WO2018008737A1 - Dihydroxy compound or salt thereof, and therapeutic or prophylactic drug for parkinson's disease - Google Patents

Abstract

The present invention addresses the problem of providing a compound which exerts its effect on the onset mechanism of Parkinson's disease by inhibiting the degeneration and cell death of dopamine-secreting cells, and a therapeutic or prophylactic drug for Parkinson's disease. The present invention provides a compound represented by formula (1) or a salt thereof. (In formula (1), R¹-R⁴ each independently represent a group represented by formula (I) or formula (II), or three among R¹-R⁴ represent a group represented by formula (I) or formula (II), and the remaining one represents a hydrogen atom or a substituent, and in formula (I) and formula (II), R⁵ represents an optionally substituted monovalent branched chain hydrocarbon group having 3 or more carbon atoms, an optionally substituted 5-10 membered mono- to tri-cyclic monovalent carbocyclic group, or an optionally substituted 3-10 membered mono- to tri-cyclic monovalent heterocyclic group, and X¹ represents a single bond or an optionally substituted divalent hydrocarbon group having 1-10 carbon atoms.)

Description

Dihydroxy compound or salt thereof, and Parkinson's disease therapeutic or prophylactic agent

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.

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.

However, 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.

For this reason, there has been a demand for a therapeutic agent that acts on the pathogenesis of Parkinson's disease by suppressing the degeneration and cell death of dopamine-secreting cells, and is expected to be a fundamental treatment for Parkinson's disease. There was no disease 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.

In the cultured cell system, 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 α-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.

[1] A compound represented by the following formula (1) or a salt thereof.

(In the formula (1), 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,
In the formula (I) and the formula (II), 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 X ¹ is a divalent hydrocarbon group having 1 to 10 carbon atoms which may have a single bond or a substituent,
In the formula (I), R ⁶ is a hydrogen atom or an oxo group, and the dotted line is the presence or absence of a bond. )

[2] 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 compound or a salt thereof according to [1], which is an adamantyl group.

[3] 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 The compound or salt thereof according to any one of [1] to [3], wherein the monocyclic to tricyclic monovalent heterocyclic group is substituted with an electron donating group.

[5] 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.

(In the formula (1), 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,
In formula (2), 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,
In the formula (I), the formula (II), the formula (III) and the formula (IV), 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, and X ¹ is a C 1-10 divalent hydrocarbon group which may have a single bond or a substituent,
In the formula (I), R ⁶ is a hydrogen atom or an oxo group, and the dotted line is the presence or absence of a bond. )

According to 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 α-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 α-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.

Hereinafter, embodiments of the present invention will be described, but the present invention is not limited thereto and can be appropriately changed.

<Compound>
The present invention is a compound represented by the following formula (1) or a salt thereof.

In formula (1), 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.

In the compound of the present invention, at least three of 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). Here, 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. When the three-dimensional structure is stabilized, high activity is easily obtained when acting on proteins and the like in the pathogenesis of Parkinson's disease. For these reasons, 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. Of these, 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.

In the above formula (I) or the above formula (II), 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. In the above formula (I), 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 (excluding the carbon number of the substituent) 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.

Specific examples of the monovalent branched chain hydrocarbon group include groups represented by the following formulas (V) and (IV). In addition, the hydrogen atom couple | bonded with the carbon atom in the group represented by the following formula | 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, alkylsulfinyl group, alkenylsulfinyl group, alkynylsulfinyl group, Mono or di Alkylamino group, carbonylamino group, and the like. Further, among the above substituents, 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. Among the substituents of the above monovalent branched chain hydrocarbon group, 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 σ defined by the Hammett formula described in 165-195 means a negative substituent.

Of the substituents of the monovalent branched chain hydrocarbon group, 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. Group, tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, cyclopentyl And a linear or branched alkyl group such as a cyclohexyl group. Among the monovalent branched chain hydrocarbon groups, 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. Among the monovalent branched chain hydrocarbon groups, examples of the alkynyl group include linear or branched alkynyl groups such as ethynyl group, propargyl group, butynyl group, and pentynyl group. Among the substituents of the monovalent branched chain hydrocarbon 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. Of the substituents of the above monovalent branched chain hydrocarbon group, 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. Of the substituents of the monovalent branched chain hydrocarbon group, 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.

Among the substituents of the monovalent branched chain hydrocarbon group, 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.

Among the substituents of the above monovalent branched chain hydrocarbon group, examples of the hetero atom contained in the heterocyclic group 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). Specific examples of the 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, pyrazinyl group. Group, pyrimidinyl group, pyridazinyl group, indolyl group, isoindole group, quinolyl group, quinoxalyl group, isoquinolyl group, isoxazolyl group, tetrazolyl group, phthalazyl group, imidazopyridyl group, naphthyridyl group, quinazolyl group, acridinyl group and the like.

Among the substituents of the above monovalent branched chain hydrocarbon group, the acyl group is, for example, formyl group, alkyl (or cycloalkyl) -carbonyl group (for example, acetyl group, propionyl group, butyryl group, isobutyryl group). 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.

Among the substituents of the monovalent branched chain hydrocarbon group, alkoxy in the alkoxycarbonyl group can exemplify the above alkoxy group. Of the monovalent branched chain hydrocarbon groups, the acyl in the acyloxy group can be exemplified by the above acyl group. Of the monovalent branched chain hydrocarbon groups, the aryl in the aryloxy group can exemplify the above aryl group. Among the monovalent branched chain hydrocarbon groups, 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. Among the monovalent branched chain hydrocarbon groups, the alkenyl in the alkenylthio group, alkenylsulfonyl group and alkenylsulfinyl group can exemplify the above alkenyl group. Among the monovalent branched chain hydrocarbon groups, alkynyl in the alkynylthio group, alkynylsulfonyl group, and alkynylsulfinyl group can exemplify the above alkynyl group.

Of the substituents of the monovalent branched chain hydrocarbon 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. When the monovalent branched chain hydrocarbon group has a substituent, 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.

Among the substituents of the monovalent branched chain hydrocarbon group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkynyl group, an aryl group, a heteroaryl group, an acyl group, Alkoxy, alkenyloxy, alkynyloxy, alkoxycarbonyl, acyloxy, aryloxy, alkylthio, alkenylthio, alkynylthio, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, alkylsulfinyl, alkenyl The sulfinyl group, alkynylsulfinyl 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, A non- or di-alkylamino group, an alkoxy group, an aryloxy group, etc.), more preferably an electron-donating group, more preferably an alkoxy group, and among the alkoxy groups, A methoxy group is particularly preferred.

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. As the aryl 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. Among the substituents, 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. Accordingly, the substituent is preferably an electron donating group, and particularly preferably an alkoxy group among the electron donating groups. Among the substituents of the monovalent carbocyclic group, 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. Of the alkoxy group. The substituent which the monovalent carbocyclic group may have is particularly preferably a methoxy group among the alkoxy groups.

Of the substituents of the monovalent carbocyclic group, 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. In the case where the monovalent carbocyclic group has a substituent, 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.

Among the substituents of the above monovalent carbocyclic group, 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 Kiruamino group, an alkoxy group, that is substituted by an aryl group and the like) Preferably, among the electron-donating group, more preferably substituted by an alkoxy group, among the alkoxy groups, a methoxy group is particularly preferred.

Particularly preferred examples of the monovalent carbocyclic group include a group (phenyl group) represented by the following formula (VII). In 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.

In the group represented by the formula (VII), it is preferable that at least the ortho position with respect to the carbon atom to which X ¹ is bonded in the formula (I) or the formula (II) is substituted, that is, in the formula (VII) , R ⁷ or R ¹¹ is preferably substituted.

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.

Specific examples of 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. Group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, indolyl group, isoindole group, quinolyl group, quinoxalyl group, isoquinolyl group, isoxazolyl group, tetrazolyl group, phthalazyl group, imidazopyridyl group, naphthyridyl group, quinazolyl group, acridinyl group, etc. Can be mentioned.

