SU520918A3 - The method of obtaining derivatives of diazepine - Google Patents

Description

The invention relates to the isolation method of newer diazepine derivatives with better pharmacological properties than the known structural analogues of such dey sgvi. A method based on the ammonolysis of carboxylic acids or their functional derivatives is proposed for the preparation of a compound of the general formula where R. is a hydrogen atom or alkyl group with 1 to 3 carbon atoms; and Rj is an hydrogen atom of an alkyl ring with 1-6 carbon atoms or an oxyalkyl & P: l.; t; atoms; -. carbonYes dialkylamino;: iia jynj: i, u: i with 4-7 carbon atoms or a,:: kl: g; / n;: ъ :. with 7–9 carbon atoms, with HHa: j – i; e s of the H and R groups, and can be directly charged with each other or in pi - 1; l; to 7G - opopets through an oxygen atom, Chl; gro; gru; .i:) h; -1mzlzuyu alkylimino group with ihphdi; 11-a-a-group with a maximum of 4 atoms of a yyrod DB5 is a bright residue, sadar Agadim .ia ;; -; o; j, 1O carbon atoms; : sol :: 5;: dA And 3 can be replaced with a gagla / Mg. to t: Tn :: viHoro numbers 35, alkyl or ajuksgrupp & with 1-6 carbon atoms k, ::;,. treform-etkl-- or nitro groups, wmi of their 5 - EkaseZ, or their salts with inorganic or herp; a1; gic acids, B compound; bc; of the general formula 1, the radical .a..sgwe .gruapes are e-ts, for example- .G: -:, noivi kgk spill, in chaignosgi me-. avtighely R., and R, each as a C, elkgia can be , for example, iOMs with ispropyl, butyl, isobuty-., a; tylo1a, - isop.enggil or hexyl,. -rra-T3Jib; io or ethyl. At -: about:; s;: a; them;: Schenny groups with 2-6 atoms

carbon are, in harnesses, 2-hydroxypropyl-, 3-hydroxypropyl-, 2-hydroxybutyl, 3-hydroxybutyl, 2-hydroxy-1-methylpropyl-, 2-hydroxy-THJt-, 2-hydroxyhexyl-, in particular , 2-hydroxy; dialkylaminoalkyl groups with 4-7 carbon atoms - for example, 2- (dimethylamino) -, 2- (dimethylamino) -propyl-, 3- (dimethylamino) -propi-J-, 2- (diethylamino) -ethyl 3- (diethylamino) -propyl alcohol, and aral kilos with a maximum of 7–9 carbon atoms — for example, benzyl, phenethyl, (-, o, p-methylbenzyl, 3-phenylpropyl, or cC-methylphenethyl group).

The alkyls R and Rj linked together in the above manner form together with the adjacent nitrogen atom, i.e. as a SKjR group, for example, 1-aziridinyl-, 1-azetidinyl-, 1-pyrrolidinyl-, pyrididino-, hexahydro-1H-azepine -1-yl-, morpholino-, 1-piperazinyl- or hexahydro- 1H-1, 4-diazepin-1-ylgroup. Both of the latter groups can be substituted in position 4, i.e. in the imino group, for example, by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl or 3-hydroxybutyl, while then all of the above rings at carbon atoms can still be replaced by ethyl, propyl or, in particular, methyl. As C-alkyl-substituted or C- and N-substituted NR R residues, 2-methyl-1-aziridinyl, 3,3-dimethylacetidinyl, 2,5-dimethyl-1- -pyrrolidinyl, 2-methyl, 3 -methyl and 4-methylpiperidino-, 2,6-dimethylpiperidino-, 2,4,6-trimethylpiperidino-, 2,2,6,6-tetramethylpiperidino-2, 5-dimethyl 1-piperazinyl-, 2.4, 5-trimethyl-1-piperazinyl-, 2,4, 6-trimethyl-1-piperazinyl- and 3,4,5-Trimethyl-1-piperaz nylgroup.

The a-volumes of the halogen as substituents for rings A and B are fluorine, chlorine or bromine atoms. Examples of alkyl or alkoxy groups with 1 to 6 carbon atoms are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2,2-dimethylpropyl, hexyl or isohexyl, or megoxy, ethoxy. , propoxy-, isopropoxy-butoxy-, isobutoxy-, pentyloxy-, isopentyloxy-, 2,2-dimethylpropoxy-, hexyloxy- or isohexyloxy-group.

Ring A substituent is preferably fluoro, bromo, trifluoromethyl, and especially chlorine or nitro. Such a substituent is in particular in position 8. Ring B is preferably unsubstituted or substituted by fluorine, chlorine, bromine, trifluoromethyl or nitro in any position, in particular fluorine or chlorine in the ortho-position.

According to the invention, the compounds of general formula 1 or their 5-oxides, or their salts thereof, are obtained by the interaction of carboxylic acid of general formula

where i is as defined above, rings A and B can be substituted as indicated above, or its reactive functional derivative, or its 5-oxide with a compound of the general formula

R,

H-NC R,

1U

where r 2 and rj

have the indicated meanings., or with its reactive function. ONAL PRODUCTION.

The resulting product is appropriately oxidized to 5-oxide or, if necessary, converted to the salt of an inorganic or organic acid.

