• 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:
    Novel compound, 1,2-bis(nicotinamido)propane and its pharmaceutically acceptable salts, a process for preparing the same and a pharmaceutical composition containing the same as an active ingredient are disclosed. The compound acts to prevent or spasmolyse cerebral vasospasms, to prevent cerebral apoplexy and to lower the lipoperoxide level in blood.
    公开号:SU1053749A3
    申请号:SU803009644
    申请日:1980-11-21
    公开日:1983-11-07
    发明作者:Мори Такаси；Такаку Сакае；Мацуура Фумиаки；Мураками Ясуси；Нода Юкифуми；Ямазаки Тамоцу；Неити Томохиро；Накакимура Хироси；Катаока Сигеюки；Мацуно Такаси；Хата Сун-Ти；Таканаси Сигеру
    申请人:Чугаи Сейяку Кабусики Кайся (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of a novel 1, 2-bic- {nicotinam (do) -propane of the formula CQ -2IH-CH-lfH-XJO-f and H or its salts with a pharmaceutically acceptable acid, which have valuable pharmaceutical properties and can be used in medicine Amines are acylated by acid anhydrides, acid halides, esters of acids, and also acids in the presence of catalysts. The reaction is usually carried out in an inert solvent both with cooling and with heating, if necessary in the presence of Cl base. The purpose of the invention is to develop a method for obtaining new 1,2-bis- (nicotinamide) propane or its salts with a pharmaceutically acceptable acid that have the property of removing or preventing brain spasms, preventing hemorrhages in the brain, and reducing the content of lipoperease in the blood. This goal is achieved by the proposed method of obtaining 1, 2-bis- (nicotinamido) -propane or its salts with a pharmaceutically acceptable acid, consisting in that nicotinic acid, its anhydride, mixed anhydride, acid halide or alkyl ester are reacted with 1,2 -Diaminopropane and the desired product are isolated in free form or in the form of a salt with a pharmaceutically acceptable acid. In this case, the reaction is preferably carried out at a temperature of from -10 to. In addition, the interaction of nicotinic acid or its acid halide with T, 2-diaminopropane is preferably carried out in an inert organic solvent, such as pyridine, tetrahydrofuran, dioxane. The reaction is carried out at a temperature of from 5 to, in the presence of an inorganic or organic base, for example, triethyl amine or pyridine. In addition, the interaction of the nicotinic acid alkyl ester with 1,2-diaminopropane is carried out at 100-130 C. The molar ratio of 1,2-diaminopropane and nicotinic acid or its acid halide or its alkyl ester is preferably 1: {2.3 -five). The synthesized 1,2-bis- (nicotinamide) propane is used to prevent or relieve vascular spasms caused by various causes. Even a small dose of this compound prevents death from hemorrhage in the brain, experimentally caused by the administration of arachidonic acid, and reduces the concentration of lipid peroxides in the blood. In addition, the proposed compound possesses the necessary physiological activity with respect to systems for synthesizing prostaglandin in vivo, which means that the ratio of formed prostaglandin Dy to thromboxane A2 increases (VA2b) The proposed compound has low toxicity, the magnitude of acute toxicity. By definition, acute toxicity in mice exceeds 1000 mg / kg. The proposed compound is formulated in the form of tablets, granules, powder, capsules using conventional pharmaceutical agents. for oral administration or in the form of injectable formulations for parenteral administration. The daily dosage is usually in the range of 0 mg, more preferably 5-500 mg. Compounds of the formulas ((jHgCJHg Kii OH-TL P l r - COllflCHCHgT HCJO, Co: mSnS gT HCo Closest in structure to the proposed compound. For the compounds of the {) and / and) biological activity is unknown and the possibility of their use in medicine is not indicated. The compound of formula (1iI) has extremely poor pharmacological activity. Test 1. Male rats of the Sprigue Douley species (weight 200-250 g) were orally administered test compounds each and 30 minutes after the injection were injected with anesthesia into the left carotid artery of arachidonic acid, each at a dose of 20 mg / kg 1 hour after injection counted dead rats .. The results are presented in table. 1, .Table 1 10537 5. 10 J5 20 25 2Q 94 hydrochloric acid and water (5: 11: 2: 10, upper phase). After the application, the applied plate was scanned for radioactivity and the areas corresponding to the radioactive bands of thromboxane B2 (TCVL) and 6-keto-prostaglandin (6-keto-nrF j j) were scraped to extract silica gel and measured on a liquid scintillation counter. The conversion of arachidonic acid to TCB 2 and b-keto-PGR was calculated, and the number of each TCB2I b-keto-CGR was determined. Under the described conditions, all TCA2 and turned into TCB2 and 6-keto-CGR, respectively. Thus, it can be assumed that the total amount of TXB2 and b-keto-PRR-jc is equal to the number of TXAL and PGE2, which was formed in the reaction system. In tab. 2 shows the ratio of CGD to TXA for each test compound. In all experiments, the final concentration of the test compound was adjusted to. Table 2 Compound I / A
