• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:
    The method of producing xanthine derivatives of the general formula I vr RI-0, / (JHi where one of the U and Rg radicals is methyl, and the other is a group of the general formula - () where R - is hydrogen, unsubstituted C-C acyl or substituted by phenyl, halo-phenyl, C, -C4) -alkylphenyl,) -alkoxyphenyl, hydroxyphenyl, nitrophenyl, aminophenyl, cyclopropyl, furancarbonyl or tyrphenecarbonyl group, or their acid addition salts, characterized in that the compound of the general formula O II-o2 2 has 2 O2. of the radicals R, is hydrogen, and the other is methyl, is subjected to with a compound of the general formula III (L x CCH 3) where R has the indicated values, X is chlorine, bromine, followed by isolation of the desired product as the base or acid addition salt, or acylation of the compound of formula 1, where R is hydrogen , to obtain a compound of formula 1, wherein said acyl, or by hydrogenating a compound of formula I, where, QD is substituted with nitrophenyl, to obtain a compound of formula I, where acyl is substituted with aminophenyl, and the desired product is added as a base or acid addition salt.
    公开号:SU1079176A3
    申请号:SU802925604
    申请日:1980-05-26
    公开日:1984-03-07
    发明作者:Фрибе Вальтер-Гунар；Тиль Макс；Кампе Вольфганг；Вильхельмс Отто-Хеннинг；Роеш Андроники
    申请人:Берингер Маннхайм Гмбх (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of new xanthine derivatives possessing bronchodil to tsimi properties, and can be used in medicine. The known reaction of the alkylation of purine derivatives to alkyl halides is carried out, in particular, when heated in an organic solvent, such as isopropyl alcohol, at the boiling point l. The purpose of the invention is a method of obtaining new xanthine derivatives with valuable bronchodilatory properties. The goal is achieved by the fact that according to the method of obtaining xanthine derivatives of the general formula ..c, II / 1 Rg in where one of the radicals is p methyl, and the other group of the general formula is (eH2) 5- (NKz where RJ is hydrogen, unsubstituted acyl or substituted by phenyl, halophenyl, () -alkylphenyl, (Cf-C4) -alkoxyphenyl, hydroxyphenyl, nitrophenyl, aminophenyl, cyclopropyl, furancarbonyl or thiophenocarbonyl group, or their acid addition salts, or the body, or in the form of the body; of the radicals are hydrogenated, and the other is methyl. is reacted with a compound of the general formula X- (CH2) where R has the indicated values; X is chlorine, bromine, followed by isolation of the desired product as a base or an acid additive salt, or acylation of a compound of formula 1, where hydrogen, to obtain compounds of formula 1, where R is the specified acyl, or by hydrogenating a compound of formula 1, where Rj-acyl, substituted by nitgo, to obtain compounds of formula 1, where the substituted amino, and release J - acylation of the target product as a base or acid additive salt. Example 1. 7 - ((4-fluorobenzamido) piperidino-propyl theophylline. To a solution of 0.46 g (0.02 mol) of sodium in 100 ml of isopropyl alcohol. Add 3.6 g (0.02 mol) of theophylline, kip. 10 g under reflux, cool and add 6.5 g (o, 22 mol) (4-phorbenzamido) piperidine propyl chloride. After 6 h stirring and boil, allow to cool, then filter, and the npONTJBa precipitate with 2N sodium hydroxide solution and water and recrystallized from ethyl acetate to obtain 5.8 g of 7- {s- - (4-fluoro-benzamido) piperidino propyl theophylline (66% of theory) with a mp of 192-193 pp. Example 2. Analogous m manner as described in prilgere 1 "the compounds listed in Table L. 1.-. Table 1
    b) 7- 3- 1,4- (4-tert-butylbenzamido piperidino propyl theophylline from theophylline and 3- 4-: 4-tert-butyl benzamido piperidinoTpropyl chloride
    (163-165)
    47 (ethyl acetate ligroin)
    in 7- З- (4-acetamidopiperidino) propyl1-theophylline from theophylline and 3- (4-acetamidopiperidine)) - propyl chloride
    d) 4- (2-methylbenzamido) piperidine qj-propyl teofillin from theophylline and 3-4 (Z-methyl ethylbenzamido) piperidine propyl chloride
    e) 7- 3- 4-phenylacetamido; piperidino) propyl theophylline from theophylline and 3- {4-phenylacetamido-piperidino) propyl chloride
    e) (4-benzamidopiperidino propyl -theobromine from theobromine and 3- (4-benzamidopiperidiio) -propyl chloride
    g) 1- {3-G4- (4-fluorobenzamido) piperidine-propyl theobromine from theobromine and (4-fluorobenzamido) -piperidino propyl chloride
    h) 4- (2-methoxybenzamido) piperidi but propyl theophylline hydrochloride from theophylline and 3- | 4- 2-methoxybenzamido) piperidino} propyl chloride
    Primerz, 7- | 3-G4- (2-furancarbonamilamido) piperidine propyl theophylline. - To a mixture of 8.0 g (0.025 mol) of 7-z-4-aminopiperidino) propyl theophylline, 100 ml of an IV solution of sodium hydroxide and 50 MP of tetrahydrofuran is added dropwise a solution of 7.8 g (0.06 mol) 2 α-furancarbonyl chloride in 30 Nft of tetrahydrofuran, stirred for 5 hours at room temperature, filtered and recrystallized from methanol.
