US3772318A - Certain triazolobenzodiazepinone compounds and their production - Google Patents

Abstract

WHEREIN R1, R2, R3, R4, AND R5 ARE DEFINED AS ABOVE, WITH A BASE AND THEN WITH AN ALKY HALIDE OR ALKENY HALIDE. THE COMPOUNDS OF FORMULA II AND THE PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF CAN BE USED AS SEDATIVES AND TRANQULIZERS FOR MAMMALS AND BIRDS.

TRIAZOLO(4,3-A)(1,4)BENZODIAZEPINE

1-(O=),4-R1,6-(R2,R3-PHENYL),R4,R5-2,4-DIHYDRO-1H-S-

WHEREIN R AND R0 ARE SELECTED FROMTHE GROUP CONSISTING OF ALKYL OF 1 TO 3 CARBON ATOMS, INCLUSIVE, AND ALKENYL OF 3 TO 4 CARBON ATOMS, INCLUSIVE, WHEREIN R1 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, ALKYL OF 1 TO 3 CARBON ATOMS, INCLUSIVE, AND ALKENYL OF 3 TO 4 CARBON ATOMS, INCLUSIVE; WHEREIN R2, R3, R4, AND R5 AE SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, ALKYL DEFINED AS ABOVE, AMINO, HALOGEN, NITRO, CYANO, TRIFLUOROMETHYL, AND ALKOXY, ALKYLTHIO, ALKYLSULFONYL, AND ALKYLSULFINYL, ALKANOYLAMINO, IN WHICH THE CARBON MOIETIES ARE OF 1 TO 3 CARBON ATOMS, INCUSIVE, AND DIALKYLAMINO, IN WHICH THE ALKYL GROUP IS DEFINED AS ABOVE; IS PREPARED BY REACTING A 2,4-DIHYDRO--1H-S-TRIAZOLO(4,3-A)(1,4)BENZODIAZPIN-1ONE OF THE FORMULA:

1H-S-TRIAZOLO(4,3-A)(1,4)BENZODIAZEPINE

1-(O=),2-R,3-R0,4-R1,6-(R2,R3-PHENYL),R4,R5-2,3-DIHYDRO-

2,3-DISUBSTITUTED -2,3 -DIHYDRO-6-PHENYL-1H-S-TRIAZOLO(4,3-A)(1,4)BENZODIAZEPIN-1-ONE OF THE FROMULA II

Description

United States Patent 3,772,318 CERTAIN TRIAZOLOBENZODIAZEPINONE COM- POUNDS AND THEIR PRODUCTION Robert B. Molfett, Kalamazoo, Mich., assignor to The Upjohn Company, Kalamazoo, Mich. No Drawing. Filed Dec. 8, '1971, Ser. No. 206,166 Int. Cl. C0711 57/02 U.S. Cl. 260--308 C 4 Claims ABSTRACT OF THE DISCLOSURE 2,3-disubstituted 2,3 dihydro-6-phenyl-lH-s-triazolo- [4,3-a] [1,4]benzodiazepin-1-one of the Formula II II wherein R and R are selected from the group consisting of alkyl of 1 to 3 carbon atoms, inclusive, and alkenyl of 3 to 4 carbon atoms, inclusive, wherein R is selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms, inclusive, and alkenyl of 3 to 4 carbon atoms, inclusive; wherein R R R and R are selected from the group consisting of hydrogen, alkyl defined as above, amino, halogen, nitro, cyano, trifluoromethyl, and alkoXy, alkylthio, alkylsulfonyl, and alkylsulfinyl, alkanoylamino, in which the carbon moieties are of 1 to 3 carbon atoms, incusive, and dialkylamino, in which the alkyl group is defined as above; is prepared by reacting a 2,4-dihydro-lH-s-triazolo [4,3-a] 1,4] benzodiazepin-lone of the formula:

M R5 l R1 R4 N f wherein R R R R and R are defined as above, with a base and then with an alkyl halide or alkenyl halide.

The compounds of Formula II and the pharmacologically acceptable acid addition salts thereof can be used as sedatives and tranquilizers for mammals and birds.

BACKGROUND OF THE INVENTION Field of the invention This invention is directed to new organic compounds and is particularly concerned with novel 3-substituted 2,3- dihydro-lH-s-triazolo[4,3-a] [l,4]benzodiazepin 1 one (II) and a process for the production thereof.

3,772,318 Patented Nov. 13, 1973 p CC R5 R R5 R Bi 4 H R2 R1 R3 R3 R I Ra Alternative Method B I f N-Rn n N II I R5 5 R R4 R1 4 l R Ru 0 I I I] HN-N- OR R1 QR: RI Ia II Alternative Method R R H RNHNHRu (IV) wherein R and R are selected from the group consisting of alkyl of 1 to 3 carbon atoms, inclusive, and alkenyl of 3 to 4 carbon atoms, inclusive; wherein R is selected from the group consisting of hydrogen, alkyl defined as above and alkenyl defined as above; wherein R R R and R are selected from the group consisting of amino, fluoro, chloro, bromo, iodo, cyano, nitro, trifluoromethyl, and alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkanoylamino in which the carbon moieties are of 1 to 3 carbon atoms, inclusive, and dialkylamino, in which alkyl is defined above, and wherein R is an alkyl group defined as above.

