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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Ixchelsis, a start-up company that has come out of Pfizer’s former R D site at Sandwich, UK, is progressing a treatment for premature ejaculation boosted by the backing of Eli Lilly.
Lilly, through its venture fund set up with TVM Capital Life Science, has
invested in Ixchelsis, made up of former Pfizer scientists and headed by Gary
Muirhead. The company is based on an oxytocin receptor antagonist called IX-01
originally discovered at Sandwich which the investors say “has the potential to
be the best-in-class pharmacological approach for the treatment of
PE”.
Ixchelsis, which is based at the Sandwich site, now called Discovery
Park, will collaborate with the autonomous early phase virtual drug discovery
arm of Lilly, known as Chorus. Dr Muirhead told PharmaTimes that the
TVM model will fund through to the agreed exit point, which is completion of
proof-of-concept and this requires about $14 million.
read all at
http://www.pharmatimes.com/Article/13-08-08/Lilly_backs_Ixchelsis_a_start-up_born_at_Pfizer.aspx
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Oral Anti-Cancer Therapy Pomalidomide Now Approved by European Commission as Treatment for Patients with Relapsed/Refractory Multiple Myeloma – a Rare Form of Blood Cancer
POMALIDOMIDE
4-amino-2-(2,6-dixopiperidin-3- yl)isoindoline-l,3-dione; 3-(4-amino-l,3-dioxo-l,3-dihydro-isoindol-2-yl)-piperidine- 2,6-dione; 3-(4-amino-l ,3-dioxoisoindolin-2-yl)piperidine-2,6-dione; 1 ,3-dioxo-2-(2,6- dioxopiperidin-3-yl)-4-aminoisoindoline; 3-(l,3-dioxo-4-aminoisoindolin-2-yl)- piperidine-2,6-dione;
BOUDRY, Switzerland–(BUSINESS WIRE)–Aug. 9, 2013–Celgene International Sàrl, a wholly-owned subsidiary of Celgene Corporation (NASDAQ: CELG) today announced that the European Commission (EC) has granted approval for Pomalidomide Celgene®▼(pomalidomide),
in combination with dexamethasone, for the treatment of relapsed and refractory multiple myeloma (rrMM) in adult patients who have received at least two prior therapies including both lenalidomide and bortezomib and have demonstrated disease progression on the last therapy.1 Celgene intends to launch Pomalidomide Celgene in the EU under the trade name “IMNOVID®”, following submission of a regulatory notification to the European Medicines Agency (EMA) to change the trade name.
READ ALL AT
http://www.pharmalive.com/ec-approves-celgene-blood-cancer-drug
CAS 19171-19-8
Pomalidomide, an analogue of thalidomide, is an immunomodulatory antineoplastic agent. FDA approved on February 8, 2013.
Pomalidomide is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy.
Pomalidomide (INN, originally CC-4047 or 3-amino-thalidomide, trade name Pomalyst[1] in the US) is a derivative of thalidomidemarketed by Celgene. It is anti-angiogenic and also acts as an immunomodulator. Pomalidomide was approved in February 2013 by the U.S. Food and Drug Administration (FDA) as a treatment for relapsed and refractory multiple myeloma.[2] It received a similar approval from the European Commission in August 2013, and is expected to be marketed in Europe under the brand nameImnovid.[3]
Origin and development
The parent compound of pomalidomide, thalidomide, was originally discovered to inhibit angiogenesis in 1994.[4] Based upon this discovery, thalidomide was taken into clinical trials for cancer, leading to its ultimate FDA approval for multiple myeloma.[5] Further structure activity studies done in Dr. Robert D’Amato’s lab at Boston Children’s Hospital led to the first claim in 1995 that amino-thalidomide had antitumor activity.[6] Interestingly, the pronounced anti-tumor activity is due to its ability to directly inhibit both the tumor cell and vascular compartments of myeloma cancers.[7] This dual activity of pomalidomide makes it more efficacious than thalidomide in vitro and in vivo.[8]
Clinical trials
Phase I trial results showed tolerable side effects.[9]
Phase II clinical trials for multiple myeloma and myelofibrosis reported ‘promising results’.[10][11]
Phase III results were reported at ASH in 2012 and showed significant extension of progression-free survival (median 3.6 months vs. 1.8 months; P < 0.001), and overall survival in patients taking pomalidomide and dexamethasone v. dexamethasone alone.[12]
Mechanism
Pomalidomide directly inhibits angiogenesis and myeloma cell growth. This dual effect is central to its activity in myeloma, rather than other pathways such as TNF alpha inhibition, since potent TNF alpha inhibitors including rolipram and pentoxifylline do not inhibit myeloma cell growth nor angiogenesis.[7] Up regulation of Interferon gamma, IL-2 and IL-10 as well as down regulation of IL-6 have been reported for pomalidomide. These changes may contribute to pomalidomide’s anti-angiogenic and anti-myeloma activities.
