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WO2009119528A1 - Composé hétérocyclique - Google Patents

Composé hétérocyclique Download PDF

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Publication number
WO2009119528A1
WO2009119528A1 PCT/JP2009/055716 JP2009055716W WO2009119528A1 WO 2009119528 A1 WO2009119528 A1 WO 2009119528A1 JP 2009055716 W JP2009055716 W JP 2009055716W WO 2009119528 A1 WO2009119528 A1 WO 2009119528A1
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Prior art keywords
substituent
compound
ring
ethyl acetate
phenyl
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PCT/JP2009/055716
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English (en)
Japanese (ja)
Inventor
栄治 本多
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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Publication of WO2009119528A1 publication Critical patent/WO2009119528A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D487/08—Bridged systems

Definitions

  • the present invention has an excellent monoamine neurotransmitter reuptake inhibitory activity, and is useful as a therapeutic / preventive agent for neurological diseases such as central diseases, particularly depression, anxiety and attention deficit hyperactivity disorder (ADHD). Related to a heterocyclic compound.
  • the monoamine neurotransmitters serotonin (5-HT), norepinephrine (NE) and dopamine (DA) are widely present in the brain and have various functions including neurotransmission via their receptors. . After they are released from the nerve endings, they are rapidly re-uptaked from the nerve gap by the respective transporters (serotonin transporter: SERT, norepinephrine transporter: NET and dopamine transporter: DAT), and nerve transmission is terminated. . On the other hand, compounds exhibiting reuptake inhibitory activity are known to be effective in various diseases including neuropsychiatric diseases such as depression, and are widely used as therapeutic agents.
  • depression treatment drugs include tricyclic antidepressants (TCA) typified by imipramine, selective serotonin reuptake inhibitors (SSRI) typified by fluoxetine, and selective serotonin norepinephrine typified by venlafaxine.
  • TCA tricyclic antidepressants
  • SSRI selective serotonin reuptake inhibitors
  • norepinephrine typified by venlafaxine.
  • Norepinephrine / dopamine reuptake inhibitors such as reuptake inhibitors (SNRI), bupropion, or monoamine oxidase inhibitors are used, all of which require several weeks to develop their effectiveness, improvement rate, or side effects. It cannot be said that the degree of satisfaction is necessarily high from the point (Non-Patent Documents 1 and 2).
  • TCA, SSRI and SNRI are not only for depression but also for symptomatic improvement in neurodegenerative diseases such as anxiety and attention deficit hyperactivity disorder and neurodegenerative diseases such as Alzheimer's disease, and pain treatment such as diabetic pain and myofibrosis.
  • neurodegenerative diseases such as anxiety and attention deficit hyperactivity disorder and neurodegenerative diseases such as Alzheimer's disease, and pain treatment such as diabetic pain and myofibrosis.
  • urinary diseases such as overactive bladder or gastrointestinal diseases such as irritable bowel syndrome.
  • Many other monoamine neurotransmitter reuptake inhibitors have been reported so far besides commercially available drugs.
  • cycloalkylamine derivatives Patent Document 1
  • pyrrolidine derivatives Patent Document 2
  • bicycloamine derivatives Patent Document 3
  • indole derivatives Patent Document 4 are known.
  • Patent Document 5 discloses a formula as a prophylactic / therapeutic agent for blood coagulation related diseases.
  • Patent Document 6 discloses a formula as a therapeutic agent for central nervous system diseases.
  • Patent Document 7 discloses a prophylactic / therapeutic agent for inflammatory diseases and the like.
  • Patent Document 8 as a prophylactic / therapeutic agent for central nervous disease, a formula
  • Patent Document 9 discloses a formula as a prophylactic / therapeutic agent for central nervous disease.
  • R a is a hydrogen atom, alkyl optionally substituted with halogen, etc.
  • R b is aryl optionally substituted with halogen, etc.
  • R 2 , R 2 ′ , R 3 , R 3 ′ , R 5 , R 5 ′ , R 6 , R 6 ′ , R 7 and R 7 ′ independently represent a hydrogen atom or alkyl (provided that R 2 , R 2 ′ , R 3 , R 3 ′ , R 5 , At least one of R 5 ′ , R 6 , R 6 ′ , R 7 and R 7 ′ is alkyl).
  • the compound represented by this is described.
  • Compounds that have reuptake inhibitory activity in brain monoamines are useful for the prevention or treatment of neuropsychiatric disorders such as depression, anxiety, attention deficit hyperactivity disorder (ADHD), etc. Conceivable. Therefore, it is desired to develop a novel compound having excellent brain monoamine reuptake inhibitory activity.
  • the present invention provides a novel compound (useful as a prophylactic / therapeutic agent for a neuropsychiatric disorder such as depression, anxiety, ADHD, etc.) having excellent brain monoamine reuptake inhibitory activity. It is an object of the present invention to provide a novel compound that is more effective and / or more effective and / or safer than drugs for preventing / treating diseases (SSRI and the like).
  • the novel compound shown in the following formula (I) has an unexpectedly superior pharmaceutical activity such as brain monoamines (serotonin / norepinephrine / dopamine) reuptake inhibitory activity.
  • the present invention has been completed.
  • Ar is (1) phenyl having a substituent (substituents of the phenyl are bonded to each other, and together with the carbon atom to which the substituent is bonded, an optionally substituted 4- to 7-membered saturated allocyclic ring, substituent A 4- to 7-membered saturated heterocyclic ring or a benzene ring which may have a substituent may be formed), (2) a condensed aromatic heterocyclic group which may have a substituent, or (3) a monocyclic aromatic heterocyclic group which may have a substituent (however, pyrazolyl having a substituent, substituted Except imidazolyl having a group and thiazolyl having a substituent);
  • L is (1) a bond, or (2) an optionally substituted C 1-3 (poly) methylene;
  • R 1 represents a hydrogen atom or an optionally substituted hydrocarbon group;
  • R 2 represents a hydrogen atom or an optionally substituted hydrocarbon group;
  • R 3 represents
  • R 1a to R 5a are the same or different and each represents (1) a hydrogen atom, or (2) a C 1-6 alkyl group which may have a substituent
  • R 6a to R 9a are the same or different and represent (1) a hydrogen atom, (2) a halogen atom, or (3) an optionally substituted C 1-6 alkyl group
  • Any combination of R 1a and R 4a , R 4a and R 6a and R 8a and R 9a is bonded to each other to form — (CH 2 ) n′— (where n ′ is an integer of 1 to 3).
  • Ar is (1) phenyl having a substituent (substituents of the phenyl are bonded to each other, and together with the carbon atom to which the substituent is bonded, an optionally substituted 4- to 7-membered saturated allocyclic ring, substituent A 4- to 7-membered saturated heterocyclic ring or a benzene ring which may have a substituent may be formed), (2) a condensed aromatic heterocyclic group which may have a substituent, or (3) a monocyclic aromatic heterocyclic group which may have a substituent (however, pyrazolyl having a substituent, substituted Except imidazolyl having a substituent and thiazolyl having a substituent) Indicates.
  • R 1a ′ represents (1) a hydrogen atom or (2) a C 1-6 alkyl group which may be substituted with a phenyl group
  • R 4a ′ represents (1) a hydrogen atom, or (2) a C 1-6 alkyl group which may be substituted with a C 1-3 alkoxy group
  • R 6a ′ represents (1) a hydrogen atom, or (2) a C 1-6 alkyl group
  • R 8a ′ and R 9a ′ are the same or different and each represents (1) a hydrogen atom, (2) a halogen atom, or (3) a C 1-6 alkyl group
  • Any one of R 1a ′ and R 4a ′ , R 4a ′ and R 6a ′ and R 8a ′ and R 9a ′ is bonded to each other to form — (CH 2 ) n′— (where n ′ Represents an integer of 1 to 3).
  • Ar is (1) phenyl having a substituent (substituents of the phenyl are bonded to each other, and together with the carbon atom to which the substituent is bonded, an optionally substituted 4- to 7-membered saturated allocyclic ring, substituent A 4- to 7-membered saturated heterocyclic ring or a benzene ring which may have a substituent may be formed), (2) a condensed aromatic heterocyclic group which may have a substituent, or (3) a monocyclic aromatic heterocyclic group which may have a substituent (however, pyrazolyl having a substituent, substituted Except imidazolyl having a substituent and thiazolyl having a substituent) Indicates.
  • the compound of the above-mentioned [5], represented by [7] Ar is (1) phenyl having a substituent, (2) indanyl which may have a substituent, (3) an indolyl optionally having a substituent, (4)
  • Ar is (1) (a) a fluorine atom, (b) a chlorine atom, (c) C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms or an oxo group, (d) cyano , (E) methoxy and (f) phenyl having 1 or 2 substituents selected from phenyl, (2) indanyl optionally substituted with an oxo group, (3) In-drill, (4)
  • the compound according to the above [5] which is benzofuranyl, or (5) naphthyl optionally substituted with a C 1-3 al
  • R 1b to R 9b are the same or different and each represents (1) a hydrogen atom, or (2) a C 1-6 alkyl group, R 6b and R 7b may combine with each other to form — (CH 2 ) n′— (where n ′ represents an integer of 1 to 3);
  • Ar is (1) phenyl having a substituent (substituents of the phenyl are bonded to each other, and together with the carbon atom to which the substituent is bonded, an optionally substituted 4- to 7-membered saturated allocyclic ring, substituent A 4- to 7-membered saturated heterocyclic ring or a benzene ring which may have a substituent may be formed), (2) a condensed aromatic heterocyclic group which may have a substituent, or (3) a monocyclic aromatic heterocyclic group which may have a substituent (however, pyrazolyl having a substituent, substituted Except imidazolyl having a substituent and thiazolyl having a
  • R 6b ′ and R 7b ′ are the same or different and each represents (1) a hydrogen atom or (2) a C 1-6 alkyl group, R 6b ′ and R 7b ′ may combine with each other to form — (CH 2 ) n′— (wherein n ′ represents an integer of 1 to 3);
  • Ar is (1) phenyl having a substituent (substituents of the phenyl are bonded to each other, and together with the carbon atom to which the substituent is bonded, an optionally substituted 4- to 7-membered saturated allocyclic ring, substituent A 4- to 7-membered saturated heterocyclic ring or a benzene ring which may have a substituent may be formed), (2) a condensed aromatic heterocyclic group which may have a substituent, or (3) a monocyclic aromatic heterocyclic group which may have a substituent (however, pyrazolyl having a substituent, substituted Except imidazolyl having a substituent and
  • Ar is (1) Substitution selected from (a) fluorine atom, (b) chlorine atom, (c) C 1-6 alkyl optionally having 1 to 3 halogen atoms, (d) cyano and (e) phenyl Phenyl having one or two groups, (2) the compound according to [11] above, which is indanyl optionally having substituent (s), or (3) naphthyl optionally having substituent (s); [14] R 6b ′ and R 7b ′ are the same or different and each represents (1) a hydrogen atom or (2) a C 1-6 alkyl group, R 6b ′ and R 7b ′ may combine with each other to form — (CH 2 ) n′— (wherein n ′ represents an integer of 1 to 3); Ar is (1) Substitution selected from (a) fluorine atom, (b) chlorine atom, (c) C 1-6 alkyl optionally having 1 to 3 halogen atoms,
  • Dopamine reuptake inhibition method [24] A method for preventing or treating a disease caused by serotonin, norepinephrine, or dopamine, which comprises administering an effective amount of the compound of the above-mentioned [1] or a salt thereof or a prodrug thereof to a mammal.
  • the compound of the present invention or a salt thereof or a prodrug thereof has excellent brain monoamines (such as serotonin / norepinephrine / dopamine) reuptake inhibitory activity, and therefore has a mental state such as depression, anxiety or attention deficit hyperactivity disorder. It is useful as a prophylactic / therapeutic agent for neurological diseases.