The invention also encompasses the pharmacologically acceptable acid addition salts thereof.

The process of this invention comprises: (A) reacting a 2,4 dihydro-1H-s-triazolo[4,3-a] [l,4]benzodiazepin-1- one (I) with an alkyl or alkenyl halide in the presence of a base, or, alternatively, (B) heating together a 1,3- dihydro 5 phenyl-2H-1,4-benzodiazepine-2-thione with an alkyl or alkenyl substituted carbazic acid ester of the Formula III HN-N-k-OR 111 wherein R is alkyl of 1 to 3 carbon atoms, inclusive, and R and R are defined as above, to about 50-100 C. and the resulting product to about 180-250 C. or, alternatively, (c) heating together a 1,3-dihydro-5-phenyl-2H- 1,4-benzodiazepine-2-thione with a 1,2-dialkyl or 1,2-dialkenyl hydrazine RNHNHR wherein R and R are defined as above and treating the intermediate 2 (1,2-disubstituted-hydrazine-1,4-benzodiazepine with a one carbon dibasic acylating agent of the formula 0 xii-X wherein X and X' are leaving groups, to obtain the compound of Formula II above.

DESCRIPTION OF THE PREFERRED EMBODIMENT Lower alkyl groups of 1 to 3 carbon atoms, inclusive, are exemplified by methyl, ethyl, propyl, and isopropyl.

Lower alkenyl groups of 3 to 4 carbon atoms, inclusive, are allyl, methallyl and crotonyl.

The carbon chain moiety of alkoxy, alkylthio, alkylsulfonyl, alkylsulfinyl, and dialkylamino is of l to 3 carbon atoms, inclusive, and can be defined as lower alkyl of 1 to 3 carbon atoms, inclusive, above.

The alkanoylamino group of 1 to 3 carbon atoms con- SlStS Of formamldo acetamido and propionamido.

The novel compounds of the Formula II pharmacologically acceptable acid addition salts thereof have sedative, hypnotic, anticonvulsant, tranquilizing, and muscle relaxant effects in mammals and birds. Also as feed additives they are useful to increase growth rate and feed eificiency of livestock and poultry.

The pharmacologically acceptable acid addition salts of compounds of Formula II contemplated in this invention, are the hydrochlorides, hydrobromides, hydriodides, sulfates, phosphates, cyclohexanesulfamates, methanesulfonates and the like, prepared by reacting a compound of Formula II with the selected pharmacologically acceptable acid.

Sedative effects of 8-chloro-6-(o-chlorophenyl)-2,3-dihydro-2,3-dimethyl- 1 H-s-triazolo [4,3-a] [1,4] benzodiazepinl-one are shown by the following tests in mice:

CHIMNEY TEST [Med. Exp. 4, (1961)] The efiective intraperitoneal dosage for 50% of mice (ED is 11 mg./kg. The test determines the ability of mice to back up and out of a vertical glass cylinder within 30 seconds. At the eflFective dosage, 50% of the mice failed doing it.

DISH TEST Mice in Petri dishes (10 cm. diameter, 5 cm. high, partially embedded in wood shavings), climb out in a very short time, when not treated. Mice remaining in the dish for more than 3 minutes indicates tranquilization. ED equals the dose of test compound at which 50% of the mice remain in the dish. The ED (intraperitoneal administration) in this test was 56 mg./ kg.

PEDESTAL TEST The untreated mouse leaves the pedestal in less than a minute to climb back to the floor of the standard mouse box. Tranquilized mice will stay on the pedestal for more than 1 minute. The ED (intraperitoneal administration) is 11 mg./kg.

NICOTINE ANTAGONISM TEST Mice in a group of 6 are injected with the test compound 8 chloro 6-(0-chl0rophenyl)-2,3-dihydro-2,3-dimethyl lH-s triazolo[4,3-a][1,4]benzodiaZlepin-l-one. Thirty minutes later the mice including control (untreated) mice are injected with nicotine salicylate (2 mg./kg.). The control mice show overstimulation, i.e., (1) running convulsions followed by (2) tonic extensor fits; followed by (3) death. An intraperitoneal dosage of 9 mg./kg. of the test compound protected 50% of the mice against (2) and (3) (ED The pharmaceutical forms contemplated by this invention include pharmaceutical compositions suited for oral, parenteral, and rectal use, e.g., tablets, powder packets, cachets, dragees, capsules, solutions, suspensions, sterileinjectable forms, suppositories, bougies, and the like. Suitable diluents such as carbohydrates (lactose), proteins, lipids, calcium phosphate, cornstarch, stearic acid, methylcellulose and the like may be used as carriers or for coating purposes. Oil, e.g., coconut oil, sesame oil, safflower oil, cottonseed oil, peanut oil, or water may be used for preparing solutions or suspensions of the active drug. Sweetening, coloring, and flavoring agents may be added. The acid addition salts may be used in water solutions.