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. Among the substituents, 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. Accordingly, the substituent is preferably an electron donating group, and particularly preferably an alkoxy group among the electron donating groups. Among the substituents of the above monovalent heterocyclic group, 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. Of the alkoxy group. The substituent that the monovalent heterocyclic group may have is particularly preferably a methoxy group among the alkoxy groups.

Among the substituents of the above monovalent heterocyclic group, 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. In the case where the monovalent heterocyclic group has a substituent, 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.

Among the substituents of the above monovalent heterocyclic group, 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 Kiruamino group, an alkoxy group, that is substituted by an aryl group and the like) Preferably, among the electron-donating group, more preferably substituted by an alkoxy group, among the alkoxy groups, a methoxy group is particularly preferred.

Three of 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). In some cases, 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. Among the substituents, 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. 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. However, 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. In addition, 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 (excluding the carbon number of the substituent) preferably has a smaller number of carbon atoms. Specifically, 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. The Among the substituents, 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. Accordingly, the substituent is preferably an electron donating group, and particularly preferably an alkoxy group among the electron donating groups. Among the substituents of the above monovalent heterocyclic group, 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. Of the alkoxy group. The substituent that the divalent hydrocarbon group may have is particularly preferably a methoxy group among the alkoxy groups.

Among the substituents of the above divalent hydrocarbon group, 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. In the case where the monovalent heterocyclic group has a substituent, 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.

Among the substituents of the above divalent hydrocarbon group, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, cycloalkynyl group, aryl group, heteroaryl 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, alkylsulfinyl group, alkenylsulfinyl group, alkynylsulfinyl group The 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 group) -Or gear Kiruamino group, an alkoxy group, that is substituted by an aryl group and the like) Preferably, among the electron-donating group, more preferably substituted by an alkoxy group, among the alkoxy groups, a methoxy group is particularly preferred.

In the following formula (1), 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.

When 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 more. These pharmacologically acceptable salts can be prepared according to a conventional method.

In the present invention, the compound represented by the above formula (1) or a salt thereof may be in the form of a hydrate or a solvate.

<Method for producing compound>
An example of the method for producing the compound represented by the formula (1) described above will be described below, but the method for producing the compound of the present invention is not limited to this and can be appropriately changed. Specifically, in the following, among the compounds represented by the formula (1), 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. For example, 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). For example, a known dehydration condensing agent (carbodiimide dehydration condensing agent or the like) can be used. As 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.

The above 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. For example, in the case where R ⁶ is a hydrogen atom, for example, the compound represented by the formula (7) described later instead of the step (a) using the compound represented by the formula (4) It can be obtained by using the step (c) using In the formula (1), when R ¹ to R ⁴ are a group represented by the formula (II), a sulfonyl chloride group such as p-toluenesulfonyl chloride is used instead of the compound represented by the formula (4). Can be obtained.

When the compound represented by the formula (1) is a hydrogen atom or a substituent (excluding R ¹ to R ⁴ ) out of R ¹ to R ^{4 in} the formula (1), 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 ).

<Parkinson's disease treatment or prevention agent>
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.

As the compound represented by the above formula (1), the same compounds as those of the present invention can be used.

In the above formula (2), 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).

As 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. For example, when the compound represented by the formula (2) is a derivative from β-D-glucose, the compound represented by the formula (2) can be a compound of the following formula (2-a).

Synthesis of the compound of the above formula (2-a) from β-D-glucose can be performed by a known method. For example, in the above formula (2-a), when R ⁶ to R ⁹ are groups represented by the formula (III), they can be synthesized by the following steps (c) and (d).

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.). In formula (7), 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. For example, DMF (N, N-dimethylformamide) can be used. The compound of formula (6) can be obtained from β-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 β-D-glucose, and α-D-glucose, β-L-glucose In the case of a derivative of α-L-glucose or a derivative of galactose, the same reaction can be performed. In addition, 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 In the case of the group represented by (IV), 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.

These various preparations include excipients, extenders, binders, wetting agents, disintegrants, lubricants, surfactants, dispersants, buffers, preservatives, solubilizers, preservatives, It can be produced by a conventional method using a flavoring agent, a soothing agent, a stabilizer, a tonicity agent and the like as appropriate. The pharmaceutical composition 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.

(Abbreviation)
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

<Synthesis Example 1>
[Synthesis of (1R, 2S, 3R, 4S, 5R, 6S) -5,6-dihydroxycyclohexane-1,2,3,4-tetrayl tetrakis (4-bromobenzoic acid)]
A mixture of compound (3-2) (3.05 g, 11.72 mmol), paratoluenesulfonyl chloride (2.70 g, 14.16 mmol) and pyridine (30 mL) was stirred at room temperature for 3.5 hours. The organic layers were combined, washed with water, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue (compound (9)) was dried by refluxing a mixture of anhydrous potassium carbonate (4 g, 36.23 mmol) and 80% aqueous 2-methoxy-ethanol (200 mL) for 3.5 hours and then evaporated. The residue was recrystallized from ethanol and dried by co-distillation with anhydrous benzene to obtain compound (3-1). To a stirred solution of 4-bromobenzoic acid (compound (4-1)) (167.7 mg, 0.83 mmol) and EDC (159.4 mg, 0.83 mmol) was added compound (3 in CH ₂ Cl ₂ (7 mL)). -1) (21.7 mg, 83.4 μmol) and DMAP (5.0 mg) were added. The resulting mixture was stirred at room temperature for 5 hours. The organic layers were combined, washed with water and saturated aqueous NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/4) to obtain compound (5-1) (40.7 mg, 49%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.92 (1H, t, J = 2.0 Hz), 7.90 (1H, t, J = 2.0 Hz), 7.82 (1H, t, J = 2. 0 Hz), 7.80 (1 H, t, J = 2.0 Hz), 7.60 (1 H, t, J = 2.0 Hz), 7.59 (1 H, t, J = 2.0 Hz), 7. 54 (1H, t, J = 2.0 Hz), 7.52 (1H, t, J = 2.0 Hz), 6.02 (1H, dd, J = 3.5, 6.5 Hz), 5.76 (1H, dd, J = 2.5, 9.0 Hz), 4.53 (1H, dd, J = 4.0, 8.5 Hz), 2.02-1.43 (6H, m).

A stirred solution of compound (5-1) (20.9 mg, 21.1 μmol) in 80% AcOH (7 mL) was heated at 120 ° C. for 5 hours and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/4) to obtain compound (1-6) (7.3 mg, 28%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CD ₃ OD) δ 7.89 (2H, d, J = 9.0 Hz), 7.79 (2H, d, J = 8.5 Hz), 7.59 (2H, d, J = 8) .5 Hz), 7.52 (2H, d, J = 9.0 Hz), 5.86-5.82 (2H, m), 4.32 (1H, d, J = 4.5 Hz).

<Synthesis Example 2>
[Synthesis of (1R, 2S, 3R, 4S, 5R, 6S) -5,6-dihydroxycyclohexane-1,2,3,4-tetrayl tetrakis (4-chlorobenzoic acid)]
To a stirred solution of 4-chlorobenzoic acid (136.5 mg, 0.87 mmol) and EDC (166.7 mg, 0.87 mmol) was added compound (3-1) (22.7 mg, CH ₂ Cl ₂ (7 mL). 87.2 μmol) and DMAP (5.0 mg) were added. The resulting mixture was stirred at room temperature for 5 hours. The organic layers were combined, washed with water and saturated aqueous NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/4) to obtain compound (5-2) (21.3 mg, 34%) as a white powder. The results of the NMM spectrum and the reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 8.00 (1H, t, J = 2.0 Hz), 7.98 (1H, t, J = 2.0 Hz), 7.90 (1H, t, J = 2. 0 Hz), 7.88 (1 H, t, J = 2.0 Hz), 7.44 (1 H, t, J = 2.0 Hz), 7.42 (1 H, t, J = 2.0 Hz), 7. 37 (1H, t, J = 2.0 Hz), 7.35 (1H, t, J = 2.0 Hz), 6.02 (1H, dd, J = 3.5, 6.0 Hz), 5.77 (1H, dd, J = 2.0, 8.5 Hz), 4.53 (1H, dd, J = 4.5, 8.5 Hz), 1.70-1.42 (6H, m).

