5,10-dihydro-11h-dibenzo-(b,e)(1,4)-diazepine-11-ons substituted in position 5 or their physiologica

专利摘要:
Novel 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-ones of the formula I and their physiologically tolerable salts with inorganic or organic acids, in which R<1> denotes hydrogen or chlorine, R<2> denotes hydrogen or methyl, R<3> denotes hydrogen, methyl or 2-hydroxyethyl, R<4> denotes 2-hydroxyethyl, N-morpholylcarbonylmethyl or 2-acetylaminoethyl or R<3> and R<4>, together with the N atom to which they are bonded, denote a piperazine radical which is substituted on the imino group by a (2-furanyl)carbonyl, an acetyl or a 3,4,5-trimethoxybenzoyl radical, and A denotes a group of the formula -CH2-, -CH2-CH2- or -CH(CH3)- or a direct bond, can be prepared, inter alia, by reacting a 5,10-dihydro-5-haloacyl-11H-dibenzo[b,e]- [1,4]diazepin-11-one of the formula II in which R<1>, R<2> and A have the abovementioned meaning and X denotes a halogen atom, with an amine of the formula III in which R<3> and R<4> have the abovementioned meaning, or a hydrochloride of an amine of the formula III. The compounds of the formula I have an excellent antiulcerative and secretion-inhibiting action.
公开号:SU1364623A1
申请号:SU843804098
申请日:1984-10-19
公开日:1988-01-07
发明作者:Рюгер Карла；Ренерт Хельмут；Бар Фритц；Ломанн Дитер；Хоффманн Эвелин；Барч Ренти；Шуманн Штеффен
申请人:Феб Арцнаймиттельверк Дрезден (Инопредприятие)；
IPC主号:

专利说明:

The invention relates to new 5,10-dihydro-11H-dibenzo-e-diazepin-11-one substituted in the 5th position;
o s-a-1;
R
or their physiologically compatible salts with inorganic or organic acids, in which A represents either a group of the formula -CHj-, then R is hydrogen or chlorine, Rj, is hydrogen or methyl, R and R are 2-hydroxyethyl group, or R and R. together with the N atom to which they are bonded, means a piperazine residue which is replaced by an (2-furanyl) -carbonyl residue at the imino group, or if A means a group of the formula -CH (CH), then R means chlorine, RJ - hydrogen and R, and R4, respectively, mean the 2-hydroxyethyl group, which has an anti-ulcer and suppressive secretion action.
The purpose of the invention is new diazepine derivatives with improved properties.
Example 1. 8-chloro-5,10-dihydro-5- (b.is) -2-oxyethyl (minocetyl) -11H-dibenzo in, el, 4J-diazepin-1 1-one.
6.4 g (0.02 mol) of 8-chloro-5-chloro-acetyl-5.0-dihydro-11H-dibenzo in, A-diazepin-11-one in 200 ml of chloroform is heated to boiling and 8 are added dropwise 4 g (0.08 mol) of di-ethanolamine.
The reaction mixture is stirred
Seaethyl (aminoacetyl) -11H-dibenzo 5sl, 4-diazepin-11-one is dissolved in 80 ml of isopropanol while heating and the solution is mixed with 40 ml of approximately 13% isopropanol hydrochloric acid while still warm. After cooling 10 times, the crystalline product is filtered off with suction and recrystallized from 140 ml of 93% ethanol. The yield is 4.6 g (53.8% of theory). M.p. 225-226 С (at decomposition). U Found,%: C 53.79; H 4.79; N 9.83; C1 16.34. C, qH2,
Calculated,%: C 53.53; H 4.97; N 9.86; C1 16.63.
Fumarat. 9.75 g (0.025 mol) of 8-chloro-5,10-dihydro-5-bis- (2-oxo-ethyl) aminacetyl-11H-dibenz in, e 1,4-diazepin-11-it is dissolved by heating in 400 ml of acetone, after 25 of which the prepared solution is mixed with a hot solution of 2.90 g (0.02 mol) of fumaric acid in 480 ml of ac tone. Immediately after this, the solution is evaporated by half, at 30 room temperature the crystallization is allowed to take place, filtration is performed, the crystalline product is washed with acetone and dried at room temperature. The yield is 7.5 g (59.3% of the theoretically calculated value). M.p. 208 ° C (with decomposition).
Found,%: C 54.51; H 4.66; N 8.44; C1 7.17. С „Н„ Ы, OСС1
calculated,%: C 54.61; H 4.78; N 8.31; C1 7.01.
Phosphate; 4.88 g (0.0125 mol) 8-chloro-5,10-dihydro-5-bis- (2-hydroxy35
40
about,. 45 ethyl) aminoacetyl1-11H-dibenzo Gu. E
2 h at boiling point with reverse g / t. L j
11.4-diazepin-11-it is dissolved in a cooler, concentrated in - J g
200 ml of acetone by heating to boiling point. After cooling, 100 ml of toluene are added to the solution.
vacuum, the residue is boiled with butyl acetate and recrystallized from acetonitrile with the addition of CFO-charcoal. The yield is 3.4 g (43.7% of theory). M.p. 188-192 ° С (during decomposition) ...
Found,%: C 58,32; H 4.85; N 10.69; C1 9.18.
With „NgoK, 04С1
Calculated,%: C 58.54; H 5.17; N 10.78; C1 9.09.
20
3646232
Hydrochloride. 7.8 g (0.02 mol) of 8-ChLOR-5,10-dihydro-5- (bis) -2-hydroxyethyl (aminoacetyl) -11H-dibenzo 5 sl, 4-diazepin-11-she is dissolved in 80 ml of isopropanol with heating and still warm solution is mixed with 40 ml of approximately 13% isopropanol hydrochloric acid. After cooling 10 times, the crystalline product is filtered off with suction and recrystallized from 140 ml of 93% ethanol. The yield is 4.6 g (53.8% of theory). M.p. 225-226 С (at decomposition). U Found,%: C 53.79; H 4.79; N 9.83; C1 16.34. C, qH2,
Calculated,%: C 53.53; H 4.97; N 9.86; C1 16.63.
Fumarat. 9.75 g (0.025 mol) of 8-chloro-5,10-dihydro-5-bis- (2-hydroxyethyl) aminacetyl1-11H-dibenz in, e 1,4-diazepin-11-it is dissolved by heating in 400 ml of acetone, after 25 of which the prepared solution is mixed with a hot solution of 2.90 g (0.025 mol) of fumaric acid in 480 ml of acetone. Immediately thereafter, the solution is evaporated by half, at 30 room temperature it is allowed to crystallize, filtering is performed, the crystalline product is washed with acetone and dried. at room temperature. The yield is 7.5 g (59.3% of the theoretically calculated value). M.p. 208 ° C (with decomposition).
Found,%: C 54.51; H 4.66; N 8.44; C1 7.17. С „Н„ Ы, OСС1
calculated,%: C 54.61; H 4.78; N 8.31; C1 7.01.
Phosphate; 4.88 g (0.0125 mol) 8-chloro-5,10-dihydro-5-bis- (2-hydroxy35
40
45 ethyl) aminoacetyl1-11H-dibenzo Gu. E
11.4-diazepin-11-it is dissolved in - J g g
200 ml of acetone when heated to boiling point. After cooling, 100 ml of toluene are added to the solution.
This is followed by mixing with a few drops of phosphoric acid until acidic. The crystalline product is filtered off, washed with a small amount of acetone and
5 dried in a desiccator over phosphorus pentoxide. The yield is 3.5 g (54.4% of the theoretically calculated value). M.p. 110-120 ° C (with decomposition).
 31364623
Found,%: C 44.41; H 5.10; N 7.84; C1 is 6.60; 4.90. , C1, P, Calculated,%: C 44.33; H 5.10; N 8.16; C1 6.88; 5.25.
The 8-chloro-5-chloroyl, ethyl-5, 10-DIHYDRO-1, 1H-dibenzo, e 1 used as the starting material is stirred for 6 hours at the temperature of cy-diazepin-11-one it can be obtained reflux After cooling, 200 ml of water is added to the reaction mixture, stirred well, and the mixture is filtered with suction. The filter residue is washed with water, 15 is dissolved in 100 ml of chloroform,
