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WO2018008737A1 - Composé dihydroxy ou sel correspondant, et médicament thérapeutique ou prophylactique contre la maladie de parkinson - Google Patents

Composé dihydroxy ou sel correspondant, et médicament thérapeutique ou prophylactique contre la maladie de parkinson Download PDF

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Publication number
WO2018008737A1
WO2018008737A1 PCT/JP2017/024921 JP2017024921W WO2018008737A1 WO 2018008737 A1 WO2018008737 A1 WO 2018008737A1 JP 2017024921 W JP2017024921 W JP 2017024921W WO 2018008737 A1 WO2018008737 A1 WO 2018008737A1
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group
formula
compound
substituent
monovalent
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Japanese (ja)
Inventor
井本　正哉
秀二 井岡
悦 田代
小川　誠一郎
繁 西山
信孝 服部
臣二 斉木
有紀子 吉川
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Keio University
Juntendo Educational Foundation
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Keio University
Juntendo Educational Foundation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—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
    • 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
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
    • C07C205/57—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/013—Esters of alcohols having the esterified hydroxy group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/78—Benzoic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/92—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with etherified hydroxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom 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
    • C07D307/68—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
    • 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to a dihydroxy compound or a salt thereof, and a therapeutic or prophylactic agent for Parkinson's disease.
  • Parkinson's disease is a disease that develops mainly due to degeneration and cell death of dopamine-secreting cells in the midbrain substantia nigra. Degeneration or cell death of dopamine-secreting cells results in a decrease in dopamine production, and exhibits symptoms such as resting tremor, rigidity, immobility, and postural reflex disorder. In the present age of an aging society, the number of patients with Parkinson's disease is expected to increase more and more, so an effective treatment for Parkinson's disease is desired.
  • Non-Patent Document 1 As such Parkinson's disease therapeutic agents, currently, as disclosed in Non-Patent Document 1, dopamine supplements, dopamine receptor stimulants, dopamine release promoters, and dopamine degradation inhibitors are mainly used.
  • any of the above-mentioned drugs for treating Parkinson's disease is intended to treat Parkinson's disease by supplementing the deficient amount of dopamine, and such treatment is merely symptomatic treatment.
  • the present invention has been made in view of the above circumstances, and a compound that acts on the pathogenesis of Parkinson's disease by suppressing degeneration and cell death of dopamine secreting cells, and a therapeutic or preventive agent for Parkinson's disease.
  • the purpose is to provide.
  • the present inventors have induced cell death by treating neurons with 1-methyl-4-phenylpyridinium (MPP +) and formed spots in the cells, and It was found that the spots were aggregates of ⁇ -synuclein. Furthermore, the present inventors have found a compound capable of suppressing the spots, and have completed the present invention.
  • the present invention provides the following.
  • R 1 to R 4 are each independently a group represented by the following formula (I) or (II), or Three of R 1 to R 4 are groups represented by the formula (I) or the formula (II), and the remaining one is a hydrogen atom or a substituent,
  • R 5 may have a monovalent branched chain hydrocarbon group having 3 or more carbon atoms, which may have a substituent, or a substituent.
  • X 1 is a divalent hydrocarbon group having 1 to 10 carbon atoms which may have a single bond or a substituent
  • R 6 is a hydrogen atom or an oxo group, and the dotted line is the presence or absence of a bond.
  • R 5 in the formula (I) or the formula (II) may have an aryl group which may have a substituent, a cyclohexyl group which may have a substituent, or a substituent.
  • the aryl group is a phenyl group, and in the phenyl group, at least the ortho position with respect to the carbon atom to which X 1 in the formula (I) or the formula (II) is bonded is substituted. Or a salt thereof.
  • [4] The monovalent branched chain hydrocarbon group having 3 or more carbon atoms, the 5- to 10-membered monocyclic to tricyclic monovalent carbocyclic group, or the 3- to 10-membered
  • a therapeutic or prophylactic agent for Parkinson's disease containing a compound represented by the following formula (1) or formula (2) or a pharmacologically acceptable salt thereof.
  • R 1 to R 4 are each independently a group represented by the following formula (I) or (II), or Three of R 1 to R 4 are groups represented by the formula (I) or the formula (II), and the remaining one is a hydrogen atom or a substituent
  • R 6 to R 9 are each independently a group represented by the following formula (III) or formula (IV), or Three of R 6 to R 9 are groups represented by the formula (III) or the formula (IV), and the remaining one is a hydrogen atom or a substituent
  • R 5 is a branched monovalent chain formula having 3 or more carbon atoms which may have a substituent.
