JPH06228202A - Production of readily water-soluble cyclodextrin compounded material - Google Patents

Abstract

PURPOSE:To obtain a compounded material useful as an injection preparation having extremely improved solubility of a slightly soluble specific fumagiroll derivative by making the fumagiroll derivative and a readily water-soluble cyclodextrin into an aqueous solution. CONSTITUTION:A fumagiroll derivative (salt) of the formula [R<1> is H; R<2> is halogen, S(O)nR<5>, etc.; R<5> is hydrocarbon, etc.; R<1> and R<2> are bonded to form direct bond; R<3> is 2-methyl-1-propenyl, etc., A is O or NR<8>; R<8> is H, etc.; R<4> is H, acyl, etc.] and a readily water-soluble cyclodextrin are made into an aqueous solution having >= about 100mg/ml of the readily water-soluble cyclodextrin. The fumagiroll derivative is 6-0-(N-chloroacetylcarbamonyl) fumagiroll or 6-0-(N-methylcarbamoyl)fumagiroll. Glucosyl-beta-cyclodextrin or maltosyl-beta-cyclodextrin is used as the cyclodextrin derivative and the molar ratio of the readily water-soluble cyclodextrin and the fumagiroll of 1.5-3:1.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention has an angiogenesis-inhibiting effect and is an inflammatory disease such as rheumatoid arthritis, diabetic retinopathy or tumor (eg, cancer such as breast cancer, liver cancer, colon cancer, Kaposi's sarcoma). The present invention relates to a method for producing a complex of a fumagillol derivative and a readily soluble cyclodextrin capable of enhancing the solubility in water, promoting absorption, and enhancing the pharmacological activity of a fumagillol derivative or a salt thereof having a therapeutic and preventive action such as.

[0002]

2. Description of the Related Art Conventional methods for forming a complex or inclusion complex of a poorly water-soluble drug with cyclodextrin include a method of cooling a saturated aqueous solution of the drug and cyclodextrin to precipitate the complex, and a method of precipitating the drug and cyclodextrin. Freeze-drying an aqueous solution of dextrin [M. Kurozumi]
Et al., Chemical and Pharmaceutical Bulletin, 23, 1421.
(1975)], mixed pulverization method [Y. Nakai et al., Chemical and Pharmaceutical Buretin (Ch
emical and Pharmaceutical Bulletin), 26, 2419 (19
78)] and so on. However, the solubility of the complex of a poorly water-soluble drug and cyclodextrin obtained by these methods is not so high, and the solubility is insufficient for application to an injection. In some cases, the stability of the drug may deteriorate. Further, JP-A-63-135402 discloses at least one compound group selected from the group consisting of maltosyl-β-cyclodextrin and digitonin, nifedipine, flurbiprofen, isorbide nitrate, phenytoin, progesterone and testosterone. However, there is no description of the fumagillol derivative.

[0003]

[Problems to be Solved by the Invention] Development of a complex applicable to an injectable preparation and its industrial application by further increasing the solubility and stability of the fumagillol derivative which is a poorly water-soluble drug Development of a manufacturing method is desired.

[0004]

In view of such circumstances, the present inventors have conducted diligent research to increase the solubility of the fumagillol derivative, which is poorly water-soluble, in water. As a result, the easily water-soluble cyclodextrin derivative is obtained. Solubility of fumagillol derivative is remarkably improved by suspending fumagillol derivative in an aqueous solution containing more than about 100 mg / ml, stirring and dissolving it, and filtering at the end of the progress of dissolution to remove fumagillol derivative that has not been dissolved. It is possible to obtain a liquid complex prepared by the above, and by drying this liquid,
It was discovered that it is possible to obtain a powdery complex in which the solubility of the fumagillol derivative in water is significantly improved,
As a result of further intensive research, the present invention has been completed.

1) That is, the present invention has the general formula

[Chemical 5] [Wherein R ¹ is hydrogen, R ² is halogen, N (O) mR
⁵ R ⁶ , N ⁺ R ⁵ R ⁶ R ⁷ · X ⁻ or S (O) nR ⁵ (wherein
R ⁵ , R ⁶ and R ⁷ are each a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, X ⁻ is a counter anion, and m is 0 or 1
And n is an integer of 0 to 2. R ⁵ and R ⁶ may form a nitrogen-containing or sulfur-containing heterocyclic ring which may be condensed with an adjacent nitrogen atom or sulfur atom,
These optionally condensed nitrogen-containing or sulfur-containing heterocyclic rings may have a substituent. ) Or R ¹
And R ² together represent a bond, R ³ represents a 2-methyl-1-propenyl group or an isobutyl group, A is an oxygen atom or NR ⁸ (wherein R ⁸ has hydrogen or a substituent). Represents a lower alkyl group which may be substituted or an aryl group which may be substituted), and R ⁴ is hydrogen, an optionally substituted hydrocarbon group or a substituted group. Represents an optionally substituted acyl group. ] The fumagillol derivative or a salt thereof represented by the following and an easily water-soluble cyclodextrin derivative, and an aqueous solution in which the concentration of the easily water-soluble cyclodextrin derivative is about 100 mg / ml or more, A method for producing a complex of the salt and a cyclodextrin derivative which is easily water-soluble,

2) A production method according to 1, wherein R ¹ and R ² are confused to show a bond, 3) A production method according to 1, wherein R ³ is a 2-methyl-1-propenyl group, 4) A is oxygen. 5. The production method according to 1, which is an atom, 5) The production method according to 1, wherein R ⁴ is a carbamoyl group having a substituent, 6) The fumagillol derivative is 6-O- (N-chloroacetylcarbamoyl) fumagillol Production method, 7) The production method according to 1, wherein the fumagillol derivative is 6-O- (N-methylcarbamoyl) fumagillol, 8) The general formula for the easily water-soluble cyclodextrin derivative

[Chemical 6] [Wherein q is an integer from 6 to 12, and R ⁹ , R ¹⁰ and R ¹¹ are the same or different in each repeating unit,
Each of which represents a dihydroalkyl group or a sugar residue],

