CA1340552C - O-chloroacetylcarbamoylfumagillol and production process and use thereof - Google Patents
O-chloroacetylcarbamoylfumagillol and production process and use thereofInfo
- Publication number
- CA1340552C CA1340552C CA000617081A CA617081A CA1340552C CA 1340552 C CA1340552 C CA 1340552C CA 000617081 A CA000617081 A CA 000617081A CA 617081 A CA617081 A CA 617081A CA 1340552 C CA1340552 C CA 1340552C
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- Prior art keywords
- fumagillol
- reaction
- chloroacetylcarbamoylfumagillol
- compound
- base
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/38—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D303/46—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals by amide or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Compounds (AREA)
Abstract
Disclosed is O-chloroacetylcarbamoylfumagillol of the formula:
Description
,.....
1~4~552 This is a divisional application of Canadian Patent Application Serial No. 610,076, filed on August 31, 1989.
This invention relates to a novel O-substituted fumagillol derivative, O-chloroacetylcarbamoylfumagillol of the formula:
(I) H
O O
which has angiogenesis inhibitory activity and is effective in the treatment and prevention of various inflammatory diseases (rheumatism, psoriasis, etc.), diabetic retinopathy and cancer, among others.
Angiogenesis is deeply concerned in the course of manifestation or progress of various diseases, for example various inflammatory diseases (rheumatism, psoriasis, etc.), diabetic retinopathy, and cancer. Therefore, to inhibit angiogenesis is considered to contribute to the treatment and prevention of such diseases. In fact, several groups of researchers have so far searched for angiogenesis inhibitory substances. As examples, there may be mentioned the study by CH.~
Taylor et al.[Taylor, S. et al., Nature,:'.297, 307 (l982)] on the applicability of protamine and the study by Folkman et al.
[Folkman, J. et al., Science,''2.21, 719 (1983)] on the combined use of heparin and cortisone. Furthermore, patent applications have been filed alleging, for example, that ascorbic acid ethers and related compounds (Japanese Kokai Tokkyo Koho No.
58-131978) and the sulfated polysaccharide DS1152 (Japanese Kokai Tokkyo Koho No. 63'119500) show angiogenesis inhibitory activity. However, such substances are not yet fully satisfactory from the activity viewpoint. The advent of compounds superior in activity is waited for.
Accordingly, it is an object of the invention to provide a novel compound having angiogenesis inhibitory activity.
The present inventors searched for and evaluated various compounds in an attempt to achieve the above object and, as a result, found that O-substituted derivatives of fumagillol, a hydrolyzate of fumagillin so far known as an antimicrobial and antiprotozoal agent, have potent angiogenesis inhibitory activity. Based on this finding, they have now completed the present invention. Thus, the invention relates to an O-substituted fumagillol derivative, O-chloroacetyl-carbamoylfumagillol of the formula (I).
The compound of the present invention can be produced by subjecting fumagillol [Tarbell, D. S. et al., J. Am. Chem.
Soc., 83, 3096 (1961)], which is a hydrolyzate of fumagillin W
1~~0~52 produced by microorganisms, to carbamoylation using a carbamoyl-ating agent in the manner mentioned below.
The carbamoylation reaction for the introduction of a monosubstituted carbamoyl group is carried out generally by bringing fumagillol into contact with an isocyanate according to the following equation:
R5NC0 + fumagillol -~ Compound (I) .
In the above equation, R5 is chloroacetyl. The isocyanate is used generally in an amount of about 1 to 5 moles per mole of fumagillol.
This reaction is carried out generally in the presence of a base. Usable as the base are, for example, tertiary amines, alkali metal hydrogen carbonates, alkali metal carbonates, alkali metal hydrides and organometals, such as diisopropylethylamine, triethylamine, pyridine, N,N-dimethyl-aminopyridine, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium and potassium carbonate, sodium and potassium hydride, butyl lithium, and lithium diisopropylamide. The level of addition of the base is generally about 1 to 5 moles per mole of fumagillol.
