BORONIC ESTER AND ACID COMPOUNDS, SYNTHESIS AND USES
First Claim
Patent Images
1. A compound having the formula:
- or a pharmaceutically acceptable salt thereof;
wherein;
P is hydrogen or an amino-group-protecting moiety;
B1, at each occurrence, is CH;
X1, at each occurrence, is —
C(O)—
NH—
;
X2 is —
C(O)—
NH—
;
R is hydrogen or alkyl, or R forms together with the adjacent R1, or when A is zero, forms together with the adjacent R2, a nitrogen-containing mono-, bi- or tri-cyclic, saturated or partially saturated ring system having 4-14 ring members, and one or two optional substituents selected from the group consisting of keto, hydroxy, aryl, alkoxy and aryloxy;
R1, at each occurrence, and R2 and R3 are each independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —
CH2—
R5, where the ring portion of any of said aryl or heterocycle can be optionally substituted;
R5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —
W—
R6, where W is a chalcogen and R6 is alkyl, where the ring portion of any of said aryl, aralkyl, alkaryl, or heterocycle can be optionally substituted;
provided that at least one of R1, R2, or R3 is where R9 is one of alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl;
wherein the alkyl is optionally substituted with one of C1-6alkyl, halogen, monohalo(C1-6)alkyl, and trifluoromethyl; and
wherein said cycloalkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl groups are optionally substituted with one or two of C1-6alkyl, C3-8cycloalkyl, 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;
A1 and A2 are independently one of hydrogen, halogen, C1-6alkyl, monohalo(C1-6) alkyl, or trifluoromethyl;
Z1 and Z2 are independently one of alkyl, 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 0, 1, or 2.
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Accused Products
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
7 Claims
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1. A compound having the formula:
-
or a pharmaceutically acceptable salt thereof; wherein; P is hydrogen or an amino-group-protecting moiety; B1, at each occurrence, is CH; X1, at each occurrence, is —
C(O)—
NH—
;X2 is —
C(O)—
NH—
;R is hydrogen or alkyl, or R forms together with the adjacent R1, or when A is zero, forms together with the adjacent R2, a nitrogen-containing mono-, bi- or tri-cyclic, saturated or partially saturated ring system having 4-14 ring members, and one or two optional substituents selected from the group consisting of keto, hydroxy, aryl, alkoxy and aryloxy; R1, at each occurrence, and R2 and R3 are each independently one of hydrogen, alkyl, cycloalkyl, aryl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —
CH2—
R5, where the ring portion of any of said aryl or heterocycle can be optionally substituted;R5, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, a 5-10 membered saturated, partially unsaturated or aromatic heterocycle or —
W—
R6, where W is a chalcogen and R6 is alkyl, where the ring portion of any of said aryl, aralkyl, alkaryl, or heterocycle can be optionally substituted;provided that at least one of R1, R2, or R3 is where R9 is one of alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl;
wherein the alkyl is optionally substituted with one of C1-6alkyl, halogen, monohalo(C1-6)alkyl, and trifluoromethyl; and
wherein said cycloalkyl, aryl, aralkyl, heteroaryl and heteroarylalkyl groups are optionally substituted with one or two of C1-6alkyl, C3-8cycloalkyl, 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;A1 and A2 are independently one of hydrogen, halogen, C1-6alkyl, monohalo(C1-6) alkyl, or trifluoromethyl; Z1 and Z2 are independently one of alkyl, 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 0, 1, or 2. - View Dependent Claims (2, 3, 4, 5, 6, 7)
where A1 and A2 are independently one of hydrogen, halogen, C1-6alkyl, monohalo(C1-6)alkyl, or trifluoromethyl; R9 is one of C1-8 alkyl, C3-10 cycloalkyl, C6-10 aryl, C6-10ar(C1-6)alkyl, a 5- to 10-membered heteroaryl, or a 5- to 10-membered heteroaryl(C1-6)alkyl; and the remaining R1, R2, and R3 are independently selected from the group consisting of alkyl and —
CH2—
R5, whereR5, in each instance, is one of C6-10aryl, C6-10ar(C1-6)alkyl, C1-6alk(C6-10)aryl, C3-10cycloalkyl, C1-8alkoxy, C1-8alkoxy, C1-8alkylthio, or a 5-, 6-, 9-, or 10-membered heteroaryl group, where the ring portion of any of said C6-10aryl, C6-10ar(C1-6)alkyl, C1-6alk(C6-10)aryl, C3-10cycloalkyl, C1-8alkoxy, C1-8alkoxy, C1-8alkylthio, or a 5-, 6-, 9-, or 10-membered heteroaryl 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, C2-8alkenyl, 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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5. The compound of claim 1, wherein A is zero.
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6. The compound of claim 1, wherein:
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A is zero; P is one of R7—
C(O)—
, R7—
SO2—
, R7—
NH—
C(O)—
, or R7—
O—
C(O)—
;R7 is one of quinolinyl, quinoxalinyl, pyridyl, pyrazinyl, furanyl, or pyrrolyl, or when P is R7—
C(O)—
, R7 can also be N-morpholinyl;R2 is; where A1 and A2 are independently one of hydrogen, halogen, C1-6alkyl, monohalo(C1-6)alkyl, or trifluoromethyl; R9 is one of C1-8 alkyl, phenyl, benzyl, phenethyl, or pyridylmethyl; R3 is C1-6alkyl; and Z1 and Z2 are independently one of hydroxy, C1-6alkoxy, or 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, 1,2-cyclohexanediol, 1,3-propanediol, 2,3-butanediol, glycerol, and diethanolamine.
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7. The compound of claim 1, wherein said compound is one of:
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N-(4-morpholine)carbonyl-(O-benzyl)-L-tyrosine-L-leucine boronic acid;
orN-(4-morpholine)carbonyl-[O-(2-pyridylmethyl)]-L-tyrosine-L-leucine boronic acid; or a pharmaceutically acceptable salt or boronate ester thereof.
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Specification