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    公开号:SU831073A3
    申请号:SU782680652
    申请日:1978-11-04
    公开日:1981-05-15
    发明作者:Рамуз Хенри
    申请人:Ф.Хоффманн-Ля Рош Унд Ко. Аг(Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a process for the preparation of new compounds, namely, the novelty of 2-iminoimidazolide derivatives of the general formula, 1 where R, R and R independently of one another denote a hydrogen atom, a straight or branched alkyl with 1-6 carbon atoms or a hydrogen atom. and R is linear or branched alkyl with 1-6 carbon atoms, saturated cycloalkyl with 3-6 carbon atoms, linear or branched alkenyl with 2-6 carbon atoms, unbranched or branched apkinyl with 2-6 carbon atoms, dialkylaminoalkyl with 1-6 atoms hydrochloride, oxyalkyl with 1-6 carbon atoms, cyanoalkyl with 1-6 carbon atoms, aryl alkyl with 1-6 Ug.1 carbon atoms in the alkyl part, alkylthioalkyl with 1-6 carbon atoms in the alkyl part, alkoxycarbonylalkyl, alkoxyalkoxy-alkyl, alkoxycarbonylalkenyl, alkoxyalkyl, where the alkoxy group has 1-6 carbon atoms, of a genus, or linked through the -CH (R) group unsubstituted or substituted by the-COOR group, a five-membered heterocyclic residue with one heteroatom, the heteroatom being oxygen or sulfur, or linked through , CH (R) group unsubstituted or 3 an alkyl or alkoxy-cured six-membered heterocyclic residue with a nitrogen atom as a heteroatrix, where the alkyl or alkoxyl part has 1-6 carbon atoms, R is a hydrogen atom or methyl, R is alkyl with 1-6 carbon atoms, or their acid-acid salts. These compounds regulate the biological active properties of Xen. A known method for the preparation of 1-propargyl-2-gm- (1,6-dichlorophenyl) -amiHol-2-imidazoline of the formula: Ui CHi-CaCH is that the sodium salt of 2-gm- (2,6-dichlorophenyl) -aminr3-2-imidaeoline is reacted with propargyl bromide in absolute tetrahydrofuran at room temperature IJ. This compound has biologically active properties and can be used as an analgesic agent. The purpose of the invention is to obtain new compounds expanding the arsenal of means of influencing a living organism. This goal is achieved by combining the formula where R, R and R have the indicated values, is reacted with a compound of the formula R-X (III) where R has the indicated values and X represents a halogen atom, an arylsulfonyloxy group, an alkylsulfonyloxy group or a residue a quaternary ammonium or sulfonium salt, in the presence of a base, in an aprotic polar, or aprotic nonpolar, or proton polar solvent, or in liquid ammonia, or in a two-phase system at 50-100 ° and the desired product is isolated in free form or in the form of acid addit implicit salt. O-substitution of a compound of formula (M) is carried out according to well-known methods in the presence of a base, for example, sodium hydride, potassium t-butylate, sodium ethoxide, thallium ethylate, and the like, in an aprotic polar solvent, for example dimethylformamide, dimethyl sulfoxide, aceto-nitrile, etc., in an aprotic nonpolar solvent, for example, simple ethers, for example, tetrahydrofuran or diethyl ether, aromatic hydrocarbons, for example, toluene or xylene, cyclohexane, etc., p., in a proton polar solvent , nap: rimer, alcohol, nap Emer, t-butanol or izrpropanole and the like, or liquid ammonia, etc. The choice of solvent will depend on the base used. Thus, with the use of alcohols, the reaction is carried out in a proton polar or aprotic non-polar solvent, with sodium hydride in an aprotic polar solvent, and with sodium agiid in an aprotic polar solvent or liquid cuvotoiaKe. The reaction is carried out at temperatures of between 0 ° C and 10 ° C, preferably at temperatures between 20 ° C and 45 ° C, depending on the base used. If ethylate is used as the base, then X in the compound of formula (ill) is preferably iodine atom. O-substitution can also be carried out in such a way that catalysis is carried out with phase transfer. In this case, predominantly sodium hydroxide or sodium carbonate is used as a base in a two-phase system, for example, in methylene chloride / water, in the presence of a salt, for example, tetrabutyrylmonium hydrogen sulfate. It is more expedient to work at room temperature. Compounds of formula (I) can be converted to pharmaceutically applicable acid addition salts, for example, by treatment with an inorganic acid, for example, hydrohalic acid, hydrochloric acid or hydrobromic acid. sulfuric acid, phosphoric acid, etc., or an organic acid, for example, oxalic acid, tartaric acid, citric acid, methanesulfonic acid, etc. The pharmaceutically unsuitable acid addition salt of the compound of formula (I) can be converted in a well-known manner, for example, by treatment with an alkali, into a free base and, if necessary, into a pharmaceutically applicable acid addition salt. Example. 