WO2014082286A1 - Analogue de la rapamycine et procédés de fabrication associés - Google Patents

Analogue de la rapamycine et procédés de fabrication associés Download PDF

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WO2014082286A1
WO2014082286A1 PCT/CN2012/085631 CN2012085631W WO2014082286A1 WO 2014082286 A1 WO2014082286 A1 WO 2014082286A1 CN 2012085631 W CN2012085631 W CN 2012085631W WO 2014082286 A1 WO2014082286 A1 WO 2014082286A1
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cancer
compound
mmol
substituted
immune
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PCT/CN2012/085631
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WO2014082286A9 (fr
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Bing Wang
Jonathon Zhong Zhao
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Hangzhou Zylox Pharma Co., Ltd.
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Priority to SG11201404432QA priority Critical patent/SG11201404432QA/en
Priority to KR20147024024A priority patent/KR20150003156A/ko
Priority to EP12889107.4A priority patent/EP2809675A4/fr
Priority to AU2012395673A priority patent/AU2012395673A1/en
Priority to CA2863243A priority patent/CA2863243A1/fr
Priority to US14/383,477 priority patent/US20150051242A1/en
Application filed by Hangzhou Zylox Pharma Co., Ltd. filed Critical Hangzhou Zylox Pharma Co., Ltd.
Priority to JP2015544291A priority patent/JP2016500112A/ja
Priority to PCT/CN2012/085631 priority patent/WO2014082286A1/fr
Priority to CN201280077424.7A priority patent/CN104854112A/zh
Publication of WO2014082286A1 publication Critical patent/WO2014082286A1/fr
Priority to ZA2014/05746A priority patent/ZA201405746B/en
Publication of WO2014082286A9 publication Critical patent/WO2014082286A9/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
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    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

Definitions

  • cyclosporine (cyclosporin A) has found wide use since its introduction in the fields of organ transplantation and immunomodulation, and has brought about a significant increase in the success rate for transplantation procedures.
  • macrocyclic compounds having potent immunomodulatory activity have been discovered.
  • FR-900520 and FR-900523. which differ from FK-506 in their alkyl substituent at C-21. have been isolated from S. hygroscopicus yakushimnaensis.
  • FR-900525, produced by S. tsukubaensis differs from FK- 506 in the replacement of a pipecolic acid moiety with a proline group.
  • Unsatisfactory side- effects associated with cyclosporine and FK-506. such as nephrotoxicity, have led to a continued search for immunosuppressant compounds having improved efficacy and safety, including an immunosupressive agent which is effective topically, but ineffective systemically (U.S. Pat. 5.457.1 I I).
  • Rapamycin as illustrated below, is a macrocyclic triene antibiotic produced by Streptomyces hygroscopicus. which was found to have antifungal activity, particularly against Candida albicans, both in vitro and in vivo (US 3.929.992 and US 3.993.749).
  • Rapamycin alone (US 4.885.171) or in combination with picibanil (US 4,401.653) has been shown to have antitumor activity.
  • rapamycin was also shown to be effective as an immunosuppressant in the experimental allergic encephalomyelitis model, a model for multiple sclerosis: in the adjuvant arthritis model, a model for rheumatoid arthritis: and was shown to effectively inhibit the formation oflgE-like antibodies.
  • Rapamycin was recently synthesized in its naturally occurring enantiomeric form (K. C. Nicolaou et al.. J. Am. Chem.
  • rapamycin analog is a tetrazole containing rapamycin analog (US 6,015.815). The tetrazole heterocyclic ring is used to replace the hydroxyl group to effect the analog.
  • rapamycin analogs which possess potentially enhanced efficacy against broad spectrum of cancers such as renal cell carcinoma, breast cancers, head and neck cancers, and potentially better lipophilicity. longer half live in the blood or in local tissues, or resistance to oxidative forces and better stability in a formulation.
  • One way to achieve these goals is through introduction of a tria/.ole moiety to the side chain of a rapamycin which may impart a better lipophilicity.
  • modified rapamycin may also have better potency against a variety of cancers, and potentially reduced toxicities.
  • one object of the present invention is to provide novel semi-synthetic rapamycin analogs which possess a desired tria/.ole moiety attached to either or both to 31C-. and or 42C-position of a rapamycin molecule.
  • the present invention is directed to compounds represented by the structural formula illustrated below.
  • the present invention is directed to compounds represented by the structural formula illustrated below.
  • a compound of the present invention may contain two such substitutes at both the 42C and 31 C-positions of a rapamycin.
  • A' is one of the following structures:
  • Another object of the present invention is to provide a synthetic processes for the preparation of such compounds from starting materials obtained by fermentation, as well as chemical intermediates useful in such synthetic processes.
  • a further object of the present invention is to provide pharmaceutical compositions containing, as an active ingredient, at least one of the above compounds.
  • Yet another object of the present invention is to provide a method of treating a variety of disease states, including restenosis, post-transplant tissue rejection, immune and autoimmune dysfunction, fungal growth, and cancer.
