JP4753022B2 - Prion growth inhibitor - Google Patents

Description

  The present invention relates to a prion growth inhibitor containing a sulfated sugar derivative, a pharmaceutically acceptable salt thereof, or a hydrate thereof, and a preventive or therapeutic agent for prion disease containing the prion growth inhibitor.

In recent years, prion diseases such as bovine spongiform encephalopathy (BSE, mad cow disease) and Creutzfeldt-Jakob disease (CJD) have become a problem. Abnormal prion protein, which is a causative protein of BSE and CJD, is caused by a large change in the higher order structure of normal prion protein in the brain. This reaction is continuous, and once an abnormal prion protein is formed, its degradation rate is extremely slow compared to normal prion protein, and abnormal prion protein accumulates in the brain.
Therefore, how to inhibit the transition from normal prion protein to abnormal prion protein is regarded as important from the viewpoint of prevention or treatment of prion diseases such as BSE and Creutzfeldt-Jakob disease. (Non-patent documents 1 and 2)

To date, several compounds having prion growth inhibitory effects have been searched, but no effective compounds have been found so far from the viewpoint of ease of synthesis, stability, cytotoxicity, and the like.
For example, quinacrine is known as a compound that shows the inhibitory effect of prions. However, quinacrine is known to have nephrotoxicity and liver toxicity, and it is indispensable to provide a milder compound for the living body. In particular, in the development of pharmaceuticals, it is possible to administer directly into the brain, so it is necessary to search for compounds with reduced side effects.

  Recently, it has been reported that heparan sulfate has a prion growth inhibitory function (Non-patent Document 3).

It has been reported that a sulfated sugar derivative and a polymer having this in the molecule exhibit a selectin blocker and a virus inhibitory function (Non-Patent Documents 4 to 6). Among these, a series of sulfated N-acetylglucosamine or a polymer thereof has been reported to have a high inhibitory function against sialidase possessed by human influenza virus, but has an inhibitory effect on prion growth. Is not known.
Science, vol. 278, pp. 245-251 (1997) Cell, vol. 93, pp. 337-348 (1998) EMBO Journal, 20, 377-386 (2001) Biomacromolecules, 1, 68-74 (2000) ChemBioChem, 4, 640-647 (2003) Bioorg. Med. Chem. Lett., 13, 2821-2823 (2003)

  An object of the present invention is to provide a prion growth inhibitor, BSE, a preventive agent or a therapeutic agent for prion diseases such as Creutzfeldt-Jakob disease, which is less aggressive and effectively inhibits prion growth.

  The present inventors have intensively studied to solve the above-mentioned problems, and a specific sugar derivative has a low aggression property and an excellent prion growth inhibitory effect, and is effective in prion diseases such as BSE and Creutzfeldt-Jakob disease. As a result, the present invention has been completed. In particular, it has been found that a polymer compound of a specific sugar chain derivative has a remarkable prion growth inhibitory effect. That is, the present invention includes the following.

[1]
The following general formula (I)
[In the formula (I), R ¹ represents —OH, —NHAc (where Ac represents an acetyl group) or —NHSO ₃ H;
R ^{2 to} R ⁴ each independently represents a hydrogen atom or —SO ₃ H;
At least one of R ² , R ³ and R ⁴ is —SO ₃ H, or R ¹ represents —NHSO ₃ H when R ² , R ³ and R ⁴ are all hydrogen atoms;
R ⁵ is optionally substituted C _{1 ~ 6} alkyl group which may have a substituent C _{2 ~ 6} alkenyl group, an optionally C _{2 ~ 6} alkynyl which may have a substituent a group or which may have a substituent group C _{6 ~ 10} aryl group;
In formula
Indicates an arrangement of either an equatorial arrangement or an axial arrangement. Or a pharmaceutically acceptable salt thereof, or a hydrate thereof, as an active ingredient.
[2]
The prion growth inhibitor according to [1], wherein one of R ² , R ³ and R ⁴ is —SO ₃ H, and the remaining two are —H.
[3]
The prion growth inhibitor according to [1], wherein R ¹ is —NHSO ₃ H, and R ² , R ^3, and R ⁴ are —H.
[4]
Wherein R ⁵ is optionally C _{6 - 10} aryl group optionally having an optionally substituted C _{1 ~ 6} alkyl group or a substituent, any one of [1] to [3] The prion growth inhibitor as described.
[5]
-R ¹ and -OR ³ and Glucophage arrangement is any one placement galacto configuration or manno configuration, prion inhibiting agent according to any one of [1] to [4].
[6]
The prion growth inhibitor according to [5], wherein R ¹ is —NHAc or —NHSO ₃ H, and —R ¹ and —OR ³ are in a gluco configuration or a galacto configuration.
[7]
The prion according to [2], wherein R ¹ is —NHAc or —NHSO ₃ H, —R ¹ and —OR ³ are in a gluco configuration or a galacto configuration, and R ³ or R ⁴ is —SO ₃ H. Growth inhibitor.
[8]
The prion growth inhibitor according to [3], wherein -R ¹ and -OR ³ are in a gluco configuration or a galacto configuration.
[9]
The compound represented by the general formula (I) is:
^{(1) R 1 = -NHAc,} R 2 = R 4 = H, an _{^{R 3 = -SO 3 H, R}} 5 = -C 6 H 4 -pNO 2 or -C ₆ H ₄ -pNHAc, -R ¹ And -OR ³ are in a gluco configuration (-R ¹ and -OR ³ are in an equatorial configuration),
_{^{(2) R 1 = -NHSO 3}} H, R 2 = R 3 = H, R 4 = SO 3 H, a _{^{R 5 = -C 6 H 4 -pNO}} 2 or -C ₆ H ₄ -pNHAc, -R ^A compound in which ¹ and -OR ³ are in a gluco configuration (-R ¹ and -OR ³ are in an equatorial configuration),
_{^{(3) R 1 = -NHSO 3}} H, R 2 = R 4 = H, R 3 = SO 3 H, a _{^{R 5 = -C 6 H 4 -pNO}} 2 or -C ₆ H ₄ -pNHAc, -R ^A compound in which ¹ and -OR ³ are in a gluco configuration (-R ¹ and -OR ³ are in an equatorial configuration),
^{(4) R 1 = -NHAc,} R 2 = R 3 = H, R 4 = SO 3 H, a _{^{R 5 = -C 6 H 4 -pNO}} 2 or -C ₆ H ₄ -pNHAc, -R ¹ and A compound in which —OR ³ is a galacto configuration (—R ¹ is an equatorial configuration, —OR ³ is an axial configuration);
^{(5) R 1 = -NHAc,} R 2 = R 4 = H, R 3 = SO 3 H, a _{^{R 5 = -C 6 H 4 -pNO}} 2 or -C ₆ H ₄ -pNHAc, -R ¹ and A compound in which —OR ³ is a galacto configuration (—R ¹ is an equatorial configuration, —OR ³ is an axial configuration);
^{(6) R 1 = -NHAc,} R 2 = SO 3 H, R 3 = R 4 = H, an _{^{R 5 = -C 6 H 4 -pNO}} 2 or -C ₆ H ₄ -pNHAc, -R ¹ and A compound in which —OR ³ is a galacto configuration (—R ¹ is an equatorial configuration, —OR ³ is an axial configuration);
^{(7) R 1 = -NHAc,} R 2 = R 3 = H, R 4 = SO 3 H, a _{^{R 5 = -C 6 H 4 -pNO}} 2 or -C ₆ H ₄ -pNHAc, -R ¹ and A compound in which —OR ³ is in a manno configuration (—R ¹ is an axial configuration, —OR ³ is an equatorial configuration);
^{(8) R 1 = -NHAc,} R 3 = SO 3 H, R 2 = R 4 = H, an _{^{R 5 = -C 6 H 4 -pNO}} 2 or -C ₆ H ₄ -pNHAc, -R ¹ and A compound in which —OR ³ is in a manno configuration (—R ¹ is an axial configuration, —OR ³ is an equatorial configuration);
^{(9) R 1 = -NHAc,} R 2 = SO 3 H, R 3 = R 4 = H, an _{^{R 5 = -C 6 H 4 -pNO}} 2 or -C ₆ H ₄ -pNHAc, -R ¹ and A compound in which —OR ³ is in a manno configuration (—R ¹ is an axial configuration, —OR ³ is an equatorial configuration), and (10) R ¹ = —NHSO ₃ H, R ² = R ³ = R ⁴ = H, R ⁵ = —C ₆ H ₄ —pNO ₂ or —C ₆ H ₄ —pNHAc, consisting of a compound having —R ¹ , —OR ^3, and a gluco configuration (where —R ¹ and —OR ³ are in an equatorial configuration). The prion growth inhibitor according to [1], which is any one selected from the group.
[10]
The following general formula (II)
[In the formula (II), R ¹ represents —OH, —NHAc (wherein Ac represents an acetyl group) or —NHSO ₃ H;
R ^{2 to} R ⁴ each independently represents a hydrogen atom or —SO ₃ H;
R ^{2 to} R ⁴ each independently represents a hydrogen atom or —SO ₃ H;
At least one of R ² , R ³ and R ⁴ is —SO ₃ H, or R ¹ represents —NHSO ₃ H when R ² , R ³ and R ⁴ are all hydrogen atoms;
In -A-B-, A represents an alkylene group having 1 to 6 carbon atoms, a phenylene group or an ethylene group _{((C 2 H 4 O)} m) (m is an integer of from 1 to 10), B is a single Indicates a bond, amide bond, carboxylic ester bond or sulfonamide bond;
In formula
Indicates an arrangement of either an equatorial arrangement or an axial arrangement. A prion growth inhibitor, wherein at least one of the sugar chain-containing groups represented by formula [2] contains a polymer compound bound to a polymer chain or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.
[11]
The prion growth inhibitor according to [10], wherein A is an alkylene group having 1 to 6 carbon atoms, and B is a single bond.
[12]
The prion growth inhibitor according to [10], wherein A is a phenylene group and B is an amide bond, a carboxylic acid ester bond or a sulfonamide bond.
[13]
The polymer chain has the following general formula (III)
(In Formula (III), Y ¹ , Y ² , Y ³ and Y ⁴ may each independently have a hydrogen atom, a C _1-6 alkyl group which may have a substituent, or a substituent. A C _2-6 alkenyl group, an optionally substituted C _2-6 alkynyl group, an optionally substituted C _6-10 aryl group, an amide group, a carboxylic acid ester group, or a sulfonamide group N represents an integer of 1 to 5000, and / represents that the constituent component is present in an arbitrary ratio.) The prion growth inhibition according to any one of [10] to [12] Agent.
[14]
One of Y ¹ and Y ² is a hydrogen atom or a C _1-6 alkyl group, and the other one has a C _1-6 alkyl group which may have a substituent, or a substituent. A C _2-6 alkenyl group which may have a substituent, a C _2-6 alkynyl group which may have a substituent, a C _6-10 aryl group which may have a substituent, an amide group, a carboxylate group or a sulfone The prion growth inhibitor according to [10], which is an amide group and wherein Y ³ and Y ⁴ are hydrogen atoms.
[15]
One of R ^2, R ³ and R ⁴ are -SO ₃ H, the remaining two are -H, prion inhibiting agent according to any one of [10] to [14].
[16]
-R ¹ and the -OR ³ is glucosyl arrangement is any one placement galacto configuration or manno configuration, prion inhibiting agent according to any one of [10] - [15].
[17]
R ¹ is -NHAc or -NHSO ₃ H, -R ¹ and -OR ³ and is gluco configuration, prion inhibiting agent according to any one of [10] - [16].
[18]
The prion growth inhibitor according to any one of [10] to [16], wherein R ¹ is —OH, and —R ¹ and —OR ³ are in a galacto configuration.
[19]
The compound represented by the general formula (II) is represented by the following formula (IV):
[In the formula (IV), any one of R ² , R ³ and R ⁴ is —SO ₃ H, the rest is a hydrogen atom, n represents an integer of 1 to 5000, It is present at an arbitrary ratio. ] The prion growth inhibitor according to [10].
[20]
The compound represented by the general formula (II) is represented by the following formula (V):
[In Formula (V), n shows the integer of 1-5000, / shows that a structural component exists in arbitrary ratios. ] The prion growth inhibitor according to [10].
[21]
The -A-B-polymer chain has the following formula:
[In formula, n shows the integer of 1-5000, / shows that a structural component exists in arbitrary ratios. ],
In the sugar chain-containing group, R ¹ , R ² , R ³ , R ⁴ are
^{(101) R 1 = -NHAc,} R 2 = R 3 = H, an R ⁴ = -SO ₃ H, glucosyl placement and -R ¹ and -OR ³ is (-R ¹ and -OR ³ and the equatorial arrangement ),
^{(102) R 1 = -NHAc,} R 2 = R 4 = H, R 3 = a -SO ₃ H, -R ¹ and -OR ³ and Glucophage arrangement (-R ¹ and -OR ³ and the equatorial arrangement ),
(103) R ¹ = -NHAc, R ² = -SO ₃ H, R ³ = R ⁴ = H, -R ¹ , -OR ³ and gluco configuration (-R ¹ and -OR ³ are equatorial configurations) Or (104) R ¹ = —NHSO ₃ H, R ² = R ³ = H, R ⁴ = —SO ₃ H, and —R ¹ and —OR ³ are in the gluco configuration (—R ¹ and —OR ³ And Equatorial arrangement)
(105) R ¹ = -NHAc, an ^{R 2 = R 4 = H,} R 3 = -SO 3 H, -R 1 and -OR ³ and the galacto configuration (-R ¹ is in equatorial arrangement, -OR ³ Is an axial arrangement),
(106) R ¹ = -NHAc, an ^{R 2 = R 3 = H,} R 4 = -SO 3 H, -R 1 and -OR ³ and the galacto configuration (-R ¹ is in equatorial arrangement, -OR ³ Is an axial arrangement),
_{^{(107) R 1 = -NHSO 3}} H, R 2 = R 4 = H, an R _³ = -SO ³ H, and -R ¹ and -OR ³ there is a glucosyl arrangement (-R ¹ and -OR ³ Equatorial arrangement),
(108) and _{^{R 1 = -NHSO 3 H, R}} 2 = R 4 = H, R 3 = -SO 3 H, -R 1 and -OR ³ and the galacto configuration (-R ¹ is in equatorial arrangement, - OR ³ is an axial arrangement),
(109) and _{^{R 1 = -NHSO 3 H, R}} 2 = R 3 = H, R 4 = -SO 3 H, -R 1 and -OR ³ and the galacto configuration (-R ¹ is in equatorial arrangement, - OR ³ is an axial arrangement), or
(110) R ¹ = -NHAc, an ^{R 2 = H, R 3 =} R 4 = -SO 3 H, -R 1 and -OR ³ and the galacto configuration (-R ¹ is in equatorial arrangement, -OR ³ Is a prion growth inhibitor according to [10].
[22] A prophylactic or therapeutic agent for prion diseases comprising the prion growth inhibitor according to any one of [1] to [21].
[23] The prion disease is bovine spongiform encephalopathy (BSE), Creutzfeldt-Jakob disease, sporadic Creutzfeldt-Jakob disease (sCJD), mutant Creutzfeldt-Jakob disease (vCJD), iatrogenic Creutzfeldt- Jacob disease (iCJD), familial Creutzfeldt-Jakob disease (fCJD), Gerstmann-Streisler-Scheinker syndrome (GSS), lethal familial insomnia (FFI), chronic wasting disease (CWD), feline spongiform encephalopathy The preventive or therapeutic agent for prion diseases according to [22], which is scrapie or kuru.
[24] The following general formula (I)
[In the formula (I), R ¹ represents —OH, —NHAc (where Ac represents an acetyl group) or —NHSO ₃ H;
R ^{2 to} R ⁴ each independently represents a hydrogen atom or —SO ₃ H;
At least one of R ² , R ³ and R ⁴ is —SO ₃ H, or R ¹ represents —NHSO ₃ H when R ² , R ³ and R ⁴ are all hydrogen atoms;
R ⁵ is optionally substituted C _{1 ~ 6} alkyl group which may have a substituent C _{2 ~ 6} alkenyl group, an optionally C _{2 ~ 6} alkynyl which may have a substituent a group or which may have a substituent group C _{6 ~ 10} aryl group;
In formula
Indicates an arrangement of either an equatorial arrangement or an axial arrangement. Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a hydrate thereof as an active ingredient. A method for preventing or treating a disease in which prion growth inhibition is effective.
[25] The following general formula (I) for the production of a prophylactic or therapeutic agent for diseases in which prion growth inhibition is effective
[In the formula (I), R ¹ represents —OH, —NHAc (where Ac represents an acetyl group) or —NHSO ₃ H;
R ^{2 to} R ⁴ each independently represents a hydrogen atom or —SO ₃ H;
At least one of R ² , R ³ and R ⁴ is —SO ₃ H, or R ¹ represents —NHSO ₃ H when R ² , R ³ and R ⁴ are all hydrogen atoms;
R ⁵ is optionally substituted C _{1 ~ 6} alkyl group which may have a substituent C _{2 ~ 6} alkenyl group, an optionally C _{2 ~ 6} alkynyl which may have a substituent a group or which may have a substituent group C _{6 ~ 10} aryl group;
In formula
Indicates an arrangement of either an equatorial arrangement or an axial arrangement. Or a pharmaceutically acceptable salt thereof or a hydrate thereof.
[26] A brain-administered drug, an orally-administered drug, or a parenteral-administered drug containing the prion growth inhibitor according to any one of [1] to [21].
[27] An abnormal prion protein washing solution containing the prion growth inhibitor according to any one of [1] to [21].
[28] A brain-implantable polymer material containing the prion growth inhibitor according to any one of [1] to [21].