    This gives 5.0 g of 4- (2-furancarboxylamido) piperidine-propyl | theophylline (49% of theory) with t, pl, 195196 0,
    Use as a starting material (4-aminopiperidino propyl theophylline can be obtained as follows: a mixture of 15.0 g (0.1 mol / 4-oximinopiperidine hydrochloride, 55 ml {0, 4 mol) three ethylamine and 11 ml (s, 11 mol) 1-bromo-3-continued Table 1
    155-157
    25 ((ethyl acetate ligroin)
    37
    182-183
    With and zopropilovy
    alcohol
    36
    158-160 (methanol ether)
    43
    172-173
    (isopropyl alcohol)
    48
    -196-198 ethyl acetate)
    38
    254-255 (methanol)
    -chloropropane is refluxed for 16 hours, cooled, filtered and the filtrate is concentrated. 15.8 g of 3- (4-oximino-piperidino) propyl chloride {84% of theory) are obtained in the form of oil,
    To a solution of 3.4 g (0.15 mol) of sodium in 350 ml of nopropyl alcohol was added 26.6 g (0.15 mol) of theophylline, boiled under reflux for 10 hours, and added 28.0 g
    (0.15 mol) 3- (4-oximinopiperidino) propyl chloride, heated under reflux for 16 hours, concentrated, the residue is treated with methylene chloride, passed through with water and concentrated. After trituration with ether, 28.5 g are obtained (4-hydroxyminopiperidine) Propyl theophylline (57% of theory) with m.pl, 167-170 ° C,
    A solution of 6.7 g (0.02 mol) of this
    Compounds in 150 ml of methyl alcohol and 150 ml of tetrahydrofuran are hydrogenated in the presence of 5 ml of Rene nickel at room temperature and a hydrogen pressure of bar. After termination of the absorption, hydrogen is filtered and concentrated. This gives 6.3 g of 7a) 7- fs- 4- (2-hydroxybenzamido piperidine propyl theophylline from 7- {3- (4-amino-piperidino) propyl theophylline and salicylic acid chloride
    b 7-W- (4-cyclopb opancarbonylamido-piperidino) propyl theophylline from 7-3m-4-aminopiperidino propyl theophylline and chloroanhydride Yes cyclopropanecarboxylic acid
    in 7- (s- (4-nitrobenzamido} piperidinopropyl theophylline from (4-aminopiperidine) propylTeofillin and 4-nitrbenzoyl chloride
    4- (2-thiophenecarboxamido) piperidino propyl theophylline from 7- {3- (4-amino-piperidino) propylJtheophylline and 2-thiophenecarbonyl, chloride f iijp and 5.7 - {3-4-14-aminoben3amido piperidino propyl 7teofillin. A mixture of 4.8 g (0.01 mol) of 7- {3- 4- (4-nitrobenzamido) piperidino propyl theophylline, 150 ml of methyl alcohol, 150 ml of tetrahydrofuran and 3 ml of Rene nickel is hydrogenated at room temperature TeitoepaType and hydrogen pressure of 1 bar. The mixture is then filtered, the residue is taken up with dilute hydrochloric acid, extracted with ether, basified and filtered. After recrystallization from methyl alcohol, 2.7 g of 7- (4-aminobenzamido) piperidino propyl} theophylline is obtained (60% of theory) with m.p. 203-205 C. Example 6. 7-СЗ- (4-benzamido piperidino) propyl theophylline-hydrochlor
    (4-aminopiperidino propyl α-theophylline 0% of theory) as an oil.
