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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Mavoglurant (AFQ-056) is an experimental drug candidate for the treatment of fragile X syndrome
Mavoglurant (AFQ-056) is an experimental drug candidate for the treatment of fragile X syndrome.[1] It exerts its effect as an antagonist of the metabotropic glutamate receptor 5 (mGLU5).[2]
Mavoglurant is under development by Novartis and is currently in Phase II and Phase III clinical trials.[1][3] If successful, it would be the first drug to treat the underlying disorder instead of the symptoms of fragile X syndrome.[4]
- P. Cole (2012). “Mavoglurant”. Drugs of the Future 37 (1): 7–12. doi:10.1358/dof.2012.37.1.1772147.
- Levenga, J; Hayashi, S; De Vrij, FM; Koekkoek, SK; Van Der Linde, HC; Nieuwenhuizen, I; Song, C; Buijsen, RA et al. (2011). “AFQ056, a new mGluR5 antagonist for treatment of fragile X syndrome”. Neurobiology of disease 42 (3): 311–7. doi:10.1016/j.nbd.2011.01.022. PMID 21316452.
- Jacquemont, S.; Curie, A.; Des Portes, V.; Torrioli, M. G.; Berry-Kravis, E.; Hagerman, R. J.; Ramos, F. J.; Cornish, K. et al. (2011). “Epigenetic Modification of the FMR1 Gene in Fragile X Syndrome is Associated with Differential Response to the mGluR5 Antagonist AFQ056”. Science Translational Medicine 3 (64): 64ra1. doi:10.1126/scitranslmed.3001708. PMID 21209411.
- “AFQ056 drug improves symptoms in Fragile X patients: Study”. news-medical.net. January 9, 2011.
Fragile X syndrome (FXS), Martin–Bell syndrome, or Escalante’s syndrome (more commonly used in South American countries), is a genetic syndrome that is the most widespread single-gene cause of autism and inherited cause of mental retardation among boys. It results in a spectrum of intellectual disabilities ranging from mild to severe as well as physical characteristics such as an elongated face, large or protruding ears, and large testes (macroorchidism), and behavioral characteristics such as stereotypic movements (e.g. hand-flapping), and social anxiety.
Fragile X syndrome is associated with the expansion of the CGG trinucleotide repeat affecting the Fragile X mental retardation 1 (FMR1) gene on the X chromosome, resulting in a failure to express the fragile X mental retardation protein (FMRP), which is required for normal neural development. Depending on the length of the CGG repeat, an allele may be classified as normal (unaffected by the syndrome), a premutation (at risk of fragile X associated disorders), or full mutation (usually affected by the syndrome).[1] A definitive diagnosis of fragile X syndrome is made through genetic testing to determine the number of CGG repeats. Testing for premutation carriers can also be carried out to allow for genetic counseling. The first complete DNA sequence of the repeat expansion in someone with the full mutation was generated by scientists in 2012 using SMRT sequencing.
There is currently no drug treatment that has shown benefit specifically for fragile X syndrome. However, medications are commonly used to treat symptoms of attention deficit and hyperactivity, anxiety, and aggression. Supportive management is important in optimizing functioning in individuals with fragile X syndrome, and may involve speech therapy, occupational therapy, and individualized educational and behavioral programs.
orphan drug designation EMA
http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=317238
Mavoglurant regulatory update 12/03/2012
ماووگلوران (به انگلیسی: Mavoglurant) یک ترکیب شیمیایی با شناسه پابکم ۹۹۲۶۸۳۲ است.
جستارهای وابسته[ویرایش]
Novartis investigational drug LDK378, a selective inhibitor of (ALK), shows a marked clinical response ….49th Annual Meeting of the American Society of Clinical Oncology (ASCO) on June 3, 2013
LDK378
J. Med. Chem. 2013, DOI:10.1021/jm400402q).
- CAS Number:
- 1032900-25-6
- Mol. Formula:
- C28H36ClN5O3S
- MW:
- 558.13
Novartis investigational drug LDK378, a selective inhibitor of the cancer target anaplastic lymphoma kinase (ALK), shows a marked clinical response in patients with ALK+ non-small cell lung cancer (NSCLC) during the 49th Annual Meeting of the American Society of Clinical Oncology (ASCO) on June 3, 2013.
Doctors and patients are clamoring for more ways to fight lung cancer, the leading cause of cancer deaths in the U.S., of which NSCLC is the most common form. In March, LDK378 received Breakthrough Therapy designation from the US Food and Drug Administration (FDA). The designation is intended to expedite the development and review of drugs that treat life-threatening conditions and show improvement over available therapies.
Currently, two Phase II clinical trials are actively recruiting patients worldwide. One study focuses on patients with ALK+ NSCLC who were previously treated with chemotherapy and crizotinib (NCT01685060). The second study examines LDK378 in patients who are crizotinib-naive (NCT01685138). In addition, Phase III clinical trials are planned to begin in the coming months, aiming to enroll more than 1,100 patients with ALK+ NSCLC at sites worldwide. Novartis plans to file for approval the drug in early 2014.
