WO1993014215A1 - Procede et utilisations de la 4,5-dihydrogeldanamycine et de son hydroquinone - Google Patents

Procede et utilisations de la 4,5-dihydrogeldanamycine et de son hydroquinone Download PDF

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Publication number
WO1993014215A1
WO1993014215A1 PCT/US1992/010189 US9210189W WO9314215A1 WO 1993014215 A1 WO1993014215 A1 WO 1993014215A1 US 9210189 W US9210189 W US 9210189W WO 9314215 A1 WO9314215 A1 WO 9314215A1
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Prior art keywords
compound
mammalian subject
formula
treating
proliferative disorder
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Application number
PCT/US1992/010189
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English (en)
Inventor
Walter P. Cullen
Mark T. Jefferson
Mikel P. Moyer
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Pfizer Inc.
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Publication date
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Priority to JP5512423A priority Critical patent/JPH06510913A/ja
Priority to KR1019940702334A priority patent/KR940703923A/ko
Priority to BR9207024A priority patent/BR9207024A/pt
Publication of WO1993014215A1 publication Critical patent/WO1993014215A1/fr
Priority to NO942532A priority patent/NO942532D0/no
Priority to FI943207A priority patent/FI943207A0/fi

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/10—Nitrogen as only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D225/06—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Definitions

