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WO2011036885A1 - Composé hétérocyclique - Google Patents

Composé hétérocyclique Download PDF

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Publication number
WO2011036885A1
WO2011036885A1 PCT/JP2010/005764 JP2010005764W WO2011036885A1 WO 2011036885 A1 WO2011036885 A1 WO 2011036885A1 JP 2010005764 W JP2010005764 W JP 2010005764W WO 2011036885 A1 WO2011036885 A1 WO 2011036885A1
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Prior art keywords
trifluoromethyl
salt
compound
tetrahydro
mmol
Prior art date
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PCT/JP2010/005764
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English (en)
Japanese (ja)
Inventor
倫代 望月
稔博 今枝
和義 麻生
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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Publication of WO2011036885A1 publication Critical patent/WO2011036885A1/fr
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Classifications

    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a heterocyclic compound, in particular, a heterocyclic compound having an AMPA ( ⁇ -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor function enhancing action.
  • AMPA ⁇ -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
  • Glutamate is the most abundant excitatory neurotransmitter in the mammalian central nervous system. Glutamate has an important role in the regulation of cognition, mood, and motor function, and these processes become unstable in psychiatric and neurological disorders. Glutamate receptors are classified into ion channel receptors and G protein-coupled receptors, and the ion channel receptors are further ⁇ -amino-3-hydroxy-5-methyl 4-isoxazolepropionic acid (AMPA) receptors, It is classified into N-methyl-D-aspartate (NMDA) receptor and kainic acid (KA) receptor.
  • AMPA ⁇ -amino-3-hydroxy-5-methyl 4-isoxazolepropionic acid
  • NMDA N-methyl-D-aspartate
  • KA kainic acid
  • the AMPA receptor is a type of receptor for the excitatory neurotransmitter glutamate and was named based on the selective activation of AMPA by AMPA.
  • the AMPA receptor is composed of four subunits (GluR1, GluR2, GluR3, GluR4). There are homomeric receptors composed of homologous subunits and heteromeric receptors composed of heterogeneous subunits. It has been reported that the physiological properties of AMPA receptors vary depending on the subunits that comprise them.
  • Non-patent documents 1, 2, 3 The importance of AMPA receptors in brain physiology is well known, and compounds having an AMPA receptor function enhancing action are expected to be useful as preventive or therapeutic agents for mental disorders, neurodegenerative diseases, memory disorders, sleep disorders, etc. ing.
  • Non-Patent Documents 4 and 5 The importance of AMPA receptors in brain physiology is well known, and compounds having an AMPA receptor function enhancing action are expected to be useful as preventive or therapeutic agents for mental disorders, neurodegenerative diseases, memory disorders, sleep disorders, etc. ing.
  • Patent Document 1 discloses a general formula.
  • action represented by these is disclosed.
  • Patent Document 2 discloses a general formula.
  • the heterocyclic compound which has the AMPA receptor function enhancement effect represented by these is disclosed.
  • Patent Document 3 discloses a general formula.
  • the heterocyclic compound which has the AMPA receptor function enhancement effect represented by these is disclosed.
  • Patent Document 4 discloses a general formula.
  • the heterocyclic compound which has the AMPA receptor function enhancement effect represented by these is disclosed.
  • Patent Document 5 discloses a general formula.
  • the heterocyclic compound which has the AMPA receptor function enhancement effect represented by these is disclosed.
  • Patent Document 6 discloses a general formula.
  • the heterocyclic compound which has the AMPA receptor function enhancement effect represented by these is disclosed.
  • Patent Document 7 discloses a general formula.
  • the heterocyclic compound which has the AMPA receptor function enhancement effect represented by these is disclosed.
  • Patent Document 8 discloses a general formula.
  • the heterocyclic compound which has the AMPA receptor function enhancement effect represented by these is disclosed.
  • Patent Document 9 includes a general formula. (R 2 and X 3 may form a 5- to 7-membered ring)
  • the heterocyclic compound which has the AMPA receptor function enhancement effect represented by these is disclosed.
  • Patent Document 10 discloses a general formula.
  • the heterocyclic compound which has the AMPA receptor function enhancement effect represented by these is disclosed.
  • the present invention relates to a heterocyclic compound having an AMPA receptor function-enhancing action (AMPA receptor function potentiator (AMPA receptor receptor potentiator);
  • AMPA receptor function potentiator AMPA receptor receptor potentiator
  • the purpose is to provide positive allosteric modulator, positive allosteric activator of AMPA receptor).
  • the present inventors have found that a compound represented by the following formula (I) or a salt thereof (sometimes referred to herein as compound (I)) has an AMPA receptor function enhancing action. As a result of further research, the present invention has been completed.
  • X a , Y a and Z a are nitrogen atoms at the same time.
  • Ring A represents cyclohexene
  • R 1 represents a C 1-6 alkyl group substituted with a halogen atom
  • the group represented by (Where D 1 ⁇ D 4 ring are each halogen atom, C 1-6 alkyl group substituted by a halogen atom, C 1-6 alkyl group substituted by a hydroxy group, and C 1-6 alkoxy - selected from a carbonyl group Represents a ring substituted with 1 to 3 substituents of
  • the E 1 to E 4 rings each represent a ring optionally substituted with 1 or 2 C 1-6 alkyl groups.
  • Ring A represents cyclohexene
  • R 1 represents a C 1-6 alkyl group substituted with a halogen atom
  • Partial structural formula of formula (I) Is (Wherein D 5 to D 7 rings each represent a ring substituted with 1 to 3 C 1-6 alkyl groups substituted with a halogen atom, and E 5 to E 7 rings each represent 1 Or a ring optionally substituted with two C 1-6 alkyl groups.) Or a salt thereof according to the above-mentioned [1].
  • a method for enhancing AMPA receptor function comprising administering an effective amount of the compound according to [1] above or a salt thereof, or a prodrug thereof to a mammal.
  • a method for preventing or treating depression, schizophrenia, or attention deficit / hyperactivity disorder which comprises administering an effective amount of the compound or salt thereof, or prodrug thereof according to [1] to a mammal.
  • Method. Use of the compound of the above-mentioned [1] or a salt thereof, or a prodrug thereof for producing an AMPA receptor function potentiator.
  • the present invention also provides the compounds, medicaments, methods, uses and the like described in [1 ′] to [10 ′] below.
  • [1 '] Formula (I) [Where: R 1 represents a C 1-6 alkyl group which may be substituted with a halogen atom, Ring A represents an optionally substituted carbocyclic ring having 5 to 8 carbon atoms, Partial structural formula of formula (I) A group represented by the formula (1) represents a condensed heterocyclic group which may have a substituent, containing only 1 to 4 nitrogen atoms as a hetero atom, n represents 1 or 2.
  • a method for enhancing AMPA receptor function comprising administering an effective amount of the compound or prodrug thereof according to [1 ′] to a mammal.
  • a method for preventing or treating depression, schizophrenia, or attention deficit hyperactivity disorder (ADHD) comprising administering an effective amount of the compound or prodrug thereof according to [1 '] to a mammal Method.
