US 5,532,359 AGranted

Ras farnesyl transferase inhibitors

AssigneesGenentech, Inc., Board of Regents, The University of Texas System

InventorsJames C. Marsters, Jr., Michael S. Brown, Craig W. Crowley, Joseph L. Goldstein, Guy L. James, Robert S. McDowell, David Oare, Thomas E. Rawson, Mark Reynolds, Todd C. Somers

Life of this patent

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Abstract

Benzodiazepine derivatives are disclosed that act as potent inhibitors of ras farnesyl:protein transferase. Pharmaceutical compositions containing these benzodiazepines are provided for treatment of diseases for which inhibition of the ras farnesyl:protein transferase is indicated. Also disclosed are benzazepines of the following general formula (II) having similar utility as the aforementioned benzodiazepines: ##STR1##

Claims10

Dependent claims

A compound represented by structural formula (II):

##STR3015## where R and R' are independently selected from the group
hydrogen,
halo(F, Cl, Br, I),
C.sub.1 -C.sub.6 alkyl,
halo(F, Cl, Br, I)C.sub.1 -C.sub.6 alkyl,
C.sub.1 -C.sub.6 alkoxy,
hydroxy,
hydroxy-C.sub.1 -C.sub.6 alkyl,
C.sub.1 -C.sub.6 alkylcarbonyl, and
C.sub.1 -C.sub.6 alkyloxycarbonyl;
R.sup.1 and R.sup.2 are independently selected from the group
hydrogen,
C.sub.1 -C.sub.6 alkyl,
halo(F, Cl, Br, I)-C.sub.1 -C.sub.6 alkyl, and ##STR3016## R.sup.1 and R.sup.2 taken together may form a covalent bond or fused benzene substituted with R and R';
R.sup.4 and R.sup.4' are independently selected from the group
hydrogen,
halo(F, Cl, Br, I),
C.sub.1 -C.sub.6 alkyl,
halo(F, Cl, Br, I)C.sub.1 -C.sub.6 alkyl,
phenyl, and
benzyl;
R.sup.7 selected from the group
hydrogen,
halo(F, Cl, Br, I),
C.sub.1 -C.sub.6 alkyl, and
halo(F, Cl, Br, I)C.sub.1 -C.sub.6 alkyl;
W is selected from the group
C(.dbd.O)--NR.sup.7 'R.sup.8,
CH.sub.2 --C(.dbd.O)--NR.sup.7 'R.sup.8,
CR.sup.8' (OH)--CHR.sup.7 R.sup.8,
CHR.sup.8' --CHR.sup.7 R.sup.8,
CHR.sup.8 '--CHR.sup.7 R.sup.8,
CR.sup.8' CR.sup.7 R.sup.8 (E or Z),
C(.dbd.O)--CHR.sup.7 R.sup.8,
CHR.sup.8' --NR.sup.7' R.sup.8,
CHR.sup.8' --O--R.sup.8,
CHR.sup.8' --S(O).sub.u --R.sup.8 where u is 0, 1, or 2,
CR.sup.8' .dbd.N--R.sup.8,
CHR.sup.8' --R.sup.8,
W',
C.sub.1 -C.sub.3 alkyl-W',
C.sub.6 -C.sub.12 aryl-W',
C.sub.6 -C.sub.12 aryl-C.sub.1 -C.sub.3 alkyl-W',
heterocycle-W',
heterocycle-C.sub.1 -C.sub.3 alkyl-W',
C.sub.1 -C.sub.2 alkyl-C.sub.6 -C.sub.10 aryl-W', and
C.sub.1 -C.sub.2 alkyl-heterocycle-W',
where any heterocycle is a 5- or 6-member saturated or unsaturated ring containing 1 to 3 heteroatoms selected from O, N, and S;
W' is selected from one to three substituents selected from the group
hydrogen,
SR.sup.9,
SSR.sup.9,
SC(.dbd.O)--R.sup.9,
OR.sup.9,
C(.dbd.NH)--NH.sub.2,
N.dbd.CH--NH.sub.2,
NH--CH.dbd.NH,
R.sup.8, and
V;
R.sup.7' is selected from the group
hydrogen,
benzyl,
C.sub.1 -C.sub.4 alkyl, and
halo(F, Cl, Br, I)C.sub.1 -C.sub.4 alkyl;
R.sup.8' is selected from the group
hydrogen,
C.sub.1 -C.sub.4 alkyl, and
halo(F, Cl, Br, I)C.sub.1 -C.sub.4 alkyl;
R.sup.7' and R.sup.8 together with the nitrogen to which they are bonded may form a pyrrolidinyl or piperidyl ring optionally substituted with one or two groups selected from
SR.sup.9,
SSR.sup.9,
