DK162495B - METHOD OF ANALOGUE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE IMIDAZOOE1,5-AAAOE1,4AADIAZEPIN COMPOUNDS OR PHARMACEUTICAL ACCEPTABLE SALTS THEREOF - Google Patents

Description

DK 162495B

in

Patent No. 157,615 relates to an analogous process for the preparation of novel therapeutically active imidazo [1,5-a] [1,4] diazepine compounds of general formula 5

YY

n_: ff y3 10 '' A. Y 'in which A means -C =' N, R3, R2 and R3 individually, R6 means hydrogen or lower alkyl, R6 means phenyl, or halogenophenyl, and (X means r4_CC 'vsv xw I in the owner J f

- \ —Y

Wherein X is hydrogen or chloro and R4 is halogen, lower alkyl, lower alkylamino, lower alkanoylamino, amino, hydroxy-lower alkyl, lower alkanoyl or the group R20 ~ O, only R20 is hydrogen or C1-C6 alkyl, or pharmaceutically acceptable acid addition salts of these compounds, and the peculiar feature of the main patent is that (a) dehydrogenates a compound of general formula 35

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* Γ ^ γ * 2

NINE

r / \ / r3

5 fz | WE YOU

in which A, R 1, R 2, R 3 and R 2 are as defined above for a corresponding compound of formula I, or (b) convert a 2,3-lower alkylenedioxy substituent in the benzo group to R 4 in the sense a lower alkanoyl substituent. or (c) converts a lower alkanoyl substituent present as R 4 substituent in an imidazobenzodiazepine to a hydroxy lower alkyl substituent, or (d) cyclizing a compound of the general formula

RAW

T_J

* '<X

r6-c-O wherein R R1 is C ^-CC alkyl, R4 · is chloro or bromo, and R61 er is o-halogenophenyl or (e) undergoes a compound of formula I wherein R4 represents alkanoylamino, a mild hydrolysis to form a corresponding compound of formula I wherein R 4 represents amino, or (f) R 4 in the sense converts a lower alkanoylamino substituent to R 4 in the sense lower alkylamino, or (g) oxidizes a compound of the general formula

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3 J «R2

TY

N_1 5 r / \ / r3 iz | will * XA · ^ 10 H.

I / Γ \ in which A "means —C — N, and R1, R2, R3, R6 and (z | L \

R6 H

15 has the meaning given to formula VII for a corresponding compound of formula I, or (k) dissolves a racemic compound in its optical enantiomers, whereupon if desired (i) converts a compound of formula I into a pharmaceutical 20 tic acceptable acid addition salt thereof.

The present invention relates to an analogous method for the preparation of therapeutically active imidazo [1,5-a] [1,4] diazepine compounds, which is a further development of the method of patent No. 157,615.

The process of the present invention is an analogous process for the preparation of therapeutically active, novel imidazo [1,5-a] [1,4] diazepine compounds of the general formula

GCX

In which A represents -C (R6) = N-, R1 means hydrogen, lower alkyl, phenyl, mono-lower alkylamino - lower alkyl, dilute alkylamino - lower alkyl, pyridyl or benzyl, R2 means the group -CONR12R13, wherein R ^ -2 means hydrogen, 4

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represents the group -CONR 12 R 13, in which R 12 represents hydrogen, lower alkyl or cycloalkyl of 3-7 carbon atoms, and R 13 means hydrogen, lower alkyl or phenyl, or the group - (CH 2) nNR 14 R 15, in which R 14 and R 15 each represent 5 hydrogen or lower alkyl, and n is 0 to 4, or R 12 and R 13 together form part of a pyrrolidine ring, R 6 represents phenyl or halophenyl, and ec represents the group 10

r4 -oeeiie ^ f X

B) where X is chlorine, bromine or iodine, and R4 is halogen or nitro, or pharmaceutically acceptable salts thereof.

In the present specification, the term "lower alkyl" or "alkyl" includes both straight and branched hydrocarbon groups of 1-7 carbon atoms, preferably hydrocarbon groups of 1-4 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl and butyl.

The term "halogen" encompasses all four forms thereof, i. chlorine, bromine, fluorine and iodine.

By the term "alkoxy" is meant straight or branched saturated hydrocarbon radicals containing from 1 to 7 carbon atoms, preferably from 1 to 4 carbon atoms, e.g. methoxy, ethoxy and propoxy.

A preferred group of compounds are those compounds of formula I wherein Θ: is an 8-chlorophenyl or an 8-chloro-thieno [3,2-f] -35 group, R 1 is hydrogen or methyl, R 2 is carboxamido or dimethyl carboxamido, and R 6 is 2'-fluoro or 2'-chlorophenyl.

The term "pharmaceutically acceptable salts" is used

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5 of the present specification to include salts of both inorganic and organic pharmaceutically acceptable acids, e.g. hydrochloric, hydrobromic, nitric, sulfuric, phosphoric, citric, formic, maleic, acetic, succinic, tartaric, methanesulfonic and para-toluenesulfonic. Such salts can be formed relatively easily by any person skilled in the art when considering the prior art and the nature of the compound to be salted.

The process of the invention is characterized by reacting a compound of the general formula "Vy1101" in which R 1, A and having <* a meaning given above, 20 and Y means lower alkoxy or chlorine, with an amino compound of the formula HNR12R13, in which R12 and R13 have the meaning given above, provided that when Y is lower alkoxy and R13 is the group - (CH2) nNR3-4R15, where n-0, R · · · · 2 means hydrogen, where desired dissolves a racemic compound of formula I in its optical enantiomer and, if desired, converts a compound of formula I into a pharmaceutically acceptable salt thereof.

The general reactions shown in the following Scheme A illustrate several of the reactions that can be used to prepare the starting compounds of formula XV. In the reaction scheme, R is lower alkyl and A, R4 and R6 have the meaning given above. R11, R1'1 and R1, n have the meaning given below. It will be apparent to one skilled in the art that some of the substituents may be attacked during subsequent reactions, but such vulnerable groups may be modified before or after such reaction 6.

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the corresponding N-oxides (A = -C (R6) = N (-O) -), but any N-oxide moiety present in compounds of formula IV will be removed during conversion VI - * VII.

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7

Scheme A

nRch3 o CXX «>» CH,

N-NO

θ <*> 0 ^ -0: -¾¾

1 A I

[fZ / "c ^ Jcoo,

W Λ-COOR

GkX w OCX w ^ '1 "OH H ♦

i / n VC00R

V ^ COOR H

GCX m y yZ 'w

- I nXcoor y γ-y COOR

tf - Y ~ y "

OCX »> CJGXW

X R1W H / X w X \ ^ Νν / ε00Κ / (^ (Λ ^ Λ.ν ^ ΟΟΟΗ GCa®, .OCaw 8

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Stage II -> III

Compounds of formula III are prepared by nitrosating compounds of formula II. Such nitrosation can be carried out with "in situ" nitric acid. Reagents which may be used include (1) alkali metal nitrites, i. sodium nitrite, in the presence of organic or inorganic acids, i. glacial acetic acid and aqueous or non-aqueous solvents; (2) alkylnitrites, i. 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 gaseous nitrosyl chloride in an inert solvent and in the presence of an acid acceptor such as pyridine. Such a nitrosation reaction should be carried out at about or below room temperature, i. in the range of -20 ° C to 25 ° C. An amino group or an alkylamino group present in the molecule may be protected during the nitrosation reaction, e.g. by means of acylation. Such a protecting group can be removed at a convenient later stage of the reaction sequence.

Step VIII -> IX

Compounds of formula IX can be prepared by reacting compounds of formula VIII with dimorpholino-phosphinic acid chloride. The reaction of compounds of formula VIII with the phosphorylating agent to form compounds 25 of formula IX is carried out by treating the compounds of formula VIII with a strong base sufficiently strong to ionize the compound of formula VIII to form the corresponding ion. Suitable bases include alkali metal alkoxides such as potassium tert-butyloxide or sodium methoxide, as well as alkali metal hydrides, e.g. sodium hydride, and alkyllithium compounds such as n-butyllithium. The reaction temperature can range from 0 to 100 ° C, and the reaction is preferably carried out in an aprotic polar inert solvent, ie. a solvent which would solubilize the present salts of compounds of formula VIII in total or at least partially. Preferred solvents are ethers,

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9 e.g. tetrahydrofuran or dioxane, or tertiary amides such as dimethylformamide.

It is to be understood that any amino group or substituted amino group should be present in protected form in this reaction step, the protective moiety being removed later at any convenient step, e.g. after the formation of the compound of formula XII.

Stage III or IX-t IV

Compounds of formula III or formula IX can be condensed with the anion formed from a malonic acid ester of formula

/ OOR

* CH N 1: over 15 in which R represents a lower alkyl group to form compounds of formula IV. The anion is produced by deprotonation of malonic acid ester with a suitable strong base, e.g. alkali metal or alkaline earth metal alkoxides, hydrides or amides. The reaction of compounds of formula III or IX with the malonic acid ester anion is preferably carried out in a solvent such as a hydrocarbon, e.g. benzene, toluene or hexane, an ether, e.g. dioxane, tetrahydrofuran or diethyl ether, or in dimethylformamide or DMSO, at a temperature ranging from below room temperature to 150 ° C, preferably from 0 to 100 ° C, and most conveniently at room temperature.

Step IV - »V

Compounds of formula V are prepared by decarboxylating compounds of formula IV by reacting the compound of formula IV with an alkali metal hydroxide such as NaOH or KOH in a suitable solvent, e.g. an alcohol, an ether or DMSO, at a temperature ranging from room temperature to reflux temperature, preferably from 60 to 100 ° C.

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10

Step V -4 VI

Compounds of formula VI are prepared by nitrosating compounds of formula V by reacting the latter with nitric acid, e.g. is formed from an alkali metal nitrite, an alkyl nitrite or nitrosyl chloride, by reaction with organic or inorganic acid. Suitable solvents for the nitrosation reaction include ethers, alcohols, water and acids, e.g. acetic acid, DMF, DMSO and chlorinated hydrocarbons. The reaction can be carried out approximately 10 at room temperature, although such a temperature is not critical.

Step VI -> VII

The compounds of formula VII are prepared by reducing compounds of formula VI, e.g. with Raney-nickel and hydrogen or with zinc and acetic acid. This reduction results in a predominant formation of compounds of formula VII with simultaneous formation of small amounts of several possible isomers, i.e. compounds of formulas 2 ° OR OR, NH NH,

In jj-NH, \ C00R I \ COOR V \ COOR

/ \ JT \ / - {(w &) Ove) ς®0) 2 5

It should be noted that at the reduction stage mentioned above, easily attackable groups will be reduced, if such groups are present, such as R 4, e.g. a 7-position nitro group or a 7-position CN group. These groups can be replaced by methods known per se and as set forth herein.

