Method of production of (1.2)-anilinated 1.4-benzodiazopines or their optical isomers or acid-additi

专利摘要:
Neue [1,2]-aneHierte 1,4-Benzodiazepin-Verbindungen der allgemeinen Formel l x worin X für Sauerstoff, Schwefel oder eine gegebenenfalls substituierte Iminogruppe steht, R, Wasserstoff, niederes Alkyl, Halogen, niederes Alkoxy oder Nitro bedeutet, und R2 Wasserstoff, niederes Alkyl, Halogen, niederes Alkoxy oder Nitro bedeutet oder, falls R, Wasserstoff ist, auch niederes Alkylthro oder, sofern außerdem X S oder eine Imino-Gruppe ist. auch Trifluormethyl bedeutet; oder R, und R2 an benachbarte Kohlenstoffatome gebunden sind und zusammen Methylendioxy oder Äthylendioxy bedeuten; R3 gegebenenfalls substituiertes Furyl, Thienyl, Pyrrolyl oder Pyridyl bedeutet, und n 0 oder, falls R3 Furyl oder Thienyl ist, auch 1 bedeutet, werden hergestellt. Die Verbindungen besitzen pharmakologische Wirkungen.
公开号:SU1331431A3
申请号:SU823527852
申请日:1982-12-27
公开日:1987-08-15
发明作者:Липманн Ханс；Руланд Микаэль；Мюш Херберт；Бензон Вернер；Хайнеманн Хенниг；Цойгнер Хорст
申请人:Кали-Хеми Фарма Гмбх (Фирма)；
IPC主号:

专利说明:

