WO2003051804A1 - Nouvelle substance ayant une activite antitumorale et anti-inflammatoire - Google Patents
Nouvelle substance ayant une activite antitumorale et anti-inflammatoire Download PDFInfo
- Publication number
- WO2003051804A1 WO2003051804A1 PCT/JP2002/013124 JP0213124W WO03051804A1 WO 2003051804 A1 WO2003051804 A1 WO 2003051804A1 JP 0213124 W JP0213124 W JP 0213124W WO 03051804 A1 WO03051804 A1 WO 03051804A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- compound
- alkyl group
- present
- rkb
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/12—Acetic acid esters
- C07C69/16—Acetic acid esters of dihydroxylic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/18—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with unsaturation outside the aromatic ring
- C07C39/19—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with unsaturation outside the aromatic ring containing carbon-to-carbon double bonds but no carbon-to-carbon triple bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/017—Esters of hydroxy compounds having the esterified hydroxy group bound to a carbon atom of a six-membered aromatic ring
Definitions
- the present invention relates to a novel compound useful as an active ingredient of a drug such as an antitumor agent and an anti-inflammatory agent.
- Anticancer drugs are less effective against solid tumors because when the solid tumor becomes larger than a certain size, the inside of the tumor becomes hypoxic [Cancer, Res. 58, 1408 (1998)], and Hypoxia Inducible Factor-1 (HIF-1) ) And nuclear factor B (NF-zc B) are activated, which may lead to excessive enhancement of survival signals. [Trends Mol. Med., 7, 345 (2001), Cell, 87, 13 (1996), Cell, 95, 729 (1998), Toxicology, 155, 27 (2000)], and details of the mechanism are unknown.
- hypoxia hypoxia
- various genes are promoted, such as erythropoietin, which promotes the production of red blood cells and increases oxygen supply to the whole body; VEGF and its receptors, which promote angiogenesis and increase local oxygen supply; Genes of glycolytic enzymes that synthesize ATP under anoxic conditions and confer cell resistance are activated, and work to maintain oxygen homeostasis.
- Hypoxia Inducible Factor-1 HIF-1
- Tumor tissue is hypoxic due to insufficient blood circulation, which is known to promote angiogenesis, suggesting a deep involvement of HIF-1 in angiogenesis.
- Tumor necrosis factor is a major cytokine that exists at sites of inflammation and induces cell death through apoptosis.
- TNF tumor necrosis factor
- NF- ⁇ ⁇ nuclear factor B
- Another object of the present invention is to provide a method for producing a novel compound having the above characteristics, and a medicament containing the compound as an active ingredient.
- the present inventors have conducted intensive studies to solve the above problems, and as a result, a novel compound isolated from a fermentation solution of BAUA3564 strain belonging to fungi and an analog produced from the compound by chemical synthesis (synthesis method) were obtained. However, they have found that they have antitumor activity even in a hypoxic state, and have provided this compound or an analog as a medicament containing the same as an active ingredient, thereby completing the present invention.
- a step of culturing a filamentous fungus that is a bacterium producing the compound represented by the above formulas (I) to (III) and separating and collecting the compound from the obtained culture is described. And a method for producing a compound represented by the above formulas (I) to (III) or a salt thereof.
- the present invention provides a medicament comprising the compound represented by the above formulas (I) to (III) or a physiologically acceptable salt thereof as an active ingredient.
- This drug can be used as an antitumor agent, anti-inflammatory agent, immunosuppressant, etc. Or as a medicament for the prevention and / or treatment of various diseases caused by hypoxia, such as various diseases caused by abnormal angiogenesis promoted by hypoxia, or as an inhibitor of angiogenesis in tumors. it can.
- the “alkyl group” may be linear, branched, cyclic, or a combination thereof.
- an alkyl group having 1 to 6 carbon atoms preferably a linear or branched alkyl group having 1 to 6 carbon atoms can be used. More specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc. Can be used. The same applies to the alkyl moiety of another substituent having an alkyl moiety (eg, an alkyloxycarbonyl group, an alkylamino group, etc.).
- the aryl group may be a single ring or a condensed ring, and examples thereof include a phenyl group and a naphthyl group.
- the number of double bonds contained in the alkenyl group is not particularly limited, but is, for example, about 1 to 3 and preferably 1 or 2. The same applies to the alkenyl moiety of the alkyloxycarbonylalkenyl group containing the alkenyl moiety.
- the alkylamino group may be either a monoalkylamino group or a dialkylamino group, and the two alkyl groups present in the dialkylamino group may be the same or different.
