WO1993007868A1 - Composes aromatiques nitreux liant l'adenosine-diphosphoribose polymerase efficaces en tant qu'agents antitumoraux et anti-retrovirus - Google Patents

Composes aromatiques nitreux liant l'adenosine-diphosphoribose polymerase efficaces en tant qu'agents antitumoraux et anti-retrovirus Download PDF

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WO1993007868A1
WO1993007868A1 PCT/US1991/008902 US9108902W WO9307868A1 WO 1993007868 A1 WO1993007868 A1 WO 1993007868A1 US 9108902 W US9108902 W US 9108902W WO 9307868 A1 WO9307868 A1 WO 9307868A1
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nitroso
group
compound
cancer
hydrogen
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PCT/US1991/008902
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English (en)
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Ernest Kun
Jerome Mendeleyev
William G. Rice
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Octamer, Inc.
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Priority to JP4505220A priority Critical patent/JP3070767B2/ja
Priority to AU12609/92A priority patent/AU676992B2/en
Priority to EP92904892A priority patent/EP0609211A4/fr
Publication of WO1993007868A1 publication Critical patent/WO1993007868A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/65—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/18—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted otherwise than in position 3 or 7

Definitions

  • the present invention relates generally to the field of retroviral therapeutic agents and their use in treating viral infections and cancers. More specifically it relates to those therapeutic agents which inhibit ADP-ribose transferase, and in particular various nitroso- benzopyrones, nitroso-isoquinolinones and nitroso-benzamides.
  • ADP-ribose transferase (E.C.4.2.30) is a chromatin-bound enzyme located in the nucleus of most eukaryotic cells.
  • the enzyme catalyzes the polymerization of the ADP- ribose moiety of nicotinamide adenine dinucleotide (NAD + ) to form poly (ADP-ribose).
  • the polymer is covalently attached to various nuclear proteins, including the polymerase itself.
  • ADPRT a target for drugs essentially useful for combating neoplasia and viral infections.
  • Numerous physiological activities have been detected for compounds that inhibit the polymerase activity of ADPRT.
  • Such activities include a cell cycle dependent prevention of carcinogen-induced malignant transformation of human fibroblasts (Kun, E., Kirsten, E., Milo, G.E. Kurian, P. and Kumari, H. L. (1983) Proc. Natl. Acad. Sci. USA 80:7219-7223), conferring also carcinogen resistance (Milo, G.E., Kurian, P., Kirsten, E. and Kun, E. (1985) FEBS Lett.
  • Compounds known to inhibit ADPRT polymerase activity include benzamide (Kun, E., Kirsten, E., Milo, G.E. Kurian, P. and Kumari, H. L. (1983) Proc. Natl. Acad. Sci. USA 80: 7219-7223), substituted benzamides (Borek, C, Morgan, W.F., Ong, A. and Cleaver, J.E. (1984) Proc. Natl. Acad. Sci. USA 81:243-247; Romano, F., Menapace, L. and Armato, V.
  • ADPRT polymerase activity inhibitors include 5-iodo-6-amino-1,2-benzopyrone as described in U.S. Patent application Serial No. 600,593, filed October 19, 1990 entitled “Novel 5-Iodo-6-Amino-1,2-Benzopyrones and their Metabolites Useful as Cystostatic and Anti-Viral Agents" for use as anti-tumor and anti-viral agents.
  • the cited patent discusses the possibility of using 5-iodo-6-nitroso-1,2-benzopyrone as an anti-tumor or anti-viral agent.
  • the 6-nitroso-benzopyrones have not been hitherto known or described.
  • 6-nitro-1,2-benzopyrone and 6-amino-1,2-benzopyrone (6-ABP) (J. Pharm. Soc. Jap., 498 : 615 (1923)) for which, only scarce medicinal evaluation has been reported.
  • 6-ABP 6-nitro-1,2-benzopyrone and 6-amino-1,2-benzopyrone
  • testing was done for sedative and hypnotic effects (J. Pharm. Soc. Japan, 73:351 (1953); Ibid, 74:271 (1954)), hypothermal action (Yakugaku Zasshi, 78:491 (1958)), and antipyretic, hypnotic, hypotensive and adrenolytic action (Ibid, 83:1124 (1963)).