As a functional carboxylic acid derivative of the general formula II, its esters, acid halides, anhydrides, dislocated anhydrides, preferably an acid chloride or lower alkyl ester are used.

Among the functional derivatives of the compounds of general formula 311, for example, W-trimethylsilyl, monoalkylsulfuric and dialkylphosphorous acid amides, as well as isocyanates and txhydrodiants are used. Peroxide to produce 5-oxides of compounds of general formula I is hydrogen peroxide or peracid.

The starting compound of the general formula C is obtained by a sequential conversion chain comprising diazotization of the aminobenzophenone of the general formula

rNffo

w

gQ where rings A and B can be substituted. As indicated above, the combination of the formed diazonium salts with (2-chloroalkanamido) ethers is a little acid whose chloroalkanamide group has not more than 5 carbon atoms, and the transformation of the products of the combination in the compound of the general formula SC-CH-RI where K. has the above value, rings A and B may be substituted as indicated above. Then the compound of the general formula H is reacted (after pre-treatment with potassium iodide) with aqueous ammonia or hexamethuenthene amines. In this case, the halogen atom is replaced by an amino group with simultaneous ring closure and the formation of a carboxylic acid of general formula II, cyclization to form carboxylic acids of general formula C can also be subjected to azides of general formula where Rj has the indicated value, rings A and B can be are substituted, as indicated above, which are obtained by reacting sodium azide with compounds of general formula y after treatment with potassium iodide. Pp and measures 1. 5, O8 g (0, O15 mol) 6-phenyl-8-chloro-4H-S -triazolo- (1,5-a) (1,4) -benzodiazepinecarboxylic acid boil 1 hour with 5O ml of thionyl chloride. The solution is evaporated in vacuo at 4 ° C, the residue is dissolved in 1OO ml of absolute toluene, and again evaporated. To the mixture of 6-phenyl-8-chloro-4H-S-triazolo (1,5-a) (1,4) -benzodiazepine-2-carbonyl chloride and its hypochloride, 22 g are added (0.3 mol of diethylamine in 1OO ml of absolute dioxane, cpm-t for 1 hour, then the ynaptiBaiOT reaction mixture at 4 ° C under vacuum, and the extract was dissolved in 25O ml of chloroform and 100 ml of water. Next, the organic phase was washed with water, dried with sodium sulfate and evaporated in vacuum at 40 ° C. The residue is crystallized from a mixture of benzenehexane and get I, N-diethyl-6-phenyl-8-chloro-4H- - triazolo (1,5-a) (1,4) -benzodiazepin-2- carboxamide, tpl, 173-177 C. Similarly, I get t when using the following amines, the following products are given by Dy;.; indemine-.Yi M - dimethyl-6-pheny /} - 8-chloro-4H-S g: gazolo- (1,5-a) (1, 4) -benzodiazenin-2-carboxamcd, t. Ort .. 133-137 C (from methylene chloride-1-hexane mixture); from methylamine-L-methyl-6-phenyl-8--chloro-4H-S -triazolo- (1 , 5-a) (1,4) -benzodiazepin-2-carboxamide; from ethylamine-K-ethyl-6-phenyl-8-chloro 4H-5.-Tr azolo (1., 5-a) (1 , 4) benzodiazepium-2-carboxamide; from isopropylamino-H isopropyl-6-phenyl-8-chloro-4H S -triazolo- (1,5-a) (1,4) -be; zodiazepkn-2 carboxamide; from pyrrolkdine- - 6-fe11yl-8-chloro-4ii & .-, triazo, (1.) (1,4) -benzodiases pi. il1 ™: apbonyl 3 -pyrrolidine; KZ piperdin-1- || 6 phenyl-8-chloro-4H S -Gryazo / - (1,5 - a) (1,4) -benzodiazepin-2 - Hif -carbonyl} -piperkcin; from morpholine- 4 Ife-phenyl-8-chloro-4H- - 5- Griazolo - (1,3-a) (1,4) -benzodiase pin-2-ig: gI-rbonyl-morpholine; az 1 methEL11iperaziha-: 1 1 J5-phenyl-8-chloro-4ri ™ S -triazolo- (1,5-a) (1,4) -benzodiazepine -carbonyl j-4-methi piperidineNf When This is used to dissolve the residue that forms after the reaction mixture, using a mixture of methylene chloride and., p tt3 or caustic soda. Using the following 6-phenyl-4H S -triazolo- (1,5-a) (1.4 ) -benodiazepine-2-carboxylic Kis-POT (O, O15 mol) n diethylamine (0.3 mol) or dimethylamine (0.3 mol) the following amides are obtained: from 6 Cho-chlorophenyl) -8 chloro-4H-S - triazolo (1,5-a) (1,4) -benzodiazepin-2-carbolic acid - "- NJ K -diethyl -6- (o-chlorfenkl) -8-chloro-4H S - triazolo- (1,5-a) (1,4) -benzodiazepig-1-2 carboxamide, t, mp, 156- (from isopropanol), and N, N -dimeGl-Lorophenyl) -8-chloro-4H-S -triazo-GH-blo (1.5 1) (1,4) -benzodiazhesh1N-2- "arboxamide" t. Pls 142-145 C (from isopropanol ); from 6- (o-fluorophenyl) 8-chloro-4H-S -triazolo- (1,5-a) (1,4) -benzodiaz8pi.