The invention relates to a process for the preparation of new (1,2) -incorporated 1,4-benzodiaepines of the general formula
where X is oxygen, sulfur or group
 NR,
where R4 is hydrogen, C -C-alkyl, substituted at the end of a methoxy group or by hydroxyl alkyl, Cj-Cj-alkenyl or cyclopropylmethyl;
R is hydrogen, C -C-alkyl, halogen,, -alkoxy or nitro;
R is hydrogen, C-C-alkyl or C-Cj-alkoxy group, or R and Rj are attached to adjacent carbon atoms and mean together methylenedioxy group
Rj means one of the groups a, .b, c, if X is the imino group of N - R, or if X is an oxygen atom or tgera, RJ means the group b:
 -0 or -jj) ° I, s
where R is hydrogen, C -C-alkyl or chlorine;
R is hydrogen or bromine;
R is C-Su-alkyl;
n - O or, if RJ is a group a b, also I;
their optical isomers or salts when combining acids with neuroleptic activity.
The purpose of the invention is a method of obtaining new (1,2) -ranlated 1,4-benzodiazepines having a different spectrum of biological properties than the known structural analogues.
The structures of the new compounds I were confirmed by spectroscopic studies (NMR spectrum). In the IR spectrum is determined by the -band in the region of 1600-1630 cm-.
Example 1. 1,2,4,4a-Tetragonpo 9-chlorop-7- (3-thienyl) -5H- (1,4) -oxazino (4,3-a) - (1,4) -benzodiazepine .
A. A solution of 92 g of (2-methoxyethyl-N (4-chlorophenyl) -2-hydroxy-1,3-diaminopropane and 40 g of triztilamine in 600 ml of methylene chloride at room temperature
ten
g -
jo
;
25
thirty
35
40
45
gg
gg
431
The mixture is mixed dropwise with a solution of 52 g of thiophene-3-carbo) 1g of chloride and 200 ml of methylene chloride /; a and the reaction mixture is left to react for 15 hours. After processing the reaction mixture, it is crystallized with isopropanol. 118 g of (3-thienylcarbonyl) -K2- (2-methoxyethyl) -Nj- (4-chlorophenyl) -2-hydroxy-1,3-diaminopropane are obtained, mp 141-114 C.
B. 10 g of the obtained compound is mixed with 10 ml of phosphorus oxytrichloride and left to react in an oil bath at 120 ° C for 16 hours. The reaction mixture is then diluted with chloroform, then mixed with ice and then with an aqueous solution of hydrochloride. sodium oxide. After processing the organic phase, the crude product is crystallized from ether. 8 g of 7-chloro-1- ((E-chloroethyl) -2-chloromethyl-5- (3-thienyl) -2,3-dihydro-1H-1,4-benzodiazepine are obtained, mp 115- 116 C.
B. A solution of 11 g of 7-chloro-1- (| 13-chloroethyl) -2-chloromethyl-5- (3-thienyl) -2,3-dihydro-1H-1, 4-benzodiazepine in 60 ml of dioxane and 160 ml of a 4.5% sodium hydroxide solution are refluxed for 5 hours. After removing the solvent in vacuo, the reaction product is separated from chloroform and then chromatographed on alumina in activity II with methylene chloride. After removing the methylene chloride. 6.5 g of 1,2,4,4a-tetrahydro-9-chloro-7- (3-thienyl) -5H- (1,4) -oxazino (4, 3-a) - (I , 4) -benzodiazepine in the form of an oil, which is converted into hydrochloride by reacting with an alcohol solution of hydrogen chloride, is crystallized from isopropanol as 0.3 HjO hydrochloride, m.p. 207-212 C.
Example 2. 1,2,3,4,4a-Hexa-hydro-3-methyl-7- (2-thienyl) -pyrazio (1,2-a) -1,4) -benzodiazepine.
A. 170 g (2-ethoxyethyl) NIL-2-OXY-1,3-diaminopropane in the presence of 89 g of triethylamine in 800 ml of chloroform are reacted with 118.7 g of thiophene-2-carbonyl chloride. After treatment of the reaction mixture, the reaction product is crystallized from isopropanol. 190 g of (2-thienylcarbonyl) -Y - (2-hydroxyethyl) nyl-2-oxy-l, 3-diaminopropane, m.p. 141--142 ° C.
B. 60 g of the obtained amide compound in 70 ml of phosphorus oxydrichloride is allowed to react for 2 hours in an oil bath at a bath temperature of 140 ° C. Then, the reaction mixture was sequentially treated with ice and sodium hydroxide solution and the reaction product was separated from chloroform. 51.0 g of an oily mixture of approximately 90% of 1 - (/ 3-chloroethyl) -2-chloromethyl-5 (2-thienyl) -2,3-dihydro-1H-1, A-benzodiazepine and about 10 are obtained. % 1 - (/} - chloroethyl) -3-chloro-6- (2-thienyl) -1,2,3,4-tetrahydro-1,5-benzodiazocin, which is introduced into the reaction further without Coy cleaning.
B. 20 g of the resulting mixture in 300 ml of methanol together with 20 g of methylamine are allowed to react for 14 hours at 95 ° C in an autoclave. Then the reaction mixture is treated as usual, the reaction product is purified by chromatography on alumina of activity II with a mixture of methylene chloride - chloroform and then crystallized from ether. 12.8 g of 1.2 3,4,4a-5-hexahydro-3-methyl-7- (2-thienyl) -pyrazine (1,2-a) - (1,4) -benzodiazepine are obtained. m.p. 12A-125 C.
PRI me R 3. 1, 2,3,4,4a, 5-Hexa-hydro-9-chloro-3-methyl-7- (2-furyl) -pyrazino (1,2-a) - (1,4) -Benzodiazepin-6-oxide.
A. 118.3 g of (2-methoxy-methyl) (4-hlrsphenyl) -2-hydroxy-1,3-diaminopropane in 1000 ml of chloroform in the presence of 51.0 g of triztilamine are reacted with 61.0 g of furan-2- carbon
chloride. After processing the reaction, 150 ml of methanol are reacted with 12 g of methylamine in an autoclave for 14 hours. After processing the reaction mixture, the resulting crude product is purified by chromatography on alumina of activity II with a mixture of methylene chloride-chloroform and crystallized from isopropanol. Obtain 7.3 g of 1,2, 3,4,4a, 5-hexahydro-9-chloro-3-methyl solution, the reaction product is crystallized from isopropanol. 147 g of N - (2-furylcarbonyl) (2-methoxyethyl) (4-chlorophenyl -2-hydroxy-1, 5-diaminopropane) are obtained, mp 121-123 ° C.
