DK145577B - METHOD OF ANALOGUE FOR THE PREPARATION OF S-TRIAZOLO (4,3-A) - (1,4) -BENZODIAZEPINES OR 5N-OXYDES OR ACID ADDITION SALTS. - Google Patents

Description

(φ) (19) DENMARK \ Ra / ® (12) PUBLICATION OF 145577 Β

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 5856/69 (51) intci.3 C 07 D 487/04 (22) Filing date 5 · Nov. 1969 (24) Running day Nov 5 1969 (41) Aim. available May 6, 1970 (44) Presented 15 · Dec. 1982 (86) International Application No. - (86) International Filing Day (85) Continuation Day - (62) Stock Application No. ~

(30) Priority 5 · Nov. 1968, 80815/68, JP 17 · Dec. 1968, 92928/68, JP

Dec 17 1968, 92929/68, JP Dec 17 1968, 92950/68, JP et al.

(71) Applicant TAKEM CHEMICAL INDUSTRIES LTD., Osaka, JP.

(72) Inventor Kanji Meguro, JP: Yutaka Kuwada, JP.

(74) Plenipotentiary for Industrial Excellence by Svend Schønning.

(54) Analogous process for the preparation of s-triazolo (4,5-a) - (1,4) -benz = zodiazepines or 5N-oxides or acid addition salts thereof.

The present invention relates to an analogous process for the preparation of s-triazolo [4,3-a] - [1,4] -benzodiazepines with the general formula I-12 shown in the preamble to claim 1 wherein R, R, R and R have the same meanings indicated, or 5N oxides or acid addition salts thereof. The procedure is peculiar to the characterizing part O of the claim.

o 12

Examples of alkyl groups R and R are methyl, ethyl, 3-propyl, isopropyl, butyl, sec. butyl, amyl, hexyl and t-butyl.

3 4 g Halogen substituents (R and R) in rings A and B may be a 2 chlorine, fluorine, bromine and iodine, and alkyl substituents R and R may be methyl, ethyl and propyl, while alkoxy substituents may be methoxy or ethoxy. .

When reacting a compound II with a carboxylic acid R 2 COOH or one of said reactive derivatives thereof, the carboxylic acid or its reactive derivative is generally used in an amount of 1-10 moles, especially 2-5 moles per mole of 2-hydrazine. zinobenzodiazepine derivative II. The reaction is preferably carried out in the presence of a solvent and an acid catalyst at a temperature usually between 0 ° C and 300 ° C, but the conditions vary with the reagents used. The solvent is, for example, methanol, ethanol, chloroform, methylene chloride, dimethylformamide or mixtures thereof. The acid catalyst is, for example, an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid or polyphosphoric acid, a carboxylic acid such as acetic acid or propionic acid or an organic sulfonic acid such as benzenesulfonic acid or p-toluenesulfonic acid.

The amount of the acid catalyst is 2 moles to 10 moles per mole of 2-hydrazinobenzodiazepine derivatives II.

In this reaction, as an intermediate, an acyl-hydrazino compound IIIa, an enol ether derivative 1Hb thereof, or an α-aminoalkylidene or aralkylidene compound IIIc: R 1 NH-NHCOR 1 NH-HC 2 is formed.

'or5 R3 - I' V-R2 r3 - I V-R2

4 AAi (A

E— I * - I

KA AA

ma „X mb

HN-N (A

N— ~ y XnH2 R3-- I \ R2

R4 ^ J

with the nitrogen atom in the 4-position being optionally linked to oxygen, R-R having the meanings specified in the claim, 5 and R being methyl or ethyl. These intermediates are cyclized to the compounds X when the reaction takes place under drastic conditions, so that in this reaction compound I is prepared directly by synthesis in one step without isolation of the intermediates. In preparing the compounds I in one step according to reaction a), the 2-hydrazino-benzodiazepine derivative II and the derivative of the carboxylic acid R 2 COOH are preferably reacted at fairly high temperature, e.g. 140-250 ° C.

Optionally, a solvent may be used in this reaction. Generally, good results are obtained by a melting method, especially in the presence of 2-methylimidazole.

When a compound of formula II is reacted with a reactive derivative of the acid R 2 -COOH under mild conditions, for example in a solvent and at room temperature, a compound of formula III (IIa-IIIc) can be isolated and such a compound can according to reaction b) is easily cyclized to a compound I by heating to a temperature between 130 ° C and 260 ° C. If necessary, the cyclization can be accelerated using a catalyst such as polyphosphoric acid. The cyclization is optionally carried out in the presence of a solvent, e.g., pyridine, dimethylformamide, xylene or tetralin.

The benzodiazepine derivative I prepared can be isolated in the form of free base or in the form of an appropriate acid salt, for example a chloride, a sulfate or an acetate by conventional means.

For example, the reaction mixture is neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with a suitable solvent, eg methylene chloride or chloroform, followed by distillation of the solvent to give a benzodiazepine derivative I.

The structure of the benzodiazepine derivatives I is determined from the result of X-ray analysis of 8-chloro-6-phenyl-4H-s-triazole [4,3-a] - [1,4] -benzodiazepine.

When the benzodiazepine derivative I prepared has an oxygen atom bonded in the 5-position, i.e. is a 5N-oxide, it may be reduced to the corresponding benzodiazepine derivative I without oxygen at the nitrogen atom at the 5-position if desired. The reduction may be carried out in a conventional manner, for example, by catalytic hydrogenation or by reduction using halogen phosph for compound ice such as phosphorus trichloride. The hydrogenation is usually carried out in a solvent, e.g. methanol or ethanol, at room temperature and under atmospheric pressure. Reduction with halogen phosphorus compounds can usually be accomplished by heating in a solvent such as chloroform or methylene chloride.

2-Hydrazinobenzodiazepine derivatives II used as starting material in the above reaction a) are novel compounds and can be prepared by reacting 2-aminobenzodiazepines of the general formula an I 4 is an oxygen atom and wherein R, R and R have the meanings specified in the claim with hydrazine.

The 2-amino-benzodiazepine derivatives IV may have the isomeric formula I-V "· r3- + in V1 4

«- I

3 4 where R, R and R have the above meanings.

Compounds of general formula IV can be prepared, for example, by the method of Journal of Organic Chemistry 26, 1111 5 145577 (1961) or by reacting a 2-aminobenzophenone derivative with an alkylamine to give a 2-amino-α-phenylbenzylidene alkylamine. react with an aminoacetonitrile derivative and the 2-amino-α-phenylbenzylidene-aminoacetonitrile derivative thus obtained is cyclized in the presence of an acid or a base.

The reaction between 2-aminobenzodiazepine derivatives IV and hydrazine is preferably carried out in the presence of a solvent and an acid, and usually at a temperature between 0 ° C and 150 ° C. The solvent may be, for example, methanol, ethanol, pyridine, dimethylformamide, a mixture thereof or a mixture thereof with water. Examples of usable acids are inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, and organic acids such as acetic acid and p-toluenesulfonic acid. The acids can be added in the form of salts with amines, e.g., pyridine, trialkylamines and 2-methylimidazole. It should be noted that both hydrazine and 2-aminobenzodiazepine derivatives IV can be used as their acid addition salts, in which case it is not always necessary to add additional acid or salts thereof with amine to the reaction system. The amount of hydrazine and acid used is usually between 1 and 5 moles per ml. mole of 2-aminobenzodia-zepine derivative IV, but may also be outside these limits.

The 2-hydrazinobenzodiazepine derivative II may be subjected to reaction a) after isolation from the reaction mixture in which it is formed, or in the reaction mixture. The isolation of the 2-hydrazinobenzodiazepine derivative II can be carried out in a conventional manner, for example by adding water to the reaction mixture and extraction with a suitable solvent, for example methylene chloride or chloroform, followed by evaporation of the solvent.

2-Hydrazinobenzodiazepine derivatives II, wherein the nitrogen atom at the 4-position is linked to oxygen, can also be prepared by reacting with hydrazine a compound of the general formula 14 SR6 t-CC

"-U

wherein R 1, R 2 and R 2 have the above meanings and R 2 is hydrogen or an alkyl or aralkyl group.

C

When R is hydrogen, the compounds may have the following isomeric formula

HfX V

2 3 4 wherein R, R and R have the above meanings.

For example, compounds of formula V may be prepared by the method described in Journal of Organic Chemistry 29, 231 (1964).

g

Examples of alkyl groups represented by R are preferably those having up to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, amyl and hexyl.

