WO1992013535A1 - Quinazolones substituees a activite anticonvulsivante - Google Patents

Quinazolones substituees a activite anticonvulsivante Download PDF

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Publication number
WO1992013535A1
WO1992013535A1 PCT/US1991/000788 US9100788W WO9213535A1 WO 1992013535 A1 WO1992013535 A1 WO 1992013535A1 US 9100788 W US9100788 W US 9100788W WO 9213535 A1 WO9213535 A1 WO 9213535A1
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compound
salt
methyl
formula
represented
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PCT/US1991/000788
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English (en)
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Chandradhar Dwivedi
Gary W. Omodt
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Research Corporation Technologies, Inc.
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Priority to PCT/US1991/000788 priority Critical patent/WO1992013535A1/fr
Publication of WO1992013535A1 publication Critical patent/WO1992013535A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates generally to anticonvulsant compounds and their use and specifically to substituted quinazolones that have anticonvulsant activity but limited or no sedative or hypnotic effect.
  • a still further object of the invention is to provide a composition for treating or preventing convulsions in mammals.
  • Another object of the invention is to provide methods of treating or preventing convulsions in mammals.
  • Yet another object of the invention is to provide methods for synthesizing the novel anticonvulsant compounds.
  • Still another object of the invention is to provide intermediate compounds useful in the synthesis of the anticonvulsant compounds of the invention. Additional objects and advantages of the invention will be set forth in part in the description that follows, and in part will be obvious on the description, or may be learned by the practice of the invention. The objects and advantages of the invention will be attained by means of the instrumentalities and combinations particularly pointed out in the appended claims.
  • Xi is N, S, 0, or CH
  • X 2 is N or CH
  • R_ and R 2 are H, NO2, or NH 2 except that when one of ⁇ and R 2 is N0 2 or NH 2 the other is H
  • R 3 and R 4 are alkyl with 1-5 C atoms
  • R5, s, and R7 are H or halogen, provided that when Xj. is N, S, or 0, X 2 is CH.
  • the invention also includes pharmaceutically acceptable salts of these compounds.
  • X ⁇ is N.
  • R 3 and R4 are methyl
  • R5, R Q , and R7 are H.
  • one of R ⁇ and R 2 is N0 2 or NH .
  • Xi is N or CH
  • R3 and R4 are methyl
  • R5, Rg, and R7 are H.
  • the compounds of the invention and the physiologically acceptable acid addition salts have valuable pharmacological properties. In particular, they have anticonvulsant activity with limited or no sedative or hypnotic effect.
  • the compounds, the acid addition salts, and compositions containing the compounds or salts in a pharmaceutically acceptable carrier are useful for treating or preventing convulsions in mammals in general and humans in particular.
  • the compounds of the invention are prepared in one of two ways. Where both R ⁇ and R are H or one of ⁇ and R is N0 2 , the appropriate substituted anthranilic acid is reacted with the appropriate anhydride to produce an anthranil intermediate. This compound is then reacted with the appropriate aromatic a ine to produce the desired compound of the invention.
  • R ⁇ and R 2 of the desired quinazolone is NH 2
  • the appropriate quinazolone is prepared according to the previous paragraph, with an N0 group in the desired position, and the compound is then reacted with the appropriate reducing agent to reduce the N0 2 group to a NH 2 group.
  • a person skilled in the art can prepare N 1 -oxide derivatives by reacting the compound with the appropriate oxidizing agent to oxidize the nitrogen in the 1-position.
  • the invention relates to anticonvulsant substituted quinazolones represented by Formula II and their physiologically acceptable acid addition salts.
  • ⁇ is nitrogen, sulfur, or oxygen.
  • Xi is N or S, and most preferably it is N. When Xi is N, S, or 0, X is CH.
  • one of Ri and R 2 is N0 or NH 2 .
  • one of R ⁇ and R 2 is NH 2 , and the other is H.
  • R 3 and are alkyl containing 1-3 carbon atoms.
  • at least one of R3 or R4 is methyl.
  • R3 and R4 are both methyl.
  • one or more of R5, R , and R7 are halogen.
  • Xi is N
  • X 2 is CH
  • one of R_ and R 2 is N0 2 or NH .