9) The production method according to 8, wherein at least one of R ⁹ , R ¹⁰ and R ¹¹ is a sugar residue, 10) The sugar residue is a glucosyl group, a maltosyl group, a maltotriosyl group or a dimaltosyl group. The production method according to 8 selected from the above, 11) the production method according to 1, wherein the easily water-soluble cyclodextrin derivative is glucosyl-β-cyclodextrin, 12) the easily water-soluble cyclodextrin derivative is maltosyl-β-cyclodextrin 13) The method according to 1, wherein the molar ratio of the easily water-soluble cyclodextrin derivative to the fumagillol derivative or a salt thereof is about 1.5 to 3: 1.
Manufacturing method described in 1, 14) general formula

[Chemical 7] [Wherein R ¹ is hydrogen, R ² is halogen, N (O) mR
⁵ R ⁶ , N ⁺ R ⁵ R ⁶ R ⁷ · X ⁻ or S (O) nR ⁵ (wherein
R ⁵ , R ⁶ and R ⁷ are each a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, X ⁻ is a counter anion, and m is 0 or 1
And n is an integer of 0 to 2. R ⁵ and R ⁶ may form a nitrogen-containing or sulfur-containing heterocyclic ring which may be condensed with an adjacent nitrogen atom or sulfur atom,
These optionally condensed nitrogen-containing or sulfur-containing heterocyclic rings may have a substituent. ) Or R ¹
And R ² together represent a bond, R ³ represents a 2-methyl-1-propenyl group or an isobutyl group, A is an oxygen atom or NR ⁸ (wherein R ⁸ has hydrogen or a substituent). Represents a lower alkyl group which may be substituted or an aryl group which may be substituted), and R ⁴ is hydrogen, an optionally substituted hydrocarbon group or a substituted group. Represents an optionally substituted acyl group. ] An aqueous solution containing a fumagillol derivative or a salt thereof represented by the following formula and a water-soluble cyclodextrin derivative, wherein the concentration of the water-soluble cyclodextrin derivative is about 100 mg / ml or more, and removing water. A complex of the fumagillol derivative or a salt thereof and an easily water-soluble cyclodextrin derivative,

15) A complex according to 14, wherein R ¹ and R ² are joined together to form a bond, 16) R ³ is a 2-methyl-1-propenyl group 14
17) The complex described in 17) A is an oxygen atom, and 18) The complex described in 14) R ⁴ is a carbamoyl group having a substituent.
21. The complex according to 14, wherein the fumagillol derivative is 6-O- (N-chloroacetylcarbamoyl) fumagillol, 20) The complex according to 14, 20) the fumagillol derivative is 6-O- (N-methylcarbamoyl) fumagillol 21) The easily water-soluble cyclodextrin derivative has the general formula

[Chemical 8] [Wherein q is an integer from 6 to 12, and R ⁹ , R ¹⁰ and R ¹¹ are the same or different in each repeating unit,
Each represents a dihydroalkyl group or a sugar residue. ] The complex of 14 represented by the following,

22) The complex according to 21, wherein at least one of R ⁹ , R ¹⁰ and R ¹¹ is a sugar residue, 23) The sugar residue is a glucosyl group, a maltosyl group, a maltotriosyl group or a dimaltosyl group. 21. The complex as described in 21, wherein 24) the easily water-soluble cyclodextrin derivative is glucosyl-β-cyclodextrin, 25) the easily water-soluble cyclodextrin derivative is maltosyl-β-cyclodextrin 14. The complex according to 14,
And 26) the molar ratio of the easily water-soluble cyclodextrin derivative to the fumagillol derivative or its salt is about 1.5 to 3: 1.
14. The complex according to 14 above. In the general formula (I), the halogen represented by R ² is
Examples thereof include fluorine, chlorine, bromine and iodine. When R ¹ and R ² are joined together to form a bond, an epoxy ring is formed.

The hydrocarbon group of the hydrocarbon group represented by R ⁵ , R ⁶ or R ⁷ which may have a substituent is a linear or branched alkyl group having 1 to 6 carbon atoms ( Examples, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl, etc.), C2-C6 alkenyl groups (eg, vinyl, allyl, 2-butenyl, methylallyl, 3-butenyl). , 2-pentenyl, 4-pentenyl, 5-hexenyl, etc.), an alkynyl group having 2 to 6 carbon atoms (eg, ethynyl,
Propargyl, 2-butyn-1-yl, 3-butyn-2
-Yl, 1-pentyn-3-yl, 3-pentyn-1-
Yl, 4-pentyn-2-yl, 3-hexyn-1-yl, etc.), a cycloalkyl group having 3 to 6 carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), cyclo having 3 to 6 carbon atoms Alkenyl group (eg, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, etc.), C7-13
Aralkyl groups (eg, benzyl, 1-phenethyl, 2-
Phenethyl etc.), an aryl group having 6 to 10 carbon atoms (eg,
Phenyl, naphthyl, etc.). The heterocyclic group of the optionally substituted heterocyclic group represented by R ⁵ , R ⁶ or R ⁷ includes 5 or 1 containing 1 to 4 hetero atoms (eg, nitrogen, oxygen, sulfur, etc.) 6-membered heterocyclic group (eg, 2-
Furyl, 2-thienyl, 4-thiazolyl, 4-imidazolyl, 4-pyridyl, 1,3,4-thiadiazole-2-
And 1-methyl-5-tetrazolyl), and the heterocyclic group is condensed with a 5- or 6-membered ring (eg, benzene, pyridine, cyclohexane ring) to form a bicyclic condensed ring group (eg, 8-quinolyl, 8-purinyl, etc.) may be formed.

The nitrogen-containing heterocyclic ring which R ⁵ and R ⁶ may form together with the adjacent nitrogen atom is a 4- to 7-membered nitrogen-containing heterocyclic ring (eg, pyrrolidin-1-yl, piperidino). ,
Morpholino, 4-methylpiperazin-1-yl and the like). The sulfur-containing heterocyclic ring which may be formed by R ⁵ and R ⁶ together with the adjacent sulfur atom is a 4- to 7-membered sulfur-containing heterocyclic ring (eg, tetrahydrothiophen-1-yl,
1,4-thioxan-1-yl and the like). R ⁵
And R ⁶ have 5 or 6 nitrogen-containing or sulfur-containing heterocyclic ring which may be formed together with the adjacent nitrogen atom or sulfur atom.
A bicyclic fused ring group (eg, isoindoline-2-yl, 2-isoquinolyl, 1,3-dihydro) which is condensed (condensed) with a member ring (eg, benzene, pyridine, pyrazine, pyridazine, cyclohexane ring, etc.) Benzo [c] thiophene-2-
Yl, 2,3-dihydrobenzo [b] thiophen-1-yl, 3,4-dihydro-1H-2-benzopyran-2-
Ile, 3,4-dihydro-2H-1-benzopyran-1
-Yl, 1,2,4,5-tetrahydro-3-benzothiepin-3-yl, 1,3-dihydrothieno [3,4-c]
Pyridin-2-yl, 5,7-dihydrothieno [3,4-
b] Pyrazin-6-yl, 5,7-dihydrothieno [3,
4-d] pyridazin-6-yl and the like) may be formed.