  • the compounds of the present invention may be employed as an oral tablet, oral solid or oral liquid, oral immediate or sustained release dosage, intravenous injection dosages, parenteral dosages, cream or solutions by formulation w ith pharmaceutically acceptable vehicles.
  • compositions for immediate release or sustained release of its active ingredient each comprising a compound of this invention and pharmaceutical ly acceptable excepient.
  • FIG. 1 Graph for Renal cell carcinoma tumor cell inhibition studies
  • FIG. 2 Graph for Renal cell carcinoma tumor cell inhibition studies
  • FIG. 3 Graph for Lung Cancer A549 cell inhibition studies
  • FIG. 4 Graph for Lung Cancer A549 cell inhibition studies
  • FIG. 5 Graph for Lung Cancer A549 cell inhibition studies
  • FIG. 6 Graph for Melanoma SK-MEL-28 cell inhibition studies: FIG. 7 Graph for Melanoma SK-MEL-28 cel l inhibition studies: FIG. 8 Graph for Melanoma SK-MEL-28 cell inhibition studies: FIG. 9 Graph for Epidermal cancer A43 I tumor cell model:
  • FIG. 10 Graph for Epidermal cancer A43 I tumor cel l model:
  • FIG. 1 1 Graph for Epidermal cancer ⁇ 43 I tumor cel l model :
  • FIG. 12 Graph for Glioblastoma U87 MG Tumor model studies: FIG. 13 Graph for Glioblastoma U87 MG Tumor model studies; FIG. 14 Graph for Glioblastoma U87 MG Tumor model studies: FIG. 15 Graph for Human colorectal tumor HCT l I 6 model studies; FIG. 16 Graph for H uman colorectal tumor HCT l 16 model studies; FIG. 17 C]raph for Human colorectal tumor HCT I 1 6 model studies: FIG. 18 Graph for Breast cancer MDA-MB-23 I tumor model;
  • FIG. 19 Graph for Breast cancer M DA-MB-23 l tumor model: FIG. 20 Graph for Breast cancer M DA-MB-23 I tumor model; FIG. 21 Graph for Breast cancer MCF-7 tumor model:
  • FIG. 22 Graph for Breast cancer MCF-7 tumor model
  • FIG. 23 Graph for Breast cancer MCF-7 tumor model:
  • FIG. 24 Cjraph for Prostate cancer PC-3 tumor studies:
  • FIG. 25 Graph for Prostate cancer PC-3 tumor studies
  • FIG. 26 Graph for Prostate cancer PC-3 tumor studies: FIG.27 Efficacy of rapamycin analog of the present invention in treating HCT 116.
  • prodrug. refers to compounds which are rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood.
  • a thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems.” Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., "Bioreversible Carriers in Drug Design.” American Pharmaceutical Association and Pergamon Press. 1987. both of which are hereby incorporated by reference.
  • prodrugs refers to those prodrugs of the compounds of the present invention which are. within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower mammals without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use. as well as the zwitterionic forms, where possible, of the compounds of the present invention.
  • Particularly preferred pharmaceutically acceptable prodrugs of the present invention are prodrug esters of the C-31 hydroxyl group of compounds of the present invention.
  • prodrug esters refers to any of several ester-forming groups that are hydro lyzed under physiological conditions.
  • Examples of prodrug ester groups include acetyl, ethanoy!. pivaloyl. pivaloyloxymethyl. acetoxymethyl. phthalidyl. methoxymethyl. indanyl. and the like, as well as ester groups derived from the coupling of naturally or unnaturalh-occurring amino acids to the C- 1 hydroxyl group of compounds of the present invention.
  • epimer refers to a compound having the identical chemical formula but a different optical configuration at a particular position.
  • a 42-Epi rapamycin refers to the compound that has the opposite optical rotation compared to the rapamycin obtained by a fermentation process.
  • the term “15-isomer” as used herein, refers to the analog of rapamycin that contains a 7- member ring at the 15-position as opposed to a regular rapamycin obtained from a fermentation process which contains a six-member ring. This kind of conversion is also called “tautomcrization " .
  • the 15-isomer "' as used herein, may also be referred to as a 15 tautomer of a rapamycin.
  • the compounds of the present invention may be prepared by a variety of synthetic routes. Most of the common conjugation reactions of rapamycin at 42- and/or 31-hydroxyl positions are found in the rapamycin patents mentioned above, the contents of which are incorporated herein by reference in their entireties.
  • Rapamycin Derivatives The parent rapamycin structure is shown below .
  • Example 3 Synthesis of Compound A4 [31] To a solution of rapamycin ⁇ (200 mg. 0.2 mmol) and 4- azidobenzoic acid (100 mg.0.6 mmol) in anhydrous THF (9 ml.) was added DIPEA (100 ⁇ L ⁇ . 0.6 mmol) and Cul (20 mg.0.1 mmol) under N;. The solution was stirred at rt for 3 hours. Then. 20 ml. water was added and extracted with ethyl acetate (20 ml. x 3). The combined organic layer was washed b brine and dried over anhydrous a ⁇ S .).
