FI63405C - FREQUENCY REFERENCE FOR THERAPEUTIC USE OF THERAPEUTIC IMMEDIATE (1,5-A) (1,4) DIAZEPINE-FOUNDATION - Google Patents

Description

Γ-- - lUStT'l [Β] (11) KULLUTUSJULICAISU s τ * nc »tc J e» W6 m4Ui> 5¾¾¾ (45) Γα ten t ineddolat (51) Kv.ik.Vci.3 C 07 D 487/04 , 495/14 FINLAND — FINLAND (21) p · * · "** 11» * · '"» »- p« «* ewekmni 760589 (22) HakamlipUvl - An> Bknlng * di | 08.0 3 · 76 (23) Startup · - GIM (h «t * d« | 08.03-76 (41) Tullut JulklMksI - Bllvlt offwttHf 08.02.77

Patent and Register Office * (44) Date of issue of the register

Patent · OCn regifterityrelten Af »6k« n utligd och iftl.skrlft «n publkwrud 28.02.83 (32) (33) (31) Pyr ^ Atty atuolkau * - Bajird priority 07. 08. 75 0 ^ .03.76 USA (US) 602691, 66366Ο (71) F. Hoffmann-La Roche & Co. Aktiengesellschaft, Basel, Switzerland-Switzerland (CH) (72) Armin Walser, West Caldwell, NJ, Rodney Ian Fryer, North Caldwell, NJ, USA (US) (7 ^) 0y Kolster Ah (5U) Method for therapeutically useful imidazo / l , 5-a / / l, U / for the preparation of diazepine compounds - Förfarande för framställning av therapeutiskt användbara imidazo / ϊ, 5-aJ7 /1,1,7diazepin-föreningar

The invention relates to a process for the preparation of therapeutically useful imidazo-1,5,547 / * 1,47diazepine compounds of the formula & 1 \ Nv, CON * ^ 'R12 Θ &' - j ° qt v-Qf or a) b) is hydrogen, lower alkyl, phenyl, mono-lower alkylamino-lower acyl, di-lower-alkylamino-lower alkyl, pyridyl or benzyl, denotes 2 63405 hydrogen or lower alkyl and denotes hydrogen, lower alkyl, phenyl , amino, mono-lower alkylamino, di-lower alkylamino, amino-C 1 -C 4 alkyl, mono-lower alkylamino-C 1 -C 4 alkyl, or di-lower alkylamino-C 1 -C 4 alkyl alkyl, or R 4 and together form pyrrolidinone, is hydrogen or halogen, X is chlorine, bromine or iodine, and R 1 is halogen or nitro, wherein the lower alkyl groups contain 1 to 7 carbon atoms, pharmaceutically acceptable compounds of these compounds to prepare acid addition salts.

As used herein, the term "lower alkyl" refers to both straight and branched chain C 1 -C 4 hydrocarbon groups, preferably -C 1 -C 4 hydrocarbon groups such as methyl, ethyl, propyl, isopropyl and butyl.

The term "halogen" includes all four halogens, i.e. chlorine, bromine, fluorine and iodine.

Preferred compounds of the invention are those compounds of general formula I wherein hydrogen or lower alkyl, most preferably methyl, R 1, is nitro or halogen, more preferably chlorine, and most preferably is located in the condensed benzene moiety of imidazobenzodiazepine.

at the 8-position, R 1 is halogen, most preferably fluorine, and R 1 is hydrogen and R 1 is hydrogen.

it is amino.

The term "pharmaceutically acceptable salt" includes both inorganic and organic pharmaceutically acceptable salts such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, acetic acid, succinic acid, tartaric acid, tartaric acid, tartaric acid. Such salts can be readily formed by methods known in the art, taking into account the prior art and the nature of the compound to be converted into a salt.

The process according to the invention is characterized in that the compound of formula

R .. COY

q8 <where R1, and Qc have the same meaning as. above, and Y is lower alkoxy or chlorine, is reacted with an amino compound of the formula HNR 1 R 4, wherein and have the same meaning as above, after which the racemic compound of the formula I is optionally partitioned into its optical enantiomers, and / or if desired, the compound is converted into a pharmaceutically acceptable acid addition salt.

The reaction of a compound of formula XV (wherein Y is lower alkoxy) with a compound of formula NHR 12 R 13 (wherein R 1 is hydrogen) is carried out either in an inert solvent or without a solvent. Suitable solvents include hydrocarbons, e.g. hexane, toluene; ethers, e.g. tetrahydrofuran; alcohols, e.g. methanol, ethanol; dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide. This reaction step is preferably carried out at a temperature of about 50 to 200 ° C, most preferably about 100 to 150 ° C, at normal pressure or at elevated pressure.

The reaction of a compound of formula XV (wherein Y is chlorine) with a compound of formula NHR 1 R 2 is preferably carried out in an inert solvent. Suitable solvents include hydrocarbons, e.g. hexane, toluene; ethers, e.g. tetrahydrofuran, chlorinated hydrocarbons, e.g. methylene chloride, chlorobenzene. The reaction is preferably carried out at temperatures between about -20 ° C and the boiling point of the reaction mixture, most preferably at about 0-50 ° C.

The reaction of a compound of formula XV (wherein Y is lower alkoxy) with a compound of formula NHR 1 R 2 wherein R 1 is a group - (CH 2 i 2 NR 1 R 2 (where n is 0) is carried out either in an inert solvent or without Suitable solvents are hydrocarbons, e.g. hexane, toluene, ethers, e.g. tetrahydrofuran, alcohols, such as methanol, ethanol, This reaction is preferably carried out at a temperature in the range of about 50-150 ° C, most preferably about 80-100 ° C.

The general reaction steps shown in the following scheme illustrate the reactions used to prepare the starting compounds of formula XV.

In these reaction formulas, R is lower alkyl, and Z, R, and R are as defined in Formula I. It will be apparent to one skilled in the art that some of the substituents may be subject to change in the reactions below, but such sensitive groups may be modified before or after the reaction. . The reactions shown in the scheme can also be performed using the corresponding N-oxides, but any N-oxide present in the compounds of formula VI is removed in reaction VI -; - y y VII.

4 63405 / NHCH3 h 0 (z jf ii (z ΊΓ viii

^ - 'S C = N' XH '—Apr C = N ^' H

A., A I

1 I3 ^ n — do rvK = VH 0J_A1)

CiXc = 7 / \ in a -¾ \ r6-0 i - QC ix \ 6 AA Ί 'COOR C = NIH \ H A00 * p_ff | l 1 \ / Y "V" * (z JL A IV / n ^ 00 "p ^ C = N Η ΡΊθ0

Si

C = N H H

fjl I ^ COOR

r6 ~ + vc h r ho_co ° R, xi g ^ x *., AI /

AVI A "AT- J

^ v / lM H (z T XII

(z F y \ vn xh A "[4- ^ R1V / wCOOR ^^ v / 00011 A (. AC ·

(z H XIII (z Ij XVIII

C ^> c = r \ ί xh

hö - 'A

5 63405

Phase II - »III

Compounds of formula III are obtained by nitrosation of compounds of formula II. Such nitrosation can be performed with nitric acid formed in situ. Suitable reagents for use include (1) alkali metal nitrites, m.p. sodium nitrites in the presence of an organic or inorganic acid, e.g. glacial acetic acid, and an aqueous or non-aqueous solvent; (2) alkyl nitrites, i.e. methyl nitrites, in the presence of an inert solvent such as an alcohol, a chlorinated hydrocarbon or e.g. dimethylformamide, and (3) a solution of nitrosyl chloride gas in an inert solvent in the presence of an acid scavenger such as pyridine. This nitrosation reaction should be carried out below room temperature, e.g. at a temperature in the range of -20 to + 25 ° C.

Phase VIII -? IX

Compounds of formula IX may be prepared by reacting compounds of formula VIII with dimorpholinophosphinic acid chloride. The reaction of compounds of formula VIII with phosphorylating agents to give compounds of formula IX is carried out by treating compounds of formula VIII with a strong base capable of ionizing the compound of formula VIII to the corresponding anion. Suitable bases include alkali metal alkoxides such as potassium tert-butoxide or sodium methoxide, alkali metal hydrides such as sodium hydride, and alkyllithium compounds such as n-butyllithium. The reaction temperature is in the range of 0 to 100 ° C, and the reaction is preferably carried out in an aprotic polar inert solvent, i. in one capable of dissolving all or at least part of the ambient salts of the compounds of formula VIII. Preferred solvents are ethers, e.g. tetrahydrofuran or dioxane, or tertiary amides, e.g. dimethylformamide.

Phase III or IX-> IV

Compounds of formula III or formula IX may be condensed of formula

0 ^^ COOR CH

^ "COOR

With the anion of malonic acid ester 6 63405, wherein R is lower alkyl to give a compound of formula IV. The anion is prepared by deprotonating the malonic acid ester with a suitable strong base such as an alkali metal or alkaline earth metal alkoxide, hydride or amide. The reaction of a compound of formula III or IX with a malonic acid ester anion is carried out in a solvent such as a hydrocarbon, e.g. benzene, toluene, hexane, ether, e.g. dioxane, THF, diethyl ether, DMF, DMSO, etc., at temperatures below room temperature to 150 ° C. , preferably 0-100 ° C, most preferably at room temperature.

Step IV -> V

Compounds of formula V are prepared by decarboxylation of compounds of formula IV by reacting a compound of formula IV with an alkali metal hydroxide such as NaOH or CO 2 in a suitable solvent such as alcohols, ethers or DMSO at a temperature ranging from room temperature to reflux temperature, preferably 60-100 ° C. :in.

Step V -> VI

Compounds of formula VI are prepared by nitrosation of compounds of formula V in a reaction with nitric acid developed, for example, from an alkali metal nitrite, alkyl nitrite or nitrosyl chloride in a reaction with an organic or inorganic acid. Suitable solvents for the nitrosation reaction include ethers, alcohols, water, acids, e.g. acetic acid, DMF, DMSO and chlorinated hydrocarbons. The reaction can be carried out at about room temperature, although the temperature is by no means critical.

Step VI -> VII

Compounds of formula VII are prepared by reduction of compounds of formula VI, e.g. with Raney nickel and hydrogen or zinc and acetic acid. This reduction yields mainly compounds of formula VII and, in addition, smaller amounts of several different isomers in side reactions, i. formulas for COOR Nil ,, Nil NJi H V \ »\» \

| j) - NH? V — COOR | j — COOR j> (‘OOR

N- (N — M / N --- / / \ / \ / x / \

Vila Vllb VIIe Vlld 7 63405. It should be noted that in the above reduction reaction, the NO 2 group in the 7-position may react. In this case, a compound of formula X can be used, as will be shown.

Step VII -> XII

Compounds of formula XII are prepared by reacting compounds of formula VII with an alkanoic acid orthoester of formula r1c (or) 3, wherein R is lower alkyl and R1 is hydrogen or lower alkyl, optionally with an acid catalyst, e.g. an organic or inorganic acid, e.g. in the presence of p-toluic acid, phosphoric acid, etc., at or above room temperature, i.e. At 25-150 ° C, whereby cyclization to the compound of formula XII occurs immediately. As well as the above orthoester, orthoamides are suitable, e.g. N, N-dimethylformamide dimethyl acetal, N, N, N1, N ', N ", N" -hexamethylmethanetriamine; nitriles, e.g. acetonitrile; ester imidates, e.g. CH 2 -C (C

Step VII - ^ XI

Compounds of formula XI may be prepared by acylation of compounds of formula VII of formula

R. | C0X or (R ^ O ^ O

wherein X is halogen and R 1 is hydrogen, lower alkyl, phenyl, pyridyl or benzyl.

Suitable solvents for the above step include, for example, methylene chloride, ethers, chlorinated hydrocarbons, etc., preferably in the presence of an acid scavenger such as an organic or inorganic base such as triethylamine, pyridine or alkali metal carbonate. The reaction may be carried out at room temperature, below and above it, but most preferably at room temperature. The compounds of formula XI are isomeric in nature, i. they may exist in the following stereochemical forms

C00R

NHCORj H \ H \ 1} NHCOR, I Jh-COOB I _ / 1 / - (/ ^

Xla Xlb 8 ^ 63405

Step XI - »XII

Compounds of formula XII may also be prepared by dehydrating compounds of formula XI or isomers thereof simultaneously by cyclization with heating. This reaction step can be carried out without a solvent or in a solvent, e.g. DMF, ethylene glycol, hexamethylphosphoric triamide, at a temperature in the range of 100-300 ° C, preferably 150-250 ° C, e.g. 200 ° C, using a catalyst and a water-binding solvent. with or without the substance.

