WO2002083092A1 - Water-in-stable kojic acid derivatives and method for preparing thereof, and whitening cosmetics composition containing the same - Google Patents

Water-in-stable kojic acid derivatives and method for preparing thereof, and whitening cosmetics composition containing the same Download PDF

Info

Publication number
WO2002083092A1
WO2002083092A1 PCT/KR2001/000721 KR0100721W WO02083092A1 WO 2002083092 A1 WO2002083092 A1 WO 2002083092A1 KR 0100721 W KR0100721 W KR 0100721W WO 02083092 A1 WO02083092 A1 WO 02083092A1
Authority
WO
WIPO (PCT)
Prior art keywords
kojic acid
acid derivative
organic solvent
skin
kojic
Prior art date
Application number
PCT/KR2001/000721
Other languages
English (en)
French (fr)
Inventor
Ok Sob Lee
Duk Hee Kim
Yi Seop Jang
Seong Joon Moon
Yeong Cheol Shim
Young Ha Lee
Dong Soon Park
Han Kon Kim
Hak Hee Kang
Heung Soo Baek
Jae Sung Hwang
Original Assignee
Amorepacific Corporation
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Amorepacific Corporation filed Critical Amorepacific Corporation
Priority to EP01928230A priority Critical patent/EP1372594A4/en
Priority to JP2002580896A priority patent/JP2004521936A/ja
Publication of WO2002083092A1 publication Critical patent/WO2002083092A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/345—Alcohols containing more than one hydroxy group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/55—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin

Definitions

  • the present invention relates to a water-in-stable kojic acid derivative represented by the following formula 1 (I) and to a method for preparing the same, and to a skin-whitening cosmetic composition containing the same as an active ingredient: [Formula 1]
  • kojic acid is a ⁇ -pyrone compound isolated from Aspergillus and can chelate with metal ion such as copper ion, to inhibit the activity of tyrosinase, which is an enzyme, involved in the melanin biosynthesis. Therefore, kojic acid can block abnormal pigmentation of the skin.
  • tyrosinase is an enzyme of catalyzing the formation of dopaquinone in a serial process of the melanin biosynthesis: tyrosine -» dopa - dopaquinone - dopachrome -> melanin, and kojic acid inhibits the activity of the tyrosinase by chelating copper ion in the active site of tyrosinase.
  • kojic acid has been used extensively in topical compositions for preventing hyperpigmentation such as moles and freckles.
  • JP 56-18569B, JP 53-3538A and JP 62-59084B disclosed whitening cosmetic compositions containing kojic acid as an active ingredient.
  • JP 54-92632A, JP 58-22152A and JP 60-9722A disclosed whitening cosmetic compositions containing kojic acid derivatives such as kojic mono- or di-fatty acid esters having good properties such as stability, feeling and solubility and improved tyrosinase-inhibiting activity.
  • JP 3-14508A, JP 4-145096A and JP 5-39298A proposed various kojic acid derivatives having a strong tyrosinase-inhibiting activity, such as kojic ethers, glucosylated kojic acids and amino-protected kojic amino acids.
  • an object of the invention is to provide a novel kojic acid derivative or its salts represented by the following formula 1 (I): [Formula 1]
  • Another object of the present invention is to provide a method for preparing said kojic acid derivative.
  • a further object of the present invention is to provide a skin- whitening cosmetic composition which can inhibit melanin-formation and promote fibroblast-proliferation and collagen-biosynthesis, and has good safety to the skin and good stability in cosmetic base.
  • a method for preparing the present kojic acid derivative may comprise the following steps of :
  • step (B) reacting the 2-chlorotetrahydro-2H-l,3,2-oxazaphosphorin P-oxide of step (A) with kojic acid, in an organic solvent, in the presence of a base;
  • step (C) filtering the resultant of step (B), concentrating under reduced pressure, and then hydrolyzing with addition of an acidic solution, at a temperature of 5-100 ° C, for 3-10 hours; and
  • step (D) recrystallizing the product of step (C) with a polar organic solvent, to give kojic acid derivative.
  • said method of the present invention may comprise further step (E) of neutralizing the kojic acid derivative of step (D) with a neutralizer.
  • Said method of the present invention may be schematized by the following reaction scheme 1 :
  • the reaction between 3-amino-l-propanol and phosphorus oxychloride may be performed in an equivalent ratio of 1:1-1.3. In case that the ratio is lower than 1 : 1, the objective product may not be obtained. While, in case that the ratio is higher than 1:1.3, excessive by-products as well as the objective product may be obtained.
  • the method can prevent the production of the 2:1 by-product of 3-amino-l-propanol and phosphorus oxychloride, by reacting 3-amino-l-propanol with phosphorus oxychloride in an equivalent ratio of 1:1-1.3, at a temperature of 0-5 ° C for 1-2 hours.
  • the process can be simple.
  • An organic base employed in said step (A) may be pyridine, triethylamine, etc., and preferably be triethylamine.
  • an organic solvent employed in said step (A) may be an inert solvent such as dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, chloroform, and ethyl ether, and preferably be chloroform.
  • the reaction may be preferably performed at a temperature of 0-5 ° C . If the temperature is higher than 5 ° C, two equivalents or more of 3-amino-l-propanol are substituted to phosphorus oxychloride, resulting in excessive by-products. While, if the temperature is lower than 0 ° C, the solubility of reactant may decrease, resulting that the reaction may proceed slowly and with difficulty. In this case, unreacted materials may increase, to reduce the yield.
  • a base employed in this step (B) may be an organic base such pyridine and triethylamine, as described in above step (A); or an inorganic base such as sodium, sodium hydroxide, potassium hydroxide, etc. Preferably, it may be potassium hydroxide.
  • an organic solvent employed in said step (B) may be an inert solvent such as dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, chloroform, and ethyl ether; or a polar solvent such as methanol, ethanol and propanol. Preferably, it may be methanol.
  • the residue obtained by filtering the resultant of step (B) and then concentrating the filtrate under reduced pressure may be hydrolyzed in the presence of an acidic catalyst such as strong cation exchange resin (Amberlite 15), hydrochloric acid and sulfuric acid as a conventional hydrolysis.
  • an acidic catalyst such as strong cation exchange resin (Amberlite 15), hydrochloric acid and sulfuric acid as a conventional hydrolysis.
  • an acidic solution in case of stirring the compound obtained in above step (B) at a temperature of 5-100 ° C, the P-N bond can be hydrolyzed. Therefore, after filtration and then concentration, hydrolysis may be preferably performed with addition of an acidic solution, at a temperature of 5-100 °C and more preferably of 40 ° C , for about 5 hours. pH of the acidic solution may be in a range of 1-5 and preferably of 2-4.
  • a polar organic solvent employed for recrystallization in this step may be, but not limited thereto, methanol, ethanol, isopropanol, acetone, tetrahydrofuran, acetonitrile or dioxane.
  • Said method may comprise further step (E) of neutralizing the kojic acid derivative obtained in said step (D) to form a salt thereof.
  • the form of salt obtained by neutralization may be salt by alkali metal such as sodium and potassium; salt by alkaline earth metal such as calcium and magnesium; or salt by ammonia or amine such as triethanolamine.
