• 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:
    Compound of the formula (I) <IMAGE> (I) wherein n is zero or an integer of 1 to 3; R is (a) -NHR3, wherein R3 is (a') -CON(NO)R4, in which R4 is C1-C4 alkyl either unsubstituted or substituted by halogen; or (b') -CO(CH2)m-R5, in which R5 is halogen, oxiranyl, methyloxiranyl, aziridinyl, a group <IMAGE> or a group <IMAGE> and m is zero or an integer of 1 to 4; or (b) <IMAGE> wherein either R6 and R7 are the same and are each oxiranemethyl, aziridinemethyl, or C2-C4 alkyl 2-substituted by halogen or by a group -OSO2R8 wherein R8 is C1-C4 alkyl or phenyl, or one of R6 and R7 is hydrogen and the other is as defined above; each group R1 is, independently, hydrogen or C1-C4 alkyl; R2 is a C1-C6 alkyl group terminating with (i) a basic moiety chosen from an amino group, a mono- or di- C1-C6 alkylamino group, an amidino group, a group <IMAGE> imidazolyl, imidazolinyl, tetrahydropyrimidinyl and oxazolidinyl; or (ii) a carboxy group; or (iii) a free hydroxy group -OH or a glycosilated hydroxy group -OD wherein D is a glucose, mannose or ribose sugar residue or the daunosamine amino-sugar residue; with the proviso that n is different from one when R2 is <IMAGE> and the pharmaceutically acceptable salts thereof. The compounds are useful as antiviral and antitumor agents.
    公开号:SU1609445A3
    申请号:SU874203699
    申请日:1987-11-26
    公开日:1990-11-23
    发明作者:Аркамоне Федерико；Монджелли Никол；Пенко Серджио
    申请人:Фармиталиа Карло Эрба, С.П.А. (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the field of obtaining new derivatives of distamycin AI, namely poly-4-aminopyrrol-2-carboxamide derivatives of the general formula
    Cl-CHi-CHi, Cl-CHr-CH,
    : N.
    W
    CHj
    where n is 0.1 or 2;
    R is a group of propionamidine, dimethylaminopropyl or 2-imidazole, provided that when R is not a group of propionamidine, in the form of a hydrochloric acid salt, having antiviral and antitumor activity.
    The aim of the invention is to develop, on the basis of known methods, a method of producing new compounds possessing valuable pharmacological properties with low toxicity.
    PRI me R 1. Hydrochloride / 3-N-methyl-4-N-methyl-4-nitropyrol-2-carboxamide pyrrole-2-carboxamido-propionamidine (900 mg), dissolved in 150 ml of ethanol, 75 ml water and 9 ml of 2n. hydrochloric acid is hydrogenated in a Parr apparatus for 45 minutes at a hydrogen pressure of 45 psi. an inch at room temperature over a palladium catalyst (10% on coal). The catalyst is filtered off, the filtrate is evaporated under vacuum and 930 mg is obtained.
    oh oh
    ib.
     ate
     s
    crude dihydrochloride / YM-methyl-4- -Y-m8til-4-am1 / 1-pyrrol-2-carboxam-do-pyrrole-2-carboxamido propionamidine. The residue is dissolved in methyl alcohol (60 ml), cooled before and treated with 12 ml of ethylene oxide. After 15 minutes, the temperature is allowed to rise and the mixture is left at room temperature overnight. The solution is evaporated to dryness and obtained after chromatography on SiO2, washed with hydrochloric acid, 800 mg of pure S-hydrochloride N-methyl-4-N-methyl-4-N, N-bic- (2-hydroxyethylamino) pyrrole-2-carboxamido-1 pyrrole-2-carboxamido-propionamidine,
    Similarly, N-deformin-N-N-methyl-4- -N, N-bis- (2-hydroxyethylamino) pyrrole-2-carboxamido-distamycin A. hydrochloride is obtained.
