(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2004/0067953 A1
`(43) Pub. Date:
`Apr. 8, 2004
`Stein et al.
`
`US 2004OO67953A1
`
`(54) COMBINATION THERAPY FOR TREATING,
`PREVENTING OR MANAGING
`PROLIFERATIVE DSORDERS AND
`CANCERS
`(76) Inventors: Bernd M. Stein, San Diego, CA (US);
`John K. Westwick, San Ramon, CA
`(US); Bruce W. Ennis, Carlsbad, CA
`(US)
`Correspondence Address:
`JONES DAY
`222 EAST 41ST STREET
`NEW YORK, NY 10017 (US)
`(21) Appl. No.:
`10/384,440
`(22) Filed:
`Mar. 7, 2003
`Related U.S. Application Data
`(60) Provisional application No. 60/362,705, filed on Mar.
`8, 2002.
`
`Publication Classification
`
`(51) Int. Cl." ........................ A61K 38/00; A61K 31/525
`
`(52) U.S. Cl. ............................... 514/251; 514/2; 514/283
`(57)
`ABSTRACT
`The present invention relates to methods and compositions
`designed for the treatment, management or prevention of
`cancer. The methods of the invention comprise the admin
`istration of an effective amount of one or more inhibitors of
`JNK in combination with the administration of an effective
`amount of one or more other agents useful for cancer
`therapy. The invention also provides pharmaceutical com
`positions comprising one or more inhibitors of JNK in
`combination with one or more other agents useful for cancer
`therapy. In particular, the invention is directed to methods of
`treatment and prevention of cancer by the administration of
`an effective amount of one or more inhibitors of JNK in
`combination with Standard and experimental chemothera
`pies, hormonal therapies, bone marrow transplants, Stem cell
`replacement therapies, biological therapies/immunothera
`pies and/or radiation therapies for treatment or prevention of
`cancer. Also included are methods of treatment of cancer by
`the administration of one or more inhibitors of JNK in
`combination with Surgery, alone or in further combination
`with Standard and experimental chemotherapies, hormonal
`therapies, bone marrow transplants, Stem cell replacement
`therapies, biological therapies/immunotherapies and/or
`radiation therapies.
`
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`US 2004/OO67953 A1
`
`Apr. 8, 2004
`
`COMBINATION THERAPY FOR TREATING,
`PREVENTING OR MANAGING PROLIFERATIVE
`DSORDERS AND CANCERS
`0001. This application claims the benefit of U.S. provi
`sional application 60/362,705, filed Mar. 8, 2002, the con
`tents of which are incorporated by reference herein in their
`entirety.
`
`1. FIELD OF THE INVENTION
`0002 The invention relates to combination therapies for
`the treatment, prevention or management of a disease or
`disorder in cancer patients or patients having other prolif
`erative diseases or disorders.
`
`2. BACKGROUND OF THE INVENTION
`0003 Jun N-Terminal Kinase (JNK)
`0004 The Jun N-terminal kinase (JNK) pathway is acti
`Vated by exposure of cells to environmental StreSS or by
`treatment of cells with pro-inflammatory cytokines and
`growth factors. Targets of the JNK pathway include the
`transcription factors c-jun and ATF2 (Whitmarsh A. J., and
`Davis R. J. J. Mol. Med. 74:589-607, 1996). These tran
`Scription factors are members of the basic leucine Zipper
`(bZIP) group that bind as homo- and hetero-dimeric com
`plexes to AP1 and AP-1-like sites in the promoters of many
`genes (Karin M., Liu Z. G. and Zandi E. Curr Opin Cell Biol
`9:240-246, 1997). JNK binds to the N-terminal region of
`c-jun and ATF-2 and phosphorylates two sites within the
`activation domain of each transcription factor (Hibi M., Lin
`A., Smeal T, Minden A., Karin M. Genes Dev. 7:2135-2148,
`1993; Mohit A. A., Martin M. H., and Miller C. A. Neuron
`14:67-78, 1995). Three JNK enzymes have been identified
`as products of distinct genes (Hibi et al., Supra; Mohit et al.,
`supra). Ten different isoforms of JNK have been identified.
`These represent alternatively spliced forms of three different
`genes: JNK1, JNK2, and JNK3. JNK1 and 2 are ubiqui
`tously expressed in human tissues, whereas JNK3 is Selec
`tively expressed in the brain, heart, and testis (Dong, C.,
`Yang, D., Wysk, M., Whitmarsh, A., Davis, R., Flavell, R.
