Cyclic indole and heteroindole derivatives and methods for making and using as pharmaceuticals
The invention relates to novel, substituted, fused indole and heteroindole derivatives of the general formula I their tautomers, stereoisomers, mixtures and pharmaceutically acceptable salts, their synthesis and their use as pharmaceuticals, especially as anti-tumor agents, for mammals, especially for man.
1 - 7 . (canceled)
8 . Compounds of the general formula
in which
R1 represents hydrogen, unsubstituted or fully or partly substituted, identically or differently, (C6-C14)-aryl, unsubstituted or fully or partly substituted, identically or differently, (C1-C13)-heteroaryl, having at least one to four N, NH, O and/or S as ring elements, unsubstituted or fully or partly substituted, identically or differently, (C3-C8)-cycloalkyl, or unsubstituted or fully or partly substituted, identically or differently (C1-C20)-alkyl,
A, B, C, or D, independently of one another, represents a carbon atom substituted with R2-R5,
R2, R3, R4 and R5, independently of one another represent hydrogen, halogen, cyano, nitro, hydroxy, linear or branched (C1-C6)-alkyl, linear or branched (C1-C6)-alkyl, substituted with one or more halogen atoms, linear or branched (C1-C6)-alkoxy, substituted with one or more halogen atoms, linear or branched (C1-C6)-alkoxy, linear or branched (C1-C6)-alkylenedioxy, (C1-C6)-alkylcarbonyloxy, (C1-C6)-alkoxycarbonyloxy, (C1-C6)-alkylthio, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, carboxy, carboxy (C1-C6)-alkylester, carboxamide, N-(C1-C6)-alkylcarboxamide, N,N-di-(C1-C6)-alkylcarboxamide, (C1-C6)-alkoxy-(C1-C6)-alkyl, amino, mono-(C1-C6)-alkylamino, di-(C1-C6)-alkylamino, the two (C1-C6) groups together being able to form a ring, which optionally has one or more NH, N-(C1-C6)-alkyl, O or S, (C6-C14)-aryl, (C6-C14)-aryloxy, (C6-C 14)-aryl-(C1-C6)-alkyl, (C6-C14)-aryl-(C1-C6)-alkoxy-(C1-C6)-alkyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, hydroxy, in which two directly adjacent groups can be linked to one another;
R6 represents unsubstituted or fully or partly substituted, identically or differently, (C6-C14)-aryl, unsubstituted or fully or partly substituted, identically or differently, (C1-C13)-heteroaryl, having at least one to four N, NH, O and/or S as ring elements, unsubstituted or fully or partly substituted, identically or differently, (C3-C8)-cycloaklyl, unsubstituted or fully or partly substituted, identically or differently, linear or branched (C1-C20)-alkyl, the identical or different substituents being selected from the group comprising hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, (C1-C6)-alkyl, (C1-C6)-alkoxy, carboxy, (C1-C6)-alkyl, substituted, identically or differently, with one or more halogen atoms, (C1-C6)-alkoxy, substituted identically or differently with one or more halogen atoms, linear or branched (C2-C6)-alkenyl, linear or branched (C2-C6)-alkinyl, (C3-C8)-cycloalkyl, linear or branched (C1-C6)-alkoxy, linear or branched (C1-C6)-alkylenedioxy, (C1-C6)-alkoxy-(C1-C6)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C6)-alkyl, (C6-C14)-aryl-(C1-C4)-alkoxy-(C1-C6)-alkyl;
X represents carbonyl-(C═O);
n is 0,
Z represents a carbon atom (C—R8), substituted with the R8 group wherein
