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    • 专利摘要:
    A process for the preparation of substituted 3-amino-amino-compounds of the general formula - R2 wherein R Ra — O — C — N or o R2 is hydrogen or -C R, is methyl or ethyl; H is phenyl, unsubstituted or substituted by lower alkyl, lower alkoxy, halogen, or nitro alkyl, is alkoxy, ethoxycarbonyl, cyclohexyl, adamantyl, pinanyl, methoxymethyl, or their pharmacologically acceptable acid-addition salts, of olymphores. where B has the indicated values, is cyclized in a solvent medium at O - in the presence of an acid, followed by isolation of the desired product of the general formula: kN in free form or as a salt or by reacting this compound or its salts with an acylating agent of the general formula CO vj C1-C-Cc; o or the general formula R -CO-0-CO-R, in which H has the indicated meanings; with the subsequent selection of the target product in free form or in the form of a salt.
    公开号:SU1097197A3
    申请号:SU823398796
    申请日:1982-03-01
    公开日:1984-06-07
    发明作者:Шенафингер Карл；Бейерле Руди；Бон Хельмут；Юст Мелитта；А.Марторана Пьеро；Нитц Рольф-Эберхард
    申请人:Касселла Аг (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for the preparation of pharmacologically active substituted 3-amino-like monoxides of the general formula U, n and their pharmacologically acceptable kinetically additive salts, where R O / -y R-o4-N (Vi-TT hydrogen or - c - X4 RJ - methyl, or ethyl; R is phenyl, unsubstantiated or substituted by lower alkyl, lower alkoxy, halogen or nitro) C — C alkyl, C — C alkoxy, STO sicarbonyl, cyclohexyl, adamantyl, penancl of simethyl. It is known that by acting on ot-lN -methyl-M-nitrosoamino / nitriles of nitric acid or hydrogen chloride in the ether, the salts of Sidnonimine Cl are obtained. The aim of the invention is to obtain new derivatives of sydnonimine with valuable pharmacological properties. This goal is achieved by the fact that according to the method of obtaining substituted 3-part 1-sydnonimines of the general formula 11). or their Pharmacologically acceptable acid addition salts a compound of the general formula (JN 0 where R has the indicated meanings, is cyclized in a solvent medium at O - 40 ° C in the presence of acid, followed by isolation of the desired product of general formula R.-H --- 1 j © (1 "In free form or as a salt, or by reacting a compound of formula (1") or its salt with an acylating agent with a general formula of an OR of the general formula R -CO-0-CO-R in which R has the | nor, with the subsequent isolation of the target product in free form or in the form of a salt. Compounds of formula (II) in the compound of formula tla are carried out in a suitable organic or inorganic solvent, for example, water, alkanol with 1-4 carbon atoms, in an alkyl carboxylic ester, for example ethyl acetate or in a mixture of solvents such as , water is methanol or preferably methanol ethyl acetate with addition of cyclizing agent, usually at O - 40 ° C, preferably at 0-20 ° C. Suitable cyclizing agents are those which bring the pH below 3 in an aqueous solvent, for example mineral acids such as sulfuric, nitric or phosphoric acid, preferably hydrogen chloride, however, strong organic acids. For example, trifluoroacetic acid. During cyclization, the corresponding acid addition salt of the compound of the formula (1a |) is obtained. The compounds of the formula (1a) are represented according to the invention if R2 is hydrogen. Acylation of the compounds of the formula (la) to introduce the Rj COft residue can be carried out in a known manner suitable by acylating agents of the formula (111 "IX-C-B4 where X is, for example, halogen, in particular O, -0-C-B4. / i is chlorine, -0-C-B4 Eryloxy, in particular tolyloxy, dinitrophenyloxy or nitrophenyloxy. Acylation wire t in a suitable solvent, for example water, and whether a polar organic solvent, such as dimethylformamide, dimethyl sulfoxide, pyridine, mixtures of solvents, such as water and methylene chloride, or in excess of the acylating agent, is advisable when stirring at temperatures from to the boiling point of the solvent or acylating agent, preferably at. the presence of an acid binding agent, such as pyridine, sodium hydrogencarbonate or sodium acetate. Substituted 3-amino-ednonimines of the general formula (1) form acid addition salts with inorganic or organic acids. Inorganic and organic acids are suitable for the formation of such acid addition salts. Suitable acids are, for example, hydrogen chloride, hydrogen bromide, naftalip disulfonic acids, in particular naphthalenedisulphonic acid (1,5), phosphoric, nitric, sulfuric, schav-lava, lactic, Villeneuve, acetic, salicylic, benzoic, formic, 1propionova, Pivalinova, diethyluxus, Malonov, Ntarna, Pymelinova, Fumarova, Maleinova, Blochna, Sulfaminova, Phenylpropionova gluconova, Ascorbic, Isonicotinic, methanesulfonic, p-toluenesulfonic, citric or adipic acid. Pharmacologically acceptable acid addition salts are preferred, which can be prepared in the usual way by combining the components expediently in a suitable solvent or diluent. Acid addition salts are obtained in the synthesis of compounds of formula (la). From the acid additive salts, free compounds of the general formula (1) or 11 a) can be obtained, preferably in a known manner, i.e. by dissolving or suspending in water and behavior to an alkaline state, for example, sodium hydroxide solution, followed by isolation. The required starting compounds of general formula (11) can be obtained in a known manner according to Strecker's synthesis of aminonitriles from a compound of general formula R, -NHj by reacting with formaldehyde and hydrocyanic acid or sodium cyanide in a suitable solvent, for example water, and the compound is prepared first Formula R -NH-CHj-CN, (V) which is translated by nitrosation in the compound of formula (11). The nitrosation is carried out in a known manner in a suitable solvent, preferably in water, at O-1. The acid is usually obtained from alkali metal nitrite and hydrochloric acid. It is advisable to bring the aqueous solution of the compound of the formula (Y by hydrochloric acid to a pH of 1-3 and add dropwise the alkali metal nitrite as an aqueous solution to the stirred and cooled solution of the compound. The solution of the obtained compound of the formula (11 can be directly subjected to cyclization reaction. However Typically, the nitroso compound of formula (11) is first dissolved in a suitable organic solvent and, if appropriate, carried out in this case, by adding an additional solvent, cyclization into compounds f Formulas (1I. Compounds of formula (IV) are partly known or they can be obtained according to the following reaction reactions fJ -CO-NHj R CO-NMj t Maoce (XlM (vm)). In this case, compounds of formula Y are first subjected to reaction of known with potassium cyanate (VI) into compounds of formula (UE), which are also converted in a known manner by oxidation with sodium hypochlorite by the Hoffmann reaction into compounds of formula (IV) At the indicated value of P, compounds of formula (Y) should be denoted as amines, formulas- (UP; as ureas; and compounds of formula (IV) as hydrazines. The compounds of general formula (1) and their pharmacologically acceptable acid addition salts have valuable pharmacological properties. They have a pronounced effect on the circulatory system and the heart. Compared to similar compounds in the trade in structure, they act in a low dosage for a long time. They reduce, for example, blood pressure and pressure in the pulmonary artery and presystolic pressure in the left stomach and thus facilitate the work of the heart in terms of the anti-anginal effect without causing reflex tachycardia. The compounds of formula (1) and their pharmacologically acceptable acid addition salts can be used in humans as a drug in pure form or in mixtures with each other or in the form of pharmaceutical preparations that allow intestinal or parenteral use and which, together with conventional pharmaceutically acceptable carriers and additives as an active principle contain an effective dose of at least one compound of formula (1) or its acid-additive salt. Drugs can be given orally to a person, for example, in the form of pills, tablets, varnish tablets, dragees, capes. Sul from soft and hard gelatin, solutions, syrups, emulsions, suspensions or aerosol mixtures. The drugs can be given to a person and rectally, for example, in the form of suppositories, or parenterally, for example, in the form of ointments or tinctures. A pharmaceutically inert, inorganic or organic base is used to prepare