US3734922A - Certain 4h-s-triazolo(4,3-a)(1,4)benzodiazepines - Google Patents

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

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US3734922A
US3734922A US00142419A US3734922DA US3734922A US 3734922 A US3734922 A US 3734922A US 00142419 A US00142419 A US 00142419A US 3734922D A US3734922D A US 3734922DA US 3734922 A US3734922 A US 3734922A
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carbon atoms
dihydro
benzodiazepine
pyridyl
benzodiazepin
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US00142419A
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J Hester
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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' is lower alkyl of 1 through 3 carbon atoms
  • R is selected from the group consisting of hydrogen and lower alkyl of 1 through 3 carbon atoms
  • R is selected from the group consisting of pyridyl, Z-pyrimidyl, furyl, pyrryl, thienyl, lower alkyl of 1 through 3 carbon atoms, lower alkenyl of 2 through 3 carbon atoms, cycloalkyl of 5 through 7 carbon atoms and cycloalkenyl of 5 through 7 carbon atoms
  • R and R are selected from the group consisting of hydrogen, lower alkyl of 1 through 3 carbon atoms, halogen, nitro, trifiuoromethyl and lower alkoxy, lower alkylthio and lower dialkylamino wherein their lower al
  • R is lower alkyl of 1 through 3 carbon atoms; R is selected from the group consisting of hydrogen and lower alkyl of 1 through 3 carbon atoms; R is selected from the group consisting of pyridyl, 2-pyrimidyl, furyl, pyrryl, thienyl, lower alkyl of 1 through 3 carbon atoms, lower alkenyl of 2 through 3 carbon atoms, cycloalkyl of 5 through 7 carbon atoms and cycloalkenyl of 5 through 7 carbon atoms; R, and R are selected from the group consisting of hydrogen, lower alkyl of 1 through 3 carbon atoms, halogen, nitro, trifiuoromethyl, lower alkoxy, lower alkylthio and lower dialkylamin-o wherein the lower alkyl moiety is of from 1 through 3 carbon atoms; and pharmacologically acceptable acid addition salts thereof.
  • lower alkyl examples include methyl, ethyl, propyl and isopropyl.
  • lower alkoxymethyl include methoxymethyl, ethoxymethyl, propoxymethyl and isopropoxymethyl.
  • lower (dialkylamino)methyl examples include (dimethylamino methyl, (diethylamino methyl,
  • lower alkylthiomethyl examples include (methylthio) methyl, (ethylthio methyl, (propylthio methyl and (isopropylthio methyl.
  • Examples of lower alkenyl of 2 through 3 carbon atoms include vinyl, l-propenyl, allyl and isopropenyl.
  • Examples of cycloalkyl of 5 through 7 carbon atoms include cyclopentyl, cyclohexyl and cycloheptyl.
  • Examples of cycloalkenyl of 5 through 7 carbon atoms include l-cyclopentyl, l-cyclohexenyl and l-cycloheptenyl.
  • Examples of halogen include fluoro, chloro, bromo and iodo.
  • Examples of lower alkoxy include methoxy, ethoxy, propoxy and isopropoxy.
  • lower alkylthio examples include methylthio, ethylthio, propylthio and isopropylthio.
  • lower dialkylamino examples include dimethylamino, diethylamino, dipropylamino, diisopropylamino, methylethylamino, methylpropylamino, ethylpropylamino, methylisopropylamino and ethylisopropylamino.
  • novel 4H-s-triazolo[4,3-a][1,41benzodiazepines of Formula I exist either in the non-protonated (free base) from or in the protonated (acid addition salt) form, depending on the pH of the environment.
  • pharmacologically acceptable acid addi tion salts on acidification of the free base with suitable pharmacologically acceptable acids, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, acetic, propionie palmitic, benzoic, salicylic, hexynoic, phenylbutyric, naphthoic, glycolic, succinic, nicotinic, tartaric, maleic, malic, pamoic, methanesulfonic, cyclohexanesulfonic picric and lactic acids, and the like.
  • suitable pharmacologically acceptable acids for example, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, acetic, propionie palmitic, benzoic, salicylic, hexynoic, phenylbutyric, naphthoic, glycolic, succinic, nicotinic, tartaric, maleic, malic, pamoic
  • the free bases of the novel compounds of Formula II can be obtained from a salt (e.g., from the hydrochloride or sulfate salt), by neutralization with a base such as sodium hydroxide, extracting with an immiscible solvent, for example chloroform, drying the extract, for example with anhydrous sodium sulfate, and removing the solvent by evaporation.
  • a salt e.g., from the hydrochloride or sulfate salt
  • a base such as sodium hydroxide
  • an immiscible solvent for example chloroform
  • An appropriate starting material of Formula II can be prepared by heating a known corresponding compound of the formula III wherein R R R and R have the same meaning as above, with phosphorus pentasulfide in a solvent such as pyridine, benzene, toluene or xylene at between about 80 to about 140 C. for between about 30 minutes to about 6 hours.
  • a solvent such as pyridine, benzene, toluene or xylene
  • the preparation of compounds of Formula IV are described in U.S. Pats. 3,100,770; 3,179,656; 3,268,- 586; 3,338,886; and 3,466,328; Belgian Pats. 619,101 and 662,240; French Pats. 1,391,752 and 1,455,048; Netherlands Pats. 65/07637, 67/08568 and 69/08966; and J. Pharm. Sci. 53, 264.
  • an appropriate thione starting material (II), in an inert organic solvent preferably a lower alkanol, e.g., methanol, ethanol, 1- propanol, 2-propanol, l-butanol, 2-butanol, or dioxane, dimethyl sulfoxide or the like
  • an inert organic solvent preferably a lower alkanol, e.g., methanol, ethanol, 1- propanol, 2-propanol, l-butanol, 2-butanol, or dioxane, dimethyl sulfoxide or the like
  • Nitrogen is usually bubbled through the mixture to remove the hydrogen sulfide formed in the reaction.
  • the acid hydrazide is used in excess, such as from about 2 to about 5 times the theoretically required amount, but the reaction is operative with smaller or larger amounts.
  • the reaction period is between about 1 to about 48 hours.
  • the product (I) can be isolated from the reaction mixture by conventional means, for example, when a water-miscible solvent is used, by pouring the reaction mixture into the water and separating the resulting precipitate by filtration or by extraction with waterimmiscible solvents.
