JPS6018653B2 - Process for producing novel 2,6-disubstituted 2-phenylimino-imidazolidine and its acid addition salt - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing novel 2,6-disubstituted 2-phenyliminoimidazolidines and acid addition salts thereof. For a long time, 2-phenylaminoimidazolidines have been of great interest because of their excellent pharmacological and therapeutic properties. Compounds of this type are therefore currently described in the literature, for example in Belgian patents no. 62$05, Belgian patents 6$933, Oka 687,656, Belgian patents 687,657 and Belgian patents 705,944. These reference patents also describe a basic method for producing 2-phenylaminoimidazolidine. Based on recent research, centrality Q
-Adrenergic stimulation (central, Q-adre)
Among the structural features of 2-phenylimidazolidine required for nergic stimulation, conformation was found to be of critical importance. With structure-action considerations, the phenyl ring and the imidazolidine ring are mutually in a non-planar conformation (aplana).
It has been found that only those derivatives that have a good blood pressure lowering effect (reconformation) exhibit a good blood pressure lowering effect. In this case, the free rotation of the phenyl ring surrounding the C--N single bond is prevented, and these two rings are positioned perpendicularly or almost perpendicularly to each other. AplaMrity can be achieved with 2-phenylimino-imidazolidines by substitution in the ortho-position of the aromatic part of the molecule: -The large atom or group of atoms in this position is C-N. This prevents the free rotation of the phenyl rings surrounding the single bond, causing the two rings to be in mutually coplanar positions (
Copla ship position). The object of the present invention is novel ortho- and ortho-disubstituted 2-phenyliminoimidazolidines of the general formula and their pharmaceutically compatible acid addition salts, which have useful therapeutic properties, especially antihypertensive properties. In formula 1, Z is 2-ethyl-6-methylphenyl,
2,6-difluorophenyl, 2-chloro-6-fluorophenyl, 2,6-dimethoxyphenyl, 2,6-dihydroxyphenyl, 2,6-ditrifluoromethylphenyl, 2-promo6-methylphenyl, 2-furomo Represents a group consisting of 6-chlorophenyl, 2-chloro-trifluoromethylphenyl or 2-fluoro-6-trifluoromethylphenyl. The novel compounds of formula 1 can be prepared according to one of the following methods: It often represents a halogen atom, preferably chlorine, a sulfhydryl group, an alkylthio group, an alkoxy group, a hydroxy group, an amino group or a nitroamino group, and said alkyl has 1 to 4 carbon atoms. a compound having atoms) is reacted with ethylenediamine or a salt thereof. As the raw material compound of formula D, for example, incyanide dihalides, especially isocyanide dichloride, thiourea,
0-alkylurea or its acid addition salt, S-alkylthiourea or its acid addition salt (in these two compounds, the alkyl group contains 1 to 4 carbon atoms), carbamic acid ester, thio These include carbamic acid chloride, alkylthiocarbamic acid chloride, or nitroguanidine. This reaction depends on the groups x and Y.
Perform at a temperature of o. As the solvent, a polar solvent, a neutral solvent or a non-polar solvent can be used. The reaction can also be carried out with the x and Y groups at elevated temperatures and without the use of solvents. If one or both of X and Y represents a halogen atom, it is recommended to use an acid-binding agent in this reaction. The reaction time depends on the reactivity of the compounds used and varies from several minutes to several hours. 'b1 General formula Z-NH-C3N m (in the formula Z
(has the meaning of the previous lecture) is reacted with ethylenediamine or its salt. This method needs to be carried out at high temperatures of 60°C to 180°C. No solvent is necessary. It is useful to use an excess of ethylenediamine or its acid addition salt used as a reaction partner. 'c- An aniline of formula Z-N ratio N, where Z is as defined above, is reacted with a compound of formula. This process must be carried out at high temperatures of 80 to 180 degrees. Non-polar inert solvents have proven suitable as solvents.

