Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-02-25
1999-11-02
Rotman, Alan L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
560 38, 560155, 560156, 548954, C07D30308, C07C22900
Patent
active
059773871
DESCRIPTION:
BRIEF SUMMARY
This invention relates to the fields of pharmaceutical and organic chemistry and provides novel cryptophycin compounds, intermediates for the preparation of other cryptophycin compounds and a novel process for the preparation of cryptophycin compounds having antimicrotubule activity.
Antimetabolites have been used for a number of years as chemotherapeutic agents in the treatment of cancer. A new class of antimetabolites, cryptophycin compounds, are useful for disrupting the microtubule system. In order to produce sufficient quantities of these compounds, efficient totally synthetic processes for the preparation of cryptophycin compounds are desired.
The present invention provides a rapid analog process and key intermediates for the total synthesis of cryptophycin compounds. The cryptophycin compounds prepared by this process are useful for disrupting the microtubule system of eucaryotic cells and are also useful research tools.
The present invention provides novel intermediate compounds of formula II ##STR1## wherein G is C.sub.1 -C.sub.12 alkyl, C.sub.2 -C.sub.12 alkenyl, C.sub.2 -C.sub.12 alkynyl or Ar; heteroaromatic group; tri(C.sub.1 -C.sub.6 -alkyl)ammonium, C.sub.1 -C.sub.6 -alkylthio, di(C.sub.1 -C.sub.6 -alkyl)sulfonium, C.sub.1 -C.sub.6 -alkylsulfonyl, or C.sub.1 -C.sub.6 -alkylphosphonyl; and or together form an epoxide, aziridine, episulfide, or cyclopropyl ring; C-14; -C.sub.3 -alkyl)NR.sup.51 R.sup.52, or OR.sup.51 ; and -C.sub.6 -alkynyl or (C.sub.1 -C.sub.6 alkyl)C.sub.3 -C.sub.5 cycloalkyl;
Another aspect of this invention are novel intermediates of formula IV ##STR2## wherein G, X, R.sub.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.24 are as defined supra, and R.sup.26 is an alcohol protecting group.
This invention also provides a process for preparing a compound of formula III ##STR3## wherein G, X, Y, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7, R.sup.8, R.sup.9, R.sup.10 and R.sup.13 are as defined supra, and (C.sub.3 -C.sub.8)cycloalkyl, substituted C.sub.3 -C.sub.8 cycloalkyl, a heteroaromatic or substituted heteroaromatic group, or a group of formula IIIa, III' or III": ##STR4## wherein R.sup.6a, R.sup.6b, and R.sup.6c independently are H, halo or OR.sup.18 ; -C.sub.6)alkyl, OR.sup.18, O-aryl, NH.sub.2, NR.sup.18 R.sup.19, NO.sub.2, OP0.sub.4 H.sub.2, (C.sub.1 -C.sub.6 alkoxy)phenyl, Sbenzyl, CONH.sub.2, CO.sub.2 H, PO.sub.3 H.sub.2, SO.sub.2 R.sup.23, or Z'; ##STR5## wherein R.sup.27 is H, Ar, C.sub.1 -C.sub.12 alkyl, or C.sub.1 -C.sub.6 alkyl having up to three substituents selected from halo, C.sub.1 -C.sub.3 alkoxy and C.sub.1 -C.sub.3 alkylthio;
Another embodiment of this invention is a process for preparing a compound of Formula I ##STR6## wherein G, X, Y, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9 and R.sup.10 are as defined supra; and formula V as defined supra, in the presence of a silylating agent;
The processes of this invention provide a means for preparing cryptophycin compounds by a totally synthetic route. With these processes, commercially available amino acids can be cyclized into the cryptophycin molecule. Additionally, the processes provided herein are shorter and more efficient than previously known total synthetic methods. See Barrow, et al. J. Am. Chem. Soc. 1995, 117, 2479-2490.
As used herein, the term "alkyl" refers to an alkyl group with the designated number of carbon atoms. It may be saturated or unsaturated, and branched or straight chain. "Lower alkyl" means a C.sub.1 -C.sub.5 alkyl group. Examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, propenyl, sec-butyl, n-pentyl, isobutyl, tert-butyl, sec-butyl, methyl-substituted butyl groups, pentyl, tert-pentyl, sec-pentyl, methyl-substituted pentyl groups and the like.
"Substituted alkyl" refers to a C.sub.1 -C.sub.6 alkyl group that may include up to three (3) substituents containing one or more heteroatoms. Examples of such substituents are OH, Sbenzyl, NH.sub.2, CONH.sub.2, CO.sub.2 H, PO.sub.3 H.sub.2 and SO.sub.2 R.sup.21 w
REFERENCES:
Barrow, R.A. et al.: Total synthesis of cryptophycins. revision of the structures of cryptophycins A and C. J. Am. Chem. Soc. vol. 11, pp. 2479-2490, Mar. 8, 1995.
Aulakh Charanjit S.
Boudreaux William R.
Eli Lilly and Company
Engelmann John H.
Rotman Alan L.
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