DK141965B - Analogous process for the preparation of s-triazolo (4,3-a) (1,4) benzodiazepine derivatives or N-oxides or acid addition salts thereof. - Google Patents

Description

(11) PUBLICATION 141965 (ijf / DENMARK <«) Int el.3 C 07 D 487/04 t (21) Annotation No 1 699/72 (22) Filed on 7 · Apr. 1972 (23) Life day 7 · Apr. 1972

(44) The claim presented and Q

the petition published on 20th JUi · I 980

THE DIRECTORATE OF ____ _____ L J

PATENT AND TRADE MARKET (30) Priority requested from it

Apr 8 1971, 5235/71 * CH

(7i) CXBA-GEIGY AG, Klybeckstrasse 141, 4002 Basel, CH.

(72) Inventor: Hans Allgeler, Schlosstrasse 25, 7857 Haagen, BE: Andre Gagneux, NeubadstrasBe 65, 4000 Basel, CH.

(74) Clerk of the case;

Dansk Patent Kontor ApS.

(54) Analogous process for the preparation of s-triazolo (4,> - a) (1,4) ben? = Zodiazepine derivatives or N-oxides or acid addition salts thereof.

The present invention relates to an analogous process for the preparation of novel s-triazolo [4,3-a] [1,4] benzodiazepine derivatives of the general formula R2-O? Nv i \ l / \: c - c 'n • 2 / I i

R - 0 N-C

rV \ x A I; CH - R1 (I)

v \ X

xc- N

Bee

V

Wherein R 1 is hydrogen or an alkyl group having 1-3 carbon atoms and 2 2 2 R an alkyl group having 1 to 4 carbon atoms or -R. R -en di valent, saturated aliphatic hydrocarbon group having 2 to 5 carbon atoms, and rings A and B each may be monosubstituted with fluorine, chlorine or bromine, or 5-oxides thereof or addition salts thereof with inorganic or organic acids.

In the compounds of the general formula I, R

a methyl, ethyl or propyl group. R is as an alkyl group e.g. a propyl, isopropyl, butyl, isobutyl or sec-butyl group and especially 2 2 a methyl or ethyl group, or -R. R - is as a saturated aliphatic hydrocarbon group having 2 to 5 carbon atoms, e.g. an ethylene, propylene, ethylethylene, trimethylene, tetramethylene, 2,2-dimethyl trimethylene or 2-ethyl trimethylene group.

In particular, a halogen substituent in the ring A is in the 8-position and is fluorine or bromine or, above all, chlorine. The ring B is preferably unsubstituted or substituted with fluorine, chlorine or bromine in any position, especially with fluorine or chlorine in the o-position.

The compounds of general formula I, their 5-oxides and their addition salts with inorganic and organic acids have valuable pharmacological properties. In particular, they appear anticonvulsant, central attenuating and muscle relaxing. The anticonvulsant effect may e.g. is detected by the pentetrazole cramp test in mice at doses of approx. 0.02 mg / kg. per os as well as in the strychnine cramp test, in the electroshock test and in the psychomotor electrical electroshock test in mice after oral administration. The central damping effect can be seen e.g. of the anesthetic-potentiating effect on mice after oral administration, however, it is less prominent than the anticonvulsant effect. For example, the muscle relaxation effect appears. of the inhibition of the polysynaptic reflexes in rabbits after intravenous administration. The mentioned and additional effects that can be demonstrated in selected standard experiments (cf. W. Theobald and HA Kunz, Arzneimittelforsch. 13 »122 (1963) and ¥. Theobald et al., Arzneimittelforsch. 561 (1967)) characterize the compounds with the general formula I, their 5-oxides as well as their pharmaceutically acceptable addition salts with inorganic and organic acids as active substances for tranquillizers, sedatives, muscle relaxants and antiepileptics, e.g. are useful for treating stress and arousal states, for reducing the tone of the transverse striated musculature, and for treating epilepsy.

The following test report shows the anticonvulsant effect of two of the compounds.

Test report.

Compounds I: 6- (o-Chlorophenyl) -8-chloro-4H-s-triazolo [4,3-a] [1,4] benzodiazepine-1-carboxaldehyde diethyl acetal, prepared according to the process of the invention.

