DE2220615A1 - New 1-substituted 6-phenyl-4H-s-triazolo- [4,3-a] [1,4] -benzodiazepines and processes for their preparation - Google Patents

Description

KSCH7SANWALTE

pj -. r * ifr & Ji waiter at * April 25

E * \ J:;. :. · ■ '.- ■: ■■ ·:. «■■ ·. : i-i. WOLFF FüAi ·, K ■ "· · < ί Λ / .i MAiN - HUCHSf ABUOh www isi

Our no. 17 785

The Upjohn Company
Kalamazoo, Michigan, V.St.A.

New 1-substituted 6-phenyl- ^ H-s-triazolo- Pt, 3-a JCl, 4 3-benzodiazepines and methods of making them

The present invention relates to new 6-phenyl-JlH-striazolo [i |, 3-a] [l, 4 i »enzodiazepines and methods for their Manufacturing.

The new compounds and methods of making them

can be shown as follows;

-CC-NH-NH ₂
H , .
(M)

In the above formulas, R ¹ denotes a cyano group, ITitro group, hydroxyl group, dialkylamino group with alkyl groups with 1 to 3 carbon atoms, alkoxy group with alkyl groups with 1 to 3 carbon atoms or alkyl mercapto group with alkyl groups with 1 to 3 carbon atoms, R ₁ denotes a hydrogen atom or an alkyl group with 1 to 3 Carbon atoms and Rp, R. ,, R. and R ^ hydrogen atoms, alkyl radicals with 1 to 3 carbon atoms, halogen atoms, nitro groups, cyano groups, irifluoromethyl groups or alkoxy, alkylmercapto, alkylsulfinyl, alkylsulfonyl, alkanoylamino or dialkylamino radicals, their carbon chains 1 have up to 3 carbon atoms. The Ver-

209847/1186

"Bond of the formula IHa, in which R ^{1 is} a cyano group, gives" on hydrolysis a compound of the formula III in which H = COOR ¹¹ , where R ^{11 is} an alkyl radical as defined above.

Me compounds of the formula III are thus 1-substituted 6-Phenyl-4ii-B-triazolo / ~ 4,3-a7Z ~ 1, ^ "benzodiazepine der formula

R-CH,

III

in the R

Rp, R ^, R- and R ₁ - have the above meaning and R R ¹ or -Cuök ' ⁵ ' represents, in R '' the above meaning

owns.

The inventive method is characterized in that that Di3.ii 'i', ;; - J) ihydro-5 ~ phenyl-2H-1,4-benzodiazepine-2-thione dei- i-'orwel 1 in an organic solvent, e.g. lower alkanol with 1 to 4 carbon atoms, or in cyclohex? .no] with a Siiurebydrazid of the formula II with a

2098A7 / 1 1 86

Temperature between 6o-12o ° C condenses, giving the corresponding 1-substituted 6-phenyl-4H-B-triazolo / ~ 4,3-a7 / ~ 1, <£ / -bsnzodiazepine (HIa). The compounds of the formula HIa in which R ^{1 is} a cyano group can be hydrolyzed to convert this group into a radical of the formula

RIt _- Q _- Q _{- t} whereby a product of the formula III is obtained in which R is a radical -COOR »♦.

Lower alkyl groups with 1 to 3 carbon atoms are, for example, the methyl, ethyl, propyl and isopropyl radical.

The carbon chain of the alkoxy, alkyl mercapto, alkylsulfinyl-alkylsulfonyl and dialkylamino radicals as defined above 1 to 3 carbon atoms.

The alkanoylamino group with 1 to 3 carbon atoms is a formamide, acetamido or propionamido group.

Halogen is used to denote fluorine, chlorine, bromine and iodine.

■ The new compounds of the formula III including their Acid addition salts possess sedating, tranquilizer and muscle relaxing effect in mammals and birds.

The acid addition salts of the compounds of the formula III, i.e. the hydrochlorides, hydrobromides, hydroiodides, sulfates, Phosphates, Cyclohexansulfamate, Hethansulfonate and the like., are obtained by treating a compound of formula III with an excess of the corresponding pharmacologically permissible acid treated.

The sedative effect of 8-chloro-6-phenyl-4H-s-triaeolo-Z ~ "4,3-a7 / ~~ 1,4; 7benzodia2epin-1 -acetonitrile was made by the following

209847/1186

Tests on mice found: '

Chimney test : (Med. Exp. ^, 11 / (1961)) i The effective intraperitoneal dose for 50 $ of the mice (EDc ₀ ) is 0.3 mg / kg. The test determines the ability of the mice to have one within 30 seconds climbing up and leaving the vertical glass cylinder .. At the effective dose, 50 per cent of the mice did not succeed in doing this.

Dish test: (cm, partially embedded in wood chips diameter 1o cm, height 5) from petri dishes climb unbehandeIte mice in a short time out '. If a mouse remains in the dish for more than 3 minutes, there is an indication of tranquilization. The ED ₁ - is the dose of test compound at which 5 & / o of the mice will remain in the dish. In this test (intraperitoneal administration) it is 0.3o mg / kg.