Pregnancy and sexual contact warnings
Because Pomalyst can cause harm to unborn babies when administered during pregnancy, women taking Pomalyst must not become pregnant. Women must produce two negative pregnancy tests and use contraception methods before beginning Pomalyst. Women must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with Pomalyst, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of Pomalyst therapy. Pomalyst is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing Pomalyst, even if they have undergone a successful vasectomy. Male patients taking Pomalyst must not donate sperm.
Pomalidomide simple structure, synthesis is relatively easy. The glutamine ( 1 ), the compound 2 protected amino, thionyl chloride to ring palladium on carbon hydrogenation later deprotected to give compound 3 , 3 , and 4 direct condensation Pomalidomide.
PATENTS
| US PATENT No | Patent ExpirY | patent use code |
|---|---|---|
| 5635517 | Jul 24, 2016 | U-1359 |
| 6045501 | Aug 28, 2018 | U-1361 |
| 6315720 | Oct 23, 2020 | U-1361 |
| 6316471 | Aug 10, 2016 | U-1360 |
| 6476052 | Jul 24, 2016 | U-1360 |
| 6561976 | Aug 28, 2018 | U-1361 |
| 6561977 | Oct 23, 2020 | U-1361 |
| 6755784 | Oct 23, 2020 | U-1361 |
| 6908432 | Aug 28, 2018 | U-1361 |
| 8158653 | Aug 10, 2016 | |
| 8198262 | Oct 19, 2024 | U-1360 |
| 8204763 | Aug 28, 2018 | U-1361 |
| 8315886 | Oct 23, 2020 | U-1361 |
| Exclusivity Code | Exclusivity Date |
|---|---|
| ODE | Feb 8, 2020 |
| NCE | Feb 8, 2018 |
| Country | Patent Number | Approved | Expires (estimated) |
|---|---|---|---|
| United States | 8198262 | 2013-02-08 | 2024-10-19 |
| United States | 8204763 | 2013-02-08 | 2018-08-28 |
| United States | 8315886 | 2013-02-08 | 2020-10-23 |
| Country | Patent Number | Approved | Expires (estimated) |
|---|---|---|---|
| United States | 5635517 | 2013-02-08 | 2016-07-24 |
| United States | 6045501 | 2013-02-08 | 2018-08-28 |
| United States | 6315720 | 2013-02-08 | 2020-10-23 |
| United States | 6316471 | 2013-02-08 | 2016-08-10 |
| United States | 6476052 | 2013-02-08 | 2016-07-24 |
| United States | 6561976 | 2013-02-08 | 2018-08-28 |
| United States | 6561977 | 2013-02-08 | 2020-10-23 |
| United States | 6755784 | 2013-02-08 | 2020-10-23 |
| United States | 6908432 | 2013-02-08 | 2018-08-28 |
| United States | 8158653 | 2013-02-08 | 2016-08-10 |
Pomalidomide-2013, FDA approved anticancer drugs. Pomalidomide isthalidomide (thalidomide) derivative, for the treatment of multiple myeloma. Trade name Pomalyst, developed by Celgene.
Pomalidomide simple structure, synthesis is relatively easy. (From glutamine 1 ), the compound 2 is protected amino, thionyl chloride off ring after deprotection to obtain a compound with palladium on carbon hydrogenation of 3 , 3 and 4 the direct condensation Pomalidomide.