327 mg of bromohydrate (l mmol) 2-G (2,6-dichlorophenyl) imino -1-oxyimidazolidine was dissolved in 5 ml of absolute dimethylformamide and 90 mg (2.06 mmol) of sodium hydride was added at 5 ° C. Stir at room temperature until the solution is clear, cool again to 5 ° C and add 1.2 b / l (1, 2 mmol) of a 1.0 molar solution of methyl iodide in dimethylformamide. After 30 minutes the reaction product is poured into water and the aqueous phase is extracted with ether 2 times. The organic extracts are dried and evaporated in vacuo. The residue was dissolved in 1 ml of acetonitrile and hydrochloric acid was added in dioxane. The precipitated 2-g (2,6-dichlorophenyl) imino -1-methoxyimidazolidine hydrochloride melts at 228 sec. The free base is melted after recrystallization from isopropyl ether at 123-124 ° C. Example 2. Analogously to example 1, from 2-f (2, b-dichlorophenyl) iminoJ -1-oxyimidazolidine bromohydrate and diethylaminoethyl chloride, 2- f (2, b-dichlorophenyl) imino} -1-g2- (dimethylamino) ethoxy-imidazolidine is obtained. The corresponding hydrochloride melts at 213-215 ° C (from acetonitrile / ethyl acetate). Example 3. To a solution consisting of 6.15 g (30 mmol) of 2- (2,6-dichlorophenyl) imino-1-oxy-imidazr Lidine and 45 ml of absolute dimethylformamide, 1.31 g are added at 25 ° C. (30 mmol) sodium hydride (55% suspension). After 30 minutes, 4.16 g (35 mmol / - 2.37 ml,, 579) propargyl bromide was added dropwise. After 30 minutes, this is poured into 500 ml of a saturated solution of salt and the aqueous phase is extracted with ether. The ether extracts are washed with aqueous hydrochloric acid. The aqueous extracts are basified with a 3N sodium hydroxide solution and extracted with ether. After evaporation of the solvent, the residue is dissolved in ether and hydrochloric acid in dioxane is added. The remainder of the perechristite from methanol / acetonitrile to obtain 2- (2,6-dichlorophenyl) imino -1- {2-propynyloxy) -imidazole hydrochloride, m.p. 198199 C (from methanol / acetonitrile). EXAMPLE 4: The following compounds are prepared as in angshore Example 3. From 2-G (2,6-dichlorophenyl) imino-1-oxyimidazolidine and P-phenethyl bromide, half a dose of 2-G (2,6-dichlorophenyl) imino -1- (phenetyloxy) imidazolidine, m.p. 111-112 s (from diisopropyl ether / hexane). The corresponding hydrochloride is recrystallized from the main tone / ethyl acetate, so pl. 167-1b9 ° From 2-G (2,6-dichlorophenyl) imino -1-oxy-imidazolndia and 3- (diethylamio) -2,2-dimethylpropyl chloride, 2-j (2,6-dichlorophenyl) imino -1-Tz- ( diethylamino) -2,2-dimethylpropoxy-7-imid zolidin. The corresponding () -tetrate (1: 1), which is crystallized with 1.1 mol of acid, is crystallized from acetone / ether and melted at 156-157 with Example 5. 6.15 g (25) 2- (2.6) -dichlorophenyl) imino -1-oxazamine dazolidine is stirred in 25 ml of dimethyl formamide and 45 ml of toluene at room temperature with 1.2 g (30.7 mmol of sodium amide). After 1 h, the mixture is heated to give a clear solution. temperature was added and 3.4 ml of 2-chloroethylmethyl sulfide was added, and the mixture was then heated to 60 ° C and subjected to a reciprocal action for 16 hours. After that, the reaction mixture was discharged extract into ether and extract with ether. Extract ether extracts with aqueous hydrochloric acid. Aqueous extracts are again made alkaline with 3N sodium hydroxide solution and extracted with ether. After drying and evaporation of the solvent, the oily residue is chromatographed on silica gel (chloroform / solvent acetic ester 9: 1). The resulting yellow oil is dissolved in acetone and hydrochloric acid in dioxane is added. The resulting precipitate is recrystallized from acetone to give 2-c2,6-dichlorophenyl) imino -1-f2- (methylthio) ethoxy-imidazolidine hydrochloride. m.p. 156 C (with decomposition). Similarly, ethyl-4 - {(2- (2,6-dichlorophenyl) imino-1-imidazolidinyl) oxy-urate is obtained from 2-f (2,6-dichlorophenyl) imino-l-oxioimidazolidine and 4-bromoic acid ester. The corresponding hydrochloride is lavits at 113-115 ° C (from isopropanol / acetone). Example 6. Similarly to example 5, the following compound is obtained. From 2- (2,6-dichlorophenyl) iminoJ-l-oxyimidazolidine and 4-H2- (tetrahydropyranyl) oxy} bromopropane, 3 - {(2-G (2,6-dichlorophenyl) imine9 -1-imidazolidinyl) oxy - - 1-propanol, so pl. 115-117 ° C (from methylene chloride / diisopropyl ether). The corresponding hydrochloride is melted at 150-15 L (from isopropanol / ethyl acetate). Example 7. Analogously to Example 5, the following compounds are obtained. From 2- G (2,6-dichlorophenyl) imino} n1-oxyimidazolidine and allylbromide, 1- (allyloxy) -2- (2,6-dichlorfe NIHL) hydrochloride is prepared by them with HoJ-imidazolidine, m.p. 169-171 with (from acetonitrile). From 2- (2,6-dichlorophenyl) imino -1-oxyimidazolidine and benzyl bromide, 1-benzyloxy-2-1 (2,6-dichlorophenyl) imino imidazolidine is obtained, m.p. iiS-lil C (from diisopropyl ether). From 2-f (2,6-dichlorophenyl) imine-2-l-oxides (J Shdazolidine and bromoacetic ester), ethyl- (2- (2,6-dichlorophenyl) imino -1-imidazolidine) hydroxyacetate hydrochloride was obtained, mp. 171-173 ° C (from acetonitrile / diethyl ether). From 2- G (2,6-dichlorophenyl) imino2-1-oxyimidazolidine and propyl bromide, 2- (2,6-dichlorophenyl) imino -1-propoxyimidazolidine hydrochloride is obtained, mp 217 -218 s (from methylene chloride / ethyl acetate). From 2-f (2,6-dichlorophenyl) iminoJ-1-oxyimidazolidine and 5-bromovaleronitrile, 5- (2-f (2,6-dichlorophenyl) imino -1- hydrochloride is obtained) imidazolidinyl) oxy1 | valeronitrile, mp 183185 C {from acetone a / diethyl ether). From 2-c2,6-dichlorophenyl) imino -1-hydroxyimndaeolidine and E-methoxyethyl | - | Chloroethylether get 2-f (2,6-dichlorophenyl) imino} (2-labels; siotoxy) ethoxy-imidazolidine methanesulfonate (1: 1), so pl. 103-104 s (from the bristle / diethyl ether). I 2- 1 (2,6-dichlorophenyl) imino -1-hydroxy-xydazolidine and 4-bromo-1-6-utene get 1- (3-butenyl) -2-G (2,6-dichldrphenyl) imino-3 imidazolidine-methane sulfonate, t .pl. 155-157 C (from acetone / diethyl ether). From 2- (2,6-dichlorophenyl) imino -1-oxyimidazolidine and 5-bromo-1-pentene, receive 2- (2,6-dichlorophenyl) imino2-2- (4-pentenyl) -imiazolidine hydrochloride, m.p. 2O3-2O7 ° C (from acetone).