`Science 270: 1-4, 1998). Gene transcripts are alternatively
`spliced to produce four-JNK1 isoforms, four-JNK2 iso
`forms, and two-JNK3 isoforms. JNK1 and 2 are expressed
`widely in mammalian tissues, whereas JNK3 is expressed
`almost exclusively in the brain. Selectivity of JNK signaling
`is achieved via Specific interactions of JNK pathway com
`ponents and by use of Scaffold proteins that Selectively bind
`multiple components of the signaling cascade. JIP-1 (JNK
`interacting protein-1) selectively binds the MAPK module,
`MLK->JNKK1->JNK. It has no binding affinity for a vari
`ety of other MAPK cascade enzymes. Different scaffold
`proteins are likely to exist for other MAPK signaling cas
`cades to preserve Substrate Specificity.
`0005 JNKS are activated by dual phosphorylation on
`Thr-183 and Tyr-185. JNKK1 (also known as MKK 4) and
`JNKK2 (MKK7), two MAPKK level enzymes, can mediate
`JNK activation in cells (Lin A., Minden A., Martinetto H.,
`Claret F-Z., Lange-Carter C., Mercurio F., Johnson G. L.,
`and Karin M. Science 268:286-289, 1995; Tournier C.,
`Whitmarsh A. J., Cavanagh J., Barrett T., and Davis R. J.
`Proc. Nat. Acad. Sci. USA 94:7337-7342, 1997). JNKK2
`specifically phosphorylates JNK, whereas JNKK1 can also
`phosphorylate and activate p38. Both JNKK1 and JNKK2
`
`are widely expressed in mammalian tissues. JNKK1 and
`JNKK2 are activated by the MAPKKK enzymes, MEKK1
`and 2 (Lange-Carter C. A., Pleiman C. M., Gardner A. M.,
`Blumer K. J., and Johnson G. L., Science, 260:315-319,
`1993; Yan M., Dai J. C., Deak J. C., Kyriakis J. M., Zon L.
`I., Woodgett J. R., and Templeton D. J., Nature, 372:798
`781, 1994). Both MEKK1 and MEKK2 are widely
`expressed in mammalian tissues.
`0006 Activation of the JNK pathway has been docu
`mented in a number of disease Settings, providing the
`rationale for targeting this pathway for drug discovery. In
`addition, molecular genetic approaches have validated the
`pathogenic role of this pathway in Several diseases. For
`example, autoimmune and inflammatory diseases arise from
`the over-activation of the immune System. Activated
`immune cells express many genes encoding inflammatory
`molecules, including cytokines, growth factors, cell Surface
`receptors, cell adhesion molecules, and degradative
`enzymes. Many of these genes are regulated by the JNK
`pathway, through activation of the transcription factors AP-1
`and ATF-2, including TNF-alpha, IL-2, E-selectin, and
`matrix metalloproteinases Such as collagenase-1 (Manning
`A. M. and Mercurio F., Exp Opin Invest Drugs, 6:555-567,
`1997). Monocytes, tissue macrophages, and tissue mast cells
`are key sources of TNF-alpha production. The JNK pathway
`regulates TNF-alpha production in bacterial lipopolysaccha
`ride-stimulated macrophages, and in mast cells Stimulated
`through the FceRII receptor (Swantek J. L., Cobb M. H.,
`Geppert T. D., Mol. Cell. Biol., 17:6274-6282, 1997; Ishi
`Zuka, T, Tereda N., Gerwins, P., Hamelmann E., Oshiba A.,
`Fanger G. R., Johnson G. L., and Gelfiand E. W., Proc. Nat.
`Acad. Sci. USA, 94:6358-6363, 1997). Inhibition of JNK
`activation effectively modulates TNF-alpha secretion from
`these cells. The JNK pathway therefore regulates production
`of this key pro-inflammatory cytokine. It is believed that
`JNK is pro-apoptotic under StreSS or inflammatory condi
`tions Such as exposure to UV-radiation. (Leppa and Bohman,
`Oncogene 18:6158-6162 (1999)). Matrix metalloproteinases
`(MMPs) promote cartilage and bone erosion in rheumatoid
`arthritis, and generalized tissue destruction in other autoim
`mune diseases. Inducible expression of MMPs, including
`MMP-3 and MMP-9, type II and IV collagenases, are
`regulated via activation of the JNK pathway and AP-1
`(Gum, R., Wang, H., Lengyel, E., Juarez, J., and Boyd, D.,
`Oncogene, 14:1481-1493, 1997). In human rheumatoid syn
`oviocytes activated with TNF-alpha, IL-1, or Fas ligand the
`JNK pathway is activated (Han Z., Boyle D. L., Aupperle K.
