CA1067491A

CA1067491A - Diazepine derivatives

Info

Publication number: CA1067491A
Application number: CA235,138A
Authority: CA
Inventors: Armin Walser; Rodney I. Fryer
Original assignee: F Hoffmann La Roche AG
Current assignee: F Hoffmann La Roche AG
Priority date: 1974-09-11
Filing date: 1975-09-10
Publication date: 1979-12-04
Also published as: HK63381A; NO147109C; KE3173A; NO147914B; DK157615C; NL7510620A; JPS51125099A; NO148188C; SE433080B; SE7902666L; SE7509991L; NZ178635A; SE425785B; FR2285890B1; NO146573B; NO148188B; FI752517A; PL106563B1; HU174752B; AU505998B2

Abstract

ABSTRACT OF THE DISCLOSURE

This invention is directed toward pharmacologically active com-pounds of the formula wherein A is ; R1 is selected from the group consisting of hydrogen, lower alkyl, phenyl, alkoxy lower alkyl, substituted phenyl, pyridyl and aral-kyl; R2 is selected from the group consisting of hydrogen and lower alkyl; R3 is selected from the group consisting of hydrogen and lower alkyl, R5 is selected from the group consisting of hydrogen, alkanoyloxy and hydroxy; R6 is selected from the group consisting of phenyl, mono-substituted phenyl, di-substituted phenyl, pyridyl, and mono-substituted pyridyl; and is selected from the group consisting of a) , b) , c) d) and wherein X is hydrogen, chlorine, bromine or iodine, T is hydrogen or lower alkyl and R4 is selected from the group consisting of hydrogen, halogen, nitro, cyano, trifluoromethyl, lower alkyl, substituted amino, amino, hydroxy lower alkyl and lower alkanoyl; and the pharmaceutically acceptable salts thereof, Also provided are methods for the preparation of these compounds as well as pharma-ceutical formulations which contain the active compounds of this invention.
The compounds of the formulae illustrated above and their analogs are useful as anticonvulsants, muscle relaxants, anxiolytic and sedative agents.

Description

10~ 91 T~is invention relates to the pharmaceuticall~ active :Imidazo Il,S-a]rl,4]dia7epine compounds series. The chemical structure of these compounds may ~e depicted by the following formula:

~1 ~ N ~ R2 : A 5 w~erein A ls -f=N-; Rl is selected from the group consisting of lower alkyl and phenyl; R2 is selected from the group consisting of hydrogen and lower alkyl; R3 is selected from the group consisting of hydrogen and lower alkyl;
R5 is selected from the group consisting of hydrogen, lo~er alkanoyloxy and hydroxy; R6 is selected from the group consisting of phenyl, phenyl mono-su~stituted ~y halogen, phenyl di-substituted by halogen and nitro and pyridyl; and ~ ls selected from the group consisting of ~;

X ~ X

a) ~) and c) wherein X ls hydrogen or chlorine, and R4 is selected from the group consist-ing of hydrogen, halogen, lower alkyl, lower alkanoyl amino, lower alkylamino, amino, hydroxy lower alkyl and lower alkanoyl; analogs thereof of the formula ~hereln A is selected from the group consisting o~

~`
: 10~749~
~ ~-iN~ CH - N C = N
\
R6 H ~ R

d) e) and f~
: ~ ~
is the group of formula a) above, Rl, R2, R3 and R6 are as in formula I above, except that in formula IA~with A being structure e), R6 is not nltro-substltuted, and pharmac:utically acceptable acid addition salts of all these compounds.
AS used in this disclosure, the term "lower alkyl" comprehends~both `straight~and~branched~chainl(CI-C7) carbon-hydrogen~radicalsj preferably Cl-C4 carbon-hydrogen radica~s such as methyl, ethyl, propyl, isopropyl, butyl and the like.
I0 By the term "lower alkanoyl" as utilized herein, an acyl moiety of ;~
: ~ . : .
a Cl-C7, preferably a Cl-C4 alkanoic acid is intended, e.g., acetyl, propionyl, butyryl and the like, i.e.,~moieties~of the~formula R20-C-~, wherein R20 1S I

CI-C6-alkyl or hydrogen. ~Also as~utiliz~ed herein~, the~term "low~er~alkanoyl"~
comprehends a~protected ketone such as~an acetal or ketal having 2 t~ 7 carbon atoms, e.g. a group of the formula~

~: : /C\ ~ : :

: : . : : ~

~ ~
wherein ~ is Cl-C6-alkyl or hydrogen. The ketal or aldehyde protecting group is utilized to prevent conversion of the contained ketone or aldehyde (R -I-)in oxidation, reduction and condensatlon reactions.
O ' , ~ Fhe term "halogen" is used to include all four forms thereof? i.e., - chlorine, bromine, fluorine and iodine.
The mono-substitu~nt halogen is preferably in the 2-position and the :

~ 2 .

16~67491 di-substituents are suitably in the 2,6- or 2,5~position of the phenyl moiety.
In the case of di~ferently substituted R3 and R5 substituents, opti-cal isomerism will occur and such optical antipodes and racemates are within the ambit of this invention.
~- Preferred compounds are those wherein Rl is lower alkyl, preferably methyl, R3 and R~ are hy~rogen; ~ is R4 ~ wher~ m R4 is located preferably in the 8-position of ~he imidazobenzodiazepine lecuie and is~
hydrogen~ar h~slogen, preferably chlorine ~A is -C=N- wherem R6~is phenyl mono-substituted by halogen preferably fluoro, with the fluoro substituent in the 2-position of the phenyl moiety, e.g. compounds of the formula where;n Rl' and R2 are as defined in formula IB' below.
Thus, it is apparent from the above, an especially preferred genus included within the purview of the present invention encompasses a compound of the formula 1 y~ ~ 2 R4 ~ ~ ~ IB' - ~F

wherein Rl' is lower alkyl, preferabl~ ~ethyl, R4 is hydrogen or halogenJ most 2n preferably chlorine; and in a most preferred embodiment when positioned on the fused benzo portion of the imidazobenzodiazepine is in the ~-positlon;thereof, R60 is phenyl mono-substituted by halogen, with fluorine being the preferred halogen. Preferably the substituted fluoro is positioned in the 2-position of 7~9~

the pllenyl moiety. R2 is selec~d r~m thQ group consisting of hydr~gen and lower alkyl.
Another preferred class of compounds ~alling within the scope of formula I are those wherein Rl't R2, R4, R5, R6 and A are as in formula IB' above and R3 is lowe~ alkyl, pre~erably methyl, e.g. compounds of the formula Rl ~ N ~ R2 ~ Cl ~ IC

Compounds of formula IC and their pharmaceutically acceptable salts exhibit optical isomerism. Such a compound has been resolved into its opti-cal enantiomers by a procedure similar to the one generally outlined in Ad-vanced Organ~c Chemistry, L. Fieser and M. Fieser, 1961, pp. 85-88, Reinholt Publishing Co. Both the optical isomers and the racemic form of compound IC
j exhibit pharmacological activity. For example, in the case of the tartrate salt of compounds of formula IC the ~) isomer is considerably more active than the ~-) isomer. The less active (-~ isomer may, if desired, be converted to the active racemic form thereof such as by treatment with a non-aqueous base, e.g. sodium tertiary butoxide, in the presence of an organic solvent in which the isomer is soluble.
The expression "pharmaceutically acceptable salts", is used to in-clude salts with both inorganic and organic pharmaceutically acceptable acids ..
such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phos-phoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, paratoluenesulfonic acid and the like.

Such salts can be formed quite readily by those skilled in the art, with the prior art and the nature of the compound to be placed in salt form In view.
The most preferred pharmaceutically acceptable acid addition salts -of the compounds of formula IB and IC respectively are:
8-chloro-6-~2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]ben~o-diazepine maleate;

~,, ~
-4_ .

~06749~
8-chloro_1,4-dimethyl-6-~2~fluorophenyl~-4}~-imidazo~1,5-a}[1,4]benzo-dia2epine malea~e.
Also within the ambit of the instant invention are compounds which are obtained by ring opening of formula I compounds wherein ~ is R4-phenyl.

Such compounds are of the ~ormula Rl~ N~ R2 R4~ I D

R6 :

wherein Y is the anion of an organic or inorganic acid, and Rl, R2, R3, R4 and R6 are as in formula I.
It has been found that certain compounds of formula I in solution open to corresponding compounds of formula ID. Such open compounds exist in a pH-dependent equilibrium in solution with compounds of formala I, i.e. their corresponding ring closed compounds. The compounds of formula ID can be iso-lated as acid addition salts by treatment~of their corresponding closed rm g compounds with an aqueous mineral acid followed by evaporation of solvent.
When isolated, these salts exhibit pharmacological activity comparable to their corresponding closed ring parents.
The imidazo[l,5-a]~1,4]diazepine compounds of the formula I, their analogs of formula IA and the pharmaceutically acceptable acid addition salts of these compounds as well as the compounds of ID can be prepared by a process which comprises a) for the preparation of a compound of for~ula N ~ R3 IA~

C = N

wherein Rl, R2, R3 and R6 are as in formula I abo~e and ~ is the group - ~- ~ , , j~ , ~L067491 of formula (a) above, o~idising a corresponding compound of ormula I into the N-oxide thereof with an organic peracid, or b) converting~a compound of formula : IA~ into a corresponding compound of formula I wherein R5 is lower alkanoyloxy by treatment with a lower alcanoic acid anhydride by methods known in the art> or c) hydrolysing a compound of formula I wherein R5 is alkanoyloxy to a corresponding compound of formula I wherein R5 represents hydroxy by methods known in the art, or d) for preparing a compound of formula ; Rl ~ N ~ R2 wherein Rl~ R2~ R3, R4, R6 and ~ are as in formula IA~ but R6 is not : nitro substituted, reducing a corresponding compound: of formula 1, or (e) dehydrating a compound corresponding to formula IA, but wherein A is ----C ---N to the corre~pondi~g compound of for~ul~ I by methods known In OH : l R6 ~, the art, or f) deacylating a compound corresponding to formula IA but wherein ~ A is ~ C-~--N , wherein R'7 i5 acetyl, mesyl or tosyl, to the correspond-: ¦ R'7 ~ :

ing compound of formula I by methods known in the art, or g) oxidising a com-pound of formula IA" to the corresponding compound of formula I by treatment with an oxidising agent selected from the group consistlng of chromic acid, silver oxide, silenium dioxide, mercuric acetate, mercuric oxide, manganese dioxide, ferric chloride and ferricyanide, or h) cyclizing a compound of formula : -6-~36749~L

Rl\~N~7/R~

R4 ~ ~ 3 H
R

wherein Rl, R2, R3, R4 and R6 are as in formula I, to a corresponding compound of formula I, OT i) for preparing a compound of formula IA wherein A is ~ :

C~ N~ re~c~ing a correspondine compound o~ formuls I;with~ethylene~oxlds in the presence of a Lewis acid catalyst or reacting a corresponding compound ~: of formula Rl ~ N ~ R2 r ~ ~: : n 6 XXIV :
~ : wherein Rl, R2, R3, R4 and R6 are as in formula I, except that R4 is not amino, ; ~ 10 lower alkanoylamino or lower alkylamino, with ethanolamins, or i) hydrolysing : a ketal group present as R4 substituent in an imidazo-benzodiazepine to the corresponding ketone substituent, or k) reduclng a ketone group present as R4 substituent in an imidazo-benzodiazepine to the corresponding secondary or tertiary lower alkanol substituent, or l) dehydrogenating a compound of formula R ~ N y R2 ~ R3 : . . A

wherein A is I N , Rl, R2~ R3~ R4, 6 ~ are as in formula I but !~

~674g~

R6 i~ not nitro substituted, to a corresponding com~ound of formula lJ or m) subjecting a compound of formula I, wherein ~ represents an aminophenyl group, to a Sandmeyer Reaction yielding the corresponding chloro or bromo sub-stituted compound, or n) hydrolysing a compound of formula I wherein R4 is acyl-amino to a correspond* g compound of formula I wherein R~ is amino, or o) oxidising a compound of formula Y

H
.
- .

~ wherein A is ---C ~ and Rl, R2, R3~ R~ R6 and ~ are as in formula VII, to a corresponding compound of formula I by treatment with an oxidising agent selected from the group consisting of chromic acid, silver oxide, selen-ium dioxide, mercuric acetate, mercuric oxideJ manganese dioxide, ferric chlor-.. .
ide, and ferricyanide or p) resolving a racemic compound into its optical en-antiomersj or q) conver~ing a compound of formula I or an anlog of formula IA
into a pharmaceutically acceptable acid addition salt.
Compounds of the formula IA' are formed by the conversion of cor-responding formula I compounds into the N-oxides thereof. This conversion is effected by oxidiSing a fol~ula I compound with an organic peracid. A con-ventional organic peracid, such as peracetic acid,~perpropionic acid, m-chloro-perbenzoic acid, etc., can be utilized in carrying out this reaction. The oxi-dation can be effected at room temperatureJ or above or below room temperature.
Compounds of the formula IA' may be then utilized to produce compounds of formula I, wherein R5 is lower alkanoyloxy or hydroxy, by methods known in the art, such as, ~or example, a Polonvski rearrangement utilizing an acid an-hydride to form the lower alkanoyloxy radical which may be convert&d to the hydroxy by treatment with an alkali metal hydroxide such as sodium hydroxide.
An example of such a Polonvski rearrangement is found in United States Patent ! -8-s~l .J
~ i ~06749~L
No. 3,296,249 issued Janualy 3, 1967 to S.C. Bell.
Compounds of the formula IA" are formed by thereduction of corres-ponding formula I co~pounds which may then be converted to other compounds of the formula R6 :

wherein Rl, R2, R3, R4 and R6 are as in formula IA and R7 is hydroxy, acetyl, mesyl or tosyl.
The reduction of formula I compounds to IA" compounds ls accomplished by any suitable reducing agent, but most preferably accomplished by hydrogen in the presence of a platinum oxide catalyst or zinc in the presence of acetic acid. These compounds IA" may be converted to IA"' compounds having an R7-.radical other than hydroxy by reaction with, for~example, tosyl chloride~
mesyl chloride or acetyl chloride.
This process aspect is conveniently effected in the presence of an inert organic solvent such as an alkanol, e.g. ethanol and methanol, an ether such as diethyl ether and tetrahydrofuran, dimethylformamide and the like. Suitably, an acid acceptor is provided to the reaction zone to accept the hydrogen chloride formed. Suitable acid acceptors are tertiaTy amines, e.g. triethylamine, pyridine and the like.
Temperature and pressure are not critical aspects of the first stage of the process involving the conversion of the compound of the formula I above to the corresponding compound of the formula IA"'. However, the reaction is most preferably effected at about room temperature and atmospheric pressure for the preparation of compounds IA", and room temperature or above for the conversion of compounds IA" to IA"' bearing an R7 radical other than hydroxy.
Reduction of IA' compounds with hydrogen in the presence of platinum catalyst and acetic acid leads to IA"' compounds wherein R7 is hydroxy.
.

~ 9 ~67491 Compounds of formula IA"', wherein R7 is hydroxy, may be converted to the corresponding formula I unsaturated imine by treatment with an ~cetic anhydride/pyridine mixture. No other solvent is necessary for this reaction and the temperature is not critical although the reaction is best e~fected at room temperature.
Compounds of formula IA"' above, wherein R7 is acetyl, mesyl or tosyl, may be converted to the corresponding formula I unsaturated imine by treatment with a non-aqueous base, e.g. potassium tertiary butoxide, in the ~presence of an inert solvent, e.g. TH~, DMF, etc. Such a reaction and the conditions at which it is run are well known in the art; see for example United States Patent No. 3,625,957 issued December 7, 1971 to Fryer et al. ~, Compounds of formula IA" above may be converted to the correspond-ing formula I compounds by oxidation of the secondary amine at the 5-position.
Such a selective oxidation may be accomplished by known oxidants selected from I the group consisting of chromic acid, silver oxide, selenium dioxide, mercuric acetate, mercuric oxide, manganese dioxide, ferric chloride and ferricyanide, and reaction schemes; see for example United States Pa~ent No. 3,322,753 issued May 30, 1967 to Fryer et al.
Compounds of the formula IA where A is ~ may be ormed R6 o V
by the direct reaction of formula I compounds with ethylene oxide in the presence of a Lewis acid catalyst or by the reaction of a compound of the formula + ~ I XXIII

wherein Rl, R~, R3, R4 and R6 are as in formula I except that R4 is not amino, lower alkanoyl amino or lower alkylamino, with phosphorus tribromide and sub-sequent treatment of the intermediate ~XXIV) with ethanolamine as shown in ~`

` ~ ~
~L~6749~
the fo`llowing reac~ion scheme:

84 ~ ~ R3 XXIII XXIV 6 IA""
The compounds of formula XXIII may be formed by the reaction of a .
~ ~ compound of the formula ID with sodium nitrite in the presence of a compati-:
ble solvent such as water or dilute mineral acid. The temperature of the reaction may be -10C to room temperature. The reaction of formula XXIII
compounds with phosphorus tribromide is effected, preferably in an inert organ-ic solvent such as dichloromethane at about room temperature although such temperature is not critical. ~ ~ ~

The reaction of the compound of formula XXIV with ethanolamine is effected in situ, i.e. with a suitable inert solvent such as:dichloromethane, at a temperature range of -10C to reflux, with about room temperature pre-ferred.
The direct reaction of formula I compounds with ethylene oxide is preferably catalyzed by a Lewis acid, e.g. titanium tetrachloride, borDn tri-fluoride, etc.
As stated above, compounds of formula I may be directly reacted~with ethylene oxide to produce formula IA"" compounds, i.e. oxazolo type compounds.
Reaction parameters and conditions to effect such a reaction are known in ~he art; see for example United States Patent No. 3,868,362 issued February 25, I975 to ~ryer et al.
In compolmds of formula I and their analogs wherein the ketal group e.g. R~ /
/ \
OL~O

~1 !

1(~6~4~L

is present as a subs~ituent in an imidazobenzodiazepine, such ketal group may be converted ~o ~etono by subjectin~ the kctal group to a mild acid hydrolysis. The ketone can then be converted to a secondary or tertiary alcohol which is racemic in nature. The reaction conditions therefor, for the above two steps, are found in United States Patent~
No. 3,846,410 issued November 5, 1974.
The compounds of formula VII may be dehydrogenated to yield the corresponding compounds of the~formula 1.
Preferred reactants for the dehydrogènation include manganese dioxide and palladium-on-carbon, although potassium permanganate may also be utilized. Solvents which may be utillzed include chlarinated hydro-carbon solvents, aromatic hydrocarbons, dimethylformamide, etc. The dehydrogenation is carried out at room temperature or above, i.e. in the range of aboùt 25C to 200C.
Conversion of compounds of formula 1, wherein R4 is amino, to compounds wherein R4 is chlorine or brom me may be suitably effected by, for example, the Sandmeyer Reaction wherein the amino group is replaced by a chloro or bromo group. The treatment of a formula I
compound, wherein ~ ~is mlnophenyl~ with excess sodium nitrite in the presence of a copp~r sulfate/sodium sulfite mixture and utilizing as a solvent dilute sulfuric acid may result in an intermediate of the formula Rl ~ N~R2 R ~
, N ~ - XXIII' R4' ~ 0 ~ OH

~ 6 wherein Rl3 R2, R3 and R6 are as in formula I and R4' is chlorine or bromine, which may then be converted to an analogous formula I compound. This process may be effected in a tl~o-step sequence ..~..~, .
~ - 12 -`~L06~4~

without isolation of the intermediate ~ormed by treatment of the above formula XXIII' compound with phosphorustribromide in an inert organic solvent, e.g. dichloromethane, at about -10 to 25C: ~although temperature is not critical) and then subsequent treatment is situ with ammonia, preferably liquid ammonia, which is allowed to warm to room temperature.
It is obvious to one skilled in the art that certain other substituents ma~ also be attacked during the above reactions, but such vulnerable groups may be blocked by a suitable protecting group or :
modified before the above reaction sequence is carried out. Such mPthods ~ ~ of modifying or protecting groups subject to attack are well known ;~ in the art.
The R4- acylamino group may be converted to amino by subjecting the compounds to a mild hydrolysis.
Compounds of the formula VII' can, if desired, be oxidized directly to analogous compounds of the formula I using an oxidant : : :
selected from the group consisting of chromic acid, silver oxide, selenium dioxide, mercuric acetate, mercuric oxide, manganese dioxide, ferric chloride and ferricyanide, preferably manganese dioxlde in toluene or benzene solution. Reaction conditions utilized and are found in United States Patent No. 3,322,753 issued May 30, 1967 to Fryer et al.
The compounds of formulae VII and VIII above can be prepared according to the following processes.
In one of the aforementioned processes the compounds of formula VII above may be prepared by the nitrosation of a compound of the formula :

~ ~ 11 wherein A is -C=N- or -C=N- ;
I ~ 0 -10679~91 ' R~ is hydr_gen or lower alkyl and ~ ~ and R6 are as described in formula I, to produce a compound of the formula wherein A, R3 and ~ ~re as described m for~ui~a II.

Such a nitrosation may be effected by "in situ formed" nitrous ~- acid. Reagents which may be employed include ~1) alkali metal nitritesl ~`
e.g. sodium nitrite, in the presence of OTganic or inorganic acids, e.g. glacial acetic acid, and aqueous or non-squeous so1vents;~2)~
alkyl nitrites, e.g. methyl nitrite, in the presence of an inert ~, solvent such as an alcohol, chlorinated hydrocarbon or, for example, dimethylformamide; and ~3) a nitrosy}~chloride gaseous solution in an m ert solvent and in the presence of an acid acceptor such as pyrid m e.
Such a nitrosation reaction should be effected at around or below room temperature, i.e. in the range of -20C to 25C.
~ C1~3 The 2-position nitrosoalkylamine, e.g. -~-NO, represents a ~`
"leaving group". Equivalent leaving groups which may be utilized as

2-position substituents include groups such as alkoxide, e.g. -0CH3;
alkylthio, e.g, -SCH3; halo, e.g. chloro; cyano, i.e. -CH, and phosphate, e.g. _ e " ~ Reactions which form ' the alkoxide and alkylthio 2-position substituents are aell known in the art; see for example G.A. Archer and L.}l. Sternbach, Journal of Organic Chemistry, 29, 231 (1964) and United States Patent No. 3,681,341 issued August 1, 1972 to Pryer et al.

