JPH0660168B2 - 0-substituted fumagillol derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial application] The present invention has an angiogenesis-suppressing action and a therapeutic and preventive action for various inflammatory diseases (rheumatism, psoriasis, etc.), diabetic retinopathy, cancer, etc. The present invention relates to a novel O-substituted fumagillol derivative or a salt thereof.

[Prior Art] 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 thought that suppression of angiogenesis will lead to 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. [Tayl
or, S. et al. , Nature, 297 , 307
(1982)], a combination of heparin and cortisone by Volkman et al. [Folkman, J. et al. , Science (Scien
ce), 221 , 719 (1983)], and ascorbic acid ethers and related compounds (JP-A-58-131978) and sulfated polysaccharide DS4152 (JP-A-63-119500). Has been applied for a patent as a compound showing an angiogenesis suppressing action. However, their activities are not always sufficiently satisfactory, and the emergence of compounds having even more excellent activity is desired.

[Problems to be Solved by the Invention] An object of the present invention is to provide a novel compound having an angiogenesis suppressing action.

[Means for Solving the Problems] In order to achieve the above-mentioned object, the present inventors have performed a search and evaluation of various compounds, and as a result, fumagillin, which has hitherto been known as an antibacterial agent and an antiprotozoal agent, The present invention has been completed by finding that the O-substituted derivative of the hydrolyzate fumagillol of (1) has an excellent anti-angiogenic effect. That is, the present invention has the general formula [In the formula, R ¹ represents a 2-methyl-1-propenyl or isobutyl group which may be substituted with a hydroxyl group or a di-lower alkylamino group, and R ² represents a lower alkenoyl group, a monochloroacetyl group, a dichloroacetyl group, Lower alkoxycarbonylmethyl group, carboxymethyl group, amino group, phenyl group substituted with alkyl halide, nitro or lower alkoxy group, benzoyl group, imidazole group formed with nitrogen atom of carbamoyl group, halogenated lower alkyl group , Lower alkylamino lower alkyl group, lower alkanoyloxy lower alkanoyl group, lower alkanoylthio lower alkanoyl group, lower alkylthio lower alkanoyl group, arylthio lower alkanoyl group, aromatic heterocyclic thio lower alkanoyl group, N-oxy 2-pyridylthio lower alkanoyl group, N-lower alkyl-4-pyridiniothio lower alkanoyl halide group, dilower alkylamino lower alkanoyl group, ammonio lower alkanoyl halide group, aromatic heterocyclic carbonyl group, lower alkoxycarbonyl group, phenoxy A carbamoyl group substituted with a carbonyl group, a chloroacetylcarbamoyl group, a benzoylcarbamoyl group, a phenylsulfonyl group optionally substituted with a lower alkyl group, a di (lower alkylsulfonio) lower alkanoyl halide group or a naphthylcarbamoyl group. ] O represented by
A substituted fumagillol derivative (hereinafter sometimes simply referred to as compound (I)), or a salt thereof, and a process for producing the same.

In the above general formula, R ¹ is 2-methyl-1 which may be substituted with a hydroxyl group or a di-lower alkylamino group (eg, dimethylamino, diethylamino, etc.).
-Propenyl or isobutyl groups.

In the above general formula, the carbamoyl group having a substituent represented by R ² includes a mono-substituted carbamoyl group and a di-substituted carbamoyl group, and examples of the substituent include lower alkenoyl (preferably having 1 to 6 carbon atoms, eg, acryloyl). , Metaacryloyl), monochloroacetyl, dichloroacetyl, lower alkoxycarbonylmethyl (eg, methoxycarbonylmethyl, ethoxycarbonylmethyl, etc.), carboxymethyl, amino, alkyl halide, phenyl substituted with nitro or lower alkoxy group, benzoyl And an imidazole group formed together with the nitrogen atom of the carbamoyl group. Further, as a substituent of the carbamoyl group, halogenated lower alkyl (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-benzimidazolylthio, 8-quinolylthio, [1- (2-dimethylaminoethyl) tetrazole] -5-ylthio, 2-methyl-
1,3,5-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 (eg, dimethylaminoacetyl, diethylaminoacetyl, etc.), ammonio lower alkanoyl halide (eg, trimethylammonioacetyl iodide, N-methylpyrrolidinioacetyl. Chloride, etc.), aromatic heterocyclic carbonyl (eg, 3-furoyl, nicotinyl, 2-thenoyl, etc.), lower alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.), phenoxycarbonyl, chloroacetylcarbamoyl, benzoylcarbamoyl, lower alkyl Phenylsulfonyl which may be substituted with a group (eg, benzenesulfonyl, toluenesulfonyl, etc.), di-lower alkylsulfonio-lower alkanoyl halide (eg,
Dimethyl sulfonioacetyl iodide, etc.), naphthylcarbamoyl and the like. Of these, monochloroacetyl is preferred.

In the present specification, the substituent of the phenyl group which may have a substituent includes a lower alkoxy (eg, methoxy,
Ethoxy, propoxy, etc.), alkyl halides (eg, trifluoromethyl, chloromethyl, bromomethyl, etc.), nitro, etc., and these substituents are substituted at 1 to 5 positions at any position on the phenyl ring. Good.

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 include, for example, trimethylamine, triethylamine, pyridine, picoline, N, N-dibenzylethylenediamine, ethanolamine, diethanolamine, trishydroxymethylaminomethane, dicyclohexylamine and the like, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, and organic acids such as Formic acid, acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like can be used as basic or acidic amino acids such as arginine, lysine, ornithine and aspa. Gin acid, such as glutamic acid is used. Among these salts, a salt with a base (that is, a salt with an inorganic base, a salt with an organic base, a salt with a basic amino acid) is a salt with a carboxyl group in the substituent of the compound (I) and an acid ( That is, a salt with an inorganic acid, a salt with an organic acid, a salt with an acidic amino acid means a salt that can be formed with an amino group, a lower alkylamino group, a dilower alkylamino group or the like in the substituent of compound (I). To do.

