WO2018119449A1 - Dérivés d'oxazépine ayant une activité inhibitrice de tnap - Google Patents

Dérivés d'oxazépine ayant une activité inhibitrice de tnap Download PDF

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WO2018119449A1
WO2018119449A1 PCT/US2017/068323 US2017068323W WO2018119449A1 WO 2018119449 A1 WO2018119449 A1 WO 2018119449A1 US 2017068323 W US2017068323 W US 2017068323W WO 2018119449 A1 WO2018119449 A1 WO 2018119449A1
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group
same
different
groups
optionally substituted
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PCT/US2017/068323
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Shojiro Miyazaki
Yasunobu KUROSAKI
Masaharu Inui
Masamichi Kishida
Keisuke Suzuki
Masanori Izumi
Kaori SOMA
Anthony Pinkerton
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Daiichi Sankyo Company, Limited
Sanford Burnham Prebys Medical Discovery Institute
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Publication of WO2018119449A1 publication Critical patent/WO2018119449A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders

Definitions

  • the present invention relates to a novel oxazepine compound or a pharmacologically acceptable salt thereof which has excellent tissue non-specific alkaline
  • TNAP phosphatase
  • the present invention also relates to a therapeutic agent and/or prophylactic agent (preferably a therapeutic agent) for pseudoxanthoma elasticum (PXE) , generalized arterial calcification of infancy (GACI),
  • a therapeutic agent and/or prophylactic agent preferably a therapeutic agent
  • PXE pseudoxanthoma elasticum
  • GACI generalized arterial calcification of infancy
  • CMD craniometaphyseal dysplasia
  • OYL yellow ligament
  • ACDC calcification due to deficiency of CD73
  • CALJA calcification of joints and arteries
  • IIAC idiopathic infantile arterial calcification
  • AS ankylosing spondylitis
  • TC tumoral calcinosis
  • POH progressive osseous heteroplasia
  • Keutel syndrome vascular calcification associated with chronic renal failure (including glomerulonephritis, IgA nephropathy, hypertensive nephropathy, and diabetic nephropathy) and secondary parathyroid hyperplasia, metastatic
  • FOP progressiva
  • CUA calcific uremic arteriopathy
  • IBGC immunodeficiency ossification
  • HO heterotopic ossification
  • calcific aortic valve disease aortic valve stenosis
  • calcific aortic valve disease aortic valve stenosis
  • the present invention further relates to a
  • composition for the treatment or prophylaxis of the aforementioned diseases comprising the compound or the pharmacologically acceptable salt thereof as an active ingredient, use of the compound or the pharmacologically acceptable salt thereof for manufacturing a
  • a pharmaceutical for the treatment or prophylaxis of the disease and a method for the treatment or prophylaxis of the disease, comprising administering a pharmacologically effective amount of the compound or the pharmacologically acceptable salt thereof to a mammal (preferably a human) .
  • Non Patent Literature 1 Ectopic calcification is found in diseases, for example, pseudoxanthoma elasticum
  • GCI craniometaphyseal dysplasia
  • OYL yellow ligament
  • ossification of ligamentum flavum arterial calcification due to deficiency of CD73
  • ACDC calcification of joints and arteries
  • CALJA calcification of joints and arteries
  • IIAC idiopathic infantile arterial calcification
  • AS ankylosing spondylitis
  • TC tumoral calcinosis
  • POH progressive osseous heteroplasia
  • Keutel syndrome vascular calcification associated with chronic renal failure (including glomerulonephritis, IgA nephropathy, hypertensive nephropathy, and diabetic nephropathy) and secondary parathyroid hyperplasia, metastatic
  • FOP progressiva
  • CUA calcific uremic arteriopathy
  • IBGC immunodeficiency ossification
  • HO heterotopic ossification
  • calcific aortic valve disease aortic valve stenosis
  • calcific aortic valve disease aortic valve stenosis
  • Non Patent Literatures 2 and 3 No existing therapeutic agent is effective for ectopic calcification. Thus, there are very high unmet medical needs for this disease (Non Patent Literature 4) .
  • TNAP one of alkaline phosphatases, includes
  • TNAP membrane-bound and secretory forms.
  • TNAP is expressed in the bone, the liver, and the kidney and highly expressed particularly in the matrix vesicles of chondrocytes and osteoblasts.
  • This enzyme is known to play an important role in in vivo calcification via the degradation of pyrophosphate, which is an endogenous anti-calcification factor (Non Patent Literature 5) .
  • Non Patent Literature 5 A large number of reports show the increased expression level or elevated activity of TNAP at lesion sites of ectopic calcification, and ectopic calcification also occurs in mice which overexpress human TNAP, suggesting the importance of TNAP for ectopic calcification (Non Patent Literatures 6 and 7) .
  • the inhibition of TNAP is considered to
  • Non Patent Literature 8 elevate pyrophosphate concentrations in blood and in tissues and suppress ectopic calcification.
  • Patent Literatures 1 and 2 Some compounds are known to have TNAP inhibitory activity (see e.g., Patent Literatures 1 and 2 and,
  • Non Patent Literatures 9 to 12 compounds partially having a common skeleton are disclosed.
  • Patent Literature 1 International Publication No.
  • Non Patent Literature 3 Eur. Heart. J., 2014, vol. 35, p. 1515-1525.
