CS203061B2 - Process for preparing new derivatives of n-/3,3-diphenylpropyl/propylendiamine - Google Patents

Description

The present invention relates to a process for the preparation of novel N- (3,3-diphenylpropyl) propylenediaine derivatives, as well as their salts with therapeutically useful properties, which are primarily useful in heart diseases as blood flow enhancers in coronary arteries and as antiarrhythmic drugs.

Diphenylpropylamine derivatives are known to have beneficial therapeutic properties [Arzneimittel-Forschung, 10, 569, 573, 583 (1960); Sheet. Pharm., 295, 196 (1962); J. Med. Chem. 7, 23 (1964) J. However, the salts of these compounds are difficult to dissolve in water and therefore can be used for injection purposes only to a limited extent.

Furthermore, it is known that the hexobendium ethylenedlamine derivative has an expanding effect on the coronary vessels and the phenetaminedihydro propylenediamine chloride derivative has a spasmolytic effect.

It has been found that the novel propylenediamine derivatives having a 3,3-dienylpropyl group of formula (I)

CH-CH ₂ -CH ₂ -NH-ICH ₂ j-NH-C ^ wherein R and R represent an alkyl group having 1 to 4 carbon atoms, phenyl or benzyl group, and their acid addition salts have the effect of extending the coronary and antiairytmický effect. In addition, they have a locally anesthetic effect and an anti-adrenaline effect at low toxicity. Their particularly advantageous property is the easy solubility of their salts with inorganic and organic acids and their very good resorption.

It has further been found that the compounds of formula (I) and their salts can be obtained according to the invention by providing a diamine of formula (II):

wherein A represents a hydrogen atom or an ace, ayl group, reacts with a halogen compound of formula III

R

OF

X — CH

R 1 (ΠΙ), where R and R 1 are as defined above, in the presence of an organic solvent and an acid-binding agent, the acetyl group A is cleaved by hydrolysis and the base is optionally converted into an acid addition salt.

Preferably, N- (3,3-diphenylpropyl) -N-acetylpropylene-1,3-diamine is used as the compound of formula II, and 1-phenyl-2-chloropropane is used as the compound of formula III.

The diamine compounds of formula II can be obtained in almost theoretical yields by treating acrylicitrile with 3,3-diphenylpropylamine. The thus obtained 3- (3,3-diphenylpropylamino) propionitrile (A = H), which can optionally be acylated (A = acyl group), is catalytically reduced.

As the organic solvent, ether, chloroform, benzene, acetone, an alcohol or, preferably, dimethylformamide may be used. The reaction can be accelerated by heating.

Conventional inorganic bases such as potassium carbonate are most suitable for binding the hydrohalic acid liberated during the reaction, but the reaction may also be carried out in the presence of an excess of an amine acid-binding agent.

From the compounds of the formula I prepared according to the invention, they can be obtained in a known manner by reaction with organic or inorganic acids, for example hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, lactic acid, citric acid, succinic acid, maleic acid. , nicotinic acid or fumaric acid of the corresponding salt.

The compounds of formula (I) produced by the process of the invention and their salts can be used in therapy in the form of therapeutic preparations containing the active ingredient and inert non-toxic, therapeutically suitable, organic or inorganic carriers. The formulations can be used in the form of tablets, solid or thin coatings, dragees, enteric coated dragees, pills, capsules, liquid suspensions, solutions and emulsions. Talc, starch, gelatin, water and polyethylene glycols can be used as carriers. The formulations may optionally contain other excipients such as wetting agents, emulsifying and suspending agents, salts and buffering agents for the grain, osmotic pressure, disintegrants and / or other therapeutically active agents.

The method according to the invention is illustrated in more detail by the following non-limiting example.

Example

36.4 g of 3- (3,3-diphenylpropylamino) propionic nitrile was dissolved in 30 ml of acetic anhydride and the solution was poured on ice after standing for 12 hours. Trituration of the deposited oil eliminates acetic anhydride. The reaction mixture was stirred for 3 hours and then extracted with benzene. The benzene solution is shaken with 5% potassium carbonate solution, dried, filtered and the benzene is distilled off under reduced pressure. The residue is dissolved in 250 ml of ethanol and hydrogenated in the presence of 15 g of Raney nickel catalyst at a pressure of 1 bar and at 70 DEG C. for about 5 hours. The mixture was filtered, the alcohol distilled off and the N- (3,3-diphenylpropyl) -N-acetylpropylene-1,3-diamine (31 g) thus obtained was dissolved in 100 ml of dimethylformamide. After addition of 10 g of potassium carbonate and 15.7 g of 1-phenyl-2-chloropropane, the reaction mixture was stirred at 7-0 ° C for 18 hours. After filtration, the solution was evaporated under reduced pressure, the residue was heated with 100 ml ^. ml of hydrochloric acid was boiled for 14 hours and the hydrochloric acid was distilled off. The residue was recrystallized from ethanol. N- (3,3-diphenyl-2-propyl) -N'- (1-phenyl-2-propyl) propylene-1,3-dlamine dihydrochloride is obtained, m.p. -2-3-5-236 ^° C. .