In the general formula (I), the O-substituted fumagillol derivative in which R ¹ is a 2-methyl-1-propenyl group is a fumagillol hydrolyzate produced by a microorganism, fumagillol [Tarbell, D. S. et
al. , Journal of American Chemical Society (J. Am. Chem. Soc.) 83 , 3096 (196)
1)] can be produced using a carbamoylating agent, for example, by subjecting them to a carbamoylation reaction, or by isolating an intermediate of those reactions.

In the general formula (I), the O-substituted dihydrofumagillol derivative in which R ¹ is 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 (I
I) can be produced by subjecting it to a reaction similar to that described above.

When R ² is a group that does not change by catalytic reduction, R ¹ is represented by an isobutyl group by catalytically reducing the O-substituted fumagillol derivative represented by R ¹ by a 2-methyl-1-propenyl group. It can also be converted to an O-substituted dihydrofumagillol derivative.

(Production Method) In the general formula (I), the O-substituted fumagillol derivative represented by 2-methyl-1-propenyl in which R ¹ is substituted with hydroxyl or an isobutyl group has a hydroxyl group at 6-position protected. A good 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 a carbamoylation reaction, or an intermediate thereof is isolated. It can be manufactured by When carrying out the above carbamoylation reaction, the reaction can be advantageously proceeded by protecting the hydroxyl introduced into R ^{1 as} necessary.

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.

The O-substituted fumagillol derivative represented by the general formula (I) in which R ¹ is substituted with di-lower alkylamino is a 2-methyl-1-propenyl or isobutyl group, and the O-substituted fumagillol derivative has a 4-position side chain of 2 -A fumagillol derivative in which a hydroxyl group at the 6-position, in which a hydroxyl group has been introduced to a methyl-1-propenyl or isobutyl group, may be protected, is subjected to an amination reaction, and then the protective group at the 6-position hydroxyl group is deprotected, if necessary. Then, it can be produced by subjecting to a carbamoylation reaction or by isolating an intermediate of those reactions.

When R ² is a group which is not changed by the amination reaction, an O-substituted fumagillol derivative represented by general formula (I) wherein R ¹ is a hydroxyl-substituted 2-methyl-1-propenyl or isobutyl group. Can also be produced by directly subjecting a.

In the general formula (I), R ¹ is O represented by isobutyl group substituted with hydroxyl or di (lower alkyl) amino.
-The substituted fumagillol derivative is 2-methyl- of the 4-position side chain.
The fumagillol derivative in which hydroxyl and di-lower alkylamino were introduced to 1-propenyl group and the 6-position hydroxyl may be protected was subjected to catalytic reduction reaction, and the 6-hydroxyl protecting group was deprotected as necessary. Then, it can also be produced by subjecting it to a carbamoylation reaction or by isolating an intermediate of those reactions. In carrying out the carbamoylation reaction, the hydroxyl group in R ¹ may be protected if necessary to allow the reaction to proceed advantageously.

When R ² is a group which does not change by the catalytic reduction reaction, R ¹ in general formula (I) is 3-hydroxy-2-
It can also be produced by subjecting an O-substituted fumagillol derivative represented by a 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 heterocycle in R ¹ [Reference: Gr
ren, TW, “Protective Group in Organic Synthesi
s ”, John Wiley & Sons, New York (1981)].

When the carbamoylating agent has substituents such as amino, hydroxyl, and carboxyl, these substituents are preferably protected, and an appropriate protecting group is selected depending on the stability of the product. Examples of preferable protecting groups include 4-nitrobenzyloxycarbonyl and 2-trimethylsilylethoxycarbonyl in the case of amino, and 4 in the case of hydroxyl.
-Nitrobenzyl, t-butyldimethylsilyl and the like can be mentioned, and in the case of carboxyl, for example, 4-nitrobenzyl and the like can be mentioned. As the deprotection method, a catalytic reduction or a usual method of reacting with a fluoride ion can be adopted. In the case of a carbamoylation reaction, it is also possible to use a lower alkyl group such as a methyl group or an ethyl group as a protective group for a carboxyl group, and to perform deprotection by hydrolyzing under mild alkaline conditions after the reaction. .

The carbamoylation reaction in the present invention can be carried out as follows, for example.

The carbamoylation reaction for introducing a 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 represents a substituted carbamoyl substituent represented by R ² such as chloroacetyl.) The isocyanate Is usually about 1 for 1 mol of raw alcohol.
Use from 5 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 carbonates, alkali metal hydrides, organic metals and the like are used, and the addition amount thereof is usually 1 alcohol of the raw material.
The amount 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, notoro compounds, ketones and aromatic hydrocarbons are used, and these are one or two. 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. The reaction time is about 1 hour to 5 days.

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 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 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 with respect to 1 mol of the raw material alcohol.

This reaction is usually carried out in an organic solvent that does not adversely affect 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, and these are one or two. 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 depends on the amount of carbamoyl halide, base and solvent,
Depending on the type, it is carried out at a temperature of 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 a raw material alcohol with 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 hydrogen carbonate, 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, and these are one or two. 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 ester obtained as an intermediate is 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, lower carboxylic acid, lower thiocarboxylic acid, thiol acid, 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 affect the reaction include:
The above-mentioned aliphatic saturated hydrocarbons, alcohols, amides, halogenated hydrocarbons, ethers, esters,
Nitriles, nitro compounds, ketones, and aromatic hydrocarbons are used, and these may be used alone or in admixture of two or more 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 will differ depending on the amount and type of nucleophile, base, solvent, etc., but is usually −80 to 100 ° C., preferably 0 ° C. to room temperature. The reaction time is about 20 minutes to 5 days.

The oxidation reaction in the present invention is carried out by using fumagillol in which the 6-position hydroxyl may be protected or an O-substituted fumagillol derivative represented by the general formula (I) in which R ¹ is 2-methyl-1-propenyl or isobutyl group. By reacting.

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.) are used, and two of these may be used in appropriate combination. 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 the amount and type of oxidant, solvent, etc., but is usually −80 to 100 ° C., preferably 0 ° C. to room temperature. The reaction time is about 20 minutes to 5 days.