  • Hydrocarbon group 5- to 10-membered monocyclic to tricyclic monovalent carbocyclic group which may have a substituent, or 3- to 10-membered monocyclic which may have a substituent Is a tricyclic monovalent heterocyclic group
  • X 1 is a C 1-10 divalent hydrocarbon group which may have a single bond or a substituent
  • R 6 is a hydrogen atom or an oxo group, and the dotted line is the presence or absence of a bond.
  • the present invention it is possible to act on the onset mechanism of Parkinson's disease by suppressing degeneration and cell death of dopamine secreting cells.
  • FIG. 3 is an image showing that spots composed of ⁇ -synuclein aggregates formed in MPP + treated cells were suppressed by compound (1-1).
  • FIG. It is an image of a confocal microscope after staining with thioflavin S when compound (1-1) or rapamycin is added to spots consisting of ⁇ -synuclein aggregates formed in MPP + treated cells.
  • 3 is a graph showing the area of aggregates / the area of whole cells, calculated by analyzing the image of FIG. 2. It is a figure which shows the measurement result of the cell number when a compound (1-1) is added with respect to a MPP + treatment cell.
  • the present invention is a compound represented by the following formula (1) or a salt thereof.
  • R 1 to R 4 are each independently a group represented by the following formula (I) or formula (II), or three of R 1 to R 4 are , A group represented by the following formula (I) or formula (II), and the remaining one is a hydrogen atom or a substituent.
  • R 1 to R 4 are groups represented by the formula (I) or the formula (II), that is, the compound of the present invention has at least the formula (I) or It has three R 5 in the formula (II).
  • R 5 in R 1 to R 4 is actually rotated at the bonding portion with X 1 , so that the steric structure is difficult to stabilize, but “branched chain hydrocarbon group”, “carbocycle”
  • the “group” and the “heterocyclic group” are three-dimensionally bulky structures. When these are adjacent to each other and the structure is in a dense state, these structures become a steric hindrance to the rotation described above. , Rotation is suppressed, and its three-dimensional structure becomes stable.
  • the compounds of the present invention are considered to have excellent dopamine-secreting cell degeneration and cell death inhibitory effects.
  • R 1 ⁇ R 4 are all even four, or a group represented by the above formula (I) or the formula (II), or three of the R 1 ⁇ R 4 is the following formula (I) Or it is group represented by Formula (II), and the remaining one is a hydrogen atom or a substituent.
  • all four of R 1 to R 4 are represented by the above formula (I) or the above formula (II) because the compound has a more excellent dopamine secreting cell degeneration and cell death suppressing action. It is preferably a group.
  • R 5 may have a monovalent branched chain hydrocarbon group having 3 or more carbon atoms, which may have a substituent, or a substituent. 5- to 10-membered monocyclic to tricyclic monovalent carbocyclic group, or 3- to 10-membered monocyclic to tricyclic monovalent heterocyclic group which may have a substituent And X 1 is a divalent hydrocarbon group having 1 to 10 carbon atoms which may have a single bond or a substituent.
  • R 6 is a hydrogen atom or an oxo group, and the dotted line is the presence or absence of a bond. When R 6 is a hydrogen atom, the dotted line is absence of a bond, and when R 6 is an oxo group, the dotted line is a bond.
  • the monovalent branched chain hydrocarbon group in the above formula (I) or the above formula (II) is not particularly limited, but is a substituted or unsubstituted alkyl group, alkenyl group, alkynyl group, etc. Those having a branched structure may be mentioned.
  • the chain hydrocarbon group may be a saturated chain hydrocarbon group or an unsaturated chain hydrocarbon group, and has one or more unsaturated bonds in the molecule and / or at the end (for example, 1 to 5).
  • the carbon number of the monovalent branched chain hydrocarbon group may be, for example, in the range of 3 to 50, but preferably 3 to 45. Is more preferably from 30 to 30, still more preferably from 3 to 20, and particularly preferably from 3 to 10.
  • monovalent branched chain hydrocarbon group examples include groups represented by the following formulas (V) and (IV).
  • equation (V) and (VI) may be substituted.
  • the substituent that the monovalent branched chain hydrocarbon group may have is not particularly limited, but a halogen atom, a hydroxy group, an oxo group, a carboxyl group, an amino group (—NH 2 ), an azide group, a nitro group, Group, thiol group, sulfo group, carbamyl group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, cycloalkynyl group, aryl group, heterocyclic group, acyl group, alkoxy group, alkenyloxy group, Alkynyloxy group, alkoxycarbonyl group, acyloxy group, aryloxy group, alkylthio group, alkenylthio group, alkynylthio group, alkylsulfonyl group, alkenylsulfonyl group, alkynylsulfonyl group, alkyl
  • an electron donating group (hydroxy group, amino group, mono- or di-alkylamino group, alkoxy group, aryloxy group, etc.) may be selected, and an electron withdrawing group (halogen atom) , A carboxyl group, an acyl group, a carbamoyl group, etc.), but the electron donating group has a structure in which R 1 to R 4 are electronically dense and sterically stable. It will have a more excellent effect of suppressing the degeneration and cell death of dopamine secreting cells. Accordingly, the substituent is preferably an electron donating group, and particularly preferably an alkoxy group among the electron donating groups.
