Patent EA-001055-B1 (EA)
Title: Indolylpyrrolydenemethylpyrrole derivatives, process for their preparation, pharmaceutical composition,nd combined preparation based thereon, method of treating using same and intermediate product for preparing same
Inventor: D ALESSIO ROBERTO
IPC: A61K31/404
Filed: 1998-02-27
Abstract: 1. A compound which is a (1H-indol-2-yl)-5[(2H-pyrrol-2-ylidene)methyl]-1H-pyrrole derivative of formula (I)   wherein each of  R1, R2, R3 and R4, which are the same or different, independently represents hydrogen, C1-C6 alkyl, halogen, cyano, nitro, hydroxy, C1-C6 alkoxy unsubstituted or substituted by phenyl, C1-C6 alkyl-carbonyloxy, -NRaRb in which each of Ra and Rb independently is hydrogen or C1-C6 alkyl, C1-C6 alkyl-carbonylamino, carboxy, (C1-C6 alkoxy)carbonyl, aralkyl-carbamoyl, arylcarbamoyl or -CONRcRd in which each of Rc and Rd independently is hydrogen or C1-C6 alkyl, or Rc and Rd, taken together with the nitrogen atom to which they are linked, form a morpholino or piperidino ring; R5 represents halogen, hydroxy or C1-C11 alkoxy unsubstituted or substituted by phenyl; and R6 represents hydrogen, C2-C20 alkanoyl, C3-C20 alkenoyl, phenyl, C1-C20 alkyl or C2-C20 alkenyl, wherein the alkanoyl, alkenoyl, alkyl and alkenyl groups are each unsubstituted or substituted by 1 to 3 substituents chosen independently from halogen, C1-C6 alkoxy, hydroxy, aryl, aryloxy, cyano, carboxy, (C1-C6 alkoxy)carbonyl, (C3-C4 alkenyl)carbamoyl, aralkylcarbamoyl, arylcarbamoyl and -CONRcRd wherein Rc and Rd are as defined above; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, wherein each of R1, R2, R3 and R4 independently represents hydrogen, C1-C4 alkyl, halogen, cyano, nitro, hydroxy, C1-C4 alkoxy unsubstituted or substituted by phenyl, amino, carboxy, (C1-C4 alkoxy)carbonyl or -CONRcRd in which each of Rc and Rd independently is hydrogen or C1-C4 alkyl or Rc and Rd, taken together with the nitrogen atom to which they are linked, form a morpholino or piperidino ring; R5 represents hydroxy or C1-C11 alkoxy unsubstituted or substituted by phenyl; and R6 represents hydrogen, C1-C14 alkyl or C3-C14 alkenyl, wherein the alkyl and alkenyl groups are unsubstituted or substituted by a substituent chosen from halogen, C1-C4 alkoxy, hydroxy, aryl, aryloxy, cyano, carboxy, (C1-C4 alkoxy)carbonyl, aralkylcarbamoyl, arylcarbamoyl and -CONRcRd in which each of Rc and Rd independently is hydrogen or C1-C4 alkyl, or Rc and Rd, taken together with the nitrogen atom to which they are linked, form a morpholino or piperidino ring. 3. A compound selected from: 2-(1H-indol-2-yl)-4-methoxy-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole 2-(1H-indol-2-yl)-4-methoxy-5-[(5-methyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(1H-indol-2-yl)-4-benzyloxy-5-[(5-methyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(1H-indol-2-yl)-4-methoxy-5-[(5-pentyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(1H-indol-2-yl)-4-benzyloxy-5-[(5-pentyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(1H-indol-2-yl)-4-methoxy-5-[(5-ethyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(1H-indol-2-yl)-4-methoxy-5-[(5-propyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(1H-indol-2-yl)-4-methoxy-5-[(5-isopropyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(1H-indol-2-yl)-4-methoxy-5-[(5-butyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(1H-indol-2-yl)-4-benzyloxy-5-((5-ethyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(1H-indol-2-yl)-4-benzyloxy-5-[(5-propyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(1H-indol-2-yl)-4-benzyloxy-5-[(5-isopropyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(1H-indol-2-yl)-4-benzyloxy-5-[(5-butyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(5-methoxy-1H-indol-2-yl)-4-methoxy-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(5-methoxy-1H-indol-2-yl)-4-benzyloxy-5-[(5-methyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(5-chloro-1H-indol-2-yl)-4-methoxy-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(5-chloro-1H-indol-2-yl)-4-benzyloxy-5-[(5-methyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(5-cyano-1H-indol-2-yl)-4-methoxy-5-[(5-undecyl-2H-pyrrole-2-yledine)methyl]-1H-pyrrol; 2-(5-cyano-1H-indol-2-yl)-4-benzyloxy-5-[(5-methyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(5-hydroxy-1H-indol-2-yl)-4-methoxy-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(5-hydroxy-1H-indol-2-yl)-4-benzyloxy-5-[(5-methyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(5-amino-1H-indol-2-yl)-4-methoxy-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(5-amino-1H-indol-2-yl)-4-benzyloxy-5-[(5-methyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(5-methyl-1H-indol-2-yl)-4-methoxy-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(5-benzyloxy-1H-indol-2-yl)-4-methoxy-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(5-fluoro-1H-indol-2-yl)-4-methoxy-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(5-carboxy-1H-indol-2-yl)-4-methoxy-5-(5-undecyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(5-carbamoyl-1H-indol-2-yl)-4-methoxy-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(6-carboxy-1H-indol-2-yl)-4-methoxy-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl)]-1H-pyrrole; 2-(6-carbamoyl-1H-indol-2-yl)-4-methoxy-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(6-nitro-1H-indol-2-yl)-4-methoxy-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; 2-(7-ethyl-1H-indol-2-yl)-4-methoxy-5-[(5-undecyl-2H-pyrrol-2-ylidene)methyl]-1H-pyrrole; and the C1-C6 alkyl esters and pharmaceutically acceptable salts thereof. 