AU780306B2 - Pyrazoloanthrone and derivatives thereof as JNK inhibitors and their compositions - Google Patents

Pyrazoloanthrone and derivatives thereof as JNK inhibitors and their compositions Download PDF

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AU780306B2
AU780306B2 AU67863/00A AU6786300A AU780306B2 AU 780306 B2 AU780306 B2 AU 780306B2 AU 67863/00 A AU67863/00 A AU 67863/00A AU 6786300 A AU6786300 A AU 6786300A AU 780306 B2 AU780306 B2 AU 780306B2
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Brydon L. Bennett
Shripad S. Bhagwat
Anthony M. Manning
Brion W. Murray
Eoin C. O'leary
Yoshitaka Satoh
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Signal Pharmaceuticals LLC
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Description

WO 01/12609 PCT/USOO/22727 PYRAZOLOANTHRONE AND DERIVATIVES THEREOF AS JNK INHIBITORS AND THEIR
COMPOSITIONS
TECHNICAL FIELD This invention is generally directed to pyrazoloanthrone and derivatives thereof which have utility over a wide range of indications, including activity as Jun Nterminal kinase inhibitors, and related compositions and methods.
BACKGROUND OF THE INVENTION The Jun N-terminal kinase (JNK) pathway is activated by exposure of cells to environmental stress or by treatment of cells with pro-inflammatory cytokines.
Targets of the JNK pathway include the transcription factors c-jun and ATF2 (Whitmarsh and Davis R.J. J. Mol. Med. 74:589-607, 1996). These transcription factors are members of the basic leucine zipper (bZIP) group that bind as homo- and hetero-dimeric complexes to AP-1 and AP-1-like sites in the promoters of many genes (Karin 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 Lin Smeal Minden A., Karin M. Genes Dev. 7:2135-2148, 1993; Mohit Martin and Miller C.A.
Neuron 14:67-75, 199)]. 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: JNKl, JNK2 and JNK3. JNK1 and 2 are ubiquitously expressed in human tissues, whereas JNK3 is selectively expressed in the brain, heart and testis (Dong, C., Yang, Wysk, Whitmarsh, Davis, Flavell, R. Science 270:1-4, 1998).
Gene transcripts are alternatively spliced to produce four-JNK1 isoforms, four-JNK2 isoforms and two-JNK3 isoforms. JNK1 and 2 arc 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 components and by use of scaffold proteins that selectively bind multiple components of the signaling cascade.
WO 01/12609 PCTUSOO/22727 2 JIP-I (JNK-interacting protein-1) selectively binds the MAPK module, MLK JNKKI JNK.12,13 It has no binding affinity for a variety of other MAPK cascade enzymes. Different scaffold proteins are likely to exist for other MAPK signaling cascades to preserve substrate specificity.
JNKs are activated by dual phosphorylation on Thr-183 and Tyr-185.
JNKKI (also known as MKK 4) and JNKK2 (MKK7), two MAPKK level enzymes, can mediate JNK activation in cells (Lin Minden Martinctto Claret Lange-Carter Mercurio Johnson and Karin M. Science 268:286-289, 1995; Tournier Whitmarsh Cavanagh Barrett 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 JNKKI and JNKK2 are widely expressed in mammalian tissues. JNKKI and JNKK2 are activated by the MAPKKK enzymes, MEKKI and 2 (Lange-Carter Pleiman Gardner Blumer and Johnson G.L. Science 260:315-319, 1993; Yan Dai Deak J.C., Kyriakis Zon Woodgett and Templcton D.J. Nature 372:798-781, 1994). Both MEKKI and MEKK2 are widely expressed in mammalian tissues.
Activation of the JNK pathway has been documented 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 TNFa, 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 TNFa production. The JNK pathway regulates TNFa production in bacterial lipopolysaccharide-stimulated macrophages, and in mast cells stimulated through the FceRII receptor (Swantek Cobb Geppert T.D. Mol. Cell. Biol. 17:6274- WO 01/12609 PCT/USOO/22727 6282, 1997; Ishizuka, Tereda Gerwins, Hamelmann Oshiba Fanger Johnson and Gelfland E.W. Proc. Nat. Acad. Sci. USA 94:6358-6363, 1997). Inhibition of JNK activation effectively modulates TNFa secretion from these cells. The JNK pathway therefore regulates production of this key pro-inflammatory cytokine. Matrix metalloproteinases (MMPs) promote cartilage and bone erosion in rheumatoid arthritis, and generalized tissue destruction in other autoimmune diseases.
Inducible expression of MMPs, including MMP-3 and MMP-9, type II and IV collagenases, are regulated via activation of the .NK pathway and AP-1 (Gum, R., Wang, Lengyel, Juarez, and Boyd, D. Oncogene 14:1481-1493, 1997). In human rheumatoid synoviocytes activated with TNFa, IL-1. or Fas ligand the JNK pathway is activated (Han Boyle Aupperle Bennett Manning A.M., Firestein G.S. J. Pharm. Exp. Therap. 291:1-7, 1999; Okamoto Fujisawa K., Hasunuma Kobata Sumida and Nishioka K. Arth Rheum 40: 919-92615, 1997). Inhibition of JNK activation results in decreased AP-I activation and collagenase-1 expression (Han et al., supra). The JNK pathway therefore regulates MMP expression in cells involved in rheumatoid arthritis.
Inappropriate activation of T lymphocytes initiates and perpetuates many autoimmune diseases, including asthma. inflammatory bowel disease and multiple sclerosis. The JNK pathway is activated in T cells by antigen stimulation and CD28 receptor co-stimulation and regulates production of the growth factor IL-2 and cellular proliferation (Su Jacinto Hibi Kallunki Karin Ben-Neriah Y. Cell 77:727-736, 1994; Faris Kokot Lee and Nel A.E. J. Biol. Chem. 271:27366- 27373, 1996). Peripheral T cells from mice genetically deficient in JNKKI show decreased proliferation and IL-2 production after CD28 co-stimulation and PMA Ca2+ ionophore activation, providing important validation for the role of the JNK pathway in these cells (Nishina Bachmann Oliveria-dos-Santos et Exp. Med. 186: 941-953, 1997). It is known that T cells activated by antigen receptor stimulation in the absence of accessory cell-derived co-stimulatory signals lose the capacity to synthesize IL-2. a state called clonal anergy. This is an important process by which auto-reactive T cell populations are eliminated from the peripheral circulation. Of note, anergic T cells WO 01/12609 PCT/USOO/22727 4 fail to activate the JNK pathway in response to CD3- and CD28-receptor costimulation, even though expression of the JNK enzymes is unchanged (Li Whaley Mondino and Mueller D.L. Science 271: 1272-1276, 1996). Recently, the examination of JNK-deficient mice revealed that the JNK pathway plays a key role in T cell activation and differentiation to T helper I and 2 cell types. JNK 1 or JNK2 knockout mice develop normally and are phenotypically unremarkable. Activated naive CD4+ T cells from these mice fail to produce IL-2 and do not proliferate well (Sabapathy, K, Hu, Y, Kallunki, T, Schreiber, M, David, J-P, Jochum, W, Wagner, E, Karin, M. Curr Biol 9: 116-125, 1999). It is possible to induce T cell differentiation in T cells from these mice, generating Thl cells (producers of IFN-g and TNFP) and Th2 effector cells (producers of IL-4, IL-5, IL-6, IL-10 and IL-13) [22,231. Deletion of either JNKI or JNK2 in mice resulted in a selective defect in the ability of Thl effector cells to express IFNg. This suggests that JNKI and JNK2 do not have redundant functions in T cells and that they play different roles in the control of cell growth, differentiation and death. The JNK pathway therefore, is an important point for regulation of T cell responses to antigen.
Cardiovascular disease (CVD) accounts for nearly one quarter of total annual deaths worldwide. Vascular disorders such as atherosclerosis and restenosis result from dysregulated growth of the vessel wall, restricting blood flow to vital organs. The JNK pathway is activated by atherogenic stimuli and regulates local cytokine and growth factor production in vascular cells (Yang, DD, Conze, D, Whitmarsh, AJ, et al, Immunity, 9:575, 1998). In addition, alterations in blood flow, hemodynamic forces and blood volume lead to JNK activation in vascular cndothelium, leading to AP-1 activation and pro-atherosclerotic gene expression (Aspenstrom P., Lindberg and Hall A. Curr. Biol. 6:70-77, 1996). Ischemia and ischemia coupled with reperfusion in the heart, kidney or brain results in cell death and scar formation, which can ultimately lead to congestive heart failure, renal failure or cerebral dysfunction. In organ transplantation, reperfusion of previously ischemic donor organs results in acute leukocyte-mediated tissue injury and delay of graft function. The JNK pathway is activated by ischemia and reperfusion (Li Shyy Li Lee Su B., WO 01/12609 PCT/US00/22727 Karin Chien S Mol. Cell. Biol. 16:5947-5954, 1996), leading to the activation of JNK-responsive genes and leukcoyte-mediated tissue damage. In a number of different settings JNK activation can be either pro- or anti-apoptotic. JNK activation is correlated with enhanced apoptosis in cardiac tissues following ischemia and reperfusion (Pombo CM, Bonvcntre JV, Avruch J, Woodgett JR, Kyriakis J.M, Force T.
J. Biol. Chem. 269:26546-26551, 1994).
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 transformation and cancer is a generally accepted concept. The JNK pathway leading to AP-1 appears to play a critical role 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 Sandhu Wolfgang C.D., Burrier Webb Rigel D.F. Hai 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 Riffe Steinberg Birrer Linnoila R.I. Cancer Res. 56:305-315, 1996). DNA-damaging agents, ionizing radiation 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 Gebhardt Birrer Brown P.H. Mol. Carcinogenesis 15:215-226, 1996). The oncogene BCR-Abl, associated with t(9,22) Philadelphia chromosome translocation of chronic myelogenous leukemia, activates JNK and leads to transformation of hematopoietic cells (Milne Campbell Campbell D.G., Meek D.W. J. Biol. Chem. 270:5511-5518, 1995). Selective inhibition of JNK activation by a naturally occurring JNK inhibitory protein, called JIP-I, blocks cellular transformation caused by BCR-Abl expression (Raitano Halpem Hambuch Sawyers C.L. Proc. Nat. Acad Sci USA 92:11746-11750, 1995). Thus, JNK inhibitors may block transformation and tumor cell growth.
