Method of producing 2-acylaminomethyl-1h-2,-3-dihydro-1,4-benzodiazepines or acid-connecting salts t

专利摘要:
The invention relates to the class of substituted 1,4-benzodiazepines, in particular substances of the general formula 1: 0-CbH (A) / C CbH5 (B) -and NBt-CH-CH cn 2-W2-ao. where R P, lower alkyl; R, H, lower alkenyl; : i:%; iu3-R b,. Rn, CI, Ui Br, lower alkyl, lower alkoxnl, NOj; R N,, - alkl; R C-C-alkyl; ring A is not substituted or is substituted by one to two radicals of the group lower alkyl, lower alkoxy, lower alkylthio, halogen, NO, or two adjacent C-atoms of ring A are linked by a methylenedioxy group; ring B is unsubstituted or substituted by one to three radicals of the group lower alkyl, lower alkoxyl, halo and CF,; or their salts, which have analgesic activity. To extract biological activity, new compounds of general formula 1 were synthesized based on the reaction between the corresponding amine or its salt and the carboxylic acid or its halide, or ester. The process is carried out at a temperature of -30 to in an inert organic solvent. If necessary, the resulting substance, where Rj H, alkylate or ring A nitrously Yield 60-76%. Crystalline substances, so pl. within 1tO-280 C for hydrochlorides. 7 tab. SO e IN SL SO TH & so
公开号:SU1253430A3
申请号:SU3220053
申请日:1980-12-22
公开日:1986-08-23
发明作者:Цойгнер Хорст；Ремер Дитмар；Липманн Ханс；Милковски Вольфганг
申请人:Кали-Хеми Фарма Гмбх (Фирма)；
IPC主号:

专利说明:

The invention relates to methods for the preparation of new 2-acnlaminomethyl-1, A. 1H-2,3-dihydrogen benzodiazepines of the general formula 1:
.
Chg
.CH -N-e- cc d „/ CIS o
-Hp
where is hydrogen or lower
an alkyl radical; Rj is a hydrogen atom, lower alkyl
or a lower alkynyl radical; Rj is a group of formula

