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WO2017018475A1 - Dérivé de pyrazole condensé présentant un nouveau site de liaison et utilisation médicinale de celui-ci - Google Patents

Dérivé de pyrazole condensé présentant un nouveau site de liaison et utilisation médicinale de celui-ci Download PDF

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Publication number
WO2017018475A1
WO2017018475A1 PCT/JP2016/072117 JP2016072117W WO2017018475A1 WO 2017018475 A1 WO2017018475 A1 WO 2017018475A1 JP 2016072117 W JP2016072117 W JP 2016072117W WO 2017018475 A1 WO2017018475 A1 WO 2017018475A1
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phenyl
methyl
alkyl
same
different
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PCT/JP2016/072117
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English (en)
Japanese (ja)
Inventor
久仁子 浦島
健剛 東條
英司 井手上
祥子 小池
尚明 島田
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大日本住友製薬株式会社
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Publication of WO2017018475A1 publication Critical patent/WO2017018475A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention includes a novel condensed pyrazole derivative having a negative regulatory action on a group II metabotropic glutamate (mGlu) receptor, a pharmaceutically acceptable salt thereof, and an active ingredient thereof.
  • Mood disorder depressive disorder, bipolar disorder, etc.
  • anxiety disorder general anxiety disorder, panic disorder, obsessive-compulsive disorder, social anxiety disorder, traumatic stress disorder, specific phobia, acute stress disorder, etc.
  • the present invention relates to a preventive or therapeutic agent for diseases such as schizophrenia, autism spectrum disorder, Alzheimer's disease, cognitive dysfunction, dementia, drug dependence, obesity, convulsions, tremors, pain, and sleep disorders.
  • Glutamate is a major excitatory neurotransmitter in the central nervous system, and is an ion channel receptor (N-methyl-D-aspartate (NMDA) glutamate receptor, ⁇ -amino-3-hydroxy-5-methyl- It acts on 4-isoxazolepropionic acid (AMPA) receptors, kainate receptors) and metabotropic glutamate receptors (mGlu receptors) which are G protein-coupled receptors.
  • mGlu receptors are classified into class C of G protein-coupled type (GPCR), and have a large orthosteric ligand binding site outside the cell in addition to the seven transmembrane sites (TMD) that GPCRs have in common.
  • Non-Patent Documents 1 to 3 There are eight subtypes of mGlu receptors 1-8 (mGluR1-8), and group I (mGluR1, mGluR3), group II (mGluR2, mGluR3) are based on signal transduction systems and pharmacological features coupled to homology. ) And group III (mGluR4, mGluR6, mGluR7, mGluR8).
  • mGlu2 / 3 receptor negative allosteric modulator can be an antidepressant (Non-patent document 4) and a cognitive function enhancer (Non-patent document 5).
  • NAM mGlu2 / 3 receptor negative allosteric modulator
  • Patent Documents 1 to 11 and Non-Patent Document 6 and the like compounds that act as mGlu2 / 3 receptor NAM have been reported in Patent Documents 1 to 11 and Non-Patent Document 6 and the like.
  • the problem to be solved by the present invention is to find a novel compound having a negative regulatory action on the group II mGlu receptor, mood disorder (depressive disorder, bipolar disorder etc.), anxiety disorder (general anxiety) Disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, traumatic stress disorder, specific phobia, acute stress disorder, etc.), schizophrenia, autism spectrum disorder, Alzheimer's disease, cognitive dysfunction, dementia, drug
  • mood disorder depressive disorder, bipolar disorder etc.
  • anxiety disorder general anxiety
  • panic disorder obsessive compulsive disorder
  • social anxiety disorder traumatic stress disorder
  • specific phobia specific phobia
  • acute stress disorder etc.
  • schizophrenia autism spectrum disorder
  • Alzheimer's disease cognitive dysfunction
  • dementia dementia
  • the object is to provide a useful preventive or therapeutic agent for diseases such as addiction, obesity, convulsions, tremors, pain, and sleep disorders.
  • the present inventors have found that a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as “the compound of the present invention”) solves the above problems.
  • the present invention has been completed. That is, the present invention is as follows.
  • R 1 and R 2 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-4 alkyl, a C 3-4 saturated carbocycle or a C 1-4 alkoxy (wherein the alkyl, the saturated carbocycle and the Each alkoxy is independently substituted with the same or different 1 to 5 halogen atoms)
  • R 1 and R 2 together with the carbon atom to which they are attached may form a C 3-4 saturated carbocycle
  • Ring A represents phenyl or 5 or 6 membered heteroaryl
  • R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen atom, a C 1-4 alkyl, a C 3-4 saturated carbocycle or a C 1-4 alkoxy (wherein the alkyl, the saturated carbocycle and the Each alkoxy is independently substituted with the same or different 1 to 5 halogen atoms)
  • L is the following structural
  • R 1 and R 2 are the same or different and are a hydrogen atom or C 1-4 alkyl (wherein the alkyl may be substituted with the same or different 1 to 3 halogen atoms); Ring A is phenyl, R 3 and R 4 are the same or different and are each a hydrogen atom, C 1-4 alkyl or C 1-4 alkoxy (wherein the alkyl and the alkoxy are each independently the same or different 1 to 5 Optionally substituted with a halogen atom), L is the following structural formula group: (In each structural formula, bond 1 represents a position bonded to the pyrazole ring, bond 2 represents a position bonded to B, and —L′-B represents —C (O) —O— B, —CH 2 C (O) —B, —CH 2 —B, —SO 2 —NR a —B or —single bond—B, and m and n are the same or different and represent 0 or 1 (However
  • B is a hydrogen atom, C 1-4 alkyl (wherein the alkyl may be substituted with the same or different 1 to 5 halogen atoms), phenyl, 5 or 6-membered heteroaryl or C 2- 5- cyclic amino (wherein the phenyl, the heteroaryl and the cyclic amino are the same or different and are each a halogen atom, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy and —C (O) -NR a ′ R b ′ may be substituted with 1 to 3 substituents selected from the group consisting of (wherein the alkyl and the alkoxy are each independently the same or different 1 to 5 it is also be)) substituted with a halogen atom, and R a, R a 'and R b' are the same or different, a hydrogen atom or a C 1-4 Al Le (wherein said alkyl may be the same or different 1 to have five substituted by a halogen
  • R 3 and R 4 are the same or different and each represents a hydrogen atom, C 1-4 alkyl or C 1-4 alkoxy (wherein the alkyl and the alkoxy are each independently the same or different 1 to 5 Optionally substituted with a halogen atom), Y 1 represents CR 5 R 6 , Y 2 is CR 5 R 6 or an oxygen atom, R 5 and R 6 are the same or different and are a hydrogen atom, a halogen atom or methyl; B is phenyl, 5 or 6-membered heteroaryl or C 2-5 cyclic amino (wherein the phenyl, heteroaryl and cyclic amino are the same or different and are each a halogen atom, cyano, hydroxy, amino, C 1 Optionally substituted with 1 to 3 substituents selected from the group consisting of -6 alkyl, C 1-6 alkoxy and —C (O) —NR a ′ R
  • the Y 1 and Y 2 are both CR 5 R 6 , and the R 5 and R 6 are the same or different and are a hydrogen atom, a halogen atom or methyl, A compound or a pharmaceutically acceptable salt thereof.
  • Item 1 to 3 are the items of the items 1 to 3, wherein -Y 1 -Y 2 -B is -CR 5 R 6 -OB, and R 5 and R 6 are the same or different and each is a hydrogen atom, a halogen atom or methyl
  • R 3 and R 4 are the same or different and each represents a hydrogen atom, C 1-4 alkyl or C 1-4 alkoxy (wherein the alkyl and the alkoxy are each independently the same or different 1 to 5 Optionally substituted with a halogen atom), -L'-B is -C (O) -OB, -CH 2 C (O) -B, -CH 2 -B, -SO 2 -NR a -B or -single bond -B; m and n are the same or different and are 0 or 1, B is a hydrogen atom, C 1-4 alkyl, phenyl, 5 or 6-membered heteroaryl or C 2-5 cyclic amino (wherein the phenyl, the heteroaryl and the cyclic amino are the same or different and are each a halogen atom; , Cyano, hydroxy, amino, C 1-6 alkyl, C 1-4 alkoxy (wherein the alkyl and the alkoxy are each independently
  • R 3 and R 4 are the same or different and each represents a hydrogen atom, C 1-4 alkyl or C 1-4 alkoxy (wherein the alkyl and the alkoxy are each independently the same or different 1 to 5 Optionally substituted with a halogen atom), -L'-B is -C (O) -OB, -CH 2 C (O) -B, -CH 2 -B, -SO 2 -NR a -B or -single bond -B; m is 1, n is 0 or 1, B is a hydrogen atom, C 1-4 alkyl, phenyl, 5 or 6-membered heteroaryl or C 2-5 cyclic amino (wherein the phenyl, the heteroaryl and the cyclic amino are the same or different and are each a halogen atom; , Cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy,
  • R 3 and R 4 are the same or different and each represents a hydrogen atom, C 1-4 alkyl or C 1-4 alkoxy (wherein the alkyl and the alkoxy are each independently the same or different 1 to 5 Optionally substituted with a halogen atom), -L'-B is -C (O) -OB, -CH 2 C (O) -B, -CH 2 -B, -SO 2 -NR a -B or -single bond -B; B is a hydrogen atom, C 1-4 alkyl, phenyl, 5 or 6-membered heteroaryl or C 2-5 cyclic amino (wherein the phenyl, the heteroaryl and the cyclic amino are the same or different and are each a halogen atom; , Cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 alkoxy, and optionally substituted by 1 to 3 substituent
  • Example 6 The compound according to Item 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds:
  • Example 1 3- [1- (6-Aminopyridin-2-yl) piperidin-4-yl] -7-methyl-5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazin-4 (5H) -one
  • Example 2 3- [1- (6-Aminopyridin-3-yl) piperidin-4-yl] -7-methyl-5- [4- (Trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazin-4 (5H) -one
  • Example 3 7-Methyl-3- [1- (pyridin-3-ylmethyl) Piperidin-4-yl] -5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazol
  • Example 10 The compound according to Item 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds:
  • Example 10 (7S) -7-methyl-3- [3- (pyridin-4-yl) -1,2,4-oxadiazol-5-yl] -5- [4- (trifluoromethyl) Phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazin-4 (5H) -one
  • Example 11 (7S) -7-Methyl-3- [3- (pyridin-3-yl)- 1,2,4-oxadiazol-5-yl] -5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazin-4 (5H) -one
  • Example 12 (7S) -7-methyl-3- ⁇ 3- [2-oxo-2- (pyrrolidin-1-yl) ethyl] -1,2,
  • Example 13 The compound according to Item 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds:
  • Example 13 (7S) -3- [2- (6-Aminopyridin-3-yl) ethyl] -7-methyl-5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazin-4 (5H) -one and
  • Example 14 3- (2- ⁇ (7S) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazin-3-yl ⁇ ethyl) benzamide.