- the number, location and type of the substituents present on these groups are not particularly limited. Examples of the substituent include a halogen atom, an alkyl group, an alkoxy group, an aryl group, an amino group, a hydroxy group, and an oxo group.
- the scope of the present invention includes the compounds of the present invention in free form, as well as salts of the above compounds, preferably physiologically acceptable salts.
- the form of the salt is not particularly limited.
- the compound of the formula (I) may form a sodium salt with a phenolic hydroxyl group.
- the scope of the present invention includes hydrates or solvates of the above compounds or salts thereof.
- preferred compounds are the compounds represented by the above formulas (II) and (III).
- the compound represented by the formula (II) may be referred to as RKB-3564S
- the compound represented by the formula (III) may be referred to as RKB-3564SAC.
- the compounds represented by the formulas (I) to (III) of the present invention can be separated and collected from a culture of a microorganism, or can be separated from a culture of a microorganism to start the compound of the present invention. It can be produced by a method of performing chemical modification as a raw material.
- Examples of the microorganism that can produce the compound of the present invention include BAUA3564 strain belonging to filamentous fungi.
- the microorganism is cultured under a commonly used medium composition and culture conditions, and the compound of the present invention contained in the culture can be separated and collected.
- any of a synthetic medium and a natural medium can be suitably used as long as it contains a carbon source, a nitrogen source and an inorganic salt. If necessary, benemins or other nutrients may be added as appropriate.
- Examples of the carbon source include sugars such as glucose, maltose, fructose, sucrose and starch, alcohols such as glycerol and mannitol, amino acids such as glycine, alanine and asparagine, soybean oil, and olive oil.
- One or more kinds may be appropriately selected and used from common carbon sources such as oils and fats such as oils in consideration of the assimilation of microorganisms.
- Examples of the nitrogen source include organic nitrogen-containing compounds such as soybean flour, corn starch, beef kiss, peptone, yeast extract, amino acid mixture, fish meal and the like, and inorganic nitrogen compounds such as ammonium salts and nitrates. In consideration of the above, one or more kinds may be appropriately selected and used.
- inorganic salt for example, calcium carbonate, sodium chloride, potassium chloride, magnesium sulfate, copper sulfate, manganese chloride, zinc sulfate, cobalt chloride, and various phosphates may be added as needed.
- an antifoaming agent for example, vegetable fat, polypropylene alcohol and the like can be added as needed.
- the cultivation temperature can be appropriately changed within a range in which the microorganism grows and the compound of the present invention is efficiently produced, but is preferably 10 to 32 ° C, more preferably 20 to 25 ° C.
- the pH at the start of culturing is preferably around 6 to 8, and the culturing time is usually about several days to several weeks.
- the culture may be terminated when the production amount of the compound of the present invention reaches a retrievable amount, preferably when it reaches the maximum. Any culturing method can be suitably used as long as it is a commonly used method such as solid-phase culturing or normal stirring culturing.
- the compound of the present invention can be separated and collected from the culture solution by appropriately using a method generally used for collecting microbial metabolites.
- a method generally used for collecting microbial metabolites For example, various ion-exchange resins, non-ionic adsorption resins, gel filtration chromatography, chromatography using adsorbents such as activated carbon, alumina or silica gel, or separation methods using high-performance liquid chromatography, or crystallization, concentration under reduced pressure, Or frozen Drying means can be used alone, or in appropriate combination, or repeatedly.
- R 1 is - a C0-R 3 compound
- R 1 is an alkyl group or an alkenyl group
- a compound in which R 1 is an alkyl group or an alkenyl group can be obtained by converting a compound in which R 1 is a hydrogen atom by a conventional alkylation using an alkyl halide (eg, methyl iodide) or an aryl halide (eg, propargyl bromide). It can be produced by carrying out an alkenylation reaction.
- R 2 is a formyl group or a carboxyl group can be produced by performing a usual oxidation reaction.
- the compound in which R 2 is —CH 2 —0C0R 4 (wherein R 4 is as described above) can be produced by subjecting a compound in which R 2 is hydroxymethyl to a usual esterification reaction.
- a compound in which -R 2 is CH 2 -0-R 5 (wherein R 5 is as defined above) can be produced by subjecting a compound in which R 2 is hydroxymethyl to a conventional alkylation reaction.
- Compound After converting the compounds wherein R 2 is hydroxymethyl to R2 Gaho mill group It can be produced by reacting hydroxyamine or the like.
