WO2004000837A1 - Nouveau derive de benzoxazolinone - Google Patents

Nouveau derive de benzoxazolinone Download PDF

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Publication number
WO2004000837A1
WO2004000837A1 PCT/JP2003/007952 JP0307952W WO2004000837A1 WO 2004000837 A1 WO2004000837 A1 WO 2004000837A1 JP 0307952 W JP0307952 W JP 0307952W WO 2004000837 A1 WO2004000837 A1 WO 2004000837A1
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Prior art keywords
piperidine
group
oxo
dihydro
substituted
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PCT/JP2003/007952
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English (en)
Japanese (ja)
Inventor
Tomohiro Toyoda
Masashi Tanaka
Toru Kodo
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Sumitomo Pharmaceuticals Co., Ltd.
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Priority to AU2003244160A priority Critical patent/AU2003244160A1/en
Publication of WO2004000837A1 publication Critical patent/WO2004000837A1/fr

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to novel benzoxazolinone derivatives. These novel benzoxazolinone derivatives are useful as therapeutic agents for Parkinson's disease. Background art
  • Parkinson's disease is a movement disorder caused by a deficiency of the neurotransmitter dopamine in the brain.
  • treatment of Parkinson's disease has mainly been replacement therapy with dopamine precursor L-D0PA, but long-term administration of L-D0PA shortens the action time (we aring_o phenomenon) and destabilizes (on-off phenomenon)
  • Involuntary movement disorders such as dyskinesia and mental symptoms such as hallucinations and delusions have become major problems.
  • Serotonin 5-HT A agonists have been found to have an effect on improving not only depression and anxiety, but also movement disorders such as Parkinson's disease in recent years. In fact, it has been reported that the selective 5_HT 1A agonist tandospirone quenate improves motor impairment in Parkinson's disease. Calorie, 5-ffl A agonists have been reported to reduce side effects such as suppression of vomiting by dopamine stimulation and shortening of the duration of action during long-term L-D0PA therapy. Therefore, a drug that exhibits an agonistic action on both dopamine D 2 receptor and serotonin 5-HT 1 A receptor improves the problems of conventional dopamine agonists and also increases the action time of L-D0PA. Concomitant depression ⁇ It may be a new treatment for Parkinson's disease that has an effect of improving anxiety symptoms.
  • TO00 / 1677 7 contains dopamine as a treatment for Parkinson's disease, ADHD, etc.
  • W000 / 29397 discloses piperazine and piperidine derivatives which show partial agonism at both dopamine D 2 receptor and serotonin 5- -A receptor. Disclosure of the invention
  • the present inventors have conducted intensive studies and found that the following compounds have high binding affinity and strong agonist action for both dopamine D 2 receptor and seotonin 5-HT 1A receptor. And completed the present invention.
  • ring A represents a 4- to 10-membered saturated or unsaturated nitrogen-containing heterocyclic ring.
  • R e represents a hydrogen atom, a substituted or unsubstituted alkyl group or a hydroxyl group, and two or more R e may be independently present.
  • R 1 is the formula (2)
  • R lfl and R 11 independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. Represents a hydroxyl group.
  • E is a single bond, one O—, one NR 5 —, one CO_, one CS—, one S (O) m —, -C OOs — CS—O—, one NR 5 CO—, one CONR 5 —, one O—CO— or one O—CS— (wherein, R 5 represents a hydrogen atom, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group. M represents an integer of 0 to 2) ).
  • B represents a single bond, a 6- to 16-membered aromatic hydrocarbon ring, a 3- to 8-membered aliphatic hydrocarbon ring, a 3- to 12-membered aliphatic heterocycle, or a 5- to 12-membered aromatic heterocycle .
  • Q represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, an alkyl group, an alkoxy group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkylthio group, a substituted or unsubstituted amino group, Or unsubstituted rubamoyl, carboxy, nitro, cyano, hydroxyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, Or a substituted or unsubstituted alkylsulfonyl group.
  • B represents a group other than a single bond
  • each of the groups represented by Q may be independently two or more.
  • N represents an integer of 0 to 10. ).
  • R 2 and R 3 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, or a substituted or unsubstituted alkylthio group.
  • R 4 represents a hydrogen atom or a substituted or unsubstituted alkyl group.
  • X is a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a hydroxyl group, a nitro group, a substituted or unsubstituted alkoxy group, a substituted or unsubstituted alkylthio group, a cyano group, a substituted or unsubstituted rubamoyl group, Represents a carboxy group, a substituted or unsubstituted alkyloxycarbel group, or a substituted or unsubstituted amino group.
  • Q is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxycarbonyl group, a substituted or unsubstituted alkylcarbonyl group, a substituted or unsubstituted arylylcarbonyl group, or a substituted or unsubstituted 1 to 7 above, which is a substituted alkylsulfonyl group, the compound according to any one of the above or a pharmaceutically acceptable salt thereof,
  • a medicament comprising the compound according to any one of the above 1 to 13 or a pharmaceutically acceptable salt thereof,
  • the present invention relates to a therapeutic agent for Parkinson's disease, comprising the compound described in any one of the above items 1 to 13, or a pharmaceutically acceptable salt thereof.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • alkyl group examples include methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butyl, tert-butyl, pentinole, 1-methylinobutynole, 2-methylinobutynole, 3-methylbutyl, 1-ethylpropynole, hexyl, Examples thereof include a linear or branched alkyl group having 1 to 10 carbon atoms, such as heptyl, octyl, nor or decyl.
