US3846443A - 1H-IMIDAZO{8 1,2a{9 {8 1,4{9 BENZO-DIAZEPINE-1,2(3H)-DIONES - Google Patents

1H-IMIDAZO{8 1,2a{9 {8 1,4{9 BENZO-DIAZEPINE-1,2(3H)-DIONES Download PDF

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US3846443A
US3846443A US00364616A US36461673A US3846443A US 3846443 A US3846443 A US 3846443A US 00364616 A US00364616 A US 00364616A US 36461673 A US36461673 A US 36461673A US 3846443 A US3846443 A US 3846443A
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benzodiazepine
carbon atoms
dihydro
amino
pyridyl
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R Moffett
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Pharmacia and Upjohn Co
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Upjohn Co
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Priority to BE790839D priority Critical patent/BE790839A/xx
Priority to GB4627872A priority patent/GB1365455A/en
Priority to AU47634/72A priority patent/AU474359B2/en
Priority to DE2252079A priority patent/DE2252079A1/de
Priority to NL7214469A priority patent/NL7214469A/xx
Priority to JP10764472A priority patent/JPS5545557B2/ja
Priority to FR7238639A priority patent/FR2158414B1/fr
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Priority to US00364616A priority patent/US3846443A/en
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives

Definitions

  • R and R are selected from the group con sisting of hydrogen, lower alkyl of I through 3 carbon atoms, halogen, nitro, cyano, trifluoromethyl, lower alkoxy of I through 3 carbon atoms, lower alkylthio of 1 through 3 carbon atoms, lower alkylsulfinyl of I through 3 carbon atoms, lower alkylsulfonyl of 1 through 3 carbon atoms, lower-alkanoylamino having lower alkyl moieties of 1 through 3 carbon atoms and lower dialkylamino having lower alkyl moieties of 1 a through 3 carbon atoms; R and
  • This invention relates to new benzodiazepines and is particularly concerned with novel lH-,imidazo[l,2- a][ l ,4]-benzodiazepine-l ,2(3H)-diones embraced by the formula 1 3N-R R4 4 i 8 I s R r wherein R, R R R and R have the same meaning as below, and a process for their production.
  • Benzodiazepines having the structure set forth immediately above have not heretofore been reported.
  • novel compounds (I) of this invention and a process for their production are represented by the following sequence of formulae wherein R is selected from the group consisting of hydrogen, lower alkyl of 1 through 4 carbon atoms and lower alkenyl of 3 through 4 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 2-pyridyl, 3-pyridyl, 4-pyridyl, Z-pyrimidyl, furyl, pyrryl, thienyl, lower alkyl of 1 through 3 carbon atoms, lower alkenyl of 2 through 4 carbon atoms, cycloalkyl of 5 through 7 carbon atoms, cycloalkenyl of 5 through 7 carbon atoms and wherein R and R are selected from the group consisting of hydrogen, lower alkyl of I through 3 carbon atoms, halogen, nitro, cyano, trifluoromethyl, lower alkoxy of 1 through 3 carbon atom
  • R is selected from the group consisting of 2- pyridyl, 3-pyridyl, 4-pyridyl and Rs R5 wherein R and R are selected from the group consisting of hydrogen, lower alkyl of 1 through 3 carbon atoms, halogen, nitro, cyano and trifluoromethyl.
  • halogen includes fluorine, chlorine, bromine, and iodine.
  • lower alkyl is exemplified by methyl, ethyl, propyl and isopropyl
  • the term lower alkoxy is exemplified by methoxy, ethoxy, propoxy and isopropoxy.
  • lower alkylthio is exemplified by methylthio, ethylthio, propylthio and isopropylthio.
  • lower alkylsulfinyl is exemplified by methylsulfinyl, ethylsulfinyl, propylsulfinyl and isopropylsulfinyl.
  • lower alkylsulfonyl is exemplified by methylsulfonyl, ethylsulfonyl, propylsulfonyl and isopropylsulfonyl.
  • lower alkanoylamino is exemplified by formylamino, acetylamino, propionylamino and isopropionylamino.
  • lower dialkylamino is exemplified by dimethylamino, diethylamino, methylethylamino, methylpropylamino, ethylpropylamino, dipropylamino, diisopropylamino and the like.
  • lower alkenyl is exemplified by vinyl, l-propenyl, allyl, isopropenyl, methallyl and crotyl.
  • cycloalkyl is exemplified by cyclopentyl, cyclohexyl and cycloheptyl.
  • cycloalkenyl is exemplified by lcyclopentenyl, l-cyclohexenyl, l-cycloheptenyl, 2- cyclopentenyl, 2-cyclohexenyl, Z-cycloheptenyl, 3-cyclopentenyl, 3-cyclohexenyl, 3-cycloheptenyl and 4-cycloheptenyl.
  • novel ll-I-imidazo[l,2-a][1,4]benzodiazepinel,2(3l-I)-diones of Formula I exist either in the nonprotonated (free base) form or in the protonated (acid addition salt) form, depending on the pH of the environment.
  • pharmacologically acceptable acid addition salts on acidification of the free base with suitable pharmacologically acceptable acids, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, acetic, propionic, palmitic, benzoic, salicylic, hexynoic, phenylbutyric, naphthoic, glycolic, succinic, nicotinic, tartaric, maleic, malic, pamoic, methanesulfonic, cyclohexanesulfonic, cyclohexanesulfonic, citric and lactic acids, and the like.