Accordingly, there is a need in the art for selective inhibitors of JNK, as well as for methods for preparation thereof, pharmaceutical compositions comprising such inhibitors, and methods of inhibiting JNK's and treating diseases in mammals which are responsive to JNK inhibition. The present invention fulfils these needs, and provides further related advantages.
The above discussion of documents, acts, materials, devices, articles and the like is included in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed in Australia before the priority date of each claim of this application.
Throughout the description and claims of this specification, the word "comprise" and variations of the word, such as "comprising" and "comprises", is not intended to exclude other additives, integers or process steps.
SUMMARY OF THE INVENTION In brief, the present invention is directed to compounds having activity as selective inhibitors of JNK, as well as to compositions and methods related thereto. The compounds of the present invention (also referred to herein as "JNK inhibitors") may generally be classified as "pyrazoloanthrone derivatives" having the following structure
(I)
wherein R 1 and R 2 are defined below, including pharmaceutically acceptable salts thereof.
*el W:ACO SvOaA M7883 sped PC. 0 &A (24.3.03)c 6A The present invention is also directed to methods for treating a variety of conditions by administering an effective amount of a JNK inhibitor to an animal or subject in need thereof (referred to herein as a "patient"), typically a warmblooded animal (including a human). Prior to administration, the compounds of this invention are preferably formulated as a pharmaceutical composition which contains an effective dosage amount of one or more JNK inhibitors in combination with one (or more) pharmaceutically acceptable carrier(s).
Conditions that may be treated by the compounds of this invention, or a pharmaceutical composition containing the same, include any condition which may benefit from administration of JNK inhibitors, and are particularly useful for the prevention and/or treatment of various diseases including (but not limited to) rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gout, asthma, *e o* 0• *o W:%CordleODAVID%78S3 sped pg. 6 SA (24.3.03).doc WO 01/12609 PCT/US00/22727 7 bronchitis, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, mucous colitis, ulcerative colitis, Crohn's disease, gastritis, esophagitis, hepatitis, multiple sclerosis, atherosclerosis, restenosis following angioplasty, left ventricular hypertrophy, myocardial infarction, stroke, ischemic damages to heart. kidney, liver, and brain, transplant rejection, endotoxin shock, psoriasis, eczema, dermatitis, epilepsy, Alzheimer's disease, Huntington's disease, Amyotrophic laterial sclerosis, peripheral neuropathies, spinal cord damage, Parkinson's disease, and cancer.
These and other aspects of this invention will be apparent 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 in their entirety.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates the ability of a representative compound of this invention to inhibit IL-2 in Jurkat T-Cell.
Figure 2 illustrates the ability of a representative compound of this invention to inhibit TNF-a in a mouse model of endotoxin shock.
Figure 3 illustrates the ability of a representative compound of this invention to inhibit leukocyte recruitment in rat model for inflamed lung.
Figure 4 illustrates the ability of a representative compound of this invention to inhibit paw swelling (Figure 4A), joint destruction (Figure 4B), transcription factor AP-1 activation (Figure 4C), and expression of MMP-13 (Figure 4D) in a rat model for adjuvant arthritis.
Figure 5 illustrates the ability of a representative compound of this invention to reduce kainic acid-induced seizure response.
DETAILED DESCRIPTION OF THE INVENTION As mentioned above, the present invention is directed to compounds which have activity as selective inhibitors of JNK, as well as to compositions and WO 0 1 /12609 PCT/US00122727 8 methods relating to the same. The compounds of this invention have the following structure and pharmaceutically acceptable salts thereof. wherein: R, and R, are optional substituents that are the same or different and independently represent alkyl, halogen, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy. arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy. mono- or dialkylamninoalkoxy. or a group represented by formula or /R3
R
4 (b) 0
H
(c) 0
/S-R
H
(d)
R
3 and R, taken together represent alkylidene or a heteroatom-containing alkylidene, or R, and R, are the same or different and independently represent hydrogen, alkyl, cycloalkyl. aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyal kyl, alkoxyamino, or alkoxy(mono- or di-alkylarnino); and represents hydrogen, alkyl, cycloalkyl. aryl, arylalkyl, cycloalkylalkyl, alkoxy, amnino, mono- or di-alkylamnino, arylamino, arylalkylamino, cycloalkylamnino, or cycloalkylalkylamino.
WO 01/12609 PCTIUSOO/22727 9 As used herein, the terms used above having following meaning.
"Alkvl" means a straight chain or branched, saturated or unsaturated alkyl chain having from 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl. iso-butyl, tert-butyl, propylenyl, 1-butenyl, propynyl. and the like.
"Halogen" means fluorine, chlorine. bromine or iodine.
"Trifluoromethyl" means -CF 3 "Sulfonyl" means -S031 1; "Carboxyl" means -COGH.
"Alkoxy" means -0-(alkyl), such as methoxy, ethoxy. n-propyloxy, isopropyloxy. n-butyloxy, iso-butyloxy, and the like.
"Alkoxyalkoxy" means -O-(alkyl)-0-(alkyl), such as -OCH,CH,OCH 3 and the like.
"Alkoxy carbonyl" means -C(=O)O-(alkyl), such as -C(-=0)OCH3, -C(=O)OCHCH,, and the like.
"Alkoxyalkyl" means -(alkyl)-0-(al kyl), such as -CH,OCH 3
-CH
2 ,OCH,CH,, and the like.
"Aryl" means a carhocyclic or heterocyclic aromatic group containing from 5 to 10 ring atoms. The ring atoms of a carbocyclic aryl group are all carbon atoms, and includes phenvl and naphthyl. The ring atoms of a heterocyclic aryl group contains at least one heteroatom selected from nitrogen, oxygen and sulfur, and include pyridinyl, pyrimidinyl. furanyl, thienyl. imidazolyl, thiazolyl, pyrazolyl, pyridazinyl, pyrazinyl, triazinyl, tetrazolyl, and indolyl.
"Aryloxy" means -O-(aryl), such as -0-phenyl, -0-pyridinyl, and the like.
"Arylalkyl" means -(alkyl)-(aryl), such as benzyl -CH~phenyl), -CH,-pyrindinyl, and the like.
"Arylalkyloxy" means -O-(alkyl)-(aryl), such as -0-benzyl, -0-CH,pyridinyl, and the like.
WO 01/12609 PCTIUSOO-2727 "Cycloalkyl" mean s a cyclic alkyl having from 3to 7 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl. and the like.
"Cycloalkyloxy" means -O-(cycloalkyl), such as -0-cvclohexyl, and the like.
"Cycloalkylalkyloxy" means -O-(alkyl)-(cvcloalkyl, such as -OCH.,cyclohexyl, and the like.
"Alkylidene" means the divalent radical wherein n is an integer from 1 to 8, such as -CH,CH 2
-CH,-CH
2
-CH,CH,CH.,CH,-,
-CH.CH.,CH,CH.,CH,-, and the like.
"Heteroatom-containing alkylidene" means an alkylidene wherein at least one carbon atom is replaced by a heteroatom selected from nitrogcn, oxygen or sulfur, such as -CHCHOCl-lCH,-, and the like.
"Aminoalkoxy" means -O-(alkyl)-NI such as -OCH.NH,.
-OCH,CH,NH,, and the like.
"Mono- or di-alkylamino" means -NH(alkyl) or -N(alkyl)(alkyl), respectively, such as -NHCI-1 3 -N(CH4,2, and the like.
"M~ono- or di-alkylaminoalkoxy" means -O-(alkyl)-NH(alkyl) or -O-(alkyl)-N(alkyl)(alkyl), respectively, such as -OCH,NHCH 3
-OCH-,CH
2
N(CH
3 and the like.
"Arylamino"means -NH(arvl). such as -NH-phenyl, -NH-pyridinyl. and the like.
"Arylalkylamino" means -NH-(alkyl)-(aryl), such as -NH-benzyl, -NHCH.,-pyridinyl, and the like.
"Alkylamino" means -NH(alkyl). such as -NHCH, -NHCH,CHanth like.
"Cycloalkylamino" means -NH-(cycloalkyl), such as -NH-cyclohexyl, and the like.
",Cycloalkylalkylamino" -NH-(alkyl)-(cycloalkyl), such as -NHCH,-cyclohexyl, and the like.
WO 01/12609 PCT/US00/22727 11 In the embodiment wherein R, and R, are not present, compounds of this invention have the following structure (II) (also referred to herein as "Compound
(II)
This compound is commercially available from Pfaltz-Bauer (Conn., In the embodiment wherein only one of R, and R, is present, compounds of this invention have one of the following structures (III) or (IV):
N-NH
R2
O
(III) (1V) In the embodiment wherein both R, and R, are present. compounds of this invention have one of the following structures (VI) or (VII):
N-NH
RI- R2 0 N NH R2 0
(VII)
(VII)
(VI)
WO 01/12609 PCT/US00/22727 12 Pharmaceutically acceptable salts of compounds of structure are also within the scope of this invention. To this end, the compound may generally be utilized as the free base. Alternatively, the compounds may be used in the form of acid addition salts. Acid addition salts of the free base amino compounds of the present invention may be prepared by methods well known in the art, and may be formed from organic and inorganic acids. Suitable organic acids include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic. cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids. Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids. Thus, the term "pharmaceutically acceptable salt" of a compound of structure is intended to encompass any and all acceptable salt forms.
The compounds of this invention may generally be made by organic synthesis techniques known to those skilled in the art, as well as by the following general techniques and by the procedures set forth in the Examples. To that end, the compounds of this invention may be made according to the following Reaction Schemes 1 through 7.
