Claims for Patent: 7,737,112

Summary 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):	Evan R. Lewis, Mark Nguyen Ho, Fabiana N. Fonseca
Assignee:	Onyx Therapeutics Inc
Application Number:	US11/299,265
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,737,112
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: wherein: X is oxygen; R1, R2, R3 and R4 are independently selected from C1-6alkyl or C1-6hydroxy alkyl or C1-6alkoxy alkyl, aryl, heteroaryl, C1-6heteroaralkyl, heterocyclyl, and C1-6heterocycloalkyl, and aryl-substituted C1-6alkyl, wherein such groups are optionally substituted with one or more amide linkages, amines, carboxylic acids and salts thereof, carboxyl esters, thiols and thioethers; and R5 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; R1, R2, R3, and R4 are hydrogen R5, R6, R7, and R8 are independently selected from C1-6alkyl, C1-6hydroxyalkyl, C1-6alkoxyalkyl, aryl, and C1-6aralkyl, 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 R9 is a further chain of amino acids, hydrogen, C1-6acyl, 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: wherein: X is O; R1, R2, R3 and R4 are independently selected from hydrogen and a group of formula (IIIa), with the proviso that at least one of R1, R2, R3, and R4 is a group of formula (IIIa); R6 and R8 independently are selected from C1-6alkyl, C1-6hydroxyalkyl, C1-6alkoxyalkyl, aryl, and C1-6aralkyl, 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; R9 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 SO2; L is absent or is selected from C═O, C═S, and SO2; M is absent or is C1-8alkyl; Q is absent or is selected from O, NH, and N—C1-6alkyl; X is O; Y is absent or is selected from O, NH, N—C1-6alkyl, S, SO, SO2, CHOR10, and CHCO2R10; each Z is independently selected from O, S, NH, and N—C1-6alkyl; R1, R2, R3, and R4 are each independently selected from C1-6alkyl, C1-6hydroxyalkyl, C1-6alkoxyalkyl, aryl, C1-6aralkyl, heteroaryl, C1-6heteroaralkyl, heterocyclyl, and C1-6heterocycloalkyl, any of which is optionally substituted with one or more of amide, amine, carboxylic acid (or a salt thereof), ester, thiol, or thioether substituents; R5 is N(R6)LQR7; R6 is selected from hydrogen, OH, and C1-6alkyl; R7 is selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, aryl, C1-6aralkyl, heteroaryl, C1-6heteroaralkyl, R8ZA—C1-8alkyl-, R11Z—C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-ZAZ—C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-Z—C1-8alkyl-, R8ZA-C1-8alkyl-ZAZ—C1-8alkyl-, heterocyclylMZAZ—C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-, (R10)2N—C1-8alkyl-, (R10)3N+—C1-8alkyl-, heterocyclylM-, carbocyclylM-, R11SO2C1-8alkyl-, and R11SO2NH; or R6 and R7 together C1-6alkyl-Y—C1-6alkyl, C1-6alkyl-ZA-C1-6alkyl, A-C1-6alkyl-ZA-C1-6alkyl, A-C1-6alkyl-A, or C1-6alkyl-A, thereby forming a ring; R8 and R9 are independently selected from hydrogen, metal cation, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, aryl, heteroaryl, C1-6aralkyl, and C1-6heteroaralkyl, or R8 and R9 together are C1-6alkyl, thereby forming a ring; each R10 is independently selected from hydrogen and C1-6alkyl; and R11 is independently selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C1-6aralkyl, and C1-6heteroaralkyl, provided that when R6 is H, L is C═O, and Q is absent, R7 is not hydrogen, C1-6alkyl, 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: wherein: each A is independently selected from C═O, C═S, and