• 专利附录
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    • 专利摘要:
    New 2:1 complexes of N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A or 11-aza-10-deoxo-10-dihydroerythromycin A with bivalent metals chosen from the group comprising Cu<+><2>, Zn<+><2>, Co<+><2>, Ni<+><2> and Ca<+><2>, a process for their manufacture and their use in the manufacture of antibiotically active pharmaceuticals. New 2:1 complexes of N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A or 11-aza-10-deoxo-10-dihydroerythromycin A with bivalent metals chosen from the group comprising Cu<+><2>, Zn<+><2>, Co<+><2>, Ni<+><2> and Ca<+><2> are made by reacting N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A or 11-aza-10-deoxo-10-dihydroerythromycin A in its free base form or in its water-soluble salt form with salts of said bivalent metals. The compounds possess antibiotic activity.
    公开号:SU1572416A3
    申请号:SU874203302
    申请日:1987-09-11
    公开日:1990-06-15
    发明作者:Вайтнер Зиатко；Лопотар Невенка；Дьекич Слободан
    申请人:Соур Плива Фармацойтска Кемийска, Прерамбена И Козметичка Индустрия, Н.Сол.О. (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing new metal complexes of erythromycin A derivatives with divalent metals Cu, Zn, Co, Ni or Ca in a 2: 1 ratio, showing bactericidal activity and which can be used in medicine. The structure of the target products is not installed.
    The purpose of the invention is the synthesis of new compounds exhibiting a higher bactericidal activity as compared with known compounds.
    Complexes of metals N-methyl-1-aza-10-deoxo-10-dihydroerythromycin A and
    11-aza-10-deoxo-10-dihydroerythromycin A is soluble in methanol, ethanol, acetone, chloroform, methylene chloride, benzene, and dimethylformamide, when they are not soluble in n-hexane, petroleum ether, and water.
    The N-methyl-11-aza-10-deoxo-10-dihydroerythromycin Au 11-aza-10-deoxo-10-dihydroerythromycin A Cu complexes (examples 1 and 7) have a broad maximum in the ultraviolet range of about 280 nm, and the visible region is about 485 nm (ethanol), while the Co complexes (examples 4 and 9) have a weak, wide maximum around
    Yu
    Willow
    oh
    s
    655 nm in the visible region of the spectrum (methanol). The bactericidal activity of the target products was tested in comparison with erythromycin A. The bactericidal activity of the target products with respect to Sarcina lutea A iCC 9341 (U / Mg) compared with the initial erythromycin A following, E / mg (E: erythromycin A; rN-methyl- 11-aza-10-deoxo-10-dihydro-erythromycin-A &amp; HL: 11 aza-10-deoxo-10-dihydroerythromycin A):

    910 834 852 849 852 856 495 530 435 500 517
    LD 50 of all obtained products is more than 3000 mg / kg.
    As can be seen from the data, the target products show a higher bactericidal activity than the original ligand.
    Example 1 (method A). 0.749 g of K-methyl-11-aza-10-deoxo-10-dihydro-erythromycin A is weighed in a 100 ml glass beaker and with the addition of 1N. (mol / L) HCl in 50 ml of water (0.02 mol / L of solution) is dissolved with stirring (pH about 6). Then, 0.086 g of Cu12-2H20 (0.01 mol / l solution, calculated as) is added and mixed with 0.1N with portions with stirring. (mol / l) NaOH up to pH 8.5. The reaction mixture was stirred for 2 hours while maintaining a constant pH (stationary pH), the purple precipitate was removed, washed three times with 10 ml of water, dried, and 0.64 g of product was obtained (81.8%).
    C-analysis (polarographic method, 0.1N (mol / l) HC1, E / (h - -O, 25V according to FCE (saturated calomel electrode): calculated 4.07%, found 4.1%.
    Activity: 834 U / mg Sarcina lutea ATCC 9841.
    PRI me R 2 (method B). In 30 ml of a 0.02 M solution of N-methyl-P-aza-10-deoxo-10-dihydroerythromycin
    Q
    five
    0
    five
    0
    5 0 5 Q
    five
    0.086 g of CuCl2, 2H20 (0.01 M solution calculated as Cu + 4) is dissolved on 60% methanol on A and, after adjusting the pH to 8.5 with 0.1 n. (mol / l) NaOH is stirred for 2 hours at room temperature. The reaction mixture is concentrated under reduced pressure to about half the volume, a purple colored precipitate is filtered off with suction, washed three times with 10 ml of water, dried, and dried to obtain 0.62 g of product (79.3%).
    Product analysis is identical to that of example 1.
    PRI me R 3. The procedure described in Example 1 was carried out, with the only difference being that 0.068 g of ZnCl was added instead of CCl2 and the pH was maintained at 8.6. Obtain 0.61 g of white product (77.9%).
    Zn analysis (atomic absorption spectral photometric method): calculated 4.18%; found 4.5%.
    Activity: 852 U / mg Sarcina lutea ATCC 9341.
