[go: up one dir, main page]

WO1994018207A1 - Macrolide similaire a la rapamycine et nouvelle souche de streptomyces produisant celui-ci - Google Patents

Macrolide similaire a la rapamycine et nouvelle souche de streptomyces produisant celui-ci Download PDF

Info

Publication number
WO1994018207A1
WO1994018207A1 PCT/EP1994/000284 EP9400284W WO9418207A1 WO 1994018207 A1 WO1994018207 A1 WO 1994018207A1 EP 9400284 W EP9400284 W EP 9400284W WO 9418207 A1 WO9418207 A1 WO 9418207A1
Authority
WO
WIPO (PCT)
Prior art keywords
macrolide
formula
rapamycin
treatment
streptomyces
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP1994/000284
Other languages
English (en)
Inventor
Theodor Fehr
Jean-Jacques Sanglier
Walter Schuler
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis Pharma GmbH Austria
Sandoz AG
Original Assignee
Sandoz Erfindungen Verwaltungs GmbH
Sandoz AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sandoz Erfindungen Verwaltungs GmbH, Sandoz AG filed Critical Sandoz Erfindungen Verwaltungs GmbH
Priority to AU60009/94A priority Critical patent/AU6000994A/en
Publication of WO1994018207A1 publication Critical patent/WO1994018207A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems

Definitions

  • This invention relates to a rapamycin-like macrolide which is an antagonist of FK506 and rapamycin, and to a newly isolated strain of Streptomyces which produces the macrolide.
  • Rapamycin is a macrolide antibiotic that is produced by
  • Rapamycin is an extremely potent immunosuppressant and also has anti-tumour and anti-fungal activity.
  • utility of rapamycin as a pharmaceutical is restricted by its low and variable bioavailability and its high toxicity.
  • FK506 (tacrolimus) is a macrolide antibiotic that is produced by Streptomyces tsukubaensis No 9993. The structure of FK506 is given in Tanaka et al; 1987; J. Am. Chem. Soc, 109, 5031. FK506 also is a potent immunosuppressant. However FK506 is also toxic; particularly to the nervous system.
  • FK506 and rapamycin have somewhat different mechanisms of inducing immunosuppression; however, both bind strongly to common intracellular binding proteins (macrophilins). It is believed that this binding is a prerequisite for their immunosuppressive activity and the immunosuppressive activity of their numerous immunosuppressive derivatives.
  • This invention provides a novel macrolide which is not immunosuppressive, but which binds strongly to macrophilins.
  • This novel macrolide is useful as a pharmaceutical, e.g., as an antidote to macrophilin binding immunosuppressants of the FK506 or rapamycin type, as a steroid potentiator, and as a Mip inhibitor, as well as in diagnostic and screening assays.
  • the novel macrolide is of formula
  • the macrolide of formula I binds to macrophilin with an affinity comparable to that of rapamycin and of FK506.
  • the macrophilin binding activity of the macrolide of formula I can be shown using the macrophilin binding assay (MBA), which measures the ability of the macrolide of the invention of compete with a macrophilin binding immunosuppressant for binding to a macrophilin.
  • MSA macrophilin binding assay
  • FK506, rapamycin, and immunosuppressive derivatives of these drugs are known to bind in vivo to macrophilin-12 (also known as FK506 binding protein or FKBP-12), so the ability of the macrolide to compete with FK506 or rapamycin for binding to macrophilin- 12 can be measured.
  • FK506 is coupled to bovine serum albumin (BSA) and is then used to coat microtiter wells.
  • Biotinylated recombinant human macrophilin-12 (biot-MAP) is allowed to bind in the presence or absence of the macrolide of formula I to the immobilized FK506. After washing (to remove macrophilin-12 which is not specifically bound to the immobilized FK506), the amount of bound biot-MAP is assessed by incubation with a streptavidin-alkaline phosphatase conjugate, followed by washing and subsequent addition of p- nitrophenyl phosphate as a substrate. The read-out is the OD at 405nm.
  • any binding of the macrolide of formula I to the biot-MAP results in a decrease in the amount of biot-MAP that is bound to the FK506 and thus in a decrease in the OD 405.
  • Repeating the test at various concentrations of the macrolide allows the determination of the concentration resulting in 50% inhibition of the biot-MAP binding to the immobilized FK506 (IC50).
  • the inhibitory capacity of the macrolide is then compared to the IC50 of free FK506 as a standard and expressed as a relative IC50 (i.e., IC50-macrolide/IC50-free FK506).
  • a higher relative IC50 corresponds to a lower binding affinity and hence indicates a less powerful antagonist.
  • the macrolide of formula I is not immunosuppressive and is a FK506 antagonist and can reverse the immunosuppressant effects of FK506. This can be demonstrated using a functional assay of inhibition of IL-2 gene transcription, such as an IL-2 reporter gene assay.
  • FK-506 is known to inhibit the induction of IL-2 transcription in PHA/PMA stimulated JURKAT lymphoma cells and therefore the ability of the macrolide to block the FK506-mediated inhibiton of IL-2 transcription in an IL-2 reporter gene assay may be used to demonstrate antagonism.
  • a suitable IL-2 reporter gene assay is that described by Baumann et al. (Transplantation Proceedings (1992), 24:43).
  • This assay uses JURKAT cells which have been stably transfected with a DNA construct comprising the E. coli ⁇ galactosidase gene under the control of the human IL-2 gene promoter which is activated by signals which induce IL-2 gene transcription.
  • PHA/PMA stimulation of the transfected cells results in ⁇ -galactosidase expression which is measured using a fluorogenic substrate (4-methyl-umbelliferyl- ⁇ -galactoside), and reflects activation of IL-2 expression.
  • Cultures are treated with various concentrations of FK506 either alone or in the presence of fixed concentrations of the macrolide and ⁇ -galactosidase activity is assessed at 16 hours by addition of the fluorogenic substrate.
  • FK506 inhibits IL-2 and ⁇ -galactosidase expression and this inhibition is blocked in the presence of the macrolide.
