3b R = NITRO
|
Dr. Helen P. KavithaProfessor and Head of the Department |
|||||||||
Education
|
||||||||||
Other Details:Course
Research Interests
Selected PublicationS
Working Papers
Academic Experiences
Other Professional Experiences
Achievement and Award
|
||||||||||
///////////////
To a solution of 4-(4-chlorophenyl)piperazine dihydrochloride 1 (5.0 g, 0.0185 mol) in DMSO (30 ml), anhydrous cesium carbonate (30.0 g, 0.0925 mol), sodium iodide (1.39 g, 0.0093 mol) and ethyl 2-bromo-2-methylpropanoate 2 (3.97 g, 0.02 mol) were added. The resulting mixture was stirred at 25-30oC for 12 hours. The reaction mass was diluted with water (200 ml) and extracted with ethyl acetate (2 x 200 ml). The ethyl acetate layer was washed with water (2 x 100 ml), dried over anhydrous sodium sulfate (10.0 g) and concentrated under vacuum. The crude product thus obtained was purified by column chromatography (stationary phase silica gel 60-120 mesh; mobile phase 10% ethyl acetate in hexane). The title compound 3 was obtained as a white solid (4.73 g, 82 %).
Professor at Sambalpur University, Chemistry Department
The title compound was synthesized by N-alkylation of 4-(4-chlorophenyl)piperazine with ethyl 2-bromo-2-methylpropanoate and its IR, 1H NMR, 13C NMR and Mass spectroscopic data are reported.
/////////
CCOC(=O)C(N1CCN(CC1)c1ccc(cc1)Cl)(C)C
List of female scientists before the 21st century – Wikipedia, the …
Dr Deanna D’Alessandro wins L’Oreal Australia For Women in Science …
Roxanne Bales vividly remembers the months she spent at a graduate program in organic chemistry in New England.
Ji Qi (GRS’06,’11), a graduate student pursuing a Ph.D. in chemistry, has been awarded a 2006-2007 Novartis Fellowship in Organic Chemistry for Women and …
LiveDNA: Publications of Suneela Sunil Dhaneshwar
Chemistry professor Julia Kubanek
http://chemists.princeton.edu/knowles/
The 2014 winners of the The Elsevier Foundation Awards for Early Career Women Scientists in the Developing World accept their prizes at the annual AAAS …
One Organic Chemist One Day: Five Female Chemists Win TWAS Awardsoneorganichemistoneday.blogspot.com
.
One Organic Chemist One Day: Dr. Shamsun Nahar Khan
One Organic Chemist One Day: Vinita Gupta, Group President and CEO …
Annaliese K. Franz | UC Davis Department of Chemistry
One Organic Chemist One Day: Dr. Shamsun Nahar Khan
Zakya H. Kafafi – 2007 SPIE Women in Optics Planner
Women in Chemistry—A European Journal :: ChemViews Magazine …
Associate professor of Pharmacy(Pharmacology) at Institute Of Chemical Technology
Kiran Mazumdar Shaw: (born 23 March 1953) She is the Chairman & Managing Director, Biocon Limited a biotechnology company based at Bangalore. She is on the Forbes list of the world’s 100 most powerful women and in business list on top 50 women released by the Financial Times’. In the year 1978, she started Biocon in the garage of her rented house in Bangalore with a seed capital of Rs. 10,000. Now the net worth of the company is more than $ 900 million. Now Biocon produces drugs for cancer, diabetes and auto-immune diseases. Product pipeline includes world’s first oral insulin, currently undergoing Phase III clinical trials.
Winners of the 2014 Elsevier Foundation Awards for Early Career Women Scientists in Developing Countries: (left to right) Dr. Eqbal Mohammed Abdu Dauqan (Biochemistry – Yemen), Dr. Simone Ann Marie Badal McCreath (Biochemistry – Jamaica), Dr. Taiwo Olayemi Elufioye (Pharmacology – Nigeria), Dr. Leni Ritmaleni (Medicinal Chemistry – Indonesia) and Dr. Nilufar Mamadalieva (Biochemistry – Uzbekistan). Photos by Alison BertChicago — Five chemists were presented with the Elsevier Foundation Award for Early Career Women Scientists in the Developing World for research that looks to nature for ways to address cancer, malaria and other medical problems.The winning researchers, representing five regions of the developing world, are from Indonesia, Jamaica, Nigeria, Uzbekistan and Yemen. The prizes are awarded by The Elsevier Foundation, the Organization for Women in Science for the Developing World (OWSD) and The World Academy of Sciences for the advancement of science in developing countries (TWAS) with the aim of building scientific strength and advancing scientific knowledge in developing countries.
Dr. Nilufar Mamadalieva, Senior Scientific Researcher at the Institute of the Chemistry of Plant Substances in Tashkent, Uzbekistan, was honored for her work on the phytochemical and biological investigation of active compounds derived from medicinal plants growing in Central Asia, in particular the development of efficient nutraceuticals and the discovery of new lead compounds for the pharmaceutical industry.The field of natural substances, a tradition at the Tashkent Institute, is gaining more interest in western countries for the development of efficient nutraceuticals and the discovery of new lead compounds for the pharmaceutical industry.
Dr. Mamadalieva is the recipient of a number of international fellowships, which have allowed her to travel extensively and develop a network of international collaborators.
“This award gives me confidence and confirms that I’m going for the right goal,” she said.
Dr. Leni Ritmaleni of the Faculty of Pharmacy at Gadjah Mada University in Yogyakarta, Indonesia, was honored for her work in the field of organic synthesis, focusing on the development of tropical medicines, in particular improved methods for the synthesis of sulfoxides and their application in the preparation of biologically active targets.She hopes her work will “encourage young women in Indonesia to love science, especially synthetic organic chemistry.”
“Women need science, science needs women and they need to work together,” she said.
Dr. Ritmaleni received her PhD from the School of Chemistry at Bristol University, UK after receiving a scholarship from the Indonesian government. She has won several awards in Indonesia and has published over 40 papers.
Dr. RItmaleni said researchers face various challenges at her institution, including a lack of access to scientific equipment and supplies and a scarcity of grants for basic science.
As a mother, she also strives to balance work and family, making “time management” an important priority.
She values the recognition provided by this award along with “the opportunity to connect with other scientists around the globe.”
Dr. Simone Ann Marie Badal McCreath manages the biochemistry lab at the Natural Products Institute at the University of the West Indies in Jamaica, and is designing a new cell culture lab at the same Institute. She was recognized for her work in designing a new cell culture lab to investigate the cancer-fighting properties of Jamaican natural compounds.Her interest is in screening Jamaican plant isolates for their potential properties slow down block or prevent the carcinogenic process. “Our findings have so far identified several isolates that are more potent in reducing cancer cell viability as well as potentially safer than anti-cancer drugs now on the market,” she said. “This research will pave the way for future research necessary for drug development and also the propagation and culture of novel Jamaican cancer and normal cells lines.
“Since cancer is the leading cause of death in Jamaica, such findings will prove useful in cancer treatment and prevention as well as earlier diagnosis in addition to identifying molecular targets that can improve selectivity of the isolates to cancer cells only.”
Dr. Badal McCreath has received numerous awards and has published extensively.
She said the challenges she faces in her career are less gender-based and more about the long delays in getting equipment and supplies to their lab as well as a lack of funding.
“Such challenges can cost us months even years of research,” she said. “Nonetheless, women in science do face challenges, and these become more apparent the higher the ladder you climb, the top of which is male dominated.”
Winning this award, she said, means attracting funding for cancer research in Jamaica and “the motivation of young and older women in science and other areas … to never give up but to persevere through gender-based and other issues that we daily face.”
Dr. Eqbal Mohammed Abdu Dauqan is Head of the Department of Medical Laboratories Sciences at Al-Saeed University in Taizz, Yemen. She was honored for her research on the antioxidant properties of vegetable oils and specialized research in sensory evaluation and organic chemistry.She received her PhD from the National University of Malaysia. Her interests are in biochemistry and biotechnology, and she has conducted specialist research in food science, natural antioxidents and organic chemistry. She is also a dedicated teacher.
“Not all the people around us understand what natural antioxidents are,” she said. She and her colleagues do workshops for the public, pointing out the antioxident properties in vitamins such as C and E and how to find them in the foods they eat.
Dr. Taiwo Olayemi Elufioye is acting head of the Department of Pharmacognosy at the University of Ibadan, Nigeria. She was honored for her research on the medicinal properties of native Nigerian plants, in particular the effectiveness of different species in treating malaria, wounds, memory loss, leprosy and cancer.She said she has been able to identify a compound with good activity against a chloroquine-resistant strain of malaria parasites. Also, she and her research colleagues are creating an herb tea that that may be useful for dementia.
“My main challenge has been funding, typical for most developing world,” she said. “Also been a woman can be challenging considering the fact that prevailing conditions and policies are not necessarily woman-friendly.
“It’s just so great to know that despite these challenges, my contribution to science is being recognized. I feel so proud and definitely energized to do more.”
“The winners of the 2014 Elsevier Foundation prizes are impressive not just for their research, but also for their potential,” said TWAS Executive Director Romain Murenzi. “Certainly these awards could bring them exciting new opportunities for research. We also believe that, over time, these researchers also will fulfill their potential as teachers and mentors, as partners in international projects and as advisers to governments. Such leadership can make a long-lasting contribution to global science.”
Fang Xin, president of OWSD, said: “These five women, like all women undertaking scientific research in developing countries, will certainly have faced challenges on the road to this award. But their determination, commitment and enthusiasm have paid off. The award is recognition that they are excellent scientists and that their research has made an impact both regionally and internationally. They are an inspiration to all young women considering careers in science.”At the ceremony, Samira Omar Asem, VP for the OWSD Arab Region, said OWSD and TWAS see this award as “vital for encouraging women in developing countries to be more involved in science and technology and to make a more significant contribution to social and economic developments.”
David Ruth, Executive Director of the Elsevier Foundation, said professional visibility is crucial to developing high-profile international scientific careers, especially for women. He explained that the Elsevier Foundation provides support to early-career women scholars through its New Scholars grant programs as well as mentoring, research retreats, professional visibility, childcare, work-life integration and recognition programs.
“The awards for these impressive women scientists represent a cooperative effort supported by Elsevier, OWSD, AAAS and TWAS to build research capacity and advance scientific knowledge throughout the developing world,” he said, “and what better place than the annual AAAS conference to raise awareness among scientists, policymakers, journalists and the public about the need to retain and celebrate women scientists.”
