JPH04346932A - Polysulfuric ester of cyclodextrin derivative and production thereof - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

0001

FIELD OF THE INVENTION The present invention relates to polysulfate esters of cyclodextrin derivatives having antiretroviral activity.

0002

[Prior Art] AIDS (acquired immunodeficiency syndrome) is caused by the human immunodeficiency virus (HIV), a type of retrovirus.
) is a fatal or extremely malignant disease caused by infection, and preventing and eradicating it is currently the most important issue for humanity to overcome on a global level.

[0003] Conventionally, as a compound having an antiretroviral effect, for example, azidothymidine [Medical history;
Volume 142, No. 9, pp. 619-622 (1987)]
and sulfated polysaccharides (JP-A No. 63-45223, No. 64)
-25724) etc. are known.

0004

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 has no side effects.

[0005]

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

[0006]

[C4]

(wherein A is the formula -OCONH-, -OCO
-, -O-, or -O-P(=O)(OH)-O-, R1 is a lower alkyl group, a benzyl group that may have a substituent, or a benzyl group that may have a substituent. cyclodextrin derivative polysulfate or Regarding the salt.

The polysulfate ester of the cyclodextrin derivative of the present invention is schematically shown as follows.

[0009]

[C5]

(In the formula, m is an integer from 6 to 8, n is an integer from 1 to m, and the constituent units are 1st and 4th in any order.)
It is bonded in a ring at the position. All or part of R is a sulfo group or a salt thereof, and the remainder represents a hydrogen atom. A and R1
has the same meaning as above)

In the above general formula (I), examples of R1 include lower alkyl groups such as methyl, ethyl, propyl, butyl, and heptyl, and examples of substituents for the benzyl group include lower alkoxy groups such as methoxy and ethoxy. ,
Substituents for phenyl groups include halogens such as chloro and brome; lower alkyls such as methyl and ethyl; lower alkoxys such as methoxy and ethoxy; and oxazolylmethyl groups which may have substituents. As, 2
-(4-halogenophenyl)-4-furyl-oxazolylmethyl and the like.

Among the compounds of the present invention, pharmaceutically preferred compounds have the general formula (II), where ■A is -OC
A group represented by ONH-, and R1 is a naphthyl group, chlorophenyl group, or methylphenyl group, or ■A is a group represented by -OCO-, and R1 is a thienyl group, thenyl group, or methoxybenzyl group. or ■A is a group represented by -O-, and R1
is a phenyl group, a chlorophenyl group or a methoxyphenyl group.

[0013] The number of sulfo groups contained in the target compound is 8 to
Preferably, the number is 23.

To produce compound (II) of the present invention,
6 that constitutes cyclodextrin (hereinafter abbreviated as CD)
Formula (1) in which at least one of the ~8 D-glucose units is replaced with a unit represented by the formula (I)
III) CD derivative of

[0015]

[C6]

It can be obtained by reacting ##STR1## with a sulfonating agent.

Examples of the sulfonating agent include sulfur trioxide complex (for example, sulfur trioxide-pyridine complex, sulfur trioxide-trialkylamine complex, sulfur trioxide-dioxane complex, sulfur trioxide-N, N dimethylformamide complex, etc.), sulfuric anhydride, concentrated sulfuric acid, chlorosulfuric acid, etc. can all be suitably used.

The amount of the sulfonating agent used is preferably in excess of the amount of the CD derivative (III). For example, sulfur trioxide-pyridine complex or sulfur trioxide-trialkylamine complex as sulfonating agent.
When using a complex, CD derivative (III)
It is preferable to use about 1 to 10 equivalents, especially about 2 to 5 equivalents, based on the hydroxyl group.

The reaction between the CD derivative (III) and the sulfonating agent can be carried out in a suitable solvent or without a solvent. Examples of the reaction solvent include pyridine, N,N-dimethylformamide, formamide, hexamethylene. Phosphoryltriamide, chloroform, benzene, toluene,
Xylene, water, a mixture thereof, liquid sulfite, etc. can be suitably used.

[0020] Depending on the sulfonating agent used, this reaction can be carried out under cooling or under heating (-30°C to 140°C), particularly when using a sulfur trioxide complex, under heating (50°C to 140°C). It is preferable to carry out the test at a temperature of 100°C.

After completion of the reaction, the desired 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 an alkali metal hydroxide, the product is subjected to a column packed with a cross-linked dextran gel or the like, or after being purified with an anion exchange resin, the crude product is purified using an alkali metal hydroxide. By processing with
The target product can be obtained as an alkali metal salt.

Polysulfate compound (II) of the present invention
can be suitably used either in its free form or in its pharmacologically acceptable salt form. Examples of such salts include alkali metal salts such as sodium salts, potassium salts, and lithium salts; alkaline earth metal salts such as calcium salts, magnesium salts, and barium salts; trimethylamine salts, triethylamine salts, pyridine salts, glycine ethyl ester salts, Examples include organic amine salts such as ethanolamine salts and basic amino acid salts.

