CS203063B2 - 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) dipropylenediamine derivatives and salts thereof having therapeutically useful properties, which are primarily useful in heart diseases as coronary artery blood flow enhancing drugs and as antiarrhythmic drugs.

It is known that diphenylpropylamine derivatives have advantageous therapeutic properties [Arzneimlttel-Forschiung 10, 569, 573, 533 (1960), Arch. Pharm. 295, 1196 (1962); J. Med. Chemistry 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 ethylenediamine derivative has an expanding effect on the coronary blood vessels and the propylenediamine phenetamine hydrochloride derivative has a spasmolytic effect.

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

wherein R ¹ and R ¹ are C 1 -C 4 alkyl, phenyl or benzyl, and their acid salts have coronary vascular expansion and antiarrhythmic activity. In addition, they have locally anesthetic and anti-adrenaline activity at low toxicity. Their particularly advantageous property is the easy solubility of their salts with inorganic and organic acids and their good resorption.

The compounds of the formula I and their salts can be obtained according to the invention by reacting them with diphenylpropylamine of the formula II

2030B3

with a halide of formula III

R /

X - (CH 2) 3 - N - GH

I \

AR ¹ (ΠΊ) wherein R and R ¹ are as defined above, A represents a hydrogen atom or an aralkyl group having 1 to 4 carbon atoms in alkyl and X halogen, in the presence of an organic solvent and an acid-binding agent, the aralkyl group A is hydrogenolytically cleaved; the base obtained is optionally converted with an inorganic or organic acid into an addition salt.

The organic solvents used in the process according to the invention may be ether, chloroform, benzene, acetone, alcohol or preferably dimethylformamide. The reaction can be accelerated by heating.

Conventional inorganic bases, for example potassium carbonate, are 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. In the case where A is a benzyl group, it can be exchanged for a hydrogen atom by catalytic hydrogenation in almost theoretical yield. The hydrogenation can be carried out in an organic solvent, for example an alcohol or glacial acetic acid, in the presence of a platinum or palladium catalyst.

The compounds of the formula (I) produced by the process according to the invention can be converted into organic or inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, lactic acid, citric acid, succinic acid, maleic acid, nicotinic acid or fumaric acid by known methods. salts.

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 acceptable organic or inorganic carriers. The formulations can be used in the form of solid or thin-coated tablets, dragees, enteric dragees, pills, capsules, liquid suspensions, solutions and emulsions. Talc, starch, gelatin, water and polyethylene glycols can be used as carriers. Optionally, the formulation may also contain other excipients, such as wetting agents, emulsifying and dispersing agents, salts and fluids to promote the change in osmotic pressure, disintegrants and / or other therapeutically active agents.

The process according to the invention is illustrated in more detail by the following example.

Example

(a) 30 g of N- (1-phenyl-2-propyl) -N- (3-halopropylpropylbenzylamine), 21 g of 3,3-diphenylpropylamine and 15 g of potassium carbonate are heated under stirring in 80 ml of dimethylforman for 16 hours at 70 DEG C. After filtration, the solvent is distilled off in vacuo and the residue is taken up in 80 ml of glacial acetic acid and hydrogenated in the presence of 0.5 g of platinum oxide at 70 DEG C. and at a pressure of 0.3 MPa for approximately 8 hours. The mixture was diluted with 100 ml of methanol and the solvent was distilled off, the residue was heated with 50 ml of concentrated hydrochloric acid for 4 hours, then concentrated in vacuo on a water bath and the residue was recrystallized twice from methanol to give N- (3,3-diphenylpropyl). N '- (1-phenyl-2-propyl) propylene-1,3-diamine dihydrochloride, melting at 235-236 ^° C.

(h) 65 g of N- (1-phenyl-2-propyl) -3-amino-1-propanol produced in accordance with Japanese Patent No. A 9813 ('67), 40 g of benzyl chloride, 150 ml of ethanol and 24 potassium carbonate are heated to boiling until gas evolution ceased and the cooled solution was filtered and concentrated in vacuo. The residue is reacted in 130 ml of chloroform with 80 g of thionyl chloride for 1 hour and heated in a water bath until gas evolution in the water bath is complete, analogously to the method described in U.S. Pat. No. 2,600,301. The salt is taken up in water, made alkaline with ice-cooling and extracted with ether. The ether solution is dried over sodium sulphate, filtered and distilled off to give crude N- (1-phenyl-2-propyl, 1) -N- (3-chloro-1). ^-For! propyl) benzyl, min (80 g) as an oil and as such immediately processed further.

Dilating effect of N- (3,3-diphenylpropyl) -N '- (l-phenyl-2-piropyl) propylene-l, 3-diamine dihydrochloride, ^and Compound L, manifested coronary vasodilatory effect in vitro on guinea-pig heart according to Langendorff, is as compared to prenylamine and papaverine are given in the following table:

Compound

Dose mg

TABLE Number of attempts

Increase of flow rate in% of original flow rate

Duration of action

l ^a 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, compound I ^and Antiadrenalin effect in mice found

in terms of potency and duration 'considerably more advantageous than the comparison preparations, which also shows that the compound I ^and has no detrimental effect on the heart as prenylamine.

In vivo according to Nieschulz (1955) for Compound 1 ^{and the} ED 50 = 1.9-2 (1.20-3.07) mg / kg i.v. for prenylamine, the ED 50 = 2.55 (1.50-4. 34) mg / kg iv

Antia, the rhythmic effect of Lawson (1958) for compound 1 ^{and the} ED 50 = 25.5 (19.9 to 32.6) mg / kg s.c, for prenylamine ED 50 = 84.0 (61.7-114, 3) mg / kg.

adrenaline iv lethal dose (LD 10) survival: effective dose for compound 1 ^and ED 50 = 48 (32.2 - 70.6) mg / kg s.c, for prenylamine ED 50 = 21.0 (11.8 - 37, 3 mg / kg.

Locally anesthetizing effect of compound L ^and the cornea was examined on guinea pig by requiere (1923). Concentrations effective in 50 ^well / animal of 0.38 (0.31 to 0.36]% for compounds I ^and an effective concentration prenylamine, producing the same effect of 0.2 (0.13 to 0.32%}.

Claims (4)

SUBJECT A process for the preparation of novel (N-3,3-diphenylpropyl) propylenediamine derivatives of the general formula I wherein R ¹ and R ¹ are C 1 -C 4 alkyl, phenyl or benzyl and their salts, characterized in that they are converted to propylamine of formula II acts with the halide of formula III of the invention R / X - (C 2) 3 —N — CH I \ AR ¹ (IH) wherein R and R ¹ are as defined above, A represents a hydrogen atom or a C 1 -C 4 aralkyl group and X a halogen, in the presence of an organic solvent and an acid-binding agent, the aralkyl group A is hydrogenolytically cleaved and optionally converting the base obtained with inorganic or organic acids into an addition salt. 2. A process according to claim 1, wherein N- (1-phenyl-2-propyl) -N- (3-chloro-1-propylbenzylamine) is used as the compound of formula III for the reaction with diphenylpropylamine. 3. A process according to claim 1, wherein the organic solvent is alcohol, acetone, benzene or, in particular, dimethylformamide. 4. Process according to claim 1, characterized in that the acid binding agent used is an inorganic base, in particular potassium carbonate, or an excess of the reacting base.