Step IX -> X

Compounds of formula X may be prepared by the condensation reaction of a compound of formula IX and formula

fT) ^ "COOR ^ C ^ - NHCOR

^ "COOR

wherein R 1 is lower alkyl and R 1 is hydrogen, lower, alkyl, phenyl, pyridyl or benzyl. The anion is formed by deprotonation of the acyl amino acid ester with a suitable strong base such as an alkali metal or alkaline earth metal alkoxide, hydride or amide. The reaction of compounds of formula IX with an acylaminomalonic acid ester is preferably carried out in a solvent such as a hydrocarbon, e.g. benzene, toluene, hexane, ethers, e.g. dioxane, THF, diethyl ether, DMF, DMSO, etc., at a temperature below 150 ° room temperature. C, preferably at 0-100 ° C, most preferably at room temperature.

Step X -'f XI

Compounds of formula XI and their isomers are prepared by decarboxylation of compounds of formula X with an alkali metal alkoxide in a solvent such as ethers, alcohols, DMSO, PMf, etc., at, below or above room temperature, preferably at room temperature. The compounds of formulas X and XI do not need to be isolated but can be converted in situ to the compounds of formula XII.

Step VII -> XIII

Compounds of formula XIII are prepared by reacting compounds of formula VII with an aldehyde of formula R CHO wherein R 1 is as defined in formula I. Suitable solvents for this reaction step include hydrocarbons such as benzene, alcohols, ethers, chlorinated hydrocarbons, DMF, DMSO, etc., and the reaction is carried out using a water-binding agent, e.g. molecular sieves, at room temperature, below or above, preferably at room temperature, the temperature of the solvent is redistilled.

9 63405

Step XIII -> XII

Compounds of formula XIII can be converted to compounds of formula XII by in situ oxidation with oxidizing agents such as manganese dioxide, air, oxygen, etc.

Another process for the preparation of a compound of formula XII having nitro or cyano comprises preparing compounds of formula VII. This can be prepared by reacting the corresponding compound of formula IX

^ -COOR ® C —NHZ

With a protected aminomalonic acid ester of "CO", wherein R is lower alkyl and Z is benzyloxycarbonyl, by converting the compound of formula X thus obtained, wherein R 1 is benzyloxy and R 1 is nitro, to the corresponding compound of formula X 1 above as described in Step X -9 XI, and treating the compound thus obtained with hydrogen bromide in glacial acetic acid to give a compound of formula VII wherein R 1 is nitro. Intermediates of formula X and XI do not need to be isolated.

The compound of formula VII thus obtained is then further converted to the final product XII via reaction steps VII -> XIII and XIII -> XII described above.

Step XII -) XVIII

Compounds of formula XVIII are prepared by hydrolysing compounds of formula XII to the corresponding acids, preferably with an alkali metal hydroxide, e.g. NaOH or KOH. This hydrolysis is suitably carried out in an inert solvent. Suitable solvents include alcohols, e.g. methanol, ethanol, ethers, e.g. dioxane, tetrahydrofuran; dimethylformamide together with water. This reaction step is preferably carried out at temperatures between room temperature and the boiling point of the reaction mixture.

A compound of formula XVIII can be converted to the corresponding acid chloride, i.e. a compound of formula XV wherein Y is chlorine, by reacting it with, for example, phosphorus pentachloride.

The compounds of formulas I and Id and their pharmaceutically acceptable acid addition salts are useful muscle relaxants, sedatives and anticonvulsants, and many of them are particularly suitable for use as intravenous and intramuscular preparations because their acid addition salts are water soluble.

10 63405

Known compounds (see, for example, FR Patent 1,545,214 and U.S. Patent 3,852,461) have. lower activity than the compounds of the invention. In addition, the compounds prepared according to the invention have either a better activity or a different activity (selective effect) compared to the known compounds. Thus, the compounds of formula 1 are considerably more active than the structurally related known compounds, namely the corresponding 4H-iraidazo [2 H, 2-α] -1,4-7-benzodiazepines (see, e.g., FR Patent 1,545,214 and U.S. Patent 3,852,461). ), and the compounds of formula I have a more selective activity than triazolobenzodiazepines, for example 4H-s-triazolo / 4,3-§7 / i, 4-benzodiazepines (see e.g. FI patent 50 981) - namely the new compounds have very good anxiolytic activity, but relatively little muscle relaxant effect. It should also be mentioned that, for example, the 4H-s-triazolo [4,5-a] 7β, 4β-benzodiazepines known from FI patent 54,310 differ from the new compounds in terms of both activity and structure - they mainly have an anticonvulsant effect, potentiate the anesthetic effect and distribute somatic reflexes and have a substituent at the 2-position, whereas the new compounds cannot have a substituent at the 2-position.

The pharmacological activity of the compounds of the invention was determined by standard screening experiments. The experiments were a wear screen plate test, a foot shock test, and an anesthetized cat test. In addition, experiments were performed with known reference compounds, namely 8-chloro-6-phenyl-4H-imidazo [1,2-a] β, 4-benzodiazepine and 8-chloro-1-methyl-6-phenyl-ftH-s-triazolo [ 4,3- ^ jf / Ί, b] hcv.t sod i .atsepi inilla.

63405 1 1

TABLE

Results of pharmaceutical experiments

Compound Leading Screen Foot Shock; Anesthetized Antimetrat plate 10Q- $ cat solo test PD (mg / kg) inhibitory MED (mg / kg) EDqn (mg / kg) dose (mg / kg) 8-chloro-1-methyl-6-phenyl-UH- imidazo [1,5-a] 7,7'-benzodiaziazine-3-N-methylcarboxamide 25.0.0 2.5 3.8 8-chloro-6- (2-fluorophenyl) -1-methyl-NH- imidazo / Ί, 5 ~ a7 ~

N, N-benzodiazepine-3-carboxylic acid hydrazide 0.5 0.25 0.38 8-Chloro-6- (2-fluorophenyl) -1-methyl-1H-imidazo [1,5-a] N - [N, benzodiazepine] -3-carboxylic acid 2,2-dimethylhydrazide 5 0.5 0.5 0.47 8-chloro-N, N-diethyl-6- (2-fluorophenyl) -1-methyl-4H-imidazo [5,5 α, β, β, 4-benzodiazepine-3-carboxamide 24.5 1.0 2.5 0.422 8-chloro-6- (2-fluorophenyl) -1-N, N-trimethyl-4H-imidazo - [ ~ α7,4,4-benzodiazepine-3-carboxamide 25 1.25 1.0 0.42 8-chloro-1-methyl-6-phenyl-1H-imidazo [1,5] 7,4'-benzodiazepine 3-carboxamide 2.5 5 2.1 8-chloro-6- (2-chlorophenyl) -1- (2-pyridyl) -4H-imidazo [1,5-b] 1,4] benzodiazepine-3-carboxamide 2.0 0.5 (continued) 634 0 5 12

The table continues

Compound Leading Screen Foot Shock; Anesthetized Antimetrat plate 100- $ cat cat test PD n (mg / kg) inhibitory MED (mg / kg) ED n (mg / kg) dose (mg / kg) 8-chloro-6- (2-chlorophenyl) -1 -methyl-N, N-imidazo [1,5-a] -β, N-diazepine-3-carboxamide 3.1 5 0.227 8-chloro-6- (2-chlorophenyl) -1-N, N-trimethyl-HH- imidazo-β, 5-α-thieno [3,2-f] [7,7-diazepine-3-carboxamide] 10 10 0.02 8-Chloro-6- (2-chlorophenyl) -1- (2-dimethylaminoethyl) - tH-imidazo [5, 5β, 1 + 7benzodiazepine-3-carboxamide 200 100 5 5,7 6- (2-chlorophenyl) -1-methyl-5-nitro-1H-imidazo [1,5-a] [ 1,1 + 7-Benzodiazepine-3-carboxamide 165 10 U, 6 8-Chloro-N-cyclopropyl-6- (2-fluorophenyl) -1-methyl-1 + H-imidazo [f] benzodiazepine 3-carboxamide 18 5 L 0.2 8-chloro-6- (2-chlorophenyl) -1-dimethylaminomethyl-UH-imidazo-β, 5-q7, 1,7-benzodiazepine-3-carboxamide 0.35 8-chloro-6 - (2-fluorophenyl) -1-methyl-1H-imidazo [5,5-b] β, 1 + 7 “benzodiazepine-3-carboxamide ^ 1 0.25 0.23 8-chloro-6- (2-chlorophenyl) -1-methyl-imidazo-DOS / fl , 5-α, β, β-benzodiazepine-3-carboxamide ^, δ 0.5 0.116 8-chloro-6- (2-fluorophenyl) -1 + H-imidazo [1, β, benzodiazepine-3-carboxamide> 1300 -, 5 0.1 0.025 8-chloro-6- (2-chlorophenyl) -1-N, N-trimethyl-UH-imidazo [1,5-a] ~ β, 7-benzodiazepine-3-carboxamide 1 ° 0.35 0.17 8-Chloro-6- (2-chlorophenyl) -N, N-dimethyl-1 + H-imidazo [1,5-a] E, 1,1 + 7

benzodiazepine-3-carboxamide> t00 »b 5 0.0U

(continued) 13 63405

The table continues

Compound Leading Screen Foot Shock; Anesthetized Antimetrat plate 100% cat solo test PD ^ q (mg / kg) inhibitory MED (mg / kg) (mg / kg) dose (mg / kg) 8-chloro-6- (2-chlorophenyl) -4H -imidazo [1,5-f] 7,4-benzodiazepine-3-carboxamide> 400 2.05 1 0.52 8-chloro-6- (2-chlorophenyl) -1-N-dimethyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide 39 0.625 0.025 8-chloro-6- (2-chlorophenyl) -N-methyl-4H-imidazo [1,5-a] [1,47] benzodiazepine-3 - carboxamide> 400 25 0.25 8-Chloro-6- (2-chlorophenyl) -1-ethyl-4H-imidazo [1,5-d] 2H, 4-benzodiazepine-3-carboxamide 13 3.125 0.1 8- chloro-6-phenyl-4H-imidazo [1,2-a] [1,14] benzodiazepine 300 20 2.5 17 (US 3,852,461) 8-chloro-1-methyl-6-phenyl-4H-s-triazolo73, 3-α7 / X, 4-J-benzodiazepine 2 - to 0.26 (FI 50 981 The novel compounds of formula I prepared according to the present invention and their acid addition salts can be used in pharmaceutical dosage preparations containing them in an amount of about 0.1 to about 40 mg, preferably 1-40 mg, depending on the individual patient needs. The novel compounds of the formulas I and Id can be administered orally, e.g. parenterally or enterally, in the usual pharmaceutical dosage forms. They may be incorporated, e.g., into ordinary liquid or solid media such as gelatin, starch, magnesium stearate, talc, vegetable oils, etc., and formulated into tablets, elixirs, capsules, solutions, emulsions, etc., in accordance with pharmaceutically acceptable practice.

Example 1 8-Chloro-1-methyl-6-phenyl-4H-imidazo [1,5-b] [1,17] benzodiazepine-3-carboxamide

Methyl 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [N, N] benzodiazepine-3-carboxylate (0.74 g, 2 mmol) was heated in 30 mL of ammonia. -ol solution at 120 ° for 18 hours in a sealed container. The solvent was evaporated off, and the residue was recrystallized from methylene chloride / ethanol to give 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,47] benzodiazepine-3-carboxamide as colorless crystals, m.p. . 335-340 °.