  • the “aromatic ring” means a ring that is interpreted according to the Hückel rule and has 4n + 2 electrons (n is a natural number) involved in aromaticity in the ring.
  • examples of the “aromatic ring” include “aromatic carbocycle” and “aromatic heterocycle”.
  • “non-aromatic ring” means a ring that is not an aromatic ring. Examples of the “non-aromatic ring” include “non-aromatic carbocycle” and “non-aromatic heterocycle”.
  • examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • examples of the “C 1-6 alkyl (group)” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl. Hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
  • examples of the “C 3-6 cycloalkyl (group)” include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • examples of the “C 1-6 alkoxy (group)” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, neopentyloxy, and hexyl. Oxy is mentioned.
  • examples of the “C 1-6 alkoxy-carbonyl (group)” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, and tert-butoxycarbonyl.
  • examples of the “carbocycle having 5 to 8 carbon atoms” include: Benzene ring, C 5-8 cycloalkane (eg, cyclopentane, cyclohexane, cycloheptane, cyclooctane), C 5-8 cycloalkene (e.g., cyclopentene, cyclohexene, cycloheptene, cyclooctene), and C 5-8 cycloalkadiene (e.g., cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene), and the like.
  • C 5-8 cycloalkane eg, cyclopentane, cyclohexane, cycloheptane, cyclooctane
  • C 5-8 cycloalkene e.g., cyclopentene, cyclohexene, cyclohe
  • R 1 represents a C 1-6 alkyl group which may be substituted with a halogen atom.
  • the number of the halogen atoms is 1 or more (preferably 1 to 3).
  • R 1 is preferably, for example, trifluoromethyl.
  • the A ring represents a carbocyclic ring having 5 to 8 carbon atoms which may have a substituent.
  • the “carbon ring having 5 to 8 carbon atoms” is preferably, for example, C 5-8 cycloalkene (eg, cyclopentene, cyclohexene, cycloheptene, cyclooctene), and more preferably cyclohexene.
  • the “carbocycle having 5 to 8 carbon atoms” may have one or more (preferably 1 to 3) substituents at substitutable positions.
  • substituents for example, (i) a halogen atom, (ii) a cyano group, (iii) a hydroxy group, (iv) a nitro group, (v) formyl group, (vi) an amino group, (vii) mono- or di-C 1-6 alkylamino group (eg methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino), (viii) a C 1-6 alkyl-carbonylamino group (eg acetylamino, ethylcarbonylamino), (ix) a C 1-6 alkoxy-carbonylamino group (eg, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino), (x) a C 3-8 cycloalkyl group optionally substituted with one or more (preferably 1 to 3) substituents selected from (a) a
  • a C 6-14 aryl group optionally substituted by eg, phenyl, 1-naphthyl, 2-naphthyl
  • a C 1-6 alkoxy group eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, optionally substituted with one or more (preferably 1 to 3) halogen atoms; tert-butoxy
  • a C 3-6 cycloalkyl-oxy group eg, cyclopropoxy
  • xv) C 7-16 aralkyloxy group eg, benzyloxy
  • (xvi) (a) a C 1-6 alkoxy group (eg, methoxy), (b) a C 1-6 alkyl group (eg, methyl), (c) C 3-6 cycloalkyl group (e.g.
  • cyclopropyl and (d) 1 or more selected from halogen atom (preferably 1 to 3) which may be substituted with a substituent of C 6 A -14 aryloxy group (eg phenoxy), (xvii) carboxyl group, (xviii) a C 1-6 alkoxy-carbonyl group, (xix) C 7-16 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl), (xx) C 6-14 aryloxy-carbonyl group (eg, phenoxycarbonyl), (xxi) a C 1-6 alkyl-carbonyl group (eg, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, 2,2-dimethylpropylcarbonyl), (xxii) a C 3-8 cycloalkyl-carbonyl group (eg, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentyl
  • C 1-6 alkoxy group e.g. methoxy
  • C 3-6 cycloalkyl It may be substituted with one or more (preferably 1 to 3) substituents selected from an alkyl group (eg, cyclopropyl), and may be condensed with a benzene ring (eg, benzothienyl).
  • xlii a 5- to 8-membered non-aromatic heterocyclic-carbonyl group having 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom (eg, pyrrolidinylcarbonyl, tetrahydro Furylcarbonyl, tetrahydrothienylcarbonyl, piperidylcarbonyl, tetrahydropyranylcarbonyl, morpholinylcarbonyl, thiomorpholinylcarbonyl, piperazinylcarbonyl), (xliii) a 5- to 8-membered aromatic heterocyclic-carbonyl group having 1 to 4 heteroatoms selected from a nitrogen atom, sulfur atom and oxygen atom in addition to carbon atoms (eg, furylcarbonyl, thienylcarbonyl, pyrrole) Rucarbonyl, oxazolylcarbonyl, isoxazolylcarbonyl group
  • Partial structural formula of formula (I) Is a condensed heterocyclic group which may have a substituent and contains only 1 to 4 nitrogen atoms as a hetero atom.
  • n represents 1 or 2.
  • the fused heterocyclic group is linked to the nitrogen atom constituting the amide bond represented by formula (I) at any atom constituting the 5-membered ring or 6-membered ring.
  • the condensed heterocyclic group for example, And a group formed by removing one hydrogen atom from.
  • Partial structural formula of the formula (I) As the group represented by (Wherein X, Y and Z are the same or different and represent a nitrogen atom or a carbon atom which may have a substituent, provided that all of X, Y and Z are simultaneously nitrogen atoms. Absent.) The group represented by these is preferable. When the “optionally substituted carbon atom” does not have a substituent, X, Y and Z are —CH ⁇ .
  • Partial structural formula of the formula (I) More preferably, the group represented by (Where R 2 represents a halogen atom, C 1-6 alkyl group substituted by a halogen atom, C 1-6 alkyl group substituted by a hydroxy group or C 1-6 alkoxy, - indicates a carbonyl group, X a represents a nitrogen atom or —CH ⁇ ; Y a represents a nitrogen atom or —CR 3 ⁇ (R 3 represents a hydrogen atom or a C 1-6 alkyl group); Z a represents a nitrogen atom or —CR 4 ⁇ (R 4 represents a hydrogen atom or a C 1-6 alkyl group).
  • R 2 represents a halogen atom, C 1-6 alkyl group substituted by a halogen atom, C 1-6 alkyl group substituted by a hydroxy group or C 1-6 alkoxy, - indicates a carbonyl group
  • X a represents a nitrogen atom or —CH ⁇
  • fused heterocyclic groups may have one or more (preferably 1 to 3) substituents at substitutable positions.
  • substituents include those exemplified as the substituent for ring A and the same ones.