The amination reaction is a fumagillol derivative in which a hydroxyl group is introduced into the 4-methyl-2-propenyl or isobutyl group at the 4-position side chain obtained by the above-mentioned oxidation reaction and the 6-position hydroxyl may be protected, or a general formula ( I) to the hydroxyl of the O-substituted fumagillol derivative in which R ¹ is a 2-methyl-1-propenyl or isobutyl group in which R ¹ is substituted with hydroxyl,
For example, the Mitsunobu reaction using imides such as phthalimide and succinimide [Reference: Mitunobu, O. et al. , Synthesis, 1981, p. 1], or a method of directly converting a hydroxyl into an amino acid, or by converting the hydroxyl into methanesulfonyloxy or toluenesulfonyloxy and then reacting with ammonia or amines. , Lower alkylamino, di-lower alkylamino, and the like.

In the reaction of the sulfonyloxy derivative with ammonia or amines, ammonia water such as ammonia water, ammonia gas, or liquid ammonia is used, and the amines include primary amines (eg, methylamine, ethylamine, isopropylamine, etc.), Secondary amines (eg, dimethylamine, diethylamine) are used.

This reaction is generally carried out in an amount of about 1 to 20 times, preferably 2 to 10 times the molar amount of ammonia or the amines relative to the starting materials, and is carried out in a solvent which does not adversely affect the reaction itself or the reaction. Examples of the solvent that does not adversely influence the reaction include water, the above-mentioned saturated aliphatic hydrocarbons, alcohols, amides, halogenated hydrocarbons, ethers, esters, nitriles, nitro compounds, ketones, and aromatics. Group hydrocarbons are used, and these may be used alone or as a mixture of two or more kinds at an appropriate ratio.

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.,
The temperature is preferably 0 ° C. to room temperature. The reaction time is about 20 minutes to 5 days.

Further, 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 Chemistry", Part 2
Vol., 4-11, Pergamon Press (1979)] N-
A fumagillol derivative which is alkylated and has a 6-hydroxyl group in which di-lower-alkylamino is introduced into 2-methyl-1-propenyl or isobutyl group at the 4-position side chain, or R ^{1 in the} general formula (I) is O-substituted fumagillol derivatives which are 2-methyl-1-propenyl or isobutyl groups substituted with di-lower alkylamino may be prepared.

O-substituted fumagillol derivative (I) thus produced
Can be isolated by a separation / 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.

INDUSTRIAL APPLICABILITY The compound of the present invention has an angiogenesis-inhibiting effect and is useful as a therapeutic and prophylactic agent for various inflammatory diseases (rheumatism, psoriasis), diabetic retinopathy, cancer, etc., and is pharmaceutically acceptable as it is or known per se. It can be safely administered orally or parenterally as a pharmaceutical composition mixed with carriers, excipients, etc. (eg, tablets, capsules (including soft capsules, microcapsules), solutions, injections, suppositories). it can. 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 0.1.
It is about 5 mg / kg to 20 mg / kg body weight.

[Effects of the Invention] The novel O-substituted fumagillin derivative according to the present invention has an anti-angiogenic activity and is used as an antirheumatic agent, a therapeutic agent for psoriasis, a therapeutic agent for diabetic retinopathy, and an anticancer agent.

[Action] Experimental Example With respect to the target compound (I) obtained in the following examples, the angiogenesis inhibitory action was measured by the rat corneal micropocket method and summarized in the table below.

Measuring method Gimbrone et al. [J. National Cancer Institut
e 52: 413-419 (1974)] and was carried out as follows. Sprague Dawley (Sp
Rague-Dawley) adult male rats (11-16 weeks old) were anesthetized with Nembutal, and xylocaine ophthalmic solution was dripped on the eyeball for local anesthesia. Sustained-release pellet of basic fibroblast growth factor (bFGF, bovine brain-derived purified product, R & D) and specimen by making an incision of about 2 mm with an injection needle in the cornea approximately 2 mm inward from the edge of the cornea Are inserted side by side so that the bFGF pellet is on the center side of the cornea. A bFGF pellet and a pellet containing no specimen were inserted into the control rat corneas. After 7 days and 10 days, the cornea was observed under a stereoscopic microscope, and it was determined that there was suppressive activity when angiogenesis by bFGF was delayed or weakened by the administration of the sample.

The sustained release pellet was prepared by the following method. Ethylene-vinyl acetate copolymer (Takeda Pharmaceutical Co., Ltd.) was dissolved in dichloromethane so that the concentration was 8%, and 3 μ of the solution was air-dried on a glass Petri dish, and bFGF aqueous solution (250 ng) was collected and air-dried. The ethylene-vinyl acetate copolymer solution was placed on the above and air-dried to prepare a sandwich sheet of bFGF. Roll this sandwich sheet into bFGF
It was made into pellets. Sample pellet is 20 μg / 2
It was dissolved in ethanol so as to have a thickness of μ, mixed with 6 μm of the ethylene-vinyl acetate copolymer solution, and then air-dried on a glass petri dish, and the resulting sheet was rolled to prepare.

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.

[Examples] Hereinafter, the present invention will be described in more detail with reference to Reference Examples and Examples, but the present invention is not limited to these Examples.

Elution by column chromatography (indicated by elution solvent in parentheses) in the following Reference Examples and Examples is TLC (Th
in Layer Chromatography)
Conducted under the observation of.

In the TLC observation, as the TLC plate (Merck) manufactured Kieselgel 60F ₂₅₀ (70-230 mesh)
, A solvent used as an elution solvent in column chromatography as a developing solvent, a UV detector as a detection method,
The coloring method using phosphomolybdic acid was adopted. The silica gel for columns is Kieselgel 60 (7
0-230 mesh) was used. The NMR spectrum shows proton NMR ( ¹ H-NMR), and using tetramethylsilane as an internal or external standard, the Varian (VARI
It was measured with a Gemini 200 manufactured by AN), and the δ value was shown in ppm.

The abbreviations used in Reference Examples and 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 constants, Hz: Hertz, CDCl _3: heavy chloroform, d _6-DMSO: deuterated dimethyl sulfoxide,%:
% By weight In the following Reference Examples and Examples, room temperature is about 1
It means 5 to 25 ° C. All melting points and temperatures are given in degrees Celsius.

