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US 5,493,020 AGranted
Tricyclic inhibitors of the GPII.sub.b III.sub.a receptor
AssigneeGenentech, Inc.
InventorsBrent K. Blackburn, Kirk Robarge, Todd C. Somers
Life of this patent
Estimating the term…
Abstract
A trycylic benzodiazepine derivative which acts as a nonpeptidyl platelet aggregation inhibitor is provided. This inhibitor potently inhibits fibrinogen binding to the GPII.sub.b III.sub.a receptor and is provided in therapeutic compositions for the treatment of diseases for which blocking platelet aggregation is indicated. These nonpeptidyl inhibitors are provided in combination with thrombolytics and anticoagulants.
Claims5
A compound represented by structural Formula I:
- ##STR1396## where R.sup.1 and R.sup.2 are independently selected from
- hydrogen,
- halo(F, Cl, Br, I),
- cyano,
- carboxy,
- aminocarbonyl,
- carboxamido,
- carbamoyloxy,
- formyloxy,
- formyl,
- azido,
- nitro,
- imidazolyl,
- ureido,
- thioureido,
- thiocyanato,
- hydroxy,
- mercapto,
- sulfonamido, and
- an optionally substituted radical selected from
- C.sub.1 -C.sub.12 alkyl,
- C.sub.2 -C.sub.12 alkenyl,
- C.sub.3 -C.sub.12 alkynyl,
- C.sub.3 -C.sub.12 cycloalkyl,
- C.sub.6 -C.sub.14 aryl,
- C.sub.6 -C.sub.10 arylC.sub.1 -C.sub.8 alkyl,
- C.sub.1 -C.sub.12 alkyloxy,
- C.sub.1 -C.sub.12 alkyloxyC.sub.1 -C.sub.12 alkyl,
- C.sub.6 -C.sub.14 aryloxy,
- C.sub.1 -C.sub.12 alkanoylamino,
- N,N-di(C.sub.1 -C.sub.12)alkanoylamino,
- N-(C.sub.1 -C.sub.12)alkyl-N-(C.sub.1 -C.sub.12)alkylsulfonylamino,
- C.sub.1 -C.sub.12 alkylthiocarbonyl,
- C.sub.1 -C.sub.12 alkylthio,
- C.sub.1 -C.sub.12 alkylthioC.sub.1 -C.sub.12 alkyl,
- C.sub.1 -C.sub.12 alkylsulfinyl,
- C.sub.1 -C.sub.12 alkylsulfinylC.sub.1 -C.sub.12 alkyl,
- C.sub.1 -C.sub.12 alkylsulfonyl,
- C.sub.1 -C.sub.12 alkylsulfonylC.sub.1 -C.sub.12 alkyl,
- C.sub.1 -C.sub.12 alkylsulfonato,
- N-(C.sub.1 -C.sub.12)alkylsulfonamido,
- N,N-di-(C.sub.1 -C.sub.12)sulfonamido,
- N-(C.sub.1 -C.sub.12)alkyl-N-thioformylamino,
- C.sub.1 -C.sub.12 thioalkanoylamino,
- N-(C.sub.1 -C.sub.12)alkyl-N-(C.sub.1 -C.sub.12)thioalkanoylamino,
- C.sub.1 -C.sub.12 alkylsulfinamido,
- N-(C.sub.1 -C.sub.12)alkyl-N-(C.sub.1 -C.sub.12)alkylsuifinylamino,
- C.sub.1 -C.sub.12 carbalkoxy,
- C.sub.1 -C.sub.12 alkylcarbonyl,
- C.sub.1 -C.sub.12 alkyloxycarbonyl,
- C.sub.1 -C.sub.12 alkanoyloxy,
- N-(C.sub.1 -C.sub.12)alkylcarboxamido,
- N-(C.sub.1 -C.sub.12)alkylaminocarbonyl,
