前苏联专利SU1402258A3 Method of producing derivatives of 5h-2,3-benzodiazepene or additive acid salts thereof

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专利摘要:
New 5H-2,3-benzodiazepine derivatives of the formula <IMAGE> I wherein R is phenyl having a trifluoromethyl or halogen substituent, R1 is methyl, R2 is hydrogen, R3 is methoxy and R4 is methoxy, and the pharmaceutically acceptable acid addition salts thereof, are potent tranquilizers.
公开号:SU1402258A3
申请号:SU792832177
申请日:1979-10-18
公开日:1988-06-07
发明作者:Кереши Ене；Ланг Тибор；Секели Йожеф；Андраши Ференц；Зольоми Габор；Борши Йожеф；Гольдшмидт Каталин；Хамори Тамаш；Сабо Габриелла；Месарош Жужа；Миглец Эржебет
申请人:Эдьт Дьедьсерведьесети Дьяр (Инопредприятие)；
IPC主号:

专利说明:

I The invention relates to a process for the preparation of new derivatives of 5H-2,3-; benadiazepine of the general formula
(I)
where R is -substituted or substituted by halogen, trifluoromethyl, one or two alkoxy groups with 1-4 carbon atoms, a phenyl or 2-furyl group; R - C, - C-alkyl; R is hydrogen or C-alkyl; R - C, - C-hydroxyl or
alkoxy; R is C-alkoxy, and in
when R is a 3,4-dimethoxyphenyl group, R is methyl, and R is an ethyl group, R and R each have a different meaning than the methoxyl group, or their acid addition salts that affect the central nervous system .
The purpose of the invention is to obtain new derivatives of 5H-2,3-benzodiazepine, which have a stronger effect on the central nervous system than the known structural analogues.
Example 1. 1- (4-Methoxyphenyl) A-methyl-5-ethyl-7,8-dimethoxy-5H-2, 3-benzodiazepine.
Ijl9 g (2.73 mmol) of 1- (4-methoxy-phenyl-3-methyl-4-ethyl-6,7-dimethoxy-2-benzopyrynium-perchlorate is suspended in 10 ml of methanol, heated to boiling and smoked with 0, 51 ml (10 mmol) of 98% hydrazine hydrate are mixed in and the residue is washed on a filter with water to give 0.83 g (2.35 mmol) of the dried product, which melts at 153-156 ° C. By recrystallization from 20 ml of etaiol, 0.705 is obtained g (2.0 mmol, 73.3%) of a white crystalline substance, which melts at 157-159 ° C. Cj ,, mol.m. 352.4.
Example 1, p. 2. 1- (2-Chlorophenyl) -4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine.
A mixture of 10.37 g (28.9 mmol) of 2- (1-ethylionon-4,5-dimethoxy-2-chloro
0
50
5 o
, g 5
0
benzophenone, 10.5 ml of glacial acetic acid and 2.65 ml of concentrated hydrochloric acid are heated with stirring to 95 ° C. After cooling to 60 ° C, 2.14 ml of 98% hydrazine hydrate is added in portions, To a solution whose temperature is raised to 85 ° C, a solution of 1.44 g of sodium hydroxide in 4.5 ml of water is mixed after 30 minutes then 10 ml of methanol. The solution is then poured into 130 ml of water, the separated 5H-2,3-benzodiazepine derivative is isolated. 9.04 g are obtained (88% of the product which melts at 129-131 ° C. C H ClNjO; mol. M. 356.9. The crude product is recrystallized from ethanol and it then melts at 147-1 49 C.
Rodanide recrystallized from isopropanol (mol. M. 425.92) melts at 169-171 C.
EXAMPLE 3. 1-Phenyl-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine (purification via rohanide).
To 1.2 g (approximately 2.8 mmol) of crude, obtained by the method of Example 1,1-phenyl-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine, is poured 1, 5 ml of 15% hydrochloric absolute ethanol (6 mmol HC1).