Chemical Name of LDK378
5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine
Chemical Synthesis of LDK378
Technical Data of LDK378
1H NMR (400 MHz, DMSO-d6 + trace D2O) δ 8.32 (s,1H), 8.27 (d, 1H), 7.88 (d, 1H), 7.67 (dd, 1H), 7.45 (dd, 1H), 7.42 (s, 1H), 6.79 (s, 1H), 4.56 – 4.48(m, 1H), 3.49 – 3.32 (m, 3H), 3.10 - 2.91 (m, 3H), 2.09 (s, 3H), 1.89 – 1.77 (m, 4H), 1.22 (d, 6H), 1.13 (d, 6H); ESMS m/z 558.1 (M + H+).
The compound LDK378, a highly selective inhibitor of ALK, has been granted “Breakthrough Therapy Designation” by the FDA for the treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) who have already received treatment with crizotinib (Xalkori).
ClinicalTrials.gov. A Dose Finding Study With Oral LDK378 in Patients With Tumors Characterized by Genetic Abnormalities in Anaplastic Lymphoma Kinase (ALK) (Phase 1). http://www.http://clinicaltrials.gov/show/NCT01283516; Accessed June 7, 2013; currently recruiting participants.
ClinicalTrials.gov. LDK378 in crizotinib naïve adult patients with ALK-activated non-small cell lung cancer (Phase 2). http://www.clinicaltrials.gov/ct2/show/NCT01685138; Accessed June 7, 2013; currently recruiting participants.
ClinicalTrials.gov. LDK378 in adult patients with ALK-activated NSCLC previously treated with chemotherapy and crizotinib (phase 2) http://www.clinicaltrials.gov/ct2/show/NCT01685060; Accessed June 7,2013; currently recruiting participants.
Mehra R, Camidge DR, Sharma S, et al. First-in-human phase I study of the ALK inhibitor LDK378 in advanced solid tumors. J Clin Oncol 30, 2012 (suppl; abstr 3007).
Alice Tsang Shaw, et al., Clinical activity of the ALK inhibitor LDK378 in advanced, ALK-positive NSCLC; 2013 ASCO Annual Meeting; Abstract Number: 8010; Citation: J Clin Oncol 31, 2013 (suppl; abstr 8010)
Tom H. Marsilje, Wei Pei, Bei Chen, Wenshuo Lu, Tetsuo Uno, Yunho Jin, Tao Jiang, Sungjoon Kim, Nanxin Li, Markus Warmuth, Yelena Sarkisova, Fangxian Sun, Auzon Steffy, AnneMarie C. Pferdekamper, Sean B Joseph, Young Kim, Tove Tuntland, Xiaoming Cui, Nathanael S Gray, Ruo Steensma, Yongqin Wan, Jiqing Jiang, Jie Li, Greg Chopiuck, W. Perry Gordon, Allen G Li, Wendy Richmond, Johathan Chang, Todd Groessl, You-Qun He, Bo Liu, Andrew Phimister, Alex Aycinena, Badry Bursulaya, Christian Lee, Donald S Karanewsky, H Martin Seidel, Jennifer L Harris, and Pierre-Yves Michellys, Synthesis, Structure-Activity Relationships and In Vivo Efficacy of the Novel Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor LDK378 Currently In Phase 1 and 2 Clinical Trials, Journal of Medicinal Chemistry, 2013
Carlos Garcia-Echeverria, Takanori Kanazawa, Eiji Kawahara, Keiichi Masuya, Naoko Matsuura, Takahiro Miyake, Osamu Ohmori, Ichiro Umemura; 2, 4- di (phenylamino) pyrimidines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders; WO2004080980 A1
Greg Chopiuk, Qiang Ding, Carlos Garcia-Echeverria, Nathanael Schiander Gray, Jiqing Jiang, Takanori Kanazawa, Donald Karanewsky, Eiji Kawahara, Keiichi Masuya, Naoko Matsuura, Takahiro Miyake, Osamu Ohmori, Ruo Steensma, Ichiro Umemura, Yongqin Wan, Qiong Zhang; 2, 4-pyrimidinediamines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders; WO2005016894 A1
Novartis teams with India’s Biological E for typhoid vaccine development
Novartis teams with India’s Biological E for typhoid vaccine…
| Novartis and Indian biopharma Biological E have entered into a development and licensing agreement to deliver accessible and affordable typhoid and paratyphoid A vaccines to the developing world. Yearly, over 21 million cases and 5 million cases of typhoid and paratyphoid A… read more › |
read all at
Array Starts First Phase 3 Trial, Shifts to Late-Stage Development
HY-15202
MEK162
(Synonyms ARRY-162; ARRY-438162; MEK 162; ARRY 162; ARRY 438162)
MEK162 M.Wt: 441.23
MEK162 Formula: C17H15BrF2N4O3
MEK162 Storage: at -20℃ 2 years
MEK162 CAS No.: 606143-89-9
http://clinicaltrials.gov/ct2/show/NCT00959127
|
Array Starts First Phase 3 Trial, Shifts to Late-Stage Development read all at |
DRUG SPOTLIGHT-Afinitor (everolimus) , Novartis:
Afinitor (everolimus)
40-O-(2-hydroxyethyl)-rapamycin
Company: Novartis
Approval Status: Approved July 2012
Treatment Area: hormone receptor-positive, HER2-negative breast cancer
Everolimus is a derivative of Rapamycin (sirolimus), and works similarly to Rapamycin as an mTOR (mammalian target of rapamycin) inhibitor. It is currently used as an immunosuppressant to prevent rejection of organ transplants. In a similar fashion to other mTOR inhibitors Everolimus’ effect is solely on the mTORC1 protein and not on the mTORC2 protein.