  • suitable pharmacologically acceptable acids for example, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, acetic, propionic, palmitic, benzoic, salicylic, hexynoic, phenylbutyric, naphthoic, glycolic, succinic, nicotinic, tartaric,
  • the free bases of the novel compounds of Formula I 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,
  • an appropriate corresponding Z-amino- (alkylamino or alkenylamino)-3l-l- 1,4-benzodiazepine (11) starting material in an inert organic solvent is mixed in the cold, in the presence of a base, with an oxalyl halide.
  • Suitable inert organic solvents include tetrahydrofuran, dimethylformamide, dioxane, benzene and the like.
  • Suitable bases include 3 pyridine, triethylamine, ethylisopropylamine, dimethylphenylamine, sodium carbonate and the like.
  • Suitable oxalyl halides are oxalyl bromide, oxalyl chloride and oxalyl fluoride.
  • Equimolar quantities of the amino starting material (II) and the oxalyl halide are usually employed, but the reaction is operative with smaller or larger proportions of either reactant.
  • the reaction is carried out at between about 30 to below C., preferably at about 75 C., and usually under an atmosphere of nitrogen.
  • the reaction period is between about several minutes to about 6 hours.
  • the termination of the reaction can be determined by thin layer chromatography, and/or infrared and nuclear magnetic resonance spectra.
  • 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 water and separating the resulting precipitate by filtration or by extraction with water-immiscible 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 combination 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.
  • R is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, fury], pyrryl, thienyl, cycloalkyl of'5 through 7 carbon atoms, cycloalkenyl of 5 through 7 carbon atoms and R, R R and R have the same meaning as above, can be prepared by heating known corresponding compounds of the formula wherein R R and R. have the same meaning as above and R has the same meaning as immediately above, with phosphorus pentasulfide in a solvent such as pyridine, benzene, toluene or xylene at between about 80 to about 140 C.
  • a solvent such as pyridine, benzene, toluene or xylene
  • novel compounds of Formula I and the pharmacologically acceptable acid addition salts thereof are central nervous system depressants, having sedative, hypnotic, anticonvulsant, tranquilizing and muscle relaxant effects in mammals and birds.
  • Substances depressing the central nervous system have a variety of manifestations, the mildest being tranquilization. Tranquilizers also cause a state of sedation, hypnosis or indifference in test animals.
  • the first manifestation of depression of the CNS in the mouse is motor weakness (muscle relaxant) and this activity is related to anticonvulsant activity.
  • the general methods used to test for CNS activity are found in chapters 6, 7 and 14 of Turner, Screening Methods in Pharmacology, Academic Press, N.Y., 1965, Volume I Tranquilizing, sedative and hypnotic effects of the compounds of this invention are shown by the following tests in mice:
  • subhypnotic dose of ethanol (5 ml./kg. of a 50 percent aqueous solution) is given orally to groups of six mice 30 minutes after the test compound is given intraperatoneally. Thirty minutes later each mouse is examined for loss of righting reflex.
  • Anticonvulsant activity of the compounds of this invention are shown by the following tests in mice.
  • Electroshock [1. Med. Chem. 8, 548 (1965)]. This test is a measure of the ability of an anticonvulsant drug to abolish the tonic extensor component in the hind limb of a mouse by the maximal seizure pattern induced by 50 mA of current delivered for 0.2 second. Mice are injected with the test compound intraperitoneally and then challenged with the electric current. The ED is the dose at which 50 percent of the animals do not extend the hind limb after electrical stimulation. Thiosemicarbazide Lethality. [1. Med. Chem. 8, 548 (1965)]. Protection against thiosemicarbazide is a measure of the anticonvulsant effect.
  • the test compound is injected into six mice'immediately prior to injection of thiosemicarbazide mg./kg., intraperitoneally). Protection against letholity 4 hours after thiosemicarbazide is the end point.
  • Pentylenetetrazole [1. Med. Chem. 14, 1078 (1971- An aqueous solution of pentylenetetrazole (85 mg./kg.) isadministered to a group of 6 mice minutes after the test compound. The mice are then observed for a period of 20 minutes for symptoms of clonic convulsions.