The lower alkyl group of the optionally substituted lower alkyl group represented by R ⁸ has 1 to 1 carbon atoms.
6 alkyl groups (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl, etc.). R ⁸
Examples of the aryl group of the aryl group which may have a substituent include a C 6-10 aryl group (eg, phenyl, naphthyl, etc.). The hydrocarbon group which may have a substituent represented by R ⁴ is the hydrocarbon group which may have a substituent which is represented by R ⁵ , R ⁶ and R ⁷ described above. Etc. In addition,
When the hydrocarbon group represented by R ⁴ is an alkenyl group, it is preferably unsubstituted. The acyl group which may have a substituent represented by R ⁴ includes an acid residue (acyl sulfonate, acyl sulfonate, carbamoyl, thiocarbamoyl, sulfamoyl, etc., which may have a substituent) Acid-derived acyl group), and examples thereof include alkanoyl, aroyl, heterocyclic carbonyl, carbamoyl, thiocarbamoyl, arylsulfonyl, alkylsulfonyl, sulfamoyl, alkoxycarbonyl and aryloxy, each of which may have a substituent. Carbonyl etc. are mentioned.

Examples of the alkanoyl group which may have a substituent include an alkanoyl group having 1 to 6 carbon atoms (eg, formyl, acetyl, propionyl, isopropionyl, butyryl, pentanoyl, hexanoyl, etc.). Can be mentioned. Examples of the aroyl group which may have a substituent include an aroyl group having 7 to 11 carbon atoms (eg, benzoyl, 1-naphthoyl, 2-naphthoyl, etc.). The heterocyclic carbonyl group in the heterocyclic carbonyl group which may have a substituent has 1 to 10 heteroatoms (eg, nitrogen, oxygen, sulfur, etc.)
Examples include 4- or 5-membered 6-membered heterocyclic carbonyl groups (eg, 2-furoyl, 2-thenoyl, nicotinyl, isonicotinyl, etc.). Examples of the arylsulfonyl group of the arylsulfonyl group which may have a substituent include an arylsulfonyl group having 6 to 10 carbon atoms (eg, benzenesulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.). Examples of the alkylsulfonyl group of the alkylsulfonyl group which may have a substituent include an alkylsulfonyl group having 1 to 6 carbon atoms (eg, methylsulfonyl, ethylsulfonyl, etc.). Examples of the alkoxycarbonyl group which may have a substituent include an alkoxycarbonyl group having 2 to 7 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, etc.). As the aryloxycarbonyl group of the aryloxycarbonyl group which may have a substituent, an aryloxycarbonyl group having 7 to 11 carbon atoms (eg, phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl, etc.) Is mentioned.

An optionally substituted hydrocarbon group or heterocyclic group represented by R ⁵ , R ⁶ or R ⁷ , R
⁵ and R ^{6 each} have an optionally condensed condensed nitrogen-containing or sulfur-containing heterocyclic group which may be formed together with the adjacent nitrogen atom or sulfur atom, and each of which has a substituent represented by R ^8. A lower alkyl group or aryl group which may be substituted, and a hydrocarbon group which may have a substituent represented by R ⁴ or an acyl group which may have a substituent (eg, an alkanoyl group, an aroyl group, a hetero group) Ring carbonyl group, carbamoyl group, thiocarbamoyl group, arylsulfonyl group,
(Alkylsulfonyl group, sulfamoyl group, alkoxycarbonyl group, aryloxycarbonyl group, etc.)
May have 1 to 3 substituents at possible positions.

Examples of the substituent include a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl, etc.), a C _2-6 alkenyl group ( For example, vinyl, allyl, 2-butenyl, methylallyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 5-hexenyl, etc., C _2-6 alkynyl group (eg, ethynyl, propargyl, 2-butyn-1-). Yl, 3-butyn-2-yl, 1-pentyl-3-yl, 3-pentyl-1-yl, 4-pentyl-2-yl, 3-hexyn-1-yl, etc.), C _3-6 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C _3-6 cycloalkenyl group (e.g., cyclobutenyl, cyclopentenyl, cyclohexadienyl Alkenyl, such cyclohexadienyl), C _6-10 aryl group (e.g., phenyl,
Naphthyl etc.), amino, C _1-6 alkylamino group (eg methylamino, ethylamino, isopropylamino etc.), di C _1-6 alkylamino group (eg dimethylamino, diethylamino etc.), azide, nitro, Halogen (eg, fluorine, chlorine, bromine, iodine, etc.), hydroxyl, C _1-4 alkoxy group (eg, methoxy, ethoxy, etc.), C _6-10 aryloxy group (eg, phenoxy, naphthyloxy, etc.), C _1-6 alkylthio group (eg, methylthio, ethylthio, propylthio, etc.), C _6-10 arylthio group (eg, phenylthio, naphthylthio, etc.), cyano, carbamoyl group, carboxyl group, C
_1-4 alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, etc.), C _7-11 aryloxycarbonyl group (eg, phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl, etc.), carboxy-C _{1 -4} alkoxy group (eg, carboxymethoxy, 2-carboxyethoxy, etc.), C _1-6 alkanoyl group (eg, formyl, acetyl, propionyl, isopropionyl, butyryl, pentanoyl, hexanoyl, etc.), C _7-11 aroyl group (Eg benzoyl,
1-naphthoyl, 2-naphthoyl, etc.), C _6-10 arylsulfonyl group (eg, benzenesulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.), C _1-6
Alkylsulfinyl group (eg, methylsulfinyl,
Ethylsulfinyl, etc.), C _6-10 arylsulfinyl group (eg, benzenesulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl, etc.), C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, etc.), hetero atom (Eg, nitrogen, oxygen, sulfur, etc.) 5- or 6-membered heterocyclic group containing 1 to 4 (eg, 2-furyl, 2-thienyl, 4-thiazolyl, 4-imidazolyl, 4-pyridyl, 1,3, 4-thiadiazol-2-yl, 1-methyl-5-tetrazolyl, etc.), a 5- or 6-membered heterocyclic carbonyl group containing 1 to 4 heteroatoms (eg, nitrogen, oxygen, sulfur, etc.) (eg, 2-furoyl) , 2-thenoyl, nicotinyl, isonicotinyl, etc.) and a 5- or 6-membered heterocyclic thio group containing 1 to 4 heteroatoms (eg, nitrogen, oxygen, sulfur, etc.) (eg, 4-pyridylthio, 2-pyrimidylthio, 1,3,4-thiadiazol-2-ylthio,
1-methyl-5-tetrazolylthio, etc.), and the heterocyclic thio group is condensed with a benzene ring to form a bicyclic condensed ring thio group (eg, 2-benzothiazolylthio, 8-quinolylthio, etc.). You may have. When R ⁴ represents a di-substituted carbamoyl group, thiocarbamoyl group, or sulfamoyl group, respectively, a nitrogen-containing heterocyclic ring (eg, pyrrolidine-1-) together with the nitrogen atom of the carbamoyl group, thiocarbamoyl group, or sulfamoyl group. Yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-phenylpiperazin-1-yl, etc.) may be formed.

