• 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:
    Distamycin A analogs of the following formula (I): <CHEM> wherein n is 2, 3 or 4; A is a divalent radical chosen from <CHEM> and -Het-, wherein Het is a pentatomic or hexatomic heteromonocyclic ring, except pyrrole, the said radical being unsubstituted or substituted by one or more substituents chosen from C1-C6 alkyl, C1-C6 alkoxy, cyano and trifluoromethyl; and either one of R1 and R2 is hydrogen and the other is a) a group <CHEM> in which R3 is C1-C6 alkyl unsubstituted or substituted by halogen atoms; phenyl; or cyclohexyl; or b) a group -CO-(CH2)m-R4 in which m is zero, 1, 2 or 3 and R4 is hydrogen, halogen, hydroxy, aziridinyl or oxiranyl; or R1 and R2 are the same and they are both hydrogen or both a C1-C6 alkyl group unsubstituted or substituted by halogen, hydroxy or C1-C6 alkoxy; and the pharmaceutically acceptable salts thereof; are antitumor and antiviral agents.
    公开号:SU1528316A3
    申请号:SU874202591
    申请日:1987-05-18
    公开日:1989-12-07
    发明作者:Лаццари Этторе；Аркамоне Федерико；Пенсо Серджо；Антониетта Верини Мария；Монгелли Никола
    申请人:Фармиталиа Карло Эрба С.Р.Л. (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the field of obtaining new derivatives of distamycin A of the general formula
    R2
    / N-A-CO
    HNI
    sn,
    h J-CO-.-NH-CHi-CHj-Cf,
    n
    and mi
    NH
    NH,
    where n is 3 or 4; A is a radical
    when one of
    R and Rj is hydrogen, and the other is the group —CO-N-Rj, in which
    N0
     R - - C, -Sc, -alkyl, unsubstituted or. Substituted by an atom
     O1
    3152831
    Loitsa, silt and the group -CO-CCH) -R, where m O, and R - aziridinyl or oxyrchyl A - radical
    c1

    SNS
    or
    r-n v
    where R and R are the same and mean
    C, -C-alkyl, substituted by halogen,
    or their hydrochlorides possessing antitumor and antiviral activities.
    The aim of the invention is to develop, on the basis of known methods, a method for producing new derivatives of distamycin A, which possess valuable pharmacological properties with low toxicity.
    Example 1. P- / l- ethyl-4- / l-methyl-4- / 1-methyl-4- 4-N-methyl-N - nitrosoureidobenzene / - -carboxamo-do1pyrrol-2-carboxamido / pyrrole-2- carboxamido / pyrrole-2-carboxami- do / propionamidine, hydrochloride.
    A solution of 0.1 ml of triethylamine in 1 ml of dimethylformamide (DOP) is added over 5 minutes to a stirred solution of 0.41 g of N-deformyl distamycin in 2.5 ml of DMF at room temperature under nitrogen atmosphere. After 15 minutes, 0.17 g of 4- (N-nitroso-N-methylureido) benzoic acid and 0.16 g of dicyclohexylcarbodiimide are added in small portions. The reaction mixture is stirred for 2 hours and 25 ml of ethyl ether is added. The solid product collected by filtration is purified by column chromatography on silica gel with mixtures of ethyl acetate, methanol and acetic acid to give 0.175 g of the desired compound, m.p. 205-210 ° С (with decomposition), from isopropanol.
    Similarly, ft- / 1-methyl-4- / 1-methyl-4- / 1-methyl-4- 4-N- / 2-chloro-1-H-nitrosouridobenzene / -carboxamido-pyrrole-2-carboxyamido / pyrrole-2-carboxyami- to / pyrrol-2-carboxamido / propionamidine, hydrochloride, so pl. 182 C (decomposition).
    Example 2. p) - / l-Netil-4- / l-methyl-4- / l-methyl-4- 4-N, N-bic / 2-chloroethyl / aminothiophene-2-carbox-2-propanol-2-carboxy-Uprupole 2-cap
    0
    five
    0
    five
    O., e 0 45
    55
    50
    64
    boxed w / pyrrol-2-carboxamido / pro | pionamidine, hydrochloride.
