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Claims for Patent: 6,617,317

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Claims 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): 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:10/125,997
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) ##STR52##

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, alky, cycloalkyl, aryl, or --CH.sub.2 --R.sup.3 ; 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 both hydroxy; and A is zero.

2. The composition of claim 1, wherein: R is hydrogen or C.sub.1-8 alkyl; and R.sup.3 is C.sub.1-6 alkyl.

3. The composition of claim 2, wherein R.sub.3 is C.sub.4 alkyl.

4. The composition of claim 1, wherein R is hydrogen or C.sub.1-8 alkyl.

5. The composition 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 alkynyl, 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 composition of claim 1, wherein R.sup.3 is C.sub.1-12 alkyl.

7. The composition of claim 1, wherein R.sup.3 is C.sub.1-6 alkyl.

8. The composition of claim 1, wherein R.sup.3 is C.sub.4 alkyl.

9. The composition of claim 1, wherein R.sup.3 is isobutyl.

10. The composition of claim 1, wherein R.sup.2 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 C.sub.1-8 alkyl; R.sup.3 is isobutyl; and R.sup.2 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): ##STR53##

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, furyl, pyrrolyl, 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 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-.beta.-(1-naphthyl)-L-alanine-leucine boronic acid, N-(8-quinoline)sulfonyl-.beta.-(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 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 13.

16. The composition of claim 13, 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.

17. The composition of claim 13, 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.

18. The composition of claim 13, wherein R.sup.2 is: ##STR54##

19. The composition of claim 13, wherein: 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.

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): ##STR55##

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 both hydroxy; and A is zero.

22. The composition of claim 21, wherein R.sup.3 is isobutyl.
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