This reaction is carried out generally in an organic solvent which will not interfere with the reaction. Usable as such inert organic solvent are amides, halogenated hydrocarbons, ethers, esters, nitriles, nitro compounds, ketones and aromatic hydrocarbons, such as dimethylformamide, dimethylacetamide, dichloromethane, chloroform, 1,2-dichloroethane, diethyl ether, 1~4455~
tetrahydrofuran, dioxane, methylacetate, ethylacetate, isobutylacetate, methylpropionate, acetonitrile, propionitrile, nitromethane, nitroethane, acetone, methyl ethyl ketone, benzene and toluene. They may be used either singly or in the form of a mixture of two or more of them mixed together in an appropriate ratio. When a tertiary amine is used as the base, the tertiary amine as such may also serve as a solvent.
The optimal reaction temperature may depend on the base and solvent and amounts thereof but is generally within the range of -80~C to 100~C, preferably from 0~C to room temperature. The reaction time required amounts to about 1 hour to 5 days.
The carbamoylation may also be effected by reacting fumagillol with a chloroacetyl carbamoyl halide.
The carbamoyl halide is used generally in an amount of about 1 to 5 moles per mole of fumagillol.
This reaction is carried out generally in the presence of a base. Usable as the base are those tertiary amines, alkali metal hydrogen carbonates, alkali metal carbonates, alkali metal hydrides and organoalkali metals mentioned above. The level of addition of the base is generally about 1 to 5 moles per mole of fumagillol.
This reaction is carried out generally in an organic solvent which will not interfere with the reaction. Usable as such inert organic solvent are those amides, halogenated hydrocarbons, ethers, esters, nitriles, nitro compounds, '~ 13~055~
ketones and aromatic hydrocarbons mentioned above. They may be used either singly or in the form of a mixture, in.an appropriate mixing ratio, of two or more of them. When a tertiary amine is used as the base, the tertiary amine as such may also serve as a solvent.
The optimal reaction temperature may vary depending on the base and solvent and amounts thereof. Generally, however, the reaction is carried out at a temperature from about 0~C to a temperature approximately equal to the refluxing temperature of the reaction medium, preferably from about 25~C
to the refluxing temperature.
_ The O-substituted fumagillol derivative (I) thus produced can be isolated by ~ se known means of separation and purification (e. g. chromatography, crystallization) or by other appropriate means.
The compound (I) has asymmetric centers within the molecule and accordingly is optically active. The absolute configuration comes from the starting material fumagillol.
Therefore, it is to be noted that the compound (I) has the same absolute configuration that fumagillol has.
The compound according to the invention exhibits angiogenesis inhibitory activity and is useful as a therapeutic and prophylactic agent for various inflammatory diseases (rheumatism, psoriasis), diabetic retinopathy, or cancer. It can be safely administered either orally or nonorally as such or in the form of pharmaceutical preparations [e. g. tablets, capsules (inclusive of soft capsules and microcapsules), solutions, injections, suppositories] prepared by admixing with ~ se known pharmaceutically acceptable carriers or excipients or the like. The dose may vary depending on the target of administration, route of administration, symptoms and other factors. Generally, however, in adults, it is used, for example, at a dose of about 0.1 mg/kg to 40 mg/kg body weight, preferably about 0.5 mg/kg to 20 mg/kg body weight.
Experimental Example The product compound (I) obtained in the example given below was evaluated for angiogenesis inhibitory activity by the rat cornea micropocket method. The data obtained are shown in the table given below.
Method of Measurement Essentially the method of Gimbrone et al. [J.
National Cancer Institute, 52, 4l3-419 (1974)] was followed.
Thus, adult male Sprague-Dawley rats (11 to 16 weeks of age) were anesthetized with nembutal and locally anesthetized by instillation of xylocaine eyedrops onto the eyeball. The cornea was incised to a length of about 2 mm at about 2 mm inside from the corneal circumference by means of an injection needle, and a sustained release pellet containing basic fibro-blast growth factor (bFGF; bovine brain-derived, purified product; R & D) and a sustained release pellet containing the test sample were inserted side by side into the incision so that the bFGF pellet was located on the central side in the cornea. In the control group, the bFGF pellet and a sample-free ,,~ 1340552 pellet were inserted into the cornea. After 7 days, the cornea was observed under a stereoscopic microscope. When the sample administration resulted in retardation or reduction of bFGF-induced angiogenesis, the sample was judged to have inhibitory activity.
