Intermediates useful in making mappicine and related compounds

Details Intermediates useful in making mappicine and related compounds Intermediates useful in making mappicine and related compounds

2000-02-22

2001-05-22

Dentz, Bernard (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S183000, C546S298000, C546S302000

Reexamination Certificate

active

06235907

ABSTRACT:

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):
Group 1.
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).
Group 2.
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 usefull 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, 12B-2(S), 12GB-2(R), 12G, 12G(S), 12G(R), 13G, 13G(S), or 13G(R),
where R
1
is any optionally substituted C
1-8
alkyl, including lower alkyl, C
3-10
cycloalkyl, lower alkyl-C
3-10
cycloalkyl, alkenyl, aryl, substituted aryl, alkylaryl, or substituted alkylaryl, including benzyl and substituted benzyl;
where R
2
is H,
a) any optionally substituted alkyl, including C
1-8
alkyl, alkylaryl, including C
1-6
alkyl-aryl, C
1-8
alkyl-C
6
aryl, substituted benzyl and unsubstituted benzyl;
b) —C(O)—R
3
, or
c) —C(R
7
)
2
—O—R
3
where each R
7
is independent of the other;
where R
3
is H, optionally substituted C
1-8
alkyl, including lower alkyl cycloalkyl, alkenyl, aryl, substituted aryl, and alkylaryl, or substituted alkylaryl, including benzyl and substituted benzyl;
where R
4
is H, optionally substituted C
1-8
alkyl, including lower alkyl, C
3-10
cycloalkyl, lower alkyl-C
3-10
cycloalkyl, alkenyl, aryl, substituted aryl, alkylaryl, or substituted alkylaryl, including benzyl and substituted benzyl;
where R
5
is H, optionally substituted C
1-8
alkyl, including lower alkyl, aryl, substituted aryl, or two R
5
groups may be combined to form cyclopentane or cyclohexane, or substituted derivatives thereof;
where R
6
is optionally substituted C
1-8
alkyl, lower alkyl, including ethyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, including benzyl and substituted benzyl, C
3-10
cycloalkyl, lower alkyl-C
3-10
cycloalkyl, heteroaryl, or substituted heteroaryl,
where R
7
is independently H, optionally substituted C
1-8
alkyl, including lower alkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, or two R
7
groups may be combined to form cyclopentane or cyclohexane or substituted derivatives thereof.
where R
8
is optionally substituted C
1-6
alkyl, including lower alkyl, including t-butyl, C
3-10
cycloalkyl lower alkyl-C
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, 7CPTA, 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-I(R), 12CPTB-2, 12CPTB-2(S), 12CPTB2(R), 12CPT, 12CPT(S), 12CPT(R), 13CPT, 13CPT(S), and 13CPT(R) where R
1
-R
9
is defined above.
Other specific compounds of the invention are selected from the compounds described and labeled in the specification as 6MG, 7MG, 8MG, 9MG, 10MG, 11MG, 12MG, 13MG, except where 13MG has an R
6
that is C
1-2
alkyl, where the variables have the same definition as the variables above.
Other specific compounds of the invention are selected from the compounds described and labeled in the specification as 5MM, 6MM, 7MM, 8MM, 9MM, 10MM, 11MM, or 12MM.
In addition to the compounds, various procedures labeled as STEPS are also described and claimed in this invention. Those STEPS include the STEPS described and labeled in the specification as CHART G comprising, STEP 2, or STEP 3, or STEP 4, or STEP 5, or STEP 5a, or STEP 5b, or STEP 6, or STEP 7GG, or STEP 7GA, or STEP 8GG, or STEP 8GA, or STEP 8GB, or STEP 9GG, or STEP 9GA, or STEP 9GB, or STEP 10GG, or STEP 10GA, or STEP 10 Resolution, or STEP 11, or STEPS 12, or STEP 13, or STEP 14 or any combination thereof combining two or more STEPS.
Also described and claimed are those STEPS described and labeled in the specification as CHART CPT comprising, STEP 7G, or STEP 7A, or STEP 8G, or STEP 8A, or STEP 8B, or STEP 9G, or STEP 9A, or STEP 9B, or STEP 10G, or STEP 10A, or STEP 11, or STEP 12, or STEP 13, or STEP 14 or any combination thereof combining two or more STEPS.
Also described and claimed are those STEPS described and labeled in the specification as CHART M-G comprising, STEP 5, or STEP 6, or STEP 7, or STEP 8 or STEP 9, or STEP 10, or STEP 11, or STEP 12, or STEP 13, or any combination thereof combining two or more STEPS.
Also described and claimed are those STEPS described and labeled in the specification as CHART M-M comprising, STEP 5, or STEP 6, or STEP 7, or STEP 8 or STEP 9, or STEP 10, or STEP 11, or STEP 12, or STEP 13, or any combination thereof combining two or more STEPS.
Additional Description of the Invention and Description of the Preferred Embodiment(s)
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are identified in two ways: by descriptive names and by reference to structures indicating various chemical entities. In appropriate situations, the proper stereochemistry is also described either with writing or represented in the structures. In some cases, when a molecule has two chiral centers, only the stereochemistry of one chiral center is indicated, unless the stereochemistry of the other chiral center is taught, the stereochemistry of the other chiral chiral center is unresolved or racemic. All the temperatures provided are in degrees centigrade, whether indicated with “°” or “C.°” or not. Minute may be written m or min. Hour may be written H or h. Abbreviations are standard or obvious to a chemist unless indicated otherwise. When compounds are added or exposed in any fashion to other compounds they may be said to be “mixed” with those compounds. Usually the purpose in mining compounds is to promote chemical reactions among one or more of the mixed compounds The following terms may also be used.
OPTIONALLY SUBSTITUTED The term “substituted” or “optionally substituted” usually appears first before “C
1-8
alkyl” but should be understood to modify all variations of all r groups. The term shall mean a group or radical that is substituted with halogen, lower alkyl, mono- or di(lower alkyl)-substituted lower alkyl, (lower alkyl)thio, halo-substituted lower alkyl, amino-substituted lower alkyl, mono- or di(lower awl)substituted amino, lo

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