KR810000631B1 - Process for preparing substitued 2-phenyl amino-imidazdines-(2) - Google Patents

Abstract

Title compds.(I; R1.R2,R3 = H, F, Cl, Br, Me, trifluoro methyl or cyano; R4 = III; n = 2, 3, 4 or 5), useful as analgesic, were manufd. by reaction of II and cycloalkylmethylhalide. Thus, 2-(2,6-dichlorophenylimino)-imidazolidine was refluxed with chloromethylcyclopropane and sodium hydroxide in unhydrous toluene for 32 hr, melted in HCl and extracted in ether to give 2-[N-(cyclopropylmethyl)-N-(2,6-dichlorophenyl)-amino -2-imidazoline. I have analgesic activity up to 100 times that of morphine.

Description

[Name of invention]

Method for preparing substituted 2-phenylamino-imidazoline- (2) derivatives

Detailed description of the invention

The present invention relates to a substituted 2-phenylamino-imidazoline- (2) derivative of the following formula (I) useful as an analgesic agent and an antihypertensive agent, and a method for preparing a physiologically toxic acid addition salt thereof.

In the above structural formula

R ₁ , R ₂ and R ₃ may be the same or different and are hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, hydroxy, trifluoro methyl or cyano

R ₄ is a group of the following structural formula.

Where n is 2, 3, 4 or 5.

U.S. Patent No. 4,025,607 describes propargyl-substituted-2-anilino-2-imidazolines and their pharmaceutically toxic acid addition salts having the following structural formulas, which exhibit analgesic and hypotensive action, wherein the substituents are cyclo There is no description of compounds which are alkyl-methyl.

In the above structural formula

R ₁ , R ₂ and R ₃ may be the same or different and are hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, or trifluoro methyl

R ₄ and R ₅ are each hydrogen or propargyl

Provided that R ₄ and R ₅ may not be hydrogen at the same time or propargyl at the same time.

The compound of formula (I) of the present invention is prepared as follows. In other words, 2-phenylamino-imidazolidine of formula (II) is prepared by reacting with a halide of formula (III).

In the above structural formula

R ₁ , R ₂ , R ₃ , and n are as described above and Hal is chlorine, bromine or iodine.

When alkylating the 2-arylamino-imidazolidine of formula (II), the substitution takes place only at the nitrogen atom, which acts as a bridge.

The location of the substituents can be known by NMR-spectrum analysis.

[Note: K. H. Pook and H. stable Liebigs. Ann. Chem. 751, 159ff (1971)]

In the reaction of the present invention, it is effective to heat the reactants to 50 to 150 ° C., preferably in the presence of a polar or nonpolar organic solvent. The specific reaction conditions depend greatly on the reactivity of the reactants. It is preferable to use excess halides during alkylation and to react in the presence of an acid binder.

Starting materials of formula (II) are prepared, for example, by the methods described in Belgian patents 623,305, 687,657 and 705,944.

Starting materials of formula (III) can be prepared by halogenating the underlying primary alcohol.

2-phenylamino-imidazoline- (2) of formula (I) according to the invention can be converted to its physiologically toxic acid addition salt by conventional methods.

Acids suitable for salt formation include hydrochloric acid, bromic acid, iodide, hydrogen 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, manic acid, benzoic acid, P-hydroxybenzoic acid, P-aminobenzoic acid, phthalic acid, cinnamic acid, salicylic acid, ascorbic acid, methanesulfonic acid, 8-chlorotheophylline and the like.

The compound of the present invention and acid addition salts thereof have analgesic action and thus can be used for various pain treatments such as those caused by micrograins.

The analgesic action of the compounds according to the invention is examined by torsion test and hot plate test in rats.

[Reference: 1) Torsion Test: Blumberg, Wolf and Dayton, Proc. Soc. Exp. Biol. Med. 118 (1965) 763,

2) Hotplate Test: Woolfe and MacDonald, J. Pharmacol Exp. Ther. 80 (1944) 300]

Test results show that the new 2-phenylamino-imidazoline is 100 times stronger than the analgesic action of morphine.

Compared with N-allyl-2-phenylamino-imidazoline- (2) described in JP 1,958,201, it can be seen that the action of the compound of the present invention is 100 times stronger.