    Isopropyl-4-hydrochloride (2-f (2, b-c-dichlorophenyl) imino} -1-imidazolidinyl) oxy-butyrate is obtained from 2- f (2, b-dichlorophenyl) imino-g1-oxyimidazolidine and isopropyl bromobutyric ester m.p. 134-135®C (from ethyl acetate).
    2-G (2, b-dichlorophenyl) imino} -1-G {3,4-dimethoxyphenethyl) oxy imidazolidine oxalate (1) gives 2-G (2, b-dichlorophenyl) imino} -1-G from 2- (2,6-dichlorophenyl) HMHHoJ-1-oxyimidazolidine and homoveratryl-, chloride. : 1), mp, 167-168 ° C (from acetonitrile).
    From 2- G (2, b-dichlorophenyl) imino2-1-oxyimidazolidine and 4-chlorobutyro-5 nitrile, 4- | (2-f (2, b-dichlorophenyl) iminoj-l-imidazolidinyl) oxy) butyronitrile in the form of oil, the corresponding hydrochloride melts at 183-184 ° C (from acetonitrile / ethyl acetate 20).
    From 2-C2, b-dichlorophenyl) imino} -1-oxyimidazolidine and 5-bromo-v-eryanoic acid ethyl ester, ethyl-5- (2- (2, b-dichlorophenyl) imi-25but} -1-imidazolidinyl) oxy5 is obtained -valerate oxalate. (1: 1), m.p. 9b ° C (from ethyl acetate).
    From 1-hydroxy-2- (phenylimino) imidazoline and ethyl bromoate,., Acids, ethyl-4- (phenylimino) -1-imidazalidinyl-oxy butyrate is obtained as an oil.
    From 2-G (b-chloro-2-methylphenyl) imine-J-1-oxyimidazolidine and 4-bromobutyric acid ethyl ester, ethyl 4- {(2-f (6-chloro-2-methylphenyl) imino-1-imidazolidinyl) is obtained. ) hydroxy butyrate in the form of oil.
    Ethyl 4- {(2-G (2, b-dimethylphenyl) imino-1 imidazolidinyl) oxy butyrate is obtained from 1-OXY-2-G (2,6-dimethylphenyl) imino-imidazolidine and 40 4-bromo-acid ethyl ester in the form of butter.
    From 2-G (2, b-dichlorophenyl) imino -1-oxyimidazolidine and c-chlorbutyl- (2-tetrahydropyranyl) ether and the subsequent treatment with 3N hydrochloric acid, get the hydrochloride 4 - {(2-f (2; b-dichlorophenyl ) imino -1-imidazolidinyl) ok-, “si} -1-butanol, m.p. 175-17b ° C (from methanol / acetonitrile).
    Example 8. Analogously to Example 5, the following compounds are obtained.
    Ie 2-G (2,6-dichlorophenyl) imino} rl-oxyimidazolidine and 4-bromo-crotonic acid ethyl ester give ethyl 4- (2-G (2, b-dichlorophenyl) iminoJ-1-imidazolidinyl) oxy} -crotonate, m.p. 137-138 ° C (from acetonitrile), the corresponding hydrochloride melts 60 at 139-140 ° C (from acetone / diethyl ether).
    2-G (2-chlorophenyl) jiMH-fi5 hydrochloride is obtained from 2- (2-chlorophenyl) iminoJ-1-oxyimidazolidine and propargyl bromide
    HoJ-1- (2-propynyloxy) imidazolidine, m.p. 174-175s (from methanol / acetoniryl).
    Ethyl 4- (2-G (2-chlorophenyl) imino-7-imidazolidinyl) oxy} butyrate is obtained in the form of an oil from 2-P2-chlorophenyl) imino -1-oxyimidazolidine and 4-bromobutyric acid ethyl ester. Ethyl 4- (2-G (2,6-dichlorophenyl) imino J-1-imidazolidinyl) is obtained from 2-G (2, b-dichlorophenyl) imino -1-oxyimidazolidine and 4-bromo-2-methylbutyric acid ethyl ester ox1 2-methylbutyrate as an oil.