preparations. For the manufacture of pills, tablets, dragees, and hard gelatin capsules, for example, lactose, corn starch or their derivatives talc, stearic acid or its salts, etc. are used. Basically for soft. gelatin capsules and suppositories are, for example, fats, waxes, lactic and liquid multi-alcohols, natural or hardened oils, etc. Water, sucrose, | inert sugar, glucose can be used as bases for making solutions and syrups myoic alcohols, etc. As bases for the manufacture of injections, for example, water, alcohols, glycerin, polyols and vegetable oils, etc. can be used. Together with the active substances and the bases, the pharmaceutical preparations may contain additives, such as, for example, fillers, agents for & uhan, binding, lubricating, wetting agents, stabilizers emulsifier:. Preservatives, sweeteners, colorants, flavoring or flavoring agents, thickeners, diluents, buffers and, in addition, solvents or dissolving agents or substances to achieve prolonged action, as well as salts for altering the osmotic pressure, coating agents or antioxidants. They may contain two or more compounds of the formula (l 1 or their pharmacologically with acceptable acid-protecting salts and also other therapeutically effective substances. Such other therapeutically effective substances are, for example, substances that cause beta-receptor blockade, such as propiolol, pindolol, metopropol, vazodil ForYg such as, for example, carbocromene, sedatives, such as, for example, derivatives of carbituric acid, 1,4-benzodiazepines and meprobromate, diuretics, such as chlortiazide, heart tonic substances such as, for example, drugs based on a thimble, substances that lower blood pressure, such as hydralazine, dihydrolazine, prazosin, clodinine, rauwolFal alkaloids, substances that lower the level of fats in the blood, such as Bezafibrate, fenofibrate, means for preventing thrombosis, such as fenprocomon. Compounds of formula (1), their pharmacologically acceptable acid addition salts, and pharmaceutical npe paratha, which contain as active factors compounds of formula (1I or their pharmaceutical Acologically acceptable acid addition salts can be used in humans for the prevention of cardiovascular diseases or their control, for example, as anti-hypertensive drugs for various types of high blood pressure, for the prevention or control of angina pectoris, etc. The dosage can vary widely and in each case must be adapted to the patient's conditions. Typically, if given orally, the daily dosage of about 0.5-100 mg, preferably 1-L 20 mg, is suitable for each person. And for other uses, the daily dose due to the good absorbability of the active substances varies in similar quantitative limits, i.e. it is usually about 0.5-100 mg per person. The daily dose is usually divided into several, for example 2 or A partial doses. For evidence of the anti-anginal effect of the proposed compound, human dogs of both sexes are tested under pentobarbital anesthesia (30-50 mg / kg intravenously) or under urethanchloralose anesthesia (3 mg / kg urethanchlolose mixture intravenously 20 mg / kg chlorallose and 250 mg / kg of urethane). Artificial respiration of animals is carried out in water; Bird-Mark-7Respirator. The carbon dioxide content of the maximum output (measured by the instrument used for recording the absorption of infrared rays) was 4.5–5 vol.%. During the whole trial, animals with pentabarbital anesthesia receive a continuous infusion of pentobarbital intravenously (4 mg / kg, 6 ml / h) in order to achieve a constant depth of anesthesia, animals with urethanchloralose anesthesia do not receive a prolonged infusion. Infusion is infused into the head vein. After the test animals are cooked, wait approximately one more hour for all hemodynamic parameters to be established (steady state). The tests are then started. To determine the average peripheral blood pressure (BD), the peripheral systolic and diastolic blood pressure in the femoral artery is measured using a Statham pressure measurement device. A Miller-Tip-Katheter catheter inserted through the carotid artery into the left ventricle shows the presystolic pressure in the left ventricle (LVEDP) and heart rate (HF). Another catheter inserted into the strap vein measures
    mean blood pressure (PAP) in the pulmonary artery.
