JPH04226502A - Polysulfate of acylaminocyclodextrin derivative and its production - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as an anti-retrovirus drug, etc., with industrial advantage by reacting a sulfonating agent with an acylaminocyclodextrin derivative in which a part of glucose constituent is acylaminated, and subsequently converting the resultant product to its salt. CONSTITUTION:Pyridine and sulfur trioxide-pyridine complex are added to an acylaminocyclodextrin derivative [e.g. heptakis(6-benzoylamino-6-deoxy)-beta- cyclodextrin] in which one or more D-glucose units amoung 6-8 D-glucose units constituting cyclodextrin are replaced with a unit represented by formula I [R<1> is (substituted)alkyl, (substituted)phenyl or sulfur-containing heterocyclic group; R<2> is H, lower alkanoylamino or lower alkyl substituted with benzoylamino group]. The resultant mixture is allowed to react at 70 deg.C for 6hr, thus obtaining the objective polysulfate of the acylaminocyclodextrin derivative or salt thereof.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a polysulfate ester of an acylaminocyclodextrin derivative having antiretroviral activity and a method for producing the same.

0002

[Prior Art] AIDS (acquired immunodeficiency syndrome) is caused by human immunodeficiency virus (HIV), a type of retrovirus.
) is a fatal or extremely malignant disease caused by infection, and its prevention and eradication is currently the most important problem for humanity to overcome on a global level. Conventionally, as a compound having an antiretroviral effect, for example, azidothymidine [Igaku no Ayumi; Vol. 142, No. 9, 619-622
Page (1987)] and sulfated polysaccharides (JP-A-63-4)
No. 5223, No. 64-25724), etc. are known.

0003

OBJECTS OF THE INVENTION An object of the present invention is to provide a novel pharmaceutical compound that has excellent antiretroviral activity, particularly excellent antiproliferative activity against HIV, and is free from side effects.

0004

[Means for Solving the Problems] The present invention provides that at least one of the 6 to 8 D-glucose units constituting cyclodextrin is

[0005]

[C4]

(However, R1 represents an alkyl group; an optionally substituted phenyl group; a lower alkyl group substituted with a phenyl group or a pyrenylcarbonyl group; or a sulfur-containing heterocyclic group, and R2 is a hydrogen atom; or a lower alkyl group substituted with a lower alkanoylamino group or a benzoylamino group) [hereinafter referred to as a polysulfate ester compound] or a salt thereof of an acylaminocyclodextrin derivative substituted with a unit represented by Regarding.

The polysulfate ester compound of the present invention is schematically illustrated as follows.

[0008]

[C5]

(However, n is an integer of 6 to 8, m is an integer from 1 to n, and R is -SO3H in whole or in part.
, the remainder are hydrogen atoms, and R1 and R2 have the same meanings as above. ) The above general formula (I) is 6 to 8
It represents that the constituent units are bonded in a ring at the 1st and 4th positions in any order. Furthermore, in general formula (I), n
The compound where n is 6 is a derivative of α-cyclodextrin, the compound where n is 7 is a derivative of β-cyclodextrin, and the compound where n is 8 is a derivative of γ-cyclodextrin.

Specific examples of the polysulfate ester compound of the present invention include, for example, in the general formula (I), R1 is a linear or branched alkyl group having 1 to 20 carbon atoms; a hydroxyl group, a methyl group, an ethyl group; 1 to 1 selected from lower alkyl groups such as and lower alkoxy groups such as methoxy and ethoxy groups;
A phenyl group which may be substituted with two groups; a lower alkyl group such as a methyl group or an ethyl group substituted with a phenyl group or a pyrenylcarbonyl group; or a sulfur-containing heterocyclic group such as a thienyl group; , R2 is a hydrogen atom; or a lower alkyl group such as a methyl group or an ethyl group substituted with a lower alkanoylamino group such as an acetylamino group or a propionylamino group or a benzoylamino group.