  • the alkoxy group is, for example, a straight chain such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a tert-butoxy group, or the like. Or a branched alkoxy group is mentioned.
  • the substituent that the monovalent branched chain hydrocarbon group may have is particularly preferably a methoxy group among the alkoxy groups.
  • the electron donating group is a chemical review, 1991, Vol. 91, p.
  • the value of ⁇ defined by the Hammett formula described in 165-195 means a negative substituent.
  • the alkyl group is, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, or a sec-butyl group.
  • examples of the alkenyl group include linear or branched alkenyl groups such as a vinyl group, a propenyl group, a butenyl group, and a pentenyl group.
  • examples of the alkynyl group include linear or branched alkynyl groups such as ethynyl group, propargyl group, butynyl group, and pentynyl group.
  • the cycloalkyl group includes, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a norbornyl group, and the like. Is mentioned.
  • the cycloalkenyl group includes, for example, a 1-cyclobutenyl group, 1-cyclopentenyl group, 3-cyclopentenyl group, 1-cyclohexenyl group, 3 -Cyclohexenyl group, 3-cycloheptenyl group, 4-cyclooctenyl group can be mentioned.
  • the cycloalkynyl group includes, for example, a 1-cyclobutynyl group, a 1-cyclopentynyl group, a 3-cyclopentynyl group, and a 1-cyclohexynyl group. , 3-cyclohexynyl group, 3-cycloheptynyl group, 4-cyclooctynyl group and the like.
  • the aryl group is a monocyclic to tricyclic aromatic group (phenyl group, naphthyl group, naphthoyl group, phenalenyl group, anthryl group, phenanthryl group). Etc.).
  • the aryl group is particularly preferably a phenyl group.
  • hetero atom contained in the heterocyclic group examples include an oxygen atom, a sulfur atom, and a nitrogen atom.
  • the heterocyclic group refers to a group derived from, for example, a 3-membered to 10-membered heterocycle, and may be an unsaturated ring or a saturated ring. Further, the heterocyclic group may be a single ring or a condensed ring (for example, a condensed ring of 2 to 8 rings).
  • heterocyclic group examples include, for example, epoxy group, thienyl group, benzothienyl group, furyl group, benzofuranyl group, isobenzofuranyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, pyrrolyl group, pyridyl group, pyrazinyl group.
  • the acyl group is, for example, formyl group, alkyl (or cycloalkyl) -carbonyl group (for example, acetyl group, propionyl group, butyryl group, isobutyryl group).
  • valeryl group valeryl group, pivaloyl group, hexanoyl group, etc.
  • alkenyl (or cycloalkenyl) -carbonyl group for example, acryloyl group, methacryloyl group, etc.
  • aryl for example, monocyclic to tricyclic aromatic group (phenyl group, Naphthyl group, naphthoyl group, phenalenyl group, anthryl group, phenanthryl group, biphenyl group, etc.))-Carbonyl group and the like.
  • the alkyl-carbonyl group may be, for example, linear or branched having 1 to 12 carbon atoms, and the cycloalkyl-carbonyl group may be, for example, 3 to 10 carbon atoms.
  • the alkenyl-carbonyl group may be linear or branched having 2 to 12 carbon atoms, for example, and the cycloalkenyl-carbonyl group may be 3 to 10 carbon atoms, for example.
  • the aryl-carbonyl group may have, for example, 6 to 14 carbon atoms.
  • alkoxy in the alkoxycarbonyl group can exemplify the above alkoxy group.
  • the acyl in the acyloxy group can be exemplified by the above acyl group.
  • the aryl in the aryloxy group can exemplify the above aryl group.
  • the alkyl in the alkylthio group, the alkylsulfonyl group, the alkylsulfinyl group, and the mono- or di-alkylamino group can exemplify the above alkyl group.
  • the alkenyl in the alkenylthio group, alkenylsulfonyl group and alkenylsulfinyl group can exemplify the above alkenyl group.
  • alkynyl in the alkynylthio group, alkynylsulfonyl group, and alkynylsulfinyl group can exemplify the above alkynyl group.
  • the total carbon number of the substituent having a carbon atom is preferably 1 to 50, more preferably 1 to 30, and still more preferably. Is 1 to 20, particularly preferably 1 to 10.