63405 The starting material was prepared as follows:

Potassium tert-butoxide (26 g, 0.232 mol) was added to a mixture of 300 ml of dimethylformamide and 50 ml (0.1 mol) of dimethyl malonate. After stirring under nitrogen, a solution of 66 ml was added over 10 minutes. g (0.209 mol) of 7-chloro-2- (N-nitrosomethylamino) -5-phenyl-3H-1,1-benzodiazepine-U-oxide in 100 ml of dimethylformamide The mixture was then slowly heated in a water bath and kept at 65 ° for 10 minutes: After cooling to room temperature, ^0 ml of glacial acetic acid were added, followed by 1 liter of water over 30 minutes with occasional scraping, and the precipitated crystals were collected, washed with water and dissolved in methylene chloride. 7-Chloro-1,3-dihydro-2- (dimethoxymanonylidene) -5-phenyl-β-1,1-benzodiazepine-U-oxide, mp 188-190 ° The analytical sample was recrystallized from of a ethylene chloride / hexane mixture, m.p. 19U-1950.

A) A mixture of U0.8 g (0.1 mol) of 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -5'-phenyl-2H-1H-benzodiazepine-4-oxide, 250 ml of methanol, 250 ml of tetrahydrofuran and 1 tablespoon of Raney nickel were hydrogenated at atmospheric pressure for 5 hours. The catalyst was removed by filtration and the filtrate was evaporated to dryness. Crystallization of the residue from methylene chloride / 2-propanol gave 7-chloro-1,3-dihydro-2- (dimethoxymorylidene} -5-phenyl-2H-1,1-benzodiazepine as colorless crystals, mp 160-163 ° It was recrystallized for analysis from 2-propanol, mp 165-166 °.

In some cases, a second crystal transformer was obtained, the crystals of which melted at 138 ° I + 0 °.

B) Phosphorus trichloride (U ml) was added to a solution of U g (0.01 mol) of 7-chloro-1,3-dihydro-2- (2-dimethoxymalonylidene.l) -5-enyl-2H-1 , U-benzodiazepine-α-oxide in 100 ml of methylene chloride. Seisctukser. after room temperature overnight, the solution was washed with 10 drops of aqueous sodium carbonate solution. The methylene chloride layer was dried and evaporated to dryness. Crystallization of the residue from 2-propanol and recrystallization from methylene chloride / 2-propanol gave 7-chloro-1,3-dihydro-2- (dimethoxymalylene) -5-phenyl-2I. - 1, lt-benzodiazepine, m.p. 165-166 °.

A mixture of 115 g (0.3 mol) of 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -5-phenyl-2H-1,1,4-benzodiazepine, 1.5 l of methanol and IA, l | g (0.36 moles) of sodium hydroxide, was heated to reflux for 5 hours under a nitrogen blanket. The cooled reaction mixture was gradually diluted with 2.5 liters of water under ice-cooling. The precipitated crystals were collected, washed with water and dried in vacuo at 60 ° to give 7-chloro-1,3-dihydro-2- (methoxycarbonylmethylene) -5-phenyl-2H-1,1-benzodiazepine as an off-white product, mp. 167-170 °. An analytical sample was recrystallized from ether, m.p. 171-173 °.

Sodium nitrite (2.8 g, 0.04 mol) was added to a solution of 8 g (0.025 mol) of 7-chloro-1,3-dihydro-2- (methoxycarbonylmethylene) -5-phenyl-2H-1,1 * -benzodiazepine in 100 ml of glacial acetic acid. The mixture was stirred under nitrogen for 10 minutes. The product started to crystallize after a few minutes. After diluting the mixture with 100 ml of water, the precipitated product was collected, washed with water, dried and recrystallized from tetrahydrofuran / methanol to give 7-chloro-alpha-hydroxyimino-5-phenyl-3H-1H-benzodiazepine. -2-acetic acid methyl ester as yellow crystals, m.p. 235-237 ° (dec.).

7-Chloro-alpha-hydroxyimino-5-phenyl-3H-1,4-benzodiazepine-2-acetic acid methyl ester (3.6 g, 0.01 mol) was dissolved with heating in a mixture of 200 ml of tetrahydrofuran and 100 ml of methanol. Raney nickel (1 teaspoon) was added and the mixture was hydrogenated at atmospheric pressure until hydrogen binding ceased (1 hour and 10 minutes). The catalyst was removed by filtration and the filtrate was evaporated to dryness, finally azeotropically with toluene. The residue was dissolved in 20 ml of methanol. 3 ml of triethyl orthoacetate and 0.3 ml of ethanolic hydrochloric acid solution (5%) were added, and the solution was refluxed for 5 minutes. The residue obtained after evaporation to dryness was partitioned between methylene chloride and saturated aqueous sodium hydrogen carbonate solution. The organic phase was separated, dried and evaporated to dryness. Recrystallization of the residue from ether gave methyl 8-chloro-1-methyl-6-phenyl-14H-imidazo [1,5-b] benzodiazepine-S-carboxylate, m.p. recrystallized from methylene chloride / ether / hexane. ^ -256 °.

Example 2 8-Chloro-1-methyl-6-phenyl-1H-imidazo [1,5-b] [1,1 '] benzodiazepine-3-N-methylcarboxamide

A mixture of 0.73 g (2 mmol) of methyl 8-chloro-1-methyl-6-enyl-1H-imidazole, 5-α / Z1,7-benzodiazepine-3-carboxylate and 20 ml of ethanol, containing 25 L of methylamine was heated at 120 ° for 18 hours in a sealed vessel. The solvent was evaporated and the residue was crystallized from methylene chloride / ethanol to give 8-chloro-1-methyl-6-phenyl-1 + H-imidazo [1,5-b] 1,1'-benzodiazepine-3-N-methyl -carboxyamidia, m.p. 260-263 °. The analytical sample was recrystallized from tetrahydrofuran / ethanol.

16 63405

Example 3 8-Chloro-6- (2-fluorophenyl) -1-methyl-1H-imidazo [1,5-a] Z3, U7-benzodiazepine-3-carboxylic acid hydrazide

A mixture of 7.7 g of methyl-8-chloro-6- (2-fluorophenyl) -1-methyl-1H-imidazo [1,5-a] 2,7-benzodiazepine-3-carboxylate, 100 ml of isobutanol and 20 ml of isobutanol ml of hydrazine, was refluxed for one hour. The crude product obtained after evaporation to dryness was chromatographed on 250 g of silica gel using 5% ethanol in methylene chloride. The pure fractions were combined and evaporated to dryness. Crystallization of the residue from methylene chloride / ether gave 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazol-1,5% 7β, β-benzodiazepine-3-carboxylic acid hydrazide as colorless crystals, m.p. 235-237 ° · The starting material was prepared as follows:

A solution of 200 g (0.695 moles) of 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2H-1,1'-benzodiazepin-2-one in 2 l of tetrahydrofuran and 250 ml of Bent -enene, was saturated with methylamine in an ice bath under cooling. A solution of 190 g (1 mole) of titanium tetrachloride in 250 ml of benzene was added dropwise through a funnel over 15 minutes. After the addition, the mixture was stirred and refluxed for 3 hours. Water (600 ml) was slowly added to the cooled reaction mixture. The inorganic material was separated by filtration and washed well with tetrahydrofuran11a. The aqueous layer was separated and the organic phase was dried over sodium sulfate and evaporated to dryness. 7-Chloro-5- (2-fluorophenyl) -2-methylamino-3H-1,1-benzodiazepine obtained as a crystalline residue was collected, m.p. 20U-206 ° C. An analytical sample was recrystallized from methylene chloride-ethanol, m.p. 204-206 ° C · A) 8.63 g (0.125 moles) of sodium nitrite were added in three portions over 15 minutes to a solution of 30.15 g (0.1 moles) of β-chloro-5- (2-fluorophenyl). ) -2-methylamino-3H-1,1-benzodiazepine in .50 ml of glacial acetic acid.

After stirring for 1 hour at room temperature, the reaction mixture was diluted with water and extracted with methylene chloride. The extracts were washed with saturated sodium hydrogen carbonate solution, dried over sodium sulphate and evaporated to dryness, finally azeotropically with toluene to give 29 g of crude 7-chloro-5- (2-fluorophenyl) -2- (N-it rosomethylamino) - 3H-1,1-Benzod azepine as a yellow oil.

B) Sodium nitrite (27.6 g, 0.1 U moles) was added portionwise over 30 minutes to a solution of 90.1 → 5 g (0.3 moles) of 7-chloro-N- (2-fluorophenyl) -2-methylamino -3H-1, U-benzodiazepine in Uoo m] glacial acetic acid. After the addition of 63405 was complete, the mixture was stirred at room temperature for one hour, diluted with one liter of water and extracted with methylene chloride. The extracts were washed twice with water and then with 10% aqueous sodium carbonate solution. The solution was dried and evaporated to dryness to give crude 7-chloro-5- (2-fluorophenyl) -2- (N-nitrosomethylamino) -3H-1,1-benzodiazepine as a yellow oil.

This material was dissolved in 300 ml of dimethylformamide and added to a mixture of 150 ml of dimethylmalonate, 10.0 g of potassium tert-butoxide and 500 ml of dimethylformamide stirred at room temperature for 10 minutes. The reaction mixture was stirred overnight under nitrogen at room temperature, acidified by the addition of 50 ml of glacial acetic acid, diluted with water and aqueous sodium carbonate solution, dried over sodium sulphate and evaporated to dryness. Crystallization of the residue from ethanol gave 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -5- (2-fluorophenyl) -2H-1,1-benzodiazepine as colorless crystals, m.p. 170-172 °. For analysis, the product was recrystallized from methylene chloride / ethanol; the melting point did not change.

A mixture of 20 g (0.05 mol) of 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -5- (2-fluorophenyl) -2H-1,1-benzodiazepine, 100 ml of methanol and 3 x 3 g (0.059 moles) of potassium hydroxide was heated to reflux under nitrogen for 5 hours. After part of the solvent was evaporated, the residue was gradually diluted with water, and the precipitated crystals were collected, washed with water and dried to leave 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2- (dimethoxycarbonylmethylene). -2H-1, U-benzodiazepine, m.p. I58-16O0.

For analysis, recrystallization from methylene chloride / hexane was performed, m.p. 161-1620.

Sodium nitrite (8.8 g, 0.125 mol) was added to a solution of 28 g (0.08 mol) of 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2- (methoxycarbonylmethylene) -2H -1, Η-benzodiazepine in 250 ml of glacial acetic acid. The mixture was stirred at room temperature for 10 minutes and then diluted with 250 ml of water. The crystalline product was filtered, washed with water, methanol and ether and dried to leave 7-chloro-5- (2-fluorophenyl) -alpha-hydroxyimino-3H-1,1 + benzodiazepine-2-acetic acid methyl ester as yellow crystals, m.p. 238-2 ^ 1 ° (dec.).

7-Chloro-5- (2-fluoro-phenyl) -alpha-hydroxyimino-3H-1,1'-benzodiazepine-2-acetic acid methyl ester (11.5 g, 0.03 mol) was hydrogenated at atmospheric pressure over Raney nickel. using in a mixture of 750 ml of tetrahydrofuran and 500 ml of methanol. The nickel was filtered off and the filtrate was evaporated to dryness.

1340405 The residue was dissolved in 100 ml of methanol, and to the solution were added 11 ml of triethyl orthoacetate and 5 ml of ethanolic hydrochloric acid solution (5%). The mixture was heated to reflux for 10 minutes, evaporated to dryness and the residue partitioned between methylene chloride and aqueous sodium hydrogen carbonate solution. The methylene chloride solution was dried and evaporated to dryness and the residue was chromatographed on 300 g of silica gel eluting with methylene chloride / ethyl acetate 1: 3 (v / v). The pure fractions were combined, evaporated to dryness and crystallized from ether to give methyl 8-chloro-6- (R-fluorophenyl) -1-methyl-1H-imidazo [1,5-a] benzodiazepine-3-carboxylate, mp. 162-16U °. The analytical sample was recrystallized from ethyl acetate / hexane.

Example N, N-β-chloro-6- (2-fluorophenyl) -1-methyl-1H-imidazo [1,5-a] benzodiazepin-3-yl] pyrrolidine

Pyrrolidine (t ml) was added to a solution of 1.85 g of 8-chloro-6- (2-fluorophenyl) -1-methyl-1H-imidazo [1,5-d] benzodiazepine-3-carboxylate. oxylic acid and 1.25 g of phosphorus pentachloride in 250 ml of methylene chloride. Then, 100 ml of 10-5 aqueous aqueous sodium carbonate solution was added, and the biphasic mixture was stirred at room temperature for one hour. The organic phase was separated, dried and evaporated to dryness. Crystallization of the residue from 2-propanol / ether gave 1- [S-chloro-6- (2-fluorophenyl) -1-methyl-UH-iridazo [1,5-a] zfi, (ι / Bent sodi at sepin-3- yl7 pyrrolidine as a colorless product, mp 220-221 ° C after recrystallization from ethyl acetate / hexane.