B. 146 g of the above amide in 150 ml of phosphorus oxytrichloride is heated on an oil bath for 4 hours at a bath temperature of 120 ° C, then the reaction mixture is successively treated with ice and an aqueous solution of sodium hydroxide and treated as usual. The reaction product is isolated from chloroform. 106.5 g of an oily mixture of 7-chloro-1- (p-chloroethyl) -2-chloromethyl-5- (2-furyl) -2,3-dihydro-1H-1,4-benzodiazepine and 3 are obtained. 8-dichloro-1- (p-chloroethyl) -6- (2-furyl) -1,2,3,4-tetrahydro-1,5-benzodiazocin.
50
7- (2-furyl) -pyrazino {1,2-a) - (l, 4 -) - benzodiazepine-6-oxide, mp 202-204 ° C.
EXAMPLE 4 1,2,3,4,4a, 5-Hexa-hydro-9-chloro-3-methyl-7- (2-furyl) -pipysene (1,2-a) - (1,4) -benzodiazepine.
3.4 g of 7-chloro-1- (, L-chloroethyl) -2-xlop methyl-5- (2-furyl) -2,3-DIG1ZDRO-1H- (I, 4) benzodiazepine in 100 ml of methanol are injected in interaction with 0.8 g
During the processing of this mixture, Tfnrom crystallized A7.8 g of the above-mentioned benz (1dylzepi11a with m.p..90-.
After removal of the solvent in vacuo and purification of the residue on alumina) 1 and activity stage II-III using methylene chloride, 43 g of a mixture of approximately equal parts of the benzodiazepine and benzodiazocine isomers are obtained from the mayor efflorescence. This mixture is refluxed in 215 ml of tetrachloroztan for 1 hour. After removing the solvent in vacuo, the reaction product is treated with an aqueous solution of sodium hydroxide and purified again by chromatography on alumina and then crystallized from ether. Get 3h g of benzodiazepine with so pl.92- 94 C.
B. A solution of 17.8 g of 7-chloro-1- (-chlorostil) -2-chloromethyl-5- (2-furyl) -2,3-di-hydro-1H-1,4-benzodiazopine in 250 ml methylene chloride, together with 10.4 g of 3-chlorobenzoic acid, is refluxed for 2 h. After that, the reaction solution is basified with an aqueous dilute sodium hydroxide solution and treated in the usual way, the reaction product is isolated, then purified by chromatography on alumina of activity II with methylene chloride and crystallized from methanol. 13 g of 7-chloro-1 - (- chloroethyl) -2-chloromethyl-5- (2-furyl) -2,3-dihydro-1H-1,4-benzodiazepin-4-oxide are obtained, m.p. 158-I59 ° C.
G. 12 g of the specified N-oxide in
0
7- (2-furyl) -pyrazino {1,2-a) - (l, 4 -) - benzodiazepine-6-oxide, mp 202-204 ° C.
EXAMPLE 4 1,2,3,4,4a, 5-Hexa-hydro-9-chloro-3-methyl-7- (2-furyl) -pipysene (1,2-a) - (1,4) -benzodiazepine.
3.4 g 7-chloro-1- (, L-chloroethyl) -2-chloro-methyl-5- (2-furyl) -2,3-DIG1ZDRO-1H- (I, 4) benzodiazepine in 100 ml of methanol, input t per interaction with 0.8 g
five
sodium hydroxide in 1 ml of water and 2.5 g of methylamine at 95 ° C in an autoclave for 5 hours. Then the reaction mixture is washed with water, the organic phase is dried over Naj50 and evaporated, the residue is purified by chromatography on alumina of activity II using methylene chloride - chloroform, the fractions containing the mid-polar product are separated and the resulting 1,2,3,4,4а, 5-hexahydro-9-chloro-3-methyl-7- (2-furyl) -pyrazine (1,2-a) -benzodiaeepin is dissolved in isopropanol and, with the help of an alcoholic solution of hydrogen chloride, translated into its salt, allylate from isopropanol as a dehydrochloride hemihydrate with 0.1 mol of isopropanol, m.p. 240 ° C, yield 0.8 g
PRI mme R 5. 1,2,3,4,4а, 5-Hexa-hydro-9-chloro-3-methyl-7- (2-4) - pyrazino) - (1,2-a) - (1,4) -benzodiazepine.
1 g of 7-chloro-1 - ((- chloroethyl) -2-chloro-methyl-5- (2-furyl) -2,3-dihydro-1H-1,4 benzodiazepine in 40 ml of methanol is reacted with 0 , 8 g of methylamine at 50 ° C for 3 hours. Then, the reaction mixture is treated as described in Example 4. With chromatographic purification, fractions containing more polar title compound are isolated and 0.4 g of them are obtained 1.2 , 3,4,4а, 5-hexahydro-9-chloro-3-methyl-7- (2-furyl) -pyrazino- (1,2-a) - (1,4) -benzodiazepine.
EXAMPLE 6: 1,2,3,4,4a, 5-Hexa-hydro-9-chloro-3-methyl-7- 2- (N-methyl) -pyrrolyl-pyrazino (1,2- a) - (1,4) -benzodiazepine.
19 g of 7-chloro-1 - (- chloroethyl) -2-chloromethyl-5- (2-furyl) -2,3-dihydro-1H-1,4-benzodiazepine in 300 ml of methanol are reacted with 15 g of methyl-ammonia at 95 s in an autoclave for 14 hours. After treatment of the reaction mixture and chromatographic purification of the crude product on alumina of activity II with a mixture of methylene chloride and chloroform, obtained 1,2, 3,4,4a, 5-hexahydro -9-chloro-3-methyl-7- 2- (N-methyl) -pyrrolyl-pyrazino (1,2-a) - (1,4) -benzodiazepine in ethanol with a salt solution of hydrogen chloride is converted into its salt recrystallized from mixture tanol with ether in the form of dihydrochloride with 0.75 mol of water, so pl. 7,230 С, yield 13,4 g.
314316
Example. 1,2,3,4,4a, 5-Hexa-hydro-3-methyl 7- (4-bromtii-2-yl) -pyrozino (1,2-a) - (1, A) -bezodiazepine.
A.32.2 g of N, (2-oxystil) -M, -phenyl-5 2-hydroxy-1,3-diaminopropane is introduced into
interacting at room temperature in the presence of 16.9 g of triethylamine in 300 ml of methylene chloride with 29.1 g of 4-brotiofsn-2-carbonyl chloride.
10 After treatment of the reaction mixture, the reaction product is recrystallized from isopropyl alcohol. As a result, 41.0 g of (2-hydroxyethyl) -H, -phenyl-K - (4-bromothio 5 phen-2-carbonyl) -2-hydroxy-1,3-diaminopropane, m.p. 147-148 s.
B. 25 g of the above amide compound is reacted with 25 ml of phosphorus trichloroxide, and the reaction is carried out for 16 hours at 120 ° C. Immediately after this, the reaction mixture is treated in accordance with Example 2. As a result, 16.0 g are obtained. oily 1- (2-chloroethyl) -2-chloro 5 mrtil-5- (4-bromothien-2-yl) -2,3-dihydro-1H-1, 4-benzodiazepine, which is further used without further purification.
B.16.0 g of the obtained compound is dissolved in 150 ml of methyl