  • one of R_ and R 2 is NH
  • the other is H.
  • R3 and R4 are methyl and further that R5, Re, and R7 are H.
  • X ⁇ is N
  • X 2 is CH
  • R ⁇ and R 2 are H.
  • R3 and R4 are methyl and R5-R7 are H, which provides the especially preferred compound 2-methyl-3-(3- methyl-2-pyridyl)-4-quinazolone.
  • Xi in Formula II is CH, X 2 is CH, and one of Ri and R 2 is N0 2 or NH 2 .
  • one of R ⁇ or R 2 is NH 2 and the other is H.
  • R 3 and R4 are preferably methyl, and R5, R ⁇ , and R7 are H.
  • another especially preferred compound of the invention is 2-methyl- 3-o-tolyl-7-amino-4-quinazolone.
  • This scheme is a modification of the scheme for synthesizing methaqualone, which is disclosed in references 1 and 2.
  • a substituted anthranilic acid represented by Formula III above is reacted with an anhyride represented by the Formula IV to prepare an anthranil precursor represented by Formula V.
  • both Ri and R 2 are H or one is N0 and the other is H.
  • R is alkyl with 1-5 carbon atoms.
  • the substituted anthranilic acid is refluxed in the presence of the anhyride under conditions readily determinable by persons skilled in the art, given the teachings contained therein.
  • anthranil intermediate is then reacted with an aromatic amine represented by the following formula (and shown as RNH 2 above) :
  • substituted quinazolones of the invention which are recovered by known techniques.
  • the recovered compounds are recrystallized one or more times to enhance their purity.
  • R ⁇ or R 2 in Formula II is NH
  • the desired substituted quinazolone is prepared according to the above scheme where one of R_ and R is N0 2 and the other is H.
  • the N0 group is then reduced to NH 2 through the application of known reduction techniques and under reaction conditions that will be readily determinable to persons skilled in the art, given the teachings contained herein.
  • reduction is accomplished by reacting the compound with a reducing agent, most preferably a mixture of iron and ammonium chloride.
  • the invention also relates to Ni-oxide derivatives of the compounds of the invention.
  • Such compounds have the following formula:
  • Such compounds may be produced through the application of known techniques for oxidizing the nitrogen atom in compounds similar to the claimed compounds by a person skilled in the art without undue experimentation, once given the teachings contained herein.
  • the compounds of Formula II are refluxed with hydrogen peroxide under reaction conditions readily determinable by persons skilled in the art, given the teachings contained herein, for a sufficient time to produce the compounds of Formula VII.
  • the compounds of the invention are useful for treating or preventing convulsions in mammals.
  • such compounds or salts are in admixture with a pharmaceutically acceptable carrier, providing a composition for treating or preventing convulsions in mammals.
  • the preferred animal host is any animal that may be subject to convulsions for which treatment or prevention is desired. These include, but are not limited to, humans and other primates, dogs, cats, cattle, swine, and horses.
  • the compounds and compositions are administered to humans.
  • the pharmaceutically acceptable acid addition salts of this invention can be prepared by standard methods known in the art, employing those acids of sufficient acidity to form acid addition salts with the N 1 or N ⁇ —oxide oxygen of the compounds of this invention.
  • These include salts derived from inorganic acids, such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydriodic acid, phosphorous acid, and the like, as well as salts derived from organic acids, such as aliphatic mono- and di-carboxylic acids, phenyl-substituted alkanoic acids, hydroxy-alkanoic and -alkanedioic acids, aromatic acids, aliphatic, and aromatic sulfonic acids.
  • Such pharmaceutically acceptable salts thus include the sulfate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, oxalate, maleate, benezene-sulfonate, toluenesulfonate, chlorobenzenesulfonate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2- sulfonate salts, and the like.
  • the preferred salts are those derived from inorganic acids, especially hydrochloric acid.
  • the compounds of the invention may be administered as an anticonvulsant agent by various routes, including oral, parenteral rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal routes.
  • the preferred routes are oral and parenteral. They are usually employed in the form of a pharmaceutical composition.
  • the invention includes a pharmaceutical composition comprising from about 1% to about 95% by weight of the compounds, or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable carrier.