  • Example 15 The compound according to Item 1 or a pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds:
  • Example 15 (7S) -7-methyl-3-[(pyridin-3-yloxy) methyl] -5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5- a] pyrazin-4 (5H) -one
  • Example 16 (7S) -7-methyl-3-[(pyridin-4-yloxy) methyl] -5- [4- (trifluoromethyl) phenyl] -6, 7-Dihydropyrazolo [1,5-a] pyrazin-4 (5H) -one
  • Example 17 (7S) -7-methyl-3- (phenoxymethyl) -5- [4- (trifluoromethyl) Phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazin-4 (5H) -one.
  • Item 16 A pharmaceutical composition comprising the compound according to any one of Items 1 to 15 or a pharmaceutically acceptable salt thereof.
  • Item 20 A metabotropic glutamate receptor subtype 2 (mGluR2) and / or a metabotropic glutamate receptor subtype 3 (mGluR3) containing the compound according to any one of Items 1 to 15 or a pharmaceutically acceptable salt thereof ) For treating mental disorders or neurodegenerative diseases.
  • mGluR2 metabotropic glutamate receptor subtype 2
  • mGluR3 metabotropic glutamate receptor subtype 3
  • Item 16 The compound according to any one of Items 1 to 15, for producing a therapeutic agent for a disease involving metabotropic glutamate receptor subtype 2 (mGluR2) and / or metabotropic glutamate receptor subtype 3 (mGluR3) Or use of a pharmaceutically acceptable salt thereof.
  • mGluR2 metabotropic glutamate receptor subtype 2
  • mGluR3 metabotropic glutamate receptor subtype 3
  • Item 16 Use of the compound according to any one of Items 1 to 15 or a pharmaceutically acceptable salt thereof for producing a therapeutic agent for a disease involving metabotropic glutamate receptor subtype 2 (mGluR2).
  • mGluR2 metabotropic glutamate receptor subtype 2
  • a method for treating and / or preventing diseases involving body subtype 2 (mGluR2) and / or metabotropic glutamate receptor subtype 3 (mGluR3) characterized by administering a therapeutically effective amount of the compound according to any one of Items 1 to 15 or a pharmaceutically acceptable salt thereof to a patient in need of treatment.
  • mGluR2 body subtype 2
  • mGluR3 metabotropic glutamate receptor subtype 3
  • [Claim 25] Diseases involving metabotropic glutamate receptor subtype 2 (mGluR2) and / or metabotropic glutamate receptor subtype 3 (mGluR3) are mood disorders, anxiety disorders, Alzheimer's disease, cognitive impairment, dementia, drug dependence, Item 25.
  • Item 16 The compound according to any one of Items 1 to 15 for use in the treatment of a disease involving metabotropic glutamate receptor subtype 2 (mGluR2) and / or metabotropic glutamate receptor subtype 3 (mGluR3) or Its pharmaceutically acceptable salt.
  • mGluR2 metabotropic glutamate receptor subtype 2
  • mGluR3 metabotropic glutamate receptor subtype 3
  • the compound of the present invention has a strong negative regulatory action on the group II metabotropic glutamate (mGlu) receptor, that is, a negative allosteric modulator activity. Therefore, the compounds of the present invention are mood disorders (depressive disorder, bipolar disorder etc.), anxiety disorders (general anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, traumatic stress disorder, specific phobias, Acute stress disorder, etc.), cognitive dysfunction, dementia, obesity and the like are useful as therapeutic and / or preventive agents.
  • mood disorders depressive disorder, bipolar disorder etc.
  • anxiety disorders general anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, traumatic stress disorder, specific phobias, Acute stress disorder, etc.
  • cognitive dysfunction dementia, obesity and the like are useful as therapeutic and / or preventive agents.
  • halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • a fluorine atom or a chlorine atom is mentioned.
  • C 1-4 alkyl is linear or branched alkyl having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, sec-butyl. Etc. Preferably, methyl, ethyl, propyl or isopropyl is used.
  • C 1-6 alkyl is linear or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, sec-butyl. , Isopentyl, neopentyl, tert-pentyl, 1,2-dimethylpropyl and the like.
  • methyl, ethyl, propyl or isopropyl is used.
  • the “C 3-4 saturated carbocyclic ring” is a monocyclic saturated hydrocarbon group having 3 to 4 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl and the like. Preferably, cyclopropyl is used.
  • C 1-4 alkoxy is linear or branched alkoxy having 1 to 4 carbon atoms, and includes, for example, methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy, tert-butoxy, sec- Butoxy and the like can be mentioned.
  • methoxy, ethoxy, propoxy or isopropoxy is used.
  • C 1-6 alkoxy is linear or branched alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy, tert-butoxy, sec- Examples include butoxy, isopentyloxy, neopentyloxy, tert-pentyloxy, 1,2-dimethylpropoxy and the like. Preferably, methoxy, ethoxy, propoxy, butoxy or isopropoxy is used.
  • “5-membered heteroaryl” includes thienyl, pyrrolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl and the like. Preferred are thienyl, pyrrolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, isoxazolyl or oxadiazolyl.
  • 6-membered heteroaryl includes pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and the like. Preferably, pyridyl or pyrimidinyl is mentioned.
  • C 2-5 cyclic amino means a monocyclic saturated heterocyclic ring containing one nitrogen atom and 2 to 5 carbon atoms, and further containing one or more of the same or different heteroatoms. Means a group such as aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and the like. Preferably, pyrrolidinyl or piperidinyl is mentioned.
  • the bonding position on the cyclic amino may be a nitrogen atom or a carbon atom.
  • Heteroatom includes nitrogen atom, oxygen atom, sulfur atom and the like. Preferably, a nitrogen atom or an oxygen atom is used.
  • R 1 and R 2 are preferably a hydrogen atom, methyl, ethyl or trifluoromethyl. More preferably, a hydrogen atom and methyl are mentioned. More preferably, R 1 is methyl and R 2 is a hydrogen atom. Even more preferably, R 1 is methyl, R 2 is a hydrogen atom, and the configuration is S-form.
  • R 3 and R 4 are preferably a hydrogen atom, a halogen atom, methyl, methoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy or difluoromethoxy. More preferably, a hydrogen atom, a fluorine atom, a chlorine atom, methyl, trifluoromethyl or trifluoromethoxy is exemplified. More preferably, a hydrogen atom, trifluoromethyl, or trifluoromethoxy is mentioned.
  • R a , R a ′ and R b ′ are preferably a hydrogen atom, methyl or ethyl. More preferably, a hydrogen atom or methyl is mentioned.
  • Ring A is preferably phenyl or pyridyl. More preferably, phenyl is mentioned.
  • B is preferably a hydrogen atom, phenyl, pyridyl, pyrimidyl, pyrazinyl, thienyl or thiazolyl. More preferably, phenyl or pyridyl is mentioned.
  • examples of the preferred C 1-4 alkyl substituent include a fluorine atom.
  • preferred 5- or 6-membered heteroaryl and C 2-5 cyclic amino substituents include halogen atom, hydroxy, amino, methyl, trifluoro And methyl or —C (O) —NR a R b . More preferred are amino, methyl, and —C (O) —NR a R b .
  • L is preferably the following structural formula group: Is mentioned. More preferably, the following structural formula group: Is mentioned.
  • B is a C 2-5 cyclic amino and the atom bonded to B in L is a heteroatom, the heteroatom is not bonded to the nitrogen atom of the C 2-5 cyclic amino of B.
  • m and n are preferably both 0.
  • m and n are preferably 1 when a double bond is included in the ring, the case where both m and n are preferably 1 is mentioned.
  • Y 1 and Y 2 are preferably both CR 5 R 6 (wherein R 5 and R 6 in Y 1 and Y 2 may be the same or different from each other), or Y 1 is CR 5 R 6 , when Y 2 represents an oxygen atom.
  • R 5 and R 6 are preferably a hydrogen atom, a halogen atom, or C 1-4 alkyl. More preferably, a hydrogen atom is mentioned.
  • stereoisomers such as tautomers and geometric isomers and optical isomers may exist depending on the type of substituent, and the present invention also includes them. That is, when one or more asymmetric carbon atoms are present in the compound of the present invention, diastereomers and optical isomers exist, but mixtures and isolated isomers of these diastereomers and optical isomers exist. Are also included in the compounds of the present invention.
  • the compounds of the present invention also include various hydrates, solvates and polymorphic substances.
  • the compounds of the present invention are substituted with isotopes (eg, D, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 35 S, 18 F, 125 I, etc.) These compounds may also be included in the compounds of the present invention.
  • isotopes eg, D, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 35 S, 18 F, 125 I, etc.
  • the pharmaceutically acceptable salt means an acid addition salt or a base addition salt that is pharmaceutically acceptable.
