WO2005067933A1 - 1-benzyl-5-piperazin-1-yl-3,4 dihydro-1h-quinazolin-2-one derivatives and the respective 1h-benzo(1,2,6)thiadiazine-2,2-dioxide and 1,4-dihydro-benzo(d) (1,3)oxazin-2-one derivatives as modulators of the 5-hydroxytryptamine receptor (5-ht) for the treatment of diseases of the central nervous system - Google Patents
1-benzyl-5-piperazin-1-yl-3,4 dihydro-1h-quinazolin-2-one derivatives and the respective 1h-benzo(1,2,6)thiadiazine-2,2-dioxide and 1,4-dihydro-benzo(d) (1,3)oxazin-2-one derivatives as modulators of the 5-hydroxytryptamine receptor (5-ht) for the treatment of diseases of the central nervous system Download PDFInfo
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- WO2005067933A1 WO2005067933A1 PCT/EP2005/000095 EP2005000095W WO2005067933A1 WO 2005067933 A1 WO2005067933 A1 WO 2005067933A1 EP 2005000095 W EP2005000095 W EP 2005000095W WO 2005067933 A1 WO2005067933 A1 WO 2005067933A1
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- dihydro
- benzyl
- piperazin
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- quinazolin
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- 0 C**(C)Cc1c(*(C)C)cc(C)cc1C Chemical compound C**(C)Cc1c(*(C)C)cc(C)cc1C 0.000 description 2
- QLLXWADSIGOEQZ-UHFFFAOYSA-N [O-][N+](c1c(CO)c(Br)ccc1)=O Chemical compound [O-][N+](c1c(CO)c(Br)ccc1)=O QLLXWADSIGOEQZ-UHFFFAOYSA-N 0.000 description 2
- JBJXIXKCVYWJDD-UHFFFAOYSA-N CC(C)(C)OC(N(C)Cc(c(Br)ccc1)c1N)=O Chemical compound CC(C)(C)OC(N(C)Cc(c(Br)ccc1)c1N)=O JBJXIXKCVYWJDD-UHFFFAOYSA-N 0.000 description 1
- KGBIKLOCPIWVEA-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CCN1c(c(C#N)c(CNCc1ccccc1)cc1)c1F)=O Chemical compound CC(C)(C)OC(N(CC1)CCN1c(c(C#N)c(CNCc1ccccc1)cc1)c1F)=O KGBIKLOCPIWVEA-UHFFFAOYSA-N 0.000 description 1
- SXCYZPBKFOMTJB-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CCN1c(c(CN)c(cc1)NCc2ccccc2)c1F)=O Chemical compound CC(C)(C)OC(N(CC1)CCN1c(c(CN)c(cc1)NCc2ccccc2)c1F)=O SXCYZPBKFOMTJB-UHFFFAOYSA-N 0.000 description 1
- FXOYDGBNJHLOIR-UHFFFAOYSA-N CC(C)(C)OC(N(CC1)CCN1c1cc(OC)cc(NC(c2cccc(F)c2)=O)c1C#N)=O Chemical compound CC(C)(C)OC(N(CC1)CCN1c1cc(OC)cc(NC(c2cccc(F)c2)=O)c1C#N)=O FXOYDGBNJHLOIR-UHFFFAOYSA-N 0.000 description 1
- HHWLXBAFBRSXCQ-UHFFFAOYSA-N CC(OCc(c([N+]([O-])=O)ccc1)c1Br)=O Chemical compound CC(OCc(c([N+]([O-])=O)ccc1)c1Br)=O HHWLXBAFBRSXCQ-UHFFFAOYSA-N 0.000 description 1
- YIEVTWZFLULETM-UHFFFAOYSA-N CN(CC1)CCN1c(cccc1[N+]([O-])=O)c1C#N Chemical compound CN(CC1)CCN1c(cccc1[N+]([O-])=O)c1C#N YIEVTWZFLULETM-UHFFFAOYSA-N 0.000 description 1
- CIFSQTUSLGMDLW-UHFFFAOYSA-N CN(CC1)CCN1c1c(COC(N2)=O)c2ccc1 Chemical compound CN(CC1)CCN1c1c(COC(N2)=O)c2ccc1 CIFSQTUSLGMDLW-UHFFFAOYSA-N 0.000 description 1
- SZMUQIIVLVKCCL-UHFFFAOYSA-N CN(Cc(c(Br)ccc1)c1N1)C1=O Chemical compound CN(Cc(c(Br)ccc1)c1N1)C1=O SZMUQIIVLVKCCL-UHFFFAOYSA-N 0.000 description 1
- GGBGDXRCXIFJRB-UHFFFAOYSA-N CN(Cc(c([BrH]C)ccc1)c1N1Cc2cccc(F)c2)C1=O Chemical compound CN(Cc(c([BrH]C)ccc1)c1N1Cc2cccc(F)c2)C1=O GGBGDXRCXIFJRB-UHFFFAOYSA-N 0.000 description 1
- GQVVUUVQKDEZEA-UHFFFAOYSA-N CNCc(c(N)ccc1)c1Br Chemical compound CNCc(c(N)ccc1)c1Br GQVVUUVQKDEZEA-UHFFFAOYSA-N 0.000 description 1
- XTRDKALNCIHHNI-UHFFFAOYSA-N Cc(c([N+]([O-])=O)ccc1)c1[N+]([O-])=O Chemical compound Cc(c([N+]([O-])=O)ccc1)c1[N+]([O-])=O XTRDKALNCIHHNI-UHFFFAOYSA-N 0.000 description 1
- XKHXIJYEONCWQF-UHFFFAOYSA-N Cc1cc(F)cc([N+]([O-])=O)c1Cl Chemical compound Cc1cc(F)cc([N+]([O-])=O)c1Cl XKHXIJYEONCWQF-UHFFFAOYSA-N 0.000 description 1
- SCBZBMXPJYMXRC-UHFFFAOYSA-N Fc1cc(CBr)ccc1 Chemical compound Fc1cc(CBr)ccc1 SCBZBMXPJYMXRC-UHFFFAOYSA-N 0.000 description 1
- OGWBVTDYXWQJSM-UHFFFAOYSA-N Nc1cccc(Br)c1CO Chemical compound Nc1cccc(Br)c1CO OGWBVTDYXWQJSM-UHFFFAOYSA-N 0.000 description 1
- AEZNVTOBDUUZAK-UHFFFAOYSA-N O=C(NC1)N(Cc(cccc2)c2F)c2c1c(N1CCNCC1)cc(C(F)(F)F)c2 Chemical compound O=C(NC1)N(Cc(cccc2)c2F)c2c1c(N1CCNCC1)cc(C(F)(F)F)c2 AEZNVTOBDUUZAK-UHFFFAOYSA-N 0.000 description 1
- SYVNVEGIRVXRQH-UHFFFAOYSA-N O=C(c1cc(F)ccc1)Cl Chemical compound O=C(c1cc(F)ccc1)Cl SYVNVEGIRVXRQH-UHFFFAOYSA-N 0.000 description 1
- MDOWEUXXLVBZIU-UHFFFAOYSA-N [O-][N+](c1cc(F)cc([N+]([O-])=O)c1O)=O Chemical compound [O-][N+](c1cc(F)cc([N+]([O-])=O)c1O)=O MDOWEUXXLVBZIU-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- 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
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- 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
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- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- 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
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- 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
- A61P25/24—Antidepressants
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- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/80—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
- C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/15—Six-membered rings
- C07D285/16—Thiadiazines; Hydrogenated thiadiazines
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- 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
- C07D405/06—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 linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- This invention relates to substituted quinazolinone compounds of formula I:
- the invention also relates to compositions containing the compounds of the invention, use thereof for the preparation of medicaments and methods of preparation thereof.
