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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/402—1-aryl substituted, e.g. piretanide
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/4035—Isoindoles, e.g. phthalimide
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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  • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
  • A61K35/13—Tumour cells, irrespective of tissue of origin
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  • A61K39/00—Medicinal preparations containing antigens or antibodies
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  • 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
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
• • A—HUMAN NECESSITIES
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  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• Immuno-DASH (I-DASH) inhibitors potent inhibitors of the post-proline cleaving enzymes DPP4, DPP8 and DPP9, act as checkpoint inhibitors of a newly described immuno- checkpoint involving DASH enzymes. Inhibition of these target enzymes, which include both intracellular and extracellular targets, results in (inter alia) pyroptosis of tumor-associated macrophages, and the release of IL-lbeta and perhaps other immunostimulatory cytokines, and the effects of treatment with an I-DASH inhibitor include redistribution and altered activity of tumor associated MDSCs, enhanced priming of T- cells and dendritic cells, and enhanced trafficking of T-cells and other immune cells to the tumor.
• Valine-boroProline Treatment with the early prototypical I-DASH inhibitor Valine-boroProline (Talabostat, PT-100) was reported to result in immune-related adverse events (irAEs), including pneumonitis. See Cunningham 2007 Journal Expert Opinion on Investigational Drugs 16: 1459-1465 and Uprichard et al. (2005) Journal of Clinical Oncology 23:7563.
• DPP-IV dipeptidyl peptidase IV
• CD26 dipeptidyl peptidase IV
• DPP-8 and DPP-9 dipeptidyl peptidases 8 and 9
• FAP fibroblast activation protein
• DPPs-8 and -9 are cytosolic proteases and their inhibition by talabostat has been shown to cause caspase-1 activation and IL- ⁇ induction in macrophages, which in turn causes upregulation of the cytokines and chemokines that characterize the responses to talabostat, both in vitro and in tumor-bearing mice.
• the biological activities of the cytokines and chemokines upregulated by talabostat suggest that both innate and adaptive immunity are evoked.
• talabostat enhanced the production of cytokines in tumor tissue and lymphoid organs, resulting in enhanced tumor-specific T-cell-dependent and T-cell- independent immunity.
• chemotherapeutic agents including cisplatin, gemcitabine, paclitaxel, 5-fluorouracil, and the monoclonal antibody lituximab.
• Val-boroPro entered phase I clinical trials in humans in which the compound appeared to be well tolerated and some activity was seen.
• a phase I trial in thirteen patients treated concomitantly with immunosuppressive chemotherapy five patients showed improvement in grade 3 neutropenia and most developed elevations in serum cytokine levels.
• a phase I trial of talabostat and rituximab in rituximab-resistant lymphoma showed cytokine elevations in most patients with partial response in 3 patients.
• Val-boroPro did not meet the endpoints for efficacy.
• the present invention is based on the discovery that Talabostat, along with other immuno-DASH inhibitors, may be used as part of anti-cancer therapies when administered in combination with PGE2 antagonists such as cyclcooxygenase inhibitors, in part based on the observati ons described herein that the combination of immuno-DASH inhibitor and PGE2 antagonist produces a profound increase in safety for certain immuno-DASH inhibitor (increasing the maximum tolerated dose), and in certain instances, also produces a synergistic improvement to antitumor efficacy of the immuno-DASH inhibitor, further increasing the therapeutic window of these drugs to the point that treatment of patients becomes tractable even where dose limiting toxicities previously prevented efficacy and caused abandonment of Talabostat as a drug candidate.
• PGE2 antagonists such as cyclcooxygenase inhibitors
• One aspect of the present invention relates to a method of enhancing a cell- mediated immune response against a cancer, comprising administering to a mammal in need thereof a therapeutically effective amount of an immuno-DASH (I-DASH) inhibitor and a PGE2 antagonist (i.e., a PGE2 pathway inhibitor), wherein the I-DASH inhibitor inhibits the enzymatic activity of DPP8, DPP9 and DPP-4, and optionally FAP, and wherein the combination of immuno-DASH inhibitor and PGE2 antagonist induces and/or enhances T cell-mediated immune response against the tumor.
• I-DASH immuno-DASH
• PGE2 antagonist i.e., a PGE2 pathway inhibitor
• the subject immuno-DASH inhibitors and PGE2 antagonists are co-formulated.
• the subject immuno-DASH inhibitors are co-formulated with a PGE2 antagonist such as a cyclo-oxygenase inhibitor.
• the subject immuno-DASH inhibitors are co-formulated, i.e., into a single dosage formulation, for oral administration with a PGE2 antagonist such as a cyclo-oxygenase inhibitor.
• the immuno-DASH inhibitor and PGE2 antagonist are co-formulated in a form suitable for once daily or twice daily dosages, such as tablets, capsules or the like.
• the PGE2 antagonist increases the maximum tolerated dose of the I-DASH inhibitor by at least 30%, and more preferably at least 50%, 75%, 100%, or even at least 2, 5, 10, 20, 40 or even more than 50-fold compared to the MTD of the I-DASH inhibitor in the absence of the PGE2 antagonist.
• the PGE2 antagonist improves the efficacy rate and/or complete response rate of the I-DASH inhibitor by at least 30%, and more preferably at least 50%, 75%, 100%, or even at least 2, 5, 10, 20, 40 or even more than 50-fold compared to the efficacy and/or complete response rate of the I-DASH inhibitor in the absence of the PGE2 antagonist.
• the PGE2 antagonist reduces the dose of immuno-DASH inhibitor required, compared to administration of the immuno-DASH inhibitor alone, to produce a given antitumor effect (such as average percentage reduction in tumor volume over time compared to placebo and/or average rate of survival compared to placebo). In certain embodiments, the PGE2 antagonist reduces the dose of immuno-DASH inhibitor required, compared to administration of the immuno-DASH inhibitor alone, to produce a given antitumor effect by 10%, and more preferably at least 15%, 20%, 30%, 40%, 50% or even 75%.
• the PGE2 antagonist reduces the effect dose (ED) of immuno-DASH inhibitor required, compared to administration of the immuno-DASH inhibitor alone, to produce a given antitumor effect by 10%, and more preferably at least 15%, 20%, 30%, 40%, 50% or even 75%. In certain embodiments, the PGE2 antagonist reduces the minimum effect dose of immuno-DASH inhibitor required, compared to administration of the immuno-DASH inhibitor alone, to produce a given antitumor effect by 10%, and more preferably at least 15%, 20%, 30%, 40%, 50% or even 75%.
• ED effect dose
• the PGE2 antagonist reduces the minimum effect dose of immuno-DASH inhibitor required, compared to administration of the immuno-DASH inhibitor alone, to produce a given antitumor effect by 10%, and more preferably at least 15%, 20%, 30%, 40%, 50% or even 75%.
• the PGE2 antagonist reduces the maximum effect dose of immuno-DASH inhibitor required, compared to administration of the immuno-DASH inhibitor alone, to produce a given antitumor effect by 10%, and more preferably at least 15%, 20%, 30%, 40%, 50% or even 75%.
• the PGE2 antagonist increases the therapeutic index for an immuno-DASH inhibitor, compared to administration of the immuno-DASH inhibitor alone, by at least a factor of 2, and more preferably at least 5, 10, 15, 20, 25, 30, 40, 50, 75 or even 100.
• the PGE2 antagonist is a cyclooxygenase (COX) inhibitor, i.e., an inhibitor of COX-1 , COX-2 or both.
• COX inhibitor is a COX-2 selective inhibitor.
• the COX inhibitor is selected from the group consisting of celecoxib, deracoxib, parecoxib, valdecoxib, rofecoxib, lumiracoxib, etoricoxib, meloxicam, and mixtures and prodrugs thereof.
• the PGE2 antagonist does not bind PPARy and modulate PPARy activity at pharmacologically relevant concentrations in the combination with an I-DASH inhibitor. In certain embodiments of the present invention, the PGE2 antagonist is not indomethacin.
• the PGE2 antagonist is a phospholipases A2 inhibitor, and more preferably an inhibitor of cytosolic phospholipases A2 (cPLA2).
• the immuno-DASH- inhibitor possess an intracellular IC 50 for DPP8 and DPP9 inhibition less than 100 nM, an in vitro IC 50 of less than 100 nM for DPP4 inhibition, an IC 50 of less than 100 nM for inducing pyroptosis of macrophage in cell culture, and a koff rate for interaction with DPP4 less than 1 x 10 -4 /sec.
• the I-DASH inhibitor has IC 50 values for inhibition of DPP4, DPP8 and DPP9 that are within 2 orders of magnitude of each other.
• the immuno-DASH inhibitor has: i) an in vivo IC 50 for DPP4 inhibition of less than 200 nM, and ii) an intracellular IC 50 for DPP8 and DPP9 inhibition less than 200 nM.
• the in vivo IC 50 for DPP4 inhibition is less than 100 nM, 10 nM, 1.0 nM, 0.1 nM, 0.01 nM or even 0.001 nM.
• the in vitro cell-free IC 50 for DPP4 inhibition is less than 100 nM, 10 nM, 1.0 nM, 0.1 nM, 0.01 nM or even 0.001 nM.
• the EnPlex IC 50 for DPP4 inhibition is less than 100 nM, 10 nM, 1.0 nM, 0.1 nM, 0.01 nM or even 0.001 nM.
• the in vivo IC 50 for DPP4 inhibition is less than 100 nM, 10 nM, 1.0 nM, 0.1 nM, 0.01 nM or even 0.001 nM. In certain embodiments, the in vitro cell- free IC 50 for DPP4 inhibition is less than 100 nM, ⁇ ⁇ , l.O nM, 0.1 nM, 0.01 nM or even 0.001 nM.
• the EnPlex IC 50 for DPP4 inhibition is less than 100 nM, 10 nM, 1.0 nM, 0.1 nM, 0.01 nM, 0.001 nM (1 picomolar) or even 0.0001 nM (100 femtomolar).
• the Ri for DPP4 inhibition is less than 100 nM, 10 nM, 1.0 nM, 0.1 nM, 0.01 nM, 0.001 nM (1 picomolar) or even 0.0001 nM (100 femtomolar).
• the in vitro cell-free IC 50 for DPP8 and/or DPP9 (and preferably for both DPP8 and DPP) inhibition is less than 100 nM, 10 nM, 1.0 nM, 0.1 nM, 0.01 nM or even 0.001 nM.
• the EnPlex IC 50 for DPP8 and/or DPP9 (and preferably for both DPP8 and DPP) inhibition is less than 100 nM, 10 nM, 1.0 nM, 0.1 nM, 0.01 nM, 0.001 nM (1 picomolar) or even 0.0001 nM (100 femtomolar).
• the Ri for DPP8 and/or DPP9 (and preferably for both DPP8 and DPP) inhibition is less than 100 nM, 10 nM, 1.0 nM, 0.1 nM, 0.01 nM, 0.001 nM (1 picomolar) or even 0.0001 nM (100 femtomolar).
• the in vitro cell-free IC 50 for DPP8 and/or DPP9 (and preferably for both DPP8 and DPP) inhibition is within 100-fold of the IC 50 for DPP4 inhibition. In certain embodiments, the in vitro cell-free IC 50 for DPP8 and/or DPP9 (and preferably for both DPP8 and DPP) inhibition is at least 5 -fold less (more potent) than the IC 50 for DPP4 inhibition, and even more preferably at least 10, 50, 100, 500 or even 1000-fold less (more potent) than the IC 50 for DPP4 inhibition.
• the EnPlex IC 50 for DPP8 and/or DPP9 (and preferably for both DPP8 and DPP) inhibition is within 100-fold of the IC 50 for DPP4 inhibition. In certain embodiments, the EnPlex IC 50 for DPP8 and/or DPP9 (and preferably for both DPP8 and DPP) inhibition is at least 5 -fold less (more potent) than the IC 50 for DPP4 inhibition, and even more preferably at least 10, 50, 100, 500 or even 1000-fold less (more potent) than the IC 50 for DPP4 inhibition.
• the Ki for DPP8 and/or DPP9 (and preferably for both DPP8 and DPP) inhibition is within 100-fold of the Ki for DPP4 inhibition. In certain embodiments, the Ki for DPP8 and/or DPP9 (and preferably for both DPP8 and DPP) inhibition is at least 5-fold less (more potent) than the Ki for DPP4 inhibition, and e ven more preferably at least 10, 50, 100, 500 or even 1000-fold less (more potent) than the Ki for DPP4 inhibition.
• the subject immuno-DASH inhibitors also inhibit Fibroblast Activating Protein (FAP) within the concentration range of the drug being an effective antitumor agent.
• FAP Fibroblast Activating Protein
• the immuno-DASH inhibitor can have a Ki for inhibition FAP less than 100 nM, 10 nM, 1.0 nM, 0.1 nM, 0.01 nM, 0.001 nM (1 picomolar) or even 0.0001 nM (100 femtomolar).
• the I-DASH inhibitor exhibits slow binding inhibition kinetics.
• the I-DASH inhibitor has a k off rate for interaction with DPP4 less than lxl0 -4 /sec, and preferably less than 5 x 10 -5 /sec, 3 x 10 -5 /sec or even less than 1 x 10 -5 /sec.
• the I-DASH inhibitor a Cmax in human patients or mice, when administered in a single oral dose, that is less than 80% of the Cmax produced by oral administration of 10 millgrams of Val-boroPro as an immediate release formulation, and even more preferably has a Cmax less than 70%, 60%, 50%, 40%, 30% or even 20% of the Cmax produced by oral administration of 10 millgrams of immediate release Val-boroPro.
• the I-DASH inhibitor is formulated an an intermediate or extended release formulation so as to produce a Cmax in human patients or mice, when admini stered in a single oral dose, that is less than 80% of the Cmax produced by oral administration of 10 millgrams of Val-boroPro formulated as an immediate release formulation, and even more preferably has a Cmax less than 70%, 60%, 50%, 40%, 30% or even 20% of the Cmax produced by oral administration of 10 millgrams of immediate release Val-boroPro.
• I-DASH-inhibitor is administered in an amount that produces, within 6 hours of administration, at least a 100% increase in mean plasma levels of one or more of G-CSF, IL-6, IL-8 and/or IL-18, and even more preferably a 150%, 200%, 250%, 300%, 400%, or even 500% increase in mean plasma levels of one or more of G-CSF, IL-6, IL-8 and/or IL-18.
• I-DASH-inhibitor is administered in an amount that produces, within 6 hours of administration, at least a 100%, 150%, 200%, 250%, 300%, 400%, or even 500% increase in mean plasma levels of G-CSF.
• the single dosage formulations include an amount of I- DASH-inhibitor that produces, within 6 hours of administration, at least a 100%, 150%, 200%, 250%, 300%, 400%, or even 500% increase in mean plasma levels of G-CSF.
• the I-DASH inhibitor is administered to the patient in a sufficient amount to cause an increase in serum concentration of CXCL10.
