WO2020158870A1 - Agent thérapeutique pour le traitement de la maladie de parkinson - Google Patents

Agent thérapeutique pour le traitement de la maladie de parkinson Download PDF

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WO2020158870A1
WO2020158870A1 PCT/JP2020/003462 JP2020003462W WO2020158870A1 WO 2020158870 A1 WO2020158870 A1 WO 2020158870A1 JP 2020003462 W JP2020003462 W JP 2020003462W WO 2020158870 A1 WO2020158870 A1 WO 2020158870A1
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hydrogen atom
alkyl group
parkinson
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匡彦 増野
知之 大江
恭子 高橋
大輔 安田
嘉一 田▲崎▼
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学校法人慶應義塾
国立大学法人旭川医科大学
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Priority to JP2020568598A priority Critical patent/JP7402467B2/ja
Publication of WO2020158870A1 publication Critical patent/WO2020158870A1/fr

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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
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    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
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    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
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    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/82—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to a therapeutic agent for Parkinson's disease and the like.
  • the present invention also relates to novel compounds useful as therapeutic agents for Parkinson's disease and the like.
  • Parkinson's disease It is said that more than 100,000 patients with Parkinson's disease exist in Japan, but the current drug therapy is mainly symptomatic therapy represented by dopamine replacement therapy. It is considered that the cause of Parkinson's disease is a lack of dopamine due to a decrease in nerve cells that produce dopamine, but there is no one on the market as a fundamental therapeutic agent. Therefore, it is desired to develop a drug that can be a fundamental therapeutic drug for Parkinson's disease. In addition, such a fundamental therapeutic agent for Parkinson's disease is expected to be utilized in the treatment of Parkinson's syndrome which exhibits the same symptoms as those in Parkinson's disease.
  • meloxicam which is an oxicam non-steroidal anti-inflammatory drug, has been reported to exhibit an MPP + -induced neuronal cell death inhibitory effect and a motor dysfunction reducing effect in MPTP-administered Parkinson's disease model mice (Non-Patent Documents 1 to 3). .. Therefore, meloxicam is considered to be a candidate drug such as a therapeutic drug for Parkinson's disease, but it also has a problem. For example, meloxicam has a strong COX inhibitory activity and causes side effects such as gastrointestinal disorders, so it is not desirable as a therapeutic agent for Parkinson's disease and the like.
  • a novel therapeutic agent for Parkinson's disease which can be a fundamental therapeutic agent for Parkinson's disease.
  • a therapeutic agent for Parkinson's disease may be useful as a therapeutic agent for Parkinson's syndrome or a pharmaceutical agent for protecting nerve cells.
  • one embodiment of the present invention aims to provide a novel compound useful as a therapeutic agent for Parkinson's disease and the like.
  • a pharmaceutical composition for treating Parkinson's disease or Parkinson's syndrome which comprises a compound represented by the formula (1), (2) or (8) or a pharmaceutically acceptable salt thereof.
  • -XY- is, -NR 3 -SO 2 -, - CR 4 R 5 -SO 2 -, - CR 4 R 5 -SO -, - CR 4 R 5 -S -, - SO 2 -CR 4 R 5 - , -SO-CR 4 R 5 -, -CR 4 R 5 -CR 6 R 7 -, or -NR 3 -CR 4 R 5 -
  • R 3 represents a hydrogen atom or an alkyl group
  • R 4 , R 5 , R 6 and R 7 each independently represent a hydrogen atom, a halogen atom or an alkyl group
  • Z represents O or S
  • R 8 represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, OH, NH 2 or CN
  • n represents an integer of 1 to 4
  • R 1 represents a group selected from the following
  • R 9 represents a hydrogen atom, a halogen atom, an
  • a pharmaceutical composition for protecting nerve cells comprising a compound represented by the formula (1), (2) or (8) or a pharmaceutically acceptable salt thereof.
  • -XY- is, -NR 3 -SO 2 -, - CR 4 R 5 -SO 2 -, - CR 4 R 5 -SO -, - CR 4 R 5 -S -, - SO 2 -CR 4 R 5 - , -SO-CR 4 R 5 -, -CR 4 R 5 -CR 6 R 7 -, or -NR 3 -CR 4 R 5 -
  • R 3 represents a hydrogen atom or an alkyl group
  • R 4 , R 5 , R 6 and R 7 each independently represent a hydrogen atom, a halogen atom or an alkyl group
  • Z represents O or S
  • R 8 represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, OH, NH 2 or CN, n represents an
  • [3]-XY- represents -NR 3 -SO 2 -, -CR 4 R 5 -SO 2 -, -SO 2 -CR 4 R 5 -, or -CR 4 R 5 -CR 6 R 7 -.
  • the compounds of the invention may have neuronal protective effects.
  • the compound of the present invention may improve symptoms in Parkinson's disease or Parkinson's syndrome, in particular, motor symptoms.
  • a pharmaceutical composition for treating Parkinson's disease or Parkinson's syndrome can be provided.
  • a pharmaceutical composition for protecting nerve cells can be provided.
  • the results of the control group, MPTP group, and evaluation compound group (IY-065 administered at 30 mg ⁇ 2 or IY-069 administered at 10 mg ⁇ 2) are shown. *: p ⁇ 0.05 It is a graph which shows the result of the Pole test using the MPTP induction Parkinson's disease model mouse. The results for the control group, MPTP group, and evaluation compound group (IY-053 administered at 10 mg ⁇ 2 or IY-060 administered at 10 mg ⁇ 2 or 30 mg ⁇ 2) are shown. ***: p ⁇ 0.001 It is a graph which shows the result of the Pole test using the MPTP induction Parkinson's disease model mouse.
  • the results of the control group, MPTP group, and evaluation compound group (10 mg ⁇ 1 administration or 7.5 mg ⁇ 2 administration of IY-053) are shown. ***: p ⁇ 0.001, **: p ⁇ 0.01 It is a graph which shows the result of the Pole test using the MPTP induction Parkinson's disease model mouse.
