US3878205A - Diazepine derivatives - Google Patents

Diazepine derivatives Download PDF

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US3878205A
US3878205A US272088A US27208872A US3878205A US 3878205 A US3878205 A US 3878205A US 272088 A US272088 A US 272088A US 27208872 A US27208872 A US 27208872A US 3878205 A US3878205 A US 3878205A
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chloro
benzodiazepine
methyl
triazolo
acid
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Andre Gagneux
Roland Heckendorn
Rene Meier
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Novartis Corp
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Ciba Geigy Corp
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • DIAZEPINE DERIVATIVES Inventors: Andre Gagneux, Basel; Roland Heckendorn, Arlesheim; Rene Meier, Buus, all of Switzerland Assignee: Ciba-Geigy Corporation, Ardsley,
  • the present invention relates to new diazepine derivatives. to processes for their production. to therapeutic preparations containing the new compounds. and to the use thereof.
  • the compounds according to the invention correspond to the general formula l wherein R, represents hydrogen. or an alkyl group having from 1 to 3 carbon atoms.
  • R- and R represent a hydrogen atom. an alkyl or hydroxyalkyl group having from l to 6 carbon atoms. or an aralkyl group having from 7 to 9 carbon atoms. whereby. when R;- and R simultaneously represent alkyl groups as aforesaid. these alkyl groups may optionally be bound together in the B- or y-position either directly or via an oxygen atom or imino group. or alkylimino or hydroxyalkylimino group having at most 4 carbon atoms. and wherein each of the rings A and B. independently of the other. is unsubstituted or substituted by one or more chlorine atoms. fluorine atoms. bromine atoms. trifluoromethyl groups. nitro groups and/or alkyl and/or alkoxy groups having from I to 6 carbon atoms.
  • the invention also relates to the S-osides of the compounds of the general formula I. and to the addition salts of the compounds of the general formula I and of their S-oxides with inorganic and organic acids.
  • alkyl group e.g. the methyl. ethyl or propyl group.
  • Suitable alkyl groups as substituents of the rings A and B each having I to 6 carbon atoms are. e.g. the methyl. ethyl. propyl. isopropyl. butyl. isobutyl. tert.butyl. pentyl. isopentyl. neopentyl. tert.pentyl or hexyl group: and suitable alkosy groups having 1 to 6 carbon atoms are. e.g. the methoxy. ethoxy. propoxy. isopropoxy. butoxy. isobutoxy.
  • substituents of the rings A and B are fluorine. chlorine or bromine atoms. trifluoromethyl groups and/or nitro groups.
  • R, and R are. e.g. ethyl. propyl. isopropyl. butyl. isobutyl. pentyl. isopentyl or hexyl groups. and preferably methyl groups: as hydroxyalkyl groups having at most 6 carbon atoms.
  • R: and R;, are. e.g. Z-hydroxypropy'l. 3-hydroxypropyl. 2- hydroxybutyl.
  • R- and R are. e.g.. benzyl. phenethyl. a. o-. mor p-methylbenzyl. 3- phenylpropyl or a-methylphenethyl groups.
  • the two last-mentioned groups can be substituted in the -l-position. i.e. in the imino group. e.g. by a methyl. ethyl. propyl. isopropyl. butyl. isobutyl.
  • a preferred class of diazepine derivatives are those. wherein R, is hydrogen and wherein the rings A and B are unsubstituted or substituted by a single substituent defined under formula l.
  • These diazepine derivatives correspond to the general formula la and R, and R independently of each other. represent a hydrogen. fluorine. chlorine or bromine atom. a trifluoromethyl or nitro group or an alkyl or alkoxy group having from 1 to 6 carbon atoms.
  • the radical R is preferably in the 8-position and is. in particular. one of the mentioned halogen atoms. especially chlorine. also the nitro group or the trifluoromethyl group.
