Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2001-01-19
2004-02-03
Bernhardt, Emily (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C514S250000, C544S339000, C544S340000, C544S341000, C544S342000, C560S029000
Reexamination Certificate
active
06686470
ABSTRACT:
Throughout this application, various publications may be referenced by Arabic numerals in brackets. Full citations for these publications may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
FIELD OF INVENTION
The disclosed invention relates to novel compounds of the saframycin-ecteinascidin series having cytotoxic properties and to schemes for the total synthesis of such compounds.
BACKGROUND OF THE INVENTION
The screening of natural product sources for new drug candidates with useful therapeutic margins has led to a variety of novel structures. One of the most fascinating and promising of these is ecteinascidin 743 (ET 743) derived from the marine tunicate
Ecteinascidia turbinata
. (1) The novel structure of Et 743, its difficult availability, and its exceedingly potent cytotoxicity render it an attractive target for total synthesis. This goal was undertaken and accomplished in a most interesting fashion by E. J. Corey and coworkers.(2) Follow-up studies by Corey, Schreiber (3) and co-workers resulted in the demonstration that a significantly simplified version of ET 743 (ie: phthalascidin) retains the cytotoxicity of the natural product. Previously, well before the ecteinascidins were known, some of the named inventors had accomplished what was then the only total synthesis of quinocarcinol. (4) The central Mannich-like envelopment strategy, learned from work in the quinocarcin series, was adapted to the ET problem.
While ET 743 was previously known, the total synthesis of ET 743 was first accomplished by Corey in 1996 and, prior to this invention, was the only total synthesis of an ecteinascidin.
It is known that saframycin B, saframycin A (13, 14), saframycin S (15), ecteinascidin 729 (Et 729) (16), Et 743 and Phthalascidin (3) all posses cytotoxic antitumor and antibiotic characteristics. It is also known that saframycin S, saframycin B, saframycin A, Et 729, Et 743 (17), and phthalascidin (3) all possess a two tetrahydroisoquinoline aromatic carbon nitrogen framework. Saframycins and ecteinascidins have been shown to interact with DNA. Interactions are believed to occur between DNA and the tetrahydroisoquinoline aromatic carbon nitrogen framework. (2, 18)
SUMMARY OF THE INVENTION
The subject invention provides compounds of the saframycin-ecteinascidin series with cytotoxic properties having the following general formula, their uses and synthesis:
wherein R
1
and R
4
is H, a C
1
to C
4
alkyl group, or an acyl group;
wherein R
2
is an ether, ester, amide, a phthalimide group, a substituted phthalimide group or is covalently bound to R
6
;
wherein R
3
is ═O, OH, an ether group, an acyl group such as OC(O)Me, OC(O)Bn and OC(O)Et, or a sulfide group;
wherein R
5
is H, halogen, OH, an ether group, an acyl group, or an amide group;
wherein R
6
is ═O, OH, OCH
3
, CN, or an acyloxy group or is covalently bound to R
2
;
wherein R
7
, is ═O, OH, halogen, an ether group, or an acyl group;
wherein R
8
and R
9
are independently H, CH
3
, OCH
3
, OC
2
H
5
, CF
3
, halogen such as Br and F, or R
8
and R
9
are joined together as a methylenedioxy group, or other five or six membered ring;
wherein R
10
and R
11
are independently CH
3
, OCH
3
, OC
2
H
5
, SCH
3
, or SC
2
H
5
;
wherein R
12
is H, a C
1
to C
4
alkyl group, or an acyl group; and
wherein the chiral center marked * has the R or the S configuration.
The subject invention also provides for a group of saframycin-ecteinascidin series compounds with cytotoxic properties having the following general formula, their uses and synthesis:
wherein R
1
and R
4
is H, a C
1
to C
4
alkyl group, or an acyl group;
wherein R
2
is an ether, ester, amide, an aromatic group or is covalently bound to R
2
;
wherein R
3
is ═O, OH, an ether group, an acyl group such as OC(O)Me, OC(O)Bn and OC(O)Et, a sulfide group or H;
wherein R
5
is H, halogen, OH, an ether group, an acyl group, or an amide group;
wherein R
6
is ═O, OH, OCH
3
, CN, or an acyloxy group or is covalently bound to R
2
;
wherein R
7
, is ═O, OH, halogen, an ether group, or an acyl group;
wherein R
8
and R
9
are independently H, CH
3
, OCH
3
, OC
2
H
5
, CF
3
, halogen such as Br and F, or R
8
and R
9
are joined together as a methylenedioxy group, or other five or six membered ring;
wherein R
10
and R
11
are independently CH
3
, OCH
3
, OC
2
H
5
, SCH
3
, or SC
2
H
5
;
wherein R
12
is H, a C
1
to C
4
alkyl group, or an acyl group; and wherein the chiral center marked * has the R or the S configuration.
REFERENCES:
patent: 5721362 (1998-02-01), Corey et al.
patent: 6124292 (2000-09-01), Corey
patent: 6348467 (2002-02-01), Corey
patent: WO9951238 (1999-10-01), None
patent: WO0018233 (2000-04-01), None
International Preliminary Examination Report for International Application No. PCT/US01/01877.
Arai T, Takahashi K, Kubo A: New antibiotics saframycins A, B, C, D and E, J Antibiot. (Tokyo) vol. 30, No. 11, Nov. 1977, pp. 1015-1018 (Exhibit 1).
Bobbitt J, et al.: Synthesis of Isoquinolines. III. A New Synthesis of 1,2,3,4-tetrahydrisoquinolines,J. Org. Chemvol. 30, Jul. 1965, pp. 2247-2250 (Exhibit 2).
Cabre-Castellvi J, Polomo-Coll A, Palomo-Coll AL: Convenient Synthesis of Carboxilic Acid Anhydrides using N,N-Bis[2-oxo-3-oxazolidinyl]phosphorodiamidic Chloride,Synthesis. No. 7, Jul. 1981, pp. 616-620 (Exhibit 3).
Caldwell C., et al.: Synthesis of the Lipophilic Side Chain of the Cyclic Hexadepsipeptide Antibiotic L-156,602.J. Org. Chem. vol. 44, (1990), pp. 2355-2361 (Exhibit 4).
Caron M, Carlier P, Sharpless K: Highly Enantioselective Solvolyses of L and D- Phenylalanine p-Nitrophenyl Esters by an L-Histidyl Dipeptide in Surfacant Coaggregates Formed by Cholesterol-Containing Amphiphiles.J. Org. Chem. vol. 53, No. 21, Oct. 14, 1988, pp. 5187-5189 (Exhibit 5).
Corey E, Gin D, Kania R: Enantioselective Total Synthesis of Ecteinacidin 743,J. Am. Chem. Soc. vol. 118, (1996), pp. 9202-9203 (Exhibit 6).
Danishefsky S, et al.: Total synthesis of Quinocarcinol Methyl Ester,J. Am. Chem. Soc. vol. 107, No. 5, Mar. 6, 1985, pp. 1421-1423 (Exhibit 7).
Fukuyama T, et al.: Total Synthesis of (±) Saframycin A,J. Am. Chem. Soc. vol. 112, No. 8, Apr. 11, 1990, pp. 3712-3713 (Exhibit 8).
Fukuyama T, Linton S, Tun M: A Sterocontrolled Total Synthesis of (±) Reniramycin A,Tetrahedron Lett. vol. 31, No. 42, (1990), pp. 5989-5982 (Exhibit 9).
Fukuyama T, Sachleben R: Stereocontrolled total Synthesis of (±) Saframycin B,J. Am. Chem. Soc. vol. 104, No. 118, (1982), 4957-4958 (Exhibit 10).
Gao Y, et al.: Catalytic Asymmetric Expoxidation and Kinetic Resolution: MOdified Procedures Including in Situ Derivatization,J. Am. Chem. Soc. vol. 109, No. 18, Sep. 2, 1987, pp. 5765-5780 (Exhibit 11).
Guan Y, et al.: Molecular and crystal structures of ecteinascidins: potent antitumor compounds from the Caribean tunicate Ecteinascidia tur binata, J. Biomol Struct. Dyn., vol. 10, No. 5, Apr. 1993, pp. 793-818 (Exhibit 12).
Kishi K, et al.: Structure-activity relationships of saframycins, J. Antibiot. (Tokyo), vol. 37, No. 8, Aug. 1984 pp. 847-852 (Exhibit 13).
Kitahara Y, et al.: Synthesis of 4,7-Indolequinones. The Oxidative Demethylation of 4,7-Dimethoxyindoles with Ceric Ammonium Nitrate. Chem. Phar. Bull. (Japan), vol. 33, No. 5, (1985), pp. 2122-2128 (Exhibit 14).
Kubo A, et al.: Stereoselective total Synthesis of (±) Saframycin B,J. Org. Chem. vol. 53, No. 18, Sep. 2, 1988, pp. 4295-4310 (Exhibit 15).
Martinez E, et al: Phthalascidin, a synthetec antitumor agent with potency and mode of action comparable to ecteinacidin 743,Proc. Natl. Acad. Sci. vol. 96, Mar. 1999, pp. 3496-3501 (Exhibit 16).
Medina E, et al. Enantioselective synthesis of N-Boc-1-naphthylglycine,Tetrahedron Asym. vol. 8, No. 10, 1997, pp. 1581-1586 (Exhibit 17).
M
Danishefsky Samuel J.
Zhou Bishan
Bernhardt Emily
Cooper & Dunham LLP
The Trustees of Columbia University in the City of New York
White John P.
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