AU479220B2 - Process forthe production of new diazepine derivatives - Google Patents

Description

55,7 33 The present invention relates to new diazenine derivatives, to a process for their production, to pharmaceutical preparations containing the new compounds,

and to the use thereof.

The new diazepine derivatives correspond to the general formula I

6 R2 A- N4

7NC I Il 9

101 11 11b o/2

1

wherein

R1 represents hydrogen or an alkyl group having 1 to 3 carbon atoms,

A represents an alkylene group having 1 to 3 carbon

atoms,

R2 represents the hydroxyl group, the benzyloxy group, the m- or p-chlorobenzyloxy group, the or p-methylbenzyloxy group, the m- or p-methoxy- benzyloxy group or the 3,4,5-trimethoxy-benzyloxy

group or diarylmethoxy group, or

R2-A together represent a dialkoxynethyl group of which the alkoxy radicals contain 1 to 4 carbon atoms, or an alkylenedioxymethyl group having in all 3 to 6 carbon atons, and the rings B and C can be substituted by halogen up to atomic

47 9 number 35, trifluoromethyl, alkyl or alkoxy groups having

1 to 6 carbon atoms.

As an alkyl group in the compounds of the general

formula I, R 1 is, for example, the methyl, ethyl or propyl

group. By an alkylene group A is meant any desired bivalent,

saturated aliphatic hydrocarbon radical having 1 to 3 carbon

atoms, such as the methylene, ethylidene, 1-methylethylidene,

ethylene, propylene or trimethylene groups; of particular

importance among these groups is the methylene group.

R 2 is the m- or p-chlorobenzyloxy group, the

m- or p-methylbenzyloxy group, the m- or p-methyl-

benzyloxy group, the m- or p-methoxybenzyloxy group or

the 3,4,5-trimethoxy-benzyloxy group, particularly the

benzyloxy group; and as a diarylmethoxy group, R 2 is, in

particular, the diphenylmethoxy group.

R 2 -A.as a dialkoxymethyl group is, in particular,

the dimethoxymethyl or diethoxymethyl group.

Halogen atoms as substituents of the rings B and C

are fluorine, chlorine or bromine atoms, while alkyl groups

or alkoxy groups having 1 to 6 carbon atoms are,

4 7 9 for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl, isopentyl, 2,2-dimethyl- propyl, hexyl or isohexyl groups; or methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy,

2 2 isopentyloxy, -dimethylpropoxy, hexyloxy or iso-

hexyloxy groups. A substituent of the.ring B is

especially in the 10-position, and is preferably fluorine,

bromine, the trifluoromethyl group and, in particular,

chlorine. The ring C is preferably unsubstituted, or

substituted in any desired position by fluorine,

chlorine or bromine, particularly by fluorine or

chlorine in the o-position.

The compounds of the general formula I possess

valuable pharmacological properties. They have a central

depressant action, especially an anticonvulsive action; and

they also inhibit somatic reflexes. The anticonvulsive

effectiveness can be verified, for example, in the case of

oral administration to the mouse in the electroshock

test, in the psychomotor electroshock test and, in particular,

in the strychnine convulsion test, as well as in the

pentetrazole test.. The stated properties and others,

which can be determined by selected standard tests

[cp. W. Theobald and H.A. Kunz, Arzneimittelforsch. 13,

122 (1963), as well as W. Theobald et al., Arzneimittel-

forsch. 17, 561 (1967)], distinguish the compounds of the

general formula I as being suitable active substances for

4 47 9220

700Js

tranquillisers and anticonvulsants, which are applicable,

for example, for the treatment of conditions of tension

and agitation, as well as for the treatment of epilepsy.

Of particular importance are compounds of the

general formula I having hydrogen as R, -the methylene

group as A and the benzyloxy or p-methoxybenzyloxy group

and, in particular, the hydroxyl group as R2; and

among these compounds particularly those having a

chlorine atom in ring B in the 10-position and ring C

unsubstituted or substituted in the o-position by

fluorine or especially chlorine. Also of particular

importance are compounds of the general formula I in

which R 2 -A together represent the diinethoxymethyl group,

and particularly the diethoxymethyl group, while R,

represents hydrogen, and the rings B and C have the

aforementioned preferred substitution characteristics.

The compounds of the general formula I are produced

according to the invention by a process in which light

is allowed to act on a compound of the general formula II N 11 R.2' A -C- N 2 N---C

B)Y C RR 1 (II) C

0"

947 wherein RI, R 2 and A have the meanings given under formula I, and rings B and C can be substituted as defined there; and, optionally, a reaction product of the general formula I wherein R 2 is a mono- or diaryl- methoxy group split to form the corresponding compound in which R2 is a hydroxyl group.