  • the results of the control group, MPTP group, and evaluation compound group (IY-067 administered at 30 mg ⁇ 2 or IY-068 administered at 30 mg ⁇ 2) are shown. **: p ⁇ 0.01, *: p ⁇ 0.05 It is a graph which shows the result of the Pole test using the MPTP induction Parkinson's disease model mouse.
  • the results for the control group, MPTP group, and evaluation compound group (3 mg ⁇ 2 administration or 10 mg ⁇ 2 administration of IY-093) are shown. ***: p ⁇ 0.001, **: p ⁇ 0.01
  • a pharmaceutical composition is a compound represented by the following formula (1), (2) or (8) or a pharmaceutically acceptable salt thereof (herein, these are referred to as “the present invention: Also referred to as a "compound”).
  • -XY- is, -NR 3 -SO 2 -, - CR 4 R 5 -SO 2 -, - CR 4 R 5 -SO -, - CR 4 R 5 -S -, - SO 2 -CR 4 R 5 - , -SO-CR 4 R 5 -, -CR 4 R 5 -CR 6 R 7 -, or -NR 3 -CR 4 R 5 -
  • R 3 represents a hydrogen atom or an alkyl group
  • R 4 , R 5 , R 6 and R 7 each independently represent a hydrogen atom, a halogen atom or an alkyl group
  • Z represents O or S
  • R 8 represents a hydrogen atom, a halogen atom, an alkyl
  • R 2 of the compound represented by the formula (1) and the compound represented by the formula (2) is a hydrogen atom
  • R 2 of the compound represented by the formula (1) and the compound represented by the formula (2) is a hydrogen atom
  • a high abundance ratio of either keto type or enol type can often occur, but a tautomeric organism is rarely present in the form of only keto type or enol type. Therefore, in the pharmaceutical composition of the present invention, the keto-type compound and the enol-type compound may exist in a mixed manner.
  • each R 8's when a plurality of R 8 's are present, each R 8's may be the same or different.
  • each R 9 may be the same or different.
  • the “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the “alkyl group” means a linear or branched, monovalent saturated hydrocarbon group.
  • the alkyl group for example, there may be mentioned C 1-12 alkyl group having 1 to 12 carbon atoms, but is not limited thereto.
  • the alkyl group can be a C 1-3 alkyl group C 1-6 alkyl group, or 1-3 carbon atoms having 1 to 6 carbon atoms.
  • alkoxy group means a group in which the alkyl group is bonded to an oxygen atom.
  • the alkoxy group for example, there may be mentioned C 1-12 alkoxy group having 1 to 12 carbon atoms, but is not limited thereto.
  • alkoxy groups may be C 1-3 alkoxy group C 1-6 alkoxy group, or 1 to 3 carbon atoms having 1 to 6 carbon atoms.
  • alkylcarbonyl group means a group in which the above alkyl group is bonded to a carbonyl group.
  • Alkyl group in the alkyl group is, for example, C 1-12 alkyl group having 1 to 12 carbon atoms, C 1-6 alkyl group having 1 to 6 carbon atoms, or C 1-3 alkyl group having 1 to 3 carbon atoms
  • the alkylcarbonyl group include groups such as acetyl group, propionyl group, n-butyryl group, isobutyryl group, valeryl group, pivaloyl group, and hexanoyl group.
  • the “alkyl group in which a hydrogen atom is substituted with 1 to 3 halogen atoms” means a group in which a hydrogen atom in the alkyl group is substituted with 1 to 3 halogen atoms.
  • -XY- is -NR 3 -SO 2 -, -CR 4 R 5 -SO 2 -, -SO 2 -CR 4 R 5 -, or -CR 4 R 5 -CR 6 R 7 - is preferred.
  • the compound having a structure represented by -XY- may be more useful in terms of neuronal cell protective effect, reduced COX inhibitory activity, and/or intracerebral transferability.
  • R 3 is preferably an alkyl group, more preferably a C 1-6 alkyl group, and further preferably a C 1-3 alkyl group. And particularly preferably a methyl group.
  • R 4 and R 5 are each independently a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom. And particularly preferably all are hydrogen atoms.
  • R 4 and R 5 are each independently a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom. And particularly preferably all are hydrogen atoms.
  • R 4 and R 5 are each independently a hydrogen atom, a halogen atom or an alkyl group, and more preferably hydrogen.
  • R 6 and R 7 are each independently a hydrogen atom or a halogen atom, more preferably a hydrogen atom or It is a fluorine atom, and particularly preferably both are hydrogen atoms.
  • R 8 is preferably a hydrogen atom, an alkyl group or an alkoxy group, more preferably a hydrogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group, and further preferably a hydrogen atom, C 1-3 alkyl.
  • R 1 is preferably Is.
  • R 9 is preferably a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, or an alkyl group in which the hydrogen atom is substituted with 1 to 3 halogen atoms, more preferably a hydrogen atom, a halogen atom, C 1-6 alkyl group, a C 1-6 alkyl group a C 1-6 alkoxy group, or one to three hydrogen atoms with a halogen atom is substituted, more preferably a hydrogen atom, a halogen atom, C 1 -3 alkyl group, a C 1-3 alkoxy group, or one to three C 1-3 alkyl group wherein a hydrogen atom is substituted with a halogen atom, particularly preferably a hydrogen atom, a fluorine atom, a chlorine atom, methyl A group, a methoxy group, or a trifluoromethyl group, and
  • R 2 is preferably a hydrogen atom, a fluorine atom or OH, and more preferably a hydrogen atom.
  • any combination of the preferred groups of the respective substituents relating to the compound represented by formula (1), (2) or (8) can be used.
  • R 3 is preferably an alkyl group, more preferably a C 1-6 alkyl group.
  • R 8 is preferably a hydrogen atom
  • R 1 is preferably
  • R 9 is preferably a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, or an alkyl group in which 1 to 3 halogen atoms are substituted for the hydrogen atom, and more preferably a hydrogen atom or a halogen atom.