  • halogen atom represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • C 1-6 alkyl means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.
  • C 2-6 alkenyl refers to vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl and the like.
  • C 2-6 alkynyl refers to ethynyl, propargyl, butynyl, 1-hexynyl and the like.
  • C 3-8 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • C 6-14 aryl refers to phenyl, 1-naphthyl, 2-naphthyl, 2-anthryl and the like.
  • Ar represents (1) phenyl having a substituent (the substituents of the phenyl are bonded to each other, and may have a substituent together with the carbon atom to which the substituent is bonded 4). Or a 7-membered saturated allocyclic ring, an optionally substituted 4- to 7-membered saturated heterocyclic ring or an optionally substituted benzene ring)), (2) a substituent Or (3) a monocyclic aromatic heterocyclic group optionally having a substituent (provided that pyrazolyl having a substituent, imidazolyl having a substituent, and (Excluding thiazolyl having a substituent).
  • a halogen atom eg, chlorine atom
  • C 1-3 alkylenedioxy eg, methylenedioxy, ethylenedioxy, etc.
  • Nitro (4) cyano, (5) having 1 to 3 substituents selected from a halogen atom and C 1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.) C 1-6 alkyl, optionally (6) C 2-6 alkenyl optionally having 1 to 3 halogen atoms, (7) C 2-6 alkynyl optionally having 1 to 3 halogen atoms, (8) C 3-8 cycloalkyl optionally having 1 to 3 halogen atoms, (9) C 6-14 aryl optionally having 1 to 3 halogen atoms,
  • any two of these substituents are bonded to each other, together with the carbon atom to which the substituent is bonded, together with the substituent
  • Examples of the ring formed by the “optionally substituted 4- to 7-membered saturated homocyclic ring” and “substituted phenyl” include, for example, bicyclo [4.2.0] octa-1, Examples include 3,5-triene, 2,3-dihydro-1H-indene, 1,2,3,4-tetrahydronaphthalene and the like.
  • Examples of the ring formed by the “optionally substituted 4- to 7-membered saturated heterocyclic ring” and “phenyl having a substituent” include 2,3-dihydro-1-benzofuran, 2,3 -Dihydro-1H-indole, 1,3-dihydro-2-benzofuran, 2,3-dihydro-1H-isoindole, 3,4-dihydro-2H-chromene, 1,2,3,4-tetrahydroquinoline, 3 , 4-dihydro-1H-isochromene, 1,2,3,4-tetrahydroisoquinoline and the like.
  • substituent examples include a halogen atom, C 1-3 alkyl (eg, methyl, ethyl, propyl, isopropyl), oxo and the like, and the number of substituents is 1 to 3.
  • substituents include a halogen atom, C 1-3 alkyl (eg, methyl, ethyl, propyl, isopropyl), oxo and the like, and the number of substituents is 1 to 3.
  • Examples of the “substituent” of the “optionally substituted benzene ring” include a halogen atom, C 1-3 alkyl (eg, methyl, ethyl, propyl, isopropyl) and the like. Is 1 to 3.
  • the “condensed aromatic heterocyclic group” of the “optionally substituted condensed aromatic heterocyclic group” represented by Ar for example, benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, Quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, ⁇ -carbolinyl, ⁇ -carbolinyl, ⁇ -carbolinyl, acridinyl, phenoxazinyl, phenothiaziny
  • the “substituent” of the “fused aromatic heterocyclic group optionally having substituent (s)” represented by Ar the “substituent” of “phenyl having substituent (s)” represented by Ar above Similar ones are used.
  • the “fused aromatic heterocyclic group” may have, for example, 1 to 5 substituents, preferably 1 to 3 substituents at the substitutable positions. When the number of substituents is 2 or more, The substituents may be the same or different.
  • the “monocyclic aromatic heterocyclic group” of the “monocyclic aromatic heterocyclic group optionally having substituents” represented by Ar for example, a nitrogen atom, a sulfur atom and Examples thereof include 5- or 6-membered aromatic heterocyclic groups containing 1 or more (for example, 1 to 4) heteroatoms selected from oxygen atoms. Specific examples include thienyl, furanyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isothiazolyl, oxazolyl, isoxazolyl and the like.
  • the “substituent” of the “monocyclic aromatic heterocyclic group optionally having substituent (s)” represented by Ar the “substituent” of “phenyl having substituent (s)” represented by Ar above
  • the above substituents may be used, for example, the substituent may have 1 to 5, preferably 1 to 3 substituents at substitutable positions. When the number of substituents is 2 or more, The groups may be the same or different.
  • Ar includes (1) a phenyl having a substituent (the C 4-7 cycloalkane optionally having a substituent together with the carbon atom to which the substituents of the phenyl are bonded to each other and the substituent is bonded); A benzene ring which may have a substituent may be formed), (2) a condensed aromatic heterocyclic group which may have a substituent, or (3) a substituent which may have a substituent.
  • Preferred 6-membered aromatic heterocyclic groups are preferred.
  • Ar includes (1) (1 ′) halogen atom, (2 ′) cyano, (3 ′) C 1-6 alkyl optionally having 1 to 3 halogen atoms, (4 ′ ) C 6-14 aryl, (5 ′) C 1-6 alkoxy and (6 ′) phenyl having 1 to 3 substituents selected from C 1-6 alkyl-carbonyl, (2) having 1 oxo Preferred are indanyl which may be present, (3) naphthyl which may have one C 1-6 alkoxy, (4) indolyl and (5) benzofuryl.
  • Ar has (1) (1 ′) fluorine atom, (2 ′) chlorine atom, (3 ′) bromine atom, (4 ′) cyano, (5 ′) 1 to 3 fluorine atoms.
  • L represents (1) a bond or (2) C 1-3 (poly) methylene which may have a substituent.
  • C 1-3 (poly) methylene include methylene, ethylene, trimethylene and the like.
  • the “substituent” of the “optionally substituted C 1-3 (poly) methylene” represented by L is the “substituent” of the “phenyl having a substituent” represented by Ar. And the number of substituents is 1 or 2.
  • L is preferably a bond.
  • the substituents on the ring A (that is, substituents other than R 1 to R 5 and R 1 to R 5 ) are bonded to each other and may have a substituent together with the ring atom to which the substituent is bonded.
  • a good ring (preferably a 3- to 8-membered homocyclic or heterocyclic ring) may be formed.
  • the “substituent” other than R 1 , R 2 , R 3 , R 4 and R 5 on ring A is the same as the “substituent” of “phenyl having a substituent” represented by Ar described above. , Oxo, thioxo and the like are used, and may have 1 to 5, preferably 1 to 3, at substitutable positions. When the number of substituents is 2 or more, each substituent may be the same or different.
  • Ring A has, in addition to R 1 , R 2 , R 3 , R 4 and R 5 , 1 to 2 substituents selected from halogen atoms, C 1-6 alkyl, hydroxy, oxo and ethylene. Preferred 7 to 8 membered rings are preferred. Among them, as ring A, in addition to R 1 , R 2 , R 3 , R 4 and R 5 , there may be one substituent selected from a fluorine atom, methyl, hydroxy, oxo and ethylene 7 An 8-membered ring is preferred.
  • R 1 , R 2 , R 3 , R 4 and R 5 are the same or different and each represents a hydrogen atom or a hydrocarbon group which may have a substituent.
  • Examples of the “hydrocarbon group optionally having substituent (s)” represented by R 1 , R 2 , R 3 , R 4 and R 5 include alkyl and substituent optionally having substituent (s). Examples thereof include alkenyl which may have, alkynyl which may have substituent, cycloalkyl which may have substituent, aryl which may have substituent and the like.
  • the “optionally substituted alkyl” is, for example, the same as the “substituent” of the above-mentioned “phenyl having a substituent” represented by Ar, a substituent selected from oxo, thioxo and the like And C 1-6 alkyl optionally having 1 to 3 thereof.
  • Examples of the “optionally substituted alkenyl” include those similar to the “substituent” of the above-mentioned “phenyl having a substituent” represented by Ar, a substituent selected from oxo, thioxo and the like And C 2-6 alkenyl which may have 1 to 3 thereof.
  • Examples of the “optionally substituted alkynyl” include those similar to the “substituent” of the above-mentioned “phenyl having a substituent” represented by Ar, a substituent selected from oxo, thioxo and the like And C 2-6 alkynyl which may have 1 to 3 thereof.
  • Examples of the “optionally substituted cycloalkyl” include those similar to the “substituent” of the above-mentioned “phenyl having a substituent” represented by Ar, a substituent selected from oxo, thioxo and the like And C 3-8 cycloalkyl optionally having 1 to 3 groups.
  • the “aryl optionally having substituent (s)” for example, it may have 1 to 3 of the same “substituent” as the above-mentioned “phenyl having substituent (s)” represented by Ar. Good C 6-14 aryl and the like can be mentioned.
  • the substituents on ring A may be bonded together to form a “having substituent” which may be formed together with the ring atom to which the substituent is bonded.
  • substituents on the optionally substituted 3- to 8-membered homocyclic or heterocyclic ring include a C 3-8 cycloalkane which may have a substituent and a C 4-8 cyclo which may have a substituent.
  • C 3-8 cycloalkane is, for example, the same as the “substituent” of the above-mentioned “phenyl having a substituent” represented by Ar, oxo, thioxo C 3-8 cycloalkane (eg, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane) which may have 1 to 3 substituents selected from the above.
  • the “optionally substituted C 4-8 cycloalkene” is, for example, the same as the “substituent” of the above-mentioned “phenyl having a substituent” represented by Ar, oxo, thioxo C 4-8 cycloalkene (eg, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene) which may have 1 to 3 substituents selected from the above.
  • Examples of the “optionally substituted 3- to 8-membered heterocyclic ring” include those similar to the “substituent” of the above-mentioned “phenyl having a substituent” represented by Ar, oxo, A 3- to 8-membered heterocyclic ring optionally having 1 to 3 substituents selected from thioxo and the like (eg, aziridine, oxirane, azetin, oxetane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, morpholine, thiol) Morpholine and the like).
  • substituents selected from thioxo and the like (eg, aziridine, oxirane, azetin, oxetane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, morpholine, thiol)
  • ring formed by combining the substituents on ring A that is, substituents other than R 1 to R 5 and R 1 to R 5
  • substituents other than R 1 to R 5 and R 1 to R 5 substituents other than R 1 to R 5 and R 1 to R 5
  • substituents other than R 1 to R 5 and R 1 to R 5 substituents other than R 1 to R 5 and R 1 to R 5
  • ring atoms to which the substituents are bonded include octahydro -1H-pyrrolo [1,2-a] [1,4] diazepin-1-one, 3,9-diazabicyclo [4.2.1] nonane-4-one, 3,9-diazabicyclo [4.2. 1] Nonan-2-one, 3,6-diazabicyclo [3.2.2] nonane-4-one, 5,8-diazaspiro [2.6] nonane-6-one, 5,8-diazaspiro [2. 6] nonan-4-one and the like.
  • R 1 is preferably a hydrogen atom or an optionally substituted alkyl. Of these, R 1 is preferably a hydrogen atom or C 1-6 alkyl optionally having one C 6-14 aryl. In particular, R 1 is preferably a hydrogen atom, methyl, ethyl, isopropyl or benzyl, more preferably a hydrogen atom, methyl or ethyl. R 2 is preferably a hydrogen atom or alkyl optionally having a substituent. Of these, a hydrogen atom or C 1-6 alkyl is preferable, and a hydrogen atom, methyl, ethyl, propyl, isopropyl or benzyl is more preferable.
  • R 3 is preferably a hydrogen atom or an optionally substituted alkyl.
  • R 3 is preferably a hydrogen atom or an optionally substituted alkyl.