Step VII -> XII

Compounds of formula XII are then formed by reacting compounds of formula VII with an alkanoic acid orthoester of formula R1, C (OR) 3, where R is lower alkyl and R1 'is hydrogen or lower alkyl, optionally

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11 in the presence of an acid catalyst, e.g. an organic or inorganic acid, such as p-toluenesulfonic acid or phosphoric acid, and at room temperature or above, i.e. at 25 to 150 ° C, in which case a cyclization to the compound 5 of formula XII occurs spontaneously.

Technical equivalents to the above-mentioned ortho-ester include ortho-amides, e.g. the dimethyl acetal of Ν, Ν-dimethylformamide, Ν, Ν, Ν'Ν ', N ", N" -hexamethylroethane triamine, nitriles, e.g. acetonitrile, and ester imidates, e.g. CH3-10 C (= NH) -OC2H5.

It is clear that any amino or alkylamino group present must be protected during this reaction.

Step will - XI

The compounds of formula XI can be prepared by acylating compounds of formula VII with a compound of formula RinCOX or (R1MCO) 20, where X represents a halogen atom and R1 'is hydrogen, lower alkyl, phenyl, pyridyl or benzyl.

Solvents for use in this process step include methylene chloride, ethers and chlorinated hydrocarbons, preferably in combination with an acid acceptor such as an organic or inorganic base, e.g. triethylamine, pyridine or an alkali metal carbonate. The reaction may be carried out above or below room temperature, but preferably carried out at room temperature. Compounds of formula XI are isomers by nature, i.e. that they may exhibit one or the other of the following stereochemical structures:

NHCOR COOR

. ·

(3a) (> bJ

Step XI - »XII

Compounds of formula XII may also be prepared by dehydrogenating compounds of formula XI or 12

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isomers thereof with subsequent cyclization upon heating. In this reaction step, the meaning of the symbol R1 "in compounds of formulas XI and XII is limited to hydrogen, lower alkyl, phenyl, pyridyl and benzyl. This reaction step can be carried out with or without a solvent, e.g. and in a temperature range of 100 to 300 ° C, preferably at 150 to 250 ° C, for example at 200 ° C, with or without the presence of catalysts and water-binding agents.

Step IX -> X

Compounds of formula X can be prepared by a condensation reaction between a compound of formula IX and the anion formed from an acylaminomalonic acid ester of formula

/ COOR

15 θ / C-NHCOR1

'NiOOR

in which R represents lower alkyl and R1 "is hydrogen, lower alkyl, phenyl, pyridyl or benzyl, to form a compound of formula X. The anion is produced by de-titration of the acylaminomaloic acid ester with a suitable strong base, e.g. The reaction of compounds of Formula IX with the acylaminomalonic acid ester anion is preferably carried out in a solvent such as a hydrocarbon, for example benzene, toluene or hexane, an ether such as dioxane. , THF, diethyl ether, DMF, DMSO, at a temperature range from below room temperature to 150 ° C, preferably from 0 to 100 ° C, especially at 30 room temperature.

Step X - * XI

Compounds of formula XI and isomers thereof are formed by decarboxylating compounds of formula X with an alkali metal alkoxide in a solvent such as an ether, an alcohol, DMSO or DMF, at above or below room temperature, preferably at room temperature. Compounds of Formulas 13

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X and xi need not be isolated, the calm can be converted in situ to compounds of formula XII.

Step VII XIII

Compounds of formula XIII are formed by reacting compounds of formula XII with an aldehyde of formula R 1 '' 'cho, wherein R 1' '' has the same meaning as R 1 of formula I or halo-lower alkyl, but any amino group or substituted amino group and preferably any RCO group should be present in protected form. The protective portion 10 may be removed later, e.g. after the formation of the compound of formula XII. Solvents suitable for this reaction step are hydrocarbons such as benzene, alcohols, ethers, chlorinated hydrocarbons, DMF and DMSO, with or without the presence of water-binding agents, e.g. molecular sieves, at above or below room temperature, preferably from room temperature to the reflux temperature of the solvent.

Step XIII XII

Compounds of formula XIII can be converted to the compounds of formula XII by in situ oxidation with 20 oxidizing agents such as manganese dioxide, air and oxygen.

As indicated above, a final compound of formula XII in which R 4 represents amino can be converted to a corresponding compound wherein R 4 represents nitro or cyano via a Sandmeyer reaction as defined in this specification.

Another method for preparing compounds of formula XII, in which R 4 is nitro, consists in the preparation of a corresponding compound of formula VII. The latter compound can be prepared by reacting a corresponding compound of formula IX with a protected 30 amino acid ester of formula

/ COOR

Θ /

C-NH

wherein R is lower alkyl and z is benzyloxycar- 14

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bonyl, converting the compound of formula X wherein R 1 is benzyloxy and R 4 is nitro thus obtained to a corresponding compound of formula XI as described above in step X-X X and subjecting it to thus compound obtained a treatment with hydrogen bromide in glacial acetic acid to give a compound of formula VII in which R 4 represents nitro. The intermediates of formulas X and XI need not be isolated. The compound of formula VII thus obtained is then further converted to the final product of formula XII via reaction steps VII - XIII and XIII - XII as described above.

Step XII -> XVIII

Compounds of formula XVIII are formed by hydrolysis for compounds of formula XII to the corresponding acids, preferably with alkali metal hydroxides such as NaOH or KOH. This hydrolysis is conveniently carried out in an inert solvent. Suitable solvents are alcohols, e.g. methanol and ethanol, ethers, e.g. dioxane and tetrahydrofuran, as well as dimethylformamide, in combination with water. It is preferred to carry out this reaction step at a temperature between room temperature and the boiling point of the reaction mixture.

The compound of formula XVIII can be converted to the corresponding acid chloride, i. a compound of formula XV wherein Y is chloro, e.g. with phosphorus pentachloride.

Compounds of formula I can be prepared by aminolysis and hydrazinolysis, respectively, of compounds of formula XV with a compound of formula HG, where G is R12 -N, where R12 and R13 have the above R13 meaning.

The reaction of a compound of formula XV wherein Y is lower alkoxy, with a compound of formula HG where G is the group -NR 12 R 13 where R 13 is hydrogen and R 12 is as indicated above is conveniently carried out in an inert solvent or in the absence. of a solvent. Suitable solvents are hydrocarbons, e.g. hexane,

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Toluene, ethers, e.g. tetrahydrofuran, alcohols, e.g. methanol or ethanol, dimethylformamide, dimethylsulfoxide and hexaraethylphosphoric triamide. It is preferred to carry out this reaction step at a temperature between ca. 50 ° C and approx. 200 ° C, especially at a temperature between 100 ° C and about 150 ° C, using atmospheric pressure or atmospheric pressure.

The reaction of a compound of formula xv wherein Y is chlorine with a compound of formula HG is conveniently carried out in an inert solvent. Suitable solvents are hydrocarbons, e.g. hexane and toluene, ethers, e.g. tetrahydrofuran, chlorinated hydrocarbons, e.g. methylene chloride or chlorobenzene. It is preferred to carry out this reaction at a temperature between ca. -20 ° C and the boiling point of the reaction mixture, preferably at a temperature between ca. 0 and approx. 50 ° C.

It is clear that a hydroxyalkyl substituent must be protected during this reaction step.

The reaction of a compound of formula XV, wherein Y is lower alkoxy, with a compound of formula HG, wherein G is the group ^^ R3-4 -N (R12) N wherein R12, R14 and R15 \ r15 have the above meaning, conveniently performed in an inert solvent. Suitable solvents are hydrocarbons, e.g. hexane or toluene, ethers, e.g.

tetrahydrofuran, and alcohols such as methanol and ethanol.

The reaction is preferably carried out at a temperature between ca.

50 and approx. 150 ° C, especially between ca. 80 and approx. 100 ° C. The same 30 restrictions with respect to substituents which may be expected to be affected during this reaction step should be observed as indicated for the reaction with a compound HG where G represents the group / R 12

-N

35 nR13

Compounds of formula I and their pharmaceutically acceptable acid addition salts are useful muscle relaxants, sedatives and anticonvulsants, and many are

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particularly useful when used in intravenous and intramuscular preparations because of the solubility of the acid addition salts in aqueous solution.

The pharmacological activity of some representative compounds of the present invention has been determined by standard experiments. The compounds used in these experiments were as follows: 8-Chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo- [1,5-a] [1,4] benzodiazepine-3 -10 carboxamide (Compound A), 8-Chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo- [1,5-a] [1,4] benzodiazepine-3-carboxylic acid, 2.2- dimethylhydrazide (Compound B) and 8-Chloro-N, N-diethyl-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine 3-carboxamide (Compound C).

The results obtained from experiments on the 20 inclined plate, the foot shock test and the non-anesthetized cat test using the above-mentioned compounds prepared according to the invention are given in the following table:

Foot Shock 100% 25 Connecting - Sloping plate blocking Non-anesthetic PD 50_ dose_ straight cat MED_ A 3 mg / kg p.o. 0.5 mg / kg p.o.

B 5 mg / kg p.o. 0.5 mg / kg p.o. 0.5 mg / kg p.o.

30 C 24.5 mg / kg p.o. 1 mg / kg p.o. 2.5 mg / kg p.o.

The novel compounds of formula I and their acid addition salts according to the invention can be incorporated into pharmaceutical dosage compositions containing from about 0.1 to 35 approx. 40 mg, preferably 1-40 mg, the dose being adjusted according to species and individual requirements. The novel compounds of alfalfa I as well as their pharmaceutically acceptable salts may be administered internally, e.g. parenterally or enterally, in conventional pharmaceutical dose forums. For example, the 40 may be incorporated into conventional liquid or solid carriers.

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17, such as water, gelatin, starch, magnesium stearate, talc, vegatable oils or the like for the preparation of tablets, elixirs, capsules, solutions, emulsions and the like in accordance with accepted pharmaceutical practice.

5

Example 1 0.74 g (2 mmol) of methyl 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate is heated in 30 ml of methanolic ammonia at 120 * 0 for 18 hours in a sealed container. The solvent is evaporated and the residue is recrystallized from a mixture of methylene chloride and ethanol to give 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide in form of colorless crystals with m.p. 335 to 340 * 0.

