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Claims for Patent: 7,737,112

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Claims for Patent: 7,737,112

Title:Composition for enzyme inhibition
Abstract: 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.
Inventor(s): Lewis; Evan R. (Pacifica, CA), Ho; Mark Nguyen (San Jose, CA), Fonseca; Fabiana N. (New York, NY)
Assignee: Onyx Therapeutics, Inc. (South San Francisco, CA)
Application Number:11/299,265
Patent Claims: 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: ##STR00031## wherein: X is oxygen; R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are independently selected from C.sub.1-6alkyl or C.sub.1-6hydroxy alkyl or C.sub.1-6alkoxy alkyl, aryl, heteroaryl, C.sub.1-6heteroaralkyl, heterocyclyl, and C.sub.1-6heterocycloalkyl, and aryl-substituted C.sub.1-6alkyl, 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.sub.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 ##STR00032## wherein: X is O; R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are hydrogen R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are independently selected from C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, C.sub.1-6alkoxyalkyl, aryl, and C.sub.1-6aralkyl, 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.sup.9 is a further chain of amino acids, hydrogen, C.sub.1-6acyl, 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: ##STR00033## wherein: X is O; R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently selected from hydrogen and a group of formula (IIIa), with the proviso that at least one of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 is a group of formula (IIIa); R.sup.6 and R.sup.8 independently are selected from C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, C.sub.1-6alkoxyalkyl, aryl, and C.sub.1-6aralkyl, 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.sup.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: ##STR00034## wherein: each A is independently selected from C.dbd.O, C.dbd.S, and SO.sub.2; L is absent or is selected from C.dbd.O, C.dbd.S, and SO.sub.2; M is absent or is C.sub.1-8alkyl; Q is absent or is selected from O, NH, and N--C.sub.1-6alkyl; X is O; Y is absent or is selected from O, NH, N--C.sub.1-6alkyl, S, SO, SO.sub.2, CHOR.sup.10, and CHCO.sub.2R.sup.10; each Z is independently selected from O, S, NH, and N--C.sub.1-6alkyl; R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are each independently selected from C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, C.sub.1-6alkoxyalkyl, aryl, C.sub.1-6aralkyl, heteroaryl, C.sub.1-6heteroaralkyl, heterocyclyl, and C.sub.1-6heterocycloalkyl, 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.sup.5 is N(R.sup.6)LQR.sup.7; R.sup.6 is selected from hydrogen, OH, and C.sub.1-6alkyl; R.sup.7 is selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkynyl, aryl, C.sub.1-6aralkyl, heteroaryl, C.sub.1-6heteroaralkyl, R.sup.8ZA--C.sub.1-8alkyl-, R.sup.11Z--C.sub.1-8alkyl-, (R.sup.8O)(R.sup.9O)P(.dbd.O)O--C.sub.1-8alkyl-ZAZ--C.sub.1-8alkyl-, (R.sup.8O)(R.sup.9O)P(.dbd.O)O--C.sub.1-8alkyl-Z--C.sub.1-8alkyl-, R.sup.8ZA-C.sub.1-8alkyl-ZAZ--C.sub.1-8alkyl-, heterocyclylMZAZ--C.sub.1-8alkyl-, (R.sup.8O)(R.sup.9O)P(.dbd.O)O--C.sub.1-8alkyl-, (R.sup.10).sub.2N--C.sub.1-8alkyl-, (R.sup.10).sub.3N.sup.