Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-12-07
1999-10-12
Trinh, Ba K.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
549510, 549511, C07D26304, C07D30514, C07D26306
Patent
active
059657391
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Taxol is a member of the taxane family of diterpenes, having the structure shown below: ##STR2## The numbering system shown for taxol is that recommended by IUPAC (IUPAC, Commission on the Nomenclature of Organic Chemistry, 1978).
The chemistry of the potent anticancer diterpenoid taxol and analogs thereof is reviewed, with an emphasis on isolation and analysis, structural modifications, partial synthesis, and structure-activity relationships by David G. I. Kingston, The Chemistry of Taxol, Pharmac. Ther., Vol 52, pp 1-34, 1991.
The clinical pharmacology of taxol is reviewed by Eric K. Rowinsky and Ross C. Donehower, The Clinical Pharmacology and Use of Antimicrotubule Agents in Cancer Chemotherapeutics, Pharmac. Ther., Vol 52, pp 35-84, 1991. Clinical and preclinical studies with taxol are reviewed by William J. Slichenryer and Daniel D. Von Hoff, Taxol: A New and Effective Anti-cancer Drug, Anti-Cancer Drugs, Vol. 2, pp 519-530, 1991.
Taxol and analogs thereof are the subject of various patents including, for example, U.S. Pat. Nos. 4,814,470; 4,857,653; 4,942,184; 4,924,011; 4,924,012; 4,960,790; 5,015,744; 5,157,049; 5,059,699; 5,136,060; 4,876,399; 5,227,400 as well as PCT Publication No. WO 92/09589, European Patent Application 90305845.1 (Publication No. A2 0 400 971), 90312366.9 (Publication No. A1 0 428 376), 89400935.6 (Publication No. A1 0 366 841) and 90402333.0 (Publication No. 0 414 610 A1), 87401669.4 (A 1 0 253 739), 92308608.6 (A1 0 534 708), 92308609.4 (A1 534 709) and PCT Publication Nos. WO 91/17977, WO 91/17976, WO 91/13066, WO 91/13053.
Various processes for the preparation of taxol (and intermediates and analogs thereof) are described in Tetrahedron Letters, 1992, 36, 5185; J. Org. Chem., 1991, 56, 1681 and J. Org. Chem., 1991, 56, 5114.
Chen et al., Serendipitous Synthesis of a Cyclopropane-Containing Taxol Analog via Anchimeric Participation of an Unactivated Angular Methyl Group, Advance ACS Abstracts, Vol 1, No. 2., Jul. 15, 1993 reported the treatment of a 7-epi taxol derivative with DAST in dichloromethane led to an unexpected reaction involving participation of the C-19 methyl group and clean formation of a cyclopropane ring. See also J. Org. Chem., 1993, 58, 4520 (Aug. 13, 1993).
Chen, et. al., Tetrahedron Letters, 1994, 35, 41-44, have reported that the reaction of 2'-O -Cbz-taxol with DAST gave 2'-O-Cbz-7-deoxy-7.alpha.-fluorotaxol and 2'-O-Cbz-7-deoxy-7.beta.,8.beta.-methanotaxol. Removal of the 2'-O-Cbz protecting groups from the latter two compounds gave 7-deoxy-7.alpha.-fluorotaxol and 7-deoxy-7.beta.,8.beta.-methanotaxol. 7,8-Cyclopropataxanes are the subject of U.S. Pat. No. 5,254,580. Klein, et. al., J. Org. Chem., 1994, 59, 2370, report formation of 7.beta.,8.beta.-methanotaxols.
U.S. Pat. No. 5,294,637 (granted Mar. 15, 1994) relates 7-fluorotaxal derivatives.
U.S. Pat. No. 5,248,796 (granted Sep. 28, 1993) relates to 10-desacetoxy-11,12-dihydrotaxol-10,12(18)-diene derivatives and the preparation of 10-desacetoxytaxol.
Chaudhary, A. G.; et. al., J. Am. Chem. Soc., 1994, 116, 4097-8 discloses several meta and para-substituted 2-benzoyl analogs of taxol.
Didier, E., et. al., Tetrahedron Lett., 1994, 35, 2349-52 describe the use of 2-arylox-arylidines as protecting groups for the taxol side-chanin precursor fragment.
Ojima, I., et. al., Bioorganic Med. Chem. Lett. 1993, 3, 2479-2482 describe several side chain urea analogs (including a t-butyl urea analog).
SUMMARY OF THE INVENTION
This invention provides oxazolidine protected taxol analogs of the Formula: ##STR3## wherein R.sub.1 is selected from the group consisting of
--CH.sub.3,
--C.sub.6 H.sub.5 or phenyl substituted with one, 2 or 3 C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.3 alkoxy, halo, C.sub.1 -C.sub.3 alkylthio, trifluoromethyl, C.sub.2 -C.sub.6 dialkylamino, hydroxy or nitro,
-2-furyl, 2-thienyl, 1-naphthyl, 2-naphthyl or 3,4-methylenedioxyphenyl;
R.sub.11 is phenyl substituted with --(OC.sub.1 -C.sub.2 alkyl).sub.n where n is 1 to 3; and
R.sub.12 is selected from the group co
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Mathew, A.E., Mejillano, Magdale
Kelly Robert C.
Skulnick Harvey I.
Jameson William G.
Pharmacia & Upjohn Company
Trinh Ba K.
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