Claims for Patent: 6,083,903

Summary for Patent: 6,083,903

Title:	Boronic ester and acid compounds, synthesis and uses
Abstract:	Disclosed herein are boronic ester and acid compounds, their synthesis and uses. More specifically, 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.
Inventor(s):	Julian Adams, Yu-Ting Ma, Ross Stein, Matthew Baevsky, Louis Grenier, Louis Plamondon
Assignee:	Millennium Pharmaceuticals Inc
Application Number:	US08/442,581
Patent Claims:	1. A compound of the structure: ##STR84## where P is, ##STR85## or ##STR86## where R7 is selected from the group consisting of ##STR87## or P is ##STR88## X2 is selected from the group consisting of ##STR89## 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 is aryl, aralkyl, alkaryl, cycloalkyl, heterocycle or --Y--R6, where Y is a chalcogen, and R6 is alkyl; Z1 and Z2 are independently alkyl, hydroxy, alkoxy, aryloxy, or together form 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. 2. A compound of claim 1, wherein P is N-morpholinylcarbonyl. 3. A compound of claim 1, wherein X2 is --C(O)NH--. 4. A compound of claim 1, wherein R2 and R3 are independently selected from the group consisting of alkyl and --CH2 R5, wherein R5 is as defined in claim 1. 5. A compound of claim 1, wherein R2 and R3 are independently selected from the group consisting of C1-4 alkyl or --CH2 R5, wherein R5 is selected from the group consisting of cycloalkyl, aryl or heterocycle. 6. A compound of claim 1, wherein R3 is isobutyl and R2 is --CH2 R5, wherein R5 is C5-10 aryl where one or more ring carbon atoms can be replaced by O, N or S. 7. A compound of claim 1, wherein R2 is: ##STR90## 8. A compound of claim 1, wherein Z1 and Z2 are both hydroxy. 9. A compound of claim 1, wherein Z1 and Z2 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. 10. A compound of claim 1, wherein X2 is --C(O)--NH--;R is hydrogen or alkyl; R3 is isobutyl; R2 is --CH2 R5, wherein R5 is C5-10 aryl where one or more ring carbon atoms can be replaced by O, N or S; and Z1 and Z2 are both hydroxy, or together Z1 and Z2 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. 11. The compound of claim 1, wherein said compound is one 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, or N-(8-quinoline)sulfonyl-L-phenylalanine-L-leucine boronic acid. 12. A compound of claim 1 selected from the group consisting of:N-(4-morpholine)carbonyl-β-(1-naphthyl)-L-alanine-L-leucine boronic acid, N-(8-quinoline)sulfonyl-β-(1-naphthyl)L-alanine-L-leucine boronic acid, 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, and N-(4-Morpholine)carbonyl-L-phenylalanine-L-leucine boronic acid. 13. A compound of the structure: ##STR91## where P is H or an amino-group-protecting moiety;X2 is selected from the group consisting of ##STR92## R is hydrogen or alkyl; R3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycle and --CH2 --R5, R2 is naphthylmethyl, pyridylmethyl, or quinolylmethyl, R5 is aryl, aralkyl, alkaryl, cycloalkyl, heterocycle or --Y--R6,where Y is a chalcogen, and R6 is alkyl; Z1 and Z2 are independently alkyl, hydroxy, alkoxy, aryloxy, or together form 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. 14. A compound of claim 13, wherein X2 is --C(O)NH--. 15. A compound of claim 13, wherein R3 is isobutyl. 16. A compound of claim 13, wherein Z1 and Z2 are both hydroxy. 17. A compound of claim 13, wherein Z1 and Z2 together form a dihydroxy moiety 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. 18. A compound of claim 13, whereinX2 is --C(O)--NH--; R is hydrogen or alkyl; R3 is isobutyl; and Z1 and Z2 are both hydroxy, or together Z1 and Z2 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. 19. A method for reducing the rate of muscle protein degradation in a cell comprising contacting said cell with a proteasome inhibitor of the structure: ##STR93## where P is H or an amino-group-protecting moiety;X2 is selected from the group consisting of ##STR94## R is hydrogen or alkyl; R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycle and --CH2 --R5, heterocycle, or -chalcogen-alkyl; Z1 and Z2 are independently alkyl, hydroxy, alkoxy, aryloxy, or together form 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. 20. The method of claim 19 wherein P is ##STR95## and R7 is alkyl, aryl, alkaryl, aralkyl, or if P is ##STR96## or ##STR97## heterocycle. 21. The method of claim 19 wherein X2 is ##STR98## 22. The method of claim 19 wherein R2 selected from the group consisting of alkyl and --CH2 --R5, where R5 is aryl, alkaryl, cycloalkyl, or heterocycle. 