Fumagillol derivative and the medical use thereof

The disclosure relates to a fumagillol compound which can be usefully used not only as an angiogenesis inhibiting agent showing a superior angiogenesis inhibitory effect with less toxicity, but also as a cancer metastasis inhibitor and a therapeutic agent against cancer and other various inflammatory diseases such as rheumatic disease, psoriasis, etc., and diabetic retinopathy related to angiogenesis, and also a method for preparing the same.

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Description
CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of prior application Ser. No. 11/494,026 filed on Jul. 26, 2006 and incorporated herein by reference in its entirety, which is a divisional of U.S. Pat. No. 7,087,768 issued on Aug. 8, 2006 and incorporated herein by reference in its entirety, which claimed priority of Korean Application No. 2001-60017 filed on Sep. 27, 2001 and Korean Application No. 2002-29915 filed on May 29, 2002.

TECHNICAL FIELD

The present invention is directed to a fumagillol derivative or a pharmaceutically acceptable salt thereof, showing excellent angiogenesis inhibitory effect, with low toxicity; a preparation method thereof; and a medical use thereof.

PRIOR ART

Angiogenesis is a phenomenon of forming new vessels at the capillary level by a series of processes, such as proliferation, infiltration and transfer, and interactions of vein endothelial cells. This phenomenon is considered to be not only a normal physiological process but also a pathological process of various diseases. Angiogenesis, properly controlled by various physiological substances, is an important physiological process, which is seen upon healing of wounded parts or formation of uterine endothelia after birth or menstruation.

However, in the uncontrolled state, angiogenesis that excessively generates novel capillary vessels is regarded as a pathological condition. Such angiogenesis is known to be closely associated with growth and metastasis of solid cancers, diabetic retinopathy, rheumatic arthritis and psoriasis [Billington, D. C. Drug Design and Discovery, (1991), 8, 3.].

Much research on inhibition of such angiogenesis regarded as a pathological condition has been performed. Judah Folkman of the Medical College of Harvard University suggested a new concept of treating solid cancer by inhibiting angiogenesis in 1971 [J. Folkman, New Engl. Med., 185 (1971), 1182-1185]. In other words, an angiogenesis inhibitory agent is responsible for decrease or inhibition of growth of solid cancers, resulting in blocking metastasis of solid cancer. Such an angiogenesis inhibitory agent has a useful therapeutic effect for other inflammatory diseases, such as diabetic retinopathy, rheumatoid arthritis, psoriasis, etc, in addition to solid cancers.

Compounds inhibiting angiogenesis have been developed through many efforts up to the present, and so various compounds are known as novel angiogenesis inhibitory agents.

In this regard, European Pat. Nos. 0 354 787, 0 357 061 and 0 415 294, and Japanese Pat. No. JP-AO1-233275 disclose fumagillol derivatives.

Further, it has been reported that 6-amino-6-deoxyfumagillol [Chem. Pharm. Bull., 40, 575-579 (1992)], 6-O-acyl, 6-O-sulfonyl, 6-O-alkyl, 6-O-(N-substituted carbamoyl)fumagillol [Chem. Pharm. Bull., 40, 96-101 (1992)] have angiogenesis inhibitory functions.

However, there is required a continuous development of angiogenesis inhibitory agents exhibiting excellent angiogenesis inhibitory effect with less toxicity, and having novel chemical structure.

DISCLOSURE OF THE INVENTION

Leading to the present invention, the intensive and thorough research into novel compounds having high inhibitory effect on angiogenesis, carried out by the present inventors, resulted in the finding that an aniline derivative having various substituents can be introduced to a known fumagillol, whereby a compound of the formula I, which has angiogenesis inhibitory effect and low toxicity, can be prepared.

It is therefore an object of the present invention to provide a fumagillol derivative or a pharmaceutically acceptable salt thereof, exhibiting excellent angiogenesis inhibitory effect.

It is another object of the present invention to provide a method of preparing such a fumagillol derivative.

It is a further object of the present invention to provide a pharmaceutical composition for angiogenesis inhibition, usable as an angiogenesis inhibitor, comprising a fumagillol derivative or a pharmaceutically acceptable salt thereof as a useful ingredient.

The above objects are achieved by providing the fumagillol derivative or the pharmaceutically acceptable salt thereof of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a view showing the decrease of the tumor size of mice treated with the compounds of Ex. 1, Ex. 11, Ex. 63 and Ex. 64 according to the present invention compared with that of mice treated with vehicle alone.

FIG. 2 is a series of photographs showing the size of tumor cells in xenografted nude mice treated with buffer alone or treated with Ex. 1 and Ex. 64 according to the present invention.

BEST MODES FOR CARRYING OUT THE INVENTION

The present invention provides a fumagillol derivative represented by the following general formula I, or a pharmaceutically acceptable salt thereof:

(wherein,

X is —OH and Y is halogen, or X and Y are linked together to form an oxirane ring,

B represents —(C═O)— or —CH2—,

R1 represents hydrogen; hydroxy; —CN; —NO2; —CF3; formyl; C1-C4 thioalkyl; acetamido; acetoxy; C1-C6 alkyl; C1-C4 aminoalkyl; C1-C4 alkylaminoalkyl; C1-C4 dialkylaminoalkyl; C1-C6 alkoxy; C1-C6 aminoalkoxy; C1-C4 alkylaminoalkoxy; C1-C4 dialkylaminoalkoxy; amino; C1-C6 alkylamino; C1-C4 dialkylamino; C1-C4 hydroxyalkyl; C1-C4 alkyloxycarboxylic acid, or

in which R2, R3, R4, R5 and R6, which are the same or different, each represents hydrogen; hydroxy; —CN; —NO2; —CF3; formyl; C1-C4 thioalkyl; acetamido; acetoxy; C1-C6 alkyl; C1-C4 aminoalkyl; C1-C4 alkylaminoalkyl; C1-C4 dialkylaminoalkyl; C1-C6 alkoxy; C1-C6 aminoalkoxy; C1-C4 alkylaminoalkoxy; C1-C4 dialkylaminoalkoxy; amino; C1-C6 alkylamino; C1-C4 dialkylamino; C1-C4 hydroxyalkyl; or C1-C4 alkyloxycarboxylic acid; or, R2 and R3, R3 and R4, R4 and R5, or R5 and R6, are linked together to form a C1-C3 alkylene dioxy ring, and

Z1, Z2, Z3, Z4 and Z5 each represent carbon or nitrogen).

Preferably, X and Y are linked together to form the oxyran ring, and B is —(C═O)—,

R1 is hydrogen; hydroxy; —CN; —NO2; —CF3; formyl; acetamido; acetoxy; C1-C6 alkyl; C1-C4 aminoalkyl; C1-C4 alkylaminoalkyl; C1-C4 dialkylaminoalkyl; C1-C6 alkoxy; C1-C6 aminoalkoxy; C1-C4 alkylaminoalkoxy; C1-C4 dialkylaminoalkoxy; amino; C1-C6 alkylamino; C1-C4 dialkylamino; C1-C4 hydroxyalkyl; C1-C4 alkyloxycarboxylic acid, or

R2, R3, R4, R5 and R6, which are the same or different, each represents hydrogen; hydroxy; —CN; —NO2; —CF3; formyl; acetamido; acetoxy; C1-C6 alkyl; C1-C4 aminoalkyl; C1-C4 alkylaminoalkyl; C1-C4 dialkylaminoalkyl; C1-C6 alkoxy; C1-C6 aminoalkoxy; C1-C4 alkylaminoalkoxy; C1-C4 dialkylaminoalkoxy; amino; C1-C6 alkylamino; C1-C4 dialkylamino; C1-C4 hydroxyalkyl; or C1-C4 alkyloxycarboxylic acid, or

R2 and R3, R3 and R4, R4 and R5, or R5 and R6 are linked together to form the C1-C3 alkylene dioxy ring, and

Z1, Z2, Z3, Z4 and Z5 each represent carbon or nitrogen.

More preferably, R1 is selected from the group consisting of hydrogen; hydroxy; methyl; chlorine; methoxy; methylpropoxy; isopropoxy; allyloxy; propyloxy; acetoxy cyano; amino; dimethylaminomethyl; methylpropoxy; dimethylethoxy; 3,5-diisopropyl-4-methoxy; 3,5-dimethyl-4-methoxy; isopropyl-4-ethoxy; dimethylamino; ethylamino; methylenedioxy; nitro; acetoxy; trifluoromethyl; and hydroxyethoxy,

R2, R3, R4, R5 and R6 is independently selected from the group consisting of hydrogen; hydroxy; methyl; chlorine; methoxy; methylpropoxy; isopropoxy; allyloxy; propyloxy; acetoxy cyano; amino; dimethylaminomethyl; methylpropoxy; dimethylethoxy; 3,5-diisopropyl-4-methoxy; 3,5-dimethyl-4-methoxy; isopropyl-4-ethoxy; dimethylamino; ethylamino; methylenedioxy; nitro; acetoxy; trifluoromethyl; and hydroxyethoxy, and

Z1, Z2, Z3 Z4 and Z5 each represent carbon or nitrogen.

The fumagillol derivative of the above formula I has at least 6 chiral centers, as represented by the following formula, and in the scope of the present invention, each optical isomer or mixtures thereof is included:

In addition, the present invention further comprises 6-O-(chloro)acetyl fumagillol as an intermediate represented by the formula II, for use in preparation of the fumagillol derivative of the formula I:

Among the compounds of the formula I, preferred are:

  • 1) 6-O-(4-methoxyaniline)acetyl fumagillol;
  • 2) 6-O-(3,4,5-trimethoxyaniline)acetyl fumagillol;
  • 3) 6-O-(2,4-dimethoxyaniline)acetyl fumagillol;
  • 4) 6-O-(3,4-dimethoxyaniline)acetyl fumagillol;
  • 5) 6-O-(3,4-dimethoxy-6-nitroaniline)acetyl fumagillol;
  • 6) 6-O-(3,4-dimethoxy-6-cyanoaniline)acetyl fumagillol;
  • 7) 6-O-(4-allyloxyaniline)acetyl fumagillol;
  • 8) 6-O-(4-(2-acetoxyethoxy)aniline)acetyl fumagillol;
  • 9) 6-O-(3-cyano-4-methoxyaniline)acetyl fumagillol;
  • 10) 6-O-(3-(dimethylaminomethyl)-4-methoxyaniline) acetyl fumagillol;
  • 11) 6-O-(4-(2-methylpropoxyaniline)acetyl fumagillol;
  • 12) 6-O-(3-isopropoxy-4-methoxyaniline)acetyl fumagillol;
  • 13) 6-O-(4-(N,N-dimethylethoxy)aniline)acetyl fumagillol;
  • 14) 6-O-(3,5-diisopropyl-4-methoxyaniline)acetyl fumagillol;
  • 15) 6-O-(3,5-dimethyl-4-methoxyaniline)acetyl fumagillol;
  • 16) 6-O-(3-isopropyl-4-ethoxy-6-methylaniline)acetyl fumagillol;
  • 17) 6-O-(4-propyloxyaniline)acetyl fumagillol;
  • 18) 6-O-(aniline)acetyl fumagillol;
  • 19) 6-O-(4-chloroaniline)acetyl fumagillol;
  • 20) 6-O-(4-dimethylaminoaniline)acetyl fumagillol;
  • 21) 6-O-(4-hydroxyaniline)acetyl fumagillol;
  • 22) 6-O-(4-aminoaniline)acetyl fumagillol;
  • 23) 6-O-(3,4-methylenedioxyaniline)acetyl fumagillol;
  • 24) 6-O-(4-nitroaniline)acetyl fumagillol;
  • 25) 6-O-(2,3,4-trimethoxy-6-aminoaniline)acetyl fumagillol;
  • 26) 6-O-(4-acetoxy-3,5-dimethoxyaniline)acetyl fumagillol;
  • 27) 6-O-(3,4-dimethoxy-5-hydroxyaniline)acetyl fumagillol;
  • 28) 6-O-(4-dimethylaminoethoxyaniline)acetyl fumagillol;
  • 29) 6-O-(4-ethylaminoaniline)acetyl fumagillol;
  • 30) 6-O-(4-ethylaminoethoxyaniline)acetyl fumagillol;
  • 31) 6-O-(3-dimethylaminomethyl-4-methoxyaniline)acetyl fumagillol;
  • 32) 6-O-(4-trifluoromethylaniline)acetyl fumagillol;
  • 33) 6-O-(4-acetoxy aniline)acetyl fumagillol;
  • 34) 6-O-(4-cyanoaniline)acetyl fumagillol;
  • 35) 6-O-(4-hydroxyethoxyaniline)acetyl fumagillol;
  • 36) 6-O-(5-amino-2-methoxypyridine)acetyl fumagillol;
  • 37) 6-O-(5-methoxypyrimidine-2-amino)acetyl fumagillol;
  • 38) 6-O-(3-methoxy-6-aminopyridazine)acetyl fumagillol;
  • 39) 4-((4-methoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol;
  • 40) 4-((3,4,5-trimethoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol;
  • 41) 6-O-(ethylamino)acetyl fumagillol;
  • 42) 6-O-(isopropyl amino)acetyl fumagillol;
  • 43) 6-O-(1-propyl amino)acetyl fumagillol;
  • 44) 6-O-(1-butyl amino)acetyl fumagillol;
  • 45) 6-O-(sec-butyl amino)acetyl fumagillol;
  • 46) 6-O-(2-methyl-butylamino)acetyl fumagillol;
  • 47) 6-O-(t-butyl amino)acetyl fumagillol;
  • 48) 6-O-(pentyl amino)acetyl fumagillol;
  • 49) 6-O-(1-methyl-butyl amino)acetyl fumagillol;
  • 50) 6-O-(1-ethyl-propyl amino)acetyl fumagillol;
  • 51) 6-O-(1-methyl-pentylamino)acetyl fumagillol;
  • 52) 6-O-(1,2-dimethyl-butylamino)acetyl fumagillol;
  • 53) 6-O-(1,2,2-trimethyl-propylamino)acetyl fumagillol;
  • 54) 6-O-(1-isopropyl-2-methylpropylamino)acetyl fumagillol;
  • 55) 6-O-(3-methylbutylamino)acetyl fumagillol;
  • 56) 6-O-(2-methylallylamino)acetyl fumagillol;
  • 57) 6-O-(4-methyl-hepta-2,4-dienylamino)acetyl fumagillol;
  • 58) 6-O-(1,5-dimethyl-4-hexenylamino)acetyl fumagillol;
  • 59) 6-O-(1,1-dimethyl-2-propynylamino)acetyl fumagillol;
  • 60) 6-O-(prop-2-enylamino)acetyl fumagillol;
  • 61) 6-O-(2-bromo-ethylamino)acetyl fumagillol;
  • 62) 6-O-(chloroethynylamino)acetyl fumagillol;
  • 63) 6-O-(cyclopropylamino)acetyl fumagillol;
  • 64) 6-O-(cyclobutylamino)acetyl fumagillol;
  • 65) 6-O-(cyclopentylamino)acetyl fumagillol;
  • 66) 6-O-(cyclohexylamino)acetyl fumagillol;
  • 67) 6-O-(4-tert-butylcyclohexylamino)acetyl fumagillol;
  • 68) 6-O-(2-dimethylamino-1-methylethylamino)acetyl fumagillol;
  • 69) 6-O-(2-dimethylamino-propylamino)acetyl fumagillol;
  • 70) 6-O-(2-methoxy-2-methyl-propylamino)acetyl fumagillol;
  • 71) 6-O-(2-oxo-propylamine)acetyl fumagillol;
  • 72) 6-O-(1,1-dimethyl-3-oxobutylamino)acetyl fumagillol;
  • 73) 6-O-(ethyl-2-aminoacetate)acetyl fumagillol;
  • 74) 6-O-(alanine-methylesteramino)acetyl fumagillol;
  • 75) 6-O-(methyl-2-amino-3,3-dimethylbutanoate)acetyl fumagillol;
  • 76) 6-O-(allylglycine-methylester)acetyl fumagillol;
  • 77) 6-O-(2,2-dimethoxy-ehtylamino)acetyl fumagillol;
  • 78) 4-((cyclopropylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol;
  • 79) 4-((cyclobutylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol; and
  • 80) 6-O-(chloro)acetyl fumagillol.

