WO2002014321A9 - Utilisation d'inhibiteurs de stat-6 comme agents therapeutiques - Google Patents

Utilisation d'inhibiteurs de stat-6 comme agents therapeutiques

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Publication number
WO2002014321A9
WO2002014321A9 PCT/US2001/025175 US0125175W WO0214321A9 WO 2002014321 A9 WO2002014321 A9 WO 2002014321A9 US 0125175 W US0125175 W US 0125175W WO 0214321 A9 WO0214321 A9 WO 0214321A9
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WO
WIPO (PCT)
Prior art keywords
alkanoyl
alkyl
phenyl
compound
benzo
Prior art date
Application number
PCT/US2001/025175
Other languages
English (en)
Other versions
WO2002014321A1 (fr
Inventor
Howard B Cottam
Lorenzo M Leoni
Dennis A Carson
Sylvie Barchechath
Original Assignee
Univ California
Howard B Cottam
Lorenzo M Leoni
Dennis A Carson
Sylvie Barchechath
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.)
Filing date
Publication date
Priority claimed from US09/637,531 external-priority patent/US6696441B1/en
Application filed by Univ California, Howard B Cottam, Lorenzo M Leoni, Dennis A Carson, Sylvie Barchechath filed Critical Univ California
Priority to AU2001294515A priority Critical patent/AU2001294515A1/en
Publication of WO2002014321A1 publication Critical patent/WO2002014321A1/fr
Priority to US10/364,663 priority patent/US20030232794A1/en
Priority to US10/367,639 priority patent/US7135171B2/en
Publication of WO2002014321A9 publication Critical patent/WO2002014321A9/fr
Priority to US11/077,986 priority patent/US20060040934A1/en
Priority to US11/271,511 priority patent/US7601846B2/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • IL-4/IL-13 interact with receptors on target B cells, and stimulate the production of IgE and other mediators of allergy.
  • IL-4/IL-13 signaling also (1) inhibits apoptosis in malignant B cells and other cancer cells, (2) prevents the rejection of tumors by the body, (3) promotes the survival of fibroblasts and therefore increases fibrosis, and (4) stimulates the differentiation of antigen-presenting cells.
  • the STAT4 and STAT6 genes encode transcription factors that when phosphorylated by Janus kinases are activated and transported to the nucleus where they regulate cytokine-induced gene expression. See, e.g., J. T. Me, Stem Cells SuppL 1, 105 (1997); M. Heim, J. Recept. Signal. Transduction Res.. 19, 75 (1999); K. S. Liu et al., Curr. Qpin. Immunol.. 10, 271 (1998).
  • STAT-6 is the common transcription factor for IL-4 and IL-13.
  • STAT4 and STAT6 are essential for the development of CD4 + Thl and
  • Th2 development respectively.
  • Tumor immunologists have hypothesized that Thl cells are critical in tumor immunity because they facilitate differentiation of CD8 + T cells, which are potent anti-tumor effectors.
  • BALB/c and knockout mice were challenged in the mammary gland with the highly malignant and spontaneously metastatic BALB/c-derived 4T1 mammary carcinoma. Primary tumor growth and metastatic disease were reduced in STAT6 ⁇ ⁇ mice relative to BALB/c and STAT4 _ " mice.
  • Sumitumo Pharmaceutical Co. discloses certain imidazo [2,l-b]thiazole derivatives that are capable of inhibiting STAT-6.
  • the compounds are disclosed to be useful for the treatment and prevention of allergic diseases and parasitic infectious diseases.
  • p53 the product of the p53 tumor suppressor gene, is a multifunctional tumor suppressor protein, involved in the negative control of cell growth. In response to a variety of stressors, p53 induces growth arrest or apoptosis, thereby eliminating damaged and potentially dangerous cells. T. M. Gottleib et al, Biochim. Biophvs. Acta. 1287. 77 (1996).
  • Mutations in the p53 gene are frequently associated with the metastatic stage of tumor progression, and lack of functional p53 is accompanied by rapid tumor progression, resistance to anti- cancer therapy and increased tumor angiogenesis. See, e.g., A. J. Levine et al., Br. J. Cancer. 69, 409 (1994); R. J. Steele et al, Br. J. Surg.. 85, 1460 (1998); C. Cordon-Cardo et al., Surg. Oncol. 13, 319 (1997). p53 deficiency in mice is associated with a high frequency of spontaneous cancers. L. A. Donehower et al., Nature. 356, 215 (1992); T. Jacks et al., Curr. Biol.. 4, 1 (1994). On the basis of these reports, the inactivation of p53 was viewed as an unfavorable event, and it has been speculated that cancer can be inhibited by restoration of p53 function.