  • the total number of carbons contained in the monovalent branched chain hydrocarbon group and the substituent is, for example, 3 to 50. However, it is preferably 3 to 40, more preferably 3 to 30, still more preferably 3 to 20, and particularly preferably 3 to 10.
  • alkynylsulfinyl group, mono- or di-alkylamino group, and carbonylamino group may be substituted or unsubstituted, but when substituted, an electron
  • the monovalent carbocyclic group for R 5 is not particularly limited as long as it is a 5- to 10-membered monocyclic to tricyclic group, but is a substituted or unsubstituted aryl group, cycloalkyl group, cycloalkenyl group. And cycloalkynyl group.
  • the monovalent carbocyclic group may be a saturated carbocyclic group or an unsaturated carbocyclic group, and one or more unsaturated bonds may be present in the molecule and / or at the end (for example, 1 to 5).
  • the monovalent carbocyclic group is particularly preferably an aryl group, a cyclohexyl group, or an adamantyl group.
  • a phenyl group, a naphthyl group, a naphthoyl group, a phenalenyl group, an anthryl group, and a phenanthryl group are preferable.
  • the aryl group is particularly preferably a phenyl group.
  • the carbon number of the monovalent carbocyclic group (excluding the carbon number of the substituent) may be, for example, in the range of 3 to 50, preferably 3 to 45, and 3 to 30. More preferably, it is more preferably 3 to 20, and particularly preferably 3 to 10.
  • the substituent that the monovalent carbocyclic group may have is not particularly limited, and examples thereof include the same substituents as those of the monovalent branched chain hydrocarbon group.
  • an electron donating group (hydroxy group, amino group, mono- or di-alkylamino group, alkoxy group, aryloxy group, etc.) may be selected, and an electron withdrawing group (halogen atom, carboxyl group).
  • An acyl group, a carbamoyl group, etc. but the electron donating group has a structure in which R 1 to R 4 are electronically dense and sterically stable, and the compound is superior. It will have the effect of inhibiting degeneration of dopamine secreting cells and cell death.
  • the substituent is preferably an electron donating group, and particularly preferably an alkoxy group among the electron donating groups.
  • the alkoxy group is, for example, a linear or branched chain such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, or a tert-butoxy group.
  • the substituent which the monovalent carbocyclic group may have is particularly preferably a methoxy group among the alkoxy groups.
  • the total carbon number of the substituent having a carbon atom is preferably 1 to 50, more preferably 1 to 30, and further preferably 1 to 20 And particularly preferably 1-10.
  • the total number of carbon atoms contained in the monovalent carbocyclic group and the substituent may be in the range of 3 to 50, for example. Is preferably 3 to 40, more preferably 3 to 30, still more preferably 3 to 20, and particularly preferably 3 to 10.
  • alkyl group alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, cycloalkynyl group, aryl group, heteroaryl group, acyl group, alkoxy group, alkenyl Oxy, alkynyloxy, alkoxycarbonyl, acyloxy, aryloxy, alkylthio, alkenylthio, alkynylthio, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkylsulfinyl, alkenylsulfinyl, alkynyl
  • the sulfinyl group, mono- or di-alkylamino group and carbonylamino group may be substituted or unsubstituted, but when substituted, an electron-donating group (hydroxy group, amino group, Mono- or gear Kir
  • the monovalent carbocyclic group include a group (phenyl group) represented by the following formula (VII).
  • R 7 to R 11 are each independently a hydrogen atom or a substituent, and examples of the substituent include the same substituents as the monovalent branched chain hydrocarbon group described above. Is done.
  • the monovalent carbocyclic group is preferably a phenyl group, but may not be a phenyl group.
  • the monovalent heterocyclic group for R 5 is not particularly limited as long as it is a 3- to 10-membered monocyclic to tricyclic group, and is a substituted or unsubstituted heterocyclic group.
  • the monovalent heterocyclic group may be a saturated heterocyclic group or an unsaturated heterocyclic group, and one or more unsaturated bonds may be present in the molecule and / or at the end (for example, 1 to 5).
  • the hetero atom contained in the monovalent heterocyclic group may be an oxygen atom, a sulfur atom, a nitrogen atom or the like.
  • the monovalent heterocyclic group include, for example, epoxy group, thienyl group, benzothienyl group, furyl group, benzofuranyl group, isobenzofuranyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, pyrrolyl group, pyridyl group.
  • the carbon number of the monovalent heterocyclic group (excluding the carbon number of the substituent) may be, for example, in the range of 1 to 50, preferably 2 to 45, and 3 to 30. More preferably, it is more preferably 3 to 20, and particularly preferably 3 to 10.