Among the compounds of the formula I, most preferred are:

  • 1) 6-O-(4-methoxyaniline)acetyl fumagillol;
  • 2) 6-O-(3,4,5-trimethoxyaniline)acetyl fumagillol;
  • 3) 6-O-(4-(N,N-dimethylethoxy)aniline)acetyl fumagillol;
  • 4) 6-O-(cyclopropylamino)acetyl fumagillol;
  • 5) 6-O-(cyclobutylamino)acetyl fumagillol;
  • 6) 4-((cyclopropylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol; and
  • 7) 4-((cyclobutylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol.

Structural formulas of the above compounds are shown in Tables 1a to 1d, below.

TABLE 1a Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Ex. 8 Ex. 9 Ex. 10 Ex. 11 Ex. 12 Ex. 13 Ex. 14 Ex. 15 Ex. 16 Ex. 17 Ex. 18 Ex. 19 Ex. 20

TABLE 1b Ex. 21 Ex. 22 Ex. 23 Ex. 24 Ex. 25 Ex. 26 Ex. 27 Ex. 28 Ex. 29 Ex. 30 Ex. 31 Ex. 32 Ex. 33 Ex. 34 Ex. 35 Ex. 36 Ex. 37 Ex. 38 Ex. 39 Ex. 40

TABLE 1c Ex. 41 Ex. 42 Ex. 43 Ex. 44 Ex. 45 Ex. 46 Ex. 47 Ex. 48 Ex. 49 Ex. 50 Ex. 51 Ex. 52 Ex. 53 Ex. 54 Ex. 55 Ex. 56 Ex. 57 Ex. 58 Ex. 59 Ex. 60

TABLE 1d Ex. 61 Ex. 62 Ex. 63 Ex. 64 Ex. 65 Ex. 66 Ex. 67 Ex. 68 Ex. 69 Ex. 70 Ex. 71 Ex. 72 Ex. 73 Ex. 74 Ex. 75 Ex. 76 Ex. 77 Ex. 78 Ex. 79 Inter- medi- ate

The fumagillol derivative of the present invention, represented by the formula I, may be used in a form of a pharmaceutically acceptable salt. In particular, an acid addition salt formed by a pharmaceutically acceptable free acid is usefully used. As the free acid, an inorganic acid and an organic acid may be used. Examples of the inorganic acid include hydrochloric acid, bromic acid, sulfuric acid and phosphoric acid. The organic acid is exemplified by citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, umaric acid, gluconic acid, methansulfonic acid, glyconic acid, succinic acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid or aspartic acid.

Additionally, the present invention provides a method of preparing an acetyl fumagillol derivative and a pharmaceutically acceptable salt thereof, as represented by the following Reaction Scheme 1.

Specifically, the preparation method of the fumagillol derivative compound in which B is —(C═O)—, comprises the steps of:

(a) acylating a compound of the formula 2 with α-halocarboxylic acid derivative in the presence of a base, to give a compound of the formula 3; and

(b) reacting the compound of the formula 3 with an amine compound of the formula 4, to prepare the fumagillol derivative represented by the formula 1a via substitution.

(wherein, R1 is as defined above)

In the present invention, the prepared compound of the formula 1a is treated with an acid, or reacted with a salt in the presence of an acid catalyst, to perform an oxirane ring-opening reaction, thereby yielding the fumagillol derivative represented by the formula 1b, as shown in the following Reaction Scheme 2:

(wherein, R1, X and Y are as defined above)

Below, a description will be given of each step.

(1) Acylation Step

The compound of the formula 2 as a starting material is acylated with α-halocarboxylic acid derivative having high reactivity, in the presence of the base, to give the compound of the formula 3, as seen in the following Reaction Scheme 3.

Specifically, the compound of the formula III is a fumagillol, which is a hydrolyzed product of fumagillin produced by microbial fermentation [Tarbell, D, S. et. al., J. Am. Chem, Soc., 83, 3096 (1961)]81).

The above α-halocarboxylic acid derivative is selected from among chloroacetyl chloride, chloroacetyl bromide, chloroacetyl iodide, and chloroacetyl fluoride, and used in the amount of 1-5 equivalents, preferably in 1-1.5 equivalents, based on the compound of the formula 2.

As for the base, an acid anhydride, a mixed anhydride or an acid chloride may be commonly used, and preferably, tertiary amines, such as triethylamine, diisopropylethyl amine, pyridine, dimethylamino pyridine, etc., are used in the amount of 1-10 equivalents. More preferably, 1-3 equivalents of triethylamine, or dimethylaminopyridine is used.

The solvent used for acylation is selected from the group consisting of dimethylformamide, dichloromethane, chloroform, diethylether, tetrahydrofuran, dioxane, acetonitrile, benzene and toluene. Preferably, dimethylformamide, dichloromethane or tetrahydrofuran is used.

As such, acylation is carried out at 0-50° C., preferably at 20-50° C.

2) Halogen-Amine Substitution Step

The compound of the formula 0.3, obtained from the previous acylation step, is reacted with the compound of the formula 4 as the amine derivative, to yield the compound of the formula 1a having a substituted amine compound, as seen in the following Reaction Scheme 4.

(wherein, R1 is as defined above)

The aromatic compound of the formula 4, used in the above substitution reaction, is used in the amount of 1-10 equivalents, preferably 1-3 equivalents, based on the compound of the formula 3.

As for the amine compound, aliphatic or aromatic amine compound can be used. Such derivatives are specifically stated in the examples of the present invention.

The solvent used in this substitution reaction is selected from the group consisting of dimethylformamide, dichloromethane, chloroform, diethylether, tetrahydrofuran, dioxane, acetonitrile, benzene and toluene. It is preferred that dimethylformamide, dichloromethane or tetrahydrofuran is used.

The substitution reaction is performed at 0-100° C., preferably at 20-50° C.

3) Oxirane Ring-Opening Step

The compound of the formula 1a, resulting from the above step, is treated with the acid, or reacted with the salt in the presence of the acid catalyst, to perform the oxirane ring-opening reaction, thereby yielding the fumagillol derivative represented by the formula 1b, as in the following Reaction Scheme 5.

(wherein, R1, X and Y4 are as defined above)

Examples of the acid used in the ring-opening reaction include hydrochloric acid, bromic acid or iodic acid. The acid usable as the catalyst comprises acetic acid, sulfuric acid, para-toluene sulfonic acid, hydrochloric acid, phosphoric acid or nitric acid. Of the acid catalysts, acetic acid or hydrochloric acid is preferably used.

The salt used in this reaction is selected from the group consisting of bromolithium, chlorolithium, sodium chloride, potassium chloride, potassium bromide, sodium bromide, potassium iodide, sodium iodide and lithium iodide. Preferably, chlorolithium, bromolithium, lithium iodide or sodium hydrogen carbonate.

Meanwhile, the preparation method of the compound in which B is —CH2— is specifically shown in the following Reaction Scheme 6.

Further, the present invention provides a pharmaceutical composition for angiogenesis inhibition, comprising the fumagillol derivative of the formula I or a pharmaceutically acceptable salt thereof as an effective ingredient.

In order to investigate activity of the fumagillol derivative on cell growth, proliferation inhibition activity was measured using HUVECs (human umbilical vein endothelial cells). As the result, it was found that the inventive fumagillol derivative has superior growth inhibition effect, up to 2000 times greater than TNP-470, a conventional angiogenesis inhibitory agent.

Therefore, it is expected that the fumagillol derivative of the formula I can strongly inhibit proliferation of vein endothelial cells, thus having excellent angiogenesis inhibitory effect. Such a fumagillol derivative can be usefully used for decreasing and inhibiting growth and metastasis of cancer as well as treating other various inflammatory diseases, including diabetic retinopathy, rheumatic arthritis and psoriasis. Hence, the fumagillol derivative is usable as a cancer metastasis inhibitor, or a therapeutic agent against cancer, rheumatic arthritis, psoriasis and diabetic retinopathy.

With a view to evaluating general toxicity of the compound of the formula I according to the present invention, experiments on acute toxicity were carried out using mice. As a result, it was found that the half lethal dose (LD50) of each compound upon single oral administration was not less than 2 g/kg, whereby the compound was evaluated as a very safe compound.

The compound of the formula I according to the present invention may be formulated, upon clinical administration, as a pharmaceutical solid, semi-solid or liquid type formulation which is suitable for oral or parenteral administration by blending this compound with a pharmaceutically acceptable inert carrier.

The pharmaceutical composition of the present invention is formulated into dosage form for oral administration, for instance, tablet, troches, lozenge, water- or oil-soluble suspension, prepared powder or grain, emulsion, hard or soft capsule, syrup or elixir. For formulation of the tablet and capsule form, used are binders such as lactose, sacharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin; vehicles such as dicalcium phosphate; disintegrating agents, such as corn starch or sweet-potato starch; and lubricants, such as magnesium stearate, calcium stearate, sodium stearylfumaric acid or polyethyleneglycol wax. In the case of capsule formulation, liquid carriers including fatty oil may be further included, in addition to the above materials.

Pharmaceutical preparations for parenteral administration comprise sterile aqueous solution, water-insoluble solvent, suspension, emulsion, and lyophilized agent. As the water-insoluble solvent and suspension, use may be made of vegetable oil such as propylene glycol, polyethylene glycol, olive oil, and injection ester, such as ethyl oleate.

In typical medical substances, effective doses of the compound of the formula I according to the present invention may range from 0.2 to 2.0 mg/kg, and they can be administered in a single dose or in divided daily doses. However, it should be understood by anyone skilled in the art that the amount of the active ingredient actually administered ought to be determined in light of various relevant factors including constitutional peculiarity and body weight of the individual subject, kinds and severity of diseases, properties of dosage form, properties of medicinal administration, and administration period or interval.

A better understanding of the present invention may be obtained in light of the following examples which are set forth to illustrate, but are not to be construed to limit the present invention.

EXAMPLE 1 Preparation of 6-O-(4-methoxyaniline)acetyl Fumagillol Step 1: (Acylation) Preparation of 6-O-chloroacetyl Fumagillol

Fumagillol (500 mg) in dichloromethane (10 ml) was added with dimethylaminopyridine (432 mg) and chloroacetyl chloride (199 mg), and stirred at room temperature for 1 hour. The reaction was vacuum concentrated, to give the residue, which was then purified by silica gel column chromatography (ethyl acetate:n-hexane=1:4), yielding 270 mg of the title compound as a light yellow oil.