  Hereinafter, the meaning of terms, symbols, and the like described in the present specification will be described, and the present invention will be described in detail.

  In the present specification, the structural formula of a compound may represent a certain isomer for convenience, but unless otherwise specified, the present invention includes all the geometric isomers and asymmetric carbons that occur in the structure of the compound. It includes isomers such as optical isomers, stereoisomers, and tautomers, and isomer mixtures, and is not limited to the description of the formula for convenience, and may be either isomer or mixture. Therefore, the compound of the present invention may have an asymmetric carbon atom in the molecule, and an optically active substance and a racemate may exist. However, the present invention is not limited and includes both. In addition, there are cases where crystal polymorphism may exist, but it is not limited in the same manner, and any one of the crystal forms may be a single crystal form or a mixture of crystal forms. The compounds according to the present invention include anhydrides and hydrates. Furthermore, the compounds according to the invention include solvates that have absorbed certain other solvents. Furthermore, so-called metabolites generated by the decomposition of the compound according to the present invention in vivo are also included in the scope of the present invention.

The "C _{1 ~ 6} alkyl group" in the present specification, a monovalent group derived by removing one hydrogen atom from a 1-6 aliphatic hydrocarbons having a carbon number from 1 to the number of carbon atoms 6 linear or branched alkyl groups, specifically, for example, methyl group, ethyl group, 1-propyl group, 2-propyl group, 2-methyl-1-propyl group, 2 -Methyl-2-propyl group, 1-butyl group, 2-butyl group, 1-pentyl group, 2-pentyl group, 3-pentyl group, 2-methyl-1-butyl group, 3-methyl-1-butyl group 2-methyl-2-butyl group, 3-methyl-2-butyl group, 2,2-dimethyl-1-propyl group, 1-hexyl group, 2-hexyl group, 3-hexyl group, 2- Methyl-1-pentyl group, 3-methyl-1-pentyl group, 4-methyl-1-pentyl group, 2-methyl 2-pentyl group, 3-methyl-2-pentyl group, 4-methyl-2-pentyl group, 2-methyl-3-pentyl group, 3-methyl-3-pentyl group, 2,3-dimethyl-1- Butyl group, 3,3-dimethyl-1-butyl group, 2,2-dimethyl-1-butyl group, 2-ethyl-1-butyl group, 3,3-dimethyl-2-butyl group, 2,3-dimethyl And 2-butyl group.

In the present specification, the “C _2-6 alkenyl group” means a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, for example, a vinyl group, an allyl group, 1 -Propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, pentenyl group, hexenyl group and the like can be mentioned.

In the present specification, the “C _2-6 alkynyl group” means a linear or branched alkynyl group having 2 to 6 carbon atoms, and specifically includes, for example, an ethynyl group, a 1-propynyl group. 2-propynyl group, butynyl group, pentynyl group, hexynyl group and the like.

The “C _6-10 aryl group” in the present specification refers to an aromatic hydrocarbon cyclic group having 6 to 10 carbon atoms, and specifically includes, for example, a phenyl group, a 1-naphthyl group, 2- And a naphthyl group.

  The “halogen atom” in the present specification means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

In the present specification, the “C _1-6 alkoxy group” means an oxy group to which the “C _1-6 alkyl group” defined above is bonded.
Specifically, for example, methoxy group, ethoxy group, 1-propyloxy group, 2-propyloxy group, 2-methyl-1-propyloxy group, 2-methyl-2-propyloxy group, 1-butyloxy group, 2 -Butyloxy group, 1-pentyloxy group, 2-pentyloxy group, 3-pentyloxy group, 2-methyl-1-butyloxy group, 3-methyl-1-butyloxy group, 2-methyl-2-butyloxy group, 3 -Methyl-2-butyloxy group, 2,2-dimethyl-1-propyloxy group, 1-hexyloxy group, 2-hexyloxy group, 3-hexyloxy group, 2-methyl-1-pentyloxy group, 3- Methyl-1-pentyloxy group, 4-methyl-1-pentyloxy group, 2-methyl-2-pentyloxy group, 3-methyl-2-pentyloxy group, 4 Methyl-2-pentyloxy group, 2-methyl-3-pentyloxy group, 3-methyl-3-pentyloxy group, 2,3-dimethyl-1-butyloxy group, 3,3-dimethyl-1-butyloxy group, Examples include 2,2-dimethyl-1-butyloxy group, 2-ethyl-1-butyloxy group, 3,3-dimethyl-2-butyloxy group, 2,3-dimethyl-2-butyloxy group and the like.

The "acyl group" in the present specification, a group represented by -COR, as the R, C 1 _{~ 6} alkyl group, C 2 _{~ 6} alkenyl group, C 2 _{~ 6} alkynyl or C _{6 ~, A 10} aryl group. The group represented by R may have a substituent of the following group A.

<Substituent group A>
Halogen atom, hydroxyl group, C _1-6 alkoxy group, mercapto group, nitro group, cyano group, formyl group, carboxyl group, acyl group, trifluoromethyl group, trifluoromethoxy group, amino group, C _1-6 alkylamino group , Sulfate amino group, acylamino group, oxo group, and imino group.

The “C _1-6 alkylamino group” in the present specification means a group in which one or two hydrogen atoms of an amino group are substituted with the C _1-6 alkyl group.

In the present specification, the “sulfuric acid amino group” means a group in which one or two hydrogen atoms of an amino group are substituted with a sulfuric acid group —SO ₃ H.

  As used herein, “acylamino group” means a group in which one or two hydrogen atoms of an amino group are substituted with the acyl group.

  In the present specification, “may have a substituent” means that one or more substituents may be optionally combined at the substitutable site. Specific examples of the substituent include groups selected from the following substituent group A.

<Substituent group A>
Halogen atom, hydroxyl group, C _1-6 alkoxy group, mercapto group, nitro group, cyano group, formyl group, carboxyl group, acyl group, trifluoromethyl group, trifluoromethoxy group, amino group, C _1-6 alkylamino group , Sulfate amino group, acylamino group, oxo group, and imino group.

Among these substituents, at least one selected from a hydroxyl group, a C _1-6 alkoxy group, a nitro group, a carboxyl group, an amino group, a C _1-6 alkylamino group, a sulfate amino group, and an acylamino group is preferable.

More preferred substituents in the “optionally substituted C _1-6 alkyl group” include a hydroxyl group, a C _1-6 alkoxy group, and the like.

Preferred substituents than in the "optionally substituted C _{2 ~ 6} alkenyl group", a hydroxyl group, such as C 1 _{~ 6} alkoxy group.

Preferred substituents than in the "optionally substituted C _{2 ~ 6} alkynyl group", a hydroxyl group, such as C 1 _{~ 6} alkoxy group.

Preferred substituents than in the "optionally substituted C _{6 ~ 10} aryl group", a nitro group, an amino group, C 1 _{~ 6} alkyl amino group, an amino group and an acylamino group, sulfate.

  The “salt” in the present specification is not particularly limited as long as it forms a salt with the compound according to the present invention and is pharmacologically acceptable, and examples thereof include inorganic acid salts, organic acid salts, and inorganic bases. Examples thereof include salts, organic base salts, and acidic or basic amino acid salts.

  Preferable examples of inorganic acid salts include hydrochloride, hydrobromide, sulfate, nitrate, phosphate and the like, and preferable examples of organic acid salts include, for example, acetate, succinate and fumarate. Acid salts, maleates, tartrate, citrate, lactate, stearate, benzoate, methanesulfonate, p-toluenesulfonate, and the like.

  Preferable examples of the inorganic base salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt and ammonium salt. Preferred examples of organic base salts Examples thereof include diethylamine salt, triethylamine salt, diethanolamine salt, meglumine salt, N, N′-dibenzylethylenediamine salt and the like.

  Preferable examples of the acidic amino acid salt include aspartate and glutamate, and preferable examples of the basic amino acid salt include arginine salt, lysine salt and ornithine salt.

In the present specification, “equatorial arrangement” means arrangement in the horizontal axial direction on the sugar pyranose ring forming the ⁴ C ₁ (chair-type arrangement) conformation, and “axial arrangement” means ⁴ C 1 ₁ (Chair-type arrangement) This means arrangement in the axial direction perpendicular to the sugar pyranose ring forming the conformation.

The “polymer chain” in the present specification is not particularly limited as long as sugar chain-containing groups are bonded in a desired ratio, and examples thereof include a polymer chain represented by the following formula (III).

In formula (III), Y ^{1 to} Y ⁴ each independently represent a hydrogen atom, a C _1-6 alkyl group which may have a substituent, or a C _2-6 alkenyl group which may have a substituent. Represents a C _2-6 alkynyl group which may have a substituent, a C _6-10 aryl group, an amide group, a carboxylic acid ester group or a sulfonamide group which may have a substituent. n represents an integer of 1 to 5000, preferably an integer of 50 to 3000.

  The number average molecular weight Mn of the polymer compound is preferably in the range of about 3 to 1,500,000, more preferably about 10,000 to 1,000,000.

“/” Indicates that the component (D) containing a sugar chain-containing group and the component (E) containing Y ¹ and Y ² are present in an arbitrary ratio, but the introduction ratio of D (of D The number of structural units / (number of structural units of D + E) × 100 (%)) is preferably such that the structural unit (D) is 0.1 to 100% and the structural unit (E) is 0 to 99.9%. More preferably, the structural unit (D) is in the range of 0.5 to 50% and the structural unit (E) is in the range of 50 to 99.5%.

The confirmation of the polymer compound and the determination of the sugar chain content can be carried out by ¹ H-NMR, ¹³ H-NMR, IR or the like. The number average molecular weight can be determined by separation with a molecular sieve (gel filtration) column and comparison with a standard polymer such as polystyrene polymer. Further, the molecular size and molecular weight can be determined by comparison with a standard polymer such as a polystyrene polymer by a light scattering dynamic analyzer. Furthermore, it is possible to determine the molecular weight by supercentric separation.
The structural unit D and the structural unit E may be arranged randomly, in blocks, or alternately, and among these, it is preferable that they are arranged randomly.

More specifically, “Y ¹ ”, “Y ² ”, “Y ³ ”, “Y ⁴ ” are, for example, a hydrogen atom, an optionally substituted C _1-6 alkyl group, a substituted group. A C _2-6 alkenyl group which may have a group, a C _2-6 alkynyl group which may have a substituent, a C _6-10 aryl group which may have a substituent,
Amido groups such as NH ₂ —CO—, HCO—NH—, NH ₂ —CO—Z—, HCO—NH—Z—;
_{RCO 2 -, RCO 2 Z-,} ROC (= O) - carboxylic acid ester group (R is an alkyl group having 1 to 6 carbon atoms) and the like;
Examples thereof include sulfonamide groups such as NH ₂ —SO ₂ —, HSO ₂ —NH—, NH ₂ —SO ₂ —Z—, and HSO ₂ —NH—Z—.

Examples of Z include a C _1-6 alkylene group, a phenylene group, an ethyleneoxy group ((C ₂ H ₄ O) _n ) (n is an integer of 1 to 10), and the like.

In the present specification, in the linking group “—A—B—” included in the sugar chain-containing group, “A” represents an alkylene group having 1 to 6 carbon atoms, a phenylene group or an ethyleneoxy group ((C ₂ H ₄ O) _m ) (m is preferably an integer of 1 to 10, more preferably 1 to 3). Examples of the alkylene group having 1 to 6 carbon atoms include a methylene group, an ethylene group, a propylene group, and a butylene group. Among these, a methylene group is preferable.

In the present specification, “B” represents, for example, —NH—CO— (polymer), —CO—NH— (polymer), —NH—CO—Z— (polymer), —CO—NH—Z— (polymer). Amide bonds such as;
-CO ₂ R- (polymer) (R is an alkyl group having 1 to 6 carbon atoms) bonded carboxylic acid esters and the like;
Sulfonamide bonds such as —NH—SO ₂ — (polymer), —SO ₂ —NH— (polymer), —NH—SO ₂ —Z— (polymer), —SO ₂ —NH—Z— (polymer), etc. Can be mentioned.
Examples of Z include an alkylene group having 1 to 6 carbon atoms, a phenylene group, an ethyleneoxy group ((C ₂ H ₄ O) _n ) (n is an integer of 1 to 10), and the like.

Among the B, an amide bond is preferable, and among the amide bonds, those having an amino group on the sugar chain-containing group side are more preferable. For example, —NH—CO— (polymer), —NH—CO—Z— (Polymer) is more preferable, and —NH—CO— (polymer) is particularly preferable.
In the present specification, “-(polymer)” indicates that the bonding group B is bonded to the polymer side.

  In this specification, “prion” is a general term for infectious agents.

In the present specification, “prion disease” is a neurological disease caused by prion infection, and abnormal prion protein (PrP ^Sc ), which is a main component of prion, accumulates in the prion-infected brain. . Prion disease is synonymous with transmissible spongiform encephalopathy (TSE). These include, for example, scrapie, kuru, bovine spongiform encephalopathy (BSE), Creutzfeldt-Jakob disease, mutant Creutzfeldt-Jakob disease (vCJS), sporadic Creutzfeldt-Jakob disease (sCJD, sporadic CJD), family Creutzfeldt-Jakob disease (fCJD, familial CJD), iatrogenic Creutzfeldt-Jakob disease (iCJD, iatrogenic CJD), chronic wasting disease, fatal familial insomnia FFI), feline spongiform encephalopathy, Gerstmann-Streisler-Scheinker syndrome (GSS) and the like.

  In the compound represented by the general formula (I) (hereinafter sometimes referred to as “compound I”) contained in the prion growth inhibitor of the present invention, examples of suitable compounds include the following compounds.

(I-1) A compound wherein R ¹ is preferably —NHAc or NHSO ₃ H, more preferably —NHAc.

(I-2) A compound in which any one of R ² , R ³ and R ⁴ is —SO ₃ H and the remaining two are hydrogen atoms, preferably R ³ or R ⁴ is —SO ₃ H A compound.

(I-3) A compound wherein R ² is a hydrogen atom, R ³ is —SO ₃ H, and R ⁴ is a hydrogen atom.

(I-4) A compound wherein R ¹ is NHSO ₃ H and R ² , R ³ and R ⁴ are hydrogen atoms.
(I-5) wherein R ⁵ is an optionally substituted C _{1 ~ 6} alkyl group, or may have a substituent group C _{6 ~ 10} aryl group compound.

(I-6) A compound wherein R ⁵ is a C _1-6 alkyl group which may have a substituent. As the substituent, a hydroxyl group or a C _1-6 alkoxy group is preferable.

(I-7) The compound wherein R ⁵ is a methyl group, an ethyl group, a propyl group, a 2 (R) -3-dihydroxy-propyl group, or a 2 (S) -3-dihydroxy-propyl group.

