WORLD RECORD VIEWS holder on THIS BLOG, ………live, by DR ANTHONY MELVIN CRASTO, Worldpeaceambassador, Worlddrugtracker, Helping millions, 100 million hits on google, pushing boundaries,2.5 lakh plus connections worldwide, 45 lakh plus VIEWS on this blog in 227 countries, 7 CONTINENTS ……A 90 % paralysed man in action for you, I am suffering from transverse mylitis and bound to a wheel chair, [THIS BLOG HOLDS WORLD RECORD VIEWS ]
DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was
with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international,
etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules
and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc
He has total of 32 International and Indian awards
Yusuf Hamied made his name a decade ago when he faced down Big Pharma on patents for HIV/AIDS drugs and Cipla started selling them at a cost of about $1 a day. His disdain for what he considers Big Pharma’s “obscene prices” born out of monopolies is well documented. Hamied has the industry’s rapt attention again with his new attack on cancer meds and his avowal that Cipla will soon take on biologics.
Yusuf Khwaja Hamied is a leading Indian scientist and chairman of Cipla, a socially conscious generic pharmaceuticals company founded by his father Khwaja Abdul Hamiedin 1935.[2]
Born in Vilnius, Lithuania, Yusuf Hamied was raised in Bombay (now known as Mumbai). His Indian Muslim father and Russophone Jewish mother met in Berlin, where they both were graduate students. He holds a Ph.D. in chemistry from Christ’s College, Cambridge. He still uses his chemistry notebooks from Cambridge when he develops new syntheses of drugs.[3]
He is an alumnus of the Cathedral and John Connon School in Bombay. Affectionately called Yuku by his close friends, Hamied is fond of Western classical music and has been close friends with the world-famous conductor Zubin Mehta since boyhood.
Hamied has led efforts to eradicate AIDS in the developing world and to give patients life-saving medicines regardless of their ability to pay,[4] and has often been characterized as a modern-day Robin Hood figure[5][6][7][8] as a result.
Former head of Johnson and Johnson Ajit Dangi says plainly “In Africa, Cipla is a temple and Dr. Hamied is God.” [9] To this Hamied has countered “I don’t want to make money off these diseases which cause the whole fabric of society to crumble”. [10]
In September 2011, in a piece about how he was trying to radically lower costs of biotech drugs for cancer, diabetes and othernoncommunicable diseases, The New York Times wrote of Hamied:
Dr. Yusuf K. Hamied, chairman of the Indian drug giant Cipla Ltd., electrified the global health community a decade ago when he said he could produce cocktails of AIDS medicines for $1 per day — a fraction of the price charged by branded pharmaceutical companies. That price has since fallen to 20 cents per day, and more than six million people in the developing world now receive treatment, up from little more than 2,000 in 2001.[11]
Yusuf Hamied has also been enormously influential in pioneering development of multi-drug combination pills (also known as fixed-dose combinations, or FDCs), notably for HIV/AIDS, tuberculosis (TB), asthma and other ailments chiefly affecting developing countries, as well as development of pediatric formulations of drugs, especially those benefiting children in poor settings.[12] These innovations have greatly expanded access to medicine and increased drug safety by ensuring proper dosages are taken. He is also highly regarded for his leading role in expanding the production of bulk drugs and “active pharmaceutical ingredients” (APIs, the active chemical components in medicines) in India.[13]
Yusuf Hamied has been the subject of in-depth profiles in The New York Times, Time magazine, The Guardian, Le Monde, The Economist, the Financial Times, The Times (London), Corriere della Sera, Der Spiegel, Wired and numerous other leading publications, as well as on television outlets such as ABC News, the BBC, CNN and CBS’ 60 Minutes.
Yusuf Hamied was awarded the ‘Indian Of The Year’ in the category of business by CNN-IBN in 2012.[15]
Bristol, UK (Scicasts) – New research into the fight against Dengue, an insect-borne tropical disease that infects up to 390 million people worldwide annually, may influence the development of anti-viral therapies that are effective against all four types of the virus.
