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US 5,294,616 AGranted
Fibrinogen receptor antagonists
AssigneeMerck & Co., Inc.
InventorsMark E. Duggan, Melissa S. Egbertson, Wasyl Halczenko, George D. Hartman, Laura M. Turchi, William L. Laswell
Life of this patent
Estimating the term…
Abstract
A series of non-peptide derivatives that are antagonists of the fibrinogen IIb/IIIa receptor and thus are platelet aggregation compounds useful in the prevention and treatment of diseases caused by thrombus formation.
Claims16
A compound of the formula ##STR161## or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is ##STR162## NR.sup.6 R.sup.7 wherein R.sup.6 and R.sup.7 are independently hydrogen,
- C.sub.1-10 alkoxycarbonyl or unsubstituted or substituted C.sub.1-10 alkyl and cycloalkyl wherein said substituents are
- C.sub.1-10 alkoxy,
- C.sub.1-10 alkoxyalkyl,
- C.sub.1-10 alkoxyalkyloxy,
- C.sub.1-10 alkoxycarbonyl,
- C.sub.1-10 alkylcarbonyl,
- C.sub.1-6 alkylaminocarbonyl,
- C.sub.1-10 aralkylcarbonyl,
- C.sub.1-10 alkylthiocarbonyl,
- C.sub.4-10 aralkylthiocarbonyl,
- thiocarbonyl,
- C.sub.1-10 alkoxythiocarbonyl,
- phenyl,
- C.sub.1-4 alkanoylamino,
- C.sub.1-6 alkoxycarbonyl-C.sub.1-6 alkylamino,
- C.sub.1-10 alkylsulfonylamino,
- C.sub.4-10 arlkylsulfonylamino,
- C.sub.4-10 aralkyl,
- C.sub.1-10 alkylthio,
- C.sub.4-10 aralkylthio,
- C.sub.1-10 alkylsulfinyl,
- C.sub.4-10 aralkylsulfinyl,
- C.sub.1-10 alkylsulfonyl,
- C.sub.4-10 aralkylsulfonyl,
- aminosulfonyl,
- C.sub.1-10 alkylaminosulfonyl,
- C.sub.4-10 aralkylsulfonylamino,
- oxo,
- unsubstituted or mono- or di-substituted 1-ethenyl, 2-ethenyl or 3-propenyl wherein said substituents are selected from the group consisting of hydrogen, C.sub.1-10 alkyl and C.sub.7-10 aralkyl,
- carboxy,
- hydroxy,
- amino,
- C.sub.1-6 alkylamino
- C.sub.1-6 dialkylamino
- halogen, where halogen is defined as Cl, F, Br, or I,
- nitro, or
- cyano,
- and further wherein said N can additionally be substituted to form a quaternary ammonium ion wherein said substituent is as previously defined for R.sup.6 and R.sup.7 ;
- R.sup.2 and R.sup.3 are independently hydrogen, phenyl, naphthyl unsubstituted or substituted C.sub.1-10 alkyl or cycloalkyl wherein said substituent is
- C.sub.1-10 alkoxyalkyl,
- phenyl
- C.sub.4-10 aralkyl,
- carboxy,
- C.sub.1-10 alkylcarbonyl,
- C.sub.1-10 alkylthiocarbonyl,
- C.sub.4-10 aralkylcarbonyl,
- C.sub.4-10 aralkylthiocarbonyl,
- C.sub.1-6 alkoxycarbonyl,
- C.sub.4-10 aralkoxycarbonyl,
- C.sub.1-6 alkoxy,
- C.sub.4-10 aralkoxy,
- C.sub.1-6 alkylamino,
- C.sub.1-12 dialkylamino,
- C.sub.1-6 alkanoylamino,
- C.sub.4-12 aralkanoylamino,
- C.sub.4-10 aralkylamino;
- R.sup.4 is
- hydrogen,
- phenyl
- C.sub.1-10 alkyl or cycloalkyl
- C.sub.4-10 aralkyl,
- arylcarbonyl, aminocarbonyl,
- C.sub.1-10 alkylcarbonyl, C.sub.1-6 alkylaminocarbonyl,
- C.sub.1-10 alkylthiocarbonyl, C.sub.1-6 dialkylaminocarbonyl,
- C.sub.1-10 alkylthiocarbonyl,
- arylC.sub.1-6 alkylaminocarbonyl,