  • 6-ABP 6-nitro-1,2-benzopyrone and 6-amino-1,2-benzopyrone
  • ADPRT a DNA-binding nuclear protein present in all mammalian cells
  • ADPRT polymerase activity inhibitors for use as anti- viral and anti-tumor agents.
  • the subject invention provides for novel nitroso-1,2-benzopyrone, nitroso-benzamide and nitroso- isoquinolinone compounds, and various structurally related other nitroso compounds for use as anti-viral and anti-tumor therapeutic agents.
  • the compounds taught for use in the subj ect invention are believed to be significantly less toxic and far more (500 to 1000 fold) potent than structurally analogous amino compounds.
  • the subject invention provides for novel anti-tumor and anti-viral compounds. These compounds include 6-nitroso-1, 2-benzopyrone, 3-nitrosobenzamide, 5-nitroso-1(2H)-isoquinolinone, 7-nitroso-1(2H)-isoquinolinone, 8-nitroso-1(2H)-isoquinolinone.
  • the invention also provides for compositions containing one or more of the compounds, and for methods of treating viral infections and cancer with these compounds and compositions.
  • composition containing one or more of these compounds is also provided for.
  • Figure 1 is a graph comparing the degree of ADRPT polymerase activity (ADPRP) inactivation exhibited by different concentrations of 6- nitroso-1,2-benzopyrone, 3-nitroso-benzamide, and nitroso-1(2H)-isoquinolinones (NOQ) (a mixture of the 5 and 7 nitroso isomers).
  • ADPRP ADRPT polymerase activity
  • Figure 2 is a composite of graphs displaying the inhibitory effects of the ADRPT ligands on (A) 855-2 cells (a cell line of human B-cell lineage acute lymphoblastic leukemia), (B) H9 cells (a cell line of human T-cell lineage acute lymphoblastic leukemia), (C) HL-60 cells (a cell line of human acute nonlymphoblastic leukemia) and (D) K562 cells (a cell line of human chronic myelogenous leukemia).
  • FCS fetal bovine serum
  • E and F the 855-2 cells were cultured in the presence of autocrine growth factor activity (AGF) or low molecular weight-B-cell growth factor (BCGF, a T-cell derived lymphokine), respectively.
  • ALF autocrine growth factor activity
  • BCGF low molecular weight-B-cell growth factor
  • Figure 3 is a graph showing the inhibition of increasing levels of leukemic cell growth (in response to increasing concentrations of FCS) of 855-2 cells by 6-nitroso-1,2-benzopyrone (NOBP) and 3-nitrosobenzamide (NOBA).
  • NOBP 6-nitroso-1,2-benzopyrone
  • NOBA 3-nitrosobenzamide
  • Figure 4 is a graph showing that NOBP and NOBA inhibit the ability of human leukemic cells (855-2 and HL-60) to form colonies (CFU) from single cells in a semi-solid medium.
  • Figure 5 shows graph of the relative inhibitory effects of anti-leukemic doses of ADRPT ligands on the ability of (A) normal rhesus bone marrow stem cells or (B) human peripheral blood stem cells to form colonies in soft agar. Note that the NOBP and NOBA had minimal effect on normal cells.
  • Figure 6 shows graphs displaying the inhibitory effects of NOBP, NOBA and NOQ on four human brain tumor cell lines.
  • Figure 7 is a graph comparing the effectiveness of NOBP with vincristine.
  • Figure 8 is a graph displaying the effects of NOBP, NOBA and NOQ on human breast tumor cell line MDA 468.
  • Figure 9 is a graph displaying the effects of NOBP, NOBA and NOQ on murine leukema cell line L 1210. Description of Specific Embodiments
  • the subject invention provides for several nitroso compounds that are ADPRT polymerase activity inhibitors. These compounds find use as anti-tumor and anti-viral compounds.
  • Compound (I) has the following formula:
  • R 1 , R 2, R 3 , R 4 , R 5 , and R 6 are selected from the group consisting of hydrogen and nitroso, and only one of R 1 , R 2 , R 3 , R 4 , R 5 , and R 5 is a nitroso group.
  • a preferred embodiment of compound I is where R 4 is the nitroso group, i.e., the molecule 6- nitroso-1,2-benzopyrone.