• the I-DASH inhibitor is administered to the patient in a sufficient amount to cause a decrease in the number of tumor-associated macrophages.
• the I-DASH inhibitor is administered to the patient in a sufficient amount to reduces monocytic myeloid-derived suppressor cells in the tumor.
• the I-DASH inhibitor is administered to the patient in a sufficient amount to reduces T-cell suppressive acti vity of granulocytic myeloid-deri ved suppressor cells in the tumor.
• the I-DASH inhibitor produces full tumor regression at the therapeutically effective amount and the therapeutically effective amount is less than the immuno-DASH inhibitor's maximum tolerated dose.
• the I-DASH inhibitor has a therapeutic index of at least 10, and more preferably at least 20, 40, 60, 80 or even at least 100.
• the I-DASH inhibitor has a maximum tolerated dose of at least 50 mg in C57BL/6 mice, and even more preferably at least 100 mg, 150 mg, 200 mg, 250 mg or even at least 300 mg, and able to induce full tumor regression in the C57BL/6 mice at doses less than the maximum tolerated dose, preferably at a dose less than 75% of the maximum tolerated dose, and even more preferably at a dose less than 50%, 25%, 10% or even less than 5% of the maximum tolerated dose.
• the I-DASH inhibitor has a maximum tolerated dose, alone or in combination with a PGE2 inhibitor, the produces a Cmax of at least 50 nM in Sprague Dawley rats, and even more preferably at least 100 nM, 500 nM, 1000 nM, 1500 nM, 2000 nM, 3000 nM, 5000 nM, 10,000 nM or even at least 20,000 nM, and able to induce full tumor regression in the C57BL/6 mice at serum concentrations less than the maximum tolerated dose in those mice, preferably at a dose producing a Cmax less than 75% of the maximum tolerated dose, and even more preferably at a dose producing a Cmax less than 50%, 25%, 10% or even less than 5% of the maximum tolerated dose.
• the immuno-DASH inhibitor for use in the method of the present invention are represented by the general formula
• A represents a 4-8 membered heterocycle including the N and the Ca carbon:
• Z represents C or N
• R l represents a C-terminally linked amino acid residue or amino acid analog, or a C- terminally linked peptide or peptide analog, or an amino-protecting group, or
• R2 is absent or represents one or more substitutions to the ring A, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl (such as a carboxyl, an ester, a fonnate, or a ketone), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido,— (CH 2 ) m — R7,— ( (CH 2 )m— OH,— ((CH 2 )m— O-lower alkyl,—((CH 2 )m— O-lower alkenyl,— (CH 2 )n— O— (CH 2
• R3 represents hydrogen, if X is N, R3 represents hydrogen, if X is C, R3 represents hydrogen or a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl (such as a carboxyl, an ester, a formate, or a ketone), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido,— (CH 2 )m— R7,— (CH 2 ) m — OH,— (CH 2 )m—O-lower alkyl,— (CH 2 )m— O- lower alkenyl,— (CH 2 )n— O— (CH 2 )
• R5 represents H, an alkyl, an alkenyl, an alkynyl,— C(X1 )(X2)X3,— (CH 2 )m— R7, — (CH 2 )n-OH,— (CH 2 )n—O-alkyl,— (CH 2 )n-O-alkenyl,— (CH2)n-0-alkynyl,— (CH 2 )n -O— (CH 2 )m-R7,— (CH 2 )n-SH,— (CH 2 )n-S-alkyl,— (CH 2 )n-S-alkenyl,— (CH 2 )n -alkynyl,— (CH 2 )n-S— (CH 2 )m-R7,— C(0)C(0)NH 2 ,— C(0)C(0)OR'7;
• R6 represents hydrogen, a halogen, a alkyl, a alkenyl, a alkynyl, an aryl,— (CH 2 ) m — R7, -((CH 2 )m-OR— (CH 2 )m— O-lower alkyl,— (CH 2 )m— O-lower alkenyl,— (CH 2 )n— O— (CH 2 )m— R7,— (CH 2 )m— SH,— (CH 2 )m— S-lower alkyl,— (CH 2 )m— S-lower alkenyl, — (CH 2 )n— S— (CH 2 )m— R7,
• R7 represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle;
• R'7 represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle;
• Yl and Y2 can independently or together be OH, or a group capable of being hydrolyzed to a hydroxyl group, including cyclic derivatives where Yl and Y2 are connected via a ring having from 5 to 8 atoms in the ring structure (such as pinacol or the like),
• R50 represents O or S
• R51 represents N 3 , SH 2 , NH 2 , N0 2 or OR'7:
• R52 represents hydrogen, a lower alkyl, an amine, OR'7, or a pharmaceutically acceptable salt, or R51 and R52 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure
• XI represents a halogen
• X2 and X3 each represent a hydrogen or a halogen
• n is zero or an integer in the range of 1 to 8.
• n is an integer in the range of 1 to 8.
• Another aspect of the invention relates to the immuno-DASH inhibitor represented by formula I, or a pharmaceutical salt thereof:
• ring A represents a 3-10 membered ring structure
• ring Z represents a 4-10 membered heterocycle including the N and the Ca carbon;
• X is O or S
• X I represents a halogen
• Y 1 and Y 2 are independently OH, or together with the boron atom to which they are attached represent a group that is hydrolysable to a boronic acid, or together with the boron atom to which they are attached form a 5-8 membered ring that is hydrolysable to a boronic acid;
• R 1 is absent or represents a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido,— CF3,— ((CH 2 )m— R 3 ,— (CH 2 )mOH,— ((CH 2 )m— O- lower alkyl,— (CH 2 )m— O-lower alkenyl,— (
• R 3 represents, for each occurrence, hydrogen, or a substituted or unsubstituted lower alkyl, lower alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle;
• R 4 represents a Irydrogen, a lower alkyl, a lower alkenyl, a lower alkynyl,— (CH 2 )n— R 3 ,— (CH 2 )n— OH,— (CH 2 )n— O-lower alkyl,— (CH 2 )n— O-alkenyl,— (CH 2 )n— O- alkynyl,— (CH 2 )n— O— (CH 2 ) m — R7,— (CH 2 )n—SH,— (CH 2 )n— S-lower alkyl,— (CH 2 )n—S-lower alkenyl,— (CH 2 )n— S-lower alkynyl,— (CH 2 )n— S— (CH 2 )m— R 3 ,— C(0)C(0)NH 2 , or— C(0)C(0)OR 8 ;
• R 5 represents O or S
• R 6 represents N 3 , SH, NH 2 , N0 2 or OR 8 ;
• R 7 represents hydrogen, a lower alkyl, an amine, OR 8 , or a pharmaceutically acceptable salt, or R 5 and R 6 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure;
• R 8 represents, hydrogen, a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl;
• R 9 and R 10 are absent or represents one, two, or three substitutions to the ring A or to the ring Z to which they are appended, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl (such as a carboxyl, an ester, a formate, or a ketone), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an amino, an acylamino, an amido, a cyano, an isocyano, a thiocyanato, an isothiocyanato, a cyanato, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, lower alkyl-C(0)OH, -0-(lower alkyl)-C(0)OH,
• n 0, 1, 2, or 3;
• Another aspect of the invention relates to the immuno-DASH inhibi tor represented by formula II, or a pharmaceutical salt thereof:
• ring A along with each occurrence of R 1a , represents a 7-12 membered polycyclic ring structure
• ring Z represents a 4-10 membered heterocycle including the N and the Ca carbon;
• X is O or S
• X I represents a halogen
• Y is C orN
• Y 1 and Y 2 are independently OH, or together with the boron atom to which they are attached represent a group that is hydrolysable to a boronic acid, or together with the boron atom to which they are attached form a 5-8 membered ring that is hydrolysable to a boronic acid;
• R 1a represents a lower alkyl,— (CH 2 )m— ,— (CH 2 ) m — O— (CH 2 )m— ;— (CH 2 )m— N— (CH 2 )m— ; or— (CH 2 )m— S— (CH 2 )m— ;
• R 3 represents, for each occurrence, hydrogen, or a substituted or unsubstituted lower alkyl, lower alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle;
• R 4 represents a hydrogen, a lower alkyl, a lower alkenyl, a lower alkynyl,—
• R 5 represents O or S:
• R 6 represents N 3 , SH, NH2, NO2 or OR 8 ;
• R 7 represents hydrogen, a lower alkyl, an amine, OR 8 , or a pharmaceutically acceptable salt, or R 5 and R 6 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure;
• R 8 represents, hydrogen, a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl;
• R 9 and R 10 are absent or represents one, two, or three substitutions to the ring A or to the ring Z to which they are appended, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl (such as a carboxyl, an ester, a formate, or a ketone), a thiocarbonyl (such as a thioester, a thioacetate, or athioformate), an amino, an acylamino, an amido, a cyano, an isocyano, a thiocyanato, an isothiocyanato, a cyanato, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, lower alkyl-C(0)OH, -0-(lower alkyl)-C(0)OH,
• n 0, 1, 2, or 3;
• n 0, 1, 2, or 3;
• p 1, 2, or 3.
• Another aspect of the invention relates to the immuno-DASH inhibitor represented by formula III, or a pharmaceutical salt thereof:
• ring Z represents a 4-10 membered heterocycle including the N and the Ca carbon;
• X is O or S
• X 2 is absent or represents a halogen or lower alkyl
• Y 1 and Y 2 are independently OH, or together with the boron atom to which they are attached represent a group that is hydrolysable to a boronic acid, or together with the boron atom to which they are attached form a 5-8 membered ring that is hydrolysable to a boronic acid;
• R 1 represents, independently for each occurrence, a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido,— C F 3 ,— ((CH 2 )m— R 3 ,— (CH 2 )mOH,— ((CH 2 )m— O-lower alkyl,— (CH 2 )m—O-lower alkenyl,— (CH 2 )n— O— (CH 2 )m— R 3 ,— (CH 2 )m— SH,— (CH 2 )m— S-lower alkyl,—(CH 2 )m— S-lower alkenyl, or
• R 3 represents, for each occurrence, hydrogen, or a substituted or unsubstituted lower alkyl, lower alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle;
• R 4 represents a hydrogen, a lower alkyl, a lower alkenyl, a lower alkynyl,— (CH 2 )m— R 3 ,— (CH 2 )n—OH,— (CH 2 )n— O-lower alkyl,— (CH 2 )n— O-alkenyl,— (CH 2 )n—O-alkynyl,— (CH 2 )n— ( (CH 2 )m—R7,— (CH 2 )n— SH,—((_H 2 )*— S-lower alkyl,— (CH 2 )n— S-lower alkenyl,— (CH 2 )n— S-lower alkynyl,— (CH 2 )n— S— (CH 2 ) m — R 3 ,— C(0)C(0)NH2, or— C(0)C(0)OR 8 ;
• R 5 represents O or S
• R 6 represents N 3 , SH, NH2, NO2 or OR 8 ;
• R 7 represents hydrogen, a lower alkyl, an amine, OR 8 , or a pharmaceutically acceptable salt, or R 5 and R 6 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure;
• R 8 represents, hydrogen, a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl;
• R 10 is absent or represents one to three substitutions to the ring Z to which they are appended, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl (such as a carboxyl, an ester, a formate, or a ketone), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an amino, an acylamino, an amido, a cyano, an isocyano, a thiocyanato, an isothiocyanato, a cyanato, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, lower alkyl-C(0)OH, -0-(lower alkyl)- C(0)OH, -guanidinyl;— (CH 2 )m—
• n 0, 1 , 2, or 3;
• n 0, 1, 2, or 3.
• Another aspect of the invention relates to the immuno-DASH inhibitor represented by formula IV, or a pharmaceutical salt thereof:
• ring A represents a 3-10 membered ring structure including the N;
• ring Z represents a 4-10 membered heterocycle including the N and the Ca carbon;
• X is O or S
• X I represents a halogen
• Y 1 and Y 2 are independently OH, or together with the boron atom to which they are attached represent a group that is hydrolysable to a boronic acid, or together with the boron atom to which they are attached form a 5-8 membered ring that is hydrolysable to a boronic acid;
• R 1 is absent or represents a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido,— CF 3 ,— ((CH 2 )m— R 3 ,— ((CH 2 )mOH,— (CH 2 )n— O- lower alkyl,— (CH 2 )m— O-lower alkenyl,— (CH 2 )n— O— (CH 2 ) m — R 3 ,— (CH 2 )m— SH,— (CH 2 )m— S-lower alkyl,— (CH-V— S-lower alkenyl, or— (CH 2 )n— S— (CH 2 )m— R 3
• R 3 represents, for each occurrence, hydrogen, or a substituted or unsubstituted lower alkyl, lower alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle;
• R 4 represents a hydrogen, a lower alkyl, a lower alkenyl, a lower alkynyl,—
• R 5 represents O or S
• R 6 represents N 3 , SH, NH 2 , N0 2 or OR 8 ;
• R 7 represents hydrogen, a lower alkyl, an amine, OR 8 , or a pharmaceutically acceptable salt, or R 5 and R 6 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure;
• R 8 represents, hydrogen, a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl;
• R 9 and R 10 each independently, are absent or represents one to three substitutions to the ring A or to the ring Z to which they are appended, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl (such as a carboxyl, an ester, a formate, or a ketone), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an amino, an acylamino, an amido, a cyano, an isocyano, a thiocyanato, an isothiocyanato, a cyanato, a nitro, an azid
• n 0, 1, 2, or 3:
• n 0, 1, 2, or 3.
• the immuno-DASH inhibitor is a boronic acid inhibitor of the DASH enzymes DPP8 and DPP9 (and optionally also DPP-4 and/or FAP).
• the immuno-DASH inhibitor is a dipeptide boronic acid inhibitor of the DASH enzymes DPP8 and DPP9 (and optionally also DPP-4 and/or FAP).
• the immuno-DASH inhibitor the dipeptide boronic acid has a proline or proline analog in the PI position.
• the subject immuno-DASH inhibitors can mediate tumor regression by immune-mediated mechanisms.
• the subject I- DASH inhibitors induce macrophage pyroptosis, and directly or indirectly have such activities as immunogenic modulation, sensitize tumor cells to antigen-specific CTL killing, alter immune-cell subsets and function, accelerate T cell priming via modulation of dendritic cell trafficking, and invoke a general T-cell mediated antitumor activity.
• the subject combination of immuno-DASH inhibitor and PGE2 antagonist can be administered as part of a therapy involving one or more other chemotherapeutic agents, immuno-oncology agents or radiation. It can also be used a part of therapy including tumor vaccines, adoptive cell therapy, gene therapy, oncolytic viral therapies and the like.