  • Additional purification of the product can be accomplished by conventional means, for example, by elution chromatography from an adsorbent column with a suitable solvent such as acetone, ethyl acetate, ether, methylene chloride or Skellysolve B (hexanes), mixtures and combinations of these solvents; also by gradient elution chromatography from an adsorbent column with a suitable mixture of solvents, such as methylene chloride-Skellysolve B, acetone-Skellysolve B, and the like.
  • novel compounds of Formula I and the pharmacologically acceptable acid addition salts thereof have sedative, hypnotic, anticonvulsant, tranquilizing and muscle relaxant effects in mammals and birds, and as feed additives for increasing the growth rate and feed etficiency of livestock poultry.
  • Pedestal test The untreated mouse leaves a standard 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.
  • Nicotine antagonism test Mice in a group of 6 are injected with the test compound. 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.
  • Antagonism to strychnine (as sulfate): The test consists in orally administering into groups of 6 mice the test compound, 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.
  • compositions contemplated by this invention include pharmaceutical compositions suited for oral, parenteral and rectal use, e.g., tablets, powder packets, cachets, dragees, capsules, solutions, suspensions, sterile injectable 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 can be used as carriers or for coating purposes.
  • Oil, e.g., coconut oil, sesame oil, safilower oil, cottonseed oil, peanut oil can be used for preparing solutions or suspensions of the active drug. sweetening, coloring, and flavoring agents can be added.
  • the compounds of Formula I can be used in dosages of 0.01 mg. to 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 travelling.
  • a stirred solution of 6.53 g. of 7-bromo-1,3-dihydro- 5-(2-pyridyl)2H-1,4-benZodiazepin-2-one (prepared as in J. Pharm. Sci. 53, 264) in 400 ml. of dry pyridine is heated in an oil bath, under nitrogen, with 5.05 g. of phosphorus pentasulfide at between about 110 to 120 C. for about 1 hour, cooled and concentrated under vacuum.
  • l g. (5 mmoles) of 7-chloro-1,3- d-ihydro-S-methyl-ZH-1,4-benzodiazepin-2-one prepared as in French Patent 1,391,752
  • 1.1 g. (5 mmoles) of phosphorus pentasulfide is added.
  • the mixture is heated under reflux in a nitrogen atmosphere for about 4 hours.
  • the reaction mixture is cooled and filtered, with the filtrate containing only a small amount of material.
  • the filtered solid is treated with hot water and filtered again.
  • the filtrate is treated with 20% sodium hydroxide to give a pH of 6 to 8 and the white solid removed by extraction with ethyl acetate to give 129 mg. of crude product.
  • the initial solid is again treated with water, the aqueous phase made basic with sodium bicarbonate and then extracted with hot ethyl acetate to give 1 got brown solid.
  • This material plus the 129 mg. of crude product are chromatographed on 130 g. of silica gel using 50% ethyl acetate:50% cyclohexane as eluting solvent. The product taken from the column is recrystallized from ethyl acetate to give 455 mg.
  • benzodiazepin-Z-one 21) 7-bromo-1,3-dihydro-3-methyl-5- (4-pyridyl) 2H-1,4-benzodiazepin-2-one, (22) 1,3-dihydro-7-fluoro-3-propyl-5-(4-pyridyl) -2H- 1,4-benzodiazepin-2-one, (23) 7-chloro-1,3-dihydro-5- (Z-pyrryl) -2I-I-1,4-benzodiazepin-2-one, (2;) 1,3-dihydro-5-(2-pyrryl) -2H-l,4-benzodiazepin- -one, (25) 1,3-dihydro-7-nitro-5- (Z-thienyl) -2H-l,4-benzodiazepin-Z-one, (26) 1,3-dihydro-9-methoxy-5-(2-thienyl)-2H-1,4-
  • benzodiazepin-2-one (31 1,3-dihydro-9-methylthio-7-nitro-5- (Z-pyn'dyl 2H-l,4-benzodiazepin-2-one, (32) 7-bromo-8-fluoro-1,3-dihydro-5- (2-pyridy1)-2H- 1,4-benzodiazepin-2-one, (3 3) 7-chloro-1,3-dihydro-8-ethoxy-5- (2-pyridyl) -2H- 1,4-benzodiazepin-2-one, (3;) 1,3-dihydro-5- (4-pyridyl)-2H-1,4-benzodiazepin- -one, (35) 7-bromo-1,3-dihydro-5- (4-pyridyl)-2H-1,4-benzodiazepin- -one, (35) 7-bromo-1,3-dihydro-5- (4-pyridyl)-2H-1,4-benzodiazepin- -
  • benzodiazepin-Z-one (40) 7-chloro-1,3-dihydro-9-propyl-5-(4-pyridyl) -2H- '1,4-benzodiazepin-2-one, (41) 7 -bromo-1,3-dihydro-5-(2-furyl) -2H-l,4-benzodiazepin-Z-one, (42) 1,3-dihydro-5- (4-furyl) -2H-1,4-benzodiazepin- 2-one,
  • Example 3 8-bromo-1-methyl-6- (2-pyridyl) -4H-striazolo [4,3-a] [1,4]benzodiazepine (I)
  • Example 4.8-chloro-1,6-dimethyl-4H-s-triazolo- [4,3-a] [1,4]benzodiazepine (I) A solution of 581 mg. (2.6 mmoles) of 7-ch1oro-1,3- dihydro 5 methyl 2H 1,4 benzodiazepine-Z-thione (obtained as in Example 2) and 576 mg. (7.8 mmoles) of acethydrazide in 50 ml. of n-butanol is heated under reflux for about 6 hours. During the first few hours, a stream of nitrogen is passed through the reaction mixture; for the remaining time the reaction is maintained under an atmosphere of nitrogen.
  • reaction mixture is successively concentrated, treated with chloroform, Washed with water and then brine. Concentration of the organic layer gives a residue that is chromatographed on a column of silica gel using methanol:90% chloroform as eluting solvent. The product is removed as an oil which solidifies upon treatment with ethyl acetate. It is recrystallized from ethyl acetate to yield 8-chloro-1,6- dimethyl 4H s triazolo[4,3-a][1,4]benzodiazepine (I), melting at 219 to 219.5 C.
  • R is selected from the group consisting of hydrogen, lower alkyl of 1 through 3 carbon atoms and lower alkoxymethyl, lower dialkylaminomethyl and lower alkylthiomethyl wherein their lower alkyl moieties are of from 1 through 3 carbon atoms; R is selected from the group consisting of hydrogen, lower alkyl of 1 through 3 carbon atoms and hydroxymethyl; R is selected from the group consisting of hydrogen, halogen, trifluoromethyl and nitro; and a pharmacologically acceptable acid addition salt thereof.
  • R is methyl, R is hydrogen and R is S-bromo, namely, 8-bromo-1-methyl- 6- (2-pyridyl)-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)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
US00142419A 1971-05-11 1971-05-11 Certain 4h-s-triazolo(4,3-a)(1,4)benzodiazepines Expired - Lifetime US3734922A (en)