  • the number of animals in each group which were protected against the pentylenetetrazole induced convulsions is used as a quantal response parameter for calculating the effective dose (ED of the test compound. Strychnine Antagonism. [1. Med. Chem. 8, 548 (1965)]. Protection against strychnine lethality is tested by injecting strychnine sulfate 3 mg./kg. i.p., 30 minutes after the test compound. This dose of strychnine is usually always fatal to all of the animals. Lethality is assessed 30 minutes after administration of strychnine.
  • mice are injected with the test compound and 30 minutes later they are injected with nicotine salicylate (2 mg./kg.).
  • Control mice show overstimulation, i.e., (1) running convulsions followed by (2) tonic extensor fits followed by (3) death.
  • the animals are considered pine-l,2(3l-l)-dione (B) A (ED B an' Test mgJkg.) mg./kg.)
  • Electroshock 200 Thiosemicarbazide 0.18 6.3 Pentylenetetrazole 2.0 50 Strychnine 12.0 100 Nicotine 1.1 63
  • Myorelaxant or muscle relaxing properties are shown by many agents which exhibit anticonvulsant activity.-
  • the compounds of this invention also show muscle relaxing properties as evidenced by electroshock, strychnine and nicotine tests performed above
  • 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, 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.
  • Water and oil e.g., coconut oil, sesame oil, safflower oil, cottonseed oil, peanut oil can be used for preparing solutions or suspensionsof the active drug. Sweetening,
  • coloring, and flavoring agents can be added.
  • the compounds of Formula I and their pharmacologically acceptable acid addition salts can be used in dosages of 0.01 mg. to 2.0 mg./kg. in oral or injectable preparations as described above. They can be used to alleviate tension and anxiety in mammals, or birds, e.g., such as occurs when animals are traveling; or to alleviate muscle cramps in pets and domestic animals as occur, for example, after strenuous activity.
  • the filtered solid is treated with hot water and filtered again.'The filtrate is treated with percent 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 g. of brown solid.
  • This material plus the 129 mg. of crude product are chromatographed on 130 g. of silica gel using 50 percent ethyl acetate: 50 percent cyclohexane as eluting solvent. The product .taken from the column is recrystallized from ethyl acetate to give 455 mg.
  • EXAMPLE 1 8-chloro-6-phenyl-1l-l-imidazo[1,2-a][ 1,4]benzodiazepine-l,2(3H)-dione (l)
  • Hg. for about 3 hours has a melting point of 226 to 245 C. after sintering at about C.
  • This material is shown by its nmr (nuclear magnetic resonance) spectrum and melt solvate to contain about A: mole of tetrahydrofuran.
  • Infrared, ultraviolet, nmr and mass spectral data confirm the structure predicted for the compound, 8-chloro-6-phenyl-1H-imidazo[1,2- a][1,4]benzodiazepine-l,2(3H)-dione tetrahydrofuran solvate (3:1) (1).
  • EXAMPLE 2 8-chloro-3-methyl-6-phenyl-lH-imidazo[1,2-a]- [1,4lbenzodiazepine-1,2(3H)-dione (l)
  • a mixture of 2.02 ml. (0.025 mole) of dry pyridine, 25 ml. of tetrahydrofuran and 1.03 ml. (1.53 g.) ofoxalyl chloride is cooled to about 76 C. by a mixture of solid carbon dioxide and acetone, and a solution of 2.84 g. (0.01 mole) of 7-chloro-2-(methylamino)-5- phenyl-3H-l,4-benzodiazepine (11) ]prepared as in J.
  • EXAMPLE 3 8-chloro-6-(o-chlorophenyl)-lH-imidazo[1,2- a][1,4]benzodiazepine-1,2(3H)-dione
  • Nmr data confirms the structure proposed for the compound, 8-chloro-6-(o-chlorophenyl)-1H- imidazo[ l ,2-a] 1,4]benz0diazepine- 1 ,2( 3H )-di0ne isopropanol solvate (2:1) (1), showing about 1/2 molecule of isopropanol/molecule. Infrared and ultraviolet spectra are also in agreement with the predicted structure of the compound.
  • R is selected from the group consisting of hy drogen, lower alkyl of I through 4 carbon atoms and lower alkenyl of 3 through 4 carbon atoms;
  • R is seleeted from the group consisting of hydrogen and lower alkyl of I through 3 carbon atoms;
  • R is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl and a Rn Rs wherein R and R are selected from the group consisting of hydrogen, lower alkyl of 1 through 3 carbon atoms, halogen, nitro, cyano and trifluoromethyl; R and R, have the same meaning as R and R above; or a pharmaeologically acceptable addition salt thereof.
  • R, R, and R are hydrogen
  • R is wherein R and R are hydrogen and R is 8-chloro
  • R is methyl, R, and R, are hydrogen, R is I wherein R and R are hydrogen and R is 8-ehloro, namely, 8-ehloro-3-methyl-6-phenyl-I H-imidazo[ l ,2- a][ l,4]benzodiazepine-l ,2( 3H)-dione.
  • R, R, and R are hydrogen
  • R is XX R5 R5 wherein R is hydrogen and R is o-chloro
  • R is 8-chl0ro, namely, 8-chloro-6-(o-ehlorophenyl)-1H- imidazo[1,2-a][ l ,4]benzodiazepine-l ,2( 3H)-di0ne.
  • R is hydrogen and R is o-chloro, and R is 8- ehloro, namely, 8-chloro-6-(o-chlorophenyl)-1H- imidazo[ l,2-a][1,4]b'en2odiazepine-1,2(3H)-dione isopropyl alcohol solvate.

