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EP1307459A2 - Composes indoliques utilises dans le traitement du cancer - Google Patents

Composes indoliques utilises dans le traitement du cancer

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Publication number
EP1307459A2
EP1307459A2 EP01962006A EP01962006A EP1307459A2 EP 1307459 A2 EP1307459 A2 EP 1307459A2 EP 01962006 A EP01962006 A EP 01962006A EP 01962006 A EP01962006 A EP 01962006A EP 1307459 A2 EP1307459 A2 EP 1307459A2
Authority
EP
European Patent Office
Prior art keywords
cells
cancer
etodolac
compound
lower alkyl
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP01962006A
Other languages
German (de)
English (en)
Inventor
Dennis A. Carson
Lorenzo M. Leoni
Howard B. Cottam
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of California
University of California Berkeley
University of California San Diego UCSD
Original Assignee
University of California
University of California Berkeley
University of California San Diego UCSD
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 US09/634,207 external-priority patent/US7151100B1/en
Application filed by University of California, University of California Berkeley, University of California San Diego UCSD filed Critical University of California
Publication of EP1307459A2 publication Critical patent/EP1307459A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • 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
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Prostate cancer is the second leading cause of cancer death among males in the United States. In 1998, an estimated 185,000 men were diagnosed with prostate cancer, and more than 39,000 men died of the disease. See, S. H. Landis et al., Cancer Statistics, CA Cancer J. Clin.. 48, 6 (1998). Although survival rates are good for prostate cancer that is diagnosed early, the treatments for advanced disease are limited to hormone ablation techniques and palliative care. Hormone ablation techniques (orchiectomy and anti-androgen treatments) generally allow only temporary remission of the disease. It usually recurs within 1-3 years of treatment, with the recurrent tumors no longer requiring androgens for growth and survival. D. G. Tang et al., Prostate. 32, 284 (1997). Therapy with conventional chemotherapeutic agents, such as progesterone, estramustine and vinblastine, has also not been demonstrated to be effective to halt progression of the disease.
  • conventional chemotherapeutic agents such as progesterone, estramustine and vinblastine
  • NSATDs nonsteroidal anti-inflammatory drugs
  • the NSATDs available in the U.S. include meclofenamate sodium, oxyphenbutazone, phenylbutazone, indomethacin, piroxicam, sulindac and tolmetin for the treatment of arthritis; mefenamic acid and zomepirac for analgesia; and ibuprofen, fenoprofen and naproxen for both analgesia and arthritis. Ibuprofen, mefenamic acid and naproxen are used also for the management of dysmenorrhea.
  • Phenylbutazone has been implicated in hepatic necrosis and granulomatous hepatitis; and sulindac, indomethacin, ibuprofen and naproxen with hepatitis and cholestatic hepatitis.
  • the NSAIDs can cause fluid retention and decrease sodium excretion, followed by hyperkalemia, oliguria and anuria. Moreover, all of these drugs can cause peptic ulceration. See, Remington's Pharmaceutical Sciences, Mack Pub. Co., Easton, PA (18th ed., 1990) at pages 1115-1122.
  • NSAIDs recited by the claims are acemetacin, indomethacin, sulindac, sulindac sulfide, sulindac sulfone, tolmetin and zomepirac. Naproxen and piroxicam were reported to be inactive. Recently, W. J. Wechter et al, Cancer Res.. 60, 2203 (2000) reported that the NSATD, R-flurbiprofen, inhibited progression of prostate cancer in the TRAMP mouse, a prostate cancer model.
  • the present invention provides indole compounds of formula (I):
  • R 1 is lower alkyl, lower alkenyl, (hydroxy)lower alkyl, lower alkynyl, phenyl, benzyl or 2-thienyl
  • R 2 , R 3 , R 4 and R 5 are the same or different and are each hydrogen or lower alkyl
  • each R 6 is individually hydrogen, lower alkyl, hydroxy, (hydroxy)lower alkyl, lower alkoxy, benzyloxy, lower alkanoyloxy, nitro or halo
  • n is 1-3
  • R 7 is hydrogen, lower alkyl or lower alkenyl
  • X is oxy and thio
  • Y is carbonyl, (CH 3 , (CB ⁇ CCO), or (CH 2 ) ] _ 3 SO 2 and Z is ( ⁇ -(4- ⁇ yridyl)(C 2 -C 4 alkoxy), ( ⁇ -((R 8 )(R 9 ) amino)(C 2 -C 4 alkoxy), wherein R 8 and R
  • R 8 is OH, (C 2 -C 4 )acyloxy, SO 3 H, PO 4 H 2 , N(NO)(OH), SO 2 NH 2 , PO(OH)NH 2 , or tetrazolyl; or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a therapeutic method to inhibit the growth of cancer cells and/or to sensitize cancer cells to inhibition by a chemotherapeutic agent.