-2-carboxylic acid-I, N-diethyl-6- (o -phosphonyl) -8-chloro-4H-S -rpHaaoflo-djS-a) (1,4) -benzodiazepium-2-carboxamide, m.p. 20O-202 ° C (from isopropanol), and I, N-dimethyl-e- (o-phorfenyl) -8-chloro-4H-S -triazolo- (1,5-a) (1,4} -benzodiazepine 2 -carboxamide, mp. 1SO-182 C (from isopro-panol); from 6- (° C, L ,, ° C —triftor oh lil) - 8-chloro-4H-S; -triazolo- (l, 5 -a) (1,4) -benzaz azepine-2-carboxylic acid C, U -dimethyl- and N 1N-dimethyl-6 - ("/., cC, o1-trifto-o-tolyl) -8- chloro-4H-S -triazolo- (1,5-a.) (1,4) benzodiazepi-2-carboxamide; from 6-phenyl-8-fluoro-4H-S -triazolo- (1,5-a ) (1,4) -benzodiazepine 2-carboxylic acid-N, N-diethyl- and N, -dimethyl-6-phenyl-8-fluoro-4H-triazole (1,5-a) (1,4) - benzodiazepin-2 carboxamide; from 6-phenyl-8-bromo-4H-S -triazolo- (1,5-a) (1,4) benz diazepin-2-carboxylic acid - K, N-diethyl- and N. And -dimegl-6-phenyl-8-bromo-4H-S -phriazolo- (1,5-a) (1,4) -benzodiazepi -2 carboxamide. 6-Phenyl-8-chloro-4H-S -triazolo - (1,5-a) (1,4) -benzodiazepin-2-carbonoic acid is prepared as follows: 58.0 g (0.25 mol) 2-amino-5-chlorobenzopheno5I in a mixture of 310 ml of glacial acetic acid and concentrated hydrochloric acid (4: 1) are diazotized at room temperature with 50 ml (0.25 mol) of sodium nitrite sodium nitrate, 150 g are added to the diazonium salt obtained. ice, added dropwise after successively 52.4 g (O, 2O8 mol) of d-ethyl ether (2-chloroacetate Medo) -1 lalonovoy acid in 600 ml of acetone for 2O minutes at - 276.0 g (2 mol) of potassium carbonate in 500 ml vodi then stirred 1 hour, and poured benzene and a saturated sodium chloride solution. The benzene solution is then separated, washed with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated. Obtain 121 g of crude diethyl ether (2-chloroacetamido) - (2-benzoyl-4-chlorophenyl-azo) -malonic acid, which solution ;; 1.5 l of diokean are added to the solution; 3 6 g (0.9 mol) of sodium hydroxide are added to the resulting solution in 2 l of water, the mixture is transferred 30 min and the dioxane is evaporated in vacuo. The residue is dissolved in 5OO ml of water, 2Og of activated carbon is added, the mixture is vigorously stirred and filtered through purified diatomaceous earth. 2 N hydrochloric acid is poured into the filtrate with vigorous stirring until acidic, the precipitated carboxylic acid is sucked off washed with water and recrystallized from hot methanol. 1- (2 Benzoyl 4-chlorophenyl) -5- (chloromethyl) -1 H-1,2,4-ariazole-3-carboxylic acid is obtained, m.p. 169-171 C (with sec.). Analogously, the following is obtained: from 2-amino-2, 5-dichloro-benzenesfonone: l-2- (o chlorobenzoyl) 4-chlorophenyl-5- (chloromethyl) -1H-1,294-griazole-3-carboxylic acid, mp, 17О-175 C (dec,); the substance is precipitated from solution in aqueous ammonia with the help of 2 n hydrochloric acid; from 2-amino-5-chloro-2-fluorobenzophenone-1 2i (o-phorbenzoyl) -4 chlorophenyl D-5- (chloromethyl) -1H-1,2,4-triazole-3-carboxylic acid; from 2-amino-5-op-2 (trifluoromethyl) -benzofbnon - 2- (oL ,, cL -trifogor o-tolyl) -4 chlorophenyl 3 -5- (chloromethyl) -1 H-l, 2s4- pHa3O№ -3-carboxylic acid; from 2-mino-5-fluorobenzophenone-1- (2-benzoic 4-fluorophenyl) -5- (chloromethyl) -1 H-152,4-triazole-3-carboxylic acid; from 2-amino-5-bromobenzophenone- - (2- -benzoi-bromophenyl) 5- (chloromethyl) -1 H-1,2, 4-triazole-3-carboxylic acid, 33.2 g (O, 2 mol) iodide potassium is dissolved in 85 ml of water. The resulting solution was diluted with 850 ml of dioxane and at 25 ° C was added with stirring to 71.5 g (o, 175 mol) of 1- (2-benzoyl-4-chlorophenyl) -5 (chloromethyl) -1 H-1,2, 4-triazole-3 - "Arboxylic acid containing an equivalent mol amount of methanol. The reaction solution is heated} 01–1 hour to 45–5 ° C, then 0.5 l of aqueous ammonia is poured, heated at 45–5 ° C for 2 hours and evaporated in vacuo, the residue is dissolved in 2 l of water and t 2 n, hydrochloric acid until the reaction with a kiol, excretes carboxylic acid, which is sucked off, washed with water until neutral. Then it is further washed with methanol and dried in vacuum at 12O-13O C. The resulting 6-phenyl-8-chloro-4H-S -triazolo- (1,5-a) (1,4) - -benzodiazepi-2-carboxylic acid the acid decomposes at 17 ° C. In a similar way, from: 1- 2- (o-chlorobenzoyl) -4 chlorophenyl5-5 ™ (chlorme: hydro) 1H-1,2,4-triazole-3-carboxylic acid-in- (o- chlorophenyl) -8-chloro-4H-S -triazolo- (1,5-a) (1,4) -benzodiazepy: n - 2-carboxylic acid, m.p., 19O-19 C (from methanol ); from 1- 2 (o-fluorobenzoyl) -4-chlorophenyl 3 -5- (chlorophenyl) 1 H-1,2,4-triazole-3-carboxylic acid 6 (o-fluorophenyl) -8-chloro-4H-S -triazolo- (1,) (1,4) -benzodonazepin9,

