• 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 derivatives of heterocyclic condensed compounds, in particular those of theophylline I, substituted at the 7th position by the group AX, where A is C, -Ci-alkylene (straight or branched) or (OH) -CH-; X group, -0-N C-C-; R, - pr my or branched C, -C, -alkyl, which may be substituted by halogen, HE; Su-C-cycloalkyl; 2-ethoxyethyl; carbonyl-C, -Cd-alkyl; aminoalkyl formyl - (CH i -CHj-N, with or 2; R and I or straight or branched C g C alkyl, or RJ + H together with nitrogen form a piperidine, pyrrolidine or piperazine cycle, in which the nitrogen can be replaced SI; or R, is OH, benzyl, phenyl, not- or substituted by chlorine or OH-group; 2,2-diphensh1ethyl, or their acid addition salts, which have an antitussive effect. a new class has been obtained. They are synthesized from theophylline and the corresponding halogen-AX compound in the presence of base of theophylline or alkaline salt in an inert solvent at the boil. Tests I show that they are of low toxicity and have a better effect against coughing than codeine.
    公开号:SU1297729A3
    申请号:SU843703572
    申请日:1984-02-23
    公开日:1987-03-15
    发明作者:Карбонитш Деже；Сомор Мариа；Хейа Гергей；Свобода Ида；Кишш Пал；Генци Чаба；Палоши Эндре；Ковач Габор；Кун Юдит；Минкер Эмиль；Вираг Шандор；Шебештьен Дьюла；Сютш Тамаш
    申请人:Хиноин Дьедьсер Еш Ведьесети Термекек Дьяра Рт (Инопредприятие)；
    IPC主号:
    专利说明:

    ,
    The invention relates to a process for the preparation of new theophylline derivatives with valuable pharmacological properties.
    The purpose of the invention is a method of obtaining new theophylline derivatives with antitussive action with less toxicity than known derivatives with antitussive properties.
    Example 1. A mixture of 20.2 g of theophylline sodium, 300 ml of isopropanol and 13.2. g 3-chloromethyl 5-methyl-1,2,4 oxadiazole is boiled for 10 hours with stirring. After the treatment, 20.5 g - (74.2%) 7 are obtained (5 methyl-1,2,4 oxadiazole G- psh) methyl theophylline, m.p., 135,136 ° C (methanol).
    EXAMPLE 2 A mixture of 2.92 g of 3- (2-x. Propylethyl) -3-methyl-, 2.4: oxadiazole, 50 ml of isopropanol and 4.0 g of theophylline sodium is boiled over 8 It gives 5.3 g (91%) (5-methyl 1,2,4-oxadiazol-3-yl) -ethan-1-yl theophylline, which is liquid at 113 (water).
    14 ° С
    Similarly, the following compounds are prepared from the corresponding starting materials:
    7- (5-hlsrmetil- 1, 2 ,, 4-oxadiazol-) methyl teofshin 5T.sh1. 146--148 C;
    7- (5-diesel 1X1 aminomethyl 1,2,4-oxadiazol-3-yl) methyl theophylline, m.p. 68 - 70 ° C;
    7- (5-diethylaminomethyl 1, 2.4 - ox diazol-3-yl) meteshth theophylline hydrochloride IHD, so pl. 208 - 210 ° C;
    7- (5- | 2 diethylaminoethane- 1,2,4 - oxadiazole - 3-yl) methyl theophylline maleipat, mp 127 - 128 C;
    7- (5-- 2-diethylaminoethan-1-yl | -1, 2,4-oxadiazole 3 yl) methyl theophylline, m.p. 69 - 70 ° C (cyclohexane);
    7-L 5- | 2-diethylamino-ethan-1 yl | -1, 2,4-oxadiazole-3-nl) methyl theophylline, ie 78 -
    7-. (5-2 diethylaminostan-1-yl -1, 2,4-oxadiazol-3 yl) methyl 1-theophylline malelenate, m.p. 126 -
    7- (.5-butan-3-one-1 -yl -1,2,4-oxadiazol-3-yl) methyl theophylline, m.p. 135-140 ° C (ethanol);
    7 t (5 W-diethylaminopropan-1-yl} - 1,2,4 oxadiazol-3-yl) methyl theophylline-maleate, m.p. 119-321С;
    7- (5- {4-diethylaminobutan-1-yl - 1,2,4-oxadiazol-3-sh1) methyl theophylline maleate, mp, 130-132 ° C;
    five
    five
    0
    five
    thirty
    40
    j
    Q
    55
    162 С
    ) 2
    7- 2- (5-methyl-1, 2, 4-oxadiazole-3-yl) ethan-1-yl j theophylline, m.p. 115 - 116 C (ethyl acetate);
    7- 2 (5-methyl-, 2,4-oxadiazol-3-yl) ethan-1-yl theophylline, t, pl. 113 - 1150 (ethanol);
    7- 2-hydroxy-3- (3-methyl-1,2,4-oxadiazol-3-yl) propan-1-yl theophylline, m.p. 148 - (ethanol);
    . 7- 2-hydroxy 3- (5- 2-piperidinoethane-1-yl) -1,2,4-oxadiazol-3-yl) propan-1-yl theophylline, m.p. BY -
    (5--5 2 - diethylaminoethan-yl} - 1, 2,4-oxadiazole - 3 yl) propan-1-yl teofillin-maleiate 5 mp, 134-113 C;
    7- 4- (5-methyl 1, 2, 4-oxadiazol-3-yl) butan-1-yl theophylline, m.p. 131 - 132 C (ethanol) 5
    7 - (4-1 2-piperidine ethan-1 -yl) -1,2,4-oxadiazol-3-yl) butan-1-yl theophylline maleate, m.p. 46-147 ° C;
     (5 methyl-1, 2, 4-oxadiazol-3-yl) pentane-ILI theophylline, t, pl.