The starting material can be prepared as follows: 26 g (0.232 mmol) of potassium tert.butoxide are added to a mixture of 300 ml of dimethylformamide and 50 ml (0.44 mol) of dimethyl malonate. After stirring under nitrogen for 10 min. to a solution of 66 g (0.209 mol) of 7-chloro-2-20 (N-nitrosomethylamino) -5-phenyl-3H-1,4-benzodiazepine-4-oxide in 100 ml of dimethylformamide over 10 minutes. The mixture is then slowly heated on a steam bath and kept at 65 ° C for 10 minutes. After cooling to room temperature, 40 ml of glacial acetic acid is added followed by 1 liter of water over 30 minutes. under 25 scraping from time to time. The precipitated crystals are collected, washed with water and dissolved in methylene chloride. The solution is dried over sodium sulfate and concentrated to low volume. The product is crystallized by the addition of hexane to give 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -30-phenyl-2H-1,4-benzodiazepine-4-oxide, m.p. 188 to 190 ° C.

An analytical sample is recrystallized from a mixture of methylene chloride and hexane and has m.p. 194 to 195 "C.

A) A mixture of 40.8 g (0.1 mole) of 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -5-phenyl-2H-1,4-benzodiazepine-4-oxide, 250 ml of methanol, 250 ml of tetrahydrofuran and 1 teaspoon of Raney nickel are hydrogenated at atmospheric pressure for 5 hours.

ICE

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The catalyst is removed by filtration and the filtrate is evaporated.

Crystallization of the residue from a mixture of methylene chloride and 2-propanol gives 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -5-phenyl-2H-1,4-benzodiazepine as 5 colorless crystals with m.p. 160 to 163 ° C. For analysis, the compound is recrystallized from 2-propanol and has m.p.

165 to 166 ° C.

Another modification of the crystals with m.p. 138 to 140 ° C is available in some cases.

B) 4 ml of phosphorus trichloride are added to a solution of 4 g (0.01 mole) of 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -5-phenyl-2H-1,4-benzodiazepine-4 oxide in 100 ml of methylene chloride. After standing at room temperature overnight, the solution is washed with 10% aqueous sodium carbonate solution. The methylene chloride layer is dried and evaporated, and crystallization of the residue from 2-propanol and recrystallization from a mixture of methylene chloride and 2-propanol gives 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -5-phenyl-2H 1,4-benzodiaze pin with m.p. 165 ° C 166 ° C.

A mixture of 115 g (0.3 mol) of 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -5-phenyl-2H-1,4-benzodiazepine, 1.5 liters of methanol and 14.4 g (0.36 mol) of sodium hydroxide is heated to reflux for 5 hours under a nitrogen atmosphere. The cold reaction mixture is gradually diluted with 2.5 25 liters of water under ice-cooling. The precipitated crystals are collected, washed with water and dried in vacuo at 60 ° C to give 7-chloro-1,3-dihydro-2- (methoxycarbonylmethylene) -5-phenyl-2H-1,4-benzodiazepine in the form of a grayish white product with m.p. 167-170 ° C. An analytical sample is recrystallized from 30 ether and m.p. 171 to 173 "C.

2.8 g (0.04 mole) of sodium nitrite are added to a solution of 8 g (0.025 mole) of 7-chloro-1,3-dihydro-2- (methoxycarbonylmethylene) -5-phenyl-2H-1,4-benzodiazepine in 100 ml glacial vinegar. The mixture is stirred under nitrogen for 10 min. The product begins-35 is to crystallize after a few minutes. After dilution with 100 ml of water, the precipitated product is collected, washed with 19

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water, dried and recrystallized from a mixture of tetrahydrofuran and methanol to give 7-chloro-α-hydroxyimino-5-phenyl-3H-1,4-benzodiazepine-2-acetic acid methyl ester in the form of yellow crystals, m.p. 235 to 237 ° C during disintegration.

3.6 g (0.01 mole) of 7-chloro-α-hydroxyimino-5-phenyl-3H-1,4-benzodiazepine-2-acetic acid methyl ester is dissolved in a mixture of 200 ml of tetrahydrofuran and 100 ml of methanol by heating. Add 1 teaspoon of Raney nickel and the mixture 10 is hydrogenated at atmospheric pressure until the hydrogen uptake subsides (1 hour and 10 minutes). The catalyst is removed by filtration and the filtrate is evaporated towards the end azeotropically with toluene. The residue is dissolved in 20 ml of methanol. After adding 3 ml of triethyl orthoacetate and 0.3 ml of ethanolic hydrogen chloride (5%), the solution is refluxed for 5 minutes. The residue left after evaporation is partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic phase is separated, dried and evaporated. Crystallization of the residue from ether 20 gives methyl 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate which, after recrystallization from a mixture of methylene chloride, ether and hexane has m.p. 254 to 256 ° C.

Example 2

A mixture of 0.74 g (2 mmol) of methyl 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate and 20 ml of ethanol containing 25% methylamine is heated to 120 ° C for 18 hours in a closed container. The solvent was evaporated and the residue was crystallized from a mixture of methylene chloride and ethanol to give 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3N-methyl -carbo-xamide with m.p. 260-263 ° C. An analytical sample is recrystallized from a mixture of tetrahydrofuran and ethanol.

35 20

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Example 3

A mixture of 7.7 g of methyl 8-chloro-6- (2-fluorophenyl) -1-methyl 1-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate, 100 ml of isobutanol and 20 ml of hydrazine are heated to reflux for 1 hour. The crude product obtained after evaporation is chromatographed over 250 g of silica gel using 5% ethanol in methylene chloride. The pure fractions are combined and evaporated. Crystallization of the residue from a mixture of methylene chloride and ether gives 8-chloro-6- (2-fluoro-10-phenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3 -carboxylic acid hydra z id in the form of colorless crystals with m.p.

235 to 237 ° C.

The starting material can be prepared as follows:

A solution of 200 g (0.695 mol) of 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2H-1,4-benzodiazepin-2-one in 2 liters of tetrahydrofuran and 250 ml of benzene are saturated with methylamine while cooling in an ice bath. A solution of 190 g (1 mole) of titanium tetrachloride in 250 ml of benzene is added through a dropping funnel over 15 minutes. After the addition, the mixture is stirred and refluxed for 3 hours. 600 ml of water are slowly added to the cooled reaction mixture. The inorganic material is separated by filtration and washed thoroughly with tetrahydrofuran. The aqueous layer is separated and the organic phase is dried over sodium sulfate and evaporated. The crystalline residue of 7-chloro-5- (2-fluorophenyl) -2-methylamino-3H-1,4-benzodiazepine is collected and has m.p. 204 to 206 ° C. An analytical sample is recrystallized from a mixture of methylene chloride and ethanol and has m.p. 204 to 206 ° C.

A) 8.63 g of sodium nitrite (0.125 mol) is added in three portions over a period of 15 minutes. to a solution of 30.15 g (0.1 mole) of 7-chloro-5- (2-fluorophenyl) -2-methylamino-3H-1,4-benzodiazepine in 150 ml of glacial acetic acid. After stirring for 1 hour at room temperature, the reaction mixture is diluted with water and extracted with methylene chloride. The extracts are washed with saturated sodium bicarbonate solution, dried over sodium sulfate and finally evaporated azeotropically with toluene to give 21

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29 g of crude 7-chloro-5- (2-fluorophenyl) -2- (N-nitrosomethylamino) -3H-1,4-benzodiazepine are obtained as a yellow oil.

B) 27.6 g of sodium nitrite (0.4 mol) are added in portions over 30 minutes. to a solution of 90.45 g (0.3 mole) of 7-5 chloro-5- (2-fluorophenyl) -2-methylamino-3H-1,4-benzodiazepine in 400 ml glacial acetic acid. After complete addition, the mixture is stirred at room temperature for 1 hour and diluted with 1 liter of water and extracted with methylene chloride. The extracts are washed twice with water and then with 10% aqueous sodium 10 carbonate solution. The solution is dried and evaporated to give crude 7-chloro-5- (2-fluorophenyl) -2- (N-nitrosomethylamino) -3H-1,4-benzodiazepine in the form of a yellow oil.

This material is dissolved in 300 ml of dimethylformamide and added to a mixture of 150 ml of dimethyl malonate, 40.4 g of potassium tert. butoxide and 500 ml of dimethyl formamide which have been stirred at room temperature for 10 min. The reaction mixture is stirred under nitrogen overnight at room temperature, sieved by adding 50 ml of glacial acetic acid, diluted with water and aqueous sodium carbonate solution, dried over sodium sulfate 20 and evaporated. Crystallization of the residue from ethanol gives 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -5- (2-fluorophenyl) -2H-1,4-benzodiazepine as colorless crystals, m.p. 170 to 172 ° C. For analysis, the product is recrystallized from a mixture of methylene chloride and ethanol and the melting point is thereby unchanged.

A mixture of 20 g (0.05 mol) of 7-chloro-1,3-dihydro-2- (dimethoxymalonylidene) -5- (2-fluorophenyl) -2H-1,4-benzodiazepine, 400 ml of methanol and 3.3 potassium hydroxide (g) (0.059 mol) is heated to reflux under nitrogen for 5 hours. After evaporation of the majority of the solvent, the residue is gradually diluted with water and the precipitated crystals are collected, washed with water and dried, leaving 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2- (dimethoxycarbonylme) -thylene) -2H-1,4-benzodiazepine, m.p. 158 to 160 ° C.

For analysis, the compound is recrystallized from a mixture of methylene chloride and hexane and m.p. is then 22

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161 to 162 AD.

8.8 g of sodium nitrite (0.125 mole) are added to a solution of 28 g (0.08 mole) of 7-chloro-1,3-dihydro-5- (2-fluorophenyl) -2- (methoxycarbonylmethylene) -2H- 1,4-benzodiazepine in 250 5 ml glacial acetic acid. The mixture is stirred at room temperature for 10 min. and then diluted with 250 ml of water. The crystalline product is separated by filtration, washed with water, methanol and ether and dried to give 7-chloro-5- (2-fluorophenyl) -α-hydroxyimino-3H-1,4-benzodiazepine-2-acetic acid methyl -10 ester in the form of yellow crystals with m.p. 238 to 241 ° C with decomposition.

11.25 g (0.03 mol) of 7-chloro-5- (2-fluorophenyl) -α-hydroxyamino-3H-1,4-benzodiazepine-2-acetic acid methyl ester is hydrogenated at atmospheric pressure with Raney nickel in a mixture of 15 ml of tetrahydrofuran and 500 ml of methanol. The nickel is separated by filtration and the filtrate is evaporated. The residue is dissolved in 100 ml of methanol and 11 ml of triethyl orthoacetate and 5 ml of ethanolic hydrogen chloride (5%) are added. The mixture is heated to reflux for 10 minutes, evaporated and the residue partitioned between methylene chloride and aqueous sodium bicarbonate solution. The methylene chloride solution is dried and evaporated and the residue is chromatographed over 300 g of silica gel using a mixture of methylene chloride and ethyl acetate in a 1: 3 volume ratio. The pure fractions are combined and evaporated and crystallized from ether to give methyl 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate, m.p. 162 to 164 ° C.

