WO2006028342A1 - A novel xanthine oxidase inhibitor and a pharmaceutical composition containing the same - Google Patents
A novel xanthine oxidase inhibitor and a pharmaceutical composition containing the same Download PDFInfo
- Publication number
- WO2006028342A1 WO2006028342A1 PCT/KR2005/002933 KR2005002933W WO2006028342A1 WO 2006028342 A1 WO2006028342 A1 WO 2006028342A1 KR 2005002933 W KR2005002933 W KR 2005002933W WO 2006028342 A1 WO2006028342 A1 WO 2006028342A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- xanthine oxidase
- pharmaceutical composition
- decursinol
- hyperuricemia
- oxidase inhibitor
- Prior art date
Links
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 title claims abstract description 15
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 15
- 239000003064 xanthine oxidase inhibitor Substances 0.000 title claims abstract description 15
- 201000001431 Hyperuricemia Diseases 0.000 claims abstract description 26
- 208000017169 kidney disease Diseases 0.000 claims abstract description 13
- 201000005569 Gout Diseases 0.000 claims abstract description 11
- 239000004480 active ingredient Substances 0.000 claims abstract description 11
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 9
- BGXFQDFSVDZUIW-UHFFFAOYSA-N Decursinol Natural products O1C(=O)C=CC2=C1C=C1OC(C)(C)C(O)CC1=C2 BGXFQDFSVDZUIW-UHFFFAOYSA-N 0.000 claims description 36
- BGXFQDFSVDZUIW-LBPRGKRZSA-N decursinol Chemical compound O1C(=O)C=CC2=C1C=C1OC(C)(C)[C@@H](O)CC1=C2 BGXFQDFSVDZUIW-LBPRGKRZSA-N 0.000 claims description 36
- 240000001810 Angelica gigas Species 0.000 claims description 6
- 235000018865 Angelica gigas Nutrition 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 239000000284 extract Substances 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 abstract description 7
- 230000000694 effects Effects 0.000 description 20
- 108010093894 Xanthine oxidase Proteins 0.000 description 17
- 102100033220 Xanthine oxidase Human genes 0.000 description 17
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- 241000700159 Rattus Species 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
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- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 7
- 229940116269 uric acid Drugs 0.000 description 7
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- 206010010904 Convulsion Diseases 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
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- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- UIERETOOQGIECD-UHFFFAOYSA-N Angelic acid Natural products CC=C(C)C(O)=O UIERETOOQGIECD-UHFFFAOYSA-N 0.000 description 1
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
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- 108010010803 Gelatin Proteins 0.000 description 1
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- 239000004471 Glycine Substances 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 241000011102 Thera Species 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
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- 150000004781 alginic acids Chemical class 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- UIERETOOQGIECD-ARJAWSKDSA-N angelic acid Chemical compound C\C=C(\C)C(O)=O UIERETOOQGIECD-ARJAWSKDSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 208000015337 arteriosclerotic cardiovascular disease Diseases 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
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- 239000003086 colorant Substances 0.000 description 1
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- 230000001419 dependent effect Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
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- -1 etc. Chemical class 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
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- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
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- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
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- 235000012054 meals Nutrition 0.000 description 1
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- 238000002156 mixing Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229950000193 oteracil Drugs 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
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- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
- A61K31/37—Coumarins, e.g. psoralen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
Definitions
- the present invention relates to a novel xanthine oxidase inhibitor, a phar ⁇ maceutical composition for preventing or treating hyperuricemia comprising the same inhibitor as an active ingredient, and a pharmaceutical composition for preventing or treating gout, cardiovascular diseases, renal diseases and preecalampsia, caused by hy ⁇ peruricemia, comprising the same inhibitor as an active ingredient.
- Xanthine oxidase is an enzyme producing uric acid.
- a rapid increase of uric acid in the human body results in hyperuricemia, which causes gout.
