| PATENT ASSIGNEE'S COUNTRY | Korea |
| UPDATE | 05.00 |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 16.05.00 |
| PATENT TITLE |
Fumagillol derivatives and processes for preparing the same |
| PATENT ABSTRACT |
Compounds useful as angiogenesis inhibiting agents and processes for their preparation are disclosed. In one embodiment, the compounds of the invention are represented by Formula 1: ##STR1## Also disclosed is a pharmaceutical composition for inhibiting angiogenesis in a mammal, said composition comprising a compound of Formula 1, or a pharmaceutically acceptable salt thereof, as an active ingredient. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | 13.05.99 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT REFERENCES CITED |
Tarbell, D. S., et al., "The Chemistry of Fumagillin," J. Amer. Chem. Soc., 83:3096-3113 (1961). Marui,S. and Kishimoto,S., "Chemical Modification of Fumagillin. II. 6-Amino-6-deoxyfumagillol and Its Derivatives," Chem. Pharm. Bull., 40:575-579 (1992). Marui et al., "Chemical Modification of Fumagillin. I. 6-O-Acyl, 6-O-Sulfonyl, 6-O-Alkyl, and 6-O-(N-Substituted-carbamoyl)fumagillols," Chem. Pharm. Bull., 40:96-101 (1992). Billington, David C., "Angiogenesis and Its Inhibition: Potential New Therapies In Oncology and Non-Neoplastic Diseases," Drug Design and Discovery, 8:3-35 (1991). |
| PATENT CLAIMS |
We claim: 1. A compound, or a pharmaceutically acceptable salt thereof, represented by Formula 1: ##STR6## wherein: a) X is --OH and Y is halogen or X and Y taken together form an oxirane ring; b) B is selected from O and H.sub.2 ; and c) R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are independently chosen from --H, --OH, acetoxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted aminoalkoxy, C.sub.1 -C.sub.6 alkoxy, halogen, cyano, trifluoromethyl, nitro, alkylenedioxy, formyl, acetamido and methylenoxycarboxy, with the proviso that R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are not each --H. 2. A compound, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are independently chosen from --H, --OH, acetoxy, amino, alkylamino, dialkylamino, dialkylaminoalkyl, akylaminoalkoxy, dialkylaminoalkoxy, C.sub.1 -C.sub.6 alkoxy, halogen, cyano, trifluoromethyl, nitro, and methylenedioxy. 3. A compound according to claim 1, chosen from the group consisting of: O-(3,4-dimethoxycinnamoyl)fumagillol, O-(4-methoxycinnamoyl)fumagillol, O-(3,4,5-trimethoxycinnamoyl)fumagillol, O-(4-Chlorocinnamoyl)fumagillol, 4-(3,4,5-trimethoxycinnamoyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-met hoxy-1-chloromethyl-1-cyclohexanol, O-(4-trifluoromethylcinnamoyl)fumagillol, O-(4-nitrocinnamoyl)fumagillol, O-(3,4-dimethoxy-6-nitrocinnamoyl)fumagillol, O-(4-acetoxycinnamoyl)fumagillol, O-(4-hydroxycinnamoyl)fumagillol, O-(4-acetoxy-3,5-dimethoxycinnamoyl)fumagillol, O-(3,5-dimethoxy-4-hydroxycinnamoyl)fumagillol, 4-(4-methoxycinnamoyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1- chloromethyl-1-cyclohexanol, O-(4-dimethylaminocinnamoyl)fumagillol, O-(4-aminocinnamoyl)fumagillol, O-(4-cyanocinnamoyl)fumagillol, O-(3,4,5-trimethoxycinnamyl)fumagillol, O-(4-dimethylaminoethoxycinnamoyl)fumagillol, O-(3-dimethylaminomethyl-4-methoxycinnamoyl)fumagillol, O-(3,4-methylenedioxycinnamoyl)fumagillol, O-(3,4-dimethoxy-6-aminocinnamoyl)fumagillol, O-(4-ethylaminocinnamoyl)fumagillol, O-(4-ethylaminoethoxycinnamoyl)fumagillol, O-(4-dimethylaminocinnamyl)fumagillol, and 4-(4-dimethylaminocinnamoyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-meth oxy-1-chloromethyl-1-cyclohexanol. 4. A compound according to claim 1, wherein the pharmaceutically acceptable salt thereof is selected from the hydrochloride, bromate, sulfate, phosphate, nitrate, formate, acetate, trifluoroacetate, oxalate, fumarate, tartarate, maleate, methanesulfonate, benzenesulfonate and p-toluenesulfanate salt. 5. A process for preparing a compound, or a salt thereof, of Formula 5, said process comprising the steps of: a) reacting a fumagillol compound with a compound of Formula 3 ##STR7## or a corresponding acid-anhydride, mixed anhydride, acid chloride, acid p-toluenesulfonic anhydride, acid mesylic anhydride, 2-pyridine thiol ester or phenyl ester; and b) obtaining a compound of Formula 5, ##STR8## wherein Y is halogen; and R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are independently chosen from --H, --OH, acetoxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted aminoalkoxy, C.sub.1 -C.sub.6 alkoxy, halogen, cyano, trifluoromethyl, nitro, alkylenedioxy, formyl, acetamido and methylenoxycarboxy, with the proviso that R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are not each --H. 6. A process for preparing a compound, or a salt thereof, of Formula 8, said process comprising the steps of: a) reacting a fumagillol compound with a compound of Formula 6 ##STR9## or the corresponding tosylate, mesylate or halide; and b) obtaining a compound of Formula 8, ##STR10## wherein Y is halogen; and R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are independently chosen from --H, --OH, acetoxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted aminoalkoxy, C.sub.1 -C.sub.6 alkoxy, halogen, cyano, trifluoromethyl, nitro, alkylenedioxy, formyl, acetamido and methylenoxycarboxy, with the proviso that R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are not each --H. 7. A pharmaceutical composition for inhibiting angiogenesis in a mammal, said composition comprising a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, according to claim 1, and a pharmaceutically acceptable carrier. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
1. Technical Field The present invention relates to a novel fumagillol derivative or a pharmaceutically acceptable salt thereof which exhibits excellent angiogenesis inhibiting activities, to a process for preparing the same and to a pharmaceutical composition comprising the same as an active ingredient. 2. Background Art Angiogenesis is a phenomenon of generating a new capillary vessel, which is one of normal physiological functions as well as one of the pathological functions caused by various diseases. Angiogenesis has a deep connection with growth and transfer of solid cancer, rheumatic arthritis, diabetic retinopathy, psoriasis, or the like [Billington, D. C. Drug Design and Discovery, (1991), 8, 3.]. Judah Folkman of Medical College of Harvard University suggested a novel concept of treating solid cancer by inhibiting angiogenesis in 1971 [J. Folkman, New Engl. Med., (1971), 185, 1182]. Recently, clinical importance of therapeutic agents by means of controlling angiogenesis has been emphasized, and various researches on angiogenesis have been performed. According to clinical results of anticancer medicines using angiogenesis inhibitors, in particular, it is expected that they cause little problems caused by general anticancer medicines, including adverse effect and tolerance. In other word, an angiogenesis inhibitor does not directly act on tumor cells, but acts on endothelial cells of a living organism, and thus, the problem of tolerance does not probably occur, and a synergistic anticancer effect is expected by a therapy in combination with conventional anticancer medicines which have been employed up to the present. Various fumagillin compounds inhibiting angiogenesis have been reported. For example, it is known that fumagillin having angiogenesis inhibiting action is produced by culturing Aspergillus fumigatus, a productive strain isolated from a soil sample. [Eble, T. E., Hanson, F. R. Antibiotics & chemotherapy, 1, 54 (1951), Eble, T. E., Hanson, F. R. J. Bact., 58, 527 (1949)] [Ingber, G., Fujita, T., Kishimoto, S., Sudo, K., Kanmaru, T., Bre, H., Folkman, J., Nature 248, 555(1990)] Besides, EP-A-354787, EP-A-357061, JP-A01-233275 and EP-A-415294 have been disclosed; and 6-amino-6-deoxy fumagillol [Chem. Pharm. Bull., (1992), 40, 575], 6-acyl, 6-O-sulfonyl, 6-O-alkyl and 6-O-(N-substituted carbamoyl) fumagillol [Chem. Pharm. Bull., (1992), 40, 10 96] are reported to have angiogenesis inhibiting action. However, continuous development of angiogenesis inhibitors having less toxicity and more excellent effect is further required. DISCLOSURE OF THE INVENTION The present inventors have performed intensive studies to solve the problems described above, and, as a result, developed novel fumagillol derivatives derived from fumagillol, the hydrolyzed product of fumagillin which is produced by fermentation of microorganism, to complete the invention. The object of the present invention is to provide fumagillol derivatives represented by Chemical Formula 1. Another object of the present invention is to provide processes for preparing the fumagillol derivatives represented by Chemical Formula 1. The present invention relates to a fumagillol derivative represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof: ##STR2## herein, X