  • C 1-6 alkyl group, a C 1-6 alkyl group a C 1-6 alkoxy group, or 1 to a hydrogen atom at three halogen atoms are replaced, more preferably a hydrogen atom, a halogen atom, C A 1-3 alkyl group, a C 1-3 alkoxy group, or a C 1-3 alkyl group in which a hydrogen atom is substituted with 1 to 3 halogen atoms, particularly preferably a hydrogen atom, a fluorine atom, a chlorine atom, It is a methyl group, a methoxy group or a trifluoromethyl group, m is preferably 1, 2 or 3, and R 2 is preferably a hydrogen atom.
  • -XY- is -CR 4 R 5 -SO 2 -, - CR 4 R 5 -SO-, or -CR 4 may represent R 5 -S-
  • R 4 and R 5 are each independently a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom, particularly preferably both a hydrogen atom, and an Ar ring is preferably
  • R 8 is preferably a hydrogen atom
  • R 1 is preferably
  • R 9 is preferably a hydrogen atom, a halogen atom, an alkyl group, or an alkoxy group, more preferably a hydrogen atom, a halogen atom, a C 1-6 alkyl group, or a C 1-6 alkoxy group, More preferably a hydrogen atom, a halogen atom, a C 1-3 alkyl group or a C 1-3 alkoxy group, particularly preferably a hydrogen atom, a fluorine
  • R 4 and R 5 are respectively Independently, preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom, particularly preferably both hydrogen atoms, Ar ring, preferably, And R 8 is preferably a hydrogen atom, and R 1 is preferably And R 9 is preferably a hydrogen atom or a halogen atom, more preferably a hydrogen atom or a fluorine atom, m is preferably 1, and R 2 is preferably a hydrogen atom.
  • R 4 and R 5 are each independently a hydrogen atom.
  • a halogen atom or an alkyl group more preferably a hydrogen atom, a halogen atom or a C 1-6 alkyl group, further preferably a hydrogen atom, a halogen atom or a C 1-3 alkyl group, and even more preferably hydrogen.
  • Atom, a fluorine atom or a methyl group, particularly preferably both a fluorine atom or a combination of a hydrogen atom and a methyl group, R 6 and R 7 are each independently, preferably a hydrogen atom or a halogen.
  • R 8 is preferably a hydrogen atom, an alkyl group or an alkoxy group, more preferably a hydrogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group, further preferably a hydrogen atom, C 1 -3 alkyl group or C 1-3 alkoxy group, particularly preferably hydrogen atom, methyl group or methoxy group, n is preferably 1 or 2, more preferably 1, and R 1 is Preferably, And R 9 is preferably a hydrogen atom, a halogen atom, an alkyl group or an alkoxy group, more preferably a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group, and further preferably Is a hydrogen atom, a halogen atom, a C 1-3 alkyl group or a C 1-3
  • the compound represented by formula (1), (2) or (8) can be produced based on the technical common sense of those skilled in the art, and can be produced, for example, according to the following method.
  • [Production method 1] In the formula, -XY-, Ar ring, R 1 and R 2 are the same as those defined in the formula (1) or (2).
  • the compound represented by the formula (3) can be reacted with the compound represented by the formula (4) in a suitable solvent, for example, an organic solvent such as m-xylene.
  • Reaction conditions such as reaction time and reaction temperature can be appropriately selected according to the compound to be used, and the reaction may be carried out with stirring under reflux.
  • the compound represented by the formula (8) is the compound represented by the formula (3) in the production method 1, wherein —XY— is —NR 3 —CR 4 R 5 — (for example, When R 4 and R 5 are hydrogen atoms), they can be produced together with the compound represented by the formula (2) in which —XY— is —NR 3 —CR 4 R 5 —.
  • the compound represented by the formula (1), (2) or (8) in which Z is S can be obtained by using a thioester corresponding to the compound represented by the formula (3).
  • the keto type is shown in the above reaction formula, the enol type can be similarly produced.
  • the compound represented by the formula (3) and the compound represented by the formula (4) a commercially available product or a synthesized product may be used.
  • synthesizing the compound represented by the formula (3) it may be synthesized as follows.
  • the compound represented by formula (3) can be synthesized by reacting the compound represented by formula (5) with dimethyl carbonate or methyl cyanoformate.
  • dimethyl carbonate for example, a base such as sodium hydride can be used.
  • methyl cyanoformate for example, a base such as potassium carbonate and a solvent such as acetone can be used. Reaction conditions such as reaction time and reaction temperature can be appropriately selected depending on the compound used.
  • the compound represented by the formula (6) can be prepared by reacting a compound represented by the formula (6) in the presence of a base such as sodium hydride or potassium carbonate in a suitable solvent, for example, a suitable organic solvent such as THF or dimethylformamide. It can be reacted with the compound represented by (7).
  • a base such as potassium carbonate
  • an organic solvent such as acetone may be used. Reaction conditions such as reaction time and reaction temperature can be appropriately selected according to the compound to be used, and the reaction may be carried out with stirring under reflux.
  • the compound represented by formula (1) or (2) in which Z is S can be obtained by using a thioisocyanate corresponding to the compound represented by formula (7).
  • the enol type is shown in the above reaction formula, the keto type can be similarly produced.
  • purification and extraction operations can be carried out based on the technical common sense of those skilled in the art.
  • the compound represented by the formula (1), (2) or (8) may be in the form of a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt include, for example, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, inorganic salt such as phosphate, acetate, propionate, lactate, Organic acid salts such as oxalate, malonate, succinate, fumarate, maleate, malic acid, tartrate, benzoate, salicylate and phthalate, methanesulfonate, benzenesulfonate Examples thereof include salts and organic sulfonates such as p-toluenesulfonate, but are not limited thereto.
  • the compound of the present invention has a neuronal cell protective effect and improves the movement disorder of Parkinson's disease model mice.
  • the compounds of this invention may be useful in treating Parkinson's disease.
  • the compounds of the invention may also be useful in treating Parkinson's syndrome.