Shake all in 100 ml of water and s-piperazinyl (acetyl) -11H-dibenzo in, e 1.4 diazepin-1 1-one.
12.8 g (0.04 mol) 8-chloro-5-chloro-f-acetyl-5, 10-dihydro-1 1-H-dibenzo in, 43 diazepin-1 1-one in 200 ml of toluene, together with 15 , 4 g (0.08 mol) of 1- (2-furanyl) carbonyl piperazine
thus concentrated in vacuo. The residue is mixed twice with chloroform and each time concentrated in vacuo,
crystallized after seeding, sucked off and recrystallized from 200 ml of isopropanol with the addition of CFO-coal. In the outgoing way.
39.2 g (0.16 mol) of 8-chloro-5,10-β-dihydro-11H-dibenzo b, e 1, azepin-11-it is suspended in 400 ml of xylene, heated in an oil bath at a bath temperature of 100 ° C , mixed with 18.1 g (0.16 mol) of chloroacetyl chloride and stirred for 3 hours at the same temperature. Then added dropwise
once again 9.04 g (0.08 mol) of chlora- -. 20 is then added with 20 ml of isopropanol, tilchloride, stirred for 1 hour at a heat of 10 minutes on a steam bath, in the bath, after cooling, the crystallized crystal is sucked off and dried at room temperature. The crude product is recrystallized from run 25 of 12.6 g (67.8% of those with 800 ml of acetonitrile with the addition of ori). M.p. 190-193 C. EPN-coal. The yield is 34.1 t. Found:%: 62.68; H 4.74;
N 11.42; C1 7.68.
Cz4HziN404Cl
30 Calculated,%: C 62.00, H 4.55}; N 12.05; C1 7.63.
Hydrochloride. 22 g (0.047 mol) 8-chloro-5,10-dihydro-5- 4- (2-furanyl) - -carbonyl- (1-piperazinyl) acetyl „g –11H-dibenzo b, e l, 4J diazepin-11 The α-β is dissolved in 350 ml of isopropanol with gentle heating and, after gentle cooling, 200 ml of an approximately 19% solution is added.
(66.3% of theory). M.p. 245.5 - 247, (during decomposition).
Similarly, by reacting the appropriate products, the following products are obtained from their starting compounds:
with chloroacetyl chloride in xylene as a solvent 5-chloroacetyl-5,10-dihydro-11H-dibenzo in, e Cl, 4-diazepin-11-one, so pl. 238.5 - 240 ° C (from butyl acetate);
with chloroacetyl chloride in toluene in
as the solvent 8-chloro-5-chloro-40 isopropanol hydrogen chloride.
stir for 6 h at the boiling temperature under reflux. After cooling, 200 ml of water is added to the reaction mixture, stirred well, and the mixture is filtered with suction. The filter residue is washed with water, dissolved in 100 ml of chloroform,
-piperazinyl (acetyl) -11H-dibenzo in, e 1,4 diazepin-1 1-one.
12.8 g (0.04 mol) of 8-chloro-5-chloro-acetyl-5, 10-dihydro-1 1-H-dibenzo in, 43 diazepin-1 1-one in 200 ml of toluene, together with 15.4 g (0.08 mol) 1- (2-furanyl) carbonyl piperazine
thus concentrated in vacuo. The residue is mixed twice with chloroform and each time concentrated in vacuo,
crystallized after seeding, sucked off and recrystallized from 200 ml of isopropanol with the addition of a CFO coal. 20 ml of isopropanol are added to the solution, heated for 10 minutes on a steam bath, the rate is 12.6 g (67.8% of the volume). M.p. 190-193 C. Found,%: C 62.68; H 4.74;
acetyl-5,10-dihydro-10-methyl-11H- -dibenzo fB, e l, 4-diazepin-11-one, so pl. 220-221, 5-chloroacetyl-5,10-dihydro-10-methyl-11H-dibenzo in, l, 4 -diazepin-11-one, so pl. 178.5-181 s (from acetonitrile);
with 2-bromop15opionyl chloride in toluene as a solvent 5- (2- -bromo) propionyl-8-chloro-5,10-dihydro-11 H-dibenzo-b, e l, 4-diazepin--11-one, m.p. . 268-289,
with 2-chloropropionyl chloride in toluene as a solvent 5- (2After standing for 1 h, the solution is concentrated in vacuo to dryness, a little isopropanol is added again, concentrated again and the ointment of 100 g of n-propanol is recrystallized 45 g yr - lem. Then recrystallized once more from 50% ethanol. The yield is 15.2% (61.8% of theory), mp 209-215 ° C (decomposition).
Found,%: C 54.99; H 4.93; N 11.37; C1 13.70.
50
-chloro-propionyl-8-chloro-5,10-dihydro-11 H-dibenzo b, e 1,4-diazepin-11- Calculated,%: C 55.50; H 4.66; - he, so pl. 281-284 ° C (with decomposition-N 10.79; C1 13.65.
 nii) .Primep 3. 5,10-Dihydro-5P p and mre 2. 8-Chloro-5,10-di-bis- (2-oxystil) aminoacetyl-11Hydro-5-4 - (2-furanyl) -carbonylZ-1 - dibenzo a, e J3, 4 diazepin-11-one.
After standing for 1 hour, the solution is concentrated in vacuo to dryness, a little isopropanol is added again, the mixture is again concentrated and the somewhat oily residue is recrystallized from 100 g of n-propanol with CFO-yr. Then again recrystallized from 50% ethanol. The yield is 15.2% (61.8% of theory). M.p. 209-215 ° С (during decomposition).
Found,%: C 54.99; H 4.93; N 11.37; C1 13.70.
513646236
5.73 g (0, t) 2 mol). 5-chloroacetyl-. diazepin-11-one, 100 ml of chloroform-5,10-DIHYDRO-11H-dibenzo-b.e and 7.2 g (0.04 mol) of 1- (2-furan) carbonylZpiperazine for 7 hours at
while stirring, the mixture is heated under reflux. After the reaction, the cooled reaction solution is shaken twice with 30 ml of water, twice with 10 ml and once with 5 ml
Diazepin-11-one and 100 ml of chloroform are heated to boiling, 8.44 g (0.08 mol) of diethanolamine in a small amount of chloroform are added dropwise within 1 hour and stirred for 3 hours at boiling point. After
cooling the chloroform phase in a diluted 1: 1 hydrochloric acid,
with 20 ml of NaHCOj solution (2 g of combined hydrochloric acid phases