the prepared solution is mixed with a solution of 11.9 g of methylamine in 100 ml of ketyl alcohol, after which the reaction mixture is placed in an auto clavine and reacted for 16 hours at 90 ° C. Immediately after this, the reaction mixture is treated as in Example 2, after Purified by chromatography, the product is crystallized from ether. 7.5 g of 1,2,3,4,4a-5-hexahydro-3-metshl-7- (4-bromothien-2-yl) -pirazino (1,2-a) - (1,4 ) -benzodiazepine, so pl. 139-140.
45 By analogy with the method described above (Example 7B), 1,2,3,4,4a, 5-hexahydro-3-methyl-7- (5-chlorofur-2-yl) -pyrazino (1,2-a ) - (1,4) -benzodiazepine-6-oxide.
50
For the preparation of the starting compound 18.4 (2-oxyethyl) -N-phenyl-2-hydroxy-1,3-diaminopropane in the presence of B; 7 g of triethylamine are added to the reaction mixture in 400 ml of methylene chloride with 14.4% g 5-chlorofuryl-2-carboiyl chloride. The result is in the form of an oily substance 25 g (2-hydroxyethyl) -N -fellill-N2 - (5-chlorf 13
Ry, h-2-carbonyl) -2-hydroxy-1, 3-diamiyoprops pgl, KOTOpbrfi are then used without prior purification. 25 g of oil-phosphoric amide in 25 ml of trichloride-: phosphorus oxide are introduced into the cyclization reaction in an autoclave for 16 hours. The reaction mixture is processed by analogy with Example 7B. As a result, 23 g of 1- (2-chloroethyl) -2-chloromethyl-5- (5-chlorofur-2-yl) -2,3-dihydro-1H-1, A-benzodiazepine are obtained in the form of an oily substance. In the example of pollutants, this compound is introduced in conjunction with 1, 1, 8 g of 3-chlorobenzoic acid in 250 mp of methylene chloride, and the reaction is carried out for 3 hours at room temperature. Immediately thereafter, the reaction mixture is processed by analogy with example 3. As a result, 14.4 g of crude 1- (2-chloroethyl) -2-chloromethyl-5- (5-chlorofur-2-yl) -2.3- dihydro-1H-1,4-benzodiazepin-4-oxide as an oily residue.
The resulting starting material was dissolved in 200 ml of methyl alcohol, after which the prepared solution was reacted with 10.8 g of methylamine in an autoclave at 90 ° C for 16 hours. Immediately after this, the reaction mixture is treated by analogy with example SG. The result 10.9 g 1,2,3, 4,4a, 5-hexahydro-3-methyl-7- (5-hLorfur-2-Sh1) -pyrazino- (1,2-a) - ( 1,4) -benzodiazepin-6-oxide as an oily base. The resulting compound is converted into its hydrochloride salt as a result of interaction with an alcoholic solution of hydrogen chloride, which is cross-crystallized from isopropyl alcohol. Thus, 1, 2,3,4,4a, 5-hexa-hydro-3-methyl-7- (5-chlorofur-2-yl) -pyrosino-CI, 2-a) - (1,4-hydrochloride) hydrochloride is obtained. ) -benzodiazepine-6-oxide, so pl. (with decomposition).
EXAMPLE 8: 1,2,3,4,4a-5-Hexa-hydro-9-nitro-3-methyl-7- (2-thienyl) -pyrazino S1,2-a) - (1, 4) benzodiazepine,
A. A solution of 15.5 g of 1- (| 5-chloroethyl) -2-chloromethyl-5- (2-thienyl) -2,3-dihydro-1H-, 4-benzodiazepine in 110 ml of acetanhydride at 45 ° C portions are mixed with 12 g of copper (II) nitrate trihydrate. At the end of the reaction, the reaction mixture is mixed with ice water and treated with alkalization.
one
The reaction product is purified chromatographically on alumina stage II of activity with methylene chloride.
This gives 7.3 g of 7-yitro-1 - (- chloroethyl) -2-chloromethyl-5- (2-thienyl) -2,3-dihydro-1 I-1,4-benzodiazepine P as an oil.
B. 2.7 g of the obtained compound in 100 ml of methanol are reacted with 10 g of methylamine at 14 hours in the autoclave. After processing the reaction mixture, the reaction product is cleaned (chromatography on aluminum oxide of activity II).
using a mixture of methylene chloride - chloroform and crystallized from ether. 1.1 g of 1,2,3,4,4a, 5-hexahydro-9-nitpo-3-methyl-7- (2-thienyl) -pirazino (1, 2-a) - (1,4 ) -benzodiazepine, so pl.
174-175 C.
PRI me R 9. I, 2,3,4,4a, 5-Hexa-hydro-3-n-butyl-9-methyl-7- (2-furyl) - pyrazino (I, 2-a) - (1,4) -benzodiazepine-6-oxide.
4 g of 7-methyl-1 - (- chloroethyl) -2-chloromethyl-5- (2-furyl) -2,3-dig1adro-1H-1,4-benzodiazepin-4-oxide (obtained analogously to Example 3 A-B ) is dissolved in 10 ml of n-butylamine and the solution is heated at 90 ° C for 14 hours in an autoclave. After treatment of the reaction mixture, the resulting crude product is purified by chromatography on alumina of activity II with methylene chloride-chloroform and crystallized from ether. 2.1 g of I, 2,3,4, 4a, 5-1 exahydro-3- (n-butyl) -9-methyl-7 - (- 2-furyl) -pyrazino (1,2-a) are obtained. ) - (1,4) -benzodiazepin-6-oxide, so pl. 104-106 s.
PRI me R 10. 1,2,4,4a-Tetrahydro-9,1O-ethylenedioxy-7- (2-thienyl) -5P- (1,4) -oxazino (4,3-a) - (I, 4) -benzodiazepine.
A. 29.6 g (2-tisnilkarbonsh1) - N - (2-hydroxyethyl) -H. (3,4-ethylenedioxyphenyl) -2-hydroxy-I, 3-diaminopropane is allowed to react in 30 ml of phosphoroxide trichloride for 14 h.
in an oil bath at 120 ° С. It is then diluted with chloroform and the solution is treated successively with ice and sodium hydroxide solution. The organic phase is separated and processed. The resulting reaction product solidifies after removal of the solvent. By crystallization from propanol, 25.6 g of 7.8-ethylenedioxy-l- (p) -chloroethyl) -2-chloromethyl-5- (2-thienyl) -2,3-dihydro-1H-1,4-benzodiazodia are obtained. Pin, m.p. 18A-187 C.
B. A solution of 13 g of the product obtained in 60 ml of dioxane is heated under reflux with 35 ml of a 25% sodium hydroxyl solution and 100 ml of water for 4 hours. After evaporation of the solvent in vacuum, the reaction product is isolated from chloroform and then chromatographed on alumina degrees of activity II methylene chloride. After removal of methylene chloride, the product crystallizes.