Reaction Scheme 1 O X N-NH R R NH2NH2
R
2 Ri R2 In Reaction Scheme 1, pyrazoloanthrones of this invention may be prepared by condensation of appropriate anthraquinones having a leaving group at the 1-position (such as fluoro, chloro, bromo, iodo, nitro, methanesulfonyloxy, tosyloxy or phenoxy) with hydrazine in a suitable solvent (such as pyridinc, dimethylformamide, methylene chloride, chloroform, or dioxane). The reaction is carried out at temperatures WO 01/12609 PCT/USOO/22727 13 ranging 0°C to 200 0 C for 1 to 16 hours. Suitable anthraquinone starting materials are commercially available from a variety of sources with the R, and/or R. groups at various positions on the anthraquinone ring. For purpose of illustration, the following reaction schemes depict synthesis of 5- and/or 7-substituted pyrazoloanthrones. One skilled in the art will recognize that pyrazoloanthrones substituted at other positions may be made in a similar manner from the appropriately substituted pyrazoloanthrone starting material.
Reaction Scheme 2 'NH NH R3NHR4 O Cl O R3N In Reaction Scheme 2, pyrazoloanthrones with 5-amino substituents may be prepared by condensation of 5-chloropyrazoloanthrone with mono- or disubstituted amines at 0 to 250 0 C for 1 to 16 hours, either in the absence or the presence of a solvent. Typically solvents are pyridine, dimethylformamide, dimethylsulfoxide, dichloroethane, chloroform, tetrahydrofuran, dioxane, diglyme, or triglyme in the presence of excess amount of the amine, or in the presence of an acid quenching agent such as triethylamine, diisopropylethylamine, sodium bicarbonate, potassium carbonate, or sodium hydroxide.
WO 01/12609 PCT/US00/22727 14 Reaction Scheme 3 -NH N-NH R3NHR34 R4 CI O R3N O In Reaction Scheme 3, pyrazoloanthrones with 7-amino substituents may be prepared by condensation of 7-chloropyrazoloanthrone with mono- or disubstituted amines at 0 to 250 0 C for 1 to 16 hours either in the absence or the presence of a solvent.
Typically solvents are pyridine, dimethylformamide, dimethylsulfoxide, dichloroethane, chloroform, tetrahydrofuran, dioxane, diglyme. or triglymc in the presence of excess amount of the amine, or in the presence of an acid quenching agent such as triethylamine, diisopropylethylamine, sodium bicarbonate, potassium carbonate, or sodium hydroxide.
WO 01/12609 PCT/US00/22727 Reaction Scheme 4 O ONH 0 NO 2
MEM-CI
NaHMDS
,MEM
0 NO 2 0 N02 H2. Pd/C
MEM
N--NH N-N 1 R6COCI or R 6
SO
2 C1 2) H+ O INH O NH2 Y(O)nR 6 Y=C, n= 1 Y=S, n 2 In Reaction Scheme 4, pyrazoloanthrones with 5-acyl- or sulfonylamino substituents may be prepared by condensation of 5-amino-2-(2methoxyethoxymethyl)pyrazoloanthrone with acid chlorides and sulfonyl chlorides followed by the deprotection. Condensation of 5-amino-2-(2methoxyethoxymethyl)pyrazoloanthrone with appropriate acid chlorides RCOCI or sulfonyl chlorides RSOCI is carried out in the presence of an acid quenching agent such as triethylamine, diisopropylethylamine, sodium bicarbonate, potassium carbonate, or sodium hydroxide at -20 to 50 0 C for 0.5 to 16 hours in solvents such as methylenc chloride, chloroform, tetrahydrofuran, dioxane, dimethylformamide, and ethyl acetate.
The deprotection step may be performed by the treatment of the product mentioned above with an acid such as trifluoroacetic acid, aqueous hydrochloric acid, aqueous hydrobromic acid, or aqueous sulfuric acid.
WO 01/12609 PCT/US00/22727 16 The starting material may be prepared in two steps. The 2-position of nitropyrazoloanthrone may be protected by a protective group such as methoxymethyl (MOM), methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), or 4methoxybenzyl (PMB) with an aid of a base such as triethylamine, diisopropylethylamine, pyridine, sodium hexamethyldisilazide, potassium hexamethyldisilazide, or lithium diisopropylamide. N-dimethylamino)pyridine (DMAP) may be used as a catalyst when a tertiary amine is used as a base. The reaction is typically carried out at -40 to 60 0 C for 1 to 16 hours in a solvent such as methylene chloride, chloroform, tetrahydrofuran, dioxane, or dimethoxyethane. As the nitrogen protective group, MEM group is preferred.
N-Protected 5-nitropyrazoloanthorone is then reduced to its derivative by a variety of reducing agents such as Sn or Fe metal in acidic media such as acetic acid or aqueous hydrochloric acid. The reaction is typically run at 20 to 160 0
C
for 1 to 16 hours. The same transformation can be carried out by hydrogenation in the presence of a transition-metal catalyst such as palladium, platinum, rhodium, or iridium with or without a support such as charcoal in a solvent such as ethanol, ethyl acetate, tetrahydrofuran, dioxane, or dimethoxyethane at 1 to 20 atmospheres of hydrogen at to 60 0 C for 1 to 16 hours. The procedure using hydrogenation with palladium on charcoal as the catalyst is preferred.
WO 01/12609 PCT/US00/22727 17 Reaction Scheme
MEM
N NI -N
MEM-CI
NaHMDS N02 O N02 0
H
2 PdIC
/MEM
N-NH N-N i) RCOCI or R6SO 2
CI
2) H+ NH 1 0 NI-12 0 Y(0)nR Y=C,n= 1 Y=S, n 2 In Reaction Scheme 5, pyrazoloanthrones with 7-acyl- or sulfonylamino substituents may be prepared by condensation of 7-amino-2-(2methoxyethoxymethyl)pyrazoloanthrone with acid chlorides and sulfonyl chlorides followed by the deprotection. Condensation of 7-amino-2-(2methoxyethoxymethyl)pyrazoloanthrone with appropriate acid chlorides R 6 COCI or sulfonyl chlorides RSO 2 CI is carried out in the presence of an acid quenching agent such as triethylamine, diisopropylethylamine, sodium bicarbonate, potassium carbonate, or sodium hydroxide at -20 to 50 0 C for 0.5 to 16 hours in solvents such as methylene chloride, chloroform, tetrahydrofuran, dioxane, dimethylformamide, or ethyl acetate.
The deprotection step may be performed by the treatment of the product mentioned above with an acid such as trifluoroacetic acid, aqueous hydrochloric acid, aqueous hydrobromic acid, or aqueous sulfuric acid.
WO 01/12609 PCT/US00/22727 18 The starting material is prepared in two steps. The 2-position of 7nitropyrazoloanthrone is protected by a protective group such as methoxymethyl (MOM), methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), or 4methoxybenzyl (PMB) with an aid of a base such as triethylamine, diisopropylethylaminc, pyridine, sodium hexamethyldisilazide, potassium hexamethyldisilazide, or lithium diisopropylamide. N-dimethylamino)pyridine (DMAP) can be used as a catalyst when a tertiary amine is used as a base. The reaction is typically carried out at -40 to 60 0 C for 1 to 16 hours in a solvent such as methylene chloride, chloroform, tetrahydrofuran, dioxane, or dimethoxyethane. As the nitrogen protective group, MEM group is preferred.
N-Protected 7-nitropyrazoloanthorone is then reduced to its 7-amino derivative by a variety of reducing agents such as Sn or Fe metal in acidic media such as acetic acid or aqueous hydrochloric acid. The reaction is typically run at 20 to 160 0
C
for 1 to 16 hours. The same transformation can be carried out by hydrogenation in the presence of a transition-metal catalyst such as palladium, platinum, rhodium, or iridium with or without a support such as charcoal in a solvent such as ethanol, ethyl acetate, tetrahydrofuran, dioxane, or dimethoxyethane at 1 to 20 atmospheres of hydrogen at to 60'C for 1 to 16 hours. The procedure using hydrogenation with palladium on charcoal as the catalyst is preferred.
WO 01/12609 PCT/US00/22727 19 Reaction Scheme 6
MEM
H NH
N-N
1) MEM-CI 2) H 2 /Pd O OBn 0 OH 1) R 7
-X
2) H
N-NH
O OR 7 In Reaction Scheme 6, pyrazoloanthrones with 5-alkoxy substituents may be prepared by condensation of 5-hydroxy-2-(2-methoxyethoxymethyl)pyrazoloanthrone with alkyl halides and sulfonates R,-X followed by the deprotection.
As the leaving group X. chloride, bromide, iodide, methanesulfonate. tosylate, benzencsulfonate, or triflate can be used. Condensation of 5-hydroxy-2-(2methoxyethoxymethyl)pyrazoloanthrone with appropriate alkyl halides and sulfonates is carried out in the presence of an acid quenching agent such as triethylamine, diisopropylethylamine, sodium bicarbonate, potassium carbonate, or sodium hydroxide at -20 to 50°C for 0.5 to 16 hours in solvents such as methylene chloride, chloroform, tetrahydrofuran, dioxane, dimethylformamide, or ethyl acetate. The deprotection step is performed by the treatment of the product mentioned above with an acid such as trifluoroacetic acid, aqueous hydrochloric acid, aqueous hydrobromic acid, or aqueous sulfuric acid.
The starting material is prepared in two steps. The 2-position of benzvloxypyrazoloanthrone is protected by a protective group such as methoxymethyl WO 01/12609 PCT/US00/22727 (MOM), methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), or 4methoxybenzyl (PMB) with an aid of a base such as triethylamine, diisopropylethylamine, pyridinc, sodium hexamethyldisilazide, potassium hexamethyldisilazide, or lithium diisopropylamide. N-dimethylamino)pyridine (DMAP) can be used as a catalyst when a tertiary amine is used as a base. The reaction is typically carried out at -40 to 60 0 C for 1 to 16 hours in a solvent such as methylene chloride, chloroform, tetrahydrofuran, dioxane, or dimethoxyethane. As the nitrogen protective group, MEM group is preferred.