- hyperuricemia is related with various cardiovascular diseases and renal diseases (Alderman and Aiyer, 2004; CurrMedRes Opin, 20, 369-379, 2004).
- hyperuricemia is related with preecalampsia (Lam C et al., Uric Acid and preecalampsia, Semin Nephrol.,2005 Jan; 25(l):56-60).
- an object of the present invention is to provide a novel xanthine oxidase inhibitor, a pharmaceutical composition for preventing or treating hyperuricemia comprising the same inhibitor as an active ingredient, and a pharmaceutical composition for preventing or treating gout, cardiovascular diseases, renal diseases and preecalampsia, caused by hyperuricemia.
- FlG. 1 is a graph showing the reduction effect by decursinol on mortality of the mice in which xanthine oxidase was administrated into their cerebral ventricle.
- FlG. 2 is a graph showing the inhibition effect of decursinol on the activity of xanthine oxidase.
- FlG. 3 is a graph showing a significant drop in concentration of uric acid in blood, resulting from administration of decursinol, of the rats suffering from hyperuricemia.
- FlG. 4 is a graph showing a significant drop of albuminuria, resulting from admin ⁇ istration of decursinol, in the rats suffering from hyperuricemia. Best Mode for Carrying Out the Invention
- a novel xanthine oxidase inhibitor comprising decursinol represented by the following formula I or a derivative thereof, a pharmaceutical composition for preventing or treating hyperuricemia comprising the same inhibitor as an active ingredient, and a pharmaceutical composition for preventing or treating gout, cardiovascular diseases, renal diseases and preecalampsia, caused by hyperuricemia, comprising the same inhibitor as an active ingredient.
- each [12] R' independently represents a hydrogen atom, methyl group, phenyl group or isopropyl group; and each R" independently represents a hydrogen atom, or the two R" in combination represent OH group or
- decursinol and a derivative thereof may be in the form of S(+)-isomer as well as R(-)-isomer.
- Decursinol whose use as xanthine oxidase inhibitor has been identified for the first time according to the present invention, can be obtained by a chemical synthesis process, according to Cairns, N et al., D.P.J. Chem. Commun., 1264 (1986); W.Can., J.Chem., 49, 2297 (1971); and Jacobsen, E.N. et al., J. Am. Chem. Soc, 113, 7063 (1991); Han, H. et al., Tetrahedron Lett, 42, 4001 (2001); and Kim, S. et al., Tetrahedron Lett., 42, 7641 (2001). It can be also obtained by extraction from Angelica gigas, according to Phytochemistry, 30, 710-712 (1991), followed by isolation and pu- rif ⁇ cation.
- Decursinol may be used in the form of a pharmaceutically acceptable salt thereof.
- Examples of pharmaceutically acceptable salts of decursinol include, but are not limited to, salts with inorganic bases such as sodium, potassium, magnesium, calcium, etc., and salts with organic bases such as lysine, ethanolamine, N, N'-dibenzylethylenediamine, angelic acid, etc.
- Decursinol and derivatives thereof have excellent effect for inhibiting xanthine oxidase.
- such compounds significantly and efficiently reduce mice death caused by administration of xanthine oxidase into their cerebral ventricle, and remarkably inhibit the activity of xanthine oxidase as demonstrated by measurements of xanthine oxidase activity. Therefore, it is possible to efficiently prevent or treat hy ⁇ peruricemia, and gout, cardiovascular diseases, renal diseases and preecalampsia caused by hyperuricemia, by using the compounds.
- Cardiovascular diseased caused by hyperuricemia include hypertension and arteriosclerotic cardiovascular diseases.
- Renal diseases caused by hyperuricemia include uric acid nephropathy, gouty nephropathy, hypertensive (accompanied with hyperuricemia) nephropathy and renal failure.
- the pharmaceutical composition according to the present invention can be formulated in various types for parenteral or oral administration.
- repre ⁇ sentative formulations for parenteral administration include isotonic aqueous solutions or suspensions as injection formulations.