PRI me R 70, I, 2,3,4,4a, 5-Hex hydro-10-fluoro 3-methyl-7- (2-tIenyl) -pyrazino (1,2-a) - (1, 4) -benzodiazepine.
g A. 90 g of (2-thienylcarbonyl) -Y.- (2-oxyethyl) -N - (3-fluorophenyl) -2-oxy of 1,3-diaminopropane, prepared as described in Example 2, by reacting (2-oxyethyl) (3-Fluorophenyl) -210 OKCi-I, 3-diaminopropane with thiophene-2-carbonyl chloride, is cyclized by treating with 90 ml of phosphorus trichloride at 120 ° C.
from zfira. This gives 5.5 g of 1,2,3,4,4 -15. 78 g of crude crude tetrahydro-9,10-ethylenedioxy-7- (2-oil-oily mixture containing a 1) -5H- (1, 4) oxazino (4,3-a) - (1,4) benzodiazepine, so pl. 192-194 ° C.
According to examples 1-10, (I, 2) -7ellised 7-heteroarsh-1,4-benzodiazepines of formula 1 are obtained, starting from compounds of formulas II and III, presented in Table 1.
approximately 80% of 1- (y-chloroztil) -2-chloro methyl-8-fluoro-5- (2-thienyl) -2,3-dihydro 1H-1,4-benzodiazepine and approximately 20 but 12% 1- ( (L-chlorostil) -3-chloro-9-fluoro-6- (2-thienyl) -1,2,3,4-tetrahydro-1,5-benzodiazepine.
B. The mixture obtained by the method indicated above is subjected to purification using the following procedure: ppimer 69. 1,2,3,4,4a-Tetra-5 using column chromatography, zaprohydro-8, 1O-dimethyl-7- (2-tyevil ) -5H- (1,4) -thiazino- (4,3-a) - (1,4) -benzodiazepine.
A solution of 15.4 g of 6.8 dimethyl-1- (p-chloroethyl) -2-chloromethyl-5- (2-thienyl) -2,3-dihydro-1H-1,4-benzodiazepine (or a mixture consisting of of this compound and 7,9-dimethyl 1 - ((1-chloroethyl) -3-chloro-6- (2-thienyl) -1,2,3,4-tetrahydro-1,5-benzodiazocine) isomeric to it in Example A, starting from (2-hydroxyethyl) (3,5-dimethylphenyl) -2-hydroxy-1,3-diaminopropane and thiophene-2-carbonyl chloride) in 200 ml of dioxane is mixed with 11.1 g of nonahydrate sodium sulfide in 70 ml of water, after which the reaction mixture is heated for 10 hours at
40 is separated and the oily hydrochloride is first crystallized from ethyl alcohol. The result is 6.5 g of 1- (p-chloroethyl) -3-chloro-9-fluoro-6- (2-teas, refluxing hydrochloride. He- 45 nyl) -1,2,3,4-tetrahydro 1,5-benzodo directly after this reaction-azocine, m.p. 160-165 seconds
The organic mixture is washed; the organic phase is g. J obtained by elution
the product is separated, the solvent is distilled off in vacuo, after which the remaining crude reaction product is separated from chloroform, and then purified by chromatography on alumina of activity II using methylene chloride. After that, the product is recrystallized from ether. 7 g of 1, 2,4,4a-tetrahydro-8,1O-dimethyl-7- (2-thienyl) -5H- (1,4) -thiazino- (4,3-a) - (1, 4) -benzodiazepine, t.pp.130-132 C.
the more polar fraction is 1 - (- (chloroethyl) -2-chloromethyl-8-fluoro-5- (2-ty50 enyl) -2,3-dihydro-1H-1,4-benzodiazepine, which is recrystallized from ethyl alcohol, m.p. 105-106 S.
G. 5 g of 1- (p-chloroethyl 1) 3-chloro-9-fluoro-b- (2-thienyl) -1,2,3,355 tetrahydro-1,5-benzodiazepine hydrochloride is dissolved in 100 ml of methyl alcohol, after which The prepared solution is mixed with a solution of 5.0 g of methylamine in 50 ml of methyl alcohol. Reactionary
Example 70, I, 2,3,4,4a, 5-Hexa-hydro-10-fluoro 3-methyl-7- (2-tIenyl) -pyrazino (1,2-a) - (1 , 4) -benzodiazepine.
A. 90 g of (2-thienylcarbonyl) -Y.- (2-oxyethyl) -N - (3-fluorophenyl) -2-oxy-1,3-diaminopropane, prepared as described in example 2 by reacting (2-oxy-methyl) (3-fluorophenyl) -2OKsi-I, 3-diaminopropane with thiophene-2-carbonyl chloride, is subjected to cyclization by treating with 90 ml of phosphorus trichloride oxide at a boiling point of the reaction mixture at 120 C.
78 g of a crude, oily mixture containing
approximately 80% of 1- (y-chloroztil) -2-chloromethyl-8-fluoro-5- (2-thienyl) -2,3-dihydro-1H-1,4-benzodiazepine and about 12% 1- ((L-chlorostil) -3-chloro-9-fluoro-6- (2-thienyl) -1,2,3,4-tetrahydro-1,5-benzodiazepine.
B. The mixture obtained by the above method is subjected to purification with fresh aluminum oxide with degree of activity II, using methylene chloride as a precipitating agent. The less polar fraction obtained in the course of zylation is obtained in the form of an oily substance 1 - (- chloroethyl) -3-chloro-9-fluoro-6- (2-thienyl) -1,2,3,4-tetrahydro-1.5 -Benzodiazocine. This base is dissolved in
35 diethyl ether, after which the resulting solution is treated with gaseous hydrogen chloride. The resulting hydrochloride is precipitated as an oily substance. Diethyl ether from 40 is separated and initially the oily hydrochloride is crystallized from ethyl alcohol. The result is 6.5 g of 1- (p-chloroethyl) -3-chloro-9-fluoro-6- (2-tye45 nyl) -1,2,3,4-tetrahydro-1,5-benzo-most-polar hydrochloride the fractions contained 1 - (- chloroethyl) -2-chloromethyl-8-fluoro-5- (2-ty50 enyl) -2,3-dihydro-1H-1,4-benzodiazine, which is recrystallized from ethyl alcohol, t. square 105-106 S.
G. 5 g of 1- (p-chloroethi1) -3-chloro-9-fluoro-b- (2-thienyl) -1,2,3,455 hydrochloride of tetrahydro-1,5-benzodiazepine is dissolved in 100 ml of methyl alcohol, after what the prepared solution is mixed with a solution of 5.0 g of methylamine in 50 ml of methyl alcohol. Reactionary
the mixture is heated for 12 hours in an autoclave at. Immediately thereafter, the solvent, the oily reaction product obtained as a residue, is distilled off from the reaction mixture in chloroform, after which the solution is washed with a dilute sodium hydroxide solution and immediately thereafter with water, dried over sodium sulfate and evaporated. The resulting reaction product is purified using chromatography on alumina with
20
the target compound is crystallized and diethyl ether, so pl. 128-129 C.