Assistant Professor
Specialization: Pharmaceutical Chemistry
M.Pharm., Ph. D.
http://www.azonano.com/news.aspx?newsID=30615
To download a complimentary excerpt of this report, go to:
THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D
MY BLOG ON MED CHEM
ALL FOR DRUGS ON WEB
http://scholar.google.co.uk/citations?user=bxm3kYkAAAAJ
VIETNAM
ICELAND
RUSSIA
Iloprost (ciloprost)
| MF | C22H32O4 |
|---|---|
| Formula Wgt | 360.5 |
6,9ALPHA-METHYLENE-11ALPHA,15S-DIHYDROXY-16-METHYL-PROSTA-5E,13E-DIEN-18-YN-1-OIC ACID
6,9α-
Iloprost Molecule
ILOPROST (Ventavis®) is used to treat a serious heart and lung disorder called pulmonary arterial hypertension. While iloprost inhalation solution will not cure this disorder, it is designed to improve symptoms and the quality of life. Generic iloprost inhalation solution is not yet available.
Iloprost is a second generation structural analog of prostacyclin (PGI) with about ten-
73873-87-7 CAS NO
78919-13-8 PHENACYL ESTER
Launched – 1992 bayer
Ilomedin®, Ventavis™
iloprost
An eicosanoid, derived from the cyclooxygenase pathway of arachidonic acid metabolism. It is a stable and synthetic analog of EPOPROSTENOL, but with a longer half-life than the parent compound. Its actions are similar to prostacyclin. Iloprost produces vasodilation and inhibits platelet aggregation.
BAY-q-6256 E-1030 SH-401 ZK-36374
Endoprost Ilomedin Ilomédine Ventavis Iloprost is a synthetic prostacyclin analog discovered and developed by Schering AG and Berlex which has been available for more than ten years as therapy for peripheral arterial occlusive disease (PAOD), including Raynaud’s phenomenon and Buerger’s disease.
Iloprost improves blood flow, relieves the pain associated with circulatory disturbances and improves the healing of ulcers, which can develop as a result of poor arterial blood flow. Iloprost also produces vasodilatation of the pulmonary arterial bed, with subsequent significant improvement in pulmonary artery pressure, pulmonary vascular resistance and cardiac output, as well as mixed venous oxygen saturation. In 2003, Schering AG received approval in the E.U. for an inhaled formulation of iloprost (Ventavis[R]) for the treatment of primary pulmonary hypertension and the following year, the product was launched in Germany and the U.K.
Introduction on the U.S. market took place in March 2005 by CoTherix for the same indication in patients with NYHA Class III or IV symptoms. Iloprost is also available for the treatment of pulmonary hypertension and peripheral vascular disease. CoTherix had been developing a dry powder for potential use in the treatment of pulmonary hypertension; however, no recent development has been reported for this research. In Japan, phase III clinical trials are ongoing for the treatment of pulmonary arterial hypertension. 
In 2003, CoTherix licensed exclusive rights from Schering AG to market iloprost in the U.S. for primary pulmonary hypertension while Schering AG retained rights to the product outside the U.S. In April 2005, CoTherix established a collaborative research and development agreement with Quadrant to develop an extended-release formulation of iloprost inhalation solution. Iloprost was designated as an orphan medicinal product for the treatment of pulmonary hypertension in December 2000 by the EMEA and will fall under orphan drug protection until 2013.
The FDA has assigned to iloprost several orphan drug designations. In 1989, iloprost solution for infusion was granted orphan drug designation for the treatment of Raynaud’s phenomenon secondary to systemic sclerosis followed by another orphan drug designation in 1990 for iloprost solution for injection for the treatment of heparin-associated thrombocytopenia. In 2004, an additional orphan drug designation for iloprost inhalation solution for the treatment of pulmonary arterial hypertension was assigned.
The status has also been assigned in the E.U. for this indication. In 2012, orphan drug designation was assigned in the U.S. for the treatment of purpura fulminans in combination with eptifibatide and for the treatment of pulmonary arterial hypertension. In 2007, Cotherix was acquired by Actelion.
ILOPROST
Ventavis (TN), Iloprost phenacyl ester, Iloprost-PE, Iloprost (INN), CHEMBL138694, CHEMBL236025, AC1O6009, DAP000273, CID5311181
2-oxo-2-phenylethyl 5-[(2Z)-5-hydroxy-4-[(1E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl]-octahydropentalen-2-ylidene]pentanoate
IMPORTANT PUBLICATIONS
Ciloprost Drugs Fut 1981, 6(11): 676
A carbohydrate approach for the formal total synthesis of the prostacyclin analogue (16S)-iloprost Tetrahedron Asymmetry 2012, 23(5): 388
Angewandte Chemie, 1981 , vol. 93, 12 pg. 1080 – 1081
Tetrahedron Letters, 1992 , vol. 33, 52 pg. 8055 – 8056
Helvetica Chimica Acta, 1986 , vol. 69, 7 pg. 1718 – 1727
Journal of Medicinal Chemistry, 1986 , vol. 29, 3 pg. 313 – 315
US5286494 A1
| US 2013253049 |
uS 2013184295
WO 1992014438
WO 1993007876
WO 1993015739
WO 1994008584
WO 2013040068
WO 2012174407
WO 2011047048
| EP0011591A1 * | Oct 18, 1979 | May 28, 1980 | Schering Aktiengesellschaft | Prostane derivatives, their production and pharmaceutical compositions containing them |
| EP0084856A1 * | Jan 19, 1983 | Aug 3, 1983 | Toray Industries, Inc. | 5,6,7-Trinor-4, 8-inter-m-phenylene prostaglandin I2 derivatives |
| EP0099538A1 * | Jul 11, 1983 | Feb 1, 1984 | Schering Aktiengesellschaft | Carbacyclines, process for their preparation and their use as medicines |
……………………………………
was first found by J.R. Vane et.al. in 1976 and is biosynthe- sized from arachidonic acid via endoperoxide(PGH2 or PGG2) in the vascular wall. PGI2 is well known to show potent activity to inhibit platelet aggregation and to dilate peripheral blood vessels(C & EN, Dec. 20, 1976, page 17 and S. Moncade et al., Nature, 263,633(1976)).
is named as 16-methyl-18,19-tetradehydro-5,6,7-trinor-4,8-inter-m-phenylene PGI2.
The term “synthetic prostacyclins” as used herein can refer to any prostacyclin that can be prepared via synthetic organic chemistry, including those prostacyclins that are also naturally occurring, such as Prostacyclin (PGI2):
which is also known as Epopreostenol.
Thus, examples of synthetic prostacyclins include, but are not limited to: Prosta
lloprost, which has the structure:
Trepro inil (also known as Rumodolin), which has the structure:
Beraprost, which has the structure:
as well as the esters, stereoisomers, and salts thereof, or other analogues or derivatives of the recited synthetic prostacyclins, such as compounds comprising other aliphatic linker groups linking the carboxylic acid group to the cyclic components of the synthetic prostacyclins, compounds containing additional alkene and/or alkyne bonds, and/or compounds containing additional substituents on the cyclic components of the synthetic prostacyclins.
iloprost, in contrast to PGI.sub.2 a stable prostacyclin derivative, has been known since 1980 by European patent application EP 11591, no other prostacyclin derivative has previously been tested in this indication. It is therefore reasonable to assume that a spontaneous healing is involved in the published case.
It has now been found, surprisingly, that iloprost is effective in the case of cerebral malaria.
For salt formation of iloprost, inorganic and organic bases are suitable, as they are known to one skilled in the art for the formation of physiologically compatible salts. For example, there can be mentioned: alkali hydroxides, such as sodium and potassium hydroxide, alkaline-earth hydroxides, such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris-(hydroxymethyl)-methylamine, etc.
The β-cyclodextrin clathrate formation takes place according to EP 259468.
The production of iloprost is described in detail in EP 11591.
and their salts with physiologically acceptable bases and cytoprotective effect in the kidney.
see paper
(EJCorey et al., J. Amer. Chem. 93, 1490 (1971)) transformed with dihydropyran in the presence of catalytic amounts of p-toluenesulfonic acid in the tetrahydropyranyl ether V.
wherein D, E and R 2 have the meanings given above is reacted in a Olefinicrungsreaktion to a ketone of the formula XXV.
THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D GLENMARK SCIENTIST , NAVIMUMBAI, INDIA
did you feel happy, a head to toe paralysed man’s soul in action for you round the clock need help, email or call me
I was paralysed in dec2007, Posts dedicated to my family, my organisation Glenmark, Your readership keeps me going and brings smiles to my family
FAVIPIRAVIR
Toyama (Originator)
RNA-Directed RNA Polymerase (NS5B) Inhibitors
| Chemical Formula: | C5H4FN3O2 | |
| CAS #: | 259793-96-9 | |
| Molecular Weight: | 157.1 | |
Anti-influenza compound |
||
| clinical trials | http://clinicaltrials.gov/search/intervention=Favipiravir | |
| Chemical Name: | 6-fluoro-3-hydroxy-2-pyrazinecarboxamide | |
| Synonyms: | T-705, T705, Favipiravir |
T-705 is an RNA-directed RNA polymerase (NS5B) inhibitor which has been filed for approval in Japan for the oral treatment of influenza A (including avian and H1N1 infections) and for the treatment of influenza B infection.
The compound is a unique viral RNA polymerase inhibitor, acting on viral genetic copying to prevent its reproduction, discovered by Toyama Chemical. In 2005, Utah State University carried out various studies under its contract with the National Institute of Allergy and Infectious Diseases (NIAID) and demonstrated that T-705 has exceptionally potent activity in mouse infection models of H5N1 avian influenza.
T-705 (Favipiravir) is an antiviral pyrazinecarboxamide-based, inhibitor of of the influenza virus with an EC90 of 1.3 to 7.7 uM (influenza A, H5N1). EC90 ranges for other influenza A subtypes are 0.19-1.3 uM, 0.063-1.9 uM, and 0.5-3.1 uM for H1N1, H2N2, and H3N2, respectively. T-705 also exhibits activity against type B and C viruses, with EC90s of 0.25-0.57 uM and 0.19-0.36 uM, respectively. (1) Additionally, T-705 has broad activity against arenavirus, bunyavirus, foot-and-mouth disease virus, and West Nile virus with EC50s ranging from 5 to 300 uM.
Studies show that T-705 ribofuranosyl triphosphate is the active form of T-705 and acts like purines or purine nucleosides in cells and does not inhibit DNA synthesis
In 2012, MediVector was awarded a contract from the U.S. Department of Defense’s (DOD) Joint Project Manager Transformational Medical Technologies (JPM-TMT) to further develop T-705 (favipiravir), a broad-spectrum therapeutic against multiple influenza viruses.
