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US 6,440,966 B1Granted
Benzenesulfonamide derivatives and their use as MEK inhibitors
AssigneeWarner-Lambert Company
InventorsStephen Douglas Barrett, Haile Tecle, Richard John Booth
Life of this patent
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Abstract
Benzenesulfonamides of formula (I), in which W is OR1, NR2OR1, NRARB, NR2NRARB, or NR2(CH2)2-4NRARB and the other variables as defined in the claims, are inhibitors of MEK and are effective in the treatment of proliferative diseases, cancer, stroke, heart failure, xenograft rejection, arthritis, cystic fibrosis, hepatomegaly, cardiomegaly, Alzheimer's disease, complications of diabetes, septic shock, and viral infection.
Claims40
A compound of formula (I):
- wherein
- W is OR1, NR2OR1, NRARB, NR2NRARB, or NR2(CH2)2-4NRARB;
- R1 is H, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, phenyl, (phenyl)C1-4 alkyl, (phenyl)C3-4 alkenyl, (phenyl)C3-4 alkynyl, (C3-8 cycloalkyl)C1-4 alkyl, (C3-8 cycloalkyl)C3-4 alkenyl, C3-8 cycloalkyl)C3-4 alkynyl, C3-8 heterocyclic radical, (C3-8 heterocyclic radical)C1-4 alkyl, (C3-8 heterocyclic radical)C3-4 alkenyl, (C3-8 heterocyclic radical)C3-4 alkynyl or (CH2)2-4NRARB;
- R2 is H, phenyl, C1-4 alkyl, C3-4 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, or (C3-8 cycloalkyl)-C1-4 alkyl;
- RA is H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, phenyl, (C3-8 cycloalkyl)C1-4 alkyl, (C3-8 cycloalkyl)C3-4 alkenyl, (C3-8 cycloalkyl)C3-4 alkynyl, C3-8 heterocyclic radical, (C3-8 heterocyclic radical)C1-4 alkyl, (aminosulfonyl)phenyl, [(aminosulfonyl)phenyl]C1-4 alkyl, (aminosulfonyl)C1-6 alkyl, (aminosulfonyl)C3-6 cycloalkyl, or [(aminosulfonyl)C3-6 cycloalkyl]C1-4 alkyl;
- RB is H, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, or C6-8 aryl;
- R3 is H, F, Cl, Br, or NO2;
- R4 is H or F;
- R5 is H, methyl or Cl;
- R6 is H, C1-4 alkyl, hydroxyethyl, hydroxypropyl, (CH2)2-4(NRCRD), phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or CH2Ar, where Ar is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
- R7 is H, C1-4 alkyl, hydroxyethyl, hydroxypropyl, (CH2)2-4(NRCRD), phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or CH2Ar′, where Ar′ is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
- each of RC and RD is independently selected from H, C1-6 alkyl, C3-4 alkenyl, C3-4 alkynyl, C3-6 cycloalkyl, C3-6 heterocyclic radical, and phenyl;
- NRCRD is also selected from the group consisting of morpholinyl, piperazinyl, pyrrolidinyl, and piperadinyl;
- wherein each hydrocarbon radical or heterocyclic radical above is optionally substituted with between 1 and 3 substituents independently selected from halo, C1-4 alkyl, C3-6 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, hydroxy, amino, (amino)sulfonyl, and NO2, wherein each substituent alkyl, cycloalkyl, alkenyl, alkynyl or phenyl is in turn optionally substituted with between 1 and 3 substituents independently selected from halo, C1-2 alkyl, hydroxy, amino, and NO2;
- or a pharmaceutically-acceptable salt or C1-6 ester thereof.
12 more elements
A compound of formula (I):
- wherein
- W is OR1, NR2OR1, NRARB, NR2NRARB, or NR2(CH2)2-4NRARB;
- R1 is H, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, phenyl, (phenyl)C1-4 alkyl, (phenyl)C3-4 alkenyl, (phenyl)C3-4 alkynyl, (C3-8 cycloalkyl)-C1-4 alkyl, (C3-8 cycloalkyl)C3-4 alkenyl, (C3-8 cycloalkyl)C3-4 alkynyl, C3-8 heterocyclic radical, (C3-8 heterocyclic radical)C1-4 alkyl, (C3-8 heterocyclic radical)C3-4 alkenyl, (C3-8 heterocyclic radical)C3-4 alkynyl or (CH2)2-4NRARB;
- R2 is H, phenyl, C1-4 alkyl, C3-4 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, or (C3-8 cycloalkyl)-C1-4 alkyl;
- RA is H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, phenyl, (C3-8 cycloalkyl)C1-4 alkyl, (C3-8 cycloalkyl)C3-4 alkenyl, (C3-8 cycloalkyl)C3-4 alkynyl, C3-8 heterocyclic radical, (C3-8 heterocyclic radical)C1-4 alkyl, (aminosulfonyl)phenyl, [(aminosulfonyl)phenyl]C1-4alkyl, (aminosulfonyl)C1-6 alkyl, (aminosulfonyl)C3-6 cycloalkyl, or [(aminosulfonyl)C3-6 cycloalkyl]C1-4 alkyl;
- RB is H, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-8 cycloalkyl, or C6-8 aryl;
- R3 is H, F, Cl, Br, or NO2;
- R4 is H or F;
- R5 is H, methyl or Cl;
- R6 is (CH2)0-1(NRCRD);
- R7 is H, C1-4 alkyl, hydroxyethyl, hydroxypropyl, (CH2)2-4(NRCRD), phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or CH2Ar′, where Ar′ is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
- each of RC and RD is independently selected from H, C1-6 alkyl, C3-4 alkenyl, C3-4 alkynyl, C3-6 cycloalkyl, C3-6 heterocyclic radical, and phenyl;
- NRCRD is also selected from the group consisting of morpholinyl, piperazinyl, pyrrolidinyl, or piperadinyl;
- wherein each hydrocarbon radical or heterocyclic radical above is optionally substituted with between 1 and 3 substituents independently selected from halo, C1-4 alkyl, C3-6 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, hydroxy, amino, (amino)sulfonyl, and NO2, wherein each substituent alkyl, cycloalkyl, alkenyl, alkynyl or phenyl is in turn optionally substituted with between 1 and 3 substituents independently selected from halo, C1-2 alkyl, hydroxy, amino, and NO2;
- or a pharmaceutically-acceptable salt or C1-6 ester thereof.
12 more elements
Dependencies are inferred from the claim text.