WO1993012113A1 - 3-SUBSTITUE IMIDAZO (1,5-a) ET IMIDAZO (1,5-a)-TRIAZOLO (1,5-c) QUINOXALINES ET QUINAZOLINES AGISSANT SUR LE SYSTEME NERVEUX CENTRAL (SNC) - Google Patents

3-SUBSTITUE IMIDAZO (1,5-a) ET IMIDAZO (1,5-a)-TRIAZOLO (1,5-c) QUINOXALINES ET QUINAZOLINES AGISSANT SUR LE SYSTEME NERVEUX CENTRAL (SNC) Download PDF

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Publication number
WO1993012113A1
WO1993012113A1 PCT/US1992/010388 US9210388W WO9312113A1 WO 1993012113 A1 WO1993012113 A1 WO 1993012113A1 US 9210388 W US9210388 W US 9210388W WO 9312113 A1 WO9312113 A1 WO 9312113A1
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Prior art keywords
imidazo
triazol
methyl
quinazoline
quinoxalin
Prior art date
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PCT/US1992/010388
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English (en)
Inventor
Ronald B. Gammill
Louis L. Skaletzky
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The Upjohn Company
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Publication date
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Publication of WO1993012113A1 publication Critical patent/WO1993012113A1/fr

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • C07D487/12—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 three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • Compounds of the present invention are therapeutically active compounds of imidazo-
  • U.S. Patent 4,440,929 and 4,866,065 discloses 4-thio, 4-imino, 4-hydroxyimino, 4- oxoimidazo(1,5-a)quinoxaline compounds containing nitrile, carboxaldehyde, carboxylic acid, ester, amide and methylalcohol substituents at the 3-position and H, alkyl, alkenyl, alkynyl, aryl, aralkyl, hydroxy, and alkanoyl at the 5-position.
  • European Patent 202,441-A discloses imidazo(1,5-a)quinazoline compounds useful as anxiolytic and hypnotic agents, containing an oxadiazole at the 3-position and halogen, nitrile, methyl and trifluoromethyl groups at the 6-position.
  • U.S. Patent 4,968,682 and 4,999,354 discloses 4-oxoimidazo(1,5-a)quinoxaline compounds useful as anxiolytic and hypnotic agents, containing oxadiazole or ester substituents at the 3-position and hydrogen or halogen substituents at the 6-position.
  • the ring atom at position 6 may be carbon or nitrogen.
  • European Patent 283,162; U.S. Patents 4,902,686 and 4,873,244 disclose 4- oxoimidazo(1,50a)quinoxalines and 5-oxoimidazo(1,5-a)quinazolines having anticonvulsant and anxiolytic activity, with oxadiazoles, esters, and amides at position 3.
  • U.S. Patent 4,745,112 discloses imidazobenzodiazepines useful as anticonvulsants and anxiolytics containing an oxadiazole at the 3-position.
  • U.S. Patent 4,999,353 discloses 4-oxoimidazoquinoxalines useful as anxiolytics and hypnotics with an oxadiazole at position 3 and tert-butyl at position 5.
  • U.S. Patent 5,034,530 discloses imidazo(1,5-a)quinoxalines useful as anxiolytics and hypnotics with oxadiazoles at position 3 and no substitution at position 5 (imino) or 5 N-oxide-
  • U.S. Patent 4,939,139 discloses imidazo(1,5-a)benzodiazepines useful as anxiolytics containing an oxadiazole at position 3.
  • J. Med. Chem (1991) 34, 281-290 discloses 5-oxo(1,2,4)triazolo(1,5-c)quinazoIines with affinity for the benzodiazepine receptor, with phenyl, pyridinyl, CF 3 , ester, fiiranyl, thienyl, tetrahydrofuranyl at position 2.
  • J. Med. Chem. (198831 , 1098-1115 discloses 4-oxoimidazo(1,5-a)quinoxalines with an ester at position 3.
  • the subject of the paper is antiallergy agents.
  • EP 347.094A discloses imidazo(1,5-a)quinoxaline-4,5-enes useful for treating CNS disorders with no substitution at N 5 .
  • U.S. Patent 5,075,304 discloses certain imidazoquinoxaline, and U.S. Patent 5,100,895 discloses them as well with an additional fourth, fused heterocyclic ring.