NaHCOj in 50 ml of water), twice with 10 ml of boiling water once with 30 ml of chlorine once with 5 ml of diluted 1: 1 form and poured into 100 ml of dilute hydrochloric acid. The combined salt 1: 1 solution of ammonia, and the acidic phases are poured into 50 ml of an oily product, which is added 1: 1 ammonia solution. After merging the aqueous alkaline solution
The main solution is extracted then the phase is dissolved in 50 ml of chloroform,
three times with 50 ml of chloroform, dry the water-alkaline phase phase shake twice with 50 ml of chloroform and the combined
The 20 chloroform phases, after drying, are concentrated in vacuo.
uniform chloroform phases over and concentrate to dryness. The residue is mixed with 10 ml of isopropanol.
dry up The residue is boiled with 20 ml of toluene, after cooling, the crystallized precipitate is filtered off with suction and 25 of 110 ml of 96% ethanol with CFO-charcoal are recrystallized. The yield is 3.8 g (44.2% of theory), m.p. 230-233 ° C.
when heated, transferred to the solution and after seeding crystallized aspirated. Recrystallized from 35 ml of acetonitrile. The yield is 1.8 g (25.3% of theory), m.p. 144 With (at decomposition).
Found,%: C 64.65; H6.12; N 11.82
.NjO,
Calculated,%: C 64.21; H 5.96; At 11.82.
Hydrochloride. 7 g (0.015 mol) of 5,1O-dihydro-5-bis- (2-hydroxyethyl) - -aminoacetyl - 1H-dibenzo) diazepin-11-one is dissolved in 210 ml of isopropanol by heating. After cooling, 7 ml of an isopropanol solution of hydrogen chloride hydrochloric acid (approximately 19%) are added with stirring and then 35 ml of ether are added, the reaction mixture is left to stand for 12 hours, the crystallized material is filtered off with suction and dried in a desiccator. The crude product is recrystallized from 60 ml of methanol with CFO-charcoal. The yield is 2.99 g (39.5% of theory), m.p. 211-214 ° С (during decomposition).
- Found,%: C 58.23; H 5.73; N 11.01; C1 9.15.
dry up The residue is boiled with 20 ml of toluene, after cooling, the crystallized precipitate is filtered off with suction and 25 of 110 ml of 96% ethanol with CFO-charcoal are recrystallized. The yield is 3.8 g (44.2% of theory), m.p. 230-233 ° C.
Found,%: C 66.54; H 5.19;
N 12.33.
thirty
C ,,,, 04
C, 66.97; H 5.15;
Calculated, / N 13,02.
Hydrochloride. 10 g (0.023 mol) 5,1O-dihydro-5- 2- (4- (2-furanyl) -2-carbonyl -1-piperazinyl) acetyl-11H-dibenzo in, e 1,4-diazepin-11H-one is dissolved in 675 ml of isopropanol, pt tons for 15 minutes with CFO-carbon, sucked off and mixed with hot 10 ml of isopropanol solution of HCl (approximately 19%). The hydrochloride crystallizes with 1 mol of water upon cooling.
Found,%: C 59.08; H 5.38; 45 N 11.03; C1 7.17; .3,4.
CI H N OJ-CI
Calculated,%: C 59.44; H 5.20; N 11.55; C1 7.31; Hj.0 3.7.
40
C ,,, 0, C1
Calculated,%: C 57.24; H 5.66; N 10.72; C1 9.05.
Example 4. 5,10-Dihydro-550 Example 5. 5,10-Dihydro-5- - bis- (2-hydroxyethyl) aminoacet-10-methyl-11H-dibenzo in, e 1,4 diazepin-1 1- he is HCl.
6.02 g (0.02 mol) of 5-chloroacetyl- (2- (4- (2-furanyl) carbonyl) -1-pipa-55 5 10 Dihydro-10-methyl-11H-dibenzo razinil acetylZ-11H-dibenzo in ,, f) 1,4 diazepin-11-one in 100 ml
l, 4 -diazepin-11-on.1,2-dichloroethane is heated to a temp. 5.8 g (0.02 mol) of a 5-chloro-acetyl boiling mixture with reverse refrigeration-5, 10-DIHYDRO-1 lll-dibenzo in, e3l, 4 | -HJIKOM, 8.44 g are slowly added dropwise
stirring, the mixture is heated to reflux. After the reaction, the cooled reaction solution is shaken twice with 30 ml of water, twice with 10 ml and once with 5 ml
The 20 chloroform phases, after drying, are concentrated in vacuo.
dry up The residue is boiled with 20 ml of toluene, after cooling, the crystallized precipitate is filtered off with suction and 25 of 110 ml of 96% ethanol with CFO-charcoal are recrystallized. The yield is 3.8 g (44.2% of theory), m.p. 230-233 ° C.
Found,%: C 66.54; H 5.19;
N 12.33.
C ,,,, 04
C, 66.97; H 5.15;
Calculated, / N 13,02.
Hydrochloride. 10 g (0.023 mol) 5,1O-dihydro-5- 2- (4- (2-furanyl) -carbonyl -1-piperazinyl) acetyl-11H-dibenzo in, e 1,4-diazepin-11H-one dissolved in 675 ml of isopropanol, boiled for 15 min with CFO-charcoal, sucked off and mixed with hot 10 ml of isopropanol solution of HCl (approximately 19%). The hydrochloride crystallizes with 1 mol of water upon cooling.
Found,%: C 59.08; H 5.38; N 11.03; C1 7.17; .3,4.
CI H N OJ-CI
Calculated,%: C 59.44; H 5.20; N 11.55; C1 7.31; Hj.0 3.7.
(0.08 mol) of diethanolamine and the reaction mixture is stirred for 4 hours at reflux temperature. After cooling, shake once with 30 ml of 10% NaHCO solution, twice with 10 ml and once with 5 ml of diluted 1: 1 hydrochloric acid, and the combined hydrochloric acid phases are shaken once with 30. ml of chloroform.
100 ml of a diluted 1: 1 ammonia solution are added to the hydrochloric acid phases, shaken three times with 30 ml of chloroform, the chloroform phases are dried over and concentrated in vacuo to dryness. The residue is dissolved in 30 anhydrous acetone and hydrogen chloride is passed until acidic. Before this, an ointment-like product is released which crystallizes at the boiling point; SRI (expulsion). The hydrochloride is recrystallized from AO ml of 96% ethanol with CFO-charcoal and dried at 100 C and a pressure of 1 Torr. The yield is 4.0 g (49.3% of theory), m.p. 196-199 ° C (with decomposition).
Found,%: C H 5.97;