About s i
Q
or
where RJ is a hydrogen atom or Cj-Cj-alkyl;
RI is a hydrogen atom, halogen, preferably Zyur or bromine.
25 boiled salt, dried over sodium sulfate and filtered. After distilling off the solvent, 21 g of the substance is obtained, which is subsequently chromatographed with cyclohexane, toluene, methylene alkyl, lower alkoxy chloride chloride and ethanol for 300 g of the atro or nitro radical; Minium Oxide 1. Toluene and Methylene Ri. Alkyl; Chloride Eluates (19.4 g) are combined,
dissolved in ether and mixed with a solution of 7.8 g of racemic tartaric acid in ethanol. Salt is precipitated by the addition of ether and after filtration is recrystallized from ethanol at temperatures ranging from -70 to. 10 g of 1-methyl-2- (thiophen-2-carboxyl) -amino iets J-5-phenyl-1H-2, 3-dihydro are obtained. -1,4-benzodiaceptantartrate XO, 4 mol of ethanol with m.p. 110 ring A is unsubstituted or substituted by 1-2 substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkyl, halo, nitro radical, or two adjacent C-atoms of the phenyl rings are linked together through a methylenedioxy group;
the ring is unsubstituted or 1 to 3 fold substituted by substituents selected from the group consisting of lower alkyl, lower alkoxy, halo, or trifluoromethyl radical,
or their acid addition salts, which have analgesic activity.
The purpose of the invention is to obtain new benzodiazepine derivatives with a different spectrum of biological properties than the known structural analogues, which is achieved by the properties described by 2-acylaminomethyl-1H, 2,3-dihydro-1,4-benzodiazepigyuv.
The structures of the new compounds were confirmed using spectroscopic studies, in particular, using an accurate analysis of the NMR spectrum. In the tables, if not available
35
40
45
50
55
 (with different). Output 36.4% in terms of the initial product II. The base has so pl. 112-115 ° C.
Example 2. 1-Methyl-2- (thiophen-3-carbonyl) -aminomethyl 3-5-phenyl-1 H-2, 3-dihydro-1,4-benzodiazepine.
13.5 g of thiophene 3-carboxylic acid (formula 111, Rj P) is dissolved in 300 ml of methylene chloride and cooled to, Then 14.5 ml of triethylamine are added and then 11.2 ml of ethyl ether are added dropwise after 5-10 minutes chloroformic acid. The reaction solution is stirred for another 30 minutes at 0-5 ° C and then, at this temperature, 27.9 g of 1-methyl-2-aminomethyl-5-fed data are added dropwise to the melting point of monohydrochlorides. If necessary, indications are given for the presence of water, acetone,
ethanol and the like. If no salt is indicated, the amide-C 0 bands in the region of 1630–1650 cm were measured for the oil bases in the QC spectrum (Perkin-El wer instrument IR spectrophotometer 157).
Example 1. 1 Netil-2- (thiophen-2-carbonyl) -aminomethyl} -5-phenyl-1H-2, 3-dihydro-1,4-beisodiazepine.
13.4 g of 1-methyl-2-aminomethyl-5-phenyl-1H-2, 3-dihydro-1,4-benzodiazepine
and 7.65 ml of triethylamine are dissolved in 320 ml of methylene chloride and, with stirring and cooling with ice, mixed with a solution of 8.12 g of 2-carboxylic acid thiophene chloride in 20 ml of methylene chloride. The reaction solution is then allowed to stand overnight at room temperature. After that, it is washed with water, sodium carbonate solution (T0%) and saturated sodium chloride solution, dried over sodium sulfate and filtered. After distillation of the solvent, 21 g of substance are obtained, which are subsequently chromatographed
 (with different). Output 36.4% in terms of the initial product II. The base has so pl. 112-115 ° C.
Example 2. 1-Methyl-2- (thiophen-3-carbonyl) -aminomethyl 3-5-phenyl-1 H-2, 3-dihydro-1,4-benzodiazepine.
13.5 g of thiophene 3-carboxylic acid (formula 111, Rj P) is dissolved in 300 ml of methylene chloride and cooled to, Then 14.5 ml of triethylamine are added and then 11.2 ml of ethyl ether are added dropwise after 5-10 minutes chloroformic acid. The reaction solution is stirred for another 30 minutes at 0-5 ° C and then, at this temperature, 27.9 g of 1-methyl-2-aminomethyl-5-phenyl-1H-2, 3-dihydro-1,4-benaidiazepi- in 200 ml of methylene chloride so that the temperature remains between and. After that, the reaction solution is stirred for another 4 hours at room temperature, washed with water, diluted with 10% ammonia solution and sodium chloride solution, dried over sodium sulfate and filtered. The solvent is then distilled off. 37.8 g of product are obtained.