Daylight can be used for the production of small

amounts of compounds of the general formula I. For

larger amounts it is possible to employ the usual

sources of light, such as normal filament lamps; also,

for example, mercury vapour lamps having a main wave

band of 300 to 400 mu, i.e. high-pressure lamps or

medium-pressure lamps, these having a Pyrex-glass filter for the elimination of the rays below ca. 300 rnp which would

decompose the compounds of the general formula I. The

solvents used are inert organic solvents; for example,

ethereal liquids, particularly tetrahydrofuran, also

esters, ketones, hydrocarbons or chlorinated hydrocarbons.

The irradiation is performed preferably with the exclusion

of oxygen; for example, under nitrogen or under an inert gas

such as argon or helium. The reaction temperature can

vary within a wide range, i.e. between ca. -70'C and

+150'C; it is however preferably between ca. +10 0 C and 0 C.

The 5-oxides of the general formula II which are

required as starting materials are preferably produced

6 47 92

55.7 33 P

from the corresponding compounds, not oxidised in the

by treatment with hydrogen peroxide or 0 peroxy acids at a temperature of ca. 0° to 70 C.

Suitable peroxy acids are, for example, peroxyacetic

acid or peroxybenzoic acids, such as peroxybenzoic acid

and particularly m-chloro-peroxybenzoic acid. The

oxidising agents are preferably used in a solvent,

e.g. peroxyacetic acid in acetic acid, and the peroxy-.

benzoic acids in halogenated hydrocarbons such as

methylene chloride or chloroform. The compounds not

oxidised in the 5-position which are required as

intermediates are for their part new substances. The

starting materials from which they are produced are e.g.,

compounds of the general formula III

X B CH R C IN

wherein

X represents a mercapto group, a lower alkoxy or

alkylthio group optionally activated by a substituent,

or an optionally mono- or disubstituted amino group,

R1 has the meaning given under formula I, and the rings

B and C can be substituted as defined under formula I.

7 47 9220

55,7 3 ,73,

X is preferably a methylthio, mercapto, methoxy, amino,

methylamino, benzylamino or dimethylamino group; and

as an alkoxy or alkylthio group activated by a substituent

it is, for example, the o- or p-nitrobenzyloxy group or

the o- or p-nitrobenzylthio group.

The compounds of the general formula III defined

above are reacted with acid hydrazides of the general

formula IV

R2 A CO NH NH2 (IV)

wherein R 2 and A have the meanings given under formula I;

and, optionally, an obtained product of which the

radical R 2 is a monoarylmethoxy or diarylmethoxy group

split to form a corresponding compound of which the

radical R2 is the hydroxyl group.

The reaction according to the process is performed

preferably at a reaction temperature of ca. 800 to 180°C

in an inert solvent. Suitable inert solvents are, for

example, hydrocarbons such as toluene or xylene, halogenated

hydrocarbons such as chlorobenzene, ethereal liquids such

as diethylene glycol dimethyl ether, diethylene glycol

diethyl ether or dioxane, amides, particularly

N",N"-hexamethyl-phosphoric acid triamide or N,N-dimethyl-

acetamide, sulphoxides such as dimethylsulphoxide, and

alcohols such as n-butanol. The reaction times are

preferably between ca. one and twentyfour hours.

8 47 92

III are Compounds embraced by the general formula

see inter alia L.H. Sternbach described in the literature; S.C. Bell and E. Reeder, J.Org.Chem. 26, 1111 (1961),

et al., J.Med.Chem. 5, 63 (1962), G.A. Archer and

L.H. Sternbach, J.Org.Chem. 29, 231 (1964) and

J. Farber et al., J.Med.Chem. 7, 235 (1964). Also

formula IV, described are compounds embraced by the general and glycolic. such as 2-benzyloxy-acetic acid hydrazide

acid hydrazide [cp. Th. Curtius and N. Schwan, J.prakt.

Chem. [21 51, 364 (1895)1, as well as dimethoxyacetic

Polya, J.Chem. acid hydrazide (cp. E.J. Browne and J.B.

Soc. 1962, 5149). Further compounds of the general

to the formulae III and IV can be produced analogously

known compounds

compounds of The optionally performed splitting of

radical R 2 is the general formula I or II of which the to form corre- a monoarylmethoxy or diarylmethoxy group

radical R 2 is the sponding compounds of which the with the aid of hydroxyl group is preferably performed acid, hydriodic hydrohalic acids such as hydrochloric

acid or, in particular, hydrobromic acid. It is advantageous Suitable solvents to use the hydrohalic acids in a solvent. acid. The reaction are carboxylic acids such as acetic 0 C. Compounds which can be temperature is ca. 200 to 150 in which R 2 is split particularly well are compounds

a p-methoxybenzyloxy group.

