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    • 专利摘要:
    N-(1-lower alkyl or alkenyl-2-pyrrolidinylmethyl)-2-lower alkoxy-4-amino-5-lower alkylsulphonylbenzamides and derivatives thereof which have antiapomorphine and antiserotonin activity.
    公开号:SU820659A3
    申请号:SU792714652
    申请日:1979-01-19
    公开日:1981-04-07
    发明作者:Томине Мишель；Аше Жак；Монье Жан-Клод
    申请人:Сосьете Д,Этюд Сьянтифик Э Эндюстриельде Л,Иль-Де-Франс (Фирма)；
    IPC主号:
    专利说明:

    the alkyl ether, halide and others are treated with an amine of the general formula. n-sngt where R is as defined above. In addition, compounds of the formula (T can be obtained by reacting 2-methoxy-4-amino-5-alkylsulfonylbenoic acid of formula (II) with a dihaloalkylsminmine of the general formula HgM-SnI Hoi Hoi where Hal is bromine or chlorine, and subsequent processing of the obtained compound of the formula CHg-L Fully No.il Yao "UN, V amine, where R has the indicated. Higher values. Amidation reactions can be carried out as in a solvent (alcohols, ketones, benzene, chloroform, etc.) as well without black- , as the solvent, you can use an excess amine. The reaction is preferably carried out at the boiling point of the solvent. The resulting compounds of the formula (l) can be converted to pharmaceutically acceptable salts in the usual way. Ex. 1. M- (1-Ethyl-2-pyrrh dylmethyl) -2 -methoxy-4-amino-5-these sulphonylbenzamide, 2-methoxy-4-amino-5-ethylthiobenzoic acid, 159 g of 2-methoxy-4-amino-3-mercap of benzoic acid, 355 ml of water and 160 ml of caustic solution soda is loaded into a flask equipped with a chill nickname. The mixture is heated to dissolve the solid, then 123 g of ethyl sulfate is added. The mixture is then heated under reflux, dried with 10 ml of a 30% caustic soda solution and heated under reflux for 1 hour. After cooling, 800 ml of water are added and the solution is filtered. To the resulting precipitate, 100 ml of concentrated hydrochloric acid and ether are added, the solution is treated with water and dried. I 162 g of 2-methoxy-4-amino-5-ethylthiobenzoic acid are obtained. Yield 88%. . 2-Methoxy-4-amino-5-ethylsulfonylbenzoic acid. 123 g of 2-methoxy-4-amino-5-methylthiobenvoic acid is dissolved in 542 ml of acetic acid with heating. The resulting solution is cooled to 35 ° C and 185 ml (131 volume) of hydrogen peroxide is added to it in small portions. The temperature rises to. The temperature is reduced to and the mixture is held at this temperature for several hours and then cooled to 10 ° C. The precipitate formed is drained, water is pumped and dried. It is further dissolved in 600 ml of water and 100 ml of 20% ammonia. To the resulting precipitate, 70 ml of concentrated hydrochloric acid are added, cooled, allowed to drain, washed with water and dried. . 61.5 g of 2-methoxy-4-amino-5-ethylsulfonyl benboic acid are obtained (hydrate, yield 42%, mp 95100 ° C). N- (1-Ethyl-2-pyrrolidyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide. 81 g of 2-methoxy-4-tamine-5-ethylsulfonylbenzoic acid and 297 ml of acetone are loaded into a flask equipped with a stirrer, a thermometer and a dropping funnel, and 38 g of triethylamine are added. The solution is cooled to, then 30 g of ethyl chloroformate are added dropwise at a temperature from 0 to 5 ° C. Further, at a temperature from 0 to under stirring, 51 g of 1-ethyl-2-aminomethylpyrrolidine is added dropwise. The mixture is stirred at and then at room temperature. The precipitated hydrochloric triethylamine, yes, can be drained, after which aceto is distilled off. The residue is dissolved in 600 ml of water in the presence of a solution of caustic soda. The base crystallizes after being seeded with a crystal, is allowed to drain, washed with water and dried. After purification of the crystals through the