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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
  • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/42—Oxazoles
  • A61K31/423—Oxazoles condensed with carbocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/428—Thiazoles condensed with carbocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
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• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
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  • A61P31/04—Antibacterial agents
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• • A—HUMAN NECESSITIES
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  • A61P31/18—Antivirals for RNA viruses for HIV
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  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the present invention relates to methods useful for treating or preventing disease-related wasting in a patient, comprising administering an effective amount of a JNK Inhibitor to a patient in need thereof.
• JNK Jun N-terminal inase pathway
• Targets of the JNK pathway include the transcription factors c-jun and ATF2 (Whitmarsh A.J., and Davis RJ. J. Mol. Med. 74:589-607, 1996). These transcription factors are members of the basic leucine zipper (bZD?) group that bind as homo- and hetero-dimeric complexes to AP-1 and AP-1-like sites in the promoters of many genes (Karin M., Liu Z.G. and Zandi E. Curr. Opin. CellBiol. 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 require Minden A., Karin M. Genes Dev. 7:2135-2148, 1993; Mohit A.A., Martin M.H., and Miller CA. Neuron 14:67-75, 1995).
• 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: JTSIKl, 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 D. 5 Wysk M., Whitmarsh A., Davis R., Flavell R. Science 270:1-4, 1998).
• Gene transcripts are alternatively spliced to produce four-JNKl isoforms, four-JNK2 isoforms 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 components and by use of scaffold proteins that selectively bind multiple components of the signaling cascade.
• JIP-1 JNK-interacting protein-1
• JIP-1 selectively binds the MAPK module, MLK 6 JNKK2 6 JNK.
• JIP-1 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.
• JNKKl also known as MKK 4
• JNKK2 MKK7
• JNKK2 JNKK2
• JNKK2 JNKK2
• JNKK2 JNKK2
• JNKK2 JNKK2
• JNKKl can also phosphorylate and activate p38.
• JNKKl and JNKK2 are widely expressed in mammalian tissues.
• JNKKl and JNKK2 are activated by the MAPKKK enzymes, MEKKl and 2 (Lange-Carter C.A., Pleiman CM., Gardner AM., 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 MEKKl 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.
• molecular genetic approaches have validated the pathogenic role of this pathway in several diseases.
• 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 ⁇ , IL-2, E-selectin and matrix metalloproteinases such as collagenase-1 (Manning A.M. and Mercurio F. Exp.
• Monocytes, tissue macrophages and tissue mast cells are key sources of TNF ⁇ production.
• the JNK pathway regulates TNF ⁇ production in bacterial lipopolysaccharide-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; Ishizuka T., Tereda N., Gerwins P., Hamelmann E., Oshiba A., Fanger G.R., Johnson G.L., and Gelfland E.W. Proc. Nat. Acad. Sci.
• MMPs Matrix metalloproteinases
• 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 B., Jacinto E., Hibi M., Kallunki T., Karin M., Ben-Neriah Y. Cell 77:727-736, 1994; Faris M., Kokot N., Lee L., and Nel A.E. J. Biol. Chem. 271 :27366-27373, 1996).
• T cells from mice genetically deficient in JNKKl 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 H., Bachmann M., Oliveria-dos-Santos A.J., et al. J. 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.
• JNK1 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,
• Thl cells producers of IFN-g and TNF/3
• Th2 effector cells producers of IL-4, IL-5, IL-6, IL-10 and IL-13.
• JNK2 in mice resulted in a selective defect in the ability of Thl effector cells to express IFNg. This suggests that JNK1 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.
• TNF-alpha tumor necrosis factor-alpha
• Pentoxyfylline is an inhibitor of TNF-alpha which has been tested as a therapeutic in the treatment of cachexia. Studies with pentoxyfylline have not shown efficacy in reversing weight-loss despite evidence of TNF-alpha inhibition (Haslett, P.A., 1998, Semin. Oncol. 25:53-7).
• Protein and calorie (energy) malnutrition which occurs commonly inpatients with end-stage renal disease and is associated with an increase in morbidity and mortality (Hakim, R.M. et al., 1993 Am. J. Kidney Dis. 21:125-37; Chen, Y. et al., 2001, J. Ren. Nutr. 11 :62-6), can result in end-stage renal disease-related wasting.
• the prevalence of malnutrition in the chronic dialysis population ranges from 10-54% depending on the parameter measured, and clinicians have long recognized that malnourished dialysis patients had a poorer prognosis than non-malnourished patients (Don, B.R., 2000, J. of Nephrology 13:249-59).
• the cancer anorexia-cachexia syndrome is one of the most common causes of death among cancer patients and is present in 80% at death. Tumors produce both direct and indirect abnormalities which result in anorexia and weight loss. There is no current treatment to control or reverse the process (Horvitz, H.R., 2000, Semin. Oncol. 27:64-8). 2.2.3 HIV- and/or AIDS-Reia ⁇ e ⁇ wasting
• Body-composition associated with weight loss and HIV differs from that seen as a result of starvation in that starvation-associated weight loss is characterized by increased fat catabolism with relative sparing of lean body tissue as opposed to HIN-related wasting which is characterized by significant depletion of lean body mass (Cahill G.S., ⁇ . Eng. J. of Med. 282: 668-691). Loss of lean body mass is particularly prominent in association with secondary infections (Kotler, D.P. et al. Am. J. Clin. ⁇ utr. 42:1255-1265).
• T ⁇ F tumor necrosis factor
• EL-l interleukin-1
• JFK interferon
• T ⁇ F and IL-1 have been found to produce skeletal muscle catabolism, the effects of which were found to be independent from and additive to those resulting from semi-starvation (Ling, P.R. et al., 1996, Am. J. Physiol. 270:E305; Ling P.R., et al., 1997, Am. J. Physiol. 272:E333). Additionally, interference with TNF production by anti-TNF antibodies blocks muscle proteolysis in vivo (Costelli, P., 1993, J. Clin. Invest. 92:2783).
• Body wasting is a common feature of several chronic diseases (Pichard C, Kyle U.G., 1998, Curr. Opin. Clin. Nutr. Metab. Care. 1:357-61).
• Chronic diseases other than those discussed above, which wasting is associated with are tuberculosis (Schwenk, A., 2000, Curr. Opin. Clin. Nutr. Metab. Care 3:285-91), chronic obstructive pulmonary disease (Farber, M.O., 2000, Neurol. Clin. 18:245-62), chronic heart failure (Franssen F.M., 2002, Clin. Nutr. 21:1-14), rheumatoid arthritis, chronic inflammatory diseases (e.g., scleroderma or mixed connective tissue disease) and chronic infectious diseases (e.g., osteoarthritis and bacterial endocarditis).
• chronic inflammatory diseases e.g., scleroderma or mixed connective tissue disease
• chronic infectious diseases e.g.,
• the present invention provides methods useful for treating or preventing disease-related wasting in a patient, comprising administering to a patient in need thereof an effective amount of a JNK Inhibitor.
• the disease is HIV.
• the disease is AIDS.
• the disease is cancer.
• the disease is end-stage renal disease.
• the disease is kidney failure.
• the disease is chronic heart disease, hi another embodiment, the disease is obstructive pulmonary disease.
• the disease is tuberculosis.
• the disease is rheumatoid arthritis.
• the disease is a chronic inflammatory disease including, but not limited to, scleroderma and mixed connective tissue disease.
• the disease is a chronic infectious disease including, but not limited to, osteoarthritis and bacterial endocarditis.
• the present invention also provides methods useful for treating or preventing disease-related wasting in a patient, comprising administering to a patient in need thereof an effective amount of a JNK Inhibitor and an effective amount of a therapeutic or prophylactic agent.
• the therapeutic or prophylactic agents include, but are not limited to, those useful in the treatment or prevention of HIV, AIDS, cancer, rheumatoid arthritis, chronic infections (e.g., tuberculosis, osteoarthritis and bacterial endocarditis), chronic inflammatory diseases (e.g., scleroderma and mixed connective tissue disease), end-stage renal disease, kidney failure, chronic heart disease or obstructive pulmonary disease.
• Such methods and regimens can encompass concurrent, sequential, synchronized or alternating/cyclic administration of a JNK Inhibitor with the therapeutic or prophylactic agent.
• the term "patient” means an animal (e.g., cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig), preferably a mammal such as a non-primate and a primate (e.g., monkey and human), most preferably a human.
• animal e.g., cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig
• a mammal such as a non-primate and a primate (e.g., monkey and human), most preferably a human.
• Alkyl means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms.
• “Lower alkyl” means alkyl, as defined above, having from 1 to 4 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-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhex
• alkenyl group or “alkylidene” mean 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 2 -C 10 )alkenyls include - vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-l- butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl, -3-hexenyl,
• a "cyclic alkylidene" is a ring having from 3 to 8 carbon atoms and including at least one carbon-carbon double bond, wherein the ring can have from 1 to 3 heteroatoms.
• 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 2 -C ⁇ o)alkynyls include - acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-l- butynyl, -4-pentynyl, -1-hexynyl, -2-hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl -6- heptynyl, -1-octynyl, -2-octynyl, -7-octynyl, -1-nonynyl, -2-
• Halogen and "Halo” mean fluorine, chlorine, bromine or iodine.
• Haloalkyl means an alkyl group, wherein alkyl is defined above, substituted with one or more halogen atoms.