    From 2-f (2, b-dichlorophenyl) iminoj-1-oxime imidazolidine and iodide isopropyl, 2- (2,6-dichlorophenyl) imino -1-isopropoxy imidaeroline hydrochloride, m.p. 204-205 ° C (from acetonitrile).
    From 2-f (2,6-dichlorophenyl) imino -1-oxyimidazolidine and 2-bromoyl acid ethyl ester, ethyl 2- (2-G (2,6-dichlorophenyl) imino -1-imidazolI | Zinyl) is obtained hydroxy} butyrate, m.p. 176-177 C (from acetonitrile).
    Ethyl 4- {(2- (2-iodophenyl) imino} -1-imidazolidinyl) oxy butyrate is obtained from 1-OXY-2-I2-iodophenyl) imino7-imidazolidine and 4-bromobutyric acid ethyl ester as an oil.
    Ethyl 2-5 (2-G (2,6-dichlorophenyl) iminoO-1-imidazolidinyl) oxy} -2- is obtained from 2- (2,6-dichlorophenyl) imino-1-hydroxy-imidazolidine and ethyl l-bromo-butyric acid ethyl ester. methyl propionate, so pl. 171-172 ° (from ethyl acetate / hydrochloric acid in dioxane / diethyl ether).
    From 2-2, b-dichlorophenyl imino -1-oxyimidazolidine and 3-methoxypropyl chloride, 2-f 2,6-dichlorophenyl imino-Cz-methoxypropoxy) imidazolidine is obtained, m.p. 95-96 ° C (from isopropyl ether).
    From 2- (2,6-dichlorophenyl) imino -1-oxyimidazolidine and ethyl iodide, 2-f (2,6-dichlorophenyl) imino-imino-ethoxyimidazolidine hydrochloride, m.p. 219-221 ° С (from acetone).
    From 2- f (2,6-dichlorophenyl) imino -1-oxyimidazolidine and transcinamyl bromide, 1- (cinamyloxy) -2-L (2,6-dichlorophenyl) imino imidazolidine hydrochloride is obtained, m.p. 123-125 ° C (from acetonitrile / hydrochloric acid in dioxane / diethyl ether) ..
    Example 9. Analogously to Example 3, the following compounds were prepared. From 2- (2,6-dichlorophenyl) imino-1-oxyimidazolidine and 1-bromo-2-butine, using benzene as a solvent, get 1- (2-butynyloxy) -2- (2, b-dichlorophenide) imino im schazolidine hydrochloride m.p. 198P: Cc decomposition) (from acetonitrile / hydrochloric acid in dioxane). From 2- C (2, b-dichlorophenyl; imino} -1-oxyimidazolidine and 2-chloromethylfur) using toluene as a solvent, 2-G (2,6-dichlorophenyl) HNWHoJ-1- (furfuryloxy) imidazolidine, t. mp 123-124 ° C (from isopropyl ether); the corresponding 1CHI hydrochloride melts at 162-164 ° C (from acetonitrile / dioxane / diethyl ether). From 2-f (2,6-dichlorophenyl) imino -1-oxyimidazolidine and ethyl Ethyl 2-f (2-f (2,6-dichlorophenyl) imino -1-imidazolidinyl) oxy methyl) -3-furoate, m.p. 99 C (from isopropyl ether) f the corresponding fumarate melts at 154-156 s (from methanol / acetonitrile. From 2- (2,6-dichlorophenyl imino -1-oxyimidazolidine and 2-chloromethylthiophene using toluene as a solvent, 2-f is obtained (2,6-dichlorophenyl) imino -1-C2 thienyl markers CI) -imidazolidine, mp 101-102 0 (from methylene chloride / cyclohexane); the corresponding hydrochloride is melted at 21lc (with decomposition) (from acetone / hydrochloric acid in dioxane.) Example 10. In a similar manner to Example 3, such compounds are prepared. From 2- [(2,6-dichlorophenyl) imino} -1g-oxyimidazo idine and f-methoxyethyl chloride get 2- (2,6 dichlorophenyl) imino -1- (2-methoxyethoxy) imidazolidine hydrochloride, mp 125-127 C (from acetone / hydrochloric acid in dioxane / diethyl ether). From 2- 11 (2,6-dichlorophenyl) imino -1-oxyimidazolidine and 4-bromo-3-methylcrotonic acid methyl ester (cis-trans mixture) give methyl 4- {(2- (2,6-dichlorophenyl) imino-imidazolidinyl) ) hydroxy-3-methylcrotonate in the form of a cis-trans mixture (1: 1), so pl. 84-85t (of isopropyl ether). Example 11 14.12 g (41.6 mmo of tetrabutylammonium hydrogensulfate, 9.84 g (40 mmol) of 2- (2,6-dichlorophenyl) imino - 1-hydroxy-imidazolidine / 7.97 g (44 mmol) of ethyl -bromopropionic acid ester and 140 ml of methylene chloride are stirred at room temperature. 