II: 6- (o-Fluorophenyl) -8-chloro-4H-s-triazolo [4,3-a] [1,4] benzodiazepih-1-carboxaldehyde diethyl acetal, prepared according to the process of the invention.

2. Experimental methodology;

Pentetrazole cramp test in mice.

The test substance was given orally in increasing doses to white male mice weighing 17-25 g · For each dose of test substance 10 animals were used. 60 minutes after administration of the test substance, intraperitoneal injection of 80 mg / kg of a 0.8% solution of pentetrazole was injected. The presence of clonic and tonic cramps as well as of the Straubsk tail position was assessed by observation. The observation time extended over 2 hours after the application of pentetrazole.

The dose of the test substance at which 80 mg / kg i.p. pentetrazole-triggered clonic seizures are inhibited in 50% of animals 5. Results:

Pentetrazolkrampe test:

Compound Dose (DE ™) / 50% inhibitory

of the mice 2U

mgAg per os I 0.02 II 0.32

It is seen that the compounds I and II prepared according to the invention show a strong anticonvulsant effect.

4 141965

Of particular importance are compounds of general formula I wherein E is hydrogen or a methyl group and R is a methyl or ethyl group, ring A is unsubstituted or substituted by fluorine, chlorine or bromine, and ring B is either unsubstituted or supported at least one of the substituents mentioned for ring A, whereby preferably at least one of the rings A and B is substituted ep. Particularly valuable within this group are those compounds wherein E is hydrogen and R is a methyl group and especially an ethyl group, the ring A is unsubstituted or is substituted at the 8-position with one of the above substituents, especially chlorine, and ring B is unsubstituted or substituted at the o-position with fluorine or chlorine, whereby at least one of the rings A and B carries one of the substituents for said substituent, ring A in particular a chlorine atom. Examples of highly effective compounds of this group include 6-phenyl-8-ehloro-4H-s-triazolo [4,3- * a] [1,4] benzodiazepine-1-carboxaldehyde diethyl acetal, 6- (o-fluorophenyl ) -8-chloro-4H-s-tri-azolo [4,3-a] [1,4] henzodiazepine-1-carboxaldehyde diethyl acetal, 6- (o-chlorophenyl) -8-chloro-4H-s-triazolo [4,3-a] [1,4] benzodiazepine-1-carb-oxaldehyde diethyl acetal, and 6- (o-chlorophenyl) -4H-s-triazolo [4,3-a] [1,4] benzodiazepine l-carboxaldehyde diethyl acetal. In addition to its own valuable pharmacological properties, 5-0xides of the compounds of the general formula I and especially of the preferred types are also important as intermediates for the preparation of further pharmacologically active compounds.

The process according to the invention is characterized by the characterizing part of the claim.

According to process a) according to the invention, the compounds of general formula I, 5-oxides and acid addition salts thereof are prepared by condensing a compound of the general formula

X

N-C

fV \ A J CH - IT (II) 'r7

BEE

V

wherein X is a mereapto group, a lower alkoxy or alkylthio group optionally activated by a substituent, or an optionally mono- or disubstituted amino group, has the meaning of formula I and rings A and B may be substituted as indicated under formula I, with a compound of the general formula

r2 n H

wherein R or -R. R - is as defined in Formula I and, if desired, oxidizes the reaction product obtained to its 5-oxide or transfers it to an addition salt with an inorganic or organic acid.

As lower alkylthio or alkoxy groups, X is preferably a methylthio or ethylthio group or a methoxy or ethoxy group. These groups may be activated by a substituent. Such activated groups are e.g. an o- or p-nitro-benzylthio or o- or p-nitro-benzyloxy group. In particular, as a monosubstituted amino group, X is a lower alkylamino group such as a methylamino group or an aralkylamino group such as a benzylamino group. As a disubstituted amino group, X is in particular a lower di alkylamino group such as a dimethylamino group.

