat ^ ^ (51) K» .ik.3 / iot.a.3 C 07 D 307/52 | FINLAND — FINLAND (21) ρ »ν» «ιμιμιιιιι · —r * mm * kntot 763715 (22) Hakmitopaivi —AmBknlnpdag 28.12.76 (23) Alkupllv · —GIMsMtidic 28.12.76 (41) Tullut | utkiMk« l - Kiwis offanclig 30. 06. 77

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Patent- och registarttyraluen '' Anaeku utlagd odi utUkrtlUn public «r * d 31.01.83 (32) (33) (31) Pyy4« * Y etueUcuu * —Buglrd prtorkac 29.12.75

Hungary-Hungary (HU) CI-1632 (71) Chinoin Pharmaceuticals and Chemical Products Gyära RT., 1-5 To u.,

Budapest IV, Hungary-Hungary (HU) (72) Jozsef Knoll, Budapest, Zoltan Ecsery, Budapest, Judit Hermann nee Vörös, Budapest, Zoltan Török, Budapest, Fiva Somfai, Budapest, Gäbor Bernath, Szeged, Hungary-Hungary (HU) () Oy Kolster Ab (5 * 0 Process for the preparation of new therapeutically useful N- / 2- (2-furyl) -ethyl-7-amine derivatives etyl7-Ain-derivative of

The invention relates to a process for the preparation of novel therapeutically useful n- [2- (2-furyl) -ethyl] -amine derivatives and their pharmaceutically acceptable acid addition salts. The formula of the new compounds is r- ^ ^ 3

J 1 -CH 9 -CH-N-R 3 (I) 0-13 wherein R is hydrogen or methyl and R is bromopropenyl or propynyl.

The compounds of formula I and their acid addition salts can be prepared by a) an N- (2-furylethyl) amine derivative of the formula -R 1 CH

Il '

II U-CH 0 -CH-NH (II) CT * 2 63227 wherein Ra is as defined above is reacted with a compound. 3, wherein R is X -X (III) 3 wherein R is as defined above 3a X is halogen or a sulfonic acid ester group, or b) an N- (2-furylethyl) amine derivative of the formula 1--1 r1 ch3 IL}) - CH9-CH-NH (II) o having the same meaning as above is reacted with proparylaldehyde of the formula HC = C-CHO (IV) with reduction at the same time or after the reaction, or c) 2- a furyl derivative of the formula ___ R 1 I i II U - CH.-CO (VI) wherein R 1 is as defined above is reacted with an amine of the formula CH 2

I J

HN-R 3 (V) 3 wherein R is as defined above, reducing at the same time or after the reaction, or d) a 2-furylethyl derivative of the formula -R 1 and J-CH 2 -CH-X (VII)

O

wherein and X are as defined above are reacted with an amine of formula CHo

I J

HN-R 3 (V) 3 wherein R is as defined above, or e) an N- (2-furylethyl) amine derivative of the formula __ R 1 CHo I -! (R)) - CH2-CH-NH (II) o in which R1 is as defined above, is condensed with formaldehyde and acetylene and, if desired, obtained from a compound of formula I in which R is bromopropenyl is cleaved in a manner known per se from hydrogen bromide to give a compound of the formula I in which R is propynyl and / or the compound of the formula I obtained is converted into a pharmaceutically acceptable acid addition salt in a manner known per se.

Furylethylamines are known to have phenylethylamine-like pharmacological activity (J. Pharmacol., 72, 265 (1941)). The novel compounds of formula I do not have the undesirable "amphetamine" effect, but are capable of selectively inhibiting monoamine oxidase. Some known compounds, which differ in chemical structure from the compounds now described, have been reported to have selective inhibition of monoamine oxidase, (Biochemical Pharmacology, 18, (1969), 1447, Br.

J. Pharmacology, 45, (1972), 490). However, said compounds mainly inhibit the oxidation of 5-hydroxytryptamine. It is known that N, N-dimethyl-N-β-phenyl-N-propynylamine (British Patent No. 1,031,425) inhibits the oxidation of benzylamine (Br. J. Pharmacology, 45,490 (1972)). However, the compounds of formula I have more advantageous properties than the above-mentioned phenylethylpropynylamine derivatives.