Among these, preferred compounds include R1
is substituted with one or two groups selected from a linear or branched alkyl group having 1 to 17 carbon atoms; a hydroxyl group, an alkyl group having 1 to 4 carbon atoms, and an alkoxy group having 1 to 4 carbon atoms; a phenyl group; an alkyl group having 1 to 4 carbon atoms substituted with a phenyl group or a pyrenylcarbonyl group; or a thienyl group, in which R2 is a hydrogen atom; or an alkanoylamino group or benzoylamino group having 2 to 5 carbon atoms; Examples include compounds in which R1 is an alkyl group having 1 to 4 carbon atoms substituted with a group, and even more preferred compounds include R1 being a straight or branched alkyl group having 1 to 17 carbon atoms; a phenyl group;
Or, it is an alkyl group having 1 to 4 carbon atoms substituted with a pyrenylcarbonyl group, and R2 is a hydrogen atom; or a compound in which R2 is an alkyl group having 1 to 4 carbon atoms substituted with a benzoylamino group. Further, the number of sulfate groups contained in the polysulfate compound (I) of the present invention is 8 to 2.
Preferably, there are three.

[0012] In the polysulfate ester compound of the present invention, at least one of the 6 to 8 D-glucose units constituting the cyclodextrin has the general formula

[0013]

[C6]

(However, the symbols have the same meanings as above.) It can be produced by reacting an acylaminocyclodextrin derivative substituted with the unit shown below with a sulfonating agent. The above reaction is schematically illustrated as follows.

[0015]

[C7]

(However, the symbols have the same meanings as above.) Examples of the sulfonating agent include sulfur trioxide complex (for example, sulfur trioxide-pyridine complex, sulfur trioxide-trialkylamine complex, sulfur oxide-dioxane complex,
Sulfur trioxide-dimethylformamide complex, etc.), sulfuric anhydride, concentrated sulfuric acid, chlorosulfuric acid, etc. can all be suitably used. Further, the amount of the sulfonating agent used is preferably in excess of the amount of the acylaminocyclodextrin derivative (II). For example, when using a sulfur trioxide-pyridine complex or a sulfur trioxide-trialkylamine complex as a sulfonating agent, the amount is 1 to 10 equivalents, especially 2 to 10 equivalents, based on the hydroxyl group of the acylaminocyclodextrin derivative (II). It is preferable to use about 5 equivalents.

Acylaminocyclodextrin derivative (
The reaction between II) and the sulfonating agent can be carried out in a suitable solvent or without a solvent. Examples of reaction solvents include tertiary amines (e.g. pyridine, picoline, lutidine, N,N-dimethylaniline). ), N,N-dimethylformamide, formamide, hexamethylenephosphoryltriamide, chloroform, benzene, toluene, xylene, water, a mixture thereof, liquid sulfite, and the like can be suitably used. This reaction can be carried out under cooling to heating (-30 to 140°C) depending on the sulfonating agent used, and especially when using a sulfur trioxide complex, it can be carried out under heating (50 to 100°C). It is desirable to do so. After the reaction is completed, the target product can be isolated and purified by conventional methods, if necessary. For example, after neutralizing or salt-exchanging the crude product obtained from the reaction-completed liquid with alkali metal hydroxide, alkali metal acetate, etc., the target product is obtained as an alkali metal salt by subjecting it to a column packed with cross-linked dextran gel, etc. be able to.

The polysulfate ester compound of the present invention can be suitably used either in its free form or in its pharmacologically acceptable salt form. Such salts include, for example, alkali metal salts such as sodium salts, potassium salts, and lithium salts; calcium salts, magnesium salts,
Examples include alkaline earth metal salts such as barium salts; organic amine salts such as trimethylamine salts, triethylamine salts, pyridine salts, glycine ethyl ester salts, ethanolamine salts, and basic amino acid salts. The polysulfate compound of the present invention or a pharmacologically acceptable salt thereof can be administered orally or parenterally (e.g., intravenously, intramuscularly, subcutaneously), and can be administered in the form of tablets, granules, etc. in a conventional manner. agent,
It can be used in appropriate pharmaceutical formulations such as capsules, powders, suppositories, vaginal preparations, creams, and injections. The dosage of the polysulfate compound of the present invention or a pharmacologically acceptable salt thereof varies depending on the age, weight, condition, and type of disease of the patient, but is usually about 0.1 to 200 mg/day.
0 mg/kg is suitable, especially about 0.5 to 50 mg/kg.
It is preferable to set it to about kg.

The acylaminocyclodextrin derivative (II), which is the raw material compound of the present invention, is a new compound, in which cyclodextrin is combined with a sulfonic acid halide having a substituent (for example, mesitylenesulfonyl chloride, naphthylsulfonyl chloride). It can be produced by reacting it, and if necessary, after separating and purifying it, reacting it with ammonia or lower alkylene diamine, and then suitably acylating the product.

