Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-02-22
2002-02-19
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S229000, C544S342000, C544S338000
Reexamination Certificate
active
06348467
ABSTRACT:
BACKGROUND OF THE INVENTION
The ecteinascidins (herein abbreviated Et or Et's) are exceedingly potent antitumor agents isolated from the marine tunicate
Ecteinascidia turbinata
. Several ecteinascidins have been reported previously in the patent and scientific literature. See, for example:
U.S. Pat. No. 5,721,362, which describes a synthetic process for the formation of ecteinascidin compounds and related structures, such as the saframycins. In one particularly preferred embodiment, the patent provides a synthetic route for the formation of ecteinascidin 743, an exceedingly potent marine-derived antitumor agent, now in clinical trials. The process of this patent is enantio- and stereocontrolled, convergent and short. Also disclosed are novel process intermediates, useful not only in the total synthesis of ecteinascidin 743, but also other known ecteinascidin compounds, including derivatives and analogs thereof.
U.S. Pat. No. 5,256,663, which describes pharmaceutical compositions comprising matter extracted from the tropical marine invertebrate,
Ecteinascidia turbinata,
and designated therein as ecteinascidins, and the use of such compositions as antibacterial, anti-viral, and/or antitumor agents in mammals.
U.S. Pat. No. 5,089,273, which describes novel compositions of matter extracted from the tropical marine invertebrate,
Ecteinascidia turbinata,
and designated therein as ecteinascidins 729, 743, 745, 759A, 759B and 770. These compounds are useful as antibacterial and/or antitumor agents in mammals.
U.S. Pat. No. 5,478,932, which describes ecteinascidins isolated from the Caribbean tunicate
Ecteinascidia turbinata,
which provide in vivo protection against P388 lymphoma, B16 melanoma, M5076 ovarian sarcoma, Lewis lung carcinoma, and the LX-1 human lung and MX-1 human mammary carcinoma zenografts.
U.S. Pat. No. 5,654,426, which describes several ecteinascidins isolated from the Caribbean tunicate
Ecteinascidia turbinata,
which provide in vivo protection against P388 lymphoma, B16 melanoma, M5076 ovarian sarcoma, Lewis lung carcinoma, and the LX-1 human lung and MX-1 human mammary carcinoma zenografts.
See also: Corey, E. J.,
J. Am. Chem. Soc.,
1996, 118 pp. 9202-9203; Rinehart, et al.,
Journal of National Products,
1990, “Bioactive Compounds from Aquatic and Terrestrial Sources”, vol. 53, pp. 771-792; Rinehart et al.,
Pure and Appl. Chem.,
1990, “Biologically active natural products”, vol. 62, pp. 1277-1280; Rinehart, et al.,
J. Org. Chem.,
1990, “Ecteinascidins 729, 743, 745, 759A, 759B, and 770: Potent Antitumor Agents from the Caribbean Tunicate
Ecteinascidia turbinata”
, vol. 55, pp. 4512-4515; Wright et al.,
J. Org. Chem.,
1990, “Antitumor Tetrahydroisoquinoline Alkaloids from the Colonial Ascidian
Ecteinascidia turbinata”, vol.
55, pp. 4508-4512; Sakai et al.,
Proc. Natl. Acad. Sci. USA
1992, “Additional antitumor ecteinascidins from a Caribbean tunicate: Crystal structures and activities in vivo”, vol. 89, 11456-11460;
Science
1994, “Chemical Prospectors Scour the Seas for Promising Drugs”, vol. 266, pp. 1324; Koenig, K. E., “Asymmetric Synthesis,” ed. Morrison, Academic Press, Inc., Orlando, Fla., vol. 5, 1985, p. 71; Barton, et al.,
J. Chem Soc. Perkin Trans.,
1, 1982, “Synthesis and Properties of a Series of Sterically Hindered Guandidine Bases”, pp. 2085; Fukuyama et al.,
J. Am Chem Soc.,
1982, “Stereocontrolled Total Synthesis of (+)-Saframycin B”, vol. 104, pp. 4957; Fukuyama et al.,
J. Am Chem Soc.,
1990, “Total Synthesis of (+)-Saframycin A”, vol. 112, p. 3712; Saito, et al.,
J. Org. Chem.,
1989, “Synthesis of Saframycins. Preparation of a Key Tricyclic Lactam Intermediate to Saframycin A”, vol. 54, 5391; Still, et al.,
J. Org. Chem.,
1978, “Rapid Chromatographic Technique for Preparative Separations with Moderate Resolution”, vol. 43, p. 2923; Kofron, W. G.; Baclawski, L. M.,