A stirred solution of compound (5-2) (7.3 mg, 89.0 μmol) in 80% AcOH (3 mL) was heated at 120 ° C. for 8 hours and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/4) to obtain compound (1-7) (4.4 mg, 67%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.96 (2H, d, J = 8.5 Hz), 7.87 (2H, d, J = 8.5 Hz), 7.42 (2H, d, J = 8. 5 Hz), 7.35 (1H, d, J = 8.5 Hz), 5.88-5.83 (2H, m), 4.33 (1H, d, J = 5.0 Hz).

<Synthesis Example 3>
[Synthesis of (1R, 2S, 3R, 4S, 5R, 6S) -5,6-dihydroxycyclohexane-1,2,3,4-tetrayl tetrakis (4-fluorobenzoic acid)]
To a stirred solution of 4-fluorobenzoic acid (280.2 mg, 1.94 mmol) and EDC (383.4 mg, 1.94 mmol) was added compound (3-1) (50.6 mg, CH ₂ Cl ₂ (6 mL). 0.19 μmol) and DMAP (5.0 mg) were added. The resulting mixture was stirred at room temperature for 24 hours. The organic layers were combined, washed with water and saturated aqueous NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/4) to obtain compound (5-3) (47.3 mg, 31%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
H NMR (CDCl ₃ ) δ 8.09-8.07 (2H, m), 8.00-7.97 (2H, m), 7.12 (2H, t, J = 8.5 Hz), 7. 05 (1H, t, J = 8.5 Hz), 6.04 (1H, dd, J = 3.5, 6.0 Hz), 5.79 (1H, dd, J = 2.5, 8.5 Hz) 4.55 (1H, dd, J = 4.0, 8.0 Hz), 2.03-1.42 (6H, m).

A stirred solution of compound (5-3) (76.9 mg, 102.7 μmol) in 80% AcOH (7 mL) was heated at 120 ° C. for 12 hours and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/2) to give compound (1-8) (19.3 mg, 28%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CD ₃ OD) δ 8.27 (2H, dd, J = 5.5, 9.0 Hz), 8.13 (2H, t, J = 7.0 Hz), 7.40 (2H, t , J = 9.0 Hz), 7.34 (1H, t, J = 9.0 Hz), 6.06 (1H, s), 5.96 (1H, dd, J = 3.0, 8.5 Hz) 4.56 (1H, dd, J = 3.0, 8.0 Hz).

<Synthesis Example 4>
[Synthesis of (1R, 2S, 3R, 4S, 5R, 6S) -5,6-dihydroxycyclohexane-1,2,3,4-tetrayl tetrakis (4-iodobenzoic acid)]
To a stirred solution of 4-iodobenzoic acid (227.7 mg, 0.92 mmol) and EDC (176.0 mg, 0.92 mmol) was added compound (3-1) (23.9 mg, CH ₂ Cl ₂ (7 mL)). 91.8 μmol) and DMAP (5.0 mg) were added. The resulting mixture was stirred at room temperature for 27 hours. The organic layers were combined, washed with water and saturated aqueous NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/4) to give compound (5-4) (45.5 mg, 42%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.83 (1H, t, J = 2.0 Hz), 7.81 (1H, t, J = 2.0 Hz), 7.75 (2H, dd, J = 2. 0, 8.5 Hz), 7.73 (2H, dd, J = 2.0, 8.5 Hz), 7.65 (1H, t, J = 2.0 Hz), 7.63 (1H, t, J = 2.0 Hz), 6.00 (1H, dd, J = 3.5, 6.0 Hz), 5.74 (1H, dd, J = 3.5, 8.5 Hz), 4.52 (1H, dd, J = 4.5, 8.5 Hz), 1.69-1.41 (6H, m).

A stirred solution of compound (5-4) (11.8 mg, 11.0 μmol) in 80% AcOH (5 mL) was heated at 120 ° C. for 4 hours and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/2) to give compound (1-9) (2.5 mg, 22%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.84 (1H, s, J = 2.0 Hz), 7.82 (1H, t, J = 2.0 Hz), 7.77 (1H, t, J = 2. 0 Hz), 7.75 (2H, dd, J = 2.0, 5.0 Hz), 7.73 (1H, t, J = 2.0 Hz), 7.65 (1H, s), 7.63 ( 1H, s), 5.85-5.81 (2H, m), 4.31 (1H, d, J = 5.0 Hz).

<Synthesis Example 5>
[Synthesis of (1R, 2S, 3R, 4S, 5R, 6S) -5,6-dihydroxycyclohexane-1,2,3,4-tetrayl tetrakis (2-fluorobenzoic acid)]
To a stirred solution of 2-fluorobenzoic acid (110.5 mg, 0.79 mmol) and EDC (151.3 mg, 0.79 mmol) was added compound (3-1) (22.9 mg, CH ₂ Cl ₂ (7 mL). 78.9 μmol) and DMAP (5.0 mg). The resulting mixture was stirred at room temperature for 6 hours. The organic layers were combined, washed with water and saturated aqueous NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/4) to give compound (5-5) (44.5 mg, 75%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.92-8.00 (2H, m), 7.56-7.48 (2H, m), 7.24-7.21 (1H, m), 7.17 −7.01 (3H, m), 6.11 (1H, dd, J = 3.5, 5.5 Hz), 4.55 (1H, dd, J = 2.0, 8.5 Hz); 53 (1H, dd, J = 4.0, 8.0 Hz), 1.37-1.61 (6H, m).

A stirred solution of compound (5-5) (26.3 mg, 35.1 μmol) in 80% AcOH (5 mL) was heated at 120 ° C. for 22 hours and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/2) to give compound (1-10) (4.6 mg, 20%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.98-7.94 (1H, m), 7.89-7.85 (2H, m), 7.56-7.49 (2H, m), 7.22 (1H, t, J = 2.5 Hz), 7.15 (1H, d, J = 7.0 Hz), 5.95 (1H, d, J = 6.0 Hz), 5.92-5.89 ( 1H, m), 4.31 (1H, m).

<Synthesis Example 6>
[Synthesis of (1R, 2S, 3R, 4S, 5R, 6S) -5,6-dihydroxycyclohexane-1,2,3,4-tetrayl tetrakis (3,4-difluorobenzoic acid)]
To a stirred solution of 3,4-difluorobenzoic acid (121.7 mg, 0.77 mmol) and EDC (147.6 mg, 0.77 mmol) was added compound (3-1) (20.) in CH ₂ Cl ₂ (7 mL). 1 mg, 77.0 μmol) and DMAP (5.0 mg) were added. The resulting mixture was stirred at room temperature for 19 hours. The organic layers were combined, washed with water and saturated aqueous NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/4) to give compound (5-6) (24.7 mg, 39%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.90-7.85 (2H, m), 7.80-7.73 (2H, m), 7.29-7.25 (1H, m), 7.23 −7.16 (1H, m), 5.98 (1H, dd, J = 3.5, 6.0 Hz), 5.74 (1H, dd, J = 2.5, 8.5 Hz), 4. 54 (1H, dd, J = 4.5, 8.5 Hz), 2.02-1.44 (6H, m).

A stirred solution of compound (5-6) (13.8 mg, 16.8 μmol) in 80% AcOH (5 mL) was heated at 120 ° C. for 7 hours and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/4) to obtain compound (1-11) (7.9 mg, 64%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.89-7.83 (2H, m), 7.79-7.73 (2H, m), 7.29-7.27 (1H, m), 7.22 −7.17 (1H, m), 5.84 (1H, t, J = 5.5 Hz), 5.79 (1H, dd, J = 2.5, 8.5 Hz), 4.33 (1H, s).

