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WO1994010843A1 - Derives de rapamycine - Google Patents

Derives de rapamycine Download PDF

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Publication number
WO1994010843A1
WO1994010843A1 PCT/US1993/010922 US9310922W WO9410843A1 WO 1994010843 A1 WO1994010843 A1 WO 1994010843A1 US 9310922 W US9310922 W US 9310922W WO 9410843 A1 WO9410843 A1 WO 9410843A1
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WO
WIPO (PCT)
Prior art keywords
compound
animal
human
amount
rapamycin
Prior art date
Application number
PCT/US1993/010922
Other languages
English (en)
Inventor
James Amigo Chan
Robert Gerber
Randall Keith Johnson
Juan Ignacio Luengo
Original Assignee
Smithkline Beecham Corporation
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 Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to AU56019/94A priority Critical patent/AU5601994A/en
Publication of WO1994010843A1 publication Critical patent/WO1994010843A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N63/00—Biocides, pest repellants or attractants, or plant growth regulators containing microorganisms, viruses, microbial fungi, animals or substances produced by, or obtained from, microorganisms, viruses, microbial fungi or animals, e.g. enzymes or fermentates
    • A01N63/20—Bacteria; Substances produced thereby or obtained therefrom
    • A01N63/28—Streptomyces

Definitions

  • the present invention relates to a novel compound and derivatives thereof, to processes for their production, to pharmaceutical compositions containing them, and to their use as antifungal agents, tumor cell growth inhibiting agents and as immunosuppressants.
  • This invention also relates to a biologically pure culture of a microorganism which has the identifying characteristics of ATCC 55367.
  • Rapamycin is a naturally occurring macrocyclic triene antibiotic which can be produced by culturing a producing organism in an aqueous nutrient medium. Rapamycin was first isolated as an extract of Streptomyces hygroscopicus and has been reported to have antifungal activity (British Patent 1436447). Subsequently rapamycin has been implicated as an immunosuppressant (Martel R.R. et al., Can J. Phvsiol. Pharmacol..55, 48-51, 1977). There is a need for more agents of this type.
  • the present invention provides a novel, naturally occurring rapamycin derivative, i.e., 16-nor-rapamycin, as well as derivatives thereof.
  • 16-nor-rapamycin has been found to have useful antifungal activity and also immunosuppressant properties, and is expected to have useful tumor cell growth-inhibiting activity.
  • This invention relates to 16-nor-rapamycin as well as derivatives thereof.
  • the invention in a second aspect, further provides a process for the production of 16-nor- rapamycin which comprises cultivating a 16-nor-rapamycin producing microorganism and subsequently isolating therefrom 16-nor-rapamycin or derivatives thereof.
  • This invention also relates to the compound produced by such process.
  • This invention also relates to a biologically pure culture of a microorganism which has the identifying characteristics of ATCC 55367 and active mutants thereof.
  • This invention further relates to a pharmaceutical composition comprising an effective, non-toxic amount of 16-nor-rapamycin or a derivative thereof, and a pharmaceutically acceptable carrier or diluent.
  • this invention relates to a method for treating fungal infection in an animal or human in need thereof which comprises administering to such animal or human an effective, non-toxic, anti-fungal amount of 16-nor-rapamycin or a derivative thereof.
  • this invention relates to a method for effecting immunomodulation in an animal or human in need thereof which comprises administering to such animal or human an effective, non- toxic, immunomodulatory amount of 1 -nor-rapamycin or a derivative thereof.
  • this invention relates to a method for inhibiting the growth of tumor cells sensitive to 16-nor-rapamycin in an animal or human in need thereof which comprises administering to such animal or human an effective, non-toxic, tumor cell growth inhibiting amount of 16-nor-rapamycin or a derivative thereof.
  • 16-nor-rapamycin is believed to have the following structure:
  • the compound of the invention has the following characteristics: i) apparent molecular weight of 899 by Electrospray Ionization (ESI) mass spectroscopy; and ii) ⁇ NMR spectroscopy consistent with the proposed structure.
  • ESI Electrospray Ionization
  • 16-nor-rapamycin may be obtained by the cultivation of a producing organism and the recovery of it or a derivative thereof from the culture.
  • the term 'cultivation' (and derivatives of that term) as used herein means the deliberate aerobic growth of an organism in the presence of assimilable sources of carbon, nitrogen, sulphur and mineral salts. Such aerobic growth may take place in a solid or semi-solid nutritive medium, or in a liquid medium in which the nutrients are dissolved or suspended.
  • the cultivation may take place on an aerobic surface or by submerged culture.
  • the nutritive medium may be composed of complex nutrients or may be chemically defined.
  • suitable microorganisms for use in the cultivation process according to the invention include bacterial strains belonging to the genus Streptomyces which are capable of elaborating 16-nor-rapamycin.
  • One such producing organism was deposited on October 15, 1992 with the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A., in accordance with the provisions of the Budapest Treaty, and such organism was assigned ATCC accession number 55367. It has been found that ATCC 55367, which was isolated from nature, and also mutants thereof, are capable of producing 16-nor-rapamycin.
  • this invention also relates to a biologically pure culture of a microorganism which has the identifying characteristics of ATCC 55367, and mutants thereof.