Examples of aralkyl groups R 1 are benzyl and phenethyl.

The reaction is usually carried out in the presence of a solvent such as methanol, ethanol or an aqueous mixture thereof, at room temperature or under heating, if necessary, to the boiling temperature of the solvent used. The amount of hydrazine used is in practice 1-10 moles per ml. mol of compound V.

The thus obtained 2-hydrazinobenzodiazepine derivatives II can be isolated in conventional manner, for example by evaporation of the solvent from the reaction mixture. The benzodiazepine derivatives I or salts thereof prepared have muscle relaxant, anticonvulsant, sedative and anesthetic effect and are therefore useful as a muscle relaxant, anticonvulsant, as sedative, and as a sedative.

Pharmacological trials

Pharmacological tests were carried out on a number of the compounds prepared by the process of the invention and for the control of a related compound not included in the invention. The results are shown in the experiments below.

The antimorphine effect in mice was investigated as follows:

Groups of 5 mice were orally administered the test compound in at least 3 different dose sizes, followed by a dose of morphine hydrochloride in an amount of 50 mg / kg subcutaneously, this administration being 1/2 hour later.

The mice were placed in each glass container, and here the frequency of circular movements was determined for 30 seconds, counting 6 times at 10 minute intervals after morphine administration, and the counts were summed for the whole group. The activity is indicated as the dose (ED + -q) which causes a 50% reduction in the frequency of the circular motion, comparing the total value for the whole treated group with the value for a corresponding group that has only been given morphine.

The antipentylenetetrazole effect in mice was determined as follows:

In experiments performed 45 minutes after oral administration of the compound under study, examining at least 5 different doses in groups of 8 mice, ED50 is calculated as the dose that prevented tonic hindlimb extension in half of the mice for one hour after pentylene tetrazole administration. (150 mg / kg subcutaneously).

LDjjq, expressed in mg / kg in mice of the control compound, was studied according to Psychotropic Drugs and Related Compounds (second edition), US Department of Health, Education and Welfare (1972), 159.

145577 δ t - 5- ο «^ ν, ° Ύλ § ° A? Α ff s \ / td 3 V / O 3 a, V — Λ [-> φΐ <\ \ Μ P * h λ / \ φ // \\ / 'Hl Φ // \\ _ / V_ ti /' \ —L go m L / ij! s wlf & s ^, λΛ / B ^ É? a ° * Φ

OH

Hl W 01 η ω Φ w

H S

3 I

§ 3 & H- cp

Knee knee oawMg jl tu M tu Μ Μ H «ω ffi co co to £ cn ^

ononnngnnsoid R

µ ^^ ί_.Μ1τ | ΟΗ *! ΟΗίΟ Hl ω to co to ^

Oo ^ oaffiætEKaaw S

Μ Μ η ω g

P

if o I I I ........

island

tP

_ H- 3> H tn P · 3 H tf

3 ft P

iq H-3 P

Η H S Λ Λ * ~ ΟΟΟΟιΡ> · ΙΟίΟ (ΟΌίΟΜ ^ ΗΗ · Η ·

JiHCO ^ lMCnCOI- · CO 01 Jj] Η · 3 ρ οι ft ρ <ί Φ Φ 01 Η · Η ft Η Η- W 3 = I ιΡ Η σ ______ ϋΐ 3 * r +>> ο Ο Η 3 3 οι ρ ft ι + _ Ν Η- Η- 3 3 ΟΌ if ιρ OOOOOtOOOHOtO 'J ΡΗΦΟ \' κ s Ρ Ρ £ «ooHOi ^ cncototO'Jto on S.

ΟΙ to ω ο ^ cn 00 Η Kj, Ρ 3 Φ 01 Η- 3 Η · 3 f + Ο ιρ Φ Ρ ________! _ Ν Ο a PJ tr * ίο Η Η Φ σ ο σ «σι Ρ Η οκη ο to Κ Κ 1 η ° ο οοο ο rt 3 C -ο- .------—-- οι 3 ν 3 Ό ιρ κ \ ΦΦ3 \ ο σι ^ μ ρ Η rt if ο £ »w ο ο οο οο ft rt ρ '

Ο I

__III.

145577 9

The subject benzodiazepine derivatives I and their acid addition salts can be administered orally or parenterally as such or in appropriate form, for example as powders, granules, tablets or injection solutions mixed with a pharmaceutically acceptable carrier. The dose of the benzodiazepine derivatives I or their acid addition salts depends on the nature of the benzodiazepine derivative I, the severity of the disease, etc. and is usually in the range of 1-30 mg by oral administration, and at 0.5-10 mg by parenteral administration for adults. . day.

The process according to the invention will be explained in greater detail by means of a number of exemplary embodiments including the preparation of starting materials, where the relation between weight parts and volume parts is as between g and ml.

I. Starting materials

Example A

To a suspension of 3.4 parts by weight of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine, dihydrochloride, in 60 parts by volume, 1.25 parts by weight of 80% hydrazine hydrate are added. The suspension is stirred for 40 minutes, diluted with water and extracted with methylene chloride. The extract is washed with water and dried over anhydrous sodium sulfate, then the solvent is evaporated. The residue is recrystallized from a mixture of methylene chloride and benzene to give 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine as colorless prisms. Brown staining at 170 ° C and decomposition at 202-204 ° C.

Calculated for C 15 H 15 ClN 4: C 63.27 H 4.60 N 19.68 Found: C 63.43 H 4.48 N 19.27.

Example B

To a suspension of 3 parts by weight of 2-amino-7-chloro-5- (p-methoxyphenyl) -3H-1,4-benzodiazepine in a mixture of 50 parts by volume of methanol and 0.6 parts by volume of glacial acetic acid is added dropwise with stirring 1.5 parts by volume. 100% s hydrazine hydrate. The mixture is stirred for 30 minutes and poured into ice water, then extracted with chloroform. The chloroform layer is washed with water, dried over sodium sulfate and the solvent is evaporated. Treatment of the residue with benzene gives 7-chloro-2-hydrazino-5- (p-methoxyphenyl) -3H-1,4-benzodiazepine as colorless crystals, m.p. 214-220 ° C.

Calculated for C C ^HH gClN ^O: C 61.05 H 4.80 N 17.80 Found: C 60.93 H 4.67 N 17.83.

Example C

To a mixture of 2.35 parts by weight of 2-amino-5-phenyl-3H-1,4-benzodiazepine, 50 parts by volume of ethanol and 1.2 parts by volume of glacial acetic acid, 1.5 parts by volume of 100% hydrazine hydrate are added and the mixture is stirred for 1 hour. room temperature. Treatment of the mixture in the same manner as in Example B gives 2-hydrazino-5-phenyl-3H-1,4-benzodiazepine as white crystals. Recrystallization from a mixture of methylene chloride and benzene yields white crystals melting at 116-118 ° C (foam).

Calcd for c15 H14 N4.1 / 3C6H6: C 73.89 H 5.84 N 20.28

Found: C, 73.86; H, 5.47; N, 20.44.

Example D

To a mixture of 9.1 parts by weight of 2-amino-5-phenyl-7-trifluoromethyl-3H-1,4-benzodiazepine, 150 parts by volume of ethanol and 3.6 parts by volume of glacial acetic acid, 4.5 parts by volume of 100% hydrazine hydrate are added. The mixture is stirred for 30 minutes at room temperature and treated in the same manner as in Example A to give 2-hydrazino-5-phenyl-7-trifluoromethyl-3H-1,4-benzodiazepine as a crystalline powder. Mp. 127 ° C (sintering), 133-135 ° C (foam).

Calculated for C C ^HHF ^K ^: / / 37H 4.12 N 17.60

Found: C, 60.05; H, 3.96; N, 17.40.

Example E

To a mixture of 2.5 parts by weight of 2-amino-7-methyl-5-phenyl-3H-1,4-benzodiazepine, 100 parts by volume of methanol and 1.2 parts by weight of glacial acetic acid is added 2.5 parts by weight of 100% hydrazine hydrate. . The mixture is stirred for 1 hour at room temperature and treated in the same manner as in Example A to give 2-hydrazino-7-methyl-5-phenyl-3H-1,4-benzodiazepine as crystals. Recrystallization from a mixture of chloroform and diethyl ether gives colorless crystals melting at 240-241 ° C (decomposition).

Calculated for C C-HH g g: ^ ^ 2.70 H 6.10 N 21.20 Found: C 72.70 H 6.08 N 21.31.

