US3743652A - 1-aminophenyl-4h-s-triazolo(4,3-a)(1,4)benzodiazepines - Google Patents

1-aminophenyl-4h-s-triazolo(4,3-a)(1,4)benzodiazepines Download PDF

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US3743652A
US3743652A US00194911A US3743652DA US3743652A US 3743652 A US3743652 A US 3743652A US 00194911 A US00194911 A US 00194911A US 3743652D A US3743652D A US 3743652DA US 3743652 A US3743652 A US 3743652A
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benzodiazepine
phenyl
dihydro
thione
triazolo
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US00194911A
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R Moffett
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Pharmacia and Upjohn Co
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Upjohn Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • R and R are 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 is selected from the group consisting of hydrogen, alkyl defined as above, COOCH COOC H and and 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 moiety is of 1 to 3 carbon atoms, inclusive, and dialkylamino, in which the alkyl group is defined as above.
  • the process of this invention consists in heating a 1,3- dihydro-S-phenyl-ZH-1,4-benzodiazepine-2-thione of the Formula I H i N R R R4 1 wherein R R R R and R are defined as above, with an aminobenzoyl hydrazide of the Formula III wherein R and R are defined as above, in an organic solvent, to give the compounds of Formula II above.
  • the compounds of Formula II above, and the pharmacologically acceptable acid salts thereof are sedative and tranquilizing reagents.
  • This invention is directed to new organic compounds and is particularly concerned with novel l-aminophenyl- Patented July 3, 1973 6 phenyl s-triazolo[4,3-a][l,4]benzodiazepines and a process for the production thereof.
  • novel compounds and the process of production therefor can be illustratively represented as follows.
  • R and R are 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 is selected from the group consisting of hydrogen, alkyl defined as above, COOCH -COOC H and COOCH CH CH DESCRIPTION OF THE PREFERRED EMBODIMENT Lower alkyl groups of 1 to 3 carbon atoms, inclusive, are exemplified by methyl, ethyl, propyl, and isopropyl.
  • the carbon chain moiety of alkoxy, alkylsulfinyl, alkylsulfonyl, and alkylthio, which is of 1 to 3 carbon atoms, inclusive, can be defined as lower-alkyl of 1 to 3 carbon atoms, inclusive, as above.
  • the alkanoylamino group of 1 to 3 carbon atoms consists of formamido (sari).
  • halogen includes fluorine, chlorine, and bromine.
  • novel compounds of the Formula II and pharmacologically acceptable addition salts thereof have sedative, hypnotic, anticonvulsant, tranquilizing, and muscle relaxant effects in mammals and birds. Also as feed additives they increase growth rate and feed efiiciency of livestock and poultry.
  • the pharmacologically acceptable acid addition salts of compounds of Formula II contemplated in this invention are the hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates, cyclohexanesulfamates, methanesulfonates, acetates, toluenesulfonates, lactates, tartrates, citrates, malates, maleates, and the like, prepared by reacting a compound of Formula II with the selected pharmacologically acceptable acid.
  • mice Sedative efiects of l-(p-aminophenyl)-8-chloro-6-phenyl-4H-s-thiazolo[4,3-a] [1,4]benzodiazepine are shown by the following tests in mice:
  • Chimney test [Med. Exp. 4, 145 (1961)]: The effective 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 effective dosage, 50% of the mice failed doing it.
  • mice 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