  • Preferred alkyl groups include linear or branched alkyl groups having 1 to 6 carbon atoms. More preferably, methyl or ethyl is used.
  • alkenyl group examples include straight-chain or branched alkenyl groups having 2 to 5 carbon atoms having at least one double bond, such as vinylol, propyl, methylpropyl, butenyl or methylputur. -Alkyl group.
  • Preferred alkenyl groups include linear or branched alkenyl groups having 3 to 4 carbon atoms.
  • alkynyl group examples include a linear or branched alkynyl group having 2 to 5 carbon atoms and having at least one triple bond, such as ethur, propiel, methylpropynyl, butynyl or methylbutynyl.
  • Preferred alkyl groups include linear or branched alkynyl groups having 3 to 4 carbon atoms.
  • alkoxy group examples include those having 1 to 1 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, heptoxy, otoxy, nonyloxy, and decyloxy. And 0 linear or branched alkoxy groups.
  • Preferred alkoxy groups include linear or branched alkoxy groups having 1 to 6 carbon atoms. More preferably, methoxy or ethoxy is used.
  • alkylthio group examples include, for example, methylthio, ethylthio, propylthio, petitnorethio, isopropinorethio, isoptinorethio, sec-puchinorethio, tert-butylthio, pentinorecio, hexinorethio, heptinorethio, octinorethio, And an alkylthio group having 1 to 10 carbon atoms such as o, decylthio and the like.
  • Preferable alkylthio groups include alkylthio groups having a linear or branched alkyl group having 1 to 6 carbon atoms.
  • Examples of the substituent in the substituted alkyl group, the substituted alkoxy group, and the substituted alkylthio group include the above-mentioned halogen atom (the same carbon atom may be substituted by 1 to 3), hydroxyl group, methoxy, ethoxy, propoxy and the like.
  • Alkoxy amino, methinoleamino, ethynoleamino, alkylamino such as propylamino, dimethylamino, dimethylamino, methylethylamino, dialkylamino such as dipropylamino, acetylamino, propionylamino, benzoylamino, naphthoamino, naphthoamino, etc.
  • Alkoxycarbamino groups such as methoxycarbonylamino, ethoxycarbonylamino, tert-butoxycarbonylamino, etc., such as methinolesulfenole and etinolesulfonyl Examples include olequinorenolehonyl group, benzensorenohonore, and honoreensorehonenole group.
  • alkoxy group such as a hydroxyl group, methoxy, ethoxy, and propoxy.
  • aryl group examples include aryl groups having 10 or less carbon atoms, such as phenyl and naphthyl.
  • heteroaryl group examples include a 5- or 6-membered aromatic heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom.
  • Pyridyl the nitrogen atom may be oxidized
  • thienyl furyl
  • pyrrolyl the nitrogen atom may be oxidized
  • virazolyl imidazolyl, virazyl
  • pyrimidyl pyridazyl
  • oxazolyl thiazolyl
  • lyxadiazolyl triazolyl, tetrazolyl and the like.
  • substituents of the substituted aryl group and the substituted heteroaryl group include a halogen atom, a hydroxyl group, an alkyl group such as methyl, ethyl and propyl, and an alkoxy group such as methoxy, ethoxy, and propoxy.
  • substituents may be bonded to two adjacent ones to form a ring.
  • R 6 represents a hydrogen atom, a lower alkyl group, an benzyl group or a protecting group for a nitrogen atom.
  • Examples of the 6- to 16-membered aromatic hydrocarbon ring include a benzene ring, a naphthalene ring, and an anthracene ring.
  • Examples of the 3- to 8-membered aliphatic hydrocarbon ring include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclootaten And a saturated or unsaturated aliphatic hydrocarbon ring.
  • Preferred aliphatic hydrocarbon rings include those having 5 to 6 members.
  • Examples of the 3- to 12-membered aliphatic heterocycle include a saturated or unsaturated aliphatic heterocycle containing 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom.
  • Examples include aziridine, azetidine, pyrrolidine, piperidine, azepine, azepan, imidazolidine, piperazine, diazepine, dihydrofuran, tetrahydrofuran, tetrahydrothiophene and the like.
  • the above aliphatic heterocyclic ring may have an amide bond or an imido bond in the ring, for example, a 5- to 6-membered cyclic imido group such as an succinic imid group or a glutaric imid group. Or a cyclic amide group.
  • a 5- to 6-membered cyclic imido group such as an succinic imid group or a glutaric imid group.
  • a cyclic amide group for example, the following formula is given.
  • Preferred aliphatic heterocycles include those having 5 to 6 members. More preferably Pyrrolidine and piperidine.
  • the above-mentioned aliphatic heterocyclic ring may be a condensed ring condensed with another ring, and such “other ring” includes a hydrocarbon ring and a heterocyclic ring.
  • the hydrocarbon ring include a benzene ring and an aliphatic hydrocarbon ring (for example, the above-mentioned 5- to 6-membered saturated or unsaturated aliphatic hydrocarbon ring).
  • the heterocyclic ring is, for example, a 5- to 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom, and is a saturated or unsaturated aliphatic heterocyclic ring.