For mammals and birds food premixes, with starch, oatmeal, dried fishmeat, fishmeal, flour, and the like can be prepared. A feed containing from 1-100 g. per ton of feed of compound II or salts thereof is useful to produce faster growth, or higher milk or egg production in farm animals.

As tranquilizer the compounds of Formula II and its pharmacologically acceptable acid addition salts thereof can be used in dosage of 0.01-20.0 mg./kg. in oral or injectable preparations as described above, to alleviate tension and anxiety in mammals, or birds, such as e.g., occurs when animals are shipped. This is not only important for farm animals like cattle, sheep, swine, and house animals, dogs, cats, parrots, but also for many zoo animals during transport.

Other acid addition salts of the compounds of Formula II can be made such as the fiuosilicic acid addition salts which although not useful as pharmaceutical products, are useful as mothproofing compounds, or the trichloroacetates useful as herbicides against Johnson grass, Bermuda grass, yellow foxtail, green foxtail, and quack grass.

The starting materials of Formula I of this invention, 2,4 dihydro 6 phenyl-1H-[4,3-a] [1,4]benzodiazepinl-ones, are described in British patent specifications 1,254,403; the starting material IA, 1,3-dihydro-5-phenyl- 2H-1,4-benzodiazepine-Z-thiones, are described by Archer et al., J. Org. Chem. 29,231 (1964). Compounds (II) are made by the reaction of the known substituted or unsubstituted 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2- thiones (IA) with a carbazate as shown in Preparations 1 and 2.

In carrying out the process A of this invention, the starting material of Formula I is treated in a solvent with a strong base. As base sodium hydride, potassium hydride, thallous, sodium or potassium ethoxide, or the like can be used. As solvents dialkyl acid amides or ethers are useful, e.g. dimethyland diethylformamide or acetamide, tetrahydrofuran, dioxane, ethylene glycol (or ethylene glycol), dimethyl or diethyl ether, or the like. In the preferred embodiment of this reaction the base is used in a slight excess of the calculated amount such as %25% above the stoichiometrically requirement, and the reaction is performed at room temperature or below. However, temperatures of 78 to 50 C. are operational. The time of reaction is between 1 minute and 3 hours, with minutes suflicient, if the reaction is carried out at room temperature. Thereafter the reaction mixture is treated with an alkyl halide or alkenyl halide. Useful alkyl and alkenyl halides are particularly the methyl, ethyl, propyl, isopropyl, allyl, methallyl, and crotonyl bromides, and iodides. The reaction can be carried out at to 100 C., preferably with stirring between 2-30 hours. After the reaction is terminated the product II is recovered by separating from it the different other products, 1- and 4- substituted triazolobenzodiazepines, by chromatography.

In carrying out the process (B) of this invention, a selected 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione (IA), in an inert organic solvent, preferably in a lower alkanol, e.g., methanol, ethanol, 1-propanol, 2-propanol, l-butano, 2-butanol, 1,1-dimethylethanol, dioxane, tetrahydrofuran, dimethyl sulfoxide or the like is heated to between 60-100 C., preferably to the reflux temperature of the mixture, with alkyl carbazate of Formula III (preferably in excess). The solvent is then removed and the intermediate heated at 180 to 250 either neat or in a higher boiling inert solvent. In the preferred embodiment of this invention'the reaction is carried out with nitrogen bubbling through the reaction mixture during a period of 4 to 48 hours. After the reaction is terminated, the product is obtained by concentrating the mixture, and the residue is purified by crystallization. The product, a

'substituted 2-4-dihydro-2,3-di(alky1 or alkenyl)-6-phenyl- 6 lH-s-triazolo[4,3-a] [1,4]bnezodiazepin-1-one II, is obtained.

The following preparations and examples are illustrative of the process and products of the present invention, but are not to be construed as limiting.

PREPARATION 1 3-(7-chloro-5-phenyl-3H-1,4-benzodiazepin-2-yl) carbazic acid ethyl ester A mixture of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4- benzodiazepine-Z-thione (1.43 g.; 0.005 mole), ethyl carbazate (1.29 g.; 0.015 mole) and absolute ethanol (50 ml.) was refluxed for 14 hours with a slow stream of nitrogen bubbling through the mixture. The mixture was then concentrated to give a residue and the residue was crystallized from methylene chloride-ethyl acetate to give 1.38 g. (77% yield) of 3-(7-chloro-5-phenyl-3H-1,4- benzodiazepin-Z-yl)carbazic acid ethyl ester of melting point l95.5-197.5 C. (dec.). The analytical sample, prepared by recrystallization from the above solvent mixture, had a melting point of 198199 C. (dec.).