  • the substituent that the monovalent heterocyclic group may have is not particularly limited, and examples thereof include the same substituents as those of the above monovalent branched chain hydrocarbon group.
  • an electron donating group (hydroxy group, amino group, mono- or di-alkylamino group, alkoxy group, aryloxy group, etc.) may be selected, and an electron withdrawing group (halogen atom, carboxyl group).
  • An acyl group, a carbamoyl group, etc. but the electron donating group has a structure in which R 1 to R 4 are electronically dense and sterically stable, and the compound is superior. It will have the effect of inhibiting degeneration of dopamine secreting cells and cell death.
  • the substituent is preferably an electron donating group, and particularly preferably an alkoxy group among the electron donating groups.
  • the alkoxy group is, for example, a linear or branched chain such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, or a tert-butoxy group.
  • the substituent that the monovalent heterocyclic group may have is particularly preferably a methoxy group among the alkoxy groups.
  • the total number of carbon atoms of the substituent having a carbon atom is preferably 1 to 50, more preferably 1 to 30, and further preferably 1 to 20 And particularly preferably 1-10.
  • the total number of carbon atoms contained in the monovalent heterocyclic group and the substituent may be in the range of 3 to 50, for example. Is preferably 3 to 40, more preferably 3 to 30, still more preferably 3 to 20, and particularly preferably 3 to 10.
  • the sulfinyl group, mono- or di-alkylamino group and carbonylamino group may be substituted or unsubstituted, but when substituted, an electron-donating group (hydroxy group, amino group, Mono- or gear Kiru)
  • R 1 to R 4 are groups represented by the above formula (I) or the above formula (II), and the remaining one is a hydrogen atom or a substituent (excluding a hydrogen atom).
  • the substituent (provided that the substituent is different from the above formula (I) or the above formula (II)) is not particularly limited, but the substituent of the above monovalent branched chain hydrocarbon group and The same thing can be illustrated.
  • an electron donating group hydroxy group, amino group, mono- or di-alkylamino group, alkoxy group, aryloxy group, etc.
  • an electron withdrawing group halogen atom, carboxyl group).
  • the electron donating group has a structure in which R 1 to R 4 are electronically dense and sterically stable, and the compound is superior. It will have the effect of inhibiting degeneration of dopamine secreting cells and cell death. Therefore, the remaining one substituent is preferably an electron donating group, particularly preferably an alkoxy group among the electron donating groups, and particularly preferably a methoxy group among the alkoxy groups.
  • X 1 is a divalent hydrocarbon group having 1 to 10 carbon atoms which may have a single bond or a substituent.
  • the structure is denser and sterically stable, and the compound is superior in dopamine-secreting cells. It is preferable that it is a single bond, since it has the action of suppressing the degeneration of and cell death.
  • the divalent hydrocarbon group having 1 to 10 carbon atoms in X 1 may be a substituted or unsubstituted divalent aliphatic group or a divalent aromatic group, and may be a saturated hydrocarbon. Group may be an unsaturated hydrocarbon group.
  • the divalent hydrocarbon group may be any of linear, branched, and cyclic forms, and may be a combination of these structures, but the divalent hydrocarbon group is The chain is preferably branched (branched).
  • the divalent hydrocarbon group having 1 to 10 carbon atoms preferably has a smaller number of carbon atoms.
  • the carbon number is preferably 9 or less, 7 or less, more preferably 6 or less, even more preferably 5 or less, even more preferably 4 or less, and 3 or less. It is more preferable that the number of carbon atoms is 2 or less, and it is particularly preferable that the number of carbon atoms is 2 or less.
  • the substituent that the divalent hydrocarbon group having 1 to 10 carbon atoms may have is not particularly limited, and examples thereof are the same as the substituents of the above monovalent branched chain hydrocarbon group.
  • an electron donating group (hydroxy group, amino group, mono- or di-alkylamino group, alkoxy group, aryloxy group, etc.) may be selected, and an electron withdrawing group (halogen atom, carboxyl group).
  • An acyl group, a carbamoyl group, etc. but the electron donating group has a structure in which R 1 to R 4 are electronically dense and sterically stable, and the compound is superior. It will have the effect of inhibiting degeneration of dopamine secreting cells and cell death.
  • the substituent is preferably an electron donating group, and particularly preferably an alkoxy group among the electron donating groups.
  • the alkoxy group is, for example, a linear or branched chain such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, or a tert-butoxy group.
  • the substituent that the divalent hydrocarbon group may have is particularly preferably a methoxy group among the alkoxy groups.
  • the total carbon number of the substituent having a carbon atom is preferably 1 to 6, more preferably 1 to 5, and further preferably 1 to 4. And particularly preferably 1 to 3.