+--C.sub.1-8alkyl-, heterocyclylM-, carbocyclylM-, R.sup.11SO.sub.2C.sub.1-8alkyl-, and R.sup.11SO.sub.2NH; or R.sup.6 and R.sup.7 together C.sub.1-6alkyl-Y--C.sub.1-6alkyl, C.sub.1-6alkyl-ZA-C.sub.1-6alkyl, A-C.sub.1-6alkyl-ZA-C.sub.1-6alkyl, A-C.sub.1-6alkyl-A, or C.sub.1-6alkyl-A, thereby forming a ring; R.sup.8 and R.sup.9 are independently selected from hydrogen, metal cation, C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkynyl, aryl, heteroaryl, C.sub.1-6aralkyl, and C.sub.1-6heteroaralkyl, or R.sup.8 and R.sup.9 together are C.sub.1-6alkyl, thereby forming a ring; each R.sup.10 is independently selected from hydrogen and C.sub.1-6alkyl; and R.sup.11 is independently selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C.sub.1-6aralkyl, and C.sub.1-6heteroaralkyl, provided that when R.sub.6 is H, L is C.dbd.O, and Q is absent, R.sup.7 is not hydrogen, C.sub.1-6alkyl, 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: ##STR00035## wherein: each A is independently selected from C.dbd.O, C.dbd.S, and SO.sub.2; L is absent or is selected from C.dbd.O, C.dbd.S, and SO.sub.2; M is absent or is C.sub.1-8alkyl; Q is absent or is selected from O, NH, and N--C.sub.1-6alkyl; X is O; Y is absent or is selected from O, NH, N--C.sub.1-6alkyl, S, SO, SO.sub.2, CHOR.sup.10, and CHCO.sub.2R.sup.10; each Z is independently selected from O, S, NH, and N--C.sub.1-6alkyl; R.sup.2 and R.sup.4 are each independently selected from C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, C.sub.1-6alkoxyalkyl, aryl, and C.sub.1-6aralkyl, 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.sup.5 is N(R.sup.6)LQR.sup.7; R.sup.6 is selected from hydrogen, OH, and C.sub.1-6alkyl; R.sup.7 is selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkynyl, aryl, C.sub.1-6aralkyl, heteroaryl, C.sub.1-6heteroaralkyl, R.sup.8ZA-C.sub.1-8alkyl-, R.sup.11Z--C.sub.1-8alkyl-, (R.sup.8O)(R.sup.9O)P(.dbd.O)O--C.sub.1-8alkyl-ZAZ--C.sub.1-8alkyl-, (R.sup.8O)(R.sup.9O)P(.dbd.O)O--C.sub.1-8alkyl-Z--C.sub.1-8alkyl-, R.sup.8ZA-C.sub.1-8alkyl-ZAZ--C.sub.1-8alkyl-, heterocyclylMZAZ--C.sub.1-8alkyl-, (R.sup.8O)(R.sup.9O)P(.dbd.O)O--C.sub.1-8alkyl-, (R.sup.10).sub.2N--C.sub.1-8alkyl-, (R.sup.10).sub.3N.sup.+--C.sub.1-8alkyl-, heterocyclylM-, carbocyclylM-, R.sup.11SO.sub.2C.sub.1-8alkyl-, and R.sup.11SO.sub.2NH; or R.sup.6 and R.sup.7 together are C.sub.1-6alkyl-Y--C.sub.1-6alkyl, C.sub.1-6alkyl-ZA-C.sub.1-6alkyl, A-C.sub.1-6alkyl-ZA-C.sub.1-6alkyl, A-C.sub.1-6alkyl-A, or C.sub.1-6alkyl-A, thereby forming a ring; R.sup.8 and R.sup.9 are independently selected from hydrogen, metal cation, C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkynyl, aryl, heteroaryl, C.sub.1-6aralkyl, and C.sub.1-6heteroaralkyl, or R.sup.8 and R.sup.9 together are C.sub.1-6alkyl, thereby forming a ring; each R.sup.10 is independently selected from hydrogen and C.sub.1-6alkyl; and R.sup.11 is independently selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C.sub.1-6aralkyl, and C.sub.1-6heteroaralkyl; provided that when R.sub.6 is H, L is C.dbd.O, and Q is absent, R.sup.7 is not hydrogen, C.sub.1-6alkyl, 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: ##STR00036##

21. The pharmaceutical composition of claim 1, wherein the proteasome inhibitor is represented by structural formula (VII) or a pharmaceutically acceptable salt thereof: ##STR00037## wherein: each A is independently selected from C.dbd.O, C.dbd.S, and SO.sub.2; each B is independently selected from C.dbd.O, C.dbd.S, and SO.sub.2; D is absent or is C.sub.1-8alkyl; G is selected from O, NH, and N--C.sub.1-6alkyl; K is absent or is selected from C.dbd.O, C.dbd.S, and SO.sub.2; L is absent or is selected from C.dbd.O, C.dbd.S, and SO.sub.2; M is absent or is C.sub.1-8alkyl; Q is absent or is selected from O, NH, and N--C.sub.1-6alkyl; X is O; each V is independently