  • the compound of the present invention has excellent properties in terms of TNAP inhibitory activity, solubility, cell membrane permeability, oral absorbability, concentration in blood, metabolic
  • BA in vitro activity
  • in vivo activity in vitro activity
  • ex vivo activity quick onset of drug efficacy
  • persistence of drug efficacy physical
  • PXE pseudoxanthoma elasticum
  • GCI generalized arterial calcification of infancy
  • CMD craniometaphyseal dysplasia
  • OYL ossification of the yellow ligament
  • ACDC ossification due to deficiency of CD73
  • CALJA calcification of joints and arteries
  • arthrosis deformans e.g., arthrosis deformans
  • osteoarthritis e.g., ankylosis of the joint
  • IIAC idiopathic infantile arterial calcification
  • AS ankylosing spondylitis
  • TC tumoral calcinosis
  • POH progressive osseous heteroplasia
  • Keutel syndrome vascular calcification associated with chronic renal failure (including glomerulonephritis, IgA nephropathy, hypertensive nephropathy, and diabetic nephropathy) and secondary parathyroid hyperplasia, metastatic
  • FOP progressiva
  • CUA calcific uremic arteriopathy
  • IBGC immunodeficiency ossification
  • HO heterotopic ossification
  • calcific aortic valve disease aortic valve stenosis
  • calcific aortic valve disease aortic valve stenosis
  • the present invention provides: (1) a compound represented by the following general formula ( I ) :
  • a Cl-6 alkyl group (wherein the alkyl group is optionally substituted by one to three groups, which may be the same or different, selected from substituent group A B ) , a C6-10 aryl group (wherein the aryl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A B ) , or a 3- to 10-membered heterocyclyl group containing one to four heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur (wherein the heterocyclyl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A B ) ,
  • R 2 represents
  • a hydrogen atom a Cl-6 alkyl group (wherein the alkyl group is optionally substituted by one to three groups, which may be the same or different, selected from substituent group A B ) , a C3-8 cycloalkyl group (wherein the cycloalkyl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A B and) ,
  • heterocyclyl group containing one to four heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur (wherein the heterocyclyl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A B and
  • aminocarbonyl group optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups ,
  • a 4- to 7-membered saturated heterocyclylcarbonyl group containing one or two heteroatoms which may be the same or different, selected from nitrogen, oxygen, and sulfur, an aminocarbonyloxy group optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups,
  • a 4- to 7-membered saturated heterocyclylcarbonyloxy group containing one or two heteroatoms which may be the same or different, selected from nitrogen, oxygen, and sulfur,
  • cycloalkylcarbonyl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A B ) , a C6-10 arylcarbonyl group (wherein the arylcarbonyl group is optionally substituted by one or two groups, which may be the same or different, selected from
  • heterocyclylcarbonyl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A B and a Cl-6 halogenoalkyl group
  • cycloalkyloxycarbonyl group is optionally substituted by one to three groups, which may be the same or different, selected from substituent group A E ) ,
  • a 4- to 7-membered saturated heterocyclyloxycarbonyl group containing one or two heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur wherein the heterocyclyloxycarbonyl group is optionally substituted by one to three groups, which may be the same or different, selected from substituent group A F ), an aminocarbonyl group (wherein the aminocarbonyl group is optionally substituted by one or two groups, which may be the same or different, selected from the following substituents :
  • a Cl-6 alkyl group is optionally substituted by one to three groups, which may be the same or different, selected from substituent group A D ,
  • a C3-8 cycloalkyl group is optionally substituted by one to three groups, which may be the same or different, selected from substituent group A D ,
  • a C6-10 aryl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A B and
  • arylaminocarbonyl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A F and
  • heterocyclylaminocarbonyl group containing one to four heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur (wherein the heterocyclylaminocarbonyl group is
  • R 3 and R 4 are the same or different and each
  • a Cl-6 alkyl group (wherein the alkyl group is optionally substituted by one to three groups, which may be the same or different, selected from the following substituents : a hydroxy group,
  • a 3- to 10-membered heterocyclyl group containing one to four heteroatoms which may be the same or different, selected from nitrogen, oxygen, and sulfur and optionally substituted by one or two groups selected from
  • an aminocarbonyl group optionally substituted by one or two groups which may be the same or different Cl-6 alkyl groups
  • a 4- to 7-membered saturated heterocyclylcarbonyl group containing one or two heteroatoms which may be the same or different, selected from nitrogen, oxygen, and sulfur
  • an aminocarbonyloxy group optionally substituted by one or two groups which may be the same or different Cl-6 alkyl groups
  • a 4- to 7-membered saturated heterocyclylcarbonyloxy group containing one or two heteroatoms which may be the same or different, selected from nitrogen, oxygen, and sulfur,
  • aryl group is optionally substituted by one or two groups, which may be the same or different, selected from the following substituents : a hydroxy group,
  • Cl-6 alkoxy group optionally substituted by one to three groups, which may be the same or different halogeno groups ,
  • aminocarbonyl group optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups ,
  • a 4- to 7-membered saturated heterocyclylcarbonyl group containing one or two heteroatoms which may be the same or different, selected from nitrogen, oxygen, and sulfur, an aminocarbonyloxy group optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups,
  • a 4- to 7-membered saturated heterocyclylcarbonyloxy group containing one or two heteroatoms which may be the same or different, selected from nitrogen, oxygen, and sulfur,
  • heterocyclyl group containing one to four heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur (wherein the heterocyclyl group is optionally substituted by one or two groups, which may be the same or different, selected from the following substituents :
  • Cl-6 alkoxy group optionally substituted by one to three groups, which may be the same or different halogeno groups ,
  • a 3- to 10-membered heterocyclyl group containing one to four heteroatoms which may be the same or different, selected from nitrogen, oxygen, and sulfur, and
  • an aminocarbonyl group optionally substituted by one or two groups which may be the same or different Cl-6 alkyl groups
  • a 4- to 7-membered saturated heterocyclylcarbonyl group containing one or two heteroatoms which may be the same or different, selected from nitrogen, oxygen, and sulfur
  • an aminocarbonyloxy group optionally substituted by one or two groups which may be the same or different Cl-6 alkyl groups
  • a 4- to 7-membered saturated heterocyclylcarbonyloxy group containing one or two heteroatoms which may be the same or different, selected from nitrogen, oxygen, and sulfur,
  • arylcarbonyl group (wherein the arylcarbonyl group is optionally substituted by one or two groups, which may be the same or different, selected from
  • substituent group A F and a Cl-6 halogenoalkyl group a 3- to 10-membered heterocyclylcarbonyl group containing one to four heteroatoms, which may be the same or
  • heterocyclylcarbonyl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A F and a Cl-6 halogenoalkyl group) , a carboxyl group,
  • aminocarbonyl group (wherein the aminocarbonyl group is optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups each
  • arylaminocarbonyl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A F and
  • heterocyclylaminocarbonyl group containing one to four heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur (wherein the heterocyclylaminocarbonyl group is
  • the Cl-6 alkyl groups of R 3 and R 4 are optionally bonded to each other to form a 3- to 6-membered saturated carbocyclic ring or to form a 4- to 6-membered saturated heterocyclic ring via one nitrogen or oxygen atom
  • R 5 and R 6 are the same or different and each
  • a Cl-6 alkyl group (wherein the alkyl group is optionally substituted by one to three groups, which may be the same or different, selected from substituent group A G ) , a C6-10 aryl group (wherein the aryl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A D ) , or a 3- to 10-membered heterocyclyl group containing one to four heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur (wherein the heterocyclyl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A D ) ,