The starting material was prepared as follows:

A mixture of 7.7 g (0.02 moles) of methyl Q-chloro-6- (2-fluorophenyl) -1-methyl-1H-imidazo [1,5-a] [1,7] benzodiazene in 3 carboxylate, 2.2 g (0 → 0 mol) of potassium hydroxide, 0 ml of methanol and nl of water, was heated under reflux for 3 1/2 hours. The solvent was partially evaporated off and the residue was acidified with glacial acetic acid and diluted with hot water. Cooled with ice / water and the precipitated crystals were collected and dried to give 8-chloro-6- (2-fluorophenyl) -1-methyl-UH-imidazo [η 5,5] -isodiazepine-3-carboxylic acid. . For analysis, a portion was recrystallized from methylene chloride / methanol / ethyl acetate, m.p. 271-270 ° (dec.).

Example 5 8-Chloro-6- (2-fluorophenyl) -1-methyl-1H-imidazo [1,5-a] H, U-benzodiazepine-3-carboxylic acid 2,2-dimethylhydrazide 2,2-dimethylhydrazine (10 ml) was added to a solution of 1.85 g of 8-chloro-6- (2-fluorophenyl) -1-methyl-UH-imidazo / 1.5% 7 ~ 19 63405 [λ, U. Benzodiazepine-3-carboxylic acid and 1.25 g of phosphorus pentachloride in 250 ml of methylene chloride. After adding 100 ml of 10% aqueous sodium carbonate solution, the mixture was stirred for 30 minutes at room temperature. The organic layer was separated, dried and evaporated to dryness. Crystallization of the residue from ether / ethanol gave 8-chloro-6- (2-fluorophenyl) -1-methyl-1 H -imidazo [f, 5-a] β, N7-benzodiazepine-3-carboxylic acid 2,2-dimethylhydrazide as colorless matter. product. The analytical sample was purified by chromatography on 30 times silica gel using a 10% (v / v) mixture of methylene chloride in ethanol. The product was crystallized from methylene chloride / ethyl acetate / hexane, m.p. 238-210 °.

Example 6 8-Chloro-N, N-diethyl-6- (2-fluorophenyl) -1-methyl-1H-imidazo [1,5-a] [[2,6] benzodiazepine-3-carboxamide

Phosphorus pentachloride (1.25 g → 0.006 moles) was added to a suspension of 1.85 g (0.005 moles) of 8-chloro-6- (2-fluorophenyl) -1-methyl-1 * H-imidazoZT1.5-7 , Β-benzodiazepine-3-carboxylic acid in 250 ml of methylene chloride. After the mixture was stirred for 30 minutes in an ice bath, 15 ml of diethylamine was added, followed by 100 ml of 10% aqueous sodium hydrogencarbonate solution. The biphasic system was stirred for 30 minutes at room temperature. The organic layer was separated, dried over sodium sulfate and evaporated to dryness. Crystallization of the residue from methylene chloride / ether gave 8-chloro-N, N-diethyl-6- (2-fluorophenyl) -1-methyl-1H-imidazole, 5-α, 10,7-benzodiazepine-3-carboxamide, mp. 182-188 °.

An analytical sample was recrystallized from ethyl acetate / hexane, m.p. 183-185 °.

Example 7 8-Chloro-N- (2-dimethylaminoethyl) -6- (2-fluorophenyl) -1-methyl-1H-imidazo [1,5-a] E, l] benzodiazepine-3-carboxamide 2- (dimethylamino) Ethylamine (5 mL) was added to a solution of 1.85 g (5 mmol) of 8-chloro-6- (2-fluorophenyl) -1-methyl-1H-imidazo [1,5-a] Z, as described in Example 6. , ii) benzodiazepine-3-carboxylic acid and 1.25 g of phosphorus pentachloride in 250 ml of methylene chloride. After adding 100 ml of 10% aqueous sodium carbonate solution, the mixture was stirred for 30 minutes at room temperature. The methylene chloride layer was separated, dried and evaporated to dryness. Crystallization of the residue from 2-propanol / ether gave 8-chloro-N- (2-dimethylaminoethyl) -6- (2-fluorophenyl) -1-methyl-1H-imidazo [1,5-a] benzodiazepine-3 -carboxyamidia, m.p. 209-211 °. An analytical sample was recrystallized from ethyl acetate / hexane, m.p. 210-213 °.

20 63405

Example 8 8-Chloro-6- (2-fluorophenyl) -1-methyl-1H-iroids, i.e., 5- [5,7] benz, * + 7-benzodiazepine-3-carboxamide

A methanolic solution of ammonia (20 ml, 25%) was added to a solution of 1.85 g of 3-chloro-6- (2-fluorophenyl) -1-methyl-1H-imidazole as described in Example 6, 5-% 7 N, N-benzodiazepine-3-carboxylic acid and acid chloride prepared from 25 g of phosphorus pentachloride in 250 ml of methylene chloride.

After stirring for 10 minutes, 50 ml of 10% aqueous sodium carbonate solution was added and stirring was continued for 1 hour at room temperature. The methylene chloride layer was separated, dried and evaporated to dryness. The residue was dissolved in a mixture of methylene chloride and ethanol. The solution was filtered through a pad of silica gel and the filtrate was evaporated to dryness. Crystallization of the residue from ethanol gave 8-chloro-6- (2-fluorophenyl) -1-methyl-1H-imidazo [1,5-d] benzodiazepine-3-carboxamide as colorless crystals. The analytical sample was recrystallized from ethanol / tetrahydrofuran. , mp 300-305 °.

Example 9 8-Chloro-6- (2-fluorophenyl) -1-N, N-trimethyl-UK-imidazole, u-α7β · β-benzodiazepine-3-carboxamide

Dimethylamine (U mL) was added to a solution of 1.85 g (0.005 moles) of 8-chloro-6- (2-fluorophenyl) -1-methyl-kH-imidazo [5.0% 7Z3] as described in Example 6. , (* 7-benzodiazepine-3-carboxylic acid and 1.25 g (0.006 mol) of phosphorus pentachloride, prepared in 250 ml of methylene chloride. After stirring for 1 hour at room temperature, the reaction mixture was washed with 10 to 10% aqueous sodium carbonate solution. The residue was purified by chromatography on silica gel using a mixture of 5% (v / v) ethanol in methylene chloride to give 8-chloro-6- (2-fluorophenyl) as a mixture of 5% (v / v) ethanol and methylene chloride. 1-N, N-trimethyl-UH-imidazo, H, β- [7ΖΪ, N] benzodiazepine-3-carboxamide as colorless crystals, mp 177-179 ° It was also found to have a lower melting variant with a mp of 158-> 6 °. °.

Example 10 N, N-Dimethyl-N-chloro-6- (2-fluorophenyl) -1-phenyl-1H-iridazo [1,5-a] [[N, N] benzodepine] -3-carboxamide

A solution of 1.0 g (2.31 mmol) of 8-chloro-6- (2-fluorophenyl) -1-phenyl-1H-imidazo [1,5-b] benzodiazepine-3-carboxylic acid in 5 ml of thionyl chloride , was heated to reflux for i / 2 hours, after which it was carefully added dropwise to 1 mL of cold hO% aqueous dimethylamine solution. The brown solid was collected, washed with water, dried and chromatographed on silica gel using ethyl acetate as eluent to give N, N-dimethyl- [8-chloro-6- (2-fluorophenyl) -1-phenyl-1H-imidazo [1,5]. -ej- [1,7] benzodiazepine-3-carboxamide as a brown foam. Recrystallization three times from acetone / water gave an analytical sample, m.p. 221-223 °.

The starting material was prepared as follows:

A solution of 3.75 g (0.01 mol) of 7-chloro-5- (2-fluorophenyl) -alpha-hydroxyimino-3H-1,1-benzodiazepine-2-acetic acid methyl ester in 300 ml of tetrahydrofuran and 200 ml of in 1 ml of methanol, hydrogenated at atmospheric pressure for 1 1/2 hours in the presence of Raney nickel (1 teaspoon). The catalyst was separated by filtration through Celite and the filtrate was evaporated to dryness in vacuo, finally azeotropically with toluene. The residue was dissolved in 20 ml of pyridine and the solution was treated with b ml of benzoyl chloride. After standing for 15 minutes at room temperature, the reaction mixture was partitioned between methylene chloride and 1N sodium hydroxide solution. The organic layer was dried and evaporated to dryness, finally azeotropically with toluene. Crystallization of the residue from ether gave 2- [(benzoylamino) -methoxycarbonylmethylene] -7-chloro-5- (2-fluorophenyl) -1,3-dihydro-2H-1H-benzodiazepine, m.p. 210-213 ° C. An analytical sample was recrystallized from ethyl acetate / hexane, m.p.

217-219 °, softening at 150-160 °.

A solution of 1.15 g (2.5 mmol) of 2- (benzoylamino) methoxycarbonylmethylene-7-7-chloro-5- (2-fluorophenyl) -1,3-d: hydro-2H-1,1i-benzodiazepine in 10 ml of hexamethyl-phosphoric acid triamide, was heated to reflux for 10 minutes. The dark mixture was partitioned between water and the ether / methylene chloride mixture. The organic layer was washed with water, dried and evaporated to dryness. The residue was dissolved in methylene chloride and filtered through activated alumina using ethyl acetate. The filtrate was evaporated to dryness and chromatographed on 20 g of silica gel using 10%. (v / v) a mixture containing ethyl acetate in methylene chloride. Crystallization of the combined pure fractions from ether / hexane gave methyl 8-chloro-6- (2-fluorophenyl) -1-phenyl-1H-imidazo [1,5-b] benzodiazepine-3-carboxylate, m.p. 203-209 °.

To a solution of 2.66 g (5.77 mmol) of methyl 8-chloro-η 5 - (2-fluorophenyl) -1-phenyl-1H-imidazo [1,5-a] ZZ, 7,7-benzodiazepine-3 carboxylate in 50 ml of boiling methanol, a solution of 755 mg (11.5 mmol) of 22 63405 potassium hydroxide in 10 ml of water was added and the resulting mixture was heated for 2.5 hours.

The solvent was removed in vacuo, the residue was dissolved in 50 ml of hot acetic acid and the solution was then poured into 100 ml of cold water. The product was collected, washed with water and air dried to give 8-chloro-6- (2-fluorophenyl) -1-phenyl-UH-imidazo [1,5] a7/7, (* 7-benzodiazepine-3-carboxylic acid as an off-white solid). The analytical sample was recrystallized from benzene, mp 267-269 °.

Example 11 8-Chloro-6- (2-fluorophenyl) -1-phenyl-1H-imidazo [1D, 7] benzodiazepine-3-carboxamide

A solution of 1.0 g (2.31 mmol) of 8-chloro-6- (2-fluorophenyl) -1-phenyl-1H-imidazo [3β, N] benzodiazepine-3-carboxylic acid in 5 ml of thionyl chloride was heated to reflux. 1/2 hour, after which it was carefully added dropwise to 70 ml of cold ammonium hydroxide. The rose-red solid was collected, washed with water, air-dried and chromatographed on silica gel eluting with ethyl acetate to give 8-chloro-6- (2-fluorophenyl) -1-phenyl-1H-imidazole, 5% to 7%, (* 7-Benzodiazepine-3-carboxamide as a brown foam. Trituration with acetone gave an analytical sample as a white powder, mp 260-262 °.

Example 12 8-Chloro-6- (2-chlorophenyl) -1-methyl-1H-imidazo [1,5 '] 7β-benzodiazepine-3-carboxamide

A stirred suspension of 1.2 g (0.0031 moles) of ethyl 8-chloro-6- (2-chlorophenyl) -1-methyl-UH-imidazo-β, 5-§7 β, (t-benzodiazepine-3 carboxylate in 25 ml of methylene chloride, cooled in an ice bath and treated with 0.7 g (0.00¾ mol) of phosphorus pentachloride, which was added portionwise, the mixture was protected by a drying tube and stirred for a further 30 minutes, during which time most of the solid dissolved. Continuing to cool and stir, the mixture was treated with gaseous ammonia for 5 minutes and then stirred cold for an additional 30 minutes.The mixture was evaporated to dryness in vacuo to give a pale solid which was mixed with dilute aqueous ammonia and filtered through a coarse sintered glass funnel. the material was air dried in a funnel to give 8-chloro-6- (2-chlorophenyl) -1-methyl-1H-imidazo [1,5] 7Z * 1, 7-benzodiazepine-3-carboxamide. a. Recrystallization of the sample from methylene chloride / ethanol 2: 1 gave white plates, m.p. 318-320 ° (dec.).