The orange solution is evaporated, the residue is dissolved in 5 ml of water and moistened with 0.5 g (6.6 mmol) of ammonium rhodanide, with the release of a hydrochloride acid salt. It is filtered, washed with 6 X 2 ml of water and then dried. 1.33 g of crude product is obtained which melts at 170-1 73 ° C. After recrystallization from absolute ethanol, m.p. 175-177 C. From the recrystallized rhodanide, it is possible to isolate the pure 5H-2,3-benzodiazepine derivative with alkali or ammonium hydroxide. mol.m. 340.4, melting point; begins to liquefy (ethanol-water).
EXAMPLE 4 1- (3,4-Dimethoxyphenyl) -4-methyl-5-ethyl-6-hydroxy-8-methoxy-5-5-2,3-benzodiazepine.
A. To a solution of 115 g (0.325 mol) of 1, 4-dimethoxyphenyl-3-methyl-4-et-7-methoxy-bN-2-benzopyran-6-one in 115 ml of glacial acetic acid at 80-100 ° C for 5 minutes and with stirring, 34.5 ml of 97% hydrazine hydrate are added dropwise. The solution is kept in a water bath in flow U02258
hour at 95-100 ° C, then by diluting the phenolic THflpoKctuibHofi group with 140 ml of a 2% aqueous solution of caustic, the following compounds are obtained: sodium and cooled. Produc- tion was precipitated. PRI me R 5. 1 - (3,4-Limethox 1-nodal 5H-2,3-benzodiazepine as cream colored crystals. They are filtered, washed with 4x50 ml of water and then dried. 111.7 g of crude product, cotophenyl) -4-methyl-5-ethyl-7-sec-butoxy 8-methoxy-5H-2,3-benzodiazepine.
Cr5-H, gKa04, mol.m.425.5, so pl. 130-132 ° C (50% ethanol).
EXAMPLE 6: 1- (3,4-Dimethyl current melts at 210-212 ° C. With the purpose of the phenyl) -4-methyl-5-ethyl-7-n-propoxy phenyl THflpoKctuibHofi group, the following compounds are obtained. : PRI mme R 5. 1 - (3,4-Limethox 1-
phenyl) -4-methyl-5-ethyl-7-sec-butoxy-8-methoxy-5H-2,3-benzodiazepine.
Cr5-H, gKa04, mol.m.425.5, so pl. 130-132 ° C (50% ethanol).
PRI me R 6. 1- (3,4-Dimecurrent and
After purification, the product was dissolved in hot dimethylformamide, taken in an amount of 223 ml, and the solution was clarified with 2 g of active carbon. After filtering, the active carbon is washed with 3 x X 50 ml of dimethylformamide and the washing liquid is added to the solution. The solution is diluted with 1300 ml of distilled water, and the pure product is obtained in the form of crystals. Yield 110.35 g (94%), m.p. 210-212 ° C. Measured by gas chromatography purity: over 99%. (C, j, N, N, mol. M. 368.4. Hydrochloride recrystallized from isopropanol (has a decomposition point of 218-220 s.
B. To a suspension of 4.35 g (0.01 mol) of 1- (3,4-dimethoxyphenyl) -3-methyl-4-ethyl-6-hydroxy-7-methoxy-2- heated to 80-100 C benzopyrylium bromide in 15 ml of 5p% acetic acid was added dropwise with stirring 1.2 ml of 98% hydrazine hydrate. Then to
8-methoxy-5H-2,3-benzodiazepine.
,, mol.m. 410.5, mp. PO-112 ° C (50% ethanol).
Example 7. 1- (3-Chlorophenyl) 15 4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine.
A mixture of 22 g (0.044 mol) of 1- (3-chlorophenyl-3-methyl-6,7-dimethoxy-2-benzopyryl hydrogen sulfate. 1/2
20 HjSG - 2 (mp. 175-178 ° C),
100 ml of isopropanol and 6.5 ml (0.13 mol) of 98-100% hydrazine hydrate are heated under reflux for 1 hour with stirring.
25 fridge: the waste mixture quickly becomes bright, a solution is formed. The precipitation of the crystals ends at about 0 s for 10-15 hours. It is then filtered, and
30 3x30 ml of water, and the wet crude product, which also contains some more hydrazine hydrate, is washed with 100 ml of hot water and dried (drink. Yield 7.6 g (52.5%), mp.
., ".,
163-166 ° C is added to the reaction mixture at 90-1.00 ° C. Recrystallization is carried out with 200 ml of a 10% aqueous solution of the chloride from isopropanol and sodium sulfate, after which 6.8-7.04 are precipitated g melted at the 166- in the sediment crude product. For purification of 168 С pure title compound, it is dissolved in dimethylformamide, C jH, -, mol.m. 328.8. or ethanol and then precipitated with water. The output of 92-95%, so pl. 210-212 ° C. Compared to the product obtained in section A, the substance has no melting point depression .45