The crude base is dissolved in ether and mixed with a saturated solution of hydrogen chloride in ether. The precipitated crystals are filtered and boiled with acetone / ethyl acetate. 21.9 g of 1-methyl-2- ((thiophen-3-carboxyl) methyl 3-5-fench 1-111-2., 3-dihydro-1,4-benzodiazepine hydrochloride are obtained with mp, 234-237 ,. Output 50.4% in terms of the initial product II.
Example 3- {1-nitro-1-metsh-2- (thiophene-2-carbonyl) -aminomethyl-5-phenyl-1H-2,3-dihydro-1.4 benzodiazepine.
2.5 g of 1-methyl-2-I (thiophen-2-carbonyl) -aminometsI J-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine is dissolved in 9 moons of adhetahydride and at 30-35 ° C portionwise mixed with 1.58 g of copper (II) - nitrate ZI2O. At the end of the addition of the copper salt, the reaction mixture is fed to a saturated solution of sodium bicarbonate and ice. The alkaline solution is extracted with methylene chloride (50 ml) and processed as in example 1,
After transferring to the hydrochloride salt, 0.7 g of 7-nitro-1-methyl-2- (thiophene-2-carbonrsh) -amino-mn-1-5-phenyl-1H-2,3-dihydro-1., 4 benzo hydrochloride are obtained. - Diazepine with so pl. 254-256 ° C. 23% yield in terms of the original product
Example 4. 7-Nitro 1 methyl-2-
Example 7. 82- (1-methylpyrrol-2-to methyl-5- (2-chlorophenyl
(thiophen-2-base) -aminomethyl-5-fe-5 po-t, 4-benzodiazepine.
NIL-1I-2,3-dihydro-1,4-benzodiazepine. 2 g of 7-nitpo-1-methyl-2-amylshmethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine is dissolved in 100 ml of methylene chloride. After adding 0.65 g of tri-50 ethylamine while cooling with ice, it is mixed with a solution of 0.93 g of thiophene-2-carboxylic acid chloride in 20 ml of methylene chloride. After treatment as in Example 1, 1.8 g of hydrochloride 55 7-nitro-1-methyl-2- (thiophene-2-carbonyl) -aminomethyl-1H-2,3-dihydro-1,4-benzodiazepine are obtained with tonnes. square 254-256 C. Exit
9.2 g of 8-methoxy-1-ethyl-5- (2-chlorophenyl) 1, 4-benzodiazepine methylene chloride and mixed triethylamine. Then add 1-methylpyrrole-2 acid solution in 25 ml of methyl after the addition is completed using the ice method, measure 1. Get 2.4 which contains 0.66 m.p. 178-225 ° С (with pa
O
five
0
five
0
five
ABOUT
6, 27, p in terms of the starting compound II.
Example 5. 7-Hpor-1-met1 {l-2-I (furan-2-carbonyl) -aminomethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine.
.3) 1 g of 7-chloro-1-metsh1-2-aminomethyl-5-fekip-1H-, -dihydro-1,4-benzodD1 azepine is dissolved in 30 ml of methylene chloride and mixed with 1.05 triethyl amine. Then, while cooling with ice MH and excluding moisture, a solution of 1.36 furan-2-carboxylic acid chloride in 10 ml of methylene chloride is added dropwise. After that, the reaction solution is stirred for another 2 hours at room temperature and processed as in Example 1.
After conversion to gndroch-porid, 2.67 g of hydrochloride 7 - chloro-1-methyl-2-; 1 (furan-2-carbonyl) -aminomethyl} - 5-phenyl-1H-2,3 - dihydro- 1,4-bsnzod - azepine with m.p. 235-236 ,. The output of 60.2% in terms of the starting compound II.
Example 6. 1-Methyl-2- (furan-3-carbonyl) -aminomethyl-5- (2-fluorophenyl) -H-2, 3-dihydro-1, 4-benzodiazine- pin.
t, 5 g of dihydrochloride 1 - mtsch1-2-aminomethyl-5- (2-fluoride 111 l) -1P-2,3-dihydro-1,4-benzodiazepine is dissolved in 160 ml of methylene chloride with the addition of 15.9 ml of triethylamine. Then, while cooling with ice, a solution of 5.0 g of furan-3-carboxylic acid chloride in 50 ml of methylene chloride is added dropwise. After that, the reaction solution is stirred for another 3 hours at room temperature and processed as in Example 1. 9.0 g of hydrochloride are obtained. Mp. 227-228 C. Output 62, calculated on the original product.
Example 7. 8 Metox-1-methyl- 2- (1-methylpyrrole-2-carbonyl) -aminomethyl-5- (2-chlorophenyl) -1I-2,3 dihyd5 po-t, 4-benzodiazepine.
9.2 g of 8-methoxy-1methyl-2-aminomethyl-5- (2-chlorophenyl) 1H-2, 3-dihydro-1,4-benzodiazepine is dissolved in 230 ml of methylene chloride and mixed with 4.0 ml of triethylamine . Then, while cooling with ice, a solution of 4.0 g of 1-methylpyrrole-2carboxylic acid chloride in 25 ml of methylene chloride is added dropwise. At the end of the addition, it is immediately processed in the manner described in Example 1. 2.4 g of hydrochloride are obtained, which contains 0.66 mol of fljO, m.p. 178-225 ° C (with decomp.). Yield 17.7%.
Example 8, 2- (Thiophen-2 carbonyl) -aminomethyl15-phenyl-1H-2,3-dihydro-1,3-benzodiazepine.