Salts of the compounds of formula I may be formed with inorganic or organic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, maleic acid, tartaric acid, succinic acid, or lactic acid.

According to process variant a), a compound of formula II is reacted with a compound of formula III wherein B is, for example, chlorine, bromine, benzenesulphonyloxy, p-toluenesulphonyloxy or methanesulphonyloxy. The reaction can be carried out with or without a solvent. It is preferred to add an acid scavenger to the reaction mixture. Inorganic or organic bases, for example alkali or alkaline earth metal hydroxides, carbonates or tertiary amines, can be used as acid-binding agents.

Excess amine of formula II can also act as an acid scavenger. In this case, the excess amine is preferably used both as an acid-binding agent and as a reaction medium. The reaction is preferably carried out at a temperature of 20 to 120 ° C. As the solvent, aliphatic and aromatic hydrocarbons such as gasoline, benzene or its homologues, alkanols, for example ethanol, methanol or butanol, or ketones, for example methyl ethyl ketone or cyclohexanone, can be used. According to a particularly preferred embodiment, the amine of the formula II is dissolved in toluene and propargyl bromide and aqueous sodium hydroxide solution is added dropwise. If necessary, the reaction is completed by heating.

The product is isolated from the reaction mixture by adding a base, followed by extraction. If the reaction is carried out in a water-immiscible solvent, it is preferable to remove this solvent by distillation and add aqueous sodium hydroxide solution to the residue. The biphasic mixture is extracted with a water-immiscible solvent, for example ether or benzene, the extract is dried, evaporated and the residue is purified by fractional distillation.

The resulting evaporated residue can be preferably purified by acylation. In this case, the unreacted starting material of formula II (secondary base) is acylated. The acylated product thus obtained is insoluble in dilute acids and the tertiary base of formula I can be isolated pure by extraction with dilute acid. The acylation can be carried out with conventional acylating agents, for example acid anhydrides or acid chlorides, such as acetic anhydride or benzoyl chloride, in the presence of a base. After acylation, the reaction mixture is extracted with cold dilute hydrochloric acid, the acidic extract is basified, the precipitated tertiary amine of the formula I is extracted as a solvent, dried, evaporated and the residue is separated by distillation. The product can be salified with an organic or inorganic acid.

According to process variant b), the capped compound of formula II is reacted with propargyl aldehyde by reduction at the same time or after the reaction. The reaction may be carried out in a solvent or without a solvent. The reaction medium used is preferably immiscible solvents, for example, benzene or its homologues, such as toluene, xylene or solvent gasoline.

In this case, the water formed in the reaction is separated off and this directs the reaction to form a Schiff base. The Schiff base formed is then reduced to the corresponding compound of formula I. Condensation and reduction can also be performed simultaneously. The reduction is preferably carried out with hydrogen in statu nascendi.

According to process variant c), the 2-furyl derivative of the formula VI is reacted with an amine of the formula V at the same time as or after the reaction. The reduction is preferably carried out with hydrogen in statu nascendi.

5,63227

According to process variant d), the 2-furylethyl derivative of formula VII is reacted with an amine of formula V. The reaction can be carried out with or without a solvent. Hydrocarbons, for example benzene or its homologues, or the solvent petrol, alcohols or ketones can be used as reaction media. The excess amine component can also act as a reaction medium. The reaction is preferably carried out in the presence of an acid scavenger. Organic or inorganic bases or an excess of the amine of formula V may be used. The reaction can be carried out at a temperature of 20 to 130 ° C. The isolation and purification of the product can be carried out by known physical methods, for example by extraction, distillation or crystallization.

According to process variant e), a compound of formula II is reacted with formaldehyde and acetylene. The reaction is carried out in a high-boiling ether, for example butyl ether or dioxane in the presence of cuproacetylide. The reaction is preferably carried out at a temperature of 80 to 150 ° C. The compound of formula II is preferably dissolved in dioxane, a cuproacetylide or a cuproacetylide-forming compound, for example cupro chloride, is added and the mixture is introduced into the mixture with heating and stirring. The compound of formula I can be isolated by methods known per se.

3

From a compound of formula I in which R is bromopropenyl, hydrogen bromide may, if desired, be cleaved with an alkali metal hydroxide, alkaline earth metal hydroxide or organic base to give a compound of formula I wherein R is propynyl.