The reaction is preferably carried out at a reaction temperature of approx. # 0 ° to about 160 ° C in an inert solvent. As inactive solvents, e.g. hydrocarbons such as toluene or xylene; halogenated hydrocarbons such as chlorobenzene; ethanol or butanol, ether-like liquids such as diethylene glycol dimethyl flakes, diethylene glycol diethyl ether or dioxane, and amides, especially N, N, Nr, Nr, Νη, Νη-hexamethylphosphoric acid triamide, or sulfoxides such as dimethyl sulfoxide. The reaction times are between approx. 1 and approx. 24 hours.

Starting substances that fall under the general formula II are described in the literature, see, e.g. L. H. Sternbach and E. Reeder, J. Org.Chem. 26. 1111 (1961), S.C. Bell et al., J.Med.Chem. £, 63 (1962), G.A. Archer and L.H. Sternbach, J. Org.Chem. 2, 231 (1964), and J. Farber et al., J.Med. Chem. 2> 235 (1964). Also disclosed are compounds which fall within the general formula III, such as dimethoxyacetic acid hydrazide (cf. E.J. Browne and J.B. Polya, J.Chem.Soc. 1962. 5149). Further compounds of the general formulas II and III may be prepared analogously to the known ones. Eg. further starting substances of the general formula II with an optionally substituted amino group X are obtained by reducing the corresponding 4-oxides described in the literature.

As oxidizing agents for the subsequent conversion of compounds of the general formula I to their 5-oxides, hydrogen peroxide or peracids are preferably suitable at a temperature of approx. 0 to approx. 70u. Suitable peracids are e.g. peracetic acid or perbenzoic acids such as perbenzoic acid or especially m-chloro perbenzoic acid. The oxidizing agents are preferably used in a solvent, e.g. peracetic acid in acetic acid or perbenzoic acid in halohydrocarbons such as methylene chloride or chloroform.

According to process b) according to the invention, compounds of the general I or their 5-oxides and their additions are all prepared with inorganic or organic acids by reacting an aldehyde of the general formula

C

I II

K-c fs / \, A | CH - Rx (IV) v \ / 9 = n B |

V

wherein R 1 is as defined in Formula I, and rings A and B may be substituted as set forth in Formula I, with a compound of general formula R 1 - OH (V) or

R1 - OH

I (VI) I o

R 2 - OH

Wherein R or -R. R - is as defined in Formula I and, if desired, oxidizes the reaction product obtained to its 5-oxide or transfers it to an addition salt with an inorganic or organic acid.

141965 7

The reaction is preferably carried out in a solvent, for example in an excess of the alkanol of general formula V used or an alkanediol of general formula VI, in the presence of a catalyst. As a catalyst, for example, a mineral acid, e.g. sulfuric acid or phosphoric acid, an aromatic sulfonic acid, e.g. o- or p-toluenesulfonic acid, or a Lewis acid, e.g. boron trifluoride. The reaction temperature is at about 20 to approx. 170 ° C, especially at the boiling point of the solvent used.

The starting materials of general formula IV may e.g. available as follows:

Compounds of the above-defined general formula II are taken and reacted with benzyloxyacetic acid hydrazide to corresponding 1-benzyloxymethyl-4H-s-triazolo [4,3-a] [1,4] benzodiazepines to which hydrobromide is cleaved to corresponding 4H-s-triazolo [4,3-a] [1,4] benzodiazepine-1-methanols; the alcohols obtained are then oxidized with dimethyl sulfoxide in the presence of dicyclohexylcarbodilmide and phosphoric acid.

The oxidation of the obtained compounds of general formula I to their 5-oxides is described in connection with process a).

According to process c) of the invention, the compounds of general formula I, their 5-oxides and their addition salts with inorganic or organic acids are obtained by condensing a compound ... of the general formula m0 -------- -------------- I 2

NH

N == - Cv ✓Y \ i A | J CH - R1 (VII)

-N

wherein R 1 is as defined in Formula I, and rings A and B may be substituted as indicated, with a reactive ester of a compound of general formula R 2 - O? '' \ I! C - C - OH (VIII)

R2 - J

Wherein R or -R. R - is as defined in Formula I and, if desired, oxidizes the reaction product obtained to its 5-oxide or transfers it to an addition salt with an inorganic or organic acid.

As reactive esters of a compound of general formula VIII, e.g. lower alkyl esters, especially methyl or ethyl esters are used.

