JP2001505940A - 抗増殖活性を有する新規な酪酸エステルおよびこれを含む薬剤組成物 - Google Patents
抗増殖活性を有する新規な酪酸エステルおよびこれを含む薬剤組成物Info
- Publication number
- JP2001505940A JP2001505940A JP52427698A JP52427698A JP2001505940A JP 2001505940 A JP2001505940 A JP 2001505940A JP 52427698 A JP52427698 A JP 52427698A JP 52427698 A JP52427698 A JP 52427698A JP 2001505940 A JP2001505940 A JP 2001505940A
- Authority
- JP
- Japan
- Prior art keywords
- butyrate
- polysaccharide
- acid
- ester
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 title claims abstract description 47
- 230000001028 anti-proliverative effect Effects 0.000 title claims abstract description 30
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
- 229920001282 polysaccharide Polymers 0.000 claims abstract description 79
- 239000005017 polysaccharide Substances 0.000 claims abstract description 79
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- 150000002148 esters Chemical class 0.000 claims abstract description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 14
- 150000002338 glycosides Chemical class 0.000 claims abstract description 10
- 229930182470 glycoside Natural products 0.000 claims abstract description 6
- 239000000178 monomer Substances 0.000 claims abstract description 5
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- 229920002674 hyaluronan Polymers 0.000 claims description 43
- 229960003160 hyaluronic acid Drugs 0.000 claims description 43
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical group CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 42
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 229920001503 Glucan Polymers 0.000 claims description 7
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 claims description 7
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- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 claims description 3
- AEMOLEFTQBMNLQ-UHFFFAOYSA-N beta-D-galactopyranuronic acid Natural products OC1OC(C(O)=O)C(O)C(O)C1O AEMOLEFTQBMNLQ-UHFFFAOYSA-N 0.000 claims description 3
- 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 claims description 3
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 241001099105 Grateloupia doryphora Species 0.000 claims description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 2
- 229920001499 Heparinoid Polymers 0.000 claims description 2
- IAJILQKETJEXLJ-SQOUGZDYSA-N L-guluronic acid Chemical compound O=C[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O IAJILQKETJEXLJ-SQOUGZDYSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-JFNONXLTSA-N L-mannopyranose Chemical compound OC[C@@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O WQZGKKKJIJFFOK-JFNONXLTSA-N 0.000 claims description 2
- SRBFZHDQGSBBOR-OWMBCFKOSA-N L-ribopyranose Chemical compound O[C@H]1COC(O)[C@@H](O)[C@H]1O SRBFZHDQGSBBOR-OWMBCFKOSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- PNNNRSAQSRJVSB-BXKVDMCESA-N aldehydo-L-rhamnose Chemical compound C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O PNNNRSAQSRJVSB-BXKVDMCESA-N 0.000 claims description 2
- 239000000783 alginic acid Substances 0.000 claims description 2
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- 150000004781 alginic acids Chemical class 0.000 claims description 2
- AEMOLEFTQBMNLQ-WAXACMCWSA-N alpha-D-glucuronic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-WAXACMCWSA-N 0.000 claims description 2