N-Protected 5-benzyloxypyrazoloanthorone is then reduced to its hydroxy derivative by hydrogenation in the presence of a transition-metal catalyst, such as palladium platinum, rhodium, or iridium with or without a support such as charcoal in a solvent such as ethanol, ethyl acetate, tetrahydrofuran, dioxane, or dimethoxyethane at 1 to 20 atmospheres of hydrogen at 20 to 60 0 C for 1 to 16 hours. The procedure using hydrogenation with palladium on charcoal as the catalyst is preferred.
Reaction Scheme 7
MEM
-NH N 1) MEM-Cl 2) H 2 /Pd OBn O OH O 1) R 7
-X
2) H N NH OR7 0 WO 01/12609 PCT/USOO/22727 21 In Reaction Scheme 7, pyrazoloanthrones with 5-alkoxy substituents may be prepared by condensation of 7-hydroxy-2-(2-methoxyethoxymethyl)pyrazoloanthrone with alkyl halides and sulfonates R,-X followed by the deprotection.
As the leaving group X, chloride, bromide, iodide, methanesulfonate, tosylate, benzencsulfonate, or triflate can be used. Condensation of 7-hydroxy-2-(2methoxyethoxymethyl)pyrazoloanthrone with appropriate alkyl halides and sulfonates is carried out in the presence of an acid quenching agent such as triethylamine, diisopropylethylamine, sodium bicarbonate, potassium carbonate, or sodium hydroxide at -20 to 50°C for 0.5 to 16 hours in solvents such as methylene chloride, chloroform, tetrahydrofuran, dioxane, dimethylformamide, or ethyl acetate. The deprotection step is performed by the treatment of the product mentioned above with an acid such as trifluoroacetic acid, aqueous hydrochloric acid, aqueous hydrobromic acid, or aqueous sulfuric acid.
The starting material is prepared in two steps. The 2-position of 7benzyloxypyrazoloanthrone is protected by a protective group such as methoxymethyl (MOM), methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), or 4methoxybenzyl (PMB) with an aid of a base such as triethylamine, diisopropylethylamine, pyridine, sodium hexamethyldisilazide, potassium hexamethyldisilazide, or lithium diisopropylamide. N-dimethylamino)pyridine (DMAP) can be used as a catalyst when a tertiary amine is used as a base. The reaction is typically carried out at -40 to 60 0 C for 1 to 16 hours in a solvent such as methylene chloride, chloroform, tetrahydrofuran, dioxane, or dimethoxyethane. As the nitrogen protective group, MEM group is preferred.
N-Protected 7-benzyloxypyrazoloanthorone is then reduced to its 7hydroxy derivative by hydrogenation in the presence of a transition-metal catalyst, such as palladium platinum, rhodium, or iridium with or without a support such as charcoal in a solvent such as ethanol, ethyl acetate, tetrahydrofuran, dioxane, or dimethoxyethane at 1 to 20 atmospheres of hydrogen at 20 to 60 0 C for 1 to 16 hours. The procedure using hydrogenation with palladium on charcoal as the catalyst is preferred.
WO 01/12609 PCT/US00/22727 22 Compounds of structures (VI) and (VII) may be made by the same procedures as outlined above by utilizing starting materials having multiple reactive sites at the corresponding positions to the desired product.
In another embodiment of the invention, pharmaceutical compositions containing one or more compounds of this invention are disclosed. For purpose of administration, a compound of structure is preferably formulated as a pharmaceutical composition. Pharmaceutical compositions of the present invention comprise a compound of this invention and a pharmaceutically acceptable carrier, wherein the compound is present in the composition in an amount which is effective to treat the condition of interest. Preferably, the pharmaceutical compositions of the present invention include a compound of structure in an amount from 0.1 mg to 250 mg per dosage depending upon the route of administration, and more typically from 1 mg to mg. Appropriate concentrations and dosages can be readily determined by one skilled in the art.
Pharmaceutically acceptable carriers are familiar to those skilled in the art. For compositions formulated as liquid solutions, acceptable carriers include saline and sterile water, and may optionally include antioxidants, buffers, bactcriostats and other common additives. The compositions can also be formulated as pills, capsules, granules, or tablets which contain, in addition to a compound of this invention, diluents, dispersing and surface active agents, binders, and lubricants. One skilled in this art may further formulate the compounds of this invention in an appropriate manner, and in accordance with accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, PA 1990.
In another embodiment, the present invention provides a method for treating a variety of conditions by administering an effective amount of a JNK inhibitor to a patient in need thereof. Conditions that may be treated by the compounds of this invention, or a pharmaceutical composition containing the same, include any condition which is responsive to JNK inhibition, and thereby benefit from administration of a JNK inhibitor. Representative conditions in this regard include (but not limited to) rheumatoid arthritis, rheumatoid spondylitis. ostcoarthritis, gout, asthma, bronchitis, WO 01/12609 PCT/USOO/22727 23 cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, mucous colitis, ulcerative colitis, Crohn's disease, gastritis, esophagitis, hepatitis, multiple sclerosis, atherosclerosis, restenosis following angioplasty, left ventricular hypertrophy, myocardial infarction, stroke, ischemic damage to the heart, kidney, liver, or brain, transplant rejection (such as kidney, liver, heart, lung, and the like), endotoxin shock, psoriasis, eczema, dermatitis, epilepsy, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic laterial sclerosis, peripheral neuropathies, spinal cord damage, and cancer.
The methods of this invention include systemic administration of a compound of this invention, preferably in the form of a pharmaceutical composition.
As used hercin, systemic administration encompasses both oral and parenteral methods of administration. For oral administration, suitable pharmaceutical compositions include powders, granules, pills, tablets, and capsules as well as liquids, syrups, suspensions, and emulsions. These compositions may also include flavorants, preservatives, suspending, thickening and emulsifying agents, and other pharmaceutically acceptable additives. For parental administration, the compounds of the present invention can be prepared in aqueous injection solutions which may contain buffers, antioxidants, bacteriostats, and other additives commonly employed in such solutions.
The following examples are offered by way of illustration, not limitation.
EXAMPLES
EXAMPLE 1 Synthesis of Representative Compounds
H
X
NH
2
NH
2
N-
R
2 0 R 1
R
2 0 R 1 X CI, NO, WO 01/12609 PCT/US00/22727 24 A. Anthra 1.9cd]pyrazol-6(2H)-one ("Compound I")
H
N-
0 Anhydrous hydrazine is added to a solution of 2-chloroanthraquinone (Aldrich) in 10 mL pyridine, and the mixture heated at 100 0 C for 16 hours. The mixture is cooled and the solvent is evaporated in vacuo. The residue is taken in hot 6N HCI, and the solid is collected by filtration. Flash chromatography of the crude material on silica gel affords anthra[l,9cd]pyrazol-6(2H)-one ("Compound as yellow solids.
Due to limited solubility of Compound 1, purification of the same may be achieved by first derivatizing Compound 1 to a more soluble intermediate, such as the corresponding acetate, recrystallizing the intermediate, and then converting the intermediate to yield purified Compound 1 in good yield. More specifically, to solution of the pyrazoloanthrone (9.67 g, 43.9 mmol) in acetic acid (700 mL) is added acetic anhydride (12.4 mL, 132 mmol). The solution is heated to 80 0 C for 5 hours and then cooled to room temperature. After 16 hours, the reaction is cooled to 0oC for 2 hours.
The reaction is then filtered to give the N-acetylpyrazoloanthrone intermediate. This intermediate is recrystallized in acetic acid to give the pure intermediate (5.96 g, 52%).
'H NMR (CDCL 3 a 10.6 (br s, 1H), 8.46 1H), 8.33 1H), 8.26 1H), 8.08 (d, 1H), 7.96-7.87 2H), 7.78 1H), 2.83 3H); ES-MS 263 To a solution of the pure intermediate (5.96 g, 23 mmol) in methanol (600 mL) is added ammonium hydroxide (60 mL). The reaction is stirred at room temperature for 16 hours and then filtered and dried in a vacuum oven. A second crop of crystals is recovered to give a total of 4.8 g of Compound 1 at greater than 98% purity. ES-MS 221 [M WO 01/12609 PCT/USOO/22727 1B. 5-Chloroanthra[ I .9cdIPYrazol-6(2H)-one
H
N-
N N 0 C1 This compound may be made in the same manner from 1,4dichioroanthraquinone (commercial product).
C. 7-Chioroanthraf I .9cdlpyrazgl-6(2H)-one
H
N-
C1 0 This compound may be made in the same manner from dichioroanthraquinone (commercial product).
D. 5-Nitroanthraf 1 .9cdlpyrazol-6(2H)-one
N-
N 0 NO 2 This compound may be made from I ,4-dinitroanthraquinone (Krapcho, A. Avery, K. Jr. J Org Chem. 55.,5562-4, 1990).
WO 0 1 /12609 PCTIUSOO/22727 26 E. .7-Nitroanthral I .9cdjpyrazoI-6(2H)-one
H
N-
I
N0 2 0 This compound may be made in the same manner from dichioroanithraquinone (commercial product).
F. 5-Benzyloxyanthira[ I .9cdlpyrazo1-6(2H)-one
N-
0 OBn This compound may be made in the same manner from I -nitro-4benzyloxyanthraquinone. This starting material may be prepared as follows. Benzyl bromide is added to I -nitro-4-hydroxyanthraquinone (Aldrich) and potassium carbonate in dimethylformamide, and the mixture is stirred for 16 hours. Water is added and the mnixture is extracted with ethyl acetate The combined organic layer is washed sequentially with sodium bicarbonate solution, water, IN hydrochloric acid, and brine, dried, and evaporated. The residue is chromatographed on silica gel to afford l-nitro-4benzyloxyanthraquinone.
