WO1991001982A1 - Discodermolide compounds, compositions containing same and methods of preparation and use - Google Patents
Discodermolide compounds, compositions containing same and methods of preparation and use Download PDFInfo
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- WO1991001982A1 WO1991001982A1 PCT/US1990/004493 US9004493W WO9101982A1 WO 1991001982 A1 WO1991001982 A1 WO 1991001982A1 US 9004493 W US9004493 W US 9004493W WO 9101982 A1 WO9101982 A1 WO 9101982A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/30—Oxygen atoms, e.g. delta-lactones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- DISCODERMOLIDE COMPOUNDS COMPOSITIONS CONTAINING SAME AND METHODS OF PREPARATION AND USE FIELD OF THE INVENTION
- This invention relates to new organic compounds and compositions which have useful therapeutic properties. More particularly, the invention concerns novel lactone compounds having immunomodulatory and antitumor activities, pharmaceuti- cal compositions comprising such compounds, methods for the preparation of the novel compounds and compositions and methods of their use for therapeutic purposes.
- Immunomodulation is a developing segment of immunopharmacology.
- Immunomodulator compounds and compositions are useful for modulating or regulating immunological functions in warm blooded animals.
- Immunomodulators may be immunostimulants for building up immunities to or initiate healing of certain diseases and disorders. Conversely, they may be immunoinhibitors or immunosuppressors for preventing undesirable immuno reactions of the body to foreign materials and autoimmue diseases.
- Immunomodulators have been found to be useful for treating systemic autoimmue diseases, such as lupus erythematosus, as well as immunodeficiency diseases. Further, immunomodulators may be useful for immunotherapy of cancer or to prevent rejections of foreign organs or other tissues in transplants, e.g., kidney, heart or bone marrow.
- immunomodulator compounds including muramylic acid dipeptide derivatives, levamisole, niridazole, oxysuran, flagyl and others from the groups of interferons, interleukins, leukotrienes, corticosteroids and cyclosporins. Many of these compounds have been found, however, to have undesirable side effects and/or high toxicity. New immunomodulator compounds are therefore needed to provide a wider range of immunomodulator function for specific areas with a Minimum of undesirable side effects.
- Marine sponges have proved to be such a source and a number of publications have been issued disclosing organic compounds derived from marine sponges including Scheuer, P.J. Ed., Marine Natural Products, Chemical and Biological Perspectives ; Academic Press, New York, 1978, Vol. I, pp 175-240; Uemura et al., J. Am. Chem. Soc, 1985, 107, 4796-4798; Minale, L., et al., Fortschr. Chem. org. Naturst. 1976, 33, 1-72; Faulkner, D.J., Nat. Prod. Rep. 1987, 4, 539- 576 and references cited therein.
- the present invention has added to the arsenal of immunomodulator and antitumor compounds by the discovery of new organic compounds possessing useful immunomodulator and antitumor activity isolated from extracts of the marine sponge Discodermia dissoluta .
- a principal object of this invention is the provision of novel biologically active, lactone compounds and compositions comprising such compounds. Additional objects are the provision of methods for producing the new compounds and compositions.
- Yet another object is the provision of methods of using the new compounds and compositions, particularly, methods to modify immune systems, inhibit tumor growth and mitigate cancerous cachexia.
- R -H, -A, -CH 2 -Q, -COA or -COZ
- Y -H, -A, -Z, -CH 2 -Z, -COA, -COZ, and acid- addition salts thereof.
- Compounds of the invention also include the octahydro and 23,24-dihydro derivatives of compounds according to the above formula.
- the new compounds may be a single geometrical isomer or mixtures thereof (E or Z isomer).
- R -H, or -COCH 3 , or -CH 3
- the new compounds are substantially pure, i.e., contain at least 95% of the compound as determined by established analytical methods.
- lower alkyl groups A in compounds of the invention preferably contain 1-6 carbon atoms and include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, 2,2-dimethylpropyl, hexyl and 2-ethylamyl.
- monocyclicaryl groups Z in compounds of the invention include phenyl, p-tolyl, m-tolyl, p-bromophenyl, p-chlorophenyl, 3-ethyl-4-bromophenyl, 2,4-diethylphenyl, 2-methyl-3-hydroxyphenyl, 2,4-dimethyl-3-chlorophenyl, 2-bromo-3-amino-4-methylphenyl and 2-iodo-3-ethyl-5-aminophenyl.
- Also provided by the discoveries of the invention are new pharmaceutical compositions containing between about 0.1% to 55% by weight, particularly 1% to 30%, based on the total weight of the composition, of one of the new compounds of the invention or a mixture of two or more such compounds and one or more pharmaceutically acceptable carrier or diluent.
- the invention provides a variety of processes for the production of compounds of the invention.
- a preferred method of producing them comprises the steps of collecting marine sponge of the species Discodermia dissoluta , extracting such sponge with a selected organic solvent system to obtain an extract, fractioning the extract and isolating lactone compounds from the fractioned extract.
- the sponge Discodermia has two literature references.
- new salts within the scope of the invention are made by adding mineral acids, e.g., HCl, H 2 SO 4 , etc., or strong organic acids, e.g., formic, oxalic, etc., in appropriate amounts to form the acid addition salt of the parent compound or its derivative.
- mineral acids e.g., HCl, H 2 SO 4 , etc.
- strong organic acids e.g., formic, oxalic, etc.
- synthesis type reactions may be used pursuant to known procedures to add or modify various groups in the preferred compounds to produce other compounds within the scope of the invention.
- the invention also comprises methods of use of the new compounds and compositions of the invention, e.g., methods of inhibiting tumors in a mammal, therapeutic methods for treating cancerous cachexia and methods of regulating immunological functions in warm blooded animals.
- methods for inhibiting tumors in a host comprise contacting tumor cells with an effective amount of the new pharmaceutical compositions of the invention.
- This example concerns the preparation of discodermolide having the formula:
- the sponge Discodermia dissoluta was homogenized with methanol-toluene (3:1). After filtration and evaporation at reduced pressure below 35oC, a brown colored extract was obtained. The extract was then partitioned between EtOAc and H 2 O. The biologically active EtOAc soluble fraction was fractionated first by column chromatography on SiO 2 gel using CH 2 Cl 2 and MeOH gradient and monitored by biological activity. The biologically active (AT, ID) fraction was chromatographed on RP-C18 with H 2 O-MeOH gradient. The fractions that eluted with (30-70% H 2 O-MeOH) gave impure discodermolide.