hydrochloride salt and recrystallization, 66 g of M- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide are obtained. Yield 61%, mp. 126-127 ° C. Example 2. M- (1-Methyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbeneEamide. .144 g of 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid, 440 ml of acetone and 44.5 g of triethylamine are loaded into a flask equipped with a stirrer, a thermometer and a dropping funnel. The solution is cooled to 0 ° C and then, at a temperature from 0 to, 48 g of ethyl chloroformate is added dropwise. The mixture is stirred for 30 minutes at 0-5 ° C and then 67 g of 1-methyl-2-aminomethylpyrrolidine is added dropwise to it at-5-10 C. The mixture is first stirred at, then at room temperature. The resulting product is drained, washed with acetone, treated with 500 ml of water, allowed to drain, washed with water and dried. The resulting substance is crystallized from absolute alcohol and purified through hydrochloride salt. After further recrystallization from absolute alcohol, 101 N- (1-methyl-2-pyrrolidylmethyl) -2-meroxy-4-amino-5-ethylsulfonylbenzamide is obtained. Yield 65%; m.p. 157-158 ° C. Example 3, N- (1-Allyl-2-pi rolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide. 132 g of 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid, 510 ml of acetone and 51.5 g of triethylamine are loaded into a flask equipped with a stirrer, a thermometer and a dropping funnel. The resulting solution is cooled to then at a temperature from 0 to 55.5 g of methyl chloroformate is added dropwise to it. The mixture is stirred for 30 minutes at 5 ° C, after which 1-allyl-2-aminomethylpyrrolidine is added dropwise to it at a temperature of from 5 to 96 g. The mixture was stirred at 10 ° C and then at room temperature. The precipitated hydrochloric 3 ethylamine is allowed to drain, and then acetone is distilled off. The residue is dissolved in water with 60 ml of concentrated hydrochloric acid, the resulting solution is filtered and treated with a 30% solution of caustic soda. The resulting oil is extracted with methylene chloride, the resulting organic solution is dried over carbon dioxide and potassium, and methylene chloride is distilled off. After purification, 131 g of N- (1-allyl-2-pyrrolidyl-1-methyl) -2-methoxy-4-amine-5-ethylsulfonyl benzamide are obtained. Yield 67%, mp. 111-112 ° C. Example 4. N- (1-ethyl-2-pyrrolidylmethyl -2-methoxy-4-amino-5-ethylsulfonylbenzamide) dehydrating tartrate Dehydrating N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy -4-amino-5-ethylsulfonylbenzamide.The work according to the method of example 1 95 g of 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid, dissolved in 370 ml of acetone and in the presence of 37 g of triethylamine, treated with 40 g of this chloroformate, then 57 g of right-rotating 1-ethyl-2-aminomethyl-nrrolidine. To obtain 115 g of right-rotating, N- (1-ethyl 2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide. 84% yield. M- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide, a crushing tartrate. To 133 g of the programmer H- (1-ethyl -2 -2-pyrrolidylmethyl) -2-methoxy-4-amino- 5-ethylsulfonylbenzamide, dissolved in 500 ml of methanol, 54 g of degrading tartaric acid, dissolved in 80 ml of methanol are added. The crystals formed after the seed are allowed to drain, then washed with methanol and dried. After recrystallization from methanol, 106 g are obtained. dextrusive tartrate of N- (l-ethyl-2-pyprolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide. Yield 56%, mp. 98108 C, -7.5 (in 5% aqueous solution). Example 5. Levorovacidium tartrate N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfone and forehead n 3 amide a. Following the procedure of Example 1, 104-g of 2-methoxy-4-amino-5-methylsulfonyl benzoic acid, dissolved in 380 ml of acetone in the presence of 38 g of triethylamine, is treated with 41 g of ethyl chloroformate and then 58 g of the levorotatory 1-ethyl-2-aminomethylpyr1Yulidine . 