Details for Patent: 6,465,433

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 (Needham, MA), Stein; Ross (Sudbury, MA), Baevsky; Matthew (Jamaica Plain, MA), Grenier; Louis (Belmont, MA), Plamondon; Louis (Belmont, MA)
Assignee:	Millennium Pharmaceuticals, Inc. (Cambridge, MA)
Filing Date:	Sep 14, 2001
Application Number:	09/953,540
Claims:	1. A method for inhibiting HIV replication in an animal in need of said inhibiting, comprising administering to said animal an effective amount a proteasome inhibitor of formula (1a) ##STR51## or a pharmaceutically acceptable salt thereof; wherein P is R.sup.7 --C(O)-- or R.sup.7 --SO.sub.2 --, where R.sup.7 is pyrazinyl; X.sup.2 is --C(O)--NH--, R is hydrogen or alkyl; R.sup.2 and R.sup.3 are independently hydrogen, alkyl, cycloalkyl, aryl, or --CH.sub.2 --R.sup.5 ; R.sup.5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, 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 alkaryl in 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; Z.sup.1 and Z.sup.2 are independently one of 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 zero. 2. The method of claim 1, wherein: A is zero; X is --C(O)--NH--; R is hydrogen or C.sub.1-8 alkyl; and R.sup.3 is C.sub.1-6 alkyl. 3. The method of claim 2, wherein R.sub.3 is C.sub.4 alkyl. 4. The method of claim 1, wherein P is one of 2-pyrazinecarbonyl, or 2-pyrazinesulfonyl. 5. The method of claim 1, wherein R is hydrogen or C.sub.1-8 alkyl. 6. The method of claim 1, wherein: R.sup.2 and R.sup.3 are each independently one of hydrogen, C.sub.1-8 alkyl, C.sub.3-10 cycloalkyl, or C.sub.6-10 aryl, 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, or C.sub.1-8 alkylthio; where the ring portion of any of said aryl, aralkyl, or alkaryl groups of 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. 7. The method of claim 1, wherein R.sub.3 is C.sub.1-12 alkyl. 8. The method of claim 1, wherein R.sub.3 is C.sub.1-6 alkyl. 9. The method of claim 1, wherein R.sub.3 is C.sub.4 alkyl. 10. The method of claim 1, wherein R.sup.3 is isobutyl. 11. The method of claim 1, wherein R.sup.2 is one of isobutyl, 1naphthylmethyl, 2-naphthylmethyl, benzyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4-(benzyloxy)benzyl, benzylnaphthylmethyl or phenethyl. 12. The method of claim 1, wherein Z.sup.1 and Z.sup.2 are independently one of hydroxy, C.sub.1-6 alkoxy, or C.sub.6-10 aryloxy. 13. The method of claim 12, wherein Z.sup.1 and Z.sup.2 are both hydroxy. 14. The method of claim 1, wherein 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, diethylene glycol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, glycerol or diethanolamine. 15. The method of claim 1, wherein: P is one of quinolinecarbonyl, pyridinecarbonyl, quinolinesulfonyl, quinoxalinecarbonyl, quinoxalinesulfonyl, pyrazinecarbonyl, pyrazinesulfonyl, furancarbonyl, furansulfonyl or N-morpholinylcarbonyl; A is zero; X.sup.2 is --C(O)--NH--; R is hydrogen or C.sub.1-8 alkyl; 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, C.sub.6-10 ar(C.sub.1-6)alkyl, pyridylmethyl, or quinolinylmethyl; and Z.sup.1 and Z.sup.2 are both hydroxy, C.sub.1-6 alkoxy, or C.sub.6-10 aryloxy, 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, diethylene glycol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3butanediol, glycerol or diethanolamine. 16. The method of claim 1, wherein: P is one of 2-pyrazinecarbonyl, or 2-pyrazinesulfonyl; A is zero; X.sup.2 is --C(O)--NH--; R is hydrogen or C.sub.1-8 alkyl; R.sup.3 is isobutyl; R.sup.2 is one of isobutyl, 1-naphthylmethyl, 2-naphthylmethyl, benzyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4-(benzyloxy)benzyl, benzylnaphthylmethyl or phenethyl; and Z.sup.1 and Z.sup.2 are independently one of hydroxy, C.sub.1-6 alkoxy, C.sub.6-10 aryloxy, 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, diethylene glycol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, glycerol and diethanolamine. 