  • a ring or an aromatic heterocyclic ring examples of such a condensed ring include those represented by the following formula.
  • Examples of the 5- to 12-membered aromatic heterocyclic ring include an aromatic heterocyclic ring containing 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom.
  • pyridine nitrogen atom may be oxidized
  • thiophene furan, pyrrole, pyrazole, imidazole, pyrazine, pyrimidine, pyrimidine Dazine, oxazoline, thiazoline, oxaziazoline, triazole, tetrazole and the like.
  • the above aromatic heterocyclic group may form a condensed ring with another ring, and examples of such another ring include the same as the “other ring” described in the above aliphatic heterocyclic ring.
  • a fused heterocyclic ring include, for example, quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline, quinazoline, indole, isoindole, benzofuran, benzothiophene and the like. Preferred are those having 9 to 10 members.
  • substituent of the substituted amino group examples include the above-mentioned substituted or unsubstituted alkyl group, alkenyl group having 7 or less carbon atoms such as acetyl, propionyl, and butyryl; and carbon atom having 11 or less such as benzoyl and naphthoyl.
  • alkoxycarbonyl groups having 7 or less carbon atoms such as an arylone group, methoxycarbole, ethoxycanoleboninole, and tert-butoxycarbonyl.
  • substituted amino group examples include, for example, methylamino group, ethylamino group, dimethylamino group, acetylamino group, propionylamino group, benzoylamino group, naphthoylamino group, methoxycarbonylamino, ethoxycarbonylamino, tert-butoxycano. Leponinoleamino and the like.
  • the substituent in the rubamoyl group includes, for example, the above-mentioned substituted or unsubstituted alkyl group, alkenyl group having 7 or less carbon atoms such as acetyl, propionyl, and butyryl, and arylo group having 11 or less carbon atoms such as benzoyl and naphthoyl. And so on.
  • substituent rubamoyl group examples include, for example, a monomethylcarbamoyl group, a dimethinolecanolebamoinole group, an ethylcarbamoinole group, an acetinolecanolebamoyl group, and a benzoylcarbamoyl group.
  • the substituents in the substituted alkyloxycarbonyl group, the substituted alkylcarbonyl group, the substituted aryl group and the substituted alkylsulfonyl group are the same as the above-mentioned substituents in the substituted alkyl group, the substituted alkoxy group and the substituted alkylthio group. Groups.
  • n an integer of 0 to 10, preferably 0 to 6.
  • the 4- to 10-membered saturated or unsaturated nitrogen-containing heterocyclic ring represented by ring A includes, for example, 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom. Represents a 4- to 10-membered saturated or unsaturated nitrogen-containing heterocyclic ring;
  • Preferred ring A includes a 5- or 6-membered saturated or unsaturated nitrogen-containing heterocyclic ring.
  • the ring A may have a substituent represented by R ° as appropriate.
  • the compound (1) of the present invention or a pharmaceutically acceptable salt thereof can be produced by a method represented by the following formula.
  • Examples of the leaving group LG include a halogen atom such as a chlorine atom, a bromine atom, and an iodine atom, and an acyloxy group such as acetoxy, tosyloxy, and mesiloxy.
  • a halogen atom such as a chlorine atom, a bromine atom, and an iodine atom
  • an acyloxy group such as acetoxy, tosyloxy, and mesiloxy.
  • the compound (1) of the present invention or a salt thereof can be obtained by reacting the compound ( 1 ⁇ ) or a salt thereof with the compound (3) or a salt thereof.
  • the reaction is carried out in a suitable inert solvent at a temperature ranging from about 120 ° C to the boiling point of the solvent used for 10 minutes in the presence of a base, if necessary, and optionally a phase transfer catalyst.
  • the reaction can be carried out for up to 48 hours.
  • the base examples include organic bases such as triethylamine and pyridine; inorganic bases such as lithium carbonate, sodium hydroxide and sodium hydride; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.
  • phase transfer catalyst examples include tetrabutylammonium hydrogen sulfate and the like.
  • the inert solvent examples include, for example, halogenated hydrocarbons such as acetonitrile II, chloroform, dichloromethane and the like, aromatic hydrocarbons such as benzene and toluene, ether solvents such as getyl ether, tetrahydrofuran (THF), and 1,4-dioxane.
  • aprotic polar solvents such as lower alcohols such as methanol, ethanol, and isopropanol; dimethinolephonamide, N-methylpyrrolidone, and dimethyl sulfoxide; and mixed solvents thereof.
  • the compound represented by the formula (la) or a salt thereof can also be produced by the following method.
  • n ' is an integer from 1 to 10
  • E A single bond or one NR 5 (wherein R 5 is the same as defined above).
  • Intermediate (5) can be produced by reacting compound (1 °) or a salt thereof with compound (4) or a salt thereof to form an amide bond.
  • the amide bond formation reaction may be performed by an acid chloride method using thiol chloride, oxalyl chloride, or the like; an acid anhydride method using a corresponding acid anhydride; It can be carried out by a usual method such as a method using a condensing agent such as oral hexylcarbodiimide ⁇ carbodilidimidazole.
  • the intermediate (5) is converted to a suitable inert solvent (eg, ether such as getyl ether, tetrahydrofuran (THF), 1,4-dioxane, etc.) using a suitable reducing agent (eg, lithium aluminum hydride or diborane).