140 g of levorotatory N- (1-ethyl-2-pyrrolidylmethyl) -2-meth- are obtained. oxy-4-amino-5-ethylsulfonylbenzamide. The yield is 100%. Levorotatory tartrate of N- (1 ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide. 136 g of the levoradate M- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-methylsulfonylbenzamide is dissolved in 500 ml of methanol, then 58 g of levorotating tartrate acid, dissolved in 70 ml of methanol, are added. The resulting crystals are allowed to drain, then washed with methanol and dried .. After recrystallization from methanol, 103 g of levorotatory N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylcyl-4-benzylbenzamide are obtained. Yield 54%, mp. 100 C, M 6.3O (in 5% aqueous solution). Example 6. Progravity M- (1-methyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-methylsulfonylbenzamide. Following the procedure of Example 1, 117 g of 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid, dissolved in 450 ml of acetone in the presence of 46 g of triethylamine, are treated with 49 g of ethyl formate and then 69 g of the correcting 1-methyl-2-aminomethylpyrroline. 69 g of the programe of - (1-methyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide are obtained. Yield 44%, mp; 125-12bs, in +35.3 (in 5% solution of dimeti formamide). Example 7. N- (1-Ethyl-2-pyrro l "edeylmethyl) -2-methoxy-4-amino-5-propylsulfonylbenzamide. 2-Methoxy-4-amino-5-propylthiobeneic acid. Following the procedure of Example 1, but starting from 2-methoxy-4-amino-5-mercapto Oenzoic acid, 2-methoxy-4-amino-5-propylthiobenzoic acid is obtained, m.p. 104-105®C. 2-Methoxy-4-amino-5-propylsulfonylbenzoic acid. Following the procedure of Example 1, 187 g of 2-methoxy-4-amino-5-propylthiobenzoic acid, dissolved in 570 ml of acetic acid, are treated with 233 m (110 vol.) Of hydrogen peroxide. I get 108 g of 2-methoxy-4-amino-5-propylsulfonylbenzoic acid. Yield 69%, mp. 165-166 C. N- (1-Ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-propylsulfonylbenzamide. Following the procedure of Example 1, -160 g of 2-methoxy-4-amino-5-propylsulfonyl benzoic acid, dissolved in 590 ml of acetone in the presence of 59 g of triethylamine, is treated with 64 g of ethyl chloroformate, then 101 g of ethyl aminomethylpyrrolidine. After purification, 151 g of N- (l-ethyl-2-pypo-lzdilmethyl) -2-methoxy-4-amino-5-propylphosphonylbenzamide are obtained. Yield 67%, mp. 105-106 C. Frost. M- (1-Methyl-2-pyr rolidylmethyl) -2-methoxy-4-amino-5-methylsulfonylbenzamide. 2-Methoxy-4-amino-5-methylthiobene | isoic acid. Following the procedure of Example 1 and starting from 2-methocai-4-amino-5-mercaptobenzoic acid, 2-mutoxy-4-amino-5-methylthiobenzoic acid is obtained. .pl. 151-152 C. 2-methoxy-4-amino-5-methylsulfonylbenzoic acid. Following the procedure of yrimer 1, 158 g of 2-methoxy-4-amino-5-methylthiobenzoic acid, dissolved in 742 ml of hydrochloric acid, are treated with 310 ml (110 vol.) Of hydrogen peroxide. 114.5 g of 2-methoxy-4-amino-5-methylsulfonylbenzoic acid are obtained. Yield 63%, mp. 178-180 C. N- (1-Methyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-methylsulfonylbene Following the procedure of Example 1, 131 g of 2-methoxy-4-amino-5-methylsulfonylbenzoic acid, dissolved in 538 ml of acetone in the presence of 54 tricethylamine are treated with 58.5 g of ethyl chloroformate, and then 73 g of 1-methyl-aminomethylpyrrolidine. After purification of the resulting substance, 114 g of M- (1-methyl-2-., -Pyrrolidylmethyl) -2-methoxy-4-amino-5-methylsulfonylbenzamide are obtained. Yield 62%, mp. 191-192 C. Example 