SO2; L is absent or is selected from C═O, C═S, and SO2; M is absent or is C1-8alkyl; Q is absent or is selected from O, NH, and N—C1-6alkyl; X is O; Y is absent or is selected from O, NH, N—C1-6alkyl, S, SO, SO2, CHOR10, and CHCO2R10; each Z is independently selected from O, S, NH, and N—C1-6alkyl; R2 and R4 are each independently selected from C1-6alkyl, C1-6hydroxyalkyl, C1-6alkoxyalkyl, aryl, and C1-6aralkyl, any of which is optionally substituted with one or more of amide, amine, carboxylic acid or a salt thereof, ester, thiol, or thioether substituents; R5 is N(R6)LQR7; R6 is selected from hydrogen, OH, and C1-6alkyl; R7 is selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, aryl, C1-6aralkyl, heteroaryl, C1-6heteroaralkyl, R8ZA-C1-8alkyl-, R11Z—C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-ZAZ—C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-Z—C1-8alkyl-, R8ZA-C1-8alkyl-ZAZ—C1-8alkyl-, heterocyclylMZAZ—C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-, (R10)2N—C1-8alkyl-, (R10)3N+—C1-8alkyl-, heterocyclylM-, carbocyclylM-, R11SO2C1-8alkyl-, and R11SO2NH; or R6 and R7 together are C1-6alkyl-Y—C1-6alkyl, C1-6alkyl-ZA-C1-6alkyl, A-C1-6alkyl-ZA-C1-6alkyl, A-C1-6alkyl-A, or C1-6alkyl-A, thereby forming a ring; R8 and R9 are independently selected from hydrogen, metal cation, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, aryl, heteroaryl, C1-6aralkyl, and C1-6heteroaralkyl, or R8 and R9 together are C1-6alkyl, thereby forming a ring; each R10 is independently selected from hydrogen and C1-6alkyl; and R11 is independently selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C1-6aralkyl, and C1-6heteroaralkyl; provided that when R6 is H, L is C═O, and Q is absent, R7 is not hydrogen, C1-6alkyl, 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: 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 SO2; each B is independently selected from C═O, C═S, and SO2; D is absent or is C1-8alkyl; G is selected from O, NH, and N—C1-6alkyl; K is absent or is selected from C═O, C═S, and SO2; L is absent or is selected from C═O, C═S, and SO2; M is absent or is C1-8alkyl; Q is absent or is selected from O, NH, and N—C1-6alkyl; X is O; each V is independently absent or is selected from O, S, NH, and N—C1-6alkyl; W is absent or is independently selected from O, S, NH, and N—C1-6alkyl; Y is absent or is selected from O, NH, N—C1-6alkyl, S, SO, SO2, CHOR10, and CHCO2R10; each Z is independently selected from O, S, NH, and N—C1-6alkyl; R1, R2, R3, and R4 are each independently selected from C1-6alkyl, C1-6hydroxyalkyl, C1-6alkoxyalkyl, aryl, C1-6aralkyl, heteroaryl, C1-6heteroaralkyl, heterocyclyl, and C1-6heterocycloalkyl, and R14DVKOC1-3alkyl-, wherein at least one of R1 and R3 is R14DVKOC1-3alkyl-; R5 is N(R6)LQR7; R6 is selected from hydrogen, OH, and C1-6alkyl; R7 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, C1-5alkyl; or R7 is selected from C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C1-6aralkyl, C1-6heteroaralkyl, R8ZA-C1-8alkyl-, R11Z—C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-ZAZ—C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-Z—C1-8alkyl-, R8ZA-C1-8alkyl-ZAZ—C1-8alkyl-, heterocyclylMZAZ—C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-, (R10)2N—C1-8alkyl-, (R10)3N+—C1-8alkyl-, heterocyclylM-, carbocyclylM-, R11SO2C1-8alkyl-, and R11SO2NH; or R6 and R7 together are C1-6alkyl-Y—C1-6alkyl, C1-6alkyl-ZA-C1-6alkyl, A-C1-6alkyl-ZA-C1-6alkyl, A-C1-6alkyl-A, or