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    • 专利摘要:
    4-[(3,4-Dialkoxyphenyl)alkyl]-2-imidazolidinone derivatives having the formula I <IMAGE> (I) wherein R1 stands for a cycloalkyl group containing from 3 to 6 carbon atoms or benzyl group; R2 stands for hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms; R3 stands for hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms; R4 stands for hydrogen atom, or an alkyl group containing from 1 to 4 carbon atoms or an alkoxycarbonyl group containing from 1 to 4 carbon atoms; and R5 stands for hydrogen atom or an alkoxycarbonyl group containing from 1 to 4 carbon atoms, are prepared by (a) reducing a hydantoin derivative having the general formula II, wherein R1 and R2 are as defined above, with lithium aluminum hydride in a neutral organic solvent, or (b) hydrogenating catalytically an 1,3-dihydro-2H-imidazol-2-one derivative having the general formula III, wherein R1 and R3 are as defined above, while the meaning of R4 is hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms, or (c) reacting a carbamate derivative having the general formula IV, wherein R1 is as defined above, while R6 stands for an alkyl group containing from 1 to 4 carbon atoms, with an organic or inorganic base. The compounds having the formula I possess valuable therapeutical properties, mainly anorexigenic activity.
    公开号:SU1003756A3
    申请号:SU792832901
    申请日:1979-10-31
    公开日:1983-03-07
    发明作者:Шнайдер Геза；Андраши Ференц；Берженьи Пал；Лазар Арпад；Елек Шандор；Елекеш Иштван；Полгари Иштван
    申请人:Дьедьсеркутато Интезет (Инопредприятие)；
    IPC主号:
    专利说明:

    (5) THE WAY OF OBTAINING SUBSTITUTED DERIVATIVES IMIDAZOLID 1H-2-SHE 31.) 5 (3 Phenylmethoxy-methoxyphenyl) -methylene j-2, is imidazolidinone. 24.23 g (100 mmol) 2-phenylmethox-4-methoxybenzaldehyde and 10.01 g hydantoin (100 mmol) are heated in a mixture of 38 ml of anhydrous acetic acid e 19) 5 g of anhydrous sodium acetate, with shaking, at 140 ° C The resulting clear solution at 15B-1b2 C was boiled for 2.5 hours under the action of a reflux condenser, then cooled and poured into 250 ml of iced water. The resulting resin after 30 minutes, precipitated crystals. The crystals are filtered, washed twice with 50 ml of water, twice with 50 ml of ethanol and, finally, twice with 50 ml of ether. 14.75 g (45.5) of product are obtained, m.p. 249-251С. Elemental analysis. Calculated: C 66.66; H 4.97; N 8.64. (Mol. Mo 324.34) Found,%: C 66.33; H 5.22; N 8.45. S} 5-L (3-Phenylmethoxy-4-methoxyphenyl) -methyl -2,4-imidazolidinone. 34.43 g of the obtained product (100 mmol) are suspended in 200 ml of water. 43 ml of 10N sodium hydroxide solution are added to the suspension. Then, 342 g of 2% sodium amalgam is introduced into the reaction mixture with stirring for 45 minutes. During the addition, the temperature is maintained at 50-58 ° C using ice cooling. The resulting clear solution together with sodium amalgam is stirred for an additional 45 min at 50 s. After this, the solution is decanted from mercury; mercury is washed twice with 30 ml of water. The combined aqueous phases are cooled to minus 10 ° C and then acidified with 60 ml of concentrated hydrochloric acid under stirring, while taking care that the temperature does not exceed + 50 ° C. After 10 min., The precipitated crystals are filtered and washed twice with 100 ml of water. The filtered product is dissolved in 350 ml of chloroform and washed with sodium bicarbonate solution until neutral. The solution is dried over anhydrous magnesium sulphate and evaporated in vacuo. 300 ml of benzene was added to the residue, and again, it was added. The residue after evaporation is triturated with 80 ml of ether, after 30 minutes, the crystals are filtered off and washed with 30 ml of ether. Get 23,62 g (72,41) of the product, so pl. 147-149 ° C. Elemental analysis. Calculated D: C, 66.25; H 5.5b; N 8.58 N (mol.m. 326.35) Found D: C 66.25; H 5.6l; N 8.39 S) (3-Phenylmethoxy-methoxyphenyl) -methyl t 2-imidazolidinone. 19) 0 g (500 mmol) of lithium aluminum hydride is dissolved in 250 ml of anhydrous ether. 32.6 g (100 mmol) of the product obtained according to Example 16 are added to the solution in small portions over 30 minutes. During the addition, the suspension is boiled under the action of a reflux condenser. 