9 g of 2-aminomethyl-5-phenyl-1H-2,3-β-dihydro-1,4-benzodiazepine (formula II) is dissolved in 250 ml of methylene chloride by adding 3.6 g of triethylamine and with stirring and cooling mixed with raznivom- 5,2-G chloride thiophene-2-carboxylic acid in 25 ml of methylene chloride. The reaction solution is stirred for 2 hours at room temperature and peregatyuyut as in example 1. Obtain 20 g of an oily residue, which is Toluene is matched with 200 g of alumina-ioxide II. The desired product is obtained in fractions. After evaporation of toluene, it is taken up in 200 ml of methylene chloride. The methylene chloride solution is stirred with 50 g of alumina, filtered and the filtrate is evaporated. 14.2 g of crude product is obtained as a residue, which is recrystallized from toluene. 6.7 g of base are obtained with t, pl. 172-174 C. Yield 49.3%.
Example 9. 1-Met1Sh-2- (thiophen-2-carbonyl) -K-methylaminomers1} - 5-phenyl-1H-2, 3-dihydro-1,4 benzodiazepine.
7.6 g of 1-metsh-2- (thiophene-2-carbonyl) -aminomethyl-5-phenyl-1H-2, 3-dihydro-1, 4-benzodiagesia is dissolved in 100 ml of tetrahydrofuran and mixed and at room temperature, 0.66 g of sodium hydride (80% in oil) is mixed. The reaction mixture is then cooled before and slowly mixed with a solution of 1.36 ml of methyl iodide in 10 ml of tetrahydrofuran (addition time about 30 minutes). Thereafter, the reaction solution is stirred for 2 hours at, then diluted with 10 ml of ice water, and in such an amount of toluene that, after adding further water, two phases are formed. The organic phase is washed several times with water, dried over sodium sulfate and filtered. After distilling off the solvent, 7.5 g of a crude product are obtained :,
The crude product is dissolved in 50 ml of dried ether and mixed with a saturated solution of 7.8 g of B, B-acid in ethanol: .. With the further addition of ether, a tertrat is precipitated, which is filtered and recrystallized from ethanol.
6
15
20
25
thirty
35
40
45
50
55
253430
9 g of l-methyl-2-f (thiophen-2-carboxyl) -N-methylaminomethyl 35-phenyl-1-1H-2,3-dihydro-1, 4-benzodiazepartartite x 0.4 mol of ethanol with t are obtained. gsh 110-125 C. Yield 79.6%.
Example 10. 1-Methyl-2- (thiophen-2-carOnyl) -N-y-propylaminomethyl - 5-phenyl-1H-2,3-dihydrobenzodiazepine.
8 g of 1-metsh-1-2-propylaminomethyl-5-d fensh-1-1H-2, 3-dihydro-1,4-beisodiazepine is dissolved in 150 ml of methylene chloride with the addition of 2.6 g of triethyl amine and with stirring and cooling ice is mixed with a solution of 3.8 g of thiophene-2 carboxylic acid chloride B with 20 ml of methylene chloride. The reaction solution is stirred at room temperature for 2 hours, then washed with water, 10% sodium carbonate solution, and a saturated sodium chloride solution. After drying over sodium sulfate and filtering, the solvent is distilled off. The residue (9 g) is mixed in ethanol with 2 mol of racemic tartaric acid and crystallized from ethanol / ether.
7 g of base are obtained, which is crystallized from 1.6 mol of tartaric acid and 0.5 mol. M.p. t08- (with decomp.). By 64.8%. . .
According to the method described in the examples, by reacting, respectively, the 1-substituted 1-alkyl-2-aminomethyl-8-phenyl-1H-2,3-dihydro-1,4-benzodiazepines of formula II with thiophene-2-carboxylic acid chloride are derived -alkyl-2-Utio-phen-2-carboxyl) -aminomethyl-5-phenyl-1 H-2,3-dihydro-1,4-benzodiazepine
 3
the substituents in the rings a and b, and cd are indicated in table. cheni.
The yield of the target products is shown in Table. 1, varies in terms of starting product II.
By reacting the correspondingly substituted 1-alkyl-2-aminomers1-5-phenyl-1H-2,3-dihydro-1,4-benzodiazine - pins of formula 11 with thiophen-3-carboxylic acid chlorides, 1-alkyl-2 derivatives are obtained Kthiofen-3-carbonyl); - aminomethyl-5-phenyl-1-H-2,3-dihydro-1,4-benzodiazepine of the general formula 1
where, Rj is H batch; 1
total 1, where R.
R, R,
1 signs A and B, R listed in Table. 2
.7
Rj and R values.
1253430
eight
The output of the final products 1 listed in table. 2 is 25-85% based on the starting compound 11,
By reacting the correspondingly substituted 1-methyl-2-aminomethyl-5-phenyl-1H-2, 3-dihydro-1,4-benzodisepines II with furan-2-carboxylic acid chlorides, 1-methyl-2- derivatives (furan- 2-carbonyl) -aminomethyl-5-phenyl-1H-2, 3-dihydro-1, 4-benzodiazepine of the general formula 1, where R is methyl; Cd - H;
R TG .irHtf.a substituents in the rings
 ABOUT
A and B and RI have the meanings given in table. 3