- C.sub.1-10 alkoxycarbonyl,
- C.sub.4-10 aralkylcarbonyl,
- C.sub.4-10 aralkoxycarbonyl,
- C.sub.1-10 carboxylalkyl and
- further wherein any of the substitutents for R.sup.4 may be substituted by one or more substituents selected from the group as defined for R.sup.6, or an L- or D-amino acid joined by an amide linkage;
- R.sup.5 is ##STR163## wherein R.sup.8 is hydroxy,
- C.sub.1-10 alkyloxy,
- C.sub.4-10 aralkyloxy,
- C.sub.4-10 aralkylcarbonyloxy,
- C.sub.1-10 alkoxyalkyloxy,
- C.sub.1-10 alkoxylalkylcarbonyloxy,
- C.sub.1-10 alkoxycarbonyloxyalkyl,
- C.sub.1-10 alkylcarbonyloxyalkyloxy,
- an L- or D-amino acid joined by an amide linkage, and wherein the carboxylic acid moiety of said amino acid is as the free acid or is esterified by C.sub.1-6 alkyl, ##STR164## wherein R.sup.9 and R.sup.10 are selected from the group consisting of hydrogen, C.sub.1-10 alkyl and C.sub.4-10 aralkyl;
- X and Y are independently
- NR.sup.6,
- O, ##STR165## --C.dbd.C--, unsubstituted or substituted C.sub.1-15 alkyl or cycloalkyl wherein said substituents are independently R.sup.6 and R.sup.7, ##STR166## Z is an optional substituent that, when present, is independently chosen as defined by X and Y;
- m is an integer of from zero to ten;
- n is an integer of from zero to ten;
- and
- p is an integer of from zero to three;
- wherein aryl is phenyl or naphthyl.
85 more elements
A compound of claim 1, having the structural formula ##STR167## or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is
- NR.sup.6 R.sup.7 wherein R.sup.6 and R.sup.7 are independently hydrogen,
- C.sub.1-10 alkoxycarbonyl or unsubstituted or substituted C.sub.1-10 alkyl wherein said substitutent is
- C.sub.1-10 alkoxy,
- C.sub.1-10 alkoxycarbonyl,
- phenyl,
- C.sub.4-10 aralkyl,
- carboxy,
- hydroxy or
- amino, ##STR168## and further wherein said N can additionally be substituted to form a quaternary ammonium ion;
- R.sup.2 and R.sup.3 are independently
- hydrogen
- C.sub.1-10 alkyl,
- C.sub.4-10 aralkyl;
- R.sup.4 is
- hydrogen,
- C.sub.1-10 alkyl,
- C.sub.4-10 aralkyl,
- phenylcarbonyl,
- aralkylcarbonyl
- C.sub.1-10 alkylcarbonyl,
- C.sub.1-10 alkoxycarbonyl, or
- C.sub.4-10 aralkoxycarbonyl
- and further wherein any of the substituents for R.sup.4 may be substituted by one or more substituents from the group defined as R.sup.6 in claim 40;
- R.sup.11 is
- hydrogen or
- C.sub.1-10 alkyl;
- X and Y are independently
- O,
- --CH.dbd.CH-- ##STR169## unsubstituted or substituted C.sub.1-15 straight or branched alkyl either substituted or unsubstituted with
- carboxy,
- hydroxy, or
- C.sub.1-10 alkoxy;
- Z is an optional substitutent that, when present, is
- O, --NR.sup.6 CO--, --CONR.sup.6, R1 ? ##STR170## or C.sub.1-10 straight or branched alkyl;
- m is an integer of from zero to six;
- n is an integer of from zero to six;
- and
- p is an integer of from zero to three;
- wherein aryl is phenyl or naphthyl.
36 more elements
Dependencies are inferred from the claim text.