FI69068B - FREQUENCY REFRIGERATION OF BRAKING CARDS SUBSTITUTES 2-PHENYLAMINO-IMIDAZOLINER - Google Patents

Abstract

1. Claims for the Contracting state : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE Substituted 2-phenylamino-imidazolines-(2) of general formula (I) see diagramm : EP0030616,P7,F1 wherein R represents an n-propyl, cyclopropylmethyl, cyclopentylmethyl, allyl or methallyl group, and the physiologically acceptable acid addition salts thereof. 1. Claims for the Contracting state : AT Process for preparing substituted 2-phenylamino-imidazolines-(2) of general formula (I) see diagramm : EP0030616,P8,F1 wherein R represents an n-propyl, cyclopropylmethyl, cyclopentylmethyl, allyl or methallyl group, and the physiologically acceptable acid addition salts thereof, characterised in that a) 2-(2,6-dibromo-4-methylphenyl-imino)-imidazolidine of formula II see diagramm : EP0030616,P8,F2 is reacted with a halide of general formula III Hal-R wherein Hal represents a chlorine, bromine or iodine atom and R is as hereinbefore defined, at 40 degrees C to 150 degrees C, or b) a compound of general formula IV see diagramm : EP0030616,P8,F3 wherein R is as hereinbefore defined and A represents a cyano group or the group see diagramm : EP0030616,P8,F4 wherein Y represents an alkoxy or alkylthio group with up to 4 carbon atoms or a mercapto group or an amino group, is reacted with ethylenediamine or the acid addition salts thereof at 60 to 180 degrees C, and the end product obtained according to one of these processes is optionally converted into a corresponding acid addition salt.

Description

1 69068

Process for the preparation of bradycardically active substituted 2-phenylaminoimidazolines - Preparation of bradycardically active bradycardic network with 2-phenylaminoimidazo-1 iner

The present invention relates to a process for the preparation of bradycardically active substituted 2-phenylaminoimidazolines of the formula I

v-O- f- (J

^ Br R H

wherein R is an n-propyl, cyclopropylmethyl, cyclopentylmethyl, allyl or methallyl group, and acid addition salts thereof.

The compounds of the formula I are prepared according to the invention as follows:

2- (2,6-Dibromo-4-methylphenylimino) imidazolidine of formula II «3c - ^ - n = (J (ii>

^ Br H

is reacted with a halide of general formula III

Hal-R (III) 269068 wherein Hal is a chlorine, bromine or iodine atom and R is as defined above.

The reaction of the process takes place by heating the reaction components at temperatures of 40 to 150 ° C, preferably in the presence of a polar or non-polar solvent.

The exact reaction conditions depend greatly on the reactivity of the reaction components. In the alkylation, it is preferable to use an excess of the halide of the general formula III and to carry out the reaction in the presence of an acid-binding agent.

The starting compounds of the formula II are known from the literature (cf., for example, Belgian patent 623 305 or Chem. Ber. 107, 2644 (1974) or Liebigs Ann. Chem. 751, 159 (1971)). Compounds of formula III may be prepared by halogenation of the base alcohol.

The 2-phenylaminoimidazolines (2) of the general formula I can be converted into their physiologically acceptable acid addition salts in the customary manner. Suitable acids for salt formation include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, caproic acid, lactic acid, valeric acid, oxalic acid, malonic acid, malonic acid, malonic acid, , malic acid, benzoic acid, p-hydroxybenzoic acid, p-aminobenzoic acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulfonic acid, 8-chloroheophylline and the like.

The new compounds of the general formula I and their acid addition salts have a very bradycardic effect and are therefore suitable for the treatment of coronary heart disease. The effect on the heart rate of 3,69068 was studied in rabbits and spinal rats as well as in intact, anesthetized rats.

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

It is known that 2- [N-allyl-N- (2,6-dichlorophenyl) amino] imidazoline (St 567) is at least partially metabolized to 2- (2,6-dichlorophenylamino) imidazoline (St 155; clonidine) as follows: : Φ-Vo

Cl CH H ^ ci H

OF

ch2 st 567 st 155

It is assumed that other phenylaminoimidazolines substituted on the bridge nitrogen atom are similarly metabolized: tfrO - <^ "ä

Br H Br H

R: cyclopropylmethyl (STH 2148) St 464 R: cyclopentylmethyl (STH 2187)> 'i-Q' = (._

^ Br H Br H

R: cyclopropylmethyl (STH 2437) St 895 R: cyclopentylmethyl (STH 2453) R: allyl (STH 2434) 4 69068

Compound St 155 and Compound St 464 are both potent antihypertensive and further exhibit a clonidine-like effect. When the central nervous system is isolated (in spinal larvae), St 155 produces a hypertensive effect through stimulation of peripheral receptors. In addition, St 155 has a reflex bradycardic effect.

After rupture of the circulatory nerve (in a frequency rat), the heart rate-lowering effect with clonidine-like agents such as St 155 and St 464 remains permanent.