WO 0 1/ 12609 PCTIUSOOf22727 27 G. .7-Benzyloxyanthral 1.9cdlpyrazol-6(2-I)-one
H
N-N
OBn This compound may be made in the same manner from I henzylIo xyanthraqui none, which starting material may prepared as disclosed in German Patent No. DE 2254199 to Reubke. Hohmann and Bien.
H. 5-(Acetylamino)anthraf I .9cd Ipvrazol-6(2H)-one
H
N-N
0 NHAc This compound may be made in the same manner from 4-acetylamino-I ehioroanthraquinone. This starting material may be prepared as follows. 4-Amino- Ichloroanthraquinone is taken in pyridine and treated with acetic anhydride. The mixture is stirred for I hour, and poured onto water. The solids are collected by filtration, washed with water, and dried in vacuo to give 4-acetylamino- Ichloroanthraquinone as a colorless solid.
WO 01/12609 PCTtIJSOO/22727 28 EXAMPLE 2 Synthesis of Representative Compounds fH
H
N-N N-H I
R
4 0 10 R 3 -N R 4 A. 5-(Dimethviamino)anthraf 1 .9cdlpvrazol-6(214)-one
H
N- N 00N A mixture of 5-chloroanthra[ 1,9cd]pyrazol-6(21-)-one (Example 1-B) and dimethylamine in pyridine is heated at 100 "C for 16 hours. Thc mixture is cooled and evaporated. The residue is chromatographed on silica gel to give the desired compound as yellow solids.
B. 54( -Piperidinyl)anthra[ I .9cdlpvrazol-6(2H)-one N- N 0N 0 WO 01/12609 PCT/USOO/22727 29 This compound may be made in the same manner using piperidine as the amine.
C. 54(1 -Morpholinvlanthraf I ,9cdlpyrazoI-6(2I-I)-one
N-
0 N This compound may be made in the same manner using morpholine as the amnine.
D. 5-(Benzvlamino)anthra[ I .9cdl pyrazol-6(2HII -one
H
N-N'
This compound may be made in the same manner using benzylamine as the arme.
WO 01/12609 E. 5-f (4-PyridvlmethyI)Iamino I anthra[ I .9cdlpvrazol-6(2H)-one PCT/USOO/22727
H
N-
IN
0 H N This compound may be made in the same manner using 4pyridylmethylamine as the amine.
F. 5- 12-( I-Piperid inyl)ethy lami no I anthra I .9cd Ipvrazol -6(2 H)-onc This compound. may be made in the same manner using Ipiperidyl)ethylamine as the amine.
EXAMPLE 3 Synthesis of Representative Compounds
N-N
Ci 0
IV
3
N-H
H-
R31-Ik WO 01/12609 PCTIUS00122727 31 A. 7-(Dimethvlamino)anthraf I .9cdIpvYrazol-6(2H)-one
N-N
9 0 A mixture of 6-chloroanthraf 1 9cd]pyrazol-6(2H)-one (Example 1-C) and dimethylamine in pyridine is heated at 100'C for 16 hours. The mixture is cooled and evaporated. The residue is chromatographed on silica gel to give the desired compound as yellow solids.
B. 541 -Piperidinvl)anthral 1 .9cdlpyrazol-6(2H)-one
H
N- N N 0 00 This compound may be made in the same manner using piperidine as the amine.
W0 01/12609 .32 C. 54(1 -Morpholinyl)anthra[ I .9cdllpvrazol-6(2H)-one PCT/USOO/22727
CNO
0 This compound may be made in the same manner using morpholine as the amine.
D. 5-(Benzx'Iamino)anthraf I .9cdlpyrazol-6(2H)-one
H
N-
N 0 This compound may be made in the same manner using benzylamine as the amine.
E. 5-f (4-Pyridvlmethvl)lamninolanthrar I.9cdlpyrazol-6(21-I)-one
H
WO 01/12609 PTUO/22 PCVUSOO/22727 This compound may be made in the same manner using 4pyridylmethylarninc as the amine.
F. 5-f( 2-0 -Piperidinvl)ethylamino lanthra[ 1 .9cdhmrrazol-6(2H)-one N-N.
N
NH0 This compound may be made in the same manner using 2-(1piperidyl)ethylamine as the amine.
EXAMPLE 4 Synthesis of Representative Compounds
H
N-N
0 N0 2
MEM-CI
NaHMDS
MAEM
N-N
0 N0 2
MEM
H
2 Pd/C 0 NH 2 1) R 6 COCI or 2) H 4 Y n =1 Y n =2 WO 01/12609 PCT/US00/22727 34 A. 5-(Benzovlamino)anthra[ 1.9cdl pyrazol-6(2H)-one
H
N-
O HN OH 0 Benzoyl chloride is added to a solution of aminoanthra[l,9cd]pyrazol-6-(2H)one and triethylamine in methylene chloride at 0°C.
The mixture is stirred for 16 hours, quenched with water, and extracted with ethyl acetate The combined organic layer is washed with sodium bicarbonate solution, and brine, dried and evaporated. The crude reaction mixture is then taken in aqueous 6N hydrochloric acid, and heated at 80 0 C for 4 hours. After cooling, the mixture is extracted with ethyl acetate washed with brine, dried, and evaporated. The reside is chromatographed on silica gel to furnish the desired amide as a yellow solid.
The starting material is prepared as follows. Sodium hexamethyldisilazide is added to a cooled solution of 5-nitroanthra[1,9cd]pyrazol- 6(2H)-one (Example I-D) in tetrahydrofuran, and the mixture is stirred for 30 minutes at 0°C. MEM-chloride is added, and the mixture is stirred for 16 hours at room temperature. Water is added and the mixture is extracted with ethyl acetate The combined organic layer is washed with aqueous sodium bicarbonate solution, water, IN hydrochloric acid, and brine, dried and evaporated. The residue is chromatographed on silica gel to give 2-MEM-5-nitroanthra[1,9cd]pyrazol-6(2H)-one as an oil.
on charcoal and 2-MEM-5-nitroanthra[1,9cd]pyrazol- 6(2H)-one in ethanol is placed under I-atm of hydrogen, and the mixture was stirred for 6 hours. The catalyst is filtered off over celite, and the filtrate is evaporated to dryness to give 2-(methoxyethoxymethyl)-5-aminoanthra[ 1.9cd]pyrazol-6-(2H)one, which is used without further purification.
WO 0 1/12609 B. 5-(Isonicotinylamino)anthraf 1 .9cdlpyrazol-6(2H)-one PCT/1JSOO/22727 This compound may be made in the same manner using isonicotinoyl chloride as the acid chloride C. 5-(Nicotinvlamino)anthra[ I .9cdipyrazol-6(2F1)-one This compound may be made in the same manner using nicotinoyl chloride as the acid chloride.
D. 5-(2-Thiophenecarbonvlamino)anthra[ I .9cdkpyrazol-6(2H)-one WO 01/12609 PCTIUSOO/22727 36 This compound may be made in the same manner using 2thiophenecarboxylic acid as the acid chloride.
E. 5-(3-Methylbutyrylamino)aiithrar 1 .9cdlp~vra7zol-6(2H)-one
H
N-
This compound may be made in the same manner using isopentanoyl chloride as the acid chloride.
F. 5-(3 -Methanesulfonvlamino)anthrarlI.9cdllpyrazo1-6(2H)-one
.'H
o HN.
00 This compound may be made in the same manmer using methanesulfonyl chloride as the sulfonvi chloride.
WO 0 1112609 PCT/USOO/22727 37 G. 5-(3-Benzenesulfonvlamino)anthraf I .9cdIpyrazol-6(2H)-one
.H
N- N 0 HN.~ This compound may be made in the same manner using benzenesulfonyl chloride as the sulfonyl chloride.
EXAMPLE Synthesis of Representative Compounds
H
N-N
02
MEM-CI
NaHMDS
MEM
N-N'
02 0
MEM
H
2 Pd/C
NN
N H 2 1) R 6 COCI or R 6 S0 2
CI
2) H' Y n =1 Y n =2 WO 01/12609 PCT/USOO/22727 38 A. 7-(Benzovlamino)anthraf 1.9cdpyrazol-6(2H)-one
H
N-N
NH 0 0 Benzoyl chloride is added to a solution of 2-(methoxyethoxymethyl)-7aminoanthra[l,9cd]pyrazol-6-(2H)one and triethylamine in methylene chloride at 0°C.
The mixture is stirred for 16 hours, quenched with water, and extracted with ethyl acetate The combined organic layer is washed with sodium bicarbonate solution, and brine, dried and evaporated. The crude reaction mixture is then taken in aqueous 6N hydrochloric acid, and heated at 80 0 C for 4 hours. After cooling, the mixture is extracted with ethyl acetate washed with brine, dried, and evaporated. The reside is chromatographed on silica gel to furnish the desired amide as a yellow solid.
The starting material is prepared as follows. Sodium hexamethyldisilazide is added to a cooled solution of 7-nitroanthra[ 1,9cd]pyrazol- 6(2H)-one (Example I-E) in tetrahydrofuran, and the mixture is stirred for 30 minutes at 0°C. MEM-chloride is added, and the mixture is stirred for 16 hours at room temperature. Water is added and the mixture is extracted with ethyl acetate The combined organic layer is washed with aqueous sodium bicarbonate solution, water, IN hydrochloric acid, and brine, dried and evaporated. The residue is chromatographed on silica gel to give 2-MEM-7-nitroanthra[1,9cd]pyrazol-6(2H)-one as an oil.
on charcoal and 2-MEM-5-nitroanthra[1,9cd]pyrazol- 6(2H)-one in ethanol is placed under 1-atm of hydrogen, and the mixture was stirred for 6 hours. The catalyst is filtered off over celite, and the filtrate is evaporated to dryness to give 2-(methoxyethoxymethyl)-7-aminoanthra[1,9cd]pyrazol-6-(2H)one, which is used without further purification.
WO 01/12609 PCT[USOO/22727 39 B. 7-(lsonicotinvlamino)anthra[ I .9cdlpyrazol-6(2H)-one
H
N-
,NHO0 0 This compound may be made in the same manner using isonicotinoyl chloride as the acid chloride.