  • They are, for example, acetate, propionate, butyrate, formate, trifluoroacetate, maleate, tartrate, citrate, stearate, succinate, ethyl succinate, malonate, lactobion Acid salt, gluconate, glucoheptonate, benzoate, methanesulfonate, paratoluenesulfonate (tosylate), lauryl sulfate, malate, aspartate, glutamate, adipate, Cysteine salt, N-acetylcysteine salt, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate, undecanoate , Acid addition salts such as acrylic acid polymer salt and carboxyvinyl polymer, inorganic salts such as
  • the compounds of the present invention can be administered orally or parenterally (eg, intravenous, topical, nasal, pulmonary, rectal, etc.).
  • the dosage form includes, for example, tablets (including sugar-coated tablets and film-coated tablets), powders, granules, powders, troches, capsules (including soft capsules), liquids, injections (eg, subcutaneous injections, intravenous injections) Agents, intramuscular injections, intraperitoneal injections, etc.), inhalants, external preparations (eg, nasal preparations, transdermal preparations, ointments, creams, etc.), suppositories (eg, rectal suppositories, vagina) Suppositories, etc.), sustained-release agents (eg, sustained-release microcapsules, etc.), pellets, infusions, etc., all manufactured by conventional formulation techniques (eg, the method described in the 15th revised Japanese Pharmacopoeia, etc.) can do.
  • Additives are excipients, disintegrants, binders, fluidizers, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, sweeteners depending on the purpose. Perfumes and the like can be used.
  • lactose lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, stearin
  • examples include magnesium acid, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, and talc.
  • the dosage of the compound of the present invention is appropriately selected depending on the animal to be administered, administration route, disease, patient age, weight and symptoms.
  • administration route for example, 0.01 mg (preferably 0.5 mg) as the lower limit and 1000 mg (preferably 100 mg) as the upper limit per day for adults. It is desirable to administer in divided doses.
  • the compound of the present invention is a compound having mGlu2 and / or mGluR3 receptor negative allosteric modulator (NAM) activity, preferably mGlu2 receptor negative allosteric modulator (NAM) activity. Therefore, it can be a novel therapeutic agent for psychiatric or neurodegenerative diseases having a negative regulatory action on group II mGlu receptors.
  • NAM mGlu2 and / or mGluR3 receptor negative allosteric modulator
  • NAM mGlu2 receptor negative allosteric modulator
  • Specific mental and neurodegenerative diseases include mood disorders (depressive disorder, bipolar disorder, etc.), anxiety disorders (general anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, traumatic stress disorder, Specific phobias, acute stress disorders, etc.), schizophrenia, autism spectrum disorders, Alzheimer's disease, cognitive dysfunction, dementia, drug dependence, convulsions, obesity, tremor, pain, sleep disorders and the like.
  • Preferred diseases include mood disorders (depressive disorder, bipolar disorder, etc.), anxiety disorders (general anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, traumatic stress disorder, specific phobia, acute stress Disorders), Alzheimer's disease, cognitive dysfunction, dementia, drug dependence, convulsions, obesity, tremor, pain, sleep disorders and the like.
  • Group II mGlu receptor NAM When Group II mGlu receptor NAM is used as an active pharmaceutical ingredient, it is not intended for use only in humans but also in other non-human animals (cats, dogs, cows, chickens, fish, etc.) It is possible to use.
  • the compounds of the present invention may be used to treat one or more psychiatric or neurodegenerative diseases as described herein for mood disorders, anxiety disorders, Alzheimer's disease, cognitive dysfunction, dementia, drug dependence, convulsions, obesity, You may use in combination with the at least 1 or more types of chemical
  • the administration timing of the compounds of the present invention and their therapeutic agents is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference. Moreover, it is good also as a combination of the compound of this invention and those therapeutic agents.
  • the dosage of these therapeutic agents can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the compounds of the present invention and their therapeutic agents can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like.
  • Production method of the compound of the present invention The production method of the compound of the present invention will be described below with reference to examples, but the present invention is not limited thereto.
  • the compound of the present invention can be produced, for example, by the methods shown in the following production methods 1 to 15. These production methods can be improved as appropriate based on the knowledge of those skilled in organic synthesis.
  • the compound used as a raw material may use a salt thereof as necessary.
  • the target product can be obtained by protecting other than the reaction point as necessary and deprotecting after completion of the reaction or after a series of reactions.
  • Protecting groups include those described in the literature (TW Greene and PMGM Wuts, “Protective Groups in Organic Synthesis”, 3rd Ed., John Wiley and Sons, Inc., New York, etc. (1999)).
  • protecting groups that have been used can be used, and the introduction and removal of protecting groups can be carried out by methods commonly used in organic synthetic chemistry (for example, the methods described in the above-mentioned documents, etc.) or a method analogous thereto.
  • examples of the amino protecting group include benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl and the like
  • examples of the hydroxy protecting group include trialkylsilyl, acetyl, benzyl and the like. Can do.
  • the starting materials and intermediates in each of the following production methods can be obtained by purchasing commercially available products, synthesizing from known literature, or synthesizing from known compounds by known methods. Moreover, you may use those salts for a starting material and an intermediate as needed.
  • the intermediate and the target compound in the following production method can be converted into another compound included in the present invention by appropriately converting the functional group.
  • the conversion of the functional group is generally performed by a general method (for example, a method described in RC Larock, “ComprehensivesOrganic Transformations”, 2nd Ed., John Wiley and Sons, Inc., New York (1999)). Etc.) or a method analogous thereto.
  • an inert solvent means a solvent that does not react with raw materials, reagents, bases, acids, catalysts, ligands, etc. used in the reaction.
  • Manufacturing method 1 Compound (4) is produced, for example, by the method shown below.
  • R 1 and R 2 represent the same as in item 1
  • R 7 represents a methyl group or an ethyl group
  • PG 1 represents a protecting group (such as a tert-butoxycarbonyl group or a benzyloxycarbonyl group).
  • LG 1 represents a leaving group (iodine atom, bromine atom, chlorine atom, substituted sulfonyloxy group (for example, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, p-toluenesulfonyloxy group, etc.)).
  • Step 1 Compound (4) can be produced by subjecting Compound (2) and Compound (1) to Mitsunobu reaction conditions by a conventional method in an appropriate inert solvent. Specifically, it can be carried out in the presence of a Mitsunobu reaction reagent such as triphenylphosphine and diethyl azodicarboxylate or diisopropyl azodicarboxylate, or can be carried out using a cyanomethylene trialkylphosphorane reagent.
  • the reaction temperature is usually in the range from ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time is 1 minute to 5 days.
  • the compounds (2) and (1) commercially available compounds and compounds synthesized from known compounds by an existing method can be used.
  • the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, ether solvents such as tetrahydrofuran, diethyl ether and 1,4-dioxane, and the like.
  • halogenated hydrocarbons such as chloroform and dichloromethane
  • aromatic hydrocarbons such as benzene and toluene
  • ether solvents such as tetrahydrofuran, diethyl ether and 1,4-dioxane, and the like.
  • a mixed solvent is mentioned.
  • Step 2 Compound (4) can also be produced by reacting Compound (2) and Compound (3) in the presence of a base in an appropriate inert solvent by a conventional method.
  • the reaction may be performed in the presence of an additive or a phase transfer catalyst as necessary.
  • the reaction temperature is usually in the range from ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time is 1 minute to 5 days.
  • the compounds (2) and (3) a commercially available compound or a compound synthesized from a known compound by an existing technique can be used.
  • the base include, for example, organic bases such as triethylamine, N, N-diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, hydrogen phosphate
  • organic bases such as triethylamine, N, N-diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium dihydrogen phosphate, hydrogen phosphate
  • Inorganic bases such as dipotassium, potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride, metals such as sodium methoxide, potassium tert-butoxide An alkoxide etc. are mentioned.
  • Specific examples of the additive include potassium iodide, sodium iodide, lithium bromide and the like.
  • phase transfer catalyst include, for example, tetrabutylammonium hydrogen sulfate.
  • inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane and the like.
  • examples include ether solvents, lower alcohols such as methanol, ethanol and 2-propanol, aprotic polar solvents such as acetonitrile, N, N-dimethylformamide and N-methyl-2-pyrrolidone, and mixed solvents thereof.
  • An organic base such as pyridine can also be used as the base and inert solvent.
  • Manufacturing method 2 Compound (7) is produced, for example, by the method shown below. (Wherein ring A, R 1 , R 2 , R 3 and R 4 are the same as in item 1, R 7 represents a methyl group or an ethyl group, and PG 1 represents a protecting group (tert-butoxycarbonyl group) X represents an iodine atom, a bromine atom, a chlorine atom or a trifluoromethanesulfonyloxy group.
  • Step 3 Compound (5) can be prepared by various methods known to those skilled in the art (TW Greene and P.G.) for the protecting group PG 1 of the amine of compound (4) by a conventional method in a suitable inert solvent. M. Wuts, “Protective Groups in Organic Synthesis”, 3rd Ed., John Wiley and Sons, Inc., New York (1999)), and then cyclized in the presence of a base or acid. Can be manufactured.
  • the reaction temperature is usually in the range from ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time is 1 minute to 5 days.
  • the base include organic bases such as triethylamine and pyridine, inorganic bases such as potassium carbonate and sodium carbonate, metal alkoxides such as potassium tert-butoxide, and the like.
  • the acid include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid.
  • the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane and the like.
  • Examples include ether solvents, lower alcohols such as methanol, ethanol and 2-propanol, aprotic polar solvents such as acetonitrile, N, N-dimethylformamide and N-methyl-2-pyrrolidone, and mixed solvents thereof.
  • Step 4 Compound (7) can be produced by subjecting compound (5) and compound (6) to a coupling reaction in the presence of a transition metal catalyst and a base in an appropriate inert solvent by a conventional method. .
  • the reaction may be performed in the presence of a ligand as necessary.
  • the reaction temperature is usually in the range from room temperature to 200 ° C.
  • the reaction time is 1 minute to 5 days.
  • the compound (6) a commercially available compound or a compound synthesized from a known compound by an existing method can be used.
  • transition metal catalyst examples include, for example, palladium (II) acetate, tris (dibenzylideneacetone) dipalladium (0), bis (tri-tert-butylphosphine) palladium (0), copper (I) iodide, Examples include copper (II) oxide.