  • the method comprises contacting cancer cells with an effective amount of the compound of formula (I), preferably in combination with a pharmaceutically acceptable carrier.
  • the present compounds can be used to treat a mammal afflicted with cancer, such as a human cancer patient, and are preferably administered in conjunction with a chemotherapeutic agent, such as an alkylating agent or an anti-androgen, radiation and/or other anti-cancer therapy.
  • a chemotherapeutic agent such as an alkylating agent or an anti-androgen, radiation and/or other anti-cancer therapy.
  • the present compounds are effective against hematopoietic cancers, such as leukemias and cancers of the bone marrow, including chronic lymphocytic leukemia (CLL) and multiple myeloma (MM).
  • CLL chronic lymphocytic leukemia
  • MM multiple myeloma
  • the present compounds were unexpectedly found to be effective against cancer cells that express high levels of the nuclear hormone receptor, peroxisome proliferator activated receptor- ⁇ , (PPAR- ⁇ ), and or high levels of the anti-apoptotic proteins, Mcl-1 and/or Bag-1.
  • cancer cells include at least some types of prostate cancer cells.
  • Activated PPAR- ⁇ binds co-activator protein (CBP), a co-activator of the androgen receptor known to be overexpressed in hormone-resistant prostate cancer.
  • CBP co-activator protein
  • compounds of formula (I) that activate PPAR- ⁇ production can reduce the level of expression of the androgen receptor known to be over- expressed in hormone-resistant prostate cancer. Therefore, the present compounds can enhance the efficacy of conventional anti-androgen therapy, and can act to inhibit the spread of prostate cancer.
  • the present invention is based on the discovery by the inventors that racemic etodolac inhibits the viability of purified CLL or MM cells at concentrations that do not inhibit the viability of normal peripheral blood lymphocytes (PBLs). It was then unexpectedly found that the R(-) enantionier of etodolac is as toxic to CLL cells as is the S(+) enantiomer. It was then found that etodolac synergistically interacted with fludarabine and 2-chloroadenosine to kill CLL cells at concentration at which the chemotherapeutic agents alone were inactive. Finally, it was found that both R(-)- and S(+)- etodolac inhibited a number of prostate cancer cell lines.
  • PBLs peripheral blood lymphocytes
  • the R(-) enantiomer was at least as effective as the S(+)- "anti-inflammatory" enantiomer. This was unexpected since the R(-) enantiomer of etodolac does not possess significant anti- inflammatory activity and is not converted to the S(+) enantiomer to a significant extent in vivo. As noted above, the R-enantiomers of other R-2-arylpropionate NSAIDs are converted to the "active" anti-inflammatory S-enantiomers in vivo, and so function as pro-drugs for the NSATD.
  • a compound of formula (I) is preferred for practice of the present therapeutic method that does not exhibit undesirable bioactivities due to inhibition of cyclooxygenase (COX) that are exhibited by some NSAIDs.
  • COX cyclooxygenase
  • the preferred compounds of formula (I) would not be considered NSAIDs by the art, as they would not exhibit significant anti-inflammatory activity.
  • the present invention also provides a method for determining whether or not a particular cancer patient, such as a prostate cancer patient, is amenable to treatment by a compound of formula (I), comprising isolating cancer cells and evaluating in vitro the relative level of PPAR- ⁇ and/or Mcl-1 and/or Bag-1 relative to the level in a cancer cell line, such as prostate cancer cell line, known to be susceptible to treatment by a compound of formula (I).
  • the present invention also provides a method to determine the ability of a test agent to inhibit cancer cells, such as prostate cancer cells, comprising contacting a population of cancer cells, as from a prostate cancer cell line, with said agent and determining whether the agent increases expression of PPAR- ⁇ , or decreases the expression of Mcl-1 and/or Bag-1 (or does both).
  • the present invention also provides a general multilevel screening method to evaluate etodolac analogs, other NSAIDs or other agents for their ability to inhibit cancer, preferably etodolac-sensitive cancers, such as prostate cancer, CLL and MM.
  • Agents that exhibit a positive activity, preferably at least equal to that of R(-)- etodolac, or do not exhibit a negative activity, e.g., are no more active than R(-)- etodolac, are passed to the next screen.
  • Test agents are first evaluated for their ability to competitively inhibit the binding of etodolac, e.g., radiolabeled R(-) etodolac to its receptor(s) on etodolac-sensitive cancer cells such as CLL cells.
  • Agents that can compete effectively with R(-) etodolac for etodolac binding site(s) on the cells are then evaluated in an assay to determine if they can increase Ca +2 uptake in cancer cells, such as CLL cells, preferably as effectively as R(-) etodolac.