`R., Bennett B., Manning A. M., Firestein G. S., J. Pharm.
`Exp. Therap., 291:1-7, 1999; Okamoto K., Fujisawa K.,
`Hasunuma T., Kobata T., Sumida T., and Nishioka K., Arth
`& Rheum, 40; 919, 1997). Inhibition of JNK activation
`results in decreased AP-1 activation and collagenase-1
`expression (Han et al., Supra). The JNK pathway therefore
`regulates MMP expression in cells involved in rheumatoid
`arthritis.
`0007 Role of JNK in Cancer and Stroke
`0008 Cancer is characterized by uncontrolled growth,
`proliferation and migration of cells. Cancer is the Second
`leading cause of death with 500,000 deaths and an estimated
`1.3 million new cases in the United States in 1996. The role
`of Signal transduction pathways contributing to cell trans
`formation and cancer is a generally accepted concept. The
`JNK pathway leading to AP-1 appears to play a critical role
`
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`in cancer. Expression of c-jun is altered in early lung cancer
`and may mediate growth factor Signaling in non-Small cell
`lung cancer (Yin T., Sandhu G., Wolfgang C. D., Burrier A.,
`Webb R. L., Rigel D. F. Hai T, and Whelan J.J. Biol. Chem.
`272: 19943-19950, 1997). Indeed, over-expression of c-jun
`in cells results in transformation, and blocking c-jun activity
`inhibits MCF-7 colony formation (Szabo E., Riffe M.,
`Steinberg S. M., Birrer M. J., Linnnoila R. I., Cancer Res.
`56:305-315, 1996). DNA-damaging agents, ionizing radia
`tion, and tumor necrosis factor activate the JNK pathway. In
`addition to regulating c-jun production and activity, JNK
`activation can regulate phosphorylation of p53 and, thus, can
`modulate cell cycle progression (Chen T. K., Smith L. M.,
`Gebhardt D. K., Birrer M. J., Brown P. H. Mol. Carcino
`genesis, 15:215-226, 1996). The oncogene BCR-Abl, asso
`ciated with tC9.22) Philadelphia chromosome translocation
`of chronic myelogenous leukemia, activates JNK and leads
`to transformation of hematopoietic cells (Milne D. M.,
`Campbell L. E., Campbell D. G., Meek D. W., J. Biol. Chem.
`270:5511-5518, 1995). Selective inhibition of JNK activa
`tion by a naturally occurring JNK inhibitory protein, called
`JIP-1, blocks cellular transformation caused by BCR-Abl
`expression (Raitano A. B., Halpern J. R., Hambuch T. M.,
`Sawyers C. L., Proc. Nat. Acad. Sci USA, 92:11746-11750,
`1995). Thus, JNK inhibitors may block transformation and
`tumor cell growth.
`0009 JNK is also believed to partly responsible for
`cancer and/or tumor resistance to certain chemotherapeutics.
`The number one cause of cancers refractory against tradi
`tional chemo drugs is the upregulation of the mdr1 gene. The
`mdr1/p-glycoprotein gene has an AP-1 binding Site in its
`promoter and is believed to be stimulated by JNK. Upregu
`lation of JNK activity has also been found in tamoxifen
`resistant tumors. DN-Jun inhibits tumor growth in tamox
`ifen-resistant animals and delayS development of tamoxifen
`resistant phenotype (Daschner, et al. BreaSt Cancer ReS.
`53:229, 1999; Schiff, et al. J. Natl. Cancer Inst. 92: 1926,
`2000).