The compounds of formula I can be converted into pharmaceutically acceptable acid addition salts by means of inorganic or organic acids. The product can also be purified via salts, as the salts are crystalline and readily crystallizable substances. After purification, the base is liberated from its salt by treatment with a base. Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, maleic acid, lactic acid, citric acid, ascorbic acid, etc. can be used to form the salt.

Compositions containing a compound of formula I or an acid addition salt thereof may be in solid form, for example tablets, pills, coated pills, capsules, granules or powder mixtures, or in liquid form, for example as aqueous solutions or suspensions. The compositions are suitable for oral or parenteral administration. The compositions contain conventional 6,63227 carriers, for example talc, calcium carbonate, magnesium stearate, water, petrolatum or polyalkylene glycols. The compositions are prepared by methods known per se.

In vivo, 6.25 mg / kg of N-methyl-N- [2- (furyl-2) -ethyl] -propynylamine inhibits the oxidation of benzylamine in the liver by 79% and the oxidation of tyramine by only 44%. At a dose of 5 mg / kg of N-methyl-N- [1-methyl-2- (furyl-2) -ethyl] propynylamine, oxidation of benzylamine in the brain is inhibited by 53% and by 5-hydroxytryptamine only by 2%. On the other hand, the known compound N- <λ-dimethyl-N - (? - phenylethyl-N-propynylamine in the same dose inhibits the oxidation of benzylamine in the brain by 80% and the oxidation of 5-hydroxytryptamine by 15%. oxidation in the liver is inhibited by 78% and oxidation of 5-hydroxytryptamine by 56% The above values show that the compounds of formula I have a more selective monoaminooxidase inhibitory effect than the known phenyl derivatives.

The following is a comparison of the MAO inhibitory activity of certain compounds of formula I with that of N- (2-furylmethyl) -N-methyl-2-propynylamine (GYH-6,978) known from U.S. Pat. No. 3,211,741.

Method

The activity of monoamine oxidase in homogenized, nuclear-free samples obtained from rat brain and liver was studied. Male rats weighing 100 g and labeled CFY were used in the experiments. The brain and liver were homogenized in a 0.25 M sucrose solution containing 0.5 nM EDTA in a volume ten times the volume of the brain and liver using a glass homogenizer (Potter-Elvehjem system). The homogenate was centrifuged at 1,500 rpm (1,000 G) and the thus obtained nuclear-free homogenate was used in the experiments.

The composition of the 0.5 ml incubation solution was as follows: 0.01 M phosphate buffer (pH 7.2) 0.001 M EDTA (pH 7.5)

Substrate (radioactive indicator) 0.05 ml nuclear-free homogenate.

Using Cl4-phenylethylamine substrate (C14-PEA), the brain tissue sample was diluted 3-fold and the liver tissue sample tenfold. 7,63227 -4 -5 5 * 10 -10 dpm of radioactive substrate was used in each test tube. The pre-incubation lasted 5 minutes and the reaction was initiated by the addition of radioactive substrate. Incubation lasted 10-30 minutes and was performed in a Dubnoff apparatus (Labor) with constant shaking (100 / rain) at 37.5 ° C. The reaction was quenched by the addition of 0.2 mL of 2 M hydrochloric acid.

MAO inhibition values were calculated as the average of 5 experiments and expressed as a percentage of the control (- S.E.M.).

Substrate (radioactive indicator) 3-phenylethylamine-1-C14 * HCl (C14-PEA)

Specific activity: 9.8 / mMol »5-hydroxy-2-C14-tryptamine-creatinine sulphate (C14-5-HT)

Specific activity: 59.0 mCi / mMol.

Both compounds are manufactured by a company called Amersham. The experiments had a final concentration of C14-PEA of 50 μM and a final concentration of C 1-5-HT of 500 μM. Radioactivity was measured by radiometric method (Wurtman, R. and Axelrod, J., Biochem. Pharmacol., 12, 1414, 1963). Essential to this process is that the formaldehyde formed during the reaction is extracted as an organic solvent and the amount of formaldehyde is determined with a liquid scintillation counter. In the experiments performed, the original method was modified by using ethyl acetate instead of toluene in the extraction (Magyas, K. and Knoll, J., Polish J. Pharmacol and Pharmac 2T_, 139, 1975).