The findings, led by researchers at the University of Bristol and published in the Journal of Biological Chemistry August 2 show that there may be significant differences in specific properties of the viral proteins for the four dengue virus types.
UK chemists have used a combination of flow chemistry methods with solid-supported scavengers and reagents to synthesise the active pharmaceutical ingredient, imatinib, of the anticancer drug Gleevec. The method avoids the need for any manual handling of intermediates and allows the drug to be synthesised in high purity in less than a day.
Gleevec, developed by Novartis, is a tyrosine kinase inhibitor used for the treatment of chronic myeloid leukaemia and gastrointestinal stromal tumours.
The anti-cancer drug Gleevec® is far more effective against a drug-resistant strain of cancer when the drug wraps the target with a molecular bandage that seals out water from a critical area. This image shows the bandage (black box) on the modified version of the drug, WBZ-7. (Credit: Image courtesy of Rice University)
A new study in Cancer Research finds that the anti-cancer drug Gleevec® is far more effective against a drug-resistant strain of cancer when the drug wraps the target with a molecular bandage that seals out water from a critical area.
Currently, no definitive proof shows the use of donepezil or other similar agents alters the course or progression of Alzheimer’s disease (AD). However, 6 to 12-month controlled studies have shown modest benefits in cognition and/or behavior.Pilot studies have reported donepezil therapy may potentially have effects on markers of disease progression, such as hippocampal volume. Therefore, many neurologists, psychiatrists, and primary-care physicians use donepezil in patients with Alzheimer’s disease. In 2005, the UK National Institute for Clinical Excellence (NICE) withdrew its recommendation for use of the drug for mild-to-moderate AD, on the basis of no significant improvement in functional outcome, quality of life, or behavioral symptoms. However, NICE revised its guidelines to suggest donepezil be used in moderate-stage patients for whom the evidence is strongest.
While the drug is currently indicated for mild to moderate Alzheimer’s, evidence from two clinical trials also indicates it may be effective for moderate to severe disease. An example of this is a Karolinska Institute paper published in The Lancet in early 2006, which states donepezil improves cognitive function even in patients with severe AD symptoms. In Oct. 2006 the U.S. Food and Drug Administration also approved Aricept for treatment of severe dementia.
Research leading to the development of donepezil began in 1983 at Eisai, and the first Phase I clinical trial took place in 1989. In 1996, Eisai received approval from the United States Food and Drug Administration (USFDA) for donepezil under the brand Aricept, which it co-marketed with Pfizer. As of 2011, Aricept was the world’s best-selling Alzheimer’s disease treatment. The first generic donepezil became available in November 2010 with the USFDA approval of a formulation prepared by Ranbaxy Labs. In April 2011 a second generic formulation, from Wockhardt, received tentative USFDA marketing approval
标题:
Cyclic amine cpd., its use and pharmaceutical compsns. comprising it
AU 8818216; EP 0296560; EP 0673927; EP 0742207; JP 1989079151; JP 1998067739; US 4895841; US 5100901
合成路线图解说明:The condensation of 5,6-dimethoxy-1-indanone (I) with 1-benzylpiperidine-4-carboxaldehyde (II) by means of butyllithium and diisopropylamine in THF gives 1-benzyl-4-(5,6-dimethoxy-1-oxoindan-2-ylidenemethyl)piperidine (III), which is reduced with H2 over Pd/C in THF and treated with HCl in dichloromethane – ethyl acetate.
标题:
Synthesis of 1-benzyl-4-[(5,6-dimethoxy[2-14C]-1-indanon)-2-yl]methylpiperidine hydrochloride (E-2020-14C)
作者:
Sugimoto, H.; Mishima, M.; Iimura, Y.
来源:
J Label Compd Radiopharm 1989,27(7),835-9
合成路线图解说明:The condensation of 5,6-dimethoxy-1-indanone (I) with 1-benzylpiperidine-4-carboxaldehyde (II) by means of butyllithium and diisopropylamine in THF gives 1-benzyl-4-(5,6-dimethoxy-1-oxoindan-2-ylidenemethyl)piperidine (III), which is reduced with H2 over Pd/C in THF and treated with HCl in dichloromethane – ethyl acetate.
