CS203058B2 - 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) propylemidium derivatives as well as their salts with therapeutically useful properties, which are primarily useful in cardiac diseases as medicaments for increasing blood flow in coronary arteries and as antiarrhythmic medicaments .

Dienylpropylamta derivatives are known to have advantageous therapeutic properties [Arzneimittel-Forschung 10, 569, 573, 583 (1960); Sheet. Pharm. 295, 196 (1962); J. Med. Chem. 7, 623 (1964)]. 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 ethylenediaimine derivative has an expanding effect on the coronary blood vessels and the propylenediamine phenetamine dihydrochloride derivative has a spasmolytic effect.

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

A ^{1 2 2 111} wherein R and R 1 represent a C 1 -C 4 alkyl group, a phenyl or a bemyl group, and their acid addition salts have coronary vascular expansion and antiarrhythmic activity. In addition, they have locally anesthesia and anti-adrenaline effects at low toxicity. Their particular advantage is their easy solubility of their salts with inorganic and organic acids and their very good resorption.

Furthermore, it has been found that the compounds of the formula I and their salts can be obtained according to the invention by reacting the aminohaloigenide of the formula II (S) and A A | 2- wherein X is a halogen atom and A represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, reacts with an amine of formula III

R

OF

H2N1 — CH \

R 1 (III), wherein R and R 1 are as defined above, in the presence of an organic solvent and an acid-binding agent, the aralkyl group A is cleaved hydrogenolytically and the base is optionally converted into an acid addition salt.

Preferred compounds of formula (II) are N- (3,3-diphenylpropyl) -N- (3-chloropropyl-benzyl) benzyl amine and compounds of formula (III) are 1-phenyl-2-aminopropane.

Compounds of formula (II) may be prepared by reacting diphenylpropylamine with α, ω-hydroxyhaloalkanes and subsequently replacing the hydroxyl group with a halogen. In this process, it is preferred to protect the amino group of the α- (diphenylpropylamino) -ω-hydroxypropane temporarily with a benzyl group.

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

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

Of the compounds of formula (I) prepared by the process of the invention, known compounds can be known. by the reaction with organic or inorganic acids such as hydrochloric acid, tartaric acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, succinic acid, m-aleonic acid, nicotinic acid or fumaric acid of the corresponding salt.

The compounds of the formula I prepared according to 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 may be used in the form of solid or thin-coated tablets, expensive, enteric coated tablets, pills, capsules, liquid suspensions, solutions, emulsions. Talc, starch, gelatin, water and polyethylene glycols can be used as carriers. The formulations may optionally contain a preparation ^. adjuvants such as wetting agents, emulsifying and suspending agents, salts and buffering agents for changing the oemotic pressure, disintegrating agents and / or other therapeutically active agents.

The invention is illustrated in more detail by the following non-limiting examples.

Example 1

(a) 38 g of N- (3,3-diphenylpropyl) -N- (3-chloropropyl) benzylaimine, 13,5 g of 1-phenyl-2-aminopropane and 15 g of potassium carbonate are heated in 100 ml of dimethylformamide with stirring 16 The solvent was distilled off under reduced pressure, the residue was dissolved in 100 ml of glacial acetic acid and, after addition of 0.5 g of platinum oxide, hydrogenated at 70 DEG C. and under a pressure of 0.4 MPa. After completion of the hydrogen uptake (about 6 hours), the reaction mixture was diluted with 100 mL of methanol, filtered and the solvent was distilled off. N- (3,3-diphenyl-2-propyl) -N'- (1-phenyl-2-propyl) propylene-1,3-diamine dihydride, m.p. 234 DEG-236 ^DEG C., was obtained.

b) To a mixture of 84.32 g of 3,3-diphenylpropylamine, 100 ml of butanol and 42 g of sodium bicarbonate, 37.8 g of 3-chloropropanol are added at the boiling point of the mixture for about 1 hour, and the mixture is heated to boiling until complete. gas evolution. After cooling, the mixture was filtered, evaporated and the residue distilled. 62 g of 3- (3,3-diphenylpropylamino) -propan-1-ol having a boiling point of 205 DEG-210 DEG C./1 mm Hg are obtained.

(c) A mixture of 90 g of 3- (3,3-diphenylpropylamino) propan-1-ol, 40 g of benzyl chloride, 150 ml of ethanol and 24 g of potassium carbonate is heated under stirring to boiling until gas evolution ceases. The filtrate is evaporated under reduced pressure, the residue is dissolved in 150 ml of chloroform and heated to boiling with 80 g of thionyl chloride for 1 hour and after reacting for a further 2 hours, after distilling off the solvent and excess thionyl chloride. The solution is rendered alkaline with cooling, extracted with ether and, after drying, the solution is filtered and the ether is distilled off. The oily residue N- (3,3-diphenylpropyl) -N- (3-chloro-propyl) benzylamine is immediately processed further. .