-2-carboxylic acid, t, pl. (decomp., from meganol);

from 1-L2- (ci-jO-, o (-trifgor-o-olil) -4- -chlorophenyl7-5- (chloromethyl l) -1, 2 J 4 - triazole-3-carboxylic acid- 6-- {оС, оС, «С - -grifgor-o goal) 8 chloro-4H S - riazolo- (1,5-a) (1,4) benzodiazepine-2-carboxylic acid;

from 1- (2-benzoyl-4-phorphenyl 5 ™ (chloromethyl) -1 H-1,2,4-tr and sol 3 carboxylic acid-6-phenyl-8-fluoro-4I S -gryazolo- (1 , 5-a) (.1,4) -benzodiaz-1-2 carboxylic acid;

from 1- (2-benzoyl-4-bromobiol 1NL) -5 (chloromethyl) -1H-I, 2j4-triazol-3 carbonic acid, 15 lots of 6-phenyl 8-bromo 4H S -triazolo- (1,5- a) (1,4) -benzodiaz in 2-carboxylic acid. Example 2, 3.63 g (О, 01О2 mol) of b- (o-phyphenyl) -triazolo- (1,5-a) (lj4) - "6eH3OAf a3efiHH 2- Kap6oHOBOH acid boil for 2 hours with 60 ml of blueberry oil - reed. The clear solution is evaporated in vacuo at, the residue is dissolved in 5O ml of absolute toluene and evaporated to remove thionyl chloride. A swarm of 6 (o phorphenyl) 8-chloro-4H-- S -triazolo - (1,5-a) (1,4) -benzodiazeium - 2 -carbonyl chloride, ToPL is obtained. 196-198 C (decomposition of diode) Cfou hydrochloride dissolve south in 55 ml of dioxane and to a solution of pr & g 5DO g (O, O5O mol), 1.metzhshperazina in 5 mp of dioxane. The mixture is stirred for 3 hours at room temperature, poured onto edible water containing 2 O ml 1N. Sol. Carbonate carbonate, extracted with megenhloridom. The organic phase is washed with a saturated solution of sodium hydroxide, dried over sodium sulfate and evaporated to dryness in vacuo. The remaining crude 1-.6ChO-fluorofluxyl) --8-chloro «| H-5-7riazolo (1,5-a) (1,4) -benzodiazepine. -: carbonyl 4. methyl tpiperazine solution of subglobal B is added to a small amount of ethanol and the alcoholic solution of CHLORINE hydrogen is added to pH 3, the reaction solution is cooled with a mixture of ice and sodium chloride and added to the ether. Crystals of the gyrochid seed are filtered off and dried under vacuum. Generous 1 ".-G 6 -. (Phenyl). S -Hrcazolo. (1,5-a) {1,4) -benzodiazeshg -2-yl | - “arboiyl | - methyl shgieraznngidrokhloridh gavavs at 19O-195 The starting charbonic acid is obtained in the following way. A solution of 78.6 g (O, 315 mol) of 2-amino 5-chloro 2 phyloxy-benzo-4-enone in 384 ml of a mixture of glacial acetic acid and coshentric hydrochloric acid (4: 1) is diazotized with

lO

63 ml (0.315 mol) of an aqueous solution of sodium nitrite. 24 O g of ice is added to the diazonium salt obtained, and then 7 9.0 g are sequentially pinned.

(0.315 mol) of the diethyl ester (2-chloroacetates to) - a small amount of acid in 900 ml of acetone and for 6O min at 10-15 ° C - 433.0 g (3.14 mol) of potassium carbonate in 77O ml of water. The mixture is stirred for 1 hour,