An analytical sample is recrystallized from a mixture of ethyl acetate and hexane.

30

Example 4 4 ml of pyrrolidine is added to a solution of acid chloride prepared from 1.85 g of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine -3-carboxylic acid and 1.25 g of phosphorus pentachloride in 250 ml of methylene chloride. Next, 100 ml of a 10% aqueous sodium carbonate solution is added.

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The mixture is stirred at room temperature for 1 hour. The organic phase is separated, dried and evaporated.

Crystallization of the residue from a mixture of 2-propanol and ether gives 1- [8-chloro-6- (2-fluorophenyl) -1-methyl-5H-imidazo [1,5-a] [1, 4] benzodiazepin-3-oyl] pyrrolidine in the form of a colorless product, m.p. 220 to 221 ° C after recrystallization from a mixture of ethyl acetate and hexane.

The starting material can be prepared as follows:

A mixture of 7.7 g (0.02 mol) of methyl 8-chloro-6- (2-10 fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3 -carboxylate, 2.24 g (0.04 mole) of potassium hydroxide, 200 ml of methanol and 6 ml of water are heated to reflux for 3¾ hours. The solvent is partially evaporated and the residue is acidified with glacial acetic acid and diluted with water while warm. The 15 precipitated crystals are collected after cooling in a mixture of ice and water and dried to give 8-chloro-6- (2-fluoro-phenyl) -1-methyl-4H-imidazo [1,5-a] [1 , 4] benzodiazepine-3-carboxylic acid. For analysis, the compound is recrystallized from a mixture of methylene chloride, methanol and ethyl acetate, and it has then m.p. 271 to 274 ° C during decomposition.

Example 5 10 ml of 2,2-dimethylhydrazine are added to a solution of acid chloride prepared as described in Example 24 from 1.85 g of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1 5- [alpha] [1,4] 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 is stirred for 30 minutes. at room temperature. The organic layer is separated, dried and evaporated. Crystallization of the residue from a mixture of ether and ethanol gives 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid, 2,2-dimethylhydrazide in the form of a colorless product. An analytical sample is purified by chromatography 35 over the 30-fold amount of silica gel using 10% (volume per volume) of ethanol in methylene chloride. Connect 24

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The mixture is crystallized from a mixture of methylene chloride, ethyl acetate and hexane and m.p. 238 to 240 ° C.

Example 6 1.25 g (0.006 mole) of phosphorus pentachloride is added to a suspension of 1.85 g (0.005 mole) of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5 -a] [1,4] benzodiazepine-3-carboxylic acid in 250 ml of methylene chloride. After stirring for 30 min. In an ice bath, 15 ml of diethylamine is added, followed by 100 ml of 10% aqueous sodium carbonate solution. The two-phase system 10 is stirred for 30 minutes. at room temperature. The organic layer is separated, dried over sodium sulfate and evaporated. Crystallization of the residue from a mixture of methylene chloride and ether gives 8-chloro-N, N-diethyl-6- (2-fluoro-phenyl) -1-methyl-4H-imidazo [1,5-a] [ 1,4] benzodiazepine-3-carboxamide with m.p. 182 to 188 ° C. An analytical sample is recrystallized from a mixture of ethyl acetate and hexane and has m.p.

183 to 185 ° C.

Example 7 5 ml of 2- (dimethylamino) ethylamine are added to a solution of acid chloride prepared as described in Example 6 from 1.85 g (5 mmol) of 8-chloro-6- (2-fluorophenyl) -1-methyl -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid and 1.25 g of phosphorus pentachloride in 250 ml of methylene chloride. After addition of 100 ml of 10% aqueous sodium carbonate solution, the mixture is stirred for 30 minutes. at room temperature. The methylene chloride layer is separated, dried and evaporated. Crystallization of the residue from a mixture of 2-propanol and ether gives 8-chloro-N- (2-dimethylaminoethyl) -6- (2-fluorophenyl) -30 l-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide, m.p. 209 to 211 ° C. An analytical sample is recrystallized from a mixture of ethyl acetate and hexane and has m.p. 210 to 213 ° C.

Example 8 20 ml (25%) of methanolic ammonia are added to a solution of

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Acid chloride prepared as described in Example 6 from 1.85 g of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine -3-carboxylic acid and 1.25 g of phosphorus pentachloride in 250 ml of methylene chloride. After stirring for 5 10 min. 50 ml of 10% aqueous sodium carbonate solution is added and stirring is continued for 1 hour at room temperature. The methylene chloride layer is separated, dried and evaporated. The residue is dissolved in a mixture of methylene chloride and ethanol and the solution is filtered over a layer of silica gel, whereupon the filtrate is evaporated. Crystallization of the residue from ethanol gives 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide in the form of colorless crystals. An analytical sample is recrystallized from a mixture of ethanol and tetrahydrofuran and has m.p.

15 300 to 305 ° C.

Example 4 4 ml of dimethylamine are added to a solution of the acid chloride prepared as described in Example 6 from 1.85 g of 20 (0.005 mol) of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H -imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid and 1.25 g (0.006 mol) of phosphorus pentachloride in 250 ml of methylene chloride. After stirring at room temperature for 1 hour, the reaction mixture is washed with 10% aqueous sodium carbonate solution, dried and evaporated. The residue is purified by chromatography over 40 g of silica gel using 5% (volume per volume) of ethanol in methylene chloride. Crystallization of the combined pure fractions from a mixture of ether and hexane gives 8-chloro-6- (2-fluorophenyl) -1, N, N-trimethyl-4H-imidazo [1,5-a] [ 1,4] benzodiazepine-3-carboxamide in the form of colorless crystals, m.p. 177 to 179 ° C. A lower melting modification is also observed with m.p. 158 to 160 ° C.

Example 10 A solution of 1.0 g (2.31 mmol) of 8-chloro-6- (2-fluorophenyl) -1-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine -3-carbo- 26

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xyl acid in 5 ml of thionyl chloride is refluxed for one hour and then gently and dropwise added to 70 ml of cold, 40% aqueous dimethylamine. The brown solid is collected, washed with water, dried and chromatographed on silica gel using ethyl acetate as eluant to give N, N-dimethyl- [8-chloro-6- (2-fluorophenyl) -1-phenyl] 4H-imidazo [1,5-a] [1,4] benzodiazepine] -3-carboxamide in the form of a brown foam. Three times recrystallization from a mixture of acetone and water gives an analytical sample with m.p. 221 to 10 223 AD.

The starting material can be prepared as follows:

A solution of 3.75 g (0.01 mole) of 7-chloro-5- (2-fluoro-phenyl) -α-hydroxyimino-3H-1,4-benzodiazepine-2-acetic acid methyl ester in 300 ml of tetrahydrofuran and 200 ml of methanol is hydrogenated at atmospheric pressure for 1¾ hours in the presence of 1 teaspoon of Raney nickel. The catalyst is separated by filtration over celite and the filtrate is evaporated under reduced pressure, finally azeotropically with toluene. The residue is dissolved in 20 ml of pyridine and treated with 4 ml of bezoyl chloride. After standing 20 at room temperature for 15 min. partition the reaction mixture with methyl enchloride and 1N sodium hydroxide solution. The organic layer is finally dried and evaporated azeotropically with toluene. Crystallization of the residue from ether gives 2- [benzoylamino-methoxycarbonylmethylene] -7-chloro-5- (2-fluoro-phenyl) -1,3-dihydro-2H-1,4-benzodiazepine, m.p. 210 to 213 ° C. An analytical sample is recrystallized from a mixture of ethyl acetate and hexane and m.p. 217 to 219 ° C with softening at 150 to 160 ° C.

A solution of 1.15 g (2.5 mmol) of 2 - [(benzoylamino) -methoxycarbonylmethylene] -7-chloro-5- (2-fluorophenyl) -1,3-dihydro-2H-1,4 -benzodiazepine in 10 ml of hexamethylphosphoric acid triamide is heated to reflux for 10 min. The dark mixture is partitioned between water and a mixture of ether and methylene chloride. The organic layer is washed with water, dried and evaporated. The residue is dissolved in methylene chloride and filtered over activated alumina with ethyl acetate. Evaporate the filtrate 27

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and chromatographed over 20 g of silica gel using 10% (volume per volume) of ethyl acetate in methylene chloride.

Crystallization of the combined pure fractions from a mixture of ether and hexane gives methyl 8-chloro-6- (2-5 fluorophenyl) -1-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate, m.p. 208 to 209 ° C.

To a solution of 2.66 g (5.77 mmol) of methyl 8-chloro-6- (2-fluorophenyl) -1-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine -3-carboxylate in 50 ml of refluxing methanol is added to a solution of potassium hydroxide 755 mg (11.5 mmol) in 10 ml of water and the resulting mixture is heated for 2½ hours. The solvent is removed in vacuo, the residue is dissolved in 50 ml of hot acetic acid, and then the solution is poured into 100 ml of cold water. The product is collected, washed with water and air-dried to give 8-chloro-6- (2-fluorophenyl) -1-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3 carboxylic acid in the form of a greyish-white solid. An analytical sample is recrystallized from benzene and shows m.p. 267-269 ° C.

Example 11

A solution of 1.0 g (2.31 mmol) of 8-chloro-6- (2-fluoro-phenyl) -1-phenyl-4H-imidazo [1,5-a] [1,4-benzodiazepine-3-carboxylic acid] xyl acid in 5 ml of thionyl chloride is refluxed for one hour and then gently and dropwise added to 70 ml of cold ammonium hydroxide. The pink solid is collected, washed with water, air dried and chromatographed on silica gel using ethyl acetate as eluant to give 8-chloro-6- (2-fluorophenyl) -1-phenyl-4H-imidazo [1,5 a] [1,4] benzodiaze-pin-3-carboxamide in the form of a brown foam. Trituration with 30 acetone gives an analytical sample in the form of a white powder with m.p. 260 to 262 ° C.

Example 12

A stirred suspension of 1.2 g (0.0031 mol) of ethyl 8-35 chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine 3-carboxylate in 25 ml of methylene chloride is cooled in 28

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an ice bath and treated with 0.7 g (0.004 mol) of phosphorus pentachloride in portions. The mixture is protected with a drying tube and stirred in the cold for an additional 30 minutes, during which most of the solid dissolves. With continued cooling and stirring, the mixture is treated with ammonia gas for 5 minutes. and stir for an additional 30 min. in the cold. The mixture is evaporated in vacuo to give a light solid which is stirred with dilute aqueous ammonia and filtered through a coarse sintered glass funnel. After washing with water, the solid is air dried on the filter funnel to give 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3 carboxamide. Recrystallization of a sample from a mixture of methylene chloride and ethanol in a 2: 1 ratio gives white plates with m.p. 318 to 320 ° C with decomposition.