47 92

7 33' 7

The present invention relates also to modifications

of the aforementioned process and of the consequent

reaction mentioned subsequent to this, as well as of the

preceding steps, whereby a process is interrupted at

some stage, or whereby a compound occurring at some

particular stage is taken as the starting material and

the uncompleted steps performed, or whereby a starting

material is formed under the reaction conditions, or is

optionally used in the form of a salt.

The new active substances are administered orally,

rectally or parenterally. The dosage amount depends on

the mode of administration, on the species, on the age

and on the individual condition. The daily doses of

compounds of the general formula I vary between 0.02 mg/kg

and 2 mg/kg for warm-blooded animals. Suitable dosage

units, such as drag6es, tablets, suppositories or ampoules,

preferably contain 0.5 25 mg of an active substance

according to the invention.

Dosage units for oral administration contain as active

substance preferably between 1 and 50% of a compound

of the general formula I. They are produced by the

combination of the active substance with, for example,

pulverulent carriers such as lactose, saccharose, sorbitol or

mannitol; starches such as potato starch, maize starch

or amylopectin, also laminaria powder or citrus pulp powder;

cellulose derivatives or gelatine, optionally with the

10 A 922

,73 173

addition of lubricants such as magnesium or calcium

stearate or polyethylene glycols, to form tablets or

dragee cores. The dragee cores are coated, for example,

with concentrated sugar solutions, which may also contain,

for example, gum arabic, talcum and/or titanium dioxide;

or with a lacquer dissolved in readily volatile organic

solvents or solvent mixtures. Dyestuffs can be added to

these coatings in order, for example, to facilitate

identification of the various doses of active substance.

Further suitable oral dosage units are hard capsules

made from gelatine, as well as soft closed capsules

made from gelatine and a softener such as glycerin. The

hard capsules contain the active substance preferably

as a granulate, e.g. in admixture with fillers such as

maize starch, and/or lubricants such as talcum or

magnesium stearate, and optionally stabilisers such as

sodium metabisulphite (Na2 S2 05) or ascorbic acid. In soft

capsules, the active substance is preferably dissolved or

suspended in suitable liquids such as liquid polyethylene

glycols, to which likewise stabilisers may be added.

Suitable dosage units for rectal administration are,

for example, suppositories consisting of a combination

of an active substance with a suppository foundation

substance. Applicable suppository foundation substances

are, for example, synthetic triglycerides, paraffin

hydrocarbons, polyethylene glycols or higher alkanols.

11 4 7 922

7 33/7 Likewise suitable for the said purpose are hard gelatine

capsules consisting of a combination of the active

substance with a foundation substance. Suitable foundation

substances are, for example, liquid triglycerides,

polyethylene glycols or paraffin hydrocarbons.

Ampoules for parenteral administration, particularly

intramuscular administration, preferably contain an aqueous

dispersion of an active substance of the general formula I

in a concentration preferably of 0.1 optionally

together with suitable stabilisers and buffer substances.

The following directions serve to further illustrate

the preparation of tablets, drag6es, capsules and

suppositories.

12 47 9220

,733/

a) An amount of 50 g of 10-chloro-lib-phenyl-3,11bH-I

oxazirino[2,3-a]-s-triazolo[4,3-a][1,41benzodiazepine-

6-methanol is mixed with 175.80 g of lactose and

169.70 g of potato starch; the mixture is moistened

with an alcoholic solution of 10 g of stearic acid and

then granulated through a sieve. After the drying of the

granulate, 160 g of potato starch, 200 g of talcum,

2.50 g of magnesium stearate and 32 g of colloidal

silicon dioxide are mixed in; the mixture is pressed

to form 10,000 tablets each weighing 80 mg and each

containing 5 mg of active substance; these can be

optionally provided with grooves to allow a more precise

adjustment of the dosage amount.

b) A granulate is produced from 50 g of

phenyl-3,lbH-oxazirino[2,3-d]-s-triazolo(4,3-al[1,41

benzodiazepine-6-carboxaldeh-de-diethylacetal, 175.90 g

of lactose and the alcoholic solution of 10 g of stearic

acid; the granulate, after drying, is mixed with 56.60 g

of colloidal silicon dioxide, 165 g of talcum, 20 g of

potato starch and 2.50 g of magnesium stearate; the whole

is subsequently pressed out to form 10,000 drage cores.