  • Agents that can induce intracellular Ca +2 uptake are screened to determine if they can induce chemokinetic activity (chemokinesis or chemotaxis) in a population of lymphocytes, such as B-CLL lymphocytes, preferably as effectively as R(-) etodolac. Agents that are positive in this screen are then evaluated to determine if they can induce apoptosis or pro-apoptotic factors, such as increased caspase activity in cancer cells, such as CLL cells and other cancer cells known to be etodolac sensitive, at least as effectively as R(-) etodolac.
  • chemokinetic activity chemokinesis or chemotaxis
  • apoptosis or pro-apoptotic factors such as increased caspase activity in cancer cells, such as CLL cells and other cancer cells known to be etodolac sensitive, at least as effectively as R(-) etodolac.
  • inhibiting includes both the reduction in cellular proliferation, blockage of cellular proliferation, or killing some or all of said cells.
  • the term can be used in both the context of a prophylactic treatment to prevent development of cancer or as a treatment that will block, or slow the spread of established cancer. Whether or not the level of expression of a marker of susceptibility to etodolac treatment is sufficiently elevated to continue treatment with etodolac or an analog thereof is determined by comparison between the relative levels of expression of said marker in resistant and susceptible cancer cell lines, as disclosed hereinbelow.
  • Figure 1 is a graph depicting the sensitivity of normal peripheral blood lymphocytes (PBL) to racemic etodolac.
  • Figure 2 is a graph depicting the sensitivity of CLL cells to racemic etodolac.
  • Figure 3 is a graph depicting the synergistic effect of a combination of racemic etodolac and fludarabine against CLL cells.
  • Figure 4 is a graph depicting the synergistic effect of a combination of 50 ⁇ M etodolac with 10 ⁇ M 2CdA or 10 mM Fludara against CLL cells.
  • Figure 5 is a graph depicting the sensitivity of CLL cells to S- and R- etodolac.
  • Figures 6 and 7 depict the viability of CLL cells from two patients before and after etodolac administration.
  • Figure 8 depicts a flow cytometric analysis of CLL cells before and after etodolac treatment.
  • Figures 9 and 10 depict the selective action of R(-)-etodolac against MM cells from two patients.
  • Figure 11 is a photocopy of a SDS-PAGE gels demonstrating that etodolac induces a rapid dowmegulation in Mcl-l (Panel A) and Bag-1 (Panel B), that is blocked by MG-132.
  • Figure 12 is a photocopy of an SDS-PAGE gel depicting expression of
  • Figure 13 is a graph depicting induction of PPAR- ⁇ expression by etodolac and indomethacin.
  • Figure 14 is a graph depicting expression of CD36 induced by etodolac and TGZ, in the presence and absence of TPA in human monocytes.
  • Figure 15 is a photocopy of sections of prostate cancer tissue, untreated (A) or treated (B, C, D) with etodolac.
  • Indole compounds of the present inventions include compounds of formula (I):
  • R 1 is selected from the group consisting of lower alkyl, lower alkenyl, (hydroxy)lower alkyl, lower alkynyl, phenyl, benzyl and 2-thienyl
  • R 2 , R 3 , R 4 and R 5 are the same or different and are each selected from the group consisting of hydrogen and lower alkyl
  • each R 6 is individually selected from the group consisting of hydrogen, lower alkyl, hydroxy, (hydroxy)lower alkyl, lower alkoxy, benzyloxy, lower alkanoyloxy, nitro and halo
  • n is 1-3
  • R 7 is selected from the group consisting of hydrogen, lower alkyl and lower alkenyl
  • X is selected from the group consisting of oxy and thio
  • Y is selected from the group consisting of carbonyl (CH 2 )j.
  • R 8 wherein R 8 is OH, (C 2 -C 4 )acyloxy, SO 3 H, PO 4 H 2 , N(NO)(OH), SO 2 NH 2 , PO(OH)NH 2 , or tetrazolyl or a pharmaceutically acceptable salt thereof.
  • Lower alkyl, alkenyl, alkanoyl, etc. indicates a branched, cyclic or straight chain C r C 6 group, preferably a C r C 4 group, including cycloalkyl and (cycloalkyl)alkyl.
  • (Hydroxy)lower alkyl or alkoxy is preferably 1- or 2- hydroxyethyl.
  • the relatively low water solubility of the R(-) enantiomer of etodolac can reduce its usefulness against cancer when administered orally, or in an aqueous vehicle. Therefore, the present invention also provides novel indole compounds that exhibit enhanced water solubility and/or bioavailability over the free acid or the simple alkyl esters of etodolac.