<Synthesis Example 7>
[Synthesis of (1R, 2S, 3R, 4S, 5R, 6S) -5,6-dihydroxycyclohexane-1,2,3,4-tetrayl tetrakis (3,4,5-trifluorobenzoic acid)]
To a stirred solution of 3,4,5-trifluorobenzoic acid (143.3 mg, 0.81 mmol) and EDC (156.0 mg, 0.81 mmol) was added compound (3-1) in CH ₂ Cl ₂ (10 mL). (21.2 mg, 81.4 μmol) and DMAP (5.0 mg) were added. The resulting mixture was stirred at room temperature for 48 hours. The organic layers were combined, washed with water and saturated aqueous NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/4) to give compound (5-7) (24.8 mg, 34%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.72 (2H, t, J = 7.0 Hz), 7.59 (2H, t, J = 7.0 Hz), 5.92 (1H, dd, J = 3. 5, 5.5 Hz), 5.70 (1H, m, J = 3.5, 5.5 Hz), 4.54 (1H, m, J = 6.0, 8.0 Hz), 2.00-1 .45 (6H, m).

A stirred solution of compound (5-7) (9.4 mg, 10.5 μmol) in 80% AcOH (5 mL) was heated at 120 ° C. for 5 hours and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/10) to give compound (1-12) (5.1 mg, 59%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.70 (2H, t, J = 7.0 Hz), 7.60 (2H, t, J = 7.0 Hz), 5.81 (1H, t, J = 6. 0 Hz), 5.75 (1H, dd, J = 3.0, 8.5 Hz), 4.33 (1H, d, J = 5.0 Hz).

<Synthesis Example 8>
[Synthesis of (1R, 2S, 3R, 4S, 5R, 6S) -5,6-dihydroxycyclohexane-1,2,3,4-tetrayl tetrakis (4- (trifluoromethyl) benzoic acid)]
To a stirred solution of 4- (trifluoromethyl) benzoic acid (149.1 mg, 0.78 mmol) and EDC (149.9 mg, 0.78 mmol) was added compound (3-1) in CH ₂ Cl ₂ (7 mL) ( 20.4 mg, 78.4 μmol) and DMAP (5.0 mg) were added. The resulting mixture was stirred at room temperature for 24 hours. The organic layers were combined, washed with water and saturated aqueous NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/5) to give compound (5-8) (31.0 mg, 40%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 8.18 (2H, d, J = 8.0 Hz), 8.07 (2H, d, J = 8.0 Hz), 7.73 (2H, d, J = 8. 0 Hz), 7.66 (2H, d, J = 8.5 Hz), 6.08 (1H, dd, J = 3.5, 5.5 Hz), 5.84 (1H, dd, J = 2.0) 8.5 Hz), 4.59 (1H, dd, J = 4.5, 8.5 Hz), 1.72-1.43 (6H, m).

A stirred solution of compound (5-8) (13.3 mg, 15.5 μmol) in 80% AcOH (5 mL) was heated at 120 ° C. for 7 hours and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/5) to give compound (1-13) (4.5 mg, 37%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 8.17 (2H, d, J = 8.0 Hz), 8.07 (2H, d, J = 8.0 Hz), 7.73 (2H, d, J = 8. 3 Hz), 7.66 (2H, d, J = 8.0 Hz), 5.95 (1H, t, J = 5.2 Hz), 5.91 (1H, d, J = 6.0 Hz), 4. 39 (1H, d, J = 5.2 Hz).

<Synthesis Example 9>
[Synthesis of (1R, 2S, 3R, 4S, 5R, 6S) -5,6-dihydroxycyclohexane-1,2,3,4-tetrayl tetrakis (3- (trifluoromethyl) benzoic acid)]
To a stirred solution of 3- (trifluoromethyl) benzoic acid (155.5 mg, 0.81 mmol) and EDC (156.8 mg, 0.81 mmol) was added compound (3-1) in CH ₂ Cl ₂ (7 mL) ( 20.4 mg, 78.4 μmol) and DMAP (5.0 mg) were added. The resulting mixture was stirred at room temperature for 24 hours. The organic layers were combined, washed with water and saturated aqueous NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/5) to give compound (5-9) (31.5 mg, 45%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 8.32 (1H, s), 8.26 (1H, d, J = 8.0 Hz), 8.21 (1H, s), 8.13 (1H, d, J = 8.0 Hz), 7.85 (1H, d, J = 7.7 Hz), 7.83 (1H, d, J = 7.7 Hz), 7.62 (1H, t, J = 7.7 Hz) 7.54 (1H, t, J = 8.0 Hz), 6.06 (1H, dd, J = 3.5, 6.0 Hz), 5.84 (1H, dd, J = 2.3, 8) .6 Hz), 4.62 (1H, dd, J = 4.0, 8.6 Hz), 1.72-1.43 (6H, m).

A stirred solution of compound (5-9) (17.5 mg, 18.4 μmol) in 80% AcOH (5 mL) was heated at 120 ° C. for 7 hours and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/5) to give compound 1-14) (8.7 mg, 54%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 8.30 (1H, s), 8.24 (1H, d, J = 7.5 Hz), 8.20 (1H, s), 8.15 (1H, d, J = 8.0 Hz), 7.85 (1H, d, J = 8.0 Hz), 7.80 (1H, d, J = 7.5 Hz), 7.62 (1H, t, J = 7.5 Hz) 7.55 (1H, d, J = 7.5 Hz), 5.93 (2H, s), 4.42 (1H, d, J = 5.0 Hz).

<Synthesis Example 10>
[Synthesis of (1R, 2S, 3R, 4S, 5R, 6S) -5,6-dihydroxycyclohexane-1,2,3,4-tetrayl tetrakis (2- (trifluoromethyl) benzoic acid)]
To a stirred solution of 2- (trifluoromethyl) benzoic acid (147.5 mg, 0.78 mmol) and EDC (148.8 mg, 0.78 mmol) was added compound (3-1) in CH ₂ Cl ₂ (7 mL) ( 20.2 mg, 77.6 μmol) and DMAP (5.0 mg) were added. The resulting mixture was stirred at room temperature for 18 hours. The organic layers were combined, washed with water and saturated aqueous NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/6) to give compound (5-10) (15.8 mg, 22%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.94 (1H, dd, J = 1.5, 7.5 Hz), 7.86 (1H, dd, J = 3.5, 5.5 Hz), 7.77 ( 1H, dd, J = 3.0, 5.0 Hz), 7.74 (1H, dd, J = 1.5, 8.0 Hz), 7.64 (2H, dd, J = 3.5, 6. 0 Hz), 7.61 (1H, dd, J = 1.0, 7.5 Hz), 7.61 (1H, dd, J = 1.5, 7.5 Hz), 5.99 (1H, dd, J = 3.5, 6.0 Hz), 5.79 (1H, dd, J = 2.0, 9.0 Hz), 4.51 (1H, d, J = 4.0 Hz), 1.64-1. 56 (6H, m).

A stirred solution of compound (5-10) (12.5 mg, 13.2 μmol) in 80% AcOH (5 mL) was heated at 120 ° C. for 3 hours and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/1) to obtain compound (1-15) (8.2 mg, 72%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.88 (1H, d, J = 6.5 Hz), 7.86-7.84 (1H, m), 7.79-7.77 (1H, m), 7 .72 (1H, d, J = 7.5 Hz), 7.66-7.63 (2H, m), 7.61-7.58 (2H, m), 5.88 (1H, t, J = 5.5 Hz), 5.82 (1H, dd, J = 2.5, 8.5 Hz), 4.31 (1H, d, J = 5.0 Hz).