  • R 7 represents
  • R 7 is a carbon substituent of the pyridinyl ring, not a nitrogen substituent
  • each substituent R may be the same or different and may be each represent
  • a Cl-6 alkyl group (wherein the alkyl group is optionally substituted by one to three groups, which may be the same or different, selected from substituent group A B )
  • a Cl-6 alkoxy group (wherein the alkoxy group is
  • aryl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A D
  • substituent group A D a 3- to 10-membered heterocyclyl group containing one to four heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur
  • heterocyclyl group is optionally substituted by one or two groups, which may be the same or different, selected from substituent group A G )
  • amino group (wherein the amino group is optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups each optionally
  • substituent group A J substituted by one to three groups, which may be the same or different, selected from substituent group A J ) , a carboxyl group, a Cl-6 alkoxycarbonyl group (wherein the alkoxycarbonyl group is optionally substituted by one to three groups, which may be the same or different, selected from
  • aminocarbonyl group (wherein the aminocarbonyl group is optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups each
  • n an integer selected from 1 to 4, the substituent groups represent
  • a B a hydroxy group
  • a 3- to 10-membered heterocyclyl group containing one to four heteroatoms which may be the same or different, selected from nitrogen, oxygen, and sulfur,
  • aminocarbonyl group (wherein the aminocarbonyl group is optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups), an amino group (wherein the amino group is optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups),
  • a c a C6-10 aryl group
  • a 3- to 10-membered heterocyclyl group containing one to four heteroatoms which may be the same or different, selected from nitrogen, oxygen, and sulfur, and
  • a D a hydroxy group
  • a E a hydroxy group
  • amino group (wherein the amino group is optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups),
  • a F a hydroxy group
  • a 3- to 10-membered heterocyclyl group containing one to four heteroatoms which may be the same or different, selected from nitrogen, oxygen, and sulfur,
  • amino group (wherein the amino group is optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups),
  • a G a Cl-6 alkoxy group
  • a 3- to 10-membered heterocyclyl group containing one to four heteroatoms which may be the same or different, selected from nitrogen, oxygen, and sulfur,
  • a H a hydroxy group
  • a J a Cl-6 alkoxy group
  • a C6-10 aryl group a 3- to 10-membered heterocyclyl group containing one to four heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur,
  • aminocarbonyl group (wherein the aminocarbonyl group is optionally substituted by one or two groups, which may be the same or different Cl-6 alkyl groups),
  • R 2 represents a 3- to 10-membered heterocyclyl group containing one nitrogen, a Cl-6 alkylcarbonyl group
  • alkylcarbonyl group is optionally substituted by a hydroxy group, a Cl-6 alkoxy group, a 4- to 7-membered saturated heterocyclyl group containing one or two heteroatoms, which may be the same or
  • alkoxycarbonyl group is optionally substituted by a hydroxy group or a Cl-6 alkoxy group) , an aminocarbonyl group (wherein the aminocarbonyl group is optionally substituted by one or two groups, which may be the same or different, each optionally substituted by a Cl-6 alkyl groups), 3- to 10-membered heterocyclylcarbonyl group containing one nitrogen, 4- to 7-membered saturated heterocyclylcarbonyl group containing one or two
  • heteroatoms which may be the same or different, selected from nitrogen and oxygen, 3- to 10-membered
  • heterocyclylaminocarbony group containing one nitrogen or 4- to 7-membered saturated heterocyclyloxycarbonyl group containing one oxygen,
  • R 3 and R 4 are the same or different and each
  • each substituent R 8 may be the same or different and may represent a Cl-6 alkoxy group or a halogeno group, m represents an integer selected from 1 to 2,
  • R 2 is a Cl-6 alkoxycarbonyl group (wherein the alkoxycarbonyl group is optionally substituted by a hydroxy group or a Cl-6 alkoxy group, or 4- to 7-membered saturated
  • a pharmaceutical composition comprising a compound according to 1 to 10 above, or a pharmacologically acceptable salt thereof, as an active ingredient;
  • a TNAP inhibitor comprising a compound according to the 1 to 10 above, or a pharmacologically acceptable salt thereof, as an active ingredient;
  • pharmacologically acceptable salt thereof for use in the treatment of disease or condition selected from the group consisting of ectopic calcification, pseudoxanthoma elasticum (PXE) , generalized arterial calcification of infancy (GACI), calcification of joints and arteries
  • disease or condition selected from the group consisting of ectopic calcification, pseudoxanthoma elasticum (PXE) , generalized arterial calcification of infancy (GACI), calcification of joints and arteries
  • PXE pseudoxanthoma elastic
  • Cl-6 alkyl group refers to a linear or branched alkyl group having 1 to 6 carbon atoms. Examples thereof can include methyl, ethyl, n-propyl, n-butyl, isobutyl, s-butyl, tert-butyl,
  • n-pentyl isopentyl, 2-methylbutyl , neopentyl,
  • the Cl-6 alkyl group is preferably an alkyl group having 1 to 3 carbon atoms, most
  • Cl-6 halogenoalkyl group refers to the aforementioned “Cl-6 alkyl group” substituted by one to six halogen atoms.
  • C3-8 cycloalkyl group refers to a 3- to 8-membered saturated cyclic hydrocarbon group. Examples thereof can include
  • the C3-8 cycloalkyl group is preferably a 3- to 6-membered saturated cyclic hydrocarbon group, more preferably a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group.
  • the "C6-10 aryl group” refers to an aromatic hydrocarbon group having 6 to 10 carbon atoms. Examples thereof can include phenyl, indenyl, and naphthyl groups.
  • the C6-10 aryl group is preferably a phenyl group.
  • heteroatoms which may be the same or different, selected from nitrogen, oxygen, and sulfur refers to a 4- to
  • thiomorpholinyl pyrrolidinyl , pyrrolinyl, imidazolidinyl , imidazolinyl , pyrazolidinyl , pyrazolinyl, piperidinyl, piperazinyl, tetrahydrofuranyl , tetrahydropyranyl , and 5-oxo-4 , 5-dihydro-l , 2 , 4-oxadiazolyl groups .
  • the "3- to 10-membered heterocyclyl group containing one to four heteroatoms which may be the same or different, selected from
  • nitrogen, oxygen, and sulfur refers to a 3- to
  • 10-membered heterocyclic group containing one to four atoms of nitrogen, oxygen, and sulfur can include the groups listed as the examples of the aforementioned "4- to 7-membered heterocyclyl group containing one or two heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur", and aromatic heterocyclic groups such as furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, isothiazolyl , 1,2,3- oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl , pyranyl, pyridyl, pyridazinyl, pyrimidinyl , and pyrazinyl.
  • aromatic heterocyclic groups such as furyl, thienyl, pyrrolyl, azepinyl
  • the "3- to 10-membered heterocyclic group” may be condensed with an additional cyclic group.
  • additional cyclic group examples thereof can include benzofuranyl , chromenyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl , naphthyridinyl , quinoxalinyl , quinazolinyl , isoindolinyl , 2, 3-dihydro-l-benzofuranyl, 3, 4-dihydro-lH-isochromenyl, 1,2,3, 4-tetrahydroquinolinyl , and 1 , 2 , 3 , 4-tetrahydroisoquinolinyl groups.
  • the "Cl-6 alkoxy group” refers to the aforementioned "Cl-6 alkyl group” bonded to an oxygen atom.
  • Examples thereof can include linear or branched alkoxy groups each having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentoxy, isopentoxy,
  • the Cl-6 alkoxy group is preferably a methoxy or ethoxy group.
  • Cl-6 alkylcarbonyl group refers to the aforementioned "Cl-6 alkyl group” bonded to a carbonyl group.
  • Examples thereof can include methylcarbonyl , ethylcarbonyl , n-propylcarbonyl , n-butylcarbonyl , isobutylcarbonyl , s-butylcarbonyl , tert- butylcarbonyl , n-pentylcarbonyl , isopentylcarbonyl ,
  • the Cl-6 alkylcarbonyl group is preferably an alkylcarbonyl group having 1 to 3 carbon atoms, most preferably a
  • cycloalkylcarbonyl group refers to the aforementioned "C3-8 cycloalkyl group" bonded to a carbonyl group.
  • Examples thereof can include cyclopropylcarbonyl,
  • C6-10 arylcarbonyl group refers to the aforementioned "C6-10 aryl group” bonded to a carbonyl group. Examples thereof can include phenylcarbony, indenylcarbony, and naphthylcarbony groups.
  • the "4- to 7-membered saturated heterocyclylcarbonyl group containing one or two heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur” refers to the aforementioned "4- to 7-membered saturated heterocyclyl group containing one or two heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur" bonded to a carbonyl group.