  • One embodiment of the invention relates to a pharmaceutical composition for treating Parkinson's disease or Parkinson's syndrome.
  • “treating” means ameliorating a subject's symptoms or suppressing the progression of a disease in a subject. That is, the pharmaceutical composition for treating Parkinson's disease or Parkinson's syndrome may improve Parkinson's symptom (Parkinsonism), or may suppress the progression of Parkinson's disease or Parkinson's syndrome.
  • Parkinson's symptoms include motor symptoms and non-motor symptoms, the pharmaceutical composition of the present invention can be particularly useful for improving motor symptoms.
  • protecting nerve cells means reducing the number of deaths of nerve cells.
  • protecting nerve cells can be suppressing nerve cell death caused by a substance harmful to nerve cells.
  • the nerve cell can be, for example, a nerve cell that produces dopamine, but is not limited thereto.
  • suppressing cell death caused by 1-methyl-4-phenylpyridinium (MPP + ) is an example of protecting nerve cells. ..
  • the pharmaceutical composition of the present invention may contain pharmaceutically acceptable additives such as pharmaceutically acceptable carriers, diluents, excipients, stabilizers, disintegrants and binders.
  • pharmaceutically acceptable additives such as carriers, diluents, excipients, stabilizers, disintegrants, binders and the like, those well known in the technical field of the present invention can be used. ..
  • the administration method of the pharmaceutical composition of the present invention is not particularly limited, and the pharmaceutical composition of the present invention can be used for oral administration or parenteral administration such as injection. Specific routes of administration by injection include, but are not limited to, intravenous administration, intraperitoneal administration, subcutaneous administration, intramuscular administration and the like.
  • the pharmaceutical composition of the present invention does not have the oxicam skeleton that meloxicam has, it may have no COX inhibitory activity or have a reduced COX inhibitory activity. Therefore, when the pharmaceutical composition of the present invention is orally administered, the possibility of causing gastrointestinal disorders is lower than when orally administered meloxicam, and in that it is easy to take, the pharmaceutical composition of the present invention has a great advantage.
  • the administration subject of the pharmaceutical composition of the present invention is not particularly limited, and may be a human or a mammal other than human. In the pharmaceutical composition of the present invention, the dose and the frequency of administration can be determined based on the condition of the test subject, the degree of disease and the like.
  • Another aspect of the invention includes a method of treating Parkinson's disease or Parkinson's syndrome.
  • the treatment method comprises an effective amount of the compound represented by formula (1), formula (2) or formula (8) or a pharmaceutically acceptable salt thereof, or an effective amount of formula (1) or formula (2).
  • a compound represented by formula (8) or a pharmaceutically acceptable salt thereof may be administered to a subject in need of treatment for Parkinson's disease or Parkinson's syndrome.
  • Another aspect of the present invention includes a method of protecting nerve cells or a method of suppressing nerve cell death.
  • Such a method comprises an effective amount of the compound represented by formula (1), formula (2) or formula (8) or a pharmaceutically acceptable salt thereof, or an effective amount of formula (1) or formula ( 2) or a compound represented by formula (8) or a pharmaceutical composition containing a pharmaceutically acceptable salt thereof, which comprises administering to a subject in need of protection of nerve cells or inhibition of nerve cell death.
  • an “effective amount” is an amount that is administered to a subject as a single dose or as part of a dose in a series of administration schedules, and has the desired therapeutic effect, neuronal cell protective effect, or neuronal cell effect. By an amount effective to produce a death control effect.
  • Example 1 Synthesis of IY-027 (N-(5-methylthiazol-2-yl)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxamide) 2-Amino-5-methylthiazole (8.43 g, 73.8 mmol, 3.3 eq) was dissolved in m-xylene (240 mL) and stirred at room temperature for 1 minute to give 1-oxo-1,2,3,4-tetrahydro. Methyl naphthalene-2-carboxylate (4.53 g, 22.2 mmol) was added, and the mixture was stirred under reflux at 160° C. for 22 hours.
  • Example 2 Synthesis of IY-066 (4-hydroxy-N-(4-fluorophenyl)-2H-thiochromene-3-carboxamide 1,1-dioxide) Methyl 4-hydroxy-2H-thiochromene-3-carboxylate-1,1-dioxide (1.04 g, 4.10 mmol) and 4-fluoroaniline (2.35 g, 21.1 mmol, 5.1 eq) in m-xylene (50 mL). After dissolution, the mixture was stirred under reflux at 150°C for 19.5 hours.
  • Example 3 of IY-068 (N-(2,5-difluorophenyl)-4-hydroxy-1-methyl-1H-benzo[c][1,2]thiazine-3-carboxamide 2,2-dioxide) Synthesis Under a nitrogen atmosphere, commercially available 4-hydroxy-1-methyl-1H-benzo[c][1,2]thiazine 2,2-dioxide (1.42 mmol, 300 mg) was dissolved in anhydrous THF (20 mL), and hydrogen was added. Sodium chloride (2.13 mmol, 85.4 mg, 1.5 equivalents) was added, and the mixture was stirred at room temperature.
  • Example 4 of IY-69 (N-(2,4-difluorophenyl)-4-hydroxy-1-methyl-1H-benzo[c][1,2]thiazine-3-carboxamide 2,2-dioxide) Synthesis
  • 4-hydroxy-1-methyl-1H-benzo[c][1,2]thiazine 2,2-dioxide (2.47 mmol, 500 mg) and 2,4-fluorophenyl isocyanate were used.
  • the yellow solid (540.4 mg) obtained by condensing (4.26 mmol, 660.4 mg, 1.8 eq) was recrystallized from ethyl acetate to obtain IY-069 (285.2 mg, yield 33%) as colorless needle crystals.