Compounds of formula III may then be condensed with a ? l - 14 -. ~,, -:

: `
~6749 nitroalkane tc form a novel intermediate of the` formula H ~
A ~ IV

wherein R2 is hydrogen or lower alkyl, A, R3 and ~: ' . `
are as described in formula II.

The condensation reaction is effected with a nitroalkane . .
(R2-CH2-N02), i.e. nitromethane, nitr~oethane,~etc., in the presence of a base which is strong enough to generate the nitroalkane anion.
Suitable bases include the alkali m:tal or alkaline earth metal alkoxides, e.g. potassium tertiary butoxide; amides, e.g. lithium amidei or hydrides, e.g. sodium hydrid:. The reaction is preferably carried out in an inert solvent, such as dimethylformamide, dimethyl-sulfoxide, or an ether, e.g. l~IF, at temperatures below or above room ~1 temperature, i.e. in the range of -5~C to 150C., preferably at about room temperature.
Compounds of formula IV may th:n b: cat:lytically hydrogenated, for example, with Raney nickel in the presence of hydrogen or by oth:r reductants such as llthium aluminum hydride Cwith limitation that A is not N-oxid:) to produce a~compound of formula \2 H ~ R2 ~ ~ ~ > 3 V

wherein A is -C-N-; R3, ~ and R6 are as in ;
Formula II, except that R6 is not nitro substituted, and R2 is hydrogen or lower alkyl.
The exclusion of nitro above from the substituent groups iO67~91 present results ~rom the conversion o$ nitro into amino under the reaction conditions empl~ed ln the ste~ IV -~ V.
Solvents sulta~le for hydrogenation with Raney nickel include alcohols, e.g. ethanol; ethers, e.g. TH~, diethylether, etc.; hydrocarbon solvents, e.g. toluene; and dimethylformamide. The reaction temperaturG
may ~e above OT below room temperature (i.e. -50C to 150C) and the re-action may be carried out with or without pressure, i.e. pressure of one atmosphere or higher.
Solvents suitable ~or hydrogenation employing a reductant such as lithium aluminum hydride include ethers, e.g. TH~, dioxane, diethylether and mixtures of ethers and hydrocarbon solvents, e.g. THF and benzene.
The reaction may be carried out from below room temperature to reflux temperature, i.e. preferablr in the range of -50C to 60C.
The compounds of ~ormula V may then be acylated with an acylating agent such as an acid halide or acid anhydride, i.e. a group of the formula (RlC0~20 wherein Rl is as in formula I, e.g. acetic anhydride and acetyl chloride, to produce a compound of the formula H
RlOC y ~ 2 XH VI

wherein A, R2, R3 and ~ are as descrlbed in 2a ~ormula V, Rl is as in ~ormula I and Y is hydrogen or -CORl.
In acylating the compounds of formula V to compounds of formula VI, there may be present a mixture consisting of the predominant monoacylated product, i.e. wherein the MH2-group of V (position 2) is converted to NHCORl, and the diacylated product wherein both the NH2 of ~ ~position 2) and l-position nitrogen are acylated. The yield of ~V~7491 diacylated prcduct ma~ ~e lncreased ~y su~ecting the compo~mds of ormula to more rigorous conditions, i.e. excess o~ acylating agent and increased reaction time.
The acylation is preferably carried out in the presence of an aqueous or non-aqueous solvent, e.g. water, methylene chloride, benzene, chloroform, etc., and preerably ~ith an acid acceytor such as an organic or inorganic base, such as triethylamine, pyridine or an alkali metal carbon-ate. The compounds of formula VI may then be cyclized to the compounds of the formula VII.
The cyclization reaction is effected with a dehydrating agent such as phosphorus pentoxide, polyphosphoric acid or other suitable acid catalysts, i.e. organic or inorganic acids, e.g. conc. H2SO4. A solvent is not required, but a solvent such as an aromatic hydrocarbon solvent, e.g. toluene, xylene, may be employed. The reaction is carried out at a temperature range of from a~out 100C to 200C.
The compounds o ormula ~ may also be reacted with an acylating agent such as an orthoester, e.g. triethylorthoacetate; an orthoamide, e.g.
the dimethylacetal of N, N-dimethylformamide, or a compound o~ the formula CH

Nl CH3 ICH3 CH N CH
Nl-CH3 CH3 ~
optionally in the presence of an acid catalyst, such as an organic or in-organic acid, e.g. p-toluene sulfonic acid, phosphoric acid, etc., and at room temperature or above, i.e. 25C to 150CJ in which instance the cycliza-tion to compound ~IT occurs spontaneously. Other useful acylating agents include esters, e.g. methyl acetate; amidines, e.g. acetamidine; nitriles, e.g. acetonitrile; and ester imidates, e.g. a compound o the ormula CH3~CaNH

3LlD67~
The above novel process ma~ proceed, if deslred, ~rom intermediate compounds IV or ~ to compounds of formula I without the requlrement of isolat-ing any formed intermediate compounds including the compounds of formula VII
before proceeding to the next process step.
It should be noted in acylating the compounds o~ Formula ~ to the compounds of Formula VI, when R4 is amino, that the amino may also be acylated to acylamino. The acylamino ma~ be converted back to amino by subjecting the compounds of formula VII to a mild hydrolysis.
The reaction of a compound of the formula ~ with acetic acid and zinc or any other suitable reductants, e.g. hydrogen in the presence of a cata-lyst, e.g. platinum in dilute acetic acid solution, produces a compound of the formula NH
H r v .

~ ~ H
A

wherein A is - CH-NH- and R2, R3, ~ and R6 are as in ~ormula V.

Depending on the above method of reduction chosen, formula V~ when R2 is hydrogen can be isolated as a racemic mixture of either o~ the two pos~
sible diastereomers.
A compound of the formula ~' may be conveTted to its dihydroimidazo derivative of the formula 1 y / 2 A H ~r~

f"
wherein ~ , A, R2 and R3 are as in ~ormula V' and Rl is hydrogen or lower alkyl, with retention of sterochemistry~ by utillzing the direct reaction set ~ 18 ~

~L~67491 forth a~ove, i.e. the reac~ion o~ formula V compounds with an acylating agent such as an orthoester, e.g. triethylorthoacetate, and maintaining the reaction parameters set forth above for such a reaction.
Compounds of foTmula VII' can also be prepared by reduction of a compound of formula VII by utili~ing reductants as mentioned above, e.g. ace-tic acid and zinc or H2/platinum catalyst in dilute acetic acid, with the partlcular steroisomer produced dependent on the reductant chosen.
: ~ Another process to produce the novel intermedia~es of formula V, .
- where R6 is other than nitro substituted consists of the reduction of com-pounds of the formula : ~-~ : CN :~
I
~ ~ ~ N ~ R3 ' ' W, /\H X
A

wherein A is -C-N- and R3, ~ and R6 are as described m formula:II ex- :
~: ~ 6 ~ :

cept that R6 is not nitro substituted.
The reduction comprises the reaction of the compounds of formula X with a known reductant su.ch as Raney nickel in the presence of hydrogen or by other reductants such as lithium aluminum hydride. Solvents suitable for hydrogenation with Raney nickel include alcohols, e.g. ethanol; ethers e;g.
THF; hydrocarbon solvents, e.g. toluene; and dimethylformamide. The reaction tamperature may be above or below room tempera.ture (i.e. -50C to 150C) and the reaction may be carried out with or without pressure, i.e. pressure of one atmosphere or higher.

Solvents suitable for hydrogenation employing a reductant such as lithium aluminum hydride include ethers, such as dioxane, diethyl ether and TIIF. The reaction may be carried out from below room temperature to reflux temperature, preferably in the range of -50C to 60C.
A variation of the above process comprises a mild acid hydrolysis ~ . f ~ -19-1~67~

of the compoun~s Gf formula X to produc~ compounds of the formula H

R3`
, ~_ /
wherein A, R3 and ~ ~ are as in formula X. ;

The mild acid hydrolysis is suitably effected by a dilute mineral .
acid, e.g. aqueous H2S04 in aqueous alcohol. The reaction temperature may range from room temperature, i.e. about Z5C, to above room temperature, i.e.
about 60C. The compounds of formula Xl may~then be reduced to the novel intermediates of formula V.
~; Compounds of formula I~ above may also he~produced by the success-:~ : : :
10 ive reaction of the compounds of the formula N
A

.
~/ :
wherein A, ~ and R3 are as in formula Il, except that R4 is not amiùo, ;~ lower alkanoylamino or loweralkylam mo, with dimorpholinophosphinic chloride to produce compounds of the formul~

N~) ~ .
wherein A, ~ and R3 are as in formula XII; which imino phosphates are then displaced by the anion of a nitroalkane to produce the novel intermedi--20- ~

~674~ IL
ates IV.
Th0 displacement reaction is effected with a nitro-alkane; i.e.
nitrometllane, nitroethane, etc., in the presence of a base which is strong ; enough to generate the nitroalkane anion. Suitable bases include the alkali metal or alkaline earth metal alkoxides, hydrides, amides or hydroxides. The reaction is preferably carried out in an inert solvent, such as dimethylform-amide, dimethylsulfoxide, or an ether, at temperatures~below or above room temperature, i.e. in the range of -50C to 150C.
Another process to produce intermediates of formula IV, wherein ~

io R2 is hydrogen and A is an N-oxide, comprises the ring expansion of compounds of the formulae H

@~ ~CHCI o- (~ C C12 VIII IX
:

wherein A is -f=N- ; R6,~ ~ and R3 are as described in formula Il except that R4 is not amino.
The ring expansion comprises the reaction of the compounds of formulae VIII or IX with nitromethane in the presence of a base strong enough to generate the nitromethane anion, Suitable bases include the alkali metal and alkaline earth metal alkoxides, e.g. potassium tertiary butoxide; amides, e.g. lithium amide; or hydrides, e.g. sodium hydride. The reaction may pre-ferably be carried out in an inert solvent such as anhydrous ether, e.g. THFj dimethylformamide, dimethylsulfoxide, etc. and at a temperature in the range of about -20C to 25C.
Compounds of the formulae I, IA and ID, and their pharmaceutically acceptable acid addition salts, are useful as muscle relaxants, sedatives and anticonvulsants, and many are particularly useful when utili~ed in intravenous and intramuscular prepara~ions because of the acid addition salts' solubility ~0~74~1 -.n aqueous solution. As contemplat~d by this invention, the novel compounds of the formula I and their acid addition salts can be embodied in pharmaceuti-cal dosage formulations containing from about 0.1 to about 40 mgs, most pre-ferably 1-40 mg, Wit]l dosage adjusted to species and individual requirements.
The novel compounds of formulae I, IA and ID and their pharmaceutically acceptable salts can be administered internally, for example pa~enterally or enterally, in conventional pharamceutical dosage forms. For example, they ` can be incorporated in conventional liquid or solid vehicles such as water, gelatin, starch, magnesium stearate, talc, vegetable oils and the llke to provide tablets, elixirs, capsules, solutions, emulsions and the like accord-ing to acceptable pharmaceutical practices.
, The following examples are illustrative but not limitative of the present invention. All temperatures are stated in degrees Centigrade.

~ ' ' :

.. ~.. , ~l -22-, 1~67~91 Example 1 A solution af 200 g ~0.695 m) o~ 7-chloro-1,3-dihydro-5-~2~1uorophenyl)-2H-1,4-benzodiazepin-2-one in 2 1 of tetra-hydrofuran and 250 ml of benzene was saturated with methylamine with cooling in an ice bath. A solution of 190 g (1 m) of tltanium tetrachloride in 250 ml of benzene was added through a dropping funnel within 15 minutes. After addition the mixture was stirred and refluxed for 3 hours. Water ~600 ml) was .
added slowly to the cooled reaction mixture. The inorganic material was separated by filtration and was washed well with tetrahydrofuran. The water layer was separated and the organic phase was dried over sodiumsulfate and evaporated. The crys-talline residue of 7-chloro-5-~2-fluorophenyl)-2-methyl-amino-3H-1,4-benzodiazepine was collected, m.p. 204 - 206.
The analytical sample was recrystallized from meth~lene chloride/ethanol, m.p. 204 - 206.
Sodium nitrite, 8.63 g ~0.125 m), was added in three portions over a 15 minute period to a solution of 30.15 g (0.1 m) of 7-chloro-5-~2-fluorophenyl)-2-methylamino-3H-1,4-benzodiazepine in 150 ml of glacial acetic acid. After stir-ring for 1 hour at room temperature the reaction mixture was dlluted with water and extracted wlth methylene chloride.
The extracts were washed wi~h saturated sodium bicarbonate solution, were dried over sodium sulfate and evaporated, at the end azeotropically with toluene to yield 29 g of crude _ 23 ~

1~6749~

7-chloro-5-(2-fluorophenyl)-2~ nitrosome-thyla~ino)-3H-1,4-benzodiazepine as a yellow oil.

~ his material was dissolved in 100 ml of dimethylfor-mamide and added to a mixture of 200 ml of dimethylformamide, : .
50 ml of nitromethane and 11.1 g (0.1 m) of po-tassium t-buto-xide which had been stirred under nitrogen ~or 15 minutes.
: , After stirring for 1 hour at room temperature, the reaction mixture was ~cidified by addition o~ glacial acetlo acid, was diluted with water and extraoted with methylene chloride. ~he extracts were washed with water, dried over sodium sulfate and evaporated.

Crystallization of the residue from ether yielded 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine, m.p. 170-172. The~analytical sample was reorystallized from methylene chloride/ethanol, m.p, 174-176.

A solution of 16.5 g (0.05 m) of 7-chloro-1,3-dihydro-~; 5-(2-fluorophenyl)-2-nitromethylene-2X-1,4-benzodiazepine in 500 ml of tetrahydrofuran and 250 ml of methanol was 20` hydrogenated with 5 teaspoons of Raney nickel for 2 1/2 hours at atmospheric pressure. Separation of the catalyst~and evapo-ration left crude 2-aminomethyl-7-chloro-2,3-dihydro-5-(2-~luorophenyl)-lH 1,4-benzodiazepine.

, ~., ~6qa.~9'1 ~

Propionic anhydride (20 ml) was added to a solution of 12 g of the above material in 300 ml of methylene chlorid~.
The solution was layered with 300 ml of lO~o aqueous sodium carbonate and the two phase mixture was stirred at room tempe-rature for 30 minutes. The organic layer was separated, washedwith sodium carbonate solution and dried over sodium sulfate.
~vaporation yielded crude 7-chloro-2,3-dihydro-5-(2-fluoro-phenyl)-2-propionylaminomethyl-lE-1,4-benzodiazepine.

This material was heated in 50 g of polyphosphoric acid at 150-170 for 10 minutes. The reaction mixt~re was oooled, dissolved in water and made al~aline with concentra-ted ammonia and ice. The base was extracted with methylene chloride and the extracts were dried over sodium sulfate and evaporated. Tke residue was chromatographed over 300 g of siIica geI using 20% meth~nol in methylene chloride. The clean fractions ~ere combined, evaporated and the residue was j crystàllized from ether to yield 8-chloro-3a,4-dihydro-1-ethyl-6-(2-fluorophenyl)-3H-imidazo[1,5-a][1,4]benzodiazepine m.p. 131-133.

: ' A mixture of 3~4 g of 8-chloro-3a,4-dihydro-1-ethyl-6-(2-~luorophenyl)-4~-imidazo[1,5-a][1~4]benzodiazep;ne, 400 ml toluene and 30 g activated manganese dio~ide was refluxed with ~eparation of water in a Dean-Star~ trap for 2 hours. The manganese dioxide was separated by filtration over celite and the filtrate was evaporated. Crystallization of the residue from ether yielded 8-chloro-1-ethyl-6-(2-*luorophenyl)~X-~ ~ .

~,,,. _ ~ _ ' . . ..

~ ~67491 o imidazo[l,5-a][l,~]benzodiazepil1e, m.p. 140-143. For analysis it was recrystallized ~rom ether, m.p. 143-145.

' Acetic anhydrlde (7 ml) waa added to a solution of 6.16 g of crude 2-amlnomethyl-7-ohloro-2,3-dihydro-5-(2~-~luoro-pheny1)-IH-1,4--benzodiazepine in 200 ml of methylene chloride. ; , he solution was la~ered with 200 of saturated aqUeOUS
sodium bicarbonate and the mixture was stirred ~or 20 minutes.
The organic layer was separated, washed with sodlum~bicarbonate, dried over sodium sulfate and evaporated to leave resinous :
2-acetaminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl3 1,4-benzodiazep1ne. Thls materlal~was heated;with 40 g of polyphosphoric acld at~l50~for~10 minutes. ~he cooled~reactlon migtu e~was dissolved 1n uater, made alkaline uith~ammonia 15~ snd~ioe and extracted;with methylene chloride. ~he extracts were~dried an~d evaporated and the reeidue was ohromatographed over 120 g of sllica gel using 20 ~ methanol in methylene ohloride. ~he clean fractions were combined and evaporated to yield resinous 8-chloro-3a,4-dihydro-6-(2-fluorophenyl)-I-20 ~ methyl-4H-imidazo[1,~5-æ~[1,4]benzodiazepine. A mixture of this~
~ , ~
~ material with 500 ml of toluene and 30 g of~manganese dio~ide ~ ~ , was heated to reflu~ for 1 1/2 hours. The manganese dio~ide was separated by filtration over celite. The filtrate was ~
, ; :
evaporated and ~he residue was crystallized from ether to .
yield 8-chloro-6-(2-fluorophenyl)~l-methyl-4X-imidezo[1,5-a~-[1~,4~benzodiazepine, m.p. 152-154. The analytical sample was , .. .

.......... ... , ... , ... .. . ... .... , - - : ~ , ~67491 .
recrystallized from methylene chIoride/hexane.

Example 3 Reaction as in the first paragraph o~ Example~l of 152.5 g t-~ m~ of 7-chloro-5-(2-chlorophenyl3-1,3-dihydro-~ :
5 ~ 2H-1,4-benzod1a~epin-2-one saturated~with methyla~ine with 133~g~(0.7 m) of tiitaniumtetrachloride in 2 1 of tetra~ dro~
furan and~400 ml of~benzene yielded~7-chloro-5-(2-&hloro~
phenyl)-2-methylamino-3H-1,4-benzod1azepine,~m.p. 216-219.: ~ . ,.~:
he analytical sample was recrystallized from methylene chloride/ethanol and had m.p. 217-219.

Sodium nitrite (lO~g, 0 145~m) was added in~portions~
over~45 minutes to~a solution~o~22.~4 g (0.07~m)~of~7-ohloro-;5-(2-chlorophenyl~-2 methylamino-~H-1,4-benzodiazepin in l50 ml of~ ~ cia~ adetio aoid. After addition~atlrring~was cont1nued~
5 ~ for 20 minutes under nitrogen. The~product~was pre~cipitated~
by addition of ice-water, collected~and dissolved in toluene.
The æolution was washed with saturated aqueous æodium bioarbona-te,~dried and evaporated under~reduced pressure.~The yellow ; YiSCoUS oil consisted-aocord1ng to thin layer chromstogram ~; mainly of the desired nitrosoamidine.~This material was .
dissolved n 100 m} o~f dimethylformam1de and was added~to a mix-ture of 30 ml of nitromethane, 100 ml of dimethylfor-mamide and 10 g of potassium t-butoxide. The reactio~ mixture was slowly heated up to 85 with~stirr1ng under a nitrogen stream. After 5 minutes9 the reaction mixture was cooled, : . .. : : ~

, " ~

:: . :~ ~ :., .

, ~a6749~
., .
acidiied by addition of 10 ml o~ glacial acetic acid. 'l`he product was crystallized by gradual addition of water with seeding (seeds were obtained by chromatography over silica gel using 10% ethyl acetate in methylene chloride). ~he separated ~ 5 crystals were collected, washed with water and recrystallized from methylene chloride/ethanol to yield 7-chloro-5-(2-chloro-phengl)-1,3-dihydro-2-nitromethylene-2H-1,4-ben~odiazepine, ; m.p. 182-185.
~?~
Eydrogenation of 7 g of 7-chloro-5-~2-chlorophenyl)~
1,3-di~ydro-2-nitromethylene-2H-1,4-benzodiazeplne in 300 ml o~ tetrahydrofuran and 150 ml of methanol in the prese~ce of Xaney nickel (5 teaspoonsful) for 1 hour yielded orude 2-aminomethyl-7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1~-1,4-benzodiazepine. This~material~was aoetylated 1n the usual fashion to leave oily 2-acetaminomethy1-7-chloro-5-(2-ohloro-~ . ~
phènyl)-2,3-dihydro-lX-1,4-benzodiazeplne which was heated in 15 g of polyphosphoric acid for lQ minutes at 140-150.
The usual workup afforded a yellow resin which was chromato-graphed over 250 g of silica gel using 20~o methanol in ~ 20 methylene chloride.

: ~ :
The clean fractions left resinous a-chloro-6- (2-ohloro-phenyl)-3a,4-dihydro-1-methyl-4H-i~nidazoC1,5-a][1,4]benzodia-~
~epine. This material was oxidized with lO g of manganese dio-~ide in 200 ml of toluene. After heating to reflux for 1 1/2 hour, the manganese dioxide was separated and the filtrate was evaporated. Crystallization of the residue Prom ~ ~& ~ , .

