WO1996040704A1 - Derives apparentes au pirazole presentant des activites antitumorales et antivirales, procedes de preparation, formulations pharmaceutiques les contenant - Google Patents

Derives apparentes au pirazole presentant des activites antitumorales et antivirales, procedes de preparation, formulations pharmaceutiques les contenant Download PDF

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Publication number
WO1996040704A1
WO1996040704A1 PCT/EP1996/002485 EP9602485W WO9640704A1 WO 1996040704 A1 WO1996040704 A1 WO 1996040704A1 EP 9602485 W EP9602485 W EP 9602485W WO 9640704 A1 WO9640704 A1 WO 9640704A1
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WIPO (PCT)
Prior art keywords
compound
formula
cooch
ocoph
obtaining
Prior art date
Application number
PCT/EP1996/002485
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English (en)
Inventor
Paolo La Colla
Stefano Manfredini
Daniele Simoni
Pier Giovanni Baraldi
Alessandra Pani
Original Assignee
Sardinian Antiviral Research Consortium Sarc S.C.R.L.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Sardinian Antiviral Research Consortium Sarc S.C.R.L. filed Critical Sardinian Antiviral Research Consortium Sarc S.C.R.L.
Priority to AU61256/96A priority Critical patent/AU6125696A/en
Publication of WO1996040704A1 publication Critical patent/WO1996040704A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/052—Imidazole radicals

