JPH0314571A - 6-amino-6-desoxyfumagillol and its derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is 2-methyl-1-propenyl or isobutyl; R<2> and R<3> are H, (substituted) hydrocarbon group or (substituted) acyl or R<2> and R<3>, together with the adjacent N, may form a ring; formula II is alpha- or beta-bond] or salt thereof. EXAMPLE:6alpha-Amino-desoxyfumagillol. USE:A medicine, having inhibitory action on vascularization, cell proliferation, immunity, etc., and useful for treating and preventing various inflammatory diseases, such as rheumatism or psoriasis, diabetic retinopathy, arteriosclerosis, cancer, rejection to organ transplantation, etc. PREPARATION:For example, 6-oxo-6-desoxyfumagillol and ammonium acetate are reduced with a metal hydride, such as sodium cyanoborohydride, in a solvent, such as methanol, to provide the compound expressed by formula I (formula II is alpha-bond; R<2> and R<3> are H; R<1> is 2-methyl-1-propenyl).

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention has angiogenesis-inhibiting action, cell proliferation-inhibiting action, immunosuppressing action, etc., and is effective against various inflammatory diseases (rheumatism, dark blue, etc.), diabetic diseases, etc. The present invention relates to a novel 6-amino-6-desoxyfumagillol and its derivatives or salts thereof, which have therapeutic and preventive effects on retinopathy 5, arteriosclerotic cancer, rejection during organ transplantation, and the like.

[Prior Art] Angiogenesis is deeply involved in the onset or progression of various diseases, such as various inflammatory and other diseases (rheumatism, insui, diabetic retinopathy, cancer, etc.). Therefore, it is thought that inhibiting angiogenesis will lead to the treatment and prevention of these diseases, and several research groups have so far searched for substances that inhibit straight tube formation. For example, the application of protamine by Tiller et al.
ay for, 3. et al. , Naichi+-
(Nature), 2 9 7, 3 0 7 (+
(982)), Combination of hevarin and cortisone by Folkman et al. (Folkman, J. et al., Science, 22 Sat., 71
Examples include research on ascorbic acid ether and related compounds (Japanese Patent Application Laid-Open No. 58131978) and sulfated polysaccharide DS415.
2 (Japanese Unexamined Patent Publication No. 63-119500) and the like have been patented as compounds that exhibit an angiogenesis-inhibiting effect. However, their activity is still not necessarily fully satisfactory, and the emergence of compounds with even more excellent activity is desired.

Furthermore, cell proliferation is an indispensable function for living organisms to grow or maintain life.

In higher animals, many tissues and organs each have their own proliferation mechanisms, which are regulated by various control mechanisms. In recent years, dozens of substances that positively control the proliferation of cells in living organisms, namely "cell growth factors," have been isolated and purified, and it has been revealed that they play an important role in the formation and maintenance of individuals. On the other hand, there are many reports that abnormalities in cell proliferation, especially uncontrolled proliferation, are associated with various diseases.For example, cancer and arteriosclerosis can be said to be one type.

In addition, it has been found that various cell growth factors are involved in the activation of immunocompetent cells, especially lymphocytes, and an excess of these cell growth factors is one of the exacerbating factors of autoimmune or allergic diseases. It is thought that this may be caused by overproduction or an overresponse. Therefore, if a drug that selectively inhibits or suppresses the response to cell growth factors involved in the above-mentioned diseases and exhibits immunosuppressive effects is developed, it will be possible to effectively prevent and treat these diseases. It can be a useful tool and is also thought to be effective in suppressing rejection reactions during organ transplants.

[Problems to be solved by the invention] The purpose of the present invention is to suppress angiogenesis, suppress cell proliferation,
The object of the present invention is to provide a new compound having immunosuppressive effects.

[Means for Solving the Problems] In order to achieve the above object, the present inventors searched and evaluated various compounds and found that fumagillin, which is conventionally known as an antibacterial agent and an antiprotozoal agent.
The present invention was completed based on the discovery that 6-amino-6-desoxyfumagillol, which was chemically induced and synthesized from 6-amino-6-desoxyfumagillol, and related compounds have excellent angiogenesis-inhibiting, cell proliferation-inhibiting, and immunosuppressing activities.

That is, the present invention provides a general formula N /\RI R3 [wherein R1 is a 2-methyl-1-probenyl group or an isobutyl group, and R' and R3 each have a hydrogen atom and a substituent] represents an optionally substituted hydrocarbon residue or an optionally substituted acyl group, and R1 and R3 may form a ring together with adjacent nitrogen atoms. The bond symbol ``A'' indicates an α bond or a β bond. ] 6-Amino-6-desoxyfumagillol and its derivatives or salts thereof.

Hydrocarbon residues of the hydrocarbon residues that may have substituents represented by Rt and R3 above include aliphatic hydrocarbon residues (straight-chain or branched alkyl groups, alkenyl groups, alkynyl groups). groups, cycloaliphatic hydrocarbon residues, etc.) and aromatic hydrocarbon residues (IJ groups, etc.), and particularly preferred are alkyl groups and aryl groups.

The acyl group of the acyl group which may have a substituent represented by Rl or R3 includes various organic or inorganic residues (e.g., alkanoyl group, aroyl group, aromatic atomyl ring) via a carbonyl group or sulfonyl group. Carbonyl group, carbamoyl group, benzenesulfonyl group, alkylsulfonyl group.
(thiocarbamoyl group, alkoxycarbonyl group, phenoxy carbonyl group, etc.).

In particular, R3 is preferably a hydrogen atom, an alkyl group or an aryl group which may have a substituent, and R3 is preferably a hydrogen atom, or an acyl group or an alkyl group which may have the above-mentioned substituents.

Preferred embodiments of the above R'' and R3 are described. As the alkamyl group which may have a substituent represented by R3, for example, amino, lower alkylamino (
e.g., methylamino, ethylamino-isopropylamino, etc.), di-lower alkylamino (e.g., dimethylamino,
diethylamide 7, etc.), nitro, halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), hydroxyl, lower alkoxy (e.g., methoxy/, ethoxy, etc.), cyano, carbamoyl, carboxyl, lower alkoxycarbonyl (
(e.g., methoxycarbonyl, ethoxycarbonyl, etc.),
Carboxy lower alkoxy (e.g. carboxymethoxy,
(2-carpoxyethoxy, etc.), phenyl which may have a substituent, aromatic heterocyclic group (preferably nitrogen, oxygen,
A 5- to 6-membered aromatic heterocyclic group containing 1 to 4 heteroatoms such as sulfur, such as 2-furyl, 2-chenyl, 4-thiazolyl, 4-imidazolyl, 4-biridyl, etc.), preferably is an alkanoyl group which may be substituted 1 to 3 times (
Preferably, the unsubstituted alkanoyl group has 2 to 20 carbon atoms, such as formyl, acetyl, propionyl, imbropionyl, butyryl, pentanoyl, hexanoyl, heptanoyl octa/yl, 7 nanoyl, lauroyl, undecanoyl, myristoyl, balmitoyl, stearoyl, arachinoyl, etc.). Among them, acetyl, butyryl, octanoyl, 3-carboxybrobionyl, 4-carboxybutyryl and the like are preferred.

Examples of the aroyl group represented by R3 which may have a substituent include those having 2 to 6 carbon atoms such as ethyl and propyl.
Preferably 1 to 3 substituted with lower alkyl, amino, halogen (e.g., fluorine, chlorine, bromine, etc.), hydroxyl, lower alkoxy (e.g., methoxy, ethoxy, etc.), cyano, carbamoyl, carboxyl, etc. Good examples include benzoyl, 1-naphthoyl, and 2-naphthoyl.

Among them, benzoyl and 2-carpoxybenzoyl are preferred.

As the substituent for the aromatic heterocyclic carbonyl group which may have a substituent represented by R3, the same substituents as those for the aroyl group having the above-mentioned substituent can be used.