Further, a substituent in a hydrocarbon group or a heterocyclic group represented by R ⁵ , R ⁶ or R ⁷ , which may have a substituent, a nitrogen atom or a sulfur atom in which R ⁵ and R ⁶ are adjacent to each other. A substituent in a nitrogen-containing or sulfur-containing heterocyclic group which may be condensed with an atom and which may be condensed, R ⁸
And a substituent in a lower alkyl group or an aryl group, which may have a substituent, and a hydrocarbon group or an acyl group, which may have a substituent, represented by R ⁴ (eg, an alkanoyl group , An aroyl group, a heterocyclic carbonyl group, a carbamoyl group, a thiocarbamoyl group, an arylsulfonyl group, an alkylsulfonyl group, a sulfamoyl group, an alkoxycarbonyl group, an aryloxycarbonyl group or the like) is further substituted at the substitutable position with 1 It may have up to 3 substituents.

As the substituent, there are C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group and C as described above.
_3-6 cycloalkyl group, C _3-6 cycloalkenyl group, C
_6-10 aryl group, amino group, C _1-6 alkylamino group,
Di C _1-6 alkylamino group, azido group, nitro group, halogen, hydroxyl group, C _1-4 alkoxy group, C _6-10 aryloxy group, C _1-6 alkylthio group, C _6-10 arylthio group, cyano Group, carbamoyl group, carboxyl group, C _1-4 alkoxycarbonyl group, C _7-11 aryloxycarbonyl group, carboxy C _1-4 alkoxy group, C
_1-6 alkanoyl group, C _7-11 aroyl group, C _6-10 arylsulfonyl group, C _1-6 alkylsulfinyl group, C
_{A 6-10} arylsulfinyl group, a C _1-6 alkylsulfonyl group, a 5- or 6-membered heterocyclic group, a 5- or 6-membered heterocyclic carbonyl group, a 5- or 6-membered heterocyclic thio group and the like are used.

[0018] by X ^- as the counter anion represented, for example, halogen ions (e.g., iodide ion, bromine ion, chloride ion), sulfur ion, phosphate ion, nitrate ion, perchlorate ion, tetrafluoroborate ion, Methane sulfate ion, p-tolyl sulfate ion, benzene sulfate ion, hydroxide ion, carboxylate ion of organic acid (eg, oxalate ion, maleate ion, fumarate ion,
Succinate ion, citrate ion, lactate ion, trifluoroacetate ion, lactobionate ion, acetate ion, propionate ion,
(Tartrate ion, ethyl succinate ion, etc.)
And so on. In the compound (I), R ¹ and R ²
A meeting or a bond combine, R ² R ¹ is hydrogen is ^{N (O) mR 5 R 6} , N + R 5 R 6 R 7 · X - is preferably a and S (O) nR ⁵ . Further, a compound in which R ¹ and R ² are combined to form a bond is particularly preferable. A is preferably an oxygen atom or NH. Further, A is particularly preferably an oxygen atom. R ³ is preferably 2-methyl-1-propenyl. R ⁴
Is preferably a carbamoyl group having a substituent. The substituent of the carbamoyl group having a substituent is particularly preferably a C _1-6 alkanoyl group or a C _1-6 alkyl group which may be substituted with halogen.

Specific preferred examples of the compound (I) include:
For example, 6-O- (N-chloroacetylcarbamoyl) fumagillol, 6-O- (N-methylcarbamoyl) fumagillol, 6α- (N'-chloroacetylureido)-
6-desoxyfumagillol, 4- (N-chloroacetylcarbamoyloxy) -2- (1,2-epoxy-1,5
-Methyl-4-hexenyl) -1- (1,3-dihydrobenzo (C) thiophen-2-ylio) methyl-3-methoxycyclohexanol chloride and the like. Among these, 6-O- (N-chloroacetylcarbamoyl) fumagillol and 6-O- (N-methylcarbamoyl) fumagillol are particularly preferable. The compound (I) has an asymmetric center in the molecule and has optical activity, but its absolute structure is based on the raw material fumagillol, and in the case of being explicitly indicated, it means that which matches the absolute structure of fumagillol. The bonding mode of the substituents on the cyclohexane ring is

[Chemical 9] Represents the case.

Compound (I) has an acidic substituent (eg,
When it has a carboxyl group) or a basic substituent (eg, amino, lower alkylamino, dilower alkylamino, nitrogen-containing heterocyclic group, etc.), it can be used as a physiologically acceptable salt. Examples of physiologically acceptable salts include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Inorganic bases that can form these salts include alkali metals (eg, sodium, potassium, etc.), alkaline earth metals (eg, calcium, magnesium, etc.), and organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline,
N, N-dibenzylethylenediamine, ethanolamine, diethanolamine, trishydroxymethylaminomethane, dicyclohexylamine and the like, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, and organic acids such as Formic acid, acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc., are basic or acidic amino acids such as arginine, lysine, ornithine, asparagine. acid,
Glutamic acid or the like is used. Of these salts, salts with bases (that is, salts with inorganic bases, salts with organic bases, salts with basic amino acids) are salts with the carboxyl group in the substituent of compound (I) and also with acids ( That is, a salt with an inorganic acid,
(Salt with organic acid, salt with acidic amino acid) means a salt capable of forming with an amino group, a lower alkylamino group, a di-lower alkylamino group, a nitrogen-containing heterocyclic ring group, etc. in the substituent of compound (I). To do.