-.. ~, . . .

i~06749~
ether yielded 8-chloro-6-(2-chlorophen~ l~methyl-4H-imidazo-[1,5-a][l,~]benzodiazepine, m.p. 140-144. ~or analysis it was recrystallized from methylene chloride/hexane, m.p. 142-144.

.
xamE~

A æolution of 94.6 g (0.3 m) of 5-(2-chlorophenyl)-I,3-dih~dro-7-nitro-2~I-1,4-benzodiazepin-2-one in 2 1 of tetrahydrofuran~and 300 ml of benzene ~7as cooled in ice-water and saturated with methylamine. A solution of 40.2 ml to.36 m) of titaniumtetrachloride in 300 ml of benzene wa~s added through a dropping funnel. Af-ter addition the mixture was stlrred and refluxed for 3 hours. Water (300 ml) uas added slowly to the cooled reactio~ mixture. The inorganic solids were separated by~flltration and washed well with tetrahydrofuran. The wa~er was separabed from the filtrate and the organic phase was dried over sodiumsulfate and evaporated. ~he residue was chromatographed over 500 g of silica gel using 10% (v/v) ethanol in methylene chloride.
Crystallization o* the clean fractions from methylene chloride¦ethanol yielded 5-(2-chlorophenyl)-7-nitro-2~-methyl-amino-3E-1,4-benzodiazepine as a yellow product~with m.p. 219-2:21.

Sodium nitrite ~8.63 ~, 0.125 m~ was ~dded in three portions over a 15 minute period to a solution of 3~.9 g (0.1 m) of 5-~-chlo~ophenyl)-7-nitro-2-methylamino-~3~-1,4-benzodiazepine in 200 ml of glacial acetic acid. After ..... .
~J~
,~ ....
... , .. . ~ ~,~ .. . . . . . . .

~067491 .

addition stirring was continued for 1 1/2 hours at room temperature and the product was precipitated by addition of ~ater. The yellow solids were collected, washed with water, sucked dry and recry~tallized from ethanol to gield 5-(2-chlorophenyl)-7-nitro-2-~N-nit~osomethylamino)-3H-1,4-benzodiazepine as yellow crystals with m.p. 164-166.
The analytical sample was recrystallized from methylene chloride/ethanol, m.p. 167-169.

A mixture of 3.58 g ~0.01 m) of 5-(2-chlorophenyl)-7-nitro-2-(N-nitrosomethylamino)-3H-1,4-benzodiazepine, 20 ml of dimethylfoxmamide, 5 ml of nitromethane and 1.3 g (0.0115 m) of potassium t-butoxlde was stirred at room temperature for 15 minutes under nitrogen. After addition of 2 ml of glacial - acetic acid the reaction mixture was partitioned between methylene chloride and water. The organic phase was washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed o~er 80 g of silica gel using 10% (v/v) ethyl ace-tate in methylene chloride. ~rystalliza~
tion of the clean fractions from methylene chloride/ethanol yielded stra~ colore~ crystals of 5-(2-chlorophenyl)-1~3-di-hydro-7-nitro-2-nitromethylene-2H-1,4-benzodiazepine with m.p. 240-243 (dec.).

Example 5 A solution of 33 g (0.1 m~ of 7-chloro-2-(N-nitroso-methyla~ino)-5-phenyl-3X-1,4-benzodiazepine 4-oxide in 100 ml ~067491 ; ' . , of dimethylformamide was added to a ~ixture of 50 ml of nltromethane, 12.5 g (0.11 m) of potassiu~ t-butoxide and 100 ml of dimethylformamide. The reaction mixture was stirred under a stream o* nitrogen for 1 hour. After addition of 10 ml of glacial acetic acid, the produot ~.ias c~rystallized by gradual addition of 250 ml of water. The precipitated yel10-,J material was colleoted, washed uith water, methanol and ether to leave 7-chlo-ro-1,3-dihydro-2-ni-tromethylene-5-~ e~ 2~-174-benzodiazepine 4-oxide,~m.p. 253-255 (deo.~).The analytical sample .was recrystal- ~
10~ lized from methylene chloride and showed the same melti~ point. ~;

' :
Raney nickel (5 teaspoons) was added to a solution of 16.5 g (0.05 m) of 7-chloro-1,3~-dihydro-2-nitromsthylene-5-pheny1-2H-1,4-benzodiazepine 4-oxide in 500 ml of tetra- ;~
hydrofuran~and 250 ml of~methanol.~The mlxture ~Jàs~hydrogena~
~ ~ted for 5 hours at atmospheric pressure. The catalyst was removed by f1ltration and the filtrate was evaporated. The`
residue was dissolved in 2-propanol and the solution was made strongly acidic wibh ethanolio hydrogen chloride. ~he dihydrochloride of the product crystalIized upon evaporation ;;~ 20 o~ part of the solvent. The orange crystals were coll~ected~
to leave~2-aminomethy1-7-chloro-2,~-dihydro-5-pheny1-IH-1,4-benzodiazepins dihydrochloride, m.p. 230-240.

Acetic anhydride (lO ml) ~Jas added to a solution of .
10 g of the above dihydrochloride in 50 ml of water and 50 ml of methanol. A 10% aqueous solution of sodium carbonate (100 ml) was added with stirring over a period of 5 minutes~ After 1~6749~L

addition the mixture was stirred for an additional ten minutes and ~Tas then extracted ~Jith methylene chloride.
The extracts were washed with sodium carbonate solution?
dried over sodium sul~ate and evaporated, at the end azeotropically with toluene. 2-Acetaminomethyl-7-chloro-2 9 3-dihydro-5-phenyl-IH-1,4-benzodiazepine was obtained as a yellow resin.

The above material was heated in 50 ~ o po~yphosphoric acid to 1~5-140 ~or 10 minutes. The initially orange color of the reaction mixture faded to a light yellow. The cooled reac-tion mixture was dissolved in water, made alkaline wi-th con-centrated ammonia and ice and extracted with methylene chloride.
The extracts were dried and evaporated. The yellow resin was dissolved in 2-propanol and treated with ethanolic hydrogen chloride whereupon the colorless dihydrochloride of the product ; crystallized. Melting point was 240-245.

~ , This hydrochloride was partitioned between methylene chloride and aqueous ammonia. The organic phase was dried and evaporated. Crystallization of the residue from ether yielded 8-chloro-3a,4-dihydro-1-methy1-6-pheny1-3H-imidazo ClJ5-a]El,4]benzodiazepine as a colorless product with m.p. 116-118.

A mixture o~ 3.1 g (0.01 m) of 8-chloro-3a,4-dihydro-l-methyl-6-phenyl-3H-imidazoC1,5-a][1,4]benzodiazepine, 20 g o~ activated manganese dio~ide and 150 ml of toluene was ~ ~ ~ 3~

, . ~ .

- rePluxed ~or 1 hour. The manganese dioxide was re~oved by filtration over celite and was washed well with methylene chloride. ~he filtrate was evaporated and the residue was crystallized from ether to yield 8-chloro-1-methy1-6-phenyl-4H-imidazo[1,5-a][l,~]benzodiazepine as colorless crystals with m.p. 187-188.

~xample 6 A mixture of 11.2 ~ (0.1 m) o~ potassium tert.butoxide, 50 ml of nitroethane and 200 ml of dimethylformamide was stirred at room temperature Por 15 min. A solution oP 29 g (0.088 m) of crude 7-chloro-5-(2-Pluoropheny1)-2-(N-nitroso-:
methylamino)-3H-1,4-ben~odiazepine in 100 ml of~dimethyl~or~
mamide was then added and stirring under nitrogen was contl-nued for 6 hrs. ~he reaction mixture was neutralized by 15~ addition of glacial acetic acid and diluted with water. ~he product~was extracted with ether.~he extracts were washed with ~aturated aqueous sodiumblcsrbonate solution, dried over sodium sulfate and evaporated. ~rystalIization from ether yielded 7-chloro-1,3-dihydro-5-(2-fluorophenyl-2-(1-nitro-~
ethylene)-2H-1,4-benzodiazeplne as yellow crys-tals with m.p. 1~6-142, :.
Raney nickel (5 teaspoonsful~ was added to a solution of 17.3 g (0.05 m) of 7-chloro-1,3-dihydro 5-(2--~luorophenyl)-2-(1-nitroethylene)-2H~1,4-benzodiazepine in 750 ml of tetra-hydrofuran. ~he mixture was hydrogenated at atmospheric pressure

3~
.c~ "'f ~367~91 , ~or 4 hrs. The catalyst was removed by filtration over celite and was washed well with met~lanol. The -filtrate was evaporated to leave crude 2~ aminoethyl)-7-chloro-2~3-dihydro-5-(2-fluorophenyl)-lX-1,4-benzodiazepine as a reddish oil.
: ,, his material was dissolved in 300 ml o-f methylene chloride. ~ollowing the addition o~ 1~ ml of acetic anhy-dride, 300 ml of saturated aqueoue sodium bioarbonate solu-tion was added and the two-phase mixture was stirred at room tempera-ture for 1 hr. The methylene chloride layer was separated, washed with bicarbonate~ dried over sodium ~ulfate and evaporated. The residu0 was heated with 40 g ; of polyphosphoric acid for 10 minutes at 160-170~;. The~cool reaction mixture was~diluted~with~water, made alkaline~with ~ . :
15~ ammonia and extracted uit~ methylene chloride. The;extracts were;~ashed~wi~h water, dried and evaporated to~leave a brown reeidue which was chromatographed on 250 g o~ silica gel u~ing 20% (v/v) methanol in methylene chloride, The thin layer chromatographically homo~eneous fractions were~oombined to yield a resin which was subjected to the following o~idation.
:
~ ~ :
A mixture of the above material, 20 g of ao~ivated ~
manganese dioxide and ~00 ml of toluene was keated to reflux for 3 hrs using a Dean-Stark trap to remove the water. The manganese dioxide was separated by filtration over celite~
and was washed well with meth~lene chloride. The filtrate - was evaporated and ~he residue was chromatographed with pressure . '~, ~ 7L
~ .

~1~6~491 over 150 g of silica gel H using 3% ethanol in methylene chlori.-de. The ~irs~ eluted major component was 8~chloro-1,4-dimethyl-6-(2-fluorophenyl)-4H-imidazo[1,5-a~[1,4~benzodiazepine.

It was converted to a crystalline dihydrochloride by treatment with ethanolic hydrogen chloride in ether, Mp.
247-250 (dec.).

:
~:
The more polar co~ponent oould be crystallized from methylene chloride/ether/hexane to y1eld 8-chloro-1,3-d:~methyl-~
6-(2-fluoropheny1)-4X-imidazo[l,S-a][1,4]benzodiaæepine with ~; 10 mpO 178-180.

A miæture of 3~.1 g (0.01 m) of 8-chloro~ methy1-6-phenyl-4H-imidazo~1,5-a~[1,4]benzodlazepine, 2.15 e~ (0.0125 m) of~ ~ oroperbenzoic acld and~100 ml o~f methylene chloride ~; 15 was ~tirred ~or 48 hrs. at room temperature. It was then .
waE~hed with 10% aqueous sodium carbonate solution and water.
:
The residue was chromatographed o~er 80 g of silica gel using 10% (v/v) o~ ethanol in methylene chloride. ~he Tlc-homogeneous~
ractions were combined~and evaporated. Crystallization of the :: .
reE;idue from methylene chloride/ether yielded 8-chloro-1- ~
methyl-6-phenyl-4H-imidazo[1,5-a~[1,4]benzodiazeplne 5-oxide, mp. 260-261.
.

, ._~ ~, , , . .. , . . --.---- . .. _.--_ . =__. _ ._ __.. _ ........

!L06~49 ,~ , . . .

; Example_8 A solutlon o~ 1 g o~ 8-chloro-1-methyl-6-phenyl-4H-; imidazo[l-5-a][l,~benzodiazepine 5-o~ide i~ ~0 ml of acetic ; ~ anhydride~was heated on the steam bath~for 24 hrs. The reagent ~5 was evaporated under reduced pressure and the ~residue ~as crystallized ~rom ether to yield 4-acetoxy-8-chloro-1-methyl-~6-pheryl-4H-imidazo[1,5-a]~[1,4]benzo~dlazeplne, mp. 200-201.

Example 9 .

Sodium metho~ide (0,54 g) was added -to a solution o~
~10 0.73 g {2 mmol) of 4-acetoxy-8-chloro-1-methyl-6-phenyl-4H-imidazo[1,;5-a][l,O]ber~odlazepine ln 20 ml;of methe~ol.~;A~t~er~
sitting a~ room~temperature~for~0 min, -the solvent~was~evapo-rated under reduoed~ pressure~after~ne~tralizatlon~with~
acetio aoid.~he residue was partitioned between methylene ~ ~;
5;~ ohloride and sodium~bioarbonate~ solution. The organio layer waæ dried over sodlum~sulfate and evaporated. Crystallization o~the residue from ether yielded~ 8-ohloro-4-hydroxy-1-methyl-6-phenyl-4H-imidazo~1,5-a][1,4]benzodiazepine, mp. 173-174.

E~am ~ A warm solu-tion of 6.5 g (0.02 m) o~ 8 chlo~o-6-f2-fluo-rophenyl)-l-methyl~4X-imidazo[1,5-a][1,4]benzodlazepine in 30 ml of ethanol was combined with~a warm solution of 2~.6 g ~ (0.022 m) of maleic acid in 20 ml of ethanol. ~he mi~ture was :~

~ ~ 3 ~067~9~

diluted with 150 ml of ether and heated on the stea~ ba~h ~or 3 min. A~ter cooling, the crystals were collected, washed with ether and dried in vacuo to yield 8-chloro-6-(2-fluorophenyl)-l-methyl-4H-imidaæo~1,5-a~[1,4~benzodiazepine maleate, mp~
148-151.
.. :
xa~mple_ll A mixture of 17.4 g (0.05 m) of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-~1-nitromethylene)-2H-1,4-benzodiazepine

4-o~ide, 500 ml o~ tetrahydro-furan, 200 ml of methanol and 5 teaspoonsful of Raney nickel was hydrogenated at a~mospheric pressure ~or 5 hrs. ~he catalyst was removed by filtration and the filtrate was evaporated at the end azeotropically ~with xylene to leave crude 2-aminomethyl-7-chloro-5 (2-fluorophe~yl)-2,3-dihydro~ 1,4-benzodiazepine.

. .
This material waæ dissolYed in 200 ml of ethanol and the æolution was heated to re*lux ~or 2 hrs. after addition o~ 14 ml of triethylorthoaoetate and 2.8 g of p-toluenesul~o-nic acid. ~he solvent was evaporated under reduced pressure and the residue was partitioned between methylene chloride and 10% aqueous sodium carbonate solution. ~he organic layer ~a~ dried and evaporated to yield oily 8-chloro-3a,4-dihydro-6-(2--fluorophenyl)-1-methyl 3H-imidaæo[195-a][1,4]benzodiaze-pine. Thiæ crude product was dissolved in 500 ml o~ xylene.
A~ter addition of 50 g o* activated manganese dioxide, the mixture was stirred and heated to reflux for 1 1/2 hrs with ... .. .... . _ _ .. . .. . .. .. .... ... .. . .

\

~6749'1 separation of water in a Dean-Stark trap. The inor~anic material was removed by filtration and the ~iltrate was evaporated to leave 10 g of brown oil A warm solution of 4.65 g (0.04 m) of maleic acid in 50 ml of ethanol was added to this residue. A~ter the solu-tion was complete, the produot was crystallized by addition of ether. It was collected and washed with ether to leave 8-chloro-6-(2- n uorophenyl~-1-methyl-4H-imldazo[1,5-a~[1,4~-benæodiazepine maleate, mp. 112-115. Xeating under vacuum at 90 to 100 converts this product to the higher melting ~orm with mp. 148-151.

' ~ , A solution of 0.32 g (1 mmol) of 8-chloro-6-(2-~luoro-phenyl?-l-methyl-4H-imidazo[1,5-a][1,4]benæodiazeplne in 5 ml o~ ethanol was treated with exoess ethanolio hydrogen chloride.
~he salt wa~ crystallized by addition of 2-propanol and ether.
The oolorless crystals were collected, washed with ether and ~ried to lea~e 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imi-dazo[l,5-a][1,4]benzodiazepine dihydrochloride, mp. 290-295.

A solution o~ 0.325 g (1 mmol) o~ 8-ohloro-6-(~ fluoro-phenyl)~l-methyl-4H-imidazo[1,5-a]~1,4]benzodiazepine in 3 ml of ethanol was combined with a suspension of 0.4 g (l mmol) o~

.. ... .... . . . . . . . .. . ..

~0674~
.

the dihydrochloride of this compound in 5 ml o~ ethanol.
After filtration, the solu-tion was -treated with ether and heated on the steambath for 5 min to crystallize. The crystals were collected, washed wi-th ether and dried -to leave 8-chloro-6-(2~Pluorophenyl)-l-methyl-4X-imidazo~1,5-a]~1,4]benzodiazepi-ne hydrochloride, mp. 295-297.

E~ample 14 A solution of 2~.6 g ~0.10 mole) of 1,~-dihydro-5-phenyl~ ;
2H-1,4-benzodiazepin-2-one in 1 liter of tetrahydrofuran (containing about 20 moles o~ monomethylamine) was c~hilled ln an ice bath. To this mixture was added 14 ml. (d=1.7~, 0,125 mole) of titanium tetrachloride in 200 ml of benzene.

;~ ~ This mlxture uas stirred at room temper-ture for -two~
` da~s. The~titanium complex was destroyed with 20 ml of water.
.
The inorganic salts that precipitated, were removed by filtra~
tion. The solvent was evaporated ln vacuo, the resldue was partitioned between methylene chloride and water. A colorless amorphous solid mp. 227-229 was removed by filtration. An addltional sample, mp. 226-22~ of a oolorless solid was obtai-ned from the methylene chloride ~other liquors after dryingover anhydrous sodium sulfate, evaporation to dryness, and c~stallization from ethyl acetate.
: ' ' :
An analytical sample was prepared by recrystallization from dimethylformamide to yield colorless prisms, mp. 227-229C

, ~9 . ,.. ~ ,.. , . ..... ~ .. ...... .... ...... .. ... .. .. .. . . . . . . .. . .. .

~ o a cooled (10), stirred solution of 10.0 g (0.04 ~) of 2-meth~lamino~5-pheny1-3H-1,4-benzodiazepine i~ 100 ml of pyridine was added 100 ml of a saturated solution o~ nitrosyl chloride in acetic anhydride. The solution was stirred for 3O5 hr. during which time it was allowed to rarn to ambient temperature. The solution was poured into ~00 ml of ice-water, and the aqueous solution was egtracted with five 150 ml portions of methylene chloride. The combined organic extracts were washed with water and brine, dried (CaS0~), and the sol~ent removed under reduced pressure affording a dark semi-solid. Chromatography on 500 g of silica gel (chloroform elution) afforded the 2~ nitrosomethylamino)-5-phenyl-3H~
1,4-benzodiazepine, mp 192-199 (dec.). ~his material was used in the following step: ~

' ~he conjugate base of nitromethane was prepared by treatment of 50 ml of nitromethane in 200 ml of dimethylfor-mamide with 5.7 g (0.05 m) of potassium tert-butoæide. ~he ~-resultant stirred yellow suspension was treated with 10.9 g of crude 2-(N-nitrosomethylamino3~5-phenyl-3X-1,4-benzodia-zepine in 100 ml of dimethylformamide. The dark mixture thus ob-tained was stirred for 2 hrs. at 25 and for 1 hr at 85 and then cooled to 25 and poured onto 1 1 of water. After acidification with acetic acid, the aqueous solution vas ~xtracted with four 250 ml portions of methylene chloride, and the combined org~anic extracts were then washed with water and brine, dried (CaS04), and concentrated in vacuo to give a dark oil which was purified by chromatography over 1 kg of g~ '' ~o . ~,, ~ . ... .. .

~6q491 - ~
silica ~el (C~IC13 elution) to afford crude 1,3-dih~dro~
2-nitro.ne~hylene-5-phenyl 2~I~1,4-benzodiazepine, mp. 131-1~2..

An analytical sample, mp 141-142, was prepared by recrystallization ~rom ethanol.

. . .
A mi~ture o~ 8.4 g (0.03 m) o~ dihydro-2-nitrome-thylene-5-phenyl-2H-1,4-benzodiazepine, 75 ml of tetrahydro-furan, 75 ml o~ methanol and 2 teaspoonsful of Raney nic~el was hydrogenated at atmospheric pressure for ~ hrs. The ~-catalyst was removed by filtration and -the flltrate was evaporated to lea~e crude 2-aminomethyl-2,3~dihydr~-5-phenyl- ~`
IH-l,4-benzodiazepine.
- ~ ~
~his material was dissolved in 50 ml of methylene chloride a~d was treated with 6 ml of acetic anhydride and -200 ml of saturated aqueous ~odium bicarbonate solution for ~ . . .
15 min. with stirring. The methylene chloride la~er was separated9 washed with bicarbonate solution, dried and evæpora-ted. The residue was treated with 25 g of polyphosphoric acid to 130~150 for 15 min. ~he oooled~reaction mixture was partitioned between water and ether. The aqueous phase was made alkaline with ammonia and was extracted uith methylene ;
chloride. ~he e~tracts were dried and evaporated. Chromato~ra-phy of the residue over 70 g of silica gel with 20~ (vlv) ethanol in methylene chloride yielded 3a,4-dihydro-1-methyl-6 phenyl-3H-imidazo[1,5-a][1,4]benzodiazepine as a light yellow resin.

,?