  • Such analogs include (pyridinyl) lower alkyl esters, (amino)lower alkyl esters, (hydroxy)lower alkyl esters and 1 '-D-glucuronate esters of etodolac, e.g., compounds of formula (II) wherein (a) Y is carbonyl and (b) Z is ( ⁇ -(4- pyridyl)(C 2 -C 4 alkoxy), ( ⁇ -((R 8 )(R 9 ) amino)(C 2 -C 4 alkoxy), wherein R 8 and R 9 are each H, (C 1 -C 3 )alkyl or together with N are a 5- or 6-membered heterocyclic ring comprising 1-3 N(R 8 ), S or nonperoxide O; an amino acid ester of ( ⁇ - (HO)(C 2 -C 4 )alkoxy, e.g., the L- valine or L-glycine ester of 2-hydroxyetl ⁇ oxy
  • racemate has been resolved by fractional crystallization of RS- etodolac using optically active 1-phenylethylamine and HPLC has been used to determine racemic etodolac and enantiomeric ratios of etodolac and two hydroxylated metabolites in urine (U. Becker-Scharfenkamp et al.,
  • Etodolac itself (l,8-diethyl-l,3,4,9-tetrahydro[3,4-6]indole-l-acetic acid) is a NSATD of the pyranocarboxylic acid class, that was developed in the early 1970s. Its structure is depicted as formula (II), below, wherein (*) denotes the chiral center. See also, The Merck Index. (11th ed.), at page 608.
  • R(-) etodolac is not a NSATD.
  • R(-) etodolac paradoxically was found to have potent activity against cancer cells that is at least equivalent to that of the S(+) enantiomer.
  • Etodolac possesses several unique disposition features due to their stereoselective pharmacokinetics.
  • concentrations of the "inactive" R-enantiomer of etodolac are about 10-fold higher than those of the active S-enantiomer, an observation that is novel among the chiral NSAIDs. See, D. R. Brocks et al., Clin. Pharmacokinet.. 26, 259 (1994).
  • the maximum plasma concentration of the R-enantiomer was about 33 ⁇ M.
  • the maximum concentration of the S-enantiomer was 5-fold lower.
  • the typical dosage of the racemic mixture of etodolac is 400 mg BID, and the drug has an elimination half-life between 6-8 hours.
  • the administration of the purified R-enantiomer will not display the side effects associated with cyclooxygenase (COX) inhibitors, such as ulcers and renal insufficiency, and thus can be given at considerably higher dosages.
  • COX cyclooxygenase
  • the relatively low solubility of R(-)-etodolac in water can impede attaining plasma levels in humans that can inhibit cancer cells, particularly prostate cancer cells.
  • the compounds of formula (I) can be dissolved in water and other aqueous carriers at substantially higher concentrations than R(-) etodolac.
  • the compounds of formula (I) can also be prepared in the form of their pharmaceutically acceptable salts or their non-pharmaceutically acceptable salts.
  • the non-pharmaceutically acceptable salts are useful as intermediates for the preparation of pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects.
  • salts examples include (a) acid addition salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; and salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p- toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, and the like; and (b) salts formed from elemental anions such as chlorine, bromine, and iodine.
  • inorganic acids for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, ni
  • Preferred carboxylic acid salts are those of hydrophihc amines, such as glucamine or ⁇ (C j -C ⁇ alkylglucamine (see, Adger et al. (U.S. Pat. No. 5,811,558)).
  • a prophylactic or therapeutic dose of a compound or compounds of formula (I) in the acute or chronic management of cancer will vary with the type and/or stage of the cancer, the adjunct chemotherapeutic agent(s) or other anti-cancer therapy used, and the route of administration.
  • the dose, and perhaps the dose frequency will also vary according to the age, body weight, condition, and response of the individual patient.
  • the total daily dose range for a compound or compounds of formula (I), for the conditions described herein is from about 50 mg to about 5000 mg, in single or divided doses.
  • a daily dose range should be about 100 mg to about 4000 mg, most preferably about 1000-3000 mg, in single or divided doses, e.g., 750 mg every 6 hr of orally administered compound. This can achieve plasma levels of about 500-750 ⁇ M, which can be effective to kill cancer cells.
  • the therapy should be initiated at a lower dose and increased depending on the patient's global response. It is further recommended that infants, children, patients over 65 years, and those with impaired renal or hepatic function initially receive lower doses, particularly of analogs which retain COX inhibitory activity, and that they be titrated based on global response and blood level. It may be necessary to use dosages outside these ranges in some cases.
  • an effective inhibitory or amount or “an effective sensitizing amount” are encompassed by the above- described dosage amounts and dose frequency schedule.
  • Any suitable route of administration may be employed for providing the patient with an effective dosage of a compound of formula (I).
  • oral, rectal, parenteral (subcutaneous, intravenous, intramuscular), intrathecal, transdermal, and like forms of administration may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, and the like.
  • the compound may be administered prior to, concurrently with, or after administration of chemotherapy, or continuously, i.e., in daily doses, during all or part of, a chemotherapy regimen.