These are afterwards coated with a concentrated syrup made

from 502.28 g of crystallised saccharose, 6 g of shellac,

g of gum arabic, 0.22 g of dyestuff and 1.5 g of

titanium dioxide, and finally dried. The obtained dragdes

each weigh 100 mg and each contain 5 mg of active substance.

13 47 9220

73!" 3

c) In order to produce 1000 capsules each containing

mg of active substance, 5 g of

3,llbH-oxazirino[2,3-dl-s-triazolo[4,3-a][l,4]benzo-

diazepine-6-methanol is mixed with 268 g of lactose;

the mixture is evenly moistened with an aqueous solution

of 2 g of gelatine, and then granulated through a

suitable sieve sieve III according to Ph.Helv. V).

The granulate is mixed with 10.0 g of dried maize starch

and 15.0 g of talcum, and the mixture uniformly filled

into 1000 hard gelatine capsules, size I.

d) A suppository mixture is prepared from 1.0 g of

10-chloro-llb-phenyl-3,llbH-o;:azirino[2,3-d]-s-triazolo

4 ]benzodiazepine-6-carboxaldehyde-diethylacetal

and 169.0 g of adeps solidus; the mixture is used to pour

100 suppositories each containing 10 mg of active

substance.

As the active substance for tablets, drag6es and

capsules, it is also possible to use, for example, the

0.4-fold amounts of

3,llbH-oxazirino[2,3-d]-s-triazolo[4,3-a][l,4]benzo-

diazepine-6-carboxaldehyde-diethylacetal.

The following examples further illustrate the production

of new compounds of the general formula I and of inter-

mediates not hitherto described; the examples do not, however,

in any way limit the scope of the invention. Temperatures are

in degrees Centigrade. The petroleum ether used is always

one having a boiling range of 40-65°C. 14 4 7 92 2 0

551 73

Example I

A solution of 0.6 g of 6-phenyl-8-chloro-4H-s- 5 triazolo[4-,3-al [l,4lbenzodiazepine-l-methafol- -oxide

in 60 ml of tetrahydrofuran is allowed to stand in a

closed flask for 10 days in daylight. The solution is

afterwards concentrated by evaporation. The oily residue

is chromatographed in ethyl acetate/methanol on

silica gel. The eluted crude reaction product is

recrystallised from tetrahydrofuran/petroleum ether

to obtain 10-chloro-llb-phenyl3,llbH-oxazirii-io[2,3>dI

-s-triazolol4,3-al [l,4lbenzodiazepile-6-ethalol,

M.P. 167-1690.

Thne following are obtained in an analogous manner

with the use of the same amount of starting material: 4 from 1- Cbenzyloxymethyl)6phenyl8chloro H-striazolo

14,3-al 1l,4lbenzodiazepine-5oxide:- 6-(benzyloxymethyl)-

-10-chloro-llb-phefyl3,llbHoxazirifo[2,3dl-striazolo

14,3-al 11,41benzodiazepine;

from 6-(o-chlorophenyl)8chloro-4Hstriazolo[4,3-aI 5 l0-chlorolIlb-

[1,4benzodiazepinelmethano- -oxide:- 3 (o-chlorophienyrl> llbH-oxazirino 12, 3-dI -s-triazolo

(4,3-al tl,41benzodiazepine-6-methanol, and

47 9220 from 1-I (p-'ctloxyben yLoy)-methyl -6-(o-chlorophenyl)-8- chloro-4H-s-triaolo[4,3-a[l, 4

6- thoxybenzyloxy) -meth:yli]- lO-ci-loro- Ilb- (o- chlorophenyl)-3,llbH-oxziino[2,3-d]-s-i[

benzodiazepine.

The 5-oxides required as starting materials are produced as follows:

a) A solution of 30 g of 2 -(mthylthio)-5-phcnyl-7- chloro3Hl-1,4-benzodizepic [cp. G.A. Archer et al., J.Org. Chem. 29 231 (1964)] and 19.8 g of 2-benzyloxy- acetic acid hydrazide [cp. Th. Curtius N. Schwan, J.prakt.Chem. 51, 353 (1895)] in 160 ml of hexanethyl phosphoric acid triamide is heated for 8 hours at 1400. The solvent is then distilled off in vacua and the residue distributed between methylene chloride and water. The organic phase is separated,*washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. l-(Benzyloxymethyl) 6 -phenyl-8-chloro.4H-s-triazolo[4,3-a] l,4]benzodiazepine crystallises out; it melts at 163-1650.

