Patent EA-005273-B1 (EA)
Title: Cyclic substituted fused pyrrolocarbazoles and isoindolones
Inventor: HUDKINS ROBERT L
IPC: A61P/
Filed: 2000-02-11
Abstract: 1. A compound having the Formula I wherein: ring B and ring F each together with the carbon atoms to which they are attached, are phenyl; R<1>, R<4> and R<6> are H; R<2> is selected from the group consisting of H, alkyl having from 1 to 4 carbons, -OH and -O(CH2)pOR<10>; R<3> is selected from the group consisting of: H, F, Cl, Br, I; -OR<9>, wherein R<9> is alkyl having from 1 to 8 carbons; -CH2OR<10>; -C(=O)R<2>, wherein R<2> is -O(CH2)pOR<10>, wherein R<10> is selected from the group consisting of H and alkyl having from 1 to 4 carbons and p is from 1 to 4; alkyl having from 1 to 8 carbons substituted with C1-C8alkyloxyC1-C8alkoxy group; R<5> is H or -OR<9>; R<7> is wherein: m is 0-4; G is a bond; or alkylene having 1 to 4 carbons, wherein the alkylene group is substituted with OH; R<8> is selected from the group consisting of H; phenyl substituted with halogen; -O(C=O)NR<11>R<12>; -CN; acyloxy, wherein acyl is a straight-chain or branched alkanoyl group having 1 to 6 carbon atoms; C2-C8alkenyl; -O-CH2-O-(CH2)2-O-CH3; halogen; -OR<10>, wherein R<10> is selected from the group consisting of H and alkyl having from 1 to 4 carbons; thienyl; alkyl having from 1 to 4 carbon atoms substituted with 2 hydroxy groups; R<11> and R<12> are each independently selected from the group consisting of H and alkyl having from 1 to 4 carbons; A is selected from the group consisting of O, CHR<17>, and C(=O), B is selected from the group consisting of O, NR<17>, S, CHR<17>, C(OH)R<17>, and C(=O), or A and B together can form -CH=CH-; C is selected from the group consisting of a bond, O, NR<17>, S, CHR<17>, C(=O), and CH2=C-; D is selected from the group consisting of a bond, O, CHR<17>, and C(OH)R<17>; E is selected from the group consisting of a bond, N, and CH(R<17>); F is selected from the group consisting of a bond, N, S, and CH(R<17>); R<17> is selected from the group consisting of H, optionally substituted with N-morpholinomethyl or hydroxy group C1-C8alkyl; C(=O)-CH3, C1-C8alkoxycarbonyl, and C1-C8alkoxy; wherein: 1) ring J contains 0 to 2 ring heteroatoms; 2) any two adjacent hydroxyl groups of ring J can be joined in a dioxolane ring; 3) any two adjacent ring carbon atoms of ring J can be joined to form a fused phenyl ring; 4) any two adjacent ring nitrogen atoms of ring J can be joined to form a fused heterocyclic ring which can be substituted with 1 to 2 C1-C4alkyl or phenyl groups; provided that: 1) one of A, B, C, D, E, or F contains at least one carbon atom that is saturated; 2) ring J does not contain two adjacent ring O atoms; 3) ring J contains a maximum of two ring C(=O) groups; Q is selected from the group consisting of NR<13>, and NR<7A> wherein R<7A> is the same as R<7>; W is selected from the group consisting of CR<18>R<7> and CHR<2>, wherein R<2> is H; or a straight-chain, cyclic, or branched alkyl having 1 to 4 carbon atoms; R<13> is selected from the group consisting of H, -C(=O)NR<11>R<12>, alkyl of 1-8 carbons; R<18> is H or C1-C4alkyl; A1A2 and B1B2 are H;H and =O; with the proviso that at least one of the pairs A1 and A2, or B1 and B2, form =O; with the proviso that when Q is NH or NR<7A>, and in any R<7> or R<7A> group m is 0 and G is a bond, R<8> is H, and R<7> or R<7A> contains one ring hetero oxygen atom at position A in a 5-or 6-membered ring, then B cannot be CHR<17> where R<17> is substituted or unsubstituted C1-C8alkyl; and with the further proviso that the compound of Formula I contains one R<7> or R<7A> group or both an R<7> and R<7A> group. 