  • the radical R is preferably hydrogen or a fluorine. chlorine or bromine atom or the trifluoromethyl group in any desired position. particularly. however. it is hydrogen or is a fluorine or chlorine atom in the o-position.
  • the compounds of the general formula I. their oxides and the corresponding acid addition salts are produced according to the invention by the reaction of a reactive ester of a compound of the general formula ll (1H CH C wherein R. has the meaning given under formula I. and the rings A and B can be substituted as defined there. or of the S-oxide of such a compound. with a compound of the general formula III (IIT) wherein R and R have the meaning given under formula l. or with an alkali metal derivative of such a compound: and. optionally. the conversion of the obtained reaction product into an addition salt with an inorganic or organic acid.
  • a reactive ester of a compound of the general formula ll (1H CH C wherein R. has the meaning given under formula I. and the rings A and B can be substituted as defined there. or of the S-oxide of such a compound. with a compound of the general formula III (IIT) wherein R and R have the meaning given under formula l. or with an alkali metal derivative of such a compound:
  • Suitable reactive esters of hydroxy compounds of the general formula ll are. e.g. sulphonic acid esters such as the methanesulphonic acid esters. the oand ptoluenesulphonic acid esters. the 0- or p-nitrobenzenesulphonic acid esters. or the 0- or p-chlorobenzenesulphonic acid esters.
  • Further suitable reactive esters of compounds of the general formula ll are their hydrohalic acid esters. especially chlorides or bromides. as well as the iodides produced in situ from them.
  • An excess of the basic compound to be reacted of the general formula II] can serve as reaction medium. and simultaneously as acid-binding agent. It is also possible to use as the reaction medium. in addition to.
  • an inert organic solvent e.g. a lower alkanol such as methanol. ethanol. propanol. isopropanol or butanol. a ketone such as acetone or methyl ethyl ketone. also. e.g. dioxane. tetrahydrofuran. dimethylformamide or dimethylsulphoxide. whereby. optionally. the compound of the general formula lll may be also used in excess as an aqueous solution: or. alternatively. it is'possible to use. instead of this excess. or in addition to it. another acid-binding agent. e.g. a tertiary organic base such as ethyldiisopropylamine or collidine. or an inorganic basic substance such as. e.g. potassium carbonate.
  • an inert organic solvent e.g. a lower alkanol such as methanol. ethanol. propanol. isopropanol or
  • an alkali metal derivative of such a compound is used as reaction component. e.g. a sodium. lithium or potassium derivative. then it is preferable to use hydrocarbons such as benzene. toluene or xylene. ethereal liquids such as 1.2-dimethoxyethane. tetrahydrofuran or dioxane. or acid amides such as dimethylformamide or hexamethylphosphoric acid triamide. or sulphoxides such as dimethylsulphoxide. as solvents.
  • the formation of the alkali metal derivatives of the compounds of formula III. with the exception of ammonia. is preferably effected in situ. e.g.
  • alkali metal hydride such as sodium hydride.
  • alkali metal amide such as sodium or lithium amide. or of an alkali-metaI-organic compound such as phenylor butyllithium.
  • the reaction temperatures are preferably between 0 and C. or the boiling temperature of the employed reaction medium.
  • a second process for the production of compounds of the general formula I wherein R and R are hydrogen atoms. whilst R has the meaning given under formula I. and the rings A and B can be substituted as defined there. and of their S-oxides and the corresponding acid addition salts. comprises the reduction of a compound of the general formula IV CH N M.
  • R has the meaning given under formula I. and the rings A and B can be substituted as defined there. or of the 5-oxide of such a compound; and. optionally. the conversion of the obtained reaction product into an addition salt with an inorganic or organic acid.
  • the reduction of the azides of the general formula IV. the preparation of which is described below. can be carried out both by chemical methods and by catalytic hydrogenation. e.g. in the presence of palladium charcoal catalysts. platinum oxide or Raney nickel. in an organic solvent such as dioxane. ethanol. methanol or tetrahydrofurat'i. at room temperature and under normal pressure.