  • Nicotine antagonism test Mice in a group of 6 are injected with the test compound l-(p-aminopheny1-8- chloro 6 phenyl-4H-s-triazolo[4,3-a][l,4]benzodiazepine). Thirty minutes later the mice including control (untreated) mice are injected with nicotine salicylate (2 mg./kg.). The control mice show over-stimulation, i.e., (1) running convulsions followed by (2) tonic extensor fits; followed by (3) death. An intraperitoneal dosage of 3.6 mg./kg.
  • the effective dosage ED of l-(p-aminophenyl)-8-chloro-6-phenyl- 4H-s-triazolo[4,3-a][1,4]benzodiazepine is 2.5 mg./ kg. orally in mice.
  • the test consists in orally administering into groups of 6 mice the test compound, l-(p-arninophenyl) 8 chloro 6 phenyl-4H-s-triazolo[4,3-a] [1,4] benzodiazepine, and 30 minutes later 3 mg./kg. strychnine sulfate intraperitoneally. The survivors after 4 hours reflect the activity of the compound as a muscle relaxant and antispasmodic. A dosage of 3 mg./kg. of strychnine sulfate is routinely fatal to all the control mice.
  • 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 or carriers such as carbohydrates (lactose), proteins, lipids, calcium phosphate, cornstarch, stearic acid, methylcellulose and the like may be used as carriers or for coating purposes.
  • Water or oil e.g., coconut oil, sesame oil, safiiower oil, cottonseed oil, peanut oil, may be used for preparing solutions or suspensions of the active drug. Sweetening, coloring, and flavoring agents may be added.
  • a feed containing from 10-500 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.
  • the compounds of Formula II its pharmacologically acid addition salts and N-oxides thereof can be used in dosage of ill-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 in travel.
  • acid addition salts of the compounds of Formula II can be made such as the fluosilicic acid addition salts which are useful mothproofing compounds or the trichloroacetates useful as herbicides against Johnson grass, Bermuda grass, yellow foxtail, and green foxtail, and quack grass.
  • benzodiazepine-Z-thione 8-propoxy-7-bromo-1,3-dihydro-5- [m-(ethylsulfinyl) phenyl] -2H- l,4-benzodiazepine-2-thione;
  • 6-nitro-1,3-dihydro-5-(o-cyanophenyl) -2-H-1,4-benzodiazepine-Z-thione 7 ,9-bis (dipropylamino) 1,3-dihydro-5- (o-nitrophenyl) 2H-1,4-benzodiazepine-Z-thione;
  • reaction can be followed by the IR or NMR if desired, and elevated pressures (sealed tube or autoclave) can be used to facilitate closure of the triazole ring at a convenient rate.
  • the acid hydrazide is used in excess such as from 1.1 to 4 times the theoretically required amount, in an inert atmosphere.
  • the reaction is, however, operative with smaller or larger amounts of hydrazide.
  • the reaction period is between 1 and 48 hours.
  • the reaction mixture can be evaporated to give a crude product consisting of the desired l-(aminophenyl)-6-phenyl- 4H-s-triazolo[4,3-a][l,4]benzodiazepine (II).
  • the crude Compound II is then purified by standard methods, e.g., extraction, chromatography, and/ or recrystallization from. solvents such as ethyl acetate, methylene chloride, chloroform, acetonitrile or the like.
  • EXAMPLE 1 1- (p-aminophenyl -8-chloro-6-phenyl-4H-s-triazolo [4,3-a] [1,4-] benzodiazepine A mixture of 6.31 g. (0.002 mole) of 7-chloro-1,3-dihydro-S-phenyl-ZH-l,4-benzodiazepine-2-thione and 10.0 g. (0.066 mole) of p-aminobenzoyl hydrazide in 175 ml. of l-butanol was stirred, under nitrogen, at reflux for 14 hours. Most of the solid dissolved, then other solid separated and finally this solid redissolved.
  • EXAMPLE 2 l-[p- (N-methylamino)phenyl] -8-chloro-6-(o-chlorophenyl)-4H-s-triazolo [4,3-a] [1,4]benzodiazepine