  • Compound II has the formula:
  • R 1 , R 2 , and R 3 are selected from the group consisting of hydrogen and nitroso, and only one of R 1 , R 2 , and R 3 is a nitroso group.
  • Compound III has the formula:
  • R 1 , R 2 , R 3 , R 4 , and R 5 are selected from the group consisting of hydrogen and nitroso, and only one of R 1 , R 2 , R 3 , R 4 , and R 5 is a nitroso group.
  • Preferred embodiments of compound III are where either R 4 or R 2 ,is the nitroso group, i.e., 5-nitroso-1(2H)-isoquinolinone and 7-nitroso- 1(2H)-isoquinolinone, respectively.
  • the disclosed synthesis for 5-nitroso-l (2H)-isoquinolinone may produce 2 closely related structural isomers, 7-nitroso-1(2H)-isoquinolinone and 8-nitroso-1(2H)-isoquinolinone.
  • experiments testing the biological activity of 5-nitroso-1(2H)-isoquinolinone may have contained significant quantities of 8-nitroso-1(2H)-isoquinolinone or 7-nitroso-1(2H)-isoquinolinone, all three isomers are believed to possess similar anti-tumor and anti-viral activity on the basis of their close structural similarity.
  • the nitroso compounds of the subject of invention may be synthesized by oxidizing a corresponding amino compound to a compound of the subject invention by oxidation with 3-chloroperoxybenzoic acid (or other peroxyacids) in ethyl acetate or a halocarbon solvent. Syntheses of these precursor amino compounds are described in the chemical literature and some of the compounds are commercially available. Some precursor amino compounds for oxidation to nitroso compounds of the subject invention are as follows: 3-amino- 1,2-benzopyrone (Spectrum Chemical Mfg.
  • the subject invention contemplates various structurally related compounds that have similar carcinostatic and/or anti-viral activities. These structurally related compounds could be conveniently screened on the basis of their highly potent inhibitory effect on ADPRT polymerase activity.
  • Structurally related compounds of interest include derivatives substituted by additional nitroso groups and small, e.g., C 1 -C 3 alkyl groups.
  • the compositions may be in the solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, powders, liquids, suspensions, or the like, preferably in unit dosages.
  • compositions will include an effective amount of at least one of compounds (I) to (III), or pharmaceutically acceptable salts thereof, and in addition it may include any conventional pharmaceutical excipients and other medicinal or pharmaceutical drugs or agents, carriers, adjuvants, diluents, etc., as customary in the pharmaceutical sciences.
  • compositions in addition to the compounds (I) to (III), such excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like may be used.
  • excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like may be used.
  • the compounds of the subject invention may be also formulated as suppositories using, for example, polyalkylene glycols, for example, propylene glycol, as the carrier.
  • Liquid, particularly injectable compositions can, for example, be prepared by dissolving, dispersing, etc., at least one of active compounds (I) to (III) in a pharmaceutical solution such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, DMSO and the like, to thereby form the injectable solution or suspension.
  • active compounds (I) to (III) in a pharmaceutical solution such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, DMSO and the like, to thereby form the injectable solution or suspension.
  • a pharmaceutical solution such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, DMSO and the like.
  • a pharmaceutical solution such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, DMSO and the like.
  • a pharmaceutical solution
  • Another aspect of the compounds of the subject invention are the ease with which they permeate cell membranes and their relative absence of non-specific binding to proteins and nucleic acid.
  • the ADPRT polymerase inhibitors of this invention may be administered in amounts, either alone or in combination with each other, and in the pharmaceutical form which will be sufficient and effective to inhibit neoplastic growth or viral replication or prevent the development of the cancerous growth or viral infection in the mammalian host.
  • Administration of the active compounds and salts described herein can be via any of the accepted modes of administration for therapeutic agents. These methods include systemic or local administration such as oral, parenteral, transdermal, subcutaneous, or topical administration modes.
  • the preferred method of administration of these drugs is intravenous, except in those cases where the subject has topical tumors or lesions, where the topical administration may be proper. In other instances, it may be necessary to administer the composition in other parenteral or even oral forms.
  • the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and other substances such as, for example, sodium acetate, triethanolamine oleate, etc.
  • Parenteral injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.
  • a more recently devised approach for parenteral administration employs the implantation of a slow-release or sustained-release systems, which assures that a constant level of dosage is maintained, according to U.S. Patent No. 3,710,795, which is incorporated herein by reference.