oij p -336,30 (in methyl alcohol).
25
the degree of activity II with the use of the (-) - isomer obtained in the form of a residue as an eluting agent chloroform. From the eluate, 4.2 g of the crude target compound are isolated as an oily substance, which is then crystallized from diethyl ether; 2.19 g of the resulting 1,2,3,4,4a, 5-hexahydro-1O-fluoro-3-methyl-7 - (2-thienyl) -pyrazino (1,2-a) - (1,4) -benzodiazepine (m.p. 112-114 C) and 1.61 g of maleic acid are dissolved together in 20 ml acetone. The resulting dimaleate of the title compound is gradually precipitated in crystalline form. 3.8 g of crude crystalline product is filtered off, which is then recrystallized from ethyl alcohol. The melting point of the dimaleinate of the target compound is 161-164 ° C.
PRI me R 71. Preparation of optically active isomers 1,2,3,4,4a, 5-hexahydro-IO-fluoro-3-methyl-7- (2-tyenyl) -pyrazino (1,2- a) - (1,4) -benzodiazepine.
A. Separation of the racemate 1,2,3,4, 4a, 5-hexahydro-1O-fluoro-3-methyl-7- (2-thienyl) -pyrazino (1,2-a) - (1,4) - benzodiazepine .
A1. 8.97 g of racemic 1,2,3,4,
thirty
A2. The separated mother liquor is evaporated in vacuo and the residue obtained, which contains the (-) - salt from the dimensional form, is recrystallized and mixtures of ethyl alcohol and water. The resulting crystalline substance is recrystallized from a mixture of ethyl alcohol and water to a constant angle of rotation. Immediately after this, the salt is dissolved in methylene chlorite, the solution is extracted with an aqueous solution of sodium hydroxide and the organic phase is washed with water, dried over sodium sulfate 35 and evaporated to remove the free base. The residue (-) - isomer of the title compound is crystallized from diethyl ether, m.p. 128-129 C.
o (J. -356,30 (in methyl alcohol).
B. Obtaining optical isomers is also possible by means of the separated racemic 1- (l-chloroethyl) -2-chloro.
40
4a, 5-hexadihydro-1O-fluoro-3-methyl-7-g methyl-8-fluoro-5- (2-thienyl) -2,3-dihyd (2-thienyl) -pyrazino (1,2-a) - (1,4) - beneodiazepine, prepared according to example 42 or 70, and 21.05 g of (-) - dibenzoyl-b-tartaric acid are dissolved in order to form the salt in 200 ml of ethanol when heated to the boiling point of the solution with reflux. Immediately thereafter, the solution is diluted with stirring by adding approximately 600 ml of water heated to 90 ° C, after which the solution is slowly cooled to 0-5 ° C, predominantly crystalline 1, 4-benzodiazepine (mp. 105-106 ° C; preparation see Example 70B) for its isomers and the subsequent reaction of these isomers with methylamine. gQ B1. 85.6 g of racemic 1- (L-chloro ethyl) -2-chloromethyl-8-fluoro-5- (2-thienyl) -2, 3-dihydro-1,4-benzodiazepine and 48.8 g of (-) - dibenzoyl-b-tartaric acid is dissolved to form a salt in ethyl alcohol, after which the solution
55
incubated for the purpose of crystallization, the salt of the (-) - isomeric form being predominantly precipitated in the form of crystals. Images: 1c; 11ees Chris
is C1. is (+) -isomeric form. The crystalline product is separated from the mother liquor by filtration and several times (15-20) is recrystallized from ethanol to a constant value of the angle of rotation. Directly, the salt is dissolved in MeTtmcHe chloride, the solution is used to obtain freedoms {base is mixed with an aqueous solution of sodium hydroxide, the organic phase is separated, washed with water, dried over sodium sulphate and evaporated. By
the target compound is crystallized from diethyl ether, m.p. 128-129 C.
oij p -336,30 (in methyl alcohol).
obtained as residue (-) - isomer
A2. The separated mother liquor is evaporated in vacuo and the resulting residue, which contains the (-) - isomeric salt, is recrystallized from a mixture of ethyl alcohol and water. The resulting crystalline substance is recrystallized from a mixture of ethyl alcohol and water to a constant value of the angle of rotation. Immediately after this, the salt is dissolved in methylene chloride, the solution is treated with an aqueous solution of sodium hydroxide to isolate the free base, the organic phase is washed with water, dried over sodium sulfate and evaporated. The residue (-) - isomer of the title compound is crystallized from diethyl ether, m.p. 128-129 C.
o (J. -356,30 (in methyl alcohol).
B. Obtaining optical isomers is also possible by separation of racemic 1- (l-chloroethyl) -2-chloro.
methyl 8-fluoro-5- (2-thienyl) -2,3-dihyd g methyl-8-fluoro-5- (2-thienyl) -2,3-dihydro-1, 4-benzodiazepine (m.p. 105- 106 ° C; for preparation, see Example 70B) for its isomers and the subsequent reaction of these isomers with methylamine. gQ B1. 85.6 g of racemic 1- (L-chloroethyl) -2-chloromethyl-8-fluoro-5- (2-thienyl) -2, 3-dihydro-1,4-benzodiazepine and 48.8 g (-) -dibenzoyl-b-tartaric acid is dissolved to form a salt in ethyl alcohol, after which the solution
55
incubated for the purpose of crystallization, the salt of the (-) - isomeric form being predominantly precipitated in the form of crystals. Forms: 1B; 11ees Kris-1313
Tall substance is filtered from the mother liquor and recrystallized from ethyl alcohol to a constant value of the angle of rotation. Immediately after this, the salt is dissolved in methylene chloride, the solution is mixed with an aqueous solution of sodium hydroxide to isolate the free base, the organic phase is separated, washed with water, dried over sodium sulfate and evaporated. As a result, 19 g of the (-) - isomer are obtained. This compound is recrystallized from ethyl alcohol.
about -482,10 (in ethyl alcohol),
