WO2013035826A1 - Composé hétérocyclique fusionné - Google Patents

Composé hétérocyclique fusionné Download PDF

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Publication number
WO2013035826A1
WO2013035826A1 PCT/JP2012/072857 JP2012072857W WO2013035826A1 WO 2013035826 A1 WO2013035826 A1 WO 2013035826A1 JP 2012072857 W JP2012072857 W JP 2012072857W WO 2013035826 A1 WO2013035826 A1 WO 2013035826A1
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group
optionally substituted
compound
mono
examples
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PCT/JP2012/072857
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Japanese (ja)
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英人 福士
孝彦 谷口
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武田薬品工業株式会社
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Publication of WO2013035826A1 publication Critical patent/WO2013035826A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/54—Spiro-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a condensed heterocyclic compound having an excellent phosphodiesterase 10A inhibitory action and useful as a therapeutic or prophylactic agent for schizophrenia and the like.
  • Phosphodiesterases are a superfamily of enzymes encoded by 21 genes, subdivided into 11 independent families by structural and functional properties. Since PDE selectively catalyzes the hydrolysis of 3'-ester bonds to form inactive 5'-monophosphates, these enzymes are universal intracellular second messengers, cyclic Adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are metabolically inactivated.
  • cAMP cyclic Adenosine monophosphate
  • cGMP cyclic guanosine monophosphate
  • the PDE family is based on substrate specificity and is further divided into three groups: i) cAMP-PDE (PDE4, PDE7, PDE8), ii) cGMP-PDE (PDE5, PDE6 and PDE9), and iii) dual substrate PDE (PDE1) , PDE2, PDE3, PDE10 and PDE11).
  • CAMP and cGMP are involved in the control of physiological processes such as pro-inflammatory mediator production and action, ion channel function, muscle relaxation, learning and memory formation, differentiation apoptosis, lipogenesis, glycogenolysis, and gluconeogenesis.
  • these second messengers play an important role in the control of synaptic transmission, as well as neuronal differentiation and survival in neurons (Non-Patent Document 1).
  • Control of these processes by cAMP and cGMP activates protein kinase A (PKA) and protein kinase G (PKG), thereby controlling various substrates (eg, transcription factors, ion channels, various physiological processes) This is done by phosphorylating the receptor).
  • PKA protein kinase A
  • PKG protein kinase G
  • Intracellular cAMP and cGMP concentrations are temporally, spatially and functionally partitioned by the control of adenyl cyclase and guanyl cyclase in response to extracellular signal transduction and their degradation by PDE (Non-patent Document 2).
  • PDE plays an important role in cyclic nucleotide signaling because it provides the only means of degrading cyclic nucleotides cAMP and cGMP in cells. Therefore, PDE is expected to be a target for various therapeutic agents.
  • Phosphodiesterase 10A was discovered in 1999 (Non-Patent Documents 3 to 5). The expression study reported that PDE10A is most limitedly distributed to the known PDE family, and that PDE10A mRNA is highly expressed only in the brain and testis (Non-Patent Documents 6 and 7). PDE10A mRNA and protein are present in high concentrations in striatal medium spiny neurons (MSN) in the brain (Non-patent Documents 8 and 9). MSN has two groups: direct MSN expressing D 1 dopamine receptors involved in (striatonigral system) channel, and indirect D 2 dopamine receptor involved in (striatopallidal system) path It is classified into MSN expressing.
  • the function of the direct road is planned and executed, while the indirect road acts as a brake for action activation. Since PDE10A is expressed in both MSNs, PDE10A inhibitors can activate both of these pathways.
  • the antipsychotic effects of current pharmacotherapy D 2 or D 2 / 5-HT 2A antagonists are mainly derived from activation of the indirect tract in the striatum. PDE10A inhibitors can activate this pathway. Therefore, PDE10A inhibitors are promising as antipsychotics. Excessive D 2 receptor antagonism in the brain by D 2 antagonists causes problems of extrapyramidal side effects and hyperprolactinemia.
  • PDE10A the expression of PDE10A is to be limited to these striatal pathway in the brain, in comparison with current D 2 antagonists, side effects PDE10A inhibitor is expected to be weak.
  • a PDE10A inhibitor for the pituitary D 2 receptor antagonist does not occur, prolactin is predicted that it will not increase.
  • the presence of PDE10A in the direct path enhances the possibility of having several advantages PDE10A inhibitor over current D 2 antagonists.
  • the direct path thought to promote the desired action, activation of this pathway by PDE10A inhibitors may prevent extrapyramidal symptoms induced by excessive D 2 receptor antagonist.
  • Activation of this pathway can also promote striatal-thalamic outflow and allow procedural strategies to be performed.
  • increasing the concentration of second messengers without blocking dopamine and / or other neurotransmitter receptors has side effects (eg, hyperprolactinemia, weight gain) compared to current antipsychotics. There may also be a therapeutic benefit of less.
  • This unique distribution and function in the brain can make PDE10A an important new target for the treatment of neurological and psychiatric disorders, particularly mental disorders such as schizophrenia.
  • Patent Document 1 discloses that as an apoptosis inducer that inhibits glyoxalase I activity, the formula:
  • the present invention relates to a fused heterocyclic compound having a PDE10A inhibitory action, which has a chemical structure different from that of known compounds (including the aforementioned compounds), and a prophylactic or therapeutic agent for diseases such as schizophrenia containing the fused heterocyclic compound The purpose is to provide.
  • R 1 represents an optionally substituted C 1-6 alkoxy group or a hydroxy group
  • R 2 and R 3 each independently represent a substituent, or R 2 and R 3 are bonded to form a C 3-6 cycloalkane which may be further substituted with an adjacent carbon atom.
  • R 4 represents a hydrogen atom or a substituent
  • L represents —Y—, —O—Y—, or —NR 5 —Y— (R 5 represents a hydrogen atom or a substituent, and Y represents an optionally substituted C 1-6 alkylene group. .
  • Ring A represents a heterocyclic ring which may be further substituted. )
  • a salt thereof
  • R 2 and R 3 are each independently an optionally substituted C 1-6 alkyl group, or R 2 and R 3 are bonded together with an adjacent carbon atom, The compound or salt thereof according to the above [1], which further forms an optionally substituted C 3-6 cycloalkane;
  • R 1 is a methoxy group, and R 2 and R 3 are each a methyl group, or R 2 and R 3 are bonded to form a cyclopentane with adjacent carbon atoms;
  • R 4 is a pyridyl group, L is a C 2-3 alkylene group, and ring A is each optionally substituted with an optionally substituted C 1-4 alkyl group, benzimidazole, quinoline, or The compound or a salt thereof according to the above [1], which is 2,3-dihydroimidazo [1,2-a] benzimidazole; [4] 5'-Methoxy-6 '-[3- (1-methyl-1H-benzimidazol-2-yl) prop
  • a medicament comprising the compound or salt thereof according to [1] above; [8] The medicament according to the above [7], which is a phosphodiesterase 10A inhibitor; [9] The medicament according to [7] above, which is a therapeutic or prophylactic agent for schizophrenia; [10] A method for inhibiting phosphodiesterase 10A, comprising administering an effective amount of the compound or salt thereof according to [1] above to a mammal; [11] A method for preventing / treating schizophrenia, comprising administering an effective amount of the compound or salt thereof according to [1] to a mammal; [12] Use of the compound of the above-mentioned [1] or a salt thereof for producing a prophylactic / therapeutic agent for schizophrenia; [13] The compound of the above-mentioned [1] or a salt thereof for use in the prevention / treatment of schizophrenia; Etc.
  • a compound represented by formula (I) (hereinafter sometimes referred to as compound (I)) or a salt thereof has an excellent PDE10A inhibitory action and is useful as a preventive or therapeutic agent for schizophrenia and the like. (Detailed description of the invention)
  • halogen atom examples 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, hexyl and the like can be mentioned, and examples of the “C 1-4 alkyl (group)” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
  • examples of the “C 2-6 alkenyl (group)” include vinyl, 1-propen-1-yl, 2-propen-1-yl, isopropenyl, 2-butene. -1-yl, 4-penten-1-yl, 5-hexen-1-yl and the like.
  • examples of the “C 2-6 alkynyl (group)” include ethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 4-pentyne-1- And 5-hexyn-1-yl.
  • C 3-7 cycloalkyl (group) examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • C 6-14 aryl (group) examples include phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-biphenyl. Anthril etc. are mentioned.
  • examples of the “C 7-16 aralkyl (group)” include benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, Examples include 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 2-biphenylylmethyl, 3-biphenylylmethyl, 4-biphenylylmethyl, and the like.
  • C 6-14 aryl -C 2-6 alkenyl (group) the above substituted by “C 6-14 aryl (group)”
  • C 2- means 6 alkenyl (group) ", for example, styryl and the like.
  • examples of the “C 1-6 alkylene (group)” include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and the like, and “C 2-3 Examples of the “alkylene (group)” include ethylene and trimethylene.
  • examples of the “carbon ring having 5 or 6 carbon atoms” include C 5-6 cycloalkane (eg, cyclopentane, cyclohexane), C 5-6 cycloalkene (eg, Cyclopentene, cyclohexene), C 5-6 cycloalkadiene (eg, cyclopentadiene, cyclohexadiene), benzene and the like.
  • examples of “C 3-6 cycloalkane” include cyclopropane, cyclobutane, cyclopentane, cyclohexane and the like.