The output of the final products I are presented in table. 3 is 35-755J, calculated on the starting compound II.
By interacting respectively. but substituted 1-alkyl-2-amino-methyl-1-5-phenyl-1H-2J3-dihydro-1,4-benzodiazepines of formula II with furan-3-carboxylic acid chlorides, 1-methyl-2- ( furan-3-carbonyl) -aminomethyl-5-phenyl-1H-2,3-dihydro-1J4-benzodiazinesIna total
Formula I, where R3 fr
ABOUT
Replacers in rings A and B, and R, E and R are listed in Table. 4 values.
The yield of the final products I, point HHbix in the table. 4 is 40-80% based on the starting compounds of formula II.
By reacting the correspondingly substituted 7-methyl-2-aminomethyl-5-fench 1-tH-2, 3-dihydro-1,4-benzodiazepines of the formula II with pyrrol-2-carboxylic acid chlorides, 1-meth t- derivatives are obtained. 2- (K -2-Carbonyl) -aminomethyl-5-phenyl-1H-2, 3-dihydro-1, 4-benzodiazhesha of the general formula I, where R, is methyl, R H, and the substituents in the rings A and B and H are listed in Table. 5 values.
The output of the final products G, are given in table. 5, is 35- .60% based on the starting compounds II.
By reacting the appropriately substituted 1-methyl-2-anino-methyl, 5-phenyl-1H-2,3-dihydro-1,4-benzodisepines of formula II with the corresponding pyridinecarboxylic acid chlorides are obtained with the corresponding pyridinecarboxylic acid chlorides. - (pyridinecarbonylaminomethyl) -5-phenyl-1H-2,3-dihydro o-1,4-baH 3 Odiaz epine of the total for- ny I, where is methyl; Rj is H, and the substituents in rings A and B and the group RjCO have the meanings given in Table. 6
The output of the final products I listed in table. 6, is 20-60%. In terms of the starting compounds I.
15 Preparation of starting materials for example 1.
202 g of NJ-benzene-K-Methyl-M-Phenyl-2-HYDROXY-1,3-diaschnopropane are boiled in 1000 ml of phosphorooxide and chloroform for 20 hours with reverse reflux. The excess phosphoric acid is then distilled off and the residue is taken up in chloroform (1000 ml). The chloroform solution is stirred with 1000 ml of an ice / water mixture, and the organic phase is separated. And washed 5 to 6 times with 200 ml water. The organic phase is then shaken in a separatory funnel with 1200 ml of sodium alkali (20%) and then washed.
30 wate with water to neutrality. Then
The chloroform phase is dried and discolored. is added by adding sodium sulfate and Y-alumina (Giul i-ni alumina). After filtration, the solution is evaporated.
68.4 g of the obtained cyclized mixture of 1-methyl-2-chlorometh 11l-5 phen; t1-1H-2,3-dihydro-1,4-benzodiazepine and
40 1-methyl-3-chloro-6-fenzsh-1,2,3,4-tetrahydrobenzodiazepine is heated with 47.2 g of sodium azide in 450 ml of dimethylformamide for 4 hours to 100 ° C. After that dimethylformamide distilled under vacuum
45 and the residue is partitioned between 300 ml of toluene and 200 ml of water. The organic phase is separated, washed with 10% sodium chloride solution, cjinaT over sodium sulfate and filtered. Then
50 distilled off the solvent (crude product, 56.1 g).
The residue is dissolved in ether and mixed with a saturated solution of chlorine-hydrogen in zofira. The precipitated crystals are filtered and recrystallized from acetone / isopropanol. Get 36.7 g guide
eight
The output of the final products I listed in table. 6, is 20-60%. In terms of the starting compounds I.
5 Preparation of starting materials for example 1.
202 g of NJ-benzene-K-Methyl-M-Phenyl-2-HYDROXY-1,3-di-Shnopropane are boiled in 1000 ml of phosphorooxide and chloroform for 2.5 hours with reverse reflux. The excess phosphoric acid is then distilled off and the residue is taken up in chloroform (1000 ml). The chloroform solution is mixed with 1000 ml of an ice / water mixture and the organic phase is separated. And washed 5 to 6 times with 200 ml water. The organic phase is then shaken in a separatory funnel with 1200 ml of sodium alkali (20%) and then washed.
0 wate with water to neutrality. Then
The chloroform phase is dried and discolored. is added by adding sodium sulfate and Y-alumina (Giul i-ni alumina). After filtration, the solution is evaporated.
68.4 g of the obtained cyclized mixture of 1-methyl-2-chlorometh 11l-5 phen; t1-1H-2,3-dihydro-1,4-benzodiazepine and
0 1-methyl-3-chloro-6-fenzsh-1,2,3,4-tetrahydrobenzodiazepine is heated with 47.2 g of sodium azide in 450 ml of dimethylformamide for 4 hours to 100 ° C. After that dimethylformamide distilled under vacuum