Dilatation effect of N- (3,3-diphenyl-2-propyl) -N'- (1-phenyl-2-propyl) -propynyl-1,3-diamine dihydrochloride compound 1 ^and -, manifested by in vitro coronary artery dilatation in the heart of the Swine Heart according to La-ngendorff, as compared to the effect of prenylamine, is shown in the following table:

TABLE

compound dose mg number attempts l ^a 50 15 Dec 100 ALIGN! 11 500 4 Prenylamine 50 14 100 ALIGN! 10 600 4 Papaverin 50 14 100 ALIGN! 11 500 4

increase in flow in% time.

The original flow effect

51j5 ± 6.5 2.7 ± 0.5 54.3 ± 7.3 2.5 ± 0.4 84.5 • ± 19.3 6.0 + 0.5 36.4 + 6.4 2.1 ± 0.4 31.8 6.8 1.6 + 0.4 21.6 ± 3.7 1.5 ± 0.3 26.4 + 3.1 1.4 + 0.2 57.1 + 12.0 2.7 + 0.6

As is apparent from the results, the compound is ^{l, and} in terms of potency and duration considerably more advantageous than the comparison preparations, which is also reflected in the fact that the compound I ^and manufactured according to the invention has no detrimental effect on the heart as prenylamine.

In vivo according to Nieschulz (1955) for sloučeniny ED 50 = 1.92 (1.20-3.07 J mg / kg iv; for premylamine ED 50 = 2.55 (1.50 to 4.34) mg / kg i. V.

The antiarrhythmic effect of Lawson (1958) for compound 1 ^{and the} ED 50 = 25.5 · (19.9 to 32.6) mg / kg sc; for trans laminate ED 50 = 84.0 (61.7 - 114.3) mg / kg.

Antiadrenaline effect in mice as determined by the survival of the lethal dose (LD10) of adrenaline

iv: effective dose for compound 1 ^and ED 50 = 48 (32.2 - 70.6] mg / kg sc; for prenylamine ED 50 = 21.0 (11.8 - 37.3) mg / kg.

Locally anesthetizing effect of compound L ^and is determined on the cornea of guinea pig by requiere (1923). Concentrations effective in 50% of the animals: for compounds l ^and amounts to 0.38 (0.31 to 0.36) ° / o; the effective concentration of prenylamine producing the same effect is 0.2 (0.13-0.32%).

Claims (4)

203061 TABLE Compound Dose mg Number of experiments la 50 15 100 11 500 4 Prenylamine 50 14 100 10 500 4 Papaverine 50 14 100 11 500 4 Increase in flow rate% Original time of effect flow 51j5 ± 6.5 2.7 ± 0.5 54, 3 ± 7.3 2.5 ± 0.4 84.5 '± 19.3 6.0 + 0.5 36.4 + 6.4 2.1 ± 0.4 31.8 6.8 1.6 + 0.4 21.6 ± 3.7 1.5 ± 0.3 26.4 + 3.1 1.4 + 0.2 57.1 + 12.0 2.7 + 0.6 As the results show, The laco compound, in terms of potency and duration, is considerably more advantageous than the preparations to be compared, which also shows that the compound la produced by the process of the invention does not have a harmful effect on the heart such as prenylamine. In vivo according to Nieschulz (1955), the compounds Γ ED 50 = 1.92 (1.20-3.07 J mg / kg iv; for prenylamine ED 50 = 2.55 (1.50 to 4.34) mg / kg i V. The antiarrhythmic effect of Lawson (1958) for compound la ED 50 = 25.5 '(19.9 to 32.6) mg / kg sc; for trans laminate ED 50 == 84.0 (61.7 - 114.3) mg / kg Antiadrenaline effect in mice at the lethal dose (LD10) of adrenaline iv: effective dose for compound la ED 50 - = 48 (32.2 - 70.6) mg / kg sc, for prenylamine ED 50 = 21, 0 (11.8 - 37.3) mg / kg The locally anesthetizing effect of lase was detected on the guinea pig's cornea according to Requier (1923) Concentration effective in 50% of animals: for compound la was 0.38 (0.31 to 0). The effective concentration of prenylamine producing the same effect is 0.2 (0.13-0.32) percent. A process for the preparation of novel N- (3,3-diphenylpropyl) propylenediamine derivatives of the general formula I wherein R and R 1 are C 1 -C 4 alkyl, phenyl, or benzyl, and acid addition salts thereof, characterized in that the diamine of formula (II) is: where A is a hydrogen atom or an acetyl group, reacts with the halogen compound of formula III R 2 -OH \ R 1 (ΙΠ), where R and R 1 are as defined above, in the presence of an organic solvent and an acid-binding agent, acetyl group A The base is hydrogenolytically cleaved and the base obtained is optionally converted into an acid addition salt. 2. A process according to claim 1, wherein the compound of formula (II) is preferably N- (3,3-diphenylpropyl) -N-acetylpropylene-1,3-diamine, and the compound of formula (III) is 1-phenyl-2. -chlorpro-panu, 3. Process according to claim 1, characterized in that ether, chloroform, benzene, acetone, alcohol, in particular dimethylformamide, are used as the organic solvent. 4. A process according to any one of claims 1 to 3, characterized in that potassium carbonate is used as the acid-binding agent. a. tfvo * T, u * «t