after which ether and saturated sodium chloride solution are added, the ether solution is separated, washed with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated. The solid residue is dissolved in a minimum amount of methylene chloride and hot t-hexane is added until cloudy. The resulting diethyl ether (2-chloroacetamido) -2 (o-4 torbenzoyl) -4-chlorophenylazo-malonic acid melts at 98-1OO ° C. To 51.2 g (0.10 mol) of diagal ether (2-chloroacetate RPO) - 2- ((| this barbenzoyl) ™ 4. Chloro | Leuilazo | - 1 elon cyoloty in 600 ml of dcoxane for 2 -lac is added dropwise a solution of 8.0 g (0.20 mo gpe) of sodium in 4OO ml of water. At the same time, the rei rnepaiypa increases: from 2 ° to 30 ° C, and the pM reaches a value of 8.5 - 9.0, Mixing mixture: - 45 min The mixture is kept at room temperature, then neutralized with glacial acetic acid and reduced by evaporation. Ice is added to the residue to a 5% solution of sodium carbonate, a mixture of vstrh / g mixture with ether and the aqueous phase is preserved. hololdi1 .5% - kb: with a solution of bi- carbo 5: Sodium soda, water, cjiuau сульф sulfate katrk k is evaporated in vacuo. The residue of regisphalgizyrene from isopropanol is obtained. Ethyl ether 1 (o phorbenzoyl) 4 chlorophenyl.yl 5- (chloromethyl ) 1,2,4-triazole-3-carboxylic acid, mp 97-. Rasgvor 8j44 g (O, O2 mol) ethyl p-, t, 2- (o-fluorobenzoyl) -4-chlorophenyl o ( hlbrmetil), 254 triazole-3-carboxylic acid 5.6 g (O, O4 mol) of hexamethylenetetramine in 14O ml of absolute ethanol boil 6 hours; They are then evaporated at 4 ° C under vacuum, 4OO ml of ice water is added to the residue and extracted with methylene chloride. The organic phase is washed with cold 1 g of hydrochloric acid, water, cyiuaT sodium sulfite and evaporated in an ampoule. & „The residue is recrystallized from isopropanol. The ethyl ester is 6 -. (&Amp; phyhorphenyl) - 8-chloro 4K-- -triazolo (1.5.a) (1.4) benzodiazepine-2-carboxylic acid, T.L. 177-179 C.

eleven

4.81 g (0, О125 mol) of 6- (o-fluorophenyl) -8-chloro-4H-S-triazolo- (1,5-a) (1,4) -benzodiazepine-2-carboxylic acid ethyl ester 30 minutes in 250 ml of methanol and 25.5 ml (0.0255 mol) 1 n. caustic soda solution. The reaction solution is evaporated, the residue is pacTBOpjnoT in 50 ml of water and added 2N. hydrochloric acid before the reaction. The precipitated carboxylic acid is sucked off, washed with water until neutral, then with methanol and dried in vacuo at 10 ° C. The resulting 6- (o-phyhorphenyl) -8-chloro-1H-9 -triazolo- (1,5-a) (1, 4) benzodiazepiv -2-carboxylic acid decomposes at 179-182 C.

Example 3. From 5.58 g (0.015 mol of 6-phenyl-8- (trifluoromethyl) -4H-S -triazolo- (1,5-a) (1,4) -benodiazepi-2-carboxylic acid and 5O ml of thionyl chloride Analogously to Example 1, crude chlorohydrin-iodine is obtained and it is reacted with 1OO ml of a 20% dimethyl-amine solution in absolute dioxane. After treatment as in Example 1, L, N-dimethyl 6-phenyl-8- (triformethyl) -4H-S-triazolo- (1,5-a) (1,4) -benzodiazepin-2-carbox-

MFA, t, pl. 195-197 C (from ether).

Similarly from diethylamine to absolute

dioxane, N, i -diethp-6-phenyl-8- (trifluoromethyl) -4H-S-triazolo-1,5-a) (1,4) benaodiazepine-2-carboxamide is obtained.

The original carboxylic acid was prepared as in Example 2.

Diethyl ether (2-chloro-petamide o) - (2-benzoyl-ot, ° C, s, trifluoro-p-tolylazo) malonic acid is obtained from 2-amino-5- (trifluormethyl) -benzophenone, which is converted to ethyl ester 1 - (2-benzoyl-CX, ct., Ci-trifluoro-p-tolyl) -5- (chloromethyl) -1H-1,2,4-triazole-3-carboxylic acid, so pl. 110-111 C (from a mixture of ether-petroleum ether).

This compound then produces 6-phenyl-8- (trifluoromethyl) -4h- -griazolo- (1,5-a) (1,4) -benzodiazepin-2-carboxylic acid ethyl ester, m, 162-164 With (from absolute ethanol) s the hydrolysis of which is 6-phenyl 8- (triform tp) - -4H-S -triazolo- (1,5-a) (1,4) -benzodi-a3enHrf-2-carboxylic acid, decomposes - us at 195 С „

Example 4, From 2.4 g (0.0069 mol of 6-phenyl-8-nitro-4H-S -triazolo- () (1,4) -benzodiazepin-2 carboxylic acid and 5O ml of thionyl chloride, analogously to Example 1, crude acid chloride is obtained which is reacted with a 5O ml of a 20% dimeglylamine solution in absolute dioxane to give 1, -N-dimethyl No.

12

-6-phenyl-8-nitro-4H-S -triazolo- (1,5-a) (1,4) -benzodiazepin-2-carboxamide, so pl. 2.07-211 ° C (from ethyladetate).

When using 50 ml of a solution of diethylamine in dioxane, I get i, α-diethyl-6-phenyl-8-nitro-4H- & -triazolo- (1,5-a) (1,4) -benzodiazepin-2 - «arboxamide.