  • the substituent is preferably, for example, (1) a halogen atom (preferably a fluorine atom, a chlorine atom, a bromine atom), (2) a C 1-6 alkyl group (preferably, optionally substituted with one or more (preferably 1 to 3) substituents selected from (a) a halogen atom, and (b) a hydroxy group Methyl, ethyl, trifluoromethyl), and (3) a C 1-6 alkoxy-carbonyl group (preferably methoxycarbonyl).
  • a halogen atom preferably a fluorine atom, a chlorine atom, a bromine atom
  • C 1-6 alkyl group preferably, optionally substituted with one or more (preferably 1 to 3) substituents selected from (a) a halogen atom, and (b) a hydroxy group Methyl, ethyl, trifluoromethyl
  • a C 1-6 alkoxy-carbonyl group preferably methoxycarbony
  • D 1 ⁇ D 4 ring are each halogen atom, C 1-6 alkyl group substituted by a halogen atom, C 1-6 alkyl group substituted by a hydroxy group, and C 1-6 alkoxy - selected from a carbonyl group
  • a ring substituted with 1 to 3 substituents of The E 1 to E 4 rings each represent a ring optionally substituted with 1 or 2 C 1-6 alkyl groups.
  • R a is halogen atom, C 1-6 alkyl group substituted by a halogen atom, C 1-6 alkyl group substituted by a hydroxy group or C 1-6 alkoxy, - indicates a carbonyl radical
  • R b and R c are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group. It is group represented by these.
  • the number of substituents on the D 1 to D 4 rings is preferably one, and the number of substituents on the E 1 to E 4 rings is preferably 0 or 1.
  • Partial structural formula of formula (I) And the ring A is, for example, an unsubstituted carbocyclic ring having 5 to 8 carbon atoms (more preferably, for example, a C 5-8 cycloalkene, particularly preferably, for example, And cyclohexene) are more preferable.
  • Compound (I) is preferably, for example, R 1 is trifluoromethyl; Ring A is a C 5-8 cycloalkene, Partial structural formula of formula (I)
  • a halogen atom preferably a fluorine atom, a chlorine atom, a bromine atom
  • (2) (a) one or more (preferably 1 to 3) halogen atoms
  • (b) a C 1-6 alkyl group optionally substituted with a substituent selected from a hydroxy group (preferably, Methyl, ethyl, trifluoromethyl)
  • C 1-6 alkoxy-carbonyl group preferably methoxycarbonyl
  • ring A represents cyclohexene
  • R 1 represents a C 1-6 alkyl group substituted with a halogen atom
  • the E 1 to E 4 rings each represent a ring optionally substituted with 1 or 2 C 1-6 alkyl groups.
  • the number of substituents on the D 1 to D 4 rings is preferably one
  • the number of substituents on the E 1 to E 4 rings is preferably 0 or 1.
  • Partial structural formula The group represented by (Wherein, R a is halogen atom, C 1-6 alkyl group substituted by a halogen atom, C 1-6 alkyl group substituted by a hydroxy group or C 1-6 alkoxy, - indicates a carbonyl radical, R b and R c are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group. It is group represented by these.
  • ring A represents cyclohexene
  • R 1 represents a C 1-6 alkyl group substituted with a halogen atom
  • Partial structural formula Is (Wherein D 5 to D 7 rings each represent a ring substituted with 1 to 3 C 1-6 alkyl groups substituted with a halogen atom, and E 5 to E 7 rings each represent 1 Or a ring optionally substituted with two C 1-6 alkyl groups.)
  • the number of substituents in the D 5 to D 7 rings is preferably 1, and the number of substituents in the E 5 to E 7 rings is preferably 0 or 1.
  • R a represents a C 1-6 alkyl group substituted with a halogen atom
  • R b and R c are the same or different and each represents a hydrogen atom or a C 1-6 alkyl group. It is group represented by these.
  • Example 6 N- [3-Methyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-8-yl] -2- [3- (trifluoromethyl) -4,5,6 , 7-Tetrahydro-1H-indazol-1-yl] acetamide, or a salt thereof.
  • Example 8 N- [6- (Trifluoromethyl) imidazo [1,2-a] pyridin-8-yl] -2- [3- (trifluoromethyl) -4,5,6,7-tetrahydro -1H-indazol-1-yl] acetamide, or a salt thereof.
  • Example 11 N- [3-Methyl-6- (trifluoromethyl) [1,2,4] triazolo [4,3-a] pyridin-8-yl] -2- [3- (trifluoromethyl ) -4,5,6,7-tetrahydro-1H-indazol-1-yl] acetamide, or a salt thereof.
  • Example 12 N- [2-Methyl-6- (trifluoromethyl) [1,2,4] triazolo [1,5-a] pyridin-8-yl] -2- [3- (trifluoromethyl ) -4,5,6,7-tetrahydro-1H-indazol-1-yl] acetamide, or a salt thereof.
  • Example 13 2- [3- (Trifluoromethyl) -4,5,6,7-tetrahydro-1H-indazol-1-yl] -N- [6- (trifluoromethyl) [1,2, 4] Triazolo [1,5-a] pyridin-8-yl] acetamide, or a salt thereof.
  • Example 14 2- [3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-indazol-1-yl] -N- [6- (trifluoromethyl) [1,2, 4] Triazolo [4,3-a] pyridin-8-yl] acetamide, or a salt thereof.
  • examples of such a salt include a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, and a basic or acidic amino acid.
  • examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt; ammonium salt and the like.
  • salts with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like.
  • salts with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Preferable examples of the salt with organic acid include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- Examples thereof include salts with toluenesulfonic acid and the like.
  • Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like.
  • Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
  • Compound (I) is, for example, 1) Compound (II): (Wherein each symbol is as defined above) and compound (III): (Wherein n represents an integer of 0 or 1) is condensed with a known dehydrating condensing agent; or 2) the carboxyl group of compound (II) is activated by a known activation method, and then the compound ( A method of reacting III); Etc. can be manufactured.
  • Compound (I) can be produced by condensing compound (II) and compound (III) with a known dehydration condensation agent.
  • the dehydrating condensing agent used in this reaction include N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) or its hydrochloride, N, N′-carbonyl Diimidazole, 1H-benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluro Nitrohexafluorophosphate (HATU), 2-chloro-1,3-dimethylimidazolium chloride, and bromotripyrrolidinophosphonium hexafluorophosphate (PyBrop), diethylphosphorocyanidate
  • This reaction may be carried out as necessary, for example, 1-hydroxybenzotriazole (HOBt); or a base such as N, N-diisopropylethylamine, N-methylmorpholine, triethylamine, and 4- (N, N-dimethylamino) pyridine.
  • HOBt 1-hydroxybenzotriazole
  • a base such as N, N-diisopropylethylamine, N-methylmorpholine, triethylamine, and 4- (N, N-dimethylamino) pyridine.
  • This reaction is preferably carried out in a known solvent, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate Hydrocarbons such as cyclohexane and n-hexane; aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran, diethyl ether, dioxane and 1,2-dimethoxyethane; or solvents such as nitriles such as acetonitrile Done in.
  • amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone
  • halogenated hydrocarbons such as dichloromethane
  • esters such as ethyl acetate Hydrocarbons such as cyclohexane and n-hex
  • compound (II) and compound (III) are dissolved in a solvent such as N, N-dimethylformamide, and O- (7-aza) is used as a dehydrating condensing agent in the presence of N, N-diisopropylethylamine. This is done by adding benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (HATU).
  • the compound (III) is usually used in an amount of about 1 to about 5 moles per mole of the raw material compound (compound (II)), and the amount of the condensing agent is about 1 to about 100 equivalents, preferably 1 to 5 equivalents.
  • the reaction temperature is usually 0 ° C. to 100 ° C., preferably 0 ° C. to 60 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 60 hours.
  • Compound (I) can also be produced by reacting compound (III) after activating the carboxyl group of compound (II) by a known activation method.
  • a method for activating the carboxyl group of compound (II) a general method is adopted, for example, acid anhydride using chloroformate, pivaloyl chloride, 2,4,6-trichlorobenzoyl chloride or the like. How to make; Examples thereof include a method of forming an acid halide using thionyl chloride or oxalyl chloride; and a method of forming an ester with 1-hydroxybenzotriazole or pentafluorophenol using a dehydrating condensing agent.
  • a typical example is a method of acid halide, and as acid halide, Compound (IIa): (Wherein X represents a halogen atom, and other symbols are as defined above).
  • the acid halide can be produced, for example, by treating compound (II) with a halogenating agent such as thionyl chloride or oxalyl chloride.
  • a halogenating agent such as thionyl chloride or oxalyl chloride.
  • N, N-dimethylformamide may be added as an additive.
  • This reaction is preferably performed in a known solvent, for example, halogenated hydrocarbons such as dichloromethane; ethers such as tetrahydrofuran and diethyl ether; or aromatic hydrocarbons such as toluene or without solvent. .
  • This reaction is preferably carried out by adding oxalyl chloride to compound (II) in the presence of N, N-dimethylformamide in tetrahydrofuran.
  • the halogenating agent is usually used in an amount of about 1 to about 100 equivalents, preferably 1 to 5 equivalents, relative to 1 mol of the starting compound (Compound II).
  • the reaction temperature is usually ⁇ 78 ° C. to 100 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • reaction of compound (IIa) with compound (III) is preferably carried out in a known solvent, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone; halogenation such as dichloromethane Hydrocarbons; Esters such as ethyl acetate; Hydrocarbons such as cyclohexane and n-hexane; Aromatic hydrocarbons such as toluene; Ethers such as tetrahydrofuran, diethyl ether, dioxane and 1,2-dimethoxyethane It is carried out in a solvent. These solvents may be mixed in an appropriate ratio or may not be used.
  • amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone
  • halogenation such as dichloromethane Hydrocarbons
  • Esters such as ethyl acetate
  • This reaction preferably uses about 0.5 to about 10 moles, preferably about 1 to about 5 moles of compound (III) per mole of compound (IIa), and the base is about 0.1 To about 100 equivalents, preferably from about 1 to about 5 equivalents.
  • the reaction temperature is generally 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Compound (I) is, for example, Compound (IV): (Wherein R 2 represents an optionally substituted C 1-6 alkyl (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, etc.) ester; Wherein each symbol is as defined above) and compound (III): It can also be produced by reacting. This reaction is performed, for example, by a method in which compound (IV) and compound (III) coexist and are heated.
  • R 2 represents an optionally substituted C 1-6 alkyl (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, etc.) ester; Wherein each symbol is as defined above) and compound (III): It can also be produced by reacting. This reaction is performed, for example, by a method in which compound (IV) and compound (III) coexist and are heated.
  • This reaction may be carried out in the presence of a base such as sodium hydride, sodium methoxide, alkyllithium, Grignard reagent; and a metal reagent such as trimethylaluminum as necessary.
  • a base such as sodium hydride, sodium methoxide, alkyllithium, Grignard reagent; and a metal reagent such as trimethylaluminum as necessary.
  • This reaction is preferably carried out in a known solvent, for example, amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; halogenated hydrocarbons such as dichloromethane; esters such as ethyl acetate Hydrocarbons such as cyclohexane and n-hexane; aromatic hydrocarbons such as toluene; ethers such as tetrahydrofuran, diethyl ether, dioxane and 1,2-dimethoxyethan
  • reaction temperature is usually 0 ° C. to 200 ° C., preferably 40 ° C. to It is carried out at a reaction temperature of 200 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Compound (II) used for the production of compound (I) is, for example, Compound (IV): (Wherein each symbol is as defined above) can be produced by the method 1) or 2) of hydrolysis.
  • This reaction generally employs a method in which an ester is hydrolyzed under basic conditions.
  • the reaction is carried out by treatment with an alkali such as lithium hydroxide, sodium hydroxide, or potassium hydroxide.
  • an alkali such as lithium hydroxide, sodium hydroxide, or potassium hydroxide.
  • the compound (IV) is dissolved in an alcohol such as methanol and ethanol; or a water-soluble solvent such as tetrahydrofuran and dioxane; or a mixed solvent thereof, an aqueous sodium hydroxide solution, an aqueous lithium hydroxide solution, or the like. It is carried out by treating with an alkaline aqueous solution.
  • reaction temperature is generally 0 ° C. to 100 ° C., preferably 20 ° C. to 100 ° C.
  • reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Compound (II) can also be produced by a method in which an ester of compound (IV) is hydrolyzed under acidic conditions. For example, it is carried out by treatment with an acid such as hydrochloric acid, sulfuric acid, and nitric acid.
  • an acid such as hydrochloric acid, sulfuric acid, and nitric acid.
  • compound (IV) is dissolved in alcohols such as methanol and ethanol; or water-soluble solvents such as tetrahydrofuran and dioxane; or a mixed solvent thereof, and treated with an aqueous acid solution such as hydrochloric acid and sulfuric acid. Is done.
  • the reaction temperature is generally 0 ° C. to 100 ° C., preferably 20 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • Compound (IV) used for the production of compound (II) is, for example, Compound (V): (Each symbol in the formula is as defined above) and Compound (VI): (Wherein, Xa represents a leaving group, and other symbols are as defined above).
  • Examples of the “leaving group” represented by Xa include halogen atoms; sulfonyloxy groups such as p-toluenesulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, etc., preferably chlorine, bromine And halogen atoms such as iodine.
  • the reaction between compound (V) and compound (VI) is preferably potassium tert-butoxide, sodium hydride, triethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), carbonic acid
  • a base such as potassium and cesium carbonate
  • a solvent such as aromatic hydrocarbons such as toluene; ethers such as 1,4-dioxane and tetrahydrofuran; or amides such as N, N-dimethylformamide Done.
  • This reaction is preferably carried out by dissolving compound (V) in a solvent such as N, N-dimethylformamide, adding potassium tert-butoxide, and then adding compound (VI).
  • reaction about 1 to about 5 mol of compound (VI) is usually used per 1 mol of the starting compound (compound (V)), and the amount of the base is about 0.1 to about 100 equivalents, preferably 1 ⁇ 5 equivalents.