Analysis.Calcd. for C H ClN O (percent): C, 60.59; H, 4.80; Cl, 9.94; N, 15.70. Found (percent): C, 60.57; H, 4.73; Cl, 9.98; N, 15.40.

PREPARATION 2 8-chloro-2,4dihydroF6-phenyllH-s-triazolo- [4,3-a] [1,41benz0diazepin-1-one 3 (7 chloro 5 phenyl-3H-1,4-benzodiazepin-2-yl) carbazic acid ethyl ester (0.5 g.; 0.0014 mole) was heated under nitrogen at 197-207 C. for 15 minutes. The cooled melt was crystallized from ethanol to give 0.28 g. of 8- chloro 2,4 dihydro 6 phenyl-lH-s-triazolo[4,3-a] [1,4]benzodiazepin-1-one, which on recrystallization from ethanol had a melting point of 255-25 6 C.

Analysis.Calcd. for C H ClN O (percent): C, 61.84; H, 3.57; Cl, 11.41; N, 18.03. Found (percent): C, 61.44; H, 3.57; Cl, 11.46; N, 17.90.

PREPARATION 3 3- [7-chloro-5- o-chlorophenyl 3H- 1 ,4-benzodiazepin- 2-yl]carbazic acid ethyl ester In the manner given in Preparation 1, 5.75 g. (0.02 mole) of 7 chloro 1,3 dihydro-5-(o-chlorophenyl)- 2H-1,4-benzodiazepine-2-thione and 5.25 g. (0.06 mole) of ethyl carbazate in 200 ml. of absolute ethanol was refluxed for 24 hours in a nitrogen atmosphere. The mixture was then concentrated to give a residue which was recrystallized from 2-propanol to give 3-[7-chloro-5-(ochlorophenyl) 3H l,4-benzodiazepin 2 yl]carbazic acid ethyl ester of melting point 191-192 C.

Analysis.Calcd. for C H Cl N O (percent): C, 55.20; H, 4.12; N, 14.32; Cl, 18.12. Found (percent): C, 55.26; H, 3.96; N, 4.41; Cl, 17.88.

PREPARATION 4 2,4-dihydro-8-chloro 6- o-chlorophenyl) lH-striazolo 4,3-a] [1,4]benzodiazepin-1-one 3 [7 chloro 5 (o chlorophenyl)-3H-1,4-benz0- diazepin-2-yl1carbazic acid ethyl ester (3.5 g. 0.01 mole) was heated under nitrogen at 225-230 for 30 minutes. The cooled melt was crystallized from ethanol ml.) to give 2.5 g. of white crystals of 2,4-dihydro-8- chloro 6 (o chlorophenyl)-lH-s-triazolo[4,3-a] [1,4] benzodiazepin-l-one.

Analysis.Calcd. for C H Cl N O (percent): C, 55.26; H, 4.12; N, 14.32; C1, 1812. Found (percent): C, 54.79; H, 4.05; N, 14.47; Cl, 18.34.

In the manner given in the preceding preparations other 2,4 dihydro 6 phenyl 1H s triazolo[4,3-a] [1,4] benzodiazepin-l-one (I) starting compounds can be synthesized. Representative starting compounds of Formula Iinclude:

8-nitro-2,4-dihydro-6- (o-chlorophenyl 1 H-s-triazolo [4,3-a] [1,4]benzodiazepin-1-one; 8-chloro-2,4-dihydro-6- (2,6-difiuorophenyl) -1H-s-triazolo [4,3-a] [1,4]benzodiazepin-1-one; 9-bromo-2,4-dihydro-6-(m-cyanophenyl) -1H-s-triazolo- [4,3-a] [1,4] benzodiazepinl-one; lO-trifluoromethyl-2,4-dihydro-6- (p-ethylphenyl)-1H-striazolo [4,3-a] [1,4]benzodiazepin-1-one; 7-methylthio-10-i0do-2,4-dihydro-6-(phenyl) lH-striazolo[4,3-a] [1,4]benzodiazepin-1-one; 7,8-dicyano-10-iodo-2,4-dihydro-6-(m-propylthiophenyl)-1H-s-triazolo [4,3-a] [1,4] benzodiazepin- 1 -one; 4,7,9-trimethyl-2,4-dihydro-6-(phenyl)-1H-s-triazolo- [4,3-a1benzodiazepin-l-one; 10-isopropyl-2,4-dihydro-6-(p-bromophenyl) -1H-s-triazolo [4,3-a] [1,4]bezodiazepin-1-one; 8-ethylsulfonyl-2,4-dihydro-6-(m-trifiuoromethyl) -1H-striazolo [4,3-a] [1,4]benzodiazepin-1-one; 7-propylsulfinyl-2,4-dihydro-6-(2,4-diethoxyphenyl) -1H- s-triazolo[4,3-a] [1,4]benzodiazepin-l-one; 7-dipropylamino-2,4-dihydro-6- p-ethylsulfinylphenyl l H-s-triazolo [4,3-a] [1,4]benzodiazepin-1-one; 8-nitro-2,4-dihydro-6-(o-formamidophenyl)-1H-striazolo[4,3-a] [1,4]benzodiazepin-1-one; 10- (N-methyl acetamido-2,4-dihydro-6-(phenyl)-1H-striazolo[4,3-a] [l,4]benzodiazepin-1-one; 9-dimethylamino-2,4-dihydro-6- (o-chlorophenyl) lH-striazolo[4,3-a] [1,4]benzodiazepin-1-one; 7,9-diethoxy-2,4-dihydro-6-(piodophenyl)-1I-I-s-triazolo- [4,3-a] [1,4]benzodiazepin-l-one; and the like.