- HRFAB m/z 702.4203, ⁇ 1.4 mm ⁇ for C 39 H 60 NO 10 (M- CH 3 COO) + ;
- LRFAB m/z (relative intensity) 762(3%), 702(5), 642(2), 581(4), 521(7), 439(3), 427(5), 411(4), 399(5), 387(12), 359(9), 334(11), 327(5), 299(5), 285(5),259(6), 232(20), 217(75), 173(42), 161(72), 147(50), 133(80), 126(100).
- a suitable solvent e.g., ethanol or methanol.
- the mixture is stirred in the presence of hydrogen in a hydrogenation apparatus capable of operation at elevated pressure, e.g., Parr apparatus, to produce octahydro discodermolide. If the reaction is too slow, it is facilitated by making the media slightly acidic. Partial reduction of discodermolide to the 23,24-dihydro derivative can be attained by hydrogenation at ambient pressure conditions.
- discodermolide was mixed with methyl iodide in dry acetone containing anhydrous K 2 CO 3 and refltiXed for 12 hrs. The mixture was filtered and the solvent evaporated under vacuum. The residue was chromatographed on silica gel to give a product, the tetramethyl ether.
- the crude ethanolic extract was tested in the two-way mixed lymphocyte reaction (MLR) and a lymphocyte viability assay (LCV) at 500 and 50 ⁇ g/ml, using murine splenocytes.
- MLR two-way mixed lymphocyte reaction
- LCV lymphocyte viability assay
- Cellular proliferation was measured using a modified form of the M.T.T. assay (Mosmann, T. 1983. Rapid colorimetric assay for cellular growth and survival: (Application to proliferation and cytotoxicity assays. J. Immunol . Methods 65:55-63). Responses were reported as a percent of the positive MLR or LCV control.
- the pure compound discodermolide I was tested for Immunosuppressive effects on the MLR and LCV assays using murine splenocyte ⁇ and in the human MLR and mitogen stimulation assays, using human peripheral blood lymphocytes (PBL). Cellular proliferation was determined using incorporation of 3 H-thymidine.
- P388 cells obtained from Dr. J. Mayo, National Cancer Institute, Bethesda, MD, were maintained in Roswell Park Memorial Institute (RPMI) medium 1640 supplemented with 10% horse serum. All cell lines were cultured in plastic tissue culture flasks and kept in an incubator at 37oC in humidified air containing 5% CO 2 . Antibiotic-free stock cultures of P388 cells were subcultured to 10 5 cells/ml by dilution in fresh growth medium at 2 to 3 day intervals. The mean generation time of primary cultures was 14 to 17 hr.
- RPMI Roswell Park Memorial Institute
- P388 cells were enumerated using 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) as described below (M.C. Alley, et al., Cancer Res. 48:589, 1988).
- MTT 4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide
- the crude extract was immunosuppressive in the MLR at a 1x concentration ( ⁇ 1% of the control MLR response, but exhibited toxicity ( ⁇ 6% of the control LCV response) at the same dosage level. Immunosuppressive activity was observed at a 1/10 dilution of the crude extract ( ⁇ 1% of the control MLR) which was associated with relatively low toxicity (>70% of the control LCV response).
- Discodermolide was immunosuppressive in the murine MLR with no associated toxicity at a dosage of 0.5 ⁇ g/ml. Higher dilutions (500, 50 and 5 ⁇ g/ml) exhibited immunosuppressive activity, but with associated toxicity (Table 1). In the human MLR, Discodermolide was immunosuppressive with >94% viability at 50, 25, 12.5, 6.3, 3.1 and 1.6 ⁇ g/ml ( Figure 2). Discodermolide suppressed Con A and PHA (10 ⁇ g/ml) stimulation of human PBL at 50 and 25 ⁇ g/ml, with >91% viability (Table 3).
- a 1:500 dilution of the crude extract inhibited the proliferation of cultured murine P388 leukemia cells by 91%.
- Discodermolide inhibited the proliferation of cultured murine P388 cells.
- the concentration resulting in 50% inhibition (IC50) was 0.5 ⁇ g/ml as reported in the following Table 4.
- compositions comprising, as an active ingredient, an effective amount of one or more of the new compounds and one or more non-toxic, pharmaceutically acceptable carrier or diluent.
- carriers for use in the invention include, ethanol, dimethyl sulfoxide, glycerol, silica, alumina, starch, and equivalent carriers and diluents.
- the new compounds are useful as immunomodulatory agents. An intended use is for immune reactions (in vivo/in vitro) that require modulation via T-cell activity. Direct application would be for human in vivo suppression of T-cell responses, e.g., transplantation and autoimmunity.
- suitable organic solvent systems for extraction can be selected from methanol, ethyl acetate, toluene, heptane, hexane, isooctane, acetone, benzene, diethyl ether, t-butyl methyl ether, ethanol, isopropanol, 1,2 dichloroethane and especially, chloroform, ammonium hydroxide and dichloromethane. Mixtures of two or more of such solvents in various ratios and combinations are advantageous.
- Preferred isolation procedures include various chromatography techniques, e.g., countercurrent chromatography with suitable columns, including multi-layer planetary coil columns.
- solvents are available for use as single or mixed eluents, such as methylene chloride, methanol, ethyl acetate, acetonitrile, n-propanol, n-butanol, water, dilute sulfuric acid, and equivalent solvents. Further purifications using such procedures may also be carried out on the recovered extractions.
- Preferred isolation techniques for further purification include chromatographic operations such as high-pressure, liquid chromatography with suitable columns with suitable solvent, particularly, methylene chloride ⁇ /methanol or methanol/water mixtures.
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Abstract
Novel lactone compounds having immunomodulatory and antitumor activities, pharmaceutical compositions comprising such compounds, methods for the preparation of the novel compounds and compositions and methods of their use for therapeutic purposes are described. The new lactone compounds have the structure according to formula (I), wherein: R = -H, -A, -CH2?-Q, -COA or -COZ, A = lower alkyl, Z = monocyclicaryl, Q = phenyl, tolyl or xylyl, X = -H, -A, -Z or -CH2?-Z, and Y = -H, -A, -Z, -CH2?-Z, -COA, -COZ, the acid-addition salts, the octahydro and 23,24-dihydro derivatives thereof.