(I-8) wherein R ⁵ is a good C _{6 ~ 10} aryl group which may have a substituent compound. Preferable substituents include a nitro group, an amino group, a C _1-6 alkylamino group, a sulfate amino group, or an acylamino group.

(I-9) A compound wherein R ⁵ is a phenyl group which may have a substituent or a naphthyl group which may have a substituent.

(I-10) A compound wherein R ⁵ is a group represented by the following general formula (VI).

In formula (VI), R ⁶ and R ⁷ each independently represents a hydrogen atom, —NO ₂ or —NHR ⁸ , and R ⁸ represents a hydrogen atom, a C _1-6 alkyl group, —SO ₃ H or —C. (= O) indicates -R ^9, R ⁹ is perforated may have a substituent group C _{1 ~ 6} alkyl group which may have a substituent C _{2 ~ 6} alkenyl group, a substituent and showing the they may be C _{2 ~ 6} alkynyl group or an optionally substituted C _{6 ~ 10} aryl group. Among these, R ⁸ is more preferably —SO ₃ H or —C (═O) —R ⁹ . R ⁹ is more preferably a C _1-6 alkyl group which may have a substituent.

(I-11) A compound wherein R ⁶ and R ⁷ are each independently a hydrogen atom, —NO ₂ , —NHAc.

(I-12) A compound in which one of R ⁶ and R ⁷ is a hydrogen atom and the other is —NO ₂ or —NHAc.

(I-13) A compound in which one of R ⁶ and R ⁷ is a hydrogen atom and the other one has —NO ₂ or —NHAc in the para position.

(I-14) A compound wherein R ⁵ is a 1-naphthyl group or a 2-naphthyl group.

(I-15) A compound in which —R ¹ and —OR ³ are in any one of a gluco configuration, a galacto configuration and a manno configuration.

(I-16) A compound in which —R ¹ and —OR ³ are preferably gluco configuration or galacto configuration, more preferably gluco configuration.

(I-17) R ¹ is —NHAc or —NHSO ₃ H, —R ¹ and —OR ³ are in a gluco configuration or a galacto configuration, and any one of R ² , R ³ and R ⁴ is —SO ₃ A compound in which H and the remaining two are hydrogen atoms. Of these, R ³ or R ⁴ is more preferably —SO ₃ H, and further preferably R ³ is —SO ₃ H.
(I-18) A compound wherein R ¹ is —NHSO ₃ H, —R ¹ and —OR ³ are in a gluco configuration or a galacto configuration, and R ² , R ³ and R ⁴ are H. Of these, -R ¹ and -OR ³ are more preferably gluco configuration.

Regarding R ⁵ ,
The preferred order increases in the order of (I-5) to (I-10), (I-14).
Regarding the arrangement, (I-16) is more preferable.

  In the polymer compound having a sugar chain-containing group represented by the general formula (II) contained in the prion growth inhibitor of the present invention (hereinafter sometimes referred to as “compound II”), a suitable polymer compound is Examples thereof include the following polymer compounds.

(II-1) A polymer compound wherein A is an alkylene group having 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, and B is a single bond.

(II-2) A polymer compound wherein A is a phenylene group and B is an amide bond, a carboxylic acid ester bond or a sulfonamide bond. B is preferably an amide bond, more preferably an amide bond represented by —NH—CO— (polymer). B is preferably bonded to the para position.

(II-3) The polymer chain has the following general formula (III)
(In Formula (III), Y ¹ , Y ² , Y ³ and Y ⁴ may each independently have a hydrogen atom, a C _1-6 alkyl group which may have a substituent, or a substituent. A C _2-6 alkenyl group, an optionally substituted C _2-6 alkynyl group, an optionally substituted C _6-10 aryl group, an amide group, a carboxylic acid ester group, or a sulfonamide group N represents an integer of 1 to 5000, preferably 10 to 5000, and / indicates that the constituent components are present in an arbitrary ratio.

(II-4) One of Y ¹ and Y ² is a hydrogen atom or a C _1-6 alkyl group, and the other one is a C _1-6 alkyl group which may have a substituent, a substituent. C _2-6 alkenyl group which may have, C _2-6 alkynyl group which may have substituent, C _6-10 aryl group which may have substituent, amide group, carboxylic acid A polymer compound which is an ester group or a sulfonamide group.

(II-5) One of Y ¹ and Y ² is a hydrogen atom, and the other is a C _1-6 alkyl group that may have a substituent, or a C that may have a substituent. _2-6 alkenyl group, optionally substituted C _2-6 alkynyl group, optionally substituted C _6-10 aryl group, amide group, carboxylic acid ester group or sulfonamide group A polymer compound.

(II-6) A polymer compound in which ^one of Y ¹ and Y ² is a hydrogen atom and the other is an amide group, a carboxylic acid ester group, or a sulfonamide group.

(II-7) A polymer compound in which ^one of Y ¹ and Y ² is a hydrogen atom and the other is an amide group.

Among the amide groups, a group having an amino group at the terminal is preferable, and examples thereof include NH ₂ —CO— and NH ₂ —CO—Z—. Among these, NH ₂ —CO— is preferable.

(II-8) Y ³ and Y ⁴ are preferably hydrogen atoms.
(II-9) A compound wherein R ¹ is —NHAc or —OH with respect to the sugar chain-containing group.

(II-10) A compound in which at least one of R ² , R ³ and R ⁴ is —SO ₃ H.

(II-11) A compound wherein R ² is a hydrogen atom, R ³ is a hydrogen atom, and R ⁴ is —SO ₃ H.

(II-12) A compound wherein R ² is a hydrogen atom, R ³ is —SO ₃ H, and R ⁴ is a hydrogen atom.

(II-13) A compound wherein R ² is —SO ₃ H, R ³ is a hydrogen atom, and R ⁴ is a hydrogen atom.

(II-14) A compound in which —R ¹ and —OR ³ are in any one of a gluco configuration, a galacto configuration and a manno configuration.

(II-15) A compound in which R ¹ is —NHAc or —NHSO ₃ H, and —R ¹ and —OR ³ are in a gluco configuration.

(II-16) A compound wherein R ¹ is —OH, and —R ¹ and —OR ³ are in a galacto configuration.

(II-17) When R ¹ is —NHAc and —R ¹ and —OR ³ are in a gluco configuration, more preferably any one of R ² , R ³ and R ⁴ is —SO ₃ H. More preferably, any one of R ² , R ³ and R ⁴ is —SO ₃ H, and the remainder is a hydrogen atom.

(II-18) When R ¹ is —OH and —R ¹ and —OR ³ are in a galacto configuration, R ⁴ is preferably —SO ₃ H, more preferably R ⁴ is —SO ₃ H. And R ² and R ³ are hydrogen atoms.

(II-19) When R ¹ is —NHSO ₃ H and —R ¹ and —OR ³ are in a gluco configuration, more preferably any one of R ² , R ³ and R ⁴ is —SO _3. H, and more preferably any one of R ² , R ³ , and R ⁴ is —SO ₃ H and the remainder is a hydrogen atom.

(II-20) When R ¹ is —NHSO ₃ H and —R ¹ and —OR ³ are in a gluco configuration, R ² , R ³ and R ⁴ are more preferably hydrogen atoms.

(II-21) When R ¹ is —NHSO ₃ H and —R ¹ and —OR ³ are in a galacto configuration, preferably any one of R ² , R ³ and R ⁴ is —SO ₃ H And the remainder is a hydrogen atom, more preferably R ⁴ is —SO ₃ H and the remainder is a hydrogen atom.

  Compound II, which is such a polymer compound, has a markedly improved prion growth inhibitory effect compared to Compound I.

  Hereinafter, specific compounds represented by the general formula (I) or (II) can be listed below, but the present invention is not limited to the compounds listed below.

The compound represented by the following general formula 1-10.
^{1: R 1 = -NHAc, R} 2 = R 4 = H, R 3 = SO 3 H, a _{^{R 5 = -C 6 H 4 -pNO}} 2 or -C ₆ H ₄ -pNHAc, -R ¹ and - Compound in which OR ³ is in gluco configuration (-R ¹ and -OR ³ are in equatorial configuration)

_{^{2: R 1 = -NHSO 3 H}} , R 2 = R 3 = H, R 4 = SO 3 H, a ^{_{R 5 = -C 6 H 4 -pNO}} 2 or -C ₆ H ₄ -pNHAc, -R ¹ And -OR ³ are in a gluco configuration (-R ¹ and -OR ³ are in an equatorial configuration)

_{^{3: R 1 = -NHSO 3 H}} , R 2 = R 4 = H, R 3 = SO 3 H, a ^{_{R 5 = -C 6 H 4 -pNO}} 2 or -C ₆ H ₄ -pNHAc, -R ¹ And -OR ³ are in a gluco configuration (-R ¹ and -OR ³ are in an equatorial configuration)

^{4: R 1 = -NHAc, R} 2 = R 3 = H, R 4 = SO 3 H, a _{^{R 5 = -C 6 H 4 -pNO}} 2 or -C ₆ H ₄ -pNHAc, -R ¹ and - Compound in which OR ³ is galacto configuration (-R ¹ is equatorial configuration, -OR ³ is axial configuration)

^{5: R 1 = -NHAc, R} 2 = R 4 = H, R 3 = SO 3 H, a _{^{R 5 = -C 6 H 4 -pNO}} 2 or -C ₆ H ₄ -pNHAc, -R ¹ and - Compound in which OR ³ is galacto configuration (-R ¹ is equatorial configuration, -OR ³ is axial configuration)

^{6: R 1 = -NHAc, R} 2 = SO 3 H, R 3 = R 4 = H, an _{^{R 5 = -C 6 H 4 -pNO}} 2 or -C ₆ H ₄ -pNHAc, -R ¹ and - Compound in which OR ³ is galacto configuration (-R ¹ is equatorial configuration, -OR ³ is axial configuration)

^{7: R 1 = -NHAc, R} 2 = R 3 = H, R 4 = SO 3 H, a _{^{R 5 = -C 6 H 4 -pNO}} 2 or -C ₆ H ₄ -pNHAc, -R ¹ and - A compound in which OR ³ is in a Manno configuration (-R ¹ is an axial configuration, -OR ³ is an equatorial configuration)

^{8: R 1 = -NHAc, R} 3 = SO 3 H, R 2 = R 4 = H, an _{^{R 5 = -C 6 H 4 -pNO}} 2 or -C ₆ H ₄ -pNHAc, -R ¹ and - A compound in which OR ³ is in a Manno configuration (-R ¹ is an axial configuration, -OR ³ is an equatorial configuration)

^{9: R 1 = -NHAc, R} 2 = SO 3 H, R 3 = R 4 = H, an _{^{R 5 = -C 6 H 4 -pNO}} 2 or -C ₆ H ₄ -pNHAc, -R ¹ and - A compound in which OR ³ is in a Manno configuration (-R ¹ is an axial configuration, -OR ³ is an equatorial configuration)

_{^{10: R 1 = -NHSO 3 H}} , R 2 = R 3 = R 4 = H, an ^{_{R 5 = -C 6 H 4 -pNO}} 2 or -C ₆ H ₄ -pNHAc, -R ¹ and -OR ³ And gluco configuration (-R ¹ and -OR ³ are equatorial configurations)

P ^{1 1 to} P ¹ 12: In the general formula (II), R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the following 1 ′ to 12 ′, and A is the number of carbon atoms in —A—B— 1 to 6 alkylene group, phenylene group or ethyleneoxy group ((C ₂ H ₄ O) _m ) (m is an integer of 1 to 10), and B is a single bond, an amide bond, a carboxylic acid ester bond or a sulfonamide A polymer compound in which a sugar chain-containing group is bonded to a polymer chain.

1 ′: R ¹ = —NHAc, R ² = R ³ = H, R ⁴ = SO ₃ H, —A—B — = — C ₆ H ₄ —pNH—CO— (polymer), and —R ¹ and -OR ³ are gluco configuration (-R ¹ and -OR ³ and the equatorial arrangement).

2 ′: R ¹ = —NHAc, R ² = R ⁴ = H, R ³ = SO ₃ H, —A—B — = — C ₆ H ₄ —pNH—CO— (polymer), and —R ¹ and -OR ³ are gluco configuration (-R ¹ and -OR ³ and the equatorial arrangement).

3 ′: R ¹ = —NHAc, R ³ = R ⁴ = H, R ² = SO ₃ H, —A—B — = — C ₆ H ₄ —pNH—CO— (polymer), and —R ¹ and -OR ³ are gluco configuration (-R ¹ and -OR ³ and the equatorial arrangement).
_{^{4 ': R 1 = -NHSO 3}} H, R 2 = R 3 = H, R 4 = SO 3 H, -A-B - = - C 6 H 4 -pNH-CO- is a (polymeric), -R ¹ and -OR ³ and Glucophage arrangement (and -R ¹ and -OR ³ is equatorial arrangement) it is.

5 ′: R ¹ = —NHSO ₃ H, R ² = R ⁴ = H, R ³ = SO ₃ H, —A—B — = — C ₆ H ₄ —pNH—CO— (polymer), —R ¹ and -OR ³ and Glucophage arrangement (and -R ¹ and -OR ³ is equatorial arrangement) it is.

6 ′: R ¹ = —NHAc, R ² = R ³ = H, R ⁴ = SO ₃ H, —A—B — = — C ₆ H ₄ —pNH—CO— (polymer), and —R ¹ -OR ³ and are galacto arrangement (-R ¹ is equatorial arrangement, -OR ³ is an axial arrangement) it is.

7 ′: R ¹ = —NHAc, R ² = R ⁴ = H, R ³ = SO ₃ H, —A—B — = — C ₆ H ₄ —pNH—CO— (polymer), and —R ¹ -OR ³ and are galacto arrangement (-R ¹ is equatorial arrangement, -OR ³ is an axial arrangement) it is.

8 ′: R ¹ = —NHAc, R ² = SO ₃ H, R ³ = R ⁴ = H, —A—B — = — C ₆ H ₄ —pNH—CO— (polymer), and —R ¹ -OR ³ and are galacto arrangement (-R ¹ is equatorial arrangement, -OR ³ is an axial arrangement) it is.

9 ′: R ¹ = —NHAc, R ² = R ³ = H, R ⁴ = SO ₃ H, —A—B — = — C ₆ H ₄ —pNH—CO— (polymer), and —R ¹ -OR ³ and is manno arrangement (-R ¹ is an axial arrangement, -OR ³ is equatorial arrangement) is.

10 ′: R ¹ = —NHAc, R ³ = SO ₃ H, R ² = R ⁴ = H, —A—B — = — C ₆ H ₄ —pNH—CO— (polymer), and —R ¹ -OR ³ and is manno arrangement (-R ¹ is an axial arrangement, -OR ³ is equatorial arrangement) is.

11 ′: R ¹ = —NHAc, R ² = SO ₃ H, R ³ = R ⁴ = H, —A—B — = — C ₆ H ₄ —pNH—CO— (polymer), and —R ¹ -OR ³ and is manno arrangement (-R ¹ is an axial arrangement, -OR ³ is equatorial arrangement) is.

12 ′: R ¹ = —OH, R ² = R ³ = H, R ⁴ = SO ₃ H, —A—B — = — C ₆ H ₄ —pNH—CO— (polymer), and —R ¹ A compound in which —OR ³ is a galacto configuration (—R ¹ is an equatorial configuration, —OR ³ is an axial configuration)

13 ′: R ¹ = —NHAc, R ² = R ³ = H, R ⁴ = SO ₃ H, —A—B — = — C ₆ H ₄ —pNH—CO— (polymer), and —R ¹ A compound in which —OR ³ is a galacto configuration (—R ¹ is an equatorial configuration, —OR ³ is an axial configuration)

14 ′: R ¹ = —NHAc, R ² = H, R ³ = R ⁴ = SO ₃ H, —A—B — = — C ₆ H ₄ —pNH—CO— (polymer), and —R ¹ A compound in which —OR ³ is a galacto configuration (—R ¹ is an equatorial configuration, —OR ³ is an axial configuration)

15 ′: R ¹ = —NHSO ₃ H, R ² = R ⁴ = H, R ³ = SO ₃ H, —A—B — = — C ₆ H ₄ —pNH—CO— (polymer), —R Compound in which ¹ and -OR ³ are in galacto configuration (-R ¹ is equatorial configuration, -OR ³ is axial configuration)

_{^{16 ': R 1 = -NHSO 3}} H, R 2 = R 3 = H, R 4 = SO 3 H, -A-B - = - C 6 H 4 -pNH-CO- is a (polymeric), -R Compound in which ¹ and -OR ³ are in galacto configuration (-R ¹ is equatorial configuration, -OR ³ is axial configuration)

  Of these, 1 'to 4' and 12 'are preferable.