250 ml of anhydrous tetrahydrofuran are then added to the suspension with stirring over 30 minutes. When tetrahydrofuran is added, the suspension boils rapidly and must therefore cool from time to time. At the end of the addition, the reaction mixture is additionally boiled for 30 minutes under the action of a reflux condenser. The exact amount of lithium aluminum hydride is decomposed by cooling with the addition of 100 ml of ethyl acetate, after which the reaction mixture, with stirring, is poured into 1200 ml of ice-cold water. The mixture is acidified with 200 ml of conc. hydrochloric acid, then extracted four times with 500 ml of chloroform. The combined organic phases are washed with 100 ml of water, dried over anhydrous magnesium sulphate and evaporated in vacuo, 300 ml of benzene are added to the gummy residue and o are again evaporated. The oily residue is mixed with 100 ml of ether at the same time, crystals fall out, which after 30 min exposure is filtered off and washed twice with 50 ml of ether. Obtain 26.03 g of product (83.4), Top. 154-1.57С (after recrystallization from isopropanol, the product has mp. 15b-158 С). Elemental analysis. Calculated,%: C 69.21; H 6.45; N 8.97. N., (Mol.m. 312.37) H 6.58; Found,%: C 69.28; N 8.85 Example 2. -C (3 Cyclopentyl hydroxy-methoxyphenyl) methyl -2-imidazolidinone. a) 3 Cyclopentyloxy-4-methoxybenzaldehyde. 15.22 g (100 mmol) of isovaniline is dissolved in 125 ml of dimethyl sulfoxy. To the solution was added 27 g of anhydrous powdered potassium carbonate. The suspension is stirred at 60–30 min, then 12.9 ml (120 mmol) of cyclopentyl bromide are added over 1 h, and the temperature is kept at the level. At this temperature, the suspension is stirred for another 8 hours, then cooled to 25 ° C and poured into 500 m of water. The aqueous emulsion times extra. 10 ml of ether. The combined ethereal phases are washed twice in 20 ml. 1N. sodium hydroxide solution, dried over anhydrous magnesium sulphate and evaporated. The residue is mixed with 100 ml of benzene and again evaporated. The remaining oil is fractionated in vacuo. ,, Obtain 20.65 g (E, 0%) of the product so kip. 136-138 ° C (0.01 mm Hg). Elemental analysis. Calculated: C 70,89; H 7.32 C. (Mol.m. 220.28). Found: C, 70.78; H 7.27. 5-C {3 Cyclopentyloxy- -methenyl) -methylene -2, A-imidazolidinedione. 22.03 g (100 mmol) of the obtained product (Example 2a) is subjected to re: exchange actions with 10.01 g (100 mmol) of hydantoin in analogy to Example Id. Obtain 13.95 g (k6,%} of product, mp. 223-225 ° C. Elemental analysis. Calculated: C 63.57; AND 6.00; N 9.26. C (, H gNi04 (Mol m 302.33) Found: C 63.15; H 5.93; N 9.1 g) 5-G (3 Cyclopentiloxy- - marks of siphenyl) -methylZ-2, | -imidazolidinedione Out of 30, 23 g (100 mmol) of the product obtained (Example 25) and work in a manner similar to Example 1. 20.82 g (68.51) of product are obtained, mp: 1A9-151 ° C. Elemental analysis Calculated: C 63.1t ; H 6, b2; N 9,20 Thu (mol.m. 30i, 35) Found,%: C 63.15 ;. H 6, N 9.0 2.) -PZ Cyclopenti1- | hydroxy-C-methoxyphenyl a) methyl 1-2 imidazolidinone; Out of 30.3 g (100 mmol) of the obtained product (Example 2), the analogous for example, 1-0. Obtain 21.05 g (72-, 5) of the product, so pl. 110-113 C (after recrystallization from acetone, mp. C). Elemental analysis. Calculated,%: C 66.18; H 7, N 9.65, (Mol. M. 290.37-) Found,%: C 66.10; H 7.80; E, 62 Example3-gQ) (3-Oxy-4-methoxyphenyl) -methyl-J-2-imidazolidinone. 31, g (100 mmol) of the product obtained analogously to example 1-S, is dissolved in a mixture of 300 ml of tetrahydrofuran and 150 ml of methanol at the boiling point. The solution is hydrogenated in the presence of 3 g of 10% palladium on activated carbon at (100 mmol of hydrogen are consumed within 75 minutes). The catalyst is filtered off and washed three times with a mixture of 100 ml of chloroform and 100 ml of methanol at boiling point. The filtrate is combined with the washing liquid and evaporated. 300 ml of benzene is added to the residue after evaporation and evaporation is continued. The residue is mixed with 100 ml of ether, the separated crystals are filtered off after 30 minutes and washed with 50 ml of ether. Obtain 20.38 g (91.5%) of the product so pl. 192-202 C (after recrystallization from methanol 20b-208 ° C). d) - (3-Cyclopentyloxy-4-methoxyphenyl) methyl 3-2-imidazolidinone. 27.22 g (100 mmol) of the obtained product (Example Over) are dissolved in 220 ml of dimethyl sulfoxide. 