US 6,274,628 B1 · Benzamide and sulfonamide substituted aminoguanidines and alkoxyguanidines as protease inhibitors

Abstract

The present invention is directed to aminoguanidine and alkoxyguanidine compounds, including compounds of Formula I: wherein X is O or NH, L is —O— or —SO2—, and R1-R4, R9-R19, Ra, Rb, Rc, Y, Z, n and m are set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof, that inhibit proteolytic enzymes such as thrombin. Also described are methods for preparing the compounds of Formula I. Certain of the compounds exhibit antithrombotic activity via direct, selective inhibition of thrombin, or are intermediates useful for forming compounds having antithrombotic activity. The invention includes a composition for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal. Other uses of compounds of the invention are as anticoagulants either embedded in or physically linked to materials used in the manufacture of devices used in blood collection, blood circulation, and blood storage.

A compound having the Formula I:

or a solvate, hydrate or pharmaceutically acceptable salt thereof;
wherein:
L represents —C(O)— or —SO2—;
R1 represents a group:
R2 represents a group:
R12 represents hydrogen, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl, aryl, or heteroaryl, which groups are optionally substituted with C1-6 alkyl or hydroxy, or R12 represents diarylmethyl, diheteroarylmethyl, dicycloalkylmethyl or (aryl)(heteroaryl)CH—;
Z and Z′ independently represent a bond, a C1-6 alkyl chain, a C3-6 alkenyl chain, or a C3-6 alkynyl chain, where one or two nitrogen, oxygen, or sulfur atoms may be optionally contained within each chain, and the chains are optionally substituted by one or more groups selected from halogen, hydroxy, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy(C1-6)alkyl, C1-6 acyloxy, NR13R14, NHCOR15, NHSO2R16, COR15, CO2R15, CONR13R14, and SO2NR17R18;
provided that when one of R1 or R2 is C3-8 alkyl, cycloalkyl, C3-8 alkenyl, C3-8 alkynyl, aryl, aralkyl, or heteroaryl, any of which is optionally substituted, then the other of R1 or R2 is other than hydrogen, alkyl, aralkyl, aryl, hydroxy(C2-10)alkyl, amino(C2-10)alkyl, monoalkylamino(C2-10)alkyl, dialkylamino(C2-10)alkyl or carboxyalkyl;
R13-R16 represent hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, mono- or di-hydroxy(C6-10)aryl, C6-10 ar(C1-4)alkyl, pyridyl, pyridyl(C1-4)alkyl, carboxy(C1-6)-alkyl, C1-4 alkoxycarbonyl(C1-4)alkyl, cyano(C2-6)alkyl, hydroxy(C2-6)alkyl, C1-4 alkoxy(C2-6)alkyl, mono- and di-(C1-4)alkylamino(C2-6)alkyl;
or R16 additionally may represent trifluoromethyl;
R17 and R18 are independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C6-10 ar(C1-4)alkyl, pyridyl, pyridyl(C1-4)alkyl, carboxy(C1-6)alkyl, C1-4 alkoxycarbonyl-(C1-4)alkyl, cyano(C2-6)alkyl, hydroxy(C2-6)alkyl, C1-4 alkoxy(C2-6)alkyl, and mono- and di-(C1-4)alkylamino(C2-6)alkyl;
R3, R4, R5 and R6 are each independently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamido, —CO2Rx, —CH2ORx or —ORx, or when present on adjacent carbon atoms, R3 and R4 may also be taken together to form —CH═CH—CH═CH— or —(CH2)q—, where q is from 2 to 6, and R5 and R6 are defined as above;
Rx is hydrogen, alkyl or cycloalkyl wherein said alkyl or cycloalkyl may optionally have one or more unsaturations;
Y is —O—, —NR19—, —S—, —CHR19— or a covalent bond;
R19, is hydrogen, C1-6 alkyl, benzyl, phenyl, C2-10 hydroxyalkyl, C2-10 aminoalkyl, C1-4 monoalkylamino(C2-8)alkyl, C1-4 dialkylamino(C2-8)alkyl or C2-10 carboxyalkyl;
R7 is hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, carboxyalkyl, hydroxy, alkoxy, aralkoxy, aryloxy, heteroaryloxy, or mono- or di-alkylamino, provided that n is other than zero when R7 is hydroxy, alkoxy, aralkoxy, aryloxy, heteroaryloxy, or mono- or di-alkylamino;
R8, R9 and R10 are each independently hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxyalkyl;
or R7 and R8 are taken together to form —(CH2)y— where y is zero, 1 or 2, while R9 and R10 are defined as above;
or R7 and R10 are taken together to form —CH2)t—, where t is zero, or 1 to 8, while R8 and R9 are defined as above;
or R8 and R9 are taken together to form —(CH2)r—, where r is 2-8, while R7 and R10 are defined as above;
X is oxygen or NH;
R11 is hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino(C2-10)alkyl, dialkylamino(C2-10)alkyl or carboxyalkyl;
Ra, Rb and Rc are independently hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or —CO2Rw;
Rw is alkyl, trichloroethyl, cycloalkyl, phenyl, benzyl,
where Rd and Re are independently hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rf is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, Rg is hydrogen, C1-6 alkyl, C2-6 alkenyl or phenyl, and Rh is aralkyl or C1-6 alkyl;
n is from zero to 8;
and m is from zero to 4.

24 more elements

Benzamide and sulfonamide substituted aminoguanidines and alkoxyguanidines as protease inhibitors

Life of this patent

Benzamide and sulfonamide substituted aminoguanidines and alkoxyguanidines as protease inhibitors

Life of this patent

Abstract

Claims64