- representative formulations for oral administration include tablets or capsules.
- Such formulations may further include a diluent such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, or a lubricator such as silica, talc, stearic acid and a magnesium or calcium salt thereof, and/or polyethylene glycol, in addition to the effective ingredient.
- the tablets may further include a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine.
- a disintegrating agent such as starch, agar, alginic acid or sodium salts thereof, or boiling mixture and/or an absorbent, a coloring agent, a flavoring agent, and a sweetening agent.
- the for ⁇ mulations are generally prepared by mixing, granulating or coating.
- the pharmaceutical composition according to the present invention is sterilized and/or may further include additives such as a preservative, a stabilizer, a hydrator or emulsion accelerator, an osmosis controlling salt and/or a buffering agent, and thera ⁇ Therapeuticically useful materials, and may be formulated by well known methods in the art.
- decursinol or derivatives thereof can be administered by parenteral or oral routes once or more times daily in an amount of 1 to 100 mg/kg(body weight) for mammals including humans.
- Example 1 Test for effect of decursinol on mortality of the mice caused by admin- istration of xanthine oxidase into their cerebral ventricle
- DMSO dimethyl sulfoxide
- mice of the control group shows the survival ratio of 0% after 12 minutes, while the group treated with decursinol shows the increased survival ratio.
- the mice of the treated group, to which 100 mg (decursinol)/kg was administered shows the survival ratio of 67%.
- Example 2 Test for inhibition effect of decursinol on the activity of xanthine oxidase
- Rat models suffering from hyperuricemia were prepared by providing twelve female rats (Sprague-Dawley rats: body weight 200 ⁇ 250g) with meal containing 2% of oxonic acid.
- decursinol according to the present invention has excellent effect of treating hyperuricemia, and also has effects of treating gout, cardiovascular diseases, renal diseases and preecalampsia, caused by hyperuricemia.
- a novel xanthine oxidase inhibitor of the present invention comprising decursinol or derivatives thereof remarkably inhibit the activity of xanthine oxidase inhibitor.
- a pharmaceutical composition comprising the same inhibitor as an active ingredient prevents and treats hyperuricemia, and gout, cardiovascular diseases, renal diseases and preecalampsia, caused by hyperuricemia.
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- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Physical Education & Sports Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The present invention relates to a novel xanthine oxidase inhibitor, a pharmaceutical composition for preventing or treating hyperuricemia comprising the same inhibitor as an active ingredient. In addition, the present invention also relates to a pharmaceutical composition for preventing or treating gout, cardiovascular diseases, renal diseases and preecalampsia, caused by hyperuricemia.
Description
Description
A NOVEL XANTHINE OXIDASE INHIBITOR AND A PHAR¬ MACEUTICAL COMPOSITION CONTAINING THE SAME
Technical Field
[1] The present invention relates to a novel xanthine oxidase inhibitor, a phar¬ maceutical composition for preventing or treating hyperuricemia comprising the same inhibitor as an active ingredient, and a pharmaceutical composition for preventing or treating gout, cardiovascular diseases, renal diseases and preecalampsia, caused by hy¬ peruricemia, comprising the same inhibitor as an active ingredient. Background Art
[2] Xanthine oxidase is an enzyme producing uric acid. A rapid increase of uric acid in the human body results in hyperuricemia, which causes gout. According to recent studies, hyperuricemia is related with various cardiovascular diseases and renal diseases (Alderman and Aiyer, 2004; CurrMedRes Opin, 20, 369-379, 2004). Also, hyperuricemia is related with preecalampsia (Lam C et al., Uric Acid and preecalampsia, Semin Nephrol.,2005 Jan; 25(l):56-60).
