UA45358C2 - 2,3-BENZODIAZEPINE DERIVATIVES, METHOD OF OBTAINING THEM, INTERMEDIATES AND PHARMACEUTICAL COMPOSITION - Google Patents

Abstract

The invention relates to the noncompetitive AMRA antagonistic combinations of the formula I, in which R1 and R2 are independently the hydrogen, halogen, C1-4 alkyl groups, C1-4 alkoxy-group, nitro-group, tri-fluorine-methyl group, or a formula NR8R9 group, in which R8 and R9 are independent hydrogen C1-4 alkyl group, or a group of formula COR10, in which R10 is a hydrogen group, C1-6 is an alkyl group, which may be substituted by the С6-10 aryl group, C1-4 alkoxy-group, С3-5 cyclo-alkyl group, С2-6 alkenyl-group, С3-5 cyclic alkoxy-group, or by a group of formula NR11R12, in which R11 and R12 mean independently the hydrogen, C1-4 alkyl group, С3-5 cyclo-alkyl group, or С6-10 aryl group, R3 is a C1-4 alkyl group, С3-5 cyclic alkyl-group, or by a group of formula CO-R13, in which R13 has the same determination, as for R10, R4 and R5 mean independently the hydrogen or C1-3 alkyl groups, R6 and R7 are independently hydrogen, chlorine, or bromine with the condition that when one of the R6 or R7 is the independently hydrogen, the other is not the hydrogen, as well as their isomers and salts, produced by adding an acid, or the isomers called further the pharmaceutical combinations, made by any of the combinations named. The invention also relates to start combinations of the formula II, in which R1, R2, R4, R5, R6 and R7 are the same as pointed for the formula I.

Description

Description of the invention

The invention relates to new 2,3-benzodiazepines, replaced by one or two halogen atoms, and to 2 pharmaceutical compositions containing the same.

Various biologically active and therapeutically used 2,3-benzodiazepines are known, in which the benzene ring is replaced by two methoxy groups or a methylenedioxy group. 7,8-dimethoxy derivative description in HO-P Moz. 155 572, 179 018, 191 702 and 195 788. These compounds have, first of all, tranquilizer and/or antidepressant activity, as well as positive inotropic activity. 710 Compounds containing a methylenedioxy substituent in the same positions of the benzene ring, lime from HO-P

As. 191 698, 191 702 and 206 719, as well as BR Mo. 5, 459, 137. In contrast to dimethoxy-2,3-benzodiazepines, methylenedioxy compounds are mainly characterized by spasm-inhibiting, muscle-relaxing properties! and neuroprotective activities.

It is known from the literature that the latter compounds exert their activity through non-competitive inhibition of the AMPA receptor. (See among others: 5.O0.Uopemap ei ai., Meigop, 10, 51 - 59 (1993); 5.O0.Oopemap ei aI,, 9U. Rpaptasoi. Ehr. Tag. 271, 25 - 29 (1994 ); also I. Tagpazha ei ai., Viogd. May. Spets. I ek., 3, 99 - 104 (1993).

Further, it is known that in the central nervous system of mammals I-glutamic acid is the most important neurotransmitter of the act of excitation. Under pathological circumstances, the concentration of glutamic acid abnormally increases in the outer space of the cell, leading to acute or chronic damage to the cells of the central nervous system.

Excitation of amino acids, such as glutamic acid, shows their effect by activating inotropic (ie, ion channels) receptors, as well as metabolo-tropic receptors, which bind to protein c. Types of ionotropic glutamate receptors are determined according to 29 agonists suitable for their selective excitation. Thus, MMOA, AMPA and kainate (formerly He) naztvaemy quisqualatnyy) receptor! differences and within each type of receptor there are further subtypes /App. Kew. Meshhgovsi., 17, 31 (1994)/.

It has been shown that glutamate receptors of the AMPA type play an important role in various acute and chronic diseases affecting the nervous system, such as epilepsy, diseases accompanied by muscle spasms, and in various neurodegenerative diseases, thus, by inhibiting AMPA receptors, they can achieve! inhibition of spasm, muscle relaxation and neuroprotective effect. / See among others: Sogobgomass. Vgaip Meiyab. Chem., 6, 225 (1994); Meigoiodu, at 44, Zurri. 8, 514 (1994); 9U. Riagtasoi. Ex. Tpeg., 260, 742 (1992) ./ Yu

Activation of AMPA receptors can be inhibited by competitive and non-competitive 35 antagonists. In contrast to competitive antagonists, the use of non-competitive antagonists can beat M preferentially, mainly because there is a higher protection at an extremely high concentration of excited amino acids /Eriierzu Kez., 15, 179 (1993.

Based on the above-mentioned facts, the fact that "2,3-benzodiazepines, replaced by a methylenedioxy group, have a spasm-inhibiting, muscle-relaxing, as well as a neuroprotective effect, as a result of their non-competitive C 40 antagonistic AMPA activity, is particularly important in the invention, thus , compounds can be used in therapy as antispasmodics, with" antiepileptics, further in acute and chronic neurodegenerative diseases and, potentially, in any diseases where inhibition of excited amino acids is desirable! at the receptor level.

Surprisingly, it was found that the therapeutically valuable non-competitive antagonistic activity of 45 AMPA receptors is significantly preserved if the benzene ring contains one or two chlorine or bromine atoms instead of methylenedioxy groups. Further, it was discovered that the new halogen compounds have more favorable properties than the known compounds.

This observation was surprising, since it is believed that the presence of a methylenedioxy group is an important condition for obtaining the above-mentioned activities. c 20 Thus, the invention relates to new 2,3-benzodiazepines of formulas I, in which B and B? represent, independently, a hydrogen, halogen, C 1.4 alkyl group, C .

VZ and VU are recognized, independently, by a hydrogen, alkyl C 14 group or a group of the formula -сОВО, in which 55

VO is a hydrogen, C 4.6 alkyl group, which can be replaced by an aryl group,

Ф, an alkoxy-C..4 group, a cycloalkylO C3.5 group, an alkenyl-Cov group, a cycloalkyl C3.5 group or a group ik) of the formulas -MAK'T872, in which КК"! and ВК! mean, independently, hydrogen, an alkyl C4 group, a cycloalkyl C3.5 group or an C10 aryl group, 60 BZ represents an alkyl Cx group, a cycloalkyl C35 group of the formula group!-b0o-v"3, in which B/Z has the same definitions, data in relations B 79,

B" and 25 mean, independently, hydrogen or alkyl Si from groups, and K" are recognized, independently, hydrogen, chlorine or bromine, with the proviso that if one of B 5 and B is hydrogen, the other differs from hydrogen, because it is also an isomer and their salts, obtained after adding acids.

In the definitions given in connection with formula I, alkyl and alkylene groups are defined as straight or branched chain groups. If an alkyl group is substituted, the substituent is an alkoxy group or a halogen. The cycloalkyl group is a cyclopropyl, cyclobutyl, or cyclopentyl group. The aryl group is a phenyl or naphthyl group.

Since the compounds of the formulas | contain a chiral center, under the isomers of the compounds of the formulas! I mean both enantiomers and, in the case of certain substitutions, the stereoisomer E and 7, as well as diastereomers, tautomers and their mixtures, such as racemates. Salts obtained after the addition of acids and compounds of formulas I! - it is a salt formed with physiologically suitable inorganic or 7/0 organic acids. A suitable inorganic acid is hydrochloric acid, hydrogen bromide, phosphoric acid or sulfuric acid. An organic acid is formic acid, acetic acid, malic acid, fumaric acid, malic acid, lactic acid, tartaric acid, citric acid or methanesulfonic acid.

A preferred subgroup of compounds of the invention consists of compounds of formulas I, in which

B" represents an amino group in position 4, b2, B" and 5 are hydrogen, 25 is a methyl group, KE / is a halogen and

BZ represents an aliphatic acyl group or an alkylcarbamoyl group.

Within this preferred subgroup, a particularly preferred species consists of compounds in which BZ is an acetyl group, a propionyl group, a cyclopropylcarbonyl group or a methylcarbamoyl group. The compounds of the invention can be prepared from the corresponding starting components of the formulas! II, in which B", 2, 7, 5, b and VK" are the same), as defined above, by analogy with the processes given in HO-R Mo. 206 719 or О5-Р Mo. 5, 459, 137. Combinations of formulas! | they can also be prepared in the following way: a suitably substituted isochroman derivative is oxidized with air to obtain a hemuketal, which is subjected to a reaction with an oxoreagent suitable for the introduction of an acyl group in the C position (for example, hydrazide of a carboxylic acid, semicarbazide, etc.), further, the benzodiazepine ring is formed by mesylation and closure of the alkaline ring.

