Composition for enzyme inhibition
View Patent ↗Compositions comprising one or more practically insoluble proteasome inhibitors and a cyclodextrin, particularly a substituted cyclodextrin, substantially increase the solubility of these proteasome inhibitors and facilitate their administration. Such compositions optionally comprise a buffer. Methods of treatment using such compositions are also disclosed.
1. A pharmaceutical composition comprising a practically insoluble peptide epoxy ketone proteasome inhibitor or a pharmaceutically acceptable salt thereof and a substituted cyclodextrin selected from hydroxypropyl beta-cyclodextrin and sulfobutyl ether beta-cyclodextrin (SBECD).
2. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is a solution.
3. The pharmaceutical composition of claim 2 , wherein the solution comprises at least 0.02 mg/mL of the proteasome inhibitor.
4. The pharmaceutical composition of claim 3 , wherein the solution comprises at least 0.1 mg/mL of the proteasome inhibitor.
5. The pharmaceutical composition of claim 4 , wherein the solution comprises at least 1 mg/mL of the proteasome inhibitor.
6. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is a water-soluble solid.
7. The pharmaceutical composition of claim 6 , wherein the pharmaceutical composition dissolves in water at a concentration of at least 0.02 mg/mL of the proteasome inhibitor.
8. The pharmaceutical composition of claim 7 , wherein the pharmaceutical composition dissolves in water at a concentration of at least 0.1 mg/mL of the proteasome inhibitor.
9. The pharmaceutical composition of claim 8 , wherein the pharmaceutical composition dissolves in water at a concentration of at least 1 mg/mL of the proteasome inhibitor.
10. The pharmaceutical composition of claim 1 , further comprising a buffer.
11. The pharmaceutical composition of claim 10 , wherein the buffer is a salt.
12. The pharmaceutical composition of claim 10 , wherein the buffer, when the pharmaceutical composition is dissolved in water, achieves a pH at which at least 10% of the inhibitor molecules are ionized.
13. The pharmaceutical composition of claim 12 , wherein the buffer, when the pharmaceutical composition is dissolved in water, achieves a pH at which at least 50% of the inhibitor molecules are ionized.
14. The pharmaceutical composition of claim 1 , further comprising a pharmaceutically acceptable carrier or diluent.
15. The pharmaceutical composition of claim 1 , wherein the proteasome inhibitor is represented by structural formula (II) or a pharmaceutically acceptable salt thereof:
wherein:
X is oxygen;
R 1 , R 2 , R 3 and R 4 are independently selected from C 1-6 alkyl or C 1-6 hydroxy alkyl or C 1-6 alkoxy alkyl, aryl, heteroaryl, C 1-6 heteroaralkyl, heterocyclyl, and C 1-6 heterocycloalkyl, and aryl-substituted C 1-6 alkyl, wherein such groups are optionally substituted with one or more amide linkages, amines, carboxylic acids and salts thereof, carboxyl esters, thiols and thioethers; and
R 5 is a further chain of amino acids, hydrogen, acetyl, or a protecting group.
16. The pharmaceutical composition of claim 1 , wherein the proteasome inhibitor is represented by structural formula (III) or a pharmaceutically acceptable salt thereof
wherein:
X is O;
R 1 , R 2 , R 3 , and R 4 are hydrogen
R 5 , R 6 , R 7 , and R 8 are independently selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl, each of which is optionally substituted with a group selected from amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxyl ester, thiol, and thioether; and
R 9 is a further chain of amino acids, hydrogen, C 1-6 acyl, a protecting group, aryl, or heteroaryl.
17. The pharmaceutical composition of claim 1 , wherein the proteasome inhibitor is represented by structural formula (IV) or a pharmaceutically acceptable salt thereof:
wherein:
X is O;
R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen and a group of formula (IIIa), with the proviso that at least one of R 1 , R 2 , R 3 , and R 4 is a group of formula (IIIa);
R 6 and R 8 independently are selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl, each of which is optionally substituted with a group selected from amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxyl ester, thiol, and thioether;
R 9 is a further chain of amino acids, hydrogen, acyl, a protecting group, aryl, or heteroaryl.