As the aromatic abdominal ring carbonyl group, a 5- or 6-membered ring containing 1 to 4 heteroatoms such as nitrogen, oxygen, sulfur, etc. is used, and among them, 2-furoyl, 2-thenoyl, nicotinoyl, isonicotinoyl etc. are preferable.

The optionally substituted carbamoyl group represented by R3 includes a carbamoyl group, a monosubstituted carbamoyl group, and a disubstituted carbamoyl group, and examples of the substituent include lower alkyl (e.g., methyl, ethyl, probyl, butyl), lower alkanoyl (preferably carbon number 1 to 6,
e.g., acetyl, propionyl, etc.), chloroacetyl,
Trichloroacetyl, lower alkoxycarbonylmethyl (e.g., methoxylponylmethyl, ethoxycarbonylmethyl, etc.), carboxymethyl, phenyl, naphthyl, benzoyl, and carbamoyl groups that may have substituents together with nitrogen atoms of cyclic amine 7 groups (e.g., , pyrrolidino, piperidino, morpholino, biverazino, 4-methylbiverazino, 4-phenylpiverazino, etc.). Among them, chloroacetyl and phenyl. Benzoyl and the like are preferred.

The alkyl group which may have a substituent represented by R2 and R3 is, for example, the same substituent as the alkamyl group which may have a substituent as described above.
A linear chain having 1 to 20 carbon atoms, which may be substituted with ~3 carbon atoms,
A branched alkyl group may be mentioned, and the alkyl group may be eboxidized at any position. Among them, methyl,
Ethyl-1-benzyl and the like are preferred.

Examples of the substituent of the benzenesulfonyl group which may have a substituent represented by R3 include lower alkyl (e.g., methyl, ethyl, etc.), halogen (e.g., fluorine, chlorine, bromine, etc.), 1 to 3 of these substituents may be substituted at any position on the benzene ring.

The optionally substituted alkylsulfonyl group represented by R3 has, for example, 1 to 3 substituents similar to those of the above-mentioned optionally substituted alkamyl group. Examples include a lower alkylsulfonyl group having 1 to 6 carbon atoms, which may be optional. Among them, methylsulfonyl and ethylsulfonyl are preferred.

The thiocarbamoyl group that may have a substituent represented by R3 includes a thiocarbamoyl group, a monosubstituted thiocarbamoyl group, and a disubstituted thiocarbamoyl group, and examples of the substituent include a thiocarbamoyl group that has the above-mentioned substituent. Examples include the same substituents as the carbamoyl group which may be substituted.

As the alkoxy carbonyl group which may have a substituent represented by R3, for example, it may be substituted with 1 to 3 substituents similar to the substituents of the alkali/yl group having the above substituents. Good linear or branched lower grade (C
,-． ) alkoxycarbonyl group. Among these, methoxycarbonyl, ethoxycarbonyl, proboxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, 1-chloroethoxycarbonyl and the like are preferred.

Examples of the substituent for the fe/xycarbonyl group which may have a substituent represented by R3 include the same substituents as the above-mentioned benzenesulfonyl group which may have a substituent, 1 to 3 of these substituents may be substituted at any position of the phenoxy group.

R! As the aryl group which may have a substituent represented by, for example, it may be substituted with 1 to 3 substituents similar to the substituents in the aroyl group which may have a substituent as described above. Examples include phenyl 1-naphthyl and 2-naphthyl.

In this specification, examples of the substituent of the phenyl group which may have a substituent include lower alkyl (e.g., methyl, ethyl, proyl, butyl, etc.), lower alkoxy (e.g., methoxy, ethoxy, propoxy, etc.) , halogen (e.g., fluorine, chlorine, bromine, etc.), halogenated alkyl (e.g., trifluoromethyl, chloromethyl, etc.), nitro, etc., and these substituents can be substituted at any position on the phenyl ring from 1 to 5. may be replaced.

In addition, in this specification, unless otherwise specified, a lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, and a lower alkoxy group refers to a straight chain or branched alkyl group having 1 to 6 carbon atoms. means 6 alkoxy groups.

When the compound (I) of the present invention has an acidic substituent (e.g., carpoxyl, etc.) or a basic substituent (e.g., amino, lower alkylamino, di-lower alkylamino, etc.) in the molecule, pharmacologically It can also be used as an acceptable salt. As pharmacologically acceptable salts, salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. are used.

Inorganic bases that can support these salts include alkali metals (e.g., sodium, potassium, etc.), alkaline earth metals (e.g., calcium, magnesium, etc.), and organic bases such as trimethylamine, triethylamine, pyridine, picoline, etc. , N,N-dibenzylethylenediamine, ethanolamine, diethanolamine,
Trishydroxymethylaminomethane, dicyclohexylamine, etc., and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid. Examples of organic acids include nitric acid and phosphoric acid, and examples of organic acids include formic acid, acetic acid, and trifluoroacetic acid. Sycholic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid. Examples of basic or acidic amino acids include p-toluenesulfonic acid, arginine, lysine, ornithine, aspartic acid, and glutamic acid. Among these salts, salts with bases (i.e., salts with inorganic bases, salts with organic bases, salts with basic amino acids) are salts with carboxyl groups in substituents of compound (1), and salts with acids ( In other words, salts with inorganic acids, salts with organic acids, salts with acidic amino acids) are salts that can be formed with amide groups, lower alkylamino groups, di-lower alkylamino groups, etc. in the substituents of compound (1). means.

In the general formula (I), R1 is a 2-methyl-1bropenyl group, R t and R3 are both hydrogen atoms, and 6-
Amino-6-desoxyfumagillol is a hydrolysis product of fumagillin produced by microorganisms, fumagillol [:Tar
bell, D. S. eL al. , Journal of the American Chemical Society (J. Am.
Chem. Soc. )83. 3 0 9
6 (1961)), and is a compound derived from the formula (
As shown in II) and (I), it exists as two types of compounds: 6α-amino 6-desoxy fumagillol and 6β-amino 6-desoxy fumagillol. These two types of compounds differ in the absolute structure of the 6-position amino group, and have the formula (II
) The 6-position amino group of 6α-amino-6-desoxyfumagillol has the same absolute structure as the 6-position hydroxyl group of fumagillol. The object compound (1) of the present application has the formula (If
) and ([[) and their related compounds are included.

Also, compound (1) has 3 positions other than the above 6-position in its molecule.
There are asymmetric centers at positions 4, 4, 5, and the 2' and bi-positions on the 4-position side chain, but their absolute structure is based on the raw material fumagillol and matches the absolute structure of fumagillol. mean something

6α-amino-6-desoxyfumagillol (If) is
Fumagillol is oxidized by the method described in JP-A-62-476 to produce 6-oxo-6-desoxy fumagillol (6-
(dehydrofumagillol) by subsequent reduction with a metal hydride such as sodium cyanoborohydride in the presence of ammonium acetate. Also, if a primary amine is used instead of ammonium acetate and the pH of the reaction solution is kept from neutral to weakly acidic for reduction, the compound (
This can lead directly to the N-monosubstituted derivatives of II).

On the other hand, when a catalytic reduction method using palladium carbon as a catalyst is used instead of the reduction method using a metal hydride, the double bond on the 4-position side chain is also reduced at the same time, and the 4'
, 5'-dihydro form can be obtained.

6β-Amino-6-desoxyfumagillol (III) can be obtained by the Mitsunobu reaction of fumagillol with diethyl azodicarboxylate, triphenylphosphine, and phthalimide or succinimide [MitsunobuO. , Synthesis 1 9 8 1 year, 1
page] to convert it into a 6β-imide form, then react it with hydrazine, methylhydrazine, etc., and then treat it with an acid.

In the general formula (1), a compound in which R' is an isobutyl group and R2 and R3 are both hydrogen atoms can be produced by catalytically reducing fumagillol under normal conditions (for example, using 5% palladium on carbon in a methanol solution). This is achieved by reacting the 4',5'-dihydro compound obtained by this method in the same manner as in the above method.

