• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:

    公开号:SU1470196A3
    申请号:SU823528900
    申请日:1982-12-27
    公开日:1989-03-30
    发明作者:Петиту Морис；Синаи Пьер；Шоай Жан；Лормо Жан-Клод
    申请人:Шоай С.А. (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the chemistry of disaccharides, and specifically to a process for the preparation of new disaccharides consisting of
    KS units of the structure of D-glucosamine and glycuronic acid of the general formula
    where Z-NH, NHCOCHa, NHSOjM;
    R - Cj- C. ,,. alkyl;
    A - COOR ,, COOM; lower alkyl; M - alkali metals., Which can be used as an active principle in drugs, allowing them to regulate some stages of blood coagulation.
    The aim of the invention is to develop an accessible method for producing 1.4 in (-disaccharides consisting of units of the structure of D-glucosamine and glycuronic acid.
    Example 1. Preparation of methyl- (methyl-2,3-di-0-benz1Sh-o -0-glycpyrazide) uronate.
    In 1 ml of methylene chloride, a mixture of 0.75 g (2 mmol) of methyl 2,3-digO-benzyl-o (-1) -glucopyranoside 20 mg (0.08 mmol) of dimethylamine pyridi on, 0.6 ml (4 mmol) of triethylamine and 0.84 g (3 mmol) of trityl chloride (triphenylmethyl chloride).
    By thin layer chromatography (methanol / chloroform 0.2 / 20, v / v), it was established that the reaction is complete.
    To this mixture, 0.6 ml (4 mmol; TRIETHYL-M
    on, 0.35 ml (3 mmol) of benzoyl chloride, 50 mg (0.20 mmol) of dimethylamine pyridine, and continue stirring for another 2 days.
    A 0.5 M solution of p-toluene sulfonic acid in methanol (20 ml) was added to the mixture to remove the trityl group. After one hour, the mixture is diluted with methylene chloride, then washed with water until neutral. The product was purified by column chromatography (40 g) using an ether / hexane CH / 1, v / v mixture. I get a pure white foam (0.84; 87.7%), which is immediately oxidized.
    Dissolve 480 mg (1 mmol) of the product in 8 ml of acetone and add a solution of oxide with stirring to the cooled solution.
    (VI) in 3.5 M sulfuric acid (1.15 ml
    Chromium solution contains 1.17 g in
    ml) ..
    The mixture was allowed to warm to ambient temperature, then ice and water were added after an hour and the product was extracted with chloroform. The chloroform phase is washed with water and the dried solvent is evaporated.
    The resulting foam was dissolved in methanol (10 mg / ml) and sodium hydroxide (5 ml of ZM solution) was added.
    After 3 hours, the aqueous phase is washed twice with ether, then acidified with hydrochloric acid. After that, the product is extracted with ether. The organic phase is washed with water, dried and concentrated.
    The solution thus obtained
    ethylated with diazomethane in ether, purified on a column of silica gel (15 g) in an ether / hexane mixture (2.1, volume / volume).
    Yield 233 mg; 57.9; S.
    The compound is crystallized from a mixture of hexane / ether and receive the following characteristics: so pl. Гс / + 17,5 (с 1, chloroform); NMR spectrum of TH (internal standard MeuSi); “; 2.9 (d, 1H, OH); 3.35 (S, 3N, OSI; 3.69 (S, 3N; COOCH, ;; 7.27 (12H; 2Ph).
    Found,%: C 65.53; H 6.29.
    Cl7H
    Calculated,%: C 65.65; H 6.51.
    PRI and MER 2, Preparation of disaccharide (3 cm, schemes in Figs. 1 and 2).
    The disaccharide (3) is synthesized starting from the monosaccharides (1) and (2) using the following procedure. The reaction is carried out under nitrogen atmosphere and protected from light.
    To a solution of compound (2). (40 mg) in anhydrous dichloromethane (2 ml) is gradually added the compound (and (98 mg), sim-collidine (35 µl) and silver triflate (silver for trifluoromethanesulfonic sprit salt) (L6.5 mg). After 1.5 h the reaction the mixture is diluted with dichloromethane (50 ml). The solution is filtered, washed with saturated sodium bicarbonate solution (two times 20 ml), then with water and then dried.