- a compound in which R 2 is —CH 2 CHCH—R 7 (wherein R 7 is as described above) is obtained by converting a compound in which R 2 is hydroxymethyl into R 2 into a formyl group. It can be produced by subjecting it to a usual W tig reaction. In the above reaction, reaction conditions, reaction reagents, and the like can be appropriately selected by those skilled in the art.
- the compounds of the present invention exhibit excellent antitumor activity in hypoxic conditions, as described in the experimental examples described below. Therefore, the compounds of the present invention can be used not only for antitumor drugs, but also for anti-inflammatory drugs, It is useful as an inhibitor, a medicament for preventing and / or treating various diseases caused by hypoxia.
- diseases caused by hypoxia include so-called “angiogenesis”, in which abnormal angiogenesis promoted by hypoxia is deeply involved in the pathology, and specifically, psoriasis, Rheumatoid arthritis, rheumatoid arthritis, diabetes, myocardial infarction, ulcerative colitis, ocular diseases such as neovascular glaucoma, arteriosclerosis, diabetic vascular complications, diabetic retinopathy, etc.
- the medicament of the present invention can also be used as an inhibitor of angiogenesis in a tumor.
- the administration method, dosage form, or dosage of the medicament of the present invention can be appropriately determined depending on the purpose of use.
- the dosage form of the medicament of the present invention may be oral or parenteral.
- the form of the medicament of the present invention is not particularly limited, for example, oral administration preparations such as powders, powders, granules, tablets, capsules, pills, and solvents; And the like. These preparations can be mixed with excipients, binders, wetting agents, disintegrants, lubricants, and other pharmaceutical additives as appropriate for the dosage form, and prepared as a pharmaceutical composition by a known method. can do. In the case of injections, they should be sterilized with a suitable carrier to produce the preparation.
- Dosage will also depend on the condition of the disease, the route of administration, the age or weight of the patient, and will ultimately be left to the discretion of the physician, but for oral administration to adults, usually 0.1 to: I00mg / kg Per day, preferably 1-20 mg / kg / day, when administered parenterally, usually 0.01-10 mg / kg / day, preferably 0.1-2 mg / kg / day. It may be administered once or divided into several doses.
- the compound of the present invention when used as a reagent, it can be used by dissolving it in an organic solvent or a water-containing organic solvent.
- an organic solvent or a water-containing organic solvent For example, direct administration to various cultured cancer cell lines under hypoxic conditions can suppress cell growth.
- usable organic solvents include, for example, methanol and dimethyl sulfoxide.
- the dosage form include a solid agent such as a powder, and a liquid agent dissolved in an organic solvent or a water-containing organic solvent.
- the effective amount of the above compound used as a reagent to exert a cancer cell growth inhibitory effect under hypoxic conditions is 0.1.
- the appropriate amount to be used varies depending on the type of the cultured cell system and the purpose of use, and can be appropriately selected. Examples in which the amount outside the above range cannot be used if necessary
- the culture solution was separated into cells and supernatant using a centrifuge, and the supernatant was adjusted to pH 7.0 and extracted with 15 liters of ethyl acetate. After the extraction, all the ethyl acetates were combined and concentrated under reduced pressure to obtain 5.3 g of a brown syrup.
- This syrup was dissolved in 10 ml of black-mouthed form and infiltrated into a silica gel column (4 cm in diameter and 60 cm in length) packed with black-mouthed form. First, elution was performed with 600 ml of black-mouthed form, and then a mixture of black-form-methanol solutions (100: 1, 50: 1, 20: 1, 10: 1, 5: 1, 1: 1) with different proportions was added. Elution was performed in 600 ml increments.
- Solubility Easily soluble in methanol and dimethyl sulfoxide. Insoluble in n-hexane.
- RKB-3564S and MB-3564SAC of the present invention show a remarkable cell killing effect under cultivation of tumor cells under hypoxic conditions and are effective as antitumor agents.
- RKB-3564S and RKB-3564SAC of the present invention are effective as anti-inflammatory agents, anti-tumor agents, immunosuppressants and the like.
- the powdered glucose 5 was added thereto so as to contain 10 mg of RKB-3564S or RKB-3564SAC, aseptically distributed and sealed in vials, sealed with an inert gas such as nitrogen or helium, and stored in a cool and dark place. Before use, dissolve in ethanol, add 100 ml of 0.85% physiological saline to give an intravenous injection, and administer 10 to 100 ml per day by intravenous injection or drip depending on symptoms.