[d} Urea or thiourea of the general formula (wherein Z is as defined above and W means oxygen or sulfur) is cyclized. This method requires heating to a temperature of 120 to 160 q○. However, it is not necessary to use a solvent. 'e-W
Aniline of the formula (wherein R'' means a new nuclear substitutable group, such as halogen, preferably chlorine, or methylthio, methoxy or hydroxy, and R means a halogen atom or aliphatic acyl) When R'' represents a hydroxy group, it is advantageous for R to mean an acyl group, for example acetyl. The reaction of the aniline of formula W with the 1-acylimidazolidin-2-one which takes place in this case is suitably carried out at a moderate temperature of about 50°C. Advantageously, the reaction is allowed to continue for several hours to several days. Subsequent hydrolytic elimination of the acyl group is necessary to produce compounds of formula 1, which is best carried out using a lower alcohol, such as methanol, to form a 1-acyl compound. circulate. The reaction of aniline of formula W with 2-methylthioimidazoline or 2-chloroimidazoline requires high temperature (10
0 to 180 qo) must be used. Solvents are not required, but may be used. As solvents, all of the above-mentioned abrasive and polar neutral solvents may come into consideration. [f' A carbodimide of the formula Z-N=C:N-Z (wherein Z has the above-mentioned meaning) is reacted with ethylenediamine or a salt thereof. The carbodimide method is carried out at room temperature in an inert solvent such as benzene, and then
It has been demonstrated that it is optimal to distill off the solvent at a high temperature of 0°C. Cough) formula (in the formula, R represents fluorine, chlorine, bromine or methyl)
The amino group in the compound is substituted with a fluorine, chlorine or bromine atom to produce a compound in which Z contains a halogen atom as a substituent. In this case, the reaction is carried out according to the known conditions of the Sidemeyer reaction. Enemies) 2,6-dialkoxyphenylimy/-
By ether-elimination of imidazolidine (wherein the alkoxy group contains 1 to 4 carbon atoms), 2,6
-dihydroxyphenyliminoimidazolidine is produced. This ether elimination is best carried out in concentrated hydrobromic acid at elevated temperatures. This can also be carried out by the action of Lewis acids under different conditions, as is known from the literature. The new 2,6-disubstituted anilines of formula W used as starting compounds are generally prepared according to one of the following reaction schemes. Reaction diagram 1: Reaction diagram 2: When using synthetic route 1, the desired benzoic acid as well as its isomers are obtained, which can be purified by column chromatography (
separated by silica gel). The synthesis of 2,6-ditrifluoromethylphenyllithium, an intermediate step in the production of 2,6-ditrifluoromethylaniline, has been described, for example, by Jason Dyers.
and Colorists (J.Soc.Dyers and
Colo Riverists), 1970, 86, 200, by G. Halas et al. Intermediates or starting compounds for the individual processes are derived from the anilines of formula W thus obtained and can be obtained by methods known in the literature. For example, carbodiimide of skin type or isocyanide dicyclolide of type 0 can be prepared from aniline N as follows: Formula 1 of 2-phenyliminoimidazo IJ dine according to the present invention can be prepared by conventional methods for its medical treatment. It can be converted into a compatible acid addition salt. Acids suitable for salt formation include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, caproic acid, cyanobic acid, oxalic acid, malonic acid, etc. Acid, succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acid,
Examples include benzoic acid, p-hydroxybenzoic acid, p-aminobenzoic acid, phthalic acid, cinnamic acid, salicylic acid, ascorpic acid, methanesulfonic acid, ethanephosphoric acid, and 8-chlorotheophylline. The novel compounds according to the invention, as well as their acid addition salts, have useful therapeutic properties, especially antihypertensive properties, and can be used in the treatment of various conditions of hypertension. Compounds of general formula 1 can be administered enterally or parenterally. Dosage is 0.1 none, 80 to 9, preferably 0
．． Corresponds to 9 of 5 to 30. The compounds of formula 1 or their acid addition salts can also be used with another type of active substance. Suitable dosage forms include, for example, tablets, capsules, suppositories, solutions or powders; their manufacture may include the usual excipients, carriers, disintegrants, lubricants or other additives to achieve sustained release properties. Auxiliary agents may be used. The following examples are intended to illustrate the invention without limiting its scope. Example 1 322 (0.96 mol) of 2-(2-ethyl-6-methylphenyl)-imidazolidine N-(2-ethyl-6-methylphenyl)-1S-methyl-isothiouronium hydroiodide was added to 96 mol of ethylenediamine. With secretion 1
Heat at 50q0 in oil for 20 minutes while shaking. Next, excess ethylenediamine is evaporated under reduced pressure. The viscous residue is taken up in a small amount of methanol and the crude base is precipitated with a 50% potassium hydroxide solution with simultaneous addition of water. This is done with ice-cooling. Remove the aqueous phase and dissolve the oily layer in chloroform. The loform solution is dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. The residue is dissolved in dilute hydrochloric acid and the solution thus obtained is dissolved at various pH values (dilute sodium hydroxide is added).
