NO774445L - ANALOGICAL PROCEDURE FOR THE PREPARATION OF A PHARMACOLOGICAL ACTIVE IMIDAZOLIDIN DERIVATIVE - Google Patents

Description

"Analogy method for the preparation of a

■ _ pharmacologically active imidaz. olidine derivative" . ■

2-phenylimino-imidazolidines have due to their

very good pharmacological properties have long been the subject of great interest. Connections of this type are thus described in a number of places in the literature, e.g. in Belgian Patents 623,305, 653,933, 687,656, 687,657 and 705,944.

These patents also describe the essential methods for producing 2-phenylimino-imidazolidines.

The present invention relates to a method for producing the new compound 2-bromo-3-chloro-N-2-imidazolidinylidene-benzamine with the formula:

and physiologically compatible acid addition salts thereof, which possess valuable therapeutic, especially anti-hypertensive properties/

The new compound of formula I is prepared according to,

to the invention as follows:

a) Reaction of an isothiourea with the general

formula

respectively acid addition salts thereof, where R means a hydrogen atom or an alkyl group of up to 4 carbon atoms, with ethylenediamine or salts thereof.

The turnover is carried out at temperatures between 100 and 250°C. Polar protic or aprotic or non-polar solvents can be used as solvents. The turnover can. also carried out without the use of solvents at an elevated temperature. The reaction time varies between a few minutes and several hours.

b) Reaction of a compound with the formula

where X means a chlorine atom or an amino group, with ethylenediamine.

When X means a chlorine atom, the reaction is carried out at temperatures between 0°C and room temperature. As solvents, inert solvents such as ethers, ketones, esters or aliphatic or aromatic hydrocarbons can be used.

When X means an amino group, acid addition salts of the compound of formula III or of ethylenediamine are preferably used. The turnover is carried out at an elevated temperature, preferably reflux temperature. Polar protic, polar aprotic or non-polar solvents can be used as solvents.

c). Reaction of a cyanamide with the formula

with ethylenediamine or acid addition salts thereof.

The turnover is carried out at temperatures between 100 and 250°C.

Polar protic, polar aprotic or non-polar solvents can be used as solvents. Preferably, the reaction components are brought together at the reflux temperature of the solvent used.

d) Cleavage of an acyl residue from one, compound with , the formula

where acyl means an acyl group, by means of aliphatic alcohols or dilute acids.

e) Reaction of 2'-'bromo-3-chloroaniline with ethyl lenurins two f. f

■in.the presence of phosphorus oxychloride.

The conversion is preferably carried out at temperatures from 100 to 200°C. Inert solvents can be used as solvents. aromatic hydrocarbons. Preferably, the reaction components are reacted at reflux temperature.

f) Cyclization of a compound with the general formula

■where R<1>means a sulfhydryl or 2-bromo-3-chlorophenyl-amino group, at temperatures ■ from 150 to 250°C..

In the reaction of 2-bromo-3-chloro-aniline with potassium thio-

cyanate and benzoyl chloride and subsequent precipitation with potassium chloride, the corresponding thiourea of formula II is formed, which can be further converted with an alkylating agent, such as an alkyl halide or dialkyl sulfate, to the isothiourpnium salt of formula II. From this, one can by acid cleavage with kalilut prepare the S-alkyl isothiourea of formula II.

The isocyanide dichloride of formula III can be prepared by reacting 2-bromo-3-chloroaniline with formic acid and further reacting the formed formanilide with a mixture of thionyl chloride and sulfur chloride.

The guanidine of formula III is formed by ammonia-

addition to the cyanamide of formula IV. 'This cyanamide can

is produced by I^S cleavage from the thiourea of formula II with mercury or lead salts.

The starting compounds: with formula V, reaction of 2-bromo-3-chloroaniline with N-acyl-imidazolidinone-(2) in the presence of phosphorus oxychloride is prepared.

The output connections with. formula VI can be prepared by reacting N-(2-bromo-3-chlorophenyl)isothiocyanate or of N,N'-di-(2-bromo-3-chlorophenyl)carbodiimide with ethylenediamine.

The new compound of formula I can be converted in the usual way to its physiologically compatible acid addition salts.

Acids that are suitable for salt formation are e.g. hydrochloric acid, brpmr

<1> hydrogenic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid,, butyric acid, caproic acid, valeric 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, : ethane-phosphonic acid, 8-chlorotheophylline, etc.

The new compound and its acid addition salts have valuable blood pressure-lowering properties, and can thus be used to treat various forms of hypertension in humans. Compounds of formula I can be used enterally or parenterally. The dosage is 0.05 to 30 mg, preferably 0.1 to 10 mg.