`0010 Stroke is the 3" leading cause of death and a
`leading cause of disability in the U.S. Stroke, along with
`neurodegenerative diseases, Such as Alzheimer's (AD) and
`Parkinson's disease (PD) impose a huge burden on the
`health care industry by impacting the quality of life of those
`affected. LOSS of neuronal cell populations in Stroke, AD, or
`PD underlies the motor and/or cognitive deficiencies in these
`patient populations. The mechanism by which neurons die in
`response to insult has not been fully elucidated; however,
`activation of the JNK pathway has been implicated as a
`major signaling pathway for neuronal apoptosis. (For review
`See Mielke K. and Herdegen T. Prog. Neurobiol. 61:45-60,
`2000). There have been a number of conflicting reports as to
`the role of JNK activity in the regulation of apoptosis. Some
`Studies Suggest that activating JNK activity induces phos
`phorylation of C-Jun protein and protects cells from apop
`tosis (Potapova, O., Basu, S., Mercola, D., Holbrook, N., J.
`Biol. Chem. 276:28546-28553, 2001). However, both pro
`survival and pro-apoptotic roles of activated JNK activity
`have also been described (Kolbus, A., Herr, I., Schreiber, M.,
`Piu, F., Beeche, M., Wagner, E. F., Karin, M., 103:897-907,
`2000; Wisdom, R., Johnson, R. S., Moore, C., EMBO J.,
`18:1888-197, 1999). A variety of insults have been shown to
`activate the JNK pathway in neurons. For example, activa
`tion of JNKS and phosphorylation of c-jun has been shown
`in brains of rats Subjected to aXotomy or ischemia with
`
`reperfusion, where neuronal cell loss was observed (Herde
`gen T., Claret F-X., Kallunki, T., Matin-Villalba A., Winter
`C., Hunter T. and Karin M. J. Neurosci. 18:5124-5135,
`1998). Further, inhibition of the mixed lineage kinase
`(MLK)-3, an upstream kinase in the JNK pathway, by
`CEP-1347 prevented motor neuron cell death following
`growth factor withdrawal in vitro (Maroney A. C., Glicks
`man M. A., Basma A. N., Walton K. M., Knight Jr. E.,
`Murphy C. A., Bartlett B. A., Finn J. P., Angeles T., Matsuda
`Y., Neff N. T. and Dionne C. A., J. Neurosci. 18:104-111,
`1998), protected cholinergic neurons following excitotoxic
`injury of the nucleus basalis magnocellularis (Saporito M.
`S., Brown, E. R., Miller M. S., Murakata C., Neff N. H.,
`Vaught J. L., and Carswell S. Neuroscience 86:461-472,
`1998), and blocked the degeneration of midbrain dopamine
`neurons in mice treated with the neurotoxin, 1-methyl-4-
`phenyl tetrahydropyridine (Saporito M. S., Brown E. M.,
`Miller M. S. and Carswell S. J. Pharm. Exp. Ther., 1999).
`While JNK1 and JNK2 enzymes have a widespread tissue
`distribution, JNK3 is selectively expressed in brain and to a
`lesser extent in the heart and testis (Dong C., Yang D., Wysk
`M., Whitmarsh A., Davis R., and Flavell R. Science 270: 1-4,
`1998). Because of this restricted distribution, JNK3 may be
`the prevailing kinase mediating neuronal apoptosis. In Sup
`port of JNK3's involvement in neuronal apoptosis, disrup
`tion of the gene encoding JNK3 in mice conferS resistance
`to kainic acid-induced Seizures and Subsequent hippocam
`pal neuronal cell death (Yang D. D., Kuan C.-Y., Whitmarsh
`A. J., Rincon M., Zheng T. S., Davis R. J., Rakic P. and
`Flavell R. A. Nature 389:865-870, 1997). Mounting evi
`dence points to a role for the JNK pathway in neuronal
`apoptosis. Therefore, selective JNK inhibitors should pre
`vent neuronal cell death observed in disorders and diseases
`of the CNS.