    Test 2. To 1 ml of a mixture containing 0.9 mg of porcine aorta microsomes and rat platelets, 10 µl of the test compound solution was added and the mixture was kept for 3 min at 23 ° C. Then 10 µl of arachidonic acid (80 nM ;, 8 Ci / mol) in a 0.1 M aqueous solution of bicarbonate, to initiate the reaction at 23 ° C for 3 min, after which the reaction was terminated by adding 50 μl of 0.5 N aqueous citric acid solution. The mixture was extracted with 8 ml of ethyl acetate . The organic layer was separated and concentrated to dryness under reduced pressure. The residue was dissolved in 100 µl of ethyl acetate and subjected to thin layer chromatography, using a silica gel plate on glass and as a developing solvent a mixture of isooctane, ethyl acetate, cc. 3. A Siamese cat weighing 22, 5 kg was anesthetized and its head was fixed in a special spatial apparatus, fix the cat on the back. An incision was made in the neck and the trachea, the esophagus and the skull were removed to reach the arteries of the base of the brain. 1 ml of arterial blood, previously taken from the same cat and aged for a week, was infused into basilar arteries. After 10 minutes, the blood was aspirated and 1 ml of an aqueous solution (pH 7i5-8.0) containing 0.5 mg of the test compound was infused into the same portion. 10 minutes after infusion of the test compound solution, the solution of ossa-.
    The percentage of spasms of the arteries that were in a state of spasm was measured and measured.
    Experimental results show that suggesting a compound gives 82% spasmolysis, while a compound of formula (I) causes only 30% spasmolysis ,.
    Experience . Male rats were divided into groups of 10 animals each and were not fed for 16 hours. Then, through the tail vein, intravenously injected and water alloxan in the amount of 75 kg / kg per alloxan. Twice after 2 and 30 hours after administration of alloxan), the proposed compound or compound of formula (II) was given orally, 200 mg / kg each time, and 48 hours after the administration, blood was taken for analysis and the plasma lipoperkisei level was determined. Lipoperokg Syd-Wako Test in order to get the value of TBA.
    The average value of TBA in each of the test groups was compared with the average value in the control groups; no test compound was given to the animals. The compound of the formula. (H) caused a decrease in TBA, while the proposed compound resulted in an AO decrease.
    Example 1. 25 g of nicotinyl chloride hydrochloride are added to a mixture of k, g of 152-diaminop () Opana, 200 ml of pyridine and 50 ml of triethylamine, while cooling with ice while stirring until. After stirring for 1 hour, 00 ml of water is added to the mixture, and the mass is concentrated under reduced pressure. Water and then potassium carbonate are added to the residue to extract the residue by extraction with tetrahydrofuran. Separated cyjuar tetrahydrofuran layer over potassium carbonate and then concentrated. For purification, the oily residue is passed through a COI-YNU filled with silica gel. Recrystallization from ethyl acetate gives 11 g of 1,2-bis- (nicotinamido) -propan with m.p. 15 ((base).
    Elemental analysis for C gH jgNAOg: Found:%: C 63.2; H 5.9; N 19.5
    Calculated: With BZ ,; H S, 7t N 19,7.
    Example 2 To a mixture of TZL g of nicotinic acid, 12.6 g of triethylamine and 500 ml of tetrahydrofuran, under ice cooling to 2-5 ° C and stirring, 12.5 g of ethyl chloroformate are added dropwise and after stirring the mixture for the next 30 minutes at once 3.7 g of 1,2-diaminopropane is added. The mixture is stirred for
    1 hour at room temperature. 300 ml of water was added to the mixture and, when salified with potassium carbonate, extracted with tetrahydrofuran.
    The extract is treated in the same manner as in the example and gives 10 g of the desired product, which does not cause any drop in the melting point when mixed with the product of the example and has the same elemental composition as the product of example 1.
    Example 3. Within 3-5 hours a mixture of 2 g of 1,2-diaminopropane and 12 g of methyl nicotinate is kept at 100120 ° C, the methanol obtained from the reaction system is distilled off. Then, after cooling, the mixture is kept and the product is purified, passing through a chromatography column with silica gel and crystallization from ethyl acetate. The result is 3 g of the target product.
    The resulting product does not cause a melting point depression when mixed with the product of Example 1. The elemental analysis data is consistent with the data for the product of Example.