Description
DISCODERMOLIDE COMPOUNDS, COMPOSITIONS CONTAINING SAME AND METHODS OF PREPARATION AND USE FIELD OF THE INVENTION
This invention relates to new organic compounds and compositions which have useful therapeutic properties. More particularly, the invention concerns novel lactone compounds having immunomodulatory and antitumor activities, pharmaceuti- cal compositions comprising such compounds, methods for the preparation of the novel compounds and compositions and methods of their use for therapeutic purposes.
BACKGROUND OF THE INVENTION
Immunomodulation is a developing segment of immunopharmacology. Immunomodulator compounds and compositions, as the name implies, are useful for modulating or regulating immunological functions in warm blooded animals. Immunomodulators may be immunostimulants for building up immunities to or initiate healing of certain diseases and disorders. Conversely, they may be immunoinhibitors or immunosuppressors for preventing undesirable immuno reactions of the body to foreign materials and autoimmue diseases.
Immunomodulators have been found to be useful for treating systemic autoimmue diseases, such as lupus erythematosus, as well as immunodeficiency diseases. Further, immunomodulators may be useful for immunotherapy of cancer or to prevent rejections of foreign organs or other tissues in transplants, e.g., kidney, heart or bone marrow.
Various immunomodulator compounds have been discovered including muramylic acid dipeptide derivatives, levamisole, niridazole, oxysuran, flagyl and others from the groups of interferons, interleukins, leukotrienes, corticosteroids and cyclosporins. Many of these compounds have been found, however, to have undesirable side effects and/or high
toxicity. New immunomodulator compounds are therefore needed to provide a wider range of immunomodulator function for specific areas with a Minimum of undesirable side effects.
In addition to work on immunomodulators, considerable research and resources have been devoted to oncology and antitumor measures including chemotherapy. While certain methods and chemical compositions have been developed which aid in inhibiting, remitting or controlling the growth of tumors, new methods and antitumor chemical compositions are needed.
In searching for new biologically active compounds, it has been found that some natural products and organisms are potential sources for chemical molecules having useful biological activity of great diversity. Marine sponges have proved to be such a source and a number of publications have been issued disclosing organic compounds derived from marine sponges including Scheuer, P.J. Ed., Marine Natural Products, Chemical and Biological Perspectives ; Academic Press, New York, 1978, Vol. I, pp 175-240; Uemura et al., J. Am. Chem. Soc, 1985, 107, 4796-4798; Minale, L., et al., Fortschr. Chem. org. Naturst. 1976, 33, 1-72; Faulkner, D.J., Nat. Prod. Rep. 1987, 4, 539- 576 and references cited therein.
The present invention has added to the arsenal of immunomodulator and antitumor compounds by the discovery of new organic compounds possessing useful immunomodulator and antitumor activity isolated from extracts of the marine sponge Discodermia dissoluta .
OBJECTS
A principal object of this invention is the provision of novel biologically active, lactone compounds and compositions comprising such compounds.
Additional objects are the provision of methods for producing the new compounds and compositions.
Yet another object is the provision of methods of using the new compounds and compositions, particularly, methods to modify immune systems, inhibit tumor growth and mitigate cancerous cachexia.
Other objects and further scope of applicability of the present invention will become apparent from the detailed descriptions given herein; it should be understood, however, that the detailed descriptions, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent from such descriptions.
SUMMARY OF THE INVENTION
The objects of the invention are accomplished by the provision of novel, biologically active compounds that have a structure according to the formula:
wherein:
R = -H, -A, -CH2-Q, -COA or -COZ,
A = lower alkyl,
Z = monocyclicaryl,
Q = phenyl, tolyl or xylyl,
X = -H, -A, -Z or -CH2-Z, and
Y = -H, -A, -Z, -CH2-Z, -COA, -COZ, and acid- addition salts thereof.
Compounds of the invention also include the octahydro and 23,24-dihydro derivatives of compounds
according to the above formula. The new compounds may be a single geometrical isomer or mixtures thereof (E or Z isomer).
Preferred compounds of the invention are represented by the formula:
wherein R = -H, or -COCH3, or -CH3
and-by the formula:
In preferred embodiments of the invention, the new compounds are substantially pure, i.e., contain at least 95% of the compound as determined by established analytical methods.
Specific examples of lower alkyl groups A in compounds of the invention preferably contain 1-6 carbon atoms and include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, 2,2-dimethylpropyl, hexyl and 2-ethylamyl.
Specific examples of monocyclicaryl groups Z in compounds of the invention include phenyl, p-tolyl, m-tolyl, p-bromophenyl, p-chlorophenyl, 3-ethyl-4-bromophenyl, 2,4-diethylphenyl, 2-methyl-3-hydroxyphenyl, 2,4-dimethyl-3-chlorophenyl, 2-bromo-3-amino-4-methylphenyl and 2-iodo-3-ethyl-5-aminophenyl.
Also provided by the discoveries of the invention are new pharmaceutical compositions containing between about 0.1% to 55% by weight, particularly 1% to 30%, based on the total weight of the composition, of one of the new compounds of the invention or a mixture of two or more such compounds and one or more pharmaceutically acceptable carrier or diluent.
The invention provides a variety of processes for the production of compounds of the invention. A preferred method of producing them comprises the steps of collecting marine sponge of the species Discodermia dissoluta , extracting such sponge with a selected organic solvent system to obtain an extract, fractioning the extract and isolating lactone compounds from the fractioned extract.
The sponge Discodermia has two literature references.
1. Y. Kato, N. Fusetani, S. Matsunaga and K. Hashimoto. J. Amer. Chem. Soc., 108, 2780, 1986.
2. S. Matsunasa, N. Fusetani and S. Konosa, Tetrahedron Letters, 25, 5165, 1985: 26, 855, 1985.
In further preferred methods of the invention, new salts within the scope of the invention are made by adding mineral acids, e.g., HCl, H2SO4, etc., or strong organic acids, e.g., formic, oxalic, etc., in appropriate amounts to form the acid addition salt of the parent compound or its derivative. Also, synthesis type reactions may be used pursuant to known procedures to add or modify various groups in the preferred compounds to produce other compounds within the scope of the invention.
As a result of the discoveries by the invention of the new compounds and their structuring, skilled chemists will be able to use known procedures to synthesize them from available stock substances.
As embodied and fully described herein, the invention also comprises methods of use of the new compounds and compositions of the invention, e.g., methods of inhibiting tumors in a mammal, therapeutic methods for treating cancerous cachexia and methods of regulating immunological functions in warm blooded animals.