27 g of anhydrous potassium carbonate powder are added to the solution. The suspension is stirred at} G min. Then, over 60 minutes, 12.9 g (120 mmol) of cyclopentyl bromide are added, the temperature is kept at 60 ° C. The suspension is then stirred for an additional 20 hours at 60 ° C, cooled to 2 ° C and poured into 800 ml of water. The aqueous emulsion is extracted A times 00 ml of chloroform; a. The combined organic phases are washed twice with 50 ml of 1N. sodium hydroxide solution, dried over anhydrous sulfate magnesium, then evaporated, the oily residue is mixed with .200 ml of benzene and again evaporated. The residue after evaporation is mixed with 150 ml of ether, the precipitated crystalline product after 30 minutes of exposure from the filter and washed with 5Q ml of ether., Obtain 21.30 g (73,%) of the product so pl. 10 -1tJ7 C (after recrystallization from acetone 115-11b C). The product on the basis of its inherent physical characteristics is identical to the product obtained according to Example 1. U Example of Obtaining a therapeutic preparation. Tablets, suitable for oral administration and serving pharmaceutical purposes, containing 10 m of biologically active substance, have the following composition, g: C (3 Cyclopentyloxy-4-methoxyphenyl) -methyl J-2-imidazolidinone 0,010 Wheat starch 0, Milky sugar0.037 Carboxymethylcellulose, 0,006 Talc 0.005 The average weight of one tablet is 0, 100 g. The appetite-reducing effect is examined in rats of the CFY type as follows. Experimental animals are deprived of food at 2 ° C, then they give compounds through their mouth and after half an hour after this they give food to full saturation. The amount of received feed is measured in the next 5 hours. The change in animal weight and the amount of solid, granulated feed, respectively of saccharified milk or potato flakes, eaten by them are also determined, then the value of the indicator ED-50 is taken from the data obtained. The results are presented in -Table.
    D-Amphethine, Atedron, Benzhedrin, tilbenzeneethanamine sulfate
    Mazindol (Sandoz), sanorex, terenak: 5 (-chlorophenyl) -2.5 Dihydro-ZN-imidazo (2, 1-C1-isoindole-ol.
    Fenfluramine (Servier): ponderax, pderal, pondimin: OH-M-these Tc-methyl-3 (trifluoromethyl) -benzoethanamine hydrochloride.
    Chlorfentermine (Warner-Lambert), pre-sat, dezopimone, (1, o-dimethyl-chloro-benzoethanamine-hydrochloride. 1a: G - (3 Cyclopentyloxy-4-metch
    hydroxyphenyl) -methyl -2-iiidazolidinone.
    X: ED (j- is such a dose (when administered via pBt), in which rats after Zt fasting for 5 hours eat half the amount of feed compared to the control ones, or their weight gain becomes half the size of the control rats.
    权利要求:
    Claims (1)
    [1]
    From the data of the table, it follows that compound 1a of the general formula 1 exhibits a better appetite-reducing effect in comparison with the known compounds with the same direction of action. The therapeutic index for this compound was better than that of the best known appetite suppressant. Presently known appetite suppressants are almost without exception psychostimulant compounds. In spite of this, the proposed compounds have a mild sedative effect and a slight ability to lower blood pressure. This beneficial side effect allows beneficial therapeutic use. . The proposed compounds can be incorporated into pharmaceutical formulations wherein the 4- (3,4-dialkoxy-phenyl) alkyl-2-imidazolidinone derivatives of the general formula I can be processed as medicinal preparations together with the use of non-toxic, physiologically tolerable,. inert diluents of ft / or carriers usually for the pharmaceutical industry. The daily dose of the compounds of the newborn is 10-50 mg. Formula of the invention. A method of obtaining 4-substituted imidazolidin-2-on-general derivatives of the formula (iU- (5H2 where R is a cyclopentyl or benzyl group, characterized in that the hydantoin of the general formula (iH-dH where R has the indicated value, the lithium aluminum hydride is reduced in an inert organic pacfigate and the desired product is isolated, where R is a benzyl group. or the resulting compound of formula 1, where R is a benzyl group, is subjected to catalytic hydrogenation in the presence of and palladium on coal followed by alkylation with a cyclopentyl halide and isolation of the target product, where R is cyclopentyl. group Information sources taken into account in the examination 1. Gaylord N. Restoration by complex metal hydrides. M., Foreign Literature, 1959, p. 855 and further
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
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