Boronic ester and acid compounds, synthesis and uses
First Claim
Patent Images
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) or a pharmaceutically acceptable salt thereof;
- whereinP 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, alkyl, cycloalkyl, aryl, or —
CH2—
R5;
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 independently one of hydroxy, alkoxy, or aryloxy, or together Z1 and Z2 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.
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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.
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Citations
39 Claims
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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)
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, alkyl, cycloalkyl, aryl, or —
CH2—
R5;
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 independently one of hydroxy, alkoxy, or aryloxy, or together Z1 and Z2 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. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17)
A is zero;
X is —
C(O)—
NH—
;
R is hydrogen or C1-8 alkyl; and
R3 is C1-6 alkyl.
- wherein
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3. The method of claim 2, wherein R3 is C4 alkyl.
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4. The method of claim 1, wherein P is one of 2-pyrazinecarbonyl, or 2-pyrazinesulfonyl.
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5. The method of claim 1, wherein R is hydrogen or C1-8 alkyl.
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6. The method of claim 1, wherein:
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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, C2-8alkenyl, 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.
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7. The method of claim 1, wherein R3is C1-12 alkyl.
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8. The method of claim 1, wherein R3is C1-6alkyl.
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9. The method of claim 1, wherein R3 is C4alkyl.
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10. The method of claim 1, wherein R3 is isobutyl.
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11. The method of claim 1, wherein R2 is one of isobutyl, 1naphthylmethyl, 2-naphthylmethyl, benzyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4-(benzyloxy)benzyl, benzylnaphthylmethyl or phenethyl.
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12. The method of claim 1, wherein Z1 and Z2 are independently one of hydroxy, C1-6alkoxy, or C6-10aryloxy.
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13. The method of claim 12, wherein Z1 and Z2 are both hydroxy.
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14. The method of claim 1, wherein 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 or diethanolamine.
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15. The method of claim 1, wherein:
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P is one of quinolinecarbonyl, pyridinecarbonyl, quinolinesulfonyl, quinoxalinecarbonyl, quinoxalinesulfonyl, pyrazinecarbonyl, pyrazinesulfonyl, furancarbonyl, furansulfonyl or N-morpholinylcarbonyl;
A is zero;
X2 is —
C(O)—
NH—
;
R is hydrogen or C1-8 alkyl;
R2 and R3 are each independently one of hydrogen, C1-8alkyl, C3-10cycloalkyl, C6-10aryl, C6-10 ar(C1-6)alkyl, pyridylmethyl, or quinolinylmethyl; and
Z1 and Z2 are both hydroxy, C1-6alkoxy, or C6-10 aryloxy, 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, 2,3butanediol, glycerol or diethanolamine.
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16. The method of claim 1, wherein:
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P is one of 2-pyrazinecarbonyl, or 2-pyrazinesulfonyl;
A is zero;
X2 is —
C(O)—
NH—
;
R is hydrogen or C1-8 alkyl;
R3 is isobutyl;
R2 is one of isobutyl, 1-naphthylmethyl, 2-naphthylmethyl, benzyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4-(benzyloxy)benzyl, benzylnaphthylmethyl or phenethyl; and
Z1 and Z2 are independently one of hydroxy, C1-6alkoxy, C6-10aryloxy, 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.
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17. The method of claim 1, wherein said proteasome inhibitor is one of:
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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-β
-(1-naphthyl)-L-alanine-L-leucine boronic acid.N-(8-quinoline)sulfonyl-β
-(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.
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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.
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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-β
- -(1-naphthyl)-L-alanine-L-leucine boronic acid, or a pharmaceutically acceptable salt or boronate ester thereof.
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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:
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or a pharmaceutically acceptable salt thereof;
whereinP is R7—
C(O)— and
R7 is pyrazinyl;
X2 is —
C(O)—
NH—
;
R is hydrogen or alkyl;
R2 and R3 are independently hydrogen, alkyl, cycloalkyl, aryl, or —
CH2—
R5;
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 C1-6alkyl, C3-8cycloalkyl, 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, C6-10aryl, C6-10 aryl(C1-6)alkyl, C6-10aryl(C1-6)alkoxy, hydroxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C6-10 arylthio, C6-10arylsulfinyl, C6-10 arylsulfonyl, C6-10aryl, C1-6alkyl (C6-10)aryl, and halo (C1-10)aryl;
Z1 and Z2 are independently one of hydroxy, alkoxy, or aryloxy, or together Z1 and Z2form 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.
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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:
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or a pharmaceutically acceptable salt thereof;
whereinP is an amino protecting group;
A is 1;
B1 is CH;
X1 is —
C(O)—
NH—
;
X2 is —
C(O)—
NH—
;
R is hydrogen or alkyl;
R1 is hydrogen, C1-8alkyl, C3-10cycloalkyl, C6-10aryl, or —
CH2—
R5, where the ring portion of said aryl can be optionally substituted;
R2 is naphthylmethyl, pyridylmethyl or quinolinylmethyl;
R3 is C4alkyl;
R5 is one of C6-10aryl, C6-10ar(C1-6)alkyl, C1-6alk(C6-10)aryl, C3-10cycloalkyl, C1-8alkoxy or —
W—
R6, where W is a chalcogen and R6 is alkyl, where the ring portion of any of said aryl, aralkyl, or alkaryl can be optionally substituted; and
Z1 and Z2 are independently one of hydroxy, alkoxy, or aryloxy, or together Z1 and Z2 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. - View Dependent Claims (22, 23, 24, 25, 26)
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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-β
- -(1-naphthyl)-L-alanine-L-leucine boronic acid or a pharmaceutically acceptable salt or boronate ester thereof.
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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:
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or a pharmaceutically acceptable salt thereof;
whereinP is R7—
C(O)—
or R7—
SO2—
, where R7 is quinolinyl, pyrazinyl, pyridyl, quinoxalinyl 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, C2-8alkenyl, 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 independently one of hydroxy, alkoxy, or aryloxy, or together Z1 and Z2 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. - View Dependent Claims (29, 30, 31, 32, 33, 34, 35)
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.
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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:
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or a pharmaceutically acceptable salt thereof;
whereinP 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 independently one of hydroxy, alkoxy, or aryloxy, or together Z1 and Z2 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. - View Dependent Claims (37, 38, 39)
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Specification