In accordance with the invention, methods for inhibiting tumors in a host comprise contacting tumor cells with an effective amount of the new pharmaceutical compositions of the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
A sore complete understanding of the invention can be obtained by reference to preferred embodiments of the invention which are illustrated by the following specific examples of compounds, compositions and methods of the invention. It will be apparent to those skilled in the art that the examples involve use of materials and reagents that are commercially available from known sources, e.g., chemical supply houses, so no details are given respecting them.
EXAMPLE 1
This example concerns the preparation of discodermolide having the formula:
The sponge Discodermia dissoluta was homogenized with methanol-toluene (3:1). After filtration and evaporation at reduced pressure below 35ºC, a brown colored extract was obtained. The extract was then partitioned between EtOAc and H2O. The biologically active EtOAc soluble fraction was fractionated first
by column chromatography on SiO2 gel using CH2Cl2 and MeOH gradient and monitored by biological activity. The biologically active (AT, ID) fraction was chromatographed on RP-C18 with H2O-MeOH gradient. The fractions that eluted with (30-70% H2O-MeOH) gave impure discodermolide.
The impure compound was then subjected to HPLC (RP C-18, 5μ, 250 × 10 mm) using 48% H2O-MeOH as eluent to give pure discodermolide (I), white crystals; m.p. 115- 116º, (α)25 D = 7.2º (c = 0.72); UV λ max (MeOH) 235 nm (∈-12500), 226sh (19500), 210 (35400);
Ir (CHCl3) 3610, 3500, 3415, 3158, 2976, 2928, 1725, 1580, 1460, 1375, 1100, 1037 cm-1;
1H NMR (CDCl3 & 5% CD3OD) δ 6.54 (1H, ddd J=16.6, 11.3, 10.0 Hz, H23), 5.95 (1H, ddd, J=11.3, 10.5, 1.1 Hz, H22), 5.37 (1H, dd, J=10.0, 7.6 Hz, H8), 5.34 (1H, dd, J=10, 9.4 HZ, H9), 5.28 (1H, dd, J=10.5, 10.5 Hz, H21), 5.13 (1H, d, J=16.6 Hz, H24), 5.05 (1H, d J=10 Hz, H24), 5.09 (1H, d, J=9.9 Hz, H13), 4.60 (1H, m, H7), 4.63 (1H, dd, J=6.1, 6.1 Hz, H19), 4.50 (1H, dt, J=9.7, 2.3HZ, H5), 3.57 (1H, t, J=4.0 Hz, H3), 3.15 (1H, t, J=5.5 Hz, H17), 3.09 (1H, t, J=6.3 Hz, H11), 2.95 (1H, ddq, J=10.5, 6.1, 6.6 Hz, H20), 2.65 (1H, ddq, J=9.4, 6.3, 6.6 Hz, H10), 2.58 (1H, dq, J=4.0, 7.3 Hz, H2), 2.45 (1H, ddq, J=9.9, 6.3, 6.6 Hz, H12), 1.82 (1H, ddq, J=4.0, 2.3, 7.1 Hz, H4), 1.84, 1.70 (2H,m, H15), 1.80 (1H, ddq, J=6.1, 5.5, 6.8 Hz, H18), 1.80 (1H, m, H16), 1.74 (1H, m, H6), 1.59 (1H, m, H6), 1.54 (3H, s, H29), 1.28 (3H, d, J=7.3 Hz,H25), 0.97 (3H, d, J=7.1 Hz, H26), 0.94 (3H, d, J=6.6 Hz, H27). 0.92 (3H, d, J=6.6 Hz, H32), 0.87 (3H, d, J=6.8 Hz, H31), 0.85 (3H, d, J=6.6 Hz, H28), 0.74 (3H, d, J=6.5 Hz, H30);
13C NMR (CDCI3 & 5% CD3OD) δ 175.2 (S, Cl), 157.7 (s,C33), 134.27 (d, C9), 133.3 (d, C21), 132.7 (S, C14), 131.9 (d, C23), 129.7 (d, C22), 132.4 (d, C8),
129.9 (d, C13), 117.8 (t, C24), 75.6 (d,C17) 78.8 (d, C19), 78.9 (d, C11), 77.0 (d, C5), 72.5 (d, C3), 63.4 (d,C7), 42.9 (d, C2) 40.9 (t, C6), 37.1 (d, C18), 35.6 (t, C15), 36.0 (d, C10), 34.4 (d, C20), 35.1 (d, C12), 35.4 (d, C4), 33.0 (d, C16), 22.9 (q, C29), 17.3 (q, C32), 18.0 (q, C27), 15.6 (q, C28), 15.5 (q, C25), 13.7 (q, C30), 12.4 (q, C26), 8.6 (q, C31).
EXAMPLE 2
This example concerns the preparation of discodermolide tetra-acetate having the formula:
Acetylation of discodermolide with acetic anhydride and pyridine at room temperature furnished discodermolide tetra-acetate, a colorless gum; (α) 25
D = 19.2 · (c=0.3, CHCl3); UV λ max (EtOH) 235 nm (∈=12,000), 227sh (21000), 222 (21400), 205 (41000);
IR (CHCl3) 3537, 3423, 2962, 1735, 1727, 1585, 1510, 1370, 1327, 1222, 1100, 1023, 965, 912, cm-1.