  • the total number of carbon atoms contained in the monovalent heterocyclic group and the substituent may be, for example, in the range of 2 to 15. Is preferably 2 to 10, more preferably 2 to 6, still more preferably 2 to 5, and particularly preferably 2 to 4.
  • the group, mono- or di-alkylamino group and carbonylamino group may be substituted or unsubstituted
  • R 1 to R 4 and each carbon atom to which the OH group is bonded will be described with reference to a to f.
  • a to d are asymmetric carbon atoms among a to f carbon atoms
  • either S configuration or R configuration may be used.
  • E and f are asymmetric carbon atoms, and may be either S configuration or R configuration.
  • the compound of the present invention may or may not contain the compounds represented by the following formulas (1-1) to (1 to 5), but it is preferable not to include them. .
  • the salt of the compound represented by the above formula (1) is not particularly limited, but is preferably a pharmacologically acceptable salt, for example, an inorganic acid (hydrochloric acid, hydrobromic acid, hydrogen iodide). Salts with acids, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids (formic acid, acetic acid, propionic acid, citric acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, succinic acid, malonic acid, maleic acid, lactic acid, malic acid Salts with carbonic acid, glutamic acid, aspartic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc., salts with alkali metals (sodium, potassium, etc.), alkaline earth metals (calcium, magnesium, etc.) And salts with metals (iron, zinc, etc.). These may be used alone or in combination of two or
  • the compound represented by the above formula (1) or a salt thereof may be in the form of a hydrate or a solvate.
  • R 1 to R 4 are groups represented by the formula (I), and R 6 is an oxo group.
  • An example of a production method for the compound (compound represented by the formula (1-a)) is shown.
  • the compound represented by the formula (1-a) can be produced through the following steps (a) and (b).
  • the step (a) is not particularly limited as long as it is a step of dehydrating and condensing the compound represented by the formula (3) and the compound represented by the formula (4) to obtain the compound represented by the formula (5).
  • a known dehydration condensing agent carbodiimide dehydration condensing agent or the like
  • the catalyst a known catalyst (for example, a strong base such as N, N-dimethyl-4-aminopyridine) can be used.
  • Step (b) is a step of obtaining the compound represented by the formula (1-a) from the compound represented by the formula (5).
  • Step (b) can be generally performed by an acetal decomposition reaction with an acid, for example, a heating reflux reaction using an 80% aqueous acetic acid solution.
  • steps (a) and (b) are examples in the case where R 1 to R 4 are a group represented by the formula (I) in the formula (1) and R 6 is an oxo group.
  • R 6 is a hydrogen atom
  • the compound represented by the formula (7) described later instead of the step (a) using the compound represented by the formula (4)
  • a sulfonyl chloride group such as p-toluenesulfonyl chloride is used instead of the compound represented by the formula (4).
  • the above formula (3) It can be produced by using one in which one of the hydroxy groups in the compound represented by the formula is a hydrogen atom or a substituent (excluding R 1 to R 4 ).
  • the present invention includes a therapeutic or prophylactic agent for Parkinson's disease.
  • the therapeutic or preventive drug for Parkinson's disease in the present invention contains a compound represented by the following formula (1) or formula (2) or a pharmacologically acceptable salt thereof as an active ingredient.
  • R 6 to R 9 are each independently a group represented by the following formula (III) or the following formula (IV), or of R 6 to R 9 Three are groups represented by the following formula (III) or the following formula (IV), and the remaining one is a hydrogen atom or a substituent.
  • the following formula (III) and R 5 in the above formula (IV) can be exemplified by the same as R 5 in the above formula (I) or Formula (II).
  • the following formula (III) and X 1 in the formula (IV) may be exemplified the same ones as the X 1 in the above formula (I) or Formula (II).
  • the compound represented by the formula (2) of the present invention a compound in which R 6 to R 9 are derived as necessary from a compound having a sugar skeleton such as glucose can be used.
  • the compound represented by the formula (2) is a derivative from ⁇ -D-glucose
  • the compound represented by the formula (2) can be a compound of the following formula (2-a).
  • Step (c) is a step of obtaining the compound represented by formula (8) by reacting the compound represented by formula (6) with the compound represented by formula (7).
  • the reaction of step (c) can be performed using a base (NaH, NaOH, KOH, etc.).
  • a 1 represents a leaving group (halogen atom (chlorine atom, bromine atom, etc.), —OTs (p-toluenesulfonyl group), —OMs (methanesulfonyl group), etc.).
  • the solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction.
  • DMF N, N-dimethylformamide
  • the compound of formula (6) can be obtained from ⁇ -D-glucose using hydrogen chloride methanol.
