US3759943A - Amido and amino triazolo benzodiazepines - Google Patents

Amido and amino triazolo benzodiazepines Download PDF

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Publication number
US3759943A
US3759943A US00138287A US3759943DA US3759943A US 3759943 A US3759943 A US 3759943A US 00138287 A US00138287 A US 00138287A US 3759943D A US3759943D A US 3759943DA US 3759943 A US3759943 A US 3759943A
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Prior art keywords
benzodiazepine
triazolo
chloro
acetamide
ethyl
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US00138287A
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English (en)
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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 and R" are hydrogen, alkyl of one to three carbon atoms, inclusive, or together are pyrrolidino, piperidino, he xamet hyleneimino, or morpholino; wherein R' is wherein R R R R and R are defined as above and R is alkyl of one to three carbon atoms, inclusive.
  • This invention is directed to novel organic compounds and is more specifically concerned with amidoand amino-triazolobenzodiazepines of the formulae below and a method of the production thereof.
  • R and R" are hydrogen, alkyl of one to three carbon atoms, inclusive, or together are pyrrolidino, piperidino, hexamethyleneimino, and morpholino; wherein R is hydrogen or alkyl defined as above; and wherein R R R and R are selected from the group consisting of hydrogen, alkyl defined as above, halogen, nitro, cyano, trifluoromethyl, and alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, and dialkylamino, in which the carbon chain moiety is of one to three carbon atoms, inciusive.
  • the process of this invention comprises treating an ester of formula I with ammonia or an amine at a temperature between 2S-200 C. in an organic solvent to obtain an amide of formula II; reducing the amide with borane or a metal aluminum hydride in a solvent between room temperature and the reflux temperature of mula above and oxidizing I lIeg. with manganese dioxide, ruthenium tetroxide or with diethyl azodicarboxylate to obtain the benzodiazepine of formula VI.
  • the active compounds of this invention II, III, and IV can be summarily represented by Formula V wherein R and R are hydrogen, alkyl of one to three carbon atoms, inclusive or together R5 n Rt are pyrrolidino, piperidino, hexamethylenemino, and
  • R morpholino wherein R' is III the reaction mixture to obtain the amine III of the for- F DESCRIPTION OF THE PREFERRED EMBODIMENT
  • Lower alkyl groups of one to three carbon atoms, inclusive, are exemplified by methyl, ethyl, propyl, and isopropyl.
  • the carbon chain moiety of alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, dialkylamino which is of one to three carbon atoms, inclusive, is defined as lower-alkyl of one to three carbom atoms, inclusive, as above.
  • halogen includes fluorine, chlorine, and bromine.
  • novel compounds of the formula V(or II, III, and IV) including pharmacologically acceptable acid addition salts thereof, have sedative, tranquilizing and muscle relaxant effects in mammals and birds.
  • the pharmacologically acceptable acid addition salts of compounds of formula -V (or II, III, and IV) contemplated in this invention are the hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates, cyclohexanesulfamates, methanesulfonates and the like, prepared by reacting a compound of formula II, III, or IV with an excess of the selected pharmacologically acceptable acid.
  • mice Sedative effects of N,N-dimethyl-8-chloro-6-phenyl- 4I-I-s-triazolo[4,3-a][ l ,4]benzodiazepinel -acetamide are shown by the following tests in mice:
  • mice The effective intraperitoneal dosage for 50 percent of mice (ED:,,,) is 8.8 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 percent of the mice failed doing it.
  • DISI-I TEST Mice in Petri dishes (IO 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 percent of the mice remain in the dish. The ED (intraperitoneal administration) in this test was 7.0 mgJkg.
  • 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 one minute.
  • the ED intraperitoneal administration
  • mice in a group of 6 are injected with the test compound N ,N-dimethyl-8-chloro-6-phenyl-4l-I-striazolo[4,3-a][ 1,4]benzodiazepine- I -acetamide.
  • 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 1.6 mg./kg. of the test compound protected 50 percent of the mice against (2) and 1.8 mg./kg. against (3).
  • 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 may be used as carriers or for coating purposes.
  • Oils, e.g. coconut oil, sesame oil, safflower 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.
  • the compounds of formula V can be used in dosages of l-20 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.
  • acid addition salts of the compounds of formula V 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.
  • the starting materials of formula I of this invention substituted or unsubstituted 6-phenyl-4H -striazolo[4,3-a] 1,4]benzodiazepinel acetic acid methyl esters are produced from 6-phenyl-4H-striazolo[4,3-a]-[ l ,4]benzodiazepinel-acetonitriles as shown in Preparation 2.