- N,N-di-(C.sub.1 -C.sub.12)carboxamido,
- N,N-di-(C.sub.1 -C.sub.12)alkylaminocarbonyl,
- N-(C.sub.1 -C.sub.12)alkylcarbamoyloxy, and
- N,N-di-(C.sub.1 -C.sub.12)carbamoyloxy,
- where any aryl is selected from the group phenyl, napthyl, biphenyl, phenanthrenyl, and napthacenyl, and
- where the substituents are one to three groups selected from
- halo (F, Cl, Br, I),
- amino,
- amidino,
- guanidino,
- imidazolyl,
- indolyl,
- cyano,
- azido,
- nitro,
- hydroxy,
- mercapto,
- morpholino,
- morpholinyl,
- piperazinyl,
- piperidinyl,
- pyrrolinyl,
- sulfonamido,
- ureido,
- thioureido,
- carboxy,
- aminocarbonyl,
- C.sub.1 -C.sub.4 aminocarbonyl,
- carboxamido,
- carbamoyloxy,
- formyloxy,
- formyl,
- C.sub.1 -C.sub.4 alkyloxycarbonyl,
- C.sub.1 -C.sub.4 alkyl,
- C.sub.1 -C.sub.4 alkylamino,
- di-(C.sub.1 -C.sub.4 )alkylamino,
- C.sub.1 -C.sub.4 alkoxy,
- hydroxyphenyl,
- phenyl, and
- phenoxy,
- optionally, R.sup.] and R.sup.2 when bonded to adjacent carbon atoms may join to form a fused unsubstituted or substituted C.sub.6 -C.sub.10 aryl ring, where any aryl is selected from the group phenyl, napthyl, biphenyl, phenanthrenyl, and napthacenyl, and where the substituents are selected from
- halo (F, Cl, Br, I),
- cyano,
- azido,
- nitro,
- hydroxy,
- mercapto,
- sulfonamido,
- ureido,
- thioureido,
- carboxamido,
- carbamoyloxy,
- formyloxy,
- formyl,
- C.sub.1 -C.sub.4 alkyl,
- haloC.sub.1 -C.sub.4 alkyl,
- C.sub.1 -C.sub.4 alkoxy,
- phenyl, and
- phenoxy;
- Q is selected from the group consisting of an amino group selected from
- NH.sub.2,
- NR.sup.3 H,
- NR.sup.3 R.sup.4, and
- NR.sup.3 R.sup.4 R.sup.5,
- R.sup.3, R.sup.4, and R.sup.5 are independently selected from
- hydrogen,
- cyano,
- NR.sup.6 R.sup.7,
- C(.dbd.NR.sup.8)--NR.sup.6 R.sup.7,
- N.dbd.CR.sup.9 --NR.sup.6 R.sup.7,
- NR.sup.10 --CR.sup.9 .dbd.NR.sup.8,
- NR.sup.10 --C(.dbd.NR.sup.8)--NR.sup.6 R.sup.7,
- halo(F, Cl, Br, I)--C.sub.1 -C.sub.4 alkyl, and
- an optionally substituted group selected from
- C.sub.1 -C.sub.12 alkyl,
- C.sub.2 -C.sub.7 alkenyl,
- C.sub.3 -C.sub.12 cycloalkyl,
- C.sub.5 -C.sub.12 cycloalkenyl,
- C.sub.6 -C.sub.14 aryl,
- C.sub.1 -C.sub.6 alkylC.sub.6 -C.sub.14 aryl,
- C.sub.2 -C.sub.6 alkenylC.sub.6 -C.sub.10 aryl,
- C.sub.1 -C.sub.6 alkyl-heterocyclyl,
- C.sub.1 -C.sub.8 alkoxy,
- C.sub.1 -C.sub.8 alkoxycarbonyl,
- C.sub.6 -C.sub.14 aryloxy,
- C.sub.6 -C.sub.14 aryloxycarbonyl, and
- C.sub.6 -C.sub.14 arylC.sub.1 -C.sub.6 alkyloxycarbonyl,