P ² 1~P ² 12: In the general formula (II), each have a corresponding carbohydrate moiety to the compound of 1'~12 ', -A-B- = -C 6 H 4 -pNH-CO- A polymer compound in which a sugar chain-containing group (polymer) is bonded to a polymer chain (III) represented by the following formula.

Preferably, ^one of Y ¹ and Y ² is a hydrogen atom, the other is an amide group, and Y ³ and Y ⁴ are hydrogen atoms. The amide group is the same as in the preferred embodiment. n represents an integer of 1 to 5000 and contains a sugar chain-containing group in a proportion of 0.1 to 100%.

P ³ 1: a polymer compound represented by the following formula (IV).
In the formula (IV), any one of R ² , R ³ and R ⁴ is —SO ₃ H, the rest is a hydrogen atom, n is an integer of 1 to 5000, and the sugar chain-containing group is 0 0.1 to 100% of the content.

P ³ 2: A polymer compound represented by the following formula (V).
In formula (V), n is an integer of 1 to 5000 and contains a sugar chain-containing group in a proportion of 0.1 to 100%.

Among the above compounds, preferably compounds ^{1, P 1 1, P 1} 2, P 1 3, P 1 12, P 2 1, P 2 2, P 2 3, P 2 12, P 3 1, P 3 2, more preferably compounds ^{1, P 1 2, P 2} 2, P 3 1 ( of which R ³ is -SO ₃ H) is.

  The compounds of the present invention are particularly less aggressive to cells (low cytotoxicity) and can effectively inhibit prion growth. In particular, the polymer compound significantly improves the prion growth inhibitory effect.

It is a photograph which shows the production inhibitory effect by continuous administration.

The prion growth inhibitor of the present invention can be easily produced according to the following method. In the following production method examples, R ¹ , R ² , R ³ , R ⁴ , A, B, Y ¹ , Y ² , Y ³ , Y ⁴ , and Z are as described above.

Scheme A

Scheme B

Scheme C

Scheme D

Scheme E

Scheme F

Scheme G

<Scheme A>
(1) Synthesis of Compound (2a) N-acetylglucosamine hydrochloride (1a; the amino group at the 2nd position and the hydroxyl group at the 4th position are both in the equatorial gluco type, as well as N-acetylgalactosamine hydrochloride; N-acetylmannosamine hydrochloride when the amino group in the equatorial arrangement and the 4-position hydroxyl group are in the axial arrangement; and the amino group in the 2-position is in the equatorial arrangement galacto-type (All commercially available products can be used) in a solvent, 1) neutralized with NaOMe / MeOH, NaOH, KOH, triethylamine, diisopropylethylamine, pyridine, etc. 2) trifluoroacetic acid ethyl ester (TFAE) ) Or a TFA-forming reagent such as trifluoroacetic anhydride (TFAA).
Examples of the solvent include methanol, ethanol, DMF, pyridine and the like. Reactions 1) and 2) may be carried out continuously in one container or may be carried out independently.
The reaction is usually carried out at about 10 to 30 ° C., preferably about 22 ° C. (room temperature) for about 10 minutes to about 2 days.

(2) Synthesis of Compound (3a) Next, halogen substitution at the 1-position hydroxyl group and protection of other hydroxyl groups are carried out.
For example, a compound (3a) can be synthesized by reacting a compound (2a) having an amino group protected with a trifluoroacetic acid group (TFA) with a halogenated acetyl compound such as acetyl chloride.
Alternatively, the compound (2a) can be reacted with acetic anhydride in pyridine and then reacted with hydrogen bromide-acetic acid (HBr-AcOH) or the like to obtain a bromo compound of the compound (3a).
The reaction can be carried out at about −20 ° C. to room temperature, preferably about −20 to 10 ° C. for about 10 minutes to about 2 days.

(3) Synthesis of Compound (4a) Compound (4a) is obtained by reacting Compound (3a) with R ⁵ —OQ in the presence of a phase transfer catalyst in a two-phase system of an organic solvent and an aqueous solution. be able to. R ⁵ has the same meaning as in formula (I), and Q is a hydrogen atom, sodium ion, potassium ion or the like, preferably a hydrogen atom.
Examples of the organic solvent include methylene chloride, THF, diethyl ether and the like. Examples of the aqueous solution include aqueous solutions of sodium hydroxide and potassium hydroxide. Examples of the phase transfer catalyst include tetrabutylammonium bromide.
The reaction is usually carried out at about 0 to 30 ° C. for about 10 minutes to about 2 days.

(4) Synthesis of Compound (5a) Compound (4a) can be treated with NaOMe / MeOH, KOMe / MeOH, or the like to obtain compound (5a) in which the protecting group for the hydroxyl group is deprotected.
The reaction is preferably carried out at −10 ° C. to 30 ° C., more preferably 0 ° C. to 4 ° C. for 1 minute to 5 hours. When the reaction temperature is 0 ° C. to 4 ° C., it is about 30 to 100 minutes.

(5) Synthesis of Compound (6a) Further, a compound (6a) in which TFA is deprotected can be obtained by treatment with an aqueous 0.1 M to 0.5 M NaOH solution. Potassium hydroxide or lithium hydroxide may be used.
The reaction is preferably carried out at −10 ° C. to 30 ° C., more preferably 0 ° C. to 4 ° C. for 1 minute to 5 hours. When the reaction temperature is 0 ° C. to 4 ° C., it is about 30 to 100 minutes.

(6) Synthesis of Compound (7a) Compound (7a) can be obtained by reacting compound (6a) with a sulfating reagent in a solvent. Examples of the sulfating reagent include sulfur trioxide trimethylamine complex, sulfur trioxide dimethylformamide complex, sulfur trioxide pyridine complex and the like. Examples of the solvent include dimethylformamide (DMF), THF (tetrahydrofuran), DMSO (dimethyl sulfoxide), pyridine and the like, and preferably dimethylformamide and pyridine are used. If necessary, a base such as triethylamine may be added.
The reaction is usually carried out at about 10 ° C. to about 60 ° C., preferably about 30-50 ° C., for about 1 hour to about 10 hours, preferably about 1 to 3 hours.

<Scheme B>
Scheme B is a step of performing N-sulfation at the 3-position, 4-position or 6-position and 2-position of the compound (5a). Step B shows an example where R ⁵ is a paranitrophenyl group in the compound (5a).
Step B1 is a step of sulfating the 6-position of the sugar chain of compound (5a ′) and further performing N-sulfation at the 2-position.
Step B2 is a step of sulfating the 3- or 4-position of the sugar chain of compound (5a ′) via compound (11a) and further performing N-sulfation at the 2-position.

(1) Synthesis of compound (8a) (step B1)
Compound (8a) can be obtained by reacting compound (5a ′) with an excess of a sulfating reagent in a suitable solvent. Excess refers to 1 to 20 molar equivalents, preferably 1.2 to 9 molar equivalents relative to the sugar raw material.

Examples of the sulfating reagent include sulfur trioxide trimethylamine complex, (sulfur trioxide dimethylformamide complex, sulfur trioxide pyridine complex) and the like. Examples of the solvent include dimethylformamide (DMF), THF (tetrahydrofuran), DMSO (dimethylsulfoxide) and the like, and preferably dimethylformamide and (pyridine) are used. If necessary, a base such as triethylamine may be added.
The reaction is usually carried out at about 10 ° C. to about 60 ° C., preferably about 30-50 ° C., for about 1 hour to about 10 hours, preferably about 1 to 3 hours.

(2) Synthesis of Compound (9a) The compound (9a) can be synthesized by a method similar to the method for producing compound (6a) from compound (5a) in Scheme A.

(3) Synthesis of Compound (10a) The compound (10a) can be synthesized by a method similar to the method for producing compound (7a) from compound (6a) in Scheme A.

(4) Synthesis of compound (11a) (step B2)
Compound (11a) can be obtained by reacting compound (5a ′) with protective reagent UX in the presence of a base in a suitable solvent. U is a protecting group, and X is a leaving group.
Here, U is a silyl protecting group or an acyl protecting group, and both selectively protect the 6-position of the sugar. Examples of the silyl protecting group include a tert-butyldimethylsilyl group and a tert-butyldiphenylsilyl group. Examples of the acyl protecting group include a pivaloyl group and a benzoyl group.

  In order to introduce a tert-butyldimethylsilyl group or a tert-butyldiphenylsilyl group into the 6-position of the sugar, the corresponding tert-butyldimethylsilyl chloride, tert-butyldimethylsilyltrimethylsulfonate, tert-butyldiphenylsilyl chloride, tert-Butyldiphenylsilyltrimethylsulfonate is reacted in the presence of pyridine, dimethylaminopyridine, triethylamine, diisopropylamine and the like, preferably at 0 ° C. to 50 ° C. for 10 minutes to 24 hours.

  On the other hand, in order to introduce a pivaloyl group and a benzoyl group at the 6-position of the sugar, preferably 10 minutes at 0 to 50 ° C. in the presence of pivaloyl chloride, benzoyl chloride and pyridine, dimethylaminopyridine, triethylamine, diisopropylamine and the like. Allow to react for ~ 24 hours.

(5) Synthesis of compounds (12a) and (14a) Compound (11a) is reacted with an excess of a sulfating reagent in an appropriate solvent to sulphate the hydroxyl group at the 3- or 4-position, and further to the 6-position. Deprotect the protecting group. Excess refers to 1 to 20 molar equivalents, preferably 1.2 to 9 molar equivalents relative to the sugar raw material.

Examples of the sulfating reagent include sulfur trioxide trimethylamine complex, (sulfur trioxide dimethylformamide complex, sulfur trioxide pyridine complex) and the like. Examples of the solvent include dimethylformamide (DMF), THF (tetrahydrofuran), DMSO (dimethylsulfoxide) and the like, and preferably dimethylformamide and pyridine are used. If necessary, a base such as triethylamine may be added.
The sulfation reaction can be carried out usually at about 10 ° C. to about 60 ° C., preferably about 30-50 ° C., for about 1 hour to about 10 hours, preferably about 1 to 3 hours.

  The selectivity of the compound in which the 3rd or 4th position is sulfated is approximately 3rd: 4th = 1: 1 to 3: 1, and both can be purified by normal phase column chromatography. Usually, silica gel is used as the filler and chloroform-methanol mixture is used as the eluent. However, separation and purification may be performed by reverse phase silica gel column chromatography (developing solvent: water) in the next step.

Next, after each component is separated, when the protecting group U is a silyl group, it can be treated with tetrabutylammonium fluoride (TBAF) or the like as a leaving reagent to obtain (12a) or (14a). .
When the protecting group U is acyl-based, it can be treated with NaOMe / MeOH, KOMe / MeOH or the like to obtain (12a) or (14a), respectively.
After the sulfation of (11a) and the subsequent deprotection of the protecting group U to obtain (12a) and (14a), each component may be separated and purified. In this case, it is preferable to use a reverse feed filler (C-18 or the like) and use water or water-methanol as the eluent.

(6) Synthesis of Compounds (13a) and (15a) Using a method similar to that shown in (5) Synthesis of Compound (6a) in Scheme A and (6) Synthesis of Compound (7a), Compound (12a ) And compound (14a), compound (13a) and compound (15a) can be obtained.

<Scheme C>
(1) Synthesis of Compound (16a) Scheme C shows a method for acetylating the amino group of Compound (6a).
Compound (16a) can be obtained by reacting compound (6a) with an acetylating agent in a solvent.
As the acetylating agent, acetic anhydride or the like can be used. As the solvent, methanol or the like can be used.
Moreover, you may perform the said reaction in presence of bases, such as a triethylamine and potassium carbonate.
The reaction is usually carried out at about 0 to 30 ° C. for about 10 minutes to about 24 hours.
In (16a), commercially available products may be used for pNP N-acetylglucosamine, pNP N-acetylgalactosamine, and pNP N-acetylmannosamine.

< Scheme D >
Scheme D shows a method for sulfation of a hydroxyl group or an amino group on a derivative when R ⁵ has a phenylene group (particularly, a paranitrophenyl group).

Process D1
Step D1 shows a method for producing compound (18a) by sulfating the 6-position of the sugar chain of compound (17a). Compound (18a) can be obtained by reacting compound (17a) with an excess of a sulfating reagent in a suitable solvent. Excess refers to 1 to 20 molar equivalents, preferably 1.2 to 9 molar equivalents relative to the sugar raw material.

Examples of the sulfating reagent include sulfur trioxide trimethylamine complex, (sulfur trioxide dimethylformamide complex, sulfur trioxide pyridine complex) and the like. Examples of the solvent include dimethylformamide (DMF), THF (tetrahydrofuran), DMSO (dimethylsulfoxide) and the like, and preferably dimethylformamide and (pyridine) are used. If necessary, a base such as triethylamine may be added.
The reaction is usually carried out at about 10 ° C. to about 60 ° C., preferably about 30-50 ° C., for about 1 hour to about 10 hours, preferably about 1 to 3 hours.
As the compound (17a) having a gluco configuration, a galacto configuration or a manno configuration, a commercially available product can be used.

Process D2
Step 2 shows a method for producing a compound (20a) or a compound (21a) by sulfating the 3-position or 4-position of the sugar chain of the compound (17a) via the compound (19a), respectively. .

(1) Compound (19a) is a step of introducing a protecting group into the hydroxyl group at the 6-position of the sugar chain of compound (17a). Compound (19a) can be obtained by reacting compound (17a) with protective reagent UX in the presence of a base in a suitable solvent. U is a protecting group, and X is a leaving group.
Here, U is a silyl protecting group or an acyl protecting group, and both selectively protect the 6-position of the sugar. Examples of the silyl protecting group include a tert-butyldimethylsilyl group and a tert-butyldiphenylsilyl group. Examples of the acyl protecting group include a pivaloyl group and a benzoyl group.

  In order to introduce a tert-butyldimethylsilyl group or a tert-butyldiphenylsilyl group into the 6-position of the sugar, the corresponding tert-butyldimethylsilyl chloride, tert-butyldimethylsilyltrimethylsulfonate, tert-butyldiphenylsilyl chloride, tert-Butyldiphenylsilyltrimethylsulfonate is reacted in the presence of pyridine, dimethylaminopyridine, triethylamine, diisopropylamine and the like, preferably at 0 ° C. to 50 ° C. for 10 minutes to 24 hours.

  On the other hand, in order to introduce a pivaloyl group and a benzoyl group at the 6-position of the sugar, preferably 10 minutes at 0 to 50 ° C. in the presence of pivaloyl chloride, benzoyl chloride and pyridine, dimethylaminopyridine, triethylamine, diisopropylamine and the like. Allow to react for ~ 24 hours.

(2) The resulting compound (19a) is subjected to sulfation of a hydroxyl group by the same method as in Step D1, whereby a compound in which the 3-position or 4-position is sulfated can be obtained. Further, in order to remove the protecting group U, the compounds (20a) and (21a) can be obtained by reacting the elimination reagent in an appropriate solvent.
Compound (19a) is reacted with an excess of a sulfating reagent in a suitable solvent to sulphate the hydroxyl group at the 3- or 4-position, and further deprotect the protecting group at the 6-position.

Examples of the sulfating reagent include sulfur trioxide trimethylamine complex, (sulfur trioxide dimethylformamide complex, sulfur trioxide pyridine complex) and the like. Examples of the solvent include dimethylformamide (DMF), THF (tetrahydrofuran), DMSO (dimethylsulfoxide) and the like, and preferably dimethylformamide and (pyridine) are used. If necessary, a base such as triethylamine may be added.
The sulfation reaction can be carried out usually at about 10 ° C. to about 60 ° C., preferably about 30-50 ° C., for about 1 hour to about 10 hours, preferably about 1 to 3 hours.