Pedestal test : Untreated mice leave the pedestal within less than 1 minute and climb back onto the floor of the mouse cage. Tranquilized mice remain on the pedestal for more than 1 minute. The ED ₁ - (intraperitoneal administration) is 0.7 mg / kg in this test.

Nicotine antagonism: In one group of six is these mice, the test compound 8-chloro-6-phenyl-4H-s-triazolo / 4,3-a7 ~ / "* 1,4.7-benzodiazepin-1-acetonitrile injected 3o minutes epäter is. Mice and untreated control animals were injected with nicotine salicylate in an amount of 2 mg / kg. The control animals show overstimulation, ie (1) successive convulsions, followed by (2) tonic extensor seizures, followed by (3) death. By an intraperitoneal dose of 0.13 mg / kg of the test compound is given by 50% of the mice against (2) and by 0.15 mg / kg (EDc ₀ ) against (3).

protects. .,.,

/own

The following compounds (intraperitoneal administration) a

209847/1188

_, according to the table below:

ED ₅₀ (in mg / kg) Compound K Sch P Ni

8-chloro-1- (ethoxymethyl) -6-phe-

nyl-4H-s-triazolo / "" 4,3-a7 / "* 1, £ 7-

benzodiazepine 1 ·, ο 1.6 1.4 ο, 6

8-chloro-1 - / "" (diethylai ^ no) -methyl7-6-phenyl-4H-s-triazolo / "~ 4,3-a7-, £ 7beIlzodiazepine 0.63 o.11 0.4 0.08

K «= chimney test

Sch = cup test

P = pedestal test

Ni = nicotine antagonism (3) test

I ' own as pharmaceutical preparation forms

819h for the products according to the invention those for oral, parenteral and rectal use, e.g. tablets, powder packets, sachets, coated tablets, capsules, solutions, Suspensions, sterile injectable forms, suppositories and the like. Suitable carriers or coating compositions can be used Diluents and carriers such as carbohydrates (lactose), proteins, lipoids, calcium phosphate, Kais starch, stearic acid, Methyl cellulose and the like can be used. For the production of solutions or suspensions, oils, e.g. coconut oil, Sesame oil, saffron oil, cottonseed oil, peanut oil and the like can be used. Furthermore, sweeteners, colors and Flavors are added.

For mammals and birds, you can feed premixes with starch, oatmeal, dried fish meat, fish meal, meal and the like.

209847/1186

produce. I.

The compounds of the formula III can be used as tranquilizers in 1 * 0 β s of 0.1 Ms 1o.rag / kg in oral or in j i egg Form administered for relief from tension. and Anxiety in mammals or birds, such as ■ for example occur during shipment.

Other acid addition salts of the compounds of the formula III can also be prepared, e.g. the salts with fluokiesiic acid, which are suitable as moth repellants * or the trichloroacetates, which are used as herbicides against Jdnson grass, Bermuda-G-ras, yellow and green foxtail and couch grass effective Gind.

The starting materials of the process of the formula I according to the invention, i.e. the substituted or unsubstituted 1,3-Mhydro-5 "phenyl-2H-1., 4-benzodiazepine-2-thione, were from ü.A. Archer and L.H. Sternbach (J. Org. Chem. 25, 251 (1964) and U.S. PS 3 422 091). These connections I are obtained by using the known substituted or unsubstituted 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-ones heated with phosphorus pentasulfide in pyridine for about 45 minutes (Archer et al., loc. eit.), the following compounds are given as examples of the starting materials I ~ named:

6-chloro-1,3-dihydro-5- (m-bromophenyl) -2H-1,4-benzodiazepine ~ 2-thiofl 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione; 8-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione; 7-bromo-1,3-dihydro-5-phenyl-2H-1 ^ -benzodiazepine - ^ - thione; 7-chloro-1,3-dihydro-5- (3,4-dimethylphenyl) -2H-1,4-benzodiazepine-2-thione;