The reaction is preferably carried out at reaction temperatures of approx. SO tf 160 ° C in an inert solvent. As inactive solvents, e.g. hydrocarbons such as toluene or xylene, halogenated hydrocarbons such as chlorobenzene, a lower alkanol preferably corresponding to the alkanol of the acetal group, such as e.g. ethanol or butanol, ether-like liquids such as diethylene glycol dimethyl ether or dioxane, and amides, especially N, M, NT, Nr, WT, W, - hexamethylphosphoric triamide. The reaction times are between approx. 1 and approx. 24 hours.

Starting materials of general formula VII are known, e.g. 2-hydrazino-5-phenyl-7-chloro-3H-1,4-benzodiazepine (cf. Kanji Meguro and Yutaka Kuwada, Tetrahedron Letters 1970, 4039). Additional compounds of this type may be prepared by analogy.

The oxidation of the obtained compounds of general formula I to their 5-oxides is described in connection with process a).

The compounds of the general formula I obtained according to the above processes are then, if desired, transferred in their usual manner to their addition salts with inorganic or organic acids. Eg. to a solution of a compound of general formula I in an organic solvent is added the acid desired as a salt component. Preferably, for the reaction, organic solvents are selected in which the salt formed is heavily soluble so that it can be separated by filtration. Such solvents are e.g. methanol, ether, acetone, methyl ethyl ketone, acetone ether, acetone ethanol, methanol ether or ethanol ether.

9 141966

As pharmaceuticals, pharmaceutically acceptable acid addition salts can be used instead of the free bases, i.e. salts with such acids, the anions of which may be toxic doses are non-toxic. Furthermore, it is an advantage if the salts to be used as pharmaceuticals are well crystallizable and not or only slightly hygroscopic. For salt formation with compounds of general formula I, e.g. hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid or perchloric acid are used.

The active substances in question are administered orally, rectally or parenterally. The dosage depends on the mode of administration, the species, the age and the individual condition. The daily doses of the free bases, their 5-oxides or pharmaceutically acceptable salts of the free bases are for warm-blooded animals between 0.02 mg / kg and 4 mg / kg. Suitable dosage unit forms such as dragees, tablets, suppositories or ampoules preferably contain 0.5-25 mg of active ingredient.

The following examples illustrate the method according to the invention. For the elution chromatography, silica gel, Merck grain size 0.05-0.2 mm is used. The boiling range of the petroleum ether used is at 40-65 ° C.

Example 1.

A solution of 60.0 g of 2-methylthio-5-phenyl-7-chloro-3H-1,4-benzodiazepine (cf. GA Archer et al., J. Org.Chem. 2 £, 231 (1964) ) and 3 $, 5 g of di-ethoxyacetic acid hydrazide in 460 ml of absolute hexamethylphosphoric acid triamide are heated for 6 hours to 140 ° C. The solvent is then distilled off in vacuo and the residue is partitioned between methylene chloride and water. The organic phase is separated, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue is crystallized by ethyl acetate-ether-petroleum ether to give the pure 6-phenyl-8-chloro-4H-s-triazolo [4,3-a] [1,4] benzodiazepine-1-carboxaldehyde diethyl acetal, which melts at 133-135 C.

The diethoxyacetic acid hydrazide used as a starting material is prepared as follows: a) 81.0 g of diethoxyacetic acid methyl ester is dissolved in 800 ml of absolute ethanol ·, 50.0 g of hydrazine hydrate is added and the mixture is left for 20 hours at 25 ° C. The reaction mixture is then filtered, the filtrate is evaporated in vacuo and the residue is distilled. The diethoxyacetic acid hydrazide obtained boils at 120-150 ° C / 0.005 mm Hg pressure, m.p. 3O-40 ° C.

Example 2.

At 10 hours heating 15.9 g of 2- (methylthio) -5- (o-fluorophenyl) -7-chloro-3H-1,4-benzodiazepine and 9.7 g of diethoxyacetic acid hydrazide in 100 ml of hexamethylphosphoric triamide to 140 ° C, work-up analogous to Example 1 and recrystallization of ethyl acetate-petroleum ether give 6- (o-fluorophenyl) -8-chloro-4H-s-triazolo [4,3-a] [1,4] benzodiazepine-1-carboxaldehyde diethyl acetal with m.p. 120-121 ° C.