absent or is selected from O, S, NH, and N--C.sub.1-6alkyl; W is absent or is independently selected from O, S, NH, and N--C.sub.1-6alkyl; Y is absent or is selected from O, NH, N--C.sub.1-6alkyl, S, SO, SO.sub.2, CHOR.sup.10, and CHCO.sub.2R.sup.10; each Z is independently selected from O, S, NH, and N--C.sub.1-6alkyl; R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are each independently selected from C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, C.sub.1-6alkoxyalkyl, aryl, C.sub.1-6aralkyl, heteroaryl, C.sub.1-6heteroaralkyl, heterocyclyl, and C.sub.1-6heterocycloalkyl, and R.sup.14DVKOC.sub.1-3alkyl-, wherein at least one of R.sup.1 and R.sup.3 is R.sup.14DVKOC.sub.1-3alkyl-; R.sup.5 is N(R.sup.6)LQR.sup.7; R.sup.6 is selected from hydrogen, OH, and C.sub.1-6alkyl; R.sup.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.sub.1-5alkyl; or R.sup.7 is selected from C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkynyl, C.sub.1-6aralkyl, C.sub.1-6heteroaralkyl, R.sup.8ZA-C.sub.1-8alkyl-, R.sup.11Z--C.sub.1-8alkyl-, (R.sup.8O)(R.sup.9O)P(.dbd.O)O--C.sub.1-8alkyl-ZAZ--C.sub.1-8alkyl-, (R.sup.8O)(R.sup.9O)P(.dbd.O)O--C.sub.1-8alkyl-Z--C.sub.1-8alkyl-, R.sup.8ZA-C.sub.1-8alkyl-ZAZ--C.sub.1-8alkyl-, heterocyclylMZAZ--C.sub.1-8alkyl-, (R.sup.8O)(R.sup.9O)P(.dbd.O)O--C.sub.1-8alkyl-, (R.sup.10).sub.2N--C.sub.1-8alkyl-, (R.sup.10).sub.3N.sup.+--C.sub.1-8alkyl-, heterocyclylM-, carbocyclylM-, R.sup.11SO.sub.2C.sub.1-8alkyl-, and R.sup.11SO.sub.2NH; or R.sup.6 and R.sup.7 together are C.sub.1-6alkyl-Y--C.sub.1-6alkyl, C.sub.1-6alkyl-ZA-C.sub.1-6alkyl, A-C.sub.1-6alkyl-ZA-C.sub.1-6alkyl, A-C.sub.1-6alkyl-A, or C.sub.1-6alkyl-A, thereby forming a ring; R.sup.8 and R.sup.9 are independently selected from hydrogen, metal cation, C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkynyl, aryl, heteroaryl, C.sub.1-6aralkyl, and C.sub.1-6heteroaralkyl, or R.sup.8 and R.sup.9 together are C.sub.1-6alkyl, thereby forming a ring; each R.sup.10 is independently selected from hydrogen and C.sub.1-6alkyl; R.sup.11 is independently selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C.sub.1-6aralkyl, and C.sub.1-6heteroaralkyl, R.sup.14 is selected from hydrogen, (R.sup.15O)(R.sup.16O)P(.dbd.O)W--, R.sup.15GB--, heterocyclyl-, (R.sup.17).sub.2N--, (R.sup.17).sub.3N.sup.+--, R.sup.17SO.sub.2GBG-, and R.sup.15GBC.sub.1-8alkyl- where the C.sub.1-8alkyl moiety is optionally substituted with OH, C.sub.1-8alkylW optionally substituted with halogen, aryl, heteroaryl, carbocyclyl, heterocyclyl, and C.sub.1-6aralkyl; R.sup.15 and R.sup.16 are independently selected from hydrogen, metal cation, C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkynyl, aryl, heteroaryl, C.sub.1-6aralkyl, and C.sub.1-6heteroaralkyl, or R.sup.15 and R.sup.16 together are C.sub.1-6alkyl, thereby forming a ring; and R.sup.17 is selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C.sub.1-6aralkyl, and C.sub.1-6heteroaralkyl; provided that when R.sub.6 is H, L is C.dbd.O, and Q is absent, R.sup.7 is not hydrogen, C.sub.1-6alkyl, 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: ##STR00038## where: each A is independently selected from C.dbd.O, C.dbd.S, and SO.sub.2; each B is independently selected from C.dbd.O, C.dbd.S, and SO.sub.2; D is absent or is C.sub.1-8alkyl; G is selected from O, NH, and N--C.sub.1-6alkyl; K is absent or is selected from C.dbd.O, C.dbd.S, and SO.sub.2; L is absent or is selected from C.dbd.O, C.dbd.S, and SO.sub.2; M is absent or is C.sub.1-8alkyl; Q is absent or is selected from O, NH, and N--C.sub.1-6alkyl; X is s O; each