  The selectivity of the compound in which the 3rd or 4th position is sulfated is approximately 3rd: 4th = 1: 1 to 3: 1, and both can be purified by normal phase column chromatography. Usually, silica gel is used as the filler and chloroform-methanol mixture is used as the eluent. However, separation and purification may be performed by reverse phase silica gel column chromatography (developing solvent: water) in the next step.

Next, after each component is separated, when the protecting group U is a silyl group, it can be treated with tetrabutylammonium fluoride (TBAF) or the like as a leaving reagent to obtain (20a) or (21a). .
When the protecting group U is acyl-based, it can be treated with NaOMe / MeOH, NaOH aqueous solution or LiOH aqueous solution to obtain (20a) or (21a), respectively.

  After the sulfation of (19a) and the subsequent deprotection of the protecting group U to obtain (20a) and (21a), the respective sentences may be separated and purified. In this case, it is preferable to use a reverse feed filler (C-18 or the like) and use water or water-methanol as the eluent.

< Scheme E >
Scheme E shows a method for converting a nitro group bonded to a benzene ring into another functional group.

Process E1
Step E1 shows a method for producing compound (22a) by N-acylating the nitro group of compound (18a).

(1) First, in a suitable solvent, in the presence of a catalyst, the nitro group of compound (18a) is reduced with hydrogen to be converted to an amino group.
(2) Furthermore, the compound (22a) can be produced by reacting with an acyl halide in a suitable solvent in the presence of a suitable base.

  In the hydrogen reduction step (1), examples of the catalyst include catalysts such as palladium. Examples of the palladium catalyst include palladium hydroxide, palladium / carbon, palladium black, and the like. Examples of the solvent include water, methanol, ethanol, ether, ethyl acetate and the like. The usage-amount of a catalyst should just be in the range of about 1-50 mass% with respect to a compound (18a). The reaction can be carried out in a hydrogen atmosphere in the range of about 1 to 100 atmospheres, usually at about 10 to 30 ° C., preferably about 22 ° C. (room temperature) for about 10 minutes to about 2 days.

In the acylation step (2), in the acylating agent XCOR ⁹ , X represents a halogen atom, and examples thereof include a chlorine atom and a bromine atom. R ⁹ is the same as R ⁹ in Formula (IV), which may have a substituent C _{1 ~ 6} alkyl group which may have a substituent C _{2 ~ 6} alkenyl group, a substituted group the indicating the optionally having C _{2 ~ 6} alkynyl group or an optionally substituted C _{6 ~ 10} aryl group. In the acylation step, an acid anhydride can also be used. For example, when an acetyl group is introduced, an acid anhydride such as acetic anhydride is preferably used.

  Examples of the base include organic bases such as potassium carbonate, sodium hydrogen carbonate, cesium carbonate, triethylamine, diisopropylamine, pyridine, and dimethylaminopyridine. You may mix these basic organic bases. As the solvent, for example, when an inorganic base is used, water, methanol and ethanol are preferable. In the case of an organic base, ether, methylene chloride, THF and the like can be mentioned. Pyridine as a base may be used as a solvent. The reaction is usually carried out at about −50 to 80 ° C. for about 10 minutes to about 2 days.

Process E2
Step E2 shows a method for producing a compound (23a) by N-sulfating the nitro group of the compound (18a).

(1) First, the nitro group of compound (18a) is reduced with hydrogen and converted to an amino group in the same manner as in step E1 (1).
(2) Furthermore, the compound (23a) can be produced by reacting with a sulfating reagent in an appropriate solvent.

  The sulfation of (2) can be carried out by reacting a compound having a nitro group converted to an amino group with 0.8 to 1.5 equivalents of a sulfating reagent in a suitable solvent.

  Examples of the sulfating reagent include sulfur trioxide trimethylamine complex, (sulfur trioxide dimethylformamide complex, sulfur trioxide pyridine complex) and the like. Examples of the solvent include dimethylformamide (DMF), THF (tetrahydrofuran), DMSO (dimethylsulfoxide) and the like, and preferably dimethylformamide and pyridine are used. If necessary, a base such as triethylamine may be added.

  The reaction is usually carried out at about 10 ° C. to about 60 ° C., preferably about 30-50 ° C., for about 1 hour to about 10 hours, preferably about 1 to 3 hours.

  The reactions according to Steps 1 to 5 can be applied to sugar chain-containing groups in any configuration of gluco configuration, galacto configuration, and manno configuration.

<Scheme F (Step F1)>
Scheme F shows a method for producing a polymer compound.
Step F1 is a step of producing a compound (25a) by copolymerizing a compound having an unsaturated double bond at the terminal of the aglycon moiety of the compound (24a) and a polymerizable monomer HY ¹ C═CY ² H. . The copolymerization reaction can be performed by a known method, and the compound (24a) and the polymerizable monomer are reacted in an appropriate solvent in the presence of a polymerization initiator as necessary.

  Specific examples of polymerizable monomers include amides such as (meth) acrylamide; carboxylic acids such as (meth) acrylic acid, methyl or ethyl esters of (meth) acrylic acid, vinyl acetate, and allyl acetate. Carboxylic acids or esters thereof; sulfonamides such as vinyl sulfonic acid amides;

  The solvent is not limited as long as it dissolves the compound (24a) and the monomer. For example, THF, methanol, DMF, DMSO and the like can be used.

  Examples of the polymerization initiator include 2,2′-azobis (isobutyronitrile) (AIBN), 1,1′-azobis (cyclohexane-1-carbonitrile), 2,2′-azobis (2-methylbutyro). Nitrile) or the like can be used. In addition to such azo compounds, peroxides, organometallic compounds, and the like can also be used.

  When using a monomer that does not dissolve in a solvent such as THF, for example, polymerization of N, N, N ′, N′-tetramethylethylenediamine, 4,4′-azobiscyanovaleric acid, etc. is started using ultrapure water as a solvent. Polymerization can be carried out using an agent.

  The polymerization varies depending on the type of raw material and is not limited, but can be usually carried out in a temperature range of about room temperature to about 100 ° C. for about 1 to 72 hours.

<Scheme G (Process G1)>
Scheme G shows a specific example of Scheme F.
In step G1, first, (1) the nitro group of compound (18a) is converted to an N-acyl group having an unsaturated bond at the terminal to produce compound (26a). (2) Further, a method for producing the polymer compound (27a) by copolymerizing the compound (26a) with an appropriate polymerizable monomer is shown.

  In the N-acylation of (1), the nitro group of compound (18a) is converted to an amino group by reduction with hydrogen in the presence of a catalyst in an appropriate solvent, and further converted to an amino group in an appropriate solvent. The compound (26a) can be produced by reacting with an acyl halide having an unsaturated group at the terminal in the presence.

  In the hydrogen reduction step, examples of the catalyst include catalysts such as palladium. Examples of the palladium catalyst include palladium hydroxide, palladium / carbon, palladium black, and the like. Examples of the solvent include water, methanol, ethanol, ether, ethyl acetate and the like. The usage-amount of a catalyst should just be in the range of about 1-50 mass% with respect to a compound (18a). The reaction can be carried out in a hydrogen atmosphere in the range of about 1 to 100 atmospheres, usually at about 10 to 30 ° C., preferably about 22 ° C. (room temperature) for about 10 minutes to about 2 days.

In the acylation step containing a terminal unsaturated group, for example, when an acylating agent XCOZCH═CH ₂ is used, X represents a halogen atom, and examples thereof include a chlorine atom and a bromine atom. Examples of Z include an alkylene group having 1 to 6 carbon atoms, a phenylene group, and an ethyleneoxy group ((C ₂ H ₄ O) _n ). Examples of the acylating agent include acrylic acid chloride and the like. The acylating agent may be crotonyl chloride, methacryloyl chloride or the like having a substituent such as a methyl group on the unsaturated carbon.

  Examples of the base include organic bases such as potassium carbonate, sodium hydrogen carbonate, cesium carbonate, triethylamine, diisopropylamine, pyridine, and dimethylaminopyridine. You may mix these basic organic bases. As the solvent, for example, when an inorganic base is used, water, methanol and ethanol are preferable. In the case of an organic base, ether, methylene chloride, THF and the like can be mentioned. About methanol and ethanol, you may use with a triethylamine etc., and it is usually used preferably. Pyridine as a base may be used as a solvent. The reaction is usually carried out at about −50 to 80 ° C. for about 10 minutes to about 2 days.

  The copolymerization reaction (2) can be carried out in the same manner as in Step F1, and is carried out by reacting the compound (26a) with a polymerizable monomer in an appropriate solvent in the presence of a polymerization initiator as necessary. As the solvent, the polymerization initiator, and the polymerizable monomer, those similar to those in the step F1 can be used.

  The polymerization varies depending on the type of raw material and is not limited, but can be usually carried out in a temperature range of about room temperature to about 100 ° C. for about 1 to 72 hours.

  In addition, the compound (25a) is obtained by reacting a polymer having a functional group on the main chain with a sugar-containing compound corresponding to the compound represented by the general formula (I) having a group capable of binding to the functional group. It can also be manufactured.

In the compounds I and II, a compound in which R ¹ is —OH can be obtained by applying the same method as described above using, for example, commercially available p-nitrophenyl β-D-galactopyranoside as a raw material. Can be sulfated.

  The above is a typical example of the production method of Compound I and Polymer Compound II (“polymer Compound II” may be referred to as “Compound II”). Or hydrates or solvates may be formed, and any of them may vary depending on the starting material, the solvent used and the like, and is not particularly limited as long as the reaction is not inhibited. The solvent to be used is not particularly limited as long as it varies depending on starting materials, reagents and the like, and can dissolve the starting material to some extent without inhibiting the reaction. When the compounds I and II according to the present invention are obtained in a free form, the compounds I and II can be converted into a salt which may be formed or a hydrate thereof according to a conventional method.

  When compounds I and II according to the present invention are obtained as salts of compounds I and II or hydrates of compounds I and II, they can be converted into the free forms of compounds I and II according to a conventional method.

  In addition, various isomers (for example, geometric isomers, optical isomers based on asymmetric carbon, rotational isomers, stereoisomers, tautomers, etc.) obtained for compounds I and II according to the present invention are usually used. Purification and isolation by using a separation means such as recrystallization, diastereomeric salt method, enzyme resolution method, various chromatography (eg thin layer chromatography, column chromatography, gas chromatography, etc.) Can do.

  When the prion growth inhibitor of the present invention is used as a therapeutic or prophylactic agent for prion disease, the administration method is oral, parenteral (intravenous, intramuscular, subcutaneous), peritoneal, topical. Administration (infusion, powder, ointment, gel or cream) and inhalation (oral or nasal spray). The dosage forms include, for example, tablets, capsules, granules, powders, pills, aqueous and non-aqueous oral solutions and suspensions, and non-filled containers adapted to be subdivided into individual doses. Examples include oral solutions. The dosage form can also be adapted to various modes of administration including controlled release formulations such as subcutaneous implantation.

  The preparation is produced by a known method using additives such as excipients, lubricants (coating agents), binders, disintegrants, stabilizers, flavoring agents, and diluents.

  Examples of excipients include starches such as starch, potato starch, and corn starch, lactose, crystalline cellulose, and calcium hydrogen phosphate.

  Examples of the coating agent include ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, shellac, talc, carnauba wax, and paraffin.

  Examples of the binder include polyvinyl pyrrolidone, macrogol and the same compound as the excipient.

  Examples of the disintegrant include the same compounds as the above excipients and chemically modified starch / celluloses such as croscarmellose sodium, carboxymethyl starch sodium, and crosslinked polyvinylpyrrolidone.

  Examples of the stabilizer include paraoxybenzoates such as methyl paraben and propyl paraben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; Mention may be made of dehydroacetic acid; and sorbic acid.

  Examples of the flavoring agent include sweeteners, acidulants, and fragrances that are commonly used.

  Moreover, ethanol, phenol, chlorocresol, purified water, distilled water, or the like can be used as a solvent for producing the liquid agent.

  Examples of the surfactant or emulsifier include polysorbate 80, polyoxyl 40 stearate, lauromacrogol and the like.

  When Compound I or II is used as a prion growth inhibitor, or a therapeutic or prophylactic agent for prion disease, the amount of Compound I, II or a pharmaceutically acceptable salt thereof used is the symptom, age, body weight, relative It depends on the general health condition, the presence of other medications, the method of administration, etc. For example, for patients (warm-blooded animals, especially humans), the generally effective amount is preferably 0.1 to 1000 mg / kg body weight per day in the case of an oral preparation as the active ingredient (Compound I), more preferably Is 1 to 300 mg per kg body weight, and the daily usage is preferably in the range of 10 to 800 mg for adult patients with normal body weight. In the case of a parenteral preparation, it is preferably 0.1 to 1000 mg per kg body weight per day, more preferably 10 to 800 mg per kg body weight. It is desirable to administer this once or several times a day according to the symptoms.

In addition, compounds I and II can also be used as infusions for intracerebral administration obtained by dissolving in physiological saline or the like.
Furthermore, water-soluble liquids in which compounds I and II are dissolved in an appropriate physiological saline are used as a washing solution for dry dura prion used in brain surgery and the like, in addition to the drip solution administered directly into the brain. sell. In other words, the dura mater of a patient who has been removed by brain surgery conventionally has been often contaminated with prions and has developed Creutzfeldt-Jakob disease because human dura mater has been transplanted and used. Since this dura mater is not suitable for heat treatment, it has been used by a method according to transplantation. Therefore, it is known that Creutzfeldt-Jakob disease develops when a dry dura mater contaminated with prions is used. By washing the dura mater contaminated with the present sulfated sugar-containing aqueous solution, prions can be safely excluded or prion formation can be suppressed.

Furthermore, the compounds I and II can also be used as an implantable material in the brain. In order to prevent future onset such as Creutzfeldt-Jakob disease, during brain surgery, compounds I and II, in particular, compound II, which is a polymer compound that tends to stay in the brain, are injected or implanted into the brain. Is also possible. In the case of surgery such as brain tumor, cerebral infarction, intracerebral hemorrhage, etc., the compounds I and II, particularly compound II, can be added to the brain prophylactically to be used as a measure for preventing the disease.
In addition, all prior art documents cited in the present specification are incorporated herein by reference.

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.
The compound synthesis process (production process 1) according to compound I and the polymer compound synthesis process (production process 2) according to compound II are shown below. Wherein, Y represents a -CONH _2.

Manufacturing process 1

Manufacturing process 2

[Production Example 1]
Synthesis of p-nitrophenyl 2-acetamido-2-deoxy-6-sulfo-β-D-glucopyranoside sodium salt (compound 2) (6SGN))
As shown in production step A, p-nitrophenyl 2-acetamido-2-deoxy-β-D-glucopyranoside (1) (1.0 g, 29.2 mmol) (manufactured by Aldrich) was converted to N, N-dimethylformamide (20 mL). Then, a solution of sulfur trioxide trimethylamine complex (2.4 g, 17.5 mmol) in N, N-dimethylformamide (10 mL) was added dropwise at 40 ° C. over 30 minutes, and magnetically stirred at 40 ° C. for 2 hours. Next, methanol (20 mL) was added to the obtained reaction mixture, and the mixture was stirred for one day and night, and then the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by reverse phase silica gel column chromatography (developing solvent: water). The obtained syrup was treated with an ion exchange resin (Dowex Na ⁺ ), filtered and freeze-dried to obtain the target compound (2) (657 mg, 51%).

¹ H-NMR (300 MHz, D ₂ O, tert-BuOH = 1.23 ppm) δ 8.136 (bd, 8.3 Hz, aromatics), 7.119 (bd, 8.3 Hz, aromatics), 5.289 (d, 8.4 Hz, H-1) , 4.409 (dd, 2.1 Hz and 11.4 Hz, H-6), 4.253 (dd, 5.7 Hz and 11.4 Hz, H-6 '), 4.057 (dd, 8.4 Hz and 10.2 Hz, H-2), 3.943 (m , H-5), 3.725 ( dd, 9.0 Hz and 10.2 Hz, H-3), 3.624 (dd, 9.0 Hz and 9.6 Hz, H-4), 2.036 (s, Ac). 13 C-NMR (75MHz, D ₂ O, tert-BuOH = 31.3 ppm) δ 176.9 (C = O), 163.5, 144.4, 127.9, 118.3, 100.4 (C-1), 75.9, 75.0, 71.2, 68.7, 56.9, 23.8. Elemental analysis: calculation Value (C ₁₄ H ₁₇ N ₂ NaO ₁₁ S) C, 37.84; H, 3.86; N, 6.30, experimental C, 37.35; H, 3.89; N, 6.28.FAB-MS 468 [M + Na + H] ⁺ .

