• 专利附录
  • 专利说明
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    • 专利摘要:
    The present invention is the following structural formula I (Ⅰ) Wherein R is a linear, branched or cyclic C 1 -C 5 -alkyl group, monounsaturated C 2 -C 3 -alkene group. C 2 -C 3 -hydroxyalkyl group or C 3 -C 6 -alkoxyalkyl group. The 4-methyl-2-oxo- 2H -1-benzopyran-7-yl 5-thio-β-D-xylpyranoside compound of The present invention also relates to methods of preparing the compounds and their therapeutic use as antithrombogenic substances.
    公开号:KR20020050282A
    申请号:KR1020027006185
    申请日:2000-11-15
    公开日:2002-06-26
    发明作者:바르베루스베로니크；보비아베네싸；사메르쓰소쓰
    申请人:포우르니에르 인더스트리 에 상뜨；
    IPC主号:
    专利说明:

    Β-D-5-thioxylose derivatives, preparation method and therapeutic use
    [2] EP-A-0421829, in particular Table 1 of this document, has been shown to be useful from a therapeutic point of view for the effect of preventing or treating venous circulatory diseases, especially venous thrombosis, the benzopyranone β-D-5-T of An oxyloside compound is disclosed.
    [3] (Io)
    [4] here:
    [5] X is O or S,
    [6] Y is especially H or COCH 3 ,
    [7] R 1 is especially C 1 -C 4 alkyl,
    [8] R 2 is especially H, C 1 -C 4 alkyl or halogen.
    [9] In particular, compound 4-methyl-2-oxo-2 H -1-benzopyran-7-yl 5-thio-β-D-xycopyyranoside (X = O, Y = H, R 1 = CH 3 and Structural formula Io), with R 2 = H, is orally administered and shows significant activity in that it reduces venous thrombus formation by 80% or more at doses of 6 mg / kg or more. This activity obtained by oral administration is extremely valuable for the most common uses of these products and is generally equivalent to prophylactic treatment.
    [10] In fact, this product is currently used both in the therapeutic field, for example, in the field of anticoagulants, ie normal heparin and small molecule heparin, which are inactive by oral administration and have to be injected intravenously or subcutaneously. Especially in chronic treatment, this form of administration is generally not preferred for patients who want to take tablets or gelatin capsules orally. In this respect, the compounds according to EP-A-0421829 show benefits in terms of the convenience, risk and cost of the patient in connection with the dosage form. It is also pointed out that these compounds do not increase the risk of bleeding compared to the products already in use.
    [11] However, the compounds described in EP-A-0421829 are not sufficiently available for them to be administered by injection. Thus they cannot be used if injection is the only possible route of administration or if injection is more desirable to administer these compounds in conjunction with other drugs by perfusion.
    [1] The present invention relates to β-D-5-thioxylose derivatives, more particularly 4-methyl-2-oxo- 2H -1-benzopyran-7-yl 5-thio, of the structural formula I It relates to a -β-D- xylopyranoside derivatives. Moreover, the present invention relates to a process for the preparation of these novel products and their pharmaceutical uses.
    [12] According to the present invention, a novel technical solution for solving the solubility problem described above is provided. This novel solution provides novel 4-methyl-2-oxo- 2H -1-benzopyran-7-yl 5-thio-β with better solubility in conventional solvents, especially injectable solutions, while maintaining oral activity at the same time. -D-xylopyranoside derivatives.
    [13] The present invention provides a compound characterized by the novel industrial product having the following structural formula (I).
    [14] (Ⅰ)
    [15] Wherein R is a linear, branched or cyclic C 1 -C 5 -alkyl group, monounsaturated C 2 -C 3 -alkene group. C 2 -C 3 -hydroxyalkyl group or C 3 -C 6 -alkoxyalkyl group.
    [16] According to another feature of the invention, there is provided a process for the preparation of a compound of formula I, wherein the process comprises:
    [17] (Ⅱ)
    [18] 4-Methyl-2-oxo- 2H -l-benzopyran-7-yl 5-thio-β-D-xylpyranoside of the following structural formula III:
    [19] (Ⅲ)
    [20] Halogenoformate and the following structural formula IV;
    [21] (Ⅳ)
    [22] Wherein R is a C 1 -C 5 -alkyl group, a C 2 -C 3 -alkene group. C 3 -C 6 -alkoxyalkyl groups or alcohol functional groups are C 2 -C 3 -hydroxyalkyl groups protected with a protecting group such as, for example, trialkylsilyl, Hal is a halogen atom (especially F, Cl or Br Wherein more preferred halogen is chlorine).