1,3-dihydro-5- (2-methyl-4-methoxyphenyl) -2H-1,4-benzodiazepine-2-thione ;. ■

209847/1186

9 ~ bromo-1, J-dihydro-iu-phenyl- ^ Hi, 4-benzodiai3epin-2-thione; "7-Kethyl ~ 1 ₎ 3 ~ dihydro-5-piienyl-2H-1,4-benzodiazepine-2-th.ion; 7-nitro-1,2 ~ dihydro-5-phenyl-2H-1,4 - ^ θηζοάίαζΘρ1η-2-ΐ3ιίοη; 7-fluorine-1,2-dihydro-5-phenyl ~ 2H-1,4-benzodiazepine-2-thione; 7-trifluoromethyl ~, 1,3-dihydro-5-plaenyl-2H -1,4- "ben2odiazepine-2-thione; 9-trifluoromethyl-1,3-dihydro-5 ~ (p-propionylaminophenyl) -2H-1 _t 4-t>enzodia2epin-2-thione; 7-cyano-1,3-dihydro-5-phenyl ~ 2H-1,4- "benzodiaaepin-2-thione; 8-cyano-1,3-dihydro-5 ~ (p-trifluoromethylphenyl) -2H-1,4 -ben2O »diazepine-2thione; 7-chloro-1,3-dihydro-5- (o-chlorophenyl) -2H-1,4-benzodj.azepine-2-thione; 6-ethylthio-1,3-dihydro-5 - (o-bromophenyl) -2H-1,4- "benzodiazepine-2-thione; 6,8-dichloro-1,3-dihydro-5- (o-fluorophenyl) -2H-1,4-benzodiazepine-2-thione; 8-propox3 "- 7 -." Hrom-1,3-dihydro-5- (m-ethylsulfiTiylphf5nyl) -2H-1,4-t>enzodiazepin-2-thione; 9-misopropylaraino-7-methyl-1- , 3-dihydro-5- (ni-propylsulfonylphenyl) -2H-1,4- "benzodiazepine-2-thione; 7-bromo-1,3-dihydro-5- (o-fluorophenyl) -2H-1,4-benzodiazepine-2-thione; 3-I'ethyl-1,3-dihydr'o-5 - (. O-fluorophenyl) -2H-1 _f 4-benzodiazepine-2-thione; 7-i'luoro-1,3-dihydro-5- (o-fluorophenyl) -2H-1,4-ben2odiazepine-2-thione; 3-ethyl-1,3-dihydro-5- (p-fluorophenyl) -2II-1 ^ -beiiZodiaZepin-2-thione; 7-NitrO "1,3 ~ dihydro-5- (o -chlorophenyl) -2H-1,4-benzodiazepine-2-thionj 8-nitro-1,3-dihydro-5- (o -chlorophenyl) -2H -1,4-benzodiazepine-2-thione; 7-bromo-1,3-dihydro-5- (o- "bromophenyl) -2H-1,4-"benzodiazepine-2-thione;

209847/1

7-methylsulfinyl-1,3-dihydro-5- (o-fluorophenyl) -2H-1,4-henzodiaacpin-2-thione;

7-ethyl-1,3-ihydro-5 ~ (p-chlorophenyl ') -2H-1,4-henzodiazepine-

2-thione; ".

7-methylthio-1 _f 3-dihydro-5-phenyl-2H-1,4-t>enzodiazepine-2-thione; 7-cyano-1,3-dihydro-5- (o-chlorophenyl) -2H-1,4- "benzodiazepine-2-thione;

3,6,8-trimethyl-1, 3 ^i-dihydro-5- (m-chlorophenyl) -2H-1,4 "benzo ~ diazeoin-i2-thione;

9-propylsulfonyl-7-methyl-1,3-dihydro-5-phenyl-2H-1,4-henaodiazepine-2-thione;

7-trifluoromethyl-1,3-dihydro-5- (o -chlorophenyl) -2H-1,4- "benzodiazepine-2-thione;

7-dimethylamino-1,3-dihydro-5-phenyl-2H-1,4-henzodiazepine-2-thione;

7-fluoro-1,3-dihydro-5- (o -chlorophenyl) -2H-1,4-henzodiazepine-2-thione;

7, ö-i) icyan-1,3-dihydro-5- (p-methylöülfonylphenyl) -2II-1,4- ■ benzodiazepine-2-thione;

6,9-Mchlor-1,3-dihydro-5- (p-isopropylphenyl) -2H-1, .4 "benzodiazepine-2-thione;

6,8-diethyl-1,3-dihydro-5- (m-ethylphenyl) -2H-1,4-henzodiazepine-2-thione;

6-nitro-1,3-dihydro-5- (o-propylthiophenyl) -2H-1,4- "benzodiazepine-2-thione;

7,9-bis-jfdipropylamino / -1,3-dihydro-5- (o-nitrophenyl) -2H-1,4- "benzodiazepine-2-thione;

9-acetylamino-1,3-dihydro-5- (p-cyanophenyl) -2H-1,4-henzodiaze - pin-2-thione; and the like

When carrying out the method according to the invention, the respective 1,3-Jihydro-5-phenyl-2H-1,4- "benzodiazepine-2-thione (I) in an inert organic solvent, preferably in a lower alkanol, e.g. 1-butanol, 2-butanol,

209847/1188

Hexanol or the like. To a temperature between 6o-12o ° C and preferably to the reflux temperature of the mixture heated, in the presence of the relevant acid hydrazide " the formula “0

Ri-CC-WH-HH ₉ (II) where the heating is 2 to 48 hours.

take. According to . a preferred embodiment of the invention the hydrazide is in a 2 to 5-fold excess used over the theoretically required amount; the. However, reaction also takes place in the presence of smaller ones or larger amounts of this reactant take place. The reaction time is 2 to 18 hours. After finished Reaction, the reaction mixture is concentrated, whereby a crude product is obtained which consists of the desired 6-phenyl-4H-s-triazolo / "" 4,3-a7 / "" i , 4,7henzodiazepine IHa. This crude product IHa is then used in a conventional manner purified, e.g. by chromatography or recrystallization from solvents such as ethyl acetate, methylene chloride, Chloroform, acetonitrile or the like.