[3] Heretofore, allopurinol has been used in order to treat hyperuricemia and gout, car¬ diovascular diseases and renal diseases, resulting from hyperuricemia, by inhibiting the activity of xanthine oxidase. However, allopurinol causes severe side effects and is limited extremely in use. Disclosure of Invention Technical Solution
[4] Therefore, an object of the present invention is to provide a novel xanthine oxidase inhibitor, a pharmaceutical composition for preventing or treating hyperuricemia comprising the same inhibitor as an active ingredient, and a pharmaceutical composition for preventing or treating gout, cardiovascular diseases, renal diseases and preecalampsia, caused by hyperuricemia. Brief Description of the Drawings
[5] FlG. 1 is a graph showing the reduction effect by decursinol on mortality of the mice in which xanthine oxidase was administrated into their cerebral ventricle.
[6] FlG. 2 is a graph showing the inhibition effect of decursinol on the activity of xanthine oxidase.
[7] FlG. 3 is a graph showing a significant drop in concentration of uric acid in blood, resulting from administration of decursinol, of the rats suffering from hyperuricemia.
[8] FlG. 4 is a graph showing a significant drop of albuminuria, resulting from admin¬ istration of decursinol, in the rats suffering from hyperuricemia.
Best Mode for Carrying Out the Invention
[9] According to the present invention, provided are a novel xanthine oxidase inhibitor comprising decursinol represented by the following formula I or a derivative thereof, a pharmaceutical composition for preventing or treating hyperuricemia comprising the same inhibitor as an active ingredient, and a pharmaceutical composition for preventing or treating gout, cardiovascular diseases, renal diseases and preecalampsia, caused by hyperuricemia, comprising the same inhibitor as an active ingredient.
[10]
(I) [11] wherein R is a hydrogen atom, methyl group, acetyl group, phenyl group,
; each [12] R' independently represents a hydrogen atom, methyl group, phenyl group or isopropyl group; and each R" independently represents a hydrogen atom, or the two R" in combination represent OH group or
λλ
[13] According to the present invention, decursinol and a derivative thereof may be in the form of S(+)-isomer as well as R(-)-isomer.
[14] Decursinol, whose use as xanthine oxidase inhibitor has been identified for the first time according to the present invention, can be obtained by a chemical synthesis process, according to Cairns, N et al., D.P.J. Chem. Commun., 1264 (1986); W.Can., J.Chem., 49, 2297 (1971); and Jacobsen, E.N. et al., J. Am. Chem. Soc, 113, 7063 (1991); Han, H. et al., Tetrahedron Lett, 42, 4001 (2001); and Kim, S. et al., Tetrahedron Lett., 42, 7641 (2001). It can be also obtained by extraction from Angelica gigas, according to Phytochemistry, 30, 710-712 (1991), followed by isolation and pu-
rifϊcation.
[15] Decursinol may be used in the form of a pharmaceutically acceptable salt thereof.
Examples of pharmaceutically acceptable salts of decursinol include, but are not limited to, salts with inorganic bases such as sodium, potassium, magnesium, calcium, etc., and salts with organic bases such as lysine, ethanolamine, N, N'-dibenzylethylenediamine, angelic acid, etc.
[16] Decursinol and derivatives thereof have excellent effect for inhibiting xanthine oxidase. For example, such compounds significantly and efficiently reduce mice death caused by administration of xanthine oxidase into their cerebral ventricle, and remarkably inhibit the activity of xanthine oxidase as demonstrated by measurements of xanthine oxidase activity. Therefore, it is possible to efficiently prevent or treat hy¬ peruricemia, and gout, cardiovascular diseases, renal diseases and preecalampsia caused by hyperuricemia, by using the compounds. Cardiovascular diseased caused by hyperuricemia include hypertension and arteriosclerotic cardiovascular diseases. Renal diseases caused by hyperuricemia include uric acid nephropathy, gouty nephropathy, hypertensive (accompanied with hyperuricemia) nephropathy and renal failure.
[17] Since decursinol and derivatives thereof are contained in Angelica gigas, which has been used as a herb medicine, their safety is as good as proved.
