CS199687B2 - Process for preparing new substituted n-cycloalkylmethyl-2-phenylamino-2-imidazolines - Google Patents

Description

The present invention provides a process for the preparation of the novel substituted N-cycloalkylmethyl-2-phenylamino-2-imidazolines of the formula I

wherein each of R 1, R 2 and R 3, which may be the same or different, represents a hydrogen, fluorine, chlorine or bromine atom, a methyl group, an ethyl group, a methoxy group, a trifluoromethyl group or a cyano group, provided at least one it has a meaning other than a hydrogen atom, and n is a number of 2, 3, 4 or 5, and its physiologically tolerable acid addition salts, which compounds have valuable therapeutic properties.

199987

In accordance with the present invention, the compounds of formula (I) above are prepared according to the invention.

R 1, R 2, R 3 and n are as defined above and

A is cyano or a radical of formula

NH

Z —C \

Y

199887 where

Y represents an alkoxy group having a maximum of 4 carbon atoms, an alkylthio group having a maximum of 4 carbon atoms, a sulfhydryl group or an amino group, and reacted with ethylenediamine or its acid addition salts.

By this reaction the constitution of the resulting products is fixed. The position of the substituents can also be confirmed by NMR spectroscopy [see H. Stáhle and K.-H. Pook, Liebigs Ann. Chem. 751, 159 et al. (1971)].

In the process according to the invention, it is necessary to operate at an elevated temperature. between 60 and 180 ° C. The presence of a solvent is not necessary. The ethylenediamine or its acid addition salt used as reaction components is used in steel in excess.

The starting materials of the formula II are prepared by a process starting from anilines which is first reacted with the compounds of the formula III

in which

Hal represents a chlorine, bromine or iodine atom and n is as defined above, converted to the secondary amines, which then react with cyanates or thiocyanates to give the corresponding ureas or thioureas. The ureas and thioureas can then be converted by treatment with alkylating agents into the corresponding isouronium salts or isothiouronium salts. The corresponding isoureas or isothioureas can be obtained from these acid addition compounds by treatment with bases. By cleavage of urea water or by cleavage of hydrogen sulfide from thioureas using lead or mercury salts, cyanamides are added to which ammonia can be added to form guanidines.

The starting materials of formula III can be obtained by halogenation of the corresponding primary alcohols.

The 2-phenylamino-2-imidazolines of the formula I according to the invention can be converted into their physiologically tolerable acid addition salts in the customary manner. Suitable acids for the preparation of salts are, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propioic 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, 8 -chlorotheophyllin and the like

The novel compounds of the formula I as well as their acid addition salts have valuable analgesic properties and can therefore be used for the treatment of various pain conditions, for example migraine. The analgesic effect of the compounds of the invention has been tested in mice in painful convulsions [see Blumberg, Wolf and Dayton. Why. Soc. Exp. Biol. Copper. 118 (1965) 763] and a hot plate assay [see Woolfe and MacDonald, J. Pharmacol. Exp. Ther. 80 (1944) 300], and it has been found that the novel 2-phenylamino-2-imidazolines exhibit an effect equivalent to up to 100 times that of morphine. Compared to the N-allyl-2-phenylamipo-2-imidazoles described in DOS No. 1 958 201, the novel compounds of the invention also exhibit a 100-fold higher effect.

The dosage of the novel compounds of the invention in their therapeutic use ranges from 0.1 to 80 mg, preferably from 1 to 30 mg.

The compounds of the formula I and their acid addition salts can also be used together with active substances of another kind. Suitable dosage forms are, for example, tablets, capsules, suppositories, solutions or powders. Conventional galenic excipients and carriers, tablet disintegrating agents or glidants, or depot effect agents, are used to prepare these dosage forms.

The invention is illustrated by the following non-limiting examples.