[Production Example 2]
p-nitrophenyl 2-acetamido-3-sulfo-2-deoxy-β-D-glucopyranoside sodium salt (6) (3SGN), p-nitrophenyl-2-acetamido-4-sulfo-2-deoxy-β-D -Synthesis of glucopyranoside sodium salt (7) (4SGN)

Synthesis of p-nitrophenyl 2-acetamido-6-tert-butyldiphenylsilyl-2-deoxy-β-D-glucopyranoside (5) p-nitrophenyl 2-acetamido-2-deoxy-β -D-glucopyranoside (1) (300 mg, 0.87 mmol) (manufactured by Aldrich) was dissolved in pyridine (10 mL), and dimethylaminopyridine (10 mg), tert-butyldiphenylsilyl chloride (TBDS-Cl) 340 μL 1.31 mmol) was added under a nitrogen atmosphere and magnetically stirred at room temperature for 24 hours. After completion of the reaction, methanol (10 mL) was added to the reaction solution and magnetically stirred for one day and night. After concentration under reduced pressure, the mixture was diluted with ethyl acetate, and the organic phase was separated and washed with a saturated aqueous sodium bicarbonate solution and water. The organic layer is dried over magnesium sulfate, and the residue is separated and purified by silica gel column chromatography (developing solvent: chloroform: methanol = 7: 1) and recrystallized from ethanol to give the target compound (yellow crystals) ( 5) (470 mg, 92%) was obtained.

p-nitrophenyl 2-acetamido-3-sulfo-2-deoxy-β-D-glucopyranoside sodium salt (6), p-nitrophenyl-2-acetamido-4-sulfo-2-deoxy-β-D-glucopyranoside sodium Synthesis of Salt (7) The obtained compound (5) (130 mg, 0.22 mmol) was dissolved in N, N-dimethylformamide (4 mL), and at 50 ° C., sulfur trioxide trimethylamine complex (186 mg, 1.32). mmol) in N, N-dimethylformamide (10 mL) was added dropwise over 30 minutes and magnetically stirred at 50 ° C. for 12 hours. Subsequently, methanol (10 mL) was added to the obtained reaction mixture and stirred for 1 hour, and then the solvent was distilled off under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL), TBAF (147 μL, 0.33 mmol) was added under a nitrogen atmosphere, and the mixture was stirred for 3 hours. The residue was distilled off under reduced pressure, and then separated and purified by reverse phase silica gel column chromatography (developing solvent: water). The obtained syrup was treated with an ion exchange resin (Dowex Na ⁺ ), filtered and freeze-dried to obtain the target compound (6) (40 mg) and compound (7) (28 mg) in a yield of 42%. Obtained.

¹ H-NMR (δppm, 500 MHz, D ₂ O, 30 ° C):
(6): 8.03 (d, 2H, H of phenyl group), 7.02 (d, 2H, H of phenyl group), 5.28 (d, 1H, J _1,2 = 8.5 Hz, H-1), 4.36 (dd , 1H, J _2,3, = 10.5, J _3,4 = 10.5 Hz, H-3), 3.99 (dd, 1H, J _1,2 = 8.5 Hz, J _2,3 = 10.5 Hz, H-2), 3.87 (dd, 1H, J _{H -5, H-6proS} = 1.5 Hz, J _{H-6proS, H-6proR} = 12.0 Hz, H-6proS), 3.68 (dd, 1H, J _{H-5, H-6proR} = 5.4 Hz, J _{H-6proR, H-6proS} 11.1 Hz, H-6proR), 3.60 (m, 1H, H-5), 3.60 (m, H-4), 1.85 (s, 3H)
(7): 8.11 (d, 2H, H of phenyl group), 7.05 (d, 2H, H of phenyl group), 5.20 (d, 1H, J _1,2 = 8.5 Hz, H-1), 4.18 (dd , 1H, J _2,3, = 10.5, J _3,4 = 10.5 Hz, H-4), 3.98 (dd, 1H, J _1,2 = 8.5 Hz, J _2,3 = 10.5 Hz, H-2), 3.80 (m, 2H, H- 6proS, H-6proR), 3.70 (m, 2H, H-5, H3), 1.87 (s, 3H)

[Production Example 3]
Synthesis of p-acetamidophenyl 2-acetamido-6-sulfo-2-deoxy-β-D-glucopyranoside sodium salt (8)
P-Nitrophenyl 2-acetamido-6-sulfo-2-deoxy-β-D-glucopyranoside sodium salt (2) (50 mg, 0.11 mmol) obtained in Production Example 1 was dissolved in deionized water (2 mL). Then, a catalytic amount of palladium hydroxide on carbon was added, and the mixture was magnetically stirred at room temperature in a hydrogen atmosphere for 2 hours. After completion of the reaction, the catalyst was removed by Celite filtration and concentrated under reduced pressure. The residue was dissolved in deionized water (2 mL) again, and potassium carbonate (46 mg, 0.33 mmol) was added at 0 ° C. and stirred for a while. At 0 ° C., acetic anhydride (32 μl, 0.33 mmol) was added dropwise and stirred for 3 hours. The reaction solution was neutralized and concentrated under reduced pressure, and the syrup was separated and purified by reverse phase silica gel column chromatography (developing solvent: water). The obtained syrup was treated with an ion exchange resin (Dowex Na ⁺ ), filtered, and lyophilized to obtain the target compound (8) (41 mg 80%) as a white solid.

¹ H NMR (δppm, 500 MHz, D ₂ O, 30 ° C) δ 7.33 (d, 2H, J = 9.0 Hz, H of phenyl group), 7.06 (d, 2H, J = 9.0 Hz, H of phenyl group) , 5.12 (d, 1H, J = 8.5 Hz, H-1), 4.37 (dd, 1H, J = 2.0, 11.5 Hz, H-6 _proS ), 4.23 (dd, 1H, J = 5.5, 11.5 Hz, H -6 _proR ), 3.97 (dd, 1H, J = 8.0, 10.5 Hz, H-2), 3.84 (m, 1H, H-5), 3.65 (dd, 1H, J = 10.0, 10.0 Hz, H-3 ), 3.61 (dd, 1H, J = 9.0, 9.5 Hz, H-4), 2.13, 2.02 (sx2, 6H, acetamido groups);
Optical rotation [α] _D = -78.9 ^o (c = 0.11 water);
IR absorption spectrum IR (KBr) 3299 (OH), 1660 and 1548 (amide), 1226 (OSO ₃ );
FAB ⁺ mass spectrum: 479 [M + Na] ⁺

[Production Example 4]
Synthesis of polymer (4) (Poly 6SGN) of p-acryloylamidophenyl 2-acetamido-6-sulfo-2-deoxy-β-D-glucopyranoside sodium salt (3)

As shown in Production Process B, Compound (2) (200 mg, 0.45 mmol) obtained in Production Example 1 was dissolved in a mixed solvent of methanol (10 mL) and water (10 mL), and 10% palladium hydroxide on carbon. (10 mg) was added, followed by vigorous magnetic stirring under a hydrogen atmosphere for 1.5 hours. The resulting reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in water (2.0 mL) and tetrahydrofuran (2.0 mL), potassium carbonate (187 mg, 0.45 mmol) was added, and the mixture was cooled to 0 ° C. Further, a solution of acrylic acid chloride (55 μL, 0.67 mmol) in tetrahydrofuran (2 mL) was added dropwise, and the mixture was magnetically stirred at room temperature for 2 hours. The obtained reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by reverse phase silica gel column chromatography (developing solvent: water). The obtained syrup was treated with an ion exchange resin (Dowex Na ⁺ ), filtered, and lyophilized to obtain the target compound (3) (130 mg, 61%).

¹ H NMR (δppm, 500 MHz, D ₂ O, 30 ° C) δ 7.41 (d, 2H, J = 9.0 Hz, H of phenyl group), 7.08 (d, 2H, J = 9.0 Hz, H of phenyl group) , 6.40 (dd, 1H, J = 10.0, 17.0 Hz, H of acryloyl group), 6.28 (dd, 1H, J = 1.0, 17.0 Hz, H of acryloyl group), 5.83 (dd, 1H, J = 1.0, 10.0 Hz, H of acryloyl group), 5.12 (d, 1H, J = 8.5 Hz, H-1), 4.38 (dd, 1H, J = 2.0, 11.5 Hz, H-6 _proS ), 4.23 (dd, 1H, J = 5.5, 11.5 Hz, H-6 _proR ), 3.97 (dd, 1H, J = 8.5, 10.0 Hz, H-2), 3.84 (m, 1H, H-5), 3.65 (dd, 1H, J = 10.0 , 10.0 Hz, H-3), 3.61 (dd, 1H, J = 10.0, 9.5 Hz, H-4), 2.02 (s, 3H, acetamide group)

  Compound (3) obtained above (10 mg, 21.3 μmol) and acrylamide (15 mg, 213 μmol) are dissolved in degassed water (100 μL), and 2,2-azobis (2-amidinopropane) dihydrochloric acid is dissolved. Salt (2.3 μmol) was added. The mixture was freeze degassed three times under reduced pressure, placed in a polymerization test tube, sealed under reduced pressure, and incubated at 60 ° C. for 12 hours. Thereafter, the polymerization test tube was opened, and then the reaction mixture was diluted in ion-exchanged water and dialyzed for 2 days in a dialysis tube (MW8000 cut off). Water was distilled off under reduced pressure, followed by freeze-drying to obtain a polymer compound (4) (10 mg, 40%) containing a sugar chain as a white solid.

Number average molecular weight Mn = 3.1 × 10 ⁵ , (identified by SEC, standard: pullulan, developing solvent: PBS);
¹ H NMR (δ ppm, 500 MHz, D ₂ O, 50 ° C.): 7.60 (brs, 2H, phenyl group H), 7.27 (brs, 2H, phenyl group H), 5.32 (brs, 1H, H-1 ), 4.57-3.78 (m, 6H, H-2, H-3, H-4, H-5, H-6, H-6 '), 2.52-2.22 (brm, main chain methine group), 2.10 (Brs, 3H, acetyl group), 2.00-1.75 (brs, main chain methylene group);
Sugar chain introduction rate in polymer compound (4) = 8% (determined by ¹ H NMR spectrum)

[Production Example 5]
Synthesis of polymer (10) (Poly 4SGN) of p-acryloylamidophenyl 2-acetamido-4-sulfo-2-deoxy-β-D-glucopyranoside sodium salt (9)

  Using p-nitrophenyl 2-acetamido-4-sulfo-2-deoxy-β-D-glucopyranoside sodium salt (7) synthesized in Production Example 2, in the same manner as in Production Example 4, p-acryloylamidophenyl 2 -Acetamide-4-sulfo-2-deoxy-β-D-glucopyranoside sodium salt (9) was prepared.

¹ H-NMR (δppm, 500 MHz, D ₂ O, 30 ° C) δ 7.30 (d, 2H, phenyl group H), 6.95 (d, 2H, phenyl group H), 6.28 (dd, 1H, J = 10.0, 17.0 Hz, H of acryloyl group), 6.19 (dd, 1H, J = 1.0, 17.0 Hz, H of acryloyl group), 5.72 (dd, 1H, J = 1.0, 10.0 Hz, H of acryloyl group), 5.02 (d, 1H, J _1,2 = 8.5 Hz, H-1), 4.17 (dd, 1H, J _3,4, = 10.5, J _4,5 = 10.5 Hz, H-4), 3.93 (dd, 1H, J _1,2 = 8.5 Hz, J _2,3 = 10.5 Hz, H-2), 3.83 (dd, 1H, J = 2.0, 12.5 Hz, H-6proS) 3.75 (dd, 1H, J = 9.0, 12.5 Hz, H-6proR), 3.64 (m, 2H, H-5, H3), 1.89 (s, 3H, Ac)

  Compound (9) (10 mg, 20.6 μmol) and acrylamide (19.4 mg, 206 μmol) obtained above are dissolved in degassed water (200 μL), and 2,2-azobis (2-amidinopropane) dihydrochloric acid is dissolved. Salt (0.6 mg, 2.3 μmol) was added. The mixture was freeze degassed three times under reduced pressure, placed in a polymerization test tube, sealed under reduced pressure, and incubated at 60 ° C. for 3 hours. Thereafter, the polymerization test tube was opened, and then the reaction mixture was diluted in ion-exchanged water and dialyzed for 2 days in a dialysis tube (MW8000 cut off). Water was distilled off under reduced pressure, and the residue was freeze-dried to obtain polymer compound (10) (15 mg, 50%) as a white solid.

Sugar chain introduction rate in polymer compound (10) = 7.7 mol% (determined by ¹ H NMR spectrum). ¹ H NMR (δppm, 500 MHz, D ₂ O, 50 ° C.): 7.39 (brs, 2H, phenyl group H), 7.08 (brs, 2H, phenyl group H), 5.15 (brs, 1H, H-1 ), 4.30 (brt, 1H, H-4), 4.06-3.73 (brm, 5H, H-2, H-3, H-5, H-6, H-6 '), 2.23-2.17 (brm, main Chain methine group), 2.02 (brs, 3H, acetyl group), 1.77-1.60 (brm, main chain methylene group).

[Production Example 6]
Synthesis of polymer (12) (Poly 3SGN) of p-acryloylamidophenyl 2-acetamido-3-sulfo-2-deoxy-β-D-glucopyranoside sodium salt (11)

  Using p-nitrophenyl 2-acetamido-3-sulfo-2-deoxy-β-D-glucopyranoside sodium salt (6) synthesized in Production Example 2, in the same manner as in Production Example 4, p-acryloylamidophenyl 2 -Acetamide-3-sulfo-2-deoxy-β-D-glucopyranoside sodium salt (11) was prepared.

¹ H-NMR (δppm, 500 MHz, D ₂ O, 30 ° C) δ7.31 (d, 2H, phenyl group H), 6.95 (d, 2H, phenyl group H), 6.28 (dd, 1H, J = 10.0, 17.0 Hz, H of acryloyl group), 6.19 (dd, 1H, J = 1.0, 17.0 Hz, H of acryloyl group), 5.72 (dd, 1H, J = 1.0, 10.0 Hz, H of acryloyl group), 5.02 (d, 1H, J _1,2 = 8.5 Hz, H-1), 4.33 (dd, 1H, J _2,3, = 10.5, J _3,4 = 10.5 Hz, H-3), 3.93 (dd, 1H, J _1,2 = 8.5 Hz, J _2,3 = 10.5 Hz, H-2), 3.83 (dd, 1H, J = 2.0, 12.5 Hz, H-6proS) 3.75 (dd, 1H, J = 9.0, 12.5 Hz, H-6proR), 3.64 (m, 2H, H-5, H4), 1.87 (s, 3H, Ac)

  Compound (11) (10 mg, 20.6 μmol) and acrylamide (19.4 mg, 206 μmol) obtained above are dissolved in degassed water (200 μL), and 2,2-azobis (2-amidinopropane) dihydrochloric acid is dissolved. Salt (0.6 mg, 2.3 μmol) was added. The mixture was freeze degassed three times under reduced pressure, placed in a polymerization test tube, sealed under reduced pressure, and incubated at 60 ° C. for 3 hours. Thereafter, the polymerization test tube was opened, and then the reaction mixture was diluted in ion-exchanged water and dialyzed for 2 days in a dialysis tube (MW8000 cut off). Water was distilled off under reduced pressure, and the residue was freeze-dried to obtain a polymer compound (12) (11 mg, 40%) as a white solid.

Sugar chain introduction rate in polymer (12) = 9.0 mol% (determined by ¹ H NMR spectrum). ¹ H NMR (δ ppm, 500 MHz, D ₂ O, 50 ° C.): 7.37 (brs, 2H, phenyl group H), 7.08 (brs, 2H, phenyl group H), 5.25 (brs, 1H, H-1 ), 4.05 (brt, 1H, H-3), 3.95-3.63 (brm, 5H, H-2, H-4, H-5, H-6, H-6 '), 2.31-2.19 (brm, main Chain methine group), 1.99 (brs, 3H, acetyl group), 1.76-1.54 (brm, main chain methylene group).