63405 The starting material was prepared as follows:

A stirred suspension of 1 g (0.09 moles) of a 5% suspension of sodium hydride in 315 ml of dimethylformamide under argon was treated with 21 g (0.096 moles) of diethylacetamidomalonate, which was added in several portions. Stirring was continued at room temperature for 30 minutes and then 31 g (0.06 mol) of 7-chloro-5- (2-chlorophenyl) -2- [bis (morpholino) phosphinyloxy] -3H-1,1 * -benzodiazepine was added in one portion. . After stirring for a further 7 hours at room temperature, the dark mixture was poured onto a mixture of ice and acetic acid with stirring and diluted with water (about 2 L) to give a cream solid. The solid was filtered, washed with water and air dried in a funnel to give acetylamino-p-chloro-5- (2-chlorophenyl) -3H-1,1-benzodiazepin-2-yl-malonic acid diethyl ester. The dried product was mixed with a small amount of 2-propanol while heating in a water bath until dissolution occurred. Upon cooling to room temperature, an off-white solid was obtained. Recrystallization of the sample from 8 times the amount of ethanol gave a fine crystalline off-white precipitate, m.p. 153-155 °.

A sodium methylate solution was prepared by dissolving 0.8 g (0.0 U g) of sodium metal in 50 ml of anhydrous ethanol and protecting with a drying tube. To the stirred solution was added acetylamino-7-chloro-5- (2-chloro-phenyl) -3H-1,1-benzodiazepin-2-yl] -malonic acid diethyl ester (10.1 g, 0.02 mol) in one portion and stirring was continued under a dry atmosphere. at room temperature for 5 hours. The resulting mixture was acidified with acetic acid and concentrated in vacuo. The residue was partitioned between dilute ammonium hydroxide and methylene chloride. After separation of the layers, the organic layer was dried over sodium sulfate and evaporated to dryness in vacuo to give a brown, amorphous solid. The solid was dissolved in 75 ml of dry ether and added to a warm solution of t g of maleic acid in 200 ml of ether. After decanting over a small brown resin residue, the solution was concentrated in a water bath to about 100 mL. After cooling to room temperature with occasional scraping, crystals formed after about 30 minutes. Upon completion of crystallization, the orange crystals were filtered, washed with ether and dried in a funnel to give 2-Z (acetylamino) ethoxycarbonylmethylene-7- (chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,1 + benzodiazepine maleate). Recrystallization of a small sample from ethyl acetate (5 ml / g) gave a fine crystalline yellow precipitate, m.p. 139-11 * 2 ° (dec.).

24 6 3 4 0 5

A solution of 3.2 g (0.0073 moles) of 2- (acetylamino) ethoxycarbonylmethylene-7-chloro-5- (2-chlorophenyl) -1,1-dihydro-2H-1,4-benzodiazepine In 15 mL of hexamethylphosphoramide, stirred under nitrogen and heated at 200-210 ° for 10 minutes. After cooling to room temperature, the solution was poured into ice water and diluted by adding water until precipitation ceased. The brown solid was filtered, washed with water and air dried in a funnel. Upon stirring with ethyl acetate (2 ml / g), the solid dissolved and recrystallized immediately. The brown solid was filtered, washed with 1: 1 ethyl acetate / petroleum ether and air dried to give ethyl 8-chloro-6- (2-chlorophenyl) -1-methyl-1H-imidazo [1,5-a] β > Enzodiazepine-3-carboxylate. Recrystallization of the sample from the methylene chloride / ethyl acetate solution by removal of the methylene chloride by boiling gave off-white needles, mp 214-215 °.

Example 13 8-Chloro-6- (2-chlorophenyl) -1- (2-pyridyl) -NH-imidazo [1,5%] 7β, β-benzodiazepine-3-carboxamide In an ice-water cooled suspension of 4 g (0, 8-chloro-6- (2-chlorophenyl) -1- (2-pyridyl) -4H-imidazo [1,5-a] 2,7,4-benzodiazepine-3-carboxylic acid in 250 ml of methylene chloride was added 3 g ( 0.0145 moles) of phosphorus pentachloride. Stirring was continued under ice-cooling for 30 minutes, and ammonia gas was bubbled into the mixture until the reaction of the mixture was alkaline. Aqueous ammonia (20 mL) and methylene chloride (200 mL) were then added and stirring was continued for 15 minutes. The organic layer was separated, dried over sodium sulfate and passed through a pad of silica gel using a 5'95 (v / v) ethanol-methylene chloride mixture. The solution was evaporated and the residue was crystallized from ethanol / ethyl acetate to give off-white crystals which were recrystallized from methylene chloride / ethyl acetate for analysis, m.p. 255-257 °, after solidification m.p. was 275-278 °.

The starting material was prepared as follows: 7 'Chloro-5- (2-fluorophenyl) -2- [bis (morpholino) phosphinyloxy] -3H-1,1'-benzodiazepine (5.3 g, 0.01 mol) was added to a mixture of 10 ml of dimethyl malonate, 20 ml of dimethylformamide and 2.2 g (0.02 mol) of potassium tert-butoxide, which had been stirred at room temperature for 5 minutes under nitrogen. The reaction mixture was then stirred and heated on a water bath for 15 minutes. After 1.5 ml of glacial acetic acid was added to the mixture, the product was crystallized, gradually diluting with 0 · 25 63405 water. The precipitated crystals were collected, washed with water and dried in vacuo to give 7-chloro-5- (2-chlorophenyl) -2-dimethoxymalonylidene-1,3-dihydro-2H-1,1-benzodiazepine, which was recrystallized for analysis from ethyl acetate, m.p. . 205-207 °.

A mixture of 12.6 g (0.03 mol) of 7-chloro-5- (2-chlorophenyl) -2-dimethoxymalonylidene-1,3-dihydro-2H-1,1-benzodiazepine, 300 ml of methanol and 2, 1 g (0.0375 moles) of potassium hydroxide was heated under reflux under nitrogen for 1/2 hour, 200 ml of methanol were distilled off and the residue was diluted with water. The separated crystals were collected, washed with water and dried to give 7-chloro-5- (2-chlorophenyl) -2,3-dihydro-2- (methoxycarbonyl) methylene] -1H-1,1-benzodiazepine, m.p. I5I-1580. It was recrystallized for analysis from methylene chloride / methanol, mp 158-159 °.

Sodium nitrite (2.2 g, 0.031 mol) was added portionwise over 5 minutes to a stirred solution of 7.2 g (0.02 mol) of 7-chloro-5- (2-chlorophenyl) -2,3-dihydro- 2- [(methoxycarbonyl) methylene] -1H-1,1-benzodiazepine in 75 ml of glacial acetic acid. After stirring for an additional 15 minutes, the mixture was diluted with 100 mL of water and the precipitated crystals were collected, washed with water, methanol and ether to give crude 7-chloro-5- (2-chlorophenyl) -alpha-hydroxyimino- 3H-1,1'-Benzodiazepine-2-acetic acid methyl ester, which was recrystallized from tetrahydrofuran / methanol to give pale yellow crystals, m.p. 223-225 ° (dec.).

7-Chloro-5- (2-chloro-phenyl) -alpha-hydroxy-imino-3H-1,1 + -benzodiazepine-2-acetic acid methyl ester (7.8 g, 0.02 mol) was dissolved with heating in a mixture of 200 ml of tetrahydrofuran. and 100 ml of ethanol. The solution was hydrogenated in the presence of Raney nickel (2 teaspoons) at atmospheric pressure for 2 hours. The catalyst was filtered off through Celite and the filtrate was evaporated to dryness in vacuo. Crystallization of the residue from ethanol gave 2-β. amino) methoxycarbonylmethylene-7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,2-benzodiazepine as orange crystals, m.p. was 115-117 ° (dec.). Recrystallization of this solvated product from ether / hexane gave yellow needles with m.p. was 1U5-1500 (dec.).

Methyl 8-chloro-6- (2-chlorophenyl) -1- (2-pyridyl) -1H-imidazo [1,5-a] -β, 7-benzodiazepine-3-carboxylate

A mixture of 8.5 g (0.02 mol) of 2 - [(aminomethoxycarbonylmethylene) -7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,1-benzodiazepine ethenolate, 200 ml toluene 1 mL of pyridine-2-carboxaldehyde and 15 g of molecular sieves were heated to reflux for 1.0 minute. 20 g of activated manganese dioxide were then added and heating and stirring were continued for a further 10 minutes. The mixture was filtered through Celite, and the filtrate was evaporated. Crystallization of the residue from ethyl acetate from ether gave off-white crystals, m.p. 282-285 °. An analytical sample was obtained by recrystallization from methylene chloride / ethyl acetate, m.p. 283-285 °.

8-Chloro-6- (2-chlorophenyl) -1- (2-pyridyl) -1H-imidazole, 5'a7β, ** 7'-benzodiazepine-3-carboxylic acid

A mixture of k, 3 g (0.009 mol) of methyl 8-chloro-6- (2-chlorophenyl) -1- (2-pyridyl) -NH-imidazole-5,7-benzodiazepine-3- carboxylate, 200 ml of methanol, 10 ml of water and 1.7 g (0.03 mol) of potassium hydroxide were heated to reflux for 2 h. The solvent was partially evaporated, the residue was acidified with glacial acetic acid and diluted with water. The precipitated product was collected, washed with water and dried to give a crystalline material which, after recrystallization from methylene chloride / methanol / ethyl acetate, melted at 262-265 °, (dec.).

Example 1k 8-Chloro-6- (2-chlorophenyl) -1-propyl -4H-imidazo [5,5] aβ, 1,1'-benzodiazepine-3-carboxamide

By reacting 1.5 g (3.5 mmol) of methyl 8-chloro-6- (2-chlorophenyl) -1-propyl-1H-imidazo [1,5-a] β-benzodiazepine-3-carboxylate with a solution of ammonia in methanol ( 20 ml) under the conditions described in Example 15, crystallization of the final product from methylene chloride / ethanol gave the final product, m.p. 298-300 °.

The starting material was prepared as follows:

Methyl 8-chloro-6- (2-chlorophenyl) -1-propyl-1H-imidazo [1,5-b] β, β-benzodiazepine-3-carboxylate

A mixture of J +, 5 g (0.0107 moles) of 2- (amino) methoxycarbonylmethylene] -7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1H-benzodiazepine ethanolate, 100 ml of methylene chloride, 2 ml of butyl aldehyde and 5 g of molecular sieves 5A were stirred at room temperature for 15 minutes. 10 g of activated manganese dioxide were then added and stirring was continued for a further 15 minutes.

The mixture was filtered through Celite and the filtrate was evaporated. Crystallization of the residue from ether gave the final product, cp. 196-198 °. An analytical sample was obtained by crystallization from ethyl acetate / tetrahydrofuran / beccan, m.p. V> F-198 °.

y 27 63405

Example 15 8-Chloro-6- (2-chlorophenyl) -1-isopropyl-UH-imidazo [1,5-a] [?] Yter zodiazepine-3-carboxamide

A mixture of 1.3 g (3 mmol) of methyl 8-chloro-6- (2-chlorophenyl) -1-isopropyl-1H-imidazo [1,5-a], 1-benzodiazepine-3-carboxylate and 20 ml methanol containing 20% by weight of ammonia was heated in an autoclave at 130 ° for 20 h. The solvent was evaporated and the residue was crystallized from methylene chloride / ethanol to give the final product, m.p. 328-330 °. The analytical sample was recrystallized from the same solvents.

The starting material was prepared as follows:

Methyl 8-chloro-6- (2-chlorophenyl) -1-isopropyl-1H-imidazo [1,5-a] -ΔΔ, 7,7-benzodiazepine-3-carboxylate

Following the procedure of Example 1U, item 2, but using isobutylaldehyde instead of butyl aldehyde, the final product was crystallized from ether. For analysis, it was recrystallized from ethyl acetate / tetrahydrofuran / hexane, m.p. 23 ^ -235 °.