The sustained release pellets were prepared in the following manner. An ethylene-vinyl acetate copolymer (Takeda Chemical Industries) was dissolved in dichloromethane to a concentration of 8%. A 3-ul portion of the solution was air-dried on a glass dish, an aqueous solution of bFGF (250 ng) was then placed thereon and air-dried and, finally 3 ~1 of the above ethylene-vinyl acetate copolymer solution was placed further thereon and air-dried to give a laminate consisting of two copolymer layers and a bFGF layer sandwiched therebetween.
This sandwich sheet was made round into a bFGF pellet. The test sample pellets were prepared by dissolving each sample in ethanol in a concentration of 20 ~rg/2 ul, mixing the solution (2 N1) with 6 ul of an ethylene-vinyl acetate copolymer solution, air-drying the mixed solution on a glass dish and making the thus-obtained sheet round.
Table - Angiogenesis Inhibitory Activity Compound Inhibition Rate Judgement (I) 6/6 +
Judged after 7 days.
In the above table, the inhibition rate is the ratio of the number of rats in which angiogenesis inhibitory activity was observed to the number of rats tested.
i340~~2 Example The following example is further illustrative of the present invention but is by no means limitative of the scope of the invention.
In the following example, elution in column chromato-graphy(the eluent being given in the parentheses) was performed under TLC (thin layer chromatography) observation. In TLC
observation, Merck Kieselgel 60F250 (70-230 mesh) was used for preparing TLC plates and the solvent used as the eluent in column chromatography was used also as the developing solvent.
For detection, a UV detector or colouration with phosphomolybdic acid, for example, was used. Merck Kieselgel 60 (70-230 mesh) was used also as the column Backing silica gel. Each NMR
spectrum is a proton NMR (1H-NMR) spectrum measured on a Varian model Gemini 200 NMR spectrometer with tetramethyl-silane as an internal or external standard and reported in terms of d values in ppm.
In the example, the following abbreviations are used:
s: singlet; br: broad; d: doublet; dd: double doublet; ddd: doublet doublet doublet; t: triplet; q:
quartet; m: multiplet; ABq: AB quartet; J: coupling constant; Hz: hertz; CDC13: deuteriochloroform; d6-DMSO:
deuterated dimethyl sulfoxide; ~: ~ by weight.
In the following example, the term "room temperature"
means about 15-25~C. The melting point and temperature data Trade-mark _ g -~.
1340'~~~
are all given on the Celsius scale.
Example 0-Chloroacetylcarbamoylfumagillol O
., ' ~~OCH 3 OCONHCOCH2 Cl To a solution of fumagillol (314 mg) in dichloro-methane (5 ml) was added dropwise chloroacetyl isocyanate (160 mg) under ice cooling, followed by addition of dimethyl-aminopyridine (130 mg). The mixture was stirred at 0~C for 2 hours. To this reaction mixture was added water and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography. The eluate obtained with a mixture of n-hexane and ethyl acetate (3:1) was concentrated under reduced pressure to give colourless, powdery O-chloroacetylcarbamoylfumagillol (318 mg) (71$ yield).
1H-NMR (CDC13) 6: 1.10 (1H, m), 1.21 (3H, s), 1.66 (3H, s), 1.75 (3H, s), 1.93 (1H, d, J=11.4 Hz), 1.8-2.5 (5H, m), 2.57 (1H, d, J=4.2 Hz), 2.58 (1H, m), 2.99 (1H, d, J=4.2 Hz), 3.47 (3H, s), 3.68 (1H, dd, J=l1.4 Hz, J=2.8 Hz), 4.44 (2H, s), 5.20 (1H, m), 5.61 (1H, m), 8.33 (1H, br s).
_ g -
1~4~552 This is a divisional application of Canadian Patent Application Serial No. 610,076, filed on August 31, 1989.
This invention relates to a novel O-substituted fumagillol derivative, O-chloroacetylcarbamoylfumagillol of the formula:
(I) H
O O
which has angiogenesis inhibitory activity and is effective in the treatment and prevention of various inflammatory diseases (rheumatism, psoriasis, etc.), diabetic retinopathy and cancer, among others.