42 ml 2.0 and a solution of sodium hydroxide are slowly added to the mixture, and the reaction immediately starts. Chloride methylene is distilled off in vacuo and replaced with ether. The ether solution is washed with water, dried over magnesium sulfate and evaporated under vacuum to give 15 g of crystalline product. a and recrystallized from cyclohexane to obtain ethyl -2- (2-G (2,6-dichlorophenyl) imino -1 | -imidazolidi "yl) oxy} propionate, mp 79-80 C. The hydrochloride melts at 185- 186 ° C (from acetonitrile / hydrochloric acid in dioxane / diethyl ether). The following compounds are prepared in a similar way. 2- (2,6-dichlorophenyl) iminoJ-1-oxyimidazolidine and 3-bromomethylthiophene give 2- (2,6-hydrochloride) dichlorophenyl) imoJ -1- (3-thienylmethoxy) -imidazolidine, m.p. 204-20bs (from acetone / hydrochloric acid in dioxane / diethyl ether). From 2-f (2,6-dichlorophenyl) iminoJ-l-oxyimidazolidine and 4-bromo-2-methyl-2-butene, 2- (2,6-di chloroform) imino chloro} -1- f (h- methyl 2-butenyl) oxy imidazolidine, m.p. 153-154 ° C. (from acetonitrile / hydrochloric acid in dioxane / diethyl ether /. From 2-G (2,6-dichlorophenyl) imino -1-oxyimidazolidine and 3-bpOlVI methyl-pyrene, 2-G (2,6-dichlorophenyl) imino -1- ( 3-furylmethoxy) -imidazolidine, mp 204-206 s (from acetonitrile) Example 12. In analogy to example 11, the following compound is obtained using toluene as a solvent instead of methylene chloride and 28% instead of 2N sodium hydroxide solution caustic soda solution: from 2- (2,6-dichlorophenyl) imino -1-oxyimidazolidine and 2-chloromethylpyridine get 2- (2- (2,6-dichlorophenyl) im but -1-imidazolidinyl) oxy) methyl-pyridine, m.p. 116-117 ° C (of isopropyl ether), the corresponding; dichlorohydrate melts at 175-176 s. decomposition of ces methanol / acetonitrile). Example 13. Similarly to Example 3, a compound is obtained from 2-G (2.6 dichlorophenyl) imino -1-oxyimidazolidine and pentinZ-yl-p-toluenesulfonate to obtain 2-G (2,6-dichlorophenylimino -1- (3-pentynyloxy) imidazolidine, m.p. 104-105 ° C (from isopropyl ether X. Example 14. The following compounds are prepared analogously to example 11. From 2- (2,6-dichlorophenyl) imino -1-oxyimidazolidine and 3-chloromethylpyridine, 3 - {{f 2- f (2,6-dichlorophenyl) imino -1-imidazolidinyl) oxy5 methyl) -pyridine, m.p. 151-152-C (from methylene chloride / isopropyl ether), the corresponding dihydrochloride is melted by decomposition (from acetonitrile / dioxane). From 2-G (2,6-dichlorophenyl) imino -1-oxyimidazolidine and 4-chloromethylpyridine, 4- // f (2-G (.2,6-dichloro-phenyl) imino-1-imidazolidinyl) oxy} me are obtained. .til // -pyridine, m.p. 160-161 ° C (from acetonitrile / isopropyl ether), the corresponding dihydrochloride melts at 180 ° C with decomposition (from methanol / acetonitrile).
    From 2-G 2, 3-di} {lorofenyl HMHHoJ-oxoimidazolidine and 2-chloromethylpyridine, 2 - // (2- (2,3-dichlorophenyl) HMHHoJ -1-imidazolidinyl) oxy methyl // / pyridine, t. square 154155 0 with decomposition (from methanol / acetone). .
    From 2-f (2,4-dichlorophenyl iminoJ-1-oxyimidazolidine and 2-chloromethylpyridine, 2- // f (2- f (2, 4-dichlorophenide) imino-3-imidazolidinyl) oxy} methyl // -pyridine , mp 179-180 with decomposition (from acetone),
    From 2- (2, 5-dichlorophenyl) imino -1-oxyimidazolidine and 2-chloromethylpyridine, 2-11 (2-f (2, 5-dichlorophenyl) imino methyl 1-imidazolidinyl) oxy methyl // -pyridine is obtained as an oil.
    From 2-G (2, b-dichlorophenyl) imino-7-oxyimidazolidine and 2-chloromethyl-5-methylpyridine, 2- // f 2-C (2, b-dichlorophenyl) iminr -1-imidazolidinyl) oxy-methyl // -5-methylpyridine, so pl. 147-148 ° C (from methylene chloride / isopropyl ether) the corresponding dibromohydrate melts at 163164 0 with decomposition (from acetonitrile).
    From 2-1 (2,6-dichlorophenyl) imino} -1-oxyimidazolidine and 2-chloromethyl-methylpyridine, 2 - // {{(2- 2,6-dichlorophenyl) imino -1-imidazolidinyl) oxy-methyl // - b-methylpyridine, so pl. 132-133 ° C (from acetone / isopropyl ether; the corresponding dihydrochloride melts at 1.9b ° C with decomposition (ns of acetone).
    From 2-f (2, b-dichlorophenyl) imino} -1-oxyimidazolidine and 2-chloromethyl-5-. ethylpyridine get 2 - // {1 2-G (2, b-dichlorophenyl) imino} -1-imidazolidinyl) oxy; -methyl // -5-ethylpyridine, mp. 103-104 with 3 isopropyl ether).
    From 2- (. (2, b-dichlorophenyl) imino-J-1-oxides of 4 idazolidine and 2-o1-chloroethylpyridine) receive di-hydrochloride of ras-2- (2-G (2, b-dichlorophenyl) imino -1-imidazolidinyl) oxy ethyl / f - pyidine, mp. 218-219 ° С from gschetonitil / acetone.