  • the present invention provides compounds that act to inhibit the activity of STAT-6 in mammalian cells, and a method to effectively inhibit signal transduction through the IL-4 and IL-13 pathways, in vitro or in vivo, in the cells- of a mammal, such as a human, subject to pathology that is ameliorated by such inhibition. Accordingly, there is provided a method of suppression comprising administering to a mammal in need of said suppression an effective amount of a compound of formula (I):
  • R 1 , R 2 and R 3 are independently hydrogen, halo, hydroxy, cyano, N(RJ(R b ), S(R a ), NO 2 , (C r C 6 )alkyl, (C r C 6 )alkoxy, (C 2 -C 6 )alkynyl, (C 2 -C 6 )alkenyl, (C 2 -C 7 )alkanoyl, (C 2 -C 7 )alkanoyloxy, or (C 3 -C 7 )cycloalkyl or R 1 and R 2 taken together are benzo, optionally substituted by R 1 , or are (C 3 -C 5 )alkylene or methylenedioxy; wherein R- and R b are each independently hydrogen, (C r C 3 )alkyl, (C 2 -C 4 )alkanoyl, phenyl, benzyl, or phenethyl; or R a and R b together
  • Ar is aryl, heteroaryl, or a 5-6 membered heterocyclic ring, preferably comprising 1-3 N(R a ), nonperoxide O or S atoms, such as a pyrrolidino, piperidino or mo ⁇ holino ring, optionally substituted with 1-5, preferably 1-2, halo, CF 3 , hydroxy, CN, N(R-)(R b ), (C r C 6 )alkyl, (C r C 6 )alkoxy, (C 2 -C 7 )alkanoyl, (C 2 -C 7 )alkanoyloxy, (C 3 -C 7 )cycloalkyl, (C 2 -C 6 )alkanoyl, (C 2 -C 6 )alkenyl, or phenyl;
  • Y is oxy (-O-), S(O) 0 . 2 , Se, C(R J )(R 3 ), N(R-), or-P-; or a pharmaceutically acceptable salt thereof.
  • Ar is not substituted with halo or alkoxy.
  • Ar is heteroaryl or a heterocyclic ring.
  • R 1 and R 2 are not benzo or (C 3 -C 5 )alkylidenyl when Ar is aryl, e.g., is phenyl or napthyl.
  • Novel compounds of formula (I) are also within the scope of the present invention, e.g., preferably Y is -O-, -Se-, C(R ! )(R 3 ) or P.
  • Ar is heteroaryl.
  • Ar is substituted with CN, (C 2 -C 7 )alkanoyl), (C 2 -C 7 )alkanoyloxy, (C 3 -C 7 )cycloalkyl, (C 2 -C 6 )alkenyl or combinations thereof.
  • R 1 , R 2 and R 3 are independently, OH, CN (N(R a )(R b ), S(R-), NO 2 , (C 2 -C 7 )alkanoyl, or (C 2 -C 7 )alkanoyloxyl.
  • the present method also provides a therapeutic method comprising suppressing STAT-6 or the TL-A/ L-13 pathways in mammalian cells in vitro or in vivo, and thus treating a pathological condition ameliorated by said suppression, comprising administering to a mammal in need of said suppression an effective amount of a compound of formula (JJ):
  • R 4 is the same as, but independent from, R l5 R 2 and R 3 .
  • R 4 in combination with R x can also be benzo, C 3 -C 5 alkylidene or methylenedioxy. These compounds are imidazo[l,2-a]- quinazolines.
  • Compounds of formula (II) also include (Ila) and (lib):
  • R l5 R 2 , R 3 and R 4 are as defined herein. Novel compounds of formulae ⁇ , Ha and Hb are also within the scope of the invention.
  • R 4 is not OH in IJa or Ub, e.g., where R j and R 2 or ⁇ and R 4 are benzo.
  • R t and R 2 are preferably not benzo when Ar is phenyl.
  • the present invention also includes compounds of formula HI:
  • R l3 R 2 and R 4 as well as Ar are defined as herein, for formula (I).
  • R l9 R 2 and R , as well as Ar are defined as above, for formula (If), as well as methods for their use to treat conditions ameliorated by a suppression of STAT-6 or by inhibition of signal transduction through the IL-4/IL-13 pathways in mammalian cells in vitro or in vivo.