- the compounds of the present invention have excellent antitumor activity in hypoxic conditions. Therefore, the compounds of the present invention include antitumor agents, especially antitumor agents against solid tumors in which the inside is hypoxic and the antitumor agents are considered to be ineffective, as well as anti-inflammatory agents, immunosuppressants, It is useful as a medicament for preventing and / or treating various diseases caused by oxygen status, and as an active ingredient of an inhibitor of angiogenesis in tumors.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/498,341 US7528169B2 (en) | 2001-12-17 | 2002-12-16 | Substance having antitumor/anti-inflammatory activity |
EP02790777A EP1464636B1 (en) | 2001-12-17 | 2002-12-16 | Novel substance having antitumor/anti-inflammatory activity |
DE60221045T DE60221045D1 (de) | 2001-12-17 | 2002-12-16 | Neue substanz mit antitumorwirkung/entzündungshemmender wirkung |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2001/382539 | 2001-12-17 | ||
JP2001382539A JP3942422B2 (ja) | 2001-12-17 | 2001-12-17 | 抗腫瘍・抗炎症作用を有する新規物質 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2003051804A1 true WO2003051804A1 (fr) | 2003-06-26 |
Family
ID=19187493
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2002/013124 WO2003051804A1 (fr) | 2001-12-17 | 2002-12-16 | Nouvelle substance ayant une activite antitumorale et anti-inflammatoire |
Country Status (6)
Country | Link |
---|---|
US (1) | US7528169B2 (ja) |
EP (1) | EP1464636B1 (ja) |
JP (1) | JP3942422B2 (ja) |
AT (1) | ATE366234T1 (ja) |
DE (1) | DE60221045D1 (ja) |
WO (1) | WO2003051804A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006016143A1 (en) * | 2004-08-09 | 2006-02-16 | Cancer Research Technology Limited | Alpha-ketoglutarates and their use as therapeutic agents |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP5523760B2 (ja) * | 2009-07-31 | 2014-06-18 | 株式会社ダイセル | アルコール性水酸基含有アリールエステルの製造法 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL109161A0 (en) * | 1993-03-31 | 1994-06-24 | Cell Therapeutics Inc | Amino alcohol derivatives, methods for the preparation thereof, and pharmaceutical compositions containing the same |
AR030689A1 (es) | 2000-03-14 | 2003-09-03 | Smithkline Beecham Corp | Compuestos de 3-aminosulfonil-2-hidroxifenil urea, composiciones farmaceuticas que los comprenden, y uso de dichos compuestos en la manufactura de medicamentos para tratar enfermedades mediadas por quimioquinas |
-
2001
- 2001-12-17 JP JP2001382539A patent/JP3942422B2/ja not_active Expired - Fee Related
-
2002
- 2002-12-16 AT AT02790777T patent/ATE366234T1/de not_active IP Right Cessation
- 2002-12-16 DE DE60221045T patent/DE60221045D1/de not_active Expired - Lifetime
- 2002-12-16 EP EP02790777A patent/EP1464636B1/en not_active Expired - Lifetime
- 2002-12-16 US US10/498,341 patent/US7528169B2/en not_active Expired - Fee Related
- 2002-12-16 WO PCT/JP2002/013124 patent/WO2003051804A1/ja active IP Right Grant
Non-Patent Citations (2)
Title |
---|
HAMADA Y. ET AL.: "Efficient total synthesis of AI-77-B, a gastroprotective substance from bacillus pumilus AI-77", TETRAHEDRON, vol. 47, no. 40, 1991, pages 8635 - 8652, XP002965207 * |
MALI R.S. ET AL.: "Novel AlCl3 catalyzed syntheses of naturally occurring (+/-) 8-hydroxy-3-methyl-3,4-dihydroisocoumarins", JOURNAL OF THE CHEMICAL SOCIETY, CHEMICAL COMMUNICATIONS, no. 12, 1992, pages 883 - 884, XP002965208 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006016143A1 (en) * | 2004-08-09 | 2006-02-16 | Cancer Research Technology Limited | Alpha-ketoglutarates and their use as therapeutic agents |
JP2008509209A (ja) * | 2004-08-09 | 2008-03-27 | キャンサー・リサーチ・テクノロジー・リミテッド | αケトグルタレート類および治療薬としてのその使用 |
Also Published As
Publication number | Publication date |
---|---|
US20050176824A1 (en) | 2005-08-11 |
ATE366234T1 (de) | 2007-07-15 |
JP2003183205A (ja) | 2003-07-03 |
DE60221045D1 (de) | 2007-08-16 |
US7528169B2 (en) | 2009-05-05 |
EP1464636A4 (en) | 2006-01-11 |
EP1464636B1 (en) | 2007-07-04 |
EP1464636A1 (en) | 2004-10-06 |
JP3942422B2 (ja) | 2007-07-11 |
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