  • examples of the “5- or 6-membered heterocyclic ring” include 5 or 6 containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom.
  • a 6-membered heterocyclic ring is mentioned.
  • examples of the “5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom” include pyrrolidine , Tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, morpholine, thiomorpholine, piperazine, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1, 2,4-oxadiazole, 1,3,4-oxadiazole, furazane, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3- Triazole, 1,2,4-triazole, tetrazole, pyridine, pyrid
  • the “heterocyclic group” includes a non-aromatic heterocyclic group and an aromatic heterocyclic group, and includes, for example, 1 to 3 selected from a nitrogen atom, a sulfur atom, and an oxygen atom. Examples thereof include 3 to 14 membered heterocyclic groups having 5 heteroatoms.
  • the “heterocyclic group” may be monocyclic, bicyclic, or tricyclic.
  • examples of the “3- to 14-membered heterocyclic group” include pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (eg, 2-furyl, 3-furyl), thienyl (eg, 2-thienyl, 3-thienyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl) ), Isoxazolyl (eg, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (eg, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isothiazolyl (eg, 3-isothiazolyl, 4-isothiazolyl, 5- Isothiazolyl), thiazolyl (eg, 3-iso
  • examples of the “5- to 7-membered heterocyclic group having 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom” include the above-mentioned “heterocycle Among the “5- to 14-membered aromatic heterocyclic groups having 1 to 5 heteroatoms selected from nitrogen, sulfur and oxygen atoms” exemplified for “group”, from nitrogen, sulfur and oxygen atoms Examples thereof include those having 5 to 7 members having 1 to 4 heteroatoms selected.
  • examples of the “heterocycle” include a ring corresponding to the above “heterocyclic group”.
  • examples of the “5- or 6-membered ring” include benzene, “5- or 6-membered non-aromatic hydrocarbon ring”, “5- or 6-membered aromatic heterocycle”, And “5- or 6-membered non-aromatic heterocycle”.
  • examples of the “5- or 6-membered non-aromatic hydrocarbon ring” include benzene, “5- or 6-membered non-aromatic hydrocarbon ring”, “5- or 6-membered aromatic heterocycle”, And “5- or 6-membered non-aromatic heterocycle”.
  • the “5- or 6-membered non-aromatic hydrocarbon ring” cyclopentane, cyclohexane, cyclopentene, cyclohexene, 1,3-cyclopentadiene, 1,3-cyclohexadiene, 1,4-cyclohexadiene , Cyclopentine, cyclohexyne and the like.
  • the “5- or 6-membered aromatic heterocycle” is selected from, for example, an oxygen atom, a sulfur atom (the sulfur atom may be oxidized) and a nitrogen atom in addition to a carbon atom as a ring-constituting atom.
  • 5- or 6-membered monocyclic aromatic heterocycles containing 1 to 4 heteroatoms are selected from, for example, an oxygen atom, a sulfur atom (the sulfur atom may be oxidized) and a nitrogen atom in addition to a carbon atom as a ring-constituting atom.
  • Suitable examples of such 5- or 6-membered monocyclic aromatic heterocycle include furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, Oxadiazole (eg, 1,2,5-oxadiazole, 1,3,4-oxadiazole), thiadiazole (eg, 1,2,3-thiadiazole, 1,3,4-thiadiazole), triazole ( Examples include 1,2,4-triazole, 1,2,3-triazole), tetrazole, triazine (eg, 1,2,4-triazine) and the like.
  • the 5- or 6-membered non-aromatic heterocyclic ring is selected from, for example, an oxygen atom, a sulfur atom (the sulfur atom may be oxidized) and a nitrogen atom in addition to a carbon atom as a ring-constituting atom.
  • 5- or 6-membered monocyclic non-aromatic heterocycles containing 1 to 4 heteroatoms are selected from, for example, an oxygen atom, a sulfur atom (the sulfur atom may be oxidized) and a nitrogen atom in addition to a carbon atom as a ring-constituting atom.
  • Suitable examples of such 5- or 6-membered monocyclic non-aromatic heterocycle include pyrrolidine, piperidine, homopiperidine, tetrahydropyridine (eg, 1,2,3,6-tetrahydropyridine), dihydropyridine (eg, 1,2-dihydropyridine, 2,3-dihydropyridine), morpholine, thiomorpholine, 1,1-dioxidethiomorpholine, piperazine, oxazolidine, thiazolidine, imidazolidine, 2-oxoimidazolidine, oxazoline, thiazoline, imidazoline, dioxol (Eg, 1,3-dioxole), dioxolane (eg, 1,3-dioxolane), dihydrooxadiazole (eg, 4,5-dihydro-1,2,4-oxadiazole), pyran, tetrahydropyran, Thiopyran, tetrahydr
  • examples of the “5-membered ring” include 5-membered rings among the “5- or 6-membered rings”.
  • examples of the “6-membered ring” include 6-membered rings among the “5- or 6-membered rings”.
  • examples of the “C 1-6 alkoxy (group)” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, And hexyloxy.
  • C 3-7 cycloalkyloxy (group) examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.
  • examples of the “C 6-14 aryloxy (group)” include phenyloxy, 1-naphthyloxy, 2-naphthyloxy and the like.
  • examples of the “C 7-16 aralkyloxy (group)” include benzyloxy, phenethyloxy and the like.
  • heterocycle-oxy (group) specifically includes, for example, 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. 3-14 membered heterocyclic-oxy (group) and the like.
  • aromatic heterocycle-oxy (group) specifically includes, for example, 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom.
  • aromatic heterocyclic-oxy (group) having the following.
  • examples of the “C 1-6 alkyl-carbonyloxy (group)” include acetoxy, propionyloxy and the like.
  • C 1-6 alkoxy-carbonyloxy (group) examples include methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy and the like.
  • examples of the “C 3-7 cycloalkyl-carbonyloxy (group)” include cyclopropylcarbonyloxy, cyclobutylcarbonyloxy, cyclopentylcarbonyloxy, cyclohexylcarbonyloxy and the like. It is done.
  • examples of the “C 6-14 aryl-carbonyloxy (group)” include benzoyloxy, 1-naphthylcarbonyloxy, 2-naphthylcarbonyloxy and the like.
  • heterocycle-carbonyloxy (group) specifically includes, for example, 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom.
  • heterocycle-carbonyloxy (group) specifically includes, for example, 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom.
  • examples of the “mono- or di-C 1-6 alkyl-carbamoyl (group)” include mono-C 1-6 alkyl-carbamoyl such as methylcarbamoyl and ethylcarbamoyl. (Group); di-C 1-6 alkyl-carbamoyl (group) such as dimethylcarbamoyl, diethylcarbamoyl and the like.
  • examples of the “mono- or di-C 3-7 cycloalkyl-carbamoyl (group)” include cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl, cyclohexylcarbamoyl and the like. Can be mentioned.
  • examples of the “mono- or di-C 6-14 aryl-carbamoyl (group)” include phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl and the like. .
  • examples of the “mono- or di-C 1-6 alkyl-carbamoyloxy (group)” include mono-C 1-6 such as methylcarbamoyloxy and ethylcarbamoyloxy.
  • examples of the “mono- or di-C 6-14 aryl-carbamoyloxy (group)” include phenylcarbamoyloxy, 1-naphthylcarbamoyloxy, 2-naphthylcarbamoyloxy, and the like.
  • examples of the “C 1-6 alkylsulfonyloxy (group)” include methylsulfonyloxy, ethylsulfonyloxy and the like.
  • examples of the “C 1-6 alkylsulfanyl (group)” include methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, sec-butylsulfanyl, tert-butyl. And sulfanyl.
  • C 3-7 cycloalkylsulfanyl (group) examples include cyclopropylsulfanyl, cyclobutylsulfanyl, cyclopentylsulfanyl, cyclohexylsulfanyl and the like.
  • C 6-14 arylsulfanyl (group) examples include phenylsulfanyl, 1-naphthylsulfanyl, 2-naphthylsulfanyl and the like.
  • examples of the “C 7-16 aralkylsulfanyl (group)” include benzylsulfanyl, phenethylsulfanyl and the like.
  • heterocycle-sulfanyl (group) specifically includes, for example, 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. 3-14 membered heterocycle-sulfanyl (group).
  • C 1-6 alkyl-carbonyl (group) examples include acetyl, propionyl, pivaloyl and the like.
  • examples of the “C 3-7 cycloalkyl-carbonyl (group)” include cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl and the like.
  • examples of the “C 6-14 aryl-carbonyl (group)” include benzoyl, 1-naphthoyl, 2-naphthoyl and the like.
  • examples of the “C 7-16 aralkyl-carbonyl (group)” include phenylacetyl, 3-phenylpropionyl and the like.
  • heterocycle-carbonyl (group) specifically includes “a heterocycle having 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom”
  • heterocycle-carbonyl (group) specifically includes “a heterocycle having 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom”
  • To 14-membered heterocycle-carbonyl (group) more specifically, for example, picolinoyl, nicotinoyl, isonicotinoyl, 2-thenoyl, 3-thenoyl, 2-furoyl, 3-furoyl, 4-morpholinyl.
  • examples of the “C 1-6 alkylsulfonyl (group)” include methylsulfonyl, ethylsulfonyl and the like.
  • examples of the “C 3-7 cycloalkylsulfonyl (group)” include cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl and the like.