  • R_ and R 2 are not benzo when R 4 is H or OH.
  • R l5 R 2 , R 3 and R 4 as well as Ar are defined as above, for formula (H), as well as methods for their use as discussed above.
  • Ar is not 4-methoxyphenyl when R x and R 2 are benzo and R 4 is H.
  • Compounds of formulae (I)-(N) are small molecule antagonists of IL-4/TL-13 signal transduction in mammalian cells in vitro and in vivo. These molecules can inhibit the survival of malignant B cells and sensitize them to other chemotherapeutic agents, but are relatively nontoxic to normal lymphocytes. Antibodies to IL-4 and IL-13 receptors and to other receptors are in clinical trials. However, JL-4 and IL-13 have redundant activities, and thus blocking only one of them is insufficient in many instances.
  • Preferred compounds ( ⁇ )-(IN) can block both IL-4 and EL- 13 signaling. They may act by inhibiting expression of the STAT-6 gene, and thus by inhibiting STAT-6, the common transcription factor for IL-4 and IL-13. They can be useful to treat cancer, fibrotic diseases and inflammatory diseases. More specifically, compounds (i)-(N) may be useful for:
  • IL-4 and/or IL-13 receptors e.g., gliomas and head and neck cancers.
  • IL-4 and IL-13 are survival factors for malignant cells in chronic lymphocytic leukemia and Hodgkin's disease (a form of lymphoma).
  • the present compounds should be useful for treatment of these diseases.
  • the invention also provides pharmaceutical compositions comprising novel compounds of formula (I)-(V), or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.
  • novel compounds of formula (I), or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier can be represented by compounds of formula (I), with the proviso that when Y is S, Ar is not phenyl (C 6 H 5 ).
  • the invention provides a therapeutic method for preventing or treating a pathological condition or symptom in a mammal, such as a human, wherein the activity of STAT-6 or IL-4/1L- 13 -mediated signal transduction is implicated and antagonism or suppression of their action is desired, comprising administering to a mammal in need of such therapy, an effective amount of one or more compounds of formula (I)-(V), or a pharmaceutically acceptable salt thereof.
  • pathological conditions or symptoms include treatment of cancers expressing IL-4 and/or DL- 13 receptors, sensitization of cancer cells to chemotherapy or radiation, increasing T c cell responses and the treatment of proliferative fibrotic disease.
  • the invention provides a compound of formula (I)-(V) for use in medical therapy as well as the use of a compound of formula (I)-(V) for the manufacture of a medicament for the treatment of a pathological condition or symptom in a mammal, such as a human, which is associated with STAT-6 activation, activation of the JJL-4 and/or DL-13 pathways, or p53-induced cellular damage, i.e., with unwanted apoptosis.
  • the invention also includes a method for binding a compound of formula (I)-(V) to cells and biomolecules comprising JL-4 and/or DL-13 receptors, in vivo or in vitro, comprising contacting said cells or biomolecules with an amount of a compound of formula (I)-(V) effective to bind to said receptors.
  • Cells or biomolecules comprising ligand-bound IL-4/1L-13 receptor sites can be used to measure the selectivity of test compounds for specific receptor subtypes, or can be used as a tool to identify potential therapeutic agents for the treatment of diseases or conditions associated with IL-4/DL-13 pathway activation, by contacting said agents with said ligand-receptor complexes, and measuring the extent of displacement of the ligand and/or binding of the agent, by methods known to the art.
  • the present invention provides a compound of formula ( ⁇ )-(V) that act to suppress p53 activity in mammalian cells, and a method to effectively suppress p53 activity in the cells of a mammal subject to a stress or pathology that is ameliorated by such suppression. Accordingly, there is provided a method of p53 suppression comprising administering to a mammal in need of said suppression an effective amount of a compound of formula (I)-(V).
  • novel p53 suppressor compounds as well as pharmaceutical compositions comprising novel compounds of formula (I)-(V), or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or carrier.
  • Such compounds can be represented by compounds of formula (I), with the proviso that when Y is S, Ar is not phenyl (C 6 H 5 ).
  • the invention provides a therapeutic method for preventing or treating a pathological condition or symptom in a mammal, such as a human, wherein the activity of p53 is implicated and antagonism or suppression of its action is desired, comprising administering to a mammal in need of such therapy, an effective amount of a compound of formula (I)-(N), or a pharmaceutically acceptable salt thereof.