[0020]

[Example] Example 1 heptakis (6-benzoylamino-6-deoxy)-
Add 75 ml of pyridine to 1 g of β-cyclodextrin, then add 3.6 ml of sulfur trioxide-pyridine complex.
g and reacted at 70°C for 6 hours. The supernatant is removed from the reaction solution, and the residue is treated with methanol and ethanol to powder. The powder is collected by filtration, dried, and then dissolved in 5 ml of water. After adding a 30% aqueous sodium acetate solution to form a sodium salt, the solution was purified using a column packed with Sephadex G-10 (manufactured by Pharmacia).
heptakis(6-benzoylamino-6-deoxy)-
0.87 g of the sodium salt of β-cyclodextrin polysulfate is obtained as a light brown powder. IRNujo
lνmaxcm-1: 1640, 1600, 1240,
1040,830 1H-NMR (D2O) δ: 7.1-7.5 (br
s), 7.6-7.8 (br s) Number of sulfate ester groups in the molecule calculated from elemental analysis value: 14

0021
Examples 2 to 25 The corresponding starting compounds were treated in the same manner as in Example 1 to obtain the compounds listed in Tables A and B below.

[0022]

[Table 1]

[0023]

[Table 2]

[0024]

[Table 3]

[0025]

[Table 4]

[0026]

[Table 5]

[0027]

[Table 6]

Example 26 By treating hexakis[6-(2-tenoylamino)-6-deoxy]-α-cyclodextrin in the same manner as in Example 1, hexakis[6-(2-tenoylamino)-6-deoxy] ]-α-Cyclodextrin polysulfate ester sodium salt is obtained as a white powder. Yield: 77.5% IRNujolνmaxcm-1:16
30,1550,1240,1040,1000,83
0 1H-NMR (D2O) δ: 6.7 (br), 7.4 (
br) Number of sulfate ester groups in the molecule calculated from elemental analysis values: 10

Reference Example 1 30 ml of methanol and 1.7 g of benzoic anhydride were added to 1 g of heptakis(6-amino-6-deoxy)-β-cyclodextrin, and the mixture was heated under reflux for 18 hours. The reaction solution was dried under reduced pressure, ethyl ether was added to the residue, the insoluble matter was collected by filtration, and after drying, it was separated and purified by silica gel column chromatography to obtain heptakis (6-benzoylamino-6-
1 g of (deoxy)-β-cyclodextrin is obtained as a white powder. Yield: 61% 1H-NMR (DMSO-d6) δ: 4.96 (d),
7.0-7.8 (m), 7.9-8.2 (br m)

Reference Example 2 1g of heptakis(6-amino-6-deoxy)-β-cyclodextrin and 60ml of 10% sodium bicarbonate
was added, 1.4 g of 2-thenoyl chloride was added dropwise, and the mixture was vigorously stirred at room temperature for 3 days. The precipitate was collected by filtration, washed, dried, and then separated and purified by silica gel column chromatography to obtain heptakis[6-(2-tenoylamino)-6-
0.6 g of [deoxy]-β-cyclodextrin is obtained as a white powder. Yield: 59% 1H-NMR (DMSO-d6) δ: 3.1-4.0 (
br m), 5.0(br s), 5.9(br
s), 5.95 (br s), 6.86 (dd),
7.55(d), 7.70(d), 8.10(br
s)

Reference Example 3 (1) 126 g of β-cyclodextrin was mixed with 2.0 g of pyridine.
Dissolve in 5 liters. 30 g of mesitylene sulfonyl chloride was added little by little to the solution at 25°C and stirred for 2 hours, and then 6 g of mesitylene sulfonyl chloride was added and
Stir for an hour. After adding water to the reaction solution and leaving it overnight, the solvent was distilled off. Dissolve the residue in 1 liter of water and dilute the solution with CH
The solution is passed through a column filled with P-20 resin (manufactured by Mitsubishi Kasei Corporation). The column was mixed with 10 liters of water and 3 liters of 10% methanol.
After sequentially washing with 1 liter and 3 liters of 20% methanol, 3 liters of 50% methanol was passed through and the eluate was collected (eluate ■). Next, 3 liters of 80% methanol was passed through the column, and the eluate was collected (eluate ■), and then 3 liters of 100% methanol was passed through the column, and the eluate was collected (eluate ■). The solvent is distilled off from these eluates ① to ②, and the residue is dried under reduced pressure to obtain the following compounds i) to iii).