Example F

To a mixture of 26.5 parts by weight of 2-amino-7-methoxy-5-phenyl-3H-1,4-benzodiazepine, 500 parts by volume of methanol and 1.2 parts by weight of glacial acetic acid, 25 parts by weight of 100% hydrazine hydrate are added. The mixture is stirred for 1 hour at room temperature and treated in the same manner as in Example 4 to give 2-hydrazino-7-methoxy-5-phenyl-3H-1,4-benzodiazepine as crystals melting at 110-120 ° C .

Example G

To a mixture of 5.6 parts by weight of 2-amino-7-nitro-5-phenyl-3H-1,4-benzodiazepine, 200 parts by volume of ethanol and 2.4 parts by volume of glacial acetic acid, 5 parts by volume of 80% by volume of hydrazine hydrate are added. The mixture is stirred for 30 minutes at room temperature and treated in the same manner as in Example A to give 2-hydrazino-7-nitro-5-phenyl-3H-1,4-benzodiazepine as a red viscous oily substance.

Example H

To a solution of 16 parts by weight of 2-amino-7-chloro-3-iso-butyl-5-phenyl-3H-1,4-benzodiazepine and 25 parts by weight of 100% hydrazine hydrate in 400 parts by volume of methanol, 6 parts by weight of glacial acetic acid are added with stirring and ice-cooling. . Then the whole mixture is stirred for 5 hours at room temperature. Water is added to the reaction mixture and then extracted with chloroform. The chloroform layer is washed with water, dried over sodium sulfate and the solvent is evaporated. By treating the residue with isopropyl ether, 7-chloro-2-hydrazino-3-isobutyl-5-phenyl-3H-1,4-benzodiazepine is obtained as colorless crystals melting at 165-168 ° C.

This product is identical to the product made in Example K.

Example I

To a solution of 2 parts by weight of 7-chloro-2-methylmercapto-5-phenyl-3H-1,4-benzodiazepine in 70 parts by volume of ethanol is added 5 parts by volume of 80% s of hydrazine hydrate and the mixture is left at room temperature for 3 days. After evaporation of the solvent, a small amount of water is added to the residue to give 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine as crystals. There is recrystallized from a mixture of methylene chloride and benzene. Brown staining at 175 ° C and decomposition at 205-207 ° C.

The product thus produced is identical to the product prepared in Example A.

Example J

To a solution of 2.9 parts by weight of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione in a mixture of 2.5 parts by volume of dimethylsulfoxide and 100 parts by volume of ethanol is added 5 parts by volume 80 % s hydrazine hydrate and the mixture is left for 24 hours. After evaporation of the solvent under reduced pressure, the residue is diluted with water and then extracted with methylene chloride. The methylene chloride layer is dried over sodium sulfate and the solvent is evaporated. Treatment of the residue with benzene gives 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodizepine. Crystallization from a mixture of methylene chloride and benzene gives crystals with m.p. 205-207 ° C (decomposition), which product is identical to the product prepared in Examples A and I.

Example K

To a solution of 1.6 parts by weight of 7-chloro-3-isobutyl-2-methylmercapto-5-phenyl-3H-1,4-benzodiazepine in 150 parts by volume of methanol is added 40 parts by weight of 100% hydrazine hydrate. The mixture is heated at reflux for 4 1/2 hours and poured into water, then extracted with chloroform. The chloroform layer is washed with water, dried over sodium sulfate and the solvent is evaporated. Treatment of the residue with diethyl ether gives 7-chloro-2-hydrazino-3-isobutyl-5-phenyl-3H-1,4-benzodiazepine as crystals. Recrystallization from a mixture of chloroform and N-hexane gives colorless crystals melting at 168-169 ° C. Calculated for C, 66.95; H, 6.21; N, 16.44

Found: C, 67.21; H, 6.19; N, 16.70.

II. Method according to the invention

Example 1

To a suspension of 8.1 parts by weight of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine in 180 parts by volume of methanol is added 3.6 parts by weight of 2-methylimidazole, hydrochloride and 2.25 parts by volume of 80% hydrazine hydrate. . The suspension is stirred at room temperature for 1.5 hours, after which 25 parts by weight of ethyl orthoformate are added without isolation of the resulting 2-hydrazine compound.

To the mixture is added dropwise with stirring 3 parts by volume of ethanol containing 10% hydrogen chloride. After stirring for an additional 1 hour, the mixture is heated for a while to complete the reaction. After evaporation of the solvent, an aqueous solution of sodium bicarbonate is added to the residue for neutralization. The mixture is then extracted with methylene chloride. The methylene chloride layer is washed with water and dried over sodium sulfate, then the solvent is evaporated. The residue is recrystallized from a mixture of acetone and N-hexane to give 8-chloro-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzo-diazepine as colorless flakes. Mp, 226-227 ° C Calculated for c16 H11 ClN4: C 65.20 H 3.76 N 19.01 Found: C 65.30 H 3.48 N 19.03.

Example 2

To a solution of 2.8 parts by weight of 7 ”chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine and 7.4 parts by weight of ethyl orthoformate in volume parts of chloroform, 2 parts by weight of concentrated sulfuric acid are added with stirring. The mixture is stirred at room temperature for 30 minutes, then saturated aqueous sodium bicarbonate is added to neutralize the mixture. The chloroform layer is washed with water and dried over anhydrous sodium sulfate, then the solvent is evaporated. The residue is recrystallized from a mixture of acetone and n-hexane to give 8-chloro-6-phenyl-4H-s-triazole [4,3-a] - [1,4] -benzodiazepine as colorless flakes. Mp. 226-227 ° C.

The product thus produced is identical to the product prepared in Example 1.

Example 3

To a solution of 2.85 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 100 parts by volume of methanol is added 7.4 parts by weight of ethyl orthoformate and 20 parts by volume of methanol saturated with hydrogen chloride. The mixture is stirred for two hours and warmed slightly under reflux for 30 minutes. The solvent is distilled off under reduced pressure. To the residue is added saturated aqueous bicarbonate to make the mixture alkaline, then extracted with chloroform. The chloroform extract is extracted with water and dried over anhydrous sodium sulfate, then the solvent is evaporated. The residue is recrystallized from ethyl acetate to give 8-chloro-6-phenyl-4H-s-triazol [4,3-a] - [1,4] -benzodiazepine as colorless flakes. Mp.

226-227 ° C.

The product thus produced is identical to the product prepared in Examples 1 and 2.

Example 4

A solution of 2.8 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 20 parts by volume of formic acid is left overnight. The solution is diluted with water, neutralized with an aqueous solution of sodium bicarbonate and extracted with chloroform. The chloroform extract is washed with water, dried over anhydrous sodium sulfate and the solvent is evaporated. The residue is recrystallized from a mixture of acetone and n-hexane to give 8-chloro-6-phenyl-4H-s-triazole- [4,3-a] ~ [1,4] -benzodiazepine as colorless flakes. Mp. 226-227 ° C.

The product thus produced is identical to the product prepared in Examples 1-3.

Example 5

To a suspension of 2.8 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 40 parts by volume of formamide is added 1 part by volume of concentrated sulfuric acid. The resulting solution is left for 6 hours and then heated on a water bath for 30 minutes. The solution is diluted with water, neutralized with sodium bicarbonate and extracted with chloroform. The chloroform extract is washed with water and dried over anhydrous sodium sulfate, then the solvent is evaporated. The residue is recrystallized from ethyl acetate to give 8-chloro-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine as colorless flakes. Mp. 226-227 ° C.

The product thus produced is identical to the product prepared in Examples 1-4.

Example 6

A mixture of 2.8 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine, 2.4 parts by weight of formamidine, hydrochloride and 2.5 parts by weight of 2-methylimidazole is melted at 160 ° C. 10 minutes. Water is added to the mixture and then extracted with methylene chloride. The methylene chloride layer is washed with water, dried over sodium sulfate and the solvent is evaporated to give 8-chloro-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] benzodiazepine. Recrystallization from ethyl acetate gives colorless flakes melting at 226-227 ° C.

The product thus produced is Identical to the product prepared in Examples 1-5.