  • the macrolide of formula I is a rapamycin antagonist and can reverse the immunosuppressant effects of rapamycin. This can be demonstrated using an IL-6-dependent cell proliferation assay. Rapamycin is known to inhibit the IL-6 induced proliferation of the IL-6-dependent B cell hybridoma cell line B 13-29, and therefore the ability of the macrolide to block the rapamycin-mediated inhibition of the proliferation of this cell line may be used to demonstrate antagonism.
  • B 13-29 cells are treated with various doses of rapamycin in the presence of fixed concentrations of the macrolide.
  • IL-6-induced cell proliferation (at 0.03 ng IL6/ml) is then measured by 3 H-thymidine incorporation at 72 hours.
  • the macrolide blocks the rapamycin-mediated inhibition of cell proliferation in a dose dependent manner, having an antagonistic activity comparable to that of
  • the macrolide of formula I binds strongly to macrophilin and is a FK506 antagonist and a rapamycin antagonist, it is useful in the treatment of overdoses of macrophilin-binding immunosuppressants, such as FK506 and rapamycin.
  • the macrophilin binding activity of the compound of the invention also makes it useful in enhancing or potentiating the action of corticosteroids.
  • the compound of formula I exhibits a synergistic effect in combination with glucocorticosteroids, e.g. with dexamethasone, in allergic contact dermatitis in mice. This activity can be shown in the following manner.
  • mice Groups of 8 female, 5 week old NMRI mice are sensitized with 10 ⁇ l of 2% oxazolone applied to the shaved ventral abdomen on day 1. Oxazolone is dissolved in acetone. On day 8 the second exposure (challenge) is performed by the application of 10 ⁇ l of 2% oxazolone to the inner aspect of the right pinnae of test and control animals. Topical application of the test compounds (dissolved in ethanol) is performed once (30 minutes after the challenge). The efficacy is determined on day 9 by determination of the individual differences of both pinnal weights in test and control animals. The results are summarized in the following table.
  • glucocorticosteroid e.g. dexamethasone
  • the indicated daily dosage is of course dependent on the mode of administration and the type of treatment. Satisfactory results are obtained in larger mammals with a dosage topically administered of about 0.05- 1% of glucocorticosteroid and of about 0.01 %-2% of the compound of the invention.
  • the invention further includes a method of treatment, curative or supportive, of conditions as described above comprising administering to a subject in need of such treatment a therapeutically effective amount of the combination. It further comprises the combination for use in the above indications, expecially for use as an antiallergic agent.
  • the macrolide of the invention binds to and blocks a variety of Mip (macrophage infectivity potentiator) and Mip-like factors, which are structurally similar to macrophilin.
  • Mip and Mip-like factors are virulence factors produced by a wide variety of pathogens, including those of the genera Chlamidia. e.g., Chlamidiatrachomatis; Neisseria. e.g. Neisseria menin ⁇ itidis; and Le ⁇ ionella. e.g. Leqionella pneumophilia: and also by the obligately parasitic members of the order Rickettsiales. These factors play a critical role in the establishment of intracellular infection.
  • the efficacy of the macrolide of the invention in reducing the infectivity of pathogens which produce Mip or Mip-like factors can be shown by comparing infectivity of the pathogens in cells culture in the presence and absence of the macrolides, e.g., using the methods described in Lundemose, et a., Mol. Microbiol. (1993) 7: 777.
  • the compound of the invention has a marked advantage over FK506, rapamycin and their immunosuppressant derivatives for use in this indication for the reason that it is not immunosuppressive, thus it does not compromise the body's natural immune defenses against the pathogens.
  • this invention also provides a macrolide of the formula I, for use as a pharmaceutical; for example as an antidote for overdoses of a macrophilin binding immunosuppressant, e.g., FK506 or rapamycin; or as a steroid potentiator; or as an anti-infective agent.
  • a macrophilin binding immunosuppressant e.g., FK506 or rapamycin
  • a steroid potentiator e.g., as a steroid potentiator
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a macrolide of formula I together with a pharmaceutically acceptable diluent or carrier.
  • the composition is useful for treating the effects of an overdose of a macrophilin binding immunosuppressant, e.g., FK506 or rapamycin; or as a steroid potentiator (alone or in combination with one or more corticosteroids); or as an anti-infective agent (alone or in combination with other anti-infective agents).
  • a macrophilin binding immunosuppressant e.g., FK506 or rapamycin
  • a steroid potentiator alone or in combination with one or more corticosteroids
  • an anti-infective agent alone or in combination with other anti-infective agents.
  • the invention further provides the use of a.