  • a hydrogen atom or C 1-6 alkyl is preferable, and a hydrogen atom, methyl, ethyl, propyl, isopropyl or benzyl is more preferable.
  • a hydrogen atom is particularly preferable.
  • R 4 is preferably a hydrogen atom or an optionally substituted alkyl.
  • a hydrogen atom or C 1-6 alkoxy and C 6-14 C 1-6 alkyl is preferably optionally having one substituent selected from aryl, hydrogen atom, methyl, ethyl, propyl, isopropyl More preferred are butyl, isobutyl, tert-butyl, ethoxymethyl or benzyl.
  • R 5 is preferably a hydrogen atom.
  • the formula (I-II) [wherein each symbol is as defined above.
  • a salt thereof that is, a compound in which, in the formula (I), L is a bond, m is 2, and n is 0 (ring A is a 7-membered ring) or The salt is preferred.
  • the compound represented by the formula (I-II) or a salt thereof include the formula (I-III) [wherein each symbol is as defined above.
  • R 1a ′ represents (1) a hydrogen atom or (2) a C 1-6 alkyl group which may be substituted with a phenyl group
  • R 4a ′ represents (1) a hydrogen atom, or (2) a C 1-6 alkyl group which may be substituted with a C 1-3 alkoxy group
  • R 6a ′ represents (1) a hydrogen atom, or (2) a C 1-6 alkyl group
  • R 8a ′ and R 9a ′ are the same or different and each represents (1) a hydrogen atom, (2) a halogen atom, or (3) a C 1-6 alkyl group, Any combination of R 1a ′ and R 4a ′ , R 4a ′ and R 6a ′ and R 8a ′ and R 8a ′ and
  • Ar is (1) (a) a fluorine atom, (b) a chlorine atom, (c) C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms or an oxo group, (d) cyano, (e ) Phenyl having 1 or 2 substituents selected from methoxy and (f) phenyl; (2) indanyl optionally substituted with an oxo group, (3) In-drill, (4) benzofuranyl, or (5) naphthyl optionally substituted with a C 1-3 alkoxy group, Examples thereof include a compound represented by the formula (I-III) or a salt thereof.
  • Ar is (1) phenyl having a substituent, (2) indanyl which may have a substituent, (3) an indolyl optionally having a substituent, (4) benzofuranyl which may have a substituent, or (5) naphthyl which may have a substituent.
  • examples thereof include a compound represented by the formula (I-II) or a salt thereof.
  • Ar is (1) (a) a fluorine atom, (b) a chlorine atom, (c) C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms or an oxo group, (d) cyano, (e ) Phenyl having 1 or 2 substituents selected from methoxy and (f) phenyl; (2) indanyl optionally substituted with an oxo group, (3) In-drill, (4) benzofuranyl, or (5) naphthyl optionally substituted with a C 1-3 alkoxy group, Examples thereof include a compound represented by the formula (I-II) or a salt thereof.
  • the formula (I-IV) [wherein each symbol is as defined above.
  • a salt thereof that is, a compound in which, in the formula (I), L is a bond, m is 1, and n is 1 (ring A is a 7-membered ring) or The salt is preferred.
  • Preferred examples of the compound represented by the formula (I-IV) or a salt thereof include the formula (IV) [wherein each symbol is as defined above.
  • a salt thereof that is, a compound or a salt thereof in which R 1b , R 2b , R 3b , R 4b , R 5b , R 8b and R 9b are hydrogen atoms in the formula (I-IV) Is mentioned.
  • R 6b ′ and R 7b ′ are the same or different and each represents (1) a hydrogen atom or (2) a C 1-6 alkyl group, R 6b ′ and R 7b ′ may combine with each other to form — (CH 2 ) n′— (wherein n ′ represents an integer of 1 to 3),
  • Ar is (1) Substitution selected from (a) fluorine atom, (b) chlorine atom, (c) C 1-6 alkyl optionally having 1 to 3 halogen atoms, (d) cyano and (e) phenyl Phenyl having one or two groups, (2) indanyl optionally substituted with an oxo group, or (3) naphthyl, Examples thereof include compounds represented by the formula (IV) or salts thereof.
  • Ar is (1) Substitution selected from (a) fluorine atom, (b) chlorine atom, (c) C 1-6 alkyl optionally having 1 to 3 halogen atoms, (d) cyano and (e) phenyl Phenyl having one or two groups, (2) indanyl which may have a substituent, or (3) naphthyl which may have a substituent. Examples thereof include compounds represented by the formula (IV) or salts thereof.
  • a 4- to 7-membered saturated heterocyclic ring which may have a substituent or a benzene ring which may have a substituent) or (2) may have a substituent.
  • a “7-membered homopiperazinone compound” is a 6-membered aromatic heterocyclic group and L is a bond.
  • compound (Ia) a compound represented by the following formula (hereinafter sometimes abbreviated as compound (Ia)) or a salt thereof is preferable.
  • Ar a is (1) phenyl having a substituent (the substituents of the phenyl are bonded to each other, and together with the carbon atom to which the substituent is bonded, the optionally substituted 4- to 7-membered saturated allotrope) A ring, a 4- to 7-membered saturated heterocyclic ring optionally having substituent (s) or a benzene ring optionally having substituent (s)) or (2) having a substituent.
  • L a is a bond
  • R 1a represents a hydrogen atom or an optionally substituted hydrocarbon group
  • R 2a represents a hydrogen atom or an optionally substituted hydrocarbon group
  • R 3a represents a hydrogen atom or an optionally substituted hydrocarbon group
  • R 4a represents a hydrogen atom or an optionally substituted hydrocarbon group
  • R 5a is a hydrogen atom or an optionally substituted hydrocarbon group
  • Ring A a is a 7-membered ring optionally having a substituent other than R 1a to R 5a (the ring A a).
  • the above substituents may be bonded to each other to form an optionally substituted ring together with the ring atom to which the substituent is bonded.) Indicates. ]
  • Ar a is (1) (1 ′) a halogen atom, (2 ′) cyano, (3 ′) C 1-6 alkyl optionally having 1 to 3 halogen atoms, (4 ′) C 6 -14 aryl, (5 ′) C 1-6 alkoxy and (6 ′) phenyl having 1 to 3 substituents selected from C 1-6 alkyl-carbonyl, (2) having 1 oxo Good indanyl, (3) naphthyl optionally having one C 1-6 alkoxy, (4) indolyl and (5) benzofuryl; La is a bond; R 1a may have a hydrogen atom or one C 6-14 aryl, C 1-6 alkyl; R 2a is a hydrogen atom or C 1-6 alkyl; R 3a is a hydrogen atom; R 4a is (1) hydrogen atom or (2) C 1-6 alkoxy and C 6-14 C 1-6 alkyl optionally having one substituent selected from aryl; R 5a is a hydrogen
  • Ar a has (1) (1 ′) fluorine atom, (2 ′) chlorine atom, (3 ′) bromine atom, (4 ′) cyano, (5 ′) 1 to 3 fluorine atoms Phenyl having 1 to 3 (preferably 2) substituents selected from methyl (preferably trifluoromethyl), (6 ′) phenyl, (7 ′) methoxy and (8 ′) acetyl, 2) indanyl optionally having one oxo, (3) naphthyl optionally having one methoxy, (4) indolyl and (5) benzofuryl; R 1a is a hydrogen atom, methyl, ethyl, isopropyl or benzyl; R 2a is a hydrogen atom or methyl; R 3a is a hydrogen atom; R 4a is a hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert
  • the compounds described in Examples 1 to 19, 22 to 65, 82 to 112, and 116 to 127 are preferable.
  • Ar is (1) (a) a fluorine atom, (b) a chlorine atom, (c) C 1-6 alkyl optionally having 1 to 3 halogen atoms, (d) cyano and (e) C 6 -10 is phenyl having 1 or 2 substituents selected from aryl, (2) indanyl which may have substituents, or (3) naphthyl which may have substituents, and L is “7-membered homopiperazinone compound” which is a bond is also mentioned.
  • compound (Ib) a compound represented by the following formula (hereinafter sometimes abbreviated as compound (Ib)) or a salt thereof is preferable.
  • Ar b is (1) (a) a fluorine atom, (b) a chlorine atom, (c) C 1-6 alkyl optionally having 1 to 3 halogen atoms, (d) cyano and (e) C Phenyl having 1 or 2 substituents selected from 6-10 aryl, (2) indanyl optionally having substituents, or (3) naphthyl optionally having substituents; L b is a bond; R 1b represents a hydrogen atom or an optionally substituted hydrocarbon group; R 2b represents a hydrogen atom or an optionally substituted hydrocarbon group; R 3b represents a hydrogen atom or an optionally substituted hydrocarbon group; R 4b represents a hydrogen atom or an optionally substituted hydrocarbon group; R 5b is a hydrogen atom or an optionally substituted hydrocarbon group; and Ring A b is a 7-membered ring optionally having a substituent other than R 1b to R 5b (on Ring A b Of the substituents may be combined with
  • Ar b is (1) (a) a fluorine atom, (b) a chlorine atom, (c) C 1-6 alkyl optionally having 1 to 3 fluorine atoms, (d) cyano and (e) C Phenyl having 1 or 2 substituents selected from 6-10 aryl, (2) indanyl optionally having 1 oxo, or (3) naphthyl; L b is a bond; R 1b is a hydrogen atom or C 1-6 alkyl; R 2b is a hydrogen atom; R 3b is a hydrogen atom; R 4b is a hydrogen atom; A compound wherein R 5b is a hydrogen atom; and ring A b is a 7-membered ring optionally having one C 2-4 alkylene in addition to R 1b , R 2b , R 3b , R 4b and R 5b Is preferred.
  • Ar b is a substitution selected from (1) (a) a fluorine atom, (b) a chlorine atom, (c) methyl optionally having 1 to 3 fluorine atoms, (d) cyano and (e) phenyl Phenyl having 1 or 2 groups, (2) indanyl optionally having 1 oxo, or (3) naphthyl; L b is a bond; R 1b is a hydrogen atom or methyl; R 2b is a hydrogen atom; R 3b is a hydrogen atom; R 4b is a hydrogen atom; A compound in which R 5b is a hydrogen atom: and ring A b is a 7-membered ring optionally having one ethylene other than R 1b , R 2b , R 3b , R 4b and R 5b is preferred.
  • the compounds described in Examples 20, 21, 66 to 81 and 108 are preferable.
  • the compound of the present invention represented by the formula (I) or a salt thereof particularly preferably, 1- (3,4-dichlorophenyl) -1,4-diazepan-2-one (compound of Example 1), 1- (3,4-dichlorophenyl) -3-methyl-1,4-diazepan-2-one (compound of Example 6), 1- (3,4-dichlorophenyl) -3-ethyl-1,4-diazepan-2-one (compound of Example 101), 1- (3,4-dichlorophenyl) -3-propyl-1,4-diazepan-2-one (the compound of Example 106), 1-naphthalen-2-yl-1,4-diazepan-2-one (compound of Example 25), 3-methyl-1-naphthalen-2-yl-1,4-diazepan-2-one (compound of Example 117), 3-ethyl-1-naphthalen-2-yl-1,4-diazepan-2
  • room temperature usually indicates 0 to 30 ° C.
  • each symbol in the chemical structural formula described in the scheme has the same meaning as described above unless otherwise specified.
  • the compound in the formula includes a case where a salt is formed. Examples of such a salt include the same salts as the salt of compound (I).
  • the compound obtained in each step can be used in the next reaction as a reaction solution or as a crude product, but can be isolated from the reaction mixture according to a conventional method, such as recrystallization, distillation, chromatography, etc. It can be easily purified by this separation means.
  • the schematic diagram of the reaction formula is shown below, when a compound in the formula is commercially available, a commercially available product can be used as it is.