Details of preparation of compounds of the formula I indications! in Examples.

In a preferred example of the preparation of the compounds of the invention, the usual method is used! with the synthesis of 2,3-benzodiazepine. Thus, the amino group is alkylated with an alkyl halide or using Щ3 reductive amination with an oxo compound. Acylation is mainly carried out with acid chloride, anhydride, mixed anhydride or alkyl, or phenyl-chlorocarbonate - in the case of catalysis with an acid-binding agent and/or a pyrimidine derivative at room temperature - or at an elevated temperature in a solvent.

Carbamoyl groups are formed by reaction with the corresponding isocyanate. However, it is also possible to acylate with an active compound, such as phenyl chlorocarbonate, and react the resulting compound with a primary or secondary amino compound.

Nitro groups are reduced, generally, catalytically, in the presence of Ryzyna nickel, palladium or platinum catalyst. In addition to hydrogen gas, hydrazine hydrate or, for example, ammonium formate can also be used as a source of hydrogen. with Starter compound formulas! And they are recognized as new, so the invention also refers to these "with" compounds. They are prepared in accordance with the process described in HO-R Mo. 191 702 or by analogy with the manufacture of lime compounds. Details of the process are shown in Examples.

As stated above, the compounds of the invention have significant non-competitive AMPA with 75 antagonistic activity, so they can be used! in therapy as antispasmodics, for muscle relaxation, as well as for neuroprotection, further in the treatment of other neurological and mental 1 disorders that can affect others! to the state of increased AMPA receptor excitation. o Combinations of formulas! they can be transformed into pharmaceutical compositions), which can be administered parenterally or parenterally. There are many uses for this purpose! suitable organic or inorganic carriers or excipients of the pharmaceutical industry, such as water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, poly(ethylene glycol), etc.

The pharmaceutical composition can be in the form of a solid dose, such as a tablet, dragee, suppository, or capsule, or it can be prepared in the form of a liquid dose, such as a solution, suspension, or emulsion. In addition to the carriers and excipients mentioned above, further additives with preserving, stabilizing, emulsifying, buffering, etc. effects can be used.

GF) For parenteral administration, the dosage form consists of a sterile solution or suspension of the active 7 ingredient. In this case, the sterile carrier may contain one or more adjuvants, i.e. local anesthetic, stabilizing agent or buffer.

The dosage administered to the patient depends on the method of administration, the type and severity of the disease, as well as the patient's weight and age. The daily dose is from 0.5 to 100 mg, preferably from 20 to 22 mg, and can be administered in one portion or in several portions.

The AMPA antagonist activity of compounds of formula I is demonstrated by the following test.

The antagonistic effect of the environment (test ip mi(go).

The activity of IP compounds was determined on a preparation of isolated chicken retina /M.). b5 and

Zpeagaomp, Vgaip Kez., 607, 189 (19939. White spreading depression stimulated by 5 micrograms of kainate

(chemical name of kainate acid 2-carboxy 4 isopropyl-3-pyrrolidineacetic acid), and meanings

ICs were determined by ZPeagaom'"pl. The compounds were tested in at least three concentrations.

Compounds that have antagonistic AMPA activity inhibit the response to kainate, which has AMPA agonistic activity, and the inhibition depends on the concentration of the compounds. IC values in the readings in Table 1. o 2 3.2

A 3.6 g 8.2 8 46 2.5 12 12

The mentioned compound: A: 5-(4-aminophenyl)-9H-1,3-dioxolo/4,5-p//2,3/benzodiazepine (SUKI 52 466; HO-P Mo. 191 698, Example 8).

The compounds of the present invention and the process of their preparation are explained further by the following example, without limiting the scope of the invention.

Example 1

Z-acetyl-7-chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine 0.72g (2.2 mmol) 7-chloro-4-methyl-1-( 4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine is stirred in 4 ml of acetic anhydride at 25" for 3 hours, then the reaction mixture is poured into 20 ml of ice water, the crystalline product is filtered and washed with water several times The resulting crude product is purified by suspending it in 4 ml of hot ethanol. After filtration and drying, 0.69 g (8895) of the named compound is obtained. Melting point: 174 - 17576.

The starting compound of Example I is prepared as follows:

Step A with b-chloro-3-methyl-1-(4-nitrophenyl)isochroman

To a solution of 17.0 g (1000 mmol) of 1-(3Z-chlorophenyl)-2-propanol / prepared by the method analogously described in .). Med.Spet., 21, 454 (1978)3/ and 15.11 g (1/00 mmol) 4 -nitrobenzaldehyde in 100 ml of anhydrous me) benzene add 13.65 g (1000 mmol) of zinc chloride (zinc chloride was ignited before addition), and anhydrous hydrogen chloride gas was directed into the reaction mixture for 3 hours.

The mixture is boiled for 2.5 hours and, after cooling, mixed with 100 ml of water. The organic phase is separated, washed with water, an aqueous solution of sodium bicarbonate, then saturated with an aqueous solution of sodium chloride, dried and evaporated. The final 30.95g of the crude oil product was crystallized from 200ml of hot ethanol to obtain 23.49g (7790) of the named compound. Melting point: 118 - 12070.

Step B With b-chloro-3-methyl-1-(4-nitrophenyl)-2-benzopyrylium perchlorate "» 26.9 g (88.5 mmol) of the isochroman derivative prepared in step A are dissolved in 270 ml of acetone and 11 b ml are added to the resulting solution (310 mmol) of Jones reagent, drop by drop, under ice-cooling for 1 hour, then the reaction mixture was stirred at 25" for 4 hours. The chromium salt separated during the reaction is filtered and the filtrate is evaporated. The remaining crystals are suspended in 100 ml of water , then filter again. Dissolve the crystal in 4 ml of hot glacial acetic acid, add 5.91 ml of 7095 perchloric acid, then, after cooling, separate the crystal, filter and wash 4 times, each time using 100 ml of glacial acetic acid. , obtain 6.84g (1995) of the named compound. Melting point: 236 - 2372C (decomposition). 70 Step B 7-chloro-4-methyl-1-(4-nitrophenyl)-5H-2,3-benzodiazepine with 6.43g (1bmmol) of benzopyrylium perchlorate, prepared on stage B, solution is added to 32 ml of dimethylformamide and 2.31 ml (48 mmol) of hydrazine hydrate 9895 is added drop by drop to the resulting solution, and the reaction mixture is stirred at 25"C for 1 hour. The mixture is poured into 320 ml of water, 22 separated products are filtered and washed 5 times, using 1 ml of water each time. The crude product (PI is purified by suspending it in 50 ml of hot ethanol. Thus, 4.41 g (8795) of the named compound are obtained. Melting point: 227 - 2287 b. o Step 7-chloro-4-methyl-1-(4--itrophenyl )-4,5-dihydro-ZH-2,3-benzodiazepine and 1.5 g (4.7 mmol) of the benzodiazepine derivative obtained in step B are suspended in 1 mL of methanol and 4.64 g (57.3 mmol) of concentrated hydrochloric acid is added to the resulting suspension! And then, with cold water cooling, 2.07 g (54.8 mmol) of sodium borohydride is added in portions. The suspension is stirred at 25"C for 1 hour, then solid sodium carbonate is added to bring the pH of the mixture to a value of about 8. The mixture is diluted with bOml of water , the separated product is filtered, washed 4 times, each time using 5095 ml of aqueous methanol, and dried to obtain 1.47 g (97.495) of the named compound. Melting point: 152 - 15476.

Example 2

Z-acetyl-1-(4-aminophenyl)-7-chloro-4-methyl-4,5-dihydro-ZH-2,3-benzodiazepine 0.bbg (1.8 mmol) Z-acetyl-7-chloro-4 -methyl-1-(4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine (prepared in Example 1) is suspended in Zbml of methanol, then approximately 0.5 g of wet Rzyny nickel catalyst is added and, with intensive stirring, 0.32 ml (6.5 mmol) 9895 of hydrozine hydrate.

The reaction mixture is stirred for another 45 minutes, then the catalyst is removed by filtration, washed with methanol, and the mixture is filtered! evaporate and the residue is treated with 1 mL of water to obtain a solid product. 0.54 g of the crude product was recrystallized from 2 ml of ethanol to obtain 0.44 g (75905) of the named compound. Melting point: 90 - 927 C.