Results 6 different concentrations (10 ~ ®-10 ~ M) of GYH-6 978 were used and the effect was compared in in vitro experiments with N- (2-furylethyl) -N-methyl-2-propynylamine of formula I (TZ-945 ) and N- (2-furylisopropyl) -4-methyl-2-propynylamine (Ul 424). C14-5-HT and C14-PEA were used as selective substrates for A- and B-MAO. The results are shown in Tables 1 and 2. At the concentrations used, none of the three compounds mentioned prevented the oxidative deamination of C14-5-HT, i.e. they practically did not affect the type A MAO. In brain tissue, GYH-6,978 did not inhibit oxidative deamination of the type B substrate C14-PEA at a concentration of 10-5 M, whereas at the same concentration, TZ-945 and U-1424 produced an inhibitory effect of about 26% and about 53%, respectively. All compounds have a stronger effect on liver MAO activity, but even in this case, GYH-6 978 has the weakest effect. At a concentration of 10 μm, the inhibitory effect was: 8 63227 GYH-6 978 about 10%, TZ-945 about 50% and U-1442 u 60%. Thus, the experiments clearly show that GYH-6 978 is ineffective and that U-1424 is the most effective of the three compounds. The LD50 concentration of U-1424 in brain tissue is 10 8M. Thus, TZ-945 and U-1424 are inhibitors selective for type B MAO.

Table 1 MAO inhibitory activity of GYH-6 978, TZ-945 and U-1424 in nuclear brain homogenate from rat brain and liver in in vitro experiments using C14-5-HT substrate

Tissue Compound Concentration, M

____ 10 ~ 8 10 ~ 7 5 · 10 ~ 7 10 ~ 6 5 · 10 ~ 6 10 ~ 5_

Mvot GYH-6978 0 0 0.05 ± 0.1 0.2 ± 0.3 0.2 ± 0.4 0.3 + 0.7 TZ-945 2.0 ± 2.7 2.9 ± 3, 4 1.9 ± 3.1 0.1 ± 0.2 3.4 + 3.1 4.4 ± 6.7 ____ U-1424 0.1 + Qpl 3.1 + 1.2 2.0 ± 1, 1 0.5 ± 0.4 3.8 ± 1.4_ 2.6 ± 1.5.

yiaksa GYH-6978 0 0 0 0 0 1.6 ± 2.4 TZ-945 0.3 ± 0.6 0.8 ± 1.3 0.8 ± 1.9 0.6 ± 1.4 1.1 ± 1.8 3.4 ± 2.7 U-1424 4.3 ± 1.7 4.7 ± 1.1 5.8 ± 1.3 7.2 ± 1.0 6.7 ± 2.8 8 5 ± 1.1

Inhibition values are expressed as a percentage of control + S.E.M.

Table 2 MAO inhibitory activity of GYH-6 978, TZ-945 and U-1424 in a nuclear-free homogenene obtained from rat brain and liver in in vitro experiments using C14-PEA substrate P | ^ "Γ ~ n 1" '- I I I I -

Tissue Compound Concentration, M

___ 10 ~ 8 10 ~ 7 5.10 ~ 7 10 ~ 6 5.10 ~ 6 10 ~ 5_

Brain GYH-6978 0.3-0.7 1.8 ± 2.6 1.5 ± 1.1 0.1 ^ 0.2 0.8 ^ 1.2 0.3-0.6 TZ-945 1 , 0-1.7 1.9-1.6 1.1-2.3 0.5 ± 1.0 12.8-3.8 26.7-3.4 U-1424 1.9-3, 3 2.4-2.0 14.6-2.2 7.9 ^ 5.7 39.7 ± 2.3 53.6-1.1

Payment GYH-6978 0 0 0 0 1.6 ^ 1.3 11.9 * 3.2 TZ-945 0.1 + 0.3 0.2 * 0.4 2.7-2.9 6.7- 3.8 26.5-4.5 51.5 * 6.3 __U-1424 lp_0 2.8-3.2 Il4.7-3.5 45.5 * 4.5 60.7-3.7__

Inhibition values expressed as a percentage of control - S.E.M.

Using N-2- [1-methyl-2- (2-furyl) -ethyl] -N-methyl-N-2-bromopropenylamine of formula I and C14-5-HT as a substrate, a brain MAO inhibitory concentration of 0 was obtained. 0001 M. When Cl4-PEA was used as a substrate, e.g. the compound inhibited MAO in both brain and liver at a concentration of 0.0000008 M.