CD derivative (I
II) is a new compound, in which A is -OCO
A compound which is an NH- group or an -O-P(=O)(OH)-O- group is a cyclodextrin and a compound having the general formula R1 NC
A compound represented by O (wherein the symbols have the same meanings as above) or the general formula R1 -O-P(=O)X2 (wherein, X represents a halogen atom, and R1 has the same meanings as above) It can be obtained by reacting the compounds shown in .). In addition, compounds in which A is -OCO- group,
Cyclodextrin or mono- or poly(6-halogeno-6-deoxy)cyclodextrin and general formula R1
It can be obtained by reacting a compound represented by -COOH (in the formula, the symbols have the same meanings as above), a reactive derivative thereof, or a salt thereof. Compounds in which A is -O- group include mono- or poly(6-halogeno-6-deoxy)cyclodextrin and compounds represented by the general formula R1 -OH (wherein the symbols have the same meanings as above). Alternatively, it can be obtained by reacting a salt thereof. The above raw material production method is a well-known reaction method, and is schematically shown as follows.

[0024]

[Chemical formula 7] (In the formula, X1 represents a halogen atom, and the other symbols have the same meanings as above)

[0025]

[Effect of the invention] The polysulfate ester compound (II
) and its salts have an excellent antiretroviral effect, especially an excellent anti-proliferation effect against HIV, as shown in the experimental examples below, and are also characterized by low toxicity and high safety as medicines. Furthermore, the polysulfate ester compound of the present invention has weak side effects such as anticoagulant effect, which is known from sulfated polysaccharides.

Polysulfate compound (II) of the present invention
and its salts can be administered orally or parenterally (e.g., intravenously, intramuscularly, subcutaneously), and can be administered by conventional methods such as tablets, granules, capsules, powders, injections, suppositories, etc. It can be used as an appropriate pharmaceutical preparation such as a vaginal preparation or cream. The dosage varies depending on the patient's age, weight, condition and type of disease, but is usually about 0.1 per day.
~200mg/kg is suitable, especially about 0.5~50mg/kg.
It is preferable to set it to about mg/kg.

[0027]

EXAMPLES The method for producing the raw material compound (III) of the present invention and the method for producing the sulfuric acid ester compound (II) of the present invention are shown below as examples.

Examples 1 to 3 Poly{6-O-[(4-
chlorophenyl)aminocarbonyl]}-β-cyclodextrinβ-cyclodextrin 5.0g (44mm
ol) in 150 ml of pyridine, and 2.70 g (176 mmol) of 4-chlorophenylisocyanate was dissolved in 150 ml of pyridine.
The mixture was added dropwise over 40 minutes at 4 to 25°C. After stirring at 60 to 65° C. for 1 hour, pyridine was distilled off under reduced pressure, 100 ml of toluene was added to the residue, and the mixture was distilled off again. methanol 1
After heat immersion in 00 ml, the mixture was cooled to room temperature and insoluble matter was filtered off. The mother liquor was distilled off under reduced pressure, and the residue was mixed with 25 ml of methanol and 40 ml of water.
ml of solution, and the soluble portion was distilled off under reduced pressure to obtain 1.15 g of colorless powder of poly{6-O-[(4-chlorophenyl)aminocarbonyl]}-β-cyclodextrin of Example 1.
I got it.

Further, the above-mentioned insoluble part was treated with 100 ml of acetone and 50 ml of chloroform to remove the soluble part, which was suspended in a solution of 100 ml of methanol and 100 ml of acetone. 2.7 g of colorless powder of poly{6-O-[(4-chlorophenyl)aminocarbonyl]}-β-cyclodextrin of Example 3 was extracted from the soluble part. Colorless powder 2.0g
I got it.

Compound of Example 1 (n average 1.6) mp:
>240℃ IR (KBr)cm-1: 3400, 1720,
1590, 1540, 1150, 10201H
-NMR (DMSO-d6)δ, ppm: 3.2
-4.0 (m), 4.1-4.5 (m), 4.15
(m), 4.3-5.0 (m), 5.6-5.8 (m
), 7.32(d), 7.45(d), 9.72
(br. s) Determination of n by HPLC: 1 (50%), 2 (40%)
, 3 (10%)

Compound of Example 2 (n average 2.6) mp:
>240℃ IR (KBr)cm-1: 3400, 1720,
1590, 1540, 1140, 10201H
-NMR (DMSO-d6)δ, ppm: 3.2
-4.0(m), 4.1-4.5(m), 4.5-
5.0(m), 5.6-5.9(m), 7.1-7
．． 6 (m), 9.56, 9.71 (br. s) Determination of n by HPLC: 1 (3%), 2 (30%),
3 (45%), 4 (20%)

Compound of Example 3 (n average 3) mp: 20
0-225℃ (decomposition) IR (KBr) cm-1: 3400, 1720,
1600, 1540, 1150, 10301H
-NMR (DMSO-d6)δ, ppm: 3.2
-4.0(m), 4.1-5.0(m), 5.6-
5.9(m), 7.1-7.6(m), 9.60,
9.72 (br. s) Determination of n by HPLC: 1
(0%), 2 (25%), 3 (45%), 4 (30%)