    Pr im ep 2, A stirred solution of the hydrochloride / 3-M-methyl-4-M-methyl-4-S, M-bis- (2-hydroxyethylamino) pyrrole-2-carboxamido-pyrrole-2-carboxamido- -propionamidine (717 mg) in dry pyridine {10 ml) is cooled in an ice bath, treated under a nitrogen atmosphere to solutions of methanone phenonyl chloride in pyridine (1.27 mol, 2.7 ml) and stirred at 5 ° C in for 45 minutes. After cooling with methyl alcohol, the mixture is allowed to warm to room temperature and evaporated to dryness. The crude product is chromatographed on silica to give 440 mg of S-N-methyl-4-N-methyl-4-N, N-bis hydrochloride (2-chloroethylamino) pyrrole-2-carboxamido-pyrrol-2- carboxamido-propionamidine,
    The following compounds are prepared analogously:
    N-deformin-N-N-methyl, -, N-bis- (2-chloroethylamino) pyrrol-2-carboxamido distamicin A hydrochloride;
    M-deformyl-L-M-methyl 4-N-methyl-4-N, J-bis- (2-chloroethylamino) -pyrrole-2-carboxamido-pyrrole-2-carboxamido-distamycin A hydrochloride;
    3-N-methyl-4-M-methyl-4-N-methyl-4-S, N-bis- (2-chloroethylaminr) pyrrole-2-carboxamido pyrrole-2-carbs1-xamido pyrrol-2- hydrochloride carboxamido propyl dimethylamine;
    / 5-N-methyl-4-M-methyl-4-M-methyl-4-N-methyl-4-N, M-bis (2-chloroethylamino) pyrrol-2-carboxamido pyrrole-2-carboxes - Dopirol-2-carboxamido pyrrol-2-carb6-xamido ethyl- {2-imidazole) hydrochloride;
    / 3-M-methyl-4-M-methyl-4-M-methyl-4-M-methyl-4-S, M-bis- (2-chloroethylamino) pyrrol-2-carboxamido pyrrole-2-carboxes - to pyrrole-2-carboxamido pyrrol-2-carboxamido ztil-2- (2-imidazoline) hydrochloride;
    3-G-methyl-4-N-methyl-4-N-methyl-4-M-methyl-4-M, M-bis- (2-chlorostilamino) pyrrole-2-carOoxamido pyrrole-2- hydrochloride
    carboxamido pyrrole-2-carboxamido pyrr ol-2-carboxamido propyldimethylamine:
    / 3-N-methyl-4-N-methyl-4-tN-methyl-4-Nmethyl-4-S, N-bis- (2-chloro-ethylamino) pyrr-ol-2-carboxamido-pyrrole-2-carboxam- to -pyrrol-2-carboxamido pyrrol-2-carbamoxamido ethyl 2- {3,4,5,6-tetrahydropyrimidine) hydrochloride.
    PRI me R 3. Gaseous chloride
    5 hydrogen is bubbled into the ethanol solution of M-deformyl-M-N-methyl-4-M, N-bis (2-chloro-ethylamino) -pyrrole-2-carboxamido distamycin A (100 mg) with external cooling in an ice bath water After half an hour the precipitate is filtered under nitrogen and the resulting solid is dried in vacuo to give 80 mg of N-deformyl-M-methyl-4-M, N-bis- {2-chloro-ethylamino) PIr-2-carboxamido-distamycin A hydro5 chloride.
    The proposed compounds show significant efficacy in suppressing the reproductive activity of pathogenic viruses and in protecting tissue cells from viral
    0 infections, They are active against DNA viruses, such as lichen viruses, lichen deprive and shingles, and adenoviruses, as well as retroviruses, such as sarcoma viruses and
    5 leukemia. So, for example, lichen viruses, resyner-syncytial viruses are tested in a liquid medium. Successive twofold dilutions of the compounds from 200 to 1.5 µg / ml were distributed (two) in the amount of 0.1 ml / well in 96 microplates with tissue culture wells.
    Cell suspensions (2x10 cells / ml) - non-infected, to verify the pitotoxicity, or infected in an amount of approximately 5x10 TCI DSO virus / cell were immediately added in an amount of 0.1 ml / well. After incubation for 3-5 days. at 37 ° C in an atmosphere of 5% C02. The cell culture was evaluated by microscopic observation and the maximum tolerant dose (MksTD), as well as the minimum inhibitory concentration (BMD) was determined. MaxTD is the maximum concentration of the compound, allowing for the growth of mono-5 layers, similar to the control in density and morphology. BMD is the minimum concentration at which a decrease in cytopathic effect is observed compared with infected control cultures.
    Compounds were considered active if their activity index, calculated by the MCSD / MP ratio, was 2..
