Proteasome inhibitors and methods of using the same
The present invention provides boronic acid compounds, boronic esters, and compositions thereof that can modulate apoptosis such as by inhibition of proteasome activity. The compounds and compositions can be used in methods of inducing apoptosis and treating diseases such as cancer and other disorders associated directly of indirectly with proteasome activity.
1. A method for treating a cancer selected from the group consisting of skin, prostate, colorectal, pancreas, kidney, ovary, mammary, liver, tongue, smooth muscle tissue, leukemia, lymphoma, non-Hodgkin lymphoma, myeloma, and multiple myeloma comprising administering to a mammal having or predisposed to said cancer a therapeutically effective amount of a compound of Formula (I)
or a pharmaceutically acceptable salt, stereoisomeric or tautomeric form thereof, wherein:
R 1 is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or C 3 -C 7 cycloalkyl;
R 2 is H;
Q is —B(OH) 2 , —B(OR 14 ) 2 , or a cyclic boronic ester wherein said cyclic boronic ester contains from 2 to 20 carbon atoms, and, optionally, a heteroatom which can be N, S, or O;
R 14 is H, C 1 -C 4 alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl;
X is R A C(═O)—; R A NHC(═O)—, R A S(O) 2 —, R A SC(═O)—, or R A ;
R A is C 1 -C 20 alkyl optionally substituted with R 20 ;
C 2 -C 20 alkenyl optionally substituted with R 20 ;
C 2 -C 20 alkynyl optionally substituted with R 20 ;
carbocyclyl optionally substituted with 1-5 R 22 ; or
heterocarbocyclyl optionally substituted with 1-5 R 22 ;
R 20 is selected from the group consisting of:
—OR 20a , —SR 20a —S(═O)R 20a , —S(═O) 2 R 20a , —S(═O) 2 NHR 20a , —SC(═O)R 20a , —C(═O)R 20a , —C(═O)NHR 20a , —C(═O)O—R 20a , phthalimido, —(O-alkyl), —O-alkyl-OH, —(O-alkyl) r -OH, —OR 20c , —SR 20c , —O—alkyl-R 20c , —S(═O) 2 —R 20c , —S(═O) 2 —NHR 20c , —SC(═O)R 20c , —C(═O)R 20c , —C(═O)OR 20c , —C(═O)NHR 20c , carbocyclyl optionally substituted with 1-5 R 22 ; and heterocarbocyclyl optionally substituted with 1-5 R 22 ;
R 20a is C 1 -C 20 alkyl, C 2 -C 20 alkenyl, or C 2 -C 20 alkynyl; wherein said alkyl, alkenyl, or alkynyl is optionally substituted by one or more halo, C 1 -C 4 alkyl, aryl, heteroaryl or —NHR 20b ;
R 20c is carbocyclyl optionally substituted with 1-5 R 22 ; or heterocarbocyclyl optionally substituted with 1-5 R 22 ;
R 22 is selected from the group consisting of:
C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino, carboxyl, alkyl-OC(═O)—, alkyl-C(═O)—, aryl-OC(═O)—, alkyl-OC(═O)NH—, aryl-OC(═O)NH—, alkyl-C(═O)NH—, alkyl-C(═O)O—, (alkyl-O) r -alkyl, HO-(alkyl-O) r -alkyl-, —OH, —SH, —CN, —N 3 , —CNO, —CNS, alkyl-S(═O)—, alkyl-S(═O) 2 —, H 2 NS(═O)—, and H 2 NS(═O) 2 —; and
r is 2, 3, 4, 5, 6, 7, 8, 9, or 10.
2. The method of claim 1 , wherein X is R A C(═O)—.
3. The method of claim 1 , whereinX is R A C(═O)— and R A is aryl optionally substituted with 1-3 substituents selected from the group consisting of C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino, alkyl-OC(═O)—, alkyl-C(═O)—, alkyl-OC(═O)NH—, alkyl-C(═O)NH—, —OH, —CN, alkyl-S(═O)—, and alkyl-S(═O) 2 .
4. The method of claim 1 , wherein the cancer is selected from the group consisting of skin, prostate, colorectal, pancreas, kidney, ovary, mammary, liver, tongue, and smooth muscle tissue.
5. The method of claim 1 , wherein the cancer is selected from the group consisting of leukemia, lymphoma, non-Hodgkin's lymphoma, myeloma, and multiple myeloma.
6. The method of claim 1 , wherein the cancer is multiple myeloma.
7. The method of claim 1 , comprising administering the compound in combination with one or more antitumor or anticancer agents and/or radiotherapy.
8. The method of claim 1 , wherein the cancer is leukemia.
9. The method of claim 1 , wherein the cancer is non-Hodgkin's lymphoma.
10. The method of claim 1 , wherein the cancer is lymphoma.