  • examples of the “C 6-14 arylsulfonyl (group)” include phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl and the like.
  • heterocycle-sulfonyl (group) specifically has, for example, 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. 3-14 membered heterocycle-sulfonyl (group).
  • C 1-6 alkylsulfinyl (group) examples include methylsulfinyl, ethylsulfinyl and the like.
  • examples of the “C 3-7 cycloalkylsulfinyl (group)” include cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentylsulfinyl, cyclohexylsulfinyl and the like.
  • examples of the “C 6-14 arylsulfinyl (group)” include phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl and the like.
  • heterocycle-sulfinyl (group) specifically has, for example, 1 to 5 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. 3-14 membered heterocycle-sulfinyl (group).
  • examples of the “mono- or di-C 1-6 alkyl-amino (group)” include mono-C 1-6 such as methylamino, ethylamino, propylamino and the like. Alkyl-amino (group); di-C 1-6 alkyl-amino (group) such as dimethylamino, diethylamino and the like.
  • examples of the “mono- or di-C 3-7 cycloalkyl-amino (group)” include cyclopropylamino, cyclopentylamino, cyclohexylamino and the like.
  • examples of the “mono- or di-C 6-14 aryl-amino (group)” include phenylamino, diphenylamino and the like.
  • examples of the “mono- or di-C 7-16 aralkyl-amino (group)” include benzylamino and the like.
  • examples of the “mono- or di- (C 1-6 alkyl-carbonyl) amino (group)” include acetylamino, propionylamino, pivaloylamino and the like.
  • examples of the “mono- or di- (C 3-7 cycloalkyl-carbonyl) amino (group)” include cyclopropylcarbonylamino, cyclopentylcarbonylamino, cyclohexylcarbonylamino. Etc.
  • examples of the “mono- or di- (C 6-14 aryl-carbonyl) amino (group)” include benzoylamino, 1-naphthoylamino, 2-naphthoyl. Amino and the like.
  • examples of the “mono- or di- (C 1-6 alkoxy-carbonyl) amino (group)” include methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxy And carbonylamino.
  • examples of the “mono- or di- (C 3-7 cycloalkoxy-carbonyl) amino (group)” include cyclopropoxycarbonylamino, cyclopentyloxycarbonylamino, cyclohexyloxy and the like. And carbonylamino.
  • examples of the “mono- or di- (C 1-6 alkylsulfonyl) amino (group)” include methylsulfonylamino, ethylsulfonylamino and the like.
  • examples of the “mono- or di- (C 3-7 cycloalkylsulfonyl) amino (group)” include cyclopropylsulfonylamino, cyclopentylsulfonylamino, cyclohexylsulfonylamino and the like. Is mentioned.
  • examples of the “mono- or di- (C 6-14 arylsulfonyl) amino (group)” include phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonyl. Amino and the like.
  • examples of the “C 1-6 alkoxy-carbonyl (group)” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like.
  • examples of the “C 6-14 aryloxy-carbonyl (group)” include phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl and the like.
  • examples of the “C 7-16 aralkyloxy-carbonyl (group)” include benzyloxycarbonyl, phenethyloxycarbonyl and the like.
  • examples of the “optionally substituted silyloxy-carbonyl (group)” include trimethylsilyloxycarbonyl (TMS—O—CO—), triethylsilyloxycarbonyl (TES—O), and the like.
  • TMS—O—CO— trimethylsilyloxycarbonyl
  • TES—O triethylsilyloxycarbonyl
  • -CO- tert-butyldimethylsilyloxycarbonyl
  • TIPS-O-CO- triisopropylsilyloxycarbonyl
  • TDPS-O-CO- tert-butyldiphenylsilyloxycarbonyl
  • heterocycle-C 1-6 alkyl (group) is specifically represented by “ 1-5 heterocycles selected from a nitrogen atom, a sulfur atom, and an oxygen atom”. And a 3 to 14-membered heterocycle having an atom -C 1-6 alkyl (group) ".
  • the “substituent group A” (1) a halogen atom; (2) a nitro group; (3) a cyano group; (4) an optionally substituted C 1-6 alkyl group; (5) an optionally substituted C 2-6 alkenyl group; (6) an optionally substituted C 2-6 alkynyl group; (7) an optionally substituted C 3-7 cycloalkyl group; (8) an optionally substituted C 6-14 aryl group; (9) an optionally substituted C 7-16 aralkyl group; (10) an optionally substituted C 6-14 aryl-C 2-6 alkenyl group; (11) an optionally substituted heterocyclic group; (12) a hydroxy group; (13) an optionally substituted C 1-6 alkoxy group; (14) an optionally substituted C 3-7 cycloalkyloxy group; (15) an optionally substituted C 6-14 aryloxy group; (16) an optionally substituted C 7-16 aralkyloxy group; (17) an optionally substituted
  • “Optionally substituted C 1-6 alkyl group” in substituent group A “Optionally substituted C 2-6 alkenyl group”, “Optionally substituted C 2-6 alkynyl group”, “Optionally substituted C 1-6 alkoxy group”, “Optionally substituted C 1-6 alkyl-carbonyloxy group”, “Optionally substituted C 1-6 alkoxy-carbonyloxy group”, “Optionally substituted mono- or di-C 1-6 alkyl-carbamoyl group”, “Optionally substituted mono- or di-C 1-6 alkyl-carbamoyloxy group”, “Optionally substituted C 1-6 alkylsulfonyloxy group”, “Optionally substituted C 1-6 alkylsulfanyl group”, “C 1-6 alkyl-carbonyl group which may be substituted”, “Optionally substituted C 1-6 alkylsulfonyl group”, “Optionally substituted C 1-6 alkylsulfinyl group”, “
  • the substituent group B is: (a) a halogen atom; (b) a hydroxy group; (c) a nitro group; (d) a cyano group; (e) an optionally substituted C 6-14 aryl group (the C 6-14 aryl group, a halogen atom, hydroxy group, cyano group, amino group, optionally substituted with one to three halogen atoms Good C 1-6 alkyl group, mono-, or di-C 1-6 alkyl-amino group, mono-, or di-C 6-14 aryl-amino group, mono-, or di-C 7-16 aralkyl- Amino group, C 3-7 cycloalkyl group, C 1-6 alkoxy group, formyl group, C 1-6 alkyl-carbonyl group, C 3-7 cycloalkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7-16 aralkyl - carbonyl group, C
  • C 1-6 alkyl group (provided that the "one to three C 1-6 alkyl group optionally substituted with a halogen atom" exemplified as substituent group for an amino group, a C 1-6 alkyl group, and location of the C 2-6 alkenyl group Not a group), mono - or di -C 1-6 alkyl - amino, mono - or di -C 6-14 aryl - amino, mono - or di -C 7-16 aralkyl - amino group, C 3-7 cycloalkyl group, C 1-6 alkoxy group, formyl group, C 1-6 alkyl-carbonyl group, C 3-7 cycloalkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, C 1-6 alkoxy-carbonyl group, C 3-7 cycloalkyloxy-carbonyl group, C 6-14 aryloxy-carbonyl group, C 7-16 aral
  • the substituent group B ′ is (a) an optionally substituted C 1-6 alkyl group (the C 1-6 alkyl group is a halogen atom, a hydroxy group, a cyano group, an amino group, a mono- or di-C 1-6 alkyl-amino group) Group, mono- or di-C 6-14 aryl-amino group, mono- or di-C 7-16 aralkyl-amino group, C 3-7 cycloalkyl group, C 1-6 alkoxy group, formyl group, C 1-6 alkyl-carbonyl group, C 3-7 cycloalkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7-16 aralkyl-carbonyl group, C 1-6 alkoxy-carbonyl group, C 6-14 aryloxy - carbonyl group, C 7-16 aralkyloxy - carbonyl group, C 1-6 alkylsulfanyl group, C 1-6
  • the “substituent group A ′ group” (1) a halogen atom; (2) a nitro group; (3) a cyano group; (4) an optionally substituted C 1-6 alkyl group; (5) an optionally substituted C 3-7 cycloalkyl group; (6) an optionally substituted C 6-14 aryl group; (7) an optionally substituted C 7-16 aralkyl group; (8) an optionally substituted C 6-14 aryl-C 2-6 alkenyl group; (9) an optionally substituted heterocyclic group; (10) hydroxy group; (11) an optionally substituted C 1-6 alkoxy group; (12) an optionally substituted C 3-7 cycloalkyloxy group; (13) an optionally substituted C 6-14 aryloxy group; (14) an optionally substituted C 7-16 aralkyloxy group; (15) an optionally substituted heterocyclic-oxy group; (16) an optionally substituted C 1-6 alkyl-carbonyloxy group; (17) an optionally
  • each group having the term “optionally substituted” may have a substituent group that each corresponding group in the substituent group A may have.
  • the same thing as a substituent is mentioned.
  • the number of the substituents is 1 to the maximum number that can be substituted, more preferably 1 to 3, and still more preferably 1.
  • R 1 represents an optionally substituted C 1-6 alkoxy group or hydroxy group.
  • the “C 1-6 alkoxy group” of the “optionally substituted C 1-6 alkoxy group” represented by R 1 is preferably methoxy, ethoxy and the like, more preferably methoxy.
  • the “C 1-6 alkoxy group” may have one or more (preferably 1 to 3, more preferably 1) substituents at any substitutable position. Examples of such a substituent include a substituent selected from the above-mentioned substituent group B. When the number of the substituents is 2 or more, these substituents may be the same or different.
