KR800001477B1 - Process for preparing substituted 4-phenyl-imidazolines - Google Patents

Abstract

Substituted 4-phenyl-imidazoline derivs. =DI; R1 = Cl, Br, F,or methyl R2, R3 = H, Cl or methyl; R4 = H, methyl or ethyl; R5, R6 = methyl, ethyl or C2-4alkoxyalkyl=E, useul as an antithrombotic, were manufd. by reaction of imidazoline of II and amine III. Thus, 4-(2,6-dichlorophenyl-2-methylmercaptoimidazoline hydrochloide and 1,3-bis-diethylamino-isopropyl-aminewere reacted at 100≰C and crystallized to give 2-(1,3-bis-diethylamino-isopropylamino)-4-(2,6-dichlorophenyl)-imidazoline-(2) hydrochloride.

Description

Method for preparing substituted 4-phenyl-imidazoline derivatives

The present invention relates to a substituted 4-phenyl-imidazoline derivative of the following structural formula (I) useful as a therapeutic agent for thrombosis and a method for preparing physiologically toxic acid addition salts thereof.

Wherein R ₁ is chlorine, bromine, fluorine or methyl, R ₂ and R ₃ may be the same or different from each other, hydrogen, chlorine or methyl, R ₄ is hydrogen, methyl or ethyl group, and R ₅ and R ₆ are Which may be the same or different and are methyl, ethyl or alkoxyalkyl groups of 2 to 4 carbon atoms, or together form a five-, six- or seven-membered ring, optionally substituted with nitrogen or oxygen.

The compound of formula (I) is a cyclic sphere anidine, which may exist as tautomers. Since the compound of formula (I) has a subtitle carbon, it may exist in racemic form as well as optically.

Compounds of formula (I) are prepared by reacting imidazolines of formula (II) with amines of formula (III).

Wherein R ₁ -R ₆ are as defined above and X is chlorine, bromine, iodine or an alkoxy- or alkyl mercapto group having 1 to 4 carbon atoms.

This reaction is effective to heat the components and is preferably carried out in the presence of a solvent such as dimethylsulfoxide, dimethylformamide, alkoxy or ether.

The compound of formula (II) wherein X is halogen used as a starting material is reacted with a carboxylic ethylene derivative having two functional groups such as phosgene, chlorocarbonate, or orthocarbonate by reacting the substituted phenylethylenediamine of formula (IV) The urea is then prepared by halogenating it with an inorganic acid halide such as phosphoxychloride or bromide, phosphorus pentachloride, orbine or phosphorus iodide or thionyl halide.

R ₁ -R ₃ in the above formula is as described above.

Compounds of formula (II), wherein X is an alkyl mercapto group, are for example reacted with substituted phenylethyl diamines of formula (IV) with carbon disulfide and inorganic phenylethylene thioureas such as alkyl halides or dimethyl sulfate Prepared by alkylation with esters.

Phenyl ethylene diamine of formula IV is prepared by reacting the corresponding substituted benzaldehyde with ammonium cyanide and halogenating the resulting α-cyano-benzylamine in the above manner.

The compounds of formula (I) according to the invention can be converted to physiologically toxic acid addition salts by conventional means. Acids suitable for salt formation include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid or nitric acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, capric acid, oxalic acid, malonic acid, Succinic acid, glutaric acid, maleic acid, fumaric acid, lactic acid, lartaric acid, citric acid, malic acid, gluconic acid, benzoic acid, P-hydroxybenzoic acid, phthalic acid, cinnamic acid, salicylic acid ascorbic acid, 8-chloroleophylline, methanesulfonic acid, etc. There is an organic acid such as.

The compound of formula (I) and acid addition salts thereof according to the present invention have a therapeutic action. In particular, it has a blood flow promoting and thromboside coagulation inhibitory activity. In an in vitro glass test for thrombosite coagulation according to Born's method, the compound is blocked at a concentration of about 10 ^-5 mol. The compound is therefore a suitable drug for the prevention and treatment of thrombosis. In addition, it is effective for promoting blood flow in capillaries.

The compound of formula (I) and acid addition salts thereof may be enterally or parenterally administered. In oral administration, the dosage is about 0.05 to 80 mg, preferably 0.1 to 20 mg. Structural formula (I) compounds and acid addition salts thereof can be used together with active ingredients in the form of antispasmodics, sedatives, mental stabilizers and the like, respectively. Suitable galenic dosage forms include tablets, capsules, suppositories, solvents, emulsions or powders, which may be prepared with conventional galenic excipients, carriers, disintegrants or suspending agents or materials for sustained release formulations. This formulation is prepared by conventional methods according to known methods.

For example, corresponding tablets may comprise the active ingredient in an inert diluent such as calcium carbonate, calcium phosphate or lactose; Disintegrants such as corn starch or alginic acid; Binders such as starch or gelatin; Prepared by mixing with a suspending agent such as magnesium stearate or talc and / or known excipients such as carboxypolymethylene, carbomethyl cellulose, cellulose acetate phthalate or sustained release formulations such as polyvinyl acetate.

Tablets also include a degree of multilayering and coating tablets are prepared by coating cores prepared in a similar manner to tablets with coatings such as polyvinyl pyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. In order to obtain a sustained release agent or an incompatibility agent, the nucleus may be a multilayer tablet. For slow release formulations, the coating may be in several layers and the above-mentioned excipients may be used.

The active ingredient is mixed with vegetable oil to obtain a soft gelatin capsule or similar sealed capsule. Hard capsules are granulated by mixing solid carriers such as lactose, saccharose, sorbitol, mannitol, starch (e.g. potato starch, corn starch or amylopectane), cellulose derivatives or gelatin in powder form and granulated by mixing with active ingredients. It contains.