Angiogenesis is deeply concerned in the course of manifestation or progress of various diseases, for example various inflammatory diseases (rheumatism, psoriasis, etc.), diabetic retinopathy, and cancer. Therefore, to inhibit angiogenesis is considered to contribute to the treatment and prevention of such diseases. In fact, several groups of researchers have so far searched for angiogenesis inhibitory substances. As examples, there may be mentioned the study by CH.~
Taylor et al.[Taylor, S. et al., Nature,:'.297, 307 (l982)] on the applicability of protamine and the study by Folkman et al.
[Folkman, J. et al., Science,''2.21, 719 (1983)] on the combined use of heparin and cortisone. Furthermore, patent applications have been filed alleging, for example, that ascorbic acid ethers and related compounds (Japanese Kokai Tokkyo Koho No.
58-131978) and the sulfated polysaccharide DS1152 (Japanese Kokai Tokkyo Koho No. 63'119500) show angiogenesis inhibitory activity. However, such substances are not yet fully satisfactory from the activity viewpoint. The advent of compounds superior in activity is waited for.
Accordingly, it is an object of the invention to provide a novel compound having angiogenesis inhibitory activity.
The present inventors searched for and evaluated various compounds in an attempt to achieve the above object and, as a result, found that O-substituted derivatives of fumagillol, a hydrolyzate of fumagillin so far known as an antimicrobial and antiprotozoal agent, have potent angiogenesis inhibitory activity. Based on this finding, they have now completed the present invention. Thus, the invention relates to an O-substituted fumagillol derivative, O-chloroacetyl-carbamoylfumagillol of the formula (I).
The compound of the present invention can be produced by subjecting fumagillol [Tarbell, D. S. et al., J. Am. Chem.
Soc., 83, 3096 (1961)], which is a hydrolyzate of fumagillin W
1~~0~52 produced by microorganisms, to carbamoylation using a carbamoyl-ating agent in the manner mentioned below.
The carbamoylation reaction for the introduction of a monosubstituted carbamoyl group is carried out generally by bringing fumagillol into contact with an isocyanate according to the following equation:
R5NC0 + fumagillol -~ Compound (I) .
In the above equation, R5 is chloroacetyl. The isocyanate is used generally in an amount of about 1 to 5 moles per mole of fumagillol.
This reaction is carried out generally in the presence of a base. Usable as the base are, for example, tertiary amines, alkali metal hydrogen carbonates, alkali metal carbonates, alkali metal hydrides and organometals, such as diisopropylethylamine, triethylamine, pyridine, N,N-dimethyl-aminopyridine, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium and potassium carbonate, sodium and potassium hydride, butyl lithium, and lithium diisopropylamide. The level of addition of the base is generally about 1 to 5 moles per mole of fumagillol.
This reaction is carried out generally in an organic solvent which will not interfere with the reaction. Usable as such inert organic solvent are amides, halogenated hydrocarbons, ethers, esters, nitriles, nitro compounds, ketones and aromatic hydrocarbons, such as dimethylformamide, dimethylacetamide, dichloromethane, chloroform, 1,2-dichloroethane, diethyl ether, 1~4455~
tetrahydrofuran, dioxane, methylacetate, ethylacetate, isobutylacetate, methylpropionate, acetonitrile, propionitrile, nitromethane, nitroethane, acetone, methyl ethyl ketone, benzene and toluene. They may be used either singly or in the form of a mixture of two or more of them mixed together in an appropriate ratio. When a tertiary amine is used as the base, the tertiary amine as such may also serve as a solvent.
The optimal reaction temperature may depend on the base and solvent and amounts thereof but is generally within the range of -80~C to 100~C, preferably from 0~C to room temperature. The reaction time required amounts to about 1 hour to 5 days.
The carbamoylation may also be effected by reacting fumagillol with a chloroacetyl carbamoyl halide.
The carbamoyl halide is used generally in an amount of about 1 to 5 moles per mole of fumagillol.
This reaction is carried out generally in the presence of a base. Usable as the base are those tertiary amines, alkali metal hydrogen carbonates, alkali metal carbonates, alkali metal hydrides and organoalkali metals mentioned above. The level of addition of the base is generally about 1 to 5 moles per mole of fumagillol.