159351-69-6 CAS NO
BRANDS
| Afinitor | Novartis |
| Certican | Novartis |
| VOTUBIA | Novartis |
| Zortress | Novartis |
Afinitor (everolimus), an inhibitor of mTOR (mammalian target of rapamycin), is an antineoplastic agent.
Afinitor is specifically approved for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole.
Afinitor is supplied as a tablet for oral administration. The recommended dose of Afinitor for breast cancer is 10 mg, to be taken once daily, at the same time every day, either consistently with food or consistently without food.
FDA Approval
The FDA approval of Afinitor for the treatment of advanced hormone receptor-positive, HER2-negative breast cancer was based on a randomized, double-blind, multicenter study in 724 postmenopausal women with estrogen receptor-positive, HER 2/neu-negative advanced breast cancer with recurrence or progression following prior therapy with letrozole or anastrozole.
Everolimus is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. Indicated for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease. Indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. Indicated for the treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. Indicated in pediatric and adult patients with tuberous sclerosis complex (TSC) for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected.
Everolimus (RAD-001) is the 40-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an inhibitor of mammalian target of rapamycin (mTOR).
It is currently used as an immunosuppressant to prevent rejection of organ transplants and treatment of renal cell cancer and other tumours. Much research has also been conducted on everolimus and other mTOR inhibitors for use in a number of cancers.
It is marketed by Novartis under the tradenames Zortress (USA) and Certican (Europe and other countries) in transplantation medicine, and Afinitor in oncology.
AFINITOR (everolimus), an inhibitor of mTOR, is an antineoplastic agent.
The chemical name of everolimus is (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18- dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20pentaone.
The molecular formula is C53H83NO14 and the molecular weight is 958.2. The structural formula is:
 |
AFINITOR Tablets are supplied for oral administration and contain 2.5 mg, 5 mg, 7.5 mg, or 10 mg of everolimus. The tablets also contain anhydrous lactose, butylated hydroxytoluene, crospovidone, hypromellose, lactose monohydrate, and magnesium stearate as inactive ingredients.
AFINITOR DISPERZ (everolimus tablets for oral suspension) is supplied for oral administration and contains 2 mg, 3 mg, or 5 mg of everolimus. The tablets for oral suspension also contain butylated hydroxytoluene, colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, mannitol, and microcrystalline cellulose as inactive ingredients.
- R.N Formica Jra, K.M Lorberb, A.L Friedmanb, M.J Biaa, F Lakkisa, J.D Smitha, M.I Lorber (March 2004). “The evolving experience using everolimus in clinical transplantation”. Elsevier 36 (2): S495–S499.
- “Afinitor approved in US as first treatment for patients with advanced kidney cancer after failure of either sunitinib or sorafenib” (Press release). Novartis. 2009-03-30. Retrieved April 6, 2009.
- “Novartis receives US FDA approval for Zortress (everolimus) to prevent organ rejection in adult kidney transplant recipients” (Press release). Novartis. 2010-04-22. Retrieved April 26, 2010.
- “Novartis’ Afinitor Cleared by FDA for Treating SEGA Tumors in Tuberous Sclerosis”. 1 Nov 2010.
- http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm254350.htm
- “US FDA approves Novartis drug Afinitor for breast cancer”. 20 Jul 2012.