  • macrolide of formula I in the manufacture of a medicament to be used as an antidote for overdoses of a macrophilin binding immunosuppressant, e.g., FK506 or rapamycin; or as a steroid potentiator, e.g., as an anti-inflammatory agent, or for one of the other uses kown for corticosteroids; or as an anti-infective agent, e.g., in the prophylaxis and treatment of infections or infectious diseases caused by organisms producing Mip or Mip-like factors, including organisms of the genera Chlamidia. e.g.. Chalmidiatrachomatis; Neisseria, e.g.
  • a macrophilin binding immunosuppressant e.g., FK506 or rapamycin
  • a steroid potentiator e.g., as an anti-inflammatory agent, or for one of the other uses kown for corticosteroids
  • an anti-infective agent
  • Neisseria meninoitidis and Leqionella. e.g. Leqionella pneumophilia; and also the obligately parasitic members of the order Rickettsiales.
  • Appropriate dosages of the macrolide will of course vary depending upon the condition to be treated (for example the severity of the overdose or the disease type), the effect desired, the mode of administration and the like.
  • 0.05 to 1.0 mg/kg/day and more preferably 0.1 to 1.0 mg/kg/day can be used.
  • Suitable daily dosages for patients are thus of the order of from 2.5 to 500 mg p.o., preferably 5 to 250 mg p.o., more preferably 5 to 100 mg p.o., or of the order of from 0.5 to 250 mg i.v., preferably 2.5 to 125 mg i.v. and more preferably 2.5 to 50 mg i.v..
  • Dosaging may also be arranged in a patient specific manner to provide pre-determined trough blood levels, as determined by the RIA technique.
  • patient dosaging may be adjusted to achieve regular on-going trough blood levels, as measured by RIA, of the order of from 50 to 1000 ng/ml, preferably 150 to 500 ng/ml; analogously to methods of dosaging currently employed for Ciclosporin immunosuppressive therapy.
  • the macrolide of formula I may be administered by any conventional route, in particular enterally or parenterally. Suitable enterally administered forms are solutions for drinking, tablets or capsules. Suitable parenteral forms are injectable solutions or suspensions.
  • Suitable unit dosage forms for oral administration may comprise from 1 to 50 mg of the macrolide of formula I; usually 1 to 10 mg.
  • the macrolide of formula I may be produced synthetically, e.g. by total synthesis using a procedure analogous to that described for rapamycin by
  • the macrolide of formula I is produced by a newly isolated Streptomyces strain, Streptomyces so. A 91-261402 which was deposited with the Deutsche
  • the invention includes biologically pure isolates of the strain Streptomyces sp. A 91 -261402 (DSM 7348) and mutants, recombinants and modified forms thereof which are capable of producing the macrolide of Formula I. The isolation and characteristics of this new strain are described in greater detail in Example 1.
  • the macrolide of formula I may be obtained by cultivating the strain in an appropriate culture medium and then isolating the macrolide by chromatography.
  • this invention provides a process for the production of a macrolide of formula I comprising cultivating Streptomyces sp.
  • the sources of carbon in the culture medium are carbohydrates such as glucose, xylose, galactose, glycerin, starch, and dextrin.
  • Preferred sources of nitrogen are yeast extract, meat extract, peptone, gluten meal, cottonseed meal, soybean meal, casein hydrolysates, soybean hydrolysates, yeast hydrolysates, and the like and inorganic and organic nitrogen-containing compounds such as ammonium salts, urea, amino acids and the like. Conventional fermentation agents and trace materials may also be added.
  • the fermentation is conducted under submerged aerobic conditions at a temperature between 20 and 40°C, more preferably between 23°C and 27°C.
  • the macrolide of formula I may also be used as a diagnostic tool to determine the presence of FK506 type immunosuppressants in broths. This can be done using standard competitive assays based on the FK506 antagonistic properties of the macrolide of formula I.
  • the macrolide of formula I is immobilised in microtiter wells and then allowed to bind in the presence of a test broth to labelled macrophilin-12.
  • Figure 1 is the infrared spectrum of the macrolide of formula I
  • Figure 2 is the proton NMR spectrum of the macrolide of formula I.
  • Example 1 Description and Fermentation of strain Streptomyces so. DSM 7348
  • Streptomyces sp. A91-261402 was deposited with the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Mascheroder Weg 1b, D-3300 Braunschweig, Germany on December 3 1992 under the terms of the Budapest Treaty, and has been assigned the reference number DSM 7348.
  • Streptomyces sp. A91-261402 was isolated from a soil sample (pH 7,7) collected along the Virgin River, Utah, U.S.A. The strain belongs to the genus Streptomyces according to the description in Bergey's Manual, 8th edition, 1974, the new edition of the Bergey'Manual (1989) and The Prokaryotes (1992).
  • the cell walls contain LL-diaminopimelic acid.