- 5-hydroxytryptamine (5-HT) as a major modulatory neurotransmitter in the brain are mediated through a number of receptor families termed 5-HT1, 5-HT2, 5- HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7. Based on a high level of 5-HT6 receptor mRNA in the brain, it has been stated that the 5-HT6 receptor may play a role in the pathology and treatment of central nerve system disorders.
- 5-HT2-selective and 5-HT6 selective ligands have been identified as potentially useful in the treatment of certain CNS disorders such as Parkinson's disease, Huntington's disease, anxiety, depression, manic depression, psychoses, epilepsy, obsessive compulsive disorders, mood disorders, migraine, Alzheimer's disease (enhancement of cognitive memory), sleep disorders, feeding disorders such as anorexia, bulimia and obesity, panic attacks, akathisia, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus.
- CNS disorders such as Parkinson's disease, Huntington's disease, anxiety, depression, manic depression, psychoses, epilepsy, obsessive compulsive disorders, mood disorders, migraine, Alzheimer's disease (enhancement of cognitive memory), sleep disorders, feeding disorders such as anorexia, bulimia and obesity, panic attacks
- Such compounds are also expected to be of use in the treatment of certain gastrointestinal (GI) disorders such as functional bowel disorder.
- GI gastrointestinal
- the invention further provides compositions comprising, and uses of the compounds of the invention for preparing medicaments.
- the invention provides substituted quinolinone compounds, associated compositions, methods for use as therapeutic agents, and methods of preparation thereof.
- the invention provides piperazinyl- substituted quinolinone compounds and associated pharmaceutical compositions, and methods for using the same in the treatment of central nervous system (CNS) diseases and gastrointestinal tract disorders.
- CNS central nervous system
- Alkyl means the monovalent linear or branched saturated hydrocarbon moiety, consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms.
- Lower alkyl refers to an alkyl group of one to six carbon atoms (i.e., " - C ⁇ alkyl”). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.
- Alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene, and the like.
- Alkoxy means a moiety of the formula -OR, wherein R is an alkyl moiety as defined herein. Examples of alkoxy moieties include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.
- Antagonist refers to a compound that diminishes or prevents the action of another compound or receptor site.
- Aryl means a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono-, bi- or tricyclic aromatic ring. The aryl group can be optionally substituted as defined herein.
- aryl moieties include, but are not limited to, phenyl, naph hyl, naphthalenyl, phenanthryl, fluorenyl, indenyi, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofiiranyl, benzodioxylyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like, including partially hydrogenated derivatives thereof.
- Arylene means a divalent aryl radical wherein aryl is as defined herein.
- Arylene includes, for example, ortho-, meta- and para- phenylene (1,2-phenylene, 1,3-phenylene and 1,4-phenylene respectively), which maybe optionally substituted as defined herein.
- Cycloalkyl means a saturated carbocyclic moiety consisting of mono- orbicyelic rings. Cycloalkyl can optionally be substituted with one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino, unless otherwise specifically indicated. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including partially unsaturated derivatives thereof such as cyclohexenyl, cyclopentenyl, and the like.
- Cycloalkylalkyi means a moiety of the formula -R'-R", where R' is alkylene and R" is cycloalkyl as defined herein.
- Heteroalkyl means an alkyl radical as defined herein wherein one, two or three hydrogen atoms have been replaced with a substituent independently selected from the group consisting of -OR , -NR b R c , and -S(O) n R d (where n is an integer from 0 to 2), with the understanding that the point of attachment of the heteroalkyl radical is through a carbon atom, wherein R a is hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyi; R b and R c are independently of each other hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyi; and when n is 0, R d is hydrogen, alkyl, cycloalkyl, or cyclo
- Representative examples include, but are not limited to, 2-hydroxyethyl, 3- hydroxypropyl, 2-hydroxy-l-hydroxymethylethyl, 2,3-dihydroxypropyl, 1- hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxy-l-methylpropyl, 2- aminoethyl, 3-aminopropyl, 2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl, methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.
- Heteroaryl means a monocyclic or bicyclic monovalent radical of 5 to 12 ring atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C, with the understanding that the attachment point of the heteroaryl radical will be on an aromatic ring.
- the heteroaryl ring may be optionally substituted as defined herein.
- heteroaryl moieties include, but are not limited to, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyridinyl, pyridazyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzooxazolyl, benzooxadiazolyl, benzofhiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxaliny
- Heteroarylene means a divalent heteroaryl radical wherein heteroaryl is as defined herein. "Heteroarylene” maybe optionally substituted as defined herein. "Heteroarylene” includes, for example, indolylene, pyrimidinylene, and the like.
- halo and halogen, which may be used interchangeably, refer to a substituent fluoro, chloro, bromo, or iodo.
- Haloalkyi means alkyl as defined herein in which one or more hydrogen has been replaced with same or different halogen.
- haloalkyls include -CH 2 C1, -CH 2 CF 3 , -CH 2 CC1 3 , perfluoroalkyl (e.g., -CF 3 ), and the like.
- Heterocycloamino means a saturated ring wherein at least one ring atom is N, NH or N-alkyl and the remaining ring atoms form an alkylene group.
- Heterocyclyl means a monovalent saturated moiety, consisting of one to three rings, incorporating one, two, or three or four heteroatoms (chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring may be optionally substituted as defined herein.
- heterocyclyl moieties include, but are not limited to, piperidinyl, piperazinyl, homopiperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, hiazolidinyl, isothiazolidinyl, quinuclidinyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolylidinyl, benzothiazohdinyl, benzoazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, thiamorpholinyl, fhiamorpholinylsulfoxide, thiamorpholin
- phenylene means an aryl, arylene, phenyl, phenylene, heteroaryl, heteroarylene, or heterocyclyl which is optionally substituted independently with one to four substituents, preferably one or two substituents selected from alkyl, cycloalkyl, cycloalkylalkyi, heteroalkyl, hydroxyalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino, haloalkyi, haloalkoxy, heteroalkyl, -COR (where R is hydrogen, alkyl, phenyl or phenylalkyl), - (CR'R") n -COOR (where n is an integer from 0 to 5, R' and R" are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl
- leaving group means the group with the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under substitution reaction conditions.