  • the ligand include, for example, tri-tert-butylphosphine, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 4,5-bis (diphenylphosphino) -9, Examples thereof include 9-dimethylxanthene and N, N′-dimethylethylenediamine.
  • the base include metal alkoxides such as sodium tert-butoxide, and inorganic bases such as tripotassium phosphate and potassium carbonate.
  • the inert solvent include, for example, aromatic hydrocarbons such as benzene and toluene, ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane, N, N-dimethylformamide, and the like.
  • aprotic polar solvents such as N, N-dimethylacetamide, and mixed solvents thereof.
  • Production method 3 Compound (7) is also produced, for example, by the method shown below. (In the formula, ring A, R 1 , R 2 , R 3 and R 4 are the same as in item 1, and R 7 represents a methyl group or an ethyl group.)
  • Step 5 The compound (10) can be produced by reacting the compound (8) and the compound (9) in an appropriate inert solvent by a conventional method.
  • the reaction may be performed in the presence of an additive, a base or an acid, and further in the presence of a phase transfer catalyst, if necessary.
  • the reaction temperature is usually in the range from ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time is 1 minute to 10 days.
  • the compounds (8) and (9) a commercially available compound or a compound synthesized from a known compound by an existing method can be used.
  • the additive include lithium bromide, bismuth chloride, montmorillonite K10 and the like.
  • the base include organic bases such as triethylamine and pyridine, and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide.
  • Specific examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as p-toluenesulfonic acid and trifluoroacetic acid.
  • the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane and the like.
  • halogenated hydrocarbons such as chloroform and dichloromethane
  • aromatic hydrocarbons such as benzene and toluene
  • tetrahydrofuran diethyl ether
  • 1,4-dioxane 1,2-dimethoxyethane and the like.
  • ether solvents lower alcohols such as methanol, ethanol and 2-propanol
  • aprotic polar solvents such as acetonitrile, N, N-dimethylformamide and N-methyl-2-pyrrolidone, and mixed solvents thereof.
  • Step 6 Compound (11) can be produced by subjecting compound (10) and compound (2) to a reaction under a Mitsunobu reaction condition by a conventional method in a suitable inert solvent. Specifically, it can be carried out in the presence of triphenylphosphine and Mitsunobu reagent such as diethyl azodicarboxylate or diisopropyl azodicarboxylate, or using a cyanomethylenetrialkylphosphorane reagent.
  • the reaction temperature is usually in the range from ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time is 1 minute to 5 days.
  • the compound (2) a commercially available compound or a compound synthesized from a known compound by an existing technique can be used.
  • the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, ether solvents such as tetrahydrofuran, diethyl ether and 1,4-dioxane, and the like.
  • halogenated hydrocarbons such as chloroform and dichloromethane
  • aromatic hydrocarbons such as benzene and toluene
  • ether solvents such as tetrahydrofuran, diethyl ether and 1,4-dioxane, and the like.
  • a mixed solvent is mentioned.
  • Step 7 Compound (7) can be produced by subjecting compound (11) to a cyclization reaction in the presence of a base or acid in a suitable inert solvent.
  • the reaction temperature is usually in the range from ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time is 1 minute to 5 days.
  • the base include organic bases such as triethylamine and pyridine, inorganic bases such as potassium carbonate, sodium carbonate and cesium carbonate, metal alkoxides such as sodium hydride and potassium tert-butoxide, and the like.
  • the acid include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid, methanesulfonic acid, and formic acid.
  • the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane, and the like.
  • halogenated hydrocarbons such as chloroform and dichloromethane
  • aromatic hydrocarbons such as benzene and toluene
  • tetrahydrofuran diethyl ether
  • 1,4-dioxane 1,2-dimethoxyethane
  • examples include ether solvents, lower alcohols such as methanol, ethanol and 2-propanol, aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, N-methyl-2-pyrrolidone and dimethyl sulfoxide, and mixed solvents thereof. It is done.
  • Manufacturing method 4 Compound (12) is produced, for example, by the method shown below. (In the formula, ring A, R 1 , R 2 , R 3 and R 4 are the same as in item 1, and X represents an iodine atom, bromine atom or chlorine atom.)
  • Step 8 Compound (12) can be produced by reacting compound (7) with a halogenating agent in an appropriate inert solvent by a conventional method.
  • the reaction may be performed in the presence of an additive or an acid as necessary.
  • the reaction temperature is usually in the range from ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time is 1 minute to 5 days.
  • halogenating agent examples include, for example, N-iodosuccinimide, N-bromosuccinimide, N-chlorosuccinimide, 1,3-diiodo-5,5-dimethylhydantoin, iodine, iodine monochloride, bromine and the like. Is mentioned.
  • Specific examples of the additive include cerium (IV) ammonium nitrate, sodium acetate, iron and the like.
  • the inert solvent include, for example, halogenated hydrocarbons such as chloroform, dichloromethane and carbon tetrachloride, aprotic polar solvents such as ethyl acetate and N, N-dimethylformamide, protic polar solvents such as acetic acid, And a mixed solvent thereof.
  • halogenated hydrocarbons such as chloroform, dichloromethane and carbon tetrachloride
  • aprotic polar solvents such as ethyl acetate and N, N-dimethylformamide
  • protic polar solvents such as acetic acid
  • a mixed solvent thereof a mixed solvent thereof.
  • Manufacturing method 5 Compound (14) is produced, for example, by the method shown below. (Wherein ring A, R 1 , R 2 , R 3 and R 4 are the same as in item 1, X represents an iodine atom, bromine atom or chlorine atom, and R 8 represents C 1-4 alkyl. To express.)
  • Step 9 Compound (13) is prepared by subjecting Compound (12) to normal (high pressure) carbon monoxide atmosphere in a suitable inert solvent in the presence of a palladium catalyst, a base, and a lower alcohol such as methanol and ethanol. Can be produced by alkoxycarbonylation.
  • the reaction may be performed in the presence of a ligand as necessary.
  • the reaction temperature is usually in the range from room temperature to the boiling point of the solvent used.
  • the reaction time is 1 minute to 10 days.
  • the palladium catalyst include, for example, tetrakis (triphenylphosphine) palladium (0), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0), palladium (II) acetate, Examples thereof include dichlorobis (triphenylphosphine) palladium (II), dichlorobis (acetonitrile) palladium (II), palladium (II) chloride and the like.
  • the ligand include, for example, tri-tert-butylphosphine, triphenylphosphine, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 4,5-bis (diphenylphosphino ) -9,9-dimethylxanthene and the like.
  • the base include organic bases such as triethylamine, metal alkoxides such as sodium tert-butoxide, inorganic bases such as tripotassium phosphate and potassium carbonate.
  • the inert solvent include, for example, aromatic hydrocarbons such as benzene and toluene, ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane, N, N-dimethylformamide, and the like. And aprotic polar solvents such as N, N-dimethylacetamide, and mixed solvents thereof.
  • a compound (14) can also be directly manufactured from a compound (12) by adding water instead of lower alcohols, such as methanol and ethanol.
  • Step 10 Compound (14) can be produced by subjecting compound (13) to a hydrolysis reaction in the presence of an acid or base and water in an appropriate inert solvent by a conventional method.
  • the reaction temperature is usually in the range from ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time is 1 minute to 5 days.
  • the acid include hydrochloric acid and sulfuric acid.
  • Specific examples of the base include potassium hydroxide, sodium hydroxide, lithium hydroxide or potassium carbonate.
  • Specific examples of the inert solvent include lower alcohols such as methanol and ethanol, ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane, and mixed solvents thereof. .
  • Step 11 Compound (14) is subjected to lithiation reaction in the presence of an organolithium reactant in an inert gas atmosphere in an appropriate inert solvent, and then bubbled with carbon dioxide. Can be manufactured.
  • the reaction temperature is usually in the range from ⁇ 100 ° C. to 0 ° C.
  • the reaction time is 1 minute to 5 days.
  • the inert gas include nitrogen and argon.
  • the organolithium reactant include methyl lithium, phenyl lithium, n-butyl lithium, sec-butyl lithium, and t-butyl lithium.
  • Specific examples of the inert solvent include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane and 1,2-dimethoxyethane, hydrocarbon solvents such as normal hexane and normal heptane, and mixed solvents thereof. Is mentioned.
  • Step 12 Compound (16) can be produced by subjecting compound (12) and compound (15) to a coupling reaction in the presence of a catalyst and a base in an appropriate inert solvent by a conventional method.
  • the reaction may be performed in the presence of a ligand as necessary.
  • the reaction temperature is usually in the range from room temperature to 200 ° C.
  • the reaction time is 1 minute to 5 days.
  • the compound (15) a commercially available compound or a compound synthesized from a known compound can be used.
  • the catalyst include, for example, tetrakis (triphenylphosphine) palladium (0), bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) dipalladium (0), dichlorobis (triphenylphosphine) palladium. (II), dichlorobis (acetonitrile) palladium (II), palladium chloride (II), etc. are mentioned.
  • the ligand include, for example, tri-tert-butylphosphine, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 4,5-bis (diphenylphosphino) -9, Examples thereof include 9-dimethylxanthene.
  • Specific examples of the base include organic bases such as triethylamine, metal alkoxides such as sodium tert-butoxide, and inorganic bases such as tripotassium phosphate, potassium carbonate and cesium carbonate.
  • the inert solvent include, for example, aromatic hydrocarbons such as benzene and toluene, ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane, N, N-dimethylformamide, and the like. And aprotic polar solvents such as N, N-dimethylacetamide, water, and mixed solvents thereof.
  • the boron-containing substituent include boronic acid groups, boronic acid ester groups (for example, pinacol boronic acid ester groups), trifluoroborate groups, cyclic triol borate groups, MIDA boronate groups, and the like.
  • a pinacol boronic acid ester group is used.
  • Step 13 The compound (17) is prepared by a conventional method (for example, literature TW Greene and PMGM Wuts, “Protective Groups in Organic Synthesis”, 3rd Ed., John Wiley and Sons, Inc., New.