SC(.dbd.O)--R.sup.9,
OR.sup.9,
C(.dbd.O)NHOH,
NHR.sup.9,
C(.dbd.O)NR.sup.27 R.sup.28, and
V;
R.sup.8 is selected from the group unsubstituted and substituted
C.sub.1 -C.sub.8 alkyl,
C.sub.1 -C.sub.4 alkyl-Z-C.sub.1 -C.sub.4 alkyl, where Z is S or O,
C.sub.2 -C.sub.4 alkyl-NR-C.sub.2 -C.sub.4 alkyl,
C.sub.2 -C.sub.8 alkenyl,
C.sub.6 -C.sub.12 arylC.sub.1 -C.sub.3 alkyl,
indol-3-yl-C.sub.1 -C.sub.3 alkyl, and
imidazol-4-yl-C.sub.1 -C.sub.3 alkyl,
where any aryl moiety is optionally substituted with --OR.sup.9 and V, and
where any alkyl or alkenyl group is optionally substituted with one to three groups selected from
SR.sup.9,
SSR.sup.9,
SC(.dbd.O)--R.sup.9,
OR.sup.9,
C(.dbd.NH)--NH.sub.2,
N.dbd.CH--NH.sub.2,
NH--CH.dbd.NH,
NH--C(.dbd.NH)--NH.sub.2,
C(.dbd.O)NHOH,
NHR.sup.9,
C(.dbd.O)NR.sup.27 R.sup.28, and
V;
V is selected from the group
COR.sup.10,
SO.sub.3 R.sup.13,
NHSO.sub.2 CF.sub.3,
PO(OR.sup.13).sub.2,
SO.sub.2 NHR.sup.10,
CONHOR.sup.13,
C(OH)R.sup.10 PO(OR.sup.13).sub.2,
CN,
SO.sub.2 NH-heteroaryl where the heteroaryl is a 5- or 6-member aromatic ring containing 1 to 3 heteroatoms selected from O, N, and S and where the heteroaryl is unsubstituted or substituted with one or two substituents selected from the group
OH,
SH,
C.sub.1 -C.sub.4 alkyl,
C.sub.1 -C.sub.4 alkoxy,
CF.sub.3,
halo(F, Cl, Br, I),
NO.sub.2,
COOH,
COO--(C.sub.1 -C.sub.4 alkyl),
NH.sub.2,
NH(C.sub.1 -C.sub.4 alkyl), and
N(C.sub.1 -C.sub.4 alkyl).sub.2,
CONHSO.sub.2 R.sup.15,
SO.sub.2 NHCOR.sup.15,
CONHSO.sub.2 R.sup.13,
CH.sub.2 CONHSO.sub.2 R.sup.15,
NHCONHSO.sub.2 R.sup.15,
NHSO.sub.2 NHCOR.sup.15,
CONHNHSO.sub.2 CF.sub.3,
CON(OH)R.sup.13,
CONHCOCF.sub.3,
CONHSO.sub.2 R.sup.10,
CONHSO.sub.2 R.sup.11,
CONHSO.sub.2 R.sup.13, ##STR3017## R.sup.9 is selected from the group hydrogen,
methyl,
ethyl,
isopropyl,
phenyl, and
benzyl;
R.sup.10 is selected from the group
hydroxy,
C.sub.1 -C.sub.8 -alkoxy,
C.sub.3 -C.sub.12 -alkenoxy,
C.sub.6 -C.sub.12 -aryloxy,
C.sub.1 -C.sub.6 -alkyl-C.sub.6 -C.sub.12 -aryloxy,
di-C.sub.1 -C.sub.8 -alkylamino-C.sub.1 -C.sub.8 -alkoxy,
alkanoylamino-C.sub.1 -C.sub.8 -alkoxy selected from the group
acetylaminoethoxy,
nicotinoylaminoethoxy, and
succinamidoethoxy, and
C.sub.1 -C.sub.8 -alkanoyloxy-C.sub.1 -C.sub.8 -alkoxy,
C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.8 -alkoxy where the aryl group is unsubstituted or substituted with one to three of the groups
nitro,
halo(F, Cl, Br, I),
C.sub.1 -C.sub.4 -alkoxy, and
amino,
hydroxy-C.sub.2 -C.sub.8 -alkoxy,
dihydroxy-C.sub.3 -C.sub.8 -alkoxy, and
NR.sup.11 R.sup.12 ;
R.sup.11 and R.sup.12 are independently selected from the group
hydrogen,
C.sub.1 -C.sub.6 alkyl,
C.sub.2 -C.sub.6 alkanoyl,
C.sub.1 -C.sub.6 alkanoyl substituted with from one to three groups selected from
nitro,
halo(F, Cl, Br, I),
C.sub.1 -C.sub.4 -alkoxy, and
amino, and
C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.8 -alkyl where the aryl group is unsubstituted or substituted with one to three of the groups selected from
nitro,
halo(F, Cl, Br, I), and
C.sub.1 -C.sub.4 -alkoxy;
R.sup.13 is selected from the group
hydrogen,
C.sub.1 -C.sub.6 alkyl,
halo(F, Cl, Br, I)-C.sub.1 -C.sub.6 alkyl,
phenyl,
benzyl, and
CH.sub.2 --O--COCH.sub.3 ;
R.sup.15 is selected from the group