5 and the residue is partitioned between 300 ml of toluene and 200 ml of water. The organic phase is separated, washed with 10% sodium chloride solution, cjinaT over sodium sulfate and filtered. Then
0 distills off the solvent (crude product 56.1 g).
The residue is dissolved in ether and mixed with a saturated solution of chlorine hydrogen in the ether. The precipitated crystals are filtered and recrystallized from acetone / isopropanol. 36.7 g of 1-methyl-2-acidomethyl-5-phenyl-1H-2,3-dihydro-1,4-6-benzodiazepine hydrochloride are obtained, m.p. 181-183 S.
21.7 g of 1-methyl-2-azomethyl-5-phenyl-1H-2,3-dihydro-1,4-benzodiazepine hydrochloride are dissolved in 325 ml of methanol and, after adding 9.5 ml of triethanolamine, mixed with 13, 5 ml of hydrazine hydrate; Then the reaction solution at room temperature is mixed with stirring with 10 g of Rene nickel (Rene nickel additive is finished after 3 h), the reaction mixture is stirred for another 1 h, then Rene nickel is removed, the filtrate is evaporated in vacuum, taken up in methylene chloride and washed with water and 10 % solution of salt. Then the organic phase is dried over sodium sulphate, filtered. 20 j. Consider how the protected ones are tested and evaporated. 17.1 g of 1-metsh1-2-amsyumeti are obtained: L-5-frnil-1H-2,3-dihydro-1,4-benzodiazepine, the dihydrochloride of which 209-213 C., The resulting compounds have a dehydrating effect, which was studied using two pharmacologically standard methods - a heat exposure test on the muscles and a white test of arthritis on the rats.
. Determination of the maximum toxic dose.
Three male mice weighing 20–25 g peros were administered maximum doses of 300 mg / kg of the test substance and, after 3 hours, they were carefully monitored to determine symptoms of toxicity. 24 hours after administration, all symptoms and deaths are recorded. Observe and record associated symptoms. Test substances, examined for solubility in water, are obtained either as aqueous solutions or as suspensions, without any solvents. To keep the test substance in the form of a stable suspension, add a drop of Tween-80 and mechanically homogenize the mixture. If death or a toxic symptom is observed, the subsequent mice are administered reduced doses until the appearance of toxic syndromes cessation occurs. The lowest doses that cause toxic symptoms are taken as minimal toxic doses.
Pain test arthritis in rats.
Male rats of the genus OFA weighing 160-180 g are anesthetized with 20 mg / kg inside
s
peritoneal pentobarbitolitis and intradermally in the left hind paw are injected with 0.1 ml of suspension into Mycobacterium Snugmue (Si 043) in liquid paraffin (0.6 mg Mycobact / 0.1 ml of oil). After 14 days, when pronounced secondary arthritis develops in the right hind paw, the effect of the test substances is studied. 30 minutes before applying the test substances, a control measurement is carried out for which the ankle joint of the right hind paw is bent three times and the number of sounds made is counted. Rats that do not react sort out. Three hours after oral administration of the test substances, the folding procedure is repeated. Animals that make a sound only once or not at all give a sound of pain. 9-20 rats are used to determine each dose. RD- (95% reliable area), determined by the method of Litchfild and Wilcaxoh (1949), is referred to as the dose that protects 50% of treated animals.
Heat Irradiation Test: Fatted male and female mice weighing 16–25 g are used. For 30 minutes before treatment with the test substance, each mouse is separately planted in a cylindrical vessel so that it cannot turn and move forward. Her tail is removed from the vessel and placed in a narrow chute. A certain point of the tail of each animal (approximately 35 mm of distance from the root of the tail) is subjected to thermal irradiation of a lamp of known strength and temperature, which is directly under the tail. The time in seconds for which the mouse removes the tail from the luminous flux is determined twice: once for 30 and once for 15 minutes before the subcutaneous administration of the test substance (10 mg / kg), M1, the reaction time. than 25% exclude. The reaction times are changed again 15 and 30 minutes after treatment, and the duration of the response to more than 75% of the mean to the treatment of the same mouse is considered as an analgesic effect. RDdd (95% reliable area). Each test substance is evaluated 30 minutes after administration by Litchfild and Wilcoxor,
eleven
The data obtained are presented in Table. 7