  • a suitable chemical method is. in particular. the reduction with tin(ll)-chloride in lower alkanolicaqueous. especially ethanolic-aqueous. alkali solution. particularly sodium hydroxide solution. at temperatures of between ca. and the boiling temperature of the reaction mixture. preferably between ca. 0 and room temperature.
  • a third process for the production of compounds of the general formula I of which the radical R is hydrogen. or in which the lower alkyl groups R; and R are bound in the B- or y-position by an imino group. whilst R, has the meaning given under formula I. and the rings A and B can be substituted as defined there. as well as of oxides of such compounds and the corresponding acid addition salts. comprises the hydrolysis of a compound of the general formula V CH N A l ⁇ N N l (v) CH R wherein R represents an acyl radical. or a lower alkyl group bound to a lower alkyl group R in the B- or 'y-position by an acylimino group.
  • R and R- have the meanings given under formula I. and the rings A and B can be substituted as defined there. or of the S-oxide of such a compound: and. optionally. the conversion of the obtained reaction product into an addition salt with an inorganic or organic acid.
  • R or the acyl radical of the imino group is. in particular. a lower alkanoyl group such as the acetyl or formyl group. the cyano group. a lower alkoxycarbonyl group such as the methoxycarbonyl. ethoxycarbonyl or tert- .butoxycarbonyl group. a phenoxycarbonyl or benzyloxycarbonyl group. also a corresponding thiocarbonyl group. or the acyl radical of another monofunctional derivative ofcarbonic acid such as. e.g. the chlorocarbonyl group. or an arenecarbonyl group such as the benzoyl group.
  • Hydrolysis can be performed with the aid of an alkali metal hydroxide. e.g. potassium or sodium hydroxide. at a temperature of ca. 50 to'l2()C. e.g. in a higher boiling organic solvent containing hydroxyl groups.
  • an alkali metal hydroxide e.g. potassium or sodium hydroxide.
  • a temperature of ca. 50 to'l2()C e.g. in a higher boiling organic solvent containing hydroxyl groups.
  • hydrolysis can also be carried out in an acid medium. e.g. with hydrogen bromide or hydrogen chloride in acetic acid. or with alkanolic hydrochloric acid. at a temperature of ca. 50 to lC or at the boiling temperature of the reaction mixture.
  • the compounds of the general formula ll. on which the reactive esters required as starting materials for the first process are based. are obtained. for example. starting with compounds of the general formula VI CO (VI) wherein the rings A and B can be substituted as defined under formula I.
  • Such compounds are described in the literature. e.g. Z-amino-S-chlorobenzophenone lcp. F. D. Chattaway. .l.Chem.Soc. 85. 344 (1904)]. or 2- amino-Z'.5-dichlorobenzophenone ]cp. L. H. Sternbach et al.. J. Org. Chem. 26. 4488 (196] )1.
  • the cornpounds of the general formula Vl are diazotised.
  • the carboxylic acids of the general formula [X are converted in a manner known per se. e.g. with ethanol or methanol containing hydrogen chloride. into their ethyl or methyl esters; and these reduced with lithium aluminium hydride. in an ethereal solvent such as tetrahydrofuran and at temperatures of around 0C. to compounds of the general formula ll.
  • the ethyl esters of the carboxylic acids of the general formula IX required for the reducation can also be obtained by the treatment of the aforementioned coupling products with at most the double-molar amount of sodium hydroxide under mild reaction conditions. i.e. at room temperature and with neutralisation before processing: and the subsequent reaction of the ethyl esters of carboxylic acids of the general formula VI! obtained as the main product.
  • the compounds of the general formula ll obtained by reduction are converted in a manner known per se. e.g. by reaction with a sulphonic acid chloride such as methanesulphonic acid chloride or p-toluenesulphonic acid chloride. in an inert organic solvent such as methylene chloride. in the presence of an organic base such as triethylamine or ethyl-diisopropylamine. or by reaction with thionyl chloride or phosphorus tribromide and. optionally. subsequently with potassium iodide. into suitable reactive esters.