Starting from 6- (o-fluorophenyl) -8-nitro-4H- & -triazolo- (1,5-a) (1,4) -benzodiazepin-2-cyrboxylic acid, thionylchloride and a solution of diamethylamine or diethypamine in absolute dioxane , N, N-dimethyl-b- (o-fluorophenyl) -8-nitro-4H-S - -triazolo- (1,5-a) (1,4) -benzodiazepin-3- "arboxamide ny 1, U -diethyl-6- (o-fluoropheny-8-nitro-4H-5 -triazolo - (1,5-a) (1,4-benzdiasesh-3-carboxamide.

The carboxylic acids required as starting materials are prepared as follows.

20 g (0, О826 mol) of 2-amino-5-nitrobenzsphenone in 4OO ml of glacial acetic acid and 20 ml of concentrated hydrochloric acid are diazotized at 2O-25 C of 16.5 ml (O, O826 mol) of an aqueous solution of sodium nitrite. To the obtained diazonium salt, 4OO g of ice was added, and then 17.4 g (0.69 mol) of (2-chloroacetamido)-malone diethyl ether were added dropwise. acids in 40O ml of acetone and at 5-10 ° C for 20 minutes, 114 g (O, 826 mol) of potassium carbonate in 25O ml of water. The mixture was stirred for 1 hour, then benzene was added and the sodium chloride solution, 6ejf-salt: the solution was separated, washed with a mixture of our sodium chloride solution and 5% sodium bicarbonate solution until the acid was removed, dried with sodium sulfate and evaporated. The crude diethyl ester of (2-chloroacetamido) - (2-benzoic-4-nitrophenylazo) -monoic acid is obtained.

Similarly, crude diethyl ester of (2-chlorodetamido) -2- (o-fluorobenzoyl-4-nitrophenylazo) -malonic acid is obtained from 2p-5-nit-ro-2-phyorbenzophenone 2p.

To 42 g (0, O82 mol) of diethyl ether (2-chloroacetamide), - (2-benzoyl l-4-ntpc phenylazo) -malonic acid in 1 liter of dioxane is added dropwise within 2 hours 310 ml (OD55 mole) 0.5 n solution of caustic soda, maintaining the temperature of 17 -. By the end of the operation, the pH of the reaction mixture is 8.0 - 8.5. The mixture was stirred for another 3 min at 17-2 ° C, then neutralized with glacial acetic acid and evaporated in vacuo to a volume of 300 ml. Ice and 5% sodium bicarbonate solution are added to the concentrate, extracted with ethyl acetate. the organic phase is washed with cold 5% sodium bicarbonate solution and water, then dried with sodium sulfate and evaporated in vacuo. After addition of 25 ml of ether to the residue, crystallization occurs. By recrystallization from benzene ether nofiy4aiOT ethyl ether 1- (2-benzoyl-4-nitrophenyl) -5- {chloromethane) -1H- 1,2,4-triazole-3-carboxylic acid, tl 151-152 ° a Similarly, 1- (2- (o-fluorobenzoyl) -4- nitrophenyl-5- (chloromethyl) ethyl ester is obtained from diethyl ether (acetamido) -1,2.- (o-fluoro-zoyl) 4 ntrophenylazo-malonic acid. -1H-1g2,4-griazol-3-carboxylic acid, 11.8 g (O, O185 mol) of 1- (2-benzoyl-4-. Nitrophenyl) ethyl ester 5- (chloromethyl J-lH-1, 2j4- triazole-3-zmrboxylic acid and -10 / r oIt-gV 12 g (O, O855 mol) hexamettimeter, - per / .50 ml of solvent solution — about boil for 6 hours, then evaporated at 40 ° C in vacuum, to the rest of the tide with 5 CO ml of ice water and extracted with Chlorine-1 M methylene organic (н ap01-lysed) from cold 1 N, hydrochloric acid and water; Suiat sul Phaazism sodium and yjjapaiiaioi / s vacuum. Residual recryohalization 1: Shyug from ethanol. Ethyl ester 6-phenyl 8-nitro-4-S -.triazolo (1) (1.4}. benzod a: azepium 2, melted by bonose acid) at 145-147 ° C. The 6- - (o fluorophenyl) -8 - g1Itro-4H S -triazolo (1,5-a) (1,4) benzoyl azurega {n - 2 Carboxylic acid ethyl ester is likewise obtained. , to 2.85 g of ethyl 8-feiil-8 n itro-4H-S triazolo ™ (1,) (1,4) -benzodiazepine-2-carboxylic acid in 25 ml of dioxane was added a solution of 1 ml (0, O1 moi) of the end of the atriuCovain (40% aqueous solution of caustic jiarpa in 5M of methane. The mixture is left to stand for 30 minutes at room temperature, then 1.O ml of 1 N is poured in hydrochloric acid and evaporated in vacuo. 45 The residue is washed with ЕО.аой and dried at 8О100 С in a vacuum. Ps uchitne: 6 phenyl-8-β-nitro-4H-S-t-rcazols- (1-) (1,4) -benzodiazepine "2 carbo-1ЕЕа kloglog" decomposes at 2 ° -8 ° and A1-6, 6- (o-phyhorphenyl) -8- -nitro-4H-S-griazodo- (1,5-a) (1,4) -bone zodiaepi-2, carbonic acid is obtained. Example 5 "3.67 g (0.010 mol) of ethyl ester in phenol l 8-chloro" 4H-S -triazolo- (1,5-a) (1,4) -benzodiazine 11ik- 2 -carboxylic acid Rash .- The thief at 40 ° C in 300 ml of ethano / w, started at & 50 ml of concentrated aqueous ammonia and the mixture was kept for a day at room temperature. Next, the reaction solution is evaporated in vacuum at 40 ° C. The residue is shaken with 1OO ml of water, sucked off and washed with water. After recrystallization from methanol and drying at 1OO-120 C, 6-phenyl-8-.chloro-4H-S -griazolo- (1,5-a) (1,4) -benzodiaepin-2-carboxamide, t, mp, 252-254 ° C. In a similar way, from: 6- (o-chlorophenyl) -8- -chloro-4H-S-ethyl ester- (1,5-a) (1,4) -benzodiazepin-2 ethyl ester -carboxylic acid- -6- (o-chlorophenyl) -8-HLOR-4H-S -triazolo- {1,5-a) (1,4) -benzodiazepine -2-carboxamic acid. square 283 - 285 C (from methanol): from 6- (o-fluorophenyl) -8-chloro 4H-5 ethyl ester (1,5-a) (1,4) -benzodiazepine-2-carboxylic acid ethyl ester 6 - (o-fluoro-fbnyl) -chloro-4H - S -triazolo - (1,5-a) T-., .., t. a / V -Lj S -enzodiaospin -2-carboxamide, so pl. (with paciii., from ethanol); KZ of this 6-phenyl-8- (trifluoro-msgyl) 5 -triazolo- (1,5-a) (1,4) -be) ester; - Znadase: and # 2-carbopic acid – 6-phenyl 3 - (trifluormethine) 4H-S - C1-giazolo,) (1,4) benzodisepine-2-carboxamy; from 6-phenyl-8-nitro-4H- „b - triazolo- () (1,4) -benzodiazepine-2-ethyl ester, 2 carbopic acid-tsmb-phenyl-8-nitro 4- - S ... triazolo- () (1,4) -benzodiazepine-2-carboxamide. The starting ethyl ether is obtained as follows: 6.77 g (O, 02O mol) 6-phenyl-8-chloro-4H-S-triazolo- (1) -1,4-benzodiazepine-2. Carboxylic acid are suspended in B 25O ml absolute ethanol, the reaction mixture is evaporated with hydrogen chloride with stirring and heating, boiled for 10 hours and evaporated under vacuum gfI of 4O C, Ostatum is dissolved in B 1OO ml of cold sodium bicarbonate solution and 100 ml of methylene chloride, the organic phase is separated, washed water, dried with sodium sulfate and evaporated in vacuo at 4 ° C. The crude residue is boiled for 1 hour. B 10 O of ether, cooled allowed to 0 ° C, the resulting crystals were filtered off and washed with ether. 6-. F8nCl-8 chloro-4H-S-trnazolo- (1,5-l) (1S 4) -benzodiazepine-2-carboxylic acid ethyl ester is obtained. 138 ° C. , 137 Similarly, from 6- (o-chlorophenyl) -8-xnoj. -4B S - sriazolo- (1,5-a) (1,4) -benzod azepine-2-carboxylic acid 1luchak t its ethyl ester, t. pl, 211-213 С (from this-