• Acyl means an -C(O)alkyl group, wherein alkyl is defined above, including -C(O)CH 3 , -C(O)CH 2 CH 3 , -C(O)(CH 2 ) 2 CH 3, -C(O)(CH 2 ) 3 CH 3 , -C(O)(CH 2 ) 4 CH 3 ,
• Alkyloxy means an -OC(O)alkyl group, wherein alkyl is defined above, including -OC(O)CH 3 , -OC(O)CH 2 CH 3 , -OC(O)(CH 2 ) 2 CH 3, -OC(O)(CH 2 ) 3 CH 3 , - OC(O)(CH 2 ) 4 CH 3 , -OC(O)(CH 2 ) 5 CH 3 , and the like.
• Ester means and -C(O)Oalkyl group, wherein alkyl is defined above, including -C(O)OCH 3 , -C(O)OCH 2 CH 3 , -C(O)O(CH 2 ) 2 CH 3, -C(O)O(CH 2 ) 3 CH 3 , -
• Alkoxy means -O-(alkyl), wherein alkyl is defined above, including - OCH 3 , -OCH 2 CH 3 , -O(CH 2 ) 2 CH 3 , -O(CH 2 ) 3 CH 3 , -O(CH 2 ) 4 CH 3 , -O(CH 2 ) 5 CH 3 , and the like.
• “Lower alkoxy” means -O-(lower alkyl), wherein lower alkyl is as described above.
• Alkoxyalkoxy means -O-(alkyl)-O-(alkyl), wherein each alkyl is independently an alkyl group defined above, including -OCH 2 OCH 3 , -OCH 2 CH 2 OCH 3 , -
• Alkoxyalkyl means -(alkyl)-O-(alkyl), wherein each alkyl is independently an alkyl group defined above, including -CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , -(CH 2 ) 2 OCH 2 CH 3 , - (CH 2 ) 2 O(CH 2 ) 2 CH 3 , and the like.
• Aryl means a carbocychc aromatic group containing from 5 to 10 ring atoms.
• Representative examples include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, pyridinyl and naphthyl, as well as benzo-fused carbocychc moieties including 5,6,7,8-tetrahydronaphthyl.
• a carbocychc aromatic group can be unsubstituted or substituted, hi one embodiment, the carbocychc aromatic group is a phenyl group.
• Aryloxy means -O-aryl group, wherein aryl is as defined above.
• An aryloxy group can be unsubstituted or substituted.
• the aryl ring of an aryloxy group is a phenyl group
• Arylalkyl means -(alkyl)-(aryl), wherein alkyl and aryl are as defined above, including -(CH 2 )phenyl, -(CH 2 ) 2 phenyl, -(CH 2 ) 3 phenyl, -CH(phenyl) 2 , - CH(phenyl) 3 , -(CH 2 )tolyl, -(CH 2 )anthracenyl, -(CH 2 )fluorenyl, -(CH 2 )indenyl, - (CH )azulenyl, -(CH 2 )pyridinyl, -(CH 2 )naphthyl, and the like.
• Arylalkyloxy means -O-(alkyl)-(aryl), wherein alkyl and aryl are defined above, including -O-(CH 2 ) 2 ⁇ henyl, -O-(CH 2 ) 3 phenyl, -O-CH(phenyl) 2 , -O-CH(phenyl) 3 , -O- (CH 2 )tolyl, -O-(CH 2 )anthracenyl, -O-(CH 2 )fluorenyl, -O-(CH 2 )indenyl, -O-(CH 2 )azulenyl, -O-(CH 2 )pyridinyl, -O-(CH 2 )naphthyl, and the like.
• Aryloxyalkyl means -(alkyl)-O-(aryl), wherein alkyl and aryl are defined above, including -CH 2 -O-(phenyl), -(CH 2 ) 2 -O-phenyl, -(CH 2 ) 3 -O-phenyl, -(CH 2 )-O-tolyl, - (CH )-O-anthracenyl, -(CH 2 )-O-fluorenyl, -(CH 2 )-O-indenyl, -(CH 2 )-O-azulenyl, -(CH 2 )- O-pyridinyl, -(CH 2 )-O-naphthyl, and the like.
• Cycloalkyl means a monocyclic or polycyclic saturated ring having carbon and hydrogen atoms and having no carbon-carbon multiple bonds.
• Examples of cycloalkyl groups include, but are not limited to, (C 3 -C 7 )cycloalkyl groups, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturated cyclic and bicyclic terpenes.
• a cycloalkyl group can be unsubstituted or substituted.
• the cycloalkyl group is a monocyclic ring or bicyclic ring.
• Cycloalkyloxy means -O-(cycloalkyl), wherein cycloalkyl is defined above, including -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, -O- cycloheptyl and the like.
• Cycloalkylalkyloxy means -O-(alkyl)-(cycloalkyl), wherein cycloalkyl and alkyl are defined above, including -O-CH 2 -cyclopropyl, -O-(CH 2 ) 2 -cyclopropyl, -O-(CH 2 ) 3 - cyclopropyl, -O-(CH ) 4 -cyclopropyl, O-CH 2 -cyclobutyl, O-CH -cyclopentyl, O-CH 2 - cyclohexyl, O-CH 2 -cycloheptyl, and the like.
• Aminoalkoxy means -O-(alkyl)-NH 2 , wherein alkyl is defined above, such as -O-CH 2 -NH 2 , -O-(CH 2 ) 2 -NH 2 , -O-(CH 2 ) 3 -NH 2 , -O-(CH 2 ) 4 -NH 2 , -O-(CH2) 5 -NH 2 , and the like.
• “Mono-alkylamino” means -NH(alkyl), wherein alkyl is defined above, such as -NHCH 3 , -NHCH 2 CH 3 , -NH(CH 2 ) 2 CH 3 , -NH(CH 2 ) 3 CH 3 , -NH(CH 2 ) 4 CH 3 , -
• Di-alkylamino means -N(alkyl)(alkyl), wherein each alkyl is independently an alkyl group defined above, including -N(CH ) 2 , -N(CH 2 CH 3 ) 2 , -
• “Mono-alkylaminoalkoxy” means -O-(alkyl)-NH(alkyl), wherein each alkyl is independently an alkyl group defined above, including -O-(CH 2 )-NHCH , -O-(CH 2 )- NHCH 2 CH 3 , -O-(CH 2 )-NH(CH 2 ) 2 CH 3 , -O-(CH 2 )-NH(CH 2 ) 3 CH 3 , -O-(CH 2 )-NH(CH 2 ) 4 CH 3 ,
• Di-alkylaminoalkoxy means -O-(alkyl)-N(alkyl)(alkyl), wherein each alkyl is independently an alkyl group defined above, including -O-(CH 2 )-N(CH ) 2 , -O-(CH 2 )-
• Arylamino means -NH(aryl), wherein aryl is defined above, including -
• Arylalkylamino means -NH-(alkyl)-(aryl), wherein alkyl and aryl are defined above, including -NH-CH 2 -(phenyl), -NH-CH 2 -(tolyl), -NH-CH 2 -(anthracenyl), - NH-CH 2 -(fluorenyl), -NH-CH 2 -(indenyl), -NH-CH 2 -(azulenyl), -NH-CH 2 -(pyridinyl), -NH-NH-(alkyl)-(aryl), wherein alkyl and aryl are defined above, including -NH-CH 2 -(phenyl), -NH-CH 2 -(tolyl), -NH-CH 2 -(anthracenyl), - NH-CH 2 -(fluorenyl), -NH-CH 2 -(indenyl), -NH-CH 2 -(azulen
• Alkylamino means mono-alkylamino or di-alkylamino as defined above, such as -N(alkyl)(alkyl), wherein each alkyl is independently an alkyl group defined above, including -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N((CH 2 ) 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ) and - N(alkyl)(alkyl), wherein each alkyl is independently an alkyl group defined above, including -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N((CH 2 ) 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ) and the like.
• Cycloalkylamino means -NH-(cycloalkyl), wherein cycloalkyl is as defined above, including -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH- cyclohexyl, -NH-cycloheptyl, and the like.
• Carboxyl and “carboxy” mean -COOH.
• Cycloalkylalkylamino means -NH-(alkyl)-(cycloalkyl), wherein alkyl and cycloalkyl are defined above, including -NH-CH 2 -cyclopropyl, -NH-CH 2 -cyclobutyl, -NH- CH 2 -cyclopentyl, -NH-CH 2 -cyclohexyl, -NH-CH 2 -cycloheptyl, -NH-(CH 2 ) 2 -cyclopropyl and the like.
• Aminoalkyl means -(alkyl)-NH 2 , wherein alkyl is defined above, including
• “Mono-alkylaminoalkyl” means -(alkyl)-NH(alkyl),wherein each alkyl is independently an alkyl group defined above, including -CH 2 -NH-CH 3 , -CH 2 -NHCH 2 CH 3 , - CH 2 -NH(CH 2 ) 2 CH 3 , -CH 2 -NH(CH 2 ) 3 CH 3 , -CH 2 -NH(CH 2 ) 4 CH 3 , -CH 2 -NH(CH 2 ) 5 CH 3 , - (CH 2 ) 2 -NH-CH 3 , and the like.
• Di-alkylaminoalkyl means -(alkyl)-N(alkyl)(alkyl),wherein each alkyl is independently an alkyl group defined above, including -CH 2 -N(CH 3 ) 2 , -CH 2 -N(CH CH 3 ) 2 , - CH 2 -N((CH 2 ) 2 CH 3 ) 2 , -CH 2 -N(CH 3 )(CH 2 CH 3 ), -(CH 2 ) 2 -N(CH 3 ) 2 , and the like.
• Heteroaryl means an aromatic heterocycle ring of 5- to 10 members and having at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom, including both mono- and bicyclic ring systems.