  • a suitable inert solvent eg, ether such as getyl ether, tetrahydrofuran (THF), 1,4-dioxane, etc.
  • a suitable reducing agent eg, lithium aluminum hydride or diborane.
  • Compound (la) can be obtained by reacting at a temperature between ⁇ 20 ° C. and the boiling point of the solvent used for 10 minutes to 48 hours. More specifically, the compound (la) can be obtained by performing a reduction reaction in tetrahydrofuran (THF) with diborane under ice cooling or at room temperature for 20 minutes to 1 hour.
  • the target compound (la) or a salt thereof can be obtained by reacting the compound (1) or a salt thereof with the compound (6) or a salt thereof under reductive amination conditions.
  • a reducing agent For example, sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride can be used.
  • Compound (2) and compound (6) can be mixed as they are, or they can be formed in advance by forming enamine. The reaction may be performed afterwards.
  • the reaction is carried out in a suitable inert solvent, for example, acetonitrile, halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, ethers such as ethyl ether, tetrahydrofuran, and 1,4-dioxane.
  • a protic polar solvent such as a system solvent, methanol, ethanol, isopropanol, and acetic acid
  • an aprotic polar solvent such as dimethylformamide, N-methinolepyrrolidone, and dimethylsulfoxide, or in a mixed solvent thereof at 120 ° C. To a boiling point of the solvent used for 10 minutes to 48 hours.
  • the compound of the formula (1) may be converted to another compound of the formula (1) by appropriately converting the functional group.
  • Conversion of functional groups generally methods [eg normally performed, the completion Nshibu ⁇ Organic Transformations's (Comprehen sive Organic Transformations) N R . C. Rarokku (Larock) Author (1 9 8 9 years), etc. See ].
  • R °, RRRX, A, and LG are as described above.
  • PG represents a protecting group for a nitrogen atom.
  • the protecting group PG 2 nitrogen atoms include appropriate protecting groups for secondary Amin, e.g. downy Njiru group.
  • Compound (9) can be obtained by converting compound (7) to compound (7 ') by a method described in the literature (eg, JOC, 1982, 47, 2804-2806, W000 / 29397) or a method analogous thereto. It can be obtained by reacting with (8).
  • the compound (9) can be converted to the compound (10) by dehydration. More specifically, the reaction can be carried out in a 48% aqueous solution of hydrobromic acid at 80 to 100 ° C. for 1 to 5 hours.
  • Compound (11) can be obtained by reacting compound (10) with compound (3 ′). This transformation is carried out in a suitable inert solvent at a temperature ranging from about 120 ° C. to the boiling point of the solvent used, in the presence of a base, if necessary, and optionally a phase transfer catalyst. The reaction can be carried out by reacting for a period of from 48 minutes to 48 minutes.
  • the base include organic bases such as triethylamine and pyridine; inorganic bases such as carbonated lime, sodium hydroxide and sodium hydride; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.
  • the inert solvent examples include halogenated hydrocarbons such as acetonitrile II, chloroform, dichloromethane and the like, aromatic hydrocarbons such as benzene and toluene, ethers such as getyl ether, tetrahydrofuran (THF), and 1,4-dioxane.
  • halogenated hydrocarbons such as acetonitrile II, chloroform, dichloromethane and the like
  • aromatic hydrocarbons such as benzene and toluene
  • ethers such as getyl ether, tetrahydrofuran (THF), and 1,4-dioxane.
  • solvents lower alcohols such as methanol, ethanol, and isopropanol
  • aprotic polar solvents such as dimethylformamide, N-methylpyrrolidone, and dimethylsulfoxide
  • the desired compound (1 °) can be obtained by reducing and deprotecting the compound (11) by a conventional method.
  • compound (l ° a ) can be obtained from compound (10). More specifically, the compound (10) or compound (11) in which PG 2 is a benzyl group is heated and refluxed in ethanol for 1 to 5 hours in the presence of 10% palladium carbon and ammonium formate. By doing so, compound ( 1 ⁇ ) or compound ( a ) can be obtained.
  • the starting compound or a suitable salt of the target compound or a pharmaceutically acceptable salt is a conventional non-toxic salt and includes organic acid salts (eg, acetate, trifluoroacetate, maleate).
  • Acid addition salts such as salts, sulfates, nitrates, phosphates, etc., salts with amino acids (eg, arginine, aspartic acid, glutamic acid, etc.), or alkali metal salts (eg, sodium, potassium salts, etc.) and Metal salts such as alkaline earth metal salts (eg, calcium salt, magnesium salt, etc.), ammonium salts, organic base salts (eg, trimethylamine salts) , Triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N, dibenzylethylenediamine salt, etc.), and the like, and others can be appropriately selected by those skilled
  • Protecting groups include, for example, Protective Groups in Organic Synthesis, Guton (T. Ha, John Wiley and Sons Incorporated). nc.) (1989), and the like. More specifically, as the protecting group for amine, ethoxycarbonyl, t-butoxycarbol, Examples of acetyl, benzyl and the like, and examples of the hydroxyl-protecting group include trialkylsilyl, acetyl and benzyl.
  • protecting groups should be carried out by a method commonly used in organic synthetic chemistry [for example, see Protective Groups in Organic Synthesis (see above, Protective Groups in Organic Synthesis)] or a method analogous thereto. There is a monkey.