    From 2-G (2-chlorophenyl) imino -1-oximidazolidine and 2-chloromethylpyridine, 2-11 {2-G (2-chlorophenyl) imino -1-imidazolidinyl) xi} methyl dichloride is obtained // pyridine, m.p. 17.517 SBU 3 acetonitrile / dioxane).
    From 2-G (2-bromophenyl} imino r-1-oximidazolidine and 2-chloromethylpyridine, (2-bromophenyl) -imino} -1-imidazolidinyl) xyl methyl dibromide is obtained // m.p. 186-187 ;; (from 30% hydrogen bromide in unit acetic acid).
    From 2-C (2, b-dibromophenyl) imino} -1-oxyimidazolidine and 2-chloromethylpyriin, 2-11 (2-G (2, b-dibromophenyl) imino} -1-imidazolidinyl) oxy
    -methyl // -pyridine-dihydrochloride,
    m.p. 187-188 ° C with decomposition (from methanol-acetonitrile).
    From 1-hydroxy-2-G (2,6-dimethylphenyl) imino} imidazolidine and 2-chloromethylpyri, dyne get 2-C (2-f (2,6-dimethylLenyl) imino} -1-imidazolidinyl Joxyl methyl dichlorohydrate // - pyridine, mp. 19b-197C with decomposition (from acetonitrile.) From 2-G (b-chloro-2-methylphenyl imino} -1-oxyimidazolidine and 2-chloromethylpyridine, 2 - // f 2 hydrochloride is obtained ( b-chloro-2-methylphenyl imino -1-imidazolidinyl) oxy} methyl // pyridine, mp 187 ° C (from acetonitrile).
    5 From 2-1 (b-chloro-2-methylphenyl) imino} -1-oxyimidazolidine and 3-chloromethylpyridine, 3 - // f (2-G (b-chloro-2-methyl) imino -1-imidazolidinyl) oxy methyl // -pyridine, so pl.
    0 (from methylene chloride / isopropyl ether); the corresponding dihydrochloride melts at 221-222 ° С with decomposition (from acetonitrile).
    From 2- / (2,6-dichloro-4-fluorophenyl) by them 5 -1-oxyimidazolidine and 2-chloromethylpyridine, 2- // f (2-f (2, b-dichloro-4-fluorophenyl) dibromide} iimoj-1- imidazolidinyl) oxy} methyl // -pyridine, mp 199-200 ° C with decomposition (from methanol / acetonitrile).
     From 2-G (2, b-dichlorophenyl) imino-D-oxy-imidazolidine and (-chloroethylpyridine, dihydrochloride is obtained 4 - // //
    1 - {(2-G (2, b-dichlorophenyl) imino} -1-imidazolidinyl) oxy 3 ethyl // pyridine,
    5 m.p. (from methanol / acetonitriha).
    From 2 - {(2,6-dichlorophenyl) iminoJ-oxyimidazolidine and 5, b-dimethoxy-3-chloromethylpyridine, dichloro-hydrate (2-G (2,6-dichlorophenyl) imIoJ-1-imidazolidinyl) oxy} methyl is obtained // 2 , 3-dimethoxypyridine, m.p. 172-175 C with decomposition (from acetonitrile / dioxane).
    From 2-G (2, b-dichlorophenyl) imino -1-oxyimidazolidine and 3-chloroethylpkridine, 3- / 1-f (2-f (2,6-dichlorophenyl) dihydrochloride) is obtained: 1mino-D-1-imidazolidinyl) oxy5ethyl pyridine, t .pl. 262 С
    with decomposition (from acetonitrile / dioxane).
     Example 15: 9.84 g (-40 mmol) of 2-C (2,6-dichlorophenyl) imino -1-oxyimidazolidine was dissolved in 100 ml of 40% tetrabutylammonium hydroxide and 10.16 added. g (55 mmol) of chloropropyl benzyl ether. The solution is left overnight, then diluted with water and extracted with ether. The ether extracts are shaken with 1 and-sulfuric acid. The aqueous phase is made alkaline with ammonia and extracted with ether, the ether extracts are dried with sodium sulfate and evaporated. The oily residue is recrystallized
    5 from methylene chloride / isopropyl ether to give l-f3- (benzyloxy-propoxy -2-1 (2, b-di; slophrenyl) imino} -imidaeolidine, mp. 79-80 ° C. Similarly from 2-f ( 2, b-dichlorophenl) imino3 -1-oxyimidazolidine and cyclohexanilbrrmide, 1- (cyclohexy-siloxy) (2,6-dichlorofvnil) iminoJ-imidazolidium-fumarate, m.p. 163164 C (from acetone), Compounds of formula 1, as well their pharmaceutically applicable acid addition salts have cardiovascular activity, in particular, a blood pressure lowering action, with central sympathetic inhibitory properties or without them, so that they can be used to treat hypertension.The blood pressure lowering effect can be determined by two methods.Systolic blood pressure and heart rate are measured several times before the substance is introduced in awake, spontaneously giPerton female rats. Per test dose, five experimental animals were used at approximately 300 g. The substance was administered using a gastric probe. Both parameters are measured 1, 3, 6, and 16 hours after entry, and the percentage changes in the control values are taken into account. Systolic blood pressure was measured indirectly in the ravine sarostomy artery using the Id et al method. Systolic blood pressure and heart rate are measured before the administration of a substance to sensitizing female dogs with a body weight of 10-15 kg. In this case, a modified carotid net of those of NIKU is used according to the method of van Lee gsum. The substance is administered to animals who are starving overnight. Both parameters are measured at 0.5; Ij 1.5; 2; 3; four; 6 and 16 hours after entering, and taking into account changes in percentage of control values. At the same time, observing animals from experimental animals. The observation of the duration of 24 h after the parameter ov reached control values. The central sympathetic inhibitory effect can be determined by the following method. The effect of ischemical compounds on activity in the sympathetic nervous system is examined in cats in urethane anesthesia. The preganglionic activity of the sympathetic nerve is produced from the celiac nerve using bipolar platinum electrodes, and the postganglonic activity from the nerve branch leading to the soil, according to the method of G. Hausler. In addition, blood pressure in the femoral artery and heart rate are measured. The test substance is injected intravenously. If it slows down the activity of the sympathetic nerve in the blood pressure lowering doses not higher than 30%, for more than 30 minutes, then its recognition is a substance that has a central sympathetic inhibitory effect. The table shows the results of the study of the biological activity of the compounds of formula (I), with the maximum deviations from the control values in percent and the possible center-sympathetic inhibitory effect of these compounds.