C. 7-(Nicotinviamino)anthrarlI.9cdlpvrazol-6(2H)-one
H
N-
N yNH 0 0 This compound may be made in the same manner using nicotinoyl chloride as the acid chloride.
D. 5-(2-Thiophenecarbonylami no)anthra[ I .9cdlpvrazol-6(2H)-one WO 0 1 /12609 PCTIUSOO/22727 This compound may be made in the same manner using 2thiophenecarboxylic acid chloride as the acid chloride.
E. 7-(3-Methylbutvrvlami no)anthraf I .9cdlpvrazol-6(2H)-one
H
N-
100 F. 7-(3-Methanesulfonvlamino)anthra[ I .9cdlpvrazol-6(2H)-one
H
N-
I
-~NH 0 This compound may be made in the same manner using methanesulfonyl chloride as the sulfonvi chloride.
W0 01/1 2609 41 G. 7-(3-Benzenesuifonylamino)anthraI 1 .9cdlpyrazol-6(2F1)-one PCT[US00122727
H
N-N
NH 0 00N This compound may be made in the same manner using benzenesulfbonyl chloride as the sulfonyl chloride.
EXAMPLE 6 Synthesis of Representative Comrounds
N-NH
0 OBn
,MEM
1) MEM-CI
N
2) H 2 /Pd 0 0 OH 1) R 7
-X
2) H"
H
1I\ N -N 0 OR 7 A. 5(3 -Methylbutyloxy')anthra[lI 9cdlpvrazol-6(2H)-one
N-N
0 1\Y Isopentyl bromide is added to a mixture 1 ,9cd]pyrazol-6(2H)-one and carbonate in dimethyiformamide at room temperature. After stirring the of 3-(2potassium mixture for WO 01/12609 PCT/USOO/22727 42 sixteen hours, water is added, and the mixture was extracted with ethyl acetate (x2).
The combined organic layer is washed with aqucous sodium bicarbonate, water, IN hydrochloric acid, and brine, dried and evaporated. The reside is taken in 6N hydrochloric acid and heated at 80°C for 4 hours. After cooling, the mixture is extracted with ethyl acetate and the combined organic layer is washed with brine, dried, and evaporated. The residue is purified by column chromatography to afford the title compound as yellow solid.
The starting material is prepared as follows. Sodium hexamethyldisilazide is added to a cooled solution of benzyloxyanthra[ .9cd]pyrazol-6(2H)-one (Example 1-F) in tetrahydrofuran, and the mixture is stirred for 30 minutes at o0C. MEM-chloride is added, and the mixture is stirred for 16 hours at room temperature. Water is added and the mixture is extracted with ethyl acetate The combined organic layer is washed with aqueous sodium bicarbonate solution, water, IN hydrochloric acid, and brine, dried and evaporated. The residue is chromatographed on silica gel to give benzyloxyanthra[1,9cd]pyrazol-6(2H)-one as an oil.
Palladium( 10%) on charcoal and benzyloxyanthra[l,9cd]pyrazol-6(2H)-one in ethanol is placed under I-atm of hydrogen, and the mixture stirred for 6 hours. The catalyst is filtered off over celite, and the filtrate is evaporated to dryness to give 2-(2-methoxyethoxymethyl)-5hydroxyanthra[1,9cd]pyrazol-6-(2H)one, which is used without further purification.
B. 5-(4-Pvridvlmethoxy)anthra[1,9cdlpvrazol-6(2H)-one
H
N-N
N
WO 01/12609 PCT/USOO/22727 43 This compound may be made in the same manner using chloromethyl-4pyridine as the alkyl halide.
C. 5 -(3-Pyridvlmethoxy)anthra[ I.9cdhlvrazol-6(21H)-one
H
N-N
o 0 N This compound may be made in the same maniner using chloromethyl-3pyridine as the alkyl halide.
D. 5 -(2-Methoxvethoxy)anthrarlI.9cdlpyvrazol-6(2H)-one
H
N-N
This compound may bc made in the same manner using 2-methoxyethyl bromide as the alkyl halide.
E. 5-(2-Dimethvlaminoethoxv)anthrar I .9cdlpyrazol-6(2H)-one
H
WO 01/12609 PCT/US00/22727 44 This compound may be made in the same manner using 2dimethylaminoethyl chloride as the alkyl halide.
EXAMPLE 7 Synthesis of Representative Compounds
MEM
1) MEM-CI
N-N
2) H2/Pd OH O 1) R 7
-X
2) H'
,H
N-NO
OR
7 0 A. 7-(3-Methylbutylox)anthrar 1.9cdlpvrazol-6(2H)-one Isopentyl bromide is added to a mixture of 3-(2-methoxyethoxymethyl)- 7-hydroxyanthra[1,9cd]pyrazol-6(2H)-one and potassium carbonate in dimethylformamide at room temperature. After stirring the mixture for sixteen hours, water is added, and the mixture was extracted with ethyl acetate The combined organic layer is washed with aqueous sodium bicarbonate, water, IN hydrochloric acid, and brine, dried and evaporated. The reside is taken in 6N hydrochloric acid and heated at 80 0 C for 4 hours. After cooling, the mixture is extracted with ethyl acetate and the combined organic layer is washed with brine, dried, and evaporated. The residue is purified by column chromatography to afford the title compound as yellow solid.
WO 01/12609 PCT/US00/22727 The starting material is prepared as follows. Sodium hexamethyldisilazide is added to a cooled solution of 7benzyloxyanthra[1,9cd]pyrazol-6(2H)-one (Example I-F) in tetrahydrofuran, and the mixture is stirred for 30 minutes at 0°C. MEM-chloride is added, and the mixture is stirred for 16 hours at room temperature. Water is added and the mixture is extracted with ethyl acetate The combined organic layer is washed with aqueous sodium bicarbonate solution, water, IN hydrochloric acid, and brine, dried and evaporated. The residue is chromatographed on silica gel to give 2-MEM-7benzyloxyanthra[1,9cd]pyrazol-6(2H)-one as an oil.
Palladium(10%) on charcoal and 2-MEM-7benzyloxyanthra[l,9cd]pyrazol-6(2H)-one in ethanol is placed under 1-atm of hydrogen, and the mixture was stirred for 6 h. The catalyst is filtered off over celite, and the filtrate is evaporated to dryness to give 2-(2-methoxyethoxymethyl)-7hydroxyanthra[ 1,9cd]pyrazol-6-(2H)one, which is used without further purification.
B. 7-(4-Pvridylmethoxv)anthra[ 1,9cd]pyrazol-6(2H)-one
H
N-
O 0 This compound may be made in the same manner using chloromethyl-4pyridine as the alkyl halide.
WO 01/12609 PCTfUSOO/22727 46 C. .7-(3-Pyridylmethoxy)anthra[ 1,9cd]Rvrazol-6(21-I)-one
H
N-
N 1:1 This compound may be made in the same manner using chloromethyl-3pyridine as the alkyl halide.
D. 7-(2-Methoxvethoxy)anthra[ I .9cdl pyrazol-6(2H)-one
H
N-N
100 This compound may be made in the same manner using 2-methoxyethyl bromide as the alkyl halide.
E. 7-(2-Dimethylaminoethoxy)anthraf I .9cdlpyrazol-6(2H)-one
H
N, N N.
0 0 This compound may be made in the same manner using 2dimcthylaminoethyl chloride as the alkyl halide.
WO 01/12609 PCT/US00/22727 47 EXAMPLE 8 Activity of Representative Compound The compounds of this invention may be assayed for their activity accordingly to the following procedures.
JNK Assay To 10 pL of the test compound in 20% DMSO/80% dilution buffer consisting of 20 mM HEPES (pH 0.1 mM EDTA, 2.5 mM magnesium chloride, 0.004% Triton xl00, 2 pg/mL leupeptin, 20 mM p-glycerolphosphate, 0.1 mM sodium vanadate, and 2 mM DTT in water is added 30 pL of 50-200 ng His6-JNK1, JNK2 or JNK3 in the same dilution buffer. The mixture is preincubated for 30 minutes at room temperature. Sixty microliter of 10 pg GST-c-Jun(l-79) in assay buffer consisting of mM HEPES (pH 50 mM sodium chloride, 0.1 mM EDTA, 24 mM magnesium chloride, 1 mM DTT, 25 mM PNPP, 0.05% Triton xlOO, 11 gM ATP, and 0.5 uCi y- 32P ATP in water is added and the reaction is allowed to proceed for 1 hour at room temperature. The c-Jun phosphorylation is terminated by addition of 150 PL of 12.5% trichloroacetic acid. After 30 minutes, the precipitate is harvested onto a filter plate, diluted with 50 piL of the scintillation fluid and quantified by a counter. The ICs, values are calculated as the concentration of the test compound at which the c-Jun phosphorylation is reduced to 50% of the control value. Preferred compounds of the present invention have an ICs value ranging 0.01 10 pM in this assay. To this end, a preferred compound of this invention is Compound 1, which has an ICo according to this assay of 0.11 gM for JNKI and JNK2, and 0.15 pM for JNK3.