  • Examples thereof can include morpholinylcarbonyl , thiomorpholinylcarbonyl , pyrrolidinylcarbonyl , pyrrolinylcarbonyl ,
  • heteroatoms which may be the same or different, selected from nitrogen, oxygen, and sulfur
  • Examples thereof can include the groups listed as the examples of the aforementioned "4- to 7-membered saturated heterocyclylcarbonyl group containing one or two heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur", such as furylcarbonyl , thienylcarbonyl , pyrrolylcarbonyl , azepinylcarbonyl , pyrazolylcarbonyl , imidazolylcarbonyl , oxazolylcarbonyl , oxadiazolylcarbonyl , isoxazolylcarbonyl , thiazolylcarbonyl , isothiazolylcarbonyl , 1,2,3- oxadiazolylcarbonyl , triazolylcarbonyl , t
  • the "Cl-6 alkoxycarbonyl group” refers to the aforementioned "Cl-6 alkoxy group" bonded to a carbonyl group.
  • Examples thereof can include linear or branched alkoxycarbonyl groups each having 1 to 6 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl , n-propoxycarbonyl , isopropoxycarbonyl , n-butoxycarbonyl , isobutoxycarbonyl , s-butoxycarbonyl , tert-butoxycarbonyl , n-pentoxycarbonyl , isopentoxycarbonyl ,
  • the Cl-6 alkoxycarbonyl group is preferably a methoxycarbonyl or ethoxycarbonyl group.
  • cycloalkoxycarbonyl group refers to the aforementioned "C3-8 cycloalkyl group” bonded to a carbonyl group via an oxygen atom. Examples thereof can include
  • the "4- to 7-membered saturated heterocyclyloxycarbonyl group containing one or two heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur" refers to the aforementioned "4- to 7-membered saturated
  • heteroatoms which may be the same or different, selected from nitrogen, oxygen, and sulfur" bonded to a carbonyl group via an oxygen atom.
  • heteroatoms which may be the same or different, selected from nitrogen, oxygen, and sulfur bonded to a carbonyl group via an oxygen atom. Examples thereof can include oxetanyloxycarbonyl , pyrrolidinyloxycarbonyl ,
  • arylaminocarbonyl group refers to the aforementioned "C6-10 aryl group” bonded to a carbonyl group via an amino group. Examples thereof can include
  • the C6-10 arylaminocarbonyl group is preferably a
  • the "3- to 10-membered heterocyclylaminocarbonyl group containing one or two heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur" refers to the
  • heteroatoms which may be the same or different, selected from nitrogen, oxygen, and sulfur
  • Examples thereof can include such as furylaminocarbonyl ,
  • pyridazinylaminocarbonyl pyrimidinylaminocarbonyl , pyrazinylaminocarbonyl groups, oxetanylaminocarbonyl , pyrrolidinylaminocarbonyl , piperidinylaminocarbonyl , tetrahydrofurany1aminocarbonyl and
  • aminocarbonyloxy group refers to the aforementioned “aminocarbonyl group” bonded to an oxygen atom.
  • the "4- to 7-membered saturated heterocyclylcarbonyloxy group containing one or two heteroatoms, which may be the same or different, selected from nitrogen, oxygen, and sulfur" refers to the aforementioned "4- to 7-membered saturated
  • heteroatoms which may be the same or different, selected from nitrogen, oxygen, and sulfur" bonded to an oxygen atom.
  • heteroatoms which may be the same or different, selected from nitrogen, oxygen, and sulfur" bonded to an oxygen atom.
  • examples thereof can include morpholinylcarbonyloxy, thiomorpholinylcarbonyloxy, pyrrolidinylcarbonyloxy, pyrrolinylcarbonyloxy,
  • the "halogeno group” refers to a fluoro, chloro, bromo, or iodo group.
  • the halogeno group is preferably a fluoro, chloro, or bromo group.
  • R 1 of the present invention is a
  • R 2 of the present invention is a 3- to 10-membered heterocyclyl group containing one nitrogen, a Cl-6 alkylcarbonyl group (wherein the alkylcarbonyl group is optionally substituted by a hydroxy group, a Cl-6 alkoxy group, a 4- to 7-membered saturated heterocyclyl group containing one or two heteroatoms, which may be the same or different, selected from nitrogen and oxygen, or an aminocarbonyloxy group substituted by one Cl-6 alkyl groups), a Cl-6 alkoxycarbonyl group (wherein the alkylcarbonyl group is optionally substituted by a hydroxy group, a Cl-6 alkoxy group, a 4- to 7-membered saturated heterocyclyl group containing one or two heteroatoms, which may be the same or different, selected from nitrogen and oxygen, or an aminocarbonyloxy group substituted by one Cl-6 alkyl groups), a Cl-6 alkoxycarbonyl group (wherein the
  • alkoxycarbonyl group is optionally substituted by a hydroxy group or a Cl-6 alkoxy group) , an aminocarbonyl group (wherein the aminocarbonyl group is optionally substituted by one or two groups, which may be the same or different, each optionally substituted by Cl-6 alkyl groups), 3- to 10-membered heterocyclylcarbonyl group containing one nitrogen, 4- to 7-membered saturated heterocyclylcarbonyl group containing one or two
  • heteroatoms which may be the same or different, selected from nitrogen and oxygen, 3- to 10-membered
  • heterocyclylaminocarbony group containing one nitrogen or 4- to 7-membered saturated heterocyclyloxycarbonyl group containing one oxygen
  • R 3 and R 4 of the present invention are the same or different and each represent a hydrogen atom or a Cl-6 alkyl group, or the Cl-6 alkyl groups of R 3 and R 4 are bonded to each other to form a 3- to 6-membered saturated carbocyclic ring.
  • invention is a hydrogen atom.
  • R 7 of the present invention is a
  • each R 8 of the present invention which may be the same or different, represents a Cl-6 alkoxy group or a halogeno group.
  • the compound represented by the general formula (I) of the present invention can form a salt with a base.
  • a salt with a base is included in the scope of the present invention.
  • the salt with a base can include: alkali metal salts such as lithium salt, sodium salt, potassium salt, and cesium salt; alkaline earth metal salts such as magnesium salt, calcium salt, and barium salt; inorganic nitrogen compound salts such as ammonium salt and hydrazine salt; primary amine salts such as methylamine salt, ethylamine salt, n-propylamine salt, isopropylamine salt, n-butylamine salt,
  • tert-butylamine salt secondary amine salts such as dimethylamine salt, diethylamine salt, diisopropylamine salt, pyrrolidine salt, piperidine salt, and morpholine salt; tertiary amine salts such as triethylamine salt and N-methylmorpholine salt; and aromatic amine salts such as pyridine salt, 4- (N, N-dimethylamino ) pyridine salt, imidazole salt, and 1-methylimidazole salt.
  • the salt is preferably an alkali metal salt, most preferably sodium salt or potassium salt.
  • the compound represented by the general formula (I) of the present invention can form any ratio of a salt with a base.
  • the respective salts with bases or mixtures thereof are included in the scope of the present invention.
  • the compound represented by the general formula (I) of the present invention can form an acid-addition salt, depending on its substituent. Such an acid-addition salt is included in the scope of the present invention.
  • the compound represented by the general formula (I) of the present invention can form any ratio of an acid-addition salt, depending on its substituent.
