DE3712385A1 - 2-(Phenylimino)imidazolidines - Google Patents

Abstract

The invention relates to the use of compounds of the general formula <IMAGE> in which R1, R2 and R3 have the meaning indicated in the description, and their acid addition salts as medicaments having central nervous system-activating, cardioprotective and cytoprotective action.

Description

The invention relates to the use of substituted 2- (phenylimino) imidazolidines as Medicines, new 2- (phenylimino) imidazolidines and their manufacture.

2- (phenylimino) imidazolidines, their preparation and Use as medicinal products are known, e.g. B. from DE-OS 19 29 950 and 23 16 377, the hypotensive properties of this Connection class are in the foreground.

Compounds of the general formula:

wherein

R₁und R₂, which are the same or different can, fluorine, chlorine, bromine or iodine and R₃ is a branched or unbranched alkyl group 1 to 4 carbon atoms, optionally by Halogen or hydroxy substituted mean as well as their pharmacologically acceptable Acid addition salts

have surprising pharmacological properties.  

The compounds of general formula I are α 1 adrenergic agonists with high receptor affinity and have, for example, central nervous activating properties.
The antidepressant properties of these compounds became clear in animal experiments. Furthermore, compounds of the general formula I show cardio- and cytoprotective effects.
The cardioprotective effect was demonstrated by inhibiting isoprenaline-stimulated uptake of ⁴⁵Ca ⁺⁺ ions into the heart muscles in rats.
The cytoprotective properties of the compounds mentioned could also be demonstrated in the hypoxia tolerance test.

Based on pharmacological findings, compounds of general formula I and their acid addition salts can be used according to the invention, for example, as cardioprotective and cytoprotective in the following indications:
Protection of cells from becoming under stress, especially through hypoxia,
Prevention of disseminated necrosis in the course of coronary artery disease and heart failure,
ischemic heart disease,
cerebral metabolic disorders,
organic brain psycho syndrome,
Cerebral sclerosis,
cerebral apoplexy,
Cell damage due to drug abuse, especially alcoholism.

Preferred compounds of the general formula I are those in which R₁ is chlorine and R₂ are bromine, or Compounds of general formula I, wherein R₁ and R₂ is halogen and R₃ is the isopropyl group.  

Is particularly preferred 2- (2-bromo-6-chloro-4-isopropylphenylimino) imidazolidine and its acid addition salts.

The invention further relates to new 2- (phenylimio) - imidazolidines of the general formula

wherein

R₁und R₂, which are the same or different can, fluorine, chlorine, bromine or iodine and R₃ is a branched or unbranched alkyl group 1 to 4 carbon atoms, optionally substituted by halogen or hydroxy as well as their pharmacologically acceptable Acid addition salts with the proviso that if R₁ and / or R₂ bromine or chlorine mean R₃ not methyl and when R₁ bromine and R₂ chlorine means R₃ cannot be tert-butyl.

The compounds of the general invention Formula I can according to known analogy, so e.g. B. as disclosed in DE-OS 19 29 950 manufactured will. Appropriate procedures are in the shown below reaction scheme.  

The individual components are implemented expediently in inert organic solvents - such as B. halogenated hydrocarbons, Alcohols, acetonitrile or tetrahydrofuran - at elevated temperatures, preferably at Reflux temperature of the reaction mixture.

The starting compounds are also synthesized according to generally known analogy methods.

Compounds of the general formula I in which R₁ Chlorine and R₂ bromine can by bromination of compounds of general formula I with R₂ = hydrogen are produced. The reaction expediently takes place in inert solvents, such as B. halogenated hydrocarbons, e.g. B. Chloroform, dichloromethane etc., ethyl acetate u. a. at Temperatures between -10 ° C and room temperature Reaction with bromine. Compounds of the general formula I, wherein R₁ and R₂ are bromine can by Bromination of compounds of general formula I. can be obtained with R₁ and R₂ hydrogen. The Reaction conditions for carrying out the implementation are as previously stated.

Acids suitable for salt formation are e.g. B. hydrochloric acid, Hydrobromic acid, hydroiodic acid, Hydrofluoric acid, sulfuric acid, phosphoric acid, Nitric acid, acetic acid, propionic acid, butyric acid, Valeric acid, caproic acid, oxalic acid, malonic acid, Lactic acid, tartaric acid, citric acid, malic acid, Benzoic acid, p-hydroxybenzoic acid, phthalic acid, Cinnamic acid, salicylic acid, ascorbic acid, 8-chloropheophylline and the like.  