    Stage Intermediate 4-N, N-bis- / 2-chloroethyl / aminothiophene-2-carboxylic acid.
    Starting from 1.74 g of methyl 4-nitrothiophen-2-carboxonlate, 0.90 g of methyl 4-aminothiophene-2-carboxypate, m.p. 81-82 ° C.
    4 g of cold ethylene oxide was added to the solution of 0.9 g of methyl 4-aminothiophene-2-carboxylate in 12.5 ml of 40% aqueous acetic acid at 5 ° C with stirring. The mixture was kept overnight at room temperature in a sealed flask, then concentrated to low volume and diluted with 25 ml of water. Solid sodium bicarbonate is added and the mixture is extracted with ethyl acetate. Upon evaporation of the organic solvent, 1.3 g of methyl- / K, N-bis / 2-oxistil / aminothiophene-2-carboxylate are obtained in the form of a light brown oil, which solidifies on standing, mp. 68-69 ° C (from a mixture of 60:40 ethyl acetate: hexane).
    1.3 g of bisoxyethylamino derivative is dissolved in 1.96 ml of phosphorus oxychloride and the mixture is heated under reflux for 45 minutes. After evaporation in vacuo, the dark residue is treated with 7.75 ml of concentrated hydrochloric acid at 100 ° C for 3 hours. The mixture is cooled, 21 ml of cold water is added and the resulting solution is extracted with ethyl acetate. After purification of the organic solvent and purification of the solid by chromatography on a column of silica gel, eluting with a mixture of ethyl acetate and methanol, 0.49 g of 4-N, M-bis- / 2-chloroethip / aminothiophene-2-carboxylic acid are obtained; . 135-137 ° С (from 60:40 benzene: hexane mixture).
    Stage II. Target connection Solution O, 1 ml of triethylamine in
    0.5 ml of D1-1F is added to a solution of 0.4 g of deformyldistamycin dihydrochloride in 4.5 ml of DMF at room temperature under a nitrogen atmosphere.
    The mixture is treated with 0.23 g of 4-N, N-bis- / 2-chloroethyl / aminothiophene-2-carboxylic acid and 0.77 g of dicyclohexyl-carbodiimide in small amounts. The resulting mixture is stirred all night, then filtered and evaporated to dryness in vacuo. The solid residue is purified by chromatography on silica2995.
    5.15
    kagel, using as eluent a mixture of. ethyl acetate and ethanol (9: 1 and 8: 2 by volume). Obtain 0.22 g of the title compound, m.p. 199-204 ° C (after recrystallization from isopropyl alcohol).
    Similarly, the following compounds can be prepared:
    fi - / 1-methyp-4- / 1 -methyl-4- / 1-methyp-4-L4-N, N-bis- / 2-chloroethyl / aminoimide "sol-l-methyl-2-carbox-II propo-2 - carbamide / propol-2-carbamide-. before pyrr6l-2-carboxamido / propi6n amidine, hydrochlorochlor;
    P- / I-methyl-4- / 1-methyl-4- / 1-methyl-, N-bis- / 2-chloroethyl / amino-imidazole-1-methyl-2-carboxamo pyrrole-2- carb-xamido / pyrrole- 2-carboxamido / - pyrrole-2-carboxamido / propionamidine, hydrochloride;
     1-methyl-4- / 1-methyl-4- / 1-methyl-, N-6is- / 2-chloroethyl / aminothiazole-2-carboxamido pyrrole-2-carboxamido / pyrrole-2-carboxamnzo / pyrrole-2-car - boxam / propionamidine, hydrochloride
    P- / I-methyl-4- / 1-methyl-4- / I-metip-4-r5-N, N-bis- / 2-chloroethyl / aminothenazole-2-carboxamido | pypropol-2-carboxamide / propol-2-carbamide / propol-2- carbamine / propionamidine, gudproxlo-RVD.
