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US 5,891,909 AGranted
Amidinohydrazones as protease inhibitors
Assignee3-Dimensional Pharmaceuticals, Inc.
InventorsRichard M. Soll, Tianbao Lu, Cynthia L. Fedde, Bruce E. Tomczuk, Carl Illig
Life of this patent
Estimating the term…
Abstract
Amidino and benzamidino compounds, including compounds of the formula: ##STR1## wherein R.sup.1 -R.sup.4, R.sup.6 -R.sup.9, 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 are described. Also described are methods for preparing the compounds of Formula I.
Claims76
A compound having the Formula I:
- ##STR18## or solvates, hydrates or pharmaceutically acceptable salts thereof, wherein:
- R.sup.1 is one of cycloalkyl, alkenyl, alkynyl, aryl, aralkyl or heteroaryl, any of which may be optionally substituted;
- Z is one of --NR.sup.10 SO.sub.2 --, --SO.sub.2 NR.sup.10 --, --NR.sup.10 C(R.sup.y R.sup.z)--, --C(R.sup.y R.sup.z)NR.sup.10 --, --OSO.sub.2 --, --SO.sub.2 O--, --OC(R.sup.y R.sup.z)--, --C(R.sup.y R.sup.z)O--, --NR.sup.10 CO-- or --CONR.sup.10 --;
- R.sup.y and R.sup.z are each independently one of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxy;
- R.sup.2, R.sup.3 and R.sup.4 are each independently one of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamido, --CO.sub.2 R.sup.x, --CH.sub.2 OR.sup.x or --OR.sup.x, or when present on adjacent carbon atoms, R.sup.2 and R.sup.3 may also be taken together to form one of --CH.dbd.CH--CH.dbd.CH-- or --(CH.sub.2).sub.q --, where q is from 2 to 6;
- R.sup.x, in each instance, is independently one of hydrogen, alkyl or cycloalkyl wherein said alkyl or cycloalkyl groups may optionally have one or more unsaturations;
- Y is one of --O--, --NR.sup.10 --, --S--, --CHR.sup.10 -- or a covalent bond;
- R.sup.a, R.sup.b and R.sup.c are independently hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or --CO.sub.2 R.sup.w ;
- R.sup.w is alkyl, cycloalkyl, phenyl, benzyl, ##STR19## where R.sup.d and R.sup.e are independently hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl or phenyl, R.sup.f is hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl or phenyl, R.sup.g is hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl or phenyl, and R.sup.h is aralkyl or C.sub.1-6 alkyl;
- R.sup.6 is one of hydrogen, alkyl, aralkyl, aryl, amino, hydroxyalkyl, aminoalkyl, monoalkylamino(C.sub.2-10)alkyl, dialkylamino(C.sub.2-10)alkyl or carboxyalkyl;
- R.sup.7 and R.sup.8 are each independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl, and R.sup.8' is hydrogen;
- or R.sup.7 and R.sup.8 are taken together to form --(CH.sub.2).sub.y --, where y is zero, 1 or 2, and R.sup.8' is hydrogen;
- or R.sup.7 is hydrogen, and R.sup.8 and R.sup.8' are taken together to form --(CH.sub.2).sub.t --, where t is from 2 to 5;
- R.sup.9 is one of hydrogen, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl can be optionally substituted with amino, monoalkylamino, dialkylamino, alkoxy, hydroxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, aryl, heteroaryl, acylamino, cyano or trifluoromethyl;
- R.sup.10, in each instance, is independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl, monoalkylamino(C.sub.2-10)alkyl, dialkylamino(C.sub.2-10)alkyl, carboxyalkyl or alkoxycarbonylalkyl;
- n is from zero to 8;
- and
- m is from zero to 4.
15 more elements
A compound having the formula:
- ##STR21## or solvate, hydrate, pharmaceutically acceptable salt or prodrug thereof;
- wherein
- R.sup.21 is one of phenyl, naphthyl, thiophenyl, pyridyl, pyrazolyl, benzthiadiazolyl, quinolinyl, or isoquinolinyl, any of which optionally substituted by one, two or three substituents independently selected from the group consisting of fluoro, chloro, bromo, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, trifluoromethyl, cyano, nitro, amino or dimethylamino;
- R.sup.24 is hydrogen or C.sub.1-4 alkyl;
- Y' is one of O, NH or a covalent bond;
- and
- a is 0, 1 or 2.
4 more elements
A compound having the formula:
- ##STR22## or a solvate, hydrate, pharmaceutically acceptable salt or prodrug thereof;
- wherein
- R.sup.21 is one of phenyl, naphthyl, thiophenyl, pyridyl, pyrazolyl, benzthiadiazolyl, quinolinyl, or isoquinolinyl, any of which optionally substituted by one, two or three substituents independently selected from the group consisting of fluoro, chloro, bromo, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, trifluoromethyl, cyano, nitro, amino or dimethylamino;
- R.sup.24 is hydrogen or C.sub.1-4 alkyl;
- Y' is one of O, NH or a covalent bond;
- and
- b is 0, 1 or2.