  • the teim 'mutant' as used herein includes any mutant strain derived from ATCC
  • Ionizing radiation e.g. X-rays and g-rays
  • a photosensitizing agent e.g. 8-methoxypsoralen
  • nitrous acid hydroxylamine
  • pyrimidine base analogues e.g. 5-bromouracil
  • acridines alkylating agents (e.g. mustard gas, ethyl-methane sulphonate), hydrogen peroxide, phenols, formaldehyde, heat, and
  • the fermentation medium for cultivating ATCC 55367 suitably contains sources of assimilable carbon and assimilable nitrogen.
  • sources of nitrogen include yeast extract, soyabean flour, and protein hydrolysates.
  • Suitable carbon sources include glucose, and malt extract.
  • the cultivation may suitably be effected at a temperature of about 28 °C, and the culture may suitably be harvested up to 7 days, advantageously about 3 to 4 days, after the initiation of fermentation in order to give an optimum yield of the desired product.
  • This invention also relates to the product produced by such process.
  • the desired product or a derivative thereof may then be isolated from the culture medium and worked up and purified using conventional techniques for such compounds. All such isolation and purification procedures may conveniently be effected at cool to ambient temperature, for example at a temperature within the range of from 4 to 40°C, conveniently from 20 to 35°C. ,
  • the desired compound may readily be identified in a routine manner by testing for antifungal activity and/or by monitoring the h.p.l.c. retention time with photodiode array detector, or silica thin layer chromatography (TLC) Rp value.
  • the separation procedure may include a high-performance liquid chromatography (HPLC) step, preferably as the last step. Elution may be effected using aqueous methanol or buffered aqueous acetonitrile.
  • 16-nor-rapamycin and its derivatives may be crystalline or non -crystalline, and, if crystalline, may optionally be hydrated or solvated.
  • the 16-nor-rapamycin derivatives are preferably pharmaceutically acceptable derivatives.
  • Derivatives may include salts with pharmaceutically acceptable counter ions.
  • the compounds according to the invention are suitably provided in substantially pure form, for example at least 50% pure, suitable at least 60% pure, advantageously at least 75% pure, preferably at least 85% pure, more preferably at least 95% pure, especially at least 98% pure, all percentages being calculated as weight/weight.
  • An impure or less pure form of a compound according to the invention may, for example, be used in the preparation of a more pure form of the same compound or of a related compound (for example a corresponding derivative) suitable for pharmaceutical use.
  • a compound of of the invention is administered in conventional dosage form prepared by combining a therapeutically effective amount of the compound ("active ingredient") with standard pharmaceutical carrier or diluents according to conventional procedures. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • the pharmaceutical carrier employed may be, for example, either a solid or liquid.
  • solid carrier are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the carrier or diluent may include time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate along or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate and the like.
  • the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but preferably will be from about 25 mg to about 1 g.
  • the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampule or vial or nonaqueous liquid suspension.
  • a pharmaceutically acceptable salt of a compound of the invention is dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3M solution of succinic acid, or, preferably, citric acid.
  • an organic or inorganic acid such as a 0.3M solution of succinic acid, or, preferably, citric acid.
  • acidic derivatives can be dissolved in suitable basic solutions.
  • a suitable cosolvent or combinations thereof include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0-60% of the total volume.
  • Tests indicate that the compound of this invention are useful in prophylactically or therapeutically inhibiting the growth of pathogenic fungi in a human or other animal in need thereof.
  • the invention includes methods of inhibiting the growth of pathogenic fungi in a human or other animal in need thereof which comprises administering to such human or animal an effective, non-toxic amount of a compound of of the invention.
  • pathogenic fungi is meant fungi capable of producing disease in a human or other animal. Examples of pathogenic fungi include, but are not limited to Candida albicans and other Candida species, Microsporum gypseum, Trichophyion mentagrophytes, Asperqill s sp. and Sporotrichum sp.
  • the compounds may be used for the treatment of topical fungal infections in man caused by, among other organisms, species of Candida. Trichophvton. Microsporum or Epidermophvton or in mucosal infections caused by Candida albicans (e.g. thrush and vaginal candidiasis). They may also be used in the treatment of systemic fungal infections caused by, for example andida lt ⁇ c ns, Crvptococcus neoformans. Aspereillus fumigatus. Coccidiodes. Paracocciciodes. Histoplasma or Blastomvces a ⁇ .
  • the compounds of this invention may also be of use in treating eumycotic mycetoma, chromoblastomycosis and phycomycosis.
  • the ability of the compound of this invention to inhibit the growth of pathogenic fungi may be demonstrated or predicted by standard tests known and used for this purpose, for example, the yeast assay described hereinbelow.
  • an effective dosage will be in the range of about 0.05 to 100 milligrams per kilogram body weight per day.
  • Tests indicate that the compound of this invention are also useful for immunomodulation, i.e., inducing a suppression of a human's or animal's immune system.
