Claims for Patent: 6,617,317

Summary for Patent: 6,617,317

Title:	Boronic ester and acid compositions
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:	US10/125,997
Patent Claims:	1. A composition, which upon combination with a physiologically acceptable saline carrier forms a solution suitable for intravenous, intramuscular or subcutaneous administration to a patient, said solution comprising a compound of the formula (1a) or a pharmaceutically acceptable salt thereof; wherein P is R7—C(O)— or R7—SO2—, where R7 is pyrazinyl; X2 is —C(O)-NH—; R is hydrogen or alkyl; R2 and R3 are independently hydrogen, alky, cycloalkyl, aryl, or —CH2—R3; R5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, or —W—R6, where W is a chalcogen and R6 is alkyl; where the ring portion of any of said aryl, aralkyl, or alkaryl in R2, R3 and R5 can be optionally substituted by one or two substituents independently selected from the group consisting of C1-6 alkyl, C3-8 cycloalkyl, C1-6alkyl(C3-8)cycloalkyl, C2-8 alkenyl; C2-8 alkynyl, cyano, amino, C1-6 alkylamino, di(C1-6)alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C1-6)-alkoxy, trifluoromethyl, halogen, C1-6 alkoxy, C6-10 aryl, C6-10 aryl(C1-6)alkyl, C6-10 aryl(C1-6)alkoxy, hydroxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C6-10 arylthio, C6-10 arylsulfinyl, C6-10 arylsulfonyl, C6-10 aryl, C1-6 alkyl(C6-10)aryl, and halo(C6-10)aryl; Z1 and Z2 are both hydroxy; and A is zero. 2. The composition of claim 1, wherein: R is hydrogen or C1-8 alkyl; and R3 is C1-6 alkyl. 3. The composition of claim 2, wherein R3 is C4 alkyl. 4. The composition of claim 1, wherein R is hydrogen or C1-8 alkyl. 5. The composition of claim 1, wherein: R2 and R3 are each independently one of hydrogen, C1-8 alkyl, C3-10 cycloalkyl, or C6-10 aryl, or —CH2—R5; R5, in each instance, is one of C6-10 aryl, C6-10 ar(C1-6)alkyl, C1-6alk(C6-10)aryl, C3-10 cycloalkyl, C1-8 alkoxy, or C1-8alkylthio; where the ring portion of any of said aryl, aralkyl, or alkaryl groups of R2, R3 and R5 can be optionally substituted by one or two substituents independently selected from the group consisting of C1-6alkyl, C3-8 cycloalkyl, C1-6alkyl-(C3-8)cycloalkyl, C2-8alkynyl, 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 composition of claim 1, wherein R3 is C1-12alkyl. 7. The composition of claim 1, wherein R3 is C1-6alkyl. 8. The composition of claim 1, wherein R3 is C4alkyl. 9. The composition of claim 1, wherein R3 is isobutyl. 10. The composition of claim 1, wherein R2 is one of isobutyl, 1-naphthylmethyl, 2-naphthylmethyl, benzyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4-(benzyloxy)benzyl, benzylnaphthylmethyl or phenethyl. 11. The composition of claim 1, wherein: R is hydrogen or C1-8 alkyl; R3 is isobutyl; and R2 is one of isobutyl, 1-naphthylmethyl, 2-naphthylmethyl, benzyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4(benzyloxy)benzyl, benzylnaphthylmethyl or phenethyl. 12. A composition, which upon combination with a physiologically acceptable aqueous carrier forms a solution suitable for intravenous, intramuscular, or sub-cutaneous administration to a patient, said solution comprising N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid. 13. A composition, which upon combination with a physiologically acceptable saline carrier forms a solution suitable for intravenous, intramuscular, or subcutaneous administration to a patient, said solution comprising a compound having the formula (1a): or a pharmaceutically acceptable salt thereof; wherein P is R7—C(O)— or R7—SO2—, where R7 is quinolinyl, pyrazinyl, pyridyl, quinoxalinyl, furyl, pyrrolyl, or N-morpholinyl; X2 is —C(O)—NH—; R is hydrogen or