B. Follows the procedure of A.A. However, 1 - (3-chlorophenyl) -3-methyl-b, 7-dimentate ten times the volume of methanol and methoxy II-benzopyryl are used instead of glacial acetic acid. -chloride (m.p.
Sol nokisla salt of the title compound (C, d N, d), mol. 365.3, mp. 185-187 ° C, decomposed (isopropanol-ethyl acetate).
Proceed as described, however, in
the solution is evaporated after boiling for one hour. Under certain conditions, the residue is treated with water and then precipitated with water from the solution prepared with dimethylformamide in the manner described in section B. Yield 95%, mp. 210-212 ° C.
Examples 5-6. From 1- (3,4-Dimethoxyphenyl) -4-methyl-5-ethyl-7-hydroxy-8-methoxy-5H-2,3-benzodiazepine, example 4) in a known manner alkyl 8-methoxy-5H-2, 3 - Benzodiazepine.
,, mol.m. 410.5, mp. PO-112 ° C (50% ethanol).
PRI me R 7. 1- (3-Chlorophenyl) 4-methyl-7, 8-dimethoxy-5H-2,3-benzodiazepine.
A mixture of 22 g (0.044 mol) of 1- (3-chlorophenyl-3-methyl-6,7-dimethoxy-2-benzopyryl hydrogen sulfate. 1/2
HjSG - 2 (mp. 175-178 ° C},
100 ml of isopropanol and 6.5 ml (0.13 mol) of 98-100% hydrazine hydrate are heated under reflux for 1 hour with stirring.
by refrigerator: the waste mixture quickly becomes bright, a solution is formed. The precipitation of the crystals ends at about 0 s for 10-15 hours. It is then filtered, and
3x30 ml of water, and a wet raw product, which also contains some more hydrazine hydrate, is washed with 100 ml of hot water and dried (drink. Yield 7.6 g (52.5%), mp.
., ".,
163-166 ° C. Recrystallization is carried out from isopropanol, and 6.8-7.04 g of melting material is obtained at 166-168 ° C of the pure title compound, C jH, -, mol. 328.8.
163-166 ° C. Recrystallization is carried out from isopropanol, and 6.8-7.04 g of melting material is obtained at 166-168 ° C of the pure title compound, C jH, -, mol. 328.8.
Soloxide salt of the title compound (C, d N, d), mol.m. 365.3, mp. 185-187 ° C, decomposed (isopropanol-ethyl acetate).
Proceed as described, however, in
0
127-129 ° C, decomposed) and methanol as a medium: a pure title compound is obtained with a yield of 60%. If a 2-3 times amount of glacial acetic acid is used as the medium, it is ota, the reaction components are stirred at 0-20 ° C and the reaction is carried out at 70-90 ° C. The reaction mixture is diluted with water and then proceeds as described. A pure title compound is obtained with a yield of 64%.
one
Proceed as described, however, 1- (3-chlorophenyl) -3-methyl-6,7-dimethoxy-2-benzopyryl-perchlorate (m.p. 219-221 ° C, decomposes) and as : environment ethanol. Thus, a pure title compound was obtained with a yield of 45–50%.
EXAMPLE 8. 1- (3-Chlorophenyl) - 4,5-dimethyl-7,8-dimethoxy-5H-2,3-benzodiaeepin.
: A mixture of 2.18 g (5.08 mmol) of 1-: (3-chlorophenyl) -3,4-dimethyl-6,7-dimethoxy-2-benzopyrillium perchlorate, 50 ml of absolute ethanol and 1 ml (20 mmol) of 98% hydrazine hydrate is boiled for 1 hour, the reaction mixture is poured and stirred with 60 ml of hot water and filtered, rinsed with 3 x 6 ml of water. 1.07 g of the title compound is obtained at 151-153 0. C ,,, H,, MOL..M. 342.8, m.p. 156-158 ° C (from | isopropanol).
: EXAMPLE 9. 1- (3-Fluorophenyl) -4- Camel-7,8-dimethoxy-5H-2,3-benzodi- | azepine.,