    7 2-hydroxy-3- (5-phenyl-, 2,4-oxada-d, azol-3 yl) propan-1 -yl or theophylline, t, pl. 179 - (ethanol);
    7- (5-hydroxy-1,2,4-oxadiazol-3-yl) - methyl theophylline, m.p. 206–207 C.
    In a similar manner, the compounds shown in Table 1 are prepared.
    PRI me R 3, a Mixture of 8.0 g of anhydrous theophylline 5 420 g-w of propanol, 7.0 g of potassium carbonate and 13.2 g of 3- (2-chloromethyl) -5-methyl-152.4 oxadiazole bale t while stirring for 16 hours. The solvent is filtered off, the residue is crystallized from water, 18.4 g of 7- (5-methyl-1,2,4-oxadi-) methyl theophylline are obtained, mp 133 ° - 135 ° C. ,
    PRI me R 4, Mixture IB, O g of anhydrous theophylline, .350 ml of propanol, 4.0 g of sodium hydroxide and 15.6 g of 3- (2-chloroethyl) -5-ethyl-1,2,4 oxadiazo - the mixture was boiled under stirring for 12 hours. After evaporation, the residue was crystallized from water; 17.3 g of 7- (5-ethyl-1,2,4-oxydiazol-3-yl-ethyl) theophylline were obtained, with a mp. 113 - 114 s.
    The sedative cough effect and toxicity of the compound-3 obtained by the proposed method, in comparison with the known agents, prenoxidazine and codeine, are presented in Table 2. The sedative cough effect was demonstrated on guinea pigs (the cough was caused by iigal tsni 15% citric acid) one hour after administration of the test compound (50 mg / kg intramuscularly) and expressed as a percentage of the control.
    As can be seen from table 2, theophylline derivatives obtained by the proposed method have low toxicity and high antitussive action (Q).
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining 7-substituted theophylline derivatives of the general formula
     N-Oi
    . I
    sn
    .N-m.
    R |
    N
    H
    where A is straight or branched C — C is alkylene or —CHH — CH 2 SN — CH -; R. - my pr or branched with, - S, th - hook,
    possibly substituted by halogen or sigroup, Cj.- Cg-cycloalkyl, 2-ethoxyethyl, carbonylalkyl, where alkyl has 1 - A carbon atoms, or amino alkyl of formula - (CH), -CH2 -N R R,
    Rj p IX,
    branched C, - C-alkyl, or
    and R, is hydrogen or direct
    RJ and H together with the common nitrogen atom form a piperidine, pyrrolidine or piperazine cycle, where the nitrogen atom can be replaced by methyl, or R. is an unsubstituted or substituted chlorine or oxy group phenyl, oxy, benzyl, 2,2-diphenylethyl or their acid additive pharmaceutically acceptable salts, o tl and h and u and sh, so that the compound of the general formula
    N-4R,
    where A and R (have the indicated meanings; X is a halogen ,.
    subjected to interaction with theophile-. in the presence of a base or with an alkaline salt of theophylline in an organic solvent at the boiling point of the reaction mixture, followed by isolation of the desired product in the form of a base or salts.
    Priority featured:
    01.21.83 at
    R, is benzyl, 2,2-difenshtetil, A - all values;
    03/12/82 for all other values.
    - CH, CH,
    - (CH) CH,
    - CH (CH,) 2
    - (
    - CHjCHCCH,)
    - sssnr
    - (CHj) CH,
    - (CHj) SNS
    Cycloamil
    Table 1
    130 127 126 130 125
    132 114 105 111
    .г. СН „
    Cyclohexyl
    - (CH,) 2
    sn.