N 10.42; C1 8.70. Calculated,%:
C 59.19; H 5.96; N 10.35; C1 8.74.
Example 6. 8-Chloro-5,10-di-hydro-5-bis- (2-hydroxyethyl) aminoacetyl-10-methyl-11 H-dibeneus, e l, 4 diazepin-11 - it "HC1.
6.7 g (0.02 mol) of 8-chloro-5-chloro-acetyl-5,10-dihydro-10-methyl-11H-dibenzo in, e 1,4 diazepin-11-one and 100 ml of chloroform with stirring is heated to boiling and 8.44 g (0.08 mol) of diethyl amine in 5 ml of chloroform are slowly added dropwise. The mixture is stirred at reflux temperature for 7 hours, the cooled reaction mixture is shaken twice with 50 ml of water, the chloroform phase is extracted twice with 10 ml and once with 5 ml of 1: 1 diluted hydrochloric acid, combined hydrochloric acid. 1 11 v i. fi ti i.j 1 nuic C
Shl extracted with 50 ml of chloroform, see sew with 100 ml of diluted 1: 1



ammonia solution and shaken three times with 50 ml of chloroform, and the leached product is dissolved.
The combined chloroform phases are shaken with 50 ml of water, dried over and concentrated in vacuo to dryness. The residue is dissolved in 30 ml.
isopropanol when heated, the solution is cooled again and pass hydrogen chloride until acidic. A greasy product is isolated which crystallizes on boiling. It is sucked off and dried at room temperature. The yield is 6.2 g (70.4% of theory), m.p. 127 (at decomposition). Found,%: C 54.43; H 6.01;
150 ° C
five
N 9.03; C1
15.48,
g
C, 54.56; H 5.27;
10 ", 4
Calculated; 5 N, 9.54; C1 16.10.
Found,%: C 58.09; H 4.91; N 11.37; C1 9.45. C, gH, gN, 04Cl Calculated,%:
0
f
C 57.60; H 4.83; N 11.18; C1 9.44.
Example 7. 8-Chloro-5,10-di-hydro-5- (4- (2-furanyl) carbonyl-α-piperazin-1-yl) acetyl-10-methyl-11H-dibenzo b, e l, 4j diazepin-11-one.
6.7 g (0.02 mol) 8-chloro-5-chloro-acetyl-5,10-dihydro-10-methyl-11H-dibenzo in, e 1.4 diazepin-11-one 8.8 g ( 0.04 mol) of 1- (2-furanyl) carbonyl piperazine hydrochloride and 6.0 g (0.06 mol) of triethylamine in 70 ml of chloroform are stirred for 7 hours at reflux temperature. To the cooled reaction solution, 100 ml of water are added, mixed well, the phases are separated and the chloroform phase is extracted with 100 ml of diluted 2: 1 hydrochloric acid. X hydrochloric acid phase is added with 100 ml of chloroform and 140 ml of diluted 1: 1 ammonia solution, mixed well, the separated chloroform phase is dried over and concentrated to dryness in vacuo. The residue is boiled with 10 ml of isopropanol, sucked off, dried at room temperature and recrystallized from absolute alcohol in CFO-charcoal. The yield is 5.4 g (56.01% of theory), m.p. 189-194 ° С (at times 5
0
five
 bed)
Found,%: C 62.33; H 4.89; N 11.43; C1 7.61. С „Н„ Ы О С1
55 Calculated,%: C, 62.70; H 4.84; N 11.70; C1 7.40.
Hydrochloride. 14.4 g (0.03 mol) 8-CHLOR-5,10-DIHIDRO-5- (4- (2-furanyl) carbonyl -1-piperazinyl) ace 9
Tyl-10-methyl-11H-dibenzo-Gv, e1 Cl “diazepin-11-it” is suspended in 80 isopropanol and mixed with 100 ml of isopropanol hydrochloric acid (approximately 19%). It is then slightly heated, and all free base is dissolved. The solution is concentrated in vacuo to dryness and boiled with alcohol, and the ointment-like solid crystallizes. The residue is again taken up in solution with isopropanol and the hydrochloride is precipitated with 500 ml of ether. The crystallized acid is sucked off, dried in a desiccator over NaOH (vacuum water jet pump) and for 8 hours at a pressure of 2 torr over 5-. The yield is 11.4 g (72.3% of theory), m.p. 100 ° С (160-169 С at decomposition).
Found,%: C 57.43; H 5.04; N 10.48; C1 13.53; 0.5 mol 2.40 ..
Cj5H2sN, 0, .5 Cl,
Calculated,%: C 57.26; H 4.81; N iO, 68; C1 13.73; 0.5 mol 1.72. ,
Example 8. 5,10-Dihydro-5- - bis- (2-hydroxyethyl) aminoacetate-11H -dibenzo LB, ry, 4 diazepin-11-one to HC1.




