• 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:
    Disubstituted piperazines of the formula: <IMAGE> wherein: <IMAGE> is naphthyl, benzo [b] furanyl, benzo [b] thienyl, benzodioxolyl, benzodioxanyl, benzodioxacycloheptanyl, coumaranyl, chromanyl, DELTA 3-chromenyl, thiochromanyl or DELTA 3-thiochromenyl, X is nitrogen and simultaneously Y is oxygen or sulfur, or X is sulfur, imino (NH) or methylimino (N CH3) and simultaneously Y is nitrogen, and R is hydrogen, lower alkyl, phenyl, halophenyl, lower-alkylphenyl or lower alkoxyphenyl. These compounds possess interesting pharmacological and therapeutic properties, and may be used as medicines, especially in the treatment of hypertension, peripheral vascular disorders and Parkinson's disease.
    公开号:SU793397A3
    申请号:SU782699397
    申请日:1978-12-21
    公开日:1980-12-30
    发明作者:Ренье Жильбер；Канвари Роже；Лоби Мишель；Пуанян Жан-Клод
    申请人:Сьянс Юньон Э Ко；Сосьете Франсез Де Решерш Медикаль (Фирма)；
    IPC主号:
    专利说明:

    (54) METHOD FOR PREPARING DERIVATIVES OF PIPERAZINE OR THEIR SALTS
    one
    This invention relates to a process for the preparation of piperizin derivatives, which can be used in medicine.
    The reaction of alkylation of piperazine alkyl- and aryl-halogenamic ij is known.
    The purpose of the present invention is a process for the preparation of new piperazine derivatives with valuable pharmacological properties.
    The goal is achieved based on a known reaction method for producing piperazine derivatives of general formula (I)
    A-CH, -: N 4O4-R III
     / -v
    l
    where A is naphthyl, enzo 8 furanyl, benzo E1 thienyl, benzodioxolyl, benzodioxanil, benzodioxacycloheptanyl, coumaranyl, chromanyl, 4-chromoyl, thiochromanyl or L-thiochromyl, X is nitrogen, when Y is oxygen or sulfur, or X is sulfur-thiochromyl, X is nitrogen, when Y is oxygen or sulfur, or X is sulfur-thiochromyl, X is nitrogen, when Y is oxygen or sulfur, or X is sulfur. imino, methylimino group, when Y is nitrogen /
    R is hydrogen, alkyl with 1-5 carbon atoms, phenyl, substituted by halogen or alkyl or alkoxy p
    1-5 carbon atoms, or their salts.
    The method consists in the fact that the compound of the general formula ® 5 ГHal -iO R p)

    where X, Y, and R are as defined above, and Hal is chlorine or bromine, they are interacting with piperazOJO
    general formula® /
    A- (, (W)
    where A is as defined above, followed by isolation of the desired product as a base or salt. Condensation is advantageously carried out in a polar solvent, for example, in
    权利要求:
    Claims (1)
    [1]
    20. High boiling alcohol, such as buta.nol or pentanol, or in gishiphatic amide, for example, in dimethyl form amide. The process is usually carried out at a temperature of 110-140 seconds in the presence of a hydrogen halide acceptor formed during the reaction. Alkali or alkaline-earth salts of carbonic acid, such as, for example, bicarbonate 30 or sodium and potassium carbonates, can be used as an acceptor. calcium carbonate; and organic bases, such as dimethylamine and triethylamine. If desired, these salts or bases may be replaced with an excess of monosubstituted piperazine having formula III). Derivatives of general formula (1) are weak bases that are mo. Can be converted with acids into the corresponding salts. as acids, krorye can be used to form such salts, it is possible to mention, for example, a number of inorganic acids — hydrochloric, hydrobromic, sulfuric and phosphoric, and a variety of organic acid — acetic, propionic, maleic, fumaric, tartaric, citric oxalic , benzoic acid, methane sulfonic acid and isoetonic acid. Derivatives of general formula (I) can be purified by various physical methods, such as distillation, crystallization or chromatography, or by conventional chemical methods, for example, salt formation, crystallization by their decomposition and decomposition with alkaline agents. Derivatives of general formula (I) and their salts. have interesting pharmaceutical and therapeutic