1NMR (CDCI3) δ 6.71 (1H, dddd, J=16.6, 11.3, 10.0, 1.3 HZ, H23), 6.03 (1H, ddd, J=10.5, 11.3, 1.1 Hz, H22), 5.65 (1H, ddd, J=1.8, 8.3, 10.0 Hz, H7), 5.49 (1H, dd, J=10.7, 10.7 HZ, H9), 5.31 (1H, ddd, J=10.5, 10.5, 1.3HZ, H21), 5.28 (1H, ddd, J=10.7, 10.0, 1.0 Hz, H8), 5.21 (1H, d, J=10.0 Hz, H24), 5.15 (1H, dd, J=16.6, 1.1 HZ, H24), 4.94 (1H, d, J-9.9 Hz, H13), 4.89 (1H, dd, J=5.8, 5.8 Hz, H3), 4.78 (1H, dd, J=5.8, 5.6 Hz, H17), 4.60 (1H, dd, J=6.1, 6.1 Hz, H19), 4.60 (2H, br s, NH2), 4.27 (IH, dd, J=4.8, 6.4 Hz, H11), 4.26 (1H, dt, J=2.0, 9.7 Hz, H5), 3.12 (IH, ddq, J=6.1, 10.5, 6.6 Hz, H20), 2.89 (1H, ddq, J=10.7, 6.4, 6.6 Hz, H10), 2.70 (1H, dq, J=5.8, 7.3 Hz, H2), 2.47 (1H, ddq,
J=9.9, 4.8, 6.6 Hz, H12), 2.10 (1H, ddd, J=12.6, 9.7,8.3 Hz, H6), 2.09 (1H, ddq, J=5.8, 2.0, 6.9 Hz, H4), 2.08 (3H, s, H35), 2.08(3H, s, H41), 2.03 (1H, dddq, J=11.8, 10.0, 5.8, 6.6 Hz, H16), 2.02 (3H, s, H37), 2.00 (3H, s, H39), 1.98 (1H, ddq, J=6.1, 5.6, 6.8 Hz, H18), 1.86 (1H,dd, J=12.6, 11.8 Hz, H15), 1.67 (1H, dd, J=12.6, 10.0 Hz, H15), 1.64 (1H, ddd, J=12.6, 9.7, 1.8 HZ, H6), 1.61 (3H, s, H29), 1.29 (3H, d, J=7.3, Hz,H25), 0.97 (3H, d, J=6.9 Hz, H26), 0.96 (3H, d, J=6.6 Hz, H32), 0.95 (3H, d,J=6.6 Hz, H27), 0.89 (3H, d, J-6.8 Hz, H31), 0.85 (1H, d, J=6.6 Hz, H28), 0.68 (3H, d, J-6.6 Hz, H30);
13C NMR (CDCl3) S 171.7 (s, C1), 170.9 (s,C34), 170.6 (s, C36), 170.4 (s, C40), 169.8 (S, C38), 156.7 (s, C33), 135.1 (d, J=160 Hz, C9), 133.4 (s, C14), 133.0 (d, J=159 Hz, C21), 132.2 (d, J=153 Hz, C23), 130.2 (d, J=159 Hz, C22), 128.9 (d, J=147 Hz, C13), 128.2 (d, J=161 Hz, C8), 118.2 (t, J=160 Hz, C24), 80.2 (d, J=151 HZ,C11), 77.9 (d, J=145 Hz, C17), 77.8 (d, J=145 HZ, C19), 76.8 (d, J=147HZ, C5), 74.5 (d, J=156 HZ, C3), 66.5 (d, J=148 Hz, C7), 40.0 (d, J=130HZ, C2), 38.7 (t, J=126 Hz, C6), 36.4 (d, J=123 Hz, C18), 35.6 (t, J=125HZ, C15), 35.1 (d, J-124 Hz, C10), 34.1 (d, J=126 Hz, C20), 34.1 (d, J=126 Hz, C12), 33.7 (d, J=127 Hz, C4), 31.8 (d, J=124 Hz, C16), 22.8 (q, J=123 Hz, C29), 21.2 (q, J=127 Hz, C41), 20.9 (q, J=127 Hz, C37), 20.9 (q, J=127 Hz, C39), 20.9 (q, J=127 Hz, C35), 17.5 (q, J=124 Hz, C32), 17.5 (q, J=124 Hz, C27), 16.6 (q, J=124 Hz, C28), 15.3 (q, J=124 Hz, C25), 13.6 (q, J=124 HZ, C30), 12.4 (q, J=124 Hz, C26), 9.5 (q, J=121 Hz, C31);
HRFAB: m/z 702.4203, Δ 1.4 mmμ for C39H60NO10 (M- CH3COO)+; LRFAB: m/z (relative intensity) 762(3%), 702(5), 642(2), 581(4), 521(7), 439(3), 427(5), 411(4), 399(5), 387(12), 359(9), 334(11), 327(5), 299(5),
285(5),259(6), 232(20), 217(75), 173(42), 161(72), 147(50), 133(80), 126(100).
EXAMPLE 3
This example concerns the preparation of the octahydro derivative of discodermolide which is represented by the formula:
A portion of discodermolide and a small amount of hydrogenation catalyst, e.g., Pd/C, Pt oxide or Raney Ni, are mixed in a suitable solvent, e.g., ethanol or methanol. The mixture is stirred in the presence of hydrogen in a hydrogenation apparatus capable of operation at elevated pressure, e.g., Parr apparatus, to produce octahydro discodermolide. If the reaction is too slow, it is facilitated by making the media slightly acidic. Partial reduction of discodermolide to the 23,24-dihydro derivative can be attained by hydrogenation at ambient pressure conditions.
EXAMPLE 4
This example concerns the preparation of the methyl ether of discodermolide represented by the formula:
A portion of discodermolide was mixed with methyl iodide in dry acetone containing anhydrous K2CO3 and refltiXed for 12 hrs. The mixture was filtered and the
solvent evaporated under vacuum. The residue was chromatographed on silica gel to give a product, the tetramethyl ether.
BIOLOGICAL ACTIVITY EVALUATION
Immunomodulator Methodology
The crude ethanolic extract was tested in the two-way mixed lymphocyte reaction (MLR) and a lymphocyte viability assay (LCV) at 500 and 50 μg/ml, using murine splenocytes. Cellular proliferation was measured using a modified form of the M.T.T. assay (Mosmann, T. 1983. Rapid colorimetric assay for cellular growth and survival: (Application to proliferation and cytotoxicity assays. J. Immunol . Methods 65:55-63). Responses were reported as a percent of the positive MLR or LCV control.
The pure compound discodermolide I, was tested for Immunosuppressive effects on the MLR and LCV assays using murine splenocyteε and in the human MLR and mitogen stimulation assays, using human peripheral blood lymphocytes (PBL). Cellular proliferation was determined using incorporation of 3H-thymidine.
Antitumor Methodology
The crude ethanolic extract of the sponge and the pure compound I were tested for toxicity against murine P388 leukemia cells. P388 cells obtained from Dr. J. Mayo, National Cancer Institute, Bethesda, MD, were maintained in Roswell Park Memorial Institute (RPMI) medium 1640 supplemented with 10% horse serum. All cell lines were cultured in plastic tissue culture flasks and kept in an incubator at 37ºC in humidified air containing 5% CO2. Antibiotic-free stock cultures of P388 cells were subcultured to 105 cells/ml by dilution in fresh growth medium at 2 to 3 day intervals. The mean generation time of primary cultures was 14 to 17 hr.