  • the fatty acids are iso- and anteiso-branched straight and unsaturated.
  • the sugar spectrum is non distinctive.
  • the vegetative mycelium does not break down in fragments.
  • the aerial mycelium forms long chain of spores.
  • strain DSM 7348 is a new Streptomyces. designated A91-261402.
  • the strain DSM 7348 grows on various organic and inorganic media and in most cases form aerial mycelium.
  • the primary substrate mycelium grows as hyphae and is generally beige.
  • the aerial mycelium is white to white-greyish and forms long chains of spores which belong to the type "verticillus spira".
  • yeast extract/ growth good malt agar substrate mycelium: beige aerial mycelium: white soluble pigment: none oatmeal growth: good substrate mycelium: beige aerial mycelium: white-greyish soluble pigment: none glucose-asparagine growth: good substrate mycelium: spare, whitish soluble pigment: none nutrient agar growth: medium weak substrate mycelium: beige aerial mycelium: none soluble pigment: none Inorganic salts/ growth: good starch agar substrate mycelium: yellowish aerial mycelium: grey soluble pigment: none
  • Glycerol/ growth good asparagine agar substrate mycelium: beige aerial mycelium, white to grey soluble pigment: none
  • nitrate reduction weak starch hydrolysis: very weak tyrosine degradation: positive milk peptonisation: positive melanin formation: negative growth temperatures: 13-37°c. No growth at 45 * C. pH-range: 5-9 NaCI resistance: up to 6%. Reduced growth at 6%.
  • Streptomyces sp. A91-261402 can be mutated or modified into different forms by conventional technique, e.g., by UV radiation or by treatment with a chemical mutagen such as
  • Recombinant clones can be obtained by protoplast fusion. All such mutants or recombinants or modified forms, capable of producing the macrolide 222-662 in a quantity greater than 10 mg/l of culture fall within the scope of this application.
  • the new strain DSM 7348 may be cultured at suitable temperatures on various culture media using appropriate nutrients and mineral substances, as aerobic or immersion cultures.
  • the fermentation media should contain a utilisable source of carbon, sources of nitrogen and mineral salts including trace elements, all of which can be added in the form of well defined products or as complex mixtures, as are found in biological products of various origins.
  • the following fermentation description describes the original conditions under which the macrolide of Formula I was discovered. Improvements of the yield can be achieved by optimisation of the culture conditions (aeration, temperature, pH, quality and quantity of the carbon and nitrogen sources, quantity of the mineral salts and of the trace elements) and by controlling the fermentation conditions in bioreactors.
  • Agar slant cultures of the strain DSM 7348 are grown for 10 to 14 days at 27°C on the following agar medium:
  • the medium is adjusted to pH 6.6-6.8 with NaOH/H 2 S0 4 , then sterilised for 20 min. at 120°C.
  • the cultures can be stored at -25°-70°C.
  • a suspension in glycerol-peptone can be stored under liquid nitrogen.
  • the medium is adjusted to pH 6.8-7.2 with NaOH/H 2 S0 4 and sterilised for 20m at 121 °5C.
  • composition of the trace element solution A is as follows
  • the preculture is fermented for 96 hr. at 27 ⁇ C on a rotary shaker at 200 rpm with an eccentricity of 50 mm.
  • the composition of the main culture medium is as follows:
  • the pH is adjusted to 6.3 with KOH/HCI.
  • the medium is sterilised for 20 min at 121 °C.
  • ⁇ I of preculture fermentation broth obtained as in Example 1 part (b) is filtered through a thick paper filter to separate off the mycelia.
  • the mycelia are treated with methanol, under vigorous stirring, for about 1 ⁇ minutes and filtered.
  • the filtrate is then concentrated and combined with the first filtrate and the resulting mixture is extracted twice with ⁇ I ethyl acetate and twice with ⁇ I n-butanol.
  • the two extracts are evaporated to dryness on a rotary evaporator under reduced pressure.
  • fractions are then subjected to macrophilin binding assay analysis and active fractions ⁇ to 7 are then purified on a column of 1 ⁇ g silica gel SICAM using methylene chloride/methanol/ water in the ratio 92:7. ⁇ :0. ⁇ .
  • the fractions are again subjected to a macrophilin binding assay analysis and active fractions 3 and 4 are combined, filtered and evaporated to dryness under vacuum to yield 27 mg of pure amorphous macrolide.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Un macrolide ayant la formule (I) a les propriétés antagonistes de FK506 et de la rapamycine. Ce macrolide est un métabolite d'une souche nouvellement isolée de Streptomyces, le Streptomyces sp. A 91-261 402.
PCT/EP1994/000284 1993-02-02 1994-02-01 Macrolide similaire a la rapamycine et nouvelle souche de streptomyces produisant celui-ci Ceased WO1994018207A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU60009/94A AU6000994A (en) 1993-02-02 1994-02-01 Rapamycin-like macrolide and a new strain of streptomyces which produces it

