• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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  • 优先权
    • 专利摘要:
    A METHOD FOR OBTAINING DERIVATIVES OF THEOFILLIN of the general formula H3C- - "YT-CHr {XYi-CH" -1 | ( - chlorofensh1, 4-fluorophenyl, furyl; n - 0.1, characterized in that the compound of the general formula O HCl-No. 1 H-CHg - (CH) - CH 2 -HQI CH j where R and n is reacted with a compound of the general formula Hiqy xy-Ar where X, Y and AG have the indicated values in the melt at 90-120 seconds for 1-3 hours, and the target product is isolated in free form.
    公开号:SU1114337A3
    申请号:SU823464552
    申请日:1982-07-16
    公开日:1984-09-15
    发明作者:Тиле Курт；Гейссманн Феликс；Цирнгибл Лудвиг；Ян Ульрих
    申请人:Зигфрид Аг (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for the preparation of new biologically active compounds derived from theophylline region of the gadows and valuable pharmacologist with properties that can be used in medicine. A known method for producing theophylline derivatives (for example, 7- (N-methyl-Ht (-p-3,4-dichlorophenethyl) -3-aminopropyl-theophylline) by reacting theophylline with gallon alkyl (K-methyl-M- (b - 3,4-dichlorophenethyl) -3 aminochloropropropane) in an organic solvent when heated (boiling point of the solvent) in the presence of an alkali metal alcohol tJ The purpose of the invention is to obtain new derivatives of theophylline possessing high histaminolytic activity. derivatives of t eofillina of the general formula p Hcc-w A w-cHj - ((JH) th-7-7-1 (-th-AH (T where R is hydrogen, hydroxyl; X is azd, CH group; U is oxygen, carbon; Ar is 4-methylphenyl, 4-chlorophenkl, 4-fluorophenyl, furyl; n is 0.1, meaning that compounds of the general formula CHj are (CH), g QSrSr (where Kip has the indicated values; Hal is halo, is subjected to interaction with the compound of the general formula nc (x-UAH (1P) where X, Y and Ar have the indicated values in the melt at 90-120 ° C for 1-3 hours, and the target product is given free form. EXAMPLE 1 7- (2- [4- (p-tolyloxy) -piperidino] -ethyl / -theophylline. 2.4 g (0.01 mol) of 7- (2-chloroethyl) -theophylline with 3.8 g (0.02 mol) of 4- (P-tolyloxy) -piperidine in the solid state are thoroughly mixed and in a round bottom flask in an oil bath, heated at 90 ° C. In this case, a clear melt is first formed and then, after 15 minutes, the mixture solidifies again. Continue to keep the reaction mixture at the same temperature until the control by thin layer chromatography (CHC1, + 10% methanol) indicates the end of the reaction (after 6 hours). It is then allowed to cool, water is added and the mixture is extracted with chloroform. After extracting the substance over MgSOj, chloroform is distilled off. The residue is recrystallized twice from isopropanol. 3.0 g of a 58.2% product are melted with a melting point of 121-122 ° C. Calculated: C 63.62; H 6.61; N 17.66; About 12.11. Cj lLJl50, (M.Bec 397.47) Found; A: C 62.75; H 6.96; N 17.42; About 13.02. Example 2. 7- / 2- / 4- (P-f-lorbenzo l) -piperidino / -ethyl / -theophylline. 25.6 g (0.124 mol) of the 4- (G-fluorobenzoyl) pipa (together with 15.0 g (0.062 mol) of 7- (2-chloroethyl) -theophylline in the solid state in a round bottom flask is heated for 1 hour to 100 C. Then cooled to 60 ° C and stirring, add ethyl acetate until a homogeneous suspension is formed. After cooling and 4N elimination of the separated fluorobenzoylpiperidine hydrochloride, the filtrate is mixed with 2N hydrochloric acid to precipitate the crude product. water and ethyl acetate, then acetic ether and 100 C. 2 N. of sodium hydroxide. After shaking and separating the phases, the main amount of the product is in the organic phase. To obtain further quantities of the product, the aqueous phase is shaken twice with 100 ml of ethyl acetate. The combined organic phases are washed with a saturated NaCl solution, treated with active carbon, dried over MgSO4 and filtered. From the slurry by distillation of the solvent, 20.4 g (80% -) of a crude crystalline product is obtained, which is suspended in 250 ml of carbon tetrachloride and heated under reflux. The resulting dark brown solution is treated with activated charcoal and after cooling 14.5 g (56.9%) of pure white product is obtained with a melting point of 143-145 ° C. Calculated,%: C 61.00; H 5.85; N F 4.60. CjjlHjHlNjOj (m.ves. 4t3.46) Found,%: C 60.80; H 5.66; N 17.11; F 4.46. PRI mme R 3. 