Details for Patent: 6,548,668

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 (Brookline, MA), Ma; Yu-Ting (Lexington, MA), Stein; Ross (Sudbury, MA), Baevsky; Matthew (Boston, MA), Grenier; Louis (Medford, MA), Plamondon; Louis (Watertown, MA)
Assignee:	Millennium Pharmaceuticals, Inc. (Cambridge, MA)
Filing Date:	Mar 18, 2002
Application Number:	10/100,295
Claims:	1. A compound having the formula: ##STR52## 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 heteroaryl or a saturated or partially unsaturated heterocycle; A is 1; B.sup.1 is CH; X.sup.1 is --C(O)--NH--; X.sup.2 is --C(O)--NH--; R is hydrogen or alkyl; R.sup.1 is hydrogen, C.sub.1-8 alkyl, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, or --CH.sub.2 --R.sup.5, where the ring portion of said aryl can be optionally substituted; R.sup.2 is hydrogen, C.sub.1-8 alkyl, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, or --CH.sub.2 --R.sup.5, where the ring portion of said aryl can be optionally substituted; R.sup.3 is C.sub.4 alkyl; R.sup.5 is one of C.sub.6-10 aryl, C.sub.6-10 ar(C.sub.1-6)alkyl, C.sub.1-6 alk(C.sub.6-10)aryl, C.sub.3-10 cycloalkyl, C.sub.1-8 alkoxy or --W--R.sup.6, where W is a chalcogen and R.sup.6 is alkyl, where the ring portion of any of said aryl, aralkyl, or alkaryl can be optionally substituted; 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. 2. The compound of claim 1, wherein P is R.sup.7 --C(O)--, and R.sup.7 is quinolinyl, pyrazinyl, pyridyl, quinoxalinyl or N-morpholinyl. 3. The compound of claim 1, wherein R.sup.3 is isobutyl. 4. The compound of claim 1, wherein Z.sup.1 and Z.sup.2 are independently one of hydroxy, C.sub.1-6 alkoxy, or C.sub.6-10 aryloxy. 5. The compound of claim 4, wherein Z.sup.1 and Z.sup.2 are both hydroxy. 6. A compound having the formula: ##STR53## 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 heteroaryl or a saturated or partially unsaturated heterocycle; A is 1; B.sup.1 is CH; X.sup.1 is --C(O)--NH--; X.sup.2 is --C(O)--NH--; R is hydrogen or alkyl; R.sup.1 and R.sup.2 are each independently --CH.sub.2 --R.sup.5, where R.sup.5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, or --W--R.sup.6, where W is a chalcogen and R.sup.6 is alkyl; where the ring portion of any of said aryl, aralkyl, or alkaryl in R.sup.1, R.sup.2 and R.sup.5 can be optionally substituted by one or two substitutes independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, C.sub.1-6 alkyl(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.6-10 aryl, C.sub.1-6 alkyl(C.sub.6-10)aryl, and halo(C.sub.6-10)aryl; R.sup.3 is C.sub.4 alkyl; 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. 7. The compound of claim 6, wherein P is R.sup.7 --C(O)--, and R.sup.7 is quinolinyl, pyrazinyl, pyridyl, quinoxalinyl or N-morpholinyl. 8. The compound of claim 6, wherein R.sup.3 is isobutyl. 9. The compound of claim 6, wherein Z.sup.1 and Z.sup.2 are independently one of hydroxy, C.sub.1-6 alkoxy, or C.sub.6-10 aryloxy. 10. The compound of claim 6, wherein Z.sup.1 and Z.sup.2 are both hydroxy. 11. The compound of claim 6, wherein R.sup.5 is C.sub.6-10 aryl. 12. A compound having the formula: ##STR54## or a pharmaceutically acceptable salt thereof, wherein: P is R.sup.7 --C(O)-- and R.sup.7 is pyrazinyl; A is 1; B.sup.1 is CH; X.sup.1 is --C(O)--NH--; X.sup.2 is --C(O)--NH--; R is hydrogen or alkyl; R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycle, and --CH.sub.2 --R.sup.5, where R.sup.5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, or --W--R.sup.6, where W is a chalcogen and R.sup.6 is alkyl; where the ring portion of any of said aryl, aralkyl, or alkaryl in R.sup.1, R.sup.2 and R.sup.5 can be optionally substituted by one or two substitutes independently selected from the group consisting of C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, C.sub.1-6 alkyl(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.6-10 aryl C.sub.1-6 alkyl(C.sub.6-10)aryl, and halo(C.sub.6-10)aryl; R.sup.3 is C.sub.4 alkyl; 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. A compound having the formula: ##STR55## 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 heteroaryl or a saturated or partially unsaturated heterocycle; A is 1; B.sup.1 is CH; X.sup.1 is --C(O)--NH--; X.sup.2 is --C(O)--NH--; R is hydrogen; R.sup.1 --CH.sub.2 --R.sup.5, where R.sup.5 is C.sub.6-10 aryl; 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. 14. The compound of claim 13, wherein P is R.sup.7 --C(O)--, and R.sup.7 is quinolinyl, pyrazinyl, pyridyl, quinoxalinyl or N-morpholinyl. 15. The compound of claim 13, wherein P is 2-pyrazinecarbonyl. 16. The compound of claim 13, wherein R.sup.3 is isobutyl. 17. The compound of claim 13, wherein R.sup.5 is phenyl. 18. The compound of claim 13, wherein Z.sup.1 and Z.sup.2 are both hydroxy. 19. A compound having the formula: ##STR56## or a pharmaceutically acceptable salt thereof, wherein: P is 2-pyrazinecarbonyl; A is 1; B.sup.1 is CH; X.sup.1 is --C(O)--NH--; X.sup.2 is --C(O)--NH--; R is hydrogen; R.sup.1 is --CH.sub.2 --R.sup.5, where R.sup.5 is phenyl; R.sup.2 is benzyl; R.sup.3 is isobutyl; and Z.sup.1 and Z.sup.2 are both hydroxy.