  • compositions may contain 0.1-99%, preferably 1-70% of the active ingredient.
  • composition or formulation to be administered will, in any event, contain such quantity of the active compound(s) that will assure that a therapeutically effective amount will be delivered to a patient.
  • a therapeutically effective amount means an amount effective to prevent development of or to alleviate the existing symptoms of the subject being treated.
  • the amount of active compound administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • an effective dosage may be in the range of 1 to 12 mg/kg/day, preferably 1 to 5 mg/kg/day, given only for 1- 2 days at one treatment cycle.
  • the upper limit for the drug dose determination is its efficacy balanced with its possible toxicity.
  • 6-nitroso-1,2-benzopyrones An example of a method for the preparation of 6-nitroso-1,2-benzopyrones is provided as follows: To a stirred solution of 6-amino-1,2-benzopyrone hydrochloride (4.00 g, 20 mmol) in water (40 ml) at 22oC was added a solution of sodium tungstate (5.93 g, 20 mmol) in water (20 ml) followed by 30% aqueous hydrogen peroxide (5 ml) and stirring was continued for 1.5 hours. The oxidation product was extracted from the green-colored mixture with two 100 ml volumes of ethyl acetate, the combined extracts washed with 0.1 N HCl (50 ml) and then water (100 ml). The ethyl acetate was removed by rotary evaporation and the residue recrystallized from warm ethanol (250 ml).
  • This nitroso-compound may also be prepared by reacting 6-amino-1,2-benzopyrone (as the free base) with 3-chloroperoxybenzoic acid in ethyl acetate or halocarbon solvents. II. Synthesis of 3-nitrosobenzamide
  • the 2-nitrosobenzamide and 4-nitrosobenzamide isomers may be similarly prepared by performing the above oxidation on 2-aminobenzamide and 4- aminobenzamide, respectively.
  • An absorption maximum at 750nm is characteristic of monomeric arylnitroso compounds.
  • the compounds of the subject invention were tested for their ability to inactivate the polymerase activity of adenosinediphosphoribosyl transferase (ADPRT). Assays were performed according to the method of Buki and Kun, Biochem. 27:5990-5995 (1988), using calf thymus ADPRT. The assay results as given in Table I provide the I 50 (the concentration of the compound that inhibits enzyme activity 50%) values for ADPRT of the nitroso precursor (6- amino-1,2-benzopyrone) and the more potent 5- iodo-derivative (Table I, compounds 1 and 2, respectively).
  • I 50 the concentration of the compound that inhibits enzyme activity 50%
  • nitroso compounds (3,4,5 in Table I) are all highly active as anti-tumor and anti-HIV molecules (as shown in later sections) and are effective even after exposure of cells for a period as short as 30 minutes.
  • 5-I-6- nitroso-1,2-benzopyrone compound 6 in these studies has been shown to be a relatively poor inhibitor of ADRPT (It is believed that the iodo substitution deactivates the NO group as an electrophile) and its biological action is 10 times weaker than that of 6-NO-1,2-benzopyrone.
  • the compositions of the present invention are believed to be superior to 5-I-6-nitroso-1,2 benzopyrone, which has been shown to be a poor permeant molecule.
  • Assay conditions ADPRT, 0.4 ⁇ q; coDNA, 4 ⁇ q; inhibitor diluted between 0.8 and 600 ⁇ M, in 50 ⁇ l of 50 mM Tris-HC-l, 50 mM KCl, 5 mM 2-mercaptoethanol, 0.5 mM EDTA, 0.1 mM NAD ([32-P]-labelled), pH 7.5. Polymerization at 25oC for 4 minutes.
  • Figure 1 illustrates the % inactivation of ADPRT polymerase activity observed after 2 hours of incubation with the nitroso-compound inhibitors at several concentrations.
  • NOBP, NOBA, NOQ the nitroso-containing ligands
  • NOBP demonstrated about a 30% decrease in thymidine uptake at 10 ⁇ M, and an almost complete inhibition of uptake at 100 ⁇ M.
  • NOBA demonstrated about 75% level of inhibition at 10 ⁇ M, about 85% inhibition at 100 ⁇ M, and almost complete inhibition at 250 ⁇ M. The remaining amino and nitro compounds were significantly less potent and did not display complete inhibition until concentrations of 1000 ⁇ M were reached.