Several novel anti-influenza compounds are in various phases of clinical development. One of these, T-705 (favipiravir), has a mechanism of action that is not fully understood but is suggested to target influenza virus RNA-dependent RNA polymerase. We investigated the mechanism of T-705 activity against influenza A (H1N1) viruses by applying selective drug pressure over multiple sequential passages in MDCK cells. We found that T-705 treatment did not select specific mutations in potential target proteins, including PB1, PB2, PA, and NP. Phenotypic assays based on cell viability confirmed that no T-705-resistant variants were selected. In the presence of T-705, titers of infectious virus decreased significantly (P < 0.0001) during serial passage in MDCK cells inoculated with seasonal influenza A (H1N1) viruses at a low multiplicity of infection (MOI; 0.0001 PFU/cell) or with 2009 pandemic H1N1 viruses at a high MOI (10 PFU/cell). There was no corresponding decrease in the number of viral RNA copies; therefore, specific virus infectivity (the ratio of infectious virus yield to viral RNA copy number) was reduced. Sequence analysis showed enrichment of G→A and C→T transversion mutations, increased mutation frequency, and a shift of the nucleotide profiles of individual NP gene clones under drug selection pressure. Our results demonstrate that T-705 induces a high rate of mutation that generates a nonviable viral phenotype and that lethal mutagenesis is a key antiviral mechanism of T-705. Our findings also explain the broad spectrum of activity of T-705 against viruses of multiple families.
favipiravir
Favipiravir also known as T-705 is an experimental anti-viral drug with activity against many RNA viruses. It, like some other experimental antiviraldrugs—T-1105 and T-1106, is apyrazinecarboxamide derivative. Favipiravir is active against influenza viruses, West Nile virus, yellow fever virus, foot-and-mouth disease virus as well as other flaviviruses, arenaviruses, bunyavirusesand alphaviruses.[1]
The mechanism of its actions is thought to be related to the selective inhibition of viral RNA-dependent RNA polymerase. Favipiravir does not inhibit RNA of DNA synthesis in mammalian cells and is not toxic to them.[1]
……………………………………………………………………………………
Influenza virus is a central virus of the cold syndrome, which has attacked human being periodically to cause many deaths amounting to tens millions. Although the number of deaths shows a tendency of decrease in the recent years owing to the improvement in hygienic and nutritive conditions, the prevalence of influenza is repeated every year, and it is apprehended that a new virus may appear to cause a wider prevalence.
For prevention of influenza virus, vaccine is used widely, in addition to which low molecular weight substances such as Amantadine and Ribavirin are also used
……………………………….
Synthesis of Favipiravir
ZHANG Tao1, KONG Lingjin1, LI Zongtao1,YUAN Hongyu1, XU Wenfang2*
(1. Shandong Qidu PharmaceuticalCo., Ltd., Linzi 255400; 2. School of Pharmacy, Shandong University, Jinan250012)
ABSTRACT: Favipiravir was synthesized from3-amino-2-pyrazinecarboxylic acid by esterification, bromination with NBS,diazotization and amination to give 6-bromo-3-hydroxypyrazine-2-carboxamide,which was subjected to chlorination with POCl3, fluorination with KF, andhydrolysis with an overall yield of about 22％.
………………………………..
| subs G1 | G2 | G3 | G4 | R2 |
| compd 32 N | CH | C—CF3 | N | H |
…………………
EP2192117
Example 1-1
To a 17.5 ml N,N-dimethylformamide solution of 5.0 g of 3,6-difluoro-2-pyrazinecarbonitrile, a 3.8 ml water solution of 7.83 g of potassium acetate was added dropwise at 25 to 35° C., and the solution was stirred at the same temperature for 2 hours. 0.38 ml of ammonia water was added to the reaction mixture, and then 15 ml of water and 0.38 g of active carbon were added. The insolubles were filtered off and the filter cake was washed with 11 ml of water. The filtrate and the washing were joined, the pH of this solution was adjusted to 9.4 with ammonia water, and 15 ml of acetone and 7.5 ml of toluene were added. Then 7.71 g of dicyclohexylamine was added dropwise and the solution was stirred at 20 to 30° C. for 45 minutes. Then 15 ml of water was added dropwise, the solution was cooled to 10° C., and the precipitate was filtered and collected to give 9.44 g of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyradinecarbonitrile as a lightly yellowish white solid product.
1H-NMR (DMSO-d6) δ values: 1.00-1.36 (10H, m), 1.56-1.67 (2H, m), 1.67-1.81 (4H, m), 1.91-2.07 (4H, m), 3.01-3.18 (2H, m), 8.03-8.06 (1H, m), 8.18-8.89 (1H, broad)
Example 1-2
4.11 ml of acetic acid was added at 5 to 15° C. to a 17.5 ml N,N-dimethylformamide solution of 5.0 g of 3,6-difluoro-2-pyrazinecarbonitrile. Then 7.27 g of triethylamine was added dropwise and the solution was stirred for 2 hours. 3.8 ml of water and 0.38 ml of ammonia water were added to the reaction mixture, and then 15 ml of water and 0.38 g of active carbon were added. The insolubles were filtered off and the filter cake was washed with 11 ml of water. The filtrate and the washing were joined, the pH of the joined solution was adjusted to 9.2 with ammonia water, and 15 ml of acetone and 7.5 ml of toluene were added to the solution, followed by dropwise addition of 7.71 g of dicyclohexylamine. Then 15 ml of water was added dropwise, the solution was cooled to 5° C., and the precipitate was filtered and collected to give 9.68 g of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile as a slightly yellowish white solid product.
Examples 2 to 5
The compounds shown in Table 1 were obtained in the same way as in Example 1-1.
| TABLE 1 | |||
 |
|||
| Example No. | Organic amine | Example No. | Organic amine |
| 2 | Dipropylamine | 4 | Dibenzylamine |
| 3 | Dibutylamine | 5 | N-benzylmethylamine |
Dipropylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile
1H-NMR (DMSO-d6) 6 values: 0.39 (6H, t, J=7.5 Hz), 1.10 (4H, sex, J=7.5 Hz), 2.30-2.38 (4H, m), 7.54 (1H, d, J=8.3 Hz)
Dibutylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile
1H-NMR (DMSO-d6) 6 values: 0.36 (6H, t, J=7.3 Hz), 0.81 (4H, sex, J=7.3 Hz), 0.99-1.10 (4H, m), 2.32-2.41 (4H, m), 7.53 (1H, d, J=8.3 Hz)
Dibenzylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile
1H-NMR (DMSO-d6) δ values: 4.17 (4H, s), 7.34-7.56 (10H, m), 8.07 (1H, d, J=8.3 Hz)
N-benzylmethylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile
1H-NMR (DMSO-d6) δ values: 2.57 (3H, s), 4.14 (2H, s), 7.37-7.53 (5H, m), 8.02-8.08 (1H, m)
Preparation Example 1
300 ml of toluene was added to a 600 ml water solution of 37.5 g of sodium hydroxide. Then 150 g of dicyclohexylamine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile was added at 15 to 25° C. and the solution was stirred at the same temperature for 30 minutes. The water layer was separated and washed with toluene, and then 150 ml of water was added, followed by dropwise addition of 106 g of a 30% hydrogen peroxide solution at 15 to 30° C. and one-hour stirring at 20 to 30° C. Then 39 ml of hydrochloric acid was added, the seed crystals were added at 40 to 50° C., and 39 ml of hydrochloric acid was further added dropwise at the same temperature. The solution was cooled to 10° C. the precipitate was filtered and collected to give 65.6 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a slightly yellowish white solid.
1H-NMR (DMSO-d6) δ values: 8.50 (1H, s), 8.51 (1H, d, J=7.8 Hz), 8.75 (1H, s), 13.41 (1H, s)
………………….
jan 2014
Investigational flu treatment drug has broad-spectrum potential to fight multiple viruses
First patient enrolled in the North American Phase 3 clinical trials for investigational flu treatment drug
BioDefense Therapeutics (BD Tx)—a Joint Product Management office within the U.S. Department of Defense (DoD)—announced the first patient enrolled in the North American Phase 3 clinical trials for favipiravir (T-705a). The drug is an investigational flu treatment candidate with broad-spectrum potential being developed by BD Tx through a contract with Boston-based MediVector, Inc.
Favipiravir is a novel, antiviral compound that works differently than anti-flu drugs currently on the market. The novelty lies in the drug’s selective disruption of the viralRNA replication and transcription process within the infected cell to stop the infection cycle.
“Favipiravir has proven safe and well tolerated in previous studies,” said LTC Eric G. Midboe, Joint Product Manager for BD Tx. “This first patient signifies the start of an important phase in favipiravir’s path to U.S. Food and Drug Administration (FDA) approval for flu and lays the groundwork for future testing against other viruses of interest to the DoD.”
In providing therapeutic solutions to counter traditional, emerging, and engineered biological threats, BD Tx chose favipiravir not only because of its potential effectiveness against flu viruses, but also because of its demonstrated broad-spectrum potential against multiple viruses. In addition to testing favipiravir in the ongoing influenzaprogram, BD Tx is testing the drug’s efficacy against the Ebola virus and other viruses considered threats to service members. In laboratory testing, favipiravir was found to be effective against a wide variety of RNA viruses in infected cells and animals.
“FDA-approved, broad-spectrum therapeutics offer the fastest way to respond to dangerous and potentially lethal viruses,” said Dr. Tyler Bennett, Assistant Product Manager for BD Tx.
MediVector is overseeing the clinical trials required by the FDA to obtain drug licensure. The process requires safety data from at least 1,500 patients treated for flu at the dose and duration proposed for marketing of the drug. Currently, 150 trial sites are planned throughout the U.S.
SOURCE BioDefense Therapeutics
Malpani Y, Achary R, Kim SY, Jeong HC, Kim P, Han SB, Kim M, Lee CK, Kim JN, Jung YS.