2. The compound of claim 1 wherein: A is selected from the group consisting of O, CHR<17>, and C(=O); B is selected from the group consisting of O, NR<17>, S, CHR<17>, C(OH)R<17>and C(=O); R<17> is selected from the group consisting of H, optionally substituted with N-morpholinomethyl or hydroxyl group C1-C8alkyl, and C1-C4alkoxy; wherein: 1) ring J contains 0 to 2 ring heteroatoms; 2) any two adjacent hydroxyl groups of ring J can be joined in a dioxolane ring; 3) any two adjacent ring carbon atoms of ring J can be joined to form a fused phenyl ring; provided that: 1) one of A, B, C, D, E, or F contains at least one carbon atom that is saturated; 2) ring J does not contain two adjacent ring O atoms; 3) ring J contains a maximum of two ring C(=O) groups; and R<8> is selected from the group consisting of H; -O(C=O)NR<11>R<12>; acyloxy, wherein acyl is a straight-chain or branched alkanoyl group having 1 to 6 carbon atoms; C2-C8alkenyl; -O-CH2-O-(CH2)2-O-CH3; halogen; phenyl substituted with halogen; -OR<10>; thienyl; alkyl having from 1 to 4 carbon atoms substituted with 2 hydroxyl groups. 3. The compound of claim 2 wherein A1, A2 or is H, H and B1,B2 is =O. 4. The compound of claim 2 wherein Q is NR<13>. 5. The compound of claim 4 wherein Q is NR<7A>. 6. The compound of claim 2 wherein W is CR<18>R<7>. 7. The compound of claim 2 wherein R<7> is a 3-, 4-, 5-or 6-membered carbocyclic ring, or a 5- or 6-membered heterocyclic ring which contains one or two ring O, N, or S atoms. 8. The compound of claim 7 wherein R<7> is a heterocyclic ring having one ring O, N, or S hetero atom. 9. The compound of claim 2 wherein G is a bond or CH2. 10. The compound of claim 2 wherein R<8> is H, OH, halogen, ethenyl, acyloxy, wherein acyl is alkanoyl having 1 to 6 carbon atoms, C1-C4alkoxy, phenyl substituted with halogen, thienyl, or hydroxyC1-C4alkyl. 11. The compound of claim 10 wherein G is a bond or CH2. 12. The compound of claim 2 wherein W is CH2 or CR<18>R<7>. 13. The compound of claim 2 wherein one of A1,A2 or B1,B2 is H, H and the other is =O; R<3> is selected from the group consisting of H, C1-C8alkoxy, F, Cl, Br, I, C1-C4alkoxymethyl, C1-C4alkoxy-C1-C4alkoxymethyl and C1-C4alkoxy C1-C4alkoxycarbonyl; R<5> is H or C1-C4alkoxy, G is a bond or CH2, W is CH2 or CR<18>R<7>; R<8> is selected from the group consisting of H, OH, halogen, ethenyl, acyloxy, wherein acyl is alkanoyl having 1 to 6 carbon atoms, C1-C4alkoxy, phenyl substituted with halogen, thienyl, or hydroxyC1-C4alkyl; and Q is NR<13> or NR<7A>. 14. The compound of claim 2 wherein Q is NR<13>, where R<13> is H, G is a bond; W is CR<18>R<7> where R<18> is H or lower alkyl; and R<3> is selected from the group consisting of H, C1-C4alkoxy, and C1-C4alkoxyC1-C4alkoxycarbonyl, and R<5> is H or C1-C4alkoxy. 15. The compound of claim 14 wherein R<7> is a heterocyclic ring having one ring O, N, or S heteroatom. 