  • NOBP was almost as potent as NOQ and produced about 90% inhibition at a concentration of 10 ⁇ M, and almost complete inhibition at a concentration of 100 ⁇ M .
  • the other 3 compounds tested were significantly less potent.
  • Experiments with 855-2 cells grown in 10% fetal bovine serum (Fig. 2A) found that NOQ, and NOBP produced almost complete inhibition at a concentration of 10 ⁇ M .
  • At a concentration of 1 ⁇ M NOQ produced somewhat more inhibition than NOBP, and NOBP produced somewhat more inhibition than NOBA.
  • HL-60 cells Fig. 2C
  • the other 3 compounds tested were significantly less potent. The effect of different growth factors on the growth inhibitory effects of NOBP was tested.
  • Tumor cell inhibitory concentrations of NOBP and NOBA were shown not to affect adversely the viability of normal cells.
  • Experiments were performed in which the functions of various cancer cells (855-2 and HL-60 leukemia cells, D32, D37 and CRL 7712 glioblastoma cell lines, 186 medulla tumor cell line, L1210 murine leukemia cell line, MDA-468 human breast tumor cell line) and normal cells (neutrophil leukocytes and bone marrow or peripheal blood stream cells) were assessed in the absence or presence of the compounds.
  • the results are shown in Figures 4-9. Together, the data indicate that a concentration of 10 ⁇ M of the nitroso-containing ligands effectively suppressed cancer cell growth but demonstrated only modest effects the functions on normal cells.
  • cytotoxicity of 0, 2 ⁇ M, 4 MM, 8 ⁇ M and 10 ⁇ M NOBP was measured by examining the effect of the compound on the colony formation (CFU-GM) of normal human stem cells (PBSC). The results of the experiments are provided in figure 5B. Toxicity was not detected, even though levels of NOBP sufficient to block 855-2 cell proliferation completely were tested.
  • 6-amino-1,2-benzopyrone, 5-I-6-amino-1,2-benzopyrone and the 6-nitro derivative were toxic at the tested given doses, the almost ineffective (against tumor cells) 6-nitro derivative and the highly effective (against tumor cells) NOBP and NOBA were non-toxic.
  • Vincristine a highly toxic chemetherapeutic compound
  • Vincristine is the currently used in the treatment of leukemia and other malignancies. Studies were performed in order to determine the concentration of vincristine that produces the same level of growth inhibition as 10 ⁇ M NOBP, when assayed on 855-2 leukemia cells grown in vitro. Vincristine was tested in doses of 0.1, 1, 10 and 100 ⁇ M. As shown in Figure 7. 100 ⁇ M of vincristine (a highly toxic concentration) was required to produce the same level of inhibition as 10 ⁇ M of NOBP, thus NOBP is about 10 times more potent than an equal concentration of vincristine, and is not toxic to normal cells.
  • aromatic nitroso molecules that are also inhibitors of ADPRT polymerase activity may be useful chemotherapeutic cytostatic agents because of their effectiveness combined with low toxicity.
  • NOBP 6-nitroso-1,2- benzopyrone
  • NOBA 3-nitrosobenzamide

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Abstract

L'invention décrit de nouveaux composés antitumoraux et antiviraux. Lesdits composés comprennent 6-nitroso-1,2-benzopyrone, 3-nitrosobenzamide, 5-nitroso-1(2H)-isoquinolinone, 7-nitroso-1(2H)-isoquinolinone, 8-nitroso-1(2H)-isoquinolinone. L'invention décrit également des compositions contenant un ou plusieurs desdits composés, ainsi que des procédés de traitement d'infections virales et du cancer au moyen desdits composés et desdites compositions.
PCT/US1991/008902 1991-10-22 1991-11-26 Composes aromatiques nitreux liant l'adenosine-diphosphoribose polymerase efficaces en tant qu'agents antitumoraux et anti-retrovirus WO1993007868A1 (fr)

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JP4505220A JP3070767B2 (ja) 1991-10-22 1991-11-26 抗腫瘍及び抗―レトロウィルス剤として有用なアデノシンジホスホリボースポリメラーゼ結合性ニトロソ芳香族化合物
AU12609/92A AU676992B2 (en) 1991-10-22 1991-11-26 Adenosine diphosphoribose polymerase binding nitroso aromatic compounds useful as anti-tumor and anti-retroviral agents
EP92904892A EP0609211A4 (fr) 1991-10-22 1991-11-26 Composes aromatiques nitreux liant l'adenosine-diphosphoribose polymerase efficaces en tant qu'agents antitumoraux et anti-retrovirus.