  • Example 5 Synthesis of IY-075 (4-hydroxy-1-methyl-N-(p-tolyl)-1H-benzo[c][1,2]thiazine-3-carboxamide 2,2-dioxide)
  • 4-hydroxy-1-methyl-1H-benzo[c][1,2]thiazine 2,2-dioxide (1.42 mmol, 300 mg) and p-tolyl isocyanate (2.84 mmol) were used. , 379.4 mg, 2.0 eq.) to give a yellow solid (642.6 mg) which was recrystallized from ethyl acetate to give IY-075 (323.7 mg, yield 66%) as yellow plate crystals.
  • Example 6 IY-077 (4-hydroxy-1-methyl-N-(2,3,4-trifluorophenyl)-1H-benzo[c][1,2]thiazine-3-carboxamide 2,2- Dioxide) synthesis
  • 4-hydroxy-1-methyl-1H-benzo[c][1,2]thiazine 2,2-dioxide (1.42 mmol, 300 mg) and 2,3,4-fluorophenyl were used.
  • the yellow solid (673.1 mg) obtained by condensation of isocyanate (2.84 mmol, 491.3 mg, 2.0 eq) was recrystallized from ethyl acetate to obtain IY-077 (311.6 mg, 57% yield) as colorless needle crystals.
  • Example 7 IY-078 (4-hydroxy-1-methyl-N-(2,4,6-trifluorophenyl)-1H-benzo[c][1,2]thiazine-3-carboxamide 2,2- Dioxide) synthesis
  • 4-hydroxy-1-methyl-1H-benzo[c][1,2]thiazine 2,2-dioxide (1.42 mmol, 300 mg) and 2,4,6-fluorophenyl were used.
  • the yellow solid (675.0 mg) obtained by condensing isocyanate (2.84 mmol, 491.3 mg, 2.0 equivalents) was recrystallized from ethyl acetate to give IY-078 (68.9 mg, yield 13%) as colorless needle crystals. Obtained.
  • Example 8 IY-079 (N-(3-chloro-4-methylphenyl)-4-hydroxy-1-methyl-1H-benzo[c][1,2]thiazine-3-carboxamide 2,2-dioxide ) Synthesis In the same manner as in Example 3, 4-hydroxy-1-methyl-1H-benzo[c][1,2]thiazine 2,2-dioxide (1.42 mmol, 300 mg) was mixed with anhydrous THF (20 mL) and 3 A yellow solid (669.8 mg) obtained by condensation of -chloro-4-methylphenylisocyanate (2.84 mmol, 474.3 mg, 2.0 eq) was recrystallized from ethyl acetate to give IY-079 (269.1 mg, 50% yield).
  • Example 9 IY-080 (N-(4-chloro-3-(trifluoromethyl)phenyl)-4-hydroxy-1-methyl-1H-benzo[c][1,2]thiazine-3-carboxamide 2 ,2-Dioxide)
  • 4-hydroxy-1-methyl-1H-benzo[c][1,2]thiazine 2,2-dioxide (1.42 mmol, 300 mg) and 3-trifluoromethyl-4-
  • the yellow solid (1.0 g) obtained by condensation of chlorophenyl isocyanate (2.84 mmol, 629.3 mg, 2.0 eq) was recrystallized from ethyl acetate to give IY-080 (405.3 mg, 66% yield) as colorless needle crystals.
  • Example 10 IY-081 (N-(4-chloro-3-methylphenyl)-4-hydroxy-1-methyl-1H-benzo[c][1,2]thiazine-3-carboxamide 2,2-dioxide ) Synthesis In the same manner as in Example 3, 4-hydroxy-1-methyl-1H-benzo[c][1,2]thiazine 2,2-dioxide (1.42 mmol, 300 mg) and 3-methyl-4-chlorophenylisocyanate were used.
  • Example 11 Synthesis of IY-082 (4-hydroxy-N-phenyl-1H-isothiochromene-3-carboxamide) Under a nitrogen atmosphere, isothiochroman-4-one (948 mg, 5.77 mmol) dissolved in anhydrous THF (40 mL) was added to sodium hydride (315 mg, 7.88 mmol, 1.4 equivalents) washed with dehydrated hexane, and the mixture was stirred at room temperature. And stirred for 5 minutes. Then, phenyl isocyanate (1750 mg, 14.7 mmol, 2.5 equivalents) dissolved in anhydrous THF (5 mL) was added, and the mixture was refluxed and stirred at 80° C. for 3 hours.
  • the reaction mixture was adjusted to pH 2 with diluted hydrochloric acid and extracted three times with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and a black solid (2600 mg) was obtained. Got Since impurities were found in the crude product, methanol (20 mL) was added and the precipitated ocher solid was isolated by suction filtration to obtain IY-082 (1280 mg, yield 78.2%).
  • Example 12 Synthesis of IY-72 (4,4-difluoro-1-oxo-N-phenyl-1,2,3,4-tetrahydronaphthalene-2-carboxamide) Sodium hydride (115.2 mg, 2.88 mmol, 1.6 equivalents) washed with dehydrated hexane under a nitrogen atmosphere was suspended in dehydrated THF (6.7 mL), and 4,4-difluoro-3,4-dihydronaphthalene-1 (2H )-One (327.7 mg, 1.80 mmol) was added, and the mixture was stirred at room temperature for 5 minutes.
  • phenyl isocyanate (450.2 mg, 3.76 mmol, 2.1 equivalents) dissolved in dehydrated THF (6.7 mL) was added in 3 portions, and the mixture was refluxed and stirred at 80° C. for 8.5 hours. 2 M hydrochloric acid was added to the reaction solution, which was extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a brown paste (715.9 mg).
  • Example 13 Synthesis of IY-73 (2-fluoro-1-oxo-N-phenyl-1,2,3,4-tetrahydronaphthalene-2-carboxamide) Sodium hydride (214.9 mg, 5.37 mmol, 1.7 eq) washed with dehydrated hexane under a nitrogen atmosphere was suspended in dehydrated THF (11.5 mL), and 2-fluoro-3,4-dihydronaphthalene-1(2H)- ON (505.9 mg, 3.08 mmol) was added, and the mixture was stirred at room temperature for 5 minutes.