Example 4 Heptakis {6-O-[(4
-chlorophenyl)aminocarbonyl]}-β-cyclodextrin 5.0 g (44 mmol) of β-cyclodextrin was dissolved in 150 ml of pyridine, and 5.0 g (326 mmol) of 4-chlorophenyl isocyanate was heated at -5 to -10°C.
After stirring at room temperature for 1 day and at 70°C for 3 hours,
It was concentrated under reduced pressure. After washing the residue with ether, it was dissolved in 100 ml of ethyl acetate with heating, and the precipitated crystals were filtered off. The mother liquor was concentrated and purified by silica gel column chromatography (ethyl acetate-methanol 0-30%). The main fraction was recrystallized from ethanol to obtain 2.5 g of colorless powder of heptakis {6-O-[(4-chlorophenyl)aminocarbonyl]}-β-cyclodextrin.
I got it.

mp: 251-256°C IR (KBr) cm-1: 1705, 1600,
1530, 1490, 1225, 1150,
1080, 1040 1H-NMR (DMSO-d6) δ, ppm: 5
．． 0(s), 5.2-6.0(m), 7.2(d)
, 7.3(d), 9.6(s)

Compounds of Examples 5 to 10 were prepared according to the method of Example 4.

Example 5 Bis{6-O-[(4-methylphenyl)aminocarbonyl]}-β-cyclodextrin mp: 260°C (decomposition) IR (KBr) cm-1: 1710, 1605,
1540, 1410, 1320, 1230,
1150, 1080, 1040 1H-NMR (DMSO-d6) δ, ppm: 2
．． 1-2.4 (m), 6.9-7.4 (m), 9.
46(br.s)

Example 6 Tetrakis {6-O-[(4
-methylphenyl)aminocarbonyl]}-β-cyclodextrin mp: 245°C (decomposition) IR (KBr) cm-1: 1710, 1605,
1540, 1410, 1320, 1230,
1150, 1080, 1040 1H-NMR (DMSO-d6) δ, ppm: 2
．． 0-2.3 (m), 6.9-7.4 (m), 9.
2-9.5 (m)

Example 7 Heptakis {6-O-[(4
-methylphenyl)aminocarbonyl]}-β-cyclodextrin mp: 265°C (decomposition) IR (KBr) cm-1: 1705, 1600,
1535, 1410, 1320, 1225,
1150, 1080, 1040 1H-NMR (DMSO-d6) δ, ppm: 2
．． 16(s), 5.96(d), 7.3(d),
9.34(s)

Example 8 Tris(6-O-n-butylaminocarbonyl)-β-cyclodextrin mp: 2
38-241℃ (decomposition) IR (KBr) cm-1: 1700, 1540,
1250, 1055, 1080, 10301H
-NMR (DMSO-d6)δ, ppm: 0.8
5(t), 1.1-1.5(m), 2.7-3.1
(m), 6.8-7.2(br)

Example 9 Tris{6-O-[(2-naphthyl)aminocarbonyl]}-β-cyclodextrin mp: 245°C (
decomposition) IR (KBr) cm-1: 1710, 1635,
1600, 1545, 1505, 1230,
1155, 1080, 1030 1H-NMR (DMSO-d6) δ, ppm: 7
．． 2-8.2(m), 9.3-9.6(br)

00
41] Example 10 Heptakis {6-O-[(2-naphthyl)aminocarbonyl]}-β-cyclodextrin mp: 216°C (decomposition) IR (KBr) cm-1: 1710, 1630,
1600, 1540, 1500, 1230,
1150, 1080, 1035 1H-NMR (DMSO-d6) δ, ppm: 7
．． 0-8.3(m), 9.3-9.5(m)

004
2] Example 11 Heptakis (6-O-benzoyl)
-β-cyclodextrin heptakis (6-iodo-6
-deoxy)-β-cyclodextrin 0.5g (0.
26 mmol) in dimethylformamide (DMF) 20
ml of sodium benzoate, 0.53 g (3.7
mmol) and reacted at 90°C for 20 hours with stirring. After the reaction, it was concentrated under reduced pressure, and the resulting residue was added to 50 ml of water, and the formed precipitate was collected by filtration, washed with water, and dried to obtain 0.4 g of white powder of heptakis(6-O-benzoyl)-β-cyclodextrin. I got it. Yield 82.6%

00
43] mp: 225-228℃ (decomposition) IR (Nuj
ol) cm-1: 3380, 2950, 1720
, 1600, 1150, 1280, 1050 1H-NMR (DMSO-d6) δ, ppm: 3
．． 4-3.48(m), 4.9(br.s), 5
．． 82(br.s), 7.25(br.s),
7.65 (br.d)

Compounds of Reference Examples 12 to 16 were prepared according to the method of Example 11.

Example 12 Heptakis [6-O-(4
-methoxybenzoyl)]-β-cyclodextrin Form: White powder mp: 235-238°C (decomposition) IR (Nujol) cm-1: 3400, 171
0, 1600, 1510, 1260, 1100
, 1050 1H-NMR (Nujol) cm-1: 3.2-4
．． 7(br.s), 4.91(br.s), 5
．． 85(br.s), 6.7-7.1(br.s
), 7.7-8.0 (br. m)

Example 13 Heptakis {6-O-[(4-methoxybenzyl)carbonyl]}-β-cyclodextrin Form: White powder mp: 170-173°C (decomposed) IR (Nujol) cm-1: 3380, 174
0, 1610, 1510, 1300, 1150
, 1050 1H-NMR (DMSO-d6) δ, ppm: 3
．． 2-4.0(m), 4.0-4.6(br.m)
, 4.75(br.s), 5.75(br.s)
, 6.5-6.8(d), 6.9-7.2(d)

