Indolyl-pyrrolydenemethylpyrrole derivatives and process for the

Details Indolyl-pyrrolydenemethylpyrrole derivatives and process for the Indolyl-pyrrolydenemethylpyrrole derivatives and process for the

1998-11-12

2000-06-06

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514415, 514422, 514427, 544 32, 544 34, 544143, 546 81, 546 84, 546201, 546208, 548490, 548523, 548524, A61K 314025, A61K 31405, C07D207333, C07D20912, C07D40314

Patent

active

060719478

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to new indolyl-pyrrolydenemethylpyrrole derivatives and their use as therapeutic agents, e.g. as immunomodulating agents, in particular as immunosuppressive agents, to a process for their preparation and to pharmaceutical compositions comprising them.
Presently, cyclosporin A, an immunosuppressive agent, used in combination with other adjunctive therapies, such as azathioprine and corticosteroids, is the treatment of choice for the prevention of organ transplantation rejection.
Other immunosuppressive agents such as FK506, mycophenolate mofetil, and rapamycin, have been used or have been suggested to be useful in the treatment and/or prevention of organ transplantation rejection.
Use of any of these known immunosuppressive compounds, either alone or in combination, is associated with a high incidence of side effects such as nephrotoxicity and/or hepatotoxicity. Thus, there presently exists a need for improved therapies to replace or to be used in combination with cyclosporin or other currently known immunosuppressive drugs for the treatment and/or prevention of organ transplantation rejection, graft versus host disease, autoimmune diseases, and chronic inflammatory diseases, including but not limited to psoriasis and rheumatoid arthritis.
The indolyl-pyrrolydenemethylpyrrole compounds of the present invention are useful as single therapy agents as well as in combination with other compounds currently used in these clinical regimens such as cyclosporin. In view of their biological properties the compounds of the present invention should be useful to permit the administration of reduced doses of other immunosuppressive agents used in combination therewith, thereby reducing the adverse effects of these agents.
Object of the present invention are new 2-(1H-indol-2-yl)-5[(2H-pyrrol-2-ylidene)methyl]-1H-pyrrole compounds having the following formula (I) ##STR1## wherein each of R1, R2, R3 and R4, which are the same or different, independently represents hydrogen, C.sub.1 -C.sub.6 alkyl, halogen, cyano, nitro, hydroxy, C.sub.1 -C.sub.6 alkoxy unsubstituted or substituted by phenyl, C.sub.1 -C.sub.6 alkyl-carbonyloxy, --NRaRb in which each of Ra and Rb independently is hydrogen or C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkyl-carbonylamino, carboxy, (C.sub.1 -C.sub.6 alkoxy)carbonyl, aralkyl-carbamoyl, arylcarbamoyl or --CONRcRd in which each of Rc and Rd independently is hydrogen or C.sub.1 -C.sub.6 alkyl or Rc and Rd, taken together with the nitrogen atom to which they are linked, form a morpholino or piperidino ring; substituted by phenyl; and alkenoyl, phenyl, C.sub.1 -C.sub.20 alkyl or C.sub.2 -C.sub.20 alkenyl, wherein the alkanoyl, alkenoyl, alkyl and alkenyl groups are unsubstituted or substituted by 1 to 3 substituents chosen independently from halogen, C.sub.1 -C.sub.6 alkoxy, hydroxy, aryl, aryloxy, cyano, carboxy, (C.sub.1 -C.sub.6 alkoxy)carbonyl, (C.sub.3 -C.sub.4 alkenyl)carbamoyl, aralkyl-carbamoyl, arylcarbamoyl and --CONRcRd wherein Rc and Rd are as defined above;
The present invention includes within its scope all possible isomers, stereoisomers and optical isomers and their mixtures, and the metabolites and the metabolic precursors or bioprecursors of the compounds of formula (I).
The compounds of the invention can be represented also by the following tautomeric formula (Ia) ##STR2## wherein R1, R2, R3, R4, R5 and R6 are as defined above.
Accordingly, the chemical compounds provided by the present invention are named throughout the description of the invention according to the chemical nomenclature provided for the compounds of either formula (I) or (Ia), on the basis of the structural evidence validated by people skilled in the art.
A halogen atom is preferably chlorine or fluorine. The alkyl, alkoxy, alkenyl, alkanoyl, alkenoyl, alkadienoyl and alkylidene groups may be branched or straight chain groups.
An aryl group as a substituent as well as a moiety in an aryloxy, aralkyl or arylcarbamoyl group is, e.g., an aromatic C.sub.6 -C.sub.20 mono- or poly-nuclear mo

REFERENCES:
patent: 5607960 (1997-03-01), Wythes
patent: 5691334 (1997-11-01), Doria et al.
patent: 5847127 (1998-12-01), D'Alessio et al.

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