• Representative heteroaryls are triazolyl, tetrazolyl, oxadiazolyl, pyridyl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, quinazolinyl, pyrimidyl, o
• Heteroarylalkyl means -(alkyl)-(heteroaryl), wherein alkyl and heteroaryl are defined above, including -CH -triazolyl, -CH 2 -tetrazolyl, -CH 2 -oxadiazolyl, -CH 2 - pyridyl, -CH 2 -furyl, -CH 2 -benzofuranyl, -CH 2 -thiophenyl, -CH 2 -benzothiophenyl, -CH 2 - quinolinyl, -CH 2 -pyrrolyl, -CH 2 -indolyl, -CH 2 -oxazolyl, -CH 2 -benzoxazolyl, -CH 2 - imidazolyl, -CH 2 -benzimidazolyl, -CH 2 -thiazolyl, -CH 2 -benzothiazolyl, -CH 2 -isox
• Heterocycle means a 5- to 7-membered monocyclic, or 7- to 10-membered bicyclic, heterocyclic ring which is either saturated, unsaturated, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring.
• the heterocycle can be attached via any heteroatom or carbon atom.
• Heterocycles include heteroaryls as defined above.
• heterocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
• Heterocycle fused to phenyl means a heterocycle, wherein heterocycle is defined as above, that is attached to a phenyl ring at two adjacent carbon atoms of the phenyl ring.
• Heterocycloalkyl means -(alkyl)-(heterocycle), wherein alkyl and heterocycle are defined above, including -CH 2 -morpholinyl, -CH 2 -pyrrolidinonyl, -CH 2 - pyrrolidinyl, -CH 2 -piperidinyl, -CH 2 -hydantoinyl, -CH 2 -valerolactamyl, -CH 2 -oxiranyl, - CH 2 -oxetanyl, -CH 2 -tetrahydrofuranyl, -CH 2 -tetrahydropyranyl, -CH 2 -tetrahydropyridinyl, - CH -tetrahydroprimidinyl, -CH 2 -tetrahydrothiophenyl, -CH2-tetrahydrothiopyranyl, -CH 2 - tetrahydropyrimidinyl, -
• substituted means any of the above groups (i.e., aryl, arylalkyl, heterocycle and heterocycloalkyl) wherein at least one hydrogen atom of the moiety being substituted is replaced with a substituent.
• each carbon atom of the group being substituted is substituted with no more that two substituents.
• each carbon atom of the group being substituted is substituted with no more than one substituent.
• two hydrogen atoms are replaced with an oxygen which is attached to the carbon via a double bond.
• Haloalkyl means alkyl, wherein alkyl is defined as above, having one or more hydrogen atoms replaced with halogen, wherein halogen is as defined above, including -CF 3 , -CHF 2 , -CH 2 F, -CBr 3 , -CHBr 2 , -CH 2 Br, -CC1 3 , -CHC1 2 , -CH 2 C1, -CI 3 , -
• Hydroalkyl means alkyl, wherein alkyl is as defined above, having one or more hydrogen atoms replaced with hydroxy, including -CH 2 OH, -CH CH OH, -
• “Sulfonyl” means -SO 3 H.
• “Sulfonylalkyl” means -SO 2 -(alkyl), wherein alkyl is defined above, including -SO 2 -CH 3 , -SO 2 -CH 2 CH 3 , -SO 2 -(CH 2 ) 2 CH 3 , -SO 2 -(CH 2 ) 3 CH 3 , -SO 2 -(CH 2 ) 4 CH 3 , -
• “Sulfinylalkyl” means -SO-(alkyl), wherein alkyl is defined above, including
• “Sulfonamidoalkyl” means -NHSO 2 -(alkyl), wherein aklyl is defined above, including -NHSO 2 -CH 3 , -NHSO 2 -CH 2 CH 3 , -NHSO 2 -(CH 2 ) 2 CH 3 , -NHSO 2 -(CH 2 ) 3 CH 3 , -
• Thioalkyl means -S-(alkyl), wherein alkyl is defined above, including -S- CH 3 , -S-CH 2 CH 3 , -S-(CH 2 ) 2 CH 3 , -S-(CH 2 ) 3 CH 3, -S-(CH 2 ) 4 CH 3 , -S-(CH 2 ) 5 CH 3 , and the like.
• JNK Inhibitor means a compound capable of inhibiting the activity of JNK in vitro or in vivo.
• the JNK Inhibitor can be in the form of a pharmaceutically acceptable salt, free base, solvate, hydrate, stereoisomer, clathrate or prodrug thereof.
• Such inhibitory activity can be determined by an assay or animal model well-known in the art including those set forth in Section 5.
• Inhibitor is a compound of structure (I)-(III).
• JNK means a protein or an isoform thereof expressed by a JNK 1, JNK 2, or JNK 3 gene (Gupta, S., Barrett, T., Whitmarsh, A.J., Cavanagh, J., Sluss, H.K., Derijard,
• an effective amount when used in connection with a JNK Inhibitor means an amount of the JNK Inhibitor that is useful for for treating or preventing disease-related wasting.
• an effective amount when used in connection with a therpeutic or prophylactic agent means an amount of the therapeutic or prophylactic agent that is useful for for treating or preventing disease-related wasting when administered while the JNK Inhibitor exerts its activity.
• the term "pharmaceutically acceptable salt(s)” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an organic acid and base.
• Suitable pharmaceutically acceptable base addition salts of the JNK Inhibitor include, but are not limited to metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
• Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid.
• Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and methanesulfonic acids.
• polymorph means a particular crystalline arrangement of the JNK Inhibitor. Polymorphs can be obtained through the use of different work-up conditions and/or solvents. In particular, polymorphs can be prepared by recrystallization of a JNK Inhibitor in a particular solvent.
• prodrug means a JNK Inhibitor derivative that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide an active compound, particularly a JNK Inhibitor.
• prodrugs include, but are not limited to, derivatives and metabolites of a JNK
• biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
• prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of the carboxylic acid.
• the carboxylate esters are conveniently formed by esterifying any of the carboxylic acid moieties present on the molecule.
• Prodrugs can typically be prepared using well- known methods, such as those described by Burger's Medicinal Chemistry and Drug Discovery 6 th ed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh).
• optically pure or “stereomerically pure” means one stereoisomer of a compound is substantially free of other stereoisomers of that compound.
• a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound.
• a stereomerically pure a compound having two chiral centers will be substantially free of other diastereomers of the compound.
• a typical stereomerically pure compound comprises greater than about 80%o by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.
• Component of the JNK pathway means any biological molecule that has a direct or indirect effect on the activity of JNK.
• HIV therapy or "AIDS therapy” refers to a therapeutic protocol used to treat HIV or AIDS or HIV/AIDS related symptoms comprising administering an agent useful in treating HIV or AIDS including, but not limited to, a reverse transcriptase inhibitor and/or a protease inhibitor.
• the ADDS therapeutic agent is a protease inhibitor including, but not limited to: amprenavir (sold as a formulation under the trade name AGNERASE); nelfinavir (sold as a formulation under the trade name VIRACEPT); saquinavir (sold as a formulation under the trade name FORTOVASE); indinavir (sold as a formulation under the trade name CRIXIVAN); saquinavir (sold as a formulation under the trade name INVIRASE); lopinavir (sold as a formulation under the trade name KALETRA); ritonavir (sold as a formulation under the trade name NORVTR); or GW433908.
• amprenavir (sold as a formulation under the trade name AGNERASE); nelfinavir (sold as a formulation under the trade name VIRACEPT); saquinavir (sold as a formulation under the trade name FORTOVASE); indinavir (sold as a formulation under the trade
• the AIDS therapeutic agent is a reverse transcriptase inhibitor including, but not limited to: a composition comprising 3TC and lamivudine (sold as a formulation under the trade name EPIVIR); a composition comprising ddc and zalcitabine (sold as a formulation under the trade name HIVID); delavirdine (sold as a formulation under the trade name RESCRIPTOR); zidovudine (sold as a formulation under the trade name RETRO VIR); efavirenz (sold as a formulation under the trade name SUSTIVA); a composition comprising abacavir, zidovudine and lamivudine (sold as a formulation under the trade name TRIZIVIR); a composition comprising ddl and didanosine (sold as a formulation under the trade name VIDEX); nevirapine (sold as a formulation under the trade name V1RAMUNE); tenofovir disoproxil fumarate (sold
• therapeutically effective amount includes the amount of the therapeutic agent sufficient to delay or minimize symptoms associated with disease-related wasting.
• a therapeutically effective amount also includes the amount of the therapeutic agent that provides a therapeutic benefit in the treatment or management of disease-related wasting.
• prolactic agent includes any agent that can be used in the prevention of a disease (e.g, HIV, AIDS, cancer, end-stage renal disease, kidney failure, chronic heart disease, obstructive pulmonary disease, tuberculosis, rheumatoid arthritis, a chronic inflammatory disease, scleroderma, a mixed connective tissue disease, a chronic infectious disease, osteoarthritis or bacterial endocarditis).
• a disease e.g, HIV, AIDS, cancer, end-stage renal disease, kidney failure, chronic heart disease, obstructive pulmonary disease, tuberculosis, rheumatoid arthritis, a chronic inflammatory disease, scleroderma, a mixed connective tissue disease, a chronic infectious disease, osteoarthritis or bacterial endocarditis.
• the term "therapeutic agent” includes any agent(s) that can be used in the treatment of a disease (e.g, HIV, AIDS, cancer, end-stage renal disease, kidney failure, chronic heart disease, obstructive pulmonary disease, tuberculosis, rheumatoid arthritis, a chronic inflammatory disease, scleroderma, a mixed connective tissue disease, a chronic infectious disease, osteoarthritis or bacterial endocarditis).
