Cannabidinoid derivatives
The disclosure relates to cannabinoid derivative compounds, pharmaceutical compositions made thereof, and methods for treating various diseases and disorders including cancer.
1. A compound having the structure of Formula III:
or a pharmaceutically acceptable salt, or prodrug thereof, wherein:
X is independently either a C or N;
R 2 -R 3 are each independently a hydroxyl or (C 1 -C 2 )alkoxy;
R 6 is selected from the group consisting of a (C 1 -C 12 )alkyl, a hetero(C 1 -C 11 )alkyl, a (C 1 -C 12 )alkenyl, a -hetero(C 1 -C 11 )alkenyl, a (C 1 -C 12 )alkynyl, and a hetero(C 1 -C 11 )alkynyl;
R 11 -R 18 are each independently selected from the group consisting of hydrogen, deuterium, FG, optionally substituted (C 1 -C 8 )alkyl, optionally substituted hetero(C 1 -C 8 )alkyl, optionally substituted (C 1 -C 8 )alkenyl, optionally substituted hetero(C 1 -C 8 )alkenyl, optionally substituted (C 1 -C 8 )alkynyl, optionally substituted hetero(C 1 -C 8 )alkynyl; and
R 21 -R 31 are each independently selected from the group consisting of hydrogen, deuterium, FG, optionally substituted (C 1 -C 8 )alkyl, hetero(C 1 -C 8 )alkyl, optionally substituted (C 1 -C 8 )alkenyl, optionally substituted hetero(C 1 -C 8 )alkenyl, optionally substituted (C 1 -C 8 )alkynyl, optionally substituted hetero(C 1 -C 8 )alkynyl, optionally substituted (C 5 -C 8 )cycloalkyl, optionally substituted (C 5 -C 8 )cycloalkenyl, optionally substituted (C 5 -C 8 )cycloalkynyl, optionally substituted (C 4 -C 8 )heterocycle, optionally substituted aryl, and optionally substituted extended mixed ring system,
wherein if X are carbon atoms and the bonds represented by a dash lines are doubly covalent bonds, then at least one of R 21 -R 31 are not hydrogen atoms, thereby affording a substituted aryl group.
2. The compound of claim 1 , wherein:
X is C,
R 2 -R 3 are hydroxyl,
R 11 -R 18 are each independently hydrogen or deuterium, and
R 21 -R 31 are each independently selected from the group consisting of hydrogen, deuterium, FG, optionally substituted (C 1 -C 8 )alkyl, hetero(C 1 -C 8 )alkyl, optionally substituted (C 1 -C 8 )alkenyl, optionally substituted hetero(C 1 -C 8 )alkenyl, optionally substituted (C 1 -C 8 )alkynyl, optionally substituted hetero(C 1 -C 8 )alkynyl, optionally substituted (C 5 -C 8 )cycloalkyl, optionally substituted (C 5 -C 8 )cycloalkenyl, optionally substituted (C 5 -C 8 )cycloalkynyl, optionally substituted (C 4 -C 8 )heterocycle, optionally substituted aryl, and optionally substituted extended mixed ring system.
3. The compound of claim 2 , wherein:
R 21 -R 26 and R 29 -R 31 are each independently hydrogen or deuterium, and
R 27 -R 28 are each independently selected from the group consisting of hydrogen, deuterium and FG.
4. The compound of claim 3 , wherein FG is selected from group consisting of alkyls, alkenyls, alkynyls, aryls, hetero-alkyls, hetero-alkenyls, hetero-alkynyls, cycloalkyls, cycloalkenyls, cycloalkynyls, heterocycles, halos, hydroxyls, anhydrides, carbonyls, carboxyls, carbonates, carboxylates, aldehydes, haloformyls, esters, hydroperoxy, peroxy, ethers, orthoesters, carboxamides, amines, imines, imides, azides, azos, cyanates, isocyanates, nitrates, nitriles, isonitriles, nitrosos, nitros, nitrosooxy, pyridyls, sulfhydryls, sulfides, disulfides, sulfinyls, sulfos, thiocyanates, isothiocyanates, carbonothioyls, phosphinos, phosphonos, phosphates, silyls, and Si(OH) 3 .
5. The compound of claim 3 , wherein FG is a halo.
6. The compound of claim 5 , wherein R 27 -R 28 are both Cl or both F.
7. The compound of claim 3 , wherein R 27 is a halo and R 28 hydrogen or deuterium.
8. The compound of claim 3 , wherein R 28 is hydrogen or deuterium.
9. The compound of claim 6 , wherein the compound has the structure:
10. A pharmaceutical composition comprising the compound of claim 1 .
11. The pharmaceutical composition of claim 10 , wherein the composition further comprises an additional therapeutic agent.