alkyl; R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycle, and —CH2—R5, where R5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, or —W—R6, where W is a chalcogen and R6 is alkyl; where the ring portion of any of said aryl, aralkyl or alkaryl in R2, R3 and R5 can be optionally substituted by one or two substituents independently selected from the group consisting of C1-6 alkyl C3-8 cycloalkyl, C1-6alkyl(C3-8)cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, cyano, amino, C1-6 alkylamino, di(C1-6)alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C1-6)alkoxy, trifluoromethyl, halogen, C1-6 alkoxy, C6-10 aryl, C6-10 aryl(C1-6)alkyl, C6-10 aryl(C1-6)alkoxy, hydroxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C6-10 arylthio, C6-10 arylsulfinyl, C6-10 arylsulfonyl, C6-10 aryl, C1-6 alkyl(C6-10)aryl, and halo(C6-10)aryl; Z1 and Z2 are both hydroxy; and A is zero. 14. The composition of claim 13, wherein said compound 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-(4morpholine)carbonyl-L-phenylalanine-L-leucine boronic acid, N-(4-morpholine)carbonyl-β-(1-naphthyl)-L-alanine-leucine boronic acid, N-(8-quinoline)sulfonyl-β-(1-naphthyl)-L-alanine-L-leucine boronic acid, N-(4morpholine)carbonyl-(O-benzyl)-L-tyrosine-L-leucine boronic acid, N-(4morpholine)carbonyl-L-tyrosine-L-leucine boronic acid, and N-(4-morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronic acid. 15. The composition of claim 13, wherein R2 and R3 are independently selected from the group consisting of alkyl and —CH2R5, wherein R5 is as defined in claim 13. 16. The composition of claim 13, wherein R2 and R3 are independently selected from the group consisting of C1-4 alkyl and —CH2R5, wherein R5 is selected from the group consisting of cycloalkyl, aryl, and heterocycle. 17. The composition of claim 13, wherein R3 is isobutyl and R2 is —CH2R5, wherein R5 is C5-10 aryl where one or more ring carbon atoms can be replaced by O, N or S. 18. The composition of claim 13, wherein R2 is: 19. The composition of claim 13, wherein: R is hydrogen or C1-8 alkyl; R2 and R3 are each independently one of hydrogen, C1-8 alkyl, C3-10 cycloalkyl, C6-10 aryl, C6-10 ar(C1-6)alkyl, pyridylmethyl, or quinolinylmethyl. 20. The composition of claim 13, wherein the compound 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. 21. A composition, which upon combination with a physiologically acceptable saline carrier forms a solution suitable for intravenous, intramuscular, or subcutaneous administration to a patient, said solution comprising a compound having the formula (1a): or a pharmaceutically acceptable salt thereof; wherein P is H or an amino-group-protecting moiety; X2 is —C(O)—NH—; R is hydrogen or alkyl; R2 is naphthylmethyl, pyridylmethyl, or quinolylmethyl; R3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycle, and —CH2—R5, where R5 is one of aryl, aralkyl, alkaryl, cycloalkyl or —W—R6, where W is a chalcogen and R6 is alkyl; where the ring portion of any of said aryl, aralkyl, or alkaryl in R2, R3 and R5 can be optionally substituted by one or two substituents independently selected from the group consisting of C1-6 alkyl, C3-8 cycloalkyl, C1-6alkyl(C3-8)cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, cyano, amino, C1-6 alkylamino, di(C1-6)alkylamino, benzylamino, dibenzylamino, nitro, carboxy, carbo(C1-6)alkoxy, trifluoromethyl, halogen, C1-6 alkoxy, C6-10 aryl, C6-10 aryl(C1-6)alkyl, C6-10 aryl(C1-6)alkoxy, hydroxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C6-10 arylthio, C6-10 arylsulfinyl, C6-10 arylsulfonyl, C6-10 aryl,C1-6 alkyl(C6-10)aryl, and halo(C6-10)aryl; Z1 and Z2 are both hydroxy; and A is zero. 22. The composition of claim 21, wherein R3 is isobutyl.