4 more elements
A compound having the Formula I:
- ##STR23## or a solvate, hydrate or pharmaceutically acceptable salt thereof;
- wherein:
- R.sup.1 is one of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl or heteroaryl, any of which may be optionally substituted;
- Z is one of --NR.sup.10 SO.sub.2 --, --SO.sub.2 NR.sup.10 --, --NR.sup.10 C(R.sup.y R.sup.z)--, --C(R.sup.y R.sup.z)NR.sup.10 --, --OSO.sub.2 --, --SO.sub.2 O--, --OC(R.sup.y R.sup.z)--, --C(R.sup.y R.sup.z O)--, --NR.sup.10 CO-- or --CONR.sup.10 --;
- R.sup.y and R.sup.z are each independently one of hydrogen, alkyl, cycloalkyl, aryl, aralkyl, hydroxyalkyl, carboxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl or carboxy;
- R.sup.2, R.sup.3 and R.sup.4 are each independently one of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, trifluoromethyl, halogen, hydroxyalkyl, cyano, nitro, carboxamido, --CO.sub.2 R.sup.x, --CH.sub.2 OR.sup.x or --OR.sup.x, or when present on adjacent carbon atoms, R.sup.2 and R.sup.3 may also be taken together to form one of --CH.dbd.CH--CH.dbd.CH-- or --(CH.sub.2).sub.q --, where q is from 2 to 6;
- R.sup.x, in each instance, is independently one of hydrogen, alkyl or cycloalkyl wherein said alkyl or cycloalkyl groups may optionally have one or more unsaturations;
- Y is one of --O--, --NR.sup.10 --, --S--, --CHR.sup.10 -- or a covalent bond;
- R.sup.w is alkyl, cycloalkyl, phenyl, benzyl, ##STR24## where R.sup.d and R.sup.e are independently hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl or phenyl, R.sup.f is hydrogen or methyl, R.sup.g is hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl or phenyl, and R.sup.h is benzyl or t-butyl;
- and:
- A. R.sup.7 and R.sup.9 are taken together to form --(CH.sub.2).sub.o --, where o is 1, 2 or 3;
- R.sup.8 is hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl;
- R.sup.8' is hydrogen;
- R.sup.a, R.sup.b and R.sup.c are hydrogen, hydroxy, ##STR25## where R.sup.h is benzyl or t-butyl, and where R.sup.f is hydrogen or methyl;
- and R.sup.6 is hydrogen, C.sub.1-4 alkyl, C.sub.2-4 hydroxyalkyl, C.sub.2-4 carboxyalkyl, C.sub.2-4 aminoalkyl, dimethylamino(C.sub.2-8)alkyl, or methylamino(C.sub.2-8)alkyl;
- or
- B. R.sup.7 is hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl;
- R.sup.8 and R.sup.9 are taken together to form --CH.sub.2 --CH.sub.2 --(CH.sub.2).sub.p --, where p is 1, 2 or 3;
- R.sup.8' is hydrogen;
- and
- R.sup.a, R.sup.b and R.sup.c are hydrogen, hydroxy, ##STR26## where R.sup.h is benzyl or t-butyl, and where R.sup.f is hydrogen or methyl;
- and R.sup.6 is hydrogen, C.sub.1-4 alkyl, C.sub.2-4 hydroxyalkyl, C.sub.2-4 carboxyalkyl, C.sub.2-4 aminoalkyl, dimethylamino(C.sub.2-8)alkyl, or methylamino(C.sub.2-8)alkyl;
- or
- C. R.sup.6 and R.sup.b are taken together to form .dbd.CH--N.dbd.CH--NH-- or --CH.sub.2 --(CH.sub.2).sub.r --,
- where r is 1, 2 or 3;
- R.sup.a is hydrogen or hydroxy;
- R.sup.c is hydrogen, alkyl, hydroxy, alkoxy, aryloxy, aralkoxy, alkoxycarbamoyloxy, cyano or --CO.sub.2 R.sup.w, where R.sup.w is as defined above;
- R.sup.7 and R.sup.8 are each independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl, or R.sup.7 and R.sup.8 are taken together to form --(CH.sub.2).sub.y --, where y is zero, 1 or 2;
- R.sup.8' is hydrogen;
- and R.sup.9 is one of hydrogen, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl may be optionally substituted with amino, monoalkylamino, dialkylamino, alkoxy, hydroxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, aryl, heteroaryl, acylamino, cyano or trifluoromethyl;
- or
- D. R.sup.a and R.sup.c are taken together to form --CH.sub.2 --(CH.sub.2).sub.s --, where s is 1 or 2;
- R.sup.b is hydrogen, hydroxy ##STR27## where R.sup.h is benzyl or t-butyl and where R.sup.f is hydrogen or methyl;
- and
- R.sup.6 is hydrogen, alkyl, alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or --CO.sub.2 R.sup.w, where R.sup.w is as defined above;
- R.sup.7 and R.sup.8 are each independently one of hydrogen, alkyl, aralkyl, aryl, hydroxyalkyl or carboxyalkyl, or R.sup.7 and R.sup.8 are taken together to form --(CH.sub.2).sub.y --, where y is zero, 1 or 2;
- R.sup.8' is hydrogen;
- and R.sup.9 is one of hydrogen, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl may be optionally substituted with amino, monoalkylamino, dialkylamino, alkoxy, hydroxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, aryl, heteroaryl, acylamino, cyano or trifluoromethyl.
35 more elements
Dependencies are inferred from the claim text.