  • Intermediates and target compounds in each of the above production methods are purified methods commonly used in organic synthetic chemistry, for example, neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatographs It can be isolated and purified. In addition, the intermediate can be subjected to the next reaction without purification.
  • Some of the compounds (1) of the present invention may have tautomers, and the present invention includes all possible isomers, including these, and mixtures thereof.
  • the compound (1) of the present invention When it is desired to obtain a pharmaceutically acceptable salt of the compound (1) of the present invention, if the compound (1) can be obtained in the form of a pharmaceutically acceptable salt, it can be purified as it is, When it is obtained in the form of a salt, it may be dissolved or suspended in an appropriate organic solvent, and an acid or a base may be added to form a salt by a usual method.
  • the compound (1) and its pharmaceutically acceptable salt may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention.
  • the compound (1) of the present invention may include one or more stereoisomers based on an asymmetric carbon atom, and such heterogeneous to living organisms and mixtures thereof are all included in the scope of the present invention.
  • the scope of the present invention also includes prodrugs of the compound (1) of the present invention.
  • the term “prodrug” refers to a derivative which is decomposed in vivo by acid hydrolysis or enzymatically to give the compound of the above formula (1).
  • the compound of the formula (1) has a hydroxyl group or a carboxy group, these groups can be modified according to a conventional method to produce a prodrug.
  • the compound (1) of the present invention and a pharmaceutically acceptable salt thereof have a pharmacological action such as dopamine agonist action. Therefore, it is useful for treating or preventing diseases mediated by dopaminergic neurons, such as Parkinson's disease, anxiety, depression, hypertension, associated hypertension, and schizophrenia. Furthermore, the compound (1) of the present invention and a pharmaceutically acceptable salt thereof also have a pharmacological action such as a seroto-agonist action.
  • Mood disorders anxiety disorders, including obsessive-compulsive disorders and panic disorders; memory disorders, including dementia, amnesia and age-related memory disorders; disorders of eating behavior, including anorexia nervosa and neural starvation; Obesity; sleep disorders; drug dependence such as a / recall, tobacco, and nicotine; cluster headache; migraine; pain; Alzheimer's disease; chronic seizures migraine; Parkinson's disease, including B-immobilized dyskinesia, striatum It is also useful for treating or preventing motor disorders such as substantia nigra, progressive supranuclear palsy, and cerebellar degenerative disorders.
  • the compound (1) of the present invention and a pharmaceutically acceptable salt thereof further include endocrine disorders such as hyperprolactinemia; vasospasm (especially of the cerebrovascular system); gastrointestinal tract in which motility and secretory changes are involved. Sexual dysfunction, including premature ejaculation; and treatment or prevention of drug dependence.
  • endocrine disorders such as hyperprolactinemia; vasospasm (especially of the cerebrovascular system); gastrointestinal tract in which motility and secretory changes are involved.
  • sexual dysfunction including premature ejaculation; and treatment or prevention of drug dependence.
  • compound (1) of the present invention and pharmaceutically acceptable salts thereof may be used topically, enterally, intravenously, intramuscularly, by inhalation, intranasally, intraarticularly, intrathecally, intratracheally or transocularly It can be used in the form of a pharmaceutical preparation as a mixture with a pharmaceutically acceptable carrier such as a solid or liquid organic or inorganic excipient suitable for oral and parenteral administration including external administration, and external application.
  • a pharmaceutically acceptable carrier such as a solid or liquid organic or inorganic excipient suitable for oral and parenteral administration including external administration, and external application.
  • the pharmaceutical preparations include capsules, tablets, pellets, dragees, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, cataplasms, gels, tapes, eye drops Solids, semi-solids or liquids such as solutions, solutions, syrups, aerosols, suspensions and emulsions.
  • These preparations can be manufactured by a usual method. If desired, auxiliaries, stabilizers, wetting or emulsifying agents, buffers and other conventional additives can be added to these preparations.
  • the dose of Compound (1) and its pharmaceutically acceptable salts may be reduced depending on the age and condition of the patient, but the average single dose of Compound (1) is about 0.1 mg, lmg, 1 Omg, 50mg, 100mg, 250mg, 500mg and 1000mg strength Mood disorders including Parkinson's disease, schizophrenia, depression, seasonal affective disorder and dysthymia; including general anxiety disorder and panic disorder It is effective for diseases such as anxiety and other movement disorders.
  • an amount of 0.1 mg / B to about 1,000 mg / individual / B, preferably 1 mg / Z to about 100 mg / Z / day can be administered. .
  • Example 1 Example 1
  • tert-Ptinole 3-fluorophenylcanolebamate (1.20 g, 5.71 mmo 1) in tetrahydrofuran (50 mL) was added to N, N, ⁇ ,, N, 1-tetramethynoleethylenediamine.
  • the reaction system was cooled with a dry ice-acetone bath, and tert-butyllithium (1.56 M heptane solution, 8.55 mL, 12.6 mmo) was added. 1) was slowly added dropwise.
  • Example 2 Using the same method as in Example 1, the following compounds of Examples 2 and 3 were produced.
  • Example 2 Using the same method as in Example 1, the following compounds of Examples 2 and 3 were produced.
  • Example 2 Using the same method as in Example 1, the following compounds of Examples 2 and 3 were produced.