作者:
Casta馿r, J.; Prous, J.
来源:
Drugs Fut 1991,16(1),16
合成路线图解说明:The condensation of 5,6-dimethoxy-1-indanone (I) with 1-benzylpiperidine-4-carboxaldehyde (II) by means of butyllithium and diisopropylamine in THF gives 1-benzyl-4-(5,6-dimethoxy-1-oxoindan-2-ylidenemethyl)piperidine (III), which is reduced with H2 over Pd/C in THF and treated with HCl in dichloromethane – ethyl acetate.
标题:
Synthesis of 1-benzyl-4-[(5,[C-11]6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine: A promising ligand for visualisation of acetylcholine esterase by PET
作者:
Santens, P.; DeReuck, J.; Dierckx, R.A.; Siegers, G.; Vermeirsch, H.; De Vos, F.
来源:
J Label Compd Radiopharm 2000,43(6),595
合成路线图解说明:11C-Labeled donepezil was prepared by methylation of 2-(1-benzylpiperidin-4-ylmethyl)-6-hydroxy-5-methoxyindan-1-one (I) with 11CH3I by means of tetrabutylammonium hydroxide in DMF.
Donepezil hydrochloride is a useful memory enhancer introduced by the Japanese pharmaceutical company Eisai. Its preparation was described in patent no. EP 296560. In this patent Donepezil was produced by reaction of 5,6-dimethoxy-1- indanone with 1 -benzyl-4-formylpiperidine in the presence of a strong base, such as lithium diisopropylamide followed by reduction of the double bond. According to this method, Donepezil was obtained (Scheme 1).Patent application WO 99/36405 describes another process for the synthesis of Donepezil. According to this patent, 2-alkoxycarbonyl-1-indanones are reacted with (4-pyridinyl) methyl halide moiety followed by hydrolysis and decarboxylation to give the 2-(4-pyridinyl)methyl-1-indanone derivative. This is followed by reaction with benzyl halides to obtain the corresponding quaternary ammonium salt, and followed by hydrogenation of the pyridine ring to obtain Donepezil (Scheme 2).Patent application WO 97/22584 describes the preparation of Donepezil by reaction of pyridine-4-carboxyaldehyde with malonic acid to give 3-(pyridin-4-yl)-2- propenoic acid, followed by hydrogenation of the double bond to give 3-(piperidin-4-yl)-2-propionic acid. Reaction of this intermediate with methyl chloroformate afforded 3-[N-(methyloxycarbonyl) piperidin-4-yl]propionic acid. This was followed by reaction with oxalyl chloride to give methyl 4-(2-chlorocarbonylethyl)piperidin-1-carboxylate. Reaction with 1,2-dimethoxybenzene in the presence of aluminum chloride afforded methyl 4-[3-(3,4-dimethoxyphenyl)-3-oxopropyl]piperidin-1 -carboxylate. Reaction with tetramethyldiaminomethane afforded 4-[2-(3,4-dimethoxybenzoyl)allyl] piperidin-1-carboxylate. Reaction with sulfuric acid afforded methyl 4-(5,6-dimethoxy-1-oxoindan-2-yl)methylpiperidin-1- carboxylate. This was followed by treatment with base to give 5,6-dimethoxy-2-(piperidin-4-ylmethyl) indan-1-one, then reaction with benzyl bromide afforded Donepezil (Scheme 3).
Patent application EP 711756 describes the preparation of Donepezil by reaction of 5,6-dimethoxy-1- indanone with pyridin-4-aldehyde to give 5,6-dimethoxy-2-(pyridin-4-yl)methylene indan-1-one. Reaction with benzyl bromide afforded 1-benzyl-4-(5,6-dimethoxyindan-1-on-2-ylidene)methylpyridinium bromide. Hydrogenation in the presence of platinum oxide afforded Donepezil (Scheme 4).
cas no 808118-40-3 FG 4592
FG-4592 oral presentation at ASN 2012
FG-4592 is an orally administered small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase activity.