V is independently absent or is selected from O, S, NH, and N--C.sub.1-6alkyl; W is absent or is independently selected from O, S, NH, and N--C.sub.1-6alkyl; Y is absent or is selected from O, NH, N--C.sub.1-6alkyl, S, SO, SO.sub.2, CHOR.sup.10, and CHCO.sub.2R.sup.10; each Z is independently selected from O, S, NH, and N--C.sub.1-6alkyl; R.sup.1 and R.sup.3 are each independently selected from C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, C.sub.1-6alkoxyalkyl, aryl, C.sub.1-6aralkyl, and R.sup.14DVKOC.sub.1-3alkyl-, wherein at least one of R.sup.1 and R.sup.3 is R.sup.14DVKOC.sub.1-3alkyl-; R.sup.5 is N(R.sup.6)LQR.sup.7; R.sup.6 is selected from hydrogen, OH, and C.sub.1-6alkyl; R.sup.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.sub.1-5alkyl; or R.sup.7 is selected from C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkynyl, C.sub.1-6aralkyl, C.sub.1-6heteroaralkyl, R.sup.8ZA-C.sub.1-8alkyl-, R.sup.11Z--C.sub.1-8alkyl-, (R.sup.8O)(R.sup.9O)P(.dbd.O)O--C.sub.1-8alkyl-ZAZ--C.sub.1-8alkyl-, (R.sup.8O)(R.sup.9O)P(.dbd.O)O--C.sub.1-8alkyl-Z--C.sub.1-8alkyl-, R.sup.8ZA-C.sub.1-8alkyl-ZAZ--C.sub.1-8alkyl-, heterocyclylMZAZ--C.sub.1-8alkyl-, (R.sup.8O)(R.sup.9O)P(.dbd.O)O--C.sub.1-8alkyl-, (R.sup.10).sub.2N--C.sub.1-8alkyl-, (R.sup.10).sub.3N.sup.+--C.sub.1-8alkyl-, heterocyclylM-, carbocyclylM-, R.sup.11SO.sub.2C.sub.1-8alkyl-, and R.sup.11SO.sub.2NH; or R.sup.6 and R.sup.7 together are C.sub.1-6alkyl-Y--C.sub.1-6alkyl, C.sub.1-6alkyl-ZA-C.sub.1-6alkyl, A-C.sub.1-6alkyl-ZA-C.sub.1-8alkyl, A-C.sub.1-6alkyl-A, or C.sub.1-6alkyl-A, thereby forming a ring; R.sup.8 and R.sup.9 are independently selected from hydrogen, metal cation, C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkynyl, aryl, heteroaryl, C.sub.1-6aralkyl, and C.sub.1-6heteroaralkyl, or R.sup.8 and R.sup.9 together are C.sub.1-6alkyl, thereby forming a ring; each R.sup.10 is independently selected from hydrogen and C.sub.1-6alkyl; and R.sup.11 is independently selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-8alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C.sub.1-6aralkyl, and C.sub.1-6heteroaralkyl, R.sup.14 is selected from hydrogen, (R.sup.15O)(R.sup.16O)P(.dbd.O)W--, R.sup.15GB--, heterocyclyl-, (R.sup.17).sub.2N--, (R.sup.17).sub.3N.sup.+--, R.sup.17SO.sub.2GBG-, and R.sup.15GBC.sub.1-8alkyl- where the C.sub.1-8alkyl moiety is optionally substituted with OH, C.sub.1-8alkylW optionally substituted with halogen, aryl, heteroaryl, carbocyclyl, heterocyclyl, and C.sub.1-6aralkyl; R.sup.15 and R.sup.16 are independently selected from hydrogen, metal cation, C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkynyl, aryl, heteroaryl, C.sub.1-6aralkyl, C.sub.1-6heteroaralkyl, or R.sup.15 and R.sup.16 together are C.sub.1-6alkyl, thereby forming a ring; R.sup.17 is selected from hydrogen, C.sub.1-6alkyl, C.sub.1-6alkenyl, C.sub.1-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C.sub.1-6aralkyl, and heteroaralkyl; provided that when R.sub.6 is H, L is C.dbd.O, and Q is absent, R.sup.7 is not hydrogen, C.sub.1-6alkyl, 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: ##STR00039## wherein: X is O; R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are hydrogen; and R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are independently selected from H, C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, C.sub.1-6alkoxyalkyl, aryl, C.sub.1-6aralkyl, heteroaryl, C.sub.1-6heteroaralkyl, heterocyclyl, and C.sub.1-6heterocycloalkyl, 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: ##STR00040## wherein: X is