Method of obtaining derivatives of 1,2,5-oxadizol-3,4-bis-carbonic acid or their pharmaceutically ac

专利摘要:
The method of obtaining 1,2,5-oxadiazole-3 derivatives, 4-bis-carboxylic acid of the general structural formula (i | COR // N K 0 where R is -NHR -NIPR group; R2 is alkyl containing 1-6 carbon atoms , cyclopentyl, cyclohexyl, aralkyl, which - ry can be unsubstituted or substituted by 1 or 2 methoxy groups, 2-pyridyl-methyl, -CHj-CH5- (CH2) m -OCH, -group pa, in which n) 0 , and-pi 1,2-hydroxyethyl, 2-diethyl-amia. no-ethyl; R and R are independently of each other lower alkyl or R and R together with the nitrogen atom to which they are bound form morLoline, piperidyl or pyrrolyl, or their pharmacologically acceptable acid addition salts, characterized in that amide 1,2, 5-oxadiazole-2-oxide-3,4-bis-carO) bonoic acid of the structural form COR ly II N L, NO / 0 in which R has the indicated values, is subjected to reduction of three (C-C alkyl) phosphite, or three (C -C4-alkyl) phosphine, or triphenylphosphine in an inert solvent when heated, followed by separation of the target product in the by free form or in salt form.
公开号:SU1138026A3
申请号:SU823486446
申请日:1982-09-01
公开日:1985-01-30
发明作者:Шенафингер Карл；Бейерле Руди；Антонио Марторана Пьеро；Нитц Рольф-Эберхард
申请人:Касселла Аг (Фирма)；
IPC主号:

专利说明:

This invention relates to a process for the preparation of p) derivatives of 1, 2,5-oxadiaool-3, 4-bis-carboxylic acid of the general structural formula B Oms-gg-JUK NVI or their pharmacologically acceptable acid addition salts, where R is the group-NHR or NRR; R is alkyl containing 1-6 carbon atoms, cyclopentyl, .cyclohexyl, aralkyl, which can be unsubstituted or substituted by 1 or 2 methoxy groups, 2-pyridyl-methyl, -CH2-CH2- (CH) n - OCH -group, PA, in which m 0 or 1,2oxyethyl, 2-diethyl-amino ethyl; R and R are independently of each other lower alkyl, or R and R, together with the nitrogen atom to which they are bound, form morpholinyl, piperidyl or pyrrolyl. Cleavage of the extracyclic oxygen atom with preservation of the furazan cycle can occur under the action of tin chloride in a mixture of glacial acetic and concentrated hydrochloric acids or upon reduction with hydroiodic acid in the presence of red phosphorus. The purpose of the invention is to obtain new derivatives of 1,2,5-oxadiazole-3 , 4-bis-carboxylic acid with valuable pharmacological properties. The goal has been achieved by a process for the preparation of 1,2, 5-oxadiazole-3,4-bis-carboxylic acid derivatives of the general formula (I), comprising: 1,2,5-oxadiazole amide 2 tooxide-3,4-bis -carboxylic acid of the general formula o / -o In which R has the indicated meanings, is subjected to reduction with three (alkyl) phosphite, or three (C (-C4-alkyl with phosphine, or triphenylphosphine in an inert solvent when heated, followed by isolation of the desired product in in free form or in salt form. Aliphatic or aromatic, for example, are suitable solvents. Hydrocarbons, such as low- and high-boiling petroleum ether, benzene, toluene or xylene, or halogenated hydrocarbons, such as chlorobenzene. The reaction temperatures are 50-150 ° C, preferably 100-140 ° C. Depending on the desired reaction temperature, the solvent should be chosen. with the appropriate boiling point. The required starting materials of formula (II) can be obtained from oxamoyl chlorides of formula (III) by cleavage of HC1 and subsequent dimerization: base 2R-CO-C C1-2-2H1 The reaction is carried out in a suitable solvent or ispergatore, HA, an example in dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, a lower alcohol (methanol, ethanol), but preferably in water. It is also possible to use mixtures of various solvents or dispersants, in particular, homogeneous, and heterogeneous mixtures with water, for example, water with methanol or. water with diethyl ether. The reaction is carried out at 0-50 ° C, preferably at 10-25 ° C. ; After the compound (III) is introduced into the solvent or dispersant, the reaction often proceeds spontaneously. However, it can be significantly accelerated by adding a base that binds the cleaved hydrogen chloride. The following bases can be used: primary, secondary or tertiary organic amines, for example methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, tritnlamine; pyridine; alkali metal hydroxides, for example sodium or potassium hydroxide; alkali metal carbonates or bicarbonates, for example, potasa, soda and sodium bicarbonate; alkali metal acetates, for example sodium