- where any aryl is selected from the group phenyl, napthyl, biphenyl, phenanthrenyl, and napthacenyl, and
- where each R.sup.6, R.sup.7, R.sup.8, R.sup.9, and R.sup.10 is independently selected from
- hydrogen,
- cyano,
- C.sub.1 -C.sub.6 alkyl, and
- R.sup.11,
- and where the substituents are one to three R.sup.11,
- R.sup.11 is selected from optionally substituted
- C.sub.6 -C.sub.12 aryloxy,
- C.sub.6 -C.sub.12 arylamino,
- C.sub.6 -C.sub.12 aroyl,
- C.sub.1 -C.sub.8 alkoxy,
- C.sub.1 -C.sub.8 alkoxyalkyl,
- C.sub.1 -C.sub.8 alkoxyalkyloxy,
- C.sub.1 -C.sub.8 alkoxycarbonyl,
- C.sub.1 -C.sub.8 alkylcarbonyl,
- C.sub.1 -C.sub.8 aralkylcarbonyl,
- C.sub.1 -C.sub.8 alkylthiocarbonyl,
- C.sub.6 -C.sub.12 aralkylthiocarbonyl,
- C.sub.2 -C.sub.8 alkoxythiocarbonyl,
- C.sub.6 -C.sub.12 aryl,
- C.sub.1 -C.sub.4 alkanoylamino,
- C.sub.1 -C.sub.6 alkoxycarbonyl-C.sub.0 -C.sub.6 alkylamino,
- C.sub.1 -C.sub.8 alkylsulfonylamino,
- C.sub.6 -C.sub.10 aralkylsulfonylamino,
- C.sub.6 -C.sub.10 aralkyl,
- C.sub.6 -C.sub.10 alkaryl,
- C.sub.1 -C.sub.8 alkylthio,
- C.sub.6 -C.sub.10 aralkylthio,
- C.sub.1 -C.sub.8 alkylsulfinyl,
- C.sub.6 -C.sub.10 aralkylsulfinyl,
- C.sub.1 -C.sub.8 alkylsutfonyl,
- C.sub.6 -C.sub.10 aralkylsulfonyl,
- C.sub.2 -C.sub.8 alkylaminosulfonyl,
- C.sub.6 -C.sub.10 aralkylsulfonylamino, and
- C.sub.2 -C.sub.8 alkenyl,
- where any aryl is selected from the group phenyl, napthyl, biphenyl, phenanthrenyl, and napthacenyl, and
- where the substituents are one to three R.sup.12,
- R.sup.12 is selected from
- nitro,
- amino,
- C.sub.1 -C.sub.8 alkylamino,
- di-(C.sub.1 -C.sub.8)alkylamino,
- amidino,
- aminomethyleneimino,
- imino,
- iminoC.sub.1 -C.sub.4 alkyl,
- iminomethyleneamino,
- guanidino,
- C.sub.6 -C.sub.10 arylamino,
- C.sub.1 -C.sub.8 alkanoylamino,
- C.sub.1 -C.sub.4 alkylsulfonamino,
- azido,
- cyano,
- hydroxy,
- hydroxyC.sub.1 -C.sub.8 alkyl,
- C.sub.1 -C.sub.8 alkoxy,
- phenyloxy,
- C.sub.1 -C.sub.8 alkanoyloxy,
- C.sub.1 -C.sub.8 alkanoyl,
- C.sub.6 -C.sub.12 aroyl,
- benzamido,
- phenyl,
- halo(F, Cl, Br, I),
- haloC.sub.1 -C.sub.8 alkyl,
- C.sub.1 -C.sub.8 alkyl,
- aminosulfonyl,
- oxo,
- thio,
- thiocarbonyl,
- hydroxy,
- mercapto,
- formyl,
- formyloxy,
- carboxy,
- ureido,
- glycyl,
- phthalimido,
- succinimido,
- morpholino, and
- C.sub.3 -C.sub.7 cycloalkyl,
- optionally R.sup.3 and R.sup.4 taken together may form optionally substituted
- tetramethylene,
- pentamethylene,
- 3-oxopentamethylene, and
- 3-azapentamethylene,