  • Example 5 Using the same method as that in Example 4, the following compound of Example 5 was produced.
  • Example 7 Using the same method as in Example 6, the compound of Example 7 was prepared from the compound of Example 2 and the compound of Example 8 from the compound of Example 3.
  • Example 10 Using the same method as in Example 9, the compound of Example 10 was produced from the compound of Example 7 and the compound of Example 11 was produced from the compound of Example 8.
  • Example 54 IR (cm-1); 956, 1028, 1105, 1142, 1458 Using the same method as in Example 53, starting from the compound of Example 4 and starting with the compound of Examples 54 and 55, starting with the compound of Example 5 From the compounds of Examples 56 to 58, the compounds of Example 9 and the compounds of Example 59, the compounds of Examples 60 to 68 were prepared from the compounds of Example 10.
  • Example 54
  • t Bu represents a t er t—ptinole group.
  • Example 70 Using the same method as in Example 69, the compound of Example 70 was produced from the compound of Example 57, and the compound of Example 71 was produced from the compound of Example 58.
  • Example 69 To a solution of the compound of Example 69 (5.5 mg, 0.024 mmol) in ethanol (5 mL) was added 10% palladium on carbon (50% wet, 50 mg) and ammonium formate (200 mg) for 1 hour Heated to reflux. After completion of the reaction, the mixture was filtered using celite, and the solvent was distilled off under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the residue, and the mixture was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. 7- (1-Methylbiperidin-1-inole) -1, 3-benzoxazo-inole-1 (3H) -one (amonorefase, 4. 2 mg) was obtained.
  • Example 73 The compound of Example 73 was produced in the same manner as in Example 72.
  • reaction mixture was diluted with chloroform and washed with saturated aqueous sodium hydrogen carbonate.
  • the organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure.
  • This product was dissolved in methanol (2.0 mL), 2N potassium hydroxide solution (1.0 mL) was added, and the mixture was stirred at 50 ° C for 4 hours. After the completion of the reaction, the reaction mixture was diluted with a black hole form and washed with water.
  • 2-pyridinepropanol (3 g, 21.87 mmo 1) was dissolved in acetic acid (9 mL) at room temperature, platinum oxide (containing 33% water, 391 mg) was added, and hydrogenation was performed using an autoclave. (100 kg / cm 2 ). After filtration through celite, the solvent was concentrated under reduced pressure to obtain 3-piperidine- 12 -ylpropane-111-acetic acid salt (brown oil, 8.04 g).
  • tert-butyl 2- (3-hydroxypropyl) piperidine-one-pot olepoxylate (2 g, 8.22 mmo 1) was dissolved in dichloromethane (20 mL) at room temperature, and triethylamine (2. 3 m 1, 1.66 g,
  • Example 10 The compound of Example 10 (200 mg, 0.92 mmo 1) was dissolved in dimethyl sulfoxide (1.5 mL) at room temperature under a nitrogen atmosphere, and the solution was dissolved in tert-butyl 2- (
  • One-strength noreboxylate (3 64 mg, 0.92 mmo 1) was added, and the mixture was stirred at 70 to 80 ° C for 9 hours.
  • the reaction solution was added to saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate.
  • Example 78 The compound of Example 78 was produced in the same manner as in Example 77.
  • Example 7 To a solution of the compound of 9 (50 mg, 0.12 mmo 1) in 1 N sodium hydroxide (1 mL) and 1,4-dioxane (1 mL) was added acetic anhydride (1 mL) at room temperature. Add 0.19 mmo 1) and stir the reaction mixture at room temperature for 1.5 hours. Stirred. Subsequently, acetic anhydride (10 / iL, 0.1 mmo 1) was added, and the reaction mixture was stirred at room temperature for 1 hour. Then, ethyl acetate and water were added to separate the layers, and the aqueous layer was extracted again with ethyl acetate.
  • Triethylamine (0.10 mL, 0.72 mL) was added to a solution of the compound of Example 80 (100 mg, 0.240 mmo 1) in dimethinolevenolemamide (3.0 m 1).
  • Example 97 The compound of Example 97 was produced in the same manner as in Example 96. .
  • (+)-7-Pyridin-3-yl-1,3-benzoxazole-2 (3H) -one is shown in the table below. It will be described. Furthermore, compounds prepared from (+)-7-piperidin-3-yl-1,3-benzoxazol-2 (3H) -one should be indicated by adding * to the asymmetric carbon. And
  • Example 98 Liquid chromatography in which the retention time is described in Example 98 and Example 99
  • the conditions for carrying out one analysis are as follows.
  • Triethylamine (4.1 raL, 30 mmol) was added to a methylene chloride solution (70 mL) of methyl (3S) -3- (hydroxymethinole) pyrrolidine-1-carboxylate (1.7 g, 10.7 mmol), and chloride was added under ice cooling.
  • P-toluenesulfonyl (3.8 g, 20 mmol) and stir at room temperature for 2 hours did.
  • Triethylamine (4.0 m, 29 ramol) and p-toluenesulfonyl chloride (3.8 g, 2 O mmol) were added, and the mixture was further stirred at room temperature for 2 hours.
  • the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the purified product obtained was dissolved in ethyl acetate (50 mL) and washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution.
  • the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain (436 mg, y. 30%). Retention time: 16.9 min. ⁇ 103 compounds were prepared.