Extract with ethanol into sections. The pure fractions are collected by thin layer chromatography and evaporated to dryness under reduced pressure. Further purification is done by chromatography on AI203 (using chloroform as scaling agent). 32.4 ml of highly pure imidazolidine base with a melting point of 134-13 (corresponding to 16.6% of the theoretical amount) is obtained. Example 2 2-(2,6-difluorophenylimino)-imidazolidine produced from 2,6-difluoroaniline [Reference: Journal of Medicinal Chemistry 11/
4, 814 (1968)] Thiourea (melting point 148-14
9oo) Heat 5.8 g of methyl iodide in 30 g of absolute methanol at reflux temperature for 30 minutes. Ethylene diamine ( 150%) 3. Heat to 155-160 qo. Methyl mercaptan and ammonia are released during this process. After 15 minutes, the reaction product is taken up in methanol 200 ml and purified with activated carbon. After filtration, the clear light yellow solution is made alkaline with 50% potassium hydroxide solution and the solid imidazolidine base separated is taken off with suction. After washing with water and then drying, melting point 1
Thin-layer chromatography at 69 DEG -170 DEG C. gives 1.3 ml of pure base (corresponding to 21.4% of theory). 2
-(2,6-difluorophenylimino)-imidazolidine hydrochloride melts at 248-250 pm. It is white in color and highly soluble in water and alcohol. Example 3 2-(2-chloro-6-fluorophenylimino)-imidazolidine prepared according to Scheme 1, melting point 179-
2-Chloro-6-fluoro-aniline hydrochloride at 180°C is reacted with ammonium rhodanide in chlorobenzene to give N-(2-chloro-6-fluoro-phenyl)-thiourea (melting point 135°C), and this product is further iodine N-(2-chloro-6-fluorophenyl)-S-methylisothiouronium hydroiodide is obtained. 13.2 ml of this isothiouronium-hydriodide salt is heated to 150-160 ml in an oil bath for 18 minutes with 3.8 ml of ethylenediamine (150%). After cooling, the clear, homogeneous melt is dissolved in about 30 ml of methanol and the solution is purified with activated charcoal. Here, the imidazolidine base was precipitated with a 50% potassium hydroxide solution (
(with ice cooling), the precipitate is taken off in a suction oven, washed with water and then dried. Yield: 1.8 days (corresponding to 22.2% of the theoretical amount). Melting point: 139-14 o The hydrochloride salt prepared by a conventional method has a melting point of 260-26 o. This material is thin layer chromatographically pure. Example 4 1.77 g of 2-(2,6-dimethoxyphenyl)-S-methylisothiouronium hydroiodide having a melting point of 193 to 195 qo of 2-(2,6-dimethoxyphenylimino)-imidazolidine was mixed with 0.00 g of ethylenediamine. Reflux in 10' of n-butanol for 1 hour. 0.5 ml of 2-(2,6-dimethoxyphenylimi/)-imidazolidine hydroiodide having a melting point of 207 DEG -208 DEG C. is obtained. This product is soluble in water, but readily dissolves in ethanol and dimethyl sulfoxide. Preparation of imidazolidine base: 1.5 ml of the hydroiodide salt obtained above is dissolved in 75 ml of water and the imidazolidine base is liberated with sodium hydroxide solution. This residue is first dissolved. After salting out this with common salt, it is separated in solid form. This is taken up in chloroform, the chloroform phase is separated, dried over anhydrous sodium sulfate and then evaporated to a small volume under reduced pressure. After addition of the anhydrous ether, the base crystallizes out. Yield: 0.5 yen, melting point: 1
55-1570. Example 5 2-(2,6-dihydroxyphenylimi/)-imidazolidine hydrobromide 2-(2,
6-dimethoxyphenylimino)-imidazolidine is heated in a boiling water bath for 6 hours with 100% 48% hydrobromic acid. The reaction mixture is then evaporated under reduced pressure at a nominal temperature of about 50 oo. Imidazolidine hydrobromide is recrystallized from isopropanol 75, which remains as a residue. Theoretical quantity 46.