  • Step (d) is a step of obtaining a compound represented by the formula (2-a) by reacting a compound represented by the formula (8) with acetic acid.
  • the reaction in the step (d) can be performed using, for example, an acid (sulfuric acid, HCl / SrCl 2 or the like).
  • the reactions (c) and (d) are examples of the case where the compound represented by the formula (2) is a derivative of ⁇ -D-glucose, and ⁇ -D-glucose, ⁇ -L-glucose In the case of a derivative of ⁇ -L-glucose or a derivative of galactose, the same reaction can be performed.
  • the reactions (c) and (d) above are examples in which R 6 to R 9 are groups represented by the formula (III) in the formula (2), and R 6 to R 9 are represented by the formulas
  • the compound represented by the above formula (4) is used instead of the step (c) using the compound represented by the formula (7) It can be obtained by performing a).
  • the Parkinson's disease therapeutic agent or prophylactic agent of the present invention may be formulated.
  • the dosage form is not particularly limited, and includes, for example, injections (intravenous injections (including infusion), intramuscular injections, intraperitoneal injections, subcutaneous injections, etc.), tablets, capsules, liquids, suppositories, It may be formulated into an ointment or the like, and in the case of an injectable preparation, it may be provided in the form of a unit dose ampoule or a multi-dose container.
  • compositions of the present invention may have components other than the compound represented by the above formula (1) or (2) or a pharmacologically acceptable salt thereof for the purpose of formulation. , You do not have to.
  • the administration method of the therapeutic agent or prophylactic agent of the present invention is not particularly limited, and may be oral administration or parenteral administration, and can be appropriately selected according to the dosage form.
  • EDC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
  • DMAP 4-dimethylaminopyridine
  • PTLC preparative thin layer chromatography
  • EtOAc ethyl acetate
  • AcOH acetic acid
  • OMe methoxy group
  • Bn benzyl group
  • Bz Benzoyl group
  • BzCl Benzoyl chloride
  • the compound (1-4) was synthesized with reference to “Tetsuo SUAMI et al., BULLETIN OF CHEMICAL SOCIETY OF JAPAN, VOL. 44, 835-841 (1971)”.
  • the compound (2-1) was prepared according to “Andreas M. Doepner, et al,“ 2′-Deoxy-2 ′, 2′-difluorourine analogues for radiolapping with fluorinet 18 ”. 3293-3297 (2015) ".
  • Compound (2-2) is “Peng Wei, et al,“ Iodine Monochloride (ICl) as a Highly Efficient, Green Oxidant for the Coordination of Alcohols to CoL. 2015) ”and synthesized.
  • Differentiated PC12D cells were treated with 0.3 mM MPP + for 24 hours to form spots in the cells. Then 10 ⁇ g / mL of the compound of the present invention (1-1) or 10 ⁇ g / mL SO82 (control compound) was added. Predetermined staining was performed 8 hours after the addition, and the cells were observed. The results of cell observation are shown in FIG.
  • phase-contrast is the result of observation of cells before staining with a phase contrast microscope.
  • ProteoStat dye is a result of staining the aggresome with ProteoStat Aggresome Detection Kit (manufactured by Enzo) and observing with a confocal microscope.
  • ⁇ -synuclein is the result of immunostaining with anti- ⁇ -synuclein antibody and observation with a confocal microscope.
  • Colocalization is the result of merging the aggresome detected by ProteoStat Aggresome Detection Kit with the ⁇ -synuclein antibody detected by the anti- ⁇ -synuclein antibody.
  • Control indicates an untreated cell.
  • Compound (1-1) indicates a cell to which only compound (1-1) was added without being treated with MPP + .
  • MPP + indicates a cell that has been treated only with MPP + .
  • MPP + + compound (1-1) and “MPP + + SO82” indicate cells to which compound (1-1) or SO82 was added after MPP + treatment, respectively.
  • the chemical formula of SO82, which is a reference compound, is shown below.
  • spots were formed in the cells by MPP + treatment, but these spots were reduced by administration of the compound (1-1) of the present invention, and spot clearance was observed.
  • ⁇ Study-2 using MPP + treated cells Differentiated PC12D cells were treated with 0.3 mM MPP + for 24 hours to form spots in the cells. Subsequently, 10 ⁇ g / mL of the compound (1-1) of the present invention or 10 ⁇ M rapamycin (autophagy inducer) was added. 8 hours after the addition, the cells were stained with Thioflavin S and the cells were observed with a confocal microscope. Thioflavin S stains aggregated proteins. The portion stained with Thioflavin S was considered to be an aggregate of protein containing ⁇ -synuclein. The results of cell observation are shown in FIG. Further, from the image shown in FIG. 2, image analysis was performed using Image J, and the area of the aggregate was calculated.