C.sub.6 -C.sub.14 aryl, heteroaryl, where the heteroaryl is a 5- or 6-member aromatic ring containing 1 to 3 heteroatoms selected from O, N, and S and where the heteroaryl is unsubstituted or substituted with one or two substituents selected from the group
OH,
SH,
C.sub.1 -C.sub.4 alkyl,
C.sub.1 -C.sub.4 alkoxy,
CF.sub.3,
halo(F, Cl, Br, I),
NO.sub.2,
COOH,
COO--(C.sub.1 -C.sub.4 alkyl),
NH.sub.2,
NH(C.sub.1 -C.sub.4 alkyl), and
N(C.sub.1 -C.sub.4 alkyl).sub.2,
C.sub.3 -C.sub.7 -cycloalkyl,
C.sub.1 -C.sub.4 -alkyl, unsubstituted or substituted with a substituent selected from the group
C.sub.6 -C.sub.14 aryl,
heteroaryl as defined above,
OH,
SH,
C.sub.1 -C.sub.4 -alkyl,
C.sub.1 -C.sub.4 -alkoxy,
C.sub.1 -C.sub.4 -alkylthio,
CF.sub.3,
halo(F, Cl, Br, I),
NO.sub.2,
CO.sub.2 H,
CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl,
NH.sub.2,
N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
NH[(C.sub.1 -C.sub.4)-alkyl],
PO.sub.3 H, and
PO(OH)(C.sub.1 -C.sub.4)-alkoxy, and
(C.sub.1 -C.sub.4)-perfluoroalkyl;
R.sup.16 is selected from the group
CN,
NO.sub.2,
COOR.sup.13,
C.sub.1 -C.sub.6 -perfluoroalkyl, and
CF.sub.3 ;
R.sup.19 is selected from the group
hydrogen,
C.sub.1 -C.sub.6 alkyl,
C.sub.2 -C.sub.6 alkenyl,
C.sub.1 -C.sub.6 alkoxy,
C.sub.2 -C.sub.6 alkoxyalkyl,
CH.sub.2 --O--COCH.sub.3, and
benzyl, where the phenyl moiety is unsubstituted or substituted with a group selected from
NO.sub.2,
NH.sub.2,
OH, and
OCH.sub.3 ;
X is selected from the group
NR.sup.24 --C(.dbd.O)--R.sup.25,
NR.sup.24 --CH(OH)--R.sup.25, and
NR.sup.24 --S(O).sub.u --R.sup.25 where u is 0, 1, or 2,
R.sup.24 is selected from the group
C.sub.1 -C.sub.6 alkyl, and
halo(F, Cl, Br, I)C.sub.1 -C.sub.6 alkyl;
R.sup.25 is selected from R.sup.25', ##STR3018## R.sup.25' is selected from the group C.sub.1 -C.sub.6 alkyl,
C.sub.2 -C.sub.6 alkenyl,
C.sub.1 -C.sub.6 alkylamine,
C.sub.2 -C.sub.6 alkenylamine, and
halo(F, Cl, Br, I)C.sub.1 -C.sub.6 alkyl
where any alkyl or alkenyl moiety is substituted with NR.sup.27 R.sup.28 and one or more groups selected from
SH and
SSR.sup.26 ;
R.sup.26 is selected from
hydrogen,
C.sub.1 -C.sub.6 alkyl,
halo(F, Cl, Br, I)C.sub.1 -C.sub.6 alkyl, and
C.sub.1 -C.sub.6 alkanoyl;
R.sup.27 and R.sup.28 are independently selected from the group
hydrogen,
C.sub.1 -C.sub.6 alkyl,
phenyl,
napthyl,
benzyl,
CH.sub.2 napthyl (a or b),
C.sub.1 -C.sub.6 alkanoyl,
C.sub.1 -C.sub.6 cycloalkanoyl.
C.sub.6 -C.sub.10 aroyl,
C.sub.6 -C.sub.10 arylC.sub.1 -C.sub.6 alkanoyl,
C.sub.1 -C.sub.6 alkylsulfonyl,
C.sub.6 -C.sub.10 arylsulfonyl,
C.sub.6 -C.sub.10 arylC.sub.1 -C.sub.6 alkylcarbamoyl,
cinnamoyl,
heterocyclecarbonyl,
C.sub.1 -C.sub.6 alkoxycarbonyl,
C.sub.6 -C.sub.10 aryloxycarbonyl,
C.sub.6 -C.sub.10 arylC.sub.1 -C.sub.6 alkoxycarbonyl, and
pyroglutamyl;
R.sup.27 and R.sup.28 together with the nitrogen atom to which they are bonded may form a cyclic amine represented by ##STR3019## or a cyclic imide represented by ##STR3020## G is selected from --CH.sub.2 --, O, S(O).sub.u where u is 0, 1, or 2, and NR.sup.28 ;
J-M is selected from C.sub.2 -C.sub.4 alkylene and C.sub.2 -C.sub.4 alkenylene;
R.sup.29 is selected from hydrogen and C.sub.1 -C.sub.3 alkyl;
and
pharmaceutically acceptable salts thereof.

