Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-08-25
1996-10-15
O'Sullivan, Peter
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514821, 514824, 514825, 514886, 514887, 514929, 540523, A61K 3155
Patent
active
055654487
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/US93/01619 filed 24 Feb. 1993.
FIELD OF THE INVENTION
The present invention relates to the treatment and prevention of conditions wherein protein kinase C (PKC) inhibition is indicated. In particular, it relates to the treatment of cardiovascular and renal disorders, inflammation, central nervous system disorders, immunosuppression, and septic shock, and to the use of certain 4,5, 6, 7-tetrahydropyrrolo (2, 3-c) azepine-8-ones in the manufacture of medicaments for the treatment of such conditions.
BACKGROUND OF THE INVENTION
Protein kinase C is a calcium and phospholipid activated enzyme that plays a significant role in mediating the effects of a host of hormones, neurotransmitters, growth factors, antigens, and inflammatory mediators (Nishizuka, Y. (1988) Nature, 334:661). When these extracellular agents bind to their specific cell surface receptors, they stimulate the hydrolysis of phosphatidylinositol, phosphatidylcholine, or phosphatidylethanolamine, resulting in the accumulation of diacylglycerol which activates protein kinase C. This activation of PKC causes specific cellular substrates to be phosphorylated, resulting in the regulation of cellular processes which are closely linked to the physiological control of contractile, secretory, and proliferative processes (Nishizuka, Y. (1984) Nature, 308: 693). As examples of physiological response induced by the system in which protein kinase C participates, there have been reported serotonin release from platelets (Kaibuchi, et al. (1982) Cell Calcium, 3:323; Kaibuchi, et al. (1985) J. Biol. Chem., 258:6701), lysosomal enzyme release and superoxide generation from neutrophils (Kajikawa, et al. (1983) Biochem. Biophys. Res. Commun.; 116:743; Sehau, et al. (1983) Biochem. Biophys. Acta, 762:420), histamine release from mast cells (Kata Kami, et al. (1982) Biochem. Biphys- Res. Commun., 121:573), secretion of aldosterone from adrenal glomerulus (Kojima, et al. (1983) Biochem Biophys. Res Commun., 116:555), and contraction of vascular smooth muscle (Rasmussen, et al. (1984) Biochem. Biophys. Res. Commun., 122:776. Thus, it has been demonstrated that protein kinase C takes part in many important physiological responses in vivo. Therefore, an inhibitor of protein kinase C would be expected to be useful in the treatment of cardiovascular and renal disorders, inflammation, immunosuppression, septic shock and central nervous system disorders.
It has now been found that certain 4,5,6,7-tetrahydropyrrolo (2, 3-c) azepine-8-ones previously described as alpha-adrenoceptor blocking agents and antineoplastic agents are also protein kinase C inhibitors and hence are expected to have utility in the treatment of conditions wherein protein kinase C inhibition is indicated.
SUMMARY OF THE INVENTION
The present invention provides a method of inhibiting protein Kinase C in mammals which comprises administering to the mammal in need of such treatment an effective amount of a compound of Formula (I) : ##STR1## in which R is H or Br; or a pharmaceutically acceptable salt thereof.
The invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of conditions wherein inhibition of protein kinase C is indicated, for example in the treatment of cardiovascular and renal disorders, inflammation, central nervous system disorders, immunosuppression, and septic shock.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is a therapeutic method for treating diseases in mammals, including humans, for which inhibition of protein kinase C is indicated. The method utilizes a class of inhibitors of Formula (I).
Accordingly, the PKC inhibiting Formula (I) compounds of this invention can be used for the treatment of cardiovascular diseases, that is heart and circulatory diseases, such as thrombosis, atherosclerosis, arteriosclerosis, ischemia, reperfusion injury, and hypertension, immunosuppressive and inflammatory disorders, such as asthma, rh
REFERENCES:
Journal of Natural Products, vol. 48, No. 1 pp. 47-53 Jan.-Feb. 1985.
J. Org. Chem. vol. 50, pp. 4163-4164 1985.
Experientia 42 pp. 1064-1065 1986.
Pettit et al., "Antineoplastic Agents," etc. Canadian J of Chem. vol. 68 (1990) pp. 1621-1624.
Kobayashi et al., ".alpha.-Adrenoreceptor Blocking Action, etc." Experimentia 44 (1988) pp. 86-87.
Wright et al., Chem. Abst. 110: 147852 (1989).
Nambi Ponnal
Patil Ashok D.
Lentz Edward T.
McCarthy Mary E.
O'Sullivan Peter
SmithKline Beecham Corporation
Venetianer Stephen
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