properties, in particular, antihypertensive, the ability to expand peripheral blood vessels, inhibit Parkinson's disease and can be used as medications, in particular, to combat hypertension, peripheral cardiovascular diseases and Parkinson's disease. Their toxicity is low and their index is 1-D .., in mice with intraperitoneal administration of more than 200 mg / kg. Neurological properties are established by changes in rats and in the stereotype of motor function and excitability. In the stomach, for intraperitoneal administration, the average effective dose is 50 mg / kg. At this dose, a decrease in motor function and then nousa is observed. The determination of the degree of excitability or stereotype is carried out by a known method. On the other hand, a sustained increase in femoral rate is observed, reaching up to 40% when the substances proposed in this invention are intravenously administered to the dog in doses of 0.5 to 2 mg / kg. Example. 1-Piperonyl- (1,3, 4-thia1-diazolyl-2) -4-piperazine. During 8 hours, a solution of 11.2 g (O, O78 mol) of 2-bromo-1, 3,4-thiadiazole and 29.8 g (O, 136 mol 1 piperonyl piperazine in 400 ml of anhydrous dimethylformamide is heated. Then the solvent is evaporated in vacuo and the oily residue is placed in 200 ml of benzene and 400 ml of water. After separating the organic layer, it is concentrated in vacuo.The crystalline residue is obtained, which crystallizes from 60 ml of ethyl alcohol, to obtain 9.9 g of crystalline 1-piperonyl-4 - (1,3,4-thiadiazolyl-2) -piperazine; mp. 112-114 ° C. Examples 2-19. Similarly, the following compounds are prepared; 1- (2-methylna Tyl) -4- (1,3,4-thiadiazolyl-2) piperazine; 110-112 ° C ethyl alcohol), starting from 1- (2-methylnaphthyl) piperazine and 2-bromo-1, 3,4.- thiadiazole; 1- (3,4-ethylenedioxybenzyl) -4- (1, 3,4-thiadiazolyl-2) -piperazine; m.p. 116-117 with (ethyl alcohol), starting from 1- (3,4-ethylenedioxybenzyl) piperazine and 2-bromo-1,3,4-thiadiazole 1- (5-methylcumaranil) -4- (1,3,4 -ti adiazolyl-2) -piperazine; m.p. 103104c (ethyl alcohol, starting from / - (5-methylcumarail) -piperazine and 2-bromo-1,3,4-thiadiazole; 1- (5-methylcumaranyl-) -4- (5-methyl-1, 3,4 -thiadiazolyl-2) piperazine, mp. Ib-IZ C (ethyl alcohol), starting from 1- (5-methylcumaranyl-piperazine and 5 methyl-2-bromo-1,3,4-thiadiazole; 1- ( 5-methylbenzo | althienyl) -4- (5-methyl-1, 3,4-thiadiazolyl-2) -piperazine, mp 134-136 s / ethyl alcohol starting from 1- (5-methylbenzoC J thienyl - piperazine and 5-methyl-2-bromo-1,3,4-thiadiazole; 1-piperonyl-4- (5-methyl-1,3,4-thiadiazolyl-2) piperazine; mp. 8890 0 / Hchi1aen by liquid chromatography), starting from 1-piperonylpiperazine and 5-methyl-2-bromo-1,3,4-thiadiazole, 1- (3,4-ethylenedioxybenzyl) -4 - (5 methyl-1, 3,4-thiadiazolyl-2) piperazine; mp. 110-111 ° C (purified by liquid chromatography), starting from 1- (3,4-ethylenedioxybenzyl) piperazine and 5-methyl-2-bromo-1,3,4-thiadiazole 1- (3,4-trimethylenedioxybenzyl) - 4 - (1,3,4-thiadiazolyl-2) -piperazine / mp. 104-107 C / acetonitrile-petroleum ether), starting from 1- (3,4-trimethylene dihydroxybenzyl) -4-piperazine and 2- bromo-1,3,4-thiadiazole; 1- (5-methylbenzoYFURanyl) -4- (1,3, 4-thiadiazolyl 2) piperazine, mp 9899 C (purified by liquid chromatography}, starting from 1- (5-methylbenzoX YFuranyl) piperazine and 2 β-bromo-1, 3,4-thiadiazole, 1-piperonyl-4- (1,2,4-triazolyl-3) piperazine, starting from 1-piperonyl piperazine and 3-bromo-1,2,4-triazole, 1 - (3,4-ethylenedioxybenzyl) -4- (1, 2,4-triazolsh1-3) -piperazine, starting from 1- (3,4-ethylenedioxybenzyl) piperazine and 3-bromo-1, 2, 4-triazole , 1-piperonyl-4- (3-methyl-1,2,4-oxa diazolyl-5) -piperazine; mp. 225227 C (methanol), starting from 1-piperonyl piperazine and 3-methyl-5-chloro 1,2, 4-oxadiazole / 1- (3,4-ethylenediamine ibeneil) -4 - (3-methyl-1, 2,4-oxadiazol-5) -piperazine) m.p. 101-102 C, starting from 1- (3., 4-ethylenedioxybenzyl-4-piperazine and E - 1-methyl-5-chloro-1,2,4-oxadiazole} 1-piperonyl 