  • This invention is concerned with a new process for the preparation of 4,5- dihydrogeldanamycin and its hydroquinone by fermenting the microorganism Streptomvces hygroscopicus.
  • Pfizer culture collection number FD 29068 a derivative by subculture from NRRL 3602, now deposited as ATCC 55256, using standard fermentation methods and conditions, followed by isolating the compounds of this invention using standard separation methods.
  • the hydroquinone can also be chemically synthesized from 4,5-dihydrogeldanamycin.
  • Both 4,5-dihydrogeldanamycin and its hydroquinone are chemical compounds belonging to the ansamycin benzoquinone family of antibiotics.
  • 4,5- Dihydrogeldanamycin and its hydroquinone are considered to be derivatives of geldanamycin, a well-known member of the ansamycin benzoquinone family.
  • Geldanamycin itself is obtained by fermenting the microorganism Streptomvces hygroscopicus, NRRL 3602, and separating it out from the fermentation broth.
  • Geldanamycin is known to be useful against certain microorganisms, primarily yeast and fungi.
  • Geldanamycin's preparation and utility are disclosed in U.S. Patent 3,595,955.
  • 4,5-Dihydrogeldanamycin has previously been synthesized by catalytically hydrogenating geldanamycin. Reference to the semisynthesis of 4,5- dihydrogeldanamycin is found in Progress in the Chemistry of Organic Natural Products, Chemistrv of the Ansamvcin Antibiotics. 33, 1976, p. 278. As of this date, no utility for 4,5-dihydrogeldanamycin has been disclosed in the art. Semisynthetic derivatives of geldanamycin and their use as antitumor agents are described in Derwent abstracts 82-98300E, 81-70796D, 80-72388C and 80- 62760C. Summary of the Invention This invention provides a process for preparation of 4,5-dihydrogeldanamycin which has the chemical formula I, and the hydroquinone of 4,5-dihydrogeldanamycin which has the chemical formula II, below.
  • the process comprises the submerged aerobic propagation in aqueous nutrient media of the microorganism Streptomvces hygroscopicus. ATCC 55256, followed by isolation of the compounds of formulae I and II.
  • the inventors have discovered that 4,5-dihydrogeIdanamycin and its hydroquinone can be obtained by fermenting Streptomvces hygroscopicus.
  • ATCC 55256 a microorganism not previously known to produce the compounds of this invention.
  • 4,5-Dihydrogeldanamycin is also shown to have valuable utility in treating proliferative disorders, especially cancer, in mammals and, more specifically, in humans.
  • 4,5-Dihydrogeldanamycin is also expected to be useful in treating certain gram-positive and -negative bacterial infections; useful as a virucidal agent and as a herbicide and possess antifungal and antiprotozoal properties. Because the compound also possesses immunosuppressive properties, it is expected to be useful in treating a variety of autoimmune diseases including but not limited to rheumatoid arthritis and graft versus host diseases.
  • the hydroquinone of 4,5-dihydrogeldanamycin is a novel compound that can be isolated from a natural source or chemically synthesized.
  • the hydroquinone can be isolated from the fermentation broth of Streptomyces hygroscopicus in essentially the same manner that geldanamycin and 4,5-dihydrogeldanamycin is isolated.
  • the hydroquinone can also be chemically synthesized by reducing 4,5- dihydrogeldanamycin with a chemical reducing agent.
  • the hydroquinone of 4,5- dihydrogeidanamycin is expected to be useful against all of the same diseases as listed above for 4,5-dihydrogeldanamycin.
  • the instant invention provides a new process for the preparation of 4,5-dihydrogeldanamycin and 4,5- dihydrogeldanamycin hydroquinone from a natural source, namely Streptomvces hygroscopicus. ATCC 55256, and provides new uses for the compounds of this invention. Also, the chemical synthesis of the hydroquinone from 4,5- dihydrogeldanamycin is provided.
  • Compounds (I) and (II) are natural products which can be isolated from the fermentation broth of Streptomvces hygroscopicus. ATCC 55256.
  • the method of propagating Streptomvces hygroscopicus. ATCC 55256, to obtain 4,5- dihydrogeldanamycin and its hydroquinone is the same as for propagating it to obtain geldanamycin.
  • the method of propagation is standard in the art and can be found in U.S. Patent 3,595,955, the teachings of which are incorporated herein by reference.
  • the Streptomvces hygroscopicus The Streptomvces hygroscopicus.
  • ATCC 55256 culture can be grown at 24° to 36° C under submerged conditions with agitation and aeration on media consisting of carbohydrate sources such as sugars, starches, glycerol; organic nitrogen sources such as soybean meal, casamino acids, yeast extract; growth substance such as grain solubles, fish meal, cotton seed meal; mineral salts containing trace elements such as iron, cobalt, copper, zinc, etc.
  • carbohydrate sources such as sugars, starches, glycerol
  • organic nitrogen sources such as soybean meal, casamino acids, yeast extract
  • growth substance such as grain solubles, fish meal, cotton seed meal
  • mineral salts containing trace elements such as iron, cobalt, copper, zinc, etc.
  • Inoculum is prepared by scraping vegetative cells from slants inoculated with the ATCC 55256 culture.
  • a suitable solid medium for initial growth on slants is ATCC no. 172, the components of which are listed below.
  • NZ Amine A is a registered trademark of Kraft, Inc., Product of Quest International (Sheffield Products). Cultivating Streptomvces hygroscopicus. ATCC 55256, and isolating the compounds of formulae I and II is conducted in a similar manner to those employed in previous fermentations yielding geldanamycin. See, for example, U.S. Patent Number, 3,595,955. Cultivation preferably takes place in aqueous nutrient media under submerged aerobic conditions with agitation at a temperature of 24° to 36° C.
  • Nutrient media useful for cultivation include a source of assimilable carbon such as sugars, starches and glycerol; a source of organic nitrogen such as soybean meal, casamino acids and yeast extracts.
  • a source of growth substances such as grain solubles, fish meal and cotton seed meal as well as mineral salts such as sodium chloride and trace elements such as iron, cobalt, copper and zinc. Buffering agents such as calcium carbonate and phosphates are used as well. If excessive foaming is encountered during fermentation, antifoam agents such as vegetable oils or silicones may be added to the fermentation medium. Aeration of the medium in tanks for submerged growth is preferably maintained at the rate of about 1/2 to 2 volumes of sterile free air per volume of fermentation broth per minute forced into the broth through a sparger.
  • Agitation may be maintained by means of agitators generally familiar to those skilled in the fermentation art.
  • the rate of agitation depends on the type of agitator employed.
  • a shaker flask is usually run at 150 to 200 cycles per minute whereas a fermentor is usually run at 300 to 1700 revolutions per minute.
  • Aseptic conditions must, of course, be maintained through the transfer of the organism and throughout its growth.
  • Inoculum for the preparation of the antibiotics according to this invention may be obtained by employing growth from a slant of the culture or Roux bottles inoculated with the culture.
  • a solid medium suitable for initial growth of the organism on slants and in Roux bottles is ATCC medium no. 172.
  • the growth may be used to inoculate either shaker flasks or inoculum tanks or the inoculum tanks may be seeded from the shaker flasks. Growth in shaker flasks will generally have reached its maximum in 4 to 5 days whereas inoculum in submerged inoculum tanks will usually be in the most favorable period in 2 to 3 days.