272 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/328,595Filed 25 Oct 1994 · continuation
Priority: 14 May 1993
Granted: 2 Jul 1996
Term ends: Not estimatedThe source records don’t support an estimate.

Classification30 codes

C07D 223/16
Condensed with carbocyclic rings or ring systems: benzazepines; Hydrogenated benzazepines
A61P 31/04
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antibacterial agents
A61P 35/00
Antineoplastic agents
C07D 243/10
Having the nitrogen atoms in positions 1 and 4: condensed with carbocyclic rings or ring systems

Family

Serial61,961Parent of this continuation-in-part · filed 14 May 1993
Serial82,202Parent of this continuation · filed 24 Jun 1993
US 5,532,359 AThis patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound represented by structural formula (II):

##STR3015## where R and R' are independently selected from the group
hydrogen,
halo(F, Cl, Br, I),
C.sub.1 -C.sub.6 alkyl,
halo(F, Cl, Br, I)C.sub.1 -C.sub.6 alkyl,
C.sub.1 -C.sub.6 alkoxy,
hydroxy,
hydroxy-C.sub.1 -C.sub.6 alkyl,
C.sub.1 -C.sub.6 alkylcarbonyl, and
C.sub.1 -C.sub.6 alkyloxycarbonyl;
R.sup.1 and R.sup.2 are independently selected from the group
hydrogen,
C.sub.1 -C.sub.6 alkyl,
halo(F, Cl, Br, I)-C.sub.1 -C.sub.6 alkyl, and ##STR3016## R.sup.1 and R.sup.2 taken together may form a covalent bond or fused benzene substituted with R and R';
R.sup.4 and R.sup.4' are independently selected from the group
hydrogen,
halo(F, Cl, Br, I),
C.sub.1 -C.sub.6 alkyl,
halo(F, Cl, Br, I)C.sub.1 -C.sub.6 alkyl,
phenyl, and
benzyl;
R.sup.7 selected from the group
hydrogen,
halo(F, Cl, Br, I),
C.sub.1 -C.sub.6 alkyl, and
halo(F, Cl, Br, I)C.sub.1 -C.sub.6 alkyl;
W is selected from the group
C(.dbd.O)--NR.sup.7 'R.sup.8,
CH.sub.2 --C(.dbd.O)--NR.sup.7 'R.sup.8,
CR.sup.8' (OH)--CHR.sup.7 R.sup.8,
CHR.sup.8' --CHR.sup.7 R.sup.8,
CHR.sup.8 '--CHR.sup.7 R.sup.8,
CR.sup.8' CR.sup.7 R.sup.8 (E or Z),
C(.dbd.O)--CHR.sup.7 R.sup.8,
CHR.sup.8' --NR.sup.7' R.sup.8,
CHR.sup.8' --O--R.sup.8,
CHR.sup.8' --S(O).sub.u --R.sup.8 where u is 0, 1, or 2,
CR.sup.8' .dbd.N--R.sup.8,
CHR.sup.8' --R.sup.8,
W',
C.sub.1 -C.sub.3 alkyl-W',
C.sub.6 -C.sub.12 aryl-W',
C.sub.6 -C.sub.12 aryl-C.sub.1 -C.sub.3 alkyl-W',
heterocycle-W',
heterocycle-C.sub.1 -C.sub.3 alkyl-W',
C.sub.1 -C.sub.2 alkyl-C.sub.6 -C.sub.10 aryl-W', and
C.sub.1 -C.sub.2 alkyl-heterocycle-W',
where any heterocycle is a 5- or 6-member saturated or unsaturated ring containing 1 to 3 heteroatoms selected from O, N, and S;
