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WO2008150899A1 - Thérapies combinées pour le traitement du cancer et des maladies inflammatoires - Google Patents

Thérapies combinées pour le traitement du cancer et des maladies inflammatoires Download PDF

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WO2008150899A1
WO2008150899A1 PCT/US2008/065132 US2008065132W WO2008150899A1 WO 2008150899 A1 WO2008150899 A1 WO 2008150899A1 US 2008065132 W US2008065132 W US 2008065132W WO 2008150899 A1 WO2008150899 A1 WO 2008150899A1
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substituted
heterocycle
aryl
heteroaryl
alkyl
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Haian Fu
Dennis C. Liotta
Shala L. Thomas
James P. Snyder
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Emory University
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Emory University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to combinations of compounds useful for the treatment of cancer and inflammatory diseases.
  • the combination provides a synergistic effect allowing for improved treatments.
  • Curcumin (diferuloylmethane), the aromatic yellow pigment in curry, turmeric and mustard, has been shown to have anti-angiogenic, anti-tumor, and anti-tumor promoting properties. In addition, curcumin exhibits numerous other therapeutic effects, including anti-oxidative, anti-thrombotic, anti-inflammatory, anti-cholesterol and anti-diabetic properties. Curcumin has particularly demonstrated great potential as a chemopreventative and therapeutic agent due to its ability to negatively modulate cancer-related biomarkers and inhibit the proliferation of tumor cells but retain pharmacological safety. This anti-cancer activity has been in part attributed to the inhibition of nuclear factor-kappa B (NF- ⁇ B), a transcription factor that controls the expression of genes involved in cellular survival, the anti-apoptotic machinery, and the inflammatory response.
  • NF- ⁇ B nuclear factor-kappa B
  • curcumin Despite the broad activity of curcumin, its in vivo activity can be limited due to its rapid excretion. Recently, various curcumin-derived analogs and derivatives have been developed having similar activity to curcumin; however, these synthetic compounds have been shown in various models to have greater potency both in vitro and in vivo. See, for example, U.S. Patent No. 6,664,272 and U.S. Patent No. 7,371,766, both of which are incorporated herein by reference in their entirety.
  • curcumin analogs have also been demonstrated to be anti-NF- kB agents, although the mechanism may differ. Many intercellular pathways cross talk in order to transduce highly regulated cellular signals, and there are multiple hypotheses around the interplay between the NF -kB pathway and other cell signaling events. Published reports include the establishment of links between NF -kB and the mitogen-activated protein kinase (MAPK) pathways in terms of NF-kB regulation and activity. See Tang G, et al. "Inhibition of JNK activation through NF-kappaB target genes", Nature, 414 (2001): 313-7; Vanden Berghe W, et al.
  • MAPK mitogen-activated protein kinase
  • the MAPK pathways are three-tiered kinase pathways, which: 1) are activated upon stimulation with growth factors; 2) signal to transcription factors and other protein kinases; and 3) ultimately elicit some biological response.
  • the three major MAPK family members include p38 MAPK along with the extracellular-regulated kinase (ERK) and the c-jun N-terminal kinase (JNK). Activation of ERK has been widely accepted to lead to cell growth and differentiation while JNK and p38 MAPK are considered stress-induced kinases since they not only can respond to mitogens but also a variety of cellular stresses including inflammatory cytokines. See Raingeaud J, et al.
  • p38 MAPK is selectively activated in homogenates of non-small cell lung tumors compared with normal tissue and thus, may be involved in malignant cell growth or transformation at least in this particular cancer. See Greenberg AK, et al. "Selective p38 activation in human non-small cell lung cancer", Am. J. Respir. Cell. MoI. Biol. 26 (2002): 558-64, which is incorporated herein by reference. Research on the development and use of p38 MAPK inhibitors is ongoing, particularly in relation to rheumatoid arthritis, skin disorders, and other inflammatory diseases. For example, p38 MAPK inhibitors have been found to inhibit the production of pro-inflammatory cytokines and therefore inhibit the propagation of the inflammatory response. While there are numerous reported treatments for various types of cancer and inflammatory diseases, many have toxic side effects. Thus, there is a need for improved treatments for cancer and inflammatory diseases with high efficacy and reduced clinical toxicity.
  • the present invention is directed to combinations of NF- ⁇ B (nuclear factor- kappa B) inhibiting compounds and p38 MAPK (mitogen activated protein kinase) inhibiting compounds, compositions providing the combinations, and methods of using the combinations.
  • NF- ⁇ B nuclear factor- kappa B
  • MAPK mitogen activated protein kinase
  • Such combinations are useful in the treatment of multiple diseases and conditions, including but not limited cancers and inflammatory conditions.
  • the combinations can be useful for decreasing the toxic effect of cancer therapies.
  • the combinations can also be useful for decreasing the toxic effect of inflammatory disease therapies.
  • the combinations can further be useful for increasing the effectiveness of cancer treatments and/or inflammatory condition treatments.
  • specific NF- ⁇ B inhibitors e.g., curcumin analogs
  • the combination of an NF -KB inhibitor with a p38 MAPK inhibitor according to the invention can be effective to increase the activity of the NF -KB inhibitor.
  • Such increase particularly exceeds any additive effect of the combination and actually exhibits synergism (i.e., an increase in activity that exceeds any effect that may be expected from combining the compounds).
  • the present invention provides combinations of NF- ⁇ B inhibiting compounds and p38 MAPK inhibiting compounds.
  • the combinations may be formed of a single NF -KB inhibitor and a single p38 inhibitor, a single NF- ⁇ B inhibitor and a plurality of p38 inhibitors, a plurality of NF- ⁇ B inhibitors and a single p38 inhibitor, or a plurality of NF- ⁇ B inhibitors and a plurality of p38 inhibitors.
  • the active agents forming the combination may also be provided as one or more pharmaceutical compositions (e.g., in combination with pharmaceutically acceptable carrier). The type of pharmaceutical composition can vary depending upon the desired use.
  • the invention encompasses a single composition formed with the NF -KB inhibitor(s) and the p38 inhibitor(s).
  • the invention also encompasses multiple compositions (e.g., a composition formed with the NF- ⁇ B inhibitor(s) and a separate composition formed with the p38 inhibitor(s)).
  • the combination of the invention can be administered in a variety of embodiments.
  • the NF- ⁇ B inhibitor and the p38 inhibitor could be administered simultaneously, either in the same composition or in separate compositions administered at the same time or in very close proximity of time (e.g., within only a few minutes).
  • the active agents could also be administered sequentially (e.g., administration of one composition comprising either the NF -KB inhibitor or the p38 inhibitor followed thereafter by a composition comprising the remaining active agent.
  • administration of one composition comprising either the NF -KB inhibitor or the p38 inhibitor followed thereafter by a composition comprising the remaining active agent.
  • a skilled person would recognize the variety of methods whereby the active agents could be administered depending upon the final desired effect of the combination.
  • the methods of treatment described herein may exhibit optimized effectiveness arising from separate administration of the NF -KB inhibitor and the p38 inhibitor spaced over a specific time frame, and the present invention would encompass any such methods of administration.
  • the NF -KB inhibiting compound may be chosen from a wide variety of compounds, as described herein.
  • the NF- ⁇ B inhibiting compound is a compound that performs one or more of the following functions: inhibits activity of NF- ⁇ B directly, inhibits activation of the NF -KB pathway, increases the sensitivity of NF- ⁇ B to conventional chemotherapy, or inhibits phosphorylation or degradation of naturally occurring NF- ⁇ B inhibitors.
  • the NF- ⁇ B inhibiting compound is a curcumin analog.
  • the curcumin analog can be a compound according to the structure of Formula (1)
  • Ar is an optionally substituted ring structure comprising 5-20 ring atoms and is selected from the group consisting of aryl, substituted aryl, heteroaryl having 1 -3 heteroatoms selected from O, S, and N, substituted heteroaryl, heterocycle having 1 -3 heteroatoms selected from O, S, and N, and substituted heterocycle; any substituent on Ar is selected from the group consisting of halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, hydroxyl, CF 3 , alkenyl, alkynyl, aryl, substituted aryl, alkaryl, arylalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, amino, alkylamino, dialkylamino, carboxylic acid, carboxylic ester, carboxamide, nitro, cyano, azide, alkylcarbonyl, acyl, trialkylammonium, NH- aa, and O-aa
  • A is selected from the group consisting of:
  • n 1-8;
  • X is selected from the group consisting of -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, O, -0-NR 3 -, S, SO, SO 2 , -S-S-, NR 3 , and -NR 3 -NR 3 -;
  • Q is NH or NR 3 ;
  • Vi- 4 are each independently OH, OR 2 , or halogen
  • R 1 , R 2 , and R 3 are independently H, alkyl, substituted alkyl, alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, acyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl; the dashed lines indicate the presence of optional double bonds; and
  • L is the point of bonding of A to the compound structure; as well as pharmaceutically acceptable esters, amides, salts, solvates, enantiomers, and prodrugs thereof.
  • curcumin analogs could be chosen from the group encompassed by Formula (1).
  • a curcumin analog useful as an NF- ⁇ B inhibiting compound according to the invention may be a compound according to the structure of Formula (3)
  • X is optional and is selected from the group consisting of -CH 2 -, -CH 2 -CH 2 -, - CH 2 -CH 2 -CH 2 -, O, -O-NR 3 -, S, SO, SO 2 , -S-S-, NR 3 , and -NR 3 -NR 3 -;
  • R 3 is H, alkyl, substituted alkyl, alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, acyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl; each Yi and Y 2 is optional and is independently selected from the group consisting of halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, hydroxyl, CF 3 , alkenyl, alkynyl, aryl, substituted aryl, alkaryl, arylalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, amino, alkylamino, dialkylamino, carboxylic acid, carboxylic ester, carboxamide, nitro, cyano, azide, alkylcarbonyl, acyl, trialkylammonium, NH-aa, and O-aa, where a
  • Formula (3) wherein X is NR 3 , R 3 is H, alkyl, substituted alkyl, or alkoxy, Yi is absent, and Y 2 is halo, hydroxyl, alkoxy, or CF 3 .
  • An especially useful curcumin analog in the inventive combination is the compound provided in Formula (6).
  • the p38 MAPK inhibiting compounds useful according to the invention may also encompass a large variety of compounds. Many p38 inhibiting compounds have been identified and may have great diversity of structure. The synergistic effect arising from the combination of the invention, however, is believed to extend across the diversity of structure and arise from the activity of the compounds, which is not necessarily limited by structure.
  • p38 inhibitors useful in the inventive combinations may be chosen from the following groups of compounds having multiple representatives known to exhibit p38 inhibiting activity: a) l-aryl-2- pyridinyl/pyrimidinyl heterocycles; b) 2-methoxypyrimidinylimidazoles; c) pyrazoles; d) oxazoles; e) thiazoles; f) compounds formed of a central heterocycle with vicinal groups selected from benzoimidazoles, benzothiazoles, and quinolines; g) compounds formed of a 6-membered heterocyclic cores selected from the group of pyridazines, pyrazines, pyridines; h) compounds formed of a fused bicyclic heterocyclic core that is an imidazopyrimidine; i) compounds formed of ketone-containing compounds selected from benzophenones and pyrazoles; j) cyclic ureas; k) piperazine-based indole
  • a p38 MAPK inhibiting compound useful according to the invention may be defined by a variety of generic structures.
