• 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:
    For use as, inter alia, an anti-neoplastic agent, there is disclosed a compound of the formula:- <CHEM> wherein X is an acid having a total of from three to six carbon atoms, two to five hydroxy groups and an acidic group selected from -CO2H and -OPO3H2 with the proviso that, when the total number of carbon atoms is three or four, the acidic group is -OPO3H2. These particular salts of 4 min -(9-acridinylamino)methanesulfon-m-anisidide remain in solution for a reasonable period and hence permit the use of the compound in this salt form for introduction into a mammal. Also disclosed are the processes for producing the salts and pharmaceutical compositions including the salts.
    公开号:SU1192619A3
    申请号:SU813254200
    申请日:1981-03-10
    公开日:1985-11-15
    发明作者:Р.Фишер Джеймс；П.Кулир Чарльз
    申请人:Варнер-Ламберт Компани (Фирма)；
    IPC主号:
    专利说明:

    1 The invention relates to a process for the preparation of new chemical compounds, namely the (9-acridinyl amino) -methanesulfon-m anisidine salts of the general formula where X is acid, having a total number of carbon atoms from 3 to 6, 2 to 5 oxide groups and an acid group selected of the —COOH or —OPO H groups, the acid group being that if the total number of carbon atoms is 3 or 4, which can be used as biologically active compounds. The purpose of the invention is to develop, on the basis of the well-known reaction of the interaction of vimines with acids, a method of obtaining new compounds with valuable pharmaceutical properties. Example 1, A- (9-Acridine-1-amino methane sulfone m-anisidide B-gluconate (m-AMC D-gluconate A solution of 3.93 g of 4- (e-acridinyl but) -methasulfone-m-anisidine (m-AMCA and 5.16 g of D-gluconic acid, dissolved in e water (38% solution) in 305 ml of anhydrous ethanol is filtered by suction at TO – SO C. The filtrate is cooled to 30–35 ° C and 100 ml of anhydrous diethyl are added with stirring After quenching to 0-5 ° C with stirring, the mixture is kept for about 16 hours at 5 C. The product is collected, washed with anhydrous ethanol in a mixture with anhydrous diethyl ether (3: 1), then with several portions of anhydrous ether and dried under reduced pressure at 50-55c, which gives 3.95 g of m-AMCA D-gluconate.The salt obtained by this method retains a small amount of ethanol (about 1%). Example 2. (9-Acridinyl amino) -methanesulfon-m-anisidide D-ralacturonate (m-AMSA D-galacturonate), Solution of 3.93 g m-AMSA and 2.12 g of D-galacturonic acid monohydrate 325 ml of anhydrous ethanol at 192 yO-SO C is filtered using suction. The filtrate is stirred and quenched to -5 ° C, then kept at -20 ° C for about 16 hours. The product is collected, washed with chilled (approximately -20 ° C) anhydrous ethanol, then anhydrous diethyl ether, and dried at 50-55 ° C, which is - gives 3.9 g of m-AMSA D-ralacturanate. The salt obtained by this method retains a small amount of ethanol (about 3%). Example 3. (9- / kridinylamino) -methanesulfone-m-anisidide D-glucose-6-phosphate (m-AMC D-glucose-6-phosphate). A mixture of 1.804 g of m-AMCA and 0.8576 g (91%) of D-glucose-6-phosphoric acid monohydrate in 19.3 g of dimethylformamide is heated on a hot plate until completely dissolved, which occurs at a temperature of about 100 C. Then hot dark colored solution is diluted with an equal volume of warm (65-70 ° C) anhydrous ethanol and immediately filtered. An additional amount of warm (about 70 ° C) anhydrous ethanol is used to rinse the funnel so that the total amount of ethanol used is 96.5 ml. The mixture is allowed to cool to approximately 20-25 ° C while stirring the contents of the flask from time to time to form a swirling liquid. The mixture is cooled for several hours at 3-5 ° C, then a similar period of time at -8 - (- 20jC. The solid is collected, thoroughly rinsed with cold (3-5 ° C) anhydrous ethanol, then anhydrous diethyl ether and dried under reduced pressure at 39 -40 ° C, which gives 1.38 g of m-AMSA D-glucose-b-phosphate. Example 4. 4 - (9-Acridinylmino) -methanesulfon-m-anisidide-B-gluuronate (D-glucuronate) A solution of 3.93 g of m-AMCA and 2.0 g of β-glucuronic acid in 325 ml of anhydrous ethanol is filtered by suction at 70-80 ° C. After cooling to 30-35 ° C, 45 MP anhydrous diethyl ether is added. tilvoy ester under stirring and cooled rapidly about 5 C. After subsequent cooling at 5 ° C for 16 h, the ol is collected, washed with cold (0-5 ° C) anhydrous ethanol, then anhydrous di 3
    ethyl ether and dried under reduced pressure at, which gives 4.5 g of m-AMSA D-glucuronate,
    It has been found that certain acids that react with m-AMCA give salts that are highly soluble in water. Data on the relative conductivity of m-AMCA salts in water are presented in the table.