    [23] It characterized in that it comprises a carbonation reaction with a reagent selected from the group consisting of pyrocarbonate.
    [24] This method involves the protection of the OH functional groups of R = C 2 -C 3 -hydroxyalkyl before the carbonation reaction and then the deprotection thereof after the carbonation reaction.
    [25] This process depends on the characteristics of the R group as follows. R = R '= a reaction II + III or II + IV when a linear, branched or cyclic C 1 -C 5 -alkyl group, monounsaturated C 2 -C 3 -alkene group or C 3 -C 6 -alkoxyalkyl group Is performed.
    [26] When R = R '= C 2 -C 3 -hydroxyalkyl group, 4-methyl-2-oxo-2 H -1-benzopyran-7-yl 5-thio-β-D-xylopy of formula II The carbonation reaction of ranosides is represented by the structure IIIbis:
    [27] (IIIbis)
    [28] Wherein R ″ is a C 2 -C 3 -hydroxyalkyl group with an OH functional group protected and Hal is a halogen atom as described above.
    [29] The reaction compound is then subjected to deprotection of the hydroxy group, for example if the protecting group is a trialkylsilyl group, reacting with a hydrofluoric acid solution so that R is C 2 -C 3 -hydro Obtain the compound of formula I which is a oxyalkyl group.
    [30] According to another feature of the invention there is provided a pharmaceutical composition comprising on the one hand a therapeutically effective amount of at least one compound of formula I in combination with a medically acceptable excipient, and on the other hand The present invention provides the use of a compound of formula I, wherein the compound of formula I is used to obtain an antithrombotic drug intended for therapeutic use in combating venous circulation diseases.
    [31] Among the suitable C 1 -C 5 -alkyl groups according to the invention are methyl, ethyl, propyl, 1-methylethyl, cyclopropyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl and pentyl groups Can be.
    [32] Among the suitable C 2 -C 4 -alkene groups according to the invention are vinyl and allyl groups. In this case, monounsaturated alkene groups represent aliphatic groups containing only one C═C double bond.
    [33] Among the suitable C 3 -C 6 -alkoxyalkyl groups according to the invention are methoxyethyl, ethoxyethyl, methoxyethoxyethyl and ethoxyethoxyethyl groups.
    [34] Among the suitable C 2 -C 3 -hydroxyalkyl groups according to the invention are 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl groups.
    [35] It is preferred that R is an ethyl group or a methyl group in the compound of formula I, which is 4-methyl-2-oxo- 2H -1-benzopyran-7-yl 5-thio-β-D-xyclopyranoside tricarbonate. .
    [36] Compounds of Structural Formula I
    [37] a) the following structural formula II:
    [38] (Ⅱ)
    [39] 4-Methyl-2-oxo- 2H -l-benzopyran-7-yl 5-thio-β-D-xylpyranoside of the following structural formula IIIa:
    [40] (IIIa)
    [41] Of chloroformate or of the following structural formula IV;
    [42] (Ⅳ)
    [43] Wherein R is a linear, branched or cyclic C 1 -C 5 -alkyl group, monounsaturated C 2 -C 3 -alkene group. C 3 -C 6 -alkoxyalkyl group or C 2 -C 3 -hydroxyalkyl group wherein the hydroxy group is protected with a protecting group, in particular a t-butyldimethylsilyl group.
    [44] Reacts with pyrocarbonate of, at a temperature of 10 ° C. to 80 ° C., in an anhydrous solvent such as dimethylformamide, for example in the presence of a nonpolar base such as 4- (dimethylamino) pyridine, Carbonation reaction to be carried out for 10 to 10 hours to obtain a compound of formula I wherein R is maintained as in reagents IIIa or IV; And
    [45] b) if necessary, in the case of the preparation of compounds of the formula (I) in which R is a hydroxyalkyl group, the deprotection reaction of the hydroxy groups, especially if the protecting group is a t-butyldimethylsilyl group, at room temperature, for example acetonitrile with hydrofluoric acid Reaction in a solvent such as;
    [46] It can be produced by the means of.
    [47] When R is a C 2 -C 3 -hydroxyalkyl group, the carbonation reaction is preferably effected by means of chloroformate. The protecting group of the OH functional group can be dissociated faster than the O-CO-O functional group so that it can be removed between deprotection reactions without affecting the O-CO-O functional group, with the preferred protecting group being a trialkylsilyl group.