- Examples of leaving groups include, but are not limited to, halogen, alkane- or arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy, dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, acyloxy, and the like.
- “Modulator” means a molecule that interacts with a target.
- the interactions include, but are not limited to, agonist, antagonist, and the like, as defined herein.
- “Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
- Disease state means any disease, condition, symptom, or indication.
- Inert organic solvent or “inert solvent” means the solvent is inert under the conditions of the reaction being described in conjunction therewith, including for example, benzene, toluene, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert- butanol, dioxane, pyridine, and the like.
- the solvents used in the reactions of the present invention are inert solvents.
- “Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
- “Pharmaceutically acceptable salts” of a compound means salts that are pharmaceutically acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound.
- Such salts include: acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic, camphorsulfonic acid, citric acid, ethanesulfonic acid, furnaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphtoic acid, 2- hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like; or salts formed when an acidic proton present in the parent compound either is
- Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like.
- Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
- the preferred pharmaceutically acceptable salts are the salts formed from acetic acid, hydrochloric acid, sulphuric acid, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc, and magnesium. It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (poiymorphs) as defined herein, of the same acid addition salt.
- pro-drug and “prodrug”, which may be used interchangeably herein, refer to any compound which releases an active parent drug according to formula I in vivo when such prodrug is administered to a mammalian subject.
- Prodrugs of a compound of formula I are prepared by modifying one or more functional group(s) present in the compound of formula I in such a way that the modification(s) maybe cleaved in vivo to release the parent compound.
- Prodrugs include compounds of formula I wherein a hydroxy, amino, or sulfhydryl group in a compound of Formula I is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively.
- prodrugs include, but are not limited to, esters (e.g., acetate, formate, andbenzoate derivatives), carbamates (e.g., N,N- dimethylaminocarbonyl) of hydroxy functional groups in compounds of formula I, N- acyl derivatives (e.g. N-acetyl) N-Mannich bases, Schiff bases and enaminones of amino functional groups, oximes, acetals, ketals and enol esters of ketone and aldehyde functional groups in compounds of Formula I, and the like, see Bundegaard, H. "Design of Prodrugs" pl-92, Elesevier, New York-Oxford (1985), and the like.
- esters e.g., acetate, formate, andbenzoate derivatives
- carbamates e.g., N,N- dimethylaminocarbonyl
- N- acyl derivatives e.g. N-acetyl
- Protecting group means the group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Certain processes of this invention rely upon the protective groups to block reactive nitrogen and/or oxygen atoms present in the reactants.
- the terms "amino-protecting group” and “nitrogen protecting group” are used interchangeably herein and refer to those organic groups intended to protect the nitrogen atom against undesirable reactions during synthetic procedures.
- Exemplary nitrogen protecting groups include, but are not limited to, trifiuoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl (carbobenzyloxy, CBZ), p- mefhoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like.
- Bn benzyloxycarbonyl
- CBZ benzyloxycarbonyl
- p- mefhoxybenzyloxycarbonyl p-nitrobenzyloxycarbonyl
- tert-butoxycarbonyl BOC
- Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H 2 O, such combination being able to form one or more hydrate. "Subject" means mammals and non-mammals.
- Mammals means any member of the mammalia class including, but not limited to, humans; non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, and the like.
- the term "subject” does not denote a particular age or sex.
- “Therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state.
- the "therapeutically effective amount” will vary depending on the compound, disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgment of the attending medical or veterinary practitioner, and other factors.
- the terms "those defined above” and “those defined herein” when referring to a variable incorporates by reference the broad definition of the variable as well as preferred, more preferred and most preferred definitions, if any.
- Treating" or “treatment” of a disease state includes: (i) preventing the disease state, i.e.
- treating when referring to a chemical reaction means adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or the desired product.
- reaction which produces the indicated and/or the desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or the desired product.
- Chemical structures shown herein were prepared using ISIS version 2.2. Any open valency appearing on a carbon, oxygen or nitrogen atom in the structures herein indicates the presence of a hydrogen.
- the invention provides compounds of the formula I:
- X, Y, Z, A, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , m, n, and p are as defined herein.
- n may be 1.
- Z may be -(CR a R b ) r - , and R a and R b in such embodiments are. preferably hydrogen.
- X is N and q is 2 and, in certain instances, r is 1.
- X is joined to the 5-position of the quinazolinone ring system.
- R 2 is optionally substituted phenyl or optionally substituted naphthyl.
- Preferred R 2 in such embodiments include phenyl, 2-halophenyl, 3-halophenyl, 4-halophenyl, 2-cyanophenyl, 3-cyanophenyl, 4- cyanophenyl, 2-mefhoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dihalophenyl, 2,4-dihalophenyl, 2,5-dihalophenyl, 2,6-dihalophenyl, 3,4-dihalophenyl, 3,5- dihalophenyl, 2-methylphenyl, 3-mefhylphenyl, and 2,2-dimethyl-2,3-dihydro- benzofuranyl, wherein each halo is independently fluoro or chloro.
- R 2 may be heteroaryl optionally substituted by one or more trifluoromefhlyl, halo, cyano, -C 6 alkyl or Ci-C 6 alkoxy.
- p is 0 or 1 and R 1 is halo, alky, haloalkyi, or alkoxy.
- R 1 is fluoro, chloro, methyl, ethyl, trifluorometyl, or methoxy.
- A is -NR 3 -.
- R 4 and R 5 are hydrogen.
- R 3 may hydrogen in such embodiments, or R 3 may be alkyl.
- R 6 , R 7 , R 8 and R 9 are hydrogen.
- A is -O-. 27.
- Y is C and m is 1.
- R 2 ma be optionally substituted phenyl or optionally substituted naphthyl.
- Preferred R 2 in such embodiments include phenyl, 2-halophenyl, 3-halophenyl, 4- halophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 2,3-dihalophenyl, 2,4-dihalophenyl, 2,5- dihalophenyl, 2,6-dihalophenyl, 3,4-dihalophenyl, 3,5-dihalophenyl, 2-methylphenyl, 3- methylphenyl, and 2,2-dimefhyl-2,3-dihydro-benzofuranyl, wherein each halo is independently fluoro or chloro.
- Y is C and m is 1
- R 1 is halo, alkyl, haloalkyi or alkoxy.
- R 4 and R 5 may be hydrogen.
- A is -NR 3 -
- R 3 may be hydrogen, or R 3 may be alkyl.
- R 6 , R 7 , R 8 and R 9 are preferably hydrogen.
- Y is S and m is 2.
- A is -O-, while in other embodiments A is -NR 3 -.
- R 2 may, in such embodiments, be optionally substituted phenyl or optionally substituted naphthyl.
