Cyclic prodrugs of duocarmycin analogs
The invention provides prodrugs of DNA-reactive analogs of duocarmycin and CC-1065 anticancer agents, wherein a cyclic prodrug form, such as carbamate, thionocarbamate, or carbamimidate, can be hydrolyzed by the patient in vivo to yield a respective bioactive agent comprising a DNA-alkylating moiety and a binding/targeting moiety. The DNA-reactive moiety is a γ-spirocyclohexenone fused to a heterocyclyl group which can be produced by endogenous hydrolysis of a cyclic carbamate prodrug of the invention. The cyclic carbamate prodrug produces no residual byproduct during activation in vivo. Methods of synthesis and biological methods and data are also provided.
1. A compound of formula (I)
wherein a dotted line indicates a double bond or a single bond, provided that when the N has a double bond thereto, R is absent;
X is a leaving group,
Y is O, S, SR, or NR,
each R is independently H, (C 1 -C 6 )alkyl, or substituted (C 1 -C 6 )alkyl, and
Ar is heteroaryl optionally substituted by one or more substituents J;
J is selected from the group consisting of F, Cl, Br, I, OR′, OC(O)N(R′) 2 , CN, NO, NO 2 , ONO 2 , azido, CF 3 , OCF 3 , R′, O (oxo), S (thiono), methylenedioxy, ethylenedioxy, N(R′) 2 , SR′, SOR′, SO 2 R′, SO 2 N(R′) 2 , SO 3 R′, C(O)R′, C(O)C(O)R′, C(O)CH 1 C(O)R′, C(S)R′, C(O)OR′, OC(O)R′, C(O)N(R′) 2 , OC(O)N(R′) 2 , C(S)N(R′) 2 , (CH 2 ) 0-2 N(R′)C(O)R′, (CH 2 ) 0-2 N(R′)N(R′) 2 , N(R′)N(R′)C(O)R′) 2 , N(R′)N(R′)C(O)OR′, N(R′)N(R′)CON(R′) 2 , N(R′)SO 2 R′, N(R′)SO 2 N(R′) 2 , N(R′)C(O)OR′, N(R′)C(O)R′, N(R′)C(S)R′, N(R′)C(O)N(R′), N(R′)C(S)N(R′) 2 , N(COR′)COR′, N(OR′)R′, C(═NH)N(R′) 2 , C(O)N(OR′)R′ and C(═NOR′)R′; wherein
R′ is selected from the group consisting of hydrogen, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, wherein any alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, and heteroarylalkyl;
or any salt thereof, or a hydrate thereof.
2. The compound of claim 1 wherein Y is O.
3. The compound of claim 1 wherein Y is NH.
4. The compound of claim 1 wherein Y is S.
5. The compound of claim 1 wherein Y is SR, wherein R is (C 1 -C 6 )alkyl, or substituted (C 1 -C 6 )alkyl.
6. The compound of claim 1 wherein X is a halo or a sulfonic ester.
7. The compound of claim 1 wherein X is a chloro or a mesylate.
8. The compound of claim 1 wherein R is H.
9. The compound of claim 1 wherein Ar comprises an indole bonded at an indole 2-position.
10. The compound of claim 9 wherein the indole is further substituted with a heteroaroylamino group.
11. The compound of claim 10 wherein the heteroaroylamino group is an unsubstituted or a substituted 2-indoloylamino group.
12. The compound of claim 1 of formula
wherein R, X, and Y are as defined in claim 1 ;
or any salt thereof, or a hydrate thereof.
13. The compound of claim 1 of formula
wherein X is as defined in claim 1 .
14. The compound of claim 1 of any one of the following formulae
wherein Alk is (C 1 -C 6 )alkyl, or,
15. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
16. A synthetic intermediate for preparation of a compound of formula (I) of claim 1 , of formula (III)
wherein R, X, and Y, are as defined in claim 1 , or an enantiomer thereof.
17. A compound of formula
or an enantiomer thereof.