• 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:
    This invention provides certain 4-substituted benzamide derivatives, their pharmaceutical formulations, and their use as anticonvulsant agents.
    公开号:SU1750419A3
    申请号:SU884355259
    申请日:1988-02-17
    公开日:1992-07-23
    发明作者:Ерл Бидл Эдвард；Вейн Робертсон Дэвид
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to organic chemistry, and in particular to a method for the preparation of new derivatives of 4-substituted benzamides of the formula where R, R 2 is hydrogen or (C, -C 3 ) alkyl;
    R 3 - (C, -C 3 ) alkyl, o H 3 C
    RrO-C-NH-O
    N L C F • group CF 3 , —CN, —SCC ^ —C ^) alkyl or NR Z R 3 ;
    (C, -C 3 ) alkyl, which have anticonvulsant activity and can be used in medicine.
    Known 2-cyanobenz-2,5 ~ dimethylanilide, which when used as an anticonvulsant agent, is insufficiently active.
    The aim of the invention is to develop an affordable method for producing compounds (I) that exhibit high anticonvulsant activity.
    Example 1. Y- (2,6-dimethylphenyl) -4- (trifluoromethyl) benzamide ..
    A solution of 25 g of 4-trifluoromethylbenzoyl chloride in tetrahydrofuran is added to 14.5 g of 2,6-dimethyliniline and 16.7 ml of tetrahydrofuran in tetrahydrofuran. Reaction mixture
    CW Ah! νοα / 1 <n) '175 stirred at ambient temperature all night, quickly cooled and filtered. The filtrate was evaporated in vacuo and the residue was dissolved in chloroform, washed successively with 1 M hydrochloric acid, 1 M sodium hydroxide, water and saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated in vacuo. Crystallization from methanol gives the target product in 85% yield, mp. 206 - 207 ° C.
    Calculated,%: C 65.52; H 4.81; N, 4.78. ''
    Found,%: C 65.62:; H 4.57; N, 4.88. .
    Examples 2-5. The following benzimides are prepared from properly substituted benzoyl chloride according to the procedure of Example 1.
    PRI me R 2. 4-cyano-I - '(2,6-dimethylphenyl) benzamide, yield 67%, so pl. 185 - 18 ° C.
    . Calculated,%: C 76.78 '; H 5.64; N, 11.19.
    Found,%: C 76.84; H 5.36; N, 11.11.
    Example Z.M- (2,6-dimethylphenyl) -1 -methylbenzamide, yield 83%, mp. 163 - 164 ° C.
    Calculated,%: C 80.30; H 7.16; N, 5.85.
    C <gH 17 fTO
    Found,%: C 80.47; H 7.02; N, 5.69.
    PRI me R 4. N- (2,6-dimethylphenyl) -4-methoxybenzamide, yield 94%, so pl. 168 - 170 ° C.
    Calculated,%: C 75.27; H 6.71; N, 5.49. .
    C 16 H 17 NO 2 Found,%: C 75.15; H 6.58; N, 5.19.
    Example 5. No.- (2,6-dimethylphenyl) -4- (methylthio) benzamide. Yield 76%, mp. 183 - 185 ° C.
    Calculated,%: C 70.81; H, 6.31; N, 5.16; S 11.82.
    c 16 h I7 nos
    Found,%: C 71.08; H 6.48; N, 5.19; S. 11.99.
    An example. 6 (dimethylamino) N- (2,6-dimethylphenyl) benzamide.
    4
    Preparation of N- (2,6-dimethylphenyl) 4-fluorobenzamide ..
    The intermediate compound is obtained in 68% yield from 4-fluorobenzoyl chloride, following the procedure of example 1, so pl. 180 - 181 ° C.
    Calculated,%: C 74.06; H 5.80; N, 5.76.
    C { 5 H 14 FN0
    On the
    Found,%: C 73.83; H 5.76; N, 5.76.
    The following products are obtained according to the method of example 6.
    PRI me R 7. N- (2,6-dimethylphenyl) -4- (ethylamino) benzamide, yield 56%, so pl. 145 - 147 ° C.
    Calculated,%: C 7b, 09; H 7.51; N, 10.44.
    47 8 Ζο '^' ζθ
    Found,%: C 75.86; H 7.27; N, 10.14.
    PRI me R 8. N- (2,6-dimethylphenyl) -4- (methylamino) benzamide, yield 35%, so pl. 163’- 164 ° С.
    . Calculated,%: C 75.56; H, 7.13; N, 11.01.
    C f6 H lg N 2 0
    Found; %: C 75.80; H 7.18; N, 10.99.
    PRI me R 9. N- (2,6-dimethylphenyl) -4- (methylropylamino) benzamide, yield 49%, mp 159 ~ 160 ° C.
    Calculated,%: C 78.99; H 8.16; N.9.29.
    C.19 Η 29N2O 2.
    Found,%: C 76.88; H 7.96; N, 9.29.