  • the compound can be produced from the compound (16) by a deprotection reaction of a protecting group described in York (1999)) or the like).
  • Manufacturing method 7 Compound (20) is produced, for example, by the method shown below. (In the formula, m, n, ring A, B, R 1 , R 2 , R 3 , R 4 and L ′ are the same as in item 1, and X represents an iodine atom, bromine atom or chlorine atom. .)
  • Step 14 Compound (18) is prepared by a conventional hydrogenation reaction technique (for example, RC Larock, “Comprehensive Organic Transformations”, 2nd Ed., John Wiley and Sons, Inc., New York (1999)). It can be produced from compound (17) by the method described or the like or a method analogous thereto.
  • a conventional hydrogenation reaction technique for example, RC Larock, “Comprehensive Organic Transformations”, 2nd Ed., John Wiley and Sons, Inc., New York (1999)
  • transition metal catalyst examples include, for example, palladium (II) acetate, tris (dibenzylideneacetone) dipalladium (0), bis (tri-tert-butylphosphine) palladium (0), copper (I) iodide, Examples include copper (II) oxide.
  • the ligand include, for example, tri-tert-butylphosphine, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 4,5-bis (diphenylphosphino) -9, Examples thereof include 9-dimethylxanthene and N, N′-dimethylethylenediamine.
  • the base include metal alkoxides such as sodium tert-butoxide, and inorganic bases such as tripotassium phosphate and potassium carbonate.
  • the inert solvent include, for example, aromatic hydrocarbons such as benzene and toluene, ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane, N, N-dimethylformamide, and the like.
  • aprotic polar solvents such as N, N-dimethylacetamide, and mixed solvents thereof.
  • the compound (20) is also produced by the method shown in the following steps 16 and 17.
  • Step 16 Compound (22) can be produced by subjecting compound (18) and compound (21) to reaction by the same method as in step 15.
  • Step 17 Compound (20) can be produced by subjecting compound (22) to reaction by the same method as in Step 13.
  • the desired product can be obtained by introducing an appropriate protecting group as necessary and deprotecting after completion of the reaction.
  • Manufacturing method 8 Compound (24) is produced, for example, by the method shown below. (In the formula, m, n, ring A, B, R 1 , R 2 , R 3 and R 4 represent the same as in item 1.)
  • Step 18 Compound (24) can be produced by subjecting compound (18) and compound (23) to reductive amination reaction conditions in an appropriate inert solvent by a conventional method.
  • the reaction temperature is usually in the range from 0 ° C to 100 ° C.
  • the reaction time is 1 minute to 5 days.
  • the compound (23) a commercially available compound or a compound synthesized from a known compound can be used.
  • the reducing agent include sodium cyanoborohydride, sodium borohydride, or sodium triacetoxyborohydride.
  • the inert solvent include halogenated hydrocarbon solvents such as dichloromethane, chloroform and dichloroethane, aromatic hydrocarbons such as benzene and toluene, tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2- Examples include ether solvents such as dimethoxyethane, aprotic polar solvents such as N, N-dimethylformamide and N, N-dimethylacetamide, and mixed solvents thereof.
  • the desired product can be obtained by introducing an appropriate protecting group as necessary and deprotecting after completion of the reaction.
  • Manufacturing method 9 Compound (28) is produced, for example, by the method shown below. (Wherein m, n, ring A, R 1 , R 2 , R 3 and R 4 are the same as in item 1)
  • Raw material compound As the compound represented by the compound (26), a commercially available product or one produced by the following step 19 can be used.
  • Step 19 Compound (25) is reacted with tert-butanol and DMAP in an inert solvent using a known synthesis method (for example, Org. Lett. 2001, 3, 2241., etc.). 26) can be manufactured.
  • the reaction temperature is usually in the range from 0 ° C to 100 ° C.
  • the inert solvent include, for example, aromatic hydrocarbons such as benzene and toluene, ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane, N, N-dimethylformamide, and the like.
  • aprotic polar solvents such as N, N-dimethylacetamide, halogenated hydrocarbon solvents such as dichloromethane, chloroform and dichloroethane, and mixed solvents thereof.
  • Step 20 The compound (27) can be produced by reacting the compound (18) and the compound (26) by an ordinary method in an appropriate inert solvent.
  • the reaction may be performed in the presence of a base as necessary.
  • the reaction temperature is usually in the range from room temperature to 200 ° C.
  • the reaction time is 1 minute to 5 days.
  • the base include, for example, triethylamine, diisopropylethylamine and the like.
  • Specific examples of the inert solvent include lower alcohols such as methanol, ethanol and 2-propanol, ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane and 1,2-dimethoxyethane, ethyl acetate and acetic acid.
  • ester solvents such as isopropyl
  • aprotic polar solvents such as N, N-dimethylformamide and N, N-dimethylacetamide
  • halogenated hydrocarbon solvents such as dichloromethane, chloroform and dichloroethane, and mixed solvents thereof.
  • Step 21 Compound (28) can be produced by subjecting compound (27) to reaction by the same method as in Step 13.
  • Manufacturing method 10 Compound (18) is produced, for example, by the method shown below. (In the formula, m, n, ring A, R 1 , R 2 , R 3 and R 4 are the same as in item 1, and X and X ′ represent an iodine atom, a bromine atom or a chlorine atom.)
  • Step 22 Compound (30) is prepared by reacting zinc activated by an appropriate additive and compound (29) with an organic zinc compound and compound (12) in an appropriate inert solvent by a conventional method. It can be produced by a coupling reaction in the presence of a transition metal catalyst and a ligand. The reaction temperature is usually in the range from room temperature to 200 ° C. The reaction time is 1 minute to 5 days.
  • the compound (29) a commercially available compound or a compound synthesized from a known compound by an existing method can be used.
  • the activation of zinc by the additive can be performed, for example, by a method described in the document Tetrahedron, 1987, 43, 2203, or the like or a method based thereon.
  • Specific examples of the additive include acid, iodine, lithium chloride, 1,2-dibromoethane, trimethylsilyl chloride and the like.
  • Specific examples of the transition metal catalyst include, for example, palladium (II) acetate, tris (dibenzylideneacetone) dipalladium (0), bis (tri-tert-butylphosphine) palladium (0), copper (I) iodide, Examples include copper (II) oxide.
  • ligand examples include, for example, tri-tert-butylphosphine, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, tri (2-furyl) phosphine, 4,5-bis (Diphenylphosphino) -9,9-dimethylxanthene, N, N′-dimethylethylenediamine and the like.
  • the inert solvent include, for example, aromatic hydrocarbons such as benzene and toluene, ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane, N, N-dimethylformamide, and the like.
  • aprotic polar solvents such as N, N-dimethylacetamide, halogenated hydrocarbon solvents such as dichloromethane, chloroform and dichloroethane, and mixed solvents thereof.
  • Step 23 Compound (18) can be produced by subjecting compound (30) to reaction by the same method as in Step 13.
  • Manufacturing method 11 Compound (31) is produced, for example, by the method shown below. (In the formula, m, n, ring A, B, R 1 , R 2 , R 3 , R 4 and L ′ are the same as in item 1, and X represents an iodine atom, bromine atom or chlorine atom. .)
  • Step 24 Compound (31) can be produced from Compound (17) and Compound (19) by using the conditions according to Step 15 above.
  • Step 25 Compound (32) can be produced from compound (17) and compound (21) by using the conditions according to the above step 16.
  • Step 26 Compound (31) can be produced from compound 32 by using the conditions according to Step 17 above.
  • the desired product can be obtained by introducing an appropriate protecting group as necessary and deprotecting after completion of the reaction.
  • Production method 12 Compound (35) is produced, for example, by the method shown below. (In the formula, ring A, B, R 1 , R 2 , R 3 , R 4 and L ′ are the same as in item 1.)
  • Step 27 Compound (34) can be produced by condensing compound (14) and compound (33) using a condensing agent in an appropriate inert solvent by a conventional method.
  • the reaction may be performed in the presence of a base and an additive as necessary.
  • the reaction temperature is usually in the range from ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time is 1 minute to 5 days.
  • the compound (33) a commercially available compound or a compound synthesized from a known compound by an existing technique can be used.
  • condensing agent examples include, for example, O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate, O- (benzotriazole-1 -Yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate, (1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylaminomorpholinocarbenium hexafluorophosphate, N , N′-dicyclohexylcarbodiimide, N, N′-carbonyldiimidazole, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and the like.
  • the base include triethylamine, N, N-diisopropylethylamine, pyridine and the like.
  • Specific examples of the additive include 1-hydroxybenzotriazole monohydrate, 1-hydroxy-7-azabenzotriazole, 4-dimethylaminopyridine and the like.
  • Specific examples of the inert solvent include, for example, halogenated hydrocarbons such as chloroform, dichloromethane and 1,2-dichloroethane, ethers such as tetrahydrofuran, diethyl ether, 1,4-dioxane and 1,2-dimethoxyethane. Examples thereof include solvents, aprotic polar solvents such as N, N-dimethylformamide and N, N-dimethylacetamide, and mixed solvents thereof.
  • Step 28 Compound (35) can be produced by subjecting compound (34) to a cyclization reaction in the presence of an acid or a base in an appropriate inert solvent by a conventional method.
  • the reaction temperature is usually in the range from room temperature to 200 ° C.
  • the reaction time is 1 minute to 5 days.
  • the acid include acetic acid, sulfuric acid, formic acid, trifluoroacetic acid and the like.
  • Specific examples of the base include tetrabutylammonium fluoride, sodium acetate, potassium carbonate, pyridine and the like.
  • Specific examples of the inert solvent include, for example, halogenated hydrocarbons such as chloroform, dichloromethane and 1,2-dichloroethane, ethers such as tetrahydrofuran, diethyl ether, 1,4-dioxane and 1,2-dimethoxyethane.
  • Examples include solvents, lower alcohols such as methanol, ethanol and 2-propanol, aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and acetonitrile, water, and mixed solvents thereof.
  • the desired product can be obtained by introducing and removing an appropriate protecting group.