    The results are shown in the table.
    Note, cc. - intravenously; A - 3-N-methyl-N- (tetrahydro-3-thienyl-5, S-dioxide) -amio -sidonimine hydrochloride; B - 3- (4-ethoxycarbonylpiperazii 1-yl) -sidnoimin-hydrochloride C-3- -methyl- - (tetrahydro-3-thienyl-dioxide) -amino- (4-nitrobenzene) -sidnoimin; D - 3 - (N-methyl-V- (tetrahydro-3-thienyl-5,5-dioxid) -gNo-M-cyclohexylcarbonyl sulfoimine hydrochloride E - 3- (4-ethoxycarboyl-piperazin-1-yl) -M-cyclohexylcarbonyl sidimimimii; F (4-ethoxycarboyl) piperazin1-yl) -N-acetylsidnomin; G - 3 -, {4-ethoxycarbonylpiperazi1-yl) (ethoxycarbonylcarbonyl) - -. sidnoimii; H - 3 - N-methyl- (| &-( tetrahydro-3thienyl-S, S-dioxide) -amino - M-marks of siacetyl sidnoimine; MOL - molsidomin (standard substance); ISDN - isosorbiddinitrate (standard substance); LVEDP - presystolic pressure in the left ventricle of the heart; PAP - the average pressure in the pulmonary artery; BD - the average peripheral blood pressure; HF - the heart rate (heart rate per minute); - the lethal dose administered intravenously to mice, mg / kg. M-Methyl-H- (tetrahydro-3-thienyl-5, 3-dioxid) -e1-mino-sidnonimigidrokhlorid. 20.5 g of 1-methyl-1 (tetrahydro-3-yenyl-5.5-diox id) -hydroazine hydrochloride is dissolved in 120 ml of water. A solution of 4.9 g of sodium cyanide in 10 ml of water and then also 8.3 ml of a 40% formalin solution is added dropwise to this solution. The reaction mixture is then heated to room temperature and further stirred for 15 hours, then cooled to 0-5 ° C and adjusted to pH 1-2 with about 8 ml of concentrated hydrochloric acid, 6.9 g of sodium nitrite is dissolved in 15 ml of water and added at with oil being released. This oil is shaken with 100 ml of ethyl acetate and the organic phase is dried with sodium sulfate. After the addition of 100 ml of methanol, about 70-80 g of hydrogen chloride are introduced at about 2-3 hours, cooled to 0 ° C and stirred for an additional 2 hours, sucked off and recrystallized from an isopropanol-water mixture. M.p. 117-179 ° C, yield 8.3 g (35% of theor). Cyclization is similarly carried out if sulfuric, azoic, phosphoric or trifluoroacetic acid is used instead of hydrogen chloride and / or cyclization is carried out at about 40 ° C and / or methanol is replaced with an appropriate amount of ethyl acetate, ethanol, i-propanol, n -pro panol, i-butanol or n-butanol PRI mme 2. 2- (4-ethoxycarbonylpiperazin-1-yl) -sulfonimine hydrochloride. 21 g of 1-ethoxycarbonyl-4-amino piperazine hydrochloride are dissolved in 120 ml of water. Then, a solution of 4.9 g of sodium cyanide in 10 ml of water and then also at 8.3 ml of a 40% formalin solution is added in Kal at 0-5C. The mixture is then heated to room temperature and stirred for an additional 15 hours, cooled to 6-5, and the pH is adjusted to 1-2 with approximately 8 ml of concentrated hydrochloric acid. 6.9 g of sodium nitrite are dissolved in 15 ml of water and added are dripped at 0-5 ° C, and an oil is released. This oil is shaken with 100 ml of ethyl acetate, the organic phase is dried with sodium sulfate. After the addition of 100 ml of methanol, a total of 70-80 ° g of hydrogen chloride is removed at 2-3 hours. The mixture is cooled to 0 ° C and further stirred for 2 h, sucked off and recrystallized from isopropanol, m.p. 170 171 ° C; yield 12.6 g (45% of Theor.). Cyclization proceeds similarly / if instead of hydrogen chloride sulfuric, nitric, phosphoric and trifluoroacetic acids are used and / or if cyclization is carried out at 0 and 40 ° C and / or methanol is replaced with the corresponding the amount of ethyl acetate, ethanol, i-propanol, n-propanol, and-butanol or n-butanol. Froze 3-N-methyl-N (tetrahydro-3-thienyl-5,5-dioxide) amino 3-M-ethoxycarbonyl sidnonimine. 