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http://www.google.com/patents/WO2012177678A2?cl=en
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Figure 1: Chronological view of the history of thalidomide and its analogs
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| Systematic (IUPAC) name | |
|---|---|
| 4-Amino-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione | |
| Clinical data | |
| Trade names | Imnovid, Pomalyst |
| Licence data | EMA:Link, US FDA:link |
| Pregnancy cat. |
|
| Legal status | |
| Routes | Oral |
| Pharmacokinetic data | |
| Protein binding | 12–44% |
| Metabolism | Hepatic (mostly CYP1A2 andCYP3A4 mediated; some minor contributions by CYP2C19 andCYP2D6) |
| Half-life | 7.5 hours |
| Excretion | Urine (73%), faeces (15%) |
| Identifiers | |
| CAS number | 19171-19-8  |
| ATC code | L04AX06 |
| PubChem | CID 134780 |
| Chemical data | |
| Formula | C13H11N3O4 |
| Mol. mass | 273.24 g/mol |
Figure 2: The mechanism of TLP in multiple myeloma. TLP refers to thalidomide, lenalidomide and pomalidomide.
CLIP
HONORED
Celgene’s George Muller (left) and Roger Shen-Chu Chen celebrate at the Heroes of Chemistry banquet.
Credit: Linda Wang/C&EN
The satisfaction of helping patients is what drives George Muller as an industrial scientist. Muller is coinventor of Celgene’s Polamyst for multiple myeloma.
“It’s wonderful to be able to think that the work one did in the lab ended up helping patients,” he says. “Over my career, I’ve met patients who were taking drugs on which I had worked. It’s always amazing to see the positive effects on the lives of these patients. Some of them get their lives back.”
Muller says that during the course of developing Pomalyst, they made hundreds of compounds. “We worked on the project for probably 15-plus years,” he says. The drug was approved in 2014.
References
- “Pomalyst (Pomalidomide) Official Website”. Celgene Corporation. Retrieved 2013-08-10.
- “Pomalyst (Pomalidomide) Approved By FDA For Relapsed And Refractory Multiple Myeloma”. The Myeloma Beacon. Retrieved 2013-08-10.
- “Pomalidomide Approved In Europe For Relapsed And Refractory Multiple Myeloma”. The Myeloma Beacon. Retrieved 2013-08-10.
- D’Amato, Robert J.; Loughnan, Michael S.; Flynn, Evelyn; Folkman, Judah (1994). “Thalidomide is an inhibitor of angiogenesis”. Proceedings of the National Academy of Sciences of the United States of America 91 (9): 4082–5. Bibcode:1994PNAS…91.4082D. doi:10.1073/pnas.91.9.4082. JSTOR 2364596. PMC 43727. PMID 7513432.
- http://vectorblog.org/2013/04/from-thalidomide-to-pomalyst-better-living-through-chemistry/
- http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=1&f=G&l=50&co1=AND&d=PTXT&s1=5,712,291.PN.&OS=PN/5,712,291&RS=PN/5,712,291
- D’Amato, R; Lentzsch, S; Anderson, KC; Rogers, MS (2001). “Mechanism of action of thalidomide and 3-aminothalidomide in multiple myeloma”. Seminars in Oncology 28 (6): 597–601. doi:10.1016/S0093-7754(01)90031-4. PMID 11740816.
- Lentzsch, S; Rogers, MS; Leblanc, R; Birsner, AE; Shah, JH; Treston, AM; Anderson, KC; D’Amato, RJ (2002). “S-3-Amino-phthalimido-glutarimide inhibits angiogenesis and growth of B-cell neoplasias in mice”. Cancer Research 62 (8): 2300–5. PMID 11956087.
- Streetly, Matthew J.; Gyertson, Kylie; Daniel, Yvonne; Zeldis, Jerome B.; Kazmi, Majid; Schey, Stephen A. (2008). “Alternate day pomalidomide retains anti-myeloma effect with reduced adverse events and evidence of in vivo immunomodulation”. British Journal of Haematology 141 (1): 41–51. doi:10.1111/j.1365-2141.2008.07013.x. PMID 18324965.
- Jump up^ “Promising Results From 2 Trials Highlighting Pomalidomide Presented At ASH” (Press release). Celgene. December 11, 2008. Retrieved October 28, 2012.