46 g (0.16 mol) of 5-chloroacetyl-5,10-DIHIDRO-11H-dibenzo in, e diazepin-11-one, 200 ml of dimethylforma 30 with 100 ml of chloroform and mixed with cooling and stirring with 100 ml of diluted 1: 1 ammonia solution. The separated chloroform phase is dried over sulphate in „„. three, evaporated in vacuo, the residue
The MFA and 33.76 g (0.32 mol) of diethanol-35 are mixed with 3 ml of isopropanol and the mixture is stirred for 8 hours and the crystallized glass is sucked off. The code is at room temperature and is Q (7.44% of theory). M.p. stand for 12 hours at this temperature - 169-174 seconds
perature. Then mix the reaction Found,%: C 59.98; H 5.91; mixture with 1 g of CFO-carbon, mix N 10 10-C1
1 h at room temperature, coal g and s p h
1 and
sucked off and the solution is concentrated Calculated,%: C 59.48; H 5.49; in vacuum to dryness. Liquid residue N 10 40- C1 8 78
mixed with 200 ml of chloroform, injected - example 10. 5,10-dihydro: is boiled with 20 ml of water and concentrated again. 5 5-G4- (2-phenyl) -carbonyl 1-1-pyrite . After that, perazinyl-acetyl-10-methyl-11H-acetone is added and mixed with freshly prepared g-C g7 / i nlp. a solution of HCl in acetone or with concentrated benzo b, e 1 4 diazepin-11-one. - „„ „/ 6.02 g (0.02 mol) with 5-chloro-acetylated hydrochloric acid (approximately. P.
g - 5,1O-dihydro-1O-methyl-11H-dibenzo
but 15 ml) until acidic. 50 g - n / 1,
,. „„ „„ „„ „A, e 1,4 diazepin-11-one move First, ointment may be released, - n n c
sew in 100 ml of chloroform with 0.5 g
Ca, which slowly crystallizes% a
f g / o l g (0.05 mol) of triethylamine and 6.5 g (yield 54 g, 86.1% of theory). Sy / A o. g / t l. h t
(0.03 mol) 1-G (2-furansh1) carbonyl swarm product is sucked off, washed with L-v v
. O., 0piperazine; x HC1 for 5 hours
in a tone that is dissolved in 1Z-1J
the amount of methanol is heated by a half-hour reflux condenser. Ca with 5 g of CFO-coal, sucked off the light. After precipitation, the reaction mixture
The solution is concentrated, the sample is shaken twice with 50 ml of water,
but 1/3 and mixed with 200 mp acetate-twice with 10 ml and once with dilution 10