  • the respective acid- addition salts e.g., monoacid salt and hemi-acid salt
  • mixtures thereof are included in the salt of the present invention.
  • acceptable salt thereof can form an anhydrate, a hydrate, or a solvate.
  • the respective forms or mixtures thereof are included in the scope of the present invention.
  • pharmacologically acceptable salt thereof has at least one asymmetric center, carbon-carbon double bond, axial chirality, tautomerism, or the like, optical isomers
  • acceptable salt thereof can form an isotopic compound by the replacement of one or more atoms constituting the compound or the salt with isotopes at nonnatural ratios.
  • the isotopes can be radioactive or nonradioactive.
  • Examples thereof include deuterium ( 2 H; D) , tritium
  • the radioactive or nonradioactive isotopic compound may be used as a pharmaceutical for the
  • a reagent for research e.g., a reagent for assay
  • a diagnostic agent e.g., a diagnostic imaging agent
  • the present invention encompasses these radioactive or nonradioactive isotopic compounds.
  • the compound represented by the general formula (I) of the present invention can be produced by, for example, the following method:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , m, and X are as defined in the formula (I) ;
  • L 1 represents a halogeno group or an amino group (wherein the amino group is optionally substituted by Cl-6 alkoxycarbonyl group) , and is preferably a bromo group;
  • L 2 represents a halogeno group and is preferably a fluoro group or a chloro group.
  • a compound serving as a reactive substrate in the reaction of each step in the method A has a group inhibiting the reaction of interest, such as an amino group, a hydroxy group, or a carbonyl group, an amino group, a hydroxy group, or a carbonyl group, an amino group, a hydroxy group, or a carbonyl group, an amino group, a hydroxy group, or a carbonyl group, an amino group, a hydroxy group, or a carbonyl group, an amino group inhibiting the reaction of interest, such as an amino group, a hydroxy group, or a carbonyl group
  • a protective group may be introduced to the functional group and the introduced protective group may be removed, if necessary.
  • a protective group is not particularly limited as long as the protective group is one usually used.
  • the protective group can be a
  • the solvent for use in the reaction of each step in the method A is not particularly limited as long as the solvent partially dissolves starting materials without inhibiting the reaction.
  • the solvent is selected from, for example, the following solvent group: aliphatic hydrocarbons such as hexane, pentane, heptane, petroleum ether, and cyclohexane ; aromatic hydrocarbons such as toluene, benzene, and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon
  • ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone ; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, and diethyl carbonate; nitriles such as acetonitrile, propionitrile, butyronitrile, and isobutyronitrile ;
  • organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, and pentafluoropropionic acid
  • alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-l-propanol, and 2-methyl-2-propanol
  • amides such as formamide
  • N-methylpyrrolidone N, N ' -dimethylpropyleneurea, and hexamethylphosphortriamide
  • sulfoxides such as dimethyl sulfoxide and sulfolane
  • water and mixtures thereof.
  • the acid for use in the reaction of each step in the method A mentioned below is not particularly limited as long as the acid does not inhibit the reaction.
  • the acid is selected from the following acid group: inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, and nitric acid; organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, and
  • organic sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, and camphorsulfonic acid.
  • the base for use in the reaction of each step in the method A mentioned below is not particularly limited as long as the base does not inhibit the reaction.
  • the base is selected from the following base group: alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium
  • alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide
  • alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide
  • alkali metal phosphates such as sodium phosphate and potassium phosphate
  • alkali metal hydrides such as lithium hydride, sodium hydride, and potassium hydride
  • alkali metal amides such as lithium amide, sodium amide, and potassium amide
  • metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide
  • lithium amides such as lithium diisopropylamide (LDA) , lithium cyclohexylisopropylamide, and lithium tetramethylpiperazide
  • alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide
  • alkaline earth metal hydroxides such as calcium hydroxide and bar
  • silylamides such as lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, and potassium
  • alkyllithiums such as methyllithium, n-butyllithium, sec-butyllithium, and tert-butyllithium
  • alkyl magnesium halides such as methyl magnesium chloride, methyl magnesium bromide, methyl magnesium iodide, ethyl magnesium chloride, ethyl
  • reaction temperature differs
  • reaction time differs depending on solvents, starting materials, reagents, etc.
  • the compound of interest of each step is isolated from the reaction mixture according to a routine method.
  • the compound of interest is
  • the compound of interest of each step may be used directly in the next reaction without being purified.
  • optical isomers can be resolved by resolution using a chiral column.
  • Step A-l is the step of reductive condensation of compound (1) and compound (2) to produce compound (3) .
  • the compound (1) and (2) are known in the art or is easily obtained from a compound known in the art.
  • the method for reductive condensation of a carbonyl compound and an amine differs depending on the type of the carbonyl compound and the amine can be generally carried out by a method well known in the techniques of organic synthetic chemistry, for example, a method described in Comprehensive Organic Transformations
  • the method is preferably a method using a combination of a reducing agent and an additive.
  • Examples of the reducing agent used can include:
  • boran tetrahydrofuran complex boran pyridine complex, boran dimethylsulfide complex, lithium borohydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum hydride,
  • the reducing agent is preferably sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride.
  • Examples of the additive used can include: acetic acid, propionic acid, trifluoroacetic acid, benzoic acid, methanesulfonic acid, ethanesulfounic acid,
  • 10-camphorsulfonic acid hydrogen chloride, hydrogen bromide, sulfuric acid, anhydrous magnesium sulfate and anhydrous sodium sulfate.
  • the method is preferably a method using a
  • solvent used can include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated
  • the solvent is preferably a halogenated hydrocarbon, more preferably methylene chloride .
  • the reaction temperature is preferably 0°C to 100°C, more preferably room temperature.
  • the reaction time is preferably 15 minutes to
  • Step A-2 is the step of reacting the compound (3) obtained in the step A-l with allylating agent in the presence of a base to produce compound (4) .
  • the method for allylation of a nitrogen atom of a cyclic amine differs depending on the type of the amine can be generally carried out by a method well known in the techniques of organic synthetic chemistry, for example, a method described in T. W. Greene,
  • the method is preferably a method using an allylating agent in the presence of a base.
  • allylating agent used can include allylchloride, allylbromide, allyliodide, allyl acetate, allyl methanesulfonate, allyl benzenesulfonate and allyl p-toluenesulfonate .
  • the allylating agent is preferably allylbromide .
  • Examples of the base used can include alkali metal carbonates, alkali metal bicarbonates , alkali metal hydrides, lithium amides, alkali metal silylamides, alkyllithiums , and organic amines.
  • the base is
  • an alkali metal carbonate preferably potassium carbonate or cesium carbonate.
  • solvent used can include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated
  • the solvent is preferably a nitrile and an amide, more preferably acetonitrile or N, N-dimethylformamide .
  • the reaction temperature is preferably 0°C to 120°C, more preferably room temperature to 80°C.
  • the reaction time is preferably 30 minutes to
  • Step A-3 is the step of intramolecularly cyclizing the compound (4) obtained in the step A-2 in the presence of a base to produce compound (5) .
  • the compound (5) of interest of this step can also be converted, if necessary, to another compound (5) of interest through N-Boc amide forming reaction on the halogeno group of L 1 .