The co.mPpound 1- [(p-fe thoxybenzyloxy) meti yll6- (o-chlorophenyl)-8-chloro-4H-s-triazolo[ 4 3 1 [l,4]benzo- diazepine, IH.P. 200-2030 (from ethyl acetate) is produced in an analogous manner by reaction 2 of 33.4 g of -(methyl- thio)-5-(o-chlorophenyl)-7-cloro3l-1, 4 -b

[obtainable from the corresponding 2 -oxo compound (described

16- 47 9.2

7 33/n7 in J.Org.Chem. 27, 3988 (1962)) by conversion into the

corresponding 2-thion, and methylation of the latter

with dimethyl sulphate in methanolic sodium hydroxide

solution, analogously to the process described in J.Org.

Chem. 29, 231 (1964)] with 33.0 g of 2-(p-methoxybenzyl-

oxy)-acetic acid hydrazide [obtainable by reaction of 2 58 g of -(p-methoxybenzyloxy)-acetic acid methyl ester

(described in Compt.rend. 237, 1162 (1953)) with 22.7 g

of hydrazine hydrate in ethanolic solution for 3 days at 2501.

b) An amount of 25 g of 1-(benzyloxyinethyl)-6-phenyl-

8-chloro-4H-s-triazolo[4,3-a][l,4]benzodiazepine is

dissolved in 200 ml of glacial acetic acid; there is then

added to the solution 170 ml of 48% aqueous hydrobromic

acid. The mixture is heated for 90 minutes at 800 and

then cooled to while stirring is maintained, the mixture

is adjusted to pH 6 with concentrated sodium hydroxide

solution, and water as well as methylene chloride subsequently

added. The organic phase is separated, washed with saturated

aqueous sodium chloride solution, dried over sodium

sulphate and concentrated by evaporation. The residue is

dissolved in ethyl acetate/methanol the solution is

filtered through a column of 150 g of silica gel (Merck

particle size 0.05 0.2 mm), and the column eluted with

ethyl acetate/methanol to The eluate is

concentrated by evaporation and the residue crystallised

from ethyl acetate/ether to obtain 6-phenyl-8-chloro-4H-s-

17 47 9220

333 /7.

triazolo[ 4 ,3-a[l,4]benzodiazepine-l-methanol, M.P. 210-211°.

c) An amount of 72 ml of 48% aqueous hydrobromic acid

is added at 20° to a solution of 9.7 g of

methoxybenzyloxy)-methyl] -6-(o-chlorophenyl)-8-chloro-

4H-s-triazolo[4,3-a][l,4]benzodiazepine in 90 ml of glacial

acetic acid. The reaction mixture is stirred for

minutes; it is then neutralised with 30% sodium hydroxide

solution and extracted with methylene chloride. The organic phase is separated, washed with water, dried over

sodium sulphate and concentrated by evaporation.

Crystallisation of the residue from ethyl acetate/

petroleum ether yields 6 -(o-chlorophenyl)-8-chloro-411-

s-triazolo[4,3-a][l,4]benzodiazepine-l-methanol, M.P.

235-2370°

d) A solution of 3.11 g of m-chloroperbenzoic acid

in 40 ml of methylene chloride is added dropwise in the course of 10 minutes at with stirring, to a solution of 3.0 g of 6 -phenyl-8-chloro-4H-s-triazolo[4,3-a][l,4]

benzodiazepine-l-methanol in 80 ml of methylene chloride.

In an ice bath being allowed to melt, the reaction mixture

is stirred for a further 16 hours; it is subsequently

concentrated in vacuo, and ether and petroleum ether are

then added. The precipitated crystals are filtered with

suction, and recrystallised twice from methanol/ethyl

acetate/ether. The obtained 6 -phenyl-8-chloro-4H-s-triazolo

18 47 9220

S -j 3 3 /!731 14,3-al [l,4lbenzodiazepine-l-mnethanol-5-oxide melts

at 267-2690.

The following are obtained in an analogous manner:

starting with 3.84 g of l-(benzyloxymethyl)-6-phenyl-8-

chloro-4H-s-triazolo[4,3-a) [l,4]benzodiaZepine:-

1- (benzyloxymitethyl)-6-ph.enyl-8-chloro-4H-s-triazol-o

14,3-a] [l,4lbenzodi-azepine-5-oxide-, M.P. 189-193'

(from ether);

starting with 3.30 g of 6-(o-chlorophenyl)-8-chloro-4H-s-

triazolo[4,3-a] 1l,4]benzodiazepine-l-methanol:-

6-(o-chlorophenyl)-8-chloro-411-s-triazolo[4,3-al [1,41

and

starting with 3.95 g of 1-[(p-methoxybenzyloxy)7methyll-6-

(o-chlorophenyl)-8-chloro-4H-s-triazolo[4,3-a] [1,41

benzodiazepine:- (p-methoxybenzyloxy)-methyl]-6-

(o-chlorophenyl)-8-chloro-4H--s-triazolo[4,3-a] [1,41

19 47 92

55,7 33;7

Example 2

A solution of 0.6 g of 6-phenyl-8-chloro-4H-s-

triazolo[4,3-a][l,4]benzodiazepine-I-carboxaldehyde-

in 60 ml of tetrahydrofuran is

allowed to stand in a closed flask for 6 days in daylight.