9. N- (1-Ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-methylsulfonylbenzamide. . Following the procedure of Example 1, 129 g of 2-methoxy-4-amino-5-methylsulfonylbenzoic acid, dissolved in 526 ml of acetone in the presence of 53 g of triethylamine, is treated with 57 g of ethyl chloroformate and then 81 g of 1-methyl-2-amino: methylpyrrolidine. After purification of the resulting substance, 96 g of M- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-methylsulfonylbenzamide are obtained. Yield 52%, mp. 151-151 ,. Example 10: N-Oxide N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide. 258.3 g of N- (1-ZTIL-2-PIRROLIDYLmethyl) -2-methoxy-4-amino-5-methylsulfonylbenzamide and 875 ml of absolute ethanol are loaded into a two-liter flask equipped with a stirrer and a thermometer, and then 142 ml are added with stirring (110 vol.) Hydrogen peroxide. The mixture is heated at several hours, then cooled to and added in portions to it with 2 g of manganese dioxide. After adding charcoal and filtering, the solvent is removed in vacuo. The resulting residue is dissolved in 200 ml of Zanol and 150 ml of acetone, then the solution is filtered and poured into 2 L of sulfuric ether. The crystals formed are allowed to drain, and they are then washed with ether and dried. Obtain 140 g of N-oxide M- (1-methyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide, so pl. 190 ° C (with decomp.), Yield 52%. V EXAMPLE 11 N-Oxide M- (1-methyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide. 48.5 g of H- (1-methyl-2-lyrrolidylmethyl) -2-methoxy-4-amino-5-methylsulfonylbenzamide and 875 ml of absolute ethanol are loaded into a two-liter flask equipped with a stirrer and thermometer, then 142 ml of peroxide are added with stirring hydrogen. A mixture. The mixture is heated at 45 ° C for several hours, then cooled to 40 ° C and 2 g of manganese dioxide is added in portions to it. The solution is filtered, after which the solvent is removed in vacuo and the residue is dissolved in 500 ml of acetone. The resulting crystals are allowed to drain, then they are dried and dissolved by heating in 1 liter of ethanol. After adding 20 g of plant carbon, the solution is cooled and poured into 1 liter of sulfuric ether. The resulting crystals are allowed to drain, then they are washed and dried. 190 g of M- (1-methyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide N-oxide, 190 g, m.p. 200-210 ° C, yield 73%. Example 12, M- {1-Ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amine-5-ethylsulfonylbenzamide, Mixed ethylbicarbonate anhydride and 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid. 77.7 g of 2-methoxy-4-amino-5-ethyl sulfonyl benzoic acid and 500 ml of anhydrous dioxane are loaded into a flask equipped with a stirrer, a thermometer, a cooler and a dropping funnel, 30.3 triethylamine is added dropwise. The mixture is cooled before and then 32, ethyl chloroformate is added dropwise, maintaining the temperature at 20 ° C. The mixture is stirred and filtered, the filtrate is evaporated in vacuo. The residue is dissolved in 500 m of carbon tetrachloride and then crystallized. The crystals, after forming a mixture after cooling the mixture, are filtered, washed and dried. Obtain 74 g of anhydride, t, pl. , yield 74.5%. N- (2,5-Dichloropentyl) -2-Methoxy-4-amino-5-ethylsulfonylbenzamide. 