Example C 7-chloro-4-methyl-3-(methylcarbamoyl)-1-(4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine 0.72 g (2.2 mmol) 7-chloro-4-methyl -1-(4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine, prepared in /5 Example 1, at step G is dissolved in 15 ml of anhydrous dichloromethane and 1.3 ml (22.00 mmol) is added to the resulting solution ) methyl isocyanate, and the reaction mixture is left for 10 days at 25"C. The mixture is evaporated and the residue is recrystallized from 3 ml of hot methanol. The crystals were filtered, washed 3 times, each time using 1 ml of ethanol, then dried. Thus, 0.78 g ( 9595) of the named compound.Melting point: 224 - 22670.

Example 4 1--4-aminophenyl)-7-chloro-4-methyl-3-(methylcarbamoyl)-4,5-dihydro-3H-2,3-benzodiazepine 0.75g (2.Omol) 7-chloro-4- methyl-3-"methylcarbamoyl)-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine, prepared as described in Example 3, is reduced according to the method of Example 2 and the obtained crude product is recrystallized from of hot ethanol. Thus, 0.55 g (8095) of the title compound are obtained. Melting point: 134 - 13670.

Example 5 o

Z-acetyl-8-chloro-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine 0.69g (2.19 mmol) 8-chloro-4-methyl-I-(4-nitrophenyl) -4,5-dihydro-3H-2,3-benzodiazepine is acetylated by the method described in example 1. 0.70 g (8995) of the named compound are obtained. Melting point: 227 - 22976. p

The starting compound of Example 5 is prepared as follows:

Step A about 7-chloro-3-methyl-1-(4-nitrophenyl)-isochroman so

Example 1, Step A is repeated, with the exception that the starting compound consists of 11.94 g (/Omol) 1--4-chlorophenyl)-2-propanol /). Honey. Spent 21, 454 (1978)/ and the reaction mixture is heated for 1.5 hours

35 hours. Thus, 6.8 g (3290) of the named compound are obtained. Melting point: 120 - 12390. "I

Step B 7-chloro-3-methyl-1-(4-nitrophenyl)-2-benzopyrylium perchlorate 6.8 g (22.4 mmol) of the isochroman derivative obtained in Step A is oxidized by the method of Example 1, Step B with Jones reagent. Salt is prepared in glacial acetic acid using perchloric acid. Thus, 3.7 g (4295) of the named compound are obtained. Melting point: 247 - 25576. - c Step B c 8-chloro-4-methyl-1-(4-nitrophenyl)-5H-2,3-benzodiazepine "» 4.1 g (10.25 mmol) of benzopyrylium perchlorate obtained in Step B , add to the mixture 20.5 ml of dimethylformamide and 1.5 ml (70.7 mmol) of hydrazine hydrate 9895 while cooling with cold water. The reaction mixture is stirred at 25"C for 1.5 hours, then 25 ml of water is added, the separated coarse product g" is filtered, washed 4 times, using 5 ml of water each time, then recrystallize from 25 ml of isopropanol.

Thus, 2.82 g (8795) of the named compound are obtained. Melting point: 199 - 20376. o Step o 8-chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine 1.62 g (5.16 mmol) of a benzodiazepine derivative obtained at Step B is restored according to the method described in Example 1, Step G. Thus, 1.59 g (9895) of the named compound are obtained. Point (melting point: from 132 to 13576.

Example 6

Z-acetyl-1-(4-aminophenyl)-8-chloro-4-methyl-4,5-dihydro-ZH-2,3-benzodiazepine 0.81g (2.2 mmol) Z-acetyl-8-chloro-4-methyl -1-(4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine obtained in Example 5 is reduced according to the method described in Example 2. The crude product i) is recrystallized from 5095 aqueous ethanol to obtain 0.64g (8695) of the named compound. Melting point: name) 187 - 18976.

Example 7 60 8-chloro-4-methyl-3-methylcarbamoyl-1-(4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine

Starting with 0.79 g (2.5 mmol) of 8-chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine g obtained in Example 5, Step G, repeat the procedure of Example 3. The crude product was recrystallized from isopropanol to obtain 0.85 g (9195) of the named compound. Melting point: 190 - 19276.

Example 8 65 1--4-aminophenyl)-8-chloro-4-methyl-3-methylcarbamoyl-4,5-dihydro-3H-2,3-benzodiazepine 0.65 g (1.74 mmol) 8-chloro-4-methyl -3-methylcarbamoyl-1-(4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodazepine,

obtained in Example 7, is restored according to the method described in Example 2. Thus, 0.59 g (9995) of the named compound is obtained. Melting point: 115 - 11870.

Example 9

Z-acetyl-7 8-dichloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-Z3H-2,3-benzodiazepine 0O.35g (0.99 mmol) 7,8-dichloro-4-methyl -1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine is acetylated by the method described in Example 1. Thus, 0.3 g (9395) of the named compound are obtained. Melting point: 198 - 20070.

The starting compound of Example 9 is prepared as follows: 70 Step 6,7-dichloro-3-methyl-1-(4-nitrophenyl)-isochromane

The procedure of Example 1, Step A is repeated with the exception that the starting compound consists of 10.47 g (51.Omol) of 1-(3,4-dichlorophenyl)-2-propanol, and that the reaction mixture is boiled for 3 hours. Thus, 4.29 g (2595) of the named compound are obtained. Melting point: 189 - 19176.

Step B 7,8-dichloro-4-methyl-1-(4-nitrophenyl)-5H-2,3-benzodiazepine 4.75 g. (14.0 mmol) of the isochroman derivative prepared in Step A is oxidized according to the method of Example 1, Step B, using the Jones reagent with the exception that instead of reacting the crude product with perchloric acid, the 1-acetonyl-3,4-dichloro derivative -4--nitrobenzophenone (2o melting point: 121 - 122 "C) is isolated by chromatography. A solution of the above-mentioned derivative in isopropanol is reacted with 9895 hydrazine hydrate at 2573 to obtain a monohydrazone derivative (melting point: 167 - 1697"). The monohydrazone compound is subjected to a reaction with methanol containing 1590 hydrogen chloride, then the hydrochloride of the named compound is treated with tristilamine to obtain the free base, which is purified by recrystallization from hot dimethylformamide. Melting point: c 231 - 23376. schi Step B i) 7,8-dichloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine 0.74g (2.immol ) of the benzodiazepine derivative, prepared in Step B, is restored using the method of Example 1, Step G. Thus, 0.70 g (9595) of the named compound are obtained. Melting point: 182 - so z 1847c.

Example 10 o

Z-acetyl-1-(4-aminophenyl)-7,8-dichloro-4-methyl-4,5-dihydro-3H-2,3-benzodiazepine with 0.34 g (0.8 mmol) Z-acetyl-7, 8 -dichloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine obtained in Example 9 is reduced using the method described in Example 2. The crude product of

Z5 is purified by suspension in hot ethanol. Thus, 0.25 g (8095) of the named compound is obtained. "Mr

Melting point: 242 - 24376.

Example 11 7,8-dichloro-4-methyl-3-methylcarbamoyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine 0.3 g (0.94 mmol) 7,8-dichloro-4 -methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine obtained in Example 9, Step B, is subjected to a reaction with methyl isocyanate in accordance with Example 3. Crude product cleaned by suspending it in hot ethanol. Thus, 0.37 g (9790) of the named compound is obtained.

Melting point: 221 - 22376. ;" Example 12 1--4-aminophenyl)-7,8-dichloro-4-methyl-3-methylcarbamoyl-4,5-dihydro-3H-2,3-benzodiazepine 0.35 37 (0.85 mmol) of 7,8-dichloro- 4-methyl-3-methylcarbamoyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine obtained in

Example 11 is reconstituted using the method given in Example 2. The crude product is recrystallized from 5090 ml of aqueous ethanol. Thus, 0.27 g (8490) of the named compound is obtained. Melting point: 224 - 22576. oo Additional sample!