  • phenyl isocyanate 803.5 mg, 6.75 mmol, 2.2 equivalents
  • dehydrated THF 11.5 mL
  • 2M hydrochloric acid was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate.
  • the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.41 g of a brown paste.
  • Example 14 Synthesis of IY-084 (N-(4-fluorophenyl)-4-hydroxy-1H-isothiochromene-3-carboxamide 2,2-dioxide) 14-1.Synthesis of methyl 2,2-dioxide 4-hydroxy-1H-isothiochromene-3-carboxylate Isothiochroman-4-one-2,2-dioxide (105 mg, 0.537 mmol) in K 2 CO 3 (307 mg, 2.22 mmol, 4.1 eq) and methyl cyanoformate (358 mg, 4.21 mmol, 7.8 eq) were dissolved in acetone (15 mL) and stirred at room temperature for 27 hours.
  • Example 16 Synthesis of IY-091 (N-(4-tolyl)-4-hydroxy-1H-isothiochromene-3-carboxamide 2,2-dioxide)
  • methyl 4-hydroxy-1H-isothiochromene-3-carboxylate 2,2-dioxide (79.1 mg, 0.311 mmol) and p-toluidine (77.6 mg, 0.724 mmol, 2.3 equivalents) were added to m. -Dissolved in xylene (10 mL), and stirred under reflux at 150°C for 16 hours.
  • Example 17 Synthesis of IY-092 (N-(2,4-difluorophenyl)-4-hydroxy-1H-isothiochromene-3-carboxamide 2,2-dioxide)
  • methyl 4-hydroxy-1H-isothiochromene-3-carboxylate 2,2-dioxide (200.0 mg, 0.785 mmol) and 2,4-difluoroaniline (308.0 mg, 2.39 mmol, 2.3 equivalents) was dissolved in m-xylene (15 mL), and the mixture was refluxed with stirring at 150° C. for 3 hours.
  • Example 18 Synthesis of IY-093 (N-(2,3,4-trifluorophenyl)-4-hydroxy-1H-isothiochromene-3-carboxamide 2,2-dioxide)
  • methyl 4-hydroxy-1H-isothiochromene-3-carboxylate 2,2-dioxide 225.0 mg, 0.885 mmol
  • 2,3,4-trifluoroaniline 515.0 mg, 3.50 mmol
  • 4.0 equivalents was dissolved in m-xylene (20 mL), and the mixture was stirred under reflux at 150° C. for 3.5 hours.
  • Example 19 Synthesis of IY-094 (N-(2-methoxyphenyl)-4-hydroxy-1H-isothiochromene-3-carboxamide 2,2-dioxide)
  • methyl 4-hydroxy-1H-isothiochromene-3-carboxylate 2,2-dioxide 220.0 mg, 0.866 mmol
  • 2,-methoxyaniline 291.0 mg, 2.37 mmol, 2.7 equivalents
  • Example 20 Synthesis of IY-095 (4-methyl-1-oxo-N-phenyl-1,2,3,4-tetrahydronaphthalene-2-carboxamide) Sodium hydride (304.1 mg, 7.61 mmol, 1.7 equivalents) washed with dehydrated hexane under a nitrogen atmosphere was suspended in dehydrated THF (17 mL), and 4-methyl-3,4-dihydronaphthalene-1(2H)-one was suspended. (707.6 mg, 4.42 mmol) was added, and the mixture was stirred at room temperature for 5 minutes.
  • phenyl isocyanate (1.15 g, 9.70 mmol, 2.2 equivalents) dissolved in dehydrated THF (17 mL) was added, and the mixture was refluxed and stirred at 80° C. for 21 hours. 2 M hydrochloric acid was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a brown paste (1.79 g).
  • Example 21 Synthesis of IY-101 (4-oxo-N-phenyl-4,5,6,7-tetrahydro[b]thiophene-3-carboxamide) Under a nitrogen atmosphere, commercially available 6,7-dihydrobenzo[b]thiophen-4(5H)-one (300.0 mg, 1.97 mmol) was dissolved in anhydrous THF (15 mL), cooled to -78 °C, and potassium hexahydrate was added. Methyldisilazide solution (6.0 mL, 2.96 mmol, 1.5 eq) was added and stirred for 30 minutes.
  • Example 22 Synthesis of IY-102 (N-phenyl-4-hydroxy-1-methyl-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide)
  • 4-hydroxy-1-methyl-1H-pyrido[2,3-c][1,2]thiazine 2,2-dioxide (200.0 mg, 0.94 mmol)
  • phenyl isocyanate The red-white solid (272.0 mg) obtained by condensation of 112 mg, 1.88 mmol, 2.0 equivalent) was recrystallized from ethyl acetate to obtain IY-102 (100.0 mg, yield 32%) as orange crystals.
  • Example 23 IY-103 (N-(2.4-difluorophenyl)-4-hydroxy-1-methyl-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ) Synthesis In the same manner as in Example 3, 4-hydroxy-1-methyl-1H-pyrido[2,3-c][1,2]thiazine 2,2-dioxide (300 mg, 1.42 mmol) and 2.4-difluorophenyl were used.
  • Example 24 IY-104 (N-(4-tolyl)-4-hydroxy-1-methyl-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide) Synthesis of In the same manner as in Example 3, 4-hydroxy-1-methyl-1H-pyrido[2,3-c][1,2]thiazine 2,2-dioxide (150.0 mg, 0.71 mmol) and 4-tolyl isocyanate were used. The yellowish white solid (337.0 mg) obtained by condensation of nato (186.0 mg, 1.40 mmol, 2.0 eq) was recrystallized from ethyl acetate to obtain IY-104 (158.0 mg, yield 64%) as yellow plate crystals.