  • R 1 is preferably a C 1-6 alkoxy group (preferably methoxy).
  • R 1 is particularly preferably a methoxy group.
  • R 2 and R 3 each independently represent a substituent, or R 2 and R 3 may combine to form a C 3-6 cycloalkane which may be substituted with an adjacent carbon atom. Good.
  • Examples of the “substituent” represented by R 2 or R 3 include substituents selected from the above-mentioned Substituent group A.
  • the “substituent” represented by R 2 or R 3 preferably includes a substituent selected from the above-mentioned substituent A ′ group.
  • the “substituent” represented by R 2 or R 3 is more preferably an optionally substituted C 1-6 alkyl group.
  • C 1-6 alkyl group of the "optionally substituted C 1-6 alkyl group” as “substituent” is preferably methyl, ethyl, more preferably Is methyl.
  • the “C 1-6 alkyl group” may have one or more (preferably 1 to 3, more preferably 1) substituents at any substitutable position. Examples of such a substituent include a substituent selected from the above-mentioned substituent group B. When the number of the substituents is 2 or more, these substituents may be the same or different.
  • C 3-6 cycloalkane of “optionally substituted C 3-6 cycloalkane” formed by combining R 2 and R 3 together with the adjacent carbon atom is preferably cyclopentane, cyclohexane And more preferably cyclopentane.
  • the “C 3-6 cycloalkane” may have one or more (preferably 1 to 3, more preferably 1) substituents at any substitutable position. Examples of such a substituent include a substituent selected from the above-mentioned substituent group A. When the number of the substituents is 2 or more, these substituents may be the same or different.
  • R 2 and R 3 are preferably each independently an optionally substituted C 1-6 alkyl group (preferably methyl), or R 2 and R 3 are bonded and adjacent to each other. Together with the carbon atom, it forms an optionally substituted C 3-6 cycloalkane (preferably cyclopentane).
  • R 2 and R 3 are more preferably each independently a C 1-6 alkyl group (preferably methyl), or R 2 and R 3 are bonded together with adjacent carbon atoms to form C 3-6 cycloalkane (preferably cyclopentane) is formed.
  • R 2 and R 3 are particularly preferably each a methyl group or R 2 and R 3 are joined to form a cyclopentane with adjacent carbon atoms.
  • R 4 represents a hydrogen atom or a substituent.
  • the “substituent” represented by R 4 include a substituent selected from the above-mentioned Substituent group A.
  • the “substituent” represented by R 4 is preferably an optionally substituted C 1-6 alkyl group; an optionally substituted C 1-6 alkyl-carbonyl group; an optionally substituted C 1-6 A 6-14 aryl group; or an optionally substituted heterocyclic group.
  • the “C 1-6 alkyl group” of the “ optionally substituted C 1-6 alkyl group” includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclohexyl, cyclopentyl and the like, More preferably, it is methyl or isobutyl.
  • the “C 1-6 alkyl-carbonyl group” of the “optionally substituted C 1-6 alkyl-carbonyl group” includes acetyl, propionyl and the like, and more preferably acetyl.
  • the “C 6-14 aryl group” of the “ optionally substituted C 6-14 aryl group” is preferably phenyl.
  • heterocyclic group of the “optionally substituted heterocyclic group” is preferably pyridyl, pyrimidyl, pyrazolyl, oxazolyl, tetrahydropyranyl, tetrahydrofuranyl, etc., more preferably pyridyl.
  • the “C 1-6 alkyl group” and “C 1-6 alkyl-carbonyl group” have one or more (preferably 1 to 3, more preferably 1) substituents at any substitutable position. You may have.
  • Examples of such a substituent include a substituent selected from the above-mentioned substituent group B. When the number of the substituents is 2 or more, these substituents may be the same or different.
  • the “C 6-14 aryl group” and the “heterocyclic group” have one or more (preferably 1 to 3, more preferably 1) substituents at any substitutable position. Also good. Examples of such a substituent include a substituent selected from the above-described substituent group B and substituent group B ′. When the number of the substituents is 2 or more, these substituents may be the same or different.
  • R 4 is preferably a hydrogen atom; an optionally substituted C 1-6 alkyl group; an optionally substituted C 1-6 alkyl-carbonyl group; an optionally substituted C 6-14 aryl group Or an optionally substituted heterocyclic group, more preferably a hydrogen atom; a C 1-6 alkyl group (more preferably methyl, isobutyl), mono-, or di-C 1-6 alkyl-amino; A C 1-6 alkyl-carbonyl group (preferably acetyl) optionally substituted with a group (preferably dimethylamino); a C 6-14 aryl group (preferably phenyl); or a heterocyclic group (preferably, Pyridyl).
  • R 4 is particularly preferably a pyridyl group.
  • L represents —Y—, —O—Y—, or —NR 5 —Y— (R 5 represents a hydrogen atom or a substituent, and Y represents an optionally substituted C 1-6 alkylene group. .)
  • R 5 represents a hydrogen atom or a substituent
  • Y represents an optionally substituted C 1-6 alkylene group. .
  • the left bond is bonded to the ring A, and the right bond is bonded to the oxygen atom (O). That is, when L is “—O—Y—”, it is represented by the following formula (IA).
  • L is “—NR 5 —Y—”, it is represented by the following formula (IB).
  • R 5 examples include substituents selected from the above-mentioned Substituent group A.
  • R 5 is preferably a hydrogen atom.
  • the “C 1-6 alkylene group” of the “ optionally substituted C 1-6 alkylene group” represented by Y is preferably ethylene, trimethylene and the like.
  • the “C 1-6 alkylene group” may have one or more (preferably 1 to 3, more preferably 1) substituents at any substitutable position. Examples of such a substituent include a substituent selected from the above-mentioned substituent group A. When the number of the substituents is 2 or more, these substituents may be the same or different.
  • L is preferably —Y—, —O—Y—, or —NH—Y— (Y is an optionally substituted C 1-6 alkylene group (preferably ethylene, trimethylene).) It is. L is more preferably a C 2-3 alkylene group (eg, ethylene, trimethylene).
  • Ring A represents a heterocyclic ring which may be further substituted.
  • the “5- to 14-membered aromatic heterocycle” is preferably pyridine, imidazo [1,2-a] pyridine, benzimidazole, quinoline, imidazo [4,5-b] pyridine, quinoxaline, imidazo [1,2 -B] pyridazine.
  • the “3 to 14-membered non-aromatic heterocyclic ring” is preferably 2,3-dihydroimidazo [1,2-a] benzimidazole.
  • the “heterocycle” may have one or more (preferably 1 to 3, more preferably 1) substituents at any substitutable position.
  • substituents include a substituent selected from the above-mentioned substituent group A. When the number of the substituents is 2 or more, these substituents may be the same or different.
  • the “substituent” is preferably a halogen atom, an optionally substituted C 1-6 alkyl group, or an optionally substituted C 1-6 alkoxy group. More preferably, they are a halogen atom (preferably a bromine atom), a C 1-6 alkyl group (preferably methyl, propyl), or a C 1-6 alkoxy group (preferably methoxy).
  • a halogen atom preferably a bromine atom
  • an optionally substituted C 1-4 alkyl group preferably methyl, propyl
  • a C 1-6 alkoxy group preferably Is methoxy
  • Particularly preferred is an optionally substituted C 1-4 alkyl group (preferably methyl, propyl).
  • Ring A is preferably a group selected from a halogen atom (preferably a bromine atom), a C 1-6 alkyl group (preferably methyl, propyl), and a C 1-6 alkoxy group (preferably methoxy).
  • 5- to 14-membered aromatic heterocycle optionally substituted with three substituents (preferably pyridine, imidazo [1,2-a] pyridine, benzimidazole, quinoline, imidazo [4,5-b Pyridine, quinoxaline, imidazo [1,2-b] pyridazine) or 3-14 membered non-aromatic heterocycle (preferably 2,3-dihydroimidazo [1,2-a] benzimidazole).
  • ring A preferably a halogen atom (preferably a bromine atom), an optionally substituted C 1-4 alkyl group (preferably methyl, propyl), and a C 1-6 alkoxy group
  • a 5- to 14-membered aromatic heterocycle preferably pyridine, imidazo [1,2-a] pyridine, benzoate
  • Ring A is more preferably benzimidazole, quinoline, or 2,3-dihydroimidazo [1,2-a] benzo, each optionally substituted with an optionally substituted C 1-4 alkyl group. Imidazole.
  • R 1 is a C 1-6 alkoxy group (preferably methoxy);
  • R 2 and R 3 are each independently a C 1-6 alkyl group (preferably methyl), or R 2 and R 3 are joined together with an adjacent carbon atom to form a C 3-6 cyclo Forming an alkane (preferably cyclopentane);
  • R 4 may be substituted with a hydrogen atom; a C 1-6 alkyl group (more preferably, methyl, isobutyl); a mono- or di-C 1-6 alkyl-amino group (preferably dimethylamino).
  • a C 1-6 alkyl-carbonyl group (preferably acetyl); a C 6-14 aryl group (preferably phenyl); or a heterocyclic group (preferably pyridyl);
  • L is —Y—, —O—Y—, or —NH—Y— (Y is an optionally substituted C 1-6 alkylene group (preferably ethylene, trimethylene));
  • 1 to 3 ring A is selected from a halogen atom (preferably a bromine atom), a C 1-6 alkyl group (preferably methyl, propyl), and a C 1-6 alkoxy group (preferably methoxy).