When compound (I) has a di-lower alkylamino group, a nitrogen-containing heterocyclic group or a nitrogen-containing aromatic heterocyclic group in the molecule, the nitrogen atom in these substituents is further alkyl. To form a quaternary ammonio group (eg, trimethylammonio, N-methylpyridinyl, N-methylpyrrolidin-1-ylium, etc.), and the counter anion is the counter anion represented by X ^−. Similar counter anions can be mentioned. The compound represented by the general formula (I) or a salt thereof is
Fumagillol, a hydrolysis product of fumagillin produced by microorganisms
Tarbell, DS et al., Journal of American Chemical Society (J. Am. Chem. Soc.)
83 , 3096 (1961)] as a starting material, and its production method, physicochemical and biological properties are described in EP-A-359,036, EP-A-3.
57,061, EP-A-354,787, EP-A-
386, 667, EP-A-415, 294 and the like.

The easily water-soluble cyclodextrin derivative used in the present invention is preferably a cyclic oligosaccharide consisting of 6 to 12 glucose units, which has hydrogen atoms at some or all of the hydroxyl groups at the 2, 3 and 6 positions of glucose. Is a compound substituted with a functional group (for example, a dihydroxyalkyl group, a sugar residue, a hydroxyalkyl group, etc.). The easily water-soluble cyclodextrin derivative (hereinafter sometimes abbreviated as CyD) has a solubility in water of about 100 mg / ml or more, preferably about 130 mg / ml or more.

Preferred specific examples of the easily water-soluble cyclodextrin derivative include those represented by the general formula:

[Chemical 10] [In the formula, q is an integer satisfying 6 to 12, and R ⁹ , R ¹⁰ and R ¹¹ are the same or different in each repeating unit and each represents a dihydroxyalkyl group or a sugar residue. ] The compound represented by these is mentioned. Specific examples thereof include α-CyD (q = 6) and β-CyD (q
= 7), γ-CyD (q = 8), δ-CyD (q = 9), and other ether derivatives of hydroxyl groups. Of these, ether derivatives of β-CyD hydroxyl groups are preferred.

The dihydroxyalkyl group represented by R ^{9 to} R ¹¹ is, for example, a dihydroxy-C _1-6 alkyl group (eg, dihydroxymethyl, 2,2-dihydroxyethyl, 2,2-dihydroxypropyl, 2,2- Dihydroxypentyl, 2,2-dihydroxyhexyl, etc.), preferably dihydroxy-C _1-4 alkyl group (eg, dihydroxymethyl, 2,2-dihydroxyethyl, 2,2-
Dihydroxypropyl etc.) is used. Examples of the sugar residue represented by R ^{9 to} R ¹¹ include C _3-24 sugar residue (erythrosyl, threosyl, arabinosyl, ribosyl, glucosyl, galactosyl, glycero-gluco-heptosyl,
Maltosyl, lactosyl, maltotriosyl, dimaltosyl, etc.), preferably a C _6-24 sugar residue (eg, glucosyl,
Galactosyl, glycero-gluco-heptosyl, maltosyl, lactosyl, maltotriosyl, dimaltosyl, etc.), particularly preferably a C _6-12 sugar residue (eg, glucosyl,
Galactosyl, glycero-gluco-heptosyl, maltosyl, lactosyl, etc.) are used.

More desirable specific examples of the easily water-soluble cyclodextrin derivative include compounds represented by the general formula (II) in which at least one of R ^{9 to} R ¹¹ is a sugar residue. As examples thereof, for example, glucosyl-α, β, γ, δ-CyD, maltosyl-α,
β, γ, δ-CyD, maltotriosyl-α, β, γ,
δ-CyD, dimaltosyl-α, β, γ, δ-CyD and the like can be mentioned. Among these, maltosyl-α, β,
γ, δ-CyD, glucosyl-α, β, γ, δ-CyD
Is preferred. Furthermore, maltosyl-β-CyD and glucosyl-β-CyD are particularly preferable. These easily water-soluble cyclodextrin derivatives may be used alone or in combination of two or more. The amount of the easily water-soluble cyclodextrin derivative used is preferably about 1 to 5 times the molar amount of the fumagillol derivative or a salt thereof. About 1.5
˜3 times moles are more preferably used.

As the form of the complex of the present invention, generally, the drug is more stable in the solid state, and it is preferable that the coexisting water is distilled off to obtain a powder. Examples of the method for distilling off include freeze-drying or vacuum drying, and sometimes vaporization under normal pressure. To stabilize the drug, freeze-drying in which freeze-drying is performed and then freeze-drying under reduced pressure are suitable. The method for producing the composite of the present invention is performed, for example, as follows. That is, the easily water-soluble cyclodextrin derivative and the fumagillol derivative (I) or a salt thereof are usually made into an aqueous solution with water or a buffer solution at around -5 ° C to 35 ° C. The aqueous solution is, for example, a water or buffer solution of an easily water-soluble cyclodextrin derivative and a fumagillol derivative (I) or a salt thereof is mixed, and a water or buffer solution of an easily water-soluble cyclodextrin derivative and a fumagillol derivative (I) or A water-soluble cyclodextrin derivative and a fumagillol derivative (I) or a salt thereof and water or a buffer solution are mixed, or a water-soluble cyclodextrin derivative and a fumagillol derivative are mixed. It is obtained by mixing (I) or a salt thereof with water or a buffer suspension. At this time, an aqueous solution may be prepared by cooling or heating if necessary. The concentration of the easily water-soluble cyclodextrin derivative is usually preferably about 100 mg / ml or more, more preferably about 130 mg / ml or more. As described above, the fumagillol derivative (I) or its salt is about 1 to 5 when the water-soluble cyclodextrin derivative is a drug.
It is preferable to add them so that the molar ratio is double. About 1.5
A 3-fold molar amount is more preferable. The easily water-soluble cyclodextrin derivative and the fumagillol derivative (I) or a salt thereof are mixed and then the suspension is stirred to gradually dissolve the fumagillol derivative (I) or a salt thereof. Usually, the stirring is stopped for 1 minute or more, and the stirring is stopped when the progress of the dissolution is completed. When the solution remains undissolved, it is filtered to obtain a complex containing the fumagillol derivative (I) or its salt having improved solubility. To obtain a powder of the complex, the obtained solution is freeze-dried, dried under reduced pressure, or dried under normal pressure.