Obtained according to example 2 (-) - isomeric 1 - (- chloroethyl) -2-chloromethyl-8-fluoro 5- (2-thienyl) -2,3-dihydro-1, 4-benzodiazepine is reacted with methylamine . 10.3 g of (-f -) - H30Mepa 1, 2, 3, 4.4a, 5-hexahydro-10-fluoro-3-methyl-7- (2-thienyl) -pyrazino (1, 2- a) - (1,4) diazepine, so pl. 128-129 C.
With with +359.30 (in methyl alcohol).
B2. The solvent was distilled off from the mother liquor obtained above, after which the remaining salt was dissolved in methylene chloride. In order to isolate the free base, the solution is mixed with an aqueous solution of sodium hydroxide, the organic phase is separated, washed with water, dried over sodium sulfate and evaporated. The residue is dissolved in ethyl alcohol to form a salt with (+) - dibsonol-B-tartaric acid, after which the solution is held until the resulting salt crystallizes. The crystalline substance is filtered and recrystallized from ethanol to a constant value of the angle of rotation. In order to isolate the free base, the salt is dissolved in methylene chloride and the solution is mixed with an aqueous solution of sodium hydroxide, the organic phase is separated, washed with water, dried over sodium sulfate and evaporated. As a result, 21.3 g of the (t -) - isomeric form of 1- (ft-chloroethyl) -2-chloromethyl-8-fluoro-5- (2-thienyl) -2.3-dihydro-1H 1, 4 benzodiazepine.
r / ta
spipte).
 +480.50 (in ethyl
15
0
25
The main bases are introduced into a t-ring with methylamine in Example 2 B. In D pe ul1, tlte get 11.8 I (-) - isomeric forms 1,2,3,4, 4а, 5 - gox agro- 10-fluoro-3-methyl-7- (2-tii) yl) -pirzino (1, 2-a) - (1, 4) -ben-a11DI, m.p. 128-129 C.
  -356.0 (in methyl alcohol 0).
Pharmacological studies.
Acute toxicity.
Acute 7-dose toxicity was determined after a single administration of the substance orally on an empty stomach of a white CMC-1 mouse, LD, (calculated through EDV due to Probit analysis.
Neuroleptic properties.
Determination of the active dose to suppress the induced creeping apomorphine (Kletter-halLen) on (modified Protais P method, et al. - Psychopbarcology, 50, 1976, 1-6).
Iskolzkp groups of 10 males each NMR-ohs of 18-24 g each After 60 minutes, animals were injected subcutaneously at 1.0 mg / kt-anomorphine and each BOTHOf TOiMTif animal was inoculated with a PG of a vertical grill closed to the mirror after the injection (diameter 13 cm. 1 cm from 16 cm) after injection. After 10. 0 and 30 min., The animals creep state according to the following point systems: O - points - no paws. on the wg of the bar; 1 - point - one or two paws in contact with the lattice; 2 points - three or all grab the grating or M1,:
Dp each test group three times set the sum of points (the largest number of points 20) and take an average of three values to determine the creep state suppression caused by the test substance.
Sedative (soothing central-nsrvvuk) system) properties.
Allodrye active dose to increase pr (; duration of hexobarbital drug in the mouse (modified) and; the established Keshr method IW et al. Arch. Int.Pharmacy.l.igy, 193, 197 1, 37-47) .
The group of 10 male mice weighing 22-26 g each is used. The test substance injects g: eoralia in the form of a 2% suspension in a solution of tylose. After
0
five
0
0
five
15
60 min. Animals are intravenously injected with 50 mg / kg sodium hexobarbital (narcotic dose). The duration of the loss of the straightening reflex in one tenth minute is measured. The increase in the duration of the reflex loss caused by the test substance was determined by comparing with the duration of the loss of the reflex in the case of control animals treated with the solution of the test and sodium hexobarbital without the test substance.
Tables 2 and 3 show the test results of the test substance for neuroleptic and sedative effects, as well as toxicity.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining (1,2) -anlisted 1, A-beisodiazepines of the general formula .1
Q -
R. 16
locally denoted methylenedioxy;
if X - N - R means any of the following groups a, b, c, or if X is oxygen or sulfur, group b;
-, one
R means
  LI
Q o. S.
where R is hydrogen, C, -C2-alkyl, or
chlorine;
R is hydrogen or bromine; R - C, -Cj-alkyl; p - O or if R is a group
or b, also 1,
trm of their optical isomers or acid addition salts, characterized in that the compound of general formula II or III
where X is oxygen, sulfur or group
N - R
. . -f
where R is a hydrogen,.-alkyl, C 2 -C-alkyl, substituted at the end of a methoxy or oxy group, C — C —.-alkenyl or a cyclopropylmethyl radical; hydrogen, C-C-alkyl, halogen, C-Cd-alkoxy or nitro;
hydrogen, C-C-alkyl or C-C-alkoxy, or R and RJ are attached to adjacent carbon atoms and together
five
ai
C1 (III)
,, and n have specified
 Sh
0 or a mixture thereof, where the R, R, R values;
Y is halogen
(subjected to interaction with hydroxide or alkali metal sulfide or amine of formula
R4 - NHj,
where R has the indicated meanings, followed, if necessary, by separating the obtained racemic mixture of the target product into optical isomers and isolating the target product as a base or acid addition salt.
Table I
Orykechaiya: - decomposition; S - sintering.
59
2-Tnen.
N-CH, -CH,
Note: In column 10: .0 it means that there is no Himaxoro action; The nS factor is an increase in duration, since it is an increase only in a few experimental animals at each dose group (n-u). No toxicity at a dose of 300 mg / kg; With higher doses, no ns-tortured
Diazepam - 1-netil-7-chloro-5-phenip-1,3-dihydro-2H-1,3-bRizodiazepni-2-one
Compiled by G.Konnov Editor I.Rybenko Tehred M.Hodanich Proofreader V.Girn to
Order 3596/58 Circulation 371Subscription
VNIIPI USSR State Committee
for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
production and printing company, Uzhgorod, Projecto st., 4
70
33.0
g, Oh
730