O; R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently selected from hydrogen and a group of formula (IXa); and R.sup.6 and R.sup.8 are independently selected from H, C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, C.sub.1-6alkoxyalkyl, aryl, and C.sub.1-6aralkyl, 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: ##STR00041## wherein: X is O; R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are each independently selected from C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, C.sub.1-6alkoxyalkyl, aryl, C.sub.1-6aralkyl, heteroaryl, C.sub.1-6heteroaralkyl, heterocyclyl, and C.sub.1-6heterocycloalkyl, any of which is optionally substituted with one or more of amide, amine, carboxylic acid, ester, thiol, or thioether substituents; R.sup.5 is N(R.sup.6)R.sup.7; R.sup.6 is selected from hydrogen, OH, and C.sub.1-6alkyl; and R.sup.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: ##STR00042## wherein: X is O; R.sup.2 and R.sup.4 are each independently selected from C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, C.sub.1-6alkoxyalkyl, aryl, and C.sub.1-6aralkyl, any of which is optionally substituted with one or more of amide, amine, carboxylic acid, ester, thiol, or thioether substituents; R.sup.5 is N(R.sup.6)R.sup.7; R.sup.6 is selected from hydrogen, OH, and C.sub.1-6alkyl; and R.sup.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: ##STR00043## wherein: each Ar is independently an aromatic or heteroaromatic group optionally substituted with 1 to 4 substituents; L is selected from C.dbd.O, C.dbd.S, and SO.sub.2; X is s O; Y is absent or is selected from C.dbd.O and SO.sub.2; Z is absent or is C.sub.1-6alkyl; R.sup.1, R.sup.2, and R.sup.3 are each independently selected from C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, C.sub.1-6alkoxyalkyl, aryl, C.sub.1-6aralkyl, heteroaryl, C.sub.1-6heteroaralkyl, heterocyclyl, and C.sub.1-6heterocycloalkyl, any of which is optionally substituted with one or more of amide, amine, carboxylic acid, ester, thiol, or thioether substituents; R.sup.4 is N(R.sup.5)L-Z--R.sup.6; R.sup.5 is selected from hydrogen, OH, C.sub.1-6aralkyl, and C.sub.1-6alkyl; R.sup.6 is selected from hydrogen, C.sub.1-6alkenyl, Ar--Y--, carbocyclyl, and heterocyclyl; and R.sup.7 and R.sup.8 are independently selected from hydrogen, C.sub.1-6alkyl, and C.sub.1-6aralkyl.

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: ##STR00044## wherein: each Ar is independently an aromatic or heteroaromatic group optionally substituted with 1-4 substituents; L is selected from C.dbd.O, C.dbd.S, and SO.sub.2; X is O; Y is absent or is selected from C.dbd.O and SO.sub.2; Z is absent or is C.sub.1-6alkyl; R.sup.1 and R.sup.3 are each independently selected from C.sub.1-6alkyl, C.sub.1-6hydroxyalkyl, C.sub.1-6alkoxyalkyl, aryl, and C.sub.1-6aralkyl, any of which is optionally substituted with one or more of amide, amine, carboxylic acid, ester, thiol, or thioether substituents; R.sup.4 is N(R.sup.5)L-Z--R.sup.6; R.sup.5 is selected from hydrogen, OH, C.sub.1-6aralkyl, and C.sub.1-6alkyl; R.sup.6 is selected from hydrogen, C.sub.1-6alkenyl, Ar--Y--, carbocyclyl, and heterocyclyl; and R.sup.7 and R.sup.8 are independently selected from hydrogen, C.sub.1-6alkyl, and C.sub.1-6aralkyl.

29. A pharmaceutical composition comprising a compound having a structure ##STR00045## 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 ##STR00046## 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 ##STR00047## or a pharmaceutically acceptable salt thereof.
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