Example 14 Heptakis [6-O-(2
-thenoyl)]-β-cyclodextrin Form: White powder, yield 91.7% mp: 132-135°C (decomposition) IR (Nujol) cm-1: 3400, 171
0, 1520, 1260, 1150, 1040
1H-NMR (DMSO-d6) δ, ppm: 3
．． 3-4.8(m), 4.92(br.s), 5
．． 85(br.s), 7.05(t), 7.75
(t)

Example 15 Heptakis {6-O
-[(2-thienyl)methylcarbonyl}-β-cyclodextrin Form: light brown powder, yield 80% mp: 185-190°C (decomposed) IR (Nujol) cm-1: 3350, 174
0, 1250, 1160, 10501H-NMR
(DMSO-d6)δ, ppm: 3.4-4.7
(m), 3.88 (br. s), 4.8 (br.
s), 5.75(br.s), 6.9(t),
7.35 (m)

Example 16 Heptakis(6-O-n-hexanoyl)-β-cyclodextrin Form: White powder, yield 92.7% mp: 225-230°C (decomposed) IR (Nujol) cm-1: 3350 , 174
0, 1380, 1250, 1160, 1040
1H-NMR (DMSO-d6) δ, ppm: 0
．． 84(t), 1.0-1.8(br.m), 2
．． 25(t), 3.1-4.6(br.m), 4.
85(br.s), 5.8(br.s)

005
Example 17 Heptakis[6-O-(4-chlorobenzoyl)-β-cyclodextrin 11.35 g (10 mmol) of β-cyclodextrin was dissolved in pyridine 10
14.0 g (80 mmol) of 4-chlorobenzoyl chloride was dissolved in 0 ml and 100 ml of DMF.
The mixture was added dropwise at -10°C, the temperature was gradually raised, and the mixture was stirred at room temperature for 2 hours. After adding 50 ml of methanol and stirring for 30 minutes, the mixture was concentrated under reduced pressure, and 500 ml of ethyl acetate and 300 ml of water were added to separate the layers. The organic layer was washed with dilute hydrochloric acid and then with saturated brine, dried over magnesium sulfate, concentrated, developed on a silica gel column, and washed with trichloromethane-methanol (2
0:1 to 10:1), and 5.1 g of a fraction with an Rf of 0.52 was obtained on TLC (silica gel plate, developed with trichloromethane-methanol (4:11)). Recrystallization from ethanol gave 3.23 g of heptakis[6-O-(4-chlorobenzoyl)]-β-cyclodextrin as colorless microcrystals.

[0051] mp: 219-225°C IR (KBr) cm-1: 3400, 1720,
1595, 1270, 1090, 1050,
760 1H-NMR (CDCl3) δ, ppm: 3.4
7(t), 3.78(dd), 4.0-4.5(m
), 4.81(d), 4.94(d), 5.25
(s), 6.73(s), 7.35(d), 7.
80(d)

Example 18 Mono{6-O-{[2-(
4-chlorophenyl)-5-(2-furyl)-4-oxazolyl]methylcarbonyl}-β-cyclodextrin 2-(4-chlorophenyl)-5-(2-furyl)-4
- Suspend 3.04 g (10 mmol) of oxazolyl acetic acid in 20 ml of chloroform, and suspend 20 ml of oxazolyl chloride.
ml was added and refluxed for 3 hours, and then concentrated under reduced pressure. Dissolve the residue in 30 ml of chloroform and add β-cyclodextrin 11
．． 35g (10mmol) suspended in DMF 100ml
and 1,100 ml of pyridine were added at room temperature. The solution was stirred as it was, concentrated under reduced pressure, and the residue was washed with acetone. Subsequently, the insoluble portion was removed by hot soaking in 200 ml of water, and mono{6-O-{[2-(4-chlorophenyl)-5-(2-furyl)-4-oxazolyl]methylcarbonyl}} was precipitated from the aqueous layer. -1.12 g of -β-cyclodextrin was obtained as a colorless powder.

[0053] mp: >240°C IR (KBr) cm-1: 3400, 1740,
1650, 1500, 1485, 1230,
1155, 1080, 1025, 9501H-NM
R(DMSO-d6)δ, ppm: 3.1-4.
2(m), 4.3-4.7(br), 4.8-5.
0 (br. s), 5.57, 5.75 (br. d
), 7.25(d), 7.50-7.75(m),
7.90(d), 8.0-8.2(m)

0054
] Example 19 Heptakis(6-O-phenyl)-β
- 0.52 g (5.5 mmol) of cyclodextrin phenol in DMF20
ml, cool with ice water, and add 0.18 g (60%) of sodium hydride (4.05 mmol) while stirring.
Heptakis (6-
1 g of iodo-6-deoxy)-β-cyclodextrin
Add a solution of (0.53 mmol) and 20 ml of DMF,
The reaction was carried out at 90° C. for 10 hours, and the resulting residue was added to 50 ml of water to form a precipitate. This was collected by filtration, washed with water, dried, and heptakis(6-O-phenyl)-β
-0.43g of cyclodextrin as light brown powder
Obtained.

mp: 240-245°C (decomposition) IR (
Nujol) cm-1: 3350, 1600, 1
220, 1160, 10401H-NMR (DM
SO-d6) δ, ppm: 3.0-4.5 (br.
m), 4.95(br.s), 5.6-6.0
(br), 6.5-7.0(br.m)

