CS211283B1 - Fluorinated 1-phenoxy-2- (3,3-diphenylpropylamino) propane, their salts e. - Google Patents

Abstract

The subject of the invention is a method for preparing coronary vasodilating fluorinated amines of general formula I, in which one of the substituents R1 and R2 represents fluorine and the other hydrogen or both substituents represent fluorine, by reductive alkylation of 3,3-bis(R2-phenyl)propylamines with 4-R1-phenoxyacetone.

Description

The present invention provides a process for the preparation of the coronary vasodilatory fluorinated amines of formula I,

wherein one of R 1 and R 4 is fluoro and the other hydrogen or both are fluoro, by reductive alkylation of 3,3-bis (R 2 -phenyl) propylamines with 4-R, -phenoxyacetone.

21,283

The invention relates to 1-phenoxy-2- (3,3-diphenylpropylamino) propane fluorine derivatives of the general formula I,

CHq (I) r ₂ -A: chch ₂ ch ₂ nchch ₂ wherein one of R 1 and R 8 is fluorine and the other hydrogen or both are fluorine atoms and pharmaceutically acceptable salts thereof with inorganic or organic acids, as well as A process for the preparation of the fluorine derivatives of the general formula (I).

Fluorivatives of formula (I) are novel substances not yet described. In pharmacological evaluation in dogs under pentobarbital anesthesia, they increase coronary blood flow and partial oxygen pressure in the blood flowing out of the coronary sinus, i.e. in doses of the order of 10 ' or 10 -6 mol / kg.

Also in the isopranaline-impaired myocardial hamsters stress test, which measures the duration of the test animals as compared to the control group, the fluorinated amines I are highly effective and outperform some clinically used coronary vasodilators such as fendilin. Also, oral toxicity in mice is comparable to that of fendilin (LD50 = 400 to 750 mg / kg; LD50 of fendilin = 650 mg / kg). These results indicate the usefulness of fluorinated amines I for the treatment of ischemic heart disease, angina pectoris and some other circulatory diseases.

According to the invention, the fluorinated amines I can be prepared by reacting the amines of formula II with a ketone of formula XII, and the resulting imine of formula IV is reduced without isolation. The substituents in formulas II, III and IV (R1 and R2) have the same meaning as in formula I.

The reaction can be carried out in a lower aliphatic alcohol, preferably methanol, and the resulting imine IV is hydrogenated without isolation using conventional hydrogenation catalysts such as platinum oxide, palladium on charcoal or Raney nickel at 20 ° C to the boiling point of the solvent used. . Upon completion of the hydrogen uptake, the solvent used is evaporated and the crude base I residue is converted by neutralization in a lower aliphatic alcohol such as methanol or ethanol by treating the crystalline salts with pharmaceutically usable inorganic or organic acids.

The starting amines II and ketones III are mostly known. 3,3-Diphonylpropylamine can be prepared, for example, according to Polish Patent 56,369 (Chem. Abstr. 71, 30,202 (1969)) by pressure hydrogenation of 3,3-diphenylpropionitrile on Raney nickel in methanol saturated with ammonia at 90 to 00 ° C. The preparation of phenoxyacetone is also described in the literature (Moed H. D. and van Dijk J., Rec. Trav. Chim. 75, 1 215 (1959)). 3,3-Bis (4-fluorophenyl) propylamine can be prepared by a known method by reducing 3,3-bis (4-fluorophenyl) propionitrile with a mixture of lithium aluminum hydride and aluminum chloride (Spanish Pat. 398,516; Chem. Abstr. 83, 78,816 (1975)) or in a novel manner, by degradation of the known 4,4-bis (4-fluorophenyl) butanoic acid (cf. author, certificate 176 805) by azoimide in chloroform or benzene in the presence of sulfuric acid. Details of this procedure are given in the examples.

Of the starting ketones III, the novel substance is 4-fluorophenoxyacetone. One can prepare a reaction of the known 4-fluorophenol (Benington F. et al., J. Org. Chem. 18, 1 506 (1953)) with chloroacetone in boiling acetone in the presence of anhydrous potassium carbonate and a small amount of sodium iodide.

Further details of the preparation of the fluorinated amines I and of some of the starting materials are described in the examples, which are only illustrative of the possibilities of the invention, but are not intended to fully describe all these possibilities.

He did

4-Fluorophenoxyacetone

To a mixture of 60 g of 4-fluorophenol, 112 g of anhydrous potassium carbonate and 2 g of sodium iodide in 270 ml of anhydrous acetone, a solution of 69.2 g of chloroetone in 90 ml of anhydrous acetone was added dropwise with stirring over 1.5 hours. The mixture was stirred and heated to boiling for 4 hours. After cooling, dilute with 1000 ml of water and shake the product three times with 200 ml of ether. The combined ethereal solutions are washed 6x with 50 ml of 5% sodium hydroxide solution and, after drying over anhydrous sodium sulfate, the ether is distilled off. The oily residue was fractionated under reduced pressure. The main fraction, bp 119-121 ° C at 2 kPa (61.9 g, 68.8 µl), is 4-fluorophenoxyacetone sufficiently pure for further use (n = 0 = 1.4970).