  • R and B have the following structures in some examples of the B series of rapamycin derivatives.: HO
  • CDCI 3 67.88 (m.311).7.12 (m.211).6.39-6.01 (m.4H).5.42-4.63 (m.4H): I.CMS (m/z) ES- 1148 (M-H) " .
  • m TOR kinase activity is regulated by several upstream signaling pathwa s and its dysreg lation has been implicated in several forms of cancer.
  • a Terbium labeled ant i- phosphorv lated 4I/-BPI antibodv to detect phosphorylation of the Of ['-labeled substrate b ⁇ m TOR. This ⁇ - ⁇ RITI based assay can be used to screen inhibitors of mTOR in vitro.
  • DMSO was 10-fold diluted with ddH20. so the compounds were in 10% DMSO.
  • the kinase reaction was started by the addition of 2.5 ⁇ of a solution of ATP (ATP.200 ⁇ > inal cone, in the 5 ⁇ volume is 10 ⁇ ) and substrate (0.8 ⁇ > final cone, in the 5 ⁇ assa> volume is 0.4 ⁇ ) in assay buffer and the resulting mixture was incubated for 18 min at 22°C.
  • ATP ATP.200 ⁇ > inal cone, in the 5 ⁇ volume is 10 ⁇
  • substrate 0.8 ⁇ > final cone, in the 5 ⁇ assa> volume is 0.4 ⁇
  • Y was the normalized "oinhibition value.
  • X was the log value of the test compound concentration, i 50 was the concentration of compound where half of maximal inhibition was achieved.
  • Preparation of culture media and cell culture conditions [91] Prepare the compounds and condition the cells the next day. each chemical compound to be assaved was diluted to 10 mM stock solution with 100% DMSO. followed by additional dilution with 1 0% DMSO diluted to 2 mM. followed serial 5X dilution using serum-free cell culture medium to a final 10 different diluted concentrations points (2000.400.80. 16.3.2.0.64. 0.128.0.0256.0.00512.0.00102 ⁇ ). plus 0.5% DMSO (no compound) as a maximum control and ⁇ Rapamycin as a minimum control. A solution of 0.5 ⁇ of each diluted compound is added to the ⁇ of cell culture plate, the final compound concentration of 10 points ( 10.2.0.4. 0.08.
  • Fpidermal cancer ⁇ 431 tumor cell model Fig9, Fig 10 and Figl 1.
  • n animal number: Dosing volume: adjust dosing volume based on bod weight 10 ⁇ /g). Treatment schedule may be adjusted ifbodv weight loss > 15%.
  • [1011 l-ndpoints The major endpoinl is to see if the tumor growth can be delayed or mice can be cured. Tumor sizes will be measured t ice w ekly in two dimensions using a caliper, and the volume will be expressed in mm3 using the formula: V - 0.5 a x b2 where a and b are the long and short diameters of the tumor, respectively. The tumor sizes are then used for the calculations of both T-C and T/C values. f-C is calculated with T as the median time (in days) required for the treatment group tumors to reach a predetermined size (e.g.. 500 mm3). and C is the median time (in days) for the control group tumors to reach the same size.
  • T the median time (in days) required for the treatment group tumors to reach a predetermined size (e.g.. 500 mm3).
  • C is the median time (in days) for the control group tumors to reach the same size.
  • the /C value (in percent) is an indication of antitumor effectiveness.
  • T and C are the mean volume of the treated and control groups, respectively, on a given day. Tumor tissues will be collected for the tumor weight and photo at the end of (he si Lid ⁇ .
  • lop line (diamond) is for Vehicle
  • second line (triangle) is for B7 at 3 mg/kg dose:
  • third line (purple cross) represents B7 at 9gm kg dose:
  • fourth line from the top (pink squared represent Afinitor at 9 mg/kg dose),
  • the bottom line (blue cross) represents B7 a I 8 mg kg dose.
  • the compounds of the present invention possess immunomodulatory and anti-tumor activity in mammals (especially humans).
  • immunosuppressants the compounds of the present invention are useful for the treatment and prevention of immune-mediated diseases such as the resistance by transplantation of organs or tissue such as heart, kidney, liver, medulla ossium. skin, cornea, lung, pancreas, intestinum tonne, limb, muscle, nerves, duodenum, small-bowel, pancrcatic-islet-cell. and the like: diseases brought about by medulla ossium transplantation: autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus.
  • Hashimoto's th oiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyelitis, glomerulonephritis, and the like further uses include the treatment and prophylaxis of inilammatory and by perproliferative skin diseases and cutaneous manifestations of immunologically-mediated illnesses, such as psoriasis, atopic dermatitis, contact dermatitis and further eczematous dermatitises, is scborrhocis dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedemas.
  • vasculitides erythemas, cutaneous eosinophijias. lupus erythematosus, acne and alopecia areata: various eye diseases (autoimmune and otherwise) such as keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialts corneae. corneal leukoma, and ocular pemphigus.
  • various eye diseases such as keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialts corneae. corneal leukoma, and ocular pemphigus.
