CS203060B2 - 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 medicaments for increasing blood flow in coronary vessels and as antiarrhythmic medicaments.

Diphenylpropylamine derivatives are known to have beneficial therapeutic properties [Arzneimittel-Forschung, 10, 569, 573, 583 (1960); Sheet. Pharm. 295, 196 (1962); J. Med. Che ©

CH-CH3CH3N-CH3JH

IstryοΊ Masters 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 hexohendium diamine derivative has an expanding effect on coronary vessels and the propylenediamine phenetadiamine dihydrochloride 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 is an alkyl group having 1 to 4 carbon atoms, and their acid addition salts have a coronary vascular expansion and antiarrhythmic effect. In addition, they have a local anesthesia and anti-adrenaline effect at low toxicity. Their particular property is the easy solubility of their (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 reacting the amines of the formula II

CH-CH ₃ CH ₃ -N- (CH ₂ OH, ^H where R is as defined above) in a Friedel-Crafts reaction with benzene at the boiling point of the solvent and the compounds of formula I thus obtained are optionally converted by reaction with an inorganic or organic acid to their salt .

The compound of the formula II is preferably N- [3-phenyl-3-hydroxypropyl) -N- (1-phenyl-2-propyl) propylene-1,3-diamine hydrochloride and aluminum chloride catalyst.

The above reaction can be carried out according to Swiss Patent No. 438,352. The reaction is carried out by means of a Fredel-Crafts catalyst, for example aluminum chloride, conveniently at the boiling point of the solvent. As the solvent, benzene alone or another inert solvent may be used. The reaction may also be carried out starting from 1-phenyl-1,2-alkyl amine derivatives, which may be prepared from the corresponding compounds of formula II by cleavage of water or hydrohalic acid.

The compound of formula (II), as the starting compound for the reaction, can be prepared by reacting 1-phenyl-1-hydroxy-3- (2-cyanomethylamino) propane obtained by the reaction

3-phenyl-3-hydroxypropylamine with acrylonitrile, catalytically reduced, and the thus obtained propylenediamine is condensed with the corresponding carbonyl compound while reducing. .

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

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 may be used in the form of solid or coated tablets, dragees, pills, capsules, liquid suspensions, solutions and emulsions. Talc, starch, gelatin, water and propylene glycols can be used as carriers. The formulations may optionally contain other excipients, for example wetting agents, emulsifying and suspending agents, salts and buffering agents for altering the osmotic pressure, disintegrants and / or other therapeutically active agents.

The process according to the invention is explained in more detail

(II), however, the invention is not limited thereto.

Example

To 15.1 g of 3-phenyl-3-hydroxypropyl amine, 5.4 g of distilled acrylonitrile was added with stirring at 40 ° C, and the mixture was kept at 60 ° C for 5 hours. The crude 1-phenyl-1-hydroxy-3- (2-cyainoethylamino) propane thus obtained is dissolved in 100 ml of 2% alcoholic ammonia and, after addition of 5 g of Raney nickel catalyst, is hydrogenated at 60 ^DEG C. and at 11 atm. After completion of hydrogen uptake (after about 6 hours), the cooled solution was filtered and evaporated under reduced pressure. The remaining N- (3-phenyl-3-hydroxypropyl) propylle-1,3-diamine was dissolved in 50 ml of hemenuene and added to the solution.

14.5 g of phenylacetone. The solution was heated to boiling for 1 hour and after benzene was distilled off, the residue was dissolved in 50 ml of methanol. 2 ml of water are then added and the mixture is treated with 3.5 g of sodium borohydride for 2 hours at 30-40 ° C with stirring. The solvent was distilled off, the residue was taken up in ether and the solution was filtered. Acidification with an alcoholic solution of hydrogen chloride gives crystalline N- (3-phenyl-3-hydroxypropyl) -N '- (1-phenyl-2-propyl) propylene-1,3-diamine dihydrochloride. The reaction mixture was suspended in 100 ml of benzene and not stirred with 40 ml of thionyl chloride for 30 minutes with stirring, the suspension was kept at 40 DEG C. for 1 hour, concentrated by water pump and the residue was taken up in 100 ml of benzene. allowed to react for 1 hour at a temperature of 55 to 60 ^Q C. the reaction mixture was further heated to reflux for 2 hours to. terminate the reaction and after cooling, poured onto a mixture of hydrochloric acid and ice. the benzene layer was separated, washed with water and benzene. the combined aqueous The extracts are made strongly alkaline under ice-cooling, extracted with ether, and the ether solution is dried over sodium sulphate. 1,3-dia m.p. 230 DEG-234 DEG C. After recrystallization from ethanol, the temperature is raised to 235 DEG to 236 DEG C. The melting point of the solid is about 100 DEG.

Dilating effect obtained compound (l ^a), manifested as coronary vasodilatory effect in vitro on guinea-pig heart according to Langendorff, compared to the effect prenylámihu is given in the following table:

duration of action

TABLE Compound Dose mg Number of Flow Increases in% of Original Flow Experiments

, l ^a 50 100 ALIGN! 500 16 11 4 Prenylamine 50 14 100 ALIGN! 10 500 4 PapaveTin 50 14 100 ALIGN! 11 500 4 As follows from the results, is sioučelnina

in terms of potency and duration considerably more advantageous than comparable preparations, which also appears in Itoi, the compound I according to the invention ^and has no deleterious effect on the heart as prenylamine.

In accordance νί'νο Nieschulze (1955) is the compound l ^and: ED = 1.92 (1.20 to 3.07) mg / kg

i.'v .; for laminate prEN: ED50 = 2.55 (1.50-4.34) mg / kg i.v.

Antiarrhythmic effect by Lawson (1958) is the compound l ^and: ED = 25.5 (19.9 to 32.6) mg / kg sc; for prenylamine: ED 50 =

51.5 + 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

= 84.0 (61.7-114.3), mg / kg s.c.

Anti-adrenaline effect in mice, determined by the survival of the lethal dose (LD10) of adrenaline

also effective dose in the compounds l ^and: ED = 48 (32.2 to 70.6) mg / kg sc; for prenylamine: ED 50 = 21.0 (11.8 - 37.3) mg / kg sc

Locally anesteizující effect of Compound I ^and is determined on the cornea of guinea pigs share requiere (1923). Concentrations effective in 50% of the animals is 0.38 (0.31 to 0.36)% for compounds l ^and. The effective prenylamine concentration producing the same effect is 0.2 (0.13 - 0.32)%.

Claims (2)

OBJECT OF THE INVENTION A process for the preparation of novel N- (3,3-diphenylpropyl propylenediamine derivatives of the general formula I) CH-CH3NfCH3N-CH R (II wherein R is C 1 -C 4 alkyl, and acid addition salts thereof, characterized in that the amine of formula (II)) wherein R is as defined above is mentioned in a Friedel-Oraft reaction with benzene to the boiling point of the solvent and the compound of formula I thus obtained are optionally converted by reaction with an inorganic or organic acid into their salt. 2. A process according to claim 1, wherein N- (3-phenyl-3-hydroxypropyl) -N '-( 1-phenyl-2-propyl) propylene-1,3- diamine and as an aluminum chloride catalyst.