  • the compound in some cases, may be combined with the same carrier or vehicle used to deliver the anti-cancer chemotherapeutic agent.
  • 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 incorporated directly with the food of the patient's diet.
  • 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 be obtained.
  • 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 disintegrated 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.
  • tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like.
  • Tablets, capsules, pills, granules, microparticles and the like can also comprise an enteric coating, such as a coating of one of the Eudragit ® polymers, that will permit release of the active compound(s) in the intestines, not in the acidic environment of the stomach. This can be advantageous in the case of elderly or frail cancer patients treated with any compound that retains a significant COX-inhibitory activity, and concomitant ulceration.
  • a syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated 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 non-toxic 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.
  • 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, non-toxic glyceryl 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. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating 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.
  • 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.
  • Useful dosages of the compounds of formula I 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. Patent No. 4,938,949.
  • compounds of formula (I) that elevate PPAR- ⁇ levels, to lower the expression of the androgen receptor known to be overexpressed in hormone-refractory prostate cancer compounds that upregulate PPAR- ⁇ are advantageously used in combination with steroidal and non- steroidal anti-androgens used in the treatment of prostate cancer.
  • These compounds include leuprolide or goserelin acetate, bicalutamide and flutamide, nilutamide, cycloproterone acetate, among others.
  • chemotherapeutic agents used to treat cancers such as prostate cancer, including estramustine, vinblastine, mitoxanthrone, prednisone and the like, or melphalan to treat MM.
  • Other chemotherapeutic agents, irradiation or other anti-cancer agents such as anti-tumor antibodies, or cytokines can be used with the present compounds. See, e.g., Remington's Pharmaceutical Sciences (18th ed. 1990) at pages 1138-1162. The invention will be further described by reference to the following detailed examples.
  • Example 1 Sensitivity of Normal Peripheral Blood Lymphocytes and CLL Cells to Etodolac Mononuclear cells were isolated from the peripheral blood of B-CLL patients and normal donors using density gradient centrifugation (Ficoll-Paque). Cells were cultured at 2 x 10 6 cells per mL in RPMI with 20% autologous plasma in 96-well plates with or without the indicated ⁇ M concentrations of etodolac (racemic, S-etodolac, R-etodolac) and in combination with 2-chloro-2'- deoxyadenosine (2CdA) or fludarabine. At indicated times (12, 24, 36, 48, 60, 72 hours), viability assays were performed using the erythrocin B exclusion assay, as described by D. Carson et al., PNAS USA. 89, 2970 (1992).
  • Fludarabine is a nucleoside analog commonly used for the treatment of CLL.
  • the in vitro survival of CLL cells at the indicated time points was compared in cultures containing medium alone ("Con", squares), fludarabine 10 nM (diamonds), etodolac 10 ⁇ M (closed circles), and fludarabine 10 nM plus etodolac 10 ⁇ M (open circles).
  • the two drugs together exhibited a synergistic cytotoxic effect.
  • Figure 3 shows that the combination killed 50% of CLL cells during 48 hours of culture, while either drug alone was ineffective.
  • Figure 4 demonstrates synergy between 50 ⁇ M etodolac and 10 nM 2- chlorodeoxyadenosine and fludarabine, under the same test conditions.
  • Example 3 Effect of R(- and S(+) Etodolac Against CLL Cells
  • Etodolac tablets were ground in a mortar and extracted from the formulation using ethyl acetate.
  • the resulting racemic mixture of enantiomers was separated into R and S isomers on a preparative scale by fractional crystallization by the procedure of Becker-Scharfenkamp and Blas.chke,
  • Heparinized blood was taken from two patients (JK and NA) with CLL. Then each patient immediately took a 400 mg etodolac tablet, and a second tablet 12 hours later. After another 12 hours, a second blood specimen was obtained. The CLL cells were isolated and their survival in vitro were compared in RPMI 1640 medium containing 10% autologous plasma, as described in
  • Example 1 The circles show CLL cells before etodolac treatment.
  • the upward pointing triangles represent CLL cell viability after etodolac treatment, wherein the cells are dispersed in medium containing the pretreatment plasma.
  • the downward pointing triangles are CLL cells after treatment ' maintained in medium with the post-treatment plasma.
  • Figure 6 shows the different survivals of the two cell populations from patient JK. Note that the cells after treatment had a shortened survival compared to the cells before treatment.
  • Figure 7 shows a less dramatic but similar effect with patient NA.
  • Figure 8 is a flow cytometric analysis of CLL cells from patient JK before and after etodolac treatment.
  • DiOC 6 is a dye that is captured by mitochondria.
  • the X axis on the four panels in Figure 8 shows the DiOC 6 staining.