18. The pharmaceutical composition of claim 1 , wherein the proteasome inhibitor is represented by structural formula (V) or a pharmaceutically acceptable salt thereof:
wherein:
each A is independently selected from C═O, C═S, and SO 2 ;
L is absent or is selected from C═O, C═S, and SO 2 ;
M is absent or is C 1-8 alkyl;
Q is absent or is selected from O, NH, and N—C 1-6 alkyl;
X is O;
Y is absent or is selected from O, NH, N—C 1-6 alkyl, S, SO, SO 2 , CHOR 10 , and CHCO 2 R 10 ;
each Z is independently selected from O, S, NH, and N—C 1-6 alkyl;
R 1 , R 2 , R 3 , and R 4 are each independently selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, C 1-6 aralkyl, heteroaryl, C 1-6 heteroaralkyl, heterocyclyl, and C 1-6 heterocycloalkyl, any of which is optionally substituted with one or more of amide, amine, carboxylic acid (or a salt thereof), ester, thiol, or thioether substituents;
R 5 is N(R 6 )LQR 7 ;
R 6 is selected from hydrogen, OH, and C 1-6 alkyl;
R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, C 1-6 aralkyl, heteroaryl, C 1-6 heteroaralkyl, R 8 ZA—C 1-8 alkyl-, R 11 Z—C 1-8 alkyl-, (R 8 O)(R 9 O)P(═O)O—C 1-8 alkyl-ZAZ—C 1-8 alkyl-, (R 8 O)(R 9 O)P(═O)O—C 1-8 alkyl-Z—C 1-8 alkyl-, R 8 ZA-C 1-8 alkyl-ZAZ—C 1-8 alkyl-, heterocyclylMZAZ—C 1-8 alkyl-, (R 8 O)(R 9 O)P(═O)O—C 1-8 alkyl-, (R 10 ) 2 N—C 1-8 alkyl-, (R 10 ) 3 N + —C 1-8 alkyl-, heterocyclylM-, carbocyclylM-, R 11 SO 2 C 1-8 alkyl-, and R 11 SO 2 NH; or
R 6 and R 7 together C 1-6 alkyl-Y—C 1-6 alkyl, C 1-6 alkyl-ZA-C 1-6 alkyl, A-C 1-6 alkyl-ZA-C 1-6 alkyl, A-C 1-6 alkyl-A, or C 1-6 alkyl-A, thereby forming a ring;
R 8 and R 9 are independently selected from hydrogen, metal cation, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl, or R 8 and R 9 together are C 1-6 alkyl, thereby forming a ring;
each R 10 is independently selected from hydrogen and C 1-6 alkyl; and
R 11 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl,
provided that when R 6 is H, L is C═O, and Q is absent, R 7 is not hydrogen, C 1-6 alkyl, or aryl or heteroaryl.