  • useful p38 inhibitors may include: structures according to Formula (23)
  • Het indicates a 5-membered heterocycle with 1-3 ring carbons replaced with an atom selected from N, O, and S or a 6-membered heterocycle with 1-4 ring carbons replaced with an atom selected from N, O, or S; each Ar is optionally substituted and is independently a ring structure comprising 5-20 ring atoms selected from the group consisting of aryl, substituted aryl, heteroaryl having 1 -3 heteroatoms selected from O, S, and N, substituted heteroaryl, heterocycle having 1-3 heteroatoms selected from O, S, and N, and substituted heterocycle; a Z substituent may be present on any ring atom not bonded to an Ar group;
  • Z and any substituent on Ar are independently selected from the group consisting of H, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, hydroxyl, carbonyl, CF 3 , alkenyl, alkynyl, aryl, substituted aryl, alkaryl, arylalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, amino, alkylamino, dialkylamino, carboxylic acid, carboxylic ester, carboxamide, nitro, cyano, amide, imide, azide, alkylcarbonyl, acyl, sulfonyl, alkylsulfonyl, sulf ⁇ nyl, alkylsulf ⁇ nyl, sulfenyl, alkylsulfenyl, and trialkylammonium, or two Z groups may be combined to form a five or six-membered fused ring with Het, optionally including
  • Het indicates a 5-membered heterocycle with 1-3 ring carbons replaced with an atom selected from N, O, or S;
  • A is a heteroatom selected from N, O, or S; each Z is independently selected from the group of H, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, hydroxyl, carbonyl, CF 3 , alkenyl, alkynyl, aryl, substituted aryl, alkaryl, arylalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, amino, alkylamino, dialkylamino, carboxylic acid, carboxylic ester, carboxamide, nitro, cyano, amide, imide, azide, alkylcarbonyl, acyl, sulfonyl, alkylsulfonyl, sulf ⁇ nyl, alkylsulfinyl, sulfenyl, alkylsulfenyl, and trialkylammonium, or two Z groups may be combined to form a five or six-membered fused ring
  • each Ar is optionally substituted and is independently a ring structure comprising 5-20 ring atoms and is selected from the group consisting of aryl, substituted aryl, heteroaryl having 1-3 heteroatoms selected from O, S, and N, substituted heteroaryl, heterocycle having 1-3 heteroatoms selected from O, S, and N, and substituted heterocycle;
  • Ri and R 2 are optionally substituted and are independently selected from the group consisting of halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, hydroxyl, carbonyl, CF 3 , alkenyl, alkynyl, aryl, substituted aryl, alkaryl, arylalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, amino, alkylamino, dialkylamino, carboxylic acid, carboxylic ester, carboxamide, nitro, cyano, amide, imide, azide, alkylcarbonyl, acyl, sulfonyl, alkylsulfonyl, sulf ⁇ nyl, alkylsulf ⁇ nyl, sulfenyl, alkylsulfenyl, and trialkylammonium;
  • X is -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, O, -0-NR 4 -, S, SO, SO 2 , -S-S-, NR 4 , and -NR4-NR4-;
  • R 4 is H, alkyl, substituted alkyl, alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, acyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl;
  • R 1 , or R 2 are independently selected from the group consisting of H, halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, hydroxyl, carbonyl, CF 3 , alkenyl, alkynyl, aryl, substituted aryl, alkaryl, arylalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, amino, alkylamino, dialkylamino, carboxylic acid, carboxylic ester, carboxamide, nitro, cyano, amide, imide, azide, alkylcarbonyl, acyl, sulfonyl, alkylsulfonyl, sulf ⁇ nyl, alkylsulfinyl, sulfenyl, alkylsulfenyl, and trialkylammonium; as well as pharmaceutically acceptable esters, amides, salts, solvates, enanti
  • Nc is a nitrogen atom that may be replaced by a carbon atom
  • each Z is independently selected from the group consisting of halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, hydroxyl, carbonyl, CF 3 , alkenyl, alkynyl, aryl, substituted aryl, alkaryl, arylalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, amino, alkylamino, dialkylamino, carboxylic acid, carboxylic ester, carboxamide, nitro, cyano, amide, imide, azide, alkylcarbonyl, acyl, sulfonyl, alkylsulfonyl, sulfinyl, alkylsulfinyl, sulfenyl, alkylsulfenyl, and trialkylammonium, or two Z groups may be combined to form a five or six-membere
  • each Ar is optionally substituted and is independently a ring structure comprising 5-20 ring atoms and is selected from the group consisting of aryl, substituted aryl, heteroaryl having 1-3 heteroatoms selected from O, S, and N, substituted heteroaryl, heterocycle having 1-3 heteroatoms selected from O, S, and N, and substituted heterocycle; and any substituents on Ar are independently selected from the group consisting of halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, hydroxyl, carbonyl, CF 3 , alkenyl, alkynyl, aryl, substituted aryl, alkaryl, arylalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, amino, alkylamino, dialkylamino, carboxylic acid, carboxylic ester, carboxamide, nitro, cyano, amide, imide, azide, alkylcarbonyl, acyl, sulf
  • p38 MAPK inhibiting compounds for use in the invention may be chosen from specific structures. Examples of such compounds are described herein by Formulas (26) - (55), (58) - (84), (86) - (97), and (99) - (153). Any of these particular p38 inhibiting compounds could be combined with an NF- ⁇ B inhibitor, as described herein, particularly for use in the various methods of the invention.
  • a combination according to the invention comprises an NF -KB inhibiting compound that is a curcumin analog according to the structure of Formula (6) and a p38 MAPK inhibiting compound according to any of the structures of Formulas (26) - (55), (58) - (84), (86) - (97), and (99) - (153).
  • the present invention provides a variety of methods of treatment.
  • the invention provides a method of treating cancer.
  • the invention provides a combination of an NF- ⁇ B inhibiting compound and a p38 MAPK inhibiting compound for use in a method of treating cancer.
  • the method may comprise the use of any combination of NF- ⁇ B inhibitors and p38 inhibitors described herein.
  • the invention provides a method of treating an inflammatory disease or condition.
  • the invention provides a combination of an NF- ⁇ B inhibiting compound and a p38 MAPK inhibiting compound for use in a method of treating an inflammatory condition.
  • the method may comprise the use of any combination of NF- ⁇ B inhibitors and p38 inhibitors described herein.
  • the invention provides methods for increasing the therapeutic activities of NF- ⁇ B inhibitors.
  • various curcumin analogs exhibit activity for treating cancer and inflammatory conditions.
  • the present invention provides methods for increasing such activity.
  • the invention provides a method for enhancing the anti-cancer activity of an NF- ⁇ B inhibitor, and particularly curcumin analogs.
  • the method may comprise administering a p38 MAPK inhibiting compound in combination with the NF- ⁇ B inhibitor, thus enhancing the activity of the NF -KB inhibitor.
  • the invention can be directed to a p38 MAPK inhibiting compound for use in a method of enhancing the anti-cancer activity of a curcumin analog, the method comprising administering the p38 MAPK inhibiting compound in combination with the curcumin analog.
  • the administration of the combination can vary (e.g., can be simultaneous in the same or different compositions or may be sequential).
  • the enhanced activity of the NF- ⁇ B inhibitor can vary. It is believed that the synergistic effect exhibited by the inventive combinations is conserved across a wide array of NF- ⁇ B inhibitor activities, a wide array of NF- ⁇ B inhibitor compounds, and a wide array of p38 inhibitor compounds.
  • the inventive methods are useful for increasing the activity of the NF- KB inhibitor for inhibiting growth of cancer cells.
  • the inventive methods are useful for increasing the activity of the NF- ⁇ B inhibitor for inducing apoptosis of cancer cells.
  • FIG. 1 is a graph illustrating cell viability over time of A549 lung cancer cells treated with curcumin or the curcumin analog EF24;
  • FIG. 2 is images of immunoblot assays of A549 lung cancer cells treated with curcumin or EF24 to evaluate activation of ERK, p38 MAPK, or JNK using phospho- specif ⁇ c antibodies for the Thr/Tyr activation motifs;
  • FIG. 3 A is a graph illustrating cell viability of A549 lung cancer cells treated with EF24 alone, SB203580 (SB80) alone, or a combination of EF24 and SB80 at varying concentrations;
  • FIG. 3B is a graph illustrating cell viability of A549 lung cancer cells treated with EF24 alone, SB202190 (SB90) alone, or a combination of EF24 and SB90 at varying concentrations;
  • FIG. 3 C is a graph comparing the ability of SB80 and SB90 at varying concentrations to affect viability of A549 lung cancer cells
  • FIG. 3D is images of a western blot of A549 lung cancer cells treated with EF24 and varying concentrations of SB80 to evaluate phosphorylation and protein expression of MAPKAPK-2 using specific antibodies;
  • FIGS. 4A and 4B are graphs illustrating growth inhibition of A549 lung cancer cells with treatment of EF24 alone and in combination with SB80 as measured by 48h SRB assay and graphed as a function of dose-response;
  • FIGS. 4C and 4D are graphs illustrating growth inhibition of A549 lung cancer cells with treatment of curcumin alone and in combination with SB80 as measured by 48h SRB assay and graphed as a function of dose-response;
  • FIG. 5A is images from immunoblot assays illustrating A549 lung cancer cells transfected with siRNA targeting p38 MAPK;
  • FIG. 5B provides two graphs illustrating levels of reduction of p38 and ERK expressed after transfection with the siRNA
  • FIG. 5C is a graph illustrating cell viability of cells transfected and then treated with EF24, SB80, or the combination of EF24 and SB80;
  • FIG. 6A is images illustration colony formation of A549 lung cancer cells 10 days after no treatment, treatment with SB80 alone, treatment with EF24 along, or treatment with the combination of EF24 and SB 80;
  • FIG. 6B is a graph illustrating the number of colonies formed based on the specified treatment
  • FIG. 7A is an illustration of cell cycle distribution for A549 lung cancer cells treated with EF24 and SB 80 and evaluated by flow cytometry to define the cycle cell distribution in comparison to the control (0.5% DMSO);
  • FIG. 7B is a graph illustrating the % of sub-Gl cells after no treatment, treatment with EF24, treatment with SB80, treatment with EF24 and SB80, treatment with curcumin, or treatment with curcumin and SB80;
  • FIG. 7 C is a graph illustrating the % of total cells undergoing apoptosis as a function of the specific treatment as evaluated using Western blot analysis of A549 lysates and using a specific antibody to evaluate the amount of full length and cleaved PARP;
  • FIG. 7D is an image from a Western blot analysis of A549 lung cancer cells treated with EF24, curcumin, SB80, or combinations thereof and evaluated for evidence of apoptosis; and FIG. 7E is a graph illustrating viability of A549 lung cancer cells pretreated with the caspase inhibitor zVAD-fmk for 1 hr before treatment with EF24, SB80, or combinations thereof.
  • the present invention is directed to combinations of compounds, pharmaceutical compositions providing the combinations, and methods of using the combinations and compositions for treating cancer and inflammatory diseases.
  • the combinations comprise NF-kB inhibiting compounds and/or p38 MAPK inhibiting compounds.
  • NF -KB inhibiting compound means any compound that inhibits activity of NF- ⁇ B directly, inhibits activation of the NF -KB pathway, increases the sensitivity of NF- ⁇ B to conventional chemotherapy, or inhibits phosphorylation or degradation of naturally occurring NF- ⁇ B inhibitors (e.g., naturally occurring inhibitory IKB proteins, such as I ⁇ B ⁇ , I ⁇ B ⁇ , I ⁇ B ⁇ , plO5, and plOO).
  • p38 MAPK inhibiting compound as used herein means any compound that inhibits activity of p38 MAPK either directly or indirectly.
  • alkyl as used herein means saturated straight, branched, or cyclic hydrocarbon groups.
  • alkyl refers to groups comprising 1 to 10 carbon atoms ("C 1-10 alkyl”).
  • alkyl refers to groups comprising 1 to 8 carbon atoms (“C 1-8 alkyl”), 1 to 6 carbon atoms (“C 1-6 alkyl”), or 1 to 4 carbon atoms ("C 1-4 alkyl”).
  • alkyl refers to methyl, trifluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3- methylpentyl, 2,2-dimethybutyl, and 2,3-dimethylbutyl.
  • Substituted alkyl refers to alkyl substituted with one or more non-interfering substituents, such as but not limited to halo (e.g., Cl, F, Br, and I); halogenated alkyl (e.g., CF 3 , 2-Br-ethyl, CH 2 F, CH 2 Cl, CH 2 CF 3 , or CF 2 CF 3 ); hydroxyl; amino; carboxylate; carboxamido; alkylamino; arylamino; alkoxy; aryl; aryloxy; nitro; cycloalkyl; acetylene; alkanoyloxy; ketone; azido; cyano; thio; sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate.
  • halo e.g., Cl, F, Br, and I
  • halogenated alkyl e.g., CF 3 , 2-Br
  • alkenyl as used herein means alkyl moieties wherein at least one saturated C-C bond is replaced by a double bond.
  • alkenyl refers to groups comprising 1 to 10 carbon atoms ("C 1-10 alkenyl”).
  • alkyl refers to groups comprising 1 to 8 carbon atoms (“C 1-8 alkenyl”), 1 to 6 carbon atoms (“C 1-6 alkenyl”), or 1 to 4 carbon atoms (“C 1-4 alkenyl”).
  • alkenyl can be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2- hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl.