The starting material can be prepared as follows:

A stirred suspension of 4 g (0.09 mol) of a 54% sodium oil suspension of sodium hydride in 315 ml of dimethylformamide under argon atmosphere is treated with 21 g (0.096 mol) of diethylacetamidomalonate in several portions. Stirring at room temperature is continued for 30 minutes, then in one portion is added 31.4 g (0.06 mol) of 7-chloro-5- (2-chlorophenyl) -2- [bis- (morpholino) -phosphinyloxy] - 3H-1,4-benzodiazepine. After stirring for an additional 7 hours at room temperature, the dark mixture is poured over ice and acetic acid with stirring and diluted with water (about 2 liters) to form a cream-colored solid. The solid is separated by filtration, washed with water and air-dried on the filter to give acetylamino- [7-chloro-5- (2-chlorophenyl) -3H-1,4-benzodiazepin-2-yl] -malonic acid diethyl ester. The dried product is stirred with a small amount of 2-propanol under heating on a steam bath until dissolution takes place. On cooling to room temperature, a grayish white solid is obtained. Recrystallization of a sample from the eight-fold ethanol yields greyish-white microneedles with m.p. 153 to 155 ° C.

35 A solution of sodium ethyl to be prepared by dissolving 0.8 g (0.04 g-atm.) Of sodium metal in 50 ml of absolute 29

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ethanol and protected by a drying tube. 10.1 g (0.02 mole) of acetylamino [7-chloro-5- (2-chlorophenyl) -3H-1,4-benzodiazepin-2-yl] -malonic acid diethyl ester are added in one portion to the stirred solution. and stirring in a dry atmosphere is continued at room temperature for 5 hours. The resulting mixture is acidified with acetic acid concentrated in vacuo. The residue is partitioned between dilute ammonium hydroxide and methylene chloride. After separating the layers, the organic layer is dried over sodium sulfate and evaporated at reduced pressure to give a light brown, amorphous solid. The solid is dissolved in 75 ml of anhydrous ether and added to a warm solution of 5 g of maleic acid in 200 ml of ether. After decanting from a small amount of brown rubbery substance, the solution is concentrated on a steam bath to ca. 100 ml. Cooling at room temperature with 15 scrapes from time to time gives rise to crystallization after approx. 30 min. When the crystallization is complete, the orange crystals are separated by filtration, washed with ether and air dried on the filtrate to give 2 - [(acetylamino) ethoxycarbonylmethyl] -7-chloro-5- (2-chlorophenyl) -1 3-20 dihydro-2H-1,4-benzodiazepine maleinate. Recrystallization of a small sample from ethyl acetate (5 ml per g) gives yellow micro-needles with m.p. 139 to 142 ° C during decomposition.

A solution of 3.2 g (0.0073 mol) of 2 - [(acetylamino) ethoxycarbonylmethyl] -7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine in 15 ml of hexamethylphosphoramide is stirred under nitrogen and heated to 200 to 210 ° C for 10 minutes. After cooling to room temperature, the solution is poured into ice water and diluted with more water until the precipitate is complete.

The light brown solid is filtered, washed with water and air dried on the filter. Stirring with 2 ml of ethyl acetate per ml. grams, the solid dissolves and recrystallizes immediately. The light brown solid is separated by filtration, washed with a mixture of ethyl acetate and petroleum ether in a 1: 1 ratio and air dried to give ethyl 8-chloro-6- (2-chlorophenyl) -1-methyl-4 imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate. Recrystallization of a sample from a solution

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Removal of a mixture of methylene chloride and ethyl acetate by removal of the methylene chloride by boiling gives greyish white needles with m.p. 214 to 215 ° C.

EXAMPLE 13 8-Chloro-6-12-chlorophenyl-1- (2-pyridyl) -4H-imidazori-5-a1-1,1,4-benzodiazepine-3-carboxamide 3 g (0.0145 mole) of phosphorus pentachloride is added to a suspension of 4 g (0.0089 mol) 8-Chloro-6- (2-chlorophenyl) -Ι-ΙΟ (2-pyridyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid in 250 ml of methylene chloride cooled with a mixture of ice and water. After stirring for 30 minutes over a mixture of ice and water, ammonia gas is introduced until the mixture shows an alkaline reaction. Aqueous ammonia (20 ml) and methylene chloride (200 ml) are then added and stirring is continued for 15 minutes. The organic layer is separated, dried over sodium sulfate and passed over a pad of silica gel using 5% ethanol in methylene chloride (by volume). The solution is evaporated and the residue is crystallized from a mixture of ethanol and ethyl acetate to give greyish white crystals which are recrystallized from methylene chloride and ethyl acetate for a mp. 255 to 257 ° C, re-solidification and melting again at 275-278eC.

The starting material can be prepared as follows: 5.3 g (0.01 mole) of 7-chloro-5- (2-chlorophenyl) -2- [bis (morpholino) -phosphinyloxy] -3H-1,4-benzodiazepine is added to a mixture of 10 ml of dimethyl malonate, 20 ml of dimethyl formamide and 2.2 g (0.02 mol) of potassium tert. but oxide which is stirred at room temperature for 5 min. under nitrogen atmosphere. The reaction mixture is then stirred and heated on a steam bath for 15 minutes.

After adding 1.5 ml of glacial acetic acid, the product is crystallized by gradual dilution with water. The precipitated crystals are collected, washed with water and dried in vacuo to give 7-chloro-5- (2-chlorophenyl) -2-dimethoxymalonylidene-1,3-dihydro-2H-1,4-benzodiazepine which is recrystallized analy- 31

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see from ethyl acetate and exhibit m.p. 205 to 207 ° C.

A mixture of 12.6 g (0.03 mole) of 7-chloro-5- (2-chloro-phenyl) -2-dimethoxyimonylidene-1,3-dihydro-2H-1,4-benzodiazepine, 300 of methanol and 2.1 g (0.0375 mole) of potassium hydroxide 5 are heated to reflux under nitrogen for 4½ hours, distilled off 200 ml of methanol and diluted with water. The separated crystals are collected, washed with water and dried to give 7-chloro-5- (2-chlorophenyl) -2,3-dihydro-2 - [(methoxycarbonyl) methylene] -1H-1,4 benzodiazepine with 10 m.p. 154 to 158 ° C. The compound is recrystallized for analysis from a mixture of methylene chloride and methanol and mp 158 to 159 ° C.

2.2 g (0.031 mol) of sodium nitrite are added in portions 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-1,4 benzodiazepine in 75 ml glacial acetic acid. After stirring for an additional 15 min. the mixture is diluted with 100 ml of water and the precipitated crystals collected, washed with water, methanol and ether to give crude 7-chloro-5- (2-chloro-phenyl) -α-hydroxyimino-3H-1,4 benzodiazepine-2-acetic acid methyl ester which is recrystallized from a mixture of tetrahydrofuran and methanol to give pale yellow crystals, m.p. 223 to 225 ° C under decomposition.

7.8 g (0.02 mol) of 7-chloro-5- (2-chlorophenyl) -α-hydroxy-imino-3H-1,4-benzodiazepine-2-acetic acid methyl ester are dissolved in a mixture of 200 ml of tetrahydrofuran and 100 ml. ml of ethanol under heating. The solution is hydrogenated in the presence of Raney nickel (2 teaspoons) at atmospheric pressure for 2 hours. The catalyst is separated by filtration over celite and the filtrate is evaporated under reduced pressure. Crystallization of the residue from ethanol gives 2- [(amino) -methoxycarbonylmethylene] -7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine in the form of orange crystals with m.p. 115 to 117 ° C, during decomposition. Recrystallization of this solvated product from a mixture of ether and hexane gives yellow needles, m.p. 145 to 150 ° C under decomposition.

32

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Methyl 8-chloro-6- (2-chlorophenyl) -1- (2-pyridyl) -4H-imidazone-5-a1 (11-benzodiazepine-s-carboxylate

A mixture of 8.5 g (0.02 mol) of 2 - [(amino methoxycarbonylmethylene) -7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine ethanolate , 200 ml of toluene, 4 ml of pyridine-2-carboxaldehyde and 15 ml of molecular sieve 4A are heated to reflux for 10 minutes. The mixture is filtered over celite and the filtrate is evaporated. mp 282 to 285 C. An analytical sample is recrystallized from a mixture of methylene chloride and ethyl acetate and shows mp 283 to 285 ° C.

8-Chloro-6- (2-chlorophenyl) -1- (2-pyridyl) -4H-imidazori [5-a] 1,4-benzodiazepine-3-carboxylate A mixture of 4.3 g (0.009 mol) of methyl-8 -chloro-6- (2-chlorophenyl) -1- (2-pyridyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate, 200 ml of methanol, 10 ml of water and 1.7 g (0.03 mole) of potassium hydroxide are heated to reflux for 4 hours. After partial evaporation of the solvent, the residue is acidified with glacial acetic acid and diluted with water. The precipitated product is collected, washed with water and dried, leaving a crystalline material which is recrystallized for analysis from a mixture of methylene chloride, methanol and ethyl acetate to give m.p. .262 to 265 ° C under 25 decomposition.

Example 14 8-Chloro-6- (2-chlorophenyl) -1- (propyl) -4H-imidazone, 5-amino-benzodiazepine-3-carboxamide Reaction of 1.5 g (3.5 mmol) of methyl-8 chloro-6- (2-chlorophenyl) -1- (propyl) -4H-imidazo [1,5-a] [1,4] benzodiaze-pin-3-carboxylate with 20 ml of methanol ischemic ammonia gives under the conditions of Example 15 described conditions a final product which, after crystallization from a mixture of methylene chloride and ethanol, shows m.p. 298 to 300 ° C.

The starting material can be prepared as follows: 33

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Methyl 8-chloro-6- (2-chlorophenyl) -1-propyl-4H-imidazone-5-a] benzodiazepine-3-carboxylate

A mixture of 4.5 g (0.0107 mol) of 2 - [(amino) methoxycarbonylmethylene] -7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,4 benzodiazepine ethanolate, 100 ml of methylene chloride, 2 ml of butyl aldehyde and 5 g of molecular sieve 5A are stirred at room temperature for 15 minutes. 10 g of activated manganese dioxide are then added and stirring is continued for a further 15 minutes. The mixture is filtered over celite and the filtrate is evaporated.