  • Such pathological conditions or symptoms include blocking, moderating or reversing the deleterious effects of chemotherapeutic agents, particularly those which damage DNA; radiation, particularly radiation therapy (gamma-, beta- or UN-radiation), ischemic event, including stroke, infarct, ischemia-reperfusion injury and ischemia due to organ, tissue or cell transplantation; environmental pollution or contamination and the like.
  • chemotherapeutic agents particularly those which damage DNA
  • radiation particularly radiation therapy (gamma-, beta- or UN-radiation)
  • ischemic event including stroke, infarct, ischemia-reperfusion injury and ischemia due to organ, tissue or cell transplantation; environmental pollution or contamination and the like.
  • the invention also includes a method for binding a compound of formula (I) to cells and biomolecules comprising p53 receptors, in vivo or in vitro, comprising contacting said cells or biomolecules with an amount of a compound of formula (I) effective to bind to said receptors.
  • Cells or biomolecules comprising ligand-bound p53 receptor sites can be used to measure the selectivity of test compounds for specific receptor subtypes, or can be used as a tool to identify potential therapeutic agents for the treatment of diseases or conditions associated with p53 activation, by contacting said agents with said ligand-receptor complexes, and measuring the extent of displacement of the ligand and/or binding of the agent, by methods known to the art.
  • p53 or "p53 activity” refers to p53 protein.
  • the invention is believed to work by temporarily suppressing expression of the p53 gene and/or activity of p53 protein.
  • Figure 1 depicts the effects of D3T and PFT- ⁇ on B-CLL viability.
  • Figure 2 depicts the protective effect of D3T against spontaneous apoptosis and against fludarabine-induced apoptosis.
  • Figure 3 shows the ability of the various compounds to block the expression of a STAT-6 dependent reporter gene.
  • Figure 4 shows the ability of compounds of the invention to reduce the survival of malignant B cells from a patient with chronic lymphocytic leukemia maintained in tissue culture for 72 hours.
  • Figure 5 shows the structures of compounds numbered in Figures 3-4.
  • Compound 1 is D3T (control). DETAILED DESCRIPTION
  • halo is fluoro, chloro, bromo, or iodo.
  • Alkyl, alkoxy, alkenyl, alkynyl, etc. denote both straight and branched groups; but reference to an individual radical such as "propyl” embraces only the straight chain radical, a branched chain isomer such as "isopropyl” being specifically referred to.
  • Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic.
  • Heteroaryl encompasses a radical attached via a ring nitrogen or carbon of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(X) wherein X is absent or is H, O, (C ⁇ -C 4 )alkyl, phenyl or benzyl.
  • Heteroaryl also includes a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms, particularly a benzo-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto.
  • Preferred heteroaryls include pyridin-4-yl and thiophen-2-yl.
  • heterocyclic ring “heterocycle,” or “heterocycyl,” is defined as above for formula (I).
  • R 4 is OH
  • enol or keto forms of compounds (II)-(N) are also within the scope of the invention, wherein the adjacent ⁇ may be replaced by ⁇ (R .
  • Specific and preferred values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
  • (C r C 6 )alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;
  • (C 3 -C 7 )cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • the term cycloalkyl includes (cycloalkyl)alkyl of the designated number of carbon atoms;
  • (C 3 -C 5 )cycloalkyl(C 2 -C 4 )alkyl can be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, or 2-cyclohexylmethyl;
  • R 1 and R 2 is hydroxy, cyano, N(R a )(R b ), S(R-), NO 2 , (C 2 -C 7 )alkanoyl, or (C 2 -C 7 )alkanoyloxy
  • R 1 and R 2 together is butylene or benzo.
  • R 1 and R 4 together is butylene or benzo.
  • a specific value for R 3 is H.
  • a specific value for R 4 is H.
  • a specific value for Ar is aryl or heteroaryl, optionally substituted with 1-5, preferably 1 -2, halo, CF 3 , hydroxy, CN, N(R-)(R b ), (C r C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 2 -C 7 )alkanoyl, (C 2 -C 7 )alkanoyloxy, (C 3 -C 7 )cycloalkyl, (C 2 -C 6 )alkanoyl, (C 2 -C 6 )alkenyl, or phenyl.
  • a specific value for Ar is heteroaryl or phenyl substituted with CN, (C 2 -C 7 )alkanoyl, (C 2 -C 7 )alkanolyoxy, (C 2 -C 7 )cycloalkyl or (C 2 -C 6 )alkenyl.
  • a specific value for Ar is phenyl, 2, 3 or 4-pyridyl or 2-thienyl; pyrrolidino, piperidino or mo ⁇ holino.