represents hydroxy group and Y represents a halogen, or X and Y may form an oxirane ring; B represents oxygen or hydrogen; and R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 independently represent hydrogen, hydroxy, acetoxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted aminoalkoxy, C.sub.1 -C.sub.6 alkoxy, halogen, cyano, trifluoromethyl, nitro, alkylenedioxy, formyl, acetamido or methylenoxycarboxyl, provided that R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 do not represent hydrogen at the same time. The pharmaceutically acceptable salts of the compound of Chemical Formula 1 include hydrochloride, bromate, sulfate, phosphate, nitrate, formate, acetate, trifluoroacetate, oxalate, fumarate, tartarate, maleate, methanesulfonate, benzensulfonate and p-toluenesulfonate. Among the compounds of Chemical Formula 1, preferred are those compounds or pharmaceutically acceptable salts thereof, wherein, X represents hydroxy group and Y represents a halogen, or X and Y form an oxirane ring; B is oxygen or hydrogen; and R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 independently represent hydrogen, hydroxy, acetoxy, amino, alkylamino, dialkylamino, dialkylaminoalkyl, alkylaminoalkoxy, dialkylaminoalkoxy, C.sub.1 -C.sub.6 alkoxy, halogen, cyano, trifluoromethyl, nitro or methylenedioxy, provided that R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 do not represent hydrogen at the same time. Among the compounds of Chemical Formula 1, more preferred are O-(3,4-dimethoxycinnamoyl)fumagillol; O-(4-methoxycinnamoyl)fumagillol; O-(3,4,5-trimethoxycinnamoyl)fumagillol; O-(4-Chlorocinnamoyl)fumagillol; 4-(3,4,5-trimethoxycinnamoyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-exenyl)-3-meth oxy-1-chloromethyl-1-cyclohexanol; O-(4-trifluoromethylcinnamoyl)fumagillol; O-(4-nitrocinnamoyl)fumagillol; O-(3,4-dimethoxy-6-nitrocinnamoyl)fumagillol; O-(4-acetoxycinnamoyl)fumagillol; O-(4-hydroxycinnamoyl)fumagillol; O-(4-acetoxy-3,5-dimethoxycinnamoyl)fumagillol; O-3,5-dimethoxy-4-hydroxycinnamoyl)fumagillol; 4-(4-methoxycinnamoyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1- chloromethyl-1-cyclohexanol; O-(4-dimethylaminocinnamoyl)fumagillol; O-(4-aminocinnamoyl)fumagillol; O-(4-cyanocinnamoyl)fumagillol; O-(3,4,5-trimethoxycinnamyl)fumagillol; O-(4-dimethylaminoethoxycinnamoyl)fumagillol; O-(3-dimethylaminomethyl-4-methoxycinnamoyl)fumagillol; O-(3,4-methylenedioxycinnamoyl)fumagillol; O-(3,4-dimethoxy-6-aminocinnamoyl)fumagillol; O-(4-ethylaminocinnamoyl)fumagillol; O-(4-ethylaminoethoxycinnamoyl)fumagillol; O-(4-dimethylaminocinnamyl)fumagillol; and 4-(4-dimethylaminocinnamoyl)oxy-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-meth oxy-1-chloromethyl-1-cyclohexanol. The compounds of Chemical Formula 1 may be prepared from the compound represented by Chemical Formula 2 (fumagillol), which is a hydrolyzed product of fumagillin produced by fermentation of microorganisms [Tarbell, D. S. et al., J Am. Chem. Soc., 83, 3096 (1961)]. ##STR3## According to a preferred embodiment of the present invention, the compounds represented by Chemical Formula 1 can be prepared via acylation or etherification. The processes are explained by means of Reaction Schemes here-in-below: (1) Acylation ##STR4## [In the formula, X, Y, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are the same as defined in the above.] The acylation of Reaction Scheme 1 may be performed by reacting the compound of Chemical Formula 2 as a starting material with a substituted cinnamoyl acid derivative represented by Chemical Formula 3, or a reactive derivative thereof such as an acid anhydride, a mixed anhydride, an acid chloride, an acid p-toluenesulfonic anhydride, an acid mesylic anhydride, a 2-pyridine thiol ester and a phenyl ester, in the presence of a base. The amount of the compound of Chemical Formula 3 or a reactive derivative thereof used in the acylation may be 1 to 10 equivalents, preferably 1 to 3 equivalents on the basis of the amount of the compound of Chemical Formula 2. As a base used in the acylation, a tertiary amine such as triethyl amine, diisopropylethyl amine, pyridine and dimethylaminopyridine, or an alkaline metal hydride such as sodium hydride and potassium hydride may be used in an amount of 1 to 10 equivalents. Preferably, triethyl amine, dimethylaminopyridine or sodium hydride may be used in an amount of 1 to 3 equivalents. As a solvent for the