5.4 g of 3-N-methyl-N- (tetrahydro-3-thienyl-5,5-dioxide) -aminoJ-visible-imine hydrochloride and 4.2 g of sodium hydrogencarbonate are dissolved in 50 ml of water and combined with a solution of 3.25 g of ethyl chloroformic acid ester in 50 ml of methylene chloride. After stirring for 24 hours at g of room temperature, it is sucked off, the methylene chloride phase is combined, the residue is combined with sucked solid and recrystallized from 30 ml of methanol. M.p. 139142 ° C, yield 2.3 g (38% of Theor.) .. Similarly to this example, the following compounds can be synthesized, and after the melting point it is indicated in which solvent and at what reaction temperature the acylation is carried out: 3-fN-methyl-N - (tetrahydro-3-thienyl 5, 5-dioxide) -aminoZ-N-benzoyl sidnonimine, m.p. 152-153s, in water or methylene chloride at 10 ° С, yield 3.7g (54% of theor.); 3 -IN-methyl-N - (tetrahydro-3-thionyl-5,5-dioxide) -amino - (4-nitrobenzoyl) -sidnonimine, m.p. 211-223 ° C (decomp.), In water or methylene chloride at, yield 3.5 g (46% of theory.); -methyl-N- (tetrahydro-3-thienyl, 5, Gdioksid) -amino-N-cyclohexylcarbonylsulfonimine hydrochloride, so pl. 150C (decomp.), In water at, yield 4.3 g (63% of theory); H-CN-methyl-M- (tetrahydro-3-thienyl 5, 3-dioxide) -amino-N - (4-methylbenzoyl) -sidnonimine, m.p. 146-149 ° C, in water or methylene chloride at, yield 3.5 g (50% of theory) 3- (4-ethoxycarbonylpiperazin-1; yl) -N-ethoxycarbonyl sidnonimine. M.p. 170-172С, in water at 20 ° С, yield 3.6 g (58% 01 theor); 3- (4-eth6-xycarbonylpiperazin-1yl) -N -cyclohexylcarbonyl-sidnonimine, m.p. 136-137С, in water at 0 ° С, yield 4.3 g (61% of theor); 3- (4-ethoxycarbonylpiperazin-1yl) - -benzoyl sidnonimine, mp. 159 GBO with, in water or methylene chloride at 25 ° C, yield 4.5 g (66% of theor); 3- (4-ethoxycarbonylpiperazin-1yl) (ethoxycarbonylcarbonyl) sidnonimine, m.p. 123-124 ° C, in water or methylene chloride at 0 ° C, yield 2.0 g (30% of theor); 3- (4-ethoxycarbonylpiperazin-1yl) (4-chlorobenzoyl sidnonimine, Tpl. 203-207 ° C (with decomp.), In water or methylene chloride at 20 ° C, yield 4.8 g (63% of theory. ); 3- (4-ethoxycarbonylpiperazin-1il) -N-pivaliolsidnonimine, mp 151152 C, in water at 10c, yield 3.4 g (53% of the theory); 3- (4-ethoxycarbonyl piperazin-1il) -tH ° - (1-adamantylcarbonyl) -sidnonimine, mp 21-216 ° C, in water or methylene chloride at 20 ° C, yield 3.8g (47% of theor); 3- (4-ethoxycarbonylpiperazin-1yl ) (3-G-3-pinanylcarbonyl) -sidnonimine, m.p.145-146 ° C, in water or methylene chloride at, yield 3.7 g (47% of theor); -methyl-N- (tetrahydro 3 tieni -5, 5-dioxide) -aminoZ-M - (4-methoxybenzoyl) -sidnonimin, m.p. 140143 ° C, in dimethylformamide at, yield 4.7 (64% of theory);
     -ethyl-N- (tetrahydro-3-thienyl, 5-dioxide) -amino-N-methoxycarbonyl sidnonimine, m.p. 140-153 °, in water at, yield 2.5 g (40% of e Theor.