This reaction is carried out generally in an organic solvent which will not interfere with the reaction. Usable as such inert organic solvent are those amides, halogenated hydrocarbons, ethers, esters, nitriles, nitro compounds, '~ 13~055~
ketones and aromatic hydrocarbons mentioned above. They may be used either singly or in the form of a mixture, in.an appropriate mixing ratio, of two or more of them. When a tertiary amine is used as the base, the tertiary amine as such may also serve as a solvent.
The optimal reaction temperature may vary depending on the base and solvent and amounts thereof. Generally, however, the reaction is carried out at a temperature from about 0~C to a temperature approximately equal to the refluxing temperature of the reaction medium, preferably from about 25~C
to the refluxing temperature.
_ The O-substituted fumagillol derivative (I) thus produced can be isolated by ~ se known means of separation and purification (e. g. chromatography, crystallization) or by other appropriate means.
The compound (I) has asymmetric centers within the molecule and accordingly is optically active. The absolute configuration comes from the starting material fumagillol.
Therefore, it is to be noted that the compound (I) has the same absolute configuration that fumagillol has.
The compound according to the invention exhibits angiogenesis inhibitory activity and is useful as a therapeutic and prophylactic agent for various inflammatory diseases (rheumatism, psoriasis), diabetic retinopathy, or cancer. It can be safely administered either orally or nonorally as such or in the form of pharmaceutical preparations [e. g. tablets, capsules (inclusive of soft capsules and microcapsules), solutions, injections, suppositories] prepared by admixing with ~ se known pharmaceutically acceptable carriers or excipients or the like. The dose may vary depending on the target of administration, route of administration, symptoms and other factors. Generally, however, in adults, it is used, for example, at a dose of about 0.1 mg/kg to 40 mg/kg body weight, preferably about 0.5 mg/kg to 20 mg/kg body weight.
Experimental Example The product compound (I) obtained in the example given below was evaluated for angiogenesis inhibitory activity by the rat cornea micropocket method. The data obtained are shown in the table given below.
Method of Measurement Essentially the method of Gimbrone et al. [J.
National Cancer Institute, 52, 4l3-419 (1974)] was followed.
Thus, adult male Sprague-Dawley rats (11 to 16 weeks of age) were anesthetized with nembutal and locally anesthetized by instillation of xylocaine eyedrops onto the eyeball. The cornea was incised to a length of about 2 mm at about 2 mm inside from the corneal circumference by means of an injection needle, and a sustained release pellet containing basic fibro-blast growth factor (bFGF; bovine brain-derived, purified product; R & D) and a sustained release pellet containing the test sample were inserted side by side into the incision so that the bFGF pellet was located on the central side in the cornea. In the control group, the bFGF pellet and a sample-free ,,~ 1340552 pellet were inserted into the cornea. After 7 days, the cornea was observed under a stereoscopic microscope. When the sample administration resulted in retardation or reduction of bFGF-induced angiogenesis, the sample was judged to have inhibitory activity.
The sustained release pellets were prepared in the following manner. An ethylene-vinyl acetate copolymer (Takeda Chemical Industries) was dissolved in dichloromethane to a concentration of 8%. A 3-ul portion of the solution was air-dried on a glass dish, an aqueous solution of bFGF (250 ng) was then placed thereon and air-dried and, finally 3 ~1 of the above ethylene-vinyl acetate copolymer solution was placed further thereon and air-dried to give a laminate consisting of two copolymer layers and a bFGF layer sandwiched therebetween.
This sandwich sheet was made round into a bFGF pellet. The test sample pellets were prepared by dissolving each sample in ethanol in a concentration of 20 ~rg/2 ul, mixing the solution (2 N1) with 6 ul of an ethylene-vinyl acetate copolymer solution, air-drying the mixed solution on a glass dish and making the thus-obtained sheet round.
Table - Angiogenesis Inhibitory Activity Compound Inhibition Rate Judgement (I) 6/6 +
Judged after 7 days.
In the above table, the inhibition rate is the ratio of the number of rats in which angiogenesis inhibitory activity was observed to the number of rats tested.
i340~~2 Example The following example is further illustrative of the present invention but is by no means limitative of the scope of the invention.