6-Phenyl-4H-s-triazolo / ~ 4,3-a7 _i / ~ 1,4; 7henzodiasepin-1-acetonitrile (ie compounds of the formula IHa in which R ^{1 is} a cyano group) can be used in a lower alkanol, e.g. Methanol; Ethanol, propanol or 2-propanol, hydrolyzed in the presence of anhydrous hydrogen chloride. During the addition of hydrogen chloride, the system must be cooled, since the reaction preferably takes place at from 0 to 50.degree. Ethyl ether can be used as a diluent. After the reaction has ended, the reaction mixture is mixed with water, neutralized, for example with sodium or potassium bicarbonate, then the product is worked up in a conventional manner, for example by extraction and evaporation, chromatography, recrystallization or a combination of these measures.

209847/1186

example 1

8-chloro-1- (ethoxymethyl) -6-plienyl-4H-s-triazolo / ~ 4,5-a7

A solution of 5.74 g (0.02 mole) 1,3-dihydro-7 ~ chloro-5-phenyl-2H ~ 1 ^ -benzodiazepine - ^ - thione and 7, o8 g (0.06 mole) ethoxyacetic acid hydrazide in 300 ml of n-butyl alcohol is refluxed for about 3 hours while a slow nitrogen syrup is passed through the reaction mixture. The mixture is then cooled and concentrated in vacuo, the residue is suspended in water and extracted with methylene chloride. The extract is dried over anhydrous potassium carbonate and concentrated to dryness, this residue is crystallized from methylene chloride / methanol, 0.66 g of starting material being recovered. The mother liquors are concentrated and chromatographed on 400 g of silica gel using 405% ethyl acetate / 60 ^ Skellysolve B hexanes to 100 g of ethyl acetate. The product obtained from the column is crystallized from ethyl acetate / Skellysolve B-hexanes, 1.74 g of 8-chloro-1- (ethoxymethyl) -6-phenyl-4H ~ s-triazolo / ~ 4,3-a7, .. Z "~ i ¹ 1,47benzodiazepin from 168-17o ° C The analytical sample melted at 168-169 ⁰ C, Anal Calcd for C ₁₉ H ₁₇ O GLN _4..:

C: 64.68; H: 4.86; Cl: 10.05; N: 15.88; Found: i C: 64.7o; H: 4.72; Cl: 9.98; N: 15.5o, 15.99.

Example 2

8-chloro-6-phenyl-4H-s-triazolo / ~ 4,3-a7 / ~ 1,47benzodiazepine-1 acetonitrile. ... ■

209847/1186

A mixture of 5.72 g (0.02 moles) 1,3-uihydro-7-chloro-5-phenyl-2ii-1 ^ - "benaooiazepin ^ -thione, 5.95 g (0.06 Hoi) cyanoacetic acid hydraside. and 275 ml of n-butyl alcohol is refluxed for 71/2 hours while a slow stream of nitrogen is passed through the mixture. The reaction mixture is then concentrated in vacuo, the residue is suspended in water and extracted with methylene chloride. The extract is dried and concentrated to dryness, the residue is chromatographed on 400 g of silica gel using 2% methanol / 98% chloroform The product eluted from the column is crystallized from ethyl acetate / Skellysolve B-hexanes to give 2 , 62 g of 8-chloro-6-phenyl-4H-striazolo ^ ~ 4,3-a7 / ~~ 1,4_7 "benzodiazepine-1-acetonitrile from P. 198-201 ⁰ C.
Anal. Ber. for C ₀ H _-10 ClNr-:

C: 64.77; H: 3.63; Cl: 10.62; Found: C: 64.52; H: 3.86; Cl: 1o, 51.

Example 3

8-chloro-6-phenyl-4H-s-triazolo / ~ 4,3-a7 / "" i, 47benzodiazepine-1-acetic acid methyl ester.

A mixture of 1, oo g (o, oo3 Hol) 8-chloro-6-phenyl-4H-striazolo / ~ "4,3-a7 / ~ 1 , ^ bensodiazepine-i-acetonitrile, 2 ml of methanol and 6 ml of ether is cooled with stirring in a salt-ice bath and with a stream of anhydrous hydrogen chloride Saturated for 15 minutes. The mixture is then allowed to warm to room temperature and stand for 18 hours, then it is poured into water. The resulting mixture is neutralized with sodium bicarbonate and with chloroform extracted, the extract is mixed with sodium chloride solution

209847/1186

wash, dried over anhydrous magnesium sulfate and. constricted. The residue is crystallized from methanol to thereby obtain o, 149 g of a by-product from P. 184.5 to 188 ⁰ C (decomposition). The residues of the mother liquor are crystallized from methanol / Ä Hiylaeetat and give o, 126 g of a by-product, 1- (aminomethyl) -7-chloro-5-phenyl-striazolo / ~ 4 _f 3-α7-quinoline-1-carboxylic acid methyl ester of melting point '2o5.5-2o7.5 ° C (decomposition). The mother liquors from this crystallization are concentrated and chromatographed on 50 g of silica gel with 20% methanol / 98 / ί chloroform. The first compound eluted from the column is crystallized from kethanol / ethyl acetate and gives 0.169 g of 8-chloro-6-phenyl-4H-s-triazolo / ~ "4,3-a7 / ~ 1,47henzodiazepine-1 methyl acetate from P. 2o2.5-2o3.5 ° C. (decomposition) and o.125 g of this product from P. 2oo.5-2o2.5 ° C. (decomposition). The analytically pure sample melted at 2o2-2o3 ° C. .

