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Details for Patent: 8,378,099

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Details for Patent: 8,378,099

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 Pharmacueticals, Inc. (Cambridge, MA)
Filing Date:Aug 19, 2011
Application Number:13/213,157
Claims:1. A compound having the formula: ##STR00052## or a pharmaceutically acceptable salt thereof; wherein: P is hydrogen or an amino-group-protecting moiety; B.sup.1, at each occurrence, is independently one of N or CH; X.sup.1, at each occurrence, is independently one of --C(O)--NH--, --CH.sub.2--NH--, --CH(OH)--CH.sub.2--, --CH(OH)--CH(OH)--, --CH(OH)--CH.sub.2--NH--, --CH.dbd.CH--, --C(O)--CH.sub.2--, --SO.sub.2--NH--, --SO.sub.2--CH.sub.2--, or --CH(OH)--CH.sub.2--C(O)--NH--, provided that when B.sup.1 is N, then the X.sup.1 attached to said B.sup.1 is --C(O)--NH--; X.sup.2 is one of --C(O)--NH--, --CH(OH)--CH.sub.2--, --CH(OH)--CH(OH)--, --C(O)--CH.sub.2--, --SO.sub.2--NH--, --SO.sub.2--CH.sub.2--, or --CH(OH)--CH.sub.2--C(O)--NH--; 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 ring system selected from the group consisting of: ##STR00053## when A is 2, the R.sup.1 that is not adjacent to N--R is one of hydrogen, alkyl, cycloalkyl, aryl, a 5- to 10-membered saturated, partially unsaturated or aromatic heterocycle, or --CH.sub.2--R.sup.5; when A is 1 or 2, the R.sup.2 is one of hydrogen, alkyl, cycloalkyl, aryl, a 5- to 10-membered saturated, partially unsaturated or aromatic heterocycle, or --CH.sub.2--R.sup.5; R.sup.3 is one of hydrogen, alkyl, cycloalkyl, aryl, a 5- to 10-membered saturated, partially unsaturated or aromatic heterocycle, or --CH.sub.2--R.sup.5; R.sup.5, in each instance, is independently one of aryl, aralkyl, alkaryl, cycloalkyl, a 5- to 10-membered saturated, partially unsaturated or aromatic heterocycle or --W--R.sup.6, where W is a chalcogen and R.sup.6 is alkyl; 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 saturated or partially saturated heterocycle.

3. The compound of claim 2, 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.6-10ar(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 1, wherein B.sup.1 is CH, and X.sup.1 and X.sup.2 are each --C(O)--NH--.

5. The compound of claim 1, wherein R.sup.1 and R.sup.2 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.1-8alkylthio, 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, or 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.

6. The compound of claim 1, wherein A is zero.

7. The compound of claim 1, wherein P is hydrogen.

8. The compound of claim 1, wherein: A is zero; P is hydrogen; 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 forms together with the adjacent R.sup.2, a nitrogen-containing ring system selected from the group consisting of ##STR00054## R.sup.3 is C.sub.1-6alkyl; Z.sup.1 and Z.sup.2 are both 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.

9. A pharmaceutical composition, comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit proteasome function in a mammal, and a pharmaceutically acceptable carrier or diluent.
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