1H-NMR (CDCl3) δ: 5.76-5.74 (m, 1H), 5.22 (br t, 1H, J=7.3 Hz), 4.19 (s, 2H), 3.71 (dd, 1H, J=2.8, 11.1 Hz), 3.47 (s, 3H), 3.01 (d, 1H, J=4.3 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.56 (d, 1H, J=4.3 Hz), 2.41-1.81 (m, 9H), 1.75 (s, 3H), 1.66 (s, 3H), 1.24 (s, 3H), 1.18-1.06 (m, 1H).

Step 2: (Substitution) Preparation of 6-O-(4-methoxyaniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (160 mg), obtained from the above step 1, was dissolved in dimethylformamide (1 ml), to which 4-methoxyaniline (0.055 mg) was added. The mixture was further with K2CO3 (61.48 mg) and KI (73.84 mg) and stirred at 70° C. for 6 hours.

Thereafter, the resultant reaction was diluted with ethyl acetate (20 ml), and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The organic layer was separated, dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 112 mg of the title compound as a white solid.

1H-NMR (CDCl3) δ: 6.57 (s, 2H), 5.70-5.73 (m, 1H), 5.19 (br t, 1H, J=7.3 Hz), 4.21 (s, 2H), 3.86 (s, 3H), 3.72 (dd, 1H, J=2.9, 11.1 Hz), 3.45 (s, 3H), 3.01 (d, 1H, J=4.2 Hz), 2.56 (t, 1H, J=6.4 Hz), 2.54 (d, 1H, J=4.2 Hz), 2.43-1.83 (m, 6H), 1.78 (s, 3H) 1.63 (s, 3H) 1.25 (s, 3H) 1.19-1.03 (m, 1H).

EXAMPLE 2 Preparation of 6-O-(3,4,5-trimethoxyaniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (166 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), to which 3,4,5-trimethoxyaniline (0.079 mg) was added. Then, this mixture was further added with K2CO3 (63.78 mg) and KI (76.61 mg), and stirred at 70° C. for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The organic layer was separated, and dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 136 mg of the title compound as a white solid.

1H-NMR (CDCl3) δ: 6.54 (s, 2H), 5.73-5.73 (m, 1H), 5.21 (br t, 1H, J=7.3 Hz), 4.21 (s, 2H), 3.89 (s, 9H), 3.72 (dd, 1H, J=2.9, 11.1 Hz), 3.44 (s, 3H), 3.01 (d, 1H, J=4.2 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.54 (d, 1H, J=4.2 Hz), 2.43-1.83 (m, 6H), 1.75 (s, 3H) 1.67 (s, 3H) 1.23 (s, 3H) 1.15-1.04 (m, 1H).

EXAMPLE 3 Preparation of 6-O-(2,4-dimethoxyaniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (168 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), to which 2,4-dimethoxyaniline (0.072 mg) was added. Then, the mixture was further added with K2CO3 (64.54 mg) and KI (77.52 mg) and stirred at 70° C. for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The organic layer was separated, dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 140 mg of the title compound as a white solid.

1H-NMR (CDCl3) δ: 6.57-6.48 (m, 3H), 5.73-5.71 (m, 1H), 5.24 (br t, 1H, J=7.2 Hz), 4.23 (s, 2H), 3.91 (s, 6H), 3.72 (dd, 1H, J=2.9, 11.0 Hz), 3.49 (s, 3H), 3.01 (d, 1H, J=4.3 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.54 (d, 1H, J=4.3 Hz), 2.43-1.83 (m, 6H), 1.77 (s, 3H) 1.66 (s, 3H) 1.24 (s, 3H) 1.15-1.01 (m, 1H).

EXAMPLE 4 Preparation of 6-O-(3,4-dimethoxyaniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (164 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), to which 3,4-dimethoxyaniline (0.07 mg) was added. Then, the mixture was added with K2CO3 (63.01 mg) and KI (75.68 mg), and stirred at 70° C. for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The separated organic layer was dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 132 mg of the title compound as a colorless oil.

1H-NMR (CDCl3) δ: 6.54-6.47 (m, 3H), 5.73-5.69 (m, 1H), 5.21 (br t, 1H, J=7.2 Hz), 4.25 (s, 2H), 3.86 (s, 6H), 3.72 (dd, 1H, J=2.9, 11.1 Hz), 3.51 (s, 3H), 3.03 (d, 1H, J=4.2 Hz), 2.56 (t, 1H, J=6.4 Hz), 2.54 (d, 1H, J=4.2 Hz), 2.41-1.81 (m, 6H), 1.75 (s, 3H) 1.67 (s, 3H) 1.26 (s, 3H) 1.18-1.02 (m, 1H).

EXAMPLE 5 Preparation of 6-O-(3,4-dimethoxy-6-nitroaniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (154 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), to which 3,4-dimethoxy-6-nitroaniline (0.085 mg). Then, the mixture was added with K2CO3 (59.18 mg) and KI (71.08 mg) and stirred at 70° C. for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The separated organic layer was dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 161 mg of the title compound as a white solid.

1H-NMR (CDCl3) δ: 6.73-6.66 (m, 2H), 5.75-5.71 (m, 1H), 5.23 (br t, 1H, J=7.2 Hz), 4.27 (s, 2H), 3.93 (s, 6H), 3.72 (dd, 1H, J=2.9, 11.1 Hz), 3.49 (s, 3H), 3.01 (d, 1H, J=4.2 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.54 (d, 1H, J=4.2 Hz), 2.43-1.83 (m, 6H), 1.75 (s, 3H) 1.64 (s, 3H) 1.25 (s, 3H) 1.18-1.03 (m, 1H).

EXAMPLE 6 Preparation of 6-O-(3,4-dimethoxy-6-cyanoaniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (160 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), to which 3,4-dimethoxy-6-cyanoaniline (0.079 mg) was added. The mixture was further added with K2CO3 (61.48 mg) and KI (73.84 mg), and stirred at 70° C. for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 128 mg of the title compound as a white solid.

1H-NMR (CDCl3) δ: 6.77-6.64 (m, 2H), 5.73-5.70 (m, 1H), 5.21 (br t, 1H, J=7.2 Hz), 4.26 (s, 2H), 3.90 (s, 6H), 3.72 (dd, 1H, J=2.9, 11.1 Hz), 3.51 (s, 3H), 3.03 (d, 1H, J=4.1 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.54 (d, 1H, J=4.1 Hz), 2.46-1.80 (m, 6H), 1.76 (s, 3H) 1.66 (s, 3H) 1.23 (s, 3H) 1.19-1.04 (m, 1H).

EXAMPLE 7 Preparation of 6-O-(4-allyloxyaniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (165 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), to which 4-allyloxyaniline (0.085 mg) was added. The mixture was further added with K2CO3 (63.40 mg) and KI (76.14 mg) and stirred at 70° C. for 7 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The separated organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 151 mg of the title compound as a colorless oil.

1H-NMR (CDCl3) δ: 6.58-6.54 (m, 2H), 6.32-6.29 (m, 2H), 5.87-5.85 (m, 1H), 5.73-5.70 (m, 1H), 5.41-5.35 (m, 2H), 5.21 (br t, 1H, J=7.2 Hz), 4.61 (d, 2H, J=7.4 Hz), 4.26 (s, 2H), 3.72 (dd, 1H, J=2.9, 11.1 Hz), 3.51 (s, 3H), 3.03 (d, 1H, J=4.1 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.54 (d, 1H, J=4.1 Hz), 2.46-1.80 (m, 6H), 1.76 (s, 3H) 1.66 (s, 3H) 1.23 (s, 3H) 1.19-1.04 (m, 1H).

EXAMPLE 8 Preparation of 6-O-(4-(2-acetoxyethoxy)aniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (160 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), to which 4-(2-acetoxyethoxy)aniline (0.08 mg) was added. Then, the mixture was further added with K2CO3 (61.48 mg) and KI (73.84 mg) and stirred at 70° C. for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The separated organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 153 mg of the title compound as a colorless oil.

1H-NMR (CDCl3) δ: 6.54-6.52 (m, 2H), 6.38-6.34 (m, 2H), 5.73-5.70 (m, 1H), 5.21 (br t, 1H, J=7.2 Hz), 4.52 (t, 2H, J=7.0 Hz), 4.29 (t, 2H, J=7.0 Hz), 4.24 (s, 2H), 3.73 (dd, 1H, J=2.9, 11.1 Hz), 3.53 (s, 3H), 3.01 (d, 1H, J=4.3 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.52 (d, 1H, J=4.3 Hz), 2.45-1.82 (m, 6H), 2.02 (s, 3H), 1.79 (s, 3H) 1.65 (s, 3H) 1.24 (s, 3H) 1.17-1.02 (m, 1H).

EXAMPLE 9 Preparation of 6-O-(3-cyano-4-methoxyaniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (150 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), to which 3-cyano-4-methoxyaniline (0.062 mg) was added. Then, the mixture was further added with K2CO3 (57.64 mg) and KI (69.22 mg) and stirred at 70° C. for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 124 mg of the title compound as a white solid.

1H-NMR (CDCl3) δ: 6.77-6.64 (m, 3H), 5.73-5.70 (m, 1H), 5.21 (br t, 1H, J=7.2 Hz), 4.25 (s, 2H), 3.92 (s, 3H), 3.72 (dd, 1H, J=2.9, 11.1 Hz), 3.54 (s, 3H), 3.03 (d, 1H, J=4.1 Hz), 2.60 (t, 1H, J=6.4 Hz), 2.53 (d, 1H, J=4.1 Hz), 2.46-1.80 (m, 6H), 1.79 (s, 3H) 1.69 (s, 3H) 1.24 (s, 3H) 1.18-1.02 (m, 1H).

EXAMPLE 10 Preparation of 6-O-(3-(dimethylaminomethyl)-4-methoxyaniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (153 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), to which 3-(dimethylaminomethyl)-4-methoxyaniline (0.092 mg) was added. Then, the mixture was further added with K2CO3 (58.79 mg) and KI (70.61 mg), and stirred at 70° C. for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The separated organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 161 mg of the title compound as a white solid.

1H-NMR (CDCl3) δ: 6.43-6.19 (m, 3H), 5.73-5.70 (m, 1H), 5.23 (br t, 1H, J=7.2 Hz), 4.23 (s, 2H), 3.93 (s, 3H), 3.74 (dd, 1H, J=2.9, 11.1 Hz), 3.66 (s, 2H), 3.52 (s, 3H), 3.00 (d, 1H, J=4.1 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.52 (d, 1H, J=4.1 Hz), 2.46-1.80 (m, 6H), 2.26 (s, 6H), 1.78 (s, 3H) 1.66 (s, 3H) 1.25 (s, 3H) 1.16-1.04 (m, 1H)

EXAMPLE 11 Preparation of 6-O-(4-(2-methylpropoxyaniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (152 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), to which 4-(2-methylpropoxy)aniline (0.07 mg) was added. This mixture was further added with K2CO3 (58.41 mg) and KI (70.15 mg), and stirred at 70° C. for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The separated organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 123 mg of the title compound as a white solid.

1H-NMR (CDCl3) δ: 6.59-6.55 (m, 2H), 6.37-6.33 (m, 2H), 5.74-5.71 (m, 1H), 5.25 (br t, 1H, J=7.2 Hz), 4.23 (s, 2H), 3.91 (d, 2H, J=6.5 Hz), 3.74 (dd, 1H, J=2.9, 11.1 Hz), 3.52 (s, 3H), 3.03 (d, 1H, J=4.1 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.52 (d, 1H, J=4.1 Hz), 2.45-1.80 (m, 7H), 1.78 (s, 3H) 1.66 (s, 3H) 1.25 (s, 3H), 1.19 (d, 6H, J=6.1 Hz), 1.15-1.01 (m, 1H)

EXAMPLE 12 Preparation of 6-O-(3-isopropoxy-4-methoxyaniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (161 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), to which 3-(isopropoxy)-4-methoxyaniline (0.081 mg) was added. This mixture was added with K2CO3 (61.87 mg) and KI (74.3 mg), and stirred at 70° C. for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The separated organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 151 mg of the title compound as a white solid.

1H-NMR (CDCl3) δ: 6.43-6.11 (m, 3H), 5.73-5.70 (m, 1H), 5.23 (br t, 1H, J=7.2 Hz), 4.23 (s, 2H), 4.11 (q, 1H, J=6.7 Hz), 3.93 (s, 3H), 3.74 (dd, 1H, J=2.9, 11.1 Hz), 3.52 (s, 3H), 3.00 (d, 1H, J=4.1 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.52 (d, 1H, J=4.1 Hz), 2.46-1.80 (m, 6H), 1.78 (s, 3H) 1.66 (s, 3H), 1.40 (d, 6H, J=6.7 Hz), 1.25 (s, 3H) 1.16-1.04 (m, 1H).