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US3182067A|1964-04-09|1965-05-04|Hoffmann La Roche|Benzodiazepine compounds|

---

BE790839A|1971-11-02|1973-04-30|Upjohn Co|NEW BENZODIAZEPINES, THEIR PREPARATION PROCESS AND THE MEDICINAL PRODUCT CONTAINING THEM|

---

DE2265371C3|1972-05-03|1980-12-11|Kali-Chemie Ag, 3000 Hannover|N- anilines|

---

DE2314993A1|1973-03-26|1974-10-03|Kali Chemie Pharma Gmbh|5-benzo-1,4-diazepines - sedatives etc. prepd. by cyclisation of N-anilines|

---

US3933816A|1974-09-12|1976-01-20|The Upjohn Company|3--7-substituted-3,5-dihydro-as-triazino[4,3-a][1,5]benzodiazepines|

---

US4073784A|1977-03-09|1978-02-14|The Upjohn Company|Certain as-triazino 4,3-a! 1,4!benzodiazepine-1,2-dione compounds|

---

DE2835708A1|1978-08-16|1980-03-06|Kali Chemie Pharma Gmbh|NEW ANGLE BRACKET TO 1.2 ANGLE BRACKET TO-FURNISHED 7-PHENYL-1,4-BENZODIAZEPINE DERIVATIVES, METHOD FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS|

---

DE2952279A1|1979-12-24|1981-06-25|Kali-Chemie Pharma Gmbh, 3000 Hannover|NEW 2-ACYLAMINOMETHYL-1,4-BENZODIAZEPINE AND ITS SALTS AND METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|

---

DE3151597A1|1981-12-28|1983-07-07|Kali-Chemie Pharma Gmbh, 3000 Hannover| -Anellated 1,4-BENZODIAZEPINE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|DE3151597A1|1981-12-28|1983-07-07|Kali-Chemie Pharma Gmbh, 3000 Hannover| -Anellated 1,4-BENZODIAZEPINE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|

---

US4596799A|1985-01-29|1986-06-24|Ciba-Geigy Corporation|9H-pyrrolo[2,1-c]-1,2,4-triazolo[4,3-a][1,4]benzodiazepines|

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US4882323A|1988-02-23|1989-11-21|American Home Products|1,2,3,4,5,6-hexahydro[1,3,6]triazocino[1,1-a]benzimidazoles|

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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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