  • Nigercin and elaiophilin which are active against gram-positive and negative microorganisms, are coproduced in the fermentation broth and are good indicators of growth associated with the production of 4,5-dihydrogeldanamycin. Therefore, the bioactivity of the fermentation broth can be monitored by biological assay of the broth employing a sensitive strain of Staphylococcus aureus ATCC 6538P or Bacillus subtilis ATCC 6633. Standard plate assay techniques are employed in which the zone of inhibition surrounding a filter paper disc saturated with the broth is used as a measure of antibiotic potency.
  • thin-layer chromatography employing silica gel is a useful tool for detecting the antibiotics produced in the fermentation media and analyzing the composition of the crude and purified materials extracted from the fermentation broths.
  • the chromatograms are developed with ethyl acetate and the antibiotic compounds are visualized by spraying with vanillin reagent and heating the TLC plate at 80° C.
  • the developed plate can also be overiayed with agar seeded with either S. aureus or B. subtilis and incubated at 37° C for 16 hours to visualize the antibiotics.
  • Compounds of formulae I and II produced by fermentation of Streptomvces hygroscopicus. ATCC 55256, may be separated and recovered by conventional methods, e.g., extracting the whole, unfiltered fermentation broth with an organic solvent such as chloroform, ethyl acetate, methyl isobutyl ketone or butanol at the naturally prevailing pH.
  • an organic solvent such as chloroform, ethyl acetate, methyl isobutyl ketone or butanol at the naturally prevailing pH.
  • the mycelium can be separated after growth has been completed and the mycelium extracted with an organic solvent.
  • the solvent extract can then be concentrated to a thin syrup and the pure antibiotic obtained by chromatography.
  • a typical method of separation and recovery of the compounds of formulae I and II is as follows.
  • the whole broth from fermentation of Streptomvces hygroscopicus. ATCC 55256, is extracted with methyl isobutyl ketone.
  • the solvent is evaporated to yield a thin syrup.
  • the syrup is dissolved in methylene chloride, loaded onto a silica gel column and eiuted with a gradient of neat methylene chloride to neat ethyl acetate.
  • the eluates are examined by thin-layer chromatography. Fractions containing compound I are combined and evaporated to dryness. Fractions containing compound II are combined and evaporated to dryness.
  • the products may be further purified by crystallization or by column chromatography " if desired.
  • the compounds of formulae I and II are expected to be useful against certain genera of fungal plant pathogens, gram-positive and negative bacteria and certain parasitic microorganisms.
  • 4,5-Dihydrogeldanamycin and its hydroquinone can be tested for use against the above mentioned microorganisms using the method disclosed in U.S. Patent 3,595,955.
  • the compound of formula I also inhibits the growth of certain human carcinoma cells.
  • the in vitro activity of 4,5-dihydrogeldanamycin was determined according to the method contained in M.C. Alley et al. Cancer Research 48, 589- 601 , Feb. 1 , 1988, and using SKBR3 and MCF7 cell lines. Therefore, 4,5- dihydrogeldanamycin is particularly valuable in treating cancer, and especially breast, ovarian and gastric cancer in humans.
  • the compound of formula II is expected to be useful for the same purpose.
  • 4,5-Dihydrogeldanamycin also has potent immunosuppressive effects as determined by methods well known to those skilled in the art. This activity can be conveniently determined by assessing the inhibition of T-cell proliferation stimulated by IL-2 and phorbol 12-myristate 13-acetate (PMA) as measured by a reduction in uptake of tritiated thymidine relative to non-drug treated controls.
  • Compound II is also expected to have immunosuppressive effects.
  • the compounds of formulae I or II When the compounds of formulae I or II are to be used as an antiproliferative agent, such as an anticancer agent, it can be administered to a mammalian subject either alone or, preferably, in combination with pharmaceutically-acceptable carriers or diluents in a pharmaceutical composition according to standard pharmaceutical practice. The compounds can be administered orally or parenterally. Parenteral administration includes intravenous, intramuscular, intraperitoneal, subcutaneous and topical administration.
  • the compound can be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension.
  • carriers which are commonly used include lactose and corn starch, and lubricating agents, such as magnesium stearate, are commonly added.
  • useful diluents are lactose and dried corn starch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents can be added.
  • sterile solutions of the active ingredient are usually prepared, and the pH of the solutions should be suitably adjusted and buffered.
  • the total concentration of solutes should be controlled to render the preparation isotonic.
  • the weight ratio of carrier to active ingredient will normally be in the range from 1 :10 to 10:1. However, in any given case, the ratio chosen will depend on such factors as the solubility of the active component, the dosage contemplated and the precise route of administration.
  • the daily dosage will normally be determined by the prescribing physician.
  • the dosage will vary according to the age, weight and response of the individual patient, as well as the severity of the patient's symptoms and the potency of the particular compound being administered.
  • an effective dose in most instances will be 0.01 to 0.5g as needed (e.g., every four to six hours).
  • an effective dose will be from 0.01 to 1.0 g per day, and preferably 20 to 250 mg per day, in single or divided doses.
  • the following examples are being provided solely for the purpose of further illustration.
  • a solid medium suitable for initial growth on slants and Roux bottles is ATCC medium No. 172.
  • Streptomyces hygroscopicus ATCC 55256, culture grown on ATCC no. 172 medium agar. The flasks were shaken at 28° C on a shaker having a displacement of 1-1/2 to 2-1/2 inches and 150 to 200 cycles per minute (CPM) for 3 to 5 days. Shaker flasks are prepared using one of the following media: JDYTT Grams/liter
  • the bioactivity of the broth and subsequent recovery streams was followed by using a sensitive strain of Bacillus subtilis ATCC 6633 or Staphylococcus aureus ATCC 6538P.
  • the components in the broth and recovery streams were visualized by using silica gel plates in the following system: neat ethyl acetate.
  • the developed plates were sprayed with vanillin reagent (3 g vanillin dissolved in 75 ml of ethanol and diluted to 100 ml with 85% phosphoric acid) then heated to 80°C.
  • the antibiotics appear as a deep blue/purple coloration.
  • the developed thin-layer chromatography (TLC) plate was also visualized by viewing in a dark box with 254 ⁇ m light. When fermentation was completed the fermenters were stopped.
  • the whole broth was extracted with 1/3 volume of methyl isobutyl ketone at broth pH, separated on a DeLaval separator and the solvent phase concentrated in vacuo to an oil.
  • the oil was subjected to a 3 tube countercurrent using hexane/acetonitrile
  • Dihydrogeldanamycin was crystallized from hot isopropyl ether and dried in a vacuum oven at 50° C overnight, m.p. 221 -222° C.
  • the aqueous layer was extracted twice with ethyl acetate. Then, the solvent layer was back extracted with pH 7.0 phosphate buffer. The solvent was dried over anhydrous Na 2 SO 4 and concentrated to a gum. The residue was taken up in isopropyl ether (IPE), heated to a boil and then stirred for 3 hours. The isopropyl ether solution was filtered and the solid dried on the filter. The dried 4,5-dihydrogeldanamycin was kept under house vacuum at 50°C.
  • IPE isopropyl ether