  • alkynyl as used herein means alkyl moieties wherein at least one saturated C-C bond is replaced by a triple bond.
  • alkynyl refers to groups comprising 1 to 10 carbon atoms ("C 1-10 alkynyl”).
  • alkyl refers to groups comprising 1 to 8 carbon atoms (“C 1-8 alkynyl”), 1 to 6 carbon atoms (“C 1-6 alkynyl”), or 1 to 4 carbon atoms (“C 1-4 alkynyl”).
  • alkynyl can be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1- hexynyl, 2- hexynyl, 3 -hexynyl, 4-hexynyl, or 5 -hexynyl.
  • alkoxy as used herein means straight or branched chain alkyl groups linked by an oxygen atom (i.e., -O-alkyl or -alkyl-O-alkyl), wherein alkyl is as described above.
  • alkoxy refers to oxygen-linked groups comprising 1 to 10 carbon atoms ("C 1-10 alkoxy”).
  • alkoxy refers to oxygen-linked groups comprising 1 to 8 carbon atoms ("C 1-8 alkoxy"), 1 to 6 carbon atoms (“C 1-6 alkoxy”), or 1 to 4 carbon atoms ("C 1-4 alkoxy”).
  • heterocycle or “heterocyclic” as used herein means one or more rings of 5, 6 or 7 atoms with or without unsaturation or aromatic character and having at least one ring atom which is not carbon. Preferred heteroatoms include sulfur, oxygen, and nitrogen. Multiple rings may be fused, as in quinoline or benzofuran. "Substituted heterocycle” is heterocycle having one or more side chains formed from non-interfering substituents.
  • aryl as used herein means a stable monocyclic, bicyclic, or tricyclic carbon ring of up to 8 members in each ring, wherein at least one ring is aromatic as defined by the Huckel 4n+2 rule. Multiple aryl rings may be fused, and aryl rings may be fused or unfused with one or more cyclic hydrocarbon, heteroaryl, or heterocyclic rings. Exemplary aryl groups according to the invention include phenyl, naphthyl, tetrahydronaphthyl, and biphenyl.
  • the aryl group can be substituted with one or more non-interfering substituents, such as, for example, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate.
  • substituents such as, for example, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate.
  • heteroaryl as used herein means an aryl group containing from one or more (particularly one to four) non-carbon atom(s) (particularly N, O, or S) or a combination thereof, which heteroaryl group is optionally substituted at one or more carbon or nitrogen atom(s) with alkyl, -CF 3 , phenyl, benzyl, or thienyl, or a carbon atom in the heteroaryl group together with an oxygen atom form a carbonyl group, or which heteroaryl group is optionally fused with a phenyl ring.
  • Heteroaryl rings may also be fused with one or more cyclic hydrocarbon, heterocyclic, aryl, or heteroaryl rings.
  • Heteroaryl includes, but is not limited to, 5-membered heteroaryls having one hetero atom (e.g., thiophenes, pyrroles, furans); 5 membered heteroaryls having two heteroatoms in 1,2 or 1,3 positions (e.g., oxazoles, pyrazoles, imidazoles, thiazoles, purines); 5-membered heteroaryls having three heteroatoms (e.g., triazoles, thiadiazoles); 5-membered heteroaryls having 3 heteroatoms; 6-membered heteroaryls with one heteroatom (e.g., pyridine, quinoline, isoquinoline, phenanthrine, 5,6- cycloheptenopyridine); 6-membered heteroaryls with two heteroatoms (e.g., pyridazines, cinnolines, phthalazines, pyrazines, pyrimidines, quinazolines); 6- membered here
  • aralkyl and "arylalkyl” as used herein mean an aryl group as defined above linked to the molecule through an alkyl group as defined above.
  • alkaryl and "alkylaryl” as used herein means an alkyl group as defined above linked to the molecule through an aryl group as defined above.
  • acyl as used herein means a carboxylic acid ester in which the non-carbonyl moiety of the ester group is selected from straight, branched, or cyclic alkyl or lower alkyl; alkoxyalkyl including methoxymethyl; aralkyl including benzyl; aryloxyalkyl such as phenoxymethyl; aryl including phenyl optionally substituted with one or more non-interfering substituents, such as halogen, C 1 -C 6 alkyl or C 1 -Ce alkoxy; sulfonate esters such as alkyl or aralkyl sulphonyl including methanesulfonyl; mono-, di-, or triphosphate ester; trityl or monomethoxytrityl; substituted benzyl; trialkylsilyl such as dimethyl -t-butylsilyl or diphenylmethylsilyl.
  • Aryl groups in the esters optimally comprise
  • amino as used herein means a moiety represented by the structure NR 2 , and includes primary amines, and secondary and tertiary amines substituted by alkyl (i.e., alkylamino).
  • R 2 may represent two hydrogen atoms, two alkyl moieties, or one hydrogen atom and one alkyl moiety.
  • alkylamino and arylamino as used herein mean an amino group that has one or two alkyl or aryl substituents, respectively.
  • non-interfering substituents means any groups that yield stable compounds. Suitable non-interfering substituents or radicals include, but are not limited to, halo, C 1- C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1- C 10 alkoxy, C 7 -C 12 aralkyl, C 7 -C 12 alkaryl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkenyl, phenyl, substituted phenyl, toluoyl, xylenyl, biphenyl, C 2 -C 12 alkoxyalkyl, C 7 -C 12 alkoxyaryl, C 7 -C 12 aryloxyalkyl, C O -C I2 oxyaryl, C 1 -Ce alkylsulfinyl, C 1 -C 10 alkylsulfonyl, -
  • analogue as used herein means a compound in which one or more individual atoms or functional groups have been replaced, either with a different atom or a different functional, generally giving rise to a compound with similar properties.
  • derivative as used herein means a compound that is formed from a similar, beginning compound by attaching another molecule or atom to the beginning compound. Further, derivatives, according to the invention, encompass one or more compounds formed from a precursor compound through addition of one or more atoms or molecules or through combining two or more precursor compounds.
  • prodrug as used herein means any compound which, when administered to a mammal, is converted in whole or in part to a compound of the invention.
  • active metabolite as used herein means a physiologically active compound which results from the metabolism of a compound of the invention, or a prodrug thereof, when such compound or prodrug is administered to a mammal.
  • intermittent administration means administration of a therapeutically effective dose of a composition according to the invention, followed by a time period of discontinuance, which is then followed by another administration of a therapeutically effective dose, and so forth.
  • “Pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” refers to an excipient that can be included in the compositions of the invention and that causes no significant adverse toxicological effects to the patient. "Pharmacologically effective amount,” “physiologically effective amount,”
  • therapeutically effective amount and “therapeutically effective dose” are used interchangeably herein to mean the amount of a conjugate of the invention present in a pharmaceutical preparation that is needed to provide a desired level of active agent and/or conjugate in the bloodstream or in the target tissue.
  • the precise amount will depend upon numerous factors, e.g., the particular active agent, the components and physical characteristics of the pharmaceutical preparation, intended patient population, patient considerations, and the like, and can readily be determined by one skilled in the art, based upon the information provided herein and available in the relevant literature.
  • antiproliferative agent as used herein means a compound that decreases the hyperproliferation of cells.
  • abnormal cell proliferation means a disease or condition characterized by the inappropriate growth or multiplication of one or more cell types relative to the growth of that cell type or types in an individual not suffering from that disease or condition.
  • cancer as used herein means a disease or condition characterized by uncontrolled, abnormal growth of cells, which can spread locally or through the bloodstream and lymphatic system to other parts of the body.
  • the term includes both tumor- forming or non-tumor forming cancers, and includes various types of cancers, such as primary tumors and tumor metastasis.
  • tumor as used herein means an abnormal mass of cells within a multicellular organism that results from excessive cell division that is uncontrolled and progressive, also called a neoplasm.
  • a tumor may either be benign or malignant.
  • inflammatory disease or "inflammatory condition” as used herein means any disease or condition causing a localized protective response resulting from injury or destruction of tissues and evidenced by one or more of pain, heat, redness, swelling, and loss of function. The inflammation may arise from a variety of events, including but not limited to dilatation of arterioles, capillaries, and venules, with increased permeability and blood flow; exudation of fluids, including plasma proteins; and leukocyte migration into the site of inflammation.
  • the transcription factor NF- ⁇ B can be involved in cellular alterations such as self-sufficiency in growth signals; insensitivity to growth inhibition; evasion of apoptosis; immortalization; sustained angiogenesis; and tissue invasion and metastasis. It has also been shown to be constitutively activated in some types of cancer cell. Activated NF- ⁇ B has been associated with several aspects of tumorigenesis, including promoting cancer cell proliferation, preventing apoptosis, and increasing a tumor's angiogenic and metastatic potential. Furthermore, constitutive activation of NF- ⁇ B in cancer cells may be critical in their development of drug resistance to certain cytoxicity agents. Inhibitors of NF- ⁇ B activation can thus be useful anticancer agents, particularly antitumor agents. Still further, NF- ⁇ B inhibitors can also be useful for reversing chemoresistance in cancer cells. The activity of NF- ⁇ B is tightly regulated by its interaction with inhibitory
  • NF- ⁇ B is sequestered in the cytoplasm in an inactive form associated with inhibitory molecules such as I ⁇ B ⁇ , I ⁇ B ⁇ , I ⁇ B ⁇ , plO5, and p 100. This interaction blocks the ability of NF- ⁇ B to bind to DNA and results in the NF- ⁇ B complex being primarily localized to the cytoplasm due to a strong nuclear export signal in I ⁇ B ⁇ . Following exposure to stimulus, such as inflammatory cytokines, UV light, reactive oxygen species, or bacterial and viral toxins, the NF- ⁇ B signaling cascade is activated, leading to the complete degradation of IKB.
  • stimulus such as inflammatory cytokines, UV light, reactive oxygen species, or bacterial and viral toxins
  • HDAC3 histone deacetylase 3
  • One of the target genes activated by NF- ⁇ B is that encoding I ⁇ B ⁇ .
  • Newly synthesized I ⁇ B ⁇ can enter the nucleus, remove NF- ⁇ B from DNA, and export the complex back to the cytoplasm to restore its original latent state.
  • any compound exhibiting activity for inhibiting NF- ⁇ B i.e., an NF- ⁇ B inhibiting compound
  • the NF- ⁇ B inhibiting compound can be any compound that inhibits activity of NF- ⁇ B directly.
  • the NF- ⁇ B inhibiting compound can be any compound that inhibits activation of the NF -KB pathway.
  • the NF- ⁇ B inhibiting compound can be any compound that increases the sensitivity of NF- ⁇ B to conventional chemotherapy.
  • the NF- ⁇ B inhibiting compound can be any compound that inhibits phosphorylation or degradation of naturally occurring NF- ⁇ B inhibitors, such as described herein.
  • the combination of the invention can comprise one or more NF- ⁇ B inhibiting compounds selected from the group consisting of lipoic acid, tocopherol, allicin, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, N- acetyldopamine dimmers (e.g., from P.
  • Extract pitavastatin, prodelphinidin B2 3,3' di-O-gallate, pyrrolinedithiocarbamate (PDTC), quercetin, red orange extract, rotenone, roxithromycin, rutin, S-allyl-cysteine (SAC), salogaviolide (Centaurea ainetensis), sauchinone, silybin, spironolactone, strawberry extracts, taxifolin, tempol, tepoxaline, thio avarol derivatives, thymoquinone, tocotrienol, tomato peel polysaccharide, UDN glycoprotein (ulmus davidiana nakai), vaccinium stamineum (deerberry) extract, vanillin (2-hydroxy-3-methoxybenzaldehyde), vitamin B6, alpha- torphyrl succinate, alpha-torphyryl acetate, PMC (2,2,5, 7,8-pentamethyl-6- hydroxychromane), Ya
  • NF- KB inhibiting compound in relation to phosphorylation or degradation of IKB, activation of NF- ⁇ B, IKB upregulation, nuclear translocation, nuclear expression, DNA binding, transactivation, or other mechanism of action that may result in inhibition of NF- ⁇ B
  • IKB upregulation nuclear translocation
  • nuclear expression DNA binding, transactivation, or other mechanism of action that may result in inhibition of NF- ⁇ B
  • a NF- ⁇ B inhibiting compound useful according to the invention may particularly comprise a curcumin analog.