2.3 hours of pure title imidazolidine hydrobromide, corresponding to 6%, are obtained. Melting point: 208°C. Example 6 2-(2,6-di-trifluoromethylphenylimine/
)-Imidazolidine N-(2,6-di-trifluoromethylphenyl)-isocyanide dichloride [1,3-di(trifluoromethyl)-benzene to 2,6-di(trifluoromethyl)-benzoic acid (melting point 136-1
380C), 2,6-di(trifluoromethyl)-benzamide (melting point 200-2020), 2,6-di-(
trifluoromethyl)-aniline and 2,6-di(
trifluoromethyl)-formanilide (melting point 179~
18ro)] 1.25 evening (0.00
4 mol) of ethylenediamine was reacted with 2.7 mol of ethylenediamine at 10° C. in 15 ml of anhydrous ether. After the addition of isocyanide dichloride is complete, the mixture is allowed to rise to room temperature and the rope ritual is continued for an additional 3 minutes. The reaction mixture is evaporated to dryness under reduced pressure and the residue is then dissolved in dilute hydrochloric acid. For purification, two ether extractions are carried out at a pH of approximately 5.5. The imidazolidine hydrochloride aqueous solution is then made alkaline with sodium hydroxide solution, with simultaneous addition of petroleum ether. After crystallization and vacuuming the crystals, they are washed with a small amount of water and petroleum ether, then dried,
A slightly contaminated imidazolidine base with a melting point of 170-174 qo is obtained. Yield: 9 of 360 (30.2% of theoretical amount
). For purification, the crude base is chromatographed on silica gel. A mixture of methanol:acetone:chloroform=6:3:15 is used as a scaling agent. In this way, completely pure melting point 177 ~] 7800 ~ 21 (
2,6-ditrifluoromethylphenylimino)-imidazolidine is obtained. Example 72-(2-bromo-6-methylphenylimino)-imidazo IJ dine 2-bromo-6-methylaniline synthesized according to scheme 2 was reacted with N-(2-bromo-6-methylphenyl)-thiourea (melting point 166-168 °C) to N-(2-fromo-6
-methylphenyl)-S-methylisothiouronium hydroiodide is obtained. 17.4 mol (0.045 mol) of this compound is refluxed with 4.5 mol of ethylene diamine in 50 ml of ethylene glycol-monomethyl ether for 1 hour. The reaction mixture is then evaporated to dryness under reduced pressure and the semi-solid residue is dissolved in methanol. After treatment with activated carbon, the methanolic solution is made alkaline with 50% potassium hydroxide solution. The precipitated imidazolidine base is removed by suction. For further purification, the product is dissolved in dilute hydrochloric acid and the hydrochloric acid solution is extracted several times with ether. The nearly pure crab fraction is then collected by thin layer chromatography with extraction with ether at various pH-values, dried and evaporated over anhydrous magnesium sulfate. The remaining residue is crystallized with a small amount of anhydrous ether. Yield: 2.6 hours, melting point: 140-14500. To convert to a highly pure base, column chromatography is performed on silica gel using methanol:acetone:chloroform=6:3:15 as the eluent. The title compound thus purified has a melting point of 142-14400.
become. Example 8 2-(2-bromo-6-chlorofuenylimino)-imidazolidine hydrochloride Required 2-bromo-6
-Chloraniline is 3-chloro- which corresponds to reaction scheme 2
2 Synthesized from nitrobenzoic acid through the following steps: 3-
Chlor-2 nitro-penzoyl chloride, melting point 62
~64°C; 3-chloro-2-nitrobenzamide, m.p. 200-203 oo; 3-chloro-2-nitroaniline, m.p. 60-6500 and reduction to 3-chloro-2-nitrobromobenzene and aniliso. 2-bromo-6-chloroaniline is reacted with methyl iodide via N-(2-bromo-6-chlorophenyl)-thiourea to produce N-(2-bromo-6-chlorophenyl).