- Preferred R 2 include phenyl, 2-halophenyl, 3-halophenyl, 4-halophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dihalophenyl, 2,4-dihalophenyl, 2,5-dihalophenyl, 2,6-dihalophenyl, 3,4- dihalophenyl, 3,5-dihalophenyl, 2-methylphenyl, 3-methylphenyl, or 2,2-dimethyl-2,3- dihydro-benzofuranyl, wherein each halo is independently fluoro or chloro.
- R 4 and R 5 maybe hydrogen.
- R 6 , R 7 , R 8 and R 9 may also be hydrogen.
- R 3 in some embodiments may be hydrogen, while in other embodiments R 3 may be alkyl.
- the subject compounds maybe more specifically of the formula III:
- each R 11 independently is alkyl, alkoxy, halo, cyano or haloalkyi; and X, Y, A, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R a , R b , m, n, p and r are as defined herein.
- formula III wherein X is N and is attached at the 5-position of the quinazolinone ring system, the subject compounds may be represented by the formula IV:
- Y, A, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R u , R a , R b , m, n, p, r and s are as defined herein.
- n maybe 1.
- R and R are preferably hydrogen.
- r is 1.
- R 4 and R 5 are hydrogen.
- s is 0, 1 or 2
- R 11 is halo, alkyl, haloalkyi or alkoxy.
- R ⁇ is fluoro, chloro, methyl, trifluoromethyl or methoxy.
- p is 0 or 1 and R 1 is halo, alkyl, haloalkyi or alkoxy.
- R 1 is fluoro, chloro, methyl, ethyl, trifluoromethyl, or methoxy.
- A is -NR 3 -.
- R 4 and R 5 are hydrogen.
- R 3 may hydrogen in such embodiments, or R 3 may be alkyl.
- R 6 , R 7 , R 8 and R 9 are hydrogen.
- A is -O-.
- Y is S and m is 2.
- A is -O-, while in other embodiments A is -NR 3 -.
- the variable s is 0, 1 or 2 in many such embodiments, and R ⁇ is halo, alkyl, haloalkyi or alkoxy.
- R 11 is fluoro, chloro, methyl, trifluoromethyl or methoxy.
- p is preferably 0 or 1
- R 1 is halo, methyl or methoxy.
- R 4 and R 5 may be hydrogen.
- R 6 , R 7 , R 8 and R 9 may also be hydrogen.
- R 3 in some embodiments may be hydrogen, while in other embodiments R 3 may be alkyl.
- s is preferably 0, 1 or 2
- R 11 is halo, alkyl, haloalkyi or alkoxy.
- R 11 is fluoro, chloro, methyl, trifluoromethyl or methoxy.
- the subject compounds may be more specifically of the formula V:
- R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 9 , R 10 , R n , p and s are as defined herein.
- R ⁇ is halo, alkyl, haloalkyi or alkoxy.
- R 11 is fluoro, chloro, methyl, trifluoromethyl or methoxy.
- p is 0 or 1 and R 1 is halo, alkyl, haloalkyi or alkoxy.
- R 1 is fluoro, chloro, methyl, ethyl, trifluoromethyl, or methoxy.
- R 4 and R 5 are hydrogen.
- R 3 may hydrogen in such embodiments, or R 3 ma be alkyl In certain embodiments R 3 ma be acetamidyl.
- R ⁇ , R 7 , R 8 and R 9 are hydrogen.
- the subject compounds maybe more specifically of the formula VI:
- R 1 , R 2 , R 3 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , p and s are as defined herein.
- s is 0, 1 or 2
- R ⁇ is halo, alkyl, haloalkyi or alkoxy.
- R u is fluoro, chloro, methyl, trifluoromethyl or methoxy.
- p is 0 or 1 and R 1 is halo, alkyl, haloalkyi or alkoxy.
- R 1 is fluoro, chloro, methyl, ethyl, trifluoromethyl, or methoxy.
- R 4 and R 5 are hydrogen.
- R 6 , R 7 , R 8 and R 9 are hydrogen.
- any of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R a , R , R c and R are alkyl or an alkyl moiety, such alkyl is preferably are lower alkyl, i.e. C Cealkyl, and more preferably C ⁇ -C alkyl.
- Y is S
- A is preferabl -NR 3 -.
- Another aspect of the invention provides a composition comprising a therapeutically effective amount of at least one compound of formula (I) and a pharmaceutically acceptable carrier.
- Yet another aspect of the invention provides a method for treating a central nervous system (CNS) disease state in a subject comprising administering to the subject a therapeutically effective amount of a compound of formula I.
- the disease state may comprise, for example, psychoses, schizophrenia, manic depressions, neurological disorders, memory disorders, attention deficit disorder, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease or Huntington's disease.
- Still another aspect of the present invention provides a method for treating a disorder of the gastrointestinal tract in a subject comprising administering to the subject a therapeutically effective amount of a compound of formula (I).
- Another aspect of the present invention provides a method for producing a compound of formula (I).
- Compounds of the present invention can be made by a variety of methods depicted in the illustrative synthetic reaction schemes shown and described below.
- the starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions, Wiley & Sons: New York, 1991, Volumes 1-40.
- the following synthetic reaction schemes are merely illustrative of some methods by which the compounds of the present invention can be synthesized, and various modifications to these synthetic reaction schemes can be made and will be suggested to one skilled in the art having referred to the disclosure contained in this Application.
- the starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.
- reaction described herein preferably are conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about -78 °C to about 150 °C, more preferably from about 0 °C to about 125 °C, and most preferably and conveniently at about room (or ambient) temperature, e.g., about 20 °C.
- Scheme A illustrates one synthetic procedure usable to prepare compounds of the invention, wherein p, q, R 1 , R 2 , R 6 , R 7 , R 8 , R 9 , and R 10 are as defined herein.
- Numerous synthetic routes to quinazolinones and corresponding sulfonamides are known and maybe used in preparation of the subject compounds, and the procedure of Scheme A is only exemplary. Specific examples of the procedure of Scheme A are provided in the following Experimental section.
- step 1 of Scheme A dinitrobenzonitrile a is reacted with a heterocyclic amine b to afford an amino nitrobenzonitrile c.
- This reaction may be effected by heating under polar aprotic solvent conditions.
- a BOC or other removable protecting group may be used to protect the nitrogen bound to R 10
- the amino nitrobenzonitrile c produced in step 1 is selectively reduced in step 2 to provide an aniline compound d.
- the reduction of step 2 may be carried out, for example, using hydrogen in the presence of palladium on activated carbon under mild pressure and ethanolic solvent conditions.
- an aryl (or heteroaryl) amide compound f is obtained by reaction of the aniline d of step 2 with an aryl (or heteroaryl) acid halide e.
- the reaction of step 3 may be achieved in a polar aprotic solvent such as tetrahydrofuran in the presence of triethylamine or other amine.
- aryl amide f is subject to a second, more rigorous reduction to convert the carbonyl group of compound f to a methylene, convert the nitrile group of compound f to an amine, and thus provide the benzylamine compound g.
- step 4 may by carried out, for example, using boron hydride or like reducing agent under dry polar aprotic solvent conditions.