acylation, dimethylformamide, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, dioxane, acetonitrile, benzene or toluene may be used. Among the solvents, preferred are dimethylformamide, dichloromethane, tetrahydrofuran, acetonitrile and benzene. The reaction temperature of acylation is -80 to 100.degree. C., preferably 0 to 50.degree. C. The compound of Chemical Formula 4 thus obtained is subjected to oxirane ring opening reaction to provide the compound of Chemical Formula 5. The oxirane ring opening reaction is performed by reacting the compound of Formula 4 with 1 to 3 equivalents of acid, or reacting with a salt in the presence of an acid catalyst. As an acid used for the oxirane ring opening reaction, hydrochloric acid, bromic acid or iodic acid may be used, and as a catalyst, acetic acid, sulfuric acid, p-toluenesulfonic acid, hydrochloric acid, phosphoric acid or nitric acid may be used, but preferred is acetic acid or hydrochloric acid. As a salt for the oxirane ring opening, lithium bromide, lithium chloride, sodium chloride, potassium chloride, potassium bromide, sodium bromide, potassium iodide, sodium iodide or lithium iodide may be used. Among these salts, lithium chloride, lithium bromide and lithium iodide are preferred. (2) Etherification ##STR5## [In the formula, X, Y, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are the same as defined in the above.] The etherealization of Reaction Scheme 2 is performed by reacting the compound of Chemical Formula 2 as a starting material with a substituted cinnamyl alcohol of Chemical Formula 6 or a reactive derivative thereof such as tosylate, mesylate and halide (chloride, bromide or iodide), in the presence of a base to obtain a compound of Chemical Formula 7. The amount of the compound of Chemical Formula 6 or a reactive derivative thereof used in the etherification may be 1 to 10 equivalents, preferably 1 to 3 equivalents on the basis of the amount of the compound of Chemical Formula 2. As a base used in the etherification, a tertiary amine such as triethyl amine, diisopropylethyl amine, pyridine and dimethylaminopyridine, or sodium hydride, potassium hydride, butyl lithium, lithium diisopropylamide may be used in an amount of 1 to 10 equivalents, preferably, 1 to 3 equivalents. As a solvent for the etherification, dimethylformamide, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, dioxane, acetonitrile, benzene or toluene may be used. Among the solvents, preferred are dimethylformamide, dichloromethane, tetrahydrofuran, acetonitrile and benzene. The reaction temperature of etherealization is -80 to 150.degree. C., preferably 0 to 100.degree. C. The present invention also provides an angiogenesis inhibiting composition which comprises a therapeutically effective amount of the compound of Chemical Formula 1 or the salt thereof as an active ingredient, and a pharmaceutically acceptable carrier. A compound of Chemical Formula 1 and a salt thereof according to the present invention may be formulated as a pharmaceutical solid, semisolid or liquid type formulation which is suitable for oral or parenteral administration by blending the compound or salt with a pharmaceutically acceptable inert carrier. As the compounds of Chemical Formula 1 or salts have excellent angiogenesis inhibiting effect, they can be used as an anticancer medicine or an inhibitor for a cancer transfer, or a therapeutic agent for treating rheumatic arthritis, psoriasis or diabetic retinitis. In order to evaluate general toxicity of the compound of Chemical Formula 1 according to the present invention, experiments on acute toxicity were carried out by using mice. As a result, the half lethal dose (LD.sub.50) of each compound in case of oral administration was not less than 2 g/kg, thereby the compound was evaluated as a considerably safe compound. Thus, the compound of Chemical Formula 1 according to the present invention may be administered in an amount of 0.2 mg/kg to 2 g/kg per day, more preferably 0.2 to 200 mg/kg for the first stage. But the dose may be varied depending on the requirement of a patient, the condition of disease to be treated, and the compound to be used. The invention is described in more detail by referring to the examples below, but it should be noticed that the present invention is not restricted to the examples by any means. |
| PATENT EXAMPLES | This data is not available for free |
| PATENT PHOTOCOPY | Available on request |
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