Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1996-01-18
1997-04-15
Bond, Robert T.
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C07D48704
Patent
active
056210990
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a process of producing of hymenialdisine, its derivatives, and their salts of the formula (I): ##STR2## (wherein X.sup.1 is a halogen atom or hydrogen atom.) The present invention further relates to intermediates for producing the above compound (I) and processes for producing the same.
BACKGROUND ART
In recent years, there have been intense exploration and study of bioactive substances derived from the sea. Among these, useful substances holding forth promise as pharmaceuticals and lead compounds for pharmaceuticals have been discovered. For example, hymenialdisine and debromohymenialdisine have been isolated from sponges.
For example, hymenialdisine has been isolated from Axinella verrucosa, Acanthella aurantiaca (Cimino, G. et al: Tetrahedron Lett., 23, 767 (1982)), Hymeniacidon aldis (Kitagawa, I. et al: Chem. Pharm. Bull., 31, 2321 (1983)), and an unconfirmed Kololevu sponge (Schmitz, F. et al: J. Nat. Prod., 48, 47 (1985)), while debromohymenialdisine has been isolated from Phakellia flabellata (Sharma, G. et al: J. Chem. Soc., Chem. Commun., 435 (1980)) and Hymeniacidon aldis (Kitagawa, I. et al: Chem. Pharm. Bull., 31, 2321 (1983); Endo, M. et al: Pure & Appl. Chem., 58, 387 (1986)).
In the above formula (I), the compound having an X.sup.1 of a bromine atom is hymenialdisine, while the compound having an X.sup.1 of a hydrogen atom is debromohymenialdisine. These compounds have interesting biological activities.
Hymenialdisine and debromohymenialdisine are known to have antineoplastic activities (Pettit, G. et al: Can. J. Chem., 68, 1621 (1990)). Furthermore, debromohymenialdisine is known to have .alpha.-adrenoceptor blocking effect (Kobayashi, J. et al: Experimentia., 44, 86 (1988)).
Recently, it has been shown that hymenialdisine and debromohymenialdisine have an inhibitory action against protein phosphokinases, in particular, protein kinase C (Nishizuka, Y.: Nature, 334, 661 (1988); idem, JAMA, 262, 1826 (1989)), which plays an important role in cellular signal transduction (Nambi, P. et al: International Disclosure W093/16703). They are expected to have applications as drugs for the alleviation and treatment of conditions believed to involve the activation of protein kinase C, for example, cerebral ischemic disorders, cerebral vasospasm, ischemic cardiac diseases, high blood pressure, arteriosclerosis, inflammation, asthma, kidney disorders, rheumatoid arthritus, and sthenia of immunofunctions.
Hymenialdisine and debromohymenialdisine, however, can only be obtained in minute quantities when extracted and isolated from nature, so there has been a strong demand for the development of an efficient process of production enabling economical mass production of hymenialdisine and its derivatives. Such a technique, however, has not yet been known. There has just been a few studies on conversion from aldisin. Even these have not given satisfactory results. Complete synthesis is not yet achieved (Prager, R. et al: Aust. J. Chem., 43, 367 (1990); idem, ibid. 45, 1771 (1992)).
DISCLOSURE OF THE INVENTION
In view of the above situation, the objective of the present invention is to provide a process for economically and efficiently producing of hymenialdisine and its derivatives at a mass production.
The other objectives of the present invention are to provide synthetic intermediates useful for the production of these compounds and a process for producting the same.
The present inventors succeeded in the complete chemical synthesis of hymenialdisine and its derivatives having the formula (I): ##STR3## (wherein X.sup.1 is a halogen atom or hydrogen atom.)
BEST MODE FOR CARRYING OUT THE INVENTION
It should be noted that natural substances such as hymenialdisine have Z-configuration at the double bond of the 4-position of the pyrrolo[2,3-c]azepine skeleton. However, according to the present invention, the resultant hymenialdisine and its derivatives are surprisingly obtained only in the z-configuration form. The halogen atom referred to in the present i
REFERENCES:
patent: 5206239 (1993-04-01), Mizuno et al.
Annoura et al, "Total Syntheses of Hymenialdisine and Debromohymenialdisine: Stereospecifc Construction of the 2-Amino-4-Oxo-2-Imidazolin-5(Z)-Disubstituted Ylidene Ring System", Tetrahedron Letters, 36(3):413-416 (1995).
Cimino et al, "Isolation and X-ray Crystal Structure of A Novel Bromo-Compound from Two Marine Sponges", Tetrahedron Letters, 23(7):767-768 (1982).
Endo et al, "Pharmacologically Active Substances from Southern Pacific Marine Invertebrates", Pure & Appl. Chem., 58(3):387-394 (1986).
Kitagawa et al, "Marine Natural Products. XII..sup.1) On the Chemical Constituents of the Okinawan Marine Sponge Hymeniacidon aldis", Chem. Pharm. Bull., 31(7):2321-2328 (1983).
Kobayashi et al, ".alpha.-Adrenoceptor Blocking Action of Hymenin, a Novel Marine Alkaloid", Experientia 44, 86-87 (1988).
Y. Nishizuka, "The Family of Protein Kinase C for Signal Transduction", JAMA, 262(13):1826-1833 (1989).
Y. Nishizuka, "The Molecular Heterogeneity of Protein Kinase C and its Implications for Cellular Regulation", Nature, 334(25):661-665 (1988).
Pettit et al, "Antineoplastic Agents. 168. Isolation and Structure of Axinohydantoin.sup.1 ", Can. J. Chem., 68:1621-1624 (1990).
Prager et al, "Knoevenagel Reactions of 6,7-Dihydro-pyrrolo[2,3-c]azepine-4,8(1H,5H)-dione: An Approach to the Synthesis of Pyrrolic Marine Natural Products", Aust. J. Chem., 45:1771-1777 (1992).
Prager et al, "Approaches to the Synthesis of 5-Benzylidene-2-imidazolin-4-ones", Aust. J. Chem., 43:367-374 (1990).
Schmitz et al, "Marine Natural Products: Pyrrololactams from Several Sponges", Journal of Natural Products, 48(1):47-53 (1985).
Sharma et al, "Characterizatioin of a Yellow Compound Isolated from the Marine Sponge Phakellia flabellata", J.C.S. Chem. Comm., 435-436 (1980).
Annoura Hirokazu
Tatsuoka Toshio
Bond Robert T.
Suntory Limited
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