i) Mono(6-O-mesitylenesulfonyl)-β-cyclodextrin White powder Yield: 52.6g IRNujolνmax cm-1: 1160,10
80,1030 1H-NMR (DMSO-d6) δ: 2.29 (s, 3
H), 2.54 (s, 6H), 2.7-4.6 (m, 4
8H), 4.6-4.9 (m, 7H), 5.70 (br
s, 14H), 7.10(s, 2H) ii) Bis(
6-O-mesitylenesulfonyl)-β-cyclodextrin white powder yield: 13.0 g IRNujolνmax cm-1: 1610,13
55,1160,1030 1H-NMR (DMSO-d6) δ: 2.29 (s, 6
H), 2.52 (s, 12H), 3.1-4.6 (m,
47H), 4.74(brs, 4H), 4.84(br
s, 3H), 5.6-5.9 (m, 14H), 7.
07(s,2H),7.10(s,2H)iii) Tris(6-O-mesitylenesulfonyl)-β-cyclodextrin White powder yield: 1.0g IRNujolνmax cm-1: 1610,13
50, 1190, 1170, 1160, 1080, 10
30 1H-NMR (DMSO-d6) δ: 2.3-2.4 (
m, 9H), 2.4-2.7 (m, 18H), 3.1-
4.6 (m, 46H), 4.7-4.9 (m, 7H),
5.6-6.0 (m, 14H), 7.0-7.2 (m,
6H)

(2)-(i) 26.4 g of mono(6-O-mesitylenesulfonyl)-β-cyclodextrin and 350 ml of 10% ammonia-methanol were placed in a sealed tube.
Stir at 0°C for 3 days. After cooling, the crystals are collected by filtration and dried to obtain 18.1 g of mono(6-amino-6-deoxy)-β-cyclodextrin as a white powder. Yield: 79
．． 8% m. P. 262℃ (decomposition) IRKBrνmax cm-1: 3300, 1638
, 1158, 1080, 1030 (2)-(ii) Bis(6-O-mesitylenesulfonyl)-β-cyclodextrin in the above (2)-(i)
Bis(6-amino-6-deoxy)
- β-Cyclodextrin is obtained as a white powder. Yield: 71% m. p. 245℃ (decomposition) IRKBrνmax cm-1: 3300, 1630
,1158,1080,1030

(3) Mono(6-amino-6-deoxy)
-1.13 g of β-cyclodextrin and 10 g of methanol
ml, added with 0.34 g of benzoic anhydride, and heated under reflux for 5 hours. After cooling, the precipitated crystals are collected by filtration and reprecipitated from methanol to obtain 1.09 g of mono(6-benzoylamino-6-deoxy)-β-cyclodextrin as a white powder. Yield: 88% 1H-NMR (DMSO-d6) δ: 4.3-4.6 (
m), 4.7-5.0 (m), 5.5-5.9 (m),
7.3-7.6 (m), 7.7-7.9 (m), 8.2
-8.3 (br)

Reference Example 4 2.27 g of mono(6-amino-6-deoxy)-β-cyclodextrin was suspended in 20 ml of methanol, and 3.
Add 1.38 g of 5-diacetoxybenzoic anhydride and heat under reflux for 8 hours. After cooling, 20 ml of concentrated ammonia water was added, stirred overnight at room temperature, and the solvent was distilled off. After cleaning the residue,
The crude product is filtered and dissolved in water, and the solution is passed through a column packed with CHP-20 resin (manufactured by Mitsubishi Chemical Corporation). After sequentially washing the column with 500 ml of water and 500 ml of 10% methanol, 50% methanol was passed through the column and the eluate was collected. The solvent is distilled off from the eluate, and the residue is washed and dried to obtain 2.22 g of mono[6-deoxy-6-(3,5-dihydroxybenzoylamino)]-β-cyclodextrin as a white powder. Yield: 87% 1H-NMR (DM
SO-d6) δ: 4.3-4.6 (m), 4.7-5.
0 (m), 5.5-5.9 (m), 6.34 (t), 6
．． 64(d), 7.92(t), 9.40(s)