  • a neutralizer employed in this step (E) may be alkali metal salt such as sodium carbonate, sodium hydroxide, potassium carbonate and potassium hydroxide; alkaline earth metal salt such as calcium hydroxide; metal oxide such as calcium oxide and magnesium oxide; basic amino acid such as lysine, arginine and histidine; ammonia or amine such as triethanolamine; cationic polymer such as polyquaternium-4, -6, -7, -10, -11 and -16; and cationic surfactant such as lauryldimethylbenzyl ammonium chloride and stearyldimethylbenzyl ammonium chloride. But, it may not be limited thereto.
  • the obtained kojic 3-aminopropanol phosphoric acid diester (hereinafter, "Kojyl-APPA”) or its salt may be incorporated into a skin-whitening cosmetic composition in an amount of 0.01-10% by weight and preferably of 0.02-4.0% by weight based on the total weight of composition. If the amount is less than 0.01wt%, it may be difficult to obtain aimed effect. While, if the amount is more than 10wt%, there may be no benefit in increase of effect or in stability of formulation.
  • the skin-whitening cosmetic composition of the present invention may be formulated, but not limited thereto, into skin softners, astringents, nutrient toilet water, nutrient creams, massage creams, essences, eye creams, eye essences, cleansing creams, cleansing foams, cleansing water, packs, powders, body lotions, body creams, body essences and the like. And, the composition may further incorporate other ingredients depending on the formulation or the final purposes thereof.
  • 34.1m#(0.36mol) of phosphorus oxychloride was dissolved in 400m# of dichloromethane and then cooled to a temperature of 0-5 ° C in an ice bath.
  • 30m£(0.39mol) of 3-amino-l-propanol and 102m£(0.73--.ol) of triethylamine were diluted with 200m# of dichloromethane and then gradually added to the above solution for 2 hours. After the addition, the resulting mixture was filtered to remove triethylammonium chloride. The filtrate was washed with lOOm of distilled water, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure.
  • Example 3 Preparation of potassium salt of kojic 3-aminopropanol phosphoric acid diester
  • Example 4 Preparation of calcium salt of kojic 3-aminopropanol phosphoric acid diester 1G of Kojyl-APPA obtained in Example 1 was dissolved in 30ml of distilled water, and thereto was added calcium hydroxide, adjusting to pH7. The obtained solution was freeze dried, to give calcium salt of kojic 3-aminopropanol phosphoric acid diester as white powder.
  • the obtained solution was freeze dried, to give magnesium salt of kojic 3-aminopropanol phosphoric acid diester as white powder.
  • Aqueous phase(materials 15-19) and oily phase(materials 1-14) were heated to be dissolved, respectively. Two mixtures were admixed under stirring, and then cooled to room temperature, to produce cosmetics.
  • Oily phase(materials 1-6) was heated to be dissolved and materials 7 and 8 were added and dispersed with homo-mixer.
  • pigment mixture of meterial 8 were prepared by mixing 70.0wt% of titanium dioxide, 20.0wt% of ferric oxide and 10.0wt% of talc and pulverizing twice. Then, aqueous phase(materials 9-11) was heated to be dissolved and then added to said oily phase. After stirring, thereto were added materials 12 and 13 and then emulsified. The emulsion was cooled, to produce cosmetics.
  • the skin obtained from new epidermal tissue was treated with Type 1 collagenase to remove epidermis.
  • the obtained fibroblast was cultured on Dulbecco's modified Eagle's media (DMEM). Amount of fibroblast was measured by way of MTT method. The result indicates that Kojyl-APPA of Example 1 shows an effective fibroblast-proliferation at a concentration as low as 30mM.
  • Kojyl-APPA to the living body toxicity and irritation of Kojyl-APPA to the body were examined through the following experiments.
  • the results indicate that Kojyl-APPA of Example 1 is a safe material without toxicity and irritation as a cosmetic ingredient.
  • Test was performed for twelve (12) of New Zealand White male rabbits whose backs were depilated before 24 hours of the application of the test sample. And, 1.0ml of Kojyl-APPA of Example 1 was diluted with physiological saline to give 50% of test sample. Test sample(0.5m ⁇ per site) was applied to two sites (2.5cmx2.5cm) of the right back which of one is intact skin and the other is abraded skin. As a control, two sites (2.5cmx2.5cm) of the left back were treated with 1.0ml of physiological saline. Each tested site was covered with gauze, which was fixed using a non-irritative tape. 24 Hours later, the tested sites were washed with physiological saline.
  • compositions containing Kojyl-APPA are no irritative to the skin.
  • Kojyl-APPA (Examples 7 and 8) is similar to that of the compositions containing kojyl dipalmitate (Comp. Examples 4 and 9) which is conventional whitening material, while it is slightly less than that of the compositions containing kojic acid (Comp. Examples 2 and 7).
  • the composition containing Kojyl-APPA of Ex. 8 did not cause precipitation or discoloration at 5 ° C and 25 °C and caused only discoloration of pale yellow with naked eye at 45 ° C . It indicates that the compound of the present invention has improved stability, in comparison with kojyl dipalmitate.
  • the kojic acid derivative of the present invention kojic 3-aminopropanol phosphoric acid diester or its salt is very stable in aqueous base and has high purity, to be applied to aqueous cosmetics. And, it can be decomposed to kojic acid having an activity of inhibiting melanin-formation and 3-aminopropanol phosphoric acid having effects on fibroblast-proliferation and collagen-biosynthesis and good safety to the skin. Accordingly, water-in-stable kojic acid derivative of the present invention can be used extensively in skin- whitening and skin aging-preventing cosmetics.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Birds (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Dermatology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Emergency Medicine (AREA)
  • Cosmetics (AREA)
PCT/KR2001/000721 2001-03-09 2001-05-02 Water-in-stable kojic acid derivatives and method for preparing thereof, and whitening cosmetics composition containing the same WO2002083092A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP01928230A EP1372594A4 (en) 2001-03-09 2001-05-02 KOJINIC ACID DERIVATIVES STABLE IN WATER AND METHOD FOR THE PRODUCTION THEREOF, AND THE LIGHTENING COSMETIC COMPOSITIONS CONTAINING THE SAME
JP2002580896A JP2004521936A (ja) 2001-03-09 2001-05-02 水安定型コウジ酸誘導体及びその製造方法、並びにこれを含有する美白化粧料組成物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR2001/12231 2001-03-09
KR10-2001-0012231A KR100376088B1 (ko) 2001-03-09 2001-03-09 3-아미노프로필코질포스페이트 및 그의 염을 함유한미백화장료 조성물