  • reversible obstructive airway disease which includes conditions such as asthma (for example, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma), particularly chronic or inveterate asthma (for example, late asthma and airway hyper-responsiveness), bronchitis, allergic rhinitis, and the like are targeted by compounds of the present invention.
  • asthma for example, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma
  • chronic or inveterate asthma for example, late asthma and airway hyper-responsiveness
  • bronchitis allergic rhinitis
  • Inllammalion of mucosa and blood vessels such as gastric ulcers, vascular damage caused by ischemic diseases and thrombosis.
  • lerativ e vascular diseases such as intimal smooth muscle cell hyperplasia, restenosis and vascular occlusion, particularly following biologically- or mechanically-mediated vascular injury, may be treated or prevented by the compounds of the present invention.
  • Other treatable conditions include ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal inflammations/allergies such as Coeliac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis. Crohn's disease and ulcerative colitis: nervous diseases such as multiple myositis. (iuillain-Barre syndrome.
  • Meniere's disease, polyneuritis, multiple neuritis, mononeuritis and radiculopathy endocrine diseases such as hyperthyroidism and Basedow's disease: hematic diseases such as pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia and anerythroplasia: bone diseases such as osteoporosis: respiratory diseases such as sarcoidosis, fibroid lung and idiopathic interstitial pneumonia: skin disease such as dermalomyositis.
  • leukoderma vulgaris ichthyosis vulgaris, photoallergic sensitivity and cutaneous T cell lymphoma
  • circulatory diseases such as arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa and myocardosis: collagen diseases such as scleroderma.
  • adiposis eosinophilic fasciitis: periodontal disease such as lesions of gingiv a, periodontium, alveolar bone and substantia ossea dentis: nephrotic syndrome such as glomerulonephritis: male pattern aleopecia or alopecia senilis by preventing epilation or prov iding hair germination and'or promoting hair generation and hair growth: muscular dystrophy: Pyoderma and Sevan ' s syndrome: Addison's disease: active oxygen-mediated diseases, as for example organ injury such as ischemia-reperl ' usion injury of organs (such as heart, liver, kidney and digestive tract) which occurs upon pres rvation, transplantation or ischemic disease (lor example, thrombosis and cardiac infarction): intestinal diseases such as endotoxin-shock.
  • organ injury such as ischemia-reperl ' usion injury of organs (such as heart, liver, kidney and digestive tract) which
  • renal diseases such as ischemic acute renal insufficiency and chronic renal insufficiency: pulmonary diseases such as toxinosis caused by lung-oxygen or drug (for example, paracort and bleomycins), lung cancer and pulmonary emphysema: ocular diseases such as cataracta. sidcrosis.
  • retinitis, pigmentosa, senile macular degeneration, vitreal scarring and corneal alkali burn dermatitis such as erythema multiforme, linear IgA ballous dermatitis and cement dermatitis: and others such as gingivitis, periodontitis, sepsis, pancreatitis, diseases caused b_ ⁇ environmental pollution (for example, air pollution), aging, carcinogenesis, metastasis of carcinoma and hypobaropalhy : diseases caused by histamine or lcukotricne-C ' .siib.4 release: Behcet's disease such as intestinal-, vasculo- or neuro-Behcet's disease, and also Behcet's which affects the oral cav ity, skin.
  • Behcet's disease such as intestinal-, vasculo- or neuro-Behcet's disease, and also Behcet's which affects the oral cav ity, skin.
  • the compounds of the present invention may be useful for the treatment and prevention of hepatic disease such as immunogenic diseases (for example, chronic autoimmune liver diseases such as autoimmnune hepatitis, primary biliary cirrhosis and sclerosing cholangitis), partial liver resection, acute liver necrosis (e.g. necrosis caused by toxin, viral hepatitis, shock or anoxia).
  • immunogenic diseases for example, chronic autoimmune liver diseases such as autoimmnune hepatitis, primary biliary cirrhosis and sclerosing cholangitis
  • partial liver resection e.g. necrosis caused by toxin, viral hepatitis, shock or anoxia.
  • non-A/non-B hepatitis cirrhosis (such as alcoholic cirrhosis) and hepatic failure such as fulminant hepatic failure, late-onset hepatic failure and " acute-on-chronic " liver failure (acute liver failure on chronic liver diseases), and moreover are useful for various diseases because of their useful activity such as augmention of chemotherapeutic effect, cytomegalovirus infection, particularly I IC V infection, antiinflammatory activity, sclerosing and llbrotic diseases such as nephrosis, scleroderma, pulmonary fibrosis, arteriosclerosis, congestive heart failure, ventricular hypertrophy, postsurgical adhesions and scarring, stroke, myocardial infarction and injur associated with ischemia and rcperfusion. and the like.
  • compounds of the present invention possess ⁇ -506 antagonistic properties.
  • the compounds of the prcsenl invention may thus be used in the treatment of immunodepression or a disorder involving immunodepression.
  • Rxamplcs of disorders involving immunodepression include AIDS, cancer, fungal infections, senile dementia, trauma (including wound healing, surgery and shock) chronic bacterial infection, and certain central nervous system disorders.