EXAMPLE 13 Preparation of 6-O-(4-(N,N-dimethylethoxy)aniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (154 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), to which 4-(N,N-dimethylethoxy)aniline (0.077 mg) was added. This mixture was further added with K2CO3 (59.18 mg) and KI (71.08 mg), and stirred at 70° C. for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The separated organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 158 mg of the title compound as a white solid.

1H-NMR (CDCl3) δ: 6.61-6.57 (m, 2H), 6.39-6.35 (m, 2H), 5.74-5.70 (m, 1H), 5.26 (br t, 1H, J=7.2 Hz), 4.23 (s, 2H), 4.03 (t, 2H, J=6.8 Hz), 3.75 (dd, 1H, J=2.9, 11.1 Hz), 3.52 (s, 3H), 3.05 (d, 1H, J=4.1 Hz), 2.57 (t, 1H, J=6.4 Hz), 2.79 (t, 2H, J=6.8 Hz), 2.59 (s, 6H), 2.50 (d, 1H, J=4.1 Hz), 2.45-1.80 (m, 6H), 1.77 (s, 3H) 1.65 (s, 3H) 1.26 (s, 3H), 1.17-1.02 (m, 1H).

EXAMPLE 14 Preparation of 6-O-(3,5-diisopropyl-4-methoxyaniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (160 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), to which 3,5-diisopropyl-4-methoxyaniline (0.092 mg) was added. This mixture was further added with K2CO3 (61.48 mg) and KI (73.84 mg), and stirred at 70° C. for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The separated organic layer was dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 171 mg of the title compound as a white solid.

1H-NMR (CDCl3) δ: 6.58-6.54 (m, 2H), 5.74-5.71 (m, 1H), 5.25 (br t, 1H, J=7.2 Hz), 4.23 (s, 2H), 3.91 (s, 3H), 3.74 (dd, 1H, J=2.9, 11.1 Hz), 3.52 (s, 3H), 3.19 (q, 2H, J=6.3 Hz), 3.03 (d, 1H, J=4.1 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.52 (d, 1H, J=4.1 Hz), 2.45-1.80 (m, 6H), 1.78 (s, 3H) 1.69 (s, 3H), 1.32 (d, 12H, J=6.3 Hz), 1.25 (s, 3H), 1.18-1.00 (m, 1H).

EXAMPLE 15 Preparation of 6-O-(3,5-dimethyl-4-methoxyaniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (155 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), to which 3,5-dimethyl-4-methoxyaniline (0.065 mg) was added. This mixture was further added with K2CO3 (59.56 mg) and KI (71.53 mg), and stirred at 70° C. for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The separated organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 145 mg of the title compound as a white solid.

1H-NMR (CDCl3) δ: 6.56-6.51 (m, 2H), 5.75-5.72 (m, 1H), 5.27 (br t, 1H, J=7.2 Hz), 4.25 (s, 2H), 3.93 (s, 3H), 3.72 (dd, 1H, J=2.9, 11.1 Hz), 3.55 (s, 3H), 3.04 (d, 1H, J=4.1 Hz), 2.56 (t, 1H, J=6.4 Hz), 2.50 (d, 1H, J=4.1 Hz), 2.45-1.80 (m, 12H), 1.78 (s, 3H) 1.69 (s, 3H), 1.25 (s, 3H), 1.18-1.00 (m, 1H).

EXAMPLE 16 Preparation of 6-O-(3-isopropyl-4-ethoxy-6-methylaniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (158 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), to which 3-isopropyl-4-ethoxy-6-methylaniline (0.101 mg) was added. This mixture was added with K2CO3 (60.71 mg) and KI (72.91 mg), and stirred at 70° C. for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The separated organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 166 mg of the title compound as a white solid.

1H-NMR (CDCl3) δ: 6.54-6.51 (m, 2H), 5.75-5.72 (m, 1H), 5.27 (br t, 1H, J=7.2 Hz), 4.21 (s, 2H), 3.97 (q, 2H, J=6.2 Hz), 3.74 (dd, 1H, J=2.9, 11.1 Hz), 3.52 (s, 3H), 3.14 (q, 1H, J=6.5 Hz), 3.03 (d, 1H, J=4.1 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.52 (d, 1H, J=4.1 Hz), 2.45-1.80 (m, 9H), 1.78 (s, 3H) 1.69 (s, 3H), 1.35 (t, 3H, J=6.2 Hz), 1.28 (d, 6H, J=6.5 Hz), 1.25 (s, 3H), 1.18-1.00 (m, 1H).

EXAMPLE 17 Preparation of 6-O-(4-propyloxyaniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (160 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), to which 4-propyloxyaniline (0.084 mg) was added. This mixture was added with K2CO3 (61.48 mg) and KI (73.84 mg), and stirred at 70° C. for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The separated organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 105 mg of the title compound as a white solid.

1H-NMR (CDCl3) δ: 6.63-6.58 (m, 2H), 6.40-6.36 (m, 2H), 5.74-5.71 (m, 1H), 5.25 (br t, 1H, J=7.2 Hz), 4.23 (s, 2H), 3.95 (t, 2H, J=6.8 Hz), 3.74 (dd, 1H, J=2.9, 11.1 Hz), 3.55 (s, 3H), 3.01 (d, 1H, J=4.1 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.52 (d, 1H, J=4.1 Hz), 2.45-1.82 (m, 6H), 1.77-1.74 (m, 5H) 1.68 (s, 3H) 1.26 (s, 3H), 1.15-1.01 (m, 4H).

EXAMPLE 18 Preparation of 6-O-(aniline)acetyl Fumagillol

6-O-chloroacetyl fumagillol (157 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), to which aniline (0.04 mg) was added. This mixture was added with K2CO3 (60.33 mg) and KI (72.46 mg), and stirred at 70° C. for 6 hours.

The resultant reaction was diluted with ethyl acetate (20 ml), and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 118 mg of the title compound as a white solid.

1H-NMR (CDCl3) δ: 7.66-7.14 (m, 5H), 5.75-5.71 (m, 1H), 5.20 (br t, 1H, J=7.3 Hz), 4.18 (s, 2H), 3.72 (dd, 1H, J=2.8, 11.1 Hz), 3.45 (s, 3H), 3.00 (d, 1H, J=4.3 Hz), 2.59 (t, 1H, J=6.4 Hz), 2.58 (d, 1H, J=4.3 Hz), 2.41-1.81 (m, 6H), 1.78 (s, 3H) 1.66 (s, 3H), 1.26 (s, 3H), 1.17-1.04 (m, 1H).

EXAMPLES 19-38

The fumagillol derivatives represented by the formula I were prepared in the same manner as in the above example 1, except that aromatic compounds were changed. The results are given in Table 2, below.

TABLE 2 Ex. No. Fumagillol Derivative Aromatic Compound 19 6-O-(4-chloroaniline)acetyl fumagillol 4-chloroaniline 20 6-O-(4-dimethylaminoaniline)acetyl fumagillol 4-dimethylaminoaniline 21 6-O-(4-hydroxyaniline)acetyl fumagillol 4-hydroxyaniline 22 6-O-(4-aminoaniline)acetyl fumagillol 4-aminoaniline 23 6-O-(3,4-methylenedioxyaniline)acetyl 3,4-methylenedioxyaniline fumagillol 24 6-O-(4-nitroaniline)acetyl fumagillol 4-nitroaniline 25 6-0-(2,3,4-trimethoxyaniline)acetyl 2,3,4-trimethoxyaniline fumagillol 26 6-0-(4-acetoxy-3,5-dimethoxyaniline)acetyl 4-acetoxy-3,5-dimethoxyaniline fumagillol 27 6-0-(3,4-dimethoxy-4-hydroxyaniline)acetyl 3,4-dimethoxy-4-hydroxyaniline fumagillol 28 6-O-(4-dimethylaminoethoxyaniline)acetyl 4-dimethylaminoethoxyaniline fumagillol 29 6-0-(4-ethylamino)acetyl fumagillol 4-ethylamino 30 6-0-(4-ethylaminoaniline)acetyl fumagillol 4-ethylaminoaniline 31 6-O-(3-dimethylaminomethyl-4- 3-dimethylaminomethyl-4- methoxyaniline)acetyl fumagillol methoxyaniline 32 6-O-(4-trifluoromethylaniline)acetyl 4-trifluoromethylaniline fumagillol 33 6-O-(4-acetoxyaniline)acetyl fumagillol 4-acetoxyaniline 34 6-O-(4-cyanoaniline)acetyl fumagillol 4-cyanoaniline 35 6-O-(4-hydroxyethoxyaniline)acetyl fumagillol 4-hydroxyethoxyaniline 36 6-O-(5-amino-2-methoxypyridine)acetyl 5-amino-2-methoxypyridine fumagillol 37 6-O-(5-methoxypyrimidine-2-amino)acetyl 5-methoxypyrimidine-2-amino fumagillol 38 6-O-(3-methoxy-6-aminopyridazine)acetyl 3-methoxy-6-aminopyridazine fumagillol

Each of the fumagillol derivatives, obtained from the above examples 1 and 2, was treated with an acid, or reacted with a salt in the presence of an acid catalyst, to perform an oxirane ring-opening reaction.

EXAMPLE 39 Preparation of 4-((4-methoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol

6-O-(4-methoxyaniline)acetyl fumagillol (100 mg), obtained from the above example 1, was dissolved in tetrahydrofuran (10 ml), to which chlorolithium (48 mg) and acetic acid (0.12 ml) were added. This mixture was stirred at 30° C. for 36 hours. The resultant reaction was added with water (10 ml) and ethyl acetate (100 ml). The organic layer was separated, washed with saturated brine (10 ml), dried over anhydrous magnesium sulfate and filtered, followed by distilling off the solvent under reduced pressure. Then, thusly obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2), to give 85 mg of the title compound as a white solid.

1H-NMR (CDCl3) δ: 6.57 (s, 2H), 5.70-5.73 (m, 1H), 5.19 (br t, 1H, J=7.3 Hz), 4.21 (s, 2H), 3.86 (3s, 9H), 3.72 (dd, 1H, J=2.6, 11.1 Hz), 3.45 (s, 3H), 3.01 (d, 1H, J=4.2 Hz), 2.56 (t, 1H, J=6.4 Hz), 2.54 (d, 1H, J=4.2 Hz), 2.43-1.83 (m, 6H), 1.78 (s, 3H) 1.63 (s, 3H) 1.25 (s, 3H) 1.19-1.03 (m, 1H)

EXAMPLE 40 Preparation of 4-((3,4,5-trimethoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol

6-O-(3,4,5-trimethoxyaniline)acetyl fumagillol (100 mg), obtained from the above example 2, in tetrahydrofuran (10 ml), was added with hydrochloric acid (0.14 ml) and stirred for 32 hours. This mixture was added with water (10 ml) and ethyl acetate (100 ml). The organic layer was separated, washed with saturated brine (10 ml), dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, to give the residue, which was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2), yielding 72 mg of the title compound as a white solid.

1H-NMR (CDCl3) δ: 6.54 (s, 2H), 5.73-5.73 (m, 1H), 5.21 (br t, 1H, J=7.3 Hz), 4.21 (s, 2H), 3.89 (3s, 9H), 3.72 (dd, 1H, J=2.6, 11.1 Hz), 3.44 (s, 3H), 3.01 (d, 1H, J=4.2 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.54 (d, 1H, J=4.2 Hz), 2.43-1.83 (m, 6H), 1.75 (s, 3H) 1.67 (s, 3H) 1.23 (s, 3H) 1.15-1.04 (m, 1H).

EXAMPLE 41 Preparation of 6-O-(ethylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (130 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), added with ethylamine (16 mg) and stirred at room temperature for 5 hours. The reaction was diluted with ethyl acetate (20 ml) and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 84 mg of the title compound as a colorless oil.

1H-NMR (CDCl3) δ: 5.72-5.70 (m, 1H), 5.21 (br t, 1H, J=7.2 Hz), 3.67 (dd, 1H, J=2.8, 11.1 Hz), 3.58-3.39 (m, 5H), 3.48 (s, 3H), 3.00 (d, 1H, J=4.3 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.54 (d, 1H, J=4.3 Hz), 2.50 (q, 2H, J=11.0 Hz), 2.41-1.81 (m, 9H), 1.73 (s, 3H), 1.66 (s, 3H), 1.25 (s, 3H), 1.18-1.05 (m, 4H), 1.00 (t, 3H, J=11.0 Hz).

EXAMPLE 42 Preparation of 6-O-(isopropylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (134 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), added with isopropylamine (22 mg) and stirred at room temperature for 5 hours. The reaction was diluted with ethyl acetate (20 ml) and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 93 mg of the title compound as a colorless oil.

1H-NMR (CDCl3) δ: 5.73-5.71 (m, 1H), 5.19 (br t, 1H, J=7.2 Hz), 3.65 (dd, 1H, J=2.8, 11.1 Hz), 3.56-3.37 (m, 5H), 3.47 (s, 3H), 3.02 (d, 1H, J=4.2 Hz), 2.59 (t, 1H, J=6.4 Hz), 2.55 (d, 1H, J=4.2 Hz), 2.50 (q, 1H, J=11.2 Hz), 2.44-1.82 (m, 9H), 1.72 (s, 3H), 1.64 (s, 3H), 1.23 (s, 3H), 1.13-1.05 (m, 7H), 1.01 (d, 1H, J=11.2 Hz).