Abstract

Procédé de fermentation et d'isolation des composés de formules (I) et (II), appartenant à la famille des antibiotiques à l'ansamycine de benzoquinone ainsi que synthèse chimique du composé (II) à partir du composé (I). Les composés de la présente invention sont utilisés contre les maladies prolifératives, notamment le cancer chez les mammifères, et en particulier chez l'homme. Les composés de la présente invention sont également susceptibles d'être utilisés contre certains microorganismes et peuvent servir d'agent immunosuppresseur contre les maladies auto-immunes.
PCT/US1992/010189 1992-01-06 1992-12-03 Procede et utilisations de la 4,5-dihydrogeldanamycine et de son hydroquinone WO1993014215A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP5512423A JPH06510913A (ja) 1992-01-06 1992-12-03 ４，５‐ジヒドロゲルダナマイシン及びそのヒドロキノンの製造及び使用
KR1019940702334A KR940703923A (ko) 1992-01-06 1992-12-03 4,5-디히드로겔다나마이신 및 그의 하이드로퀴논의 제조 방법 및 용도(Process and Uses for 4,5-Dihydrogeldanamycin and Its Hydroquinone)
BR9207024A BR9207024A (pt) 1992-01-06 1992-12-03 Processo e utilizações para 4,5-DI-hidrogeldanamicina e sua hidroquinona
NO942532A NO942532D0 (no) 1992-01-06 1994-07-05 Fremgangsmåte og anvendelser for 4,5-diydrogeldanamycin og dets hydrokinon
FI943207A FI943207A0 (fi) 1992-01-06 1994-07-05 4,5-dihydrogeldanamysiinin ja sen hydrokinonin valmistusmenetelmä ja käyttö