`0011 Cancer Therapy
`0012 Currently, cancer therapy may involve Surgery,
`chemotherapy, hormonal therapy and/or radiation treatment
`to eradicate neoplastic cells in a patient (see, for example,
`Stockdale, 1998, “Principles of Cancer Patient Manage
`ment', in Scientific American: Medicine, vol. 3, Rubenstein
`and Federman, eds., Chapter 12, Section IV). Recently,
`cancer therapy could also involve biological therapy or
`immunotherapy. All of these approaches pose significant
`drawbacks for the patient. Surgery, for example, may be
`contraindicated due to the health of the patient or may be
`unacceptable to the patient. Additionally, Surgery may not
`completely remove the neoplastic tissue. Radiation therapy
`is only effective when the neoplastic tissue exhibits a higher
`Sensitivity to radiation than normal tissue, and radiation
`therapy can also often elicit Serious Side effects. Hormonal
`therapy is rarely given as a Single agent and although can be
`effective, is often used to prevent or delay recurrence of
`cancer after other treatments have removed the majority of
`the cancer cells. Biological therapies/immunotherapies are
`limited in number and may produce Side effects Such as
`rashes or Swellings, flu-like Symptoms, including fever,
`chills and fatigue, digestive tract problems or allergic reac
`tions.
`0013 With respect to chemotherapy, there are a variety of
`chemotherapeutic agents available for treatment of cancer. A
`Significant majority of cancer chemotherapeutics act by
`inhibiting DNA synthesis, either directly, or indirectly by
`inhibiting the biosynthesis of the deoxyribonucleotide triph
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`osphate precursors, to prevent DNA replication and con
`comitant cell division (see, for example, Gilman et al.,
`Goodman and Gilman's: The Pharmacological Basis of
`Therapeutics, Eighth Ed. (Pergamom Press, New York,
`1990)). These agents, which include alkylating agents, Such
`as nitroSourea, anti-metabolites, Such as methotrexate and
`hydroxyurea, and other agents, Such as etoposides, campath
`ecins, bleomycin, doxorubicin, daunorubicin, etc., although
`not necessarily cell cycle Specific, kill cells during S phase
`because of their effect on DNA replication. Other agents,
`Specifically colchicine and the Vinca alkaloids, Such as
`vinblastine and Vincristine, interfere with microtubule
`assembly resulting in mitotic arrest. Chemotherapy proto
`cols generally involve administration of a combination of
`chemotherapeutic agents to increase the efficacy of treat
`ment.
`Despite the availability of a variety of chemothera
`0.014.
`peutic agents, chemotherapy has many drawbacks (see, for
`example, Stockdale, 1998, “Principles Of Cancer Patient
`Management” in Scientific American Medicine, vol. 3,
`Rubenstein and Federman, eds., ch. 12, Sect. 10). Almost all
`chemotherapeutic agents are toxic, and chemotherapy
`causes significant, and often dangerous, Side effects, includ
`ing Severe nausea, bone marrow depression, immunoSup
`pression, etc. Additionally, even with administration of
`combinations of chemotherapeutic agents, many tumor cells
`are resistant or develop resistance to the chemotherapeutic
`agents. In fact, those cells resistant to the particular chemo
`therapeutic agents used in the treatment protocol often prove
`to be resistant to other drugs, even those agents that act by
`mechanisms different from the mechanisms of action of the
`drugs used in the Specific treatment; this phenomenon is
`termed pleiotropic drug or multidrug resistance. Thus,
`because of drug resistance, many cancers prove refractory to
`Standard chemotherapeutic treatment protocols.
`0.015 There is a significant need for alternative cancer
`treatments, particularly for treatment of cancer that has
`proved refractory to Standard cancer treatments, Such as
`Surgery, radiation therapy, chemotherapy, and hormonal
`therapy. Further, it is uncommon for cancer to be treated by
`only one method. Thus, there is a need for development of
`new therapeutic agents for the treatment of cancer and new,
`more effective, therapy combinations for the treatment of
`CCC.
`0016. There is also a clear need for cancer chemothera
`peutics or therapeutic regimens for treating cancer patients
`while reducing or avoiding the toxicities and/or side effects
`asSociated with conventional therapies.
`0017 Citations or identification of any reference in Sec
`tion 2 of this application is not to be construed that Such
`reference is prior art to the present application.
`
`3. SUMMARY OF THE INVENTION
`0.018. The present invention is based, in part, on the
`recognition that inhibitors of JNK potentiate and Synergize
`with, enhance the effectiveness of, improve the tolerance of,
`and/or reduce Side effects caused by, other cancer therapies,
`including conventional and experimental chemotherapies,
`hormonal therapies, bone marrow transplants, Stem cell
`replacement therapies, biological therapies/immunothera
`pies and radiation therapies. Thus, the invention encom
`passes treatment regimens or protocols that provide better
`
`therapeutic profiles than current Single agent therapies or
`current combination therapy regimens. Encompassed by the
`invention are combination therapies that have additive
`potency or an additive therapeutic effect. The invention also
`encompasses Synergistic combinations where the therapeu
`tic efficacy is greater than additive. Preferably, Such com
`binations also reduce or avoid unwanted or adverse effects.