EXAMPLE 43 Preparation of 6-O-(propylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (131 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), added with propylamine (22 mg) and stirred at room temperature for 8 hours. The reaction was diluted with ethyl acetate (20 ml) and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 98 mg of the title compound as a colorless oil.

1H-NMR (CDCl3) δ: 5.72-5.70 (m, 1H), 5.22 (br t, 1H, J=7.2 Hz), 3.65 (dd, 1H, J=2.8, 11.1 Hz), 3.59-3.40 (m, 5H), 3.46 (s, 3H), 3.00 (d, 1H, J=4.4 Hz), 2.56 (t, 1H, J=6.4 Hz), 2.55 (d, 1H, J=4.4 Hz), 2.51 (t, 2H, J=11.0 Hz), 2.40-1.79 (m, 9H), 1.75 (s, 3H), 1.67 (s, 3H), 1.24 (s, 3H), 1.20-1.05 (m, 6H).

EXAMPLE 44 Preparation of 6-O-(1-butylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (128 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), added with 1-butylamine (26 mg) and stirred at room temperature for 5 hours. The reaction was diluted with ethyl acetate (20 ml) and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 102 mg of the title compound as a colorless oil.

1H-NMR (CDCl3) δ: 5.73-5.71 (m, 1H), 5.21 (br t, 1H, J=7.2 Hz), 3.66 (dd, 1H, J=2.8, 11.1 Hz), 3.59-3.40 (m, 5H), 3.46 (s, 3H), 3.00 (d, 1H, J=4.3 Hz), 2.57 (t, 1H, J=6.3 Hz), 2.54 (d, 1H, J=4.3 Hz), 2.51 (t, 2H, J=11.0 Hz), 2.40-1.79 (m, 9H), 1.76 (s, 3H), 1.69 (s, 3H), 1.25 (s, 3H), 1.21-1.00 (m, 8H).

EXAMPLE 46 Preparation of 6-O-(2-methyl-butylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (130 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), added with 2-methyl-butylamine (32 mg) and stirred at room temperature for 7 hours. The reaction was diluted with ethyl acetate (20 ml) and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 114 mg of the title compound as a colorless oil.

1H-NMR (CDCl3) δ: 5.74-5.72 (m, 1H), 5.20 (br t, 1H, J=7.1 Hz), 3.67 (dd, 1H, J=2.8, 11.1 Hz), 3.60-3.40 (m, 5H), 3.47 (s, 3H), 3.01 (d, 1H, J=4.3 Hz), 2.56 (t, 1H, J=6.3 Hz), 2.53 (d, 1H, J=4.3 Hz), 2.50 (t, 2H, J=11.2 Hz), 2.40-1.77 (m, 9H), 1.75 (s, 3H), 1.69 (s, 3H), 1.26 (s, 3H), 1.21-0.95 (m, 10H).

EXAMPLE 47 Preparation of 6-O-(2,2-dimethyl-propylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (130 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), added with 2,2-dimethyl-propylamine (32 mg) and stirred at room temperature for 10 hours. The reaction was diluted with ethyl acetate (20 ml) and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 103 mg of the title compound as a colorless oil.

1H-NMR (CDCl3) δ: 5.73-5.70 (m, 1H), 5.20 (br t, 1H, J=7.2 Hz), 3.67 (dd, 1H, J=2.9, 11.1 Hz), 3.57-3.36 (m, 5H), 3.46 (s, 3H), 3.00 (d, 1H, J=4.1 Hz), 2.60 (t, 1H, J=6.4 Hz), 2.55 (d, 1H, J=4.1 Hz), 2.45-1.80 (m, 10H), 1.71 (s, 3H), 1.66 (s, 3H), 1.23 (s, 3H), 1.01 (s, 9H).

EXAMPLE 50 Preparation of 6-O-(1-ethyl-propylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (130 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), added with 1-ethyl-propylamine (32 mg) and stirred at room temperature for 6 hours. The reaction was diluted with ethyl acetate (20 ml) and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 99 mg of the title compound as a colorless oil.

1H-NMR (CDCl3) δ: 5.73-5.71 (m, 1H), 5.19 (br t, 1H, J=7.1 Hz), 3.68 (dd, 1H, J=2.7, 11.1 Hz), 3.57-3.35 (m, 5H), 3.46 (s, 3H), 3.01 (d, 1H, J=4.2 Hz), 2.58 (t, 1H, J=6.4 Hz), 2.54 (d, 1H, J=4.2 Hz), 2.52 (t, 1H, J=11.0 Hz), 2.46-1.80 (m, 9H), 1.74 (s, 3H), 1.65 (s, 3H), 1.31-1.00 (m, 14H), 1.21 (s, 3H).

EXAMPLE 54 Preparation of 6-O-(1-isopropyl-2-methyl-propylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (135 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), added with 1-isopropyl-2-methyl-propylamine (43 mg) and stirred at room temperature for 10 hours. The reaction was diluted with ethyl acetate (20 ml) and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 97 mg of the title compound as a colorless oil.

1H-NMR (CDCl3) δ: 5.73-5.70 (m, 1H), 5.19 (br t, 1H, J=7.0 Hz), 3.65 (dd, 1H, J=2.6, 11.1 Hz), 3.56-3.37 (m, 5H), 3.47 (s, 3H), 3.01 (d, 1H, J=4.3 Hz), 2.60 (t, 1H, J=6.4 Hz), 2.57 (d, 1H, J=4.3 Hz), 2.52 (d, 1H, J=11.2 Hz), 2.47-1.81 (m, 12H), 1.73 (s, 3H), 1.67 (s, 3H), 1.25 (s, 3H), 0.99 (d, 12H, J=10.8 Hz).

EXAMPLE 55 Preparation of 6-O-(3-methylbutylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (134 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), added with 3-methylbutylamine (48 mg) and stirred at room temperature for 5 hours. The reaction was diluted with ethyl acetate (20 ml) and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 111 mg of the title compound as a colorless oil.

1H-NMR (CDCl3) δ: 5.73-5.71 (m, 1H), 5.17 (br t, 1H, J=7.0 Hz), 3.66 (dd, 1H, J=2.8, 11.1 Hz), 3.57-3.36 (m, 5H), 3.49 (s, 3H), 3.01 (d, 1H, J=4.2 Hz), 2.60 (t, 1H, J=6.4 Hz), 2.57 (d, 1H, J=4.2 Hz), 2.54-2.52 (m, 1H), 2.46-1.79 (m, 13H), 1.74 (s, 3H), 1.65 (s, 3H), 1.23 (s, 3H), 1.03-0.98 (m, 13H).

EXAMPLE 56 Preparation of 6-O-(2-methyl-allylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (129 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), added with 2-methyl-allylamine (26 mg), and stirred at room temperature for 5 hours. The reaction was diluted with ethyl acetate (20 ml) and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 105 mg of the title compound as a colorless oil.

1H-NMR (CDCl3) δ: 5.74-5.71 (m, 1H), 5.52-5.48 (m, 2H), 5.21 (br t, 1H, J=7.2 Hz), 3.67 (dd, 1H, J=2.8, 11.1 Hz), 3.59-3.41 (m, 5H), 3.48 (s, 3H), 3.11 (br s, 2H), 3.03 (d, 1H, J=4.3 Hz), 2.57 (t, 1H, J=6.3 Hz), 2.55 (d, 1H, J=4.3 Hz), 2.40-1.77 (m, 13H), 1.79 (s, 3H), 1.74 (s, 3H), 1.65 (s, 3H), 1.22 (s, 3H)

EXAMPLE 63 Preparation of 6-O-(cyclopropylamino)acetyl fumagillol

6-O-chloroacetyl fumagillol (51.4 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), added with cyclopropylamine (8 mg) and stirred at room temperature for 8 hours. The reaction was diluted with ethyl acetate (10 ml) and washed with saturated aqueous sodium hydrogen carbonate (3 ml) and saturated brine (3 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 38 mg of the title compound as a colorless oil.

1H-NMR (CDCl3) δ: 5.74-5.71 (m, 1H), 5.21 (br t, 1H, J=7.0 Hz), 3.64 (dd, 1H, J=2.7, 11.1 Hz), 3.57-3.39 (m, 5H), 3.48 (s, 3H), 3.00 (d, 1H, J=4.3 Hz), 2.62 (t, 1H, J=6.4 Hz), 2.56 (d, 1H, J=4.3 Hz), 2.47-1.81 (m, 7H), 1.71 (s, 3H), 1.66 (s, 3H), 1.31-1.01 (m, 5H), 1.21 (s, 3H), 0.98-0.87 (m, 1H), 0.55-0.41 (m, 2H).

EXAMPLE 64 Preparation of 6-O-(cyclobutylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (50.3 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), added with cyclobutylamine (10 mg) and stirred at room temperature for 6 hours. The reaction was diluted with ethyl acetate (10 ml) and washed with saturated aqueous sodium hydrogen carbonate (3 ml) and saturated brine (3 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 40 mg of the title compound as a colorless oil.

1H-NMR (CDCl3) δ: 5.77-5.70 (m, 1H), 5.20 (br t, 1H, J=7.1 Hz), 3.64 (dd, 1H, J=2.8, 11.1 Hz), 3.56-3.34 (m, 6H), 3.46 (s, 3H), 3.02 (d, 1H, J=4.4 Hz), 2.61 (t, 1H, J=6.4 Hz), 2.56 (d, 1H, J=4.4 Hz), 2.48-2.37 (m, 1H), 2.21-1.60 (m, 17H), 1.74 (s, 3H), 1.64 (s, 3H), 2.22-1.01 (m, 4H), 1.19 (s, 3H).

EXAMPLE 65 Preparation of 6-O-(cyclopentylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (51.0 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), added with cyclopentylamine (12 mg) and stirred at room temperature for 6 hours. The reaction was diluted with ethyl acetate (10 ml) and washed with saturated aqueous sodium hydrogen carbonate (3 ml) and saturated brine (3 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 36 mg of the title compound as colorless oil.

1H-NMR (CDCl3) δ: 5.73-5.67 (m, 1H), 5.22 (br t, 1H, J=7.1 Hz), 3.62 (dd, 1H, J=2.8, 11.1 Hz), 3.57-3.36 (m, 5H), 3.44 (s, 3H), 3.21-3.10 (m, 1H), 2.99 (d, 1H, J=4.2 Hz), 2.60 (t, 1H, J=6.7 Hz), 2.55 (d, 1H, J=4.2 Hz), 2.44-2.35 (m, 1H), 2.21-1.60 (m, 15H), 1.74 (s, 3H), 1.64 (s, 3H), 1.56-1.43 (m, 2H), 1.39-1.31 (m, 2H), 1.22-1.01 (m, 4H), 1.20 (s, 3H).

EXAMPLE 66 Preparation of 6-O-(cyclohexylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (53.5 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), added with cyclohexylamine (15 mg) and stirred at room temperature for 6 hours. The reaction was diluted with ethyl acetate (10 ml) and washed with saturated aqueous sodium hydrogen carbonate (3 ml) and saturated brine (3 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 42 mg of the title compound as a colorless oil.

1H-NMR (CDCl3) δ: 5.75-5.68 (m, 1H), 5.19 (br t, 1H, J=7.3 Hz), 3.64 (dd, 1H, J=2.8, 11.0 Hz), 3.57-3.34 (m, 6H), 3.45 (s, 3H), 3.00 (d, 1H, J=4.3 Hz), 2.61 (t, 1H, J=6.7 Hz), 2.55 (d, 1H, J=4.3 Hz), 2.46-2.33 (m, 2H), 2.23-1.57 (m, 14H), 1.76 (s, 3H), 1.63 (s, 3H), 1.36-1.02 (m, 10H), 1.20 (s, 3H).

EXAMPLE 67 Preparation of 6-O-(4-tert-butyl-cyclohexylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (128 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), added with 4-tert-butyl-cyclohexylamine (55 mg) and stirred at room temperature for 6 hours. The reaction was diluted with ethyl acetate (20 ml) and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:10), yielding 104 mg of the title compound as a colorless oil.

1H-NMR (CDCl3) δ: 5.75-5.68 (m, 1H), 5.19 (br t, 1H, J=7.4 Hz), 3.65 (dd, 1H, J=2.7, 11.3 Hz), 3.56-3.35 (m, 6H), 3.46 (s, 3H), 3.03 (d, 1H, J=4.4 Hz), 2.61 (t, 1H, J=6.7 Hz), 2.56 (d, 1H, J=4.4 Hz), 2.46-2.33 (m, 2H), 2.23-1.72 (m, 10H), 1.78 (s, 3H), 1.65 (s, 3H), 1.36-1.19 (m, 4H), 1.21 (s, 3H), 1.16-0.94 (m, 6H), 0.82 (s, 9H)

EXAMPLE 68 Preparation of 6-O-(2-dimethylamino-1-methylethylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (132 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), added with 2-dimethylamino-1-methylethylamine (38 mg) and stirred at room temperature for 6 hours. The reaction was diluted with ethyl acetate (20 ml) and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:5), yielding 104 mg of the title compound as a colorless oil.