  • R 1 is a C 1-6 alkoxy group (preferably methoxy);
  • R 2 and R 3 are each independently a C 1-6 alkyl group (preferably methyl), or R 2 and R 3 are joined together with an adjacent carbon atom to form a C 3-6 cyclo Forming an alkane (preferably cyclopentane);
  • R 4 may be substituted with a hydrogen atom; a C 1-6 alkyl group (more preferably, methyl, isobutyl); a mono- or di-C 1-6 alkyl-amino group (preferably dimethylamino).
  • a C 1-6 alkyl-carbonyl group (preferably acetyl); a C 6-14 aryl group (preferably phenyl); or a heterocyclic group (preferably pyridyl);
  • L is —Y—, —O—Y—, or —NH—Y— (Y is an optionally substituted C 1-6 alkylene group (preferably ethylene, trimethylene));
  • Ring A is selected from a halogen atom (preferably a bromine atom), an optionally substituted C 1-4 alkyl group (preferably methyl, propyl), and a C 1-6 alkoxy group (preferably methoxy).
  • a 5- to 14-membered aromatic heterocyclic ring preferably pyridine, imidazo [1,2-a] pyridine, benzimidazole, quinoline, imidazo [4, 5-b] pyridine, quinoxaline, imidazo [1,2-b] pyridazine) or 3-14 membered non-aromatic heterocycle (preferably 2,3-dihydroimidazo [1,2-a] benzimidazole)
  • Compound (I) More preferred specific examples of compound (I) include the following.
  • R 1 is a methoxy group
  • R 2 and R 3 are each independently a methyl group, or R 2 and R 3 are combined to form a cyclopentane with adjacent carbon atoms
  • R 4 is a pyridyl group
  • L is a C 2-3 alkylene group
  • ring A is benzoimidazole, quinoline or 2,3-dihydroimidazo [1,2-a] benzimidazole, each optionally substituted with an optionally substituted C 1-4 alkyl group (I).
  • salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basic or acidic amino acids, and the like.
  • metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • salt with organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl.
  • salts with ethylenediamine and the like Preferable examples of the salt 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, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene And salts with sulfonic acid, p-toluenesulfonic acid and the like.
  • salt with basic amino acid examples include salts with arginine, lysine, ornithine and the like.
  • salt with acidic amino acid examples include salts with aspartic acid, glutamic acid and the like. Of these, pharmaceutically acceptable salts are preferred.
  • an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt)
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, phthalic acid, fumaric acid
  • organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid.
  • the compound (I) and salts thereof are collectively referred to as the compound of the present invention.
  • compound (I) has an isomer such as a tautomer, an optical isomer, a stereoisomer, a positional isomer, a rotational isomer, etc., either one of the isomers or a mixture is included in the compound of the present invention. Is included. Furthermore, when compound (I) has an optical isomer, an optical isomer resolved from a racemate is also encompassed in compound (I).
  • 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.
  • 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, stability, etc.). It means a crystalline substance composed of a simple solid.
  • the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
  • Compound (I) may be a solvate (for example, hydrate etc.) or a non-solvate (for example, non-hydrate), and both are included 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, etc.) is also encompassed in compound (I).
  • Compound (I) labeled or substituted with an isotope can be used, for example, as a tracer (PET tracer) used in positron emission tomography (PET), and is useful in fields such as medical diagnosis.
  • a 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.
  • Compound (I) prodrugs include compounds in which the amino group of compound (I) is acylated, alkylated and phosphorylated (for example, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.); Compounds in which the hydroxy group of compound (I) is acylated, alkylated, phosphorylated, borated (for example, the hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated , Alanylated, dimethylaminomethylcarbonylated compounds, etc.
  • each raw material compound used for the production of compound (I) may form a salt, and as such a salt, the same salt as the salt of compound (I) described above can be used. Can be mentioned.
  • each raw material compound used for the production of compound (I) can be used in the next reaction as a reaction liquid or as a crude product, but can also be isolated from a reaction mixture according to a conventional method, and is known per se. It can be easily purified by means such as extraction, concentration, neutralization, filtration, distillation, recrystallization, chromatography and the like.
  • the solvent used for the recrystallization include water, alcohols, ethers, hydrocarbons, amides, halogenated hydrocarbons, nitriles, ketones, esters, sulfoxides, organic acids, and the like.
  • solvents can be used alone, or two or more kinds of solvents can be mixed at an appropriate ratio, for example, a ratio of 1: 1 to 1:10.
  • a ratio of 1: 1 to 1:10 can be used when the compound in a formula is marketed, a commercial item can also be used as it is, and what was manufactured by the method known per se or a method according to it can also be used.
  • Convertible functional group eg, carboxyl group, amino group, hydroxyl group, carbonyl group, mercapto group, C 1-6 alkoxy-carbonyl group, C 6-14 aryloxy-carbonyl group
  • various compounds can be produced by converting these functional groups by a method known per se or a method analogous thereto. .
  • the substituent When the substituent is a carboxyl group, it can be converted by a reaction such as esterification, reduction, amidation, or a conversion reaction to an amino group which may be protected. When the substituent is an amino group, it can be converted by a reaction such as acylation, sulfonylation, nitrosation, alkylation, arylation, imidation and the like. When the substituent is a hydroxyl group, it can be converted by a reaction such as esterification, carbamoylation, sulfonylation, alkylation, arylation, oxidation, halogenation, and the like.
  • the substituent When the substituent is a carbonyl group, it can be converted by a reaction such as reduction, oxidation, iminization (including oximation or hydrazonation), (thio) ketalization, alkylideneization, thiocarbonylation, and the like.
  • the substituent When the substituent is a mercapto group, it can be converted by a reaction such as alkylation or oxidation.
  • the substituent is a C 1-6 alkoxy-carbonyl group, a C 6-14 aryloxy-carbonyl group, or a C 7-16 aralkyloxy-carbonyl group, it can be converted by a reaction such as reduction or hydrolysis. .
  • the substituent when the substituent is a sulfo group, it can be converted by, for example, a reaction such as sulfonamidation or reduction.
  • a reaction such as sulfonamidation or reduction.
  • the substituent when the substituent is a halogen atom, it can be converted by, for example, various nucleophilic substitution reactions, various coupling reactions, and the like.
  • amino-protecting group examples include a formyl group, a C 1-6 alkyl-carbonyl group (eg, acetyl, ethylcarbonyl, etc.) each optionally having a substituent, a phenylcarbonyl group, C 1-6.
  • Alkyloxy-carbonyl groups eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl (Boc), etc.
  • allyloxycarbonyl (Alloc) groups phenyloxycarbonyl groups, fluorenylmethoxycarbonyl (Fmoc) groups, C 7- 10 alkyl-carbonyl groups (eg, benzylcarbonyl, etc.), C 7-10 aralkyl-oxycarbonyl groups (eg, benzyloxycarbonyl (Z), etc.), C 7-10 aralkyl groups (eg, benzyl, etc.), 2- ( Trimethylsilyl) ethoxymethyl (SEM) group, trityl group, fluorine Royle group, N, N-dimethylaminomethylene group, etc.
  • SEM Trimethylsilyl
  • substituents include a phenyl group, a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), C 1-6 alkyl-carbonyl group (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.) , A nitro group or the like is used, and the number of substituents is about 1 to 3.
  • a phenyl group e.g, a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), C 1-6 alkyl-carbonyl group (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.) , A nitro group or the like is used, and the number of substituents is about 1 to 3.
  • Examples of the protecting group for the carboxyl group include, for example, C 1-6 alkyl groups (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, etc.) each optionally having a substituent, An allyl group, benzyl group, phenyl group, trityl group, trialkylsilyl group and the like are used.
  • C 1-6 alkyl groups eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, etc.
  • An allyl group, benzyl group, phenyl group, trityl group, trialkylsilyl group and the like are used.
  • substituents examples include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), formyl group, C 1-6 alkyl-carbonyl group (eg, acetyl, ethylcarbonyl, butylcarbonyl, etc.), A nitro group or the like is used, and the number of substituents is about 1 to 3.
  • halogen atom eg, fluorine atom, chlorine atom, bromine atom, iodine atom
  • formyl group eg, C 1-6 alkyl-carbonyl group (eg, acetyl, ethylcarbonyl, butylcarbonyl, etc.)
  • C 1-6 alkyl-carbonyl group eg, acetyl, ethylcarbonyl, butylcarbonyl, etc.
  • a nitro group or the like is used, and the number of substituents is about 1 to 3.
  • hydroxyl-protecting group examples include a C 1-6 alkyl group (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, etc.), which each may have a substituent, C 7-10 aralkyl group (eg, benzyl, etc.), formyl group, C 1-6 alkyl-carbonyl group (eg, acetyl, ethylcarbonyl, etc.), benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl, etc.) ), Tetrahydropyranyl group, furanyl group, silyl group and the like.
  • C 1-6 alkyl group eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, etc.
  • C 7-10 aralkyl group eg
  • substituents include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), C 1-6 alkyl group (eg, methyl, ethyl, n-propyl etc.), phenyl group, C 7 A -10 aralkyl group (eg, benzyl etc.), a C 1-6 alkoxy group (eg methoxy, ethoxy, n-propoxy etc.), a nitro group etc. are used, and the number of substituents is about 1 to 4.