  • (+) _7-piperidin-3-yl-1,3-benzoxazole-2 (3H) -one 500 mg, 2.3 mmol
  • t-ptinole (2S) -2- (2-oxoethyl ) Pyridine-1-carboxylate 518 mg, 2.3 mmol
  • acetic acid 1 mL
  • methanol 5 mL
  • sodium cyanoborohydride 170 mg, 2.7 mmol
  • Example 104 The compounds of Examples 105 to 107 were produced in the same manner as in Example 104.
  • Triethylamine (1.79 mL) was added to a methylene chloride solution (10 mL) of (4S) -4- (hydroxymethinole) -1-[(IS) -1-phenylethyl] pyrrolidin-2-one (937 mg, 4.27 mmol). , 12.8 mmo 1), p-toluenesulfol chloride (L 22 g, 6.41 ranol) was added under ice cooling, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was diluted with chloroform and washed successively with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium hydrogencarbonate.
  • Dimethyl malonate (13.7 g, 103 mol) was added dropwise to a suspension of sodium hydride (2.47 g, 103 mmol) in dimethylformamide (150 mL) over 10 minutes under ice-cooling, and then the temperature was raised to room temperature. Heated and agitated for 1 hour.
  • a methanol solution (30 mL) of methyl (3S) -3- (3-oxopropyl) pyrrolidine-1-carboxylate (1.10 mg, 5.95 mraol) acetic acid (3 mL), sodium cyanoborohydride (630 rag, 10 mol) was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was added to a saturated aqueous solution of sodium hydrogen carbonate, and extracted with chloroform.
  • Example 109 The compounds of Examples 109 to 111 were produced in the same manner as in Example 108.
  • Feninole 3 [3— (2 oxo-1,2,3-dihydro-1,3—benzoxazo 1-71-yl) piperidine-1-11-yl] propylcarpamate
  • Membrane preparations were prepared according to the method of Levant et al. (J. Pharmacol. Exp. Ther., 262, 929-935 (1992)). That is, a male rat was decapitated, the whole brain was immediately removed, and the striatum was collected under ice cooling. To this was added 20 volumes of a buffer solution (50 mM Tris-HCl, 5 raM KCl, 2 mM MgCl 2 , 2 raM CaCl 2 , pH 7,4) based on the wet weight, and Teflon-glass homog Homogenized using an enizer.
  • a buffer solution 50 mM Tris-HCl, 5 raM KCl, 2 mM MgCl 2 , 2 raM CaCl 2 , pH 7,4
  • [ 3 H] quinpirole binding was measured according to the method of Levant et al. That, 5 mM K Cl, 2 mM MgCl 2 and 2 mM containing CaCl 2 50 mM Tris-HCl ( pH 7. 4) was diluted in buffer [3 H] quinpirole (final concentration 2 nM) 50/1, line A striatal membrane sample of 447.51 and 2.5 ⁇ l of the test drug solution dissolved in dimethyl sulfoxide were added to make a total volume of 500 ⁇ l. This solution was reacted at 23 ° C. for 5 hours, and then quickly filtered under low pressure on glass fiber filter paper.
  • the glass fiber filter paper was washed three times with 5 ml of the same buffer, transferred to a glass spiral containing 4ral of ACS-II (Amersham), and the radioactivity remaining on the filter paper was measured using a liquid scintillation counter.
  • Non-specific binding of [ 3 H] quinpirole was defined as the amount of binding in the presence of ⁇ (+)-butaclamol.
  • Binding inhibition rate 1 0 0 _ 1 0 0 X ⁇ [ test substance present under [3 H] quinpirole binding amount] one [10 ⁇ (+) (° /.) - butaclamol in the presence [3 H] quinpirole binding amount] ⁇ Z ⁇ [test substance in the absence [3 H] quinpriole binding amount] one.
  • - quinpriole bond amount [10 ⁇ (+) [3 H in the presence Butaclamol]] ⁇
  • Test example 2 [ 3 H] 8-0H-DPAT binding test
  • the resulting precipitate was dispersed using Physcotron tau M in ice-cold buffer (50 mM Tris-HCl (pH 7.4)), 40, 000 Xg by centrifugation for 10 minutes (4 ° C) was. Furthermore, the cells were resuspended and the washing operation was repeated once. The resulting precipitate was dispersed using Physcotron tau M in ice-cold buffer (50 raM Tris-HCl (pH 7.4)), 1 hour Inki-menu collected by centrifugation then 10 minutes at 40,000Xg at 3 7 Separated (4 ° C). In addition, resuspension Then, the washing operation was repeated once. The obtained membrane preparation was suspended in the above buffer solution and stored frozen at 180 ° C.
  • Non-specific binding was defined as the amount of binding in the presence of 1 / zM 8-0H-DPAT.