  • the acetonitriles are produced as in preparation 1 from l,3-dihydro-5-phenyl-2H-1,4- benzodiazepine-Z-thiones [described by G. A. Archer et al., J. Org. Chem. 29, (231) 1964].
  • a compound of formula I is reacted with aqueous ammonia or aqueous lower dialkylamine in dimethylformamide, dioxane, tetrahydrofuran or the like or with a dialkylamine, or an lower N-heterocyclicamine, preferably in a solvent, e.g. dimethylformamide, dimethylacetamide or the like, between 25-200 C.
  • a solvent e.g. dimethylformamide, dimethylacetamide or the like, between 25-200 C.
  • the N- heterocyclicamines useful for these are piperidine, pyrrolidine, morpholine, hexamethyleneimine.
  • the product (II) obtained is recovered and purified by standard methods e.g. extraction, chromatography, and crystallization.
  • Compound III can be oxidized in part with active manganese dioxide preferably in benzene, tetrahydrofuran or other anhydrous solvent or with ruthenium tetroxide in a solvent such as chloroform or carbontetrachloride.
  • the temperature of this reaction is between 25-80 C. and the time is between 1 and 18 hours.
  • the product IV is isolated and purified by conventional means e.g. extraction, chromatography, and recrystallization.
  • the first compound eluted from the column was crystallized from methanol-ethyl acetate to give 0.169 g. of melting point 202.5-203.5 C. (d.) and 0.125 g. of melting point 200.5202.5 C. (d.) of 8-chloro-6-phenyl-4l-l-s-triazolo 4,3- a][1,4]benzodiazepine-1-acetic acid methyl ester.
  • the analytical sample had a melting point of 202203 C.
  • EXAMPLE 8 4-[ [9-dipropy1amino-8-ethylsulfony1-6-(pmethoxyphenyl)-4l-l-s-triazolo[4,3- a][ 1 ,4]benzodiazepine-1-yl] acetyl ]morpholine
  • 9-dipropylamino- 8-ethylsu1fonyl-6-(p-methoxypheny1)-4l-l-striazo1o[4,3-a]-[1,4]benzodiazepine-l-acetic acid propyl ester was reacted with morpholine in dimethylformamide to give 4-[[9-dipropy1amino-8-ethy1su1fony1-7- (p-methoxyphenyl)-4H-s-triazo1o ⁇ 4,3- a] l ,4]benzodiazepine-1-yl]acetyl]morpho
  • EXAMPLE 1O 7 ,S-Dicyano-10-fluoro-6-(p-isopropylsulfonyl)- phenyl)-4H-s-triazo1o[4,3-a][1,4]benzodiazepine-1- acetamide
  • 7,8-dicyano-10- fluoro-(p-isopropylsulfonylphenyl)-4H-s-triazo1o[4,3- a]-[1,4]benzodiazepine-l-acetic acid methyl ester was reacted with aqueous ammonium hydroxide in dioxane to give 7,8-dicyano-10-f1uoro-6-(pisopropylsulfonylphenyl)-4l-l-s-triazo1o[4,3- a][1,4]benzodiazepine-1-acetamide.
  • EXAMPLE 13 1-[2-(dimethylamino)ethyl]-8-chloro-5,6-dihydro-6- phenyl-4l-l-s-triazo1o[4,3-a][1,4]benzodiazepine
  • a solution of 1.5 g. of N,N-dimethy1-8-chloro-6- pheny1-4H-s-triazolo[4,3-a][ 1 ,4]benzodiazepine-1- acetamide was slowly added to a solution of borane in tetrahvdrofuran. The reaction mixture was heated to 40 C. and was kept at this temperature for 15 hours.
  • EXAMPLE 27 1- 2-( diethylamino )ethyl -8-chloro-6-( 2,6- difluorophenyl)-4I-I-s-triazolo[4,3- a][ l,4]benzodiazepine
  • a suspension of l-[2-(diethylamino)ethyl]-8-ch1oro-5 ,6-dihydro-6- (2,6-difluorophenyl )-4H-s-triazolo[ 4,3 a][ 1,4]benzodiazepine was oxidized with diethyl azodicarboxylate to give l-[2-(diethylamino)ethyl1-8- chIoro-6-( 2,6-difluorophenyl )-4I-I-s-triazolo 4,3 a][ I ,4]benzodiazepine.
  • the pharmacologically acceptable acid addition salts of compounds of formula V can be prepared and isolated by conventional processes, such as reacting a compound of formula V with a selected pharmacologically acceptable acid.
  • Such acids include hydrochloric, hydrobromic, phosphoric, sulfuric, acetic, tartaric, lactic, citric, malic, maleic, methanesulfonic, benzenesulfonic, cyclohexanesulfonic acids, and the like.
  • the reaction is conveniently performed in an organic solvent e.g. ether, dioxane, tetrahydrofuran and the salts recovered by evaporating the solvent.
  • R and R are hydrogen, or alkyl of one to three carbon atoms, inclusive, or together are pyrrolidino, piperidino, hexamethyleneimino, or morpholino; wherein R is hydrogen or alkyl, defined as above; wherein R R R and R are selected from the group consisting of hydrogen, alkyl defined as above halogen, nitro, cyano, trifluoromethyl, and alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, and dialkylamino, in which the carbon chain moiety is of one to three carbom atoms, inclusive, and the pharmacologically acceptable acid addition salts thereof.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
US00138287A 1971-04-28 1971-04-28 Amido and amino triazolo benzodiazepines Expired - Lifetime US3759943A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3948931A (en) * 1972-11-28 1976-04-06 Ciba-Geigy Corporation Triazolo benzodiazepine-1-carboxamides
US4155913A (en) * 1973-02-08 1979-05-22 Hoffmann-La Roche Inc. Thienotriazolodiazepine derivatives
US4514407A (en) * 1983-03-17 1985-04-30 The Upjohn Company 1-Ethanamine-triazolo-benzodiazepines as diuretics
US4689413A (en) * 1983-03-17 1987-08-25 The Upjohn Company Triazolo-benzodiazepine-1-ethanamines as diuretics