15 Example 6. 5. О О (0.013 mol) of 6- (o-fluorophenyl) -8-chloro-4H-S ethyl ester of griazolo (1,5-a) (1э4) -benzodiazepin-2-carboxylic ester Acids are dissolved by heating in 15O ml of methanol, then 5.0 g is added at 30-4 ° C (ODbmol of methylamine in 25 ml of methanol and stirred for 20 hours at room temperature. The reaction mixture is evaporated in vacuo to dryness, the residue is dissolved in methyleshloride and filtruvat through a layer (2 cm.) of neutral alumina, (activity 1) “Then it is further washed with methylene chloride and the filtrate is evaporated to dryness in a vacuum. The residue will cross llyzyvayut from a mixture of methylene chloride-hexane Get L -methyl-6- (o fluorophenyl) -8-chloro-4H S -Tpnaso o-dsS a) (1,4) -benzodiaz pin-.2 Carboxam Dz t, pl 2 O 2 -2 О 3 С „In a similar way, the following is obtained from ethyl ether & (o chlorophenyl) 8-chloro-4H-S griazolo-Yab-a) {1,4) -Bon zodiazepi -2 carboxylic acid - H-megyl-e- (o-chlorophenyl) S triazo-lino (1,5 ™ a) (1,4) -. benzodiazepi & 2. ™ karboK samid, TopPLo. C (from isopropanol) from ethyl 6 ™ phenyl-8- (methyl trifluoro) -4H S - riazolo (1.5-a) (.1.4). -Benzodiazhesh1n-2-carboxylic acid - I - meg-6 -phenyl 8- (trifluorometip) -4H-S -triazolo- (1J). (1,4). benzodiazepine-2-carboxamide; from 6-f8nyl 8-nitro-4H-S-triazolo- (155-a) (1,4) benzodiazepiH -2-carboxylic acid ethyl ester- K. methyl-pheny-8-nitro-4H S griazolo- (185 a) (1., 4) - Odiazepine ben - 2 - carboxamide. Example 7 “In suspension Zz85 g (o, 01 mol) of ethyl ester 6- (o fluorophenyl) -8-. S -triazolo CXgB-a) (1,4-benzodiazepi11-2 carboxylic acid in 2OO ml of methanol VODEGG with stirring and at room temperature for 2 hours gaseous, methylamine-free methylamine. Transparent peaioiHOHHyy evaporated: under vacuum, dry. t get crystallization from isopropanol.: H, N-dimethium-6 - ((| Yunil) -. 4H-S -gryazole - (1a-5a) (ls4) .6eH3OAH "azepin-2-carboxes Det" pl "18O .-182 C Similarly, the following tfacts are obtained: from ethylamine, which is passed as a gas for 4 hours at 5O-ethyl-6- (with fluorophenyl) S azolo- (1 g5-a) (1,4) - benzodiazepin-2 1shrb ksamid, fuels 232-2-34 C (from isopropane la).;