PREPARATION 6 7-chloro-2-(1,2-dimethylhydrazino)-5-phenyl- 1,4-benzodiazepine To a suspension of 10.8 g. (0.037 mole) of 7-chloro- 1,3 dihydro phenyl 2H 1,4-benzodiazepin-2- thione in 400 ml. of methanol and 28 ml. (0.2 mole) of triethylamine under nitrogen was slowly added with stirring at room temperature a suspension of 10 g. (0.075 mole) of symdimethylhydrazine dihydrochloride in 200 ml. of methanol. The mixture was stirred under reflux for 10 hours, allowed to stand at room temperature for 3 days, filtered, and evaporated to dryness in vacuo. The residue was shaken with water and neutralized with acetic acid. The resulting solid was collected, washed with water and dried. Recrystallization from 2-propanol yielded 10.1 g. (95%) of light greenish crystals, of melting point 167 175. A second recrystallization from 2-propanol gave white crystals of 7-chloro-2-(1,2-dimethylhydrazino)-5- phenyl 1,4-benzodiazepine of melting point 175.5- 176.5 C.

Analysis.Calcd. for C17H17C1N4 (percent): C, 65.28; H, 5.48; Cl, 11.33; N, 17.91. Found (percent): C, 65.89; H, 5.42; CI, 11.32; N, 18.01.

EXAMPLE 1 8 chloro 6 (o-chlorophenyl)-2,3-dihydro-2-methyl- 1H s triazolo[4,3-a] [1,4]benzodiazepin-1-one; 8-chloro 6 (o-chlorophenyl)-2,4-dihydro-2,4-dimethyl-lH-striaz0lo[4,3-a] [1,4]benzodiazepin-1-one; and 8-chloro-6- (o chlorophenyl) 2,3 dihydro-2,3-dimethyl-lH-s-triazolo[1,2-a] [1,4]benzodiazepine-l-one.

A stirred solution of 8 chloro 2,4 dihydro-G-(ochlorophenyl) 1H-s-triazolo[4,3-a][l,4]benzodiazepinl-one (8.70 g., 0.03 mole) in dimethylformamide (150 ml.), under nitrogen, was treated with 2.2 ml. (0.03 mole) of thallous ethoxide. The resulting mixture was stirred for minutes, 2.4 ml. (0.038 mole) of methyl iodide was added dropwise to the above mixture and stirring was continued at room temperature for 4 hours. The resulting reaction mixture was filtered and the residue was washed thoroughly with dimethylformamide. The filtrate was diluted with 300 ml. of water, providing a yellow solid. This was extracted with ether (thrice) and the ether solution was washed with water, dried, filtered, and concentrated in vacuo giving an orange oil which by thin layer chromatography on silica gel (50% ethyl acetate/ cyclohexane) appeared to be a mixture of three compounds. The oil Was chromatographed on silica gel (2 kg.) and eluted with 50% ethyl acetate-cyclohexane taking ml. fractions.

Fractions 35-44 were combined and crystallized from 2-propanol to give 550 mg. of 8-chloro-2,3-dihydro-2,3- dimethyl 6 (o-chlorophenyl) 1H-s-triazolo[4,3-a] [1,4]benzodiazepin-1-one of melting point 208-210 C.

Analysis.-Calcd. for C H Cl N O (percent): C, 57.90; H, 3.78; N, 15.00; Cl, 19.00. Found (percent): C, 57.70; H, 3.91; N, 14.96; Cl, 19.17.

The other products were isolated and had the following characteristics:

Fractions 68-77 were combined and crystallized from ether to give 1.1 g. of 8-chloro-6-(o-chlorophenyl)-2,4- dihydro 2,4 dimethyl lH-s-triazolo[4,3-a] [1,41benzodiazepin-l-one of melting point 153-155 C.

Analysis.Calcd. for C H Cl N O (percent): C, 57.90; H, 3.78; N, 15.00; Cl, 19.00. Found (percent): C, 57.94; H, 3.70; N, 15.25; Cl, 19.09.

Fractions 99-12O were combined and crystallized from ether-Skelly B hexanes to give 3.3 g. of 8 chloro 6-(0- chlorophenyl) 2,4 dihydro 2 methyl 1H-s-triazol0- [4,3-a][1,4]benzodiazepin 1 one of melting point 82-84.