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US81723592A 1992-01-06 1992-01-06
US817,235 1992-01-06

Publications (1)

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WO1993014215A1 true WO1993014215A1 (fr) 1993-07-22

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JP (1) JPH06510913A (fr)
KR (1) KR940703923A (fr)
CN (1) CN1074937A (fr)
AU (1) AU3225693A (fr)
BR (1) BR9207024A (fr)
CA (1) CA2127457A1 (fr)
CZ (1) CZ390592A3 (fr)
FI (1) FI943207A0 (fr)
HU (1) HU9401936D0 (fr)
IL (1) IL104289A0 (fr)
MX (1) MX9300011A (fr)
NO (1) NO942532D0 (fr)
PT (1) PT101169A (fr)
WO (1) WO1993014215A1 (fr)
ZA (1) ZA9333B (fr)

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995001342A1 (fr) * 1993-06-29 1995-01-12 Pfizer Inc. Derives de l'ansamycine utilises comme agents anti-oncogenes et anticancereux
US5932566A (en) * 1994-06-16 1999-08-03 Pfizer Inc. Ansamycin derivatives as antioncogene and anticancer agents
EP1483395A1 (fr) * 2002-02-25 2004-12-08 Pharmacia & Upjohn Company Processus pour preparer et isoler la geldanamycine
US6852496B1 (en) 1997-08-12 2005-02-08 Oregon Health And Science University Methods of screening for agents that promote nerve cell growth
US6855705B1 (en) 2003-11-12 2005-02-15 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
US6870049B1 (en) 2003-11-12 2005-03-22 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
US6872715B2 (en) * 2001-08-06 2005-03-29 Kosan Biosciences, Inc. Benzoquinone ansamycins
US6875863B1 (en) 2003-11-12 2005-04-05 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
US6887993B1 (en) 2003-11-12 2005-05-03 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
WO2005053744A1 (fr) * 2003-11-26 2005-06-16 Entelos, Inc. Traitement de la polyarthrite rhumatoide au moyen d'antagonistes du facteur 1$g(a) inductible par hypoxie
WO2005063714A1 (fr) 2003-12-23 2005-07-14 Infinity Pharmaceuticals, Inc Analogues d'ansamycines contenant de la benzoquinone pour le traitement du cancer
WO2007009007A2 (fr) * 2005-07-13 2007-01-18 Infinity Discovery, Inc. Methodes de traitement utilisant des ansamycines d'hydroquinone
US7241754B2 (en) 2003-06-13 2007-07-10 Kosan Biosciences, Inc. 2-Desmethyl ansamycin compounds
EP1923061A1 (fr) 2001-09-24 2008-05-21 Conforma Therapeutic Corporation Procédé pour la préparation de 17-allyl amino geldanamycine (17-AAG) et autres ansamycines
WO2008094438A1 (fr) 2007-01-26 2008-08-07 Kosan Biosciences Incorporated Macrolactames obtenus par biosynthèse modifiée
US7465718B2 (en) 2002-02-08 2008-12-16 Conforma Therapeutics Corporation Ansamycins having improved pharmacological and biological properties
US7544672B2 (en) 2005-03-30 2009-06-09 Conforma Therapeutics Corporation Alkynyl pyrrolo[2,3-d]pyrimidines and related analogs as HSP90-inhibitors
US7579462B2 (en) 2001-09-24 2009-08-25 Conforma Therapeutics Corporation Process for preparing 17-allyl amino geldanamycin (17-aag) and other ansamycins
WO2009130706A1 (fr) * 2008-04-21 2009-10-29 Biocon Limited Procédé d’isolement et de purification de la geldanamycine
US20110021481A1 (en) * 2006-11-09 2011-01-27 Christine Martin Novel Compounds and Methods for Their Production
US7947670B2 (en) 2006-12-12 2011-05-24 Infinity Pharmaceuticals Inc. Ansamycin formulations and methods of use thereof
US8778921B2 (en) 2008-10-15 2014-07-15 Infinity Pharmaceuticals, Inc. Ansamycin hydroquinone compositions

