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Claims for Patent: 6,083,903

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Claims 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): Adams; Julian (Brookline, MA), Ma; Yu-Ting (Cambridge, MA), Stein; Ross (Sudbury, MA), Baevsky; Matthew (Cambridge, MA), Grenier; Louis (Cambridge, MA), Plamondon; Louis (Cambridge, MA)
Assignee: LeukoSite, Inc. (Cambridge, MA)
Application Number:08/442,581
Patent Claims: 1. A compound of the structure: ##STR84## where P is, ##STR85## or ##STR86## where R.sup.7 is selected from the group consisting of ##STR87## or P is ##STR88## X.sup.2 is selected from the group consisting of ##STR89## 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 is aryl, aralkyl, alkaryl, cycloalkyl, heterocycle or --Y--R.sup.6,

where Y is a chalcogen, and R.sup.6 is alkyl;

Z.sup.1 and Z.sup.2 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 X.sup.2 is --C(O)NH--.

4. A compound of claim 1, 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 1.

5. A compound of claim 1, wherein R.sup.2 and R.sup.3 are independently selected from the group consisting of C.sub.1-4 alkyl or --CH.sub.2 R.sup.5, wherein R.sup.5 is selected from the group consisting of cycloalkyl, aryl or heterocycle.

6. A compound of claim 1, 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.

7. A compound of claim 1, wherein R.sup.2 is: ##STR90##

8. A compound of claim 1, wherein Z.sup.1 and Z.sup.2 are both hydroxy.

9. A 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, 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 X.sup.2 is --C(O)--NH--;

R is hydrogen or alkyl;

R.sup.3 is isobutyl;

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; and

Z.sup.1 and Z.sup.2 are both hydroxy, 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.

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-.beta.-(1-naphthyl)-L-alanine-L-leucine boronic acid,

N-(8-quinoline)sulfonyl-.beta.-(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;

X.sup.2 is selected from the group consisting of ##STR92## R is hydrogen or alkyl; R.sup.3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocycle and --CH.sub.2 --R.sup.5,

R.sup.2 is naphthylmethyl, pyridylmethyl, or quinolylmethyl,

R.sup.5 is aryl, aralkyl, alkaryl, cycloalkyl, heterocycle or --Y--R.sup.6,

where Y is a chalcogen, and R.sup.6 is alkyl;

Z.sup.1 and Z.sup.2 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 X.sup.2 is --C(O)NH--.

15. A compound of claim 13, wherein R.sup.3 is isobutyl.

16. A compound of claim 13, wherein Z.sup.1 and Z.sup.2 are both hydroxy.

17. A compound of claim 13, wherein Z.sup.1 and Z.sup.2 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, wherein

X.sup.2 is --C(O)--NH--;

R is hydrogen or alkyl;

R.sup.3 is isobutyl; and

Z.sup.1 and Z.sup.2 are both hydroxy, 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.

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;

X.sup.2 is selected from the group consisting of ##STR94## 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, heterocycle, or -chalcogen-alkyl;

Z.sup.1 and Z.sup.2 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 R.sup.7 is alkyl, aryl, alkaryl, aralkyl, or if P is ##STR96## or ##STR97## heterocycle.

21. The method of claim 19 wherein X.sup.2 is ##STR98##

22. The method of claim 19 wherein R.sup.2 selected from the group consisting of alkyl and --CH.sub.2 --R.sup.5, where R.sup.5 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-.beta.-(1-naphthyl)-L-alanine-L-leucine boronic acid,

N-(8-quinoline)sulfonyl-.beta.-(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 R.sup.7 is alkyl, aryl, aralkyl or heterocycle.

25. The method of claim 24, wherein R.sup.7 is ##STR100##

26. The method of claim 19, wherein R.sup.2, or R.sup.3 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 R.sup.2, or R.sup.3 is

28. A method for reducing the rate of intracellular protein breakdown comprising contacting cells with a proteasome inhibitor of the structure: where

P is H or an amino-group-protecting moiety;

X.sup.2 is selected from the group consisting of ##STR101## 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 is aryl, aralkyl, alkaryl, cycloalkyl, heterocycle, or -chalcogen-alkyl;

Z.sup.1 and Z.sup.2 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;

X.sup.2 is selected from the group consisting of ##STR103## 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 is aryl, aralkyl, alkaryl, cycloalkyl, heterocycle, or -chalcogen-alkyl;

Z.sup.1 and Z.sup.2 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;

X.sup.2 is selected from the group consisting of ##STR105## 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 is aryl, aralkyl, alkaryl, cycloalkyl, heterocycle, or -chalcogen-alkyl;

Z.sup.1 and Z.sup.2 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;

X.sup.2 is selected from the group consisting of ##STR107## 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 is aryl, aralkyl, alkaryl, cycloalkyl, heterocycle, or -chalcogen-alkyl;

Z.sup.1 and Z.sup.2 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;

X.sup.2 is selected from the group consisting of ##STR109## 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 is aryl, aralkyl, alkaryl, cycloalkyl, heterocycle, or -chalcogen-alkyl;

Z.sup.1 and Z.sup.2 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-.kappa.B dependent cell adhesion in an animal comprising administering to said animal a compound of claim 1.

42. A method for inhibiting NF-.kappa.B dependent cell adhesion in an animal comprising administering to said animal a compound of claim 13.
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