Reference Example 1 Dihydrofumagillol Fumagillol (1.12g) in ethanol (13m)
The solution was subjected to catalytic reduction at room temperature for 1 hour under atmospheric pressure using 5% palladium carbon (120 mg) as a catalyst. After filtering the reaction solution,
The solvent was concentrated under reduced pressure and the resulting residue was subjected to silica gel chromatography (developing solvent: n-hexane-ethyl acetate =
2: 1) and purified, Journal of the American Chemical Society, Vol. 78, page 4675 (1
956) to obtain 871 mg of dihydrofumagillol (yield 77%).

Example 1 O-chloroacetylcarbamoyl fumagillol Fumagillol (314 mg) in dichloromethane (5 m)
Chloroacetyl isocyanate (160
mg) was added dropwise, and then dimethylaminopyridine (130
mg) was added and the mixture was stirred at 0 ° C. for 2 hours. 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 2 O-carboxymethylcarbamoyl fumagillol sodium salt As in Example 1, 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) to give a colorless oil. The product 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). 1N sodium hydroxide (2 m) was added to a solution of O-ethoxycarbonylmethylcarbamoylfumagillol in ethanol (3 m), 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 and extracted with ethyl acetate,
It was 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
Water (1 m) was added to 0 mg), and sodium hydrogen carbonate (4
0 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 (1 H, m), 1.23 (3 H, 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 3 O- (m-trifluoromethylphenylcarbamoyl)
Fumagillol In the same manner as in Example 1, 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). ,
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 4 O- [N- (1-naphthylcarbamoyl) -N- (1-
Naphthyl) carbamoyl] fumagillol In the same manner as in Example 1, fumagillol (220 mg) and 1-naphthylisocyanate (135 mg) were stirred at room temperature for 15 hours, purified by silica gel column chromatography (n-hexane: ethyl acetate = 9: 1), and colorless. Powder O- [N- (1-naphthylcarbamoyl) -N- (1-
215 mg (44% yield) of naphthyl) carbamoyl] fumagillol were obtained.

