Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-11-15
1998-05-12
Higel, Floyd D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548416, A61K 3140, C07D48714, C07D48722
Patent
active
057505551
DESCRIPTION:
BRIEF SUMMARY
This application is a 317 of PCT/EP93/03611, filed Dec. 20,1993
BACKGROUND
Protein kinase C plays an important key role for intracellular signal transduction and is closely connected with the regulation of contractile, secretory, and proliferative processes. On the basis of these properties, the compounds according to the present invention can be used for the treatment and/or prevention of cancer, viral diseases (for example HIV infections), heart and blood vessel diseases, for example blood pressure, thromboses, heart rhythm disturbances, atherosclerosis, broncho-pulmonary diseases, degenerative diseases of the central nervous system, for example Alzheimer's disease, inflammatory diseases, such as rheumatism and arthritis, diseases of the immune system, such as allergies, as well as psoriasis. Furthermore, the compounds can be used as immune suppressives.
From the literature, synthetic derivatives and compounds which are derived from substructures of the staurosporin aglycone are known as potent inhibitors of protein kinase C (see J. Med. Chem., 35, 177 (1992) ; J. Med. Chem., 35, 994(1992)). The activity mechanism thereof depends upon the displacement of ATP from the catalytic subunit of protein kinase C.
The compounds of Formula I below of the present invention, have been found to be a new group of PKC inhibitors. They contain an amino acid portion which, on the one hand, is derived from a highly-affinity substrate of PKC, represented by the amino acid serine, and on the other hand from an inhibitor, represented by the amino acid alanine (see Science, 238, 1726 (1987) ; Cell. Signalling, 2, 187 (1990)). Surprisingly, these new compounds of Formula I prove to be not only highly potent but also, as is shown in some of the examples, selective inhibitors of protein kinase C. The action thereof on myosin light chain kinase proves to be considerably weaker.
SUMMARY OF THE INVENTION
The instant invention concerns new amino acid derivatives of formula ##STR1## and X, Y, E, n, and R.sup.5 are as described below.
The compounds are potent inhibitors of PKC as can be used in the treatment and/or prevention of cancer, viral diseases including HIV infection, heart and blood vessel diseases, i.e., blood pressure, thrombosis, heart rhythm disturbances, atherosclerosis, broncho-pulmonary, degenerative diseases of the central nervous system, i.e., Alzheimer's disease, inflammatory diseases, i.e., rheumatism and arthritis, diseases of the immune system such as allergies, as well as psoriasis. The compounds can also be used as immune suppressives.
DETAILED DESCRIPTION
The present invention is a new amino acid derivatives of the formula ##STR2## wherein R.sup.1 is hydrogen or alkyl of from 1 to 4 carbon atoms and (------) is open or a valency bond; wherein ##STR3## or formula ##STR4## wherein R.sup.2 is as above and when m is 1, R.sup.3 is hydrogen or the side group of a natural .alpha.-amino acid and, when m is from 2 to 6, R.sup.3 is hydrogen; and to 4 carbon atoms or hydrogen when E is Formula IV and R.sup.5 is hydrogen when E is Formula V.
Compounds of Formula I are preferred in which A is a bis-indolylmaleinimide or indolopyrrolocarbazole of Formula III, in which R.sup.1 is hydrogen or an alkyl of from 1 to 4 carbon atoms, X is alkylene of from 1 to 10 carbon atoms, Y is NH or CO, E is an aminocarboxylic acid of Formula IV or of Formula V, in which R.sup.2 is a hydrogen atom, when m is 1 then R.sup.3 is a hydrogen atom or the side group of one of the natural .alpha.-amino acids and when m is 1 to 6 then R.sup.3 is hydrogen and n is preferably from 1 to 6. The terminal carboxylic acids present in the Formula IV can also be amidated with ammonia or can be esterified with a lower alcohol, for example methanol, ethanol, or propanol.
Furthermore, compounds of Formula I are preferred in which A is bis-indolylmaleinimide or indolopyrrolo-carbazole of Formula III in which R.sup.1 is methyl, X is methylene, propylene, butylene, pentylene, octylene, or nonylene, Y is either NH or CO, --E.sub.n --R.sup.5 is alanine, alan
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Barth Hubert
Hartenstein Johannes
Kolch Walter
Reck Reinhard
Rudolph Claus
Anderson Elizabeth M.
Goedecke Aktiengesellschaft
Higel Floyd D.
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