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):	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)
Application Number:	10/392,165
Patent Claims:	1. A compound having the formula (1a) ##STR52## or a pharmaceutically acceptable salt thereof; wherein P is R.sup.7 --C(O)--, where R.sup.7 is heteroaryl or heteroarylalkyl; 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, that can be optionally substituted by one or two of keto, hydroxy, alkyl, aryl, aralkyl, alkoxy or aryloxy; R.sup.1, at each occurrence, is 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, aralkyl, alkaryl or heterocycle can be optionally substituted; R.sup.2 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.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, 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; 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 0; and A is zero. 2. The compound of claim 1, wherein R.sup.7 is heteroaryl or heteroaryl(C.sub.1-4)alkyl. 3. The compound of claim 2, wherein the heteroaryl portion of R.sup.7 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, .beta.-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, and phenoxazinyl. 4. The compound of claim 1, wherein R is hydrogen or C.sub.1-8 alkyl. 5. The compound of claim 1, wherein: R.sup.1, at each occurrence, and R.sup.2 and R.sup.3 are each independently one of hydrogen, C.sub.1-8, alkyl, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, a 5-, 6-, 9- or 10-membered heteroaryl group, or --CH.sub.2 --R.sup.5 ; R.sup.5, in each instance, 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, C.sub.1-8 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 R.sup.1, R.sup.2, R.sup.3 and R.sup.5 can be optionally substituted by one or two substituents 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. 6. The compound of claim 1, wherein: R is hydrogen or C.sub.1-8 alkyl; and R.sup.3 is C.sub.1-6 alkyl. 7. The compound of claim 1, wherein R.sup.3 is C.sub.1-12 alkyl. 8. The compound of claim 1, wherein R.sup.3 is C.sub.1-6 alkyl. 9. The compound of claim 1, wherein R.sup.3 is C.sub.4 alkyl. 10. The compound of claim 1, wherein R.sup.3 is isobutyl. 11. The compound of claim 1, wherein R.sup.2 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 Z.sup.1 and Z.sup.2 are independently one of C.sub.1-6 alkyl, hydroxy, C.sub.1-6 alkoxy, or C.sub.6-10 aryloxy. 13. The compound of claim 1, wherein Z.sup.1 and Z.sup.2 are both hydroxy. 14. The compound of claim 1, wherein Z.sup.1 and Z.sup.2 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.