By crystallization of the residue from ether, a final product of m.p. 196 to 198 ° C. An analytical sample is obtained by recrystallization from a mixture of ethyl acetate, tetrahydrofuran and hexane and m.p. 197 to 198 ° C.

Example 15 8-Chloro-6- (2-chlorophenyl) -1-isopropyl-4H-imidazone-5-α1,4-benzodiazepine-3-carboxamide

A mixture of 1.3 g (3 mmol) of methyl 8-chloro-6- (2-chlorophenyl) -1-isopropyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate and 20 ml of methanol containing 20% by weight of ammonia are heated in an autoclave to 130 ° C for 20 hours. The solvent is evaporated and the residue is crystallized from a mixture of methylene chloride and ethanol to give a final product, m.p. 328 to 330 ° C. An analytical sample is recrystallized from the same solvents.

The starting material can be prepared as follows: Methyl 8-chloro-6- (2-chlorophenyl) -1-isopropyl-4H-imida-zophyl-5-aryl-benzodiazepine-S-carboxylate

Using the procedure described in Example 14, second paragraph 30, but replacing butylaldehyde with isobutylaldehyde, a final product crystallized from ether is obtained. The product is recrystallized for analysis from a mixture of ethyl acetate, tetrahydrofuran and hexane and then shows m.p. 234 to 235 ° C.

35 34

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Example 16 1.1 g (5.2 µmol) of phosphorus pentachloride is added to a suspension of 1.6 g (4 mmol) of 6- (2-chlorophenyl) -1-methyl-8-nitro-4H-imidazo [1,5- a] [1,4] Benzodiazepine-3-carboxylic acid in 100 ml of methylene chloride cooled in ice water. After stirring for 30 min. in ice water, a stream of ammonia is added until the mixture is alkaline and stirring is continued for 1 hour at room temperature. Water is added and the organic layer is separated, dried and evaporated. Crystallization of the residue from a mixture of methanol and ethyl acetate gives 6- (2-chlorophenyl) -1-methyl-8-nitro-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide in the form of yellow crystals with m.p. 300 ° C. An analytical sample is obtained by recrystallization from the same solvents.

The starting material can be prepared as follows: 43 g (0.2 mole) of diethylacetamidomalonate is added to a suspension of 10 g (0.2 mole) of sodium hydride (50% in mineral oil) in 500 ml of dry dimethylformamide. The mixture is heated to 50 ° C for 30 minutes. under argon. After the addition of 53 g of 20 (0.1 mole) of 5- (2-chlorophenyl) -2- [bis (morpholino) -phosphinyloxy] -7-nitro-3H-1,4-benzodiazepine, the reaction mixture is heated on a steam bath. 1 hour. The cooled brown mixture is partitioned between water and a mixture of methylene chloride and ether.

The organic phase is washed with water, dried and evaporated.

The residue is chromatographed over 1 kg of silica gel using ethyl acetate. The pure fractions are combined and evaporated. Crystallization of the residue from a mixture of methylene chloride and ether gives ethyl 6- (2-chlorophenyl) -1-methyl-8-nitro-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate 30 form of light yellow crystals with m.p. 233 to 234 ° C. An analytical sample is recrystallized from ethyl acetate to give m.p.

234 to 235 ° C.

A mixture of 4.25 g (0.01 mole) of ethyl 6- (2-chloro-phenyl) -1-methyl-8-nitro-4H-imidazo [1,5-a] [1,4] benzodiazepine 3-carboxylate, 100 ml of methanol, 1.12 g (0.02 mole) of potassium hydroxide and 4 ml of water are heated to reflux under nitrogen.

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gene for 3 hours. Most of the methanol is evaporated and the residue is partitioned between water and ether. The aqueous phase is washed with ether, acidified with acetic acid and extracted with methylene chloride. The extracts are dried and evaporated. Crystal 1 isat ion 5 of the residue from a mixture of methylene chloride and ethyl acetate gives 6- (2-chlorophenyl) -1-methyl-8-nitro-4H-imidazo- [1,5-a] [1,4] benzodiazepine -3-carboxylic acid, m.p. 272 to 274 ° C during decomposition. An analytical sample is recrystallized from a mixture of methanol and ethyl acetate and has m.p. 274 10 to 276 ° C with decomposition.

Example 17

To 0.8 g (0.00204 mol) of 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] thieno [3,2-f] [1,4] diazepine-3-carboxylic acid in 100 ml of dry dichloromethane in an ice bath is added 0.46 g (0.0022 mol) of phosphorus pentachloride. After 30 min. During this process ammonia is bubbled for 5 minutes. under stirring.

After 2 hours, 75 ml of water is added and the product is separated by filtration. The dichloromethane is separated, dried and evaporated. The product obtained by crystallization of the residue from ethanol is combined with the first precipitate and recrystallized from a mixture of chloroform and ethanol to give 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1 , 5- [alpha] thieno [3,2-f] [1,4] diazepine-3-carboxamide in the form of white rods with m.p. 300 to 305 ° C.

The starting material can be prepared as follows:

A solution of 50 g (0.161 mol) of 7-chloro-5- (2-chloro-phenyl) -1,3-dihydro-2H-thieno [2,3-e] [1,4] diazepin-2-one 900 ml of dry tetrahydrofuran and 300 ml of dry benzene are cooled in an ice bath which is bubbled with methylamine until the solution is saturated and a solution of 40 g (0.209 mol) of titanium tetrachloride in 100 ml of benzene is added dropwise with stirring. After 4 hours at room temperature, a few grams of ice are added and the reaction mixture is filtered. The precipitate is washed several times with hot tetrahydrofuran and the combined filtrates are evaporated. The residue is partitioned between 250 ml of dichloromethane and 200 36

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ml of water and filtered. The dichloromethane solution is separated, dried and evaporated. This residue and the precipitate are recrystallized from a mixture of tetrahydrofuran and ethanol to give 7-chloro-5- (2-chlorophenyl) -2-methylamino-3H-thie-5 [2,3-e] [1,4] -diazepin. A sample is recrystallized for analysis from a mixture of tetrahydrofuran and hexane to give pale yellow prisms with m.p. 259 to 262 ° C.

A mixture of 40 g (0.123 mol) of 7-chloro-5- (2-chloro-phenyl) -2-methylamino-3H-thieno [2,3-e] [1,4] diazepine, 700 ml of dichloromethane and 350 ml of pyridine is cooled in an ice bath and nitrosyl chloride is bubbled for 20 minutes. under stirring. After 1 hour, nitrosyl chloride is bubbled for an additional 5 minutes, and slowly 600 ml of water is slowly added. The dichloromethane layer is separated, washed with 200 ml of water, dried over 15 anhydrous sodium sulfate and evaporated to dryness. The oil is dissolved in dichloromethane and filtered through 400 g of florisil. The material is eluted with dichloromethane and then with ether. Crystallization of the dichloromethane fraction from a mixture of ether and petroleum ether gives 7-chloro-5- (2-chlorophenyl) -2- (N-nitrosomethylamino) -3H-thieno [2,3-e] [1,4 ] diazepine, and additional product is obtained from the ether fraction. A sample is recrystallized for analysis from a mixture of ether and petroleum ether to give yellow prisms with m.p. 104 to 107 ° C.

A mixture of 3.4 g (0.03 mole) of potassium tert.butoxide, 7 ml of dimethyl malonate and 20 ml of dimethyl formamide is stirred for 5 minutes. under nitrogen atmosphere. After addition of 3.55 g (0.01 mol) of 7-chloro-5- (2-chlorophenyl) -2- (N-nitrosomethylamino) -3H-thieno [2,3-e] [1,4] diazepine is stirred the mixture and heated on a steam bath for 5 minutes, acidified by the addition of 3 30 ml of acetic acid and crystallized by the slow addition of water. The precipitated material is collected, washed with water and methanol and dissolved in methylene chloride. The solution is dried and evaporated and the residue is crystallized from ethanol to give 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2-dimethoxymalonylidene-2H-thieno [2,3-e] [ 1,4] diazepine in the form of pink crystals recrystallized from ethanol for analysis and 37

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exhibits m.p. 158 to 1608C.

A mixture of 2.15 g (5 mmol) of 7-chloro-5- (2-chloro-phenyl) -1,3-dihydro-2-dimethoxymalonylidene-2H-thieno [2,3-e] [1,4 ] diazepine, 50 ml of methanol and 0.7 g (1.25 mmol) of potassium hydroxide are heated to reflux under nitrogen for 3 hours. The solvent is partially evaporated and the residue partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic phase is dried and evaporated. The resulting crude 7-chloro-5- (2-chlorophenyl) -2,3-dihydro-2- (methoxycarbonylmethylene) -2H-thieno [2,3-e] [1,4] diazepine is dissolved in 20 ml glacial vinegar. 0.5 g of sodium nitrite is added and the mixture is stirred for 15 min. at room temperature, diluted with water and extracted with methylene chloride. The extracts are washed with water and sodium bicarbonate solution, dried and evaporated.

Crystallization of the residue from a mixture of methylene chloride and ether and recrystallization from a mixture of tetrahydrofuran and methanol give 7-chloro-5- (2-chlorophenyl) -α-hydroxyimino-3H-thieno [2,3-e ] [1,4] diazepine-2-acetic acid remethyl ester in the form of yellow crystals, m.p. 242 to 20 2458C under decomposition.

0.4 g (1 mmol) of 7-chloro-5- (2-chlorophenyl) -α-hydroxyimino-3H-thieno [2,3-e] [1,4] diazepine-2-acetic acid methyl ester is dissolved by heating in 30 ml of tetrahydrofuran and 20 ml of ethanol. After addition of 1 teaspoon of Raney nickel, the mixture is hydrogenated for 45 min. at atmospheric pressure. The catalyst is separated by filtration and the filtrate is evaporated. The residue is dissolved in 10 ml of methanol and treated with 0.4 moles of triethyl orthoacetate and 3 drops of ethanolic hydrogen chloride.

After heating to reflux for 10 min. the solvent is evaporated and the residue partitioned between methylene chloride and sodium bicarbonate solution. The organic layer is dried and evaporated. Chromatography of the residue over 10 g of silica gel using a mixture of methylene chloride and ethyl acetate in a volume ratio of 3: 5 and crystallization of the resulting residue after removal of the eluent from ethanol gives methyl 8-chloro-6- (2-chlorophenyl ) -L-metal

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38 Thyl 4H-imidazo [1,5-a] thieno [3,2-f] [1,4] diazepine-3-carboxylate, m.p. 211 to 212 ° C.