Definitions

  • R is H. CH 2 OH, CH 2 OCOPh. CH 2 0 Si(CH 3 ) 2 C(CH 3 ) 3 , CH 2 OPO 3 Na 2 , CH 2 OPO[OCH 2 0-
  • This invention refers also to pharmaceutically acceptable salts and soluble derivatives of compounds of formula (I), to processes for their preparation and to their use in pharmaceutical formulations for the treatment of tumors and viral infections, with pa ⁇ icular regard to infections carried out by human immunodeficiency viruses (HTV) and herpesviruses.
  • HTV human immunodeficiency viruses
  • Ribavirin l- ⁇ -D-ribofuranosyl-l,2,4-triazole-3-carboxamide
  • IMPDH inosine monophosphate dehydrogenase
  • tiazofurin (2- ⁇ -D-ribofuranosyl-tiazole-3-carboxamide)
  • selenazofurin (2- ⁇ -D-ribofuranosyl- selenazole-4-carboxamide)
  • ribamidin l- ⁇ -D-ribofuranosyl-l,2,4-triazole-3- carboxamidine
  • FICAR fluoro-l- ⁇ -D-ribofuranosyl-imidazole-4-carboxamide
  • EICAR 5-ethynyl- 1 - ⁇ -D-ribofuranosy l-imidazole-4-carboxamide).
  • Ribavirin Besides their activity against a wide variety of human tumours, the above cited derivatives, and in particular ribavirin, are active against orthomyxoviruses (Influenza A and B), paramyxoviruses (parainfluenza. measles, respiratory svncvtial virus), arenaviruses and bunyaviruses. They are also active against pox, picoma-, toga and reoviruses. Ribavirin has been reported to prolonge the survival of monkeys infected with Lassa fever virus; it is used for the treatment of infections caused by respiratory svncvtial virus and. so far, is the sole drug endowed with some efficacy in the treatment of viral haemorragic fevers in man.
  • R may be H or CH3 and R 1 may be Br. I. N02- NH2 or H.
  • the present invention refers to processes for the preparation of compounds having general formula (I) and to their use in pharmaceutical formulations useful for the antitumor chemotherapy and for the treatment of viral infections such as those caused by human immunodeficiency viruses (HIV) and herpesviruses.
  • HIV human immunodeficiency viruses
  • compounds of formula (I) were able to enhance the antiviral activity of 2'.3'-dideoxy-inosine (ddl) 2 ⁇ 3'-dideoxy-adenosine (ddA), 9-[2-(phosphono-methoxy)ethyl]-adenine (PMEA), 9-[2-(phosphono- methoxy)propyl]-guanine (PMPG), 9-[2-(phosphono-methoxyjpropyl]-adenine (PMPA). acyclovir (ACG). 9-[2-(phosphono-methoxy)-ethyl]-guanine (PMEG) and adenine- arabinoside (araA).
  • the present invention also refers to the use of compounds of formula (I) with the aim of potentiating the anti-HIV activity of ddl. ddA. PMEA. PMPG. PMPA and the antiherpes activity of ACG. PMEG and araA. It also refers to pharmaceutical formulations containing the compounds of formula (I) with at least one antiviral agent such as ddl. ddA. PMPG. PMPA for the treatment of HIV infections or in combination with antiviral agents such as ACG, PMEG and araA useful for the treatment of herpetic infections also in AIDS patients. Another fundamental feature of this invention is that it refers to new intermediates of the above preparation processes. DETAILED DESCRIPTION OF THE INVENTION
  • R COOCH 2 CH 3 .
  • R 1 CH(OH)CH 2 N0 2 .
  • n 0.
  • R 2 CH 2 OBz,
  • R COOCH 2 CH 3 .
  • R 1 C ⁇ CH.
  • n 1.
  • R COOCH 2 CH 3 .
  • R 1 CH(OH)CH 2 N0 .
  • n 1.
  • R COOCH3.
  • R 2 CH 2 OSi(CH 3 ) 2 -t-Bu
  • R COOCH 3 .
  • R 2 CH 2 OPO[OCH 2 OCOC(CH 3 ) 3 ] 2 .
  • R 2 CH 2 OH.
  • R 3 and R 4 isopropylidene;
  • R 2 CH 2 OPO[OCH 2 CH 2 SCOC(CH 3 ) 3 ] 2
  • R 3 and R 4 isopropylidene:
  • Compounds of general formula (I) may be prepared by the processes described below (in the formulae Me indicates the CH3 group, Et the CH3CH2 group and Bu the CH3CH2CH2CH2 group).
  • the carboxylic acid derivative 19 may be easily obtained by hydrolysis of 2 with a base, for example sodium hydroxide, preferentially at concentrations of 0.35 M.
  • a base for example sodium hydroxide
  • the hydroxyl groups of the sugar moiety of compound 2 may be protected in a conventional manner, for example with terbutyldimethylsilylchloride (TBDMS).
  • TDMS terbutyldimethylsilylchloride
  • the persilylated intermediate 20 may be treated for example with an alcohol R'OH wherein R" is - alkyl, preferably butanol and sodium hydride in an organic solvent such as benzene to afford the protected butyl ester.
  • Silyl protecting groups may be removed by conventional means, conveniently with ammoniumfluoride (NH4F) in methanol, preferentially in the presence of acetic acid, to give the expected compound 21
  • Solid tumor-derived cells were grown in their specific media supplemented with 10% FCS and antibiotics.
  • the cell lines used were the following: CHO-K1, Chinese hamster ovary; HT- 29, human colon adenocarcinoma; HeLa. human cervix carcinoma; ACHN, human renal adenocarcinoma; 5637, human bladder carcinoma; IMR-32, human neuroblastoma.
  • Cell cultures were incubated at 37 * C in a humidified, 5% C ⁇ 2 atmosphere. The absence of mycoplasma contamination from both suspension and monolayer cultures was checked periodically by the Hoechst staining method.
  • Viruses Human immunodeficiency virus type-1 (HIV-1.
  • Antiproliferative assays Exponentially growing leukemia and lymphoma cells were resuspended at a density of 1x10 cells/mL in growth medium containing serial dilutions of the drugs, alone or in combination. Cell viability was determined after 96 hrs at 37 * C by the 3-(4.5- ⁇ imethylthiazol-2-yl)-2.5-diphenyi-tetrazoiium bromide (MTT) method, as previously described by Denizot F. and Lang R. (J. Immunol. Methods 89, 271-277. 1986) and by Pau Stamm et al. (J. Virol. Methods 20. 309-321. 1988). Activity against solid tumor-derived cells was evaluated in exponentially growing cultures
  • non-adherent cells were resuspended at 1x10 cells/mL in growth medium, stimulated with PHA (2.5 ⁇ g/mL) for 24 hrs before dilution to 1x10 cells/mL in medium containing PHA (2.5 ⁇ g mL), IL-2 (50 U/ml) and various concentrations of the test compounds. Viable cell numbers were determined six days later. Under these conditions, untreated PBL were able to undergo exponential growth up to four cell cycles, as determined by viable cell counts.
  • CFU-GM Myeloid precursors of granulocyte-monocytes