Example 13 about 3-acetyl-8-chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine c (The method of preparation differs from that described in Example 5). 6.35 g (about 16.0 mmol) of crude acetic acid (1--2-(2-hydroxypropyl)-5-chlorophenyl/-4-nitrophenyl-methylene| hydrazine) are dissolved in 7 Oml of anhydrous dichloromethane and the solution is cooled to -157C. To the solution with stirring, add 4.10 ml (29.33 mmol) of tristhylamine, then add 1.25 ml (21.2 mmol) of mesyl chloride, drop by drop, over approximately 5

F) minutes. After 20 minutes, the reaction mixture is washed with 3 ml of 1 M hydrochloric acid cooled on ice, then twice! cooling on ice with an aqueous solution of sodium chloride, using ZOml of the solution each time. The organic phase is dried and evaporated. The solid, foamy residue is suspended in 80 ml of ethanol and 0.9 ml (17.1 mmol) of 5095 sodium hydrochloride solution is added to the suspension, drop by drop, while cooled on ice. The main part of the semi-product dissolves and after a few minutes a yellow crystal begins to form. The mixture is stirred for the next 4 hours, then, drop by drop, under ice cooling, add 100 ml of water for 45 minutes, filter the precipitate and rinse with water. 65 The dry coarse product is dissolved in approximately 450 ml of hot ethanol and the solution is concentrated to approximately one-third of its volume. After cooling, the precipitate is filtered to obtain 3.92 g of the named compound in the form of yellow crystals. Melting point: 226 - 228 2С. (Output: 6795, calculated for the isochroman derivative described in Example 5, Step A).

The starting compound of Example 13 is prepared as follows:

Step A 1-hydroxy-7-chloro-3-methyl-I-(4-nitrophenyl)-isochromane 7.44 g (24.5 mmol) derivative of 7-chloro-3-methyl-1--4-nitrophenyl)-isochromane (prepared, as described in Example 5, Step A) is dissolved in a mixture of 500 ml of dimethylformamide and 24 ml of dimethyl sulfoxide and the solution is cooled with ice water at the moment when air is introduced through a capillary placed under the 7/0 surface of the liquid. With intensive bubbling, 2.0 ml (49.00 mmol) of 5095 aqueous sodium hydroxide solution is added to the reaction mixture, which becomes violet-black. After 2 hours, the mixture is poured into 240 ml of ice-cooled 0.5 M hydrochloric acid! and the flaky precipitate is extracted 3 times, using 1000 ml of ethyl acetate each time. The combined organic solution is mixed with 100 ml of a saturated aqueous solution of sodium hydrogen carbonate and an aqueous solution of sodium chloride to neutrality, 7/5 is dried and evaporated. They get 8.70 g of powder, which consists of only one compound, as shown by thin-layer chromatography (Kg - approximately 0.2, when using a mixture of p-hexane and ethyl acetate in a ratio of 4:1).

Based on H NMR research, the compound consists of a mixture of two possible stereoisomers and has a purity of approximately 9095.

The resulting compound is used for further steps of the reaction in the form described above.

Shag B.

Acetic acid (|1-/2-(2-hydroxypropyl)-5-chlorophenyl/-4-nitrophenshshethylene hydrazide

A mixture of 5.85g (16.3mmol) hemiketal prepared in Step A (having a purity of approximately 89 to 9090), 1.45g (19.5mmol) hydrazide acetate, 10ml isopropanol, 2O0ml water and 2ml 1M hydrochloric acid! with Kkypyatyat. At the beginning of the boiling reagent! dissolve After 3.5 hours of boiling, 0.3 g (4.45 mmol) of acetic acid hydrazide and 1 ml of 1 M hydrochloric acid are added to the mixture, and the reaction is carried out for the next 3.5 hours. Then the reaction mixture is evaporated and the residue is dissolved in a mixture of 150 ml of ethyl acetate and 100 ml of an aqueous solution of sodium bicarbonate. After separation, the aqueous phase is extracted with a second 50 ml of ethyl acetate, the combined organic solution is washed with an aqueous solution of sodium chloride, (ee) dried and evaporated. The aqueous component of the foamy residue is removed by adding and layering benzene, and the resulting 6b.3B5g yellow resin is used in Example 13 for mesylation and the ring-closing reaction. co

Example 14

3-carbamoyl-8-chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine about 6.13 g (about 16.27 mmol) of crude 1-/2-(2 -hydroxypropyl)-5-chlorophenyl/-4-nitrophenylmethylene|-semicarbazide is dissolved in bOml of anhydrous pyridine and 1.7 bml (22.77 mmol) of mesyl chloride is added to the resulting solution, drop by drop, with stirring, at a temperature of -5"C. The reaction mixture is stirred at room temperature for 23 hours, then another 0.17 ml (2.8 mmol) of mesyl chloride is added. After 3 hours, the mixture is poured into 10 ml of a 1.5 M hydrochloric acid solution, and the product is extracted three times with dichloromethane, using 1 ml of dichloromethane each time. the solution is washed with an aqueous solution of sodium chloride, dried and evaporated. The semi-product obtained in the form of a solid powder is placed in 100 ml of ethanol and 1.0 ml (19.5 mmol) of 5095 aqueous sodium hydroxide solution is added drop by drop while stirring at room temperature. After 4 hours of stirring, 150 ml of water is added to the reaction mixture, drop by drop, under ice cooling, the precipitated crystallization product g" is filtered and washed with water.

The resulting 4.18 g (7695) of the crude product is recrystallized by dissolving it in 270 ml of ethanol and evaporating the solution to approximately one-third of its original volume. (95) Thus, 3.1 g (5495) of the named compound are obtained. Melting point: 233 - 2347C (when decomposed). The i-th starting connection of Example 14 is prepared as follows:

IR f) 1-/2-(2-hydroxypropyl)-5-chlorophenyl/-4-nitrophenyl-methylene|-semicarbazide 6.19 g (approximately 18 mmol) of hemuketal, prepared as described in Example 13, Step A, is subjected to the reaction with 3.01 g (27 mmol) of semicarbazide hydrochloride in a mixture of 140 ml of isopropanol and bOml of water. After 5 hours of boiling, another 0.60 g (5.4 mmol) of polucarbazid hydrochloride is added to the reaction mixture, which is boiled for the next 5 hours. The mixture is evaporated, the residue is suspended in water, the product is filtered and washed with water. ime) 6.62 g (9895) of the named compound are obtained, which is used in the obtained form for mesylation and ring-closing reactions. For analytical purposes, the sample is purified by column chromatography (silica gel, solvent: a mixture of chloroform and methanol in a ratio of 1:1). As proved by H NMR, this sample consists of stereoisomers in a ratio of 1:1 and has a purity of approximately 9095. According to mass spectroscopy, M is 376/378.

Example 15 1--4-aminophenyl)-3-carbamoyl-8-chloro-4-methyl-4,5-dihydro-3H-2,3-benzodiazepine 65 3.16 g (8.8 mmol) 3-carbamoyl-8-chloro -4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (prepared as described in Example 14) is reduced in methanol in the presence of a nickel catalyst Ryzyny with 5 equivalents of hydrazine hydrate in accordance with by the method described in Example 2. 2.171g of the crude product is recrystallized from 5095% aqueous ethanol.

Thus, 2.29 g (7995) of the named compound are obtained. Melting point: 218 - 22076.

Example 16

Z-Zthoxycarbonyl-8-chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-Z3H-2,3-benzodiazepine 2.36g (5.81 mmol) Zthyl 3-(/2-(2-hydroxypropyl) )-5-chlorophenyl/-4-nitrophenylmethylene carbazate is dissolved in 25 ml of anhydrous dichloromethane, 1.4 bml (10.43 mmol) of tristylamine is added to the resulting solution, and the mixture is reacted with 0.bOml (7.700 mmol) of mesyl chloride at -157 C. After 1 hour, the reaction mixture / 20 ml of dichloromethane are added, washed with ice-cooled 1 M hydrochloric acid, then with an aqueous sodium chloride solution, dried and evaporated. The final resin is dissolved in 34 ml of ethanol and 0.32 ml (b.1 mmol) of 5095 aqueous sodium hydroxide solution is added to the stirred solution.

The reaction mixture is stirred for 2 hours, then, drop by drop, 100 ml of water is added while cooled with ice, the precipitated product is filtered and washed with water.

Thus, 1.83 g (8195) of the named compound are obtained. Melting point: 124 - 12676.

The starting connection of Example 16 is prepared as follows:

Ztyl 3-(/2-(2-hydroxypropyl)-5-chlorophenyl/-4-nitro-phenylmethylene|icarbazate 2.10 g (about bmmol) of hemuketal, prepared in accordance with Example 13, Step A, is subjected to the reaction with 1.25 g (12 .O0mmol) of zylcarbazate in a mixture (8Oml of ethanol and bOml of water) containing 0.1ml of concentrated hydrochloric acid, at boiling. After 2 hours of boiling, another 0.12 g (1.2 mmol) of zylcarbazate and 1 drop of hydrochloric acid are added! to the mixture that boils for the next 2 hours.