  • the immunodepression to be treated ma be caused by an overdose of an immunosuppressive macroe die compound, for example derivatives ol ' 12-(2-cyclohcxyl- 1 -methyl vinyl )- 1 .19.21 ,27-tetramethyl- 11.28-dioxa4-azatricyclo
  • an immunosuppressive macroe die compound for example derivatives ol ' 12-(2-cyclohcxyl- 1 -methyl vinyl )- 1 .19.21 ,27-tetramethyl- 11.28-dioxa4-azatricyclo
  • an immunosuppressive macroe die compound for example derivatives ol ' 12-(2-cycl
  • I he compounds of the present invention possess anti-tumor activity in mammals (especially humans).
  • the compounds of the invention can be used to treat brain and neurovascular tumors, head and neck cancers, breast cancer, lung cancer, mesothelioma, lymphoid cancer, stomach cancer, kidney cancer, renal carcinoma, liver cancer and liver cirrhosis, ovarian cancer, ovary endometriosis, testicular cancer, skin cancer, melanoma, neuro and all endocrine cancers, spleen cancers, pancreatic cancers, blood proliferative disorders such as I lodgkin ' s cancer, lymphoma, leukemia, and anv cancer disorders that result from uncontrolled cellular proliferations.
  • the compounds of the present invention may be mixed with commonly known pharmaceutical excipients such as udragit. sodium carboxymelhv lcellulosc (N'a CM), sodium carboxypropv (cellulose, anv oilier natural Ix derived or svnthetic excipients to effect an efficacious pharmaceutical formulation.
  • the formulation comprising the compounds of the invention mav be made as a immediate release formulation, or a sustained release formulation, or site injection depot formulation, depending on the medical needs.
  • the compound of the present invention ma ⁇ also be combined with a medical device, such as a stent, a balloon, a balloon catheter, an orthopedic dev ice, lo further enhance the efficacy of the medical device.
  • the compound of the present invention may be the main lunction component of a medical treatment regime, such as a local injection formulation, or an ancillary function, such as a coaling on a medical device, or in combination with a low -molecular weight or polymer excipient. and used as a coaling or lillcr of a medical device.
  • a medical treatment regime such as a local injection formulation
  • an ancillary function such as a coaling on a medical device, or in combination with a low -molecular weight or polymer excipient.
  • the compounds of the present invention When used to treat restenosis following a balloon angioplasty or stent placement, the compounds of the present invention, and the native rapamycin. are thought to exhibit their therapeutic functions through the inhibition of the mammalian target of rapamycin or m ' l OR.
  • a therapeutically effective amount of one of the compounds of the present invention may be employed in pure form or. where such forms exist, in pharmaceutical! acceptable salt, ester or prodrug form.
  • the compound may be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable excipients.
  • therapeutically effective amount means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention w ill be decided by the attending ph sician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder: activity of the spec i tic compound employed: the specific composition employed: the age. body weight, general health, sex and diet oflhe patient: the time of administration, route of administration, and rate of excretion of the specific compound employed: the duration o lhe treatment: drugs used in combination or coincidental with the specific compound employed: and like factors well known in the medical arts.
  • the total daily dose of the compounds oflhe present invention administered to a human or lower mammal may range from about 0.01 to about 20 mg/kg/day. l or purposes of oral administration, more preferable doses may be in the range of from about 0.001 to about 3 mg/kg/day. If desired, the effective daily dose may be divided into multiple doses for purposes of administration: consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • I opical administralion may involve doses ranging from 0.001 to 10 percent mg/kg/day. depending on the site of application. When administered locally to treat restenosis and vulnerable plaque, the dose may range from about I microgram '' mm stent length to about 100 microgram/mm stent length.
  • compositions of the present invention comprise a compound and a pharmaceutically acceptable carrier or excipient. which may be administered orally, recta 11 ⁇ . parenteral ly . intracisternall . intrav aginally . intraperiionealry . topically (as by powders, ointments, drops or transdermal patch), hucally. or as an oral or nasal spray.
  • pharmaceutical! acceptable earner means a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • parenteral. refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal. subcutaneous and intraarticular injection and infusion.
  • compositions of the present invention for parenteral inieetion comprise pharmaceutical!) acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol. polyols (such as glycerol, propylene glycol, polyethylene gl eol. and the like), carboxv methylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • Proper lluiditv ma) be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle si/e in the case of dispersions, and by the use of surfactants.
  • I hese compositions mav also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms mav be ensured bv the inclusion of various antibacterial and antifungal agents, for example, paraben. chlorobutanol. phenol sorbic acid, and the like. It mav also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical fo m mav be brought about by the inclusion of agents w hich delay absorption such as aluminum monostearate and gelatin.
  • Injectable depot forms arc made bv forming mieroencapsulc matrices of the drug in biodegradable polymers such as po laetide-polv gh colide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release may be controlled. I ' xamples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or niicroemulsions which arc compatible with body tissues.