  • curcumin analogs useful according to the invention are provided in U.S. Patent No. 6,664,272 and U.S. Patent No. 7,371,766, both of which are incorporated herein by reference in their entirety.
  • a curcumin analog useful as a NF- ⁇ B inhibiting compound according to the invention is any compound encompassed by the structure of Formula (1) provided below
  • each Ar is optionally substituted and is independently a ring structure, typically comprising 5-20 ring atoms, selected from the group consisting of aryl (e.g.,C 6 -C 10 aryl), substituted aryl, heteroaryl (e.g., 5-10-membered rings with 1-3 heteroatoms selected from O, S, and N), substituted heteroaryl, heterocycle (e.g., 5- 10-membered rings with 1-3 heteroatoms selected from O, S, and N), and substituted heterocycle; any substituent on Ar is selected from the group consisting of halo (i.e., chloro, bromo, iodo, or fluoro), alkyl, substituted alkyl, alkoxy, substituted alkoxy, hydroxyl, CF 3 , alkenyl, alkynyl, aryl, substituted aryl, alkaryl, arylalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, amino,
  • A is selected from the group consisting of:
  • n 1-8;
  • X is selected from the group consisting of -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, O, -0-NR 3 -, S, SO, SO 2 , -S-S-, NR 3 , and -NR 3 -NR 3 -;
  • Q is NH or NR 3 ;
  • Vi- 4 are each independently OH, OR 2 , or halogen;
  • R 1 , R 2 , and R 3 are independently H, alkyl, substituted alkyl, alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, acyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl; the dashed lines indicate the presence of optional double bonds; and L is the point of bonding of A to the compound structure; as well as pharmaceutically acceptable esters, amides, salts, solvates, enantiomers, and prodrugs thereof.
  • a curcumin analog useful as a NF- ⁇ B inhibiting compound according to the invention is any compound encompassed by the structure of Formula (2) provided below
  • each Ar is optionally substituted and is independently a ring structure, typically comprising 5-20 ring atoms, selected from the group consisting of aryl (e.g., C 6 -C 10 aryl), substituted aryl, heteroaryl (e.g., 5-10-membered rings with 1-3 heteroatoms selected from O, S, and N), substituted heteroaryl, heterocycle (e.g., 5- 10-membered rings with 1-3 heteroatoms selected from O, S, and N), and substituted heterocycle; any substituent on Ar is selected from the group consisting of halo (i.e., chloro, bromo, iodo, or fluoro), alkyl, substituted alkyl, alkoxy, substituted alkoxy, hydroxyl, CF 3 , alkenyl, alkynyl, aryl, substituted aryl, alkaryl, arylalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, amino,
  • X which is optional (i.e., the ring structure can be a five-membered carbocycle), is selected from the group consisting of -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 - CH 2 -, O, -O-NR 3 -, S, SO, SO 2 , -S-S-, NR 3 , and -NR 3 -NR 3 -;
  • R 3 is H, alkyl, substituted alkyl, alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, acyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl;
  • Yi represents one or more optional substituents of any carbon atom of the designated ring structure, and may be present as one or two substituents on the same carbon atom or as multiple substituents on different carbon atoms, each of the one or more Yi groups being independently selected from the group consisting of halo (i.e., chloro, bromo, iodo, or fluoro), alkyl, substituted alkyl, alkoxy, substituted alkoxy, hydroxyl, CF 3 , alkenyl, alkynyl, aryl, substituted aryl, alkaryl, arylalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, amino, alkylamino, dialkylamino, carboxylic acid, carboxylic ester, carboxamide, nitro, cyano, azide, alkylcarbonyl, acyl, trialkylammonium, NH-aa, and O-aa, where aa is an amino acid (e.
  • a curcumin analog useful as a NF- ⁇ B inhibiting compound according to the invention is any compound encompassed by the structure of Formula (3) provided below
  • X which is optional (i.e., the ring structure can be a five-membered carbocycle), is selected from the group consisting of -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 - CH 2 -, O, -O-NR 3 -, S, SO, SO 2 , -S-S-, NR 3 , and -NR 3 -NR 3 -;
  • R 3 is H, alkyl, substituted alkyl, alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, acyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl; each Yi and Y 2 individually represents one or more optional substituents of any carbon atom of the designated ring structures, and may be present as one or two substituents on the same carbon atom or as multiple substituents on different carbon atoms, each of the one or more Yi and Y 2 groups being independently selected from the group consisting of halo (i.e., chloro, bromo, iodo, or fluoro), alkyl, substituted alkyl, alkoxy, substituted alkoxy, hydroxyl, CF 3 , alkenyl, alkynyl, aryl, substituted aryl, alkaryl, arylalkyl, heteroaryl, substituted hetero
  • Ar is preferably selected from the following ring structures, which may be optionally substituted with one or more Y 2 substituents: phenyl, naphthyl, indyl, azulyl, pentalyl, heptalyl, biphenylenyl, indacenyl, acenaphthyl, phenalyl, imidazolidinyl, indolinyl, isoindolinyl, morpholinyl, piperazinyl, piperidinyl, pyrazolidinyl, pyrrolidinyl, benzofuranyl, carbazolyl, benzopyranyl, furanyl, imidazolyl, indazolyl, indolizinyl, isobenzofuryl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl,
  • Ar groups include substituted or unsubstituted phenyl, furanyl, pyridinyl, pyrimidinyl, quinolinyl, and naphthyridinyl.
  • each Ar group is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted naphthyridinyl, substituted or unsubstituted quinolinyl, or a substituted or unsubstituted six-membered heteroaryl ring comprising 1-3 nitrogen atoms.
  • the number of Yi and/or Y 2 groups present on any give ring structure, whether the central ketone ring or the outer Ar rings, can vary, but is typically 0-8 (i.e., 0, 1, 2, 3, 4, 5, 6, 7, or 8 Y groups), more typically 0-4. As noted above, two Y groups can be substituted on the same carbon atom in the case of non-aromatic rings.
  • the outer Ar rings are ortho-substituted with Y 2 substituents, particularly halo, alkoxy (e.g., methoxy), hydroxyl, or CF 3 .
  • X is NH or NR 3 .
  • R 3 is H or lower alkyl (e.g., C 1 -Ce).
  • curcumin analogs useful as a NF- ⁇ B inhibiting compound according to the invention are provided by the structure of Formula (4)
  • R 3 is H, alkyl, substituted alkyl, alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, acyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl; Yi represents one or more optional substituents of any carbon atom of the designated ring structure, and may be present as one or two substituents on the same carbon atom or as multiple substituents on different carbon atoms, each of the one or more Y groups being independently selected from the group consisting of halo (i.e., chloro, bromo, iodo, or fluoro), alkyl, substituted alkyl, alkoxy, substituted alkoxy, hydroxyl, CF 3 , alkenyl, alkynyl, aryl, substituted aryl, alkaryl, arylalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted hetero
  • curcumin analogs useful as a NF- ⁇ B inhibiting compound according to the invention are provided by the structure of Formula (5)
  • Y 2 represents one or more optional substituents of any carbon atom of the designated ring structure, and may be present as one or two substituents on the same carbon atom or as multiple substituents on different carbon atoms, each of the one or more Y 2 groups being independently selected from the group consisting of halo (i.e., chloro, bromo, iodo, or fluoro), alkoxy (e.g., methoxy), hydroxyl, and CF 3 ; the dashed lines indicate the presence of optional double bonds; as well as pharmaceutically acceptable esters, amides, salts, solvates, enantiomers, and prodrugs thereof.
  • halo i.e., chloro, bromo, iodo, or fluoro
  • alkoxy e.g., methoxy
  • hydroxyl hydroxyl
  • CF 3 the dashed lines indicate the presence of optional double bonds; as well as pharmaceutically acceptable esters, amides, salts, solvates
  • a curcumin analog useful as a NF- ⁇ B inhibiting compound according to the invention is provided by the structure of Formula (6), which may be referred to herein as the compound EF24.
  • the compound EF24 may particularly be in the form of a salt, such as the acetate salt.
  • the compound may have the structure provided in Formula (6b)
  • A- is an appropriate salt forming anion, such as OAc.
  • curcumin analogs useful as NF- ⁇ B inhibiting compounds according to the invention are provided below in Tables I-IV.
  • curcumin analogs useful as a NF -KB inhibiting compounds according to the present invention may be prepared according to methods known in the art, particularly in light of the disclosure and examples set forth herein.
  • the starting materials used to synthesize the curcumin analog compounds are commercially available or capable of preparation using methods known in the art.
  • curcumin analogs according to the present invention may be prepared by reaction of an aromatic aldehyde, such as hydroxybenzaldehyde or fluoro-substituted benzaldehyde, with a ketone, such as acetone, cyclohexanone, cyclopentanone, tetrahydro-4-H-pyran-4-one, N-methyl-4-piperidone, piperidin-4-one, and the like, under basic aldol condensation conditions.
  • curcumin analogs according to the present invention may be prepared by reaction of an alkoxy- substituted benzaldehyde or anisaldehyde with a ketone.
  • Salts of the curcumin analogs may be prepared, in general, by reaction of a curcumin analog according to the invention with the desired acid or base in solution. After the reaction is complete, the salts can be crystallized from solution by the addition of an appropriate amount of solvent in which the salt is insoluble.
  • the mitogen-activated protein kinase (MAPK) pathways are three -tiered kinase pathways, which are activated upon stimulation with growth factors, signal to transcription factors and other protein kinases, and ultimately elicit some biological response.
  • the three major MAPK family members include p38 MAPK along with the extracellular-regulated kinase (ERK) and the c-jun N-terminal kinase (JNK).
  • JNK and p38 MAPK are considered stress-induced kinases since they not only can respond to mitogens but also a variety of cellular stresses including inflammatory cytokines.
  • p38 MAPK has also been implicated in the transcriptional up- regulation of NF -kB, further suggesting a connection between inflammation, cancer, and NF-kB.
  • p38 kinases are activated by MAP kinase kinases (MAPKKs/MKKs) with MKK3 and MKK6 being the two main MAPKKs known to activate p38.
  • MAPKKs/MKKs MAP kinase kinases
  • MKK3 and MKK6 the two main MAPKKs known to activate p38.
  • p38 MAPK has been identified as the upstream kinase of MAP kinase-activated protein kinase-2 (MAPKAPK-2/MK2), activating transcription factor-2 (ATF-2), mitogen- and stress-activated kinase (MSK), and even p53.
  • ATF-2 activating transcription factor-2
  • MSK mitogen- and stress-activated kinase
  • p38 MAPK plays a role in human cancers, and there are reports that p38 MAPK is selectively activated in homogenates of non-small cell lung tumors compared with normal tissue and thus, may be involved in malignant cell growth or transformation.
  • MAPK inhibitors Development of MAPK inhibitors is on-going, and p38 MAPK inhibiting compounds are believed to be useful in the treatment of at least rheumatoid arthritis, skin disorders, and other inflammatory diseases. Moreover, p38 MAPK inhibitors can inhibit the production of pro-inflammatory cytokines and therefore inhibit the propagation of the inflammatory response.
  • any compound useful to inhibit activity of p38 MAPK may be used in a combination according to the present invention.
  • many known p38 inhibiting compounds are characterized by inclusion of an azole or imidazole ring, typically bonded to one or more further aromatic ring structures.
  • the combinations of the present invention particularly encompass any azole or imidazole containing compound having activity to inhibit p38 MAPK.
  • This general structure may also give rise to further p38 inhibitors, such as compounds based on a 6-membered central ring structure.
