CS203057B2 - Method of producing novel derivatives of n-/3,3-diphenyl propyl/-propylendiamine - Google Patents

Abstract

Title compds. are of formula:- Ph2CH(CH2)2N(A)(CH2)3N(B)CHRR1 (I), where A and B = H, acyl, alkyl, or aralkyl; R1 and R = alkyl, aryl or aralkyl, or CRR1 = cycloalkyl, and salts of (I). (I) are prepd. by condensation or reductive condensation of appropriate fragments, e.g. (a) reductive condensation of: Ph2CH(CH2)2N(A)(CH2)3NH with RR1C=O, or of Ph2CHCH2-CHO, with HN(A')(CH2)3N(B)CHRR1, where A H, alkyl or aralkyl, or (b) condensation of Ph2CH(CH2)2NHA' and Hal(CH2)3N(B)CHRR1 or Ph2CH(CH2)2Hal and HN(A'(CH2)3N(B)CHRR1.

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 increasing blood flow in coronary arteries and as antiarrhythmic medicaments .

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, 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.

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

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

where A and B are hydrogen or acetyl, R and R ¹ are each independently methyl, phenyl or benzyl or together with the carbon atom to which they are attached form a cyclohexyl group and their acid addition salts have -distributing effect on coronary blood vessels and antiarrhythmic effect. In addition, they have locally anesthesia and α-adrenaim effect at low toxicity. Their particularly advantageous property is the ease of solubility of their salts with inorganic and organic acids and their very good absorption.

It has further been found that the compounds of formula (I) and their salts can be obtained according to the invention by reacting N- (3,3-diphenylpropyl) propylenediamine of formula (II).

Wherein A is as hereinbefore defined, condenses, reductively, preferably in the presence of an organic solvent, with a ketone of formula III

R

Z o = c

R 1 (Ш), wherein R and R 1 are as hereinbefore defined, in one or two steps in the presence of an organic solvent, and in the compounds of formula I thus obtained, the group A and / or V are optionally replaced, for example by acylation, alkylation , aralkylation, debenzylation, and / or neibo, the obtained compounds are converted into their salts by inorganic or organic acids.

The reduction condensation can be carried out in two steps, whereby the diamines of the formula II and the carbonyl compounds of the formula III give rise to a Schiff base, which is then further reduced. The condensation can be carried out preferably in an organic solvent, for example benzene or toluene. This step can be accelerated by using an azeotropic distillation head. The reduction of the Schiff base can preferably be carried out by catalytic hydrogenation in the presence of conventional metal catalysts or noble metal catalysts such as palladium, platinum or nickel. The solvent used is, for example, alcohol or diexane. The reduction can also be carried out with hydrogen at birth, for example in the presence of aluminum amalgam and alcohol, sodium amalgam, sodium hydride borohydride, lithium aluminum hydride and alcohol. The reduction can also be carried out electrolytically.

Reductive condensation of the carbonyl compounds of formula III can also be carried out in one step when the condensation is carried out in the same vessel. It is preferably used as an ethanol solvent and as a palladium-on-carbon catalyst.

The diamine compounds of formula II can be obtained in almost theoretical yield when treated with acrylonitrile to 2,3-diphenylpropylamine. The 3- (3,3-diphenylamino) propionitrile thus obtained (where A = H), which can optionally be acylated (A = an aryl group), is catalytically reduced.

Compounds of formula (II) may preferably be N- (3,3-diphenylpropyl) propylene-1,3-diamine or N- (3,3-diphenylpropyl) -N-acetylpropylene-1,3-diamine and may be used as compounds of general formula (II). of formula III of phenylacetone or cyclohexanone.

In the compounds of formula I, groups A and / or V can be interchanged. The conversion can be effected by known methods, for example, if the symbolic are glycols and / or В hydrogen, these can be exchanged for the acyl s.kup ^Nu. An acid anhydride or halide is used as the acylating agent 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. Inertillation may be carried out with inert organic solvents such as benzene, but a solvent such as acetic anhydride may also be used as the acylating agent. When A and / or V are hydrogen, the hydrogen atom can be converted into alkyl or aralkyl groups using alkyl halides or aralkyl halides, alkyl sulfates, aralkyl sulfates or the like. The reactions are conveniently carried out in an organic solvent and in the presence of an acid binding agent (e.g., an alkali metal carbonate, an acidic alkali metal carbonate), but bases to be alkylated may also be used as the acid binding agent. As solvents, alcohols, acetone or dimethylformamide may be advantageously used. When A and / or N are acyl in the compounds of the formula I, they can be replaced by a hydrogen atom by heating with aqueous acid to boiling. Hydrochloric acid is preferably used as the acid. The benzyl group can be replaced by a hydrogen atom in the usual manner.