  • the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper, or other container.
  • a carrier which may be in the form of a capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient.
  • the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium) , ointments containing, for example, up to 10% by weight of the active compounds, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • suitable carriers and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl- and propyl-hydroxbenzoates, talc, magnesium stearate, and mineral oil.
  • the formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, flavoring agents, or other active ingredients.
  • the compositions of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient.
  • compositions will be preferably formulated in a unit dosage form, each dosage containing from about 50 to about 200 mg, preferably about 75 to about 150 mg, and most preferably about 80 to about 100 mg of the active ingredient.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier.
  • the compounds are effective over a wide dosage range.
  • dosages per day will normally fall within the range of about 2 to about 8 mg/kg of body weight.
  • the range of about 1 to 2 mg/kg, in single or divided doses is preferred.
  • the amount of the compound actually administered will be determined by a physician or other person skilled in the art, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the specific anticonvulsant substituted quinazolone or N i -oxide derivative selected for use.
  • Acetanthranils were prepared by refluxing substituted anthranilic acids (0.27 mole) in acetic anhydride (200 ml) for 2 hours. Acetic anhydride was removed in vacuo. and the residues were recrystallized from benzene. 8-Azaacetanthranil was prepared by refluxing 2- aminonicotinic acid (0.1 mole) in acetic anhydride (50 ml) for 2 hours. Acetic anhydride was removed under reduced pressure, and the solid obtained was recrystallized from benzene.
  • Substituted quinazolones were prepared by heating equimolar proportions of appropriate primary amine and anthranil at a low flame. The jelly-like mass obtained on cooling was washed with ether. The solid separated out and was filtered and recrystallized from suitable solvents. All the quinazolones synthesized are listed in Table 2. Details about the sythesis of the most active compounds are found in Examples 3 and 4.
  • Acetanthranil (4.5 g, 0.028 mole) was mixed with 2- amino-3-picoline (2.7 g, 0.025 mole) and the mixture was heated in an erlenmeyer flask, first at low. heat and then at high heat over an open flame. The product was washed with ether and recrystallized from ethanol/water mixture. The yield was 3.7 g (58%), mp 135-137°C.
  • This compound was prepared from 2-methyl-3-o-tolyl-7- nitro-4-quinazolone, which was prepared as follows. 7- nitro-acetanthranil (2.1 g, 0.011 mole) was mixed with o- toluidine (1.1 g, 0.010 mole) and heated in an erlenmeyer flask, first over a low flame and then over a high flame to complete the reaction. On cooling overnight, the reaction mixture solidified. The solid mass was stirred and broken up after the addition of ether. Suction filtration yielded 2.7 g (98%), mp 183-186°C. After recrystallization from ethanol, the yield was 2.5 g (91%), mp 181-183°C.
  • This compound is prepared from butyranthranil, which is prepared as follows. Anthranilic acid (37.0 g, 0.270 mole) is refluxed with 200 ml butyric anhydride for two hours. The solvent is removed in vacuo (15 mm) with magnetic bar stirring, and the residue is dissolved in 100 ml benzene, filtered, and transferred to a beaker. The reaction flask is washed with 50 ml hot benzene. The washing is filtered and added to the benzene in the beaker. The benzene solution is concentrated to 100 ml by heating and allowed to cool to room temperature. The mixture is placed in the refrigerator overnight, then ground up in a mortar and pestle and suction-filtered. The crystals are air-dried and weighed.
  • Butyranthranil (5.3 g, 0.028 mole) is mixed with 2- methyl-4-chloro-aniline (3.6 g, 0.025 mole), and the mixture is heated in an erlenmeyer flask over an open flame, first at low heat and then at high heat to complete the reaction. The product is washed with ether and recrystallized from the appropriate solvent.
  • Anticonvulsant activity was determined • in male mice (Swiss-Webster, 20-25 g) .
  • the mice were divided in groups of 10, keeping the group weights equal as far as possible.
  • the quinazolones shown in Table 2 as well as methaqualone were injected ip (100 mg/kg) in a 5% aqueous suspension of gum acacia to one group of 10 animals.