• a disease e.g, HIV, AIDS, cancer, end-stage renal disease, kidney failure, chronic heart disease, obstructive pulmonary disease, tuberculosis, rheumatoid arthritis, a chronic inflammatory disease, scleroderma, a mixed connective tissue disease, a chronic infectious disease, osteoarthritis or bacterial endocarditis.
• the disease is HIV or AIDS and the prophylactic or therapeutic agents include amprenavir (sold as a formulation under the trade name AGNERASE); nelfinavir (sold as a formulation under the trade name VD ACEPT); saquinavir (sold as a formulation under the trade name FORTOVASE); indinavir (sold as a formulation under the trade name CRIXIVAN); saquinavir (sold as a formulation under the trade name INVIRASE); lopinavir (sold as a formulation under the trade name KALETRA); ritonavir (sold as a formulation under the trade name NORVIR); or GW433908.
• amprenavir (sold as a formulation under the trade name AGNERASE); nelfinavir (sold as a formulation under the trade name VD ACEPT); saquinavir (sold as a formulation under the trade name FORTOVASE); indinavir (sold as a formulation under the trade name C
• the AIDS therapeutic agent is a reverse transcriptase inhibitor including, but not limited to: a composition comprising 3TC and lamivudine (sold as a formulation under the trade name EPIVIR); a composition comprising ddc and zalcitabine (sold as a formulation under the trade name HIVID); delavirdine (sold as a formulation under the trade name RESCR1PTOR); zidovudine (sold as a formulation under the trade name RETRO VIR); efavirenz (sold as a formulation under the trade name SUSTIVA); a composition comprising abacavir, zidovudine and lamivudine (sold as a formulation under the trade name TRIZIVIR); a composition comprising ddl and didanosine (sold as a formulation under the trade name VEDEX); nevirapine (sold as a formulation under the trade name V__RAMJJNE); tenofovir disoproxil
• the disease is end-stage renal disease and the prophylactic or therapeutic agents include angiotensin ⁇ , cisplatin, dialysis and lisinopril.
• the disease is kidney failure and the prophylactic or therapeutic agents include angiotensin II, cisplatin, dialysis and lisinopril.
• the disease is cancer and the prophylactic or therapeutic agents include paclitaxel, irinotecan, camptothecin, cyclophosphamide, 5-fluorouracil, cisplatinum, carboplatin, methotrexate, trimetrexate, erbitux, thalidomide, actimid and revimid.
• the disease is chronic heart disease and the prophylactic or therapeutic agents include perindopril.
• the disease is obstructive pulmonary disease and the prophylactic or therapeutic agents include budesonide, prednisolone, beta(2)-agonists, ipratropium bromide and oral antibiotics.
• the disease is a chronic infectious disease. In one embodiment, the disease is a chronic inflammatory disease.
• the disease is tuberculosis and the prophylactic or therapeutic agents include infliximab, rifampicin and streptomycin.
• non-responsive/refractory is used to describe a condition of patients treated with currently available HIV, AIDS, end-stage renal disease, kidney failure, cancer, chronic heart disease, obstructive pulmonary disease, chronic infectious diseases (e.g., osteoarthritis and bacterial endocarditis), chronic inflammatory diseases (e.g., scleroderma and mixed connective tissue disease) or tuberculosis therapies wherein the therapy is not clinically adequate to treat the patients such that these patients need additional effective therapy, e.g., remain unsusceptible to therapy.
• the phrase includes a condition of patients who respond to therapy yet suffer from side effects.
• the phrase “low tolerance” refers to a state in which the patient suffers from side effects from treatment so that the patient does not benefit from and/or will not continue therapy because of its adverse effects.
• the term “potentiate” refers to an improvement in the efficacy of a therapeutic agent at its common or approved dose.
• side effects encompasses unwanted and adverse effects of a prophylactic or therapeutic agent. Adverse effects are always unwanted, but unwanted effects are not necessarily adverse. An adverse effect from a prophylactic or therapeutic agent might be harmful or uncomfortable or risky. Many are described in the Physicians ' Desk Reference (56 th ed. 2002).
• the term "manage" when used in connection with a disease or condition means to provide beneficial effects to a patient being administered with a prophylactic or therapeutic agent, which does not result in a cure of the disease.
• a patient is administered with one or more prophylactic or therapeutic agents to manage a disease so as to prevent the progression or worsening of the disease.
• prevent and “preventing” include the prevention of the recurrence, spread or onset of disease-related wasting.
• treat and “treating” include the eradication, removal, modification, management or control of disease-related wasting.
• the present invention is directed to methods useful for treating or preventing disease-related wasting in a patient, comprising administering an effective amount of a JNK Inhibitor.
• a JNK Inhibitor Illustrative JNK Inhibitors are set forth below.
• the JNK Inhibitor has the following structure (I):
• Ri is aryl, heteroaryl or heterocycle fused to phenyl, each being optionally substituted with one to four substituents independently selected from R 3 ;
• R is alkyl, aryl, arylalkyl, heterocycle or heterocycloalkyl, each being optionally substituted with one to four substituents independently selected from R 3 , or R t is halogen or hydroxy;
• R 5 , Re and R 7 are the same or different and at each occurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle or heterocycloalkyl, wherein each of R 5 , R 6 and
• R 7 are optionally substituted with one to four substituents independently selected from R 3 ;
• R 8 and R 9 are the same or different and at each occurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle, or heterocycloalkyl, or R 8 and R taken together with the atom or atoms to which they are bonded form a heterocycle, wherein each of R 8 , R , and R 8 and R 9 taken together to form a heterocycle are optionally substituted with one to four substituents independently selected from R 3 .
• R 2 is 3-triazolyl or 5-tetrazolyl.
• R 2 is 3-triazolyl or 5-tetrazolyl.
• R 2 is R 4
• R 4 is 3-triazolyl, optionally substituted at its 5-position with:
• R 2 is R 4 , and R is 3-triazolyl, optionally substituted at its 5-position with: methyl, n-propyl, isopropyl, 1-hydroxyethyl, 3-hydroxypropyl, methylaminomethyl, dimethylaminomethyl, l-(dimethylamino)ethyl, 1-pyrrolidinylmethyl or 2-pyrrolidinyl.
• the compounds of structure (I) have structure (IA) when A is a direct bond, or have structure (IB) when A is -(CH 2 ) ⁇ -:
• Ri of structure (I) is aryl or substituted aryl, such as phenyl or substituted phenyl as represented by the following structure (IE):
• b 0 and the compounds have the following structure (IF):
• alkyl such as methyl, ethyl and isopropyl
• haloalkyl such as trifluoromethyl
• hydroxy, alkoxy such as methoxy, ethoxy, n-propyloxy and isobutyloxy
• amino, mono- or di-alkylamino such as dimethylamine
• aryl such as phenyl
• carboxy such as nifro, cyano
• sulfinylalkyl such as methylsulfinyl
• sulfonylalkyl such as methylsulfonyl
• sulfonamidoalkyl such as -NHSO 2 CH 3
• the compounds of structure (I) can be made using organic synthesis techniques known to those skilled in the art, as well as by the methods described in International Publication No. WO 02/10137 (particularly in Examples 1-430, at page 35, line 1 to page 396, line 12), published February 7, 2002, which is incorporated herein by reference in its entirety. Further, specific examples of these compounds are found in this publication.
• JNK Inhibitors of structure (I) are:
• the JNK Inhibitor has the following structure (II):
• Ri is aryl or heteroaryl optionally substituted with one to four substituents independently selected from R 7 ;
• R 2 is hydrogen;
• R 3 is hydrogen or lower alkyl; represents one to four optional substituents, wherein each substituent is the same or different and independently selected from halogen, hydroxy, lower alkyl and lower alkoxy;
• R 8 , R 9 , R 10 and R ⁇ are the same or different and at each occurrence independently hydrogen, alkyl, aryl, arylalkyl, heterocycle, heterocycloalkyl; or R 8 and R taken together with the atom or atoms to which they are attached to form a heterocycle; a and b are the same or different and at each occurrence independently selected from 0, 1, 2, 3 or 4; and c is at each occurrence 0, 1 or 2.
• Ri is a substituted or unsubstituted aryl or heteroaryl.
• Ri When Ri is substituted, it is substituted with one or more substituents defined below.” hi one embodiment, when substituted, Ri is substituted with a halogen, -SO 2 R 8 or -SO 2 R 8 R 9 .
• Ri is substituted or unsubstituted aryl, furyl, benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl, indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl or quinazolinyl.
• Ri is substituted or unsubstituted aryl or heteroaryl. When Ri is substituted, it is substituted with one or more substituents defined below. In one embodiment, when substituted, Ri is substituted with a halogen, -SO 2 R 8 or -SO R 8 R 9 .
• Ri is substituted or unsubstituted aryl, preferably phenyl.
• the substituents are defined below, hi one embodiment, when substituted, Ri is substituted with a halogen, -SO 2 R 8 or -SO 2 R 8 R 9 .
• R 5 and Re taken together with the nitrogen atom to which they are attached form a substituted or unsubstituted nitrogen-containing non- aromatic heterocycle, in one embodiment, piperazinyl, piperidinyl or morpholinyl.
• R 5 and Re taken together with the nitrogen atom to which they areattached form substituted piperazinyl, piperadinyl or morpholinyl, the piperazinyl, piperadinyl or morpholinyl is substituted with one or more substituents defined below.
• the substituent is alkyl, amino, alkylamino, alkoxyalkyl, acyl, pyrrolidinyl or piperidinyl.
• R is hydrogen and R 4 is not present
• the JNK Inhibitor has the following structure (HA):
• Ri is phenyl optionally substituted with R 7 , and having the following structure (IIB): and pharmaceutically acceptable salts thereof.