It has surprisingly been found that for the new compound 2-bromo-3-chloro'-N-2-imidazolidihylidene-benzamine the duration of the blood pressure-lowering effect at the same dosage is longer than for clonidine, which is likewise a potent antihypertensive, which it appears in the following table.

The blood pressure-lowering effect was determined on rabbits under urethane anesthesia. The painting of the blood pressure was carried out on

carotid artery using a mercury manometer. ED2Q is the dose that permanently lowers blood pressure by 20 mm Hg.

The compound of formula I. and the acid addition salts thereof can

used together with other active substances. Suitable galenic preparations are e.g. tablets, capsules, suppositories, solutions or powders, and for the production of these the commonly used galenic aids, carriers, explosives or lubricants or substances which cause a depot effect can be used.

The following examples shall serve to illustrate the invention.

Example 1•

2- bromo- 3- chloro- N- 2- imidazolidinylidene- benzamine- monohydrochloride (Procedure a)

31.6. g-(0.0777 mol) N-(2-bromo-3-chlorophenyl)-S-methyl-isothiouronium iodide is heated together with . 7.8 ml of ethylenediamine (150%) in 93 ml of n-butanol for 6 hours with stirring at reflux temperature. It is then evaporated to dryness in vacuo, the remaining residue is dissolved in a little methanol and the solution is filtered. The filtrate is alkalized with 50% potassium hydroxide while adding ice and Petri dishes, whereby the imidazolidine base is precipitated.

It is extracted, washed with water and petroleum ether and dried.

Yield: 15.2 g, corresponding to 71.3% of the theoretical, m.p. 132-134°C. The hydrochloride with a melting point of 223-224°C is obtained by adding ethereal hydrochloric acid to an ethereal solution of the imidazolidine base until the Congo acid reaction.

Molecular weights and melting points • for further acid addition salts are given in the following:

Hydrochloride: CgHgBrClN'3x HC1

Molar weight: 311.01

Sm.p. : ,223-224°C

Hydrobromide: CgHgBrClN3x KBr

Mol weight: 355, 47' ■ Melting point: 238-240°C

Nitrate: CgHgBrClN3x NH03

Mol weight: 337.57,

Melting point: 16 5°C (dec.)

Maleinate: CgHgBrClN3 x HOOC-CH=CH-G0OH (C4H404)

Molar weight: 390.62

Melting point: 167-170°C

Oxalate: CnHnBrClN_ x HOOC-COOH (C„H_0.)

y y oi.2. 4 Molar weight: 36 4.59

Melting point: 110-115°C (dec.)'

8-chlorotheophylline: CgHgBrClN3 x C7H7C1N402

Molar weight:'489.17

Sm.p. : 241-243°C...

Tosylate: CnHnBrClN_ x C_Ho0oS x ,H_0

y yi loiz

Molar weight: . 4 6 4 , 77

Melting point: 162-165°C.

Benzoate: CnHnBrClN^ x C_H,0„

y y 3 / o z

Molar weight: 39 6.68 Melting point: 177-178°C

Tartrate: C„HnBrClNnx C.H,0^

99 3 466

Molar weight: 424.64

Melting point: 99-105°C (dec.)

Methanesulfonate: .. CgHgBrClN3 x CH4O3S

Molar weight: 370.66 Melting point: 217-221°C

Citrate: CgHgBrClN3x CgHgO7

Molar weight: 466.68

Melting point: 97-105°C (dec.)

Example 2

2- bromo- 3- chloro- N- 2- imidazolidinidenebenzamine (Procedure b)

8.62. g (0.03 mol) 2-bromo-3-chloro-phenylisocyanide dichloride-prepared from' 2-bromo-3-chloro-formanilide (m.p.: 139-141°C) • by reaction with a mixture of thionyl chloride and sulfuryl chloride,

is reacted with 9.0 g (500%) of ethylenediamine in 75 ml of absolute ether at 5°C with stirring. After complete addition of the isocyanide dichloride, the mixture is stirred for a further 5 to 10 minutes at 5°C.

The mixture is allowed to reach room temperature and stirred for 30 minutes at this temperature. The reaction mixture is evaporated to dryness in vacuo, and the residue is dissolved in dilute hydrochloric acid. At a pH value of 7 (adjustment with dilute caustic soda), extraction is carried out with ether to purify, and the ether phase is discarded. It is then made alkaline with dilute NaOH, and the precipitated imidazolidine base is filtered off, washed neutral with water and dried.