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9302016.2 1993-02-02
GB939302016A GB9302016D0 (en) 1993-02-02 1993-02-02 Compounds

Publications (1)

Publication Number Publication Date
WO1994018207A1 true WO1994018207A1 (fr) 1994-08-18

Family

ID=10729706

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1994/000284 Ceased WO1994018207A1 (fr) 1993-02-02 1994-02-01 Macrolide similaire a la rapamycine et nouvelle souche de streptomyces produisant celui-ci

Country Status (3)

Country Link
AU (1) AU6000994A (fr)
GB (1) GB9302016D0 (fr)
WO (1) WO1994018207A1 (fr)

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999041258A1 (fr) * 1998-02-13 1999-08-19 President And Fellows Of Harvard College Agents de dimerisation, production et utilisation
US6187757B1 (en) 1995-06-07 2001-02-13 Ariad Pharmaceuticals, Inc. Regulation of biological events using novel compounds
WO2005084673A1 (fr) * 2004-03-02 2005-09-15 Wyeth Nouveaux ligands d'immunophilines non immunosuppressives utilises comme agents neuroprotecteurs et/ou neuroregenerateurs
WO2005085257A1 (fr) * 2004-03-02 2005-09-15 Wyeth Macrolides et méthode de production des macrolides
US6984635B1 (en) 1998-02-13 2006-01-10 Board Of Trustees Of The Leland Stanford Jr. University Dimerizing agents, their production and use
WO2005121327A3 (fr) * 2004-06-03 2006-06-22 Wyeth Corp Groupe de genes biosynthetiques utilise dans la production d'un polyketide complexe
US7067526B1 (en) 1999-08-24 2006-06-27 Ariad Gene Therapeutics, Inc. 28-epirapalogs
US7196192B2 (en) 1999-08-24 2007-03-27 Ariad Gene Therapeutics, Inc. 28-epirapalogs
WO2009039102A1 (fr) * 2007-09-17 2009-03-26 President And Fellows Of Harvard College Inhibiteurs de copn (cpn) pour le traitement d'infections bactériennes
EP2181704A2 (fr) 2002-12-30 2010-05-05 Angiotech International Ag Liberation de medicaments a partir d'une compostion polymere a gelification rapide
US7745457B2 (en) 2006-03-07 2010-06-29 Wyeth Llc Meridamycin analogues for the treatment of neurodegenerative disorders
CN101486975B (zh) * 2008-01-18 2012-04-18 浙江海正药业股份有限公司 一种链霉菌、用其产生他克莫司的方法及其应用
WO2013093493A1 (fr) 2011-12-23 2013-06-27 Biotica Technology Limited Nouvel analogue de rapamycine
US8921642B2 (en) 2008-01-11 2014-12-30 Massachusetts Eye And Ear Infirmary Conditional-stop dimerizable caspase transgenic animals
WO2018148508A1 (fr) 2017-02-10 2018-08-16 Mount Tam Biotechnologies, Inc. Analogue de rapamycine
EP3663405A1 (fr) 2013-06-11 2020-06-10 Takara Bio USA, Inc. Microvésicules enrichies en protéines et leurs procédés de fabrication et d'utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
B. E. BIERER ET AL: "Probing immunosuppressant action with a nonnatural immunoplilin ligand", SCIENCE, vol. 250, no. 4980, 26 October 1990 (1990-10-26), LANCASTER, PA US, pages 556 - 559 *

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6187757B1 (en) 1995-06-07 2001-02-13 Ariad Pharmaceuticals, Inc. Regulation of biological events using novel compounds
US6649595B2 (en) 1995-06-07 2003-11-18 Ariad Gene Therapeutics, Inc. Regulation of biological events using novel compounds
WO1999041258A1 (fr) * 1998-02-13 1999-08-19 President And Fellows Of Harvard College Agents de dimerisation, production et utilisation
US6984635B1 (en) 1998-02-13 2006-01-10 Board Of Trustees Of The Leland Stanford Jr. University Dimerizing agents, their production and use
US7067526B1 (en) 1999-08-24 2006-06-27 Ariad Gene Therapeutics, Inc. 28-epirapalogs
US7196192B2 (en) 1999-08-24 2007-03-27 Ariad Gene Therapeutics, Inc. 28-epirapalogs
EP2181704A2 (fr) 2002-12-30 2010-05-05 Angiotech International Ag Liberation de medicaments a partir d'une compostion polymere a gelification rapide
JP2007526307A (ja) * 2004-03-02 2007-09-13 ワイス マクロライドおよびその製造方法
WO2005084673A1 (fr) * 2004-03-02 2005-09-15 Wyeth Nouveaux ligands d'immunophilines non immunosuppressives utilises comme agents neuroprotecteurs et/ou neuroregenerateurs
US7247650B2 (en) 2004-03-02 2007-07-24 Wyeth Macrolides and methods for producing same
WO2005085257A1 (fr) * 2004-03-02 2005-09-15 Wyeth Macrolides et méthode de production des macrolides
JP2008501342A (ja) * 2004-06-03 2008-01-24 ワイス 複合ポリケチドを生成するための生合成遺伝子クラスター
US7507752B2 (en) 2004-06-03 2009-03-24 Wyeth Biosynthetic gene cluster for the production of a complex polyketide
WO2005121327A3 (fr) * 2004-06-03 2006-06-22 Wyeth Corp Groupe de genes biosynthetiques utilise dans la production d'un polyketide complexe
US8030325B2 (en) 2004-06-03 2011-10-04 Wyeth Llc Biosynthetic gene cluster for the production of a complex polyketide
US7745457B2 (en) 2006-03-07 2010-06-29 Wyeth Llc Meridamycin analogues for the treatment of neurodegenerative disorders
WO2009039102A1 (fr) * 2007-09-17 2009-03-26 President And Fellows Of Harvard College Inhibiteurs de copn (cpn) pour le traitement d'infections bactériennes
US8921642B2 (en) 2008-01-11 2014-12-30 Massachusetts Eye And Ear Infirmary Conditional-stop dimerizable caspase transgenic animals
CN101486975B (zh) * 2008-01-18 2012-04-18 浙江海正药业股份有限公司 一种链霉菌、用其产生他克莫司的方法及其应用
WO2013093493A1 (fr) 2011-12-23 2013-06-27 Biotica Technology Limited Nouvel analogue de rapamycine
EP3663405A1 (fr) 2013-06-11 2020-06-10 Takara Bio USA, Inc. Microvésicules enrichies en protéines et leurs procédés de fabrication et d'utilisation
EP4491726A2 (fr) 2013-06-11 2025-01-15 Takara Bio USA, Inc. Microvésicules enrichies en protéines et leurs procédés de fabrication et d'utilisation
WO2018148508A1 (fr) 2017-02-10 2018-08-16 Mount Tam Biotechnologies, Inc. Analogue de rapamycine