`In certain embodiments, the combination therapies encom
`passed by the invention provide an improved overall therapy
`relative to administration of either a JNK inhibitor or any
`other cancer therapy alone. Given the invention, in certain
`embodiments, doses of existing or experimental cancer
`therapies can be reduced or administered less frequently
`which increaseS patient compliance, improves therapy and
`reduces unwanted or adverse effects.
`0019. In one embodiment, the inhibitor of JNK is a small
`organic molecule capable of directly inhibiting JNK activity.
`In another embodiment, the inhibitor of JNK is an antibody
`or a fragment thereof that immunospecifically binds to JNK
`or another component of the JNK pathway thus inhibiting
`JNK activity.
`0020. Accordingly, the present invention relates to phar
`maceutical compositions and prophylactic and therapeutic
`regimens designed to prevent, treat, or manage cancer in a
`patient comprising administering one or more inhibitors of
`JNK in combination with one or more other cancer therapies
`other than the administration of a JNK inhibitor. In particu
`lar, the present invention provides methods of preventing,
`treating, or managing cancer in a patient comprising admin
`istering to Said patient a therapeutically or prophylactically
`effective of one or more inhibitors of JNK in combination
`with the administration of a therapeutically or prophylacti
`cally effective amount of one or more chemotherapies,
`hormonal therapies, bone marrow transplants, Stem cell
`replacement therapies, biological therapies/immunothera
`pies and/or radiation therapies other than the administration
`of a JNK inhibitor. It is also contemplated that such methods
`can include the administration of one or more JNK inhibitors
`in combination with Surgery, alone or in combination with
`the administration of one or more chemotherapies, hormonal
`therapies, bone marrow transplants, Stem cell replacement
`therapies, biological therapies/immunotherapies and/or
`radiation therapies other than the administration of a JNK
`inhibitor. In certain embodiments, the administration of
`inhibitors of JNK and the other cancer therapies is a thera
`peutic or prophylactic regimen or protocol. Such methods
`and regimens can encompass concurrent, Sequential, Syn
`chronized or alternating/cyclic administration of the inhibi
`tors of JNK with one or more other cancer therapies.
`0021. The present invention is directed to methods of
`treating or preventing cancer by administering an effective
`amount of JNK inhibitor to a patient in need thereof
`(referred to herein as a “patient'), typically a warm-blooded
`animal (including a human) in combination with one or
`more anti-cancer agents or radiation therapy or both. Prior to
`administration, one or more compounds of this invention are
`typically formulated as a pharmaceutical composition which
`contains an effective dosage amount of one or more of Such
`compounds in combination with one (or more) pharmaceu
`tically acceptable carrier(s). Conditions that may be treated
`by the compounds of this invention, or a pharmaceutical
`composition containing the Same, include cancer.
`
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`Apr. 8, 2004
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`0022. In one embodiment, the JNK inhibitor is
`2H-Dibenzo(cd.g) indazol-6-one. In another embodiment,
`the JNK inhibitor is 3-(4-fluoro-phenyl)-5-(2H-(1,2,4)tria
`Zol-3-yl)-1H-indazole. In another embodiment, the JNK
`inhibitor is 3-(4-(2-Piperidin-1-yl-ethoxy)-cyclohexa-1,5-
`dienyl)-5-(2H-(1,2,4)triazol-3-yl)-1H-indazole.
`0023 These and other aspects of this invention will be
`evident upon reference to the following detailed description.
`To that end, certain patent and other documents are cited
`herein to more Specifically Set forth various aspects of this
`invention. Each of these documents are hereby incorporated
`by reference herein in their entirety.
`
`3.1. BRIEF DESCRIPTION OF THE FIGURES
`0024 FIG. 1A: FIG. 1A shows the effect of JNK inhibi
`tor A (2H-Dibenzo(cdg) indazol-6-one) in combination with
`various chemotherapeutic agents on Lewis Lung Carcinoma
`(LLC) proliferation.