As part of the agreement, the deal will focus on US, China and all major markets except the Commonwealth of Independent States, the Middle East, South Africa, Japan and Europe, while both companies can exercise the option to extend their collaboration to other anemia indications.
AstraZeneca will pay FibroGen at least $350 million as part of a strategic collaboration to develop and commercialize FG-4592, a first-in-class oral compound in late stage development for the treatment of anaemia associated with chronic kidney disease (CKD) and end-stage renal disease (ESRD).
This broad collaboration focuses on the US, China and all major markets excluding Japan, Europe, the Commonwealth of Independent States, the Middle East and South Africa, which are covered by an existing agreement between FibroGen and Astellas Pharma. The AstraZeneca-FibroGen joint effort will be focused on the development of FG-4592 to treat anaemia in CKD and ESRD, and may be extended to other anaemia indications. The companies plan to undertake an extensive FG-4592 Phase III development program for the US, and to initiate Phase III trials in China, with anticipated regulatory filings in China in 2015 and in the US in 2017.
In addition to $350 million in up front and non-contingent payments, AstraZeneca could pay FibroGen potential future development related milestone payments of up to $465 million, and potential future sales related milestone payments in addition to tiered royalty payments on future sales on FG-4592 in the low 20% range. Additional development milestones will be payable for any subsequent indications which the companies choose to pursue. AstraZeneca will be responsible for the US commercialization of FG-4592, with FibroGen undertaking specified promotional activities in the ESRD segment in this market. The companies will also co-commercialize FG-4592 in China where FibroGen will be responsible for clinical trials, regulatory matters, manufacturing and medical affairs, and AstraZeneca will oversee promotional activities and commercial distribution.
FG-4592 is a small molecule inhibitor of hypoxia-inducible factor (HIF), a protein that responds to oxygen changes in the cellular environment and meets the body’s demands for oxygen by inducing erythropoiesis, the process by which red blood cells are produced. The firms claim FG-4592 has the potential to address the considerable unmet medical need for an effective treatment for anaemia that offers the convenience of oral administration and an improved safety profile when compard with current standards of care. At present, treatment options involve a combination of injectable erythropoiesis-stimulating agents (ESAs) and iron supplements.
“Our collaboration with FibroGen on FG-4592 is an important addition to AstraZeneca’s growing late-stage portfolio in cardiovascular and metabolic disease, one of our core therapy areas,” comments Pascal Soriot, AstraZeneca CEO. “We know from our research into complications of renal disease that anaemia continues to be a challenge for patients with chronic kidney disease, due in part to the inconvenience and complexity of existing injectable and intravenous therapies and the safety concerns associated with them. The science behind this compound is compelling. Through our collaboration with FibroGen we aim to offer a first-in-class, convenient treatment option for doctors and patients.”
“FG-4592 has the potential to offer anaemia patients an oral therapy that provides coordinated erythropoiesis, that increases natural erythropoietin within the normal physiological range, and that is effective without intravenous iron supplementation and without an increased risk for hypertension,” adds Thomas B. Neff, FibroGen CEO. “We are especially pleased that AstraZeneca will share our commitment to making China the first-to-launch country for FG-4592 and join our effort to bring important innovation in anaemia therapy to CKD and ESRD patients in the US and other countries. This agreement secures proper development and commercialization resources for FG-4592, and ensures US clinical trial efforts are fully funded.”
Novavax has announced positive preclinical results for its virus-like particle (VLP) vaccine candidate against A (H7N9) influenza.
The study examined the immunogenicity, the ability to provoke an immune response, and efficacy of two doses of its A(H7N9) VLP vaccine candidate against a lethal wild-type challenge mouse model.