After mixing the easily water-soluble cyclodextrin derivative and the fumagillol derivative (I) or a salt thereof, a base may be added to the resulting suspension or solution for stabilization if desired. Examples of the base include alkali metal hydroxides (eg, potassium hydroxide, sodium hydroxide, etc.), alkali metal hydrogen carbonates (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal carbonates (eg, sodium carbonate, Potassium carbonate), alkali metal phosphates (eg, sodium phosphate, sodium monohydrogen phosphate, potassium phosphate, potassium monohydrogen phosphate, etc.), such as organic monocarboxylic acid alkali metal salts (eg, acetic acid) Organic bases such as sodium and potassium acetate).
The addition amount of these bases is preferably about 0.0002 to 0.2 mol based on the fumagillol derivative (I) or a salt thereof. Furthermore, about 0.001 to 0.035 mol is particularly preferable. The base may be added as it is or as an aqueous solution having an appropriate concentration. The powder obtained according to these operations forms an inclusion body or a complex by electrostatic or hydrophobic interaction or hydrogen bond. In addition to the inclusion complex or complex, the powder is fumagillol derivative (I).
Alternatively, it may contain a salt thereof and / or an easily water-soluble cyclodextrin derivative, and such powder is also the complex of the present invention.

The complex of the present invention can be used as a preparation for parenteral administration. The complex of the present invention is formulated, for example, by the following method. The powder of the present invention obtained by the above, powder characteristics (fillability in vials, specific volume, antistatic etc.) sugars that are usually used in injections to improve (eg, glucose, mannitol, inositol, etc.),
Preservatives (eg, methylparaben, propylparaben, benzil alcohol, chlorobutanol, etc.), tonicity agents (eg, sodium chloride, glycerin, sorbitol, glucose, etc.), antistatic agents (eg, magnesium stearate, etc.) You may add. The powder obtained by this operation, according to a method known per se, for example, distilled water for injection,
Sodium chloride, sugars (eg glucose, mannitol, inositol, etc.) or dispersants (eg Tween)
en) 80 (manufactured by Atlas Powder), HCO60 (manufactured by Nikko Chemicals) polyethylene glycol, carboxymethylcellulose, sodium alginate, etc.) and the like, and easily dissolved in an aqueous solution. After dissolution, a sparingly water-soluble drug may be administered at an effective concentration for the target disease as an injectable preparation intravenously, intramuscularly, subcutaneously, in an organ (eg, hepatic artery), or in a lesion such as a tumor. it can.

Further, the conjugate obtained by the present invention is a preparation for parenteral administration other than injection administration according to a conventional method, for example,
It is also possible to use external preparations (eg, nasal preparations, transdermal preparations) and suppositories (eg, rectal suppositories, vaginal suppositories, etc.). For example, to prepare an external preparation, the complex of the present invention can be made into a solid, semi-solid or liquid nasal administration agent according to a method known per se. For example, as the above solid, the complex of the present invention may be used as it is, or an excipient (eg, glycol, mannitol, starch, microcrystalline cellulose, etc.), a thickener (eg, natural gums, cellulose derivative, Acrylic acid polymer, etc.) is added and mixed to obtain a powdery composition. The above-mentioned liquid form is almost the same as the case of the injection, and is an oily or aqueous suspension. In the case of semi-solid form, an aqueous or oily gel or ointment form is preferable. In addition, all of these are pH adjusters (eg, carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, paraoxybenzoic acid esters, chlorobutanol, benzalkonium chloride, etc.), etc. May be added. For example, in the case of a suppository, the complex of the present invention can be made into an oily or aqueous solid, semisolid or liquid suppository according to a method known per se.
Examples of the oily base used in the composition include glycerides of higher fatty acids [eg, cacao butter, witepsols (manufactured by Dynamite Nobel), etc.], intermediate fatty acids [eg, migliols (manufactured by Dynamite Nobel), etc.], or Vegetable oil (eg, sesame oil, soybean oil, cottonseed oil, etc.) and the like can be mentioned. Examples of the aqueous base include polyethylene glycols and propylene glycol, and examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers and acrylic acid polymers.

The complex of the present invention has low toxicity and angiogenesis inhibitory effect, and has a strong pharmacological action, for example, inflammatory diseases such as rheumatoid arthritis, diabetic retinopathy or tumors (eg, breast cancer, liver cancer, colon cancer, It has therapeutic and preventive effects on cancers such as Kaposi's sarcoma), and inflammatory diseases such as rheumatoid arthritis, diabetic retinopathy or tumors (eg, breast cancer, liver cancer) in mammals (monkey, cow, dog, human etc.) ，
It is useful as a therapeutic and prophylactic drug for colorectal cancer, cancer of Kaposi's sarcoma, etc.). For example, when the complex of the present invention is administered by injection for the purpose of treating an adult cancer-bearing patient, the dose varies depending on the type of drug, the strength of activity, etc. About 1.0 mg of complex
˜5.0 g, preferably about 25 mg to 2.0 g, particularly preferably about 50 mg to 1.0 g are administered.