23. The method of claim 19 wherein the proteasome inhibitor is selected from the group consisting of: N-(4-morpholine)carbonyl-β-(1-naphthyl)-L-alanine-L-leucine boronic acid,N-(8-quinoline)sulfonyl-β-(1-naphthyl)L-alanine-L-leucine boronic acid, 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, and N-(4-Morpholine)carbonyl-L-phenylalanine-L-leucine boronic acid. 24. The method of claim 19, wherein P is ##STR99## and R7 is alkyl, aryl, aralkyl or heterocycle. 25. The method of claim 24, wherein R7 is ##STR100## 26. The method of claim 19, wherein R2, or R3 is arylalkyl of 6 to 14 carbon atoms, wherein 1 or more carbon is replaced by oxygen, nitrogen, or sulfur. 27. The method of claim 26, wherein R2, or R3 is 28. A method for reducing the rate of intracellular protein breakdown comprising contacting cells with a proteasome inhibitor of the structure: whereP is H or an amino-group-protecting moiety; X2 is selected from the group consisting of ##STR101## 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 is aryl, aralkyl, alkaryl, cycloalkyl, heterocycle, or -chalcogen-alkyl; Z1 and Z2 are independently alkyl, hydroxy, alkoxy, aryloxy, or together form 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. 29. A method for reducing the rate of degradation of p53 protein in a cell comprising administering to said cell a proteasome inhibitor of the structure: ##STR102## where P is H or an amino-group-protecting moiety;X2 is selected from the group consisting of ##STR103## 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 is aryl, aralkyl, alkaryl, cycloalkyl, heterocycle, or -chalcogen-alkyl; Z1 and Z2 are independently alkyl, hydroxy, alkoxy, aryloxy, or together form 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. 30. A method for inhibiting cyclin degradation in a cell comprising contacting said cell with a proteasome inhibitor of the structure: ##STR104## where P is H or an amino-group-protecting moiety;X2 is selected from the group consisting of ##STR105## 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 is aryl, aralkyl, alkaryl, cycloalkyl, heterocycle, or -chalcogen-alkyl; Z1 and Z2 are independently alkyl, hydroxy, alkoxy, aryloxy, or together form 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. 31. A method for inhibiting antigen presentation in a cell comprising administering to said cell a proteasome inhibitor of the structure: ##STR106## where P is H or an amino-group-protecting moiety;X2 is selected from the group consisting of ##STR107## 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 is aryl, aralkyl, alkaryl, cycloalkyl, heterocycle, or -chalcogen-alkyl; Z1 and Z2 are independently alkyl, hydroxy, alkoxy, aryloxy, or together form 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. 32. A method for inhibiting cell adhesion in an animal comprising administering to said animal a proteasome inhibitor of the structure: ##STR108## where P is H or an amino-group-protecting moiety;X2 is selected from the group consisting of ##STR109## 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 is aryl, aralkyl, alkaryl, cycloalkyl, heterocycle, or -chalcogen-alkyl; Z1 and Z2 are independently alkyl, hydroxy, alkoxy, aryloxy, or together form 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. 33. A method for treating cancer in a patient, comprising administering to said patient a compound of claim 1. 34. A method for treating cancer in a patient, comprising administering to said patient a compound of claim 13. 35. A method for inhibiting HIV infection in an animal comprising administering to said animal a compound of claim 1. 36. A method for inhibiting HIV infection in an animal comprising administering to said animal a compound of claim 13. 37. A method for reducing the rate of degradation of p53 protein in a cell comprising administering to said cell a compound of claim 1. 38. A method for reducing the rate of degradation of p53 protein in a cell comprising administering to said cell a compound of claim 13. 39. A method for inhibiting cyclin degradation in a cell comprising contacting said cell with a compound of claim 1. 40. A method for inhibiting cyclin degradation in a cell comprising contacting said cell with a compound of claim 13. 41. A method for inhibiting NF-κB dependent cell adhesion in an animal comprising administering to said animal a compound of claim 1. 42. A method for inhibiting NF-κB dependent cell adhesion in an animal comprising administering to said animal a compound of claim 13.