19. The pharmaceutical composition of claim 18 , wherein the proteasome inhibitor is represented by structural formula (VI) or a pharmaceutically acceptable salt thereof:
wherein:
each A is independently selected from C═O, C═S, and SO 2 ;
L is absent or is selected from C═O, C═S, and SO 2 ;
M is absent or is C 1-8 alkyl;
Q is absent or is selected from O, NH, and N—C 1-6 alkyl;
X is O;
Y is absent or is selected from O, NH, N—C 1-6 alkyl, S, SO, SO 2 , CHOR 10 , and CHCO 2 R 10 ;
each Z is independently selected from O, S, NH, and N—C 1-6 alkyl;
R 2 and R 4 are each independently selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl, any of which is optionally substituted with one or more of amide, amine, carboxylic acid or a salt thereof, ester, thiol, or thioether substituents;
R 5 is N(R 6 )LQR 7 ;
R 6 is selected from hydrogen, OH, and C 1-6 alkyl;
R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, C 1-6 aralkyl, heteroaryl, C 1-6 heteroaralkyl, R 8 ZA-C 1-8 alkyl-, R 11 Z—C 1-8 alkyl-, (R 8 O)(R 9 O)P(═O)O—C 1-8 alkyl-ZAZ—C 1-8 alkyl-, (R 8 O)(R 9 O)P(═O)O—C 1-8 alkyl-Z—C 1-8 alkyl-, R 8 ZA-C 1-8 alkyl-ZAZ—C 1-8 alkyl-, heterocyclylMZAZ—C 1-8 alkyl-, (R 8 O)(R 9 O)P(═O)O—C 1-8 alkyl-, (R 10 ) 2 N—C 1-8 alkyl-, (R 10 ) 3 N + —C 1-8 alkyl-, heterocyclylM-, carbocyclylM-, R 11 SO 2 C 1-8 alkyl-, and R 11 SO 2 NH; or
R 6 and R 7 together are C 1-6 alkyl-Y—C 1-6 alkyl, C 1-6 alkyl-ZA-C 1-6 alkyl, A-C 1-6 alkyl-ZA-C 1-6 alkyl, A-C 1-6 alkyl-A, or C 1-6 alkyl-A, thereby forming a ring;
R 8 and R 9 are independently selected from hydrogen, metal cation, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl, or R 8 and R 9 together are C 1-6 alkyl, thereby forming a ring;
each R 10 is independently selected from hydrogen and C 1-6 alkyl; and
R 11 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl;
provided that when R 6 is H, L is C═O, and Q is absent, R 7 is not hydrogen, C 1-6 alkyl, or aryl or heteroaryl.
20. The pharmaceutical composition of claim 19 , wherein the proteasome inhibitor is represented by the following structural formula or a pharmaceutically acceptable salt thereof:
21. The pharmaceutical composition of claim 1 , wherein the proteasome inhibitor is represented by structural formula (VII) or a pharmaceutically acceptable salt thereof:
wherein:
each A is independently selected from C═O, C═S, and SO 2 ;
each B is independently selected from C═O, C═S, and SO 2 ;
D is absent or is C 1-8 alkyl;
G is selected from O, NH, and N—C 1-6 alkyl;
K is absent or is selected from C═O, C═S, and SO 2 ;
L is absent or is selected from C═O, C═S, and SO 2 ;
M is absent or is C 1-8 alkyl;
Q is absent or is selected from O, NH, and N—C 1-6 alkyl;
X is O;
each V is independently absent or is selected from O, S, NH, and N—C 1-6 alkyl;
W is absent or is independently selected from O, S, NH, and N—C 1-6 alkyl;
Y is absent or is selected from O, NH, N—C 1-6 alkyl, S, SO, SO 2 , CHOR 10 , and CHCO 2 R 10 ;
each Z is independently selected from O, S, NH, and N—C 1-6 alkyl;
R 1 , R 2 , R 3 , and R 4 are each independently selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, C 1-6 aralkyl, heteroaryl, C 1-6 heteroaralkyl, heterocyclyl, and C 1-6 heterocycloalkyl, and R 14 DVKOC 1-3 alkyl-, wherein at least one of R 1 and R 3 is R 14 DVKOC 1-3 alkyl-;
