JPH06256331A - Neovascularization inhibitor - Google Patents

Abstract

PURPOSE:To obtain a new O-substituted fumagillin derivative having neovascularization inhibiting action and useful as an antirheumatic agent, treating agent for psoriasis, treating agent for diabetic retinopathy and carcinostatic agent. CONSTITUTION:The compound of the formula [R<1> is (substituted)2-methyl-1- propenyl or isobutyl; R<2> is substituted alkanoyl, (2-6C alkyl, NH2, halogen, OH, lower alkoxy, CN, carbamoyl or carboxyl)substituted aroyl or aromatic heterocyclic carbonyl, alkyl, benzenesulfonyl, alkylsulfonyl, sulfamoyl, alkoxycarbonyl or phenoxycarbonyl any of which may be substituted] or its pharmacologically permissible salt, e.g. 0-(3-carboxypropionyl)fumagillol. A compound of the formula wherein R<1> is 2-methyl-1-propenyl can be produced by the acylation, carbamoylation, alkylation or sulfonylation of fumagillol which is a hydrolytic product of fumagillin produced by microorganism.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel O having an angiogenesis-inhibiting effect and a therapeutic and preventive effect against various inflammatory diseases (rheumatism, psoriasis, etc.), diabetic retinopathy or cancer.
A substituted fumagillol derivative or a salt thereof.

[0002]

BACKGROUND OF THE INVENTION Angiogenesis is deeply involved in the onset or progression of various diseases such as various inflammatory diseases (rheumatism, psoriasis, etc.), diabetic retinopathy and cancer. Therefore, it is considered that suppression of angiogenesis will lead to the treatment and prevention of these diseases, and several research groups have searched for angiogenesis inhibitors so far. For example, the application of protamine by Taylor et al. [Taylor, S. et al. et al. , Nature, 297 , 307 (1982)], and Volkman et al.'S combined use of heparin and cortisone [Folkma.
n, J. et al., Science, 221 , 719
(1983)] and the like, and ascorbic acid ethers and related compounds (Japanese Patent Application Laid-open No. Sho 5 (1993) -58).
8-131978) and the sulfated polysaccharide DS4152 (Japanese Patent Laid-Open No. 63-119500) have been applied for patents as compounds exhibiting angiogenesis inhibitory action. However, their activities are not always sufficiently satisfactory, and the emergence of compounds having even more excellent activity is desired.

[0003]

The object of the present invention is to provide a novel compound having an angiogenesis inhibitory action.

[0004]

[Means for Solving the Problems] In order to achieve the above object, the present inventors have searched and evaluated various compounds, and as a result, fumagillin, which has been conventionally known as an antibacterial agent and an antiprotozoal agent, is used. The hydrolyzate of fumagillol (fum
The present invention has been completed by finding that the O-substituted derivative of agillol) has an excellent angiogenesis inhibitory action. That is, the present invention has the general formula

[0005]

[Chemical 2]

[In the formula, R ¹ represents an optionally substituted 2-methyl-1-propenyl or isobutyl group, R ²
Is (1) an alkanoyl group having a substituent, (2) a carbon number of 2 to 6
Of alkyl, amino, halogen, hydroxyl, lower alkoxy, cyano, carbamoyl or carboxyl substituted aroyl group, (3) optionally substituted aromatic heterocyclic carbonyl group, (4) having a substituent Alkyl group which may have, (5) a benzenesulfonyl group which may have a substituent, (6) an alkylsulfonyl group which may have a substituent, (7) which has a substituent Is a sulfamoyl group, a (8) alkoxycarbonyl group optionally having a substituent or a (9) phenoxycarbonyl group optionally having a substituent. ] The present invention relates to a pharmacological composition for suppressing angiogenesis in an animal, which comprises an O-substituted fumagillol derivative represented by the following formula or a pharmacologically acceptable salt thereof.

In the above general formula, the substituent in 2-methyl-1-propenyl or isobutyl group which may have a substituent represented by R ¹ is hydroxyl, amino or lower alkylamino (eg methylamino). , Ethylamino, isopropylamine etc.), di-lower alkylamino (eg dimethylamino, diethylamino etc.) or 5
To 6-membered nitrogen-containing heterocyclic ring (eg, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, etc.) Among them, hydroxyl or di-lower alkylamino is preferable. The number of substituents is preferably 1 to 3. In the above general formula, examples of the alkanoyl group having a substituent represented by R ² include amino, lower alkylamino (eg, methylamino, ethylamino, isopropylamino, etc.), di-lower alkylamino (eg, dimethylamino, diethylamino). Etc.), nitro, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), hydroxyl, lower alkoxy (eg, methoxy, ethoxy, etc.), cyano, carbamoyl, carboxyl,
Lower alkoxycarbonyl (e.g., methoxycarbonyl,
Ethoxycarbonyl, etc.), carboxy lower alkoxy
(Eg, carboxymethoxy, 2-carboxyethoxy, etc.), optionally substituted phenyl, aromatic heterocyclic group (preferably 1 hetero atom such as nitrogen, oxygen, sulfur, etc.)
A 5- to 6-membered aromatic heterocyclic group containing 4 to 4, for example, 2-furyl,
2-thienyl, 4-thiazolyl, 4-imidazolyl, 4
-Pyridyl etc.) and the like, preferably 1 to 3 substituted alkanoyl groups (preferably 1 to 20 carbon atoms, examples of the unsubstituted alkanoyl group include formyl, acetyl,
Propionyl, isopropionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, lauroyl, undecanoyl, myristoyl, palmitoyl, stearoyl, araquinoyl and the like). Of these, 3-carboxypropionyl and 4-carboxybutyryl are preferable.

The aroyl group having a substituent represented by R ² includes, for example, ethyl, propyl and the like having 2 to 2 carbon atoms.
6 lower alkyl, amino, halogen (eg, fluorine, chlorine, bromine, etc.), hydroxyl, lower alkoxy (eg, methoxy, ethoxy, etc.), benzoyl preferably substituted by 1 to 3 cyano, carbamoyl, carboxyl, etc., Examples thereof include 1-naphthoyl and 2-naphthoyl. Of these, 2-carboxybenzoyl is preferable.

As the substituent of the optionally substituted aromatic heterocyclic carbonyl group represented by R ² , the same substituents as those of the aroyl group having the above-mentioned substituent can be used. The aromatic heterocyclic carbonyl group is nitrogen,
5 to 6 containing 1 to 4 heteroatoms such as oxygen and sulfur
A membered ring is used, and among them, 2-furoyl, 2-thenoyl, nicotinoyl, isonicotinoyl, imidazol-1-carbonyl and the like are preferable. The optionally substituted carbamoyl group represented by R ² includes a carbamoyl group, a mono-substituted carbamoyl group and a di-substituted carbamoyl group, and examples of the substituent include lower alkyl.
(Eg, methyl, ethyl, propyl, butyl, etc.), lower alkanoyl (preferably having 1 to 6 carbon atoms, eg, acetyl,
Propionyl, acryloyl, methacroyl, etc.),
Nitrogen of chloroacetyl, dichloroacetyl, trichloroacetyl, lower alkoxycarbonylmethyl (eg, methoxycarbonylmethyl, ethoxycarbonylmethyl, etc.), carboxymethyl, amino, optionally substituted phenyl, naphthyl, benzoyl and carbamoyl groups. Cyclic amino group with atoms (e.g., pyrrolidin-1-yl, piperidin-1-yl, morpholino, piperazino, 4-methylpiperazin-1-yl, 4-ethylpiperazin-1-yl, 4-phenylpiperazin-1-yl , Imidazol-1-yl) and the like. Further, as a substituent of the carbamoyl group, a lower alkyl halide (eg, 2-chloroethyl,
2-bromoethyl, 3-chloropropyl etc.), di-lower alkylamino lower alkyl (eg, 2-dimethylaminoethyl, 2-diethylaminoethyl, 3-dimethylaminopropyl etc.), lower alkanoyloxy lower alkanoyl (eg, acetoxyacetyl, Propionyloxyacetyl etc.), lower alkanoylthio lower alkanoyl (eg, acetylthioacetyl, propionylthioacetyl etc.), lower alkylthio lower alkanoyl (eg, methylthioacetyl, ethylthiopropionyl etc.), arylthio lower alkanoyl (eg, phenylthioacetyl, Naphthylthioacetyl, etc.), aromatic heterocyclic thio lower alkanoyl (eg, 4-pyridylthio, 2-pyridylthio, 2-benzothiazolylthio, 2-benzoxazolylthio, 2-benzimidazoli) Thio, 8 Kinoriruchio, [1- (2-dimethylaminoethyl) tetrazole]
-5-ylthio, 2-methyl-1,3,4-thiadial-5-ylthio, 1-methyl-2-methoxycarbonyl-1,3,4-triazol-5-ylthio, etc.),
N-oxy-2-pyridylthio lower alkanoyl (eg,
N-oxy-2-pyridylthioacetyl, etc.), N-lower alkyl-4-pyridiniothio lower alkanoyl halide (eg, N-methyl-4-pyridinioacetyl iodide, etc.), di-lower alkylamino lower alkanoyl
(E.g., dimethylaminoacetyl, diethylaminoacetyl, etc.), ammonio lower alkanoyl halide (e.g.,
Trimethylammonioacetyl iodide, N-methylpyrrolidinioacetyl chloride, etc.), aromatic heterocyclic carbonyl (eg, 3-furoyl, nicotinyl, 2-thenoyl, etc.), lower alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl) ), Phenoxycarbonyl, chloroacetylcarbamoyl, benzoylcarbamoyl, optionally substituted phenylsulfonyl (eg, benzenesulfonyl, toluenesulfonyl, etc.), di-lower alkylsulfonio-lower alkanoyl halide (eg, dimethylsulfonio). Acetyl iodide, etc.), etc. Of these, chloroacetyl, phenyl, benzoyl and the like are preferable.

The alkyl group which may have a substituent represented by R ² may be substituted by 1 to 3 substituents similar to the substituents in the above-mentioned alkanoyl group having a substituent. Examples thereof include a linear or branched alkyl group having 1 to 20 carbon atoms, and the alkyl group may be epoxidized at any position. Of these, methyl, ethyl, benzyl and the like are preferable. Examples of the substituent of the optionally substituted benzenesulfonyl group represented by R ² include lower alkyl (eg, methyl, ethyl, etc.),
Halogen (eg, fluorine, chlorine, bromine, etc.) and the like, these substituents are 1 to any position on the benzene ring.
Three may be substituted. Examples of the alkylsulfonyl group which may have a substituent represented by R ² include, for example, the number of carbon atoms which may have 1 to 3 substituents similar to the substituents of the alkanoyl having a substituent described above. 1 to
And the lower alkylsulfonyl group of 6 and the like. Of these, methylsulfonyl and ethylsulfonyl are preferable.
Examples of the substituent of the optionally substituted sulfamoyl group represented by R ² include lower alkyl (eg, methyl, ethyl, propyl, isopropyl, isobutyl, etc.), and optionally substituted phenyl. Etc., and these substituents may be one, or may be the same or different and two. The alkoxycarbonyl group which may have a substituent represented by R ² is, for example, a linear or branched lower group which may be substituted by 1 to 3 substituents similar to the above-mentioned substituents. An alkoxycarbonyl group can be mentioned. Of these, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, 1-chloroethoxycarbonyl and the like are preferable. Examples of the substituent of the phenoxycarbonyl group which may have a substituent represented by R ² include those similar to the above-mentioned substituents of the benzenesulfonyl group which may have a substituent. 1 to 3 substituents may be substituted on any position of the phenoxy group.

In the present specification, examples of the substituent of the phenyl group which may have a substituent include lower alkyl (eg, methyl, ethyl, propyl, butyl, etc.), lower alkoxy (eg, methoxy, ethoxy, Propoxy, etc.), halogen (eg, fluorine, chlorine, bromine, etc.), alkyl halide (eg, trifluoromethyl, chloromethyl, bromomethyl, etc.), nitro, etc., and these substituents can be any group on the phenyl ring. 1 to 5 may be substituted at the position. In the present specification, unless otherwise specified, the lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, and the lower alkoxy group means 1 to 6 carbon atoms. It means 6 alkoxy groups. When the compound (I) of the present invention has an acidic substituent (eg, carboxyl etc.) or a basic substituent (eg, amino, lower alkylamino, dilower alkylamino etc.) in the molecule, it is pharmacologically It can also be used as an acceptable salt. As the pharmacologically acceptable salt, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like are used. Inorganic bases that can form these salts include alkali metals (eg, sodium, potassium, etc.), alkaline earth metals (eg, calcium, magnesium, etc.), and organic bases such as 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, phosphoric acid and the like, 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 and the like are used, and examples of the basic or acidic amino acid include arginine, lysine, ornithine, aspartic acid and glutamic acid. Of these salts, salts with bases (that is, salts with inorganic bases, salts with organic bases, salts with basic amino acids) are salts with carboxyl groups in the substituents of compound (I) and also with acids.
(That is, a salt with an inorganic acid, a salt with an organic acid, a salt with an acidic amino acid) is a salt that can be formed with an amino group, a lower alkylamino group, a di-lower alkylamino group or the like in the substituent of compound (I). means.

In the general formula (I), R ¹ is 2-methyl-
An O-substituted fumagillol derivative represented by a 1-propenyl group is a fumagillin produced by a microorganism.
Hydrolyzed product of fumagillol (Tarbel
l, DS et al., Journal of American Chemical Society (J. Am. Chem. Soc.) 83 , 309
6 (1961)] with an acylating agent, a carbamoylating agent, an alkylating agent, or a sulfonylating agent, for example, by subjecting it to an acylating, carbamoylating, alkylating or sulfonylating reaction, or It can be prepared by isolating the intermediate of those reactions. In the general formula (I), the O-substituted dihydrofumagillol derivative in which R ¹ represents an isobutyl group is subjected to catalytic reduction of fumagillol under normal conditions (for example, using 5% palladium carbon in a methanol solution. See Reference Example 1). 4 ', 5'-dihydrofumagillol (II) obtained by the above) can be produced by subjecting it to the same reaction as above.

[0013]

[Chemical 3]

When R ² is a group which is not changed by catalytic reduction, R ¹ is catalytically reduced to an O-substituted fumagillol derivative represented by a 2-methyl-1-propenyl group, whereby R ¹ is an isobutyl group. It can also be converted into an O-substituted dihydrofumagillol derivative represented by.

(Production Method) In the general formula (I), the O-substituted fumagillol derivative represented by 2-methyl-1-propenyl or isobutyl group in which R ¹ is substituted with hydroxyl is protected at the 6-position hydroxyl. Optionally, fumagillol is subjected to an oxidation reaction to introduce a hydroxyl group, and then, if necessary, the protecting group at the 6-position hydroxyl group is deprotected, and then subjected to an acylation, carbamoylation, alkylation, or sulfonylation reaction. Or by isolating intermediates in those reactions. In carrying out the above-mentioned acylation, carbamoylation, alkylation or sulfonylation reaction, the hydroxyl introduced into R ¹ may be protected if necessary so that the reaction can proceed advantageously. . When R ² is a group which does not change by the oxidation reaction, the O-substituted fumagillol derivative represented by the general formula (I) in which R ¹ is a 2-methyl-1-propenyl or isobutyl group is directly subjected to the oxidation reaction. It can also be produced by introducing hydroxyl. In the general formula (I), R ¹ is O, lower alkylamino, dilower alkylamino or O represented by 2-methyl-1-propenyl or isobutyl group substituted with a 5- to 6-membered nitrogen-containing heterocyclic ring. -Substituted fumagillol derivative is a 2-methyl group of 4-position side chain due to the above-mentioned oxidation reaction.
After the fumagillol derivative in which the 6-position hydroxyl in which 1-propenyl or isobutyl group has a hydroxyl group introduced therein may be protected, is subjected to an amination reaction, and then the 6-hydroxyl protecting group is optionally deprotected, It can be prepared by subjecting to acylation, carbamoylation, alkylation, or sulfonylation reaction, or by isolating the intermediate of those reactions. When performing the above acylation, carbamoylation, alkylation, or sulfonylation reaction, the amino, lower alkylamino, and nitrogen-containing heterocyclic ring introduced into R ¹ are protected, if necessary. And the reaction can proceed advantageously.

When R ² is a group which is not changed by the amination reaction, O 1 represented by 2-methyl-1-propenyl or isobutyl group in which R ¹ is substituted with hydroxyl in the general formula (I) is used. It can also be produced by subjecting a substituted fumagillol derivative directly to an amination reaction. An O-substituted fumagillol derivative represented by the general formula (I) in which R ¹ is hydroxyl, amino, lower alkylamino, dilower alkylamino or an isobutyl group substituted with a 5- to 6-membered nitrogen-containing heterocyclic ring is A hydroxyl group, amino, lower alkylamino, dilower alkylamino or 5 to 6 is added to the 2-methyl-1-propenyl group of the 4-position side chain.
Membered nitrogen-containing heterocyclic ring-introduced 6-hydroxyl-protected fumagillol derivative is subjected to catalytic reduction reaction, and if necessary, the 6-hydroxyl protecting group is deprotected, followed by acylation. , Carbamoylation, alkylation,
Alternatively, it can be produced by subjecting to a sulfonylation reaction, or by isolating an intermediate of the reaction. When carrying out the acylation, carbamoylation, alkylation or sulfonylation reaction, it is necessary to protect the hydroxyl, amino, lower alkylamino and nitrogen-containing heterocyclic ring in R ^{1 as} necessary. It can be advantageously advanced. When R ² is a group which does not change by the catalytic reduction reaction, R ¹ in the general formula (I) is 3
It can also be produced by subjecting an O-substituted fumagillol derivative represented by -hydroxy-2-methyl-1-propenyl group to a direct catalytic reduction reaction.