  • 7-chloro-l,3-dihydro-5-(o-chlorophenyl)-2H-1,4,-benzodiazepine-2 thione and p-[N-methylamino1benzoyl hydrazide can be heated in l-butanol to give 1-[p-(N-methylamino)phenyl]-8- chloro 6 (o chlorophenyl) 4H s triazolo[4,3-a] [1,4] benzodiazepine.
  • EXAMPLE 3 1-[p-(N-dimethylamino)phenyl]-8-chloro-6-(2,6-difluor0- phenyl)-4H-s-triazolo [4,3-a] [1,4] benzodiazepine
  • 7-chloro-1,3-dihydro 5 (2,6 difluorophenyl) 2H 1,4 benzodiazepine-Z-thione and p-(N-dimethylamino)benzoyl hydrazide can be heated in 2-butanol to give l-[p-(N-dimethylamino)phenyl] 8 chloro 6 (2,6 difluorophenyl)- 4H-s-triazolo [4,3-a] [1,4] benzodiazepine.
  • EXAMPLE 6 1 (p aminophenyl 9 trifluoromethyl 6 [(p propionylamino)phenyl] 4H s triazolo[4,3 a][1,4]- benzodiazepine
  • 9-trifiuoromethyl- 1,3 dihydro 5 [(p propionylamino)phenyl] 2H- l,4-benzodiazepine-2-thione and p-aminobenzoyl hydrazide can be heated in l-butanol to give 1-(p-aminophenyl)- 9 trifluoromethyl 6 [(p propionylamino)phenyl]- 4H-s-triazolo [4,3-a] [1,4]benzodiazepine.
  • EXAMPLE 7 1 [p (N dipropylamino)phenyl] 8,9 dicyano-6- [p- (methylsulfonyl)phenyl] 4H s triazolo[4,3-a] [1,4] benzodiazepine
  • 7,8-dicyano-1,3- dihydro 5 [(p methylsulfonyl)phenyl] 2H 1,4-ben- 7 zodiazepine-Z-thione and [p-(N-dipropylamino)benzoyl] hydrazide can be heated in ethanol to give l-[p-(N-dipropylamino)phenyl] 8,9 dicyano 6 [(P methylsulfonyl)phenyl] 4H s triazolo[4,3-al] [1,4]benzodiazepine.
  • EXAMPLE 8 l-(o-aminophenyl)-7,9-diethyl-6-(m-ethylphenyl) -4H- s-triazolo [4,3-a] [1,4] benzodiazepine
  • 6,8-diethy1-1,3-dihydro 5 (m ethylphenyl) 2H 1,4 benzodiazepine 2- thione and (o-amino)benzoyl hydrazide can be heated in l-propanol to give 1-(o-aminophenyl)-7,9-diethy1-6-(methylphenyl -4H-s-triazolo [4,3-a] [1,4] benzodiazepine.
  • Treating the compounds of Formula 'II with pharmacologically acceptable acids such as hydrochloric, hydrobromic, phosphoric, sulfuric acetic, propionic, toluenesulfonic, mcthanesulfonic, tartaric, citric, lactic, malic, maleic, cyclohexanesulfamic acids produces the pharmacologically acceptable salts of these compounds of Formula H which can be used like the free base compound of Formula II.
  • Salt formation is achieved in conventional manner by reacting the compounds of Formula II with excess of a selected acid in a suitable medium e.g. water, a lower alkanol, ether, or acetone and recovering the salt by evaporating the solvent, preferably in vacuo.
  • R, R R R R and R are hydrogen, the group is in p-position, R is 8-chloro and the compound is therefore l-(p-aminophenyl)-8-chloro-6-phenyl-4H-s-triazolo- [4,3-a] [1,4]benzodiazepine.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Fodder In General (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
US00194911A 1971-11-02 1971-11-02 1-aminophenyl-4h-s-triazolo(4,3-a)(1,4)benzodiazepines Expired - Lifetime US3743652A (en)

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US (1) US3743652A (xx)
JP (1) JPS4852799A (xx)
BE (1) BE790838A (xx)
DE (1) DE2251673A1 (xx)
FR (1) FR2158413B1 (xx)
GB (1) GB1354627A (xx)
NL (1) NL7214468A (xx)

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Publication number Priority date Publication date Assignee Title
US3987052A (en) * 1969-03-17 1976-10-19 The Upjohn Company 6-Phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines
CH545803A (xx) * 1971-01-21 1974-02-15
US3709898A (en) * 1971-02-09 1973-01-09 Upjohn Co Process for the production of triazolobenzodiazepines and intermediates

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DE2251673A1 (de) 1973-05-10
FR2158413B1 (xx) 1977-01-14
BE790838A (fr) 1973-04-30
GB1354627A (en) 1974-06-05
FR2158413A1 (xx) 1973-06-15
NL7214468A (xx) 1973-05-04
JPS4852799A (xx) 1973-07-24

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