• R 7 is at the para position of the phenyl group relative to the pyrimidine, as represented by the following structure (IIC):
• JNK Inhibitors of structure (II) can be made using organic synthesis techniques known to those skilled in the art, as well as by the methods described in International Publication No. WO 02/46170 (particularly Examples 1-27 at page 23, line 5 to page 183, line 25), published June 13, 2002, which is hereby incorporated by reference in itsr entirety. Further, specific examples of these compounds are found in the publication. Illustrative examples of JNK Inhibitors of structure (II) are:
• the JNK Inhibitor has the following structure (III):
• Ro is -O-, -S-, -S(O)-, -S(O) 2 -, NH or -CH 2 -; the compound of structure (III) being: (i) unsubstituted, (ii) monosubstituted and having a first substituent, or (iii) disubstiruted and having a first substituent and a second substituent; the first or second substituent, when present, is at the 3, 4, 5, 7, 8, 9, or 10 position, wherein the first and second substituent, when present, are independently alkyl, hydroxy, halogen, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoal
• R 3 and 1?U are taken together and represent alkylidene or a heteroatom-containing cyclic alkylidene or R and are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono- alkylaminoalkyl, or di-alkylaminoalkyl; and
• R 5 is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino, di-alkylamino, arylamino, arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl, mono- alkylaminoalkyl, or di-alkylaminoalkyl.
• the JNK Inhibitor has the following structure (IIIA):
• first and second substituent when present, are independently alkyl, hydroxy, halogen, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono- alkylaminoalkoxy, di-alkylaminoalkoxy, or a group represented by structure (a), (b), (c), (d), (e), or (f):
• R 3 and R 4 are taken together and represent alkylidene or a heteroatom-containing cyclic alkylidene or R 3 and K 4 are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono- alkylaminoalkyl, or di-alkylaminoalkyl; and
• R 5 is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino, di-alkylamino, arylamino, arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl, mono- alkylaminoalkyl, or di-alkylaminoalkyl.
• a subclass of the compounds of structure (IIIA) is that wherein the first or second substituent is present at the 5, 7, or 9 position. In one embodiment, the first or second substituent is present at the 5 or 7 position.
• a second subclass of compounds of structure (IIIA) is that wherein the first or second substituent is present at the 5, 7, or 9 position; the first or second substituent is independently alkoxy, aryloxy, aminoalkyl, mono-alkylaminoalkyl, di-alkylaminoalkyl, or a group represented by the structure (a), (c), (d), (e), or (f);
• R 3 and R 4 are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, or cycloalkylalkyl;
• R 5 is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, or cycloalkylalkyl.
• the JNK Inhibitor has the following structure (IIIB):
• first and second substituent when present, are independently alkyl, halogen, hydroxy, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a group represented by structure (a), (b) (c), (d), (e), or (f):
• R 3 and R4 are taken together and represent alkylidene or a heteroatom-containing cyclic alkylidene or R 3 and R 4 are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono- alkylaminoalkyl, or di-alkylaminoalkyl; and
• R 5 is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino, di-alkylamino, arylamino, arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl, mono- alkylaminoalkyl, or di-alkylaminoalkyl.
• a subclass of the compounds of structure (IIIB) is that wherein the first or second substituent is present at the 5, 7, or 9 position, hi one embodiment, the first or second substituent is present at the 5 or 7 position.
• a second subclass of the compounds of structure (IIIB) is that wherein the first or second substituent is independently alkoxy, aryloxy, or a group represented by the structure (a), (c), (d), (e), or (f);
• R 3 and R 4 are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, or cycloalkylalkyl; and R 5 is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, or cycloalkylalkyl.
• the JNK Inhibitor has the following structure (IIIC):
• first and second substituent when present, are independently alkyl, halogen, hydroxy, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a group represented by structure (a), (b), (c) (d), (e), or (f): -
• R 3 and R 4 are taken together and represent alkylidene or a heteroatom-containing cyclic alkylidene or R 3 and R 4 are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono- alkylaminoalkyl, or di-alkylaminoalkyl; and
• R 5 is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino, di-alkylamino, arylamino, arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl, mono- alkylaminoalkyl, or di-alkylaminoalkyl.
• a subclass of the compounds of structure (IIIC) is that wherein the first or second substituent is present at the 5, 7, or 9 position, h one embodiment, the first or second substituent is present at the 5 or 7 position.
• a second subclass of the compounds of structure (IIIC) is that wherein the first or second substituent is independently alkoxy, aryloxy, aminoalkyl, mono- alkylaminoalkyl, di-alkylaminoalkyl, or a group represented by the structure (a), (c), (d),
• R 3 and 4 are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, or cycloalkylalkyl;
• R 5 is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, or cycloalkylalkyl.
• the JNK Inhibitor has the following structure (HID):
• first and second substituent when present, are independently alkyl, halogen, hydroxy, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylamin
• R 3 and R 4 are taken together and represent alkylidene or a heteroatom-containing cyclic alkylidene or R 3 and R are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono- alkylaminoalkyl, or di-alkylaminoalkyl; and R 5 is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino, di-alkylamino, arylamino, arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl, mono- alkylaminoalkyl, or di-alkylaminoalkyl
• a subclass of the compounds of structure (HID) is that wherein the first or second substituent is present at the 5 or 7 position.
• a second subclass of the compounds of structure (HID) is that wherein the first or second substituent is independently alkyl, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy, di- alkylaminoalkoxy, or a group represented by structure (a), (c), (d), (e), or (f).
• Another subclass of the compounds of structure (IIID) is that wherein the first and second substituent are independently alkoxy, aryloxy, or a group represented by the structure (a), (c), (d), (e), or (f);
• R 3 and R_ t are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, or cycloalkylalkyl;
• R 5 is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, alkoxycarbonyl, or cycloalkylalkyl.
• the JNK Inhibitor has the following structure (HIE):
• first and second substituent when present, are independently alkyl, halogen, hydroxy, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono-alkylaminoalkoxy, di-alkylaminoalkoxy, or a group represented by structure
• R 3 and R 4 are taken together and represent alkylidene or a heteroatom-containing cyclic alkylidene or R 3 and R_ are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono- alkylaminoalkyl, or di-alkylaminoalkyl; and
• R 5 is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino, di-alkylamino, arylamino, arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl, mono- alkylaminoalkyl, or di-alkylaminoalkyl.
• a subclass of the compounds of structure (IIIE) is that wherein the first or second substituent is present at the 5 or 7 position.
• a second subclass of the compounds of structure (IIIE) is that wherein the compound of structure (IIIE) is disubstituted and at least one of the substituents is a group represented by the structure (d) or (f).
• Another subclass of the compounds of structure (IIIE) is that wherein the compounds are monosubstituted. Yet another subclass of compounds is that wherein the compounds are monosubstituted at the 5 or 7 position with a group represented by the structure (e) or (f).
• the JNK Inhibitor has the following structure (IIIF):
• first and second substituent when present, are independently alkyl, hydroxy, halogen, nitro, trifluoromethyl, sulfonyl, carboxyl, alkoxycarbonyl, alkoxy, aryl, aryloxy, arylalkyloxy, arylalkyl, cycloalkylalkyloxy, cycloalkyloxy, alkoxyalkyl, alkoxyalkoxy, aminoalkoxy, mono- alkylaminoalkoxy, di-alkylaminoalkoxy, or a group represented by structure (a), (b), (c), (d), (e), or (f):
• R 3 and R_j are taken together and represent alkylidene or a heteroatom-containing cyclic alkylidene or R 3 and R* are independently hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, aryloxyalkyl, alkoxyalkyl, aminoalkyl, mono- alkylaminoalkyl, or di-alkylaminoalkyl; and R 5 is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, cycloalkylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, amino, mono-alkylamino, di-alkylamino, arylamino, arylalkylamino, cycloalkylamino, cycloalkylalkylamino, aminoalkyl, mono- alkylaminoalkyl, or di-alkylamino
• the JNK Inhibitors of structure (III) can be made using organic synthesis techniques known to those skilled in the art, as well as by the methods described in International Publication No. WO 01/12609 (particularly Examples 1-7 at page 24, line 6 to page 49, line 16), published February 22, 2001, as well as International Publication No. WO 02/066450 (particularly compounds AA-HG at pages 59-108), published August 29, 2002, each of which is hereby incorporated by reference in its entirety. Further, specific examples of these compounds can be found in the publications.
• JNK Inhibitors of structure (III) are:
• J ⁇ K Inhibitors that are useful in the present methods include, but are not limited to, those disclosed in International Publication No. WO 00/39101, (particularly at page 2, line 10 to page 6, line 12); International Publication No. WO 01/14375 (particularly at page 2, line 4 to page 4, line 4); International Publication No. WO 00/56738 (particularly at page 3, line 25 to page 6, line 13); International Publication No. WO 01/27089 (particularly at page 3, line 7 to page 5, line 29); International Publication No. WO 00/12468 (particularly at page 2, line 10 to page 4, line 14); European Patent
• Publication 1 110 957 (particularly at page 19, line 52 to page 21, line 9); International Publication No. WO 00/75118 (particularly at page 8, line 10 to page 11 , line 26); International Publication No. WO 01/12621 (particularly at page 8, line 10 to page 10, line 7); International Publication No. WO 00/64872 (particularly at page 9, line 1 to page, 106, line 2); International Publication No. WO 01/23378 (particularly at page 90, line 1 to page 91, linel 1); International Publication No. WO 02/16359 (particularly at page 163, line 1 to page 164, line 25); United States Patent No. 6,288,089 (particularly at column 22, line 25 to column 25, line 35); United States Patent No.