The remaining 2-bromo-3-chloro-N-2-imidazolidinylidene-benzamine is only slightly contaminated (thin-layer chromatogram control) and can be chromatographed over silica gel with methanol:acetone:chloroform =6:3:15 as eluent for further purification . ' Yield: 6.3 g, corresponding to 76.5% of the theoretical.

Sm.p. 132.0 to 134.0°C.

Example 3

2- bromo- 3- chloro- N- 2- imidazolidinidenebenzamine (Procedure c)

6.1 g (0.026 mol) of 2-bromo-3-chloro-phenylcyanamide are heated together with 8.4 g' (150%) of ethylenediamine-monotoluenesulfonate for approx. 50 ml of amyl alcohol for 5 hours with stirring at reflux temperature. The clear reaction mixture is allowed to cool overnight

and evaporated in a vacuum. The residue is taken up in IN HC1, insoluble components are filtered off, and the hydrochloric acid solution is extracted.

fractionated with ether at increasing pH values (alkalization with 2N caustic soda). From the total approx. 10 ether fractions are collected, those containing only the new imidazolidine derivative (thin-layer chromatogram control). After drying them. combined ether extracts, the ether is evaporated in a vacuum. The remaining imidazolidine base crystallizes through after some time.

Yield: 0.8 g, corresponding to 11.1% of the theoretical.

Melting point: 135 to 139°C.

The compound obtained is identical to authentic material.

Example 4.

2- bromo- 3- chloro- N^- 2- imidazolidinylidene-benzamine (Procedure d)

2.85 g (0.01 mol) of N-(2-bromo-3-chlorophenyl)-guanidine hydrochloride are heated together with 0.68 ml (.0.01 mol) of ethylenediamine in 25 ml of amyl alcohol with good stirring for 20 hours , at reflux^ temperature. The reaction mixture is evaporated to dryness in vacuo.

and the residue is dissolved in 2N HCl and water. At increasing pH values (addition of 2N NaOH), fractional extraction is carried out with ether, and the thin-layer chromatographically uniform ether fractions are collected. After drying over anhydrous calcium sulphate, evaporation is carried out in a vacuum. constant .weight. This precipitates the formed

imidazolidine derivative in oily form to crystallize through after some time. The compound is shown in several thin-layer chromatogram systems to be identical to 2-bromo-3-chloro-N-2-imidaz.olidinylidene-

benzamine with melting point: 132.0 to 134.0°C.

Yield: 1.0 g, corresponding to 36.42% of the theoretical.

Example 5

2- bromo- 3- chloro- N- 2- imidazolidinylidene-benzamine (Procedure d)

a) Preparation of 1-acetyl-2-(2-bromo-3-chlorophenylimidazolidine)-imidazolidine.

8.25 g (.0.04 mol) of .2-bromo-3-chloro-aniline is heated together with 5.64 g (0.044 mol) of 1-acetyl-imidazolidin-2-one in 58 ml of phosphorus oxychloride for approx. 40 hours with stirring at a temperature of SS^C. The excess phosphorus oxychloride is then driven off in a vacuum. The residue is immediately stirred for approx. 180 ml of ice water. After filtration, the filtrate is alkalized under ice cooling with 5N caustic soda, whereby 1-acetyl-2-(2-bromo-3-chloro-phenylimino)-imidazolidine is precipitated. The

aspirated, washed neutrally with ice water and dried.

Yield: 8.4 g, corresponding to 66.34% of the theoretical.

Melting point: 140-146°C. b) Preparation of 1-acetyl-2-(2-bromo-3-chlorphenylimino)-imidazolidine to 2-bromo-3-chloro-N-2-imidazolidinylidene-benzamine. 6.3 g (0.020 mol) of 1-acetyl-2-(2-bromo-3-chlorophenylimino)-imidazolidine are heated together with 1.5 ml of concentrated hydrochloric acid in 80 ml of methanol for 6 hours with stirring at reflux temperature. The imidazolidine derivative thus formed turns out to be identical with 2-bromo-3-chloro-N-2-imidazolidinylidene-benzamine with m.p. 132.0 to 134.0°C in several thin layer chromatographic systems, e.g. in ben zen: dioxane : conc . ammonia.: ethanol = 50:40:5:5.

(Rf = 0.75).