After evaporation, the residue is dissolved in an aqueous solution of sodium bicarbonate, the crystalline product is filtered and washed with water.

2.36bg (9795) of the named compound are obtained. The product is a mixture of stereoisomers in a ratio of about 11. Melting point: 123 - 12576.

Example 17 i) 1--4-aminophenyl)-3-zoxycarbonyl-8-chloro-4-methyl-4,5-dihydro-3H-2,3-benzodiazepine 1.93g (4.97 mmol) 8-chloro-3-zoxycarbonyl -4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine is reduced in a mixture of methanol and dichloromethane in a ratio of 4:1 in the presence of nickel oxide with the Rzyna catalyst with hydrazine using the method described in Example 2. The product is purified by column chromatography (silica gel, solvent: a mixture of p-hexane and ethyl acetate in a ratio of 1:1). i am

1.46 g (82905) of the named compound are obtained in the form of a solid stump. Melting point: 95 - 9870. p

Example 18

3-p-Butylcarbamoyl-8-chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine o 2.L0g (4.85mmol) 1-Y/3 -chloro-6-(2-hydroxypropyl)/-4-nitrophenylmethylene|)|-4-p-butyl-semicarbazide "E is acylated 0.53 ml (6.79 μmol) of mesyl chloride in dichloroaztane in the presence of 1.22 ml (8.7 μmol) of tristhylamine in accordance with by the method described in Example 14. The crude intermediate is cycled using 0.28 ml (5.3 mmol) of 5095 aqueous sodium hydroxide solution as described in Example 14. 1.40 g of the obtained crude product is recrystallized from methanol. "

Thus, 1.14 g (5695) of the named compound are obtained. Melting point: 15070. shsh s The starting compound of Example 18, namely 1-1/3-chloro-6-(2-hydroxypropyl)/-4-nitrophenylmethylene|)|-4-p-butyl-semicarbazide is prepared from 1-hydroxy-7-chloro-3-methyl-1-(4-nitrophenyl)-isochroman (Example 13, Step A) and 4-p-butyl-semicarbazide, using the method described in the starting substance ratio of Example 14. Crude product , which is separated in the form of resins, is purified by column chromatography (silica gel, solvent: a mixture of hexane and ethyl acetate in their ratio 1:1, Ke - approximately 0.2), then used in the process of Example 18.

Example 19 o 1--4-aminophenyl)-3-p-butylcarbamoyl-8-chloro-4-methyl-4,5-dihydro-3H-2,3-benzodiazepine 2) 1.14 g (2.75 mmol)

3-p-butylcarbamoyl-8-chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine (prepared as described in Example 18) is reduced to 0.7 Oml (13.74 mmol ) of hydrazine hydrate in 9 UOml of methanol in the presence of a nickel catalyst is separated according to the method described in Example 2. The product is purified by column chromatography (silica gel, solvent: a mixture of dichloromethane and methanol in a ratio of 98:2). After evaporation, the product separates in the form of resins, which can be powdered.

0.93 g (8895) of the named compound are obtained. Melting point: 89 - 91760.

Example 20

F) 3-acetyl-7 8-dichloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (The preparation method is different from that described in Example 9) 6.26g ( about 15.Zmmol) of crude acetic acid because 11-42-(2-hydroxypropyl)-4,5-dichlorophenyl/-4-nitrophenylmethylene| hydrazide (see Step B of this Example) is mesylated and closed in a cycle by alkaline treatment in accordance with Example 13.

Thus, 3.b5g (6495, calculated for the isochroman as described in Example 9, Step A) of the named compound in the form of yellow crystals are obtained. Melting point: 190 - 19576.

The starting compound is prepared as follows: 65 Step 1-hydroxy-6b,7-dichloro-3-methyl-1-(4-nitrophenyl)isochroman

6.0 g (17.7 mmol) of 6,7-dichloro-3-methyl-1-(4-nitrophenyl) isochroman is oxidized using the method described in Example 13, Step A. 6.03 g (9695) of the named compound are separated in the form of yellow crystals . The crude product, consisting of a mixture of two possible stereoisomers, is used in the next step of the reaction without further purification.

Shag B

Acetic acid (|/2-(2-hydroxypropyl)-4,5-dichlorophenyl/-4-nitrophenylmethylene hydrazide 5.18 g (14.bmol) hemuketal prepared in Example 20, Step A) is subjected to a reaction with acetic hydrazide using the method of Example 13 , Step B. 6.26g of the named compound is obtained in the form of a yellow resin, 7/0, which is used in mesylation and ring-closing reactions.

Example 21 7,8-dichloro-4-methyl-3-methylcarbamoyl-1-(4-nitrophenyl)-1-4,5-dihydro-3H-2,3-benzodiazepine (The method of preparation differs from that described in Example 11). 8.6 mg (about 20.4 mmol) of crude 1-(3,4-dichloro-6-(2-hydroxypropyl)-(4-nitrophenylmethylene)|-4-methyl-semicarbazide) is mesylated and closed in a ring according to the method described in Example 13.

The resulting crude product is recrystallized from aqueous dimethylformamide.

Thus, 3.12 g (3395, calculated for isochroman as described in Example 9, Step A) of the named compound in the form of yellow crystals are obtained. Melting point: 218 - 22076.

The starting compound, namely 1-(/3,4-dichloro-6-(2-hydroxypropyl)/-4-nitrophenylmethylene|)|-4-methyl-semicarbazide is prepared from 1-hydroxy-6,7-dichloro-3- methyl-1-(4-nitrophenyl)isochroman (Example 20, Step A) and 4-methyl-semicarbazide in a manner similar to that described in the ratio of the starting compound of Example 14. The crude product separated as a yellow resin is used in Example 21 without further purification. with

Example 22

Z-acetyl-8-bromo-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine i) 0.82g (2.28mmol) 8-bromo-4-methyl-1 - (4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine is acylated according to the method of Example 1. Thus, 0.84 g (9195) of the named compound are obtained. Melting point: 228 - 23070. со со The starting compound of Example 22 is prepared as follows:

Step 7-bromo-3-methyl-1-(4-nitrophenyl)isochroman p

The process of Example 1, Step A, is repeated, with the exception that 14.69 g (68.0 mmol) of 1-(4-bromophenyl)-2-isopropanol /) are used. Honey. Spet., 21, 454 (1978)/ as a starting compound. In this way, 10.94 g (46905) of the named compound are obtained. Melting point: 130 - 13370. "g

Step B 8-bromo-3-methyl-1-(4-nitrophenyl)-2-benzopyrylium perchlorate 10.8 g (32.5 mmol) of the isochroman derivative prepared in Example 22, Step A, is oxidized with a reagent

Jones, as described in Example 1, Step B. The product is prepared in glacial acetic acid with perchloric acid.

Thus, 4.91 g (3495) of the named compound are obtained. Melting point: 253 - 25670.

Step B with 8-bromo-4-methyl-1-(4-nitrophenyl)-5H-2,3-benzodiazepine. 4.0 g (9-0 mmol) of benzopyrylium perchlorate, prepared in Example 22, Step B, is treated with hydrate and hydrazine according to the method of Example 1, Step B. Thus, 2.30 g (7195) of the named compound are obtained.

Melting point; 200 - 20576. Their Step 8-bromo-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-Z3H-2, Z-benzodiazepine with 3.0 g (8.3 mmol) of the benzodiazepine derivative prepared according to Example 22, Step B, 2) was reduced as described in Example 1, Step G. Thus, 2.79g (9290) of the named 5p compound are obtained. Melting point: 131 - 13576. o Example 23 with 3-acetyl-1-(4-aminophenyl)-8-bromo-4-methyl-4,5-dihydro-3H-2,3-benzodiazepine 0.8 g (2.Omol ) 3-acetyl-8-bromo-4-methyl-1-(4-nitro-phenyl)-4,5-dihydro-3H-2,3-benzodiazepine (prepared in Example 22) is reduced according to the method of Example 2. The crude product is crystallized from ethanol. Thus, 0.62 g (8395) of the named compound is obtained. Melting point: 205 - 20876.