  • Example 25 IY-114 (1-methyl-4-oxo-N-(4-tolyl)-1,2,3,4-tetrahydroquinoline-3-carboxamide) and IY-115 (1-methyl-4- Synthesis of oxo-N-(4-tolyl)-1,4-dihydroquinoline-3-carboxamide) Methyl 1-methyl-4-oxo-1,2,3,4-tetrahydroquinoline-3-carboxylate (100.0 mg, 0.46 mmol) and p-toluidine (147.9 mg, 1.38 mmol) in m-xylene (12 mL) And was stirred under reflux at 150° C. for 25 hours.
  • IY-XXX three-digit number
  • IY-027 in Example 1 means a compound represented by sample number: KO-IY-NA-027 in Table 1 below.
  • COX cyclooxygenase
  • Example 26 Cyclooxygenase (COX) Inhibition Test Using a COX Fluorescent Inhibitor Screening Kit (CAYMAN CHEMICAL), the inhibitory activity of each compound on COX-1 and COX-2 was evaluated. Tris-HCl buffer (pH 8.0), Heme solution, and a solution (10 ⁇ M) of the evaluation compound dissolved in DMSO were added to a 96-well plate. Separately, a well to which DMSO was added instead of the evaluation compound solution was prepared as a control. COX-1 or COX-2 solution was added to each well and incubated at room temperature for 5 minutes. ADHP solution and arachidonic acid solution were added to all wells and incubated at room temperature for 2 minutes.
  • COX-1 or COX-2 solution was added to each well and incubated at room temperature for 5 minutes.
  • ADHP solution and arachidonic acid solution were added to all wells and incubated at room temperature for 2 minutes.
  • the excitation wavelength was 530 nm and the emission wavelength was 585 nm.
  • SC-560 was used for COX-1 and DuP-697 was used for COX-2.
  • meloxicam was used instead of the evaluation compound, and the same evaluation was performed. The results are shown in Table 1 below. The meloxicam had a very strong COX-2 inhibitory activity, whereas the compounds evaluated had a lower COX-2 inhibitory activity than meloxicam.
  • COX-2 inhibitory activity is significantly weaker than that of meloxicam
  • COX-2 of IY-091, IY-092, IY-093, IY-094, IY-101, IY-102, IY-103 and IY-104 No inhibitory activity was detected.
  • Example 27 Evaluation of protective effect against MPP + -induced cultured neuronal cell death
  • MPP + (1-methyl-4-phenylpyridinium
  • DMEM Dulbecco's modified Eagle medium
  • SIGMA penicillin (100 U/mL) streptomycin (100 ⁇ g/mL).
  • Example 28 Evaluation of drug efficacy using MPTP-induced Parkinson's disease model mouse MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced Parkinson's disease model for drug efficacy evaluation of many therapeutic drugs for Parkinson's disease
  • the mouse is being used.
  • the model mouse can be used to evaluate the drug efficacy dose and the safety.
  • MPTP-induced Parkinson's disease model mice were used to evaluate the improving effect of the evaluated compounds on experimental Parkinsonism by the Pole test method.
  • the mice and samples used are as follows. ⁇ Mice: Male C57BL/6 mice (SLC, 9 weeks old at the start of administration, 11 weeks old at the time of behavior evaluation, 20-25 g) Acclimatized for 7 days after arrival.
  • ⁇ MPTP 30 mg/kg subcutaneously administered to mice (dissolved in Saline)
  • -Evaluation compound Intraperitoneally or orally administered to mice at 3, 7.5, 10, 20 or 30 mg/kg (dissolved in 0.5% CMC)
  • ⁇ Meloxicam reference example: Intraperitoneally administered to mice at 10 mg/kg (dissolved in Saline) The administration was performed by grouping as follows.
  • ⁇ Control group CMC twice daily intraperitoneal administration (morning and evening) for 15 days, Saline once daily subcutaneous administration (daytime) for the first 5 days
  • MPTP group CMC twice daily intraperitoneal administration (morning and evening) 15 days
  • MPTP + evaluation compound group Evaluation compound once or twice daily intraperitoneally or orally (10 mg administration once in the morning, or 3, 7.5, 10 , 20 or 30 mg once a day in the morning and evening) 15 days, MPTP 30 mg/kg once a day subcutaneously (day)
  • MPTP + meloxicam group meloxicam once a day intraperitoneally (once day) 10 mg administration) 15 days
  • IY-027, IY-053, IY-060, IY-065, IY-067, IY-068, IY-069, and IY-093 are used in consideration of the measurement results of neuronal cell protective effect.
  • IY-027 was intraperitoneally administered, and the others were orally administered to mice.
  • the Pole test was performed as follows. Before the administration on the 15th day, the mouse was grasped upward by the tip of a rod having a diameter of 8 mm and a height of 55 cm, and the time from the beginning of movement until the mouse turned completely downward was defined as T turn . The longer this time is, the greater the degree of movement disorder is.
  • Each mouse was acclimated once, and the same measurement was performed 5 times per mouse, and the average value was used. The results are shown in FIGS.
  • Each of the compounds to be evaluated shortened the T turn lengthened by the administration of MPTP to the same extent as the control group not administered with MPTP. Thus, it was shown that any of the evaluated compounds improved the movement disorder.
  • a significant difference was observed between the MPTP group and the MPTP+evaluated compound group (IY-027, IY-053, IY-060, IY-093) at a significance level of 0.1%.
  • a significant difference was observed between the MPTP group and the MPTP+assessed compound group (IY-067) at the 1% significance level.
  • Example 29 Measurement of plasma and brain concentrations
  • the mice and samples used are as follows. ⁇ Mouse: Male C57BL/6 mouse (self breeding, 22-30 g) Evaluation compound: 10 mg/kg (dissolved in 0.5% CMC) 1, 4 and 8 hours after oral or intraperitoneal administration of the compound to be evaluated, blood was collected from the inferior vena cava using a 26G injection needle + 1 mL syringe anesthetized and heparinized, and the microcooled centrifuge (KUBOTA3780 was cooled to 4°C. ) was centrifuged at 5000 rpm for 5 minutes, and the supernatant was used as plasma. Next, the whole brain was taken out and the brain weight was measured.
  • KUBOTA3780 was cooled to 4°C.