Reference Example 5 0.46 g of anisic acid was suspended in 10 ml of chloroform,
Add and dissolve 0.42 ml of triethylamine. Add 0.29 ml of ethyl chlorocarbonate while stirring on ice and stir for 15 minutes to obtain a mixed acid anhydride. Mono(6-amino-6-deoxy)-β-cyclodextrin 2.26
Dissolve g in 20 ml of pyridine, add the chloroform solution of the mixed acid anhydride while stirring on ice, and stir overnight at room temperature. After distilling off the solvent and washing, the powder is collected by filtration, dissolved in 50 ml of 0.2N aqueous potassium hydroxide solution, and heated to 90° C. for 30 minutes. After cooling, acidify with hydrogen chloride and convert the solution into CHP.
The solution is passed through a column filled with -20 resin (manufactured by Mitsubishi Kasei Corporation). After sequentially washing the column with 500 ml of water and 1 liter of 10% methanol, 30% methanol was passed therethrough and the eluate was collected. The solvent was distilled off from the eluate, and the residue was washed and dried to obtain 0.71 g of mono[6-deoxy-6-(4-methoxybenzoylamino)]-β-cyclodextrin.
is obtained as a white powder. Yield: 28% 1H-NMR (D
MSO-d6) δ: 3.80 (s), 4.3-4.6 (
m), 4.7-5.0 (m), 5.4-5.9 (m),
6.36(d), 7.79(d), 8.0-8.2(b
r)

Reference Example 6 (1) 114 g of β-cyclodextrin was mixed with 1.1 g of pyridine.
The mixture was dissolved in 2 liters, and 52 g of 2-naphthylsulfonyl chloride was added thereto under ice-cooling and stirring. After stirring at room temperature for 1 day, water was added to the reaction solution to stop the reaction. The solvent was distilled off, 1 liter of water was added to the residue and heated, and after washing the candy with water, the residue was reduced to 70%
Heat and dissolve in 1.5 liters of methanol. Concentrate the solution to about 1 liter, collect the precipitate by filtration, heat and dissolve in 1 liter of 70% methanol, remove insoluble matter by filtration, leave the filtrate to stand, collect the precipitated crystals by filtration, and dry. Then, Tris [6-O
1:1 mixture of -(2-naphthylsulfonyl)]-β-cyclodextrin and tetrakis[6-O-(2-naphthalenesulfonyl)]-β-cyclodextrin 23
．． Obtain 0 g as a white powder. Yield: 13% IRNuj
olνmax cm-1: 1350, 1160, 10
80,1030 1H-NMR (DMSO-d6) δ: 7.5-8.5 (
br m, 24H)

(2) The product of (1) above was prepared in Reference Example 3-(
2) - Tris(6-amino-
A 1:1 mixture of 6-deoxy)-β-cyclodextrin and tetrakis(6-amino-6-deoxy)-β-cyclodextrin is obtained as a white powder. Yield: 68
．． 8% m. p >220℃ IRKBrνmax cm-1: 3300, 1630
,1155,1080,1030

(3) The product of (2) above was treated in the same manner as in Reference Example 1 or 2 to form tris(6-stearoylamino-6-deoxy)-β-cyclodextrin and tetrakis(6-stearoylamino-6-deoxy)-β-cyclodextrin. A 1:1 mixture of 6-deoxy)-β-cyclodextrin is obtained as a light brown powder. Yield: 76% 1H-NMR (DMSO-d6) δ: 0.82 (t),
0.9-1.7 (m), 1.9-2.3 (br), 4.
2-4.6 (br), 4.7-5.1 (m), 5.5-
6.1 (m)

Reference Example 7 (1) 13.2 g of mono(6-O-mesitylenesulfonyl)-β-cyclodextrin and 100 g of ethylenediamine
ml were mixed, heated under reflux for 6 hours, and then concentrated under reduced pressure. Water and xylene were added to the reaction mixture, azeotropically distilled three times, the solvent was distilled off, and the mixture was dissolved in 50 ml of water. The solution is passed through a column packed with a strongly acidic ion exchange resin SK-1B (H+) (manufactured by Mitsubishi Chemical Corporation). After washing the column with water, a 2N ammonium hydroxide solution is passed through the column and the eluate is collected. The solvent is distilled off from the eluate and the residue is dried to obtain 4.6 g of mono(6-aminoethylamino-6-deoxy)-β-cyclodextrin as a white powder. Yield: 39% 1H-
NMR (DMSO-d6) δ: 2.4-2.7 (m),
2.6-2.8 (br), 2.7-3.0 (m), 3.
2-3.5 (m), 3.5-3.9 (m), 3.0-4
．． 2(m), 4.2-5.5(br), 4.82(br
s)