Example 16 6- (2-Chlorophenyl) -1-methyl-8-nitro-4H-imidazol-1,5-a7 [Δ, V7] benzodiazepine-3-carboxamide

Phosphorus pentachloride (1.1 g, 5.2 mmol) was added to an ice-cooled suspension of 1.6 g (1 mmol) of 6- (2-chlorophenyl) -1-methyl-8-nitro-1H-imidazol 2 %% 7Ζΐ, 7-benzodiazepine-3-carboxylic acid in 100 ml of methylene chloride. After the mixture was stirred in ice water for 30 minutes, ammonia was bubbled in until the mixture was alkaline, and stirring was continued for 1 hour at room temperature. Water was added and the organic layer was separated, dried and evaporated to dryness. Crystallization of the residue from a methanol / ethyl acetate mixture gave 6- (2-chlorophenyl) -1-methyl-8-nitro-1H-imidazo [1,5] 7% benzodiazepine-3'-carboxamide as yellowish crystals. mp 300. The analytical sample was recrystallized from the same solvents.

The starting material was prepared as follows:

Diethyl acetamidomalonate (t3 g, 0.2 mol) was added to a suspension of 10 g (0.2 mol) of sodium hydride (50 to 50 # of its mineral oil) in 500 ml of dry dimethylformamide. The mixture was heated at 50 ° for 30 minutes under argon. After adding 53 g (0.1 mol) of 5 '(2-chlorophenyl) -2-Zbis- (morpholino) phosphinyloxy-7-7-nitro-3H-1,1-benzodiazepine, the reaction mixture was heated on a water bath for one hour. I drive. The cooled brown mixture was partitioned between water and the methylene chloride / ether mixture. The organic phase was washed with water, dried and evaporated to dryness. The residue was chromatographed on 1 kg of silica gel using ethyl acetate. The pure fractions were combined and evaporated to dryness. Crystallization of the residue from methylene chloride / ether gave ethyl 6- (2-chlorophenyl) -1-methyl-3-nitro-1H-imidazo [1,5] benzodiazepine-3-carboxylate as pale yellow crystals, m.p. ^ 233-23 °. An analytical sample was recrystallized from ethyl acetate, m.p. 231-235 °.

A mixture of 1.25 g (0.01 mol) of ethyl 6- (2-chlorophenyl) -1-methyl-8-nitro-1H-imidazo [1,5-a] benzodiazepine-3-carboxylate, 100 ml of methanol, 1.12 g (0.02 mol: potassium hydroxide and 1 ml of water, heated under reflux under nitrogen for 3 hours, the majority of the methanol was evaporated off and the residue partitioned between water and ether. The aqueous phase was washed with ether, acidified with acetic acid and extracted with methylene. The extracts were dried and evaporated to dryness, and the residue was crystallized from methylene chloride / ethyl acetate to give 6- (2-chlorophenyl) -1-methyl-8-nitro-1H-iminoazo [1,5-b] benzodiazepine-3-carboxylic acid. mp 272-271 ° · The analytical sample was recrystallized from methanol / ethyl acetate, mp 271-276 ° (dec.).

Example 17 8-Chloro-6- (2-chloro-6- (2-chloroenyl) -1-methyl-1H-imidazo [1,5-a] thieno [3,2-f] 2,17-diazepine-3-carboxamide In an ice bath to a mixture of 0.8 g of (. ', PQ? ol mcolia) 8-chloro-6- (2-chlorophenyl) -1-methyl-1H-imidazole, 5-α Tino, 3,2 - [7], di di at s epin-3-carboxylic acid in 100 [mu] l of dry dichloroethane, 0.16 g (0.0022 mol) of phosphorus pentachloride were added. After 30 minutes, ammonia gas was bubbled into the mixture for 5 minutes with stirring, after 7 hours 75 ml of water were added and the product was filtered off, the dichloromethane layer was separated, dried and evaporated to dryness, the product obtained by crystallization from ethanol was combined with the first precipitate and recrystallised to give 8-chloro-6- (2-chloro-6- (2-chlorophenyl} -1-methyl-11-imidazo-5,5-thiothieno, D, 2- [7D, l 3-carboxamide as white rods, mp 300-305 °.

The starting material was prepared as follows:

A solution of 50 g (0.161 moles) of 7-N-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-thieno [2,3-d] thiazepin-2-one 902 ι ·: 1: ο: ι dry tetrahydrofuran and 300 ml of dry benzene, cooled in an ice bath and charged with 29 6340 5 methylamine gas until the solution was saturated, then a solution of 10 g (0.209 mol) of titanium tetrachloride in 100 ml of benzene was added dropwise with stirring. After k hours at room temperature, a few grams of ice were added and the reaction mixture was filtered, the precipitate was washed several times with hot tetrahydrofuran, and the combined filtrates were evaporated to dryness. The residue was partitioned between 250 ml of dichloromethane and 200 ml of water and filtered. The dichloromethane solution was separated, dried and evaporated to dryness. This residue and the precipitate were recrystallized from a mixture of tetrahydrofuran and ethanol to give 7-chloro-5- (2-chlorophenyl) -2-methylamino-3H-thieno [2,3-b] 7-diazepepine. A sample of this was recrystallized for analysis from a mixture of tetrahydrofuran and hexane to give pale yellow prisms, m.p. 259-262 °.

A mixture of 1 * 0 g (0.123 moles) of 7-chloro-5- (2-chlorophenyl) -2-methylamino-3H-thieno / 2,3-e7Z3, N-diazepine, 700 ml of dichloromethane and 350 ml of pyridine was cooled in an ice bath and it was passed with stirring nitrosyl chloride for 20 minutes. After 1 hour, the gas was continued for a further 5 minutes and then 600 ml of water were added slowly. The dichloromethane layer was separated, washed with 200 ml of water, dried over anhydrous sodium sulfate and evaporated to dryness. The oil was dissolved in dichloromethane and filtered through Florisil using UOO g. This was eluted with dichloromethane and then ether. Crystallization of the dichloromethane fraction from a mixture of ether and petroleum ether gave 7-chloro-5- (2-chlorophenyl) -2- (N-nitrosomethylamino) -3H-thieno [2,3-e] 1,1'-diazepine and more product was obtained as ether. fraction. A sample of the product was recrystallized for analysis from a mixture of ether and petroleum ether to give yellow prisms, m.p. 10U-107 ° ·

A mixture of 3.1 g (0.03 mol) of potassium tert-butoxide, 7 ml of dimethyl malonate and 20 ml of dimethylformamide was stirred for 5 minutes under nitrogen. To this was added 3.55 g (0.01 mol) of 7-chloro-5- (2-chlorophenyl) -2-nitrosomethylamino) -3H-thieno [2,3-e] N, N-diazepine, the mixture was stirred and heated on a water bath for 5 minutes. , the mixture was acidified by adding 3 ml of acetic acid and crystallized by slow addition of water. The precipitate was collected, washed with water and methanol and dissolved in methylene chloride. The solution was dried and evaporated to dryness and the residue was crystallized from ethanol to give 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2-dimethoxymalonylidene-2H-thieno [2,3-d] azepepine as pink crystals. , which were recrystallized from ethanol for analysis, m.p. 158-16Ο0.

63405 30

A mixture of 2, <5 g (5 mmol) of 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2-dimethoxymalonylidene-2H-thiacyl, 3-e7Z, 1,1'-diazepine , 50 ml of methanol and 0.7 g (1.25 mmol) of potassium hydroxide were heated under reflux for 3 hours under nitrogen. A portion of the solvent was evaporated and the residue was partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic phase was dried and evaporated to dryness. The obtained 7-chloro-5- (2-chlorophenyl) -2,3-dihydro-2- (methoxycarbonylmethylene) -2H-thieno [3,3-e] -1,1,7-diazepine was dissolved in 20 ml of glacial acetic acid. Sodium nitrite (0.5 g) was added and the mixture was stirred for 15 minutes at room temperature, diluted with water and extracted with methylene chloride. The extracts were washed with water and sodium hydrogen carbonate solution, dried and evaporated to dryness. Crystallization of the residue from methylene chloride / ether and recrystallization from tetrahydrofuran / methanol gave 7 "chloro-5- (2-chlorophenyl) -alpha-hydroxyimino-3H-thieno [2,3-d] [?], 1 * 7-diazepine-2-acetic acid methyl ester as yellow crystals, mp 2l * 2-2i * 5 ° (dec.).

7-Chloro-5- (2-chloro-phenyl) -alpha-hydroxy-imino-3H-thieno [3,2-e] -diazepine-2-acetic acid methyl ester (0.1 g, 1 mmol) was dissolved in 30 mL with heating. tetrahydrofuran and 20 ml of ethanol. After the addition of Raney nickel (1/2 teaspoon), the mixture was hydrogenated for 1 * 5 minutes at atmospheric pressure. The catalyst was filtered off and the filtrate was evaporated to dryness. The residue was dissolved in 10 ml of methanol, and 0.1 * ml of triethyl orthoacetate and 3 drops of ethanolic hydrochloric acid were added to the solution. After heating the mixture to reflux for 10 minutes, the solvent was evaporated and the residue was partitioned between methylene chloride and sodium hydrogen carbonate solution. The organic layer was dried and evaporated to dryness. Chromatography of the residue on 10 g of silica gel, eluting with a 3: 5 (v / v) mixture of methylene chloride and ethyl acetate and crystallizing the residue from ethanol after removal of the eluent, gave methyl 8-chloro-6- (2-chlorophenyl) -1-methyl. <* H-imidazo [f] [5,7-thieno-O] [2,1-f] [[1,1] diazepine-3-carboxylate, m.p. 211-21? °.

To 10 ml of methanol and 1 ml of water was added 0.1 g (0.0021 * 7 mmol) of methyl 8-chloro-6- (2-chlorophenyl) -1-methyl-1 * H-imidazo / Tl , 5-α / thieno [3,2-f] -β, l-diazepine-3-carboxylate and 0.026 g (0.000 · * 93 moles) of potassium hydroxide. The reaction mixture was heated to reflux for 2 hours and evaporated to dryness. The residue was dissolved in 10 ml of water, the solution was washed with 1: 1 ml of ether 31 63405 and then acidified with acetic acid. This mixture was extracted with 30 ml of dichloromethane, dried over anhydrous sodium sulfate, concentrated, cooled and filtered. Recrystallization of the precipitate from a mixture of dichloromethane and ether gave 8-chloro-6- (2-chlorophenyl) -1-methyl-1 + H-imidazo [3,5-a] thieno [3,2-f] [1,1 '] 7-diazepine. 3-carboxylic acid as white prisms, mp 2b2-2hrJ °.

Example 18 8-Chloro-6- (2-chlorophenyl) -1-N, N-trimethyl-UH-imidazo [1,5] 7-thieno-Z * 3, 2- [7Z * 1, U7] diazepine-3-carboxamide

Phosphorus pentachloride, 0.16 g (2.2 mmol) was added to a suspension of 0.785 g (2 mmol) of 8-chloro-6- (2-chlorophenyl) -1-methyl-1H-imidazo [1,5-a] thieno [3] 1,2- [1,7,7'-diazepine-3-carboxylic acid in 50 ml of methylene chloride.

After the mixture was stirred under nitrogen in an ice bath for 30 minutes, dimethylamine was bubbled in until the reaction mixture was alkaline. Stirred for 30 minutes at room temperature and washed with saturated sodium hydrogen carbonate solution, dried and evaporated to dryness. Crystallization of the residue from ethyl acetate / ether gave 8-chloro-6- (2-chlorophenyl) -1-N, N-trimethyl-1H-imidazo [1,5-a] thieno] -3,2-fjβ, N-diazepine-3-carboxamide almost as white crystals which were recrystallized for analysis from ethyl acetate, mp 197-200 °.

Example 19 8-Chloro-6- (2-chlorophenyl) -1- (2-dimethylaminoethyl) -1 + H-imidazo [b] benzodiazepine-3-carboxamide

A mixture of 0.1 + 6 g of methyl 8-chloro-6- (2-chlorophenyl) -1- (2-dimethylaminoethyl) -1 + H-imidazo [1,5-a] 2Z, 1,1 + 7benzodiazepine The 3-carboxylate and 10 ml of methanol containing 20% ammonia were heated in a bomb at 130 ° for 20 h. The solvent was evaporated and the residue was chromatographed on silica gel (7 g) using ethanol-methylene chloride 20:80. Crystallization of the pure fractions from 2-propanol gave the pure product, m.p. 2U9 ~ 251 °.