  • a sulphonic acid chloride such as methanesulphonic acid chloride or p-toluenesulphonic acid chloride.
  • an inert organic solvent such as methylene chloride.
  • an organic base such as triethylamine or ethyl-diisopropylamine.
  • thionyl chloride or phosphorus tribromide and.
  • the compounds of the general formula IV serving as starting materials for the second process are produced by the reaction of reactive esters of compounds of the general formula ll. e.g. methanesulphonic acid esters. with alkali metal azides such as sodium azide. in inert organic or organic-aqueous solvents. such as. e.g. aqueous acetone.
  • the starting materials of the general formula V used in the third process. in which R is an acyl group. are obtained. for example. analogously to the firstmentioned process by employing. instead of an alkali metal compound of a starting material of the general formula 11]. e.g. an alkali metal compound of a formamide. acetamide or cyanamide substituted in the amide group by R. or of a carbamic acid-lower alkyl ester. -phenyl ester or -benzyl ester substituted on the nitrogen atom by R.
  • the compounds of the general formula I obtained by the processes according to the invention. and also the S-oxides of these compounds. are optionally converted. in the usual manner. into their addition salts with inorganic and organic acids.
  • the acid desired as salt component is added to a solution of a compound of the general formula I in an organic solvent.
  • Organic solvents in which the formed salt is difficultly soluble are preferably chosen for the reaction. so that the salt can be separated by filtration.
  • solvents are. e.g. methanol. ether. acetone. methyl ethyl ketone. acetone/ether. acetone/ethanol. methanol/ether or ethanol/ether.
  • salts to be used as pharmaceutical active substances crystallise well and are not. or only slightly. hygroscopic.
  • the following may be used. for example. for salt formation with compounds of the general formula 1: hydrochloric acid. hydrobromic acid. sulphuric acid. phosphoric acid. methanesulphonic acid. ethanesulphonic acid. Z-hydroxyethanesulphonic acid. acetic acid. lactic acid. succinic acid. fumaric acid. maleic acid. malic acid. tartaric acid. citric acid. benzoic acid. salicylic acid. phenylacetic acid. mandelic acid and embonic acid.
  • the new active substances are administered orally. rectally or parenterally.
  • the dosage amount depends on the mode of administration. on the species. on the age and on the individual condition.
  • the daily doses of the free bases. of their 5-oxides. or of pharmaceutically acceptable salts of the free bases vary between 0.02 mg/kg and 2 mg/kg for warm-blooded animal's.
  • Suitable dosage units. such as dragees. tablets. suppositories or ampoules. preferably contain 0.5-25 mg of an active substance according to the invention.
  • Dosage units for oral administration contain as active substance preferably between 1-50 percent of a compound of the general formula 1. or of a pharmaceutically acceptable salt thereof.
  • the dosage units are prepared by the combination of the active substance with. e.g. solid pulverulent carriers such as lactose. saccharose. sorbitol. mannitol: starches such as potato starch. maize starch or atnylopectin. also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine. optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols. to form tablets or dragee cores.
  • the dragee cores are coated. for example. with concentrated sugar solutions which may also contain. e.g. gum arabic. talcum and/or titanium dioxide; or with a lacquer dissolved in readily volatile organic solvents or solvent mixtures.
  • Dyestuffs can be added to these coatings in order to facilitate. for example. identification of the various doses of active substance.
  • suitable oral dosage units are hard gelatine capsules. as well as soft closed capsules made from gelatine and a softener. such as glycerin.
  • the hard capsules contain the active substance preferably as a granulate. in admixture. for example. with fillers such as maize starch. and/or lubricants such as talcum or magnesium stearate. and optionally stabilisers such as so-- dium metabisulphite (Na- 5 or ascorbic acid.
