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US 5,672,611 AGranted
Tricyclic compounds useful for inhibition of G-protein function and for treatment of proliferative diseases
AssigneeSchering Corporation
InventorsRonald J. Doll, Alan K. Mallams, Adriano Afonso, Dinanath F. Rane, Randall R. Rossman, F. George Njoroge
Life of this patent
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Abstract
Novel compounds of Formula ##STR1## are disclosed. Also disclosed is a method of inhibiting Ras function and therefore inhibiting the abnormal growth of cells. The method comprises administering a compound of the Formula 1.0 to a biological system. In particular, the method inhibits the abnormal growth of cells in a mammal such as a human being.
Claims27
A compound of the formula:
- ##STR134## or a pharmaceutically acceptable salt or solvate thereof, wherein:
- (1) R.sup.I is a group selected from:
- ##STR135## or R.sup.2 is selected from:
- (1) H,
- (2) C.sub.1 to C.sub.8 alkyl,
- (3) C.sub.2 to C.sub.8 alkenyl,
- (4) C.sub.2 to C.sub.8 alkynyl, ##STR136## wherein said alkyl, alkenyl, or alkynyl is optionally substituted with one or more groups independently selected from:
- (a) aryl, aralkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl;
- said aryl, aralkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl optionally substituted with one or more groups independently selected from:
- (1) C.sub.1 to C.sub.4 alkyl,
- (2) (CH.sub.2).sub.t OR.sup.8 wherein t is 1 to 4,
- (3) (CH.sub.2).sub.t NR.sup.8 R.sup.9 wherein t is 1 to 4, or
- (4) halogen,
- (b) C.sub.3 to C.sub.6 cycloalkyl,
- (c) --OR.sup.8 s,
- (d) --SR.sup.8,
- (e) --S(O)R.sup.8,
- (f) --S0.sub.2 R.sup.8,
- (g) --NR.sup.8 R.sup.9, ##STR137## R.sup.3 is halogen;
- R.sup.4 is halogen;
- R.sup.5 is selected from:
- H, ##STR138## R.sup.6 is selected from H or C.sub.1 to C.sub.6 alkyl;
- R.sup.7 is selected from H, C.sub.1 to C.sub.6 alkyl, haloalkyl, or --C(O)R.sup.11 wherein R.sup.11 is selected from C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy or --NHR.sup.12 (wherein R.sup.12 is C.sub.1 to C.sub.6 alkyl or H), or R.sup.7 is an acyl radical of a naturally occurring amino acid;
- R.sup.8, R.sup.9 and R.sup.10 are independently selected from H, C.sub.1 to C.sub.4 alkyl, C.sub.3 to C.sub.6 cycloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, aryl or aralkyl;
- said alkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, aryl or aralkyl are optionally substituted with C.sub.1 to C.sub.4 alkoxy, aryl, heteroaryl, heterocycloalkyl, cyclopropyl, halogen, --OH, --C(O)R.sup.13, --SO.sub.2 R.sup.13, or --NR.sup.14 R.sup.15 wherein R.sup.13 is selected from C.sub.1 to C.sub.4 alkyl or aralkyl, and wherein R.sup.14 and R.sup.15 are independently selected from H, C.sub.1 to C.sub.4 alkyl or aralkyl;
- with the proviso that R.sup.8 is not H in substituents (e), (f) or (k), and with the proviso that R.sup.9 is not H in substituent (h) or (n), and with the proviso that R.sup.8, R.sup.9, or R.sup.10 is not --CH.sub.2 OH or --CH.sub.2 NR.sup.14 R.sup.15 when R.sup.8, R.sup.9, or R.sup.10 is directly attached to a heteroatom;
- optionally, when R.sup.8 and R.sup.9 are bound to the same nitrogen, R.sup.8 and R.sup.9, together with the nitrogen to which they are bound, form a 5 to 7 membered heterocycloalkyl ring;
- optionally, when R.sup.9 and R.sup.10 are bound to the same nitrogen, R.sup.9 and R.sup.10, together with the nitrogen to which they are bound, form a 5 to 7 membered heterocycloalkyl ring;
- represents an optional bond;
- W is selected from CH when the optional bond is present, or O, S or CH.sub.2 when the optional bond is absent;
- X is selected from CH;
- and
- Y is selected from N or CH.