    The compounds of the invention also exhibit cytostatic properties against tumor cells, as a result of which they can be used to inhibit the growth of various tumors,
    The table shows the activity data of some compounds (I), indicated by the internal code, in comparison with the closest and most studied known compound - distamycin A,
    The compounds listed in the table were tested for cytotoxicity (which is an expression of antitumor activity) against leukemia cells of L 1210 mice.
    权利要求:
    Claims (1)
    [1]
    Cells were isolated from tumors in vivo and maintained in cell culture. Cells were used until the tenth cycle of reproduction. Cytotoxicity was determined by counting the surviving cells after 4 hours of drug exposure and 48 hours of growth in a drug-free medium. The percentage of cell growth in the treated cultures was compared with the control. Values of LDso (doses inhibiting 50% of cell growth relative to control) were calculated from dose-response curves. The invention The method for producing poly4-aminopyrrol-2-carboxamido hydrochlorides derived from the general formula
    ac-chi
     -w
    cn,
     v
    cvb
    n
    XN
    Tri and
    ats
    where p O, 1 or 2;
    R is a group of propionamidine, dimethylaminopropyl or 2-imidazole, provided that when R is not a propionamidine group, characterized in that the amine dihydrochloride of the general formula
    H, N
    where p and R have the indicated meanings, are reacted with ethylene oxide of the formula
    dream
    H-
    with the subsequent chlorination of the hydrochloride thus obtained with 2-hydroxyethylene-on the general formula
    30 NO-CH, -CH, NO-CH -CH,
    : N.
     - ((1 I lci I l / i- - rh-me I il, | -OIS - (, C-HLOR
    ethylamino) pyrrole-2-carboxamido-pyrrole-2-carboxamido 1 distamycin A hydrochloride: MUJM I,
    FCE 24661: M-deformyl-N-N-methyl-4-N, N-bis- (2-chlorostilamino) pyrrole-2-carbox (: amido distamycin A hydrochloride- FCE25603: /: N-methyl-4- N- methyl-4-N, N-bis- (2-chloroethylamino) pyrrole-2-carboxamido pyrrole-2-carboxamido | propionamidine hydrochloride:
    FCE 25550: chlorohydrate-N-methyl-4-N-methyl-4-N-methyl-4-N-methyl-, N-bis (2-chloro-ethylamino) pyrrole-2-carboxamido pyrrol-2-, carboxamido ; pyrrole-2-carboxamido pyrroldimethylamine:
    FCE 25486: hydrochloride / - M-methyl-4-N-methyl-4-N-methyl-4-N-methyl-4-, N-bis- (2-chlorostilamino) pyrrole-2-carboxamido pyrrole-2-car - boxamido pyrrol-2-carboxamido ethyl-2-imidazole:
    35 where R has the indicated meanings.
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1609445A3|1990-11-23|Method of producing hydrochlorides of poly-4-aminopyrrol-2-carboxamide derivatives
    SU1528316A3|1989-12-07|Method of producing derivatives of distamycin a or hydrochlorides thereof
    CA1308516C|1992-10-06|Oligopeptide anticancer and antiviral agents
    SU1535378A3|1990-01-07|Method of producing hydrochlorides of derivatives of distamine a
    FI106864B|2001-04-30|A process for the preparation of therapeutically useful indolopyrrolocarbazole derivatives
    FI95463B|1995-10-31|Process for the preparation of acryloyl-substituted pyrrole derivatives useful as anti-tumor agents
    US4681933A|1987-07-21|2&#39;,3&#39;-dideoxy-5-substituted uridines and related compounds as antiviral agents
    DK166080B|1993-03-08|ANALOGY PROCEDURE FOR THE PREPARATION OF AN N-OE4- | AMINOBUTYLAA-2- | -2-SUBSTITUTED ETHANAMIDE OR SALT THEREOF
    CA2271299A1|1998-05-22|Benzoheterocyclic distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents
    CA2244139C|2005-06-07|Distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents
    CA2260060C|2007-01-30|Acryloyl substituted distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents
    AU721140B2|2000-06-22|Distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents
    IE59073B1|1994-01-12|Poly-4-aminopyrrole-2-carboxamido derivatives and process for their preparation
    EA000033B1|1998-02-26|Bis| aminophenyl substituted distamycin derivatives as antitumor and antiviral agents
    MXPA97001949A|1997-06-01|Derivatives of distamycine substituted with bis- | aminophenylene as anatomy agents yantivira
    US5310752A|1994-05-10|Site specific alkylating agents
    MXPA98009426A|1999-10-14|Derivatives of distamycine, processes for the preparation of them and their use as antitumoral agents and antivira
    MXPA99000875A|1999-10-14|Acryloyl substituted distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents
    同族专利:
    公开号 | 公开日
    SU1544185A3|1990-02-15|
    ZA865263B|1987-03-25|
    GB8517922D0|1985-08-21|
    US4766142A|1988-08-23|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    CA547128A|1957-10-08|American Cyanamid Company|Substituted pyrrolecarboxamidopyrroles|
    CA557568A|1958-05-20|J. Weiss Martin|Substituted aminopyrrolecarboxylic acids and esters|
    FR86210E|1963-04-04|1966-03-23|
    FR90359E|1963-07-26|1968-02-14|
    FR4158M|1963-07-26|
    NL130086C|1964-07-14|1970-06-15|GB8612218D0|1986-05-20|1986-06-25|Erba Farmitalia|Site specific alkylating agents|
    US5310752A|1986-05-20|1994-05-10|Farmitalia Carlo Erba Spa|Site specific alkylating agents|
    DD261844A1|1986-07-09|1988-11-09|Adw Ddr|METHOD FOR PRACTICING FIBRINMONOMERS|
    GB8906709D0|1989-03-23|1989-05-10|Creighton Andrew M|Acryloyl substituted pyrrole derivatives|
    IT1247878B|1991-02-15|1995-01-05|Menarini Farma Ind|POLY-4-AMINOPYRROL-2-CARBOXYXID DERIVATIVES, PREPARATION PROCESSES AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM|
    US5670506A|1993-04-05|1997-09-23|Cell Therapeutics, Inc.|Halogen, isothiocyanate or azide substituted xanthines|
    US6020337A|1993-04-05|2000-02-01|Cell Therapeutics, Inc.|Electronegative-substituted long chain xanthine compounds|
    EP0791581B1|1995-09-12|2001-10-10|Kyowa Hakko Kogyo Co., Ltd.|Uch15 compounds|
    JP2000503999A|1996-02-02|2000-04-04|フアルマシア・エ・アツプジヨン・エツセ・ピー・アー|Distamycin derivatives, their preparation, and their use as antitumor and antiviral agents|
    US6559125B1|2000-01-28|2003-05-06|California Institute Of Technology|Polyamide-alkylator conjugates and related products and method|
    US7078536B2|2001-03-14|2006-07-18|Genesoft Pharmaceuticals, Inc.|Charged compounds comprising a nucleic acid binding moiety and uses therefor|
    WO2001074898A2|2000-03-16|2001-10-11|Genesoft, Inc.|Charged compounds comprising a nucleic acid binding moiety and uses therefor|
    EP2289888A3|2000-06-30|2011-07-13|Seikagaku Corporation|Epoxycarboxylic acid amides, azides and amino alcohols and processes for preparation of alpha-keto amides by using them|
    ITTO20010633A1|2001-07-02|2003-01-02|Univ Ferrara|NEW USE OF HETEROCYCLIC AND BENZOHETEROCYCLIC POLYAMIDS STRUCTURALLY RELATED TO NATURAL ANTIBIOTIC DISTAMYCIN A.|
    ITMI20021455A1|2002-07-02|2004-01-02|Ugo Raffaello Citernesi|PHOSPHOLIPIDIC FORMULATIONS OF LEXITROPSINS THEIR PREPARATION AND THERAPEUTIC USE|
    WO2004012736A1|2002-08-02|2004-02-12|Genesoft Pharmaceuticals, Inc.|Biaryl compounds having anti-infective activity|
    WO2004039318A2|2002-10-25|2004-05-13|Genesoft Pharmaceuticals, Inc.|Anti-infective biaryl compounds|
    EP1587529A4|2002-12-10|2009-08-12|Oscient Pharmaceuticals Corp|Antibacterial compounds having a -- motif|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB858517922A|GB8517922D0|1985-07-16|1985-07-16|Carboxamido derivatives|
    [返回顶部]