    +9 +5
    -54 -21 -19
    -36
    not,
    -20
    0 3 -23 -18
    not
    -9
    -24
    yes yes -20
    3 3
    -13 -14
    -37
    Yes
    -13
    -7
    -13
    -19 note D F G I 1 h L M Formula of the invention
    Method for preparing 2-yminoimidazolidine derivatives of general formula (I)
    VK OB
    where R, K2- and R independently of one another denote a hydrogen atom, a straight or branched alkyl with 1-6 carbon atoms or a halogen atom, and R is a branched or branched alkyl with 1-6 carbon atoms, saturated cycloalkyl with 3-6 volumes carbon, unbranched whether branched alkenyl with 2-6 carbon atoms, unbranched or branched alkynyl with 2-6 carbon atoms, dialkylaminoalkyl with 1-6 carbon atoms, oxyalkyl with 1-6 carbon atoms, cyanoalkyl with 1-6 carbon atoms, arylalkyl with 1-6 carbon atoms in the alkyl part, alk ltioalkil with 1-6 carbon atoms in the alkyl portion hydrochloric, alkoxycarbonylalkyl, alkoxyalkoxyalkyl, alkoksikarbonilalkenil, alkoxyalkyl wherein alkoksiProdolzhe ction t ablation,
    -eight
    -20
    Yes
    -21
    -13
    yes -32 -3
    the group has 1-6 carbon atoms, or bonded via the —CH group (h5} unsubstituted or substituted by the —COOR group, the five-membered heterocyclic residue
    40 with one heteroatom, the heteroatom being oxygen or sulfur, or a six-membered heterocyclic residue unsubstituted or substituted by an alkyl or alkoxy group bound to the nitrogen atom with a nitrogen atom as a heteroatom, where the alkyl or alkoxy portion has 1-6 carbon atoms , R is a hydrogen atom or methyl, and R is an alkyl with 1-6 carbon atoms, or their acid addition salts, characterized in that a compound of general formula (II)
    1H
    where R, R5 have the indicated values,
    subjected to interaction with the compound of the formula (III)
    R4-X,
    where Kd has the indicated values, and X65 is a halogen atom, arylsulfonyloxygroup hydrochloride 4 {(2-G (-2, b-dichlorophenyl) imino -1-imidazolidine) -oxy butyrate ethyl 2-C (2-G12, b-dichlorophenyl) imino} -1-imidazolidine) oxy-butyrate 2 - {(2,6-dichlorophenyl) imino} hydrochloride -1- (2-propynyloxy) -imidazolidine ethyl 4-f (2- (2, b-dichlorophenyl) imino7 -1-imidazolidine) OKCHj-crotonate 2-G hydrochloride (2, 6-dichlorophenyl) imino-1-ethoxyimidazolidine 1- (2-butynyloxy) -2-G hydrochloride (2,6-dichlorophenyl) imino-imidazolidine chlorohydrochloride hydride, 2-g (2, b-dichlorophenyl) imino -1- (furfuryloxy) -imidazolidine but; a pa, gshylsulfonyloxy group or residue of a quaternary ammonium or sulfonium salt, in the presence of a base, in an aprotic polar or aprotic nonpolar or proton polar solvent, or in liquid ammonia, or in a two-phase system at 50-100 ° C, and the target product are in free form or in the form of an acid addition salt. Priority signs: 07.11.77 with R4 - unbranched or branched alkyl with 1-6 carbon atoms, saturated cycloshkyl with 3-6 carbon atoms, unbranched or branched alkenyl with 2-6 carbon atoms, in the main chain TVlenny or branched alkynyl with 2-6 carbon atoms, dialkylaminoalkyl with 1-6 carbon atoms, hydroxyalkyl with 1-6 carbon atoms, cyanoogshyl with 1-6 carbon atoms / arylalkyl with 1-6 carbon atoms in the alkyl part, alkylthioalkyl with 1-6 carbon atoms in the gshkin part, alkoxycarbonylalkyl, alkoxyalkoxyalkyl, alkoxy orbonylalkenyl, alkoxyalkyl, where the alkoxy group has 1-6 carbon atoms, or linked through the -CH (R) group unsubstituted or substituted five-membered heterocyclic residue with one re-i theratom, or the heteroatom is oxygen or sulfur, and R , R, R and R are as defined in the claims. 09/15/78 with R4 linked through a -CH (Rf) group, a six-membered heterocyclic residue unsubstituted or substituted by an alkyl or alkoxy group with a nitrogen atom as a heteroatom, and R, Rj, R and R have the meanings indicated in the claims. Sources of information taken into account in the examination 1. US patent 4025607, cl. C 07 D 233/50 published 05/24/07.