In the general formula (1), compounds in which R2 or R3 are simultaneously or only one of them represented by a substituent other than a hydrogen atom include the compound (It) or its N-monosubstituted product, the compound (
(2) and their 4',5'-dihydro forms as raw materials, for example, by acylation, carbamoylation, thiocarbamoylation, alkylation, or sulfonylation, or by intermediates of these reactions. It can be produced by isolating the body.

R again! or R3 is a group that does not change upon catalytic reduction, 6-(N-monosubstituted amino)-6-desoxyfumagillols can be catalytically reduced to form 6-(N-monosubstituted amino)-4' , 5'-dihydro-6-desoxy fumagillols. When substituents such as amino, hydroxyl, and carboxyl are present in the acylating agent, carbamoylating agent, thiocarbamoylating agent, alkylating agent, sulfonylating agent, etc., these substituents are preferably protected, Appropriate protecting groups are selected depending on the stability of the product. Examples of preferred protecting groups include 4-nitropenzyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, etc. in the case of amino, and 4-nitropenzyloxycarbonyl, etc. in the case of hydroxyl.
Examples include nitrobenzyl, t-butyldimethylsilyl, and in the case of carboxyl, 4-nitrobenzyl and the like. As the deprotection method, catalytic reduction or a conventional method of reacting with fluoride ions can be employed. In the case of carbamoylation and alkylation reactions, a lower alkyl group such as a methyl group or ethyl group is used as a protecting group for the carpoxyl group, and after the reaction, deprotection is performed by hydrolysis under mild alkaline conditions. is also possible.

l) Acylation reaction The acylation reaction comprises 6-amino-6-denxyfumagillol, 6-amino-4',5'-dihydro-6-desoxyfumagillol or their N monoalkyl or N
- Monoaryl it conversion (hereinafter abbreviated as raw material amine) is carried out by reacting reactive derivatives of activated carboxylic acids such as acid anhydrides, acid halides, active amides, active esters, and active thioesters.

That is, the reaction is usually carried out by the reaction shown by the following formula.

Reactive derivative of R50H + raw material amine → compound (1)
[R'=Rs] (wherein, R5 is an alkanoyl group that may have a substituent as defined in R3, an aroyl group that may have a substituent, or an aroyl group that may have a substituent) (Indicates an aromatic heterocyclic carbonyl group.) Specific examples of such reactive derivatives are as follows.

1) Acid halide: For example, acid chloride, acid bromide, etc. are used.

2) Acid anhydride: For example, a mono-lower alkyl carbonic acid mixed acid anhydride is used.

3) Active amides: For example, amides with pyrazole, imidazole, 4-monosubstituted imidazole, dimethylvirazole, penzotriazole, etc. are used.

4) Active esters: For example, methoxymethyl ester, penzotriazole ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester,
In addition to esters such as pentacrophenyl ester,
Esters with 1-hydroxy-IH-2-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, etc. are used.

5) Active thioester: For example, thioesters with abdominal ring thiols such as 2-pyridylthiol and 2-penzothiazolylthiol are used.

The reactive derivative of carboxylic acid is generally used in an amount of about 1 to 10 times, preferably 1 to 5 times, per mole of the raw material amine. Further, when the carboxylic acid is used in its free form, it is preferable to carry out the reaction in the presence of a condensing agent. Examples of condensing agents include N,N'-dicyclohexylcarbodiimide, N-cyclohexylN'monomorpholinoethylcarbodiimide, N-cyclohexylN'
-(4-diethylaminocyclohexyl)carbodiimide, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, etc. are used.

This reaction is usually carried out in the presence of a base.

Examples of the base include diisopropyl ethylamine, tributylamine, triethylamine, pyridine, picoline,
Tertiary amines such as N,N-dimethylaminopyridine, N-methylmorpholine, and N-methylbiveridine; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal carbonates such as potassium carbonate and sodium carbonate; hydrogen Alkali metal hydrides such as sodium chloride and potassium hydride, and organic metals such as butyllithium and lithium diisopropylamide are used.
The amount added is usually about 1 mole to 10 times the mole of the raw material amine.

This reaction is usually carried out in an organic solvent that does not adversely affect the reaction. Examples of organic solvents that do not adversely affect the reaction include amides such as dimethylformamide and dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethanato, and ethers such as diethyl ether, tetrahydrofuran, and dioxane. methyl acetate. Esters such as ethyl acetate, isobutyl acetate, and methyl propionate, nitriles such as acetonitrile brobionitrile, nitro compounds such as nitromethane and nitroethane, ketones such as acetone and methyl ethyl ketone, aromatic hydrocarbons such as benzene and toluene, etc. are used, and these may be used alone or in a mixture of two or more in an appropriate ratio. Further, the tertiary amine used as the base may be used as it is as the solvent.

The reaction temperature varies depending on the amount and type of carboxylic acid derivative, base, solvent, etc., but ranges from -80 to 100°C, preferably from O0C to room temperature (here, room temperature means about 20 to 35°C. (The same applies hereinafter unless otherwise specified). The reaction time is about 30 minutes to 5 days.

2) Alkylation reaction In the alkylation reaction, the raw material amine is given the formula R'Y (in the formula,
R8 means an optionally substituted alkyl group in the definition of R3, and Y is a leaving group (e.g., halogen (chlorine, bromine,
iodine, etc.)). This is carried out by reacting an alkylating agent such as an alkyl halide represented by the following formula, dialkyl sulfate (eg, dimethyl sulfate, diethyl sulfate, etc.). The alkylating agent is usually used in an amount of about 1 to 5 times the molar amount per mole of the raw material amine.

This reaction is usually carried out in the presence of a base.

As the base, the aforementioned alkali metal hydrogen carbonates, alkali metal carbonates, alkali metal hydrides, organic metals, etc. are used, and the amount added is usually about 1 to 5 moles per 1 mole of the raw material amine. This is twice the molar amount.

This reaction is usually carried out in an organic solvent that does not adversely affect the reaction. As organic solvents that do not have an adverse effect on the reaction, the aforementioned amides, halogenated hydrocarbons, ethers, esters, nitriles, nitro compounds, ketones, and aromatic hydrocarbons are used, and these can be used in combination with one or two of them. More than one species may be mixed and used in an appropriate ratio.

The reaction temperature varies depending on the alkylating agent, base, amount and type of solvent, etc., but is from -80 to OO'C, preferably O'
C to room temperature. The reaction time is about 20 minutes to 5 days.

When a dihalogenated alkyl is used as the alkylating agent, 6-(cyclic amino)-6desoxyfumagillols can be obtained.

The product can also be further reacted with an alkyl halide to lead to ammonium type derivatives (see Example 20).

The alkylation reaction is carried out using 6-amino-6-desoxyfumagillol or its 4'. It can also be carried out by reacting the 5'-dihydro compound with a ketone or aldehyde under reducing conditions. Catalytic reduction may be used as the reduction condition. Preferred catalysts for this purpose include palladium on carbon, palladium black, and Raney nickel. The reaction involves alcohols (e.g. methanol, ethanol),
It is preferable to carry out the reaction in an ether (eg, tetrahydrofuran, dimethquinethane, etc.) or a mixture of these and water in the presence of hydrogen gas at a temperature of from water cooling to about 80°C, preferably around room temperature.

As the reduction condition, reduction using a metal hydride may be performed. As the metal hydride, sodium borohydride and sodium cyanoborohydride are preferred.

The reaction involves alcohols (e.g. methanol, ethanol),
It is preferable to conduct the reaction in a solvent such as ethers (e.g., tetrahydrofuran, dimethoxyethane), nitriles (% I, acetonitrile), or a mixture of these and water. It is best to maintain a weakly acidic state (pH approximately 3 to 6), and add a buffer solution, mineral acids (e.g., hydrochloric acid), organic acids (e.g., acetic acid), or their aqueous solutions to adjust the liquid properties. good.