    -SN
    .
    sn - (snr shsnssnrz
    CH, - (s)
    sn - (snL- O
    CHj - (CE (
    sn.
    (-CH,
    CH, - (CH,), NQ
    CH, - (CH,), N
    CHj- (CH), N (С
    CHjP-CI-C H
    CHjo-HO-CgH
    (CH)
    (CH) s- (CH) 4CH
    (CHj,) Cyclohexyl
    (CH) .- CHjCl
    (CH) (CH,) C1
    (CH) (CH2), C1,
    (CH,) jCH (OH) CH3
    Continuation of table 1
    112 - 113
    212 - 213 (hydrochloride)
    2d3 - 206 (Hz hydrochloride)
    212 - 213
    (hydrochloride)
    96 - 98
    217-218; 212 - 213
    (hydrochloride)
    78 - 80 (maleate) .; 127 - 128
    87 - 89
    203 - 204 (pvdrokhlory
    206 - 208
    (hydrochloric
    119 - 121 (maleate)
    181 - 183 201 - 202 OF - 114
    106 - 108 108-109
    134 -138
    140 -143
    124 -127
    129 -130
    (CHP, CHjNCC Hj),
    (CH) (CE NHCHCCH,)
    (CH), (CHp.NQ
    (CH,), (CH,), N;
    (CH,), (CH), N o
    (CE ,, (СгНгг)
    (SNS
    (CHj,) N
    (CH.,), N (
    Cghp
    p - C1 - CgH
    o-HO-CgH
    -HE
    CH,
    Cyclohexyl
    (CH) C1
    (CE (
    (CH), (CH,), NQO (CE) (CE) TCE (CE
    (CH) s (CH) i N-N CH,
    203-205 (hydrochloride)
    125 - 127 (maleate)
    207 - 210 (hydrochloride)
    204-205 (hydrochloride)
    180
    (hydrochloride)
    119 - 120
    (maleate)
    165
    (dimaleinat)
    203 - 204 (hydrochloride)
    200 - 201
    (hydrochloride tnd)
    183 - 185 190 - 191 202 - 205 205 - 206 120 - 122 97 - 98 111 - 112
    158 - 159 (maleate)
    134 - 136 (maleate)
    128 - 130 (maleate)
    171 - 172
    (dimaleinat)
    table 2
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    同族专利:
    公开号 | 公开日
    EP0089028B1|1988-05-25|
    HU190377B|1986-08-28|
    FI72320B|1987-01-30|
    PL240990A1|1985-01-02|
    JPS5910586A|1984-01-20|
    DK118083A|1983-09-13|
    US4565817A|1986-01-21|
    NO159794C|1989-02-08|
    NO830843L|1983-09-13|
    GR78450B|1984-09-27|
    BG60434B2|1995-03-31|
    SU1322981A3|1987-07-07|
    SU1344756A1|1987-10-15|
    PL249225A1|1985-06-04|
    SK170183A3|1995-09-13|
    PL138857B1|1986-11-29|
    DD207377A5|1984-02-29|
    FI72320C|1987-05-11|
    PL138550B1|1986-10-31|
    SK278001B6|1995-09-13|
    DK118083D0|1983-03-11|
    DE3376749T2|1988-06-30|
    FI830831A0|1983-03-11|
    JPH0532395B2|1993-05-14|
    DK161385B|1991-07-01|
    IL68093D0|1983-06-15|
    EP0089028A1|1983-09-21|
    ES534146A0|1985-07-01|
    FI830831L|1983-09-13|
    DE3376749D1|1988-06-30|
    ES8504195A1|1985-04-16|
    DK161385C|1991-12-16|
    NO159794B|1988-10-31|
    ES520860A0|1985-04-16|
    ES8505999A1|1985-07-01|
    AT34575T|1988-06-15|
    引用文献:
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    HU198933B|1987-11-02|1989-12-28|Chinoin Gyogyszer Es Vegyeszet|Process for producing new xanthine derivatives and pharmaceutical compositions comprising same as active ingredient|
    HU206884B|1990-11-22|1993-01-28|Chinoin Gyogyszer Es Vegyeszet|Process for producing purin derivatives and pharmaceutical compositions containing them|
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    US20070215201A1|2006-03-17|2007-09-20|Lawrence Curtin|Photovoltaic cell with integral light transmitting waveguide in a ceramic sleeve|
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    WO2009140517A1|2008-05-14|2009-11-19|Hydra Biosciences, Inc.|Compounds and compositions for treating chemical warfare agent-induced injuries|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    HU82762A|HU190377B|1982-03-12|1982-03-12|Process for preparing theophyllinyl-alkyl-oxadiazoles|
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