• the combination of PGE2 antagonist and immuno-DA SH inhibitor can be administered as part of a broader combination therapey with other immuno-oncology treatments, such as, to illustrate, PD-1 antagonists (such as anti-PD-1 and anti-PD-Ll antabodies and small molecule antagonists of PD-1/PD-L1 signalling), a
• CTLA-4 antagonist such as anti-CTLA4 antibodies
• VEGF antagonist such as an anti-CTLA4 antibodies
• VEGF-2 like Cyramza
• an EGFr antagonist such as an anti-EGFr antibody like Necitumumab
• an IDO inhibitor such as NLG919), an IDOl inhibtor (such as Epacadostat), an anti-B7-H3 antibody (such as MGA271), an anti-GITR antibody (such a MK-4166), an HDAC inhibitor (such as entiostat), an anti-CD 137 antibody (such as Urelumab or PF- 05082566), an anti-CD20 antibody (such as Ublituximab or Gazyva), a PI3K delta inhibitor (such as TGR-1202), an IL-15 agonist (such as IL15Ra-Fc fusion protein ALT-803), a CXCR4 antagonist (such as Ulocuplumab, Plerixafor and BL-8040), a CXCL12 antagonist (such as the Spiegelmer NOX-A12), a DNMT inhibitor (such as
• Another aspect of the present invention relates to a method of enhancing a cell- mediated immune response against a cancer, comprising administering to a mammal in need thereof a therapeutically effective amount of a PD-1 inhibitor and a PGE2 antagonist (i.e., a PGE2 pathway inhibitor).
• Figure 1 is a graphical representation of the immune mechanism mediated by extracellular and intracellular targets of the subject immuno-DASH inhibitors, with the up- and down-arrows (and associated text) indicating the inhibition or stimulation/prolongation of a particular effect (direct or indirect).
• MDSC Myeloid-derived Suppressor Cell.
• TAM Tumor Associated Macrophage. Immune wheel adapted from Chen and Mellman 2013, Immunity 39(1): 1-10.
• FIG. 2 depicts tumor-associated macrophages (TAMs) as central immune regulators of the tumor microenvironment. Adapted from Noy and Pollard. Immunity (2014) 41, 49-81.
• Figure 3 is a simple graphical representation of the interplay between DPP8 and DPP9 inhibition as an induction event, and DPP4 inhibition as a prolongation event.
• Figure 4 shows the developing correlation between potency for inhibition of DPP8 and DPP9 when used to treat whole cells (intracellular IC 50 or IIC 50 ) and the IC 50 for inducing pyroptosis of macrophages in cell culture.
• Figure 5 is a schematic showing the caspase-1 dependent pyroptosis pathway, and IL-lb release, that I-DASH inhibitors are understood to trigger, as well as the induction of a prostaglandin pathway that is consistent with the dose limiting toxicities of Talabostat.
• Figure 6 shows the maximum tolerated dose study results (single dose) of treating Sprague Dawley rats with Val-boroPro (Valine-boroProline) with and without combination with the cyclooxygenase inhibitors celecoxib (a COX-2 selective nonsteroidal antiinflammatory drug), indomethacin (a nonselective inhibitor of COX-1 and COX-2) and SC- 560. Bars show the MTD single dose in SD rats prior to seeing animal death. Based on serum drug levels, the addition of a cyclooxygenase inhibitor to the 1-DASH inhibitor increases that MTD dose from 47 to 75-fold. See also Figure 17 for a similar comparison using cPLA2 inhibitors instead of COX inhibitors.
• Figures 7-10 show the results of treating MB49 tumor bearing mice with Val- boroPro (Valine-boroProline) with and without combination with celecoxib.
• Figures 7, 8 and 9 show the measured tumor volumes over time, while Figure 10 shows the individual animal tumor growth curves for the Val-boroPro (+/- celecoxib) treated groups.
• Treatment with vehicle (control) or Val-boroPro began at Day 3 after tumor innoculation, and was administered on days 4-8, 11-15 and 18-22.
• Figure 11 depicts high potency, as measured by EnPlex, of ARI-5544, ARI- 4175CH, ARI-3102C, AR1-5836, AR1-4175, ARI-3102A, ARI-2107, and AR1-2054 as inhibitors of DPP8/9 (IC 50 s for DPP9 ⁇ 50 pM).
• Figure 12 indicates that ARI-4268 displays antitumor activity in the MB49 mouse tumor model at doses indicating improved therapeutic index - even with truncated dosing schedules.
• Figures 13 and 14 show the antitumor activity of ARI-5870 in the MB49 mouse tumor model, alone or when combined with Celebrex (COX inhibitor) or an anti-PD- 1 antibody or both.
• Figures 15 and 16 show the antitumor activity of ARI-4268 in the MB49 mouse tumor model, alone or when combined with Celebrex (COX inhibitor) or an anti-PD-1 antibody or both.
• Figure 17 shows the maximum tolerated dose study results (single dose) of treating Sprague Dawley rats with Val-boroPro (Valine-boroProline) with and without combination with cPLA2 inhibitors Pyrrophenone and AACOCF3. Bars show the MTD single dose in SD rats prior to seeing animal death. Based on serum drug levels, the addition of a cPLA2 inhibitor to the I-DASH inhibitor increases that MTD dose by at least 20 -fold.
• the immuno-DASH (I-DASH) inhibitors of the combination therapies of the present invention are multimediator immuo-oncology agents targeting a novel checkpoint pathway involving macrophages through DPP8 and DPP9 inhibition, and chemokine/cytokine signaling pathways (such as CXCL10) though DPP4 and (potentially) FAP inhibition.
• Figure 1 shows the direct and indirect effects on tumor-directed immune responses that are brought about by treatment with the immuno-DASH inhibitors of the present invention.
• the present immuno-DASH inhibitors are able to:
• tumor-associated macrophages express an array of effector molecules that inhibit the antitumor immune responses; this includes cell surface receptors, cytokines, chemokines, and enzymes.
• immuno-DASH inhibitors can remove multiple immune checkpoint in the tumor microenvironment.
• Figure 4 illustrates that more effective and potentially safer immuno-DASH inhibitors can be identified by optimizing inhibitors according to intracellular IC50 ("HC50") for DPP8 and DPP9 inhibition, and that (again, not wishing to be bound by any particular theory), the potency of the agent being able to induce pyroptosis in macrophages in vitro.
• HC50 intracellular IC50
• the present invention derives from the discovery of the antitumor mechanism of action of I-DASH inhibitors involving selective pyroptosis of macrophages. As illustrated in
• the present invention is based on the additional observations that: (i) induction of pyroptosis in other contexts also results in the activation of eicosanoid production pathway(s) involving cyclooxygenase(s) and phospholipase enzymes with the production of such inflammatory eicosanoids as prostaglandin E2 (PGE2); (ii) retrospective analysis of the Talabostat clinical trial revealed two features - a dose limiting toxicity' that was consistent with inflammatory eicosanoids release, particularly PGE2, and that in the one phase 2 study involving cohorts of two different drug doses there were signals of potential efficacy (albeit modest) amongst the secondary endpoints measured, indicating that could the dose limiting toxicity be mitigated and Talabostat be dosed at 2, 5 or even 10 times higher concentration that the primary and secondary endpoints of the study might have been met.
• Figure 6 shows the maximum tolerated dose study results (single dose) of treating Sprague Dawley rats with Val-boroPro ( Valine-boroProline) with and without various cyclooxygenase inhibitors, such as celecoxib (a COX-2 selective nonsteroidal antiinflammatory drug), indomethacin (a nonselective inhibitor of COX-1 and COX-2) and SC- 560. Bars show the MTD single dose in SD rats prior to seeing animal death. Based on serum drug levels, the addition of a cyclooxygenase inhibitor to the I-DASH inhibitor increases that MTD dose from 47 to 75-fold.
• various cyclooxygenase inhibitors such as celecoxib (a COX-2 selective nonsteroidal antiinflammatory drug), indomethacin (a nonselective inhibitor of COX-1 and COX-2) and SC- 560. Bars show the MTD single dose in SD rats prior to seeing animal death. Based on serum drug levels, the addition of a cyclooxygenas
• alkyl refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
• a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), for example, 20 or fewer.
• certain cycloalkyls have from 3-10 carbon atoms in their ring structure, for example, 5, 6 or 7 carbons in the ring structure.
• Alkyl (or “lower alkyl) as used throughout the specification and claims is intended to include both “unsubstituted alkyls" and "substituted alkyls”.
• aralkyl refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
• alkenyl and alkynyl refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
• lower alkyl as used herein means an alkyl group, as defined above, but having from one to ten carbons, for example, from one to four or one to six carbon atoms in its backbone structure.
• lower alkenyl and “lower alkynyl” have similar chain lengths.
• alkyl groups are lower alkyls.
• a substituent designated herein as alkyl is a lower alkyl.
• aryl as used herein includes 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and tlie like.
• aryl heterocycles or "heteroaromatics”.
• the aromatic ring can be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphionate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, -CN, or the like.
• substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphionate
• aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
• heterocyclyl or “heterocyclic group” refer to 3- to 10-membered ring structures, for example, 3- to 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can also be polycycles.
• Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenantliroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine,
• the heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.
• substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl,
• heteroaryl refers to a monovalent aromatic monocyclic ring system wherein at least one ring atoms is a heteroatom independently selected from the group consisting of O, N and S.
• 5-membered heteroaryl refers to a heteroaryl wherein the number of ring atoms is 5. Examples of 5-membered heteroaryl groups include pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, furazanyl, imidazolinyl, and triazolyl.
• heterocycloalkyl refers to a monocyclic or bicyclic monovalent saturated or non-aromatic unsaturated ring system wherein from 1 to 4 ring atoms are heteroatoms independently selected from the group consisting of O, N and S.
• the term "3 to 10-membered heterocycloalkyl” refers to a heterocycloalkyl wherein the number of ring atoms is from 3 to 10. Examples of 3 to 10-membered heterocycloalkyl include 3 to 6- membered heterocycloalkyl.
• Bicyclic ring systems include fused, bridged, and spirocyclic ring systems.
• heterocycloalkyl groups include azepanyl, azetidinyl, aziridinyl, imidazolidinyl, morpholinyl, oxazolidinyl, oxazolidinyl, piperazinyl, piperidinyl, pyrazolidinyl, pyrrolidinyl, quinuclidinyl, and thiomorpholinyl.
• polycyclyl or “polycyclic group” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings.
• Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, etlier, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.
• substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, si
• carrier refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.
• heteroatom as used herein means an atom of any element other than carbon or hydrogen.
• Examplery heteroatoms are nitrogen, oxygen, sulfur and phosphorous.
• nitro means -NO2; the term “halogen” designates -F, -CI, -Br or -I; the term “sulfliydryl” means -SH; the term “hydroxyl” means -OH: and the term “sulfonyl” means -SO2-.
• Halogen or "halo" by themselves or as part of another substituent refers to fluorine, chlorine, bromine and iodine, or fluoro, chloro, bromo and iodo.
• substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
• substituted is contemplated to include all permissible substituents of organic compounds.
• the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
• substituents include, for example, those described hereinabove.
• the permissible substituents can be one or more and the same or different for appropriate organic compounds.
• Substituents can include, for example, a halogen, a hydroxy., a carbonyl (such as a carboxyl, an ester, a formyl, or a ketone), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfony
• the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.
• the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylases, and esters), -CF3, -CN and the like.
• Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, - CN, and the like.
• the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
• abbreviations used herein for designating the amino acids and the protective groups are based on
• Met, IIe, Leu, Ala and Gly represent "residues" of methionine, isoleucine, leucine, alanine and glycine, respectively.
• residue is meant a radical derived from the corresponding alpha-amino acid by eliminating the OH portion of the carboxyl group and the H portion of the alpha-amino group.
• amino acid side chain is that part of an amino acid exclusive of the ⁇ CH(NH2)COOH portion, as defined by K. D. Kopple, "Peptides and Amino Acids", W. A. Benjamin Inc., New York and Amsterdam, 1966, pages 2 and 33.
• amino acids used in the application of this invention are those naturally occurring amino acids found in proteins, or the naturally occurring anabolic or catabolic products of such amino acids which contain amino and carboxyl groups.
• Particularly suitable amino acid side chains include side chains selected from those of the following amino acids: glycine, alanine, valine, cysteine, leucine, isoleucine, serine, threonine, methionine, glutamic acid, aspartic acid, glutamine, asparagme, lysine, arginine, proline, histidine, phenylalanine, tyrosine, and tryptophan, and those amino acids and amino acid analogs which have been identified as constituents of peptidylglycan bacterial cell walls.
• amino acid residue further includes analogs, derivatives and congeners of any specific amino acid referred to herein, as for instance, the subject compound can include an amino acid analog such as, for example, cyanoalanine, canavanine, djenkolic acid, norleucine, 3-phosphoserine, homoserine, dihydroxy-phenylalanine, 5-hydroxytryptophan, 1- methylhistidine, 3-methylhistidine, diaminiopimelic acid, ornithine, or diaminobutyric acid.
• amino acid analog such as, for example, cyanoalanine, canavanine, djenkolic acid, norleucine, 3-phosphoserine, homoserine, dihydroxy-phenylalanine, 5-hydroxytryptophan, 1- methylhistidine, 3-methylhistidine, diaminiopimelic acid, ornithine, or diaminobutyric acid.
• amino acid analog such as, for example, cyanoalanine, canavanine,
• certain compounds of the present invention may exist in particular geometric or stereoisomeric forms.
• the present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)- isomers, the racemic mixtures thereof, and other mixtures thereof, as, falling within the scope of the invention.
• Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
• a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
• the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by- resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
• prodrug encompasses compounds that, under physiological conditions, are converted into therapeutically active agents.
• a common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule.
• the prodrug is converted by an enzymatic activity of the host animal.
• IC 50 refers to the concentration of an inhibitor where the response (or binding) is reduced by half, and can be measured in whole cell, animals or in vitro cell-free (purified enzyme) systems. Inhibition of cell-free enzyme may also be reported as Ki values with some formal kinetics measurements.
• ICIC 50 or "IIC 50” is the measure of DPP8 and DPP9 inhibition in the context of a whole cell such that cell permeability becomes a factor (DPP8 and DPP9, which are cell permeable, the purified enzymes miss the cell permeable requirements for measuring IC 50 )
• DPP4 refers to the protein dipeptidyl peptidase 4.
• DPP8 refers to the protein dipeptidyl peptidase 8.
• DPP9 refers to the protein dipeptidyl peptidase 9.
• the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version. Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.
• the term "hydrocarbon” is contemplated to include all permissible compounds having at least one hydrogen and one carbon atom.
• the permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds which can be substituted or unsubstituted.
• EnPlex refers to a purified enzyme activity assay described in Bachovchin et al. Nature Chemical Biology 10, 656-663 (2014). Briefly, purified enzymes are coupled to Luminex microspheres, with a different bead color for each enzyme.
• Multiplexed bead complexes are incubated with a compound before being treated with a biotinylated activity-based probe and a streptavidin R-phycoerythrin conjugate (SAPE).
