Substituted N-Aryl pyridinones
Disclosed herein are substituted N-Aryl pyridinone fibrotic inhibitors and/or collagen infiltration modulators of Formula I, process of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.
1. A compound having structural Formula I
or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are independently selected from the group consisting of hydrogen and deuterium;
at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 is deuterium; and
if R 7 , R 8 , R 9 , R 10 , and R 11 are deuterium, then at least one of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is deuterium.
2. The compound as recited in claim 1 , wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 independently has deuterium enrichment of no less than about 98%.
3. The compound as recited in claim 1 , wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 independently has deuterium enrichment of no less than about 90%.
4. The compound as recited in claim 1 , wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 independently has deuterium enrichment of no less than about 50%.
5. The compound as recited in claim 1 , wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 independently has deuterium enrichment of no less than about 10%.
6. The compound as recited in claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
7. The compound as recited in claim 6 , wherein each of said positions represented as D has deuterium enrichment of at least 98%.
8. The compound as recited in claim 6 , wherein each of said positions represented as D has deuterium enrichment of at least 90%.
9. The compound as recited in claim 6 , wherein each of said positions represented as D has deuterium enrichment of at least 50%.
10. The compound as recited in claim 6 , wherein each of said positions represented as D has deuterium enrichment of at least 10%.
11. A pharmaceutical composition comprising the compound having structural Formula II
or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are independently selected from the group consisting of hydrogen and deuterium; and
at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 is deuterium.
12. A pharmaceutical composition as recited in claim 11 , further comprising one or more release-controlling excipients.
13. The pharmaceutical composition as recited in claim 11 , further comprising one or more non-release controlling excipients.
14. The pharmaceutical composition as recited in claim 11 , wherein the composition is suitable for oral, parenteral, or intravenous infusion administration.
15. The pharmaceutical composition as recited in claim 14 , wherein the oral dosage form is a tablet or capsule.
16. The pharmaceutical composition as recited in claim 14 , wherein the compound is administered in a dose of about 0.5 milligram to about 1,000 milligram.
17. The pharmaceutical composition as recited in claim 11 , further comprising another therapeutic agent.
18. The pharmaceutical composition as recited in claim 17 , wherein the therapeutic agent is selected from the group consisting of sepsis agents, anti-bacterials, anti-fungals, anti-coagulants, thrombolytics, steroidal drugs, non-steroidal anti-inflammatory drugs (NSAIDs), opioids, anesthetics, calcium channel blockers, Beta-blockers, nitrates or nitrites, ACE inhibitors, statins, platelet aggregation inhibitors, adenosine, digitoxin, anti-arrhythmic agents, sympathomimetic drugs, endothelin converting enzyme (ECE) inhibitors, thromboxane enzyme antagonists, potassium channel openers, thrombin inhibitors, growth factor inhibitors, platelet activating factor (PAF) antagonists, anti-platelet agents, Factor VIIa Inhibitors, Factor Xa Inhibitors, renin inhibitors, neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors, HMG CoA reductase inhibitors, squalene synthetase inhibitors, fibrates, bile acid sequestrants, anti-atherosclerotic agents, MTP Inhibitors, potassium channel activators, alpha-PDE5 agents, beta-PDE5 agents, diuretics, anti-diabetic agents, PPAR-gamma agonists, mineralocorticoid enzyme antagonists, aP2 inhibitors, protein tyrosine kinase inhibitors, antiinflammatories, antiproliferatives, chemotherapeutic agents, immunosuppressants, anticancer agents, cytotoxic agents, antimetabolites, farnesyl-protein transferase inhibitors, hormonal agents, microtubule-disruptor agents, microtubule-stablizing agents, topoisomerase inhibitors, prenyl-protein transferase inhibitors, cyclosporins, TNF-alpha inhibitors, cyclooxygenase-2 (COX-2) inhibitors, gold compounds, antalarmin, Z-338 and platinum coordination complexes.
19. The pharmaceutical composition as recited in claim 18 , wherein the therapeutic agent is a steroidal drug.
20. The pharmaceutical composition as recited in claim 19 , wherein the steroidal drug is selected from the group consisting of aldosterone, beclometasone, betamethasone, deoxycorticosterone acetate, fludrocortisone acetate, hydrocortisone (cortisol), prednisolone, prednisone, methylprenisolone, dexamethasone, and triamcinolone.
21. The pharmaceutical composition as recited in claim 18 , wherein the therapeutic agent is a NSAID.
22. The pharmaceutical composition as recited in claim 21 , wherein the NSAID is selected from the group consisting of aceclofenac, acemetacin, amoxiprin, aspirin, azapropazone, benorilate, bromfenac, carprofen, celecoxib, choline magnesium salicylate, diclofenac, diflunisal, etodolac, etoracoxib, faislamine, fenbuten, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicyl salicylate, sulindac, sulfinprazone, suprofen, tenoxicam, tiaprofenic acid, and tolmetin.