  • a bead crusher bead crusher ⁇ T-12
  • the compound in which -XY- represents -CR 4 R 5 -CR 6 R 7- has higher intracerebral transferability (brain/plasma concentration ratio) than meloxicam, but its plasma concentration is It was low and tended to decrease rapidly with time.
  • the compound in which -XY- represents -CR 4 R 5 -SO 2- showed a high concentration in the brain, and had higher intracerebral transferability (brain/plasma concentration ratio) than meloxicam.
  • the other evaluated compounds behaved similarly to meloxicam.
  • the results of using IY-027 manufactured in Example 1, using IY-065, and using IY-093 are shown in Table 2 below.
  • the lower limit of quantification of plasma concentration was 0.003 ⁇ M
  • the lower limit of quantification of brain concentration was 0.012 nmol/g
  • the lower limit of quantification of plasma concentration was 0.01 ⁇ M
  • the lower limit of quantification is 0.04 nmol/g.
  • the lower limit of quantification of plasma concentration is 0.1 ⁇ M
  • the lower limit of quantification of brain concentration is 1.0 nmol/g.
  • the compound of the present invention has a neuronal cell protective effect and improves motor disorders in Parkinson's disease model mice, and thus may be useful as a therapeutic agent for Parkinson's disease. It is considered that the compound of the present invention can suppress the progression of Parkinson's disease and stop the progression thereof. In addition, the compound of the present invention is considered to be applicable to the treatment of Parkinson's syndrome which exhibits the same symptoms as those in Parkinson's disease. Since the existing drugs bromocriptine, levodopa, and dopamine itself do not have a protective effect on MPP + -induced neuronal cell death, the compounds of the present invention have utility over these existing drugs for the treatment of Parkinson's disease and the like. I will get it.
  • oral administration of the compound of the present invention markedly improves the movement disorder of Parkinson's disease model mice, and no remarkable toxicity is observed in the mice, and therefore, it can be easily taken and can contribute to improvement of QOL of patients.
  • the compounds of the present invention are less likely to cause gastrointestinal disorders and may be more useful because of their lower COX inhibitory activity compared to meloxicam.

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Abstract

Dans un mode de réalisation de la présente invention, l'objet de la présente invention est de fournir un agent thérapeutique pour le traitement de la maladie de Parkinson, etc. Un composé représenté par les formules (1), (2) ou (8) ou un sel pharmacologiquement acceptable associé peut être utilisé dans le traitement de la maladie de Parkinson, etc. (chaque substituant dans les formules est tel que décrit dans la description).
PCT/JP2020/003462 2019-01-30 2020-01-30 Agent thérapeutique pour le traitement de la maladie de parkinson WO2020158870A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1259415A (fr) * 1969-11-26 1972-01-05
JP2008504291A (ja) * 2004-06-24 2008-02-14 バーテックス　ファーマシューティカルズ　インコーポレイテッド Ａｔｐ結合カセットトランスポーターのモジュレーター
JP2010535172A (ja) * 2007-08-02 2010-11-18 エフ．ホフマン−ラ ロシュ アーゲー Ｃｎｓ障害の処置のためのベンズアミド誘導体の使用
JP2010539185A (ja) * 2007-09-14 2010-12-16 バーテックス ファーマシューティカルズ インコーポレイテッド 嚢胞性線維症膜コンダクタンス制御因子の調節因子
JP2013513617A (ja) * 2009-12-11 2013-04-22 バーテックス ファーマシューティカルズ インコーポレイテッド Ａｔｐ結合カセット輸送体のモジュレーターとしての４−オキソ−１ｈ−キノリン−３−カルボキサミド
KR20150044675A (ko) * 2013-10-17 2015-04-27 (주)아모레퍼시픽 아마이드 유도체 화합물
WO2019028456A1 (fr) * 2017-08-04 2019-02-07 Axial Biotherapeutics, Inc. Inhibiteurs de la formation d'amyloïdes induite par voie microbienne

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1259415A (fr) * 1969-11-26 1972-01-05
JP2008504291A (ja) * 2004-06-24 2008-02-14 バーテックス　ファーマシューティカルズ　インコーポレイテッド Ａｔｐ結合カセットトランスポーターのモジュレーター
JP2010535172A (ja) * 2007-08-02 2010-11-18 エフ．ホフマン−ラ ロシュ アーゲー Ｃｎｓ障害の処置のためのベンズアミド誘導体の使用
JP2010539185A (ja) * 2007-09-14 2010-12-16 バーテックス ファーマシューティカルズ インコーポレイテッド 嚢胞性線維症膜コンダクタンス制御因子の調節因子
JP2013513617A (ja) * 2009-12-11 2013-04-22 バーテックス ファーマシューティカルズ インコーポレイテッド Ａｔｐ結合カセット輸送体のモジュレーターとしての４−オキソ−１ｈ−キノリン−３−カルボキサミド
KR20150044675A (ko) * 2013-10-17 2015-04-27 (주)아모레퍼시픽 아마이드 유도체 화합물
WO2019028456A1 (fr) * 2017-08-04 2019-02-07 Axial Biotherapeutics, Inc. Inhibiteurs de la formation d'amyloïdes induite par voie microbienne

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
TASAKI YOSHIKAZU ET AL.: "Meloxicam ameliorates motor dysfunction and dopaminergic neurodegeneration by maintaining Akt-signaling in a mouse Parkinson's disease model", NEUROSCIENCE LETTERS, vol. 521, 2012, pages 15 - 19, XP028495776, DOI: 10.1016/j.neulet.2012.05.045 *
UKRAINE TS I. V ET AL.: "New synthesis and analgesic and diuretic activity of halo- substituted 4-hydroxy-l-methyl-2,2-dioxo-lH-2A6, 1-benzothiazine-3-carboxanilides", PHARMACEUTICAL CHEMISTRY JOURNAL, vol. 50, no. 9, 2016, pages 589 - 594 589, XP036113895, DOI: 10.1007/s11094-016-1496-9 *

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