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US (1) US3734922A (enrdf_load_stackoverflow)
JP (1) JPS554110B1 (enrdf_load_stackoverflow)
BE (1) BE783272A (enrdf_load_stackoverflow)
CH (1) CH582179A5 (enrdf_load_stackoverflow)
DE (1) DE2220623C2 (enrdf_load_stackoverflow)
FR (1) FR2137714B1 (enrdf_load_stackoverflow)
GB (1) GB1324318A (enrdf_load_stackoverflow)
NL (1) NL7206301A (enrdf_load_stackoverflow)
ZA (1) ZA722627B (enrdf_load_stackoverflow)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3886174A (en) * 1971-11-22 1975-05-27 Upjohn Co 1-Substituted-6-phenyl-4H-s-triazolo{8 4,3-a{9 {8 1,4{9 benzodiazepines
US3904641A (en) * 1971-06-18 1975-09-09 Yoshitomi Pharmaceutical Triazolothienodiazepine compounds
US3995043A (en) * 1974-05-13 1976-11-30 The Upjohn Company Composition and process
US4155913A (en) * 1973-02-08 1979-05-22 Hoffmann-La Roche Inc. Thienotriazolodiazepine derivatives
US4455307A (en) * 1982-01-04 1984-06-19 The Upjohn Company Antihypertensive use of triazolobenzodiazepines
US4987131A (en) * 1985-12-13 1991-01-22 Roussel Uclaf 4H-triazolo[4,3-a][1,4]benzodiazepines
WO2021198124A1 (en) * 2020-03-31 2021-10-07 F. Hoffmann-La Roche Ag Benzodiazepine derivatives as gaba a gamma1 pams
US12344614B2 (en) 2021-10-06 2025-07-01 Hoffmann-La Roche Inc. Benzodiazepine derivatives as GABA a GAMMA1 PAM
US12365687B2 (en) 2021-09-29 2025-07-22 Hoffmann-La Roche Inc. Benzodiazepine derivatives as GABA A gamma 1 PAM

