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):	Adams; Julian (Chestnut Hill, MA), Ma; Yu-Ting (Needham, MA), Stein; Ross L. (Sudbury, MA), Baevsky; Matthew (Grafton, MA), Grenier; Louis (Medford, MA), Plamondon; Louis (Belmont, MA)
Assignee:	Millennium Pharmaceuticals, Inc. (Cambridge, MA)
Application Number:	10/730,231
Patent Claims:	1. A compound having the formula (1a): ##STR00052## or a pharmaceutically acceptable salt thereof; wherein P is hydrogen or an amino group protecting moiety; A is zero; X.sup.2 is --C(O)--NH--; R is hydrogen or C.sub.1-8 alkyl; R.sup.2 is --CH.sub.2--R.sup.5; R.sup.3 is C.sub.4 alkyl; R.sup.5 is aryl or cycloalkyl, wherein R.sup.5 is optionally substituted by one or two substituents independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, C.sub.1-6alkyl(C.sub.3-8)cycloalkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, cyano, amino, C.sub.1-6 alkylamino, di(C.sub.1-6)alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C.sub.1-6)alkoxy, trifluoromethyl, halogen, C.sub.1-6 alkoxy, C.sub.6-10 aryl, C.sub.6-10 aryl(C.sub.1-6)alkyl, C.sub.6-10 aryl(C.sub.1-6)alkoxy, hydroxy, C.sub.1-6 alkylthio, C.sub.1-6 alkylsulfinyl, C.sub.1-6 alkylsulfonyl, C.sub.6-10 arylthio, C.sub.6-10 arylsulfinyl, C.sub.6-10 arylsulfonyl, C.sub.1-6 alkyl(C.sub.6-10)aryl, and halo(C.sub.6-10)aryl; Z.sup.1 and Z.sup.2 are each independently one of alkyl, hydroxy, alkoxy, or aryloxy, or together Z.sup.1 and Z.sup.2 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 R.sup.3 is isobutyl. 4. The compound of claim 1, wherein P is R.sup.7--C(O)-- or R.sup.7--SO.sub.2--, where R.sup.7 is one of alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, wherein the ring portion of R.sup.7 is optionally substituted. 5. The compound of claim 1, wherein P is R.sup.7--NH--C(O)-- or R.sup.7--O--C(O)--, where R.sup.7 is one of alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl, wherein the ring portion of R.sup.7 is optionally substituted. 6. The compound of claim 4 or 5, wherein R.sup.7 is an optionally substituted aryl or aralkyl. 7. The compound of claim 4 or 5, wherein R.sup.7 is an optionally substituted heteroaryl or heteroaralkyl. 8. The compound of claim 1, wherein R.sup.5 is an optionally substituted C.sub.6-10 aryl. 9. The compound of claim 1, wherein R.sup.5 is phenyl. 10. The compound of claim 9, wherein Z.sup.1 and Z.sup.2 are both hydroxy. 11. The compound of claim 9, wherein Z.sup.1 and Z.sup.2 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): ##STR00053## or a pharmaceutically acceptable salt thereof; wherein P is R.sup.7--C(O)-- or R.sup.7--SO.sub.2--, and R.sup.7 is an optionally substituted aryl or aralkyl; A is zero; X.sup.2 is --C(O)--NH--; R is hydrogen; R.sup.2 is benzyl; R.sup.3 is C.sub.4 alkyl; and Z.sup.1 and Z.sup.2 are independently one of hydroxy, alkoxy, or aryloxy, or together Z.sup.1 and Z.sup.2 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 R.sup.7 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): ##STR00054## or a pharmaceutically acceptable salt thereof; wherein P is hydrogen or an amino group protecting moiety; A is zero; X.sup.2 is --C(O)--NH--; R is hydrogen or C.sub.1-8 alkyl; R.sup.2 is --CH.sub.2--R.sup.5; R.sup.3 is C.sub.4 alkyl; R.sup.5 is aryl or cycloalkyl, wherein R.sup.5 is optionally substituted by one or two substituents independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, C.sub.1-6alkyl(C.sub.3-8)cycloalkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, cyano, amino, C.sub.1-6 alkylamino, di(C.sub.1-6)alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C.sub.1-6)alkoxy, trifluoromethyl, halogen, C.sub.1-6 alkoxy, C.sub.6-10 aryl, C.sub.6-10 aryl(C.sub.1-6)alkyl, C.sub.6-10 aryl(C.sub.1-6)alkoxy, hydroxy, C.sub.1-6 alkylthio, C.sub.1-6 alkylsulfinyl, C.sub.1-6 alkylsulfonyl, C.sub.6-10 arylthio, C.sub.6-10 arylsulfinyl, C.sub.6-10 arylsulfonyl, C.sub.1-6 alkyl(C.sub.6-10)aryl, and halo(C.sub.6-10)aryl; Z.sup.1 and Z.sup.2 are both hydroxy. 15. The composition of claim 14, wherein R is hydrogen. 16. The composition of claim 14, wherein R.sup.3 is isobutyl. 17. The composition of claim 14, wherein P is R.sup.7--C(O)-- or R.sup.7--SO.sub.2--, where R.sup.7 is one of alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, or a saturated or partially unsaturated heterocycle, wherein the ring portion of R.sup.7 is optionally substituted. 18. The composition of claim 14, wherein P is R.sup.7--NH--C(O)-- or R.sup.7--O--C(O)--, where R.sup.7 is one of alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl, wherein the ring portion of R.sup.7 is optionally substituted. 19. The composition of claim 17 or 18, wherein R.sup.7 is an optionally substituted aryl or aralkyl. 20. The composition of claim 17 or 18, wherein R.sup.7 is an optionally substituted heteroaryl or heteroaralkyl. 21. The composition of claim 14, wherein R.sup.5 is an optionally substituted C.sub.6-10 aryl. 22. The composition of claim 14, wherein R.sup.5 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): ##STR00055## or a pharmaceutically acceptable salt thereof; wherein P is R.sup.7--C(O)-- or R.sup.7--SO.sub.2--, and R.sup.7 is an optionally substituted aryl or aralkyl; A is zero; X.sup.2 is --C(O)--NH--; R is hydrogen; R.sup.2 is benzyl; R.sup.3 is C.sub.4 alkyl; and Z.sup.1 and Z.sup.2 are both hydroxy. 24. The composition of claim 23, wherein R.sup.7 is phenyl.