that The crystallisate is dissolved once more in a 15-fold amount of methanol, heated again with 2.5 g of CFO-coal, sucked off, concentrated to 1/3 and the crystallized mixture is sucked off. The product is boiled with 5 times the amount of acetone. The yield is 43.5 g (69.4% of theory). M.p. 208 ° C (during decomposition).
Example 9. 8-Chloro-5,10-dihydro-5 2-bic- (2, 2-HYDROXYETSH1) - amino propionyl-11H-dibenzo C, e 1,43 diazepin-11-one.
7.6 g (0.02 mol) 5-2-bromo (pro5 pionyl) -8-chloro-5,1O-dihydro-11H-dibenzo C, e3 1,4-diazepin-11-one in 100 ml With the addition of 2.46 g (0.03 mol) of sodium acetate, cyclohexanone is heated to a bath temperature of 150 ° C. and mixed with 3.13 g (0.03 mol) of diethanolamine for 30 minutes. The reaction mixture is stirred for 7 hours at the indicated bath temperature, then it is evaporated in a vacuum, the residue is taken up in 100 ml of chloroform, shaken with 100 ml of water and immediately thereafter with a diluted 1: 2 hydrochloric acid.
The acid phase is mixed with
0 100 ml of chloroform and with cooling and stirring, mixed with 100 ml of a diluted 1: 1 ratio of ammonia solution. The separated chloroform phase is dried over sulfate.
1,113
1: 1 hydrochloric acid (5 ml). The combined hydrochloric acid phases are shaken with 50 ml of chloroform, combined with 100 ml of a diluted 1: 1 ammonia solution, and shaken three times with 50 ml of chloroform.
The combined chloroform phases are shaken once more with 50 ml of water, dried over sodium sulfate and evaporated in vacuo to dryness. The residue is dissolved in boiling isopropanol and allowed to stand until crystallization at room temperature.
The yield is 5.8 g (65.2%
from theory). M.p. (1bGs) 1b6-170 with.
Hydrochloride. 5 g (0,0113 mol) of 5,10-dihydro-5- (4- (2-furanyl) -carbonyl -1-piperazinyl acetyl) -10-methyl-11 H-dibeiso, e 1, 4-Diazepin-11-it is dissolved in 110 ml of ethyl ester of ethanoic acid with heating, the solution for clarification is boiled slightly with activated carbon. Hydrogen chloride is passed into the still warm solution with stirring for an acid reaction, and the hydrochloride crystallizes.
The yield is 5 g (89.1% of theory). M.p. (different).
Found,%: C 59.51; H 5.17; N 10.99; C1 7.70; 3.65.
WITH .
Calculated%: C, 60.18; H 5.45; N 11.23; C1 7.11; H, jO 3.65.
The inhibitory effect on the formation of stress-induced gastric ulcers was determined according to the IABrodce method in female rats weighing 150-180 g. The food intake before the start of the test is 48 hours. The test substances are administered immediately before the start of the experiment. gastric probe. The immobilization was carried out using a plaster dressing for 18 hours. Throughout the experiment, the room temperature was constant at 20 ° C. At the end of the experiment, the animals are sacrificed with ether, the stomach is removed from them, a sample is taken along the minor curvature and the defects in the mucous membrane of the gland are evaluated by number and length in comparison with the control group. For statistical calculation, a probit-regression analysis is used.
The effect of substances on the size of the pupil is examined in female mice weighing 18-23 g according to the test method R.Pennka. After 30.60, 90, 120, 180 and 240 minutes after drug administration

