• 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:
    5(4-Pyridyl)-6(4-fluorophenyl)-2,3-dihydroimidazo -[2,1-b] thiazole has significant antiarthritic and immunoregulatory activity compared with its 5,6-transposed isomer. The compound is prepared by reacting 4-(4-pyridyl-5-[4-fluorophenyl) -2-mercaptoimidazole with a reactive ethylene dihalide then separating the isomeric mixture of products.
    公开号:SU940649A3
    申请号:SU792818061
    申请日:1979-09-26
    公开日:1982-06-30
    发明作者:Эллиот Бендер Пол；Лэнтос Иван
    申请人:Смитклайн Корпорейшн (Фирма)；
    IPC主号:
    专利说明:

    or oxide lot-additive derivative. 1, 2-bromoethane or 1 bromo-2-chloroethane is preferably used as dihaloethane. In this case, the process is carried out in glacial acetic acid or dimethylformamide in the presence of sodium hydride. The physiological activity of a compound of formula (D) is determined as follows. Inhibition of arthritis in rats, defined as a decrease in edema swelling, is caused by a compound of formula (1) with daily oral doses of 3.12 50 mg / kg, when controlled with indomethacin and methotrexate. In this method, arthritis in rats is caused by a single subcutaneous injection of 0.75 mg of Mycobacterium but. Suspended in paraffin oil into the left hind paw. The paw is inflamed (volume increase) and reaches its maximum size within three to five days (primary damage). In the initial period, animals lose weight. Secondary damage occurs approximately 10 days later and is characterized by inflammation of the right hind paw, into which no injection was made, weight loss and a further increase in the volume of the left paw, into which the injection was made. The compound is administered daily, starting on the day of injection for 17 days, with the exception of days k, 5, 11, and 12. Anti-arthritis activity is characterized by the ability to protect animals from the development of primary and secondary damage. E, n-, In this test, 5 - (+ pyridyl; -6- (+ -fluorophenyl) -2, 3-di hydroimide 30 - {2,1-in -thiazol shows positive activity at oral doses of 6.25; 12, 5; 25 and 50 mg / kg and gives an ED of 26, (15,) mg / kg per day for the volume of the left paw on day 3. Q, (5.3-10.19) mg / kg per day for the volume of the left paw paws on day 16 and 7.5 (2.7-15.6) mg / kg per day for the right paw on day 16. ED is the calculated dose, which gives a 25% reduction against the control value (see table). The opposite isomer of 6- (4-pyridyl) -5- (-fluorophenyl) -2,3-dihydroimidazo-C2, 1-b1-thiazole does not show any activity at a dose of 50 mg / kg day: 5,6-bis - (- pyridyl) -2, 3-dihydroimidazo-2,1-b-thiazole (50 mg / kg per day) is also not active. With a stack of rat paws caused by carrageenan, anti-inflammatory the activity is manifested at oral doses of 50 and 100 mg / kg. Compounds having immune regulating activity are beneficial in treating rheumatoid arthritis. The compound of formula C1 shows the ability to regulate cellular immunity, which is confirmed by standard test methods. oxazolone contact sensitivity when tested on l apah mice. When tested for oxazolone, 5- (-pyridyl) -6- (-fluorophenyl) -2-3-di hydroimidazo-2,1-in -thiazole is significantly active after oral administration.
