• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:
    Metallic derivatives of anthracycline glycosides such as doxorubicin and daunorubicin are prepared by admixing divalent or trivalent metal cations, preferably Fe(III), with the glycoside and adjusting pH to promote chelation of the metal by bidentate ligands of the glycoside. The derivatives are isolated in essentially monomeric form, and preferably lyophilized for later reconstitution immediately before use in the treatment of transplanted tumors in mice. As compared with the parent glycosides, the derivatives exhibit greatly diminished cardiotoxicity and less general, hematological and digestive toxicity as well. At the same time, the antineoplastic efficacy of the derivatives in transplanted mouse tumor test systems appears to be approximately equivalent to that of the parent glycoside on a mg. to mg. basis. As a result, the therapeutic index of the derivative is greatly elevated over that of the parent, since the derivative may be safely administered in greater quantities.
    公开号:SU886748A3
    申请号:SU772439103
    申请日:1977-01-14
    公开日:1981-11-30
    发明作者:Госалвес Марио
    申请人:Марио Госалвес (Фирма)；
    IPC主号:
    专利说明:

    (5) METHOD OF OBTAINING / STRUCTURED GLYCOSIDES
    one
    The invention relates to a process for the preparation of novel anthracycline GLYCOSID derivatives with valuable pharmacological properties .5
    A known method for producing new derivatives of anthracycline glycosides, based on the known reaction
    metal chelation by bidentate gandami 1J.
    The purpose of the invention is to obtain new useful compounds expanding the arsenal of means of influencing a living organism.
    The goal is achieved by the method of obtaining anthracycline glycosides obtszy formulas where one or more bidentate ligands (a), (b) and (c) are occupied by chelated metal cations selected from the group consisting of Cd (ll), Fe (ll), Zn (ll), Co (11), Pb (ll), Ni (ll Al (III), Cud I), Hg (ll) and Fed II), whose means for the ligands of glycoside molecules is expressed by an association factor of 10, R is - COCH or -COCHO OH, which means that doxorubicin is reacted with the salt of the above metal cation in a molar ratio of 1: (1-3, by adding The pH of the system was adjusted to 6.5-7.5, until soluble monomeric metal-containing glycosides were formed, the resulting solution was separated from solid metal-containing products, and the solution was subjected to rapid freezing. Of these metal cations, the preferred option is to interact with Fe cations ( II), Fe (III, Cu (II) and Co (II). The described metal chelates can be used to control metal ions, especially because of their ability to serve as sources of trace metals for purposes such as growth control plants. Fe metal gels can be of particular importance for use in the treatment of iron chlorosis or in its deficiency in plants. The amount of ferric iron chelate to be used should preferably be sufficient to exclude chlorine conditions for a period of one to two weeks. In addition, the compounds can also serve as stabilizers for various systems, for example plastics derived from vinylidene chloride, in which traces of chloride lead to non-plastic abilities. In such systems, the metal chelate can preferably be used at concentrations sufficient to cover the effects of the maximum amount of chloride that can be released. A biochemical and pharmacological study of the products obtained by the proposed method. in tab. 1 shows the dissociation constants of doxorubicin and daunorubicin with various metals. Metals are listed in order of their common affinity for chelation. Constants are defined for some of them. Table 1 The dissociation constant of the metal derivative with etall doxorubicin. As can be seen from the table. 1, the metal with the highest affinity for doxorubicin is trivalent iron, and the metal with the lowest affinity is calcium. The percent inhibition of DNA synthesis with increasing concentrations of anthracycline is presented in Table. 2; The results table. 2 show that trivalent iron derivatives have the same inhibitory effect on DNA synthesis as the Rhodel antibiotic, and therefore the antitumor activity, as determined by the inhibition of DNA synthesis, remains the same in metal derivatives. in tab. 3 shows the comparative toxicity data for doxorubicin and ferridoxorubicin. This experiment was carried out with samples of ferridoxorubicin, obtained with different proportions of iron (0; 50-, 70; 80-, exceeding 2: 1) with respect to the antibiotic, and all samples gave similar results. The drugs were administered only through one.