1H-NMR (CDCl3) δ: 5.74-5.71 (m, 1H), 5.19 (br t, 1H, J=7.0 Hz), 3.68 (dd, 1H, J=2.7, 11.1 Hz), 3.56-3.37 (m, 5H), 3.49 (s, 3H), 3.03 (d, 1H, J=4.4 Hz), 2.91-2.88 (m, 1H), 2.65 (d, 2H, J=7.8 Hz), 2.61 (t, 1H, J=6.4 Hz), 2.56 (d, 1H, J=4.4 Hz), 2.50 (s, 6H), 2.45-1.76 (m, 10H), 1.74 (s, 3H), 1.66 (s, 3H), 1.25 (s, 3H), 1.04 (d, 3H, J=8.1 Hz)

EXAMPLE 69 Preparation of 6-O-(2-dimethylamino-propylamino)acetyl Fumagillol

6-O-chloroacetyl fumagillol (126 mg), obtained from the above step 1 of the above example 1, was dissolved in dimethylformamide (1 ml), added with 2-dimethyl-propylamine (36 mg) and stirred at room temperature for 7 hours. The reaction was diluted with ethyl acetate (20 ml) and washed with saturated aqueous sodium hydrogen carbonate (5 ml) and saturated brine (5 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was vacuum concentrated to give the residue, which was purified by silica gel column chromatography (methanol:dichloromethane=1:5), yielding 118 mg of the title compound as a colorless oil.

1H-NMR (CDCl3) δ: 5.75-5.72 (m, 1H), 5.20 (br t, 1H, J=7.0 Hz), 3.66 (dd, 1H, J=2.8, 11.1 Hz), 3.57-3.38 (m, 5H), 3.45 (s, 3H), 3.17-3.14 (m, 1H), 3.01 (d, 1H, J=4.2 Hz), 2.81 (d, 2H, J=8.4 Hz), 2.62 (t, 1H, J=6.4 Hz), 2.57 (d, 1H, J=4.2 Hz), 2.47 (s, 6H), 2.44-1.78 (m, 10H), 1.73 (s, 3H), 1.64 (s, 3H), 1.24 (s, 3H), 1.02 (d, 3H, J=8.6 Hz).

EXAMPLES 45, 48, 49, 51-53, 57-62 and 70-77

The fumagillol derivatives, as represented by the formula I, were prepared in the same manner as in the above example 1, except that amine compounds were changed. The results are presented in the following Table 3.

TABLE 3 Ex. No. Fumagillol Derivative Amine Compound 45 6-O-(sec-butylamino)acetyl fumagillol sec-butylamine 48 6-O-(pentylamino)acetyl fumagillol Pentylamine 49 6-O-(1-methyl-butylamino)acetyl 1-methyl-butylamine fumagillol 51 6-O-(1-methyl-pentylamino)acetyl 1-methyl-pentylamine fumagillol 52 6-0-(1,2-dimethylbutylamino)acetyl fumagillol 1,2-dimethylbutylamine 53 6-O-(1,2,2-trimethylpropylamino)acetyl fumagillol 1,2,2-trimethylpropylamine 57 6-O-(4-methyl-hepta-2,4- 4-methyl-hepta-2,4- dienylamino)acetyl fumagillol dienylamine 58 6-O-(1,5-dimethyl-4-hexenylamino)acetyl 1,5-dimethyl-4- fumagillol hexenylamine 59 6-O-(1,1-dimethyl-2-propinylamino)acetyl 1,1-dimethyl-2- fumagillol propinylamine 60 6-O-(prop-2-enylamino)acetyl fumagillol prop-2-enylamine 61 6-O-(2-bromoethylamino)acetyl fumagillol 2-bromoethylamine 62 6-O-(chloroethynylamino)acetyl chloroethynylamine fumagillol 70 6-0-(2-methoxy-2-methyl- 2-methoxy-2-methyl- propylamino)acetyl fumagillol propylamine 71 6-O-(2-oxo-propylamino)acetyl fumagillol 2-oxo-propylamine 72 6-O-(1,1-dimethyl-3-oxobutylamino)acetyl 1,1-dimethyl-3- fumagillol oxobutylamino 73 6-O-(ethyl-2-aminoacetate)acetyl ethyl-2-aminoacetate fumagillol 74 6-O-(alaninemethylesteramino)acetyl Alaninemethylesteramine fumagillol 75 6-O-(methyl-2-amino-3,3- methyl-2-amino-3,3- dimethylbutanoate)acetyl fumagillol dimethylbutanoate 76 6-O-(allylglycinemethylester)acetyl Allylglycinemethylester fumagillol 77 6-O-(2,2-dimethoxyethylamino)acetyl 2,2-dimethoxyethylamine fumagillol

Each of the fumagillol derivatives obtained from the above examples 63 and 64 was treated with the acid, or reacted with the salt in the presence of the acid catalyst, to perform the oxirane ring-opening reaction.

EXAMPLE 78 Preparation of 4-((cyclopropylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol

6-O-(cyclopropylamino)acetyl fumagillol (100 mg), obtained from the above example 63, in tetrahydrofuran (10 ml), was added with hydrochloric acid (0.14 ml) and stirred for 32 hours. The reaction was added with water (10 ml) and ethyl acetate (100 ml). The organic layer was separated, washed with saturated brine (10 ml), dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure to give the residue, which was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2), yielding 54 mg of the title compound as a white solid.

1H-NMR (CDCl3) δ: 5.77-5.70 (m, 1H), 5.20 (br t, 1H, J=7.1 Hz), 3.64 (dd, 1H, J=2.8, 11.1 Hz), 3.56-3.34 (m, 6H), 3.49 (s, 3H), 3.02 (d, 1H, J=4.4 Hz), 2.61 (t, 1H, J=6.4 Hz), 2.56 (d, 1H, J=4.4 Hz), 2.48-2.37 (m, 1H), 2.21-1.60 (m, 17H), 1.74 (s, 3H), 1.64 (s, 3H), 2.22-1.01 (m, 4H), 1.19 (s, 3H)

EXAMPLE 79 Preparation of 4-((cyclobutylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol

6-O-(cyclobutylamino)acetyl fumagillol (100 mg), obtained from the above example 64, in tetrahydrofuran (10 ml) was added with chlorolithium (48 mg) and acetic acid (0.12 ml), and stirred at 30° C. for 36 hours. The reaction was added with water (10 ml) and ethyl acetate (100 ml). The organic layer was separated, washed with saturated brine (10 ml), dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure to give the residue, which was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2), yielding 49 mg of the title compound as a white solid.

1H-NMR (CDCl3) δ: 5.77-5.70 (m, 1H), 5.20 (br t, 1H, J=7.1 Hz), 3.64 (dd, 1H, J=2.8, 11.1 Hz), 3.56-3.34 (m, 6H), 3.46 (s, 3H), 3.02 (d, 1H, J=4.4 Hz), 2.61 (t, 1H, J=6.4 Hz), 2.56 (d, 1H, J=4.4 Hz), 2.48-2.37 (m, 1H), 2.21-1.60 (m, 17H), 1.74 (s, 3H), 1.64 (s, 3H), 2.22-1.01 (m, 4H), 1.19 (s, 3H)

PREPARATION EXAMPLE 1 Preparation of Tablet

A tablet containing the fumagillol compound of the present invention as an effective ingredient was prepared according to the following processes.

The compound of the above example 1 was sieved, mixed with lactose, starch and pregelatinized corn starch. To the mixture, purified water was added in a suitable volume. The paste was granulated, dried, mixed with magnesium stearate, and then compressed, to obtain the tablet.

Such a tablet comprises the following components:

Compound of example 1  5.0 mg Lactose BP 150.0 mg  Starch BP 30.0 mg Pregelatinized corn starch BP 15.0 mg Magnesium stearate  1.0 mg

PREPARATION EXAMPLE 2 Preparation of Capsule

A capsule containing the fumagillol compound of the present invention as the effective ingredient was prepared as follows.

The compound of the example 1 was mixed with a predetermined amount of a vehicle and magnesium state. Thusly obtained mixture was filled in a gelatin capsule.

Such a capsule comprises the following components:

Compound of the example 1 5.0 mg Starch 1500 100.0 mg  Magnesium sterate BP 1.0 mg

PREPARATION EXAMPLE 3 Preparation of Injection

An injection containing the fumagillol compound of the present invention as the effective ingredient was prepared as follows.

The compound of the example 1 was dissolved in a suitable volume of saline for injection BP. The pH of the resultant solution was controlled with dilute hydrochloric acid BP to be 3.5, and then the solution volume was controlled with saline for injection BP. The solution was filled in 5 ml type 1 ampule made of transparent glass, and the top of ampule was fused for sealing. The solution contained in the ampule was autoclaved at 120° C. for at least 15 minutes to be sterilized, giving the injection.

Such an injection comprises the following components:

Compound of example 1 100 μg/ml Dilute hydrochloric acid BP to be pH 3.5 Saline for injection BP maximal 1 ml

EXPERIMENTAL EXAMPLE 1 Inhibitory Effect of Fumagillol Derivative on Cell Growth

Using the HUVECs (human umbilical vein endothelial), the effect of the fumagillol derivative of the present invention on cell growth was evaluated.

The HUVECs were added to M199 medium supplemented with 20% FBS (fetal bovine serum), 100 U/ml penicillin, 100 μg/ml streptomycin, 1.5 g/L sodium bicarbonate, 0.1 mg/ml endothelial cell growth supplement (Sigma) and 0.1 mg/ml heparin (Sigma), after which the cells were incubated in an incubator at 37° C. under 5% CO2. Cells were subcultured a maximum of 8 times before being discarded.

In order to evaluate inhibitory activity of the fumagillin derivative on growth of HUVECs, the inventive compound was dissolved in DMSO and its concentration was adjusted from 10 mM to 1 mM. Cells were aliquotted to 96 well plates at a density of 2×103 cells per well and incubated for about 12-24 hours to be properly attached to the plate. Thereafter, the medium was replaced with new medium. The cells were treated with the compound obtained from each of the above examples at various concentration ranges of from 10 μM to 0.001 μM, and cultured for 2-3 days, followed by removing 100 μl of the medium from each well.

Colorimetry was performed to determine the extent of cell growth. The cells on each plate was added with 20 μl of aqueous one solution and then incubated at 37° C. under 5% CO2 for 2 hours. Using a 96-well plate reader, absorption was measured at 490 nm. The results are given in Table 4, below.

As such, a conventional TNP-470 having angiogenesis inhibitory effect was used as a control.

TABLE 4 Compound IC50 (η g/ml) TNP-470 29 Ex. 1 0.0071 Ex. 2 0.15 Ex. 3 0.09 Ex. 4 0.08 Ex. 5 142 Ex. 6 19 Ex. 7 21 Ex. 8 42 Ex. 9 0.63 Ex. 10 0.06 Ex. 11 0.08 Ex. 12 0.07 Ex. 13 0.016 Ex. 14 14 Ex. 15 0.06 Ex. 16 0.17 Ex. 17 0.61 Ex. 18 17 Ex. 19 174 Ex. 20 162 Ex. 21 185 Ex. 22 179 Ex. 23 0.24 Ex. 24 181 Ex. 25 0.31 Ex. 26 179 Ex. 27 88 Ex. 28 102 Ex. 29 178 Ex. 30 0.09 Ex. 31 0.06 Ex. 32 128 Ex. 33 109 Ex. 34 98 Ex. 35 116 Ex. 36 0.021 Ex. 37 0.017 Ex. 38 0.019 Ex. 39 0.019 Ex. 40 0.18 Ex. 41 20 Ex. 42 12 Ex. 43 2400 Ex. 44 3200 Ex. 45 370 Ex. 46 2600 Ex. 47 16 Ex. 48 3000 Ex. 49 44 Ex. 50 24 Ex. 51 32000 Ex. 52 290 Ex. 53 162 Ex. 54 11 Ex. 55 17 Ex. 56 28 Ex. 57 420 Ex. 58 415 Ex. 59 174 Ex. 60 185 Ex. 61 2800 Ex. 62 340 Ex. 63 0.008 Ex. 64 0.07 Ex. 65 250 Ex. 66 0.6 Ex. 67 0.06 Ex. 68 240 Ex. 69 260 Ex. 70 178 Ex. 71 260 Ex. 72 330 Ex. 73 1200 Ex. 74 800 Ex. 75 2400 Ex. 76 1490 Ex. 77 330 Ex. 78 0.014 Ex. 79 0.037 Intermediate 2000

From the above Table 4, it can be seen that the inventive compound exhibits superior inhibitory effect on cell proliferation, compared to conventionally known fumagillin. In particular, the compound in which R1 is aromatic is superior in angiogenesis inhibitory effect to the compound in which R1 is aliphatic. For instance, in the case where R1 is aromatic, 6-O-(4-methoxyaniline)acetyl fumagillol of the above example 1 has excellent inhibitory effect, 2000 times greater than known TNP-470. In the case where R1 is aliphatic, 6-O-(cyclopropylamino)acetyl fumagillol and 6-O-(4-(cyclobutylamino)acetyl fumagillol of the above examples 63 and 64, respectively, are 100-1000 times higher in inhibitory effect on HUVEC, compared to TNP-470.

EXPERIMENTAL EXAMPLE 2 Acute Toxicity Test for Oral Administration of Fumagillol Derivative Using Rats

To investigate acute toxicity of the compound of the formula I, the following experiment was performed.