- Jump up^ Tefferi, Ayalew (December 8, 2008). “Pomalidomide Therapy in Anemic Patients with Myelofibrosis: Results from a Phase-2 Randomized Multicenter Study”. 50th ASH Annual Meeting and Exposition. San Francisco. Retrieved October 28, 2012.
- Jump up^ “Phase III Study (MM-003) of Pomalidomide Plus Low-Dose Dexamethasone Demonstrates Significant Progression-Free and Overall Survival Improvement for Patients with Relapsed or Refractory Multiple Myeloma.”. 11 Dec 2012.
External links
POMALYST is an immunomodulatory antineoplastic agent. The chemical name is (RS)-4-Amino-2-(2,6-dioxo-piperidin-3-yl)-isoindoline-1,3dione and it has the following chemical structure:
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The empirical formula for pomalidomide is C13H11N3O4 and the gram molecular weight is 273.24.
Pomalidomide is a yellow solid powder. It has limited to low solubility into organic solvents and it has low solubility in all pH solutions (about 0.01 mg/mL). Pomalidomide has a chiral carbon atom which exists as a racemic mixture of the R(+) and S(-) enantiomers.
POMALYST is available in 1 mg, 2 mg, 3 mg and 4 mg capsules for oral administration. Each capsule contains pomalidomide as the active ingredient and the following inactive ingredients: mannitol, pregelatinized starch and sodium stearyl fumarate. The 1 mg capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide, white ink and black ink. The 2 mg capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide, FD&C red 3 and white ink. The 3 mg capsule shell contains gelatin, titanium dioxide, FD&C blue 2, yellow iron oxide and white ink. The 4 mg capsule shell contains gelatin, titanium dioxide, FD&C blue 1, FD&C blue 2 and white ink.
NDA 204026
APPR..2013-02-08
Dosages/Routes/Forms
Celgene
| Strength | Form/Route | Marketing Status | RLD | TE Code |
|---|---|---|---|---|
| 1MG | CAPSULE;ORAL | 1 | 0 | |
| 2MG | CAPSULE;ORAL | 1 | 0 | |
| 3MG | CAPSULE;ORAL | 1 | 0 | |
| 4MG | CAPSULE;ORAL | 1 | 1 |
Approval History
2013-10-03
001
Manufacturing Change or Addition
Yusuf Hamied – Cipla
Name: Yusuf Hamied
Title: Chairman and Managing Director, Cipla
http://www.fiercebiotech.com/special-reports/yusuf-hamied-cipla
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.
Read more: Yusuf Hamied – Cipla – FierceBiotech http://www.fiercebiotech.com/special-reports/yusuf-hamied-cipla#ixzz2b9oexHpH
Subscribe at FierceBiotech
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 is best known outside India for defying large Western pharmaceutical companies in order to provide generic AIDS drugs and treatments for other ailments primarily affecting people in poor countries. He was awarded the Padma Bhushan by the Government of India in 2005.
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]
In 2009 the Yusuf Hamied Centre was opened at Christ’s College, Cambridge.[1][14]
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]
- “Christ’s officially opens Yusuf Hamied Centre”. University of Cambridge News. 2009-04-20. Retrieved 2009-04-20.
- Sarah Boseley (2003-02-18). “Yusuf Hamied, generic drugs boss | World news”. London: The Guardian. Retrieved 2010-09-01.
- Selling Cheap ‘Generic’ Drugs, India’s Copycats Irk Industry, By DONALD G. McNEIL Jr, Published: December 01, 2000
- “Interview of the week: Yusuf Hamied. – United Press International | HighBeam Research – FREE trial”. Highbeam.com. 2001-02-22. Retrieved 2010-09-01.
- “[Esplora il significato del termine: Yusuf Hamied, un Robin Hood contro l’ Aids “Così sconfiggerò l’ Aids senza le multinazionali”] Yusuf Hamied, un Robin Hood contro l’ Aids “Così sconfiggerò l’ Aids senza le multinazionali””.
- Bobin, Frédéric (2010-07-06). “India fears generic drugs for poor are endangered by proposed EU trade deal”. The Guardian(London).