<Synthesis Example 11>
[Synthesis of (1R, 2S, 3R, 4S, 5R, 6S) -5,6-dihydroxycyclohexane-1,2,3,4-tetrayl tetrakis (4-nitrobenzoic acid)]
To a stirred solution of 4-nitrobenzoic acid (145.0 mg, 0.87 mmol) and EDC (166.4 mg, 0.87 mmol) was added compound (3-1) (22.6 mg, CH ₂ Cl ₂ (7 mL). 86.8 μmol) and DMAP (5.0 mg) were added. The resulting mixture was stirred at room temperature for 60 hours. The organic layers were combined, washed with water and saturated aqueous NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/2) to give compound (5-11) (21.8 mg, 36%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 8.34 (1H, t, J = 2.0 Hz), 8.32 (1H, t, J = 2.0 Hz), 8.27-8.24 (4H, m) 6.09 (1H, dd, J = 3.5, 5.5 Hz), 5.85 (1H, dd, J = 3.5, 2.5 Hz), 4.63 (1H, dd, J = 4) 0.0, 8.5 Hz), 1.67-1.40 (6H, m).

A stirred solution of compound (5-11) (13.3 mg, 15.5 μmol) in 80% AcOH (5 mL) was heated at 120 ° C. for 4 hours and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/2) to give compound (1-16) (4.5 mg, 37%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 8.32 (3H, t, J = 9.5 Hz), 8.29 (1H, s), 8.25 (2H, d, J = 3.0 Hz), 8.22 (2H, d, J = 2.0 Hz), 6.00-5.96 (1H, m), 5.90 (1H, t, J = 6.0 Hz), 4.43 (1H, d, J = 5.0 Hz).

<Synthesis Example 12>
[Synthesis of (1R, 2S, 3R, 4S, 5R, 6S) -5,6-dihydroxycyclohexane-1,2,3,4-tetrayl tetrakis (furan-2-carboxylic acid)]
To a stirred solution of 2-furancarboxylic acid (94.3 mg, 0.84 mmol) and EDC (161.2 mg, 0.84 mmol) was added compound (3-1) (21.9 mg, CH ₂ Cl ₂ (7 mL). 84.1 μmol) and DMAP (5.0 mg) were added. The resulting mixture was stirred at room temperature for 18 hours. The organic layers were combined, washed with water and saturated aqueous NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/4) to give compound (5-12) (25.4 mg, 47%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.57 (1H, q, J = 0.5 Hz), 7.53 (1H, q, J = 1.0 Hz), 7.24 (1H, d, 1.0 Hz) 7.12 (1H, dd, J = 1.0, 3.5 Hz), 6.49 (1H, dd, J = 2.0, 3.5 Hz), 6.44 (1H, dd, J = 1) .5, 3.5 Hz), 5.93 (1H, dd, J = 3.5, 6.0 Hz), 5.67 (1H, dd, J = 2.0, 3.5 Hz), 4.46 ( 1H, dd, J = 4.5, 8.5 Hz), 1.22-1.65 (6H, m).

A stirred solution of compound (5-12) (17.3 mg, 26.3 μmol) in 80% AcOH (5 mL) was heated at 120 ° C. for 12 hours and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/1) to obtain compound (1-17) (9.4 mg, 64%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CD ₃ OD) δ 7.78 (1H, dd, J = 1.0, 2.0 Hz), 7.73 (1H, dd, J = 1.0, 2.0 Hz), 7.35 (1H, d, J = 3.5 Hz), 7.23-7.20 (1H, m), 6.62 (1H, dd, J = 2.0, 3.5 Hz), 6.57 (1H, dd, J = 1.5, 3.5 Hz), 5.81-5.73 (1H, m), 5.63 (1H, dd, J = 3.0, 8.5 Hz), 4.19 (1H , Dd, J = 3.0, 8.5 Hz).

<Synthesis Example 13>
[Synthesis of (1R, 2S, 3R, 4S, 5R, 6S) -5,6-dihydroxycyclohexane-1,2,3,4-tetrayl tetrakis (thiophene-2-carboxylic acid)]
To a stirred solution of 2-thiophenecarboxylic acid (104.3 mg, 0.81 mmol) and EDC (156.0 mg, 0.81 mmol) was added compound (3-1) (21.2 mg, ₂ mL in CH ₂ Cl ₂ (7 mL). 81.4 μmol) and DMAP (5.0 mg) were added. The resulting mixture was stirred at room temperature for 3 hours. The organic layers were combined, washed with water and saturated aqueous NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/4) to obtain compound (5-13) (28.3 mg, 50%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.86 (1H, dd, J = 1.5, 4.0 Hz), 7.76 (1H, dd, J = 1.5, 4.0 Hz), 7.59 ( 1H, dd, J = 1.5, 5.0 Hz), 7.54 (1H, dd, J = 1.0, 5.0 Hz), 7.10 (1H, dd, J = 1.0, 5. 0 Hz), 7.04 (1H, dd, J = 4.0, 5.0 Hz), 5.99 (1H, dd, J = 3.5, 6.0 Hz), 5.70 (1H, dd, J = 2.5, 9.0 Hz), 4.50 (1H, dd, J = 3.5, 8.0 Hz), 1.67-1.56 (6H, m).

A stirred solution of compound (5-13) (16.0 mg, 23.0 μmol) in 80% AcOH (5 mL) was heated at 120 ° C. for 5 hours and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/4) to give compound (1-18) (5.0 mg, 35%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.86 (1H, dd, J = 1.0, 4.0 Hz), 7.77 (1H, dd, J = 1.5, 4.0 Hz), 7.61 ( 1H, dd, J = 1.0, 5.0 Hz), 7.55 (1H, dd, J = 1.0, 5.0 Hz), 7.11 (1H, dd, J = 4.0, 5. 0 Hz), 7.05 (1H, dd, J = 3.5, 5.0 Hz), 5.81-5.77 (2H, m), 4.30 (1H, s, J = 4.5 Hz).

<Synthesis Example 14>
[Synthesis of (1R, 2S, 3R, 4S, 5R, 6S) -5,6-dihydroxycyclohexane-1,2,3,4-tetrayl tetrakis (2-bromobenzoic acid)]
To a stirred solution of 2-bromobenzoic acid (151.3 mg, 0.75 mmol) and EDC (144.4 mg, 0.75 mmol) was added compound (3-1) (19.6 mg, CH ₂ Cl ₂ (6 mL). 75.0 μmol) and DMAP (5.0 mg) were added. The resulting mixture was stirred at room temperature for 24 hours. The organic layers were combined, washed with water and saturated aqueous NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/4) to give compound (5-14) (42.1 mg, 57%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.93-7.95 (1H, m), 7.84 (1H, dd, J = 1.5, 7.5 Hz), 7.65 (1H, dd, J = 1.5, 7.5 Hz), 7.64-7.62 (1H, m), 7.40-7.34 (2H, m), 7.32 (2H, t, J = 4.0 Hz), 6.04 (1H, dd, J = 3.5, 6.0 Hz), 5.90 (1H, dd, J = 1.5, 9.5 Hz), 4.55 (1H, dd, J = 4. 5, 8.5 Hz), 1.94-1.39 (6H, m).

A stirred solution of compound (5-14) (17.1 mg, 17.2 μmol) in 80% AcOH (5 mL) was heated at 120 ° C. for 7 hours and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/2) to give compound (1-19) (14.8 mg, 94%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.88 (1H, dd, J = 2.5, 7.5 Hz), 7.83 (1H, dd, J = 2.0, 7.5 Hz), 7.68− 7.65 (1H, m), 7.63-7.61 (1H, m), 7.39-7.36 (2H, m), 7.34-7.31 (2H, m), 5. 96-5.92 (2H, m), 4.37 (1H, d, J = 5.0 Hz).