[Production Example 7]
Synthesis of polymer (15) (Poly6SGal) of p- (N-acrylamide) phenyl 6-O-sulfo-β-D-galactopyranoside sodium salt (14)

Synthesis of p-nitrophenyl 6-sulfo-β-D-galactopyranoside sodium salt (13) Commercially available p-nitrophenyl (pNP) β-D-galactopyranoside (Sigma N1252, 600 mg, 1.99 mmol) and bistributyltin oxide (0.764 mL, 1.5 mmol) were suspended in THF-benzene (1: 1, total amount 50 mL), and water formed by azeotroping with heating at reflux for 3 hours was removed. Thereafter, the solvent was distilled off, the residue was dissolved in 10 ml of dry DMF, sulfur trioxide trimethylamine complex (1.4 g, 0.01 mol) was added, and the mixture was reacted at 60 ° C. for 3 hours. Benzyl alcohol (8 mL) was added to the reaction mixture, and the solvent was concentrated under reduced pressure.

The residue was purified with an ODS (C-18) column, treated with an ion exchange resin (Dowex Na ⁺ ), and pNP 3,6-di-O-sulfo-β-D- into which two sulfate groups were introduced. Galactopyranoside sodium salt was obtained (980 mg, 97%).

[α] _D = -35 ^o (c = 0.7 in H ₂ O);
¹ H NMR (D ₂ O, t-BuOH = 1.23 ppm) δ 8.271 and 7.278 (d, J = 9.3 Hz, pNP), 5.330 (d, J = 7.8 Hz, H-1), 4.484 (dd, J = 3.3 and 9.6 Hz, H-3), 4.429 (d, J = 3.3Hz, H-4), 4.34-3.93 (m, H-6 and H-6 '), 4.013 (dd, J = 7.8 and 9.6 Hz , H-2); ¹³ C NMR (t-BuOH = 31.3 ppm) δ 163.6, 144.5, 128.0, 118.4, 101.3, 81.3, 74.7, 70.2, 68.8, 68.3; FABMS 527 [M ⁺ + Na-1].

Next, 80 mg of the disulfated saccharide compound thus obtained was dissolved in 0.25 M acetate buffer (pH 6.8, 2 mL) and commercially available sulfatase (Sigma S9626, EC3.1.6.1, Helix pomatia And 5 mg), and the mixture was reacted at 37 ° C. for 2 days. The reaction solution was purified in order of Sephadex LH-20 and ODS, and treated with an ion exchange resin (Dowex Na ⁺ ) to obtain pNP 6-sulfo-β-D-galactopyranoside sodium salt (13) (60 mg, 94%).

[α] _D = -64.4 ^o (c = 3.1 in H ₂ O);
¹ H NMR (D ₂ O, t-BuOH = 1.23 ppm) δ 8.195 and 7.213 (d, J = 9.2 Hz, pNP), 5.174 (d, J = 7.3 Hz, H-1), 4.29-4.17 (m, H-6 and H-6 '), 4.075 (bd, J = 3.0 Hz, H-4), 3.875 (dd, J = 7.3 and 9.9 Hz, H-2), 3.823 (dd, J = 3.0 and 9.9 Hz , H-3); ¹³ C NMR (t-BuOH = 31.3 ppm) δ 163.5, 144.1, 127.8, 118.2, 101.6, 74.9, 73.9, 71.9, 69.9, 68.7. FABMS 426 [M ⁺ + Na]. Anal. Calcd for C ₁₂ H ₁₄ NNaO ₁₁ S ・ 2H ₂ O: C, 32.81; H, 4.13; N, 3.19; S, 7.30.Found: C, 32.42; H, 3.44; N, 2.95; S, 6.88.

Synthesis of p- (N-acrylamide) phenyl 6-O-sulfo-β-D-galactopyranoside sodium salt. (14) 6-sulfo-β-D-galactopyranoside sodium salt synthesized above (13 (100 mg, 0.62 mmol) and a catalytic amount of palladium were added to 10 ml of methanol and reduced under a hydrogen stream. Further, in the same manner as in Production Example 4, it was reacted with acrylic acid chloride to obtain 85 mg of p- (N-acrylamide) phenyl 6-O-sulfo-β-D-galactopyranoside sodium salt (14).

¹ H NMR (D ₂ O, rt) δ (ppm) 7.40 (d, 2H, J = 9.0 Hz, aromatic-H), 7.15 (d, 2H, J = 9.2 Hz, aromatic-H), 6.35 (m, 2H, vinyl H, 5.80 (d, 1H, vinyl H), 5.00 (d, 1H, J = 7.8 Hz, H-1), 4.29-4.00 (m, 3H, H-6S + H-6R + H-4 ), 3.80 (d, 2H, H-3 + H-2).

Synthesis of p- (N-acrylamide) phenyl 6-O-sulfo-β-D-galactopyranoside sodium salt. (14) polymer (15) In the same manner as in Production Example 4, the above compound (14) was prepared. , Acrylamide (15 mg, 213 μmol) and 2,2-azobis (2-amidinopropane) dihydrochloride in the presence of 6-O-sulfo-β-D-galactopyranoside in the side chain A polymer compound (15) was obtained.

(Gal: acrylamide = 6:94):
¹ H NMR (D ₂ O, 60 ° C) δ (ppm) 7.55 (br, aromatic-H), 7.25 (br, aromatic-H), 5.27 (br, Gal H-1), 4.4-4.2 (br, Gal H-4 + H-6S + H-6R), 3.9 (br, Gal H-3 + H-5 + H-2), 2.6-2.3 (br, CH-CH ₂ ), 2.0-1.5 (br, CH -CH _2- ).

[Production Example 8]
Synthesis of p-acryloylamidophenyl 2-deoxy-2-acetamido-β-D-glucopyranoside (16) and its polymer (17) (PolyGlcNAc)

  p-Nitrophenyl 2-deoxy-2-acetamido-β-D-glucopyranoside (pNP GlcNAc) (1) (200 mg, 0.53 mmol) (Aldrich) mixed with methanol (10 mL) and water (10 mL) After dissolving in a solvent and adding 10% palladium hydroxide on carbon (10 mg), the mixture was vigorously magnetically stirred for 3 hours under a hydrogen atmosphere. The resulting reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in water (4 mL) and tetrahydrofuran (2 mL), potassium carbonate (242 mg, 1.75 mmol) was added, and the mixture was cooled to 0 ° C. Further, a solution of acrylic acid chloride (71 μL, 0.88 mmol) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was magnetically stirred at room temperature for 1 hour. The obtained reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by reverse phase silica gel column chromatography (developing solvent: water). The desired compound (16) (166 mg, 78%) was obtained by lyophilization.

  Compound (16) (10 mg, 27.3 μmol) and acrylamide (19.4 mg, 274 μmol) obtained above were dissolved in dimethyl sulfoxide (200 μL), and 2,2′-azobisisobutyronitrile (0.4 mg , 2.6 μmol). The mixture was freeze degassed three times under reduced pressure, placed in a polymerization test tube, sealed under reduced pressure, and incubated at 60 ° C. for 12 hours. Thereafter, the polymerization test tube was opened, and then the reaction mixture was diluted in ion-exchanged water and dialyzed for 2 days in a dialysis tube (MW8000 cut off). Water was distilled off under reduced pressure, and the residue was freeze-dried to obtain a polymer compound (17) (15 mg, 50%) as a white solid.

Sugar chain introduction rate in polymer compound (17) = 7.7 mol% (determined by ¹ H NMR spectrum). ¹ H NMR (δ ppm, 500 MHz, D ₂ O, 50 ° C.): 7.35 (brs, 2H, phenyl group H), 7.05 (brs, 2H, phenyl group H), 5.10 (brs, 1H, H-1 ), 3.90-3.32 (m, 6H, H-2, H-3, H-4, H-5, H-6, H-6 '), 2.30-2.17 (brm, main chain methine group), 2.00 (Brs, 3H, acetyl group), 2.01-1.60 (brm, main chain methylene group).

Manufacturing process 3

[Production Example 9]
Synthesis of 2-deoxy-2-trifluoroacetamide-D-glucopyranoside (19)
20.1 g (93.1 mmol) of D-glucosamine hydrochloride (18) and 7.5 g (13 mmol) of NaOMe were dissolved in 250 ml of methanol and stirred for 1 hour. Next, 2 molar equivalents of CF ₃ COOEt were added and stirred. After 5 hours, 2.5 g (46 mmol) of CF ₃ COOEt was further added and stirred. After 18 hours, the mixture was neutralized with sodium bicarbonate water, and the precipitate was removed by filtration. When the filtrate was allowed to stand at room temperature, crystals (salts) precipitated and were removed by filtration. This was repeated 3 times to remove the salt to obtain compound (19). Yield: 35.0 g Yield> 99%

[Production Example 10]
Synthesis of 1-chloro-2-deoxy-2-trifluoroacetamide-3,4,6-tri-O-acetyl-α-D-glucopyranoside (20) (19) 75 ml of acetyl chloride was added to 20.0 g at 0 ° C. Carefully added dropwise. After 18 hours, 500 ml of CHCl ₃ was added and washed with sodium bicarbonate water and water in this order. Purification by silica gel column chromatography (eluent: CHCl ₃ ) gave the target compound (20). Yield: 9.03 g Yield: 29.6%

¹ H-NMR (500MHz, rt CDCl ₃ )
δ 6.74 (d, 1H, J = 9Hz, N H TFA) 6.24 (d, 1H, J _H1-H2 = 4 Hz, H1) 5.39 (dd, 1H, J _H2-H3 = 10.5 Hz, J _H3-H4 = 10 Hz, H3) 5.25 (t, 1H, J _{H3-H4 H4-H5} = 10 Hz, H4) 4.50 (ddd, 1H, J _H1-H2 = 4 Hz, J _{H2-N H TFA} = 8.5 Hz, J _{H2 -H3} = 11 Hz, H2) 4.22 (m, 2H, H5, H6) 4.14 (m, 1H, H6) 2.12 (s, 3H, 6-Ac) 2.08, 2.07 (s, each 3H, 3 or 4 Ac)

[Production Example 11]
Synthesis compound of p-nitrophenyl 2-deoxy-2-trifluoroacetamide-3,4,6-tri-O-acetyl-β-D-glucopyranoside (21) (20) 5.50 g (13.1 mmol), CH ₂ Cl _{2. To a} solution of 55 ml and 1N NaOH aqueous solution 55 ml, para-nitrophenol 3.64 g (26.2 mmol) and Bu ₄ NBr 4.2 g (13.1 mmol) were added and vigorously stirred. After 2 hours, a small amount of CHCl ₃ was added, washed twice with 1N NaOH and once with brine, and purified by silica gel chromatography (hexane: ethyl acetate = 4: 1) to obtain compound (21). Yield: 2.64 g Yield: 23.5%

¹ H-NMR (500MHz, rt CDCl ₃ )
δ 8.22 (d, 2H, J = 2 Hz, H-ortho of pNP) 7.06 (d, 2H, J = 2.5 Hz, H-meta of pNP) 6.60 (d, 1H, J _H1-H2 = 9 Hz, H1 ) 5.38 (dd, 1H, J _H2-H3 = 10.5 Hz, J _H3-H4 = 9.5 Hz, H3) 5.35 (d, 1H, J = 8 Hz, N H TFA) 5.20 (t, 1H, J _{H3-H4, H4-H5} = 9.5 Hz, H4) 4.31 (dd and dd, 2H, J _H1-H2 = 9 Hz, J _{H2 + NHTFA-H3} = 18.5 Hz, and J _H5-H6 = 5.5 Hz, J _H6-H6 = 12.5 Hz, H2 and H6 _ProR ) 4.20 (dd, 1H, J _H5-H6 = 2.5 Hz, J _H6-H6 = 12.5 Hz, H6 _ProS ) 3.96 (ddd, 1H, J _H5-H6ProR = 5.5 Hz, J _H5-H6ProS = 2.5 Hz, J _H4-H5 = 9.5 Hz, H5) 2.10 (s, 3H, 6-Ac) 2.09, 2.08 (each s, each 3H, 3 or 4-Ac)

[Production Example 12]
Synthesis of p-nitrophenyl 2-deoxy-2-trifluoroacetamide-β-D-glucopyranoside (22) (21) 1.51 g (2.9 mmol) is dissolved in 100 ml of methanol, and NaOMe 15.6 mg (0.29 mmol) is dissolved. The mixture was further stirred at room temperature for 3 hours and 30 minutes.
Purification by silica gel chromatography (chloroform: methanol = 10: 1) gave compound (22). Yield: 1.10 g Yield: 95.7%

¹ H-NMR (500MHz, rt CD ₃ OD)
δ 8.22 (d, 2H, J = 9.5 Hz, H-ortho of pNP) 7.17 (d, 2H, J = 9.5 Hz, H-meta of pNP) 5.26 (d, 1H, J _H1-H2 = 8.5 Hz, H1 ), 4.02 (dd, 1H, J _H1-H2 = 8.5 Hz, J _H2-H3 = 10.5 Hz, H2), 3.94 (dd, 1H, J _H5-H6 = 2.5 Hz, J _H6-H6 = 12.5 Hz, H6 _ProS ), 3.73 (dd, 1H, J _H5-H6 = 5.5 Hz, J _H6-H6 = 12.5 Hz, H6 _ProR ), 3.40 (dd, 1H, J _H2-H3, J _H3-H4 = 10.5 Hz, H3) , 3.51 (m, 1H, H5), 3.36 (dd, 1H, J _H3-H4, J _H4-H5 = 9.5 Hz, H4)

[Production Example 13]
149 mg (0.38 mmol) of p-nitrophenyl 2-amino-2-deoxy-β-D-glucopyranoside (23) compound (22) was dissolved in 2 ml of 0.1M aqueous sodium hydroxide solution at 0 ° C. and stirred for 30 minutes. did. Thereafter, the solution was carefully adjusted to pH 7 with 0.1N aqueous HCl, filtered and concentrated. Purification by reverse phase column (ODS C-18) gave 100 mg (89%) of compound (23).

¹ H-NMR (500MHz, rt CD ₃ OD)
δ 8.22 (d, 2H, J = 9.5 Hz, H-ortho of pNP) 7.26 (d, 2H, J = 9.0 Hz, H-meta of pNP) 5.02 (d, 1H, J _H1-H2 = 8.0 Hz, H1 ), 3.90 (dd, 1H, J _H5-H6 = 2.5 Hz, J _H6-H6 = 12.0 Hz, H6 _ProS ), 3.71 (dd, 1H, J _H5-H6 = 5.5 Hz, J _H6-H6 = 12.0 Hz, H6 _ProR ), 3.51 (m, 1H, H5), 3.40 (dd, 1H, J _H2-H3, J _H3-H4 = 8.5 Hz, H3), 3.36 (dd, 1H, J _H3-H4, J _H4-H5 = 9.0 Hz, H4), 2.89 (dd, 1H, J _H1-H2 = 8.0 Hz, J _H2-H3 = 9.5 Hz, H2)

[Production Example 14]
207 mg (0.69 mmol) of p-nitrophenyl 2-sulfamide-2-deoxy-β-D-glucopyranoside sodium salt (24) compound (23) 207 mg (0.69 mmol) was dissolved in DMF 50 ml, and Me ₃ NSO ₃ was dissolved in 144 mg ( 1.03 mmol). The mixture was stirred at room temperature, and the progress of the reaction was confirmed by reversed-phase TLC (10% CH ₃ COOH: methanol = 2: 1). After completion of the reaction, 10 ml of methanol was added and concentrated. The residue was purified by reverse phase silica gel column chromatography (eluent: water), and then treated with an ion exchange resin (Dowex Na ⁺ ) to give compound (24). Obtained. Yield: 158 mg Yield: 60.3%

¹ H-NMR (300MHz, 30.0 ℃ D ₂ O)
δ 8.19 (d, 2H, J = 9.5 Hz, H-ortho of pNP), 7.18 (d, 2H, J = 9.5 Hz, H-meta of pNP) 5.31 (d, 1H, J _H1-H2 = 8.0 Hz, H1), 3.69 (dd, 1H, J _H5-H6 = 2.5 Hz, J _H6-H6 = 12.5 Hz, H6 _ProS ), 3.67 (dd, 1H, J _H5-H6 = 5.5 Hz, J _H6-H6 = 12.5 Hz , H6 _ProR ), 3.67 (dd, 1H, J = 9.0 Hz, J = 10.5 Hz, H3), 3.61 (m, 1H, H5), 3.49 (dd, 1H, J _H3-H4, J _H4-H5 = 9.5 Hz, H4), 3.27 (dd, 1H, J _H1-H2 = 8.0 Hz, J _H2-H3 = 10.0 Hz, H2)

[Production Example 15]
Synthesis of p-nitrophenyl 2-sulfamide-2-deoxy-6-O-sulfo-β-D-glucopyranoside disodium salt (25)
Using compound (22) produced in production process 3 as a starting material, compound (25) was synthesized using the same method as for synthesizing compounds 5a to 10a shown in Scheme B in the specification.
[Production Example 16]
Synthesis of p-nitrophenyl 2-acetamide-4-O-sulfo-2-deoxy-β-D-galactopyranoside, sodium salt (4SGalNAc) (26)

  100 mg of commercially available 4-nitrophenyl N-acetyl-β-D-galactosaminide (Sigma, N9003) was dissolved in 2 mL of dry DMF, and 179 mg of sulfur trioxide-DMF complex was added thereto and reacted at 40 ° C. for 6 hours. . 1 mL of methanol was added to the reaction solution, stirred for 1 hour, and concentrated under reduced pressure to obtain a crude product, which was purified by reverse column chromatography to obtain 40 mg (31%) of the desired 4SGalNAc (compound (26)). .