    An example. To a solution of 1,2-bis- (nicotinamide) propane (15 g) in ethanol (225 ml) is added hydrochloric acid (10.5 ml) with stirring, and then acetone (kQQ ml). The resulting crystals are filtered and 18 g of crude crystals are obtained. The crystals were dissolved in 180 ml of methanol and 180 ml of acetone was added. The resulting crystals are again filtered off and 15 g of 1, 2 bis- (nicotinamido) propane-hydrochloride (m.p.) are obtained.
    Example 5. A mixture of 7, g of 1, 2-propanediamine, 10.1 triethylamine and 100 ml of chloroform is cooled in an ice bath, and a mixture of 45.6 g of nickel anhydride (howl of acid and 200 MTJ of chloroform is added dropwise to the mixture at stirring and then the mixture is heated under reflux for 30 memes.
    After cooling, hydrochloric acid is added to the reaction mixture, followed by saturated aqueous sodium chloride solution. The mixture was dried over anhydrous sodium sulphate and distilled under vacuum. The residue is treated according to the method of example and get L, 5 g of 1,2-bis- (nicotinamide) -0-propane.
    When mixed with the product of Example 1, no decrease in the melting point of this product is observed.
    Example 6. A mixture of 120 g of anhydrous potassium carbonate water, 150 ml of water, 250 ml of chloroform and 15 g of 1,2-propanediamine are cooled in an ice bath
    and 77 g of nicotinyl chloride hydrochloride is added to the mixture with stirring. The mixture is then stirred at IS-IS C for 1 hour.
    The precipitate was filtered off and the chloroform layer was separated. The residual aqueous layer is extracted with chloroform and the extract is combined with the initial layer of chloroform. The combined layer is treated according to the method of example k and receive 29 g of 1,2-bis- (nicotinamido) -propan.
    When mixed with the product of example k, no decrease in the melting point of this product is observed.
    The 1,2-bis (nicotinamido) propane obtained by the proposed method can be used in medicine.
    权利要求:
    Claims (7)
    [1]
    1. A method for producing a 1,2-bis- (nicotinamido) propane of the formula or its salts with a pharmaceutically acceptable acid, characterized in that the nicotinic acid, its anhydride, mixed anhydride, acid halide or alkyl ester are reacted with 1,2-diaminopropane and the target product are isolated in free form or in the form of a salt with a pharmaceutically acceptable acid.
    [2]
    2. The method of claim 1, wherein the reaction is carried out at a temperature of from -10 to 150 ° C.
    [3]
    3. The method according to claim 2, characterized in that the interaction of • nicotinic acid or its acid halide with 1, 2-diaminopropane is carried out in an inert organic solvent, such as pyridine, tetrahydrofuran, dioxane.
    [4]
    4. The method of pop.Z, characterized in that the reaction is carried out at a temperature of from -5 to 10 ° C.
    [5]
    5. The method of pop. 4, characterized in that the reaction is carried out in the presence of an inorganic or organic β-base, for example triethylamine or pyridine.
    [6]
    6. The method of pop. 2, characterized in that the interaction of the alkyl ester of nicotinic acid with 1,2-diaminopropane is carried out at 100-130 ° C.
    [7]
    7. The method of pop. 2, characterized in that the molar ratio of 1,2-diaminopropane and nicotinic acid or its halide or its alkyl ester is 1: (2.3-5).
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    同族专利:
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    引用文献:
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    FR1196M|1960-06-27|Eprova Ag|New drugs with antibacterial activity consisting of new derivatives of nicotic acid.|
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    GB1339764A|1971-03-29|1973-12-05|Ici Ltd|Pyridine derivatives|IT1170214B|1983-09-12|1987-06-03|Crinos Industria Farmaco|PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF PERIPHERAL ARTERIOPATHIES|
    FR2556722B1|1983-12-15|1986-09-26|Merck Clevenot Laboratoires|N-VALPROYL-NICOTINAMIDE, PROCESS FOR PREPARATION AND THERAPEUTIC USE|
    EP0376185B1|1988-12-27|1994-08-17|Chugai Seiyaku Kabushiki Kaisha|Process for purification of 1,2-bispropane|
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    JPH09315972A|1996-03-22|1997-12-09|Chugai Pharmaceut Co Ltd|Therapeutic drug for damaged spinal code|
    US20030032655A1|2000-03-17|2003-02-13|Toshio Tanaka|Heme oxygenase-1 inducers or induction enhancers|
    JPWO2002028392A1|2000-09-29|2004-02-12|中外製薬株式会社|Cerebral circulation disorder treatment|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP54150674A|JPS6155911B2|1979-11-22|1979-11-22|
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