  • FIG. 3 shows a graph relating to the area of the aggregate / the area of the whole cell (ratio where MPP + is 1 ), which is derived from the calculation result. 2 and 3, “NT” indicates untreated cells. “MPP + ” indicates cells treated with MPP + alone. “MPP + + compound (1-1)” and “MPP + + rapamycin” indicate cells to which the compound (1-1) or rapamycin of the present invention was added after MPP + treatment, respectively.
  • spots are formed on the cells by treatment with MPP + ( “MPP +”).
  • the spots were decreased by administration of the compound (1-1) of the present invention, and the clearance of the spots was observed (“MPP + + compound (1-1)”).
  • the clearance effect was equivalent to or better than rapamycin.
  • “Ctrl” indicates an untreated cell.
  • “MPP + ” indicates cells treated with MPP + alone.
  • “MPP + + compound (1-1)” indicates a cell to which compound (1-1) 1 or 10 ⁇ g / mL of the present invention was added simultaneously with MPP + .
  • F represents the number of cells in the subG1 phase
  • E represents the G1 phase
  • D represents the S phase
  • C represents the G2 / M phase.
  • the horizontal axis is the fluorescence intensity
  • the vertical axis is the number of cells.
  • the numbers (unit:%) in FIG. 4 indicate the ratio of the number of cells in the subG1 phase to the total number of cells.
  • the compound of the present invention can be used as a new therapeutic agent for Parkinson's disease that can suppress degeneration and cell death of dopamine secreting cells.

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Abstract

La présente invention vise à procurer un composé qui produit son effet sur le mécanisme de déclenchement de la maladie de Parkinson par inhibition de la dégénérescence et de la mort cellulaire des cellules sécrétant de la dopamine, et un médicament thérapeutique ou prophylactique contre la maladie de Parkinson. La présente invention concerne un composé représenté par la formule (1) ou un sel correspondant. (Dans la formule (1), R1 à R4 représentent chacun indépendamment un groupe représenté par la formule (I) ou la formule (II), ou trois groupes parmi R1 à R4 représentent un groupe représenté par la formule (I) ou la formule (II), le reste représentant un atome d'hydrogène ou un substituant, et dans la formule (I) et la formule (II), R5 représente un groupe hydrocarboné ramifié monovalent éventuellement substitué possédant 3 atomes de carbone ou plus, un groupe carbocyclique monovalent monocyclique à tricyclique de 5 à 10 chaînons éventuellement substitué, ou un groupe hétérocyclique monovalent monocyclique à tricyclique de 3 à 10 chaînons éventuellement substitué, et X1 représente une liaison simple ou un groupe hydrocarboné divalent éventuellement substitué possédant 1 à 10 atomes de carbone.)
PCT/JP2017/024921 2016-07-07 2017-07-07 Composé dihydroxy ou sel correspondant, et médicament thérapeutique ou prophylactique contre la maladie de parkinson Ceased WO2018008737A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993011731A2 (fr) * 1991-12-12 1993-06-24 The Trustees Of The University Of Pennsylvania Peptidomimetisme alicyclique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993011731A2 (fr) * 1991-12-12 1993-06-24 The Trustees Of The University Of Pennsylvania Peptidomimetisme alicyclique

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
GAREGG, PER J. ET AL.: "Synthesis of some benzyl and methyl ethers of myo-inositol", CARBOHYDRATE RESEARCH, vol. 173, 1988, pages 205 - 216, XP026622192 *
LEE, B.-Y. ET AL.: "Synthesis of glycosylphosphatidylinositol (GPI)-anchor glycolipids bearing unsaturated lipids", CHEMICAL COMMUNICATIONS, vol. 52, 28 January 2016 (2016-01-28), pages 1586 - 1589, XP055452449 *
SAITO, SHINTARO ET AL.: "Diastereoselective synthesis of D- and L-myo-inositol 3,4,5,6- tetrakisphosphates from D-glucose via dihydroxylation of (+)-conduritol B derivatives", CHEMICAL & PHARMACEUTICAL BULLETIN, vol. 52, 2004, pages 727 - 732 *
SUAMI, TETSUO ET AL.: "p-Toluenesulfonylation of 1 , 2-0 -cyclohexylidene-myo-inositol", BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN, vol. 44, 1971, pages 835 - 41 *
SWARTS, BENJAMIN M. ET AL.: "Synthesis of a Glycosylphosphatidylinositol Anchor Bearing Unsaturated Lipid Chains", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 132, 19 May 2010 (2010-05-19), pages 6648 - 6650, XP055452441 *

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