  • protecting groups P 1 and P 2 are protecting groups for nitrogen atoms of amines and amides
  • P 3 is a protecting group for alcohol oxygen atoms, and those known per se can be used.
  • P 1 and P 2 are preferably tert-butyl carbamate, benzyl carbamate, benzyl and the like
  • P 3 is preferably tert-butyl diphenylsilyl and the like.
  • P 1 itself may be R 1 . Examples include methyl and benzyl.
  • Examples of the “leaving group” represented by X include a halogen atom (for example, chlorine atom, bromine atom, iodine atom, etc.), C 1-6 alkylsulfonyloxy (for example, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethane). Sulfonyloxy, etc.), C 6-10 arylsulfonyloxy (eg, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.) and the like are used.
  • a halogen atom for example, chlorine atom, bromine atom, iodine atom, etc.
  • C 1-6 alkylsulfonyloxy for example, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethane.
  • Sulfonyloxy, etc. C 6-10 aryl
  • reaction when performing alkylation reaction, hydrolysis reaction, amination reaction, esterification reaction, amidation reaction, etherification reaction, oxidation reaction, reduction reaction, reductive amination reaction, etc.
  • the reaction is carried out according to a method known per se. Such methods include, for example, Organic Functional Group Preparations, 2nd Edition, Academic Press, Inc., 1989; Comprehensive Organic Transformation (Comprehensive Organic Transformation). ) VCH Publishers Inc. Examples include the method described in 1989.
  • Each step described below can be carried out without solvent or by dissolving or suspending in an appropriate solvent.
  • solvent examples include hydrocarbon solvents, alcohol solvents, ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, sulfoxide solvents, ketone solvents, esters. It refers to a system solvent, a carboxylic acid solvent, water, etc., and these may be used in a mixture of two or more at an appropriate ratio.
  • Compound (III) can be produced by deprotection of compound (II).
  • Deprotection can be performed, for example, according to the method described in Protective Groups in Organic Synthesis, Third Edition, Wiley-Interscience (1999). Specifically, it is carried out by acid treatment, alkaline hydrolysis, catalytic hydrogenation reaction or the like.
  • the protecting group P 1 those known per se can be used. Preferred examples include tert-butyl carbamate, benzyl carbamate, benzyl, methyl and the like.
  • the protecting group P 1 is tert- butyl carbamate, it can be deprotected by using an acid.
  • the “solvent” include ester solvents (for example, ethyl acetate and the like) and alcohol solvents (for example, ethanol and the like), and ester solvents are particularly preferable.
  • the “acid” include hydrochloric acid, hydrobromic acid, trifluoroacetic acid and the like. In particular, hydrochloric acid, trifluoroacetic acid and the like are preferable.
  • the amount of the acid to be used is generally 1 to 50 molar equivalents, preferably 1 to 10 molar equivalents, per 1 mol of compound (II).
  • the reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C.
  • the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.1 hour to about 24 hours. It's time.
  • deprotection can also be performed by a catalytic hydrogenation reaction or the like.
  • the “catalytic hydrogenation reaction” can be performed in a hydrogen atmosphere in the presence of a catalyst.
  • the catalyst include palladium (eg, palladium carbon, palladium hydroxide, palladium oxide, etc.), nickel (eg, developed nickel catalyst), platinum (eg, platinum oxide, platinum carbon, etc.), rhodium ( For example, rhodium carbon and the like.
  • the amount of the catalyst to be used is generally 0.001 to 1 molar equivalent, preferably 0.01 to 0.1 molar equivalent, per 1 mol of compound (II).
  • the “solvent” is preferably an alcohol solvent (eg, methanol, ethanol, propanol, butanol, etc.), an ether solvent (eg, diethyl ether, dioxane, tetrahydrofuran, etc.), an ester solvent (eg, ethyl acetate, etc.), An acid solvent (for example, acetic acid etc.), water, or mixtures thereof are mentioned.
  • the hydrogen pressure at which the reaction is carried out is usually about 1 to about 50 atmospheres, preferably about 1 to about 10 atmospheres.
  • the reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 100 ° C.
  • the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 hours to about 40 ° C. It's time.
  • Compound (I) can be produced by alkylation, alkenylation, alkynylation, cycloalkylation or the like of compound (III).
  • This reaction includes an alkylating agent corresponding to the substituent R 1 (eg, iodomethane, benzyl bromide, etc.), an alkenylating agent (eg, allyl bromide), an alkynylating agent (eg, propargyl bromide), cycloalkyl, etc.
  • An agent such as cyclopropylmethyl bromide can be used.
  • the amount of the alkylating agent used is usually 0.5 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (III).
  • the “solvent” is preferably an amide solvent (for example, dimethylformamide, etc.).
  • this reaction may be performed by adding an appropriate base.
  • base Alkali metal or alkaline earth metal hydrides (eg, lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), alkali metal or alkaline earth metal amides (eg, lithium amide, sodium) Amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, etc.), alkali metal or alkaline earth metal lower alkoxides (eg, sodium methoxide, Strong bases such as sodium ethoxide, potassium tert-butoxide and the like; 2) Alkali metal or alkaline earth metal hydroxides (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydro
  • Amidines for example, pyridine, dimethylaminopyridine, imidazole, 2,6-lutidine And organic bases such as basic heterocyclic compounds. Preferred are sodium hydride, cesium carbonate, potassium carbonate and the like.
  • the amount of the base to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (III).
  • the hydrogen atom on the nitrogen atom of compound (III) may be previously substituted with a metal atom, for example, an alkali metal such as lithium or sodium.
  • Compound (I) (when R 1 is optionally substituted alkyl) can also be produced by reductive alkylation of compound (III).
  • This reaction is carried out by subjecting compound (III) and an imine intermediate produced from the corresponding aldehyde or ketone to a reduction reaction.
  • the amount of aldehyde or ketone to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (III).
  • the reduction reaction can be carried out by a method known per se, but is usually carried out by a reaction using a reducing agent or the “catalytic hydrogenation reaction” described in the above (Step A-1).
  • Examples of the “reducing agent” include an aluminum reagent (eg, lithium aluminum hydride (LiAlH 4 ), diisobutylaluminum hydride (DIBAL-H), sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al), Alane (AlH 3 ), etc.), boron reagent (eg, borane (BH 3 ), 9-borabicyclo [3.3.1] nonane (9-BBN), sodium borohydride (NaBH 4 ), sodium cyanoborohydride (NaBH 3 CN), sodium triacetoxyborohydride (NaBH (OAc) 3 ) and the like. Borane, sodium triacetoxyborohydride and the like are preferable.
  • an aluminum reagent eg, lithium aluminum hydride (LiAlH 4 ), diisobutylaluminum hydride (DIBAL-H), sodium bis (2-methoxyethoxy) aluminum hydride (Red-
  • the amount of the reducing agent to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (III).
  • an acid may be added to accelerate the reaction.
  • Preferred examples of the “acid” include acetic acid.
  • the amount of the acid to be used is generally 0.1 to 10 molar equivalents, preferably 0.1 to 1 molar equivalent, per 1 mol of compound (III).
  • the “solvent” is preferably an ether solvent (for example, tetrahydrofuran).
  • the reaction temperature is usually about ⁇ 100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
  • Compound (III) can be produced by the method of [Production method G] in addition to (Step A-1).
  • Compound (III) includes, for example, compound (IIIe), and the compound (IIIe) can be produced by the following method.
  • Compound (IIIe) can be produced by a ring closure reaction by intramolecular alkylation of compound (XLVI).
  • the “base” to be added include amines, and triethylamine is particularly preferable.
  • the amount of the base to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XLVI).
  • an appropriate inorganic salt may be added.
  • tetra-n-butylammonium iodide is preferable.
  • the amount of the inorganic salt to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XLVI).
  • the “solvent” is preferably a halogen-based solvent (eg, dichloromethane).
  • the reaction temperature is usually about ⁇ 100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
  • Step B-2 This coupling reaction is performed by a method according to (Step B-4) described later.
  • Preferred examples of the “metal catalyst” include copper iodide.
  • examples of the “ligand” include 2- (2-methylpropanoyl) cyclohexanone, and examples of the “base” include cesium carbonate.
  • the amount of the metal catalyst to be used is generally 0.001 to 3 molar equivalents, preferably 0.001 to 0.3 molar equivalents, per 1 mol of compound (XLVII).
  • the amount of the ligand to be used is generally 0.001 to 10 molar equivalents, preferably 0.001 to 3 molar equivalents, per 1 mol of compound (XLVII).
  • the amount of the base to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XLVII).
  • the “solvent” include amide solvents (for example, dimethylformamide and the like).
  • the reaction temperature can be ⁇ 100 ° C. to 300 ° C., preferably 0 ° C. to 150 ° C.
  • the reaction time is, for example, 1 minute to 10 days, and preferably 0.5 to 48 hours. (Process G-3)
  • This amidation reaction is carried out by a method according to (Step B-1) described later. For example, a method using an activated carboxylic acid derivative (acid halide or the like) is preferable.
  • the “solvent” is preferably a halogen-based solvent, an ether-based solvent, or a mixed solvent thereof with water, and a mixed solvent of 1,4-dioxane and water is particularly preferable.
  • this reaction may be performed by adding an appropriate base.
  • the “base” the same “base” as described in the above (Step A-2) can be used, and for example, sodium carbonate and the like are preferable.
  • the reaction temperature is usually about ⁇ 100 ° C. to about 150 ° C., preferably about ⁇ 20 ° C. to about 60 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24. It's time.
  • Step A-4 This deprotection reaction is carried out by a method according to (Step A-1).
  • the “solvent” is preferably an ester solvent (for example, ethyl acetate) or an ether solvent (for example, 1,4-dioxane). Ether solvents are preferred.
  • Preferred examples of the “acid” include hydrochloric acid, hydrobromic acid, trifluoroacetic acid and the like. In particular, hydrochloric acid, trifluoroacetic acid and the like are preferable.
  • the reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 60 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.1 hour to about 24 hours. It's time.
  • Compound (II) can be produced by the following [Production Method B] to [Production Method F].
  • [Production method F] shows the production method of compound (IId).
  • Compound (VI) can be produced by amidation of compound (IV).
  • This amidation reaction is carried out by reacting the corresponding carboxylic acid derivative with a condensing agent (for example, N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide, 4- (4,6-dimethoxy [1.3.5] triazine- 2-yl) -4-methylmorpholinium chloride) or a reaction using an activated carboxylic acid derivative (such as acid chloride).
  • a condensing agent for example, N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide, 4- (4,6-dimethoxy [1.3.5] triazine- 2-yl) -4-methylmorpholinium chloride
  • an activated carboxylic acid derivative such as acid chloride.
  • the amount of the carboxylic acid derivative to be used is generally 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, per
  • the amount of the condensing agent to be used is generally 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, per 1 mol of compound (IV).
  • the “solvent” is preferably an amide solvent, and N, N-dimethylformamide is particularly preferable.
  • this reaction may be performed by adding an appropriate base.
  • the “base” the same “base” as described in the above (Step A-2) can be used, and for example, triethylamine and the like are preferable.
  • the amount of the base to be used is generally 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, per 1 mol of compound (IV).
  • the reaction temperature is usually about ⁇ 100 ° C.
  • Compound (VI) can also be produced by deprotecting only one protecting group of compound (V) having both protecting groups P 1 and P 2 . Deprotection can be performed by a method according to (Step A-1). Further, as the protecting groups P 1 and P 2 , those known per se can be used in combination. Specific examples include a combination of tert-butyl carbamate and benzyl, benzyl and benzyl, and the like.
  • the combination of protecting groups is tert-butyl carbamate and benzyl
  • deprotection of only tert-butyl carbamate can be performed using an acid.