There were three control groups, including Novavax’ non-homologous A(H7N3) VLP vaccine candidate, its A(H5N1) VLP vaccine candidate, and a placebo. All vaccine candidates were administered with or without Iscomatrix, a saponin-based adjuvant.
Poor pre-clinical data and an absence of negative results are pushing candidate molecules into the clinic too soon
The reporting of animal studies is biased, inflating the efficacy of drug candidates and pushing them into the clinic before they are ready. This is the verdict of new research, which finds that more treatments go from pre-clinical to human trials than ought to, wasting valuable resources and potentially putting trial participants in danger.1 It adds to a growing body of evidence pointing to problems in the way animal testing is reported and managed.
Schematic representation of the wild type counterpart of the typically used recombinant viral vectors. (A) Gammaretroviruses and (B) lentiviruses share similar structures, but differ greatly in their genomes and their impact on cellular function. Gag, pro, pol and env genes encode structural proteins of the capsid, protease, reverse transcriptase and envelope proteins, respectively. The additional lentiviral genes perform regulatory functions as well as alter cellular function. (C) The serotype 5 adenovirus has a protein capsid (non-enveloped) and a large, complex genome that encodes critical genes for viral replication (E1a, E1b) as well as structural and functional genes that regulate both viral and cellular activities.
Introduction
Gene therapy, the therapeutic transfer of genetic information to a target cell, continues to be a promising alternative in the fight against cancer. In the case of melanoma, the use of an experimental treatment is justified since this disease is incurable in its advanced stages. Is gene therapy a viable option for the treatment of melanoma patients? In this chapter, we will attempt to answer this question by exploring the intersection between the technology of gene therapy and the biology of melanoma, a point at which opportunities for intervention are revealed.
Gene Therapy for Melanoma: Progress and Perspectives
Bryan E. Strauss1 and Eugenia Costanzi-Strauss2
[1] Cancer Institute of Sao Paulo, University of Sao Paulo School of Medicine, Brazil
[2] University of Sao Paulo, Biomedical Sciences Institute, Brazil
Vical’s (VICL) Allovectin-7 is a pure immune therapy.(1) Which means it does not directly kill cancer cells, but activates the immune system to do so. Vical will soon announce A-7 phase 3 results in Melanoma, but the mechanism of action is not specific to Melanoma, and can be used in any solid tumor cancer.(2) For this reason, I expect that Allovectin-7 will become one of the best selling cancer drugs of all time.
Allovectin-7 is a substance that is being studied as a gene therapy agent in the treatment of cancer, such as malignant melanoma. It is a plasmid/lipid complex containing the DNA sequences encoding HLA-B7 and ß2 microglobulin – two components of major histocompatibility complex (MHC, class I). It increases the ability of the immune system to recognize cancer cells and kill them.
In 1999, FDA granted Allovectin-7 orphan drug designation for the treatment of invasive and metastatic melanoma.
Allovectin-7 entry in the public domain NCI Dictionary of Cancer Terms
Allovectin is a first-class DNA-based immunotherapeutic designed to stimulate both innate and adaptive immune responses in local tumors and distal metastases. The goal is to become a first-line treatment for Stage III and IV melanoma, where it is intended to provide improved efficacy, a better safety profile, and simple outpatient administration.
As last reported, the company is approaching completion of a Phase III registration trial versus chemotherapy in patients with metastatic melanoma. The reporting of end results has had numerous delays, but the results are now expected by Q3.
Outside of Allovectin, Vical has ten clinical trials ongoing, three of those independent and the rest in collaboration. Clearly, Vical is not totally dependent on this immunotherapy though it is the most advanced independent program in the company’s pipeline.
Vical has a market cap of $257M, so clearly a homerun therapy could send the stock soaring.
Biocon is looking at gaining market share and improving its margins with a greater focus on its product mixes and organizational efficiencies. Biocon Chairman and Managing Director Kiran Mazumdar-Shaw tells Financial Express that the company has outpaced the market, despite various challenges and that the pharmaceutical market needs to have a more robust regulatory set-up. Edited excerpts:
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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This article incorporates 
New Drug Approvals 