1S-methylisothiouronium hydroiodide was obtained, and 8.3 mol (0.021 mol) of this product was mixed with 2.1 mol of ethylenediamine while stirring 20 ml of n-butanol underground. Allow the song time to flow. It is then allowed to cool, whereby the precipitate separates. The precipitate is vacuum-fed and the mother liquor is evaporated to dryness under reduced pressure. The oil remaining as a residue is dissolved in dilute hydrochloric acid and this dilute hydrochloric acid solution is extracted. Discard the ether extract. The aqueous phase is then ether extracted into sections at different pH values. The pure fraction is collected by thin layer chromatography, dried over anhydrous magnesium sulfate and then evaporated under reduced pressure. After dissolving the residue in ether, the title hydrochloride is precipitated with ethereal hydrochloric acid, taken up with suction and then dried. yield:
1.5 pm, melting point 297-300 qo. Example 9 2-Chlor-6-trifluoromethylphenylimino)-imidazolidine hydrochloride N-(2-chloro-6-trifluoromethylphenyl)-isocyanide dichloride [reaction scheme 1 above via the following steps] According to 3-chlor-
Produced from penzotrifluoride: 2-chloro-6
-trifluoromethyl-benzoic acid (melting point 120-123
°C), 2-chloro-6-trifluoromethyl-aniline (oil) and 2-chloro-6-trifluoromethyl-formanilide (melting point 167-170 °C)]99 with 21.6 mmol of ethylenediamine (10 times excess) and anhydrous The reaction was carried out at 10° C. in 100 cc of ether with candlelight. After a reaction time of 30 minutes, the reaction mixture is evaporated to dryness under reduced pressure and the remaining oil is dissolved in dilute hydrochloric acid. - After two extractions with ether, the aqueous phase is separated off and treated with activated carbon. The pH value is then increased (alkalinized with sodium hydroxide solution) and the sections are extracted with ether. The pure Able fraction is collected by thin-layer chromatography, dried and then mixed with ethereal hydrochloric acid until a Congoic acid reaction precipitates the title imidazolidine hydrochloride. Yield of pure 2-(2-chloro-6-trifluoromethylphenylimino)-imidazolidine hydrochloride: 3.2 min (corresponding to 32.9% of theory). Melting point: 277-279 pm○. This white, crystalline substance is soluble in water and lower alcohols. Example 10 2-(2-Fluoro-6-trifluoromethyl-phenylimino)-imidazolidine-hydrochloride In the same manner as Example 9, according to Scheme 1, the intermediate 2-fluoro-6-trifluoromethylbenzoic acid (mp 81 ~ 8400), 2-fluoro-6-trifluoromethylaniline (oil), 2-fluoro-6-trifluoromethylformanilide (melting point 116-118°C), and the resulting isocyanide dichloride is then reacted with ethylenediamine. The title compound is prepared by: Yield: 44.9% of theory, melting point: 262-26400
Example 112 2-Ethyl-6-methyl-phenylucyanamide with 8.1 ml of ethylenediamine-monotoluol sulfonate dissolved in 50% of [(2-ethyl-6-methyl-phenyl)-imino]-imidazolidine amyl alcohol 4.0 mol (0.025 mol) is refluxed for 5 hours. The clear reaction mixture is allowed to cool overnight, then the solvent is evaporated under reduced pressure. Take up the residue into the INHC. Decant the liquid phase and prepare the acid solution at various pH values (by addition of dilute sodium hydroxide) with increasing pH values.
