NO792406L - ANALOGUE PROCEDURE FOR PREPARING SUBSTITUTED 2-PHENYLAMINO-IMIDAZOLINES - Google Patents

Description

"Analogy method for the preparation of

substituted 2-phenylamino-imidazolines"

This invention relates to the preparation of new, substituted 2-phenylamino-imidazoline-(2)-compounds with the general formula

and physiologically compatible acid addition salts thereof with valuable/therapeutic properties..

In formula I, Ar means the residue 2,6-dibromophenyl, 2-fluoro-6-trifluoromethylphenyl, 2-fluoro-6-chlorophenyl, 2-chloro-6-bromophenyl, 2,6-difluorophenyl, 2,4-dichlorophenyl, 2- bromo-3-chlorophenyl, 2,6-dichloro-4-hydroxycarbonylphenyl, 2,6-dichloro-4-ethoxycarbonylphenyl, 2,6-dichloro-4-methoxyphenyl or 2-bromo-6-fluorophenyl.

The compounds of formula I are prepared by:

a) Reaction of a 2-phenylimino-imidazolidine with it general formula

where Ar has the meanings given above, with a halide of the general formula

wherein Hal means a chlorine, bromine or iodine atom; or

b) Reaction of a compound with the general formula

where Ar is as indicated above, and A means a cyano group or

where Y represents an alkoxy- or alkylthio-

group with up to 4 C atoms or a sulfhydryl or amino group, with ethylenediamine or acid addition salts thereof.

In the alkylation of the 2-arylimino-imidazolidines of formula II by method a), the substitution takes place exclusively on the bridge nitrogen atom. In the case of turnover according to procedure b)

the constitution of the final compound is determined by the synthesis. In addition to the synthesis, the position of the substituents can also be determined by NMR spectroscopy. (cf. H. Stahle and'K.H. Pook, Liebigs Ann. Chem. 751, 159 ff (1971) ).

The reaction according to method a) conveniently takes place by heating the reaction components, preferably in the presence of a polar or non-polar organic solvent, to temperatures of approx. 50-150°C. The special reaction conditions are strongly dependent on the reactivity of the reaction components. It is recommended to use the halide in excess during the alkylation

and carrying out the reaction in the presence of an acid-binding agent.

In method b) it is necessary to work at too high a temperature, between 60 and 180°C. Solvents are not required. It is appropriate that the ethylenediamine used as reaction component resp. acid addition salts thereof, are used in excess.

Starting compounds of formula II are e.g. described

in Belgian patents 623,305, 687,657 and 705,944.

Compounds of formula IV are obtained by starting from anilines, by reaction with compounds of formula III and subsequent reaction of the resulting secondary amines with cyanates or thiocyanates, whereby ureas or thioureas are formed, respectively. Ureas and thioureas can then be further transferred with alkylating agents to corresponding isouronium salts or isothiouronium salts, respectively. From these acid addition compounds, bases can be used to extract the corresponding isoureas or isothioureas, respectively. The separation of water from urea or I-^S cleavage from thioureas with lead or mercuric salts leads to cyanamides, to which ammonia can be deposited with the formation of guanidines.

The new 2-phenylamino-imidazoline-(2) compds

the general formula I can be conventionally transferred to its physiologically compatible acid addition salts. Acids that are suitable for salt formation are e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, caproic acid, valerian acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, p- hydroxybenzoic acid, p-aminobenzoic acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulfonic acid, 8-chlorotheophylline etc.

The new compounds of the general formula I and

their acid addition salts have a strong bradycardic effect and are therefore suitable for the treatment of coronary disorders. Effects on heart rate have been investigated in rabbits and in spinally anesthetized rats in addition to intact, anesthetized rats.

The dosage is 0.1 to 80 mg, preferably 1 to 30 mg.

The compounds of formula I and their acid addition salts can also be used together with other active substances. Suitable galenic preparations are e.g. tablets, capsules, suppositories, solutions or powders, and for the preparation one can use the commonly used galenic aids, carriers, explosives or lubricants or substances that have a depot effect.