  • a p38 inhibiting compound useful according to the present invention may be any compound having the structure provided in Formula (23) below
  • Het indicates a 5-membered heterocycle with 1-3 ring carbons replaced with an atom selected from N, O, or S or a 6-membered heterocycle with 1-4 ring carbons replaced with an atom selected from N, O, or S; each Ar is optionally substituted and is independently a ring structure, typically comprising 5-20 ring atoms, selected from the group consisting of aryl (e.g., C 6 -C 10 aryl), substituted aryl, heteroaryl (e.g., 5-10-membered rings with 1-3 heteroatoms selected from O, S, and N), substituted heteroaryl, heterocycle (e.g., 5- 10-membered rings with 1-3 heteroatoms selected from O, S, and N), and substituted heterocycle; a Z substituent may be present on any ring atom not bonded to an Ar group;
  • aryl e.g., C 6 -C 10 aryl
  • substituted aryl e.g., heteroaryl (e.g
  • Z and any substituent on Ar are independently selected from the group consisting of H, halo (i.e., chloro, bromo, iodo, or fluoro), alkyl, substituted alkyl, alkoxy, substituted alkoxy, hydroxyl, carbonyl, CF 3 , alkenyl, alkynyl, aryl, substituted aryl, alkaryl, arylalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, amino, alkylamino, dialkylamino, carboxylic acid, carboxylic ester, carboxamide, nitro, cyano, amide, imide, azide, alkylcarbonyl, acyl, sulfonyl, alkylsulfonyl, sulf ⁇ nyl, alkylsulfinyl, sulfenyl, alkylsulfenyl, and trialkylammonium, or two Z groups may be combined
  • Het indicates a 5-membered heterocycle with 1-3 ring carbons replaced with an atom selected from N, O, or S; each Ar is optionally substituted and is independently a ring structure, typically comprising 5-20 ring atoms, selected from the group consisting of aryl (e.g., C 6 -C 10 aryl), substituted aryl, heteroaryl (e.g., 5-10-membered rings with 1-3 heteroatoms selected from O, S, and N), substituted heteroaryl, heterocycle (e.g., 5- 10-membered rings with 1-3 heteroatoms selected from O, S, and N), and substituted heterocycle; each Z and any substituent on Ar are independently selected from the group consisting of H, halo (i.e., chloro, bromo, iodo, or fluoro), alkyl, substituted alkyl, alkoxy, substituted alkoxy, hydroxyl, carbonyl, CF 3 , alkenyl, alkynyl,
  • a p38 inhibiting compound useful according to the invention is any compound having the structure provided in Formula (25) below
  • Het indicates a 5-membered heterocycle with 1-3 ring carbons replaced with an atom selected from N, O, and S;
  • A is a heteroatom selected from N, O, and S; each Z is independently selected from the group consisting of H, halo (i.e., chloro, bromo, iodo, or fluoro), alkyl, substituted alkyl, alkoxy, substituted alkoxy, hydroxyl, carbonyl, CF 3 , alkenyl, alkynyl, aryl, substituted aryl, alkaryl, arylalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, amino, alkylamino, dialkylamino, carboxylic acid, carboxylic ester, carboxamide, nitro, cyano, amide, imide, azide, alkylcarbonyl, acyl, sulfonyl, alkylsulfonyl, sulfinyl, alkylsulfinyl, sulfenyl, alkylsulfenyl, and trialkylammoni
  • a p38 inhibiting compound useful according to the invention can be any compound that is a l-aryl-2-pyridinyl/pyrimidinyl heterocycle.
  • the p38 inhibiting compound could be a compound such as shown in Formula (26) - also known as SB203580- and Formula (27) - also known as SB202190.
  • the invention encompasses 2-methoxypyrimidinylimidazole compounds, such as the compound exemplified in Formula (28).
  • the central imidazole ring may be replaced with non- imidazole 5-membered rings (e.g., pyrazoles, oxazoles, and thiazoles). Examples of such compounds useful according to the invention are illustrated in Formulas (29) - (38).
  • p38 inhibitor compounds according to the invention While it is useful for p38 inhibitor compounds according to the invention to include a pyridine or pyrimidine group vicinal to the central heterocycle, such groups may be replaced (e.g., with a benzoimidazoles, benzothiazoles, and quino lines). Such compounds are exemplified below in Formulas (40) - (44).
  • the p38 inhibiting compounds of the invention may include a core 5-membered heterocycle
  • other types of p38 inhibiting compounds may also be useful in the inventive combinations.
  • the compounds may be based on 6-membered heterocyclic cores, such as pyridazines, pyrazines, pyridines, and fused bicyclic heterocycle, such as imidazopyrimidines.
  • 6-membered heterocyclic cores such as pyridazines, pyrazines, pyridines, and fused bicyclic heterocycle, such as imidazopyrimidines.
  • Such compounds are exemplified below in Formulas (45) - (55).
  • the p38 inhibiting compounds useful in the combinations of the present invention may also encompass further types of compounds.
  • benzophenone -based compounds useful according to the invention can include any compound encompassed by the structure of Formula (56)
  • each Ar is optionally substituted and is independently a ring structure, typically comprising 5-20 ring atoms, selected from the group consisting of aryl (e.g., C 6 -C 10 aryl), substituted aryl, heteroaryl (e.g., 5-10-membered rings with 1-3 heteroatoms selected from O, S, and N), substituted heteroaryl, heterocycle (e.g., 5- 10-membered rings with 1-3 heteroatoms selected from O, S, and N), and substituted heterocycle;
  • aryl e.g., C 6 -C 10 aryl
  • substituted aryl e.g., heteroaryl
  • heteroaryl e.g., 5-10-membered rings with 1-3 heteroatoms selected from O, S, and N
  • substituted heteroaryl e.g., 5- 10-membered rings with 1-3 heteroatoms selected from O, S, and N
  • substituted heterocycle e.g., 5- 10-membered rings with 1-3 hetero
  • Ri and R 2 are optionally substituted and are independently selected from the group consisting of halo (i.e., chloro, bromo, iodo, or fluoro), alkyl, substituted alkyl, alkoxy, substituted alkoxy, hydroxyl, carbonyl, CF 3 , alkenyl, alkynyl, aryl, substituted aryl, alkaryl, arylalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, amino, alkylamino, dialkylamino, carboxylic acid, carboxylic ester, carboxamide, nitro, cyano, amide, imide, azide, alkylcarbonyl, acyl, sulfonyl, alkylsulfonyl, sulf ⁇ nyl, alkylsulfinyl, sulfenyl, alkylsulfenyl, and trialkylammonium, or two Ri or R 2
  • X is -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, O, -0-NR 4 -, S, SO, SO 2 , -S-S-, NR 4 , or -NR 4 -NR 4 -;
  • R 4 is H, alkyl, substituted alkyl, alkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, acyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl; and
  • Z and any substituent on Ar, R 1 , or R 2 are independently selected from the group consisting of H, halo (i.e., chloro, bromo, iodo, or fluoro), alkyl, substituted alkyl, alkoxy, substituted alkoxy, hydroxyl, carbonyl, CF 3 , alkenyl, alkynyl, aryl, substituted aryl, alkaryl, arylalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, amino, alkylamino, dialkylamino, carboxylic acid, carboxylic ester, carboxamide, nitro, cyano, amide, imide, azide, alkylcarbonyl, acyl, sulfonyl, alkylsulfonyl, sulfinyl, alkylsulfinyl, sulfenyl, alkylsulfenyl, and trialkylammonium;
  • benzophenone -based compounds useful according to the invention can include any compound encompassed by the structure of Formula (57) below
  • Ri, R 2 , and R 3 are independently selected from the group consisting of halo (i.e., chloro, bromo, iodo, or fluoro), alkyl, substituted alkyl, alkoxy, substituted alkoxy, hydroxyl, carbonyl, CF 3 , alkenyl, alkynyl, aryl, substituted aryl, alkaryl, arylalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, amino, alkylamino, dialkylamino, carboxylic acid, carboxylic ester, carboxamide, nitro, cyano, amide, imide, azide, alkylcarbonyl, acyl, sulfonyl, alkylsulfonyl, sulfinyl, alkylsulfinyl, sulfenyl, alkylsulfenyl, and trialkylammonium, or two R 3 groups may be combined
  • benzophenone -based compounds useful according to the invention are shown below in Formulas (58) - (63).
  • Exemplary pyrazole ketones and amino pyrroles ketones are shown in Formulas (64) - (66).
  • Inhibitors of p38 useful according to the present invention may also include compounds based on cyclic ureas. Exemplary embodiments of such compounds are provided below in Formulas (67) - (84).
  • p38 inhibiting compounds useful according to the invention include piperazine -based indole molecules.
  • piperazine -based indole compounds useful according to the invention can include any compound encompassed by the structure of Formula (85)
  • Nc is a nitrogen atom that may be replaced by a carbon atom; each Z is independently selected from the group consisting of H, halo (i.e., chloro, bromo, iodo, or fluoro), alkyl, substituted alkyl, alkoxy, substituted alkoxy, hydroxyl, carbonyl, CF 3 , alkenyl, alkynyl, aryl, substituted aryl, alkaryl, arylalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, amino, alkylamino, dialkylamino, carboxylic acid, carboxylic ester, carboxamide, nitro, cyano, amide, imide, azide, alkylcarbonyl, acyl, sulfonyl, alkylsulfonyl, sulf ⁇ nyl, alkylsulfinyl, sulfenyl, alkylsulfenyl, and
  • Urea-based compounds exhibiting p38 inhibiting activity may also be used in the combinations of the present invention.
  • urea-based compounds useful according to the invention can include any compound encompassed by the structure of Formula (98)
  • each Ar is optionally substituted and is independently a ring structure, typically comprising 5-20 ring atoms, selected from the group consisting of aryl (e.g., C 6 -C 10 aryl), substituted aryl, heteroaryl (e.g., 5-10-membered rings with 1-3 heteroatoms selected from O, S, and N), substituted heteroaryl, heterocycle (e.g., 5- 10-membered rings with 1-3 heteroatoms selected from O, S, and N), and substituted heterocycle; and any substituent on Ar are independently selected from the group consisting of halo (i.e., chloro, bromo, iodo, or fluoro), alkyl, substituted alkyl, alkoxy, substituted alkoxy, hydroxyl, carbonyl, CF 3 , alkenyl, alkynyl, aryl, substituted aryl, alkaryl, arylalkyl, heteroaryl, substituted heteroaryl, heterocycle, substitute
  • urea-based p38 inhibitor compounds are provided below in Formulas (99) - (104).
  • the invention also encompasses the use of p38 inhibiting compounds based on methylbenzamides, N-p-tolylamides, bis-aryl amides, and bis-aryl benzamides. Exemplary embodiments of such compounds are provided below in Formulas (105) - (128).
  • p38 inhibiting compounds useful according to the invention should not be viewed as limiting the scope of the invention. Rather further compounds having p38 inhibiting activity could also be used in the invention.
  • additional compounds known to have p38 inhibiting activity include the following compounds provided in Formulas (129) - (153).
  • Still further compounds having p38 inhibiting activity may be used in the combinations of the invention.
  • compounds known by the following names could also be used: ARRY-791; SB681323; ISIS101757; VX-702; SCIO323; PS540446; SB856553; KC706; and SB281832.
  • Any of the above -provided specific p38 inhibiting compounds, as well as further compounds exhibiting p38 inhibiting activity, may be disclosed in additional documents.
  • any p38 inhibiting compound disclosed in any of the following documents may be used in the combinations of the present invention. All of the following documents are incorporated herein by reference in their entirety: Foster ML and Halley FS, Drug News Perspect.
  • Biologically active variants of the compounds set forth above are particularly also encompassed by the invention. Such variants should retain the general biological activity of the original compounds; however, the presence of additional activities would not necessarily limit the use thereof in the present invention. Such activity may be evaluated using standard testing methods and bioassays recognizable by the skilled artisan in the field as generally being useful for identifying such activity.
  • suitable biologically active variants comprise one or more analogues or derivatives of the compounds described above.
  • a single compound, such as those described above may give rise to an entire family of analogues or derivatives having similar activity and, therefore, usefulness according to the present invention.
  • a single compound, such as those described above may represent a single family member of a greater class of compounds useful according to the present invention. Accordingly, the present invention fully encompasses not only the compounds described above, but analogues and derivatives of such compounds, particularly those identifiable by methods commonly known in the art and recognizable to the skilled artisan.
  • the compounds disclosed herein may contain chiral centers, which may be either of the (R) or (S) configuration, or may comprise a mixture thereof.
  • the present invention also includes stereoisomers of the compounds described herein, where applicable, either individually or admixed in any proportions.
  • Stereoisomers may include, but are not limited to, enantiomers, diastereomers, racemic mixtures, and combinations thereof. Such stereoisomers can be prepared and separated using conventional techniques, either by reacting enantiomeric starting materials, or by separating isomers of compounds of the present invention.
  • Isomers may include geometric isomers. Examples of geometric isomers include, but are not limited to, cis isomers or trans isomers across a double bond. Other isomers are contemplated among the compounds of the present invention. The isomers may be used either in pure form or in admixture with other isomers of the compounds described herein.
  • optical isomers of the compounds according to the present invention include the following: i) physical separation of crystals whereby macroscopic crystals of the individual enantiomers are manually separated.