• compositions including dosage forms of the invention, which comprise an effective amount of a JNK Inhibitor can be used in the methods of the invention. 4.2 METHODS OF USE
• the present invention provides methods useful for treating or preventing disease-related wasting in a patient comprising administering an effective amount of a JNK Inhibitor.
• the disease is HIV.
• the disease is AIDS.
• the disease is cancer.
• the disease is end-stage renal disease. hi another embodiment, the disease is kidney failure.
• the disease is chronic heart disease. In another embodiment, the disease is obstructive pulmonary disease.
• the disease is tuberculosis. hi another embodiment, the disease is rheumatoid arthritis.
• the disease is a chronic inflammatory disease including, but not limited to, scleroderma and mixed connective tissue disease.
• the disease is a chronic infectious disease including, but not limited to, osteoarthritis and bacterial endocarditis.
• the present invention also provides methods useful for treating or preventing disease-related wasting in a patient, comprising administering to a patient in need thereof an effective amount of a JNK Inhibitor and a prophylactic or therapeutic agent.
• the prophylactic or therapeutic agent is useful for the treatment or prevention of HIV or ADDS.
• Agents useful for treating or preventing HIN or AIDS include, but are not limited to, amprenavir (sold as a formulation under the trade name AG ⁇ ERASE); nelfmavir (sold as a formulation under the trade name VIRACEPT); saquinavir (sold as a formulation under the trade name FORTOVASE); indinavir (sold as a formulation under the trade name CRIXIVAN); saquinavir (sold as a formulation under the trade name ENTVTRASE); lopinavir (sold as a formulation under the trade name KALETRA); ritonavir (sold as a formulation under the trade name NORVIR); or GW433908.
• the AIDS therapeutic agent is a reverse transcriptase inhibitor including, but not limited to: 3TC / lamivudine (sold as a formulation under the trade name EPrVIR); ddc / zalcitabine (sold as a formulation under the trade name HINID); delavirdine (sold as a formulation under the trade name RESCRIPTOR); zidovudine (sold as a formulation under the trade name RETRO VIR); efavirenz (sold as a formulation under the trade name SUSTIVA); a combintion of abacavir, zidovudine and lamivudine (sold as a formulation under the trade name TRIZIVIR); ddl / didanosine (sold as a formulation under the trade name VIDEX); nevirapine (sold as a formulation under the trade name VIRAMU ⁇ E); tenofovir disoproxil fumarate (sold as a formulation under the trade name VI
• the prophylactic or therapeutic agent is useful for the treatment or prevention of end-stage renal disease.
• Agents or methods useful for treating or preventing end-stage renal disease include, but are not limited to, angiotensin ⁇ , cisplatin, dialysis or lisinopril.
• the prophylactic or therapeutic agent is useful for the treatment or prevention of kidney failure.
• Agents or methods useful for treating or preventing kidney failure include, but are not limited to, angiotensin II, cisplatin, dialysis or lisinopril.
• the prophylactic or therapeutic agent is useful for the treatment or prevention of chronic heart disease.
• Agents useful for treating or preventing chronic heart disease include, but are not limited to, perindopril.
• the prophylactic or therapeutic agent is useful for the treatment or prevention of obstructive pulmonary disease.
• Agents useful for treating or preventing obstructive pulmonary disease include, but are not limited to, such as budesonide, prednisolone, beta(2)-agonists, ipratropium bromide or oral antibiotics.
• the prophylactic or therapeutic agent is useful for the treatment or prevention of cancer.
• Agents useful for treating or preventing cancer include, but are not limited to, acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin, aldesleukin, alfretarnine, ambomycin, ametantrone acetate, aminoglutethimide, amsacrine, anastrozole, anthra nycin, asparaginase, asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa, bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium, bropirimine, busulfan, cactinomycin, calusterone, caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedef
• anti-cancer drugs include, but are not limited to, 20-epi-l,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti- dorsalizing morphogenetic protein- 1 ; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-
• B betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRestM3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-po hyrin; cladribine; clomifene analogues; clotrimazole; collismycin
• the prophylactic or therapeutic agent is useful for the treatment or prevention of tuberculosis.
• Agents useful for treating or preventing tuberculosis include, but are not limited to, infliximab, rifampicin or streptomycin.
• the prophylactic or therapeutic agent is useful for the treatment or prevention of rheumatoid arthritis.
• Agents useful for treating or preventing rheumatoid arthritis include, but are not limited to, hydroxycholoquine, NSAIDs (e.g., aspirin, ibuprofen and naproxen), arava, enbrel, remicade, kineret, azulfidene and aralen.
• the prophylactic or therapeutic agent is useful for the treatment or prevention of chronic inflammatory disease including, but not limited to, scleroderma and mixed connective tissue disease.
• Agents useful for treating or preventing a chronic inflammatory disease include, but are not limited to, NSAIDs (e.g., aspirin, ibuprofen and naproxen), arava, enbrel, remicade, kineret, azulfidene and aralen.
• the prophylactic or therapeutic agent is useful for the treatment or prevention of a chronic infectious disease including, but not limited to, osteoarthritis and bacterial endocarditis.
• Agents useful for treating or preventing a chronic infectious disease include, but are not limited to, acetominophen and NSAIDs (e.g., aspirin, ibuprofen and naproxen).
• the disease-related wasting is associated with a weight loss of greater than about 5% of baseline body weight, which is optionally accompanied by chronic diarrhea, chronic weakness or fever.
• compositions of the invention are useful not only in untreated patients but are also useful in the treatment of patients partially or completely refractory to current standard and experimental disease-related wasting therapy, including but not limited to appetite stimulants, hormonal therapy, and/or biological therapy/immunotherapy.
• the methods of the invention allow the treatment of disease-related wasting using lower and/or less frequent doses of appetite stimulants, hormonal therapy, and/or biological therapy/immunotherapy to reduce the incidence of unwanted or adverse effects caused by administration of current/conventional agents while maintaining or enhancing the efficacy of treatment.
• lower and/or less frequent doses of a JNK Inhibitor can be used for the treatment and/or prevention of disease-related wasting.
• a JNK Inhibitor and a prophylactic or therapeutic agent are administered to an animal, preferably a mammal, more preferably a human, in a sequence and within a time interval such that the JNK Inhibitor can act together with the other agent to provide an increased benefit than if they were administered otherwise.
• each prophylactic or therapeutic agent can be administered at the same time or sequentially in any order at different points in time; however, if not administered at the same time, they should be administered sufficiently close in time so as to provide the desired therapeutic or prophylactic effect.
• the JNK Inhibitor and the prophylactic or therapeutic agent exert their effect at times which overlap.
• Each prophylactic or therapeutic agent can be administered separately, in any appropriate form and by any suitable route.
• the JNK Inhibitor is administered before, concurrently or after administration of the therapeutic or prophylactic agent. Surgery can also be performed as a preventive measure or to relieve pain.
• the JNK Inhibitor and prophylactic or therapeutic agent are admimstered less than about 1 hour apart, at about 1 hour apart, at about 1 hour to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, no more than 24 hours apart or no more than 48 hours apart.
• the JNK Inhibitor and prophylactic or therapeutic agent are admimstered concurrently.
• the JNK Inhibitor and prophylactic or therapeutic agent is administered at about 2 to 4 days apart, at about 4 to 6 days apart, at about 1 week part, at about 1 to 2 weeks apart, or more than 2 weeks apart.
• the prophylactic or therapeutic agents are administered in a time frame where both agents are still active. One skilled in the art would be able to determine such a time frame by determining the half life of the admimstered agents.
• the JNK Inhibitor and optionally the prophylactic or therapeutic agent are cyclically administered to a patient. Cycling therapy involves the administration of a first agent for a period of time, followed by the administration of a second agent and/or third agent for a period of time and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improve the efficacy of the treatment.
• the JNK Inhibitor and optionally the prophylactic or therapeutic agent are administered in a cycle of less than about 3 weeks, about once every two weeks, about once every 10 days or about once every week.
• One cycle can comprise the administration of a JNK Inhibitor and optionally the therapeutic or prophylactic agent by infusion over about 90 minutes every cycle, about 1 hour every cycle, about 45 minutes every cycle.
• Each cycle can comprise at least 1 week of rest, at least 2 weeks of rest, at least 3 weeks of rest.
• the number of cycles administered is from about 1 to about 12 cycles, more typically from about 2 to about 10 cycles, and more typically from about 2 to about 8 cycles.
• the JNK Inhibitor is administered in metronomic dosing regimens, either by continuous infusion or frequent administration without extended rest periods. Such metronomic administration can involve dosing at constant intervals without rest periods. Typically the JNK Inhibitors, are used at lower doses. Such dosing regimens encompass the chronic daily administration of relatively low doses for extended periods of time. In preferred embodiments, the use of lower doses can minimize toxic side effects and eliminate rest periods.
• the JNK Inhibitor is delivered by chronic low-dose or continuous infusion ranging from about 24 hours to about 2 days, to about 1 week, to about 2 weeks, to about 3 weeks to about 1 month to about 2 months, to about 3 months, to about 4 months, to about 5 months, to about 6 months.
• courses of treatment are administered concurrently to a patient, i.e., individual doses of the therapeutic or prophylactic agent are administered separately yet within a time interval such that the JNK Inhibitor can work together with the therapeutic or prophylactic agent.
• one component can be administered once per week in combination with the other components that can be administered once every two weeks or once every three weeks.
• the dosing regimens are carried out concurrently even if the therapeutics are not administered simultaneously or during the same day.