  • Ar is phenyl, 4-pyridyl or 2-thienyl.
  • a specific value for Y is oxy (-O-), S(O) 0.2 , C ⁇ XR 3 ), N(R-), or -P-.
  • a specific value for Y is S, O, N(R a ), or -P-.
  • a specific value for Y is P, Se, SO, SO 2 or C ⁇ R ⁇ R ⁇ ).
  • a specific value for Y is P, Se, S(O) or SO 2 .
  • a more specific value for Y is S, O, or NH 2 ,
  • N(R-)(R b ) is amino.
  • N(R-)(R b ) is pyrrolidino, piperidino or mo ⁇ holino.
  • a specific value for halo is Br or F.
  • Processes for preparing compounds of formula (I) are provided as further embodiments of the invention and are illustrated by the procedures disclosed below in which the meanings of the generic radicals are as given above unless otherwise qualified. Intermediates useful for preparing compounds of formula (I), are also within the scope of the present invention.
  • the present invention is based on the discovery that PFT- ⁇ is both cytotoxic to mammalian cells and unstable in aqueous solution under in vivo conditions. PFT- ⁇ undergoes spontaneous ring closure in protic solvents, such as alkanols, to fo ⁇ n the imidazo[2,l-b]benzothiazole derivative, abbreviated IBT, as shown in Scheme 1.
  • IBT is actually responsible for the observed p53 inhibition observed by Komarov et al. (Science. 285, 1733 (1999)).
  • IBT and compounds of formula (I) are expected to be both less toxic and more stable than imino compounds such as PFT- ⁇ , they are desirable agents for protection of mammalian cells against a wide variety of stressors, including therapeutic agents, and clinical and environmental trauma.
  • the compounds of formula (I) are disclosed to be useful for "the treatment and prevention of allergic disease and parasitic infectious diseases, or the like.” Certain of the compounds of formula (I) are useful as intermediates to prepare other compounds of formula (I), as would be recognized by the art.
  • a general method for preparation of imidazo[l,2-a]quinazolines of formula (D) is found in Coppola, et al, wherein a functionalized isatoic anhydride is first alkylated with the alpha-haloketone and then condensed with a suitable thiopseudourea, as shown below for a pyridinyl derivative:
  • Imidazo[l,2-c]quinazolines of formula (V) maybe prepared according to the procedure outlined by Gueffier, et al, wherein a 4-aminoquinazoline is reacted with a bromomethyl aryl ketone in refluxing ethanol. Heteroaryl ketones may also be used as shown below for a pyridinyl derivative:
  • salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, ⁇ -ketoglutarate, and ⁇ -glycerophosphate.
  • Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
  • compositions may be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • a sufficiently basic compound such as an amine
  • a suitable acid affording a physiologically acceptable anion.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example, calcium) salts of carboxylic acids can also be made.
  • the compounds of formula ( ⁇ )-(V) can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human cancer patient, in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
  • the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be inco ⁇ orated directly with the food of the patient's diet.
  • a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
  • the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
  • the amount of active compound in such therapeutically useful compositions is such that an effective dosage level will
  • the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • a liquid carrier such as a vegetable oil or a polyethylene glycol.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound maybe inco ⁇ orated into sustained-release preparations and devices.
  • the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. hi all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glycerol esters, and suitable mixtures thereof.
  • a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glycerol esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like, h many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride.
  • Prolonged abso ⁇ tion of the injectable compositions can be brought about by the use in the compositions of agents delaying abso ⁇ tion, for example, aluminum monostearate and gelation.
  • Sterile injectable solutions are prepared by inco ⁇ orating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization, h the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
  • a dermatologically acceptable carrier which may be a solid or a liquid.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
  • Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • Examples of useful dermatological compositions which can be used to deliver the compounds of formula (I)-(V) to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
  • Useful dosages of the compounds of formula (I)-(V) can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
  • the concentration of the compound(s) of formula (I)-(V) in a liquid composition will be from about 0.1-25 wt %, preferably from about 0.5-10 wt %.
  • concentration in a semi-solid or solid composition such as a gel or a powder will be about 0.1-5 wt %, preferably about 0.5-2.5 wt %.
  • a suitable dose will be in the range of from about 0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day.
  • the compound is conveniently administered in unit dosage form, for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form.
  • the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.5 to about 75 ⁇ M, preferably, about 1 to 50 ⁇ M, most preferably, about 2 to about 30 ⁇ M. This maybe achieved, for example, by the intravenous injection of a 0.05 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1-100 mg of the active ingredient. Desirable blood levels may be maintained by continuous infusion to provide about 0.01-5.0 mg/kg/hr or by intermittent infusions containing about 0.4-15 mg/kg of the active ingredient(s).