W' is selected from one to three substituents selected from the group
hydrogen,
SR.sup.9,
SSR.sup.9,
SC(.dbd.O)--R.sup.9,
OR.sup.9,
C(.dbd.NH)--NH.sub.2,
N.dbd.CH--NH.sub.2,
NH--CH.dbd.NH,
R.sup.8, and
V;
R.sup.7' is selected from the group
hydrogen,
benzyl,
C.sub.1 -C.sub.4 alkyl, and
halo(F, Cl, Br, I)C.sub.1 -C.sub.4 alkyl;
R.sup.8' is selected from the group
hydrogen,
C.sub.1 -C.sub.4 alkyl, and
halo(F, Cl, Br, I)C.sub.1 -C.sub.4 alkyl;
R.sup.7' and R.sup.8 together with the nitrogen to which they are bonded may form a pyrrolidinyl or piperidyl ring optionally substituted with one or two groups selected from
SR.sup.9,
SSR.sup.9,
SC(.dbd.O)--R.sup.9,
OR.sup.9,
C(.dbd.O)NHOH,
NHR.sup.9,
C(.dbd.O)NR.sup.27 R.sup.28, and
V;
R.sup.8 is selected from the group unsubstituted and substituted
C.sub.1 -C.sub.8 alkyl,
C.sub.1 -C.sub.4 alkyl-Z-C.sub.1 -C.sub.4 alkyl, where Z is S or O,
C.sub.2 -C.sub.4 alkyl-NR-C.sub.2 -C.sub.4 alkyl,
C.sub.2 -C.sub.8 alkenyl,
C.sub.6 -C.sub.12 arylC.sub.1 -C.sub.3 alkyl,
indol-3-yl-C.sub.1 -C.sub.3 alkyl, and
imidazol-4-yl-C.sub.1 -C.sub.3 alkyl,
where any aryl moiety is optionally substituted with --OR.sup.9 and V, and
where any alkyl or alkenyl group is optionally substituted with one to three groups selected from
SR.sup.9,
SSR.sup.9,
SC(.dbd.O)--R.sup.9,
OR.sup.9,
C(.dbd.NH)--NH.sub.2,
N.dbd.CH--NH.sub.2,
NH--CH.dbd.NH,
NH--C(.dbd.NH)--NH.sub.2,
C(.dbd.O)NHOH,
NHR.sup.9,
C(.dbd.O)NR.sup.27 R.sup.28, and
V;
V is selected from the group
COR.sup.10,
SO.sub.3 R.sup.13,
NHSO.sub.2 CF.sub.3,
PO(OR.sup.13).sub.2,
SO.sub.2 NHR.sup.10,
CONHOR.sup.13,
C(OH)R.sup.10 PO(OR.sup.13).sub.2,
CN,
SO.sub.2 NH-heteroaryl where the heteroaryl is a 5- or 6-member aromatic ring containing 1 to 3 heteroatoms selected from O, N, and S and where the heteroaryl is unsubstituted or substituted with one or two substituents selected from the group
OH,
SH,
C.sub.1 -C.sub.4 alkyl,
C.sub.1 -C.sub.4 alkoxy,
CF.sub.3,
halo(F, Cl, Br, I),
NO.sub.2,
COOH,
COO--(C.sub.1 -C.sub.4 alkyl),
NH.sub.2,
NH(C.sub.1 -C.sub.4 alkyl), and
N(C.sub.1 -C.sub.4 alkyl).sub.2,
CONHSO.sub.2 R.sup.15,
SO.sub.2 NHCOR.sup.15,
CONHSO.sub.2 R.sup.13,
CH.sub.2 CONHSO.sub.2 R.sup.15,
NHCONHSO.sub.2 R.sup.15,
NHSO.sub.2 NHCOR.sup.15,
CONHNHSO.sub.2 CF.sub.3,
CON(OH)R.sup.13,
CONHCOCF.sub.3,
CONHSO.sub.2 R.sup.10,
CONHSO.sub.2 R.sup.11,
CONHSO.sub.2 R.sup.13, ##STR3017## R.sup.9 is selected from the group hydrogen,
methyl,
ethyl,
isopropyl,
phenyl, and
benzyl;
R.sup.10 is selected from the group
hydroxy,
C.sub.1 -C.sub.8 -alkoxy,
C.sub.3 -C.sub.12 -alkenoxy,