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- 125000001142 dicarboxylic acid group Chemical group 0.000 claims description 2
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- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
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- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0045—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Galacturonans, e.g. methyl ester of (alpha-1,4)-linked D-galacturonic acid units, i.e. pectin, or hydrolysis product of methyl ester of alpha-1,4-linked D-galacturonic acid units, i.e. pectinic acid; Derivatives thereof
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
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- C08B37/0036—Galactans; Derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
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- Polysaccharides And Polysaccharide Derivatives (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Claims (1)
- 【特許請求の範囲】 1.多糖の酪酸エステルであって、前記多糖のヒドロキシル基が部分的にあるい は全体的に酪酸残基でエステル化されており、グリコシド残基の付加的な遊離 なヒドロキシル基がジカルボン酸残基でエステル化の可能性があることを特徴 とする酪酸エステル。 2.前記多糖はグリコシド環の炭素原子上に低級アルキル基、−NH2,−NH −COR,−OSO3H,−OPO3H2,−COOH,−COO−(CH2)n −COOH,−COOR,−COR,−ORおよび−O−(CH2)n−O−C OR(ここで、n=1〜4およびR=C1〜C10のアルキル基である)からな る群から選択される少なくとも1つの置換基を有することを特徴とする請求項 1記載の酪酸エステル。 3.グリコシド残基の前記遊離なヒドロキシル基が1またはそれ以上のジカルボ ン酸C2〜C9でエステル化されることを特徴とする請求項1記載の酪酸エステ ル。 4.前記ジカルボン酸がコハク酸、酒石酸、リンゴ酸、およびアゼライン酸から なる群から選択されることを特徴とする請求項3記載の酪酸エステル。 5.酪酸残基でエステル化されたヒドロキシル基の、各グリコシド単量体に対す る数が0.001より多いことを特徴とする請求項1記載の酪酸エステル。 6.酪酸残基でエステル化されたヒドロキシル基の前記数が0.001〜3の範 囲であることを特徴とする請求項5記載の酪酸エステル。 7.酪酸残基でエステル化されたヒドロキシル基の前記数が0.01〜1の範囲 であることを特徴とする請求項6記載の酪酸エステル。 8.前記酪酸エステルの平均分子量が2×103より大きいことを特徴とする請 求項1記載の酪酸エステル。 9.前記酪酸エステルの平均分子量が1×104〜5×106の範囲であることを 特徴とする請求項8記載の酪酸エステル。 10.前記多糖が直線状または分岐状であり、D−グルコース、D−リボース、 D−グロース、D−キシロース、D−アラビノース、D−およびL−マンノー ス、D−ガラクトース、L−フコース、L−ラムノース、D−ウロン酸、D− グルクロン酸、D−マンヌロン酸、L−グルロン酸、およびD−ガラクツロン 酸からなる群から選択されるグリコシド残基を含むことを特徴とする請求項1 記載の酪酸エステル。 11.前記多糖はβ−(1→3)グリコシド結合、β−(1→4)−D−グリコ シド結合、α−(1→3)グリコシド結合、α−(1→4)グリコシド結合、 またはα−(1→6)グリコシド結合を有する主骨格を有し、およびβ−(1 →3)、β−(1→4)、β−(1→6)またはα−(1→4)結合で結合さ れたD−グリコシド残基からなる側鎖を有することを特徴とする請求項1記載 の酪酸エステル。 12.前記多糖が中性であることを特徴とする請求項1記載の酪酸エステル。 13.前記中性の多糖がグルカンであることを特徴とする請求項12記載の酪酸 エステル。 14.前記グルカンがβ−(1→3)およびβ−(1→6)グルコシド残基を含 むことを特徴とする請求項13記載の酪酸エステル。 15.前記グルカンがスクレログルカンであることを特徴とする請求項14記載 の酪酸エステル。 16.前記多糖が陰性であることを特徴とする請求項1記載の酪酸エステル。 17.前記陰性多糖が硫酸化基および/またはカルボキシル基を含むことを特徴 とする請求項16記載の酪酸エステル。 18.前記陰性多糖がヒアルロン酸、アルギン酸、ペクチン、ムカデノリドリホ ラ(Grateloupia doryphora)から単離された多糖類、ヘパリン、ヘパリノイド およびカラゲナンからなる群から選択されることを特徴とする請求項17記載 の酪酸エステル。 19.請求項1〜18のうちいずれか1項に記載の多糖の酪酸エステルの調製法 であって、前記多糖を酪酸あるいは活性化形態の酪酸で、均一あるいは不均一 な系において、可能な適当な溶媒および/または適当な触媒の存在下で処理す ることを含んで構成される方法。 20.異常に細胞が増殖する疾患を治療または予防するための抗増殖薬剤を製造 するために、請求項1〜18のうちいずれか1項に記載の多糖の酪酸エステル を使用する方法。 21.前記増殖が腫瘍細胞、滑液細胞、または胃腸管の細胞を含むことを特徴と する請求項20記載の使用法。 22.前記酪酸エステルが口、静脈内、腹腔内、筋肉内、関節内、直腸内、膣内 、皮下、または局所を投与経路として投与されることを特徴とする請求項20 記載の使用法。 23.前記酪酸エステルが0.2〜500mg/kg/日の範囲の投与量で、1 〜15日の期間、投与されることを特徴とする請求項20記載の使用法。 24.薬剤組成物であって、活性化合物として、治療的に効果的な量で、請求項 1〜18のうちいずれか1項に記載の少なくとも1つの多糖の酪酸エステルを 、薬剤的に許容される賦形剤および/または希釈剤と組み合わせて含む薬剤組 成物。 25.前記薬剤組成物が顆粒、錠剤、丸薬、またはゲルの形態で経口的に投与可 能であることを特徴とする請求項24記載の薬剤組成物。 26.前記薬剤組成物が全身性、静脈内、腹腔内、関節内、皮下、または筋肉内 を投与経路として、水溶液または懸濁液の形態で、投与できることを特徴とす る請求項24記載の薬剤組成物。 27.前記薬剤組成物がさらに1またはそれ以上の抗腫瘍薬を含むことを特徴と する請求項24記載の薬剤組成物。 28.前記抗腫瘍薬が5−フルオロウラシル、シスプラチン(cisplatin)、およ びシクロホスファミドからなる群から選択されることを特徴とする請求項27 記載の薬剤組成物。