A method known per se is used for the protection and deprotection of the 6-position hydroxyl and the hydroxyl, amino, lower alkylamino and nitrogen-containing heterocyclic ring in R ¹ [Reference: Grren, TW, "Protective Group in Organic"].
Synthesis ", John Wiley & Sons, New York (1981)]. When an acylating agent, a carbamoylating agent, an alkylating agent, a sulfonylating agent and the like have substituents such as amino, hydroxyl and carboxyl, these substituents are It is preferably protected and a suitable protecting group is selected depending on the stability of the product, examples of preferred protecting groups in the case of amino are eg 4-nitrobenzyloxycarbonyl, 2-trimethylsilylethoxy. Examples thereof include carbonyl, examples of hydroxyl include 4-nitrobenzyl, t-butyldimethylsilyl, etc., and examples of carboxyl include 4-nitrobenzyl, etc. The deprotection method includes catalytic reduction. Alternatively, a usual method of reacting with a fluoride ion can be adopted. In the case of the alkylation reaction, a methyl group as a protecting group of the carboxyl group, using a lower alkyl group such as ethyl group, it can be deprotected by hydrolysis under mild alkaline conditions after the reaction.

1) Acylation Reaction The acylation reaction is carried out by activating fumagillol or dihydrofumagillol (hereinafter abbreviated as raw material alcohol) such as acid anhydride and acid halide (eg, acid chloride, acid bromide, etc.). It is carried out by reacting the reactive derivative of the carboxylic acid. That is, it is usually carried out by the reaction represented by the following formula. Reactive derivative of R ³ OH + source alcohol → Compound (I) [R ² ═R ³ ] (In the formula, R ³ is an alkanoyl group having a (1) substituent as defined for R ² , and (2) has 2 carbon atoms. ~ 6 alkyl, amino, halogen, hydroxyl, lower alkoxy, cyano, carbamoyl or carboxyl substituted aroyl group, and
(3) represents an aromatic heterocyclic carbonyl group which may have a substituent. ) The reactive derivative of the carboxylic acid is usually about 1 mol to 10 times mol amount, preferably 1 to 5 mol, per mol of the raw material alcohol.
Double molar amount is used. This reaction is usually performed in the presence of a base. Examples of the base include tertiary amines such as diisopropylethylamine, triethylamine, pyridine, N, N-dimethylaminopyridine, sodium hydrogencarbonate,
Alkali metal hydrogen carbonate such as potassium hydrogen carbonate, alkali metal carbonate such as potassium carbonate and sodium carbonate,
Alkali metal hydrides such as sodium hydride and potassium hydride, organometals such as butyllithium and lithium diisopropylamide are used, and the addition amount thereof is usually about 1 to 10 times per mole of the raw material alcohol. It is a molar amount. This reaction is usually carried out in an organic solvent that does not adversely influence the reaction. Examples of the organic solvent that does not adversely influence the reaction include amides such as dimethylformamide and dimethylacetamide, dichloromethane, chloroform,
Halogenated hydrocarbons such as 1,2-dichloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane, esters such as methyl acetate, ethyl acetate, isobutyl acetate, methyl propionate, nitriles such as acetonitrile and propionitrile. , Nitro compounds such as nitromethane and nitroethane, ketones such as acetone and methyl ethyl ketone, aromatic hydrocarbons such as benzene and toluene, and these may be used alone or in admixture of two or more at an appropriate ratio. . Also,
The tertiary amine used as a base may be used as it is as a solvent. The reaction temperature varies depending on the amount and type of the carboxylic acid derivative, the base, the solvent, etc., but is −80 to 100 ° C.
Preferably from 0 ° C. to room temperature (where room temperature is about 20 to 3
It means about 5 ° C. Unless otherwise specified, the same shall apply hereinafter). The reaction time is about 30 minutes to 5 days.

2) Alkylation Reaction In the alkylation reaction, the starting alcohol is represented by the formula R ⁴ Y [wherein R ⁴ is (5) an alkyl group which may be substituted in the definition of R ² ; Represents a leaving group (eg, halogen (chlorine, bromine, iodine, etc.)). ] It is carried out by reacting an alkylating agent such as an alkyl halide or a dialkylsulfate (eg, dimethylsulfate, diethylsulfate, etc.) represented by The alkylating agent is usually used in an amount of about 1 to 5 times the molar amount of the starting alcohol. This reaction is
Usually, it is carried out in the presence of a base. As the base, the above-mentioned alkali metal hydrogencarbonates, alkali metal carbonates, alkali metal hydrides, organic metals and the like are used, and the addition amount thereof is usually about 1 to 5 mol per mol of the raw material alcohol. It is a double molar amount. This reaction is usually carried out in an organic solvent that does not adversely influence the reaction. As the organic solvent that does not adversely affect the reaction, the above-mentioned amides, halogenated hydrocarbons, ethers, esters, nitriles, nitro compounds, ketones, and aromatic hydrocarbons are used. You may use it in mixture by 1 or more types in an appropriate ratio. The reaction temperature varies depending on the amount and type of the alkylating agent, the base, the solvent, etc., but is −80 to 100 ° C., preferably 0 ° C. to room temperature. The reaction time is about 20 minutes to 5 days.

3) Carbamoylation Reaction The carbamoylation reaction for introducing the mono-substituted carbamoyl group is usually carried out by reacting the starting alcohol with an isocyanate. For example, it is produced by the reaction represented by the following formula. R ⁵ NCO + source alcohol → compound (I) [R ² ═R ⁵ NHCO] (In the formula, R ⁵ may have a substituent represented by R ² such as lower alkyl, lower alkanoyl, chloroacetyl and the like. It represents a substituent of carbamoyl.) Usually, the isocyanate is used in an amount of about 1 to 5 times the molar amount of the starting alcohol. This reaction is usually performed in the presence of a base. As the base, the above-mentioned tertiary amine, alkali metal hydrogen carbonate, alkali metal carbonate, alkali metal hydride, organic metal and the like are used, and the addition amount thereof is usually about 1 mol of the raw material alcohol. It is 1 to 5 times the molar amount. This reaction is usually carried out in an organic solvent that does not adversely influence the reaction. As the organic solvent that does not adversely affect the reaction, the above-mentioned amides, halogenated hydrocarbons, ethers, esters, nitriles, nitro compounds, ketones, and aromatic hydrocarbons are used. You may use it in mixture by 1 or more types in an appropriate ratio. Further, the tertiary amine used as the base may be directly used as the solvent. The reaction temperature will differ depending on the amount and type of isocyanate, base, solvent, but is usually about -80 to 100 ° C, preferably 0 ° C to room temperature. Reaction time is from 1 hour to 5
It's about a day. Among the compounds having a mono-substituted carbamoyl group thus obtained, for example, compounds having chloroacetylcarbamoyl, trichloroacetylcarbamoyl and the like can be prepared by a conventional method (for example, from room temperature to warming under basic conditions). It is also possible to convert the compound having a carbamoyl group by removing the group and the trichloroacetyl group. The carbamoylation reaction is also carried out by reacting the raw material alcohol with a carbamoyl halide. The carbamoyl halide is usually used in an amount of about 1 mol to 5 mol per mol of the raw material alcohol.
Use a double molar amount. This reaction is usually performed in the presence of a base. As the base, the above-mentioned tertiary amine, alkali metal hydrogencarbonate, alkali metal carbonate, alkali metal hydride, organic alkali metal and the like are used, and the addition amount thereof is usually 1 mol of the raw material alcohol. It is about 1 to 5 times the molar amount. This reaction is usually carried out in an organic solvent that does not adversely affect the reaction. Examples of the organic solvent that does not adversely affect the reaction include the above-mentioned amides, halogenated hydrocarbons,
Ethers, esters, nitriles, nitro compounds,
Ketones and aromatic hydrocarbons are used, and these may be used alone or in combination of two or more kinds at an appropriate ratio. Further, the tertiary amine used as the base may be directly used as the solvent. The reaction temperature varies depending on the amount and kind of the carbamoyl halide, the base and the solvent, but the reaction temperature is about 0 ° C. to about the reflux temperature of the reaction medium, preferably about 25 ° C. to the reflux temperature. The carbamoylation reaction is carried out by reacting the raw material alcohol with a chloroformate (eg, phenyl chloroformate, ethyl chloroformate, isobutyl chloroformate, 1-chloro-ethyl chloroformate, etc.) or 1,1-carbonyldiimidazole. It is also carried out by making an active ester and then reacting it with a primary or secondary amine. The chloroformic acid esters, 1,1-carbonyldiimidazole and amines are usually used in an amount of 1 to 5 times the molar amount of the starting alcohol.
In this reaction, the reaction between the starting alcohol and chloroformate is usually carried out in the presence of a base. As the base, the above-mentioned tertiary amine, alkali metal hydrogencarbonate, alkali metal carbonate, alkali metal hydride, organic alkali metal and the like are used, and the addition amount thereof is usually 1 mol of the raw material alcohol. It is about 1 to 5 times the molar amount.
This reaction is usually carried out in an organic solvent that does not adversely influence the reaction. As the organic solvent that does not adversely affect the reaction, the above-mentioned amides, halogenated hydrocarbons, ethers, esters, nitriles, nitro compounds, ketones, and aromatic hydrocarbons are used. You may use it in mixture by 1 or more types in an appropriate ratio. The reaction temperature will differ depending on the amounts and types of chloroformates, bases, amines, solvents, etc., but is -20 ° C to the reflux temperature of the reaction medium, preferably 0 ° C to 50 ° C. The active esters obtained as intermediates are also included in the target compound (I) of the present application. Of the compounds having a mono-substituted carbamoyl group, the compound having a lower alkanoylcarbamoyl group having a substituent can also be produced by reacting a compound having chloroacetylcarbamoyl with a nucleophile. As the nucleophile, a lower carboxylic acid,
Lower thiocarboxylic acids, thiols, amines and the like or metal salts thereof are used. This reaction is usually carried out in an organic solvent that does not adversely affect the reaction. Examples of the organic solvent that does not adversely influence the reaction include the above-mentioned saturated aliphatic hydrocarbons, alcohols, amides, halogenated hydrocarbons, ethers, esters, nitriles, nitro compounds, ketones and aromatics. Hydrocarbons are used, and these may be used alone or as a mixture of two or more kinds at an appropriate ratio.
In addition, this reaction is usually performed in the presence of a base. As the base, the above-mentioned tertiary amine, alkali metal hydrogen carbonate,
Alkali metal carbonates, alkali metal hydrides, organic alkali metals and the like are used, and the addition amount thereof is usually about 1 to 5 times the molar amount of the raw material. The reaction temperature is
The temperature is usually −80 to 100 ° C., preferably 0 ° C. to room temperature, though it varies depending on the amounts and types of nucleophiles, bases, solvents and the like. The reaction time is about 20 minutes to 5 days.

4) Sulfonylation Reaction The sulfonylation reaction is carried out by using a raw material alcohol, for example, an activated sulfonic acid derivative such as sulfonic acid anhydride, sulfonic acid halide (eg, sulfonyl chloride, sulfonyl bromide, etc.), or sulfamoyl halide.
(Eg, sulfamoyl chloride, sulfamoyl bromide, etc.) by reacting with an activated sulfamic acid derivative. That is, it is performed by reacting as in the following formula.

Reactive derivative of R ⁶ OH + source alcohol → compound (I) [R ² ═R ⁶ ] (wherein R ⁶ is (6) benzene which may have a substituent in the definition of R ² ) A sulfonyl group, (7) an alkylsulfonyl group which may have a substituent, or (8) a sulfamoyl group which may have a substituent.) The reactive derivative of the sulfonic acid is the starting alcohol 1 It is usually used in an amount of about 1 to 5 times the molar amount. This reaction is usually performed in the presence of a base. As the base, the above-mentioned tertiary amine, alkali metal hydrogen carbonate, alkali metal carbonate, alkali metal hydride, organic metal and the like are used, and the addition amount thereof is usually about 1 mol of the raw material alcohol. The amount is 1 to 10 times the molar amount. This reaction is usually carried out in an organic solvent that does not adversely influence the reaction. As the organic solvent that does not adversely affect the reaction, the above-mentioned amides, halogenated hydrocarbons, ethers, esters, nitriles, nitro compounds, ketones, and aromatic hydrocarbons are used. You may use it in mixture by 1 or more types in an appropriate ratio. Further, the tertiary amine used as the base may be directly used as the solvent. The reaction temperature varies depending on the amounts and types of the sulfonic acid or sulfamic acid derivative, the base and the solvent, but is -80 to 100 ° C, preferably 0 ° C to room temperature. The reaction time is about 10 minutes to 5 days.

5) Oxidation reaction In the oxidation reaction, fumagillol in which the 6-position hydroxyl may be protected or 2-methyl-1-propenyl in which R ¹ in the general formula (I) may have a substituent, or It is carried out by reacting an O-substituted fumagillol derivative represented by an isobutyl group with an oxidizing agent. Examples of the oxidizing agent include selenium dioxide, osmium tetroxide, hydrogen peroxide solution, organic peroxides (eg, t-butyl hydroperoxide, etc.), organic peracids (eg, phosphoric acid, peracetic acid, trifluoroperacetic acid, peroxides, etc.). Benzoic acid, metachloroperbenzoic acid, etc.) and the like, and two of them may be appropriately combined and used. The oxidizing agent is usually used in an amount of about 1 to 5 times the molar amount of the raw material. This reaction is usually performed in a solvent that does not adversely influence the reaction. Examples of the solvent that does not adversely affect the reaction include water, hexane, and saturated aliphatic hydrocarbons such as pentane, alcohols such as methanol and ethanol, the aforementioned halogenated hydrocarbons, ethers, and aromatic hydrocarbons. These may be used and one kind or two or more kinds may be mixed and used at an appropriate ratio. The reaction temperature will differ depending on factors such as the amount and type of oxidizing agent and solvent, but is usually −80 to 100 ° C., preferably 0 ° C. to room temperature. The reaction time is about 20 minutes to 5 days.

6) Amination reaction In the amination reaction, even if the 6-position hydroxyl in which hydroxyl is introduced into 2-methyl-1-propenyl or isobutyl group of the 4-position side chain obtained by the above-mentioned oxidation reaction is protected. Good fumagillol derivative or general formula (I)
2-methyl-1 in which R ¹ is substituted with hydroxyl at
-Propenyl or isobutyl group is performed on the hydroxyl of the O-substituted fumagillol derivative, for example, Mitsunobu reaction using imides such as phthalimide and succinimide [Reference: Mitunobu, O., Synthesis]
(Synthesis), 1981, p. 1], or a method of directly converting hydroxyl into amino, or converting the hydroxyl into methanesulfonyloxy or toluenesulfonyloxy, and then reacting with ammonia or amines to give amino, lower Examples thereof include a method of converting to alkylamino, di-lower alkylamino or a nitrogen-containing heterocyclic group. In the reaction of the sulfonyloxy derivative and ammonia or amines, ammonia water, ammonia gas, or liquid ammonia is used as the ammonia, and the amines are primary amines.
(Eg, methylamine, ethylamine, isopropylamine, etc.), secondary amine (eg, dimethylamine, diethylamine), or 5- to 6-membered nitrogen-containing heterocyclic ring (eg, pyrrolidine, piperidine, morpholine, piperazine, N-methyl) Piperazine, N-ethylpiperazine and the like) are used. In this reaction, ammonia or the amine is usually used in a molar amount of about 1 to 20 times, preferably 2 times.
It is carried out in a solvent which does not adversely affect the reaction by itself or in a molar amount of 10 to 10 times. As the solvent that does not adversely affect the reaction, for example, water, the above-mentioned aliphatic saturated hydrocarbons,
Alcohols, amides, halogenated hydrocarbons, ethers, esters, nitriles, nitro compounds, ketones, aromatic hydrocarbons are used, and these are mixed singly or in a suitable proportion. You may use. Further, this reaction may be carried out in the presence of a base such as alkali metal hydrogen carbonate or alkali metal carbonate. As the alkali metal hydrogen carbonate or the alkali metal carbonate, those used in the above-mentioned alkylation reaction are applied as they are. The reaction temperature varies depending on the amount and type of ammonia or amines, base, solvent, etc., but is usually -80 to 100
C, preferably 0 C to room temperature. The reaction time is 20
It takes about 5 days to 5 minutes.

The amino or lower alkylamino introduced by the above-mentioned method can be prepared by a method known per se [Reference:
Sutherland, IO, "Comprehensive Organic Chemis
try ", Volume 2, pages 4-11, Pergamon Press (197)
9)] is N-alkylated with 2-methyl-1 at the 4-position side chain.
A fumagillol derivative in which lower alkylamino or dilower alkylamino is introduced to a propenyl or isobutyl group and the 6-position hydroxyl may be protected, or R ^{1 in the} general formula (I) is lower alkylamino or dilower alkylamino 2-methyl-1-substituted
O-substituted fumagillol derivatives that are propenyl or isobutyl groups may be prepared. The O-substituted fumagillol derivative (I) thus produced can be isolated by separation and purification means known per se (eg, chromatography, crystallization method) and the like. 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 means that it matches the absolute structure of fumagillol.

[0026]

The compound of the present invention exhibits an anti-angiogenic effect and is useful as a therapeutic and prophylactic agent for various inflammatory diseases (rheumatism, psoriasis), diabetic retinopathy, cancer, etc. Safely orally or parenterally administered as a pharmaceutical composition [eg, tablets, capsules (including soft capsules, microcapsules), liquids, injections, suppositories] mixed with an acceptable carrier, excipient, etc. can do. Although the dose varies depending on the administration subject, administration route, symptoms, etc., for example, for adults, it is usually about 0.1 mg / kg to 40 mg / kg body weight per day, preferably about 0.5 mg / kg to 20 mg / kg body weight. Is.