Example 7

To a suspension of 1.35 parts by weight of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine in 25 parts by volume of methanol are added 0.6 parts by weight of 2-methylimidazole, hydrochloride, and 6 parts by volume of 1 mol of methanol solution. of hydrazine hydrate. The mixture is stirred at room temperature for 1.5 hours, after which 4.8 parts by weight of ethyl orthoacetate and 10 parts by volume of ethanol containing 10% hydrogen chloride are added without isolation of the formed hydrazine compound. The mixture is heated at reflux for 30 minutes, then the solvent is evaporated. The residue is neutralized with saturated aqueous sodium carbonate and extracted with methylene chloride. The methylene chloride extract is washed with water and dried over sodium sulfate, then the solvent is evaporated. The residue is purified by silica gel column chromatography to give 8-chloro-1-methyl-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine. Recrystallization from a mixture of acetone and n-hexane gives colorless needles. Mp. 225-226 ° C.

Calculated for C C ^HH gClNN: C 66.13 H 4.24 N 18.15 Found: C 66.39 H 4.08 N 18.07.

Example 8

To a solution of 2.84 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 50 parts by volume of chloroform are added 10 parts by weight of ethyl orthoacetate and 4 parts by weight of p-toluenesulfonic acid. The solution is left at room temperature for 6 hours and heated for a while on a water bath to complete the reaction. The mixture is washed with saturated aqueous sodium bicarbonate, then with water and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue is treated in the same manner as in Example 7 to give 8-chloro-1-methyl-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] benzodiazepine like colorless needles.

Mp. 224-225 ° C.

Example 9

To a suspension of 2.84 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 50 parts by volume of acetic anhydride is added 1 part by volume of concentrated sulfuric acid. The resulting solution is left at room temperature for 1 hour, poured into ice water, neutralized with sodium bicarbonate and extracted with methylene chloride. The methylene chloride extract is washed with water and dried over anhydrous sodium sulfate, then the solvent is evaporated. The residue is recrystallized from a mixture of acetone and n-hexane to give 8-chloro-1-methyl-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine as colorless needles. Mp. 224-225 ° C.

The product thus produced is identical to the product prepared in Examples 7-8.

Example 10

To a solution of 2.84 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 60 parts by volume of chloroform is added 2.46 parts by weight of ethyl acetoimidate, hydrochloride. The mixture is stirred for 8 hours, then the aqueous sodium bicarbonate solution is added to neutralize the mixture. The chloroform layer is separated, washed with water and dried over anhydrous sodium sulfate, then the solvent is evaporated. The residue is recrystallized from ethyl acetate to give 8-chloro-1-methyl-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine as colorless needles. Mp. 225-226 ° C.

The product thus prepared is identical to that of Examples 7-9.

Example 11

A mixture of 2.8 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine, 2.8 parts by weight of acetamidine, hydrochloride, and 2.5 parts by weight of 2-methylimidazole is melted under heating at 160 ° C. for 10 minutes. Water is added to the mixture and then extracted with methylene chloride. The methylene chloride layer is washed with water and dried over sodium sulfate. The solvent is distilled off to give 8-chloro-1-methyl-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine. Recrystallization from ethyl acetate yields colorless needles melting at 223-225 ° C.

The product thus produced is identical to the product prepared in Examples 7-10.

Example 12 18 145577 a) Starting material

A mixture of 2.8 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine, 2.8 parts by weight of acetamidine, hydrochloride, 2.5 parts by weight of 2-methylimidazole and 100 parts by volume of chloroform is stirred at room temperature. 24 hours. The chloroform layer is washed with water, dried over sodium sulfate and the solvent is evaporated. After treatment of the residue with diethyl ether, the resulting crystals are subjected to extraction with hot methanol. Evaporation of the methanol gives 2- (α-aminoethylethyl) -hydrazino-7-chloro-5-phenyl-3H-1,4-benzodiazepine as crystals. Recrystallization from acetone produces pale yellow needles that melt at 203-205 ° C (foam).

Calcd. For C 17 H 16 ClN 5: C 62.67 H 4.95 N 21.50 Found: C 62.99 H 4.84 N 21.53.

b) Process according to the invention 3.5 parts by weight of 2- (α-aminoethylethyl) -hydrazino-7-chloro-5-phenyl-3H-1,4-benzodiazepine prepared as above heated on an oil bath at 200 ° C for 10 minutes, melts during foaming and then solidifies. Recrystallization from ethyl acetate gives 8-chloro-1-methyl-6-phenyl-4H-s-triazole- [4,3-a] - [1,4J-benzodiazepine as colorless needles melting at 225.5-226.5 ° C.

The product thus produced is identical to the product prepared in Examples 7-11.

Example 13 a) Starting material

To a solution of 1.4 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in 30 parts by volume of chloroform is added with stirring 0.47 parts by volume of acetic anhydride. The mixture is stirred for 1 hour and washed with a saturated aqueous solution of sodium bicarbonate and then with water. The chloroform layer is dried over sodium sulfate and the solvent is evaporated. Addition of methanol gives 2- (2-acetylhydrazino) -7-chloro-5-phenyl-3H-1,4-benzodiazepine as white crystals. Recrystallization H5577 19 from a mixture of chloroform and methanol gives powdery crystals melting at 202-204 ° C (foaming).

Calcd for C17 H15 ClN4 O: C 62.48 H 4.63 N 17.15 Found: C 62.38 H 4.44 N 17.23.

b) Process of the Invention 3.3 parts by weight of 2- (2-acetylhydrazino) -7-chloro-5-phenyl-3H-1,4-benzodiazepine prepared as above are heated to 215 ° C for 10 minutes under slightly reduced pressure. The molten substance is recrystallized from ethyl acetate to give 8-chloro-1-methyl-6-phenyl-4H-s-triazole- [4,3-a] phenyl] benzodiazepine as colorless needles melting at 225 -226 ° C.

The product thus produced is identical to the product prepared in Examples 7-12.

Example 14

A suspension of 3.3 parts by weight of 2- (2-acetylhydrazino) -7-chloro-5-phenyl-3H-1,4-benzodiazepine prepared as in Example 13 a) in 20 parts by volume of pyridine is heated at reflux, gradually dissolving the crystals. After 2 hours, the solvent is evaporated under reduced pressure. The residue is recrystallized from a mixture of acetone and n-hexane to give 8-chloro-1-methyl-6-phenyl-4H-s-triazole- [4,3-aJ- [1,4] -benzodiazepine as colorless needles melting at 224-225 ° C.

The product thus produced is identical to the product prepared in Examples 7-13.

Example 15

To a mixture of 1.4 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine prepared as in Example 1, 50 parts by volume of ethanol and 4 parts by volume of ethyl orthopropionate is added 0.5 parts by volume of concentrated sulfuric acid. The mixture is stirred for 30 minutes at room temperature and then treated in the same manner as in Example 3 to give 8-chloro-1-ethyl-6-phenyl-4H-s-triazole- [4,3-a] - [1, 4] -benzodiazepine as crystals.

Recrystallization from acetone gives colorless prisms that melt at 229-230 ° C.

Calcd for C C gHHClN:: q 66.97 H 4.68 N 17.36 Found: C 67.18 H 4.48 N 17.53.

Example 16 a) Starting material

To a solution of 1.4 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine prepared as in Example A in 30 parts by volume of chloroform is added with stirring 0.65 parts by volume of propionic anhydride. The mixture is stirred for 1 hour, washed with a saturated aqueous solution of sodium carbonate and then with water, and dried over sodium sulfate. After evaporation of the chloroform, methanol is added to the residue to give 7-chloro-5-phenyl-2- (2-propionylhydrazino) -3H-1,4-benzodiazepine as crystals. Recrystallization from a mixture of chloroform and methanol gives colorless prisms melting at 186-187 ° C (foam).

Calcd. For C 18 H 17 Cl 1 N 4 O: C 63.43 H 5.03 N 16.44 Found: C 63.54 H 4.88 N 16.70.

b) Method according to the invention

Under slightly reduced pressure, 3.4 parts by weight of 7-chloro-5-phenyl-2- (2-propionylhydrazino) -3H-1,4-benzodiazepine are heated at 195 ° C for 15 minutes. The molten substance is recrystallized from acetone to give 8-chloro-1-ethyl-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine as colorless prisms melting at 229-230 ° C.

The product thus produced is identical to the product prepared in Example 15.