The solution is afterwards concentrated by evaporation

to 20 ml; petroleum ether is then added.

phenyl-3,llbH-oxazirino[2,3-d]-s-triazolo[4,3-a][1,4] 6 benzodiazepine- -carboxaldehyde-diethylacetal crystallises

out and is filtered off, M.P. 136-1370.

In an analogous manner there is obtained, with the

use of the same amount of 6 -phenyl-8-chloro-4H-s-triazolo

[4,3-a][1,4]benzodiazepine-l-carboxaldehyde-dimethyl-

10-chloro-llb-phenyl-3,llbH-oxazirino

[2,3-d]-s-triazolo[4,3-al[l,4]benzodiazepine-6-

carboxaldehyde-dimethylacetal.

The 5-oxides required as starting materials are

produced as follows:

a) A solution of 60.0 g of 2-methylthio-5-phenyl-7-

chloro-3H-1,4-benzodiazepine (cp. G.A. Archer et al.,

J.Org.Chem. 29, 231 (1964)] and 38.8 g of diethoxyacetic

acid hydrazide [produced by the storing of a mixture

of 81.0 g of diethoxyacetic acid methyl ester, 50.0 g

of hydrazine hydrate and 800 ml of abs. ethanol for

hours at 250, filtration, concentration by evaporation

of the filtrate and distillation of the residue in high

20- 47 9220

7 C3j7,

vacuum, B.P. 120-1500/0.005 Torr, M.P. 30-40°] in 460 ml

of abs. hexamethyl-phosphoric acid triamide is heated

for 6 hours at 1400. The solvent is then distilled off

in vacuo, and the residue distributed between methylene

chloride and water. The organic phase is separated,

washed with saturated sodium chloride solution, dried

over sodium sulphate and concentrated by evaporation.

The residue is recrystallised from ethyl acetate/ether/

petroleum ether to obtain pure 6-phenyl-8-chloro-4H-s-

triazolo[4,3-a][l,4]benzodiazepine-l-carboxaldehyde-

diethylacetal, which melts at 133-135°.

In an analogous manner there is obtained 6-phenyl-

8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-

carboxaldehyde-dimethylacetal, M.P. 166-1720, by the

heating of 12.0 g of 2-methylthio-5-phenyl-7-chloro-3H-

1,4-benzodiazepine with 7.0 g of dimethoxyacetic acid

hydrazide (cp. E.J. Browns and J.B. Polya, J.Chem.Soc.

1962, 5149-5152) in 100 ml of abs. hexamethyl-phosphoric

acid triamide for 9 hours at 140".

b) A solution of 7.64 g (0.024 mole) of m-chloro-

peroxybenzoic acid in 140 ml of methylene chloride is

added dropwise within 15 minutes at 0-50, with stirring,

to a solution of 5.0 g (0.0126 mole) of 6-phenyl-8-chloro-

4H-s-triazolo[4,3-a][1,4]benzodiazepine-l-carboxaldehyde-

diethylacetal in 100 ml of methylene chloride. The reaction

mixture is stirred for a further 16 hours in a melting

-21 479220 ice bath. The reaction mixture is subsequently concentrated in vacuo, and ether added. The precipitated crystals are filtered under suction and washed twice with hot ethyl acetate. The obtained 6 -phenyl-8-chloro-'4H-s-triazolo

[4,3-al [1,4lbenzodia-zepine-1.-carboxaldehyde-diethylacetal-

melts at 200-202'.

There is obtained in an analogous manner, with the

use of 4.65 g of 6 -phenyl-8-chloro-411-s-triazolo[4,3.aJ

[1,4 lbenzodiazepine-l-carboxaldehyde-dimethylacetal:- 6 -phenyl-8-chiloro-4H-s-triazolo[4,3>a][1, 4 lbenzodiazepine-

479.220

55,7331

Example 3

A solution of 1.0 g of 6-(o-chlorophenyl)-8-chloro-

4H-s-triazolo[4,3-a] 1,4)benzodiazepine-i-carboxaldehyde-

1:&I in 100 ml of tetrahydrofuran is allowed

to stand in a closed flask for 3 days in-daylight. The

solution is then concentrated in vacuo. The residue is

adsorbed from benzolic solution on a column of silica gel,

and eluted with a benzene/ethanol mixture V/V).