Example 14 O-methyl fumagillol Example 5 O-carbazoyl fumagillol With O-phenoxycarbonyl fumagillol (400 mg)
Stir the hydrazine (120 mg) at room temperature for 1 hour, then add silica.
Gel column chromatography (developing solvent: n-hexa
-Ethyl acetate = 1: 2) to give a pale yellow powder.
169 mg of O-carbazoyl fumagillol (yield 50%)
Got 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), 2.55 (1H, d, J =
4.2Hz), 2.56 (1H, t, J = 6.4Hz), 2.98 (1H, d, J = 4.2Hz), 3.4
7 (3H, s), 3.65 (1H, dd, J = 11.2Hz, J = 2.8Hz), 3.70 (2H, br
s), 5.20 (1H, m), 5.55 (1H, m), 6.19 (1H, brs). Example 6 O- (1-imidazolylcarbonyl) fumagillol Fumagillol (236mg) in dichloromethane (5m)
To the solution, 1,1'-carbonyldiimidazole (410
mg) was added and the mixture was stirred at room temperature for 1 day. The reaction solution is concentrated under reduced pressure,
The obtained residue is subjected to silica gel column chromatography.
(Developing solvent: n-hexane-ethyl acetate = 3: 2)
Purify to a colorless oil, O- (1-imidazolylcarboyl.
Nil) fumagillol (275 mg, yield 90%) 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 7 O- (2-dimethylaminoethylcarbamoyl) fumag
roll O- (1-imidazolylcarbonyl) fumagillol (2
70 mg) in dichloromethane (3 m) was added with 2-dimension.
Add tylaminoethylamine (90mg) and stir at room temperature for 1 day.
I stirred. The reaction mixture was diluted with ethyl acetate and saturated sodium hydrogen carbonate was added.
Wash with thorium solution, water, saturated sodium chloride solution
did. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure.
The solvent was distilled off and the resulting residue was purified by silica gel column chromatography.
Fee (developing solvent: chloroform-methanol = 20:
1) and purified by colorless powder O- (2-dimethylamido)
Noethylcarbamoyl) fumagillol 139 mg (yield 5
3%) was obtained. 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), 2.4
1 (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 8 O-dichloroacetylcarbamoyl fumagillol Fumagillol (570 mg) and dichloro as in Example 1
Stir acetyl isocyanate (500 mg) at room temperature for 10 minutes.
Stir, silica gel column chromatography (development
Purified with a medium: n-hexane-ethyl acetate = 3: 1)
Colorless candy-like O-dichloroacetylcarbamoyl fuma
789 mg of guirol (yield 90%) was obtained. 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 9 O-benzoylcarbamoyl fumagillol Fumagillol (510 mg) and benzoi as in Example 1
Diisocyanate (530 mg) at room temperature for 30 minutes,
Silica gel column chromatography (developing solvent: n-
Colorless powder purified by hexane-ethyl acetate = 3: 1)
450 mg of O-benzoylcarbamoyl fumagillol
(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), 3.4
2 (3H, s), 3.68 (1H, dd, J = 11.4Hz, J = 2.6Hz), 5.19 (1H, br
t, 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 10 O-methacryloylcarbamoyl fumagillol Fumagillol (1 g) and methacryloyl as in Example 1
Diisocyanate (900 mg) was stirred at room temperature for 10 minutes,
Silica gel column chromatography (developing solvent: n-
Colorless powder purified by hexane-ethyl acetate = 2: 1)
O-methacryloylcarbamoyl fumagillol 511
mg (yield 37%) 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 11 O- (2-chloroethylcarbamoyl) fumagillol Fumagillol (263 mg) and 2-chloro as in Example 1
Stir the ethyl acetate (150mg) for 1 day at room temperature
Silica gel column chromatography (developing solvent:
Purified with n-hexane-ethyl acetate = 3: 1)
Color powder O- (2-chloroethylcarbamoyl) fumagugi
100 mg of rolls (28% yield) were obtained. ¹ H-NMR (CDCl ₃ ) Δ: 1 (3H, s), 1.66 (3H, s), 1.7
5 (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 12 O- (p-nitrophenylcarbamoyl) fumagillol Fumagillol (290 mg) and p-nit as in Example 1.
Rophenyl isocyanate (500mg) at room temperature at 20:00
Stir for 1 hour, and then silica gel column chromatography (development
Purify with solvent: n-hexane-ethyl acetate = 5: 1)
Light yellow powder O- (p-nitrophenylcarbamoy
Lu) Fumagillol (255 mg, yield 56%) was obtained. 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 13 O- (p-toluenesulfonylcarbamoyl) fumagiro
The Fumagillol (213 mg) and p-tolu as in Example 1.
Ensulphonyl isocyanate (250 mg) at room temperature for 2
After stirring for an hour, silica gel column chromatography
Purification with open solvent: n-hexane-ethyl acetate = 2: 1)
And colorless powder O- (p-toluenesulfonylcarbamo
247 mg (yield: 68%) of fumagillol was obtained. 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 14 O-acetoxyacetylcarbamoyl fumagillol O-chloroacetylcarbamoyl fumagillol (201
(mg) in dimethylformamide (3 m) solution,
Thorium (200 mg) was added, and the mixture was stirred at 60 ° C for 1 hr.
The reaction mixture was diluted with ethyl acetate, water and saturated sodium chloride.
Wash with aqueous solution, dry over anhydrous magnesium sulfate, and depressurize
The solvent was distilled off underneath. The residue obtained is a silica gel column.
Chromatography (developing solvent: n-hexane-acetic acid)
Chill = 2: 1) and colorless powder of O-acetoxy
165 mg of ciacetylcarbamoyl fumagillol (yield 7
7%). 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 15 O-Acetylthioacetylcarbamoyl fumagillol O-chloroacetylcarbamoyl fumagillol (155
(mg)) in dimethylformamide (2m) solution, thiovinegar
Potassium acid (70 mg) was added and stirred at room temperature for 1 minute. Anti
Dilute the reaction solution with ethyl acetate, and then add water and saturated aqueous sodium chloride.
Wash with solution, dry over anhydrous magnesium sulfate, and then under reduced pressure.
The solvent was distilled off. The residue obtained is purified by silica gel column chromatography.
Romanography (Developing solvent: n-hexane-ethyl acetate
= 2: 1) and colorless powder of O-acetylthio
Oacetylcarbamoyl fumagillol 156 mg (yield 9
2%) 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 16 O- (2-benzothiazolylthioacetylcarbamoy
Le) Fumagillol O-chloroacetylcarbamoyl fumagillol (160
mg) in dimethylformamide (2 m) solution,
Add lucaptobenzothiazole sodium salt (95mg)
The mixture was stirred at room temperature for 1.5 hours. Dilute the reaction mixture with ethyl acetate.
And wash with water and saturated sodium chloride solution,
After drying with magnesium acidate, the solvent was distilled off under reduced pressure. Profit
The residue obtained is subjected to silica gel column chromatography (extension).
Purification with open solvent: n-hexane-ethyl acetate = 3: 1)
To obtain a colorless powder of O- (2-benzothiazolylthioacetate.
152 mg of tilcarbamoyl) fumagillol (yield 72
%) Was obtained. 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 17 O-[(pyridin-N-oxide-2-yl) thioacetate
Chillcarbamoyl] fumagillol O-Chloroacetylcarbamoyl sulfe as in Example 16
Magillol (144 mg) and pyridine-N-oxide-2
Stir thiol sodium salt (60 mg) for 10 minutes at room temperature
Stir, silica gel column chromatography (development
Purified with a medium: chloroform-methanol = 20: 1)
And colorless powder O-[(pyridine-N-oxide-2-
Il) 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 18 O-diethylaminoacetylcarbamoyl fumagillol O-chloroacetylcarbamoyl fumagillol (154
mg) and triethylamine (35 mg) in toluene (2 m
) To the solution was added diethylamine (70 mg) at room temperature for 1
Stir the day. Dilute the reaction mixture with ethyl acetate and wash with water and saturated salt.
Wash with aqueous sodium chloride solution and dry over anhydrous magnesium sulfate.
After drying, the solvent was distilled off under reduced pressure, and the resulting residue was converted to silica.
Gel column chromatography (developing solvent: n-hexa
-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
(12H, 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 19 O-chloroacetylcarbamoyldihydrofumagillol Dihydrofumagillol (150 mg) as in Example 1
R-O-chloroacetylcarbamoyldihydrofumagiro