(2) 1.18 g of the product obtained in (1) above is suspended in 30 ml of methanol, 0.41 g of acetic anhydride is added, and the mixture is heated under reflux for 8 hours. After drying the reaction solution, it is washed with acetone, dissolved in water, and treated with activated carbon. The aqueous solution was poured into acetone to crystallize, collected by filtration, and dried to obtain 1.23 g of mono[6-deoxy-6-(N,N'-diacetylaminoethylamino)]-β-cyclodextrin in a white color. Obtained as a powder. Yield: 97% 1H-NMR (DMSO-d6) δ
:1.77(s), 1.91(s), 2.8-4.0(
m), 4.0-4.7 (m) 4.84 (brs), 5.
4-6.1 (m), 7.7-8.1 (m)

[0042]
Reference Example 8 (1) Bis(6-O-mesitylenesulfonyl)-β-cyclodextrin and ethylenediamine were mixed in Reference Example 7-(
Treat in the same manner as in 1) to obtain bis(6-aminoethylamino-6-deoxy)-β-cyclodextrin. Yield: 36% 1H-NMR (DMSO-d6) δ: 2.
3-3.0 (m), 3.0-3.5 (m), 3.5-4
．． 0(m), 4.81(s), 5.0-6.2(br)
(2) The product of (1) above was treated in the same manner as in Reference Example 7-(2) to obtain bis[6-deoxy-6-(N,N'-dibenzoylaminoethylamino)]-β-cyclo Dextrin is obtained as a white powder. Yield: 91% 1H-NMR
(DMSO-d6) δ: 3.0-4.0 (m), 4.2
-4.7 (m), 4.7-5.1 (m), 5.6-6.
2(m), 7.0-8.0(m), 8.3-8.7(m
)

Reference Example 9 (1) Tris(6-O-mesitylenesulfonyl)-β-
Reference Example 7 - Cyclodextrin and ethylenediamine
Tris(6-aminoethylamino-6-deoxy)-β-cyclodextrin is obtained by treatment in the same manner as in (1). Yield: 27% 1H-NMR (DMSO-d6) δ
:2.3-2.7 (m), 2.7-3.0 (m), 3.
0-3.5 (m), 3.5-3.9 (m), 3.9-5
．． 5(br), 4.83(s) (2) The product of (1) above was treated in the same manner as in Reference Example 7-(2) to obtain tris[6-deoxy-6-(N,N'- dibenzoylaminoethylamino)]-β-cyclodextrin is obtained as a white powder. Yield: 90% 1H-NM
R(DMSO-d6)δ: 2.7-4.1(m), 4.
3-4.7 (m), 4.7-5.2 (m), 5.5-6
．． 3 (m), 6.9-7.9 (m), 8.3-9.0 (
br)

Reference Examples 10 to 23 The corresponding starting compounds were treated in the same manner as in Reference Examples 1 to 6 to obtain the compounds listed in Table C below.

[0045]

[Table 7]

[0046]

[Table 8]

[0047]

[Table 9]

Reference Examples 24 and 25 The corresponding raw material compounds were treated in the same manner as in Reference Example 7 to obtain the following D.
The compounds listed in the table are obtained.

[0049]

[Table 10]

Reference Example 26 In a mixture of 0.6 g of hexakis(6-amino-6-deoxy)-α-cyclodextrin hydrochloride and 60 ml of a 10% aqueous sodium bicarbonate solution, 0.0 g of 2-thenoyl chloride was added.
．． Add 6 g and stir at room temperature for 3 days. After the reaction, the precipitate was collected by filtration, washed and dried to obtain Hexakis [6
0.54 g of -(2-thenoylamino)-6-deoxy-α-cyclodextrin is obtained as a white powder. m. P. 258-260℃ (decomposition)

[0051]

[Action] Experimental example HIV-1 proliferation inhibitory action (Principle) Human T-cell leukemia virus type I [human
T-cell Leukemia virus, HTLV
-I] HIV-1 in MT-4 cells, a persistently infected cell line
It is known that when infected with MT-4, HIV-1 rapidly proliferates, and MT-4 cells die due to cytotoxicity in 5 to 6 days. Therefore, using the number of viable MT-4 cells infected with HIV-1 as an index, it is possible to examine the HIV-1 proliferation inhibitory effect of the sample.