  • This technique may particularly be used when crystals of the separate enantiomers exist (i.e., the material is a conglomerate), and the crystals are visually distinct; ii) simultaneous crystallization whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; iii) enzymatic resolutions whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme; iv) enzymatic asymmetric synthesis, a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; v) chemical asymmetric synthesis whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which may be achieved using chiral catalysts or chiral auxilia
  • the resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer; vii) first- and second-order asymmetric transformations whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer.
  • the desired enantiomer is then released from the diastereomers; viii) kinetic resolutions comprising partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions; ix) enantiospecif ⁇ c synthesis from non-racemic precursors whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase.
  • the stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions; xi) chiral gas chromatography whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; xii) extraction with chiral solvents whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent; and xiii) transport across chiral membranes whereby a racemate is placed in contact with a thin membrane barrier.
  • the barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier.
  • the NF -KB inhibiting compounds and/or p38 inhibiting compounds of the invention may be provided in an enantiomerically enriched form, such as a mixture of enantiomers in which one enantiomer is present in excess (given as a mole fraction or a weight fraction).
  • Enantiomeric excess is understood to exist where a chemical substance comprises two enantiomers of the same compound and one enantiomer is present in a greater amount than the other enantiomer. Unlike racemic mixtures, these mixtures will show a net optical rotation. With knowledge of the specific rotation of the mixture and the specific rotation of the pure enantiomer, the enantiomeric excess (abbreviated "ee”) can be determined by known methods.
  • the compounds of the invention can have a specific degree of enantiomeric purity for a single enantiomer (e.g., at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5%).
  • esters, amides, salts, solvates, prodrugs, and other derivatives of the compounds of the present invention may be prepared according to methods generally known in the art, such as, for example, those methods described by J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4 th Ed. (New York: Wiley-Interscience, 1992), which is incorporated herein by reference.
  • Examples of pharmaceutically acceptable salts of the compounds useful according to the invention include acid addition salts. Salts of non-pharmaceutically acceptable acids, however, may be useful, for example, in the preparation and purification of the compounds.
  • Suitable acid addition salts according to the present invention include organic and inorganic acids. Preferred salts include those formed from hydrochloric, hydrobromic, sulfuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, oxaloacetic, methanesulfonic, ethanesulfonic, p- toluenesulfonic, benzesulfonic, and isethionic acids.
  • compositions include propionic acid, glycolic acid, oxalic acid, malic acid, malonic acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, and the like.
  • pharmaceutically acceptable salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-l,6-dioates,
  • An acid addition salt may be reconverted to the free base by treatment with a suitable base.
  • Preparation of basic salts of acid moieties which may be present on a compound useful according to the present invention may be prepared in a similar manner using a pharmaceutically acceptable base, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, triethylamine, or the like.
  • Esters of the compounds according to the present invention may be prepared through functionalization of hydroxyl and/or carboxyl groups that may be present within the molecular structure of the compound.
  • Amides and prodrugs may also be prepared using techniques known to those skilled in the art. For example, amides may be prepared from esters, using suitable amine reactants, or they may be prepared from anhydride or an acid chloride by reaction with ammonia or a lower alkyl amine.
  • esters and amides of compounds of the invention can be made by reaction with a carbonylating agent (e.g., ethyl formate, acetic anhydride, methoxyacetyl chloride, benzoyl chloride, methyl isocyanate, ethyl chloroformate, methanesulfonyl chloride) and a suitable base (e.g., 4-dimethylaminopyridine, pyridine, triethylamine, potassium carbonate) in a suitable organic solvent (e.g., tetrahydrofuran, acetone, methanol, pyridine, N,N-dimethylformamide) at a temperature of 0 °C to 60 °C.
  • a carbonylating agent e.g., ethyl formate, acetic anhydride, methoxyacetyl chloride, benzoyl chloride, methyl isocyanate, ethyl chloroformate, methanes
  • Prodrugs are typically prepared by covalent attachment of a moiety, which results in a compound that is therapeutically inactive until modified by an individual's metabolic system.
  • Examples of pharmaceutically acceptable solvates include, but are not limited to, compounds according to the invention in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
  • compositions of the invention may exist in different forms.
  • the compounds may exist in stable and metastable crystalline forms and isotropic and amorphous forms, all of which are intended to be within the scope of the present invention.
  • the desired salt may be prepared by any suitable method known to the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acids such as glucuronic acid and galacturonic acid, alpha-hydroxy acids such as citric acid and tartaric acid, amino acids such as aspartic acid and glutamic acid, aromatic acids such as benzoic acid and cinnamic acid, sulfonic acids such a p-toluenesulfonic acid or ethanesulfonic acid, or the like.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
  • the desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal or alkaline earth metal hydroxide or the like.
  • an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal or alkaline earth metal hydroxide or the like.
  • suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • the present invention further includes prodrugs and active metabolites of the compounds of the invention. Any of the compounds described herein can be administered as a prodrug to increase the activity, bioavailability, or stability of the compound or to otherwise alter the properties of the compound.
  • Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound.
  • Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, and/or dephosphorylated to produce the active compound.
  • curcumin analogs described herein particularly could be provided as prodrugs.
  • U.S. Patent Application Publication No. 2007/0270464 the disclosure of which is incorporated herein by reference, describes a number of curcumin analog prodrugs that could be used according to the present invention.
  • prodrugs useful according to the invention are provided below in Formulas (154), (155), (156), or (157):
  • Z is S or NR', where R' is H or the residue of an amine-containing molecule
  • R is the residue of a thiol-containing molecule when Z is S or the residue of an amine-containing molecule when Z is NR' ;
  • each Ri and R 2 which can be the same or different, is selected from the group consisting of hydrogen, alkyl (e.g., C1-C8 alkyl), substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle;
  • R 3 is selected from the group consisting of CF 3 , alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, or R 2 and R 3 together complete a 5 to 8-membered carbocycle ring or heterocycle ring comprising one heteroatom selected from the group consisting of O, S, and NR 4 , wherein R 4 is H, alkyl, substituted alkyl, acyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl; X, which is optional (i.e., the ring structure can be a five-membered carbocycle), is selected from the group consisting of -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 - CH 2 -, O, -0-NR 4 -, S, SO, SO 2 , -S-S-, NR 4
  • X' is selected from the group consisting of -CH 2 -, O, -0-NR 4 -, S, SO, SO 2 , -S- S-, NR 4 , and -NR 4 -NR 4 -;
  • Y represents one or more optional substituents of any carbon atom of the designated ring structures, and may be present as one or two substituents on the same carbon atom or as multiple substituents on different carbon atoms, each of the one or more Y groups being independently selected from the group consisting of halo (i.e., chloro, bromo, iodo, or fluoro), alkyl, substituted alkyl, alkoxy, substituted alkoxy, hydroxyl, CF 3 , alkenyl, alkynyl, aryl, substituted aryl, alkaryl, arylalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, amino, alkylamino, dialkylamino, carboxylic acid, carboxylic ester, carboxamide, nitro, cyano, azide, alkylcarbonyl, acyl, trialkylammonium, NH-aa, and O-aa, where aa is an amino acid (
  • Ar is a ring structure, typically comprising 5-20 ring atoms, selected from the group consisting of aryl (e.g., C6-C10 aryl), substituted aryl, heteroaryl (e.g., 5-10- membered rings with 1-3 heteroatoms selected from O, S, and N), substituted heteroaryl, heterocycle (e.g., 5-10-membered rings with 1-3 heteroatoms selected from O, S, and N), and substituted heterocycle, the substituting groups preferably selected from the Y groups set forth above; each dotted line indicates an optional bond; as well as pharmaceutically acceptable esters, amides, salts, solvates, enantiomers, and prodrugs thereof.
  • Table V-IX Certain exemplary sulfur-linked curcumin analog conjugates according to each one of Formulas (I)-(IV) are set forth in Tables V-IX below.
  • prodrugs applies universally to the various compounds described herein and is not simply limited to prodrugs of curcumin analogs. Of course, a skilled person viewing the above disclosure would be able to envision the preparation of prodrugs of any of the curcumin analogs described herein.
  • prodrug ligands are known.
  • alkylation, acylation, or other lipophilic modification of one or more heteroatoms of the compound, such as a free amine or carboxylic acid residue reduces polarity and allows passage into cells.
  • substituent groups that can replace one or more hydrogen atoms on the free amine and/or carboxylic acid moiety include, but are not limited to, the following: aryl; steroids; carbohydrates (including sugars); 1,2-diacylglycerol; alcohols; acyl (including lower acyl); alkyl (including lower alkyl); sulfonate ester (including alkyl or arylalkyl sulfonyl, such as methanesulfonyl and benzyl, wherein the phenyl group is optionally substituted with one or more substituents as provided in the definition of an aryl given herein); optionally substituted arylsulfonyl; lipids
  • phospholipids including phospholipids); phosphotidylcholine; phosphocholine; amino acid residues or derivatives; amino acid acyl residues or derivatives; peptides; cholesterols; or other pharmaceutically acceptable leaving groups which, when administered in vivo, provide the free amine and/or carboxylic acid moiety. Any of these can be used in combination with the disclosed compounds to achieve a desired effect.
  • compositions of the present invention comprise the pharmaceutically active compounds, as described above, or pharmaceutically acceptable esters, amides, salts, solvates, analogs, derivatives, or prodrugs thereof.
  • inventive compositions can be prepared and delivered in a variety of combinations.
  • the composition can comprise a single composition containing all of the active ingredients.
  • the composition can comprise multiple compositions comprising separate active ingredients but intended to be administered simultaneously, in succession, or in otherwise close proximity of time.
  • compositions of the present invention may include short-term, rapid-onset, rapid-offset, controlled release, sustained release, delayed release, and pulsatile release compositions, providing the compositions achieve administration of a compound as described herein. See Remington 's Pharmaceutical Sciences (18 th ed.; Mack Publishing Company, Eaton, Pennsylvania, 1990), herein incorporated by reference in its entirety.
  • compositions according to the present invention are suitable for various modes of delivery, including oral, parenteral (including intravenous, intramuscular, subcutaneous, intradermal, intra-articular, intra-synovial, intrathecal, intra-arterial, intracardiac, subcutaneous, intraorbital, intracapsular, intraspinal, intrastemal, and transdermal), topical (including dermal, buccal, and sublingual), vaginal, urethral, and rectal administration. Administration can also be via nasal spray, surgical implant, internal surgical paint, infusion pump, or via catheter, stent, balloon or other delivery device. The most useful and/or beneficial mode of administration can vary, especially depending upon the condition of the recipient and the disorder being treated.
  • compositions may be conveniently made available in a unit dosage form, whereby such compositions may be prepared by any of the methods generally known in the pharmaceutical arts.
  • methods of preparation comprise combining (by various methods) the active compounds of the invention with a suitable carrier or other adjuvant, which may consist of one or more ingredients.
  • the combination of the active ingredients with the one or more adjuvants is then physically treated to present the composition in a suitable form for delivery (e.g., shaping into a tablet or forming an aqueous suspension).
  • Pharmaceutical compositions according to the present invention suitable for oral dosage may take various forms, such as tablets, capsules, caplets, and wafers (including rapidly dissolving or effervescing), each containing a predetermined amount of the active agent.
  • compositions may also be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, and as a liquid emulsion (oil-in-water and water-in-oil).
  • the active agents may also be delivered as a bolus, electuary, or paste. It is generally understood that methods of preparations of the above dosage forms are generally known in the art, and any such method would be suitable for the preparation of the respective dosage forms for use in delivery of the compositions according to the present invention.
  • compound may be administered orally in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an edible carrier.
  • Oral compositions may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets or may be incorporated directly with the food of the patient's diet.
  • the percentage of the composition and preparations may be varied; however, the amount of substance in such therapeutically useful compositions is preferably such that an effective dosage level will be obtained.
  • Hard capsules containing the compound may be made using a physiologically degradable composition, such as gelatin.
  • Such hard capsules comprise the compound, and may further comprise additional ingredients including, for example, an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin.
  • Soft gelatin capsules containing the compound may be made using a physiologically degradable composition, such as gelatin.
  • Such soft capsules comprise the compound, which may be mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.
  • Sublingual tablets are designed to dissolve very rapidly. Examples of such compositions include ergotamine tartrate, isosorbide dinitrate, and isoproterenol HCL.
  • compositions of these tablets contain, in addition to the drug, various soluble excipients, such as lactose, powdered sucrose, dextrose, and mannitol.
  • suitable coating materials include, but are not limited to, cellulose polymers (such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate), polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and methacrylic resins (such as those commercially available under the trade name EUDRAGIT ® ), zein, shellac, and polysaccharides.
  • cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate
  • polyvinyl acetate phthalate acrylic
  • compositions of a pharmaceutical preparation of the invention may be prepared using known methods. Such compositions may be administered directly to a patient or used in the preparation of further dosage forms, such as to form tablets, fill capsules, or prepare an aqueous or oily suspension or solution by addition of an aqueous or oily vehicle thereto. Each of these compositions may further comprise one or more additives, such as dispersing or wetting agents, suspending agents, and preservatives. Additional excipients (e.g., fillers, sweeteners, flavoring, or coloring agents) may also be included in these compositions.
  • additives such as dispersing or wetting agents, suspending agents, and preservatives.
  • Additional excipients e.g., fillers, sweeteners, flavoring, or coloring agents
  • Liquid compositions of the pharmaceutical composition of the invention which are suitable for oral administration may be prepared, packaged, and sold either in liquid form or in the form of a dry product intended for reconstitution with water or another suitable vehicle prior to use.
  • a tablet containing one or more compounds according to the present invention may be manufactured by any standard process readily known to one of skill in the art, such as, for example, by compression or molding, optionally with one or more adjuvant or accessory ingredient.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agents.
  • Adjuvants or accessory ingredients for use in the compositions of the present invention can include any pharmaceutical ingredient commonly deemed acceptable in the art, such as binders, fillers, lubricants, disintegrants, diluents, surfactants, stabilizers, preservatives, flavoring and coloring agents, and the like. Binders are generally used to facilitate cohesiveness of the tablet and ensure the tablet remains intact after compression. Suitable binders include, but are not limited to: starch, polysaccharides, gelatin, polyethylene glycol, propylene glycol, waxes, and natural and synthetic gums.
  • Acceptable fillers include silicon dioxide, titanium dioxide, alumina, talc, kaolin, powdered cellulose, and microcrystalline cellulose, as well as soluble materials, such as mannitol, urea, sucrose, lactose, dextrose, sodium chloride, and sorbitol.
  • Lubricants are useful for facilitating tablet manufacture and include vegetable oils, glycerin, magnesium stearate, calcium stearate, and stearic acid.
  • Disintegrants which are useful for facilitating disintegration of the tablet, generally include starches, clays, celluloses, algins, gums, and crosslinked polymers.
  • Diluents which are generally included to provide bulk to the tablet, may include dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.
  • Surfactants suitable for use in the composition according to the present invention may be anionic, cationic, amphoteric, or nonionic surface active agents.
  • Stabilizers may be included in the compositions to inhibit or lessen reactions leading to decomposition of the active agents, such as oxidative reactions.
  • Solid dosage forms may be formulated so as to provide a delayed release of the active agents, such as by application of a coating. Delayed release coatings are known in the art, and dosage forms containing such may be prepared by any known suitable method.
  • Such methods generally include that, after preparation of the solid dosage form (e.g., a tablet or caplet), a delayed release coating composition is applied.
  • Application can be by methods, such as airless spraying, fluidized bed coating, use of a coating pan, or the like.
  • Materials for use as a delayed release coating can be polymeric in nature, such as cellulosic material (e.g. , cellulose butyrate phthalate, hydroxypropyl methylcellulose phthalate, and carboxymethyl ethylcellulose), and polymers and copolymers of acrylic acid, methacrylic acid, and esters thereof.
  • Solid dosage forms according to the present invention may also be sustained release (i.e., releasing the active agents over a prolonged period of time), and may or may not also be delayed release.
  • Sustained release compositions are known in the art and are generally prepared by dispersing a drug within a matrix of a gradually degradable or hydro lyzable material, such as an insoluble plastic, a hydrophilic polymer, or a fatty compound.
  • a solid dosage form may be coated with such a material.
  • compositions for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may further contain additional agents, such as anti- oxidants, buffers, bacteriostats, and solutes, which render the compositions isotonic with the blood of the intended recipient.
  • the compositions may include aqueous and non-aqueous sterile suspensions, which contain suspending agents and thickening agents.
  • Such compositions for parenteral administration may be presented in unit- dose or multi-dose containers, such as, for example, sealed ampoules and vials, and may be stores in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water (for injection), immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind previously described.
  • compositions according to the present invention may also be administered transdermally, wherein the active agents are incorporated into a laminated structure (generally referred to as a "patch") that is adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • patches are available as single layer “drug-in-adhesive" patches or as multi-layer patches where the active agents are contained in a layer separate from the adhesive layer. Both types of patches also generally contain a backing layer and a liner that is removed prior to attachment to the skin of the recipient.
  • Transdermal drug delivery patches may also be comprised of a reservoir underlying the backing layer that is separated from the skin of the recipient by a semi -permeable membrane and adhesive layer. Transdermal drug delivery may occur through passive diffusion or may be facilitated using electrotransport or iontophoresis.
  • compositions for rectal delivery of the compositions of the present invention include rectal suppositories, creams, ointments, and liquids.
  • Suppositories may be presented as the active agents in combination with a carrier generally known in the art, such as polyethylene glycol.
  • a carrier generally known in the art, such as polyethylene glycol.
  • Such dosage forms may be designed to disintegrate rapidly or over an extended period of time, and the time to complete disintegration can range from a short time, such as about 10 minutes, to an extended period of time, such as about 6 hours.
  • Topical compositions may be in any form suitable and readily known in the art for delivery of active agents to the body surface, including dermally, buccally, and sublingually.
  • Typical examples of topical compositions include ointments, creams, gels, pastes, and solutions.
  • Compositions for topical administration in the mouth also include lozenges.
  • the compounds and compositions disclosed herein can be delivered via a medical device.
  • a medical device can generally be via any insertable or implantable medical device, including, but not limited to stents, catheters, balloon catheters, shunts, or coils.
  • the present invention provides medical devices, such as stents, the surface of which is coated with a compound or composition as described herein.
  • the medical device of this invention can be used, for example, in any application for treating, preventing, or otherwise affecting the course of a disease or condition, such as those disclosed herein.
  • the pharmaceutical composition comprising one or more compounds described herein is administered intermittently.
  • Administration of the therapeutically effective dose may be achieved in a continuous manner, as for example with a sustained-release composition, or it may be achieved according to a desired daily dosage regimen, as for example with one, two, three, or more administrations per day.
  • time period of discontinuance is intended a discontinuing of the continuous sustained-released or daily administration of the composition.
  • the time period of discontinuance may be longer or shorter than the period of continuous sustained-release or daily administration.
  • the level of the components of the composition in the relevant tissue is substantially below the maximum level obtained during the treatment.
  • the preferred length of the discontinuance period depends on the concentration of the effective dose and the form of composition used.
  • the discontinuance period can be at least 2 days, at least 4 days or at least 1 week. In other embodiments, the period of discontinuance is at least 1 month, 2 months, 3 months, 4 months or greater.
  • the discontinuance period must be extended to account for the greater residence time of the composition in the body.
  • the frequency of administration of the effective dose of the sustained-release composition can be decreased accordingly.
  • An intermittent schedule of administration of a composition of the invention can continue until the desired therapeutic effect, and ultimately treatment of the disease or disorder, is achieved.
  • Administration of the composition according to the invention comprises administering a single pharmaceutically active compound as described herein; administering a pharmaceutically active compound as described herein with one or more further pharmaceutically active compounds described herein; or administering one or more pharmaceutically active compounds described herein in combination with one or more further pharmaceutically active compounds (i.e., co-administration).
  • the pharmaceutically active compounds in the compositions of the invention can be administered in a fixed combination (i.e., a single pharmaceutical composition that contains both active materials).
  • the pharmaceutically active compounds may be administered simultaneously (i.e., separate compositions administered at the same time).
  • the pharmaceutically active compounds are administered sequentially (i.e., administration of one or more pharmaceutically active compounds followed by separate administration or one or more pharmaceutically active compounds).
  • One of skill in the art will recognized that the most preferred method of administration will allow the desired therapeutic effect.
  • a therapeutically effective amount of a composition according to the invention may be obtained via administration of a therapeutically effective dose of the composition.
  • a therapeutically effective amount is an amount effective to treat abnormal cell proliferation.
  • a therapeutically effective amount is an amount effective to treat inflammation.
  • a therapeutically effective amount is an amount effective to: inhibit viability of a cancerous cell line; inhibit formation of new cancerous cells; and/or induce apoptosis of cancerous cells.
  • the active compounds are included in the pharmaceutical composition in an amount sufficient to deliver to a patient a therapeutic amount of a compound of the invention in vivo in the absence of serious toxic effects.
  • the concentration of active compound in the drug composition will depend on absorption, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the medical professional administering or supervising the administration of the compositions, and that the dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions including the inventive combinations.
  • the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
  • a therapeutically effective amount according to the invention can be determined based on the body weight of the recipient. Alternatively, a therapeutically effective amount can be described in terms of a fixed dose.
  • the effective dosage range of pharmaceutically acceptable salts and prodrugs can be calculated based on the weight of the parent compounds to be delivered. If a salt or prodrug exhibits activity in itself, the effective dosage can be estimated as above using the weight of the salt or prodrug, or by other means known to those skilled in the art.
  • compositions of the invention comprising one or more compounds described herein will be administered in therapeutically effective amounts to a mammal, preferably a human.
  • An effective dose of a compound or composition for treatment of any of the conditions or diseases described herein can be readily determined by the use of conventional techniques and by observing results obtained under analogous circumstances.
  • the effective amount of the compositions would be expected to vary according to the weight, sex, age, and medical history of the subject.
  • a dosage from about 0.5 to about 20 mg/kg body weight, preferably from about 1.0 to about 5.0 mg/kg, will have therapeutic efficacy.
  • compositions to be delivered including, but not limited to, the specific disease involved, the degree of involvement or the severity of the disease, the response of the individual patient, the particular compound administered, the mode of administration, the bioavailability characteristics of the preparation administered, the dose regimen selected, and the use of concomitant medication.
  • the compound is preferentially administered for a sufficient time period to alleviate the undesired symptoms and the clinical signs associated with the condition being treated.
  • Methods to determine efficacy and dosage are known to those skilled in the art. See, for example, Isselbacher et al. (1996) Harrison 's Principles of Internal Medicine 13 ed., 1814- 1882, herein incorporated by reference.
  • the present invention also includes an article of manufacture providing a composition comprising the compounds described herein.
  • the article of manufacture can include a vial or other container that contains a composition suitable for use according to the present invention together with any carrier, either dried or in liquid form.
  • the article of manufacture can comprise a kit including a container with a composition according to the invention.
  • the composition can be delivered in a variety of combinations.
  • the composition can comprise a single dosage comprising all of the active ingredients in the inventive combination.
  • the composition can comprise multiple dosages, each comprising one or more of the active ingredients forming the inventive combination, the dosages being intended for administration in combination, in succession, or in other close proximity of time.
  • the dosages could be solid forms (e.g.
  • the article of manufacture further includes instructions for carrying out the methods of the invention.
  • Such instructions may be in various forms, such as a label on the container, an insert included in a box in which the container is packaged, or a variety of computer readable formats.
  • the instructions can also be printed on the box in which the vial is packaged.
  • the instructions contain information such as sufficient dosage and administration information so as to allow the subject or a worker in the field to administer the pharmaceutical composition(s) providing the inventive combination of active agents. It is anticipated that a worker in the field encompasses any doctor, nurse, technician, spouse, or other caregiver that might administer the composition(s).
  • the pharmaceutical composition(s) can also be self-administered by the subject.
  • the susceptibility of cancer cells to chemotherapeutic -induced cell death can be dependent upon a balance between cell death and survival signaling. Increased survival signaling could counteract drug efficacy.
  • Taxol is known to induce phosphorylation and degradation of IKB , leading to the nuclear translocation of the NF- ⁇ B deterodimer, and this increased NF- ⁇ B activation may lead to Taxol resistance.
  • NF- KB inhibiting compounds and p38 MAPK inhibiting compounds can provide a synergistic effect in treating and preventing cancers and inflammatory conditions.
  • NF -KB inhibitors e.g., the curcumin analog EF24
  • the present invention has illustrated that combinations of specific NF- ⁇ B inhibitors and p38 MAPK inhibitors exhibit synergy in cancer models indicating that p38 MAPK is a survival pathway induced by the administration of the NF- ⁇ B inhibitor.