- step 5 the benzylamine g_of step 4 is reacted with phosgene to provide the cyclic urea or quinazolinone compound h in accordance with the invention.
- the quinazolinone h is a compound of formula (I) wherein Y is carbon, X is nitrogen, Z is -(CR a R b ) r - m, n and r are 1, and R 3 , R 4 , R 5 , R a and R b are hydrogen.
- step 6 may instead be carried out wherein benzylamine compound g is treated with sulfarnide or sulfuryl chloride to form the sulfonamide compound i,
- Sulfonamide i is a compound of formula (I) wherein Y is sulfur, X is nitrogen, Z is -(CR a R b ) r - m is 2, n is 1, r is 1, and R 3 , R 4 , R 5 , R a and R b are hydrogen.
- selective N-alkylation may be carried out using well-known techniques following step 4 or step 5 to introduce a desired R 3 substituent of formula (I) other than hydrogen.
- Selective alkylation of the benzylic carbon of compound i may also be carried out using well-known techniques to introduce an R 4 and/or R 5 substituent.
- Phenylacetyl halides or phenylpropionyl halides may alternatively be used as the aryl halide e to provide compounds of formula (I) wherein r is 2 or three, and wherein one or more of R a and R b may be alkyl.
- an aryl (or heteroaryl) sulfonyl halide ay be used in place acid halide e to provide compounds of formula (I) wherein Z is -SO 2 -.
- heterocyclic amine b may be a piperazine of the formula ⁇ .
- step 1 of Scheme B bromonitrobenzyl bromide compound k is reacted with protected amine 1 to yield a protected nitrobenzylamine m.
- This reaction may be effected in the presence of sodium hydride or other metal hydride under dry polar aprotic solvent conditions.
- Compound k may be prepared by treatment of the corresponding toluene with N-bromosuccinamide in the presence of benzoyl peroxide to afford the benzyl bromine.
- the protected nitrobenzylamine m thus produced is reduced in step 2 to afford aniline compound n.
- the reduction of step 2 maybe achieved using Raney nickel and hydrazine under polar protic solvent conditions.
- step 3 the benzylic amine functionality of aniline compound n is deprotected by removal of the Boc group in order to provide aminobenzylamine o. Boc removal in this step may utilize hydrochloric acid in ethanolic solvent.
- the deprotected aminobenzylamine o may then undergo reaction with phosgene in step 4 to afford the cyclic urea or quinazolinone compound p_. This reaction may be effected in polar aprotic solvent using triphosgen or other phosgene source.
- Step 5 an N-alkylation of the cyclic urea compound p_ is carried out by treatment of compound p_ with a strong base under dry, polar aprotic conditions, followed by reaction with an ⁇ -haloalkyl aryl compound g to provide the N-arylalkyl- quinazolinone compound r.
- other ⁇ -haloalkylphenyl halides according to the desired R a and R b substituent configuration.
- Compound q may also be heteroaryl in nature, such as a haloalkyi pyridine, haloalkyi thiene, haloalkyi furan, haloalkyi quinoline, or the like.
- step 6 a cross-coupling amination reaction is carried out wherein heterocyclic amine b displaces the bromine group of compound r to yield quinazolinone compound s. This reaction is facilitated in the presence of palladium catalyst and non-polar solvent conditions.
- the quinazolinone s is a compound of formula (I) wherein Y is carbon, X is nitrogen, Z is -(CR a R ) r , m and n are 1, and R 4 and R 5 are hydrogen.
- step 7 may be carried out wherein aminobenzylamine compound o is treated with sulfamide or sulfuryl chloride to form the sulfonamide compound t.
- Sulfonamide t may then undergo N-alkylation in step 8 by treatment with strong base followed by reaction with an ⁇ -haloalkyl aryl (or heteroaryl) compound q, in the manner described above for step 5, to provide the N-arylalkyl-sulfonamide compound u.
- Sulfonamide v is a compound of formula (I) wherein Y is sulfur, X is nitrogen, Z is - (CR R b ) -, m is 2, n is 1, and R 4 and R 5 are hydrogen.
- Y is sulfur
- X is nitrogen
- Z is - (CR R b ) -
- m is 2
- n is 1, and R 4 and R 5 are hydrogen.
- the benzylic bromine of compound k in step 1 may be replaced by other leaving group
- the Boc group may be replaced by other removable protecting group.
- the cross-coupling amination of steps 6 and 9 is shown in Scheme B as being carried out at the 5-position of the quinazolinone system, where a bromine leaving group is provided by compounds u and r.
- heterocyclic amine b may also be introduced at the 6-, 7- or 8- position of the quinazoline ring system.
- the cross-coupling amination reaction used in steps 6 and 9 of Scheme B is described in An Improved Catalyst System For Aromatic Carbon-Nitrogen Bond Formation: The Possible Involvement Of Bis(Phosphine) Palladium Complexes As Key Intermediates. Wolfe et al., J. Am. Chem. Soc. (1996), 118(30), 7215-7216.
- the heterocyclic amine b used in Scheme B may be a piperazine of the formula j . .
- step 1 of Scheme C quinazolinone w is treated with an alkyllithium reagent such n-butyl lithium under anhydrous polar aprotic conditions and dry ice/acetone temperature, to generate a lithiated intermediate (not shown) wherein the bromine group is replaced by lithium.
- This lithiated intermediate is then directly reacted in-situ with heterocyclic ketone x to effect an alkylation and provide a heterocyclyl-substituted quinazolinone y . .
- Step 2 the heterocyclyl-substituted quinazolinone y_ is dehydrated by treatment with mild acid to yield the compound z wherein the heterocyclyl moiety is partially unsaturated. In certain embodiments this dehydration may occur spontaneously, making step 2 unnecessary.
- compound z_of Step 3 is hydrogenated to provide quinazolinone compound aa. This reaction may be achieved via hydrogenation using a platinum or palladium catalyst under mild ethanolic conditions.
- the quinazolinone aa is a compound of formula (I) wherein X is carbon, Z is -(CR a R b ) r , m and n are 1, and R 4 and R are hydrogen.
- Scheme D wherein p, q, R 1 , R 2 , R 6 , R 7 , R 8 , R 9 , R 10 R a and R b are as defined herein.
- bromonitrobenzyl bromide compound k is converted to nitrobenzyl ester compound bb by treatment with potassium acetate or other alkyl acetate salt under polar solvent conditions.
- Compound k may be prepared by treatment of the corresponding toluene with N-bromosuccinamide in the presence of benzoyl peroxide.
- bromonitrobenzyl ester bb is hydrolyzed to afford bromonitrobenzyl alcohol cc. This hydrolysis may be carried out by treatment with KOH or like base under aqueous conditions.
- the bromonitrobenzyl alcohol cc may then be reduced in step 3 to yield bromoamino benzyl alcohol dd.
- step 4 benzoxazinone compound ee is made by reaction of bromoamino benzyl alcohol dd with phosgene. This cyclization may be carried out under dry polar aprotic conditions.