4.33 g of hydrochloric 2,5-dichloropentylamine, 65 ml of dimethylformamide and 2.27 g of triethylamine are loaded into a flask equipped with a stirrer, a thermometer and a condenser, then 7.47 g of mixed ethyl bicarbonate anhydride and 2-methoxy-4-amino 5-ethylsulfonylbenzoic acid. The mixture was stirred for 1 hour at room temperature, after which 10 ml of hydrochloric acid and 100 ml of water were added. The resulting suspension is evaporated to dryness in vacuo and then the residue is dissolved in 100 ml of water. The crystals formed are filtered off, washed with water and dried in a cupboard at. 6.5 g of N- (2,5-dichloropentyl) -2-toxico-4 are obtained. -amino-5-ethyl-nylbenec-amide, m.p.,, yield 73 N- (1-Ethyl-2-pyrrolidylmethyl) -2-methbxy-4-amino-5-ethylsulfonylbenzamide, 5.95 g of N- (2.5- Dichloropentyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide and 22 ml of a 56% aqueous solution of ethylamine are loaded into flasks equipped with a stirrer. The mixture is stirred until the solid is completely dissolved, after which the solution is heated in a cabinet at 40-45 ° C until the end of the reaction. The solvent is evaporated and the residue is treated with a solution of 5 m of caustic soda in 100 ml of water. After extraction with methylene chloride twice, the organic phase is dried over magnesium sulphate and filtered, then the solvent is evaporated under reduced pressure. The residue was dissolved in 10 ml of acetone at the boiling point, the crystals formed after cooling, were filtered off and dried in a closet at 50 ° C. 3 g of H- (1-ethyl-2-pyrro-idylmethyl) -2-methoxy-4-amino- 5-ethylsulfonylbenzamide, mp, 125 ° C, yield 54%. Compounds obtained by the proposed method are used in the form of capsules, tablok, pills, in granulated form and in the form of solutions for injections, their preparation is known perse. Substances inert to the substances according to the invention, for example levilite, lauryl, alkali metal sulfates, sucrose and carriers commonly used in medical preparations can be used. Compounds according to the invention can be administered in doses from 50 to 750 mg per day as one or more servings. The preferred dose is from 150 to 200 mg per day. Examples 13-15 show the formulations of pharmaceutical preparations made in the usual way from the compounds according to the invention. Example 13, Tablets, Sotav (per 1 tablet), mg: N- (1-Ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamvd100 Dry starch (sludge) 20 Lactose. 100 Methylcellulose (1500 SP). 1.5 Levilit9,5 Magnesium stearate 4 Example 14, Tablets, Composition (per 1 tablet), mg: N- (1-Methyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-etylsulfonylbenzamide 50 Lactose50 Dried starch10 Methylcellulose (1,500 cP; 3% water) 0.687 Levilite6.803 Magnesium stearate 2.51 Example 15, Solution for injection. Composition, mg: N- (l-Allyl-2-pyropolydyl-methyl) -2-methoxy-4-amino-5-ethyl-sulfonylbenzamide 1 N, hydrochloric acid, acid 0.26 Sodium chloride8 Water for injection preparations up to 2 ml The acute toxicity of the compounds is 0.26%. according to the method according to iobreniya, was investigated in mice. Fixed doses in mice (males) are shown in the table.
    V
    No. 1: N- (1-ethyl-2-pyrrolidylmethyl -2-methoxy-4-amino-5-ethylsulfonylbenzamide;
    Grade 2: N- {1-methyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide;
     3; N- (l-allyl-2-pyprolidylmethyl) -2-methoxy-4-amino-5-ethyl-nylphenylbeneamide;
    No. 4; programing N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide tartrate;
    No. 5: levogyrate N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide tartrate; .
    No. 6: programal N- (1-methyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide;
    No. 7: N- (1-ethyl-2-pyrrolidylmethyl) -2 methoxy-4-amino-5-propylsulfonylbenzamide;
     8: M- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amiIo-5-methylsulfonylbenzamide;
    No. 9: N- (l-methyl-2-pyropolydylmethyl).-2-methoxy-4-amino-5-methylsulfonylbenzamide.
    Cataleptic action was investigated as follows.
    Veneamides were administered subcutaneously to rats1-males. The criterion for cataleptic condition was the immobility of the animal for 30 days with the rear legs arranged on a 4-cm-high wooden cube in such an unusual and uncomfortable position.