  • the subject invention is a compound of Formula (I)
  • Z is -N(R 1 )-C(O)- or -C(O)-N(R 1 )-; where, R 1 is C 1-6 alkyl, C 3-7 cycloalkyl (optionally substituted with C 1-6 alkyls), C 1-6 alkyl-C 6-12 aryl, C 1-6 alkyI-C 6-12 heteroaryl, -(CH 2 ) n -R f , -(CH 2 ) n - CO-R d , -(CH 2 ) d -CHOH-R e , -CH 2 CH 2 OCH 3 , -CH(CH 3 )CH 2 OH, -CH(CH 3 )CH 2 OCH 3 , -CH 2 -(2- furan), -CH 2 -(3-furan) or -CH 2 -(2-pyran);
  • G is CH 2 , O, S, S(O) y , NR 6 and Q is -CHO, OH, NR, OR;
  • each R is independently choosen from H, F, Cl, Br, I, C 1-6 alkyl, CF 3 , CN, NO 2 , CONH 2 , CONH-R 6 , C(O)OR 6 , OR 6 ;
  • R 5 is H, F, Cl, Br, I, CF 3 , CN, -CH 2 CH 2 CF 3 , -CH 2 CH(CF 3 )CH 3 , C 3-6 cycloalkyl
  • R 6 are independently H, C 1-6 alkyl, C 6-12 aryl, C 1-6 alkyl-C 6-1 2 aryl, C 6-12 heteroaryl, C 1-6 alkyl-C 6-12 heteroaryl, -(CH 2 ) n -CO-(C 1-6 alkyl, -C 6-12 aryl or -C 6-12 heteroaryl), or when two -R 6 's are attached to the same nitrogen atom they can form a cyclic system containing, in addition to the specified nitrogen atom, one other oxygen or nitrogen atom;
  • R 9 is C 1-6 alkyl, C 6-12 aryl, C 1-6 alkyl-C 6-12 aryl, C 6-12 heteroaryl, C 1-6 alkyl-C 6-12 heteroaryl;
  • R a is -R 6 , CH(OH)R 9 , CO 2 R 9 , CON(R 6 ) 2 , (CH 2 ) n OR 6 , (CH 2 ) n SR 6 , (CH 2 ) n S(O) y R 9 , (CH 2 ) n N(R 6 ) 2 ;
  • R b is -(CH 2 ) d -OR 6 , -(CH 2 ) d -SR 6 , -(CH 2 ) n -OR 9 , -(CH 2 ) n -SR 9 , -(CH 2 ) d -S(O) y R 9 , - (CH 2 ) n N(R 6 ) 2 , -(CH 2 ) n -C 1-6 alkyl, -(CH 2 ) n -C 6-12 aryl, -(CH 2 ) n -C 6-12 heteroaryl;
  • R c is -(CH 2 ) d -OR 6 , -(CH 2 ) d -S(O) y R 9 , -(CH 2 ) d -NO 6 ) 2 , -(CH 2 ) n -C 1-6 -alkyl, -(CH 2 ) n -C 6-12 aryl, -(CH 2 ) n -C 6-12 heteroaryl, -(CH 2 ) n -C 6-12 heteroaryl;
  • R d is -(CH 2 ) d -OR 9 , -(CH 2 ) d -OR 6 , -(CH 2 ) d -SR 6 , -(CH 2 ) d -S(O) y R 9 , -(CH 2 ) n -N(R 6 ) 2 , (CH 2 ) n C 1-6 alkyl, -(CH 2 ) n -C 6-12 aryl, -(CH 2 ) n -C 6-12 heteroaryl;
  • R e is -(CH 2 ) 4 -OR 6 , -(CH 2 ) d -SR 6 , -(CH 2 ) d -S(O) y R 9 , -(CH 2 ) d -N(R 6 ) 2 , -(CH 2 ) d -N(O)(R 6 ) 2 , - (CH 2 ) n -C 1-6 alkyl, -(CH 2 ) n -C 6-12 aryl, -(CH 2 ) n -C 6-12 heteroaryl;
  • R f is -O-R 6 , -SR 6 ,-S(O) y R 9 , -O-(CH 2 )nN-R 6 , -S-(CH 2 ) n -R 6 , -S(O) y -(CH 2 ) n -R 9 , -N(R 6 ) 2 , -
  • R 1 cannot be C 1-6 alkyl, C 1-6 alkyl-C 6-12 aryl, C 1-6 alkyl-C 6-12 heteroaryl or -(CH 2 ) n -R f (to avoid the compounds disclosed in US Patent 4,440,929);
  • the subject invention is a compound of formula (II)
  • G is CH 2 , O, S, S(O) y , NR 6 ;
  • Q is -CHO, OH, NR, OR 1 ; and
  • n is 0-3;
  • R are each independently choosen from H, F, Cl, Br, I, C 1-6 alkyl, CF 3 , CN, NO 2 , CONH 2 , CONHR 6 , C(O)OR 6 , OR 6 ;