Eur J Med Chem. 2013 Apr;62:534-44. doi: 10.1016/j.ejmech.2013.01.015. Epub 2013 Jan 29.
| US3631036 * | Nov 4, 1969 | Dec 28, 1971 | American Home Prod | 5-amino-2 6-substituted-7h-pyrrolo(2 3-d) pyrimidines and related compounds |
| US3745161 * | Apr 20, 1970 | Jul 10, 1973 | Merck & Co Inc | Phenyl-hydroxy-pyrazine carboxylic acids and derivatives |
| US4404203 * | May 14, 1981 | Sep 13, 1983 | Warner-Lambert Company | Substituted 6-phenyl-3(2H)-pyridazinones useful as cardiotonic agents |
| US4545810 * | Mar 25, 1983 | Oct 8, 1985 | Sds Biotech Corporation | Herbicidal and plant growth regulant diphenylpyridazinones |
| US4565814 * | Jan 18, 1984 | Jan 21, 1986 | Sanofi | Pyridazine derivatives having a psychotropic action and compositions |
| US4661145 * | Sep 20, 1984 | Apr 28, 1987 | Rohm And Haas Company | Plant growth regulating 1-aryl-1,4-dihydro-4-oxo(thio)-pyridazines |
| US5420130 | May 16, 1994 | May 30, 1995 | Synthelabo | 2-aminopyrazine-5-carboxamide derivatives, their preparation and their application in therapeutics |
| US5459142 * | Aug 23, 1993 | Oct 17, 1995 | Otsuka Pharmaceutical Co., Ltd. | Pyrazinyl and piperazinyl substituted pyrazine compounds |
| US5597823 | Jun 5, 1995 | Jan 28, 1997 | Abbott Laboratories | Tricyclic substituted hexahydrobenz [e]isoindole alpha-1 adrenergic antagonists |
| US6159980 * | Sep 15, 1997 | Dec 12, 2000 | Dupont Pharmaceuticals Company | Pyrazinones and triazinones and their derivatives thereof |
| EP0023358A1 * | Jul 28, 1980 | Feb 4, 1981 | Rohm And Haas Company | Process for the preparation of pyridazine derivatives |
| GB1198688A | Title not available | |||
| HU9401512A | Title not available | |||
| JPH09216883A * | Title not available | |||
| JPS5620576A | Title not available |
THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D
GLENMARK SCIENTIST , NAVIMUMBAI, INDIA
did you feel happy, a head to toe paralysed man’s soul in action for you round the clock
need help, email or call me
I was paralysed in dec2007, Posts dedicated to my family, my organisation Glenmark, Your readership keeps me going and brings smiles to my family
suramin
A polyanionic compound with an unknown mechanism of action. It is used parenterally in the treatment of African trypanosomiasis and it has been used clinically with diethylcarbamazine to kill the adult Onchocerca. (From AMA Drug Evaluations Annual, 1992, p1643) It has also been shown to have potent antineoplastic properties.
A polyanionic compound with an unknown mechanism of action. It is used parenterally in the treatment of African trypanosomiasis and it has been used clinically with diethylcarbamazine to kill the adult Onchocerca. (From AMA Drug Evaluations Annual, 1992, p1643) It has also been shown to have potent antineoplastic properties. Suramin is manufactured by Bayer in Germany as Germanin®.
Also known as: Naphuride, Germanin, Naganol, Belganyl, Fourneau, Farma, Antrypol, Suramine, Naganin
8,8′-{Carbonylbis[imino-3,1-phenylenecarbonylimino(4-methyl-3,1-phenylene)carbonylimino]}di(1,3,5-naphthalenetrisulfonic acid) …FREE FORM
8,8′-[Ureylenebis[m-phenylenecarbonylimino(4-methyl-m-phenylene)carbonylimino]]di(1,3,5-naphthalenetrisulfonic acid) hexasodium salt
CAS 145-63-1 FREE FORM
129-46-4 of hexa sodium
LAUNCHED 1940 BAYER
| Formula | C51H40N6O23S6 |
|---|---|
| Mol. mass | 1297.29 |
The molecular formula of suramin is C51H34N6O23S6. It is a symmetric molecule in the center of which lies urea, NH-CO-NH. Suramin contains eightbenzene rings, four of which are fused in pairs (naphthalene), four amide groups in addition to the one of urea and six sulfonate groups. When given as drug it usually contains six sodium ions that form a salt with the six sulfonate groups.
Suramin is a drug developed by Oskar Dressel and Richard Kothe of Bayer, Germany in 1916, and is still sold by Bayer under the brand nameGermanin.
Suramin sodium is a heparanase inhibitor that was first launched in 1940 by Bayer under the brand name Antrypol for the treatment of helminthic infection. It was later launched by Bayer for the treatment of trypanosomiasis (African sleeping sickness).
More recently, the product has entered early clinical development at Ohio State University for the treatment of platinum-pretreated patients with stage IIIB/IV non-small cell lung cancer, in combination with docetaxel or gemcitabine.
The National Cancer Institute (NCI) is conducting phase II clinical studies for the treatment of glioblastoma multiforme and for the treatment of adrenocortical carcinoma.
According to the National Cancer Institute there are no active clinical trials (as of April 1, 2008). Completed and closed clinical trials are listed here:[1]
In addition to Germanin, the National Cancer Institute also lists the following “Foreign brand names”: 309 F or 309 Fourneau,[1] Bayer 205, Moranyl, Naganin, Naganine.
It is used for treatment of human sleeping sickness caused by trypanosomes.[2]
Also, suramin as treatment for autism is being evaluated. [5]
Kidney damage and exfoliative dermatitis occur less commonly.
Suramin has been applied clinically to HIV/AIDS patients resulting in a significant number of fatal occurrences and as a result the application of this molecule was abandoned for this condition. http://www.ncbi.nlm.nih.gov/pubmed/3548350
Suramin is also used in research as a broad-spectrum antagonist of P2 receptors[6][7] and agonist of Ryanodine receptors.[8]
suramin
Its effect on telomerase has been investigated.[9]
It may have some activity against RNA viruses.[10]
In addition to antagonism of P2 receptors, Suramin inhibits the acitivation of heterotrimeric G proteins in a variety of other GPCRs with varying potency. It prevents the association of heteromeric G proteins and therefore the receptors Guanine exchange functionality (GEF). With this blockade the GDP will not release from the Gα subunit so it can not be replaced by a GTP and become activated. This has the effect of blocking downstream G protein mediated signaling of various GPCR proteins including Rhodopsin, the A1 Adenosine receptor, and the D2 dopamine receptor.[11]
A polyanionic compound with an unknown mechanism of action. It is used parenterally in the treatment of African trypanosomiasis and it has been used clinically with diethylcarbamazine to kill the adult Onchocerca. (From AMA Drug Evaluations Annual, 1992, p1643) It has also been shown to have potent antineoplastic properties. Suramin is manufactured by Bayer in Germany as Germanin®.
|
8-1-2012
|
InCl3-catalysed synthesis of 2-aryl quinazolin-4(3H)-ones and 5-aryl pyrazolo[4,3-d]pyrimidin-7(6H)-ones and their evaluation as potential anticancer agents.
|
Bioorganic & medicinal chemistry letters
|
|
9-1-2012
|
Identification of a sirtuin 3 inhibitor that displays selectivity over sirtuin 1 and 2.
|
European journal of medicinal chemistry
|
|
1-1-2013
|
Inhibition of the human deacylase Sirtuin 5 by the indole GW5074.
|
Bioorganic & medicinal chemistry letters
|
|
5-9-2013
|
Discovery of thieno[3,2-d]pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2, and SIRT3.
|
Journal of medicinal chemistry
|
SURAMIN
Enterovirus-71 (EV71) is one of the major causative reagents for hand-foot-and-mouth disease. In particular, EV71 causes severe central nervous system infections and leads to numerous dead cases. Although several inactivated whole-virus vaccines have entered in clinical trials, no antiviral agent has been provided for clinical therapy. In the present work, we screened our compound library and identified that suramin, which has been clinically used to treat variable diseases, could inhibit EV71 proliferation with an IC50 value of 40μM. We further revealed that suramin could block the attachment of EV71 to host cells to regulate the early stage of EV71 infection, as well as affected other steps of EV71 life cycle. Our results are helpful to understand the mechanism for EV71 life cycle and provide a potential for the usage of an approved drug, suramin, as the antiviral against EV71 infection.
Synonyms
Suramin Sodium, is an anticancer agent with a wide variety of activities.
Recently suramin was shown to inhibit FSH binding to its receptor (Daugherty, R. L.; Cockett, A. T. K.; Schoen, S. R. and Sluss, P. M. “Suramin inhibits gonadotropon action in rat testis: implications for treatment of advanced prostate cancer” J. Urol. 1992, 147, 727-732).
This activity causes, at least in part, the decrease in testosterone production seen in rats and humans that were administered suramin(Danesi, R.; La Rocca, R. V.; Cooper, M. R.; Ricciardi, M. P.; Pellegrini, A.; Soldani, P.; Kragel, P. J.; Paparelli, A.; Del Tacca, M.; Myers, C. E, “Clinical and experimental evidence of inhibition of testosterone production by suramin.” J. Clin. Endocrinol. Metab. 1996, 81, 2238-2246).
Suramin is the only non-peptidic small molecule that has been reported to be an FSH receptor binding antagonist.
Suramin is 8,8′ – (carbonylbis(imino-3,1-phenylenecarbonylimino (4-methyl-3,1-phenylene) carbonylimino)) bis-1,3 ,5-naphthalenetrisulfonic acid (GB Patent No. 224849). This polyanionic compound has been used for many decades as a prophylactic and therapeutic agent for try- panosomiasis. It was subsequently shown that suramin is able to block the activity of a variety of proteins like cellular and viral enzymes and growth factors (Mitsuya, M. et al. Science 226 : 172 (1984), Hosang, M. J. Cell. Biochem. 29 : 265 (1985), De Clercq, E. Cancer Lett. 8 : 9 (1979)).