The amount of metal hydride to be used varies depending on the raw materials and the type of carbonyl compound used, but it is best to use a slightly excessive amount to about 100 times the theoretical amount, preferably a slightly excessive amount to about 10 times the theoretical amount, and depending on the progress of the reaction. Good to add.

The reaction temperature is about -20'C to 80'C, preferably about 08
C to 30°C.

3) Carbamoylation reaction monosubstitution power The carbamoylation reaction for introducing a rubamoyl group is usually carried out by reacting the raw material amine with incyanate. For example, it is produced by the reaction shown by the following formula.

R'NGO + raw material amine → compound ([)[R'
=R'NHCO] (wherein, R7 represents a carbamoyl substituent which may have a substituent represented by R3 described above, such as lower alkyl, lower alkanoyl, and chloroacetyl.

) The isocyanate is usually used in an amount of about 1 to 5 times the molar amount per mole of the raw material amine.

This reaction is usually carried out in the presence of a base.

The bases include the aforementioned tertiary amines, alkali metal hydrogen carbonates, alkali metal carbonates, alkali metal hydrides,
Organic metals and the like are used, and the amount added is usually about 1 mol to 5 times the molar amount per 1 mol of the raw material amine.

This reaction is usually carried out in an organic solvent that does not adversely affect the reaction. As organic solvents that do not have an adverse effect on the reaction, the aforementioned amides, halogenated hydrocarbons, ethers, esters, nitriles, nitro compounds, ketones, and aromatic hydrocarbons are used, and these can be used in combination with one or two of them. More than one species may be mixed and used in an appropriate ratio. Further, the tertiary amine used as the base may be used as it is as the solvent.

The reaction temperature varies depending on the amounts and types of incyanate, base, and solvent, but is usually about -80 to 100°C, preferably from 0°C to room temperature. The reaction time is about 1 hour to 5 days.

Among the compounds having a monosubstituted carbamoyl group obtained in this way, compounds having, for example, chloroacetylcarbamoyl, trichloroacetylcarbamoyl, etc., can be prepared by a conventional method (for example, under basic conditions at room temperature or with heating). It is also possible to convert the compound to a compound having a carbamoyl group by removing the group or trichloroacetyl group.

The carbamoylation reaction can also be carried out by reacting a raw material amine with a carbamoyl halide.

The carbamoyl halide, per mole of raw material amine,
It is usually used in an amount of about 1 mole to 5 times the mole.

This reaction is usually carried out in the presence of a base. The bases include the aforementioned tertiary amines, alkali metal hydrogencarbonates,
Alkali metal carbonates, alkali metal hydrides, organic alkali metals, etc. are used, and the amount added is usually about 1 mol to 5 times the molar amount per 1 mol of raw material amine.

This reaction is usually carried out in an organic solvent that does not have an adverse effect on the reaction. As organic solvents that do not have an adverse effect on the reaction, the aforementioned amides, halogenated hydrocarbons, ethers, esters, nitriles, nitro compounds, ketones, and aromatic hydrocarbons are used, and these can be used in combination with one or two of them. More than one species may be mixed and used in an appropriate ratio. Further, the tertiary amine used as the base may be used as it is as the solvent.

The reaction temperature depends on the amount of carbamoyl halide, base, solvent,
Although it varies depending on the type, the reaction is carried out at a temperature of about O0C to about the reflux temperature of the reaction medium, preferably about 25C to the reflux temperature.

In addition, the carbamoylation reaction can be performed using a chloroformate ester (eg, phenyl chloroformate, ethyl chloroformate, isobutyl chloroformate, l-chloroethyl chloroformate, etc.) or 1. It can also be carried out by reacting 1'-carponyldiimidazole to form an active ester and then reacting it with primary or secondary amines. The chloroformates, l,1'-carbonyldiimidazole and amines are usually used in an amount of 1 to 5 times the molar amount per mole of the raw material amine.

In this reaction, the reaction between the raw material amine and the chloroformate is usually carried out in the presence of a base.

The bases include the aforementioned tertiary amines, alkali metal hydrogen carbonates, alkali metal carbonates, alkali metal hydrides,
Organic alkali metals and the like are used, and the amount added is usually about 1 mol to 5 times the molar amount per 1 mol of the raw material amine.

This reaction is usually carried out in an organic solvent that does not adversely affect the reaction. As organic solvents that do not have an adverse effect on the reaction, the aforementioned amides, halogenated hydrocarbons, ethers, esters, nitriles, nitro compounds, ketones, and aromatic hydrocarbons are used, and these can be used in combination with one or two of them. More than one species may be mixed and used in an appropriate ratio. The reaction temperature varies depending on the amount and type of chloroformate, base, amine, solvent, etc., but it is carried out from -20'C to the reflux temperature of the reaction medium, preferably from 0°C to 50'C. Note that active esters obtained as intermediates are also included in compound (1), which is the object of the present application.

4) Thiocarbamoylation reaction In the above carbamoylation reaction, a derivative into which a monosubstituted thiocarbamoyl group has been introduced can be synthesized by performing the same reaction using inthiocyanate instead of isocyanate. The reaction is shown, for example, by the following formula.

RIINCS + raw rice amine → compound (1) [R
3=R8NHCS] [In the formula, R8 represents a substituent of a thiocarbamoyl group which may have a substituent in the definition of R3. [5) Sulfonylation reaction The sulfonylation reaction is carried out by reacting the raw amine with an activated sulfonic acid derivative such as sulfonic anhydride, sulfonic acid halide (eg, sulfonyl chloride, sulfonyl bromide, etc.).

That is, it is carried out by reacting as shown in the following formula.

Reactive derivative of R”OH + Raw material amine → Compound (I[
R'=R9 (However, R8 represents a benzenesulfonyl group which may have a substituent or an alkylsulfonyl group which may have a substituent in the definition of R3.) Reactivity of the sulfonic acid The derivative is usually used in an amount of about 1 to 5 times the molar amount per mole of the raw material amine.

This reaction is usually carried out in the presence of a base.

The bases include the aforementioned tertiary amines, alkali metal hydrogen carbonates, alkali metal carbonates, alkali metal hydrides,
Organic metals and the like are used, and the amount added is usually about 1 mol to 10 times the molar amount per 1 mol of fumagillol.

This reaction is usually carried out in an organic solvent that does not adversely affect the reaction. The above-mentioned amides, chlorinated hydrocarbons, ethers, esters, nitriles, nitro compounds, ketones, and aromatic hydrocarbons are used as organic solvents that do not have a negative effect on the reaction. Alternatively, two or more types may be mixed and used in an appropriate ratio. Further, the tertiary amine used as the base may be used as it is as the solvent.

The reaction temperature varies depending on the amount and type of the sulfonic acid derivative, base, and solvent, but is from -80°C to 100°C, preferably from 0'C to room temperature. The reaction time is about 1 hour to 5 days.

6-Amino-6-desoxyfumagillol and related compounds (f) thus produced can be isolated by known separation and purification means (eg, chromatography, crystallization method), and the like.

The compounds of the present invention exhibit angiogenesis inhibitory effects, cell proliferation inhibitory effects, immunosuppressive effects, etc., including various inflammatory diseases (rheumatism, xerosis), diabetic retinopathy, arteriosclerosis, cancer, and rejection reactions during organ transplantation. It is useful as a therapeutic and preventive agent for
a pharmaceutically acceptable carrier as is or known per se;
It can be safely administered orally or parenterally as a pharmaceutical composition mixed with excipients (e.g., tablets, capsules (including soft capsules, microcapsules), liquids, injections, suppositories). The dosage varies depending on the subject, route of administration, symptoms, etc., but for example, for adults, it is usually 0.5 mg per day. 1 mg/kg ~ 40 m
g/kg body weight, preferably 0. 5 mg/
kg to 20 mg/kg body weight.

[Effect] Experimental Example 1 The angiogenesis inhibitory effect of the target compound (1) obtained in the following example was measured by the rat corneal micropocket method and summarized in Table 1.