    The cataleptic effect was determined at the maximum effect, i.e. 5-7 hours after administration.
    With doses of benzamides No. 1-4 and 6-8,200 mg / kg, administered subcutaneously, absolutely no cataleptic effect was observed and compound No. 5 caused a cataleptic condition in only 30% of animals after 7 hours.
    The compounds obtained in accordance with the invention were subjected to other facial-dynamic tests, in particular, anti-emetic force with respect to apsmorphine was determined. Tests were carried out on dogs according to the method of Chen and Enzor. Compounds
    0 according to the invention was administered subcutaneously 30 minutes before apomorphine, which was administered at a dose of 100 µg / kg. The following results were obtained: the lethality of EDj (j (in µg / kg) for anti-5 apomorphine in dogs with administration of compounds 1–9 subcutaneously is: 0.29 0.8 0.8 0.6; 12; 0, 6) 2 ,, 0
    The results of this test, confirming antagonism of apomorphine, show that the effectiveness of the compounds obtained by the proposed synthesis is 5–20 times greater than the effectiveness of the known compounds of the same series.
    55 Thus, the compounds obtained according to the invention have a stronger effect on the central nervous system. A pharmacodynamic study of such compounds was completed by testing new anti-serotoni60 effects in connection with gastric cancer in rats and bronchospases in guinea pigs.
    Female rats were given subcutaneously 30 mg / kg serotonin in two stages with
    权利要求:
    Claims (2)
    [1]
    65 at intervals of 16 hours. The test compound was administered subcutaneously simultaneously with serotonin. For each dose, a group of 30 animals was changed, a group of 60 animals was a control. The animals were killed 33 h after the first injection of serotonin and their stomachs were examined. The percentage of protection provided by each dose and dose of ED was determined (in 50% of the animals protected, determined graphically due to the incidence of gastric cancer. The following results were obtained: ED, in mg / kg of antiserotonin, in relation to the disease of stomach cancer of rats with the administration of compounds 1; 2; 3) 4; 6} 7; eight; 9 subcutaneously, respectively; 1; 0.4; 0.65; 0.46; 0,34-0,44; 3.2; 3.0; 1.14. The antiserotonin effect on bronchospasm was investigated in guinea pigs. Bronchospasms were recorded by the method of Konzett and Rossler, connecting the guinea pig trachea with an artificial respiration pump, which supplied a constant volume of air, slightly larger, than the respiratory ability of the animal, to the bronchi at physiological rhythms. Excess air, which changed depending on the diameter of the bronchi, entered a special gauge device, which measured the volume of air during each breath. Serotonin was administered intravenously to guinea pigs at a dose of 20 µg / kg. Pigs were pre-anesthetized with ethyl carbamate to cause bronchial spasm. The test product was then administered intravenously, and then serotonin was injected again after 1 min. The percent inhibition of bronchospasm was determined after each dose of the test product, then the ED was calculated relative to the bronchospasm. The results were as follows: I EDGg (in µg / kg) for bronchospasm of guinea pigs with the administration of compounds 1 and 4 is 74 and 106, respectively. These antiserotonin properties distinguish the compounds according to the invention from sulpiride, for which rat gastric cancer is 110 mg / kg Low toxicity of the compounds obtained by the method according to the invention, and the absence of any undesirable side