However, the metabolite St 895 acts differently in this respect. In contrast to St 464, the clonidine-like side effect of said metabolite is severely reduced, as shown by the values shown in the following table. The table shows the experimental results for the clonidine-like effect of the compounds. In the experiments, spinal rats and frequency rats have been used as experimental animals

Table I

Spinal rat: D30 = Dose (pg / kg) that produces a 30 mm Hg reduction in blood pressure (n = 18)

Frequency rat: D50 = Dose (pg / kg) that causes a reduction in heart rate of 50 beats / min.

(n = 18).

Spinal rat Frequency rat ----- ^ 30 Pg / kg _____ D5n pg / kg_

St 895 600 300

St 464 21 65

Clonidine 9.1 1) 7 ^ 3 2) 1) n = 126 2) n = 144 5 69068 n means the number of experimental animals tested.

In addition, the compounds of the formula I have been tested on rabbits for their effects on lowering the heart rate, with the following results:

Table II

Change in heart rate (beats / min) 16 min. test compound _R__Esim. (i.v., 1 mg / kg) after administration of -CH 2 - ^ 1 - 52 ^ CH 3 -CH 0 -C 2 - 27 ^ CH 2 n -C 3 H 7 3 - 62 -CH 2 -CH = CH 2

The object of the invention was to find a process for the preparation of a compound having a general clonidine structure which lowers the heart rate but has little or no effect on blood pressure. Clonidine has a very strong effect on both heart rate and blood pressure.

The compounds St 567, STH 2148, 2187, 2437, 2453 and 2434 are examples of compounds which satisfy the preceding requirement. The fundamental difference between these compounds and clonidine is the group attached to the bridged nitrogen tower.

69068

The compounds prepared by the process of the invention in which the bridge nitrogen atom is substituted lower the heart rate, as shown in Table II. A potential disadvantage is that such compounds are metabolized (only to a limited extent) to clonidine-type metabolites (St 155, 464, 895) in which the bridged N atom is unsubstituted, and such metabolites can have an effect on blood pressure as well as heart rate.

It can be seen from Table I, under the heading "spinal rat", that the effect of the metabolite St 895 on blood pressure, measured in the spinal rat, is 60 times smaller than that of clonidine and 30 times smaller than that of structurally close St 464.

Because conversion to the metabolite occurs only to a relatively small extent, the D30 / D50 ratio is of little importance, but in the case where the heart rate-lowering effect of the metabolites is appreciable, it can again be stated that St 895 is a much more favorable compound than St 464.

The compound of the formula I or its acid addition salt can also be used with other active ingredients. Suitable galenical administration forms are, for example, tablets, capsules, sticks, solutions or powders; in which case they may be prepared using galenical auxiliaries, carriers, enhancers or lubricants commonly used in the preparation of these dosage forms, or substances which produce a lasting effect.

The following examples illustrate the invention.

II

7

Example 1 69068 2- [N- (Cyclopropylmethyl) -N- (2,6-dibromo-4-methyl-phenyl) -amino] -2-imidazoline hydrochloride -N-Br3- (Cy- «- ^ x HCl)

Br CH2 h

A

4.2 g (0.013 mol) of 2 - [(2,6-dibromo-4-methyl-phenyl) -imino] -imidazolidine and 1.7 g (150S) of chloromethylcyclopropane are heated at reflux for 42 hours with stirring in 25 ml of acetonitrile. The reaction mixture is then evaporated to dryness in vacuo and the residue is dissolved in about 1N hydrochloric acid. The hydrochloric acid solution is extracted twice with ether (the ether extracts are discarded) and then the fraction is extracted with ether at increasing pH (alkalization with 2N sodium hydroxide). From the 12 ether fractions obtained, the homogeneous fractions are combined (control by thin-layer chromatogram), dried over magnesium sulfate and ethereal hydrochloric acid is added until a Congo acid reaction is obtained. This precipitates new imidazoline hydrochloride. It is filtered off, washed with ether and dried.

Yield: 1.9 g (corresponding to 36.5% of theory).

M.p .: 140 ° C.

69068

In analogy to the previous example, the following compounds of formula I were prepared:

Eg Saanto Sp.

n: ___ R_ (% of theory) _ (° C) _ CH3 / 2 -CHo-C 57.7 152-153% CH2 (base) 3 -C3H7n 77.5 280 (hydrobromide) 4 -CH2-J 9.3 92-93 (base) δ -CH 2 ~ CH = CH 2 80.7 272-274 (hydrobromide)

Claims (1)

A process for the preparation of bradycardically active substituted 2-phenylaminoimidazolines of the formula I in which R is an n-propyl, cyclopropylmethyl, cyclopentylmethyl, allyl or methallyl group, and their acid addition salts, characterized in that 2- (2,6-dibromo-4-methylphenylimino) imidazolidine-dj 1r H of formula (II) is reacted with a halide of general formula (III) Hal-R (III) in which Hal is chlorinated , a bromine or iodine atom and R have the same meaning as above, and the final product obtained is optionally converted into an acid addition salt.