Pharmaceutically active compounds

Details Pharmaceutically active compounds Pharmaceutically active compounds

1997-12-18

2000-11-28

Ramsuer, Robert W.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

5462774, 548455, A61K 31404, A61P 3700, C07D40304

Patent

active

061536415

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to novel bisindolylmaleimides, methods for their preparation and use, intermediates therefore and pharmaceutical compositions comprising them.


BACKGROUND AND PRIOR ART

Protein kinase C (PKC) is a family of phosplolipid-dependent serine/threonine-specific protein kinases which play an important role in cellular growth control, regulation and differentiation.
Since the activation of PKC has been implicated in several human disease processes, including various forms of cancer, different forms of inflammatory and/or immunological disorders as well as some neurological disorders, inhibition of PKC could be therapeutic value in treating these conditions.
Several classes of compounds have been identified as PKC inhibitors, e.g., isoquinoline sulfonamides, sphingosine and related sphingolipids and indolocarbazoles.
EP, B1, 0328026 discloses the use of certain bisindolylmaleimides, a class of compounds related to the indolocarbazoles, in medicaments for the treatment of various diseases.
Little work has been done on the design of PKC inhibitors with a favorable topical/systemic effect ratio. In fact, PKC is an ubiquitous enzyme with wide-ranging physiological functions, and the use of non-specific PKC inhibitors would be expected to be accompanied by severe systemic side effects.


OUTLINE OF THE INVENTION

We have found a group of novel bisindolylmaleimides which, relative to known PKC inhibitors, have improved ability to inhibit PKC and/or are more quickly metabolised to less active compounds. The compounds of formula (I) and pharmaceutically acceptable salts thereof are active topically, and have the potential to become deactivated systemically as indicated by Example 23 hereinafter. Compounds of the present invention are preferably administered via inhalation therefore a rapid lung metabolism is highly desirable in order that the compound may exert its therapeutic effect at the target site and then be rapidly degraded to a relatively inactive metabolite.
The object of the present invention is to provide these novel bisindolylmaleimides, methods for their preparation and intermediates used for their preparation.
Another object of the present invention is the use of the novel compounds for the treatment of inflammatory and immunological disorders and preferably of the topical treatment of inflammatory and immunological disorders, such as the topical treatment of airway diseases involving inflammatory conditions, e.g. asthma; bronchitis and atopic diseases, e.g. rhinitis and atopic dermatitis; psoriasis; inflammatory bowel diseases, e.g. Chrohn's disease and colitis; rheumatoid arthritis and malignant diseases (e.g. skin and lung cancer).
Still another object of the invention is a pharmaceutical composition comprising a compound according to the invention, as active ingredient, together with a pharmaceutically acceptable adjuvant, diluent or carrier.


DETAILED DESCRIPTION OF THE INVENTION

According to the present invention we provide novel compounds of formula (I) ).sub.n -group thorough an indolyl nitrogen, heterocyclic ring containing N or S, R.sub.5, -alkyl)amino)methyl or pyridiniummethyl, and same or different, are each hydrogen, hydroxy, C.sub.1-4 -alkoxy, C.sub.1-4 -alkyl, tri)C.sub.1-4 -alkyl)silyl(C.sub.1-4 -alkoxy) or halogen, or R.sub.2 when in a position contiguous to the bond connecting R to the --(CH.sub.2).sub.n -- group and n is 1 may, together with the 2-carbon atom on the indole to which the --(CH.sub.2) group is attached, form a ring,
Preferred compounds of formula (I) are compounds of formula (IA): ##STR1## wherein: A.sub.1, A.sub.2, A.sub.3, A.sub.4, B.sub.1, B.sub.2, B.sub.3, and B.sub.4, which may be the same or different, are each hydrogen, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, carboxy C.sub.1 -C.sub.4 alkyl or halogen; the bond connecting R to the --(CH.sub.2).sub.n -group and n is 1, may together with X form a bond, or
Particularly preferred compounds of the present invention include: dione, dione, le-2,5-dione, l-3-yl)

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