    2t, 2 + 7.8
    1 +, 3 + 2.4
    ol
    25.3 + 5.9
    27.2 + Y, 3
    18.5 + 1.9
    + b9Significantly
    + 86Vastly
    + 100Vastly
    + 36Slightly
    Note: Opposite Isomer. The opposite isomer showed little activity when administered orally 25 mg / kg. 5,6-di (-pyridyl) also showed no significant activity when prescribing 25 Ig / kg orally. The compound of formula (1) has LD 2J, 2 mg / kg for mice after I days, Example 1. To an aqueous solution (75 ml) of sodium cyanide (19.6 g, AOO mM) and benzyl triethyl monium (3.0 g, 13 mM) isonicotaldehyde (10 g, 93 mM) in 100 ml of methylene chloride at 0 ° C is added. With vigorous stirring, a solution of benzoyl chloride in methylene chloride (, 0.100 mm, 50 ml) is slowly added over 15 minutes. After half an hour of reaction, cooling is stopped and the mixture is allowed to reach room temperature. The organic layer is separated, washed with 5% sodium carbonate and brine, dried, evaporated, and an oil is obtained, which is carefully extracted with ether (4 L). The ether solution is concentrated to 500 ml, crystallized and 5.0 g of isonicotinaldehyde-0-benzoyl cyanohydrin are obtained. Cyanohydrin (3.0 g 12 mM) is stirred in 50 ml of tert-butyl alcohol with para-fluorobenzaldehyde (12 mM) and sodium hydride (12 mM). Stirring is continued for another 1-1 / 2 h at room temperature and a suspension of sodium hydride in mineral oil (suspension, 4 ml) is carefully added. Test using chromatography in a thin layer of an aliquot of the reaction mixture after 11/2 h shows the formation of a single product. It is processed by the ohContinuity of the table.
    5,6-di (2-pyridyl) -analogue by depositing a suspension in 200 ml of a mixture of ice-water and then extraction with chloroform. The chloroform extract is evaporated to a crystalline residue, which is then crystallized from ether. The resulting crystalline product is optionally purified by crystallization from a mixture of methylene-ether about 9.0 g (37 ml) of hydroxyketone-a and boiling k g under reflux in ml of dimethylformamide with 5.3 g (70 mM) of thiourea. The solution is concentrated to half the original volume, until crystalline 2-mercaptoimidazole is precipitated, the crystallization is completed overnight in the refrigerator. The compound is purified by crystallization from ethanol. j- (4-pyridyl) -5 - (- fluorophenyl) -2-mercaptoimidazole is obtained with a total yield of crude material of 0%, considering benzoyl cyanohydrin condensation, mp 386-388 ° Co, Found,%: C 61.58; H, 21; N 15.11. Calculated for 1/8 NPO, I: C 61.46; H t, 37, - N 15.39. 2-mercaptoimidazole (12.5 ml) was suspended in 100 ml of dimethylformamide and sodium hydride was added. The salt is formed 1/2 hour at room temperature and at this time 1-bromo-2-chloroethane is added by pipette and the solution is stirred overnight under an atmosphere of argon. Solid anhydrous sodium carbonate is added to the reaction mixture and the mixture is heated under reflux 2 , 5 and. Dilution of the dimethylformamide solution with an ice-water mixture to 300 ml causes the oil to precipitate.
    权利要求:
    Claims (5)
    [1]
    Claim
    1. The method of obtaining 5 “(4-pyridyl) -6- (4-fluorophenyl) -2,3 - dihydroimidazo [2,1-b] thiazole of the formula or its acid addition salt or oxide derivative, characterized in that 4- (4-pyridyl) -5 ~ (4-fluorophenyl) -2-mercury ptoimidazole is reacted with 1,2-dihaloethane and the resulting mixture 5- (4-pyridyl) -6- (4-fluorophenyl) -2.3 -dihydroimidazo [2,1-b] thiazole and 5 (4-fluorophenyl) -6- (4-pyridyl) -2,3-dihydroimidazo [2,1-b] thiazole are separated by fractional crystallization or chromatography and the desired the product is isolated in the form of a free base, an acid addition salt or oki Nogo derivative.
    [2]
    2. The method of pop. 1, characterized in that as the dihaloethane use 1,2-dibromoethane.
    [3]
    3. The method of pop. 1, characterized in that 1-bromo-2-chloroethane is used as dihaloethane.
    [4]
    4. The method according to paragraphs. 1 and 2, characterized in that the process is conducted in an environment of glacial acetic acid.
    [5]
    5. The method according to PP. 1 and 3, about t and. Characterized in that the process is conducted in a medium of dimethylformamide in the presence of sodium hydride.
    Circulation 445 Subscription branch PPP Patent, Uzhhorod, st. Project, 4
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    引用文献:
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US05/946,260|US4175127A|1978-09-27|1978-09-27|Pyridyl substituted 2,3-dihydroimidazo[2,1-b]thiazoles|
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