Compounds of formula (I), in particular compounds having a cyclopropyl methyl or cyclobutylmethyl group as substituents and acid addition salts thereof, are useful in the treatment of coronary artery disease because they exhibit potent bradycardia in addition to analgesic action. The effect on heart rate was examined in rabbits and cats.

The dosage unit may be 0.1 to 80 mg, preferably 1 to 30 mg.

Compounds of formula (I) or acid addition salts thereof may be used with other active substances. Suitable forms for galenic administration are tablets, capsules, suppositories, solutions or powders which are prepared using conventional galenic excipients, carriers, disintegrants and suspending agents, or materials for sustained release preparations.

The following examples illustrate the invention and thereby do not limit the invention.

Example 1

2- [N- (cyclopropylmethyl) -N- (2,6-dichlorophenyl) -amino-2-imidazoline

6.9 g (0.03 mole) of 2- (2,6-dichlorophenylamino) -imidazolidine in 50 ml of anhydrous toluene with 2.9 g (= 110%) of chloromethylcyclopropane and 4 g of sodium hydroxide solution The mixture is refluxed for 32 hours with stirring, evaporated to dryness in vacuo, and the residue is dissolved in about 1N hydrochloric acid. Extract several times with ether to remove the ether layer, add recovered sodium oxide solution to make the pH alkaline, and then extract with ter. After thin layer chromatography, the pure fractions were combined, dehydrated on magnesium sulfate and evaporated under vacuum to yield 2- [N- (cyclopropylmethyl) -N- (2,6-dichlorophenyl) -amino having a melting point of 126 ° to 129 ° C. ] 0.9g (10.6% of theory) of 2-imidazoline are obtained.

Example 2

2- [N- (cyclopropylmethyl) -N- (2-fluoro-6-trifluoromethylphenyl)

-Amino] -2-imidazoline

8 g (0.032 mol) of 2-fluoro-6-tripulouromethylphenylimino-imidazolidine with 25 ml of anhydrous with 4.6 g (= 105%) bromomethylcyclopropane and 5 cc triethylamine Heat to 120 ° C. for 18 hours in the tube in the presence of toluene. After cooling, the mixture was decanted to separate a solid residue, which was dissolved in 150 cc of 1N hydrochloric acid. Extraction of ether several times removes the ether layer, alkalines it with the addition of recovered sodium oxide, and then extracts with ether. The obtained ether fractions are collected by thin layer chromatography, pure fractions are dehydrated on anhydrous calcium sulfate, and then evaporated and dried in vacuo.

The residue was crystallized by stirring with petroleum ether and then suction filtered and dried to give 2- [N- (cyclopropylmethyl) -N- (2-fluoro-6-trifluoromethylphenyl) having a melting point of 126 ° to 127 ° C. 5.7 g (58.4% of theory) of -amino] -2-imidazoline are obtained.

In the same manner as above, the compounds of the following table are obtained.

Formulation Example

Example A Tablet

2- [N- (2,6-dichlorophenyl) -N- (cyclopropylmethyl) amino] -imidazoline- (2)

quite

The active ingredient is mixed with a portion of the excipient and granulated completely with an aqueous solution of soluble starch and then using a sieve in the usual manner. The granules are mixed with the remaining excipients and compressed into 250 mg uncoated tablets and coated with sucrose, talc and gum arabic in the usual manner.

Example B Ampoule

2- [N- (2,6-dichlorophenyl) -N- (cyclopropylmethyl) amino] -imidazoline- (2)

Legislation

The active ingredient and sodium chloride are dissolved in water and filled in a glass ampoule under nitrogen gas.

Example C Dropping Agent

2- [N- (2,6-dichlorophenyl) -N- (cyclopropylmethyl) amino] -imidazoline- (2)

Claims (1)

N-cycloalkylmethyl-2-phenylamino of formula (I) is characterized by reacting 2-phenyl-iminoimidazolidine of formula (II) with cycloalkylmethyl-halide of formula (III) -How to prepare imidazoline- (2) and acid addition salts thereof.

In the above structural formula R ₁ , R ₂ and R ₃ may be the same or different and are hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, hydroxy, trifluoro methyl or cyano R ₄ is a group of

(n is 2, 3, 4 or 5.) Hal is chlorine, bromine or iodine.