Patent ID: 6448283
Filing Date: 2002-09-10
Classification: A61K,A61P

Abstract:
A method for preventing hearing loss in a subject, said method comprising:administering to said subject an effective amount of a fused pyrrolocarbazole of Formula I having the formula: or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:ring D is selected from phenyl and cyclohexene with double bond a-b; ring B and ring F are independently selected from: (a) a 6-membered carbocyclic ring in which from 1 to 3 carbon atoms may be replaced by heteroatoms; (b) a 5-membered carbocyclic ring; and (c) a 5-membered carbocyclic ring in which either: (1) one carbon atom is replaced with an oxygen, nitrogen, or sulfur atom; (2) two carbon atoms are replaced with a sulfur and a nitrogen atom, an oxygen and a nitrogen atom, or two nitrogen atoms; or (3) three carbon atoms are replaced with three nitrogen atoms, one oxygen and two nitrogen atoms, or one sulfur and two nitrogen atoms; G-X-W is selected from: (a) (Z1Z2)C-N(R1)-C(Z1Z2); (b) CH(R1)-C(&boxH;O)-N(R1); and (c) N(R1)-C(&boxH;O)-CH(R1); Z1 and Z2, at each occurrence, are independently selected from H, H; H, OR; H, SR; H, N(R)2; and a group wherein Z1 and Z2 together form a moiety selected from &boxH;O, &boxH;S, and &boxH;NR; with the proviso that at least one of the pairs Z1 and Z2 forms &boxH;O; R is independently selected from H, optionally substituted alkyl, OH, alkoxy, OC(&boxH;O)R1a, OC(&boxH;O)NR1cR1d, O(CH2)pNR1cR1d, O(CH2)pOR1b, optionally substituted arylalkyl and optionally substituted heteroarylalkyl; R1 is independently selected from: (a) H, optionally substituted alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl; (b) C(&boxH;O)R1a; (c) OR1b; (d) C(&boxH;O)NHR1b, NR1cR1d, (CH2)pNR1cR1d, (CH2)pOR1b, O(CH2)pOR1b and O(CH2)pNR1cR1d; R1a is independently selected from optionally substituted alkyl, optionally substituted aryl and optionally substituted heteroaryl; R1b is independently selected from H and optionally substituted alkyl; R1c and R1d are each independently selected from H, optionally substituted alkyl and a linking group of the formula (CH2)2â€”X1â€”(CH2)2; X1 is independently selected from O, S and CH2; Q is selected from NR2, O, S, NR22, CHR23, X4CH(R23), CH(R23)X4, wherein X4 is selected from O, S, CH2, NR22 and NR2; R2 is selected from H, SO2R2a, CO2R2a, C(&boxH;O)R2a, C(&boxH;O)NR2CR2d, optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl, wherein said optional substituents are one to about three R5 groups; R2a is independently selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, OR2b, CONH2, NR2cR2d, (CH2)pNR2cR2d and O(CH2)pNR2cR2d; R2b is selected from H and optionally substituted alkyl; R2c and R2d are each independently selected from H and optionally substituted alkyl, or together form a linking group of the formula (CH2)2â€”Xâ€²â€”(CH2)2; R3 and R4 are each independently selected from: (a) H, aryl, heteroaryl, F, Cl, Br, I, CN, CF3, NO2, OH, OR9, O(CH2)pNR11R12, OC(&boxH;O)R9, OC(&boxH;O)NR11R12, O(CH2)pOR11, CH2OR10, NR11R12, NR10S(&boxH;O)2R9 and NR10C(&boxH;O)R9; (b) CH2OR14; (c) NR10C(&boxH;O)NR11R12, CO2R10, C(&boxH;O)R9, C(&boxH;O)NR11R12, CH&boxH;NOR10, CH&boxH;NR10, (CH2)pNR11R12, (CH2)pNHR14 