12. The pharmaceutical composition of claim 11 , wherein the additional therapeutic agent is Δ 9 -tetrahydrocannabinol (“THC”) or a THC derivative.
13. The pharmaceutical composition of claim 12 , wherein the THC derivative is selected from the group consisting of Δ 9 -tetrahydrocannabinol-C 4 , Δ 9 -tetrahydrocannabivarin, tetrahydrocannabiorcol, Δ 9 -tetrahydro-cannabinolic acid A, Δ 9 -tetrahydro-cannabinolic acid B, Δ 9 -tetrahydro-cannabinolic acid-C 4 A, Δ 9 -tetrahydro-cannabinolic acid-C 4 B, Δ 9 -tetrahydro-cannabivarinic acid A, Δ 9 -tetrahydro-cannabiorcolic acid A, Δ 9 -tetrahydro-cannabiorcolic acid B, (−)-Δ 8 -trans-(6aR, 10aR)-Δ 8 -tetrahydrocannabinol, (−)-Δ 8 -trans-(6aR, 10aR)-tetrahydrocannabinolic acid A, and (−)-(6aS, 10aR)-Δ 9 -tetrahydrocannabinol.
14. The pharmaceutical composition of claim 11 , wherein the additional therapeutic agent is selected from the group consisting of alkylating agents, cancer immunotherapy monoclonal antibodies, anti-metabolites, mitotic inhibitors, anti-tumor antibiotics, topoisomerase inhibitors, photosensitizers, tyrosine kinase inhibitors, anti-cancer agents, chemotherapeutic agents, anti-migraine treatments, anti-tussives, mucolytics, decongestants, anti-allergic non-steroidals, expectorants, anti-histamine treatments, anti-retroviral agents, CYP3A inhibitors, CYP3A inducers, protease inhibitors, adrenergic agonists, anti-cholinergics, mast cell stabilizers, xanthines, leukotriene antagonists, glucocorticoid treatments, antibacterial agents, antifungal agents, sepsis treatments, steroidals, local or general anesthetics, NSAIDS, NRIs, DARIs, SNRIs, sedatives, NDRIs, SNDRIs, monoamine oxidase inhibitors, hypothalamic phoshpholipids, anti-emetics, ECE inhibitors, opioids, thromboxane receptor antagonists, potassium channel openers, thrombin inhibitors, growth factor inhibitors, anti-platelet agents, P2Y(AC) antagonists, anti-coagulants, low molecular weight heparins, Factor VIa inhibitors, Factor Xa inhibitors, renin inhibitors, NEP inhibitors, vasopepsidase inhibitors, squalene synthetase inhibitors, anti-atherosclerotic agents, MTP inhibitors, calcium channel blockers, potassium channel activators, alpha muscarinic agents, beta-muscarinic agents, anti-arrhythmic agents, diuretics, thrombolytic agents, anti-diabetic agents, mineralocorticoid receptor antagonists, growth hormone secretagogues, aP2 inhibitors, phophodiesterase inhibitors, anti-inflammatories, anti-proliferatives, antibiotics, farnesyl-protein transferase inhibitors, hormonal agents, plant-derived products, epipodophyllotoxins, taxanes, prenyl-protein transferase inhibitors, anti-TNF antibodies and soluble TNF receptors, and Cyclooxygenase-2 inhibitors.
15. The pharmaceutical composition of claim 14 , wherein the additional therapeutic agent is selected from the group consisting of alkylating agents, cancer immunotherapy monoclonal antibodies, anti-metabolites, mitotic inhibitors, anti-tumor antibiotics, topisomerase inhibitors, photosensitizers, tyrosine kinase inhibitors, anti-cancer agents, and chemotherapeutic agents.
16. The pharmaceutical composition of claim 15 , wherein the additional therapeutic agent is an anti-cancer agent.
17. The pharmaceutical composition of claim 16 , wherein the anti-cancer agent is paclitaxel and/or temozolomide.
18. A method for modulating helix-loop-helix Id protein expression, cell proliferation, cell invasion, metastasis or a combination thereof in vivo and/or in vitro by administering a compound of claim 1 .
19. A method for treating a disease or disorder in a subject, comprising administering to a subject a therapeutically effective amount of a compound of claim 1 , wherein the disease or disorder can be ameliorated by inhibiting the expression of an Id polypeptide, by activating cannabinoid type 2 (“CB 2 ”) receptors or a combination thereof.