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994009776A1 (fr) * 1992-11-02 1994-05-11 Octamer, Inc. Composes nitroso aromatiques se fixant a l'adenosine diphosphoribose polymerase, utiles comme agents antiretroviraux et agents antitumoraux
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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5877185A (en) * 1991-10-22 1999-03-02 Octamer, Inc. Synergistic compositions useful as anti-tumor agents
US5652260A (en) * 1991-10-22 1997-07-29 Octamer, Inc. Adenosine diphosphoribose polymerase binding nitroso aromatic compound useful as retroviral inactivating agents, anti-retroviral agents and anti-tumor agents
US5753674A (en) * 1991-10-22 1998-05-19 Octamer, Inc. Adenosine diphosphoribose polymerase binding nitroso aromatic compounds useful as retroviral inactivating agents, anti-retroviral agents, anti-retroviral agents and anti-tumor agents
WO1994009776A1 (fr) * 1992-11-02 1994-05-11 Octamer, Inc. Composes nitroso aromatiques se fixant a l'adenosine diphosphoribose polymerase, utiles comme agents antiretroviraux et agents antitumoraux
WO1994026730A2 (fr) 1993-05-12 1994-11-24 Octamer, Inc. Nouveaux composes aromatiques nitro et nitroso et leurs metabolites, aptes a etre utilises comme agents antiviraux et antitumoraux
US6015827A (en) * 1994-03-09 2000-01-18 Newcastle University Ventures Limited Benzoxazole-4-carboxamides and their use in inhibiting poly (adp-ribose) polymerase activity and improving cytotoxic effectiveness of cytotoxic drugs or radiotherapy
US5756510A (en) * 1994-03-09 1998-05-26 Newcastle University Ventures Limited Benzamide analogs useful as PARP (ADP-ribosyltransferase, ADPRT) DNA repair enzyme inhibitors
WO1995024379A1 (fr) * 1994-03-09 1995-09-14 Newcastle University Ventures Limited Analogues de benzamides utiles en tant qu'inhibiteurs de l'enzyme parp (adp-ribosyltransferase, adprt) de reparation de l'adn
US6316455B1 (en) 1994-03-09 2001-11-13 Newcastle University Ventures Limited Method of improving the effectiveness of a cytotoxic drug or radiotherapy using a quinazolinone compound
US5852195A (en) * 1994-05-06 1998-12-22 Pharmacia & Upjohn Company Pyranone compounds useful to treat retroviral infections
US6169181B1 (en) 1994-05-06 2001-01-02 Pharmacia & Upjohn Company Compounds useful to treat retroviral infections
EP1904468A2 (fr) * 2005-06-10 2008-04-02 Bipar Sciences, Inc. Modulateurs de parp et traitement du cancer
EP1904468A4 (fr) * 2005-06-10 2009-04-22 Bipar Sciences Inc Modulateurs de parp et traitement du cancer
EP2059802A2 (fr) * 2006-09-05 2009-05-20 Bipar Sciences, Inc. Procedes de conception d'inhibiteurs de parp et leurs utilisations
EP2059802A4 (fr) * 2006-09-05 2010-09-08 Bipar Sciences Inc Procedes de conception d'inhibiteurs de parp et leurs utilisations
US11433075B2 (en) 2017-06-22 2022-09-06 Triact Therapeutics, Inc. Methods of treating glioblastoma
US11433074B2 (en) 2017-06-22 2022-09-06 Triact Therapeutics, Inc. Methods of treating glioblastoma
US11628144B2 (en) 2017-09-29 2023-04-18 Triact Therapeutics, Inc. Iniparib formulations and uses thereof

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JP3070767B2 (ja) 2000-07-31
CA2121900A1 (fr) 1993-04-29
JPH07502975A (ja) 1995-03-30
EP0609211A4 (fr) 1995-02-01
AU676992B2 (en) 1997-04-10
EP0609211A1 (fr) 1994-08-10

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