  • the injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which may be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutical I ⁇ acceptable excipient or carrier such as sodium citrate or dicaleium phosphate and/or a) tillers or extenders such as starches, lactose, sucrose, glucose, mannitol. and silicic acid, b) binders such as carboxy melliy lcellulose.
  • the dosage form may also comprise b ffering agents.
  • Solid composilions of a similar type may also be employed as fillers in soft, semi-solid and hard-filled gelatin capsules or liquid-lllled capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees. capsules, pills, and granules may be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredient(s) only, or preferentially , in a certain part of the intestinal tract, optionally, in a delayed manner, bxamples of embedding compositions which may be used include polymeric substances and waxes.
  • the active compounds may also be in a micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid do>agc forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art. for example, water or other solvents, solubilizing agents and emulsi!lers such as ethyl alcohol, isopropvl alcohol, ethyl carbonate. ethyl acetate, benzyl alcohol, benzv I benzoale. propylene glycol. 1.3-butylene glycol, dimethyl I rmamide. oils (in particular, cottonseed, groundnut, corn. germ, olive, castor, and sesame oils), glycerol, tetrah drofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan. and mixtures thereof.
  • inert diluents commonly used in the art. for example, water or other solvents, solubilizing
  • the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, s eetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, s eetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, for example, cthoxy lated isostcary I alcohols. polyoxy ethylene sorbitol and sorbitan esters, microcry stalline cellulose, aluminum metahydroxide. bentonite. agar--agar. and tragacanth. and mixtures thereof.
  • suspending agents for example, cthoxy lated isostcary I alcohols. polyoxy ethylene sorbitol and sorbitan esters, microcry stalline cellulose, aluminum metahydroxide. bentonite. agar--agar. and tragacanth. and mixtures thereof.
  • Topical administration includes administration to the skin or mucosa, including surfaces of the lung and eye.
  • Compositions for topical administration may be prepared as a dry powder which may be pressurized or non-pressurized.
  • the active ingredient in finely divided form may be used in admixture with a larger-sized pharmaceutically acceptable inert carrier comprising particles having a size, for example, of up to 100 micrometers in diameter.
  • Suitable inert carriers include sugars such as lactose. Desirably at least > percent by weight of the particles of the active ingredient have an effective particle size in the range of 0. 1 to 10 micrometers.
  • Compositions for topical use on the skin also include ointments, creams, lotions, and gels.
  • the composition may lie pressurized and contain a compressed gas. such as nitrogen or a liquefied gas propel lant.
  • the liquelled propel lanl medium and indeed the total composition is preferably such that the active ingredient does not dissolve therein to any substantial extent.
  • the pressurized composition may also contain a surface active agent.
  • the surface active agent ma> be a liquid or solid non-ionic surface active agent or may be a solid anionic surface active agent. It is preferred to use the solid anionic surface active agent in the form of a sodium salt.
  • a further form of topical administration is to the eye. as for the treatment of immune- mediated conditions of the eye such as autoimmune diseases, allergic or inflammatory conditions, and corneal transplants.
  • I he compound of the present invention is delivered in a pharmaceutically acceptable ophthalmic vehicle, such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the corneal and internal regions of the eye. as for example the anterior chamber, posterior chamber, vitreous bod). ac
  • the pharmaceutical!) acceptable ophthalmic vehicle may. for example, be an ointment, vegetable oil or an encapsulating material.
  • compositions for rectal or vaginal administration are preferably suppositories or retention enemas which may be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at bod) temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at bod) temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Liposomes are general! derived from phospholipids or other lipid substances, l iposomes are formed mono- or multi-lamellar hvdralcd liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologicall) acceptable and metaboli/able lipid capable of forming liposomes can be used.
  • the present compositions in liposome form ma ⁇ contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients. and the like.
  • the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and s nihetic. Methods to orm liposomes are known in the art. See. for example. Prescott. I d.. Methods in Cell Biology. Volume XIV. Academic Press. Ne York. N.Y. (1976). p.33 el seq.
  • Compounds of the present invention may also be coadministered ith one or more immunosuppressant agents.
  • the immunosuppressant agents within the scope of the present invention include IMURAN. RTM. a/athioprine sodium, brequinar sodium. SPANIDIN.RTM. gusperimus trih) drochloride (also known as dcoxyspergualiii). mizoribine (also known as bredinin).
  • CI I I ⁇ PT.R I ' M. mofetil.
  • NUORAI ..RTM Cylosporin A (also marketed as different formulation of Cyclosporin ⁇ under the trademark SANDIMMl : NI ..R ' l AT).
  • PROCRAI .RTM. tacrolimus also known as l ' k ()6). sirolimus and RAPAMl NI ' .R I ' M., lellunomide (also known as IIW A-1 6).
  • glucocorticoids such as prednisolone and its derivatives
  • antibody therapies such as orthoclone (OK 1 ) and /cnapax.R I M.. and antith) mvocvie globulins, such as ihymoglobulins.
  • the local deliver ⁇ of drug/drug combinations from a stent or other implantable device has the following advantages: namely, the prevention of vessel recoil and remodeling through the scaffolding action of the stent and the prevention of multiple components of neointimal hyperplasia or restenosis as well as a reduction in inflammation and thrombosis.