To assess the antiproliterative effects of agents against P388 cells, 200 μl cultures (96-well tissue culture plates, Nunc, Denmark) were established at 1 × 105 cells/ml in drug-free medium or medium containing the crude extract at a final dilution of 1:500 or discodermolide at various concentrations. Solvent for all dilutions was methanol, which was removed from plates under vacuum. All experimental cultures were initiated in medium containing Gentamycin sulfate (50 μg/ml; Schering Corporation, Kenilworth, NJ). After 48-h exposures, P388 cells were enumerated using 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) as described below (M.C. Alley, et al., Cancer Res. 48:589, 1988).
To quantitate the effects on cell proliferation, 75 μl of warm growth medium containing 5 mg/ml MTT was added to each well and cultures were returned to the incubator for 90 minutes. To spectrophotometrically quantitate formation of reduced formazan, plates were centrifuged (900 × g, 5 minutes), culture fluids removed by aspiration, and 200 μl of acidified isopropanol (2 ml concentrated HCl/liter isopropanol) added per well. The absorbance of the resulting solutions were measured at 570 nm with a plate reader (MR700 Microplate Reader, Dynatech, Laboratories, Chantilly, VA). The absorbance of test wells was divided by the absorbance of drug-free wells, and the concentration of agent that resulted in 50% of the absorbance of untreated cultures was determined by linear regression of logit-transformed data (D. J. Finney, Statistical Method in Biological Assay, third ed., pp. 316-348, Charles Griffin Co., London, 1978). A linear relationship between P388 cell number and formazan production was found over the range of cell densities observed in these experiments.
Immunomodulator Activity:
The crude extract was immunosuppressive in the MLR at a 1x concentration (<1% of the control MLR response, but exhibited toxicity (<6% of the control LCV response) at the same dosage level. Immunosuppressive activity was observed at a 1/10 dilution of the crude extract (<1% of the control MLR) which was associated with relatively low toxicity (>70% of the control LCV response).
Discodermolide was immunosuppressive in the murine MLR with no associated toxicity at a dosage of 0.5 μg/ml. Higher dilutions (500, 50 and 5 μg/ml) exhibited immunosuppressive activity, but with associated toxicity (Table 1). In the human MLR, Discodermolide was immunosuppressive with >94% viability at 50, 25, 12.5, 6.3, 3.1 and 1.6 μg/ml (Figure 2). Discodermolide suppressed Con A and PHA (10 μg/ml) stimulation of human PBL at 50 and 25 μg/ml, with >91% viability (Table 3).
Table 1
Immunosuppressive Effect of Discodermolide On
The Murine Mixed Lymphocyte Reaction Conc. μg/ml 1% MLR 2% LCV
Control Control
0.0 (control) 100 90
0.5 18 151
5 25 68
50 <1 26
500 <1 <1
1Percent of the control MLR response.
2Percent of the control LCV response.
Table 2
Immunosuppressive Effect of Discodermolide On
The Human Mixed Lymphocyte Reaction Conc. μg/al 1CPM 2% Viability 0.0 (control) 48064 100
0.4 64211 115
0.8 49509 ND
1.6 26336 110
3.1 8532 94
6.3 4996 94
12.5 2091 94
25 1728 102
50 1932 204
1Counts per minute of incorporate 3H-thymidine
2% Viable cells as measured by M.T.T. metabolism Table 3
Immunosuppressive Effect of Discodermolide On Con A and PHA Mitogenesis of Human Lymphocytes
Conc. μg/ml 1Con A 2PHA 0.0 (control) 262000 412200 6.3 299518 441580 12.5 213740 391633 25 11567 14425
50 10230 16984
1Counts per minute of incorporated 3H-thymidine.
Cone, of Con A = 10.0 μg/ml
2Counts per minute of incorporated 3H-thymidine.
Cone, of PHA - 10.0 μg/ml Antitumor Activity
A 1:500 dilution of the crude extract inhibited the proliferation of cultured murine P388 leukemia cells by 91%.
Discodermolide inhibited the proliferation of cultured murine P388 cells. The concentration resulting in 50% inhibition (IC50) was 0.5 μg/ml as reported in the following Table 4.
Table 4. P388 Cytotoxicity
Concentration (μg/ml) %Inhibition 20 92
10 90
5 88
2.5 87
1.0 75
0.5 49
0.25 12
0.125 2
Discussion of Variables
The scope of the invention is not limited by the specific examples and suggested procedures and uses related herein since modifications can be made within such scope from the general information provided by this specification to those skilled in the art.
Therapeutic application of the new compounds and compositions containing them can be contemplated to be accomplished by any suitable therapeutic method and technique presently or prospectively known to those skilled in the art. Further, the compounds of the invention have use as starting materials or intermediates for the preparation of other useful compounds and compositions.
In accordance with the invention, pharmaceutical compositions comprising, as an active ingredient, an effective amount of one or more of the new compounds and one or more non-toxic, pharmaceutically acceptable carrier or diluent. Examples of such carriers for use in the invention include, ethanol, dimethyl sulfoxide, glycerol, silica, alumina, starch, and equivalent carriers and diluents.
The new compounds are useful as immunomodulatory agents. An intended use is for immune reactions (in vivo/in vitro) that require modulation via T-cell activity. Direct application would be for human in vivo suppression of T-cell responses, e.g., transplantation and autoimmunity.
In preferred embodiments for production of the new compounds by extraction from marine sponges, etc., suitable organic solvent systems for extraction can be selected from methanol, ethyl acetate, toluene, heptane, hexane, isooctane, acetone, benzene, diethyl ether, t-butyl methyl ether, ethanol, isopropanol, 1,2 dichloroethane and especially, chloroform, ammonium hydroxide and dichloromethane. Mixtures of two or more of such solvents in various ratios and combinations are advantageous.
Compounds of the invention are isolated by various fractionation and chromatographic techniques from -the extracts obtained as disclosed. Preferred isolation procedures include various chromatography techniques, e.g., countercurrent chromatography with suitable columns, including multi-layer planetary coil columns. A variety of solvents are available for use as single or mixed eluents, such as methylene chloride, methanol, ethyl acetate, acetonitrile, n-propanol, n-butanol, water, dilute sulfuric acid, and equivalent solvents. Further purifications using such procedures may also be carried out on the recovered extractions. Preferred isolation techniques for further purification include chromatographic operations such as high-pressure, liquid chromatography with suitable columns with suitable solvent, particularly, methylene chloride¬/methanol or methanol/water mixtures.