F) Example 24 ka 8-bromo-4-methyl-1-(4-nitrophenyl)-3-trifluoroacetyl-4,5-dihydro-3H-2,3-benzodiazepine 1.51 g (4.20 mmol) 8-bromo-4- methyl-1-(4-nitrophenyl)-4, 5-dihydro-ZH-2,3-benzodiazepine (prepared 6bo in Example 22, Step G) is stirred in a mixture with 5 ml of anhydrous dichloromethane and 5 ml of trifluoroacetic anhydride at 25"C for hours, then the reaction mixture is diluted with dichloromethane. The organic phase is washed with water and 295% aqueous sodium bicarbonate solution, dried and evaporated. The crude product is purified by suspension in 5 ml of hot methanol. After filtration and drying, 1.66 g (8695) of the named compound are obtained. Melting point: 193 - 196260. 65 Example 25 1-(4-aminophenyl)-8-bromo-4-methyl-3-fluoroacetyl-4,5-dihydro-3H-2,3-benzodiazepine 1.64g (3.6bmmol) 8-bromo-4 -methyl-1-(4-nitrophenyl)-3-fluoroacetyl-4,5-dihydro-3H-2,3-benzodiazepine

(prepared in Example 24) is restored according to the method of Example 2. The crude product is purified by chromatography on a silica gel column, then diluted with a mixture of chloroform and methanol in a ratio of 99:1.

Thus, 1.33 g (8795) of the named compound are obtained. Melting point: 93 - 967.

Example 26 8-bromo-4-methyl-1-(4-nitrophenyl)-3-propionyl-4,5-dihydro-3H-2,3-benzodiazepine 1.33 g (3.7 mmol) 8-bromo-4-methyl-1 -(4-nitrophenyl)-3-trifluoroacetyl-4,5-dihydro-3H-2,3-benzodiazepine (prepared in 7/0 Example 22, Step G) is acetylated with propionic anhydride using the method of Example 1. The crude product is purified chromatography on a silica gel column, then diluted with a mixture of hexane and ethyl acetate in a ratio of 9:1. Thus, 1.07 g (70905) of the named compound are obtained. Melting point: 178 - 18070.

Example 27 1--4-aminophenyl)-8-bromo-4-methyl-3-propionyl-4,5-dihydro-ZH-2,3-benzodiazepine 1.05 g (2.52 mmol) 8-bromo-4-methyl-1 -(4-nitrophenyl)-3-propionyl-4,5-dihydro-3H-2,3-benzodiazepine (prepared in Example 26) is reduced according to the method of Example 2. The crude product is crystallized from ethanol. Thus, 0.85 g (87905) of the named compound are obtained. Melting point: 99 - 10276.

Example 28 8-bromo-3-cyclopropionyl-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine 0.90 g (2.5 mmol) 8-bromo-4-methyl-1 -(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (prepared in

Example 22, Step G) acylate 0.27 ml (mmol) of cyclopropanecarbonyl chloride in 15 bml of anhydrous dichloromethane in the presence of 0.22 ml (mmol) of tristylamine at 257°C. The reaction mixture is poured onto 25 g of crushed ice and extracted with dichloromethane. The organic phase is washed with water and hydrogen g of sodium bicarbonate solution, dried and evaporated. The crude product is suspended in Zml of hot ethanol. After filtration and drying, 0.88 g (8295) of the named compound is obtained. Melting point: 172 i) - 17876.

Example 29 1--4-aminophenyl)-8-bromo-3-cyclopropionyl-4-methyl-4,5-dihydro-3H-2,3-benzodiazepine salt 0.79 g (1.77 mmol) 8-bromo-3-cyclopropionyl -4-methyl-1-4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (prepared in Example 28) is reduced according to the method of Example 2. The crude product is crystallized from a mixture of ethanol and hexane in ratios of 1:4. Thus, 0.55 g (7890) of the named compound are obtained. Melting point: 113 - 11676.

Example 30 o 8-bromo-4-methyl-3-methylcarbamoyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine "E 0.v4g (2.333mmol) 8-bromo-4 -methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (prepared in

Example 22, Step D) react with methyl isocyanate according to the method of Example 3. The crude product is suspended in bml of hot ethanol. After filtration and drying, 0.82 g (8490) of the named compound are obtained. Melting point: 197 - 20070.

Example 31 with 1-(4-aminophenyl)-8-bromo-4-methyl-3-methylcarbamoyl-4,5-dihydro-ZH-2,3-benzodiazepine. 0.g (1.92 mmol) 8-bromo-4-methyl-3-methylcarbamoyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine and? (prepared in Example 30) is reduced according to the method of Example 2. The crude product is crystallized from Zml ethyl acetate.

Thus, 0.50 g (68905) of the named compound is obtained. Melting point: 121 - 12426. "iz" Example 32 8-bromo-3-zthoxycarbonyl-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine and 8.11 g (1 mmol ) ztil 3-(/5-bromo-2-(2-hydroxypropyl) phenyl/-4--itrophenylmethylene-carbazate is exposed

Ge) reaction with mesyl chloride, then with 5095 aqueous sodium hydroxide solution according to the method described in Example 16. The product is extracted with dichloromethane, the organic phase is washed with water, and dried and evaporated. 6.78 g (8795) of the named compound is obtained in the form of a solid resin, which is also used in this form in Example 33.

The starting connection is prepared as follows:

Step 7-bromo-1-hydroxy-3-methyl-1-(4-nitrophenyl)isochroman 15.56 g. (44.7 mmol) of 7-bromo-1-hydroxy-3-methyl-1-(4-nitrophenyl)isochroman (prepared in Example iF) 22, Step A) is oxidized using the method described in Example 13, Step A. The product is extracted benzene, which is dried and evaporated. Thus, 14.80 g (9195) of the named compound, which is a mixture of possible isomers, is obtained. The product is used without further purification. 6o Shag B

Zyl 3-/5-bromo-2-(2-hydroxypropyl)phenyl/-4-nitrophenyl-methylene carbazate 6.82 g (18.72 mmol) of the semiketal derivative, prepared in Example 32, Step A, is reacted with zyl carbazate , using the method described for the preparation of the starting compound of Example 16. The product is extracted with ethyl acetate, the organic phase is washed with water, dried and evaporated. 65 Thus, 8.11 g (9695) of the named compound are obtained. The product, consisting of a mixture of possible isomers, is used without further purification.

Example 33 1--4-aminophenyl)-8-bromo-3-zthoxycarbonyl-4-methyl-4,5-dihydro-ZH-2,3-benzodiazepine 1.58 g. (3.6 mmol) of 8-bromo-3-zthoxycarbonyl-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine (prepared in Example 32) is reduced according to the method , described in Example 2.

The crude product is crystallized from 4 ml of ethyl acetate. Thus, 1.20 g (8195) of the named compound are obtained. Melting point: 114 - 117276.

Example 34 8-bromo-3-carbamoyl-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine 70 Solution 1.80 g (bmmol) 8-bromo-4-methyl- 1-(4-nitrophenyl)-4,5-dihydro-3ZH-2,3-benzodiazepine in 1 Oml of glacial acetic acid! process 0.53 g (b.bmmol) of potassium cyanate. After 1 hour, the solution is poured into water and the suspended crystals are filtered. The crude product is suspended in 15 ml of hot ethanol. After filtration and drying, 1.56 g (77905) of the named compound are obtained. Melting point: 193 - 20370.

The starting compound of Example 34 is prepared as follows: 8-bromo-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (The compound is identical to the product

Example 22, Step G.) 5.20 g (12 mmol) of 8-bromo-3-zoxycarbonyl-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (prepared in Example 32 ) boiled in 104 ml of methanol with 1 ml of 10 M sodium hydroxide solution for 2 hours. After cooling, the reaction mixture is diluted with 104 ml of water and the precipitated crystals are filtered.

Thus, 3.99 g (9295) of the named compound are obtained. Melting point: 125 - 13070.

Example 35 1--4-aminophenyl)-8-bromo-3-carbamoyl-4-methyl-4,5-dihydro-3H-2,3-benzodiazepine 1.55 g (3.84 mmol) 8-bromo-3-carbamoyl-4 -methyl-1-(4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine (prepared in Example 34) is reduced using the method of Example 2. The crude product is crystallized in 3 mL of ethanol. Thus, 1.19 g (8395) of the named compound are obtained. Melting point: 218 - 22196.

Example 36 o 8-chloro-4-methyl-1-(4--itrophenyl)-3-trifluoroacetyl-4,5-dihydro-3H-2,3-benzodiazepine 0.bg (1.9 Uummol) 8-chloro- 4-methyl-1-(4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine (prepared in

Example 5, Step D) is acylated with trifluoroacetic anhydride according to the method of Example 24. 0.76 g (9790) of the named compound are obtained. Melting point: 150 - 15270.