  • One hour after the administration of quinazolones the mice were injected with pentylenetetrazol (90 mg/kg) sc under the loose skin of the back. This dose of pentylenetetrazol has been shown to produce convulsions in all untreated mice. The mice were then observed for the following 60 minutes for the occurrence of seizures.
  • compound no. 2 was also tested against Maximal Electric Shock (MES) seizure.
  • MES Maximal Electric Shock
  • Compound no. 2 exhibited 100% protection against MES at 30 mg/kg ip in mice.
  • Compound No. 2 was also tested in rats. Four rats were treated with compound no. 2 at a dosage of 50 mg/kg orally. Anticonvulsant effects of compound no. 2 were observed at different time periods against both maximal electric shock seizures (MES) and pentylenetetrazol-induced seizure. The toxic symptoms were also observed. Data are given in Table 5. It can be seen from this table that compound no. 2 protected against both MES and pentylenetetrazol-induced seizure at all time periods without exhibiting any toxic symptoms.
  • MES maximal electric shock seizures
  • pentylenetetrazol-induced seizure The toxic symptoms were also observed.
  • Table 5 It can be seen from this table that compound no. 2 protected against both MES and pentylenetetrazol-induced seizure at all time periods without exhibiting any toxic symptoms.
  • Approximate LD50 was determined in male ICR mice. Approximate LD5 0 was found to be about lOOOmg/kg, i.p.
  • Compound no. 2 was given at a dosage of 50 mg/kg orally in 0.5% methylcellulose suspension.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne des quinazolones substituées et leurs dérivés oxyde-N1, des procédés de synthèse de ces composés ainsi que des prcédés d'utilisation de ces derniers pour traiter ou prévenir les convulsions chez les mammifères. Les quinazolones substituées sont représentées par la formule (I) dans laquelle X1 représente N, S, O ou CH, X¿2? représente N ou CH, R1 et R2 représentent H, NO2, ou NH2 excepté que lorsque R1 ou R2 représente NO2 ou NH2, l'autre élément représente H, R3 et R4 représentent alkyle comprenant de 1 à 5 atomes de carbone, et R5, R6 et R7 représentent H ou halogène, à condition que lorsque X1 représente N, S, ou O, X2 représente CH.
PCT/US1991/000788 1991-02-06 1991-02-06 Quinazolones substituees a activite anticonvulsivante WO1992013535A1 (fr)

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5502048A (en) * 1993-06-10 1996-03-26 Zeneca Limited Substituted nitrogen heterocycles
WO1997010221A1 (fr) * 1995-09-15 1997-03-20 Torrey Pines Institute For Molecular Studies Synthese de banques de quinazolinones
EP0807633A2 (fr) * 1996-05-15 1997-11-19 Pfizer Inc. (5,6)-Pyrimidin-4-ones condensées à hétéroaryle, substituées en 2,3
WO1997043276A1 (fr) * 1996-05-15 1997-11-20 Pfizer Inc. Nouvelles 4(3h)-quinazolinones disubstituees en position 2,3
US5801168A (en) * 1994-06-09 1998-09-01 Zeneca Limited Substituted nitrogen heterocycles
WO1998038187A1 (fr) * 1997-02-28 1998-09-03 Pfizer Products Inc. Atropisomeres de 3-heteroaryl-4(3h)-quinazolinones pour le traitement des troubles neurodegeneratifs et des troubles lies a un traumatisme du systeme nerveux central
EP0900568A2 (fr) * 1997-09-05 1999-03-10 Pfizer Products Inc. Antagonistes d'AMPA pour le traitement des dyscinésies associées à la thérapie aux agonistes de la dopamine