The following examples shall serve to illustrate the invention further, without limiting it.

Example 1

3, 5- dichloro- 4-[ N-( allyl)- N-( 2- imidazoliny1-( 2)- amino]- benzoic acid

0.7 g (0.002045 mol) of 3,5-dichloro-4-[N-(allyl)-N-(2-imidazolinyl-(2))amino]-benzoic acid ethyl ester is heated together with 0.4 g (0, 00716 mol) potassium hydroxide, 0.5 ml of water and 1 ml of ethanol 1 for a short time at 60°C. It is then diluted with water, the reaction mixture is freed from alcohol in a vacuum, and the solution is buffered with glacial acetic acid to pH 5 after filtration. The precipitated white substance is suctioned off and washed with water and dried. By salting out the mother liquor with common salt, additional quantities of material can be recovered. Yield: 0.42 g (65.4% of theory), mp: 321-323°C.

RH: 0.3, system: ethyl acetate 70, isopropanol 50, conc. NH^OI-I 20. Carrier: Silica gel G + light pigment, detector: UV and potassium iodoplatinate.

C13H13C12N3°2<314'17>

Calculated: C 49.70, H 4.17, Cl 22.57, N 13.38%

Found: C 49.50, H 4.35, Cl 22.36, N 13.40%.

Example 2

2-[ N-(allyl)- N-( 2, 6- dibromophenyl)- amino]- 2- imidazoline

6.38 g (0.02 mol) of 2-(2,6-dibromophenylimino)-imidazolidine are heated together with 10 ml of allyl bromide in 25 ml of methanol for 60 hours in a tube at 100°C. After cooling, there are two phases. The lower phase (oily mass) is dissolved in water for further processing.

The solution is then fractionally extracted with ether at increasing pH values (stepwise alkalization with 2N caustic soda). The thin-layer chromatographically uniform ether extracts are collected, dried over MgSO 4 , filtered off and evaporated in vacuo. This first precipitates an oil which after a short time crystallises through (white crystals). Yield: 1.6 g (22.3% of the theoretical), m.p.: 134-136°C.

RH: 0.5, system: benzene 50, dioxane 40, ethanol"5, conc. NH^OH 5. Carrier: silica gel G + light pigment, detector: UV and potassium iodoplatinate.

C12H13Br2N3 (359.08)

Calculated: C 40.14, H 3.65, Br 44.51, N 11.70%

Found: C 40.26, H 3.60, Br 44.25, N 11.49%.

Analogous to the previous examples, the following compounds were prepared. The melting points apply to the bases of formula I unless the salt form is indicated.

Claims (1)

Analogous process for the preparation of therapeutically active substituted 2-phenylamino-imidazoline-(2)-compounds of the general formula where Ar means the residue 2,6-dibromophenyl, 2-fluoro-6-trifluoromethylphenyl, 2-fluoro-6-chlorophenyl, 2-chloro-6-bromophenyl, 2,6-difluorophenyl, 2,4-dichlorophenyl, 2-bromo- 3-chlorophenyl, 2,6-dichloro-4-hydroxycarbonylphenyl, 2,6-dichloro-4-ethoxycarbonylphenyl, 2,6-dichloro-4-methoxyphenyl or 2-^bromo-6-fluorophenyl, and acid addition salts thereof, characterized in that a) a 2-phenyl-iminoimidazolidine with the general formula where Ar has the meanings given above, is reacted with an allyl halide of the general formula wherein Hal means a chlorine, bromine or iodine atom; orb) a compound of the general formula where Ar is as indicated above, and A means a cyano group or the residue where Y represents an alkoxy- or alkylthio- group with up to 4 carbon atoms or a sulfhydryl or amino group, is reacted with ethylenediamine or the acid addition salt thereof, and a compound prepared as stated above is optionally transferred to an acid addition salt thereof.