0056
Compounds of Reference Examples 20 to 22 were prepared according to the method of Example 19.

Example 20 Heptakis [6-O-(4
-methylphenyl)]-β-cyclodextrin shape:
Light brown powder mp: 245-250°C (decomposition) IR (Nujol) cm-1: 3400, 161
0, 1240, 1510, 1160, 1040
1H-NMR (DMSO-d6) δ, ppm: 2
．． 15(s), 3.1-4.4(br), 4.9(
br. s), 5.5-5.9(br), 6.4-
7.2 (br)

Example 21 Heptakis[6-O-(4-methoxyphenyl)]-β-cyclodextrin Form: Brown powder mp: 245-250°C (decomposed) IR (Nujol) cm-1: 3400, 164
0, 1510, 1230, 1150, 1040
1H-NMR (DMSO-d6) δ, ppm: 3
．． 3-4.3(br.m), 4.85(br.s
), 5.74(br.s), 6.5-6.9(b
r. m)

Example 22 Heptakis [6
-O-(4-chlorophenyl)]-β-cyclodextrin Form: Brown powder, yield 65.3% mp: 225-230°C (decomposition) IR (Nujol) cm-1: 3400, 160
0, 1500, 1240, 1160, 1030
1H-NMR (DMSO-d6) δ, ppm: 3
．． 2-4.4 (br. m), 4.9 (br. s)
, 5.75(br.s), 6.7-7.3(br.s)
．． m)

Example 23 Tris {6-O-
[(4-chlorophenyl)phosphono]}-β-Cyclodextrin 2.52 g of β-cyclodextrin was dissolved in 100 ml of pyridine, cooled to -10°C, and while stirring, 3.51 g of 4-chlorophenylphosphorodichloridate was added.
was dripped. Thereafter, the reaction mixture was stirred at room temperature for 20 hours, concentrated under reduced pressure, dissolved in methanol, and poured into acetone with stirring. The precipitate was collected by filtration and dried to give Tris{6-O-[
4.15 g of 4-chlorophenyl)phosphono]}-β-cyclodextrin was obtained as a colorless powder.

mp: 165°C (decomposition) IR (KBr) cm-1: 1638, 1540,
1492, 1232, 1156, 1080,
1033, 903 1H-NMR (DMSO-d6) δ, ppm: 7
．． 0-7.5(m)

Example 24 Tetrakis {6-O-[(4-chlorophenyl)phosphono]}
-β-cyclodextrin Produced according to the method of Example 23. These compounds were used in the next step without purification.

Example 25 Heptakis {6-O-[(
4-chlorophenyl)phosphono]}-β-cyclodextrin 2.52 g of β-cyclodextrin was dissolved in 100 g of pyridine.
ml, cooled to -20°C, and 6.87 g of 4-chlorophenylphosphorodichloridate was added dropwise while stirring. Thereafter, the reaction mixture was stirred at room temperature for 20 hours, concentrated under reduced pressure, dissolved in methanol, and poured into water. Filter the precipitate,
After drying, purify by removing soluble materials with ether and acetone,
6. Heptakis {6-O-[(4-chlorophenyl)phosphono]}-β-cyclodextrin as colorless powder.
I got 50g.

mp: 202°C (decomposition) IR (Nujol) cm-1: 1630, 159
0, 1220, 1160, 1030, 9501
H-NMR (DMSO-d6) δ, ppm: 6.
9-7.5 (m)

Example 26 Hexakis {6-O-[(2-thienyl)methylcarbonyl]}
-α-Cyclodextrin 1 g of hexa(6-bromo-6-deoxy)-α-cyclodextrin and 30 m of N,N-dimethylformamide
1.1 of sodium 2-thienyl acetate.
7 g was added, and the mixture was stirred and reacted at 90°C for 20 hours. The reaction solution was concentrated under reduced pressure, and the residue was added to 100 ml of water, producing a brown precipitate. This precipitate was collected by filtration, washed with water, and dried to give 1.13 g of hexakis {6-O-[(2-thienyl)methylcarbonyl]}-α-cyclodextrin (yield: 88
．． 9%).

mp: 223-226°C (decomposition) IR (
Nujol) cm-1: 1740, 1050, 7
001H-NMR (DMSO-d6) δ, ppm:
3.2-4.1(m), 4.25(br.s),
4.8(br.s), 5.4-5.7(br.s),
6.8-6.9(m), 7.1(d)

[0067]
Example 27 Hexakis(6-O-phenyl)-α-
Cyclodextrin phenol 0.63g N,N-
Dissolved in 30 ml of dimethylformamide, 62.7% N
To a solution made into a sodium salt with 0.25 g of aH, 1 g of hexa(6-bromo-6-deoxy)-α-cyclodextrin was added, and the mixture was stirred and reacted at 90° C. for 20 hours. The reaction solution was concentrated under reduced pressure, and the residue was added to 150 ml of water to form a precipitate. This precipitate was collected by filtration, washed with water, and dried.
0.45 g (yield: 42.5%) of hexa(6-O-phenyl)-α-cyclodextrin was obtained as a light brown powder.