  • R 5 is H, F, Cl, Br, I, CF 3 , CN, -CH 2 CH 2 CF 3 , -CH 2 CH(CF 3 )CH 3 , C 3-6 cycloalkyl
  • R 6 are independently H, C 1-6 alkyl, C 6-12 aryl, C 1-6 alkyl -C 6-12 aryl, C 6 -12 heteroaryl, C 1-6 alkyl-C 6-12 heteroaryl, -(CH 2 ) n -CO-(C 1-6 alkyl, -C 6-12 aryl or -C 6-12 heteroaryl), or when two R 6 's are attached to the same nitrogen atom they can form a cyclic system containing, in addition to the specified nitrogen atom, one other oxygen or nitrogen atom;
  • R 9 is C 1-6 alkyl, C 6- 12 aryl, C 1-6 alkyl-C 6-12 aryl, C 6-12 heteroaryl, C 1-6 alkyl-C 6-12 heteroaryl;
  • R a is -R 6 , CH(OH)R 9 , CO 2 R 9 , CON(R 6 ) 2 , (CH 2 ) n OR 6 , (CH 2 ) n SR 6 , (CH 2 ) n S(O) y R 9 , (CH 2 ) n N(R 6 ) 2 ;
  • R b is -(CH 2 ) d -OR 6 , -(CH 2 ) d -SR 6 , -(CH 2 ) n -OR 9 , -(CH 2 ) n -SR 9 , -(CH 2 ) d -S(O) y R 9 ,
  • R c is -(CH 2 ) d -OR 6 , -(CH 2 ) d -S(O) y -R 9 , -(CH 2 ) d -N(R 6 ) 2 , -(CH 2 ) n -C 1-6 alkyl, -(CH 2 ) n -C 6-12 aryl, -(CH 2 ) n -C 6-12 heteroaryl;
  • the subject invention is a compound of an imidazo(1,5- a)quinoxaline of formula (III)
  • R are independentiy H, F, Cl, C 1-6 alkyl, CN, O-C 1-6 alkyl, CONH 2 , CONHR 6 , CO 2 R 6 , or OH;
  • R 5 is -(CH 2 ) P -N(R 6 ) 2 or C 3-7 cycloalkyl (substituted with F, Cl, C 2 -6 alkyl, or methyl provided at least one R is F or Cl);
  • R 6 is independently H, C 1-6 alkyl, C 6-12 aryl, C 6-12 heteroaryl, C 1-6 alkyl-C 6-12 aryl, C 1-6 alkyl-C 6-12 heteroaryl, or when two R 6 's are attached to the same nitrogen atom they can form a cyclic system, containing, in addition to the specified nitrogen atom, one other nitrogen or oxygen atom.
  • Preferred compounds of imidazo(1,5-a)quinoxaline of Formula III are where X is structure (a); R is H or F; and R 1 is a C 1 -6 alkyl.
  • Especially preferred compounds of Formula III are a. 3-(5-(1-Methycyclopropyl)-1,2,4-oxadiazol-3-yl)-5-(1-methylethyI)-imidazo(1,5- a)quinoxalin-4(5H)-one;
  • the subject invention is a method or use of compounds from
  • Formula I, II or III for the preparation of a medicament useful in treating central nervous syste disorders associated with benzodiazepine receptors by administering to a subject in need of such treatment a therapeutically-effective amount of the compound to alleviate such disorder.
  • Alkyl are one to six carbon atoms or, as otherwise indicated, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, and isomeric forms thereof.
  • Aryl are six to twelve carbon atoms such as phenyl, ⁇ -naphthyl, ⁇ -naphthyl, m- methylphenyl, p-trifluoromethylphenyl and the like.
  • the aryl groups can also be substituted with one to 3 hydroxy, OR 8 , -OCOR 8 , fluoro, chloro, or bromo groups.