Measurement method Gimbrone et al. [Journal of National Cancer Institute J. Nationa
lCancer Institute 52:41
3 419 (L974)) as follows. Sprague Dawley
-Dawley) strain mature male rat} (11-16 weeks old)
The patient was anesthetized with Nembutal, and Xylophyne ophthalmic solution was instilled into the eyeball for local anesthesia. Approximately 21 minutes from the limbus of the cornea! lrr
An approximately 2 m II incision is made in the inner cornea with a syringe needle, and basic fibroblast growth factor (bFGF, a purified product derived from Un's brain, R&D Co., Ltd.) and a slow-release pellet of the specimen are injected into the bFGF.
Insert the two GF pellets side by side so that they are toward the center of the cornea.

A bFGF pellet and a pellet containing no specimen were inserted into the corneas of rats in the control group. After 10 days, the cornea was observed under a stereomicroscope, and if bFGF-induced angiogenesis was delayed or weakened by administration of the sample, it was determined that there was inhibitory activity.

Sustained-release pellets were prepared by the following method. Ethylene-vinyl acetate copolymer (Takeda Pharmaceutical Co., Ltd.) was dissolved in dichloromethane to a concentration of 8%, 3 μg of the solution was air-dried on a glass petri dish, a bFGF aqueous solution (250 ng) was collected, air-dried, and 3 μQ of The above ethylene-vinyl acetate copolymer solution was placed on top and air-dried to produce a bPGF sandwich sheet. This sandwich-like sheet was rolled into bFGF pellets. Dissolve the sample in ethanol to give a concentration of 20μg/2μg,
6 μg of ethylene-vinyl acetate copolymer ifJ
After the mixture was combined, it was air-dried on a glass petri dish, and the resulting pellets were rolled into balls.

In addition, in Table 1 below, the inhibition rate means the lanoto 1 in which the angiogenesis inhibitory effect on the number of test rats was observed.

Table 1 Experimental Example 2 of Angiogenesis Inhibition Effect [Assay of inhibition of cell proliferation of human venous vascular endothelial cells] Human vascular endothelial cells were obtained from the human zonal vein by perfusion method with a tribucin narcotic solution, and in GIT medium ( Daigo Nutritional Chemicals), 2.5% fetal bovine serum and 2. Ong
/d human recombinant fibroblast growth factor (rFG)
Abbreviated as F. (produced at our biotechnology research laboratory) was used.

Suspension of 2XIO3 human vascular endothelial cells, 100μQ
are seeded in a 96-well culture dish (Nunc, l-67008) and cultured in a gas-controlled constant temperature bath. The next day, final concentration 2ng
100 μQ of rFGF and a medium containing various concentrations of the specimen were added at a concentration of 100 μQ/ml. The specimen was dissolved in a dimethyl sulfoxide (hereinafter referred to as DMSO) solution and diluted with a culture medium so that the final DMSO concentration was 0.25% or less. 5
After culturing for 1 day, the culture solution containing the specimen was removed by suction, and l m
g/ MTT solution (3-(4.5-dimethyl-2-
Add lOOμQ of thiazolyl-2,5-diphenyl-2H-tetrazolium bromide) dissolved in the culture medium, and
It was kept warm for hours. Then, 100 μa of 10% SDS solution (sodium dodecyl sulfate aqueous solution) was added to
The cells and MTT dye were solubilized by incubation for 6 hours, and the OD5ao value was measured using a spectrophotometer. The OD value of the control group to which no sample is added is {00%, and the compound concentration that gives an OD value of 50%, IC. Table 2 shows the endothelial cell proliferation inhibitory activity of each sample based on the values.

Table 2 Endothelial Cell Proliferation Inhibitory Effect [Example] The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited to these Examples.

The elution in column chromatography (the elution solvent is shown in parentheses) in the following examples is TLC (Thin
The analysis was carried out by layer chromatography (thin layer chromatography) under close observation. In TLC observation, Kieselgel 60F, manufactured by Merck was used as a TLC plate. (7 0 ~ 2
30 mesh), the solvent used as the elution solvent in column chromatography was used as the developing solvent, and a UV detector, a coloring method using phosphomolybdic acid, etc. were used as the detection method. As the silica gel for the column, Kieselgel 60 (70 to 230 mesh), also manufactured by Merck, was used. N.M.
R spectra show proton NMR ('H-NMR) and MARIAN? using tetramethylsilane as internal or external reference. [Measurement was made with GIEMINI 200, and the δ value was expressed in ppm.

The abbreviations used in the examples have the following meanings.

S: Singlet, br: Broad, d:
doublet, dd: double doublet, ddd: doublet doublet, t: triplet, q
; quartet, m: multi-bullet, ABq: A
B quartet, J: coupling constant, Hz: hertz, CDCffs: deuterochloroform, d, -DMSO
: heavy dimethyl sulfoxide, % : weight % Also, in the following examples, room temperature refers to approximately 15 to 25
It means °C. All melting points and temperatures are given in Setsu.

Example l 6α-aminodesoxyfumagillol (1) 6-oxo6-desoxyfumagillol (4-(12-epoxy-
1,5-dimethyl-4-hexenyl)-5-methoxy-
1-Oxaspi o[2.5]octan-6-one: 0.
50g) and ammonium acetate (1.4g) were dissolved in methanol (15g), sodium cyanoborohydride (0.11g) was added, and the mixture was stirred for 1 hour. After distilling off the solvent under reduced pressure, the resulting residue was dissolved in ethyl acetate (food).
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 resulting residue was subjected to silica gel column chromatography (developing solvent: chloroform-methanol-concentrated aqueous ammonia = 20: 1:0
．． 1) to obtain 6α-amino-6-desoxyfumagillol (0.20 g).

NMR spectrum (CDC (23.δ value):
l. 05 (1B, m), 1. 24 (3H, s
), 1. 66 (311, s), 1. 75 (3
H, s), 1. 80 (ill, m), 1. 9
7 (11, d, 1011z), 2. 08-2.
47 (3H, m), 2. 51 (III, d
, 411z), 2. 59 (IH, t, 6tl
z), 2. 90(ill, d, 411z),
3. 44 (31!, s), 3. 60(l}I,
dd, 311z, 10Hz), 3. 66(lt
l, m), 5. 21 (ift, m) Example 2 6α-phenylamino-6-deso beef sifmagirol (2
) 6-oxo6-desoquine fumagillol (0.30 g, aniline (0.lld) and acetic acid (0.12 g) were dissolved in methanol (LOD), and molecular sieve 3A
After adding (0.20 g), shea/sodium borohydride (67 mg) was added and stirred for 1 hour. After distilling off the solvent under reduced pressure, the resulting residue was diluted with ethyl acetate (501n
1) and washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane-1; 9) to obtain 6α- Phenylamino-6-desoxyfumagillol (0.20g)
I got it.

NMR spectrum (CDC Q..δ value): 1
．． 25 (18, m), 1. 31 (3H.s)
, l. ．． 66 (311, s), 1. 75 (3
t{, s), 1. 80-2. 47 (6H, m
), 2. 55 (III, d, 4Hz), 2.
66 (LH, t, 611z), 2. 88(i
ll. d, 4[1z). 3. 34 (311, s
), 3. 78(ill, dd, 3Hz, lO
Hz), 4. 02 (LH, m). 5. 21 (l
}l, m), 8. 73 (311, m), 7.
19 (211, m). Example 3 6α-(acetyl)methylamino-6-desoxyfumagillol (dan) 6-oxo-6-desoxyfumagillol (0.30g)
and methylamine (40% methanol solution: I 4 females) and acetic acid (1.1 mol) were dissolved in methanol (15 mol), sodium cyanoborohydride (0.llg) was added, and the mixture was stirred for 2 hours. After evaporating the solvent under reduced pressure, the resulting residue was dissolved in chloroform (50rn1) and washed with a saturated aqueous sodium hydrogen carbonate solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in dichloromethane (2).
6TnI. ) and acetic anhydride (0.30d) to make 2
After stirring for 0 minutes, ethyl acetate (30d) was added to dilute the mixture, and the mixture was washed with a 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 7-liter gel strength ram chromatography (developing solvent:
ethyl acetate) to obtain 6α(acetyl)methylamino-6-tenquin fumaquirol (0.34 g).