mp: 250-252°C (decomposition) IR (
Nujol) cm-1: 1600, 1500, 1
150, 1040, 7501H-NMR (DMS
O-d6) δ, ppm: 3.2-4.4 (br.
s), 6.6-7.3(br)

Example 28 Poly{6-O-[(4-chlorophenyl)aminocarbonyl]}-β-cyclodextrin (n average 1.6) polysulfate ester lithium salt Poly{6 obtained in Example 1 -O-[(4-chlorophenyl)aminocarbonyl]}-β-cyclodextrin (n
Average 1.6) 1.00 g (0.71 mmol) was dissolved in 50 ml of pyridine, and anhydrous sulfuric pyridine complex 6.
48 g (41 mmol) was added at 70°C, and the reaction was stirred for 6 hours. The reaction solution was cooled, the supernatant liquid was removed, and the residue was powdered with 150 ml of methanol and collected by filtration. The obtained colorless powder was dissolved in 10 ml of water, and resin SK-1B (25 ml
After stirring with l) for 1 hour, remove the resin and pip with a LiOH aqueous solution.
The title compound was adjusted to 7.3 and lyophilized to 0.6
I got 3g.

IR (KBr) cm-1: 1720,
1640, 1540, 1230, 1000,
825 1H-NMR (D2O) δ, ppm: 7.1-7
．． 5 (br. m) Number of sulfate ester groups in the molecule calculated from elemental analysis value: 13

Examples 2 to 27 according to the method of Example 28
The compound was prepared.

Example 29 Poly{6-O-[(4-chlorophenyl)aminocarbonyl]}-β-cyclodextrin (n average 2.6) polysulfate ester lithium salt IR (KBr) cm-1: 1720 , 1645,
1605, 1550, 1240, 1040,
1010, 830 Number of sulfate ester groups in the molecule calculated from elemental analysis value: 16.5

Example 30 Poly{6-O-[(4-chlorophenyl)aminocarbonyl]}-β-cyclodextrin (n average 3) polysulfate ester lithium salt IR (KBr) cm-1: 1710, 1640 ，
1540, 1230, 1000, 8301H-
NMR (D2O) δ, ppm: 6.9-7.5 (
m) Number of sulfate ester groups in the molecule calculated from elemental analysis values: 16

Example 31 Heptakis {6-O-[(
4-chlorophenyl)aminocarbonyl}-β-cyclodextrin polysulfate ester potassium salt IR
(KBr) cm-1: 1710, 1640, 15
45, 1240, 1040, 1010, 830 1H-NMR (D2O) δ, ppm: 6.5-7
．． 3(m) Number of sulfate ester groups in the molecule calculated from elemental analysis value: 12

Example 32 Bis{6-O-[(4-methylphenyl)aminocarbonyl]}-β-cyclodextrin polysulfate potassium salt IR (KB
r) cm-1: 1720, 1640, 1540,
1240, 1040, 1000, 940, 8
20, 740 1H-NMR (D2O) δ, ppm: 2.0-2
．． 4(m), 6.8-7.5(m) Number of sulfate ester groups in the molecule calculated from elemental analysis value: 16

Example 33 Tetrakis {6-O-[(
4-methylphenyl)aminocarbonyl}-β-cyclodextrin polysulfate ester potassium salt IR
(KBr) cm-1: 1720, 1630, 15
30, 1240, 1040, 1000, 945
, 820 1H-NMR (D2O) δ, ppm: 1.9-2
．． 4(m), 6.5-7.4(m) Number of sulfate ester groups in the molecule calculated from elemental analysis value: 15

Example 34 Heptakis {6-O-[(
4-methylphenyl)aminocarbonyl}-β-cyclodextrin polysulfate ester potassium salt IR
(KBr) cm-1: 1710, 1605, 15
40, 1460, 1410, 1320, 124
0, 1130, 1000, 8201H-NMR (
D2O) δ, ppm: 1.88 (br. s),
6.2-7.5 (m) Number of sulfate ester groups in the molecule calculated from elemental analysis value: 8

Example 35 Tris(6-O-n-butylaminocarbonyl)-β-cyclodextrin polysulfate potassium salt IR (KBr) cm-1: 1710, 1640,
1540, 1470, 1240, 1160,
1000, 945, 8281H-NMR (D2O
) δ, ppm: 0.892(t), 1.1-1.
6 (m), 3.12 (br. s) Number of sulfate ester groups in the molecule calculated from elemental analysis value: 14

Example 36 Tris{6-O-[(2-
naphthyl) aminocarbonyl]}-β-cyclodextrin polysulfate potassium salt IR (KBr) cm-1: 1710, 1635,
1545, 1505, 1240, 1005,
945, 810 1H-NMR (D2O) δ, ppm: 6.8-8
．． 2(m) Number of sulfate ester groups in the molecule calculated from elemental analysis value: 15

Example 37 Heptakis {6-O-[(
2-naphthyl)aminocarbonyl}-β-cyclodextrin polysulfate potassium salt IR (KB
r) cm-1: 1710, 1635, 1600,
1545, 1505, 1240, 1030,
1010, 820 1H-NMR (D2O) δ, ppm: 6.0-8
．． 0(m) Number of sulfate ester groups in the molecule calculated from elemental analysis value: 14