Example 17

To a mixture of 2.85 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine, 50 parts by volume of chloroform and 2 parts by volume of triethylamine is gradually added a solution of 1.6 parts by weight of enantyl chloride in 20 parts by volume of diethyl ether. ice cooling. The mixture is stirred for a while to complete the reaction. After evaporation of the solvent at reduced pressure, the residue is treated with methanol to give 7-chloro-2- (2-enantylhydrazino) -5-phenyl-3H-1,4-benzodiazepine as crystals. Recrystallization from a mixture of dimethylformamide and water gives colorless needles melting at 205-206 ° C (foaming).

Calculated for C C ^H ^ CCIB ^O: C 66.57 H 6.35 N 14.12 Found: C 66.43 H 6.24 N 14.29.

Example 18

A mixture of 1.98 parts by weight of 7-chloro-2- (2-enantyl-hydrazino) -5-phenyl-3H-1,4-benzodiazepine and 30 parts by weight of polyphosphoric acid is heated to 170-180 ° C for 2 hours. To the mixture is added 200 parts by volume of ice water and the resulting solution is neutralized with concentrated ammonia water under ice cooling, then extracted with chloroform. The chloroform layer is washed with water, dried over sodium sulfate and the solvent is evaporated. The residue is recrystallized from aqueous acetone to give 8-chloro-1-hexyl-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine as colorless plates melting at 75 -78 ° C (sintering).

Calcd for C 22 H 23 ClN 4,2H 2 O: C 63.68 H 6.56 N 13.50 Found: C 63.71 H 6.15 N 13.60.

The product thus prepared was further dried under reduced pressure to give a compound containing 1 / 4H 2 O which sintered at 61-63 ° C.

Example 19

A suspension of 4 parts by weight of 7-chloro-2- (2-enantylhydrazino) -5-phenyl-3H-1,4-benzodiazepine prepared in Example 17 in 20 parts by volume of pyridine is heated at reflux for approx.

3 hours. After evaporation of pyridine, water is added to the residue to give 8-chloro-1-hexyl-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine as crystals. Recrystallization from aqueous acetone yields colorless flakes melting at 75-78 ° C (sintering).

The product thus produced is identical to the product prepared in Example 18.

Example 20 22 145577 a) Starting material

To a solution of 1.4 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine prepared in Example A in 25 parts by volume of tetrahydrofuran is added 0.62 parts by volume of benzoyl chloride and the mixture is stirred at room temperature for 1 hour. 2 hours to complete the reaction. The reaction mixture is neutralized with a saturated aqueous solution of sodium bicarbonate.

The resulting white precipitate is separated, washed with water and then with methanol and dried to give 2- (2-benzoylhydrazino) -7-chloro-5-phenyl-3H-1,4-benzodiazepine as crystals. Recrystallization from a mixture of chloroform and methanol gives white needles melting at 207-208 ° C (foaming).

Calcd. For 222.77.11 ° C C 67.95 H 4.41 N 14.41 Found: C 67.87 H 4.20 N 14.49.

b) Method according to the invention

A mixture of 38.8 parts by weight of 2- (2-benzoylhydrazino) -7-chloro-5-phenyl-3H-1,4-benzodiazepine and 400 parts by weight of polyphosphoric acid is heated to 150 ° C for 1.5 hours. The mixture is treated in a similar manner to Example 18 to give 8-chloro-1,6-diphenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine as crystals. Recrystallization from ethyl acetate gives colorless needles melting at 191-192 ° C.

Calculated for C 22 H 15 Cl - N 4: c 71.25 H 4.08 N 15.11 Found: C 71.11 H 4.10 N 14.98.

Example 21

Under slightly reduced pressure, 3.9 parts by weight of 2- (2-benzoylhydrazino) -7-chloro-5-phenyl-3H-1,4-benzodiazepine, prepared as in Example 20 a), are heated to 215 ° C for approx. 15 minutes until foaming ceases. Recrystallization of the molten substance from ethyl acetate gives 8-chloro-1,6-diphenyl-4H-s-triazole- [4,3-a '] - [1,4] -benzodiazepine as colorless needles melting at 193-194 ° C .

23 US577

The product thus produced is identical to the product prepared in Example 20.

Example 22

A solution of 1.4 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine and 1.8 parts by weight of ethylbenzimidate hydrochloride in 30 parts by volume of chloroform is stirred at room temperature for 24 hours and then washed with water. The chloroform layer is dried over sodium sulfate and the solvent is evaporated. Treatment of the residue with diethyl ether gives 8-chloro-1,6-diphenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine as crystals. Recrystallization from a mixture of ethyl acetate and n-hexane yields colorless needles melting at 192-193.5 ° C.

The product thus produced is identical to the product prepared in Examples 20-21.

Example 23 a) Starting material In the same manner as in Example 17, a solution of 0.85 parts by weight of phenylacetyl chloride in 10 parts by volume of diethyl ether is added to a mixture of 1.4 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4. -benzodiazepine, 1 volume triethylamine and 25 volume chloroform. The whole mixture is stirred for 40 minutes to give 7-chloro-2- (2-phenylacetylhydrazino) -5-phenyl-3H-1,4-benzodiazepine as crystals. Recrystallization from a mixture of dimethylformamide and water gives colorless fine prisms melting at 220-221 ° C (foaming).

Calculated for C C ^H ^Cl₂O: C 68.57 H 4.75 N 13.91 Found: C 68.72 H 4.79 N 13.71.

b) Method according to the invention

A mixture of 4 parts by weight of 7-chloro-2- (2-phenylacetylhydrazino) -5-phenyl-3H-1,4-benzodiazepine and 50 parts by weight of polyphosphoric acid is heated at 180 ° C for 2 hours. The mixture is treated in the same manner as in Examples 18 and 20 b) to give 1-benzyl-8-chloro-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzo -diazepine. Recrystallization from ethyl acetate gives colorless 24 rods melting at 190-192 ° C.

Calcd. For: C 23.77 H 4.45 N 14.56 Found: C 72.07 H 4.34 N 14.74

Recrystallization from methanol gives colorless needles melting at 101-103 ° C (foaming).

Calcd for C 23 H 17 ClN 4, CH 3 OH: C 69.14 H 5.08 N 13.44 Found: C 69.31 H 5.02 N 13.59.

Example 24 4 Weight portions of 7-chloro-2- (2-phenylacetylhydrazino) -5-phenyl-3H-1,4-benzodiazepine prepared as in Example 23 a) are melted under heating at 230 ° C for 10 minutes under slightly reduced pressure until foaming ceases. Recrystallization of the molten substance from ethyl acetate gives 1-benzyl-8-chloro-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine as colorless prisms melting at 19 192 ° C.

The product thus produced is identical to the product prepared in Example 23.

Example 25

To a suspension of 1.6 parts by weight of 7-chloro-2-hydrazino-5- (p-methoxyphenyl) -3H-1,4-benzodiazepine prepared in Example B in 50 parts by volume of ethanol is added 3.0 parts by weight of ethyl orthoformate and then added dropwise with stirring 0.5 parts by volume of concentrated sulfuric acid. The whole mixture is stirred for a while, then neutralized with an aqueous mixture of sodium bicarbonate, after which the solvent is evaporated.

Water is added to the residue to give 8-chloro-6- (p-methoxyphenyl) -4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine as crystals. Recrystallization from acetone and then from ethyl acetate gives pale yellow flakes which melt at 216-217 ° C.

Calcd for C 17 H 13 ClN 4 O: C 62.87 H 4.03 N 17.25 Found: C 62.98 H 3.95 N 17.57.

Example 26 255577

To a mixture of 2.1 parts by weight of 7-chloro-2-hydrazino-5- (p-methoxyphenyl) -3H-1,4-benzodiazepine prepared as in Example B, 4.33 parts by weight of ethyl orthoacetate and 60 parts by volume of ethanol is added dropwise 0 , 75 parts by volume of concentrated sulfuric acid. The mixture is stirred for approx. 15 minutes. Upon completion of the reaction, the reaction mixture is neutralized with a saturated aqueous solution of sodium bicarbonate, whereby 8-chloro-1-methyl-6- (p-methoxyphenyl) -4H-s-triazole- [4,3-a] - [1,4] -benzo-diazepine is available as crystals. Crystallization from a mixture of methanol and chloroform gives colorless needles melting at 268-269 ° C.

Calculated for C C ^H ^ClN₂O: C 63.81 H 4.46 N 16.54 Found: C 63.76 H 4.31 N 16.58.