106749iL

~ his material was heated in 50 ml of toluene with 7 g of activated manganese dioxide to reflux for 1 1/2 hrs. ~he inor-ganic material was ~iltered of~ and the ~Lltrate was evaporated The residue was purified by chromatograph~ over 30 g of silica gel using 10% ethanol in methylene chloride. The clean fractions were combined and evaporated Crystallization of the residue ~rom ether yielded l-methyl-6-phenyl-4H-imidazo[1,5-a][1,4~-benzodiazepine xample 15 ~-~o a stirred solution of 6 g (0.02 m) of 7-chloro-~ dihydro-5-(2-fluorophenyl)-3-methyl-2H-1,`4-benzodiazepin-2-one in 100 ml of dry tetrahydrofuran was added 1.05 g (0.25 m) of 57% sodium hyd~ide dispersion in mineral oil.
~he mixt~r~ was placed under argon and refluxed for 1 hr.
After cooling to room temperature, the mixture was treated with 7.4 g (0 03 m) of dimorpholinophosphinic chloride and st~rring under argon was continued at room temperature for 2 hrs. The mixture was filtered and evaporated at reduced pressure to give a gummy residue. Stirring the gum with 100 ml of anhydrous ether gave white crystal3 which were collected by ~iltration, washed with a little ether and air dried.
7-C~loro-2-di-(morpholino)-phosphinyloxy-5-(2-fluorophenyl~
3-methy1-~H-1,4-benzodiazepine thus obtained had a mp. of 90-95.

A stirred solution of 2.4 g (0 04 m) of nitromethane in 50 ml of dry dimethylfo~mamide was treated with 1 g (0.024 m~
r$~ ~a ~067491 of 57~ sodium hydride dispersion in mineral oil at roo~ te~e-rature ~mder argon. After stirring for 1 hr. at room te~erætu-re, the mixture was treated with 5.2 g (0.01 m) of 7-chloro-2-di(-morpholino)-phosphinyloxy-5-(2~fluorophenyl)-3-~ethyl-3H-1,4-benzodiaz,epine in one portion and stirring under argon was continued at room temperature for 24 hrs. The dark ~ixture was poured over a mixture of icé and glacial acetio acid ~ith stirring to give a yellow solid. Stirr mg was conti~ued until the ice had melted. The solid was ~ ered, washed with water and air dried on the funnel to yield 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-3-methyl-2-nitromethylene-2H-1,4-benzodiaze-pine having mp of 215 (dec.). Recrystallization oP a sample from 1:1 methanollmethylene chloride gave yellow needles, mp. 219-221 (dec.).
' A ~olution o-f 5~2 g (0.015 m) of 7~chloro-1,3-dikydro-

5-(2-fluorophenyl)-3-methyl-2-nitromethylene-ZH-1,4-benzodia-zepine in 450 ml of 2:1 tetrahydrofuran methanol was hydrogR-nated for 3 hrs. using a Parr apparatus, Xaney nickel catalyst (3 teaspoonsful) and an initial pressure of 18 psi. The mlxture wa~ filtersd and e~aporated at reduced pressure to give crude 2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-3-methyl-lH-1,4-benzodiazepine as a yellow oil~

The crude aminomsthyl compound was miged with 5 ml of triethyl orthoacetate and 0.5 g of p-toluenesulfonic acid monohydrate in 100 ml of ethanol. After heating under reflu~

for 2 hxs, the solution ~as evaporated at reduced pressure.

. . .. , ~, .

~L06749~
. . .
~he residue was cooled to room temperature, treated with a mixture of ice and concentrated a~monium hydroxide and extrac~
ted with methylenechloride. ~vaporation of the dried extracts in vacuo gave crude 8-chloro-~a,~-dihydro--1,4-dimethyl-6-(2-fluo~ophenyl)-3H-i~idazo[1,5-a][1,4]benzodiazepine as a gum.
, The crude dihydroimidazobenzodiazepine was mixed with 20 g of acti~ated manganese dioxide and 200 ml o~ toluene and heated under reflux for 2 hrs. ~he mixture was filtered and the manganese dioxide was washed with methylene chloride. ~vapora-tion of the combined filtrate and washings at reduced pressuregave a brown gum. The dihydrochloride of 8-chloro-1,4-dimethyl-

6-(2-fluorophenyl)-4H-imidazo~1,5-a][1,4~-ben~odiazepine was~
obtained as a white powder by stirrin~ the gum with ethanolic ~
hydrogen chloride for a few minutes. The salt melted at 247-250.

: . :
:
E~

Zinc dust, 3 g, was added to a solution of 2.8 g of 8~chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1~4]-benzodiazepine in 75 ml of methylene chloride and 75 ml o~ -glacial acetic acid. After stlrring at room temperature for 2 hrs, the inorganic material was flltered of~ and washed .
with methylene chloride and water.

~ he filtrate was diluted with 100 ml of methylene chloride and 200 ml of water and was made alkaline with ammonia~ ~he methylene chloride layer was separated, dried ~. ' ' ....

-~L~)674~1 and evaporated. ~rystallization of the residue from ether/
hexane yielded 8-chloro-5J6-dihydro 6 (2-P:Luorophen~
methyl-4H-imidazo~1,5-a]~1,4]benzodiazepine, mp. 200-203.

~xam~le 17 A mixture of 100 g (0.8 m) of chloroaGetaldehyde dimethylacetal and 100 ml of 1.5 N hydrochloric ac~d was heated under reflux for 15 min. and then cooled and added ~o a solution of 130 g (0.5 m) of 2-amino2'~fluoro-5-nit;ro-benzophenone and 46 g (0.28 m) of hydroxylamine sulfate and 1 1 of ethanol. The mixture was stlrred at room temperature for 2 hr. and then heated to reflux for 1.5 hr. The mixture was cooled and the product obtained by filtration. Recrystal-li~ation from a mixture of chloroform and methanol ga~e pure Z-chloromethyl-4-(2-fluorophenyl)-6-nltro-1,2-dihydroquina-zoline 3-oxide as yellow prisms, mp. 220-224.

A solution of 142 g (0.423 m) o~ 2-chloromethyl-4-(2-fluorophenyl)-6-nitro-132-dihydroquinazoline 3-oxide in 293 1 of dichloromethane was treated with 400 g of manganese dioxide, and after stirring for 18 hr. the solution was filte-red. The manganese dioxide was washed with 600 ml of tetra-hydrofuran and 800 ml of dichloromethane. ~he ombined filtra~
tes were concentrated to 400 ~1 and 1 1 of ether was added.
This was cooled and filtered to gi~e 2-chlorome-thyl-4-(2-~luorophe~y1)-6-nitroquinazoline 3-oxide. A sample ~as recrys-talli~ed from a mi~ture of diohloromethane and methanol , . . .
s ~L06~91 r to give the pure product as pale yellow pris~s, mp. 127-130.

~o 500 ml of dimethylsulfoxide and 75 ml (1.4 m) of nitromethane was added with.stirring under nitrogen 15.6 B
(0.678 m) o~ lithium amide. After 30 minu~es the solution was cooled to 5 and 104 g (0.31 m) of 3-chlorometbyl-:~ . 4-(2-fluorophenyl)~6-nitroquinazoline 3-oxide was added slowly, ; keeplng the temperature below 8. After 68 hr. at room tempera-ture~the reactlon~was poured into a mixture~of 2~.5 1 of in~e and~
water and 25 ml o~ acetic acid, and the solution was ~iltered.
: ~ ~
The~gummy precipltate was dissolved in 1 1 o~ diohloromethane which was washed with dilute ammonium hydroxide, dried over anhgdrous sodium sulfate and evaporated. ~he residue was o~ystalllzed from ethyl aoetate to give 1,3-d1hydro-5-(2-~

fluorophenyl)-7-nltro-2-nitromethylene-2X-1,4-benzodiazeplne~
15~-~ 4-oxide, and the filtrates were evaporated, dissolved~in dichlo.romethane and:fil~:ered thro~gh a sintered:glass funnel cont~ining~200 g of Floris~ he~lorlcil was~:eluted with : ;~;
: ; dichloromethane (600 ml), ether (600 ml) and~ethy:l acetate (1,2 1). ~he ether and ethyl acetate fractlons were combined :
: and concentrated to give additional:final product.:A sample ::
:: was recrystallized from a mi2ture of tetrahydrofuran and hexane to give the pure product as yellow prisms9 mp.~ 216-220.

~ . . .
: A suspension of 25 g (0.0698 m) of 1,3-dibydro-5-(2- : :

.~luorophenyl)-7-nitro~2-nitromethylene-2~-1,4-benzodia~epine ~ : , :
4-oxide in 1.~ 1 of absolute ethanol was treated with 10 tea~poons of Raney nickel.and hydrogenated at atmospheric ~ ~ ~f ~d QrnQ rk - ~ .~ . :

- ~6749~

pressure and room temperature ~or 9 hr. The mixture was fil~e rea through ~elite and the filtrate was e~aporated to dryness.
A sample o~ the oil was crystallized from tetrahydrofuran to give the inte~ediate 7-amino-2-aminomethyl-1,3-dihydro-5-~2-fluorophen~ 2H-1,4-benzodiazepine as yellow prisms ~Ihich melted with decomposition at 185-192.

Without further purificatlon, the oil obtained from the reduction was heated under reflux for 2 hr. in a solution o~ 300 ml of absolute ethanol, containing 4.5 ml (0.0257 m) of ethanolic hydrogen chloride and 50 g (0.309 m) of triethyl-orthoacetate. ~he mixture was then evaporated to dryness and the re~idue was dissolved in 150 ml of dichloromethane which was washed with 100 ml of dilute ammonium hydroxide, d~led over anhydrous sodium sulfate and evaporated to dryness.

.
~ The;residual oil, ~rhich wa~ crude 8-acetylamino-~a,4-dihydro-6-(2-fluorophenyl)-1-met~ 3H-imidazo[1,5-a]~1,4]-~' benzodiazepine, was dissolved in 500 ml of benzene and treated with 100 g of activated manganese dioxide. The mixture was refluxed and stirred for 9 hr. using a Dean Stark trap. An additional 25 g of activated manganese dio~ide was added and after 4 hr. of refluxing the manganese dio~ide was removed by filtrati.on and was washed with 500 ml o~ tetrahydrofuran.
~he ~iltrates were oombined and evaporated to dryness. The residual oil, which was 8-acetylamino-6-(2- M uorophenyl~
methyl-4H-imidazo-[1J5-a][1,4]benzodiazepine9 was dissolved in 75 ml of methanol and an excess of ethanolic hydrogen chloride was added. After 10 min~ 100 ml of water was added, ~ , . . - .

~0674~t1 and a~ter an addlt~onal 20 min, during which time the 8-acetyl group was hydrol~zed, a mixture o~ ice and dilute ammonium hrdr~ide ~as added until the solution was basic. The reaction was ~iltered and the precipitate and ~iltrates were extracted separately with dichloromethane. The extracts were dried, and evaporated. The extract from the filtrates ~ere crystallized ~rom isopropanol *o give 8-amino-6-~2-fluorophenyl)-l-methyl-4H-imidazo-[1,5-a}[1,4]benzodiazepine isopropanol and the extract from the precipitate was chromato-graphed through Florisil, first with dichlorom:thane and then with ether and ethyl acetate containing 10% ~v/v) o~ methanol gave, a~ter evaporation and crystallization from isopropanol, additional product. Recrystalllzation of the combined products from isopropanol gave the product as white reds, m.p. 135 -Example 18 A mixture o~ 17 g ~0.05 m) of raoemic 8-chloro-1,4-dimethy1-6-~2-~luorophenyl)-4H-imidazo[1,5-a]~1,4]benzo-diazepine which had b0en liberated from its dihydrochloride by partitioning between methylene chloride and aqueous ammonia, 18,8 g tO.05 m) of 0,0~-dibenzoyl-d-tartaric acid hydrate and 170 ml of ethanol was boiled until solution was complete. For crystallization the solution was allowed to sit overnight.
The separated crystals were collected, washed with ethanol and ether to yield the 0,0'-dibenzoyl-d-tartaric with m.p. 140 -142. Recrystallization from ethanol/ether yielded a product with m.p. 141 - 142 and [a]D5 - 43.39 ~c = 1% in methanol).

_ 48

7~91 A solution of 1.6 g ~0.0106 m) of l-tartaric acld in 11 ml of ethanol was added to a solution of 3.5 g of the levo-rotator~ base liberated from the above 0,0'-di~enzoyl-d-tartrate in 11 ml o~ ethanol. The cr~stals obtained were collected and washed with ethanol and ether to yield (~)-8-chloro-1,4-dimethyl-6~(2-fluoropheny~1)-4H-imidazo[1,5-a][1,4]benzodiazepine 1-tartrate, m.p. 178 - 180. Recrystalllzation from ethanol gave product with m.p. 183 - 185 and [~]D +25.69 ~c = 1.012% in methanol). The amorphous b-aseliberated from this salt showed a rotation of [~]25 -36.74 ~c = 0.939% in methylene chloride).

Example 19 The ~other liquor left after separation of the errs-talline salt with 0,O'-dibenzo~l-d-tartaric acid described in the preceding example was evaporated and recoverted to the base by partitioning between aqueous ammonia and =ethylene chloride.
The methylene chloride solution was dried over sodium sulfate and evaporated to yield partly resolved base.
A solution of 9.7 g ~0.029 m) of this material in 15 ml of ethanol was treated with a solution of 4.4 g of d-2a tartaric acid in 14 ml of ethanol. The crystals which separat-ed after several hours were collected to yield ~-)-8-chloro-1,4-dimeth~1-6-~1-fluorophenyl)-4H-Imidazo[1~5-a][1,4]benzo-d~azepine d-tartrate, m.p. 176 - 178. Recrystallization from ethanol gave product with m.p. 182 - 184 and [~]25 (0.9616%
in methanol). The amorphous base liberated from this salt showed a rotation of [~]25 +37.6 ~c = 1.0% in methylene chlo-ride).

~IL06~49 xamPle ?

A solution of 19.3 g (0 06 m) of 1,3~dihydro-7-(2-methyl-1,3-dioxolan-2-yl)-5-phenyl-2~ 4-benzodiazepin-2-one in 300ml of dry tetrahydrofuran was treated under an atmosphere of argon S with 3.1 g (0.075 m) of a 57%~suspension of sodium hydride in mineral oil. The mixture was heated under reflux for 1 hr., cooled to room temperature when 22.2 g (0.087 m) o~ dimorpho-linophosphinic chloride was added. ~he mixture was allowed to stir at room temperature for 2 hr. and then stand overni~ht.
Sodium chloride was removed by fil-tratlon and the arude 7-(2-methyl-1,3-dioxolan-2-yl)-2-[bis(morpholino)phosphinyloxy]-5-phenyl-3H-1,4-benzodiazepine was obtained by removal of the ` solvent and crystallization of the residue from ether.
~; ' :
A mi~ture of 100 ml of dry ~ dimethylformamide and ~ 6.8 g of nitr~Qmethane was treated under an atmosphere of argon with 2.8 g (0.066 m) of a 57~ suspension of sodium hydride in v mineral oil. The mixture was stirred for 1 hr. at room tempe-rature when a solu-tion of 18 g (0.033 m) o-f crude 7-(2-methyl-1,~-dioxolan-2-yl)-2~bis(morpholino)phosphinyloxy] 5-phenyI-3H-1,4-benzodiazepine in 50 ml of dry N,N-dimethylformamide was added. The reactlon ml~ture was alloued to stand at room -tempera-ture for 15 hrs. when the dark VlSCOUS liquid was poured over a mixture of ice and dilute acetic acid. ~he bright yellow precipitate was removed by filtration, dissolved in dichloro-~5 methane which was washed with dilute ammonlum hydroxide andwater, dried over anhydrous sodil~ sul~ate and evaporated. ~he .

`

~(~67D~9~L

original ~iltrate ~as extracted with dichloromethane which was washed, dried and evaporated as above. The two crude residues were combined and chromatographed over ~lorisil.
Using dichloromethane, 10% (v/v) ether as the eluent and monitoring the fractions by tlc, several fractions contain-ing the product were collected and evaporated. Crystal-lization and recrystallization from a mlxture o~ dichloro-methane and hexane gave the pure 2,3-dihydro-7-(2-methyl-1,3-dioxolan-2-yl)-2-nitromethylene-5-phenyl-lH-1,4-benzo-l~ diazepine as pale yellow prisms, m.p. 158 - 161.
Hydrogenation of 5 g ~0.0137 m) of 2,3-dihydro-7-Cl-methyl-1,3-dioxolan-2-yl)-2-nitromethylene-5-phenyl-lH- , 1,4-~enzodiazepine in 250 ml of absolute ethanol in the presence of 1 teaspoon of Raney nickel for 3.5 hours yield-ed crude 2-aminometh~1-2,3-dihydro-7-~1-methyl-1,3-dioxolan-2-yl)-5-phenyl-lH-1,4-benzodiazepine. To a solution of 4 g Co.0119 m) of this compound in 75 ml of absolute ethanol was added 0.7 g ~0.0037 m) of p-toluene sulfonic acid and 6 g ~0.037 m) of triethyl orthoacetate. The mixture was refluxed for 2 hours, evaporated to dryness and the residue was dissolved in 50 ml of dichloromethane. This was washed with 25 ml of dilute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated to give crude 3a,4-dihydro-1-methyl-8-~1-methyl-2,3-dioxolan-2-yl)-6-phenyl-3H-imidazo [1,5-a][1,4]benzodiazepine as an oil.
A solution containing 3.8 g ~0.0105 m) of this crude oil, ~)6~49~
and 18 g o~ activated manganese dioxide in 100 ml o~ toluene ~as re~luxed and stirred ~or 2 hours using a Dean Stark trap.
lt was filtered and washed with a mixture of 250 ml of di-chloromethane and 250 ml of tetrahydro~uran. The filtrates were evaporated and dissolved in a small amount of isopropanol and treated with 1.4 g ~0.0121 m) of maleic acid in ethanol.
Ether was added and the precipitate was filtered and recrystal-lized from a mixture of methanol and ether to give l-methyl-8-(2-methyl-1,3-dioxolan-2-yl)-6-phenyl-4H-imidazoIl,5-a]~1~4~-benzodiazepine maleate methanol ~2/1) as off-white prisms, m.p. 179 - 182.

A solution of 0~ g (0.1000607 m) of 1-methyl-8-C2-methyl-1,3-dioxolan-2-yl)-6-phenyl-4H-imldazo[1,5-a][1,4]
benzodiazepine maleate methanol (2/1) in 10 ml ~0.01 m) of lN hydrochloric acid was allowed to stand for 18 hours. A
small amount of charcoal was added and the reaction mixture was filtered. The solution was made basic with ammonium hydroxide, extracted with 25 ml of dichloromethane, dried over anhydrous sodium sulfate and evaporated to dryness.
The residue was dissolved in isopropanol and 0.35 g ~0.10015 m) of picric acid in 5 ml of ethanol was added. The solution was e~aporated and the residue was crystallized from methanol.
Recrystallization from a mixture of tetrahydrofuran and isopropanol gave 8-acetyl-1-methyl-6-phenyl-4H-imidazo ,5-a]rl,4]benzodiazepine dipicrate as yellow prisms _ 52 -~6~49~ ~
.
m.p. 225-230 Example 22 A solution Qf 1 g (0.00317 m) o~ 8-acetyl-1-methyl~
6~phenyl-4H~imidazo~1,5-a]~1,4]benzodiazepine dipicrate in 75 ml of absolute ethanol was treated with 0.78 g ~0.0205 m) of sodium borohydride and after 18 hours the solution was evaporated -~o dryness. ~he residue was acidified with dllut~e acetic acid, made basic with ammonium hydroxide and the mixture was extracted with 75 ml of diohloromethane. ~he organic layers were combined, drled over anhydrous sodium sulfate and e~aporated to dryness. ~he oil thus obtained ; ~ uas dissolved ln isopropanol and~1.6~ e (0.007 m) of piorlc ; acid in 20 ml of ethanol was added. The precipitated salt ~
;was~filtered and reorystallized twice ~rom methanol to give ~. :
~5 8~ hydroxyethgl)-1-methy1-6-phenyl-4H--imidazo~1,5-a][1,4]-benzodiazepine dipicrate as yellow r~ds, m.p 223-225.

ExamPle ?~

The filtrates from the reaction of Example 22 were concentrated and the crude product was filtered o-~f. Re-.
crystallization twice from a mi~ture of tetrahydrofuran a~d methanol gave pure 8-(1-hydrogyethyl~ methyl-6-phenyl-5,6-dihydro~4H-imidazo~1,5-a~1,4]benzodiazepine dipiorate as yellow rods, m.p. 143 145.

.,~

.. - ..... .

~L067491 : , A solution of 56.4 g (0.20 mole) of 1,3-dihydro 7-ethyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one in 2.0 1 of tetrahydro~uran containing 4 moles of mono~ethyl-amine was chilled in an ice bath. To this was added 33.0 ml (0.30 mole) of titanium tetraohloride in 350 ml of benzene.
~he mixture was stirred at room tempsrature~for three days.

The titanium tetrachloride was decomposed with 100 ml of water. ~he inorganic salts were removed by filtra-.
tion. ~he filtrate was evaporated to dryness in vacuo. ~he ; ~ re~idue was partitioned between methylene chloride and waterO
Ths~methylene chloride layer~was dried over anhydrous~sodium :
ulfate, svaporated to dryness 1n vacuo. The residue on;
ry~tallization from acetonitrile yielded 7-ethyl-5-(2-fluoro-phen~l)-2-methylamino-~H-1,4-benzodiazepine as light ~ellow prisms, m.p. 172-174.
'~ ' ' : : ~
An analytical sample was prepared by recrystallization rom acetonitrile~to givs light yellow~prisms, m.p.~l72-174:.

Sodium nitrite (8.6 g, 0.125 m~ was added in three portions o~er a 1/2 hour period to a solution of 2905 g -(0.1 m) of 7-ethyl-5-(2-fIuorophenyl)-2-methylamino-~H-1,4 benzodiazepine in 100 ml of glacial acetic acid. After ~tirri~ for another 112 hour at room temperature, the mixture was diluted with ice-water and e~tracted with me~hylene ....... ~ .. ... . .... . .. . ~ . . --~67~91 chloride. The extracts were ~lashed ,.ith t.a~ter and aqueous bicarbonate, dried over sodium sulfate and evaporated to leave crude 7-ethyl-5-(2-fluorophenyl)-2-(N-ni-trosomethyl-amino)-3X-1,4-benzodiazepine as a yellow o:il.