The compounds can be used alone or optionally in combination with other pharmacologically active Active ingredients. Suitable Application forms are, for example, tablets, Capsules, suppositories, solutions, juices, emulsions or dispersible powder. Appropriate tablets can for example by mixing the active ingredient (s) with known auxiliaries, for example inert ones Diluents, such as calcium carbonate, Calcium phosphate or milk sugar, disintegrants, such as Corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talk, and / or means to achieve the Depot effects, such as carboxypolymethylene, Carboxymethyl cellulose, cellulose acetate phthalate, or Polyvinyl acetate can be obtained. The tablets can also consist of several layers.

Correspondingly, drag'es can be made by covering analog the cores usually produced in tablets Drag'e covers used means, for example Kollidon or shellac ,, gum arabic, talc, Titanium dioxide or sugar. For To achieve a deposit effect or to avoid The core can consist of several incompatibilities Layers exist. The same can also Drag'hülle to achieve a deposit effect consist of several layers, the above in the Tablets mentioned excipients can be used.

Juices of the active ingredients according to the invention, respectively Active ingredient combinations can also be a Sweeteners such as saccharin, cyclamate, glycerin or Sugar as well as a taste-improving agent, e.g. B. Flavorings, such as vanillin or orange extract, contain. You can also use suspension aids  or thickeners, such as sodium carboxymethyl cellulose, Wetting agents, for example condensation products from Fatty alcohols with ethylene oxide, or protective substances, such as p-hydroxybenzoates.

Injection solutions are made in the usual way, e.g. More colorful Addition of preservatives, such as p-hydroxybenzoates, or stabilizers, such as Alkali salts of ethylenediaminetetraacetic acid made and in injection bottles or ampoules bottled.

The the active ingredient, or the Capsules containing active ingredient combination can for example, by making the Active ingredients with inert carriers, such as milk sugar or Sorbitol, mixes and encapsulates in gelatin capsules.

Suitable suppositories can be, for example Mix with the appropriate carriers, such as Neutral fats or polyethylene glycol, respectively its derivatives.

For the purpose of transdermal application, the Active substances according to the invention in correspondingly suitable Carriers (plasters), for example made of polyacrylates, be incorporated. Suitable adjuvants can can be used to increase the release rate.

As a therapeutically effective single dose, oral Applications suggested a dose of 1 to 50 mg.  

Pharmacological test results

Hypoxia tolerance test (Mod. According to Hoffmeister et al., Pharmaceutical research (Drug Res. 32, 346-360 (1982).

Test animal: mouse, number of animals 10 Application type: p. O. Substance: 2- (2-bromo-6-chloro-4-isopropylphenylimino) - imidazolidine · HBr

Radio ⁴⁵Ca test (Mod. After D. Arndts, Arzneimittelforschung 25, 1279-1284 (1975)
Substance: 2- (2-bromo-6-chloro-4-isopropylphenylimino) imidazolidine · HBr
IC₅₀: 0.18 mg / kg (rat)

example 2- (2-bromo-6-chloro-4-isopropylphenylimino) imidazolidine hydrobromide

a) 16.1 g KSCN (0.167 mol) are in 565 ml acetone dissolved and at 15 ° C 19.25 ml of benzoyl chloride stirred in. 28.4 g are added to the mixture 2-chloro-4-isopropylaniline (0.167 mol) and heated 3¼ hours at reflux. After cooling, pour one on 925 ml ice water, the resulting one is separated amorphous precipitate and washes with water. The N- (2-chloro-4-isopropylphenyl) - N'-benzoylthiourea is with 38 ml of water, 38 g KOH and 112 ml of ethanol are added and during Heated to 60 ° C for 1 hour. Then dilute with 350 ml of water and distilled the ethanol reduced pressure. The separated one The precipitate is filtered off, washed with water and dried; this gives 27 g (2-chloro-4-isopropylphenyl) thiourea (Yield 70.5%), m.p .: 144-146 ° C.

b) 27 g (2-chloro-4-isopropylphenyl) thiourea with 120 ml of methanol and 11 ml of methyl iodide added and heated under reflux for 2 hours. The homogeneous solution obtained becomes in a vacuum Evaporated to dryness; this gives 43.75 g N- (2-chloro-4-isopropylphenyl) -S-methyl- isothiuronium iodide (yield 100%).

c) 43.75 g of N- (2-chloro-4-isopropylphenyl) -S-methyl-isothiuronium iodide, 120 ml of methanol and 11.8 ml of ethylenediamine are combined and heated under reflux for 14 hours.
The solution is evaporated to dryness under reduced pressure, the residue is taken up in dilute HCl and extracted twice with ether. The aqueous phase is adjusted to pH 6 by adding dilute NaOH, mixed with a further 6 ml of 5N NaOH and extracted twice with ether. The aqueous phase is then made strongly alkaline by means of 5 N NaOH, an oil separating out which crystallizes. The crystals are filtered off, washed with water, dried and recrystallized from isopropanol; 6.2 g of 2- (2-chloro-4-isopropylphenyl-imino) imidazolidine (yield 22%), mp: 139-140 ° C.

