CS213322B2 - Method of making the new derivatives of n-/3,3-diphenylpropyl/-propylendiamine - Google Patents

Description

CZECHOSLOVENSKAIÓfclAilSnCKAli 6 ø U B l! SH9) POPTS OF THE INVENTION 213322 (lij jii) (22) Registered 24 04 73 (21) (PV 7722-78) (51) Int. Cl.5 C 07 C 85/08 11¾ (32) (31) (33) Priority from 24 04 72 (01-1226) Hungarian People's Republic OftAD FOR INVENTIONS; AND DISCOVERY (40) Published 31 07 81 (45) Published 15 08 84 (72), ..

Author of the invention KORBONITS DEZŠO dr., HARSÁNYI KÁLMÁN dr "LESZKOVSZKY GYORGY dr., BUDAPEST, MOLŇÁR ERZSÉBET dr., SZODLIGET (MLR) (73) · ................... ......

Patent holder CHINOIN GYŮGYSZER ÉS VĚGĚYÉSŽETL TÉRMÉKÉK GÝÁRA RT., BUDAPEST (MLR) (54) Method for the production of new N- (3,3-thienyl-propyl-propylenediamine derivatives)

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BACKGROUND OF THE INVENTION The present invention relates to a process for the preparation of novel N- (3,3-diphenylpropyl) propylene diamine derivatives and their salts with therapeutically useful properties which are primarily useful in cardiac diseases as coronary blood flow enhancing and anti-rhythmic drugs. drugs.

It is believed that the diphenylpropylaminate derivatives have advantageous therapeutic properties (Arz-neimittel-Forschung 10, 569, 573, 583 (1960); Arch.Pharm. 295, 1196 (1962); J. Med. Cheese 7, 623 (1964)). However, the salts of these compounds are not readily soluble in water and can be used for injection purposes only to a limited extent, and it is further known that the hexobendium ethylenediamine derivative has an enhancing effect on coronary vessels and the propylene diamine phenethamine hydrochloride derivative has a spasmolytic effect.

It has been found that the novel propylenediamine derivatives with the 3,3-diphenylpropyl group of formula I

wherein A and B are hydrogen or acetyl, R and R 1 are independently methyl, phenyl or benzoyl, or together with the atom to which they are attached form a alkoxy group and the acid addition salts thereof; -riaWii have an expanding effect on coronary arteries and anti-rhythmic effects. In addition, it has a locally anesthetizing and anthiadrelin agent at low toxicity. Their particularly advantageous property is their ease of solubility with their inorganic and organic acids 213322 213322 and their very good resorption. Furthermore, it has been found that the

Formula I and salts thereof can be obtained according to the invention in such a way that the diphenylpropional dehydrochloride of Formula II is obtained

reductively condenses with the diamine of formula III

R /

H - N— (CH 2 N-N-Cl-II) R 1 R (ΙΠ) wherein A is hydrogen, B, R and R 1 are as defined above, in the presence of an organic solvent and the compound of formula I is optionally converted to its salts by inorganic or organic acids.

The reduction can be carried out preferably by catalytic hydrogenation in the presence of customary metal catalysts or noble metal catalysts such as palladium, platinum or nickel. As the solvent, for example, an alcohol or dioxane is used. It can be reduced. It is also possible to carry out the process with hydrogen in the presence of, for example, aluminum amalgam and alcohol, sodium amalgan, sodium borohydride, lithium aluminum hydride and alcohol. The reduction can be performed electrolytically.

Preferred compounds of formula (III) are N- (1-phenyl-2-propyl) -1,3-propyleridamine or N- (1-phenyl-2-propyl) -N-acetylpropylene-1,3-diamine.

In the compounds of formula (1), groups A and / or B can be exchanged. The transformation is effected by known methods, for example, when A and / or B are hydrogen, they can be exchanged for acylo. The acylating agent used is an acid anhydride or acid halide and the acylation is carried out in the presence of an acid binding agent, preferably in the presence of a tertiary amine such as triethylamine or pyridine. In acylation, inert organic solvents such as benzene may be used, but a solvent such as acetic anhydride may serve as acylating agent. When A and / or Batom are hydrogen, the hydrogen atom can be converted into alkyl or aralkyl groups by alkyl halides or aralkyl halides, alkyl sulfates, aralkyl sulfates or the like. The reactions are conveniently carried out in an organic solvent in the presence of an acid scavenger (for example, an alkali metal carbonate, an alkali metal carbonate), but bases for alkylation can also be used as the acid scavenger. Alcohols, acetone or dimethylformamide may preferably be used as solvents. When A and / or B are acyl in the compounds of formula (I), they may be substituted by hydrogen for heating with aqueous acid. Hydrochloric acid is preferably used as the acid. The benzyl group can be conveniently substituted with a hydrogen atom.

Salts of the compounds of the formula I can be obtained by reaction with organic or inorganic acids, for example hydrochloric, sulfuric, phosphoric, tartaric, succinic, maleic, lactic, citric, nicotinic or fumaric acids.