  • An increased number of dots in the left lower box indicates cell death by apoptosis. If one compares the cells taken from the patient before etodolac treatment, and after etodolac treatment, one can see that the number of dots in the left lower box is much higher after the drug. This effect is detectable at 12 hours, and increases further after 24 hours.
  • the mitochondrial transmembrane potential was analyzed by 3,3' dihexyloxacarboncyanide iodide (DiOC 6 ), cell membrane permeability by propidium iodide (PI) 3 and mitochondrial respiration by dihydrorhodamine 123 (DHR) (See J. A. Royall et al, Arch. Biochem. Biophvs.. 302. 348 (1993)).
  • DiOC 6 3,3' dihexyloxacarboncyanide iodide
  • PI propidium iodide
  • DHR dihydrorhodamine 123
  • Cells were also cultured for 3 hours with the indicated amount of etodolac, spun down at 200 x g for 10 minutes and resuspended in fresh respiration buffer (250 mM sucrose, 1 g/L bovine serum albumin, 10 mM MgCl 2 , 10 mM K/Hepes, 5 mM KH 2 PO 4 (pH 7.4)) and cultured for 10 minutes at 37° C with 0.04% digitonin. Then cells were loaded for 5 minutes with 0.1 ⁇ M dihydrorhodamine (DHR). Cells were analyzed within 30 minutes in a Becton Dickinson FAC-Scalibur cytofluorometer. After suitable comprehension, fluorescence was recorded at different wavelength: DiOC 6 and DHR at 525 nm (Fl-1) and PI at 600 nm (FL-3).
  • DHR dihydrorhodamine
  • the marrow contained a mixture of malignant cells, as enumerated by high level expression of the CD38 membrane antigen, and normal cells.
  • the suspended marrow cells were incubated for 72 hours in RPMI 1640 medium with 10% fetal bovine serum, and various concentrations of the purified R-enantiomer of etodolac. Then the dead cells were stained with propidium iodide, and the multiple myeloma cells were stained with fluorescent monoclonal anti-CD38 antibodies. The data were analyzed by fluorescent activated cell sorting.
  • Figures 9-10 show that R-etodolac did not kill the normal bone marrow cells (light bars), but dose-dependently killed the multiple myeloma cells (dark shaded areas), in the marrow cells from both patients.
  • Table 1 summarizes the cytotoxic effects of R(-)-etodolac toward prostate cancer cell lines and one colon cancer cell line are indeed within clinically achievable concentrations, given that a 1 gram dosage of R(-)-etodolac should yield a maximal plasma concentration in a human subject of about 400 ⁇ M.
  • PC-3 Prostate 340 20* 150 ⁇ 15* 800 + 30* Sensitive
  • etodolac and other NSAIDS can readily insert into cell and organ membranes, and can disrupt their structure and function (S. B. Abramson et al., Arthritis and Rheumatism. 32, 1 (1989)).
  • the proteins Mcl-l and Bag-1 are anti-apoptotic members of the bcl-2 family that are found in mitochondria (X. Wang et al., Exp. Cell Res.. 235. 210 (1997)).
  • Mcl-l and Bag-1 levels fell in an etodolac sensitive prostate cancer cell line (LNCaP).
  • Mcl-l and Bag-1 levels were prevented by co-incubation of the prostate cells with 5.0 ⁇ M MG-132, a recently described inhibitor of the proteasome (Figure 11, Panels A and B, respectively) (D. H. Lee at al., Trends Cell Biol.. 8, 397 (1998)).
  • Detergent lysates (20 ⁇ g per lane) were subjected to SDS-PAGE and immunoblotted with anti-Mcl-1 and anti-Bag- 1 antibodies.
  • Z-VAD a broad-spectrum caspase inhibitor
  • Etodolac incubation did not alter Bcl-2 and Bax levels (data not shown).
  • etodolac did not interfere with Mcl-l synthesis, but probably accelerated its turnover. Both R- and S-etodolac induced Mcl-l degradation at equivalent concentrations.
  • Example 8 Expression of PPAR- ⁇ in Cancer Cell Lines
  • Detergent lysates (20 ⁇ g per lane) obtained from subconfluent cell lines were subjected to SDS-PAGE and immunoblotted with anti-PPAR- ⁇ antibodies.
  • the membrane was reblotted with an anti-actin monoclonal antibody.
  • Lane 1 PC-3
  • Lane 2 SW260
  • Lane 3 A549
  • Lane 4 MDA-MB-231
  • Lane 5 Alva-31
  • Lane 6 LNCaP
  • Lane 7 HCT-116 (see Table 1). It was observed that some etodolac- susceptible prostate cells (PC3 especially) expressed remarkably high levels of immunoreactive PPAR- ⁇ ( Figure 12).