    The compounds of formula (I) are anticonvulsants with a large therapeutic ratio and a long duration. For these reasons, they are suitable for the treatment and prevention of seizures in mammals. The anticonvulsant compounds of the invention, unlike some known anticonvulsant benzamides, do not have genetic toxicity and do not cause hemolysis. Compounds are effective against tonic extension of seizures, seizures, apoplexy shock conditions caused by maximum electric shock and for these reasons should be useful for the treatment of generalized conditions: tonic-clonic seizures (epilepsy seizure), cortical 5 focal, complex-partial (temporal lobar epilepsy), simple private (local motor) and after traumatic in humans. Such activity is demonstrated in an evaluation test to prevent and reduce seizures caused by electric shock.
    When tested for the inhibition of electroshock-induced seizures (ES), the compounds to be tested are suspended in Arabian gum and administered for therapeutic purposes using the stomach tube of each of the 10 albino male mice of standard Cox breed (18-24 g) at the studied dosage level. 30 to 180 m after the introduction for therapeutic purposes, the mouse is subjected to electric shock lasting 0.1 s at 5'0 mA, applied through the corneal membrane. The animals are examined and evaluated immediately after electroshock for the presence of clonic, flexion tonic and extensor tonic seizures, or death, also ED 5Q . Determinations are made for each compound at a dose that inhibits the appearance of extensor-tonic seizures in half of the animals immediately after electroshock. 18 mA was usually enough. ' to provide tonic extensor cramps in about half of the control animals, at 50 mA almost all control animals (receiving only the inactive active part of the drug) died. The test results summarized in the table are reported as ED 5q values over the time of the found interval to ensure an optimal response after dosing.
    3D 5o data are oral dosages of the respective compounds necessary to inhibit the manifestation of tonic extensor seizures in one half of the animals. This measurement is carried out at the optimum time of action following the introduction of the compound. Compounds are compared with 2-cyanobenz-2,5-dimethylanilide (Hodd Compounds), which is a position isomer related to the cyano compound 5 of Example 2 of the invention. Compound
    Hodda is inactive at dosages of up to 300 mg / kg at any time after administration of the compound. In contrast, compounds 10 'I all exhibit biological activity at or below 225 mg / kg. Compounds I are classified as medium toxic.
    权利要求:
    Claims (1)
    [1]
    15 claims
    The method of obtaining derivatives
    4-substituted benzamides of the general formula wherein R 4 is CF 3 , CN, —S (C-alkyl,
    30 a compound of the general formula NR ^ R ^, where R ^ is “hydrogen or C ^ C ^ -alkyl; K 3 C 1 -C - ^ - alkyl; characterized in that the aniline derivative of the formula is acylated with a benzoyl compound of the general formula.
    45 r ^ -Xo / coci, where R, | has the indicated values of ilp, followed by isolation of the target product or in the case when R ^ -F, by treatment with the corresponding amine NHR ^ R ^, where R and R 2 has the indicated meanings
    Example Electroshockmg / kg * The time interval after dosing, min * 1 About 225 60 2 13,2 60 3 About 250 zo 4 fifteen thirty 5 About 75 180 6 3,6.5 120 7 2.45 60 8 2.0 120 9 .4.6 120 Hodd > 300
    * Oral dose at optimal exposure time after drug administration.
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    同族专利:
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    IL85425A|1993-02-21|
    PT86771A|1988-03-01|
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    AU597790B2|1990-06-07|
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    引用文献:
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    FR2224153B1|1973-04-04|1977-11-10|Upjohn Co|
    US4004029A|1974-05-13|1977-01-18|The Upjohn Company|Compositions and method for treating epilepsy and convulsions|
    IT1126509B|1979-12-07|1986-05-21|Medea Res Srl|BENZIMIDES WITH LOCAL ANESTHETIC AND ANTI-ARRHYTHMIC ACTIVITY, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|
    DE3042482A1|1980-11-11|1982-06-24|A. Nattermann & Cie GmbH, 5000 Köln|N-BENZOYL- -ANILINOALCANCARBONIC ACIDS, SALTS AND -ESTERS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM|
    US4379165A|1981-05-18|1983-04-05|Research Corporation|Anti-convulsant|
    US4629740A|1984-04-10|1986-12-16|Eli Lilly And Company|Anticonvulsant agents|
    US4638014A|1985-08-26|1987-01-20|Research Corporation|Anticonvulsant method and formulations|
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    KR890006573A|1987-10-26|1989-06-14|메리 엔 터커|N-phenylalkylbenzamide fungicides|
    IT1232252B|1989-02-22|1992-01-28|Rotta Research Lab|DERIVATIVES OF N N PHENYL BENZAMIDE WITH ANTI-ULTER AND ANTIALLERIC ACTIVITY AND PROCEDURE FOR THEIR PREPARATION|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US07/016,047|US4835181A|1987-02-18|1987-02-18|Anticonvulsant agents using cyano dimethylphenyl benzamides|
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