Analysis.Calcd. for C H Cl N O (percent): C, 56.85; H, 3.38; N, 15.59; Cl, 19.71. Found (percent): C, 56.45; H, 3.51; N, 15.12; Cl, 19.33.

EXAMPLE 2 8-chloro-2,3-dihydro-2,3-dipropyl-6-phenyl-l H-striazolo [4,3-a] [1,4]benzodiazepin-1-one In the manner given in Example 1, 8 chloro 2,4- dihydro 6 phenyl 1H-s-triazolo[4,3-a][1,4]benzodiazepin-l-one can be treated with thallous ethoxide and then with propyl bromide to give after chromatographic separation 8 chloro 2,3 dihydro 2,3-dipropyl-6- phenyl-lH-s-triazolo [4,3-a] [1,4] benzodiazepin-1-one.

EXAMPLE 3 8-chloro-2,3-dihydro-2,3-diethyl-6- (2,6-difluorophenyl) 1H-s-triazolo[4,3-a] [1,4]benzodiazepin-1-one In the manner given in Example 1, 8-chloro-2,4-dihydro 6 (2,6-difluorophenyl)-1H-s-triazolo[4,3-a][1,4] benzodiazepin-l-one can be treated with thallous ethoxide and then with ethyl iodide to give after chromatographic separation 8 chloro 2,3 dihydro 2,3 diethyl 6- (2,6 difluorophenyl) 1H-s-triazolo[4,3-a][1,4]benzodiazepin-l-one.

EXAMPLE 4 8-nitro-2,3-dihydro-2,3-dimethyl-6- (o-chlorophenyl) 1H-s-triazolo[4,3-a] [l,4]benzodiazepin-1-one In the manner given in Example 1, 8-nitro-2,4-dihydro- 6 (o-chlorophenyl) 1H-s-triazolo[4,3-a] [1,4]benzodiazepin-l-one can be treated with thallous ethoxide and then with methyl iodide to give after chromatographic separation 8 nitro 2,3 dihydro 2,3 dimethyl 6- (o-chlorophenyl) 1H-s-triazolo[4,3 a][1,4]benzodiazepin-l-one.

EXAMPLE 5 10 isopropyl 2,3 dihydro 2,3 diisopropyl 6-(pbromophenyl) 1H-s-triazolo[4,3 a][1,4]benzodiazepin-l-one In the manner given in Example 1, 10-isopropyl-2,4-

dihydro 6 (p-bromophenyl) 1H-s-triazolo[4,3-a]

[1,4]benzodiazepin-l-one can be treated with thallous Y ethoxide and then with isopropyl bromide to give after chromatographic separation isopropyl 2,3 dihydro 2,3 diisopropyl 6-(p-bromophenyl)-1H-s-triazolo [4,3-a] [1,4]benzodiazepin-l-one.

EXAMPLE 6 8 ethylsulfonyl 2,3 dihydro 2,3 diallyl 6 (mtrifluoromethylphenyl) lH-s-triazolo[4,3 a] [1,4] benzodiazepin-l-one In the manner given in Example 1, 8-ethylsulfonyl2,4- dihydro 6 (m-trifluoromethylphenyl)-1H-s-triazolo[4,3- a] [1,4]benzodiazepin-l-one can be treated with thallous ethoxide and then with allyl bromide to give after chromatographic separation 8 ethylsulfonyl-Z,3-dihydro- 2,3 diallyl 6 (m-trifluoromethylphenyl)-1H-s-triaz0lo- [4,3-a] [1,4]benzodiazepin-1-one.

EXAMPLE 7 4,7,9-trimethyl-2,3-dihydro-2,3-dicrotyl-6-phenyl-lH-s triazolo [4,3-a] [1,4]benzodiazepine-1-one (A) A mixture of 3,6,8-trimethyl-1,3-dihydro-5-phenyl- 2H-1,4-benzodiazepine-Z-thione, 2,3-dicrotyl carbazic acid ethyl ester, and ethanol can be refluxed for 14 hours under nitrogen to give 3-[3,6,8-trimethyl-5-phenyl-3H-1,4-benzodiazepin-2-yl]-2,3-dicrotyl carbazic acid ethyl ester.

(B) This ester can be heated to about 250 C. in a nitrogen atmosphere for minutes, the melt is cooled and recrystallized from ethanol to give 4,7,9-trimethyl- 2,3 dihydro 2,3 dicrotyl 6 phenyl lI-I-s-triazolo- [4,3-a] [1,4] benzodiazepin-l-one.

EXAMPLE 8 8-nitro-2,3-dihydro-2,3-diethyl-6- (o-chlorophenyl) -1H- s'triazolo [4,3-a] [1,41benzodiazepin-1-one EXAMPLE 9 8-chloro 2,3 dihydro 2 methyl-3-allyl-6-(o-chlorophenyl) 1H s triazolo[4,3-a] [1,4]benzodiazepinel-one (A) A mixture of 7-chloro-1,3-dihydro-5-(o-chlorophenyl) 2H 1,4-benzodiazepine-Z-thione, 2-methyl-3- allylcarbazic acid ethyl ester, and ethanol can be refluxed for 14 hours under nitrogen to give 3-[7-chloro-5-(o-chlorophenyl)-3H1,4-benzodiazepin-2-yl] 2 methyl-B-allylcarbazic acid ethyl ester.