  • This invention therefore relates, to a method of prophylactically or therapeutically inducing immunomodulation in a human or other animal in need thereof which comprises administering an effective, non-toxic amount of such a compound of this invention to such human or other animal.
  • the ability of the compound of this invention to induce immunosuppression may be demonstrated in standard tests used for this purpose, for example, a mixed lymphocyte reaction test or a test measuring inhibition of T-cell proliferation measured by thimidine uptake.
  • the compound of this invention have utility in inducing immunosuppression means that they are useful in, inter alia, the treatment or prevention of resistance to or rejection of transplanted organs or tissues (e.g., kidney, heart, lung, bone marrow, skin, cornea, etc.); the treatment or prevention of autoimmune, inflammatory, proliferative and hyperproliferative diseases, and of cutaneous manifestations of immunologically mediated diseases (e.g., rheumatoid arthritis, lupus erythematosus, systemic lupus erythematosus, Hashimotos thyroiditis, multiple sclerosis, myasthenia gravis, type 1 diabetes, uveitis, nephrotic syndrome, psoriasis, atopical dermatitis, contact dermatitis and further eczematous dermatitides, seborrheic dermatitis, Lichen planus, Pemplugus, bullous Pemphigold, Epidermolysis bullo
  • an effective dosage will be in the range of about 0.05 to 100 milligrams per kilogram body weight per day.
  • the compound of this invention should also be useful for inhibiting the growth of tumor cells sensitive to a compound of the invention in an animal or human in need thereof. More specifically, the compounds should be useful for reducing tumor size, inhibiting tumor growth and/or prolonging the survival time of an animal or human bearing a tumor which is sensitive to a compound of this invention. Accordingly, this invention also relates to a method of inhibiting the growth of tumor cells sensitive to a compound of the invention in a human or other animal in need thereof comprising administering to such human or animal an effective, non-toxic amount of a compound of of the invention.
  • an effective dosage is expected to be in the range of about .0.05 to 100 milligrams per kilogram body weight per day.
  • the compound of the invention may be administered to a human or other animal in accordance with the aforementioned methods of treatment in an amount sufficient to produce such effect to a therapeutic or prophylactic degree.
  • Such compound of the invention can be administered to such human or other animal in a conventional dosage form prepared by combining the compound of the invention with a conventional pharmaceutically acceptable carrier or diluent according to known techniques. It will be recognized by one of skill in the art that the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables.
  • the route of administration of the compound of the invention may be oral, parenteral, by inhalation or topical.
  • parenteral as used herein includes intravenous, intramuscular, subcutaneous, rectal, vaginal or intraperitoneal administration.
  • the subcutaneous and intramuscular forms of parenteral administration are generally preferred.
  • the daily parenteral and oral dosage regimens for employing compound of the invention to prophylactically or therapeutically inhibit the growth of pathogenic fungi, to prophylatically or therapeutically induce immunosuppression, or to therapeutically treat carcinogenic tumors will generally be in the range of about 0.05 to 100, but preferably about 0.5 to 10, milligrams per kilogram body weight per day.
  • the compound of the invention may also be administered by inhalation.
  • inhalation is meant intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
  • the preferred dosage amount of a compound of the invention to be employed is generally within the range of about 10 to 100 milligrams.
  • the compound of the invention may also be administered topically.
  • topical administration is meant non-systemic administration and includes the application of a compound of the invention externally to the epidermis, to the buccal cavity and instillation of such a compound into the ear, eye and nose, and where the compound does not significantly enter the blood stream.
  • systemic administration is meant oral, intravenous, intraperitoneal and intramuscular administration.
  • the amount of a compound of the invention (hereinafter referred to as the active ingredient) required for therapeutic or prophylactic effect on pathogenic fungi growth inhibition or immunosuppression induction upon topical administration will, of course, vary with the compound chosen, the nature and severity of the condition being treated and the animal undergoing treatment, and is ultimately at the discretion of the physician.
  • a suitable topical dose of a compound of the invention will generally be within the range of about 1 to 100 milligrams per kilogram body weight daily.
  • an active ingredient may be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation.
  • the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, e.g., from 1% to 2% by weight of the formulation although it may comprise as much as 10% w/w but preferably not in excess of 5% w/w and more preferably from 0.1% to 1% w/w of the formulation.
  • topical formulations of the present invention comprise an active ingredient together with one or more acceptable carrier(s) therefore and optionally any other therapeutic ingredient(s).
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and no deleterious to the recipient thereof.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of where treatment is required such as: liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent.
  • the resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 90-100 °C for half an hour.
