Tylophorine analogs as antitumor agents
View Patent ↗Compounds of Formula I are described: preferably subject to the proviso that either (a) R 2 and R 3 together form —O—CH(R 10 )—O—, or (b) R 5 and R 6 together form —O—CH(R 10 )—O—, wherein R 10 is H, halo, or loweralkyl. Pharmaceutical salts, formulations, and methods of using the same in the treatment of cancer are also described.
1. A compound of Formula I:
wherein:
R is C1-C4 alkylene;
B is H, halo, loweralkyl, or loweralkenyl; and
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of H, halo, alkoxy, loweralkyl, and loweralkenyl;
subject to the proviso that at least one of R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is alkoxy;
and subject to the proviso that either (a) R 2 and R 3 together form —O—CH(R 10 )—O—, or (b) R 5 and R 6 together form —O—CH(R 10 )—O—, wherein R 10 is H, halo, or loweralkyl;
wherein A is —NR 11 R 12 , wherein R 11 is selected from the group consisting of H, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, and aminoalkyl, and wherein R 12 is selected from the group consisting of alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, aminoalkyl, alkylaminoalkyl, alkylthio, and alkylthioalkyl;
or A is
wherein:
X′ is N or C, and
each R′ and R″ is independently selected from the group consisting of H, alkyl, hydroxyalkyl, alkenyl, alkoxy, halo, oxo, ═S, amino, alkoxyalkyl, alkylthiolkyl, and aryl;
and pharmaceutically acceptable salts thereof.
2. A compound of claim 1 having Formula Ia:
wherein A, B, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 R 8 and R 10 are as given above; and salts thereof.
3. A compound of claim 1 having Formula Ib:
wherein A, B, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 R 8 and R 10 are as given above; and salts thereof.
4. A compound of Formula
wherein:
R is C1-C4 alkylene;
A is selected from the group consisting of:
B is H, halo, loweralkyl, or loweralkenyl; and
R 1 , R 2 , R 3 , R 4 , R 5 , 6 , R 7 and R 8 are each independently selected from the group consisting of H, halo, alkoxy, loweralkyl, and loweralkenyl;
subject to the proviso that at least one of R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is alkoxy;
and subject to the proviso that either (a) R 2 and R 3 together form)—O—CH(R 10 )—O—, or (b) R 5 and R 6 together form —O—CH(R 10 )—O—, wherein R 10 is H, halo, or loweralkyl;
and pharmaceutically acceptable salts thereof.
5. The compound of claim 4 , wherein said compound is N-(2,3-Methylenedioxy-6-methoxy-phenanthr-9-ylmethyl)-(4-hydroxyphenyl)-piperazine (compound 29) or a pharmaceutically acceptable salt thereof.
6. The compound of claim 4 , wherein said compound is N-(2,3-Methylenedioxy-6-methoxy-phenanthr-9-ylmethyl)-L-4-piperidinemethanol (compound 24a) or a pharmaceutically acceptable salt thereof.
7. A compound of Formula I:
wherein:
R is C1-C4 alkylene;
A is —NR 11 R 12 , wherein R 11 is selected from the group consisting of H, alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, and aminoalkyl, and wherein R 12 is selected from the group consisting of alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, amino, aminoalkyl, alkylaminoalkyl, alkylthio, and alkylthioalkyl
B is H, halo, loweralkyl, or loweralkenyl; and
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of H, halo, alkoxy, loweralkyl, and loweralkenyl;
subject to the proviso that at least one of R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is alkoxy;
and subject to the proviso that either (a) R 2 and R 3 together form —O—CH(R 10 )—O—, or (b) R 5 and R 6 together form —O—CH(R 10 )—O—, wherein R 10 is H, halo, or loweralkyl;
or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical formulation comprising a compound of claim 1 in a pharmaceutically acceptable carrier.
9. The pharmaceutical formulation of claim 8 , wherein said carrier is an aqueous carrier.