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3879406A (en) * 1972-07-13 1975-04-22 Hoffmann La Roche Preparation of triazolobenzodiazepines
FR2220257A1 (en) * 1973-03-09 1974-10-04 Lipha 5,6-Dihydro-(4H)-s-triazolo-(4,3-a) (1,5)benzodiazepines - as antiinflam-matory and analgesic agents without tranquillising effects
IE41197B1 (en) * 1973-05-29 1979-11-07 Squibb & Sons Inc 4h-s-triazolo (4,3-a)(1,5)benzodiazepin-5-ones
JPS591395U (ja) * 1982-06-25 1984-01-06 株式会社東芝 縦形アイロン収納ケ−ス

Family Cites Families (2)

* Cited by examiner, † Cited by third party
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
DE1955349C2 (de) * 1969-11-04 1982-01-28 Takeda Chemical Industries, Ltd., Osaka s-Triazolo [4,3-a] [1,4] benzodiazepine

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3904641A (en) * 1971-06-18 1975-09-09 Yoshitomi Pharmaceutical Triazolothienodiazepine compounds
US3886174A (en) * 1971-11-22 1975-05-27 Upjohn Co 1-Substituted-6-phenyl-4H-s-triazolo{8 4,3-a{9 {8 1,4{9 benzodiazepines
US4155913A (en) * 1973-02-08 1979-05-22 Hoffmann-La Roche Inc. Thienotriazolodiazepine derivatives
US3995043A (en) * 1974-05-13 1976-11-30 The Upjohn Company Composition and process
US4455307A (en) * 1982-01-04 1984-06-19 The Upjohn Company Antihypertensive use of triazolobenzodiazepines
US4987131A (en) * 1985-12-13 1991-01-22 Roussel Uclaf 4H-triazolo[4,3-a][1,4]benzodiazepines
WO2021198124A1 (en) * 2020-03-31 2021-10-07 F. Hoffmann-La Roche Ag Benzodiazepine derivatives as gaba a gamma1 pams
US11739095B2 (en) 2020-03-31 2023-08-29 Hoffmann-La Roche Inc. Substituted benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepines as GABA A GAMMA1 positive allosteric modulators
US12365687B2 (en) 2021-09-29 2025-07-22 Hoffmann-La Roche Inc. Benzodiazepine derivatives as GABA A gamma 1 PAM
US12344614B2 (en) 2021-10-06 2025-07-01 Hoffmann-La Roche Inc. Benzodiazepine derivatives as GABA a GAMMA1 PAM

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NL7206301A (enrdf_load_stackoverflow) 1972-11-14
FR2137714A1 (enrdf_load_stackoverflow) 1972-12-29
ZA722627B (en) 1973-02-28
DE2220623A1 (de) 1972-11-16
DE2220623C2 (de) 1985-04-25
GB1324318A (en) 1973-07-25
JPS554110B1 (enrdf_load_stackoverflow) 1980-01-29
BE783272A (fr) 1972-11-10
CH582179A5 (enrdf_load_stackoverflow) 1976-11-30
FR2137714B1 (enrdf_load_stackoverflow) 1975-12-26

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