• 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:
    The invention relates to compounds of general formula <IMAGE> wherein R1 stands for a hydrogen atom or a C1-6 alkyl-, a C2-4 hydroxyalkyl, a C3-6 cycloalkyl or a phenyl group, R2 stands for a hydrogen, fluorine, chlorine or bromine atom or a C1-6 alkyl, a C2-4 hydroxyalkyl, a nitro or an -NR5R6 group, wherein R5 and R6 may have the same or different meaning and stand each for a hydrogen atom or a C1-4 alkyl or a C2-4 hydroxyalkyl group, R3 stands for a hydrogen atom or a C1-6 alkyl, a C2-4 hydroxyalkyl, a C3-6 cycloalkyl or a phenyl group, a chlorine atom or a hydroxyl, amino or methoxy group, R4 stands for a carbamoyl, a cyano or an -NR7-NHR8 group, wherein R7 and R8 may have the same or different meaning and stand each for a hydrogen atom or a C1-4 alkyl, a C2-4 hydroxyalkyl, a C1-4 alkoxycarbonyl or an -NR9R10 group, wherein R9 and R10 may have the same or different meaning and stand each for a hydrogen atom or a C1-5 alkyl, a C2-4 hydroxyalkyl, a C3-6 cycloalkyl, a phenyl or a benzyl group, or -NR9R10 may represent a morpholine, piperidine or piperazine ring, and their pharmaceutically acceptable acid-addition salts. Furthermore, the invention relates to a process for preparing these compounds. The novel compounds of general formula I have valuable pharmacological properties. Thus they show a considerable hypotensive effect and are capable to inhibit enzymes regulating the catabolism of prostaglandins.
    公开号:SU845786A3
    申请号:SU792803900
    申请日:1979-08-23
    公开日:1981-07-07
    发明作者:Силадьи Геза；Кастрайнер Эндре；Тардош Ласло；Коша Эдит；Яслитш Ласло；Чех Дьердь；Ковач Илона；Толнаи Пал；Элек Шандор；Элекеш Иштван；Полгари Иштван
    申请人:Рихтер Гедеон Ведьесети Дьяр Рт(Инопредприятие)；
    IPC主号:
    专利说明:

    The compound of the 3- {l-pyrazol I l-pyradazine series of the general formula (I) obtained by the proposed method has a significant hypotensive effect and is able to significantly inhibit prostaglandine dehydrogenase and prostaglandin A-isomerase enzymes), regulating catabolism of prostaglandins, shows to increase the content of endogenous prostaglandins.
    The hypotensive effect of the compound was studied in cats of both sexes, 2-4 kg in height, anesthetized by intraperitoneal administration of 30 mg / kg of pentabarbital 5-ethyl-5- (1-methylbutyl) -barbituric acid), the test substances were administered to animals in doses of 5, 2.5 and 1 mg / kg, and hydralazine (1-hydrazinophthalazine hydrochloride) was used as a reference substance. The hypotensive effect of the substances obtained in accordance with the invention, shown in the table. one,
    Table D
    The substance () has an inhibitory effect (prostaglandin catabolism).
    The inhibitory effect of the compounds (O with respect to the enzyme prostaglandin-A-isomerase (PHAI) was measured on a prostaglandin-A-isomerase preparation obtained from porcine blood plasma. The inhibitory effect of the compounds on the prostaglandine dehydrogenase enzyme (PHDG) was determined on a PHDG preparation from a light sgie. Table 2 shows the inhibitory effect of substances (l) on prostaglandin-A-isomerase and prostaglandine hydrogenase.
    Table 2
    The hypotensive effect of substance (l) has also been studied on spontaneously arising hypertension.
    The systolic blood pressure was measured in the caudal artery by an indirect method after oral administration of the compound to experimental rats. The substance (1) when administered in a dose equal to the dose of hydrolazine, showed the same efficacy in reducing blood pressure and the same duration of action. The advantage of substance (l) compared to hydralazine in its low toxicity and that it does not cause tachycardia , as well as its effectiveness in renapal (renal) hypertension, the latter is due to that.
    (triiodothyroacetic acid)
    0,005
    Note. I5o is defined as the concentration of substances, providing 50% inhibition of the function of the corresponding enzyme.
    Example 1. 3-hydrazino-6- (3,5-dimethyl-4-amino-1-pyrazolyl) -pyridazine dihydrochloride.
    A mixture of 3.19 g () 0 mmol) (tert.-butoxycarbonyl) -1-hydrazino} -6- (3,5-dimethyl-4-amino-1-pyrazolyl) pyridazine and 64 ml of 20% hydrochloric the acids are boiled for 40 minutes, then they are evaporated to dryness in vacuo. The residue is recrystallized from alcohol. The output of the dihydrochloride of the above product is 2.19 g (75X). M.p. 260264 ° C.
    The original substance is obtained as follows.