     -methyl-N- (tetrahydro-3-thienyl, 5-dioxide) -amino - (4-chloro-benzoid synonimine, mp. 141-143 ° C, in water or methylene chloride at 20 s, yield 4.4 g (61 % of theory);
     -methyl-N -, (tetrahydro-3-thienyl-5, 5-dioxide) -aminoZ-M -pivaloylsidione, so pl. 160-162 s, c. water at, the output of 3.7 g (58% of theory.)
    3 M-methylM- (tetrahydro-3-thieiyl5, 5-dioxide) -amino - M-ethoxycarbo-, | Nilcarbonylsidnoiimin, m.p. 147150s, in water or methylene chloride at, yield 2.6 g (37% of theory.);
    3- (4-Ethoxycarbonylpiperizin-lyl) -N-methoxycarbonylsulfonimine, m.p. 181-183 C, in water at, yield 2.6 g (44% of theor.);
    3- (4-ethoxycarboyl) piperaein-1yl) -N - (4-methylbeisoyl) -sidnoimine, m.p. 165-166 C, in water or methylene chloride at 20 ° C, yield 5.0 g (70% of theory);
    3- (4-ethoxycarbonylpipazin-yl) (4-nitrobeneo-sydnonimine, mp 210-212 0, in water or methylene chloride at, yield 4.3 g (55% of theor.));
    I PRI mme R 4. 3- (4-ethoxycarbonylpiperazin-1-yl) -K-acetyl sidnonimine.
    5.6 g of 3- (4-ethoxycarboiylpiper-. ZIN-1-IL) -sidonimine hydrochloride are stirred in a mixture of 20 ml of acetic anhydride and 20 ml of absolunt pyridine for 14 hours at room temperature. The precipitate is sucked off and further washed with methylene chloride, so pl. 164-165 C, yield 3.5 g (62% of theory.
    Similarly, the following compounds can be synthesized in this example, and after the melting point it is indicated which of the acylating agent and at what temperature of the reaction the acylation is carried out:
    3- -methyl-N- (tetrahydro-3-thienyl-5,5-dioxide) -eu HHo3-N -MeTOKCH acetyl sidnonimine, m.p. 151-153С, in methoxyacetic anhydride) pyridine at 20 ° С, yield 3.6 g (60% of theor.)
    3-N-ethyl-M- (tetrahydro-3-thienyl 5, 5-dioxide) -amine-N-acetylsidione, so pl. 162-G64 ° C, in acetanhydride at 5 ° C, yield 2.8 (49% of theor);
    3- (4-methoxycarbonylpiperazin-1yl) -N-acetylsidnonimine, m.p. 188191 ° С, in acetic anhydride at, yield 3.8 g (63% of theory);
    3- (4-methoxycarbonylpiperazii-1il) -M-methoxy-acetylsidnonimine,
    one
    l 148-151 ° C, in methoxyacetanide) pyridine at 40 ° C, yield 9 g (48% of theor.);
    Complete analysis of compounds; In example 1
    Calculated,%: C 31.4; H 4.8; 20.9; O 17.9; C1 13.2; (rf 11.9.
    Found,%: S 3; H 4.6; | H 20.5; 17.3; C1 13.5; S 12.2.
    In example 2
    Calculated,%: C 38.9; H 5.8; 25.2; About 17.3; C1 12.8.
    Found,%: C 38.7; And 5.9; N 24.9; 17.3; C1 13.3.
    By example
    calculated%; C 39.5; H 5.2; 18.4; O 26.3; 9 10.5.