[0031]

EXAMPLES The present invention will be described in more detail below with reference to Examples, Comparative Examples and Experimental Examples, but this does not limit the present invention. Comparative Example 1 Maltosyl-β-cyclodextrin (hereinafter referred to as G2βCy
(Also abbreviated as D) (5 mg of an aqueous solution containing 1000 mg) was added to 6-O- (N-chloroacetylcarbamoyl)
Fumagillol (hereinafter abbreviated as TNP-470) (25
0 mg) was added, and the mixture was stirred at 25 ° C. for 8 hours and dissolved. Undissolved TNP-470 was removed by filtration, the filtrate was filled in a vial, and freeze-dried to obtain a powder. When water (5 ml) was added to the whole amount of the obtained powder, a uniform aqueous solution was obtained. On the other hand, as a conventional method, G2βCyD (110 mg) was dissolved in 5 ml of water, and TNP-470 (250 mg) was added to the solution.
Stir at 5 ° C. After 8 hours, filtration was performed, and TNP-470 in the homogeneous solution and the solution after filtration was quantified by the high performance liquid chromatography (HPLC) method under the following measurement conditions. Furthermore, the saturation solubility of TNP-470 alone was similarly quantified by the HPLC method. As a result, the results shown in [Table 1] were obtained. Although the solubility was hardly improved by the conventional method, the solubility of the composite obtained by the method of the present invention was dramatically improved. High-performance liquid chromatography (HPLC) measurement conditions Carrier: ODS, YMC-Pack A-312 (manufactured by Yamamura Chemical Laboratory Co., Ltd.) Mobile phase: Water-acetonitrile = 1: 1 (volume ratio) Flow rate: 1.0 ml / min Detection method: UV absorption, wavelength 210nm

[Table 1] Solubility comparison Present invention 36.7 mg / ml Conventional method 6.7 TNP-470 only 1.9

Comparative Example 2 Glucosyl-β-cyclodextrin (hereinafter referred to as G1βCy
(Sometimes abbreviated as D) (500 mg) in an aqueous solution (5 ml) containing TNP-470 (250 mg).
It stirred at 8 degreeC for 8 hours, and melt | dissolved. The obtained aqueous solution was filtered and freeze-dried to give a powder. Water (5
ml) was added to form a uniform aqueous solution. On the other hand, as a conventional method, G1βCyD (100 mg) was dissolved in water (5 ml), and TNP-470 (250 mg) was added to the homogeneous solution and TNP-470 in the solution after filtration by the same HPLC method as in Comparative Example 1. Was quantified. Further, the saturation solubility of TNP-470 alone was similarly quantified by the HPLC method. As a result, the results shown in [Table 2] were obtained. Although the solubility was hardly improved by the conventional method, the solubility of the composite obtained by the method of the present invention was dramatically improved.

[Table 2] Solubility comparison Present invention 23.1 mg / ml Conventional method 6.5 TNP-470 only 1.9

Example 1 TNP-470 (100 mg) was added to an aqueous solution (5 ml) containing maltosyl-β-cyclodextrin (1000 mg), and the mixture was stirred at 25 ° C. for 30 minutes and dissolved. The aqueous solution was filtered, 5 ml of the filtrate was filled in a vial and freeze-dried to give a powder. Example 2 TNP-470 (100 mg) was added to an aqueous solution (5 ml) containing maltosyl-β-cyclodextrin (750 mg), and the mixture was stirred at 25 ° C. for 30 minutes and dissolved. The aqueous solution was filtered and the filtrate (5 ml) was filled in a vial and freeze-dried to give a powder. Example 3 100 mg of TNP-470 was added to an aqueous solution (5 ml) containing maltosyl-β-cyclodextrin (500 mg), and the mixture was stirred at 25 ° C. for 30 minutes to be dissolved. The aqueous solution was filtered and the filtrate (5 ml) was filled in a vial and freeze-dried to give a powder. Example 4 TNP-470 (100 mg) was added to the aqueous solution (5 ml) containing glucosyl- (beta) -cyclodextrin (750 mg), and it stirred for 30 minutes at 25 degreeC, and melt | dissolved. The aqueous solution was filtered and the filtrate (5 ml) was filled in a vial and freeze-dried to give a powder. Example 5 TNP-470 (100 mg) was added to an aqueous solution (5 ml) containing glucosyl-β-cyclodextrin (500 mg), and the mixture was stirred at 25 ° C for 30 minutes and dissolved. The aqueous solution was filtered and the filtrate (5 ml) was filled in a vial and freeze-dried to give a powder.

Example 6 TNP-470 (100 mg) was added to an aqueous solution (5 ml) containing maltosyl-β-cyclodextrin (726 mg), and the mixture was stirred at 25 ° C. for 180 minutes and dissolved. The aqueous solution was filtered and the filtrate (5 ml) was filled in a vial and freeze-dried to give a powder. The stability of this powder and TNP-470 alone was compared by storing at 40 ° C for 1 month. TNP-
The quantification of 470 was performed by the HPLC method in the same manner as in Comparative Example 1. The results are shown in [Table 3]. The powder of the present invention was extremely stable.

[Table 3] Stability

Example 7 Maltosyl-β was added to water (4950 ml) in a 10 L beaker.
-After dissolving cyclodextrin (719 g), TN
P-470 (99 g) was added, and the mixture was stirred at 25 ° C. for 3 times.
Stir for hours. After confirming that almost all of TNP-470 was dissolved, the solution was filtered through a filter having a pore size of 0.22 μm, 5 ml each of the obtained drug solution was filled in a vial, and freeze-dried to produce an injection. Example 8 Maltosyl-β-cyclodextrin (72.3 g) was dissolved in water (400 ml) in a 10-liter beaker, TNP-470 (10 g) was added, and the mixture was stirred using a stirrer 25
The mixture was stirred at ℃ for 1.5 hours. A 0.1 N NaOH aqueous solution (0.9 ml) was added thereto, and the mixture was further stirred at 25 ° C. for 1.5 hours. After confirming that TNP-470 was dissolved, the total amount was adjusted to 500 ml with water, filtered through a filter having a pore size of 0.22 μm, and the filtrate was freeze-dried to prepare an injection.
The stability of this injection was examined by storing it at 40 ° C. for 1 month. The quantification of TNP-470 was performed by the HPLC method in the same manner as in Comparative Example 1. The survival rate of TNP-470 is 97.
%, And the injection of the present invention was extremely stable.

Example 9 A preparation containing TNP-470 (30 mg) was obtained in the same manner as in Example 8 except that the amount of the 0.1N NaOH aqueous solution added was 5.4 ml. Example 10 In Example 8, 0.1NK was used instead of 0.1N NaOH aqueous solution.
In addition to adding OH aqueous solution (0.6 ml), TN
A formulation containing P-470 (30 mg) was obtained.

[0037]

INDUSTRIAL APPLICABILITY The production method of the present invention can be industrially carried out, and the complex obtained by the production method of the present invention is easily soluble in water, has good stability, and is used as an injectable preparation. .