Experimental Example 1 With respect to the target compound (I) obtained in the following examples, the angiogenesis-inhibiting action was measured by the rat corneal micropocket method and summarized in the table below. Measurement method Gimbrone et al. [J. National Cancer Institu
te 52: 413-419 (1974)]. Sprag
Ue-Dawley) adult male rats (11-16 weeks old) were anesthetized with Nembutal, and xylocaine ophthalmic solution was dripped on the eyeball for local anesthesia. In the cornea approximately 2 mm inside from the edge of the cornea,
Make an incision of about 2 mm with an injection needle, and use a sustained-release pellet of basic fibroblast growth factor (bFGF, bovine brain-derived purified product, R & D) and the sample so that the bFGF pellet is on the center side of the cornea. Insert two side by side. BF in control rat corneas
A GF pellet and a pellet containing no specimen were inserted.
After 7 days and 10 days, observe the cornea under a stereomicroscope,
When the administration of the sample delayed or weakened the angiogenesis induced by bFGF, it was judged to have suppressive activity. The sustained release pellet was prepared by the following method. Ethylene-vinyl acetate copolymer (Takeda Yakuhin) was dissolved in dichloromethane so as to be 8%, and 3 μl thereof was air-dried on a glass petri dish, bFGF aqueous solution (250 ng) was collected and air-dried, and 3 μl The ethylene-vinyl acetate copolymer solution was placed on the above and air-dried to prepare a bFGF sandwich sheet. This sandwich-like sheet was rolled into a bFGF pellet.
The pellet of the sample was prepared by dissolving the sample in ethanol so as to have a concentration of 20 μg / 2 μl, mixing it with 6 μl of the ethylene-vinyl acetoit copolymer solution, and air-drying on a glass petri dish, and rolling the resulting sheet.

Table 1 Examples of anti- angiogenic action Suppression rate Judgment 2 6/6 + 4 6/7 + 5 8/8 * + 6 6/7 + 8 6/6 * + 11 9/9 * + 14 4 / 8 ± 17 7/8 * + 18 7/7 + 20 3/4 + 21 4/4 + 22 5/8 ± 23 6/8 + 24 5/12 ± 25 6/8 + 26 6/6 + 27 3/7 ± 28 11/11 + 29 7/7 + 30 4/8 ± 31 5/6 + 32 9/12 + 33 4/6 ± 34 4/4 + 35 4/8 ± 37 11/11 + 38 13/15 + 39 8/8 + 40 6/6 + 41 2/4 ± 42 7/7 + 43 7/7 + 44 7/7 + 45 8/13 ± 46 7/10 + 49 4/5 + 51 7/14 ± 52 6/8 + 53 8/8 + 54 5/5 + 55 3/4 + 56 4/7 ± 57 6/6 + 58 6/6 + 60 4/6 ± 61 / 7 + 62 7/7 + 63 6/6 + 64 5/5 + 65 8/8 + 67 5/5 ± 69 6/6 + 70 5/5 + 75 8/8 + ※: determining after 7 days. Others are judged after 10 days. In the above table, the inhibition rate means the number of rats for which an angiogenesis-inhibiting effect on the number of test rats was found.

Experimental Example 2 Inhibition of human endothelial cell proliferation Human umbilical vein endothelial cells (HUVE) were isolated by perfusion of the umbilical vein with a solution containing trypsin. HUVE is 2.5%
GIT medium (Diago Nutritional Chemistry, Japan) containing fetal bovine serum and 2.0 ng / ml recombinant human basic fibroblast growth factor (rbFGF, Takeda, Institute of Biotechnology, Japan, Osaka) at 37 ° C, 5 Cultured under% CO ₂ and 7% O ₂ .
The HUVE, at a cell density of 2 × 10 ³ / medium 100 [mu] l, 96
Well Microtiter Plate (Nunc, 1-67
008). The next day, 100 μl of rbFGF (final concentration 2 ng / ml) -containing medium and various concentrations of each compound (I) (indicated by the example number) were added to each well. Compound (I) was dissolved in dimethyl sulfoxide (DMSO) and then diluted with medium so that the final DMSO concentration did not exceed 0.25%. After culturing for 5 days, the medium was removed and 1 mg / ml of MTT (3- (4,5-dimethyl-2
100 μl of -thiazolyl) -2,5-diphenyl-2H-tetrazolium bromide) solution was added to the wells, then the microtiter plate was kept at 37 ° C for 4 hours. Then 100 μl of 10% sodium dodecyl sulfate (SDS) solution was added to the wells and the microtiter plate was kept at 37 ° C. for 5-6 hours. To measure the effect on cell number, the absorbance of each well (590 μm) was measured using an absorptiometer. Absorbance of control well is 100%
The concentration showing 50% growth inhibitory activity (IC ₅₀ ) was calculated as

Experimental Example 3 Inhibition of tumor growth in vivo In this assay, male C57BL / 6N was used as the tumor.
Mouse reticulosarcoma (M5076) maintained by intraperitoneal transplantation into mice was used. The tumor cells in the ascites were collected by centrifugation, suspended in physiological saline, and the cell suspension (2
X 10 ⁶ cells / 100 μl / mouse) was inoculated into the right flank of the mouse. Tumor-bearing mice were treated subcutaneously with Compound (I) (indicated by the example number) suspended in 5% gum arabic solution containing 1% ethanol for 12 days starting 1 day after tumor inoculation ( 10 injections). Tumor growth was quantified by measuring the size of the tumor in two directions with calipers at intervals of several days. The tumor volume one day after the final injection was 3rd
It was as shown in the table. The tumor volume was calculated by the following formula. Tumor volume (mm ³ ) = length × (width) ² +2 T / C (%) = (tumor volume of treated mouse / tumor volume of control mouse) × 100

In the following Experimental Examples 4 to 6, the later-described Example 8 was used.
The fumagillol derivative compound described in Section 1 above was further evaluated for angiogenesis inhibitory activity. Experimental Example 4 Inhibition of capillary endothelial cell migration in vivo As described below, the method of Falk et al. [J.Immunol.Met
h.) 33 , 239-247 (1980)] was modified to perform Boyden container measurement. That is, bovine capillary endothelial cells in serum-free DMEM (Dulbecco's modified Eagle medium) were added per well to 1.
5 × so that 10 ^4, fibronectin (7.3μg / m
It was dispensed on one side of a nucleopore filter pre-coated with 1 PBS). Dissolve AGM-1470 in ethanol and make sure that the final concentration of ethanol does not exceed 0.01%.
Diluted with MEM. Cells at 200 μg / ml were treated with endothelial mitogen [Biomedical Technologies, Massachusetts.
s)] and serum-free DM of various concentrations of AGM-1470
The EM solution was reacted at 37 ° C. for 4 hours. At the end of this culturing, the number of cells that had migrated through the 8 μm pores of the filter was counted by a 100 × eyepiece grid of 4 sheets. When AGM-1470 was administered at 100 μg / ml, cell migration could be completely suppressed in this measurement. Remarkable migration inhibition is observed even at a dose as low as 10 femtogram / ml. The 50% inhibition value of migration of endothelium-derived mitogen is about 100 pg / ml.

Experimental Example 5 Inhibition of angiogenesis in chicken embryo chorioallantoic membrane Method of Folkman et al. [R.Crum, S.Sazbo, J.Folkman ); Science 230 , 1
375 (1985)], the extra-shell eggs chicken chorioallantoic membrane (CAM) assay method was performed as follows. That is, 3-day-old chicken embryos were taken from their shells in Petri dishes [Falcon 1005] under a sterile hood, and further cultured for 3 days. AG
M-1470 was dissolved in a 0.45% aqueous solution of methylcellulose, and an aliquot of 10 μl was pipetted onto a Teflon rod. After the solution was dried, a methylcellulose disk (about 2 mm in diameter) containing the compound was added to a CAM of a 6-day-old embryo.
Transplanted on. It was confirmed by a stereoscope that an avascular zone was formed around the disc when cultured for 48 to 72 hours. The avascular zone is the region where the regression of the previously existing blood vessels has occurred. The percentage of avascular zone was calculated by counting the number of avascular zone forming discs per total test disc. 12 ~ in each group
16 embryos were used. As shown in Table 4, AGM-14
70 showed a strong angiogenesis inhibitory activity by CAM measurement.

Experimental Example 6 Inhibition of growth of in vivo formed tumor Folkman et al., Science (Scienc
e) B16 mouse melanoma described in 221 , 719-725 (1983) was used to further evaluate the angiogenesis inhibitory activity of AGM-1470. About 9 to 10 days after the inoculation, the tumor is about 70 to
When it reached 100 mm ³ , the treatment (Rx) was usually started. Tumor sizes were matched before inclusion in treated and untreated groups. AGM-1470 was dissolved in an isotonic solution by culturing with glass beads and vigorously stirring at 4 ° C. overnight, and 30 mg / kg thereof was subcutaneously administered every other day. Tumor growth is expressed as a T / C ratio, as defined below. In essence, a ratio of "+1" means not suppressed, a ratio of "0" means completely suppressed proliferation, and a negative ratio means ,
Means tumor regression. T / C =% increase in treated tumor volume /% increase in control tumor volume After 37 days, 100% of untreated ones die, AGM-1470
The treatment killed 50% (50% of the treated ones survived after 55 days) AGM-1470 was found to exert its inhibitory effect with little or no toxicity. The animal's activity is not lost, it does not lose weight, and it is consistently infected with the disease.

[Examples] Examples of raw material production and examples will be given below.
The present invention will be described in more detail, but the present invention is not limited to these examples. The following raw material production examples and elution by column chromatography (indicated by elution solvent in parentheses) of the examples are TLC (Thin Layer Chromatograph).
y, thin layer chromatography). In TLC observation, as a TLC plate (Me
The rck) manufactured Kieselgel 60F ₂₅₀ (70-230 mesh), the solvent used as an elution solvent in column chromatography as a developing solvent, UV detector as a detection method, employing a chromogenic method with phosphorus molybdate. The column silica gel is Kieselgel 60 also from Merck.
(70-230 mesh) was used. The NMR spectrum shows proton NMR ( ¹ H-NMR), and using tetramethylsilane as an internal or external standard, Varian (VARIA
It was measured with a Gemini 200 manufactured by N) and the δ value was shown in ppm.
The raw material production examples and the abbreviations used in the examples have the following meanings. s: singlet, br: broad (wide), d: doublet, dd: double doublet, ddd: doublet doublet doublet, t: triplet, q: quartet, m: multiplet, ABq: AB quartet, J: coupling constant, Hz: Hertz, CDCl ₃ : Deuterated chloroform, d ₆ -DM
SO: Heavy dimethylsulfoxide,%:% by weight In the following raw material production examples, room temperature is about
It means 15 to 25 ° C. All melting points and temperatures are given in degrees Celsius.

Raw Material Production Example 1 Dihydrofumagillol

[0036]

[Chemical 4]

A solution of fumagillol (1.12 g) in ethanol (13 ml) was catalytically reduced at room temperature for 1 hour using 5% palladium carbon (120 mg) as a catalyst. After filtering the reaction solution, the solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (developing solvent: n-hexane-ethyl acetate = 2: 1) to obtain Journal of the American Chemicals. Society Vol. 78, Vol. 4675
871 mg of dihydrofumagillol described on page (1956)
(Yield 77%) was obtained.

Example 1 O- (3-carboxypropionyl) fumagillol

[0039]

[Chemical 5]

Succinic anhydride (250 mg) was added to a solution of fumagillol (240 mg) and dimethylaminopyridine (100 mg) in anhydrous pyridine (1 ml), and the mixture was stirred at room temperature for 3 days.
The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and washed with water. Next, the organic layer was extracted with a saturated aqueous sodium hydrogen carbonate solution, the aqueous layer was adjusted to pH 4 with diluted hydrochloric acid, re-extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to obtain 252 mg (yield 78%) of colorless candy-like O- (3-carboxypropionyl) fumagillol. ¹ H-NMR (CDCl ₃ ) δ: 1.08 (1H, m), 1.20 (3H, s),
1.65 (3H, s), 1.75 (3H, s), 1.6-2.2 (5H, m), 2.39 (1H, m), 2.
56 (1H, d, J = 4.2Hz), 2.65 (5H, m), 2.98 (1H, d, J = 4.2Hz),
3.40 (3H, s), 3.63 (1H, dd, J = 11.2Hz, J = 2.8Hz), 5.22 (1H,
m), 5.68 (1H, brs), 7.10 (brs).

Example 2 O- (3-carboxypropionyl) fumagillol sodium salt

[0042]

[Chemical 6]

Water (2 ml) was added to O- (3-carboxypropionyl) fumagillol (612 mg), and sodium hydrogen carbonate (135 mg) was added little by little to dissolve it, and then the solvent was concentrated under reduced pressure to obtain colorless crystals of O-. (3-Carboxypropionyl) fumagillol sodium salt 614 mg (yield 95
%). Melting point: Gradually decomposed at 120 ° C. or higher ¹ H-NMR (D ₂ O) δ: 1.08 (1H, m), 1.23 (3H, s), 1.67
(3H, s), 1.78 (3H, s), 1.6-2.7 (10H, m), 2.77 (1H, d, J = 3.8H
z), 2.90 (1H, t, J = 6.2Hz), 3.10 (1H, d, J = 3.8Hz), 3.41 (3
H, s), 3.85 (1H, dd, J = 11.0Hz, 2.6Hz), 5.27 (1H, m), 5.62 (1
H, brs).

Example 3 O- (4-carboxybutanoyl) fumagillol

[0045]

[Chemical 7]

As in Example 1, fumagillol (200 mg) and brutalic anhydride (260 mg) were stirred at room temperature for 24 hours,
235 mg (yield 84%) of colorless candy-like O- (4-carboxybutanoyl) fumagillol was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.08 (1H, m), 1.21 (3H, s),
1.65 (3H, s), 1.75 (3H, s), 1.7-2.6 (12H, m), 2.58 (1H, d, J =
4.2Hz), 2.63 (1H, t, J = 6.4Hz), 2.99 (1H, d, J = 4.2Hz), 3.4
3 (3H, s), 3.65 (1H, dd, J = 11.0Hz, J = 2.6Hz), 5.20 (1H, m),
5.67 (1H, brs), 8.60 (1H, brs).

Example 4 O- (4-carboxybutanoyl) fumagillol sodium salt

[0048]

[Chemical 8]

As in Example 2, O- (4-carboxybutanoyl) fumagillol (604 mg) and sodium hydrogen carbonate.
From (128 mg), colorless crystals of O- (4-carboxybutanoyl) fumagillol sodium salt 565 mg (yield 8
9%). Melting point: Gradually decomposed above 120 ° C. ¹ H-NMR (D ₂ O) δ: 1.10 (1H, m), 1.23 (3H, s), 1.67
(3H, s), 1.77 (3H, s), 1.7-2.55 (12H, m), 2.78 (1H, d, J = 3.4
Hz), 2.88 (1H, t, J = 6.4Hz), 3.09 (1H, d, J = 3.4Hz), 3.41 (3
H, s), 3.84 (1H, dd, J = 11.2Hz, J = 2.8Hz), 5.28 (1H, m), 5.6
4 (1H, brs).

Example 5 O-carboxymethoxyacetyl fumagillol

[0051]

[Chemical 9]

In the same manner as in Example 1, fumagillol (205 mg) and diglycolic anhydride (255 mg) were stirred at room temperature for 20 hours to obtain 205 mg (yield 71%) of colorless candy-shaped O-carboxymethoxyacetyl fumagillol. Obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.10 (1H, m), 1.21 (3H, s),
1.63 (3H, s), 1.72 (3H, s), 1.6-2.6 (8H, m), 2.94 (1H, d, J =
4.2Hz), 3.41 (3H, s), 3.63 (1H, dd, J = 11.2Hz, J = 2.8Hz),
4.25 (2H, s), 4.30 (2H, s), 5.21 (1H, m), 5.73 (1H, brs), 8.22
(1H, brs).

Example 6 O- (2-carboxybenzoyl) fumagillol

[0054]

[Chemical 10]

In the same manner as in Example 1, fumagillol (187 mg) and phthalic anhydride (147 mg) were stirred at room temperature for 3 days, purified by silica gel column chromatography (ethyl acetate), and colorless powder of O- (2- 190 mg (yield 67%) of carboxybenzoyl) fumagillol was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.08 (1H, m), 1.24 (3H, s),
1.68 (3H, s), 1.77 (3H, s), 1.9-2.5 (5H, m), 2.35 (1H, d, J = 1
1.6Hz), 2.60 (1H, d, J = 4.1Hz), 2.94 (1H, d, J = 4.1Hz), 3.1
6 (1H, dd, J = 7.8Hz, J = 5.6Hz), 3.50 (3H, s), 3.75 (1H, dd, J
= 11.6Hz, J = 2.3Hz), 5.22 (1H, m), 5.99 (1H, d, J = 2.3Hz),
7.45-7.65 (3H, m), 7.8-7.9 (1H, m).

Example 7 O-nicotinoyl fumagillol

[0057]

[Chemical 11]

To a solution of fumagillol (500 mg) and dimethylaminopyridine (870 mg) in anhydrous dichloromethane (15 ml) was added nicotinic acid chloride chloride (470 mg),
Stir for 30 minutes at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and the eluate with ethyl acetate was concentrated under reduced pressure to obtain 629 mg (yield 92%) of O-nicotinoyl fumagillol as a colorless oily substance. ¹ H-NMR (CDCl ₃ ) δ: 1.20 (1H, m), 1.24 (3H, s),
1.67 (3H, s), 1.76 (3H, s), 2.04 (1H, d, J = 11.0Hz), 1.95-2.
47 (5H, m), 2.61 (1H, d, J = 4.2Hz), 2.63 (1H, t, J = 6.4Hz),
3.05 (1H, d, J = 4.2Hz), 3.50 (3H, s), 3.77 (1H, dd, J = 11.0H
z, J = 2.8Hz), 5.22 (1H, m), 5.95 (1H, m), 7.39 (1H, ddd, J =
7.9Hz, J = 4.9Hz, J = 1.0Hz), 8.29 (1H, dt, J = 7.9Hz, J = 2.
0Hz), 8.78 (1H, dd, J = 4.9Hz, J = 2.0Hz), 9.22 (1H, dd, J =
2.0Hz, J = 1.0Hz).