  • the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
  • bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).
  • Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
  • Lotions according to the present invention include those suitable for application to the skin or eye.
  • An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
  • Lotions or liniments for application to the skin may also include an 94/108 agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
  • Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy basis.
  • the basis may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives, or a fatty acid such as stearic or oleic acid together with an alcohol such as propylene glycol or macrogols.
  • the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surface active such as sorbitan esters or polyoxyethylene derivatives thereof.
  • Suspending agents such as natural gums, cellulose derivatives or in organic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
  • Agar slants prepared from 10ml of the slant medium [dextrose lOg/L; dextrin 40g/L; yeast extract 5g/L; NZ Amine Type A (Shefield) 2g/L; 94 / 10843 soy peptone 20g/L; CaCO3 lg/L; agar 18g L; in deionized water] were inoculated with approximately 0.1 ml of frozen culture stock, and incubated at 28°C for 5 to 10 days.
  • a 2L Ehrlenmyer flask containing 500 ml of seed medium [glucose 5g/L; dextrin 40g/L; soy peptone 20g/L; yeast extract 5g L; NZ Amine Type A 2g L; CaCO3 lg/L; in deionized water] was inoculated with the cells scraped from one agar slant.
  • the flask was incubated at 28°C, and agitated at 250 rpm on a gyratory shaker (1 inch throw). The seed was maintained under these conditions for 72 hours.
  • a 15L fermentor containing 10L of sterile production medium [glucose 2g/L; malt extract lOg L; yeast extract lOg L; in deionized water] was inoculated with 300 to 500 ml of the seed culture. This culture was maintained at 28°C, 300 to 400 RPM agitation, 5 L/min. air, and a back pressure of 0.5 barr. The initial pH was 6.8 to 7.0, and was not controlled.
  • Agar slant prepared from 10ml of the slant medium [dextrose lOg L; dextrin 40g/L; yeast extract 5g/L; NZ Amine Type A (Shefield) 2g/L; soy peptone 20g/L; CaCO3lg L; agar 18g/L; in deionized water] were inoculated with approximately 0.1ml of frozen culture stock, and incubated at 28°C for 5 to 10 days.
  • a 150L fermentor containing 100L of sterile production medium [glucose 2g L; malt extract lOg/L; yeast extract lOg/L; in deionized water] was inoculated with 500 to 1500ml of the seed culture. This culture was maintained at 28°C, 200 RPM agitation, 75 L/min. air, and a back pressure of 0.5 barr. The initial pH was 6.8 to 7.0, and was not controlled.
  • the silica gel column was eluted sequentially with a step gradient of hexane in acetone (80:20; 60:40; 40:60 and 0:100).
  • the hexane-acetone eluate (40:60) was concentrated under reduced pressure to give a crude residue.
  • the crude residue was dissolved in methanol and injected onto a reversed phase column (E. Merck, Lobar Lichroprep, 40-63 ⁇ m, 25x310mm) and eluted with a step gradient of methanol in water (60% to 100%) at a flow rate of 8mL min and monitored at 280 nm.
  • Active fractions were pooled according to HPLC analysis with photodiode array detector using Altex Ultrasphere ODS column (4.6x250mm, Beckman, USA) at a flow rate of lmL/min using a mobile phase of 60:40 acetonitrile-ammonium acetate buffer (0.05M, pH 6.5). Fractions containing 16-nor-rapamycin were pooled and evaporated to dryness to give a crude residue.
  • the crude residue was further purified using reversed phase semi-preparative HPLC (Altex Ultrasphere ODS column, 10x250mm, Beckman, USA) at a flow rate of 4 ml/min and eluted with a step gradient of 50 to 60% of acetonitrile in 0.05M ammonium acetate buffer (pH6.5).
  • Fractions containing 16-nor-rapamycin were combined and desalted using reversed phase Cjg Sep- Pak cartridge (Waters Associates, USA).
  • the final purification step employed preparative TLC (E. Merck, Silica gel 60, Germany) using 70:15:15 cyclohexane- isopropanol-methylene chloride as eluent to yield 4 mg of 16-nor-rapamycin.
  • BIOLOGICAL ACTIVITY EXAMPLES Compounds of the invention were analyzed for antifungal and immunosuppressive activity using the following assays.
  • Yeast organism Sacharomyces cerevisiae in logarithmic growth were plated on complete agar medium (YPD). Compounds dissolved in an appropriate aqueous or organic solvent were placed in wells punched in the agar.
  • Spleen cells from BDF1 female mice were established in RPMI with 10% fetal calf serum at 5 x lOfymL.
  • RPMI fetal calf serum
  • One hundred mL aliquots of this suspension (5 x 10 ⁇ cells) were dispensed into 96- well round-bottomed microtiter plates (Linbro, Flow Laboratories).
  • Concanavalin A (5 mg ml) was added as the mitogenic stimulus, and the final volume in the microtiter wells was adjusted to 200 mL with RPMI.
  • Cell cultures were incubated for 72 hours at 37°C in a 5% CO2 atmosphere and pulsed with 0.5 mCi ⁇ H-thymidine (specific activity 2.00 Ci/mole) for the last 18 hours of the 72 hour culture.
  • the cells were harvested on an automated multiple sample harvester and cell-associated radioactivity counted in a Beckman liquid scintillation counter. The results arc expressed as the mean values derived from quadruplicate measurements. Cell viability was determined by rypan blue exclusion after 72 hours of incubation. Compounds to be tested were added to the microtiter plates at the appropriate dilutions prior to the addition of cells. 16-nor- rapamycin showed IC 12 of 2 ng/ml against Saccharomyces cerevisiae and
  • IC50 °f ⁇ ° in the mitogenesis assay refers to the concentration of drug in the 94/10843 aforementioned antifungal agar diffusion assay where produces a 12 mm zone of inhibition.