16. The compound of claim 1 wherein the constituent variables of the compounds of Formula I are selected in accordance with the following Table: A1A2 B1B2 R3 R5 R18 m R8 A B C D E F H2 O H H H 0 OH CH2 CH2 N(Bn) Bond CH2 CH2 H2 O H H H 0 OH CH2 CH2 O Bond CH2 CH2 H2 O H H H 1 H O CH2 CH2 CH2 Bond Bond H2 O H H H 0 H O C(=O) CH2 CH2 CH2 Bond H2 O H H H 0 H O C(=O) CH2 CH2 Bond Bond H2 O H H H 0 H O CH2 CH2 CH2 Bond Bond H2 O H H H 0 (n)-F-phenyl O CH2 CH2 CH2 Bond Bond H2 O H H H 0 2-thienyl O CH2 CH2 CH2 Bond Bond H2 O H H H 0 OH CH2 CH2 N(Me) Bond CH2 CH2 H2 O H H H 0 H CH2 S CH2 CH(OH) Bond Bond H2 O H H H 1 H O CH2 CH2 CH2 CH2 Bond H2 O H H H 0 H O CH2 CH2 CH2 CH2 Bond H2 O H H H 0 OH CH2 CH2 S Bond CH2 CH2 H2 O H H H 0 OH CH2 1,6-benzofused Bond CH2 CH2 H2 O H H H 0 OH CH2 N(Et) CH2 Bond CH2 CH2 H2 O H H H 0 OH CH(CH2-N((CH2)2)2 CH2 Bond Bond CH2 CH2 H2 O H H H 0 OH CH2 CH2 CH2 Bond Bond Bond H2 O H H H 3 Cl O CH2 CH2 CH2 Bond Bond H2 O H H H 1 O(C=O)-t-Bu O CH2 CH2 CH2 Bond Bond H2 O H H H 1 OH O CH2 CH2 CH2 Bond Bond H2 O H H H 1 O(C=O)CH3 O CH2 CH2 CH2 Bond Bond H2 O H H H 0 H O CH(OH) CH2 CH2 Bond Bond H2 O H H H 0 OH CH2 CH2 N[(C=O)CH3]) Bond CH2 CH2 H2 O H H H 1 H O CH2 -C(=CH2)- CH2 Bond Bond H2 O H H H 1 H O CH2 -C[(OH)(CH2OH)]- CH2 Bond Bond H2 O H H H 1 H O CH2 -C(=O)- CH2 Bond Bond H2 O H H H 0 -CH=CH2 O CH2 CH2 CH2 Bond Bond H2 O H H H 0 -CH(OH)CH2-OH O CH2 CH2 CH2 Bond Bond H2 O H H H 1 H O CH2 CH2 CH2 Bond Bond H2 O H H H 1 H O CH2 CH2 CH2 Bond Bond H2 O H H H 1 -OCH2OCH2-CH2OCH3 O -C(=O) CH2 CH2 Bond Bond H2 O H H Et 1 -0(C=O)CH2-tBu O CH2 CH2 CH2 Bond Bond H2 O H H H 1 OH O -C(=O)- CH2 CH2 Bond Bond H2 O H H Et 1 OH O CH2 CH2 CH2 Bond Bond H2 O H H H 1 OH O CH2 CH2 CH2 Bond Bond H2 O H H H 1 OH O CH2 CH2 CH2 Bond Bond O H2 H H H 1 H O CH2 CH2 CH2 Bond Bond H2 O H H H 0 H O CH(OH) CH2 CH2 Bond Bond H2 O H H H 0 H O CH(Oet CH2 CH2 Bond Bond H2 O H H H 0 H O CH(Oet) CH2 CH2 Bond Bond H2 O H H H 0 OH O CH2 CH2 CH2 Bond Bond H2 O H H H 0 H O CH2 CH2 CH(OH) Bond Bond H2 O H H H 1 Cl O CH2 CH2 CH2 Bond Bond H2 O H H H 0 H O 1,6-{2,4-(OMe)2]-benzofused CH2 Bond Bond H2 O H H H 0 H O 1,6-[2,4-(OMe)2])-benzofused CH2 Bond Bond H2 O H H Et 0 H O 1,6-[2,4-(OMe)2])-benzofused CH2 Bond Bond H2 O H H H 0 OH C(=O) O CH2 -C[(CH3)2]- Bond Bond H2 O H H H 0 OH O -CH[O(CMe2)O]CH-   Bond  H2 O H H H 0 OH CH2 CH2 CH2 CH2 CH2 Bond H2 O H H H 1 H O CH(OEt) CH2 O CH2 Bond H2 O H H H 1 H O CH(OEt) CH2 O Bond Bond H2 O H H H 1 H O CH(OEt) CH2 O Bond Bond H2 O 3-C(=O)O-CH2CH2-OCH3 H H 0 H O CH(OOCH2-CH2OCH3) CH2 CH2 Bond Bond H2 O H 10-O-Me H 1 OH O CH2 CH2 CH2 Bond Bond H2 O H 10-O-Me H 1 OH O CH(OEt) CH2 CH2 Bond Bond H2 O H H H 0 H CH(COOEt) C(=O) CH2 CH2 Bond Bond H2 O H H H 0 H CH(COOEt) C(=O) CH2 CH2 Bond Bond H2 O H H H 0 H CH2 CH2 CH2 CH2 Bond Bond H2 O H H H 0 H C(=O) O CH2 CH2 Bond Bond H2 O H H H 1 OC(=O)NHEt O CH2 CH2 CH2 Bond Bond H2 O H H H 1 OH O CH2 CH2 CH2 Bond Bond 17. The compound of claim 2 wherein Q is NR<7A>; R<5> and R<8> are H; W is CH2; m is O; G is a bond or CH2; and R<3> is independently selected from the group consisting of H, F, Cl, Br, I, C1-C4alkoxymethyl, and C1-C4 alkoxyC1-C4alkoxycarbonyl. 18. The compound of claim 17 wherein R<7A> is a 3-, 4-, 5-or 6-membered carbocyclic ring, or a 5-or 6-membered heterocyclic ring which contains one or two ring O, N, or S atoms. 19. The compound of claim 17 wherein R<7A> is a 3-, 4, 5-or 6-membered heterocyclic ring which contains one ring O atom. 20. The compound of claim 1 wherein the constituent variables of the compounds of Formula I are se