30 more elements
A compound of the formula:
- ##STR145## or a pharmaceutically acceptable salt or solvate thereof, wherein:
- (1) R.sup.1 is a group selected from:
- ##STR146## or R.sup.2 is selected from:
- (1) H,
- (2) C.sub.1 to C.sub.8 alkyl,
- (3) C.sub.2 to C.sub.8 alkenyl,
- (4) C.sub.2 to C.sub.8 alkynyl, ##STR147## wherein said alkyl, alkenyl, or alkynyl is optionally substituted with one or more groups independently selected from:
- (a) aryl, aralkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl;
- said aryl, aralkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl optionally substituted with one or more groups independently selected from:
- (1) C.sub.1 to C.sub.4 alkyl,
- (2) (CH.sub.2).sub.t OR.sup.8 wherein t is 1 to 4,
- (3) (CH.sub.2).sub.t NR.sup.8 R.sup.9 wherein t is 1 to 4, or
- (4) halogen,
- (b) C.sub.3 to C.sub.6 cycloalkyl,
- (c) --OR.sup.8,
- (d) --SR.sup.8,
- (e) --S(O)R.sup.8,
- (f) --SO.sub.2 R.sup.8,
- (g) --NR.sup.8 R.sup.9, ##STR148## R.sup.3 is selected from H, halogen or C.sub.1 to C.sub.6 alkyl;
- R .sup.4 is selected from H, halogen or C.sub.1 to C.sub.6 alkyl;
- R .sup.5 is selected from:
- H, ##STR149## R.sup.6 is selected from H or C.sub.1 to C.sub.6 alkyl;
- R.sup.7 is selected from H, C.sub.1 to C.sub.6 alkyl, haloalkyl, or --C(O)R.sup.11 wherein R.sup.11 is selected from C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy or --NHR.sup.12 (wherein R.sup.12 is C.sub.1 to C.sub.6 alkyl or H), or R.sup.7 is an acyl radical of a naturally occurring amino acid;
- R.sup.8, R.sup.9 and R.sup.10 are independently selected from H, C.sub.1 to C.sub.4 alkyl, C.sub.3 to C.sub.6 cycloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, aryl or aralkyl;
- said alkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, aryl or aralkyl are optionally substituted with C.sub.1 to C.sub.4 alkoxy, aryl, heteroaryl, heterocycloalkyl, cyclopropyl, halogen, --OH, --C(O)R.sup.13, --SO.sub.2 R.sup.13, or --NR.sup.14 R.sup.15 wherein R.sup.13 is selected from C.sub.1 to C.sub.4 alkyl or aralkyl, and wherein R.sup.14 and R.sup.15 are independently selected from H, C.sub.1 to C.sub.4 alkyl or aralkyl;
- with the proviso that R.sup.8 is not H in substituents (e), (f) or (k), and with the proviso that R.sup.9 is not H in substituent (h) or (n), and with the proviso that R.sup.8, R.sup.9, or R.sup.10 is not --CH.sub.2 OH or --CH.sub.2 NR.sup.14 R.sup.15 when R.sup.8, R.sup.9, or R.sup.10 is directly attached to a heteroatom;
- optionally, when R.sup.8 and R.sup.9 are bound to the same nitrogen, R.sup.8 and R.sup.9, together with the nitrogen to which they are bound, form a 5 to 7 membered heterocycloalkyl ring;
- optionally, when R.sup.9 and R.sup.10 are bound to the same nitrogen, R.sup.9 and R.sup.10, together with the nitrogen to which they are bound, form a 5 to 7 membered heterocycloalkyl ring;
- represents an optional bond;
- W is selected from CH when the optional bond is present, or O, S or CH.sub.2 when the optional bond is absent;
- X is selected from CH;
- and
- Y is selected from N or CH.