  • the active substance is preferably dissolved or suspended in suitable liquids such as polyethylene glycols. to which likewise stabilisers may be added.
  • Suitable dosage units for rectal administration are. e.g. suppositories consisting of a combination of an active substance and a suppository foundation substance.
  • base substances natural or synthetic triglycerides. paraffin hydrocarbons. polyethylene glycols or higher alkanols. Hard gelatine capsules consisting of a combination of the active substance and a foundation substance are likewise suitable. Suitable foundation substances are. e.g. liquid triglycerides. polyethylene glycols or paraffin hydrocarbons.
  • Ampoules for parenteral administration particularly for intramuscular administration. preferably contain a water-soluble salt of an active substance in a concentration of preferably 0.1 2 percent. optionally together with suitable stabilisers and buffer substances. in aqueous solution.
  • a granulate is produced from 50 g of 2- I (dimethylamino )-methyl ]-6-(o-fluorophenyl )-8- chloro-4H-s-triazolo 1.5-a][ 1.4]benzodiazepine. 175.90 g of lactose and the alcoholic solution of 10 g of stearic acid: after drying.
  • the granulate is mixed with 56.60 g of colloidal silicon dioxide. 165 g oftalcum. 20 g of potato starch and 2.50 g of magnesium stearate: and the mixture finally pressed to obtain 10.000 dragee cores.
  • These are then coated with a concentrated syrup made from 502.28 g of crystallised saccharose. 6 g of shellac. 10 g of gum arabic. 0.22 g of dyestuff and 1.5 g of titanium dioxide; the coated dragees are finally dried.
  • the obtained dragees each weigh 100 mg and each contain 5 mg of active substance.
  • a suppository mixture is prepared from 1.0 g of 2- [(dimethylamino)-methyl]-6-pheny1-8-chloro-4H-striazolol 1.5-a1l 1.4]benzodiazepine and 169.0 g of adeps-solidus; from the prepared mixture are then poured 100 suppositories each containing 10 mg of active substance.
  • EXAMPLE 1 a An amount of 8.05 (0.02 mole) of methanesulphonic acid ester of 6-phenyl-8-chloro-4H striazolol 1.5-all1.4]benzodiazepine-Z-methanol is dissolved in ml of dimethylsulphoxide; the solution is then added dropwise at 510. with stirring. to a mixture of 10 g (0.09 mole) of 40.5 percent aqueous dimethylamine solution and 20 ml of dimethylsulphoxide. The reaction mixture is then allowed to warm up to room temperature. and is stirred for a further hour at 2025. It is thereupon poured on 0.5 litre of icecold water. and extraction carried out twice with 250 ml of benzene each time.
  • the methanesulphonic acid ester required as starting material is producedas follows:
  • This carboxylic acid can also be produced according to d) from the chloromethyl compound obtained by procedure b):
  • EXAMPLE 2 The methanesulphonic acid ester prepared according to Example 1 g) from 4.9 g (0.015 mole) of 6-phenyl-8- ch1oro-4H-s-triazo1ol 1 .5-a1l 1.4 lbenzodiazepine-Z- methanol and 2.58 g (0.023 mole) of methanesulphonic acid chloride is dissolved in 50 m1 of methanol: the solution is then added dropwise to 100 ml of boiling methanol. which is continuously saturated by the introduction of ammonia gas. Refluxing is carried out for 4 hours with the further introduction of ammonia gas. and the reaction mixture then concentrated in vacuo to dryness.
  • Sodium hydroxide solution (0.1N) is added to the residue and extraction performed with benzene.
  • the benzene extract is washed once with water. and at terwards repeatedly extracted with 0.1N acetic acid.
  • the acid extracts are combined. rendered alkaline with conc. ammonia. and extracted with benzene.
  • the combined benzene extracts are washed with water and with saturated sodium chloride solution. dried over sodium sulphate. and concentrated to dryness.