    权利要求:
    Claims (3)
    [1]
    Claim
    The method of obtaining derivatives
    [2]
    2-iminoimidazolidine of General formula (I)
    OV * where (C, R2-H R s independently mean hydrogen atom, unbranched or branched alkyl with 1-6 carbon atoms or a halogen atom, and R 4 - unbranched or branched alkyl with 1-6 carbon atoms, saturated cycloalkyl with 3-6 carbon volumes, unbranched * whether branched alkenyl with 2-6 carbon atoms, unbranched or · branched alkynyl with 2-6 carbon atoms, dialkylaminoalkyl with 1-6 carbon atoms, hydroxyalkyl with 1-6 carbon atoms, cyanoalkyl with - 1-6 carbon atoms, arylalkyl with 1-6 carbon atoms 60 in the alkyl part , alkylthio-alkyl with 1-6 carbon atoms in the alkyl part, alkoxycarbonylalkyl, alkoxyalkoxyalkyl, alkoxycarbonylalkenyl, alkoxyalkyl, where the alkoxy50 group has 1-6 carbon atoms, or a five-membered heterocyclic moiety attached through the —CH (n5) group or unsubstituted or substituted by —COOR group with one heteroatom, the heteroatom being oxygen or sulfur, or a six-membered heterocyclic moiety with a nitrogen atom as a heteroatom linked through an —CH (R ^) group unsubstituted or substituted by an alkyl or alkoxy group, where the alkyl or alkoxyl moiety has 1-6 carbon atoms, R 'is a hydrogen or methyl atom, and R is alkyl of 1-6 carbon atoms, or their acid addition salts, characterized in that the compound of general formula (II) • where R * 7 , R 2 h R 3 HMeioT indicated values are reacted with a compound of formula (III)
    R 4 -X, where R 4 has the indicated meanings, and Xatom halogen, arylsulfonyloxy group 17 pa, alkylsulfonyloxy group or the residue of a quaternary ammonium or sulfonium salt, in the presence of a base, in an aprotic polar or aprotic non-polar or protonic polar solvent, or in liquid ammonia or in a two-phase system at 50-100 ° C, and the target product is isolated in free form or in the form of an acid addition salt.
    Priority by signs:
    11/07/77 when - unbranched * or branched alkyl with 1-6 carbon atoms, saturated cycloalkyl with
    [3]
    3-6 carbon atoms, unbranched or branched alkenyl with 2-6 carbon atoms, unbranched or branched 1 alkynyl e 2-6 carbon atoms, dialkylaminoalkyl with 1-6 carbon atoms, hydroxyalkyl with 1-6 carbon atoms, cyanoalkyl with 1 -6 carbon atoms, arylalkyl with 1-6 carbon atoms in the alkyl part, alkylthioalkyl with 1-6 carbon atoms in the alkyl part, alkoxycarbonylalkyl, alkoxyalkoxyalkyl, alkoxycarbonylalkenyl, alkoxyalkyl, where the alkoxy group has 1-6 carbon atoms, or linked via -CH (r ^ ·) unsubstituted sludge -COOR group substituted five-membered heterocyclic radical having one ge-> teroatomom, wherein the heteroatom is oxygen or sulfur, a R ^, R ^, R 3, Rj and R are as defined in the claims.
    09/15/78 at R4 - a six-membered heterocyclic residue with a nitrogen atom as a heteroatom bonded through the group -CH (Rj-) unsubstituted or substituted by an alkyl or alkoxy group, and R_p R a , Rj and R ^ have the meanings indicated in the claims.
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    同族专利:
    公开号 | 公开日
    GB2086379A|1982-05-12|
    PL210759A1|1980-03-10|
    ES480112A1|1980-04-01|
    DK494978A|1979-05-08|
    US4355033A|1982-10-19|
    MC1223A1|1979-07-20|
    EP0002010B1|1982-07-14|
    ES480113A1|1980-04-01|
    PT68752A|1978-12-01|
    EG13665A|1982-03-31|
    DE2847766A1|1979-05-10|
    NO783719L|1979-05-08|
    IT1160046B|1987-03-04|
    AU4132478A|1979-05-17|
    MTP837B|1979-10-22|
    OA06084A|1981-06-30|
    SU910119A3|1982-02-28|
    FI783393A|1979-05-08|
    IL55832D0|1978-12-17|
    CA1106847A|1981-08-11|
    US4511720A|1985-04-16|
    GB2008579B|1982-11-03|
    DD139847A5|1980-01-23|
    NZ188798A|1981-04-24|
    IT7829486D0|1978-11-06|
    FR2407919A1|1979-06-01|
    SE7811455L|1979-07-02|
    US4244957A|1981-01-13|
    DE2861952D1|1982-09-02|
    EP0002010A1|1979-05-30|
    BR7807317A|1979-07-24|
    AT371112B|1983-06-10|
    CS212309B2|1982-03-26|
    GB2008579A|1979-06-06|
    AR223656A1|1981-09-15|
    ES480111A1|1980-04-01|
    NL7811070A|1979-05-09|
    ATA791378A|1982-10-15|
    GB2086379B|1982-11-10|
    RO76151A|1981-08-30|
    JPS5473779A|1979-06-13|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    LU78467|1977-11-07|
    CH966878|1978-09-15|
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