• SAPE streptavidin R-phycoerythrin conjugate
• the mixtures are scanned on a Luminex flow cytometer, where one laser detects the bead color (enzyme identity) and a second laser detects the R-phycoerythrin signal (enzyme activity).
• the enzyme concentration is calculated assuming 100% of the protein was coupled to the beads.
• Enplex IC 50 is the IC 50 for enzyme inhibition as measured using EnPlex.
• PI position and "P2 position", in the case of a dipeptide (or dipeptide analog), refer to the carboxy and amino terminal residues, respectively.
• the PI position is the amino acid (or amino acid analog) in which the boronic acid replaces the carboxy terminus.
• One aspect of the present invention relates to a method of enhancing a cell- mediated immune response against a cancer, comprising administering to a mammal in need thereof a therapeutically effective amount of an immuno-DASH (I-DASH) inhibitor and a PD-1 antagonist, wherein the I-DASH inhibitor inhibits the enzymatic activity' of DPP8, DPP9 and DPP 4, the I-DASH inhibitor having IC 50 values for inhibition of DPP4, DPP8 and DPP9 that are within 2 orders of magnitude of each other; and wherein the combination of immuno-DASH inhibitor and PD-1 pathway inhibitor induces and/or enhances cell-mediated immune response against the tumor.
• I-DASH immuno-DASH
• the immuno-DASH- inhibitor possess an intracellular IC 50 for DPP8 and DPP9 inhibition less than 100 nM, an in vitro IC 50 of less than 100 nM for DPP4 inhibition, an IC 50 of less than 100 nM for inducing pyroptosis of macrophage in cell culture, and a koff rate for interaction with DPP4 less than 1 x 10- 4 /sec.
• cancer is selected from the group consisting of basal cell carcinoma, biliary tract cancer, bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, choriocarcinoma, CNS cancer, colon and rectum cancer, connective tissue cancer, cancer of the digestive system, endometrial cancer, esophageal cancer, eye cancer, cancer of the head and neck, gastric cancer, intra-epithelial neoplasm, kidney cancer, larynx cancer, leukemia, acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphoid leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, melanoma, myeloma, myeloproliferative disease, neuroblastoma, oral cavity cancer,
• Another aspect of the present i n vention relates to any one of the foregoing methods, wherein: the maximum tolerated dose of the immune-DASH inhibitor in C57BL/6 mice is at least lOmg/kg; and the immune-DASH inhibitor induces fill cancer regression in C57BL/6 mice at a dose less than the maximum tolerated dose in C57BL/6 mice.
• a representative class of immune-DASH inhibitors for use in the subject methods of the present invention are represented by the general formula
• A represents a 4-8 membered heterocycle including the N and the Ca carbon
• Z represents C or N
• R2 is absent or represents one or more substitutions to the ring A, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl (such as a carboxyl, an ester, a formate, or a ketone), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido,— (CH 2 ) m — R7,— ((CH 2 )m— OH,— ((CH 2 )m— O-lower alkyl,— (CH 2 )m—O-lower alkenyl,— (CH 2 )n— O— (CH 2 )m— R
• R3 represents hydrogen, if X is N, R3 represents hydrogen, if X is C, R3 represents hydrogen or a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl (such as a carboxyl, an ester, a formate, or a ketone), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido,— (CH 2 )m— R7,— (CH 2 )m— OH,— (CH 2 )m— O-lower alkyl,— (CH 2 )m— O- lower alkenyl,— (CH 2 )n— O— (CH 2 )m—
• R6 represents hydrogen, a halogen, a alkyl, a alkenyl, a alkynyl, an aryl,— (CH 2 )m— R7, -((CH 2 )m-OH ; — (CH 2 )nr—O-lower alkyl,— (CH 2 )m— O-lower alkenyl,— (Cth)*- O— (CH 2 )m— R7,— (CH 2 )m— SH,— (CH 2 )m— S-lower alkyl,— (CH 2 ) m — S-lower alkenyl, — (CH 2 )n— S— ((CH 2 )m— R7,
• R7 represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle;
• R'7 represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle:
• Yl and Y2 can independently or together be OH, or a group capable of being hydrolyzed to a hydroxyl group, including cyclic derivatives where Yl and Y2 are connected via a ring having from 5 to 8 atoms in the ring structure (such as pinacol or the like),
• R50 represents O or S
• R51 represents N 3 , SH 2 NH 2 , N0 2 or OR'7;
• R52 represents hydrogen, a lower alkyl, an amine, OR'7, or a pharmaceutically acceptable salt, or R51 and R52 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure
• XI represents a halogen
• X2 and X3 each represent a hydrogen or a halogen
• n is zero or an integer in the range of 1 to 8.
• the ring A is a 5, 6 or 7 membered ring, e.g., represented by the formula
• n is 1 or 2, though n may also be 3 or 4.
• the ring may, optionally, be further substituted.
• W represents
• W represents
• Rl is N
• R36 is a small hydrophobic group, e.g., a lower alkyl or a halogen and R38 is hydrogen, or, R36 and R37 together form a 4-7 membered heterocycle including the N and the Cos carbon, as defined for A above; and R40 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino-protecting group.
• R36 is a lower alkyl (C1-C6), such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl group, and R38 and R40 are each hydrogen.
• Rl is a valine amino acid residue.
• Rl is a t-bytyl glycine residue.
• R2 is absent, or represents a small hydrophobic group such as a lower alkyl or a halogen.
• R3 is a hydrogen, or a small hydrophobic group such as a lower alkyl or a halogen.
• R5 is a hydrogen, or a halogenated lower alkyl.
• XI is a fluorine
• X2 and X3, if halogens, are fluorine
• the subject method utilizes, as a immuno- DASH inhibitor, a boronic acid analogs of an amino acid.
• a boronic acid analogs of an amino acid For example, the present invention contemplates the use of boro-prolyl derivatives in the subject method.
• Exemplary boronic acid derived inhibitors of the present invention are represented by the general formula:
• Rl represents a C-terminally linked amino acid residue or amino acid analog, or a terminally linked peptide or peptide analog, or
• R6 represents hydrogen, a halogen, a alkyl, a alkenyl, a alkynyl, an aryl,— (CH 2 )m— R7, (CH 2 )m— OH,— (CH 2 )m— O-lower alkyl,— (CH 2 )m— O-lower alkenyl,— (CH 2 )H— O— (Cm) R7,— (CH 2 )m— SH,— (CH 2 )m— S-lower alkyl,— (CH 2 )m— S-lower alkenyl,— (CH 2 )H— S— (CH 2 )m— R7,
• R7 represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle
• Rl 1 and R12 each independently represent hydrogen, a alkyl, or a pharmaceutically acceptable salt, or R l 1 and Rl 2 taken together with the O— B— O atoms to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure:
• n is zero or an integer in the range of 1 to 8.
• n is an integer in the range of 1 to 8.
• R l is
• R36 is a small hydrophobic group, e.g., a lower alkyl or a halogen and R38 is hydrogen, or, R36 and R37 together form a 4-7 membered heterocycle including the N and the Cos carbon, as defined for A above; and R40 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino-protecting group.
• R36 is a lower alkyl (C1-C6), such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl group, and R38 and R40 are each hydrogen.
• Rl is a valine amino acid residue.
• Rl is a t-bytyl glycine residue.
• the immuno-DASH inhibitor is a peptide or peptidomimetic including a prolyl group or analog thereof in the PI specificity position, and a nonpolar (and preferably hydrophobic) amino acid in the P2 specificity position, e.g., a nonpolar amino acid such as alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan or methionine, or an analog thereof.
• the P2 position an amino acid with charged sidechain, such as Arginine, Lysine, Aspartic acid or Glutamic Acid.
• the immuno-DASH inhibitor may include an Ala-Pro or Val-Pro dipeptide sequence or equivalent thereof, and be represented in the general formulas:
• the ring A is a 5, 6 or 7 membered ring, e.g., represented by the formula
• R32 is a small hydrophobic group, e.g., a lower alkyl or a halogen.
• R30 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino- protecting group.
• R2 is absent, or represents a small hydrophobic group such as a lower alkyl or a halogen.
• R3 is a hydrogen, or a small hydrophobic group such as a lower alkyl or a halogen.
• the immuno-DASH inhibitor of the present methods is represented by formula I, or a pharmaceutical salt thereof:
• ring A represents a 3-10 membered ring structure
• ring Z represents a 4-10 membered heterocycle including the N and the Ca carbon:
• X is O or S
• X I represents a halogen
• Y 1 and Y 2 are independently OH, or together with the boron atom to which they are attached represent a group that is hydrolysable to a boronic acid, or together with the boron atom to which they are attached form a 5-8 membered ring that is hydrolysable to a boronic acid;
• R 1 is absent or represents a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido,— CF 3 ,— ((CH 2 )m— R 3 ,— (CH 2 )m OH,— (CH 2 )m— O- lower alkyl,— ((CH 2 )m— O-lower alkenyl,— (CH 2 )n— O— (CH 2 ) m — R 3 ,— ((CH 2 )m— SH,— (CH 2 )m— S-lower alkyl,— (CH 2 )m— S-lower alkenyl, or— (CH 2 )n— S— (CH 2 )
• R 3 represents, for each occurrence, hydrogen, or a substituted or unsubstituted lower alkyl, lower alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle;
• R 4 represents a hydrogen, a lower alkyl, a lower alkenyl, a lower alkynyl,—
• R 5 represents O or S
• R 6 represents N 3 , SH, NHi, N0 2 or OR 8 ;
• R 7 represents hydrogen, a lower alkyl, an amine, OR 8 , or a pharmaceutically acceptable salt, or R 5 and R 6 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure;
• R 8 represents, hydrogen, a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl;
• R 9 and R 10 are absent or represents one, two, or three substi tutions to the ring A or to the ring Z to which they are appended, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl (such as a carboxyl, an ester, a formate, or a ketone), a thiocarbonyl (such as a thioester, a thioacetate, or athioformate), an amino, an acylamino, an amido, a cyano, an isocyano, a thiocyanato, an isothiocyanato, a cyanato, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, lower alkyl-C(0)OH, -0-(lower alkyl)-C(0)OH
• n 0, 1, 2, or 3;
• n 0, 1, 2, or 3.
• the immuno-DASH inhibitor of Formula I is represented in Formula la, or is a pharmaceutical salt thereof:
• R 1 is a lower alkyl
• R 9 is absent, or independently for each occurrence, is a lower alkyl, -OH, -NH_, -N3, -(lower alkyl)-C(0)OH, -O-lower alkyl, -0-(lower alkyl)-C(0)OH, -guanidinyl
• X is O
• each R 2 is hydrogen
• R 10 is absent, or represents a single substitution of -OH, -NH2, -CN or -N3
• W is -B(OH)2 or - CN (and more preferably -B(OH)2).
• the immuno-DASH inhibitor of Formula I is represented in Formula lb, or is a pharmaceutical salt thereof:
• R 1 is a lower alkyl
• R 9 is absent, or independently for each occurrence, is a lower alkyl, -OH, -NH2, -N3, -(lower alkyl)-C(0)OH, -O-lower alkyl, -0-(lower alkyl)-C(0)OH, -guanidinyl
• X is O
• each R 2 is hydrogen
• R 10 is absent, or represents a single substitution of -OH, -NH2, -CN or -N3
• W is -B(OH)2 or - CN (and more preferably -B(OH)2).
• the immuno-DASH inhibitor of Formula I is represented in Formula Ic, or is a pharmaceutical salt thereof:
• R 1 is a lower alkyl
• R 9 is absent, or independently for each occurrence, is a lower alkyl, -OH, -NH2, -N3, -(lower alkyl)-C(0)OH, -O-lower alkyl, -0-(lower alkyl)-C(0)OH, -guanidinyl
• X is O
• each R 2 is hydrogen
• R 10 is absent, or represents a single substitution of -OH, -NH2, -CN or -N3
• W is -B(OH)2 or - CN (and more preferably -B(OH) 2 ).
• the immuno-DASH inhibitor is represented by:
• Another aspect of the invention relates to the immuno-DASH inhibitor represented by formula II, or a pharmaceutical salt thereof:
• ring A along with each occurrence of R 1a , represents a 7-12 membered polycyclic ring structure
• ring Z represents a 4-10 membered heterocycle including the N and the Ca carbon;
• X is O or S
• X I represents a halogen
• Y is C or N
• Y 1 and Y 2 are independently OH, or together with the boron atom to which they are attached represent a group that is hydrolysable to a boronic acid, or together with the boron atom to which they are attached form a 5-8 membered ring that is hydrolysable to a boronic acid;
• R 1a represents a lower alkyl,— (CH 2 )m— ,— (CH 2 ) m — O— (CH 2 )m— ;— (CH 2 )m— N— (CH 2 )m— ; or— (CH 2 ) m — S— (CH 2 )m— ;
• R 3 represents, for each occurrence, hydrogen, or a substituted or unsubstituted lower alkyl, lower alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle;
• R 4 represents a hydrogen, a lower alkyl, a lower alkenyl, a lower alkynyl,—
• R 5 represents O or S
• R 6 represents N 3 , SH, NH2, NO2 or OR 8 ;
• R 7 represents hydrogen, a lower alkyl, an amine, OR 8 , or a pharmaceutically acceptable salt, or R 5 and R 6 taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure;
• R 8 represents, hydrogen, a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl;
• R 9 and R 10 are absent or represents one, two, or three substitutions to the ring A or to the ring Z to which they are appended, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl (such as a carboxyl, an ester, a formate, or a ketone), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an amino, an acylamino, an amido, a cyano, an isocyano, a thiocyanato, an isothiocyanato, a cyanato, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, lower alkyl-C(0)OH, -0-(lower alkyl)-C(0)OH,
• n 0, 1, 2, or 3;
• n 0, 1, 2, or 3;
• p 1, 2, or 3.
• the immuno-DASH inhibitor of Formula II is represented in Formula Ila, or is a pharmaceutical salt thereof:
• R 9 is a lower alkyl, -OH, -NH2, -N3, -(lower alkyl)-C(0)OH, -O-lower alkyl, -O- (lower alkyl)-C(0)OH, -guanidinyl;
• X is O;
• each R 2 is hydrogen, R 10 is absent, or represents a single substitution of -OH, -NH2, -CN or -N3; and W is -B(OH)2 or -CN (and more preferably -B(OH) 2 ).
• the immuno-DASH inhibitor of Formula II is represented in Formula lib, or is a pharmaceutical salt thereof:
• R 9 independently for each occurrence, is a lower alkyl, -OH, -NH2, -N3, -(lower alkyl)-C(0)OH, -O-lower alkyl, -O- (lower alkyl)-C(0)OH, -guanidinyl;
• X is O;
• each R 2 is hydrogen, R 10 is absent, or represents a single substitution of -OH, -NHz, -CN or -N3; and W is -B(OH)2 or -CN (and more preferably -B(OH) 2 ).