    Example 4: Proceed as described in Example 1, with the only difference that, instead of CuCl, 0.118 g is added and the pH is maintained at 8.6. Obtain 0.63 g of the product is a light green color (80,7%).
    Co-analysis (polarographic method, 0.1 N. (mol / l) HC1 - 0.1 N. (mol / l) KC1 (1:25), E -1.60 V according to SCE): calculated, 3 , 79%; found, 4.1%.
    Activity: 849 U / mg Sarcina lutea ATCC 9341.
    PRI me R 5. Proceed as described in Example 1, with the only difference being that instead of CyCl, 0.119 g of NiCl2-6H20 is added and the pH is maintained at 8.6. light green color.
    Ni-analysis (polarographic method, 0.1 n. (Mol / l) HC1 - 0.1 n. (Mol / l) KC1 (1:25), E / 2 1.55 V according to SCE (saturated calomel electrode ): calculated, 3.77%, found, 4.3%.
    Activity: 852 U / mg Sarcina lutea ATCC 9341.
    PRI me R 6. Proceed as in example 1, with the only difference that BMedTO CuCl2 is added 0.074 g of CaCl2 12HyO and support
    pH 8.6. Obtain 0.60 g (77.9%) of white color of the product.
    Ca-analysis (atomic absorption spectral-photometric method): calculated, 2.60%, found, 3.3%.
    Activity: 856 U / mg Sarcina lutea ATCC 9341.
    Example. Proceed as in example 1, with the difference that, in conjunction with N-methyl-11-aza-I0-deoxo-10-dihydroerythromycin A, we weigh 0.735 g of 11-aza-10-deoxo-10-dihydro-erythromycin A and support pH 9.0. 0.62 g of a violet-colored product (80.8%) was isolated.
    C-analysis (polarographic method, 0.1 N (mol / l) HC1): calculated, 4.14%; found 4.4%.
    Activity: 495 U / mg Sarcina lutea ATCC 9341.
    Primer Proceed as described in Example 2, with the difference that instead of N-methyl-1 1 -az-1 0 deoxo-10-dihydroerythromycin A, 0.735 g 1 of 1-aza-10-deoxo-Yudihydroerythromycin A is weighed. and instead of CuCl, 0.068 g of ZnCl2 is used and the pH is maintained at 10.0 for 3 hours. 0.53 g (69.0%) of the white color of the product is isolated.
    Zn analysis (atomic absorption spectral photometric method): calculated, 4.10%; found, 4.6%.
    Activity: 530 U / mg Sarcina lutea ATCC 9341.
    Example 9. Proceed as described in example 4, with the difference that instead of N-methyl-11-aza-10-deoxo-10-dihydroerythromycin A we weigh 0.735 g 1 of 1-aza-Yu-deoxo-Yudihydroerithromycin A and maintain a pH of 10. 0.54 g (70.6%) of light green product is recovered.
    Co-analysis (polarographic method, 0.1 n. (Mol / l) HC1 −0.1 n. (Mol / l) KC1): calculated, 3.72% J found, 4.1%.
    Activity: 435 U / mg Sarcina lutea ATCC 9341.
    Example 10. Proceed as opsano in Example 9, with the only difference being that 0.118 g of NiCl2-6K20 is added instead of CoCl2. 0.56 g (73.2%) of the light green color of the product is recovered.
    Ni-analysis polarographic method, 0.1 n. (mol / l) HC1 - 0.1 n.
    (mol / l) KS1): calculated, 3.70%; found, 4.1%.
    Activity: 500 U / mg Saricina lutea ATCC 9341.
    Example 11 Proceed as described in Example 9, with the only difference being that 0.074 g of CoCl Co is added. 0.52 g (68.9%) of the white color of the product is recovered.
    Ca-analysis (atomic absorption spectral-photometric method): calculated, 2.55%; found, 3.0%.
    Activity: 517 U / mg Saricina lutea ATCC 9341.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining metal complexes of erythromycin A derivatives of the formula
    25
    Nz / SNZ
    N
    ° HX
    Hic
    about
    CH3
    oh he
    H3CO CH3
    35
    five
    0
    five
    0
    la R - SNE Ib R - H
    with divalent metals Cu, Zn, Co, Ni, or Ca in a 2: 1 ratio, showing bactericidal activity, characterized in that N-methyl-11-aza-10-deoxo-10-dihydro-erythromycin A of formula 1a, or 11-azo-10-deoxo-10-dihydroerythromycin A of formula Ib, directly or after treatment with hydrochloric acid, as a result of which the corresponding hydrochloride is obtained, is reacted with an appropriate metal halide salt in a 2: 1 molar ratio in water water-alcohol medium at room temperature ie at pH 8.5 - 10.0, maintained by adding alkali, followed by removal .s alcohol under reduced pressure, and the title product isolation by filtration.
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    引用文献:
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    YU1592/86A|YU44599B|1986-09-12|1986-09-12|Process for preparing complex of n-methyl-11-aza-10-deoxo-10-dihydroeritromicine a and 11-aza-10-deoxo-10-dihydroeritromicine a with metals|
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