- where any aryl is selected from the group phenyl, napthyl, biphenyl, phenanthrenyl, and napthacenyl, and
- where the substituents are selected from one to three R.sup.12 ;
- an amidino group selected from
- C(.dbd.NH)--NH.sub.2,
- C(.dbd.NH)--NHR.sup.3,
- C(.dbd.NR.sup.4)--NHR.sup.3,
- C(.dbd.NH)--NR.sup.3 R.sup.4, and
- C(.dbd.NR.sup.5)--NR.sup.3 R.sup.4,
- where R.sup.3, R.sup.4, and R.sup.5 are defined above;
- an aminoalkyleneimino group selected from
- N.dbd.CH--NH.sub.2,
- N.dbd.CH--NHR.sup.3,
- N.dbd.CH--NR.sup.3 R.sup.4, and
- N.dbd.CR.sup.5 --NR.sup.3 R.sup.4,
- where R.sup.3, R.sup.4, and R.sup.5 are defined above;
- an iminoalkyleneamino group selected from
- NH--CH.dbd.NH,
- NH--CH.dbd.NR.sup.3,
- NH--CR.sup.4 .dbd.NR.sup.3, and
- NR.sup.5 -CR.sup.4 .dbd.NR.sup.3,
- where R.sup.3, R.sup.4, and R.sup.5 are defined above;
- a guanidino group selected from
- NH--C(.dbd.NH)--NH.sub.2,
- NH--C(.dbd.NH)--NR.sup.3 H,
- NH--C(.dbd.NH)--NR.sup.3 R.sup.4,
- NH--C(.dbd.NR.sup.3)--NR.sup.3 R.sup.4,
- NR.sup.3 -C(.dbd.NR.sup.3)--NR.sup.3 R.sup.4,
- NR.sup.3 -C(.dbd.NH)--NR.sup.3 R.sup.4,
- NR.sup.3 -C(.dbd.NR.sup.3)--NH.sub.2,
- NR.sup.3 -C(.dbd.NH)--NH.sub.2,
- NR.sup.3 -C(.dbd.NR.sup.3)--NHR.sup.4, and
- NR.sup.3 -C(.dbd.NH)--NHR.sup.4,
- where R.sup.3, R.sup.4, and R.sup.5 are defined above;
- an optionally substituted saturated heterocyclic group selected from ##STR1397## where n is 0, 1, 2,or 3, R.sup.13 is selected from R.sup.6,
- CR.sup.9 .dbd.NR.sup.8,
- CR.sup.9 (.dbd.NR.sup.8)--NR.sup.6 R.sup.7,
- C(.dbd.NR.sup.8)--NR.sup.6 R.sup.7,
- N.dbd.CR.sup.9 --NR.sup.6 R.sup.7,
- NR.sup.10 --CR.sup.9 .dbd.NR.sup.8, and
- NR.sup.10 --(C.dbd.NR.sup.8)--NR.sup.6 R.sup.7,
- where R.sup.6 -R.sup.10 are defined above, Z.sup.2 is O, S, or NR.sup.13, and the substituents are independently one to three R.sup.12 ;
- an optionally substituted unsaturated (nonaromatic) heterocyclyl selected from ##STR1398## where m is 1, 2, or 3,
- Z.sup.2 and R.sup.13 are defined above, and
- the substituents are independently one to three R.sup.12 ;
- an optionally substituted unsaturated (aromatic) heterocyclyl selected from ##STR1399## where Z.sup.3, Z.sup.4, and Z.sup.5 are selected from O, S, N, and NR.sup.6, provided that at least one Z.sup.3, Z.sup.4, or Z.sup.5 is N or NR.sup.6,
- R.sup.13 is defined above, and the substituents are independently one to three R.sup.12 ;
- L is an optionally substituted bivalent radical selected from the group
- C.sub.3 -C.sub.7 -alkylene,