• the immuno-DASH inhibitor of Formula II is represented in Formula lie, or is a pharmaceutical salt thereof:
• R 9 independently for each occurrence, is a lower alkyl, -OH, -NH2, -N3, -(lower alkyl)-C(0)OH, -O-lower alkyl, -O- (lower alkyl)-C(0)OH, -guanidinyl;
• X is O;
• each R 2 is hydrogen, R 10 is absent, or represents a single substitution of -OH, -NH2, -CN or -N3; and W is -B(OH)2 or -CN (and more preferably -B(OH) 2 ).
• the immuno-DASH inhibitor of Formula II is represented in Formula lid, or is a pharmaceutical salt thereof:
• R 9 is a lower alkyl, -OH, -NH2, -N3, -(lower alkyl)-C(0)OH, -O-lower alkyl, -O- (lower alkyl)-C(0)OH, -guanidinyl;
• X is O;
• each R 2 is hydrogen, R 10 is absent, or represents a single substitution of -OH, -NH2, -CN or -N3; and W is -B(OH)2 or -CN (and more preferably -B(OH) 2 ).
• the immuno-DASH inhibitor of Formula II is represented in Formula IIe, or is a pharmaceutical salt thereof:
• R 9 independently for each occurrence, is a lower alkyl, -OH, -NH2, -N3, -(lower alkyl)-C(0)OH, -O-lower alkyl, -O- (lower alkyl)-C(0)OH, -guanidinyl;
• X is O; each R 2 is hydrogen, R 10 is absent, or represents a single substitution of -OH, -NH2, -CN or -N3;
• Z is a pyrrolidine or piperidine ring (and more preferably a pyrrolidine ring); and W is -B(OH)2 or -CN (and more preferably -B(OH)2).
• the immuno-DASH inhibitor is one of the following:
• Another aspect of the invention relates to the immuno-DASH inhibitor represented by formula III, or a pharmaceutical salt thereof:
• ring Z represents a 4-10 membered heterocycle including the N and the Ca carbon;
• X is O or S
• X 2 is absent or epresents a halogen or lower alkyl
• Y 1 and Y 2 are independently OH, or together with the boron atom to which they are attached represent a group that is hydrolysable to a boronic acid, or together with the boron atom to which they are attached form a 5-8 membered ring that is hydrolysable to a boronic acid;
• R 1 represents, independently for each occurrence, a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido,— CF3,— (CH 2 )m— R 3 ,— (CH 2 )m—OH,— (CH 2 )m— O-lower alkyl,— ((CH 2 )m— O-lower alkenyl,— (CH 2 )n—0—
• R 3 represents, for each occurrence, hydrogen, or a substituted or unsubstituted lower alkyl, lower alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle;
• R 4 represents a hydrogen, a lower alkyl, a lower alkenyl, a lower alkynyl,—
• R 5 represents O or S
• R 6 represents N 3 , SH, NH2, NO2 or OR 8 ;
• R 7 represents hydrogen, a lower alkyl, an amine, OR 8 , or a pharmaceutically
• R 8 represents, hydrogen, a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl;
• R 10 is absent or represents one to three substitutions to the ring Z to which they are appended, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl (such as a carboxyl, an ester, a formate, or a ketone), a
• thiocarbonyl such as a thioester, a thioacetate, or athioformate
• n 0, 1, 2, or 3.
• X2 or F or CI and more preferably F, Rl and R2 are each lower alkyl, and more preferably methyl groups, Z is a 5 membered ring, R10 is absent, W is -B(OH)2, X is O and each occurence of R2 is hyrdogen.
• the immuno-DASH inhibitor is administered in combination with an agent that inhibits PGE2 production.
• PGE2 phospholipase A2 family members, that mobilize arachidonic acid from cellular membranes, cyclooxygenases (constitutively-active COX1 and inducible COX2) that convert arachidonic acid into prostaglandin H2 (PGH2), and prostaglandin E synthase (PGES), needed for the final formulation of PGE2.
• PHA2 phospholipase A2
• PGES prostaglandin E synthase
• the subject immuno-DASH inhibitor is administered in combination with agents which promote PGE2 degradation.
• the rate of PGE2 degradation is controlled by 15-hydroxyprostaglandin dehydrogenase (15-PGDH), suggesting that in addition to the rate of PGE2 synthesis, also the rate of PGE2 decay constitutes a target for therapeutic intervention in the subject immuno-DASH inhibitor combinations.
• the subject immuno-DASH inhibitor is administered in combination with agents that reduce PGE2 responsiveness.
• PGE2 receptors are EP1, EP2, EP3 and EP4.
• the signaling through the two Gs -coupled receptors, EP2 and EP4 is mediated by the adenylate cyclase-triggered cAMP/PKA/CREB pathway, mediating the dominant aspects of the anti-inflammatory and suppressive activity of PGE2.
• EP2 is believed to signal in a largely cAMP-dependent fashion
• EP4 also activates the PI3K-dependent ERK1/2 pathway.
• both EP2 and EP4 have been shown to activate the GSK3/p-catenin pathway.
• EP2 and the resulting responsiveness to PGE2 can be suppressed by hv-per-metiiylation, as observed in patients with idiopathic lung fibrosis.
• Agents which reduce PGE2 responsiveness also include prostaglandin (PG) signaling inhibitors.
• PG prostaglandin
• Prostaglandins signal through numerous receptors, with the key immunosuppressive effects being mediated by the activation of adenylate cyclase, the resulting elevation of the intracellular cyclic (c)AMP, PKA and the downstream activation of the PKA/CREB pathway.
• Another level of interference with the PG responsiveness includes the interference with their binging to PG receptors, hi case of PGE2, the two key cAMP- activating receptors are EP2 and EP4, for which a number of specific inhibitors exist.
• PDEs phosphodiesterases
• PDEs can be controlled by phosphodiesterase inhibitors, which include such substances as xanthines (caffeine, aminophylline, IBMX, pentoxyphylline, theobromine, theophylline, or paraxanthine), which all increase the levels of intracellular cAMP, and the more selective synthetic and natural factors, including vinpocetine, cilostazol, inaminone, cilostazol, mesembrine, rolipram, ibudilast, drotaverine, piclamilast, sildafenil, tadalafil, verdenafil, or papaverine.
• xanthines caffeine, aminophylline, IBMX, pentoxyphylline, theobromine, theophylline, or paraxanthine
• vinpocetine cilostazol
• inaminone cilostazol
• mesembrine rolipram
• ibudilast drot
• interference with PGE2 signaling can be achieved by the inhibition of downstream signals of cAMP, such as PKA or CREB.
• the subject immuno-DASH inhibitor is administered in combination with one or more prostaglandin (PG) synthesis inhibitors.
• PG prostaglandin
• PG synthesis inhibitors include nonselective inhibitors of COX-1 and COX-2, the two key enzymes in the PG synthesis pathway, and selective inhibitors of COX-2, which are believed to be more specific to COX-2 and less toxic.
• the examples of non-selective PG inhibitors include aspirin, indomethacin, or ibuprofen (Advil, Motrin).
• COX-2- selective inhibitors include Celecoxib (Celebrex) and rofecoxib (Vioxx).
• COX- 1 -specific inhibitor is sulindac (Clinoril).
• Other drugs that suppress prostaglandin synthesis include steroids (example: hydrocortisone, Cortisol, prednisone, or dexamethasone) and acetaminophen (Tylenol, Panadol), commonly used as anti-inflammatory, antipyretic and analgesic drugs.
• examples of the most commonly used selective COX2 inhibitors include celecoxib, alecoxib, valdecoxib, and rofecoxib.
• the PGE2 antagonist is not indomethacin.
• Examples of the most commonly used non-selective COX 1 and COX2 inhibitors include: acetylsalicylic acid (aspirin) and other salicylates, acetaminophen (Tylenol), ibuprofen (Advil, Motrin, Nuprin, Rufen), naproxen (Naprosyn, Aleve), nabumetone (Relafen), or diclofenac (Cataflam).
• a component of the present invention is a Cox-2 inhibitor.
• the terms "cyclooxygenase-2 inhibitor”, or "Cox-2 inhibitor”, which can be used interchangeably herein, embrace compounds which inhibit the Cox-2 enzyme regardless of the degree of inhibition of the Cox-1 enzyme, and include pharmaceutically acceptable salts of those compounds.
• a compound is considered a Cox-2 inhibitor irrespective of whether the compound inhibits the Cox-2 enzyme to an equal, greater, or lesser degree than the Cox-1 enzyme.
• the Cox-2 inhibitor compound is a non-steroidal anti-inflammatory drug (NSAID). Therefore, preferred materials that can serve as the Cox-2 inhibitor of the present invention include non-steroidal anti-inflammatory drug compounds, a pharmaceutically acceptable salt thereof, or a pure (-) or (+) optical isomeric form thereof.
• NSAID non-steroidal anti-inflammatory drug
• the Cox-2 inhibitor is a Cox-2 selective inhibitor.
• the term "Cox-2 selective inhibitor” embraces compounds which selectively inhibit the Cox- 2 enzyme over the Cox-1 enzyme, and also include pharmaceutically acceptable salts and prodrugs of those compounds.
• the selectivity of a Cox-2 inhibitor varies depending upon the condition under which the test is performed and on the inhibitors being tested. However, for the purposes of this specification, the selectivity of a Cox-2 inhibitor can be measured as a ratio of the in vitro or in vivo IC 50 value for inhibition of Cox-1, divided by the IC 50 value for inhibition of Cox-2 (Cox-1 IC 50 /C0X-2 IC 50 ).
• a Cox-2 selective inhibitor is any inhibitor for which the ratio of Cox-1 IC 50 to Cox-2 IC 50 is greater than 1. In preferred embodiments, this ratio is greater than 2, more preferably greater than 5, yet more preferably greater than 10, still more preferably greater than 50, and more preferably still greater than 100.
• IC 50 refers to the concentration of a compound that is required to produce 50% inhibition of cyclooxygenase activity.
• Preferred Cox-2 selective inhibitors of the present invention have a Cox-2 IC 50 of less than about 1 ⁇ , more preferred of less than about 0.5 uM, and even more preferred of less than about 0.2 uM.
• Preferred Cox-2 selecti ve inhibitors have a Cox-1 IC 50 of greater than about 1 uM, and more preferably of greater than 20 uM. Such preferred selectivity may indicate an ability to reduce the incidence of common NSAID-induced side effects.
• prodrugs of Cox-2-selective inhibitors are compounds that act as prodrugs of Cox-2-selective inhibitors.
• prodrug refers to a chemical compound that can be converted into an active Cox-2 selective inhibitor by metabolic or simple chemical processes within the body of the subject.
• a prodrug for a Cox-2 selective inhibitor is parecoxib, which is a therapeutically effective prodrug of the tricyclic Cox-2 selectiv e inhibitor v aldecoxib.
• An example of a preferred Cox-2 selective inhibitor prodrug is sodium parecoxib.
• a class of prodrugs of Cox-2 inhibitors is described in U.S. Pat. No. 5,932,598 (incorporated by reference).
• the Cox-2 selective inhibitor of the present invention can be, for example, the Cox-2 selective inhibitor meloxicam, (CAS registry number 71125-38-7), or a
• the Cox-2 selective inhibitor can be the Cox-2 selective inhibitor RS 57067, 6-[[5-(4-chlorobenzoyl)-l,4-dimethyl-lH-pyrrol-2- yl]methyl]-3(2H)-pyridazinone, (C AS registry number 179382-91-3), or a pharmaceutically acceptable salt or prodrug thereof.
• alkyl either alone or within other terms such as “haloalkyl” and “alkylsulfonyP'; embraces linear or branched radicals having one to about twenty carbon atoms.
• Lower alkyl radicals have one to about ten carbon atoms. The number of carbon atoms can also be expressed as "C1-C5", for example.
• Examples of lower alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl and the, like.
• alkenyl refers to an unsaturated, acyclic hydrocarbon radical, linear or branched, in so much as it contains at least one double bond.
• the alkenyl radicals may be optionally substituted with groups such as those defined below.
• suitable alkenyl radicals include propenyl, 2-chloropropylenyl, buten-lyl, isobutenyl, penten-lyl, 2- methylbuten-l-yl, 3-methylbuten-l-yl, hexen-l-yl, 3-hydroxyhexen-l-yl, hepten-l-yl, octen- 1-yl, and the like.
• alkynyl refers to an unsaturated, acyclic hydrocarbon radical, linear or branched, in so much as it contains one or more triple bonds, such radicals preferably containing 2 to about 6 carbon atoms, more preferably from 2 to about 3 carbon atoms.
• the alkynyl radicals may be optionally substituted with groups such as described below.
• alkynyl radicals examples include ethynyl, proynyl, hydroxypropynyl, butyn-l-yl, butyn-2- yl, pentyn-l-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-l-yl, hexyl- 1-yl, hexyn-2- yl, hexyn-3-yl, 3,3-dimethylbutyn-l-yl radicals, and the like.
• oxo means a single double-bonded oxygen.
• 'liydrido "— H", or "hydrogen”, denote a single hydrogen atom (H).
• This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical, or two hydrido radicals may be attached to a carbon atom to form a methylene (— CH2— ) radical.
• halo means halogens such as fluorine, chlorine, and bromine or iodine atoms.
• haloalkyl embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl, and polyhaloalkyl radicals.
• a monohaloalkyl radical for one example, may have a bromo, chloro, or a fluoro atom within the radical.
• Dihalo alkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals.
• hydroxyalkyl embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals.
• alkoxy and alkoxyalkyl embrace linear or branched oxy- containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical.
• alkoxyalkyl also embraces alkyl radicals having two or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and
• dialkoxyalkyl radicals may be further substituted with one or more halo atoms, such as fluoro, chloro, or bromo, to provide 'lialoalkoxy" or '3 ⁇ 4aloalkoxyalkyl” radicals.
• halo atoms such as fluoro, chloro, or bromo
• alkoxy radicals include methoxy, butoxy, and trifluoromethoxy.
• aryl whether used alone or with other terms, means a carbocyclic aromatic system containing one, two, or three rings wherein such rings may be attached together in a pendent manner, or may be fused.
• aryl embraces aromatic radicals such as phenyl, naphthyl, tetrahydronapthyl, indane, and biphenyl.
• '3 ⁇ 4eterocyclyl means a saturated or unsaturated mono- or multi-ring carbocycle wherein one or more carbon atoms are replaced by N, S, P, or O. This includes, for example, structures such as:
• Z, Z 1 , Z 2 , or Z 3 is C, S, P, O, or N, with the proviso that one of Z, Z 1 , Z 2 , or Z 3 is other than carbon, but is not O or S when attached to another Z atom by a double bond or when attached to another O or S atom.
• the optional substituents are understood to be attached to Z, Z 1 , Z 2 , or Z 3 only when each is C.