PATENTS
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Country
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Patent Number
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Approved
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Expires (estimated)
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|---|---|---|---|
| United States | 6440990 | 1993-09-24 | 2013-09-24 |
| Canada | 2145383 | 2004-11-16 | 2013-09-24 |
| Canada | 2225960 | 2004-05-11 | 2016-07-12 |
| United States | 7297703 | 1999-12-06 | 2019-12-06 |
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10-28-2011
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METHODS OF TREATMENT
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1-21-2011
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ANTI-IGF1R
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1-14-2011
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HISTONE H2AX (HH2AX) BIOMARKER FOR FTI SENSITIVITY
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3-24-2010
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Thermal treatment of a drug eluting implantable medical device
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1-13-2010
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Therapeutic phosphonate compounds
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10-21-2009
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Processes for preparing water-soluble polyethylene glycol conjugates of macrolide immunosuppressants
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10-16-2009
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Heparin Prodrugs and Drug Delivery Stents Formed Therefrom
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9-11-2009
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PHOSPHONATE COMPOUNDS HAVING IMMUNO-MODULATORY ACTIVITY
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12-31-2008
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Phosphonate compounds having immuno-modulatory activity
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10-8-2008
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Anti-inflammatory phosphonate compounds
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6-27-2008
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Genes Involved in Neurodegenerative Conditions
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10-24-2007
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Fluid treatment of a polymeric coating on an implantable medical device
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7-11-2007
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Oxepane isomer of 42-O-(2-hydroxy)ethyl-rapamycin
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2-9-2007
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40-O-(2-hydroxy)ethyl-rapamycin coated stent
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1-5-2007
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Methods for treating neurofibromatosis 1
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9-8-2006
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Anti-inflammatory phosphonate compounds
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| WO1994009010A1 | Sep 24, 1993 | Apr 28, 1994 | Sandoz Ag | O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants |
| WO2007135397A1 * | May 18, 2007 | Nov 29, 2007 | Christoph Beckmann | 36 -des (3 -methoxy-4 -hydroxycyclohexyl) 36 – (3 -hydroxycycloheptyl) derivatives of rapamycin for the treatment of cancer and other disorders |
| EP0663916A1 | Sep 24, 1993 | Jul 26, 1995 | Novartis AG | O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants |
| US5665772 | Sep 24, 1993 | Sep 9, 1997 | Sandoz Ltd. | O-alkylated rapamycin derivatives and their use, particularly as immunosuppressants |
| US20030125800 | Apr 24, 2002 | Jul 3, 2003 | Shulze John E. | Drug-delivery endovascular stent and method for treating restenosis |
…………………………………….
Rapamycin is a known macrolide antibiotic produced by Streptomvces hvgroscopicus. having the structure depicted in Formula A:
See, e.g., McAlpine, J.B., et al., J. Antibiotics (1991) 44: 688; Schreiber, S.L., et al., J. Am. Chem. Soc. (1991) J_13: 7433‘- US Patent No. 3 929 992. Rapamycin is an extremely potent immunosuppressant and has also been shown to have antitumor and antifungal activity. Its utility as a pharmaceutical, however, is restricted by its very low and variable bioavailabiiity as well as its high toxicity. Moreover, rapamycin is highly insoluble, making it difficult to formulate stable galenic compositions.
Everolimus, 40-O-(2-hydroxyethyl)-rapamycin of formula (1) is a synthetic derivative of rapamycin (sirolimus) of formula (2), which is produced by a certain bacteria strain and is also pharmaceutically active.
(1) (2)
Everolimus is marketed under the brand name Certican for the prevention of rejection episodes following heart and kidney transplantation, and under the brand name Afinitor for treatment of advanced kidney cancer.
Due to its complicated macrolide chemical structure, everolimus is, similarly as the parent rapamycin, an extremely unstable compound. It is sensitive, in particular, towards oxidation, including aerial oxidation. It is also unstable at temperatures higher than 25°C and at alkaline pH.
Everolimus and a process of making it have been disclosed in WO 94/09010
Synthesis
Alkylation of rapamycin (I) with 2-(tert-butyldimethylsilyloxy)ethyl triflate (II) by means of 2,6-lutidine in hot toluene gives the silylated target compound (III), which is deprotected by means of 1N HCl in methanol (1). (Scheme 21042401a) Manufacturer Novartis AG (CH). References 1. Cottens, S., Sedrani, R. (Sandoz-Refindungen VmbH; Sandoz-Patent GmbH; Sandoz Ltd.). O-Alkylated rapamycin derivatives and their use, particularly as immunosuppressants. EP 663916, EP 867438, JP 96502266, US 5665772, WO 9409010.EP 0663916; EP 0867438; JP 1996502266; JP 1999240884; US 5665772; WO 9409010
…………..
SYNTHESIS
https://www.google.com/patents/WO2012103960A1
(US 5,665,772, EP 663916). The process principle is shown in the scheme below, wherein the abbreviation RAP-OH has been used as an abbreviation for the rapamycin structure of formula (2) above, L is a leaving group and P is a trisubstituted silyl group serving as a OH- protective group.
RAP-OH + L-CH2-CH2-0-P — –> RAP-O-CH2-CH2-O-P — – > RAP-O-CH2-CH2-OH
(2) (4) (1)
Specifically, the L- group is a trifluoromethanesulfonate (triflate) group and the protective group P- is typically a tert-butyldimethylsilyloxy- group. Accordingly, the known useful reagent within the above general formula (3) for making everolimus from rapamycin is 2-(tert-butyldimethylsilyloxy)ethyl triflate of formula (3 A):
According to a known synthetic procedure disclosed in Example 8 of WO 94/09010 and in Example 1 of US application 2003/0125800, rapamycin (2) reacts in hot toluene and in the presence of 2,6-lutidine with a molar excess of the compound (3 A), which is charged in several portions, to form the t-butyldimethylsilyl-protected everolimus (4A). This compound is isolated and deprotected by means of IN aqueous HC1 in methanol. Crude everolimus is then purified by column chromatography. Yields were not reported.
(2) (3A) (4A) (1)
In an article of Moenius et al. (J. Labelled Cpd. Radiopharm. 43, 113-120 (2000)), which used the above process for making C14-labelled and tritiated everolimus, a diphenyl- tert.butylsilyloxy -protective group was used as the alkylation agent of formula (3B).