  • Specific examples include a method of introducing and deprotecting a tert-butoxycarbonyl group as a protecting group as shown in Steps 16 and 17 when B has amino as a substituent.
  • Production method 13 Compound (38) is produced, for example, by the method shown below. (In the formula, ring A, B, R 1 , R 2 , R 3 and R 4 are the same as in item 1, and X represents an iodine atom, bromine atom or chlorine atom.)
  • the palladium catalyst examples include tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (acetonitrile) palladium (II), palladium (II) chloride, and the like.
  • Specific examples of the copper catalyst include copper powder, copper (I) halide, copper (I) acetate and the like.
  • the ligand include, for example, triphenylphosphine, tri-tert-butylphosphine, 2,2-bis (diphenylphosphino) -1,1-binaphthyl, 2- (di-tert-butylphosphino) Biphenyl, 1,1′-bis (diphenylphosphino) ferrocene and the like can be mentioned.
  • Specific examples of the base include diethylamine and triethylamine.
  • Specific examples of the inert solvent include ether solvents such as tetrahydrofuran and diethyl ether, aprotic polar solvents such as N, N-dimethylformamide, and mixed solvents thereof.
  • Step 30 The compound (38) can be produced by hydrogenating the compound (37) in an appropriate inert solvent in the presence of a transition metal catalyst in a normal pressure or high pressure hydrogen atmosphere.
  • the reaction may be performed in the presence of an additive as necessary.
  • the reaction temperature is usually in the range from room temperature to the boiling point of the solvent used.
  • the reaction time is 1 minute to 10 days.
  • transition metal catalyst examples include palladium / carbon, rhodium / carbon, palladium hydroxide / carbon, platinum oxide, Raney nickel and the like.
  • additive examples include formic acid, acetic acid, ammonia, pyridine, ammonium acetate and the like.
  • inert solvent examples include lower alcohols such as methanol, ethanol and 2-propanol, ether solvents such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, ethyl acetate, isopropyl acetate and the like. Examples thereof include ester solvents, aprotic polar solvents such as N, N-dimethylformamide and N, N-dimethylacetamide, and mixed solvents thereof.
  • the desired product can be obtained by introducing an appropriate protective group as necessary and deprotecting after completion of the reaction.
  • Manufacturing method 14 Compound (41) is produced, for example, by the method shown below.
  • ring A, B, R 1 , R 2 , R 3 and R 4 are the same as in item 1, and R 9 is methanesulfonyl, toluenesulfonyl, nitrobenzenesulfonyl or trifluoromethanesulfonyl (desorbed with OR 9) .
  • X represents an iodine atom, a bromine atom or a chlorine atom.
  • Step 31 Compound (39) can be produced by reacting compound (14) with a reducing agent in an appropriate inert solvent by a conventional method.
  • the reaction may be subjected to reduction reaction conditions after reacting the compound (14) with a carboxylic acid activator additive, if necessary.
  • the reaction temperature is usually in the range from room temperature to the boiling point of the solvent used.
  • the reaction time is 1 minute to 5 days.
  • carboxylic acid activator examples include thionyl chloride, oxalyl chloride, triphosgene, methyl chloroformate, isopropyl chloroformate, N, N′-carbonyldiimidazole and the like.
  • Specific examples of the reducing agent include lithium aluminum hydride, lithium borohydride, sodium borohydride, borane and the like.
  • the inert solvent include halogenated hydrocarbons such as chloroform, dichloromethane and 1,2-dichloroethane, ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane and 1,2-dimethoxyethane, Examples thereof include aprotic polar solvents such as N, N-dimethylformamide and acetonitrile, and mixed solvents thereof.
  • Step 32 Compound (41) can be produced by subjecting compound (39) and compound (40) to the conditions of Mitsunobu reaction by a conventional method in a suitable inert solvent. Specifically, it can be carried out in the presence of a Mitsunobu reaction reagent such as triphenylphosphine and diethyl azodicarboxylate or diisopropyl azodicarboxylate, or can be carried out using a cyanomethylene trialkylphosphorane reagent.
  • the reaction temperature is usually in the range from ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time is 1 minute to 5 days.
  • the compound (40) a commercially available compound or a compound synthesized from a known compound by an existing method can be used.
  • the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, ether solvents such as tetrahydrofuran, diethyl ether and 1,4-dioxane, and the like.
  • a mixed solvent is mentioned.
  • Step 33 Compound (43) can be produced by reacting compound (39) and compound (42) in the presence of a base and an additive in an appropriate inert solvent by a conventional method.
  • the reaction temperature is usually in the range from 0 ° C. to the boiling point of the solvent used.
  • the reaction time is 1 minute to 5 days.
  • Specific examples of the base include, for example, triethylamine, pyridine, potassium carbonate and the like.
  • Specific examples of the additive include potassium iodide and lithium bromide.
  • the inert solvent include halogenated hydrocarbons such as chloroform, dichloromethane and 1,2-dichloroethane, ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane and 1,2-dimethoxyethane, Examples thereof include lower alcohols such as methanol, ethanol and 2-propanol, aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and acetonitrile, water, and mixed solvents thereof.
  • halogenated hydrocarbons such as chloroform, dichloromethane and 1,2-dichloroethane
  • ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane and 1,2-dimethoxyethane
  • lower alcohols such as methanol, ethanol and 2-propanol
  • aprotic polar solvents such as N, N-di
  • Step 34 Compound (41) can also be produced by subjecting compound (43) to substitution reaction in the presence of a base with compound (43) in a suitable inert solvent by a conventional method.
  • the reaction temperature is usually in the range from 0 ° C. to the boiling point of the solvent used.
  • the reaction time is 1 minute to 5 days.
  • Specific examples of the base include sodium hydroxide, cesium carbonate, triethylamine, potassium carbonate, sodium bicarbonate, sodium hydride and the like.
  • the inert solvent include halogenated hydrocarbons such as chloroform, dichloromethane and 1,2-dichloroethane, ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane and 1,2-dimethoxyethane, Examples thereof include lower alcohols such as methanol, ethanol and 2-propanol, aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and acetonitrile, water, and mixed solvents thereof.
  • halogenated hydrocarbons such as chloroform, dichloromethane and 1,2-dichloroethane
  • ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane and 1,2-dimethoxyethane
  • lower alcohols such as methanol, ethanol and 2-propanol
  • aprotic polar solvents such as N, N-di
  • Step 37 Compound (46) is prepared by a conventional halogenation reaction technique (for example, RC Larock, “ComprehensivesOrganic Transformations”, 2nd Ed., John Wiley and Sons, Inc., New York (1999)). It can be produced from compound (39) by the method described or the like or a method analogous thereto.
  • a conventional halogenation reaction technique for example, RC Larock, “ComprehensivesOrganic Transformations”, 2nd Ed., John Wiley and Sons, Inc., New York (1999)
  • Step 38 The compound (41) can be produced from the compound (40) and the compound (46) by using the conditions according to the above step 34.
  • the compound (41) is also produced by the method shown in the following steps 35 and 36.
  • Step 35 The compound (45) can be produced from the compound (39) and the compound (44) by using the conditions according to the above step 32.
  • Step 36 Compound (41) can be produced from compound (45) by using conditions according to Step 16 above when B has amino as a substituent.
  • the desired product can be obtained by introducing an appropriate protecting group as necessary and deprotecting after completion of the reaction.
  • Step 39 Compound (48) can be produced by subjecting compound (12) and compound (47) to a coupling reaction in the presence of a transition metal catalyst and a base in an appropriate inert solvent by a conventional method. .
  • the reaction may be performed in the presence of a ligand as necessary.
  • the reaction temperature is usually in the range from room temperature to 200 ° C.
  • the reaction time is 1 minute to 5 days.
  • As the compound (47) a commercially available compound or a compound synthesized from a known compound by an existing method can be used.
  • transition metal catalyst examples include, for example, palladium (II) acetate, tris (dibenzylideneacetone) dipalladium (0), bis (tri-tert-butylphosphine) palladium (0), copper (I) iodide, Examples include copper (II) oxide.
  • the ligand include, for example, tri-tert-butylphosphine, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl, 4,5-bis (diphenylphosphino) -9, Examples thereof include 9-dimethylxanthene and N, N′-dimethylethylenediamine.
  • the base include metal alkoxides such as sodium tert-butoxide, and inorganic bases such as tripotassium phosphate and potassium carbonate.
  • the inert solvent include, for example, aromatic hydrocarbons such as benzene and toluene, ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane, N, N-dimethylformamide, and the like.
  • aprotic polar solvents such as N, N-dimethylacetamide, and mixed solvents thereof.
  • the desired product can be obtained by introducing and removing an appropriate protecting group.
  • an appropriate protecting group As a specific example, when B has amino as a substituent, a method of introducing and deprotecting a tert-butoxycarbonyl group as a protecting group as shown in Steps 16 and 17 can be mentioned.
  • the intermediates and target compounds in the above production methods can be obtained by subjecting them to purification methods commonly used in organic synthetic chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc. It can be separated and purified.
  • each intermediate can be subjected to the next reaction without any particular purification.
  • a heating method in addition to the heating by a normal method, the heating by a microwave is also possible.
  • An optically active substance of the compound of the present invention can be produced by using an optically active starting material or intermediate, or by optically resolving an intermediate or final racemate.
  • Examples of the optical resolution method include a separation method using an optically active column and a separation method such as a fractional crystallization method.
  • the diastereomer of the compound of the present invention is produced by a separation method such as column chromatography or fractional crystallization.
  • the pharmaceutically acceptable salt of the compound represented by the formula (1) includes, for example, a compound represented by the formula (1) in a solvent such as water, methanol, ethanol, 2-propanol, and acetone, It can be produced by mixing a pharmaceutically acceptable acid or base.
  • silica gel columns and amino columns manufactured by Yamazen Co., Ltd. were used.
  • Silica gel 60F254 (Merck) was used for TLC (silica gel plate) when purified using TLC, and TLC plate NH (FujiSilisia) was used for TLC (NH silica gel plate).