The starting compound is identical to the product of Example 5, Step G, however, it can also be prepared as follows: with 10.98g. (27 mmol) of C3-zoxycarbonyl-8-chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (prepared in Example 16) is hydrolyzed using the method described in connection with the preparation about the starting connection of Example 34. "I

Thus, 8.04 g (9495) of the named compound are obtained. Melting point: 146 - 15176.

Example 37 1--4-aminophenyl)-8-chloro-4-methyl-3-trifluoroacetyl-4,5-dihydro-3H-2,3-benzodiazepine 0.75 g (1.8 mmol) 8-chloro-4-methyl-1 -(4-nitrophenyl)-3-trifluoroacetyl-4,5-dihydro-3H-2,3-benzodiazepine (prepared in Example 36) is reduced according to the method of Example 2. The crude product is purified by chromatography on a silica gel column, with a mixture of benzene and ethyl acetate in the ratio of 3:1. Thus, 0.47 g (6895) of the named compound is obtained. Melting point: 165 - 167260. "» Example 38 8-chloro-4-methyl-1-(4-nitrophenyl)-3-propionyl-4,5-dihydro-ZH-2, 3-benzodiazepine 0.bg (1.9 Uummol ) 8-chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine (prepared in

Example 5, Step G or in Example Zb, the starting compound) is acylated with propionic anhydride in g" according to the method of Example 26. The crude product is purified by chromatography on a silica gel column, diluted with a mixture of benzene and ethyl acetate in a ratio of 95:5. Thus, 0.56 g (7990) of the i-th named compound are obtained. Melting point: 160 - 16170. o Example 39 1--4-aminophenyl)-8-chloro-4-methyl-3-propionyl-4,5-dihydro-3H-2,3-benzodiazepine and 0.46 bg (1.23 mmol) of 8-chloro-4-methyl-1-(4-itrophenyl)-3-propionyl-4,5-dihydro-ZH-2,3-benzodiazepine c (prepared in Example 38) is reduced according to the method of Example 2 The crude product is crystallized from 5095% aqueous ethanol. Thus, 0.39 g (9395) of the named compound is obtained. Melting point: 118 - 12070.

Example 40

Z-cyclopropionyl-8-chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine about 0.bg (1.9 Uummol) 8-chloro-4-methyl-1 -(4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine (prepared in Example 5, Step G or in Example 36, the starting compound) is acylated with cyclopropanecarbonyl chloride according to the method of Example 28. 0.71 g (9790) of the named compound. Melting point: 158 - 6o 16076.

Example 41 1--4-aminophenyl)-3-cyclopropionyl-8-chloro-4-methyl-4,5-dihydro-ZH-2,3-benzodiazepine 0.72 g (1.87 mmol) 3-cyclopropionyl-8-chloro-4 -methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (prepared in Example 40) is reduced according to the method of Example 2. Crude product 65 is recrystallized from 5095 aqueous ethanol. Thus, 0.57 g (8695) of the named compound is obtained. Melting point: 122 - 12476.

Example 42 (1)-3-acetyl-8-chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-5H-2,3-benzodiazepine 05B1ho (1.bmmol) /(i)- 8-chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-5H-2,3-benzodiazepine is acylated with acetic anhydride according to the method of Example 1. 0.54 g of the crude product is crystallized from 28 ml of ethyl acetate at room temperature . Thus, 0.28 g (4895) of the named compound is obtained. Melting point: 259 - 2607"С. On the basis of research using chiral liquid chromatography at high pressure (SpigaYse! 0, solvent: a mixture of hexane and ethanol in a ratio of 1:1), the product consists of one isomer. 70 The starting compound of Example 42 is prepared as follows: (1)-8-chloro-4-methyl-1-(4-nitrophenyl)-4, 5-dihydro-5H-2,3-benzo-diazepine

To a solution of 6.03 g (23.bmmol) K-()-2-amino-1,1-diphenyl-3-methylbutan-1-ol /). Ogd. Spet., 49, 555 (1984);

U. Spet. Zos. RegKkeep. Thapv I. 2039 (198537/ in bOml of anhydrous dichlorostane add 2.4 ml (21.5 mmol) of borane dimethyl sulfide complex (borane concentration: about 9.2 M), drop by drop, at -207C. During /5 three hours, the temperature of the solution is allowed to rise to 0"C and keep the solution at 4"C for 15 hours. A solution of 3.37 g (10.7 mmol) of 8-chloro-4-methyl-1-(4-nitrophenyl)-4,5- of dihydro-5H-2,3-benzodiazepine (prepared in Example 5, Step B) in bOml of anhydrous dichloromethane at room temperature for 30 minutes. The reaction mixture is stirred at 60"C for 6 hours. The orange solution is cooled to 25"C, treat 500 ml of 20 1095 aqueous solution of sodium carbonate, mix with water until neutral, then dry and layer.

The obtained named compound consists of a mixture of znantiomers in a ratio of 75:25 (liquid chromatography under high pressure: SpigaiIse! 0), solvent: a mixture of hexane and ethanol in a ratio of 1:1). high school

Example 43 (-)-3-acetyl-1-(4-aminophenyl)-8-chloro-4-methyl-4,5-dihydro-5H-2,3-benzodiazepine i) 0.28g (0.7vmmol) (4) -3-acetyl-8-chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-5H-2,3-benzodiazepine (prepared in Example 42) is reduced according to the method of Example 2. Crude product crystallize from 2 ml of ethanol. Thus, 0.15 g (5895) of the named compound is obtained. Melting point: (du 219 - 22076. /o/v229--712.1 (c-0.7; chloroform). The product consists of one zantiomer (liquid chromatography at high pressure: SpigaiIse! 0, solvent: a mixture of hexane and ethanol in a ratio of 1.1) o

Example 44 with 3-(Zylcarbamoyl)-8-chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine 0.bg (1.9 Uummol) 8-chloro -4-methyl-1-(4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine (prepared in Example 5, Step G or in Example Zb, starting compound) is boiled with 0.75 ml (9.5 mmol ) of ethyl isocyanate in 25 ml of anhydrous toluene for 24 hours. The mixture is evaporated, the residue is recrystallized from 5 ml of ethanol.

Thus, 0.51 g (6995) of the named compound is obtained. Melting point: 170 - 17276.

Example 45 "1--4-aminophenyl)-3-(ethylcarbamoyl)-8-chloro-4-methyl-4,5-dihydro-3H-2,3-benzodiazepine 0.48g (1.24mmol) 8-chloro-3- (xylcarbamoyl)-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine-Sh-Zc (prepared in Example 44) is reduced according to the method of Example 2. The crude product ts are recrystallized from 4 ml of 5095 aqueous ethanol. Thus, 0.35 g (79905) of the named compound is obtained. "» Melting point: 165 - 16770.

Example 46 8-chloro-4-methyl-1-(4-nitrophenyl)-3-(p-propylcarbamoyl)-4,5-dihydro-3H-2,3-benzodiazepine "g" 0.bg (1.9Ummol) 8 -chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine (prepared in

Example 5, Step G or Example Zb, starting compound) are reacted with p-propyl isocyanate in accordance with the method described in Example 44. The crude product is recrystallized from ethanol. In this way, 0.63 g (8395) of the named compound is obtained. Melting point: 186 - 18770.

Example 47 i-th 1--4-aminophenyl)-8-chloro-4-methyl-3-(p-propylcarbamoyl)-4,5-dihydro-3H-2,3-benzodiazepine (Che O.bg (1. Bmmol) of 8-chloro-4-methyl-1-(4-nitrophenyl)-3-(p-propylcarbamoyl)-4,5-dihydro-3H-2,3-benzodiazepine (prepared in Example 46) is reduced according to the method Example 2. Thus, 0.52 g (9390) of the named compound is obtained.Melting point: 88 - 9076.

Example 48

Ф, З-(isopropylcarbamoyl)-8-chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine co 0.bg (1.9 Uummol) 8-chloro-4 -methyl-1-(4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine (prepared in

Example 5, Step G or in Example 36, the starting compound) are subjected to a reaction with isopropyl isocyanate in accordance with the method of Example 44. The crude product is recrystallized from ethanol. Thus, 0.4 g (5396) of the named compound is obtained. Melting point: 172 - 17476.

Example 49 1--4-aminophenyl)-3-"isopropylcarbamoyl)-8-chloro-4-methyl-4,5-dihydro-3H-2,3-benzodiazepine 0.38 g (0.95 mmol) 65 C-(isopropylcarbamoyl) -8-chloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (prepared in Example 48) is reduced according to the method of Example 2. Thus,

0.32 g (9195) of the named compound are obtained. Melting point: 100 - 10270.