Publications (1)

Publication Number Publication Date
WO2002083092A1 true WO2002083092A1 (en) 2002-10-24

Family

ID=19706688

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2001/000721 WO2002083092A1 (en) 2001-03-09 2001-05-02 Water-in-stable kojic acid derivatives and method for preparing thereof, and whitening cosmetics composition containing the same

Country Status (5)

Country Link
EP (1) EP1372594A4 (ja)
JP (1) JP2004521936A (ja)
KR (1) KR100376088B1 (ja)
CN (1) CN1492755A (ja)
WO (1) WO2002083092A1 (ja)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2924599A1 (fr) * 2007-12-11 2009-06-12 Oreal Composes sulfate ou phosphate de phenol et leur utilisation pour depigmenter la peau
FR2924601A1 (fr) * 2007-12-07 2009-06-12 Oreal Composes diphosphate d'hydroquinone et leur utilisation pour depigmenter la peau.

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100493726B1 (ko) * 2002-07-16 2005-06-03 주식회사 펩트론 코지산 유도체, 그 제조방법 및 용도
KR101056879B1 (ko) * 2005-06-08 2011-08-12 (주)아모레퍼시픽 세사몰 유도체 또는 그의 염, 그의 제조방법, 및 이를함유하는 피부외용제 조성물

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997024124A1 (en) * 1995-12-29 1997-07-10 Smithkline Beecham Corporation Vitronectin receptor antagonists
US6147249A (en) * 1998-05-11 2000-11-14 Shin-Etsu Chemical Co., Ltd. Ester compounds, polymers, resist composition and patterning process

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1986000306A1 (en) * 1982-12-29 1986-01-16 Sansho Seiyaku Co., Ltd. Kojic acid derivatives and whitening cosmetics containing same
JPH0655747B2 (ja) * 1985-06-18 1994-07-27 ポーラ化成工業株式会社 コウジ酸リン酸エステル化合物
KR0141616B1 (ko) * 1995-02-17 1998-06-01 한동근 아미노프로판 인산 또는 그 염을 함유하는 화장료 조성물
KR100187900B1 (ko) * 1996-09-05 1999-06-01 서경배 3-아미노프로판 인산의 제조방법
JP2000344760A (ja) * 1999-05-31 2000-12-12 Nippon Surfactant Kogyo Kk コウジ酸誘導体
KR100320037B1 (ko) * 1999-08-21 2002-01-10 서경배 수안정형 코지산 유도체 및 그의 제조방법
KR100365070B1 (ko) * 2000-08-29 2002-12-16 주식회사 태평양 토코페롤 유도체 및 그의 제조방법