Fractionate and extract with ether. The seven ether fractions containing imidazolidine (pHI ~10) (checked by thin layer chromatography) are collected and evaporated to dryness under reduced pressure to give the title imidazolidine base as crystals. Yield: 0.6 evening (
11.8% of theory); melting point: 121-12600. Example 12 2-[(2-Ethyl-6-methyl-phenyl)-imino]-imidazolidine 8.12 mol of 2-ethyl-6-methyl-aniline (0.04 mol) in 25% of anhydrous toluene
The mixture is refluxed for 1 hour with 3.44 hours (0.04 mol) of ethyl urea and 25 hours of bosphorooxychloride. The mixture is then evaporated to dryness under reduced pressure. IN the residue
It is dissolved in HC〆 and the resulting solution is fractionally extracted with ethers of various pH values of increasing pH value (by addition of dilute sodium hydroxide solution). Pure fractions were collected by thin layer chromatography and dried using NaO4.
It is then evaporated to dryness under reduced pressure. Yield: 0.65 min (80% of theory). The product was identical to the authentic material (DC-symmetric in various solvents). Example 13 2-[(2-chloro-6-fluorophenyl-imino]-imidazolidine a) 1-acetyl-2-[(2-chloro-6-fluoro.-phenyl)-imino]-imidazolidine phosphorooxychloride In 100 [ of
Acetyl imidazolidin-2-one 9.6 hours (0.0
75 mol) with 50-5y0 and 36. During the music period, heat while worshiping the rope. The phosphorooxychloride is removed under reduced pressure. The residue is then dissolved in 350 ml of ice water. After filtering with suction, the monkey fluid was made alkaline with NaOH while cooling on ice.
1-Acetyl-2-[(2-k.6-fluorophenyl)-imino]-imidazolidine is precipitated. Crystals are collected by suction, washed with ice water, and then dried. Yield: 13.0 min (73.7% of theory): Melting point: 126-129002-[(2-chloro-6-fluorophenylimino]-imidazolidine 1-acetyl-2-[(2-k. A mixture of 10.0 mol (0.039 mol) of 6-fluorophenyl)-imino-imidazolidine and 3 ml of concentrated HC is refluxed in 150 ml of methanol for 1 hour.
The reaction mixture is evaporated to dryness under reduced pressure and the residue is dissolved in water. The solution formed after filtration is fractionally extracted with ethers of various pH, with progressively increasing pH values (by addition of dilute NaOH solution). The collected thin-layer chromatography-pure fractions are dried over 400 ml of Na and evaporated to dryness under reduced pressure to yield the title compound 0.6 ml (42% of theory).
Example 14 2-[(2-Ethyl-6-methyl-phenyl)-imino]-imidazolidine N dissolved in anhydrous benzol 10
, N′-di(2-ethyl-6-methyl-phenyl)-
6.0 moles (0.022 mol) of triboimide was dissolved in 1.3 moles (0.02 mole) of ethylenediamine in 30 moles of anhydrous benzene.
2 mol) at 20-25°C (ice cooling). The mixture is allowed to react for 2 hours at room temperature and then evaporated to dryness under reduced pressure to give a compound of formula 7.0 (99% of theory) as a viscous pale yellow oil.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, Z is 2-ethyl-6-methylphenyl, 2,6
-difluorophenyl, 2-chloro-6-fluorophenyl, 2,6-dimethoxyphenyl, 2,6-dihydroxyphenyl, 2,6-ditrifluoromethylphenyl, 2-bromo-6-methylphenyl, 2-bromo-6-
chlorophenyl, 2-chloro-6-trifluoromethylphenyl or a group of the group 2-fluoro-6-trifluoromethylphenyl) and its acid addition salts. A manufacturing method, which includes formulas, mathematical formulas, chemical formulas, tables, etc. (In the formula, Z has the above meaning, (chlorine, sulfhydryl, alkylthio, alkoxy, hydroxy, amino or nitroamino group, where the alkyl group contains 1 to 4 carbon atoms)
react with ethylenediamine, optionally
A process comprising subsequently converting the compound of formula I thus obtained into a pharmaceutically compatible acid addition salt. 2 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, Z is 2-ethyl-6-methylphenyl, 2,6
-difluorophenyl, 2-chloro-6-fluorophenyl, 2,6-dimethoxyphenyl, 2,6-dihydroxyphenyl, 2,6-ditrifluoromethylphenyl, 2-bromo-6-methylphenyl, 2-bromo-6-