Anal. Eer. for C ₁ QH ₁₅ ^ ₂

C: 62.21; H: 4.12; Cl: 9.67; N: 15.28; Found: C, 62.32; H: 4.14; Cl: 10.15; K: 15.33.

Example 4

8-chloro-1-diethylaminomethyl-6-phenyl-4H-s-triazolo _i / ~ '4,3-a7 ] , 4-7henzodiazepine.

According to the procedure of Example 1, 1,3-dihydro-7-chloro-5-phenyl-2H-1,4-benzodiazepine-2-thione are obtained and (diethylamino) acetic acid hydrazide reacted in solution to form the title compound, which after recrystallization from ethyl acetate / ökellysolve B-hexanes have a melting point of 131.5-132.5 ° C owned.

Anal. Ber. for C ₂₁ H ₂₂ ClH _r :

209847/1186

C: 66.39; H: 5.84; Cl: 9.33; N: 18.44; Found: G: 66.2o; H: 6, ο6; Cl: 9.29; N: 18.55.

Example 5

8-nitro-1-diethylaminomethyl-6-phenyl-4H-s-triaaolo _J / "" 4,3-a7-

According to the procedure of Example 1, a solution of 1,3-dihydro-7-nitro-5-phenyl-2H-1,4- "benzodiazepine-2-thione in n-butanol with diethylaminoacetic acid hydrai'.id under reflux boiled, obtaining the Tite! compound.

Example 6

9-Ethyltnio-1-propoxymethyl-6- (o-chlorophenyl) -4H-s-triazolo- / ~ 4,3-a7 / "" i , 47benzodiazepine.

According to the procedure of Example 1, a solution of 1,3-dihydro-8-ethylthio-5- (o-chlorophenyl) -2H-1,4- "benzodiaze · pin-2-thione in n-butanol with propoxyacetic acid hydrazide am Refluxed to give the title compound.

Example 7

7-l ^il luorr1-methoxymethyl-6- (o-bromp! Ienyl) -4H-s-triazolo / 4,3-7- ^ £ ~ λ, 4,7tenzodiazepin.

According to the procedure of Example 1, a solution of 1,5-i) ihydx'o-6-fluoro-5- (o-bromophenyl) -2H-1,4-benzociiazepin ~ 2-thione

boiled under reflux in n-butanol with methoxyacetic acid hydrazide, whereby the title compound was obtained »

Example 8

7 ~ Trifluoromethyl-6- (m-methylsulfonylphenyl) -4H-s-triazolo ~ / * "4,5 ~ a7 /" "i, _47benzoaiazepine-1-acetonitrile.

According to the procedure of Example 1, a solution of 1, 5-Mhydro-6-trifluoromethyl-5- (In-methylsulfonylphenyl) -2H-1 ^ -benzodiazepine - ^ - thione in n-butanol / was refluxed, the l'it elver connection received. f with cyanoacetic acid hydrazide

Example 9

9-Joa-1 - metliOxymethyl-6- (2,6-difluoroHphenyl) "4H-s-triasolo - /""4,3-a7Z~" 1 1 47benzodiazepine.

According to the procedure of Example 1, a solution of 1,3-dihydro-8-iodine ~ 5 ~ (2,6-difluorophenyl) -2H ~ 1,4-benzodiazepine-2-thione in n-butanol was refluxed with methoxyacetic acid hydrazide , whereby.man received the title compound.

Example 1o

T-ethylsulfinyl-i-isopropoxymethyl-e-Cp-trifluoromethylphenyl) -

According to the procedure of Example 1, a solution of 1,3 dihydro-6-ethylsulfynyl-5- (p-trif luorinethylphenyl) -2H-1,4-

209847/1 186

benzodiazepine-2-thione in n-butanol with isopropoxyacetic acid hydraside refluxed to obtain the title compound.

Example 11

9-l ^i-1 ~ lethyl dipropylaminomethyl-6- (p-isopropylphenyl) -4H-striazolo / ~ 4,3-a7 /, "" i, 4_7benzodiazepin.

Following the procedure of Example 1, a solution of 1,5-dihydro-8-methyl-5- (p ~ isopropylphenyl) -2ii-1,4-benzodiazepine-2-thione Boiled under reflux in n-butanol with Dipropylaminoessigsäureh3''drazid, whereby "the title compound received.