  • the binding inhibition rate was calculated by the following formula:
  • Binding inhibition rate (%) 1 00- 1 0 0 X ⁇ [ test of a material presence [3 H] 8-0H-DPAT binding amount] one [1 ⁇ 8-0 ⁇ - DPAT in the presence [3 H ] 8 -0H-DPAT binding amount]] ⁇ ⁇ [[ 3 H] 8-OH-DPAT binding amount in the absence of test substance] 1 [1 ⁇ 8--0H-DPAT in the presence of [ 3 H] 8 _0H-DPAT binding amount] ⁇
  • Test Example 3 5-HT, octareceptor and D2 receptor operation test
  • buffer A (20mM HEPES, 5mM MgS0 4 ) Cells manual removal 'taken, Teflon-after homogenization with Glass homogenizer, was performed centrifugation (50,000Xg, 30min, 4 ° C ). The precipitate was resuspended in an appropriate amount of buffer A and stored at 180 ° C until use. The amount of protein in the membrane preparation was quantified by Dye Reagent Concentrate (BIO-RAD) using Albumin Bovine (SIGMA) as a standard substance.
  • BIO-RAD Dye Reagent Concentrate
  • SIGMA Albumin Bovine
  • the glass fiber filter paper washed twice with the same buffer was placed in a vial, and 4 ml of ACS-II was added thereto.
  • the radioactivity of [ 35 S] GTP ⁇ S on the filter paper was measured with a liquid scintillation counter. 10 // M GTPyS (Sigma) from non-specific binding obtained under existence [3 5 S] was determined specific binding of GTP 7 S. 5- ⁇ A receptor Oyohi receptor agonist activity of each test substance was expressed in the rate of increase when respectively the [35 S] GTPyS binding increased by 10 Myumyu of 5-HT and dopamine and 1 0 0% .
  • Test Example 1 The tests of Test Example 1, Test Example 2 and Test Example 3 described above were performed on the compounds obtained in the Examples. The results are shown in Table 6. Table 6: Test results Compound [ 3 H] quinpirole D 2 receptor [ 3 H] 8-0H-DPAT 5-HT 1A receptor
  • Binding inhibition rate (%) Agonist activity (%) Binding inhibition rate (%) Agonist activity (%)
  • the compound of the present invention was found to have high binding affinity and strong agonist action for both dopamine D2 receptor and serotonin 5- HT1A receptor did. Therefore, the present invention has made it possible to provide a new therapeutic agent for Parkinson's disease.

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Abstract

La présente invention concerne un nouveau dérivé de benzoxazolinone représenté par la formule (1). L'invention se rapporte également à un nouvel agent thérapeutique de la maladie de Parkinson qui possède une forte affinité de liaison à la fois pour un récepteur de la dopamine D2 et pour un récepteur de la sérotonine 5-HT1A, de même qu'une forte activité d'agoniste à l'encontre desdits récepteurs.
PCT/JP2003/007952 2002-06-25 2003-06-24 Nouveau derive de benzoxazolinone WO2004000837A1 (fr)

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JP2008037850A (ja) * 2006-08-10 2008-02-21 Mitsubishi Tanabe Pharma Corp 新規置換ピペリジン誘導体
US8410144B2 (en) 2009-03-31 2013-04-02 Arqule, Inc. Substituted indolo-pyridinone compounds
WO2016204268A1 (fr) * 2015-06-19 2016-12-22 アステラス製薬株式会社 Composé imidazodiazépine
CN111808007A (zh) * 2020-06-23 2020-10-23 青岛贞开生物医药技术有限公司 一种手性3-取代吡咯烷衍生物的制备方法
RU2777915C2 (ru) * 2015-06-19 2022-08-11 Астеллас Фарма Инк. Имидазодиазепиновое соединение

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Cited By (14)

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JP2008037850A (ja) * 2006-08-10 2008-02-21 Mitsubishi Tanabe Pharma Corp 新規置換ピペリジン誘導体
US8410144B2 (en) 2009-03-31 2013-04-02 Arqule, Inc. Substituted indolo-pyridinone compounds
RU2712968C2 (ru) * 2015-06-19 2020-02-03 Астеллас Фарма Инк. Имидазодиазепиновое соединение
CN107635996A (zh) * 2015-06-19 2018-01-26 安斯泰来制药有限公司 咪唑并二氮*化合物
KR20180014732A (ko) * 2015-06-19 2018-02-09 아스테라스 세이야쿠 가부시키가이샤 이미다조디아제핀 화합물
JPWO2016204268A1 (ja) * 2015-06-19 2018-04-05 アステラス製薬株式会社 イミダゾジアゼピン化合物
WO2016204268A1 (fr) * 2015-06-19 2016-12-22 アステラス製薬株式会社 Composé imidazodiazépine
CN107635996B (zh) * 2015-06-19 2020-05-26 安斯泰来制药有限公司 咪唑并二氮*化合物
CN111205292A (zh) * 2015-06-19 2020-05-29 安斯泰来制药有限公司 咪唑并二氮*化合物
CN111205292B (zh) * 2015-06-19 2022-06-21 安斯泰来制药有限公司 咪唑并二氮䓬化合物
RU2777915C2 (ru) * 2015-06-19 2022-08-11 Астеллас Фарма Инк. Имидазодиазепиновое соединение
KR102591169B1 (ko) 2015-06-19 2023-10-18 아스테라스 세이야쿠 가부시키가이샤 이미다조디아제핀 화합물
CN111808007A (zh) * 2020-06-23 2020-10-23 青岛贞开生物医药技术有限公司 一种手性3-取代吡咯烷衍生物的制备方法
CN111808007B (zh) * 2020-06-23 2023-04-21 青岛贞开生物医药技术有限公司 一种手性3-取代吡咯烷衍生物的制备方法

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