16 from isopropylaminna (4 hours, 6O C) - -isopropyl-6 (o fluorophenyl) -8-chloro-4H-8 - griazole - (1J 5-a) (1,4 -) - benzodiazepin-2-carboxamide, t mp 255-258 ° C (isopropanol); from 2-aminoethanol (3 h, 65 ° C) (2-hydroxyethyl) -6- (o-phyfensh1) -8-4H-5 -triazolo- (1,5-) (1,4) -benzodiazepin-2- carboxamide, so pl. 236-240 ° C (decomp., Of isopropanol); from morpholine (16 hours, 65 C), 6- - (o- "fluorophenyl) -8-chloro-4H-S -triazolo-" () (154) -benzodiazepin-2-yl -caronyl-morpholine, T .Sh1. 180-182 ° C (from isopropanol); from pyrrolidine (3 hours, 65 C) u6- - (o - fluorophenyl) 8-chloro-4H-S -triazolo- (1,) (1,4) -benzodiazepin-2niш1-: carbonyl-pyrrolidine, m.p. , 202-2.04 C (from czopropanol); Cp of piperidine (12 h, 65 C) -j amorphous 1 1 (o-fluorophenyl) 8 chloro-4H-S -triazolo (1,5-a) (1,4) -benzodiazepin-2 or 3: ;;; p „-piperidine; from K, dimethyl-1,3-. propanediamine (6 hrs 65 C) with the raw product treated with an ethanolic solution of chlorochlorine) hydrochloride M-3, (/ damethylamino) propyl-6- (o-fluorophenyl) -8 -chloro-4H- -triazolo- (1,5-a} (1,4) -benzodiazhesh-2-carboxamide - hydrochloride, ToPL, 16O-165 ° C (from a mixture of ethanol ethyl acetate); from N, J - diethylethylenediamine (6 hour,) with the processing of the raw product ethanolic solution of hydrogen chloride-v - 2 (diethyl / shmino) -ethyl D-6- (o-phorph 8nyl) -8-chloro-4H-S -triazolo- (1,5-a) ( 1,4) -benzodiazepin-2-carboxamide-hydrochloride. PRI mne} e 8 "K 6.8 g (0, O18 mol) N N dnmethyl-6 (o-fluorophenyl) -8-chloro-H- S -triazole- (1,5-a) (1,4) -benzodiazepin -2 carboxamide in 270 ml of methylene chloride was added dropwise at О С a solution of 6.1 g {OaO35 mol) of 75% m-chloroperoxybenzene acids in 140 ml of methylene chloride for 2 minutes. The reaction mixture is stirred for 3 hours at-5 ° C and then for 20 hours at room temperature, then evaporated in a voumouum. until dry, the residue is dissolved in a small amount of methylene chloride and ether is added to a weak dsMjrHeifflH. The crystals are filtered and the crystals are recrystallized from a mixture of methylene chloride: -ether 5 Oxide is obtained: 1., H-dimethyl-6-. (1 f1 orphenyl) -8-chloro-™ 4H S riaols-C1a5a) (1,4) -benzodiazenia - ..arboxamide,. 17О-172 С (with decomposition,) o The compound contains 0.5 mol of methylene chloride of the invention of Formula 1. A method for producing derivatives of diazenin of the general formula R. . W-Ri I where RI is a hydrogen atom or an alkyl group with 1 to 3 carbon atoms; R-, and RJ are hydrogen atoms, alkyl groups with carbon atoms or hydroxyalkyl groups with 2-6 carbon atoms, dialkylamino groups with 4-7 carbon atoms or aralkyl groups with carbon atoms, and the lower alkyl groups R and Rj can be linked directly to each other or at - or at the - position through an oxygen atom / i, imino group, lower alkyl imine or oxyalkyl amino group with 4 carbon atolls to a two-carbon residue containing a maximum of 1 O carbon atoms; Rings A and B may be substituted by halogen to atomic number 35, alkypyl or alkoxy groups with 1-6 carbon atoms, trifluoromethyl- or n-throgryaches, or their 5 oxides, or their salts, in which the carboxylic acid of the general formula . C – C CH — R, where e .j has the above meaning; the rings A and B can be; 5 a substance, as indicated above, or its reactive functional derivative, or its 5- oxide is subjected to interaction with a compound of the general formula where R, and RJ have the above values, or its reactive functional derivative with 11 subsequent isolations a base product, K-oxide and or a known method. 2 "Method according to claim 1, characterized in that hporaggndrid of carboxylic acid of general formula II is used as the starting compound. 3 The method according to Ps If if-t is h and y and TBMj that use the lower alkyl ester of the carboxylic acid of the general formula Ц.