• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    1. The method of obtaining 3,4-bis-substituted 1,2,2-oxadiazole-2-oxides of the general formula 1 O R N LT 0 where R is NHR, —NHR ORz is NHRSCOR-N-X; where R is.-alkyl, cyclopentyl, cyclohexyl; RZ and R - C-C-alkyl; (CHj), where n is 2.3 or 4; (CH,) ..-, where m - 1,2 or 3; - g - - - -. -R-methoxy, ethoxy, amine, methylamine, ethylamine, dimethylamine, diethylamino; (CH2) p-; - (CH2) 2-0- (CHj) j-; Y "CH3 (CH2) 2-N- (CH,), 4, 5 or 6, p or their pharmacologically acceptable acid-additive mudflows, characterized in that Examoyl chloride of the general formula II K-CO-C-C1 II NOH where R has the indicated values, O), are subjected to cyclodimerization in the medium of a solvent or dispersant in the presence of a base at a temperature from 0 to 50 ° C, followed by allocation of the target product in free form or in the form of a salt. 2. Method POP.1, characterized in that, as the solvent, use dimetfermamidyl dimethyl sulfoxide, N-metnylpyrrolidone, lower aliphatic alcohol, diethyl ether, water, or mixtures thereof. 3. Method POP.1, characterized in that ftheric or tertiaryn amide, hydroxide or carbonate, or bicarbonate, or alkali metal acetate is used as the base.
    公开号:SU1093246A3
    申请号:SU3367545
    申请日:1981-12-16
    公开日:1984-05-15
    发明作者:Жонафингер Карл；Бейерле Руди；Могилев Антон；Бон Гельмут；Юст Мелитта；Марторана Пьеро；Нитц Рольф-Ебергард
    申请人:Касселла Аг (Фирма)；
    IPC主号:
    专利说明:

    f The invention relates to a process for the preparation of 3,4-bis-substituted 1,2,5-oxdiazole-2-oxides of the general formula o -NHR, -NR2 R3, -NHR ORZ, -N-X; C-Cj-alkyl, cyclope-ntil, cyclohexyl, R and R.-C-C4-alkyl; (CH), where p is 2.3 or A; (CH,), where ha - 1, 2 or methoxy, ethoxy, amine, methylamino, ethylamino, dimethy amino, diethylamino, X - - (CH) -, (CH ,,) -0- (CH2) 2- (CHj ) 2-N- (CHj)., P 4, 5 or 6, W1I of their pharmacologically acceptable acid addition salts. The compounds of formula 1 and their pharmacologically acceptable acid addition compounds have pharmacological properties. They have a pronounced effect on the circulatory system, at low dosage, lower blood pressure, reduce peripheral resistance and, reducing the pressure in the pulmonary artery with only a small effect on heart rate, lead to a decrease in heart function. It is known that some aromatic nitrile oxides can be obtained from the corresponding acid halide hydroxamic acids or nitrol acids. In this way, benzonitrile oxide is obtained from benzhydroximic acid chloride under the action of an aqueous solution of sodium carbonate; or upon spontaneous decomposition of phenylnitrol acid, dimerizes benzonitrile at room temperature into diphenylfuroxane Cl}. The purpose of the invention is to obtain new derivatives of 1,2,5-ocadiazol-2-oxides with valuable pharmacological properties. The goal is achieved by the fact that according to the method of producing 6 3,4-bis-substituted 1,2,5-oxadiazole-2-oxides of the general formula 1 oxamoyl chloride of the general formula II K-CO-C-SG where R has the indicated values, is subjected to cyclo-dimerization in the medium of a solvent or dispersant in the presence of a base at O - with the subsequent allocation of the target product in free form or in the form of a salt. Preferably, dimethylformamide or dimathyl sulfoxide, N-methylpyrrolidone, lower aliphatic alcohol, diethyl ether, water or mixtures thereof are used as solvents. Preferably, a secondary or tertiary amine, hydroxide or carbonate, or bicarbonate, or alkali metal acetate is used as the base. After compound II is introduced into the solvent or dispersant, the reaction proceeds. The reaction can be accelerated by adding a base that binds the split hydrogen chloride. For example, secondary or tertiary organic amides (e.g. methylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, pyridine), alkali metal hydroxides (e.g. sodium or potassium), alkali metal carbonates and bicarbonates (e.g. potash, soda and sodium bicarbonate), alkali metal acetates (e.g. sodium acetate). It is preferred to use soda and sodium bicarbonate. The base can also be added in the form of a solution (for example, an aqueous solution, as in the case of lower organic amines) or in the form of a dispersion of a solution or a dispersion of compound II. Because of the reaction, it is advisable to add the base slowly or in portions and stir the reaction mixture. The base is added preferably in a molar amount (2 mol of base per 2 mol of compound II) or, if necessary, with an excess of up to 20%. After completion of the reaction, the obtained compound of formula I is separated and, if desired, converted into an acid addition compound. Compounds of formula I having a backbone chain together with inorganic or organic acids form salts. Such acids are, for example, hydrochloric, hydrobromic, phosphoric, sulfuric, oxalic, lactic, tartaric, acetic, salicylic, benzoic, or. monna, ascorbic, adipic