|
5-32-1977
|
Complement inhibitors
|
|
|
5-25-1977
|
Aromatic amidines as antiviral agents in animals
|
|
|
5-4-1977
|
Complement inhibitors
|
|
|
5-4-1977
|
Complement inhibitors
|
|
|
4-27-1977
|
Cyclodextrin sulfate salts as complement inhibitors
|
|
|
4-20-1977
|
Ureylenebis methyl-phenylene-carbonyl-bis-dihydro-2-oxo-naphthoxazine disultonic acids
|
|
|
3-30-1977
|
Water treatment for controlling the growth of algae employing biguanides
|
|
|
3-2-1977
|
Isoxazole substituted nitroimidazoles
|
|
|
2-16-1977
|
Amidophenyl-azo-naphthalenesulfonic complement inhibitors and method of use thereof
|
|
|
2-9-1977
|
Complement inhibitors
|
|
2-10-2011
|
MODULATION OF HUMAN MAST CELL ACTIVATION MODULATION OF HUMAN MAST CELL ACTIVATION
|
|
|
11-18-2010
|
Admixtures for inorganic binders based on a hydrogenated disaccharide, inorganic binders containing these admixtures and process for their preparation Admixtures for inorganic binders based on a hydrogenated disaccharide, inorganic binders containing these admixtures and process for their preparation
|
|
|
10-28-2010
|
THERAPEUTIC INHIBITORS OF VASCULAR SMOOTH MUSCLE CELLS
|
|
|
9-9-2010
|
APPARATUS FOR USING ELECTROPORATION MEDIATED DELIVERY OF DRUGS AND GENES
|
|
|
4-8-2010
|
PREPARATION AND USE OF SULFATED OLIGOSACCHARIDES
|
|
|
10-29-2009
|
THERAPEUTIC INHIBITOR OF VASCULAR SMOOTH MUSCLE CELLS THERAPEUTIC INHIBITOR OF VASCULAR SMOOTH MUSCLE CELLS
|
|
|
8-20-2009
|
METHOD OF MAKING MINERAL FIBRES METHOD OF MAKING MINERAL FIBRES
|
|
|
6-25-2009
|
OXYGEN-FUEL BOOST REFORMER PROCESS AND APPARATUS
|
|
|
4-23-2009
|
METHODS OF TREATING VASCULAR DISEASE WITH TNF ANTAGONISTS METHODS OF TREATING VASCULAR DISEASE WITH TNF ANTAGONISTS
|
|
|
3-26-2009
|
COPOLYMER COMPOSITIONS FOR ORAL DELIVERY
|
|
5-3-1978
|
1,3,5- Or 1,3,6-naphthalenetriyltris(sulfonylimino)aryl acids and salts
|
|
|
3-22-1978
|
Nitroimidazoles
|
|
|
2-15-1978
|
Treatment of rheumatoid arthritis and related diseases
|
|
|
1-4-1978
|
AROMATIC AMIDINES AS ANTIVIRAL AGENTS IN ANIMALS
|
|
|
1-4-1978
|
Malto-dextrin poly(H-)sulfates
|
|
|
12-14-1977
|
Disazo compounds useful as complement inhibitors
|
|
|
12-7-1977
|
Bis-substituted naphthalene-azo phenyleneazo-stilbene-disulfonic and naphthalene-sulfonic acid
|
|
|
9-28-1977
|
UREIDOPHENYLENEBIS(CARBONYLIMINO)DINAPHTHALENETRISULFONIC ACID COMPOUNDS
|
|
|
9-21-1977
|
Substituted bisnaphthylazo diphenyl ureido complement inhibitors
|
|
|
9-7-1977
|
Substituted-hydroxy-naphthalenedisulfonic acid compounds
|
|
1-12-1977
|
Complement inhibitors
|
|
|
12-22-1976
|
Complement inhibitors
|
|
|
10-13-1976
|
Complement inhibitors
|
| EP0183352A2 * | Sep 27, 1985 | Jun 4, 1986 | THE UNITED STATES OF AMERICA as represented by the Secretary United States Department of Commerce | Use of suramin for clinical treatment of infection with any of the members of the family of human-t-cell leukemia (htvl) viruses including lymphadenopathy virus (lav) |
| EP0205077A2 * | Jun 3, 1986 | Dec 17, 1986 | Bayer Ag | Suramin sodium for use as an immunostimulant |
| EP0515523A1 * | Feb 13, 1991 | Dec 2, 1992 | THE UNITED STATES OF AMERICA as represented by the Secretary United States Department of Commerce | Use of suramin to treat rheumatologic diseases |
| EP0755254A1 * | Mar 24, 1995 | Jan 29, 1997 | The Trustees Of The University Of Pennsylvania | Prevention and treatment of ischemia-reperfusion and endotoxin-related injury using adenosine and purino receptor antagonists |
| EP1460087A1 * | Feb 17, 1997 | Sep 22, 2004 | The Kennedy Institute Of Rheumatology | Methods of treating vascular disease with TNF antagonists |
| EP1940376A2 * | Oct 3, 2006 | Jul 9, 2008 | Rottapharm S.P.A. | Use of neboglamine in the treatment of toxicodependency |
| EP1945204A2 * | Oct 27, 2006 | Jul 23, 2008 | Brane Discovery S.R.L. | V-atpase inhibitors for use in the treatment of septic shock |
| US5453444 * | Oct 6, 1994 | Sep 26, 1995 | Otsuka Pharmaceutical Co., Ltd. | Method to mitigate or eliminate weight loss |
| US5534539 * | Jun 12, 1995 | Jul 9, 1996 | Farmitalia Carlo Erba S.R.L. | Biologically active ureido derivatives useful as anit-metastic agenst |
| US5596105 * | Jan 13, 1995 | Jan 21, 1997 | Farmitalia Carlo Erba S.R.L. | Therapeutically active naphthalenesulfonic pyrrolecarboxamido derivatives |
| US7476693 | Mar 26, 2003 | Jan 13, 2009 | Eastern Virginia Medical School | Suramin and derivatives thereof as topical microbicide and contraceptive |
| US7608262 | Feb 16, 1996 | Oct 27, 2009 | The Kennedy Institute Of Rheumatology | Methods of preventing or treating thrombosis with tumor necrosis factor antagonists |
| US8552064 | Dec 19, 2008 | Oct 8, 2013 | Eastern Virginia Medical School | Suramin and derivatives thereof as topical microbicide and contraceptive |
| WO1994008574A1 * | Oct 12, 1993 | Apr 28, 1994 | Otsuka America Pharmaceutical | Treatment of cachexia and inhibition of il-6 activity |
| WO1994010990A1 * | Nov 12, 1993 | May 26, 1994 | British Bio Technology | Inhibition of tnf production |
| WO1997030088A2 * | Feb 17, 1997 | Aug 21, 1997 | Kennedy Inst Of Rheumatology | Methods of treating vascular disease with tnf antagonists |
| WO2004113920A1 * | Jun 18, 2004 | Dec 29, 2004 | Babon Jeff James | Screening method for substances binding to merozoite surface protein-1/42 |
| WO2008138943A2 * | May 14, 2008 | Nov 20, 2008 | Mara Galli | Prophylactic and therapeutic use of sirtuin inhibitors in tnf-alpha mediated pathologies |
| WO2009137471A2 * | May 5, 2009 | Nov 12, 2009 | University Of Miami | Azo dye related small molecule modulators of protein-protein interactions |
| WO2010016628A1 * | Jul 10, 2009 | Feb 11, 2010 | Sammy Opiyo | Conjugated suramin amino compounds for medical conditions |
| WO2012159107A1 * | May 21, 2012 | Nov 22, 2012 | Rhode Island Hospital | Inhibition of renal fibrosis |
THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D
GLENMARK SCIENTIST , NAVIMUMBAI, INDIA
did you feel happy, a head to toe paralysed man’s soul in action for you round the clock
need help, email or call me
I was paralysed in dec2007, Posts dedicated to my family, my organisation Glenmark, Your readership keeps me going and brings smiles to my family
CASOPITANT
Tachykinin NK1 Antagonists
(2S,4S)-4-(4-Acetyl-1-piperazinyl)-N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-N-methyl-1-piperidinecarboxamide
4-(S)-(4-Acetyl-piperazin-1-yl)-2- (R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid, [1-(R)-(3,5-bis-trifluoromethyl- phenyl)-ethyl]-methylamide
414910-30-8 MESYLATE
414910-27-3 (free base)
679769
GW-679769
GW-679769B
| MF C30H35F7N4O2.CH4O3S MESYLATE | |
| Molecular Weight | 712.719 |
Casopitant (trade names Rezonic (US), Zunrisa (EU)) is an neurokinin 1 (NK1) receptor antagonist undergoing research for the treatment of chemotherapy-induced nausea and vomiting (CINV).[1] It is currently under development by GlaxoSmithKline (GSK).
In July 2008, the company filed a marketing authorisation application with the European Medicines Agency. The application was withdrawn in September 2009 because GSK decided that further safety assessment was necessary.[2] Casopitant mesylate, a tachykinin NK1 receptor antagonist, had been filed for approval in the U.S. and the E.U. by GlaxoSmithKline for the prophylaxis of chemotherapy-induced nausea/vomiting.
In 2009 the company discontinued the development of the drug candidate for this indication. An MAA had also been filed for the treatment of postoperative nausea and vomiting, and in 2009 the application was withdrawn by the company.
Additional phase II clinical trials were ongoing at GlaxoSmithKline for the treatment of depression, anxiety, sleep disorders, fibromyalgia and overactive bladder, however, no recent developments have been reported for these indications.
| WO2006061233A1 * | Dec 7, 2005 | Jun 15, 2006 | Glaxo Group Ltd | The use of medicament 4-(s)-(4-acetyl-piperazin-1-yl)-2-(r)-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid, [1-(r)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide |
| WO2001044200A2 * | Dec 14, 2000 | Jun 21, 2001 | David J Blythin | Selective neurokinin antagonists |
| WO2002010141A1 * | Jul 25, 2001 | Feb 7, 2002 | Michael Kirk Ahlijanian | Imidazole derivatives |
| WO2002032867A1 * | Oct 12, 2001 | Apr 25, 2002 | Giuseppe Alvaro | Chemical compounds |
| US20020123491 * | Dec 14, 2000 | Sep 5, 2002 | Neng-Yang Shih | Selective neurokinin antagonists |
| US20030064980 * | Jun 6, 2002 | Apr 3, 2003 | Neng-Yang Shih | Selective neurokinin antagonists |
| US20030144270 * | Nov 12, 2002 | Jul 31, 2003 | Schering Corporation | NK1 antagonists |
Casopitant (Rezonic, Zunrisa, casopitant mesylate, GW-679769, 679769, CAS #414910-27-3), 4-(4-Acetyl-piperazin-1-yl)-2-(4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid [1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide, is a NK-1 receptor antagonist.
Casopitant is under investigation for the treatment of emesis, nausea, drug-induced nausea, chemotherapy-induced nausea and vomiting, post-operative nausea and vomiting, sleep disorders, anxiety disorders, depressive disorders, overactive bladder, and myalgia (Drug Report for Casopitant, Thomson Investigational Drug Database (Sep. 15, 2008); Reddy et al., Supportive Cancer Therapy 2006, 3(3), 140-142; and WO 2006/061233).
Casopitant has also shown promise in treating disorders of the central nervous system, tinitis, and sexual dysfunction (WO 2006/061233).
compound may be of value in the treatment of Sexual dysfunctions including Sexual Desire Disorders such as Hypoactive Sexual Desire Disorder and Sexual Aversion Disorder sexual arousal disorders such as Female Sexual Arousal Disorder and Male Erectile Disorder orgasmic disorders such as Female Orgasmic Disorder, Male Orgasmic Disorder and Premature Ejaculation sexual pain disorder such as Dyspareunia and Vaginismus, Sexual Dysfunction Not Otherwise Specified; paraphilias such as Exhibitionism, Fetishism, Frotteurism, Pedophilia, Sexual Masochism, Sexual Sadism Transvestic Fetishism, Voyeurism and Paraphilia Not Otherwise Specified gender identity disorders such as Gender Identity Disorder in Children and Gender Identity Disorder in Adolescents or Adults and Sexual Disorder Not Otherwise Specified.