<Synthesis Example 15>
[Synthesis of (1R, 2S, 3R, 4S, 5R, 6S) -5,6-dihydroxycyclohexane-1,2,3,4-tetrayl tetrakis (2-chlorobenzoic acid)]
To a stirred solution of 2-chlorobenzoic acid (126.3 mg, 0.81 mmol) and EDC (161.0 mg, 0.81 mmol) was added compound (3-1) (21.2 mg, CH ₂ Cl ₂ (7 mL). 81.4 μmol) and DMAP (5.0 mg) were added. The resulting mixture was stirred at room temperature for 5 hours. The organic layers were combined, washed with water and saturated aqueous NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/4) to obtain compound (5-15) (25.2 mg, 38%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.93 (2H, dd, J = 8.5, 16.5 Hz), 7.48-7.42 (4H, m), 7.37-7.34 (1H, m), 7.31-7.28 (1H, m), 6.07 (1H, dd, J = 3.0, 5.5 Hz), 5.90 (1H, dd, J = 2.0, 8 .5 Hz), 4.55 (1H, dd, J = 1.5, 9.5 Hz), 1.40-1.86 (6H, m).

A stirred solution of compound (5-15) (17.8 mg, 22.0 μmol) in 80% AcOH (5 mL) was heated at 120 ° C. for 6 hours and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/5) to give compound (1-20) (7.7 mg, 48%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.88 (2H, t, J = 7.5 Hz), 7.64-7.54 (2H, m), 7.41 (2H, d, J = 3.5 Hz) 7.36-7.32 (1H, m), 7.30-7.27 (1H, m), 5.95-5.92 (1H, m), 4.34 (1H, d, J = 5.0 Hz).

<Synthesis Example 16>
[Synthesis of (1R, 2S, 3R, 4S, 5R, 6S) -5,6-dihydroxycyclohexane-1,2,3,4-tetrayl tetrakis (3-bromothiophene-2-carboxylic acid)]
To a stirred solution of 3-bromothiophene-2-carboxylic acid (161.5 mg, 0.78 mmol) and EDC (149.5 mg, 0.78 mmol) was added compound (3-1) in CH ₂ Cl ₂ (7 mL) ( 20.4 mg, 78.0 μmol) and DMAP (5.0 mg) were added. The resulting mixture was stirred at room temperature for 18 hours. The organic layers were combined, washed with water and saturated aqueous NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/2) to give compound (5-16) (49.1 mg, 62%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.51 (1H, d, J = 5.0 Hz), 7.46 (1H, d, J = 5.5 Hz), 7.09 (1H, d, J = 5. 0 Hz), 7.04 (1H, d, J = 5.0 Hz), 6.03 (1H, dd, J = 3.5, 5.5 Hz), 5.75 (1H, dd, J = 2.0) 8.5 Hz), 4.49 (1H, dd, J = 4.5, 8.5 Hz), 2.05-1.37 (6H, m).

A stirred solution of compound (5-16) (8.7 mg, 8.60 μmol) in 80% AcOH (5 mL) was heated at 120 ° C. for 8 hours and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/2) to give compound (1-21) (6.3 mg, 78%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.52 (1H, d, J = 5.5 Hz), 7.46 (1H, d, J = 5.0 Hz), 7.11 (1H, d, J = 5. 0 Hz), 7.05 (1H, d, J = 5.5 Hz), 5.90-5.85 (2H, m), 4.32 (1H, d, J = 5.5 Hz).

<Synthesis Example 17>
[Synthesis of (1R, 2S, 3R, 4S, 5R, 6S) -5,6-dihydroxycyclohexane-1,2,3,4-tetrayl tetrakis (4-methoxybenzoic acid)]
To a stirred solution of p-anisic acid (128.6 mg, 0.84 mmol) and EDC (162.0 mg, 0.84 mmol) was added compound (3-1) (22.0 mg, 84 in CH ₂ Cl ₂ (7 mL). 0.5 μmol) and DMAP (5.0 mg). The resulting mixture was stirred at room temperature for 26 hours. The organic layers were combined, washed with water and saturated aqueous NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/2) to give compound (5-17) (36.2 mg, 54%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.98 (1H, d, J = 8.5 Hz), 7.77 (1H, d, J = 9.0 Hz), 7.03 (1H, d, J = 9. 0 Hz), 6.96 (1H, d, J = 9.0 Hz), 5.83 (1H, dd, J = 3.0, 5.0 Hz), 5.63 (1H, d, J = 6.0 Hz) ), 4.67 (1H, d, J = 3.0 Hz), 3.80 (3H, s), 3.77 (3H, s), 1.91-1.33 (6H, m).

A stirred solution of compound (5-17) (5.7 mg, 7.20 μmol) in 80% AcOH (3 mL) was heated at 120 ° C. for 10 hours and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/1) to obtain compound (1-22) (3.8 mg, 65%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 8.02-7.99 (2H, m), 7.92 (2H, d, J = 9.0 Hz), 6.91 (2H, dd, J = 2.0, 7.0 Hz), 6.84 (2H, dd, J = 2.0, 7.0 Hz), 5.87-5.83 (2H, m), 4.31 (1H, d, J = 5.0 Hz) ), 3.86 (3H, s), 3.82 (3H, s).

<Synthesis Example 18>
[Synthesis of (1R, 2S, 3R, 4S, 5R, 6S) -5,6-dihydroxycyclohexane-1,2,3,4-tetrayl tetrakis (2-methoxybenzoic acid)]
To a stirred solution of 2-methoxybenzoic acid (124.7 mg, 0.82 mmol) and EDC (157.2 mg, 0.82 mmol), compound (3-1) (21.3 mg, 21.3 mg, in CH ₂ Cl ₂ (7 mL) was added. 82.0 μmol) and DMAP (5.0 mg) were added. The resulting mixture was stirred at room temperature for 24 hours. The organic layers were combined, washed with water and saturated aqueous NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/2) to give compound (5-18) (37.6 mg, 58%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.91 (1H, dd, J = 2.0, 8.0 Hz), 7.85 (1H, dd, J = 2.0, 8.0 Hz), 7.48- 7.45 (1H, m), 7.44-7.40 (1H, m), 6.99-6.93 (2H, m), 6.92-6.89 (2H, m), 6. 06 (1H, dd, J = 3.5, 5.5 Hz), 5.85 (1H, dd, J = 2.0, 3.5 Hz), 4.47 (1H, dd, J = 4.5, 8.5 Hz), 1.97-1.35 (6H, m).

A stirred solution of compound (5-18) (15.9 mg, 20.0 μmol) in 80% AcOH (5 mL) was heated at 120 ° C. for 3 hours and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/2) to give compound (1-23) (11.2 mg, 78%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.83 (1H, dd, J = 1.5, 7.5 Hz), 7.77 (1H, d, J = 7.5 Hz), 7.46 (2H, t, J = 8.5, 17.0 Hz), 6.99-6.89 (4H, m), 5.99 (1H, d, J = 6.0 Hz), 5.83 (1H, s), 4. 25 (1H, s), 3.87 (6H, d, J = 12.5 Hz).

<Synthesis Example 19>
[Synthesis of (1R, 2S, 3R, 4S, 5R, 6S) -5,6-dihydroxycyclohexane-1,2,3,4-tetrayl tetrakis (2,4-dimethoxybenzoic acid)]
To a stirred solution of 2,4-dimethoxybenzoic acid (87.4 mg, 0.48 mmol) and EDC (92.0 mg, 0.48 mmol) was added compound (3-1) (12.12) in CH ₂ Cl ₂ (5 mL). 4 mg, 48.0 μmol) and DMAP (5.0 mg) were added. The resulting mixture was stirred at room temperature for 62 hours. The organic layers were combined, washed with water and saturated aqueous NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to PTLC (MeOH / chloroform, 1/20) to give compound (5-19) (20.6 mg, 47%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.90 (2H, dd, J = 9.0, 17.0 Hz), 6.48 (1H, dd, J = 2.0, 8.5 Hz), 6.43 ( 1H, d, J = 2.5 Hz), 6.39 (2H, d, J = 8.5 Hz), 6.01 (1H, dd, J = 3.5, 6.0 Hz), 5.77 (1H , D, J = 6.5 Hz), 4.43 (1H, dd, J = 4.5, 8.5 Hz), 3.85 (6H, d, J = 12.5 Hz), 3.80 (1H, d, J = 7.5 Hz), 1.60-1.55 (6H, m).