R 5 is N(R 6 )LQR 7 ;
R 6 is selected from hydrogen, OH, and C 1-6 alkyl;
R 7 is a further chain of amino acids, hydrogen, a protecting group, aryl, or heteroaryl, any of which is optionally substituted with halogen, carbonyl, nitro, hydroxy, aryl, C 1-5 alkyl; or R 7 is selected from C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 aralkyl, C 1-6 heteroaralkyl, R 8 ZA-C 1-8 alkyl-, R 11 Z—C 1-8 alkyl-, (R 8 O)(R 9 O)P(═O)O—C 1-8 alkyl-ZAZ—C 1-8 alkyl-, (R 8 O)(R 9 O)P(═O)O—C 1-8 alkyl-Z—C 1-8 alkyl-, R 8 ZA-C 1-8 alkyl-ZAZ—C 1-8 alkyl-, heterocyclylMZAZ—C 1-8 alkyl-, (R 8 O)(R 9 O)P(═O)O—C 1-8 alkyl-, (R 10 ) 2 N—C 1-8 alkyl-, (R 10 ) 3 N + —C 1-8 alkyl-, heterocyclylM-, carbocyclylM-, R 11 SO 2 C 1-8 alkyl-, and R 11 SO 2 NH; or
R 6 and R 7 together are C 1-6 alkyl-Y—C 1-6 alkyl, C 1-6 alkyl-ZA-C 1-6 alkyl, A-C 1-6 alkyl-ZA-C 1-6 alkyl, A-C 1-6 alkyl-A, or C 1-6 alkyl-A, thereby forming a ring;
R 8 and R 9 are independently selected from hydrogen, metal cation, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl, or R 8 and R 9 together are C 1-6 alkyl, thereby forming a ring;
each R 10 is independently selected from hydrogen and C 1-6 alkyl;
R 11 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl,
R 14 is selected from hydrogen, (R 15 O)(R 16 O)P(═O)W—, R 15 GB—, heterocyclyl-, (R 17 ) 2 N—, (R 17 ) 3 N + —, R 17 SO 2 GBG-, and R 15 GBC 1-8 alkyl- where the C 1-8 alkyl moiety is optionally substituted with OH, C 1-8 alkylW optionally substituted with halogen, aryl, heteroaryl, carbocyclyl, heterocyclyl, and C 1-6 aralkyl;
R 15 and R 16 are independently selected from hydrogen, metal cation, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl, or R 15 and R 16 together are C 1-6 alkyl, thereby forming a ring; and
R 17 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl;
provided that when R 6 is H, L is C═O, and Q is absent, R 7 is not hydrogen, C 1-6 alkyl, or aryl or heteroaryl; and
D, G, V, K, and W are selected such that there are no O—O, N—O, S—N, or S—O bonds.
22. The pharmaceutical composition of claim 21 , wherein the proteasome inhibitor is represented by structural formula (VIII) or a pharmaceutically acceptable salt thereof:
where:
each A is independently selected from C═O, C═S, and SO 2 ;
each B is independently selected from C═O, C═S, and SO 2 ;
D is absent or is C 1-8 alkyl;
G is selected from O, NH, and N—C 1-6 alkyl;
K is absent or is selected from C═O, C═S, and SO 2 ;
L is absent or is selected from C═O, C═S, and SO 2 ;
M is absent or is C 1-8 alkyl;
Q is absent or is selected from O, NH, and N—C 1-6 alkyl;
X is s O;
each V is independently absent or is selected from O, S, NH, and N—C 1-6 alkyl;
W is absent or is independently selected from O, S, NH, and N—C 1-6 alkyl;
Y is absent or is selected from O, NH, N—C 1-6 alkyl, S, SO, SO 2 , CHOR 10 , and CHCO 2 R 10 ;
each Z is independently selected from O, S, NH, and N—C 1-6 alkyl;
R 1 and R 3 are each independently selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, C 1-6 aralkyl, and R 14 DVKOC 1-3 alkyl-, wherein at least one of R 1 and R 3 is R 14 DVKOC 1-3 alkyl-;
R 5 is N(R 6 )LQR 7 ;
R 6 is selected from hydrogen, OH, and C 1-6 alkyl;
