CS203059B2 - 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 heart diseases as coronary artery blood flow enhancing drugs 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. Chemistry 7, 623 (1964)]. The salts of these compounds are difficult to dissolve in water and therefore can be used for injection purposes only to a limited extent.

Further, it is known that the hexobendium ethylenediamine derivative has an expanding effect on the coronary vessels and the propylenediamine phenetamine dihydrochloride derivative has a spasmolytic effect.

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

CH-CH 2 CH 2 N-CH 3 -N-CH 3 H σ

wherein R represents a C 1 -C 4 alkyl group and their acid addition salts have a coronary blood vessel extending effect, as well as an athrhythmic effect. In addition, they have a local anesthetic and antiadrenaline effect at low toxicity. Their particular advantage is their easy solubility

CH (I) salts with inorganic and organic acids and their very good resorption.

It has further been found that the compounds of the formula I and their salts can be obtained according to the invention by the diphenylacetonitrile of the formula II

The talc, starch, gelatin, water and polyethylene glycols may be used in the CH-CN (II). The formulations may optionally contain other excipients such as wetting agents, emulsifying and suspending agents, salts and buffering agents, 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 non-limiting example.

in the presence of acid binding agents in reaction with a halide compound of formula III

where A is a benzyl group and R is as defined above and X is a halogen atom, the nitrile group and the benzyl groups are eliminated by reduction to a hydrogen atom in the product, and the compound of formula I so obtained is optionally converted to its compound by reaction with an inorganic or organic acid. salt.

Preferably, N-benzyl-N- (1-phenyl-2-propyl) -N‘-benzyl-N- (2-chloroethyl) propylene-1,3-diamine is used as the compound of formula III.

The reaction may be carried out in the presence of conventional acid binding agents. First, a cyano-substituted compound of formula (I) is obtained, which is obtained after removal of the nitrile group by known methods and after the exchange of the benzyl groups with a hydrogen atom of the compound of formula (I). at the same time sodium amide is used to remove the nitrile group, whereby the two reaction steps are carried out in a single inert solvent, for example benzene.

The compounds of formula (I) prepared according to the process of the invention can be prepared by reacting with the organic or inorganic acids, for example citric, tartaric, lactic, succinic, nicotinic, cinematographic, hydrochloric, sulfuric or phosphoric acids.

The compounds of formula I 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 tablets or, with a thin coating, dragees, pills, capsules, liquid suspensions, solutions and emulsions. As for example, g of N- (1-phenyl-2-propyl) -N- (3-chloro-1-propyl) -benzylamine, 10.7 g of benzylamine and 30 g of potassium carbonate are heated to 80 ml of dimethylformamide for 10 hours at a temperature of 70 DEG C., and at this temperature, 7.1 g of 2-chloroethanol are added dropwise with stirring over 1 hour, stirring is continued for another 5 hours, then the reaction mixture is filtered, the residue is washed with benzene, and the filtrate is concentrated under reduced pressure. Dissolve in 150 ml of chloroform and heat with 20 ml of thionyl chloride under reflux for a further 1 hour to complete the reaction, evaporate in a water bath, dissolve the residue in water, basify with ice cooling and extract with ether. The mixture was filtered and the ether distilled off to give an oily N-benzyl-N- (1-phenyl-2-propyl) -N'-behzyil-N'- (2-chloroethyl) propylene-1,3-diamine for further work-up.

21.7 g of this oil are dissolved in 100 ml of benzene and 9.7 g of diiphenylacetonitrile and 2.5 g of sodium amide are added thereto with stirring, and the mixture is heated at reflux for 2 hours. After cooling, water was added to the solution, after which the benzene layer was evaporated after drying and the residue dissolved in ether. Treatment with aqueous hydrochloric acid gives N- (1-phenyl-2-propyl) -N-benzyl-N '- (3,3-diphenyl-3-cyanopropyl) -N'-benzylpropylene-1,3-diamine dihydrochloride, which is then recrystallized from ethanol.

g of the above dihydrochloride is dissolved in water, made alkaline with cooling and extracted with 100 ml of benzene, then dried over sodium sulfate, filtered, the benzene is distilled off under reduced pressure and the residue is dissolved in 50 ml of glacial acetic acid. Thereafter, after addition of 0.1 g of platinum oxide catalyst, the reaction mixture was hydrogenated at 4 [deg.] C. and at 70 [deg.] C. for about 5 hours until the absorption of hydrogen was complete. The reaction mixture was diluted with 50 ml of methanol, filtered and the solvent was distilled off. The residue was heated in a water bath with 20 ml of concentrated hydrochloric acid for 3 hours. After distilling off the hydrogen chloride, the residue is recrystallized from ethanol to give N- (3,3-diphenylpropyl) -N'- (1-phenyl-2-propyl) propylene-1,3-diamine dihydrochloride, m.p. 236 ° C.

203039

Dilating effect above dihydrochloiridu - Compound ^A -projevující with coronary vasodilatory effect in vitro on guinea-pig heart according to Langendorff, compared to the effect prenylamine is given 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! 10 500 4 Papaverin 50 14 100 ALIGN! 11 500 4 As follows results, j- Compound ¹ e l

increase in flow rate in% of the time of initial flow of effect

51.5 + 6.5 2.7 ± 0.6 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

What diol · potency and duration considerably more advantageous than -srovnávané preparations, which is also reflected in the fact that the compound I ^and has no detrimental effect on -srdce as prenylamine.

In vivo according Nieschulze (1955) is the compound l ^and: ED = 1.97 (1.20 to 3.07) mg / kg IV; for prenylamine: ED 50 = 2.55 (1.50 to 4.34 µg / kg iv

Antiarrhythmic effect by Lawson (1958) is the compound L ^and ED50 = 25.5 (19.9 to 312.6) mg / kg sc; for prenylamine: ED 50 = 84.0 (61.7 - 114.3) mg / kg sc

The antiadrem-alin effect observed by the lethal dose (LD100) of adrenaline 1 v. Ne dose j, ^and L eu compound: ED = 48 (3i2,2 to 70.6) mg / kg sc; for prenylamine: ED 50 = 21.0 (11.8 - 37.3), mg / kg.

Locally, silents effect of Compound I ^and is determined on the cornea of guinea pig by requiere (1923). The concentration effective in 50% of the animals for Compound 1 ^and 0.38 (0.31-0.36) is why. The effective concentration of prenylamine producing the same effect is 0.2 (0.13-0.32) percent.

Claims (3)

A process for the preparation of the novel N- (3,3-diphenyl-propyl) propylenediamine derivatives of the general formula I CH x ¹ CH-CH 2 CH 3 N-f CH 3 -N-CH. '2 Z, Z3l \ O '(I) wherein R represents an alkyl group having from 1 to 4 atoms in the presence of a carbon-binding agent and an acid addition salt thereof in reaction with a halide compound (I), characterized in that the diphenylacetoacetate of the formula III a nitrile of formula II CH-CN (U1) (II) wherein A is a Heinzyl group and R is as defined above and X is a halogen atom, In the resulting product, the nitrile group and the benzyl groups are eliminated by reduction to a hydrogen atom, and the compound of formula I thus obtained is optionally converted into a gray salt by treatment with an inorganic or organic acid. 2. A process according to claim 1, wherein the compound of formula III is N-benzyl-N- (1-phenyl-2-propyl) -N'-benzyl- (2-chloryl) propylene-1,3-propylene. -diamina. 3. A process according to claim 1, characterized in that sodium amide is used as the acid-binding agent and for the elimination of the nitrile group.