- C.sub.3 -C.sub.7 -cycloalkylene,
- C.sub.3 -C.sub.7 -alkenylene,
- C.sub.3 -C.sub.7 -alkadienylene,
- C.sub.3 -C.sub.7 -alkynylene,
- C.sub.4 -C.sub.7 -alkadiynylene,
- C.sub.4 -C.sub.7 -alkenynylene,
- C.sub.6 -C.sub.14 -arylene,
- C.sub.6 -C.sub.14 -aryl-C.sub.2 -C.sub.4 -alkynylene,
- C.sub.1 -C.sub.3 -alkyl-C.sub.6 -C.sub.14 -aryl-C.sub.2 -C.sub.4 -alkynylene,
- C.sub.6 -C.sub.14 -aryl-C.sub.2 -C.sub.4 -alkenylene,
- C.sub.1 -C.sub.3 -alkyl-C.sub.6 -C.sub.14 -arylene,
- C.sub.1 -C.sub.3 -alkyl-C.sub.6 -C.sub.14 -aryl-C.sub.2 -C.sub.4 -alkenylene,
- C.sub.6 -C.sub.14 -aryl-C.sub.1 -C.sub.3 -alkylene,
- C.sub.6 -C.sub.14 -aryl-C.sub.1 -C.sub.3 -alkyloxyene,
- C.sub.1 -C.sub.2 -alkyl-C.sub.6 -C.sub.14 -aryl-C.sub.1 -C.sub.2 -alkylene,
- C.sub.1 -C.sub.3 -alkyloxy--C.sub.6 -C.sub.14 -arylene,
- C.sub.2 -C.sub.6 -alkyloxyene,
- C.sub.1 -C.sub.5 -alkyloxy--C.sub.1 -C.sub.5 -alkylene,
- C.sub.6 -C.sub.10 -aryloxyene,
- C.sub.6 -C.sub.10 -aryloxy-C.sub.1 -C.sub.5 -alkylene,
- C.sub.2 -C.sub.6 -alkylthioene,
- C.sub.1 -C.sub.5 -alkylthio--C.sub.1 -C.sub.5 -alkylene,
- C.sub.6 -C.sub.10 -arylthioene,
- C.sub.6 -C.sub.10 -arylthio-C.sub.1 -C.sub.5 -alkylene,
- C.sub.1 -C.sub.5 -alkylsulfoxide-C.sub.1 -C.sub.5 -alkylene,
- C.sub.1 -C.sub.5 - alkylsulfone-C.sub.1 -C.sub.5 -alkylene, ##STR1400## where any aryl is selected from the group phenyl, napthyl, biphenyl, phenanthrenyl, and napthacenyl, and
- where
- R.sup.14 is selected from
- a chemical bond,
- C.sub.1 -C.sub.8 -alkyl,
- C.sub.1 -C.sub.8 -alkyloxy,
- C.sub.3 -C.sub.7 -cycloalkyl,
- C.sub.2 -C.sub.5 -alkenyl,
- C.sub.3 -C.sub.5 -alkynyl,
- C.sub.6 -C.sub.10 -aryl,
- C.sub.1 -C.sub.3 -alkyl-C.sub.6 -C.sub.12 -aryl,
- C.sub.1 -C.sub.2 -alkyl-C.sub.6 -C.sub.10 -aryl-C.sub.1 -C.sub.2 -alkyl,
- C.sub.6 -C.sub.10 -aryl-C.sub.1 -C.sub.12 -alkyl,
- C.sub.6 -C.sub.10 -aryloxy-C.sub.1 -C.sub.2 -alkyl,
- HET, and
- piperizinyl;
- where any aryl is selected from the group phenyl, napthyl, biphenyl, phenanthrenyl, and napthacenyl, and
- R.sup.15 is selected from
- a chemical bond,
- C.sub.1 -C.sub.4 -alkyl,
- C.sub.2 -C.sub.4 -alkenyl,
- C.sub.2 -C.sub.4 -alkynyl,
- C.sub.6 -C.sub.10 -aryl, and
- C.sub.1 -C.sub.3 -alkyl-C.sub.6 -C.sub.12 -aryl;
- where any aryl is selected from the group phenyl, napthyl, biphenyl, phenanthrenyl, and napthacenyl, and
- R.sup.16 is selected from
- a chemical bond,
- C.sub.1 -C.sub.5 -alkyl,
- C.sub.3 -C.sub.7 -cycloalkyl,
- C.sub.3 -C.sub.5 -alkenyl,
- C.sub.3 -C.sub.5 -alkynyl,