• heterocycle also includes fully saturated ring structures, such as piperazinyl, dioxanyl, tetrahydrofuranyl, oxiranyl, aziridinyl, morpholinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, and others.
• heteroaryl embraces unsaturated heterocyclic radicals.
• unsaturated heterocyclic radicals include thienyl, pyrryl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, pyranyl, and tetrazolyl.
• the term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like.
• alkylsulfonyl whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals— SO2— .
• alkylsulfonyl embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined as above.
• arylsulfonyr embraces sulfonyl radicals substituted with an aryl radical.
• aminosulfonyF' denotes a sulfonyl radical substituted with an amine radical, forming a sulfonamide (— SO2— NH2).
• carboxyalkyl embraces radicals having a carboxyradical as defined above, attached to an alkyl radical.
• alkylcarbonyl embraces radicals having a carbonyl radical substituted with an alkyl radical.
• An example of an "alkylcarbonyl” radical is CH3— (CO)— .
• amino whether used alone or with other terms, such as “aminocarbonyr, denotes— NH2.
• heterocycloa]kyl embraces heterocyclic-substituted alkyl radicals such as pyridylmethyl and thienylmethyl.
• aralkyl or "aiylalkyl” embrace aryl- substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl.
• benzyl and phenylmethyl are interchangeable.
• cycloalkyl embraces radicals having three to ten carbon atoms, such as cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
• cycloalkenyl embraces unsaturated radicals having three to ten carbon atoms, such as cylopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl.
• alkylthio embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom.
• An example of “alkylthio” is methylthio, (CH3— S— ).
• alkylsulfinyl embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent— S(— O)— atom.
• acyl whether used alone, or within a term such as “acylamino", denotes a radical provided by the residue after removal of hydroxyl from an organic acid.
• cyanoalkyl refers to C ⁇ N.
• nitro denotes— NO 2 .
• the Cox-2 selective inhibitor is of the chromene/chroman structural class, which encompasses substituted benzopyrans or substituted benzopyran analogs, as well as substituted benzothiopyrans, dihydroquinolines, or dihydronaphthalenes having the structure of any one of the general Formulas shown below, and the diastereomers, enantiomers, racemates, tautomers, salts, esters, amides and prodnigs thereof.
• Benzopyrans that can serve as a Cox-2 selective inhibitor of the present invention include substituted benzopyran derivatives that are described in U.S. Pat. Nos. 6,271,253 and 6,492,390 (both of which are incorporated by reference).
• One such class of compounds is defined by the general formula shown below:
• X 1 is selected from O, S, CR c R b and NR a ; wherein R a is selected from hydrido, C1-Cs-alkyl, (optionally substituted phenyl)-C1- C3-alkyl, acyl and carboxy-C1-C6-alkyl;
• each of R b and R c is independently selected from hydrido, C1-CValkyl, phenyl-C1-C3-alkyl, C1-C3-perfluoroalkyl, chloro, C1-C6-alkylthio, C1-C6-alkoxy, nitro, cyano and cyano-C1-C3-alkyl; or wherein CR b R c forms a 3-6 membered cycloalkyl ring; wherein R 1 is selected from carboxyl, aminocarbonyl, C1-C6- alkylsulfonylaminocarbonyl and C1-C6-alkoxycarbonyl;
• R 2 is selected from hydrido, phenyl, thienyl, C1-C6-alkyl and C2-C6-alkenyl; wherein R 3 is selected from C1-C1-perfluoroalkyl, chloro, C1-C6-alkylthio, C1-C6- alkoxy, nitro, cyano and cyano-C1-C3-alkyl;
• R 4 is one or more radicals independently selected from hydrido, halo, C1-C6- alkyl, C2-C6-alkenyl, C2-C6-alkynyl, halo-C2-C6-alkynyl, aryl-C1-C3-alkyl, aryl-C2-C5- alkynyl, aryl-C2-C6-alkenyl, C1-C6-alkoxy, methylenedioxy, C1-C6-alkylthio, C1-C6- aJkylsdfinyl, aryloxy, arylthio, arylsulfinyl, heteroaryloxy, C1-C6-alkoxy-C1-CValkyl, aryl-C1-C6-alkyloxy, heteroaryl-C1-C6-alkyloxy, aryl-C1-C6-alkoxy-C1-CValkyl, ary
• a ring atoms A 1 , A 2 , A 3 and A 4 are independently selected from carbon and nitrogen with the proviso that at least two of A 1 , A 2 , A 3 and A 4 are carbon;
• R 4 together with ring A forms a radical selected from naphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl and dibenzofuryl; or an isomer or pharmaceutically acceptable salt thereof.
• Another class of benzopyran derivatives that can serve as the Cox-2 selective inhibitor of the present invention includes compounds having the structure of:
• X 2 is selected from O, S, CR c R b and NR a ;
• R a is selected from hydrido, C1-C3-alkyl, (optionally substituted phenyl)-C1- Cj-alkyl, alkylsulfonyl, phenylsulfonyl, benzylsulfonyl, acyl and carboxy-C1-C6-alkyl; wherein each of R b and R c is independently selected from hydrido, C1-C3-alkyl, phenyl-C1-CValkyl, C1-C3-perfluoroalkyl, chloro, C1-C6-alkylthio, C1-C6-alkoxy, nitro, cyano and cyano-C1-C3-alkyl; or wherein CR c R b form a cyclopropyl ring;
• R 5 is selected from carboxyl, aminocarbonyl, C1-C6- alkylsulfonylaminocarbonyl and C1-C6-alkoxycarbonyl;
• R 6 is selected from hydrido, phenyl, thienyl, C2-C6-alkynyl and C2-C6- alkenyl:
• R 7 is selected from C1-C3-perfluoroalkyl, chloro, C1-C6-alkylthio, C1-C6- alkoxy, nitro, cyano and cyano-C1-C3-alkyl;
• R 8 is one or more radicals independently selected from hydrido, halo, C1-C6- alkyl, C2-C6-alkenyl, C2-C6-alkynyl, halo-C2-C6-alkynyl, aryl-C1-C3-alkyl, aryl-C2-C6- alkynyl, aryl-C2-C6-alkenyl, C1-C6-alkoxy, methylenedioxy, C1-C6-alkylthio, C1-C6- alkylsulfinyl,— 0(CF2)20— , aryloxy, arylthio, arylsulfinyl, heteroaryloxy, C1-C6-alkoxy- C1-C6-alkyl, aryl-C1-C6-alkyloxy, heteroaryl-C1-C6-alkyloxy, aryl-C1-C6-alkoxy,
• R 8 together with ring D forms a radical selected from naphthyl, quinolyl, isoquinolyl, quinolizinyl, quinoxalinyl and dibenzofuryl; or an isomer or pharmaceutically acceptable salt thereof.
• X 3 is selected from the group consisting of O or S or NR a ;
• R a is alkyl
• R 9 is selected from the group consisting of H and aryl
• R 10 is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;
• R 11 is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally substituted with one or more radicals selected from alkylthio, nitro and alkylsulfonyl; and
• R 12 is selected from the group consisting of one or more radicals selected from H, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino,
• heteroarylalkylamino nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl,
• heterocyclosulfonyl alkylsulfonyl, hydroxyarylcarbonyl, nitroaryl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl; or
• R 12 together with ring E forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof; and including the diastereomers, enantiomers, racemates, tautomers, salts, esters, amides and prodrugs thereof.
• X 4 is selected from O or S or NR a ;
• R a is alkyl
• R 13 is selected from carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl and alkoxycarbonyl;
• R 14 is selected from haloalkyl, alkyl, aralkyl, cycloalkyl and aryl optionally substituted with one or more radicals selected from alkylthio, nitro and alkylsulfonyl; and wherein R 15 is one or more radicals selected from hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyclosulfony
• heteroarylcarbonyl arylcarbonyl, aminocarbonyl, and alkylcarbonyl
• X s is selected from the group consisting of O or S or NR b ;
• R b is alkyl
• R 16 is selected from the group consisting of carboxyl, aminocarbonyl,
• R 17 is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl and aryl, wherein haloalkyl, alkyl, aralkyl, cycloalkyl, and aryl each is independently optionally substituted with one or more radicals selected from the group consisting of alkylthio, nitro and alkylsulfonyl; and
• R 18 is one or more radicals selected from the group consisting of hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl,
• heteroarylaminosulfonyl aralkylaminosulfonyl, heteroaralkylaminosulfonyl,
• heterocyclosulfcuryl alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl; or wherein R 18 together with ring A forms a naphthyl radical ;
• the Cox-2 selective inhibitor may also be a compound of the above formula, wherein:
• X 5 is selected from the group consisting of oxygen and sulfur
• R 16 is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl;
• R 17 is selected from the group consisting of lower haloalkyl, lower cycloalkyl and phenyl;
• R 18 is one or more radicals selected from the group of consisting of hydrido, halo, lower alkyl, lower alkoxy, lower haloalkyl, lower haloalkoxy, lower alkylamino, nitro, amino, aminosulfonyl, lower alkylaminosulfonyl, 5-membered
• heteroarylalkylaminosulfonyl 6-membered heteroarylalkylammosulfonyl, lower aralkylaminosulfonyl, 5-membered nitrogen-containing heterocyclosulfonyl, 6-membered nitrogen-containing heterocyclosulfonyl, lower alkylsulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, and lower alkylcarbonyl; or
• R 18 together with ring A forms a naphthyl radical; or an isomer or pharmaceutically acceptable salt thereof
• the Cox-2 selective inhibitor may also be a compound of the above formula, wherein:
• X 5 is selected from the group consisting of oxygen and sulfur
• R 16 is carboxyl;
• R 17 is lower haloalkyl;
• R 18 is one or more radicals selected from the group consisting of hydrido, halo, lower alkyl, lower haloalkyl, lower haloalkoxy, lower alkylamino, amino, aminosulfonyl, lower alkylaminosulfonyl, 5-membered heteroarylalkylaminosulfonyl, 6-membered
• heteroarvdalkylaminosulfonyl lower aralkylaminosulfonyl, lower alkylsulfonyl, 6- membered nitrogen-containing heterocyclosulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, and lower alkylcarbonyl; or wherein R 18 together with ring A forms a naphthyl radical;
• the Cox-2 selective inhibitor may also be a compound of the above formula, wherein:
• X 3 is selected from the group consisting of oxygen and sulfur
• R 16 is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl;
• R 17 is selected from the group consisting of fiuoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, difluoromethyl, and trifluoromethyl; and
• R 18 is one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl, butyl, isobutyl, pentyl, hexyl, methoxy, ethoxy, isopropyloxy, tertbutyloxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, amino, N,N-dimethylamino, N,N-diethylamino, N- phenylmethylaminosulfonyl, N-phenyletiiylaminosulfonyl, N-(2- furylmethyl)aminosulfonyl, nitro, N,N-dimethylaminosulfonyl, aminosulfonyl, N- methylaminosulfonyl, N-ethylsulfonyl, 2,2-dimethyle
• the Cox-2 selective inhibitor may also be a compound of the above formula, wherein:
• X 5 is selected from the group consisting of oxygen and sulfur
• R 16 is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl and lower alkoxycarbonyl;
• R 17 is selected from the group consisting trifluoromethyl and pentafluoroethyl; and
• R 18 is one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy, N-phenylmetliylaminosulfonyl, N-phenylethylaminosulfonyl, N-(2- fuiylmethyl)aminosulfonyl, N,N-dimethylaminosulfonyl, N-methylaminosulfonyl, N-(2,2- dimethylethyl)aminosulfonyl, dimethylaminosulfonyl, 2-methylprop
• the Cox-2 selective inhibitor of the present invention can also be a compound having the structure of:
• X 6 is selected from the group consisting of O and S;
• R 19 is lower haloalkyl
• R 20 is selected from the group consisting of hydrido, and halo
• R 21 is selected from the group consisting of hydrido, halo, lower alkyl; lower haloalkoxy, lower alkoxy, lower aralkylcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkylaminosulfonyl, lower heteroaralkylaminosulfonyl, 5- membered nitrogen-containing heterocyclosulfonyl, and 6-membered nitrogen-containing heterocyclosulfonyl;
• R 22 is selected from the group consisting of hydrido, lower alkyl, halo, lower alkoxy, and aryl;
• R 23 is selected from the group consisting of the group consisting of hydrido, halo, lower alkyl, lower alkoxy, and aryl;
• the Cox-2 selective inhibitor can also be a compound of having the structure of the above formula, wherein: X 6 is selected from the group consisting of O and S;
• R 19 is selected from the group consisting of trifluoromethyl and pentafluoroethyl
• R 20 is selected from the group consisting of hydrido, chloro, and fluoro;
• R 21 is selected from the group consisting of hydrido, chloro, bromo, fluoro, iodo, methyl, tert-butyl, trifluoromethoxy, methoxy, benzylcarbonyl, dimethylaminosulfonyl, isopropylaminosulfonyl, methylaminosulfonyl, benzylaminosulfonyl,
• R 22 is selected from the group consisting of hydrido, methyl, ethyl, isopropyl, tert- butyl, chloro, methoxy, diethylamino, and phenyl;
• R 23 is selected from the group consisting of hydrido, chloro, bromo, fluoro, methyl, ethyl, tert-butyl, methoxy, and phenyl;
• Examples include:
• the chromene Cox-2 inhibitor is selected from (S)- 6-chloro-7-(l, l-dimethylemyl)-2-(1rifluoromethyl)-2H-l-benzopyran-3-carboxylic acid, (2S)- 6,8-dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (2S)-6-chloro-8-methyl-2- (trifluoromethyl)-2H-chromene-3-carboxylic acid, (2S)-8-ethyl-6-(trifluoromethoxy)-2- (trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6,8-dichloro-2-(trifluoromethyl)-2H-l- benzopyran-3-carboxylic acid, (2S)-6-chloro-5,7-dimethyl-2-(trifluoromethyl)-2H-chromene- 3-carboxylic acid, and
• the Cox-2 inhibitor can be selected from the class of tricyclic Cox-2 selective inhibitors represented by the general structure of:
• Z 1 is selected from the group consis ting of partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings:
• R 24 is selected from the group consisting of heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R 24 is optionally substituted at a substitutable position with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio;
• R 25 is selected from the group consisting of methyl or amino
• R 26 is selected from the group consisting of a radical selected from H, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkyltliioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl,
• aminocarbonylalkyl alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N- arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyaU ⁇ yl, alkylamino, N -arylamino, N- aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl,
• alkylaminoalkyl N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, N- alkyl-N-arylaminosulfonyl;
• the Cox-2 selective inhibitor represented by the above formula is selected from the group of compounds which includes celecoxib (B-21), valdecoxib (B-22), deracoxib (B-23), rofecoxib (B-24), etoricoxib (MK- 663; B-25), JTE-522 (B-26), or prodrugs thereof.
• the Cox-2 selective inhibitor is selected from the group consisting of celecoxib, rofecoxib and etoricoxib.