Example 12

7,9-diethyl-6- (2,4-diäi-hylphenyl) -4H-s-triazolo / 4,3-a7 / * ~ 1.47 · benzodiazepine-1-acetonitrile.

According to the procedure of Example 2, a solution of 1,3-dihydro-6 _r 8-diethyl-5- (2,4-diethylphenyl) -2H-1 _f 4-benzodiazepine-2-thione in h-butanol was treated with cyanoacetic acid hydrazide Refluxed to give the title compound.

Example 13

7,8-Dinitro-6- (2,4-dibromophenyl) -4H-s-triazolo / -4,3-a7 / -1,17-benzodiazepine-1-acetonitrile.

209847/1 186

According to the formula of Example 2, a solution of 1,3 · dihydro-6,7-dinitro-5- (2-, 4-di "bromophenyl) -2H-1,4-benzodia ά epin-2-thi on refluxed in n-butanol with cyanoacetic acid hydrazide to obtain the title compound.

Example 14

7-Trifluoromethyl-6- (in-raethylsulfonylphenyl) -4iI-s-triazolo ~

According to the procedure of Example 3 was 7-trifluoromethyl- · 6- (m-Eiethylsulfonylphenyl) -4H-s-triazolo / ~ 4 »3-a7 / ~ 1» 4.7- "benzodiazepine-i-acetonitrile hydrolyzed in ethanol with anhydrous hydrogen chloride, the ^ 'itelverbindungen received.

Example 15

7,9-I) iäthyl-6- (2,4-diethylphenyl) -4H-s-triazolo / "" 4,3-a7 / "1,47-benzodiazepine-1-acetic acid propyl ester.

According to the procedure of Example 3, 7,9-Mäthyl-6- (2,4-diethylpheriyl) -4H-s-triazolo / ~ * 4,3-a7Z "" i _f 47 "benzodiazepine-1-acetonitrile in 1- Propanol hydrolyzed with anhydrous hydrogen chloride to give the title compound.

Example 16

7,8-jjinitro-6- (2,4-dibromophenyl) -4H-s-triazolo / "~ 4,3-a7 / ~ 1 ', 4,7-in-1 -öf] o j.g acid-iuethylester.

onQRA7 / 11ft

7,8-Dinitro-6- (2 _> 4 · di "bromophenyl) -4H-s-triazolo /""4,2-a7/""i, ^ Tbenzoäiazepin-I-aoetonitril in methanol with anhydrous hydrochloric hydrolyzed., where "when you ^f I 'i te! compound received.

Example 17.

8-chloro-1 * -n _l ethylthioaethyl-6- (o- ^{chlorphe J} nyl) -4H-s-triazolo »4,7benzodiazepine.

Following the procedure of Example 1, a solution of 1,3-Dihy <aro-7-chloro-5- (o-chlorophenyl) -2H-1 ^ -benzodiazepinethione in n-butanol with methylcaptoacetic acid hydrazide refluxed to give the itel compound.

Example 18

9-nitro-1-ethylthiomethyl-6- (m-propyl-sulfonylphenyl) -4H-s

i, 4,7 ^ enzodiazepine.

According to the procedure of Example 1, a solution of 1,3-I) ihydro-8-nitro-5- (m-propylsulfonylphenyl) -2H-1 ", 4benzodiazepine-2-thione in n-butanol boiled under reflux with ethyl mercaptoacetic acid hydrazide, v / obei the title compound was obtained.

Example 19

8 "chloro-1-hydroxymethyl-6- (o ~ chlorophenyl) -4H-s-triasolo / 4,3-a / -

A solution of 9.63 g (0.03 mol) 1,3-dihydro-7 ~ chloro-5- ' (o-chlorophenyl) -2H-1,4-T3enzodiazepine-2-th.ion and 6.66 g Hydroxyacetic acid hydrazide in 300 ml of n ~ butanol was about Boiled on the reflux for 115 hours, v / o during the first Hour a slow nitrogen flow through the reaction mixture was directed. The mixture was then cooled and concentrated in vacuo. The residue was suspended in water, treated with a little ether and brought to crystallization.

The solid was filtered off, dried in vacuo and recrystallized from methylene chloride / methanol, giving 4.96 g of 8-chloro-1-hydroxymethyl-6- (o-chlorophenyl) -4H-B-triazolo / 4.3 -a7 / ~ 1.47banzodiazepiii of the mp 239.5-241 ⁰ C, 1.58 g of this product of the mp 236 ~ 239 ° C and o, 365 g of the

F. 232-236 ⁰ C. The analytically pure sample melted at 239.5-

Anal. Ber. for C ₁₇ H ₁₂ Cl ₂ N ₄ O:

C: 56.84; H: 3.37; Cl: 19.74; N: 15.60; Found: C, 56.27; H: 3.28; Cl: 19.75; N: 15.55.