    [48] Therapeutic compositions may be in the form of perfusion, in the form of solutions that can be administered intravenously as well as intravenously, or convertible into solutions, or in the form of perfusion. The therapeutic composition may also be in a form that can be administered orally, such as, for example, gelatin capsules, tablets or solutions taken orally.
    [49] The compounds of formula I are useful for the treatment of their antithrombotic activity and are of particular value in the treatment or prevention of venous circulatory diseases, in particular in correcting any hematological parameters that can be detected in the venous system.
    [50] The following examples, together with the results of pharmaceutical tests, are not intended to limit the present invention and will provide a better understanding of the value of the present invention.
    [51] Example 1
    [52] 4-methyl-2-oxo-2 H -1-benzopyran-7-yl 2,3,4-tri-O-methoxycarbonyl-5-thio-β-D-xylpyranoside
    [53] A solution of 2 g (6.17.10 -3 mol) of 4-methyl-2-oxo- 2H -1-benzopyran-7-yl 5-thio-β-D-cyclopyranoside in 20 ml of dimethylformamide It is prepared at 70 ° C. and then cooled to about 25 ° C. 10 mg (0.8.10 -3 mol) of 4-dimethylaminopyridine is added and 3.85 ml (36.10 -3 mol) of dimethyl pyrocarbonate are added. After 4 hours of stirring at room temperature (15-25 ° C.), 3.85 ml of dimethyl pyrocarbonate is further added, and the reaction medium is stirred at room temperature for 6 hours. The mixture is then filtered and concentrated under reduced pressure and the residue is purified by chromatography on silica gel using a toluene / acetone mixture (6/1; v / v) as eluent. The pure fraction is crystallized from an acetone / ether mixture, filtered and dried to give 1.92 g of the expected product in the form of a white powder (yield = 63%).
    [54] M.p. = 168 ° C
    [55] [a] D 21 = -77 ° (c = 0.37; CHCl 3 )
    [56] Example 2
    [57] 4-methyl-2-oxo-2 H -1-benzopyran-7-yl 2,3,4-tri-O-ethoxycarbonyl-5-thio-β-D-xylpyranoside
    [58] The expected product is obtained in the form of a white powder (yield = 78%) in the same manner as in Example 1 except that dimethyl pyrocarbonate is replaced by diethyl pyrocarbonate.
    [59] M.p. = 176 ° C
    [60] [α] D 22 = -72 ° (c = 0.465; CHCl 3 )
    [61] Example 3
    [62] 4-methyl-2-oxo-2 H -1-benzopyran-7-yl 2,3,4-tri-O-propoxycarbonyl-5-thio-β-D-xylpyranoside
    [63] In 12ml of pyridine 4-dimethylaminopyridine, a solution of 100mg (0.8.10 -3 mol) is prepared, propyl chloroformate 2.1ml (18.7.10 -3 mol) is added at 0 ℃, 4-methyl-2 1 g (3.1.10 -3 mol) of oxo- 2H -1-benzopyran-7-yl 5-thio-β-D-xylpyranoside is added. The reaction mixture is stirred for 1 hour, 1 ml of propyl chloroformate (8.9.10 -3 mol) is added and stirring is continued for 1 hour. The mixture is then hydrolyzed in ice water and extracted with ethyl acetate. The organic layer is washed with dilute hydrochloric acid solution and then washed with water, dried under reduced pressure and finally concentrated. The residue is purified by chromatography on silica gel using a toluene / ethyl acetate mixture (4/1; v / v) as eluent. The pure production fraction is crystallized from an ethyl acetate / diethyl ether mixture to yield 1.13 g of the expected product in the form of a fine, light white solid (yield = 63%).
    [64] M.p. = 134 ° C
    [65] [α] D 23 = -57 ° (c = 0.37; CHCl 3 )
    [66] Example 4
    [67] 4-methyl-2-oxo-2 H -1-benzopyran-7-yl 2,3,4-tri-O-butoxycarbonyl-5-thio-β-D-xylpyranoside
    [68] Except for propyl chloroformate being replaced with butyl chloroformate, the expected product is obtained in the same manner as in Example 3 after crystallization with diethyl ether in a white cottony solid form (yield = 85%).