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ZA200604863B (en) * 2003-12-23 2007-12-27 Infinity Pharmaceuticals Inc Analogs of benzoquinone-containing ansamycins for the treatment of cancer
CN100500668C (zh) * 2006-12-19 2009-06-17 中国人民解放军军事医学科学院毒物药物研究所 格尔德霉素衍生物及其制备方法和制备药物的用途
CN102030764B (zh) * 2010-11-12 2012-07-04 中国医学科学院医药生物技术研究所 4，5双氢噻嗪酮格尔德霉素及其制备方法
CN103305563B (zh) * 2013-06-14 2014-12-03 湖南农业大学 一种以链霉菌提制阿里沙霉素的方法

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Cited By (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995001342A1 (fr) * 1993-06-29 1995-01-12 Pfizer Inc. Derives de l'ansamycine utilises comme agents anti-oncogenes et anticancereux
US5932566A (en) * 1994-06-16 1999-08-03 Pfizer Inc. Ansamycin derivatives as antioncogene and anticancer agents
US6852496B1 (en) 1997-08-12 2005-02-08 Oregon Health And Science University Methods of screening for agents that promote nerve cell growth
US7282340B2 (en) 1997-08-12 2007-10-16 Oregon Health Sciences University Methods for identifying an analog that promotes nerve regeneration
US6872715B2 (en) * 2001-08-06 2005-03-29 Kosan Biosciences, Inc. Benzoquinone ansamycins
US7405208B2 (en) 2001-08-06 2008-07-29 Kosan Biosciences, Inc. Benzoquinone ansamycins
US7579462B2 (en) 2001-09-24 2009-08-25 Conforma Therapeutics Corporation Process for preparing 17-allyl amino geldanamycin (17-aag) and other ansamycins
EP1923061A1 (fr) 2001-09-24 2008-05-21 Conforma Therapeutic Corporation Procédé pour la préparation de 17-allyl amino geldanamycine (17-AAG) et autres ansamycines
US7465718B2 (en) 2002-02-08 2008-12-16 Conforma Therapeutics Corporation Ansamycins having improved pharmacological and biological properties
EP1483395A1 (fr) * 2002-02-25 2004-12-08 Pharmacia & Upjohn Company Processus pour preparer et isoler la geldanamycine
EP1483395A4 (fr) * 2002-02-25 2005-11-16 Pharmacia & Upjohn Co Llc Processus pour preparer et isoler la geldanamycine
US7241754B2 (en) 2003-06-13 2007-07-10 Kosan Biosciences, Inc. 2-Desmethyl ansamycin compounds
US6855705B1 (en) 2003-11-12 2005-02-15 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
US6887993B1 (en) 2003-11-12 2005-05-03 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
US6875863B1 (en) 2003-11-12 2005-04-05 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
US6870049B1 (en) 2003-11-12 2005-03-22 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
WO2005053744A1 (fr) * 2003-11-26 2005-06-16 Entelos, Inc. Traitement de la polyarthrite rhumatoide au moyen d'antagonistes du facteur 1$g(a) inductible par hypoxie
AU2004309395B2 (en) * 2003-12-23 2011-10-06 Infinity Discovery, Inc. Analogs of benzoquinone-containing ansamycins for the treatment of cancer
US8252779B2 (en) 2003-12-23 2012-08-28 Infinity Pharmaceuticals, Inc. Analogs of benzoquinone-containing ansamycins and methods of use thereof
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FI943207A (fi) 1994-07-05
FI943207A0 (fi) 1994-07-05
PT101169A (pt) 1994-03-31
KR940703923A (ko) 1994-12-12
NO942532L (no) 1994-07-05
ZA9333B (en) 1994-07-05
HU9401936D0 (en) 1994-09-28
NO942532D0 (no) 1994-07-05
IL104289A0 (en) 1993-05-13
CN1074937A (zh) 1993-08-04
MX9300011A (es) 1993-12-01
CA2127457A1 (fr) 1993-07-22
AU3225693A (en) 1993-08-03
JPH06510913A (ja) 1994-12-08
BR9207024A (pt) 1995-12-05
CZ390592A3 (en) 1993-08-11

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