Example 27

To a mixture of 1 part by weight of 2-hydrazino-5-phenyl-3H-1,4-benzodiazepine prepared as in Example C, 2 parts by volume of ethyl orthoformate and 20 parts by volume of ethanol, 0.44 parts by volume of concentrated sulfuric acid is added dropwise under ice-cooling. The mixture is stirred at room temperature for 30 minutes and neutralized with saturated aqueous sodium bicarbonate. The resulting oily substance is extracted with methylene chloride. The methylene chloride layer is washed with water, dried over sodium sulfate and the solvent is evaporated to give 6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine as crystals. Recrystallization from a mixture of acetone and n-hexane produces colorless needles melting at 195-196 ° C.

Calcd for ^ 73.83 H 4.65 N 21.53

Found: C, 73.71; H, 4.37; N, 21.21.

The compound is obtained as polymorphic rods which melt at 201-202 ° C by recrystallization from the same solvent and its elemental analytical data are the same as the calculated composition C

Example 28 26 145577

Proceed in the same manner as in Example 27 except that 4 parts by volume of ethyl orthoacetate is used in place of ethyl orthoformate to give 1-methyl-6-phenyl-4H-s-triazole- [4,3-a] - [ l, 4] benzodiazepine. Recrystallization from a mixture of methanol and ethyl acetate gives colorless prisms melting at 226-227 ° C.

Calculated for C C ]HH _NO: c 74.43 H 5.14 N 20.43 Found: C 74.70 H 5.17 N 20.41.

Example 29

To a mixture of 3.2 parts by weight of 2-hydrazino-5-phenyl-7-trifluoromethyl-3H-1,4-benzodiazepine prepared as in Example D, 8.5 parts by weight of ethyl orthoformate and 50 parts by volume of chloroform is added dropwise 7.6 parts by weight of p -toluenesulfonic acid at a temperature below 10 ° C. The mixture is stirred at room temperature for 2.5 hours. After completion of the reaction, the reaction mixture is neutralized with a saturated aqueous solution of sodium bicarbonate. The chloroform layer is separated, washed with water and dried over sodium sulfate. Evaporation of the solvent gives 6-phenyl-8-trifluoromethyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine as crystals. The crystals are dissolved in ethanol and the insoluble material is removed by filtration. The filtrate is concentrated and recrystallized from ethyl acetate to give colorless flakes. Mp. 258-260 ° C.

Calcd for c17 HnF3 N4: c 62.19 H 3.38 N 17.07 Found: C 61.99 H 3.46 N 16.89.

Example 30

To a mixture of 9.5 parts by weight of 2-hydrazino-5-phenyl-7-trifluoromethyl-3H-1,4-benzodiazepine prepared as in Example D, 29 parts by weight of ethyl orthoacetate and 150 parts by volume of chloroform, 23 parts by weight of p-toluenesulfonic acid are added dropwise by ice-cooling to below 10 ° C, after which the mixture is stirred at room temperature for 7 hours. After completion of the reaction, the reaction mixture is neutralized with a saturated aqueous solution of sodium bicarbonate and the chloroform layer is separated, washed with water and dried over sodium sulfate.

After evaporation of the solvent, the residue is treated with a mixture of benzene and isopropyl ether to give 1-methyl-6-phenyl-8-trifluoromethyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine as crystals containing crystallization benzene. Recrystallization from a mixture of benzene and n-hexane gives colorless needles melting at 129-130 ° C (sintering), 133-134 ° C (foaming).

Calculated for C 65.21 H 4.10 N 15.21

Found: C 65.26 H 4.20 N 14.81.

Recrystallization from aqueous acetone gives colorless needles containing 1/5 E ^ O and melts at 112-113 ° C (sintering).

Calcd. For C18H13F3N4.1 / 5H2O: C, 62.49; H, 3.90; N, 16.20.

Example 31

To a mixture of 5.3 parts by weight of 2-hydrazino-7-methyl-5-phenyl-3H-1,4-benzodiazepine prepared as in Example E, 14.8 parts by weight of ethyl orthoformate and 150 parts by volume of ethanol is added dropwise to 4 parts by weight of concentrated sulfuric acid under ice-cooling. . The whole mixture is stirred for approx. 30 minutes and neutralized with a saturated aqueous solution of sodium bicarbonate, then extracted with chloroform. The chloroform layer is washed with water and dried over sodium sulfate. After evaporation of the solvent, the residue is treated with n-hexane to give 8-methyl-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine as crystals. Recrystallization from ethyl acetate produces pale yellow prisms melting at 174-178 ° C.

Calcd for C 17 H 14 N 4: C 74.43 H 5.14 N 20.43 Found: C 74.30 H 5.15 N 20.14.

Example 32

The procedure of Example 31 is repeated except that 16.2 parts by weight of ethyl orthoacetate is used in place of ethyl orthoformate to give 1,8-dimethyl-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine as crystals. Recrystallization from ethyl acetate gives colorless needles melting at 211-211.5 ° C.

Calcd for C 18 H 16 N 4: C 74.97 H 5.59 N 19.43 Found: C 74.93 H 5.42 N 19.73

Example 33

To a mixture of 2.8 parts by weight of 2-hydrazino-7-methoxy-5-phenyl-3H-1,3-benzodiazepine prepared as in Example F, 7.4 parts by weight of ethyl orthoformate and 100 parts by volume of ethanol, 2 parts by weight of concentrated sulfuric acid are added with stirring. ice cooling. The mixture is stirred at room temperature for approx. 35 minutes to complete the turnover. After evaporation of the solvent under reduced pressure, the residue is neutralized with a saturated aqueous solution of sodium bicarbonate and then extracted with chloroform. The chloroform layer is washed with water and dried over sodium sulfate. Evaporation of the solvent under reduced pressure gives 8-methoxy-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine as crystals. Recrystallization from ethyl acetate produces pale yellow prisms melting at 209-210 ° C.

Calculated for C, 70.33; H, 4.86; N, 19.30

Found: C, 70.23; H, 4.93; N, 19.15.

Example 34

The procedure of Example 33 is repeated except that 8 parts by weight of ethyl orthoacetate is used in place of ethyl orthoformate to give 1-methyl-8-methoxy-6-phenyl-4H-s-triazole- [4,3-a] - [1, 4] -benzodiazepine as crystals. Recrystallization from ethyl acetate gives pale yellow prisms melting at 196-197 ° C.

Calculated for C C ^H- ^NON: ® ® 5.30 N 18.41

Found: C, 71.16; H, 5.44; N, 18.21.

Example 35 2-Hydrazino-7-nitro-5-phenyl-3H-1,4-benzodiazepine, prepared from 5.6 parts by weight of 2-amino-7-nitro-5-phenyl-3H-1,4-benzodiazepine in the same way as in Example G, dissolve in a mixture of 20 parts by volume of ethyl orthoformate and 100 parts by volume of chloroform, after which 10 parts by weight of p-to-luenesulfonic acid are added. The whole mixture is left at room temperature for an hour with occasional shaking. After completion of the reaction, the solution is washed with a saturated aqueous solution of sodium bicarbonate, then with water and dried over sodium sulfate. After evaporation of the solvent, the residue is treated with ethyl acetate to give 8-nitro-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine as crystals. Recrystallization from tetrahydrofuran produces pale yellow needles melting at 271-272 ° C.

Calcd for cigHiiN5 ° 2: c 67> 94 H 3 # 63 N 22.94

Found: C, 63.07; H, 3.75; N, 23.39.

Example 36

The same procedure used in Example 35 is repeated except that 20 parts by volume of ethyl orthoacetate is used in place of ethyl orthoformate to give 1-methyl-8-nitro-6-phenyl-4H-s-triazole- [4,3-a ] - [1,4] -benzo-diazepine as yellow crystals. Recrystallization from acetone gives yellow prisms melting at 227-229 ° C.

Calculated for C, 63.94; H, 4.10; N, 21.93

Found: C, 64.11; H, 4.00; N, 21.69.

Example 37

For a mixture of 1.7 parts by weight of 7-chloro-2-hydrazino-3-isobutyl-5-phenyl-3H-1,4-benzodiazepine prepared as in Example H and K, 3.7 parts by weight of triethyl orthoformate and 40 parts by volume of ethanol Add 1 part by weight of concentrated sulfuric acid with stirring and ice-cooling. The mixture is stirred for approx. 20 minutes at room temperature. After completion of the reaction, the mixture is neutralized with sodium bicarbonate and then extracted with chloroform. The chloroform layer is washed with water and dried over sodium sulfate. After evaporation of the solvent, the residue is treated with n-hexane to give t45S77 8-chloro-4-isobutyl-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzoic acid. diazepine as pale yellow crystals. Recrystallization from a mixture of benzene and n-hexane yields colorless needles melting at 140.5-141.5 °.