  • the “solvent” is preferably an ester solvent (such as ethyl acetate) or an alcohol solvent (such as ethanol).
  • Preferred examples of the “acid” include hydrochloric acid and trifluoroacetic acid.
  • the amount of the acid to be used is generally 1 to 50 molar equivalents, preferably 1 to 10 molar equivalents, per 1 mol of compound (V).
  • the reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C.
  • Compound (IIa) can be produced by a ring closure reaction of compound (VI).
  • Preferred examples of the “solvent” include dimethyl sulfoxide, N, N-dimethylformamide and the like.
  • a base may be added.
  • the base the same “base” as described in the above (Step A-2) can be used, preferably sodium hydride, cesium carbonate, potassium carbonate and the like.
  • the amount of the base to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (VI).
  • the reaction temperature is usually about ⁇ 100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C.
  • the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
  • the amount of compound (VII) to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (VIII) or compound (XI).
  • the “metal catalyst” include copper catalysts (eg, copper iodide, copper bromide), palladium catalysts (eg, palladium (II) acetate, tris (dibenzylideneacetone) dipalladium (0), palladium chloride).
  • metal catalysts such as tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), etc., and a ligand (eg, 2-dicyclohexylphos Fino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl, triphenylphosphine, tri-tert-butylphosphine, binaphthol, proline, 4,5-bis (diphenylphosphino) -9,9 -Dimethylxanthene or the like) may be added.
  • a ligand eg, 2-dicyclohexylphos Fino-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl, triphenylphosphine, tri-tert-butylphosphine, binaphthol, proline, 4,5-bis
  • the amount of the metal catalyst to be used is generally 0.001 to 3 molar equivalents, preferably 0.001 to 0.3 molar equivalents, per 1 mol of compound (VIII) or compound (XI).
  • the amount of the ligand to be used is generally 0.001 to 10 molar equivalents, preferably 0.001 to 3 molar equivalents, per 1 mol of compound (VIII) or compound (XI).
  • this reaction may be performed by adding an appropriate base.
  • the “base” the same “base” as described in the above (Step A-2) can be used, but cesium carbonate, tripotassium phosphate and the like are preferable.
  • the amount of the base to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (VIII) or compound (XI).
  • the “solvent” for this reaction is preferably a sulfoxide solvent or an amide solvent, particularly preferably dimethyl sulfoxide, N, N-dimethylformamide or the like. This reaction can be carried out at ⁇ 100 ° C. to 300 ° C., preferably 0 ° C. to 150 ° C.
  • this reduction reaction can be carried out by a method known per se, it is usually carried out using a reducing agent.
  • the “reducing agent” those similar to the “reducing agent” described in the above (Step A-2) can be used, and preferably lithium aluminum hydride, borane and the like.
  • the amount of the reducing agent to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (IX).
  • the “solvent” include ether solvents, and solvents such as diethyl ether and tetrahydrofuran are preferred.
  • This reaction can be carried out at ⁇ 100 ° C. to 300 ° C., preferably 0 ° C. to 150 ° C.
  • the reaction time is, for example, 1 minute to 10 days, and preferably 0.5 to 24 hours.
  • the “solvent” include ethyl acetate and ethanol, with ethyl acetate being particularly preferred.
  • the “acid” is preferably a hydrochloric acid solution, trifluoroacetic acid or the like.
  • the amount of the acid to be used is generally 1 to 50 molar equivalents, preferably 1 to 10 molar equivalents, per 1 mol of compound (XII).
  • the reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 60 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.1 hour to about 24 hours. It's time.
  • the protecting groups P 1 and P 2 are benzyl, only one benzyl can be deprotected by “catalytic hydrogenation reaction”.
  • the catalyst include palladium (eg, palladium carbon, palladium hydroxide carbon, palladium oxide, etc.), platinum (eg, platinum oxide, platinum carbon, etc.), and the like.
  • the amount of the catalyst to be used is generally 0.001 to 1 molar equivalent, preferably 0.001 to 0.1 molar equivalent, per 1 mol of compound (XII).
  • the “solvent” is preferably an alcohol solvent (for example, methanol, ethanol, propanol, butanol, etc.), and ethanol is particularly preferable.
  • the hydrogen pressure at which the reaction is carried out is usually about 1 to about 50 atmospheres, preferably about 1 to about 10 atmospheres.
  • the reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 100 ° C.
  • the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 hours to about 40 ° C. It's time.
  • Step B-8 This coupling reaction can be carried out by a method according to (Step B-4).
  • the amount of compound (VII) to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XIII).
  • copper iodide is used as the metal catalyst
  • L-proline is used as the ligand
  • tripotassium phosphate is used as the base.
  • the amount of the metal catalyst to be used is generally 0.001 to 1 molar equivalent, preferably 0.001 to 0.3 molar equivalent, relative to 1 mol of compound (XIII).
  • the amount of the ligand to be used is generally 0.001 to 10 molar equivalents, preferably 0.001 to 3 molar equivalents, per 1 mol of compound (XIII).
  • the amount of the base to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XIII).
  • This amidation reaction can be carried out by a method according to (Step B-1).
  • preferred protecting group P 1 is benzyl, methyl or the like.
  • Step B-10 This amidation reaction can be carried out by a method according to (Step B-1).
  • the amount of compound (XV) to be used is generally 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XVI).
  • the “solvent” is preferably an amide solvent, and N, N-dimethylformamide is particularly preferable.
  • this reaction may be performed by adding an appropriate base.
  • the “base” the same “base” as described in the above (Step A-2) can be used, and for example, triethylamine and the like are preferable.
  • the amount of the base to be used is generally 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XVI) or compound (XIV).
  • the reaction temperature is usually about ⁇ 100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
  • This reduction reaction can be carried out by a method according to (Step B-5).
  • the “reducing agent” is lithium aluminum hydride, borane or the like.
  • the amount of the reducing agent to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XVII) or compound (XIX).
  • the “solvent” include ether solvents, and solvents such as diethyl ether and tetrahydrofuran are preferred.
  • This reaction can be carried out at ⁇ 100 ° C. to 300 ° C., preferably 0 ° C. to 150 ° C.
  • the reaction time is, for example, 1 minute to 10 days, and preferably 0.5 to 24 hours.
  • This alkylation reaction can be carried out by a method according to (Step A-2).
  • the amount of the alkylating agent (compound (XVIII)) to be used is generally 0.5 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XV).
  • Preferred examples of the solvent include aromatic solvents, and particularly preferred is toluene.
  • potassium carbonate is preferable.
  • the amount of the base to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XV).
  • the reaction temperature is usually about ⁇ 100 ° C. to about 200 ° C., preferably about 0 ° C. to about 100 ° C., and the reaction time is preferably 0.5 to 24 hours.
  • the introduction reaction of this protecting group can be carried out by a method according to (Step B-6).
  • the protecting group P 1 is benzyl
  • di-tert-butyl dicarbonate can be used to introduce tert-butyl carbamate as the protecting group P 2 .
  • the amount of ditert-butyl dicarbonate to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (IV).
  • examples of the “solvent” include ether solvents, alcohol solvents and the like, and tetrahydrofuran and the like are particularly preferable.
  • the reaction temperature is usually ⁇ 50 ° C.
  • This amidation reaction can be carried out by a method according to (Step B-1).
  • a method using a corresponding activated carboxylic acid derivative (acid halide or the like) is preferable.
  • the amount of the carboxylic acid derivative to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XII).
  • the “solvent” is preferably a halogen-based solvent or an ether-based solvent, and tetrahydrofuran is particularly preferable.
  • this reaction may be performed by adding an appropriate base.
  • base the same “base” as described in the above (Step A-2) can be used, and for example, triethylamine and the like are preferable.
  • the amount of the base to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XII).
  • the reaction temperature is usually about ⁇ 100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
  • Compound (IIa) can be produced by a ring closure reaction of compound (XX).
  • This ring-closing reaction can be carried out by a method according to (Step B-3).
  • Preferred examples of the “solvent” include dimethyl sulfoxide, N, N-dimethylformamide and the like.
  • the “base” is preferably sodium hydride, potassium tert-butoxide or the like.
  • the amount of the base to be used is generally 0.1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XX).
  • the reaction temperature is usually about ⁇ 100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
  • Step B-2 This amidation reaction can be carried out by a method according to (Step B-1).
  • the amount of compound (XV) to be used is generally 0.5 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XXI).
  • Preferred examples of the condensing agent include 4- (4,6-dimethoxy [1.3.5] triazin-2-yl) -4-methylmorpholinium chloride.
  • the amount of the condensing agent to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XXI).
  • the “solvent” is preferably an alcohol solvent, and ethanol is particularly preferable.
  • the reaction temperature is usually about ⁇ 100 ° C.
  • Step A-3 This deprotection reaction can be carried out by a method according to (Step A-1).
  • the “solvent” is preferably an ester solvent (for example, ethyl acetate) or an alcohol solvent (for example, ethanol), particularly an ester solvent. Is preferred.
  • Preferred examples of the “acid” include hydrochloric acid, hydrobromic acid, trifluoroacetic acid and the like.
  • the amount of the acid to be used is generally 1 to 50 molar equivalents, preferably 1 to 10 molar equivalents, per 1 mol of compound (XXII).
  • the reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 60 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.1 hour to about 24 hours. It's time.
  • Step A-2 This reductive alkylation reaction is performed by a method according to (Step A-2).
  • the alkylating agent for example, 3-[(tert-butyldiphenylsilyl) oxy] propanal (Org. Lett. 9, 1951-1954 (2007)) is preferably used as the “reducing agent”. It is done. In particular, sodium triacetoxyborohydride is preferred.
  • the amount of the alkylating agent to be used is generally 0.5 to 5 molar equivalents, preferably 0.5 to 1.5 molar equivalents, per 1 mol of compound (XXIII).
  • the amount of the reducing agent to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XXIII).
  • the “acid” is preferably acetic acid.
  • the amount of the acid to be used is generally 0.1 to 5 molar equivalents, preferably 0.1 to 2 molar equivalents, per 1 mol of compound (XXIII).
  • the “solvent” is preferably an ether solvent (for example, tetrahydrofuran).
  • the reaction temperature is usually about ⁇ 100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is. (Process C-5)
  • the introduction reaction of this protecting group can be carried out by a method according to (Step B-6).
  • protective group P for example, tert-butyl carbamate or the like are preferable.
  • examples of the “solvent” include ether solvents, alcohol solvents and the like, and tetrahydrofuran and the like are particularly preferable.
  • the reaction temperature is usually ⁇ 50 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is, for example, 1 minute to 10 days, and preferably 0.5 to 24 hours. (Process C-6)
  • This deprotection reaction can be carried out according to the method described in, for example, Protective Groups in Organic Synthesis, Third Edition, Wiley-Interscience (1999).
  • As the protecting group P 3 tert-butyldiphenylsilyl or the like is preferable.
  • tetrabutylammonium fluoride As a reagent for deprotection at that time, tetrabutylammonium fluoride or the like is preferable.
  • the amount of tetrabutylammonium fluoride to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XXV).
  • the “solvent” include ether solvents, and tetrahydrofuran is particularly preferable.
  • the reaction temperature is usually ⁇ 50 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is, for example, 1 minute to 10 days, and preferably 0.5 to 24 hours.
  • the leaving group X is preferably methanesulfonyloxy or the like.
  • examples of the “solvent” include ether solvents, and tetrahydrofuran is particularly preferable.
  • the reaction temperature is usually ⁇ 50 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is, for example, 1 minute to 10 days, and preferably 0.5 to 24 hours.
  • Compound (IIa-d) can be produced by a coupling reaction of compound (XXVII) and compound (XXVIII). This coupling reaction can be carried out by a method according to (Step B-4).
  • the amount of compound (XXVII) to be used is generally 0.5 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XXVIII).