.
Th~s material was dissol~ed in 100 ml of dimethyl-formamide and the solution was added to a mixture of 100 ml o~ dimethylformamide, 35 ml of nitromethane and 9.9 g of potassium t-butoxide ~hich had been stirred for l/2 hour at room temperature. After completed additlon, the reaction mixture was stirred for 1 hour at r~om temperature and for 30 minutes on the steam bath The cooled solution was .
acidified with glaoial acetic acid, diluted with ~ater and extracted with methylene chloride. The extracts were washed .
with water, dried and evapora~ed. The residue was dissolved 15~ in 50 ml of ethanol and was allowed to crystallize in the refrigerator ovèrnight after seeding. The yeLlow c~ystals were collected and recrystalllzed from ethanol yielding ~:
1,3-dihydro-7-eth~1-5-(2-fluorophenyl)-2-nitromethylene~2H-1,4-benzodiazepine, m.p. 1~8-140. Seed crystals were obtained by chromatographg of the crude product over ~0-fold ; amount of silica gel using 5% (v/v) of ethylacetate in methylene chloride. The analytical sample ~as recrystallized ~rom ether/hexane, m.p. 138-141.
:
~ Dihydro-7-ethyl 5-(2-fluorophenyl~-2-nitromethylene-2H-1,4-benzodiazepille (2.6 g) was hydrogenated for 4 hours with Raney nickel (1 tea.spoonful) in 30 ml of ethanol. The catalyst ~ 67~

~as separated by filtration and the filtrate ~as evaporated.
~he residue was dissolved in ether and the amine ,~as extracted with 10% aqueous acetic acid. The extracts ~ere washed with ether and made alkaline with ammonia.,~he precipitated amine was extracted with methylene chloride. The extracts were dried and evaporated to leave 1.5 g of crude 2-aminomethy1-2,3-dihyaro-7-ethyl-5-(2-fluorophenyl)-lH-1,4-benzodiazepine. This material was dissolved in 50 ml of xylene. The solution ~..as then heated to reflux for 2 hours after addition of 3 ml of -triethyl~
orthoacetate. ~he residue obtained after evaporation under reduced pressure was chromatographed over 50 g of silica gel using 20% methanol in methylene chloride. The homogerlous fractions were combined and evaporated to yield 3a,4-dihydro-

8-ethyl-6-(2-fluorophenyl)-1-methyl-3H-imiaazoC1,5-a~[1,4]-benzodlazepine. This material was dissolved in 50 ml of toluene and the solution was heated to reflux for l hour after addition of 5 g of activated manganese dioxide. ~he inorganic material was separated by filtration and the filtrate was evaporated.
~he residue was dissolved in ether and treated with ethanolic hydrogen chloride and acetone. The crystalline dihydrochloride (m.p. 248-255) was collected and reconverted to the base by partitioning between methylene chloride and aqueous ammonia.
~he methylene chloride layer was dried and evaporated. Crys~
`tallization of the residue from ether/he~ane yielded 8-ethyl~
6-(2-fluorophenyl)-l-methyl-4H-imidazo[l~5-aJ[l~43benzodiaze pine, m.p. 152-154.

, .,, ., ~ .. . . . . .. . .

- ~6749~L

; ~xample 25 ~ SQdium nitrite (27.6 g, 0.4 m) wa~ added in portions .

~ over a period o~ 30 minutes to a~solution of 90,~5 g (0,3 m) :
o~ 7-chloro-5-(2-~luorophenyl~-2-methylamino-3H-1,4-benzo-~
aiazeplne in 400 ml o~ glaoial~acetio acid. ~ollowing oomple-: ted~ addition, the mixture was stirred at room temperature for 1 hour and was diluted with l~I o~ wa-ter and extracted T,',i th meth~lene chloride. The extracts~were washed twioe wi~h ~; uater and then with~ lO~o aqueous s~od1um oarbonate solution.
~The solution was dried and~evaporated to yield crude~7-chIoro-5-(2-fluoropheny1)-2-(N-nitrosomethy1amino)~ 1,4-benzodiaze~
pine~as a yellow oil.

i~i ' : ~

:

:
. .

~i ,~ ' :
~ ~ ~ 7 ... ~ .. , .. ~, .... .... .. . ...... . . ... .

~06749~ :
.

~ o 5 ml o~ acetic anhydride was added 0.3 g (0.0008? m) o~ 8-amino-6-(2-fluorophenyl)-1-me-thyl-4H-imidazo[1,5-a][1,4]-benzodiazepine isopropanol and the reaction was heated on the steam bath for 1 hour, and then evaporated to dryness. The residue was dissol~ed in 25 ml of dichloromethane which was washed with~15 ml of 5~0 potassium carbonate solution, dried over anhydrous sodium sul~ate and evaporated to dryness. ~he product was recrystallized twice ~rom a mixture of methanol and ethyl acetate to gi~e 8-acetamido-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a]rl,4]benzodiazepine as white rods, m.p. 326-331.

~ . .

Example 27 A solution of 0.8 g (0.0024 m) of 8-acetamido-6-(2-fluo-~, i .
rophenyl)-1-methyl-4H-lmidazo[1,5-a~[1,4]benzodiazepine in lO ml o~dry N,N-dimethyl~ormamide under nitrogen was treatéd wlth O.I3 g (0.003 m) of 55~ sodlum hydride ln mlneral oil and after 30 minutes the reaction mixture was cooled in an ice bath. ~o :: : :
the stlrred reactlon 0.43 g (0.003 m) of methyl iodide was 20 added and after 18 hours at room temperature the reaotion mix t~re was poured into water. ~iltration afforded the crude product which was recrystallized from a mi~ture of ethyl acetata and ether to give 6-(2-fluorophenyl)-1-methyl-8-(N-methylacetamldo)-4H-imidaæo~1,5--a][1,4]benzodiaæepine 25 as o~f white prisms, m.p. 217-223.

: ~ .
, ,~,,,/r~ ~ S ~

~ (~6749~
xample 28 A solution of 0~3 g (0.000828 m) of 6-(2-fluorophenyl~-l-methyl-8-(N-methylace-tamido)-4H-imidaæo[1,5-a][1,4~benzodia-~epine in 10 ml of methanol was treated with 3 ml o~ concentra-; 5 ted hydrochloric acid and refluxed for 1 hour. The solution was made basic with ammonium hydroxide and then partitioned between 50 ml of aichloromsthane and 50~ml of water. ~he organic phase was d~ied over anhydrous sodium sulfate and evaporated to dryness. The residual oil was dissolved in 10 ml of dichloro-methane and filtered though ~lorisil. It was eluted with ether ethyl acetate and finally ethyl acetate containing 5% methanol.
This last mi~ture was evaporated and crystallized from a mixture of ethyl acetate ànd ether to give 6-(2-fluorophenyI)-l-methyI-~ 8-methylamino-4H-imidazo[1,5-a][1,4~benzodiazepine as off white ; ~15~ p~isms, m.p. 255 259.

Example29 A solution of 0.3 g (O.OOOB2 m) of 8-amino-6-(2-fluoro-phenyl)-l-methyl-4H-imidazo[1,5-a~[1,4]benzodiazepine isopropa-nol in 0.5 ml of sulfuric acid was treated with 4 g of ice followed by 0.2 g (0.0029 m) of sodium nitrite. After 5 minutes this was added to a fresh solution prepared by addlng 1 g ; (0.00625 m) of copper sulfate in 10 ml of water to 1 g (Q.00794 m) of sodium sulfite in 5 ml o~ water and then adding this to 8 g (0.116 m) of sodium nitrite in 40 ml of water.
After 15 minutes the reaction was warmed to 35 for 5 minutes, 9_ . ,., ~ ~ .

1(16749~

made basic with 10% po-tassium carbonate soluJ~ion and extracte~
with 100 ml of dichloromethane. The organic layers were co bi-ned, dried over anhydrous sodium sulfate, concentrated and applied to a silioa gel thick layer pla-te~ This was developed in a mixture of ethyl acetate and ethanol (10/1~, and the spot having an Rf of 0.5 was scraped off. ~rystallization ~rom methanol and rec~ystallization from a mixture of dichloro-methane and ether gave (2-fluorophenyl)~[2-(5-hydro~ymethyl-2-methyl-l-imidazolyl)-5-nitrophen~l]methanone as off white prisms, m.p. 188-192.

~ample30 .
A solution of 0.5 g (0.00137 m) of 8-amino-6-(2-fluoro-phenyl)-l-methyl-4H-imidazo[195-a][1,4~benzodiazepine isopro-li panol in 20 ml of formic acid and 5 ml (0.062 m) o~ 37% formal-dehyde was heated on the steam bath for 3 hours, and then eva-porated -to dryness. The residue was dissolved in 50 ml of dichloromethane, which was washed with 15 ml of 10~ potassium carbonate solution, dried over anhydrous sodlum sulfatè and concentrated ~he residual oll was applied to and developed on 2 silica gel -thick layer plates in a mixture of ethyl acetate and ethanol ~7/1). The material having an Rf of 0.4 was scraped o~f~ washed with methanol, filtered and evapora-ted.
The oil was dissolved in ether and 5 ml of a 10% ethanolic solutio~ of picric acid was added. The precipitate was ~iltered and recrystallized from a mixture of -te-trahydro~uran and isopro-panol to give (2-fluorophenyl)[2-(2-methyl~5-dimethylc~mino-~L~67491 .

methyl-l-imidazolyl)-5-dimethylaminophenyl]mctllaIlone dipicrate as yello~J prisms, m.p. 228-230.

Example 31 A) A solution of 3 g (0.00920 m) of 8-chloro-6~(2-fluoro-phenyl)-1-methyl-4X-imidazo[1,5-a][1,4~benzodiazepine in 50 ml of water and 0.5 ml (0.4092 m) of concentrated sulfuric acid uas treated wlth 1.5 g (0 0217 m) of sodium nitrite. After 18 .
hours an additional 0.5 ml of sulfuric acid and 1.5 g of sodium nitrite was added, and after 10 minutes the reaotion was made basic wi-th lON sodium hydro~ide. The reaction mixture was extracted with 75 ml of dichloromethane, which was dried over anhydrous sodium sulfate and evaporated to dYyness. Crystalli-zation of the residue -from a mixture of ethyl acetate and ether gave~(2-*luoro~phenyl)-[2-(5-hydroxymethyl 2-methyl-1-imidazolyl)-~15 5-chlorophenyl]methànone~as whi-te prisms, m.p. 165-168.

~, ..
~) A ~olu~ion of 1 g (0.00240 m) of 5-aminome-thyl-1 [4-chloro-2-(2-fluorobenzoyl)-phenyl]-2-methylimidazole dihydro-chloride was dissolved in 20 ml of water and~l g (0~0145 m) of sodium nitrite was added slowly with stirring in an ice bath.
After 3 hours the reaction was made basic ~7ith lON sodium hydro~ide and extracted with 50 ml of dichloromethane. The organic phase was dried o~er anhydrous sodium sulfate and evaporated to dryness. Crystallization from ethyl acetate gave (2-fluorophenyl~-~2-(5-hydroxymethyl-2-methyl~l-imidazolyl)-5-~5 chlorophenyl]methanone as ~7hite prisms, m.p. and mmp with a .......... . .. ..... .. . . .

1~6~9~
. .
sample prepared as above 163-166.

To a mix~ure of 0.1 g (0.000273 m) of 8-amino 6-(2-~luo-rophenyl)-l-methyI-4X-imi.dazo[1,5-a][l,~]benæodiazepine isopro-panol and 5 ml of water was added 1 ml o~ concentrated hydro-chloric acid. The reaction was cooled in an ice bath and ; 0.15 g (0.00217 m) of sodium m trite was added slowJ~ with stirring. After 1 hour the reaction mixture was poured into a solution of 0.2 g (0.00202 m) of cuprous chloride in 50 ml o~
water which had been heated to 70. After 18 hours the reaction was made basic with sodium hydroxide, extracted with dichloro-methane (2 x 50 ml) dried over anhydrous sodium sul~ate and ; evaporated to dryness. ~he residue was developed on a silica gel thick layer pla-te in a mixture of ethyl acetate and methanol (10/1). ~he product which had an Rf or 0.7 ~as scraped off the ;
pl&te~, stirred with methanol and filtered. Evaporation and crystalliæation df the crude product from a mixture of ethyl acetate and ether gave (~-fluorophenyl)-~2-(5-hydroxymethyl-2-methyl-l-imidazolyl)-5~chlGrophenyl]methanone as white prisms, m.p. and mmp with an authentic sample 159-166.
, - Example 32 A solution of 0.5 g (0.00145 m) of (2~1uorophenyl)-[2-~5-hydroxymethy1-2-methyl-1-imidazolyl)-5-chlorophenyl]-methanone in 25 ml of dichloromethanone was treated with 0.15 ml (0.00155 m) o:E phosphorous tribromide in an ice bath and after 1 hour at room tempera-~ ~`J

~ L0674~
ture was poured into 50 ml of liquid am~onia. A~ter the ammonia had evaporated the reaotion was partitioned bet.~een 50 ml of dichloromethane and water. ~he organic phase was separabed and dried over;anhydrous sodium sul~ate. The solution was conoentra~ed and the residue was applled to 2 silica gel thick layer plates which were developed in a mixture o~ ethyl acetate/10~0 methanol.

~ he compound which had an R~ of 0.6 was scraped o~, s~irred with methanol and ~iltered. ~he so~lutlon was trea~ed with 0.1 g (0.000962 m) of maleic acid and evaporated.~ ~he residual salt~was crystallizea ~rom a mixture o~ isopropanol and ether to give the maleate of 8-chloro-5-(2-~luorophenyl)-methyl-4H-imidazo[1,5-a3[1,4]benzodiazeplne as white~pris~s, .
~ m,p. and mmp with an authenti~ sample 112-115 (melting point o~ ~olvated product). The base was obtained by partitioni~g the salt between~dlchloromethane and water, adjusting the~p~, ;
separating the layers and evaporating the organic phase.

.
Crystallization of the~product from ether gave ~hite pris~sJ

m.p. and ~mp with an authentlc sample 154-157.

.

16~6749:~
. .
Example33 .
A mixture of 9.75 g (0.03 m) of 8~ohloro~6-(2-~luoro phenyl)-l-methyl-4H~imidazo[1,5-a]~194~enzodia~epine, 200 ml of methylene chloride and 12 g (0.07 m) of m-chloroperbenzoic acid was stirred for 1 1/2 hours. The solu~ion was then extracted with 3 x 150 ml of 1~ hydroohloric acid. The extra~ts were washed with ether, made alkaline with ammonia and extracted with methylene chloride. The meth~lene chIorlde extracts were dried and evaporated and the residue Nas orystallized fro~ ethyl .:
acetate to leave produot which ~as further purified by chromatography over 100 g of silioa gel using 5~0 ~v/v) of ethanol in methylene chloride. The clean ~ractions were oombined and evaporated. Crystallization o~ the residue from ethyl acetate/ether yielded 8-ohloro-6-(2-fluorophen~
~15 1-methyl-4H-imidazo[1,5-a~[1,4]benzodiazepine 5-o~ide as oolorless crystals, m.p. 245-246 ~dec.).

. .
~ample 3~

A solution of 4 g of 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidaæo[1,5-a][1,4~benzodiazepine 5-oxide in 100 ml of acetic anhydride was heated on the steam bath for 24 hours.
~he reagent was evaporated under reduced pressure, a-t the end azeotropically with ~ylene. The residue was chroma-tographed over 80 g of silica gel using 20~ (v/~) methylene chloride in ethyl aoetateO ~rys-tallization of the clean fraations from ' G

1067~9~

methylene chloride/ether yielded 4-acetoxy-8-chloro-6-(2-fluo-rophenyl)-l-meth~l 4X-lmidazo~1,5-a]C1,4]benzodiazepine as colorless crystals, m.p. 201-2Q2.

, :
E~am~
' 4-Aceto~y-8-chloro-6-~2-fluorophenyl)-1-methyl-4H-imiaazo[l,5-a~1,4]benzodiazepine (0.5 g, 1,3 mmQl) was added to 40 ml of methanol containing 4 mmol o~ sodium methoxide.
Af-ter stirring under nitrogen for 1/2 hour at room temperature, the solvent was evaporated u~der reduced pressure. The residue .
was dissolved in water and the solution .~as acidified -.Jith acetic acid.The precipltated erystals were colleoted and diesolved in methylene chloride, The solutlon was drled~and~
evaporated and the residue was crystallized from methylene ~
chloride/èthsr to yield 8-ohloro-6-(2-fluorophenyl)-4-hydroxy-1-methyl-4H-imida~o[1,5-a~[1,4]benzodiazspine as oolorless crystals, m.p~ 185-186.
.

' ' ~r~
~i ~.1 .
~.. . ~, . . .

~~67491 ample 36 A solutlon of 10 g (0.0358 m) of 7-cyano-2,3-dihydro-5-~2^fluorophenyl)-lH-1,4-benzodiazepin-2-one in 150 ml of dry tetrahydro~uran under argon was treated with 2.4 g ~0.0537 m) of 54% sodium hydride and the reaction was stirred and refluxed for 1 hour. Thls was cooled to 0 and 13.7 g ~0.0537 m) of phos-phorodimorpholidic chloride was added. After 18 hours the re-action mixture was ~iltered, concentrated to a small volume and ether was added. The precipitate was filtered and recrystallized from a mixture of dichloromethane and ether to give 7-cyano-5-~2~fluorophenyl)-2-bis-~morpholino)phosphinyloxy-3H-1,4-benzo- ~ -diazepine as white rods, m.p. 194 - 197 Example 37 To a solution of 1.6 g ~5 mmoles) of 8-chloro-5,6-dihydro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzo-diazepine in 10 ml of pyridine was added 1.2 g ~6 mmoles) of p-toluenesulfonyl chloride. After standing at room temperature for 19 hours, the reaction mixture was diluted with water and extracted with methylene chloride. The organic extract was dried -2a and concentrated in vacuo to dryness. The residue was crystalli-~ 66 -1067~91 .
zed from a mixture of methylene chloride, ether and gave 8-chloro-6-(2-fluorophenyl)-5,6-dihydro-1-methyl-5-(4-methyl-phenylsul~onyl)-4H-imidaæoC195-a][1,4]benzodiazepine melting at 252-253. After recrystallization ~rom tetrahydrofuran the pure .product formed yellow prisms with the same melting point.

~o a stirred solution o~ 2,4 g (5 mmoles) of 8-chloro-6-(2-fluorQphenyl)-5,6-dihydro-1-methyl-5-(4-mebhylphenylsul-fQnyl)-4H-imidazo[1,5-a]C1,4]benæodiazepine in 120 ml of dry tetrahydrofuran was added l.l g of potassium tert-butoæide. ~' After stirring at room temperature ~or 2 hours the'reaction mixtl~e was poured into ice water and extracted with a 50% mix-ture of ether and pe~roleum ether. The organic e~tract was dried and concentrated in vacuo to dryness. The residue was crys-tallized ~rom a miæture of ether~ petroleum ether and gave ,8-chloro-6-(2-fluorophenyl)-1-methyl-4H-~ idazo[l,5-a3~194]-benzodiazepine~melting at 152-153. The miæed melting point, ~with an authentic sample gave no depression.
. ~

Ex~mple 38 , ~o a stirred solution of 1.2 g (3.5 mmoles) of 8-chloro-6-(2-fluoropheny~ methyl-4H-imidazo[l,5-a~C1,4]benzodiaze~_ne 5-oxide in 120 ml of ethanol was added slowly 1.2 g (31 mmoles) ' :

1~ ' .
~ _ 6 ~_ .

~674~L

of sodium borohydride. After stirring for 4.5 hours at room -temperature the reaction mixture ~ras diluted with about 175 ml of ~7ater and product melting at 246 248 was separated by fil-tration After recrystallization from a mixture of methylene chloride/ether, the pure 8-chloro-6-(2-fluorophenyl)-5,6-di-hydro-5~hydroxy-1-methyl-4H-imidazo[1,5-a}[l,~benzodiazeplne formed colorless needles melting at 251-252.

A solution of 0.3 g o~ 8-chloro-6-(2-fluorophenyl)-5,6-dihydro-5-hydroxy-1-methyl-4H~imidazo[1,5-a][1,4]benzo-diazepine in a mlxture of 10 ml of pyridine and 2 ml of acetic anhydride was left at room temperature for 19 hours. The reac-tion mixture was concentrated in vacuo to dryness. The residue was dissolved in 20 ml of me-thanol and 0.2 g of sodium methoxi-, de added. After standing at room temperature for 45 minutes, the reaction mixture was concentrated in vacuo to dryness. ~he ~ .
residue-was partitioned between methylene chloride and water.
~he organic layer was separated, dried and concentrated in vacuo to dryness. ~he residue was crystallized from a methylene chloride/ether mixture and gave starting material melting at 255-256. Concent~ation of the filtrate and cr~stallization Q* the residue from ether gave ~-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine melting at 158-160. ~he mixed melting point with an authentic sample gave no depression.

,;~ ,,~ .