Example 50

3-zthoxycarbonyl-7 8-dichloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine 1.41 g (about 2.0 mmol) of crude zyl 3-(/ 2-(2-Hydroxypropyl)-4,5-dichlorophenyl/-4-nitrophenyl-methylene|-carbazate is mesylated and closed in a ring as described in Example 13. Thus, 0.94 g (7595, calculated for isochroman as described in Example 9, Step A) of the named compound.Melting point: 106 - 10870.

The starting compound of Example 50 is prepared as follows: 70 ztil 3-(/2-(2-hydroxypropyl)-4,5-dichlorophenyl/-4-nitrophenyl-methylene|-carbazate 0.98g (2.8mmol) 1-hydroxy-6b,7 -dichloro-3-methyl-1-(4-nitrophenyl)isochroman (prepared in Example 20, Step A) is subjected to a reaction with zylcarbazate in accordance with the method described in the preparation ratio of the starting compound of Example 16. Thus, 1.20g are obtained (97905) of the named compound consisting of a mixture of possible isomers.The product was used without further purification.

Example 51 1--4-aminophenyl)-3-zoxycarbonyl-7,8-dichloro-4-methyl-4,5-dihydro-ZH-2,3-benzodiazepine 0.94 g (2.2 mmol)

Z-Zthoxycarbonyl-7 8-dichloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (prepared in Example 50) is reduced according to the method of Example 2. Crude product purified by X-chromatography on a column with silica gel, then diluted with a mixture of benzene and ethyl acetate in a ratio of 41.

Then the product is recrystallized from ethanol.

Thus, 0.54 g (6395) of the named compound is obtained. Melting point: 190 - 19276.

Example 52

3-butyryl-7,8-dichloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine 1.31 g (about 3 mmol) of crude butyric-I (1-/ 2-(2-Hydroxypropyl)-4,5-dichlorophenyl/-4-nitrophenylmethylene hydrazide is mesylated and closed in the i) ring according to the method of Example 13. Thus, 1.08 g (869565, calculated for isochroman as described in Example 9, Step A) of the named compound. Melting point: 75 - 7770.

The starting compound of Example 52 is prepared as follows: butyric acid-I(1-/2-(2-hydroxypropyl)-4,5-dichlorophenyl/-4-nitrophenylmethylene|-hydrazide) 1.06 g (Zmmol) of hemuketal prepared in Example 20, Step A, react with butyric hydrazide according to the method of Example 13, Step B. 1.31 g of the named compound is obtained in the form of a yellow amorphous substance, which is used without further purification for mesylation and ring-closing reactions.

Example 53 "E 1--4-aminophenyl)-3-butyryl-7,8-dichloro-4-methyl-4,5-dihydro-ZH-2,3-benzodiazepine 1.08g (2.bmmol) 3-butyryl- 7,8-dichloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (prepared in Example 52) is reduced according to the method described in Example 2. Crude product purified by chromatography on a column with silica gel, then diluted with a mixture of benzene and 70% ethyl acetate in a ratio of 8:1. Then the product is suspended in hot ethanol. in s Thus, 0.57 g (5795) of the named compound are obtained. Melting point: 193 - 19476.

And using the method! of the above examples, the following compounds are prepared: и? 7,8-dichloro-4-methyl-1-(4-nitrophenyl)-3-propionyl-4,5-dihydro-3H-2,3-benzodiazepine 1--4-aminophenyl)-7,8-dichloro-4 -methyl-3-propionyl-4,5-dihydro-3H-2,3-benzodiazepine

3-carbamoyl-7,8-dichloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-ZH-2,3-benzodiazepine and 1--4-aminophenyl)-3-carbamoyl-7, 8-dichloro-4-methyl-4,5-dihydro-ZH-2,3-benzodiazepine

Claims (10)

The formula of the invention 1 1. Production of 2,3-benzodiazepines of formula (1): 715. Y -X 2 FU and v' where B and B2 mean, independently of each other, hydrogen, halogen, C4.4 alkyl group, C.4 alkoxy group, nitro group, trifluoromethyl group or group of formulas! - MAZR, where VZ and VU mean, independently of the second CM second, hydrogen, C..4 alkyl group or group of formulas! -сОВ У, where d) ВО means hydrogen, C.6 an alkyl group which can be substituted, Сб.10 an aryl group, Сч.4 an alkoxy group, С3.5 a cycloalkyl group, Сов an alkenyl group, С3.5 a cycloalkyl group or a group of formulas -MV/ 8272, where KVK"! and 272 mean, independently of each other, hydrogen, C.4 alkyl group, C.5 with cycloalkyl group or C.lo aryl group, KZ means C.i.4 alkyl group, Cz.5 a cycloalkyl group or a group of the formulas -CO-B 73, in which VK "Z has the same meaning as VU, and B" and B? mean, independently of each other, hydrogen or a C.z alkyl group, with Вб and в" mean, independently of each other, hydrogen, chlorine or bromine, and if one of BEZ and В" means hydrogen, then the other differs from hydrogen, and also their isomers and acid addition salts of those compounds or isomers. AND 2. 2,3-benzodiazepine derivative according to claim 1, which is 3-acetyl-1-(4-aminophenyl)-8-chloro-4-methyl-4,5-dihydro-3H-2,3-benzodiazepine. 3. Derivative of 2,3-benzodiazepine according to claim 1, which is "1--4-aminophenyl)-8-chloro-4-methyl-3-methylcarbamoyl-4,5-dihydro-ZH-2,3-benzodiazepine. 4. A pharmaceutical composition that includes a combination of formulas as an active ingredient! (I) - c or ego isomer, where the radical! with B! according to B" is as defined in point 1, or pharmaceutically acceptable in the acid addition salt of that compound or its isomer together with suitable carriers, solvents, diluents and fillers used in the preparation of pharmaceutical compositions. 5. Production of 2,3-benzodiazepine according to claim 1, for use as pharmaceutical preparations. and 6. Production of 2,3-benzodiazepine according to claim 1, for the manufacture of a pharmaceutical composition suitable for the treatment of diseases accompanied by muscle spasm. 7. Production of 2,3-benzodiazepine according to claim 1, for the manufacture of a pharmaceutical composition useful for the treatment of epilepsy. p 20 8. Production of 2,3-benzodiazepine according to claim 1, for the manufacture of a pharmaceutical composition useful for the treatment of acute or chronic neurodegenerative diseases. so 9. The method of obtaining derivative 2,3-benzodiazepine formulas! (I), their isomers and acid addition salts of those compounds and their isomers, where B, 2, BZ, B", B, BZ and 2/7 have the meanings defined in point 1, which includes the introduction of BZ groups in the position of compounds of formulas (I): Ф) име) 60 b5 I sia I) ; Mk A. ; in? ouch! МН что / В ве И-и дз це КЕ сч где В", 2, 27, 85, В? and Б are as indicated above, and, if necessary, the transformation of the compound of formula (I) into the second compound of formula (I ), and, if necessary, the conversion of the compound of formula (I) into its acid addition salt, or the separation of the formula (I) compound from the acid addition salt. 10. Production of 2,3-benzodiazepine of formula (II): d (1), (ge) Z to Kk yu : de ! Yu! | | | Kh M u 7 "Kk, M Z p. ;" . g oo --82 and SHІ fe o 1 sia 70 is IR e) where B and B2 mean, independently of each other, hydrogen, halogen, C4.4 alkyl group, C.4 alkoxy group, vv nitro group, trifluoromethyl group or group of formulas ! - MEZV2, where are Z and EE? mean, independently of each other, hydrogen, a C.4 alkyl group or a group of the formula -SOV U, where BZ means hydrogen, C.6 alkyl (F, a group that can be substituted, C.1o aryl group, C.4 alkoxy group , C3.5 cycloalkyl group, their) Sov alkenyl group, C3.5 cycloalkyl group or a group of formulas! -MV'' В", where В! and 2"? mean, independently of each other, hydrogen, Sil alkyl group, C3-5 cycloalkyl group or Silo aryl group, BZ means hydrogen, B" and 5 mean, independently of each other, hydrogen or C..3 alkyl group, Vb and c" mean, independently of each other, hydrogen, chlorine or bromine, and if one of BEZ and B" means hydrogen, then the other differs from hydrogen, b5, as well as their isomers and acid addition salts of those compounds or isomers.