Example 2

3,3-bis (4-fluorophenyl) propylamine

To a mixture of 55.2 g 4,4-bis (4-fluorophenyl) butyric acid, 120 ml conc. sulfuric acid and 1000 ml of benzene, heated to 45 [deg.] C., are added portionwise over 16 hours with 16 g of sodium azide. The mixture was stirred at about 40 ° C for 4 hours. After cooling, it is poured into 1000 ml of ice-water with stirring. The benzene layer is separated and shaken twice with 200 ml of 20% sodium hydroxide solution, washed with water and, after drying with anhydrous potassium carbonate, the benzene is distilled off. Distillation of the residue (43.4 g) yielded 33.5 g (68%) of 3,3-bis (4-fluorophenyl) propylamine (bp 110-111 ° C / 6.7 Pa) which was sufficiently pure for further purification. use. For identification, it can be converted by neutralizing with hydrogen chloride in a mixture of ethanol and an excess of ether to give crystalline hydrochloride, m.p. 141.5-143 ° C.

Example 3

1- (4-Fluorophenoxy) -2- (3,3-diphenylpropylamino) propane

A mixture of 6.3 g of 3,3-diphenylpropylamine, 10.1 g of 4-fluorophenoxyacetone and 0.3 g of platinum oxide in 60 ml of methanol is shaken under an atmosphere of hydrogen at room temperature until the consumption of hydrogen (ca. 1200 ml H2, 5 hours). The catalyst was filtered off, washed with methanol and the filtrate was evaporated. The residue containing the base of the title compound was converted to crystalline hydrogen fumarate (10.6 g, 73.7%) after crystallization from ethanol / ether by neutralizing a solution in ethanol (30 mL) with 3.5 g of fumaric acid and adding 150 mL of ether. mp 145-47 ° C.

Example 1 a d 4

1-Phenoxy-2- (3,3-bis (4-fluorophenyl) propylamino) propane

Analogously to Example 3, 4.95 g of 3,3-bis (4-fluorophenyl) propylamine, 6.2 phenoxyacetone and 0.22 g of platinum oxide are hydrogenated in 40 ml of methanol at 20 ° C. Approximately 1,100 ml of hydrogen are consumed per hour. The basic product was converted to crystalline hydrogen fumarate (6.3 g, 65.3%) which had a melting point of 157-169 ° C after crystallization from a mixture of methanol and ether.

Example 5

1- (4-Fluorophenoxy) -2- [3,3-bis (4-fluorophenyl) propylamino] propane

Analogously to Example 3 are hydrogenated in a mixture of 7.4 g of 3,3-bis (4-fluorophenyl) propylstíúr.ua 10.1 g of 4-fluorfenoxyacetonu with 0.3 g platičltého oxide in 60 ml of methanol at 20 C. During ^OJ 50 1200 ml of hydrogen were consumed in minutes. The basic product was converted to crystalline hydrogen fumarate (12 g, 77.6%) which, after crystallization from a mixture of ethanol and ether, had mp 174-175 ° C.

Claims (3)

First Fluorinated 1-phenoxy-2- (3,3-diphenylpropylamines) propane of formula I, R ₂ -7 V r -A ₂ CHCH ₃ CH ₂ CH ₂ -O nhchch ₂ (I) wherein one of R, and R ₂ is fluorine and the other is hydrogen or both substituents are fluorine atoms, and their pharmaceutically acceptable salts with inorganic or organic acids. 2. A process for the preparation of 1-phenoxy-2- (3,3-diphenylpropylamino) propane fluoro derivatives of the general formula I according to claim 1, characterized in that the amine of the general formula XI, R ₂ -V in (II) r ₂ - () hch ₂ ch ₂ nh ₂ wherein R ₂ is the same as in formula I, and the ketone of formula III, CH ·, I = c-ch ₂ o-y-R 1 (III) in which R 1 is the same as in neutralization an inorganic or useful salt. of the formula I, undergoes a reductive amination, followed by conversion of the obtained product with an organic acid, optionally in a pharmaceutically acceptable salt. 3. A process according to claim 2, wherein the reductive amination of the amine 11 with the ketone 111 is carried out in a C1-C3 alkanol, preferably methanol, in the presence of a hydrogenation catalyst such as platinum oxide. at temperatures from 10 ° C to the boiling point of the reaction mixture.