A stirred solution of compound (5-19) (12.3 mg, 13.4 μmol) in 80% AcOH (5 mL) was heated at 120 ° C. for 7 hours and concentrated in vacuo. The residue was subjected to PTLC (MeOH / chloroform, 1/20) to obtain compound (1-24) (8.4 mg, 75%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.87 (1H, d, J = 8.5 Hz), 7.76 (1H, s), 6.54-6.40 (4H, m), 5.94 (1H , D, J = 6.0 Hz), 5.78 (1H, s), 4.22-4.19 (1H, m), 3.88-3.82 (12H, m).

<Synthesis Example 20>
[Synthesis of (1R, 2S, 3R, 4S, 5R, 6S) -5,6-dihydroxycyclohexane-1,2,3,4-tetrayl tetrakis (3-phenylpropanoic acid)]
To a stirred solution of 3-phenylpropionic acid (500.3 mg, 3.33 mmol) and EDC (620.1 mg, 3.23 mmol) was added compound (3-1) (40.1 mg, 4 mL in CH ₂ Cl ₂ (3 mL). 153.8 μmol) and DMAP (5.0 mg) were added. The resulting mixture was stirred at room temperature for 20 hours. The organic layers were combined, washed with water and saturated aqueous NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/4) to give compound (5-20) (51.7 mg, 43%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.38 (5H, m), 7.27 (5H, m), 5.59 (1H, dd, J = 3.5, 5.7 Hz), 5.25 (1H , Dd, J = 2.0, 8.6 Hz), 4.03 (1H, dd, J = 4.6, 8.3 Hz), 3.01 (2H, t, J = 7.7 Hz), 2. 98 (2H, t, J = 7.7 Hz), 2.74 (6H, m), 1.60-1.55 (6H, m).

A stirred solution of compound (5-20) (24.9 mg, 35.1 μmol) in 80% AcOH (5 mL) was heated at 120 ° C. for 3 hours and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/1) to obtain compound (1-25) (12.1 mg, 49%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.36 (5H, m), 7.24 (5H, m), 5.48 (1H, dd, J = 3.5, 5.7 Hz), 5.15 (1H , Dd, J = 2.0, 8.6 Hz), 4.01 (1H, dd, J = 4.6, 8.3 Hz), 2.90 (2H, t, J = 7.7 Hz), 2. 88 (2H, t, J = 7.7 Hz), 2.54 (6H, m).

<Synthesis Example 21>
[(1R, 2S, 3R, 4S, 5R, 6S) -5,6-dihydroxycyclohexane-1,2,3,4-tetrayl (2E, 2′E, 2 ″ E, 2 ′ ″ E)- Synthesis of tetrakis (3-acrylic acid phenyl)]
To a stirred solution of trans-cinnamic acid (456.3 mg, 3.08 mmol) and EDC (560.0 mg, 2.92 mmol) was added compound (3-1) (40.1 mg, 4 mL in CH ₂ Cl ₂ (3 mL). 153.8 μmol) and DMAP (5.0 mg) were added. The resulting mixture was stirred at room temperature for 20 hours. The organic layers were combined, washed with water and saturated aqueous NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/4) to give compound (5-21) (89.6 mg, 74%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.76 (1H, d, J = 16.0 Hz), 7.72 (1H, d, J = 16.0 Hz), 7.53 (2H, m), 7.49 (2H, m), 7.36 (6H, m), 6.49 (1H, d, J = 16.0 Hz), 6.42 (1H, d, J = 16.0 Hz), 5.87 (1H , Dd, J = 3.5, 5.7 Hz), 5.87 (1H, dd, J = 2.0, 8.6 Hz), 4.43 (1H, dd, J = 4.6, 8.3 Hz) ), 1.60-1.55 (6H, m).

A stirred solution of compound (5-21) (21.8 mg, 27.9 μmol) in 80% AcOH (5 mL) was heated at 120 ° C. for 4 hours and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/1) to give compound (1-26) (10.4 mg, 53%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
7.73 (1H, d, J = 16.0 Hz), 7.69 (1H, d, J = 16.0 Hz), 7.51 (2H, m), 7.49 (2H, m), 7. 33 (6H, m), 6.49 (1H, d, J = 16.0 Hz), 6.39 (1H, d, J = 16.0 Hz), 5.69 (2H, m), 4.21 ( 1H, d, J = 8.3Hz)

<Synthesis Example 22>
[Synthesis of (1R, 2R, 4R, 5R, 6S) -5,6-dihydroxycyclohexane-1,2,4-triyl tribenzoic acid]
To a stirred solution of (+)-proto-quercitol (1.2 g, 7.31 mmol) in N, N-dimethylformamide (50 mL) was added 1,1-dimethoxycyclohexane (50 mL) and p-toluenesulfonic acid (0. 1 g) was added. The resulting mixture was heated at 80 ° C. for 3 hours. The reaction mixture was cooled and added to cooled EtOH (100 mL). The resulting precipitate was filtered and washed with cooled EtOH to obtain compound (10) as a white powder. To a stirred solution of BzCl (3.0 mL, 30.1 mmol) in pyridine (20 mL) was added the resulting white powder compound (10) and DMAP (5.0 mg) in CH ₂ Cl ₂ (3 mL). It was. The resulting mixture was stirred at room temperature for 24 hours. The organic layers were combined, washed with water and saturated aqueous NaHCO ₃ , dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was subjected to silica gel column chromatography (EtOAc / hexane = 1/3) to give compound (5-22) (1.2 g, 30%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 8.01 (2H, d, J = 7.5 Hz), 7.98 (dH, d, J = 7.5 Hz), 7.90 (4H, t, J = 7. 5Hz), 7.55 (2H, t, J = 7.6 Hz), 7.46-7.40 (6H, m), 7.34-7.30 (5H, m), 6.42 (1H, t, J = 9.8 Hz), 5.95 (1H, t, J = 9.3 Hz), 5.87 (1H, t, J = 9.8 Hz), 5.50 (1H, dd, J = 2) .5, 9.3 Hz), 4.18 (1H, t, J = 8.0 Hz), 3.35 (1H, d, J = 8.0 Hz), 3.18 (1H, d, J = 2. 3Hz), 1.60-1.55 (6H, m).

A stirred solution of compound (5-22) (54.5 mg, 97.9 μmol) in 80% AcOH (5 mL) was heated at 120 ° C. for 1.5 hours and concentrated in vacuo. The residue was subjected to PTLC (EtOAc / hexane = 1/1) to obtain compound (1-27) (34.7 mg, 74%) as a white powder. The NMR spectrum results and reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 8.00 (2H, d, J = 7.2 Hz), 7.95 (dH, d, J = 7.2 Hz), 7.84 (4H, t, J = 7. 2Hz), 7.50 (2H, t, J = 7.6 Hz), 7.40-7.34 (6H, m), 7.28-7.25 (5H, m), 6.33 (1H, t, J = 10.0 Hz), 5.92 (1H, t, J = 9.2 Hz), 5.87 (1H, t, J = 10.0 Hz), 5.47 (1H, dd, J = 2) .4, 10.0 Hz), 4.13 (1 H, t, J = 8 Hz), 3.33 (1 H, d, J = 8 Hz), 3.14 (1 H, d, J = 2.4 Hz).