The compounds of formula (I) and their salts can be used in therapy in the form of therapeutic agents containing the active ingredient and inert, non-toxic, therapeutically useful organic or inorganic carriers. The compositions can be used in the form of dragees, entersoluble dragees, tablets of solid or thin coating, pills, capsules, liquid suspensions, solutions and emulsions. As carriers, talc, starch, gelatin, water and polyethylene glycols can be used. The compositions may optionally contain other excipients such as wetting agents, emulsifying and suspending agents, salts and osmotic pressure-altering promoters, dissolution enhancers and / or other therapeutically active agents.

The invention is further illustrated by the following examples. Example 1 10.5 g of 3,3-diphenylpropionaldehyde (prepared according to J. Med. Chem. 7, 623 (1964) and 9.8 g of N - (- phenyl-2-propyl) -1,3-propylenediamine (prepared by according to German Patent No. 882,002) is dissolved in 100 ml of ethanol, heated to boiling for 30 minutes and then hydrogenated at a pressure of 1.1 MPa in the presence of palladium-on-charcoal catalyst. The residue is dissolved in ether and treated with ethanolic hydrochloric acid to give the salt which is recrystallized from ethanol to give N- (3,3-di-phenyl-propyl) -N'- (1- of phenyl-2-propyl) propylene-1,3-diamine, m.p. 235-236 ° C (compound Ia).

The dilatation effect of compound 1a, manifested by coronary artery enlargement in vitro by Langendorff guinea pig lamb, is shown in the following table when compared to that of prenylamine and papaverine:

Claims (4)

5 213322 Table Compound. Dose mg Number of attempts Increase of flow rate in% of initial flow Effect time la 50 15 51,5+ 6,5 2,7 + 0,5 1,00 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 10 31.8+ 6.8 1.6 + 0.4 500 4 - - Papaverine 50 14 21,6+ 3,7 1,5 + 0,3 100 11 26,4+ 3,1 1,4 + 0,2 500 4 57,1 + 12,0 2,7 + 0,6 the compound la la: 0.38 (0.31-0.36)% of compound Ia, which is considerably more potent than the comparative formulations in the potency of action and its duration, also appears to lack the compound 1a produced by the process of the invention harmful effects on the heart such as prenylamine. In vivo, according to Nieschulz (1955), the compounds Ia and ED50 = 1.92 (1.20-3.07) mg / kg i.s. for prenylamine ED 50 = 2.55 (1.50 - - 4.34) mg / kg iv Anti-arrhythmic effect according to Lawson (1958) is for compound 1a ED 50 = 25.5 (19.9 - 32.6) mg / kg sc ; for prenylamine ED 50 = 84.0 '(61.7 - 114.3) mg / kg. The anti-adrenaline effect observed in mice by surviving the lethal dose of (LD10O) adrenaline i. V .: effective dose for compound Ia ED 50 = 48 48 (32.2-70.6) mg / kg s.c .; for prenylamine, ED 50 = 21.0 '(11.8 - 37.3) mg / kg. The locally anesthetizing effect of the compound lase is detected on the cornea by blinking according to Requier (1923). The concentration of 50% animal prenylamine concentration producing the same effect is 0.2 (0.13-0.32) pro-cent. EXAMPLE 2 21 g of 3,3-diphenylpropionaldehyde and 23.4 g of N- (1-phenyl-2-propyl) -N-acetylpropylene-1,3-diamine are dissolved in 180 ml of ethanol and heated to boiling for 40 minutes. After adding 2 ml of water, 4 g of sodium borohydride are hydrogenated with stirring at 30 DEG-35 DEG C. for 4 hours. Alcohol is distilled off and the remaining N- (3,3-diphenylpropyl) -N'- (1-phenyl-2-propyl) -N'-acetyl-propylene-1,3-diamine is heated with 2001 ml Hydrochloric acid was distilled off by boiling and the residue was recrystallized from ethanol to give N- (3,3-diphenylpropyl) -N'- (1-phenyl-2-propyl) propylene dihydrochloride. mp 234-235 ° C. SUBJECT MATTER A method for producing novel N- (3,3-diphenylpropyl) propylenediamine derivatives of Formula I R is CH-CH-CH-N- (CH 3 R 2 N-CH 3. Z is Z 2 O 2 AB fy (I) wherein A and B are hydrogen or acetyl, R and R 1 are independently methyl, phenyl or a benzyl group, or together with the carbon atom to which they are attached, form a cyclohexyl group, and their acid addition salts, characterized in that the diphenylpropionaldehyde of formula II reductively condenses with the diamines of general formula III RZ Η —N— (CH 2) 3 —N — CH 1 AB Z 1 where A represents a hydrogen atom, B, R and R (as defined above, in the presence of an organic solvent and thus the compounds of formula (I) obtained are optionally converted into their salts by inorganic or organic acids. 2. A process according to claim 1 wherein the compound of formula (III) is preferably N- (1-phenyl-2-propyl) propylene-1,3-diamine or N- (1-phenyl-2-propyl). -N-acetylpropylene-1,3-diamine. 3. A process according to claim 1 wherein the reductive condensation is carried out in the presence of palladium, platinum or nickel catalysts or hydrogen in the state of the art, preferably sodium borohydride, or lithium aluminum hydride, aluminum amalgam or sodium. 4. The process of claim 1 wherein the reductive condensation is carried out in the presence of ethyl alcohol as an organic solvent. Severografia, n. P ,, Plant 7, Most