Claims
1. A compound of the formula:
wherein:
R = -H, -A, -CH2-Q, -COA or -COZ,
A = lower alkyl,
Z = monocyclicaryl,
Q = phenyl, tolyl or xylyl,
X = -H, -A, -Z or -CH2-Z, and
Y = -H, -A, -Z, -CH2-Z, -COA, -COZ, and acid-addition salts thereof.
2. A compound of the formula:
wherein R = -H, -COCH3 or -CH3 and acid-addition salts thereof.
3. A compound of claim 2 wherein R is -H.
4. A compound of claim 2 wherein R is -COCH3.
5. A compound of claim 2 wherein R is -CH3.
6. The octahydro derivative of a compound of claim 1.
7. A compound of claim 6 wherein R -H, -COCH3 or -CH3, X = -H and Y = -H.
8. The 23,24 dihydro derivative of a compound of claim 1.
9. The octahydro derivative of a compound of claim 2.
10. The 23,24 dihydro derivative of a compound of claim 2.
11. A pharmaceutical composition comprising between about 0.1 to 55% by weight based on the total weight of said composition as an active ingredient one compound or mixture of two or more compounds of the formula:
wherein:
R = -H, -A, -CH2-Q, -COA or -COZ,
A = lower alkyl,
Z = monocyclicaryl,
Q = phenyl, tolyl or xylyl,
X = -H, -A, -Z or -CH2-Z, and
Y = -H, -A, -Z, -CH2-Z, -COA, -COZ, halide, amino, nitro, or acylates and acid-addition salts thereof and
a non-toxic pharmaceutically acceptable carrier or diluent.
12. A pharmaceutical composition comprising a between about 0.1 to 55% by weight based on the total weight of said composition as an active ingredient a compound of claim 2 and a non-toxic pharmaceutically acceptable carrier or diluent.
13. A method for treating cancerous cachexia caused by the presence of a tumor in a host comprising
treating the host with an effective antitumor amount of a compound of claim 1.
14. A method for treating cancerous cachexia caused by the presence of a tumor in a host comprising treating the host with an effective antitumor amount of a compound of claim 2.
15. A method for treating cancerous cachexia caused by the presence of a tumor in a host comprising treating the host with an effective antitumor amount of a compound of claim 6.
16. A method of modulating and/or regulating immunological functions in humans and warm-blooded animals which comprises administering to said human or animal an effective immunomodulatory amount of one or more compounds of claim 1.
17. A method of modulating and/or regulating immunological functions in humans and warm-blooded animals which comprises administering to said human or animal an effective immunomodulatory amount of one or more compounds of claim 2.
18. A method of modulating and/or regulating immunological functions in humans and warm-blooded animals which comprises administering to said human or animal an effective immunomodulatory amount of one or more compounds of claim 6.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP90912243A EP0486565B1 (en) | 1989-08-11 | 1990-08-09 | Discodermolide compounds, compositions containing same and methods of preparation and use |
| DE69018991T DE69018991T2 (en) | 1989-08-11 | 1990-08-09 | DISCODERMOLIDE COMPOUNDS, THE PREPARATIONS THEREOF, METHOD FOR THEIR PRODUCTION AND THEIR USE. |
| CA002056412A CA2056412C (en) | 1989-08-11 | 1990-08-09 | Discodermolide compounds, compositions containing same and methods of preparation and use |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/392,468 US4939168A (en) | 1989-08-11 | 1989-08-11 | Discodermolide compounds, compositions containing same and methods of preparation and use |
| US392,468 | 1989-08-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1991001982A1 true WO1991001982A1 (en) | 1991-02-21 |
Family
ID=23550726
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1990/004493 Ceased WO1991001982A1 (en) | 1989-08-11 | 1990-08-09 | Discodermolide compounds, compositions containing same and methods of preparation and use |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US4939168A (en) |
| EP (1) | EP0486565B1 (en) |
| JP (1) | JP3008985B2 (en) |
| AT (1) | ATE121739T1 (en) |
| CA (1) | CA2056412C (en) |
| DE (1) | DE69018991T2 (en) |
| DK (1) | DK0486565T3 (en) |
| ES (1) | ES2071826T3 (en) |
| WO (1) | WO1991001982A1 (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2280677A (en) * | 1993-07-30 | 1995-02-08 | Roussel Lab Ltd | Total synthesis of discodermolide |
| WO1995022550A1 (en) * | 1994-02-18 | 1995-08-24 | Harbor Branch Oceanographic Institution, Inc. | Novel cytotoxic macrolides, their isolation from a marine sponge and their use as antitumor agents |
| US5684036A (en) * | 1994-02-18 | 1997-11-04 | Harbor Branch Oceanographic Institution, Inc. | Cytotoxic macrolides and methods of use |
| WO2002012220A3 (en) * | 2000-08-07 | 2002-06-13 | Novartis Ag | Process for preparing discodermolide and analogues thereof |
| WO2003014102A1 (en) * | 2001-08-06 | 2003-02-20 | Novartis Ag | Certain substituted polyketides, pharmaceutical compositions containing them and their use in treating tumors |
| WO2002098843A3 (en) * | 2001-04-17 | 2003-05-01 | Novartis Ag | Certain salts of discodermolide acid, pharmaceutical compositions containing them and their use in treating tumors |
| WO2003080567A3 (en) * | 2002-03-27 | 2004-04-15 | Novartis Ag | Intermediates for the synthesis of discodermolide and related analogues and methods for their preparation |
| WO2009049378A1 (en) * | 2007-10-17 | 2009-04-23 | Qbiotics Limited | Lactone derivatives |
| EP2583678A2 (en) | 2004-06-24 | 2013-04-24 | Novartis Vaccines and Diagnostics, Inc. | Small molecule immunopotentiators and assays for their detection |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK0711158T4 (en) | 1993-07-29 | 2008-11-03 | Us Gov Health & Human Serv | Method of treating atherosclerosis or restenosis using microtubule stabilizer |
