Derivatives of physiologically active substance K-252

Details Derivatives of physiologically active substance K-252 Derivatives of physiologically active substance K-252

1988-11-08

1990-05-08

Shah, Mukund J.

Organic compounds -- part of the class 532-570 series

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

540543, C07D, C07D, A61K 3155

Patent

active

049239864

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to novel compounds which inhibit protein kinase C (hereinafter referred to as C-kinase) and have pharmacological activities such as anti-tumor activity.


BACKGROUND ART

C-kinase is a protein kinase which is activated depending upon phospholipids and calcium and widely distributed over tissues and organs in the living body. It has been reported that this enzyme plays an extremely important role in cell membrane receptor transduction mechanism in which many hormone, neurotransmitters, etc. are concerned. As examples of physiological response induced by signal transduction system in which C-kinase participates, there have been reported serotonin release from platelets, lysosomal enzyme release and aggregation. superoxide formation and lysosomal enzyme release from neutrophil leukocytes, epinephrine release from adrenal medulla, secretion of aldosterone from renal glomerulus, secretion of insulin from Langerhans' islet, histamine release from mast cells, acetylcholine release from ileum, contraction of vascular smooth muscle, and the like. C-kinase is also supposed to be concerned in cell growth and carcinogenetic mechanism [Y. Nishizuka, Science, 225, 1365 (1984); Rasmusen et al., Advance in Cyclic Nucleotide and Protein Phosphorylation Research, vol. 18, p. 159, edited by P. Greengard and G. A. Robinson, Raven Press, New York, 1984]. It is expected that a wide variety of diseases such as diseases of the circular system, inflammatory diseases, allergy an tumor can be prevented or treated by artificially inhibiting C-kinase activity by the use of inhibitors, etc.
On the other hand, it has been found that antipsychotic drugs such as trifluoperazine and chlorpromazine, dibenamine and tetracaine which are known as local anesthetics, calmodulin inhibitor W-7 [N-(6-aminohexy)-5-chloro-1-naphthalenesulfonamide], etc. posssess C-kinase inhibitory activity, but the C-kinase inhibitory activity is low in any of these drugs [Y. Nishizuka et al., J. Biol. Chem., 255, 8378 (1980); R. C. Schatzman et al., Biochem. Biophys. Res. Commun., 98, 669 (1981); B. C. Wise et al., J. Biol. Chem., 257, 8489 (1982)].
K-252 and KT-5556 represented by the following formula are known (with K-252, see Japanese Published Unexamined Patent Application No. 41489/85 and U.S. Pat. No. 4,555,402; with KT-5556, see Japanese Published Unexamined Patent Application No. 176531/86). ##STR2## K-252: R.sub.A =CH.sub.3, R.sub.B =H KT-5556: R.sub.A =H, R.sub.B =H
In Japanese Published Unexamined Patent Application No. 41489/85, it is described that K-252 has activity to inhibit histamine release and anti-allergic activity. In Japanese Published Unexamined Patent Application No. 176531/86, it is described that KT-5556 has activity to inhibit histamine release. Further, compounds that are assumed to be identical with K-252 or KT-5556 have been reported as antibacterial substances [M. Senzaki et al., J. Antibiotics, 38 (10), 1437 (1985)]. In this publication, a compound of the above formula wherein R.sub.A =CH.sub.3 and R.sub.B =Ac is also disclosed.
Furthermore, Staurosporine having the following structure and antibacterial activity is known as a compound having a structure relatively akin to that of K-252 [S. Omura et al., J. Antibiotics, 30 (4), 275 (1977), A. Furusaki et al., J. Chem. Soc. Chem. Commun., 800 (1978), Japanese Published Unexamined Patent Application No. 185719/85]. ##STR3##


DISCLOSURE OF THE INVENTION

According to the present invention, there are provided novel derivatives of K-252 represented by formula (I) and pharmacologically acceptable salts thereof. ##STR4##
In the formula, R.sup.1 represents hydrogen, methyl, hydroxy, hydroxymethyl, lower alkoxy, bromine, chlorine or --NR.sup.5 R.sup.6 (wherein either R.sup.5 or R.sup.6 is hydrogen and the other is hydrogen, carbamoyl or lower alkylaminocarbonyl, or both are lower alkyl) and R.sup.3 is hydrogen, or R.sup.1 and R.sup.3 are the same and represent hydrosy, lower alkoxy or amino. R.sup.2 is hydrogen or amino, and R.sup.4 is hydrogen,

REFERENCES:
patent: 4555402 (1985-11-01), Matsuda et al.
Chem. Abstracts, 101, 55460j, (1984).
Chem. Abstracts, 105, 187430s, (1986).
Chem. Abstracts, 104, 31427q, (1986).
J. Antibiotics, 30(4), 275-282, (1977), Omura et al., "A New Alkaloid AM-2282 of Streptomyces Origin . . . ".
J. Antibiotics, 39(8), 1066, (1986), Nakanishi et al., "K-252b, c and d, Potent Inhibitors of Protein Kinase C . . . ".
J. Antibiotics, 39(8), 1072, (1986), Yasuzawa et al., "The Structures of the Novel Protein Kinase C . . . ".
J.C.S. Chem. Comm., p. 800, (1978), Furasaki et al., "X-Ray Crystal Structure of Staurosporine . . . ".
J. Antibiotics, 38(10), 1437-1439, (1985), Sezaki et al., "A New Antibiotic SF-2370 Produced by Actinomadura".
J. Antibiotics, 30(4), 275-282, (1977), Omura et al., "A New Alkaloid AM-2282 of Streptomyces Origin . . . ".
J.C.S. Chem. Comm., 800-801, (1978), Furasaki et al., "X-Ray Crystal Structure of Staurosporine . . . ".
J. Antibiotics, 38(10), 1437-1439, (1985), Sezaki et al., "A New Antibiotic SF-2370 . . . ".

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