Analogously, 16.7 g of 2- (methylthio) -5- (o-chlorophenyl) -7-chloro-3H-1,4-benzodiazepine 6- (o-chlorophenyl) -8-chloro-4H-s are obtained. -triazolo [4,3-a] [1,4] benzodiazepine-1-carboxaldehyde diethyl acetal, m.p. 120-121.5 ° C (of ethyl acetate-petroleum ether);

The substituted 2- (methylthio) -5-phenyl-3H-1,4-benzodiazepines as starting materials for the above-mentioned end products can be prepared from the corresponding ones of J.Org.Chem. 2, 231 (1964), substituted 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione analogous to that of 2- (methylthio) -5-phenyl-7-chloro 3H-1,4-benzodiazepine described method.

Further, by analogy with the above example: from 15.7 g of 2- (methylthio) -3-methyl-5-phenyl-7-chloro-3H-1,4-benzodiazepine 3-methyl-6-phenyl-1 8-chloro-4H-s-triazolo [4,3-a] [1,4] benzodiazepine-1-carboxaldehyde diethyl acetal, m.p. 151-153 ° C (of ethyl acetate-petroleum ether);

The starting substituted 2- (methylthio) -5-phenyl-3H-1,4-benzodiazepines are based on the corresponding substituted 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine. -2-ones, of which the compounds containing a trifluoromethyl group are described in United States Patent No. 3,334,392 and partly also in Helv.Chim. Acta 45, 2226 (1962), and the other four compounds of J.Org.Chem. 27, 3788 (1962), by converting to the corresponding 2-thions and converting them with dimethyl sulfate in methanolic sodium hydroxide solution analogous to that of J. Org.Chem. 29, 231 (1964).

Example 3

A solution of 12.0 g of 2-methylthio-5-phenyl-7-chloro-3H-1,4-benzodiazepine and 7.0 g of dimethoxyacetic acid hydrazide (cf. EJ Browne and JBPolya, J.Chem.Soc. 1962 (5149-5152) in 100 ml of absolute hexamethylphosphoric acid triamide is heated to 140 ° C for 9 hours. The obtained 6-phenyl-8-chloro-4H-s-triazolo [4,3-a] [1,4] benzodiazepine-1-carboxaldehyde dimethyl acetal melts at 166-172 ° C.

Example 4

By reaction of 15.0 g of 2- (methylthio) -5- (o-chlorophenyl) -3H-1,4-benzodiazepine with 9.7 g of diethoxyacetic acid hydrazide in 100 ml of hexamethylphosphoric triamide analogous to Example 1 and crystallization of the crude product of ethyl acetate-petroleum ether gives 6- (o-chlorophenyl) -4H-s-triazolo [4,3-a] [1,4] benzodiazepine-1-carboxaldehyde diethyl acetal, m.p. 145-146 ° C.

The 2-methylthio compound required as a starting material is prepared from that of L.H. Sternbach et al., J.Med.Chem. 6, 261-265 (1963) disclosed 1,3-dihydro-5- (o-chlorophenyl) -2H-1,4-benzodiazepin-2-one by conversion to the corresponding 2-thione and reacting it with dimethyl sulfate in methanolic sodium hydroxide solution analogous to that of J.Org. Chem. 22, 231 (1964), described, m.p. 109-111 ° C (of ethyl acetate-petroleum ether).

Example 5

A solution of 7.0 g of 7-chloro-2-mercapto-5-phenyl-3H-1,4-benzodiazepine (cf. GAArcher and LHSternbach, J. Org.Chem. 2 £, 231 (1964)) and 5.7 g of diethoxyacetic acid hydrazide in 50 ml of absolute ethanol are refluxed for 25 hours. The reaction mixture is evaporated in vacuo and the crude product obtained is prepared as described in Example 1 to give 6-phenyl-8-chloro-4H-s-triazolo [4,3-a] [1,4] benzodiazepine-1-carboxylate. aldehyde diethyl acetal with m.p. 133-135 ° C.