  • Cycloalkyl are three to seven carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Alkyl-aryl are alkyl chains of one to six carbon atoms and isomeric forms thereof which are substituted with aryl groups of six to twelve carbon atoms as described above.
  • Heteroaryl are six to twelve carbon atoms aryl, as described above, containing the heteroatoms nitrogen, sulfur or oxygen. Examples can include pyridine, thiophene, furan, pyrimidine, 2-pyridyI, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3- pyridazinyl, 4-pyridazinyl, 3-pyrizinyl, 2-quinolyl, 3-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4- isoquinolyl, 2-quinazoIinyl, 4-quinazolinyl, 2-quinoxalinyl, 1-phthalazinyl, 2-imidazolyl, 4- imidazolyl, 3-isoxazoIyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2- oxazolyl, 4-o
  • Pharmaceutically acceptable salts include salts of both inorganic and organic acids.
  • the pharmaceutically acceptable salts are preferred over the corresponding free amines since they produce compounds which are more water soluble.
  • the preferred pharmaceutically acceptable salts include salts of the following acids: methanesolfonic, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric or maleic.
  • the subject compounds are active orally or parenterally.
  • the compounds can be given in solid dosage forms as tablets or capsules, or can be given in liquid dosage forms such as elixirs, syrups or suspensions as is known to those skilled in the art. It is preferred that the compounds be given in solid dosage form and that it be a tablet.
  • the compound can be mixed with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methylcellulose, and functionally similar materials as pharmaceutical diluents or carriers.
  • Capsules are prepared by mixing the compound with an inert pharmaceutical diluent and filling the mixture into a hard gelatin capsule of appropriate size.
  • Soft gelatin capsules are prepared by machine encapsulation of a slunry of the compound with an acceptable vegetable oil, light liquid petrolatum or other insert oil.
  • Fluid unit dosage forms for oral administration such as syrups, elixirs, and suspensions can be prepared.
  • the forms can be dissolved in an aqueous vehicle together with sugar, aromatic flavoring agents and preservatives to form a syrup.
  • Suspensions can be prepared with an aqueous vehicle with the aid of a suspending agent such as acacia, tragacanth,
  • fluid unit dosage forms can be prepared utilizing the compound and a sterile vehicle.
  • the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
  • Adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into a vial and the water removed under vacuum.
  • the lyophilized powder can then be sealed in the vial and reconstituted prior to use.
  • the compounds should be given in amounts of about 0.25 mg to about 100 mg/person, one to three times a day. Preferably, about 10 to about 50 mg/day in divided doses.
  • the compounds should be given in the amount of about 0.25 mg to about 500 mg/person, preferrably at bedtime or when sedation is needed. It is preferred the sedative/hypnotic dose be from about 10 to about 100 mg/person.
  • the exact dosage and frequency of administration depends on the particular compound used, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentration of the compound in the patient's blood and/or the patient's response to the particular condition being treated.
  • the subject compounds along with a pharmaceutically-acceptable carrier, diluent o buffer can be administrated in a therapeutic or pharmacological amount effective to alleviate th central nervous system disorder with respect to the physiological condition diagnosed.
  • the compounds can be administered intravenously, intramuscularly, topically, transdermally such as by skin patches, bucally or orally to man or other vertebrates.
  • t-Butyl 4,5-dihydro-4-oxo-5-(1-methylethyl)-imidazo(1,5-a)-quinoxaline-3-carboxylate was treated with trifluoroacetic acid in methylene chloride to remove the tert-butyl ester group.
  • 4,5-Dihydro-4-oxo-5-(1-methylethyl)-imidazo(1,5-a)-quinoxaIine-3-carboxylic acid was treated with thionyl chloride followed by sodium azide to yield 4,5-dihydro-4-oxo-5-(1-methylethyl)- imidazo(1,5-a)-quinoxaline-3-carboxyI azide.
  • That compound was heated in a hydrocarbon solvent to effect molecular rearrangement followed by trapping of the unstable intermediate with methanol to yield 3-((methoxycarbonyI)amino)-4,5-dihydro-4-oxo-5-(1-methyIethyl)-imidazo(1,5- a)-quinoxaline.
  • That carbamate was then decomposed with potassium hydroxide to yield 3- amino-4,5-dihydro-4-oxo-5-(1-methylethyI)-imidazo(1,5-a)-quinoxaline.