  • Cytotoxicity of compounds was evaluated in parallel with their antiviral activity and was based on the viability of mock-infected cells, as monitored by the MTT method.
  • Antiviral assays The antiviral activity against HSV-1 and -2 was evaluated by either the plaque reduction assay in Vero cells or the yield reduction assay in Hela cells.
  • the activity against vaccinia, VSV and Coxsackie B 2 viruses was evaluated by the MTT method in Vero cells infected at a multiplicity of infection of 0.01. Kaposi ' s model in mice.
  • Kaposi ' s sarcoma secreted products (KSsup) were e obtained from cell-free supematants of cell cultures from Kaposi's lesions as previously described by Albini A., et al. (Int. J. Oncol. 1, 723-730. 1992).
  • the standard amount of KS SU p inoculated per sample corresponded to the culture supernatant of 4x10 cells.
  • Liquid Matrigel solutions containing KSsup * heparin (22 U/ml) and various concentrations of the test compounds were injected subcutaneously into the flanks of C57bl/6 male mice (final volume 600 ⁇ l) where they formed a polymerized support.
  • Antiproliferative activity of compounds of general formula (I), in vitro was evaluated against a panel of human leukemia, lymphoma and solid tumor cell lines, together with that of ribavirin. selenazofurin and doxorubicin. used as reference drugs (Table 1).
  • inhibitory concentration fifty compound concentration ( ⁇ SD) required to reduce cell growth by 50% under conditions allowing untreated cell controls to undergo at least three consecutive rounds of multiplication.
  • L1210 mouse leukemia; Wil2-NS, human splenic B-lymphoblastoid cells; CCRF-SB, human acute B-lymphoblastic leukemia: Raji, human Burkitt lymphoma; CCRF-CEM and MOLT-4, human acute T-lymphoblastic leukemia. C8166 and MT-4.
  • Compound 2 showed potent inhibition of leukemia and lymphoma cell proliferation (IC50 in the range 0.2-2.4 ⁇ M) and turned out only 2-4 times less potent against carcinoma and neuroblastoma cell lines (IC50 in the range 2.9-8.6 ⁇ M). Overall, no significant differences could be seen in both potency and spectrum of antiproliferative activity between 2 and selenazofurin. Doxorubicin was the most potent compound (IC50 m tne range 0.03-0.9 ⁇ M), ribavirin the weaker (IC50 in the range 5.7-27 ⁇ M).
  • W.12-NS >300 21 >300 >300 14 >300 >300 >300 102
  • CCRF-SB >300 32 >300 >300 16 230 180 >300 89
  • Inhibitory concentration fifty compound concentration ( ⁇ SD) re ⁇ uired to re ⁇ uc ⁇ cell growth by 50% under conditions allowing untreated controls to undergo at least tnree consecutive multiplication rounds. Values are the mean of three separate expenments. Variability among triplicate samples was less than 12%.
  • PBL peripheral blood lymphocytes
  • CFU-GM bone marrow granulocyte monocyte
  • PBLPHA 2.6 ( ⁇ 1.0) 1.0 ( ⁇ 0.5) u. ⁇ 5 ( ⁇ 0.05) 10 ( ⁇ 4) 0.04 ( ⁇ 0.06) 0.005 ( ⁇ 0.004)
  • CFU-GM colony forming units of bone marrow hematopoietic progenitors of granuiocytes macrophages.
  • c Data are me mean IC 50 values obtained in ⁇ eu ⁇ emia cell lines.
  • Taxol 0.75+ 0.008 20 25 “Values are the mean of three separate experiments carried out in CEM cells. Variability among triplicate samples was less than 12%. "Value predicted for additive effect, tells were pretreated with compound 2 for 12 hrs. Significant synergism (the observed value is less than 70% of the predicted value).
  • the alkylating agent cisplatinum, the intercalating compound doxorubicin or the antimitotic drug taxoi gave additive antiproliferative effects.
  • the pyrazole derivative proved synergistic also in combination with 6TG and 5FU.
  • the present invention refers to a pharmaceutical composition comprising a compound of the present invention, preferentially compound 2, in combination with antiretroviral drags such as dideoxynucleosides or acyclic phosphonate nucleosides for the AIDS therapy.
  • antiretroviral drags such as dideoxynucleosides or acyclic phosphonate nucleosides for the AIDS therapy.
  • the range of haemoglobin content m control Matrigel implants was 0.681 - 2.033. c Values below 0.400 were considere ⁇ negative.
  • reaction mixture was diluted with CH2CI2 (50 mL), washed with water (50 mL), 10% citric acid/H2 ⁇ (50 mL), water (50 mL) dried and concentrated to dryness to give a residue which was purified by column chromatography (EtOAc/Hexane, 3/7).
  • reaction mixture was diluted with CH2CI2 (50 mL) washed with water (50 mL), 10% citric acid/H2 ⁇ (50 mL), water (50 mL) anhydrified evaporated in vacuo to give a residue which was purified by column chromatography (EtOAc/Hexane, 3/7).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention décrit des dérivés apparentés au pirazole de formule générale (I), dans laquelle R représente COOH, COOR', et (III) et R' représente un radical alkyle C1-C5; R1 représente I, Br, C1, F, CF¿3?, CN, SCN, CHO, CH=CH2, CH=CH Br, C C-Si (CH3)3, CH=CH COOCH2CH3, C CH, CH2=CH NO2, n vaut 0 ou 1; R?2¿ représente H, CH¿2?OH, CH2OCOPh, CH2OSi (CH3)2C(CH3)3, CH2OPO3 Na2, CH2OPO[OCH2O-COC(CH3)3]2, CH2OPO[O CH2 CH2SCOC(CH3)3]2; R?3 et R4¿ sont identiques ou différents l'un de l'autre et représentent H, OH, CH¿2?OCOPh, CH2O Si(CH3)2C(CH3)3, ou bien ils forment ensemble un groupe isopropylidène, à condition que lorsque R?2 = R3 = R4¿ = H n soit toujours égal à 1; et en excluant le composé comportant R=COOCH¿3, R?1 = I n = 0, R3 = CH2OCOPh, R3 = R4 = OCOPh. Ces composés possèdent une action antitumorale et peuvent accroître l'activité antivirale d'agents antiviraux connus. L'invention décrit également les procédés de préparation des composés de formule (I) ainsi que les préparations pharmaceutiques les contenant.
PCT/EP1996/002485 1995-06-07 1996-06-07 Derives apparentes au pirazole presentant des activites antitumorales et antivirales, procedes de preparation, formulations pharmaceutiques les contenant WO1996040704A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU61256/96A AU6125696A (en) 1995-06-07 1996-06-07 Pyrazole-related derivatives endowed with antitumor and anti viral activities, procedures for their preparation, pharmace utical formulations containing them

