Topoisomerase-targeting agents
View Patent ↗The invention provides compounds of formula I or formula II: wherein: the bond represented by --- is a single bond or a double bond, and R 1 –R 5 , X, and Y have any of the meanings defined in the specification and their pharmaceutically acceptable salts. The invention also provides pharmaceutical compositions comprising a compound of formula I or II, processes for preparing compounds of formula I or II, intermediates useful for preparing compounds of formula I or II, and therapeutic methods for treating cancer and other topoisomerase related conditions using compounds of formula I or II.
1. A compound of formula I or formula II:
wherein:
the bond represented by --- is a single bond or a double bond;
X is CH or N;
Y is CH or N when the bond represented by --- is a double bond, or Y is CH 2 or NR x when the bond represented by --- is a single bond;
one of R 1 and R 2 is nitro, halo, or (C 1 –C 6 )alkoxy and the other is hydrogen, nitro, halo, or (C 1 –C 6 )alkoxy; or R 1 and R 2 taken together are methylenedioxy;
one of R 3 and R 4 is nitro, halo, or (C 1 –C 6 )alkoxy and the other of R 3 and R 4 is hydrogen, nitro, halo, or (C 1 –C 6 )alkoxy; or R 3 and R 4 taken together are methylenedioxy;
R 5 is a solubilizing group; and
R x is hydrogen or (C 1 –C 6 )alkyl;
or a pharmaceutically acceptable salt thereof;
provided that Y is not N, when R 5 is —OH.
2. The compound of claim 1 wherein X is CH.
3. A compound of formula I or formula II:
wherein:
the bond represented by --- is a double bond;
X is CH or N;
Y is CH;
one of R 1 and R 2 is nitro, halo, or (C 1 –C 6 )alkoxy and the other is hydrogen. nitro, halo, or (C 1 –C6)alkoxy; or R 1 and R 2 taken together are methylenedioxy;
one of R 3 and R 4 is nitro, halo, or (C 1 –C 6 )alkoxy and the other of R 3 and R 4 is hydrogen, nitro, halo, or (C 1 –C 6 )alkoxy; or R 3 and R 4 taken together are methylenedioxy; and
R 5 is a solubilizing group;
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 wherein R 1 and R 2 taken together are methylenedioxy.
5. The compound of claim 1 wherein R 3 and R 4 both (C 1 –C 6 )alkoxy.
6. The compound of claim 1 wherein R 1 and R 2 taken together are methylenedioxy; and R 3 and R 4 are each methoxy.
7. The compound of claim 1 wherein R 5 is (C 1 –C 6 )alkoxycarbonyl, cyano, halo, hydroxy, mercapto, carboxy, nitro, pyrrolidinyl, piperidinyl, imidazolidinyl, imidazolinyl, piperazinyl, morpholinyl, thiomorpholinyl, or —NR f R g , wherein R f and R g may be the same or different and are chosen from hydrogen, (C 1 –C 6 )alkyl, and (C 3 –C 6 )cycloalkyl.
8. A compound of formula I or formula II:
wherein:
the bond represented by --- is a single bond or a double bond;
X is CH or N;
Y is CH or N when the bond represented by --- is a double bond, or Y is CH 2 or NR x when the bond represented by is - - - a single bond;
one of R 1 and R 2 is nitro, halo, or (C 1 –C 6 )alkoxy and the other is hydrogen, nitro, halo, or (C 1 –C 6 )alkoxy; or R 1 and R 2 taken together are methylenedioxy;
one of R 3 and R 4 is nitro, halo, or (C 1 –C 6 )alkoxy and the other of R 3 and R4 is hydrogen, nitro, halo, or (C 1 –C 6 )alkoxy; or R 3 and R 4 taken together are methylenedioxy;
R 5 is —W-Z;
W is absent, —(C═O)—, —CH 2 —, —(C═O)O—, —O(C═O)—, —O—, —NR a (C═O)—, —C(═O)NR a —, or —NR a —;
Z is (C 1 –C 4 alkyl substituted with one or more water solubilizing groups;
R a is hydrogen or (C 1 –C 4 )alkyl; and
R x is hydrogen or (C 1 –C 6 )alkyl;
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 8 wherein —W-Z is (C 1 –C 4 )alkyl substituted with one or more (C 1 –C 6 )alkoxycarbonyl, cyano, halo, hydroxy, mercapto, oxo, carboxy, nitro, pyrrolidinyl, piperidinyl, imidazolidinyl, imidazolinyl, piperazinyl, morpholinyl, thiomorpholinyl, or —NR f R g groups, wherein R f and R g may be the same or different and are chosen from hydrogen, (C 1 –C 6 )alkyl, and (C 3 –C 6 )cycloalkyl.