  • halogen atom eg, fluorine atom, chlorine atom, bromine atom, iodine atom, etc.
  • C 1-6 alkyl group eg, methyl, ethyl, n-propyl etc.
  • phenyl group eg, C 7 A -10 aralkyl group (eg, benzyl etc.)
  • the salt of compound (I) is obtained according to a method known per se, for example, when compound (I) is a basic compound, by adding an inorganic acid or an organic acid, or when compound (I) is an acidic compound Can be prepared by adding an organic base or an inorganic base.
  • R 1 ′ represents an optionally substituted C 1-6 alkyl group
  • Q represents a leaving group
  • other symbols are as defined above.
  • Examples of the leaving group represented by Q include a halogen atom (eg, chlorine atom, bromine atom, iodine atom), a C 1-6 alkylsulfonyloxy group (eg, methylsulfonyloxy, optionally halogenated).
  • C 6-10 arylsulfonyloxy group optionally substituted with a C 1-6 alkyl group (eg, benzenesulfonyloxy, p-toluenesulfonyloxy), methylsulfonyl group, etc. And is preferably a halogen atom or an optionally halogenated C 1-6 alkylsulfonyloxy group.
  • C 1-6 alkyl group" of the "optionally substituted C 1-6 alkyl group” represented by R 1 ' is preferably methyl, ethyl or the like, more preferably methyl.
  • the “C 1-6 alkyl group” may have one or more (preferably 1 to 3, more preferably 1) substituents at any substitutable position.
  • substituents include a substituent selected from the above-mentioned substituent group B. When the number of the substituents is 2 or more, these substituents may be the same or different.
  • Compound (2) and compound (6) can be produced by a method known per se or a method analogous thereto, the method shown in the following Reaction Scheme 2 or a method analogous thereto.
  • Compound (3), compound (4) and compound (5) can be produced according to a method known per se or a method analogous thereto. It can also be obtained as a commercial product.
  • Step 1 is a method for producing compound (1a) or compound (1b) by reacting compound (2) or compound (6) with compound (3) or compound (4).
  • a base When reacting compound (2) or compound (6) with compound (3), this reaction is carried out in the presence of a base.
  • the amount of compound (3) to be used is about 1-10 mol, preferably 1-5 mol, per 1 mol of compound (2) or compound (6).
  • the base include potassium carbonate, cesium carbonate, sodium hydride and the like.
  • the amount of the base to be used is about 1-10 mol, preferably 1-5 mol, per 1 mol of compound (2) or compound (6).
  • the solvent is not particularly limited as long as the reaction proceeds. For example, dimethylformamide is preferable.
  • the reaction temperature is usually desirably under ice-cooling to heating under reflux conditions, preferably room temperature.
  • the reaction time is usually 1 to 100 hours, preferably 3 to 60 hours.
  • an organophosphorus reagent and Mitsunobu reagent When reacting compound (2) or compound (6) with compound (4), this reaction is carried out in the presence of an organophosphorus reagent and Mitsunobu reagent.
  • the amount of compound (4) to be used is about 1-10 mol, preferably 1-5 mol, per 1 mol of compound (2) or compound (6).
  • the organophosphorus reagent include triphenylphosphine, and the amount thereof used is about 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (2) or compound (6).
  • Examples of the Mitsunobu reagent include di-tert-butyl azodicarboxylate, and the amount used is about 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (2) or compound (6). It is.
  • the solvent is not particularly limited as long as the reaction proceeds.
  • tetrahydrofuran is preferable.
  • the reaction temperature is usually desirably under ice-cooling to heating under reflux conditions, and preferably room temperature.
  • the reaction time is usually 10 minutes to 10 hours, preferably 30 minutes to 5 hours.
  • Step 2 is a method for producing compound (1b) or compound (15) by reacting compound (1a) or compound (14) with compound (5) in the presence of a base. If desired, this reaction can be carried out in an argon atmosphere in the presence of a palladium catalyst and an organophosphorus reagent.
  • the amount of compound (5) to be used is about 1-10 mol, preferably 1-5 mol, per 1 mol of compound (1a) or compound (14).
  • the base include sodium hydride, triethylamine, sodium tert-butoxide and the like, and the amount thereof to be used is about 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (1a) or compound (14). Is a mole.
  • Examples of the palladium catalyst include palladium acetate, and the amount thereof used is about 0.01 to 1 mol, preferably 0.03 to 0.5 mol, relative to 1 mol of compound (1a) or compound (14). It is.
  • Examples of the organic phosphorus reagent include 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene, and the amount thereof is about 0 with respect to 1 mol of the compound (1a) or the compound (14). 0.01 to 1 mol, preferably 0.03 to 0.5 mol.
  • the solvent is not particularly limited as long as the reaction proceeds. For example, dimethylformamide, tetrahydrofuran or toluene is preferable.
  • the reaction temperature is usually desirably from ⁇ 10 ° C. to heating under reflux, and preferably from 0 ° C. to 130 ° C.
  • the reaction time is usually 1 to 24 hours, preferably 3 to 16 hours.
  • Step 3 is a method for producing compound (9) by reacting compound (7) with compound (8) in the presence of aluminum chloride.
  • the amount of compound (8) to be used is about 1-5 mol, preferably 1-2 mol, per 1 mol of compound (7).
  • the amount of aluminum chloride to be used is about 0.3-3 mol, preferably 0.5-2 mol, per 1 mol of compound (7).
  • the solvent is not particularly limited as long as the reaction proceeds. For example, carbon disulfide is preferable.
  • the reaction temperature is usually desirably 0 ° C. to 50 ° C., preferably room temperature.
  • the reaction time is usually 1 to 10 hours, preferably 1 to 5 hours.
  • Step 4 is a method for producing compound (10) by reacting compound (9) with a mixed solution of concentrated sulfuric acid and concentrated nitric acid.
  • Concentrated sulfuric acid and concentrated nitric acid are each used in an amount of about 1 to 50 mol, preferably 3 to 20 mol, per 1 mol of compound (9).
  • the solvent is not particularly limited as long as the reaction proceeds.
  • acetic acid is preferable.
  • the reaction temperature is desirably ⁇ 78 ° C. to 30 ° C., preferably under ice cooling.
  • the reaction time is usually 10 minutes to 2 hours, preferably 30 minutes to 1 hour.
  • Step 5 is a method for producing the compound (11) by reacting the compound (10) in the presence of palladium on carbon in a hydrogen atmosphere.
  • the amount of palladium carbon used is about 1 to 200% by weight, preferably 10 to 50% by weight, based on compound (10).
  • the solvent is not particularly limited as long as the reaction proceeds. For example, methanol is preferable.
  • the reaction temperature is usually preferably 0 ° C. to 50 ° C., preferably room temperature.
  • the reaction time is usually 10 minutes to 5 hours, preferably 30 minutes to 2 hours.
  • Step 6 is a method for producing a compound (12) by a reaction between the compound (11) and acetic anhydride.
  • Acetic anhydride is preferably used as a solvent.
  • the reaction temperature is usually preferably 30 ° C to 150 ° C, more preferably 100 ° C.
  • the reaction time is usually 10 minutes to 3 hours, preferably 30 minutes to 2 hours.
  • Step 7 is a method for producing compound (13) by reacting compound (11) with sodium nitrite under acidic conditions and then reacting with sodium azide in the presence of sodium acetate.
  • the acid is not particularly limited as long as the reaction proceeds.
  • hydrochloric acid is preferable and it is preferably used as a solvent.
  • the amount of sodium nitrite to be used is about 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (11).
  • the reaction temperature is usually preferably from ⁇ 30 ° C. to 50 ° C., preferably under ice cooling.
  • the reaction time is usually 30 seconds to 1 hour, preferably 1 minute to 10 minutes.
  • the amount of sodium azide to be used is about 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound (11).
  • the amount of sodium acetate to be used is about 1-100 mol, preferably 10-20 mol, per 1 mol of compound (11).
  • the reaction temperature is usually preferably from ⁇ 30 ° C. to 50 ° C., preferably under ice cooling.
  • the reaction time is usually 30 seconds to 30 minutes, preferably 1 minute to 5 minutes.
  • Step 8 is a method for producing the compound (14) by reacting the compound (13) with a base.
  • the base is preferably, for example, potassium hydroxide.
  • the amount of the base to be used is about 1-10 mol, preferably 1-3 mol, per 1 mol of compound (13).
  • the solvent is not particularly limited as long as the reaction proceeds. For example, ethanol is preferable.
  • the reaction temperature is usually preferably from room temperature to low temperature, preferably at room temperature.
  • the reaction time is usually 1 to 12 hours, preferably 1 to 3 hours.
  • Step 9 is a method for producing compound (14) by reacting compound (12) with bromine and then reacting with sodium hydroxide.
  • the amount of bromine to be used is about 1-5 mol, preferably 1-3 mol, per 1 mol of compound (12).
  • the solvent is not particularly limited as long as the reaction proceeds. For example, acetic acid is preferable.
  • the reaction temperature is usually desirably 0 ° C to 80 ° C, preferably room temperature to 50 ° C.
  • the reaction time is usually 1 minute to 1 hour, preferably 10 minutes to 30 minutes.
  • the amount of sodium hydroxide to be used is about 1 to 20 mol, preferably 1 to 10 mol, relative to 1 mol of compound (12).
