|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:||Apr 01, 2009|
|Claims:||1. A compound having the formula: ##STR00051## or a pharmaceutically acceptable salt thereof; wherein: P is hydrogen or an amino-group-protecting moiety; X.sup.2 is --C(O)--NH--; R is hydrogen or alkyl, or R 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, than can be optionally substituted by one or two of keto, hydroxyl, aryl, alkoxy or aryloxy; R.sup.2 is naphthylmethyl, pyridylmethyl, or quinolinylmethyl; R.sup.3 is 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, aralkyl, alkaryl or heterocycle can be optionally substituted; R.sup.5, in each instance, is one of aryl, aralkyl, 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, or heterocycle can be optionally substituted; 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 hydroxyl 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. |
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 saturated or partially saturated heterocycle.
3. The compound of claim 1, wherein P is R.sup.7--C(O)-- or R.sup.7--SO.sub.2--; 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)--, then R.sup.7 can also be N-morpholinyl.
4. The compound of claim 3, wherein R.sup.7 is quinolinyl, pyrazinyl, pyridyl, quinoxalinyl, or N-morpholinyl.
5. The compound of claim 1, wherein R.sup.3 is isobutyl.
6. The compound of claim 1, wherein R.sup.2 is naphthylmethyl.
7. The compound of claim 1, wherein said compound is one of: N-(4-morpholine)carbonyl-.beta.-(1-naphthyl)-L-alanine-L-leucine boronic acid; or N-(8-quinoline)sulfonyl-.beta.-(1-naphthyl)-L-alanine-L-leucine boronic acid; or a pharmaceutically acceptable salt or boronate ester thereof.
8. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt or boronate ester thereof, and a pharmaceutically acceptable carrier or diluent.
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