4. A compound according to claim 3 in the form of a hydrochloride, hydrobromide or methanesulfonate salt. 5. A compound of formula (I), as claimed in claim 1, for use as an immunomodulating agent or in the treatment of adult-T-cell leukemia-lymphoma. 6. A pharmaceutical composition of formula (I) comprising a pharmaceutically acceptable carrier and/or diluent and, as an active principle, at least one compound in an effective amount (I) as defined in claim 1. 7. A composition as defined in claim 5, wherein containing a compound of formula (I) as defined in claim 1 and an additional drug as a combined preparation for simultaneous, separate or sequential use in immunosuppressive therapy in mammals. 8. A pharmaceutical composition as claimed in claim 7, wherein the additional drug is an immunosuppressive agent in an amount to produce superadditive immunosuppressant effect. 9. A composition as claimed in claim 8, wherein the immunosuppressive agent is selected from the group consisting of cyclosporin A or cyclosporin C -non-polar cyclic oligopeptide; FD506 -a fungal macrolide immunosuppressive, azathioprine or 6-[(1-methyl-4-nitro-1H imidazole -5-yl) thio]-1H-purine, methotrexate, rapamycin - a fungal macrolide immunosuppressive; mycophenolate mofetil or 6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-met hyl-4-(E)-hexenoic acid 2-(4-morpholinyl)-ethyl ester, an immunosuppressive glucocorticoid, such as prednisone or dexamethasone; and/or polyclonal antibody, such as an anti-human thymocite antibody or a monoclonal antibody, such as an anti-human CD3 antiboby; or a mixture of two or more thereof. 10. A combination preparation comprising (a) at least one compound of formula (I), as defined in claim 1 or a pharmaceutically acceptable salt thereof for simultaneous, separate or sequential use. 11. A combination preparation to claim 10, comprising a compound of formula I, as defined in claim 1 and an immunosuppressant in a quantity effective to produce a superadditive immunosuppressive effect for use in a method for lowering the side effects cause by immunosuppressant therapy in a mammal, including a human, in need thereof. 12. A combination preparation to claim 10, comprising a compound of formula 1, as defined in claim 1 and an anti-tumor agent in treating adult-T-cell leukemia-lymphoma therapy. 13. A method of treating a mammal, including a human, in need of ammunomodulating agent, wherein the method comprises administering to said mammal an effective amount of a compound of formula I as defined in claim 1. 14. The method to claim 13, wherein the method comprising administering said mammal an additional immunosuppressive agent for simultaneous, separate or sequential use in amounts effective to produce superadditive immunosuppressant effect. 15. The method to claim 14, wherein wherein the immunosuppressive agent (a) is selected from the group consisting of cyclosporin A or cyclosporin C-non-polar cyclic oligopeptide; FD506 -a fungal macrolide immunosuppressive, azathioprine or 6-[(1-methyl-4-nitro-1H imidazole -5-yl) thio]-1H-purine, methotrexate, rapamycin - a fungal macrolide immunosuppressive; mycophenolate mofetil or 6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-met hyl-4-(E)-hexenoic acid 2-(4-morpholinyl)-ethyl ester, an immunosuppressive glucocorticoid, such as prednisone or dexamethasone; and/or polyclonal antibody, such as an anti-human thymocite antibody or a monoclonal antibody, such as an anti-human CD3 antiboby; or a mixture of two or more thereof. 16. A method of treating a mammal, including a human, suffering from adult-T-cell leukemia-lymphoma, which method comprises administering to said mammal a therapeutically effective amount of a compound of formula (I), as defined in claim 1. 17. The method to claim 16, wherein the method comprises administering to said mammal an anti-tumor agent for simultaneous, separate or sequential use in amounts sufficient to produce a therapeuticcaly useful effect. 18. A process for the production of a compound as defined in claim 1, which comprises treating a compound of formula (II):   wherein R5 and R6 are as defined in claim 1 and X is a leaving group with a compound of formula (III):   whrein  R1, R2, R3 and R4 are as defined in claim 1 and R7 is hydrogen or lower alkyl chain; and, if desired, converting a compound of formula (I) into another compound of formula (I) and/or, if desired, converting a salt of a compound of formula (I) into a free compound, and/or. if desired, separating a mixture of isomers of a compound of formula (I) into the single isomers. 19. A compound of formula (III)   wherein R1, R2, R3 and R4 are as defined in claim 1 and R7 is hydrogen or a lower alkyl chain and Boc is a 1-tert-butoxycarbonyl group.