  • This local administration of drugs, agents or compounds to stented coronary arteries may also have additional therapeutic benefit. l or example, higher tissue concentrations of the drugs, agents or compounds mav be achieved utilizing local delivery, rather than systemic administration. In addition, reduced systemic toxicity may be achieved utilizing local deliver ⁇ rather than systemic administration while maintaining higher tissue concentrations.
  • a single procedure may suffice with better patient compliance.
  • An additional benefit of combination drug, agent, and. or compound therapv mav be to reduce the dose of each of the therapeutic drugs, agents or compounds, thereby limiting their to icity . while still achieving a reduction in restenosis, inflammation and thrombosis.
  • Local stent-based therapy is therefore a means of improving the therapeutic ratio (cHlcaey ⁇ toxicity) of anti-restenosis. anti-inllammalor ⁇ . antithrombotic drugs, agents or compounds.

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Abstract

La présente invention concerne un analogue de la rapamycine semi-synthétique doté d'une fraction triazole ou son sel ou promédicament pharmaceutiquement acceptable, qui est un agent cytostatique à large spectre et un inhibiteur de m TOR, et qui est utile dans le traitement de divers cancers, ou de tumeurs dans des organes comme le rein, le foie, le sein, la tête et le cou, le poumon, la prostate, de la resténose dans les artères coronaires, les artères périphériques et les artères cérébrales, et des maladies immunes et auto-immunes. L'invention concerne également des compositions inhibant la croissance fongique, la resténose, le rejet de greffe et les maladies immunes et auto-immunes ainsi qu'un procédé d'inhibition du cancer, de la croissance fongique, de la resténose, du rejet de greffe et de maladies immunes et auto-immunes chez un mammifère. Une application particulièrement préférée dudit analogue de la rapamycine contenant une fraction triazole est le traitement de l'hypernéphrome, du cancer du poumon, du cancer du côlon cancer et du cancer du sein où l'activité thérapeutique du médicament, sa demi-vie, ses propriétés de distribution dans les tissus et ses propriétés pharmacocinétiques comprenant la biodisponibilité par les voies orales et intraveineuses sont essentielles aux résultats cliniques.
PCT/CN2012/085631 2012-10-26 2012-11-30 Analogue de la rapamycine et procédés de fabrication associés WO2014082286A1 (fr)

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KR20147024024A KR20150003156A (ko) 2012-11-30 2012-11-30 라파마이신 유사체 및 이의 제조 방법
EP12889107.4A EP2809675A4 (fr) 2012-11-30 2012-11-30 Analogue de la rapamycine et procédés de fabrication associés
AU2012395673A AU2012395673A1 (en) 2012-11-30 2012-11-30 Rapamycin analogs and methods for making same
CA2863243A CA2863243A1 (fr) 2012-11-30 2012-11-30 Analogue de la rapamycine et procedes de fabrication associes
US14/383,477 US20150051242A1 (en) 2012-10-26 2012-11-30 Rafamycin analogs and methods for making same
SG11201404432QA SG11201404432QA (en) 2012-11-30 2012-11-30 Rafamycin analogs and methods for making same
JP2015544291A JP2016500112A (ja) 2012-11-30 2012-11-30 ラパマイシン類似体及びその製作方法
PCT/CN2012/085631 WO2014082286A1 (fr) 2012-11-30 2012-11-30 Analogue de la rapamycine et procédés de fabrication associés
CN201280077424.7A CN104854112A (zh) 2012-11-30 2012-11-30 雷帕霉素类似物及其制备方法
ZA2014/05746A ZA201405746B (en) 2012-11-30 2014-08-04 Rafamycin analogs and methods for making same

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CN104327097A (zh) * 2014-10-11 2015-02-04 福建省微生物研究所 雷帕霉素的三氮唑衍生物和用途
CN104341434A (zh) * 2014-10-16 2015-02-11 福建省微生物研究所 取代的雷帕霉素三氮唑衍生物和用途
CN104557975A (zh) * 2014-12-23 2015-04-29 连云港恒运医药科技有限公司 依维莫司中间体及其降解杂质的制备方法
CN104876944A (zh) * 2015-05-13 2015-09-02 上海适济生物科技有限公司 一种依维莫司的制备方法
CN105481704A (zh) * 2016-01-12 2016-04-13 西安近代化学研究所 一种键合剂n-炔丙基二乙醇胺的合成与提纯方法