effects, such as catalepsy (which usually accompanies this type of product), made it possible to carry out nic tests. They found the following highly pronounced psychotropic properties of the compounds according to the invention: they eliminate the inhibitory effect, by which they are preferred in the treatment of autism; treat sudden bouts of delirium have an anti-migraine effect. In addition, these. Derivatives can be administered in the form of additives in drugs for weaning off drugs. Because of their psycho-stimulating properties, they reduce the risk of relapse during the period of weakness following the period of weaning. Finally, the sedative effect is zero: these derivatives are not recommended for acute psychoses with convulsions. Clinical studies on several hundred patients who took daily doses of 50 to 750 mg revealed the therapeutic properties of the compounds according to the invention and showed that they are well tolerated. Compound T) was prescribed in an amount of 3 tablets (300 mg), per day to a patient suffering from frequent migraines causing him to interrupt work for three or four days; In the first month, migraines decreased and completely disappeared in the second, with continuous use of only one tablet per day (100 mg). :. Compound D) was administered in the amount of 300 mg per day in three portions to two to take to m-twins, who suffered every month from migraine attacks accompanied by vomiting. In one twin, the migraine disappeared immediately, in the other, from the second month only small bouts of nausea remained. Compound 2 was administered continuously in the amount of two tablets (200 vtrjt per day for a woman suffering a migraine attack for four years. Attacks, were not treated with ergotamine. Caffeine. Attacks became less common (1 to 2 times per month instead of 10-15), intensity they diminished and were regularly treated with two ergotamine and éfein tablets. Compound 2 was administered in the amount of three tablets per day (300 mg of a woman suffering from quasi-permanentitic atrial headache and sometimes l a few weeks later with episodes of play, right-handed oh boyu, photophobia and nausea. tre- C, rd week polnosyu migraine attacks disappeared. Claims 1. A method of producing amino-5-alkylsulfonyl-o-anizamiov general formula l-CHfS CONHBAS
    where R is methyl, ethyl, propyl, allyl;
    R is methyl, ethyl, propyl or is propyl,
    their pharmaceutically acceptable salts, quaternary ammonium salts, oxides of the left- and right-spinning isomers, t and h and h so that, 2g methoxy-4-amino-5-mercaptobenzoHV40 acid is treated with alkyl sulfate, the resulting 2- is oxidized methoxy-4-ami o-5-alkylthiobenzoic acid, then the resulting 2-methoxy-4-amio-5-alkylsulfonylbenzoic acid. of general formula,
    dooH
    odH
    j
    )
    (L)
    NH,
    where R is as defined above, is treated with an amine of the general formula
    H N-OHgAjjJ
    one
    where R is as defined above and the target product is conventional
    methods in the form of corresponding salts of salts, oxides, or left- and right-spinning isomers.
    [2]
    2. The method according to p, 1, from l and h ayu I.I. with the fact that the acid of formula 11 is treated with dihaloskhilaminom general formula,
    Hjw-CHjr
    iial hot
    where Hal is a chlorine or bromine atom, then the resulting compound of the formula
    GSNg- /}
    dowHCH
    But o eint
    is treated with an amine of the formula HgN-Rj, where R is as defined above and the product to be recovered is isolated by conventional means in the form of the corresponding soils, oxides, or left-and right-spinning isomers. .