C1-6alkyl-A, thereby forming a ring; R8 and R9 are independently selected from hydrogen, metal cation, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, aryl, heteroaryl, C1-6aralkyl, and C1-6heteroaralkyl, or R8 and R9 together are C1-6alkyl, thereby forming a ring; each R10 is independently selected from hydrogen and C1-6alkyl; R11 is independently selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C1-6aralkyl, and C1-6heteroaralkyl, R14 is selected from hydrogen, (R15O)(R16O)P(═O)W—, R15GB—, heterocyclyl-, (R17)2N—, (R17)3N+—, R17SO2GBG-, and R15GBC1-8alkyl- where the C1-8alkyl moiety is optionally substituted with OH, C1-8alkylW optionally substituted with halogen, aryl, heteroaryl, carbocyclyl, heterocyclyl, and C1-6aralkyl; R15 and R16 are independently selected from hydrogen, metal cation, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, aryl, heteroaryl, C1-6aralkyl, and C1-6heteroaralkyl, or R15 and R16 together are C1-6alkyl, thereby forming a ring; and R17 is selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C1-6aralkyl, and C1-6heteroaralkyl; provided that when R6 is H, L is C═O, and Q is absent, R7 is not hydrogen, C1-6alkyl, 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: where: each A is independently selected from C═O, C═S, and SO2; each B is independently selected from C═O, C═S, and SO2; D is absent or is C1-8alkyl; G is selected from O, NH, and N—C1-6alkyl; K is absent or is selected from C═O, C═S, and SO2; L is absent or is selected from C═O, C═S, and SO2; M is absent or is C1-8alkyl; Q is absent or is selected from O, NH, and N—C1-6alkyl; X is s O; each V is independently absent or is selected from O, S, NH, and N—C1-6alkyl; W is absent or is independently selected from O, S, NH, and N—C1-6alkyl; Y is absent or is selected from O, NH, N—C1-6alkyl, S, SO, SO2, CHOR10, and CHCO2R10; each Z is independently selected from O, S, NH, and N—C1-6alkyl; R1 and R3 are each independently selected from C1-6alkyl, C1-6hydroxyalkyl, C1-6alkoxyalkyl, aryl, C1-6aralkyl, and R14DVKOC1-3alkyl-, wherein at least one of R1 and R3 is R14DVKOC1-3alkyl-; R5 is N(R6)LQR7; R6 is selected from hydrogen, OH, and C1-6alkyl; R7 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, C1-5alkyl; or R7 is selected from C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C1-6aralkyl, C1-6heteroaralkyl, R8ZA-C1-8alkyl-, R11Z—C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-ZAZ—C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-Z—C1-8alkyl-, R8ZA-C1-8alkyl-ZAZ—C1-8alkyl-, heterocyclylMZAZ—C1-8alkyl-, (R8O)(R9O)P(═O)O—C1-8alkyl-, (R10)2N—C1-8alkyl-, (R10)3N+—C1-8alkyl-, heterocyclylM-, carbocyclylM-, R11SO2C1-8alkyl-, and R11SO2NH; or R6 and R7 together are C1-6alkyl-Y—C1-6alkyl, C1-6alkyl-ZA-C1-6alkyl, A-C1-6alkyl-ZA-C1-8alkyl, A-C1-6alkyl-A, or C1-6alkyl-A, thereby forming a ring; R8 and R9 are independently selected from hydrogen, metal cation, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, aryl, heteroaryl, C1-6aralkyl, and C1-6heteroaralkyl, or R8 and R9 together are C1-6alkyl, thereby forming a ring; each R10 is independently selected from hydrogen and C1-6alkyl; and R11 is independently selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-8alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C1-6aralkyl, and C1-6heteroaralkyl, R14 is selected from hydrogen, (R15O)(R16O)P(═O)W—, R15GB—, heterocyclyl-, (R17)2N—, (R17)3N+—, R17SO2GBG-, and