Quinazolinone inhibitors of dynein
Compounds of formula (I) in which R 3 is chosen from hydrogen, cyano, nitro, acetyl and C(═O)NH 2 , and Ar is optionally substituted monocyclic or bicyclic aryl or heteroaryl, are useful as antitumor agents.
1. A compound of formula
wherein
R 1 is chosen from —(C 3 -C 10 )hydrocarbon, —O—(C 3 -C 6 )alkyl, and -A-R 10 , wherein A is a (C 1 -C 6 )hydrocarbon and R 10 is chosen from —O—(C 1 -C 6 )alkyl, fluoro(C 1 -C 6 )alkyl, —O—(C 1 -C 6 )fluoroalkyl, hydroxy, —CN, nitro, —S—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )acyl, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino and (C 1 -C 6 )acylamino; and R 2 is hydrogen;
R 3 is chosen from cyano, nitro, acetyl and —C(═O)NH 2 ;
R 4 and R 5 are independently chosen from hydrogen and methyl;
Y is O;
and
Ar is chosen from;
a. phenyl substituted with from one to three substituents independently chosen from halogen, (C 1 -C 10 )hydrocarbon, fluoro(C 1 -C 6 )alkyl, —O(C 1 -C 6 )fluoroalkyl, —CN, nitro, (C 1 -C 6 )alkoxycarbonyl and (C 1 -C 6 )acyl; and
b. naphthyl, and thiophenyl, either of which may be optionally substituted with from one to three substituents independently chosen from halogen, (C 1 -C 10 )hydrocarbon, fluoro(C 1 -C 6 )alkyl, —O(C 1 -C 6 )fluoroalkyl, —CN, nitro, (C 1 -C 6 )alkoxycarbonyl and (C 1 -C 6 )acyl.
2. A compound according to claim 1 wherein Ar is chosen from substituted phenyl and naphthyl, and thiophenyl, any of which may be optionally substituted with from one to three substituents independently chosen from halogen, (C 1 -C 10 )hydrocarbon, fluoro(C 1 -C 6 )alkyl, —O—(C 1 -C 6 )fluoroalkyl, —CN, nitro, (C 1 -C 6 )alkoxycarbonyl and (C 1 -C 6 )acyl.
3. A compound according to claim 2 wherein Ar is phenyl substituted with from one to three halogens.
4. A compound according to claim 3 wherein Ar is 2,4-dichlorophenyl or 3,4-dichlorophenyl.
5. A compound according to claim 1 wherein R 4 and R 5 are hydrogen.
6. A compound according to claim 1 wherein R 3 is CN.
7. A compound according to claim 4 wherein R 3 is CN; and R 2 , R 4 and R 5 are H.
8. A method of inhibiting a dynein comprising bringing said dynein into contact with a compound of formula
wherein
R 1a is —(C 3 -C 10 )hydrocarbon, or —O—(C 3 -C 6 )alkyl; and
R 6 and R 7 are halogen.
9. A method of inhibiting retrograde cilial transport comprising bringing a cell having at least one cilium into contact with a compound of formula
wherein
R 1a is —(C 3 -C 10 )hydrocarbon, or —O—(C 3 -C 6 )alkyl; and
R 6 and R 7 are halogen.
10. A method according to claim 9 wherein said method of inhibiting is an in vitro method.
11. A method according to claim 9 wherein said method of inhibiting is an in vivo method.
12. A method of inhibiting the growth of a basal cell carcinoma, glioblastoma or medulloblastoma comprising bringing said basal cell carcinoma, glioblastoma or medulloblastoma into contact with a compound of formula
wherein
R 1 is chosen from —(C 3 -C 10 )hydrocarbon, —O—(C 3 -C 6 )alkyl, and -A-R 10 , wherein A is a (C 1 -C 6 )hydrocarbon and R 10 is chosen from —O—(C 1 -C 6 )alkyl, fluoro(C 1 -C 6 )alkyl, —O—(C 1 -C 6 )fluoroalkyl, hydroxy, —CN, nitro, —S—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )acyl, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino and (C 1 -C 6 )acylamino; and R 2 is hydrogen;
R 3 is chosen from hydrogen, cyano, nitro, acetyl and —C(═O)NH 2 ;
R 4 and R 5 are independently chosen from hydrogen and methyl;
Y is O;
and
Ar is chosen from:
a. phenyl substituted with from one to three substituents independently chosen from halogen, (C 1 -C 10 )hydrocarbon, fluoro(C 1 -C 6 )alkyl, —O(C 1 -C 6 )fluoroalkyl, —CN, nitro, (C 1 -C 6 )alkoxycarbonyl and (C 1 -C 6 )acyl; and
b. naphthyl, and thiophenyl, either of which may be optionally substituted with from one to three substituents independently chosen from halogen, (C 1 -C 10 )hydrocarbon, fluoro(C 1 -C 6 )alkyl, —O(C 1 -C 6 )fluoroalkyl, —CN, nitro, (C 1 -C 6 )alkoxycarbonyl and (C 1 -C 6 )acyl.