Example 8 O-chloroacetylcarbamoyl fumagillol

[0060]

[Chemical 12]

Chloroacetyl isocyanate (160 mg) was added dropwise to a solution of fumagillol (314 mg) in dichloromethane (5 ml) under ice cooling, and then dimethylaminopyridine.
(130 mg) was added, and the mixture was stirred at 0 ° C for 2 hr. Water was added to the reaction solution, extraction was performed with dichloromethane, the organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After the solvent was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and the eluate was concentrated under reduced pressure with a solution of n-hexane and ethyl acetate (3: 1) to give 318 mg of O-chloroacetylcarbamoyl fumagillol as a colorless powder. (Yield 71%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.10 (1H, m), 1.21 (3H, s),
1.66 (3H, s), 1.75 (3H, s), 1.93 (1H, d, J = 11.4Hz), 1.8-2.5
(5H, m), 2.57 (1H, d, J = 4.2Hz), 2.58 (1H, m), 2.99 (1H, d, J
= 4.2Hz), 3.47 (3H, s), 3.68 (1H, dd, J = 11.4Hz, J = 2.8H
z), 4.44 (2H, s), 5.20 (1H, m), 5.61 (1H, m), 8.33 (1H, brs).

Example 9 O- (n-propylcarbamoyl) fumagillol

[0063]

[Chemical 13]

In the same manner as in Example 8, fumagillol (200 mg) and n-propyl isocyanate (180 mg) were stirred at room temperature for 3 days and purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1). , O- (n-propylcarbamoyl) fumagillol 128 mg, colorless powder
(Yield 49%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, t, J = 7.4Hz), 1.07
(1H, m), 1.21 (3H, s), 1.4-2.5 (8H, m), 1.66 (3H, s), 1.75 (3
H, s), 2.55 (1H, d, J = 4.2Hz), 2.57 (1H, t, J = 6.4Hz), 2.98
(1H, d, J = 4.2Hz), 3.13 (2H, q, J = 6.8Hz), 3.45 (3H, s), 3.6
4 (1H, dd, J = 11.2Hz, J = 2.8Hz), 4.79 (1H, m), 5.21 (1H, m),
5.48 (1H, brs).

Example 10 O-Carboxymethylcarbamoyl fumagillol sodium salt

[0066]

[Chemical 14]

In the same manner as in Example 8, fumagillol (242 mg) and ethyl isocyanate ethyl acetate (135 mg) were stirred at room temperature for 24 hours and purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1). A colorless oily substance, O-ethoxycarbonylmethylcarbamoyl fumagillol, was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.08 (1H, m), 1.21 (3H, s),
1.29 (3H, t, J = 7.2Hz), 1.65 (3H, s), 1.74 (3H, s), 1.5-2.5
(6H, m), 2.55 (1H, d, J = 4.2Hz), 2.58 (1H, t, J = 6.7Hz), 2.9
8 (1H, d, J = 4.2Hz), 3.45 (3H, s), 3.63 (1H, dd, J = 11.2Hz, J
= 2.6Hz), 3.87 (1H, dd, J = 18.6Hz, J = 4.8Hz), 4.06 (1H, d
d, J = 18.6Hz, J = 6.0Hz), 4.22 (2H, q, J = 7.2Hz), 5.15-5.3
5 (2H, m), 6.00 (1H, m). O-Ethoxycarbonylmethylcarbamoyl fumagillol in ethanol (3ml) in 1N sodium hydroxide
(2 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was washed with ethyl acetate. The aqueous layer was adjusted to pH 3 with oxalic acid, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to obtain 251 mg (yield 76%) of O-carboxymethylcarbamoyl fumagillol as a pale yellow powder. ¹ H-NMR (CDCl ₃ ) δ: 1.07 (1H, m), 1.22 (3H, s),
1.64 (3H, s), 1.75 (3H, s), 1.5-2.5 (6H, m), 2.56 (1H, d, J =
4.2Hz), 2.68 (1H, m), 2.97 (1H, d, J = 4.2Hz), 3.44 (3H, s),
3.68 (1H, dd, J = 11.2Hz, J = 2.6Hz), 3.99 (2H, m), 5.19 (1H,
m), 5.47 (1H, m), 5.62 (1H, m). O-carboxymethylcarbamoyl fumagillol (13
0 mg) to which water (1 ml) was added, and sodium hydrogen carbonate (40 mg)
Was added little by little and dissolved in water. The solvent was concentrated under reduced pressure to obtain 135 mg (yield 98%) of O-carboxymethylcarbamoyl fumagillol sodium salt as a colorless powder. Melting point: Gradually decomposed at 200 ° C. or higher ¹ H-NMR (D ₂ O) δ: 1.10 (1H, m), 1.23 (3H, s), 1.68
(3H, s), 1.77 (3H, s), 1.5-2.5 (6H, m), 2.78 (1H, d, J = 3.2H
z), 2.90 (1H, m), 3.12 (1H, d, J = 3.2Hz), 3.45 (3H, s), 3.70
(2H, s), 3,84 (1H, dd, J = 11.5Hz, J = 2.6Hz), 5.29 (1H, m),
5.49 (1H, m). Example 11 O-phenylcarbamoyl fumagillol

[0068]

[Chemical 15]

As in Example 8, fumagillol (568 mg) and phenylisocyanate (600 mg) were stirred at room temperature for 10 hours, purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1), and colorless. Powder O
-Phenylcarbamoyl fumagillol 310 mg (yield 3
9%). ¹ H-NMR (CDCl ₃ ) δ: 1.10 (1H, m), 1.23 (3H, s),
1.66 (3H, s), 1.75 (3H, s), 1.6-2.4 (6H, m), 2.56 (1H, d, J =
4.2Hz), 2.58 (1H, t, J = 6.0Hz), 3.00 (1H, d, J = 4.2Hz), 3.4
5 (3H, s), 3.70 (1H, dd, J = 11.2Hz, J = 2.8Hz), 5.21 (1H, m),
5.57 (1H, brs), 7.0-7.6 (6H, m).

Example 12 O- (m-trifluoromethylphenylcarbamoyl) fumagillol

[0071]

[Chemical 16]

As in Example 8, fumagillol (208 mg) and m-trifluoromethylisocyanate (207 mg) were stirred at room temperature for 15 hours and purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1). Thus, 285 mg (yield: 82%) of O- (m-trifluoromethylphenylcarbamoyl) fumagillol was obtained as a colorless powder. ¹ H-NMR (CDCl ₃ ) δ: 1.12 (1H, m), 1.23 (3H, s),
1.67 (3H, s), 1.75 (3H, s), 1.99 (1H, d, J = 11.2Hz), 1.8-2.5
(5H, m), 2.59 (2H, m), 3.00 (1H, d, J = 4.2Hz), 3.48 (3H, s),
3.71 (1H, dd, J = 11.2Hz, J = 2.7Hz), 5.21 (1H, m), 5.60 (1H,
m), 7.00 (1H, brs), 7.25-7.60 (3H, m), 7.76 (1H, brs).

Example 13 O- (1-naphthylcarbamoyl) fumagillol and O-
[N- (1-naphthylcarbamoyl) -N- (1-naphthyl) carbamoyl] fumagillol

[0074]

[Chemical 17]

As in Example 8, fumagillol (220 mg) and 1-naphthylisocyanate (135 mg) were stirred at room temperature for 15 hours and subjected to silica gel column chromatography (n-).
Purified by hexane: ethyl acetate = 9: 1), colorless powder O- [N- (1-naphthylcarbamoyl) -N- (1-naphthyl) carbamoyl] fumagillol 215 mg (yield 44
%). ¹ H-NMR (CDCl ₃ ) δ: 0.50 (1H, m), 0.90 (1H, m),
0.97 (3H × 2/5, s), 1.07 (3H × 3/5, s), 1.30 (1H, m), 1.67 (3
H, s), 1.77 (3H, s), 1.45-1.80 (2H, m), 1.9-2.4 (4H, m), 2.56
(1H x 2/5, d, J = 4.2Hz), 2.69 (1H x 3/5, d, J = 4.2Hz), 3.35
-3.55 (1H, m), 3.50 (3H × 2/5, s), 3.52 (3H × 3/5, s), 5.20 (1
H, m), 5.65 (1H, brs), 7.4-8.3 (14H, m), 11.65 (1H, brs). Then, purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1). 161 mg of O- (1-naphthylcarbamoyl) fumagillol as colorless powder
(Yield 46%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.10 (1H, m), 1.24 (3H, s),
1.67 (3H, s), 1.75 (3H, s), 1.6-2.5 (6H, m), 2.55 (1H, d, J =
4.2Hz), 2.59 (1H, m), 2.99 (1H, d, J = 4.2Hz), 3.47 (3H, s),
3.70 (1H, dd, J = 11.2Hz, J = 2.6Hz), 5.22 (1H, m), 5.63 (1H,
brs), 7.19 (1H, brs), 7.4-8.0 (7H, m).

Example 14 O-methyl fumagillol

[0077]

[Chemical 18]

Fumagillol (233 mg) in anhydrous THF (1.
5 ml) and anhydrous DMF (1.5 ml) were added with 60% sodium hydride (70 mg) under ice cooling, and then methyl iodide
(230 mg) was slowly added dropwise, and the mixture was stirred at 0 ° C for 20 minutes after the addition. Water was added to the reaction solution and extracted with ether. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After the solvent was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography, and the eluate with a solution of n-hexane and ethyl acetate (2: 1) was concentrated under reduced pressure to give colorless oil O.
281 mg (yield 95%) of methyl fumagillol were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.00 (1H, m), 1.21 (3H, s),
1.65 (3H, s), 1.74 (3H, s), 1.5-1.8 (1H, m), 2.04 (1H, d, J = 1
1.2Hz), 1.95-2.25 (3H, m), 2.3-2.5 (1H, m), 2.52 (1H, d, J =
4.4Hz), 2.55 (1H, t, J = 5.8Hz), 2.96 (1H, d, J = 4.4Hz), 3.4
4 (3H, s), 3.47 (3H, s), 3.59 (1H, dd, J = 11.2Hz, J = 2.6Hz),
3.93 (1H, m), 5.21 (1H, m).

Example 15 O-octadecyl fumagillol

[0080]

[Chemical 19]

Fumagillol (100 mg) as in Example 14
And octadecyl iodide (160 mg) were reacted at room temperature for 2 days and purified by silica gel column chromatography (dichloromethane). The obtained crystals were recrystallized from methanol to give colorless crystals of O-octadecyl fumagillol 85 mg.
(Yield 45%) was obtained. Melting point: 58 to 59 ° C. ¹ H-NMR (CDCl ₃ ) δ: 0.88 (3H, t, J = 6.5Hz), 1.0
0 (1H, m), 1.21 (3H, s), 1.25 (30H, s), 1.5-1.7 (3H, m), 1.63
(3H, s), 1.73 (3H, s), 1.9-2.4 (5H, m), 2.49 (1H, d, J = 4.2H
z), 2.56 (1H, t, J = 5.8Hz), 2.94 (1H, d, J = 4.2Hz), 3.45 (3
H, s), 3.4-3.6 (3H, m), 3.98 (1H, m), 5.21 (1H, m).

Example 16 O-carboxymethyl fumagillol

[0083]

[Chemical 20]

Fumagillol (211 mg) as in Example 14
And bromoacetic acid (135 mg) were reacted at room temperature for 2 hours. After the reaction, water was added and the mixture was washed with ether, the aqueous layer was adjusted to pH 4 with diluted hydrochloric acid, extracted with ether, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to obtain 191 mg (yield 75%) of O-carboxymethyl fumagillol as a colorless oily substance. ¹ H-NMR (CDCl ₃ ) δ: 1.03 (1H, m), 1.24 (3H, s),
1.66 (3H, s), 1.76 (3H, s), 1.7-2.4 (6H, m), 2.57 (1H, d, J =
4.2Hz), 2.60 (1H, t, J = 5.8Hz), 2.95 (1H, d, J = 4.2Hz), 3.5
8 (3H, s), 3.70 (1H, dd, J = 11.2Hz, J = 2.6Hz), 3.97 (1H, br
s), 4.05 (1H, d, J = 17.5Hz), 4.30 (1H, d, J = 17.5Hz), 5.20
(1H, m).

Example 17 O-benzyl fumagillol

[0086]

[Chemical 21]

Fumagillol (119 mg) as in Example 14
And benzyl bromide (110 mg) were reacted at 0 ° C for 30 minutes,
Purification by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) gave 151 mg (yield 96%) of O-benzyl fumagillol as a colorless oily substance. ¹ H-NMR (CDCl ₃ ) δ: 1.02 (1H, m), 1.22 (3H, s),
1.68 (3H, s), 1.69 (1H, m), 1.75 (3H, s), 2.00 (1H, m), 2.1-2.
25 (3H, m), 2.45 (1H, m), 2.50 (1H, d, J = 4.2Hz), 2.57 (1H, t,
J = 5.8Hz), 2.98 (1H, d, J = 4.2Hz), 3.41 (3H, s), 3.59 (1H, d
d, J = 11.2Hz, J = 2.6Hz), 4.10 (1H, brs), 4.72 (2H, ABq, J =
13Hz), 5.23 (1H, m), 7.2-7.45 (5H, m).

Example 18 O- (p-bromobenzyl) fumagillol

[0089]

[Chemical formula 22]

Fumagillol (100 mg) as in Example 14
And p-bromobenzyl bromide (354 mg) were reacted at 0 ° C. for 1 hour and purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) to give O- (p- 135 mg (yield 84%) of bromobenzyl) fumagillol was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.01 (1H, m), 1.21 (3H, s),
1.65 (3H, s), 1.74 (3H, s), 1.55-1.7 (1H, m), 1.9-2.5 (4H,
m), 2.12 (1H, d, J = 11.0Hz), 2.52 (1H, d, J = 4.4Hz), 2.57 (1
H, t, J = 6.2Hz), 2.96 (1H, d, J = 4.4Hz), 3.41 (3H, s), 3.58
(1H, dd, J = 11.0Hz, J = 2.4Hz), 4.09 (1H, m), 4.65 (2H, ABq,
J = 12.8Hz), 5.21 (1H, m), 7.27 (2H, d, J = 8.6Hz), 7.45 (2H,
d, J = 8.6Hz).

Example 19 O- (2,3 epoxypropyl) fumagillol

[0092]

[Chemical formula 23]

Fumagillol (215 mg) as in Example 14
And epibromohydrin (125 mg) were reacted at room temperature for 5 hours and purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain a colorless oily substance O.
-(2,3-epoxypropyl) fumagillol 225mg
(Yield 87%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.98 (1H, m), 1.22 (3H, s),
1.63 (3H × 1/2, s), 1.65 (3H × 1/2, s), 1.75 (3H, s), 1.6-1.7
(1H, m), 1.9-2.4 (5H, m), 2.5-2.65 (3H, m), 2.77 (1H, m), 2.9
6 (1H, d, J = 4.2Hz), 3.17 (1H, m), 3.47 (3H, × 1/2, s), 3.50
(3H × 1/2, s), 3.35-4.05 (2H, m), 4.02 (1H × 1/2, brs), 4.07
(1H × 1/2, brs), 5.21 (1H, m).

Example 20 O- (P-toluenesulfonyl) fumagillol

[0095]

[Chemical formula 24]

Fumagillol (3.00 g) and dimethylaminopyridine (3.24 g) in anhydrous dichloromethane (30 ml)
The solution was added with p-toluenesulfonyl chloride (3.04).
g) was added and stirred at room temperature overnight. The reaction solution was diluted with dichloromethane, washed with saturated saline, and then dried over anhydrous magnesium sulfate. After the solvent was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with a solution of n-hexane and ethyl acetate (4: 1), and the eluate was concentrated under reduced pressure. The obtained crude crystals were recrystallized from diisopropyl ether to give colorless crystals of O- (p-toluenesulfonyl) fumagillol (2.88 g). Melting point: 123 to 124 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.14 (1H, m), 1.16 (3H, s),
1.67 (3H, s), 1.70 (3H, s), 1.84 (1H, m), 1.95 (1H, d, J = 10.7
Hz), 2.04-2.47 (4H, m), 2.44 (3H, s), 2.55 (1H, d, J = 4.3H
z), 2.56 (1H, t, J = 6.4Hz), 2.94 (1H, d, J = 4.3Hz), 3.02 (3
H, s), 3.50 (1H, dd, J = 10.7Hz, J = 2.5Hz), 5.07 (1H, m), 5.1
9 (1H, m), 7.33 (2H, d, J = 8.2Hz), 7.87 (2H, d, J = 8.2Hz).

Example 21 O-methylsulfonyl fumagillol

[0098]

[Chemical 25]

A solution of fumagillol (500 mg) and dimethylaminopyridine (541 mg) in anhydrous dichloromethane (5 ml) was cooled to ice with methanesulfonyl chloride (0.21 ml).
Was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with a solution of n-hexane and ethyl acetate (2: 1). The eluate was concentrated under reduced pressure to obtain O-methylsulfonyl fumagillol (561 m
g) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.12 (1H, m), 1.20 (3H, s),
1.66 (3H, s), 1.75 (3H, s), 1.93 (1H, d, J = 11.4Hz), 1.85-2.
45 (4H, m), 2.58 (1H, t, J = 6.4Hz), 2.59 (1H, d, J = 4.2Hz),
2.99 (1H, d, J = 4.2Hz), 3.14 (3H, s), 3.53 (3H, s), 3.65 (1H,
dd, J = 2.4Hz, J = 11.4Hz), 5.20 (1H, m), 5.39 (1H, m).