R8 represents unsubstituted or fully or partly substituted, identically or differently, (C6-C14)-aryl, unsubstituted or fully or partly substituted, identically or differently (C1-C13)-heteroaryl, which has at least one to four N, NH, O and/or S as ring elements, unsubstituted or fully or partly substituted, identically or differently, (C3-C8)-cycloalkyl, unsubstituted or fully or partly substituted, identically or differently, linear or branched, (C1-C20)-alkyl, the identical or different substituents being selected from the group comprising hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, (C1-C6)-alkyl, (C1-C6)-alkoxy, carboxy, (C1-C6)-alkyl, which is substituted identically or differently by one or more halogen atoms, (C1-C6)-alkoxy, which is substituted identically or differently by one or more halogen atoms, linear or branched (C2-C6)-alkenyl, linear or branched (C2-C6)-alkinyl, (C3-C8)-cycloalkyl, linear or branched (C1-C6)-alkoxy, linear or branched (C1-C6)-alkylenedioxy, linear or branched (C1-C6)-alkylthio, (C1-C4)-alkylsulfinyl, (C1-C4)-alkylsulfonyl, (C6-C14)-arylthio, (C6-C14)-arylsulfinyl, (C6-C14)-arylsulfonyl, (C1-C6)-alkoxy-(C1-C6)-alkyl, linear or branched mono-(C1-C6)-alkylamino, linear or branched di-(C1-C6)-alkylamino, wherein the two (C1-C4) groups together can form a ring, which optionally has one or more NH, N-(C1-C6)-alkyl, O or S, (C6-C14)-aryl, (C6-C14)-aryloxy, (C6-C14)-aryl-(C1-C6)-alkyl, (C6-C14)-aryl-(C1-C4)-alkoxy-(C1-C6)-alkyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, linear or branched mono-N-(C1-C6)-alkylcarbonylamino, linear or branched di-N,N(C1-C6)-alkylcarbonylamino, linear or branched di-N,N-(C1-C6)-alkoxycarbonylamino, linear or branched mono-N-(C1-C6)-alkoxycarbonylamino, linear or branched N-(C1-C6)-alkylcarbonylamino-N-(C1-C6)-alkylamino, linear or branched N-(C1-C6)-alkoxycarbonylamino-N-(C1-C6)-alkylamino, their tautomers, stereo isomers, mixtures and pharmaceutically tolerated salts.
9 . The compound of claim 1 , wherein R1 represents hydrogen, R2, R3, R4 and R5 independently of one another represent hydrogen, halogen or (C1-C6)-alkoxy, R6 represents unsubstituted or fully or partly substituted, identically or differently, linear or branched (C—C20)-alkyl or unsubstituted or fully or partly substituted, identically or differently, or (C6-C14)-aryl, which is substituted with (C1-C6)-alkoxy and halogen.
10 . The compound of claim 1 , wherein R1 represents hydrogen, R2, R3, R4 and R5 independently of one another represent hydrogen, halogen or (C1-C6)-alkoxy, R6 represents unsubstituted or fully or partly substituted, identically or differently, linear or branched (C1-C20)-alkyl or unsubstituted or fully or partly substituted, identically or differently, (C6-C14)-aryl, which is substituted with (C1-C6)-alkoxy and halogen, and Z represents the C—R8 group, in which R8 represents unsubstituted or fully or partly substituted, identically or differently, (C6-C14)-aryl substituted with (C1-C6)-alkoxy and halogen.
11 . The compound of claim 1 for use as a pharmaceutical.
12 . A method for controlling a tumor disease in a mammal, comprising administering a compound of claim 1 to a mammal in need thereof.
13 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
14 . A method for the synthesis for compounds of the general formula I
wherein A, B, C, D, R1, R2, R3, R4, R5, R6, X, Y, Z and n have the meaning in claim 1 , characterized by the reaction of the ketone of the general formula
wherein A, B, C, D, R1, R2, R3, R4, R5 and R6 have the meanings given above and R9 represents hydrogen or a suitable leaving group,
with a phenylacetic acid derivative X1-C0-CH2—R8, wherein X1 represents a suitable leaving group and R8 has the meaning given above, and subsequent ring closure in the presence of a base.
15 . The method of claim 14 , wherein R9 is selected from the group consisting of unsubstituted or fully or partly substituted, identically or differently, linear or branched (C1-C6)-alkylcarbonyl, linear or branched (C1-C6)-alkoxycarbonyl, substituted (C6-C 14)-aryl-(C1)-alkyl, linear or branched (C1-C6)-alkylsulfonyl and (C6-C14)-arylsulfonyl, which is unsubstituted or fully substituted with (C1-C6)-alkyl.
16 . The method of claim 14 , wherein X1 is halogen or (C1-C6)-alkoxy.