Selectivity For JNK WO 01/12609 PCTIUS00/22727 48 Compound 1 was also assayed for its inhibitory activity against the following protein kinases by techniques known to those skilled in this field (see, e.g., Protein Phosphorylation, Sefton Hunter, Eds., Academic Press, pp. 97-367, 1998): Enzyme p 3 8 2 >30,000 nM ERK1 >30,000 nM MEKKI >30,000 nM IKKI >30,000 nM IKK2 >30,000 nM PKA >30,000 nM PKC >10,000 nM EGF-TK >10,000 nM Jurkat T-cell 11-2 Production Assay .lurkat T cells (clone E6-1) are purchased from the American Tissue Culture Collection and maintained in growth media consisting of RPMI 1640 medium containing 2 mM L-glutamine (Mediatech), with 10% fetal bovine serum (Hyclone) and penicillin/streptomycin. All cells are cultured at 37 0 C in 95% air and 5% CO,. Cells are plated at a density of 0.2 x 106 cells per well in 200 1 pL of media. Compound stock mM) is diluted in growth media and added to each well as a 10x concentrated solution in a volume of 25 pL, mixed, and allowed to pre-incubate with cells for minutes. The compound vehicle (dimethylsulfoxide) is maintained at a final concentration of 0.5% in all samples. After 30 minutes the cells are activated with PMA (phorbol myristate acetate; final concentration 50 ng/mL) and PHA (phytohemagglutinin; final concentration 2 pg/mL). PMA and PHA are added as a concentrated solution made up in growth media and added in a volume of 25 pL per well. Cell plates are cultured for 10 hours. Cells are pelleted by centrifugation and the media removed and stored at -20 Media aliquots are analyzed by sandwich ELISA for the presence of IL-2 as per the manufacturers instructions (Endogen). The IC,, WO 01/12609 PCT/US00/22727 49 values are calculated as the concentration of the test compound at which the 11-2 production was reduced to 50% of the control value. Preferred compounds of the present invention have an IC 5 0 value ranging 0.1 30 pM in this assay. Figure 1 presents the dose dependent inhibition of IL-2 in Jarkat T-Cells by Compound 1 according to this procedure, with a resulting ICso of 5 pM Mouse in vivo LPS-Induced TNF-ac Production Assay Non-fasted mice are acclimatized for at least 7 days. Groups of 4 to 6 female BALB/c or CD-I mice (8-10 weeks of age from Charles River laboratories) are pretreated with test compound, either by intravenous injection or by oral gavage 15 180 minutes prior to the injection of 0.5 mg/kg Bacto LPS from E. coli 055:B5 (Difco Labs). Ninety minutes after LPS challenge, a terminal bleed is performed via abdominal vena cava and blood is allowed to clot at room temperature for 30 minutes in Microtainer serum separator tubes. After separation by centrifugation, the serum is stored frozen at -80 0 C. EIIZA is performed on thawed, diluted samples (1:10 to 1:20) using a Mouse TNF-alpha kit (Biosource International). The EDs 3 values are calculated as the dose of the test compound at which the TNF-cx production is reduced to 50% of the control value. Preferred compounds of the present invention have an EDo value ranging 1 30 mg/kg in this assay. Figure 2 illustrates the results of this experiment utilizing Compound 1 administered by intravenous injection at 15 and 30 mg/kg, as well as by per os at 7.5, 15 and 30 mg/kg. Vehicle alone (PEG-400, propylene glycol, cremophor EL, and ethanol in normal saline, "PPCES") and dexamethasone-21 acetate (1 mg/kg were run as controls (n 6, p 0.01). Compound 1 was administered 15 minutes pre-LPS challenge, and bleed occurred 90 minutes post
LPS.
Inhibition of Leukocyte Recruitment in Rat Inflamed Lung Aerosol administration of ovalbumun in Brown Norway Rats previously sensitized by injection of ovalbumin (OA) results in an allergic airway inflammation marked by the generation of an eosinophil- and T-lymphocyte-rich leukocytic WO 01/12609 PCT/US00/22727 infiltration in the lungs (see Richards et al., Am. J. Physiol, 271:2 Pt 1, L267-76, 1996).
Compound I was administered by subcutaneous injection at a dose of 30 mg/kg, b.i.d.
for 3 days prior to ovalbumin challenge by aerosol. Cells counts were obtained from samples of broncho-alveolar lavage, the results of which are illustrated in Figure 3 (V PPCES vehicle).
Rat In Vivo Adjuvant Arthritis Male Lewis rats were immunized with complete Freund's adjuvant on day 0 to induce an aggressive arthritis characterized by joint destruction and paw swelling. Compound 1 was administered subcutaneously once daily from day 8 to day Paw swelling was determined be water displacement plethysmometry (see Figure 4A; p<0.01). Radiographs were obtained of the right hind paw to assess bone changes using a semi-quantitative scoring system: demineralization calcaneal erosion and heterotropic bone formation with a maximum possible score 6 (see Figure 4B). Activation of AP-1 (see Figure 4C) was determined by DNA binding activity in an electrophoretic mobility shift assay (EMSA) (Ausubel et al., Short Protocols in Molecular Biology, Second Edition, John Wiley Sons Publisher, New York, 1992). Matrix metalloproteinase-13 expression (see Figure 4D) was measured by nothem blot analysis of MMP-13 mRNA (Ausebel et al., supra) (see also Winter et al., Arthritis and Rheumatism 9(3):394-404, 1966; Weichman et al., Pharmacological Methods in the Control of Inflammation, Chang and Lewis Eds., Alan R. Liss, Inc., Publ., New York, 1989).
Kainic Acid-Induced Seizure Response Compound 1 was administered to male CD rats at 10 mg/kg intravenously through a tail vein catheter. This was followed immediately by a mg/kg subcutaneous injection. Vehicle controls received the same injection volumes of the PPCES vehicle alone. Thirty minutes later, animals were given a 1- mg/kg i.p.
injection of kainic acid in normal saline solution. This dose of kainic acid has been previously reported to induce a seizure syndrome in rats (Maj et al., Eur. J. Pharm.
WO 01/12609 PCTIUS00/22727 51 359:27-32, 1992). Seizure behavior was monitored for 4 hours following kainic acid injection. As presented in Figure 5, behaviors were assessed based on the following cumulative scoring system: 1 pt. arrest of motion; 2 pts. myoclonic jerks of the head and neck (moderate); 3 pts. unilateral or bilateral forelimb clonic activity; 4 pts.
whole body clonus; 5 pts. clonic-tonic seizures; 6 pts. status epilepticus (see also Mathis and Ungerer, Exp. Brain Res. 88:277-282, 1992; Rong et al., Proc. Natl. Acad Sci. USA 96:9897-9902, 1999; Yang et al., Nature 389:865-870, 1997) It will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without departing from the spirit and scope of the invention.
Accordingly, the invention is not limited except as by the appended claims.

Claims (23)

1. A compound having the structure: or a pharmaceutically acceptable salt thereof, wherein RI and R 2 are optional substituents that are the same or different and independently represent nitro, trifluoromethyl, sulfonyl, aryl, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono- or di- alkylaminoalkoxy, or a group represented by formula or R3 -N R4 (a) ,R3 -NH-(alkyl)-N R4 (b) OR5 -N H O 'RS -N H R 3 and R 4 taken together represent alkylidene or a heteroatom-containing alkylidene, or R 3 and R 4 are the same or different and independently represent cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyamino, or alkoxy(mono- or di- alkylamino); and R 5 represents hydrogen, alkyl, cycloalkyl, carbocyclic aromatic, heterocyclic aromatic, arylalkyl, cycloalkylalkyl, alkoxy, amino, mono- or di-alkylamino, arylamino, arylalkylamino, cycloalkylamino or cycloalkylalkylamino, with the proviso that carbocyclic aromatic is not phenyl; NY2- 1387663.1 53 and with the proviso that at least R, or R 2 is present.
2. A compound having one of the following structures: N N H N N H RN
4. -TR2 or a pharmaceutically acceptable salt thereof, wherein R, represents nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, aryl, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono- or di-alkylaminoalkoxy, or a group represented by formula or -N (a) -NH-(alkyl)--N ,R 0 H 0 -N H (d) when R, is present, R 3 and R 4 taken together represent alkylidene or a heteroatom- containing alkylidene, or R 3 and R 4 are the same or different and independently-represent hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyamino, or alkoxy(mono- or di-alkylamino); when R, is present, R 5 represents hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, amino, mono- or di-alkylamino, arylamino, arylalkylamino, cycloalkylamino or cycloalkylalkylamino; NY2 1387663.1 54 R2 represents nitro, trifluoromethyl, sulfonyl, alkoxycarbonyl, aryl, arylakloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono- or di-alkylaniinoalkoxy, or a group represented by formula or 0 0 1 R 3 Q 5C gF -N -N-N R4H H (C) when R 2 is present, R 3 and R 4 taken together represent alkylidene or a heteroatom- containing alkylidene, or R(3 and R(4 are the same or different and independently represent ailkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyamino, or alkoxy(mono. or di-alkylamino) with the proviso that both R 2 and R 3 cannot be alkyl; and *:when R 2 is present, R 5 represents hydrogen, alkyl, cycloalkyl, carbocyclic aromatic, heterocyclic aromatic, arylalkyl, cycloalkylalkyl, alkoxy, amino, mono- or di- alkylamino, arylamino, arylalkylamino, cycloalkylamino or cycloalkylalkylamino with the :proviso that carbocyclic aromatic is not phenyl. 3. A compound having one of the following structures: N-NH N--NH RI I TR2 0 0 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 represent alkyl, halogen, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-or di-alkylaminoalkoxy, or a group represented by formula or -N R4 R3 -N H 0 -N H R 3 and R 4 taken together represent alkylidene or a heteroatom-containing alkylidene, or R 3 and R 4 taken together represent alkylidene or a heteroatom-containing alkylidene, or R 3 and DR4 are the same or different and independently represent alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyamino, or alkoxy (mono-or di-alkylamino); And R 5 represents hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, amino, mono-or di-alkylamino, arylamino, arylalkylamino, cycloalkylamino or cycloalkylalkylamino. 4. A compound according to claim 2 wherein R 1 and R 2 are: R3 -N R4 A compound according to claim 2 wherein RI and R 2 are: ,R3 -NH-(alkyl)--N R4 W:\BAM62883\2883 56
6. A compound according to claim 2 wherein RI and R 2 are: 0 N H
7. A compound according to claim 2 wherein RI and R 2 are: O 04 /I N H
8. A composition comprising the compound or pharmaceutically acceptable salt of the compound of claim I and a pharmaceutically acceptable carrier.