Example 38 Heptakis(6-O-benzoyl)-β-cyclodextrin polysulfate ester sodium salt IR (KBr) cm-1: 1720, 1600,
1270, 1240, 1040, 1000,
820 1H-NMR (D2O) δ, ppm: 3.7-5
．． 6 (br. m), 7.0-8.0 (br. m) Number of sulfate ester groups in the molecule calculated from elemental analysis values: 12

Example 39 Heptakis[6-O-(4
-methoxybenzoyl)]-β-cyclodextrin
Polysulfate ester sodium salt IR (KBr) cm-1: 1710, 1600,
1510, 1260, 1240, 1040,
1000, 830 1H-NMR (D2O) δ, ppm: 3.7(b
r. s), 4.0-5.7(br), 6.4-7
．． 1 (br), 7.4-7.9 (br) Number of sulfate ester groups in the molecule calculated from elemental analysis value: 14

Example 40 Heptakis {6-O-[(
4-methoxybenzyl)carbonyl}-β-cyclodextrin polysulfate ester sodium salt IR (
KBr) cm-1: 1740, 1620, 152
0, 1240, 1040, 1000, 820 1H-NMR (D2O) δ, ppm: 3.6 (b
r. s), 3.2-5.5 (br. m), 6.
5-7.3 (br. d) Number of sulfate ester groups in the molecule calculated from elemental analysis values: 12

Example 41 Heptakis [6-O-(2
-thenoyl)]-β-cyclodextrin polysulfate ester sodium salt IR (KBr) cm-1: 1710, 1520,
1460, 1240, 1040, 8301H-
NMR (D2O) δ, ppm: 3.8-5.6 (
br. m), 7.0(br.s), 7.7(b
r. s) Number of sulfate ester groups in the molecule calculated from elemental analysis values: 13

Example 42 Heptakis {6-O-[(
2-thienyl)methylcarbonyl}-β-cyclodextrin polysulfate ester sodium salt IR (K
Br) cm-1: 1740, 1640, 1240
, 1170, 1040, 1000, 830 1H-NMR (D2O) δ, ppm: 3.9(b
r. s), 4.1-5.0 (br. m), 5.
3(br.s), 6.95(br.s), 7.3
(br. s) Number of sulfate ester groups in the molecule calculated from elemental analysis values: 14

Example 43 Heptakis (6-O-n-
hexanoyl)-β-cyclodextrin polysulfate ester sodium salt IR (KBr) cm-1: 1740, 1240,
Number of sulfate ester groups in the molecule calculated from 1040, 820 elemental analysis value: 12

Example 44 Heptakis [6-O-(4
-chlorobenzoyl)]-β-cyclodextrin polysulfate ester lithium salt IR (KBr) cm-1: 1725, 1635,
1600, 1270, 1230, 1095,
1030, 1010, 850, 7601H-NM
R(D2O)δ, ppm: 6.5-7.2(m)
, 7.2-7.8 (m) Number of sulfate ester groups in the molecule calculated from elemental analysis values: 9

Example 45 Mono{6-O-{[2-(
4-chlorophenyl)-5-(2-furyl)-4-oxazolyl]methylcarbonyl}-β-cyclodextrin polysulfate ester sodium salt IR (KBr) cm-1: 1740, 1715,
1640, 1585, 1240, 1040,
1005, 820 1H-NMR (D2O) δ, ppm: 7.12 (
br. d), 7.63 (br. d), 7.75
(br. s), 8.12 (br. d), 8.8
(br. d) Number of sulfate ester groups in the molecule calculated from elemental analysis values: 15

Example 46 Heptakis(6-O-phenyl)-β-cyclodextrin polysulfate ester
Sodium salt IR (KBr) cm-1: 1600, 1500,
1240, 1160, 1040, 8201H-
NMR (D2O) δ, ppm: 3.2-5.8 (
br), 6.4-7.5 (br) Number of sulfate ester groups in the molecule calculated from elemental analysis value: 12

Example 47 Heptakis [6-O-(4
-methylphenyl)]-β-cyclodextrin polysulfate ester sodium salt IR (KBr) cm-1: 1510, 1240,
1030, 8101H-NMR (D2O)δ,
ppm: 1.8-2.3(br), 3.3-5.5
(br. m), 6.3-7.3 (br. s) Number of sulfate ester groups in the molecule calculated from elemental analysis values: 7

Example 48 Heptakis [6-O-(4
-methoxyphenyl)]-β-cyclodextrin polysulfate ester sodium salt IR (KBr) cm-1: 1510, 1230,
1040, 8201H-NMR (D2O)δ,
ppm: 3.3-5.5 (br. m), 6.4-
7.1 (br. s) Number of sulfate ester groups in the molecule calculated from elemental analysis value: 13

Example 49 Heptakis[6-O-(4
-chlorophenyl)]-β-cyclodextrin polysulfate ester sodium salt IR (KBr) cm-1: 1600, 1240,
1040, 1000, 8201H-NMR (D
2O) δ, ppm: 3.4-5.6 (br. m)
, 6.3-7.4 (br) Number of sulfate ester groups in the molecule calculated from elemental analysis value: 13

Example 50 Tris{6-O-[(4-
chlorophenyl)phosphono]}-β-cyclodextrin polysulfate potassium salt IR (KBr) cm-1: 1640, 1240,
1150, 1080, 1028, 940, 9
00, 820, 750 1H-NMR (D2O) δ, ppm: 6.9-7
．． 6(m) Number of sulfate ester groups in the molecule calculated from elemental analysis value: 6