Yielded 173 mg (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.
2Hz, J = 4.6Hz), 2.63 (1H, d, J = 4.2Hz), 2.91 (1H, d, J = 4.2
Hz), 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 20 O-[[1- (2-dimethylaminoethyl) tetrazo
Lu] -5-yl-thioacetylcarbamoyl] fumagiro
The Similar to Example 16, O-chloroacetylcarbamoyl fuma
Guilrol (195 mg) and 1- (2-dimethylaminoethyl)
) -5-Mercaptoterazol sodium salt (113
(mg) was stirred at room temperature for 1 hour and then subjected to silica gel column chromatography.
Purified by chromatography (developing solvent: ethyl acetate)
Colored powder of O-[[1- (2-dimethylaminoethyl) te
[Trazol] -5-yl-thioacetylcarbamoyl]
217 mg of fumagillol (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 21 O-[(2-methyl-1,3,4-thiadiazole-5
-Yl) Thioacetylcarbamoyl] fumagillol Similar to Example 16, O-chloroacetylcarbamoyl fuma
Guillol (283 mg) and 2-methyl-1,3,4-thia
Diazol-5-thiol sodium salt (130 mg)
Stir at room temperature for 30 minutes, then use silica gel column chromatography.
Fee (Developing solvent: n-hexane-ethyl acetate = 1:
Purified in 1), O-[(2-methyl-
1,3,4-thiadiazol-5-yl) thioacetyl
Carbamoyl] fumagillol 293 mg (yield 84%)
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 22 O- (1-naphthalenethioacetylcarbamoyl) fuma
Gilol O-chloroacetylcarbamoylf similar to that in Example 16
Magiroll (159mg) and naphthalenethiol sodium
Sodium salt (188 mg) was stirred at room temperature for 5 minutes and the silica gel column was stirred.
Rum chromatography (developing solvent: n-hexane-vinegar
Purified with ethyl acetate = 3: 1) to obtain colorless powder O- (1
-Naphthalenethioacetylcarbamoyl) fumagillol
169 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 23 O-[(N-methylpyrrolidinium) acetylcarbamo
Il] Fumagillol chloride O-chloroacetylcarbamoyl fumagillol (170
mg) and N-methylpyrrolidine (1 m) with ether (3
m) The solution was stirred at room temperature for 1 week. The resulting precipitate is filtered
The product is collected, washed with ether and dried under reduced pressure to give a colorless powder.
O-[(N-methylpyrrolidinium) acetylcarbamo
[Il] fumagillol chloride 170 mg (yield 82%)
Got 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 24 O- [2- (N, N, N-trimethylammonio) ethyl
[Lucarbamoyl] Fumagillol-iodide O- (2-dimethylaminocarbamoyl) fumagillol
(81 mg) and methyl iodide (0.5 m) were added to dichloromethane.
It was stirred in a tan (1 m) solution at room temperature for 15 hours. Solvent
Concentrate under reduced pressure and wash the resulting residue with ether to give colorless
Powdered O- [2- (N, N, N-trimethylammonium
E) Ethylcarbamoyl] fumagillol-iodide 10
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 25 O- [N-acetyl (2-dimethylaminoethylcarba
Moyle)] Fumagillol O- (2-dimethylaminocarbamoyl) fumagillol
(145 mg) and triethylamine (0.5 m)
Acetic anhydride (0.3 m) was added to the loromethane (2 m) solution.
In addition, the mixture was stirred at room temperature for 1 day. Dilute the reaction mixture with ethyl acetate.
Dilute, wash with water and saturated brine, dry magnesium sulfate
After drying with, the solvent was concentrated under reduced pressure, and the resulting residue was converted to silica.
Gel chromatography (developing solvent: dichloromethane-
Purified with methanol = 20: 1) to give a colorless oil O-
[N-acetyl (2-dimethylaminocarbamoyl)]
113 mg of fumagillol (yield 73%) was obtained. 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 26 O-acryloylcarbamoyl fumagillol Fumagillol (220 mg) and acrylo as in Example 1
Stir ylisocyanate (200 mg) for 30 minutes at room temperature
Silica gel chromatography (developing solvent: n-
Purified with xane-ethyl acetate = 3: 1), colorless powder
O-acryloylcarbamoyl fumagillol 60 mg
(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 = 1.6Hz), 6.51 (1H, dd, J = 1
7.0Hz, J = 1.6Hz), 6.92 (1H, dd, J = 17.0Hz, J = 1.6Hz), 6.9
2 (1H, dd, J = 17.0Hz, J = 10.4Hz), 7.78 (1H, brs). Example 27 O-[(1-methyl-2-methoxycarbonyl-1,
3,4-triazol-5-yl) thioacetylcarba
Moyle] Fumagillol O-Chloroacetylcarbamoyl sulfe as in Example 16
Magillol (270mg) and 1-methyl-2-methoxyca
Lubonyl-1,3,4-triazole-5-thiolna
Thorium salt (164 mg) was stirred at room temperature for 30 minutes and
Kagel chromatography (developing solvent: n-hexane-
Purified with ethyl acetate = 1: 4) to obtain colorless powder O-
[(1-Methyl-2-methoxycarbonyl-1,3,4
-Triazol-5-yl) thioacetylcarbamoy
Lu] fumagillol (288 mg, yield 80%) 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 28 O-[(2-benzoxazolyl) thioacetylcarba
Moyle] Fumagillol O-Chloroacetylcarbamoyl sulfe as in Example 16
Magiroll (230mg) and 2-mercaptobenzoxa
Stir the sol sodium salt (119 mg) for 30 minutes at room temperature.
Stir, silica gel column chromatography (development
Purified with a medium: n-hexane-ethyl acetate = 3: 1)
Colorless powder O-[(2-benzoxazolyl) thio
Acetylcarbamoyl] fumagillol 269 mg (yield 9
1%) was obtained. 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 29 O-[(2-benzimidazolyl) thioacetylcarba
Moyle] Fumagillol O-Chloroacetylcarbamoyl sulfe as in Example 16
Magiroll (257mg) and 2-mericatobenzimida
Stir the sol sodium salt (132 mg) for 30 minutes at room temperature.
Stir, silica gel column chromatography (development
Purified with a medium: n-hexane-ethyl acetate = 1: 1)
Colorless powder of O-[(2-benzimidazolyl) thio
Acetylcarbamoyl] fumagillol 297 mg (yield 9
0%). 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, brs). Example 30 O-[(8-quinolyl) thioacetylcarbamoyl] f
Magi roll O-Chloroacetylcarbamoyl sulfe as in Example 16
Magiroll (289mg) and 8-mercaptoquinoline na
Thorium salt (208 mg) was stirred at room temperature for 30 minutes and
Kagel column chromatography (developing solvent: n-hex
Sun-ethyl acetate = 7: 3) to obtain a colorless powder.
O-[(8-quinolyl) thioacetylcarbamoyl] f
382 mg (yield 99%) of magilol was obtained. 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 31 O-[(2-pyridyl) thioacetylcarbamoyl] f
Magi roll O-Chloroacetylcarbamoyl sulfe as in Example 16
Magillol (292mg) and 2-pyridinethiol nato
Stir the thorium salt (116 mg) at room temperature for 30 minutes, then add silica.
Gel column chromatography (developing solvent: n-hexa
-Ethyl acetate = 2: 1) to obtain a colorless powder of O
-[(2-Pyridyl) thioacetylcarbamoyl] huma
325 mg of guirol (yield 94%) was obtained. 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 32 O-[(4-pyridyl) thioacetylcarbamoyl] f
Magi roll O-Chloroacetylcarbamoyl sulfe as in Example 16
Magillol (290mg) and 4-pyridinethiol nato
Stir the thorium salt (115 mg) for 30 minutes at room temperature, then add silica.
Gel column chromatography (developing solvent: n-hexa
-Ethyl acetate = 1: 2) to obtain a colorless powder of O.
-[(4-Pyridyl) thioacetylcarbamoyl] huma
Guillol (314 mg, 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), 1.6-2.6 (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 33 O- (methylthioacetylcarbamoyl) fumagillol O-Chloroacetylcarbamoyl sulfe as in Example 16
Magiroll (1070mg) and Methanethiol Natriu
Silica salt (225 mg) was stirred at 10 ° C. for 1 hour and then added to silica gel.
Column chromatography (developing solvent: n-hexane-
Purified with ethyl acetate = 3: 1) to obtain colorless powder of O-
(Methylthioacetylcarbamoyl) Fumagillol 50
0 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 34 O-[(4-hydroxy-pyrimidin-2-yl) thio
Acetylcarbamoyl] fumagillol O-Chloroacetylcarbamoyl sulfe as in Example 16
Magilol (239mg) and thiouracil sodium salt
(123 mg) was stirred at room temperature for 30 minutes and was washed with silica gel.
Chromatography (developing solvent: n-hexane-acetic acid
Purified with ethyl = 1: 5) to obtain O-[(4
-Hydroxy-pyrimidin-2-yl) thioacetylcapro
Lubamoyl] Fumagillol 208mg (71% yield)
It was 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 35 O-[(1,2,3-triazol-5-yl) thioa