- step 5 a cross-coupling amination reaction is carried out wherein heterocyclic amine b displaces the bromine group of compound ee to yield a heterocyclyl-substituted benzoxazinone ff. This reaction ma be performed in the presence of palladium catalyst under non-polar solvent conditions.
- Step 6 an N-alkylation of the heterocyclyl-substituted benzoxazinone ff is carried out by treatment of compound ff with a strong base under dry, polar aprotic conditions, followed by reaction with an ⁇ -haloalkyl aryl compound q to provide the N- arylalkyl benzoxazinone compound gg.
- a variety of haloalkyi compounds q may be used in this step as described above in Scheme B.
- Compound gg is a compound of formula (I) wherein A is O, X is N, Y is C, and m is 1. Many variations on the procedure of Scheme D are possible.
- benzoxazinone compound ee may be treated with cyclic ketone x in the manner described in Scheme C.
- the resulting alkylation product can then be dehydrated and reduced as shown in Scheme C to afford a compound of formula (I) wherein X is CH and A is O. More specific details for producing compounds of formula (I) are described in the
- the compounds of the invention have selective affinity for 5-HT receptors, including the 5-HT 6 the 5-HT 2 A receptor, or both, and as such are expected to be useful in the treatment of certain CNS disorders such as Parkinson's disease, Huntington's disease, anxiety, depression, manic depression, psychosis, epilepsy, obsessive compulsive disorders, mood disorders, migraine, Alzheimer's disease (enhancement of cognitive memory), sleep disorders, feeding disorders such as anorexia, bulimia, and obesity, panic attacks, akathisia, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus.
- CNS disorders such as Parkinson's disease, Huntington's disease, anxiety, depression, manic depression, psychosis, epilepsy, obsessive compulsive disorders, mood disorders, migraine, Alzheimer's disease (enhancement of cognitive memory), sleep disorders,
- Such compounds are also expected to be of use in the treatment of certain GI (gastrointestinal) disorders such functional bowel disorder and irritable bowel syndrome.
- GI gastrointestinal
- the pharmacology of the compounds of this invention was determined by art recognized procedures. The in vitro techniques for determining the affinities of test compounds at the 5-HT 6 receptor and the 5-HT 2A receptor in radioligand binding, FLIPR and functional assays are described below.
- the present invention includes pharmaceutical compositions comprising at least one compound of the present invention, or an individual isomer, racemic or non- racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof, together with at least one pharmaceutically acceptable carrier, and optionally other therapeutic and/or prophylactic ingredients.
- the compounds of the present invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable dosage ranges are typically 1-500 mg daily, preferably 1-100 mg daily, and most preferably 1-30 mg daily, depending upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved.
- One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this Application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease.
- compounds of the present invention will be administered as pharmaceutical formulations including those suitable for oral (including buccal and sublingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
- the preferred manner of administration is generally oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
- a compound or compounds of the present invention, together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages.
- the pharmaceutical compositions and unit dosage forms maybe comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
- the pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use.
- Formulations containing about one (1) milligram of active ingredient or, more broadly, about 0.01 to about one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
- the compounds of the present invention may be formulated in a wide variety of oral administration dosage forms.
- the pharmaceutical compositions and dosage forms may comprise a compound or compounds of the present invention or pharmaceutically acceptable salts thereof as the active component.
- the pharmaceutically acceptable carriers may be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
- a solid carrier may be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
- the carrier In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component.
- the active component In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
- the powders and tablets preferably contain from about one (1) to about seventy (70) percent of the active compound.
- Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
- the term "preparation” is intended to include the formulation of the active compound with encapsulating material as carrier, providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it.
- cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges may be as solid forms suitable for oral administration.
- liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations.
- Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia.
- Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents.
- Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
- Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
- the compounds of the present invention maybe formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-fifled syringes, small volume infusion or in multi-dose containers with an added preservative.
- the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol.
- oily or nonaqueous carriers, diluents, solvents or vehicles examples include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents.
- the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
- the compounds of the present invention maybe formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch.
- Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
- Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
- Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanfh; pastilles comprising the active ingredient in an inert base such as gelatine and glycerine or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
- the compounds of the present invention maybe formulated for administration as suppositories.
- a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.
- the compounds of the present invention maybe formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
- the compounds of the present invention may be formulated for nasal administration.
- the solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray.
- the formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
- the compounds of the present invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration.
- the compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
- the active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas.
- CFC chlorofluorocarbon
- the aerosol may conveniently also contain a surfactant such as lecithin.
- the dose of drug may be controlled by a metered valve.
- the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PNP).
- the powder carrier will form a gel in the nasal cavity.
- the powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatine or blister packs from which the powder maybe administered by means of an inhaler.
- formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
- the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices.
- transdermal delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is crucial.
- Compounds in transdermal delivery systems are frequently attached to an skin- adhesive solid support.
- the compound of interest can also be combined with a penetration enhancer, e.g., Azone (l-dodecylazacycloheptan-2-one).
- Azone l-dodecylazacycloheptan-2-one
- Sustained release delivery systems are inserted subcutaneously into the subdermal layer by surgery or injection.
- the subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polylactic acid.
- the pharmaceutical preparations are preferably in unit dosage forms.
- the preparation is subdivided into unit doses containing appropriate quantities of the active component.
- the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
- the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
- Other suitable pharmaceutical carriers and their formulations are described in
- 1-BOC-piperizine (piperazine- 1 -carboxylic acid tert-butyl ester, 20.0 g, 107.4 mmol) was added to a solution of 2,6-dinitrobenzonitrile (10.27 7 g, 53.2 mmol) in dry DMF (200 ml). After stirring at 50 °C overnight, the reaction mixture was cooled to room temperature and poured into a mixture of water/ethyl acetate. The organic fraction was washed with water and brine.
- 4-(2-Cyano-3-nitro-phenyl)-piperazine-l-carboxylic acid tert-butyl ester (12.172 g, 36.6 mmol) from step 1 was dissolved in ethanol (300 ml) in a Parr flask. The flask was flushed with N 2 , and Pd/C (1.3g) was added. The solution was treated with H 2 on a Parr apparatus at 30 psi overnight. The mixture was filtered through celite, then washed with EtOAc. After concentration, the residue was purified by flash chromatography to give 4- (3-amino-2-cyano-phenyl)-piperazine-l-carboxylic acid tert-butyl ester.