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • DMSO-D 6 deuterated dimethyl sulfoxide s: single line d: double line t: triple line q: quadruple line m: multiple line br: wide dd: double line Double line td: Triple line double line J: Coupling constant Hz: Hertz
  • N Normal (for example, 2N-HCl indicates 2N hydrochloric acid)
  • M Molar concentration (mol / L) (for example, 2M methylamine indicates a 2 mol / L methylamine solution) min: minute atm: atmospheric pressure
  • HATU O- (7-aza-1H-benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate
  • Reference Example 2 1- (1- ⁇ [4- (trifluoromethyl) phenyl] amino ⁇ propan-2-yl) -1H-pyrazolo-5-carboxylate
  • ethyl 1H-pyrazole-3-carboxylate 740 mg
  • triphenylphosphine 1.73 g
  • diisopropyl azodicarboxylate 3.47 mL, 1.9 mol
  • L toluene solution was added dropwise at 0 ° C.
  • Reference Example 6 7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-3-carboxylic acid Concentrated hydrochloric acid (30 mL) was added to the compound of Reference Example 5 (570 mg), and the mixture was heated and stirred at 100 ° C. for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution to adjust the pH to about 5-6, and ethyl acetate was added to extract the desired product into the organic layer. The organic layer was concentrated under reduced pressure to obtain the title compound (542 mg).
  • Reference Example 17 (7S) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-3 -carboxylic acid
  • the compound of Reference Example 14 500 mg
  • bis (triphenylphosphine) palladium (II) dichloride 167 mg
  • THF / saturated aqueous sodium hydrogen carbonate solution (2/1, 6.0 mL)
  • carbon monoxide atmosphere Under stirring at 80 ° C. for 18 hours.
  • water and ethyl acetate were added to the reaction solution, and the target product was extracted into an organic layer.
  • Reference Example 22-1 7-methyl-3- (1,2,3,6-tetrahydropyridin-4-yl) -5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [ 1,5-a] pyrazin-4 (5H) -one
  • the compound of Example 5 (538 mg) was added to a mixed solution of 4 mol / L hydrochloric acid / 1,4-dioxane solution (7.5 mL) and chloroform (3.7 mL), and the mixture was stirred at room temperature for 30 minutes.
  • the reaction solution was concentrated under reduced pressure, toluene (10 mL) was added to the residue, and the concentration under reduced pressure was repeated three times.
  • Reference Example 22-2 7-methyl-3- (piperidin-4-yl) -5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazine-4 (5H)-ON
  • methanol 2.0 mL
  • 10% palladium-carbon 200 mg
  • the reaction mixture was filtered through celite and concentrated under reduced pressure to give the title compound (195 mg).
  • Reference Example 22-3 tert-butyl [6- (4- ⁇ 7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl] -4,5,6,7-tetrahydropyrazolo [1 , 5-a] pyrazin-3-yl ⁇ piperidin-1-yl) pyridin-2-yl] carbamate
  • the compound of Reference Example 22-2 (30 mg), tert-butyl (6-bromopyridin-2-yl) carbamate (33 mg), tris (dibenzylideneacetone) dipalladium (0) (7.3 mg), BINAP (10 mg)
  • sodium tert-butoxide 23 mg was added to toluene (1.5 mL), and the mixture was reacted at 100 ° C.
  • Reference Example 23 7-methyl-3- [1- (6-nitropyridin-3-yl) piperidin-4-yl] -5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazin-4 (5H) -one
  • the compound of Reference Example 22-2 (30 mg), 5-bromo-2-nitropyridine (24 mg), and potassium carbonate (33 mg) were added to N, N-dimethylformamide (1.5 mL) and reacted at 100 ° C. for 6 hours. . After cooling to room temperature, water and ethyl acetate were added, and the target product was extracted into the organic layer.
  • Reference Example 25 4- (dimethylamino) -1-[[[((1,1-dimethylethoxy) carbonyl] amino] sulfonyl] -pyridinium inner salt
  • Chlorosulfonyl isocyanate 800 mg was added to a mixed solvent of tert-butanol (537 ⁇ L) and dichloromethane (4.0 mL) in an ice bath, N, N-dimethyl-4-aminopyridine (1.38 g) was added, Stir for 1 hour. Water and ethyl acetate were added to the reaction solution, and the target product was extracted into an organic layer.
  • Reference Example 28 3-( ⁇ (7S) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl] -4,5,6,7-tetrahydropyrazolo [1,5-a ] Pyrazin-3-yl ⁇ ethynyl) benzamide
  • the title compound (4.91 g) was obtained using the compound of Reference Example 14 (5.0 g) and 3-ethynylbenzamide (2.08 g).
  • Example 1 3- [1- (6-Aminopyridin-2-yl) piperidin-4-yl] -7-methyl-5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazin-4 (5H) -one
  • the title compound 1.0 mg was obtained in the same manner as in Reference Example 22-1.
  • Example 2 3- [1- (6-Aminopyridin-3-yl) piperidin-4-yl] -7-methyl-5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazin-4 (5H) -one
  • methanol 1.5 mL
  • 10% palladium-carbon 20 mg
  • the reaction mixture was filtered through celite and concentrated under reduced pressure to give the title compound (18 mg).
  • Example 3 7-Methyl-3- [1- (pyridin-3-ylmethyl) piperidin-4-yl] -5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1, 5-a] pyrazin-4 (5H) -one
  • the compound of Reference Example 22-2 (30 mg), nicotinaldehyde (3.0 mg) and sodium triacetoxyborohydride (17 mg) were added to dichloromethane (0.2 mL) in an ice bath and stirred for 1 hour.
  • Acetic acid (4.5 ⁇ L) was added to the reaction solution, and the mixture was stirred at room temperature for 3.5 hours.
  • Example 4 7-Methyl-3- [1- (pyridin-2-ylmethyl) piperidin-4-yl] -5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1, 5-a] pyrazin-4 (5H) -one
  • the title compound (19 mg) was obtained from the compound of Reference Example 22-2 (30 mg) and 2-pyridinecarboxaldehyde (3.0 mg).
  • Example 5 tert-Butyl 4- ⁇ 7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine -3-yl ⁇ -3,6-dihydropyridine-1 (2H) -carboxylate
  • Compound of Reference Example 4 (480 mg), N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (370 mg), cesium carbonate (557 mg) and tetrakis (triphenylphosphine) palladium (0) (132 mg) was added to dioxane / water (2/1, 7.2 mL) and reacted at 120 ° C.
  • Example 6 3- (6′-amino-3,6-dihydro-2H-1,2′-bipyridin-4-yl) -7-methyl-5- [4- (trifluoromethyl) phenyl] -6 , 7-Dihydropyrazolo [1,5-a] pyrazin-4 (5H) -one
  • the title compound (4.5 mg) was obtained in the same manner as in Reference Example 22-1 using the compound of Reference Example 24 (20 mg).
  • Example 7 4- ⁇ 7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-3- Il ⁇ piperidine-1-sulfonamide
  • the obtained residue was purified by silica gel column chromatography (chloroform / methanol), and tert-butyl [(4- ⁇ 7 -Methyl-4-oxo-5- [4- (trifluoromethyl) phenyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazin-3-yl ⁇ piperidin-1-yl) Sulfonyl] carbamate (90 mg) was obtained.
  • the obtained compound (90 mg) was treated in the same manner as in Reference Example 22-1 to give the title compound (75.1 mg).
  • Example 8 3- [1- (6-Aminopyridin-3-yl) azetidin-3-yl] -7-methyl-5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazin-4 (5H) -one
  • tetrahydrofuran 2.0 mL
  • 4 mol / L hydrochloric acid / 1,4-dioxane solution 4.5 mL
  • the reaction solution was concentrated under reduced pressure to obtain a residue (490 mg).
  • reaction mixture was concentrated under reduced pressure, and the resulting residue was subjected to reverse-phase HPLC (XBridge C18, 3.5 ⁇ m, 4.6 ⁇ 50 mm, water (10 mM NH 4 HCO 3 ) / acetonitrile, acetonitrile 5-95%, 3 0.0 min, 1.8 mL / min, 50 ° C.) to obtain the title compound (20 mg).
  • reverse-phase HPLC XBridge C18, 3.5 ⁇ m, 4.6 ⁇ 50 mm, water (10 mM NH 4 HCO 3 ) / acetonitrile, acetonitrile 5-95%, 3 0.0 min, 1.8 mL / min, 50 ° C.
  • Example 10 (7S) -7-methyl-3- [3- (pyridin-4-yl) -1,2,4-oxadiazol-5-yl] -5- [4- (trifluoromethyl) Phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazin-4 (5H) -one HATU (71 mg) was added to a solution of the compound of Reference Example 16 (60 mg), isonicotinamide oxime (24 mg) and N, N-diisopropylethylamine (62 ⁇ L) in N, N-dimethylformamide (1.5 mL) at room temperature. Stir for 3 hours.
  • Example 11 (7S) -7-methyl-3- [3- (pyridin-3-yl) -1,2,4-oxadiazol-5-yl] -5- [4- (trifluoromethyl) Phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazin-4 (5H) -one
  • the title compound 38 mg was obtained from the compound of Reference Example 16 (50 mg) and N′-hydroxypyridine-3-carboximidamide (21 mg).
  • Example 12 (7S) -7-methyl-3- ⁇ 3- [2-oxo-2- (pyrrolidin-1-yl) ethyl] -1,2,4-oxadiazol-5-yl ⁇ -5 -[4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazin-4 (5H) -one
  • the title compound (11 mg) was obtained from the compound of Reference Example 16 (60 mg) and N′-hydroxy-3-oxo-3- (1-pyrrolidinyl) propaneimidamide (30 mg).
  • Example 13 (7S) -3- [2- (6-Aminopyridin-3-yl) ethyl] -7-methyl-5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazin-4 (5H) -one
  • a methanol (2.0 mL) solution of the compound of Reference Example 27 (20 mg) and 10% Pd / C (about 55% water-wet product, 4 mg) was stirred at room temperature for 8 hours in a hydrogen atmosphere.