  • step A-3 comprises:
  • Step A-3-1 is the step of intramolecularly cyclizing the compound (4) obtained in the step A-2 in the presence of a base to produce compound (5);
  • step A-3-2 the step of converting the bromo group of the compound obtained in the step A-3-1 to a N-Boc amide group using a metal catalyst in the presence of a base to produce another compound (5);
  • step A-3-3 the step of removal of allyl group of the amino group of the compound obtained in the
  • step A-3-2 to produce another compound (5)
  • step A-3-4 the step of modification reaction of the amino group of the compound obtained in the
  • step A-3-3 to produce another compound (5) .
  • Examples of the base used can include alkali metal carbonates, alkali metal bicarbonates , alkali metal hydrides, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal alkoxides, lithium amides, alkali metal silylamides, and organic amines.
  • the base is preferably an alkali metal hydride, more preferably sodium hydride.
  • Examples of the solvent used can include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, nitriles, ketones, and amides.
  • the solvent is preferably an ether or an amide, more preferably 1 , 2-dimethoxyethane or
  • the reaction temperature is preferably 0°C to 100°C.
  • the reaction time is preferably 30 minutes to
  • the method for converting the bromo group on the aromatic ring to a N-Boc amide group is not particularly limited as long as the method does not influence the other parts of the compound. This method can be carried out according to a method well known in the techniques of organic synthetic chemistry, for example, a method
  • the metal catalyst used is preferably a combination of tris (dibenzylideneacetone ) dipalladium ( 0 ) chloroform complex and 9, 9-dimethyl-4 , 5- bis (diphenylphosphino) xanthene (Xantphos (TM) ) or a
  • the base used is preferably an alkali metal
  • an alkali metal phosphate or an alkali metal alkoxide, more preferably potassium carbonate, cesium carbonate, potassium phosphate, or sodium tert-butoxide .
  • solvent used can include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated
  • the solvent is preferably an aromatic hydrocarbon, an ether, a nitrile, or an amide, more preferably toluene, 1,4-dioxane, acetonitrile, or N, N-dimethylformamide .
  • the reaction temperature is preferably room
  • the reaction time is preferably 1 hour to 48 hours.
  • the method for removal of allyl group on amino group is not particularly limited as long as the method does not influence the other parts of the compound.
  • This method can be carried out according to a method well known in the techniques of organic synthetic chemistry, for example, a method described in T. W. Greene,
  • the method is preferably a method using a metal catalyst in the presence of a nucleophile.
  • the metal catalyst used is preferably tetrakis ( triphenylphsphine ) palladium ( 0 ) or a combination of tris (dibenzylideneacetone ) dipalladium ( 0 ) chloroform complex and triphenylphosphine .
  • Example of the nucleophile used can include
  • N, N-dimethylbarbituric acd N, N-dimethylbarbituric acd.
  • N, N-dimethylbarbituric acd preferably N, N-dimethylbarbituric acd.
  • solvent used can include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated
  • the solvent is preferably a
  • halogenated hydrocarbons more preferably methylene chloride .
  • the reaction temperature is preferably 0°C to room temperature .
  • the reaction time is preferably 15 minutes to
  • the reaction for converting the compound (5) of interest obtained in this step to another compound (5) of interest through modification on the nitrogen atom of the amino group is not particularly limited as long as the reaction does not influence the other parts of the compound.
  • This reaction can be carried out by, for example, a method described in Comprehensive Organic Transformations (Second Edition, 1999, John Wiley & Sons, Inc., pp. 789-792, 1941-1949, 1953-1954, 1957-1958,
  • Step A-4 is the step of reacting the compound (5) obtained in the step A-3-4 with compound (6) in the presence of a base to produce compound (I) .
  • the compound (6) is known in the art or is easily obtained from a compound known in the art.
  • the compound (I) of interest of this step can also be converted, if necessary, to another compound (I) of interest through deprotection reaction.
  • the reaction for converting the obtained compound (I) of interest to another compound (I) of interest by the removal of the protective group is not particularly limited as long as the reaction does not influence the other parts of the compound. This reaction can be carried out according to a routine method, for example, a method described in T . W. Greene,
  • step A-4 comprises:
  • step A-4-1 the step of removing of the N-Boc group of the compound (5) obtained in the step A-3-4 into an amino group
  • step A-4-2) the step of reacting the compound obtained in the step A-4-1 with compound (6) in the presence of a base to produce compound (I) .
  • the method for removing of the N-Boc group is not particularly limited as long as the method does not influence the other parts of the compound. This method can be generally carried out by a method well known in the techniques of organic synthetic chemistry, for
  • the method is preferably a method using an acid.
  • Examples of the acid for use in the removing of the N-Boc group can include inorganic acids and organic acids.
  • the acid is preferably hydrochloric acid.
  • the solvent for use in the removing of the N-Boc group is not particularly limited as long as the solvent is inert to this reaction.
  • the solvent can include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, nitriles, ketones, amides, and mixtures thereof.
  • the solvent is preferably an alcohol, more preferably
  • N-Boc group is preferably 0°C to 60°C.
  • the reaction time in the removing of the N-Boc group is preferably 10 minutes to 24 hours.
  • Examples of the base used can include alkali metal carbonates, alkali metal bicarbonates , alkali metal hydrides, alkali metal hydroxides, alkali metal alkoxides, lithium amides, alkali metal silylamides, and organic amines.
  • the base is preferably an organic amine, more preferably pyridine.
  • solvent used can include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated
  • hydrocarbons ethers, esters, nitriles, ketones, and amides.
  • the solvent may not be used.
  • the solvent is not used.
  • the reaction temperature is preferably 0°C to 100°C, more preferably room temperature to 80°C.
  • the reaction time is preferably 15 minutes to
  • the reaction for converting the obtained compound (I) of interest obtained in this step to another compound (I) of interest by the removal of the protective group is not particularly limited as long as the reaction does not influence the other parts of the compound.
  • This reaction can be carried out according to a routine method, for example, a method described in T . W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, Fifth Edition, 2014, John Wiley & Sons, Inc.
  • the compound (I) can also be produced through the reaction of the compound (5) with the following compound (7) :
  • This method can be carried out according to a method well known in the techniques of organic synthetic chemistry, for
  • the metal catalyst used is preferably a combination of copper(I) iodide and N, N 1 -dimethylethane-1 , 2-diamine, and a combination of copper (I) iodide and trans-N, N 1 - dimethyleyelohexane-1 , 2-diamine .
  • the base used is preferably an alkali metal
  • an alkali metal phosphate or an alkali metal alkoxide, more preferably potassium carbonate or cesium carbonate .
  • solvent used can include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated
  • the solvent is preferably an aromatic hydrocarbon, an ether, a nitrile, or an amide, more preferably xylene, 1,4-dioxane, acetonitrile, or N, N-dimethylformamide .
  • the reaction temperature is preferably room
  • the reaction time is preferably 1 hour to 48 hours.