Cetylcarbamoyl] fumagillol O-Chloroacetylcarbamoyl sulfe as in Example 16
Magiroll (249mg) and 5-mercapto-1,2,3
-Triazole sodium salt (118 mg) at room temperature in 1
After stirring for an hour, silica gel column chromatography
Open solvent: n-hexane-ethyl acetate = 3: 2)
Then, O-[(1,2,3-triazole-
5-yl) thioacetylcarbamoyl] fumagillol 2
06 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 36 O-[(dimethylthionium) acetylcarbamoyl]
Fumagillol yogurt O- (methylthioacetylcarbamoyl) fumagillol
(167 mg) and methyl iodide (1 m) were added to acetonite.
Stir at room temperature in a ril (1 m) solution overnight. Depressurize the solvent
After concentration, ether was added to the residue and the resulting precipitate was collected by filtration.
After washing with ether, it is dried under reduced pressure to give O as colorless powder.
-[(Dimethylthionium) acetylcarbamoyl] f
79 mg (35% yield) of magilol iodide was obtained. ¹ H-NMR (d ₆ -CMSO) δ: 1.09 (3H, s), 1.32 (1
H, m), 1.62 (3H, s), 1.72 (3H, s), 1.6-2.95 (10H, m), 2.92 (6
H, s), 3.34 (3H, s), 3.66 (1H, m), 4.90 (2H, s), 5.21 (1H, m),
5.49 (1H, m). Example 37 O-[(N-methyl-pyridinium-4-yl) thioa
Cetylcarbamoyl] fumagillol-iodide O-[(4pyridyl) thioacetylcarbamoyl] huma
Gikulol (113 mg) and methyl iodide (1 m)
The loromethane (2m) solution was stirred at room temperature overnight and the solvent was removed.
After concentration under reduced pressure, ether was added and the resulting precipitate was filtered off and filtered.
Washed with ether and colorless powder O-[(N-methyl-pyridine
Dinium-4-yl) thioacetylcarbamoyl] fuma
127 mg of guirol (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 38 O- [N- (ethoxycarbonyl) -carbamoyl] f
Magi roll Fumagillol (350 mg) and ethoxy as in Example 1
Carbonyl isocyanate (200 mg) at room temperature for 30 minutes
Stir for 1 hour, and then silica gel column chromatography (development
Purified with solvent: n-hexane-ethyl acetate = 3: 1)
Of colorless powder O- [N- (ethoxycarbonyl) -carb
Lubamoyl] fumagillol 370 mg (yield 75%) was obtained.
It was 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 39 O- [N- (3-Furoyl) -carbamoyl] fumagiro
The 3-Furoylamide (167 mg) was added to dichloromethane (1
0 m), and oxalyl chloride (0.
After 20 m) was added, the reaction solution was warmed to room temperature.
After heating and refluxing for another 10 hours, the solvent is distilled off to remove 3-float.
A crude product of loyl isocyanate was obtained. Example 8
And fumagillol (213mg) for 30 minutes at room temperature.
Stir, silica gel column chromatography (development
Purified with a medium: n-hexane-ethyl acetate = 2: 1)
Colorless powder O- [N- (3-furoyl) carbamoy
Lu] fumagillol (120 mg, yield 38%) was obtained. 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 40 O- [N- (phenoxycarbonyl) carbamoyl] f
Magi roll Fumagillol (200 mg) and phenoki as in Example 1
Cycarbonylisocyanate (231 mg) at room temperature at 4 o'clock
Stir for 1 hour, and then silica gel column chromatography (development
Purified with solvent: n-hexane-ethyl acetate = 2: 1)
As a colorless powder O- [N- (phenoxycarbonyl)-
Carbamoyl] fumagillol 125 mg (yield 39%)
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 41 O- (N'-chloroacetyl allophanoyl) fumagiro
The O-carbamoyl fumagillol (200 mg) was added to dichloro
Dissolved in methane (4m), chloroacetylisocyanate
(0.10 m) was added and the mixture was stirred for 4 hours. Reaction liquid
Ethyl acetate (50 m) was added to dilute the mixture, and saturated carbonated water
With aqueous sodium chloride and saturated aqueous sodium chloride
Washed. Dry over anhydrous magnesium sulfate and dissolve under reduced pressure.
After the solvent was distilled off, the residue was chromatographed on a silica gel column.
Raffy (Developing solvent: n-hexane-ethyl acetate = 1:
Purified in 1) to obtain colorless powder of O- (N'-chloroacetate).
Cillalophanoyl) fumagillol 230 mg (yield 84
%) Was obtained. 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 42 O- (N'-benzoyl allofanoyl) fumagillol As in Example 41, O-carbamoyl fumagillol (2
00 mg) and benzoyl isocyanate (0.51 m)
The mixture was stirred at room temperature for 2 days and then subjected to silica gel column chromatography.
Fee (developing solvent: n-hexane-ethyl acetate = 3:
2) and purified by colorless powder O- (N'-benzoyl)
Alofanoyl) fumagillol 100 mg (34% yield)
Got 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 43 O-chloroacetylcarbamoyl-6'b-hydroxy
Fumagillol O-chloroacetylcarbamoyl fumagillol (711
mg) in 95% ethanol (30 m) solution and
(295 mg) was added, and the mixture was heated under reflux for 5 hours. Under reduced pressure
The solvent was evaporated, the obtained residue was dissolved in ethyl acetate, and
Aqueous sodium hydrogen carbonate solution and saturated sodium chloride
It was washed with an aqueous solution. Reduced after drying over anhydrous magnesium sulfate
The solvent was distilled off under pressure, and the resulting residue was purified by a silica gel column.
Chromatography (developing solvent: n-hexane-acetic acid)
Chill = 1: 4) to obtain colorless powder of O-chloro
Cetylcarbamoyl-6'b-hydroxyfumagillol
190 mg (yield 26%) 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 44 O-chloroacetylcarbamoyl-6'b-dimethyla
Minofumagilol (a) O-acetyl-6'b-hydroxyfumagillol O-acetyl fumagillol (1.0
0 g) was oxidized with selenium dioxide (0.68 g) to give silica.
Gel column chromatography (developing solvent: n-hexa
-Ethyl acetate = 1: 2) to obtain a colorless oil O
-Acetyl-6'b-hydroxyfumagillol 300mg
(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-dimethylamino fumagiro
The O-acetyl-6'b-hydroxyfumagillol (46
9 mg) was dissolved in dichloromethane (5 m) and cooled under ice.
Triethylamine (0.13m), followed by methanesul
Add honyl chloride (0.38m) and stir for 15 minutes
did. Dilute ethyl acetate (50m) to the reaction mixture
And washed with saturated aqueous sodium chloride solution. Anhydrous sulfuric acid
It was dried over gnesium and the solvent was distilled off under reduced pressure. The residue
Dissolve in dimethylformamide (5m), and cool under ice
Potassium water carbonate (0.95 g) and dimethylamine salt
Add acid salt (1.12 g), warm to room temperature and stir for 1 hour.
I stirred. Dilute reaction mixture with ether (50m) and saturate
It was washed with an aqueous sodium chloride solution. Anhydrous magnesium sulfate
The residue is dried under vacuum and the solvent is distilled off under reduced pressure.
Kagel column chromatography (developing solvent: chloropho
Rum-methanol-ammonia water = 20: 1: 0.1)
O-Acetyl-6'b-dime of a colorless oily substance purified by
118 mg (23% yield) of chillaminofumagillol was obtained.
It was 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-dimethylamino fumagillol O-Acetyl-6'b-dimethylaminofumagillol
Dissolve (118 mg) in methanol (2 m) and prepare 1N
Add sodium hydroxide solution (1m) and stir for 15 minutes.
I stirred. Dilute the reaction mixture with ethyl acetate (50 m) and
It was washed with an aqueous sodium chloride solution. Anhydrous magnesium sulfate
After drying over sodium chloride and distilling off the solvent under reduced pressure, the residue is filtered.
Rica gel column chromatography (developing solvent: chloro
Form-methanol-ammonia water = 20: 1: 0.
6'b-Dimethylamino as a colorless oil after purification in 1)
102 mg of fumagillol (yield 97%) was obtained. 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-dime
Chillamino fumagillol 6'b-dimethylaminofumagillol as in Example 1
(152 mg) and chloroacetyl isocyanate (67 m
g) was stirred at room temperature for 1 hour and then subjected to silica gel column chromatography.
Graphography (Developing solvent: chloroform-methanol-a
Colorless powder purified by water (20: 1: 0.1)
O-chloroacetylcarbamoyl-6'b-dimethyl
Aminofumagillol 96 mg (yield 46%) was obtained. 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).