The starting material was prepared as follows:

Methyl 8-chloro-6- (2-chlorophenyl) -1- (2-dimethylaminoethyl) -NH-imidazo [1,5-a] (h, 1) benzodiazepine-3-carboxylate

To a solution of 1.5 g (0.0107 mol) of 2- [amino] methoxycarbonylmethylene-7-7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,1 + benzodiazepine ethanolate in 100 ml: methylene chloride, 5 ml of dimethylamine and 2 ml of acrolein were added. After stirring for 10 minutes at room temperature, 12 g of activated manganese dioxide were added and stirring was continued for 15 minutes. The MnO was removed by filtration through Celite, the filtrate was evaporated. Crystallization of the residue from ethanol / ether gave the final product which was recrystallized from ethyl acetate / methanol / hexane for analysis, m.p. 203-20¾ °.

Example 20 8-Chloro-6- (2-chlorophenyl) -N-methyl-1-methylaminomethyl-1H-imidazo-D5-7β, 1H-benzodiazepine-3-carboxamide Tetrahydrofuran containing 20% methylamine (75 ml) was added. to a solution of 3 g (6.9 mmol) of methyl 8-chloro-1-chloromethyl-6- (2-chlorophenyl) -NH-imidazo [1,5-b] benzodiazepine-3-carboxylate in 50 ml in tetrahydrofuran. The mixture was heated at 100 ° for 18 h in a sealed vessel. The solvent was evaporated and the residue was crystallized from ethanol, the final product obtained was purified by chromatography on 50 g of silica gel using a 95: 5 (v / v) mixture of methylene chloride and ethanol. The combined pure fractions were obtained by evaporation and crystallization from methylene chloride / ethanol product, m.p. 270-273 °.

The starting material was prepared as follows:

Methyl 8-chloro-1-chloromethyl-6- (2-chlorophenyl) -1H-imidazo [1,5-d] benzodiazepine-3-carboxylate

A solution of chloroacetaldehyde (5 ml) prepared by refluxing a mixture of 50 ml of 2N hydrochloric acid and 50 ml of chloroacetaldehyde dimethyl acetal for 30 minutes was added to a solution of 1 *, 5 g (0.0107 mol) of 2-β, amino). methoxycarbonylmethylene-7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,1'-benzodiazepine ethanolate in 200 d of methyl ether chloride.

After stirring for 15 minutes, the reaction mixture was partitioned between methylene chloride and saturated aqueous sodium bicarbonate. The solid phase was dried and 12 g of activated manganese dioxide were added. After stirring for 15 minutes at room temperature, the MnO 2 was filtered off over Celite and the filtrate was evaporated. Crystallization of the residue from methylene chloride / ether gave the final product. The analytical sample was purified 1: 2 by 3t times on a silica gel using methylene chloride / ethyl acetate 7 '? (V / v). The pure product was obtained by crystallization from ether, m.p. ? 37 ~ 23öL (dec.).

Example 21 1-Benzyl-8-chloro-6- (2-chlorophenyl-5H-imidazo [1,5-a] Z] N-benzodiazepine-3-carboxamide

Phenylacetaldehyde (2.0 g, 0.02 mol) was added to a solution of 3.8 g (0.01 mol) of 2-zamino) methoxycarbonylmethylene-N-chloro-5- (2-chloro-33-63405 phenyl) -1 , 3-dihydro-2H-1,1-benzodiazepine in methylene chloride. After 10 g of molecular sieve 5A was added to the mixture, the mixture was stirred at room temperature for 15 minutes and treated with 10 g of activated manganese dioxide for another 15 minutes at room temperature. The inorganic material was separated by filtration through Celite. The filtrate was evaporated to dryness and the residue was crystallized from ether / hexane to give methyl 1-benzyl-8-chloro-6- (2-chlorophenyl) -NH-imidazo-η 5,7,7-benzodiazepine-3- carboxylate as colorless crystals, mp 155-158 ° The analytical sample was recrystallized from ethyl acetate / hexane, mp 160-162 °.

A mixture of 2 g (U, 2 mmol) of methyl 1-benzyl-8-chloro-6- (2-chlorophenyl) -NH-imidazo [1,5-47], benzodiazepine-3-carboxylate, 1 g of potassium hydroxide, 50 ml of methanol and 5 ml of water, refluxed for k hours under nitrogen, the solvent was evaporated, the residue was dissolved in water and the solution was acidified with acetic acid, the precipitated crystals were collected, washed with water and dissolved in methylene chloride. 1-Benzyl-8-chloro-6- (2-chlorophenyl) -NH-imidazo [1,5-a] benzodiazepine-5-carboxylic acid, mp 305-310 ° (dec.).

The material from the previous step was suspended in 30 mL of methylene chloride. Phosphorus pentachloride (0.8 g) was added and the mixture was stirred in ice / water for 30 minutes. Ammonia gas was then bubbled into the mixture until the reaction mixture was alkaline. After the mixture was stirred for 15 minutes at room temperature, aqueous ammonia solution was added and the biphasic system was stirred for another 15 minutes. The methylene chloride phase was separated, dried and evaporated to dryness. The crystalline residue was recrystallized from ethyl acetate / methanol to give 1-benzyl-8-chloro-6- (2-chlorophenyl) -4H-imidazo / 1.5% 7ΖΪ, 4,7-benzodiazepine-3-carboxamide as a colorless product, m.p. 282-28U0.

The analytical sample was chromatographed on silica gel (1 + 0-fold) eluting with methylene chloride / ethyl acetate 1: 1 (v / v), m.p. 286-288 °.

Example 22 8-Chloro-6-phenyl-14H-imidazo [1,5-a] [2,1] [] benzodiazepine-3-carboxamide A mixture of 5 g of methyl-8-chloro-6-phenyl-1H- imidazoZ ', 5 ~ 47Ζΐ> bj-benzodiazepine-3-carboxylate and 100 ml of methanol containing 20% ammonia were heated in an autoclave at 130 ° for 8 h. The precipitated crystals were collected and recrystallized from tetrahydrofuran / methanol to give the final product. , sp. 295-2960. An analytical sample was obtained by recrystallization from dimethylformamide / ether, m.p. 296-297 ° The starting material was prepared as follows:

Methyl 8-chloro-6-phenyl-kH-imidazole [1,5-a] carboxylate 2 teaspoons of Raney nickel were added to a solution of 10 g (0.028 moles) of 7-chloro-β-hydroxyimino-5 -phenyl-3H-1,1-benzodiazepine-2-acetic acid methyl ester in a mixture of methanol (200 ml) and tetrahydrofuran (200 ml). The mixture was hydrogenated under normal pressure for 5 h. The catalyst was removed by filtration through Celite, and the filtrate was evaporated to dryness. The residue was dissolved in 100 ml of methanol, and 10 ml of triethyl orthoformate and 5 ml of ethanolic hydrogen chloride solution were added to the solution. The mixture was refluxed for 10 minutes, the solvent was evaporated under reduced pressure, and the residue was partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic phase was dried and evaporated. Crystallization of the residue from ether gave the final product, which was recrystallized from methylene chloride / ether, melting point 235-236 °.

Example 23 8-Chloro-6- (2-fluorophenyl) -NH-imidazol-1,5-a, N-benzodiazepine-3-carboxamide In an ice-water cooled suspension of 3.55 g (0.01 mol) of 8-chloro-6 - (2-fluorophenyl) -NH-imidazo [1,5-af] 1,1'-benzodiazepine-3-carboxylic acid in 200 ml of methylene chloride was added 2.6 g (0.012 mol) of phosphorus pentachloride. Stirred for 30 minutes, then Ammonia gas was bubbled into the mixture until the reaction mixture was alkaline, the reaction mixture was partitioned between water and 10% (v / v) methylene chloride, the organic phase was dried and passed onto silica gel, the solution was evaporated and the solid residue was recrystallized from ethanol. was obtained by recrystallization from tetrahydrofuran / ethanol, mp 292-29 °.

The starting material was prepared as follows: 7-Chloro-5- (2-fluoro-phenyl) -alpha-hydroxyimino-3H-1H-benzyldiazepine-2-acetic acid methyl ester (11.25 g, 0.03 mol) was dissolved in the mixture with heating. with 750 ml of tetrahydrofuran and 500 ml of methanol. Raney nickel (20 g) was added and the mixture was hydrogenated at atmospheric pressure for 1 hour, the catalyst was removed by filtration and the filtrate was evaporated to dryness, finally azeotropically with toluene. The residue was dissolved in 100 ml of methanol. After adding 10 ml of triethyl orthoformate and 5 ml of ethanolic hydrochloric acid solution (5%), the mixture was heated under reflux for 10 minutes. It was then evaporated to dryness and the residue partitioned between methylene chloride and saturated aqueous sodium hydrogen carbonate solution. The methylene chloride layer was separated, dried and evaporated to dryness, and the residue was crystallized from ether to give methyl 8-chloro-6- (2-fluorophenyl) -1 + H-imidazo [1,5-s] 10.1 + 7benzodiazepine-3-carboxylate. , which was recrystallized from methylene chloride / ether / hexane, m.p. 179-181 °.

A mixture of 1.1 + 8 g (0.01 + moles) of methyl 8-chloro-6- (2-fluorophenyl) -1 + H-imidazo [1,5-a] [1,1] + 7-Benzodiazepine-3-carboxylate, 0.5 g (0.009 mol) of potassium hydroxide, 50 ml of methanol and 2 ml of water were heated under reflux for 3 hours under nitrogen. A portion of the methanol was evaporated off and the residue was acidified with glacial acetic acid and diluted with water while the solution was still hot. After cooling in ice / water, the crystals were collected and dried in vacuo to give 8-chloro-6- (2-fluorophenyl] -1 + H-imidazoZT1, 5% 7Z, 1 + 7 ′ benzodiazepine-3-carboxylic acid, mp 2l + 5-2l + T ° (dec.).

Example 21 + 8-Chloro-6- (2-chlorophenyl) -1 + H-imidazo [1,5] s-7D, 1,1 + 7-benzodiazepine-3-carboxamide

A mixture of 5 g (0.013 mol) of methyl 8-chloro-6- (2-chlorophenyl) -1 + H-imidazo [1,5-a] [1,1,11] benzodiazepine-3-carboxylate and 75 ml of 20% ammonia-containing methanol was heated in an autoclave at 130 ° for 18 h The reaction mixture from which the product had crystallized was heated in methanol / methylene chloride until all dissolved, filtered and concentrated to give the final product, mp> 300 °. The analytical sample was obtained by recrystallization from methylene chloride / ethanol.

The starting material was prepared as follows:

Methyl 8-chloro-6- (2-chlorophenyl) -1 + H-imidazo [1,5-a] 10,11 + 7benzodiazepine-3-carboxylate

A mixture of 9 g of 2- (damino) methoxycarbonylmethylene-7-7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,1 + benzodiazepine ethanolate, 100 ml of toluene and 20 ml of triethyl orthoformate was heated reflux for 15 minutes. The solvent was evaporated under reduced pressure, and the crystalline residue was taken up in ether and recrystallized from ethyl acetate / methanol to give the final product, m.p. 206-208 °.

Example 25 8-Chloro-N, N-dimethyl-6-phenyl-1 + H-imidazo [0,5 '& 771,1 + 7-benzodiazepine-3-carboxamide

A mixture of 5 g (0.01) + moles) of methyl 8-chloro-6-phenyl-1H-imidazo-β, 5-bJD A / benzodiazepine-3-carboxylate, 2.1+ g (0 .01 + 3 moles) of potassium hydroxide, 10 ml of water and 1U0 ml of methanol were heated to reflux for 6 h. The solvent was evaporated and the residue was dissolved in water. The solution was filtered and acidified with glacial acetic acid. The precipitated crystals were collected and crystallized from methylene chloride / ethanol to give 8-chloro-6-phenyl-14H-imidazoZd, 5-% 7β-benzodiazepine-3-carboxylic acid, m.p. 268-270 °.