  • the metal catalyst preferably 0.001 to 1 molar equivalent, preferably 0.001 to 0.3 molar equivalent, relative to 1 mol of compound (XXVIII).
  • the amount of the ligand to be used is generally 0.001 to 10 molar equivalents, preferably 0.001 to 3 molar equivalents, per 1 mol of compound (XXVIII).
  • the amount of the base to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XXVIII).
  • the “solvent” include aromatic solvents and ether solvents, and preferred are toluene, 1,4-dioxane and the like.
  • the reaction temperature is usually ⁇ 100 ° C. to 300 ° C., preferably 0 ° C. to 150 ° C.
  • the reaction time is, for example, 1 minute to 10 days, and preferably 0.5 to 24 hours.
  • L methylene chain
  • Compound (IIa-d) can be produced by alkylation of compound (XXVIII). This alkylation reaction can be carried out by a method according to (Step A-2).
  • Examples of the alkylating agent include 3,4-dichlorobenzyl bromide and the like.
  • the amount of the alkylating agent to be used is generally 0.5 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XXVIII).
  • Examples of the “base” include sodium hydride and the like, and examples of the “solvent” include amide solvents, and N, N-dimethylformamide and the like are particularly preferable.
  • the amount of the base to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XXVIII).
  • Step A-2 This reductive alkylation reaction can be carried out by a method according to (Step A-2).
  • the alkylating agent for example, benzyl (3-oxopropyl) carbamate is preferable.
  • the “reducing agent” a boron reagent and the like are preferable. In particular, sodium triacetoxyborohydride is preferred.
  • the amount of the alkylating agent to be used is generally 0.5 to 10 molar equivalents, preferably 0.5 to 1.5 molar equivalents, per 1 mol of compound (XXIX).
  • the amount of the reducing agent to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XXIX).
  • the “acid” is preferably acetic acid.
  • the amount of the acid to be used is generally 0.1 to 10 molar equivalents, preferably 0.1 to 1 molar equivalents, per 1 mol of compound (XXIX).
  • the “solvent” is preferably an ether solvent (for example, tetrahydrofuran).
  • the reaction temperature is usually about ⁇ 100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is. (Process D-3)
  • the introduction reaction of this protecting group can be carried out by a method according to (Step B-6).
  • protective group P 1 for example, tert- butyl carbamate and the like are preferable.
  • the “solvent” include ether solvents, alcohol solvents and the like, and tetrahydrofuran and the like are particularly preferable.
  • the reaction temperature is usually ⁇ 50 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is, for example, 1 minute to 10 days, and preferably 0.5 to 24 hours.
  • Step A-1 For example, when the protecting group P 1 is benzyl carbamate, deprotection can be performed by “catalytic hydrogenation reaction”.
  • metal catalyst examples include palladium and the like, particularly preferably palladium carbon and the like.
  • the amount of the metal catalyst to be used is generally 0.001 to 1 molar equivalent, preferably 0.001 to 0.3 molar equivalent, per 1 mol of compound (XXXI).
  • solvent examples include alcohol solvents, and ethanol and the like are particularly preferable.
  • the hydrogen pressure at which the reaction is carried out is usually about 1 to about 50 atmospheres, preferably about 1 to about 10 atmospheres.
  • the reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 100 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 hours to about 40 ° C.
  • Compound (XXVIIIa) can be produced by a ring closure reaction of compound (XXXII). This ring-closing reaction can be carried out in a suitable solvent in the presence of a base.
  • a base the same “base” as described in the above (Step A-2) can be used, and for example, sodium ethoxide, potassium carbonate and the like are preferable.
  • the amount of the base to be used is generally 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XXXII).
  • the “solvent” include alcohol solvents, and ethanol is particularly preferable.
  • the reaction temperature is usually about 0 ° C.
  • the ring closure reaction can also be carried out by hydrolyzing the ester and then amidating. These reactions can be carried out according to a method known per se.
  • Step D-6 The introduction reaction of this protecting group can be carried out by a method according to (Step B-6).
  • the protecting group P 2 is tert-butyl carbamate
  • benzyl can be introduced as the protecting group P 1 by reductive alkylation with benzaldehyde.
  • the amount of benzaldehyde to be used is generally 0.1 to 10 molar equivalents, preferably 0.5 to 1.5 molar equivalents, per 1 mol of compound (XXXIII).
  • the “reducing agent” is preferably a boron reagent or the like. In particular, sodium cyanoborohydride and sodium triacetoxyborohydride are preferable.
  • the amount of the reducing agent to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XXXIII).
  • the “acid” is preferably acetic acid.
  • the amount of the acid to be used is generally 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XXXIII).
  • the “solvent” is preferably an ether solvent (for example, tetrahydrofuran).
  • the reaction temperature is usually about ⁇ 100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
  • This amidation reaction can be carried out by a method according to (Step B-1).
  • a method using a corresponding activated carboxylic acid derivative (acid halide or the like) is preferable.
  • the amount of the carboxylic acid derivative to be used is generally 0.5 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XXXIV).
  • the “solvent” is preferably a halogen-based solvent or an ether-based solvent, and tetrahydrofuran is particularly preferable.
  • this reaction may be performed by adding an appropriate base.
  • the same “base” as described in the above (Step A-2) can be used, and for example, triethylamine and the like are preferable.
  • the amount of the base to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XXXIV).
  • the reaction temperature is usually about ⁇ 100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
  • This ring-closing reaction can be carried out by a method according to (Step B-3).
  • a base may be added.
  • the same “base” as described in the above (Step A-2) can be used, preferably sodium hydride, cesium carbonate, potassium carbonate and the like.
  • the amount of the base to be used is generally 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XXXV).
  • the reaction temperature is usually about ⁇ 100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours.
  • Compound (IIb) can be produced by a ring closure reaction of compound (XXXVII).
  • This ring-closing reaction can be carried out by a method according to (Step B-3).
  • Preferred examples of the “solvent” include dimethyl sulfoxide, N, N-dimethylformamide and the like.
  • the amount of the base to be used is generally 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XXXVII).
  • an inorganic salt such as sodium iodide may be added.
  • the amount of the inorganic salt to be used is generally 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XXXVII).
  • the reaction temperature is usually about ⁇ 100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
  • Step A-2 This reduction reaction can be performed by a method according to (Step A-1).
  • platinum oxide or the like is preferable as the “metal catalyst”, acetic acid or an alcohol solvent as the “solvent”, and hydrochloric acid or the like as the additive.
  • the amount of the metal catalyst to be used is generally 0.001 to 1 molar equivalent, preferably 0.001 to 0.3 molar equivalent, relative to 1 mol of compound (XVII).
  • the amount of the additive to be used is generally 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XVII).
  • examples of the “reducing agent” include a boron reagent, and sodium borohydride is particularly preferable.
  • the amount of the reducing agent to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XVII).
  • examples of the “solvent” include alcohol solvents, and ethanol is particularly preferable.
  • cobalt (II) chloride or the like is preferable.
  • the amount of the additive to be used is generally 0.1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XVII).
  • the reaction temperature is usually about ⁇ 100 ° C.
  • This reductive alkylation reaction can be carried out by a method according to (Step A-2).
  • the alkylating agent include chloroacetaldehyde.
  • the amount of the alkylating agent to be used is generally 0.5 to 10 molar equivalents, preferably 0.5 to 1.5 molar equivalents, per 1 mol of compound (XXXVIII).
  • the “reducing agent” include a boron reagent, and sodium triacetoxyborohydride is particularly preferable.
  • the amount of the reducing agent to be used is generally 1 to 20 molar equivalents, preferably 1 to 5 molar equivalents, per 1 mol of compound (XXXVIII).
  • the reaction temperature is usually about ⁇ 100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C., and the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
  • the introduction reaction of this protecting group can be carried out by a method according to (Step B-6).
  • protective group P for example, tert- butyl carbamate and the like are preferable.
  • examples of the “solvent” include ether solvents, alcohol solvents and the like, and tetrahydrofuran and the like are particularly preferable.
  • the reaction temperature is usually ⁇ 50 ° C. to 150 ° C., preferably 0 ° C. to 100 ° C.
  • the reaction time is, for example, 1 minute to 10 days, and preferably 0.5 to 24 hours.
  • Compound (IId) includes, for example, compound (XLV), and the compound (XLV) can be produced by the following method.
  • Compound (IId) other than the compound (XLV) can also be produced by the same method as described below.
  • This alkylation reaction can be carried out by a method according to (Step A-2).
  • the alkylating agent include methyl 3-bromopropanoate.
  • the amount of the alkylating agent to be used is generally 0.5 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XL).
  • Examples of the “base” to be added include amines. Particularly preferred is diisopropylethylamine.
  • the amount of the base to be used is generally 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XL).
  • the “solvent” is preferably an amide solvent (for example, dimethylformamide, etc.).
  • the reaction temperature is usually about ⁇ 100 ° C. to about 150 ° C., preferably about 0 ° C. to about 80 ° C.
  • the reaction time is usually about 5 minutes to about 72 hours, preferably about 1 hour to about 24 hours. It is.
  • Protected group P for example, tert- butyl carbamate and the like are preferable.
  • examples of the “solvent” include ether solvents, alcohol solvents and the like, and tetrahydrofuran and the like are particularly preferable.
  • the reaction temperature is usually about ⁇ 50 ° C. to about 150 ° C., preferably about 0 ° C.
  • Step A-3 This deprotection reaction can be carried out by a method according to (Step A-1).
  • the protecting group P 2 is benzyl carbamate
  • deprotection can be performed by “catalytic hydrogenation reaction”.
  • the “metal catalyst” include palladium and the like, particularly preferably palladium carbon and the like.
  • the amount of the metal catalyst to be used is generally 0.001 to 1 molar equivalent, preferably 0.001 to 0.3 molar equivalent, relative to 1 mol of compound (XLIII).
  • the “solvent” include alcohol solvents, and ethanol and the like are particularly preferable.
  • the hydrogen pressure at which the reaction is carried out is usually about 1 to about 50 atmospheres, preferably about 1 to about 10 atmospheres.
  • the reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 100 ° C.
  • the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 hours to about 40 ° C. It's time.
  • This ring-closing reaction can be carried out by a method according to (Step D-5).
  • the “base” for example, sodium methoxide and the like are preferable.
  • the amount of the base to be used is generally 0.1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of compound (XLIV).
  • the “solvent” examples include alcohol solvents, and methanol is particularly preferable.
  • the reaction temperature is usually about 0 ° C. to about 150 ° C., preferably about 20 ° C. to about 100 ° C.
  • the reaction time is usually about 5 minutes to about 72 hours, preferably about 0.5 hours to about 48 hours. It's time.
  • the ring closure reaction can also be carried out by hydrolyzing the ester and then amidating. These reactions can be carried out according to a method known per se.
  • Compound (I) can be isolated and purified by a known means such as phase transfer, concentration, solvent extraction, fractional distillation, liquid conversion, crystallization, recrystallization, chromatography and the like.
  • compound (I) When compound (I) is obtained as a free compound, it can be converted to the target salt by a method known per se or a method analogous thereto, and conversely when it is obtained as a salt, it is known per se. It can be converted into a free form or other desired salt by the method or a method analogous thereto.
  • the salt of compound (I) include salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, metal salts, ammonium salts, salts with organic bases, and the like.
  • salts with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid and glutamic acid, for example. It is done.
  • the 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.
  • the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl.
  • examples include salts with ethylenediamine and the like. Of these, pharmaceutically acceptable salts are preferred.
  • the compound when the compound has a basic functional group, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid Salts with organic acids such as acids, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, and alkali metal salts (eg, sodium salts, potassium salts, etc.) when the compound has an acidic functional group ), Alkaline earth metal salts (eg, calcium salts, magnesium salts, barium salts, etc.), and the like, and ammonium salts.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid
  • phthalic acid fumaric acid, oxalic acid, tart
  • the compounds represented by the formula (I) of the present invention may be in the form of their prodrugs.