Example 6

2- bromo- 3- chloro- N- 2- imidazolidinylidene-benzamine (Procedure a-)

2.0 g (0.0075 mol) of N-(2-bromo-3-chlorophenyl)-isothiourea are heated together with 0.75 ml (150%) of ethylenediamine at about. 165°C for 30 minutes. The reaction mixture is dissolved in IN hydrochloric acid. The solution is fractionally extracted with ether by rising. pH values (addition of 2N NaOH). The thin-layer chromatographically uniform ether extracts are collected, dried over MgSO4 and evaporated

..in a vacuum. There remains 0.45 g (corresponding to 21.85% of the theoretical) 2-bromo-3-chloro-N-2-imidazolidinylidene-benzamine with

melting point 129 to 134°C. The compound is identical to authentic material.

Example 7

2- bromo- 3- chloro- N- 2- imidazolidinylidene-benzamine (Procedure e)

8.25 g (0.04 mol) of 2-bromo-3-chloro-aniline is heated

together with 3.44 g (0.04 mol) of ethylene urea in 25 ml of phosphooxychloride in 25 ml of absolute toluene for 12 hours with stirring at reflux temperature. The reaction mixture is then heated • to dryness. The imidazolidine derivative formed in this way turns out to be identical to 2-bromo-3-chloro-N-2-imidazolidinylidene-benzamine with m.p.: 132.0 to 134.0°C in several thin-layer chromatographic systems, e.g. in benzene: diox an: conc ammonia: ethanol = 50:40:5:5.' (Rf = 0.75)'.

Example 8

2- bromo- 3- chloro- N- 2- imidazolidiny li den- benzamine (Procedure f)

To a mixture of 1.27 g (0.021 mol) ethylenediamine

in 30 ml of absolute benzene is placed slowly with stirring (ice-cooling) at 20 to 25°C 8.82 g (0.021 mol) N,N'-di-(2-bromo-3-chlorophenyl)-carbodiimide, dissolved in 10 ml of absolute benzene.

The mixture is then allowed to react further for 9 hours at reflux temperature and evaporated in vacuo. You get 10 g (corresponding to 99.0% of the theoretical) of the intermediate product with the formula

in the form of a viscous, brownish oil. 10 g of the viscous oil is heated for 1 hour in a water jet vacuum to 220°C. Thereby ring closure to 2-bromo-3-chloro-N-2-imidazolidinylidene-benzamine takes place. To work up the reaction product, methanol is added, and insoluble components are filtered off. The methanolic solution is evaporated in vacuo. The imidazolidine derivative thus formed appears. to be identical to 2-bromo-3-chloro-N-2-imidazolidinylidene-benzamine with m.p.: 132.0-134.0°C in several thin-layer chromatographic systems, e.g. in benzene:dioxane:conc. ammonia:ethanol = 50:40:5:5.

(Rf = 0.75).

Example 9

2- bromo- 3- chloro- N- 2- imidazolidinylidene-benzamine (Procedure f)

To a mixture of 0.31 g (0.0051 mol) of ethylenediamine in 5 ml of absolute benzene is added slowly with stirring Mcooling) at 20 to 25°C.1.35 g (0.0051 mol) N-(2- bromo-3-chlorophenyl)-isothiocyanate, dissolved in 2 ml of absolute benzene.- The mixture is then allowed to react further for 2 hours at room temperature and evaporated in vacuo. A white intermediate product is obtained. This is heated for 30 minutes at approx. 165°C. The reaction mixture is dissolved in 1N hydrochloric acid and fractionally extracted with ether at increasing pH values (addition of 2N NaOH). The thin-layer chromatographically uniform ether extracts are collected, dried over MgSO^ and evaporated in vacuo. 0.15 g (corresponding to 10.71% of the theoretical) of 2-bromo-3-chloro-N-2-imidazolidinylide remain. -benzamine with melting point 128 to 132:°C. The compound is identical to authentic material.

Claims (1)

Analogous process for the preparation of the pharmacologically active compound 2-bromo-3-chloro-N-2-imidazolidinylidene-benzamine and acid addition salts thereof, characterized by ata) an isothiourea with the general formula respectively acid addition salts thereof, where R means one hydrogen atom or an alkyl group with 1 to 4 carbon atoms, is reacted with ethylenediamine or salts thereof; or b) a compound with the formula where X means a chlorine atom or an amino group, is reacted: with ethylenediamine; or c) a cyanamide of the formula reacted with ethylenediamine; or d) from a compound of the formula where "acyl" means a. acyl group, the acyl residue is cleaved off with the help of aliphatic alcohols or dilute acids.;, or e) ' 2-bromo-3-chloro-aniline is reacted with ethylene urea in the presence of phosphorus oxychloride; or f) a compound of the general formula where R" means a sulfhydryl or 2-bromo-3-chlorophenylamino group, is ring-closed at temperatures from 150 to 250°C, and optionally the obtained compound is transferred to an acid .addition salt