    Found,%: C 39.3; H 5.3; H 18.2; 26.5; 5 10.4.
    In example 4
    Calculated,%; C, 46.6; H 6.0; 24.7; About 22.6.
    Found,%: C 46.8; H 6.3; N 24.4; 22.1.
    Connect With
    VEPisleio,%: C 44.1; H 3.9; 18.4; O 25.2; S 8.4.
    Found,%: C 44.3; H 3.8; N 18.2; 25.3; 5 8.5.
    Compound D
    Calculated,%: PS 44.4; H 6.1; 14.8; About 16.9; 3 8.8; C1 9.4.
    Found,%; C, 44.3; H 6.0; N14.6; 17.1; 3 8.5; C1 9.6.
    Compound B
    Calculated,%: C 54.6; H 7.1; N, 0; About 18.3.
    Found /%; C, 54.8; H 7.0; N 19.8 18.2.
    Compound G
    Calculated,%: With 45.7; H 5.6; N, 5; About 28.4.
    Found,%; 45.7; H 5.7; N 20.3; 28.5.
    S about e-d and N e and and N
    Calculated,%; C, 38.5; H 5.1; N, 5; O 25.6; S 10.3.
    Found,%; C 38.4; H 4.9; N 20.5; 25.8; 5 10.2.
    PRI me R 5. Gelatin capsules containing 5 mg of active ingredient per capsule. 3-n-Methyl-N- (tetrahydro-3-thienyl-5s dioxide) -yoyl sidnonimine, mg5
    Triglyceride mixture fractionated from coconut oil, mg 150
    Capsule content, mg155
    Example 6. Solution for injection containing 1 mg of active nachit ml. Z-CN-methyl-GM- (tetra-hydro-3-trienyl- $ 5 dioxide) -amino -si-nimine hydrochloride, mg1.0 Polyethylene glycol 400 / mg0.3 Sodium chloride, mg 2.7 Water for injection, mlDo 1 N p and measure 7. Emulsion containing 3 mg of active principle per 5 ml (per 100 ml of emulsion) 3- (W-Ethoxycarvonyl piperaein-1-yl) -sid0, 06 nonimine hydrochloride, g Neutral Neutral my oil to carboxymethylcellulose sodium, g Polyoxymethyne Neobh my stearate for qualities 0.2 Pure glycerin, g Needing Taste my substance for water Water (desalted and distilled), ml Up to 10 Example 8. Suppository, coagulating the beginning of the superstructure. 3- (4-Ethoxycarbonylpiperazin-1-yl) -synonymous, mg. 4 Mass for the preparation of suppositories, g Up to 2 Example 9 tablets, containing 2 mg of active ingredient on the tab, 3-M-methyl-M- (tetrahydro-3-thienyl-53 dioxide) -iino-zoyl sibnonimine lactate (finely ground) , mg2 Corn starch (white), mg150 Milk sugar, mg 60 Microcrystalline cellulose, mg Polyvinylpyrrolides, mg Magnesium stearate, mg Sodium carboxymethylcrachal, mg. "" CC 309 mg
    权利要求:
    Claims (2)
    [1]
    METHOD FOR PRODUCING SUBSTITUTED
    [2]
    3-AMINOSIDNONIMINES OR THEIR PHARMACOLOGICALLY ACCEPTABLE ACID-ADDITIVE SALTS.
    (57) A method for producing substituted 3-amino-aminosidononyms of the general formula; where R ^ or in
    -N N _ /,
    XR - hydrogen or -C:
    X
    Rj is methyl or ethyl;
    R 4 is phenyl unsubstituted or substituted with lower alkyl, lower alkoxy, halogen or nitro. J Cf-C * is alkyl, C 1 -C 6 is alkoxy, ethoxycarbonyl, cyclohexyl, adamantyl, pinanyl, methoxymethyl, or their pharmacologically acceptable acid additive Salt, characterized in that the compound of the general formula
    Bj-H-CHa-CN N = 0 where R 1 has the indicated meanings, is subjected to cyclization in a solvent medium at 0 - 40 ° C in the presence of g acid, followed by isolation of the target product of the general formula, SU ..1097197 in free as or as a salt, or by reacting the compound or its salt with an acylating agent of the general formula (or general formula
    R 4 -CO-o-co-r 4 , in which R 4 has the indicated meanings, followed by isolation of the target product in free form or in the form of a salt.