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  • Engineering & Computer Science (AREA)
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Abstract

Dérivés de rapamycine, procédés de production de ces dérivés, compositions pharmaceutiques les contenant et leur utilisation comme agents antifongiques, comme agents d'inhibition de croissance de cellules tumorales et comme immunodépresseurs.
PCT/US1993/010922 1992-11-10 1993-11-10 Derives de rapamycine WO1994010843A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU56019/94A AU5601994A (en) 1992-11-10 1993-11-10 Rapamycin derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US97391092A 1992-11-10 1992-11-10
US07/973,910 1992-11-10

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Publication Number Publication Date
WO1994010843A1 true WO1994010843A1 (fr) 1994-05-26

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998054308A3 (fr) * 1997-05-28 1999-04-08 Biotica Tech Ltd Polycetides, leur synthese et leur utilisation
US6187757B1 (en) 1995-06-07 2001-02-13 Ariad Pharmaceuticals, Inc. Regulation of biological events using novel compounds
US7019014B2 (en) 2003-05-12 2006-03-28 Wyeth Holdings Corporation Process for producing anticancer agent LL-D45042
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
US8921642B2 (en) 2008-01-11 2014-12-30 Massachusetts Eye And Ear Infirmary Conditional-stop dimerizable caspase transgenic animals
EP3663405A1 (fr) 2013-06-11 2020-06-10 Takara Bio USA, Inc. Microvésicules enrichies en protéines et leurs procédés de fabrication et d'utilisation

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5162333A (en) * 1991-09-11 1992-11-10 American Home Products Corporation Aminodiesters of rapamycin

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5162333A (en) * 1991-09-11 1992-11-10 American Home Products Corporation Aminodiesters of rapamycin

Cited By (12)

* 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
WO1998054308A3 (fr) * 1997-05-28 1999-04-08 Biotica Tech Ltd Polycetides, leur synthese et leur utilisation
US7018808B2 (en) 1997-05-28 2006-03-28 Biotica Technology Limited Polyketides and their synthesis and use
US7381546B2 (en) 1997-05-28 2008-06-03 Biotica Technology Limited Polyketides and their synthesis 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
US7019014B2 (en) 2003-05-12 2006-03-28 Wyeth Holdings Corporation Process for producing anticancer agent LL-D45042
US8921642B2 (en) 2008-01-11 2014-12-30 Massachusetts Eye And Ear Infirmary Conditional-stop dimerizable caspase transgenic animals
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

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ZA938349B (en) 1994-08-01
AU5601994A (en) 1994-06-08

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