    Ferridoxoru100 bitsin
    In tab. k shows the therapeutic activity of ferridoxorubicin in P-338 mice. Ferridoxorubicin obtained with different proportions of the metal to the antibiotic greater than and equal to 2: 1 was used in this experiment.
    Doxorubicin 11 50 C2
    Ferridoxorubicin11 50 48 42
    Experiments table. 4 show that ferridoxorubicin has a therapeutic effect the same as that of doxorubicin in leukemia mice, but it can be used at a higher dose due to its lower toxicity. Since the optimal therapeutic dose of coxorubicin could not be achieved in humans due to toxicity,
    40 30
    100 100
    70
    similar results were obtained from them. The mean survival value of the orf was done on a group of ten mice infected with 100,000 leukemic cells and treated on the first day after infection with increasing doses of doxorubicin and ferridoxorubicin.
    Table
    23
    35
    Sorubicin has a definite therapeutic advantage due to its low toxicity.
    In tab. Figure 5 shows electrocardiographic changes immediately after intravenous injection of increasing doses of doxorubicin and ferridoxorubicin 3: 1 to the rabbit. 6 intraperitoneal injections of a group of ten mice, and the number of survivors was determined after eight days. . This experiment shows that ferridoxorubicin is much less toxic than doxorubicin. When graphical presentation of the results table. 2 it is calculated that the median lethal dose of ferridoxorubicin i used is mg / kg. Table H
    This experiment shows that there is no significant change in electrocardiograms after the administration of ferric oxide of sorubicin, despite the fact that they are very intense after the administration of doxorubicin, this indicates
    Ferridoxor 10 i, 700 5,100 bicin 15, 700 i (, AOO
    Table 5
    the absence of cardiotoxicity in ferrodoxorubicin.
    In tab. 6 shows the spectral characteristics of the visible and infrared cnekTpa of doxorubicin and ferridoxorubicin ()
    Table 6
    From tab. 7, it can be seen that the hematologic toxicity observed with a dose of 20 mg / kg of doxorubicin is not achieved with ferridoxorubicin, until the concentrations are greater than 50 mg / kg.
    Biochemical and pharmacological
    The studies presented in Table 1-1 show that doxorubicin and daunorubicin form (metal chelate derivatives with all the metals listed in Table 1, and these metal chelate derivatives are especially stable if formed with ferric, copper and cobalt ions, and metal chelates The derivatives obtained with a metal-to-antibiotic ratio of 2: 1 or more are less toxic in mice and rabbits and therapeutically active in leukemia mice. In spite of the fact that most of the experiments performed with ferridoxorubicin: at different ratios of metal to antibiotic (2: 1 or higher), the results are similar for metal chelate derivatives of both antibiotics with different metals at different proportions. Example: Ferridoxorubicin 3: 1 (Triferridoxorubicin). 100 µmol doxorubicin and 300 µmol of iron (III) chloride are mixed in an aqueous solution at room temperature, with continuous stirring in a flask equipped with a pH meter. When iron comes into contact with the antibiotic, the complex begins to break out. The pH is slowly adjusted to 7.3 with concentrated NaOH solution. The solution is then diluted with water to a concentration of 1 mg of doxorubicin in 1 ml and tris-oxymethylaminomethane buffer is added at pH 7.3 to a final concentration of 12 mm. Immediately, the solution is quickly passed through a sterile filter with a pore size of 0.22 µm, poured into a small flask, frozen by immersion in liquid nitrogen, and lyophilized. The diophilized powder is sterilely sealed into ampoules containing 10 mg, which are reconstituted immediately before use with 10 ml of water. Similarly, it is possible to conduct the reaction of other anthracycline glycosides with iron chloride (Ml) to obtain the corresponding ferric gels. Example 2. Ferridoxorubicin (3.5: 1). The process is repeated as in Example 1, but using 350 µmol of ferric chloride and the reaction temperature is about. Example 3. Ferridoxorubicin (2.5: 1). The process is repeated as in Example -1, but 250 µmol of ferric chloride are used and the pH is adjusted to 6.9. Example k. Ferridoxorubicin (2: 1). The process is