acetate. Prefer 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 low organic amines) or a dispersion of the solution or dispersion of the compound (III). Because of the onset of the reaction, it is advisable to add the base gradually or in portions and stir the reaction mixture. The base is added preferably with a molar amount (2 mol of the compound (III) 2 mol of the base), sometimes with an excess of up to 20%. After completion of the reaction, the resulting compound of formula (II) is isolated. Compounds (I), which have a main side chain, form salt or acid addition compounds with inorganic or organic acids. Such acids are, for example, hydrochloric hydrobromic, phosphoric, sulfuric, oxalic, lactic, tartaric, acetic, salicylic, benzoic, citric, ascorbic, adipic and naphthalene disulfonic acid. Acid addition compounds are prepared in a known manner by combining the components in a suitable solvent and dispersant. The compounds of the formula I and their pharmacologically acceptable acid-adducting compounds possess valuable pharmacological properties. They show a pronounced effect on the circulatory system and heart. With a low dosage, they lower blood pressure, reduce peripheral resistance and, through a decrease in pressure in the pulmonary artery at a constant heart rate, result in a decrease in heart function. Because of this, compounds of formula (I) and their pharmacologically acceptable salts with acids can be used as a medicine for high blood pressure and angina pectoris, as well as for preventing an attack of stenecardia in pure form or in mixtures with each other or in the form of pharmaceuticals. preparations that allow intestinal or parenteral administration and which as an active principle contain an effective dose of at least one compound of the formula (I or its acid additive salt. along with the usual pharmaceutical carriers and Preparations can be taken orally, for example, in the form of pills, tablets, dragees, capsules made of soft and hard gelatin, solutions, syrups, emulsions or suspensions, or aerosol mixtures. Preparations can be used -Gy and rectally (suppositories), parenteral ( injection solutions) or percutaneously (ointments or tinctures). To obtain / Pharmaceutical preparations use inert inorganic inorganic or organic carriers. To obtain pills, tablets, pills and capsules made of hard gelatin, you can use lactose, corn starch or its derivatives, talc, stearic acid. or its salts, etc. Carriers for soft gelatin capsules and suppositories are fats, waxes, semi-solid and liquid polyols, natural or hardened oils, etc. Water, sucrose, invert sugar, glucose, polyhydric alcohols are suitable carriers for the preparation of solutions and syrups etc. Suitable carriers for injecting solutions are water, alcohols, glycerin, polyhydric alcohols, vegetable oils, etc. Together with the active ingredients and bases, pharmaceutical preparations may also contain additives; fillers, diluents, swelling agents, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, dyes, flavoring or aromatic substances, thickeners, diluents, buffers, solvents or dissolving agents or substances to achieve prolonged action, as well as salts for changing and osmotic pressure, coating agents or antioxidants. They may also contain two or more compounds of formula (I) or their pharmacologically acceptable acid addition salts and other therapeutic agents. Such therapeutic effective substances are: beta-receptor blockade agents; For example, propanolol, pindolol; vaso dilator, for example carbochromen:, sedatives such as barbituric acid derivatives, .1.4 benzodiazepines and meproimomat; diuretics, such as chlorothiazide; heart tonic substances such as thimble based preparations; blood pressure lowering agents, for example hydralazine, dehydralazine, prazosin, clonidine, rauwolfia alkaloids, substances that lower the level of blood fats, for example, bezafibrate, fenofibrate, means for preventing thrombosis, for example, funprocoumon.
The dosage can vary widely and must be individualized. dual. Usually, when administered orally, the daily dose is 0.4100 mg, preferably 1-20 mg. With other methods of administration, the daily dose due to the good absorbability of active substances is also about 0.4-100 mg (per 1 kg of body weight; this corresponds to a daily dose of about 0.005 mg - 1.4 mg, preferably 0.013-0.28 mg). The daily dose is usually divided into 2-4 doses. Pharmaceutical preparations contain active principles for a dose of 0.1-50 mg, preferably 0.5-10 mg.