4- (1,2.4-thiadiazole-5 a) piperazine; mp 74 C (ethanol), i.khod from 1-piperonylpiperazine and 5-bromo-1,2,4-thiadiazole; 1-pyeronyl-4- (3-methyl-1,2,4- thiadiazolyl-5) -piperazin7, m.p. 110 W (CC acetonitrile), starting from 1-piperonyl piperazine and 5-chloro-3-methyl-1, 2,4-thiadiazole; 1- (3,4-ethylenedioxybenzyl) -4- (3-methyl-1, 2, 4-thiadiazolyl-5) -piperazine; m.p. 75-7bs (acetonitrile), the result of 1- (3,4-ethylenedioxybenzyl) piperazine and 5-chloro-3-methyl-1,2,4thiadiazole) 1- (3,4-ethylenedioxybenzyl) -4- (1 , 2 4-thiadiazolyl-5) -piperazine; mp. 146 (ethanol), starting from 1- (3,4-ethylenedioxybenzyl) piperazine and 5-bromo, 1,2,4-thiadiazole; 1-piperonyl-4- (4-methyl-1,2,4-triazolyl-3) -piperazine; mp. 146-148 C (acetonitrile), starting from 1-piperonyl piperazine and 4-methyl-3-bromo-1,2,4-triazole. CLAIMS A method for the preparation of piperazine derivatives of general formula CIJ A-CH2- / 7- (PJ-B (ly X wherein A - naphthyl, benzo Jfypanil, benzo 7tienil, benzodioxolyl, benzodioxanyl, benzodioksatsiklogeptanil, kumaranil,, A -hromenil, thiochromanyl or A -thiochromenyl., X is nitrogen when Y is acid or sulfur, or X is sulfur, or the IMINO methyl group when Y is nitrogen, R is hydrogen, is bended with 1-5 carbon atoms, phenyl substituted by halogenMy or alkyl or xcoxyl with 1-5 carbon atoms, or their salts, about t and h and youc and the fact that the compound of the general formula (|) XY HoJ-tP / R (n) t where X, Y and R have the above values, and Hal, chlorine or bromine, is reacted with piperazine of the general formula W 3 (-U) where A has the above values, followed by isolation of the target product as a base or salt. tions into account during the examination 1. Heterocyclic compounds, under the editorship of R. Elderfield- M., Foreign literature, 1960, vol. 6, p. 347.
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    同族专利:
    公开号 | 公开日
    YU304377A|1983-01-21|
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    SE7714884L|1978-07-02|
    CA1100968A|1981-05-12|
    DE2758314A1|1978-07-06|
    PT67486B|1979-05-30|
    JPS6149314B2|1986-10-29|
    AU513087B2|1980-11-13|
    DD133802A5|1979-01-24|
    OA05840A|1981-05-31|
    BE862568A|1978-06-30|
    IE46284B1|1983-04-20|
    AT358591B|1980-09-25|
    DK572977A|1978-07-01|
    ATA927577A|1980-02-15|
    GB1560084A|1980-01-30|
    ZA777680B|1978-10-25|
    IL53714A|1981-07-31|
    SU703021A3|1979-12-05|
    FR2376148A1|1978-07-28|
    IL53714D0|1978-03-10|
    AR217144A1|1980-02-29|
    AR216931A1|1980-02-15|
    GR62407B|1979-04-11|
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    FR2376148B1|1981-05-29|
    PT67486A|1978-01-01|
    NL7714628A|1978-07-04|
    IE46284L|1978-06-30|
    AR217143A1|1980-02-29|
    PH14321A|1981-05-27|
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    引用文献:
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    DE1595923A1|1965-02-20|1969-11-27|Merck Ag E|1-Aralkyl-4- -piperazines and processes for their preparation|
    GB1307256A|1970-09-15|1973-02-14|Science Union & Cie|Piperazine derivatives and a process for their preparation|
    GB1369379A|1972-04-07|1974-10-09|Science Union & Cie|Benzodioxole derivatives and processes for preparing them|
    GB1407552A|1973-04-02|1975-09-24|Science Union & Cie|Disubstituted piperazines processes for their preparation and pharmaceutical compositions containing them|FR2418798B1|1978-03-03|1982-11-19|Science Union & Cie|
    US4421753A|1982-01-15|1983-12-20|American Cyanamid Company|1--4-substituted-piperazines|
    FR2519986B1|1982-01-21|1984-03-30|Adir|
    FR2799464B1|1999-10-12|2001-12-28|Norchim|PROCESS FOR THE MANUFACTURE OF PIPERONYL PIPERAZINE BY REDUCTIVE ANIMATION|
    EP3119774A1|2014-03-17|2017-01-25|reMynd NV|Oxadiazole compounds|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB54398/76A|GB1560084A|1976-12-31|1976-12-31|Disubstituted piperazines processes for their preparation and pharmaceutical mompositions containing them|
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