  • the reaction temperature is usually desirably from room temperature to 150 ° C, preferably from 50 ° C to 100 ° C.
  • the reaction time is usually 10 minutes to 3 hours, preferably 30 minutes to 2 hours.
  • Step 10 is a method for producing compound (2) or compound (6) by reaction of compound (14) or compound (15) with a base.
  • the base include potassium hydroxide, sodium cyanide, sodium iodide and the like.
  • the amount of the base used is about 1 to 100 mol, preferably 3 to 1 mol per 1 mol of the compound (14) or the compound (15). 20 moles.
  • the solvent is not particularly limited as long as the reaction proceeds. For example, ethylene glycol, dimethyl sulfoxide, acetonitrile, or the like is preferable.
  • the reaction temperature is usually desirably from room temperature to 200 ° C, and preferably from 50 ° C to 130 ° C.
  • the reaction time is usually 1 hour to 24 hours, preferably 3 hours to 12 hours.
  • the compound (I) of the present invention obtained by the above method can be isolated and purified by usual separation means such as recrystallization, distillation, chromatography and the like.
  • a known protection / deprotection reaction, acylation reaction, alkylation reaction, hydrogenation reaction, oxidation reaction, reduction reaction, carbon chain extension reaction, or substituent exchange may be performed as desired.
  • Compound (I) can be synthesized by using the reaction alone or in combination of two or more thereof.
  • Compound (I) labeled or substituted with an isotope is the compound shown in the above production method or
  • methods known per se for example, App. Radiat. Isot, 2009, 67 (1), 106-110, Biooganic & Medicinal Chemistry, 2005, 13, 1811-1818, App. Radiat. Isot, It can be produced according to the method described in 2002, 57 (1), 335-342, or Journal of Fluorine Chemistry, 2004, 125, 1879-1886.
  • the label obtained by the method or the substituted compound (I) has, for example, an “optionally substituted C 1-6 alkoxy group” represented by R 1 of the formula (I) of the present invention.
  • R 1 of the formula (I) of the present invention examples thereof include compounds in which the substituent group or alkoxy moiety which may be substituted is labeled or substituted.
  • the compound of the present invention has an excellent PDE10A inhibitory action and is toxic (eg, phototoxicity, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc., particularly phototoxicity. ) Is low, is excellent in stability (particularly metabolic stability) and pharmacokinetics (absorbability, distribution, metabolism, excretion, etc.), and further exhibits high solubility, it is useful as a pharmaceutical product.
  • toxic eg, phototoxicity, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity, etc., particularly phototoxicity.
  • Is low is excellent in stability (particularly metabolic stability) and pharmacokinetics (absorbability, distribution, metabolism, excretion, etc.), and further exhibits high solubility, it is useful as a pharmaceutical product.
  • the compound of the present invention has a PDE10A inhibitory action on mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, horses, sheep, monkeys, humans, etc.) and has the following diseases and symptoms: : (1) Psychiatric disorders (eg, short-term psychotic disorders, shared psychotic disorders), (2) alcohol, amphetamine, cannabis, cocaine, hallucinogens, obesity, inhalants, psychosis induced by opioids or phencyclidine, (3) delusional disorder, (4) Anxiety disorder, (5) Movement disorders, (6) Mood disorder, (7) major depressive disorder, (8) Major depressive disorder associated with psychosis (including delusional disorder and schizophrenia), (9) Mild, moderate or severe major depression episodes, (10) mania or mixed mood episodes, (11) contempt mood episode, (12) Depression episode with atypical features, (13) Depressive episodes with depressed features, (14) Depressive episode with tonic features, (15) postpartum onset mood episodes, (16) Depression after stroke, (17) Dys
  • compounds labeled or substituted with isotopes are used in mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, horses, sheep, monkeys, humans, etc.).
  • mammals eg, mice, rats, hamsters, rabbits, cats, dogs, cows, horses, sheep, monkeys, humans, etc.
  • it can be used for quantitative imaging of PDE10A or diagnostic imaging of the above-mentioned diseases and symptoms by PET.
  • the compounds of the present invention are useful for the prevention or treatment of schizophrenia.
  • the compound of the present invention is excellent in metabolic stability, it is expected to show an excellent therapeutic effect against the above diseases even at a low dose.
  • a pharmaceutical composition containing the compound of the present invention is a method known per se as a method for producing a pharmaceutical preparation (eg, Japanese Pharmacopoeia)
  • a pharmaceutical preparation eg, Japanese Pharmacopoeia
  • the compound of the present invention alone or mixed with a pharmacologically acceptable carrier, for example, tablets (sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.) ), Pills, powders, granules, capsules (including soft capsules and microcapsules), troches, syrups, solutions, emulsions, suspensions, controlled-release preparations (eg, immediate-release preparations, slow-release preparations) Release preparation, sustained release microcapsule), aerosol, film (eg, oral disintegrating film, oral mucosa film), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, Intraperitoneal injection , Drops, transdermal preparations
  • Orally or parenterally eg, intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, ophthalmic, intracerebral, intrarectal, intravaginal, intraperitoneal, intratumoral, near tumor Can be safely administered to the patient's position, lesion, etc.
  • Examples of the above-mentioned “pharmacologically acceptable carrier” include various organic or inorganic carrier substances that are commonly used as pharmaceutical materials.
  • excipients lubricants, binders and disintegrants in solid preparations, or liquid preparations
  • Solvent solubilizing agent, suspending agent, isotonic agent, buffering agent, soothing agent and the like.
  • 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, D-sorbitol, starch, ⁇ -starch, corn starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous
  • examples thereof include silicic acid, synthetic aluminum silicate and magnesium aluminate metasilicate.
  • examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • binders include ⁇ -starch, crystalline cellulose, sucrose, gum arabic, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, carboxymethylcellulose. And sodium carboxymethyl cellulose.
  • disintegrant include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, low-substituted hydroxypropyl cellulose, and the like.
  • solvent examples include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, macrogol, sesame oil, corn oil, olive oil, cottonseed oil and the like.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate and the like. It is done.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, carboxy
  • hydrophilic polymers such as sodium methylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polysorbate, and polyoxyethylene hydrogenated castor oil.
  • isotonic agent examples 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 the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Examples of the antioxidant include sulfite, ascorbic acid, ⁇ -tocopherol and the like.
  • Examples of the colorant include water-soluble edible tar dyes (eg, edible red Nos. 2 and 3, edible yellow Nos. 4 and 5, edible blue Nos.
  • water-insoluble lake dyes eg, the above water-soluble Edible tar pigment aluminum salts
  • natural pigments eg, ⁇ -carotene, chlorophyll, bengara
  • sweetening agent examples include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.
  • the content of the compound of the present invention in the medicament of the present invention varies depending on the dosage form, the dose of the compound of the present invention, etc., but is, for example, about 0.01 to 100% by weight, preferably about 0.1% of the whole medicament. ⁇ 95% by weight.
  • the dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, symptom, etc., but when administered orally to a patient with schizophrenia (adult, about 60 kg body weight), usually about 0.1 to about 20 mg / kg body weight, preferably about 0.2 to about 10 mg / kg body weight, more preferably about 0.5 to about 10 mg / kg body weight. These dosages are about 1 to several times a day depending on the symptoms. It is desirable to administer (eg 1 to 3 times).
  • the compounds of the invention may be administered as the sole active substance or, for example, psychosis (especially schizophrenia and bipolar disorder), obsessive compulsive disorder, major depression, Parkinson's disease, Alzheimer's disease, cognitive impairment Alternatively, it may be administered in combination with other drugs such as other drugs used for the treatment of memory loss (hereinafter sometimes referred to as “concomitant drugs”).
  • concomitant drugs other drugs used for the treatment of memory loss
  • the combination drug of the present invention is referred to as “the combination drug of the present invention”.
  • Examples of the concomitant drug include nicotinic ⁇ 7 agonist, nicotinic ⁇ 7 partial agonist, nicotinic ⁇ 7 positive allosteric modulator, PDE2 inhibitor, PDE4 inhibitor, PDE5 inhibitor, other PDE inhibitors, calcium channel blocker, muscarinic m1 and m2 modulators, adenosine receptor modulators, ampakines, glycine transporter 1 inhibitors, NMD AR modulators, mGluR modulators, dopamine modulators, serotonin modulators, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, Norepinephrine and dopamine reuptake inhibitors, triple reuptake inhibitors, cannabinoid modulators, cholinesterase inhibitors (eg, donepeji , Rivastigmine, galantamine), and the like.
  • PDE2 inhibitor PDE4 inhibitor
  • PDE5 inhibitor
  • concomitant drug examples include, but are not limited to, other suitable schizophrenia drugs (eg, haloperidol, clozapine, olanzapine, risperidone, aripiprazole, ziprasidone, paliperidone, quetiapine fumarate, etc.), bipolar disorder Drugs (eg, lithium, olanzapine, aripiprazole, valproic acid, etc.), Parkinson's disease drugs (eg, levodopa, bromocriptine, pergolide, pramipexole, tolcapone, procyclidine, trihexyphenidyl, benztropine, etc.), used for the treatment of major depression Drugs (eg, amitriptyline, protriptyline, desipramine, nortriptyline, paroxetine, fluoxetine, sertraline, bupropion, ecitalopram, mirtazapine, venlafaxine, duloxetine ),
  • 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 simultaneously administered to the administration subject. It may be administered or may be administered after 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.