  • the dione (1.02 g) was dissolved in THF (10 mL) and cooled to 0°C.
  • Potassium t- butoxide (1.0 M in THF, 5.5 mL) was added, then the reaction was cooled to -20°C and diethylchlorophosphate (795uL) was added. The reaction was warmed to 23°C for 30 minutes, then cooled to -78°C and the isonitrile (800 uL) was added.
  • Potassium t-butoxide 1.0 M in THF, 5.5 mL was added and the reaction was warmed to 23°C for 3 hours.
  • Trifluoroacetic acid 500 uL was dissolved in methylene chloride (2.0 mL) and cooled to 0°C. A solution of the ester (650 mg) in methylene chloride (3.0 mL) was added and the reaction was allowed to warm to 23°C for 2.5 hours. The solvent was evaporated and the residue was dried in a vacuum oven for 17 hours at 45°C to give the extremely insoluble acid as a tan solid (542 mg, 99%).
  • the amine (2.42 g) was dissolved in water (4.0 mL) and concentrated HCI (2.3 mL) wa added. The mixture was cooled to 0°C and sodium nitrite (760 mg) was added. The reaction was stirred for 0°CC for 2 hours, then filtered. Sodium azide (716 mg) was added and gas evolution began immediately, followed by formation of a pale yellow precipitate. The reaction was stirred at 0°C for 2 hours, then extracted with ethyl acetate (3 x 175 mL). The combined extracts were washed with water (2 x 40 mL) and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to a yellow solid.
  • 1,2,3,4-tetrahydro-2,4-dioxo-quinazoline was reacted with t-butylisocyanate using reaction conditions as described in US Patent 4,771,051 to yield t-butyl 4,5-dihydro-4-methyl-5- oxo-imidazo(1,5-a)-quinoxaline-3-carboxylate which was treated with trifluoroacetic acid in methylene chloride to remove the tert-butyl ester group.
  • 4,5-Dihydro-4-methyl-5-oxo- imidazo(1,5-a)-quinoxaline-3-carboxylic acid was treated with thionyl chloride followed by sodium azide to yield 4,5-dihydro-4-methyl-5-oxo-imidazo(1,5-a)-quinoxaline-3-carboxyl azide. That compound was heated in a hydrocarbon solvent to effect molecular rearrangement followed by trapping of the unstable intermediate with methanol to yield 3-((methoxycarbonyl)amino)-4,5- dihydro-4-methyl-5-oxo-imidazo(1,5-a)-quinoxaIine.
  • Ethyl imidazo(1,5-a)-1,2,4-triazolo(4,3-c)quinazoline-3-carboxylate was added to a mixture of water and methanol containing potassium carbonate.
  • the resulting acid, imidazo(1,5- a)-1,2,4-triazolo(4,3-c)quinazoline-3-carboxylic acid was then treated with thionyl chloride followed by sodium azide to yield imidazo(1,5-a)-1,2,4-triazolo(4,3-c)quinazoline-3-carboxyl azide.
  • That compound was heated in a hydrocarbon solvent to effect molecular rearrangement followed by trapping of the unstable intermediate with methanol to yield 3-((methoxy- carbonyl)ammino)-imidazo(1,5-a)-1,2,4-triazolo(4,3-c)quinazoline.
  • That carbamate was then decomposed with potassium hydroxide to yield 3-amino-imidazo(1,5-a)-1,2,4-triazolo(4,3- c)quinazoline.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à une oxoimidazo(1,5-a)quinoxaline et à une oxoimidazo(1,5-a)quinazoline de la formule (I), à une imidazo(1,5-a)-1,2,4-triazolo-(4,3-c)quinazoline et à une imidazo(1,5-a)-1,2,4-triazolo-(4,3-c)quinozoline de la formule (II), et ainsi qu'à une imidazo(1,5-a)quinoxaline de la formule (III), les groupes R et autres variables ont la notation ci-incluse. Les composés sont utiles dans le traitement des troubles du système nerveux central associé aux récepteurs de benzodiazépine chez un sujet nécessitant un traitement qui consiste à lui administrer une quantité thérapeutiquement efficace d'un composé des formules I, II ou III en vue d'atténuer ces troubles. Généralement, le composé des formules I, II ou III est administré sous la forme d'une composition pharmaceutique comprenant un excipient ou diluant pharmaceutiquement acceptable.
