CS203062B2 - 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) propylenediamine derivatives, as well as their salts with therapeutically useful properties, which are primarily useful in cardiac 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, 1196 (1962); J. Med. Chemistry 7, 6:23 (1964)]. However, the salts of these compounds are poorly soluble 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 vessels and the propylenediamine phenetamide 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 local anesthesia and anti-adrenaline effects 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 the diphenylpropyl halide of the formula II

C °)

C / - / - CWnC / <- X é

wherein X is a halogen atom, acts with a diamine of formula III

R

OF

H-N- (CH 2) 3 -N-CH

I I \

AB R (ΠΙ) wherein A and B are hydrogen or aralkyl group having 1 to 4 carbon alkyl, R and R ¹ have the abovementioned meanings, in the presence of an organic solvent and acid-binding agent, an aralkyl group A and / or B and the base is optionally converted with an inorganic or organic acid into an addition salt.

The organic solvents used in the process of the invention may be ether, chloroform, benzene, acetone, alcohol or the like. 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. When A and / or Inibo B are benzyl, the catalytic hydrogenation can be exchanged for a hydrogen atom 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 an platinum or palladium catalyst.

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

The compounds of the formula (I) prepared according to 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, dragees, non-ether 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 dispersing agents, salts and buffering agents for promoting osmotic pressure change, disintegrating agents and / or other therapeutically active agents.

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

Example

18.8 g of N- (1-phenyl-2-propyl) -3-aminopropionic nitrile (produced according to French Patent No. 1,458,423) is dissolved in 50 ml of pyridine and the solution is allowed to react with stirring at a temperature of not more than 50 ml. ° C with 8 g of acetyl chloride. Stirring was continued for an additional hour at 40 ° C and then the solvent was distilled off in vacuo. The residue is triturated with 50 ml of a 5% sodium hydrogen carbonate solution. It is then filtered and, after drying, the crude acetyl derivative is hydrogenated in 100 ml of ethanol after addition of 10 g of Raney nickel catalyst at 70 [deg.] C. under a pressure of 10 bar (duration about 6 hours). After filtering and distilling off the solvent, N- (1-phenyl-2-propyl) -N-acetylpropylene-1,3-diathain remains, which is dissolved in 100 ml of dimethylformamide. After addition of 10 g of potassium carbonate and 23 g of 3,3-diphenyl-propyl chloride, it is heated at 60 ° C for 14 hours with stirring. After cooling, the mixture is evaporated in vacuo and the residue is heated to boiling for 10 hours with 100 ml of 10% hydrochloric acid. The hydrochloric acid was distilled off and the residue was recrystallized from ethanol. N- (3,3-diphenylpropyl) -N- (1-phenyl-2-propyl) propylene-1,3-diamine dihydrochloride melting at 234-236 ° C is obtained.

Dilating effect of N- (3,3-difetoyilpropyl) -N '- (l-phenyl-2-propyl) propylene-l, 3-dtaimindihydrochloiridu compounds L ^and manifesting' with coronary vasodilatory effect in vitro "guinea pig Langendorff heart is compared to preinylamine and papaverine in the following table:

TABLE

Compound Dose mg Number of attempts Increase of flow rate in% of original flow rate Time of grip 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 and 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 is apparent from the results, the compound is ^{l, and} in terms of potency and duration considerably more advantageous than the comparison preparations, which also projévuije that Compound list ^{L, and} has no detrimental effect on the heart as · prenylamine.

In vivo according to Nieschulz (1955) for Compound 1 ^and ED 50 = 1.912 (1.20-3.07) mg / kg iv, for Prenylamine ED 50 = 2.55 (1.50 to 4.34) mg / kg iv

The antiarrhythmic effect according to Lawson (1958) for compound 1 ^{and the} ED 50 = 25.5 (19.9 to 32.6) mg / kg sc, for prenylamine the ED 50 = 84.0 (61.7 - 114.3) mg / kg .

Anti-adrenaline effect in mice at the lethal dose (LD10) of adrenaline iv survival: 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.

The locally anesthetizing effect of compound Γ was assessed on guinea pig cornea according to Requier (1923). The concentration of active at 50 ® / o animals: 0.38 (0.31 to 0.36)% for compounds I ^and an effective concentration prenylamine, producing the same effect is 0/2 (0.13 to 0.32) ° / o .

píedmet

Claims (4)

A process for the preparation of the novel N- (3,3-diphenylpropyl) propylenediamine derivatives of the general formula I R CH-CH 2 CH-NH- (CH 2 NH-CH 2 - (I) wherein R and R ¹ are C 1 -C 4 alkyl, phenyl or benzyl and their salts, characterized in that they are a diphenylpropyl halide of formula II * (II) wherein X is a halogen atom, acts with a diamine of formula III Η — N— (CHzja — N — CH ^{11 1} \ AB R1 (HI) wherein A and B are hydrogen or C1 -C4 aralkyl, R and R1 are as defined above, in the presence of an organic solvent and an acid-binding agent, aralkyl group A and / or B is hydrogenolytically cleaved and the base is optionally converted with an inorganic or organic acid into an addition salt. 2. A process according to claim 1, wherein 3,3-diphenylpropyl chloride is reacted with N- (1-phenyl-2H-propyl) -N-acetylpropylene-1,3-diamine. 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 organic base.