9,63227

The depressant effect of reserpine, which resists the antidepressant effect of the compounds of formula I, is clearly stronger than that of the corresponding phenyl compounds.

The compounds of the formula I have a lower toxicity than the known phenyl derivatives and thus the new compounds have a more favorable therapeutic index and a wider spectrum of action.

Example 1

7.9 g (0.0568 mol) of N-methyl-N- [1-methyl-2- (2-furyl) -ethyl] -amine were dissolved in 142 ml of toluene and added with stirring at 45-50 ° C. , 7 g (0.0568 mol) of propargyl bromide and 11.4 ml of 5N aqueous sodium hydroxide solution. The reaction mixture was refluxed with stirring for three hours. After cooling, 14.8 ml of 10N sodium hydroxide solution were added and the phases were separated. The aqueous layer was extracted twice with benzene, the benzene and toluene solutions were combined, dried over anhydrous potassium carbonate and evaporated. The residue was dissolved in 50 ml of benzene and refluxed with 6 g of acetic anhydride for one hour. After cooling, the solution was washed with 20% sodium carbonate solution until the evolution of carbon dioxide had ceased. The mixture was washed with water and extracted at 0 ° C with 5% hydrochloric acid. The chloro-hydrochloric acid solutions were combined, the mixture was allowed to stand below 10 ° C and basified. The separated oil was extracted with ether, the ether extract dried over potassium carbonate and evaporated. Distillation of the residue in vacuo gave 6.5 g of N-methyl-N- (1-methyl) -2- (2-furyl) -ethyl] -propynylamine, b.p. 115-117 ° C / 20 mm Rg, n E = 1.4922.

Example 2

The procedure described in Example 1 was repeated except that 12.5 g of N-methyl-N-2- (2-furyl) -ethylamine and 11.9 g (0.1 mol) of propargyl bromide were reacted in 70 ml of toluene and per ml of 5N sodium hydroxide solution. There was thus obtained 11.2 g of N-methyl-N / 2- (2-furyl) -ethyl] propynylamine, b.p. 105-106 ° C / 20 mm Hg, n ° + 1, 4891. The hydrochloride m.p. was 106-108 ° C (from a mixture of ethanol and ether).

Example 3 To 13.9 g (0.1 mol) of N-methyl-N- [1-methyl-2- (2-furyl) ethyl] amine was added dropwise 10 g (0.05 mol) of 1,2-dibromoamine. propylene, the reaction mixture was heated at 100 ° C for seven hours, then cooled to room temperature and dissolved in 5% hydrochloric acid. The acidic solution was extracted with ether and made. * * · Basic with 40% sodium hydroxide solution. The precipitated oil was extracted with ether, dried and evaporated.

To the remaining brown oil were added 60 ml of 40% sodium hydroxide solution and 30 ml of benzoyl chloride simultaneously dropwise over 30-45 minutes to benzolyze unreacted N-methyl-N-methyl-2- (2-furyl) ethyl] amine. During the addition, the temperature of the reaction mixture rose to 50-60 ° C. After the addition was complete, the reaction mixture was stirred for one hour at this temperature, then cooled to room temperature and benzene was added. The mixture was shaken, the benzene phase was separated and extracted with 5% hydrochloric acid. N-methyl-N, N-methyl-2- (2-furyl) ethyl] -N-2-bromopropenylamine dissolved in the acid phase and N-methyl-N, N-methyl-2- (2-furyl) ethyl] benzoylamine remained in the benzene solution. The hydrochloric acid layer was basified, the precipitated N-methyl-N- [1-methyl-2- (2-furyl) -ethyl] -N-2-bromopropenylamine was extracted with benzene, dried and evaporated. The residue was isolated by distillation in vacuo. There were thus obtained 7.1 g of N-methyl-N- [1-methyl-2- (2-furyl) ethyl] -N-2-bromopropenylamine, b.p. 112-114 ° C / 0.3 mmHg, n ^ 0 '^ = 1.5269 (m.p. 132-134 ° C of the oxalate salt).