[18] The pharmaceutical composition according to the present invention can be formulated in various types for parenteral or oral administration. Examples of repre¬ sentative formulations for parenteral administration include isotonic aqueous solutions or suspensions as injection formulations. Examples of representative formulations for oral administration include tablets or capsules. Such formulations may further include a diluent such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine, or a lubricator such as silica, talc, stearic acid and a magnesium or calcium salt thereof, and/or polyethylene glycol, in addition to the effective ingredient. The tablets may further include a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine. In some case, the tablets may include a disintegrating agent such as starch, agar, alginic acid or sodium salts thereof, or boiling mixture and/or an absorbent, a coloring agent, a flavoring agent, and a sweetening agent. The for¬ mulations are generally prepared by mixing, granulating or coating.
[19] The pharmaceutical composition according to the present invention is sterilized and/or may further include additives such as a preservative, a stabilizer, a hydrator or emulsion accelerator, an osmosis controlling salt and/or a buffering agent, and thera¬ peutically useful materials, and may be formulated by well known methods in the art.
[20] As an effective component of the inventive composition, decursinol or derivatives thereof can be administered by parenteral or oral routes once or more times daily in an
amount of 1 to 100 mg/kg(body weight) for mammals including humans.
[21] The present invention will now be described in more detail with reference to the following examples. However, the following examples are intended to illustrate the present invention in further detail and should by no means be construed as defining the scope of the invention. Mode for the Invention
[22] Examples
[23] Preparation Example: Purification of Decursinol
[24] 2€ of 80% methanol was added to lkg of chopped rhizome of Angelica gigas, followed by extracting at 40°C for 2 hours repeatedly twice. Resulting extracts were collected, subjected to a reduced-pressure reflux cooling tube to remove water from methanol, and then was dried completely with a reduced-pressure drier to obtain 29Og of extracts of Angelica gigas. Then, the extracts were subjected to high-pressure liquid chromatography (HPLC) to obtain decursinol. HPLC was performed under the following conditions:
[25] Column : Si60 (7D, 250mm X 4mm)
[26] Eluent : n-hexane:ethylacetate = 1:1
[27] Row rate : 1.0 ml/min.
[28] Detector : UV 340nm
[29]
[30] Example 1 : Test for effect of decursinol on mortality of the mice caused by admin- istration of xanthine oxidase into their cerebral ventricle
[31] In general, animals in which xanthine oxidase is administered into their cerebral ventricles have convulsions, resulting in a high mortality ratio. The following experiment was performed to determine the effect of decursinol, which is a novel xanthine oxidase inhibitor according to the present invention, on mortality caused by administration of xanthine oxidase.
[32] Decursinol(DC) obtained from the above Preparation Example was dissolved in
10% dimethyl sulfoxide (DMSO) solution. The resulting solution was orally ad¬ ministered to ICR mice (body weight 25~30g, MJ Ltd.) in a dose of 1, 10 and lOOmg decursinol/kg. After 1 hour of such pretreatment, 35D of xanthine oxidase (Sigma Chemical Co.) was administered into the cerebral ventricles of the mice, thereby causing convulsions. Then, a survival rate was checked every six minutes for 1 hour. Six mice were included per group. The control group was administrated with only 10% DMSO solution in the pretreatment. The results are shown in FIG. 1.
[33] As can be seen from FIG. 1, the mice of the control group shows the survival ratio of 0% after 12 minutes, while the group treated with decursinol shows the increased
survival ratio. Particularly, the mice of the treated group, to which 100 mg (decursinol)/kg was administered, shows the survival ratio of 67%.