7- / 3- / 4- (p-fluoride zoyl) -piperidino / -propyl / -theophylline 7- / 3- / 4- (p-fluorobenzoyl) -piperidine and 16.5 In the solid state, 7- (3-chloropropyl) -theophylline is thoroughly mixed and the e is heated in a round-bottomed flask on an oil bath (SO) At this, a clear melt is first formed and then crystals form, which transfer to a solid mass. after 10 minutes, it is allowed to cool, dissolved in acetic ether, and the solution is mixed with 2 K. hydrochloric acid, the dark oil separating from the organic phase, which after a night has stood for a night after recrystallization from 100 ml of carbon chloride mixture, 7.4 g (43.5%) of the product is obtained with a melting point of I4-119 ° C. The following is calculated: C 61.81; H 6.13; N 16.38; F 4.45 C, (m.w. 427.5) Found: C 6t, 90; H 6.01; N 16.40; F 4.29. Primer 4. Similarly, 7- / 2- (4- (chlorobenzoyl) piperazine / -2-ethyl / -theophylline with a melting point of 125-12 bs (yield: 45%). Example 5. Hydrate 7- / 3- / 4-0 - Fluorobenzosh1) -piperidino / -2-hydroxy -progosh / -theofstlin. A mixture of 8 g of 7- (3-chloro-2-hydroxy-propi-theophylline and 12.16 g of 4- (i-fluorobenzoip) -piperidine is melted in an oil bath. For 1 hour at and maintained at this temperature for 3 In this case, the viscosity of the initially flowable melt transparent continuously increases after 30 minutes, after being vigorously stirred, the mixture is treated with acetic ether for 30 minutes, the precipitated hydrochloride of 4- (p-fluorobenzyl) -piperidine is separated by filtration, the solution is mixed with 2. hydrochloric acid. After separation of the phases, the aqueous phase is shaken twice with uksu ethereal ether, alkalinized by addition of concentrated sodium hydroxide and extracted twice with ethyl acetate. The substance crystallized out of the extract, which was recrystallized from chloroform and ethanol (9: 1) and dried under high vacuum.The indicated compound is obtained with a melting point of 132138 ° C (52% yield) Calculated,%: C 57.26; H 6.12; N 15.18; F 4.12. (M.461.5). Found,%: C 57.54; H 6.15; N 15.52; F 4.10. Example 6 7- (2- / 4- (2-furyl) -1-piperazinyl / -2-ethyl / -theophylline. A mixture of 2 g (8.26 mmol) of 7- (2-chlorostil) -theophylline and 3.78 g (21 mmol) of N-furoyl-2-piperazine was melted in an oil bath for 3 hours and maintained at that temperature. After cooling, the solidified mass is dissolved in methylene chloride. The solution is extracted with water and then shaken twice with hydrochloric acid (10%). The combined aqueous phases are alkalinized with sodium hydroxide solution and extracted again with methylene chloride. The resulting extract is dried over MgSO4 and concentrated. The residue is washed twice with water at 60 ° C and again dissolved in methylene chloride. After drying over MgSO4, evaporation of the solvent, and recrystallization from ethyl acetate, a pure product is obtained with a melting point of 142-144 ° C (yield 48.5%). Calculated,%: C 55.95; H 5.74; N 21.75. (m. weight. 386.41) Found,%: C 55.86; H 5.84; N 21.71. EXAMPLE 7: 7- (3- / 4- (2-furoIl) -1-piperazine / -2-hydroxy-propyl / -theofilline. A mixture of 4 g of 7- (3-chloro-2-hydroxy-prop) -teoafine and 6.6 g of N- (2-fluoro) I-perazine is heated at 120 ° C for 1 h. The reaction mixture is dissolved in chloroform and extracted with water. The organic phase is dried over
    S11
    MgSOj and thicken. After recrystallization from isopropanol, 2.8 g (45.5%) of product with a melting point of 161-163 ° C are obtained.
    Calculated,%: C 54.80; H 5.81; N 20.18; About 19.12.
    CJtLJi.Q, (m.ves. 416.44) Found, C 54.66; H 6.01; N, 99.
    biological tests of the compounds described are reported. The table summarizes the histaminolytic activity and acute toxicity of the compounds in examples 1-7 and the known compound 7- / N-metip-N- (/ 3-3,4-trichloro7
    phenylethyl) -3-aminopropl / -theophylline 1.
    Histaminolytic activity was investigated on anesthetized guinea pigs by determining the dose at which bronchospasm caused by intravenous administration of 8 mg / kg of histamine decreased by 50%. Acute toxicity was determined in mice after intravenous administration.
    From the table it can be seen that the proposed compounds have less toxicity and a greater breadth of therapeutic effect than the known
    7- / N-methyl-K - (- 3,4-dichlorophenylethyl) -aminoprosh1 / -theofiplin.
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING THEOPHYLLINE DERIVATIVES of the general formula where R is hydrogen, hydroxyl; X is nitrogen, a SI group;
    Y is oxygen, carbonyl;
    Ar - 4-methylphenyl, 4-chlorophenyl, 4-fluorophenyl, furyl;
    η - 0.1, characterized in that the compound of General formula
    About SNg ~ SNg ~ HQl
    CHj wherein R and η are as defined above, in £ - halogen, is reacted with a compound of general formula ίώζ2 / χ- Ar ~ V wherein X, Y and Ar are as defined knowledge g cheniya melt at 90-120 ° C for 1 -3 h, and the target product is isolated in free form. *
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