  • the compound or the salt can be administered alone (i.e., as a bulk) or can be administered orally as an appropriate pharmaceutically acceptable preparation such as a tablet, a capsule, granules, a powder, or a syrup or parenterally as an appropriate pharmaceutically acceptable preparation such as an injection, a suppository, or a patch
  • compositions are produced by well-known methods using additives such as excipients, binders, disintegrants , lubricants, emulsifiers, stabilizers, corrigents, diluents, solvents for injections, oleaginous bases, and water-soluble bases.
  • additives such as excipients, binders, disintegrants , lubricants, emulsifiers, stabilizers, corrigents, diluents, solvents for injections, oleaginous bases, and water-soluble bases.
  • excipients can include organic excipients and inorganic excipients.
  • organic excipients can include: sugar derivatives such as lactose, saccharose, glucose, mannitol, and sorbitol; starch derivatives such as corn starch, potato starch, ⁇ -starch, dextrin, and carboxymethyl starch; cellulose derivatives such as crystalline cellulose,
  • excipients can include: light anhydrous silicic acid and silicate derivatives such as synthetic aluminum silicate and calcium silicate; phosphates such as calcium
  • phosphate such as calcium sulfates.
  • sulfates such as calcium sulfates.
  • binders can include: the excipients listed above; gelatin; polyvinylpyrrolidone; and
  • disintegrants can include: the excipients listed above; chemically modified starch or cellulose derivatives such as croscarmellose sodium and carboxymethyl starch sodium; and cross-linked
  • lubricants can include: talc;
  • stearic acid stearic acid
  • stearic acid metal salts such as calcium stearate and magnesium stearate
  • colloidal silica waxes such as bees wax and spermaceti
  • boric acid glycol
  • D L leucine
  • carboxylic acids such as fumaric acid and adipic acid
  • carboxylic acid sodium salts such as sodium benzoate
  • sulfates such as sodium sulfate
  • sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate
  • silicic acids such as silicic anhydride and silicic acid hydrate
  • starch derivatives listed as the excipients.
  • emulsifiers can include: colloidal clay such as bentonite and veegum; anionic surfactants such as sodium lauryl sulfate and calcium stearate;
  • cationic surfactants such as benzalkonium chloride
  • nonionic surfactants such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, and sucrose fatty acid ester.
  • stabilizers can include:
  • p-hydroxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol , benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal;
  • corrigents can include sweeteners, acidulants, and flavors usually used.
  • diluents can include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters.
  • Examples of the solvents for injections can include water, ethanol, and glycerin.
  • oleaginous bases can include cacao butter, laurin butter, coconut oil, palm kernel oil, camellia oil, liquid paraffin, white petrolatum, purified lanoline, glycerin monostearate, polyoxyethylene
  • water-soluble bases can include glycerin, polyethylene glycol, ethanol, and purified water .
  • pharmacologically acceptable salt thereof serving as an active ingredient differs depending on the symptoms and age of a patient, etc.
  • the single dose thereof is
  • 0.001 mg/kg preferably 0.01 mg/kg as the lower limit and 10 mg/kg (preferably 1 mg/kg) as the upper limit for oral administration and 0.001 mg/kg (preferably 0.01 mg/kg) as the lower limit and 10 mg/kg (preferably 1 mg/kg) as the upper limit for parenteral administration and can be administered once to six times a day according to the symptoms.
  • the compound of the present invention can be used in combination with any of various therapeutic or
  • the compound of the present invention and the agent may be administered simultaneously, separately but continuously, or at the desired time interval.
  • administered simultaneously may be formulated as a combination drug or formulated as separate preparations.
  • the oxazepine compound or the pharmacologically acceptable salt thereof, which is the compound of the present invention, has an excellent TNAP inhibitory effect and is useful as a therapeutic or prophylactic agent for pseudoxanthoma elasticum (PXE) , generalized arterial calcification of infancy (GACI),
  • CMD craniometaphyseal dysplasia
  • OYL yellow ligament
  • ACDC arterial calcification due to deficiency of CD73
  • arthrosis deformans
  • osteoarthritis ankylosis of the joint
  • IIAC idiopathic infantile arterial calcification
  • AS ankylosing spondylitis
  • TC tumoral calcinosis
  • POH progressive osseous heteroplasia
  • Keutel syndrome vascular calcification associated with chronic renal failure
  • FOP progressiva
  • CUA calcific uremic arteriopathy
  • Kawasaki disease calcification due to obesity and aging, tibial arterial calcification, bone metastasis, prosthetic calcification, Paget' s disease, or peritoneal calcification.
  • the compound of the present invention has low toxicity and excellent safety and as such, is very useful as a pharmaceutical .
  • TLC chromatography
  • chromatography was used as a developing solvent; and a UV detector or a chromogenic method using a coloring agent (e.g., a ninhydrin coloring solution, an
  • anisaldehyde coloring solution an ammonium
  • phosphomolybdate coloring solution a cerium ammonium nitrate (CAM) coloring solution, or an alkaline
  • silica gel 60 N 40-50 ⁇
  • Chromatorex NH 200-350 mesh
  • nuclear magnetic resonance (1 ⁇ 2 NMR) spectra were indicated by chemical shift ⁇ values (ppm) determined with tetramethylsilane as a standard. Splitting patterns were indicated by s for singlet, d for doublet, t for triplet, q for quartet, m for multiplet, and br for broad.
  • Mass spectrometry hereinafter,
  • EI electron spray ionization
  • EI electron spray ionization
  • APCI atmospheric pressure chemical ionization
  • ES/APCI electron spray atmospheric pressure chemical ionization
  • FAB fast atom bombardment
  • reaction solution and reaction were carried out at room temperature unless the temperature is otherwise specified.
  • triacetoxyborohydride (7.79 g, 36.8 mmol) was added thereto at room temperature, and the mixture was stirred at the same temperature as above for 1 hour.
  • the organic layer was dried over anhydrous sodium sulfate.
  • the mixture was diluted by
  • Example 9a 0.95 mmol obtained in Example (9a) were added at room temperature, and the mixture was stirred at the same temperature as above for 3 hours and 20 minutes. The mixture was diluted by addition of ethyl acetate, the organic layer was washed with a saturated aqueous
  • Example 10a 0.95 mmol obtained in Example (10a) were added at room temperature, and the mixture was stirred at the same temperature as above for 4 hours .
  • Example (11a) was added at room temperature, and the mixture was stirred at 80°C for 40 minutes in an oil bath. After cooling, the mixture was concentrated under reduced pressure, the residue was purified in an automatic
  • Example 13 (33.4 mg, 0.069 mmol) obtained in Example 13 in ethanol (0.7 mL) , a solution of 0.5 N potassium hydroxide in ethanol (0.155 mL, 0.078 mmol) was added at room temperature
  • Example (11a) was added at room temperature, and the mixture was stirred at 80°C for 70 minutes in an oil bath. After cooling, the mixture was concentrated under reduced pressure, the residue was purified in an automatic
  • N, N-dimethylformamide (5 mL) was stirred under nitrogen atmosphere at 100°C for 9 hours in an oil bath. The mixture was cooled to room temperature, and an insoluble material was filtered off through pad of Celite 545 (R) . The residue was washed with ethyl acetate, and the
  • the concentrated mixture was diluted by addition of a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate three times.