[34] Example 2: Test for inhibition effect of decursinol on the activity of xanthine oxidase
[35] The following experiment was performed to determine the inhibition effect of decursinol on the activity of xanthine oxidase. To 0.05M phosphate buffer (pH 7.8) containing 50μM of xanthine and xanthine oxidase, decursinol obtained from the above Preparation Example was added in a concentration of O.lμM, lOμM and ImM, respectively. Then, the production rate of uric acid in each group was measured through variations in absorptivity at 295 nm (Rajagopalan KV, p 21-23, in CRC Handbook of Methods for Oxygen Radical Research, Greenwald RA (editor), 1985, CRC Press). As the control group, 0.5% DMSO solution was used instead of decursinol. Additionally, neither decursinol nor 0.5% DMSO solution was added to the blank group. The results are shown in FIG. 2.
[36] As shown in FIG. 2, the activity of xanthine oxidase was inhibited by all con¬ centration of decursinol including O.lμM of decursinol and the inhibition ratio increased in a concentration-dependent manner. Finally, the activity of xanthine oxidase was inhibited completely at the concentration of ImM of decursinol.
[37]
[38] Example 3: Renal protection effect by decursinol in rats suffering from hype¬ ruricemia
[39] Rat models suffering from hyperuricemia were prepared by providing twelve female rats (Sprague-Dawley rats: body weight 200~250g) with meal containing 2% of oxonic acid.
[40] Then, six rats of them were orally administered with decursinol (dissolved in 10%
DMSO) at 100 mg/kg/day (test group), while the remaining six rats were administered orally with 10% DMSO free from decursinol (control group). Concentration of uric acid in blood and concentration of protein in urine (albuminuria) were measured with the lapse of time (1, 2 and 4 weeks), and the average values were shown in FIGs. 3 and 4, respectively.
[41] As can be seen from FIG. 3, the rats administered with decursinol showed a significant drop in concentration of uric acid in blood, from 2 weeks after the treatment. Additionally, the rats administered with decursinol showed a significant drop in albuminuria compared to the control group (see FIG. 4). Accordingly, it can be believed that decursinol according to the present invention has excellent effect of treating hyperuricemia, and also has effects of treating gout, cardiovascular diseases, renal diseases and preecalampsia, caused by hyperuricemia.
Industrial Applicability
[42] A novel xanthine oxidase inhibitor of the present invention comprising decursinol or derivatives thereof remarkably inhibit the activity of xanthine oxidase inhibitor. In addition, a pharmaceutical composition comprising the same inhibitor as an active ingredient prevents and treats hyperuricemia, and gout, cardiovascular diseases, renal diseases and preecalampsia, caused by hyperuricemia.
Claims
[1] A novel xanthine oxidase inhibitor comprising decursinol represented by the following formula I or a derivative thereof:
Tϊ
, or
I o
R' independently represents a hydrogen atom, methyl group, phenyl group or isopropyl group; and each R" independently represents a hydrogen atom, or the two R" in combination represent OH group or
[2] A pharmaceutical composition comprising the xanthine oxidase inhibitor according to claim 1 as an active ingredient, for preventing or treating hype¬ ruricemia.
[3] A pharmaceutical composition comprising the xanthine oxidase inhibitor according to claim 1 as an active ingredient, for preventing or treating gout, car¬ diovascular diseases, renal diseases and preecalampsia, caused by hyperuricemia.
[4] A pharmaceutical composition comprising the extracts of of Angelica gigas containing the xanthine oxidase inhibitor according to claim 1 as an active ingredient, for preventing or treating hyperuricemia.
[5] A pharmaceutical composition comprising the extracts of of Angelica gigas containing the xanthine oxidase inhibitor according to claim 1 as an active ingredient, for preventing or treating gout, cardiovascular diseases, renal diseases and preecalampsia, caused by hyperuricemia.