Example 6

12 161965

A solution of 200 mg of 2- (dimethylamino) -5-phenyl-7-chloro-3H-1,4-benzodiazepine (cf. J. Farber et al., J.Med.Chem. 2> 235 (1964)) and 150 mg of diethoxyacetic acid hydrazide in 3 ml of absolute hexamethyl phosphoric acid triamide are heated to 140 ° C for 10 hours. The reaction mixture is evaporated in vacuo and the crude product is prepared as described in Example 1 to give 6-phenyl - $ - chloro-4H-s-triazolo [4,3 ** a] [1,4] benzodiazepine-1-carboxaldehyde diethyl acetal with m.p. 133-135 ° C.

The same final product is obtained using the following starting materials instead of 2- (dimethylamino) -5-phenyl-7-chloro-3H-1,4-benzodiaze-pin: · 180 mg of 2-amino-5-phenyl-7- chloro-3H-1,4-benzodiazepine (cf. SC Bell et al., J. Med. Chem. 5.j 63 (1962)) or 240 mg of 2- (benzylamino) -5-phenyl-7-chloro-3H. 1,4-benzodiazepine (may be prepared according to English Patent No. 1,023,793 or from the 4-oxide described by SC Bell et al., loc. cit. analogous to LH Sternbach et al., loc. cit.) or 190 mg of 2- (methylamino) -5-phenyl-7-chloro-3H-1,4-benzodiazepine (cf. LH Sternbach et al., J. Org.Chem. 26, 1111 (1961)).

Example 7

A mixture of 300 mg of 6-phenyl-8-chloro-4H-s-triazolo [4,3-a] [1,4] benzodiazepine-1-methanol, 0.57 g of dicyclohexyl carbodiimide, 45 mg of phosphoric acid and 3 ml of absolute dimethyl sulfoxide is stirred for 6 days at 25 ° C and a further 2 days at 70-80 ° C. Methylene chloride is then added, the organic phase is washed with water and saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The crude 6-phenyl-8-chloro-4H-s-triazolo [4,3-a] [i, 4] benzodiazepine-1-carboxaldehyde is dissolved in 5 ml of ethanol. To the solution obtained is added 100 mg of p-toluene sulfonic acid and the mixture is refluxed for 10 hours. The solution is evaporated in vacuo. The residue is taken up in methylene chloride *, the organic phase is washed with 5% aqueous potassium carbonate solution and with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue of acetic acid ethyl ester-ether-petroleum ether is crystallized to give 6-phenyl-8-chloro-4H-s-triazolo [4,3-a] [1,4] benzodiazepine-1-carboxaldehyde diethyl acetal with mp. 133-135 ° C.

The starting compound is prepared as follows: a) A solution of 30 g of 2-methylthio-5-phenyl-7-chloro-3H-1,4-benzodiaze-pin (cf. GA Archer et al., J. Org.Chem. , 231 (1964)) and 19.8 g of benzyloxyacetydrazide (cf. Th. Curtius and N. Schwan, J.prakt.Chem.

[2] l, 353 (1895)) in 160 ml of hexamethylphosphoric triamide is heated for 8 hours to 140 ° C. The solvent is then distilled off in vacuo and the residue is partitioned between methylene chloride and water. The organic phase is separated, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. 1-Benzyloxymethyl-6-phenyl-8-chloro-4H-s-triazolo [4,3- a] [1,4] benzodiazepine crystallizes; it melts at 163-165 ° C.

b) Dissolve 25 g of the compound prepared according to (a) in 200 ml of glacial acetic acid and add 170 ml of 48 $ Ts hydrogen bromide to the solution. The mixture is refluxed for 90 minutes, cooled to 5 ° C, adjusted with stirring with concentrated sodium hydroxide solution to a pH of 6, then water and methylene chloride are added. The organic phase is separated, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The residue is dissolved in ethyl acetate-methanol (9: 1), the solution is filtered through a column of 150 g of silica gel (Merck®, grain size 0.05-0.2 mm), and the column is eluted with ethyl acetate-methanol (9: 1) to ( 7-'3) · The eluate is evaporated and the residue is crystallized by ethyl acetate ether. There is obtained 6-phenyl-8-chloro-4H-s-triazolo [4,3-a] [1,4] benzodiazepine-1-methanol, m.p. 209-211 ° C.