(B) This ester can be heated to about 250 C. in a nitrogen atmosphere, for 15 minutes, the melt is cooled and recrystallized from ethanol to give 8-chloro-2,3-dihydro-2-methyl-3-allyl 6 (o chlorophenyD-lH-s-triazolo [4,3-a] 1,4]benzodiazepin-1-one.

EXAMPLE 11 7,8-dicyano 2,3 dihydro-2-ethyl-3-propyl-6-(m-propylthiophenyl) 1H-s-triazolo[4,3-a] [1,4]benzodiazepinl-one (A) A mixture of 6,7-dicyano-1,3-dihydro-5-(m-propylthiophenyl)-2H-1,4-benzodiazepine-Z-thione, 2-ethyl- 3-propyl carbazic acid ethyl ester, :and ethanol can be refluxed for 14 hours under nitrogen to give 3-[6,7-dicyano 5 (m-propylthiophenyl)-3H-1,4-benzodiazepin- 2-yl]-2-ethyl-3-propyl-carbazic acid ethyl ester.

(B) This ester can be heated to about 250 C. in a nitrogen atmosphere, for 15 minutes, the melt is cooled and recrystallized from ethanol to give 7,8-dicyano-2,3-

10 dihydro-2-ethyl 3 propy1-6-(m-propylthiophenyl)-lH- s-triazolo[4,3-a] [1,4]benzodiazepin-l-one.

EXAMPLE 12 9-dimethylamino 2,3 dihydro-2,3diallyl-6-(o-chlorophenyl) 1H s triazolo[4,3-a] [1,41benzodiazepinel-one (A) A mixture of S-dimethylamino 1,3 dihydro-5- (o-chlorophenyl)-2H-l,4-benzodiazepine-2-thione, 2,3-diallylcarbazic acid ethyl ester, and ethanol can be refluxed for 14 hours in nitrogen to give 3-[8-dimethylamino-5- (o-chlorophenyl) 1,3 dihydro-3H-1,4 benzodiazepin- 2-yl]-2,3-diallyl carbazic acid ethyl ester.

(B) This ester can be heated to about 250 C. in a nitrogen atmosphere, for 15 minutes the melt is cooled and recrystallized from ethanol to give 9-dimethylamino- 2,3-dihydro 2,3 diallyl 4 6 (o-chlorophenyl)-1H-s-triazolo[4,3-a] [1,4]benzodiazepin-1-one.

EXAMPLE 13 8-chloro-2,3-dihydro-2,3-dimethyl-6-phenyllH-striazolo[4,3-a] [1,4]benzodiazepin-1-one A mixture of 6-chloro-2-(1,2-dimethylhydrazino)-5- phenyl-1,4-benzodiazepine (preparation 6) and triethylamine in tetrahydrofuran can be cooled to 78 and a slight excess of phosgene added. Warming to room temperature, evaporating, washing with water and crystallizing the resulting solid will yield 8-chloro-2,3-dihydro-2,3- dimethyl-G-phenyl 1H s triazolo[4,3-a][1,4]benzo diazepin-l-one.

In the manner illustrated by the beforegoing examples other compounds of configuration II can be prepared. Representative examples are:

8-nitro-2,3-dihydro-2-methallyl-3-methyl-6- (o-chlorophenyl) -1H-s-triazolo [4,3 -a] [1,4 benzodiazepinl-one;

8-chloro-2,3-dihydro-2,3-dicrotyl-6- (2,6-difluorophenyl) 1H-s-triazolo[4,3-a] [1,4]benzodiaZepin-1-one;

9-bromo-2,3-dihydro-2-ethyl-3-isopropyl-6- (m-cyanophenyl) -1H-s-triazolo[4,3-a] [1,4] benzodiazepin- Lone;

7,8-dicyano-2,3-dihydro-2,3-diallyl-6- (m-propylthiophenyl) -1H-s-triazo1o [4,3-a] 1,4] benzodiazepinl-one;

8-ethylsulfonyl-2,3-dihydro-2,3-diethyl-6- (m-trifluoromethylphenyl) -1H-s-triazolo [4,3-a] [1,4] benzodiazepinl-one;

7-dipropylamino-2,3-dihydro-2,3-dimethyl-6- (p-ethylsulfonylphenyl)-1H-s-triazolo [4,3-a] [1,4] benzodiazepinl-one;

10-acetamido-2,3-dihydro-2,3-diallyl-6- (phenyl) -1H-striazolo [4,3-a] [1,4]benzodiazepin-1-one;

7,9-diethoxy-2,3-dihydro-2,3-propyl-6- (p-iodophenyl) lH-s-triazolo[4,3-a] [1,4] benzodiazepin-l-one;

