Intermediates and process for the manufacture of camptothecin de

Details Intermediates and process for the manufacture of camptothecin de Intermediates and process for the manufacture of camptothecin de

1997-10-02

2000-09-19

Dentz, Bernard

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

546116, 5462837, 546298, 546299, 546302, C07D491052, C07D21379

Patent

active

061214515

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

This invention discloses and claims novel intermediates and procedures for the synthesis of camptothecin derivatives, such as irinotecan, and other compounds related to the synthesis of CPT-11. Related procedures and compounds are also disclosed, such as a novel method of making mappicine.


INFORMATION DISCLOSURE

The compound given the label 14CPT in this document is mentioned in M. Shamma, D. A. Smithers, V. St. George, Tetrahedron, 1973, 1949-1954.
The asymmetric synthesis of this compound, 14 CPT, is reported in the following documents (grouped by author):
H. Terasawa, M. Sugimori, A. Ejima, H. Tagawa, Chem. Pharm. Bull., 1989, 37, 3382-3385.
A. Ejima, H. Terasawa, M. Sugimori, H. Tagawa, J. C. S. Perkin I, 1990, 27-31.
H. Tagawa, H. Terasawa, A. Ejima, U.S. Pat. No. 4,778,891 (Oct. 18, 1988).
H. Tagawa, H. Terasawa, A. Ejima, EP 220601 (Oct 14, 1986).
M. C. Wani, A. W. Nicholas, M. E. Wall, J. Med. Chem. 1987, 2317-2319.
M. C. Wani, A. W. Nicholas, M. E. Wall, U.S. Pat. No. 5,053,512 (Oct 1, 1990).
M. E. Wall, M. C. Wani, A. W. Nicholas, G. Manikumar, U.S. Pat. No. 4,894,456 (Jan. 16, 1990).
M. E Wall, M. C. Wani, A. W. Nicholas, and G. Manikumar, WO 90/03169 (Sep. 28, 1988).


BACKGROUND

Camptothecin derivatives, such as irinotecan, are effective anticancer drugs. This invention describes an efficient method of synthetic synthesis for a variety of camptothecin derivatives, including irinotecan or CPT-11, and other useful compounds like mappicine.


SUMMARY OF THE INVENTION

This invention comprises compounds, processes, reactions and reagents as shown in the CHARTS, formulas and figures herein. The compounds, processes, reactions and reagents are useful for the manufacture of camptothecin derivatives such as CPT-11 and other related compounds such as mappicine.
Specific compounds selected from the compounds described and labeled in the specification are the compounds in the CHARTS labeled 2G, 3G, 4G, 5G, 6G, 7GG, 7GA, 8GG, 8GA, 8GB, 9GG, 9GA, 10G, 10G(S), 10G(R), 11G, 11G(S), 11G(R), 12GA-1, 12GA-1(S), 12GA-1(R), 12GA-2, 12GA-2(S), 12GA-2(R), 12GB-1, 12GB-1(S), 12GB-1(R), 12GB-2, 12GB-2(S), 12GB-2(R), 12G, 12G(S), 12G(R), 13G, 13G(S), or 13G(R), lower alkyl, C.sub.3-10 cycloalkyl, lower alkyl-C.sub.3-10 cycloalkyl, alkenyl, aryl, substituted aryl, alkylaryl, or substituted alkylaryl, including benzyl and substituted benzyl; including C.sub.1-6 alkyl-aryl, C.sub.1-8 alkyl-C.sub.6 aryl, substituted benzyl and unsubstituted benzyl; other; alkyl, cycloalkyl, alkenyl, aryl, substituted aryl, and alkylaryl, or substituted alkylaryl, including benzyl and substituted benzyl; alkyl, C.sub.3-10 cycloalkyl, lower alkyl-C.sub.3-10 cycloalkyl, alkenyl, aryl, substituted aryl, alkylaryl, or substituted alkylaryl, including benzyl and substituted benzyl; alkyl, aryl, substituted aryl, or two R.sub.5 groups may be combined to form cyclopentane or cyclohexane, or substituted derivatives thereof; including ethyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, including benzyl and substituted benzyl, C.sub.3-10 cycloalkyl, lower alkyl-C.sub.3-10 cycloalkyl, heteroaryl, or substituted heteroaryl, including lower alkyl, axyl, substituted aryl, alkylaryl, substituted alkylaryl, or two R.sub.7 groups may be combined to form cyclopentane or cyclohexane or substituted derivatives thereof. alkyl, including t-butyl, C.sub.3-10 cycloalkyl, lower alkyl-C.sub.3-10 cycloalkyl, alkenyl, aryl, substituted aryl, alkylaryl, or substituted alkylaryl, including benzyl and substituted benzyl.
Other specific compounds of the invention are selected from the compounds described and labeled in the specification are 2CPT, 3CPT, 4CPT, 5CPT, 6CPT, 7CPT, 7CPT4 8CPTG, 8CPTA, 8CPTAB, 9CPTG, 9CPTA, 9CPTB, 10CPT, 10CPT(S), 10CPT(R), 11CPT, 11CPT(S), 11CPT(R), 12CPTA-1, 12CPTA-1(S), 12CPTA-1(R), 12CPTA-2, 12CPTA-2(S), 12CPTA-2(R), 12CPTB-1, 12CPTB-1(S), 12CPTB-1(R), 12CPTB-2, 12CPTB-2(S), 12CPTB-2(R), 12CPT, 12CPTB-(S), 12CPT(R), 13CPT, 13CPT(S), and 13CPT(R) where R.sub.1 -R.sub.9 is defined above.
Other specific

REFERENCES:
patent: 4778891 (1988-10-01), Tagawa et al.
patent: 4894456 (1990-01-01), Wall et al.
patent: 5053512 (1991-10-01), Wani et al.
patent: 5405963 (1995-04-01), Fortunak et al.
M. Shamma, D.A. Smithers, V. St. George, Tetrahedron, 1973, 1949-1954.
H. Terasawa, M. Sugimori, A. Eijima, H. Tagawa. Chem. Pharm. Bull., 1989, 37, 3382-3385.
A. Ejima, H. Terasawa, M. Sugimori, H. Tagawa, J.C.S. Perkin I, 1990, 27-31.
M.C. Wani, A.W. Nicholas, M.E. Wall, J. Med. Chem. 1987, 2317-2319.

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