• parecoxib See, U.S. Pat. No. 5,932,598 (incorporated by reference)), having the structure shown in B-27, and which is a
• a preferred form of parecoxib is sodium parecoxib.
• Another tricyclic Cox-2 selective inhibitor useful in the present invention is the compound ABT-963, having the formula B-28 shown below, that has been previously described in International Publication Number WO 00/24719 (incorporated by reference).
• the Cox-2 inhibitor can be selected from the class of phenylacetic acid derivative Cox-2 selective inhibitors represented by the general structure of:
• R 27 is methyl, ethyl, or propyl
• R 28 is chloro or fluoro
• R 29 is hydrogen, fluoro, or methyl
• R 30 is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, etlioxy or hydroxyl;
• R 31 is hydrogen, fluoro, or methyl
• R 32 is chloro, fluoro, trifluoromethyl, methyl, or ethyl
• R 28 , R 29 , R 30 and R 31 are not all fluoro when R 27 is ethyl and R 30 is H.
• Cox-2 selective inliibitor that is described in WO 99/11605 (incorporated by reference) is a compound that has the structure shown in the above formula,
• R 27 is ethyl
• R 28 and R 30 are chloro
• R 29 and R 31 are hydrogen
• R 32 is methyl
• Another phenylacetic acid derivative Cox-2 selective inhibitor is a compound that has the structure shown in the above formula,
• R 27 is propyl
• R 28 and R 30 are chloro
• R 29 and R 31 are methyl
• R 32 is ethyl.
• Another phenylacetic acid derivative Cox-2 selective inhibitor that is disclosed in WO 02/20090 is a compound that is referred to as COX- 189 (also termed liimiracoxib; CAS Reg. No. 220991-20-8), having the structure shown in the above formula, wherein:
• R 27 is methyl
• R 28 is fluoro
• R 32 is chloro
• R 29 , R 30 , and R 31 are hydrogen.
• Cox-2 selective inhibitors that can be used in the present invention have the general structure shown in below, where the J group is a carbocycle or a heterocycle. Preferred embodiments have the structure:
• X 7 is 0; J is 1 -phenyl; R 33 is 2-NHS0 2 Cft ; R 34 is 4-NO2; and there is no R 35 group, (nimesulide), or
• X 7 is 0; J is l-oxo-inden-5-yl; R 33 is 2-F; R 34 is 4-F; and R 35 is 6-NHSO2CH3, (flosulide); or
• X 7 is O; J is cyclohexyl; R 33 is 2-NHSO2CH3; R 34 is 5-N0 2 ; and there is no R 35 group, (NS-398); or
• X 7 is S; J is l -oxo-inden-5-yl; R 33 is 2-F; R 34 is 4-F; and R 35 is 6-N-S0 2 CH3.Na + , (L- 745337); or
• X 7 is S; J is thiophen-2-yl; R 33 is 4-F; there is no R 34 group; and R 35 is 5-NHSO2CH3, (RWJ-63556); or
• X 7 is 0; J is 2-oxo-5(R)-methyl-5-(2,2,2-trifluoroethyl)fiiran-(5H)-3-yl; R 33 is 3-F; R 34 is 4-F; and R 35 is 4-(p-S0 2 CH 2 )C 6 H4, (L-784512).
• the Cox-2 selective inhibitor NS-398 also known as N-(2- cyclohexyloxynitrophenyl)methane sulfonamide (CAS RN 123653-11-2), having a structure as shown below in formula B-29, has been described in, for example, Yoshimi, N. et al., in Japanese J. Cancer Res., 90(4):406-412 (1999).
• Materials that can serve as the Cox-2 selective inhibitor of the present invention include diarylmethylidenefuran derivatives that are described in U.S. Pat. No. 6,180,651 (incorporated by reference). Such diarylmelhylidenefuran derivatives have the general formula shown below in:
• the rings T and M independently are a phenyl radical, a naphthyl radical, a radical derived from a heterocycle comprising 5 to 6 members and possessing from 1 to 4 heteroatoms, or a radical derived from a saturated hydrocarbon ring having from 3 to 7 carbon atoms;
• At least one of the substituents Q 1 , Q 2 , L 1 or L 2 is an— S(0)n— R group, in which n is an integer equal to 0, 1 or 2 and R is a lower alkyl radical having 1 to 6 carbon atoms, a lower haloalkyl radical having 1 to 6 carbon atoms, or an— SO2NH2 group; and is located in the para position,
• R 36 , R 37 , R 38 and R 39 independently are a hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a lower haloalkyl radical having 1 to 6 carbon atoms, or an aromatic radical selected from the group consisting of phenyl, naphthyl, thienyl, furyl and pyridyl; or,
• R 36 , R 37 or R 38 , R 39 are an oxygen atom
• R 36 , R 37 or R 38 , R 39 together with the carbon atom to which they are attached, form a saturated hydrocarbon ring having from 3 to 7 carbon atoms;
• Particular diarylmethylidenefiiran derivatives that can serve as the Cox-2 selective inhibitor of the present invention include, for example, N-(2- cyclohexyloxynitrophenyl)methane sulfonamide, and (E)-4-[(4-methylphenyl)(tetrahydro-2- oxo-3 -furanylidene) methyl]benzenesulfonamide .
• Cox-2 selective inhibitors that are useful in the present invention include darbufelone (Pfizer), CS-502 (Sankyo), LAS 34475 (Almirall Profesfarma), LAS 34555 (Almirall Profesfarma), S-33516 (Sender), SD 8381 (Pharmacia, described in U.S. Pat. No. 6,034,256), BMS-347070 (Bristol Myers Squibb, described in U.S. Pat. No.
• Compounds that may act as Cox-2 selective inhibitors of the present invention include multibinding compounds containing from 2 to 10 ligands covanlently attached to one or more linkers, as described in U.S. Pat. No. 6,395,724 (incorporated by reference).
• Conjugated linoleic as described in U.S. Pat. No. 6,077,868 (incorporated by reference), is useful as a Cox-2 selective inhibitor in the present invention.
• Compounds that can serve as a Cox-2 selective inhibitor of the present invention include heterocyclic aromatic oxazole compounds that are described in U.S. Pat. Nos. 5,994,381 (incorporated by reference) and 6,362,209 (incorporated by reference). Such heterocyclic aromatic oxazole compounds have the formula shown below in:
• Z 2 is an oxygen atom
• R 40 and R 41 is a group of the formula
• R 43 is lower alkyl, amino or lower alkylamino
• R 44 , R 45 , R 46 and R 47 are the same or different and each is hydrogen atom, halogen atom, lower alkyl, lower alkoxy, trifluoromethyl, hydroxyl or amino, provided that at least one of R 44 , R 45 , R 46 and R 47 is not hydrogen atom, and the other is an optionally substituted cycloalkyl, an optionally substituted heterocyclic group or an optionally substituted aryl; and
• R 30 is a lower alkyl or a halogenated lower alkyl
• Cox-2 selective inhibitors that are useful in the method and compositions of the present invention include compounds that are described in U.S. Pat. Nos. 6,080,876 (incorporated by reference) and 6,133,292 (incorporated by reference), and described by:
• Z 3 is selected from the group consisting of linear or branched C1-C6 alkyl, linear or branched C1-C6 alkoxy, unsubstituted, mono-, di- or tri-substituted phenyl or naphthyl wherein the substituents are selected from the group consisting of hydrogen, halo, C1- C 3 alkoxy, CN, C1-C3 fluoroalkyl C1-C3 alkyl, and— CO2H;
• R 48 is selected from the group consisting of NFb and CH3,
• R 49 is selected from the group consisting of C1-C6 alkyl unsubstituted or substituted with C3-C6cycloalkyl, and C3-C6 cycloalkyl;
• R 50 is selected from the group consisting of: C1-C6 alkyl unsubstituted or substituted with one, two or three fluoro atoms, and C3-C6 cycloalkyl;
• R 51 is selected from the group consisting of CH3, NH2, NHC(0)CF3, and NHCH 2 ;
• Z 4 is a mono-, di-, or trisubstituted phenyl or pyridinyl (or the N-oxide thereof), wherein the substituents are chosen from the group consisting of hydrogen, halo, C1- C6 alkoxy, CVC6 alkylthio, CN, C1-C6 alkyl, C1-C6 fluoroalkyl, N 3 ,— CO2R 33 , hydroxyl,— C(R 54 )(R 55 )— OH,— C1-C 6 alkyl-C02— R 56 , C1-C6fluoroalkoxy;
• R 52 is chosen from the group consisting of: halo, C1-C6 alkoxy, C1-C6alkylthio, CN, C1-Gs alkyl, C1-C6 fluoroalkyl, N 3 ,— CO2R 57 , hydroxyl,— C(R 58 )(R 59 )— OH,— C1-C6 alkyl- CO2— R 60 , C1-C6 fluoroalkoxy, NO2, NR 61 R 62 , and NHCOR 63 ;
• R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 60 , R 61 , R 62 , and R 63 are each independently chosen from the group consisting of hydrogen and C1-C6 alkyl;
• X 8 is an oxygen atom or a sulfur atom
• R 64 and R 65 are independently a hydrogen atom, a halogen atom, a C1-C6 lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxyl group, a nitro group, a nitrile group, or a carboxyl group;
• R 66 is a group of a formula: S(0)nR 68 wherein n is an integer of 0 ⁇ 2, R 68 is a hydrogen atom, a C1-C6 lower alkyl group, or a group of a formula: NR 69 R 70 wherein R 69 and R 70 , identical to or different from each other, are independently a hydrogen atom, or a C1- C6 lower alkyl group; and
• R 67 is oxazolyl, benzo[b]thienyl, furanyl, thienyl, naphthyl, thiazolyl, indolyl, pyrolyl, benzofuranyl, pyrazolyl, pyrazolyl substituted with a C1-C6 lower alkyl group, indanyl, pyrazinyl, or a substituted group represented by the following structures:
• R 71 through R 75 are independently a hydrogen atom, a halogen atom, a C1 -C6 lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a group of a formula: S(0)iiR 68 , a group of a formula: NR 69 R 70 , a trifluoromethoxy group, a nitrile group a carboxyl group, an acetyl group, or a formyl group,
• R 76 is a hydrogen atom, a halogen atom, a C1-C6 lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxyl group, a trifluoromethoxy group, a carboxyl group, or an acetyl group.
• Materials that can serve as the Cox-2 selective inhibitor of the present invention include l-(4-sulfamylar>'l)-3-substituted-5-aryl-2-pyrazolines that are described in U.S. Pat. No. 6,376,519 (incorporated by reference).
• Such l-(4-sulfamylaryl)-3-substituted-5- aryl-2-pyrazolines have the formula shown below:
• X 9 is selected from the group consisting of C1-C6trihalomethyl, preferably trifluoromethyl; C1-C5 alkyl; and an optionally substituted or di-substituted phenyl group of formula:
• R 77 and R 78 are independently selected from the group consisting of hydrogen, halogen, preferably chlorine, fluorine and bromine; hydroxyl; nitro; C1-C6 alkyl, preferably C1-C3 alkyl; C1-C6 alkoxy, preferably C1-C3 alkoxy; carboxy; C1-C6trihaloalkyl, preferably trihalomethyl, most preferably trifluoromethyl; and cyano;
• Z 5 is selected from the group consisting of substituted and unsubstituted aryl.
• Compounds useful as Cox-2 selective inhibitors of the present invention include heterocycles that are described in U.S. Pat. No. 6,153,787 (incorporated by reference). Such heterocycles have the general formulas shown below:
• R 80 is selected from the group consisting of CH3, NH2, NHC(0)CF 3 , and NHCtt;
• R 81 and R 82 are independently chosen from the group consisting of hydrogen and C1- C 10 alkyl;
• R 81 and R 82 together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms.
• X 10 is fluoro or chloro.
• Materials that can serve as the Cox-2 selective inhibitor of the present invention include 2,3,5-trisubstitiited pyridines that are described in U.S. Pat. No. 6,046,217 (incorporated by reference). Such pyridines have the general formula shown below:
• X 11 is selected from the group consisting of O, S, and a bond
• n 0 or 1
• R 83 is selected from the group consisting of CH3, NH2, and NHC(0)CF3;
• R 84 is chosen from the group consisting of halo, C1-C6alkoxy, C1-C6 alkylthio, CN, C1-C6 alkyl, C1-C6 fluoroalkyl, N3,— CO2R 92 , hydroxy!,— C(R 93 )(R 94 )— OH,— C1- C6 alkyl-CO2— R 95 , C1-C6 fluoroalkoxy, NO2, NR 96 R 97 , and NHCOR 98 ;
• R 85 to R 89 are independently chosen from the group consisting of hydrogen and C1- C 6 alkyl
• Compounds that are useful as the Cox-2 selective inhibitor of the present invention include diaryl bicyclic heterocycles that are described in U.S. Pat. No. 6,329,421 (incorporated by reference). Such diaryl bicyclic heterocycles have the general formula shown below:
• R" is selected from the group consisting of S(0) 2 CH 2 , S(0) 2 NH 2 , S(0) 2 NHCOCF 3 , S(0)(NH)CH3, S(0)(NH)NH 2 , S(0)(NH)NHCOCF 3 , P(0)(CH3)OH, and P(0)(CH 3 )NH 2 ;
• R 100 is selected from the group consisting of:
• heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, O, or N, and optionally 1, 2, or 3 additional N atoms; or the heteroaryl is a monocyclic ring of 6 atoms, said ring having one hetero atom which is N, and optionally 1, 2, 3, or 4 additional N atoms; said substituents are selected from the group consisting of:
• halo including fluoro, chloro, bromo and iodo
• R 103 , R 104 and R 105 are each independently selected from the group consisting of hydrogen and C1-C6 alkyl; or
• R 103 and R 104 together with the carbon to which they are attached form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms, or two R 105 groups on the same carbon form a saturated monocyclic carbon ring of 3, 4, 5, 6 or 7 atoms;
• R 106 is hydrogen or C1-C6 alkyl
• R 107 is hydrogen, C1-C6 alkyl or aryl;
• Compounds that may act as Cox-2 selective inhibitors include salts of 5 -amino or a substituted amino 1,2,3-triazole compound that are described in U.S. Pat. No. 6,239,137 (incorporated by reference).
• the salts are of a class of compounds of formula:
• R 108 is:
• R 111 and R 112 are independently halogen, cyano, trifluoromethyl, loweralkanoyl, nitro, loweralkyl, loweralkoxy, carboxy, lowercarbalkoxy, trifuloromethoxy, acetamido, loweralkylthio, loweralkylsulfinyl, loweralkylsulfonyl, trichlorovinyl, trifluoromethylthio, trifluoromemylsulfinyl, or trifluoromethylsulfonyl;
• R 109 is amino, mono or diloweralkyl amino, acetamido, acetimido, ureido, formamido, or guanidino;
• R 110 is carbamoyl, cyano, carbazoyl, amidino or N-hydroxycarbamoyl;
• tlie loweralkyl, loweralkyl containing, loweralkoxy and loweralkanoyl groups contain from 1 to 3 carbon atoms.