    权利要求:
    Claims (2)
    [1]
    Preparation of 3-chloro-6- (3,5-dimesh-1-4-nitro-1-pyrazolyl) pyridazine. To the mixtures of 230 ml of concentrated sulfuric acid and 230 ml of 100% nitric acid, 26 g of 3-chloro-6- (3,5-dimethyl-t-pyrazolyl) -cydazine are added over 30 minutes. The reaction mixture was stirred at 25 ° C for 2 hours and then poured into 1 liter of water. The precipitate formed is filtered off, washed with water and sugatat. Yield 26.7 g (8A, 5%). M.p. 164 1670s Preparation of (tert-butoxycarbonyl) -t-hydrazino3-6- (3,5-dimethyl-4-nitro-pyrazolyl) pyridazine A mixture of 2.29 g (9 mmol) above the obtained 3-chloro-6- {3 , 5-dimethyl-4-nitro-1-pyrazolyl) -pyridazine and 2.64 (20 mmol) of tert-butoxycarbonyl hydradeide are kept for 2 hours at I CSHC. After cooling, the reaction mixture is mixed with 25 ml of water. The precipitate is recrystallized from 40 ml of alcohol. The yield of 1.95 g (59%). T. pl. 196-198 ° C. 3-2 tert.-butoxycarbonyl) - L-hydrazino T-6- (3,5-dimethyl-4-amino-0-pyrazolyl) -pyridazine. 3.5 g (10 mmol) (tert.-butoxycarbonyl) -t-hydrazino-6- (3,5-dimethyl-4-nitro-pyrazolyl) -pyridazine is hydrogenated in 100 ml of alcohol in the presence of palladium supported on coal. After uptake of the calculated amount of hydrogen, the catalyst is filtered off, the mixture is dried to dryness and the residue is recrystallized from alcohol,. The yield is 1.65 g (51.5%), m.p. 195-198T Example
    [2]
    2. H-hydrazino-6- (3,5-diethyl-4-amino-E-pyrazolyl) pyridazine dihydrochloride. A mixture of 2.82 g (Ø mmol) 3-chloro-6- (3,5-diethyl-4-nitro-t-pyrazolyl) pyridazine and 2.64 g (20 mmol) of tert-butoxycarbonylgrazide is kept for 2 hours at 130c. After cooling, the mixture is stirred with 25 ml of water, the precipitate is filtered off, washed with water and dried. The resulting product is hydrogenated in 100 ml of methanol in the presence of 1 g of palladium on activated carbon at atmospheric pressure. After the calculated amount of hydrogen has gone, the catalyst is filtered off and washed with water. The filtrate and the washings were combined and evaporated. The residue is boiled in 50 ml of 20% hydrochloric acid for 30 min. After evaporation to dryness, the residue is mixed with alcohol, filtered and dried. Yield 35%. T. pl. 103-104 ° C. Obtaining the original substance Z-chloro-6- (3,5-diethyl-b pyrazolyl) -pyridazine. A mixture of 12.8 g (0.1 mol) 3,5-heptane-. dione, 14.5 g (0.1 mol) of 6-chloro-3-pyridazinyl hydrazine and 145 ml of alcohol are boiled for 6 hours. After evaporation of the alcohol, the residue is recrystallized from isopropanol. The yield of 12.1 g (51%). T. Sh1. 103-104 C H-chloro-6- (3, 5-diethyl-4-nitro-I-pyrazolyl) -pyridazine was prepared as in Example 1, starting from 2.37 g (0.01 mol). 3-Chloro-6 - (3,5-diethyl-1-pyrazolyl) -pyridazine. The output of 1.55 g (55%), so pl. 83-85C. Formula of the invention. Method of obtaining 1-pyrazolyl-pyridazine hydrochlorides of the general formula () KI RO HCl (11l (HNH2 de R. and Ra is alkyl,; Rj is an amino group; different from the general formula (II): RI - Ra has the indicated values; R /) is an NRg-NRt group, where one of the substituents RC or Rt is hydrogen, while the other substituent is alkoxycarbonyl C, is subjected to hydrolytic decarc 7 boxing in aqueous hydrochloric acid at boiling. Sources of information These are taken into account in the examination of 8457868 1. Weigand-Hilgetag. Experimental methods and organic x Imii. M., Himi, 1968, pp. 369.
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    同族专利:
    公开号 | 公开日
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    PL115063B1|1981-03-31|
    SU856385A3|1981-08-15|
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    CS217964B2|1983-02-25|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE1220428B|1960-03-25|1966-07-07|Takeda Pharmaceutical|Process for the preparation of 2-pyrazolyl- - pyrimidine derivatives and their salts|
    JPS5831347B2|1975-09-05|1983-07-05|Chugai Pharmaceutical Co Ltd|
    HU175471B|1977-06-13|1980-08-28|Gyogyszerkutato Intezet|Process for producing new 3-bracketul-pyrazolyl-bracket closed-pyridazine derivatives|US4302456A|1977-04-13|1981-11-24|The Upjohn Company|Process for therapeutic treatment|
    US4302457A|1977-04-13|1981-11-24|The Upjohn Company|Process for therapeutic treatment|
    DE2935359A1|1979-09-01|1981-03-26|Basf Ag, 67063 Ludwigshafen|6-IMIDAZOLYL-3-HYDRAZINO-PYRIDAZINE|
    US4304775A|1979-12-13|1981-12-08|Sterling Drug Inc.|3-Hydrazino-6- pyridazines and cardiotonic use thereof|
    US4503056A|1982-03-02|1985-03-05|Abbott Laboratories|1-pyrazoline derivatives|
    US5001125A|1984-03-26|1991-03-19|Janssen Pharmaceutica N.V.|Anti-virally active pyridazinamines|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    HU77GO1381A|HU176100B|1977-10-25|1977-10-25|Process for preparing new 3-/1-pyrazolyl/-pyridazine derivatives|
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