  • the reaction solution was filtered through celite, washed with methanol, and the obtained filtrate was concentrated under reduced pressure.
  • Example 14 3- (2- ⁇ (7S) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl] -4,5,6,7-tetrahydropyrazolo [1,5 -A] pyrazin-3-yl ⁇ ethyl) benzamide
  • the title compound (0.112 g) was obtained using the compound of Reference Example 28 (0.113 g).
  • Example 15 (7S) -7-methyl-3-[(pyridin-3-yloxy) methyl] -5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5- a] Pyrazine-4 (5H) -one
  • Diisopropyl azodicarboxylate (55 mg) and triphenylphosphine (77 mg) were added to tetrahydrofuran (2.0 mL), and the mixture was stirred at room temperature for 15 minutes.
  • To the reaction mixture were added the compound of Reference Example 29 (80 mg) and 3-hydroxypyridine (23 mg), and the mixture was stirred at 40 ° C. for 5 hours.
  • a saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution, and the target product was extracted into an organic layer.
  • the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the resulting residue was purified by amino silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (4.5 mg).
  • Example 16 (7S) -7-methyl-3-[(pyridin-4-yloxy) methyl] -5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5- a] Pyrazine-4 (5H) -one
  • the title compound 17.0 mg was obtained in the same manner as in Example 15 using the compound of Reference Example 29 (100 mg).
  • Example 17 (7S) -7-methyl-3- (phenoxymethyl) -5- [4- (trifluoromethyl) phenyl] -6,7-dihydropyrazolo [1,5-a] pyrazine-4 ( 5H)-ON
  • the title compound (62 mg) was obtained in the same manner as in Example 15 using the compound of Reference Example 29 (100 mg).
  • Example 18 N- ⁇ (7S) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] Pyrazin-3-yl ⁇ pyridine-3-sulfonamide Pyridine-3-sulfonamide (97.7 mg), potassium carbonate (131 mg) and N, N′-dimethylethylenediamine (30.7 ⁇ L) were added to a toluene solution (4 mL) of the compound of Reference Example 14 (200 mg) at 150 ° C. For 4.5 hours. Thereafter, copper iodide (18.1 mg) was added to the reaction solution, and the mixture was heated and stirred at 120 ° C.
  • Human mGlu2 receptor stable expression cells Human mGlu2 receptor stable expression cells were prepared and subjected to culture. Specifically, human mGlu2 receptor gene is inserted into pcDNA4 / TO (K1020-01, Lifetechnologies, Carlsbad, CA, USA), and TR-expressing human kidney-derived HEK cells (cat # CCL-82.2, ATCC, USA) ). Thereafter, selection with Geneticin (cat # 10131-027, Lifetechnologies, Carlsbad, CA, USA) was performed to obtain cells stably expressing human mGlu2 receptor.
  • Medium includes 10% Dialysed-FBS (cat # 26400-044, Lifetechnologies, Carlsbad, CA, USA), 50 ⁇ g / mL Blasticidin S (cat # ANT-BL-1, Lifetechnologies, Carlsbad, CA, USA), 2 High Glucose-DMEM medium (cat # 1199-065, Lifetechnologies, Carlsbad, CA, USA) containing mL G418 (cat # 16513-84, nacalai tesque, Kyoto, Japan), and flask for cell culture 13 (cat # 3 150, AGC Techno Glass, Shizuoka, Japan). During culturing, cells were collected and treated by TrypLE Express (cat # 12604-013, Lifetechnologies, Carlsbad, CA, USA) every 3-4 days.
  • Coelentetrazine h (cat # S2011, Promega, Madison, WI, USA) was added to a final concentration of 1 ⁇ mol / L (10 ⁇ L / well), and after centrifugation, allowed to stand at room temperature for 4 hours or more.
  • test compound was dissolved in DMSO to a concentration 1000 times the evaluation concentration.
  • This DMSO solution was diluted with a medium (Hanks, 20 mmol / L HEPES, 0.1% BSA) to a concentration 6 times the evaluation concentration.
  • Glutamate was diluted with Hanks / 20 mmol / L HEPES / 0.1% BSA medium to a concentration 6 times the EC 80 concentration.
  • a compound showing mGlu2 receptor negative allosteric modulator activity was found.
  • the following table shows the mGlu2 receptor negative allosteric modulator activity (IC 50 value ( ⁇ mol / l) or inhibition rate (%) at 10 ⁇ mol / L) of each compound.
  • the compound of the present invention exhibits a strong negative regulatory action on the group II metabotropic glutamate (mGlu) receptor. Therefore, the compound of the present invention is a mood disorder (depressive disorder, bipolar disorder, etc.), anxiety disorder (general anxiety disorder, panic disorder, obsessive compulsive disorder, social anxiety disorder, traumatic stress disorder, specific phobia, acute Stress disorder, etc.), cognitive dysfunction, dementia, obesity and the like are useful as therapeutic and / or preventive agents.
  • mGlu group II metabotropic glutamate

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Abstract

La présente invention concerne un agent préventif ou thérapeutique pour des maladies telles que les troubles de l'humeur, les troubles de l'anxiété, la schizophrénie, les troubles du spectre de l'autisme, et la maladie d'Alzheimer, qui font intervenir des récepteurs métabotropiques du glutamate (mGlu) du groupe II (mGlu), ledit agent comprenant comme ingrédient actif un composé représenté par la formule (I) : [dans la formule (I), R1 R2 représentent un atome d'hydrogène ou similaire; le cycle A représente phényle ou similaire; R3 et R4 représentent un atome d'hydrogène ou similaire; L représente la formule structurelle groupe (II) (dans chaque formule structurelle, la liaison 1 représente une position liée au cycle pyrazole, la liaison 2 représente la position lié à B, L' représente -C (O) -O-ou similaire, m et n représentent 0 ou 1, Y1 représente CR5R6; Y2 représente CR5R6 ou similaire, et R5 et R6 représentent un atome d'hydrogène ou similaire), B représente un atome d'hydrogène ou similaire, et Ra, Ra' et Rb' représentent un atome d'hydrogène ou similaire], ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/JP2016/072117 2015-07-29 2016-07-28 Dérivé de pyrazole condensé présentant un nouveau site de liaison et utilisation médicinale de celui-ci WO2017018475A1 (fr)

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US10806724B2 (en) 2016-09-27 2020-10-20 Merck Sharp & Dohme Corp. Chromane, isochromane and dihydroisobenzofuran derivatives as mGluR2-negative allosteric modulators, compositions, and their use
US10335399B2 (en) 2016-09-27 2019-07-02 Merck Sharp & Dohme Corp. Chromane, isochromane and dihydroisobenzofuran derivatives as mGluR2—negative allosteric modulators, compositions, and their use
JP7242548B2 (ja) 2017-11-24 2023-03-20 住友ファーマ株式会社 ６，７－ジヒドロピラゾロ［１，５－ａ］ピラジノン誘導体及びその医薬用途
CN111601811B (zh) * 2017-11-24 2023-05-05 住友制药株式会社 6,7-二氢吡唑并[1,5-a]吡嗪酮衍生物和其医药用途
KR20200090843A (ko) * 2017-11-24 2020-07-29 다이닛본 스미토모 세이야꾸 가부시끼가이샤 6, 7-디히드로 피라졸로[1, 5-a]피라지논 유도체 및 그 의약 용도
JPWO2019103070A1 (ja) * 2017-11-24 2020-11-19 大日本住友製薬株式会社 ６，７−ジヒドロピラゾロ［１，５−ａ］ピラジノン誘導体及びその医薬用途
US12150941B2 (en) 2017-11-24 2024-11-26 Sumitomo Pharma Co., Ltd. Process for preparing substituted pyrazolo[1,5-a]pyrazines
US10953008B2 (en) 2017-11-24 2021-03-23 Sumitomo Dainippon Pharma Co., Ltd. Substituted pyrazolo[1,5-a]pyrazines as negative allosteric modulators of group II metabotropic glutamate receptor
WO2019103070A1 (fr) * 2017-11-24 2019-05-31 大日本住友製薬株式会社 DÉRIVÉ DE 6,7-DIHYDROPYRAZOLO[1,5-a]PYRAZINONE ET SON APPLICATION MÉDICALE
RU2792694C2 (ru) * 2017-11-24 2023-03-23 Сумитомо Фарма Ко., Лтд. ПРОИЗВОДНОЕ 6,7-ДИГИДРОПИРАЗОЛО[1,5-a]ПИРАЗИНОНА И ЕГО ПРИМЕНЕНИЕ В МЕДИЦИНЕ
US11633395B2 (en) 2017-11-24 2023-04-25 Sumitomo Pharma Co., Ltd. Substituted pyrazolo[1,5-a]pyrazines as negative allosteric modulators of group II metabotropic glutamate receptor
KR102688238B1 (ko) 2017-11-24 2024-07-25 스미토모 파마 가부시키가이샤 6, 7-디히드로 피라졸로[1, 5-a]피라지논 유도체 및 그 의약 용도
CN111601811A (zh) * 2017-11-24 2020-08-28 大日本住友制药株式会社 6,7-二氢吡唑并[1,5-a]吡嗪酮衍生物和其医药用途
JP7472347B2 (ja) 2017-11-24 2024-04-22 住友ファーマ株式会社 ６，７－ジヒドロピラゾロ［１，５－ａ］ピラジノン誘導体及びその医薬用途
JP7266010B2 (ja) 2019-05-30 2023-04-27 住友ファーマ株式会社 ６，７－ジヒドロピラゾロ［１，５－ａ］ピラジノン誘導体又はその塩を含有する医薬
JP7550913B2 (ja) 2019-05-30 2024-09-13 住友ファーマ株式会社 ６，７－ジヒドロピラゾロ［１，５－ａ］ピラジノン誘導体又はその塩を含有する医薬
JP2020196709A (ja) * 2019-05-30 2020-12-10 大日本住友製薬株式会社 ６，７−ジヒドロピラゾロ［１，５−ａ］ピラジノン誘導体又はその塩を含有する医薬

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