The product was dissolved in 100 ml of ethanol and 14 ml of 50% aqueous potassium hydroxide solution was added. The reaction mixture was refluxed for 16 hours, the ethanol was removed by distillation, water was added to the residue, and extracted with benzene. The benzene solution was dried over anhydrous potassium carbonate and evaporated. The residue was isolated by distillation in vacuo. There was thus obtained 4.9 g of N-methyl-N 'Z 1 -methyl-2- (2-furyl) -ethyl] propynylamine, b.p. 114-115 ° C / 20 mm Hg, n = 1.4915.

Example 4

As described in Example 3, 12.5 g (0.1 mol) of N-methyl-N-2- (2-furyl) -ethylamine and 10 g (0.05 mol) of 1,2-dibromopropene were reacted with each other. There was thus obtained 7.6 g of N-methyl-N- [2- (2-furyl) -ethyl] -2-bromopropenylamine, which was reacted with 14 ml of a 50% aqueous potassium hydroxide solution in 100 ml of ethanol by boiling as described in Example 3. There were thus obtained 5.1 g of N-methyl-N- [2- (2-furyl) -ethyl] propynylamine, b.p. 105-106 ° C / 20 mm Hg, n = 1.4890. Hydrochloridine m.p. was 107-108 ° C (from a mixture of ethanol and ether).

Example 5

12.4 g (0.1 mol) of 2-furylacetone were dissolved in 100 ml of ethanol and 7.25 g (0.105 mol) of methylpropynylamine were added. The fat was removed from 3.5 g of aluminum strips with ethanol and activated with a solution of 1 g of mercuric chloride and 15 g of 63227 sodium chloride in 30 ml of water. After 6-8 minutes, the activating solution was decanted and the activated aluminum strips were washed with cold water and added to the previously prepared alcohol solution with stirring. The reaction is exothermic and the temperature was maintained at 15-30 ° C with cooling. The reaction mixture was stirred for 24 hours and then 30 ml of 40% sodium hydroxide solution was added. The phases were separated and the lower aqueous phase was extracted three times with benzene.

The benzene solutions were combined with the previously separated alcohol phase and evaporated. The residue consisted of an organic, oily layer and an aqueous layer, which was extracted with benzene and the benzene solution was dried over potassium carbonate. The benzene was removed and the residue was separated by distillation in vacuo. There was thus obtained 6.7 g of N-methyl-N- [1-methyl-2- (2-furyl) -ethyl] -propynylamine, b.p. 113-115 ° C / 20 nm Hg, n E = 1.4905.

Example 6

As described in Example 5, 13.9 g (0.1 mol) of N-methyl-N- [1-methyl-2- (2-furyl) ethyl] amine and 7 g (0.184 mol) of propargyl aldehyde were reacted with each other. In 100 ml of ethanol with 3.5 g of aluminum strips. There was thus obtained 6.1 g of N-methyl-N- [1-methyl-2- (2-furyl) -ethyl] propynylamine, b.p. 114-115 ° C / 20 nm Hg, 20 nju = 1.4910.

13.9 g (0.1 mol) of N-methyl-N- [1-methyl-2- (2-furyl) ethylamine were dissolved in 80 ml of dioxane, then 6 g of paraformaldehyde and 1 g of cuprous chloride were added and acetylene gas was introduced. solution at 80 ° C with stirring for 30 hours. The reaction mixture was filtered and the filtrate was evaporated. The residue was dissolved in benzene, the benzene solution was washed with water, dried over potassium carbonate and evaporated. The residue was separated by distillation in vacuo. There was thus obtained 6.8 g of thyrethyl N- [1-methyl-2- (2-furyl) -ethyl] -propynylamine, b.p. 114-116 ° C / 20 nm nmax = 1.4910.

Example 8

12.8 g (0.1 mol) of 1-methyl-2- (2-furyl) ethyl chloride and 15 g (0.208 mol) of methylpropynylamine were heated for four hours in a sealed bomb tube at 70-80 ° C. The reaction mixture was cooled, 30 ml of 40% sodium hydroxide solution was added, and the mixture was extracted with benzene. The benzene solution was dried, evaporated and the residue was separated by distillation in vacuo. There was thus obtained 9.8 g of N-methyl-N- [1-methyl-2- (2-furyl) -ethyl] -propynylamine, b.p. 113-115 ° C / 20 imi Hg, n ^ ° = 1.4904.