30 more elements
A compound of the formula:
- ##STR153## or a pharmaceutically acceptable salt or solvate thereof, wherein:
- (1) R.sup.1 is a group selected from:
- ##STR154## R.sup.2 is selected from:
- (1) H,
- (2) C.sub.1 to C.sub.8 alkyl,
- (3) C.sub.2 to C.sub.8 alkenyl,
- (4) C.sub.2 to C.sub.8 alkynyl, ##STR155## wherein said alkyl, alkenyl, or alkynyl is optionally substituted with one or more groups independently selected from:
- (a) aryl, aralkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl;
- said aryl, aralkyl, heteroaryl, heteroarylalkyl or heterocycloalkyl optionally substituted with one or more groups independently selected from:
- (1) C.sub.1 to C.sub. 4 alkyl,
- (2) (CH.sub.2).sub.t OR.sup.8 wherein t is 1 to 4,
- (3) (CH.sub.2).sub.t NR.sup.8 R.sup.9 wherein t is 1 to 4, or
- (4) halogen,
- (b) C.sub.3 to C.sub.6 cycloalkyl,
- (c) --OR.sup.8,
- (d) --SR.sup.8,
- (e) --S(O)R.sup.8,
- (f) --SO.sub.2 R.sup.8,
- (g) --NR.sup.8 R.sup.9, ##STR156## R.sup.3 is selected from H, halogen or C.sub.1 to C.sub.6 alkyl;
- R.sup.4 is selected from H, halogen or C.sub.1 to C.sub.6 alkyl;
- R.sup.5 is selected from:
- H, ##STR157## R.sup.6 is selected from H or C.sub.1 to C.sub.6 alkyl;
- R.sup.7 is selected from H, C.sub.1 to C.sub.6 alkyl, haloalkyl, or --C(O)R.sup.11 wherein R.sup.11 is selected from C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkoxy or --NHR.sup.12 (wherein R.sup.12 is C.sub.1 to C.sub.6 alkyl or H), or R.sup.7 is an acyl radical of a naturally occurring amino acid;
- R.sup.8, R.sup.9 and R.sup.10 are independently selected from H, C.sub.1 to C.sub.4 alkyl, C.sub.3 to C.sub.6 cycloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, aryl or aralkyl;
- said alkyl, cycloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, aryl or aralkyl are optionally substituted with C.sub.1 to C.sub.4 alkoxy, aryl, heteroaryl, heterocycloalkyl, cyclopropyl, halogen, --OH, --C(O)R.sup.13, --SO.sub.2 R.sup.13, or --NR.sup.14 R.sup.15 wherein R.sup.13 is selected from C.sub.1 to C.sub.4 alkyl or aralkyl, and wherein R.sup.14 and R.sup.15 are independently selected from H, C.sub.1 to C.sub.4 alkyl or aralkyl;
- with the proviso that R.sup.8 is not H in substituents (e), (f) or (k), and with the proviso that R.sup.9 is not H in substituent (h) or (n) , and with the proviso that R.sup.8, R.sup.9, or R.sup.10 is not --CH.sub.2 OH or --CH.sub.2 NR.sup.14 R.sup.15 when R.sup.8, R.sup.9, or R.sup.10 is directly attached to a heteroatom;
- optionally, when R.sup.8 and R.sup.9 are bound to the same nitrogen, R.sup.8 and R.sup.9, together with the nitrogen to which they are bound, form a 5 to 7 membered heterocycloalkyl ring;
- optionally, when R.sup.9 and R.sup.10 are bound to the same nitrogen, R.sup.9 and R.sup.10, together with the nitrogen to which they are bound, form a 5 to 7 membered heterocycloalkyl ring;
- represents an optional bond;
- W is selected from CH when the optional bond is present, or O, S or CH.sub.2 when the optional bond is absent;
- X is selected from CH;
- and
- Y is N.
30 more elements
Dependencies are inferred from the claim text.