- Example 3 (2.615 g, 12.2 mmol) in pyridine (50 ml) was added sulfamide (3.5 g, 36.4 mmol). The solution was heated under reflux overnight, and the cooled reaction mixture was partitioned between 2N HCl water solution and ethyl acetate. The organic layer was washed with 2N HCl solution, water, brine. After drying over MgSO , the organic fraction was concentrated in vacuo and resulting brown residue was purified by flash chromatography to give 5-bromo-3-methyl-3,4-dihydro-lH-benzo[l,2,6]thiadiazine 2,2- dioxide as a white solid. (2.32g, 69%) MS: (M+H) + 277.1. Step 2 l-Benzyl-5-bromo-3-methyl-3,4-dihydro-lH-benzo[l,2,6]thiadiazine 2,2-dioxide
- step 5 of Example 3 The benzylation procedure of step 5 of Example 3 was used to afford l-Benzyl-5- bromo-3-methyl-3,4-dihydro- IH-benzo [1,2,6] thiadiazine 2,2-dioxide. MS: 367.0 (M+H) + . Step 3 1 -Benzyl-3-methyl-5-piperazin- 1 -yl-3,4-dihydro- IH-benzo [ 1 ,2,6] thiadiazine 2,2-dioxide
- Step 2 4-(3-Benzylamino-2-cyano-6-fluoro-phenyl -piperazine-l-carboxylic acid tert-butyl ester
- Example 7 l-(3-Fluoro-benzyl)-7-me ⁇ hoxy-5-piperazin-l-yl-3,4-dihydro-lH-quinazolin-2-one
- the synthetic procedures described in this Example were carried out according to the process shown in Scheme J.
- Step 2 4-Fluoro-2,6-dinitrobenzonitrile
- 2-chloro-5-fluoro-l,3-dinitro-benzene dissolved in 20 mL dimethylformamide was added 2.63 g (1.2 eq., 29.27 mmol) copper cyanide.
- the mixture was stirred at 140°C for 2 hours, cooled and partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated under reduced pressure.
- the ingredients are mixed and dispensed into capsules containing about 100 mg each; one capsule would approximate a total daily dosage.
- the ingredients are combined and granulated using a solvent such as methanol.
- the formulation is then dried and formed into tablets (containing about 20 mg of active compound) with an appropriate tablet machine.
- the ingredients are mixed to form a suspension for oral administration.
- the active ingredient is dissolved in a portion of the water for injection. A sufficient quantity of sodium chloride is then added with stirring to make the solution isotonic. The solution is made up to weight with the remainder of the water for injection, filtered through a 0.2 micron membrane filter and packaged under sterile conditions.
- Topical Formulation The ingredients are melted together and mixed on a steam bath, and poured into molds containing 2.5 g total weight.
- Nasal Spray Formulations Several aqueous suspensions containing from about 0.025-0.5 percent active compound are prepared as nasal spray formulations.
- the formulations optionally contain inactive ingredients such as, for example, microcrystalline cellulose, sodium carboxymethylcellulose, dextrose, and the like. Hydrochloric acid may be added to adjust pH.
- the nasal spray formulations may be delivered via a nasal spray metered pump typically delivering about 50-100 microliters of formulation per actuation. A typical dosing schedule is 2-4 sprays every 4-12 hours.
- Example 9 Radioligand binding studies This example illustrates in vitro radioligand binding studies of compound of formula I.
- the binding activity of compounds of this invention in vitro was determined as follows. Duplicate determinations of 5-HT 6 ligand affinity were made by competing for binding of [ 3 H]LSD in cell membranes derived from HEK293 cells stably expressing recombinant human 5-HT 6 receptor.
- Duplicate determinations of 5-HT 2 A ligand affinity were made by competing for binding of [ 3 H]Ketanserin (3-(2-(4-(4- fluorobenzoyl)piperidinol)efhyl)-2,4(lH,3H)-quinazolinedione) in cell membranes derived from CHO-Kl cells stably expressing recombinant human 5-HT 2A receptor.
- Membranes were prepared from HEK 293 cell lines by the method described by Monsma et al., Molecular Pharmacology, Nol.43 pp. 320-327 (1993), and from CHO-Kl cell lines as described by Bonhaus et al, Br J Pharmacol. Jun;115(4):622-8 (1995).
- affinity at the 5-HT 6 receptor all determinations were made in assay buffer containing 50 mM Tris-HCI, 10 mM MgSO , 0.5 mM EDTA, 1 mM ascorbic acid, pH 7.4 at 37 °C, in a 250 microliter reaction volume.
- affinity at the 5-HT 2A receptor all determinations were made in assay buffer containing 50 mM
- Tris-HCI 5 mM ascorbic acid, 4 mM CaCl2, pH 7.4 at 32 °C, in a 250 microliter reaction volume.
- Assay tubes containing [ 3 H] LSD or [ 3 H]Ketanserin (5 nM), competing ligand, and membrane were incubated in a shaking water bath for 75 min. at 37 °C (for 5-HT 6 ) or 60 min. at 32°C (for 5-HT 2A ), filtered onto Packard GF-B plates (pre-soaked with 0.3% PEI) using a Packard 96 well cell harvester and washed 3 times in ice cold 50 mM Tris-HCI.
- Example 10 Cognition Enhancement The cognition-enhancing properties of compounds of the invention maybe in a model of animal cognition: the object recognition task model.