I Outcome of 3.98 g (0.01 mol) of 1- (fluorophenyl) -3-methyl-b, 7-dimethoxy-2-benzopyryl-perchlorate, 100 ml of absolute ethanol and 2 ml (0.04 mol 99% of the hydrazine hydratemide and then proceed as in example 8. Thus, 2.56 g of melting material at 130-134 ° C of the title product C, gH, mol 312.3, melting point 138-140 °, is obtained. C (from isopropanol). I EXAMPLE 10 1- (3-Fluorophenyl) -4 1-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine.
The initial mixture consists of 1.75 g (4.1 mmol) - (3-fluorophenyl) -3-methyl-4-ethyl-6,7-dimethoxy-2-benzopyridyl-tIeplochloride, 35 ml of absolute ethanol and 0.9 ml (18 mmol) of 100% hydrazine hydrate; Next, proceed as in example 8 and get to 1.42 g of crude product. mol.
340.4, mp. 122-124 ° C (ethanol-water).
PRI mme R 11. I-2-Methoxyphenyl 4-methyl-7,8-dimethoxy-5H-2,3-benzothiazepine.
The initial mixture consists of 3.0 g (0.0073 mol) of 1- (2-methoxyphenyl) -3-methyl-6,7-di7-U1-methoxy-2-benzopyryl-perchlorate (mp. 198-200 C, decomposes), 60 ml of isopropanol and 2.5 ml (0.05 mol) of 98% hydrazine hydrate
402258 ta
-
,about
20
)
Next, proceed as in Example 8 to obtain 1.7 g of an amorphous, somewhat soft, crude title compound that can be recrystallized well from isopropanol. , 0 ,, pier, m 324.4, mp.119-121 ° C (from isopropanol).
EXAMPLE 12 1- (3-Trifopropylmethyl-l) and 4-methyl-7,8-dimethoxy-5H-2, 3-benzodiazepine.
As a starting mixture, 3.37 g (0.0075 mol) of 1- (3-trifluoromethylphenyl) -3-methyl-6,7-dimethoxy-g si-2-benzopyrylium-perchlorate, m.p. 212-214 ° C, decomposed, 50 ml of isopropanol and 1.2 ml (0.024 mol) of 100% hydrazine hydrate. Next, proceed as in example 8
and get 2.39 g melting at 123-130 С
С „Н, 7 F,,
title compound, mol.M. 362.35, mp. 134-135 ° C (ethanol-water).
Example 13: 1- (2-Furyl) -4-25; Thyl-7,8-dimethoxy-5H-2,3-benzodiazepine.
The initial mixture consists of 3.5 g (0.0144 mol) of 1- (2-furyl) -3-methyl-6,7-dimethoxy-2-benzopyryl chloride (m.p.122-145, decomposes), 60 ml of absolute ethanol and 2,} ml (0.042 mmol) of 100% hydrazine hydrate. Next, proceed as in example 8 and get 2.18 g of the title
thirty
compounds. ,, mol.m. 284.3, mp. 155-157 ° C (dimethylformamide-water).
Example 14. (1- 3-Methoxyphenyl) 4-methyl-7,8-dimethoxy-5H-2,3-benzodiazepine.
The initial mixture consists of 5.0 g (0.012 mol) of 1 -, (3-methoxyphenyl) -3-methyl-6,7-dimethoxy-2-benzyl1Pyryl perchlorate (mp. Shrinkage, decomposed at 240-241 ° C ), 100 ml of absolute ethanol and 1.8 ml (0.036 mol) of 100% hydrazine hydrate. Next, proceed as in Example 8 and obtain 2.16 g of a crude title compound, 128-131 ° C, of the dieneum. , mol.m.324,4, mp.133 (from isopropanol.
5H-2,3-Benzodiazepines of general formula (I) have a significant effect on the central nervous system: for example, they reduce spontaneous motor (motor) activity (SMA) and act anesthetized and potentiated.
with animals, the general observations of behavior, as well as the values for the study of Fighting behavior and some characteristic representatives of the new compounds, are presented in Table. 1. Data on anesthetic potency are shown in Table 2.
From the data table. Figures 1 and 2 show the preferred properties of the proposed new compounds.
An anesthesia potentiation study was conducted in mice to which compounds were administered at doses of 12, 5, 25, 50, 100 mg / kg orally 30 minutes before measurement. It has been determined by how many percent of the compound the anesthesia caused by 50 mg / kg intravenous sodium hexobarbital is extended. The animals treated with hexobarbital sodium serve as controls.
Fighting behavior was conducted in the manner described.
The proposed compounds have low toxicity.
Formula inventions