In the following example, elution in column chromato-graphy(the eluent being given in the parentheses) was performed under TLC (thin layer chromatography) observation. In TLC
observation, Merck Kieselgel 60F250 (70-230 mesh) was used for preparing TLC plates and the solvent used as the eluent in column chromatography was used also as the developing solvent.
For detection, a UV detector or colouration with phosphomolybdic acid, for example, was used. Merck Kieselgel 60 (70-230 mesh) was used also as the column Backing silica gel. Each NMR
spectrum is a proton NMR (1H-NMR) spectrum measured on a Varian model Gemini 200 NMR spectrometer with tetramethyl-silane as an internal or external standard and reported in terms of d values in ppm.
In the example, the following abbreviations are used:
s: singlet; br: broad; d: doublet; dd: double doublet; ddd: doublet doublet doublet; t: triplet; q:
quartet; m: multiplet; ABq: AB quartet; J: coupling constant; Hz: hertz; CDC13: deuteriochloroform; d6-DMSO:
deuterated dimethyl sulfoxide; ~: ~ by weight.
In the following example, the term "room temperature"
means about 15-25~C. The melting point and temperature data Trade-mark _ g -~.
1340'~~~
are all given on the Celsius scale.
Example 0-Chloroacetylcarbamoylfumagillol O
., ' ~~OCH 3 OCONHCOCH2 Cl To a solution of fumagillol (314 mg) in dichloro-methane (5 ml) was added dropwise chloroacetyl isocyanate (160 mg) under ice cooling, followed by addition of dimethyl-aminopyridine (130 mg). The mixture was stirred at 0~C for 2 hours. To this reaction mixture was added water and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography. The eluate obtained with a mixture of n-hexane and ethyl acetate (3:1) was concentrated under reduced pressure to give colourless, powdery O-chloroacetylcarbamoylfumagillol (318 mg) (71$ yield).
1H-NMR (CDC13) 6: 1.10 (1H, m), 1.21 (3H, s), 1.66 (3H, s), 1.75 (3H, s), 1.93 (1H, d, J=11.4 Hz), 1.8-2.5 (5H, m), 2.57 (1H, d, J=4.2 Hz), 2.58 (1H, m), 2.99 (1H, d, J=4.2 Hz), 3.47 (3H, s), 3.68 (1H, dd, J=l1.4 Hz, J=2.8 Hz), 4.44 (2H, s), 5.20 (1H, m), 5.61 (1H, m), 8.33 (1H, br s).
_ g -
Claims (3)
1. The compound O-chloroacetylcarbamoylfumagillol of the formula:
2. A process for the preparation of the compound of claim 1, comprising (A) reacting fumagillol with chloroacetylisocyanate, or (B) reacting fumagillol with a chloroacetylcarbamoyl halide.
3. A process for the preparation of the compound of claim 1, according to either one of claim 2, part (A) or (B), wherein the reaction is carried out in the presence of a base in an amount of about 1 to 5 moles per mole of fumagillol in an organic solvent and wherein if the base is a tertiary amine, the tertiary amine may be used as the organic solvent as well.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000617081A CA1340552C (en) | 1988-09-01 | 1997-08-18 | O-chloroacetylcarbamoylfumagillol and production process and use thereof |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP219287 | 1988-09-01 | ||
| JP053537 | 1989-03-06 | ||
| CA000617081A CA1340552C (en) | 1988-09-01 | 1997-08-18 | O-chloroacetylcarbamoylfumagillol and production process and use thereof |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000617081A Division CA1340552C (en) | 1988-09-01 | 1997-08-18 | O-chloroacetylcarbamoylfumagillol and production process and use thereof |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000617081A Division CA1340552C (en) | 1988-09-01 | 1997-08-18 | O-chloroacetylcarbamoylfumagillol and production process and use thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1340552C true CA1340552C (en) | 1999-05-18 |
Family
ID=33315152
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000617081A Expired - Fee Related CA1340552C (en) | 1988-09-01 | 1997-08-18 | O-chloroacetylcarbamoylfumagillol and production process and use thereof |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1340552C (en) |
-
1997
- 1997-08-18 CA CA000617081A patent/CA1340552C/en not_active Expired - Fee Related
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