Example 22 O-phenoxycarbonyl fumagillol

[0101]

[Chemical formula 26]

Fumagillol (133 mg) and dimethylaminopyridine (115 mg) were dissolved in dichloromethane (3 ml), phenyl chloroformate (111 mg) was added, and the mixture was stirred at room temperature for 30 minutes.
Stir for minutes. After adding water, dichloromethane (30m
It was diluted with l) and washed with water and saturated aqueous sodium chloride solution. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane-ethyl acetate = 5: 1) to give a colorless oil O. -174 mg (92% yield) of phenoxycarbonyl fumagillol was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.10 (1H, m), 1.22 (3H, s),
1.66 (3H, s), 1.75 (3H, s), 1.8-2.45 (6H, m), 2.56 (1H, d, J =
4.4Hz), 2.59 (1H, t, J = 6.4Hz), 2.99 (1H, d, J = 4.4Hz), 3.5
0 (3H, s), 3.69 (1H, dd, J = 11.2Hz, J = 2.6Hz), 5.18 (1H, m),
5.58 (1H, brs), 7.15-7.45 (5H, m).

Example 23 O-carbamoyl fumagillol

[0104]

[Chemical 27]

O-phenoxycarbonyl fumagillol
(402 mg) was dissolved in ethanol (5 ml), concentrated aqueous ammonia (3 ml) was added, and the mixture was stirred at room temperature for 3 hr. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (developing solvent: n-hexane-ethyl acetate = 1:
Purification in 1) yielded 273 mg (yield 84%) of O-carbamoyl fumagillol as a colorless powder. Melting point: 125-1
26 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.07 (1H, m), 1.21 (3H, s),
1.66 (3H, s), 1.75 (3H, s), 1.6-2.5 (6H, m), 2.55 (1H, d, J =
4.4Hz), 2.57 (1H, t, J = 7.4Hz), 2.98 (1H, d, J = 4.4Hz), 3.4
5 (3H, s), 3.65 (1H, dd, J = 11.4Hz, J = 2.8Hz), 5.09 (2H, br
s), 5.21 (1H, brt, = 7.6Hz), 5.46 (1H, brs).

Example 24 O-morpholinocarbonyl fumagillol

[0107]

[Chemical 28]

In the same manner as in Example 23, O-phenoxycarbonyl fumagillol (173 mg) and morpholine (200 mg) were stirred at room temperature for 20 hours and subjected to silica gel column chromatography (developing solvent: n-hexane-ethyl acetate = 1: 1). ) To obtain 148 mg (yield 87%) of O-morpholinocarbonyl fumagillol as a colorless oily substance. ¹ H-NMR (CDCl ₃ ) δ: 1.11 (1H, m), 1.21 (3H, s),
1.66 (3H, s), 1.74 (3H, s), 1.6-2.5 (6H, m), 2.55 (1H, d, J =
4.2Hz), 2.57 (1H, t, J = 5.6Hz), 2.99 (1H, d, J = 4.2Hz), 3.4
6 (3H, s), 3.47 (4H, m), 3.68 (5H, m), 5.21 (1H, m), 5.57 (1H, b
rs).

Example 25 O-piperidinocarbonyl fumagillol

[0110]

[Chemical 29]

In the same manner as in Example 23, O-phenoxycarbonyl fumagillol (193 mg) and piperidine (222 mg) were stirred at room temperature for 6 hours and subjected to silica gel column chromatography.
The product was purified with (developing solvent: n-hexane-ethyl acetate = 4: 1) to obtain 187 mg (yield 99%) of O-piperidinocarbonyl fumagillol as a colorless oily substance. ¹ H-NMR (CDCl ₃ ) δ: 1.10 (1H, m), 1.22 (3H, s),
1.57 (6H, m), 1.66 (3H, s), 1.74 (3H, s), 1.8-2.5 (6H, m), 2.5
5 (1H, d, J = 4.2Hz), 2.59 (1H, t, J = 6.4Hz), 2.99 (1H, d, J =
4.2Hz), 3.42 (4H, m), 3.46 (3H, s), 3.64 (1H, dd, J = 11.0Hz,
J = 2.8Hz), 5.22 (1H, m), 5.56 (1H, brs).

Example 26 O-carbazoyl fumagillol

[0113]

[Chemical 30]

As in Example 23, O-phenoxycarbonyl fumagillol (400 mg) and hydrazine (120 mg) were stirred at room temperature for 1 hour and subjected to silica gel column chromatography.
Purified with (developing solvent: n-hexane-ethyl acetate = 1: 2), pale yellow powder of O-carbazoyl fumagillol 1
Obtained 69 mg (yield 50%).

¹ H-NMR (CDCl ₃ ) δ: 1.07 (1H, m),
1.21 (3H, s), 1.65 (3H, s), 1.74 (3H, s), 1.6-2.5 (6H, m), 2.5
5 (1H, d, J = 4.2Hz), 2.56 (1H, t, J = 6.4Hz), 2.98 (1H, d, J =
4.2Hz), 3.47 (3H, s), 3.65 (1H, dd, J = 11.2Hz, J = 2.8Hz),
3.70 (2H, brs), 5.20 (1H, m), 5.55 (1H, m), 6.19 (1H, brs).

Example 27 O- (1-imidazolylcarbonyl) fumagillol

[0117]

[Chemical 31]

Fumagillol (236 mg) in dichloromethane
(5 ml) solution, 1,1'-carbonyldiimidazole
(410 mg) was added, and the mixture was stirred at room temperature for 1 day. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane-ethyl acetate = 3: 2) to give O- (1-imidazolylcarbonyl) fumagillol as a colorless oil. 275 mg (90% yield) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.20 (1H, m), 1.23 (3H, s),
1.67 (3H, s), 1.75 (3H, s), 1.91 (1H, d, J = 11.2Hz), 1.8-2.5
(5H, m), 2.62 (1H, t, J = 6.4Hz), 2.62 (1H, d, J = 4.2Hz), 3.0
4 (1H, d, J = 4.2Hz) 3.52 (3H, s), 3.77 (1H, dd, J = 11.2Hz, J
= 2.6Hz), 5.21 (1H, m), 5.83 (1H, brs), 7.06 (1H, d, J = 1.4H
z), 7.41 (1H, t, J = 1.4Hz), 8.12 (1H, s).

Example 28 O- (2-dimethylaminoethylcarbamoyl) fumagillol

[0120]

[Chemical 32]

To a solution of O- (1-imidazolylcarbonyl) fumagillol (270 mg) in dichloromethane (3 ml) was added 2 parts.
-Add dimethylaminoethylamine (90 mg) and add 1 at room temperature.
Stir the day. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (developing solvent: chloroform-methanol = 2
0: 1) to give 139 mg of colorless powder O- (2-dimethylaminoethylcarbamoyl) fumagillol (yield 5
3%).

¹ H-NMR (CDCl ₃ ) δ: 1.08 (1H, m),
1.22 (3H, s), 1.66 (3H, s), 1.75 (3H, s), 2.23 (6H, m), 1.6-2.
5 (6H, m), 2.41 (2H, t, J = 6.0Hz), 2.55 (1H, d, J = 4.4Hz), 2.
58 (1H, t, J = 6.6Hz), 2.98 (1H, d, J = 4.4Hz), 3.23 (2H, m),
3.46 (3H, s), 3.65 (1H, dd, J = 11.2Hz, J = 2.8Hz), 5.21 (1H,
m), 5.39 (1H, brt), 5.50 (1H, brs).

Example 29 O-acetylcarbamoyl fumagillol

[0124]

[Chemical 33]

Fumagillol (700 mg) and acetyl isocyanate (500 mg) were stirred at room temperature for 10 minutes in the same manner as in Example 8 and subjected to silica gel column chromatography (developing solvent: n).
-Hexane-ethyl acetate = 2: 1) and colorless candy-like O-acetylcarbamoyl fumagillol 825mg
(Yield 91%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.10 (1H, m), 1.21 (3H, s),
1.66 (3H, s), 1.75 (3H, s), 1.8-2.5 (6H, m), 2.39 (3H, s), 2.5
7 (1H, t, J = 6.8Hz), 2.58 (1H, d, J = 4.2Hz), 2.99 (1H, d, J =
4.2Hz), 3.47 (3H, s), 3.68 (1H, dd, J = 11.4Hz, J = 2.8Hz),
5.20 (1H, m), 5.57 (1H, brs), 8.03 (1H, brs).

Example 30 O-dichloroacetylcarbamoyl fumagillol

[0127]

[Chemical 34]

As in Example 8, fumagillol (570 mg) and dichloroacetylisocyanate (500 mg) were added at room temperature for 10 minutes.
The mixture was stirred for minutes and purified by silica gel column chromatography (developing solvent: n-hexane-ethyl acetate = 3: 1) to obtain 789 mg (yield 90%) of colorless candy-like O-dichloroacetylcarbamoyl fumagillol. It was ¹ H-NMR (CDCl ₃ ) δ: 1.11 (1H, m), 1.22 (3H, s),
1.67 (3H, s), 1.75 (3H, s), 1.96 (1H, d, J = 11.2Hz), 1.6-2.6
(6H, m), 2.58 (1H, d, J = 4.2Hz), 2.99 (1H, d, J = 4.2Hz), 3.4
8 (3H, s), 3.71 (1H, dd, J = 11.2Hz, J = 2.8Hz), 5.20 (1H, m),
5.64 (1H, m), 6.38 (1H, s), 8.50 (1H, s).

Example 31 O-Trichloroacetylcarbamoyl fumagillol

[0130]

[Chemical 35]

Fumagillol (355 mg) and trichloroacetylisocyanate (355 mg) were added at room temperature to 1 as in Example 8.
The mixture was stirred for 0 minutes and purified by silica gel column chromatography (developing solvent: n-hexane-ethyl acetate = 7: 2) to obtain 258 mg (yield 44%) of O-trichloroacetylcarbamoyl fumagillol as a colorless powder. It was ¹ H-NMR (CDCl ₃ ) δ: 1.11 (1H, m), 1.22 (3H, s),
1.66 (3H, s), 1.75 (3H, s), 2.00 (1H, d, J = 11.4Hz), 1.6-2.7
(6H, m), 2.58 (1H, d, J = 4.2Hz), 3.01 (1H, d, J = 4.2Hz), 3.5
0 (3H, s), 3.73 (1H, dd, J = 11.4Hz, J = 2.8Hz), 5.20 (1H, m),
5.71 (1H, m), 8.68 (1H, brs).

Example 32 O-benzoylcarbamoyl fumagillol

[0133]

[Chemical 36]

Fumagillol (510 mg) and benzoyl isocyanate (530 mg) were stirred at room temperature for 30 minutes as in Example 8 and subjected to silica gel column chromatography (developing solvent: n).
-Hexane-ethyl acetate = 3: 1) and colorless powder O-benzoylcarbamoyl fumagillol 450 mg
(Yield 58%) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.09 (1H, m),
1.20 (3H, s), 1.65 (3H, s), 1.74 (3H, s), 1.6-2.45 (6H, m), 2.
55 (1H, d, J = 4.2Hz), 2.56 (1H, t, J = 7.0Hz), 2.97 (1H, d, J
= 4.2Hz), 3.42 (3H, s), 3.68 (1H, dd, J = 11.4Hz, J = 2.6H
z), 5.19 (1H, brt, J = 7.4Hz), 6.65 (1H, brs), 7.4-7.6 (3H,
m), 7.89 (2H, dd, J = 7.0Hz, J = 1.4Hz), 8.88 (1H, brs).

Example 33 O-methacryloylcarbamoyl fumagillol

[0137]

[Chemical 37]

Fumagillol (1 g) and methacryloyl isocyanate (900 mg) were stirred at room temperature for 10 minutes in the same manner as in Example 8 and subjected to silica gel column chromatography (developing solvent: n).
-Hexane-ethyl acetate = 2: 1) to obtain colorless powder of O-methacryloylcarbamoyl fumagillol 51
1 mg (37% yield) was obtained. Melting point: 48 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.10 (1H, m), 1.22 (3H, s),
1.66 (3H, s), 1.76 (3H, s), 2.00 (3H, s), 1.6-2.5 (6H, m), 2.5
7 (1H, d, J = 4.4Hz), 2.60 (1H, t, J = 6.0Hz), 2.99 (1H, d, J =
4.4Hz), 3.47 (3H, s), 3.70 (1H, dd, J = 11.4Hz, J = 2.8Hz),
5.21 (1H, m), 5.58 (1H, d, J = 1.6Hz), 5.64 (1H, d, J = 2.6H
z), 5.79 (1H, s), 7.94 (1H, brs).

Example 34 O- (2-chloroethylcarbamoyl) fumagillol

[0140]

[Chemical 38]

Fumagillol (263 mg) and 2 as in Example 8
-Chloroethyl isocyanate (150 mg) was stirred at room temperature for 1 day and purified by silica gel column chromatography (developing solvent: n-hexane-ethyl acetate = 3: 1).
100 mg (yield 28%) of O- (2-chloroethylcarbamoyl) fumagillol was obtained as a colorless powder. ¹ H-NMR (CDCl ₃ ) δ: 1 (3H, s), 1.66 (3H, s), 1.75
(3H, s), 1.6-2.5 (6H, m), 2.56 (1H, d, J = 4.4Hz), 2.57 (1H,
t, J = 6.0Hz), 2.98 (1H, d, J = 4.4Hz), 3.46 (3H, s), 3.4-3.7
(5H, m), 5.20 (2H, m), 5.50 (1H, brs).

Example 35 O- (p-chlorophenylcarbamoyl) fumagillol

[0143]

[Chemical Formula 39]

As in Example 8, fumagillol (248 mg) and p
-Chlorophenyl isocyanate (200 mg) at room temperature for 1.5
After stirring for hours, the product was purified by silica gel column chromatography (developing solvent: n-hexane-ethyl acetate = 5: 1) to obtain colorless powder O- (p-chlorophenylcarbamoyl).
298 mg of fumagillol was obtained (yield 78%). ¹ H-NMR (CDCl ₃ ) δ: 1.09 (1H, m), 1.24 (3H, s),
1.66 (3H, s), 1.75 (3H, s), 1.6-2.5 (6H, m), 2.56 (1H, t, J =
6.4Hz), 2.57 (1H, d, J = 4.2Hz), 2.99 (1H, d, J = 4.2Hz), 3.4
0 (3H, s), 3.69 (1H, dd, J = 11.2Hz, J = 2.6Hz), 5.20 (1H, m),
5.57 (1H, brs), 7.24 (2H, d, J = 9.0Hz), 7.32 (1H, brs), 7.37
(2H, d, J = 9.0Hz).

Example 36 O- (p-nitrophenylcarbamoyl) fumagillol

[0146]

[Chemical 40]

As in Example 8, fumagillol (290 mg) and p
-Nitrophenyl isocyanate (500 mg) at room temperature for 2
Stir for 0 hours and perform silica gel column chromatography
Purification with (developing solvent: n-hexane-ethyl acetate = 5: 1) gave O- (p-nitrophenylcarbamoyl) fumagillol (255 mg, yield 56%) as a pale yellow powder. ¹ H-NMR (CDCl ₃ ) δ: 1.01 (1H, m), 1.29 (3H, s),
1.65 (3H, s), 1.75 (3H, s), 1.8-2.5 (6H, m), 2.58 (1H, t, J =
6.2Hz), 2.61 (1H, d, J = 4.2Hz), 3.01 (1H, d, J = 4.2Hz), 3.3
9 (3H, s), 3.75 (1H, dd, J = 11.2Hz, J = 2.6Hz), 5.20 (1H, m),
5.64 (1H, brs), 7.62 (2H, d, J = 9.2Hz), 8.15 (2H, d, J = 9.2H
z), 8.29 (1H, s).

Example 37 O- (2,4-difluorophenylcarbamoyl) fumagillol

[0149]

[Chemical 41]

Fumagillol (250 mg) and 2,4-difluorophenylisocyanate (250 mg) as in Example 8
Was stirred at room temperature for 2 hours, and silica gel column chromatography (developing solvent: n-hexane-ethyl acetate = 4: 1).
Colorless powder O- (2,4-difluorophenylcarbamoyl) fumagillol 246 mg (yield 63%)
Got ¹ H-NMR (CDCl ₃ ) δ: 1.11 (1H, m), 1.23 (3H, s),
1.66 (3H, s), 1.75 (3H, s), 1.6-2.5 (6H, m), 2.58 (2H, m), 3.0
0 (1H, d, J = 4.0Hz), 3.49 (3H, s), 3.70 (1H, dd, J = 11.4Hz, J
= 2.8Hz), 5.22 (1H, brt, J = 7.4Hz), 5.60 (1H, brs), 6.8-7.
0 (3H, m), 8.05 (1H, brq, J = 7.0Hz).

Example 38 O- (p-toluenesulfonylcarbamoyl) fumagillol

[0152]

[Chemical 42]

As in Example 8, fumagillol (213 mg) and p
-Toluenesulfonyl isocyanate (250 mg) was stirred at room temperature for 2 hours and subjected to silica gel column chromatography.
The product was purified with (developing solvent: n-hexane-ethyl acetate = 2: 1) to obtain 247 mg (yield 68%) of O- (p-toluenesulfonylcarbamoyl) fumagillol as a colorless powder. ¹ H-NMR (CDCl ₃ ) δ: 1.08 (1H, m), 1.18 (3H, s),
1.66 (3H, s), 1.75 (3H, s), 2.44 (3H, s), 1.6-2.6 (6H, m), 2.5
5 (1H, d, J = 4.2Hz), 2.57 (1H, t, J = 6.3Hz), 3.26 (3H, s), 3.
60 (1H, dd, J = 11.2Hz, J = 2.6Hz), 5.19 (1H, m), 5.42 (1H, br
s), 7.34 (2H, d, J = 8.0Hz), 7.94 (2H, d, J = 8.0Hz), 8.60 (1
H, brs).