NMR spectrum (CD C ff3, δ value):
l. 28(ltl, m)1. 52 (3H, s)
．． 1. 65 (3H, s), 1. 73 (311
, s). 1. 50-1. 90 (3H, m),
2. 00-2. 86 (7tl, n+), 2.
95 (0.911, s), 3. 01 (2.
1tLs), 3. 20-3. 30(4}1, m
), 4. 20 (0. 311, m), 4, 68
(0.711, m), 5.08-5. 30(LH
, m). Example 4 6α-(N-acetyl-3-methylthiobropylamino)-6-desoxyfumagillol (4) A compound was obtained in the same manner as in Example 3.

NMR spectrum (CDCC, δ value):
1. 28(II, m), 1. 50 (1.5
H, s), 1. 51 (1.5H, s), 1
．． 65 (3H, s), 1. 73 (311, s.
), 1. 60-1. 90 (3B, m), 2.
00-2. 86 (14H, m), 3: 25 (
3tLs), 3. 19-3. 65 (3H, m
), 4. 20 (0.511, m), 4. 6
8 (0.51Lm), 5. 08-5. 30 (l
tl, m). Example 5 6α-acetylamide/-6-denki/fumagillol (dan) 6-oxo 6-desoki/fumagillol (0.30 g)
and ammonium acetate (0.8 g) in methanol (lo7
nl. ) and shea/sodium borohydride (6
7 mg) and stirred for 1 hour. After evaporation of the solvent under reduced pressure, the resulting residue was dissolved in ethyl acetate (5 (bJ)) and washed with saturated aqueous sodium bicarbonate solution 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 dissolved in dichloromethane (2 components). Pyridine (0.26 d) and acetic anhydride (0.30 d) were added, and the mixture was dissolved for 30 minutes. After stirring, ethyl acetate (50y=l2)
The mixture was diluted with saturated aqueous sodium chloride solution, saturated aqueous sodium bicarbonate solution, and washed again with saturated aqueous sodium chloride solution.

After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: chloroform-methanol-concentrated aqueous ammonia = 30:1:0.1). and 6α-acetylamino-6-desoquine fumagillol (0.31g
) was obtained.

NMR spectrum (CD C Q..δ value) River. 2
8 (311, s), 132 (lft, claw), 1.
66 (311, s). 1. 74 (311, s.
), l. 60~l. 90(3t{, m), 2.
00(3H, s), 2. 00-2. 47 (3
11, m), 2. 54(ill, d, 41!z
), 2. 66 (IH, t, 6Hz), 2.
85 (IH, d, 411z), 3. 84 (
311, s), 3. 70 (11!, da, 4
11z, 911z), 4. 46(lit, m
), 5. 20 (ltl, m) 5.79 (IH, however), Example 6 6α-(p-}luenesulfonylamino)-6desoxyfumagillol (dan) 6-oxo6-desoxyfumagillol (0 .2Og)
and ammonium acetate (0.6g) in methanol (10y
ii2) and sodium cyanoborohydride (4
5+ng) was added and stirred for Y hours. After distilling off the solvent under reduced pressure, the resulting residue was dissolved in chloroform (21), and saturated aqueous sodium hydrogen carbonate solution (11) was added.

After adding p-toluenesulfonyl chloride (93 mg) to this and stirring for 30 minutes, water was added to stop the reaction. The raw material was extracted with chloroform, and the extract was washed with a 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: ethyl acetate).
Purified with hexane (2) and purified with 6α-(p-toluenesulfonylamino)-6-desoxyfumagillol (0
．． 19 g) was obtained.

NMR spectrum (CDC f23, δ value):
l. 17 (311, s) 1. 18 (IH, m)
, 1. 65 (311, s), 1. 75 (3H
, s), 1. 60=1. 80 (3H, m),
2,00~2. 47 (3H, m), 2. 44
(3B, s), 2. 53 (18, d, 4Hz)
, 2. 55 (IH, t, 6Hz), 2. 8
6 (IH, d, 4Hz), 3. 92 (3H,
s), 3. 50 (LH, dd, 4Hz, 10
1{z), 3. 62 (1.H, m), 4. 8
a(lt{, m). 5. 27 ([1, m),
7. 33 (211, d, 811z), 7. 7
9 (2tL d, 811z). Example 7 6α-(isobutyloxysulfonylamino)=6-desoxyfumagillol (2) Compound 7 was obtained in the same manner as in Example 6.

NMR spectrum (CD C &., δ value): 0
, 91(3il, s), 0. 95 (31!.
s), 1. 29 (3tl, s), 1. 32(
lit, m), 1. 66 (38, s), 1.
74 (311, s), 1. 6Q~2. 00(4
8, m), 2. 0Q~2. 47 (38, m)
,2. 54 (III, d. 4Hz), 2. 6
5 (IH, t, 611z), 2. 84 (ill
, d, 4tlz), 3. 40(31{, s),
3. 68(lII, dd, 411z, 91
1z). 3. 84 (2tl, d, 711z) 4
．． 22 (IL m), 5. 04 (III, m)
, 5. 20(III, m). Example 8 6α-penzoylamino-6-desoquine fumagillol (
8) Compound 8 was obtained in the same manner as in Example 6.

NMR spectrum (CDC Q3.δ value): l
．． 35 (311, s), 1. 51 (IH, i)
．． 1. 66 (311, s), 1. 75 (3H
, s), 1. 60-1. 80 (311, m)
, 2. 10-2. 47 (3H, m), 2.
57 (1B, d, 4tlz), 2. 74 (1t
{, t, 6Hz), 2. 85(III, d,
4Hz), 3. 41 (3H, s), 3.
79 (IH, dd, 4Hz. 8Hz), 4.
L{(11{, m), 4. 83 (IIL m),
5. 22(ill, m)6. 44 (III,
m), 7. 45 (2H, d, 8Hz), 7
．． 78 (2H.d, 8Hz). Example 9 6α-(N'-chloroacetylureido)-6-desoxyfumagillol (YU) 6-oxo 6-desoxyfumagillol (0.50 g
) and ammonium acetate (1.4 g) in methanol (
151n1), sodium cyanoborohydride (Q.11 mg) was added, and the mixture was stirred for 1 hour. After distilling off the solvent under reduced pressure, the resulting residue was diluted with ethyl acetate (
50d) and washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution.

After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in dichloromethane (5 liters). O
Chloroacetylisocyanate (0.3d) was added dropwise at 'C. After stirring at the same temperature for 30 minutes, diluted with ethyl acetate (50d) and diluted with saturated sodium bicarbonate.
Washed with aqueous sodium chloride solution 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 purified by silica gel column chromatography (developing solvent: ethyl acetate to beef sanitation = 1:l) to obtain 6α-(N '-Chloroacetylureido)6
-Desoxyfumagillol (0.42g) was obtained.

NMR spectrum (CDCff3, δ value)・I. 31
(311, s), l, 32(ill, m), 1.
45-2. 0G (4i1, m), 1. 66(
3tt, s), 1. 75 (311, s), 2
．． lo~2. 47 (2■, m), 2. 55 (
III, d, 4Hz), 2. 68 (IH, t
, 611z), 2. 84 (IH, d, 4tl
z), 3. 43 (311, s), 3. 63(
ill, dd, 4Hz, 8Hz), 4. 12
(211, s), 4. 57 (IH, m),
5. 20 (lit, m) Example 10 6α-tN′-(.l-naphthyl)thioureido}6-desoxyfumagillol (10) Compound 10 was obtained in the same manner as in Example 9.