Casopitant is subject to CYP3A4-mediated oxidative metabolism at the 3-carbon of the piperazine ring to form a hydroxylated metabolite which may be further oxidized to the corresponding 3-oxo metabolite (Minthorn et al, Drug Metab. Disp., 2008, 36(9), 1846-1852). Adverse effects associated with casopitantadministration include: neutropenia, nausea, hiccups, headache, constipation, dizziness, pruritis, alopecia, and fatigue.
Overactive bladder is a term for a syndrome that encompasses urinary frequency, with or without urge incontinence, generally but not necessarily combined with pollacisuria and nocturia. Overactive bladder is also characterised by involuntary detrusor contractions which are either triggered by provocation or occur spontaneously. If the detrusor hyperactivity observed is based on neurological causes (e. g. Parkinson’s disease, apoplexy, some forms of multiple sclerosis, spinal cord injury or the cross section of the bone marrow) it is known as neurogenic detrusor hyperactivity. If no clear cause can be detected this is known as idiopathic detrusor hyperactivity. In addition, detrusor hyperactivity may be associated with anatomical changes in the lower urinary tract, for example, in patients with bladder outlet obstruction (an enlargement of the prostate gland in males)
International patent application WO 02/32867 describes novel piperidine derivatives. A 0 particular preferred compound described therein is 4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)- (4-fluoro-2-methyl-phenyl)-piperidine-1-carboxylic acid
…………………………………………………………………
CASOPITANT MESYLATE
EXAMPLE 4
[0330] 4-(S)-(4-Acetyl-piperazin-1-yl)-2-(R)-(4-fluoro-2-methyl-phenyl)-piperidine-1-Carboxylic Acid, [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide Methanesulphonate
[0331] A solution of intermediate 4a (7.7 g) in acetonitrile (177 mL) was added to a solution of 1-acetyl-piperazine (3.9 g) in acetonitrile (17.7 mL) followed by sodium triacetoxyborohydride (6.4 g) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 24 hours and then quenched with a saturated sodium hydrogen carbonate (23.1 mL) and water (61.6 mL). The resulting solution was concentrated in vacuo, then AcOEt (208 mL) was added; the layers were separated and the aqueous layer was back-extracted with further AcOEt (2×77 mL). The collected organic phases were washed with brine (2×118 mL), dried and concentrated in vacuo to give the crude mixture of syn and anti diastereomers (nearly 1:1) as a white foam (9.5 g).
[0332] A solution of this intermediate in THF (85.4 mL) was added to a solution of methansulfonic acid (0.890 mL) in THF (6.1 mL) at r.t. After seeding, the desired syn diastereomer started to precipitate. The resulting suspension was stirred for 3 hours at 0° C. and then filtered under a nitrogen atmosphere. The resulting cake was washed with cold THF (15.4 mL) and dried in vacuo at +20° C. for 48 hours to give the title compound as a white solid (4.44 g).
[0333] NMR (d6-DMSO): δ (ppm) 9.52 (bs, 1H); 7.99 (bs, 1H); 7.68 (bs, 2H); 7.23 (m, 1H); 6.95 (dd, 1H); 6.82 (m, 1H); 5.31 (q, 1H); 4.45 (bd, 1H); 4.20 (dd, 1H); 3.99 (bd, 1H); 3.65-3.25 (bm, 5H); 3.17 (m, 1H); 2.96 (m, 1H); 2.88-2.79 (m+m, 2H); 2.73 (s, 3H); 2.36 (s, 3H); 2.30 (s, 3H); 2.13-2.09 (bd+bd, 2H); 2.01 (s, 3H); 1.89-1.73 (m+m, 2H); 1.46 (d, 3H).
[0334] m.p 243.0° C.
[0335] The compound is isolated in a crystalline form.
intermediate 4a is needed for above syn, ignore 4b
[0168] Intermediate 4
[0169] 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-1-Carboxylic Acid, [1-(R)-3,5-bis-trifluoromethyl-phenyl)ethyl]-Methylamide (4a) and 2-(S)-(4-Fluoro-2-methyl-phenyl)-4-oxo-piperidine-1-Carboxylic Acid, [1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-Methylamide (4b) Method A
[0170] A solution of triphosgene (147 mg) dissolved in dry DCM (5 mL) was added drop-wise to a solution of intermediate 2 (250 mg) and DIPEA (860 μL) in dry DCM (15 mL) previously cooled to 0° C. under a nitrogen atmosphere. After 2 hours, [1-(R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamine hydrochloride (503 mg) and DIPEA (320 μL) in dry acetonitrile (20 mL) were added and the mixture was heated to 70° C. for 16 hours. Further [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamine hydrochloride (170 mg) and DIPEA (100 μL) were added and the mixture was stirred at 70° C. for further 4 hours. Next, the mixture was allowed to cool to r.t., taken up with AcOEt (30 mL), washed with a 1N hydrochloric acid cold solution (3×15 mL) and brine (2×10 mL). The organic layer was dried and concentrated in vacuo to a residue, which was purified by flash chromatography (CH/AcOEt 8:2) to give:
[0171] 1. intermediate 4a (230 mg) as a white foam,
[0172] 2. intermediate 4b (231 mg) as a white foam. …………….ignore
[0173] Intermediate 4a
[0174] NMR (d6-DMSO): δ (ppm) 7.98 (bs, 1H); 7.77 (bs, 2H); 7.24 (dd, 1H); 6.97 (dd, 1H); 6.89 (m, 1H); 5.24 (t, 1H); 5.14 (q, 1H); 3.61 (m, 1H); 3.55 (m, 1H); 2.71 (m, 2H); 2.56 (s, 3H); 2.50 (m, 2H); 2.26 (s, 3H); 1.57 (d, 3H).
[0175] Intermediate 4b
[0176] NMR (d6-DMSO): δ (ppm) 7.96 (bs, 1H); 7.75 (bs, 2H); 7.24 (dd, 1H); 6.98 (dd, 1H); 6.93 (dt, 1H); 5.29 (q, 1H); 5.24 (t, 1H); 3.56 (m, 1H); 3.48 (m, 1H); 2.70 (s, 3H); 2.50 (m, 4H); 2.26 (s, 3H); 1.54 (d, 3H). …….. ignore
[0177] Intermediate 4a
[0178] Method B
[0179] A saturated sodium hydrogen carbonate solution (324 mL) was added to a solution of intermediate 9 (21.6 g) in AcOEt (324 mL) and the resulting mixture was vigorously stirred for 15 minutes. The aqueous layer was back-extracted with further AcOEt (216 mL) and the combined organic extracts were dried and concentrated in vacuo to give intermediate 8 as a yellow oil, which was treated with TEA (19 mL) and AcOEt (114 mL). The solution obtained was added drop-wise over 40 minutes to a solution of triphosgene (8 g) in AcOEt (64 mL) previously cooled to 0° C. under a nitrogen atmosphere, maintaining the temperature between 0° C. and 8° C.
[0180] After stirring for 1 hours at 0° C. and for 3 hours at 20° C., [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamine hydrochloride (29.7 g), AcOEt (190 mL) and TEA (38 mL) were added to the reaction mixture which was then heated to reflux for 16 hours.
[0181] The solution was washed with 10% sodium hydroxide solution (180 mL), 1% hydrochloric acid solution (4×150 mL), water (3×180 mL) and brine (180 mL). The organic layer was dried and concentrated in vacuo to a residue, which was purified through a silica pad (CH/AcOEt 9:1) to give the title compound (21.5 g) as a brown thick oil.
[0182] NMR (d6-DMSO): 6 (ppm) 7.97-7.77 (bs+bs, 3H); 7.24 (dd, 1H); 6.97 (dd, 1H); 6.88 (td, 1H); 5.24 (m, 1H); 5.14 (q, 1H); 3.58 (m, 2H); 2.7 (m, 2H); 2.56 (s, 3H); 2.49 (m, 2H); 2.26 (s, 3H); 1.57 (d, 3H).
intermediate 2
[0152] Intermediate 2
[0153] 2-(4-Fluoro-2-methyl-phenyl)-piperidine-4-one
[0154] Method A
[0155] 2-Methyl-4-fluoro-benzaldehyde (4 g) was added to a solution of 4-aminobutan-2-one ethylene acetal (3.8 g) in dry benzene (50 mL) and the solution was stirred at r.t. under a nitrogen atmosphere. After 1 hour the mixture was heated at reflux for 16 hours and then allowed to cool to r.t. This solution was slowly added to a refluxing solution of p-toluensulphonic acid (10.6 g) in dry benzene (50 mL) previously refluxed for 1 hour with a Dean-Stark apparatus. After 3.5 hours the crude solution was cooled and made basic with a saturated potassium carbonate solution and taken up with AcOEt (50 mL). The aqueous phase was extracted with AcOEt (3×50 mL) and Et2O (2×50 mL). The organic layer was dried and concentrated in vacuo to a yellow thick oil as residue (7.23 g). A portion of the crude mixture (3 g) was dissolved in a 6N hydrochloric acid solution (20 mL) and stirred at 60° C. for 16 hours. The solution was basified with solid potassium carbonate and extracted with DCM (5×50 mL). The combined organic phases were washed with brine (50 mL), dried and concentrated in vacuo to give the title compound (2.5 g) as a thick yellow oil.
[0156] Method B
[0157] L-selectride (1M solution in dry THF, 210 mL) was added drop-wise, over 80 minutes, to a solution of intermediate 1 (50 g) in dry THF (1065 mL) previously cooled to −72° C. under a nitrogen atmosphere. After 45 minutes, 2% sodium hydrogen carbonate solution (994 mL) was added drop-wise and the solution was extracted with AcOEt (3×994 mL). The combined organic phases were washed with water (284 mL) and brine (568 mL). The organic phase was dried and concentrated in vacuo to get 1-benzyloxycarbonyl-2-(4-fluoro-2-methyl-phenyl)-piperidine-4-one as a pale yellow thick oil (94 g) which was used as a crude.
[0158] This material (94 g) was dissolved in AcOEt (710 mL), then 10% Pd/C (30.5 g) was added under a nitrogen atmosphere. The slurry was hydrogenated at 1 atmosphere for 30 minutes. The mixture was filtered through Celite and the organic phase was concentrated in vacuo to give the crude 2-(4-fluoro-2-methyl-phenyl)-piperidine-4-one as a yellow oil. This material was dissolved in AcOEt (518 mL) at r.t. and racemic camphorsulphonic acid (48.3 g) was added. The mixture was stirred at r.t for 18 hours, then the solid was filtered off, washed with AcOEt (2×50 mL) and dried in vacuo for 18 hours to give 2-(4-fluoro-2-methyl-phenyl)-piperidine-4-one, 10-camphorsulfonic acid salt as a pale yellow solid (68.5 g). (M.p.: 167-169° C.-NMR (d6-DMSO): 6 (ppm) 9.43 (bs, 1H); 9.23 (bs, 1H); 7.66 (dd, 1H); 7.19 (m, 2H); 4.97 (bd, 1H); 3.6 (m, 2H); 2.87 (m, 3H); 2.66 (m, 1H); 2.53 (m, 2H); 2.37 (s+d, 4H); 2.22 (m, 1H); 1.93 (t, 1H); 1.8 (m, 2H); 1.26 (m, 2H); 1.03 (s, 3H); 0.73 (s, 3H).
