Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-06-06
1998-01-13
Shah, Mukund J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
540 31, C07D49122
Patent
active
057081646
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP94/01858.
This invention relates to cephalostatin analogues of general formula I, ##STR1## in which
a) A and A' each stand for an alkanoyloxy group R--CO--O-- with R as a straight-chain or branched-chain C.sub.1 to C.sub.7 alkyl radical, and B and D as well as B' and D' each together stand for an additional C--C bond, or
b) A' stands for an alkanoyloxy group R--CO--O-- with R as a straight-chain or branched-chain C.sub.1 to C.sub.7 alkyl radical, and B' and D' together stand for an additional C--C bond, and A and B together stand for a keto-oxygen atom and D stands for a hydrogen atom, or
c) A stands for a .beta.-position hydroxy group, and B as well as D each stand for a hydrogen atom, and A' and B' together stand for a keto-oxygen atom, and D' stands for a hydrogen atom or
d) A and A' each stand for a .beta.-position hydroxy group, and B, D, B' and D' each stand for a hydrogen atom, pharmaceutical agents that contain these cephalostatin analogues, and their use for the production of pharmaceutical agents.
BACKGROUND OF THE INVENTION
Cephalostatins represent a group of complex steroidal pyrazine alkaloids, which were isolated from the sea worm Cephalodiscus gilchristi ((a) Pettit, G. R.; Kamano, Y.; Dufresne, C..; Inoue, M.; Christi, N.; Schmidt, J. M.; Doubek, D. L.; Can. J. Chem. 1989, 67, 1509. (b) Pettit, G. R.; Inoue, M.; Kamano, Y.; Herald, D. L.; Arm, C.; Dufresne, C.; Christie, N. D.; Schmidt, J. M.; Doubek, D. L.; Krupa, T. S.; J. Am. Chem. Soc. 1988, 110, 2006. (c) Pettit, G. R.; Inoue, M.; Kamano, Y.; Dufresne, C.; Christie, N. D.; Niven, M. L.; Herald, D. L.; J. Chem. Soc., Chem. Commun. 1988, 865. (d) Pettit, G. R.; Kamano, Y.; Inoue, M.; Dufresne, C.; Boyd, R.; Herald, D. L.; Schmidt, J. M.; Doubek, D. L.: Christie, N. D.; J. Org. Chem. 1992, 57, 429). They represent cytotoxins that are highly effective against the PS cell line (ED.sub.50 10.sup.-7 -10.sup.-9 .mu.g/ml) and are of potential interest as anti-tumor agents. They are natural marine products that occur rarely, however, and are available only in extremely small amounts. For example, only 139 mg of cephalostatin 1 and a total of 272 mg of other cephalostatins could be isolated from 166 kg of Cephalodiscus gilchristi (tubular worms 5 mm long). ##STR2##
Cephalostatin 1
Cephalostatin 1 represents an asymmetrically structured and substituted bis-steroidopyrazine, which exhibits a double bond in both the D and D' rings respectively.
Although cephalostatin 7 has become known only recently (Pettit, G. R. et al., loc. cit. (d)), it is a bis-steroidopyrazine that is structured symmetrically relative to the parent substance and is distinguished only by its F and F' rings. ##STR3##
Although cephalostatins belong to the most potent cytotoxins that have ever been screened in the PS system by the National Cancer Institute (USA), in vivo tests are hampered because of the limited availability of natural materials (S.C. Smith and C. H. Heathcock, J. Org. Chem. 1992, 57, 6379). Because of the limited availability, however, there is lively interest in implementing a procedure for total synthesis for cephalostatins. Three processes for forming bis-steroidopyrazines are described by S. C. Smith and C. H. Heathcock (loc. cit.): two of these processes can be used for the production of symmetrical bis-steroidopyrazines in high yields, while the third process makes it possible to synthesize asymmetrical analogues previously known only in the form of naturally occurring cephalostatins.
The cephalostatin analogues that are symmetrical (R=C.sub.8 H.sub.17) or asymmetrical (R=OAc) in structure and can be produced according to said bibliographic references are of the type shown below: ##STR4##
Apart from the very different D-ring substitution, these cephalostatin analogues, furthermore, exhibit neither the 12-hydroxy and 12'-keto or 12-hydroxy functions typical of cephalostatin 1 and cephalostatin 7, nor the double bonds that occur there in the D and D' rings. These double bonds are important for increased solubility of s
REFERENCES:
Pettit et al., J. Org. Chem., 1992, 57, pp. 429-431.
Pettit et al., J. Am. Chem. Soc., 1988, 110, pp. 2006-2007.
Smith et al., J. Org. Chem., 1992, 57 pp. 6379-6380.
Kramer et al., J. Chem. Soc., Perkin Trans. 1, 1993, No. 23 p. 2865.
Pan et al., "Synthesis and Pharmacological Evaluation . . . " Biorganic & Med. Chem Ltrs. vol. 2, No. 9, pp. 967-972, 1992.
Heathcock et al., "Synthesis and Biological Activity of Unsymmetrical . . . " J. Org. Chem. 1994, 59, pp. 6828-6839.
Kramer Andreas
Laurent Henry
Ullmann Ulrike
Winterfeldt Ekkehard
Schering Aktiengesellschaft
Shah Mukund J.
Sripada Pavanaram K.
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