J. Org. Chem.,
1976, vol. 41, 1879; Guan et al.,
J. Biomolec. Struc.
&
Dynam
., vol. 10 pp. 793-817 (1993); Shamma et al., “Carbon-13 NMR Shift Assignments of Amines and Alkaloids,” p. 206 (1979); Lown et al.,
Biochemistry,
21, 419-428 (1982); Zmijewski et al.,
Chem. Biol. Interactions,
52, 361-375 (1985); Ito,
CRC Crit. Rev. Anal. Chem.,
17, 65-143 (1986); Rinehart et al., “Topics in Pharmaceutical Sciences 1989” pp. 613-626, D. D. Breimer, D. J. A. Cromwelin, K. K. Midha, Eds., Amsterdam Medical Press B.V., Noordwijk, The Netherlands (1989); Rinehart et al., “Biological Mass Spectrometry,” 233-258 eds. Burlingame et al., Elsevier Amsterdam (1990); Guan et al.,
Jour. Biomolec. Struc
&
Dynam.,
vol. 10 pp. 793-817 (1993); Nakagawa et al.,
J. Amer. Chem. Soc.,
111: 2721-2722 (1989); Lichter et al., “Food and Drugs from the Sea Proceedings” (1972), Marine Technology Society, Washington, D.C. 1973, 117-127; Sakai et al.,
J. Amer. Chem. Soc.,
1996, 118, 9017; Garcia—Rocha et al.,
Brit. J. Cancer,
1996, 73: 875-883; and Pommier et al.,
Biochemistry,
1996, 35: 13303-13309.
The disclosures of the above-referenced patents and publications are hereby incorporated herein by reference.
Et 743 (NSC 648766) is currently undergoing evaluation by the National Cancer Institute on the basis of exceedingly potent activity in vivo against a variety of tumors.
In 1996, the total synthesis of Et-743 was reported. See E. J. Corey et al.,
J. Amer. Chem. Soc.,
118, 9292-9203 (1996); see also, U.S. Pat. No. 5,721,362. Disclosed in the '362 patent is the intermediate 11, with the following structure:
This intermediate compound, re-designated herein as Compound 1, has served as the starting material for a series of new synthetic ecteinascidin-like compounds.
SUMMARY OF THE INVENTION
The present invention is directed to compounds having the following formula:
wherein the substituent groups defined by R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
and R
9
are each independently selected from the group consisting of H, OH, OR′, SH, SR′, SOR′, SO
2
R′, NO
2
, NH
2
, NHR′, N(R′)
2
, NHC(O)R′, CN, halogen, ═O, C(═O)H, C(═O)R′, CO
2
H, CO
2
R′, C
1
-C
12
alkyl, C
2
-C
12
alkenyl, C
2
-C
12
alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, and substituted or unsubstituted heteroaromatic;
wherein each of the R′ groups is independently selected from the group consisting of H, OH, NO
2
, NH
2
, SH, CN, halogen, ═O, C(═O)H, C(═O)CH
3
, CO
2
H, CO
2
CH
3
, C
1
-C
12
alkyl, C
2
-C
12
alkenyl, C
2
-C
12
alkynyl, aryl, aralkyl, and heteroaromatic;
wherein each dotted circle represents one, two or three optional double bonds;
wherein R
7
and R
8
may be joined into a carbocyclic or heterocyclic ring system;
and wherein X
1
and X
2
are each independently defined as above for R
1
-R
8
and further include the definitions of X
1
and X
2
as provided below for the preferred embodiments.
Preferred compounds of the present invention have the following formula:
wherein the substituent groups defined by R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, and R
9
are each independently selected from the group consisting of H, OH, OR′, SH, SR′, SOR′, SO
2
R′, NO
2
, NH
2
, NHR′, N(R′)
2
, NHC(O)R′, CN, halogen, ═O, C
1
-C
6
alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, and substituted or unsubstituted heteroaromatic;
wherein each of the R′ groups is independently selected from the group consisting of H, OH, NO
2
, NH
2
, SH, CN, halogen, ═O, C(═O)H, C(═O)CH
3
, CO
2
H, CO
2
CH
3
, C
1
-C
6
alkyl, phenyl, benzyl, and heteroaromatic;
wherein each dotted circle represents one, two or three optional double bonds;
and wherein X
1
and X
2
are each independently defined as above for R
1
-R
8
, and further include the definitions of X
1
and X
2
as provided below for the preferred embodiments.
Suitable halogen substituents in the compounds of the present invention include F, Cl, Br and I.
Alkyl groups preferably have from 1 to about 12 carbon ato
Linek Ernest V.
Patel Sudhaker B.
President and Fellows of Harvard College
Raymond Richard L.
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