d) 2.33 g of 2- (2-chloro-4-isopropylphenylimino) - imidazolidine (9.8 mmol) in 10 ml anhydrous chloroform and dissolved at 0-8 ° C 0.5 ml of bromine (9.8 mmol) was added dropwise. The Reaction solution are 10 ml of ethyl acetate added, it being used to separate a Solid comes that with ethyl acetate / ether and finally washed with ether. To 3 g of 2- (2-bromo-6-chloro- 4-isopropylphenylimino) imidazolidine hydrobromide (Yield 70%), m.p .: 231-232 ° C.  

Example A: tablets

2- (2-bromo-6-chloro-4-isopropylphenylimino) -
imidazolidine HBr 10 mg milk sugar 65 mg corn starch 125 mg sec. Calcium phosphate 40 mg soluble starch 3 mg magnesium stearate 4 mg colloidal silica 4 mg total 250 mg

Manufacturing

The active ingredient comes with some of the excipients mixed intensively with an aqueous solution of soluble starch kneaded and in the usual way granulated with the help of a sieve. The granules will mixed with the rest of the excipients and added Drag´ cores of 250 mg weight, which are then pressed into usually with the help of sugar, talc and gum arabic be coated.

Example B: ampoules

2- (2-bromo-6-chloro-4-isopropylphenylimino) -
imidazolidine HBr 1.0 mg sodium chloride 18.0 mg dist. Water ad 2.0 ml

Manufacturing

Active ingredient and sodium chloride are dissolved in water and filled into glass ampoules under nitrogen.  

Example C: drops

2- (2-bromo-6-chloro-4-isopropylphenylimino) -
imidazolidine HBr 0.02 g methyl p-hydroxybenzoate 0.07 g propyl p-hydroxybenzoate 0.03 g demineralized water ad100 ml

Example D: solution for injection

2- (2-bromo-6-chloro-4-isopropylphenylimino) -
imidazolidine HBr 1.5 parts sodium salt of ethylenediaminetetraacetic acid 0.2 parts dist. Water ad100.0 parts

Manufacturing

The active ingredient and the sodium salt of Ethylenediaminetetraacetic acid are in enough water dissolved and with water to the desired volume replenished. The solution is made of suspended particles filtered and in 2 ml ampoules under aseptic Bottled conditions. Finally, the ampoules sterilized and sealed. Each ampoule contains 20 mg of active ingredient.

Claims (9)

1. Use of 2- (phenylimino) imidazolidines of the general formula whereinR₁ and R₂, which may be the same or different, are fluorine, chlorine, bromine or iodine and R₃ is a branched or unbranched alkyl group having 1 to 4 carbon atoms, optionally substituted by halogen or hydroxy, and their pharmacologically acceptable acid addition salts as medicaments with central nervous activating, cyto - and cardioprotective effect. 2. New 2- (phenylimino) imidazolidines of the general formula whereinR₁ and R₂, which may be the same or different, represent fluorine, chlorine, bromine or iodine and R₃ is a branched or unbranched alkyl group having 1 to 4 carbon atoms, optionally substituted by halogen or hydroxy, and their pharmacologically acceptable acid addition salts with the proviso that when R₁ and / or R₂ bromine or chlorine is not methyl and when R₁ is bromine and R₂ is chlorine R₃ cannot be tert-butyl. 3. 2- (2-bromo-6-chloro-4-isopropylphenylimino) - imidazolidine as well as its pharmacological compatible acid addition salts. 4. Analogy process for the preparation of compounds of the general formula according to claim 2, characterized in that an aniline of the general formula wherein R₁, R₂ and R₃, as previously defined, are with one of the following compounds or or implements and
the compounds containing ac according to the process optionally converted into their acid addition salts. 5. Analogous process for the preparation of 2- (phenylimino) imidazolidines of the general formula I according to claim 2 wherein R₁ and R₃ are as previously defined and R₂ is bromine, characterized in that a compound of the general formula I is brominated with R₂ = hydrogen. 6. Analogy method for making a connection of general formula I according to claim 2, wherein R₁ and R₂ represent bromine, thereby characterized in that one connects the general formula I with R₁ and R₂ both Hydrogen brominated.   7. Pharmaceutical preparations, thereby characterized in that it is an active ingredient or contain several compounds according to claim 2. 8. Process for the production of pharmaceutical Preparations according to claim 7, characterized characterized in that one or more Compounds according to claim 2 with conventional auxiliary or carriers, explosives or lubricants or substances to achieve a depot effect processed into pharmaceutical preparations. 9. Use of a compound according to claim 2 for Manufacture of a drug.