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    DE3921460A1|1991-01-03|SUBSTITUTED 3-AMINO-DYNONOMINES, PROCESS FOR THEIR PREPARATION AND THEIR USE
    US3974164A|1976-08-10|Reserpic acid derivatives
    EP0877026B1|2001-10-31|Substituted 6-r-1,3,4-thiadiazine-2-amines, the use thereof as anaesthetising, cardiovascular and hypometabolic agents, and a pharmaceutical composition containing them
    DE4031373A1|1992-04-09|3-PIPERAZINO-SYDNONIMINE, METHOD FOR THE PRODUCTION AND THEIR USE
    CA1274830A|1990-10-02|Intermediates useful for preparing substituted 3-|alkylquinazolin-2,4-|diones
    CZ317790A3|1994-05-18|Substituted 3-aminosydnonimines, process of their preparation and a pharmaceutical preparation containing thereof
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    同族专利:
    公开号 | 公开日
    CS224645B2|1984-01-16|
    RO84816B|1984-09-30|
    HU190683B|1986-10-28|
    AU545292B2|1985-07-11|
    PL235274A1|1982-10-25|
    DK149852C|1987-06-01|
    US4436743A|1984-03-13|
    DD208617A5|1984-04-04|
    KR830009062A|1983-12-17|
    PT74507A|1982-04-01|
    KR880001428B1|1988-08-08|
    PH18696A|1985-09-05|
    IL65141D0|1982-05-31|
    RO84816A|1984-08-17|
    EP0059356A1|1982-09-08|
    NO820476L|1982-09-03|
    NZ199862A|1985-04-30|
    US4551454A|1985-11-05|
    ZA821327B|1983-01-26|
    DK67682A|1982-09-03|
    DE3107933A1|1982-09-16|
    JPS57158768A|1982-09-30|
    DK149852B|1986-10-13|
    IL65141A|1984-10-31|
    EP0059356B1|1985-05-02|
    FI820518L|1982-09-03|
    AU8096682A|1982-09-16|
    ES8303404A1|1983-02-01|
    PT74507B|1983-11-08|
    PL136818B1|1986-03-31|
    AT13055T|1985-05-15|
    CA1192905A|1985-09-03|
    ES510015A0|1983-02-01|
    DE3263342D1|1985-06-05|
    引用文献:
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    DE1695897C3|1966-07-04|1979-02-15|Takeda Chemical Industries Ltd|N-acyl-sydnonimines, their salts, processes for their preparation and medicaments containing these compounds|
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    JPS5832870A|1981-08-24|1983-02-25|Hiroyoshi Hidaka|Novel sydnone imine derivative and its preparation|
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    JPS5859977A|1981-10-06|1983-04-09|Banyu Pharmaceut Co Ltd|Novel n-acylsydnoneimine derivative and its preparation|
    US4517179A|1983-04-29|1985-05-14|Pennwalt Corporation|Rapid dissolving, uniform drug compositions and their preparation|
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    DE4025604A1|1990-08-13|1992-02-20|Cassella Ag|3-DICYCLOHEXYLAMINO-SYDNONIMINE, METHOD FOR THE PRODUCTION AND USE THEREOF|
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    US6531158B1|2000-08-09|2003-03-11|Impax Laboratories, Inc.|Drug delivery system for enhanced bioavailability of hydrophobic active ingredients|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19813107933|DE3107933A1|1981-03-02|1981-03-02|SUBSTITUTED 3-AMINO-SYDNONIMINE, METHOD FOR THE PRODUCTION AND USE THEREOF|
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