Example 39 O- [1- (4-ethylpiperazinyl) carbonyl] fumagillol

[0155]

[Chemical 43]

To a solution of fumagillol (235 mg) and dimethylaminopyridine (425 mg) in dichloromethane (3 ml),
1- (4-ethylpiperazinyl) carbonyl chloride (3
25 mg) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (developing solvent: n- Purification with hexane-ethyl acetate = 5: 1) gave 134 mg (yield 38%) of colorless powder O- [1- (4-ethylpiperazinyl) carbonyl] fumagillol. ¹ H-NMR (CDCl ₃ ) δ: 1.05 (1H, m), 1.19 (3H, s),
1.22 (3H, t, J = 7.2Hz), 1.66 (3H, s), 1.75 (3H, s), 1.6-2.7
(12H, m), 2.24 (1H, d, J = 4.2Hz), 2.62 (1H, t, J = 6.2Hz), 2.
98 (1H, d, J = 4.2Hz), 3.49 (3H, s), 3.69 (1H, dd, J = 11.2Hz,
J = 2.4Hz), 3.4-4.2 (4H, m), 5.20 (1H, m), 5.70 (1H, brs).

Example 40 O-acetoxyacetylcarbamoyl fumagillol

[0158]

[Chemical 44]

Sodium acetate (200 mg) was added to a solution of O-chloroacetylcarbamoylfumagillol (201 mg) in dimethylformamide (3 ml), and the mixture was stirred at 60 ° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (developing solvent: n-hexane-
Purified with ethyl acetate = 2: 1), colorless powder O-acetoxyacetylcarbamoyl fumagillol 165 mg
(Yield 77%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.10 (1H, m), 1.21 (3H, s),
1.65 (3H, s), 1.74 (3H, s), 1.6-2.5 (6H, m), 2.18 (3H, s) 2.56
(2H, m), 2.99 (1H, d, J = 4.0Hz), 3.45 (3H, s), 3.67 (1H, dd, J
= 11.0Hz, J = 2.4Hz), 4.96 (1H, d, J = 17.4Hz), 5.06 (1H, d,
J = 17.4Hz), 5.19 (1H, brt, J = 7.0Hz), 5.56 (1H, brs), 8.55
(1H, s).

Example 41 O-Acetylthioacetylcarbamoyl fumagillol

[0161]

[Chemical formula 45]

Potassium thioacetate (70 mg) was added to a solution of O-chloroacetylcarbamoylfumagillol (155 mg) in dimethylformamide (2 ml), and the mixture was stirred at room temperature for 1 minute. The reaction mixture was diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (developing solvent: n-hexane-
Purified with ethyl acetate = 2: 1), colorless powder O-acetylthioacetylcarbamoyl fumagillol 156 mg
(Yield 92%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.10 (1H, m), 1.22 (3H, s),
1.67 (3H, s), 1.76 (3H, s), 1.8-2.5 (6H, m), 2.43 (3H, s), 2.5
9 (1H, d, J = 4.2Hz), 2.60. (1H, t, J = 6.7Hz), 3.00 (1H, d, J
= 4.2Hz), 3.48 (3H, s), 3.69 (1H, dd, J = 11.2Hz, J = 2.6H
z), 3.97 (1H, d, J = 16.2Hz), 4.07 (1H, d, J = 16.2Hz), 5.21
(1H, m), 5.63 (1H, m), 8.32 (1H, brs).

Example 42 O- (2-benzothiazolylthioacetylcarbamoyl)
Fumagillol

[0164]

[Chemical formula 46]

A solution of O-chloroacetylcarbamoylfumagillol (160 mg) in dimethylformamide (2 ml) was added with 2-mercaptobenzothiazole sodium salt (9 ml).
5 mg) was added and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (developing solvent: n-hexane-ethyl acetate = 3: 1).
Purification was performed to obtain 152 mg (yield 72%) of O- (2-benzothiazolylthioacetylcarbamoyl) fumagillol as a colorless powder. ¹ H-NMR (CDCl ₃ ) δ: 1.00 (1H, m), 1.20 (3H, s),
1.68 (3H, s), 1.78 (3H, s), 1.6-2.5 (7H, m), 2.51 (1H, d, J =
4.2Hz), 2.96 (1H, d, J = 4.2Hz), 3.48 (3H, s), 3.66 (1H, dd, J
= 11.4Hz, J = 2.8Hz), 4.05 (1H, d, J = 14.8Hz), 4.24 (1H, d,
J = 14.8Hz), 5.22 (1H, m), 5.65 (1H, brs), 7.3-7.5 (2H, m),
7.79 (1H, dd, J = 7.2Hz, J = 1.4Hz), 7.88 (1H, dd, J = 7.2Hz,
J = 1.4Hz), 10.24 (1H, brs).

Example 43 O-[(Pyridin-N-oxide-2-yl) thioacetylcarbamoyl] fumagillol

[0167]

[Chemical 47]

As in Example 42, O-chloroacetylcarbamoylfumagillol (144 mg) and pyridine-N-oxide-2-thiol sodium salt (60 mg) were stirred at room temperature for 10 minutes and subjected to silica gel column chromatography (development). Solvent: Chloroform-methanol = 20: 1) to purify and colorless powder O-[(pyridin-N-oxide-2-yl) thioacetylcarbamoyl] fumagillol 150 mg
(Yield 85%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.07 (1H, m), 1.21 (3H, s),
1.65 (3H, s), 1.74 (3H, s), 1.8-2.4 (6H, m), 2.55 (1H, d, J =
4.4Hz), 2.57 (1H, t, J = 6.4Hz), 2.98 (1H, d, J = 4.4Hz), 3.4
6 (3H, s), 3.68 (1H, dd, J = 11.4Hz, J = 2.6Hz), 3.94 (1H, d, J
= 15.4Hz), 4.13 (1H, d, J = 15.4Hz), 5.19 (1H, m), 5.60 (1H,
m), 7.1-7.35 (2H, m), 7.50 (1H, d, J = 7.2Hz), 8.33 (1H, d, J
= 6.2Hz), 9.29 (1H, brs).

Example 44 O-diethylaminoacetylcarbamoyl fumagillol

[0170]

[Chemical 48]

O-chloroacetylcarbamoyl fumagillol (154 mg) and triethylamine (35 mg) in toluene
Diethylamine (70 mg) was added to the (2 ml) solution, and the mixture was stirred at room temperature for 1 day. The reaction mixture was diluted with ethyl acetate, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (developing solvent: n- Purified with hexane-ethyl acetate = 2: 1) to obtain colorless candy-like O
-Diethylaminoacetylcarbamoyl fumagillol 8
5 mg (51% yield) were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.06 (6H, t, J = 7.2Hz), 1.10
(1H, m), 1.22 (3H, s), 1.66 (3H, s), 1.74 (3H, s), 1.5-2.7 (12
H, m), 2.99 (2H, d, J = 4.2Hz), 3.15 (2H, t, J = 7.5Hz), 3.48
(3H, s), 3.68 (1H, dd, J = 11.2Hz, J = 4.6Hz), 5.20 (1H, m),
5.67 (1H, m), 55 (1H, brs).

Example 45 O-diphenylmethyl fumagillol

[0173]

[Chemical 49]

In the same manner as in Example 14, fumagillol (221 mg) and diphenylmethane bromide (290 mg) were stirred at room temperature for 3 hours and subjected to silica gel column chromatography (developing solvent: n
-Hexane-ethyl acetate = 10: 1), and colorless oily substance O-diphenylmethyl fumagillol 100 mg
(Yield 28%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.98 (1H, m), 1.19 (3H, s), 1.
58 (1H, m), 1.65 (3H, s), 1.73 (3H, s), 1.9-2.4 (5H, m), 2.49
(1H, d, J = 4.2Hz), 2.57 (1H, t, J = 6.4Hz), 2.96 (1H, d, J =
4.2Hz), 3.22 (3H, s), 3.51 (1H, dd, J = 11.2Hz, J = 2.4Hz),
4.12 (1H, brs), 5.21 (1H, m), 5.67 (1H, s), 7.1-7.5 (10H,
m).

Example 46 O- (1-naphthylmethyl) fumagillol

[0176]

[Chemical 50]

In the same manner as in Example 14, fumagillol (221 mg) and 1-chloromethylnaphthalene (215 mg) were stirred at room temperature for 2 hours and subjected to silica gel column chromatography (developing solvent: n-hexane-ethyl acetate = 10: 1). Purification gave 269 mg (yield 78%) of colorless crystals of O- (1-naphthylmethyl) fumagillol. Melting point: 70 to 71 ° C. ¹ H-NMR (CDCl ₃ ) δ: 0.95 (1H, m), 1.22 (3H, s),
1.65 (3H, s), 1.74 (3H, s), 1.5-2.5 (6H, m), 2.49 (1H, d, J =
4.4Hz), 2.57 (1H, t, J = 6.4Hz), 2.94 (1H, d, J = 4.4Hz), 3.4
2 (3H, s), 3.59 (1H, dd, J = 11.0Hz, J = 2.4Hz), 4.20 (1H, m),
5.03 (1H, d, J = 11.4Hz), 5.21 (1H, m), 5.28 (1H, d, J = 11.4H
z), 7.4-7.6 (4H, m) 7.8-7.9 (2H, m), 8.23 (1H, m).

Example 47 O- (4-picolyl) fumagillol

[0179]

[Chemical 51]

Fumagillol (272 mg) and 4-picolyl chloride hydrochloride (240 mg) were stirred at room temperature for 2 hours in the same manner as in Example 14 and subjected to silica gel column chromatography (developing solvent: n-hexane-ethyl acetate = 1: 1). Refined in
Colorless oil O- (4-picolyl) fumagillol 308 mg
(Yield 85%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.05 (1H, m), 1.22 (3H, s), 1.
66 (3H, s), 1.74 (3H, s), 1.75 (1H, m), 1.95-2.45 (5H, m), 2.5
5 (1H, d, J = 4.2Hz), 2.59 (1H, t, J = 6.4Hz), 2.98 (1H, d, J =
4.2Hz), 3.46 (3H, s), 3.63 (1H, dd, J = 11.2Hz, J = 2.4Hz),
4.14 (1H, m), 4.67 (1H, d, J = 13.8Hz), 4.81 (1H, d, J = 13.8H
z), 5.21 (1H, m), 7.31 (2H, d, J = 5.8Hz), 8.56 (2H, d, J = 5.8)
Hz).

Example 48 O- (0-bromomethylbenzyl) fumagillol

[0182]

[Chemical 52]

As in Example 14, fumagillol (264 mg) and 1,2-dibromomethylbenzene (297 mg) were mixed at room temperature for 2 times.
Stir for 0 minutes, silica gel column chromatography
Purification with (developing solvent: n-hexane-ethyl acetate = 5: 1) to obtain O- (0-bromomethylbenzyl) as a colorless oil.
145 mg of fumagillol (yield 33%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.01 (1H, m), 1.21 (3H, s),
1.65 (3H, s), 1.66 (1H, m), 1.74 (3H, s), 2.0-2.4 (5H, m), 2.5
2 (1H, d, J = 4.2Hz), 2.55 (1H, t, J = 6.4Hz), 2.95 (1H, d, J =
4.2Hz), 3.41 (3H, s), 3.59 (1H, dd, J = 11.2Hz, J = 2.6Hz),
4.17 (1H, m), 4.68 (1H, d, J = 10.2Hz), 4.74 (1H, d, J = 8.8H
z), 4.80 (1H, d, J = 8.8Hz), 4.85 (1H, d, J = 10.2Hz), 7.2-7.
45 (4H, m).

Example 49 O- (4-chlorobutyryl) fumagillol

[0185]

[Chemical 53]

A solution of fumagillol (300 mg) and dimethylaminopyridine (260 mg) in anhydrous dichloromethane (5 ml) was added to 4-chlorobutyryl chloride (0.14 ml) under ice cooling.
1) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with a solution of n-hexane and ethyl acetate (1: 4). The eluate was concentrated under reduced pressure to obtain O- (4-
Chlorobutyryl) fumagillol (311 mg) was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.10 (1H, s),
1.21 (3H, s), 1.66 (3H, s), 1.75 (3H, s), 1.80-2.45 (7H, m),
2.58 (4H, m), 2.99 (1H, d, J = 4.2Hz), 3.43 (3H, s), 3.61 (2H,
t, J = 6.4Hz), 3.64 (1H, dd, J = 2.8Hz, J = 11.4Hz), 5.21 (1
H, m), 5.68 (1H, m).

Example 50 O- (N-methylsulfamoyl) fumagillol

[0189]

[Chemical 54]

To a solution of fumagillol (300 mg) and dimethylaminopyridine (400 mg) in anhydrous dichloromethane (2 ml) was added N-methylsulfamoyl chloride (0.30 ml).
Was added dropwise, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography to obtain a solution of n-hexane and ethyl acetate.
Elution with (1: 2) and concentration of the eluate under reduced pressure gave O- (N-methylsulfamoyl) fumagillol (367 mg) as colorless crystals. A part of this was recrystallized from isopropyl ether and the melting point was measured. Melting point: 108 to 109 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.12 (1H, s), 1.20 (3H, s),
1.66 (3H, s), 1.75 (3H, s), 1.95 (1H, d, J = 11.4Hz), 1.85-2.
45 (4H, m), 2.58 (1H, t, J = 6.6Hz), 2.60 (1H, d, J = 4.0Hz),
2.80 (3H, d, J = 5.2Hz), 2.99 (1H, d, J = 4.0Hz), 3.56 (3H,
s), 3.68 (1H, dd, J = 2.0Hz, J = 11.4Hz), 5.15-5.30 (3H,
m).

Example 51 O-chloroacetylcarbamoyldihydrofumagillol

[0192]

[Chemical 55]

Dihydrofumagillol (15
0 mg) to give 173 mg of O-chloroacetylcarbamoyl fumagillol (yield 81%). ¹ H-NMR (CDCl ₃ ) δ: 0.91 (6H, d, J = 6.6Hz), 1.13
(1H, m), 1.18 (3H, s), 1.2-2.2 (9H, m), 2.57 (1H, dd, J = 7.2H
z, J = 4.6Hz), 2.63 (1H, d, J = 4.2Hz), 2.91 (1H, d, J = 4.2H
z), 3.47 (3H, s), 3.69 (1H, dd, J = 11.4Hz, J = 2.6Hz), 4.44
(2H, s), 5.62 (1H, brs), 8.36 (1H, brs).

Example 52 O-[[1- (2-dimethylaminoethyl) tetrazole]
-5-yl-thioacetylcarbamoyl] fumagillol

[0195]

[Chemical 56]

As in Example 42, O-chloroacetylcarbamoylfumagillol (195 mg) and 1- (2-dimethylaminoethyl) -5-mercaptoterazol sodium salt (1
13 mg) was stirred at room temperature for 1 hour and purified by silica gel column chromatography (developing solvent: ethyl acetate),
A colorless powder of O-[[1- (2-dimethylaminoethyl) tetrazole] -5-yl-thioacetylcarbamoyl] fumagillol (217 mg, yield 83%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.10 (1H, m), 1.20 (3H, s),
1.66 (3H, s), 1.75 (3H, s), 1.8-2.45 (6H, m), 2.59 (2H, m), 2.
77 (2H, t, J = 6.2Hz), 2.99 (1H, d, J = 4.2Hz), 3.47 (3H, s),
3.67 (1H, dd, J = 11.4Hz), 4.37 (4H, m), 5.20 (1H, m), 5.62 (1
H, m), 8.99 (1H, brs).

Example 53 O-[(2-methyl-1,3,4-thiadiazole-5-
[Il) thioacetylcarbamoyl] fumagillol

[0198]

[Chemical 57]

As in Example 42, O-chloroacetylcarbamoyl fumagillol (283 mg) and 2-methyl-1,3,4
-Thiadiazole-5-thiol sodium salt (130m
g) was stirred at room temperature for 30 minutes and subjected to silica gel column chromatography (developing solvent: n-hexane-ethyl acetate = 1: 1).
1) to obtain a colorless powder of O-[(2-methyl-1,
293 mg (yield 84%) of 3,4-thiadiazol-5-yl) thioacetylcarbamoyl] fumagillol was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.09 (1H, m), 1.20 (3H, s),
1.66 (3H, s), 1.75 (3H, s), 1.6-2.4 (6H, m), 2.57 (2H, m), 2.7
3 (3H, s), 2.98 (1H, d, J = 4.2Hz), 3.45 (3H, s), 3.67 (1H, dd,
J = 11.2Hz, J = 2.6Hz), 4.32 (1H, d, J = 16.2Hz), 4.44 (1H,
d, J = 16.2Hz), 5.21 (1H, m), 5.61 (1H, brs), 9.43 (1H, br
s).

Example 54 O- (1-naphthalenethioacetylcarbamoyl) fumagillol

[0201]

[Chemical 58]

As in Example 42, O-chloroacetylcarbamoylfumagillol (159 mg) and naphthalenethiol sodium salt (188 mg) were stirred at room temperature for 5 minutes and subjected to silica gel column chromatography (developing solvent: n-hexane-ethyl acetate = 3). 1), and O- (1-
Naphthalenethioacetylcarbamoyl) fumagillol 1
69 mg (81% yield) were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.08 (1H, m), 1.20 (3H, s),
1.66 (3H, s), 1.75 (3H, s), 1.89 (1H, d, J = 11.2Hz), 1.6-2.4
5 (5H, m), 2.54 (2H, m), 2.73 (3H, s), 2.98 (1H, d, J = 4.2Hz),
3.45 (3H, s), 3.66 (1H, dd, J = 11.2Hz, J = 2.6Hz), 3.96 (1H,
d, J = 15.4Hz), 4.07 (1H, d, J = 15.4Hz), 5.20 (1H, m), 5.57
(1H, m), 7.35-7.9 (6H, m), 8.11 (1H, brs), 8.40 (1H, d, J = 7.
8Hz).