The KDt- des 8-chloro-1-hydroxymethyl-6- (o-chlorophenyl) -4K - s triazolo / ^, 3- & 7Ζ ~ Ί, 47 ^ enzodiazepine at Hausen is:

Cup test 0.08 mg / kg

Chimney test ■ 0.04 mg / kg

Pedestal test '0.08 mg / kg

Nicotine (3) test. 0.032 mg / kg

Example 2o

Succinic acid half-ester of 8-chloro-1-hydroxymethyl ^ 6- (ochlorphenyl) -4H-s-triazolo / "4,3-a7, / f * 1,47 benzodiazepine.

209847/1186

Mn intimate mixture of 4.61 g (o, ό13 mol) 8-CLlor-i-hydroxymethyl-6- (o ~ chlorophenyl) -4H-s ~ triazolo / ~ 4,3-a7 / ~ 1,47benzoaiazepine and 2, 6 g (0.06 moles) of succinic anhydride are melted for 5 to 10 minutes under reduced pressure at 12-15 ° C. The cooled melt is crystallized from methanol / methylene chloride, there is obtained the 4.59 ^ itelverbindung of melting point 245-248 ⁰ C. Anal g. Ber. for C ₂₁ H ₁₆ Cl ₂ N ₄ O .:

C: 54.91; H: 3.51; Cl: 15.55; N: 12.2o. Found: C: 55.00; H: 3.41; Cl: 15.45? N: 12.27.

Pharmacologically acceptable acid addition salts are obtained by adding 1 to equivalents of a pharmacologically acceptable acid to one molar equivalent of the diazepine III. Preferably the addition takes place in an anhydrous medium, e.g. in ether, ethanol or the like, in which the salt either ; fails or from which it is caused by evaporation of the Solvent can be obtained. For the production of pharmaceutical dosage forms are particularly suitable Hydrochloride Hydrobromide, Sulphate, Phosphate, Acetate, Tartrates, citrates, sulfamates and the like.

Following the procedure of the preceding examples, other 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thiones of the formula I can be reacted with acid hydrazides of the formula II to form further new 1-substituted e-phenyl ^ H-striazolo / ~ 4 _t 3-a7 / "~ 1, ^ benzodiazepine III, for example of the compounds:

io-chloro-1-ynethylthiomethyl-6- (m-isopropylphenyl) -4H-s-triasolo- L 4,3-a7 / -1,4.7benzodiazepine;

g-Dipropylamino-i-dimethylaminomethyl-G-Cp-propionylaminophenyl) 4H-s-triazolOj / "" 4,3-a7 / "~ 1,47benzod.iazepine;

> χ-. 3 -H 7 I I

8-methylsulfinyl-1-diethylarinoinethyl-6- (o-nitrophenyl) -4H-s-triazolo / ~ 4,3-a7 / ~ 1 , 47 "benzodiazepine; * 7- ^ thylsulfonyl-Ί -dipropylarninoinethylr-6- (o-cyanophenyl) -4H-s-

4-propyl-1-diisopropylarainomethyl-6 ~ (m-methylthiophenyl) ~ 4H-s-triazolo_ _(/ '"4,3-a7/"'"i,4,7" benzodia2epinj 1o-l ^l · l · uoΓ- 7-chloro-1-ethoxymethyl-6- (p-trifluorometllylpl -leriyl) -4H

7,9-methoxy-1-methoxyraethyl-6- (ni-ethoxypjaonyl) -4H-s-tria2; olo

7-propyltliio-6- (m-iodophenyl) -4H-s »triazolo _i / ~ 4,5-a2Zr" i, 4,7-benzodiazepine-1-acetonitrile;

8-acetylamino-6- (p-iodophenyl) «4H ~ s ~ triazolo / ~ 4,3-a7 /" i »47-benzodiazepine-1-acetonitrile;
4-propyl-1-nitromethyl-6- (o -iodophenyl) -4H-s-triazolo2f "4,3-a7

4-ethyl-1-methylthicraethyl-6- (o-ethylthiophenyl) -4H-s-

4-Metliyl-7, lo-dichloro-i-ethylthiomethyl-o-Cm-isopropwloxypiienyl) 4Η-ε-ΐΐ'ίΒζο1ο / "" 4.3-3.7 / "~ 1.47 ^ enzodiazepine; 9-Dipropylaraino-1 "propylthiomethyl-6- (m-propylthiophenyl) -4HTS-

7-misopropylamino-1-nitro-methyl-6- (p-dipropylamino-phenyl) - '4H-B-triazolo / "" 4,3-a7 / ~ i, 47 ^ ⁶ HZOdIaZePin; 4-isopropyl-7,9-di3od-6-phenyl-4H-s-triazolo / ~ 4,3-a7 / ~ "i | 47-" benzodiazepine-1-acetic acid ethyl ester; 8-chloro-6- (3,4-diinethylphenyl) -4H-s-triazolo _i / "" 4,3-a7 / "" i, 47- ■ benzodiazepine-1-acetic acid propyl ester; 6- (2 ~ methyl-4-methoxyphenyl) -4H-s-triazolo / "" 4,3-a7 / "" i, 47-benzodiazepine-1-acetonitrile;
8-methylthio-1-ioopropoxyI ^ etiαyl-6-phenyl-4H-s-triazolo-

4,8-] Jimethoxy-1-ätlioxymethyl-6-phenyl-4H-s-triazolo / ~ 4 »3-a7- / ~ 1 year-iiZoaiiizcTpin and the like.