    After irradiation, the irradiated syrup is chromatographed on silica gel (15 g) in an ethyl acetate / hexane system (1/3, v / v).
    The disaccharide (3) is thus obtained (60.2 mg; 74%). The NMR spectrum confirms the required structure: the observed signals (internal standard MeuSi); "f; 1.95 (s, 3H; -OCOCHj); 3.34 (S, 3N, OCHI); 3.68 (.S, 3N, -CO-O-Shz); 5.53 (d, 1H, 3.5 Hz,); 7.20 - 7.40 (t, 20H, 4Ph).
    Example 3. Getting disaccharide (6).
    In the first stage (a), saponification of the group — OSA in position 6 of the D-glucosamine unit is performed, then stage c) sulphation of the group —OH in position 6 is performed, and in stage c) hydrogenation, the protective groups Bz are removed and the group - N, in the group - NH7.
    Preparation of disaccharide (4) by saponification.
    Compound (3) was dissolved in methanol (10 ml), then 1N was added. caustic soda solution (2 ml.). After 3 hours, the solution is neutralized by passing it through a DOWEX 50W X 4 I ion exchange resin (5 ml). After concentration, the residue is methylated with diazomethane in order to reintroduce the methyl group removed simultaneously with the acetate. In this way, compound (4) is obtained.
    Preparation of disaccharide (5) by sulphoninase.
    Compound (4) was dissolved in anhydrous dimethyl ourmide (3 ml). The trimethylamine / SOj complex (20 mg) is then added and left overnight at 65 ° C. The mixture is then evaporated to dryness, dissolved in chloroform, diluted with methanol, then passed through a column of DOWEX 50-Na resin. The organic phase is washed with water, dried, and then the chloroform is evaporated. Compound (5) (40 mg) is obtained.
    Obtaining the disaccharide (6) by hydrogenation.
    Compound (5) is dissolved in methanol (10 ml) and water (1 ml). 40 mg of 5% palladium on carbon are added and subjected to hydrogen for 48 hours. After filtration and evaporation, compound (6) is obtained
    (29 mg).
    PRI me R 4. Obtaining disaccharides (7) and (8).
    These derivatives are obtained by subjecting the disaccharide (6) to the reaction of the acetylation of the group — gHH-glucose
    A new structure of glucosamine followed by saponification of the group — COOMe of the uronic acid structure unit.
    Compound (6) (14 mg) was dissolved in methanol (3 ml). The pH is adjusted to 8 with 1 n. caustic soda solution. Acetic anhydride (100 µl) is then added. After 30 min, evaporate to dryness. The residue was dissolved in water (1.5 ml) and 1N was added. caustic soda solution (0.5 ml). After overnight at ambient temperature, the solution is neutralized with hydrochloric acid. The product is then desalted by passing through a Sephadex G-25 column (1.8 x X 20 cm). The fractions containing the product are combined and chromatographed on an anion exchange resin (AG 1 x 2 200-40 U mesh; layer 1 ml). The products are eluted by increasing the concentration of eluent sodium chloride from O to 3M. After combining the fractions containing -5, compound (8), the latter is desalted by passing through a Sephadex G-25 column, applied above,: 3.4 mg.
    The structure of the compound (8) was confirmed by the determination of the content of uronic acid, glucosamine and sulfates, as well as by the NMR spectrum. Its UV spectrum shows the maximum absorption at
    205 nm.
    PRI me R 5. Obtaining disaccharides (9) and (10).
    To obtain these derivatives, the disaccharide (6) is first subjected to a sulphation reaction in order to convert the NH-i group into a group, then the sapilization reaction of the COOCHj group, as described above.
    35
    The product (6) (14 mg) is dissolved in water (5 ml). The pH was adjusted to 9.5 by adding 0.1 n. caustic soda solution and support at this level automatically. Trimethylamine / 805 complex (20 mg) is added. For good night, the complex (30 mg) is also added. After 24 hours, add 1N. sodium hydroxide solution (1 ml) and left for 1 hour at ambient temperature. After nP ° y f ««% ;; f.5 cation exchange resin (DOWEX 50 WH) and subsequent neutralization with caustic soda, compound (S) is purified as described for compound (8) (desulfurization, ion exchange, desalting
    Thus, 2.9 mg of the product (10) is obtained.