  • the reaction temperature is usually 0 ° C. to 200 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is about 0.1 to about 100 hours, preferably about 0.5 to about 50 hours.
  • the functional group in the molecule can be converted to the target functional group by combining known chemical reactions.
  • the chemical reaction include an oxidation reaction, a reduction reaction, an alkylation reaction, a hydrolysis reaction, an amination reaction, an amidation reaction, an esterification reaction, an aryl coupling reaction, and a deprotection reaction.
  • a protective group generally used in peptide chemistry or the like is introduced into these groups.
  • the target compound can be obtained by removing the protecting group as necessary after the reaction.
  • amino-protecting group examples include, for example, formyl, C 1-6 alkylcarbonyl (eg, acetyl, ethylcarbonyl, etc.), phenylcarbonyl, C 1-6 alkoxy-carbonyl (which may each have a substituent) For example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), phenyloxycarbonyl, C 7-10 aralkyl-carbonyl (eg, benzylcarbonyl, etc.), trityl, phthaloyl, N, N-dimethylaminomethylene, etc. .
  • Substituents for the “amino-protecting group” include halogen atoms (eg, fluorine, chlorine, bromine, iodine), C 1-6 alkyl-carbonyl (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), and The number of substituents including a nitro group is 1 to several (eg, 3).
  • Examples of the protecting group for the carboxyl group include a C 1-6 alkyl group, a C 7-11 aralkyl group (eg, benzyl), a phenyl group, a trityl group, a substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), and C 2-6 alkenyl groups (eg, 1-allyl). These groups may be substituted with 1 to 3 halogen atoms, C 1-6 alkoxy groups, nitro groups and the like.
  • Examples of the protecting group for the hydroxy group include a C 1-6 alkyl group, a phenyl group, a trityl group, a C 7-10 aralkyl group (eg, benzyl), a formyl group, a C 1-6 alkyl-carbonyl group, a benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert -Butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like.
  • a C 1-6 alkyl group eg, phenyl group, a trityl group, a C 7-10
  • These groups may be substituted with 1 to 3 halogen atoms, a C 1-6 alkyl group, a C 1-6 alkoxy group, a nitro group and the like.
  • the protecting group for the carbonyl group include cyclic acetals (eg, 1,3-dioxane), acyclic acetals (eg, di-C 1-6 alkylacetal) and the like.
  • the above-mentioned method for removing the protecting group can be carried out according to a known method, for example, the method described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980).
  • a method using acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (eg, trimethylsilyl iodide, trimethylsilyl bromide), A reduction method or the like is used.
  • Compounds (I), (II) and (IV) can be isolated and purified by known means, for example, solvent extraction, liquid conversion, phase transfer, concentration, crystallization, recrystallization, chromatography and the like.
  • the starting compounds of compounds (I), (II) and (IV) or salts thereof can be isolated and purified by the same known means as described above, but the following reaction mixture can be used as it is without isolation. It may be used as a raw material for the process.
  • compound (I) can be synthesized.
  • compound (I) has an isomer such as an optical isomer, a stereoisomer, a positional isomer, a rotational isomer, etc.
  • any one of the isomers and a mixture are encompassed in compound (I).
  • compound (I) has an optical isomer
  • the optical isomer resolved from the racemate is also encompassed in compound (I).
  • Each of these isomers can be obtained as a single product by a known synthesis method or separation method (concentration, solvent extraction, column chromatography, recrystallization, etc.).
  • Compound (I) may be a crystal, and it is included in compound (I) regardless of whether the crystal form is a single crystal form or a mixture of crystal forms. Crystals can be produced by crystallization by applying a crystallization method known per se.
  • Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • co-crystals or co-crystal salts are two or more unique at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). Means a crystalline substance composed of a solid.
  • the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
  • Compound (I) may be a solvate (eg, a hydrate) or a non-solvate (eg, an anhydride), and both are encompassed in compound (I).
  • a compound labeled or substituted with an isotope eg, 2 H, 3 H, 11 C, 14 C, 18 F, 35 S, 125 I and the like
  • the prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc.
  • a compound that changes to compound (I) by hydrolysis or the like due to gastric acid or the like As a prodrug of the compound (I), a compound in which the amino of the compound (I) is acylated, alkylated or phosphorylated (eg, the amino of the compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, ( 5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation or tert-butylated compounds); compounds ( Compounds wherein the hydroxy group of I) is acylated, alkylated, phosphorylated or borated (eg, hydroxy of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated
  • compound (I) can be produced from compound (I) by a method known per se.
  • the prodrug of compound (I) changes to compound (I) under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Drugs”, Volume 7, Molecular Design, pages 163 to 198. There may be.
  • Compound (I) and prodrugs thereof (hereinafter sometimes simply referred to as the compound of the present invention) exhibit an excellent AMPA receptor function-enhancing action, and are therefore useful as safe drugs based on these actions. is there.
  • the compound of the present invention having an excellent AMPA receptor function-enhancing action is effective against mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human, etc.)
  • mammals eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human, etc.
  • Psychiatric disorders eg, depression, major depression, bipolar depression, mood disorders, affective disorders (such as seasonal affective disorders), recurrent depression, postpartum depression, stress disorder, depressive symptoms, Gonorrhea, anxiety, generalized anxiety disorder, anxiety syndrome, panic disorder, phobia, social phobia, social anxiety disorder, obsessive compulsive disorder, post-traumatic stress syndrome, post-traumatic stress disorder, taurette syndrome, autism ,
  • the compound of the present invention has an excellent AMPA receptor function enhancing action, an excellent therapeutic effect on the above diseases can be expected.
  • the compounds of the present invention have excellent pharmacokinetics (eg, blood drug half-life) and low toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc.)
  • pharmacokinetics eg, blood drug half-life
  • low toxicity eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc.
  • a pharmaceutical composition mixed with a pharmaceutically acceptable carrier or the like a mammal (eg, human, monkey, cow, horse, pig, mouse, Rats, hamsters, rabbits, cats, dogs, sheep, goats, etc.) and can be safely administered orally or parenterally.
  • “Parenteral” includes intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, rectal, intravaginal, intraperitoneal, and direct lesion administration. Including.
  • the medicament containing the compound of the present invention can be obtained by singly using the compound of the present invention alone or pharmaceutically with the compound of the present invention according to a method known per se (eg, a method described in the Japanese Pharmacopoeia) as a method for producing a pharmaceutical preparation. It can be used as a pharmaceutical composition mixed with an acceptable carrier.
  • Examples of the medicament containing the compound of the present invention include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (soft capsules, microcapsules).
  • controlled-release formulations eg, immediate-
  • excipient examples include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.
  • lubricant examples include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • binder examples include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, and the like.
  • Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like.
  • Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone And hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and the like.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate
  • polyvinyl alcohol polyvinylpyrrolidone
  • hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose
  • Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
  • Examples of soothing agents include benzyl alcohol.