From the compounds of formula I prepared by the process according to the invention, they can be obtained by reaction with organic or inorganic acids, for example with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, succinic acid, maleic acid, nicotinic acid or lactic acid, citric acid. , fumaric acid of the corresponding salt.

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 preparations can be used in the form of solid or thin-coated tablets. , enteric 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, emulsifying and suspending agents

The agents, salts and buffering agents promoting osmotic pressure change, disintegrating agents and / or other therapeutically active agents.

The following examples illustrate the process according to the invention.

Example 1

(a) Dissolve 80,5 g of N- (3,3-diphenylpropyl) propylene-1,3-diamine and 40,2 g of phenylacetone in 500 ml of benzene in a flask equipped with azeotropic distillation head for water and heat the resulting solution for 4 hours. hours to boil. After the benzene was distilled off, the residue was dissolved in 500 ml of ethanol and hydrogeinated at 70 ° C and 1 bar pressure using an activated carbon catalyst and 8% palladium for 5 hours. After filtration and acidification with an ethanolic solution of hydrogen chloride, the mixture was cooled in a refrigerator and filtered. After drying, 113 g of N- (3,3-diphenylpropyl) -N- (1-phenyl-2-propyl) propylene-1,3-diamine dihydrochloride (Compound (A)), m.p. 238 DEG-237 DEG C. are obtained.

Dilating effect of compound L ^and manifesting coronary vasodilatory effect in vitro on guinea-pig heart according to Langendorff is compared with the effect prenylamine listed in the following table:

TABLE compound dose number increase flow rate in% time mg experiments original flow effect

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 is apparent from the results, the compound T in terms of potency and duration considerably more advantageous than the comparison preparations, which seems also that the compound I ^and manufactured according to the invention has no detrimental effect on the heart as prenylamine.

In vivo according to Nieschulz (1955) for Compound 1 ^and ED 50 = 1.92 (1.20-3.07) mg / kg iv; for prenylamine ED 50 = 2.55 (1.50 to 4.34) mg / kg iv

The antiarrhythmic effect of Lawson (1958) for λ ED 50 = 25.5 (19.9 to 31.6) mg / kg s.c; for prenylamine ED 50 = 84.0 (61.7 - 114.3) mg / kg.

Antiadrenaline effect in mice as determined by the survival of the lethal dose (LD 10) of adrenaline iv: 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.

Locally anesthetizing effect of compound L ^and is determined on the cornea of guinea pig by requiere (1923). Concentration effective in 50% of animals: 0.38 (0.31 - 0.36)% for compound Г. The effective prenylamine concentration producing the same effect is 0.2 (0.13 - 0.32)%.

(b) 53 g of 3- (3,3-diphenylpropylamino) propionic acid nitrile is hydrogenated in 500 ml of ethanol containing 0.08 g of ammonia / ml in the presence of 20 g of Raney nickel catalyst at 70 ° C and pressure of 1.1 MPa for about 4 hours.

After cooling, the reaction mixture was concentrated under reduced pressure to give 53 g of N- (3,3-diphenylpiropropyl) propylene-1,3-diamine as a residue. Upon dissolution in ether and addition of ethanolic hydrogen chloride solution, the hydrochloride is formed at 20 ^DEG C. with a melting point of 247 DEG to 248 DEG C. in almost theoretical yield.

(s) 53.1 g of acrylic nitrile are added over a period of 30 minutes while cooling and stirring to 211.3 g of 3,3-diphenylpriopylamine. The mixture was stirred at room temperature for 5 hours and on a water bath for 5 hours, then distilled under reduced pressure. There were obtained 243 g of the nitrile of 3- (3,3-difluoro-phenylpropyl propylamino) propionic acid, boiling point 195-197 ° C at 133 Pa, and melting point of 54 ^Q C.

Example 2

8.0 g of N- (3,3-diphenylpropyl) propylene-1,3-diamine and 4.0 g of phenylacetone are dissolved in 50 ml of benzene and the solution is heated to boiling for 4 hours in a flask equipped with an azeotropic distillation head. After benzene was distilled off, the residue dissolved in a mixture of 1 ml of water and 30 ml of methanol was treated with 1.5 g of sodium borohydride with stirring at 25-35 ° C for 40 minutes. The mixture was allowed to stand for 4 hours at 35 ° C. The methanol was distilled off and the residue was dissolved in aqueous hydrogen chloride solution. After extraction with ether, the aqueous solution is rendered alkaline, extracted with benzene and, after drying, the benzene is distilled off. 6.9 g of N- (3,3-diphenylpropyl) -N- (1-phenyl-2-propyl) -pylene-1,3-dlamine remain. From 3.86 g of the base is formed by reaction with 2.32 g of maleic acid dimalate, m.p. 215 ° C.