C.sub.6 -C.sub.12 -aryloxy,
C.sub.1 -C.sub.6 -alkyl-C.sub.6 -C.sub.12 -aryloxy,
di-C.sub.1 -C.sub.8 -alkylamino-C.sub.1 -C.sub.8 -alkoxy,
alkanoylamino-C.sub.1 -C.sub.8 -alkoxy selected from the group
acetylaminoethoxy,
nicotinoylaminoethoxy, and
succinamidoethoxy, and
C.sub.1 -C.sub.8 -alkanoyloxy-C.sub.1 -C.sub.8 -alkoxy,
C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.8 -alkoxy where the aryl group is unsubstituted or substituted with one to three of the groups
nitro,
halo(F, Cl, Br, I),
C.sub.1 -C.sub.4 -alkoxy, and
amino,
hydroxy-C.sub.2 -C.sub.8 -alkoxy,
dihydroxy-C.sub.3 -C.sub.8 -alkoxy, and
NR.sup.11 R.sup.12 ;
R.sup.11 and R.sup.12 are independently selected from the group
hydrogen,
C.sub.1 -C.sub.6 alkyl,
C.sub.2 -C.sub.6 alkanoyl,
C.sub.1 -C.sub.6 alkanoyl substituted with from one to three groups selected from
nitro,
halo(F, Cl, Br, I),
C.sub.1 -C.sub.4 -alkoxy, and
amino, and
C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.8 -alkyl where the aryl group is unsubstituted or substituted with one to three of the groups selected from
nitro,
halo(F, Cl, Br, I), and
C.sub.1 -C.sub.4 -alkoxy;
R.sup.13 is selected from the group
hydrogen,
C.sub.1 -C.sub.6 alkyl,
halo(F, Cl, Br, I)-C.sub.1 -C.sub.6 alkyl,
phenyl,
benzyl, and
CH.sub.2 --O--COCH.sub.3 ;
R.sup.15 is selected from the group
C.sub.6 -C.sub.14 aryl, heteroaryl, where the heteroaryl is a 5- or 6-member aromatic ring containing 1 to 3 heteroatoms selected from O, N, and S and where the heteroaryl is unsubstituted or substituted with one or two substituents selected from the group
OH,
SH,
C.sub.1 -C.sub.4 alkyl,
C.sub.1 -C.sub.4 alkoxy,
CF.sub.3,
halo(F, Cl, Br, I),
NO.sub.2,
COOH,
COO--(C.sub.1 -C.sub.4 alkyl),
NH.sub.2,
NH(C.sub.1 -C.sub.4 alkyl), and
N(C.sub.1 -C.sub.4 alkyl).sub.2,
C.sub.3 -C.sub.7 -cycloalkyl,
C.sub.1 -C.sub.4 -alkyl, unsubstituted or substituted with a substituent selected from the group
C.sub.6 -C.sub.14 aryl,
heteroaryl as defined above,
OH,
SH,
C.sub.1 -C.sub.4 -alkyl,
C.sub.1 -C.sub.4 -alkoxy,
C.sub.1 -C.sub.4 -alkylthio,
CF.sub.3,
halo(F, Cl, Br, I),
NO.sub.2,
CO.sub.2 H,
CO.sub.2 --(C.sub.1 -C.sub.4)-alkyl,
NH.sub.2,
N[(C.sub.1 -C.sub.4)-alkyl].sub.2,
NH[(C.sub.1 -C.sub.4)-alkyl],
PO.sub.3 H, and
PO(OH)(C.sub.1 -C.sub.4)-alkoxy, and
(C.sub.1 -C.sub.4)-perfluoroalkyl;
R.sup.16 is selected from the group
CN,
NO.sub.2,
COOR.sup.13,
C.sub.1 -C.sub.6 -perfluoroalkyl, and
CF.sub.3 ;
R.sup.19 is selected from the group
hydrogen,
C.sub.1 -C.sub.6 alkyl,
C.sub.2 -C.sub.6 alkenyl,
C.sub.1 -C.sub.6 alkoxy,