NMR spectrum (CD C C., δ value): l
, 20 ([1, m), 1. 41 (311, s
). 1. 38(III, d, 211z), 1
．． 55-1. 75 (III, Il1), 1. 6
5 (3H, s), 1. 74 (311, s).
1. 1115-2. 50 (41L m), 2.
42 (III, d, 5tlz), 2. 47 (I
H, d, 511z), 2. 83(III, t
, 611z), 2. 93 (341, s), 3
．． 52 (ill, m), 4. 76(lit,
m), 5. 20(ill, m), 6. 10(
III, m), 7. 42-7. 65 (4H,
m), 7. 80-8. 05 (411, m). Example 11 6α-{N'-(1-naphthyl)ureido}-6desoxyfumagillol (11) A compound supernatant was obtained in the same manner as in Example 1.

NMR spectrum (CDC (3+δ value): 1
．． 26(31{, s), l. 3 (1-1.8
5 (41{, m), 1. 63(31{, s),
1. 73 (3H, s), 2. 00-2. 4
7 (3H, m), 2. 4Kll{, d, 4)
lz), 2. 61(1}1, t, 6Hz),2
．． 72(1ll, d, 41{z), 3. 21
<3H, s), 3. 65 (IH, dd, 4H
z, 8Hz), 4. 43(lit, m), 5
．． 17 (1.11, m), 5. 39(l}l
, m), 7. 02(IH, m)+7. 50(
3}1, m), 7. 7 1 (2+l, ml
7. 87 (IH, m), 8. 04 (1tL
m). Example 12 6α-tN'-(2-chloroethyl)ureido}=6-
Desoxofumagilol (upper 1) Compound 12 was obtained in the same manner as in Example 9.

NMR spectrum (CD C 122, δ value):
1. 20 (LH, m), 1. 28 (311,
s), l, 65 (3H, s), 1. 74(3
H, s), 1. 60-1. 98 (311, m
), 2. lO~2. 45 (3H, m), 2.
53 (18, d, 4Hz), 2. 54 (II
I, t, 611z), 2. 84(lit, d
, 411z), 3. 37 (311, s), 3
．． 40-3. 70 (4H, m), 3. 72(
l}l, dd, 4Hz, lOHz), 4. 3
1 (II, m), 5. 10-5. 42 (3H,
II1). Example 13 6α-ureido-6-desoxyfumagillol (13) Compound 9 (0.17 g) was dissolved in tetrahydrofuran (T
The mixture was dissolved in HF, 2d), added with sodium N-methyldithiocarbamate (0.11 g), and stirred for 15 minutes. The reaction mixture was diluted with ethyl acetate (30d) and washed once with a saturated aqueous sodium hydrogen carbonate solution and once with a saturated aqueous sodium chloride solution. After drying with anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: chloroform-methanol-concentrated aqueous ammonia = 20:1:0.1), and recrystallized from benzene. 6α-ureido-6-desoxyfumagillol (86+g) was obtained.

Melting point = 124-125°C NMR spectrum (CD C &,.δ value) + 1
．． 23(Ill, m)1. 28 (3H, s).
1. 65 (3H.s), 1. 7111 (3!
Ls), 1. 65-1. 96 (3H.i),
2. to~2'; 45 (3H, m), 2. 5
4(l}I, d, 4Hz), 2. 59 (IH,
t, 6Hz), 2. 85 (IH, d, 4Hz
), 3. 93 (3H, s), 3. 71 (18
, dd, 4Hz, lGHz), 4. 32 (IH
, a+), 4. 58 (2H, m), 5. 1
9 (2H, m). Example 14 6α-(N'-chloroacetylureido)-4'5'-
Dihydro-6-desoxyfumagillol (14) compound (0.30-g) was dissolved in methanol (10%), 10% palladium on carbon (30 mg) was added, and the mixture was stirred for 1 hour under a hydrogen atmosphere. did. After the contact was separated from the furnace, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate, beef sanitation = l).
2) to obtain 6α-(N'-chloroacetylureido)-4',5'dihydro-6-desoxyfumagillol (0.19 g).

NMR spectrum (CDCQ3, δ value): 0.
89 (3H, s), 0. 82 (3 fl, s),
l, 30 (311, s), 1. 20-1.
70 (till, m). 1. 93 (21!, m
). 2. 59 (IH, d, 4Hz), 2.
65 (IH, dd, 5Hz, 'N!z), 2.7
5 (Hl, d, 4tlz), 3. 43 (3t!
, s), 3. 63 (Ill. dd, 411z
, 8Hz), 4. 12 (2Hz), 4. 54
(ill, m) Example 15 6β-phthalimido-6-desoxy fumagillol (Jotou) fumagillol (1.0 g), }liphenylphosphine (
1.22 g) and phthalimide (0.57 mg) were dissolved in tetrahydrofuran (TI{F, 30d), and diethyl azodicarbo bovine sylate (0.88 g) was dissolved in THF.
(5rn1) Melt t& was added dropwise. After stirring for 30 minutes, the reaction mixture was diluted with ethyl acetate (100 d) and washed with a saturated aqueous sodium chloride solution, followed by a saturated aqueous sodium bicarbonate solution, and again with a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane: 1:3) to obtain 6β-phthalimide-6. -Desoxyfumagillol (0.99g) was obtained.

NMR spectrum (CD C C3, δ value): I
．． 27(ltl, m), 1. 32 (311,
s), 1. 65-2. 70 (7H, m), 1
．． 67 (3H, s), 1. 73(3It, m
), 2. 58 (IH, d, 4Hz), 2.
99 (ltl, d, 4tlz), 3. 33 (3
11, s), 4. 36 (LH, m), 4.
71 (18, t, lOHz), 5. 23(lt
l, m), 7. 73 (2H, II1). 7.
88 (2H, m), Example 16 6β-amino-6-desoxyfumagillol (16) Compound 1 5 (2.0 g) was dissolved in methanol (40%), and hydrazine hydrate (1.4 g) was added and stirred for 20 minutes. After distilling off the solvent under reduced pressure, the excess amount of hydrazine hydrate was removed by azeotroping with ethanol, the resulting residue was dissolved in water (20 d), acetic acid (1.5 d) was added, and the mixture was stirred overnight. did. The precipitate was removed from the oven, concentrated aqueous ammonia (4-) was added, and then raw material 11 was extracted with chloroform. After drying the extract 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-concentrated aqueous ammonia = 30: 1: 0.03). 6β-amino-6-desoxyfumagillol (
0.90g) was obtained.

NMR spectrum CCDC i23, δ value):
1. 17 (IH, m), 1. 29 (3H,
s), l, 50-1. 95 (4H, m), 1
．． 66 (3H, s), 1.79 (3II, m)
, 2. 27 (LH, m), 2. 37 (LH,
m), 2. 52 (IH, d, 4Hz), 2.
55 (IH, t, 6Hz), 2. 90 (IH
, m), 2. 92 (IH, d, 4Hz).
3. 47 (IH, dd, 9Hz, lllllz)
, 3. 56 (3H, s). 5. 22(11{
, m). Example 17 6β-penzyloxycarbonylamino-6desoxyfumagillol (17) Compound 16 (0.50 g) and triethylamine (0
．． 74m9) was dissolved in dichloromethane (lo1nl.), and penzyloxycarbonyl chloride (0.74m9) was dissolved in dichloromethane (lo1nl.) at 0°C.
51d) was added dropwise. After stirring at the same temperature for 1 hour, the reaction mixture was diluted with ethyl acetate (50d).
Washed with saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate and beef sanitation = 1/2) to obtain 6β-penzyloxycarbonyl. Amino-6-desoxyfumagillol (0.06 g) was obtained.