Example 8.

A solution of 2-hydrazino-5-phenyl-7-chloro-3H-1,4-benzodiazepine (cf. Kanji Meguro and lutaka Kuwada, Tetrahedron Letters 1970. 4039 (1970)) and 5 g of diethoxyacetic acid ethyl ester in 50 ml Ν, Ν , Ν ', Nf, Nn, N' -hexamethyl-phosphoric acid triamide is heated to 100 ° C for 5 hours. The reaction mixture is then evaporated in vacuo and the residue is partitioned between methylene chloride and water. The organic phase is washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated. Remaining

Claims (1)

14 141905 is crystallized from acetic acid ethyl ester-ether-petroleum ether, whereupon the pure 6-phenyl - $ - chloro-4H-s-triazolor4,3-a] [1,4] benzodiazepine-1-carboxaldehyde diethyl acetal melts at 133-135. Example 9 · A solution of 7.64 g (0.024 mol) of m-chloro-perbenzoic acid in 140 ml of methylene chloride is dropped over 15 minutes at 0-5 ° C with stirring to a solution of 9.0 g (0.0126 mol) of 6-phenyl- $ -chloro-4H-s-triazolo [4,3-a] [1,4] benzoediazepine-1-carboxaldehyde diethyl acetal in 100 ml of methylene chloride. In an thawing ice bath, the reaction mixture is stirred for an additional 16 hours. Then it is evaporated in vacuo and ether is added. The precipitated crystals are sucked off and washed twice with hot ethyl acetate. The obtained 6-phenyl-B-chloro-4H-s-triazolo [4,3-a] [1,4] benzodiazepine-1-carboxaldehyde diethyl acetal-5-oxide melts at 200-202 ° C. Example 10. To a solution of 0.5 g (0.00126 mol) of 6-phenyl-5-chloro-4H-s-triazolo [4,3-a] [1,4] benzodiazepine-1-carboxaldehyde diethyl acetal in 3 ml of acetone and 3 ml of methanol are added with 0.13 g (0.0013 mole) of perchloric acid. After addition of 5 ml of petroleum ether, the salt crystallizes. After suction, 6-phenyl-8-chloro-4H-s-triazolo [4,3-a] [1,4] benzodiazepine-1-carboxaldehyde diethyl acetal perchlorate is obtained, which is decomposed at 250-265 ° C. PAIEIIEBAY Analogous Process for Preparation of S-Triazolo [4,3-a] [1,4] Benzodiazepine Derivatives of the General Formula n2 n H Nv • C - CN ^ - q / I_i ✓Y \ in AI CH - Rx (I) Λ BIV 141965 wherein Egrupp is hydrogen or an alkyl group having 1 to 5 carbon atoms and R an alkyl group having 1 to 4 carbon atoms or 2 to 2E-R - a divalent saturated aliphatic hydrocarbon group having 2 to 5 carbon atoms and the rings A and B may each be monosubstituted with fluorine, chlorine or bromine, or 5-oxides thereof or addition salts thereof with inorganic or organic acids, characterized in that a) condensing a compound of the general formula , A [CH - ΪΓ (II) 'BIV wherein X is a mercapto group, a lower alkoxy or alkylthio group optionally activated by a substituent, or an optionally mono- or disubstituted amino group, R In the meaning given, and rings A and B may be substituted as indicated below under formula I, with a compound of the general formula f - \ f! C - CO - NH - NH, (III) - 0 2 2 2 wherein R or -R. R - has the meaning given by formula I, b) converts an aldehyde of the general formula 16 II Ά-C / V \ AI CH - R1 (XV) V \ / ^ Nc- N Λ Bl V Where R "*" is as defined in Formula I, and rings A and B may be substituted as indicated, with a compound of the general formula R2 - OH (V) or R2 - OH lo (VI) sr - oh 2 2 2 Where R or -R .R - Does the meaning of formula I, or c) condense a compound with the general formula NH0 I 2 NH N = C / Y \ in AI GH - η (VII) BIV