Details for Patent: 7,531,526

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 (Boston, 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)
Filing Date:	Jan 02, 2008
Application Number:	12/006,422
Claims:	1. A compound having the formula: ##STR00051## or a pharmaceutically acceptable salt thereof; wherein: P is hydrogen or an amino-group-protecting moiety; B.sup.1, at each occurrence, is CH; X.sup.1, at each occurrence, is --C(O)--NH--; X.sup.2 is --C(O)--NH--; R is hydrogen or alkyl, or R forms together with the adjacent R.sup.1, or when A is zero, forms together with the adjacent R.sup.2, a nitrogen-containing mono-, bi- or tri-cyclic, saturated or partially saturated ring system having 4-14 ring members, and one or two optional substituents selected from the group consisting of keto, hydroxy, aryl, alkoxy and aryloxy; R.sup.1, at each occurrence, and R.sup.2 and R.sup.3 are each independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or --CH.sub.2--R.sup.5, where the ring portion of any of said aryl or heterocycle can be optionally substituted; R.sup.5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle 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, alkaryl, or heterocycle can be optionally substituted; provided that at least one of R.sup.1, R.sup.2, or R.sup.3 is ##STR00052## where R.sup.9 is one of alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl; wherein the alkyl is optionally substituted with one of C.sub.1-6alkyl, halogen, monohalo(C.sub.1-6)alkyl, and trifluoromethyl; and wherein said cycloalkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl groups are optionally substituted with one or two of C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.1-6alkyl(C.sub.3-8)cycloalkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, cyano, amino, C.sub.1-6alkylamino, di(C.sub.1-6)alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C.sub.1-6)alkoxy, trifluoromethyl, halogen, C.sub.1-6alkoxy, C.sub.6-10aryl, C.sub.6-10aryl(C.sub.1-6)alkyl, C.sub.6-10aryl(C.sub.1-6)alkoxy, hydroxy, C.sub.1-6alkylthio, C.sub.1-6alkylsulfinyl, C.sub.1-6alkylsulfonyl, C.sub.6-10arylthio, C.sub.6-10arylsulfinyl, C.sub.6-10arylsulfonyl, C.sub.6-10aryl, C.sub.1-6alkyl(C.sub.6-10)aryl, and halo(C.sub.6-10)aryl; A.sup.1 and A.sup.2 are independently one of hydrogen, halogen, C.sub.1-6alkyl, monohalo(C.sub.1-6)alkyl, or trifluoromethyl; Z.sup.1 and Z.sup.2 are 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; and A is 0, 1, or 2. 2. The compound of claim 1, wherein P is R.sup.7--C(O)--, R.sup.7--SO.sub.2--, R.sup.7--NH--C(O)--, or R.sup.7--O--C(O)--; R.sup.7 is one of alkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl, any of which can be optionally substituted, or when P is R.sup.7--C(O)--, then R.sup.7 can also be N-morpholinyl. 3. The compound of claim 1, wherein P is R.sup.7--C(O)-- or R.sup.7--SO.sub.2--; and R.sup.7 is one of C.sub.6-10 aryl, C.sub.6-10 ar(C.sub.1-6)alkyl, 5- to 10-membered heteroaryl or 5- to 10-membered heteroaryl(C.sub.1-6)alkyl, any of which can be optionally substituted, or when P is R.sup.7--C(O)--, R.sup.7 can also be N-morpholinyl. 4. The compound of claim 1, wherein one of R.sup.1, R.sup.2, or R.sup.3 is ##STR00053## where A.sup.1 and A.sup.2 are independently one of hydrogen, halogen, C.sub.1-6alkyl, monohalo(C.sub.1-6)alkyl, or trifluoromethyl; R.sup.9 is one of C.sub.1-8 alkyl, C.sub.3-10cycloalkyl, C.sub.6-10aryl, C.sub.6-10ar(C.sub.1-6)alkyl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered heteroaryl(C.sub.1-6)alkyl; and the remaining R.sup.1, R.sup.2, and R.sup.3 are independently selected from the group consisting of alkyl and --CH.sub.2--R.sup.5, where R.sup.5, in each instance, is one of C.sub.6-10aryl, C.sub.6-10ar(C.sub.1-6)alkyl, C.sub.1-6alk(C.sub.6-10)aryl, C.sub.3-10cycloalkyl, C.sub.1-8alkoxy, C.sub.1-8alkoxy, C.sub.1-8alkylthio, or a 5-, 6-, 9-, or 10-membered heteroaryl group, where the ring portion of any of said C.sub.6-10aryl, C.sub.6-10ar(C.sub.1-6)alkyl, C.sub.1-6alk(C.sub.6-10)aryl, C.sub.3-10cycloalkyl, C.sub.1-8alkoxy, C.sub.1-8alkoxy, C.sub.1-8alkylthio, or a 5-, 6-, 9-, or 10-membered heteroaryl can be optionally substituted by one or two substituents independently selected from the group consisting of C.sub.1-6alkyl, C.sub.3-8cycloalkyl, C.sub.1-6alkyl(C.sub.3-8)cycloalkyl, C.sub.2-8alkenyl, C.sub.2-8alkynyl, cyano, amino, C.sub.1-6alkylamino, di(C.sub.1-6)alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C.sub.1-6)alkoxy, trifluoromethyl, halogen, C.sub.1-6alkoxy, C.sub.6-10aryl, C.sub.6-10aryl(C.sub.1-6)alkyl, C.sub.6-10aryl(C.sub.1-6)alkoxy, hydroxy, C.sub.1-6alkylthio, C.sub.1-6alkylsulfinyl, C.sub.1-6alkylsulfonyl, C.sub.6-10arylthio, C.sub.6-10arylsulfinyl, C.sub.6-10arylsulfonyl, C.sub.6-10aryl, C.sub.1-6alkyl(C.sub.6-10)aryl, and halo(C.sub.6-10)aryl. 5. The compound of claim 1, wherein A is zero. 6. The compound of claim 1, wherein: A is zero; P is one of R.sup.7--C(O)--, R.sup.7--SO.sub.2--, R.sup.7--NH--C(O)--, or R.sup.7--O--C(O)--; R.sup.7 is one of quinolinyl, quinoxalinyl, pyridyl, pyrazinyl, furanyl, or pyrrolyl, or when P is R.sup.7--C(O)--, R.sup.7 can also be N-morpholinyl; R.sup.2 is: ##STR00054## where A.sup.1 and A.sup.2 are independently one of hydrogen, halogen, C.sub.1-6alkyl, monohalo(C.sub.1-6)alkyl, or trifluoromethyl; R.sup.9 is one of C.sub.1-8 alkyl, phenyl, benzyl, phenethyl, or pyridylmethyl; R.sup.3 is C.sub.1-6alkyl; and Z.sup.1 and Z.sup.2 are independently one of hydroxy, C.sub.1-6alkoxy, or C.sub.6-10aryloxy, or together Z.sup.1 and Z.sup.2 form a moiety derived from a dihydroxy compound selected from the group consisting of pinacol, perfluoropinacol, pinanediol, ethylene glycol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, glycerol, and diethanolamine. 7. The compound of claim 1, wherein said compound is one of: N-(4-morpholine)carbonyl-(O-benzyl)-L-tyrosine-L-leucine boronic acid; or N-(4-morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronic acid; or a pharmaceutically acceptable salt or boronate ester thereof.