R 7 is a further chain of amino acids, hydrogen, a protecting group, aryl, or heteroaryl, any of which is optionally substituted with halogen, carbonyl, nitro, hydroxy, aryl, C 1-5 alkyl; or R 7 is selected from C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 aralkyl, C 1-6 heteroaralkyl, R 8 ZA-C 1-8 alkyl-, R 11 Z—C 1-8 alkyl-, (R 8 O)(R 9 O)P(═O)O—C 1-8 alkyl-ZAZ—C 1-8 alkyl-, (R 8 O)(R 9 O)P(═O)O—C 1-8 alkyl-Z—C 1-8 alkyl-, R 8 ZA-C 1-8 alkyl-ZAZ—C 1-8 alkyl-, heterocyclylMZAZ—C 1-8 alkyl-, (R 8 O)(R 9 O)P(═O)O—C 1-8 alkyl-, (R 10 ) 2 N—C 1-8 alkyl-, (R 10 ) 3 N + —C 1-8 alkyl-, heterocyclylM-, carbocyclylM-, R 11 SO 2 C 1-8 alkyl-, and R 11 SO 2 NH; or
R 6 and R 7 together are C 1-6 alkyl-Y—C 1-6 alkyl, C 1-6 alkyl-ZA-C 1-6 alkyl, A-C 1-6 alkyl-ZA-C 1-8 alkyl, A-C 1-6 alkyl-A, or C 1-6 alkyl-A, thereby forming a ring;
R 8 and R 9 are independently selected from hydrogen, metal cation, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl, or R 8 and R 9 together are C 1-6 alkyl, thereby forming a ring;
each R 10 is independently selected from hydrogen and C 1-6 alkyl; and
R 11 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-8 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C 1-6 aralkyl, and C 1-6 heteroaralkyl,
R 14 is selected from hydrogen, (R 15 O)(R 16 O)P(═O)W—, R 15 GB—, heterocyclyl-, (R 17 ) 2 N—, (R 17 ) 3 N + —, R 17 SO 2 GBG-, and R 15 GBC 1-8 alkyl- where the C 1-8 alkyl moiety is optionally substituted with OH, C 1-8 alkylW optionally substituted with halogen, aryl, heteroaryl, carbocyclyl, heterocyclyl, and C 1-6 aralkyl;
R 15 and R 16 are independently selected from hydrogen, metal cation, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, heteroaryl, C 1-6 aralkyl, C 1-6 heteroaralkyl, or R 15 and R 16 together are C 1-6 alkyl, thereby forming a ring;
R 17 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C 1-6 aralkyl, and heteroaralkyl;
provided that when R 6 is H, L is C═O, and Q is absent, R 7 is not hydrogen, C 1-6 alkyl, or aryl or heteroaryl; and
D, G, V, K, and W are selected such that there are no O—O, N—O, S—N, or S—O bonds.
23. The pharmaceutical composition of claim 1 , wherein the proteasome inhibitor is represented by structural formula (IX) or a pharmaceutically acceptable salt thereof:
wherein:
X is O;
R 1 , R 2 , R 3 , and R 4 are hydrogen; and
R 5 , R 6 , R 7 , and R 8 are independently selected from H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, C 1-6 aralkyl, heteroaryl, C 1-6 heteroaralkyl, heterocyclyl, and C 1-6 heterocycloalkyl, each of which is optionally substituted with a group selected from amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof, carboxyl ester, thiol, and thioether.
24. The pharmaceutical composition of claim 23 , wherein the proteasome inhibitor is represented by structural formula (X) or a pharmaceutically acceptable salt thereof:
wherein:
X is O;
R 1 , R 2 , R 3 , and R 4 are independently selected from hydrogen and a group of formula (IXa); and
R 6 and R 8 are independently selected from H, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl, each of which is optionally substituted with a group selected from amide, amine, carboxylic acid or a pharmaceutically acceptable salt thereof carboxyl ester, thiol, and thioether.