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining 2-acylaminomethyl-1H-2,3-dihydro-1,4-benzodiazepine formula I:
R2 1 / CH2-K
.k-si
TO
/ CH2
C-R-1
II o
R, is a hydrogen atom i-shi lower alkylradical; Rj is a hydrogen atom, lower alkyl
or lower, alkenyl-radical; R, is a group of general formula
 -FTRtt. .
  J
N
de r
N
I
R5
R
j is a hydrogen atom or G -Cl-alkyl;
- hydrogen atom, halogen, preferably chlorine or bromine.
35
lower alkyl, lower alkoxy at a temperature of from -30 C to +50 C
-
125343012
The C-atoms of the phenyl ring are linked through the methylenedioxy group;
Ring B is unsubstituted or 1-3 fold substituted by substituents selected from the group consisting of a lower alkty, lower alkoxy, halo, or trifluoromethyl radical,
or their acid addition salts, characterized in that, the amine of the general formula IX:
ten
CH2-1SIH-R2
where A, B, R and RJ have the indicated meanings,
or its salt of acid attachment is reacted with carboxylic acid or its reactive derivative of general formula III:
W-ss:
T
where RJ has the indicated values j
3f-hydroxy, halogen, low molecular weight alkoxy group or, where Z is a low molecular weight, alkoxy group, 3 inert organic solvent
at temperatures from -30 C to +50 C
or nitroradncal; Eg - C-C-alkyl; Ring A is unsubstituted or substituted by one two substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkylthio, halo, nitro radical, or two adjacent
under normal pressure, if necessary, the target product, 1 de RJ — hydrogen, aliases the sheeghi ueaai-i.e. ring A is nitrated, followed by isolation of the desired product in the free state or as an acid addition salt.
T a b 4G1 m c a 1
J9
1253430
20 Continued tabl. 2
29
1253430
30 Continued table. 7
Editor N. Egorova
Compiled by G. Konnova
Tehred VWKadar. Proofreader M.Maksimnshynets
Order 4635/60 Circulation 379Subscription
VNII1Sh State Committee of the USSR
on affairs of inventions and discoveries 113035, Moscow,, Ra tpska nab., 4/5
Production and printing company, Uzhgorod, st. Project, 4