• the prophylactic and/or therapeutic agent can act additively or, more preferably, synergistically with the JNK Inhibitor, hi one embodiment, a JNK Inhibitor is admimstered concurrently with one or more therapeutic or prophylactic agents in the same pharmaceutical composition. In another embodiment, a JNK Inhibitor is administered concurrently with one or more therapeutic or prophylactic agents in separate pharmaceutical compositions. In still another embodiment, a JNK Inhibitor is administered prior to or subsequent to administration of a therapeutic or prophylactic agent.
• the invention contemplates administration of a JNK Inhibitor and a prophylactic or therapeutic agent by the same or different routes of administration, e.g., oral and parenteral.
• the prophylactic or therapeutic agent when a JNK Inhibitor is administered concurrently with a prophylactic or therapeutic agent that potentially produces adverse side effects including, but not limited to, toxicity, can advantageously be administered at a dose that falls below the threshold that the adverse side effect is elicited.
• compositions comprising a JNK Inhibitor include bulk-drug compositions useful in the manufacture of pharmaceutical compositions (e.g., impure or non-sterile compositions) and pharmaceutical compositions (i.e., compositions that are suitable for administration to a patient) which can be used in the preparation of unit dosage forms.
• Such compositions optionally comprise a prophylactically or therapeutically effective amount of a prophylactic and/or therapeutic agent disclosed herein or a combination of those agents and a pharmaceutically acceptable carrier.
• compositions of the invention comprise a prophylactically or therapeutically effective amount of JNK Inhibitor and another therapeutic or prophylactic agent, and a pharmaceutically acceptable carrier.
• the term "pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
• carrier refers to a diluent, adjuvant, excipient, or vehicle with which a JNK Inhibitor is administered.
• Such pharmaceutical vehicles can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
• the pharmaceutical vehicles can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like.
• auxiliary, stabilizing, thickening, lubricating and coloring agents can be used.
• the pharmaceutically acceptable vehicles are preferably sterile.
• Water can be the vehicle when the JNK Inhibitor is administered intravenously.
• Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid vehicles, particularly for mjectable solutions.
• Suitable pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propyleneglycol, water, ethanol and the like.
• excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propyleneglycol, water, ethanol and the like.
• the present compositions if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
• compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained- release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
• the pharmaceutically acceptable vehicle is a capsule (see e.g., U.S. Patent No. 5,698,155).
• suitable pharmaceutical vehicles are described in "Remington's Pharmaceutical Sciences" by E.W. Martin, hi a preferred embodiment, the JNK Inhibitor and optionally the a therapeutic or prophylactic agent are formulated in accordance with routine procedures as pharmaceutical compositions adapted for intravenous administration to human beings.
• JNK Inhibitors for intravenous administration are solutions in sterile isotonic aqueous buffer.
• the compositions can also include a solubilizing agent.
• Compositions for intravenous administration can optionally include a local anesthetic such as lignocaine to ease pain at the site of the injection.
• the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
• the JNK Inhibitor is to be administered by infusion, it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline.
• an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
• compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example.
• Orally administered compositions can contain one or more optional agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation.
• sweetening agents such as fructose, aspartame or saccharin
• flavoring agents such as peppermint, oil of wintergreen, or cherry
• coloring agents such as peppermint, oil of wintergreen, or cherry
• preserving agents to provide a pharmaceutically palatable preparation.
• the compositions can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time.
• Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for an orally administered JNK Inhibitor, hi these later platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture.
• These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations.
• a time delay material such as glycerol monostearate or glycerol stearate can also be used.
• Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Such vehicles are preferably of pharmaceutical grade.
• the effect of the JNK Inhibitor can be delayed or prolonged by proper formulation.
• a slowly soluble pellet of the JNK Inhibitor can be prepared and incorporated in a tablet or capsule.
• the technique can be improved by making pellets of several different dissolution rates and filling capsules with a mixture of the pellets. Tablets or capsules can be coated with a film which resists dissolution for a predictable period of time. Even the parenteral preparations can be made long-acting, by dissolving or suspending the compound in oily or emulsified vehicles which allow it to disperse only slowly in the serum.
• compositions for use in accordance with the present invention can be formulated in conventional manner using one or more physiologically acceptable carriers or excipients.
• the JNK Inhibitor and optionally the therapeutic or prophylactic agent and their physiologically acceptable salts and solvates can be formulated into pharmaceutical compositions for administration by inhalation or insufflation (either through the mouth or the nose) or oral, parenteral or mucosol (such as buccal, vaginal, rectal, sublingual) administration.
• parenteral or mucosol such as buccal, vaginal, rectal, sublingual
• local or systemic parenteral administration is used.
• the pharmaceutical compositions can take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. , magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate).
• binding agents e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
• fillers e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate
• lubricants e.g. , magnesium stearate, talc or silica
• disintegrants e.g., potato
• Liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use.
• Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid).
• the preparations can also contain buffer salts, flavoring, coloring and sweetening agents as appropriate.
• Preparations for oral administration can be suitably formulated to give controlled release of the active compound.
• compositions can take the form of tablets or lozenges formulated in conventional manner.
• the pharmaceutical compositions for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
• a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
• the dosage unit can be determined by providing a valve to deliver a metered amount.
• Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
• the pharmaceutical compositions can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
• Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
• the pharmaceutical compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
• the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
• compositions can also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
• the pharmaceutical compositions can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
• the pharmaceutical compositions can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
• the invention also provides that a pharmaceutical composition is packaged in a hermetically sealed container such as an ampoule or sachette indicating the quantity, h one embodiment, the pharmaceutical composition is supplied as a dry sterilized lyophilized powder or water free concentrate in a hermetically sealed container and can be reconstituted, e.g., with water or saline to the appropriate concentration for administration to a patient.
• a pharmaceutical composition is packaged in a hermetically sealed container such as an ampoule or sachette indicating the quantity
• the pharmaceutical composition is supplied as a dry sterilized lyophilized powder or water free concentrate in a hermetically sealed container and can be reconstituted, e.g., with water or saline to the appropriate concentration for administration to a patient.
• radiation therapy agents such as radioactive isotopes can be given orally as liquids in capsules or as a drink.
• Radioactive isotopes can also be formulated for intravenous injection. The skilled oncologist can determine the preferred formulation and route of administration.
• compositions can, if desired, be presented in a pack or dispenser device that can contain one or more unit dosage forms containing the active ingredient.
• the pack can for example comprise metal or plastic foil, such as a blister pack.
• the pack or dispenser device can be accompanied by instructions for administration.
• the pack or dispenser contains one or more unit dosage forms containing no more than the recommended dosage formulation as determined in the Physician 's Desk Reference (56 l ed. 2002, herein incorporated by reference in its entirety).
• Methods of administering a JNK Inhibitor and optionally a therapeutic or prophylactic agent include, but are not limited to, parenteral administration (e.g., infradermal, intramuscular, infraperitoneal, intravenous and subcutaneous), epidural, and mucosal (e.g., intranasal, rectal, vaginal, sublingual, buccal or oral routes), hi a specific embodiment, the JNK Inhibitor and optionally the prophylactic or therapeutic agents are administered intramuscularly, intravenously, or subcutaneously.
• the JNK Inhibitor and optionally the prophylactic or therapeutic agent can also be administered by infusion or bolus injection and can be administered together with other biologically active agents.
• Administration can be local or systemic.
• the JNK Inhibitor and optionally the prophylactic or therapeutic agent and their physiologically acceptable salts and solvates can also be administered by inhalation or insufflation (either through the mouth or the nose).
• inhalation or insufflation either through the mouth or the nose.
• local or systemic parenteral administration is used.
• administration can be by direct injection at the site (or former site) of an atherosclerotic plaque tissue.
• Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant.
• the JNK Inhibitor can be formulated as a suppository, with traditional binders and vehicles such as triglycerides.
• the JNK Inhibitor can be delivered in a vesicle, in particular a liposome (see Langer, 1990, Science 249:1527-1533; Treat et al, in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid.).
• the JNK Inhibitor can be delivered in a controlled release system, hi one embodiment, a pump can be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref Biomed. Eng.
• polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Florida (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J. Macromol. Sci. Rev. Macromol. Chem. 23:61; see also Levy et al, 1985, Science 228 : 190; During et al. , 1989, Ann. Neurol.
• a controlled-release system can be placed in proximity of the target of the JNK Inhibitor, e.g., the liver, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)).
• Other controlled-release systems discussed in the review by Langer, 1990, Science 249: 1527-1533) can be used.
• the amount of the JNK Inhibitor that is effective in the treatment or prevention of disease-related wasting can be determined by standard research techniques.
• the dosage of the JNK Inhibitor which will be effective in the treatment or prevention of disease-related wasting can be determined by administering the JNK Inhibitor to an animal in a model such as, e.g., the animal models known to those skilled in the art.
• in vitro assays can optionally be employed to help identify optimal dosage ranges. Selection of a particular effective dose can be determined (e.g., via clinical trials) by a skilled artisan based upon the consideration of several factors which will be known to one skilled in the art. Such factors include the disease to be treated or prevented, the symptoms involved, the patient's body mass, the patient's immune status and other factors known by the skilled artisan.
• the precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the disease-related wasting, and should be decided according to the judgment of the practitioner and each patient's circumstances.
• Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
• the dose of a JNK Inhibitor to be administered to a patient is rather widely variable and can be subject to independent judgment. It is often practical to administer the daily dose of a JNK Inhibitor at various hours of the day. However, in any given case, the amount of a JNK Inhibitor administered will depend on such factors as the solubility of the active component, the formulation used, patient condition (such as weight), and/or the route of administration.