  • Examples of preservatives include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid, and the like.
  • Examples of the antioxidant include sulfite, ascorbic acid, ⁇ -tocopherol and the like.
  • the dose of the compound of the present invention varies depending on the administration route, symptoms and the like.
  • a schizophrenic patient adult, body weight 40 to 80 kg, eg 60 kg
  • Kg body weight preferably 0.01 to 100 mg / kg body weight per day, more preferably 0.1 to 10 mg / kg body weight per day. This amount can be administered in 1 to 3 divided doses per day.
  • pharmaceutically acceptable carrier various organic or inorganic carriers conventionally used as pharmaceutical materials can be used.
  • excipients lubricants, binders and disintegrants
  • liquid preparations solvents, solubilizers, suspending agents, isotonic agents, buffering agents, and the like Soothing agents and the like are used.
  • preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.
  • the pharmaceutical composition varies depending on the dosage form, administration method, carrier, etc., but the compound of the present invention is usually 0.01 to 100% (w / w), preferably 0.1 to 95% (w / W), it can be produced according to a conventional method.
  • the compound of the present invention may be used in combination with other active ingredients (hereinafter abbreviated as concomitant drugs).
  • concomitant drug examples include the following. Benzodiazepines (chlordiazepoxide, diazepam, potassium chlorazebuate, lorazepam, clonazepam, alprazolam, etc.), L-type calcium channel inhibitors (pregabalin, etc.), tricyclic or tetracyclic antidepressants (imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, Clomipramine hydrochloride, etc.), selective serotonin reuptake inhibitors (fluvoxamine maleate, floxetine hydrochloride, citalopram hydrochloride, sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalate, etc.), serotonin-noradrenaline reuptake inhibitors (venlafaxine hydrochloride, hydrochloric acid) Duroxetine, desvenlafaxine hydrochloride, etc.
  • the dosage can be reduced.
  • the drug used in combination with the compound of the present invention can be selected according to the patient's symptoms (mild, severe, etc.), (3) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the treatment period can be set longer. (4) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the therapeutic effect can be sustained. (5) By using the compound of the present invention in combination with a concomitant drug, excellent effects such as a synergistic effect can be obtained.
  • the combination drug of the present invention is referred to as “the combination drug of the present invention”.
  • the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention or the pharmaceutical composition thereof and the concomitant drug or the pharmaceutical composition thereof are administered to the subject of administration. They may be administered at the same time or may be administered with a time difference.
  • the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • the administration form of the concomitant drug of the present invention is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration.
  • Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and (2) separate preparation of the compound of the present invention and the concomitant drug.
  • the medicament containing the compound of the present invention is a pharmacologically acceptable compound of the present compound alone or with the compound of the present invention according to a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacopoeia). It can be used as a pharmaceutical composition mixed with a carrier.
  • examples of the medicament containing the compound of the present invention include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (soft capsules, microcapsules).
  • controlled release formulations eg, immediate release formulations, sustained release
  • Examples of the pharmacologically acceptable carrier that may be used in the production of the concomitant drug of the present invention include various organic or inorganic carrier substances commonly used as a pharmaceutical material.
  • excipients lubricants, binders and disintegrants can be used.
  • solvents, solubilizers, suspending agents, tonicity agents, buffers, soothing agents, and the like can be used.
  • additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
  • excipient examples include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.
  • lubricant examples include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • binder examples include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, and the like.
  • Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like.
  • Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone And hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and the like.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate
  • polyvinyl alcohol polyvinylpyrrolidone
  • hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose
  • Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
  • Examples of soothing agents include benzyl alcohol.
  • Examples of preservatives include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid, and the like.
  • Examples of the antioxidant include sulfite, ascorbic acid, ⁇ -tocopherol and the like.
  • the compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, based on the whole preparation. More preferably, it is about 0.5 to 20% by weight.
  • the content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about the whole preparation. About 0.5 to 20% by weight.
  • the content of additives such as carriers in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. .
  • the same content may be used when the compound of the present invention and the concomitant drug are formulated separately.
  • room temperature usually indicates about 10 ° C. to about 35 ° C.
  • % Indicates weight percent unless otherwise specified.
  • Other abbreviations used in the text have the following meanings. s is a singlet, d is a doublet, t is a triplet, q is a quartet, m is a multiplet, brs is a broad singlet, J is a coupling constant (Coupling constant).
  • LC-MS Liquid chromatography-mass spectrometry spectrum
  • ESI Electrospray ionization method
  • TLC Thin layer chromatography M: Molar concentration
  • N Normal BINAP: 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl
  • BSA bovine serum albumin
  • DCM dichloromethane
  • DIAD diisopropyl azodicarboxylate
  • DIEA N, N-diisopropylethylamine
  • DMA N, N-dimethylacetamide
  • DMF N, N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • EDCI 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • EDTA ethylenediaminetetraacetic acid
  • HATU O- (7-azabenzotriazol-1-yl) -1,1,3,3-
  • Reference example 4 8-Bromo-6-chloro-2,3-dimethylimidazo [1,2-a] pyridine 3-bromo-5-chloropyridin-2-amine (4.97 g, 24.0 mmol), 3-bromobutane-2- A mixture of ON (2.81 mL, 26.3 mmol), disodium hydrogen phosphate (5.11 g, 36 mmol) and n-butanol (50 mL) was heated to reflux for 120 hours. A saturated aqueous sodium hydrogen carbonate solution was added at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Reference Example 14 8-bromo-3-methyl-6- (trifluoromethyl) imidazo [1,2-a] pyridine 2-amino-3-bromo-5-trifluoromethylpyridine (3.00 g, 12.4 mmol), 2- A mixture of bromopropanal (3.41 g, 24.9 mmol) and disodium hydrogen phosphate (2.65 g, 18.6 mmol) in n-butanol (25 mL) was stirred at 120 ° C. for 3 days and cooled to room temperature. . The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 ⁇ 50 mL).
  • Reference Example 17 8-Bromo-2-methyl-6- (trifluoromethyl) imidazo [1,2-a] pyridine 2-amino-3-bromo-5-trifluoromethylpyridine (3.00 g, 12.4 mmol), bromoacetone A mixture of (1.14 mL, 13.6 mmol) and disodium hydrogen phosphate (2.65 g, 18.6 mmol) in n-butanol (25 mL) was stirred at 120 ° C. for 3 days and cooled to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 ⁇ 50 mL).
  • Reference Example 25 8-bromo-2-ethyl-3-methyl-6- (trifluoromethyl) imidazo [1,2-a] pyridine 2-amino-3-bromo-5-trifluoromethylpyridine (500 mg, 2.07 mmol), A mixture of 2-bromopentan-3-one (856 mg, 5.19 mmol), titanium tetrachloride (171 ⁇ L, 1.55 mmol) and triethylamine (173 ⁇ L, 1.24 mmol) in chloroform (2.0 mL) was stirred with 110 Microwave irradiation at 25 ° C. for 25 minutes. The reaction mixture was diluted with dichloromethane (15 mL) and 10% aqueous potassium carbonate (15 mL).