106749:~

xample 3 :

solution of 1.5 g of 8-chloro-5,6-dihydro-6-(2-fluoro-phenyl)-l-methyl-4H-imidazo~1,5-a]~1,4]benzodiazepine in a mixture of 10 ml pyridine and 5 ml of ace~ic anhydrid~e waæ left S at room temperature for 18 hours. ~'he ~reaction mixture was concentrated in vacuo to dryness. ~he residue was dissolved in methylene chloride and washed with dilute potassium hydro xide. ~he organic layer uas æeparated, dried and conce;ntrated ~
in vacRo to dryness. The reæidue was crystallized ~rom a ~ ~ ;
lo ~ mixture of methylene ohloride, ether, pet~oleum ether and gavæ~5-acetyl-8-ohloro-6-(2-fluorophenyl)-5,6-dihydro-1-methyl-4H-imidazo[1,5-a]~1,4~benzodiazepine melting at 185-186. After recrystalliæation from mæthylenæ chloride the pure product~
formed colorless prlsms melting Bt 186-187 15~ Example 40 ~ :
To a stirred solution of 27.8 g (92 mmoles~ of D:G-2-amino-: methyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)~ ,4-benzodi~-zepine in a mixture~of 450 ml of methylene chloride and 300 ml o~ acetic acid was added slowly 27.8 g of zinc dust. Aftær stirring at room temperature ~or 4 hours the reactio~ mi2t~re -was filtered over aelite. ~he ~lltrate was diluted with ioe y k : ~

~6749~

water, made al~aline with 50~, potassium hydroxide solution and e~tracted ~ith methylene chloride. The organic ex-tract was separatedg dried and concentrated :Ln vacuo to dryness.
The residue was crystallized from ether and gave 2-aminomethyl-7-chloro~2,3,4,5-tetrahydro-5-(2-fluorophe~ 1,4-benzo-diazepine melting at 119-120. After recrystalliæation from ether the pure product formed slightly yello-l prisms melting at 127-128.
: ~ .
The hydrochloride was prepared by treating a solution of the base in isopropanol with an exces~ of concentrated hy-drochloric acid. After recrystallization of the salt from a mixture of water and isopropanol the pure product formed slightly yellow needles melting a-t 268-271.

A) A solution of 3 g (10 mmoles) of rac 2-aminomethyl-7-chloro-2,3 9 4 ~ 5-tetrahydro-1-methyl-3H-imidazo[1,5-a][1,4]ben-zodiazepine in a mixture of 30 ml of xylene and 10 ml of tri-ethylorthoacetate (97~0) was refluxed for 4 hours. The reaction mixture was diluted with ether and extracted with dilute ice cold hydrochloric acid. ~he acid extract ~as made alkaline with dilute potassium hydroxide and extracted with methylene chloride. The organic layer was separated, dried and concen-trated in vacuo to dryness. The residue was crystallized from e~her and gave 8-chloro-6-(2-fluorophenyl)-3a,4,5,6-tetrahydro-l-methyl-3H-imidaæo[1,5-a]~1,4]benzodiazepine (Isomer A) melting at 187 189. After recrystallization from a mix-ture o~ methylene chloride and ether the pure product formed slightly lOf~7~9~

.
yellow prisms melting at 189-190.

B) ~ a stirred solution of 2.5 g of 8-chloro-3a,~-dihydro-6-(2-fluorophenyl)-1-methyl-3H-imidazo[1,5-a][1,4]benzodiazepine ~n a mixture of 100 ml methylene chloride and 25 ml of acetic acid was added slowly 2.5 g of zinc dust. After stirring at room temperature ~or 4 hours, the reaction mixture was filtered over elite. ~he flltrate was diluted ~llth ice ~rater, made alkaline with 50~0 potassium hydroæide and extracted with methylene chlo-ride. The organic e~tract was separated, dried and concentrated 10 in vacuo to dryness. The residue was crystallized ~rom ether and gave 8-chloro-6-t2-fluorophenyl)-3a,4,5,6-tetrahydro-1-meth~l-3H-imidazo[1,5-a][1,4]benzodiazepine (lsomer A) which was iden-.
ical with the product prepared above, m.p. and mmp 189-190.

a~ A solution o~ 3.2 e (10 mmoles) of 8-chloro-3a,4-dihydro-!~ :
~6F(2- M uorophenyl)-1-methyl-3H-imidazo[1,5-a][1,4]benzodiazepine in 50 ml acetic acid and lO ml o~ water was hydrogenated at room temperature and atmospheric pressure in the presenae of 0.4 g o~ prehydrogenated platinum o~ide. After 1~ minutes, 10 mmoles o~ hydrogen were absorbed. ~he ca~alys-t was separated by fil-.
tration and the ~iltrate cQncentrated in vacuo to dryness. The residue was dissolved in methylene chloride and washed with an excess of ice cold dilute sodium carbonate. ~he organic layer was separated, dried and concentrated in vacuo to dryness. The ~ residue was crystallized ~rom a mixture of ether/petroleum ether and gave ~-chloro-6-(2-fluorophenyl)-3a,4~5,6-tetrahydro-l-methyl-3H-imidazo[1,5-a][1,4]benzodiazepine (Isomer B) ~3 ~ 7l 67~9~L
~elting at 108-110. After recrystallization fro~ ether the pure product formed colorless prisms meltin~ at 110-112.

A mixture of 2.9 g of 8-chloro-6-(2-fluorophenyl)-3a,4,5,6-tetrahydro-1-methyl-3H-imidazo[1,5-a]~ ]benæo-diazepine, 90 ml of toluene and 15 g of activated manganesedioxlde was stirred and refluxed for 2 hours. ~he reaction was filtered over Hyflo and the filtrate concentrated in vacuo to dryness. ~he residue was crystallized from ether and gave 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a~Clj 4 benzodiazepine which gave no meltir~ point depression with an authentic sample.

Example 41 A suspension of 17 g (0.05 m) of 7-chloro-1,3-di~dro-5-(2-fluorophenyl)O2-nitromethylene-2H-1,4-benzodiazepine-~
oxide in 200 ml of tetrahydrofuran a~d 100 ml of methanol -ias hydrogenated in presence of 17 g o~ Raney nickel at an ini~ial pressure of 155 psi for 24 hrs. The catalyst was removed by filtration and the filtrate ~las evaporated. ~he residue was dissolved in 50 ml of 2-propanol and warmed on the steambath~
A ~arm solution of 17 g of maleic acid in 60 ml o ethanol ~as added and the salt was allowed to crystallïze by cooling in the ice bath. ~he 2-aminome~hyl-7-ch1oro-2~3-dihydro-5--(2-flUOrO
phenyl)-~I-l~4-benzodiaæ0pine dimaleate consisted o-f yello7 ~6749~

crystals with mp. 196-198.

2-Amino~ethyl~7-chloro-2,~-dihydro-5~(2-fluorophen~
lH-1,4~benzodiazepine dimaleate (8.0 g, 0.015 m) was partitioned between methylene chloride and a~veous ammonia. The methylene chloride solution was washed with water, dried over sodium sulfate and evaporated. The residue was dissolved in 50 ml o~ pyridine. After addition of 10 ml of acetic anhydride the mi~ture was heated on the steam bath for 4 hours. ~he reagents were evaporated under reduced preæsure and the residue was partitioned bet~een methylene chloride and aqueous sodium bicarbo~ate solu-tion. The`organlc layer was dried and evapora-ted. arystallization of the residue from methylene chloride/
ether with seedin~ yielded l-acetyl-2-acetylaminomethyl-7-chloro~2,3-dihydro-5-(2-fluorophenyl)-IH-1,4-benzodlazepine, mp. 213-215 Seeds were obta~ned by chromatography over silica gel (40 fold amount) using 10~ (v/v) ethanol in methylene chlo-ride for elution. ~he analytical sample was recrystalllzed `
from ethylace-tate/hexane and had a melting point of 215-Z17.

A mixture of 0.5 g of 1-acetyl-2-acetylaminomethyl~-7-~
chloro~2,3-dihydro-5-(2-fluorophenyl)-IH~ benzodiazepine and 10 g of polyphosphoric acid was heated to 150-170 for 10 min. The cool reaction mixture was dissolved in ice-water and the solùtion was made alkaline with ammonia. The precipita-ted base was ex-tracted with methylene chloride. The e~tracts were washed wi~h water~ dried over sodium sul~ate and e~apora-~ed. ~he residue was chromatographed over 10 ~ of silica gel 1067~9~

using 20% methanol in methylene chloride. 'l`he clean fractions were combined and evaporated. The residue was crJs-tallized from ether to yield 8-chloro-3a,4-dihydro-6-(2-fluorophenyl)-l-methyl-~E-imidazo~1,5-a~[1,4]benzodiazepine, mp. 142-144~.

~a~

A solution of 2.9 g (0.00927 m) of 2,3-dihydro-5-(2-~luoropheny1)-2-nitromethylene-lH-1,4-benzodiazepine-4-oxide in a mixture of 1 teaspoon of Raney nickel, 90 ml of tetra-hydrofuran and 45 ml of methanol was hydrogenated at atmospheric pressure and at room temperature for 2.3 hr.~he mixture was ~iltered, and the nickel was washed with dichloromethane. ~he combined filtrated were evaporated and the resulting o:ll was dlssolved in 50 ml of dichloromethane which ~ras washed with 50 ml of dilute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated to dryness. A solution Df 2.2 g (0.019 m) of maleic acid in 15 ml of ethanol was added to the oil and after ether was added 2-aminomethyl-2,3-dihydro-5-(2-fluorophenyl)~lH 1,4-benzodiazepine dimaleate hemihydrate crystallized. Recrystallization from a mixture of methanol and ether gave a product as yellpw rods, m.p. 147-150.

A solution of ~.0 g (0.0149 m) of the ~se of 2-amino methyl-2,3-dihydro-5-(2-fluorophenyl)-IH-1,4-benzodLazepine dimaleate hemihydrate in 125 ml of absolute ethanol was treated with 4 g (0.0247 m) of triethylorthoacetate and 0.5 g (0.00263 m) o~ p-toluene sulfonic acid After refluxing the ml~ture ~or 6~491 2 hr~ the reaction was evaporated to dryness. The resulting oil was dissolved in 50 ml of dichloro~.ethane, which was washed with 50 ml o~ dilute ammonium hydro~ide, dried over anhydrous sodium sulfate and evaporated to dryness to yield the crude 3a,4-dlhydro-6-(2-fluorophenyl)-1-methyl-3H-imidaæo~1,5-a]-[1,4]benzodiazepine as an oil.

~)~ The crude produot from the previous paragraph was dissolved in 100 ml of toulene, treated wi-th 18 g of activa-ted manganese dioxide and the mixture ~7as stirred and reflu-~ed for 3.5 hr. using a Dean ~tark trap. The reaction mixture was filtered through Celite and the precipitate was washed with 100 ml of tetrahydrofuran and then 100 ml o~ dichloromethane.
The combined filtrates were evaporated~and the residue was dissolved in 25 ml of dichloromethane. This solution was chromatographed through a ~lorisil column with dichloromethane, and then eluted with ether. ~lution with ethyl acetate and then a 10% (v¦v) soIution of methanol in ethyl acetate gave the crude product, which was crystallized from ether and then ; recrystallized from ethyl acetate to give 6-(2-fluorophenyl)-1-methy1-4H-imidazo[1,5-a~[1,4~benzodiazepine as white prisms, m.p. 164-168.
.
~) A solution of 1.2 g (0.0041 m) of 3a94-dihydro-6-(2-fluo-rophenyl)-l-methyl-3H-imidazo[1,5-a]~1,4]benæodiazepine in 50 ml of mesitylene and 0.5 g of 10~ palladiwm on charcoal was stirred and reflu~ed for 28 hr., and then it was filtered and evaporated to dryness. ~rystallization from ethyl acetate , ~ 7~~_ 6749~l ,~ave 6-(2-fluoropherlyl)-l-meth~l-4H-imidazo~l,s-a~l,4J~enzo-diazepine as white prisms, m.p. 162-167, and a mixed m.p.
with authentic product melted at 162-168.

..
A solution of 0.~ g (0.00103 m) of 6-(2-fluorophenyl)-l-methyl-4H-imidazo[l,S-a][1,4]benzodiazepine in 2 ml of concentrated sulfuric acid was cooled to 0, and a solution of 0.11 g (0.0011 m) of potassium nitrate in 1.5 ml of concen-trated sulfuric acid was added dropwise. After 18 hr. at room temperature an additional 20 mg (0.00~2 m) of potassium nitra-te was added and the reaction was stired for 5 hr. and then poured into a beaker oontaining ice. The mixture was made ~asic with ammonium hydroxide, and extracted uith 50 ml of dichloromethane which was separated, dried over anhydrous sodium sulfatej and evaporated to dryness. The oil was dissolved in 3 ml of dichloromethane ana applied to a silica gel thick layer plate which was developed in a mi~-ture of ethyl acetate ~; and ethanol (3~ . The nitrated product ~las sGraped off the plate and stirred with a 1:1 (v/v) mixture of methanol and dichloromethane and filtered. The ~iltrated were evaporated and the residue was crystallized from methanol.~Recrystalliza-tio~ from a mixture o~ dichloromethane and petroleum ether gave 6-(2--~luoro-5-nitrophenyl)-1-methy1-4H-imidazo[1,5-a~
[1,4]ben~odiazepine as ~hite prisms, m.p. 199-203.

, ` 1al6749~l E~ample 4~

41.3 g of 8 chloro~ dimethy1-6-~2 fluorophenyl)-4H-imidazo[1,5-a][1,4]benzodiazepine dihydrochloride was par titloned between methylene ohloride and aqueous ammonia. The ~-methylene chloride solution was washed with water, dried over ~sodiu~ sulfate and evaporated to leave the free ba~e This material was dissolved in 50 ml of 2-propanol and the solution was tr~ated with a solution of 12 g of maleic acid in 40 ml of 2-propanol. The solution was gradually diluted with 300 ml of ether~ The precipitated crystals were collected and~dried to leave 8-chloro-1,4-di~methyl-6-(2-fluoropheny13-4H-imidaæo-, , , ~ ~ ~1,5-a]~1,4]be~zodiazepine~maleate,m.p. 130-132 a~ter recrys-: ~ .
tallization~from ethanol~etherJ

E~a~

A ~olution of 5 g (0.00153 m) of 8~chloro-6-(2-fluoro-phenyl)-l-methgl-4H-imidazo[1,5-a][1,4]benzodiazepine in 75~ml o~ dry ethylene dichloride ~as cooled in an ice bath and~5 g (0.0352 m) o~ boron trlfluoride etherate was added.~ ;
After 10 minutes s solution of 4 g~(0.091 m) o~ ethylene oxide in 5 ml of ethylene dichloride was added with stirring. After 1 hour at room temperature the mixture was made basic with a olution of potassium carbonate in water. The organic layer was separated, dried over anhydrous sodium su~fate, and evaporated.
; The residue was dissolved in 50 ml of dichloromethane and fil-tered through 150 g of ~lorisil. The Florisil was e~uted with 7 ~

1~6~49~

750 ml of dichloromethane and then with 750 ml of ether.
The dichloromethane solution was evaporated and par-titioned between 100 ml of ether and 100 ml of 0,5N hydrochloric acid. The acid layer was separated, made basic with ammonium hydroxide and extracted with 100 ml of dichloromethane which was dried and evaporated. The oil was dissolved in 15 ml of isopro-panol and 0.8 g ~0.0069 m) of maleic acid was added. The solu-tion was warmed on the steam bath for 5 minutes~, cooled and ether was added. The precipitate was filtered, and recrystal-lized from a mixture of methanol and ether to give 2-chlo~o-13a-(2-fluorophenyl)-12,13a-dihydro-6-methyl-9H-llH-imidazo[1,5-a]-oxazolo~3,2-d][1,4]benzodiazepine male~te as white prisms, m.p. 195 - 200.
The ether solution from the Florisil was concentrated, filtered and recrystallized from ether to give the base as white prisms, m.p. 178 - 180.
Example 46 A stirred solution of 29.9 g (D.l m) of 1,3-dihydro-5-(2-fluorophenyl~-7-nitro-2~-1,4-benzodia7epin-2-one in 500 ml 2Q ofdry~tetrahydrofuran was treated under argon portionwise with 5.5 g ~0.125 m) of a 54% mineral oil dispersion of sodium hydride and stirring was continued for 1 hour longer. Dimorpholino-phosphine chloride ~38 g, 0.15 m) wa~ add~d to the dark solu-tion in one portion and stirring under argon was continued for ~ 78 ~

~6~
8 hours. T~e resultant dark mixture was ~iltered over filter aid and concentrated in Yacuo at S0~ to give a dark gum. When the dark gum was stirred at room temperature in 75 ml of ethyl acetate, crystallization occurred to glve a paste. After cooling in an ice bath for 30 minutes the mix~ure was ~iltered and the light tan solid was washed 3 times with 35 ml portions of 2:1 ether/eth~l acetate and finall~ with ether. Air drying on the funnel yielded nearly pure 5-(2-fluorophen~1)-2 [bis~morpholino) phosphinyloxy]-7-nitro-3H-1,4-benzodiazepine. Recrystalliza-1~ tion from 15 fold amount of ethyl acetate gave off-white needles, m.p. 169 - 172.
Example 47 Fifty-four percent sodium hydride in mineral oil dis-persion Cll g, 0.25 m) was added in portions to a stirred solu-tion of 63.2 g ~0.2 m) of 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one in 1 1 of tetrahydro~uran under argon After refluxing on a steam bath ~or 1 hour, the solu-tion was cooled to room temperature and treated with 76.2 g ~0.3 m) o~ dimorpholinophosphinic chlorlde portionwise. Stir-ring at room temperature was continued for 5 hours. The dark mixture was filtered through Celite. Concentration of the filtrate in vacuo and boiling the dark residue with ether gaYe tan crystals of 7-bro~o-2-[bis~morpholino)phosphinrlox~]-5-C2~pyridyl)~3H-l~4-6enzodiazepine. A sample was recrystal-lized by dissolving i~ in 2 ml of me~hylene chloride, filtering, diluting with 10 ml of ethyl acetate and cooling in an ice bath to give light tan plates, m.p. 180 - 182 ~dec.).

~ 79 -~06~491 Example 48 6 g C0.125 m) o~ sodium hydride dispersion (50% in mineral oll), was added to a solution o 28.1 g ~0.1 m) o 1,3-dlhy~ro-7-nitro-5-phenyl-2H-lJ4-benzodiazepin~2-one in 3Q0 ml o~ dry~tetrahydrofuran. Ai~ter stirring i'or 1 hour at room temperature 30.2 g ~0.12 m) oi~ dimorphollnophosphinic chloride was added and stirring was continued ~or 4 hours.
The product was crystallized by addition o~ water and ether.
The precipitate was collected and dlssol~ed in methylene :
10 ~ c~loride. The solution was dried and evaporated and the re-sidue was crystallized~irom ethyl acetate to yield crude 7-nitro-2-[bis(morpholino)phosphinyloxy]-5-phenyl-3H-1,4-benæodiazepine, m.p. 208 - 209.

.
:
: ~

: ' ~: :
:
: :

~ 80 ~

.

11 6'7491 :

A solution o~ 25 g Q~ 8-chloro-6-~2-~luorophenyl)~
methyl~4H~imidazo[1,5~a][1,4]benzodiazepine in 50 ml of water `
and 50 ml of concentrated hydroohIoric acid was allo~,red to ~;- 5 stand at room temperature~for 3 hours. ~ollowing addition of 250 ml of 2-propanol the mixture was evaporated partiall~ `~
under!reduoed pressure without heating. Additlonal 200 ml o~
2-propanol were added and partial evaporation was resumed.
he precipitated crystals were collected and washed well ~ith 2-propanol and ether to yield 5-aminometh~ [4-chloro-2~
(2-fluorobenzoyl)phe~yl]-2-methylimidazole dihydrochloride~, ;
m.p.~302-~07 ~deo~ he analytical sample was recrystallized r~m~méthanol/2-propanol wlthout heating. .

' ` ' "~.. ;~ . ~/
~ ' . :

1C~674~

~ 50 A mixture o~ 49.9 (0,2 moles) of 2-amino 5-chloro-2'-fluorobenzophenone, 38.0 g (0.3 moles3 of 2,2-dichloro propa--~ ~ ~al; 18.0 g (0.11 moles~ of hydroxylamine sulfate and 500 ml o~ ethanol was stirred at room temperature for 2 days.
.
~ he mixture was diluted with 200 mI of lO~o a~ueous ~odium carbonate solution with vigorous agitation. A gu~my material precipitated from~solution and the solution was diluted with 1.0 1 of ioe-water. ~he so~ution was extracted with 3 x 300 ml of dichloromethane. The extracts were combined7 dried over sodium sulfate ~iltered and concentrated to dryness in vacuo~ The residue was orystallizea ~rom dichloromethane and pQtroleum ether giving 6-chloro-2-(1,1-dichloroethyl)-~ .
1,2-dihydro-4-(2-fluorophenyl)-quina~oline 3-oxide as yellow pri~ms, m.p. 195-8 (deo.).
'r;, 3.8 ml of Nitromethane~was added to 50.0 ml of dimet~yl- ~ -~; formamide with stirring and under an a-tmosphere of nitrogen. The solution was chilled to 0 and 1.3 g (0.012 moles) of potassium tertia~y butoxide was added in portions. ~he temperature was maintained at 0 to 10 by means of an ice wa~er bath~ ~he mixture was stirred at room temperature for 1 hour.

The mixture was chilled to 5 with stirring and 2.2 g (0.006 moles) of the quinazoline was added at 5 to 9 in portions. A~ter the addition had been completed, the mixture was ~,.,.~ , ~

... ~. ... .. . . :

`~06749~
stirred at room temperature for 17 hours.
, The reaction mi~ture was poured into ice water ~nd dichloromethane neutralizing with glacial acetic acid. ~he dichloromethane was washed with ~rater; brine and dried over ;~ 5 sodium sulfateO After ~iltration and concentration an amber residue was obtai~ed which was cr~stallized with ethyl acetate.
The crystals were collected and dried giving orange 7-chIoro~
1,3-dihydro-5-(2-fluorophenyl)~-3-methyl-2-nitromethylene-2H-1,4-benzodiazepine-4-oxide as prisms,m.p. 198-200. Recrystal~ ;~
lization ~rom dichloromethane/ethyl acetate gave pure material m.p. 2i6-218 ~dec.).