The fractions containing the desired reaction product

(Rf-value 0.73 in the system benzene/isopropanol 9:1)

are combined and concentrated in vacuo. The residue is

recrystallised from ethyl acetate/petroleum ether to

obtain 10-chloro-lb-(o-chlorophenyl)-3,llbH-oxazirino

(2,3-d]-s-triazolo[4,3-al[1,4]benzodiazepine-6-carboxaldehyde-

diethyl acetal, M.P. 141-1420.

The starting material is produced as follows:

a) 6-(o-Chlorophenyl)-8-chloro-4H-s-triazolo[4,3-al[1,41

benzodiazepine-l-carboxaldehyde-diethylacetal, M.P. 120-

121.50, is obtained by a 10-hours' heating of 16.7 g of

2-(methylthio)-5-(o-chlorophenyl)-7-chloro-3H-1,4-

benzodiazepine [see note in Example 1 and 9.7 g of

diethoxyacetic acid hydrazide in 100 ml of hexamethyl-

phosphoric acid triamide at 1400, processing analogous to

that of Example 2 a) and subsequent recrystallisation

from ethyl acetate/petroleum ether.

23 47 9 2 0

557 33

b) Analocgously to Example 2 b) there is obtained, with the use of 5.44 g (0.0126 mole) of 6 -(o-chlorophenyl)- 8-chloro-4H-s-triazolo[4,3.a1[l,4]benzodiazepine-l

carboxaldehyedetiylacetal.. 6- (o-chlorophenyl)-8- chloro-4H-s-triazolo[4,3.ajl[,4]benzodiazepine-l.

which melts at 221-222' after recrystallisation from ethyl acetate/ petroleum ether.

24 4 7 9 22 0

Example 4

A solution of 0.6 g of 6-phenyl-S-chloro-4H-s-

triazolo [4,3-al [l,4]benzodiazepine-l-carboxaldehyde- in 60 ml of tetrahydrofuran is

irradiated with a hig.h-pressurernercury-discharge lamp

through a Pyrex filter for 2 hours at 250. The solution

is afterwards concentrated to 20 ml and petroleum ether

added. l0-Chloro-lb-phenyl-3,llbll-oxazirino[2,3dL5s

triazolo[4,3-al [l,4]benzodiazepine-6-carboxaldehl-yde-

diethylacetal crystallises out and is filtered off,

M.P. 136-1370.

25 47 9220

55,7'j4/73 THE CLAIIS DEFINING THE IINVETION ARE AS FOLLOW:-

1. Diazepine derivatives of the general formula I

R2 A -6 4

8 71 II 9 B CH- R (I)

11 11b 2

wherein

R1 represents hydrogen or an alkyl group having 1 to 3 carbon atoms,

A represents an alkylene group having 1 to 3 carbon

atoms,

R2 represents the hydroxyl group, the benzyloxy group,

the r- or p-chlorobenzyloxy group, the m- or p-methylbenzyloxy group, the m- or p-methoxy-

benzyloxy group or the 3,4,5-trimethoxy-benzyloxy

group, or diarylmethoxy group, or

R2-A together represent a dialkoxymethyl group of which the alkoxy radicals contain 1 to 4 carbon atoms, or an

alkylenedioxymethyl group having in all 3 to 6

carbon atoms, and

the rings B and C are unsubstituted or substituted by

halogen up to atomic, number 35, trifluoromethyl, alkyl or

alkoxy groups having 1 to 6 carbon atoms.

4 7 9.2 2 0

55, 7 33,. 2. Diazepine derivatives of the general formula I given in Claim 1 wherein R 1 represents hydrogen. R, the hydroxyl,

benzyloxy or p-methoxybenzyloxy group and A the methylene

group, ring B is substituted in the 10-position by chlorine,

and ring C is unsubstituted or substituted in the o-position

by fluorine or chlorine.

3. Diazepine derivatives of the general formula I given

in Claim 1 wherein R 1 represents hydrogen, and R 2 -A together

represent the dimethoxymethyl or diethoxymethyl group, ring B

is substituted in the 10-position by chlorine, and ring C

is unsubstituted or substituted in the o-position by fluo-

rine or chlorine.

4. 10- Chloro-llb-phenyl-3,llbH-oxazirino s-triazolo

[1,4]benzodiazepine 6-methanol.

10-Chloro-llb-phenyl-3,llbH-oxazirino[2,3-d],s-triazolo

f4,3-al[l,4]benzodiazepine-6-carboxaldehyde-diethylacetal.