Juices containing the active ingredient or mixture of active ingredients according to the invention additionally contain sweetening agents such as saccharin, cyclates, glycerin or sugars and flavoring agents such as vanillin or orange extracts.

The formulation may also contain suspending agents or extenders such as sodium carboxymethyl cellulose, wetting agents such as condensation products of fatty alcohols with ethylene dioxide or preservatives such as P-hydroxy benzoate.

Injectables are filled in a vial or ampoule by sterilization in a conventional manner, for example, under the addition of a preservative such as P-hydroxy benzoate and a stabilizer such as complexesone. The solution may also contain stabilizers and / or buffers.

Suitable suppositories are prepared by mixing the active ingredient or mixture of active ingredients with conventional carriers such as triglycerides or polyethylene glycols or derivatives thereof. It is also possible to prepare a gelatin capsule in which the active ingredient is mixed with vegetable oil or paraffin oil.

The following examples illustrate the invention in detail and do not limit the scope of the invention.

[A. Production Example]

Example 1

[2- (1,3-Bis-diethylamino-isopropylamino) -4- (2,6-dichlorophenyl) -imidazoline- (2) hydrolide]

6.5 g (0.022 mol) of 4- (2,6-dichlorophenyl) -2-methylmercaptoimidazoline hydrochloride and 10.65 g (0.053 mol) of 1,3-bis-diethylamino-isopropylamine Stir together and slowly heat to 100 ° C.

Strong methyl mercaptans are generated and spontaneously heated to 130 ° C. Hold this temperature for 30 minutes, then cool to 40 ° C and mix with 15 ml of acetone. Crystallized 2- (1,3-bis-diethylamino-isopropylamino) -4- (2,6-dichlorophenyl) -imidazoline- (2) -monohydrochloride with acetone-ether (1: 1 ) And recrystallized from water to obtain 4.2 g of the final product with a melting point of 192 ° C.

Example 2

[2- (1,3-Bis-diethylamino-isopropylamino) -4- (2-methyl-5-chlorophenyl) -imidazoline- (2) -tritartrate]

2.0 g (0.01 mol) of 1,3-bis-diethylamino-iso in 2.77 g (0.01 mol) of 4- (2-methyl-5-chlorophenyl) -2-methyl-mercapto imidazoline hydrochloride Stir with propylamine and slowly heat to 130 ° C. Cool after 4 hours and mix with 600 ml of water. Gradually add sodium hydroxide solution and shake with ether, dry and evaporate the solution containing the product to 1.7g of crude-2- (1,3-bis-diethylamino-isopropylamino) -4- (2 -Methyl-5-chlorophenyl) -imidazoline- (2) is obtained and purified by silica gel column.

(Developing agent; acetone: benzene: methanone: ammonia = 10: 10: 8: 2) The corresponding fractions are evaporated, treated with ether and mixed with tartaric acid dissolved in alcohols. Amorphous precipitate was recrystallized from alcohol / ether with melting point of 85 ° C (decomposition).

The following example is carried out according to Examples 1 and 2 above, wherein oxalate is precipitated from base dissolved in ether in the presence of etheric oxalic acid and recrystallized from ethanol.

[B. Prescription Example

Example 23

[refine]

2- (1,3-bis-diethylamino-isopropylamino)-

4- (2,6-dichlorophenyl) -imidazoline- (2) -hydrochloride 30 mg

Corn Starch 160mg

250 mg dicalcium phosphate

Magnesium Stearate 5mg

445 mg

quite:

Each component is mixed intimately and the mixture is granulated in conventional manner. The granules are compressed into 445 mg tablets, each containing 30 mg of the active ingredient.

Example 24

[Geratin Capsules]

Content of each capsule:

2- (1,3-diethylamino-isopropylamino)-

4- (2,6-diethylphenyl) -imidazoline- (2) -tritartrate 25 mg

Corn Starch 175mg

200 mg

quite:

Closely mix the ingredients to be filled into the capsules and fill the mixture with 200 mg of the right size gelatin capsules. Each capsule contains 25 mg of active ingredient.

Example 25

[Injectable]

Injectable solutions are formulated with the following ingredients:

2- (1,3-bis-diethylamino-isopropylamino)-

4- (2,6-chlorophenyl) -imidazoline- (2) -hydrochloride1.5 parts

0.2 part sodium salt of ethylenediamine-tetraacetic acid (EDTA)

100.0 parts by adding an appropriate amount of distilled water

quite:

The active ingredient and the sodium salt of EDTA are dissolved in sufficient distilled water for injection and filled with distilled water for injection to the desired dose. The solution is filtered to remove suspended particles and aseptically filled into 2 ml ampoules.

Finally, the ampoule is sterilized and sealed.

Each ampoule contains 20 mg of active ingredient.

Claims (1)

A method for preparing a compound of formula (I) and acid addition salts thereof by reacting imidazoline of formula (I) with an amine of formula (III).

In the above formula, R ₁ is chlorine, bromine, fluorine or methyl, R ₂ and R ₃ may be the same or different from each other, group hydrogen, chlorine or methyl, R ₄ is hydrogen, methyl or ethyl group, R ₅ and R ₆ may be the same or different from each other and is methyl, ethyl or an alkoxyalkyl group having 2 to 4 carbon atoms, or together form a 5-, 6- or 7-membered ring, optionally substituted with nitrogen or oxygen, X is chlorine, bromine, iodine Or an alkoxy- or alkyl mercapto group having 1 to 4 carbon atoms.