• Pyrazole derivatives such as those described in U.S. Pat. No. 6,136,831 (incorporated by reference) can serve as a Cox-2 selective inhibitor of the present invention.
• Such pyrazole derivatives have the formula shown below:
• R 114 is hydrogen or halogen
• R 115 and R 116 are each independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxyl or lower alkanoyloxy;
• R 117 is lower haloalkyl or lower alkyl:
• X 14 is sulfur, oxygen or NH
• Z 6 is lower alkylthio, lower alkylsulfonyl or sulfamoyl
• Materials that can serve as a Cox-2 selective inhibitor of the present invention include substituted derivatives of benzosulphonamides that are described in U.S. Pat. No. 6,297,282 (incorporated by reference). Such benzosulphonamide derivatives have the formula shown below:
• X 15 denotes oxygen, sulphur or NH:
• R n8 is an optionally unsaturated alkyl or alkyloxyalkyl group, optionally mono- or polysubstituted or mixed substituted by halogen, alkoxy, oxo or cyano, a cycloalkyl, aryl or heteroaryl group optionally mono- or polysubstituted or mixed substituted by halogen, alkyl, CF3, cyano or alkoxy;
• R n9 and R 120 independently from one another, denote hydrogen, an optionally polyfluorised alkyl group, an aralkyl, aryl or heteroaryl group or a group (CH 2 )n— X 16 ; or R 119 and R 120 , together with the N— atom, denote a 3 to 7-membered, saturated, partially or completely unsaturated heterocycle with one or more heteroatoms N, O or S, which can optionally be substituted by oxo, an alkyl, alkylaryl or aryl group, or a group (CH2) ⁇ X 16 ;
• X 16 denotes halogen, NO2,—OR 121 ,—COR 121 ,— CO2R 121 ,— OCO2R 121 ,— CN,— CONR 121 R 122 ,— CONR 121 R 122 ,— SR 121 ,— S(0)R 121 ,— S(0) 2 R 121 ,— NR 121 R 122 ,— NHC(0)R 121 ,— NHS(0) 2 R 121 ;
• n denotes a whole number from 0 to 6;
• R 123 denotes a straight-chained or branched alkyl group with 1-10 C-atoms, a cycloalkyl group, an alkylcarboxyl group, an aryl group, aralkyl group, a heteroaryl or heteroaralkyl group which can optionally be mono- or polysubstituted or mixed substituted by halogen or alkoxy;
• R 124 denotes halogen, hydroxyl, a straight-chained or branched alkyl, alkoxy, acyloxy or alkyloxycarbonyl group with 1-6 C-atoms, which can optionally be mono- or polysubstituted by halogen, NO2,—OR 121 ,—COR 121 ,— CO2R 121 ,— OCO2R 121 ,— CN,— CONR 121 R 122 ,— CONR 121 R 122 ,— SR 121 ,— S(0)R 121 ,— S(0) 2 R 121 ,— NR 121 R 122 ,— NHC(0)R 121 ,— NHS(0) 2 R 121 , or a polyfluoroalkyl group;
• R 121 and R 122 independently from one another, denote hydrogen, alkyl, aralkyl or aryl;
• n denotes a whole number from 0 to 2;
• Compounds that are useful as Cox-2 selective inhibitors of the present invention include phenyl heterocycles that are described in U.S. Pat. Nos. 5,474,995 (incorporated by reference) and 6,239,173 (incorporated by reference). Such phenyl heterocyclic compounds have the formula shown below:
• X 17 — ⁇ Y 1 -Z 7 - is selected from the group consisting of:
• N CR 128 — S—
• R 125 is selected from the group consisting of:
• R 126 is selected from the group consisting of
• heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one hetero atom which is S, O, or N, and optionally 1 , 2, or 3 additionally N atoms; or the heteroaryl is a monocyclic ring of 6 atoms, said ring having one hetero atom which is N, and optionally 1, 2, 3, or 4 additional N atoms; said substituents are selected from the group consisting of:
• halo including fluoro, chloro, bromo and iodo
• R 127 is selected from the group consisting of:
• R 128 and R 128 ' are each independently selected from the group consisting of:
• R 29 , R 29 , R 30 , R 3 and R 132 are each independently selected from the group consisting of:
• Q 5 is CO2H, CO2—C1-C4 alkyl, tetrazolyl-5-yl, C(R 131 )(R 132 )(OH), or
• An exemplary phenyl heterocycle that is disclosed in U.S. Pat. No. 6,239,173 is 3-phenyl-4-(4-(metliylsulfonyl)phenyl)-2-(2H)-furanone.
• Bicycliccarbonyl indole compounds such as those described in U.S. Pat. No. 6,303,628 (incorporated by reference) are useful as Cox-2 selective inhibitors of the present invention.
• Such bicycliccarbonyl indole compounds have the formula shown below:
• a 9 is C1-C6 alkylene or— NR. 133 — ;
• Z 9 is CH or N
• Z 10 and Y 2 are independently selected from— CH2— , O, S and— N— R 133 ;
• n 1, 2 or 3;
• q and r are independently 0, 1 or 2;
• X 18 is independently selected from halogen, C1-C4 alkyl, halo-substituted C1-C4alkyl, hydroxyl, C1-C4 alkoxy, halo-substituted C1-C4 alkoxy, C1-C4 alkylthio, nitro, amino, mono- or di-(C1-C4 alkyl)amino and cyano;
• n 0, 1, 2, 3 or 4:
• L 3 is oxygen or sulfur
• R 133 is hydrogen or C1-C4 alkyl
• R 134 is hydroxyl, C1-C6 alkyl, halo-substituted C1-C6 alkyl, C1-C6 alkoxy, halo- substituted C1-C6 alkoxy, C3-C7 cycloalkoxy, C1-C4 alkyl(C 3 -C7 cycloalkoxy),— NR 136 R 137 , C1-C4 alkylphenyl-0— or phenyl-0— , said phenyl being optionally substituted with one to five substituents independently selected from halogen, C1-C4 alkyl, hydroxyl, C1-C4 alkoxy and nitro;
• R 135 is C1-C6 alkyl or halo-substituted C1-C6 alkyl
• R 136 and R 137 are independently selected from hydrogen, C1-e alkyl and halo- substituted C1-C6 alkyl.
• Materials that can serve as a Cox-2 selective inhibitor of the present invention include benzimidazole compounds that are described in U.S. Pat. No. 6,310,079 (incorporated by reference). Such benzimidazole compounds have the formula shown below:
• a 10 is heteroaryl selected from
• X 20 is independently selected from halo, C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, halo- substituted C1-C4 alkyl, hydroxyl-substituted C1-C4 alkyl, (C1-C4alkoxy)C1-C4 alkyl, halo- substituted C1-C4 alkoxy, amino, N-(C1-C4alkyl)amino, N,N-di(C1-C4 alkyl)amino, [N-(C1- C 4 alkyl)amino]C1-C4 alkyl, [N,N-di(C1-C4 alkyl)amino]C1-C4 alkyl, N-(C1- C4 alkanoyl)amonio, N-(C1-C4 alkyl)(C1-C4 alkanoyl)amino, N-[(C1- C4 alkyl)s
• X 21 is independently selected from halo, C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, halo- substituted C1-C4 alkyl, hydroxyl-substituted C1-C4 alkyl, (C1-C4alkoxy)C1-C4 alkyl, halo- substituted C1-C4 alkoxy, amino, N-(C1-C4alkyl)amino, N,N-di(C1-C4 alkyl)amino, [N-(C1- C4 alkyl)amino]C1-C4 alkyl, [N,N-di(C1-C4 alkyl)amino]C1-C4 alkyl, N-(C1- C4 alkanoyl)amino, N-(C1-C4 alkyl)-N-(C1-C4 alkanoyl)amino, N-[(C1- C4 alky
• C1-C4 alkyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, hydroxy., C1-C4 alkoxy, amino, N-(C1-C4alkyl)amino and N,N-di(C1-C4alkyl)amino;
• C3-C8 cycloalkyl optionally substituted with one to three substituent(s) wherein said substituents are indepently selected from halo, C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, amino, N-(C1-C4alkyl)amino and N,N-di(C1-C4alkyl)amino;
• C4-C8 cycloalkenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C1-C4 alkyl, hydroxyl, C1- C4 alkoxy, amino, N-(G-C4 alkyl)amino and N,N-di(C1-C4alkyl)amino;
• phenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, halo-substituted C1-C4 alkyl, nydroxyl-substituted C1-C4 alkyl, (C1-C4 alkoxy)C1-C4 alkyl, halo-substituted C1-C4 alkoxy, amino, N-(C1-C4alkyl)amino, N,N-di(C1-C4 alkyl)amino, [N-(C1-C 4 alkyl)amino]C1-C4 alkyl, [N,N-di(C1-C4 alkyl)amino]C1-C4 alkyl, N-(C1- C4 alkanoyl)amino, N-[C1-C4 alkyl)
• heteroaryl selected from: a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom: or a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom; and said heteroaryl being optionally substituted with one to three substituent(s) selected from X 20 ;
• R 139 and R 140 are independently selected from: hydrogen; halo; C1-C4 alkyl; phenyl optionally substituted with one to three substituent(s) wherein said substituents are independently selected from halo, C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, amino, N-(C1- C4 alkyl)amino and N,N-di(C1-C4alkyl)amino;
• R 138 and R 139 can form, together with the carbon atom to which they are attached, a C3-C7 cycloalkyl ring; m is 0, 1 , 2, 3, 4 or 5; and
• n 0, 1, 2, 3 or 4.
• Compounds that may be employed as a Cox-2 selective inhibitor of the present invention include indole compounds that are described in U.S. Pat. No. 6,300,363 (incorporated by reference). Such indole compounds have the formula shown below:
• L 4 is oxygen or sulfur
• Y 3 is a direct bond or C1-C4 alkylidene
• (c-1) halo, C1-C4 alkyl, halosubstituted C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, halosubstituted C1-C4 alkoxy, S(0)mR 143 , SO2NH2, S02N(C1-C4 alkyl) 2 , amino, mono- or di-(C1-C4 alkyl)amino, NHSO2R 143 , NHC(0)R 143 , CN, CO2H, C0 2 (C1-C4 alkyl), C1- C4 alkyl-OH, C1-C4 alkyl-OR 143 , CONH2, CONH(C1-C 4 alkyl), CON(C1-C4 alkyl)2 and— O— Y-phenyl, said phenyl being optionally substituted with one or two substituents independently selected from halo, C1-C4 alkyl, CF . 3, hydroxyl,
• R 141 is hydrogen or C1-C6 alkyl optionally substituted with a substituent selected independently from hydroxyl, OR 143 , nitro, amino, mono- or di-(C1-C4alkyl)amino, CO2H, CO2 (C1-C4 alkyl), CONH2, CONH(C1-C4 alkyl) and CON(C1-C4 alkyl ⁇ .;
• R 142 is:
• R 145 is selected from:
• (c-1) C1-C22 alkyl or C2-C22 alkenyl, said alkyl or alkenyl being optionally substituted with up to four substituents independently selected from:
• (c-2) C1-C22 alkyl or C2-C22 alkenyl, said alkyl or alkenyl being optionally substituted with five to forty-five halogen atoms,
• X 22 is halo, C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, halosubstitutued C1-C4alkoxy, S(0)mR 143 , amino, mono- or di-(C1-C4 alkyl)amino, NHSO2R 143 , nitro, halosubstitutued C1- C4 alkyl, CN, CO2H, C0 2 (C1-C 4 alkyl), C1-C4 alkyl-OH, C1-d alkylOR 143 , CONH2, CONH(C1-C4 alkyl) or CON(C1-Ct alkyl) 2 ;
• R 143 is C1-C4 alkyl or halosubstituted C1-C4 alkyl
• n 0, 1, 2 or 3
• p 1, 2, 3, 4 or 5
• q is 2 or 3;
• Z 11 is oxygen, sulfur or NR 144 ;
• R1441S hydrogen, C1-C6 alkyl, halosubstitutued C1-C4 alkyl or— Y s -phenyl, said phenyl being optionally substituted with up to two substituents independently selected from halo, C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, S(0)mR 143 , amino, mono- or di-(C1- C4 alkyl)amino, CF3, OCF3, CN and nitro;
• L 4 is oxygen
• R 141 is hydrogen
• R 142 is acetyl.
• Aryl phenylhydrazides that are described in U.S. Pat. No. 6,077,869 (incorporated by reference) can serve as Cox-2 selective inhibitors of the present invention. Such aryl phenylhydrazides have the formula shown:
• X 23 and Y 6 are selected from hydrogen, halogen, alkyl, nitro, amino, hydroxy, methoxy and methylsulfonyl;
• Materials that can serve as a Cox-2 selective inhibitor of the present invention include 2-aryloxy, 4-aryl furan-2-ones that are described in U.S. Pat. No. 6,140,515
• R 146 is selected from the group consisting of S CH 3 ,— S(0) 2 CH 3 and— S(0)2NH2;
• R 147 is selected from the group consisting of OR 150 , mono or di-substituted phenyl or pyridyl wherein the substituents are selected from the group consisting of methyl, chloro and F;
• R 150 is unsubstituted or mono or di-substituted phenyl or pyridyl wherein the substituents are selected from the group consisting of methyl, chloro and F;
• R 148 is H, C1-C4 alkyl optionally substituted with 1 to 3 groups of F, CI or Br: and R 149 is H, C1-C4 alkyl optionally substituted with 1 to 3 groups of F, CI or Br, with the proviso that R 148 and R 149 are not the same.
• Materials that can serve as a Cox-2 selective inhibitor of the present invention include bisaryl compounds that are described in U.S. Pat. No. 5,994,379 (incorporated by reference). Such bisaryl compounds have the formula shown below:
• Z 13 is C or N
• R 151 represents H or is absent, or is taken in conjunction with R 152 as described below:
• R 151 represents H and R 152 is a moiety which has the following characteristics:
• R 151 and R 152 are taken in combination and represent a 5- or 6-membered aromatic or non-aromatic ring D fused to ring A, said ring D containing 0-3 heteroatoms selected from O, S and N; said ring D being lipophilic except for the atoms attached directly to ring A, which are lipophilic or non-lipophilic, and said ring D having available an energetically stable configuration planar with ring A to within about 15 degrees;
• said ring D further being substituted with 1 R a group selected from the group consisting of: C1-C2 alkyl,— OC1-C2alkyl,— NHC,— C2 alkyl,— N(C1-C2 alkyl)2,— C(0)C1-C2 alkyl,— S— C1-C2 alkyl and—C(S)C1-C2 alkyl;
• Y 7 represents N, CH or C— OC1-C3 alkyl, and when Z 13 is N, Y 7 can also represent a carbonyl group;

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