`0025 FIG. 1B: FIG. 1B shows the effect of JNK inhibi
`tor B (3-(4-fluoro-phenyl)-5-(2H-(1,2,4)triazol-3-yl)-1H-in
`dazole) in combination with various chemotherapeutic
`agents on tumor cell proliferation.
`0026 FIG. 2: FIG. 2 shows the JNK inhibitor B (3-(4-
`fluoro-phenyl)-5-(2H-(1,2,4)triazol-3-yl)-1H-indazole)
`in
`combination with cyclophosphamide, a chemotherapeutic
`agent on tumor growth.
`0027 FIG. 3: FIG. 3 shows the effect of JNK inhibitor
`A (2H-Dibenzo(cdg) indazol-6-one) in combination with a
`chemotherapeutic agent on the apoptosis of tumor cells.
`0028 FIG. 4: FIG. 4 shows the effect of JNK inhibitor
`A (2H-Dibenzo(cdg) indazol-6-one) in combination with a
`chemotherapeutic agent (CTX) on Lewis Lung Carcinoma
`proliferation.
`0029 FIG. 5: FIG. 5 shows the effect of JNK inhibitor
`C (3-(4-(2-Piperidin-1-yl-ethoxy)-cyclohexa-1,5-dienyl)-5-
`(2H-(1,2,4)triazol-3-yl)-1H-indazole) in combination with a
`chemotherapeutic agent (camptosar) on human colorectal
`cancer cell (HCT-116) proliferation.
`0030 FIG. 6: FIG. 6 shows the structure of JNK inhibi
`tors A, B and C.
`
`3.2 DEFINITIONS
`0031. The terms used herein having the following mean
`ing:
`0.032 “Alkyl” means a saturated straight chain or
`branched non-cyclic hydrocarbon having from 1 to 10
`carbon atoms. Representative Saturated Straight chain alkyls
`include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-
`hexyl, -n-heptyl, -n-octyl, -n-nonyl and -n-decyl; while
`Saturated branched alkyls include -isopropyl, -Sec-butyl,
`-isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methyl
`butyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,
`2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methyl
`hexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethyl
`pentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimeth
`ylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-
`dimtheylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl,
`2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl,
`4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpen
`
`tyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-me
`thyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl,
`3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl and the
`like.
`0033. An “alkenyl group” means a straight chain or
`branched non-cyclic hydrocarbon having from 2 to 10
`carbon atoms and including at least one carbon-carbon
`double bond. Representative Straight chain and branched
`(C-C)alkenyls include -Vinyl, -allyl, -1-butenyl, -2-bute
`nyl, -isobutylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-
`butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl,
`-1-hexenyl, -2-hexenyl, -3-hexenyl, -1-heptenyl, -2-hepte
`nyl, -3-heptenyl, -1-octenyl, -2-octenyl, -3-octenyl, -1-non
`enyl, -2-nonenyl, -3-nonenyl, -1-decenyl, -2-decenyl, -3-de
`cenyl and the like. An alkenyl group can be unsubstituted or
`Substituted.
`0034. An “alkynyl group” means a straight chain or
`branched non-cyclic hydrocarbon having from 2 to 10
`carbon atoms and including at lease one carbon-carbon triple
`bond. Representative Straight chain and branched -(C-
`Co)alkynyls include -acetylenyl, -propynyl, -1-butynyl,
`-2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl,
`-4-pentynyl, -1-hexynyl, -2-hexynyl, -5-hexynyl, -1-hepty
`nyl, -2-heptynyl, -6-heptynyl, -1-octynyl, -2-octynyl, -7-oc
`tynyl, -1-nonynyl, -2-nonynyl, -8-nonynyl, -1-decynyl,
`-2-decynyl, -9-decynyl, and the like. An alkynyl group can
`be unsubstituted or Substituted.
`0035) “Halogen” means fluorine, chlorine, bromine or
`iodine.
`0036) “Keto” means a carbonyl group (i.e., C=O).
`0037 “Acyloxy means an -OC(O)alkyl group, wherein
`alkyl
`is
`defined above, including -OC(O)CH,
`–OC(O)CHCH,
`-OC(O)(CH)2CH,
`-OC(O)(CH-)-CH,
`-OC(O)(CH), CH,
`-OC(O)(CH-)-CH, and the like.