Testing of the anti-angiotic and anti-hypertensive effects of the compounds of formula (I) was carried out on the cross-breeds of dogs of both sexes under pentobarbital (30-40 mg / kg intravenous) or urethanchloralose anesthesia (3 ml / kg of urethane-hlololoza mixture intravenously 20 mg / kg chlorine intravenous and 250 mg / kg uTaHa) j. Artificial respiration of animals is performed in a Bird-Mark-7-Respirator breathing apparatus. The maximum expiratory carbon dioxide content (measured with an infrared absorption instrument) was 4.5–5 vol.%. During the entire period of testing with pentobarbital anesthesia, the animals received a continuous infusion of intravenous pentobarbital — 4 mg / kg (6 mg / hour). ) to achieve a constant depth of anesthesia; with urethane-chloral anesthesia, cattle do not receive a prolonged infusion. The infusion is carried out through the head vein. After the test animals are prepared, it takes about 1 more hour until all hemodynamic parameters are set (steady state). After this, the tests are started.
To determine the mean peripheral blood pressure (BD, peripheral systolic and diastolic blood pressure is measured in the femoral artery by means of a Stat Stat Pressure Instrument Cat. Injected through the carotid artery into the left ventricle of the heart, the Miller-Tip-Katheter catheter shows a presistolic pressure in the left ventricle (LVEDP) and heart rate (HF) .Another catheter inserted in the celiac vein is the average blood pressure (PAP) in the pulmonary artery. The results are presented in the table. (BD) means media her peripheral blood pressure).
Example 1. Methylamide 1,2,5oxadiazol-3, 4-bis-carboxylic acid.
8.0 g of methyl amide 1,2,5-oxadiazo-2-oxide, 4-biscarboxylic acid and 7.0 g of triethyl phosphite are dissolved in 100 ml of toluene, and boil for 24 hours at refluxing temperature. The still hot solution is filtered and the filtrate is cooled to room temperature, and a colorless precipitate is formed, which is recrystallized from 60 ml of isopropanol. Obtain 5.3 g (72% of theor.), So pl. 161-163 ° C.
The following compounds are obtained similarly (after the yield data, the used reducing agent, solvent and reaction temperature are indicated; the following abbreviations are used for reducing agents: TBP tributyl phosphite, TER - triethyl phosphite TMP - trimethyl phosphite, TIP - triispropyl phosphite, TPP-t {iphenylphosphine):
isopropylamide 1,2,5-oxadiazole-3 4-bis-carboxylic acid, so pl. 169173 0 (87% of theor.), TBP, chlorobenzene, 130 ° C;
propylamide 1,2,5-oxadiazole-3, 4bis-carboxylic acid, so pl. 127129 ° С (71% of theor.), TBP, chlorobenzene, 130 ° С;
1,2,5-oxadiazole-3 morpholide, 4bis-carboxylic acid, t. / pl. 112114 ° С (80% of theor.), TER, toluene, 110 ° С;
piperidide 1,2,5-oxadiazole-3, 4bis-carboxylic acid, so pl. 7980C (77% of theor.), TER, toluene, t10®C; cyclohexylamide 1,2,5-oxadiazol-3, -bps-carboxylic acid, so pl. 151-153 ° С (62% of theor.), TBP, o-dichlorobenzene, 150 С; 1,2,5-oxadiazole-3 dimethylamide, 4-bis-carboxylic acid, m.p. 128130 0 (75% of theor.), TMP, petroleum ether, 50 ° С; diethyl amide 1,2,5-oxadiazole-3, 4bis-carboxylic acid, so pl. 116118 ° С (78% of the theory.), TMP, toluene 80 ° С, 1,2,5-oxadiazole-3 butylamide, 4bis-carboxylic acid, m.p. 112114 ° С (80% of theor.), TER, toluene, 110 ° С; ethylamide 1,2,5-oxadiazole-3, 4Cis-carboxylic acid, so pl. 124125 ° С (76% of the theory), TPP, toluene, 110 ° С; 2-methoxyethylamide 1,2,5-oxadiazo 3,4-bis-carboxylic acid, so pl. 74-75c (70% of theor.), TPP, toluel, tert, butylamide 1,2,5-oxadiazole 3,4-bis-carboxylic acid, so pl. 136-138 ° C (85% of theory.), TBP, xyul, sec, butylamide 1,2,5-oxadiazole 3,4-carboxylic acid, so pl. 129130 ° C (72% of theor.), TBP, xylene, cyclopentylamide 1,2,5-oxadiazole J, 4-bis-carboxylic acid, so pl. 163-165С (73% of theor.), TIPP, xyul, 120 ° С; pyrrolidide 1,2 5-oxadiazole-3, 4-5-carboxylic