  • a prodrug of compound (I) is a compound that is converted to compound (I) by reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, (i) enzymatically causes oxidation, reduction, hydrolysis, etc.
  • a compound that changes to compound (I), (ii) a compound that undergoes hydrolysis or the like by gastric acid or the like, and changes to compound (I).
  • a prodrug of the compound (I) to be used a compound in which the amino of the compound (I) is acylated, alkylated or phosphorylated (for example, the amino of the compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.)
  • a compound in which hydroxy of (I) is acylated, alkylated, phosphorylated, borated or a salt thereof eg, hydroxy of compound (I) is acetyloxy, palmitoyloxy, propanoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, Alanyloxy, dimethylaminomethylcarbon
  • the prodrug of compound (I) is a compound that can be converted into compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Development of Pharmaceuticals”, Volume 7, pages 163 to 198, The salt may be sufficient.
  • any one of the isomers and a mixture are included in the compound (I).
  • 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 crystal form mixture.
  • the crystal can be produced by crystallization by applying a crystallization method known per se.
  • Compound (I) may be a co-crystal.
  • Compound (I) may be a solvate (such as a hydrate) or a non-solvate, and both are encompassed in compound (I) and the like.
  • Compounds labeled with isotopes eg, 2 H, 3 H, 14 C, 35 S, 125 I, etc.
  • a deuterium converter obtained by converting 1 H into 2 H (D) is also encompassed in compound (I).
  • Compound (I) or a salt thereof or a prodrug thereof (hereinafter abbreviated as a compound of the present invention) is a mammal (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.)
  • a mammal eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.
  • a substance having inhibitory activity on reuptake of brain monoamines (serotonin / norepinephrine / dopamine, etc.)
  • it inhibits the reuptake of monoamines in the brain, and prevents neuropsychiatric disorders such as depression and anxiety Improve symptoms.
  • the compound (I) of the present invention has excellent properties as a pharmaceutical product such as low toxicity and few side effects, it has a neuropsychiatric disorder including depression, anxiety and attention deficit hyperactivity disorder (ADHD) ( For example, depression (cerebrovascular disorder depression, seasonal depression, drug-induced depression, HIV depression, etc.), anxiety (eg, generalized anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder) Etc.), ADHD, bipolar disorder, mania, recurrent depression, persistent mood emotion disorder (eg, mood circulatory disorder, dysthymia etc.), depressive neurosis, sleep disorder, diurnal rhythm disorder, eating Disorder, drug dependence, premenstrual tension, autism, mood disorders due to menopause, senile dementia, mild cognitive dysfunction, hypersomnia, various analgesia, various pains (neuropathic, inflammatory, etc.), muscle Fibrosis, Alzheimer's disease and parkin Neurodegenerative diseases such as neuropathy, mood disorders associated with neurode
  • the compounds of the present invention are low in toxicity and include pharmaceutical compositions mixed with a pharmacologically acceptable carrier as it is or according to a method known per se, such as tablets (sugar-coated tablets, film-coated tablets, orally disintegrating tablets, etc.) ), Powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release agents, patches, etc., orally or parenterally (eg, topical, rectal, intravenous) Administration, etc.).
  • a pharmacologically acceptable carrier such as tablets (sugar-coated tablets, film-coated tablets, orally disintegrating tablets, etc.) ), Powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release agents, patches, etc., orally or parenterally (eg, topical, rectal, intravenous) Administration, etc.).
  • the content of the compound (I) in the present invention in the present invention is about 0.01 to about 100% by weight of the entire preparation.
  • the dosage varies depending on the administration subject, administration route, disease, etc., but when administered as an oral agent to an adult, for example, as a therapeutic agent for depression, the compound of the present invention is used in an amount of about 0.001 to about It is 20 mg / kg body weight, preferably about 0.01 to about 10 mg / kg body weight, more preferably about 0.05 to about 10 mg / kg body weight, and can be administered once or several times a day.
  • the pharmaceutical composition containing the compound of the present invention is considered to be one of the causes of the onset of depression, anxiety, etc., which is considered to be one of the causes of the onset, such as a decrease or functional impairment of serotonin, norepinephrine, dopamine, etc. It is expected to be useful for the treatment and prevention of neuropsychiatric disorders including ADHD.
  • neurodegenerative diseases eg, Alzheimer's disease, Parkinson's disease, muscle atrophy
  • Lateral sclerosis ALS
  • Huntington's disease spinocerebellar degeneration
  • multiple sclerosis MS
  • head injury spinal cord injury
  • cerebrovascular disorder cerebrovascular dementia
  • spinal cord injury polyglutamine disease
  • Odontocytic red nucleus Pallus leucoatrophy
  • bulbar spinal muscular atrophy Machado-Jacob disease
  • spinocerebellar ataxia type 6, prion disease Creutzfeldt-Jacob disease, Gerstmann-straussler-Scheinker disease
  • cerebrum Cortical basal ganglia degeneration progressive supranuclear palsy
  • AIDS encephalopathy muscular dystrophy
  • diabetic neuropathy diabetic retinopathy
  • Diabetic encephalopathy muscular dystrophy
  • diabetic neuropathy diabetic retinopathy
  • Diabetic encephalopathy muscular dystrophy
  • diabetic neuropathy diabetic
  • concomitant drugs include depression drugs, anxiety drugs such as benzodiazepines (chlorodiazepoxide, diazepam, potassium chlorazepate, lorazepam, clonazepam, alprazolam, etc.), mood stabilizers (lithium carbonate), 5 -HT2 antagonists (such as nefazodone), 5-HT1A agonists (such as tandospirone, buspirone, and Gepiron), CRF antagonists (such as Pexecerfont), ⁇ 3 agonists (such as Amibegron), melatonin agonists (rameltheon, agomelatin), ⁇ 2 antagonists Drugs (such as mirtazapine and cetiptiline), NK2 antagonists (such as Saledutant), GR antagonists (such as Mifepristone), NK-1 antagonists (such as Casopitant and Orvepitant), schizophrenia Therapeutic agents (chloropromazine, haloperidol, sulpir, 5-
  • ⁇ -amyloid vaccine ⁇ -A Lloyd degrading enzymes, etc.
  • brain function stimulants eg, aniracetam, nicergoline, etc.
  • other Parkinson's disease therapeutic agents eg, dopamine receptor agonists (L-dopa, bromocriptene, pergolide, talipexol, pripepexol, cabergoline, Adamantadine, etc.), COMT inhibitors (eg, entacapone, etc.)], attention deficit hyperactivity disorder drugs (modafinil, etc.), amyotrophic lateral sclerosis drugs (eg, riluzole, etc.), Insomnia treatment (such as etizolam, zopiclone, triazolam, zolpidem, indiplon), hypersomnia (such as modafinil), diabetes treatment, non-steroidal anti-inflammatory (eg, meloxicam, teoxicam, teoxicam, teoxi
  • DMARDs Disease-modifying anti-rheumatic drugs
  • TNF inhibitors anti-cytokine drugs
  • MAP kinase inhibitors etc.
  • steroid drugs eg, dexamethasone, hexestrol, cortisone acetate, etc.
  • sex hormones or derivatives thereof eg, Progesterone, estradiol, estradiol benzoate, etc.
  • parathyroid hormone PTH
  • compositions eg, tablet, powder, granule, capsule (including soft capsule), liquid, injection, suppository, In a sustained-release preparation, etc.
  • a single pharmaceutical composition eg, tablet, powder, granule, capsule (including soft capsule), liquid, injection, suppository, In a sustained-release preparation, etc.
  • a single pharmaceutical composition eg, tablet, powder, granule, capsule (including soft capsule), liquid, injection, suppository, In a sustained-release preparation, etc.
  • the compound of the present invention is formulated with a pharmaceutically acceptable carrier, and is orally or parenterally as a solid preparation such as a tablet, capsule, granule or powder; or as a liquid preparation such as syrup or injection. Can be administered. In addition, it should be made into transdermal preparations such as patches, poultices, ointments (including creams), plasters, tapes, lotions, solutions and solutions, suspensions, emulsions, sprays, etc. You can also.
  • Examples of the pharmacologically acceptable carrier that may be used for the production of the preparation of the present invention include various organic or inorganic carrier substances commonly used as preparation materials.
  • excipients for example, excipients, lubricants in solid preparations, examples include binders, disintegrants, solvents in liquid preparations, solubilizers, suspending agents, isotonic agents, buffers, and soothing agents.
  • additives such as ordinary preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can be used.
  • examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.
  • Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • Examples of the binder 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, croscarmellose sodium, 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.
  • solubilizer examples 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, Examples include hydrophilic polymers such as sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and the like.
  • Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • Examples of the buffer include buffer solutions such as phosphate, acetate, carbonate, citrate, and the like.
  • Examples of soothing agents include benzyl alcohol.
  • Examples of the preservative include paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Examples of the antioxidant include sulfite, ascorbic acid, ⁇ -tocopherol and the like.
  • the oral preparation may be prepared by coating by a method known per se.
  • the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68 [polyoxyethylene (160) polyoxypropylene (30) glycol], and cellulose acetate phthalate. , Hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate phthalate, Eudragit (Rohm, methacrylic acid-acrylic acid copolymer), and the like.
  • solubilizer examples include polyethylene glycol, propylene glycol, 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, glycerol monostearate; polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose Examples thereof include hydrophilic polymer substances such as sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
  • Examples of the isotonic agent include sodium chloride, glycerin, D-mannitol and the like.
  • examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
  • 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 and ascorbic acid.
  • basic silica gel for the column basic silica NH-DM1020 (100 to 200 mesh) manufactured by Fuji Silysia Chemical Co., Ltd. or Purif-Pack manufactured by Moritex Co., Ltd. was used. NMR spectra were measured with a Bruker AVANCE-300 or Varian VNMRS-400 spectrometer using tetramethylsilane as an internal or external reference, chemical shifts expressed as ⁇ values, and coupling constants expressed in Hz.
  • the numerical value shown in parentheses is the volume mixing ratio of each solvent. Further,% in the solution represents the number of grams in 100 mL of the solution. Room temperature usually means a temperature of about 10 ° C to 30 ° C.
  • NMR nuclear magnetic resonance spectrum
  • s singlet d: doublet t: triplet
  • q quartet quint: quintet
  • dd double doublet (double doublet)
  • m multiplet br: broad brs: broad singlet
  • J Coupling constant
  • THF Tetrahydrofuran MeOH: Methanol
  • DMF N, N-dimethylformamide
  • DMSO Dimethyl sulfoxide
  • MS Liquid chromatography-mass spectrometry spectrum
  • ESI Electrospray ionization method [M + H] + : Molecular ion peak
  • TFA Trifluoroacetic acid
  • M Molar concentration
  • N Normal concentration
  • DMT-MM 4- (4,6-dimethoxy [1.3.5] triazin-2-yl) -4-methylmorpholinium chloride
  • WSC N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide
  • HOBt 1-hydroxybenzotri
  • Example 9 3-(,4-Dichlorophenyl) -3-methyl-1,4-diazepan-2-one (low retention time)
  • Example 10 3- (3,4-Dichlorophenyl) -3-methyl-1,4-diazepan-2-one (large retention time)
  • the fraction containing the optically active substance having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give 1- (3,4-dichlorophenyl) -3-methyl-1,4-diazepan-2- ON (short retention time) (0.57 g,> 99% ee) was obtained.
  • LC / MS 273.1 Further, the fraction containing the optically active substance having the longer retention time is concentrated to give 1- (3,4-dichlorophenyl) -3-methyl-1,4-diazepan-2-one (large retention time) ( 0.57 g,> 99% ee).