  • RAW264.7 cells were transfected at a density of 3 x 10 5 cells/ml in six well plates using lipofectamine with the PPAR- ⁇ expression vector pCMX- PPAR- ⁇ (0.1 ⁇ g), and the PPAR- ⁇ reporter construct (AOx) 3 -TK-Luc (1 ⁇ g) as previously described by M. Ricote et al, Nature, 391, 79 (1998). Cells were treated for 24 hours with the compounds indicated on Figure 13, harvested and assayed for luciferase activity. Results are expressed as the mean ⁇ SD.
  • both the R- and S- enantiomers of etodolac activated a PPAR- ⁇ reporter gene construct at concentrations readily achieved in human plasma after in vivo administration.
  • THP-1 human monocytic cells ATCC were incubated in the presence or absence of phorbol ester (40 ng TPA) and 200 ⁇ M racemic etodolac or 20 ⁇ M troglitazone. After three days of culture, the surface expression of the scavenger receptor CD36 was measured by flow cytometry.
  • both R- and S-etodolac caused the expression of CD36, a marker of PPAR- ⁇ activation, in the human cell line THP-1 during macrophage differentiation.
  • Example 10 Etodolac Treatment of Prostate Cancer Tissue Samples Freshly obtained prostatectomy samples were cut into 3 mm 3 pieces, and incubated for 72 hours in RPMI- 1640 supplemented with 10% FBS and antibiotics in the absence (A, 400X) or presence of racemic etodolac (B, 400X) or the purified R enantiomer (C, 400X; and D, 630X). The tissues were next fixed in 4% paraformaldehyde in PBS, embedded in paraffin, sectioned and stained with hematoxylin and eosin.
  • Figure 15A shows the infiltrating tumor cells (large nuclei) and some residual normal epithelium.
  • Figures 15 B to 15 D show the effect of etodolac: note the abundant presence of pyknotic apoptotic nuclei (dark arrows, B and D), and the disintegration of the neoplastic glandular architecture (B+C).
  • Etodolac was found to be selectively toxic to the tumor cells, but did not affect normal basal cells.
  • the racemic mixture (R/S) and the purified R and S analogs were found both active.
  • Example 11 Prospective Protocol for Screening to Identify Etodolac Analogs
  • CLL chronic lymphocytic leukemia
  • Etodolac [sp.act.20-25 Ci/mmol, prepared by Sibtech] and potential competitors or buffer are incubated in at varying temperatures [4 and 37°C] and times [0-60 minutes].
  • triplicate 50 ⁇ l aliquots will be layered over 300 ⁇ l 20% sucrose in HBSS-HEPES in 1.5 ml polypropylene snap top tubes and pelleted for 2.5 minutes at 15000 rpm in a Beckman microfuge. This procedure rapidly separates the cell-bound and cell-free etodolac. The tube tips will be cut off and the cell pellets will be solubilized and counted in a scintillation counter.
  • Some of the incubation mixtures will contain excess unlabeled etodolac as a control. Specific binding is the difference in the bound cpm in tubes containing the radiolabeled etodolac minus the cpm in the tubes containing the radiolabeled etodolac and the excess cold competitor etodolac. Test agents are compared to the unlabeled cold competitor etodolac for their abilities to inhibit radiolabeled etodolac binding. Compounds that can inhibit the binding of radiolabeled etodolac to its receptor(s) are advanced to the next screen.
  • Intracellular Ca 2+ mobilization in CLL Increase of intracellular calcium levels in CLL cells by test compounds such as etodolac analogs will be measured by a flow cytometric assay (FACS) and by using a fmorometric imaging plate reader system (FLTPR, Molecular Devices Corp., Sunnyvale, CA) using the Fluo-4 dye (Molecular Probes). Briefly, CLL cells (5 x lOVml) will be loaded for 30 min with 4 ⁇ M of Fluo-4 at 37°C in serum-free medium, washed twice, and resuspended for an additional 30 min in normal cell culture medium.
  • FACS flow cytometric assay
  • FLTPR fmorometric imaging plate reader system
  • Fluo-4 dye Molecular Probes
  • the loaded cells will be then mixed in FACS tubes with medium containing a test agent, and immediately thereafter the fluorescence will be followed by FACS analysis over a period of 3 minutes.
  • FACS high-throughput screening
  • the FLTPR-based assay will allow screening in a 96-well plate format, using the same fluorometric dye (Fluo-4).
  • Positive controls will be performed using the calcium ionophore ionomycin at 50 ng/ml final concentration, with chemokines such as SDF-1 and IP- 10, and with anti-IgM cross-linking antibodies.
  • Compounds that increase the Ca +2 uptake by CLL cells, preferably to at least the level induced by R(-)-etodolac are advanced to the next screen.
  • the chamber will be incubated at 37°C with 5% CO 2 for 2 hours.
  • the membranes will then be removed, and the cells present on the bottom well will be quantified by flow cytometry.