12 63227

Example 9

As described in Example 8, 11.45 g of (0.1 mol) -2- (2-furyl) ethyl chloride was reacted with 15 g (0.208 mol) of methylpropynylamine. There was thus obtained 8.8 g of N-methyl-N- [2- (furyl-2) -ethyl] -propynylamine, b.p. 104-105 ° C / 20 nm Hg, n ° = 1.4868.

Example 10 12.5 g of (0.1 mol) 1-methyl-2- (2-furyl) -ethylamine were dissolved in 70 ml of dioxane and 6 g of paraformaldehyde and 1 g of cuprous chloride were added to the solution, followed by addition of acetylene as described in Example 7 and the solution thus obtained was treated as in Example 7. 6.3 g of N- [1-methyl-2- (2-furyl) -ethyl] -propynylamine were obtained.

ΛΑ

Kp. 55-60 ° C / 5 nm Hg, = 1.4895. Hydrochloride salt, m.p. 107-111 ° C. Analysis according to the formula C1QH13NO HCl. Calculated: C 60.15%, H 7.06%, N 7.01%, Cl 17.75%.

Experimental: C 60.39%, h 7.03%, N 6.94%, Cl 18.27%.

Claims (2)

A process for the preparation of novel therapeutically useful N- [2- (2-furyl) -ethyl] "amine derivatives of the formula I and their pharmaceutically acceptable acid addition salts, -1 R1 CH3 iJJ-ch9-ch-n-r3 (I) O wherein in the formula R1 is hydrogen or methyl and R3 is bromopropenyl or propynyl, characterized in that a) an N- (2-furylethyl) amine derivative of the formula - R1 CHo il 'U U - ch9-ch-nh (ii) CT wherein R 1 is as defined above is reacted with a compound of formula R -X (III) 3 wherein R is as defined above and X is halogen or a sulfonic acid ester group, or b) N- (2) -furylethyl) -amine derivative of the formula OR1 CH3 -CH2-CH-NH (II) O wherein R1 is as defined above is reacted with a properyl aldehyde of the formula HC - C-CHO (IV) while reducing or after the reaction, or c) a 2-furyl derivative of the formula ----- r1 1J - CH 2 --CO (VI) wherein R 1 is as defined above is reacted with an amine of formula CH 2, HN-R 3 (V) 3 wherein R is as defined above, while reducing or after the reaction , or 14 63227 d) a 2-furylethyl derivative of the formula π U.> '- CH.-CH-X (VII) 0 in which R 1 and X have the same meaning as above is reacted with an amine of the formula CH-, IJ HN-R3 (V) wherein R3 is as defined above, or e) an N- (2-furylethyl) amine derivative of the formula , is as defined above, condensed with formaldehyde and acetylene and, if desired, cleaved from a compound of formula I wherein R is bromopropenyl in a manner known per se to give a hydrogen bromide to give a compound of formula I wherein R is propynyl and / or a compound of formula I obtained converted into a pharmaceutically acceptable acid addition salt in a manner known per se. 15 63227 For the preparation of a therapeutically active compound N- ^ 2- (2-furyl) -ethyl__inders with a formula I and a pharmaceutical formulation of the following compounds, „_ R1 CH, I | «3 ί JJ -— ch9-ch-n-r3 (i) o 1 3 i vilken forme1 R is used with methyl or R is bromopropenyl or propynyl, which can be treated with N- (2-furethyl) amine in the form __ R1 CH-j i il '' li U - CH2-CH-NH (II) o rär R ^ "betecknar saitana som ovan, omsätts med en förening med Formelnel R3-X (lii) 3 dar R betecknar samma wherein the halogen or X is halogen or a sulfone-cyano ester group, or b) that the N- (2-furylethyl) amine derivative with the formula __ R1 CH i Π '' y — ch2-ch-nh (ii) is R ^ "betecknar samma in which case, with propargylaldehyde in the form of HC = C-CHO (IV) under the same or after the reaction reduction, or c) that the 2-furyl derivative with the formula R1 [ii '' II U - CH -, - CO (VI)) the R3 is selected from the group consisting of amines having the formula HN-R3 (V) 3 and the R is selected from the group consisting of the same or a further reaction after reduction, or d) that the 2-furylated derivatives of the formula