- C.sub.6 -C.sub.10 -aryl,
- C.sub.1 -C.sub.3 -alkyl-C.sub.6 -C.sub.12 -aryl,
- C.sub.6 -C.sub.10 -aryl-C.sub.1 -C.sub.2 -alkyl, and
- pyridyl;
- where any aryl is selected from the group phenyl, napthyl, biphenyl, phenanthrenyl, and napthacenyl, and
- R.sup.17 is selected from
- C.sub.3 -C.sub.4 -alkenyl,
- C.sub.3 -C.sub.4 -alkynyl, and
- C.sub.6 -C.sub.10 -aryl,
- where any aryl is selected from the group phenyl, napthyl, biphenyl, phenanthrenyl, and napthacenyl, and
- where the substituents are selected from one to three R.sup.12 ;
- R.sup.18 is selected from
- hydrogen,
- C.sub.1 -C.sub.5 alkyl,
- halo(F, Cl, Br, I),
- halo(F, Cl, Br, I)C.sub.1 -C.sub.5 alkyl,
- hydroxy,
- C.sub.1 -C.sub.5 alkoxy, and
- oxo(.dbd.O);
- R.sup.19 is selected from
- (CH.sub.2).sub.n R.sup.1, where n is 0-3, and
- (C.dbd.O)-Xaa, where Xaa is one to three D or L .alpha.-amino acid residues;
- R.sup.20 and R.sup.21 are independently selected from
- hydrogen,
- C.sub.1 -C.sub.4 alkyl,
- halo(F, Cl, Br, I)C.sub.1 -C.sub.4 alkyl,
- C.sub.1 -C.sub.4 alkoxy,
- halo(F, Cl, Br, I),
- cyano,
- carboxy,
- hydroxy,
- C.sub.1 -C.sub.4 alkoxycarbonyl, and
- C.sub.1 -C.sub.4 alkylsulfonylC.sub.0 -C.sub.3 alkyl;
- R.sup.22 is selected from the group consisting of
- 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 alkyloxy selected from the group
- acetylaminoethoxy,
- nicotinoylaminoethoxy, and
- succinamidoethoxy,
- C.sub.1 -C.sub.8 -alkoyloxy-C.sub.1 -C.sub.8 -alkoxy, and
- C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.8 -alkoxy,
- where any aryl is selected from the group phenyl, napthyl, biphenyl, phenanthrenyl, and napthacenyl, and
- where any aryl groups are 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,
- morpholino-C.sub.2 -C.sub.8 -alkoxy,
- morpholinyl-C.sub.1 -C.sub.8 -alkoxy, and
- NR.sup.23 R.sup.24 ;
- R.sup.23 and R.sup.24 are independently selected from the group
- hydrogen,
- C.sub.1 -C.sub.8 -alkyl,
- C.sub.3 -C.sub.8 -alkenyl,
- C.sub.6 -C.sub.12 -aryl,
- C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.8 -alkyl
- where any aryl is selected from the group phenyl, napthyl, biphenyl, phenanthrenyl, and napthacenyl, and
- where any aryl groups are 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;
- A.sup.1 is selected from
- CR.sup.1, and
- CHR.sup.2 ;
- A.sup.2 is selected from
- CHR.sup.1, and
- CR.sup.2 ;
- and
- pharmaceutically acceptable salts thereof.
404 more elements
Dependencies are inferred from the claim text.