Only 8% yield of the corresponding compound (4B)
and 21% yield of the compound (1) have been reported.
Little is known about the compounds of the general formula (3) and methods of their preparation. The synthesis of the compound (3 A) was disclosed in Example 1 of US application 2003/0125800. It should be noted that specification of the reaction solvent in the key step B of this synthesis was omitted in the disclosure; however, the data about isolation of the product allow for estimation that such solvent is dichloromethane. Similarly also a second article of Moenius et al. (J. Labelled Cpd. Radiopharm.42, 29-41 (1999)) teaches that dichloromethane is the solvent in the reaction.
It appears that the compounds of formula (3) are very reactive, and thus also very unstable compounds. This is reflected by the fact that the yields of the reaction with rapamycine are very low and the compound (3) is charged in high molar extent. Methods how to monitor the reactivity and/or improve the stability of compounds of general formula (3), however, do not exist.
Thus, it would be useful to improve both processes of making compounds of formula (3) and, as well, processes of their application in chemical synthesis.
xample 6: 40-O-[2-((2,3-dimethylbut-2-yl)dimethylsilyloxy)ethyl]rapamycin
In a 100 mL flask, Rapamycin (6 g, 6.56 mmol) was dissolved in dimethoxyethane (4.2 ml) and toluene (24 ml) to give a white suspension and the temperature was raised to 70°C. After 20 min, N,N-diisopropylethylamine (4.56 ml, 27.6 mmol) and 2-((2,3-dimethylbutan-2- yl)dimethylsilyloxy)ethyl trifluoromethanesulfonate (8.83 g, 26.3 mmol) were added in 2 portions with a 2 hr interval at 70°C. The mixture was stirred overnight at room temperature, then diluted with EtOAc (40 ml) and washed with sat. NaHC03 (30 ml) and brine (30 ml). The organic layer was dried with Na2S04, filtered and concentrated. The cmde product was chromatographed on a silica gel column (EtOAc/heptane 1/1 ; yield 4.47 g).
Example 7: 40-O-(2-hydroxyethyl)-rapamycin [everolimus]
In a 100 mL flask, 40-O-[2-((2,3-dimethylbut-2-yl)dimethylsilyloxy)ethyl]rapamycin (4.47 g, 4.06 mmol) was dissolved in methanol (20 ml) to give a colorless solution. At 0°C, IN aqueous hydrochloric acid (2.0 ml, 2.0 mmol) was added and the mixture was stirred for 90 min. The reaction was followed by TLC (ethyl acetate/n-heptane 3 :2) and HPLC. Then 20 ml of saturated aqueous NaHC03 were added, followed by 20 ml of brine and 80 ml of ethyl acetate. The phases were separated and the organic layer was washed with saturated aqueous NaCl until pH 6/7. The organic layer was dried by Na2S04, filtered and concentrated to yield 3.3 g of the product.
……………………….
SYNTHESIS
https://www.google.co.in/patents/WO1994009010A1
Example 8: 40-O-(2-Hydroxy)ethyl-rapamycin
a) 40-O-[2-(t-Butyldimethylsilyl)oxy]ethyl-rapamycin
A solution of 9.14 g (10 mmol) of rapamycin and 4.70 mL (40 mmol) of 2,6-lutidine in 30 mL of toluene is warmed to 60°C and a solution of 6.17 g (20 mmol) of 2-(t-butyldimethylsilyl)oxyethyl triflate and 2.35 mL (20 mmol) of 2,6-lutidine in 20 mL of toluene is added. This mixture is stirred for 1.5h. Then two batches of a solution of 3.08 g (10 mmol) of triflate and 1.2 mL (10 mmol) of 2,6-lutidine in 10 mL of toluene are added in a 1.5h interval. After addition of the last batch, stirring is continued at 60°C for 2h and the resulting brown suspension is filtered. The filtrate is diluted with ethyl acetate and washed with aq. sodium bicarbonate and brine. The organic solution is dried over anhydrous sodium sulfate, filtered and concentrated. The residue is purified by column chromatography on silica gel (40:60 hexane-ethyl acetate) to afford 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl-rapamycin as a white solid: 1H NMR (CDCl3) δ 0.06 (6H, s), 0.72 (1H, dd), 0.90 (9H, s), 1.65 (3H, s), 1.75 (3H, s), 3.02 (1H, m), 3.63 (3H, m), 3.72 (3H, m); MS (FAB) m/z 1094 ([M+Na]+), 1022 ([M-(OCH3+H2O)]+).
b) 40-O-(2-Hydroxy)ethyl-rapamycin
To a stirred, cooled (0°C) solution of 4.5 g (4.2 mmol) of 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl-rapamycin in 20 mL of methanol is added 2 mL of IN HCl. This solution is stirred for 2h and neutralized with aq. sodium bicarbonate. The mixture is extracted with three portions of ethyl acetate. The organic solution is washed with aq.
sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and
concentrated. Purification by column chromatography on silica gel (ethyl acetate) gave the title compound as a white solid:1H NMR (CDCl3) δ 0.72 (1H, dd), 1.65 (3H, s), 1.75 (3H, s), 3.13 (5H, s and m), 3.52-3.91 (8H, m); MS (FAB) m/z 980 ([M+Na]+), 926 ([M-OCH3]+), 908 ([M-(OCH3+H2O)]+), 890 ([M-(OCH3+2H2O)]+), 876 ([M-(2CH3OH+OH)]+), 858 ([M-(OCH3+CH3OH+2H2O)]+).