Dilatation effect of N- (3,3-diphenyl-2-propyl) -N'- (1-phenyl-2-propyl) hydrochloride for pollen-1,3-diamine - compound 1a ^and -, manifesting by expanding the in vitro coronary arteries at the heart of the guinea pig according to Langendorff,

TABLE

compound dose number increase in flow rate in% time mg .pokusů of the original flow rate effect 1 " 50 15 Dec 51.5 ± 6.5 2.7 ± 0.5 100 ALIGN! 11 54.3 ± 7.3 2.5 ± 0.4 500 4 84.5 ± 19.3 6.0 ± 0.5 Prenylamine 50 14 36.4 ± 6.4 2.1 ± 0.4 100 ALIGN! 10 31.8 ± 6.8 1.6 ± 0.4 500 4 - Papaverin 50 14 21.6 ± 3.7 1.5 ± 0.3 100 ALIGN! 11 26.4 ± 3.1 1.4 ± 0.2 500 4 57.1 ± 12.0 . 2.7 ± 0.6 As follows from results, a compound I ^and and the residue is taken up in 90 ml of glacial acid in terms of strength and duration acetic acid and hydrogenated at temperature 70 ° C and at more convenient than comparable preparations, which pressure of 0.4 MPa in the presence of 0.5 g of oxide also manifests itself in that Compound 1 ^and poly- platinum catalyst about 8 hours to

according to the invention has no deleterious effect on the heart such as prenylamine.

In vivo, according to Nieschulz (1955) for compound 1 ^{and the} ED 50 = 1.97 (1.20 3.07) mg / kg / kg; prenylamine: ED 50 = 2.55 (1.50 to 4.34) mg / kg iv

The antiarrhythmic effect of Lawson (19) 58) for compound 1 ^{and the} ED50 = 25.5 (19.9 to 32.6) mg / kg sc; for trans laminate ED 50 = 84.0 (61.7 - 114.3) mg / kg.

Antiadreinalinitive effect found by the lethal dose (LD100) survival of adrenaline iv; effective doses are µl ^and ED 50 = 48 (32.2-70.6) mg / kg sc; for prenylamine ED 50 = 21.0 (11.8 to 37.3) mg / kg.

Locally anesthetizing effect of compound L ^and is determined on the cornea of guinea pig by requiere (19123). Concentrations effective in 50% of animals: 0.38 (0.31 to 0.36) ° / ou l ^and compounds. The effective prenylamine concentration producing the same effect is 0.2 (0.13 - 0.32)%. Example 2 and 30 g of N- [1-phenyl-2-propyl] -N- (3-chloropropyl) benzylamine, 21 g of 3,3-diphenylpropylamine and 15 g of potassium carbonate are heated in 80 ml of dimethylformamide under stirring at 70 ^{DEG C.} for 16 hours ^{. C.} After filtration, the solvent was distilled off under reduced pressure compared with účinkeím prenylamine is given in the following table:

termination of hydrogen absorption. The mixture was diluted with methanol (100 ml) and the solvent was distilled off. The residue is heated with 50 ml of concentrated hydrochloric acid for 4 hours, then evaporated under reduced pressure in a water bath and the residue is recrystallized twice from methanol. N- (3,3-Diphenylpropyl) -N- (1-phenyl-2-propyl) propylene-1,3-diamine dihydrochloride, m.p. 235 DEG-236 DEG C., is obtained.

b) 65 g of N- (1-phenyl-2-propyl) -3-aminopropan-1-ol, obtained according to jap. No. A 9813 (1967), 40 g of benzyl chloride, 150 ml of ethanol and 24 g of potassium carbonate are heated to boiling until gas evolution ceases and the cooled solution is filtered and evaporated under reduced pressure. The residue dissolved in 150 ml of chloroform was treated with 80 g of thionyl chloride for 1 hour at elevated temperature and continued heating on a water bath until gas evolution ceased similar to the method described in Pat. No. 2,600,301. After distilling off the solvent and excess thionyl chloride, the remaining salt is taken up in water, made alkaline with ice cooling and extracted with ether. The ether solution was dried over sodium sulfate, filtered, and the ether distilled off. 80 g of crude N- (1-phenyl-2-propyl) -N- (3-chloro-1-propyl) benzylamine remained as an oil, which was further processed immediately.

Claims (4)

SUBJECT VYNALEZU CLAIMS 1. A process for the preparation of the novel N- (3,3-diphenylpropyl propylene amine derivatives of the formula I) (I) wherein R and R 1 are C 1 -C 4 alkyl, phenyl or benzyl, and their acid addition salts, characterized in that the amine halide of the formula II d1) wherein X is a halogen atom and A represents a hydrogen atom or a (C1-C4) -alkyl aralkyl group, reacts with an amine of formula III R OF HzN — CH \ R 1 (III), wherein R and R 1 are as defined above, in the presence of an organic solvent and an acid-binding agent, the aralkyl group A is cleaved hydrogenolytically and the base is optionally converted into an acid addition salt. 2. A process according to claim 1, wherein the compound of formula II is N- (3,3-diphenylpropyl) -N- (3-chloropropylpropyl) -benzylamine and the compound of formula III is 1-phenynyl-2-aminopropane. 3. The process according to claim 1, wherein the organic solvent is alcohols, acetone, benzene or dimethylformamide. 4. Process according to claim 1, characterized in that inorganic bases, in particular potassium carbonate, and / or an excess of the corresponding amine reactant are used as acid-binding agents.