权利要求:
Claims (1)
[1]
1. A method for producing H-2,3-benzodiazepine derivatives of general formula
R is unsubstituted or substituted by halogen, trifluoromethyl or one or two alkoxy groups with 1g4 carbon atoms, phenyl or 2-furyl group .;
R - C, - C-alkyl; R is hydrogen or C, is C4-alkyl; R C, - C-hydroxyl or C, - C alkoxy; R - C, - C-alkoxy, and in
when R is a 3,4-dimethoxyphenyl group, R is methyl, and R is an ethyl group, R and R each have a different meaning than the methoxy group,
their acid addition salts,
liable for
diketone of general formula
CH-CO-B
(Ii)
where R, R, R, R and R have the indicated 10 values,
or 2-benzopyryl salt of General formula
15
(Iii)
20
where R, K, K, K and R
X -
25
or 6H-2-benzopyran (mules IV
30 o
(Iv)
but ,
,
where is R, R - I have the indicated values,
in a medium of a polar organic solvent, such as a lower alcohol or carboxylic acid with 1-3 carbon atoms, at 60–100 ° C, it is reacted with a 1–5-fold equimolar amount of 98–100% hydrazine hydrate or the in situ hydrazine salt Cj-car45 of a lateral acid, and in the case of using the compound of the general formula (II) as a raw material, mineral acid and a semi-finished product, where R is hydroxyl, are added to the reaction mixture, if necessary alkylate and / or alkaline state or in the form of acid addition salts.
55 - "The method according to claim 1, wherein the extraction of the target product is carried out in the form of a salt with hydrogen chloride or hydrochloric acid,
randaxine 1 2
6
7
25
50
12.5
25
50
25
50
25
50
100
25
12.5
Table 2
one
48
160
377
520
181
364
90
173
780
132
135
1.0 2.17
4.65
13.33
2.23
3.20
1.11
1.52
3.26
1, 62
7.94
Continuation of table 2

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引用文献:

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法律状态:

优先权:

申请号 | 申请日 | 专利标题

HU78GO1426A|HU179018B|1978-10-19|1978-10-19|Process for producing new 5h-2,3-benzodiazepine derivatives|

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