    [69] M.p. = 120 ℃
    [70] [a] D 23 = −51 ° (c = 0.45; CHCl 3 )
    [71] Example 5
    [72] 4-methyl-2-oxo-2 H -1-benzopyran-7-yl 2,3,4-tri-O- (2-methylpropoxycarbonyl) -5-thio-β-D-xylpyranoside
    [73] The expected product is obtained in the form of a fine white solid (yield = 89%) in the same manner as in Example 3 except that propyl chloroformate is replaced with 2-methylpropyl chloroformate.
    [74] M.p. = 114 ° C
    [75] [α] D 23 = -43 ° (c = 0.415; CHCl 3 )
    [76] Example 6
    [77] 4-methyl-2-oxo-2 H -1-benzopyran-7-yl 2,3,4-tri-O- (2-methoxyethoxycarbonyl) -5-thio-β-D-xylpyranoside
    [78] The expected product is obtained in the form of a light white powder (yield = 80%) in the same manner as in Example 3 except that propyl chloroformate is replaced with 2-methoxyethyl chloroformate.
    [79] M.p. = 118 ° C
    [80] [a] D 23 = -69 ° (c = 0.65; CHCl 3 )
    [81] Example 7
    [82] 4-methyl-2-oxo-2 H -1-benzopyran-7-yl 2,3,4-tri-O- (2-propenylcarbonyl) -5-thio-β-D-xylpyranoside
    [83] The expected product is obtained in the form of a white solid (yield = 8%) of the powder in a similar manner to Example 3 except that propyl chloroformate is replaced by allyl chloroformate.
    [84] M.p. = 120 ℃
    [85] [α] D 22 = -57 ° (c = 0.46; CHCl 3 )
    [86] Example 8
    [87] 4-methyl-2-oxo-2 H -1-benzopyran-7-yl 2,3,4-tri-O- (ethenyloxycarbonyl) -5-thio-β-D-xylpyranoside
    [88] The expected product is obtained in the form of a white powder (yield = 57%) in the same manner as in Example 3 except that propyl chloroformate is replaced with vinyl chloroformate.
    [89] M.p. = 120 ℃
    [90] [α] D 23 = -45 ° (c = 0.47; CHCl 3 )
    [91] Manufacture Ⅰ
    [92] 2-[[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl chloroformate
    [93] 3.1 g of 2-[[(1,1-dimethylethyl) dimethylsilyl] oxy] ethanol in 15 ml of dichloromethane
    [94] (17.6.10 -3 mol) and pyridine 1.3ml (19.3.10 -3 mol) is prepared, the solution of phosgene in toluene solution, 20% (that is, the 19.3.10 -3 mol of phosgene) and 10ml of dichloromethane 10ml Is added dropwise to the mixture of and cooled to 0 ° C. At the end of the addition, the reaction medium is stirred for 2 hours and then brought to room temperature. Argons are then bubbled into the mixture for 30 minutes to remove residual phosgene. The remaining solution is used directly in the next synthesis step.
    [95] Manufacture Ⅱ
    [96] 4-methyl-2-oxo-2 H -1-benzopyran-7-yl 2,3,4-tri-O-[[2-[[(1,1-dimethylethyl) -dimethylsilyl] oxy] ethoxy] carbonyl] -5-thio- β-D-xylopyranoside
    [97] 500 mg (1.5.10 -3 mol) and 4- (dimethyl 4-methyl-2-oxo- 2H -1-benzopyran-7-yl 5-thio-β-D-xylopyranoside in 25 ml pyridine 50 mg (0.41.10 -3 mol) of amino) pyridine are prepared. This solution is added dropwise with stirring to the chloromethane solution obtained in Preparation I. The reaction mixture is stirred for 18 hours at room temperature. Then 50 ml of dichloromethane and 100 ml of water are added. The phases are separated and the aqueous layer is extracted with 50 ml of dichloromethane. The combined organic phases are washed with water and then dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel using an ethyl acetate / hexane mixture (3/7; v / v) as eluent to afford 1.13 g of the expected product in the form of a light white paste on a solid (yield = 79%).
    [98] Example 9
    [99] 4-methyl-2-oxo-2 H -1-benzopyran-7-yl 2,3,4-tri-O- (2-hydroxyethoxy-carbonyl) -5-thio-β-D-xylpyranoside
    [100] 880 mg (0.95.10 -3 mol) of the compound obtained according to Preparation II are dissolved in 40 ml of acetonitrile and 0.25 ml of 40% hydrofluoric acid is added. The reaction mixture is stirred for 5 minutes at room temperature and then concentrated under reduced pressure. The residue was chromatographed on silica gel using a dichloromethane / methanol mixture (9/1; v / v) as eluent to afford 486 mg of the expected product as a white powder (yield = 87%).