MBA (rel. IC50) 2.2
IL-6 dep. prol. (rel. IC50) 2.8
MLR (rel. IC50) 3.4
…………………..
synthesis
Everolimus (Everolimus) was synthesized by the Sirolimus (sirolimus, also known as rapamycin Rapamycin) ether from. Sirolimus is from the soil bacterium Streptomyces hygroscopicus isolated metabolites. Activation end sirolimus (triflate, Tf) the other end of the protection (t-butyldimethylsilyl, TBS) of ethylene glycol 1 reaction of 2 , because the hydroxyl group 42 hydroxyl site over the 31-bit resistance is small, so the reaction only occurs in 42. Compound 2under acidic conditions TBS protection is removed everolimus.
phase 2-LGX818, Novartis Research Foundation to treat melanoma with a specific mutation in B-RAF kinase V600E
LGX818
Methyl [(2S)-1-{[4-(3-{5-chloro-2-fluoro-3-[(methylsulfonyl)amino]phenyl}-1-isopropyl-1H-pyrazol-4-yl)-2-pyrimidinyl]amino}-2-propanyl]carbamate
Novartis Institutes for Biomedical Research and Genomics Institute of the Novartis Research Foundation to treat melanoma with a specific mutation in B-RAF kinase V600E, selective mutant B-RAF kinase inhibitor
LGX818 is currently in Phase Ib/II clinical trials. Patients with colon cancer or melanoma with the BRAF mutation, including patients resistant to other BRAF-targeted drugs, are receiving LGX818 pills alone or as part of drug cocktails to determine whether the drug is safe and efficacious
A phase Ib/II drug structure by Novartis disclosed at the spring 2013 American Chemical Society meeting in New Orleans to treat melanoma with a V600E mutation in the B-RAF kinase which it inhibits.[1][2][3]
Several clinical trials of LGX818 , either alone or in combinations with the MEK inhibitorMEK162[4], CDK4 inhibitor LEE011[5] are being run. The initial results are encouraging [6].
- C. Drahl, Liveblogging First-Time Disclosures of Drug Structures from #ACSNOLA, 2013, http://cenblog.org/the-haystack/2013/04/liveblogging-first-time-disclosures-of-drug-structures-from-acsnola/
- http://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011023773
- http://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011025927
- http://www.cancer.gov/clinicaltrials/search/view?cdrid=728588&version=HealthProfessional&protocolsearchid=11645832
- http://www.cancer.gov/clinicaltrials/search/view?cdrid=745927&version=HealthProfessional&protocolsearchid=11645832
- http://www.novartis.com/downloads/investors/event-calendar/2012/6-bridging-science-and-patients.pdf
NOVARTIS TOBI Podhaler receives FDA approval for cystic fibrosis patients with Pseudomonas aeruginosa
Tobramycin
MAR 22.2013, FDA approves TOBI Podhaler to treat a type of bacterial lung infection in cystic fibrosispatients
The U.S. Food and Drug Administration today approved TOBI Podhaler (tobramycininhalation powder) for the management of cystic fibrosis patients with Pseudomonas aeruginosa, a bacterium that causes lung infections.
Cystic fibrosis is a genetic disease that affects about 30,000 pediatric and adult patients in the United States. Cystic fibrosis causes the body to produce thick, sticky mucus that builds up in the lungs and blocks airways. The buildup of mucus makes it easy for bacteria like P. aeruginosa to grow and cause a chronic lung infection that, over time, can severely damage the lungs. Many patients with cystic fibrosis are treated with antibiotics using a nebulizer machine.
Tobramycin is an aminoglycoside antibiotic derived from Streptomyces tenebrarius and used to treat various types of bacteria infections, particularly Gram-negative infections. It is especially effective against species of Pseudomonas.
TOBI Podhaler, a plastic, handheld inhaler device, contains a dry powder formulation of tobramycin, an antibiotic used to treat P. aeruginosa infection. The powder is inhaled twice daily using the Podhaler device for 28 days. Patients should then stop TOBI Podhaler therapy for 28 days before resuming again.
“Today’s approval broadens the available delivery mechanism options for patients withcystic fibrosis who require treatment for P. aeruginosa,” said Edward Cox, M.D., M.P.H, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research. “This product is the first dry powder antibacterial drug delivered with a handheld dry powder inhaler.”