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SU904526A3|1982-02-07|Method of preparing |-annelated 7-phenyl-1,4-benzodiazepins or their salts

同族专利:

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公开号 | 公开日

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DD200274A5|1983-04-06|

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DK548080A|1981-07-23|

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IE50580B1|1986-05-14|

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PH17189A|1984-06-14|

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IE802531L|1981-06-24|

---

ES498071A0|1981-12-01|

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NZ195872A|1983-06-17|

---

IL61692A|1984-08-31|

---

DE3070798D1|1985-07-25|

---

PT72278A|1981-01-01|

---

JPS6332072B2|1988-06-28|

---

US4382030A|1983-05-03|

---

FI68050B|1985-03-29|

---

AU542701B2|1985-03-07|

---

DE2952279A1|1981-06-25|

---

AU6566480A|1981-07-02|

---

EP0031080A1|1981-07-01|

---

JPS5699477A|1981-08-10|

---

ZA807704B|1981-11-25|

---

DE3064983D1|1983-10-27|

---

NO154883B|1986-09-29|

---

PT72278B|1981-11-06|

---

ES8201142A1|1981-12-01|

---

DD155988A5|1982-07-21|

---

NO803935L|1981-06-25|

---

CA1169425A|1984-06-19|

---

US4325957A|1982-04-20|

---

ES498072A0|1981-12-01|

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NO154883C|1987-01-07|

---

PT72279A|1981-01-01|

---

ES8201143A1|1981-12-01|

---

FI68050C|1985-07-10|

---

IL61692D0|1981-01-30|

---

EP0031080B1|1983-09-21|

---

YU324780A|1983-12-31|

---

FI803988L|1981-06-25|

---

HU185398B|1985-01-28|

---

PT72279B|1981-11-06|

---

GR73080B|1984-01-31|

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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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DE19792952279|DE2952279A1|1979-12-24|1979-12-24|NEW 2-ACYLAMINOMETHYL-1,4-BENZODIAZEPINE AND ITS SALTS AND METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|

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