12
0
20

25
orally determine the width of the pupil and calculate the x-fold change from the initial value. The quality is the dose at which the pupil dilates threefold as compared with the initial value.
Acute toxicity is determined in 5 males and 5 females with a weight of 18–23 g per dose. The test substances are administered orally. The DC is calculated according to Zitchfield and Wilcoxon.
The results of all studies are presented in table 1y.
The results show that new compounds prevent the occurrence of gastric ulcers of various origins. On the model of immobilized ulcers, they show an equal force of action, which is comparable to that of the structurally similar compound of pirenzepin, respectively, better than him.
For all compounds, the ratio
thirty
35
25
40 -.
ED,
5- short
Pupil motility to ED
50

权利要求:
Claims (1)
[1]
suppression of ulcers is greater, respectively, substantially greater than for atropine. Thus, in the therapeutic area of the dose there are no mydriatic ones: actions. Invention Formula
Substituted in the 5th position of 5,10-β-dihydro-11H-dibenzo in, fl, 4 diaz PINU-11-ONY of the general formula
: I, oh
.N-c
0 C-A-15 /
R
where is either a group of the formula then
-CHj -,
R
- hydrogen or chlorine; Rj is hydrogen or methyl; R and R are a 2-hydroxyethyl group or together with the N-atom to which they are bound, a piperazine residue that is replaced by an (2-furanyl) -carbonyl residue in the imino group, or A is a group of the formula -CH (CH,), - then R, -xlope, Rj is hydrogen, RjHR is a 2-hydroxyethyl group, respectively, or their physiologically compatible salts with inorganic or organic acids, which show anti-ulcer and inhibitory activity.
Compound 5,10-dihydro-5- | (methyl) -1-piperazinyl-acetyl) -11H-dibenzo in, e3 1 (Dpdiazepin-1-one. Compound 8-chloro-5, 10-dihydro-5- L (methyl) -1-piperazinyl acetyl-11H-dibenzo b, e, 1,4 diazepin-11-one.
Compiled by G. Konnov
Editor N. Bobkova Tehred M. Didyk Proofreader A. Zimokos
Order 6534/19 Circulation 370Subscription
VNIIPI USSR State Committee
for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5

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YU175484A|1987-08-31|

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引用文献:

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FI49509C|1968-08-20|1975-07-10|Thomae Gmbh Dr K|Process for the preparation of pharmacologically active 5,10-substituted 5,10-dihydro-11H-dibenzo [b, e] -1,4] deazepin-11-ones and their salts.|

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DE1795183B1|1968-08-20|1972-07-20|Thomae Gmbh Dr K|5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one derivatives and drugs|

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US3727046A|1971-01-04|1973-04-10|D Woods|Vehicle travel speed control and monitoring method and apparatus|

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JPS4913192A|1972-06-01|1974-02-05|

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DE3028001A1|1980-07-24|1982-02-18|Dr. Karl Thomae Gmbh, 7950 Biberach|NEW 5,10-DIHYDRO-11H-DIBENZO DIAZEPINE-11-ONE SUBSTITUTED, PRODUCTION METHOD AND PRODUCTS CONTAINING THIS COMPOUND|DE3421133A1|1984-06-07|1985-12-12|Philips Patentverwaltung|CIRCUIT FOR THE SUPPLY OF THE CONTROL AND CONTROL DEVICE OF A REGULATED DC VOLTAGE CONVERTER|

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DE3643666A1|1986-12-20|1988-06-30|Thomae Gmbh Dr K|NEW CONDENSED DIAZEPINONE, METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|

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DE3726908A1|1987-08-13|1989-02-23|Thomae Gmbh Dr K|NEW CONDENSED DIAZEPINONE, PROCESS FOR THEIR MANUFACTURE AND MEDICAMENTS CONTAINING THESE COMPOUNDS|

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US4931436A|1988-08-09|1990-06-05|Dr. Karl Thomae Gmbh|Condensed diazepinones, processes for preparing them and pharmaceutical compositions containing these compounds|

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DE4117123A1|1991-05-25|1992-11-26|Dresden Arzneimittel|NEW 5-AMINOACYL-5,10-DIHYDRO-11H-DIBENZO / B, E // 1,4 / -DIAZEPIN-11-ONE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT|

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US5324832A|1991-07-03|1994-06-28|The United States Of America As Represented By The Department Of Health And Human Services|Muscarinic antagonists|

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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DD83255766A|DD236731B3|1983-10-19|1983-10-19|PROCESS FOR PREPARING NEW 5-POSITION SUBSTITUTED 5,10-DIHYDRO-11H-DIBENZO | B, E¨ | 1,4¨DIAZEPINE-11-ONEN|

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