and naphthalindisulfon. Acid addition compounds are prepared in a known manner by combining the components in a suitable solvent or dispersant. The compounds of formula 1 and their pharmacologically acceptable salts are used as a drug in pure form or in mixtures with each other or in the form of pharmaceutical preparations for enteral or parenteral administration. Oral preparations are prepared in the form of pills, tablets, lacquer tablets, dragees, capsules of soft and hard gelatin, solutions, syrups, emulsions, suspensions, or air mixtures of sol; preparations for rectal use are in the form of suppositories, and for parenteral form, for example, in the form of ointments or tinctures. Pharmaceutically inert inorganic or organic bases are used to prepare the preparations. For the manufacture of pills, tablets, dragees and hard gelatin capsules, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc. are used. The bases for soft gelatin capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyhydric alcohols, natural or hardened oils, etc. Water, sucrose, invert sugar, glucose, polyols, etc. can be used as bases for making solutions and syrups. For example, water, alcohols, glycerin, polyols and vegetable oils can be used as bases for making injections. etc. Together with the active ingredients and bases, pharmaceutical preparations may contain additives, for example, fillers, swelling agents, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavoring or flavoring agents, thickeners, thinners, buffers, and in addition, solvents or dissolving agents or substances to achieve a prolonged action, as well as salts for altering the osmotic pressure, coating substances or antioxidants. Venous preparations may contain two or more compounds of the formula 1 or their pharmacologically acceptable acid addition salts, as well as therapeutically effective substances, for example: substances that block the beta-receptor blockade (propranolol, pindolol, metoprolol); vazodil tori (carbochromen); sedatives (barbituric acid derivatives, 1,4-benzodiazepines and meprobramat); diuretics (chlorothiazide); heart tonic substances (drugs based on thimble); substances; lowering blood pressure (hydralazine, dihydralazine, prazosin, clodinin, rauwolfia alkaloids); substances that reduce the level of fat in the blood (bezafibrat, fenofibrate); means for preventing thrombosis (fenprocoumon). The compounds of formula 1, their pharmacologically acceptable acid addition salts and pharmaceutical preparations containing compounds of formula 1 or their pharmacologically acceptable acid additive salts can be used to prevent diseases of the cardiovascular system of the i-t control, for example, as antihypertensive agents for various types of povatonnyh blood pressure, for the prevention or control of angina pectoris, etc. The dosage can vary widely and in a case should be individualized. For oral administration, the daily dose is about 0.2-150 mg, preferably 1-30 mg. In other ways of administration, the daily dose due to the good absorbability of the active ingredients is co.pbells within similar quantitative limits, i.e. It is about 0.2-150 mg. The daily dose is usually divided into several, for example two or three partial doses. Pharmaceutical preparations usually contain 0.1-50 mg, preferably 0.5-10 mg / dose, of active ingredients (compounds of formula 1 and their pharmacologically acceptable acid addition salts). The anti-anginal or protizo-hypertensive effects of the compounds of Fs-p- -guly 1 are established as follows. Tests are conducted on crossbred dogs of both sexes that are under pentobarbital anesthesia (3040 mg / kg intravenously) or under Urethane-chloro-anesthesia (3 mg / kg urethane-chloral mixture of intravenous 20 mg / to chloralose and 250 mg / kg urethane) . Animal respiration is performed in a BirdMark-7-Respirator breathing apparatus. The carbon dioxide content of the maximum output (measured by an infrared absorption instrument, Uras) is 4.5–5 vol.%. During the test, animals with pentobarbital anesthesia receive a continuous infusion of pentobarbital intravenously (4 mg / kg 6 ml / h) to maintain a constant depth of anesthesia; animals with urethanhloralose anesthesia do not receive a long infusion. Infusion is infused into the head vein. After preparing the test animals, approximately one hour is given to establish all the hemodynamic parameters (steady state), after which the tests begin. Systolic and diastolic blood pressure is measured peripherally in the femoral artery by means of a Statham Pressure Gauge. The MillerTip-Kytheter catheter inserted through the carotid artery into the left ventricle of the heart shows presystolic pressure in the left ventricle and heart rate. Another catheter inserted into the strap vein measures the average blood pressure in the pulmonary artery. The results are presented in table. 1. Table 1
    -2
    0.05.
