Tricyclic Compounds Having Cytostatic and/or Cytotoxic Activity and Methods of Use Thereof

The compound according to claim 2, wherein Y═NH;

• R2═H;
• P═NR4;
• R4═H;
• X═NH;
• R1═H;
• Z═S;
• and R3=a phenyl.

A method of inhibiting receptor tyrosine kinase(s), dihydrofolate reductase, thymidylate synthase and/or dihydroorotate dehydrogenase activity in an animal or human in need thereof, comprising administering to said animal or human a therapeutically effective amount in unit dosage form of 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 R1, R2 and R3;
• X and/or Y═NH, O, S, CH2;
• P═(a) NR4, except that R4 is not H, (b) O, or (d) CR4R5 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 R1, R2, and R3;
• wherein R4=lower alkyl, alkene, alkyne, and all of R1 and R2;
• R1=an alkyl having C2 to C6, a cycloalkyl having 6 or less carbons, alkene, alkyne, aryl, heteroaryl, substituted aryl, substituted heteroaryl, alkylaryl, alkylheteroaryl, substituted alkylaryl or alkylheteroaryl, and R1 may be H when said C ring is partially or completely saturated or partially unsaturated;
• and R2═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, NR6, S—CH2, CH2—S, O—CHR6, CHR6—O, NR6—CH2, CH2—NR6, CHR6—NR7 or CR6R7, wherein R6 and/or R7═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 R3 may be directly attached to the C-ring at positions 5, 6, 7, and/or 8;
• R3═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.

A method of inhibiting receptor tyrosine kinase(s), dihydrofolate reductase, thymidylate synthase and/or dihydroorotate dehydrogenase activity in an animal or human in need thereof, comprising administering to said animal or human a therapeutically effective amount in unit dosage form of a compound of formula II:

• 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 R1, R2 and R3;
• X and/or Y═N, NH, O, S, CH2;
• P═(a) NR4, except that when P═NH and X is NH then R1 is not a phenyl moiety or a phenyl moiety having a halogen substitution, (b) O, except that when P═O and X is NH then R1 is not a phenyl moiety or a phenyl moiety having a halogen substitution, (c) S, except that when P═S and X is NH then R1 is not a phenyl moiety or a phenyl moiety having a halogen substitution, or (d) CR4R5 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 R1, R2, and R3;
• wherein R4=lower alkyl, alkene, alkyne, and all of R1 and R2;
• R1 is H, alkyl, a cycloalkyl having 6 or less carbons, alkene, alkyne, aryl, heteroaryl, substituted aryl, substituted heteroaryl, alkylaryl, alkylheteroaryl, substituted alkylaryl or alkylheteroaryl and R2 is H, 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, NR6, S—CH2, CH2—S, O—CHR6, CHR6—O, NR6—CH2, CH2—NR6, CHR6—NR7 or CR6R7, wherein R6 and/or R7═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 R3 may be directly attached to the C-ring at positions 5, 6, 7, and/or 8;
• R3═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.

A method of inhibiting receptor tyrosine kinase(s), dihydrofolate reductase, thymidylate synthase and/or dihydroorotate dehydrogenase activity in an animal or human in need thereof, comprising administering to said animal or human a therapeutically effective amount in unit dosage form of 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;
• and the C ring has an N or substituted N depending on the saturation level of the C ring, and the substitution may be all of R1, R2 and R3;
• X and Y═NH;
• P═NH;
• R1═H;
• and R2═H;
• Z═S;
• 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 when the C-ring is saturated or partially saturated the Z or R3 creates chirality, then all stereoisomers thereof both separately and as racemic and/or diastereoisomeric mixtures are included;
• R3=aryl, alkylaryl, and substituted saturated or unsaturated alkylaryl wherein said substitution may be at either the alkyl or the aryl portion of the alkylaryl group and may be one or more substituents independently selected from (i) an alkoxy group, (ii) halogen atoms including chlorine, bromine, iodine, and fluorine, (iii) alkyl groups including straight or branched chains having from one to six carbon atoms, (iv) an aryl group, (v) a heteroaryl group having at least one atom in the aryl ring that is not carbon selected from oxygen, nitrogen or sulfur, and (vi) a carboxylic acid having up to seven carbon atoms.