Using 6-week-old specific pathogen-free (SPF) Sprague-Dawley rats, acute toxicity was tested. Each of the compounds obtained from the above examples was suspended in 0.5% methylcelluose solution, and orally administered once to every two rats constituting each group in the dose of 1 g/kg/15 ml. After administration, mortality, clinical symptoms and body weight of the tested animals were observed. Hematological and blood-biochemical tests were carried out. The animals were dissected and abnormal conditions of pleural cavity and abdominal cavity were observed with the naked eye. As the test result, there were no specifically abnormal symptoms in any of the tested animals and no mortality. In addition, toxicity indicators were not observed in the body weight, hematological and blood-biochemical tests, or by dissection.

The present compounds did not show toxicity up to the amounts of 2 g/kg for all rats, and the minimal lethal dose (LD50) of each compound in case of oral administration was 2 g/kg or more, thus the present compound was evaluated as a safe compound.

EXPERIMENTAL EXAMPLE 3

Eight-week-old athymic Nu/Nu mice (Charles River Laboratories, Wilmington, Mass.) were inoculated with SNU-398 human hepatoma cells. The cells were reconstituted at 6×106 cells/ml in 20% saline and 80% phenol red-free Matrigel. Cells (0.25 ml; 1.5 million cells) were injected subcutaneously in the left upper abdominal quadrant. After postimmunization day 9, nude mice bearing a tumor of approximately 180 mm2 were subcutaneously administered MetAP2 inhibitors (50 mg/kg; n=5 per each inhibitor) twice daily and an equivalent volume of vehicle was administered to control mice (n=5). Tumor measurements were made using Vernier calipers and tumor volumes were calculated using the ellipsoid formula: length×width×height×0.52.

The present compounds showed that significant suppression of tumor growth was observed compared with that of mice treated with vehicle alone (FIG. 1). The size of tumor cells was significantly different in xenografted nude mice treated with buffer alone or treated with Ex. 1 and Ex. 64 (See series of photographs of FIG. 2). Furthermore, the tumor suppressive efficacies of Ex. 1, Ex. 11, Ex. 63 and Ex. 64 were superior to that of TNP-470. This group of MetAP2 inhibitors may therefore provide a novel hepatoma therapeutic regime (FIG. 1).

INDUSTRIAL APPLICABILITY

As described hereinbefore, the compound of the formula I of the present invention is advantageous in light of excellent angiogenesis inhibitory effect and low toxicity, and is usefully applicable as an angiogenesis inhibitory agent. As well, the inventive compound can inhibit cancer metastasis and treat cancer, rheumatic arthritis, psoriasis and diabetic retinopathy, which are associated with angiogenesis regarded as a pathogenic phenomenon.

The present invention has been described in an illustrative manner, and it is to be understood that the terminology used is intended to be in the nature of description rather than of limitation. Many modifications and variations of the present invention are possible in light of the above teachings. Therefore, it is to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described.

Claims

1. A method for inhibiting angiogenesis comprising administering to a subject in need of treatment, a fumagillol derivative represented by the following formula I or a pharmaceutically acceptable salt thereof.

wherein,
X is —OH and Y is halogen, or X and Y are linked together to form an oxirane ring, B represents —(C═O)— or —CH2—,
R1 represents hydrogen; hydroxy; —CN; —NO2; —CF3; formyl; C1-C4 thioalkyl; acetamido; acetoxy; C1-C6 alkyl; C1-C4 aminoalkyl; C1-C4 alkylaminoalkyl; C1-C4 dialkylaminoalkyl; C1-C6 alkoxy; C1-C6 aminoalkoxy; C1-C4 alkylaminoalkoxy; C1-C4 dialkylaminoalkoxy; amino; C1-C6 alkylamino; C1-C4 dialkylamino; C1-C4 hydroxyalkyl; C1-C4 alkyloxycarboxylic acid, or
in which R2, R3, R4, R5 and R6, which are the same or different, each represents hydrogen; hydroxy; —CN; —NO2; —CF3; formyl; C1-C4 thioalkyl; acetamido; acetoxy; C1-C6 alkyl; C1-C4 aminoalkyl; C1-C4 alkylaminoalkyl; C1-C4 dialkylaminoalkyl; C1-C6 alkoxy; C1-C6 aminoalkoxy; C1-C4 alkylaminoalkoxy; C1-C4 dialkylaminoalkoxy; amino; C1-C6 alkylamino; C1-C4 dialkylamino; C1-C4 hydroxyalkyl; or C1-C4 alkyloxycarboxylic acid; or, R2 and R3, R3 and R4, R4 and R5, or R5 and R6, are linked together to form a C1-C3 alkylene dioxy ring, and
Z1, Z2, Z3, Z4 and Z5 each represent carbon or nitrogen.

2. The method according to claim 1, wherein X and Y of the fumagillol derivative are linked together to form the oxirane ring, and B of the fumagillol derivative is —(C═O)—.

3. The method according to claim 1, wherein X and Y of the fumagillol derivative are linked together to form the oxirane ring,

B of the fumagillol derivative is —(C═O)—, R1 of the fumagillol derivative is hydrogen;
hydroxy; —CN; —NO2; —CF3; formyl; acetamido; acetoxy; C1-C6 alkyl; C1-C4 aminoalkyl; C1-C4 alkylaminoalkyl; C1-C4 dialkylaminoalkyl; C1-C6 alkoxy; C1-C6 aminoalkoxy; C1-C4 alkylaminoalkoxy; C1-C4 dialkylaminoalkoxy; amino; C1-C6 alkylamino; C1-C4 dialkylamino; C1-C4 hydroxyalkyl; C1-C4 alkyloxycarboxylic acid; or R2, R3, R4, R5 and R6 of the fumagillol derivative, which are the same or different, each represents hydrogen; hydroxy; —CN; —NO2; —CF3; formyl; acetamido; acetoxy; C1-C6 alkyl; C1-C4 aminoalkyl; C1-C4 alkylaminoalkyl; C1-C4 dialkylaminoalkyl; C1-C6 alkoxy; C1-C6 aminoalkoxy; C1-C4 alkylaminoalkoxy; C1-C4 dialkylaminoalkoxy; amino; C1-C6 alkylamino; C1-C4 dialkylamino; C1-C4 hydroxyalkyl; or C1-C4 alkyloxycarboxylic acid; or R2 and R3, R3 and R4, R4 and R5, or R5 and R6 of the fumagillol derivative are linked together to form the C1-C3 alkylene dioxy ring; and Z1, Z2, Z3, Z4 and Z5 each represent carbon or nitrogen.

4. The method according to claim 1, wherein X and Y of the fumagillol derivative are linked together to form the oxirane ring,

B of the fumagillol derivative is —(C═O)—
R1 of the fumagillol derivative is selected from the group consisting of hydrogen; hydroxy; methyl; chlorine; methoxy; methylpropoxy; isopropoxy; allyloxy; propyloxy; acetoxy cyano; amino; dimethylaminomethyl; methylpropoxy; dimethylethoxy; 3,5-diisopropyl-4-methoxy; 3,5-dimethyl-4-methoxy; isopropyl-4-ethoxy; dimethylamino; ethylamino; methylenedioxy; nitro; acetoxy; trifluoromethyl; and hydroxyethoxy;
R2, R3, R4, R5 and R6 of the fumagillol derivative is independently selected from the group consisting of hydrogen; hydroxy; methyl; chlorine; methoxy; methylpropoxy; isopropoxy; allyloxy; propyloxy; acetoxy cyano; amino; dimethylaminomethyl; methylpropoxy; dimethylethoxy; 3,5-diisopropyl-4-methoxy; 3,5-dimethyl-4-methoxy; isopropyl-4-ethoxy; dimethylamino; ethylamino; methylenedioxy; nitro; acetoxy; trifluoromethyl; and hydroxyethoxy; and
Z1, Z2, Z3 Z4 and Z5 each represent carbon or nitrogen.

5. The method according to claim 1, wherein the fumagillol derivative is selected from the group consisting of:

1) 6-O-(4-methoxyaniline)acetyl fumagillol;
2) 6-O-(3,4,5-trimethoxyaniline)acetyl fumagillol;
3) 6-O-(2,4-dimethoxyaniline)acetyl fumagillol;
4) 6-O-(3,4-dimethoxyaniline)acetyl fumagillol;
5) 6-O-(3,4-dimethoxy-6-nitroaniline)acetyl fumagillol;
6) 6-O-(3,4-dimethoxy-6-cyanoaniline)acetyl fumagillol;
7) 6-O-(4-allyloxyaniline)acetyl fumagillol;
8) 6-O-(4-(2-acetoxyethoxy)aniline)acetyl fumagillol;
9) 6-O-(3-cyano-4-methoxyaniline)acetyl fumagillol;
10) 6-O-(3-(dimethylaminomethyl)-4-methoxyaniline) acetyl fumagillol;
11) 6-O-(4-(2-methylpropoxyaniline)acetyl fumagillol;
12) 6-O-(3-isopropoxy-4-methoxyaniline)acetyl fumagillol;
13) 6-O-(4-(N,N-dimethylethoxy)aniline)acetyl fumagillol;
14) 6-O-(3,5-diisopropyl-4-methoxyaniline)acetyl fumagillol;
15) 6-O-(3,5-dimethyl-4-methoxyaniline)acetyl fumagillol;
16) 6-O-(3-isopropyl-4-ethoxy-6-methylaniline)acetyl fumagillol;
17) 6-O-(4-propyloxyaniline)acetyl fumagillol;
18) 6-O-(aniline)acetyl fumagillol;
19) 6-O-(4-chloroaniline)acetyl fumagillol;
20) 6-O-(4-dimethylaminoaniline)acetyl fumagillol;
21) 6-O-(4-hydroxyaniline)acetyl fumagillol;
22) 6-O-(4-aminoaniline)acetyl fumagillol;
23) 6-O-(3,4-methylenedioxyaniline)acetyl fumagillol;
24) 6-O-(4-nitroaniline)acetyl fumagillol;
25) 6-O-(2,3,4-trimethoxy-6-aminoaniline)acetyl fumagillol;
26) 6-O-(4-acetoxy-3,5-dimethoxyaniline)acetyl fumagillol;
27) 6-O-(3,4-dimethoxy-5-hydroxyaniline)acetyl fumagillol;
28) 6-O-(4-dimethylaminoethoxyaniline)acetyl fumagillol;
29) 6-O-(4-ethylaminoaniline)acetyl fumagillol;
30) 6-O-(4-ethylaminoethoxyaniline)acetyl fumagillol;
31) 6-O-(3-dimethylaminomethyl-4-methoxyaniline)acetyl fumagillol;
32) 6-O-(4-trifluoromethylaniline)acetyl fumagillol;
33) 6-O-(4-acetoxy aniline)acetyl fumagillol;
34) 6-O-(4-cyanoaniline)acetyl fumagillol;
35) 6-O-(4-hydroxyethoxyaniline)acetyl fumagillol;
36) 6-O-(5-amino-2-methoxypyridine)acetyl fumagillol;
37) 6-O-(5-methoxypyrimidine-2-amino)acetyl fumagillol;
38) 6-O-(3-methoxy-6-aminopyridazine)acetyl fumagillol;
39) 4-((4-methoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol;
40) 4-((3,4,5-trimethoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol;
41) 6-O-(ethylamino)acetyl fumagillol;
42) 6-O-(isopropyl amino)acetyl fumagillol;
43) 6-O-(1-propyl amino)acetyl fumagillol;
44) 6-O-(1-butyl amino)acetyl fumagillol;
45) 6-O-(sec-butyl amino)acetyl fumagillol;
46) 6-O-(2-methyl-butylamino)acetyl fumagillol;
47) 6-O-(t-butyl amino)acetyl fumagillol;
48) 6-O-(pentyl amino)acetyl fumagillol;
49) 6-O-(1-methyl-butyl amino)acetyl fumagillol;
50) 6-O-(1-ethyl-propyl amino)acetyl fumagillol;
51) 6-O-(1-methyl-pentylamino)acetyl fumagillol;
52) 6-O-(1,2-dimethyl-butylamino)acetyl fumagillol;
53) 6-O-(1,2,2-trimethyl-propylamino)acetyl fumagillol;
54) 6-O-(1-isopropyl-2-methylpropylamino)acetyl fumagillol;
55) 6-O-(3-methylbutylamino)acetyl fumagillol;
56) 6-O-(2-methylallylamino)acetyl fumagillol;
57) 6-O-(4-methyl-hepta-2,4-dienylamino)acetyl fumagillol;
58) 6-O-(1,5-dimethyl-4-hexenylamino)acetyl fumagillol;
59) 6-O-(1,1-dimethyl-2-propynylamino)acetyl fumagillol;
60) 6-O-(prop-2-enylamino)acetyl fumagillol;
61) 6-O-(2-bromo-ethylamino)acetyl fumagillol;
62) 6-O-(chloroethynylamino)acetyl fumagillol;
63) 6-O-(cyclopropylamino)acetyl fumagillol;
64) 6-O-(cyclobutylamino)acetyl fumagillol;
65) 6-O-(cyclopentylamino)acetyl fumagillol;
66) 6-O-(cyclohexylamino)acetyl fumagillol;
67) 6-O-(4-tert-butylcyclohexylamino)acetyl fumagillol;
68) 6-O-(2-dimethylamino-1-methylethylamino)acetyl fumagillol;
69) 6-O-(2-dimethylamino-propylamino)acetyl fumagillol;
70) 6-O-(2-methoxy-2-methyl-propylamino)acetyl fumagillol;
71) 6-O-(2-oxo-propylamine)acetyl fumagillol;
72) 6-O-(1,1-dimethyl-3-oxobutylamino)acetyl fumagillol;
73) 6-O-(ethyl-2-aminoacetate)acetyl fumagillol;
74) 6-O-(alanine-methylesteramino)acetyl fumagillol;
75) 6-O-(methyl-2-amino-3,3-dimethylbutanoate)acetyl fumagillol;
76) 6-O-(allylglycine-methylester)acetyl fumagillol;
77) 6-O-(2,2-dimethoxy-ehtylamino)acetyl fumagillol;
78) 4-((cyclopropylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol; and
79) 4-((cyclobutylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol.