6. lO-Chloro-llb-(o-chlorophenyl)-3.llbH-oxazirino

[2,3-d]-s-triazolo[4,3-a][l,4]benzodiazepine-6-carboxaldehyde

-diethylacetal.

7. Process for the production of new diazepine deriva-

tives of the general formula I given in Claim 1, wherein

R1 R 2 and A, or R 2 -A respectively have the meanings

defined in Claim 1 and the rings B and C are unsubstituted

or substituted as defined there, in which process light is

allowed to act on a compound of the general formula II

-27 -4792 2

Claims (1)

1. R2 A C N

   N C 7 (II) B CH R C N N.

   wherein R1, R2 and A have the meanings given in Claim 1

   and the rings B and C are unsubstituted or substituted as

   defined there; and, optionally, a reaction product of the

   general formula I wherein R2 is a mono- or diarylmethoxy

   group split to form the corresponding compound in which

   R2 is a hydroxyl group.

   8. Process according to Claim 7. wherein daylight is

   allowed to act on the said compound.

   9. Process according to Claim 7. wherein the source

   of light used is an incandescent-filament lamp.

   Process according to Claim 7, wherein the source

   of light used is a mercury vapour lamp having a main

   wave band of 300 to 400 mp.

   11. Process according to Claim 7, wherein the solvent

   used is tetrahydrofuran.

   28 4.7 92 O

   55,733/73

   12. Process according to Claim 7, wherein the reaction 0 0 is performed at +10 C to+30 C.

   13. Process according to Claim 7, wherein the starting

   material used is a compound of the general formula II

   givn i Claim-1 wherein R 1 represents hydrogen, R 2

   the hydroxyl, benzyloxy or p-methoxybenzyloxy group

   and A the methylene group, ring B is substituted in the

   8-position by chlorine, and ring C is unsubstituted or

   substituted in the o-position by fluorine or chlorine.

   14. Process according to Claim 7. wherein the starting

   material used is a compound of the general formula II

   gienin Cim 1 wherein R represents hydrogen, and

   R 2 -A together represent the dimethoxymethyl or diethoxy-

   methyl group, ring B is substituted in the 8-position by

   chlorine, and ring C is unsubstituted or substituted in

   the o-position by fluorine or chlorine.

   Process accroding to Claims 7 and 13, wherein the

   starting material used is 6-phenyl-8-chloro-4H-s-triazolo

   [4,3-a][1,4]benzodiazepine-l-methanol-5-oxide.

   16. Process according to Claims 7 and 14, wherein the

   starting material used is 6-phenyl-8-chloro-4H-s-triazolo

   [4,3-a][l,41benzodiazepine-l-carboxaldehyde-diethylacetal-

   4 7 92

   17. Process according to Claims 7 and 14, wherein the

   starting material used is 6-(o-chlorophenyl)-8-chloro-

   4H-s-triazolo(4,3-al[1.4]benzodiazepine-1-carboxaldehyde-

   \od4-f-c---iofs--ef- the process arcrding to Claim 7

   and of consequent reaction given there, as well as

   of the preceding teps, whereby a process is interrupted

   at soe stage, or whereb compound occurring at some

   stage is taken as the starting mat rial and the uncompleted

   tial steps performed, or whereby a starting ma, is formed

   under the reaction conditions or is optionally us in

   S+ A diazepine derivative of the general formula I

   as defined in Claim 1 whenever prepared by a process Clam 7 as claimed in any ona of Claims 7 to 1.

   A pharmaceutical composition comprising a diazepine

   derivative as claimed in Claim I together with a pharma-

   ceutically acceptable diluent or carrier therefor.

   201. A pharmaceutical composition comprising a diazepine

   derivative as claimed in Claim 2 together with a pharma-

   ceutically acceptable diluent or carrier therefor.

   2~t A pharmaceutical composition comprising a diazepine

   derivative as claimed in Claim 3 together with a therefor. pharmaceutically acceptable diluent or carrier

   30- 47 9220

   A phar:Maceutical co:.position com;prising the

   diazepine derivative claimed in Claim 4 together with a

   pharmaceutically acceptable diluent or carrier therefor.

   23,14. A pharmaceutical composition comprising the diazepine

   derivative claimed in Claim 5 together with a pharma-

   ceutically acceptable diluent or carrier therefor.

   22. A pharmaceutical composition comprising the

   diazepine derivative claimed in Claim 6 together with

   a pharmaceutically acceptable diluent or carrier therefor.

   Dated fit--^ I y

   GIBA-CEIGY AC

   EDW-°WATERS SONS PATErT ATTORNEYS RUSSELL STREET MELEOURNE AUSTRALIA

   31 47 9220