¹ H-NMR (600MHz, D ₂ O) δ 8.18 (d, J = 9.2 Hz, aromatic), 7.16 (d, J = 9.2 Hz, aromatic), 5.30 (d, J = 8.4 Hz, H-1), 4.79 (brd, J = 2.4 Hz, H-4), 4.23 (dd, J = 8.4 and 11.2 Hz, H-2), 4.07-4.03 (m, H-3 and H-5), 3.87 (dd, J = 4.2 and 12.0 Hz, H-6), 3.83 (dd, J = 2.4 and 12.0 Hz, H-6 '), 2.80 (s, -NH CH ₃ ).

[Production Example 17]
Synthesis of polymer (27)

A polymer (27) was produced in the same manner as in Production Example 7 using Compound 25 produced in Production Example 15.
[Example 1]
<Pharmacological data>
Summary of Biological and Inhibitory Tests: Add a fixed amount of dilution of test sample (sugar monomer and sugar polymer) to the culture of mouse neuroblasts (Race et al., 1988) persistently infected with mouse-acclimated scrapie Chandler strain For 72 hours. Since the prion infection titre and the presence of PrP ^Sc are correlated (Caughey et al., 1993), the anti-prion effect of the test substance was determined using PrP ^Sc as an index. PrP ^Sc produced by the cells was confirmed by SDS-PAGE electrophoresis and Western blot (WB). As a result, it was found that a specific sulfated saccharide synthesized from glucosamine and its polymer compound show a remarkable effect of suppressing abnormal prion production.

1. Bioactivity test method (PrP ^SC detection)
1) Diluted solution of a certain amount of test sample (sugar monomer and sugar polymer) in the culture solution of prion persistently infected cells I3 / I5 obtained by cloning mouse neuroblasts persistently infected with mouse-adapted scrapie Chandler strain by limiting dilution method And cultured for 72 hours.
2) Cell lysis is performed with a buffer solution (150 mM NaCl in 10 mM Tris-HCl, pH 7.5) containing a surfactant (0.5% Triton X-100, 0.5% sodium deoxycholate) and a metal chelator (5 mM EDTA). It was.
3) After enucleation by centrifugation (200 × g, 2 min), the mixture was treated with protease K (PK, 20 μg / mL PK, 37 ° C., 45 minutes).
4) After proteolysis by PK was stopped with 2 mM Pefabloc, PrP ^Sc was recovered by centrifugation (100,000 × g, 2 h), and subjected to SDS-Page electrophoresis and WB. For detection of PrP ^Sc , anti-PrP monoclonal antibody 31C6 was used as the primary antibody, and horseradish peroxidase-labeled anti-mouse immunoglobulin (Amersham Bioscience) was used as the secondary antibody. The production amount of PrP ^sc in Table 1 was obtained by quantitative analysis of photon count by taking in chemiluminescence using LAS-1000 chemiluminescence analyzer (Fuji Film). The production amount of PrP ^sc was measured with the production amount in the absence of the inhibitor as 100. In the numerical value represented by A ± B, the smaller the numerical value of A, the greater the suppression effect. B shows a deviation.

  The production-suppressing effect by continuous administration in FIG. 1 was visualized on an X-ray film using an ECL western blotting detection reagent (Amersham Bioscience).

The results in Tables 1 and 2 are compared with the following compounds (4), (10), (12), (15), (27), (7), (24), (25), and (26) (sodium salt) according to the present invention. As an example, the PrP ^sc production inhibitory effect of the compound (17) (poly-GlcNAc) and the compound (1) (GlcNAc) is compared.

Compound (4): Poly-6SGN
Compound (10): Poly-4SGN
Compound (12): Poly-3SGN
Compound (15): Poly-6SGal
Compound (27): Poly-2,6SGN
Compound (7): 4SGN
Compound (24): 2SGN
Compound (25): 2,6SGN
Compound (26): 4SGalNAc

2. Results Each of the above compounds was diluted to a concentration of 100 μg / mL, 10 μg / mL, and 1 μg / mL, a sample solution was added, cell culture was performed, and the PrP ^SC production inhibitory effect was examined by the method described above. The results are shown in Tables 1 and 2.

From Tables 1 and 2, the compounds (7), (24), (25), (26), (4), (10), (12), (15), and (27) of the present invention are 10 A high PrP ^sc production inhibitory effect was observed at a concentration of -100 μg / mL.
In addition, when compared with the inhibitor concentration (IC ₅₀ ) that reduces the production of PrP ^sc by half (about 50) when the production amount without an inhibitor is 100, the strength of the inhibitory effect is Poly-4SGN (IC ₅₀ = 2-4 μg / mL)> Poly-6SGN (5-8 μg / mL)> 4SGN (8-10 μg / mL) in this order, and a polymer effect on activity was observed.

3. Inhibition of PrP ^sc production by long-term treatment with sulfated sugar polymer Figure 1 shows cell culture of compound (4): Poly-6SGN and compound (10): Poly-4SGN at 20 μg / mL for 3, 6 and 9 days, respectively. In addition to the liquid, it has been investigated for its sustained inhibitory effect. Compound (4) (Poly-6SGN) decreased production of PrP ^Sc is with the addition of days, 9 days, PrP ^Sc production was ceased almost completely. With compound (10) (Poly-4SGN), the inhibitory effect was more prominent, and on the 6th day, production almost ended.

From the above cell experiment, it was found that the compound used in the present invention exhibits a remarkable PrP ^Sc production inhibitory effect in prion persistently infected cells. It has been found that continuous administration of these inhibitors can completely inhibit PrP ^Sc production at the cellular level.
Since the prion infectivity and the presence of PrP ^Sc are correlated, it can be determined that these compounds have prion growth inhibitory activity. The above results indicate that it is possible to develop a prion disease therapeutic agent having a prion growth inhibitory effect from glucosamine, which is an inexpensive sugar resource.

  The compounds I and II or pharmaceutically acceptable salts thereof according to the present invention have an excellent prion growth-inhibiting action, are less aggressive to cells (low cytotoxicity), and are effective in the growth of abnormal prion proteins. It is useful as a preventive or therapeutic agent for prion diseases. Therefore, the compounds I and II or pharmaceutically acceptable salts thereof according to the present invention are useful as a preventive or therapeutic agent for prion diseases such as scrapie, bovine spongiform encephalopathy (BSE), and Creutzfeldt-Jakob disease. It is.

  Furthermore, the present invention relates to a method for preventing or treating prion diseases. These methods require that a pharmaceutically effective amount of a pharmaceutical composition comprising the disclosed compounds I, II or a pharmaceutically acceptable salt thereof be required for such treatment or such a disease or condition. Administration to patients and animals suffering from

Claims (7)

The following general formula (I)
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and a bond showing either an equatorial arrangement or an axial arrangement
Is a prion growth inhibitor containing as an active ingredient a compound that is any of the following (1) to (10), or a pharmaceutically acceptable salt thereof, or a hydrate thereof :
^{(1) R 1 = -NHAc,} R 2 = R 4 = H, an _{^{R 3 = -SO 3 H, R}} 5 = -C 6 H 4 -pNO 2 or -C ₆ H ₄ -pNHAc, -R ¹ And -OR ³ are in a gluco configuration (-R ¹ and -OR ³ are in an equatorial configuration),
_{^{(2) R 1 = -NHSO 3}} H, R 2 = R 3 = H, R 4 = SO 3 H, a _{^{R 5 = -C 6 H 4 -pNO}} 2 or -C ₆ H ₄ -pNHAc, -R ^A compound in which ¹ and -OR ³ are in a gluco configuration (-R ¹ and -OR ³ are in an equatorial configuration),
_{^{(3) R 1 = -NHSO 3}} H, R 2 = R 4 = H, R 3 = SO 3 H, a _{^{R 5 = -C 6 H 4 -pNO}} 2 or -C ₆ H ₄ -pNHAc, -R ^A compound in which ¹ and -OR ³ are in a gluco configuration (-R ¹ and -OR ³ are in an equatorial configuration),
^{(4) R 1 = -NHAc,} R 2 = R 3 = H, R 4 = SO 3 H, a _{^{R 5 = -C 6 H 4 -pNO}} 2 or -C ₆ H ₄ -pNHAc, -R ¹ and A compound in which —OR ³ is a galacto configuration (—R ¹ is an equatorial configuration, —OR ³ is an axial configuration);
^{(5) R 1 = -NHAc,} R 2 = R 4 = H, R 3 = SO 3 H, a _{^{R 5 = -C 6 H 4 -pNO}} 2 or -C ₆ H ₄ -pNHAc, -R ¹ and A compound in which —OR ³ is a galacto configuration (—R ¹ is an equatorial configuration, —OR ³ is an axial configuration);
^{(6) R 1 = -NHAc,} R 2 = SO 3 H, R 3 = R 4 = H, an _{^{R 5 = -C 6 H 4 -pNO}} 2 or -C ₆ H ₄ -pNHAc, -R ¹ and A compound in which —OR ³ is a galacto configuration (—R ¹ is an equatorial configuration, —OR ³ is an axial configuration);
^{(7) R 1 = -NHAc,} R 2 = R 3 = H, R 4 = SO 3 H, a _{^{R 5 = -C 6 H 4 -pNO}} 2 or -C ₆ H ₄ -pNHAc, -R ¹ and A compound in which —OR ³ is in a manno configuration (—R ¹ is an axial configuration, —OR ³ is an equatorial configuration);
^{(8) R 1 = -NHAc,} R 3 = SO 3 H, R 2 = R 4 = H, an _{^{R 5 = -C 6 H 4 -pNO}} 2 or -C ₆ H ₄ -pNHAc, -R ¹ and A compound in which —OR ³ is in a manno configuration (—R ¹ is an axial configuration, —OR ³ is an equatorial configuration);
^{(9) R 1 = -NHAc,} R 2 = SO 3 H, R 3 = R 4 = H, an _{^{R 5 = -C 6 H 4 -pNO}} 2 or -C ₆ H ₄ -pNHAc, -R ¹ and A compound in which —OR ³ is in a manno configuration (—R ¹ is an axial configuration, —OR ³ is an equatorial configuration), or (10) R ¹ = —NHSO ₃ H, R ² = R ³ = R ⁴ = H, R ⁵ = -C ₆ H ₄ ^-pNO ₂ or -C ₆ H ₄ -pNHAc, -R ¹ and -OR ³ and glucoamylase arrangement (-R ¹ and -OR ³ and the equatorial arrangement) compound is.   The compound represented by the general formula (I) is:
(1) R ¹ = -NHAc, R ² = R ^Four = H, R ^Three = -SO _Three H, R ^Five = -C ₆ H _Four -PNO ₂ Or -C ₆ H _Four -PNHAc, -R ¹ And -OR ^Three And gluco configuration (-R ¹ And -OR ^Three And is an equatorial arrangement),
(2) R ¹ = -NHSO _Three H, R ² = R ^Three = H, R ^Four = SO _Three H, R ^Five = -C ₆ H _Four -PNO ₂ Or -C ₆ H _Four -PNHAc, -R ¹ And -OR ^Three And gluco configuration (-R ¹ And -OR ^Three And is an equatorial arrangement),
(5) R ¹ = -NHAc, R ² = R ^Four = H, R ^Three = SO _Three H, R ^Five = -C ₆ H _Four -PNO ₂ Or -C ₆ H _Four -PNHAc, -R ¹ And -OR ^Three And galacto configuration (-R ¹ Is Equatorial arrangement, -OR ^Three Is an axial configuration), or
(10) R ¹ = -NHSO _Three H, R ² = R ^Three = R ^Four = H, R ^Five = -C ₆ H _Four -PNO ₂ Or -C ₆ H _Four -PNHAc, -R ¹ And -OR ^Three And gluco configuration (-R ¹ And -OR ^Three The prion growth inhibitor according to claim 1, which is a compound having an equatorial configuration. The following general formula (II)
A prion growth inhibitor, wherein at least one of the sugar chain-containing groups represented by the formula (1) comprises a polymer compound bound to a polymer chain or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. ,
The -O- A-B-polymer chain has the formula
[In formula, n shows the integer of 1-5000, / shows that a structural component exists in arbitrary ratios. ],
In the sugar chain-containing group, R ¹ , R ² , R ³ , R ⁴ , and a bond showing any arrangement of an equatorial arrangement or an axial arrangement
Is a prion growth inhibitor, which is any of the following (101) to (104) or (111);
^{(101) R 1 = -NHAc,} R 2 = R 3 = H, an R ⁴ = -SO ₃ H, glucosyl placement and -R ¹ and -OR ³ is (-R ¹ and -OR ³ and the equatorial arrangement ),
^{(102) R 1 = -NHAc,} R 2 = R 4 = H, R 3 = a -SO ₃ H, -R ¹ and -OR ³ and Glucophage arrangement (-R ¹ and -OR ³ and the equatorial arrangement ),
(103) R ¹ = -NHAc, R ² = -SO ₃ H, R ³ = R ⁴ = H, -R ¹ , -OR ³ and gluco configuration (-R ¹ and -OR ³ are equatorial configurations) ,
_{^{(104) R 1 = -NHSO 3}} H, R 2 = R 3 = H, an R ⁴ = -SO ₃ H, and -R ¹ and -OR ³ there is a glucosyl arrangement (-R ¹ and -OR ³ Equatorial arrangement), or
(111) R ¹ = —OH, R ² = R ³ = H, R ⁴ = SO ₃ H, and —R ¹ and —OR ³ are galacto configuration (—R ¹ is equatorial configuration, —OR ³ is axial) A prion growth inhibitor. The compound represented by the general formula (II) is represented by the following formula (IV):
[In the formula (IV), any one of R ² , R ³ and R ⁴ is —SO ₃ H, the rest is a hydrogen atom, n represents an integer of 1 to 5000, It is present at an arbitrary ratio. ] The prion growth inhibitor of Claim 3 which is. The compound represented by the general formula (II) is represented by the following formula (V):
[In Formula (V), n shows the integer of 1-5000, / shows that a structural component exists in arbitrary ratios. ] The prion growth inhibitor of Claim 3 which is. A prophylactic or therapeutic agent for prion diseases, comprising the prion growth inhibitor according to any one of claims 1 to 5 . The prion diseases include bovine spongiform encephalopathy (BSE), Creutzfeldt-Jakob disease, sporadic Creutzfeldt-Jakob disease (sCJD), mutant Creutzfeldt-Jakob disease (vCJD), iatrogenic Creutzfeldt-Jakob disease iCJD), familial Creutzfeldt-Jakob disease (fCJD), Gerstmann-Streisler-Scheinker syndrome (GSS), lethal familial insomnia (FFI), chronic wasting disease (CWD), cat spongiform encephalopathy, scrapie or The prophylactic or therapeutic agent for prion disease according to claim 6 , which is kuru.