`0038 “Alkoxy” means -O-(alkyl), wherein alkyl is
`defined
`above, including -OCH, -OCHCH,
`-O(CH2)CH,
`-O(CH-)-CH,
`-O(CH2)CH,
`-O(CH-)-CH, and the like.
`0039) “Alkoxyalkoxy” means -O-(alkyl)-O-(alkyl),
`wherein each alkyl is independently an alkyl group defined
`above, including -OCHOCH, -OCHCHOCH,
`-OCHCHOCH2CH, and the like.
`0040) “Alkoxycarbonyl” means –C(=O)C)-(alkyl),
`wherein alkyl is defined above, including -C(=O)C)-
`CH, -C(=O)C)-CHCH, -C(=O)C)-(CH2)CH,
`-C(=O)C)-(CH2)CH,
`-C(=O)C)-(CH), CH,
`-C(=O)C)-(CH2)CH, and the like.
`0041) “Alkoxycarbonylalkyl” means -(alkyl)-C(=O)C)-
`(alkyl), wherein each alkyl is independently defined above,
`including -CH-C(=O)C)-CH, -CH-C(=O)C)
`CHCH, -CH-C(=O)C)-(CH2)CH, -CH
`C(=O)0-(CH2)CH, -CH-C(=O)C)-(CH2)CH,
`-CH-C(=O)C)-(CH), CH, and the like.
`0042 “Alkoxyalkyl” means -(alkyl)-O-(alkyl), wherein
`each alkyl is independently an alkyl group defined above,
`including
`-CHOCH,
`-CHOCH2CH,
`-(CH2)2OCHCH, -(CH2)(CH2)CH, and the like.
`
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`“Aryl” means a carbocyclic aromatic group con-
`[0043]
`taining from 5 to 10 ring atoms. Representative examples
`include, but are not limited to, phenyl, tolyl, anthracenyl,
`fiuorenyl, indenyl, azulenyl, pyridinyl and naphthyl, as well
`as benzo-fused carbocyclic moieties including 5,6,7,8-tet-
`rahydronaphthyl. A carbocyclic aromatic group can be
`unsubstituted or substituted. In one embodiment, the car-
`bocyclic aromatic group is a phenyl group.
`
`“Aryloxy” means —O-aryl group, wherein aryl is
`[0044]
`as defined above. An aryloxy group can be unsubstituted or
`substituted. In one embodiment, the aryl ring of an aryloxy
`group is a phenyl group
`
`
`“Arylalkyl” means -(alkyl)-(aryl), wherein alkyl
`[0045]
`and aryl are as defined above, including
`(CH2)phenyl,
`—(CH2)2phenyl,
`—(CH2)3phenyl,
`—CH(phenyl)2,
`—CH(phenyl)3, —(CH2)tolyl, —(CH2)anthracenyl,
`—(CH2)fluorenyl, —(CH2)indenyl, —(CH2)azulenyl,
`—(CH2)pyridinyl, —(CH2)naphthyl, and the like.
`
`“Arylalkyloxy” means —O-(alkyl)-(aryl), wherein
`[0046]
`and
`aryl
`are
`defined
`above,
`including
`alkyl
`—O—(CH2)2phenyl, —O—(CH2)3phenyl, —O—CH(phe-
`nyl)2,
`—O—CH(phenyl)3,
`—O—(CH2)tolyl,
`—O—(CH2)anthracenyl,
`—O—(CH2)fluorenyl,
`—O—(CH2)indeny1,
`—O—(CH2)azulenyl,
`—O—(CH2)pyridinyl, —O—(CH2)naphthyl, and the like.
`
`“Aryloxyalkyl” means -(alkyl)-O-(aryl), wherein
`[0047]
`alkyl and aryl are defined above,
`including —CH2—O-
`(phenyl), —(CH2)2—O-phenyl, —(CH2)3—O-phenyl,
`—(CH2)—O-tolyl, —(CH2)—O-anthracenyl, —(CH2)—O-
`fluorenyl, —(CIIz)—O-indenyl, —(CIIz)—O-azulenyl,
`7(CH2)7O—pyridinyl, 4(CH2)7O—naphthyl, and the like.
`
`“Cycloalkyl” means a monocyclic or polycyclic
`[0048]
`saturated ring having carbon and hydrogen atoms and hav-
`ing no
`carbon-carbon multiple bonds. Examples of
`cycloalkyl groups includ