To 10 ml of methanol and 1 ml of water are added 0.1 g (0/000247 mol) of methylene-8-chloro-6- (2-chlorophenyl) -1-methyl-5H-imidazo [1,5-a] thieno [3,2-f] [1,4] diazepine-3-carboxylate and 0.028 g (0.000493 mole) of potassium hydroxide. The reaction mixture is refluxed for 2 hours and evaporated. The residue is dissolved in 10 ml of water, washed with 10 ml of ether and. then acidified with acetic acid. The mixture is 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 gives 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] thieno [3,2-f] [1, 4] diazepine-3-carboxylic acid in the form of white prisms with m.p. 242 to 247 ° C.

Example 18 0.46 g (2.2 mmol) of phosphorus pentachloride is added to a suspension of 0.785 g (2 mmol) of 8-chloro-6- (2-chlorophenyl) -1-20 methyl-4H-imidazo [1,5-a ] thieno [3,2-f] [1,4] diazepine-3-carboxylic acid in 50 ml of methylene chloride. After stirring under nitrogen in an ice bath for 30 min. dimethylamine is introduced until the reaction mixture is alkaline. It is stirred for 30 min. at room temperature and washed with saturated sodium bicarbonate solution, dried and evaporated. Crystallization of the residue from a mixture of ethyl acetate and ether gives 8-chloro-6- (2-chlorophenyl) -1, N, N-trimethyl-4H-imidazo [1,5-a] thieno [3,2-f ] [1,4] diazepine-3-carboxamide in the form of greyish white crystals, which are recrystallized from ethyl acetate for analysis and give m.p. 197 to 200 ° C.

Example 19 8-Chloro-6- (2-chlorophenyl) -1- (2-dimethylaminoethyl) -4H-imidazone-5,1-benzodiazepine-3-carboxamide A mixture of 0.46 g of methyl-8-chloroamide 6- (2-chlorophenyl) -1- (2-dimethylaminoethyl) -4H-imidazo [1,5-a] [1,4] benzo-39

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diazepine-3-carboxylate and 10 ml of methanol containing 20% ammonia are heated in a bomb for 20 hours at 130 ° C. The solvent is evaporated and the residue is chromatographed over silica gel (7 g) using 20% ethanol in methylene chloride. Crystallization of the pure fractions from 2-propanol gives the pure product with m.p. 249-251'C.

The starting material can be prepared as follows:

Methyl 8-chloro-6- (2-chlorophenyl) -1- (2-dimethylamino-ethyl) -4H-imidazo [1,5-a] 1,4-benzodiazepine-3-carboxylate 5 ml of dimethylamine and 2 ml of acrolein are added to a solution of 4.5 g (0.0107 mol) of 2- [(amino) methoxycarbonylmethylene] -7-chloro-5- (2-chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine ethanolate in 100 ml of methylene chloride. After stirring for 10 minutes at room temperature, 12 g of activated manganese dioxide are added and stirring is continued for 15 minutes. The manganese dioxide is removed by filtration over celite and the filtrate is evaporated. Crystallization of the residue from a mixture of ethanol and ether gives a final product which is recrystallized from a mixture of ethyl acetate, methanol and hexane for analysis and shows m.p. 203 to 204 ° C.

Example 20 2.4 9 (0.02 mole) of phenylacetaldehyde is added to a solution of 3.8 g (0.01 mole) of 2 - [(amino) -methoxycarbonylmethylene] -7-chloro-5- (2- chlorophenyl) -1,3-dihydro-2H-1,4-benzodiazepine in methylene chloride. After the addition of 10 g of molecular sieve 5A, the mixture is stirred at room temperature for 15 minutes. and treated with 10 g of activated manganese dioxide for an additional 15 min. at room temperature. The inorganic material is separated by filtration over silica gel. The filtrate is evaporated and the residue is crystallized from a mixture of ether and hexane to give methyl-1-benzyl-8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate in the form of colorless crystals, m.p. 155 to 158 ° C. An analytical sample is recrystallized from a mixture of ethyl acetate and hexane and has m.p. 160 to 162 ° C.

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A mixture of 2 g (4.2 romol) methyl -1-benzyl-8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate, 1 g of potassium hydroxide, 50 ml of methanol and 5 ml of water are heated to reflux for 4 hours under a nitrogen-5 atmosphere. The solvent is evaporated, the residue is dissolved in water and the solution is acidified with acetic acid. The precipitated crystals are collected, washed with water and dissolved in methylene chloride. The solution is dried and evaporated. Crystallization from a mixture of methylene chloride and ethyl acetate gives 10 1-benzyl-8-chloro-5- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid with m.p. 305 to 310 ° C with decomposition.

The material from the previous section is suspended in 30 ml of methylene chloride. Phosphorus pentachloride 0.8 g is added and the mixture is stirred over a mixture of ice and water for 30 minutes. Ammonia gas is then added until the reaction mixture becomes alkaline. After stirring for 15 min. at room temperature, aqueous ammonia is added and the two-phase system is stirred for a further 15 minutes. The methylene chloride phase 20 is separated, dried and evaporated. The crystalline residue is recrystallized from a mixture of ethyl acetate and methanol to give 1-benzyl-8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine 3-carboxamide as a colorless product with m.p. 282 to 284 ° C.

An analytical sample is chromatographed over silica gel (40-fold) using a mixture of methylene chloride and methyl acetate in the 1: 1 volume elution. Mp. 286 to 288 ° C.

Example 21 8-Chloro-6-phenyl-4H-imidazo .51.5-α1.1.41 benzodiazepine-3-carboxaroid

A mixture of 5 g of methyl 8-chloro-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate and 100 ml of methanol containing 20% ammonia is heated to 130 ° C. C in an autoclave for 8 h. The precipitated crystals are collected and recrystallized

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from a mixture of tetrahydrofuran and methanol to give a final product of m.p. 295 to 296 ° C. An analytical sample is recrystallized from a mixture of dimethylformamide and ether and m.p. 296-297 ° C.

The starting material can be prepared as follows:

Methyl 8-chloro-6-phenyl-4H-imidazo .51.5-α1,4-benzodiazepine-3-carboxylate 2 teaspoons Raney nickel is added to a solution of 10 g (0.028 mol) of 7-chloro-a-hydroxyimino. 5-phenyl-3H-1,4-benzodiazepine-2-acetic acid methyl ester in a mixture of 200 ml of methanol and 200 ml of tetrahydrofuran. The mixture is hydrogenated at atmospheric pressure for 5 hours. The catalyst is separated by filtration over the cell and the filtrate is evaporated to dryness. The residue is dissolved in 100 ml of methanol and the solution is treated with 10 ml of triethyl orthoformate and 5 ml of ethanolic hydrogen chloride. After refluxing the mixture for 10 minutes, the solvent is evaporated under reduced pressure and the residue partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The organic phase is dried and evaporated. Crystallization of the residue from ether gives a final product which, after recrystallization from a mixture of methylene chloride and ether for analysis purposes, shows m.p. 235-236'C.

EXAMPLE 22 8-Chloro-6- (2-fluorophenyl) -4H-imidazone-5-alpha] 41-benzo-diazepine-3-carboxamide 2.6 g (0.0125 mol) of phosphorus pentachloride is added to a suspension of 3.55 g (0.01 mole) of 8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid in 200 ml of methylene chloride cooled with a mixture of ice and water. After stirring for 30 minutes, ammonia gas is introduced until the reaction mixture is alkaline. After a further 15 minutes, aqueous ammonia is added and stirring is continued for 30 minutes. The reaction mixture is then partitioned between water and methylene chloride containing 10% ethanol 42

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by volume per volume. The organic phase is dried and passed over a pad of silica gel. The solvent is evaporated and the solid residue is recrystallized from ethanol to give a final product. An analytical sample is recrystallized from a mixture of tetrahydrofuran and ethanol and m.p. 292-294 ° C.

The starting material can be prepared as follows: 11.25 g (0.03 mole) of 7-chloro-5- (2-fluorophenyl) -α-hydroxyamino-3H-1,4-benzodiazepine-2-acetic acid methyl ester is dissolved in a mixture of 750 ml of tetrahydrofuran and 500 ml of methanol on heating. 20 g of Raney nickel are added and the mixture is hydrogenated at atmospheric pressure for 4 hours. The catalyst is removed by filtration and the filtrate is evaporated, finally azeotropically with toluene. The residue is dissolved in 100 ml of methanol.

After addition of 10 ml of triethyl orthoformate and 5 ml of ethanolic hydrogen chloride (5%), the mixture is heated to reflux for 10 minutes. It is then evaporated and the residue partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution. The methylene chloride layer is separated, dried and evaporated and the residue is crystallized from ether to give methyl 8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3 -carboxylate which is recrystallized from a mixture of methylene chloride, ether and hexane and has m.p.

179 to 181 ° C.

A mixture of 1.48 g (0.004 mol) of methyl 8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4-benzodiazepine-3-carboxylate, O, 5 g (0.009 mole) of potassium hydroxide, 50 ml of methanol and 2 ml of water are heated to reflux for 3 hours under a nitrogen atmosphere. The methanol is partially evaporated and the residue is acidified with glacial acetic acid and diluted with water while the solution is still hot. The crystals are collected after cooling in a mixture of ice and water and dried in vacuo to give 8-chloro-6- (2-fluorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine 3-carboxylic acid with m.p. 245 to 247 ° C with decomposition.

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Example 23 8-Chloro-6- (2-fluoro-phenyl) -4H-imidazo [1,5-a] [1,41-benzodiazepine-3-carboxamide

A mixture of 5 g (0.013 mol) of methyl 8-chloro-6- (2-5 chlorophenyl) -4 H -imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate and 75 ml of methanol containing 20 % ammonia is heated in an autoclave to 130 ° C for 18 hours. The reaction mixture from which the product is crystallized is heated in a mixture of methanol and methylene chloride until the dissolution process 10 is complete. By filtration and concentration, a final product is obtained with m.p. > 300 ° C. The analytical sample is recrystallized from a mixture of methylene chloride and ethanol.

The starting material can be prepared as follows:

Methyl 8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate

A mixture of 9 g of 2 - [(amino) -methyxycarbonylmethyl] -7-chloro-5- (2-fluorophenyl) -1,3-dihydro-2H-1,4-benzodiaze-pin ethanolate, 100 ml of toluene and 20 ml of triethyl orthoformate are heated to reflux for 15 minutes. The solvent 20 is evaporated under reduced pressure and the crystalline residue is collected with ether and recrystallized from a mixture of ethyl acetate and methanol to give a final product of m.p. 206 to 208 ° C.