6. A method for treating cancer, rheumatoid arthritis, psoriasis or diabetic retinopathy, or for inhibiting cancer metastasis, comprising administering to a subject in need of treatment, a fumagillol derivative represented by the following formula I or a pharmaceutically acceptable salt thereof.

wherein,
X is —OH and Y is halogen, or X and Y are linked together to form an oxirane ring,
B represents —(C═O)— or —CH2—,
R1 represents hydrogen; hydroxy; —CN; —NO2; —CF3; formyl; C1-C4 thioalkyl; acetamido; acetoxy; C1-C6 alkyl; C1-C4 aminoalkyl; C1-C4 alkylaminoalkyl; C1-C4 dialkylaminoalkyl; C1-C6 alkoxy; C1-C6 aminoalkoxy; c1-C4 alkylaminoalkoxy; C1-C4 dialkylaminoalkoxy; amino; C1-C6 alkylamino; C1-C4 dialkylamino; C1-C4 hydroxyalkyl; C1-C4 alkyloxycarboxylic acid, or
in which R2, R3, R4, R5 and R6, which are the same or different, each represents hydrogen; hydroxy; —CN; —NO2; —CF3; formyl; C1-C4 thioalkyl; acetamido; acetoxy; C1-C6 alkyl; C1-C4 aminoalkyl; C1-C4 alkylaminoalkyl; C1-C4 dialkylaminoalkyl; C1-C6 alkoxy; C1-C6 aminoalkoxy; C1-C4 alkylaminoalkoxy; C1-C4 dialkylaminoalkoxy; amino; C1-C6 alkylamino; C1-C4 dialkylamino; C1-C4 hydroxyalkyl; or C1-C4 alkyloxycarboxylic acid; or, R2 and R3, R3 and R4, R4 and R5, or R5 and R6, are linked together to form a C1-C3 alkylene dioxy ring, and
Z1, Z2, Z3, Z4 and Z5 each represent carbon or nitrogen.

7. The method according to claim 6, wherein X and Y of the fumagillol derivative are linked together to form the oxirane ring, and B of the fumagillol derivative is —(C═O)—.

8. The method according to claim 6, wherein X and Y of the fumagillol derivative are linked together to form the oxirane ring,

B of the fumagillol derivative is —(C═O)—,
R1 of the fumagillol derivative is hydrogen; hydroxy; —CN; —NO2; —CF3; formyl; acetamido; acetoxy; C1-C6 alkyl; C1-C4 aminoalkyl; C1-C4 alkylaminoalkyl; C1-C4 dialkylaminoalkyl; C1-C6 alkoxy; C1-C6 aminoalkoxy; C1-C4 alkylaminoalkoxy; C1-C4 dialkylaminoalkoxy; amino; C1-C6 alkylamino; C1-C4 dialkylamino; C1-C4 hydroxyalkyl; C1-C4 alkyloxycarboxylic acid; or
R2, R3, R4, R5 and R6 of the fumagillol derivative, which are the same or different, each represents hydrogen; hydroxy; —CN; —NO2; —CF3; formyl; acetamido; acetoxy; C1-C6 alkyl; C1-C4 aminoalkyl; C1-C4 alkylaminoalkyl; C1-C4 dialkylaminoalkyl; C1-C6 alkoxy; C1-C6 aminoalkoxy; C1-C4 alkylaminoalkoxy; C1-C4 dialkylaminoalkoxy; amino; C1-C6 alkylamino; C1-C4 dialkylamino; C1-C4 hydroxyalkyl; or C1-C4 alkyloxycarboxylic acid; or
R2 and R3, R3 and R4, R4 and R5, or R5 and R6 of the fumagillol derivative are linked together to form the C1-C3 alkylene dioxy ring; and
Z1, Z2, Z3, Z4 and Z5 each represent carbon or nitrogen.

9. The method according to claim 6, wherein X and Y of the fumagillol derivative are linked together to form the oxirane ring,

B of the fumagillol derivative is —(C═O)—
R1 of the fumagillol derivative is selected from the group consisting of hydrogen; hydroxy; methyl; chlorine; methoxy; methylpropoxy; isopropoxy; allyloxy; propyloxy; acetoxy cyano; amino; dimethylaminomethyl; methylpropoxy; dimethylethoxy; 3,5-diisopropyl-4-methoxy; 3,5-dimethyl-4-methoxy; isopropyl-4-ethoxy; dimethylamino; ethylamino; methylenedioxy; nitro; acetoxy; trifluoromethyl; and hydroxyethoxy;
R2, R3, R4, R5 and R6 of the fumagillol derivative is independently selected from the group consisting of hydrogen; hydroxy; methyl; chlorine; methoxy; ethylpropoxy; isopropoxy; allyloxy; propyloxy; acetoxy cyano; amino; dimethylaminomethyl; methylpropoxy; dimethylethoxy; 3,5-diisopropyl-4-methoxy; 3,5-dimethyl-4-methoxy; isopropyl-4-ethoxy; dimethylamino; ethylamino; methylenedioxy; nitro; acetoxy; trifluoromethyl; and
hydroxyethoxy; and
Z1, Z2, Z3 Z4 and Z5 each represent carbon or nitrogen.

10. The method according to claim 6, wherein the fumagillol derivative is selected from the group consisting of:

1) 6-O-(4-methoxyaniline)acetyl fumagillol;
2) 6-O-(3,4,5-trimethoxyaniline)acetyl fumagillol;
3) 6-O-(2,4-dimethoxyaniline)acetyl fumagillol;
4) 6-O-(3,4-dimethoxyaniline)acetyl fumagillol;
5) 6-O-(3,4-dimethoxy-6-nitroaniline)acetyl fumagillol;
6) 6-O-(3,4-dimethoxy-6-cyanoaniline)acetyl fumagillol;
7) 6-O-(4-allyloxyaniline)acetyl fumagillol;
8) 6-O-(4-(2-acetoxyethoxy)aniline)acetyl fumagillol;
9) 6-O-(3-cyano-4-methoxyaniline)acetyl fumagillol;
10) 6-O-(3-(dimethylaminomethyl)-4-methoxyaniline) acetyl fumagillol;
11) 6-O-(4-(2-methylpropoxyaniline)acetyl fumagillol;
12) 6-O-(3-isopropoxy-4-methoxyaniline)acetyl fumagillol;
13) 6-O-(4-(N,N-dimethylethoxy)aniline)acetyl fumagillol;
14) 6-O-(3,5-diisopropyl-4-methoxyaniline)acetyl fumagillol;
15) 6-O-(3,5-dimethyl-4-methoxyaniline)acetyl fumagillol;
16) 6-O-(3-isopropyl-4-ethoxy-6-methylaniline)acetyl fumagillol;
17) 6-O-(4-propyloxyaniline)acetyl fumagillol;
18) 6-O-(aniline)acetyl fumagillol;
19) 6-O-(4-chloroaniline)acetyl fumagillol;
20) 6-O-(4-dimethylaminoaniline)acetyl fumagillol;
21) 6-O-(4-hydroxyaniline)acetyl fumagillol;
22) 6-O-(4-aminoaniline)acetyl fumagillol;
23) 6-O-(3,4-methylenedioxyaniline)acetyl fumagillol;
24) 6-O-(4-nitroaniline)acetyl fumagillol;
25) 6-O-(2,3,4-trimethoxy-6-aminoaniline)acetyl fumagillol;
26) 6-O-(4-acetoxy-3,5-dimethoxyaniline)acetyl fumagillol;
27) 6-O-(3,4-dimethoxy-5-hydroxyaniline)acetyl fumagillol;
28) 6-O-(4-dimethylaminoethoxyaniline)acetyl fumagillol;
29) 6-O-(4-ethylaminoaniline)acetyl fumagillol;
30) 6-O-(4-ethylaminoethoxyaniline)acetyl fumagillol;
31) 6-O-(3-dimethylaminomethyl-4-methoxyaniline)acetyl fumagillol;
32) 6-O-(4-trifluoromethylaniline)acetyl fumagillol;
33) 6-O-(4-acetoxy aniline)acetyl fumagillol;
34) 6-O-(4-cyanoaniline)acetyl fumagillol;
35) 6-O-(4-hydroxyethoxyaniline)acetyl fumagillol;
36) 6-O-(5-amino-2-methoxypyridine)acetyl fumagillol;
37) 6-O-(5-methoxypyrimidine-2-amino)acetyl fumagillol;
38) 6-O-(3-methoxy-6-aminopyridazine)acetyl fumagillol;
39) 4-((4-methoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol;
40) 4-((3,4,5-trimethoxyaniline)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol;
41) 6-O-(ethylamino)acetyl fumagillol;
42) 6-O-(isopropyl amino)acetyl fumagillol;
43) 6-O-(1-propyl amino)acetyl fumagillol;
44) 6-O-(1-butyl amino)acetyl fumagillol;
45) 6-O-(sec-butyl amino)acetyl fumagillol;
46) 6-O-(2-methyl-butylamino)acetyl fumagillol;
47) 6-O-(t-butyl amino)acetyl fumagillol;
48) 6-O-(pentyl amino)acetyl fumagillol;
49) 6-O-(1-methyl-butyl amino)acetyl fumagillol;
50) 6-O-(1-ethyl-propyl amino)acetyl fumagillol;
51) 6-O-(1-methyl-pentylamino)acetyl fumagillol;
52) 6-O-(1,2-dimethyl-butylamino)acetyl fumagillol;
53) 6-O-(1,2,2-trimethyl-propylamino)acetyl fumagillol;
54) 6-O-(1-isopropyl-2-methylpropylamino)acetyl fumagillol;
55) 6-O-(3-methylbutylamino)acetyl fumagillol;
56) 6-O-(2-methylallylamino)acetyl fumagillol;
57) 6-O-(4-methyl-hepta-2,4-dienylamino)acetyl fumagillol;
58) 6-O-(1,5-dimethyl-4-hexenylamino)acetyl fumagillol;
59) 6-O-(1,1-dimethyl-2-propynylamino)acetyl fumagillol;
60) 6-O-(prop-2-enylamino)acetyl fumagillol;
61) 6-O-(2-bromo-ethylamino)acetyl fumagillol;
62) 6-O-(chloroethynylamino)acetyl fumagillol;
63) 6-O-(cyclopropylamino)acetyl fumagillol;
64) 6-O-(cyclobutylamino)acetyl fumagillol;
65) 6-O-(cyclopentylamino)acetyl fumagillol;
66) 6-O-(cyclohexylamino)acetyl fumagillol;
67) 6-O-(4-tert-butylcyclohexylamino)acetyl fumagillol;
68) 6-O-(2-dimethylamino-1-methylethylamino)acetyl fumagillol;
69) 6-O-(2-dimethylamino-propylamino)acetyl fumagillol;
70) 6-O-(2-methoxy-2-methyl-propylamino)acetyl fumagillol;
71) 6-O-(2-oxo-propylamine)acetyl fumagillol;
72) 6-O-(1,1-dimethyl-3-oxobutylamino)acetyl fumagillol;
73) 6-O-(ethyl-2-aminoacetate)acetyl fumagillol;
74) 6-O-(alanine-methylesteramino)acetyl fumagillol;
75) 6-O-(methyl-2-amino-3,3-dimethylbutanoate)acetyl fumagillol;
76) 6-O-(allylglycine-methylester)acetyl fumagillol;
77) 6-O-(2,2-dimethoxy-ehtylamino)acetyl fumagillol;
78) 4-((cyclopropylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol; and
79) 4-((cyclobutylamino)acetyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol.

11. Use of a compound of formula I in the preparation of a medicament for inhibiting development of a hepatoma in a patient, wherein said compound of formula I is as represented by the claim 1.

Patent History
Publication number: 20070149613
Type: Application
Filed: Nov 21, 2006
Publication Date: Jun 28, 2007
Inventors: Cheol-Kyu Han (Seoul), Jeong-Hyeok Yoon (Yongin-si), Seung-Moak Kim (Daejeon-si), Nam-Doo Kim (Incheon-si), Byung-Ha Chang (Suwon-si), Jee-Young Lee (Ahnyang-si), Tae-Bo Sim (Seoul)
Application Number: 11/603,688
Classifications
Current U.S. Class: 514/475.000
International Classification: A61K 31/336 (20060101);