  • Example 12 3- (3,4-Dichlorophenyl) -3-methyl-1,4-diazepan-2-one monohydrochloride (large retention time)
  • the obtained solid was dissolved in ethyl acetate (2.0 mL), 4N hydrochloric acid ethyl acetate solution (2.0 mL) was added, and the mixture was stirred at room temperature for 2 hr.
  • the solvent was distilled off under reduced pressure, the resulting solid was purified by preparative HPLC, and the fraction collected was concentrated. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained solid was dissolved in ethyl acetate (2.0 mL), 4N hydrochloric acid ethyl acetate solution (2.0 mL) was added, and the solvent was evaporated under reduced pressure.
  • the obtained solid was recrystallized from ethanol-ethyl acetate to give the title compound as white crystals (0.45 g, 54%).
  • Example 17 1- (3,4-Dichlorophenyl) -6,6-difluoro-1,4-diazepan-2-one monohydrochloride
  • reaction mixture was diluted with 1N aqueous hydrochloric acid and washed with ethyl acetate.
  • 1N Aqueous sodium hydroxide solution was added to the aqueous layer to make it basic, and the mixture was extracted with ethyl acetate.
  • the extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the residue was purified by preparative HPLC, and the fractions collected were concentrated. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate.
  • Example 28 The LC / MS analysis in Example 28 below was measured under the following conditions.
  • Measuring instrument Waters LC / MS system HPLC part: Agilent HP1100 MS Department: Micromass ZMD Column: CAPCELL PAK C18UG120, S-3 ⁇ m, 1.5 ⁇ 35 mm (Shiseido)
  • Ionization method ESI
  • high-polar preparative HPLC purification in Example 28 below was performed under the following
  • Reaction vessel in which a toluene solution (500 ⁇ L; 100 ⁇ mol) of 2-bromonaphthalene (0.20 M) was added to a toluene solution (500 ⁇ L; 100 ⁇ mol) of 3-oxo-1,4-diazepan-1-carboxylate (0.20 M)
  • Cesium carbonate 46 mg; 140 ⁇ mol
  • 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (8.7 mg; 15 ⁇ mol)
  • tris (dibenzylideneacetone) dipalladium (0) (4. 6 mg; 5.0 ⁇ mol) was added in this order, and the reaction vessel was purged with argon and stirred at 100 ° C.
  • Example 29 to 87 The compounds described in Tables 1-1 to 1-9 (Examples 29 to 87) were obtained in the same manner as Example 28.
  • the organic layer was washed with water and saturated brine in that order, and dried by adding sodium sulfate.
  • the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure.
  • the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure.
  • the reaction mixture was cooled to room temperature, diluted with dichloromethane (10 mL), filtered through celite, and the filtrate was concentrated under reduced pressure.
  • a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to 1- (3,4-dichlorophenyl) -3-ethyl-1,4-diazepan-2-one monohydrochloride (0.72 g), and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow oil (0.61 g, 95%).
  • Example 106 1- (3,4-Dichlorophenyl) -3-propyl-1,4-diazepan-2-one monohydrochloride
  • tert-Butyl 2-tert-Butyl-4- (3,4-dichlorophenyl) -3-oxo-1,4-diazepane-1-carboxylate (0.30 g) in ethyl acetate (3.0 mL) was added 4N Hydrochloric acid ethyl acetate solution (3.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. After the solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the obtained residue, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained solid was dissolved in ethyl acetate (3.0 mL), 4N hydrochloric acid ethyl acetate solution (3.0 mL) was added, and the solvent was evaporated under reduced pressure.
  • the obtained solid was recrystallized from ethanol-ethyl acetate to give the title compound as white crystals (0.10 g, 45%).
  • the organic layer was washed with water and saturated brine in that order, and dried by adding sodium sulfate.
  • the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure.
  • the aqueous layer was neutralized with 1N aqueous sodium hydroxide solution, extracted with ethyl acetate, dried by adding sodium sulfate.
  • the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure.
  • a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to 3-ethyl-1-naphthalen-2-yl-1,4-diazepan-2-one monohydrochloride (0.85 g), and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethyl acetate-diisopropyl ether to give the title compound as white crystals (0.73 g, 97%).
  • Example 124 3-Ethyl-1-naphthalen-2-yl-1,4-diazepan-2-one (low retention time)
  • Example 125 3-Ethyl-1-naphthalen-2-yl-1,4-diazepan-2-one (large retention time)
  • the fraction containing the optically active substance having a shorter retention time under the above supercritical fluid chromatography conditions is concentrated to give 3-ethyl-1-naphthalen-2-yl-1,4-diazepan-2-one (Short retention time) (299 mg,> 99% ee) was obtained.
  • Example 130 (3,4-Dichlorophenyl) -1,5-diazacyclooctan-2-one monohydrochloride
  • the reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure.
  • Benzaldehyde (2.2 mL) was added to an ethanol (45 mL) solution of N- (3,4-dichlorophenyl) propane-1,3-diamine (12.8 g) at 0 ° C., and the mixture was stirred at 70 ° C. for 3 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. Sodium borohydride was added to a methanol (90 mL) / ethanol (45 mL) solution of the obtained residue, and the mixture was stirred at 0 ° C. for 1 hour and then at room temperature overnight. The solvent was distilled off under reduced pressure, and the resulting residue was diluted with water and extracted with ethyl acetate.
  • the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • the reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure.
  • the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • 8N aqueous sodium hydroxide solution was added to the previous aqueous layer to adjust the pH to about 9, and the mixture was extracted with ethyl acetate.
  • the extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless oil (0.15 g, 29%).
  • 1,2-dichloro-4-iodobenzene (5.46 g), 3-aminobutanoic acid (2.06 g), 1,1′-bi-2-naphthol (1.15 g) and tripotassium phosphate (12.7 g) ) was added to a DMF (20 mL) suspension, and copper bromide (0.57 g) was added thereto, followed by stirring at 40 ° C. overnight under an argon gas atmosphere. The reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the mixture was filtered through celite.
  • the reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure.
  • 1,2-dichloro-4-fluoro-5-iodobenzene 0.582 g
  • tert-butyl 3-oxo-1,4-diazepan-1-carboxylate 0.43 g
  • 4,5-bis A mixture of diphenylphosphino) -9,9-dimethylxanthene (0.087 g), tris (dibenzylideneacetone) dipalladium (0) (0.046 g), cesium carbonate (0.91 g) and toluene (20 mL).
  • the mixture was stirred at 100 ° C. overnight under an argon gas atmosphere.
  • the reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure.
  • 1,2-dichloro-3-fluoro-4-iodobenzene 0.582 g
  • tert-butyl 3-oxo-1,4-diazepan-1-carboxylate 0.43 g
  • 4,5-bis (diphenyl) A mixture of phosphino) -9,9-dimethylxanthene (0.087 g), tris (dibenzylideneacetone) dipalladium (0) (0.046 g), cesium carbonate (0.91 g) and toluene (20 mL) was added with argon gas. The mixture was stirred at 100 ° C. overnight under an atmosphere. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure.
  • tert-butyl 5-bromo-1H-indole-1-carboxylate (0.59 g)
  • tert-butyl 3-oxo-1,4-diazepane-1-carboxylate (0.43 g)
  • 4,5-bis A mixture of diphenylphosphino) -9,9-dimethylxanthene (0.087 g), tris (dibenzylideneacetone) dipalladium (0) (0.046 g), cesium carbonate (0.91 g) and toluene (20 mL) was added to argon. The mixture was stirred at 100 ° C. overnight under a gas atmosphere.
  • the reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure.
  • the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure.
  • tert-butyl ⁇ 1-[(3,4-dichlorophenyl) carbamoyl] butyl ⁇ (3-hydroxypropyl) carbamate (1.40 g) in THF (15 mL) in triethylamine (0.56 mL) and methanesulfonyl chloride (0. 31 mL) was added and stirred at room temperature for 2 hours.
  • To the reaction mixture was added potassium tert-butoxide (0.89 g), and the mixture was stirred at room temperature for 3 hours.
  • the solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate and washed with saturated brine.
  • N- (tert-butoxycarbonyl) valine (3.26 g), 3,4-dichloroaniline (2.43 g), HOBt (2.03 g) and triethylamine (2.1 mL) in DMF (45 mL) were added to WSC (45 mL). 2.88 g) was added and stirred at room temperature overnight. Ethyl acetate and saturated brine were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, the extract and the organic layer obtained earlier were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Triethylamine (0.48 mL) was added to a solution of N 2- (tert-butoxycarbonyl) -N- (3,4-dichlorophenyl) -N 2- (3-hydroxypropyl) norleucinamide (1.25 g) in THF (15 mL). And methanesulfonyl chloride (0.27 mL) were added, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added potassium tert-butoxide (0.78 g), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate and washed with saturated brine.
  • N 2- (3- ⁇ [tert-butyl (diphenyl) silyl] oxy ⁇ propyl) -N- (3,4-dichlorophenyl) leucinamide (1.57 g) in THF (10 mL) was added ditert-butyl dicarbonate ( 0.63 mL) was added, and the mixture was stirred at room temperature for 4 hours and then at 60 ° C. for 3 hours.
  • the reaction mixture was cooled to room temperature, 1M tetrabutylammonium fluoride THF solution (3.3 mL) was added, and the mixture was stirred overnight.
  • the reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure.
  • Methyl 2-amino-3-methoxypropionate monohydrochloride (synthesized by the method described in Eur. J. Med. Chem. Chim. Ther., 11, 283-286 (1976)) (2.04 g) of THF ( 50 mL) suspension was added acetic acid (0.69 mL), benzyl (3-oxopropyl) carbamate (2.49 g) and sodium triacetoxyborohydride (8.03 g), and stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate.
  • the reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure.
  • Bromoacetyl chloride (0.072 mL) was added to a solution of tert-butyl benzyl ( ⁇ 1-[(naphthalen-2-ylamino) methyl] cyclopropyl ⁇ methyl) carbamate (0.32 g) in N, N-dimethylacetamide (3 mL). It added at 0 degreeC and stirred for 30 minutes at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried by adding magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure.

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Abstract

La présente invention concerne un composé ayant une activité inhibitrice sur l'absorption d'un neurotransmetteur monoamine. Elle concerne spécifiquement un composé représenté par la formule (I) [dans laquelle chaque symbole est comme défini dans la description] ou un sel de celui-ci. (I)
PCT/JP2009/055716 2008-03-24 2009-03-23 Composé hétérocyclique Ceased WO2009119528A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012046882A1 (fr) 2010-10-07 2012-04-12 Takeda Pharmaceutical Company Limited Dérivés de 1,4-oxazépane
CN105367506A (zh) * 2015-12-08 2016-03-02 华润双鹤药业股份有限公司 手性高哌嗪环的制备方法
CN115141192A (zh) * 2022-06-22 2022-10-04 杭州国瑞生物科技有限公司 一种苏沃雷生的制备方法

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Publication number Priority date Publication date Assignee Title
WO2012046882A1 (fr) 2010-10-07 2012-04-12 Takeda Pharmaceutical Company Limited Dérivés de 1,4-oxazépane
US8722662B2 (en) 2010-10-07 2014-05-13 Takeda Pharmaceutical Company Limited Heterocyclic compounds
CN105367506A (zh) * 2015-12-08 2016-03-02 华润双鹤药业股份有限公司 手性高哌嗪环的制备方法
CN105367506B (zh) * 2015-12-08 2021-02-05 华润双鹤药业股份有限公司 手性高哌嗪环的制备方法
CN115141192A (zh) * 2022-06-22 2022-10-04 杭州国瑞生物科技有限公司 一种苏沃雷生的制备方法

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