Example 24 8-Chloro-N.N-Dimethyl-6-phenyl-4H-imidazofl-5-alpha-1,4,4-benzodiazepine-3-carboxamide

A mixture of 5 g (0.014 mol) of methyl 8-chloro-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate, 2.4 g (0.043 mol) ) potassium hydroxide, 10 ml of water and 140 ml of methanol are heated to reflux for 6 hours. The solvent is evaporated and the residue is dissolved in water. The solution is filtered and acidified with glacial acetic acid. The precipitated crystals are collected and crystallized from a mixture of methylene chloride and ethanol to give 8-chloro-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid, m.p. 268-270 ° C.

1 g of this acid is stirred together with 1.3 g of phosphorus pentachloride and 100 ml of methylene chloride at room temperature for 2 hours. Dimethylamine is bubbled through the mixture under cooling until a clear solution of basic pH is obtained.

The solution is then washed with sodium chloride solution and water. The methylene chloride layer is dried and evaporated.

Upon crystallization of the residue from ether, the final product is obtained, which is recrystallized from a mixture of methylene chloride and ethyl acetate for analysis and exhibits m.p. 231-233 ° C.

10

Example 25 8-Chloro-6- [2-chlorophenyl] -N. N-diroethvl-4 H -imidazo. 5- a) fl. 41 benzodiazepine-3-carboxamide

A mixture of 2 g of methyl 8-chloro-6- (2-chlorophenyl) -15H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate, 15 ml of hexamethylphosphoric triamide and 1.5 g of lithium chloride heated to 225 ° C. The cooled reaction mixture is partitioned between water and a mixture of methylene chloride and ether. The organic phase is washed with aqueous bicarbonate solution, dried and evaporated. Upon crystallization from ether, the final product is obtained, which is recrystallized from a mixture of ethyl acetate and methanol for analysis and exhibits m.p. 240 to 242 ° C.

Example 26 8-Chloro-6-phenyl-1,N.N-trimethyl-4H-imidazone. 5-alpha-1,1.4-benzodiazepine-3-carboxamide

A mixture of 1.5 g (4.2 mmol) of 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] (1,4) benzodiaZepin-3-carboxylic acid, 1.7 g (8 mmol) of phosphorus pentachloride and 100 ml of methylene chloride 30 are stirred under argon atmosphere for 3 hours, dimethylamine is introduced at room temperature until a clear solution of basic pH is obtained, the solution is washed with ether, dried and evaporated. mixture of ethyl acetate, ether and hexane and recrystallization from ether gives a final product, mp 173 to 175 ° C.

The starting material can be prepared as follows: 45

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A mixture of 7.3 g (0.02 mol) of methyl 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate, 2.24 g (0.04 mole) of potassium hydroxide, 200 ml of methanol and 6 ml of water are heated to reflux for 4 hours. The methanol 5 is partially removed under reduced pressure and the residue is acidified with glacial acetic acid and crystallized by the addition of water. The crystals are collected, washed with water and dried to give 8-chloro-1-methyl-6-phenyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid as a greyish white product.

10 For analysis, it is recrystallized from ethyl acetate, after which it has m.p. 270 to 273 ° C during decomposition.

Example 27 8-Chloro-6- (2-fluorophenyl 1- 1-methyl-N-phenyl-4H-imidazo [1,5-a] 1,4-benzodiazepine-3-carboxamide 1.3 g (6.25 mmol) phosphorus pentachloride is added to a suspension of 1.9 g (5 mmol) of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid in 100 After stirring for 30 minutes under cooling over a mixture of ice and water, 7 ml of aniline is added and stirring is continued for 30 minutes at room temperature. The reaction mixture is partitioned between 10% aqueous sodium carbonate solution and methylene chloride. Crystallization of the residue from ether and recrystallization from a mixture of methylene chloride and ethanol yielded a final product which was recrystallized for analysis from a mixture of tetrahydrofuran and ethanol and then mp 228 to 2888 ° C.

Example 28 8-Chloro-N-cyclopropyl-6- (2-fluoro-phenyl) -1-methyl-4H-imidazone-5-alpha [1,4-benzodiazepine-3-carboxamide 1.3 g (6.25 mmol) phosphorus pentachloride is added suspension of 1.9 g (5.1 mmol) of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid in 100 ml of methylene chloride. After stirring for 30 minutes over 46

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to a mixture of ice and water, 3 ml of cyclopropylamine is added and stirring is continued for 10 minutes. The reaction mixture is washed with aqueous sodium carbonate solution, dried and evaporated. The residue is passed over a pad of silica gel using 10% (volume per volume) of ethanol in methylene chloride.

Crystallization of the product from a mixture of ethyl acetate and hexane gives a final product in the form of crystals having m.p. 196 to 197ec.

Example 29 8-Chloro-6- (2-chlorophenyl) -1N.N-trimethyl-4H-imidazone. 5-aryl. 41-benzodiazepine-3-carboxamide

A stirred suspension of 3.6 g (0.0093 mol) of 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiaze-pinin 3-carboxylic acid in 75 ml of dichloromethane is cooled in an ice bath and treated with 2.1 g (0.01 mole) of phosphorus pentachloride in portions. The reaction mixture is protected by a drying tube and stirring in the cold is continued for an additional 30 minutes. With continued cooling, dimethylamine 20 is bubbled through the solution for 5 minutes and stirring is continued for another 30 minutes. The mixture is evaporated to dryness at reduced pressure. The rubbery residue is stirred with water and made basic with ammonium hydroxide solution. Extraction with methylene chloride followed by drying and evaporation in vacuo gives a tan foam. This foam is dissolved in 600 ml of boiling ether and filtered to remove any insoluble material. After concentrating the filtrate on a steam bath to ca. Filter 250 ml again. Further concentration to approx. 100 ml of scraping from time to time causes crystallization to begin. The flask is removed from the heat source and cooled at room temperature overnight. The greyish white prisms are separated by filtration, washed with ether and air dried on the filter funnel to give an end product with m.p. 225-230 ° C. Upon recrystallization of a sample from a mixture of benzene and ether, the melting point is raised to 228 to 232 ° C.

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The starting material can be prepared as follows:

A stirred solution of 4.1 g (0.01 mole) of ethyl 1 -3-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine pin-3-carboxylate in 100 ml of methanol containing 3 ml of water 5 and 1.2 g (0.02 mol) of potassium hydroxide are heated under reflux and under nitrogen atmosphere for 4½ hours and concentrated at reduced pressure to remove the methanol. The residue is dissolved in cold water and acidified with acetic acid to give a greyish white solid. After air drying on the filter overnight, 8-chloro-6- (2-chlorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylic acid is obtained.

Recrystallization of a sample from a mixture of methylene chloride and ethanol in a 1: 1 ratio gives white small plates, m.p. 265 to 267 ° C with decomposition.

15

Example 30 8-Chloro-6- (2-chlorophenyl) -1-dimethylaminomethyl-4H-imidazone-5,1,4,4-benzodiazepine-3-carboxamide

A mixture of 0.44 g (1 mmol) of methyl 8-chloro-6- (2-20 chlorophenyl) -1-dimethylaminomethyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3 -carboxylate and 15 ml of methanol containing 20% ammonia are heated for 16 hours to 130 ° C in an autoclave. The solvent is evaporated and the residue is crystallized from a mixture of ethanol and ether to give a final product.

An analytical sample is purified by passage over silica gel using a mixture of methylene chloride and ethyl acetate in the 1: 1 volume ratio and crystallization from ethyl acetate to give m.p. 242-245'C.

The starting material can be prepared as follows: Methyl 8-chloro-e- (2-chlorophenyl 1 -1-dimethylaminomethyl) 4-a-imidazo [1,5-a] 1,4] benzodiazepine-3-carboxylate

A mixture of 0.435 g (1 mmol) of methyl 8-chloro-1-chloromethyl-6- (2-chlorophenyl) -4H-imidazo [1,5-a] (1,4] benzodiazepine-3-carboxylate, 15 ml tetrahydrofuran and 1.5 ml of dimethylamine are heated in a sealed tube at 100 ° C for 3 hours, the solvent is evaporated and the residue is partitioned between 48

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methylene chloride and aqueous sodium bicarbonate solution. The organic phase is dried and evaporated and the residue is crystallized from ether to give a final product. An analytical sample is recrystallized from a mixture of ethyl acetate and hexane and m.p. 181 to 183 ° C.

Claims (4)

An analogous method which is a further development of the method of Patent No. 157,615 for the preparation of therapeutically active imidazo [1,5-a] [1,4] diazepine compounds of the general formula 'Vr *' - OCX - 15. which A represents -C (R6) = N-, R1 represents hydrogen, lower alkyl, phenyl, mono-lower alkylamino - lower alkyl, dilute alkylamino - lower alkyl, pyridyl or benzyl, R2 means the group -CONR12R13, in which R12 means hydrogen, lower alkyl, or cycloalkyl of 3-7 carbon atoms, and R 13 represents hydrogen, lower alkyl or phenyl or the group - (CH 2) nNR 14 R 15, in which R 14 and R 15 each represent hydrogen or lower alkyl, and n is 0 to 4, or R 12 and R 13 together form part of pyrrolidine ring, R 6 means phenyl or halophenyl, and ΘΓ means the group 30 * 4 a) b) where X means chlorine, bromine or iodine and R4 means halogen or nitro, or pharmaceutically acceptable salts of these compounds, characterized by reacting a compound with formula DK 162495 B 'ΧΓ. OCX. "in which R 1, A and are as defined above, 10 and Y are lower alkoxy or chlorine, with an amino compound of the formula HNR 12 R 13, in which R 12 and R 13 are as defined above, provided that when Y is lower alkoxy, and R13 is the group - (CH2) nNR14R15, where n = 0, R12 means hydrogen, whereupon, if desired, a racemic compound of the formula I yds optical enantiomer dissolves and if desired converts a compound of formula I into a pharmaceutically acceptable salt thereof. A process according to claim 1 for the preparation of 8-chloro-6- (2-fluorophenyl) -1-methyl-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide, characterized by treating a compound of formula XV wherein: "V4, in which R4 is chlorine in (zU represents B? - [- | 18 position, R1 is methyl, and R6 is 2-fluorophenyl, with ammonia) -25 ak. A process according to claim 1 for the preparation of 8-chloro-6- (2-chlorophenyl) -1, N, N-trimethyl-4H-imidazo [1,5a] -thieno [3,2-f] [1,4 ] diazepine carboxamide, characterized by treating a compound of formula XV wherein ecc means XX in which X is chlorine, R 1 is methyl and R 6 is 2-chlorophenyl, with dimethylamine. Process according to claim 1 for the preparation of 8-chloro-6- (2-chlorophenyl) -4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxamide, characterized in that treats a compound of formula XV in which is DK 162495 BR <-fY, wherein R4 is chlorine at the 8-position, R1 is hydrogen, and R6 is 2-chlorophenyl, with ammonia.