    —NHCHj SNCHN CH,
    -NH-Cyclohexyl 0.05 -3.5 - ShSNSNz0.05-2
    C, Nz-NH-C-CH, 0.05-2
    CH,
    15 -NHCHj COj CH3
    -SHS SNZ
    Piperidino
    -NHC4H9 (,
    -N
    60
    -70
    -3
    45 75
    -65
    -five
    -10 -75
    60
    -60
    +5
    „2
    45
    + 10
    -65
    -3
    60 -85
    -five
    -3
    120 -20 -25
    -1 -10 -70
    ,five
    thirty
    -25
    -five
    35
    -1 9 -NHCHj CHj OCHs 8 -NH-CH-CH0, 05 -2.3 CHj 0.05 -7 I -NHCH, 0.05 -2.1 -0.7 ISDN-isosorbide dinitrate (comparator)
    Example. Methylamide 1,2,5-hydroxy-. diazol-2-oxide-3, 4-bis-carboxylic acid.
    12.5 g of methylamine are dissolved in 400 mg of water. At room temperature-30 Pe (20c), 34 g of diketene is slowly added dropwise with the establishment of a stable pH value (7). 28 g of sodium nitrite are dissolved in the resulting solution. Then 35 ml of concentrated hydrochloric acid (40 g) are added dropwise so that the pH of the solution does not drop below 4. Then the mixture is stirred for 30 minutes and -4-1.5, -1.5
    at 20-40 ° C, 30 g of chlorine is added. After the solution is cooled, the solid is cooled to, sucked off and stirred in 100 ml of water, at 20 ° C in portions, gently mixed with 34 g of sodium bicarbonate, pH 7.5-8-8. The solution is then cooled until the precipitated solid is precipitated and colorless crystals are recrystallized from isopropanol. 164-165 0.
    Similarly, the compounds listed in Table 1 can be prepared. 2
    Table 2 -65 -45 -55 -19 22 Bis- (2-methoxycar6onyl-ethyl) amide 80-82 23Bis- (2-methoxycarbonylpropyl) amide Oil .20 24Bis- (dimethylaminocarbonylmethyl) amide Oil 25bis (aminocarbonylmethyl) 141-142 20 26Bis- (di-butyl) amide Oil 30 27 Bis- (ethylaminocarbonyl) Dimethylformamide M-methyl 1 Shrrolidone
    .ura synthesized compounds can be proven elementary
    analysis and IR and NMR spectra, the data are presented in table. 3. СНз ОНNaHCOj СНз ОНKj СОЗ СзН ОНKjC03 CHj ОНaHCO CjHsOCjH NaNSO3
    权利要求:
    Claims (3)
    [1]
    1. The method of obtaining 3,4-bis-substituted 1,2,5-oxadiazole-2-oxides of the General formula 1 where where
    R 2
    N ^ LH 0
    R - NHR ', -NR 2 R 3 , -NHR 4 0R 2
    - NHR 5 C0R b -N · x;
    R 1 is C ^ -C 4 ~ alkyl, cyclopentyl, cyclohexyl;
    and R 3 is C 3 -C + alkyl;
    R 4 - (CH_) „. where η is 2.3 or 4:
    R 5 - (CH 2 ) M , where t is 1.2 or 3;
    R e is methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, diethylamino;
    X- (CH 2 ) p -; - (CH 2 ) 2 -0- (CH 2 ) 2 -;
    CH 3 (ch 2 ) 2 -n- (ch 2 ) 2 p - 4, 5 or 6, or their pharmacologically acceptable acid addition salts, characterized in that oxamoyl chloride of the general formula II
    R-C0-C-C1
    II Ν0Η where R has the indicated meanings, is subjected to cyclodimerization in a solvent or dispersant medium in the presence of a base at a temperature from 0 to 50 ° C, followed by isolation of the target product in free form or in the form of a salt.
    [2]
    2. The method of pop. 1, characterized in that the solvent used is dimethylformamide or dimethyl sulfoxide, N-methylpyrrolidone, lower aliphatic alcohol, diethyl ether, water or mixtures thereof. °
    [3]
    3. The method of pop. 1, characterized in that the base used is a fluoric or tertiary amine, hydroxide or carbonate, or bicarbonate, or alkali metal acetate.
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