Tricyclic compounds having cytostatic and/or cytotoxic activity and methods of use thereof
The present invention provides tricyclic compounds having cytostatic and cytotoxic activity in a single molecule having receptor tyrosine kinase(s), dihydrofolate reductase, thymidylate synthase and/or dihydroorotate dehydrogenase inhibitory activity, which are useful as anti-angiogenic and anti-tumor agents. Also provided are methods of utilizing these inhibitors to treat tumor cells and other proliferative diseases and disorders.
1. A compound of formula I:
wherein both B and C rings may be completely or partially saturated or unsaturated with respect to bond 4b-8a, 5-6 and 7-8; the C ring may have an N or substituted N depending on the saturation level of the C ring, and the substitution may be all of R 1 , R 2 and R 3 ;
X and/or Y═NH, O, S, CH 2 ; P=(a) NR 4 except that R 4 is not H, (b) O, or (c) CR 4 R 5 when the C ring has an N or a substituted N depending on the saturation level of the C ring and the substitution may be all of R 1 , R 2 , and R 3 ; wherein R 4 and R 5 =lower alkyl, alkene, alkyne, and all of R 1 and R 2 ;
R 1 =an alkyl having C 2 to C 6 , a cycloalkyl having 6 or less carbons, alkene, alkyne, aryl, heteroaryl, substituted aryl, substituted heteroaryl, alkylaryl, alkylheteroaryl, substituted alkylaryl or alkylheteroaryl, and R 1 may be H when said C ring is partially or completely saturated or partially unsaturated; and R 2 ═H, an alkyl, a cycloalkyl having 6 or less carbons, alkene, alkyne, aryl, heteroaryl, substituted aryl, substituted heteroaryl, alkylaryl, alkylheteroaryl, substituted alkylaryl or alkylheteroaryl;
Z═S, O, NR 6 , S—CH 2 , CH 2 —S, O—CHR 6 , CHR 6 —O, NR 6 —CH 2 , CH 2 —NR 6 , CHR 6 —NR 7 or CR 6 R 7 , wherein R 6 and/or R 7 ═H or a lower alkyl, alkene or alkyne having 6 or less C atoms;
wherein Z may be attached to the C ring at positions 5, 6, 7 or 8 and may be attached to more than one of said positions 5, 6, 7, or 8 on the ring wherein Z may be the same or different;
wherein Z may be zero and R 3 may be directly attached to the C-ring at positions 5, 6, 7, and/or 8;
wherein when the C-ring is saturated or partially saturated the substituted Z or R 3 creates chirality when P═C and R 6 and R 7 are different, then all stereoisomers thereof both separately and as racemic and/or diastereoisomeric mixtures are included;
R 3 ═H, alkyl, cycloalkyl, aryl, heteroaryl, substituted aryl, substituted heteroaryl, alkylaryl, alkylheteroaryl and substituted saturated or unsaturated alkylheteroaryl and alkylheterocyclic, alkylaryl, p-, m-, o-benzoyl-L-glutamate or 2,5-, 2,4-thienoyl-L-glutamate when the benzene and thiophene ring may or may not have additional substitutions including F, mono-, bi- and tricyclic aryl, heteroaryl or combinations thereof, ring substitutions including biphenyl, bipyridyl or a phenyl-pyridyl or a fused moiety including a quinoline or naphthyl including substituted systems including a 2-chloro,4-biphenyl and tricyclic and substituted tricyclic systems.
2. The compound according to claim 1 , wherein Y═NH; R 2 ═H; P═NR 4 ; R 4 =an alkyl having from 2 to 6 carbon atoms; X═NH; R 1 ═H; Z═S and R 3 =a phenyl.
3. The compound according to claim 1 , wherein Y═NH; R 2 ═H; P═NR 4 ; R 4 =an alkyl having from 2 to 6 carbon atoms; X═NH; R 1 ═H; Z═S; and R 3 =a phenyl having a methyl substitution.
4. The compound according to claim 3 , wherein the substitution on the phenyl is at the 4 position of the phenyl ring.