Claims for Patent: 6,747,150

Summary for Patent: 6,747,150

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):	Julian Adams, Yu-Ting Ma, Ross Stein, Matthew Baevsky, Louis Grenier, Louis Plamondon
Assignee:	Millennium Pharmaceuticals Inc
Application Number:	US10/392,165
Patent Claims:	1. A compound having the formula (1a) or a pharmaceutically acceptable salt thereof; wherein P is R7—C(O)—, where R7 is heteroaryl or heteroarylalkyl; X2 is —C(O)—NH—; R is hydrogen or alkyl, or R forms together with the adjacent R1, or when A is zero, forms together with the adjacent R2, a nitrogen-containing mono-, bi- or tri-cyclic, saturated or partially saturated ring system having 4-14 ring members, that can be optionally substituted by one or two of keto, hydroxy, alkyl, aryl, aralkyl, alkoxy or aryloxy; R1, at each occurrence, is independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH2—R5, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted; R2 is one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH2—R5, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted; R3 is one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —CH2—R5, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted; R5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —W—R6, where W Is a chalcogen and R6 is alkyl, where the ring portion of any of said aryl, aralkyl, alkaryl or heterocycle can be optionally substituted; Z1 and Z2 are independently one of alkyl, hydroxy, alkoxy, or aryloxy, or together Z1 and Z2 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 0; and A is zero. 2. The compound of claim 1, wherein R7 is heteroaryl or heteroaryl(C1-4)alkyl. 3. The compound of claim 2, wherein the heteroaryl portion of R7 is selected from the group consisting of thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthenyl, furyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyzrolylo, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, and phenoxazinyl. 4. The compound of claim 1, wherein R is hydrogen or C1-8 alkyl. 5. The compound of claim 1, wherein: R1, at each occurrence, and R2 and R3 are each independently one of hydrogen, C1-8, alkyl, C3-10 cycloalkyl, C6-10 aryl, a 5-, 6-, 9- or 10-membered heteroaryl group, or —CH2—R5; R5, in each instance, is one of C6-10 aryl, C6-10ar(C1-6)alkyl, C1-6alk(C6-10)aryl, C3-10 cycloalkyl, C1-8 alkoxy, C1-8 alkylthio or a 5-, 6-, 9-, or 10-membere3d heteroaryl group; where the ring portion of any of said aryl, aralkyl, alkaryl or 6-, 6-, 9-, or 10-mebmered heteroaryl groups of R1, R2, R3 and R5 can be optionally substituted by one or two substituents independently selected from the group consisting of C1-6alkyl, C3-8cycloalkyl, C1-6alkyl-(C3-8)cycloalkyl, C2-8alkenyl, C2-8alkynyl, cyano, amino, C1-6alkylamino, di(C1-6)alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C1-6)alkoxy, trifluoromethyl, halogen, C1-6alkoxy, C6-10aryl, C6-10aryl(C1-6)alkyl, C6-10aryl(C1-6)alkoxy, hydroxy, C1-6alkylthio, C1-6alkylsulfinyl, C1-6alkylsulfonyl, C6-10arylthio, C6-10arylsulfinyl, C6-10arylsulfonyl, C6-10aryl, C1-6alkyl(C6-10)aryl, and halo(C6-10)aryl. 6. The compound of claim 1, wherein: R is hydrogen or C1-8 alkyl; and R3 is C1-6alkyl. 7. The compound of claim 1, wherein R3 is C1-12 alkyl. 8. The compound of claim 1, wherein R3 is C1-6 alkyl. 9. The compound of claim 1, wherein R3 is C4 alkyl. 10. The compound of claim 1, wherein R3 is isobutyl. 11. The compound of claim 1, wherein R2 is one of isobutyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-pyridylmethyl, 6-quinolinylmethyl, 3-indolylmethyl, benzyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4-(2′-pyridylmethoxy)benzyl, 4-(benzyloxy)benzyl, benzylnaphthylmethyl or phenethyl. 12. The compound of claim 1, wherein Z1 and Z2 are independently one of C1-6 alkyl, hydroxy, C1-6 alkoxy, or C6-10 aryloxy. 13. The compound of claim 1, wherein Z1 and Z2 are both hydroxy. 14. The compound of claim 1, wherein Z1 and Z2 together form a moiety derived from a dihydroxy compound selected from the group consisting of pinacol, perfloropinacol, pinanediol, ethylene glycol, diethylene glycol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, glycerol or diethanolamine.