    The structure of the product (10) was confirmed by determining the content of uronic acid, glucosamine, and sulfates, as well as the NMR spectrum.
    Biological activity. The anti-Xa activity was found in the Disah RIDA invention, while the other type of disaccharide described by Merchant et al. Is negative.
    Disaccharides Activity n
    Yin-Wess Ler Glucosamine glogokuron structure according to the invention - -OS03 СОО-,
    nnv
    in aced sludge or sulfate
    R alkanoyl Glucosamine-Uduronone structure according to the prior art:
    Soo
    SNGO $ Oz O
    OS03 migOa
    Advantages associated with the structure. As a result of the synthesis, it was possible to obtain a disaccharide compound, which is found in the natural chains of heparin, and this compound has a measurable biological activity. This result could not be obtained due to the depolymerization of heparin.
    Depolymerization causes a change in the structural groups of the chains. In the case envisaged in the work of Merchant and DR, the Uduronic saccharide group has a double bond.
    The production of a disaccharide, possessing biological activity and corresponding to a compound that is naturally found in heparin, by gutum represents significant progress used to produce longer chains of heparin, which is not possible with the known level of technology.
    Substrate for the study of enzyme activity.
    0
    five
    0
    25
    thirty
    35
    40
    45
    50
    55
    The use of these saccharides of formulas 8 and 10 according to the invention as a substrate for sulfamidase, the work according to the method of Hopwood I. and Eliott N. for the detection of Sanfilippo syndrome, type A, gives results that can be compared with the results obtained with the named saccharides. containing glucosamine N-sulfate, used by Hopwood and Eliott.
    Disaccharides can be used as a substrate to study enzyme activity, in particular, to carry out enzymatic cleavage.
    The substrate is placed in enzymes of the type "/ -glucosaminidase, heparitinase, heparinase, N-desulfatase, and at certain intervals determine the degree of separation by feeding the reaction product to a liquid chromatograph under high pressure.
    In this way, the decomposition of uronic acid-1 glucosamine chains of glycosaminoglycans of type 1 heparin can be investigated.
    Secondly, Disaccharides can be used as reference products.
    Due to the anti-HA activity of disaccharides (suppression of blood Xa factor), they can be used to study the relationship between structure and activity by comparison with products completely devoid of activity, or, on the contrary, which are very active, such as mucopolysaccharides or oligosaccharides, obtained by extraction or chemical or enzymatic depolymerization of heparin.
    The advantages of these disaccharides are as follows.
    Prior to the invention, a method for glycosylation at position 4 of the glycuronic unit, as well as a method for synthesizing oligosaccharides containing a saccharide unit linked to the glucuronic acid unit, have not been described.
    Hexasaccharides with 6 units of sucrose are known, having an activity of 2,000 lin-Wessler units (such activity serves as an indicator of antithrombotic activity).
    Octosaccharides are also known .8 links; along with other oligosaccharides containing a rather large number of sucrose units.
    14701 6
    However, in all the above cases, the speech is about the products obtained by the depolymerization of heparin or by extraction, and not by synthesis.
    Obviously, it is only by synthesizing mode with certainty, reproducibility and higher yield to obtain a product of a given structure with the necessary substitutions. | Q
    It is important to note that the depolymerization of heparin is accompanied by modification of the link at the beginning or at the end of the oligosaccharide chain.
    During the decomposition of heparin in an enzymatic way, at the beginning of the chain, a non-appreciating uron link is formed, and when decomposed by chemical means, the final glucosamine link transforms into a link of the structure 2,5-anhydrous. 20
    Disaccharides obtained by decomposition under the action of nitrous acid, i.e. These hexasaccharides do not possess antithrombotic activity and cannot be used as reference products in studies of the relationship between structure and activity. And due to the modification of the end link, they are of much less interest compared to. ZO ducts according to this invention, having an intact structure in relation to the links that form heparin.
    Oligosaccharides were also obtained by extraction, i.e. there was no modification of their units, as in the depolymerization. However, such oligosaccharides contain from 4 to 26
    D-glucosamine and glycuronic acid, with a general formula.