10-trifluoromethyl-2,3-dihydro-2-methyl-3-allyl-6- p-ethylphenyl) -1[H-s-triazolo[4,3-a] 1,4] benzodiazepin-l-one;

4,7,9-trimethyl-2, 3 -dihydro-2,3 -dimethyl-6- (phenyl) 1H-s-triazolo[1,2-a] [1,4]benzodiazepin-1-one;

10-isopropyl-Z,3-dihydro-2,3-diethyl-6p-bromophenyl 1H-s-triazolo[4,3-a] [1,4]benzodiazepin-1-one;

4-propyl-8-methyl-2,3-dihydro-2-allyl 3 -crotyl-6- (m-fluorophenyl) -1H-s-triazolo[4,3-a] [1,4] benzodiazepinl-one;

7-dipropylamino-2,3 -dihydro-2, 3-dimethyl-6- (p-ethylsulfinylphenyl)-1H-s-triazolo [4,3-a] 1,4] benzodiazepinl-one;

9-dimethylamino-2,3-dihydro-2, 3-dicrotyl-6- (o-chlorophenyl -1H- s-triazolo [4,3-a] 1,4]benzodiazepinl-one;

can be converted to acid addition salts by reaction with stoichiometrically calculated amounts of selected acids in water, ethanol, or with the hydrogen halides in particular, in ether. In this manner the hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates, acetates, propionates, lactates, tartrates, citrates, maleates, malates, pamoates, beneznesulfonates, p-toluenesulfonates, methanesulfonates, cycloheXanesulf-arnates, salicylates and the like of the foregoing 2,3-alkylor alkylene substituted 2,3-dihydro 6 phenyl-1H-s-triazolo[4,3-a] [l,4]benzodiazepin-l-ones can be obtained.

What is claimed is:

1. A compound selected from the group consisting of 2,3-disubstituted 2,3 dihydro 1H s triazolo[4,3-a] [1,4]benzodiazepin-1-one of the Formula II:

wherein R and R are selected from the group consisting of alkyl of 1 to 3 carbon atoms, inclusive, and alkenyl of 3 to 4 carbon atoms, inclusive; wherein R is selected from the group consisting of hydrogen, alkyl of 1 to 3 carbon atoms, inclusive, and alkenyl of 3 to 4 carbon atoms, inclusive; wherein R R R and R are selected from the group consisting of hydrogen, alkyl defined as above, amino, halogen, nitro, cyano, trifiuoromethyl, and alkoxy, alkylthio, alkylsulfonyl, and alkylsulfinyl, alkanoylamino, in which the carbon moieties are of 1 to 3 carbon atoms, inclusive, and dialkylamino, in which the alkyl group is defined as above; and the pharmacologically acceptable acid addition salts thereof.

2. The compound according to claim 1 wherein R and R are methyl, R R and R are hydrogen, R is o-chloro, R is 8-chloro and the compound is therefore 8-chloro- 2,3 dihydro 2,3 dimethyl 6 (o-chlorophenyl)- 1H-s-triazolo[4,3-a] [1,4]benzodiazepin l one.

3. The compound according to claim 1 wherein R and R are methyl, R R R and R are hydrogen, R is 8-chloro and the compound is therefore 8-chloro-2,3- dihydro 2,3 dimethyl 6 phenyl 1H s triazolo- [4,3-a] 1,4]benzodiazepin-1-one.

4. A process for the preparation of 2,3-disubstituted- 2,3-dihydro 1H s triazolo[4,3-a] [l,4]benzodiazepinl-one of the Formula II:

wherein R R R R and R are defined as above, with thallous ethoxide, in an organic solvent, at room temperature, and treating the resulting product with an alkyl or alkenyl bromide or iodide, in which alkyl and alkenyl are defined as above, to obtain the compound of Formula II above.

References Cited UNITED STATES PATENTS 3,646,055 2/1972 Hester 260308 C ALTON D. ROLLINS, Primary Examiner US. Cl. X.R.

260-239 BD, 239.3 D; 424269 Page 2 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATtNT NO. 5 772 318 DATED November 13, 1973 lNVENTORtS) Robert B. Moffett It rs certrfred that error appears in the ab0verdentif|ed patent and that sard Letters Patent are hereby corrected as shown below:

R2 H s i 75, "2-4-dl hyd ro' should read 2,4-di hyd ro Column 6, l i ne 1, "bnezodiazepln" should read benzodiazepin Column 7, l l ne 8, "bezodiazepi n" should read benzodlazep l n Column 10, l ine 57, p-echylphenyl should read (p-ethylphenyl l i ne 61 "p-b romophenyl should read (p-b romophenyl Column 11, l l ne 5, "beneznesulfona tes" should read benzenesulfonates Signed and Sealed this eighteenth Day Of November 1975 {SEALI AtteSI;

RUTH C. MASON MARSHALL DANN ('mnmissimu'r of Parents and Trudmnurks