EP3061765A1 (fr) * 2015-02-27 2016-08-31 Warszawski Uniwersytet Medyczny Dérivé de protoescigénine, son procédé de préparation, utilisation de ce composé et composition pharmaceutique comprenant ledit composé
EP3109250A1 (fr) * 2015-06-23 2016-12-28 Synbias Pharma AG Procede pour la synthese de derives de rapamycine
WO2017038925A1 (fr) * 2015-09-03 2017-03-09 日本化薬株式会社 Composition pharmaceutique contenant de la rapamycine ou un dérivé de celle-ci
CN109776569A (zh) * 2017-11-14 2019-05-21 上海医药工业研究院 一种依维莫司的制备方法
CN112057425A (zh) * 2020-09-30 2020-12-11 严鹏科 一种雷帕霉素制剂及其制备方法
US10980889B1 (en) 2018-05-01 2021-04-20 Revolution Medicines, Inc. C40-, C28-, and C-32-linked rapamycin analogs as mTOR inhibitors
US11685749B2 (en) 2018-05-01 2023-06-27 Revolution Medicines, Inc. C26-linked rapamycin analogs as mTOR inhibitors

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CN115093429A (zh) * 2017-04-05 2022-09-23 哈佛大学的校长及成员们 大环化合物及其用途
SG11201909924VA (en) * 2017-05-02 2019-11-28 Revolution Medicines Inc Rapamycin analogs as mtor inhibitors
CN108484637A (zh) * 2018-03-13 2018-09-04 福建省微生物研究所 靶向抗癌新药x-76成盐化合物及其用途、制备方法
CN109776571B (zh) * 2019-01-31 2021-06-11 哈药慈航制药股份有限公司 一种雷帕霉素类似物及其制备方法和应用
CN115160343B (zh) * 2022-06-09 2023-11-14 福建省微生物研究所 一种雷帕霉素衍生物及其制备方法和应用

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CN104327097A (zh) * 2014-10-11 2015-02-04 福建省微生物研究所 雷帕霉素的三氮唑衍生物和用途
CN104341434A (zh) * 2014-10-16 2015-02-11 福建省微生物研究所 取代的雷帕霉素三氮唑衍生物和用途
CN104557975A (zh) * 2014-12-23 2015-04-29 连云港恒运医药科技有限公司 依维莫司中间体及其降解杂质的制备方法
CN104557975B (zh) * 2014-12-23 2017-06-20 连云港恒运医药有限公司 依维莫司中间体及其降解杂质的制备方法
EP3061765A1 (fr) * 2015-02-27 2016-08-31 Warszawski Uniwersytet Medyczny Dérivé de protoescigénine, son procédé de préparation, utilisation de ce composé et composition pharmaceutique comprenant ledit composé
US10370404B2 (en) 2015-02-27 2019-08-06 Warszawski Uniwersytet Medyczny Protoescigenin derivative, process of its preparation, use of said compound and pharmaceutical composition comprising that compound
WO2016135553A1 (fr) * 2015-02-27 2016-09-01 Warszawski Uniwersytet Medyczny Dérivé de protoescigénine, son procédé de préparation, utilisation dudit composé et composition pharmaceutique le contenant
CN104876944B (zh) * 2015-05-13 2017-11-10 普济生物科技（台州）有限公司 一种依维莫司的制备方法
CN104876944A (zh) * 2015-05-13 2015-09-02 上海适济生物科技有限公司 一种依维莫司的制备方法
WO2016207205A1 (fr) * 2015-06-23 2016-12-29 Synbias Pharma Ag Procédé de synthèse de dérivés de rapamycine
US10308665B2 (en) 2015-06-23 2019-06-04 Synbias Pharma Ag Method for the synthesis of rapamycin derivatives
EP3109250A1 (fr) * 2015-06-23 2016-12-28 Synbias Pharma AG Procede pour la synthese de derives de rapamycine
RU2718058C2 (ru) * 2015-06-23 2020-03-30 Синбиас Фарма АГ Способ синтеза производных рапамицина
WO2017038925A1 (fr) * 2015-09-03 2017-03-09 日本化薬株式会社 Composition pharmaceutique contenant de la rapamycine ou un dérivé de celle-ci
CN105481704A (zh) * 2016-01-12 2016-04-13 西安近代化学研究所 一种键合剂n-炔丙基二乙醇胺的合成与提纯方法
CN109776569A (zh) * 2017-11-14 2019-05-21 上海医药工业研究院 一种依维莫司的制备方法
US10980889B1 (en) 2018-05-01 2021-04-20 Revolution Medicines, Inc. C40-, C28-, and C-32-linked rapamycin analogs as mTOR inhibitors
US11364300B2 (en) 2018-05-01 2022-06-21 Revolution Medicines, Inc. C40-, C28-, and C-32-linked rapamycin analogs as mTOR inhibitors
US11685749B2 (en) 2018-05-01 2023-06-27 Revolution Medicines, Inc. C26-linked rapamycin analogs as mTOR inhibitors
CN112057425A (zh) * 2020-09-30 2020-12-11 严鹏科 一种雷帕霉素制剂及其制备方法

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CA2863243A1 (fr) 2014-06-05
AU2012395673A1 (en) 2014-08-14
EP2809675A1 (fr) 2014-12-10
WO2014082286A9 (fr) 2014-11-13
ZA201405746B (en) 2015-11-25
SG11201404432QA (en) 2014-10-30
KR20150003156A (ko) 2015-01-08
AU2012395673A8 (en) 2015-06-11
JP2016500112A (ja) 2016-01-07
EP2809675A4 (fr) 2015-08-12

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