chlorophenyl, 2-chloro-6-trifluoromethylphenyl or a group of the group 2-fluoro-6-trifluoromethylphenyl) and its acid addition salts. A process for the preparation of a phenyl cyanamide of the formula Z-NH-C≡N III, in which Z has the meaning given above, with ethylenediamine, optionally a compound of the formula I thus obtained. and then converting it into a pharmaceutically compatible acid addition salt. 3 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, Z is 2-ethyl-6-methylphenyl, 2,6
-difluorophenyl, 2-chloro-6-fluorophenyl, 2,6-dimethoxyphenyl, 2,6-dihydroxyphenyl, 2,6-ditrifluoromethylphenyl, 2-bromo-6-methylphenyl, 2-bromo-6-
chlorophenyl, 2-chloro-6-trifluoromethylphenyl or a group of the group 2-fluoro-6-trifluoromethylphenyl) and its acid addition salts. A manufacturing method, in which aniline of the formula Z-NH_2 IV (in the formula, Z has the above-mentioned meaning) is converted to the formula ▲mathematical formula,
A method consisting of reacting the compound of formula I with a chemical formula, table, etc. and, if desired, converting the compound of formula I thus obtained into a pharmaceutically compatible acid addition salt. 4 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, Z is 2-ethyl-6-methylphenyl, 2,6-
Difluorophenyl, 2-chloro-6-fluorophenyl, 2,6-dimethoxyphenyl, 2,6-dihydroxyphenyl, 2,6-ditrifluoromethylphenyl,
2-bromo-6-methylphenyl, 2-bromo-6-chlorophenyl, 2-chloro-6-trifluoromethylphenyl or a group of 2-fluoro-6-trifluoromethylphenyl) A method for producing a disubstituted 2-phenylimino-imidazolidine and an acid addition salt thereof, the method comprising: converting aniline of the formula Z-NH_2 IV (wherein Z has the above meaning) to the formula ▲,
There are chemical formulas, tables, etc.▼ (In the formula, R'' represents a group capable of new nuclear substitution, such as halogen, preferably chlorine, or methylthio, methoxy, or hydroxy, and R'''
represents hydrogen or aliphatic acyl) with an imidazoline derivative of the formula thus obtained.
A process comprising subsequently converting a compound of I into a pharmaceutically compatible acid addition salt. 5 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, Z is 2-ethyl-6-methylphenyl, 2,6
-difluorophenyl, 2-chloro-6-fluorophenyl, 2,6-dimethoxyphenyl, 2,6-dihydroxyphenyl, 2,6-ditrifluoromethylphenyl, 2-bromo-6-methylphenyl, 2-bromo-6-
chlorophenyl, 2-chloro-6-trifluoromethylphenyl or a group of the group 2-fluoro-6-trifluoromethylphenyl) and its acid addition salts. A method of preparing a carbodiimide of the formula Z-N=C=N-Z VIII, in which Z is as defined above, with ethylenediamine, optionally comprising the step of reacting a carbodiimide of the formula I a method comprising subsequently converting the compound into a pharmaceutically compatible acid addition salt. 6 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, Z is 2-6-difluorophenyl, 2-chloro-6-fluorophenyl, 2,6-ditrifluoromethylphenyl, 2-bromo -6-methylphenyl, 2-bromo-6-chlorophenyl, 2-chloro-6-trifluoromethylphenyl or a group of the group 2-fluoro-6-trifluoromethylphenyl))
A method for producing -phenylimino-imidazolidine and its acid addition salts, in which the compound of the formula ▲ has mathematical formulas, chemical formulas, tables, etc. (in the formula, R_1 means fluorine, chlorine, bromine or methyl) Compounds of formula I in which Z contains a halogen atom as a substituent are prepared by replacing the amino group with fluorine, chlorine or bromine according to Sandmeyer, and optionally the compound of formula I thus obtained is A process comprising then converting into a pharmaceutically compatible acid addition salt. 7 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, Z represents 2,6-dihydroxyphenyl)
2,6-dialkoxyphenylimino-imidazolidine (wherein the alkoxy group has 1 to 4 carbon atoms) ether separation to produce 2,6-dihydroxyphenylimino-imidazolidine and, optionally, the formula thus obtained.
A process comprising subsequently converting a compound of I into a pharmaceutically compatible acid addition salt.