17. The method of claim 1, wherein said proteasome inhibitor is one of: N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid, N-(2-quinoline)sulfonyl-L-homophenylalanine-L-leucine boronic acid; N-(3-pyridine)carbonyl-L-phenylalanine-L-leucine boronic acid, N-(4-morpholine)carbonyl-L-phenylalanine-L-leucine boronic acid, N-(4-morpholine)carbonyl-.beta.-(1-naphthyl)-L-alanine-L-leucine boronic acid. N-(8-quinoline)sulfonyl-.beta.-(1-naphthyl)-L-alanine-L-leucine boronic acid, N-(4-morpholine)carbonyl-(O-benzyl)-L-tyrosine-L-leucine boronic acid, N-(4-morpholine)carbonyl-L-tyrosine-L-leucine boronic acid, N-(4-morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronic acid; or an isostere, pharmaceutically acceptable salt or boronate ester thereof. 18. A method for inhibiting HIV replication in an animal in need of said inhibiting, comprising administering to said animal an effective amount of N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid, or a pharmaceutically acceptable salt or boronate ester thereof. 19. A method for inhibiting HIV replication in an animal in need of said inhibiting, comprising administering to said animal an effective amount of N-(4-morpholine)carbonyl-.beta.-(1-naphthyl)-L-alanine-L-leucine boronic acid, or a pharmaceutically acceptable salt or boronate ester thereof. 20. A method for inhibiting HIV replication in an animal in need of said inhibiting, comprising administering to said animal an effective amount of a proteasome inhibitor having the formula: ##STR52## or a pharmaceutically acceptable salt thereof; wherein P is R.sup.7 --C(O)-- and R.sup.7 is pyrazinyl; X.sup.2 is --C(O)--NH--; R is hydrogen or alkyl; R.sup.2 and R.sup.3 are independently hydrogen, alkyl, cycloalkyl, aryl, or --CH.sub.2 --R.sup.5 ; R.sup.5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, 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 alkaryl in 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.1-10)aryl; Z.sup.1 and Z.sup.2 are independently one of 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 zero. 21. A method for inhibiting HIV replication in an animal in need of said inhibiting, comprising administering to said animal an effective amount of a proteasome inhibitor having the formula: ##STR53## or a pharmaceutically acceptable salt thereof; wherein P is an amino protecting group; A is 1; B.sup.1 is CH; X.sup.1 is --C(O)--NH--; X.sup.2 is --C(O)--NH--; R is hydrogen or alkyl; R.sup.1 is hydrogen, C.sub.1-8 alkyl, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, or --CH.sub.2 --R.sup.5, where the ring portion of said aryl can be optionally substituted; R.sup.2 is naphthylmethyl, pyridylmethyl or quinolinylmethyl; R.sup.3 is C.sub.4 alkyl; R.sup.5 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 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 alkaryl can be optionally substituted; and Z.sup.1 and Z.sup.2 are independently one of 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. 22. A method of claim 21, wherein P is R.sup.7 --C(O)-- or R.sup.7 --O--C(O)-- and R.sup.7 is alkyl, cycloalkyl, aryl or aralkyl. 23. The method of claim 22, wherein P is acetyl, benzoyl, benzyloxycarbonyl or tert-butoxycarbonyl. 24. A method of claim 21, wherein P is R.sup.7 --C(O)--, and R.sup.7 is quinolinyl, pyrazinyl, pyridyl, quinoxalinyl or N-morpholinyl. 25. The method of claim 21, wherein R.sup.3 is isobutyl. 26. The method of claim 21, wherein R.sup.2 is naphthylmethyl. 