EP0900567A2 (fr) * 1997-09-05 1999-03-10 Pfizer Products Inc. Quinazoline-4-ones antagonistes d'AMPA pour le traitement des dyscinésies associées à la thérapie aux agonistes de la dopamine
US6323208B1 (en) 1997-09-05 2001-11-27 Pfizer Inc Atropisomers of 2,3-disubstituted-(5.6)-heteroaryl fused-pyrimidin-4-ones
KR100358636B1 (ko) * 1997-02-28 2002-10-31 화이자 프로덕츠 인코포레이티드 3-아릴-4(3에이치)-퀴나졸리논의 회전장애이성질체 및 에이엠피에이-수용체 길항물질로서 그의 용도
WO2005060987A1 (fr) * 2003-12-23 2005-07-07 Sewon Cellontech Co., Ltd. Composition pour la therapeutique du cartilage et son procede d'utilisation
JP2008501763A (ja) * 2004-06-08 2008-01-24 ノバルティス アクチエンゲゼルシャフト バニロイドアンタゴニストとして有用なキナゾリノン誘導体
JP2009518338A (ja) * 2005-12-08 2009-05-07 ノバルティス アクチエンゲゼルシャフト バニロイドアンタゴニストとしての三置換キナゾリノン誘導体

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US3414573A (en) * 1962-06-27 1968-12-03 Squibb & Sons Inc Certain 3-alkylphenyl-quinazolones
GB997652A (en) * 1963-04-25 1965-07-07 Eprova Ltd New quinazolinone derivatives and process for their preparation
US3304304A (en) * 1964-03-24 1967-02-14 Philips Corp Quinazolone derivatives
US3755581A (en) * 1968-02-27 1973-08-28 Ciba Geigy Ag Combatting phytopathogenic bacteria and fungi with n phenylquinazolones
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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5656626A (en) * 1993-06-10 1997-08-12 Zeneca Limited Substituted nitrogen heterocycles
US5502048A (en) * 1993-06-10 1996-03-26 Zeneca Limited Substituted nitrogen heterocycles
US5801168A (en) * 1994-06-09 1998-09-01 Zeneca Limited Substituted nitrogen heterocycles
WO1997010221A1 (fr) * 1995-09-15 1997-03-20 Torrey Pines Institute For Molecular Studies Synthese de banques de quinazolinones
US6303615B1 (en) 1996-05-15 2001-10-16 Pfizer Inc 2,3 disubstituded-4(3H)-quinazolinones
EP0807633A2 (fr) * 1996-05-15 1997-11-19 Pfizer Inc. (5,6)-Pyrimidin-4-ones condensées à hétéroaryle, substituées en 2,3
WO1997043276A1 (fr) * 1996-05-15 1997-11-20 Pfizer Inc. Nouvelles 4(3h)-quinazolinones disubstituees en position 2,3
EP0807633A3 (fr) * 1996-05-15 1998-05-13 Pfizer Inc. (5,6)-Pyrimidin-4-ones condensées à hétéroaryle, substituées en 2,3
CN1103772C (zh) * 1996-05-15 2003-03-26 辉瑞大药厂 新的2,3－二取代－4(3h)－喹唑啉酮类化合物
AP1148A (en) * 1996-05-15 2003-02-28 Pfizer Novel 2,3 Disubstituted-4 (3H)- quinzolinones.
US5962457A (en) * 1996-05-15 1999-10-05 Pfizer Inc. 2,3 Disubstituted- (5,6)-heteroarylfused-pyrimidine-4-ones
AU730503B2 (en) * 1996-05-15 2001-03-08 Pfizer Inc. Novel 2,3 disubstituted-4(3H)-quinazolinones
WO1998038187A1 (fr) * 1997-02-28 1998-09-03 Pfizer Products Inc. Atropisomeres de 3-heteroaryl-4(3h)-quinazolinones pour le traitement des troubles neurodegeneratifs et des troubles lies a un traumatisme du systeme nerveux central
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US7960399B2 (en) * 2004-06-08 2011-06-14 Novartis Ag Quinazolinone derivatives useful as vanilloid antagonists
JP4703650B2 (ja) * 2004-06-08 2011-06-15 ノバルティス アーゲー バニロイドアンタゴニストとして有用なキナゾリノン誘導体
US8211902B2 (en) 2004-06-08 2012-07-03 Novartis Ag Quinazolinone derivatives useful as vanilloid antagonists
US8809528B2 (en) 2004-06-08 2014-08-19 Novartis Ag Quinazolinone derivatives useful as vanilloid antagonists
US9102653B2 (en) 2004-06-08 2015-08-11 Novartis Ag Substituted quinazolinones as vanilloid antagonists
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