~xamPle 51 A solution o-F 0.7 g (0.00203 m) of (2-fl~orophenyl)-: .
2-~5-hydroxymethyl-2-methyl-1-imldazolyl)-5-chlorophenyl]~
lS methanone in 40 ml of dry dichloromethane was cooled in an ice bath and 0.22 ml (0.00227 m) of phosphorus tribromide was added with stirring. After l hr. at room temperature the mixture was oooled in an ioe bath and 2 ml (0.0~28 m) of ethanolamine :~
. .

~i749~

was added. ~he solutio~ ~as stirred for 2 hl~s. at roo~ t~pe~
rature, refluxed for 1 hr. and then poured into 50 ml o- -ater.
~he organic la~er was separated, dried over anhydrous sodium sulfate, and concen-trated to a small volume. The residue ~as developed on 4 silica gel thick layer plates in a solution o~
5% methanol in ethyl acetate (v/~)O ~he material corresponding to an Rf of 0.5 was removed from the plate and treated with methanol. ~he solution was filtered and the ~iltrates ~lere eva-porated. ~he residue was crystallized from ether yieldi~g 2-chloro~13a-(2~fluorophengl)-12,13a dihydro-6-methyl-~H,llH-imidazo[l,5-a]oxazolo-[3,2-d][1,4]benzodiazepine. Recr~s-talli-æation from a mixture o~ methanol and ether gave pure product as white prisms, mp and mmp with an authentic sanple 176-181.

;..., ~ ' :

... , ~, ~ .A ~ . , .. , . . . --101E;749~L

~xample 52

9.5 ml o~ Nitromethane was dissol~ed in 100 ml of dimethylformamide under nitrogen and with stirring 5,0 g (0.045 moles) of potassium tertiary butoxide was added at 0-10 and the mi~ure was stirred at room temperature ~or 1 hourO ~he mi~ture was then chilled on ice and 5.1 g (0,015 moles) of 6-chloro-2-dichlo~omethy1-1,2-dihydro-4-phenyl-uinazol me 3-oxide was added slowly at a temperature below , 9. The reaction mixture was stirred at room temperature for 17 hours.

.
The mix-ture wa~ poured on~o ice-water and dichloromethane and made slightly acid wlth glacial aoetic acid. ~he aquecus phase was re-extracted three times with dichloromethane. ~he organics;were combined; washed~consecuti~ely with uater and ~ -~
15~ ~ brine,~ dried over scdium sul~ate; filtered and concentrated todryness in vaouo giving an amber residue. arystallisation from boiling ethanol a~orded 7-chlorol,3-dihydro 2-nitromethylene-5-pheny1-2H-1,4-benzodiazepine-4-oxide as yellow p~ism~, mp. 245-248 (dec.). Admixture~with authentic ~aterial gave no depression in melting point.

. : : .
Potassium tert. butoxide (3.37 g, 0.03 m), was added to a stirred suspension o~ 3.5 g (0,01 m) of 7-chloro-1,3-dihydro-5-(2~fluorophenyl)-2-nitromethylene-2H-1,4-benzodia-. .- .~ . . .

zepine 4-oxide in 100 ml of dimethylformamlde cooled to -20.
A-lter stirring under nitrogen for 10 min at this temperature 2.13 g (0,015 m) of methyliodide was added and stirring was continued for 10 min. The reaction mixture was neutralized by addition of glacial acetic acid and ~las partitioned between water and methylené chloride. The organic phase was~separated, dried over sodium sul~ate and evaporated. The residue was crystallized from methylene chloride/ethyl acetatei to yield 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-~-methyl-2-nitromethyl-ene-2H~1,4-benzodi.azepine 4-oxid.e as yellow crystals, mp.
215-218. ~he anal.ytical sample was recrystallized from t~e ~ame solvents, mp. 216-218.

.
' xample 54 A mi~ture of 7-chloro-193-dihydro-5-~2-fluorophenyl)-2H-1,4-benzodiazepine-?-carboxamide (64 mg, 0.2 mmole) an f.
lithium aluminum hydride (15 mg, 0.4 mmole) in dry T~F (3 ml) was boiled for ~5 min. The cooled reaction mixture was quenched by addition of saturated aqueous sodium sulfate solution. Tlc analysis of the resulting solution showèd the presenoe of starting material as the major, more mobile component and the free base 2-aminomethyl-7-chloro~2,3-dihydro-5-(2-fluorophenyl)-IH-1,4-benzodiazepine as the minor component. The solution wa~ trans~erred directly to a 20 x 20 cm~ preparative tlc plate (silica gel) and the plate wa~ developed with ethanol.
The lower yellow band was remo~ed and extracted twice~with methanol/methylene chloride (2:1). Evaporation of the filtered 1(:16749 .-extract left a clear, colorless oil. This ~!aS taken up in ethanol (1 ml), treated wi~h excess maleic acid (50 mg), scratched and stored overnight in the freezer. The yellow cry~tals were collected, washed with ether and air-dried.
~he product was identified as 2-aminomethyl-7-chloro-2~3-dihydro-5-(2-fluorophenyl)-IH-1,4-benzodiazepine dimaleate by comparison of its infrared spectrum in Nujol, and of ~ its melting point 185-186.5 with those of an authentic - ~ eample (mp 188). ~he mixture melting point was 184-7-.

i Example 55 A mi~ture of 10 g (0.036 m) o* 1,3-dihydro-5-phenyl-:
2H-thleno-[3,2-e][1,4]diazepine-2-one in 50 ml of benzene and 300 ml of tetrahydrofuran was stirred on an ice bath and saturated with methylamine~ gas. To this mixture was added dropwise a solution of titanium tetrachloride (9.48 g, 0.05 m) in 50 ml of benzene. After the addition was complete, the mixture was stirred on the ice bath for 15 minutes. The ice bath was then replaced with a heating mantel and the mixture refluxed *or 1/2 hour. ~he mixture;~was cooled and 100 g of ice carefully added. The mi~ture was filtered and the residue washed with tetrahydro~uran. The filtrates were combined, dried and evaporated. The product was crystallised from methylene chloride to yield 2-methylamino-5-phenyl-3X-thieno-[3,2-e]
, [1,4~diazepine~ m.p. 223-227. From the concentrated mother liquors was obtained additional product, m.p. 222-225. ~he analytical sample was recrystallized ~rom methylene chloride, ~?.~

` ~67491 m.p~ 222 229.

Nitrosyl chloride was introduced into a solution o*
7.8 g ~0.03 m) of 2~-methylamino-5-phenyl-3H-thieno[3,2-e~-[1~4~aiazepine in 100 ml o~ methylene chloride and 40 ml o~ pyridine cooled in ice water. The reaotlon was monitored by thin layer chromatography and when the starting material had~disappeared the~nitrosyl chloride addition was termina-ted and the reaction migture was~partitioned bet~een methylene chloride and water. ~he methylene chloride solution was dried and evaporated. Crystallization~of the residue from meth~lene chloride/hexane yielded 2-(N-nitrosomethylamino)-5-phenyl-~H-thieno[3,2-e}C1,4]dlazeplne as yellow orystals, m.p. 156 159.

.
he analytical sample was recr~stallized~from ether/hexane, m.p~.~158-160.

15~ 2-(N-nitrosomethylamino~)-5-phenyl-3H-thieno[~3,2-e][1,4]-diazepine~ (5.7 g,~0.02 m~ was added~to~a mlxture ~of 15;~ml of nitromethane, 4.5 g of potassium t-butoxide and 60 ml of dimethylformamide whioh had been stirred for 10 mlnutes at room temperat~re~ Follouing addition,~the~reaction mi~ture 2~ ~ was stirred under nitrogen and heated on the steam bath for

10 minutes. After acidification wikh 4 ml of glacial acetic acid the mixture was partitioned between methylene ohloride/
toluene and saturated sodium bicarbonate solution.~The organic layer was washed with water, dried and evaporated. Crystalli-zation of the residue from methanol with seedlng ylelded1,2~dihydro-2-nitromethylene-5-phenyl-3H-thieno~3~2-e][1,4]-.' .

,7'~L9~L
.'` " "
diazepine as yello.~ crystals, m.p.`l60-:L63. Seed~ ~ere obtained by chromatographic ~vrification over 30 ~old amount of silica gel using 10% (v/v) of ethyl acetate in methylene chloride. The analytical sample was recrystallized from methanol, m.p. 163-164.

A solution of 1.42 g ~5 mmol) ~f 1,2-dihydro-2-nitro-methylene-5-phenyl-3X-thieno[3,2-e~[1,4]diazepine in 200 ml of ethanol was hydrogenated over Raney nickel (2 teaspoonsful) for 1 hour at atmospheric pressure. The catalyst as removed by filtration and the filtrate ~as evaporated. ~he residue was -treated with 1.2 g of maleic acid~in lO ml of 2~propanol.
~he salt was orystallized by addi-tion of ether to yield 2-amino-methyl-2,3-dihydro-5-phenyl-lX-thieno[3,2-e][1,4]diazepine dimaleate as yellow crystals, m.p. 170-173. The anal~ical , sample was recrystallized from methanol/2-propa~ol) m.p.
187-189.

2-~minomethyl-2,3-dihydro-5-phenyl-lH-thieno[3,2-e]-[1,4]diazepine dimaleate (1 g, 2 mmol~, was partitioned between methylene chloride and aqueous ammonia. The methylene chloride layer was dried and evaporated. The residue was heated to reflux for 1 hour with 1 ml o~ triethyl orthoacetate in 20 ml of xylene. ~he solvent was evaporated under reduced pressure and the residue was crystallized from 2~propanol/ethar to yield l-methyl~a,4-dihydro-6-pheny1-3H-imidazo[1,5-a]thieno-L2,3-f~diazepine, m.p. 150-152. This material ~as heated to reflu~ in 30 ml of toluene with 2 g of acti~ated manganese ~ -~;7~91 . . .
dioxide for 2 hours. The man~anese diox:lde was filtered off and washed well w1th methylene chloride The filtrate ~ s evaporated and the residue was chromatographed over 7 g of silica gel using 3~0 (v/v) of ethanol in methylene chloride.
~he fractions containing pure product were combined and evaporated. ~xystalliza-tion from methylene chloride/ether and recrystallization from ethyl acetate/hexane yielded l-methyl-6-phenyl-4H-imidazo[1,5-a~thieno[2,3-f]d1azepine, m.p. 2Z3-225.

~a~ ':

A mixture of 7 7 g (0.278~m) of 7-chloro 1,~-dihydro-5-pheny~-2H-thieno[2,~-e]C1,4]diazepin-2-one, 50 ml of benzene :: : : : : :
; and 2$0 ml of tetrahydro~uran was stirred on an ice bath and saturated with methylamine gas. ~o this mixture ~las added a solution o~ titanium ~tetrachlor1de (7.38 g, 0.0389 m) in 50 ml o~ benzene from a dropping funnel. After the addition was~ com- ;~
..
plete, the mixture was stirred on the ice bath for 15 minutes.
; ~he ice bath was then replaced by a-heating mantel and the reaction mixture was refluxed for 20 minutes. The mlxture was cooled and 100 g o~ ice were care~ully added. The mixture was then filtered, and the residue washed with tetrahydrofuran.
~he filtrate were combined, dried and evaporated. The residue was crystallised ~rom methylene chloride/e~her yielding 7-chloro-5-phenyl-2-methylamino-3X-thieno-[2,3-e][1,4~diazepine, m.p. 246~249. The analytical sample was recrys-talIized ~ro~
methylene chloride, m.p. 247-250.

~o .

~L06749~1 .

Nitrosyl chloride was introduced into a solution~of 5.8 g (0.02 m) of 7-chloro-5-phenyl-2-methylamino-3H-thieno-~2,3-e][1,4]diazepine in 100 ml of methylene chloride and 50 ml of pyridine until the reaction was complete according to thin layer chromatogram. ~he mlxture was partitioned between water and toluene. ~he organic phase was dried and evaporated. Crys-talli~ation of the residue from ether/hegane yielded 7-chloro-- 2-(N-nitrosomethylamino)-5-phenyl-3H-thieno[2,3-e]~ ]dia~epi-ne as yellow crystals, m.p. 108-110. ~or analysis lt w9s recrystallized from ether/he~ane, m.p. 111~ .

7--~hloro-2-(N-nitrosomsth~1amino)-5~phenyl-3~-thieno-C2,3-e][1,43diazepine (3 2 g, 0.01 m) was added to a~mixture of 10 ml of nitromethane, 35 ml of dlmethyl~ormæmide and 2.26 g : . , ~ ::
(0.02 m~ of potassium t-buto~ide which had been stirred under 15~ ~ ni~rogen for 10 minutes at room temperature. After heating or 10 minutes on the steam bath the reaction mixture was aoidified by addition of 2 ml of glacial acetic acid and was partitioned between water and~toluene. ~he toluene 1aysr was washed with water, dried and evaporated. ~he residue crystalli-~ed from sthyl acstate/he~ane to yield crude 7-chloro-2,3-dih~dro-2-nitromethylene-5-phenyl-IH-thieno[2,3-è][1,4Jdia-zepine. It was puri~ied by chromatography over 40 g o~ silica gel using 10% (v/v) o~ ethyl acetate in methylene chlorids.

The pure product was obtained as yellow crystals ~lith m.p.
154_1S6.

"j ~0~749~ .

A) A solution o~ 320 mg (1 mmol) o~ 7-chloro-2,3-dihydro-2-nitromethylene~5--phen~l-IH-thieno[2,3-e][1,4]diazepine in 20 ml of ethanol was hydrogenated over Raney nickel for 5 hours at atmospheric pressure. ~he catalyst was removed by filtration and the ~iltrate was evaporated. The residue was chromatographed over 7 g of silica gel usin~ methylene chloride, methanol and -triethylamine in a ratio of 13:6~ he fractions containing pure product were combined, evapor2ted and the residue was treated with maleic acid in 2-propanol. Crystalli-.
~ation o~ the dimaleate salt from 2-propanol/ether and recrystalliæation ~rom ethyl acetate/ethanol yielded 2-amino-methyl~7-chloro-2,3-dihydro-5-phenyl-IH-thieno[2,3-e][1,4]-diazepine d~ aleate as yellow orystals, m p. 176-177.

. ~ .
B~ ~ ~ solution of 320 mg (1 mmol) o~ 7-chloro-2,3-d~ihydro-~2-nitromethylene-5-phenyl~ thieno[2,3-e][1,4]diazepine in 3 ml o~ tetrahydro~uran was aaded to a suspension of~0.8 g of lithium aluminum hydride in 20 ml of tetrahydrofuran. After ~``
heating tc reflux for 5 minutes, the reaction mixturs was cooled and hydrolyzed by addition of 5 ml of water. ~he inorga-nic matsrial was separated~by filtration and the ~lltrate was evaporated. The residue was chromatographed as described above and the pure product uas con~erted to the maleate to give 2-aminomethyl-7-chloro-2,3-dihyd~o-5-phenyl-IH-thieno[2,3-e]-¦1,4~diazepine dimaleate as, m.p. 176-178.

2-~minomethyl-7-chloro-2,3-dihydro-5-phenyl-lH-thieno-~2,3-e][1~4~diazepine dimaleate (0.52 g, 1 ~mol) ~as partitioned ..

.. . .

~674g~

be-tween methylene chloride and aqueous ammonia. ~he methylene chloride solution was dried and evaporated. The re~idue was heated to re~lux ~or 1 hour wi~h 0.5 ml o~ triethyl ortho-acetate in 10 ml of ~ylene. The crude product obtained after e~aporation under reduced pressure was dissolved in 25 ml of toluene and the solution was heated to reflux for 1 1/2 hours a~er addition of 2.5 g o* activated manganese dioxide. The manganese dioxide was then filtered off and the flltrate was evaporated. f~he residue was chromatographed over 6 g o~ silica , gel usin~ 4% (v/v) of ethanol in methylene chloride. Fractions co~taining the pure compound were oombined and e~aporated.
Crystallization of the residue ~rom etherjhexane yielded 8-chloro-1 methyl-6-pheny1-4H- midazo[1,5-a]thieno[~,2 [1,4]diazepine, m.p. 168-170.

A solution of 50 g (0.161 m~ o* 7-chloro-5-(2-chloro-~;
phenyl)-1,3-dihydro-2H-thieno[2,3-e]C1,4]diazepin 2-one in 900 ml o~ dry tetrahydrofuran and 300 ml of dry benzene was cooled in an ice bath, methylamine was bubbled in until the so7ution was saturated and a solution of 40 g (Oi209 m) o~
titanium tetrachloride in 100 ml of benzene was ~dded dropwise with stirring. A~ter 4 hours at room temperature a few grams o~
ice were added and the reaction was *iltered. The preoipitat0 was washed several times with hot tetrahydro~uran) and the combined filtrates were evaporated. ~he residue was partitioned between 250 ml of dichloromethane and 200 ml of water and fil-$ ~,lr~

.. . . . .

`` 10~7491 .
tered. ~he dichloromethane solution was separaLed, dried and evaporated. ~his residue and the precipitate were recrystaIli-zed from a mixture o~ tetrahydrofuran and ethanol to give 7-chloro-5-(2-chlorophenyl)-2-methylamino-3H-thieno[2,3-e]'-[1~4]diazepine. A sample was recrystallized for analysis ~rom ~; a migture of tetrahydrofuran and hexane to give pale yellow prisms, m p. 259-262.

A mixture of 40 g (0.123 mj o~ 7-oh}oro-5-(2-ohloro-pher~1)~2~methylamino-3H-thieno[2,3-e]C1,4]diazepine 9 ' 700 ml of dichloromethane and 350 ml of pyridine was cooled in an ice bath and nitrosyl chloride was bubbled in for 20 minutes with sti.rrlng. After l hour it was bubbled in for 5 minutes more and~bhen 600 ml of water was added slowly. ~he dichIoromethar~e layer was separated, washed with 200~ml of water, drisd over 15 ~ anhydrous~sod1um sul~ate~and evaporated to dryness. ~he~oil was"~dissolved in dichlorome-thane and filtered through 400 g of Florisil. ~hi~ was eluted with dichlorometharle, and then . .;~
e~her. arystallization of the dichloromethane fraction ~rom a mi~ture of ether and petroleum ether gave 7-chloro-5-(2-chloro-phenyl)-2~ nitrosomethylamino)-3H-thieno[2,3~e][1,4]diazepine ` and more product was obtained from the ether fraotion. A sample : :
~ was recrystalli~ed ~or analysis from a mixture of ether and : petroleum ether to give yellow prisms, m.p. 104 107.

:
:

:

.. . .

~06~4~1 .
` . .

.

A solution of 6.8 g (0.0255 m) of 6,8-dihydro-3-eth~
methyl~4-phenylpyrazolo[3,4-e}[1,4~diazepin~7(I~)-one in 125 ml o~ dry tetrahydro~uran and 50 ml of dry benzene was cooled in an ice bath and methylamine was bubbled in until the solution was saturated. A solution of 6.3 g (0.0331 m) of titanium tetra- -~chloride in 20 ml of benzene wa~ then added drop~ise with stirring and after 18 hr at room temperature the mixture ~as refluxed ~or 30 minutes. The solution was oooled, and treated ` lo with 4 g of ice. ~he reaction migture was f~ tered and~the precipltate was washed with tetrahydro~uran and then with ~; dichloromethane. The combined filtrates were evaporated to dryness ànd the residue was crystallized from a mixture of , :
m~thanol and ether, and recrys~allized from a mixture o~ dichlo- ~-romethane and ether to give 3~ethyl-1,6 dihydro-1-methyl-7-methylamino-4-phenylpyrazolo[3~4-e~[l~4~diazepine as off-white `:: : : :
~ prisms, mp. ~18-221.
- :
, A solution of 5.6 e (o.olgs m) of 3-ethyl-1~6-dihydro-methyl-7-me-thylamino-4-phenylpyrazolo[3~4~e~[1,4]diazepine in 100 ml of dichloromethane and 50 ml of pyridine was stirred in an ice bath and nitrosyl chlcride was bubbled in for 10 min.
' ~ ' .

~ 9~_ '~.i l ,1.: ', 6749:~L

A~ter 2 hr at room temperature, nitrosyl chloride wa~ bubbled : in for an additional 5 min. The mixture ~as allowed to stand~: for 30 min when it wa~ poured into 200 ml of ice water. ~he organic layer was separated, washed with 100 ml o-f water7 ~ S :dried over anhydrous sodium sulfate, and filtered through : 100 g o~ ~lorisil. The Florisi.l was ~horoughly washed with ether, and the oombined filtrates were evaporated to drynes~.
~he inter~ediate ~-nitroso derivative was not further purifled but wa~ used in the ne~t s-tep : ~ :

' ~ , ~ ' ; .

: ~ :

~ ' ~

' ~)6~7~91 .

E~xample 59 A mixture of 3.3 g (0.01 m) of 7~chloro-1,3-dihydro-2-nitromethylene-5-phenyl-2H-1,4~benzodlazepine 4-o2ide, 3.3 ml of phosphorus trichloride~and 300 ml of methylene chloride was s~irred at room temperature for 4 hours~ The ~olution was washed with 10% aqueous sodium carbonate solution5 was dried over sodium sulfate and evaporated. The crude product uas purified by chromatography over 100 g of silioa gel using 10% (v/v) ethyl acetate in methylene chloride. ~he oombined clean fractions were c~Jstallized from meth~lene chloride/
he~ane to yield 7-chloro-1,3-dihydro-2-nitromethylene~5-phenyl-2H-1,4-benzodiazepine as light yellow crystals, m.p~. 184-186.