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location A61K 31/40 ABL 7431-4C 47/40 B 7433-4C G 7433-4C C07D 303/22

Claims (26)

[Claims] 1. A general formula: [Wherein R ¹ is hydrogen, R ² is halogen, N (O) mR
⁵ R ⁶ , N ⁺ R ⁵ R ⁶ R ⁷ · X ⁻ or S (O) nR ⁵ (wherein
R ⁵ , R ⁶ and R ⁷ are each a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, X ⁻ is a counter anion, and m is 0 or 1
And n is an integer of 0 to 2. R ⁵ and R ⁶ may form a nitrogen-containing or sulfur-containing heterocyclic ring which may be condensed with an adjacent nitrogen atom or sulfur atom,
These optionally condensed nitrogen-containing or sulfur-containing heterocyclic rings may have a substituent. ) Or R ¹
And R ² together represent a bond, R ³ represents a 2-methyl-1-propenyl group or an isobutyl group, A is an oxygen atom or NR ⁸ (wherein R ⁸ has hydrogen or a substituent). Represents a lower alkyl group which may be substituted or an aryl group which may be substituted), and R ⁴ is hydrogen, an optionally substituted hydrocarbon group or a substituted group. Represents an optionally substituted acyl group. ] The fumagillol derivative or a salt thereof represented by the following and an easily water-soluble cyclodextrin derivative, and an aqueous solution in which the concentration of the easily water-soluble cyclodextrin derivative is about 100 mg / ml or more, A method for producing a complex of the salt and a readily water-soluble cyclodextrin derivative. 2. The method according to claim 1, wherein R ¹ and R ² are joined together to form a bond. 3. The method according to claim 1, wherein R ³ is a 2-methyl-1-propenyl group. 4. The method according to claim 1, wherein A is an oxygen atom. 5. The method according to claim 1, wherein R ⁴ is a carbamoyl group having a substituent. 6. The fumagillol derivative is 6-O- (N-chloroacetylcarbamoyl) fumagillol.
The manufacturing method described. 7. The method according to claim 1, wherein the fumagillol derivative is 6-O- (N-methylcarbamoyl) fumagillol. 8. A water-soluble cyclodextrin derivative represented by the general formula: [Wherein q is an integer from 6 to 12, and R ⁹ , R ¹⁰ and R ¹¹ are the same or different in each repeating unit,
Each represents a dihydroalkyl group or a sugar residue. ] The manufacturing method of Claim 1 represented by these. 9. The method according to claim 8, wherein at least one of R ⁹ , R ¹⁰ and R ¹¹ is a sugar residue. 10. The method according to claim 8, wherein the sugar residue is selected from a glucosyl group, a maltosyl group, a maltotriosyl group and a dimaltosyl group. 11. An easily water-soluble cyclodextrin derivative,
The production method according to claim 1, which is glucosyl-β-cyclodextrin. 12. A water-soluble cyclodextrin derivative,
The method according to claim 1, which is maltosyl-β-cyclodextrin. 13. The molar ratio of the easily water-soluble cyclodextrin derivative to the fumagillol derivative or a salt thereof is about 1.5.
The method according to claim 1, wherein the ratio is ˜3: 1. 14. A general formula: [Wherein R ¹ is hydrogen, R ² is halogen, N (O) mR
⁵ R ⁶ , N ⁺ R ⁵ R ⁶ R ⁷ · X ⁻ or S (O) nR ⁵ (wherein
R ⁵ , R ⁶ and R ⁷ are each a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, X ⁻ is a counter anion, and m is 0 or 1
And n is an integer of 0 to 2. R ⁵ and R ⁶ may form a nitrogen-containing or sulfur-containing heterocyclic ring which may be condensed with an adjacent nitrogen atom or sulfur atom,
These optionally condensed nitrogen-containing or sulfur-containing heterocyclic rings may have a substituent. ) Or R ¹
And R ² together represent a bond, R ³ represents a 2-methyl-1-propenyl group or an isobutyl group, A is an oxygen atom or NR ⁸ (wherein R ⁸ has hydrogen or a substituent). Represents a lower alkyl group which may be substituted or an aryl group which may be substituted), and R ⁴ is hydrogen, an optionally substituted hydrocarbon group or a substituted group. Represents an optionally substituted acyl group. ] An aqueous solution containing a fumagillol derivative or a salt thereof represented by the following formula and a water-soluble cyclodextrin derivative, wherein the concentration of the water-soluble cyclodextrin derivative is about 100 mg / ml or more, and removing water. A complex of the fumagillol derivative or a salt thereof and a readily water-soluble cyclodextrin derivative. 15. The composite according to claim 14, wherein R ¹ and R ² are joined together to form a bond. 16. The complex according to claim 14, wherein R ³ is a 2-methyl-1-propenyl group. 17. The composite according to claim 14, wherein A is an oxygen atom. 18. The composite according to claim 14, wherein R ⁴ is a carbamoyl group having a substituent. 19. The complex according to claim 14, wherein the fumagillol derivative is 6-O- (N-chloroacetylcarbamoyl) fumagillol. 20. The complex according to claim 14, wherein the fumagillol derivative is 6-O- (N-methylcarbamoyl) fumagillol. 21. A water-soluble cyclodextrin derivative is represented by the general formula: [Wherein q is an integer from 6 to 12, and R ⁹ , R ¹⁰ and R ¹¹ are the same or different in each repeating unit,
Each represents a dihydroalkyl group or a sugar residue. ] The composite_body | complex of Claim 14 represented by these. 22. The complex according to claim 21, wherein at least one of R ⁹ , R ¹⁰ and R ¹¹ is a sugar residue. 23. The complex according to claim 21, wherein the sugar residue is selected from a glucosyl group, a maltosyl group, a maltotriosyl group and a dimaltosyl group. 24. A water-soluble cyclodextrin derivative,
15. Glucosyl-β-cyclodextrin.
The described complex. 25. An easily water-soluble cyclodextrin derivative,
15. Maltosyl-β-cyclodextrin.
The described complex. 26. The molar ratio of the easily water-soluble cyclodextrin derivative to the fumagillol derivative or a salt thereof is about 1.5.
15. The complex of claim 14, which is ~ 3: 1.