  • the methanesulphonic acid esters required as starting materials are produced as follows:
  • This crude acid can be used direct for cyclisation analogously to Example 1 c) or 1 d).
  • EXAMPLE 7 a A solution of 1.69 g (0.0075 mole) of tin(ll)- chloridedihydrate in 24 m1 of 2N sodium hydroxide solution is slowly added dropwise at 05 to a solution of 1.75 g (0.005 mole) of Z-(azidomethyl)6phenyl-8- chloro-4H s-triazolol 1.5-all 1.4lbenzodiazepine in 175 ml of percent aqueous ethanol. The reaction mixture immediately becomes cloudy. After completion of the dropwise addition. the reaction mixture is stirred fora further 30 minutes at 5-1(); it is then neutralised with 2N hydrochloric acid. and concentrated in vacuo to dryness.
  • R and R have the meanings given in claim 1. and wherein each of the rings A and B. independently of the other. is unsubstituted or substituted by one fluorine atom. chlorine atom. bromine atom. trifluoromethyl group or nitro group. and the pharmaceutically acceptable acid addition salts thereof.
  • a compound according to claim 1 having the for- R and R have the meanings given in claim 1 and R and R,-.. independently of each other. represent a hydrogen. fluorine. chlorine or bromine atom. a trifluoromethyl or nitro group or an alkyl or alkoxy group having from I to 6 carbon atoms. its S-oxide and the pharmaceutically acceptable acid addition salts of said compound of the formula la or of its 5-oxide 5.
  • R represents a hydrogen. fluorine. chlorine or bromine atom or a trifluoromethyl group.
  • R and R independently of each other. represent a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms.
  • R represents a fluorine. chlorine. or bromine atom or a nitro or trifluoromethyl group.
  • 5 R represents a hydrogen. fluorine. chlorine or bromine atom or a trifluoromethyl group. and the pharmaceutically acceptable acid addition salts thereof.
  • R and R independently of each other. represent a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms.
  • R represents a chlorine atom in the 8-position and R represents hydrogen or a fluorine or chlorine atom in the ortho-position. and the pharmaceutically acceptable acid addition salts thereof.
  • R represents a chlorine atom in the 8-position and R represents hydrogen or a fluorine or chlorine atom in the ortho-position. and the pharmaceutically acceptable acid addition salts thereof.
  • a compound according to claim 1 which is 2- l(dimethylamino )-methyl ]-6-phenyl-8-chloro-4H-s- 3o triazolol l.5-a][ l .4 lbenzodiazepine.
  • a compound according to claim 1 which is l- (aminomethyl l-(i-phenyl-8-chloro-4H-s-triazolo[ 1.5- all 1.4 lbenzodiazepine.
  • a compound according to claim 1 which is 2- 35 l(methylamino)-methyl]-6-phenyl-8-chloro-4H-striazolol 1.5-aH L4 lbenzodiazepine.
  • a compound according to claim 1 which is Z- (piperidinomethyl)-6-phenyl-8-chloro-4H-striazolol 1.5-a H [.4 lbenzodiazepine. 4o
  • a compound according to claim 1 which is 2-[( lpyrrolidinyl )-methyl l-6-phenyl-8-chloro-4H-striazolol l.5-al[ l .4 lbenzodiazepine.
  • a compound according to claim I which is 2- (morpholinomethyl )-6-phenyl-8-chloro-4H-striazolol l 5-a][ 1.4 Ibenzodiazepine.
  • a compound according to claim 1 which is 2-[ (4- methyl 1 -piperazinyl )-methyl ]-6-phenyl-8-chloro-4H- s-triazolol l.5-a][ 1.4]benzodiazepine.
  • a compound according to claim 1 which is 2- 1(methylamino )-methyl ]-6-( o-fluorophenyl )-8-chloro- 4H-s-tria7.olo[l.5-a][1.4]benzodiazepine and its hy drochloride.