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  • Orthopedic Medicine & Surgery (AREA)
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US00364616A 1971-11-02 1973-05-29 1H-IMIDAZO{8 1,2a{9 {8 1,4{9 BENZO-DIAZEPINE-1,2(3H)-DIONES Expired - Lifetime US3846443A (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
BE790839D BE790839A (fr) 1971-11-02 Nouvelles benzodiazepines, leur procede de preparation et medicament les contenant
GB4627872A GB1365455A (en) 1971-11-02 1972-10-06 Imdazobensodiazepines
AU47634/72A AU474359B2 (en) 1971-11-02 1972-10-11 Benzodiazepine-1, 2(3m)-diones
DE2252079A DE2252079A1 (de) 1971-11-02 1972-10-24 Neue 1h-imidazo eckige klammer auf 1,2a eckige klammer zu eckige klammer auf 1,4 eckige klammer zu benzodiazepin-1,2(3m)dione
NL7214469A NL7214469A (enrdf_load_stackoverflow) 1971-11-02 1972-10-26
JP10764472A JPS5545557B2 (enrdf_load_stackoverflow) 1971-11-02 1972-10-28
FR7238639A FR2158414B1 (enrdf_load_stackoverflow) 1971-11-02 1972-10-31
US00364616A US3846443A (en) 1971-11-02 1973-05-29 1H-IMIDAZO{8 1,2a{9 {8 1,4{9 BENZO-DIAZEPINE-1,2(3H)-DIONES