  • dosage forms include: (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, (2) Simultaneous administration by the same route of administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug, (3) Administration of two types of preparations obtained by separately formulating the compound of the present invention and a concomitant drug with a time difference in the same administration route, (4) Simultaneous administration of two types of preparations obtained by separately formulating the compound of the present invention and the concomitant drug by different administration routes, (5) Administration of two types of preparations obtained by separately formulating the compound of the present invention and the concomitant drug at different time intervals in different administration routes (eg, administration in the order of the compound of the present invention and the concomitant drug) Or administration in the
  • the concomitant drug or a pharmaceutical composition thereof when the concomitant drug or a pharmaceutical composition thereof is administered first, the compound of the present invention or the pharmaceutical composition thereof is administered for 1 minute to 3 days, preferably 10 minutes to 1 day after administration of the concomitant drug or the pharmaceutical composition thereof. More preferably, it can be administered within 15 minutes to 1 hour.
  • the concomitant drug or the pharmaceutical composition thereof is used for 1 minute to 1 day after administration of the compound of the present invention or the pharmaceutical composition thereof, preferably 10 minutes to It can be administered within 6 hours, more preferably within 15 minutes to 1 hour.
  • an arbitrary dose can be set.
  • the dose as a concomitant drug varies depending on the dosage form, administration subject, administration route, target disease, symptom, and the like.
  • To about 20 mg / kg body weight preferably about 0.2 to about 10 mg / kg body weight, more preferably about 0.5 to about 10 mg / kg body weight. It is desirable to administer several times (eg, 1 to 3 times).
  • the dose can be reduced.
  • a concomitant drug can be selected according to the patient's symptoms (mild, severe, etc.)
  • the treatment period can be set longer.
  • a concomitant drug having a different mechanism of action from the compound of the present invention the therapeutic effect can be sustained.
  • excellent effects such as a synergistic effect can be obtained.
  • the concomitant drug of the present invention has low toxicity.
  • the compound of the present invention, or (and) the concomitant drug is mixed with a pharmacologically acceptable carrier according to a method known per se, and a pharmaceutical composition such as a tablet ( Sugar-coated tablets, film-coated tablets, etc.), powders, granules, capsules (including soft capsules), solutions, emulsions, suspensions, injections, suppositories, sustained-release agents (eg, sublingual tablets, microcapsules, etc.) ), A patch, an orally disintegrating tablet, an orally disintegrating film, and the like, and can be safely administered orally or parenterally (eg, subcutaneous, topical, rectal, intravenous administration, etc.).
  • the “pharmacologically acceptable carrier” that may be used for the production of the concomitant drug of the present invention is the above-mentioned “pharmacologically acceptable carrier” that may be used for the production of the pharmaceutical of the present invention.
  • 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, target disease and the like.
  • the concomitant drugs in the concomitant drug of the present invention may be used in combination of two or more as necessary.
  • 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 99.9% by weight, preferably about 0.1 to 50% by weight based on the whole preparation. %, More preferably 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 99.9% by weight, preferably about 0.1 to 50% by weight, more preferably based on the whole preparation. Is 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. Further, when the compound of the present invention and the concomitant drug are formulated separately, the same content may be used.
  • room temperature usually indicates about 10 ° C. to about 35 ° C. % Indicates mol / mol% for the yield,% by volume for the solvent used in the chromatography, and% by weight for the other.
  • the proton NMR spectrum that cannot be confirmed by broad such as OH and NH protons is not described in the data.
  • Kiesselgel 60 manufactured by Merck & Co., Ltd. was used.
  • Triphenylphosphine (170 mg) was added to a solution of di-tert-butyl azodicarboxylate (120 mg) in tetrahydrofuran (7 mL), and the mixture was stirred at room temperature for 10 minutes.
  • To the reaction mixture was added 6′-hydroxy-5′-methoxy-1 ′-(pyridin-3-yl) spiro [cyclopentane-1,2′-indole] -3 ′ (1′H) -one (80 mg), And 3- (1-methyl-1H-benzoimidazol-2-yl) propan-1-ol (200 mg) was added and stirred at room temperature for 3 hours.
  • Triphenylphosphine (141 mg) was added to a solution of di-tert-butyl azodicarboxylate (99 mg) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 10 minutes.
  • To the reaction mixture was added 6'-hydroxy-5'-methoxyspiro [cyclopentane-1,2'-indole] -3 '(1'H) -one (50 mg), and 2- (2,3-dihydro-1H -Imidazo [1,2-a] benzoimidazol-1-yl) ethanol (131 mg) was added, and the mixture was stirred at room temperature for 3 hours.
  • Triphenylphosphine (157 mg) was added to a tetrahydrofuran (5 mL) solution of di-tert-butyl azodicarboxylate (115 mg), and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added 6'-hydroxy-5'-methoxy-1'-phenylspiro [cyclopentane-1,2'-indole] -3 '(1'H) -one (70 mg), and 2- (quinoline- 2-yl) ethanol (120 mg) was added and stirred at room temperature for 3 hours.
  • Example 21 1 '-[(Dimethylamino) acetyl] -5'-methoxy-6'-(2- (quinolin-2-yl) ethoxy) spiro [cyclopentane-1,2'-indole] -3 '(1'H )-on
  • Triphenylphosphine (115 mg) was added to a solution of di-tert-butyl azodicarboxylate (81 mg) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added 6-hydroxy-5-methoxy-2,2-dimethyl-1- (pyridin-3-yl) -1,2-dihydro-3H-indol-3-one (50 mg), and 2- (quinoline) -2-yl) ethanol (107 mg) was added and stirred at room temperature for 3 hours.
  • the reaction mixture was diluted with ethyl acetate and washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate and further concentrated under reduced pressure.
  • the resulting residue was purified by silica gel column chromatography (methanol / ethyl acetate). The title compound (39 mg) was obtained.
  • Example 1 (1) Compound of Example 1 10.0 g (2) Lactose 70.0g (3) Corn starch 50.0g (4) 7.0g of soluble starch (5) Magnesium stearate 3.0 g The compound of Example 1 (10.0 g) and magnesium stearate (3.0 g) were granulated with an aqueous solution of soluble starch (70 mL) (7.0 g as soluble starch), then dried and lactose (70.0 g) And corn starch (50.0 g) (lactose, corn starch, soluble starch, and magnesium stearate are all compatible with the Japanese Pharmacopoeia). The mixture is compressed to obtain tablets.
  • Test Example PDE10A Enzyme Activity Inhibition Test After transducing the human PDE10A full-length gene into Sf9 or COS-7 cells, the cells were disrupted, and human PDE10A enzyme was obtained from the sediment after centrifugation. The enzyme extracted from Sf9 cells was partially purified using a Histag affinity column. The enzyme was stored at -70 ° C before use. The enzyme activity of PDE10A was measured using Scintillation Proximity Assay (SPA) (GE Healthcare).
  • SPA Scintillation Proximity Assay
  • PET analysis of compound (I) labeled or substituted with an isotope or the like is performed with a high resolution tomographic imaging apparatus (High Resolution Research Tomography system (HRRT)). Regions of interest (ROIs) are set in the striatum, whole brain, etc., magnetic resonance imaging (MRI) / PET images are obtained, and% SUV (Standardized Uptake Value: organization (Concentration ⁇ 100 / (dose / body weight)) and the like.
  • HRRT High Resolution Research Tomography system
  • the compound of the present invention exhibits an excellent PDE10A inhibitory action, it can provide a clinically useful prophylactic or therapeutic agent for diseases such as schizophrenia.
  • the compound of the present invention is useful as a pharmaceutical because it is excellent in terms of drug efficacy, low toxicity, stability, pharmacokinetics and the like.

Abstract

L'invention concerne un composé hétérocyclique fusionné qui a un excellent effet inhibiteur de PDE10A ; et une utilisation du composé hétérocyclique fusionné. L'invention porte également sur un composé représenté par la formule (I) ou un sel de celui-ci. (Dans la formule, R1 représente un groupe alcoxy en C1-6 facultativement substitué ou un groupe hydroxy ; R2 et R3 représentent chacun indépendamment un substituant, ou, en variante, R2 et R3 se combinent pour former un groupe cycloalcane en C3-6 facultativement substitué conjointement avec un atome de carbone adjacent ; R4 représente un atome d'hydrogène ou un substituant ; L représente -Y-, -O-Y- ou -NR5-Y- (dans laquelle R5 représente un atome d'hydrogène ou un substituant, et Y représente un groupe alkylène en C1-6 facultativement substitué) ; et le noyau A représente un noyau hétérocyclique facultativement substitué).
PCT/JP2012/072857 2011-09-08 2012-09-07 Composé hétérocyclique fusionné WO2013035826A1 (fr)

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WO2003074046A1 (fr) * 2002-03-01 2003-09-12 Takeda Chemical Industries, Ltd. Antidepresseur
WO2008020302A2 (fr) * 2006-08-17 2008-02-21 Pfizer Products Inc. Composés hétéro-aromatiques à base de quinoline

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003074046A1 (fr) * 2002-03-01 2003-09-12 Takeda Chemical Industries, Ltd. Antidepresseur
WO2008020302A2 (fr) * 2006-08-17 2008-02-21 Pfizer Products Inc. Composés hétéro-aromatiques à base de quinoline

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