Continuation of front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display area A61K 31/435 ABG 31/495 ADU

Claims (9)

[Claims] 1. A general formula [In the formula, R ¹ represents a 2-methyl-1-propenyl or isobutyl group which may be substituted with a hydroxyl group or a di-lower alkylamino group, and R ² represents a lower alkenoyl group, a monochloroacetyl group, a dichloroacetyl group, Lower alkoxycarbonylmethyl group, carboxymethyl group, amino group, phenyl group substituted with alkyl halide, nitro or lower alkoxy group, benzoyl group, imidazole group formed with nitrogen atom of carbamoyl group, halogenated lower alkyl group , Lower alkylamino lower alkyl group, lower alkanoyloxy lower alkanoyl group, lower alkanoylthio lower alkanoyl group, lower alkylthio lower alkanoyl group, arylthio lower alkanoyl group, aromatic heterocyclic thio lower alkanoyl group, N-oxy 2-pyridylthio lower alkanoyl group, N-lower alkyl-4-pyridiniothio lower alkanoyl halide group, dilower alkylamino lower alkanoyl group, ammonio lower alkanoyl halide group, aromatic heterocyclic carbonyl group, lower alkoxycarbonyl group, phenoxy A carbamoyl group substituted with a carbonyl group, a chloroacetylcarbamoyl group, a benzoylcarbamoyl group, a phenylsulfonyl group optionally substituted with a lower alkyl group, a di (lower alkylsulfonio) lower alkanoyl halide group or a naphthylcarbamoyl group. ] O represented by
-Substituted fumagillol derivatives or salts thereof. 2. The compound according to claim 1, wherein R ¹ is a 2-methyl-1-propenyl group optionally substituted with hydroxy or dialkylamino. 3. The compound according to claim 1, wherein R ¹ is a 2-methyl-1-propenyl group which may be substituted with hydroxy, and R ² is a carbamoyl group which is substituted with monochloroacetyl or dichloroacetyl. . 4. The compound according to claim 1, wherein R ¹ is isobutyl and R ² is a carbamoyl group substituted with monochloroacetyl or dichloroacetyl. 5. The compound according to claim 1, which is O-monochloroacetylcarbamoyl fumagillol. 6. The compound according to claim 1, which is O-dichloroacetylcarbamoyl fumagillol. 7. The compound according to claim 1, which is O-monochloroacetylcarbamoyldihydrofumagillol. 8. O-monochloroacetylcarbamoyl-6 '
The compound according to claim 1, which is b-hydroxyfumagillol. 9. Formula The method for producing a compound according to claim 1, wherein the compound represented by the formula (wherein R ¹ is as defined above) is carbamoylated.