10. The compound of claim 8 wherein —W-Z is —CH 2 CH 2 —NR f R g wherein R f and R f are each independently hydrogen or (C 1 –C 6 )alkyl.
11. The compound of claim 8 wherein —W-Z is (C 2 –C 4 ) alkylamino substituted with one or more (C 1 –C 6 )alkoxycarbonyl, cyano, halo, hydroxy, mercapto, oxo, carboxy, nitro, pyrrolidinyl, piperidinyl, imidazolidinyl, imidazolinyl, piperazinyl, morpholinyl, thiomorpholinyl, or —NR f R g groups, wherein R f and R g may be the same or different and are chosen from hydrogen, (C 1 –C 6 )alkyl, and (C 3 –C 6 )cycloalkyl.
12. The compound of claim 8 wherein —W-Z is (C 1 –C 4 )alkylaminocarbonyl substituted with one N(CH 3 ) 2 group.
13. The compound of claim 1 wherein the bond represented --- is a single bond.
14. A compound of fommia I or formula II:
wherein:
the bond represented by --- is a double bond;
X is CH or N;
Y is CH or N;
one of R 1 and R 2 is nitro, halo, or (C 1 –C 6 )alkoxy and the other is hydroaen, nitro, halo, or (C 1 –C 6 )alkoxy; or R 1 and R 2 taken together are methylenedioxy;
one of R 3 and R 4 is nitro, halo, or (C 1 –C 6 )alkoxy and the other of R 3 and R 4 is hydrogen, nitro, halo, or (C 1 –C 6 )alkoxy; or R 3 and R 4 taken together are methylenedioxy; and
R 5 is a solubilizing group;
or a pharmaceutically acceptable salt thereof;
provided that Y is not N, when R 5 is —OH.
15. A pharmaceutical composition comprising a compound as described in claim 1 in combination with a pharmaceutically acceptable diluent or carrier.
16. A method of producing an antibacterial effect in a mammal in need of such treatment comprising administering to the mammal, an amount of a compound as described in claim 1 , effective to provide an antibacterial effect.
17. A method of producing an antifungal effect in a mammal in need of such treatment comprising administering to the mammal, an amount of a compound as described in claim 1 , effective to provide an antifungal effect.
18. A compound of formula I or formula II:
wherein:
the bond represented by --- is a single bond or a double bond;
X is CH or N;
Y is CH or N when the bond represented by --- is a double bond, or Y is CH 2 or NR x when the bond represented by --- is a single bond;
one of R 1 and R 2 is nitro, halo, or (C 1 –C 6 )alkoxy and the other is hydrogen, nitro, halo, or C 1 –C 6 )alkoxy; or R 1 and R 2 taken together are methylenedioxy;
one of R 3 and R 4 is nitro, halo, or (C 1 –C 6 )alkoxy and the other of R 3 and R 4 is hydrogen, nitro, halo, or (C 1 –C 6 )alkoxy; or R 3 and R 4 taken together are methylenedioxy;
R 5 is a solubilizing group; and
R x is hydrogen or (C 1 –C 6 )alkyl;
or a pharmaceutically acceptable salt thereof; provided that R 5 is not —OH.