- “Dr. Hamied Robin Hood spoof film posters”.
- “Robin Hood and the Multinationals”.
- Hans Lofgren, The Politics of the Pharmaceutical Industry and Access to Medicine, 2012, p. 55
- Hans Lofgren, The Politics of the Pharmaceutical Industry and Access to Medicine, 2012, p. 68
- Harris, Gardiner (2011-09-18). “China and India Making Inroads in Biotech Drugs”. The New York Times.
- Hans Lofgren, The Politics of the Pharmaceutical Industry and Access to Medicine, 2012, p. 58-59
- Hans Lofgren, The Politics of the Pharmaceutical Industry and Access to Medicine, 2012, p. 63
- “The Hindu News Update Service”. Chennai, India: Hindu.com. 2009-04-22. Retrieved 2010-09-01.
- http://ibnlive.in.com/news/dr-yusuf-hamied-message-on-being-cnnibns-indian-of-the-year-2012-in-the-business-category/310908-3.html.
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New Findings Could Influence Development of Therapies to Treat Dengue Disease
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.
read all at scicasts
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Dengue from Siddharth Goyal
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The rind of the Vrikshamla (Garcinia/Garcinia indica) fruit contains an active component called hydroxycitric acid (HCA), which supports normal fat and carbohydrate metabolism, a healthy appetite level and optimum body weight
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| Kokum fruits, seeds, pulp and rinds.jpg |
The rind of the Vrikshamla (Garcinia/Garcinia indica) fruit contains an active component called hydroxycitric acid (HCA), which supports normal fat and carbohydrate metabolism, a healthy appetite level and optimum body weight. The Department of Physiology researchers at the Georgetown University Medical Center in Washington DC, called Vrikshamla a safe, natural supplement for normal weight support. In an eight-week study of 60 volunteers, they reported Vrikshamla’s effectiveness in supporting normal weight, cholesterol, triglyceride and serum lipid levels.
hydroxycitric acid (HCA)
Vrikshamla grows in India the evergreen forests of the Western Ghats, the Southern Konkan region and in Goa. It is also cultivated in the Southern districts of Maharashtra and on the lower slopes of the Nilgiris mountains.
Active constituents:
The active constituent in this herb, HCA, helps weight loss by promoting normal appetite levels and by reducing the body’s ability to form adipose (fatty) tissue. HCA also reduces blood lipid levels and naturally lowers cholesterol. Other useful phytochemicals in Vrikshamla are garcinol, isogarcinol, xanthochymol and isoxanthochymol.
Herb Functions:
Weight management: The herb known to slow down the body’s ability to store fat, potentially enabling more fat from foods to pass through the body without being stored. Additionally, HCA blocks the production and storage of fat and cholesterol when calorie consumption exceeds healthy levels. The herb is also known to reduce blood lipid levels and to naturally lower cholesterol.
read at
http://www.himalayahealthcare.com/products/pharmaceuticals/vrikshamla.htm
Garcinia indica, a plant in the mangosteen family (Clusiaceae), commonly known askokum, punar puli (tulu language), is a fruit-bearing tree that has culinary, pharmaceutical, and industrial uses.
The genus Garcinia, belonging to the family Clusiaceae, includes about 200 species found in the Old World tropics, mostly in Asia and Africa. Garcinia indica is indigenous to theWestern Ghats region of India located along the western coast of the country. Of the 35 species found in India, 17 are endemic. Of these, seven are endemic to the Western Ghats, six in the Andaman and Nicobar Islands and four in the northeastern region of India.
Garcinia indica is found in forest lands, riversides and wastelands. These plants preferevergreen forests, but sometimes they also thrive in areas with relatively low rainfall. It is also cultivated on a small scale. It does not require irrigation, spraying of pesticides or fertilizers.
Garcinia indica is known by various names across India, including aamsol, aamsul, bindin, biran, bhirand,bhrinda, brinda, bin’na, kokum (alternate spellings kokam and cocum), katambi, looikya, sour apple, panarpuli, ratamba, thekera (in Assam) and many others.