25. The pharmaceutical composition of claim 1 , wherein the proteasome inhibitor is represented by structural formula (XI) or a pharmaceutically acceptable salt thereof:
wherein:
X is O;
R 1 , R 2 , R 3 , and R 4 are each independently selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, C 1-6 aralkyl, heteroaryl, C 1-6 heteroaralkyl, heterocyclyl, and C 1-6 heterocycloalkyl, any of which is optionally substituted with one or more of amide, amine, carboxylic acid, ester, thiol, or thioether substituents;
R 5 is N(R 6 )R 7 ;
R 6 is selected from hydrogen, OH, and C 1-6 alkyl; and
R 7 comprises a detectable label.
26. The pharmaceutical composition of claim 25 , wherein the proteasome inhibitor is represented by structural formula (XII) or a pharmaceutically acceptable salt thereof:
wherein:
X is O;
R 2 and R 4 are each independently selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl, any of which is optionally substituted with one or more of amide, amine, carboxylic acid, ester, thiol, or thioether substituents;
R 5 is N(R 6 )R 7 ;
R 6 is selected from hydrogen, OH, and C 1-6 alkyl; and
R 7 comprises a detectable label.
27. The pharmaceutical composition of claim 1 , wherein the proteasome inhibitor is represented by structural formula (XII) or (XIV) or a pharmaceutically acceptable salt thereof:
wherein:
each Ar is independently an aromatic or heteroaromatic group optionally substituted with 1 to 4 substituents;
L is selected from C═O, C═S, and SO 2 ;
X is s O;
Y is absent or is selected from C═O and SO 2 ;
Z is absent or is C 1-6 alkyl;
R 1 , R 2 , and R 3 are each independently selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, C 1-6 aralkyl, heteroaryl, C 1-6 heteroaralkyl, heterocyclyl, and C 1-6 heterocycloalkyl, any of which is optionally substituted with one or more of amide, amine, carboxylic acid, ester, thiol, or thioether substituents;
R 4 is N(R 5 )L-Z—R 6 ;
R 5 is selected from hydrogen, OH, C 1-6 aralkyl, and C 1-6 alkyl;
R 6 is selected from hydrogen, C 1-6 alkenyl, Ar—Y—, carbocyclyl, and heterocyclyl; and
R 7 and R 8 are independently selected from hydrogen, C 1-6 alkyl, and C 1-6 aralkyl.
28. The pharmaceutical composition of claim 27 wherein the proteasome inhibitor is represented by structural formula (XV) or (XVI) or a pharmaceutically acceptable salt thereof:
wherein:
each Ar is independently an aromatic or heteroaromatic group optionally substituted with 1-4 substituents;
L is selected from C═O, C═S, and SO 2 ;
X is O;
Y is absent or is selected from C═O and SO 2 ;
Z is absent or is C 1-6 alkyl;
R 1 and R 3 are each independently selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, aryl, and C 1-6 aralkyl, any of which is optionally substituted with one or more of amide, amine, carboxylic acid, ester, thiol, or thioether substituents;
R 4 is N(R 5 )L-Z—R 6 ;
R 5 is selected from hydrogen, OH, C 1-6 aralkyl, and C 1-6 alkyl;
R 6 is selected from hydrogen, C 1-6 alkenyl, Ar—Y—, carbocyclyl, and heterocyclyl; and
R 7 and R 8 are independently selected from hydrogen, C 1-6 alkyl, and C 1-6 aralkyl.
29. A pharmaceutical composition comprising a compound having a structure
or a pharmaceutically acceptable salt thereof, and a substituted cyclodextrin selected from hydroxypropyl beta-cyclodextrin and sulfobutyl ether beta-cyclodextrin (SBECD).
30. A pharmaceutical composition of claim 29 , wherein the cyclodextrin is SBECD.
31. A pharmaceutical composition comprising a compound having a structure
or a pharmaceutically acceptable salt thereof, in an aqueous solution containing 10% (w/v) SBECD and 10 mM citric acid adjusted to pH 3.5.
32. A pharmaceutical composition in the form of a lyophilisate comprising SBECD and a compound having a structure
or a pharmaceutically acceptable salt thereof.