(Method) MT-4 cells were infected with HIV-1 (TA
LL-1/LAV-1 culture supernatant) at 0.001 T
CID50 (median tissue cul
true infectious dose, 50
% tissue culture infectious dose)/cell at 37°C.
RP containing various concentrations of analytes, washed after infection for an hour.
MI-1640 medium [FCS (fetal calf)
serum: 1×1 containing 10% fetal bovine serum)
The cells were suspended at a concentration of 0.05 cells/ml. This cell suspension was placed in a 24-well flat bottom culture plate at an amount of 1 ml/well and cultured at 37° C. in the presence of 5% carbon dioxide for 5 days. After culturing, the number of living cells in the cell suspension was counted by trypan blue staining. The HIV-1 proliferation inhibitory effect of the specimen was determined as the concentration of the specimen that inhibited 100% of the infectivity and cytopathic effects of HIV-1 on MT-4 cells. (Results) The results are as shown in Table E below.

[0053]

[Table 11]

[0054]

[Effects of the Invention] As mentioned above, the polysulfate ester compound of the present invention has an excellent antiretroviral effect, especially an excellent antiproliferation effect against HIV, and is also characterized by low toxicity and high safety as a medicine. be. Also,
The polysulfate ester compound of the present invention also has weak side effects such as anticoagulant effects, which are known from sulfated polysaccharides.

Claims (9)

[Claims] Claim 1: 6 to 8 constituting cyclodextrin
At least one of the D-glucose units has the general formula: ; or represents a sulfur-containing heterocyclic group,
R2 represents a hydrogen atom; or a lower alkyl group substituted with a lower alkanoylamino group or a benzoylamino group. ) A polysulfate ester of an acylaminocyclodextrin derivative or a salt thereof, which is substituted with a unit represented by: 2. R1 is an alkyl group having 1 to 17 carbon atoms;
A phenyl group optionally substituted with 1 to 2 groups selected from a hydroxyl group, an alkyl group having 1 to 4 carbon atoms, and an alkoxy group having 1 to 4 carbon atoms; carbon substituted with a phenyl group or a pyrenylcarbonyl group An alkyl group having 1 to 4 carbon atoms; or a thienyl group, in which R2 is a hydrogen atom; or an alkyl group having 2 to 5 carbon atoms
2. The compound according to claim 1, which is an alkyl group having 1 to 4 carbon atoms substituted with an alkanoylamino group or a benzoylamino group. 3. R1 is an alkyl group having 1 to 17 carbon atoms;
2. An alkyl group having 1 to 4 carbon atoms substituted with a phenyl group; or a pyrenylcarbonyl group, and R2 being a hydrogen atom; or an alkyl group having 1 to 4 carbon atoms substituted with a benzoylamino group. compound. 4. The compound according to claim 1 or 2, wherein the cyclodextrin is α-cyclodextrin. 5. The compound according to claim 1 or 2, wherein the cyclodextrin is β-cyclodextrin. 6. The compound according to claim 1 or 2, having 8 to 23 sulfate groups. Claim 7: 6 to 8 constituting cyclodextrin
At least one of the D-glucose units has the general formula: ; or represents a sulfur-containing heterocyclic group,
R2 represents a hydrogen atom; or a lower alkyl group substituted with a lower alkanoylamino group or a benzoylamino group. ) A polysulfate ester of the acylaminocyclodextrin derivative, characterized in that the acylaminocyclodextrin derivative substituted with the unit shown in ) is reacted with a sulfonating agent, and if desired, the product is converted into a salt thereof The method of making the salt. 8. The method according to claim 7, wherein the sulfonating agent is sulfur trioxide complex, anhydrous sulfuric acid, concentrated sulfuric acid or chlorosulfuric acid. Claim 9: 6 to 8 constituting cyclodextrin
At least one of the D-glucose units has the general formula: ; or represents a sulfur-containing heterocyclic group,
R2 represents a hydrogen atom; or a lower alkyl group substituted with a lower alkanoylamino group or a benzoylamino group. ) Acylaminocyclodextrin derivatives substituted with the units shown.