[0159] This material (68.5 g) was suspended in AcOEt (480 mL) and stirred with a saturated sodium hydrogen carbonate (274 mL). The organic layer was separated and washed with further water (274 mL). The organic phase was dried and concentrated in vacuo to give the title compound (31 g) as a yellow-orange oil.
[0160] NMR (d6-DMSO): 6 (ppm) 7.49 (dd, 1H); 7.00 (m, 2H); 3.97 (dd, 1H); 3.27 (m, 1H); 2.82 (dt, 1H); 2.72 (bm, 1H); 2.47 (m, 1H); 2.40 (m, 1H); 2.29 (s, 3H); 2.25 (dt, 1H); 2.18 (m, 1H).
[0161] MS (ES/+): m/z=208 [MH]+.
intermediate 9
[0220] Intermediate 9
[0221] 2-(R)-(4-Fluoro-2-methyl-phenyl)-piperidin-4-one Mandelic Acid.
[0222] A solution of L-(+)-mandelic acid (22.6 g) in AcOEt (308 mL) was added to a solution of intermediate 2 (31 g) in AcOEt (308 mL). Then isopropanol (616 mL) was added and the solution was concentrated in vacuo to 274 mL. The solution was then cooled to 0° C. and further cold isopropanol (96 mL) was added. The thick precipitate was stirred under nitrogen for 5 hours at 0° C., then filtered and washed with cold Et2O (250 mL) to give the title compound as a pale yellow solid (20.3 g).
[0223] M.p.: 82-85° C.
[0224] NMR (d6-DMSO): δ (ppm) 7.51 (dd, 1H); 7.40 (m, 2H); 7.32 (m, 2H); 7.26 (m, 1H); 7.0 (m, 2H); 4.95 (s, 1H); 4.04 (dd, 1H); 3.31 (m, 1H); 2.88 (m, 1H); 2.49-2.2 (m, 4H); 2.29 (s, 3H).
[0225] Chiral HPLC: HP 1100 HPLC system; column Chiralcel OD-H, 25 cm×4.6 mm; mobile phase: n-hexane/isopropanol 95:5+1% diethylamine; flow: 1.3 ml/min; detection: 240/215 nm; retention time 12.07 minutes.
………………….
NMR
mesylate
http://pubs.acs.org/doi/abs/10.1021/op100150b
1H NMR (600 MHz, DMSO-d6): 9.57 (br s, 1H), 7.99 (br s, 1H), 7.68 (br s, 2H), 7.23 (m, 1H), 6.95 (dd, 1H), 6.82 (m, 1H), 5.31 (q, 1H), 4.45 (m, 1H), 4.20 (dd, 1H), 3.99 (m, 1H), 3.56 (m, 1H), 3.47 (m, 3H), 3.37 (m, 1H), 3.15 (m, 1H), 2.96 (m, 1H), 2.87 (m, 1H), 2.80 (t, 1H), 2.74 (s, 3H), 2.36 (s, 3H), 2.30 (s, 3H), 2.13 (m, 1H), 2.08 (m, 1H), 2.10 (s, 3H), 1.87 (m, 1H), 1.73 (m, 1H), 1.46 (d, 3H), MS: m/z 617 [MH]+, as free base.
……………
http://pubs.acs.org/doi/full/10.1021/op100209c
11.25 M in NH3)], Na2CO3 [15% w/w solution (4 L)]. More EtOAc (4 L) was added, and the organic layer was washed with water (4 L). The organic phase was then concentrated to 2.5 L; again fresh EtOAc (4 L) was added, and the solution was concentrated to 2.5 L to give a solution of casopitant 2.
……………………………….
http://pubs.acs.org/doi/full/10.1021/jm1013264?prevSearch=casopitant&searchHistoryKey=
(2R,4S)-1′-acetyl-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4,4′-bipiperidine-1-carboxamide methanesulfonate salt 16a (casopitant)
nmr mesylate
1H NMR (600 MHz, DMSO-d6): 9.57 (bs, 1H), 7.99 (bs, 1H), 7.68 (bs, 2H), 7.23 (m, 1H), 6.95 (dd, 1H), 6.82 (m, 1H), 5.31 (q, 1H), 4.45 (m, 1H), 4.20 (dd, 1H), 3.99 (m, 1H), 3.56 (m, 1H), 3.47 (m, 3H), 3.37 (m, 1H), 3.15 (m, 1H), 2.96 (m, 1H), 2.87 (m, 1H), 2.80 (t, 1H), 2.74 (s, 3H), 2.36 (s, 3H), 2.30 (s, 3H), 2.13 (m, 1H), 2.08 (m, 1H), 2.10 (s, 3H), 1.87 (m, 1H), 1.73 (m, 1H), 1.46 (d, 3H). MS: m/z 617 [MH]+, as free base.
syn of intermediates
a(a) (i) 2-Bromo-5-fluorotoluene, Mg, THF, 60−70 °C; (ii) 4-methoxypyridine, benzyl chloroformate, THF, −20 °C, then Grignard’s reagent, −20 °C, 1 h; (b) (i) tris(triphenylphosphine)rhodium(I) chloride, 2-propanol, H2 (p = 5 atm), 60 °C, 5 h; (ii) Pd/C 5%, H2 (p = 4 atm), 20 °C, 5 h; (iii) (R,S)-10-camphorsulfonic acid, toluene; (c) CH2Cl2, H2O, 8% NaHCO3 (aq); l-(+)-mandelic acid, 2-propanol, heptanes; (d) MeNH2, EtOH, NaBH4, 25 °C, 1.5 h; (e) (i) ethyl acetate, NaHCO3 (aq. sat. soln), 5; (ii) triphosgene, triethylamine, ethyl acetate, then 5, 20 °C, 2 h; (f) R′RNH, CH3CN, NaBH(OAc)3, room temp, 24 h.
THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D
GLENMARK SCIENTIST , NAVIMUMBAI, INDIA
did you feel happy, a head to toe paralysed man’s soul in action for you round the clock
need help, email or call me
I was paralysed in dec2007, Posts dedicated to my family, my organisation Glenmark, Your readership keeps me going and brings smiles to my family
SOVAPREVIR
(2S, 4R) -1 – [(2S)-2-tert-butyl-4-oxo-4-(piperidin-1-yl) butanoyl]-N-{(1R, 2S) -1 – [(cyclopropanesulfonyl) carbamoyl]-2-ethenylcyclopropyl} -4 – [(7-methoxy-2-phenylquinolin-4-yl) oxy] pyrrolidine-2-carboxamide
http://www.ama-assn.org/resources/doc/usan/sovaprevir.pdf
PATENT
US 2009048297 ENTRY 60
WO 2008008502
CN 103420991
THERAPEUTIC CLAIM ….Treatment of hepatitis C
CHEMICAL NAMES
1. 2-Pyrrolidinecarboxamide, N-[(1R,2S)-1-[[(cyclopropylsulfonyl)amino]carbonyl]-2-
ethenylcyclopropyl]-1-[(2S)-3,3-dimethyl-1-oxo-2-[2-oxo-2-(1-piperidinyl)ethyl]butyl]-4-
[(7-methoxy-2-phenyl-4-quinolinyl)oxy]-, (2S,4R)-
2. (2S,4R)-N-{(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-1-{(2S)-
3,3-dimethyl-2-[2-oxo-2-(piperidin-1-yl)ethyl]butanoyl}-4-[(7-methoxy-2-phenylquinolin-
4-yl)oxy]pyrrolidine-2-carboxamide
MOLECULAR FORMULA C43H53N5O8S
MOLECULAR WEIGHT 800.0
SPONSOR Achillion Pharmaceuticals, Inc.
CODE DESIGNATION ACH-0141625
CAS REGISTRY NUMBER 1001667-23-7
Sovaprevir (formerly ACH-0141625), an HCV NS3 protease inhibitor, is in phase II clinical trials at Achillion for the oral treatment of naive patients with chronic hepatitis C virus genotype 1.
In 2012, fast track designation was assigned by the FDA for the treatment of hepatitis C (HCV). In 2013, a clinical hold was placed for the treatment of hepatitis C (HCV) in combination with atazanavir after elevations in liver enzymes associated with the combination of both compounds.
Sovaprevir, previously referred to as ACH-1625, is an investigational, next-generation NS3/4A protease inhibitor discovered by Achillion that is currently on clinical hold. In 2012, Fast Track status was granted by the U.S. Food and Drug Administration (FDA) to sovaprevir for the treatment of chronic hepatitis C viral infection (HCV).
Achillion has initiated a Phase 2 clinical trial (007 Study) to evaluate the all-oral, interferon-free combination of sovaprevir and its second-generation NS5A inhibitor, ACH-3102, with ribavirin (RBV), for a 12 week treatment duration, in treatment naïve, genotype 1 (GT1) HCV patients. In July 2013, sovaprevir was placed on clinical hold after elevated liver enzymes were observed in a Phase 1 healthy subject drug-drug interaction study evaluating the effects of concomitant administration of sovaprevir with ritonavir-boosted atazanavir.
In accordance with the clinical hold, the FDA provided that no new clinical trials that included dosing with sovaprevir could be initiated, however, the FDA allowed continued enrollment and treatment of patients in the Phase 2 -007 clinical trial evaluating 12-weeks of sovaprevir in combination with ACH-3102 and RBV for patients with treatment-naive genotype 1 HCV. In September 2013, after reviewing Achillion’s response, the FDA stated that although all issues identified in the June 2013 letter had been addressed, it had concluded that the removal of the clinical hold was not warranted at this time.
The FDA requested, among other things, additional analysis to more fully characterize sovaprevir pharmacokinetics and the intrinsic and extrinsic factors that may lead to higher than anticipated exposures of sovaprevir or other potential toxicities in addition to the observed liver enzyme elevations.
The FDA also requested Achillion’s proposed plan for future clinical trials in combination with other directly-acting antivirals. At the request of the FDA, Achillion plans to submit a proposed plan for analyzing the additional clinical, non-clinical and pharmacokinetic data requested before the end of 2013, and if that analysis plan is approved by the FDA, submit a complete response during the first half of 2014. Achillion retains worldwide commercial rights to sovaprevir.
Sovaprevir has demonstrated activity against all HCV genotypes (GT), including equipotent activity against both GT 1a and 1b (IC50 ~ 1nM) in vitro.