    Sources of information taken into account in the examination
    1. Patent IT 3700719, cl. C 07 C 103/28, 10.24.72.
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    SU845789A3|1981-07-07|Method of preparing d-7-/alpha-|-alpha-|-acetamido/-3-| thiomethyl-3-cephem-4-carboxylic acid
    SU1635899A3|1991-03-15|Process for preparing 3-[|methyl]-2- oxybenzene methanols
    JPH07267954A|1995-10-17|New 3-phenylsulfonyl-3,7-diazabicyclo|nonane compound,its production, and antiarrhythmic agent
    DD283602A5|1990-10-17|PROCESS FOR PREPARING COMPOUNDS AND THEIR USE
    US4409240A|1983-10-11|Derivatives of dihydroxybenzoic acid and pharmaceutical composition thereof
    US4473583A|1984-09-25|Compositions containing certain derivatives of 4-phenyl-4-oxobuten-2-oic acid and methods of treatment using them
    SU900808A3|1982-01-23|Process for preparing aminopropanol derivatives of 6-hydroxy-2,3,4,5-tetrahydro-1h-1-benzaszepine-2-one or their salts
    US4143143A|1979-03-06|Substituted imidazo[5,1-a]isoquinolines
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    JP3045354B2|2000-05-29|Thioxanthenones and their antitumor agents
    US4353923A|1982-10-12|Pharmaceutical composition containing a benzofurancarboxamide derivative as the active ingredient
    FR2465733A1|1981-03-27|NOVEL IMIDAZOLYLETHOXYMETHYLIC DERIVATIVES OF 1,3-DIOXOLOQUINOLINES USEFUL AS ANTIBACTERIAL AND ANTIFUNGAL DRUGS, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC COMPOSITIONS AND PHARMACEUTICAL FORMS CONTAINING THEM
    FR2498183A1|1982-07-23|NOVEL GUANIDINOCYCLOHEXANECARBOXYLIC ACID DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC USE THEREOF
    EP0430025A2|1991-06-05|Xanthine compound, method for preparing thereof, and a pharmaceutical composition comprising the same
    同族专利:
    公开号 | 公开日
    CA1101430A|1981-05-19|
    AR221354A1|1981-01-30|
    YU42172B|1988-06-30|
    GB2012765B|1982-09-08|
    GB2012765A|1979-08-01|
    DE2901181A1|1979-07-26|
    MX7623E|1990-03-27|
    CS226181B2|1984-03-19|
    FR2415099B1|1981-02-20|
    FI71126B|1986-08-14|
    MX5793E|1984-07-19|
    MC1232A1|1979-10-26|
    YU25483A|1983-10-31|
    JPS6049192B2|1985-10-31|
    GR64431B|1980-03-21|
    YU41278B|1986-12-31|
    SE8603773L|1986-09-09|
    PL212899A1|1980-01-14|
    YU5079A|1983-06-30|
    RO76393A|1981-03-30|
    BG31496A3|1982-01-15|
    AR220574A1|1980-11-14|
    HU179793B|1982-12-28|
    GB2083458B|1983-03-09|
    NZ189378A|1983-03-15|
    DK158346C|1990-10-08|
    CY1201A|1983-12-31|
    ES476755A1|1979-06-01|
    SE448874B|1987-03-23|
    PT69068A|1979-02-01|
    IN150226B|1982-08-21|
    NO790180L|1979-07-23|
    DK158346B|1990-05-07|
    US4401822A|1983-08-30|
    NO151320B|1984-12-10|
    CH637927A5|1983-08-31|
    BG31497A3|1982-01-15|
    NL191707C|1996-04-02|
    NO151320C|1985-04-17|
    DE2901181C2|1984-07-19|
    AT377977B|1985-05-28|
    FI71126C|1986-11-24|
    BE872585A|1979-06-07|
    IT1164655B|1987-04-15|
    JPS54145658A|1979-11-14|
    ES477782A1|1979-09-16|
    IL56411A|1982-09-30|
    SE7900380L|1979-07-21|
    PL116532B1|1981-06-30|
    IT7947706D0|1979-01-18|
    ZA79219B|1980-01-30|
    OA06156A|1981-06-30|
    ZM579A1|1979-12-21|
    IE790092L|1979-07-20|
    US4294828A|1981-10-13|
    AU4337379A|1979-07-26|
    PL118151B1|1981-09-30|
    NL7900457A|1979-07-24|
    NL191707B|1995-12-01|
    IL56411D0|1979-03-12|
    IE47798B1|1984-06-27|
    SE8603773D0|1986-09-09|
    GB2083458A|1982-03-24|
    DD141520A5|1980-05-07|
    SE460968B|1989-12-11|
    PH22287A|1988-07-22|
    LU80786A1|1979-09-07|
    PH15725A|1983-03-18|
    FI790182A|1979-07-21|
    AU528561B2|1983-05-05|
    HK12184A|1984-02-24|
    FR2415099A1|1979-08-17|
    RO80311A|1982-12-06|
    EG14045A|1983-09-30|
    DK20979A|1979-07-21|
    ATA39879A|1983-12-15|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR7801632A|FR2415099B1|1978-01-20|1978-01-20|
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