The dried skin of kokum fruits
The outer cover of fruit is dried in the sun to get aamsul or kokam. It is used as a slightly sour spice in recipes from Maharashtra. Kokum yields a peculiar flavour and blackish red colour. It is a preferred substitute for tamarind in curries and other dishes from the Konkanregion. It is also used in cuisine from Gujarat, where it is frequently used to add flavor and tartness to dal (lentil soup) for flavor balance, and parts of South India.
The vessel on the left contains syrup which is obtained from the vessel containing kokum rinds, on the right. The syrup is used to make kokum sherbet
Kokum squash or kokum concentrate is used in preparing a drink (sherbet) which is bright red in colour. Kokum sherbet improves digestion and cools the body during summers[citation needed].
Further, the extract/ concentrate of this fruit is called aagal in Konkani and Marathi. It is to added during the preparation of solkadhi, along with coconut milk.
Industrial uses
The seed of Garcinia indica contains 23–26% oil, which remains solid at room temperature. It is used in the preparation of confectionery, medicines and cosmetics.
Recently, industries have started extracting hydroxycitric acid (HCA) from the rind of the fruit.[citation needed]
The tree is ornamental, with a dense canopy of green leaves and red-tinged, tender, young leaves. The oily extract called kokum tel is used in foot massage.
Flow synthesis for Novartis anticancer drug, Gleevec, Imatinib
The flow-based route required minimal manual intervention and was achieved despite poor solubility of many reaction components
21 January 2013Michael Parkin
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.
READ ALL AT
http://www.rsc.org/chemistryworld/2013/01/flow-synthesis-anticancer-drug
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CREDIT
http://www.veomed.com/va041542042010
‘Wrapping’ Gleevec Fights Drug-Resistant Cancer, Study Shows
http://www.sciencedaily.com/releases/2007/05/070501115127.htm
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.
FDA has granted tentative approval to India-based Strides Arcolab’s HIV drug emtricitabine and tenofovir disoproxil fumarate tablets, 200 mg/300 mg.
chief executive and vice chairman Arun Kumar –Strides arcolab
Deepak Vaidya, chaiman
Headquartered in India, Strides Arcolab is a pharmaceutical company with a key focus on the development and manufacture of IP-led niche products, particularly sterile injectables. It is among the world’s largest manufacturers of soft gelatin capsules. With 14 world-class manufacturing facilities, an innovative R&D hub and a marketing network in 70 countries, Strides is well positioned to meet the demands of the global pharmaceutical industry and has partnered with several of the world’s leading pharmaceutical companies.
2 August 2013
Strides Arcolab’s HIV drug, which is generic version of Gilead Sciences’ Truvada, gets tentative approval from the US FDA.
Tentative approval implies that the drug has met all standards but cannot be marketed in the US due to existing patent protections Good news for HIV AIDS patients
FDA has granted tentative approval to India-based Strides Arcolab’s HIV drug emtricitabine and tenofovir disoproxil fumarate tablets, 200 mg/300 mg. The drug is a generic version of Truvada, 200 mg/300 mg tablets, which is manufactured by Gilead Sciences.
The product is indicated for use in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV)-1
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EMTRICITABINE
credit-chemdrug
The selective tosylation of L-gulose with tosyl chloride in pyridine, followed by complete acetylation with acetic anhydride gives tetraacetyl-6-O-tosyl-L-gulose (II), which is treated with HBr in AcOH to yield the bromo derivative (III ). The reaction of (III) with potassium O-ethylxanthate in refluxing acetone, followed by deacetylation with NH4OH in methanol affords 1,6-thioanhydro-L-gulopyranose (IV). The selective oxidative cleavage of (IV) by means of NaIO4 , followed by reduction with NaBH4 and protection of the resulting diol with acetone and TsOH provides the acetonide (V), which is silylated at the primary OH group with TBDMS-Cl giving the silyl ether (VI). Elimination of the acetonide group with TsOH in methanol yields the diol (VII), which is cleaved with Pb (OAc) 4 and oxidized with PDC in DMF to afford the carboxylic acid (VIII). The treatment of (VII) with Pb (OAc) 4/pyridine in THF furnishes the diacetate (IX), which is condensed with N4-acetyl-5-fluoro-O-(trimethylsilyl) cytosine (X) by means of TBDMS-OTf in dichloromethane yielding a mixture of the desired (-) (2R, 5S) – isomer (XI) along with its (+) – (2R, 5R)-isomer that is separated by column chromatography. Finally, deacetylation of (XI) with ammonia in methanol, followed by desilylation with TBAF in THF afforded the target compound.