Novartis’ Ilaris canakizumab has become the first biologic drug to be approved in the EU to treat the symptoms of gouty arthritis
| Monoclonal antibody | |
|---|---|
| Type | Whole antibody |
| Source | Human |
| Target | IL-1β |
Novartis’ Ilaris has become the first biologic drug to be approved in the EU to treat the symptoms of gouty arthritis in another gain for the interleukin-1 beta inhibitor.
march01,2013
First biologic drug approved for condition in Europe
The European Commission (EC) cleared llaris (canakizumab) for the treatment of adult patients who have suffered at least three gouty arthritis attacks in the previous 12 months, but who are unsuitable for treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine or repeated courses of corticosteroids.
Gouty arthritis – commonly known as gout – is an “excruciating condition”, according to Novartis division head David Epstein, who noted that Ilaris offers new hope to patients who do not currently have treatment options.
Data from two phase III trials of Ilaris in acute gouty arthritis attacks showed that patients treated with the drug experienced significantly greater pain relief compared to the injectable steroid triamcinolone acetonide, while most adverse events were mild to moderate in severity.
The most frequent side effects were infections, and particularly upper respiratory tract infections and nasopharyngitis.
Ilaris was launched in the US and EU in 2009 as a treatment for an auto-inflammatory condition called cryopyrin-associated periodic syndrome (CAPS). The rarity of that condition has meant sales have been relatively small, coming in at $72m last year, albeit a 56 per cent gain over 2011.
Gouty arthritis is a much bigger market for the drug and, along with a juvenile arthritis indication Novartis is pursuing, could push Ilaris towards blockbuster status with sales in excess of $1bn a year.
“Our vision is to realise the potential of Ilaris wherever IL-1 beta plays a key role and available treatment options don’t give patients the help they need,” said Epstein.
EU approval comes after the US FDA knocked back Ilaris for gouty arthritis, saying in 2011 that Novartis needed to provide more data on the drug’s risk-benefit profile, specifically its potential to leave patients vulnerable to infections.
Gout has been a tricky indication for drug developers to crack, with the FDA turning down another CAPS treatment – Regeneron’s IL-1 inhibitor Arcalyst (rilonacept) – in 2012 on the grounds of inadequate safety data and concern about a risk of malignancy.
One success came in 2010 when Savient secured approval for its Krystexxa (pegloticase) drug as a second-line treatment after oral xanthine oxidase inhibitors in patients with severe debilitating chronic tophaceous gout.
However, the drug has failed to make significant inroads because of a high price and tendency to stimulate neutralising antibodies that limit its therapeutic effect, according to Decision Resources.
There is still a great demand for safer and more effective therapies with the phase III pipeline featuring another potential blockbuster in the form of AstraZeneca/Ardea Biosciences URAT1 inhibitor lesinurad.
Canakinumab (INN, trade name Ilaris, previously ACZ885)[1] is a human monoclonal antibody targeted at interleukin-1 beta. It has no cross-reactivity with other members of the interleukin-1 family, including interleukin-1 alpha.[2]
Canakinumab was approved for the treatment of cryopyrin-associated periodic syndromes (CAPS) by the US FDA on June 2009[3] and by the European Medicines Agency in October 2009.[4] CAPS is a spectrum of autoinflammatory syndromes including familial cold autoinflammatory syndrome, Muckle–Wells syndrome, and neonatal-onset multisystem inflammatory disease.
Canakinumab was being developed by Novartis for the treatment of rheumatoid arthritis but this trial has been discontinued.[5] Canakinumab is also in phase I clinical trials as a possible treatment for chronic obstructive pulmonary disease.[6]
References
- Dhimolea, Eugen (2010). “Canakinumab”. MAbs 2 (1): 3–13. doi:10.4161/mabs.2.1.10328. PMC 2828573. PMID 20065636.
- Lachmann, HJ; Kone-Paut I, Kuemmerle-Deschner JB et al. (4 June 2009). “Use of canakinumab in the cryopyrin-associated periodic syndrome”. New Engl J Med 360 (23): 2416–25. doi:10.1056/NEJMoa0810787. PMID 19494217.
- “New biological therapy Ilaris approved in US to treat children and adults with CAPS, a serious life-long auto-inflammatory disease” (Press release). Novartis. 18 June 2009. Retrieved 28 July 2009.
- Wan, Yuet (29 October 2009). “Canakinumab (Ilaris) and rilonacept (Arcalyst) approved in EU for treatment of cryopyrin-associated periodic syndrome”. National electronic Library for Medicines. Retrieved 14 April 2010.
- “clinicaltrials.gov, Identifier NCT00784628: Safety, Tolerability and Efficacy of ACZ885 (Canakinumab) in Patients With Active Rheumatoid Arthritis”. Retrieved 2010-08-21.
- Yasothan U, Kar S (2008). “Therapies for COPD”. Nat Rev Drug Discov 7 (4): 285. doi:10.1038/nrd2533.
Monoclonal Antibody Therapeutic Uses
FDA grants fresh approval for Novartis’ Zortress, Everolimus
dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone
Everolimus (RAD-001) is the 40-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an inhibitor of mammalian target of rapamycin (mTOR).
It is currently used as an immunosuppressant to prevent rejection of organ transplants and treatment of renal cell cancer and other tumours. Much research has also been conducted on everolimus and other mTOR inhibitors for use in a number of cancers.