With its rapid and extensive partitioning to the liver, as well as high liver/plasma ratios, sovaprevir has been clinically demonstrated to allow for once-daily, non-boosted dosing.
Sovaprevir has demonstrated high rates of clinical cures in combination with pegylated-interferon and RBV in a challenging, real world, patient population of genotype 1 treatment-naive patients.
100% of GT1b subjects achieved a rapid virologic response (RVR) in the 007 Study evaluating the interferon-free combination of sovaprevir + ACH-3102 + RBV for 12 weeks. The Phase 2 study is ongoing.
Sovaprevir in vitro retains activity against mutations that confer resistance to 1st-generation protease inhibitors.
In clinical studies to date, sovaprevir has demonstrated a high pharmacologic barrier to resistance with no on-treatment viral breakthrough reported to date in GT1b patients.
Sovaprevir is believed to be synergistic when combined with other classes of DAAs, including the second-generation NS5A inhibitor, ACH-3102.
For more information about the next-generation NS3/4A protease inhibitor, sovaprevir, please see the Related Links on this page or visit Resources.
Sovaprevir is an investigational compound. Its safety and efficacy have not been established. (Updated December 2013)
SOVAPREVIR
An estimated 3% of the world’s population is infected with the hepatitis C virus. Of those exposed to HCV, 80% become chronically infected, at least 30% develop cirrhosis of the liver and 1-4% develop hepatocellular carcinoma. Hepatitis C Virus (HCV) is one of the most prevalent causes of chronic liver disease in the United States, reportedly accounting for about 15 percent of acute viral hepatitis, 60 to 70 percent of chronic hepatitis, and up to 50 percent of cirrhosis, end-stage liver disease, and liver cancer. Chronic HCV infection is the most common cause of liver transplantation in the U.S., Australia, and most of Europe. Hepatitis C causes an estimated 10,000 to 12,000 deaths annually in the United States. While the acute phase of HCV infection is usually associated with mild symptoms, some evidence suggests that only about 15% to 20% of infected people will clear HCV.
HCV is an enveloped, single-stranded RNA virus that contains a positive-stranded genome of about 9.6 kb. HCV is classified as a member of the Hepacivirus genus of the family Flaviviridae. At least 4 strains of HCV, GT-1-GT-4, have been characterized.
The HCV lifecycle includes entry into host cells; translation of the HCV genome, polyprotein processing, and replicase complex assembly; RNA replication, and virion assembly and release. Translation of the HCV RNA genome yields a more than 3000 amino acid long polyprotein that is processed by at least two cellular and two viral proteases. The HCV polyprotein is:
NH2-C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B-COOH.
The cellular signal peptidase and signal peptide peptidase have been reported to be responsible for cleavage of the N-terminal third of the polyprotein (C-E1-E2-p7) from the nonstructural proteins (NS2-NS3-NS4A-NS4B-NS5A-NS5B). The NS2-NS3 protease mediates a first cis cleavage at the NS2-NS3 site. The NS3-NS4A protease then mediates a second cis-cleavage at the NS3-NS4A junction. The NS3-NS4A complex then cleaves at three downstream sites to separate the remaining nonstructural proteins. Accurate processing of the polyprotein is asserted to be essential for forming an active HCV replicase complex.
Once the polyprotein has been cleaved, the replicase complex comprising at least the NS3-NS5B nonstructural proteins assembles. The replicase complex is cytoplasmic and membrane-associated. Major enzymatic activities in the replicase complex include serine protease activity and NTPase helicase activity in NS3, and RNA-dependent RNA polymerase activity of NS5B. In the RNA replication process, a complementary negative strand copy of the genomic RNA is produced. The negative strand copy is used as a template to synthesize additional positive strand genomic RNAs that may participate in translation, replication, packaging, or any combination thereof to produce progeny virus. Assembly of a functional replicase complex has been described as a component of the HCV replication mechanism. Provisional application 60/669,872 “Pharmaceutical Compositions and Methods of Inhibiting HCV Replication” filed Apr. 11, 2005, is hereby incorporated by reference in its entirety for its disclosure related to assembly of the replicase complex.
Current treatment of hepatitis C infection typically includes administration of an interferon, such as pegylated interferon (IFN), in combination with ribavirin. The success of current therapies as measured by sustained virologic response (SVR) depends on the strain of HCV with which the patient is infected and the patient’s adherence to the treatment regimen. Only 50% of patients infected with HCV strain GT-1 exhibit a sustained virological response. Direct acting antiviral agents such as ACH-806, VX-950 and NM 283 (prodrug of NM 107) are in clinical development for treatment of chronic HCV. Due to lack of effective therapies for treatment for certain HCV strains and the high mutation rate of HCV, new therapies are needed.
…………………………………………
https://www.google.co.in/patents/US20090048297
(2S,4R)-1-((S)-2-tert-butyl-4-oxo-4-(piperidin-1-yl)butanoyl)-N-((1R,2S)-1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-2-carboxamide
SOVAPREVIR IS DESCRIBED AS 60 IN CLAIM
SYNTHESIS OF INTERMEDIATE 13 BELOW AND ALSO COMPD 8 IE SOVAPREVIR IN STEP 4
Example 1
SYNTHESIS OF 1-((2S,4R)-1-((S)-2-TERT-BUTYL-4-OXO-4-(PIPERIDIN-1-YL)BUTANOYL)-4-(7-METHOXY-2-PHENYLQUINOLIN-4-YLOXY)PYRROLIDINE-2-CARBOXAMIDO)-2-VINYLCYCLOPROPANECARBOXYLIC ACID
Step 1. Preparation of N-(cyclopropylsulfonyl)-1-(BOC-amino)-2-vinylcyclopropanecarboxamide
CDI (2.98 g, 18.4 mm, 1.1 eq) is dissolved in ethyl acetate. N-Boc-cyclopropylvinyl acid (3.8 g, 16.7 mm, 1.0 eq), prepared via the procedure given by Beaulieu, P. L. et al. (J. Org. Chem. 70: 5869-79 (2005)) is added to the CDI/ethyl acetate mixture and stirred at RT until the starting material is consumed. Cyclopropyl sulfonamine (2.2 g, 18.4 mm, 1.1 eq) is added to this mixture followed by DBU (2.1 ml, 20.5 mm, 1.23 eq) and the mixture is stirred at RT for 2 h. Workup and purification by silica gel chromatography provides 2g of compound 2.
Step 2. Preparation of (2S,4R)-tert-butyl 2-(1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-1-carboxylate and (2S,4R)—N-(1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-2-carboxamide
Compound 1 (4.3 g, 9.3 mmol, 1.1 eq), prepared according to the method given ins WO 02/060926, in DMF is stirred with O-(Benzotriazol-lyl)-N,N,N′,N′-Tetramethyluronium hexafluorophosphate (4.1 g, 10.5 mmol, 1.3 eq) for 30 minutes, followed by addition of cyclopropylamine 2 (1.92 g, 8.3 mmol, 1.0 eq) and N-methylmorpholine (2.52 g, 25.0 mmol, 3.0 eq). The mixture is stirred over night and the solvent removed under reduced pressure. The resulting residue is diluted with ethyl acetate and washed with saturated aqueous NaHCO3. The organic solvent is dried over MgSO4 and concentrated under reduced pressure to afford crude 3, which is used for next step without further purification.
Compound 3 in 10 ml dry CH2Cl2 is treated with 5 mL TFA and stirred over night. The solvent is removed and the residue recrystallized from ethyl acetate to afford 4.12 g Compound 4 (61% yield two steps).
Step 3. Preparation of (3S)-3-((2S,4R)-2-(1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropylcarbamoyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-1-carbonyl)-4,4-dimethylpentanoic acid
The Acid 5 (58 mg, 0.25 mmol, 1.2 eq), prepared via the procedure given by Evans, D. A., et al. (J. Org. Chem. 64: 6411-6417 (1999)) in 1.2 mL DMF is stirred with 4 (138 mg, 0.21 mmol), HATU (160 mg, 0.42 mmol, 2.0 eq), and DIEA (0.63 mmol, 3.0 eq) overnight. The mixture is subjected to HPLC purification to afford 121 mg 6 (77% yield), which is further treated with 0.5 mL TFA in 1.0 mL DCM overnight. The solvent was removed to provide Compound 7 in 100% yield.
Step 4. Preparation of (2S,4R)-1-((S)-2-tert-butyl-4-oxo-4-(piperidin-1-yl)butanoyl)-N-(1-(cyclopropylsulfonylcarbamoyl)-2-vinylcyclopropyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-2-carboxamide
PLEASE NOTE 8 IS SOVAPREVIR
The Acid 7 (0.15 mmol) in 1.0 mL DMF is stirred with pepridine (excess, 0.6 mmol, 4 eq), HATU (115 mg, 0.3 mmol, 2.0 eq), and DIEA (0.45 mmol, 3.0 eq) for 4 hrs. The mixture is subjected to HPLC purification to afford 77.1 mg 8.
Step 5. Preparation of (3S)-3-((2S,4R)-2-(1-(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-1-carbonyl)-4,4-dimethylpentanoic acid
Step 5. Preparation of (3S)-3-((2S,4R)-2-(1-(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)-4-(7-methoxy-2-phenylquinolin-4-yloxy)pyrrolidine-1-carbonyl)-4,4-dimethylpentanoic acid
The Acid 5 (105 mg, 0.46 mmol, 1.2 eq) in 1.2 mL DMF is stirred with 9 (202 mg, 0.38 mmol), HATU (290 mg, 0.76 mmol, 2.0 eq), and DIEA (1.2 mmol, 3.0 eq) overnight. The mixture is subjected to HPLC purification to afford 204.3 mg 10 (75% yield), which is further treated with 0.5 mL TFA in 1.0 mL DCM overnight. The solvent is removed to provide 11 in 100% yield.
Step 6. Preparation of Final Product
The Acid 11 (30 mg, 0.045 mmol) in 1.0 mL DMF is stirred with pepridine (0.27 mmol, 6 eq), HATU (34 mg, 0.09 mmol, 2.0 eq), and DIEA (0.14 mmol, 3.0 eq) for 2 hrs. The mixture is subjected to HPLC purification to afford 21.2 mg 12 (65% yield), which is hydrolyzed in methanol with 2N NaOH for 6 hrs. The mixture is acidified with 6N HCl and subjected to HPLC purification to afford 7.6 mg 13.
………………………………
THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D
GLENMARK SCIENTIST , NAVIMUMBAI, INDIA
did you feel happy, a head to toe paralysed man’s soul in action for you round the clock
need help, email or call me
I was paralysed in dec2007, Posts dedicated to my family, my organisation Glenmark, Your readership keeps me going and brings smiles to my family