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Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP05700747A EP1708713B1 (en) | 2004-01-16 | 2005-01-07 | 1-benzyl-5-piperazin-1-yl-3,4 dihydro-1h-quinazolin-2-one derivatives and the respective 1h-benzo(1,2,6)thiadiazine-2,2-dioxide and 1,4-dihydro-benzo(d)(1,3)oxazin-2-one derivatives as modulators of the 5-hydroxytryptamine receptor (5-ht) for the treatment of diseases of the central nervous system |
CN2005800026123A CN1909909B (en) | 2004-01-16 | 2005-01-07 | 1-benzyl-5-piperazin-1-yl-3,4-dihydro-1H- quinazolin-2-one derivatives and the respective 1H-benzo(1,2,6)thiadiazine-2,2-dioxide and 1,4-dihydro-benzene as modulators of the 5-hydroxytryptamine recept |
JP2006548231A JP4533391B2 (en) | 2004-01-16 | 2005-01-07 | 1-Benzyl-5-piperazin-1-yl-3,4-dihydro-1H-quinazolin-2-one derivatives as modulators of 5-hydroxytryptamine receptor (5-HT) for the treatment of central nervous system diseases And the respective 1H-benzo (1,2,6) thiadiazin-2,2-dioxide and 1,4-dihydrobenzo (D) (1,3) oxazin-2-one derivatives |
DE602005005298T DE602005005298T2 (en) | 2004-01-16 | 2005-01-07 | 1-BENZYL-5-PIPERAZINE-1-YL-3,4-DIHYDRO-1H-CHINAZOLIN-2-ON DERIVATIVES AND THE EFFECTIVE 1H-BENZO (1,2,6) THIADIAZIN-2,2-DIOXIDE AND 1,4 -DIHYDRO-BENZO (D) (1,3) OXAZIN-2-ON DERIVATIVES AS 5-HYDROXYTRYPTAMINE RECEPTOR (5-HT) MODULATORS FOR THE TREATMENT OF DISEASES OF THE CENTRAL NERVOUS SYSTEM |
CA002552681A CA2552681A1 (en) | 2004-01-16 | 2005-01-07 | 1-benzyl-5-piperazin-1-yl-3,4 dihydro-1h-quinazolin-2-one derivatives and the respective 1h-benzo(1,2,6)thiadiazine-2,2-dioxide and 1,4-dihydro-benzo(d) (1,3)oxazin-2-one derivatives as modulators of the 5-hydroxytryptamine receptor (5-ht) for the treatment of diseases of the central nervous system |
AU2005205016A AU2005205016B2 (en) | 2004-01-16 | 2005-01-07 | 1-benzyl-5-piperazin-1-yl-3,4 dihydro-1H-quinazolin-2-one derivatives and the respective 1H-benzo(1,2,6)thiadiazine-2,2-dioxide and 1,4-dihydro-benzo(D) (1,3)oxazin-2-one derivatives as modulators of the 5-hydroxytryptamine receptor (5-HT) for the treatment of diseases of the central nervous system |
BRPI0506909-2A BRPI0506909A (en) | 2004-01-16 | 2005-01-07 | 1-benzyl-5piperazin-1-yl-3,4-dihydro-1h-quinazolin-2-one derivatives and their 1h-benzo (1,2,6) thiadiazine-2,2-dioxide derivatives and 1,4 -dihydro-benzo (d) (1,3) oxazin-2-one as 5-hydroxytryptamine (5-ht) receptor modulators for the treatment of central nervous system disorders |
NO20062791A NO20062791L (en) | 2004-01-16 | 2006-06-15 | 1-Benzyl-5-piperazin-1-yl-34 4 dihydro-1H-quinazolin-2-one derivatives and the respective 1H-benzo (1,2,6) thiadiazine-2,2-dioxide and 1,4-dihydro -benzo (D) (1,3) oxazin-2-one derivatives as modulators of 5-hydroxytryptamine receptor (5-HT) for the treatment of disease |
IL176631A IL176631A0 (en) | 2004-01-16 | 2006-06-29 | 1-benzyl-5-piperazin-1-yl-3,4-dihydro-1h-quinazolin-2-one derivatives and the respective 1h-benzo (1,2,6) thiadiazine-2,2-dioxide and 1,4-dihydro- benzo(d) (1,3) oxazin-2-one derivatives as modulators of the 5-hydroxytryptamine receptor (5-ht) for the treatment of diseases of the central nervous system |
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US53708004P | 2004-01-16 | 2004-01-16 | |
US60/537,080 | 2004-01-16 |
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PCT/EP2005/000095 WO2005067933A1 (en) | 2004-01-16 | 2005-01-07 | 1-benzyl-5-piperazin-1-yl-3,4 dihydro-1h-quinazolin-2-one derivatives and the respective 1h-benzo(1,2,6)thiadiazine-2,2-dioxide and 1,4-dihydro-benzo(d) (1,3)oxazin-2-one derivatives as modulators of the 5-hydroxytryptamine receptor (5-ht) for the treatment of diseases of the central nervous system |
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US (2) | US7196087B2 (en) |
EP (1) | EP1708713B1 (en) |
JP (1) | JP4533391B2 (en) |
KR (1) | KR100843053B1 (en) |
CN (1) | CN1909909B (en) |
AR (1) | AR047958A1 (en) |
AT (1) | ATE388712T1 (en) |
AU (1) | AU2005205016B2 (en) |
BR (1) | BRPI0506909A (en) |
CA (1) | CA2552681A1 (en) |
CO (1) | CO5700763A2 (en) |
DE (1) | DE602005005298T2 (en) |
ES (1) | ES2302174T3 (en) |
IL (1) | IL176631A0 (en) |
NO (1) | NO20062791L (en) |
RU (1) | RU2006129464A (en) |
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JP2009501184A (en) * | 2005-07-13 | 2009-01-15 | エフ.ホフマン−ラ ロシュ アーゲー | Benzimidazole derivatives as 5-HT6 and 5-HT24 |
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WO2010026112A1 (en) * | 2008-09-08 | 2010-03-11 | F. Hoffmann-La Roche Ag | 5-substituted benzoxazines |
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EP2301625A3 (en) * | 2004-09-30 | 2011-07-27 | F. Hoffmann-La Roche AG | Compositions and methods for treating cognitive disorders |
WO2011144059A1 (en) | 2010-05-21 | 2011-11-24 | 深圳信立泰药业股份有限公司 | Fused quinazoline derivatives and uses thereof |
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JP2008523145A (en) * | 2004-12-13 | 2008-07-03 | イーライ リリー アンド カンパニー | Spiro derivatives as lipoxygenase inhibitors |
ES2401679T3 (en) * | 2008-06-20 | 2013-04-23 | Rottapharm S.P.A. | 6-1H-imidazo-quinazoline and quinoline derivatives, new MAO inhibitors and imidazoline receptor ligands |
UA125631C2 (en) * | 2016-11-15 | 2022-05-04 | Темпл Юніверсіті-Оф Дзе Коммонвелт Сістем Оф Хайєр Едьюкейшн | Novel modulators of the 5-hydroxytryptamine receptor 7 and their method of use |
EP4048667B1 (en) * | 2019-10-21 | 2024-07-03 | Alairion, Inc. | 3-(4-(11h-dibenzo[b,e][1,4]azepin-6-yl)piperazin-1-yl)- and 3-(4-(dibenzo[b,f][1,4]oxazepin/thiazepin/diazepin-11-yl)piperazin-1-yl)-propanoic acid derivatives as h1 and 5-ht2a-receptor modulators for the treatment of sleep disorders |
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ZA200605434B (en) | 2008-02-27 |
JP2007517826A (en) | 2007-07-05 |
CO5700763A2 (en) | 2006-11-30 |
NO20062791L (en) | 2006-08-01 |
US20070149510A1 (en) | 2007-06-28 |
US7196087B2 (en) | 2007-03-27 |
US20050165001A1 (en) | 2005-07-28 |
ES2302174T3 (en) | 2008-07-01 |
CN1909909A (en) | 2007-02-07 |
KR20060126720A (en) | 2006-12-08 |
TW200530222A (en) | 2005-09-16 |
JP4533391B2 (en) | 2010-09-01 |
EP1708713A1 (en) | 2006-10-11 |
DE602005005298T2 (en) | 2009-03-12 |
US7365063B2 (en) | 2008-04-29 |
CA2552681A1 (en) | 2005-07-28 |
KR100843053B1 (en) | 2008-07-01 |
ATE388712T1 (en) | 2008-03-15 |
AU2005205016B2 (en) | 2010-07-15 |
CN1909909B (en) | 2010-12-15 |
RU2006129464A (en) | 2008-02-27 |
EP1708713B1 (en) | 2008-03-12 |
DE602005005298D1 (en) | 2008-04-24 |
BRPI0506909A (en) | 2007-05-29 |
AR047958A1 (en) | 2006-03-15 |
IL176631A0 (en) | 2006-10-31 |
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