R15GBC1-8alkyl- where the C1-8alkyl moiety is optionally substituted with OH, C1-8alkylW optionally substituted with halogen, aryl, heteroaryl, carbocyclyl, heterocyclyl, and C1-6aralkyl; R15 and R16 are independently selected from hydrogen, metal cation, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, aryl, heteroaryl, C1-6aralkyl, C1-6heteroaralkyl, or R15 and R16 together are C1-6alkyl, thereby forming a ring; R17 is selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, C1-6aralkyl, and heteroaralkyl; provided that when R6 is H, L is C═O, and Q is absent, R7 is not hydrogen, C1-6alkyl, 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: wherein: X is O; R1, R2, R3, and R4 are hydrogen; and R5, R6, R7, and R8 are independently selected from H, C1-6alkyl, C1-6hydroxyalkyl, C1-6alkoxyalkyl, aryl, C1-6aralkyl, heteroaryl, C1-6heteroaralkyl, heterocyclyl, and C1-6heterocycloalkyl, 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: wherein: X is O; R1, R2, R3, and R4 are independently selected from hydrogen and a group of formula (IXa); and R6 and R8 are independently selected from H, C1-6alkyl, C1-6hydroxyalkyl, C1-6alkoxyalkyl, aryl, and C1-6aralkyl, 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: wherein: X is O; R1, R2, R3, and R4 are each independently selected from C1-6alkyl, C1-6hydroxyalkyl, C1-6alkoxyalkyl, aryl, C1-6aralkyl, heteroaryl, C1-6heteroaralkyl, heterocyclyl, and C1-6heterocycloalkyl, any of which is optionally substituted with one or more of amide, amine, carboxylic acid, ester, thiol, or thioether substituents; R5 is N(R6)R7; R6 is selected from hydrogen, OH, and C1-6alkyl; and R7 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; R2 and R4 are each independently selected from C1-6alkyl, C1-6hydroxyalkyl, C1-6alkoxyalkyl, aryl, and C1-6aralkyl, any of which is optionally substituted with one or more of amide, amine, carboxylic acid, ester, thiol, or thioether substituents; R5 is N(R6)R7; R6 is selected from hydrogen, OH, and C1-6alkyl; and R7 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 SO2; X is s O; Y is absent or is selected from C═O and SO2; Z is absent or is C1-6alkyl; R1, R2, and R3 are each independently selected from C1-6alkyl, C1-6hydroxyalkyl, C1-6alkoxyalkyl, aryl, C1-6aralkyl, heteroaryl, C1-6heteroaralkyl, heterocyclyl, and C1-6heterocycloalkyl, any of which is optionally substituted with one or more of amide, amine, carboxylic acid, ester, thiol, or thioether substituents; R4 is N(R5)L-Z—R6; R5 is selected from hydrogen, OH, C1-6aralkyl, and C1-6alkyl; R6 is selected from hydrogen, C1-6alkenyl, Ar—Y—, carbocyclyl, and heterocyclyl; and R7 and R8 are independently selected from hydrogen, C1-6alkyl, and C1-6aralkyl. 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: 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 SO2; X is O; Y is absent or is selected from C═O and SO2; Z is absent or is C1-6alkyl; R1 and R3 are each independently selected from C1-6alkyl, C1-6hydroxyalkyl, C1-6alkoxyalkyl, aryl, and C1-6aralkyl, any of which is optionally substituted with one or more of amide, amine, carboxylic acid, ester, thiol, or thioether substituents; R4 is N(R5)L-Z—R6; R5 is selected from hydrogen, OH, C1-6aralkyl, and C1-6alkyl; R6 is selected from hydrogen, C1-6alkenyl, Ar—Y—, carbocyclyl, and heterocyclyl; and R7 and R8 are independently selected from hydrogen, C1-6alkyl, and C1-6aralkyl. 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.