    Example 4. In a similar manner as described in Example 3, the compounds listed in Table 2 are prepared. 2
    table 2
    210-213
    38
    (and.zopropyl. alcohol
    182-183
    42 (methyl alcohol)
    44
    220-222 (methyl alcohol)
    246-248
    68 X methyl alcohol) A solution of 1.0 g of 7-z-4-benzamido-piperidino propyl tbofillin in 20 ml of ethyl acetate is mixed with an excess amount of ethereal hydrogen chloride solution, filtered and the precipitate is washed with acetone and ether. 0.95 g of 7-GZ- (4-benzamido-piperidino-propyl-2-theophylline-guide) ochloride is obtained (88% of theory) with m.p. above 2900s: Pr and N- er 7. (4-benzamidog piperidine) propyl theophylline. To a solution of 0.46 g (0.02 mol) of sodium in 100 ml of isopropanol was added 3.6 g (o, 02 mol) of theophylline, boiled for 10 minutes under reflux, cooled, added 3.2 g (0.02 mol) 1-bromo-3-chloropropane, boiled for 6 hours, treated with 4.1 g (o, 02 mol) 4-benzamidopiperidine and 6.0 g (o, 06 mol) of trimethylamine, kip t for another 6 hours, filter, evaporate the filtrate in vacuo and crystallize from ethyl acetate. Get 2.95 g (-benzamidopiperidino) propyl theophylline 135% of theory) with so pl. 176178 BC
    The bronchodilatory effect of the compounds prepared according to the invention was determined using the following procedure. Animals under pentabarbital anesthesia (40 mg / kg intraperitoneally administered the U-cannula to the trachea and the venous cannula to. V. Jugular is connected to A. caret is the cannula was inserted into the measuring chamber and blood pressure was recorded through the measuring bridge. Air was injected into the animal through a pump : to rats 1–2 ml 64 times per minute, to guinea pigs 7–15 ml 72 times per minute. When bronchraspasm develops, the volume supplied is not COH: it will completely go to the lungs and its excess will be released by lateral abduction. spirit has been measured and The maximum bronchospasm was obtained by overlapping the lead to the animal and supplying the entire volume to the element to be measured. Every 30 seconds, the excess air discharge valve was shut off through the relay and the whole volume was delivered to the lungs to open the bronchus and alveoli and to achieve normal gas exchange. (% of bronchial volume (x) was calculated by the following formula:
    in - and
    X x 100
    C - a
    where a- is the deviation of the recorder at the beginning of the experiment, mm;
    B - deviation height at a certain moment, mm; с - maximum deviation after the overlap of the respiratory abduction to the animal, mm. Preparation of antisera. The antigen is twice crystallized egg albumin. Equal amounts of the antigen solution in the physiological solution of sodium chloride and the Freund's complete pharmaceutical preparation give an emulsion, which is injected with 2 x 0.5 ml intramuscularly of male male guinea pigs. Animals are exsanguinated and reserve serum is stored at. For passive sensitization to guinea pigs, 24-48 hours prior to the onset of bronchospasm, 0.5 MP serum diluted 1:50 is injected intravenously.
    The inhibition of bronchospasm induced antigenbm in passively sensitized guinea pigs is presented in Table 3.
    权利要求:
    Claims (1)
    [1]
    The method for producing xanthine derivatives of general formula I wherein wish to set up hydrogen and the other 'scrap, is reacted a compound of general formula III yavmetis x- (CH 2) 5 -1 (2Y un ^ s where one of the radicals R, and Rg is methyl and the other - a group of the general formula where R- ^ is hydrogen, unsubstituted C 2 -C ^ acyl or substituted with phenyl, halo I * where R ^ has the indicated meanings, • X is chlorine, bromine, followed by isolation of the target product in the form of a base or an acid additive salt, or acylating a compound of formula 1, where R ^ is hydrogen, to obtain a compound of formula 1, where Unspecified acyl, or by hydrogenation of a compound of formula I, where (C- ^ sHzyl substituted with nitrophenyl, to obtain a compound of formula I, where R 3 is acyl substituted with aminophenyl, and isolating the desired product as a base or an acid addition salt.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB1133989A|1964-12-08|1968-11-20|Chugai Pharmaceutical Co Ltd|Theophylline derivatives, their salts and process for preparing the same|
    DE2401254A1|1974-01-11|1975-11-27|Boehringer Mannheim Gmbh|NEW DERIVATIVES OF N HIGH 6 SUBSTITUTE ADENINES|
    DE2550000A1|1975-11-07|1977-05-12|Boehringer Mannheim Gmbh|NEW PURIN DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION|
    US4061753A|1976-02-06|1977-12-06|Interx Research Corporation|Treating psoriasis with transient pro-drug forms of xanthine derivatives|
    DE2804416A1|1978-02-02|1979-08-09|Boehringer Mannheim Gmbh|NEW PURINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
    EP0011399A1|1978-11-11|1980-05-28|FISONS plc|N-substituted theophyllines, processes for their preparation and pharmaceutical compositions containing them|US4426383A|1980-09-04|1984-01-17|Eisai Co., Ltd.|Theophylline and theobromine derivatives|
    CH648559A5|1981-07-20|1985-03-29|Siegfried Ag|THEOPHYLINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF.|
    FR2558162B1|1984-01-17|1986-04-25|Adir|NOVEL XANTHINE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|
    US4548939A|1984-10-01|1985-10-22|Janssen Pharmaceutica N. V.|1H-Indol-3-yl containing 1,3-dimethyl-1H-purine-2,6-diones|
    US7550468B2|2000-07-28|2009-06-23|Ing-Jun Chen|Theophylline and 3-isobutyl-1 methylxanthine based N-7 substituted derivatives displaying inhibitory activities on PDE-5 phospodiesterase|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE19792922159|DE2922159A1|1979-05-31|1979-05-31|NEW XANTHINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|
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