Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-03-09
2000-05-23
Stockton, Laura L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
548500, C07D48704, C07D20912
Patent
active
060667427
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to intermediates of duocarmycin SA and its derivatives, and methods for producing the same. Duocarmycin SA is a pyrroloindole derivative shown by the formula A and expected to be used as an anticancer agent. ##STR3##
BACKGROUND ART
Intermediates of duocarmycin SA, which is expected to be used as an anticancer agent, and derivatives thereof, and production of these compounds have been disclosed, for example, in J. Antibiotics 43, 1037 (1990), ibid. 44, 1045 (1991), Japanese Patent Laid-open Pub. No. Hei 2-177890, Japanese Patent Laid-open Pub. No. Hei 5-208979, Japanese Patent Laid-open Pub. No. Hei 7-53558, J. Am. Chem. Soc. 114, 10056 (1992), Tetrahedron Lett. 35, 2573 (1994), and Chem. Pharm. Bull. 43, 1064 (1995).
Among these known methods for producing duocarmycin SA and its derivatives, the method by formentation allows only a low productivity, and the chemical synthesis needs many steps for producing an optically active one or accompanies arduous optical resolution of an intermediate. Thus, it was difficult to efficiently produce optically active duocarmycin SA.
The object of the present invention is to provide intermediates for efficiently producing duocarmycin SA, which is expected to be used as an anticancer agent, and its derivatives, and methods for producing the same.
DISCLOSURE OF THE INVENTION
The inventors provide indole derivatives and pyrroloindole derivatives both of which are intermediates for duocarmycin SA and derivatives thereof, shown by the formula (1) ##STR4## wherein, R.sup.1 is a protecting group for amino group; R.sup.2 is a protecting group for hydroxyl group; R.sup.3 is a protecting group for hydroxyl group; R.sup.4 is a C.sub.1 -C.sub.6 linear or branched lower alkyl group, or benzyl group, the formula (2a) or (2b) ##STR5## wherein, R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are the same as described above, and the formula (3) ##STR6## wherein, R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are the same as described above.
The inventors also provide a method for producing a pyrroloindole derivative, which is an intermediate of duocarmycin SA and its derivatives, shown by the formula (3), ##STR7## comprising oxidative cyclization of an indole derivative shown by the formula (1), ##STR8## as well as a method for producing a pyrroloindole derivative, which is an intermediate of duocarmycin SA and its derivative, shown by the formula (3), ##STR9## comprising oxidative cyclization of an indole derivative shown by the formula (2A) or (2b). ##STR10##
R.sup.1, which is a protecting group for amino group, includes a C.sub.1 -C.sub.6 linear or branched lower alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, and t-butoxycarbonyl; a haloalkoxycarbonyl such as 2,2,2-trichloroethoxycarbonyl and 2,2,2-trichloro-1,1-dimethylethoxycarbonyl; and a substituted or unsubstituted aralkyloxycarbonyl such as benzyloxycarbonyl, 4-methylbenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, benzhydrylcarbonyl, di-(4-methoxyphenyl)methoxycarbonyl, trityloxycarbonyl, and fluorenylmethoxycarbonyl.
R.sup.2, which is a protecting group for hydroxyl group, includes a C.sub.1 -C.sub.6 linear or branched substituted or unsubstituted lower alkanoyl such as formyl, acetyl, methoxyacetyl, phenoxyacetyl, and pivaloyl; a substituted or unsubstituted aryloyl such as benzoyl, toluoyl, 3-chlorobenzoyl, and 4-phenylbenzoyl; a substituted or unsubstituted arylmethyl such as benzyl, 4-methylbenzyl, 3-chlorobenzyl, 4-methoxylbenzyl, 2,4-dimethoxybenzyl, benzhydryl, di-(4-methoxyphenyl)methyl, and trityl; and a substituted silyl such as triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl.
R.sup.3, which is a protecting group for hydroxyl group, includes a C.sub.1 -C.sub.6 linear or branched lower alkyl such as methyl and ethyl; and a substituted or unsubstituted arylmethyl such as benzyl, 4-methylbenzyl, 3-chlorobenzyl, 4-methoxylbenzyl, 2,4-dimethoxybenzyl, benzhydryl, di-(4-methoxyphenyl)methyl, and tr
REFERENCES:
Boger et al., J. Am. Chem. Soc., 1993, vol. 115, pp. 9025-9036.
Fukuda et al., Tetrahedron, 1994, vol. 50, No. 9, pp. 2793-2808.
Boger et al., J. Am. Chem. Soc., May 28, 1997, vol. 119, pp. 4977-4986.
Fukuda Yasumichi
Terashima Shiro
Kyorin Pharmaceutical Co. Ltd.
Sagami Chemical Research Center
Stockton Laura L.
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