    Relative
    Acids
    solubility
    in water
    Galakturonov
    Glucose-6-phosphorus
    Glukonova
    K-Glycerophosphate
    Glukuronova
    Glycerinova
    D-Wynna
    Slizev
    Water
    The compounds of general formula (I) exhibit antitumor activity and can be used to treat neoplasms in mammals, such as dogs, glands, etc. The characteristic painful conditions in which the compounds may be used are protein
    2619
    out (leukemia), breast cancer, hepatocellular liver cancer, melanoblastoma (melanoma), etc. The preferred route of administration is intravenous. A dosage is usually applied in the approximate range of 20 to 500 mg / m of body surface per day for 1 to 5 days, preferably 30 mg to 100 mg / m per day for about three days.
    ten
    Comparison of the anti-leukemia activity and the toxicity of m-AMCA gluconate (g7sh conate amsidine U compared with m-AMSA showed that glucoacin nathsidine is less toxic than m and ta-AMSA (in terms of mg / kg). For example, the score for Amsidine gluconate was 26 mg / kg (the dose in both experiments), while the estimate for LD, Q d.h. of meta 20 AMCA under the same conditions was 8.7 mg / kg (dd in one experiment) and 13 mg / kg (dose in the second experiment V,
    When using the mentioned doses
    25 Treatment with gluconate amidine resulted in a 10% and 112% increase in lifespan. In addition, 0.5 - reduction in tumor size was obtained with a dose of 26 mg / kg /
    30 / day of amidine gluconate. On the other hand, the treatment of meta-AMSA was somewhat less effective (55% and 87% in experiments). With such doses, meta-AMSA (8.7 and 13 mg / kg /
    35 / day) the size of the tumor even increases (and does not decrease) by 0.5 and 1.1 log.Q. Thus, with regard to the anti-leukemic activity of the two drugs, glutaate meta-AMC
    40 snnjad tumor size in comparison with the composition of meta-AMS 1.01, 5 times for.
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING 4 '(9-ACRIDINYLAMINO) -METANSULFONE-M — ANISIDINE SALTS of the general formula where X is an acid having a total number of carbon atoms of 3 to 6, 2 to 5 hydroxy groups and an acid group selected from —COOH or —OPO 9 11 2 groups, and the acid group means OPOjHg, the total number of carbon atoms is 3 or 4, characterized in that they carry out the reaction of 4 Z - (9-acridinylamino) methanesulfon-m-anisidine of the formula with acid X, where X has the indicated values.
    Π92619>
    eleven
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    引用文献:
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    HU188181B|1981-06-11|1986-03-28|Warner-Lambert Co,Us|Process for producing salts of naphtiridine and quinoline compounds of antimicrobial activity|
    US4575509A|1983-01-31|1986-03-11|Bristol-Myers Company|Water-soluble formulations of m-AMSA with pyroglutamic acid|
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    EP3707127A4|2017-11-09|2021-12-01|The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc.|Compounds for inhibiting ly6k and methods of using same|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US12950380A| true| 1980-03-11|1980-03-11|
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