• the general range of effective amounts of the JNK Inhibitor alone or in combination with the prophylactic or therapeutic agent(s) are from about 0.001 mg/day to about 1000 mg/day, more preferably from about 0.001 mg/day to 750 mg/day, more preferably from about 0.001 mg/day to 500 mg/day, more preferably from about 0.001 mg/day to 250 mg/day, more preferably from about 0.001 mg/day to 100 mg/day, more preferably from about 0.001 mg/day to 75 mg/day, more preferably from about 0.001 mg/day to 50 mg/day, more preferably from about 0.001 mg/day to 25 mg/day, more preferably from about 0.001 mg/day to 10 mg/day, more preferably from about 0.001 mg/day to 1 mg/day.
• the amount of compound administered will depend on such factors as the solubility of the active component, the formulation used, subject condition (such as weight), and/or the route of administration.
• the dosage administered to a patient is typically 0.1 mg/kg to 100 mg/kg of the patient's body weight.
• the dosage administered to a patient is between 0.1 mg/kg and 20 mg/kg of the patient's body weight, more preferably 1 mg/kg to 10 mg/kg of the patient's body weight.
• human and humanized antibodies have a longer half-life within the human body than antibodies from other species due to the immune response to the foreign polypeptides. Thus, lower dosages of human antibodies and less frequent administration is often possible.
• the invention provides for any method of administrating lower doses of known agents (e.g., appetite stimulants) than previously thought to be useful for the prevention or treatment of disease-related wasting.
• the invention provides a pharmaceutical pack or kit comprising one or more containers containing a JNK Inhibitor and optionally one or more other prophylactic or therapeutic agents useful for the treatment of HIV, AIDS, cancer, end-stage renal disease, kidney failure, chronic heart disease, obstructive pulmonary disease, chronic infectious diseases (e.g., osteoarthritis and bacterial endocarditis), chronic inflammatory diseases (e.g., scleroderma and mixed connective tissue disease) or tuberculosis.
• the invention also provides a pharmaceutical pack or kit comprising one or more containers containing one or more of the ingredients of the pharmaceutical compositions.
• Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration; or instructions for the composition's use.
• kits that can be used in the above methods.
• a kit comprises a JNK Inhibitor, in one or more containers, and optionally one or more other prophylactic or therapeutic agents useful for the treatment of HIV, AIDS, cancer, end-stage renal disease, kidney failure, chronic heart disease, obstructive pulmonary disease, chronic infectious diseases (e.g., osteoarthritis and bacterial endocarditis), chronic inflammatory diseases (e.g., scleroderma and mixed connective tissue disease) or tuberculosis, in one or more containers.
• a JNK Inhibitor in one or more containers, and optionally one or more other prophylactic or therapeutic agents useful for the treatment of HIV, AIDS, cancer, end-stage renal disease, kidney failure, chronic heart disease, obstructive pulmonary disease, chronic infectious diseases (e.g., osteoarthritis and bacterial endocarditis), chronic inflammatory diseases (e.g., scleroderma and mixed connective tissue disease) or tuberculosis, in
• JNK INHIBITOR ACTIVITY ASSAYS The ability of a JNK Inhibitor to inhibit JNK and accordingly, to be useful for the treatment or prevention of disease-related wasting, can be demonstrated using one or more of the following assays.
• IC 50 values were calculated as the concentration of 5-amino-anthra(9, 1 -cc.) ⁇ soth ⁇ azol-6-one at which the c-Jun phosphorylation was reduced to 50% of the control value.
• Compounds that inhibit JNK preferably have an IC 50 value ranging 0.01 - 10 ⁇ M in this assay.
• 5-Amino- anthra(9,l-c_ )isothiazol-6-one has an IC 50 according to this assay of 1 ⁇ M for JNK2 and 400 nM for JNK3.
• the measured IC5 0 value for 5-amino-anthra(9,l-c_ )isothiazol-6-one shows some variability due to the limited solubility of 5-amino-anthra(9,l-c ⁇ )isothiazol-6-one in aqueous media. Despite the variability, however, the assay consistently does show that 5-amino-anthra(9,l-c_ ⁇ isothiazol-6-one inhibits JNK.
• This assay demonstrates that 5-amino-anthra(9,l-c_ )isothiazol-6-one, an illustrative JNK Inhibitor, inhibits JNK2 and JNK3 and, accordingly, is useful for treating or preventing disease-related wasting.
• This assay shows that 5-amino-anthra(9,l-c_t)isothiazol-6-one, an illustrative JNK Inhibitor, selectively inhibits JNK relative to other protein kinases and, accordingly, is a selective JNK Inhibitor. Therefore, 5-amino-anthra(9,l-c_/)isothiazol-6-one, an illustrative JNK Inhibitor, is useful for selectively treating or preventing disease-related wasting.
• Jurkat T-cell IL-2 Production Assay Jurkat T cells (clone E6- 1) were purchased from the American Type Culture
• Compound stock (20 mM) was diluted in growtn media and added to each well as a lOx concentrated solution in a volume of 25 ⁇ L, mixed, and allowed to pre- incubate with cells for 30 minutes.
• the compound vehicle (dimethylsulfoxide) was maintained at a final concentration of 0.5% in all samples.
• the cells were activated with PMA (phorbol myristate acetate, final concentration 50 ng/mL) and PHA (phytohemagglutinin, final concentration 2 ⁇ g/mL).
• PMA and PHA were added as a lOx concentrated solution made up in growth media and added in a volume of 25 ⁇ L per well. Cell plates were cultured for 10 hours.
• the measured IC 50 value for 5-amino- anthra(9,l-c_f)isothiazol-6-one shows some variability due to the limited solubility of 5-amino-anthra(9, 1 -c_ )isothiazol-6-one in aqueous media. Despite the variability, however, the assay consistently does show that 5- ⁇ amino-anthra(9,l-c_f)isothiazol-6-one inhibits JNK.
• This assay shows that 5-amino-anthra(9,l-c_/)isothiazol-6-one, an illustrative JNK Inhibitor, inhibits IL-2 production in Jurkat T-cells and accordingly inhibits JNK. Therefore, 5-amino-anthra(9,l-c_ )isothiazol-6-one, an illustrative JNK Inhibitor, is useful for treating or preventing disease-related wasting.
• 5-amino-anthra(9,l-c_ )isothiazol-6-one protects rat ventral mesencephalan neurons from the toxic effects of 6-OHDA. Accordingly, 5-amino- anthra(9,l-c_/)isothiazol-6-one, an illustrative JNK Inhibitor, is useful for treating or preventing disease-related wasting.
• 5-Amino-anthra(9,l-C-f)isothiazol-6-one was administered intravenously (10 mg/kg) into the veins of Sprague-Dawley rats. After 2 hr, blood samples were obtained from the animals and their vascular systems were perfused with approximately 100 mL of saline to rid their brains of blood. The brains were removed from the animals, weighed, and homogenized in a 50 mL conical tube containing 10 equivalents (w/v) of methanol/saline (1:1) using a Tissue Tearer (Fischer Scientific).
• the homogenized material was extracted by adding 600 ⁇ L of cold methanol to 250 ⁇ L of brain homogenate vortexed for 30 sec and subjected to centrifugation for 5 min. After centrifugation, 600 ⁇ L of the resulting supernatant was transferred to a clean tube and evaporated at room temperature under reduced pressure to provide a pellet. The resulting pellet was reconstituted in 250 ⁇ L of 30% aqueous methanol to provide a brain homogenate analysis sample.
• a plasma analysis sample was obtained using the brain homogenate analysis sample procedure described above by substituting plasma for brain homogenate.
• Standard plasma samples and standard brain homogenate samples containing known amounts of 5-amino-anthra(9,l-c )isothiazol- 6-one were also prepared by adding 5 ⁇ L of serial dilutions (50: 1) of a solution of 5-amino- anthra(9,l-c_ )isothiazol-6-one freshly prepared in cold ethanol to 250 ⁇ L of control rat plasma (Bioreclamation of Hicksville, NY) or control brain homogenate.
• the standard plasma samples and standard brain homogenate samples were then subjected to the same extraction by protein precipitation, centrifugation, evaporation, and reconstitution procedure used for the brain homogenate to provide brain homogenate standard analysis samples and plasma standard analysis samples.
• the brain homogenate analysis samples, plasma analysis samples, and standard analysis samples were analyzed and compared using HPLC by injecting 100 ⁇ L of a sample onto a 5 ⁇ m C-18 Luna column (4.6 mm x 150 mm, commercially available from Phenomenex of Torrance, CA) and eluting at 1 mL/min with a linear gradient of 30% aqueous acetonitrile containing 0.1% trifluoroacetic acid to 90% aqueous acetonitrile containing 0.1% trifluoroacetic acid over 8 minutes and holding at 90% aqueous acetonitrile containing 0.1% trifluoroacetic acid for 3 min. with absorbance detection at 450 run.
• results from this study show that 5-amino-anthra(9,l-c_/)isotl_iazol-6-one, following intravenous administration, crosses the blood-brain barrier to a significant extent, hi particular, brain- drug concentrations were approximately 65 nmole/g and plasma concentrations were approximately 7 ⁇ M at 2 hr post-dose, resulting in a brain-plasma concentration ratio of approximately 9-fold (assuming 1 g of brain tissue is equivalent to 1 mL of plasma).
• This example shows that 5-amino-anthra(9,l-c_ )isothiazol-6-one, an illustrative JNK Inhibitor, has enhanced ability to cross the blood-brain barrier, h addition, this example shows that the JNK Inhibitors, in particular 5-amino-anthra(9,l-c_/)isothiazol-6-one, can cross the blood-brain barrier when administered to a patient.

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