Applications Claiming Priority (2)

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ITCA95A000005 1995-06-07
IT95CA000005A IT1281498B1 (it) 1995-06-07 1995-06-07 Pirazolo - derivati ad attivita' antitumorale, processo per la loro preparazione e composizioni farmaceutiche che li contengono , e

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1027359A2 (fr) * 1996-10-16 2000-08-16 ICN Pharmaceuticals, Inc. L nucleosides monocycliques, analogues et leurs utilisations
WO2002009684A2 (fr) * 2000-07-28 2002-02-07 Georgetown University Inhibiteur de l'erbb-2 kinase selectif de petites molecules
EP1302474A1 (fr) * 1996-10-16 2003-04-16 Ribapharm, Inc. L-nucléosides monocycliques, analogues et leurs utilisations
JP2012530113A (ja) * 2009-06-18 2012-11-29 サントル ナショナル ドゥ ラ ルシェルシュ シアンティフィク より良好な生物学的利用能を示すホスホネート誘導体の合成のためのホスホネートシントン
CN110698464A (zh) * 2018-07-10 2020-01-17 南京大学 一类含吡唑骨架的白杨素衍生物的设计、合成及其生物活性评价

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MANFREDINI S. ET AL: "Pyrazole-Related Nucleosides. Synthesis and Anitviral/Antitumor Activity of Some Substituted Pyrazole and Pyrazolo[4,3-d]-1,2,3-triazin-4-one Nucleosides", JOURNAL OF MEDICINAL CHEMISTRY, vol. 35, 1992, WASHINGTON US, pages 917 - 924, XP002018485 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1027359A2 (fr) * 1996-10-16 2000-08-16 ICN Pharmaceuticals, Inc. L nucleosides monocycliques, analogues et leurs utilisations
EP1027359A4 (fr) * 1996-10-16 2001-07-25 Icn Pharmaceuticals L nucleosides monocycliques, analogues et leurs utilisations
EP1302474A1 (fr) * 1996-10-16 2003-04-16 Ribapharm, Inc. L-nucléosides monocycliques, analogues et leurs utilisations
WO2002009684A2 (fr) * 2000-07-28 2002-02-07 Georgetown University Inhibiteur de l'erbb-2 kinase selectif de petites molecules
WO2002009684A3 (fr) * 2000-07-28 2002-04-25 Univ Georgetown Inhibiteur de l'erbb-2 kinase selectif de petites molecules
JP2012530113A (ja) * 2009-06-18 2012-11-29 サントル ナショナル ドゥ ラ ルシェルシュ シアンティフィク より良好な生物学的利用能を示すホスホネート誘導体の合成のためのホスホネートシントン
CN110698464A (zh) * 2018-07-10 2020-01-17 南京大学 一类含吡唑骨架的白杨素衍生物的设计、合成及其生物活性评价

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Publication number Publication date
ITCA950005A0 (it) 1995-06-07
IT1281498B1 (it) 1998-02-18
AU6125696A (en) 1996-12-30
ITCA950005A1 (it) 1996-12-07

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