| US5681847A (en) * | 1995-12-05 | 1997-10-28 | Harbor Branch Oceanographic Institution, Inc. | Methods of using discodermolide compounds |
| US20050065353A1 (en) * | 1996-12-03 | 2005-03-24 | Smith Amos B. | Synthetic techniques and intermediates for polyhydroxy dienyl lactones and mimics thereof |
| US5789605A (en) * | 1996-12-03 | 1998-08-04 | Trustees Of The University Of Pennsylvania | Synthetic techniques and intermediates for polyhydroxy, dienyl lactones and mimics thereof |
| US6127406A (en) * | 1998-10-09 | 2000-10-03 | Harbor Branch Oceanographic Institution, Inc. | Discodermolide compounds and methods of use |
| US6384187B1 (en) | 1999-05-15 | 2002-05-07 | Harbor Branch Oceanographic Institution, Inc. | Antiproliferative activity of microsclerodermins |
| US6495594B2 (en) | 2000-03-01 | 2002-12-17 | Harbor Branch Oceanographic Institution, Inc. | Biologically active analogs of discodermolide |
| US6541509B2 (en) | 2000-09-15 | 2003-04-01 | Albert Einstein College Of Medicine Of Yeshiva University | Method for treating neoplasia using combination chemotherapy |
| TW200408407A (en) * | 2001-11-30 | 2004-06-01 | Dana Farber Cancer Inst Inc | Methods and compositions for modulating the immune system and uses thereof |
| US7348436B2 (en) * | 2004-03-02 | 2008-03-25 | Kosan Biosciences Incorporated | Compounds useful for the synthesis of (+)-discodermolide and methods thereof |
| US7214708B2 (en) * | 2004-11-18 | 2007-05-08 | Kosan Biosciences Incorporated | Synthetic discodermolide analogs |
| US7772177B2 (en) | 2005-05-18 | 2010-08-10 | Aegera Therapeutics, Inc. | BIR domain binding compounds |
| RU2469721C2 (en) | 2006-05-09 | 2012-12-20 | Новартис Аг | Combination containing iron complex and antineoplastic agent, and use thereof |
| SG171682A1 (en) | 2006-05-16 | 2011-06-29 | Aegera Therapeutics Inc | Iap bir domain binding compounds |
| MX358013B (en) | 2009-11-13 | 2018-08-01 | Amgen Inc | Material and methods for treating or preventing her-3 associated diseases. |
| EP3263583A1 (en) | 2010-02-12 | 2018-01-03 | Pharmascience Inc. | Iap bir domain binding compounds |
| CA2815154A1 (en) | 2010-08-06 | 2012-02-09 | U3 Pharma Gmbh | Use of her3 binding agents in prostate treatment |
-
1989
- 1989-08-11 US US07/392,468 patent/US4939168A/en not_active Expired - Lifetime
-
1990
- 1990-08-09 ES ES90912243T patent/ES2071826T3/en not_active Expired - Lifetime
- 1990-08-09 DE DE69018991T patent/DE69018991T2/en not_active Expired - Lifetime
- 1990-08-09 WO PCT/US1990/004493 patent/WO1991001982A1/en not_active Ceased
- 1990-08-09 DK DK90912243.4T patent/DK0486565T3/en active
- 1990-08-09 JP JP2511555A patent/JP3008985B2/en not_active Expired - Lifetime
- 1990-08-09 EP EP90912243A patent/EP0486565B1/en not_active Expired - Lifetime
- 1990-08-09 AT AT90912243T patent/ATE121739T1/en not_active IP Right Cessation
- 1990-08-09 CA CA002056412A patent/CA2056412C/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| J. ORG. CHEM., Vol. 55, No. 16, August 1990, SARATH P. GUNASEKERA et al., "Discodermolide: A New Bioactive Polyhydroxylated Lactone from the Marine Sponge Discodermia Dissoluta", pages 4912-4915. * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2280677A (en) * | 1993-07-30 | 1995-02-08 | Roussel Lab Ltd | Total synthesis of discodermolide |
| GB2280677B (en) * | 1993-07-30 | 1997-09-24 | Roussel Lab Ltd | Chemical compounds |
| WO1995022550A1 (en) * | 1994-02-18 | 1995-08-24 | Harbor Branch Oceanographic Institution, Inc. | Novel cytotoxic macrolides, their isolation from a marine sponge and their use as antitumor agents |
| US5684036A (en) * | 1994-02-18 | 1997-11-04 | Harbor Branch Oceanographic Institution, Inc. | Cytotoxic macrolides and methods of use |
| KR100796396B1 (en) * | 2000-08-07 | 2008-01-21 | 노파르티스 아게 | Method of Making Disco-Molide and Disco-Molide Analogs |
| AU2001293726B2 (en) * | 2000-08-07 | 2005-04-14 | Novartis Ag | Process for preparing discodermolide and analogues thereof |
| WO2002012220A3 (en) * | 2000-08-07 | 2002-06-13 | Novartis Ag | Process for preparing discodermolide and analogues thereof |
| CZ300855B6 (en) * | 2000-08-07 | 2009-08-26 | Novartis Ag | Process for preparing discodermolide and analogs thereof as well as intermediates for this preparation process |
| WO2002098843A3 (en) * | 2001-04-17 | 2003-05-01 | Novartis Ag | Certain salts of discodermolide acid, pharmaceutical compositions containing them and their use in treating tumors |
| WO2003014102A1 (en) * | 2001-08-06 | 2003-02-20 | Novartis Ag | Certain substituted polyketides, pharmaceutical compositions containing them and their use in treating tumors |
| CN100522956C (en) * | 2001-08-06 | 2009-08-05 | 诺瓦提斯公司 | Substituted polyketides, pharmaceutical compositions containing them and their use in the treatment of tumours |
| WO2003080567A3 (en) * | 2002-03-27 | 2004-04-15 | Novartis Ag | Intermediates for the synthesis of discodermolide and related analogues and methods for their preparation |
| EP2583678A2 (en) | 2004-06-24 | 2013-04-24 | Novartis Vaccines and Diagnostics, Inc. | Small molecule immunopotentiators and assays for their detection |
| WO2009049378A1 (en) * | 2007-10-17 | 2009-04-23 | Qbiotics Limited | Lactone derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0486565A1 (en) | 1992-05-27 |
| DK0486565T3 (en) | 1995-10-02 |
| ES2071826T3 (en) | 1995-07-01 |
| ATE121739T1 (en) | 1995-05-15 |
| DE69018991D1 (en) | 1995-06-01 |
| EP0486565B1 (en) | 1995-04-26 |
| CA2056412A1 (en) | 1991-02-12 |
| DE69018991T2 (en) | 1995-08-24 |
| JP3008985B2 (en) | 2000-02-14 |
| JPH04507245A (en) | 1992-12-17 |
| CA2056412C (en) | 2001-04-10 |
| US4939168A (en) | 1990-07-03 |
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