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IT96MI002505A IT1286510B1 (it) | 1996-11-29 | 1996-11-29 | Esteri butirrici ad attivita' antiproliferativa e composizioni farmaceutiche che li contengono |
IT96A002505 | 1996-11-29 | ||
PCT/EP1997/006589 WO1998023648A1 (en) | 1996-11-29 | 1997-11-26 | New butyric esters with antiproliferative activity and the pharmaceutical compositions containing them |
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JP2001505940A true JP2001505940A (ja) | 2001-05-08 |
JP4256475B2 JP4256475B2 (ja) | 2009-04-22 |
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JP52427698A Expired - Lifetime JP4256475B2 (ja) | 1996-11-29 | 1997-11-26 | 抗増殖活性を有する新規な酪酸エステルおよびこれを含む薬剤組成物 |
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US (1) | US6140313A (ja) |
EP (1) | EP0941253B1 (ja) |
JP (1) | JP4256475B2 (ja) |
AT (1) | ATE241648T1 (ja) |
AU (1) | AU5751598A (ja) |
CA (1) | CA2272720C (ja) |
DE (1) | DE69722434T2 (ja) |
IT (1) | IT1286510B1 (ja) |
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JP2010514878A (ja) * | 2006-12-29 | 2010-05-06 | シジェア ソシエタ ア レスポンサビリタ リミタータ | 酸性多糖類の誘導体 |
JP2011504950A (ja) * | 2007-11-27 | 2011-02-17 | シジェア ソシエタ ア レスポンサビリタ リミタータ | 酸性多糖の酪酸−ギ酸混合エステル、ならびに肌用化粧品としてのその調製および使用 |
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- 1996-11-29 IT IT96MI002505A patent/IT1286510B1/it active IP Right Grant
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1997
- 1997-11-26 JP JP52427698A patent/JP4256475B2/ja not_active Expired - Lifetime
- 1997-11-26 DE DE69722434T patent/DE69722434T2/de not_active Expired - Lifetime
- 1997-11-26 AT AT97953702T patent/ATE241648T1/de not_active IP Right Cessation
- 1997-11-26 US US09/308,832 patent/US6140313A/en not_active Expired - Lifetime
- 1997-11-26 CA CA002272720A patent/CA2272720C/en not_active Expired - Lifetime
- 1997-11-26 WO PCT/EP1997/006589 patent/WO1998023648A1/en active IP Right Grant
- 1997-11-26 EP EP97953702A patent/EP0941253B1/en not_active Expired - Lifetime
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Cited By (5)
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JP2009510186A (ja) * | 2005-09-26 | 2009-03-12 | ノボザイムス バイオポリマー アクティーゼルスカブ | アリール/アルキル無水琥珀酸ヒアルロナン誘導体 |
JP2010514878A (ja) * | 2006-12-29 | 2010-05-06 | シジェア ソシエタ ア レスポンサビリタ リミタータ | 酸性多糖類の誘導体 |
JP2011504950A (ja) * | 2007-11-27 | 2011-02-17 | シジェア ソシエタ ア レスポンサビリタ リミタータ | 酸性多糖の酪酸−ギ酸混合エステル、ならびに肌用化粧品としてのその調製および使用 |
JP6029155B2 (ja) * | 2012-11-14 | 2016-11-24 | 国立研究開発法人産業技術総合研究所 | β−1,3−グルカン誘導体、及びβ−1,3−グルカン誘導体の製造方法 |
JP2018501385A (ja) * | 2015-01-13 | 2018-01-18 | シジェア ソシエタ ア レスポンサビリタ リミタータ | ヒアルロン酸ナトリウム塩の酪酸エステルの調製のための水中における方法 |
Also Published As
Publication number | Publication date |
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CA2272720A1 (en) | 1998-06-04 |
EP0941253A1 (en) | 1999-09-15 |
EP0941253B1 (en) | 2003-05-28 |
ATE241648T1 (de) | 2003-06-15 |
AU5751598A (en) | 1998-06-22 |
US6140313A (en) | 2000-10-31 |
ITMI962505A1 (it) | 1998-05-29 |
JP4256475B2 (ja) | 2009-04-22 |
CA2272720C (en) | 2008-01-08 |
DE69722434T2 (de) | 2004-04-08 |
IT1286510B1 (it) | 1998-07-15 |
DE69722434D1 (de) | 2003-07-03 |
WO1998023648A1 (en) | 1998-06-04 |
ITMI962505A0 (it) | 1996-11-29 |
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R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
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EXPY | Cancellation because of completion of term |