Calcd for C qH ^- CIN₂: C 68.47 H 5.46 N 15.97 Pound: C 68.56 H 5.30 N 16.11.

Example 38 a) Starting material

To a suspension of 14.3 parts by weight of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine-4N-oxide in 400 parts by volume of methanol is added 12.5 parts by volume of 100% s of hydrazine hydrate and 20 parts by volume of methanol saturated with hydrogen chloride. The mixture is heated at reflux for 10 minutes and the resulting solution is concentrated to half its original volume. The concentrate is poured into 500 parts by volume of water and the resulting oily substance is extracted with chloroform. The chloroform layer is dried over sodium sulfate and evaporated. Treatment of the residue with diethyl ether gives 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine 4N-oxide as pale yellow powder crystals melting at 262-263 ° C.

Calcd for c15 H13 ClN4O; C 59.90 H 4.36 N 18.63 Found: C 60.05 H 4.13 N 18.41.

b) The method according to the invention

To a solution of 3 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine-4N-oxide in 60 parts by volume of chloroform is added 7.4 parts by weight of ethyl orthoformate and then 1.1 drops by volume of concentrated sulfuric acid are added dropwise. . The whole mixture is stirred for approx. 20 minutes, then neutralize with aqueous sodium bicarbonate. The chloroform layer is washed and dried over sodium sulfate. Evaporation of the solvent gives 8-chloro-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine-5N-oxide as crystals. Recrystallization from a mixture of equal volumes methanol and chloroform gives colorless needles melting at 267-268 ° C (decomposition).

Calculated for C C ^H ^ClN₂O: C 61.74 H 3.57 N 18.03 Found: C 61.87 H 3.26 N 17.92.

Example 39 31 145577

To a mixture of 3 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine-4N-oxide and 20 parts by volume of formamide is added dropwise 1.1 parts by volume of concentrated sulfuric acid and the whole mixture is stirred for approx. 4 hours. After completion of the reaction, the mixture is neutralized with a saturated aqueous solution of sodium bicarbonate. The resulting crystals of 8-chloro-6-phenyl-4H-s-triazole [4,3-a] - [1,4] -benzodiazepine-5N-oxide are separated by filtration and recrystallization from chloroform to give colorless needles melting at 267-269 ° C (decomposition).

The product thus produced is identical to the product prepared in Example 38.

Example 40

A solution of 3 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine-4N-oxide in 20 parts by volume 99% of formic acid is left at room temperature overnight and the solvent is distilled off. Neutralization with saturated aqueous sodium bicarbonate gives 8-chloro-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine-5N-oxide as crystals. Recrystallization from chloroform gives colorless crystals melting at 268-269 ° C (decomposition).

The product thus produced is identical to the product prepared in Examples 38 and 39.

Example 41

To a suspension of 3 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine-4N-oxide, prepared as in Example 38, and 8 parts by weight of ethyl orthoacetate in 100 parts by volume of ethanol are added dropwise by 1.1 parts by volume. concentrated sulfuric acid.

The whole mixture is stirred for approx. 15 minutes at room temperature, after which the solvent is evaporated. The residue is neutralized with saturated aqueous sodium bicarbonate to give 8-chloro-1-methyl-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine-5N-oxide as crystals. Recrystallization from a mixture of methanol and diethyl ether gives colorless needles melting at 272-273 ° C (decomposition).

Calculated for C CH ^Cl CS₂O: C 62.87 H 4.03 N 17.25 Found: C 63.04 H 4.04 N 17.26.

Example 42

To a solution of 3 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine-4N-oxide in 100 parts by volume of ethanol is added 2.5 parts by weight of ethyl acetoimidate hydrochloride. The mixture is heated at reflux for approx. 30 minutes, after which the solvent is evaporated. The residue is neutralized with a saturated aqueous solution of sodium bicarbonate to give 8-chloro-1-methyl-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiaze-pin-5N oxide as crystals. Recrystallization from a mixture of methanol and diethyl ether gives colorless needles melting at 268-269 ° C (decomposition).

The product thus produced is identical to the product prepared in Example 41.

Example 43

A mixture of 3 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine-4N-oxide, 4 parts by weight of acetamidine hydrochloride and 5 parts by weight of 2-methylimidazole is melted under heating at 175 ° C for 10 minutes. . After cooling, water is added to the mixture and then extracted with chloroform.

The chloroform layer is washed with water and dried over sodium sulfate.

After evaporation of the solvent followed by addition of methanol to the residue, 8-chloro-1-methyl-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine-5N-oxide is obtained. crystals. Recrystallization from methanol gives colorless needles melting at 268-270 ° C (decomposition).

The product thus produced is identical to the product prepared in Examples 41 and 42.

Example 44 33 145577 a) Starting material

To a mixture of 1.5 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine-4N-oxide, 50 parts by volume of tetrahydrofuran and 1 part by volume of triethylamine is added with 0.5 parts by volume of acetic anhydride. The whole mixture is stirred for approx. for one hour, then water is added and 2- (2-acetylhydrazino) -7-chloro-5-phenyl-3H-1,4-benzodiazepine-4N-oxide is obtained as crystals. Recrystallization from a mixture of dimethylformamide and water gives fine needles that melt at 256-258 ° C (decomposition).

Calcd. For C 17 H 15 Cl 1 N 4 O 2: C 59.56 H 4.41 N 16.35 Found: C 59.38 H 4.55 N 16.30.

b) Method according to the invention

A mixture of 3.4 parts by weight of 2- (2-acetylhydrazino) -7-chloro-5-phenyl-3H-1,4-benzodiazepine-4N-oxide and 30 parts by volume of pyridine is heated at reflux for 4 hours, after which the pyridine is evaporated under reduced pressure. pressure. The residue is recrystallized from methanol to give 8-chloro-1-methyl-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine-5N-oxide as needles melting at 272-274 ° C (decomposition).

The product thus produced is identical to the product prepared in Examples 41-43.

Example 45

To a suspension of 3 parts by weight of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine-4N-oxide prepared as in Examples 38 and 8.8 parts by weight of ethyl orthopropionate in 100 parts by volume of ethanol is added dropwise by 1.1 parts by volume. concentrated sulfuric acid. The whole mixture is stirred for 20 minutes, then the solvent is evaporated. The residue is neutralized with a saturated aqueous solution of sodium bicarbonate, thereby crystallizing 8-chloro-1-ethyl-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] benzodiazepine-5N-oxide. Recrystallization from methanol gives colorless flakes melting at 273-274 ° C (decomposition).

145577 34

Calculated for C C ^H ^ CC CNNO: C 63.81 H 4.46 N 16.54 Found: C 63.60 H 4.20 N 16.34.

Example 46 a) Starting material

To a mixture of 3 parts by weight of 2-amino-7-nitro-5-phenyl-3H-1,4-benzodiazepine-4N-oxide and 100 parts by volume of ethanol is added 2.5 parts by volume of 100% hydrazine hydrate and 1.8 parts by volume of acetic acid. The whole mixture is gently heated on a water bath for some time to dissolve the mixture, then stirred at room temperature for approx. 20 minutes. The precipitated crystals are collected and washed with ethanol and then dried with diethyl ether to give 2-hydrazino-7-nitro-5-phenyl-3H-1,4-benzodiazepine-4N-oxide as yellow needles melting at 176 ° C (sintering), 226 ° C (decomposition).

Calcd. For ΐ5Ηΐ3Ν5 ° 3: C 57.87 H 4.21 N 22.50 Found: C 57.98 H 4.01 N 22.26.

b) Method according to the invention

To a suspension of 1.55 parts by weight of 2-hydrazino-7-nitro-5-phenyl-3H-1,4-benzodiazepine-4N-oxide in 100 parts by volume of ethanol is added 3.7 parts by weight of ethyl orthoformate and then 0.6 parts by volume of concentrated sulfuric acid. whereby the solid dissolves and yellow crystals precipitate. After stirring for 30 minutes, the mixture is neutralized with a saturated aqueous solution of sodium bicarbonate. The crystals are collected and washed with water, ethanol and then with diethyl ether to give 8-nitro-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine-5N-oxide as yellow crystals. Recrystallization from an aqueous dimethylformamide solution gives yellow crystals melting at 274-275 ° C (decomposition).