Example 55 O-[(N-methylpyrrolidinium) acetylcarbamoyl] fumagillol chloride

[0204]

[Chemical 59]

O-chloroacetylcarbamoyl fumagillol (170 mg) and N-methylpyrrolidine (1 ml) were stirred in a solution of ether (3 ml) at room temperature for one week. The resulting precipitate was collected by filtration, washed with ether, and dried under reduced pressure to give 170 mg of O-[(N-methylpyrrolidinium) acetylcarbamoyl] fumagillol chloride as a colorless powder (yield 82
%). ¹ H-NMR (CDCl ₃ ) δ: 0.97 (1H, m), 1.16 (3H, s),
1.63 (3H, s), 1.73 (3H, s), 1.4-2.7 (1H, m), 2.53 (1H, d, J =
4.2Hz), 2.66 (1H, t, J = 6.2Hz), 2.94 (1H, d, J = 4.2Hz), 3.4
1 (3H, s), 3.42 (2H, s), 3.64 (1H, dd, J = 11.4Hz, J = 2.6Hz),
3.8-4.1 (4H, m), 4.70 (1H, d, J = 16.8Hz), 5.14 (1H, m), 5.40
(1H, d, J = 16.8Hz), 5.60.

Example 56 O- [2- (N, N, N-trimethylammonio) ethylcarbamoyl] fumagillol iodide

[0207]

[Chemical 60]

O- (2-Dimethylaminocarbamoyl) fumagillol (81 mg) and methyl iodide (0.5 ml) were stirred in a solution of dichloromethane (1 ml) at room temperature for 15 hours. The solvent was concentrated under reduced pressure, and the obtained residue was washed with ether to give O- [2- (N, N, N-trimethylammonio) ethylcarbamoyl] fumagillol iodide 10 as a colorless powder.
5 mg (yield 95%) was obtained. Melting point: 94-95 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.03 (1H, m), 1.17 (3H, s),
1.66 (3H, s), 1.75 (3H, s), 1.5-2.4 (6H, m), 2.57 (1H, d, J =
4.2Hz), 2.68 (1H, t, J = 6.6Hz), 2.97 (1H, d, J = 4.2Hz), 3.4
4 (12H, s), 3.3-3.9 (5H, m), 5.18 (1H, m), 5.50 (1H, m), 6.80
(1H, m).

Example 57 O- [N-acetyl (2-dimethylaminoethylcarbamoyl)] fumagillol

[0210]

[Chemical formula 61]

A solution of O- (2-dimethylaminocarbamoyl) fumagillol (145 mg) and triethylamine (0.5 ml) in dichloromethane (2 ml) was added acetic anhydride (0.3 ml), and the mixture was stirred at room temperature for 1 day. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography (developing solvent: dichloromethane-methanol = 20: The product was purified in 1) to obtain 113 mg (yield 73%) of a colorless oily substance, O- [N-acetyl (2-dimethylaminocarbamoyl)] fumagillol. ¹ H-NMR (CDCl ₃ ) δ: 1.15 (1H, m), 1.20 (3H, s),
1.65 (3H, s), 1.74 (3H, s), 1.95 (3H, s), 1.9-2.6 (7H, m), 2.5
0 (3H, s), 2.53 (3H, s), 2.60 (1H, d, J = 4.4Hz), 2.78 (1H, t, J
= 6.4Hz), 2.86 (1H, m), 3.02 (1H, t, J = 6.4Hz), 3.45 (3H,
s), 3.69 (1H, dd, J = 11.4Hz, J = 2.8Hz), 4.03 (2H, m), 5.20
(1H, m), 5.71 (1H, m).

Example 58 O-acryloylcarbamoyl fumagillol

[0213]

[Chemical formula 62]

Fumagillol (220 mg) and acryloyl isocyanate (200 mg) were stirred at room temperature for 30 minutes as in Example 8 and subjected to silica gel chromatography (developing solvent: n-
60 mg of O-acryloylcarbamoyl fumagillol as colorless powder after purification with hexane-ethyl acetate = 3: 1)
(Yield 21%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.
10 (1H, m), 1.21 (3H, s), 1.66 (3H, s), 1.75 (3H, s), 1.6-2.5
(6H, m), 2.58 (1H, d, J = 4.2Hz), 2.59 (1H, m), 2.99 (1H, d, J
= 4.2Hz), 3.47 (3H, s), 3.69 (1H, dd, J = 11.2Hz, J = 2.6Hz),
5.21 (1H, m), 5.60 (1H, m), 5.88 (1H, dd, J = 10.4Hz, J = 1.6H
z), 6.51 (1H, dd, J = 17.0Hz, J = 1.6Hz), 6.92 (1H, dd, J = 1
7.0Hz, J = 1.6Hz), 6.92 (1H, dd, J = 17.0Hz, J = 10.4Hz), 7.
78 (1H, brs).

Example 59 O-[(1-methyl-2-methoxycarbonyl-1,3,
4-triazol-5-yl) thioacetylcarbamoyl] fumagillol

[0216]

[Chemical formula 63]

As in Example 42, O-chloroacetylcarbamoylfumagillol (270 mg) and 1-methyl-2-methoxycarbonyl-1,3,4-triazole-5-thiol sodium salt (164 mg) were added at room temperature for 30 minutes. Stir,
Purified by silica gel chromatography (developing solvent: n-hexane-ethyl acetate = 1: 4) to obtain O as colorless powder.
-[(1-methyl-2-methoxycarbonyl-1,3,4
288 mg (yield 80%) of -triazol-5-yl) thioacetylcarbamoyl] fumagillol was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.07 (1H, m), 1.18 (3H, s),
1.65 (3H, s), 1.75 (3H, s), 1.6-2.4 (6H, m), 2.54 (2H, m), 2.9
6 (1H, d, J = 4.2Hz), 3.44 (3H, s), 3.64 (1H, dd, J = 11.4Hz, J
= 2.4Hz), 3.91 (3H, s), 3.99 (3H, s), 4.30 (1H, d, J = 15.8H
z), 4.41 (1H, d, J = 15.8Hz), 5.19 (1H, m), 5.59 (1H, m), 9.96
(1H, brs).

Example 60 O-[(2-benzoxazolyl) thioacetylcarbamoyl] fumagillol

[0219]

[Chemical 64]

As in Example 42, O-chloroacetylcarbamoyl fumagillol (230 mg) and 2-mercaptobenzoxazole sodium salt (119 mg) were added at room temperature to 30 mg.
The mixture was stirred for minutes, purified by silica gel column chromatography (developing solvent: n-hexane-ethyl acetate = 3: 1), and colorless powder O-[(2-benzoxazolyl) thioacetylcarbamoyl] fumagillol 269 mg ( Yield 91
%). ¹ H-NMR (CDCl ₃ ) δ: 1.04 (1H, m), 1.20 (3H, s),
1.66 (3H, s), 1.75 (3H, s), 1.8-2.6 (8H, m), 2.97 (1H, d, J =
4.4Hz), 3.47 (3H, s), 3.67 (1H, dd, J = 11.2Hz, J = 2.6Hz),
4.31 (2H, s), 5.20 (1H, m), 5.63 (1H, m), 7.2-7.3 (2H, m), 7.4
7 (1H, m), 7.58 (1H, m), 9.49 (1H, brs).

Example 61 O-[(2-benzimidazolyl) thioacetylcarbamoyl] fumagillol

[0222]

[Chemical 65]

In the same manner as in Example 42, O-chloroacetylcarbamoylfumagillol (257 mg) and 2-mercaptobenzimidazole sodium salt (132 mg) were stirred at room temperature for 30 minutes and subjected to silica gel column chromatography (developing solvent: n-hexane). -Ethyl acetate = 1: 1) to obtain colorless powder of O-[(2-benzimidazolyl) thioacetylcarbamoyl] fumagillol 297 mg (yield 90
%). ¹ H-NMR (CDCl ₃ ) δ: 1.03 (1H,
m), 1.19 (3H, s), 1.71 (3H, s), 1.83 (3H, s), 1.6-2.4 (7H, m),
2.57 (1H, d, J = 4.4Hz), 2.96 (1H, d, J = 4.4Hz), 3.46 (3H,
s), 3.68 (1H, dd, J = 11.6Hz, J = 2.2Hz), 3.74 (1H, d, J = 14.
2Hz), 3.87 (1H, d, J = 14.2Hz), 5.25 (1H, m), 5.69 (1H, m), 7.
10 (2H, m), 7.3-7.5 (2H, m), 11.01 (1H, brs), 12.60 (1H, br
s).

Example 62 O-[(8-quinolyl) thioacetylcarbamoyl] fumagillol

[0225]

[Chemical formula 66]

In the same manner as in Example 42, O-chloroacetylcarbamoylfumagillol (289 mg) and 8-mercaptoquinoline sodium salt (208 mg) were stirred at room temperature for 30 minutes,
Purification by silica gel column chromatography (developing solvent: n-hexane-ethyl acetate = 7: 3) gave 382 mg (yield 99%) of O-[(8-quinolyl) thioacetylcarbamoyl] fumagillol as colorless powder. It was ¹ H-NMR (CDCl ₃ ) δ: 1.07 (1H, m), 1.25 (3H, s),
1.65 (3H, s), 1.75 (3H, s), 1.6-2.55 (8H, m), 2.95 (1H, d, J =
4.2Hz), 3.51 (3H, s), 3.74 (1H, dd, J = 11.4Hz, J = 2.8Hz),
3.77 (1H, d, J = 15.4Hz), 3.92 (1H, d, J = 15.4Hz), 5.19 (1H,
m), 5.67 (1H, m), 7.50 (1H, t, J = 7.8Hz), 7.60 (1H, dd, J = 8.
4Hz, J = 4.4Hz), 7.82 (1H, d, J = 7.8Hz), 7.91 (1H, d, J = 7.2
Hz), 8.26 (1H, dd, J = 8.4Hz, J = 1.6Hz), 9.20 (1H, dd, J = 4.
4Hz, J = 1.6Hz), 11.84 (1H, brs).

Example 63 O-[(2-pyridyl) thioacetylcarbamoyl] fumagillol

[0228]

[Chemical formula 67]

In the same manner as in Example 42, O-chloroacetylcarbamoyl fumagillol (292 mg) and 2-pyridinethiol sodium salt (116 mg) were stirred at room temperature for 30 minutes and subjected to silica gel column chromatography (developing solvent: n-hexane- Purification with ethyl acetate = 2: 1) gave 325 mg (94% yield) of O-[(2-pyridyl) thioacetylcarbamoyl] fumagillol as a colorless powder. ¹ H-NMR (CDCl ₃ ) δ: 1.08 (1H, m), 1.21 (3H, s),
1.67 (3H, s), 1.76 (3H, s), 1.6-2.6 (8H, m), 2.98 (1H, d, J =
4.2Hz), 3.47 (3H, s), 3.66 (1H, dd, J = 11.2Hz, J, = 2.6Hz),
3.77 (1H, d, J = 14.8Hz), 3.93 (1H, d, J = 14.8Hz), 5.23 (1H,
m), 5.60 (1H, m), 7.11 (1H, m), 7.31 (1H, d, J = 8.8Hz), 7.59
(1H, m), 8.45 (1H, d, J = 5.0Hz), 10.67 (1H, brs).

Example 64 O-[(4-pyridyl) thioacetylcarbamoyl] fumagillol

[0231]

[Chemical 68]

In the same manner as in Example 42, O-chloroacetylcarbamoylfumagillol (290 mg) and 4-pyridinethiol sodium salt (115 mg) were stirred at room temperature for 30 minutes and subjected to silica gel column chromatography (developing solvent: n-hexane- The product was purified with ethyl acetate = 1: 2) to obtain 314 mg (yield 91%) of O-[(4-pyridyl) thioacetylcarbamoyl] fumagillol as a colorless powder. ¹ H-NMR (CDCl ₃ ) δ: 1.10 (1H, m), 1.21 (3H, s),
1.66 (3H, s), 1.75 (3H, s), 1.6-2.6 (6H, m), 2.54 (1H, t, J =
6.2Hz), 2.57 (1H, d, J = 4.4Hz), 2.98 (1H, d, J = 4.4Hz), 3.4
8 (3H, s), 3.69 (1H, dd, J = 11.2Hz, J = 2.4Hz), 4.13 (1H, d, J
= 15.8Hz), 4.22 (1H, d, J = 15.8Hz), 5.20 (1H, m), 5.61 (1H,
m), 7.22 (2H, dd, J = 5.0Hz, J = 1.4Hz), 8.43 (2H, d, J = 6.0H
z), 8.82 (1H, brs).

Example 65 O- (methylthioacetylcarbamoyl) fumagillol

[0234]

[Chemical 69]

As in Example 42, O-chloroacetylcarbamoylfumagillol (1070 mg) and methanethiol sodium salt (225 mg) were stirred at 10 ° C. for 1 hour and subjected to silica gel column chromatography (developing solvent: n-hexane-acetic acid). Purified with ethyl = 3: 1) to give colorless powder O-
(Methylthioacetylcarbamoyl) Fumagillol 500
mg (yield 45%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.10 (1H, m), 1.21 (3H, s),
1.66 (3H, s), 1.75 (3H, s), 1.75 (3H, s), 1.93 (1H, d, J = 11.2
Hz), 2.18 (3H, s), 1.7-2.45 (5H, m), 2.58 (2H, m), 2.99 (1H,
d, J = 4.2Hz), 3.47 (3H, s), 3.48 (1H, d, J = 16.8Hz), 3.55 (1
H, d, J = 16.8Hz), 3.68 (1H, dd, J = 11.2Hz, J = 2.8Hz), 5.20
(1H, m), 5.61 (1H, m), 8.12 (1H, brs).

Example 66 O-[(4-hydroxy-pyrimidin-2-yl) thioacetylcarbamoyl] fumagillol

[0237]

[Chemical 70]

In the same manner as in Example 42, O-chloroacetylcarbamoylfumagillol (239 mg) and thiouracil sodium salt (123 mg) were stirred at room temperature for 30 minutes and subjected to silica gel column chromatography (developing solvent: n-hexane-ethyl acetate = 1: 5) to obtain a colorless powder of O-
208 mg (71% yield) of [(4-hydroxy-pyrimidin-2-yl) thioacetylcarbamoyl] fumagillol was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.09 (1H, m), 1.22 (3H, s),
1.66 (3H, s), 1.75 (3H, s), 1.5-2.6 (7H, m), 2.58 (1H, d, J =
4.2Hz), 2.99 (1H, d, J = 4.2Hz), 3.47 (3H, s), 3.68 (1H, dd, J
= 11.2Hz, J = 2.4Hz), 4.08 (1H, d, J = 15.8Hz), 4.20 (1H, d,
J = 15.8Hz), 5.21 (1H, m), 5.61 (1H, m), 6.27 (1H, d, J = 6.6H
z), 7.88 (1H, d, J = 6.6Hz), 9.07 (1H, brs).

Example 67 O-[(1,2,3-triazol-5-yl) thioacetylcarbamoyl] fumagillol

[0240]

[Chemical 71]

O-chloroacetylcarbamoyl fumagillol (249 mg) and 5-mercapto-1, as in Example 42,
2,3-Triazole sodium salt (118 mg) was stirred at room temperature for 1 hour and subjected to silica gel column chromatography.
Purified with (developing solvent: n-hexane-ethyl acetate = 3: 2), colorless powder O-[(1,2,3-triazole-
5-yl) thioacetylcarbamoyl] fumagillol 20
6 mg (71% yield) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.07 (1H, m), 1.27 (3H, s),
1.67 (3H, s), 1.76 (3H, s), 1.7-2.6 (6H, m), 2.59 (1H, d, J =
4.2Hz), 2.79 (1H, t, J = 6.2Hz), 2.99 (1H, d, J = 4.2Hz), 3.4
1 (3H, s), 3.69 (1H, dd, J = 11.2Hz, J = 2.6Hz), 3.6-3.9 (2H,
m), 5.20 (1H, m), .59 (1H, m), 7.71 (1H, s), 8.90 (1H, brs).

Example 68 O-[(Dimethylthionium) acetylcarbamoyl] fumagillol iodide

[0243]

[Chemical 72]

O- (Methylthioacetylcarbamoyl) fumagillol (167 mg) and methyl iodide (1 ml) were stirred overnight in a solution of acetonitrile (1 ml) at room temperature. After the solvent was concentrated under reduced pressure, ether was added to the residue, and the resulting precipitate was collected by filtration, washed with ether, and dried under reduced pressure to give O-[(dimethylthionium) acetylcarbamoyl] colorless powder.
Fumagilol iodide 79 mg (yield 35%) was obtained. ¹ H-NMR (d ₆ -DMSO) δ: 1.09 (3H, s), 1.32 (1H,
m), 1.62 (3H, s), 1.72 (3H, s), 1.6-2.95 (10H, m), 2.92 (6H,
s), 3.34 (3H, s), 3.66 (1H, m), 4.90 (2H, s), 5.21 (1H, m), 5.4
9 (1H, m).

Example 69 O-[(N-methyl-pyridinium-4-yl) thioacetylcarbamoyl] fumagillol iodide

[0246]

[Chemical formula 73]

O-[(4pyridyl) thioacetylcarbamoyl] fumagillol (113 mg) and methyl iodide (1 m
a solution of l) in dichloromethane (2 ml) was stirred at room temperature overnight,
After the solvent was concentrated under reduced pressure, ether was added and the resulting precipitate was filtered off and washed with ether to give O-[(N-methyl-
Pyridinium-4-yl) thioacetylcarbamoyl] fumagillol 127 mg (yield 87%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.05 (1H, m), 1.21 (3H, s),
1.65 (3H, s), 1.74 (3H, s), 1.5-2.65 (7H, m), 2.92 (1H, t, J =
6.2Hz), 2.98 (1H, d, J = 4.0Hz), 3.49 (3H, s), 3.71 (1H, dd, J
= 11.2Hz, J = 2.4Hz), 4.32 (2H, m), 4.37 (3H, s), 5.19 (1H,
m), 5.64 (1H, m), 7.90 (2H, d, J = 6.8Hz), 8.76 (2H, d, J = 6.8
Hz), 10.12 (1H, brs).