  • the organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. To obtained solid, diisopropyl ether was added, the
  • Example (18e) obtained by production according to the method described in Example (le) using methyl ( 3R) -7- [ ( ert- butoxycarbonyl ) amino] -3-methyl-2, 3-dihydropyrido [3, 2- f] [ 1 , 4 ] oxazepine-4 ( 5H) -carboxylate (162 mg, 0.48 mmol) obtained in Example (18e) as a starting material.
  • Example (18d) (100 mg, 0.36 mmol) obtained in Example (18d) and a crude product of 1- ⁇ [ (propan-2-yloxy) carbonyl ] oxy jpyrrolidine- 2,5-dione (approximately 87% content, 106 mg, 0.46 mmol) obtained in Example (19a) as starting materials.
  • Example (20b) as a starting material.
  • N, N ' -carbonyldiimidazole (85.3 mg, 0.51 mmol) was added at room temperature, and the mixture was stirred under reflux for 2 hours and 15 minutes.
  • the mixture was cooled to room temperature, a 2.0 mol/L solution of methylamine in tetrahydrofuran (0.40 mL, 0.8 mmol) was added thereto, and the mixture was stirred at room temperature for 17 hours.
  • the mixture was diluted by addition of a 1.0 mol/L hydrochloric acid, followed by extraction with ethyl acetate.
  • the organic layer was washed with a saturated aqueous solution of sodium bicarbonate, and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified in an automatic chromatography apparatus (ethyl
  • the mixture was diluted by addition of a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate.

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Abstract

La présente invention concerne un composé ou un sel pharmacologiquement acceptable de celui-ci ayant une excellente activité inhibitrice de phosphatase alcaline non spécifique tissulaire. La présente invention concerne un composé représenté par la formule générale (I) ou un sel pharmacologiquement acceptable de celui-ci.
PCT/US2017/068323 2016-12-23 2017-12-22 Dérivés d'oxazépine ayant une activité inhibitrice de tnap WO2018119449A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2020514268A (ja) * 2016-12-23 2020-05-21 第一三共株式会社 Ｔｎａｐ阻害活性を有するスルホンアミド化合物

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009017863A2 (fr) 2007-05-08 2009-02-05 Burnham Institute For Medical Research Inhibiteurs de la phosphatase alcaline non spécifiques à un tissu et leurs utilisations pour traiter une calcification vasculaire
WO2013126608A1 (fr) 2012-02-22 2013-08-29 Sanford-Burnham Medical Research Institute Composés sulfonamides et leurs utilisations en tant qu'inhibiteurs de tnap
WO2017007943A1 (fr) * 2015-07-08 2017-01-12 Daiichi Sankyo Company, Limited Dérivés de pyrido-oxazinone utilisé comme inhibiteurs de tnap

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009017863A2 (fr) 2007-05-08 2009-02-05 Burnham Institute For Medical Research Inhibiteurs de la phosphatase alcaline non spécifiques à un tissu et leurs utilisations pour traiter une calcification vasculaire
WO2013126608A1 (fr) 2012-02-22 2013-08-29 Sanford-Burnham Medical Research Institute Composés sulfonamides et leurs utilisations en tant qu'inhibiteurs de tnap
US20150011551A1 (en) 2012-02-22 2015-01-08 Sanford- Burnham Medical Reseach Institute Sulfonamide compounds and uses as tnap inhibitors
WO2017007943A1 (fr) * 2015-07-08 2017-01-12 Daiichi Sankyo Company, Limited Dérivés de pyrido-oxazinone utilisé comme inhibiteurs de tnap

Non-Patent Citations (25)

* Cited by examiner, † Cited by third party
Title
"Comprehensive Organic Transformations", 1999, JOHN WILEY SONS, INC., pages: 789 - 792,1941-1949,1953-1954,1957-1958
"Comprehensive Organic Transformations", 1999, JOHN WILEY SONS, INC., pages: 835 - 846
A. P. DISHINGTON; P. D. JOHNSON; J. G. KETTLE, TETRAHEDRON LETTERS, vol. 45, 2004, pages 3733
BIOORG. MED. CHEM. LETT., vol. 19, 2009, pages 222 - 225
BIOORG. MED. CHEM., vol. 21, 2013, pages 7981 - 7987
CLIN. KIDERY. J., vol. 7, 2014, pages 167 - 173
D. K. LUCI; J. B. JAMESON; A. YASGAR; G. DIAZ; N. JOSHI; A. KANTZ; K. MARKHAM; S. PERRY; N. KUHN; J. YEUNG, JOURNAL OF MEDICINAL CHEMISTRY, vol. 57, 2014, pages 495
EUR. HEART. J., vol. 35, 2014, pages 1515 - 1525
INT. J. NEPHROL. RENOVASC. DIS., vol. 7, 2014, pages 161 - 168
J. AM. SOC. NEPHROL., vol. 15, 2004, pages 1392 - 1401
J. BONE MINER RES, vol. 22, 2007, pages 1700 - 1710
J. BONE MINER RES, vol. 24, 2006, pages 176 - 181
J. BONE MINER RES, vol. 30, 2015, pages 824 - 836
J. BONE MINER RES, vol. 7, 2013, pages 1587 - 1598
J. HISTOCHEM. CYTOCHEM., vol. 50, 2002, pages 333 - 340
J. MED. CHEM., vol. 52, 2009, pages 6919 - 6925
P. G. M. WUTS: "Protective Groups in Organic Synthesis", 2014, JOHN WILEY & SONS, INC
RUSSELL DAHL ET AL: "Discovery and validation of a series of aryl sulfonamides as selective inhibitors of tissue-nonspecific alkaline phosphatase (TNAP)", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, vol. 52, no. 21, 12 November 2009 (2009-11-12), pages 6919 - 6925, XP002669256, ISSN: 0022-2623, DOI: 10.1021/JM900383S *
S. BHAGWANTH; A. G. WATERSON; G. M. ADJABENG; K. R. HORNBERGER, JOURNAL OF ORGANIC CHEMISTRY, vol. 74, 2009, pages 4634
T. W. GREENE; P. G. M. WUTS: "Protective Groups in Organic Synthesis", 2014, JOHN WILEY & SONS, INC
T. W. GREENE; P. G. M. WUTS: "Protective Groups in Organic Synthesis", 2014, JOHN WILEY & SONS, INC., pages: 1031 - 1034
T. W. GREENE; P. G. M. WUTS: "Protective Groups in Organic Synthesis", 2014, JOHN WILEY SONS, INC., pages: 1031 - 1034
T. W. GREENE; P. G. M. WUTS: "Protective Groups in Organic Synthesis", 2014, JOHN WILEY SONS, INC., pages: 930 - 946
W. DENG; L. LIU; C. ZHANG; M. LIU; Q.-X. GUO, TETRAHEDRON LETTERS, vol. 46, 2005, pages 7295
X. WANG; A. GURAM; M. RONK; J. E. MILNE; J. S. TEDROW; M. M. FAUL, TETRAHEDRON LETTERS, vol. 53, 2012, pages 7

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2020514268A (ja) * 2016-12-23 2020-05-21 第一三共株式会社 Ｔｎａｐ阻害活性を有するスルホンアミド化合物
JP7005629B2 (ja) 2016-12-23 2022-01-21 第一三共株式会社 Ｔｎａｐ阻害活性を有するスルホンアミド化合物

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