C.sub.2 -C.sub.6 alkoxyalkyl,
CH.sub.2 --O--COCH.sub.3, and
benzyl, where the phenyl moiety is unsubstituted or substituted with a group selected from
NO.sub.2,
NH.sub.2,
OH, and
OCH.sub.3 ;
X is selected from the group
NR.sup.24 --C(.dbd.O)--R.sup.25,
NR.sup.24 --CH(OH)--R.sup.25, and
NR.sup.24 --S(O).sub.u --R.sup.25 where u is 0, 1, or 2,
R.sup.24 is selected from the group
C.sub.1 -C.sub.6 alkyl, and
halo(F, Cl, Br, I)C.sub.1 -C.sub.6 alkyl;
R.sup.25 is selected from R.sup.25', ##STR3018## R.sup.25' is selected from the group C.sub.1 -C.sub.6 alkyl,
C.sub.2 -C.sub.6 alkenyl,
C.sub.1 -C.sub.6 alkylamine,
C.sub.2 -C.sub.6 alkenylamine, and
halo(F, Cl, Br, I)C.sub.1 -C.sub.6 alkyl
where any alkyl or alkenyl moiety is substituted with NR.sup.27 R.sup.28 and one or more groups selected from
SH and
SSR.sup.26 ;
R.sup.26 is selected from
hydrogen,
C.sub.1 -C.sub.6 alkyl,
halo(F, Cl, Br, I)C.sub.1 -C.sub.6 alkyl, and
C.sub.1 -C.sub.6 alkanoyl;
R.sup.27 and R.sup.28 are independently selected from the group
hydrogen,
C.sub.1 -C.sub.6 alkyl,
phenyl,
napthyl,
benzyl,
CH.sub.2 napthyl (a or b),
C.sub.1 -C.sub.6 alkanoyl,
C.sub.1 -C.sub.6 cycloalkanoyl.
C.sub.6 -C.sub.10 aroyl,
C.sub.6 -C.sub.10 arylC.sub.1 -C.sub.6 alkanoyl,
C.sub.1 -C.sub.6 alkylsulfonyl,
C.sub.6 -C.sub.10 arylsulfonyl,
C.sub.6 -C.sub.10 arylC.sub.1 -C.sub.6 alkylcarbamoyl,
cinnamoyl,
heterocyclecarbonyl,
C.sub.1 -C.sub.6 alkoxycarbonyl,
C.sub.6 -C.sub.10 aryloxycarbonyl,
C.sub.6 -C.sub.10 arylC.sub.1 -C.sub.6 alkoxycarbonyl, and
pyroglutamyl;
R.sup.27 and R.sup.28 together with the nitrogen atom to which they are bonded may form a cyclic amine represented by ##STR3019## or a cyclic imide represented by ##STR3020## G is selected from --CH.sub.2 --, O, S(O).sub.u where u is 0, 1, or 2, and NR.sup.28 ;
J-M is selected from C.sub.2 -C.sub.4 alkylene and C.sub.2 -C.sub.4 alkenylene;
R.sup.29 is selected from hydrogen and C.sub.1 -C.sub.3 alkyl;
and
pharmaceutically acceptable salts thereof.

272 more elements

Facts

Application

08/328,595Filed 25 Oct 1994 · continuation

Priority

14 May 1993

Granted

2 Jul 1996

Term ends

Not estimatedThe source records don’t support an estimate.

Classification30 codes

C07D 223/16
Condensed with carbocyclic rings or ring systems: benzazepines; Hydrogenated benzazepines
A61P 31/04
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antibacterial agents
A61P 35/00
Antineoplastic agents
C07D 243/10
Having the nitrogen atoms in positions 1 and 4: condensed with carbocyclic rings or ring systems