Jeong, LS; et al.; Asymmetric synthesis and biological evaluation of beta-L-(2R, 5S) – and alpha-L-(2R, 5R) -1, 3-oxathiolane-pyrimidine and-purine nucleosides as potential anti- HIV agents. J Med Chem 1993, 36, 2, 181
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TENOFOVIR
DONEPEZIL SYNTHESIS
Donepezil, marketed under the trade name Aricept by its developer Eisai and partnerPfizer, is a centrally acting reversible acetylcholinesterase inhibitor. Its main therapeutic use is in the palliative treatment of Alzheimer’s disease.Common side effects include gastrointestinal upset. It has an oral bioavailability of 100% and easily crosses the blood–brain barrier. Because it has a biological half-life of about 70 hours, it can be taken once a day.
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.
【通用名】 Donepezil hydrochloride, BNAG, E-2020, Eranz, Memorit, Memac, Aricept
【化学名】 (?-1-Benzyl-4-(5,6-dimethoxy-1-oxoindan-2-ylmethyl)piperidine hydrochloride; (?-2-(1-Benzylpiperidin-4-ylmethyl)-5,6-dimethoxyindan-1-one hydrochloride
【CAS登记号】 120011-70-3, 123958-79-2 ([2-14C]-labeled), 142057-77-0 (deleted CAS), 120014-06-4 (free base)
【分子式】 C24-H29-N-O3.Cl-H
【分子量】 415.958
【化学活性】 Alzheimer’s Dementia, Treatment of , Analgesic and Anesthetic Drugs, Antimigraine Drugs, Attention Deficit Hyperactivity Disorder (ADHD), Treatment of, Autism, Treatment of, Cognition Disorders, Treatment of, Immunologic Neuromuscular Disorders, Treatment of, Migraine, Prophylactic Treatment of, Multiple Sclerosis, Agents for, Neurologic Drugs, Psychopharmacologic Drugs, Vascular Dementia, Treatment of, Acetylcholinesterase Inhibitors
【开发阶段】 Launched-1997
【研究机构】 Eisai (Originator), National Institute of Mental Health (Not Determined), Bracco (Licensee), Pfizer (Licensee)
Donepezil inhibiting Torpedo californicaacetylcholinesterase. See Proteopedia1eve.
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 |
| 作者: | Sugimoto, H.; Tsuchiya, Y.; Higurashi, K.; Karibe, N.; Iimura, Y.; Sasaki, A.; Yamanashi, Y.; Ogura, H.; Araki, S.; Kosasa, T.; Kusota, A.; Kozasa, M.; Yamatsu, K. (Eisai Co., Ltd.) |
| 来源: | AU 8818216; EP 0296560; EP 0673927; EP 0742207; JP 1989079151; JP 1998067739; US 4895841; US 5100901 |
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| 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 |
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| 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 |
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| 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 |
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| 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. | |
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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).
United States Patent 6844440
EP 1386607 A1
FDA Grants Priority Review To New Drug Application For MNK-795 Submitted By Depomed Licensee Mallinckrodt
FDA Grants Priority Review To New Drug Application For MNK-795 Submitted By Depomed Licensee Mallinckrodt
Controlled Substance Analgesic Combination Product Uses Depomed’s Proprietary Acuform® Technology
NEWARK, Calif., July 29, 2013 /PRNewswire/ — Depomed, Inc. (NASDAQ:DEPO) announced today that the U. S. Food and Drug Administration (FDA) has accepted for filing a New Drug Application (NDA) from Mallinckrodt (NYSE: MNK) for MNK-795. MNK-795 is a controlled-release oral formulation of oxycodone and acetaminophen that has been studied for the management of moderate to severe acute pain where the use of an opioid analgesic is appropriate. MNK-795 is formulated with Depomed’s Acuform® drug delivery technology.
http://www.pharmalive.com/fda-grants-priority-review-to-new-drug-application-for-mnk-795
New Drug Approvals 