9. A method for inhibiting JNK in vivo, comprising administering to a patient in need thereof an effective amount of a compound having the structure: *2 R 2 0 or a pharmaceutically acceptable salt thereof, wherein R and R 2 are optional substituents that are the same or different and B independently represent alkyl, halogen, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, NY2 1387663.1 K 57 cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono- or di- alkylaminoalkoxy, or a group represented by formula or R R3 R3R 'R -N -NH-(alkyl)--N -N -N R 4 H (d) R 3 and R 4 taken together represent alkylidene or a heteroatom-containing alkylidene, or R 3 and R4 are the same or different and independently represent hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyamino, or alkoxy(mono- or di-alkylamino); and 15 R 5 represents hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, amino, mono- or di-alkylamino, arylamino, arylalkylamino, cycloalkylamino, or cycloalkylalkylamino. A method according to claim 9 wherein the inhibition of JNK in vivo treats 20 cancer. S'"i 11. A method according to claim 9 wherein the inhibition of JNK in vivo treats o *rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gout, asthma, bronchitis, cystic fibrosis, inflammatory bowel disease, irritable bowel syndrome, mucous colitis, 25 ulcerative colitis, Crohn's disease, gastritis, esophagitis, hepatitis, multiple sclerosis, endotoxin shock, psoriasis, excema, or dermatitis.
12. A method according to claim 9 wherein the inhibition of JNK in vivo treats atherosclerosis, restenosis following angioplasty, left ventricular hypertrophy, or myocardial infarction.
13. A method according to claim 9 wherein the inhibition of JNK in vivo treats stroke or ischemic damage to the heart, kidney, liver, or brain. W:\BAl62883\682883 P57.doc 58
14. A method according to claim 9 wherein the inhibition of JNK in vivo prevents transplant rejection.
15. A method according to claim 9 wherein the inhibition of JNK in vivo treats a central or peripheral neurological degenerative disorder.
16. A method according to claim 15 wherein the central or peripheral neurological degenerative disorder is epilepsy, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic laterial sclerosis, a peripheral neuropathy, or spinal cord damage.
17. The method of claim 9 wherein R 1 and R 2 are not present, and the compound having the following structure: 2000 N N H N---NH I I O O or a pharmaceutically acceptable salt thereof.
18. A method according to claim 9 wherein Ri or R 2 is present, and the compound o.having one of the following structures: N--NH N--NH 0 0 or a pharmaceutically acceptable salt thereof. W:\BA\a28836s2883 P58.doc
19. A method according to claim 9 wherein both Ri and R 2 are present, and the compound having one of the following structures: N-N H N--NH N-N R I I +R2 R, 0 0 0 O O O or a pharmaceutically acceptable salt thereof. A method according to claim 18 wherein Ri and R 2 are: /R3 -N R4
21. A method according to claim 18 wherein RI and R 2 are: ,R 3 NH-(alkyl)--N R4
22. A method according to claim 18 wherein R 1 and R 2 are: *O 0 -N H
23. The method of claim 18 wherein Ri and R 2 are: 1 S NY2- 1387663.1 O -N H
24. A pharmaceutical composition comprising a compound having the structure: 9* or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A compound having the structure: N---NH R 1 R2 0 or a pharmaceutically acceptable salt thereof, wherein RI and R 2 are optional substituents that are the same or different and independently represent, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, aryl, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono- or di-alkylaminoalkoxy, or a group represented buy formula or W:\BA\62M83\Sa2883P0.doc R3 -N R4 (a) ,,R3 NH-(alkyl)-N R4 0 OR5 N H 0, S 'RS -N H R 3 and R 4 are the same or different and independently represent hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyamino, or alkoxy(mono- or di-alkylamino); and R 5 represents hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, amino, mono- or di-alkylamino, arylamino, arylalkylamino, cycloalkylamino or cycloalkylalkylamino; and with the proviso that at least one of RI or R 2 is present.
26. A compound having the structure: S* S S SS*S or a pharmaceutically acceptable salt thereof, wherein RI and R 2 are optional substituents that are the same or different and independently represent: S. 4o o4 @S .5* S S* 3 3 o o *o ft f f NY2- 1387663.1 62 -NH-(alkyl)-h wherein R 3 and R 4 are the same or different and independently represent cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyamino, or alkoxy(mono- or di- alkylamino); and with the proviso that at least R, or R 2 is present.
27. A compound having one of the following structures: SN N H N-NH or O H Y(O)n-R6 OR3NR4 or a pharmaceutically acceptable salt thereof, S 15 wherein Yis C orS; n is 1 when Y is C; n is 2 when Y is S; SR3 and R 4 are the same or different and independently represent alkyl, 20 cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyamino, or alkoxy (mono- or di-alkylamino); and R 6 represents phenyl, pyridinyl, thienyl or alkyl.
28. A method for treating a condition, comprising administering to a patient in need thereof 25 an effective amount of a compound having the structure: or a pharmaceutically acceptable salt thereof, wherein Y is C or S; n is 1 when Y is C; n is 2 when Y is S; R 3 and R 4 are the same or different and independently represent alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyamino, or alkoxy(mono- or di-alkylamino); and R 6 represents phenyl, pyridinyl, thienyl or alkyl. 28. A method for treating a condition, comprising administering to a patient in need thereof an effective amount W:BA\682883M2883 _P2.doc or a pharmaceutically acceptable salt thereof, wherein RI and R 2 are optional substituents that are the same or different and independently represent alkyl, halogen, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono- or di-alkylaminoalkoxy, or a group represented by formula or ,R 3 O' 3 S R -N -NH-(alkyl)-N -N -N R4 R4 H H (d) R 3 and R 4 are the same or different and independently represent hydrogen, alkyl, S cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyamino, or alkoxy(mono- or di-alkylamino); and R 5 represents hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, amino, mono- or di-alkylamino, arylamino, arylalkylamino, cycloalkylamino, or cycloalkylalkylamino, the condition being cancer; rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; gout; asthma; bronchitis; cystic fibrosis; inflammatory bowel disease; irritable bowel syndrome; mucous colitis; ulcerative colitis; Crohn's disease; gastritis; esophagitis; hepatitis; multiple sclerosis; endotoxin shock; psoriasis; eczema; dermatitis; atherosclerosis; restenosis following S angioplasty; left ventricular hypertrophy; myocardial infarction; stroke or ischemic damage to
1387663.1 NY2-1387663.1 64 -the heart, kidney, liver, or brain; transplant rejection; or a central or peripheral neurological degenerative disorder. 29. A method according to claim 28, wherein the central or peripheral neurological degenerative disorder is epilepsy, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic laterial sclerosis, a peripheral neuropathy or spinal cord damage. A method for inhibiting JNK in a cell capable of expressing JNK, comprising contacting said cell with an effective amount of a compound having the structure: or a pharmaceutically acceptable salt thereof, wherein RI and R 2 are optional substituents that are the same or different and independently represent alkyl, halogen, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono- or di-alkylaminoalkoxy, or a group represented by formula or R3 -N R4 ,R3 NH-(alkyl)--N R4 (b) OR5 N H O O' R -N H NY2 1387663.1 R 3 and R4 are the same or different and independently represent hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyamino, or alkoxy(mono- or di-alkylamino); and Rs represents hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, amino, mono- or di-alkylamino, arylamino, arylalkylamino, cycloalkylamino, or cycloalkylalkylamino. 31. A method for inhibiting JNK, comprising contacting JNK with an effective amount of a compound having the structure: NMH -H R, 0 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are optional substituents that are the same or different and S independently represent alkyl, halogen, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono- or di-alkylaminoalkoxy, or a group represented by formula or ,R 3 RO -N -NH-(alkyl)--N -N -N *R4 R H H (d) NY2 1387663.1 66 R 3 and R 4 are the same of different and independently represent hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, alkoxyamino, or alkoxy (mono- or di-alkylamino); and R 5 represents hydrdogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, amino, mono- or di-alkylamino, arylamino, arylalkylamino, cycloalkylamino, or cycloalkylalkylamino. 32. A method according to claim 9, 30 or 31, wherein the JNK is INK1, JNK2 or JNK3. 0 33. A method according to claim 28, 30 or 31, wherein the compound has the structure: a a. a a a a a a or a pharmaceutically acceptable salt thereof. 34. A composition according to claim 8, wherein the composition is a pharmaceutical composition. 35. A composition according to claim 8, wherein the compound or pharmaceutically acceptable salt of the compound is present in an amount that is effective for inhibiting JNK. 36. A composition according to claim 8, wherein the compound or pharmaceutically acceptable salt of the compound is present in an amount that is effective for treating cancer; rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; gout; asthma; W:\BAWe\28a3\s2883 PO.doc 67 bronchitis; cystic fibrosis; inflammatory bowel disease; irritable bowel syndrome; mucous colitis; ulcerative colitis; Crohn's disease; gastritis; esophagitis; hepatitis; multiple sclerosis; endotoxin shock; psoriasis; eczema; dermatitis; atherosclerosis; restenosis following angioplasty; left ventricular hypertrophy; myocardial infarction; stroke or ischemic damage to the heart, kidney, liver, or brain; transplant rejection; or a central or peripheral neurological degenerative disorder. 37. A composition according to claim 36, wherein the central or peripheral neurological degenerative disorder is epilepsy, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic laterial sclerosis, a peripheral neuropathy or spinal cord damage. 38. A composition according to claim 34, wherein the composition is in the form of a pill, tablet or capsule. 39. A composition comprising JNK and a compound having the structure: N--NH O 0 or a pharmaceutically acceptable salt thereof, wherein the compound is present in an amount effective for inhibiting JNK. *NY2 -1387663.1 NY2 1387663.1 68 A compound, according to anyone of claims 1 to 3, 24 to 27 or 39, substantially as hereinbefore described with reference to anyone of the Examples. 41. A method according to anyone of claims 9, 28, 30 or 3 1, substantially as hereinbefore described with reference to anyone of the Examples. DATED: 24 March 2003 PHILLIPS ORMONDE FITZPATRICK Attorneys for: SIGNAL PHARMACEUTICALS, INC.
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