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US19504971A 1971-11-02 1971-11-02
US00364616A US3846443A (en) 1971-11-02 1973-05-29 1H-IMIDAZO{8 1,2a{9 {8 1,4{9 BENZO-DIAZEPINE-1,2(3H)-DIONES

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BE (1) BE790839A (enrdf_load_stackoverflow)
DE (1) DE2252079A1 (enrdf_load_stackoverflow)
FR (1) FR2158414B1 (enrdf_load_stackoverflow)
GB (1) GB1365455A (enrdf_load_stackoverflow)
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4044142A (en) * 1975-02-03 1977-08-23 Roussel Uclaf 1,2-Dihydro-6-phenyl-1H,4H-imidazobenzodiazepin-1-ones
US4134976A (en) * 1975-02-15 1979-01-16 Roussel Uclaf 1,2-Dihydro-6-phenyl-1H,4H-imidazobenzodiazepin-1-ones
US4185102A (en) * 1975-11-04 1980-01-22 Roussel Uclaf 1,2-Dihydro-6-phenyl-1H,4H-imidazobenzodiazepin-1-ones
US4508716A (en) * 1981-12-28 1985-04-02 Kali-Chemie Pharma Gmbh [1,2]-Fused 1,4-benzodiazepine compounds, process for their preparation and compositions containing them
US4545935A (en) * 1983-09-12 1985-10-08 Iowa State University Research Foundation, Inc. Amidoalkylation reactions of anilines
US20040209282A1 (en) * 2002-10-30 2004-10-21 Dana Ault-Riche Methods for producing polypeptide-tagged collections and capture systems containing the tagged polypeptides

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA755418B (en) * 1974-09-11 1977-06-29 Hoffmann La Roche Diazepine derivatives

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1545214A (fr) * 1966-11-23 1968-11-08 Hoffmann La Roche Procédé pour la préparation de dérivés de benzodiazépine
ZA713364B (en) * 1970-06-18 1972-01-26 Upjohn Co Prganic compounds and process

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Derieg et al., Chem. Abst., Vol. 69, No. 36092v (1968), QD1.A51. *
Derieg et al., Chem. Abst., Vol. 70, No. 87862z (1969), QD1.A51. *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4044142A (en) * 1975-02-03 1977-08-23 Roussel Uclaf 1,2-Dihydro-6-phenyl-1H,4H-imidazobenzodiazepin-1-ones
US4134976A (en) * 1975-02-15 1979-01-16 Roussel Uclaf 1,2-Dihydro-6-phenyl-1H,4H-imidazobenzodiazepin-1-ones
US4185102A (en) * 1975-11-04 1980-01-22 Roussel Uclaf 1,2-Dihydro-6-phenyl-1H,4H-imidazobenzodiazepin-1-ones
US4508716A (en) * 1981-12-28 1985-04-02 Kali-Chemie Pharma Gmbh [1,2]-Fused 1,4-benzodiazepine compounds, process for their preparation and compositions containing them
US4594436A (en) * 1981-12-28 1986-06-10 Kali-Chemie Pharma Gmbh Isomeric 2-chloromethyl-1,4-benzodiazepine or 3-chloro-1,5-benzodiazocine compound
US4545935A (en) * 1983-09-12 1985-10-08 Iowa State University Research Foundation, Inc. Amidoalkylation reactions of anilines
US20040209282A1 (en) * 2002-10-30 2004-10-21 Dana Ault-Riche Methods for producing polypeptide-tagged collections and capture systems containing the tagged polypeptides

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FR2158414A1 (enrdf_load_stackoverflow) 1973-06-15
FR2158414B1 (enrdf_load_stackoverflow) 1977-01-14
NL7214469A (enrdf_load_stackoverflow) 1973-05-04
AU474359B2 (en) 1976-07-22
BE790839A (fr) 1973-04-30
DE2252079A1 (de) 1973-05-03
GB1365455A (en) 1974-09-04
JPS5545557B2 (enrdf_load_stackoverflow) 1980-11-18
JPS4856699A (enrdf_load_stackoverflow) 1973-08-09
AU4763472A (en) 1974-04-26

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