acid, m.p. 8738 ° С (71% of theor.), TER, toluene, 110 ° С; 3-methoxypropylamide 1,2,5-oxa; azol-3, 4-bis-carboxylic acid, tacno (68% of theory.), TBP, ligroin, U ° C; (, 4-dimethoxyphenyl-ethyl) 1 MID 1,2,5-oxadiazole-3, 4-bis-carboxy acid, t.p. 105-107; (4-methoxybenzsh1) -amide 1,2,5-ok; adiazol-3, 4-bis-carboxylic acid. Pl. 116-117 ° C; ethanolamide 1,2,5-oxadiazole-3, 4) is-carboxylic acid, so pl. 93) (2-diztil-amino-ethyl) -amide J, 2.5) xadiazole-3,4-bis-carboxylic acid (oil); , (2-pyridyl-methyl) -amide 1,2,5-ok: adiazol-3, 4-bis-carboxylic acid -. Pl. SW-PrE. 1,2,5-oxadiazole-2-oxide-3,4-biscarboxylic acid can be obtained as follows. 400 ml of water. 34 g of diketone are slowly added dropwise at 20 ° C, and the pH is adjusted to 7. Then 28 g of sodium nitrite are dissolved in the resulting solution. Concentrated hydrochloric acid (40 g) is then added dropwise so that the pH value does not fall below 4. Additionally, it is stirred for 30 minutes and then passed at 20-40 ° C 30 g of cooling the solution to -10 ° C, it is cooled and the solid is sucked off . Suspend in 100 ml of water and carefully add in portions at 20 ° C a total of 33.6 g of sodium bicarbonate. The solution now has a pH of 7.58. It is cooled before and the precipitated solid is filtered off with suction and recrystallized from propanol. Colorless crystals are obtained. 164-165 ° C. 1,2,5-oxadiazole-2-oxide-3,4 bis-carboxylic acid amides: bis-dimethylamide (t.p. 127-129 C), bis-diethylamide (oil), bis-morpholid (t.p. 137 -139 ° C), bis-butylamide (mp. 9192 ° C), bis-pyrrolidide (mp. 10 ICON C), bis-ethylamide (mp. 116-117 ° C), bis-isopropylamide ( mp 128131 ° C), bis- (2-methoxyethyl) amide St. pl. 94-95 C), bis-piperidide (t.d. 115-116 0), bis-tert. butylamide (mp. 166-1b7 C), bis-cyclohexylamide (mp 137-139 С), bis-second. butylamide (oil), bis-cyclopentyl amide (m.p. 144-146 C), bispropylamide (m.p. 117-118 C)., bis (3-methoxypropyl) -amide (oil shell can be obtained according to the following recipe , mg The starting compound metstamide 12.5 g of methylamine is dissolved in chlorine. An Example is obtained as follows Example 2: Pills with Cyclohexylamide 1,2,5-oxadiazole 3, 5-bis-carboxylic acid. Wheat starch Lactose Secondary Calcium Phosphate 10 Soluble Starch Stearate Magnes Colloidal Silicic Acid PRI me R 3. Tablets can be made according to the following prescription 1 138 5 9 Dimethylamide 1,2,5-oxadiazole 3, 4-bis-carboxylic acid Lactose Wheat starch Soluble starch Magnesium stearate

权利要求:
Claims (1)
[1]
The method of obtaining derivatives
1.2.5- oxadiazole-3,4-bis-carboxylic acid of the general structural formula (if
R * OC cor ¹ N K where R * is a group -NHR ² -NIPR ⁴ ;
R ² is alkyl containing 1-6 carbon atoms, cyclopentyl, cyclohexyl, aralkyl, which
- - it can. be unsubstituted or substituted with 1 or 2 methoxy groups, 2-pyridylmethyl, -CHj-CH ₂ - (CHj) _m -OCH ^ -group in which m = 0, or 1,2-hydroxyethyl, 2-diethylamino -ethyl;
R and R are independently lower alkyl or R ^ and R ^4, together with the nitrogen atom to which they are attached, form morpholine, piperidyl or pyrrolyl, or their pharmacologically acceptable acid addition salts, characterized in that the amide
1,2,5-oxadiazole-2-oxide-3,4-bis-carboxylic acid of structural formula II _R 1 _OC —__ _C0R i
N
- x ₀ / in which k has the indicated meanings, is subjected to reduction with three (C ₄ -C ^ alkyl) phosphite, or three (C (-C ₄ -apkyl) phosphine, or triphenylphosphine in an inert solvent when heated, followed by isolation of the target product in free or in salt form. '

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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DE19813134849|DE3134849A1|1981-09-03|1981-09-03|1,2,5-OXADIAZOLE-3,4-DICARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AND PHARMACEUTICAL PREPARATIONS CONTAINING THE SAME|

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