  • the combinations of the present invention can be used in the treatment of cancerous tissue and the tumors associated therewith.
  • Specific, non-limiting types of benign tumors that can be treated according to the present invention include hemangiomas, hepatocellular adenoma, cavernous hemangiomas, focal nodular hyperplasia, acoustic neuromas, neurofibroma, bile duct adenoma, bile duct cystanoma, fibroma, lipomas, leiomyomas, mesotheliomas, teratomas, myxomas, nodular regenerative hyperplasia, trachomas, and pyogenic granulomas.
  • cancers treatable according to the invention include breast cancer, skin cancer, bone cancer, prostate cancer, liver cancer, lung cancer, brain cancer, cancer of the larynx, gallbladder, pancreas, rectum, parathyroid, thyroid, adrenal, neural tissue, head and neck, colon, stomach, bronchi, kidneys, basal cell carcinoma, squamous cell carcinoma of both ulcerating and papillary type, metastatic skin carcinoma, osteo sarcoma, Ewing's sarcoma, reticulum cell sarcoma, myeloma, giant cell tumor, small-cell lung tumor, gallstones, islet cell tumor, primary brain tumor, acute and chronic lymphocytic and granulocytic tumors, hairy-cell tumor, adenoma, hyperplasia, medullary carcinoma, pheochromocytoma, mucosal neuromas, intestinal ganglioneuromas, hyperplastic corneal nerve tumor, marfanoid habitus tumor, Wilm's tumor
  • the combinations of the present invention are also useful in the treatment of diseases characterized by inflammation.
  • Diseases and conditions which have significant inflammatory components are ubiquitous and include, for example, skin disorders, bowel disorders, certain degenerative neurological disorders, arthritis, autoimmune diseases and a variety of other illnesses.
  • the combinations may be used to treat inflammatory bowel diseases (IBD), Crohn's disease (CD), ulcerative colitis (UC), chronic obstructive pulmonary disease (COPD), sarcoidosis, or psoriasis.
  • IBD inflammatory bowel diseases
  • CD Crohn's disease
  • UC ulcerative colitis
  • COPD chronic obstructive pulmonary disease
  • sarcoidosis or psoriasis.
  • the disclosed combinations may also be useful in the treatment of other inflammatory diseases, for example, allergic disorders, skin disorders, transplant rejection, poststreptococcal and autoimmune renal failure, septic shock, systemic inflammatory response syndrome (SIRS), adult respiratory distress syndrome (ARDS), envenomation, lupus erythematosus, Hashimoto's thyroiditis, autoimmune hemolytic anemias, insulin dependent diabetes mellitus, and rheumatic fever, pelvic inflammatory disease (PID), conjunctivitis, dermatitis, and bronchitis.
  • inflammatory diseases for example, allergic disorders, skin disorders, transplant rejection, poststreptococcal and autoimmune renal failure, septic shock, systemic inflammatory response syndrome (SIRS), adult respiratory distress syndrome (ARDS), envenomation, lupus erythematosus, Hashimoto's thyroiditis, autoimmune hemolytic anemias, insulin dependent diabetes mellitus, and rheumatic fever, pelvic inflammatory disease
  • Subjects which can be treated include animal subjects, typically vertebrates, including both mammalian (e.g., human, cat, dog, cow, horse, sheep, pig, monkey, ape, etc.) and avian subjects (e.g., chicken, turkey, duck, goose, quail, pheasant, etc.).
  • the invention provides methods for enhancing the anti -cancer and/or anti -inflammatory activity of NF- ⁇ B inhibiting compounds, and particularly curcumin analogs.
  • Curcumin analogs such as the compound designated EF24, exhibit excellent anti-cancer and anti-inflammatory properties.
  • the present invention has made the surprising discovery that co-administration of an NF- KB inhibiting compound, such as EF24, with a p38 MAPK inhibiting compound gives rise to a synergistic effect.
  • an NF- KB inhibiting compound such as EF24
  • a p38 MAPK inhibiting compound gives rise to a synergistic effect.
  • the combination of a p38 inhibitor with EF24 synergistically increased the anti-cancer activity of the compound.
  • the increased anti-cancer activity is exemplified as an increase in the activity of the curcumin analog for inhibiting growth of cancer cells.
  • the increased anti-cancer activity is exemplified as an increase in the activity for inducing apoptosis of cancer cells.
  • the pyridinyl imidazole compounds SB203580 (Promega; Madison, WI) and SB202190 (Biosource; Camarillo, CA) were used as specific p38 ⁇ / ⁇ MAPK inhibitors. Additional materials used included the specific IKK-2 inhibitor IV (available from Calbiochem), and antibodies against total and phospho-JNK (Thr 183 /Tyr 185 ), total and phospho-p38 MAPK (Thr 180 /Tyr 182 ), total and phospho-ERK (Thr 202 /Tyr 204 ), and PARP (full length and cleaved fragments) (all available from Cell Signaling, Beverly, MA).
  • the human non-small cell lung cancer (NSCLC) cell line A549 were grown in RPMI- 1640, 10% CellGro FBS and maintained at 37°C in an atmosphere containing 10% CO 2 .
  • the media was supplemented with 1% penicillin/streptomycin.
  • IC50 is defined as the concentration of drug that kills 50% of the total cell population as compared to control cells at the end of the incubation period.
  • the pathways modulated by treatment with EF24 were analyzed using an immunoblot analysis.
  • Cells were lysed in 1% NP -40 lysis buffer supplemented with one protease inhibitor cocktail table (Roche, Indianapolis, IN) and protein (25-40 ug/lane) from the whole cell extracts were resolved by 12.5% SDS-PAGE, electrotransferred to nitrocellulose membranes, and blocked with 5% nonfat dry milk in TBS-Tween 20.
  • the blots were then incubated with the indicated primary antibodies, followed by horseradish peroxidase-conjugated secondary antiserum. Immunoreactivity was visualized by enhanced chemiluminescence reagent
  • the membranes were stripped using a strip buffer solution with BME (1 : 1000) and reprobed with the indicated antibodies.
  • EF24 is known to downregulate TNF ⁇ -induced NF -kB activation by negatively regulating the activity of the upstream kinase of IkB, IKK.
  • Cross talk is known to exist between NFkB pathway and other important in regulating cell survival and proliferation including the three-tiered MAPK signaling pathways.
  • A549 cells were treated with increasing concentrations of EF24 or curcumin for 30' and immunobloting was performed.
  • the activation of ERK, p38 MAPK, and JNK were determined using phospho-specific antibodies for the Thr/Tyr activation motifs.
  • EF24 was found to induce the activation of each of the MAPKs in a dose-dependent manner, as illustrated in FIG. 2.
  • ERK was activated in response to curcumin as well as p38 MAPK, however higher concentrations up to 50 and 100 ⁇ M were needed.
  • no phosphorylation of JNK was detected with curcumin treatment while activation of JNK was detected after 5 ⁇ M treatment of EF24.
  • JNK inhibition did not attenuate the loss of cell viability by EF24 but only caused a slightly additive drop in cell viability.
  • p38 MAPK inhibition The potential of p38 MAPK inhibition to affect the growth inhibitory effects of EF24 was evaluated.
  • the same low dose of EF24 (0.4 ⁇ M) was used as in the previous Examples.
  • EF24 treatment was combined with increasing concentration of a pyridinyl imidazole p38 MAPK inhibitor (SB203580 or SB202190) that did not significantly inhibit A549 cell viability alone.
  • A549 cells were plated at 5,000 cells/well in a 96 well plate. The following day the cells were dosed with the indicated treatments for 48 hours. The active agents used in each test were added simultaneously to the treatment media. Test results are shown in FIG. 3A - FIG. 3D.
  • MAPK activity by SB80 was also demonstrated by evaluating the phosphorylation of MAPKAPK-2, an immediate downstream effector of p38 MAPK (Fig. 3D).
  • the Chou and Talalay combination index is a well-established index to determine the pharmacologic interaction of two drugs and is based on the multiple drug-effect equation derived from enzyme kinetic models.
  • log (fa/fu) is plotted against log (D), where D represents the concentration of each single compound alone of the mixture of both while fa stands for the fraction affected (0>l) and fu is the fraction unaffected (I -fa) at each concentration D.
  • the combination of EF24 with p38 MAPK inhibitors provides a synergistic effect that exceeds a mere additive effect on growth inhibition.
  • the dose response curve for EF24 was graphed by titrating increasing amounts of this compound into the media in combination with SB80 and determining the cell viability at each concentration after 48h. This is illustrated in FIG. 4A.
  • the same dose response curve evaluation was conducted with curcumin, as shown in FIG. 4B. These curves were compared to curves for the combination of EF24 or curcumin with SB80.
  • the IC50 was shown to be 0.75 ⁇ M for EF24 alone and 0.45 ⁇ M for the combination of EF24 and SB80. This represents an approximate 40% reduction in IC50, which is significant.
  • These graphs were used to analyze the CI values of EF24 and SB 80 as described above. Synergism was observed for the combinations of EF24 and SB80 up to an EF24 concentration of 1 ⁇ M. CI values for the first two points on the graph were 0.3 ⁇ CI > 0.7, and CI values for the points up to 1 ⁇ M were 0.7 ⁇ CI > 0.85.
  • the cells were also double transfected and then treated with vehicle (0.5% DMSO) or the low dose of EF24 (0.4 ⁇ M) (FIG. 5C). Percent cell viability was analyzed after 48h and compared to a mock transfected control with a scramble siRNA. The combination of p38 siRNA and EF24 treatment significantly caused the loss of cell viability similar to that of the combination of EF24 and SB80.
  • Apoptosis was examined by flow cytometry of propidium iodide (P ⁇ )-stained cells. Unsynchronized A549 cells were exposed to the indicated drug treatment for 48h (0.4 ⁇ M EF24 and 12.5 ⁇ M SB80, alone or in combination). Attached and unattached cells were then collected, washed with 1%BSA/PBS and fixed with 75% cold ethanol for at least lhr. PI (50 ⁇ g/mL) was then used to stain the cells, and the DNA content of these stained cells was measured by a flow cytometer. The data represents the cell cycle distribution for a representative experiment.
  • FIG. 7A provides the cell cycle analysis of combined treatment of EF24 (0.4 ⁇ M) and the p38 inhibitor SB80 (12.5 ⁇ M).
  • FIG. 7B provides quantification of the % of sub- Gl cells for three independent experiments.
  • FIG. 7C provides Western blot analysis of A549 lysates treated with EF24 (0.4 ⁇ M), SB203580 (12.5 ⁇ M), curcumin (lO ⁇ M) or the combination of two drugs after 48h. The amount of full length and cleaved PARP was evaluated using the specific antibody, and these results are provided in FIG. 7D.
  • A549 cells were plated in a 96 well plate at a density of 5,000 cells/well. The following day, the cells were treated with the indicated concentrations of EF24, SB80, Cure, or the combinations of EF24 or curcumin with SB203580 for 48h. The cellular stains DAPI, Yo-Pro-1, and PI were added to each well. Yo-Pro-1 positive cells are deemed early apoptotic, Pi-positive cells are necrotic, and Yo-Pro-1 and Pi-positive cells are late apoptotic. Cells that excluded both stains but had intact nuclear staining were deemed viable. A second concentration of EF24 (0.6 ⁇ M) served as a control to ensure the assay could identify an increase in apoptosis. FIG.
  • 7E shows the results of a cell viability assay that was conducted in which A549 was pretreated with the caspase inhibitor zVAD-fmk for 1 hr before treatment with the combination of EF24 and SB 80 at the same concentrations in previous experiments.
  • A549 cells were treated with either EF24 of SB90 for 30 minutes prior to the removal of the media and the addition of the combination treatment. No significant reduction of the synergy was observed when SB90 was pretreated compared to the combination alone or pretreatment with EF24.

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Abstract

La présente invention concerne des combinaisons de composés utiles dans le traitement et la prévention du cancer et d'affections ou de maladies inflammatoires. Dans des modes de réalisation particuliers, les combinaisons comprennent un ou plusieurs composés qui sont des inhibiteurs de NF-KB ou des inhibiteurs de p38 MAPK. L'invention concerne en outre des compositions pharmaceutiques et des procédés de traitement utilisant les combinaisons. Dans un mode de réalisation, l'inhibiteur de NF-KB est un analogue de curcumine.
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