Proteasome inhibitors
Disclosed herein are compounds of Formula (I) that include a sulfonate ester, ester or ether group. Compounds of Formula (I) can be included in pharmaceutical compositions, and can be used to treating and/or ameliorating a disease or condition, such as cancer, a microbial disease and/or inflammation.
1. A compound of Formula (I), or pharmaceutically acceptable salt, ester or prodrug thereof:
wherein:
R 1 is
wherein R 4 is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: aryl, aryl(C 1-6 alkyl), heteroaryl, heteroaryl(C 1-6 alkyl), heterocyclyl, and heterocyclyl(C 1-6 alkyl);
wherein when R 4 is a substituted residue, the residue is substituted with one or more groups selected from among alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, acyl, acylamino, acyloxy, amino, mono-substituted amine, di-substituted amine, alkyl amino, aminoacyl, aminoacyloxy, oxyacylamino, halogen, mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, hydroxy, carboxylalkyl, thioketo, thiol, thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 —H, —SO 2 —OH, —SO 2 -alkyl, —SO 2 -aryl, —SO 2 -heteroaryl, boronate alkyl, boronic acid, (OH) 2 B-alkyl, phosphate and phosphate esters, phosphonooxy, phosphonooxyalkyl, azido, azidoalkyl, ammonium, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of an alkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio, carboxy, cyano, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of a guanidino, guanidinoalkyl, and
wherein A is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: heterocyclyl, aryl and heteroaryl; and
Z 1 is selected from the group consisting of O, S, N═N, O(CH 2 ) 1-6 , S(O) 2 N(R 17 ), S(O) 2 N(R 17 )(CH 2 ) 1-6 , C(═O)N(R 17 ), N(R 17 )C(═O), N(R 17 )C(═O)O(CH 2 ) 1-6 , N(R 17 )C(═O)O(CH 2 ) 1-6 , S(O) 2 , C(═O), (CH 2 ) 1-6 C═O), O(CH 2 ) 1-6 C(═O), (CH 2 ) 1-6 N(R 17 )C(═O), CH═CH—C(═O)N(R 17 ), CH═CH—C(═O), O(CH 2 ) 1-6 I, O(CH 2 ) 1-6 and N(R 17a )C(═O)N(R 17b ), wherein R 17 , R 7a and R 17b are independently selected from the group consisting of H, C 1-4 alkyl, a substituted or unsubstituted benzyl, an allyl, and t-butoxycarbonyl (t-BOC);
R 2 is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 3 -C 12 cycloalkynyl, C 3 -C 12 heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, (cycloalkyll)alkyl, (heterocyclyl)alkyl, arylthio, pyridinylalkyl, a salt of a pyridinylalkyl and a salt of a heteroarylalkyl;
R 3 is a mono-substituted, a poly-substituted or an unsubstituted C 1-6 alkyl or a mono-substituted, a poly-substituted or an unsubstituted C 2-6 alkenyl;
n is 1, 2 or 3;
provided that when R 1 is
has a molecular weight equal to or greater than 92 g/mol.
2. The compound of claim 1 , wherein R 3 is an unsubstituted C 1-6 alkyl.
3. The compound of claim 1 , wherein R 3 is methyl.
4. The compound of claim 1 , wherein n is 2.
5. The compound of claim 1 , wherein R 2 is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1 -C 12 alkyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl and aryl.
6. The compound of claim 5 , wherein R 2 is a mono-substituted, a poly-substituted or an unsubstituted C 1 -C 12 alkyl.
7. The compound of claim 6 , wherein R 2 is isopropyl.
8. The compound of claim 5 , wherein R 2 is a mono-substituted, a poly-substituted or an unsubstituted C 3 -C 12 cycloalkyl.
9. The compound of claim 5 , wherein R 2 is a mono-substituted, a poly-substituted or an unsubstituted C 3 -C 12 cycloalkenyl.
10. The compound of claim 9 , wherein R 2 is a mono-substituted, a poly-substituted or an unsubstituted cyclohexenyl.
11. The compound of claim 5 , wherein R 2 is a mono-substituted, a poly-substituted or an unsubstituted aryl.
12. The compound of claim 11 , wherein R 2 is a mono-substituted, a poly-substituted or an unsubstituted phenyl.
13. The compound of claim 1 , wherein R 4 is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: aryl, heteroaryl and heterocyclyl; wherein when R 4 is a substituted residue, the residue is substituted with one or more groups selected from among alkyl, alkoxy, acyl, acylamino, acyloxy, amino, mono-substituted amine, di-substituted amine, halogen, mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, hydroxy, carboxylalkyl, thioketo, thiol, thioalkoxy, alkoxyamino, nitro, —SO-alkyl, SO 2 —H, —SO 2 —OH, —SO 2 -alkyl, azido, ammonium, aminoalkyl, carboxyalkyl, alkylamino, dialkylamino, alkylthio, carboxy, cyano and thiocyano.
14. The compound of claim 1 having the structure:
15. The compound of claim 1 having the structure:
16. A method for treating, alleviating or diagnosing a neoplastic disease comprising administering to a subject a therapeutically effective amount of a compound of claim 1 , or pharmaceutically acceptable salt, ester or prodrug thereof, wherein the neoplastic disease is a cancer selected from the group consisting of breast cancer, sarcoma, leukemia, ovarian cancer, bladder cancer, prostate cancer, colon cancer, rectal cancer, stomach cancer, lung cancer, lymphoma, multiple myeloma, pancreatic cancer, kidney cancer, endocrine cancer, melanoma, skin cancer, angiosarcoma, sinus cancer, esophageal cancer, uretal cancer, liver cancer, angioma, central nervous system (CNS) cancer, Mantle cell lymphoma, low IgM secreting lymphoma, Burkitt's lymphoma, B-NHL lymphoma and Waldenstrom's Macroglobulimemia.
17. The method of claim 16 , wherein the compound has a structure selected from:
18. A method for inhibiting NF-κB activity comprising administering to a subject a therapeutically effective amount of a compound of claim 1 , or pharmaceutically acceptable salt, ester or prodrug thereof.
19. A method for inhibiting proteasome activity comprising administering to a subject a therapeutically effective amount of a compound of claim 1 , or pharmaceutically acceptable salt, ester or prodrug thereof.
20. A method for inhibiting the growth of a cancer cell comprising contacting the cancer cell with a therapeutically effective amount of a compound of claim 1 , or pharmaceutically acceptable salt, ester or prodrug thereof.
21. The method of claim 20 , wherein the cancer cell is selected from the group consisting of breast cancer cell, sarcoma cell, leukemia cell, ovarian cancer cell, bladder cancer cell, prostate cancer cell, colon cancer cell, rectal cancer cell, stomach cancer cell, lung cancer cell, lymphoma cell, multiple myeloma cell, pancreatic cancer cell, kidney cancer cell, endocrine cancer cell, melanoma cell, skin cancer cell, angiosarcoma cell, sinus cancer cell, esophageal cancer cell, uretal cancer cell, liver cancer cell, angioma cell, central nervous system (CNS) cancer cell, Mantle cell lymphoma cell, low IgM secreting lymphoma cell, Burkitt's lymphoma cell, B-NHL lymphoma cell and Waldenstrom's Macroglobulimemia cell.