and CH&boxH;NNR11R12; (d) S(O)yR9, (CH2)pS(O)yR9 and CH2S(O)yR14; (e) optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl, wherein said optional substituents are one to about three R5 groups; R9 is selected from alkyl, (CH2)raryl and (CH2)rheteroaryl; R10 is selected from H, alkyl, (CH2)raryl and (CH2)rheteroaryl; R11 and R12 are independently selected from H and optionally substituted alkyl, or together form a linking group of the formula (CH2)2â€”X1â€”(CH2)2; R5 is selected from aryl, heteroaryl, arylalkoxy, heterocycloalkoxy, hydroxyalkoxy, alkyloxy-alkoxy, hydroxyalkylthio, alkoxy-alkylthio, F, Cl, Br, I, CN, NO2, OH, OR9, X2(CH2)pNR11R12, X2(CH2)pC(&boxH;O)NR11R12, X2(CH2)pOC(&boxH;O)NR11R12, X2(CH2)pCO2R9, X2(CH2)pS(O)yR9, X2(CH2)pNR10C(&boxH;O)NR11R12, OC(&boxH;O)R9, OC(&boxH;O)NHR10, O-tetrahydropyranyl, NR11R12, NR10C(&boxH;O)R9, NR10CO2R9, NR10C(&boxH;O)NR11R12, NHC(&boxH;NH)NH2, NR10S(O)2R9, S(O)yR9, CO2R10, C(&boxH;O)NR11R12, C(&boxH;O)R9, CH2OR10, CH&boxH;NNR11R12, CH&boxH;NOR10, CH&boxH;NR9, CH&boxH;NNHCH(N&boxH;NH)NH2, S(&boxH;O)2NR11R12, P(&boxH;O)(OR10)2, OR14, and a monosaccharide wherein each hydroxyl group of the monosaccharide is independently either unsubstituted or is replaced by H, alkyl, alkylcarbonyloxy, or alkoxy; X2 is O, S, or NR10; Y is selected from: (a) a direct bond; (b) optionally substituted CH2, CH2CH2 or CH2CH2CH2, wherein said optional substituents are one to about three R19 groups; and (c) CH&boxH;CH, CH(OH)â€”CH(OH), O, S, S(&boxH;O), S(&boxH;O)2, C(R18)2, C&boxH;C(R19)2, C(&boxH;O), C(&boxH;NOR20), C(OR20)R20, C(&boxH;O)CH(R18), CH(R18)C(&boxH;O), C(&boxH;NOR20)CH(R18), CHR21C(&boxH;NOR20), C(&boxH;O)N(R21), N(R21)C(&boxH;O), CH2Z, ZCH2 and CH2ZCH2, where Z is selected from C(R21)2, O, S, CO2R20, C(&boxH;NOR20) and N(R20); R18 is independently selected from H, SO2R18a, CO2R18a, C(&boxH;O)R18a, C(&boxH;O)NR18cCR18d, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R18a is independently selected from optionally substituted alkyl, optionally substituted aryl, optionally substituted carbocyclyl and optionally substituted heterocyclyl; R18a and R18d are each independently selected from H and optionally substituted alkyl, or together form a linking group of the formula (CH2)2â€”Xâ€²â€”(CH2)2; R19 is independently selected from R20, thioalkyl, halogen, optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl; R20 is independently selected from H, alkyl, OH, alkoxy, OC(&boxH;O)R18a, OC(&boxH;O)NR18cR18d, OC(&boxH;S)NR18cR18d, O(CH2)pNR18cR18d, O(CH2)pOR21, optionally substituted arylalkyl, optionally substituted heterocyclylalkyl and optionally substituted carbocyclyl; R21 is independently selected from H and alkyl; Qâ€² is selected from: (a) a direct bond; (b) NR6; (c) optionally substituted CH2, CH2CH2 or CH2CH2CH2; (d) CR22R24; and (e) CH&boxH;CH, CH(OH)CH(OH), O, S, S(&boxH;O), S(&boxH;O)2, C(&boxH;O), C(&boxH;NOR11), C(OR11)(R12), C(&boxH;O)CH(R13), CH(R13)C(&boxH;O), C(R10)2, C(&boxH;NOR11)CH(R13), CH(R13)C(&boxH;NOR11), CH2Zâ€², Zâ€²â€”CH2 and CH2Zâ€²CH2; Zâ€² is selected from C(R11)(OR12), O, S, C(&boxH;O), C(&boxH;NOR11) and