PCT/US1992/010388 1991-12-17 1992-12-07 3-SUBSTITUE IMIDAZO (1,5-a) ET IMIDAZO (1,5-a)-TRIAZOLO (1,5-c) QUINOXALINES ET QUINAZOLINES AGISSANT SUR LE SYSTEME NERVEUX CENTRAL (SNC) WO1993012113A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US80956491A 1991-12-17 1991-12-17
US07/809,564 1991-12-17
US84006392A 1992-02-21 1992-02-21
US07/840,063 1992-02-21

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010101230A1 (fr) 2009-03-05 2010-09-10 アステラス製薬株式会社 Composés de quinoxaline
WO2012033101A1 (fr) 2010-09-07 2012-03-15 アステラス製薬株式会社 Composé quinoxaline
US8263630B2 (en) 2008-02-12 2012-09-11 Bristol-Myers Squibb Company 1,2,3-triazoles as 11-beta hydroxysteroid dehydrogenase type I inhibitors
JP2014506589A (ja) * 2011-02-23 2014-03-17 ファイザー・インク 神経障害治療のためのイミダゾ［５，１−ｆ］［１，２，４］トリアジン
WO2017149469A1 (fr) * 2016-03-03 2017-09-08 Emcure Pharmaceuticals Limited Composés hétérocycliques utiles en tant que modulateurs de l'ido et/ou de la tdo
CN113474346A (zh) * 2018-12-28 2021-10-01 福马治疗有限公司 用于抑制泛素特异性蛋白酶1的组合物

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EP0225013A1 (fr) * 1985-10-17 1987-06-10 A/S Ferrosan Composés hétérocycliques, leur préparation et leur utiisation
EP0226282A2 (fr) * 1985-10-17 1987-06-24 A/S Ferrosan Composés hétérocycliques, leur préparation et leur utilisation
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EP0225013A1 (fr) * 1985-10-17 1987-06-10 A/S Ferrosan Composés hétérocycliques, leur préparation et leur utiisation
EP0226282A2 (fr) * 1985-10-17 1987-06-24 A/S Ferrosan Composés hétérocycliques, leur préparation et leur utilisation
EP0283162A2 (fr) * 1987-03-18 1988-09-21 Novo Nordisk A/S Composés hétérocycliques, leur préparation et utilisation
EP0368652A1 (fr) * 1988-11-10 1990-05-16 Novo Nordisk A/S Imidazoquinoxalines et leur préparation
WO1992015591A1 (fr) * 1991-03-07 1992-09-17 Novo Nordisk A/S Derives d'imidazoquinazoline tetracyclique, procede de preparation et compositions pharmaceutiques les contenant

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US8263630B2 (en) 2008-02-12 2012-09-11 Bristol-Myers Squibb Company 1,2,3-triazoles as 11-beta hydroxysteroid dehydrogenase type I inhibitors
WO2010101230A1 (fr) 2009-03-05 2010-09-10 アステラス製薬株式会社 Composés de quinoxaline
US8357688B2 (en) 2009-03-05 2013-01-22 Astellas Pharma Inc. Substituted imidazo[1,5-a]quinoxalin-4(5H)-ones as PDE9 inhibitors
US8674096B2 (en) 2009-03-05 2014-03-18 Astellas Pharma Inc. Substituted imidazo[1,5-a]quinoxalin-4-ones as phosphodiesterase 9 inhibitors
WO2012033101A1 (fr) 2010-09-07 2012-03-15 アステラス製薬株式会社 Composé quinoxaline
US8901126B2 (en) 2010-09-07 2014-12-02 Astellas Pharma Inc. Substituted imidazo[1,5-A]quinoxalin-4-ones are useful for preventing or treating storage dysfunction, voiding dysfunction and bladder/urethral diseases
JP2014506589A (ja) * 2011-02-23 2014-03-17 ファイザー・インク 神経障害治療のためのイミダゾ［５，１−ｆ］［１，２，４］トリアジン
WO2017149469A1 (fr) * 2016-03-03 2017-09-08 Emcure Pharmaceuticals Limited Composés hétérocycliques utiles en tant que modulateurs de l'ido et/ou de la tdo
CN113474346A (zh) * 2018-12-28 2021-10-01 福马治疗有限公司 用于抑制泛素特异性蛋白酶1的组合物

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