Example 60 A mixture of 3.6 g (0~01 m? of 7-bromo-2-(N-nitrosomethyl-amino)-5-(2-pyrldyl)-3H-1,4-benzodiazeplne, 30 ml of dimethyl~
formamide, 5 ml o~ nitromethane and 2 g (0.018 m) o~ potassium t-butoxide was stirred at room ~emperature for 15 minutes and then heated up slowly. When the temperature reached 100 the ~: :
mixture was cooled and neutralized by addition of glacial acetic acid. The product was precipitated by addition of satu-rated aqueous sodium bicarbonate and was collected, washed with water and dissolved in methylene chlorlde. ~he solution was dried over sodium sul~ate and evaporated. Crystallization - of -the residue from methylene chloride/ethanol Yielded 7-bromo~
1,3-dihydro~-2-nitromethylene-5-(2-pyridyl)-2H-1,4-benzodiazepine .

~ 0~i749~L

as a light yellow product, m.p. 232-235 (dec,) 5 For analysl~
- it was recrystallizea fram tetrahydro~uran/ethanol, m p 240-245 (dec.).

~ : .

ExamPle 61 s ~ ~ ~ A æolu~ion~o~ 2.8 g (0,00932 m) o~ D~-2-aminomethyl~
7-ohloro-2,3-dihydro-5-(2-~luorophe~yl)-lH-1,4-benzodiaze-: ~ : pine in 40 ml o~ diohloromethane was treated with 2,5 g (0~0119 m) of tri~luoroacetic acid anhydride and after 5 minu- ;
; tes it was washed with 15 ml of a lO~o potassium carbon~ate solu- ~;
o; ~tion, ~ried over anhydrous~sodium sulfate and evaporated to dry~ess. ~he residue was~crystallized ~rom dichlorometha~e and~was~recry:stallized ~rom a~mixture o~ dichlorome~hane and hexane~to gi~e 7~chloro-2,3-dih~dro-5-(2-fluorophenyl)-2-trifluoroacet~minome~hyl-lH-1~4-benzodiazepine as pale 15~ yellow prisms, m.p. 140-14~. ~
`
::

~ ~ 9~

.
....... . ..... . . . .
~. .

- - , 1~)679L9~

Exemple 62 ~o a solution of 10 g (0,026~ m) of 5-(2-fluorophenyl)-1,3-dihydro-7-iodo-2H-1,4-benzodiazepin-~-one in 140 ml of dry ; tetrahydrofuran was added 1.8 g (0.039 m) of 54% of sodium hydride under argon with stirring. ~he reaction was refluxed ~or 1 hou~, oooled to s and 10.8 g (0.0422 m) of phosphoro-dimorpholidic chloride was added.~After 18 hours the solution was ~iltered, concentrated to a small ~olume and ether was added.
The solid was ~iltered and recrystallized from a mixture of dichloromethane and ether to give 5-(2-fluorophenyl)-7~iodo-2-bis~moxpholinoj-phosphinyloæy-3H-1,4-benzodiazepine~as ~ite plates, m.p. 10~-112.

; A solution o~ 27 g (0.443 m) of nitromethane in 450 ml of dry~dimethyl sul~oxide was cooled to 0 under argon and~
~5 -then 5.4 g ~0.119 m) of 54~ sodium hydride was added with stlrring. After 2 hours at room tempera-ture the miæture ~las oooled $o 0 and 39.5 g ~0.066 m) of 5-~2-fluorophe~yl)-7-iodo~2-bis-(morpholino)-phosphinylo~y-3H~1,4-benzodiazepine was added all at once. ~he reaction was stirred for 18 hours and then poured into 3 1 o~ ice and wa-ter, which con-tained 15 ml of acetic acid. This was filtered, the precipitate was dissol~ed in 700 ml of dichloromethane which was then ~ashed with 300 ml of water7 dried over anhydrous sodium sulfate and evaporated to dryness. ~he residue was crystalliæed and ?5 recrystallized from a mix-ture o~ dichlorome-thane and ether to give 2,~dihydro-5-(2-fluorophenyl)-7-iodo-2-~itromethylene-` : J I ~,, _ ~ _

11~674~
lH-1,4-henzodiazepine as yellow prisms, m.p. 214-216.

~ . ., ', ~ ' Example A

A parenteral formulation containlng the ~ollowing ingredlents~

per ml 8-~hloro-1-methyl-6-(2-fluorophenyl)-4X-imidazo-[1,5-a][1,4]ben~odiazepine maleate 1.0 mg Benzyl Alcohol 0.15 ml Tar~aric Aoid ~uffer containing Sodium hydroxide Wster for In~eotion~ q.s~aa ~ l;;: ml was~prepared as~follows (for~10 liters) In a clean glass or glass-lined vessel, 8 1 of water ~ . .
for injection were~heated to 90. It was then cooled ~o 50-60, and 1,5 1 of benzyl alcohol was added and aissolved with stirring. The solution~was then sllowed to cool~o room tempera~ureO The 10.0 g of 8-chloro-1-methyl-6-(2-fluorophenyl)-4H-imidazo[1~5-a][1,4~benzodiazepine maleate were added under an a-tmosphere of nitrogen and stirred until completely dissol-ved. ~he pH was n~w adjusted to 3.0 + 1.0, pre~erably ~.0 ~ 0.5 OV

. ,~

~06749~

with a oombination of tartaric acid bu~fer and sodium hydroxi-de solution. Su~icient water for injection was then added to make a total volume of 10 liters. ~his solution was then fil-tered through candle, ~illed into suitable size ampuls, gassed with nitrogen and sealed~

xample ~

A tablet ~ormulation containing the ~ollowing ingredients:

per tablet ~-~hloro-6 (2-fluorophenyl)-1-methyl-4~I~imidazo[1,5-a][1,4~benzodiazepine maleate10.0 mg ~actose 113.5 mg Corn Starch 70.5 mg Pregelati~ized Corn Starch 8~0 mg Caloium Stearate 3.0 mg Total Weight205.0 mg 8-Chloro 6-(2-~luorophenyl)-1-methyl-~E-imidazo[1,5-a~
[1,4]benzodiazepine maleate was mixed with -the lac-tose~ corn ~tarch and pregelatinized corn starch in a suitable size mixer and passed through a comminuting machineO ~he mixture was re-tur-ned to the mi~er and moistened with water to a thick paste. Themoist mass was passed through a comminuting machîne and the moist granules were dried on paper lined trays at 45C. The dried ~ranul~s were returned to the mixer, the calcium stearate was added and mi~ed well The granules were compressed at a tablet weight o~ 200 mg.
~'' ` .

.~.. . ~

.

)67491`

_am~

A -tablet formulation co~-taining the ~ollowing ingredients:

- :
per~tablet 8-ahloro-6-(2~fluorophe~y1)-1-methy1-4H-imiAa~oC1,5-a][194]benzodiazepine maleate 25,00 mg actose ~ 64.50 mg Corn Starch ;10,00 mg Magrlesium ~tearate ~ 0.50 mg ~otal weight 100.00 mg was prepared as follows:

8-ahlo~o-6-(2~fluorophenyl)-4H-imidazo[1,5-a]~74]-~benzodiazepine maleate was mixed rith the laotose, corn starch ana maenesium stearate in a suitable mixer. ~he mixture was further blended by passing throu~h a comminuting machine. ~he .r.:
~:
mi~ed powders were slugged on a ~ablet compressing machine and the slugs were oomminu-ted to a suitable mesh size and mi~ed well. ~he tablets were compressed at a ~ablet weight o~ 100 mg.

:
' . `~ - ~ - .

:

~,.,. /oa~ . , . . . : ~

67~gl ' ' ' Exam le D

.
A capsule formulation containing the ~ollo~in$ ingre-.
~ aîents:
. . .
per capsule : 5 ~ 8~Chloro-6-(2-fluorophenyl)-1-methy1-4H-: imidazo[1,5-a][1,43ben~odiazepine maleate 25 mg aotose ~ : 158 mg : : :
.
: aorn Sta~ch 37 mg Talc ; 5 mg . Total Weight ~25 mg was:prepared as ~ollows~

8-ahloro-6-(2-~luorophenyl~ methyl-4H-imidaso[1,5-a]-1,4~benæodiazepine maleate was mixed with the lactose and oorn staroh in a suitable mixer. ~he mixture was ~urther blen-i;
ded by passing through a comminuting machine. ~he blended powder was returned ~o the miæer, the talc added and~blended thoroughly. ~he mixture was -then filled into hard-shell gelatin :~
: oapsules on a capsula~ing machine.
,:
:

:
.

:: ~ ~ /o3 ` ~674~31 a~
' - .

capsule formulation containing the ~ollowing : ingredients: .

: : per capsule ~ 5 8-Chloro-6-(2 fluorophenyl)-1-methyl-4H-:: : imidazo[l,5-a]~1,4]benzodiazepine maleate: 50 mg :
~acto~e : 125:mg Corn Starch 30 mg Talc 5 mg Total Weight~ 210:mg :
.
~ : was:prepared as ~ollow~
~: :

8-~hloro-6-(?-fluorophenyl)-1-methyl-4H-imidazo~1,5-aJ-[1,4]benzodlazepine maleate was mixed with lactose and corn ~arch in a suitable mi~er. ~he ~ixture was ~urther blended by passing ~hrough a co~ai~uting machine~ ~he blended powder was returned to the~mixer, the talc added and blended thoroughly.:
.~ : . :
~ The mi~ture was filled into hard-shell gelatin capsules on a .
capsulating machiI~e.

' .

1067~91.
'' - ' .
~ . : ` :
.
A capsule ~ormulation containin~:the following : ingredients~
.
. per capsul.e 8-Chloro;1,4-dimethy-6-(2~fluorophenyl)~4X-: imidaæo[l,5-a~[1,4]benzodiazepine maleate 50 m~
: Iactose ~ 125~mg ::~.
: aorn Starch ~0 mg~
, Talo . ~ 5 mg : 10 Total Weight 210 mg :

was pr~pared a~ llow~

8-Chloro-1,4-dime~hyl-6-(2-fluorophe~ 4~-imidazo~
.1,5-aJ~1,:4]benzodiazepine maleate~was mixed with lactose and corn staroh in.a suitable mixer. ~he mixture was further :.d~
~ blended by passine through a oomminuting machlne. The blended powder was returned to ~he mixer, the talc:addea:and blended horoughly. The miæture was filled into hard-shell.gelatin :
capsules on a ~capsulating machi~e. ~

~:~: ` : :
:~ :
~: .

~ .
.

.
~,}'~ /,~ :
. .

67~a91 Exam~ G
~ , ' ' ' A capsule formulation containing the following ingredients:

per_ca~sule 5 ~ 8-Chloro-1,4-dimethyl-6~(2-~luorophenyl)-4H-; imidazo[1,5-a][1,4~benzodiazepine maleate 25 ~g~

Iactose ~ ~158~mg Cor~ Starch ~ 37 mg Talc 5 mg ~otal Weight 225 mg :
was prepared as ;~ollows~

8-Chloro-1,4-dimeshyl-6-(2-fluorophenyl~-4~-imidazo-1,5-a~[1,4]benzodiazepine maleate was mixed wibh the lactose and corn staroh in a suitable mixer. The mlxture was furth~er 1~ blended b~ passing through a comminuting machine. ~he blended powder was returned to the mlxer, the talo added and blended ; thoroughly. The mixture was then ~illed into hard-shell gelatln capsules on a capsulating machine.

' .~
.~ io~

1al6749~

: Example H

A table-t for~ulat1on containing the *ollowing ingredients:

: per; tablet : ~ :
, ~: 8-Chloro-1,4-d;methyl-6-(2-fluorophenyl)-4H-imidazoC1,5~a~1,4]benzodiazepi.ne maleate25.00 mg ~actose ~ 64.50 mg Corn Starch 10.00 mg Magnesium Stearate 0.50 mg : To-tal WeightlQQ.00 mg ;~ was prepared as ~OllOUB~

~: ~
~ 8-Chloro-1,4-dimethy~-6-(2-fluorophenyl)-4H-imidazo-.
1,5-a~[1,4]benzodiazepine maleate was mixed with the lactose,:
corn ~tarch and magnesium stearate in a suitable mixer. ~he : mixture was ~urther blended by passing through a comminuting -~ maohine. ~he mixed powders were slugged on a tablet compressing machine and the slugs ~ere comminuted to a suitable mesh size mixed well. ~he tablets were compressed at a table~ ~leight o~
100 mg.
' , ' ' ~

. ~ .
:~ ~ /o7 .. ,, ,, " .. .~ ...... . . . . . . . .

.
` - :

67~9 ;.`

~ . :
.
A tablet formulation containing the following ingredients: ~
~ . ~
. ~ .

8 Chloro-1,4-dimethyl-6-(2-fluoromethyl)-4H-imidazo[1,5-aJ[1,4]benzodiazepine maleate lO.O mg actos~e ~ .5 mg Corn Starch ~7005 mg Pregelatinized aorn Starch 8.0 mg ~alcium Stearate3.0 mg Total Wei~he 205.0 ~S

was~prepared as~ollows~

8-Chl~ro~ 4-dimethyl-6-(2-fluorophenyl)-~K-im~dazo[l~,9-a]-;C1,4~benzodiazepine maleate~was mixed with the lactose,' corn :
starch and pregelatinized corn starch in a suitable size mixer and passed through~a oomminuting machine. The mixture was retur-ned to the mixer and moistened with~water to a thick paste~. ~he moist mass was passed through~a comminutlng machine and molst granules were drie'd~on paper lined trays at 45C. ~he dried ~ ~ .
granules were returned to the mixer, the calcium s~earate was adQed anQ mixed well. ~he granules were compressed~at a tablet ueight of 200 mg.

.

~ ~ : /0 ~

~367~1 Exam~le J
A parenteral formulation containing the ~ollowing ingredients:
per ml 8-chloro~1,4~dimeth~1-6-(2-fluorophen~ 4H-imidazorl~5-~1,4]benzoalazepine maleate 1.O mg Benzyl Alcohol 0.15 ml Tartaric Acid Buffer containing Sodium Hydroxide ~ater for In~ection q.s.ad. 1 ml was prepared as follows ~for 10 liters):
In a clean glass or glass-lined vessel, 8 1 of water for in~ection were heated to 90. It was then cooled to 50 - 60, and 1,5 1 o~ benz~l alcohol was added and dissolved with stirring.
The solution was then allowed to cool to room temperature. The 10.0 g oE 8-chloro-1,4-dimeth~1-6-t2-fluorophenyl)-4H-imidazo-~lJ5-a][1,4]benzodiazepine maleate were added under an atmosphere o~ nitrogen and stirred until completely dissolved. The pH was now adjusted to 3.0 + 1.0, preferably 3.0 + 0.5 with a com~ina-tion o~ tartaric acid bufer and sodium hydroxide solution.
Suf~icient water for injection was then added to make a total volume of 10 liters. This solution was then filtered through a candle, filled into suitable size ampuls, gassed with nitrogen and sealed.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of imidazo[1,5-a][1,4]diazepine compounds of the general formula I

wherein A is ; R1 is selected from the group consisting of lower alkyl and phenyl; R2 is selected from the group consisting of hydrogen and lower alkyl; R3 is selected from the group consisting of hydrogen and lower alkyl;
R5 is selected from the group consisting of hydrogen, lower alkanoyloxy and hydroxy; R6 is selected from the group consisting of phenyl, phenyl mono-sub-stituted by halogen, phenyl di-substituted by halogen and nitro and pyridyl;
and is selected from the group consisting of a) b) and c) wherein X is hydrogen or chlorine, and R4 is selected from the group consist-ing of hydrogen, halogen, lower alkyl, lower alkanoyl amino, lower alkylamino, amino, hydroxy lower alkyl and lower alkanoyl; analogs thereof of the general formula IA

wherein A is selected from the group consisting of d) e) and f) is the group of formula a) above, R1, R2, R3 and R6 are as in formula I above, except that m formula I with A being structure (e), R6 is not nitro-substituted, and pharmaceutically acceptable acid addition salts of these compounds as well as compounds which are obtained by ring opening by cleavage of the C/N-double bond in the 5,6-position, and are represented by the formula ID

wherein Y? is the anion of an organic or inorganic acid, and R1, R2, R3, R4 and R6 are as in formula I, which process comprises a) for the preparation of a compound of formula IA' where m R1, R2, R3 and R6 are as in formula I above and is the group of formula (a) above, oxidising a corresponding compound of formula I into the N-oxide thereof with an organic peracid, or b) converting a compound of formula IA' into a corresponding compound of formula I wherein R5 is lower alkanoyloxy by treatment with a lower alcanoic acid anhydride by methods known in the art, or c) hydrolysing a compound of formula I wherein R5 is alkanoyloxy to a corresponding compound of formula I wherein R5 represents hydroxy by methods known in the art, or d) for preparing a compound of formula IA"

wherein R1, R2, R3, R4, R6 and are as in formula IA' but R6 is not nitro substituted, reducing a corresponding compound of formula I, or e) de-hydrating a compound corresponding to formula IA but wherein A is to the corresponding compound of form-ula I by methods known in the art, or f) deacylating a compound corresponding to formula IA but wherein A is wherein R'7 is acetyl, mesyl or tosyl, to the corresponding compound of formula I by methods known in the art, or g) oxidising a compound of formula IA" to the corresponding compound of formula I by treatment with an oxidising agent selected from the group con-sisting of chromic acid, silver oxide, selenium dioxide, mercuric acetate, mercuric oxide, manganese dioxide, ferric chloride and ferricyanide, or h) cyclizing a compound of formula wherein R1, R2, R3, R4 and R6 are as in formula I, to a corresponding compound of formula I, or i) for preparing a compound of formula IA wherein A is reacting a corresponding compound of formula I with ethylene oxide in the presence of a Lewis acid catalyst or reacting a corresponding compound of formula XXIV

wherein R1, R2, R3, R4 and R6 are as m formula I, except that R4 is not amino, lower alkanoylamino or lower alkylamino, with ethanolamine, or j) hydrolysing a ketal group present as R4 substituent in an imidazobenzodiazepine to the corresponding ketone substituent, or k) reducing a ketone group present as R4 substituent in an imidazobenzodiazepine to the corresponding secondary or ter-tiary lower alkanol substituent, or l) dehydrogenating a compound of formula VII

wherein A is , R1, R2, R3, R4, R6 and are as in formula I but R6 is not nitro substituted, to a corresponding compound of formula I, or m) subjecting a compound of formula I, wherein represents an aminophenyl group, to a Sandmeyer Reaction yielding the corresponding chloro or bromo substituted compound, or n) hydrolysing a compound of formula I wherein R4 is acylamino to a corresponding compound of formula I wherein R4 is amino, or o) oxidizing a compound of formula VII' wherein A is and R1, R2, R3, R4, R6 and are as in formula VII, to a corresponding compound of formula I by treatment with an oxidising agent selected from the group consisting of chromic acid, silver oxide, selenium dioxide, mercuric acetate, mercuric oxide, manganese dioxide, ferric chloride, and ferricyanide or p) resolving a racemic compound into its optical enantiomers, or q) converting a compound of formula I or an analog of formula IA into a pharmaceutically acceptable acid addition salt.

2, A process as claimed in claim 1 wherein where are prepared compounds of formula I wherein is A is ; R1 is lower alkyl, R2 is selected from the group consisting of hydrogen and lower alkyl;
R3 is selected from the group consisting of hydrogen and lower alkyl, R5 is selected from the group consisting of hydrogen, lower alkanoyloxy and hydroxy;
R4 is selected from the group consisting of hydrogen, halogen, lower alkyl, amino, hydroxy lower alkyl and lower alkanoyl; and R6 is selected from the group consisting of phenyl which may be mono-substituted by halogen or di-substituted by halogen and nitro and pyridyl, analogs thereof corresponding to formula I but wherein A has structure (e) or (f) as defined in claim 1, and R5 is hydrogen, except that in formula I with A being structure (e), R6 is not nitro substituted, or pharmaceutically acceptable acid addition salts thereof and wherein process embodiments a), b), c), d), 1), o) and p) of claim 1 are performed.

3. A process as claimed in claim 1 wherein there is prepared a compound of formula I wherein R1 is lower alkyl, is , R4 is hydrogen or halogen, R6 is phenyl which may be mono-substituted by halogen or di-substituted by halogen and nitro, R2 is hydrogen or lower alkyl, and R3 and R5 are hydrogen.

4. A process as claimed in claim 3, wherein R2 is hydrogen.

5. A process as claimed in claim 2, 3 or 4, wherein R4 is 8-halo and R6 is 2-halophenyl.

6. A process as claimed in claim 1 or 2, where m R3 is lower alkyl.

7. A process as claimed in claim 2, wherein R3 is methyl.

8. A process as claimed in claim 4, wherein 8-chloro-6-(2-fluoro-phenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine or the maleate thereof is prepared.

9. A process as claimed in claim 7, wherein 8-chloro-6-(2-fluoro-phenyl)-1,4-dimethyl-4H-imidazo[1,5-a][1,4]benzodiazepine or the maleate thereof is prepared.

10. A process as claimed in claim 1, wherein 2-chloro-13a-(2-fluoro-phenyl)-12,13a-dihydro-6-methyl-9H,11H-imldazo-[1,5-a]oxazolo[3,2-d][1,4]-benzodiazepine is prepared.

11. Imidazo-[1,5-a][1,4]diazepine compounds of the general formula I
and analogs thereof as defined in claim 1, and pharmaceutically acceptable acid addition salts of these compounds as well as compounds of formula ID
which are obtained by ring opening by cleavage of the C/N-double bond in the 5,6-position, whenever prepared according to the process claimed in claim 1 or by an obvious chemical equivalent thereof.

12. 8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo-[1,5-a][1,4]benzo-diazepine or the maleate thereof, whenever prepared according to the process claimed in claim 8 or by an obvious chemical equivalent thereof.

13. 8-Chloro-6-(2-fluorophenyl)-1,4-dimethyl-4H-imidazo[1,5-a][1,4]ben-zodiazepine or the maleate thereof, whenever prepared according to the process claimed in claim 9 or by an obvious chemical equivalent thereof.