Also Published As

Publication number Publication date
AU6000994A (en) 1994-08-29
GB9302016D0 (en) 1993-03-17

Similar Documents

Publication Publication Date Title
US5166135A (en) Method for the control of pneumocystis carinii
WO1994018207A1 (fr) Macrolide similaire a la rapamycine et nouvelle souche de streptomyces produisant celui-ci
JPH02288837A (ja) ニユーモシステイス・カリニの抑制方法
EP1751272B1 (fr) Production de tacrolimus (fk-506) au moyen de nouvelles especes de streptomyces
KR100659680B1 (ko) 항생 물질 카프라자마이신류 및 그 제조법
KR0135600B1 (ko) 항암 항생물질 mi43-37f11, 그 제조방법 및 그 용도
DK170892B1 (da) 14-Oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12]tetra-deca-2,4,6-trien-forbindelser, fremgangsmåde til fremstilling heraf, farmaceutiske præparater der indeholder forbindelserne samt anvendelse af forbindelserne til fremstilling af lægemidler og en kultur af mikroorganismen Streptomyces sandaensis
WO1995006649A1 (fr) Macrolides antagonistes des immunosuppresseurs fixant la macrophiline
EP0468504B1 (fr) L'antibiotique Balmimycine, procédé de sa préparation et son emploi comme médicament
RU2221870C2 (ru) Мумбайстатин, способ его получения и его применение в качестве фармацевтического препарата
EP1189908B1 (fr) Nouveaux alcaloides d'indolocarbazole issus d'un actinomycete marin
JP3830964B2 (ja) 海洋放線菌から単離した新規なチオデプシペプチド
PL195995B1 (pl) Wankoresmycyna, sposób jej wytwarzania, organizm Amycolatopsis z gatunku HIL-006734, zastosowanie wankoresmycyny oraz środek farmaceutyczny
EP0376609B1 (fr) Antibiotique A80915 et procédé de préparation
KR860001497B1 (ko) 항생제 a51568 인자 a 및 b의 제조방법
US5334613A (en) Antibacterial substance BE-24566B
EP0818464B1 (fr) Methylsulfomycin 1, procédé de sa préparation et utilisation
EP0525361B1 (fr) Antibiotiques NK374186A, NK374186B, NK374186B3 et NK374186C3, leur procédé de préparation et leur utilisation
EP0574857B1 (fr) Composés polycycliques 31668P et 31668U, procédé pour leur préparation et leur utilisation comme agents antibiotiques ou antitumoraux
US20080096856A1 (en) Antibiotic Compound
EP0159004A2 (fr) Antibiotiques do-248-A et B et leur procédé de préparation
KR960016206B1 (ko) Bu-3862t 항종양 항생제
US5348970A (en) Antifungal compound and compositions containing the compound
US4256835A (en) Process for preparing cephamycin C
JPS62294676A (ja) パチュロリドおよびその製造法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BB BG BR BY CA CN CZ FI HU JP KP KR KZ LK MG MN MW NO NZ PL RO RU SD SK UA US UZ VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA