Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-15
2004-05-11
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S231200, C514S239500, C514S315000, C514S317000, C514S408000, C514S529000, C540S450000, C540S484000, C544S107000, C544S108000, C544S401000, C544S403000, C544S404000, C546S187000, C548S579000, C548S400000, C562S106000
Reexamination Certificate
active
06734177
ABSTRACT:
BACKGROUND OF THE INVENTION
Discodermolide (1) is a novel polyketide natural product that was isolated from extracts of the marine sponge
Discodermia dissolute
by researchers at the Harbor Branch Oceanographic Institution (HBOI) (Gunasekera S P, Gunasekera M, Longley R E, Schulte G K. Discodermolide: a new bioactive polyhydroxylated lactone from the marine sponge
Discodermia dissolute
. [published erratum appears in J. Org. Chem. 1991;56:1346]. J. Org. Chem. 1990;55:4912-15.). Discodermolide lacks obvious structural resemblance to palitaxel, yet it shares with paclitaxel (the active substance in the drug Taxol) the ability to stabilize microtubules. In mechanism-based assays, discodermolide is more effective than paclitaxel. In fact, of the handful of compounds known to induce polymerization of purified tubulin, discodermolide is the most potent. However, microtubules, the major structural component in cells, are not simple equilibrium polymers of tubulin. They exist as regulated GTP-driven dynamic assemblies of heterodimers of &agr; and &bgr; tubulin. Although the dynamics are relatively slow in interphase cells, upon entering mitosis, the rate of growing and shortening increases 20 to 100-fold—the average microtubule turns over half the tubulin subunits every ten seconds. This change in rate allows the cytoskeletal microtubule network to dismantle and a bipolar spindle-shaped array of microtubules to assemble. The spindle attaches to chromosomes and moves them apart. The response to complete suppression of microtubule dynamics in cells is death. However, mitotic cells are more sensitive and the tolerance threshold appears to be cell-type specific. Molecules like paclitaxel that bind with high affinity to microtubules disrupt the dynamics process in tumor cells with lethal results even when the ratio of bound drug to tubulin is very low. Discodermolide binds to tubulin competitively with paclitaxel. Since paclitaxel has proven to be useful in treating some cancers, other compounds of the same mechanistic class may have utility against hyperproliferative disorders.
DESCRIPTION OF THE PRIOR ART
Preparation of intermediates for the synthesis of discodermolides and their polyhydroxy dienyl lactone derivatives for pharmaceutical use. Smith, Amos B. Iii; Qiu, Yuping; Kaufman, Michael; Arimoto, Hirokazu; Jones, David R.; Kobayashi, Kaoru; Beauchamp, Thomas J. (The Trustees of the University of Pennsylvania, USA). PCT Int. Appl. (2000), 201 pp. CODEN: PIXXD2 WO 0004865 A2 20000203 Designated States W: AU, CA, JP. Designated States RW: AT, BE, CH, CY, DE, DK, ES, Fl, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE. Patent written in English. Application: WO 99-US16369 19990720. Priority: US 98-121551 19980723. CAN 132:137207 AN 2000:84572
Total synthesis of the antimicrotubule agent (+)-discodermolide using boron-mediated aldol reactions of chiral ketones. Paterson, Ian; Florence, Gordon J.; Gerlach, Kai; Scott, Jeremy. Univ. Chem. Lab., Cambridge, UK. Angew. Chem., Int. Ed. (2000), 39(2), 377-380. CODEN: ACIEF5 ISSN: 1433-7851. Journal written in English. CAN 132:236926 AN 2000:76529
Gram-Scale Synthesis of (+)-Discodermolide. Smith, Amos B., III; Kaufman, Michael D.; Beauchamp, Thomas J.; LaMarche, Matthew J.; Arimoto, Hirokazu. Department of Chemistry Monell Chemical Senses Center and Laboratory for Research on the Structure of Matter, University of Pennsylvania, Pa., USA. Org. Lett. (1999), 1(11), 1823-1826. CODEN: ORLEF7 ISSN: 1523-7060. Journal written in English. CAN 132:35548 AN 1999:694867
Total synthesis of (+)-miyakolide. I. Total synthesis of (−)-discodermolide. II. Total synthesis of (+)-discodermolide. Halstead, David Patrick. Harvard Univ., Cambridge, Mass., USA. Avail. UMI, Order No. DA9921509. (1999), 199 pp. From: Diss. Abstr. Int., B 1999, 60(3), 1087. Dissertation written in English. CAN 132:194227 AN 1999:567611
Synthesis of C1-C8 and C9-C24 fragments of (−)-discodermolide: use of asymmetric alkylation and stereoselective aldol reactions. Filla, Sandra A.; Song, Jinhua J.; Chen, Lihren; Masamune, Satoru. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Mass., USA. Tetrahedron Lett. (1999), 40(30), 5449-5453. CODEN: TELEAY ISSN: 0040-4039. Journal written in English. CAN 131:271758 AN 1999:461996
A total synthesis of (−)-discodermolide. Harried, Scott S. Univ. of California, Los Angeles, Calif., USA. Avail. UMI, Order No. DA9913066. (1998), 189 pp. From: Diss. Abstr. Int., B 1999, 59(11), 5854. Dissertation written in English. CAN 131:199544 AN 1999:320599
Total Synthesis of (+)-Discodermolide. Marshall, James A.; Johns, Brian A. Department of Chemistry, University of Virginia, Charlottesville, Va., USA. J. Org. Chem. (1998), 63(22), 7885-7892. CODEN: JOCEAH ISSN: 0022-3263. Journal written in English. CAN 130:38235 AN 1998:642722
Synthetic techniques and intermediates for polyhydroxy, dienyllactones and mimics thereof. Smith, Amos B., III; Qiu, Yuping; Kaufman, Michael; Arimoto, Hirokaza; Jones, David R.; Kobayashi, Kaoru. (Trustees of the University of Pennsylvania, USA). PCT Int. Appl. (1998), 194 pp. CODEN: PIXXD2 WO 9824429 A1 19980611 Designated States W: CA, JP. Designated States RW: AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE. Patent written in English. Application: WO 97-US21798 19971201. Priority: US 96-759817 19961203. CAN 129:67649 AN 1998:394202
Syntheses of Discodermolides Useful for Investigating Microtubule Binding and Stabilization. Hung, Deborah T.; Nerenberg, Jennie B.; Schreiber, Stuart L. Howard Hughes Medical Institute, Harvard University, Cambridge, Mass., USA. J. Am. Chem. Soc. (1996), 118(45), 11054-11080. CODEN: JACSAT ISSN: 0002-7863. Journal written in English. CAN 126:31209 AN 1996:657111
Total Synthesis of (−)-Discodermolide. Smith, Amos B., III; Qiu, Yuping; Jones, David R.; Kobayashi, Kaoru. Monell Chemical Senses Center, University of Pennsylvania, Philadelphia, Pa., USA. J. Am. Chem. Soc. (1995), 117(48), 12011-12. CODEN: JACSAT ISSN: 0002-7863. Journal written in English. CAN 124:86679 AN 1995:938846
Total synthesis of discodermolide. Golec, Julian Marian Charles; Jones, Stuart Donald; Gillespie, Roger John. (Roussel Laboratories Ltd., UK). Brit. UK Pat. Appl. (1995), 57 pp. CODEN: BAXXDU GB 2280677 A1 19950208 Patent written in English. Application: GB 94-15399 19940729. Priority: GB 93-15802 19930730. CAN 123:32864 AN 1995:615210
SUMMARY OF THE INVENTION
The present invention provides new anti-tumor agents which are effective against a variety of cancer cells. More particularly, the present invention relates to certain discodermolide acid salts which exhibit a higher degree of selectivity in killing cancer cells. In addition, the present invention provides pharmaceutical compositions useful in treating tumors comprising a therapeutically effective amount of certain discodermolide acid salts. Moreover, the present invention provides a method of treating tumors comprising administering to a mammal afflicted therewith a therapeutically effective amount of certain discodermolide acid salts. Furthermore, the present invention relates to a process for preparing certain discodermolide acid salts.
DETAILED DESCRIPTION OF THE INVENTION
The essence of the instant invention is the discovery that certain discodermolide acid salts are useful in treating tumors. In one embodiment, the instant invention provides new anti-tumor agents of formula I
where R is Li
+
, Na
+
, K
+
, ½Ca
++
, ½Mg
++
, ½Mn
++
, R
1
R
2
R
3
R
4
N
+
, or a nitrogen containing ring selected from
where each of R
1
, R
2
, R
3
and R
4
, independently, is hydrogen, (C
1-12
)alkyl, hydroxy(C
2-8
)alkyl or benzyl; and n is 1-5.
Preferred compounds are those of formula I where
R is Li
+
, Na
+
, K
+
, ½Ca
++
, R
1
R
2
R
3
R
4
N
+
, or a nitrogen containing ring selected from II, III and IV
where each of R
1
, R
2
, R
3
and R
4
, independently, is hydrogen, (C
1-8
)a
Kapa Prasad K.
Kinder, Jr. Frederick R.
Loeser Eric M.
Berch Mark L.
Borovian Joseph J.
Habte Kahsay
Novartis AG
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