  • a compound according to claim 1 which is 2- ltdimethylamino )-meth vl ]-6-( o-fluorophenyl )-8- chloro-4H-s-triazolo[ l .5a][ l.4 lbenzodiazepine.
  • a compound according to claim 1 which is 2- (aminomethyl)-6-(o-fluorophenyl)-8-chloro--lH-striazolo[ l.5-a][ L4 lbenzodiazepine.
  • a compound according to claim 1 which is 2- ⁇ (rneth vlamino )-methyll-o-(o-chlorophenyl )-8-chloro- 4H-s-triazolo[ l.5-a][ 1.4]benzodiazepine and its (2:1
  • R and R have the meanings given in claim 1 and wherein each of the rings A and B. independently of the other. is unsubstituted or substituted as indicated in claim 1, and its S-oxide.

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USB563070I5 (de) * 1975-03-28 1976-03-09
US4209516A (en) * 1974-01-14 1980-06-24 Ciba-Geigy Corporation Triazole derivatives
US4209515A (en) * 1974-06-14 1980-06-24 Ciba-Geigy Corporation Triazole derivatives
US4510141A (en) * 1982-09-13 1985-04-09 Ciba-Geigy Corporation Tricyclic polyazaheterocycles for treating depression or anxiety

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JPS5747915B2 (de) * 1974-04-17 1982-10-13
WO2023052312A1 (en) 2021-09-29 2023-04-06 F. Hoffmann-La Roche Ag New benzodiazepine derivatives as gaba a gamma1 pam

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US3703525A (en) * 1969-11-15 1972-11-21 Takeda Chemical Industries Ltd Triazolo(1,5-a)(1,4)benzodiazepine derivatives

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
US3703525A (en) * 1969-11-15 1972-11-21 Takeda Chemical Industries Ltd Triazolo(1,5-a)(1,4)benzodiazepine derivatives

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4209516A (en) * 1974-01-14 1980-06-24 Ciba-Geigy Corporation Triazole derivatives
US4209515A (en) * 1974-06-14 1980-06-24 Ciba-Geigy Corporation Triazole derivatives
USB563070I5 (de) * 1975-03-28 1976-03-09
US3996230A (en) * 1975-03-28 1976-12-07 The Upjohn Company 1-Piperazino-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepines
US4510141A (en) * 1982-09-13 1985-04-09 Ciba-Geigy Corporation Tricyclic polyazaheterocycles for treating depression or anxiety

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Publication number Publication date
AU4483772A (en) 1974-01-24
IE36563L (en) 1973-01-23
IL39883A0 (en) 1972-09-28
NO134868C (de) 1976-12-29
CA967956A (en) 1975-05-20
DD99578A5 (de) 1973-08-12
PL85681B1 (de) 1976-04-30
AT319956B (de) 1975-01-27
FI52729B (de) 1977-08-01
AR194603A1 (es) 1973-07-31
AR197989A1 (es) 1974-05-24
DE2234652A1 (de) 1973-02-01
NO134868B (de) 1976-09-20
CS178450B2 (de) 1977-09-15
BE786530A (fr) 1973-01-22
FR2147092A1 (de) 1973-03-09
JPS561316B1 (de) 1981-01-13
SU497776A3 (ru) 1975-12-30
SU472505A3 (ru) 1975-05-30
HU165319B (de) 1974-08-28
CS178411B2 (de) 1977-09-15
CH553801A (de) 1974-09-13
SE380804B (sv) 1975-11-17
AT318625B (de) 1974-11-11
NL7209809A (de) 1973-01-25
IE36563B1 (en) 1976-12-08
GB1395416A (en) 1975-05-29
ZA724839B (en) 1973-04-25
FI52729C (fi) 1977-11-10
FR2147092B1 (de) 1975-08-08
IL39883A (en) 1976-06-30
AU472145B2 (en) 1976-05-20

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