  • Reference Example 28 8-bromo-2,3-dimethyl-6- (trifluoromethyl) imidazo [1,2-a] pyridine 2-amino-3-bromo-5-trifluoromethylpyridine (3.00 g, 12.4 mmol), A mixture of 3-bromobutan-2-one (2.76 g, 18.2 mmol) and disodium hydrogen phosphate (3.53 g, 23.9 mmol) in n-butanol (33.0 mL) was stirred at 120 ° C. for 3 days. And cooled to room temperature. The reaction mixture was diluted with water (75 mL) and extracted with ethyl acetate (3 ⁇ 75 mL).
  • Example 2 N- [6- (1-hydroxy-1-methylethyl) -2,3-dimethylimidazo [1,2-a] pyridin-8-yl] -2- [3- (trifluoromethyl) -4,5 , 6,7-Tetrahydro-1H-indazol-1-yl] acetamide Methyl 2,3-dimethyl-8-( ⁇ [3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-indazol-1-yl] acetyl ⁇ amino) imidazo synthesized in Example 1 [ 1,2-a] pyridine-6-carboxylate (42 mg, 0.09 mmol) and THF (0.5 mL) were mixed with methylmagnesium bromide (3 M solution in diethyl ether) (0.16 mL, 0.47 mmol) at 0 ° C.
  • Example 3 N- (6-Chloro-2,3-dimethylimidazo [1,2-a] pyridin-8-yl) -2- [3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H- Indazol-1-yl] acetamide [3- (Trifluoromethyl) -4,5,6,7-tetrahydro-1H-indazol-1-yl] acetic acid (133 mg, 0.54 mmol), 6-chloro-2,3-synthesized in Reference Example 6 HATU (205 mg, 0.54 mmol) was added to a mixture of dimethylimidazo [1,2-a] pyridin-8-amine hydrochloride (104 mg, 0.45 mmol), diisopropylethylamine (0.35 mL, 2.02 mmol) and DMF (5 mL).
  • Example 7 N- [2-Methyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-8-yl] -2- [3- (trifluoromethyl) -4,5,6,7-tetrahydro- 1H-Indazol-1-yl] acetamide HATU (795 mg, 795 mg, 2-methyl-6- (trifluoromethyl) imidazo [1,2-a] pyridin-8-amine (300 mg, 1.39 mmol) synthesized in Reference Example 19 was added to a DMF (3.5 mL) solution.
  • Example 8 N- [6- (trifluoromethyl) imidazo [1,2-a] pyridin-8-yl] -2- [3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-indazole- 1-yl] acetamide
  • 6- (trifluoromethyl) imidazo [1,2-a] pyridin-8-amine synthesized in Reference Example 13 in DMF (8.00 mL) HATU (368 mg, 0.967 mmol), N, N-diisopropylethylamine (160 ⁇ L, 0.967 mmol) and [3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-indazol-1-yl] acetic acid (195 mg, 0.967 mmol) were added at room temperature.
  • HATU (795 mg, 2.09 mmol), N, N-diisopropylethylamine (365 ⁇ L, 2.09 mmol) and 3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-indazol-1-yl] acetic acid (519 mg, 2.09 mmol) was added at room temperature.
  • the reaction mixture was stirred for 3 days at room temperature, diluted with water (50 mL) and extracted with ethyl acetate (3 ⁇ 50 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • N, N-diisopropylethylamine (162 ⁇ L, 0.925 mmol) and 3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-indazol-1-yl] acetic acid (230 mg, 0.925 mmol) was added at room temperature.
  • the reaction mixture was stirred at room temperature for 3 days, diluted with water (20 mL) and extracted with ethyl acetate (3 ⁇ 20 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Triethylamine (0.374 mL, 2.69 mmol) was added to a solution of the resulting acid chloride in dichloromethane (5.00 mL), and then 3-methyl-6- (trifluoromethyl) [1,2,4] synthesized in Reference Example 35 was obtained.
  • Triazolo [4,3-a] pyridin-8-amine (150 mg, 0.694 mmol) was added at 0 ° C. The reaction mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure. The residue was extracted with saturated aqueous sodium hydrogen carbonate solution and ethyl acetate (50 mL).
  • Example 13 2- [3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-indazol-1-yl] -N- [6- (trifluoromethyl) [1,2,4] triazolo [1 , 5-a] pyridin-8-yl] acetamide Mixture of [3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-indazol-1-yl] acetic acid (248 mg, 1.00 mmol), THF (5.0 mL) and DMF (5 drops) was added with oxalyl chloride (169 ⁇ L, 2.00 mmol) at 0 ° C. and stirred for 1 hour.
  • Example 14 2- [3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-indazol-1-yl] -N- [6- (trifluoromethyl) [1,2,4] triazolo [4 , 3-a] pyridin-8-yl] acetamide Mixture of [3- (trifluoromethyl) -4,5,6,7-tetrahydro-1H-indazol-1-yl] acetic acid (248 mg, 1.00 mmol), THF (5.0 mL) and DMF (5 drops) was added with oxalyl chloride (169 ⁇ L, 2.00 mmol) at 0 ° C. and stirred for 1 hour.
  • Example 1 (1) 10.0 g of the compound of Example 1 (2) Lactose 70.0g (3) Corn starch 50.0g (4) 7.0g soluble starch (5) Magnesium stearate 3.0 g
  • Example 1 The compound of Example 1 (10.0 g) and magnesium stearate (3.0 g) were granulated with 70 mL of an aqueous solution of soluble starch (7.0 g as soluble starch), dried, lactose (70.0 g) and corn starch ( (Lactose, corn starch, soluble starch and magnesium stearate are all conforming to the 14th revised Japanese Pharmacopoeia). The mixture is compressed to obtain tablets.
  • Test example 1 Construction of expression gene Human GluR1 flip cDNA was artificially synthesized using human brain-derived cDNA (BD Bioscience) as a template. Amplified by The amplified product was digested with restriction enzymes EcoRI and NotI (Takara Shuzo) and then incorporated into the same site of pcDNA3.1 (+) (trade name) (Invitrogen) to construct pcDNA3.1 (+) / human GluR1 flip gene.
  • Human stargazin cDNA was artificially synthesized using human hippocampal cDNA as a template, forward primer GGTCTCGAGGCCACCATGGGGCTGTTTGATCGAGGTGGTTCA (SEQ ID NO: 3) and reverse primer GTTGGATCCTTATAGGGGGGTGGTCCCGGTG
  • the amplified product was digested with restriction enzymes XhoI and BamHI (Takara Shuzo) and then incorporated into the same site of pcDNA3.1 (-) (Invitrogen) to construct pcDNA3.1 Zeo (-) / human stargazin gene.