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997024124A1 (en) * 1995-12-29 1997-07-10 Smithkline Beecham Corporation Vitronectin receptor antagonists
US6147249A (en) * 1998-05-11 2000-11-14 Shin-Etsu Chemical Co., Ltd. Ester compounds, polymers, resist composition and patterning process

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1372594A4 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2924601A1 (fr) * 2007-12-07 2009-06-12 Oreal Composes diphosphate d'hydroquinone et leur utilisation pour depigmenter la peau.
FR2924599A1 (fr) * 2007-12-11 2009-06-12 Oreal Composes sulfate ou phosphate de phenol et leur utilisation pour depigmenter la peau

Also Published As

Publication number Publication date
CN1492755A (zh) 2004-04-28
KR100376088B1 (ko) 2003-03-28
KR20020082500A (ko) 2002-10-31
EP1372594A4 (en) 2004-04-07
JP2004521936A (ja) 2004-07-22
EP1372594A1 (en) 2004-01-02

Similar Documents

Publication Publication Date Title
US5916915A (en) Water-in-stable L-ascorbic acid derivative and a method for preparation thereof, and a skin-whitening cosmetic composition containing the same
KR100365070B1 (ko) 토코페롤 유도체 및 그의 제조방법
JP3510627B2 (ja) 酸化性ストレスに対するｎ−アリールメチレンエチレンジアミントリアセテート、ｎ−アリールメチレンイミノジアセテートまたはｎ，ｎ′−ジアリールメチレンエチレンジアミンアセテートの使用
KR20080016948A (ko) 신규 트리테르펜산 유도체 및 이를 포함하는 피부 외용제
JPWO2005092905A1 (ja) アスコルビン酸誘導体および美白化粧料
JP3844866B2 (ja) セラミド類似化合物及びその製造方法並びにこれを含有する化粧料組成物
JP4268872B2 (ja) ３，４，５−トリメトキシフェニル系のエステル化合物及びこれを含有する美白化粧料組成物
US6521662B2 (en) Ceramide-like compounds having antioxidant property and a method for preparation thereof, and a cosmetic composition containing the same
WO2002083092A1 (en) Water-in-stable kojic acid derivatives and method for preparing thereof, and whitening cosmetics composition containing the same
US5523421A (en) Kojic acid derivatives
KR101826747B1 (ko) 신규한 코지산 유도체, 이의 제조 방법 및 이를 유효성분으로 함유하는 피부 미백용 조성물
JP2578394B2 (ja) 美白剤
US5723645A (en) Method for preparing 3-aminopropane phosphoric acid
KR101219281B1 (ko) 젠티식산 유도체 화합물과 그 제조방법 및 이를 함유하는미백화장료 조성물
JP4991088B2 (ja) アスコルビン酸−３リン酸の安定化誘導体
JP4879344B1 (ja) 抗酸化性ポリヒドロキシベンゼン誘導体および抗炎症用皮膚外用剤
US6566545B2 (en) Menthol derivatives and process for preparing the same
KR101625784B1 (ko) 아스코르브산 유도체 조성물 및 그 제조 방법, 아스코르브산 유도체 용액, 피부 외용제
JP6051047B2 (ja) 毛髪用の皮膚外用剤
KR0174165B1 (ko) 3-아미노프로판인산의 제조방법 및 이를 함유하는 화장료 조성물
JP4008172B2 (ja) 皮膚化粧料
JPH0655747B2 (ja) コウジ酸リン酸エステル化合物
KR100278747B1 (ko) 아스코르빈산-아미노프로판올인산디에스테르를함유한미백화장료조성물
JPH107540A (ja) 美白化粧料
JPS5929199B2 (ja) 脂溶性シルクペプタイドの製造法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 018229956

Country of ref document: CN

Ref document number: 2002580896

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 2001928230

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 2001928230

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWW Wipo information: withdrawn in national office

Ref document number: 2001928230

Country of ref document: EP