It is marketed by Novartis under the tradenames Zortress (USA) and Certican (Europe and other countries) in transplantation medicine, and Afinitor in oncology.
18 feb 2013
The US Food and Drug Administration has approved Novartis’ Zortress for preventing organ rejection in adults receiving a liver transplant.
The Swiss major noted that Zortress (everolimus) is the first mammalian target of rapamycin (mTOR) inhibitor given the green light for use following liver transplantation and the first immunosuppressant approved by the FDA in over a decade for that use. The treatment is already on the market for preventing organ rejection in kidney transplant patients.
The approval was based on the largest liver transplant study to date, conducted in 719 liver transplant patients, Novartis says. The data showed that Zortress plus reduced-exposure tacrolimus (a well-established immunosuppresant) led to comparable efficacy and higher renal function compared to standard tacrolimus at 12 months.
Novartis Pharma chief David Epstein noted that this second indication for Zortress in just three years in the USA follows the recent European approval (in the fourth quarter of 2012) of the drug for liver transplants. It is marketed there as Certican and is also approved in Europe in kidney and heart transplantation.
Everolimus is also sold as Afinitor and Volubia in various oncology indications and is licensed to Abbott Laboratories (and sublicensed to Boston Scientific) for use in drug-eluting stents.
http://www.nature.com/nrd/journal/v8/n7/full/nrd2924.html
take a tour
Eritrea, africa
Eritrea – Wikipedia, the free encyclopedia
Eritrea (/ˌɛrɨˈtreɪ.ə/ or /ˌɛrɨˈtriːə/; Tigrinya: ኤርትራ ʾErtrā ; Arabic: إرتريا … Its name Eritrea is based on the Greek name for the Red Sea (Ἐρυθρὰ …
Isaias AfwerkiIsaias Afwerki (sometimes spelled Afewerki; Tigrinya: ኢሳይያስ …
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History of EritreaHistory of Eritrea. Coat of Arms of Eritrea. Pre-colonial. Kingdom …
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asmara
asmara
Massawa Old City
Eritrea – Island of the Red Seo of Eritrea –
keren
“Asara” traditional sesami oil press – Eritrea (Saied Ibrahim Yehdego)
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Novartis gets European approval for first Meningitis B vaccine
Bexero is a vaccine indicated for the treatment of the meningococal gp B disease
Novartis has received approval from the European Commission for the first vaccine to protect children against Meningitis B.
Bexsero (4CMenB) will be used in Europe to prevent meningococcal B meningitis (MenB), one of the most common and deadly forms of the disease in babies and infants under five years of age.
There is currently no approved vaccine offering protection against this particular type of meningitis.
Novartis has committed to making the Bexsero available as soon as possible, the firm said in a statement on Tuesday.
Meningitis UK is today urging the government to introduce the vaccine into the UK, which has one of the highest incidence rates for MenB in the world.
Meningitis UK Founder Steve Dayman said; “The Government must introduce the Meningitis B vaccine into the immunisation schedule as soon as possible – it will save thousands of lives and spare families so much suffering.
“Any delay means lives will be lost.”
The Joint Committee on Vaccination and Immunisation (JCVI), which advises the government, plans to meet in June 2013 to discuss the vaccine.
MenB is caused by bacteria, leading to inflammation of the lining around the brain and spinal cord. It can kill within 24 hours.
In December 2010, Novartis submitted a Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) for bexsero based on positive results from Phase III trials.
In November 2012, the Committee for Medicinal Products for Human Use (CHMP) of EMA adopted a positive opinion for approval of the MAA.
Novartis plans to submit marketing applications in Asia, Latin America and North America.
Meningococcal is a life threatening disease which can lead to death within 24 to 48 hours of the first symptoms. The disease manifests in the form of bacterial meningitis, which leads to an infection of the membrane around the brain and spine and a bloodstream infection called sepsis.
The bacteria which causes meningococcal disease is called meningococcus and is divided into five main groups, called serogroups, namely A, B, C, W135 and Y. MenB is the most common type of bacteria causing meningococcal disease.
MenB strains can mutate making it very difficult to diagnose and treat. It has led to several outbreaks across the world. The highest rates of the disease occur in the semi-arid and sub-Saharan Africa region.
Most of the MenB cases occur in healthy patients. A person can carry the bacteria for up to six months. It is easily transmitted through physical contact, coughing and sneezing. Infants and adolescents are the most vulnerable groups of the disease.
Initial symptoms of the disease are flu-like and hence difficult to diagnose. The main symptoms such as neck stiffness and rashes appear at a later stage of the illness. Existing treatments for the disease include hospitalisation and antimicrobial therapy. The disease, however, is difficult to treat due to its rapid rate of progression.
An estimated 20,000 to 80,000 cases of MenB are reported every year. About 5-10% of the people die even after being diagnosed and treated. Those who survive the disease suffer from severe complications such as brain damage, learning disabilities, behavioural problems and hearing loss.
DR ANTHONY MELVIN CRASTO Ph.D
New Drug Approvals 