Calculated for c 59.81 H 3.45 N 21.80

Found: C, 59.58; H, 3.48; N, 21.56.

Example 47

A mixture of 3.1 parts by weight of 8-chloro-6-phenyl-4H-s-triazole [4,3-a] - [1,4] -benzodiazepine-5N-oxide, prepared as in Example 38 , 39 or 40, 200 parts by volume of chloroform, and 5.3 parts by volume of phosphorus trichloride are heated at reflux for one hour. After evaporation of the solvent, saturated aqueous sodium bicarbonate is added to the residue and then extracted with chloroform. The chloroform layer is washed with water and dried over sodium sulfate.

Evaporation of the solvent gives 8-chloro-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine as crystals. Recrystallization from ethyl acetate gives colorless flakes melting at 223.5-224.5 ° C.

The product thus produced is identical to the product prepared in Examples 1-6.

Example 48

To 200 parts by volume of methanol are added 3.1 parts by weight of 8-chloro-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine-5N-oxide and 1 part by volume of Raney nickel. The mixture is subjected to catalytic hydrogenation. After absorption of 1 mole equivalent hydrogen, the catalyst is removed by filtration and the filtrate is concentrated to dryness. Recrystallization of the residue from ethyl acetate gives 8-chloro-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine as colorless flakes melting at 222-223 ° C.

The product thus produced is identical to the product prepared in Example 47.

Example 49

A mixture of 3.4 parts by weight of 8-chloro-1-ethyl-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine-5N-oxide prepared as in Example 45 , 200 parts by volume of chloroform and 5.3 parts by volume of phosphorus trichloride are heated at reflux for 1 1/2 hours, after which the solvent is evaporated. The residue is neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The chloroform layer is washed with water and dried over sodium sulfate. After evaporation of the solvent, the residue is treated with a mixture of acetone and petroleum ether to give 8-chloro-1-ethyl-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] benzodiazepine as crystals. Recrystallization from acetone gives colorless granules melting at 229-230 ° C.

The product thus produced is identical to the product prepared in Examples 15-16.

Example 50

To a suspension of 3.2 parts by weight of 8-nitro-6-phenyl-4H-s-triazole [4,3-a] - [1,4] -benzodiazepine-5N-oxide in 600 parts by volume of chloroform is added 20 parts by volume of phosphorus trichloride. The mixture is heated at reflux for 16 hours, after which the solvent is evaporated. The residue is neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The chloroform layer is washed with water and dried over sodium sulfate. After evaporation of the solvent, the residue is treated with ethanol to give 8-nitro-6-phenyl-4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine as crystals. Recrystallization from tetrahydrofuran gives pale yellow needles melting at 266-267 ° C.

The product thus produced is identical to the product prepared according to Example 35.

Example 51 a) Starting material

A suspension of 1.60 parts of 2-amino-7-chloro-5- (2-chloro-phenyl) -3H-1,4-benzodiazepine-4N-oxide in a mixture of 40 parts by volume of methanol, 0.6 parts by volume of acetic acid and 0.75 volume of hydrazine hydrate (100%) is heated on a boiling water bath to form a clear solution (about 5 minutes). After cooling, the resulting mixture is diluted with water and extracted with chloroform. The chloroform layer is washed with water, dried over sodium sulfate and evaporated. The residue is dissolved in ethyl ether and a small amount of insoluble material is filtered off. The filtrate is concentrated to give 7-chloro-5- (2-chlorophenyl) -2-hydrazine-3H-1,4-benzodiazepine-4N-oxide as crystals. Recrystallization from ethyl acetate gives pale yellow fine crystals with m.p. 285-286 ° C (dec.).

___— 1 145577 37

Calculated for C 15 H 12 Cl 2 N 4 O: C, 53.75; H, 3.61; N, 16.72. Found: C, 53.60; H, 3.67, N, 16.39.

b) Method according to the invention

To a stirred suspension of 0.355 parts of 7-chloro-5- (2-chlorophenyl) -2-hydrazine-3H-1,4-benzodiazepine-4N-oxide in a mixture of 0.6 parts of triethyl orthoformate and 6 parts of ethanol is added. which drops 0.11 volume of concentrated sulfuric acid. The whole mixture is stirred at room temperature for 30 minutes and concentrated under reduced pressure. To the resulting concentrate aqueous sodium bicarbonate solution is added and the precipitate is collected by filtration to give 8-chloro-6- (2-chlorophenyl) -4H-s-triazole- [4,3-a] - [1,4] -benzodiazepine-5N-oxide as crystals. Recrystallization from a mixture of chloroform and methanol gives colorless plates with m.p. 271-272 ° C (dec.).

Calc'd for C₂_Hio °₂N₂N44: C 55'67 H 2 / · 92 N 16.23 Found: C 55.80 H 2.83 N 16.04%.

Example 52 a) Starting material

To a stirring mixture of 0.304 parts of 2-amino-7-chloro-5- (2-chlorophenyl) -3H-1,4-benzodiazepine, 7 parts of methanol and 0.12 parts of acetic acid, is added dropwise and with stirring 0, 15 parts hydrazine hydrate.

After stirring at room temperature for one hour, the resulting mixture is poured into 20 volumes of water and extracted with chloroform. The chloroform layer is washed with water, dried over sodium sulfate and evaporated. The resulting residue is crystallized from a mixture of chloroform and n-hexane to give 7-chloro-5- (2-chlorophenyl) -2-hydrazine-3H-1,4-benzodiazepine as pale yellow crystals, m.p. 220-223 ° C (dec.).

b) Method according to the invention

To a stirred mixture of 1.6 parts of 7-chloro-5- (2-chlorophenyl) -2-hydrazine-3H-1,4-benzodiazepine, 32 parts by volume of methanol and 0.4 part of ethyl orthoacetate is added dropwise 0 , 25 parts concentrated sulfuric acid, and the whole mixture is stirred for an additional hour at room temperature.

After evaporation of the solvent under reduced pressure, the resulting residue is neutralized with an aqueous solution of sodium bicarbonate. The resulting precipitate is collected by filtration and washed with water and ether to give 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-s-triazole- [4,3-a] - [1,4 ] -benzodiazepine as crystals. Recrystallization from ethyl acetate gives colorless prisms with m.p. 223-224 ° C.

Calcd for C 17 H 12 Cl 2 N 4; c 59.48 H 3.52 N 16.32 Found: C 59.68 H 3.25 N 16.58.

Example 53

To a stirring mixture of 0.335 part 7- chloro-5- (2-chlorophenyl) -2-hydrazino-3H-1,4-benzodiazepine-4N-oxide, 0.65 part triethyl orthoacetate and 6 parts ethanol is added dropwise 0 , 11 parts by volume of concentrated sulfuric acid. Then, the mixture is stirred at room temperature for 30 minutes and poured into a saturated aqueous sodium bicarbonate solution.

The resulting precipitate is collected by filtration to give 8- chloro-6- (2-chlorophenyl) -1-methyl-4H-s-triazolo [4,3-a] - [1,4] benzodiazepine-5N-oxide as crystals. Recrystallization from dimethylformamide / methanol gives colorless needles with m.p. 279-280 ° C (dec.).

Calcd. For C 17 H 12 Cl 2 N 4 O: C 56.84 H 3.37 N 15.60 Found: C 56.84 H 3.15 N 15.57%.

Claims (1)

Analogous Process for the Preparation of S-Triazolo [4,3-a] - [1,4] Benzodiazepines of the General Formula R * r3 "0 ^ / ~ r2 /" S E4 - B | wherein R 1 is a hydrogen atom, an alkyl group of 1-6 carbon atoms 2 or a phenyl or benzyl group, R a hydrogen atom or a alkyl group of 1-6 carbon atoms and R and R independently of each other are hydrogen or halogen atoms, nitro groups, trifluoromethyl groups. alkyl groups having 1-3 carbon atoms or alkoxy groups having 1-2 carbon atoms, or 5N oxides or acid addition salts thereof, characterized by a) reacting a 2-hydrazino-1,4-benzodiazepine derivative of the general formula .NHNH2 r3__ TW yk Wherein R, R and R have the meanings given above, or a 4N-oxide thereof having a carboxylic acid of the general formula R 1 -COOH wherein R 3 is as defined above, or a ester, acid anhydride, acid halide or acid amide thereof, or an ortho ester