  • AMPA receptor function-enhancing activity assay method for compounds using calcium influx as an indicator CHO-K1 / GluR1 flip / stargazin expressing cells were seeded at 2 ⁇ 10 4 cells / well in a 96-well black bottom transparent plate (coaster). And cultured at 37 ° C. in a CO 2 incubator (SANYO) for 2 days. The medium of the cell plate was removed, and assay buffer A (D-MEM (Invitrogen), 0.1% BSA (Serological Protein), 20 mM HEPES (Invitrogen))) was added to 50 ⁇ L / well.
  • D-MEM Invitrogen
  • BSA Surological Protein
  • 20 mM HEPES Invitrogen
  • a calcium indicator (Calcium 4 Assay Kit, Molecular Device) supplemented with 2.5 mM probenecid (Invitrogen) was added at 50 ⁇ L / well and allowed to stand in a CO 2 incubator at 37 ° C. for 1 hour.
  • a cell plate is set in CellLux (PerkinElmer), and a mixture of 9 mM glutamic acid (final concentration 3 mM) and test compound diluted with assay buffer B (HBSS (Invitrogen), 0.1% BSA, 20 mM HEPES) is prepared. 50 ⁇ L (test compound concentration: 30 ⁇ M) was added, and the change in fluorescence amount for 3 minutes was measured.
  • the compound of the present invention is useful as a preventive or therapeutic agent for depression, schizophrenia, attention deficit hyperactivity disorder (ADHD) and the like.
  • SEQ ID NO: 1 is a forward primer for GluR1 flip cDNA.
  • SEQ ID NO: 2 is a reverse primer for GluR1 flip cDNA.
  • SEQ ID NO: 3 is a forward primer for stargazin cDNA cDNA.
  • SEQ ID NO: 4 is a reverse primer for stargazin cDNA cDNA.

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Abstract

Cette invention concerne un composé hétérocyclique qui a un effet d'amélioration de la fonction de récepteur AMPA. Plus spécifiquement, un composé représenté par la formule (I) ou un sel de celui-ci est décrit. (Dans la formule, R1 représente un groupe alkyle C1-6 qui peut être substitué par un atome d'halogène ; le cycle A représente un cycle de carbone éventuellement substitué ayant de 5 à 8 atomes de carbone ; le cycle condensé lié à l'atome d'azote de la liaison amide représente un groupe hétérocyclique condensé, éventuellement substitué, qui contient seulement 1 à 4 atomes d'azote à titre d'hétéroatomes ; et n représente 1 ou 2).
PCT/JP2010/005764 2009-09-25 2010-09-24 Composé hétérocyclique Ceased WO2011036885A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8575154B2 (en) 2010-08-10 2013-11-05 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US9493484B2 (en) 2012-02-08 2016-11-15 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
WO2019070044A1 (fr) 2017-10-06 2019-04-11 武田薬品工業株式会社 Composés hétérocycliques
WO2019070043A1 (fr) 2017-10-06 2019-04-11 武田薬品工業株式会社 Composé hétérocyclique
CN113474339A (zh) * 2019-02-22 2021-10-01 詹森药业有限公司 1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-n-(2-(三氟甲基)吡啶-4-基)-1h-吡唑-4-甲酰胺一水合物的结晶形式
US12077521B2 (en) 2016-12-21 2024-09-03 Janssen Pharmaceutica Nv Pyrazole derivatives as MALT1 inhibitors
US12370192B2 (en) 2019-09-16 2025-07-29 Takeda Pharmaceutical Company Limited Azole-fused pyridazin-3(2H)-one derivatives
US12404260B2 (en) 2019-04-11 2025-09-02 Janssen Pharmaceutica Nv Pyridine rings containing derivatives as MALT1 inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007125405A2 (fr) * 2006-05-01 2007-11-08 Pfizer Products Inc. Composés hétérocycliques 2-amino-substitués à cycles fusionnés
WO2008003452A1 (fr) * 2006-07-04 2008-01-10 N.V. Organon Thiophènes substitués par pyrazolealcanamide comme potentiateurs de l'ampa
WO2008148836A1 (fr) * 2007-06-08 2008-12-11 Glaxo Group Limited Composés qui potentialisent le récepteur ampa et leurs utilisations dans des médicaments

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007125405A2 (fr) * 2006-05-01 2007-11-08 Pfizer Products Inc. Composés hétérocycliques 2-amino-substitués à cycles fusionnés
WO2008003452A1 (fr) * 2006-07-04 2008-01-10 N.V. Organon Thiophènes substitués par pyrazolealcanamide comme potentiateurs de l'ampa
WO2008148836A1 (fr) * 2007-06-08 2008-12-11 Glaxo Group Limited Composés qui potentialisent le récepteur ampa et leurs utilisations dans des médicaments

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8575154B2 (en) 2010-08-10 2013-11-05 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US8778934B2 (en) 2010-08-10 2014-07-15 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US8916551B2 (en) 2010-08-10 2014-12-23 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US9150591B2 (en) 2010-08-10 2015-10-06 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US9499568B2 (en) 2010-08-10 2016-11-22 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US9884875B2 (en) 2010-08-10 2018-02-06 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US11279713B2 (en) 2010-08-10 2022-03-22 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US10654874B2 (en) 2010-08-10 2020-05-19 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US9493484B2 (en) 2012-02-08 2016-11-15 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
US12077521B2 (en) 2016-12-21 2024-09-03 Janssen Pharmaceutica Nv Pyrazole derivatives as MALT1 inhibitors
EP3693360A4 (fr) * 2017-10-06 2021-02-17 Takeda Pharmaceutical Company Limited Composés hétérocycliques
EP3693368A4 (fr) * 2017-10-06 2021-02-24 Takeda Pharmaceutical Company Limited Composé hétérocyclique
WO2019070043A1 (fr) 2017-10-06 2019-04-11 武田薬品工業株式会社 Composé hétérocyclique
US11407748B2 (en) 2017-10-06 2022-08-09 Takeda Pharmaceutical Company Limited Substituted pyrido[1,2-a]pyrimidines and pyrazino[1,2-a]pyrimidines for enhancing AMPA receptor function
US11447488B2 (en) 2017-10-06 2022-09-20 Takeda Pharmaceutical Company Limited Heterocyclic compounds
US11939327B2 (en) 2017-10-06 2024-03-26 Takeda Pharmaceutical Company Limited Heterocyclic compounds
WO2019070044A1 (fr) 2017-10-06 2019-04-11 武田薬品工業株式会社 Composés hétérocycliques
CN113474339A (zh) * 2019-02-22 2021-10-01 詹森药业有限公司 1-(1-氧代-1,2-二氢异喹啉-5-基)-5-(三氟甲基)-n-(2-(三氟甲基)吡啶-4-基)-1h-吡唑-4-甲酰胺一水合物的结晶形式
US12404260B2 (en) 2019-04-11 2025-09-02 Janssen Pharmaceutica Nv Pyridine rings containing derivatives as MALT1 inhibitors
US12370192B2 (en) 2019-09-16 2025-07-29 Takeda Pharmaceutical Company Limited Azole-fused pyridazin-3(2H)-one derivatives

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