Example 3

Dissolve 1,3,4 g of N- (3,3-diyllenepropyl) propylein-1,3-diamine and 6,0 g of acetophenone in 80 ml of benzene and heat to boiling for 4 hours. The residue is taken up in 200 ml of ethanol and hydrogenated in the presence of 30 g of a palladium-on-charcoal catalyst containing 8% palladium at 80 DEG C. and at a pressure of 1.6 MPa for about 24 hours. addition of ethanolic hydrogen chloride solution gave 15.5 g of N- (3,3-diphenylpropyl) -N- (1-phenylethyl) propylene-1,3-diamine dihydrochloride, m.p. 223-225 ° C.

Example 4

13.4 g of N- [3,3-diphenyl-propyl] propylene-1,3-diamine and 4.9 g of cyclohexanone are dissolved in 80 ml of benzene and the solution is heated at reflux for 4 hours. After benzene was distilled off, the residue was taken up in 200 ml of ethanol and hydrogenated in the presence of 5 g of active catalyst. about 8 carbon .s / ₀ palladium, at a temperature of 80 ^C ° C and a pressure of 1.1 MPa. After filtration and concentration, 16 g of N- (3,3'-diphenylpropyl) -N'-cyclohexylpropylene-1,3-diamine dihydrochloride having a melting point of 260 DEG C. are obtained from the residue.

EXAMPLE 5 g of N- (3,3-diphenylpropyl) -N-acetylpropylene-1,3-diamine are dissolved together with 13.4 g of phthalic acid in 80 ml of benzene and heated at room temperature for 4 hours. The benzene was distilled off, the residue was dissolved in 50 ml of methanol and 1 ml of water and hydrogenated with 4 g of sodium borohydride at 35 ° C with stirring for 4 hours. 50 ml of water gave 40 g of oily ¹ N- [3,3-diphenylpropyl] -N-acetyl-N '- (1-phenyl-2-propyl) -propyl l-3-diamine. After boiling for 15 hours with 10% hydrochloric acid and distilling off the hydrochloric acid and recrystallizing from ethanol, N- (3,3-diphenylpropyl) -N'- [1-phenyl-2-propyl] propylene-1 dihydrochloride is obtained, 235 DEG-236 DEG C. 3-diamine.

Claims (5)

A process for the preparation of the novel N- [3,3-diphenylpropyl) propylenediamine derivatives of the general formula I wherein A and B are hydrogen or hydrogen. acetyl, R and Rt are each independently methyl, phenyl or benzyl; or together with an atom. the carbon to which they are attached forms a cyclohexyl group, and their acid addition salts, characterized in that the N- (3,3-diphenylpropyl) propylenediamine of formula II wherein A is as defined above is condensed with a ketone of formula III R O = C Rt (III), where R. and R 1 are as defined above, in one or two. steps in the presence of an organic solvent and as follows. the group A and / or B optionally obtained is exchanged, for example by acylation, alkylation, aralkylation, debenzylation, and / or. the obtained compounds are converted by inorganic or organic compounds. organic acids to their salts. 2. A process according to claim 1, characterized in that N- [3,3-diphenylpropyl) propyl] -1,3-dlamine or N- (3,3-iodo) (N- (3,3-diphenylpropyl) propylene) is preferably used as the compound of formula (II): N-acyl-propylene-1,3-diamine and, as compounds of formula III, phenylacetone, acetophenone or cyclohexanone. 3. A process according to claim 1, wherein the reduction condensation is carried out in two stages, firstly condensing in the presence of organic. solvent, preferably benzene or toluene, whereupon the resulting Schiff base is reduced. 4. Process according to claim 3, characterized in that the reduction is carried out by hydrogenation, preferably in the presence of palladium, platinum or nickel catalysts. hydrogen with birth, preferably aluminum or sodium amalgam, sodium borohydride or hydride in the presence of an organic lithium aluminum hydride. cements, preferably ethyl alcohol, with palladium on ac- 5. A process as claimed in claim 1 in which the carbon is a catalyst. the reduction condensation is carried out in one