Example 1

2- [N- (Cyclopropylmethyl) -N- (2,6-dichlorophenylamino) imidazoline

7.65 g of N- (cyclopropylmethyl) -N- (2,6-dichlorophenyl) guanidine, prepared by reacting N- (2,6-dichlorophenyl) guanidine with chloromethylcyclopropane, together with 1.7 ml of ethylenediamine in 65 ml of amyl alcohol under vigorous stirring stirring 20 wells is heated to reflux. The reaction mixture is evaporated to dryness in vacuo and the residue is dissolved in about 1 N hydrochloric acid. Gradual alkalization with 2 N sodium hydroxide solution and in each case extraction with ether yields 10 ether fractions at increasing pH values, from which the uniform fractions are combined, dried over magnesium sulphate and evaporated in vacuo. The residue was stirred with a small amount of absolute ether to crystallize. After suctioning and drying, 2- [N- (cyclopropylmethyl) -N- (2,6-dichlorophenyl) amino] imidazoline is obtained in a yield of 0.3 g (4.0% of theory), m.p. 120-123 ° C.

Example 2

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

8.6 g (0.03 mol) of N- (cyclopropylmethyl jN- (2,6-dichlorophenyl) -S-methylisothiomočo- _in guilt chlormethylcyklopropanu prepared by reacting with N- {2,6-dichlorophenyl) -S-methylisothiourea is together with 3 ml of eithylenediamine (150% w / w) is slowly warmed to 150 ° C with stirring and allowed to react at this temperature for about 30 minutes. The resulting 2- [N- (cyclopropylmethyl) -N- (2,6-dichlorophenyl) amino] imidazoline is identical to the imidazoline derivative prepared by another method. Identification was carried out by thin layer chromatography in the following solvent systems A, B, C. Detection was carried out with potassium iodoplatinate.

A = sec. Butanol - 85% formic acid - water (75: 15: 10)

B = benzene - dloxane - ethanol - concentrated aqueous ammonia (50: 40: 5: 5)

C = Ethyl acetate - isopropane - concentrated aqueous ammonia (70: 50: 20).

The compounds of the following examples are summarized in the following table in an analogous manner:

Table

Example R 'R'. Melting point Yield number (° Cj (% of theory))

H-CH _from 140-141 9.5

Cl ³

Cl

Whose

Br

Cl

155-157 37.7 _H y _CH -155-158 18.6

CH 3, - 157-158 44.4

F [h> ~ ^cw r ^{116-118 51.1}

Example R '

R ”

Melting point Yield

Cl

134—136 63,7

101—103 34,3

146-148 27,5

132-134 59.8

114—116 10.2

131—132 46,3

149-150 56.8 oil

37.4

Example R ’ R ” Melting point Yield number AFTER (% of theory)

May ⁵ 18 [ft> - ^CH 2- ch. ^ ₄ - ch ₄ - Br 20 May h> -ch ₂ - Ex OC ** 0- CH 2 O 22 NC - ^ -

105—106 43,6 oil 29,0

145—147 15,1

99—101 35,8

115—117 48,6

Claims (3)

Subject A process for the preparation of the novel substituted N-cycloalkylmethyl-2-phenylamino-2-iididazole of the general formula I each of R 1, R 2 and R 3, which may be the same or different, is hydrogen, fluorine, chlorine or bromine, methyl, ethyl a group, methoxy, trifluoromethyl or cyano, β in that at least one of these symbols has a meaning other than hydrogen, and the invention is n is 2, 3, 4 or 5, and their acid addition salts, characterized by The method of claim 1, wherein the compound is of the formula R 1, R 2, R 3 and n are as defined above and A is cyano or a radical of formula NH -C \ Y) where Y is alkoxy of up to 4 carbon atoms, alkylthio of up to 4 carbon atoms A compound having 4 carbon atoms, a sulfhydryl group or an amino group is reacted with ethylenediamine or its acid addition salts, and the product obtained is optionally converted into an acid addition salt. 2. The process according to claim 1, wherein the reaction is carried out at a temperature of 60 to 180 ° C. 3. The process according to claim 1, wherein the reaction is carried out in the presence of a polar or non-polar organic solvent.