<Synthesis Example 23>
[Synthesis of (1S, 2R, 3R, 4S, 5R, 6S) -5,6-dihydroxycyclohexane-1,2,3,4-tetrayl tetrakis (para-toluic acid)]
To a stirred solution of compound (3-2) (1.0 g, 3.84 mmol) in pyridine (30 mL) was added para-toluic acid chloride (4.1 mL, 31.0 mmol). The resulting mixture was stirred at room temperature for 24 hours. The reaction solution was added to cold water (150 mL), allowed to stand for 1 day, and the resulting precipitate was collected by filtration. The collected precipitate was dissolved in chloroform, and the residue was removed by filtration. The filtrate was concentrated and the residue was recrystallized from chloroform-ethanol. Filtration afforded compound (3-2) (1.98 g, 70%) as a white powder. The results of NMR spectrum and the reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.89 (4H, dd, J = 12.9, 7.3 Hz), 7.79 (4H, dd, J = 8.0 Hz, 6.3 Hz), 7.23 ( 4H, dd, J = 8.0 Hz, 2.0 Hz), 7.14 (4H, d, J = 8.3 Hz), 6.13 (1H, t, J = 10.3 Hz), 5.90 (2H M), 5.48 (1H, dd, J = 10.3 Hz, 2.9 Hz), 4.63 (1H, t, J = 2.9 Hz), 4.17 (1H, dd, J = 10. 3Hz, 2.9Hz), 2.43 (6H, s), 2.36 (1H, s), 2.02-1.43 (6H, m).

A stirred solution of compound (5-23) (1.0 g, 1.36 mmol) in 80% AcOH (7 mL) was heated at 120 ° C. for 2 hours and concentrated in vacuo. The residue was subjected to silica gel column chromatography (chloroform / methanol = 100/1) to obtain compound (1-5) (343.3 mg, 39%) as a white powder. The results of the NMM spectrum and the reaction scheme are shown below.
¹ H NMR (CDCl ₃ ) δ 7.84 (4H, dd, J = 12.9, 7.3 Hz), 7.70 (4H, dd, J = 8.0 Hz, 6.3 Hz), 7.14 ( 4H, dd, J = 8.0 Hz, 2.0 Hz), 7.04 (4H, d, J = 8.3 Hz), 6.23 (1H, t, J = 10.3 Hz), 5.80 (2H M), 5.38 (1H, dd, J = 10.3 Hz, 2.9 Hz), 4.53 (1H, t, J = 2.9 Hz), 4.07 (1H, dd, J = 10. 3Hz, 2.9Hz), 2.33 (6H, s).

The following compounds (1-1) to (1-4), compound (2-1) and compound (2-2) were synthesized according to known methods. Compound (1-1) was synthesized with reference to “Seichiro OGAWA et al., BULLETIN OF CHEMICAL SOCIETY OF JAPAN, VOL. 50 (7), 1867-1871 (1977)”. Compound (1-2) was synthesized with reference to “Sung-Kee Chunget et al., Bioorganic & Medicinal Chemistry Letters 9 (1999) 21135-2140”. The compound (1-3) was synthesized with reference to “PER J. GARESO et al., Carbohydrate Research, 173 (1988) 205-216”. 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.

<Examination using MPP ⁺ treated cells-1>
When nerve cells are treated with 1-methyl-4-phenylpyridinium (MPP ⁺ ), cell death is induced, and in the process, spots (aggregates of α-synuclein) are formed. Since the formation of the spots is an indicator of the onset of Parkinson's disease, a compound that can suppress the formation of the spots can be expected to be an effective treatment for Parkinson's disease. Therefore, hereinafter, it was examined whether the compound (1-1) of the present invention can suppress the spot formation in MPP ⁺ treated cells.

Differentiated PC12D cells were treated with 0.3 mM MPP ⁺ for 24 hours to form spots in the cells. Then 10 μg / mL of the compound of the present invention (1-1) or 10 μg / 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.

In FIG. 1, “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. “Α-synuclein” is the result of immunostaining with anti-α-synuclein antibody and observation with a confocal microscope. “Colocalization” is the result of merging the aggresome detected by ProteoStat Aggresome Detection Kit with the α-synuclein antibody detected by the anti-α-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.

As shown in FIG. 1, 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 μg / mL of the compound (1-1) of the present invention or 10 μM 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 α-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.

As shown in FIGS. 2 and 3, spots are formed on the cells by treatment with MPP ⁺ ( "MPP ^+"). On the other hand, 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.

<Study-3 using MPP ⁺ treated cells>
Differentiated PC12D cells were treated with 0.3 mM MPP ⁺ for 48 hours to induce cell death. On the other hand, simultaneously with MPP ^+, 1 or 10 μg / mL of the compound (1-1) of the present invention was treated for 48 hours. Thereafter, the cells were stained with DNA with Propium Iodide, and cell death was quantified from the ratio of SubG1 by flow cytometry. The results are shown in FIG.

In FIG. 4, “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 μg / mL of the present invention was added simultaneously with MPP ⁺ . In FIG. 4, F represents the number of cells in the subG1 phase, E represents the G1 phase, D represents the S phase, and C represents the G2 / M phase. The horizontal axis is the fluorescence intensity, and 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.

As shown in FIG. 4, the addition of the compounds of the present invention (1-1), suppression of cell death induced by MPP ⁺ was observed ( "MPP ⁺ + Compound (1-1)").

<Measurement of speckle inhibitory activity of each compound>
Differentiated PC12D cells were treated with 0.3 mM MPP ⁺ for 24 hours to form spots in the cells, and the percentage of the spot area in the cell area was calculated by cell observation. On the other hand, each of the above-mentioned compounds (1-1) to (1-27) of the present invention was added at a plurality of concentrations at the same time as MPP ⁺ , and 24 hours later, the cell observation showed that the area of the spots occupied by the cells The percentage was calculated. The concentration at which the area of the spots formed by MPP ⁺ was 50% of the cell area was identified as the IC ₅₀ value. The results are shown in Table 1 below.

As indicated by Table 1, although the numerical IC ₅₀ of the difference is, spots inhibitory activity was observed for all compounds. In particular, the activity of the methoxy group, which is an electron donating group, was higher than that of a compound having an electron withdrawing group such as a halogen atom. From this, it is considered that having an electron-donating group makes it electronically dense and has a stable structure, resulting in high activity. In addition, the compound in which the ortho position of the benzene ring was substituted was higher in activity. This is thought to be due to the fact that the ortho-position of the benzene ring is substituted, resulting in a bulky structure, and the bond portion is less likely to rotate sterically, resulting in increased activity. Further, it was found that compounds having a sugar skeleton such as compounds (2-1) and (2-2) also have speckle inhibitory activity.

From the above results, it was found that 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.

Claims (5)

1. A compound represented by the following formula (1) or a salt thereof.
   

   

   (In the formula (1), 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,
   In the formula (I) and the formula (II), 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 X ¹ is a divalent hydrocarbon group having 1 to 10 carbon atoms which may have a single bond or a substituent,
   In the formula (I), R ⁶ is a hydrogen atom or an oxo group, and the dotted line is the presence or absence of a bond. )
2. R ⁵ in the formula (I) or the formula (II) is an aryl group which may have a substituent, a cyclohexyl group which may have a substituent, or an adamantyl group which may have a substituent. The compound according to claim 1 or a salt thereof.
3. The compound according to claim 2, wherein the aryl group is a phenyl group, and the ortho position of the phenyl group 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 monocyclic The compound or a salt thereof according to any one of claims 1 to 3, wherein the tricyclic monovalent heterocyclic group is substituted with an electron donating group.
5. A therapeutic or prophylactic agent for Parkinson's disease comprising a compound represented by the following formula (1) or formula (2) or a pharmacologically acceptable salt thereof.
   

   

   (In the formula (1), 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,
   In formula (2), 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,
   In the formula (I), the formula (II), the formula (III) and the formula (IV), 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, and X ¹ is a C 1-10 divalent hydrocarbon group which may have a single bond or a substituent,
   In the formula (I), R ⁶ is a hydrogen atom or an oxo group, and the dotted line is the presence or absence of a bond. )

Images