    [101] M.p. = 97-98 ° C
    [102] [α] D 25 = -76 ° (c = 0.35; CHCl 3 )
    [103] The pharmaceutical activity of some compounds according to the invention is evidenced by tests for regenerating venous thrombosis, the manipulation protocol of which is as follows.
    [104] Experiments were performed on fasted male wisterets of 250-280 g body weight divided into 10 groups each. Test compounds are dissolved or suspended in PEG400 and orally (tubei) as well as dissolved in PEG400 and administered by intravenous injection. The concentration of the compound is calculated such that the amount of solution absorbed is 2 ml / kg by oral administration and 1 ml / kg by intravenous injection. The compound is generally administered at a dose of 5 mg / kg intravenously. If the test is performed after oral administration, the amount administered is calculated to correspond to about 2.10 -5 mol / kg. Thrombosis is triggered at time T (2, 4 or 8 hours) after compound administration and the thrombosis formed is metered out. To induce this thrombosis, venous congestion is formed under coagulation according to the technique described in WESSLER (J. Applied Physiol. 1959, pp. 943-946), and the coagulation agent used is 7.5nKat / solution of activating factor X (Xa) with a concentration of kg. The results obtained are expressed in percent inhibition calculated on the weight of the thrombus obtained in the absence of the active element in the carrier and compared to Table 1 below. The activity of the test compounds is checked at different doses after they have been administered orally (po) as well as intravenously (iv). Thrombosis is induced 4 hours or 8 hours after oral administration of the compound and 2 hours after intravenous administration. In comparison, Table 1 is also described in EP-A-0421829, cited above, and cited as D in Table 1 above, 4-methyl-2-oxo-2 H -1-benzopyran-7-yl 5- Shows the results obtained with thio-β-D-xylopyranoside (this compound is insoluble in injectable solutions, especially water and PEG400, and cannot be administered intravenously).
    [105] The compound according to the invention after intravenous administration shows an antithrombotic activity substantially equivalent to that obtained by oral administration of comparative compound D, although its active action is faster. These compounds possessing good activity for oral administration may not only be in injectable form for faster effects, but may also be in orally absorbable form to avoid the difficulty or risk of repeated injections.
    [106] They may be formulated as injectable forms, injectable forms prepared immediately prior to use, or as excipients which are medically acceptable for oral solid forms, for example gelatin capsules or tablets, each unit being at least It contains 25 to 500 mg of at least one compound of formula I.
    [107]
    [108] compoundRActive i.v. (mg / kg) T = 2hActive p.o. (mg / kg) T = 4hActive p.o. (mg / kg) T = 8h Example 1-CH 3 84% (5)87% (9)66% (9) Example 2-CH 2 -CH 3 73% (5) Example 3-(CH 2 ) 2 -CH 3 71% (5) Example 4-(CH 2 ) 3 -CH 3 60% (5) Example 5-CH 2 -CH (CH 3 ) 2 65% (5) Example 6-(CH 2 ) 2 -OCH 3 52% (5) Example 7-CH 2 -CH = CH 2 66% (5) Example 8-CH = CH 2 65% (5) Example 9-(CH 2 ) 2 -OH27% (5)93% (11)29% (11) D *-----84% (6)15% (6)Note: Numbers in parentheses represent the dosage administered in mg / kg. * D is a compound of formula II as mentioned in the detailed description.
    权利要求:
    Claims (10)
    [1" claim-type="Currently amended] 4-Methyl-2-oxo- 2H -l-benzopyran-7-yl 5-thio-β-D-xylpyranoside compound characterized by having the following structure:
    (Ⅰ)
    Wherein R is a linear, branched or cyclic C 1 -C 5 -alkyl group, monounsaturated C 2 -C 3 -alkene group. C 2 -C 3 -hydroxyalkyl group or C 3 -C 6 -alkoxyalkyl group.
    [2" claim-type="Currently amended] The 4-methyl- according to claim 1, wherein R is methyl, ethyl, propyl, 1-methylethyl, cyclopropyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl and pentyl. 2-oxo- 2H -1-benzopyran-7-yl 5-thio-β-D-xylpyranoside compound.