209847/1186

Claims (11)

Patent claims: (lj) 6-Phenyl-4H-s-triazolo substituted in the 1-position 4 3-benzodiazepine of the general formula III R-CH in which R is a cyano, hydroxy, nitro, dialkylamino radical in which the alkyl radical has 1 to 3 carbon atoms, an alkoxy radical in which the alkyl radical has 1 to 3 carbon atoms, an alkylthio radical in which the alkyl radical has 1 to 3 carbon atoms , -COOR ", where R" denotes an alkyl radical having 1 to 3 carbon atoms, R ^ a hydrogen atom or an alkyl radical having 1 to 3 carbon atoms and Rp, R-7, R / | and R ₅ hydrogen atoms, alkyl radicals with 1 to 3 carbon atoms, halogen atoms, nitro, cyano, trifluoromethyl or alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoylamino or dialkylamino radicals in which the carbon chain has 1 to 3 carbon atoms has, mean, and its pharmaceutical 209847/1186 2220618 * compatible acid addition salts. 2.) 8-chloro-l- (ethoxymethyl) -6-phenyl-4H-s-triazolo Dl, 3-a [1,4D-benzodiazepine as a compound according to claim 1, in which R of the formula is an ethoxy radical, R ₁ , Rp, Rz and R, - are hydrogen atoms and R ₁ J is a chlorine atom in the 8-position. 3.) 8-chloro-6-phenyl-4H-s-triazolo [4,3-a] [1,4 3-benzodiazepine -! - acetonitrile as a compound according to claim 1, in which R of the formula -CN, R ₁ , Rp, R, and R ^ hydrogen atoms and R || mean a chlorine atom in the 8-position. 4.) Compound according to claim 1, characterized in that R of the formula _§_ _0R »denotes, where R" denotes an alkyl radical having 1 to 3 carbon atoms. 5.) 8-chloro-6-phenyl-4H-s-triazolo- [4,3-aD [1,4 azepine-1-acetic acid methyl ester as a compound according to claim 4, in which R "the formula is a methyl radical, R ₁ , R ₂ , R, and R _{g denote} hydrogen atoms and Rh denotes a chlorine atom in the 8-position. 6.) 8-chloro-l- (diethylaminomethyl) -6-phenyl-4H-s-triazolo [4,3-1 DCl, 4 dbenzodiazepine as a compound according to claim !, in which R of the formula is a diethylamino radical, R ₁ , Rp j Rz and R ₁ - hydrogen atoms and R ^ a chlorine atom in the 8-position. 7.) 8-Chloro-1- (hydroxymethyl) -6- (o-chlorophenyl) -4H-striazolo- [4,3-a] [1,4 3benzodiazepine as a compound 209847/1186 Claim 1, in which R of the formula is a hydroxy radical, R ₁ , R, and Rf are hydrogen atoms, Rp is a _{chlorine atom in the o-position and R 1} is a chlorine atom in the 8-position. 8.) Compound according to claim 7 in the form of hydrogen succinate. 9.) Process for the preparation of a l-substituted-6-phenyl-4H-s-triazolo [4,3-a3Cl, 4 dbenzodiazepirs of the general Formula UI according to claim 1, characterized in that one l ^ -dihydro-S ^ thion of the general formula in which R ₁ , R ₂ , R ,, R ₁ J and R ^ have the meanings given in claim 1, in an inert organic solvent with a hydrazide of the general formula 209847/1186 St. ¹ -CC-NH-NH ₉ C ii) in which R 'denotes a cyano, nitro, hydroxy, dialkylamino, alkoxy or alkylthio radical, the alkyl radicals having 1 to 3 carbon atoms., heated to a temperature between 60 and 120 ° C., and ^ hydrolyzed with a mixture of alcohol, water and hydrochloric acid. / ^ Vyii.heA.xJL-x ^ PaJi & j tCrC ^^ v .. K- ' QjC ^ Q ^ _x Cvj <sU «U) \ ft ^ t 10.) Process according to claim 9 for the preparation of 8-chloro- (ethoxymethyl) -6-phenyl-4H-s-triazoloC4,3-a3Cl, 4 3tenzodiazepine, characterized in that 1,3-dihydro-7-chloro-5-phenyl-2H-1,4-benzodiazepine heated with ethoxyacetic acid hydrazide. 11.) Process according to claim 9 for the preparation of 8-chloro (hydroxymethyl) -6- (o-chlorophenyl) -4H-triazolo C4,3-a] [1,4 3-benzodiazepine, characterized in that 1,3-dihydro-7-chloro-5- (o-chlorophenyl) -2H-1,4-benzodiazepine-2-thione with hydroxyacetic acid hydrazide. Pure The UpjoWh Company Dr. H. J. WoHf (Lawyer) 209847/118 «■ ORG INSPECTED