repeated as in Example 1, but using 200 µmol of ferric chloride to obtain a metal derivative of 2: 1. Example 5. Ferridoxorubicin (1: 1). The process is repeated as in Example 1, but using 100 µmol of ferric oxide hydrate. Example 6. Copper (I) - doxorubicin. I Repeat the process as in Example 1, but using copper (II) sulfate instead of ferric chloride. (Example 7. Cobalt - doxorubicin. The process is repeated as in Example 1, but cobalt chloride is used instead of ferric chloride. Representative metal-containing salts suitable for the proposed method FeS04, HgCl, / CuS04, ZnS04, NiClQi, Cd (N03) i, CoCIj, Pb (CCOCH), AJ, (S04: The compounds obtained by the proposed method, when used for treating cancer, are administered in oncologically effective amounts, usually in combination with a pharmaceutically acceptable carrier. Thus, for example, Triferridoxoxorubicin can be given to patients suffering from eoplastic diseases, in doses from 40 to 250 mg / m of the body surface at intervals of from about 1 to 3 weeks. As a rule, these compounds are indicated for use in all those cases of cancer where the corresponding parent glycosides are used, as well as in such forms of cancer when the derivatives are active because of their new permeability characteristics (for example, brain cancer). The yield of the compounds obtained is 98-392. The structure of the metal derivatives of anthrocycline glycosides is calculated by the spectrophotometric method, by infrared, ultraviolet and visible spectra, by nuclear magnetic resonance and potentiometry.
    invention formula
    1. Method of preparation; anthracycline glycosides of general formula
    .H, cJo oh he
    where one or more bidentate ligands (a), (b) and (c) are occupied by chelated cations of a metal selected from the group consisting of Cd (ll), Fe (ll), Zn (ll) .. Co (ll ), Pb (l), Ni (ll AV (III). Cu (ll), Hg (ll) and Fe (IM), whose affinity for the ligands of molecules
    12
    the glycoside is expressed as an association factor of 10, and R is —ACCH or —ACCHpON, compared with that of doxor5 bicin is reacted with the salt of the above metal cation in a molar ratio of 1: (1-3, by adding alkali, the pH of the system is adjusted to up to 6, 5 before formation
    10 soluble monomeric metal-containing glycosides, the resulting solution is separated from solid metal-containing products and the solution is subjected to rapid freezing.
    , 5 2. The method according to claim 1, characterized in that said metal cation is selected from the group consisting of Fe (II), Fed II, Cu (I I) and Co (I I).
    20 Sources of information
    taken into account during the examination 1. Jesai Mr. D.W. , Bittman L.,
    Schwartzbach E, Pharmacodynamic sig n i f I c.ance of metal chelates of the
    25 antracycline drugs. Am. .Ass Cancer Research., Abst., 285, 197.
    权利要求:
    Claims (1)
    [1]
    Claim
    1. The method of producing anthracycline glycosides of the general formula where one or more bidentate ligands (a), (b) and (c) are occupied by chelated metal cations selected from the group consisting of Cd (ll), Fe (l I ), Zn (l I), Cod I), Pb (II), N1 (11), Al (II I), Cu (l I), Hg (lI) and Fe (III), whose affinity for the ligands of molecules
    8867 ^ 12 ^ 8 glycoside expressed by the coefficient 'associations of 10 10 and R ^ is - S0SN 3 or - COCHqOH, characterized in that doksoru s bicine reacted with a salt of the above metal cation in a molar ratio of 1: (1-3 /, by adding alkali the pH of the system is adjusted to 6.5-7.5 until the formation of soluble monomeric metal-containing glycosides, the resulting solution is separated from solid metal-containing products, and the solution is subjected to rapid freezing.
    15 2. The method according to π, 1, characterized in that said metal cation is selected from the group consisting of Fe (ll), Fe (lII), Cu (l |) and Co (II).
    20 Sources of information taken into account in the examination
    1. Jesair DW, Bittman L., Schwartzbach E. Pharmacodynamic sign ifi c.ance of metal chelates of the 25 antracycline drugs. Am. Ass Cancer Research., Abst., 285, 1974.
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    同族专利:
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    法律状态:
    优先权:
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