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations, such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • a compound of the invention to act as a suppressor of p53 activity may be determined using pharmacological models which are well known to the art, e.g., as disclosed below.
  • this ketone intermediate is suspended in acetonitrile (100 mL) containing methyl-2-thiopseudourea (0.012 mol) and sodium carbonate (0.012 mol) and the mixture is refluxed for 30 min. The solvent is then removed in vacuo and replaced with dichloromethane (100 mL). The insoluble salts are filtered off and washed with additional solvent, and the filtrate is evaporated to dryness and diglyme (50 mL) is added to the residue.
  • EXAMPLE 2 Effect of the ⁇ 53 Inhibitory Compounds on B-CLL Viability
  • the malignant lymphocytes from two patients with chronic lymphocytic leukemia [CLL] were isolated by ficoll-hypaque sedimentation and suspended at a density of 1 million cells per milliliter in RPMI 1640 medium supplemented with 10% fetal bovine serum. Two hundred microliter aliquots of cells were dispersed in the wells of culture plates containing the indicated final concentrations of either PFT- ⁇ ("PFT-open”) or IBT (PFT-closed). After 3 days culture, viable cells were enumerated by fluorescence-activated cell sorting [FACS] after staining with propidium iodide [PI].
  • FACS fluorescence-activated cell sorting
  • Fludarabine Chronic lymphocytic leukemia [CLL] cells were cultured for 3 days as described in Example 2. Some of the cultures were supplemented with one micromolar of PFT-open or PFT-closed, as indicated, h the experiment shown in the bottom panel of Figure 2, some of the cultures also contained the cytotoxic adenine nucleoside analog fludarabine [abbreviated F-AraA]. Fludarabine is the first line treatment for CLL, and the toxicity of the drug is dependent upon the p53 pathway.
  • the BEAS-2B human airway epithelial cells were transiently transfected with the human 12/15-lipoxygenase promoter/luciferase reporter gene. Cells were then incubated with the IBT analogs (Fig. 5) at 10 ⁇ M for 1 hour, followed by DL-4 (10 ng/ml). After 16 hours, luciferase was measured using a chemiluminometer. The STAT-6 induction was normalized using the B-gal results as "background.” The viability of the treated cells was visually verified at the end of the incubation, and found to be >95%. Results shown in Figure 3 are the mean of duplicate measurements.
  • CLL cells Chronic lymphocytic leukemia (CLL) cells were isolated from whole blood of patients, cultured in RPMI-1640 supplemented with 10% FB. CLL cells were pre-incubated for 1 hour with the indicated analogs (Fig. 5) at 1 ⁇ M and exposed for 24 hours to the nucleoside analogs Fludarabine (Fludara) and Cladribine (2 CdA) at 1 and 10 ⁇ M. Cells were then incubated for 10 minutes in growing medium with 5 ⁇ g/ml Propidium iodide and 40 nM DiOC 6 and analyzed by flow cytometry. Viable cells (Y axis) and high DiOC 6 (FL-1) and low PI (FL-3) fluorescence.

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Abstract

L'invention concerne des dérivés d'imidazole polycyclique servant à empêcher l'apparition du cancer ou à sensibiliser des cellules cancéreuses à des agents chimiothérapeutiques, des rayonnements ou d'autres traitements anticancéreux.
PCT/US2001/025175 2000-08-11 2001-08-10 Utilisation d'inhibiteurs de stat-6 comme agents therapeutiques WO2002014321A1 (fr)

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AU2001294515A AU2001294515A1 (en) 2000-08-11 2001-08-10 Use of stat-6 inhibitors as therapeutic agents
US10/364,663 US20030232794A1 (en) 2001-06-26 2003-02-11 Use of STAT-6 inhibitors as therapeutic agents
US10/367,639 US7135171B2 (en) 2001-08-09 2003-02-13 Endothelial precursor cells for enhancing and restoring vascular function
US11/077,986 US20060040934A1 (en) 2001-06-26 2005-03-11 Use of STAT-6 inhibitors as therapeutic agents
US11/271,511 US7601846B2 (en) 2001-06-26 2005-11-10 Compounds having activity as inhibitors of apoptosis

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US09/637,531 US6696441B1 (en) 2000-08-11 2000-08-11 Inhibition of p53-induced stress response
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