NMR spectrum (CDC Q,.δ value): 1
．． 19 (IH, m)1. 26 (311, s),
1. 45-1. 95 (3H, m), 1. 6
5 (3H, s), 1. 75 (3II, m),
2. 17 (2H, m), 2. 37(ill,
m), 2.55 (1tL d, 411z), 2.
57 (IH, t, 6Hz), 2. 95(LH,
d, 4Hz), 3. 37 (38, s), 3
．． 60-3. 90 (2H, m), 5. 13(
2H, s), 5. 21 (IH, m). Example l
8 6β-(N'-Chloroacetylureido)-6-desoxyfumagillol (18) Compound 16 (0.28g) was dissolved in dichloromethane (3 bottles), and chloroacetylisocyanate (0.5g) was dissolved at 0°C.
lOd) was added dropwise. After stirring at the same temperature for 15 minutes, the reaction solution was diluted by adding ethyl acetate (50d).
Washed with saturated aqueous sodium bicarbonate solution followed by saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane = 1:l), and further crystallized with isobrobyl ether. 6β-(N'-chloroacetylureido)-6-desoxyfumagillol (0.18 g) was obtained.

Melting point = 130-131'C NMR spectrum (CDCI23, δ value) + 1.
20 (1tL m), 1. 28 (3tl, s),
1. 55-2. 00 (3H, m), 1. 6
6 (311, s), 1. 75 (31 m), 2
．． 17 (2H, a+), 2. 37 (1B, m
), 2. 52 (IH, d, 4Hz), 2, 58
(IH, t, 611z), 2. 97(ltl,
d, 411z), 3. 44 (3fl, s),
3. 79 (IH, t, IQIIz), 4. 0
3(ill, m). 4. 14 (211, s).
5. 21 (IH, m) Example 19 6β-pyrrolidino-6-desoquine fumagillol (Jodan) Compound 16 (0.43 g) was dissolved in dimethylformamide (
Anhydrous potassium carbonate (0.52 g) was added followed by 1,4-dibromobutane (0.32 d). 7
After stirring for an hour, the reaction iffl was diluted with ether (50d), and washed with water, a saturated aqueous sodium bicarbonate solution, and a 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-concentrated aqueous ammonia-30:
1:003) to obtain 6β-pyrrolidino-6-desoxyfumagillol (0.23 g).

NMR spectrum (CD Off., δ value):
l. 27 (IH, m), 1. 29 (3H, s
), l. 5(1~2.00(7H, m).1
．． 57 (lit, d, IOtlz)1. 66(
3H, s), 1. 75 (3H, m), 2.
17(ltl, m), 2. 37 (IH, m),
2. 53 (ill. d, 411z), 2.
54 (III, t, 611z). 2. 75 (4
t{, m), 2. 83(ill, m), 2.
92 (ill d. 4Hz), 3. 55 (31
1, s), a. 71 (18, t10Hz),
5. 21 (III, m). Example 20 6β-Virrolidino-6-desoxyfumagillol methyl iodide (1) Compound 19 (0.12 g) was dissolved in chloroform (1), anhydrous potassium carbonate (49 mg) was added, followed by methyl iodide (1). 0.5d) was added. After stirring for 3 and a half hours, the insoluble matter was
? 'A+J L The residue obtained by distilling off the solvent under 88 pressure was reprecipitated with chloroform-ether to obtain 6β-pyrrolidino-6-desoxyfumagillol methyl iodide (0.10 g).

NMR spectrum (CDC Q3, δ value): l
．． 35 (311, s), 1. 37 (IH, m
), 1. 55-2. 45 (IOH, m), 1
．． 68 (3H, s), 1. 76 (3H, m)
, 2. 65 (ltl, d, 4Hz), 2.
72 (IH, t, 6Hz), 2. 99 (IH
, d, 41iz), 3. 02 (3H, s),
3. 40-4. 05 (5H, m), 3. 57
(38, s), 4. 29 (IH, t, lOHz
), 5. 26 (IH, m). Example 2l 6β-hexylamino-6-desoxyfumagillol (Eto) Compound Jodan (3.0 g), hexanal (1.4 composition) and acetic acid (1.5 d) were dissolved in methanol (60 Ml). , sodium cyanoborohydride (0.67 g) was added. After stirring for 1 hour, ethyl acetate (100%
d) was added and diluted, and the mixture was washed with a saturated aqueous sodium bicarbonate solution and a 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-concentrated aqueous ammonia = 30:
1:003) to obtain 6β-hexylamino-6desoxyfumagillol (2.35 g).

NMR spectrum (CD C Q., δ value): Q
, 89 (31L m), l. lO~2. 35(
1211, m), 1. 66 (3H, .s),
1. 74 (311, m), 2, 5l (1B. d
, 411z), 2. 92 (LH, d, 4Hz
), 3. 50 (3H, s), 3. 69 (II
I, dd, 911z, 1 1Hz), 5. 22
(18, m) Example 22 6β-(N-methanesulfonyl)hexylamine/-6-
7' Sokin Fumagironore (22) Compound 21 (0.5
0 g) and triethylamine (0.38 d) were dissolved in dichloromethane (5 components), and methanesulfonyl chloride (0.13 ae) was added dropwise at O0C. After stirring for 15 minutes at the same temperature, ethyl acetate (5
0d) was added to dilute the mixture, and the mixture was washed with a saturated aqueous sodium bicarbonate solution and a 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 7 silica gel column chromatography (developing solvent: ethyl acetate to beef sanitation 1:3). J and 6β-(N-methanesulfonylhexylamine/)-6-
De'/xifumagiroll (0.12 g) was obtained.

NMR spectrum (CDCC, δ value):
0. 85 (3H, m), 1.31 (12H, s 冫, 1.50~2, 00 (8H, m). 1.66 (3 + 1
, s), 1.75 (3tl, m), 2. 17(i
t{, m), 2. 37(kl{, m), 2.
56(ll{, d, 411z), 2. 68 (I
H, t, 6Hz), 2. 93(LH, d,
4Hz), 2. 97 (3H, s), 3. 19
(2H, m)+3. 59 (311, s), 5
．． 21(II{, m). Example 23 6α-phe/xycarbonylamino-6-deso beef shifmagi roll (Edan) 6-o beef so 6-deso kine fumagi roll (0.51 g)
and ammonium acetate (1.43g) in methanol (1!
M) and shea/sodium borohydride (0.1
2g) was added and stirred for 1 hour. After evaporating the solvent under reduced pressure, the resulting residue was dissolved in ethyl acetate (701 nl) and washed with saturated aqueous sodium bicarbonate solution 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 dissolved in dichloromethane (5-) and dimethylaminopyridine (0.4
4g) was added.

Phenyl chloroformate (0.43 g) was added dropwise to the solution at room temperature.
After stirring for an hour, it was diluted with ethyl acetate (7 (Lj2)) and washed with IM citric acid aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane = 1:4) to obtain 6
α-phenoxycarbonylamino-6-desoki/fumagillol (0.21 g) was obtained.

NMR spectrum (CD C 123, δ value) +
1. 31 (311, s), 1. 2-1. 6(
1B, m), 1. 66 (311, s), 1.
74 (31f, s), 1. 6~l 9 (311
, m), 2. 1-2. 45 (3H, m),
2. 56 (LH, d, 4Hz), 2. 69(
litt, 6Hz), 2. 85(ltl, d,
411z), 3. 44 (311, s), 3.
72 (IH, dd, 9Hz, 411z), 4
．． 32 (ill, m), 5. 20 (IH, m
), 5. 45 (IH, brd, 4Hz), 7
．． 1-7. 25 (3tl, m), 7. 3-7
．． 45 (2H, m). [Effects of the Invention] The compound (+) of the present invention has an angiogenesis-inhibiting effect, a cell growth-inhibiting effect, an immunosuppressing effect, etc., and is useful as a pharmaceutical or the like.

Claims (1)

[Claims] General formula▲ Numerical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is a 2-methyl-1-propenyl group or an isobutyl group, and R^2 and R^3 are each a hydrogen atom , represents a hydrocarbon residue that may have a substituent or an acyl group that may have a substituent, and R^2 and R
^3 may form a ring together with the adjacent nitrogen atom. The bond symbol ■ indicates an α bond or a β bond. ] 6-Amino-6-desoxyfumagillol and its derivatives or salts thereof.