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|---|---|---|---|
| KR10-2004-0070902 | 2004-09-06 | ||
| KR20040070902 | 2004-09-06 |
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|---|---|
| WO2006028342A1 true WO2006028342A1 (en) | 2006-03-16 |
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|---|---|---|---|
| PCT/KR2005/002933 WO2006028342A1 (en) | 2004-09-06 | 2005-09-05 | A novel xanthine oxidase inhibitor and a pharmaceutical composition containing the same |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2101761A1 (en) * | 2006-11-13 | 2009-09-23 | Takeda Pharmaceuticals North America | Methods for preserving renal function using xanthine oxidoreductase inhibitors |
| WO2010074453A2 (en) * | 2008-12-23 | 2010-07-01 | 한국생명건강(주) | Composition for treating gout, containing angelica gigas extract having a xanthine oxidase-inhibiting effect and an inflammation-inducing enzyme-inhibiting effect |
| CN102688340A (en) * | 2012-06-28 | 2012-09-26 | 张祥明 | Chinese medicine composition for treating gout |
| US8841333B2 (en) | 2005-05-09 | 2014-09-23 | Takeda Pharmaceuticals U.S.A., Inc. | Methods for treating nephrolithiasis |
| US9107912B2 (en) | 2010-09-10 | 2015-08-18 | Takeda Pharmaceuticals U.S.A., Inc. | Methods for concomitant treatment of theophylline and febuxostat |
| CN115154538A (en) * | 2022-08-02 | 2022-10-11 | 无限极（中国）有限公司 | Traditional Chinese medicine composition with blood uric acid reducing effect and application thereof |
-
2005
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8841333B2 (en) | 2005-05-09 | 2014-09-23 | Takeda Pharmaceuticals U.S.A., Inc. | Methods for treating nephrolithiasis |
| EP2101761A1 (en) * | 2006-11-13 | 2009-09-23 | Takeda Pharmaceuticals North America | Methods for preserving renal function using xanthine oxidoreductase inhibitors |
| EP2101761A4 (en) * | 2006-11-13 | 2010-01-27 | Takeda Pharmaceuticals North A | Methods for preserving renal function using xanthine oxidoreductase inhibitors |
| JP2010509372A (en) * | 2006-11-13 | 2010-03-25 | タケダ・フアーマシユーテイカルズ・ノース・アメリカ・インコーポレイテツド | Method for maintaining renal function using xanthine oxidoreductase inhibitor |
| WO2010074453A2 (en) * | 2008-12-23 | 2010-07-01 | 한국생명건강(주) | Composition for treating gout, containing angelica gigas extract having a xanthine oxidase-inhibiting effect and an inflammation-inducing enzyme-inhibiting effect |
| WO2010074453A3 (en) * | 2008-12-23 | 2010-09-23 | 한국생명건강(주) | Composition for treating gout, containing angelica gigas extract having a xanthine oxidase-inhibiting effect and an inflammation-inducing enzyme-inhibiting effect |
| US20110262567A1 (en) * | 2008-12-23 | 2011-10-27 | Korea Bio Health Co., Ltd. | Composition for treating gout, containing angelica gigas extract having a xanthine oxidase-inhibiting effect and an inflammation-inducing enzyme-inhibiting effect |
| JP2012513458A (en) * | 2008-12-23 | 2012-06-14 | 韓国生命健康株式会社 | A composition for treating gout comprising an extract of Hantoki which has an inhibitory effect on xanthine oxidase and an inhibitory effect on inflammation-inducing enzyme |
| US9107912B2 (en) | 2010-09-10 | 2015-08-18 | Takeda Pharmaceuticals U.S.A., Inc. | Methods for concomitant treatment of theophylline and febuxostat |
| CN102688340A (en) * | 2012-06-28 | 2012-09-26 | 张祥明 | Chinese medicine composition for treating gout |
| CN115154538A (en) * | 2022-08-02 | 2022-10-11 | 无限极（中国）有限公司 | Traditional Chinese medicine composition with blood uric acid reducing effect and application thereof |
| CN115154538B (en) * | 2022-08-02 | 2023-05-05 | 无限极（中国）有限公司 | Traditional Chinese medicine composition with blood uric acid reducing effect and application thereof |
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