27. A method for inhibiting HIV replication in an animal in need of said inhibiting, comprising administering to said animal an effective amount of N-acetyl-L-leucine-.beta.-(1-naphthyl)-L-alanine-L-leucine boronic acid or a pharmaceutically acceptable salt or boronate ester thereof. 28. A method for inhibiting HIV replication in an animal in need of said inhibiting, comprising administering to said animal an effective amount of a proteasome inhibitor having the formula: ##STR54## or a pharmaceutically acceptable salt thereof; wherein P is R.sup.7 --C(O)-- or R.sup.7 --SO.sub.2 --, where R.sup.7 is quinolinyl, pyrazinyl, pyridyl, quinoxalinyl or N-morpholinyl; X.sup.2 is --C(O)--NH--; R is hydrogen or alkyl; R.sup.2 and R.sup.3 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycle, and --CH.sub.2 --R.sup.5, where R.sup.5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, 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 alkaryl in 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; Z.sup.1 and Z.sup.2 are independently one of 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 zero. 29. The method of claim 28, wherein R.sup.2 and R.sup.3 are independently selected from the group consisting of alkyl and --CH.sub.2 R.sup.5, wherein R.sup.5 is as defined in claim 28. 30. The method of claim 28, wherein R.sup.2 and R.sup.3 are independently selected from the group consisting of C.sub.1-4 alkyl and --CH.sub.2 R.sup.5, wherein R.sup.5 is selected from the group consisting of cycloalkyl, aryl, and heterocycle. 31. The method of claim 28, wherein R.sup.3 is isobutyl and R.sup.2 is --CH.sub.2 R.sup.5, wherein R.sup.5 is C.sub.5-10 aryl where one or more ring carbon atoms can be replaced by O, N or S. 32. The method of claim 28, wherein R.sup.2 is: ##STR55## 33. The method of claim 28, wherein Z.sup.1 and Z.sup.2 are both hydroxy. 34. The method of claim 28, wherein Z.sup.1 and Z.sup.2 together form a moiety derived from a dihydroxy compound selected from the group consisting of pinacol, perfluoropinacol, pinanediol, ethylene glycol, diethylene glycol, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, glycerol, and diethanolamine. 35. The method of claim 28 , wherein the proteasome inhibitor is selected from the group consisting of: N-(2-pyridine)carbonyl-L-phenylalanine-L-leucine boronic acid; N-(2-quinoline)carbonyl-L-phenylalanine-L-leucine boronic acid; N-(3-furoyl)-L-phenylalanine-L-leucine boronic acid; N-(2-pyrrolyl)carbonyl-L-phenylalanine-L-leucine boronic acid; and N-(8-quinoline)sulfonyl-L-phenylalanine-L-leucine boronic acid. 36. A method for inhibiting HIV replication in an animal in need of said inhibiting, comprising administering to said animal an effective amount of a proteasome inhibitor having the formula: ##STR56## or a pharmaceutically acceptable salt thereof; wherein P is H or an amino-group-protecting moiety; X.sup.2 is --C(O)--NH--, R is hydrogen or alkyl; R.sup.2 is naphthylmethyl, pyridylmethyl, or quinolylmethyl; R.sup.3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycle, and --CH.sub.2 --R.sup.5, where R.sup.5 is one of aryl, aralkyl, alkaryl, cycloalkyl, 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 alkaryl in 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; Z.sup.1 and Z.sup.2 are independently one of 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 zero. 37. The method of claim 36, wherein R.sup.3 is isobutyl. 38. The method of claim 36, wherein Z.sup.1 and Z.sup.2 are both hydroxy. 39. The method of claim 36, wherein Z.sup.1 and Z.sup.2 together form a moiety derived from a dihydroxy compound selected from the group consisting of pinacol, perfluoropinacol, pinanediol, ethylene glycol, diethylene glycol, 1,2-cyclohexanediol, 1,3propanediol, 2,3-butanediol, glycerol, and diethanolamine.