Example 51 Tetrakis {6-O-[(
4-chlorophenyl)phosphono]}-β-cyclodextrin polysulfate potassium salt IR (KBr) cm-1: 1630, 1490,
1240, 1090, 1010, 900, 8
20 1H-NMR (D2O) δ, ppm: 6.9-7
．． 6(m) Number of sulfate ester groups in the molecule calculated from elemental analysis value: 10

Example 52 Heptakis {6-O-[(
4-chlorophenyl)phosphono]}-β-cyclodextrin polysulfate potassium salt IR (KBr) cm-1: 1640, 1490,
1240, 1090, 900, 840, 76
0 1H-NMR (D2O) δ, ppm: 6.3-7
．． 6(m) Number of sulfate ester groups in the molecule calculated from elemental analysis value: 5

Example 53 Hexakis {6-O-[(
2-thienyl)methylcarbonyl}-α-cyclodextrin polysulfate ester sodium salt Form: Light brown powder IR (Nujol) cm-1: 1740, 164
0, 1240, 1040, 1000, 8301
H-NMR (D2O) δ, ppm: 6.9 (br
．． s), 7.3 (br. s) Number of sulfate ester groups in the molecule calculated from elemental analysis value: 10

[0097]
Example 54 Hexakis(6-O-phenyl)-α-
Cyclodextrin polysulfate ester sodium salt Form: White powder IR (Nujol) cm-1: 1630, 160
0, 1500, 1240, 1040, 8201
H-NMR (D2O) δ, ppm: 6.8-7.
4(br) Number of sulfate ester groups in the molecule calculated from elemental analysis value: 11

Experimental Example HIV-1 proliferation inhibitory effect (principle) Human T-cell leukemia virus type I [human
T-cell Leukemia virus, HT
LV-I (ATLV)] persistently infected cell line MT-
It is known that when MT-4 cells are infected with HIV-1, HIV-1 rapidly proliferates, and the MT-4 cells die in 5 to 6 days due to cell damage. Therefore, using the number of viable MT-4 cells infected with HIV-1 as an index,
IV-1 proliferation inhibitory effect can be examined.

(Method) MT-4 cells were infected with HIV-1 (TA
LL-1/LAV-1 culture supernatant), 0.001TC
ID50 (median tissue culture)
After infecting the cells at 37°C for 1 hour, the cells were incubated with RPMI containing various concentrations of the specimen.
-1640 medium [FCS (fetal calf se
rum: contains 10% fetal bovine serum) and 1×105 c
It was suspended at a concentration of ell/ml. This cell suspension was
A volume of 1 ml/well was placed in a 4-well flat bottom culture plate, 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 shown in Table 1.

[0101]

[Table 1]

Claims (7)

[Claims] Claim 1: 6 to 8 constituting cyclodextrin
At least one of the D-glucose units has the general formula: Represents a group represented by O-, R1 is a lower alkyl group, a benzyl group that may have a substituent, a phenyl group that may have a substituent, a naphthyl group, a thienyl group, a thenyl group, or a substituent A polysulfate ester of a cyclodextrin derivative or a salt thereof, which is substituted with a unit represented by (representing an oxazolylmethyl group which may have) or a salt thereof. [Claim 2] R1 is: ■ a lower alkyl group, ■ a benzyl group optionally substituted with a lower alkoxy group, ■ a phenyl group optionally substituted with a halogen atom, a lower alkyl group, or a lower alkoxy group, ■ a naphthyl group , (1) thienyl group, (2) thenyl group, or (2) 2-(4-halogenophenyl)-4-furyl-oxazolylmethyl group. 3. ■A is a group represented by -OCONH-, and R1 is a naphthyl group, chlorophenyl group, or methylphenyl group, or ■A is a group represented by -OCO-, and R1 is a group represented by -OCO-. is a thienyl group, thenyl group or methoxybenzyl group, or ■A is -O-
Claim 1 is a group represented by and R1 is a phenyl group, a chlorophenyl group or a methoxyphenyl group.
Compounds described. 4. A compound according to claim 1, having 8 to 23 sulfate groups. Claim 5: 6 to 8 constituting cyclodextrin
At least one of the D-glucose units has the general formula: Represents a group represented by O-, R1 is a lower alkyl group, a benzyl group that may have a substituent, a phenyl group that may have a substituent, a naphthyl group, a thienyl group, a thenyl group, or a substituent A cyclodextrin derivative substituted with a unit represented by (representing an oxazolylmethyl group which may have A method for producing a polysulfate ester of the cyclodextrin derivative or a salt thereof. 6. The method according to claim 5, wherein the sulfonating agent is sulfur trioxide complex, anhydrous sulfuric acid, concentrated sulfuric acid or chlorosulfuric acid. Claim 7: 6 to 8 constituting cyclodextrin
At least one of the D-glucose units has the general formula: Represents a group represented by O-, R1 is a lower alkyl group, a benzyl group that may have a substituent, a phenyl group that may have a substituent, a naphthyl group, a thienyl group, a thenyl group, or a substituent A cyclodextrin derivative substituted with a unit represented by (representing an oxazolylmethyl group which may have).