Boronic ester and acid compounds, synthesis and uses
AssigneeMillennium Pharmaceuticals, Inc.
InventorsJulian Adams, Yu-Ting Ma, Ross Stein, Matthew Baevsky, Louis Grenier, Louis Plamondon
Life of this patent
Estimating the term…
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.
Claims27
A method for treating cancer in a patient, comprising administering to said patient
- (a) 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, C3-6 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, C1-6 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.
A method for treating cancer in a patient, comprising administering to said patient the compound N-(2-pyrazine)carbonyl-L-phenylalanine-L-leucine boronic acid, or a pharmaceutically acceptable salt or boronate ester thereof.
The method for treating cancer in a patient, comprising administering to said patient a compound having the formula:
- or a pharmaceutically acceptable salt thereof;
- wherein
- P 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, C6-10 aryl(C1-6)alkoxy, hydroxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C6-10 arylthio, C6-10 arylsulfinyl, C6-10 arylsulfonyl, C6-10aryl, C1-6alkyl (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.
A method for treating cancer in a patient, comprising administering to said patient a compound having the formula:
- or a pharmaceutically acceptable salt thereof;
- wherein
- P 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.
A method for treating cancer in a patient, comprising administering to said patient N-acetyl-L-leucine-β-(1-naphthyl)-L-alanine-L-leucine boronic acid or a pharmaceutically acceptable salt or boronate ester thereof.
Dependencies are inferred from the claim text.