Claims for Patent: 7,119,080

Summary for Patent: 7,119,080

Title:	Boronic ester and acid compounds, synthesis and uses
Abstract:	Disclosed herein is a method for reducing the rate of degradation of proteins in an animal, comprising contacting cells of the animal with certain boronic ester and acid compounds. Also disclosed herein are novel boronic ester and acid compounds, their synthesis and uses.
Inventor(s):	Julian Adams, Yu-Ting Ma, Ross L. Stein, Matthew Baevsky, Louis Grenier, Louis Plamondon
Assignee:	Millennium Pharmaceuticals Inc
Application Number:	US10/730,231
Patent Claims:	1. A compound having the formula (1a): or a pharmaceutically acceptable salt thereof; wherein P is hydrogen or an amino group protecting moiety; A is zero; X2 is —C(O)—NH—; R is hydrogen or C1-8 alkyl; R2 is —CH2—R5; R3 is C4 alkyl; R5 is aryl or cycloalkyl, wherein R5 is optionally substituted by one or two substituents independently selected from the group consisting of C1-6 alkyl, C3-8 cycloalkyl, C1-6alkyl(C3-8)cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, cyano, amino, C1-6 alkylamino, di(C1-6)alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C1-6)alkoxy, trifluoromethyl, halogen, C1-6 alkoxy, C6-10 aryl, C6-10 aryl(C1-6)alkyl, C6-10 aryl(C1-6)alkoxy, hydroxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C6-10 arylthio, C6-10 arylsulfinyl, C6-10 arylsulfonyl, C1-6 alkyl(C6-10)aryl, and halo(C6-10)aryl; Z1 and Z2 are each independently one of alkyl, hydroxy, alkoxy, or aryloxy, or together Z1 and Z2 form a moiety derived from a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms and, optionally, a heteroatom or heteroatoms which can be N, S, or O. 2. The compound of claim 1, wherein R is hydrogen. 3. The compound of claim 1, wherein R3 is isobutyl. 4. The compound of claim 1, wherein P is R7—C(O)— or R7—SO2—, where R7 is one of alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, wherein the ring portion of R7 is optionally substituted. 5. The compound of claim 1, wherein P is R7—NH—C(O)— or R7—O—C(O)—, where R7 is one of alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl, wherein the ring portion of R7 is optionally substituted. 6. The compound of claim 4 or 5, wherein R7 is an optionally substituted aryl or aralkyl. 7. The compound of claim 4 or 5, wherein R7 is an optionally substituted heteroaryl or heteroaralkyl. 8. The compound of claim 1, wherein R5 is an optionally substituted C6-10 aryl. 9. The compound of claim 1, wherein R5 is phenyl. 10. The compound of claim 9, wherein Z1 and Z2 are both hydroxy. 11. The compound of claim 9, wherein Z1 and Z2 together form a moiety derived from a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms and, optionally a heteroatom or heteroatoms independently selected from the group consisting of N, S, and O. 12. A compound having the formula (1a): or a pharmaceutically acceptable salt thereof; wherein P is R7—C(O)— or R7—SO2—, and R7 is an optionally substituted aryl or aralkyl; A is zero; X2 is —C(O)—NH—; R is hydrogen; R2 is benzyl; R3 is C4 alkyl; and Z1 and Z2 are independently one of hydroxy, alkoxy, or aryloxy, or together Z1 and Z2 form a moiety derived from a dihydroxy compound having at least two hydroxy groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms and, optionally, a heteroatom or heteroatoms which can be N, S, or O. 13. The compound of claim 12, wherein R7 is phenyl. 14. A composition, which upon combination with a physiologically acceptable saline carrier forms a solution suitable for intravenous, intramuscular or subcutaneous administration to a patient, said solution comprising a compound of the formula (1a): or a pharmaceutically acceptable salt thereof; wherein P is hydrogen or an amino group protecting moiety; A is zero; X2 is —C(O)—NH—; R is hydrogen or C1-8 alkyl; R2 is —CH2—R5; R3 is C4 alkyl; R5 is aryl or cycloalkyl, wherein R5 is optionally substituted by one or two substituents independently selected from the group consisting of C1-6 alkyl, C3-8 cycloalkyl, C1-6alkyl(C3-8)cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, cyano, amino, C1-6 alkylamino, di(C1-6)alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C1-6)alkoxy, trifluoromethyl, halogen, C1-6 alkoxy, C6-10 aryl, C6-10 aryl(C1-6)alkyl, C6-10 aryl(C1-6)alkoxy, hydroxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C6-10 arylthio, C6-10 arylsulfinyl, C6-10 arylsulfonyl, C1-6 alkyl(C6-10)aryl, and halo(C6-10)aryl; Z1 and Z2 are both hydroxy. 15. The composition of claim 14, wherein R is hydrogen. 16. The composition of claim 14, wherein R3 is isobutyl. 17. The composition of claim 14, wherein P is R7—C(O)— or R7—SO2—, where R7 is one of alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, wherein the ring portion of R7 is optionally substituted. 18. The composition of claim 14, wherein P is R7—NH—C(O)— or R7—O—C(O)—, where R7 is one of alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl, wherein the ring portion of R7 is optionally substituted. 19. The composition of claim 17 or 18, wherein R7 is an optionally substituted aryl or aralkyl. 20. The composition of claim 17 or 18, wherein R7 is an optionally substituted heteroaryl or heteroaralkyl. 21. The composition of claim 14, wherein R5 is an optionally substituted C6-10 aryl. 22. The composition of claim 14, wherein R5 is phenyl. 23. A composition, which upon combination with a physiologically acceptable saline carrier forms a solution suitable for intravenous, intramuscular or subcutaneous administration to a patient, said solution comprising a compound of the formula (1a): or a pharmaceutically acceptable salt thereof; wherein P is R7—C(O)— or R7—SO2—, and R7 is an optionally substituted aryl or aralkyl; A is zero; X2 is —C(O)—NH—; R is hydrogen; R2 is benzyl; R3 is C4 alkyl; and Z1 and Z2 are both hydroxy. 24. The composition of claim 23, wherein R7 is phenyl.