NR11; R6 is selected from H, SO2R2a, CO2R2a, C(&boxH;O)R2a, C(&boxH;O)NR1a, CR1d, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl, wherein said optional substituents are one to about three R5 groups; or alternatively, when Q is NR2 and Qâ€² is NR6 or C(R10)2, R2 and R6 or one of R10 are joined together to form: wherein R7 and R8 are each independently selected from H, OH, alkyl, alkoxy, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, (CH2)pOR10, (CH2)pOC(&boxH;O)NR11R12 and (CH2)pNR11R12; or R7 and R8 together form a linking group of the formula CH2â€”X3â€”CH2; X3 is a bond, O, S, or NR10; J is selected from a bond, O, CH&boxH;CH, S, C(&boxH;O), CH(OR10), N(R10), N(OR10), CH(NR11R12), C(&boxH;O)N(R17), N(R17)C(&boxH;O), N(S(O)yR9), N(S(O)yNR11R12), N(C(&boxH;O)R7), C(R15R16), N+(Oâˆ’)(R10), CH(OH)CH(OH) and CH(O(C&boxH;O)R9)CH(OC(&boxH;O)R9); Jâ€² is selected from O, S, N(R10), N+(Oâˆ’)(R10), N(OR10) and CH2; R13 is selected from alkyl, aryl and arylalkyl; R14 is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; R15 and R16 are independently selected from H, OH, C(&boxH;O)R10, O(C&boxH;O)R9, alkyl-OH, alkoxy and CO2R10; R17 is selected from H, alkyl, aryl and heteroaryl; R22 is X5 and X6 are independently selected from O, N, S, CHR26, C(OH)R26, C(&boxH;O) and CH2&boxH;C; X7 and X8 are independently selected from a bond, O, N, S, CHR26, C(OH)R26, C(&boxH;O) and CH2&boxH;C; X9 and X10 are independently selected from a bond, O, N, S, C(&boxH;O) and CHR26; X11 is a bond or alkylene optionally substituted with NR11R12 or OR30; R23 is selected from H, OR27, SR27, R22 and R28; R24 is selected from R, thioalkyl, and halogen; R25 is selected from R1 and OC(&boxH;O)NR1cR1d; R26 is selected from H, optionally substituted alkyl and optionally substituted alkoxy, wherein (1) ring G contains 0 to about 3 ring heteroatoms; (2) any two adjacent hydroxyl groups of ring G can be joined to form a dioxolane ring; (3) any two adjacent ring carbon atoms of ring G can be joined to form a fused aryl or heteroaryl ring; with the provisos that: (a) when X11 is a bond, ring G can be heteroaryl; and (b) ring G: (i) contains at least one carbon atom that is saturated; (ii) does not contain two adjacent ring O atoms; (iii) contains a maximum of two C(&boxH;O) groups; R27 is selected from H and alkyl; R28 is selected from aryl, arylalkyl, SO2R29, CO2R29, C(&boxH;O)R29, optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl; R29 is selected from alkyl, aryl and heteroaryl; R30 is selected from H, alkyl, acyl and C(&boxH;O)NR11R12; m is independently selected from 0, 1, and 2; p is independently selected from 1, 2, 3, and 4; r is independently selected from 0, 1, and 2; y is independently selected from 0, 1 and 2; and z is selected from 0, 1, 2, 3 and 4; with the provisos that at least one of Y and Qâ€² is a direct bond, when Y is a direct bond, Qâ€² is other than a direct bond, when Qâ€² is a direct bond, Y is other than a direct bond, and when rings B and F are phenyl, G-X-W is CH2NHC(&boxH;O), Y is a direct bond, Q is NR2 and Qâ€² is NR6 where R6 is joined with R2 to form then R3 is other than CH2SCH2CH3.