    $ 0 OzM A
    where Z - W, gaSoNz, NHSOsM;
    A - COOR ,, СООМ;
    R - C, -C4 alkyl;
    R, is lower alkyl;
    M - alkali metal, the interaction of two monosaccharides of the general formula
    - OAC COORi OJ-0
    t / g bzo | x sh
    N3
    where Ac is acyl;
    W - benzyl;
    X is halogen;
    R and I, have the indicated values, in the presence of a silver salt of trifluoromethanesulfonic acid and an acid acceptor, such as sim-collidine, in an organic solvent medium, followed by treatment of the resulting disaccharide with a strong base, and then with an alkylating agent, followed by sulfation By using the obtained disaccharide with the help of xj-v "-.1g -.-- -: - -NI SG1 llUJl J,. -
    saccharide units and have the activity of the Q complex trimethylamine / ZOe, hydlin - Wesslera top 100. By virtue of
    such activity is not such
    may be standards, as products according to this invention, suitable precisely because of their small activeness of the invention.
    The method of obtaining 1,4V-disaccharides consisting of units of the structure
    by using palladium on carbon as a catalyst, isolating the target product or treating it with acetic anhydride in a weakly basic medium 45 and isolating the obtained product or treating it with an alkali metal hydroxide and complex compound trimethylamine / V / 80d.
    ten
    D-glucosamine and glycuronic acid, with a general formula.
    $ 0 OzM A
    de Z - W, gASO3, NHSOsM;
    A - COOR ,, СООМ;
    R - C, -C4 alkyl;
    R, is lower alkyl;
    M - alkali metal, the interaction of two monosaccharides of the general formula
    - OAC COORi OJ-0
    t / g bzo | x sh
    N3
    where Ac is acyl;
    W - benzyl;
    X is halogen;
    R and I, have the indicated values, in the presence of a silver salt of trifluoromethanesulfonic acid and an acid acceptor, such as sim-collidine, in an organic solvent medium, followed by treatment of the resulting disaccharide with a strong base, and then with an alkylating agent, followed by sulfation using the obtained disaccharide with the help of SG1 llUJl J,. -
     trimethylamine / ZOe complex, trimethylamine / ZOe complex, guide
    by using palladium on carbon as a catalyst, isolating the target product or treating it with acetic anhydride in a weakly basic medium 45 and isolating the resulting product or treating it with an alkali metal hydroxide and trimethylamine / V / 80d complex.
    BnO t -o- oMe
    lifsOBn
    go oz ka soome
    LO i, / -0
    BnOn jOHe
    1 3OBn
    five)
    rOSOjNa "Soome
    LO 0 HO
    w / feY
     l go
    BUT t -O- L ome ".. /) °"

    h n
    (6)
    ososHtt soom
    AND
    about - Pome inas he m
    osoaNo cooNfl
     M
    Ш1АС,., HE
    (eight)
     SooMe

    yu SO Soome
    io LO
    ® (f®l
    knop -0- pom 1g50zKa
    (, 1) §cryc noNo
    I
    L
    d.2
    HO L-o-J oMe NHS03Na he
    (ten)
    权利要求:
    Claims (1)
    [1]
    Form
    10 ,
    D-glucosamine and glycuronic acid, of the general formula where
    0R OH
    Z A R R, m by the interaction of the General formula
    NH1, NHCOCH3, NHSO3M; COOR t , COOM;
    C, -C + = alkyl; lower alkyl ;.
    alkali metal, two monosaccharides
    QAC
    Cool where
    Ac is acyl;
    In g is benzyl;
    X is halogen;
    R, - have the indicated meanings, and
    the presence, as a catalyst, 35 of the reason for their low activity. the invention of obtaining 1,4 <sf disaccharides Methods consisting of units of the 30 R structure in a silver salt of trifluoromethanesulfonic acid and an acid acceptor, such as sim-collidine, in an organic solvent, followed by treating the obtained disaccharide with a strong base and then an alkylating agent, followed by sulfation of the obtained disaccharide with the trimethylamine / SOe complex, hydrogenation using palladium-carbon as a catalyst, Niemi desired product or treating it with acetic anhydride in a weak basic medium and isolating the resulting product or treating it with an alkali metal hydroxide and trimethylamine complex compound / / 80 e. .