  • a fixed acquisition time of 30 seconds will be used per sample, and beads will be run during each experiment to ensure a reproducibie acquisition.
  • Test agents that induce a chemokinetic response in the lymphocytes such a chemotactic response, preferably at least as effectively as R(-) etodolac, will be advanced to the next screen.
  • the pro-apoptotic activity of the test agents will be tested in primary CLL cells, as well as in other tumor cells, by using the MTT assay and by measuring the catalytic activation of caspase-3 using a fluorometric assay.
  • cells will be incubated for up to 3 days in presence of serial dilutions of the selected test agents.
  • Cells viability will be quantified in 96-well plates by adding the MTT reagent (at 1 mg/ml final) for 2-4 hours followed by SDS cell lysis and spectrophotometric analysis at 570 nm.
  • Caspase catalytic activity will be measured in a 96-well plate assay using a specific fluorometric substrate (DEVD-AMC), after lysing the treated cells with a
  • Test agents that exhibit pro-apoptotic activity e.g., that increase caspase activity, preferably at least as effectively as R(-)-etodolac, will be advanced to the next screen.
  • E. Lymphocyte depletion in mouse The selected test agent will be orally delivered to mice of various backgrounds in a single dose of 25 and 100 mg/kg. The number of white blood cells will be counted using a neubauer chamber after 4, 24 hrs, 7 and 14 days post treatment. Test agents that do not lower white cell levels substantially, preferably no more than does R(-) etodolac, will be advanced to the next screen.
  • the anti-cancer and preventive activity of the R-etodolac analogs will be tested using the pristane-induced mouse myeloma model, and the transgenic adenocarcinoma mouse prostate (TRAMP) model.
  • the mice will receive a diet supplemented with 0.05% to 0.5% of the selected test agent or control.
  • the experimental diets will be in the form of sterile pellets containing the test agent (provided by Dyets Inc., PA).
  • the diet will be initiated at the same time as the first pristane injection.
  • the transgenic prostate cancer model the diet will begin at birth.
  • the diet will begin in the TRAMP mice at week 10, when the first histological pathologic markers are usually observed. Analogs will advance to clinical trials or further development based on their activity to inhibit cancer in at least one of these screens.

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Abstract

La présente invention concerne de nouveaux dérivés indoliques utilisés pour inhiber le développement du cancer ou sensibiliser les cellules cancéreuses à des agents chimiothérapeutiques, au rayonnement ou à d'autres traitements contre le cancer.
EP01962006A 2000-08-09 2001-08-09 Composes indoliques utilises dans le traitement du cancer Withdrawn EP1307459A2 (fr)

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WO2000002555A1 (fr) 1998-07-09 2000-01-20 Nardella Francis A Procedes et compositions pour le traitement de la leucemie lymphocitaire chronique
US7129262B2 (en) 1999-07-23 2006-10-31 The Regents Of The University Of California Indole compounds useful for the treatment of cancer
US7151100B1 (en) 1999-07-23 2006-12-19 The Regents Of The University Of California Indole compounds useful for the treatment of cancer
US6545034B1 (en) 1999-07-23 2003-04-08 The Regents Of The University Of California Use of etodolac for the treatment of chronic lymphocytic leukemia
US7105560B1 (en) 1999-07-23 2006-09-12 The Regents Of The University Of California Use of etodolac in the treatment of multiple myeloma
US7361680B2 (en) 1999-07-23 2008-04-22 The Regents Of The University Of California Indole compounds useful for the treatment of cancer
US20040152672A1 (en) * 2000-08-09 2004-08-05 Carson Dennis A. Indole compounds useful for the treatment of cancer
US7211599B2 (en) 2002-09-19 2007-05-01 The Regents Of The University Of California Use of etodolac to treat hyperplasia
CA2540289A1 (fr) 2003-10-02 2005-04-14 Cephalon, Inc. Derives d'indole substitues
FR2869231B1 (fr) * 2004-04-27 2008-03-14 Sod Conseils Rech Applic Composition therapeutique contenant au moins un derive de la pyrrolobenzodiazepine et la fludarabine
EA031737B1 (ru) 2010-06-03 2019-02-28 Фармасайкликс, Инк. Применение ингибиторов тирозинкиназы брутона (btk) для лечения лейкоза и лимфомы
CN110801454A (zh) * 2011-10-19 2020-02-18 药品循环有限责任公司 布鲁顿酪氨酸激酶(btk)抑制剂的用途
EP3550031A1 (fr) 2012-07-24 2019-10-09 Pharmacyclics, LLC Mutations associées à la résistance aux inhibiteurs de la tyrosine kinase de bruton (btk)
EP3119910A4 (fr) 2014-03-20 2018-02-21 Pharmacyclics LLC Mutations de phospholipase c gamma 2 et associées aux résistances

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