Example 70 O- [N- (ethoxycarbonyl) -carbamoyl] fumagillol

[0249]

[Chemical 74]

As in Example 8, fumagillol (350 mg) and ethoxycarbonylisocyanate (200 mg) were added at room temperature in 3 parts.
Stir for 0 minutes, silica gel column chromatography
Purified with (developing solvent: n-hexane-ethyl acetate = 3: 1) to obtain colorless powder of O- [N- (ethoxycarbonyl)-
370 mg (yield 75%) of carbamoyl] fumagillol was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.08 (1H, m), 1.21 (3H, s),
1.30 (3H, t, J = 7.0Hz), 1.66 (3H, s), 1.75 (3H, s), 1.8-2.45
(6H, m), 2.56 (1H, d, J = 4.2Hz), 2.57 (1H, m), 2.98 (1H, d, J
= 4.2Hz), 3.46 (3H, s), 3.67 (1H, dd, J = 11.4Hz, J = 2.8H
z), 4.23 (2H, q, J = 7.0Hz), 5.21 (1H, m), 5.62 (1H, m), 7.21
(1H, brs).

Example 71 O- (3-furoyl) fumagillol

[0252]

[Chemical 75]

3-furancarboxylic acid (397 mg) was dissolved in dichloromethane (15 ml), and oxalyl chloride was added.
(0.62 ml) was added and the mixture was heated under reflux for 1 hour. After cooling, the solvent was distilled off under reduced pressure to obtain a crude product of acid chloride of 3-furancarboxylic acid. Fumagillol (500 mg) and dimethylaminopyridine (433 mg) were dissolved in dichloromethane (2 ml), and a solution of 3-furancarboxylic acid acid chloride in dichloromethane (5 ml) was added dropwise under ice cooling. After warming to room temperature and stirring for 30 minutes, ethyl acetate (50 m
l) was added and diluted, and the mixture was washed with 10% aqueous citric acid solution, saturated aqueous sodium chloride solution, saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate and evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (developing solvent: n
It was purified with -hexane-ethyl acetate = 1: 1) to obtain 187 mg (yield 28%) of O- (3-furoyl) fumagillol as a colorless oily substance. ¹ H-NMR (CDCl ₃ ) δ: 1.25 (1H, m), 1.23 (3H, s),
1.66 (3H, s), 1.75 (3H, s), 1.8-2.5 (5H, m), 1.98 (1H, d, 11H
z), 2.58 (1H, d, 4Hz), 2.61 (1H, t, 7Hz), 3.02 (1H, d, 4Hz), 3.
47 (3H, s), 3.72 (1H, dd, J = 3Hz, J = 11Hz), 5.21 (1H, m), 5.8
1 (1H, m), 6.72 (1H, m), 7.41 (1H, m), 8.00 (1H, m).

Example 72 O- [N- (3-Furoyl) -carbamoyl] fumagillol

[0255]

[Chemical 76]

3-Furoylamide (167 mg) was suspended in dichloromethane (10 ml), oxalyl chloride (0.20 ml) was added under ice cooling, and the reaction solution was warmed to room temperature. After further refluxing by heating for 10 hours, the solvent was distilled off to obtain a crude product of 3-furoyl isocyanate. This was stirred with fumagillol (213 mg) at room temperature for 30 minutes as in Example 8, and subjected to silica gel column chromatography (developing solvent:
Purification with n-hexane-ethyl acetate = 2: 1) gave 120 mg (yield 38%) of O- [N- (3-furoyl) carbamoyl] fumagillol as a colorless powder. ¹ H-NMR (CDCl ₃ ) δ: 1.11 (1H, m), 1.22 (3H, s),
1.66 (3H, s), 1.75 (3H, s), 1.8-2.5 (5H, m), 2.00 (1H, d, J = 1
1.2Hz), 2.57 (1H, d, J = 4.0Hz), 2.61 (1H, t, J = 6.6Hz), 2.9
9 (1H, d, J = 4.0Hz), 3.44 (4H, m), 3.70 (1H, dd, J = 11.2Hz, J
= 2.8Hz), 5.20 (1H, m), 5.63 (1H, m), 6.80 (1H, m), 7.47 (1H,
m), 8.16 (1H, m), 8.26 (1H, brs).

Example 73 O- [N- (phenoxycarbonyl) carbamoyl] fumagillol

[0258]

[Chemical 77]

As in Example 8, fumagillol (200 mg) and phenoxycarbonyl isocyanate (231 mg) were stirred at room temperature for 4 hours and subjected to silica gel column chromatography.
Purified with (developing solvent: n-hexane-ethyl acetate = 2: 1) to obtain O- [N- (phenoxycarbonyl) colorless powder.
125 mg (39% yield) of carbamoyl] fumagillol was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.09 (1H, m), 1.21 (3H, s),
1.65 (3H, s), 1.74 (3H, s), 1.5-2.5 (6H, m), 2.55 (1H, d, J =
4.1Hz), 2.57 (1H, t, J = 6.5Hz), 2.98 (1H, d, J = 4.1Hz), 3.5
0 (3H, s), 3.69 (1H, dd, J = 1.4Hz, J = 11.2Hz), 5.20 (1H, m),
5.70 (1H, m), 7.1-7.4 (5H, m), 7.66 (1H, brs).

Example 74 O- (N'-chloroacetyl allofanoyl) fumagillol

[0261]

[Chemical 78]

O-carbamoyl fumagillol (200 m
g) was dissolved in dichloromethane (4 ml), chloroacetylisocyanate (0.10 ml) was added, and the mixture was stirred for 4 hours.
The reaction mixture was diluted with ethyl acetate (50 ml) and washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate and evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (developing solvent: n-hexane-ethyl acetate =
1: 1) to obtain colorless powder of O- (N'-chloroacetyl allophanoyl) fumagillol 230 mg (yield 84
%). ¹ H-NMR (CDCl ₃ ) δ: 1.12 (1H, m), 1.21 (3H, s),
1.66 (3H, s), 1.75 (3H, s), 1.8-2.5 (6H, m), 1.92 (1H, d, J = 1
1.2Hz), 2.57 (1H, d, J = 4.2Hz), 2.59 (1H, t, J = 6.8Hz), 2.9
9 (1H, d, J = 4.2Hz), 3.48 (3H, s), 3.68 (1H, dd, J = 11.4Hz, J
= 2.8Hz), 4.39 (2H, s), 5.20 (1H, m), 5.65 (1H, m).

Example 75 O- (N'-benzoylalofanoyl) fumagillol

[0264]

[Chemical 79]

O-carbamoyl fumagillol (200 mg) and benzoyl isocyanate (0.51 m
1) was stirred at room temperature for 2 days and subjected to silica gel column chromatography (developing solvent: n-hexane-ethyl acetate = 3:
Purification in 2) yielded 100 mg (yield 34%) of colorless powder of O- (N'-benzoylalofanoyl) fumagillol. ¹ H-NMR (CDCl ₃ ) δ: 1.12 (1H, m), 1.22 (1H, m),
1.23 (3H, s), 1.66 (3H, s), 1.75 (3H, s), 1.97 (1H, d, J = 11.0
Hz), 1.8-2.5 (5H, m), 2.58 (1H, d, J = 4.2Hz), 2.62 (1H, t, J
= 6.8Hz), 3.00 (3H, d, J = 4.2Hz), 3.50 (3H, s), 3.69 (1H, d
d, J = 11.0Hz, J = 2.6Hz), 5.20 (1H, m), 5.72 (1H, brs), 7.5-
7.7 (3H, m), 7.91 (2H, m).

Example 76 O-chloroacetylcarbamoyl-6'b-hydroxyfumagillol

[0267]

[Chemical 80]

Selenium dioxide (295 mg) was added to a 95% ethanol (30 ml) solution of O-chloroacetylcarbamoyl fumagillol (711 mg), and the mixture was heated and refluxed for 5 hours. The solvent was evaporated under reduced pressure, the obtained residue was dissolved in ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane-ethyl acetate = 1: 4) to obtain a colorless powder of O. 190 mg (yield 26%) of -chloroacetylcarbamoyl-6'b-hydroxyfumagillol was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.13 (1H, m), 1.22 (3H, s),
1.70 (3H, s), 1.6-2.5 (5H, m), 1.93 (1H, d, J = 11.2Hz), 2.60
(2H, d, J = 4.2Hz), 2.63 (1H, t, J = 6.3Hz), 2.94 (1H, d, J =
4.2Hz), 3.47 (3H, s), 3.69 (1H, dd, J = 11.2Hz, J = 2.8Hz),
4.05 (2H, d, J = 5.8Hz), 5.53 (1H, m), 5.61 (1H, m), 8.18 (1H,
brs).

Example 77 O-chloroacetylcarbamoyl-6'b-dimethylaminofumagillol (a) O-acetyl-6'b-hydroxyfumagillol

[0270]

[Chemical 81]

O-Acetyl fumagillol as in Example 76
Oxygenation of (1.00 g) with selenium dioxide (0.68 g) and purification by silica gel column chromatography (developing solvent: n-hexane-ethyl acetate = 1: 2) gave O as a colorless oil.
-Acetyl-6'b-hydroxyfumagillol 300 mg
(Yield 29%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.12 (1H, m), 1.23 (3H, s),
1.71 (3H, s), 1.8-2.4 (5H, m), 1.95 (1H, d, J = 11.2Hz), 2.10
(3H, s), 2.57 (1H, d, J = 4.2Hz), 2.64 (1H, t, J = 6.4Hz), 2.9
3 (1H, d, J = 4.2Hz), 3.43 (3H, s), 3.64 (1H, dd, J = 11.2Hz, J
= 2.8Hz), 4.05 (2H, brs), 5.54 (1H, m), 5.64 (1H, m).

(B) O-acetyl-6'b-dimethylaminofumagillol

[0273]

[Chemical formula 82]

O-Acetyl-6'b-hydroxyfumagillol (469 mg) was dissolved in dichloromethane (5 ml),
Triethylamine (0.13 ml) and then methanesulfonyl chloride (0.38 ml) were added under ice cooling and the mixture was stirred for 15 minutes. Ethyl acetate (50 ml) was added to the reaction mixture to dilute it,
It was washed with saturated aqueous sodium chloride solution. It was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was dissolved in dimethylformamide (5 ml), and anhydrous potassium carbonate (0.95 g) and dimethylamine hydrochloride (1.
12 g) was added, the temperature was raised to room temperature, and the mixture was stirred for 1 hour. The reaction mixture was diluted with ether (50 ml) and washed with saturated aqueous sodium chloride solution. Dried over anhydrous magnesium sulfate,
After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent: chloroform-methanol-ammonia water = 20: 1: 0.1) to give O-acetyl-6 'as a colorless oil. 118 mg (yield 23%) of b-dimethylamino fumagillol was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.08 (1H, m), 1.22 (3H, s),
1.71 (3H, s), 1.6-2.6 (5H, m), 1.96 (1H, d, J = 11.2Hz), 2.10
(3H, s), 2.18 (6H, s), 2.55 (1H, d, J = 4.4Hz), 2.62 (1H, t, J
= 6.4Hz), 2.81 (2H, brs), 2.95 (1H, d, J = 4.4Hz), 3.44 (3H,
s), 3.65 (1H, dd, J = 11.2Hz, J = 2.8Hz), 5.41 (1H, m), 5.65
(1H, m).

(C) 6'b-dimethylaminofumagillol

[0276]

[Chemical 83]

O-Acetyl-6'b-dimethylaminofumagillol (118 mg) was dissolved in methanol (2 ml),
A 1N aqueous sodium hydroxide solution (1 ml) was added and the mixture was stirred for 15 minutes. The reaction solution was diluted with ethyl acetate (50 ml),
It was washed with saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate and evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (developing solvent: chloroform-methanol-ammonia water = 20: 1: 0.1).
And 6'b-dimethylaminofumagillol (102 mg, yield 97%) were obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.99 (1H, m), 1.23 (3H, s),
1.70 (3H, s), 1.6-2.5 (5H, m), 1.94 (1H, d, J = 11.2Hz), 2.17
(6H, s), 2.54 (1H, d, J = 4.4Hz), 2.62 (1H, t, J = 6.4Hz), 2.8
0 (2H, brs), 2.90 (1H, d, J = 4.4Hz), 3.50 (3H, s), 3.63 (1H, d
d, J = 11.2Hz, J = 2.8Hz), 5.38 (1H, m), 5.40 (1H, m).

(D) O-chloroacetylcarbamoyl-6'b-dimethylaminofumagillol

[0279]

[Chemical 84]

6'b-Dimethylaminofumagillol (152 mg) and chloroacetylisocyanate as in Example 8
(67 mg) was stirred at room temperature for 1 hour and subjected to silica gel column chromatography (developing solvent: chloroform-methanol-
Ammonia water = 20: 1: 0.1) was used for purification to obtain 96 mg (yield 46%) of O-chloroacetylcarbamoyl-6′b-dimethylaminofumagillol as colorless powder. ¹ H-NMR (CDCl ₃ ) δ: 1.12 (1H, m), 1.22 (3H, s),
1.70 (3H, s), 1.6-2.6 (6H, m), 2.18 (6H, s), 2.58 (1H, d, J =
4.2Hz), 2.61 (1H, t, J = 6.5Hz), 2.81 (2H, brs), 2.95 (1H, d,
J = 4.2Hz), 3.47 (3H, s), 3.70 (1H, dd, J = 11.2Hz, J = 2.8H
z), 4.14 (2H, s), 5.40 (1H, m), 5.62 (1H, m).

[0281]

INDUSTRIAL APPLICABILITY The novel O-substituted fumagillin derivative according to the present invention has an anti-angiogenic activity and is used as an anti-rheumatic agent, a therapeutic agent for psoriasis, a therapeutic agent for diabetic retinopathy and an anticancer agent.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location A61K 31/425 ABL 7431-4C 31/44 ABG 7431-4C 31/47 ADU 7431-4C 31/495 7431-4C 31/505 7431-4C 31/535 7431-4C 31/54 7431-4C C07D 405/14 213 7602-4C 215 7602-4C 239 7602-4C 257 7602-4C 407/14 303 7602-4C 413 / 14 303 7602-4C 417/14 303 9051-4C (72) Inventor Moses Juda Folkman Massachusetts, United States 02146 Brooklyn Chatham Circle 18 (72) Donald Ingbar Massachusetts, United States 02116 Boston Montgomery Street 71

Claims (11)

[Claims] 1. A general formula: [In the formula, R ¹ is 2-methyl-which may have a substituent.
1-propenyl or isobutyl group, R ² is (1) an alkanoyl group having a substituent, (2) an alkyl group having 2 to 6 carbon atoms,
Aroyl group substituted with amino, halogen, hydroxyl, lower alkoxy, cyano, carbamoyl or carboxyl, (3) optionally substituted aromatic heterocyclic carbonyl group, (4) having a substituent Good alkyl group, (5) optionally substituted benzenesulfonyl group, (6) optionally substituted alkylsulfonyl group, (7) optionally substituted sulfamoyl Base,
(8) An alkoxycarbonyl group which may have a substituent or (9) a phenoxycarbonyl group which may have a substituent. ] An O-substituted fumagillol derivative represented by the following or a pharmacologically acceptable salt thereof, for inhibiting angiogenesis in animals. 2. The pharmaceutical composition according to claim 1, wherein R ¹ is a 2-methyl-1-propenyl group which may be substituted with hydroxy or dialkylamino. 3. R ² is amino, alkylamino having 1 to 6 carbon atoms, di (C 1 to 6) alkylamino, nitro, halogen, alkoxy having 1 to 6 carbon atoms, cyano, carbamoyl, carboxyl, carbon number. 1 to 6 alkylcarboxy, carboxy (1 to 6 carbon atoms) alkoxy, phenyl which may have a substituent, or C 2 which is substituted with an aromatic heterocycle which may have a substituent. 6. The pharmacological composition according to claim 1, wherein the alkanoyl group is from 6 to 6. 4. R ² is alkyl having 2 to 6 carbons, amino,
The pharmaceutical composition according to claim 1, which is a benzoyl or naphthoyl group substituted with halogen, hydroxy, alkoxy having 1 to 6 carbon atoms, cyano, carbamoyl or carboxyl. 5. The pharmaceutical composition according to claim 1, wherein R ² is an aromatic heterocyclic carbonyl selected from furoyl, thenoyl, nicotinoyl, isonicotinoyl and imidazol-1-carbonyl. 6. R ¹ may be epoxidized and may be substituted with carboxyl, optionally substituted pyridyl, naphthyl or phenyl, and has 1 carbon atom.
The pharmaceutical composition according to claim 1, which is alkyl of 6 to 6. 7. The pharmaceutical composition according to claim 1, wherein R ² is benzenesulfonyl which may be substituted with alkyl having 1 to 6 carbons or halogen. 8. The pharmaceutical composition according to claim 1, wherein R ² is alkylsulfonyl having 1 to 6 carbon atoms. 9. The pharmaceutical composition according to claim 1, wherein R ² is sulfamoyl optionally substituted with alkyl having 1 to 6 carbons or phenyl. 10. The pharmaceutical composition according to claim 1, wherein R ² is alkoxycarbonyl having 1 to 6 carbon atoms which may be substituted with halogen. 11. The pharmaceutical composition according to claim 1, wherein R ² is phenoxycarbonyl which may be substituted with alkyl having 1 to 6 carbons or halogen.