Method of producing the derivatives of n-phenylbenzamide or salts thereof

专利摘要:

公开号:SU1333234A3
申请号:SU843703326
申请日:1984-02-15
公开日:1987-08-23
发明作者:Затцингер Герхард；Геррманн Манфред；Фритши Эдгар；Вейерсхаузен Уте
申请人:Гедеке Аг (Фирма)；
IPC主号:

专利说明:

The invention relates to methods for preparing N-phenylbenzamide derivatives or their salts; biologically active compounds that can be used in medicine.
The purpose of the invention is the production of new derivatives of N-phenylbenzamide-less toxic and having a higher cytotoxic activity. Example 1. A-amino-H- (2-amino-phenyl) -benzamide.
In 22.7 g of o-nitroaniline dissolved in 130 MP of anhydrous diox, a solution of 30.4 g of p-nitrobenzoyl chloride in 150 ml of dry dioxane is added dropwise. Reaction end pu-
That heating under reflux - for 60 minutes. Cooled to
15 ° C, - (2-nitros1) enyl) -4- -nitrobenzamide in the form of crystals. After recrystallization from chlorobenzene, 39 g (83% of the theoretical) dinitro product with m, pl. 217-218 C. 3.9 g of dinitroprodukt is subjected to hydrogenation in 550 ml of dimethylformamide in the presence of 10 g of Rene nickel for one hour at and
2ati. The catalyst is filtered, the solvent is removed in vacuo and the desired product is recrystallized from ethanol. The yield is 20.2 g (66% of theory); m.p. ISO-ISl C. The solution can be converted into dihydrochloride, which forms a 4% aqueous solution, by means of a solution of chlorine hydrogen gas in ethanol. Mp. Dihydrochloride 340 ° C.
PRI mme R - 2. 4-Methylamino-H - - (- 2 -aminophenyl) -H benzamide.
4.535 g (0.03 mol) of 4-methylaminobenzoic acid, stirring together with 9.19 g (0.09 mol) of acetic anhydride, are heated for 1 h to. The crystals are separated by cooling the clear solution, which is sucked off and washed with ethyl acetate; The N-acetyl-4-methylaminobenzoic acid obtained (mp. 199–201 ° C, yield 62%) is converted into acid chloride by means of thionyl chloride in dioxane. The excess thionyl chloride is then removed with a small amount of dioxane in a vacuum, which is obtained by tinting with a tetrazolium salt of a jet pump. Absorption is measured in the reaction mixture. The concentration of the test compound is determined, which provides a 50% reduction in absorption (CA) compared to.
2.76 g (0.02 mol) of o-nitroaniline in 10 mp of dry dioxane are added dropwise and 4.04 g are added to the solution.




32342
(0.04 mol) triethylamine (as an HC1 binding agent). Then it is refluxed for 1 hour (reverse. After evaporation, 40 ml of water are added to the residue and extracted with methylene chloride. After the organic phase is concentrated, 4 ml of isopropanol are added and, after 30 minutes stirring, the crystals formed are sucked off,
5.1 g (55.6%) of H- (2-nitrophenyl) -4- (K-acetyl-M-methyl) aminobenzamide are obtained, m.p. 162 C. Received
15 With the product, the product is suspended in a small amount of ethanol and subjected to hydrolysis for seven hours with seven times the amount of concentrated hydrochloric acid at the boiling point
20 reaction mixture. The reaction mixture is concentrated to dryness and brought to crystallization by the addition of isopropanol, dissolved in 40 ml of water and basified with ammonia. After extraction
25 methylene chloride obtained 1.4 g (51%) of L- (2-nitrophenyl) -4-methylaminobenzamide with m.p. 187 ° C
2.71 g of K- (2-nitrophenyl) 4-methylaminobenzamide is dissolved in 300 ml of tet30 hydrohydrofuran and, with shaking, subjected to hydrogenation in the presence of René nickel. During the hydrogenation process, the temperature rises from 21 ° C, the catalyst is filtered off, the clear solution is evaporated.
are, the residue is recrystallized
0
from ethyl acetate. 1.3 g (56.5%) of 4- -methylamino-H- (2-aminophenyl) -Y-benzamide, m.p., 189 ° C. are obtained.
Biological testing of the proposed compounds: Experience in determining the cytoxic activity by calorimetry.
The test compounds are dissolved 5 in 10% dimethyl sulfoxide at a concentration of 500 µg / ml and their effect on leukemia is determined. L 1210 cells, In this case, the test samples are distributed in a nutrient medium in microtiter plates, mixed with a suspension of cells (approximately 2000 cells), and incubated in an atmosphere containing 5% carbon dioxide at 37 ° C for 3 days. Pos0
with control experiment, in which incubate the cells without the test compound.
The table below shows the compounds under study and their activity, expressed as a dose of CA.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining derivatives of N-α-fenylbenzamide General formula
About fH, / C-1QH- /
ten
where Rt is hydrogen, methyl,
or their salts, different
in that, the compound of the formula
SOS1
.Jit / jacpi CHUI oa
4-nitroimidazol-5-yl) - Q lynom formula
-methyl is charged
Comparison of the data in the table indicates a better activity of the proposed compounds, since they should be used in a lower concentration to achieve a 50% reduction in absorption.
In addition, the new compounds obtained by the proposed method have less toxicity than the known, i.e. their oral dose of LD d is 625 and 700 mg / kg of mouse, respectively, while the oral dose of LD of a known compound is 138 mg / kg of mouse.
Jit / jacpi chui oa
other formulas
where X is a nitro group or K-acetyl-K-methylamino group, is reacted with nitroanine 25 and the resulting compound of the formula
About tg (s-1an-x
hydrolyzed if X is N-acetyl-L-methylamino, followed by hydrogenation in the presence of Rane nickel to isolate the desired product in free form or, if R is hydrogen, as a salt.
thirty
Editor N. Egorova
Compiled by V. Volkova Tehred L. Serdyukova
Order 3853 / 58- Circulation 371 - Subscription
VNIIPI USSR State Committee
for inventions and. Discoveries 1.13035, Moscow, Zh-35, Raushsk nab., 4/5
Production and printing enterprise, Uzhgorod, st. Project, 4
Proofreader Not Kstrol

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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DE3305755A|DE3305755C2|1983-02-19|1983-02-19|

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