    Example 3. p - / 1-Methyl-4- / 1-methyl-4- / 1-methyl-4-4-N, N-bis- / 2-chloroethyl / aminobenzene-1-carboxamido pyrrole-2-carboxamido / pyrrole-2-carboxamboxamido / pyrrole-2 carboxamdo / propionamidine, hydrochloride,
     A solution of 0.195 g of sodium bicarbonate in 3 ml of water is added to a cooled solution of 0.4 g of deformyl distamycin in 21 ml of ethanol. To this mixture, a solution of 0.32 g of 4-N, N-bis- / 2-chloroethyl / amino-benzoyl chloride in 3 ml of benzene is added to the mixture. The mixture is stirred for 3 hours at 5 ° C and then for 12 hours at room temperature. temperature
    After evaporation in vacuo, a solid residue is obtained which is chromatographed on a column of silica gel, eluting with mixtures of chloroform and methanol C9: 1 and 7: 3 by volume) to give 0.22 g of the desired product, mp, decomposition) from isopropyl alcohol and ethyl ether.
    The following compounds are prepared analogously:
    L- / 1-methyp-4- / 1-methyl-4- / 1-methyl-4- / 1-methyl-4- 4-N, N-bis- / 2-chloroethyl /
    ten
    15
    20
    25
    52831

    ,




     ,
    thirty
    35
    40
    45
    50
    55
    6. 6
    aminobenzene-.1-carboxamido pyrrole-2-carboxamido (pyrrole-2-carboxamido) - pyrrole-2-carboxamido / pyrrole-2-carboxamido / propionamidine, Hzcrochloroc; B- / 1-metip-4- / 1-metip-4- / 1 -methyl-1
    4-L3-N, N-bis- / 2-chloroethyl / aminobenzene-1-carboxamido pyrrole-2-carboxamo-to / pyrrole-2-carboxamido / pyrrole-2-carboxamcce / propionamccin, hydrochloride;
    (- / 1 -methyl-4- / 1-methyl-4- (I-methyl-. 4- 4- (oxyrancarbonyl) aminobenzene-1-carboxamido pyrrole-2-carboxamido) -fir; rol-2-carboximido / pyrrol -2-carboxamco / propionamidine, guadrochlorde;
    - / 1-methyl-4- / 1-methyl-4- / 1-methyl-4- 3- / oxirancarbonip / aminobenzene-1- carboxamido pyrrole-2-carboxamido / - pyrrole-2-carboxamido / pyrrole-2-car - boxamido / propionamidine, chlorohydrate;
    3- / 1-methyl-4- / 1-methyl-4- / 1-methyl-β-aziridinecarbonyl / aminobenzene-1-carboxamide pyrrole-2-carboxamo-to / pyrrole-2-carboxamido / pyrrole-2-carboxamido / propionamidine , hydrochlor
    REED;
    (B- / -methyl-4- / 1-methyl-4- / 1-methyp-aziridine / carbonylaminobenzene-1-carboxamido pyrrole-2-carboxam- | to / pyrrole-2-carboxamido Upyrrole-2-carboxamido / propionamidine, hydrochloride.
    The table shows in vitro data on antitumor activity relating to the compound b - / 1-methyl-4- / 1-methyl-4- / 1-methyl-4- 4-N, N-bis- / 2 -chloroethyl / aminobenzene-1-carboxamide-to pyrrole-2-carboxamido / pyrrole-2-carboxamido / pyrrole-2-carboxamido / - propionamidine, hydrochloride (code FCE 24517) and - / 1-methyl-4- / J-metip -4- / 1-methyl-4- 4-N, N-bis- / 2-chloroethanol / aminothiophene-2-carboxamido pyrrole-2-carboxamko-pyrrol-2-carboxamidoUpyrrol-2-carboxamido / propionamvdin hydrochlorochlor (FCE code 24690) compared with distamycin A.