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    引用文献:
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    RU2481352C2|2006-11-16|2013-05-10|Ом Фарма|Functionalised beta 1, 6 glucosamine-disaccharides and method for preparing them|US2374236A|1943-01-23|1945-04-24|Du Pont|Surface active aldoside condensation products|
    US4098995A|1976-07-12|1978-07-04|American Cyanamid Company|Polygalactosido-sucrose polysulfate salts|
    US4362720A|1977-04-14|1982-12-07|Chembiomed Ltd.|Synthesis of 2-amino-2-deoxyglycoses and 2-amino-2-deoxyglycosides from glycals|
    CA1136620A|1979-01-08|1982-11-30|Ulf P.F. Lindahl|Heparin fragments having selectiveanticoagulation activity|
    JPS6259711B2|1979-08-21|1987-12-12|Seikagaku Kogyo Co Ltd|
    IL61201A|1979-10-05|1984-09-30|Choay Sa|Oligosaccharides having no more than 8 saccharide moieties,their obtention from heparin and pharmaceutical compositions containing them|
    CA1171375A|1980-09-15|1984-07-24|Ulf P.F. Lindahl|Oligosaccharides having selective anticoagulationactivity|
    US4413120A|1981-04-06|1983-11-01|Purdue Research Foundation|Process for producing acosamine, daunosamine, 1-thioacosamine and related compounds|
    FR2504535B1|1981-04-28|1987-08-14|Choay Sa|DISACCHARIDES DERIVED FROM URONIC ACID AND GLUCOSAMINE AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM FOR THE CONTROL OF BLOOD COAGULATION|
    US4435387A|1982-10-25|1984-03-06|American Cyanamid Company|Poly-cation salts of bis 4-O-polyhexose-thio-arylene sulfate derivatives|CA1247608A|1981-12-23|1988-12-28|Jean Choay|Derivatives having uronic acid structure; process for preparing the same and their biological uses|
    FR2504535B1|1981-04-28|1987-08-14|Choay Sa|DISACCHARIDES DERIVED FROM URONIC ACID AND GLUCOSAMINE AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM FOR THE CONTROL OF BLOOD COAGULATION|
    US4818816A|1981-04-28|1989-04-04|Choay, S.A.|Process for the organic synthesis of oligosaccharides and derivatives thereof|
    AU563351C|1982-01-15|2003-06-19|Glaxo Group Limited|Synthesis of oligosaccharides|
    CA1265132A|1982-01-15|1990-01-30|Mahmoud Nassr|Process for the organic synthesis of oligosaccharides and derivatives thereof|
    FR2535323B1|1982-10-27|1987-08-14|Choay Sa|NOVEL DERIVATIVES WITH URONIC ACID STRUCTURE, THEIR PREPARATION AND THEIR BIOLOGICAL APPLICATIONS|
    FR2535324A1|1982-10-27|1984-05-04|Choay Sa|PERFECTED STATION FOR THE PURIFICATION OF WASTEWATER|
    US4847338A|1985-03-28|1989-07-11|University Of Iowa Research Foundation|Low molecular weight heparin fragments as inhibitors of complement activation|
    US4916219A|1985-03-28|1990-04-10|University Of Iowa Research Foundation|Oligosaccharide heparin fragments as inhibitors of complement cascade|
    GB8519416D0|1985-08-01|1985-09-04|Unilever Plc|Oligosaccharides|
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    GB8630721D0|1986-12-23|1987-02-04|Unilever Plc|Cosmetic compositions|
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    NL8701342A|1987-06-09|1989-01-02|Tno|Bifunctional oligosaccharides and active compounds derived therefrom.|
    US5344870A|1987-12-02|1994-09-06|Alberta Research Council|Sialic acid glycosides, antigens, immunoadsorbents, and methods for their preparation|
    US5079353A|1987-12-02|1992-01-07|Chembiomed, Ltd.|Sialic acid glycosides, antigens, immunoadsorbents, and methods for their preparation|
    IT1217458B|1988-05-02|1990-03-22|Crinos Ind Farmacoriologica S|SULFOAMINO DERIVATIVES OF CONDROITIN SULPHATES, DERMATAN SULPHATE AND HYALURONIC ACID AND THEIR PHARMACOLOGICAL PROPERTIES|
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    US5141928B1|1989-12-20|1995-11-14|Brujo Inc|Ophthalmic medication|