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3894025A (en) * 1974-03-21 1975-07-08 Upjohn Co 1-Piperazino-6-phenyl-4H-s-triazolo{8 4,3-a{9 {8 1,4{9 -benzodiazepine compounds
US4075221A (en) * 1977-01-24 1978-02-21 The Upjohn Company Process for preparing triazolobenzodiazepines

Family Cites Families (1)

* 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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Houben-Weyl, Methoden Der Organischen Chemie, Vol. 11/2, (Stuttgart, 1958), pages 20 23. *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3948931A (en) * 1972-11-28 1976-04-06 Ciba-Geigy Corporation Triazolo benzodiazepine-1-carboxamides
US4155913A (en) * 1973-02-08 1979-05-22 Hoffmann-La Roche Inc. Thienotriazolodiazepine derivatives
US4514407A (en) * 1983-03-17 1985-04-30 The Upjohn Company 1-Ethanamine-triazolo-benzodiazepines as diuretics
US4689413A (en) * 1983-03-17 1987-08-25 The Upjohn Company Triazolo-benzodiazepine-1-ethanamines as diuretics

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BE782849A (fr) 1972-10-30
FR2134585A1 (enrdf_load_html_response) 1972-12-08
NL7205707A (enrdf_load_html_response) 1972-10-31
FR2134585B1 (enrdf_load_html_response) 1975-10-17
CH573939A5 (enrdf_load_html_response) 1976-03-31
DE2220716A1 (de) 1972-11-09
ZA722259B (en) 1972-12-27
DE2220716C2 (de) 1985-08-29
GB1350722A (en) 1974-04-24

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