    [3" claim-type="Currently amended] 4. 4-Methyl-2-oxo- 2H -l-benzopyran-7-yl 5-thio- [beta] -D-xylpyranoside compound according to claim 1, wherein R is vinyl or allyl.
    [4" claim-type="Currently amended] 4. 4-Methyl-2-oxo- 2H -1-benzopyran-7-yl according to claim 1, wherein R is methoxyethyl, ethoxyethyl, methoxyethoxyethyl or ethoxyethoxyethyl. 5-thio-β-D-xylopyranoside compound.
    [5" claim-type="Currently amended] The compound of claim 1, wherein the compound is 4-ethyl-2-oxo- 2H -1-benzopyran-7-yl 2,3,4-tri-O-ethoxycarbonyl-5-thio-β-D- A compound characterized by being xylopyranoside.
    [6" claim-type="Currently amended] The compound of claim 1, wherein the compound is 4-methyl-2-oxo- 2H -1-benzopyran-7-yl 2,3,4-tri-O-methoxycarbonyl-5-thio-β-D- A compound characterized by being xylopyranoside.
    [7" claim-type="Currently amended] Structural Formula II;
    (Ⅱ)
    4-Methyl-2-oxo- 2H -l-benzopyran-7-yl 5-thio-β-D-xylpyranoside of the following structural formula III:
    (Ⅲ)
    Halogenoformate and the following structural formula IV;
    (Ⅳ)
    Wherein R is a linear, branched or cyclic C 1 -C 5 -alkyl group, monounsaturated C 2 -C 3 -alkene group or C 3 -C 6 -alkoxyalkyl group, and Hal is a halogen atom (especially F, Cl or Br).
    R is a linear, branched or cyclic C 1 -C 5 -alkyl group, monounsaturated C 2 -C 3 -alkene group or C 3 , characterized in that it comprises a carbonation reaction with a reagent selected from the group consisting of pyrocarbonates of A process for preparing the compound of formula I according to claim 1, which is a -C 6 -alkoxyalkyl group.
    [8" claim-type="Currently amended] Next Structural Formula II
    (Ⅱ)
    4-Methyl-2-oxo- 2H -l-benzopyran-7-yl 5-thio-β-D-xylpyranoside of the following structural formula IIIbis:
    (IIIbis)
    Wherein R ″ is a C 2 -C 3 -hydroxyalkyl group with an OH functional group protected and Hal is a halogen atom as described above.
    The halogeno formate of the R, characterized in that comprises the carbonation reaction, the reaction compound to a hydrogen fluoride acid solution and then reacting hydroxyalkyl group deprotection reaction of the OH functional groups of the C 2 -C 3 - Process for the preparation of the compound of formula I in which it is a hydroxyalkyl group.
    [9" claim-type="Currently amended] A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula I according to claim 1 in combination with a pharmaceutically acceptable excipient.
    [10" claim-type="Currently amended] Use of a compound of formula I according to claim 1, characterized in that the compound of formula I is used to obtain an antithrombotic drug intended for therapeutic use in combating venous circulation diseases.
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    PL356208A1|2004-06-14|
    NZ518864A|2005-07-29|
    NO20022279L|2002-05-14|
    NO20022279D0|2002-05-14|
    AU1713101A|2001-05-30|
    CZ20021589A3|2002-07-17|
    IL149620D0|2002-11-10|
    AT264338T|2004-04-15|
    FR2801055B1|2002-02-08|
    JP2003514826A|2003-04-22|
    EP1230252A1|2002-08-14|
    ZA200203570B|2003-07-30|
    EP1230252B1|2004-04-14|
    MXPA02004916A|2002-09-18|
    DE60009945D1|2004-05-19|
    DK1230252T3|2004-08-02|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1999-11-17|Priority to FR9914445A
    1999-11-17|Priority to FR1999-14445
    2000-11-15|Application filed by 포우르니에르 인더스트리 에 상뜨
    2000-11-15|Priority to PCT/FR2000/003174
    2002-06-26|Publication of KR20020050282A
    优先权:
    申请号 | 申请日 | 专利标题
    FR9914445A|FR2801055B1|1999-11-17|1999-11-17|Beta-d-5-thioxylose derivatives, preparation method and therapeutic use|
    FR1999-14445|1999-11-17|
    PCT/FR2000/003174|WO2001036437A1|1999-11-17|2000-11-15|β-D-5-THIOXYLOSE DERIVATIVES, PREPARATION METHOD AND THERAPEUTIC USE|
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