    In vitro antitumor activity was assessed using a cytotoxicological study conducted on raurine Z 1210 leukemia cells, Z-PA11 leukemia resistant cells and P388 leukemia cells, as well as HeZa cells. Cells originated from in vivo tumors) and adapted to cell culture. The cells were used before the tenth passage. Cytotoxicity is determined by.
    counting the surviving β-cells 4 h after treatment and 48 h of growth on a drug-free medium. For HeZa cells, a colony inhibition test was used. The percentage of cell growth in the treated cultures is compared with that for control. Values of LDgp (doses inhibiting 50% of cell growth relative to control) are calculated from dose-response curves.
    The proposed compounds also showed significant efficacy when pathogenic viruses overlap with reproductive activity and protect tissue cells from viral infections. So, they show activity against DNA viruses such as, for example, herpes (for example, herpes simplex and herpes zoster, RNA viruses such as rhinoviruses and adenoviruses, and against retroviruses such as sarcoma viruses.
    Herpes viruses, coxsackie (coxsachie) and respiratory-sentimental were tested in a liquid medium by the following method. Serial twofold dilutions of compounds from 200 to 1.5 µg / ml are distributed in duplicate O, 1 ml / well in 96 wells of microplates for tissue culture. Immediately, cell suspensions (2-10 cells / ml), infected with approximately S lO lCLDgQ virus / cell in 0.1 ml / well, are added. After 3-5 days of incubation at 37 ° C in 5% CO, the cell cultures are evaluated by microscopic observation and the minimum inhibitory concentration is determined, which determines the decrease in the cytopathic effect compared to the infected controls.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining derivatives of distamycin A of the general formula
    Ru
    RO
    ; N-A-COHN-Tj-PMN
     1 CO — NH — CH, —CH, —Ct N MH.
    Hj
    sn.
    but
    where p a
    3 or 4; radical
    when one of
    R and Rj is hydrogen, and the other group is —CO-N-R ,, B of which
    I
    N0
    R Cj-C is alkyl, unsubstituted or substituted by a halogen atom or the group —CO (CHj) -R4, where m O and R is aziridinyl or oxirane.
    or A is a radical
    where is r. and R2 is the same and means C —C (alkyl, substituted by halogen,
    or their hydrochlorides, characterized in that the compound of the general formula
     NH-CH i-CH.-Ct
    NH
    n
    CH
    3
    but
    where n - has the indicated meanings, is reacted with a compound of the general formula
    Ru
    {
    : M-A-CO-X
    where X is hydroxyl or g.chogen;
    R, R and A are as defined.
    with the subsequent selection of the target product in free form or in the form of hydrochloride.
     Cytotoxicity evaluated 4 hours after
    processing. Pitotoxicity was assessed 48 hours after
    processing ..
     The test on the inhibition of colonies was carried out 24 hours after treatment.
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    同族专利:
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    HUT44044A|1988-01-28|
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    US5017599A|1991-05-21|
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    IL82553D0|1987-11-30|
    GR3006163T3|1993-06-21|
    KR870011129A|1987-12-21|
    HK31993A|1993-04-08|
    GB8612218D0|1986-06-25|
    ES2046202T3|1994-02-01|
    JPH0623193B2|1994-03-30|
    PT84896B|1990-02-08|
    DK254587A|1987-11-21|
    FI872173A0|1987-05-18|
    IL82553A|1991-06-10|
    MX9203122A|1992-07-01|
    ZA873593B|1987-11-12|
    EP0246868B1|1992-09-16|
    HU201336B|1990-10-28|
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    DK254587D0|1987-05-19|
    IE871292L|1987-11-20|
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    SG3793G|1993-03-12|
    BR1101017A|1999-12-07|
    CS413791A3|1992-09-16|
    PT84896A|1987-06-01|
    KR950011408B1|1995-10-04|
    DE3781716T2|1993-03-11|
    IE60198B1|1994-06-15|
    UA5928A1|1994-12-29|
    AU7316387A|1987-11-26|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB868612218A|GB8612218D0|1986-05-20|1986-05-20|Site specific alkylating agents|
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