1 g of this acid, 1.3 g of phosphorus pentachloride and 100 ml of methylene chloride were stirred at room temperature for 2 h. Dimethylamine was bubbled into the mixture while cooling until a clear solution with a basic pH was obtained. The solution was washed with brine and water. The methylene chloride layer was dried and evaporated. The residue was crystallized from ether to give the final product, which was recrystallized from methylene chloride / ethyl acetate for the analytical sample, m.p. 231-233 °.

Example 26 8-Chloro-6- (2-chlorophenyl) -N, N-dimethyl-UH-imidazo [1β] benzodiazepine-3-carboxamide

A mixture of 2 g of methyl 8-chloro-6- (2-chlorophenyl) -1H-imidazo-β, 5-α / Z1, N-benzodiazepine-3-carboxylate, 15 ml of hexamethylphosphoric acid triamide and 1.5 g of lithium chloride, heated to 225 DEG C. The reaction mixture was cooled and partitioned between water and methylene chloride / ether The organic phase was washed with aqueous bicarbonate solution, dried and evaporated. -2l2 °.

Example 27 8-Chloro-6-phenyl-1 - Ν, Ν-triroethyl-1H-imidazol-5% 7%, β-benzodiazepine-3-carboxamide

A mixture of 1.5 g (0.2 mmol) of 8-chloro-1-methyl-6-phenyl-1H-imidazo [1,5] a, benzodiazepine-3-carboxylic acid, 1.7 g ( 8 mmol) of phosphorus pentachloride and 100 ml of methylene chloride were stirred under argon for 3 h. Dimethylamine was then added at room temperature until a clear solution with a basic pH was obtained. The solution was washed with water, dried and evaporated. Crystallization of the residue from ethyl acetate / ether / hexane and recharging from ether gave the final product, m.p. 173-175 ° · The starting material was prepared as follows:

A mixture of 7.3 g (0.02 moles) of methyl 8-chloro-1-methyl-6-phenyl-1H-imidazo [1,5-a] E, benzodiazepine-3-carboxylate,? , 2b g (0.010 mol) of potassium hydroxide, 200 ml of methanol and 6 ml of water were heated to reflux for 6 34 05 i * hours. A portion of the methanol was removed in vacuo and the residue was acidified with glacial acetic acid and crystallized by the addition of water. The crystals were collected, washed with water and dried to give 8-chloro-1-methyl-6-phenyl-1H-imidazo [1,5-f] [[],]] benzodiazepine-3-carboxylic acid as an off-white product. It was recrystallized for analysis from ethyl acetate, m.p. 270-273 ° (dec.).

Example 28 8-Chloro-6- (2-fluorophenyl) -1-methyl-N-phenyl-1H-imidazo [1,5-a] D, N-benzodiazepine-3-carboxamide 1.3 g (6.25 mmol) Phosphorus pentachloride was added to a suspension of 1.9 g (5 nunols) of 8-chloro-6- (2-fluorophenyl) -1-methyl-1 H -imidazo [5, 5% N, N'-benzodiazepine-3-carboxylic acid. In 100 ml of methylene chloride. After stirring for 30 minutes under ice-water cooling, 7 ml of aniline were added, and stirring was continued at room temperature for 30 minutes. The reaction mixture was partitioned between 10% aqueous sodium carbonate solution and methylene chloride. The organic layer was dried and evaporated. Crystallization of the residue from ether and recrystallization from methylene chloride / ethanol gave the final product, which was recrystallized from tetrahydrofuran / ethanol for analysis, m.p. 228-288 °.

Example 29 8-Chloro-N-cyclopropyl-6- (2-fluorophenyl) -1-methyl-UH-imidazo [5-, 5 ', 10'-benzodiazepine-3-carboxamide 1.3 g (6.25 mmol) of phosphorus pentachloride were added to a suspension of 1.9 g (5.1 mmol) of 8-chloro-6- (2-fluorophenyl) -1-methyl-1 + H-imidazo [1,5] 4,7ZT1,7,7-benzodiazepine-3-carboxylic acid in 100 ml of methylene chloride . After stirring in an ice-water bath for 30 minutes, then 3 ml of cycloprupylamine was added, stirring was continued for 0 minutes. The reaction mixture was washed with aqueous sodium carbonate solution, dried and evaporated. The residue was taken up in silica gel using methylene chloride containing 10% (v / v) ethanol. Crystallization of the product from ethyl acetate / hexane gave the crystalline final product, m.p. 196-197 °.

Example 30 8-Chloro-6- (2-chlorophenyl) -1-N, N-trimethyl-1H-imidazo [1,5] 4,7-H7-benzodiazepine-3-carboxamide

A stirred suspension of 3.6 g (0.0093 mol) of 8-chloro-6- (2-chlorophenyl) -1-methyl-1H-imidazo [1,5-a] 2H-benzodiazepine-3-carboxyl acid in 75 ml of dichloromethane, cooled in an ice bath, and 2.1 g (0.01 mol) of phosphorus pentachloride was added portionwise. The reaction mixture was protected with 38 63405 drying tubes, and stirring was continued under cooling for another 30 minutes. Continuing to cool, dimethylamine was bubbled into the solution for 5 minutes and stirring was continued for another 30 minutes. The mixture was evaporated to dryness under reduced pressure.

The residue was mixed with water, and the mixture was basified with ammonium hydroxide. Extraction with methylene chloride, drying of the extract and evaporation in vacuo gave a brown foam. The foam was dissolved in 600 of any boiling ether and the solution was filtered to remove a small amount of insoluble matter. The filtrate was concentrated on a steam bath to about 250 mL, then filtered again. Further concentration to about 100 ml, always in between scrapers, allowed crystallization to begin. The flask was removed from the steam bath and the mixture was allowed to cool to room temperature overnight. The off-white prisms were filtered, washed batches and air dried in a funnel to give the final product, m.p. 225-230 °.

Recrystallization of the sample from benzene / ether raised the melting point ä "· -Sr '·'". · The starting material was prepared as follows:

A stirred solution of g (0, ci) of ethyl * -8-chloro-6- (2-ionophenyl) -1-methyl-1H-imidazol-2-yl, 5'-benzodiazepine-2-carboxylic acid The acetate was treated with 100 g of methanol a containing water and 1.2 g (0.02 moles) of potassium hydroxide under reflux under nitrogen for 5 hours and concentrated in vacuo to remove methanol. The residue was dissolved in cold / front and acidified with acetic acid to give an off-white solid. After drying in an air funnel overnight * - *! ·· to give 8-chloro- ό- (? · Chlorophenyl) -1-methyl Li-AH- imi i: ·. :: 0/1 .5 - »- /, U / ben: -i. 3 n do :: · - i - · - ;; arbok cause li acid. A crystallized sample was obtained from the new plate: a white plate was obtained. M.p., m.p. 265-26 (hej.).

Example 1 8-Chloro-6- (2-chlorophenyl} -1-dimethylaminoethyl L-1H-imidazo [7,5-a] -1,7,4-benzodiazepine-3-carboxamide

A mixture of C), UU g (1 mol) i-methyl-8-chloro-6- (2-chlorophenyl-11-methylaminomethyl-1H-imidazo [1 H, 1-47 / 3,11b-nitro] diazepep The octane, tia and 5 ml of methanol containing 10% ammonium were suddenly heated in an autoclave for 16 h. The solvent was evaporated and the residue was crystallized from ethanol / ether. An analytical sample was obtained in silica gel using methylene chloride / ethyl acetate and crystallized from ethyl acetate, mp 2'L'-2i »5 °.

The starting material was prepared as followsLie tr 1:

Methyl-8-chloro-6- (2-chlorophenyl] imimethylmethyl-kH-i [d] 5-7O-benzodiazepine-3- karboksilaativ

A mixture of 0.1 x 3; v (1 mmol) methyl-8-chloro-1-chloromethyl-6-39 63405 (2-chlorophenyl) -NH-imidazo [T, 5-7D, k] benzodiazepine-3-carboxylate, 15 ml of tetrahydrofuran and 1.5 ml of dimethylamine, heated in a sealed tube at 100 ° for 3 h. The solvent was evaporated and the residue partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase was dried and evaporated and the residue was crystallized from ether to give the final product. An analytical sample was obtained by recrystallization from ethyl acetate / hexane, m.p. .18.1-183 °.

Claims (6)

40 63405 1. A method of therapeutically useful imidazo / 1,5-a? for the preparation of diazepine compounds of the formula "OfC Θθ <Jo *" is a ring or a) b) is hydrogen, lower alkyl, phenyl, mono-lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, pyridyl or benzyl, R 1 represents hydrogen or lower alkyl and R 4 represents hydrogen, lower alkyl, phenyl, amino, mono-lower alkylamino, di-lower alkylamino, amino-C 1 -C 4 alkyl, mono-lower-alkylamino-C 1 -C 4 -alkyl, or di-lower-alkylamino-C 1 -C 4 -alkyl, or R 1 and R 2 together form a pyrrolidino, is hydrogen or halogen, X is chlorine , bromine or iodine, and is halogen or nitro, the lower alkyl groups containing 1 to 7 carbon atoms, and for the preparation of pharmaceutically acceptable acid addition salts of these compounds, characterized in that the compound of formula R, v M COY Ä. •• -O 'wherein R 1, R 9 and OC are as defined above and Y is lower alkoxy or chlorine is reacted with an aramino compound of formula wherein R 12 and R 2 are the same as above, after which the resulting racemic compound of formula I is optionally partitioned into its optical enantioters, and / or the resulting compound of formula I is optionally converted into a pharmaceutically acceptable acid addition salt. Process for the preparation of 8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-b] benzodiazepine-3-carboxamide according to Claim 1, characterized in that the compound of the formula XV in which the Z ring is according to formula a), and R. is chlorine in the 8-position, R. is hydrogen and R1 is chlorine in the 4-position, is reacted with ammonia. A process according to claim 1 for 8-chloro-6- (2-chlorophenyl) -1,1N, N-trimethyl-4H-imidazo [1,5-a] thieno [3,2-b] D, N-benzodiazepine-3-carboxylate. for the preparation of a amide, characterized in that a compound of formula XV in which the Z ring is of formula b) and X is chlorine, R 1 is methyl and R 2 is chlorine in the 2-position is reacted with dimethylamine. Process for the preparation of 8-chloro-6- (2-chlorophenyl) -N, N-dimethyl-4H-imidazo [f, 5-sJ, 4] benzodiazepine-3-carboxamide according to Claim 1, characterized in that the compound of the formula XV wherein the Z ring is of formula a) and R 1 is chlorine in the 8-position, R 1 is hydrogen and R 2 is chlorine in the 2-position is reacted with dimethylamine. Process for the preparation of 8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a] -1,4-benzosadiazepine-3-carboxamide according to Claim 1, characterized in that a compound wherein the Z ring 4 is of formula a) and R is chlorine in the 8-position. R 1 is hydrogen and R 2 is fluorine in the 2-position, is reacted with ammonia. , 6 3 4 Q 5 t r \ '♦ Z. For the preparation of a therapeutically active compound imidazo [1 / 1,4] diazepine derivatives with the formula \ y \ * QfX, -0 for Qf is ring or a) b) hydrogen, alkyl, phenyl, mono-alkyl-aminoamino-alkyl, di-lagre-alkyl-amino-lägre-alkyl, pyridyl or benzyl, betecnar watt or ellgre alkyl and R betecknar whey, lagre alkyl, phenyl, amino, mono-lasg-alkylamino, di-lagre-alkylamino, amino-C -C N-alkyl, mono-alkyl-aminoamino-C 1-4 -alkyl, or di-hydrogen-alkylamino-C 1-4 -alkyl, or R 1-6 alkyl-mans-pyrrolidino, is halogen, X is chlorine, Brom is iodine, and R is halogen or nitro, colors are alkyl groups of 1-7 cholaters, and for the production of pharmaceutical products the addition of a syrup-addition of the same, , which is obtained with the formula Vy ". OCTX, rs ^ cj där R1, R & och betecknar decamma som ovin, och Y är lägre alkoxy or chloro, omsättes med en aminoförening med formuleln HNR ^^^» color R ^ och R Bete If there is a racemic reaction in the form of a compound I and then a choice of the enantiomeric, och / eller in the case of the formulation I take the form of an enantiomeric form.