    LU87766A1|1990-07-20|1992-03-11|Oreal|USE OF PYRIMIDINE 3-OXIDE DERIVATIVES FOR BRAKING HAIR LOSS AND TOPICAL COMPOSITIONS IMPLEMENTED|
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    US5336765A|1991-12-31|1994-08-09|Lever Brothers Company, Division Of Conopco, Inc.|Process of preparing N-substituted aldobionamides|
    US6750207B1|1992-05-01|2004-06-15|Yeda Research And Development Co. Ltd.|Compositions for the regulation of cytokine activity|
    IL105011A|1992-05-22|1997-07-13|Japan Res Dev Corp|Disaccharides, process for the preparation thereof from plants and their use|
    US5696100A|1992-12-22|1997-12-09|Glycomed Incorporated|Method for controlling O-desulfation of heparin and compositions produced thereby|
    US5401839A|1993-03-23|1995-03-28|Lever Brothers Company, Division Of Conopco, Inc.|Process of preparing N-substituted aldonamides having improved color and color stability|
    US5646130A|1995-06-30|1997-07-08|Ocean University Of Oingdao|Low molecular weight sulfated polysaccharides and uses thereof|
    US5750665A|1995-10-04|1998-05-12|Vosika; Gerald J.|Preparation of glucosaminyl muramic acid derivatives|
    US7390668B2|1996-10-30|2008-06-24|Provectus Pharmatech, Inc.|Intracorporeal medicaments for photodynamic treatment of disease|
    IL147318D0|1999-06-30|2002-08-14|Hamilton Civic Hospitals Res|Heparin compositions that inhibit clot associated coagulation factors|
    EP1315539A2|2000-09-08|2003-06-04|Leo Pharma A/S|Antithrombotic compositions|
    US6592985B2|2000-09-20|2003-07-15|Camco InternationalLimited|Polycrystalline diamond partially depleted of catalyzing material|
    EP1440077B1|2001-09-07|2013-05-01|Alchemia Limited|Synthetic heparin pentasaccharides|
    US7285536B2|2001-12-05|2007-10-23|Yeda Research And Development Co., Ltd.|Anti-cancer therapeutic compounds|
    US9138408B2|2002-06-21|2015-09-22|L'oreal|Use of taurine for treating alopecia|
    CN102046781A|2008-05-30|2011-05-04|动量制药公司|Saccharide structures and methods of making and using such structures|
    US8288515B2|2009-07-31|2012-10-16|Reliable Biopharmaceutical Corporation|Process for preparing Fondaparinux sodium and intermediates useful in the synthesis thereof|
    ES2358829B1|2009-10-23|2012-06-25|Lipotec, S.A.|USEFUL PEPTIDES IN THE TREATMENT AND / OR CARE OF SKIN, MUCOSES AND / OR HAIR AND ITS USE IN COSMETIC OR PHARMACEUTICAL COMPOSITIONS.|
    US8420790B2|2009-10-30|2013-04-16|Reliable Biopharmaceutical Corporation|Efficient and scalable process for the manufacture of Fondaparinux sodium|
    ES2373704B1|2010-02-18|2013-01-24|Lipotec S.A.|LIPOSOMES FOR THE TREATMENT OF TEXTILE MATERIALS.|
    ES2384060B1|2010-03-24|2013-09-23|Lipotec S.A.|LIPID NANOPARTICLES CAPSULES.|
    ES2383271B1|2010-03-24|2013-08-01|Lipotec S.A.|PROCESSING PROCESSING OF FIBERS AND / OR TEXTILE MATERIALS|
    ES2386177B1|2010-09-21|2013-09-23|Lipotec, S.A.|NANOCAPSULES CONTAINING MICROEMULSIONS|
    US10905646B2|2014-10-31|2021-02-02|Lubrizol Advanced Materials, Inc.|Thermoplastic polyurethane film for delivery of active agents to skin surfaces|
    EP3371238A1|2015-11-05|2018-09-12|Lubrizol Advanced Materials, Inc.|Thermoformable dual network hydrogel compositions|
    EP3773458A1|2018-04-12|2021-02-17|Lubrizol Advanced Materials, Inc.|Hair modification composition and method therefor|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR8108472A|FR2504535B1|1981-04-28|1981-04-28|DISACCHARIDES DERIVED FROM URONIC ACID AND GLUCOSAMINE AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM FOR THE CONTROL OF BLOOD COAGULATION|
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