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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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FDA approves new treatment Hemlibra (emicizumab-kxwh) to prevent bleeding in certain patients with hemophilia A


FDA approves new treatment to prevent bleeding in certain patients with hemophilia A

The U.S. Food and Drug Administration today approved Hemlibra (emicizumab-kxwh) to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A who have developed antibodies called Factor VIII (FVIII) inhibitors.Continue reading.

 

 

November 16, 2017

Summary

FDA approves new treatment to prevent or reduce frequency of bleeding episodes in patients with hemophilia A who have Factor VIII inhibitors.

Release

The U.S. Food and Drug Administration today approved Hemlibra (emicizumab-kxwh) to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A who have developed antibodies called Factor VIII (FVIII) inhibitors.

“Reducing the frequency or preventing bleeding episodes is an important part of disease management for patients with hemophilia. Today’s approval provides a new preventative treatment that has been shown to significantly reduce the number of bleeding episodes in patients with hemophilia A with Factor VIII inhibitors,” said Richard Pazdur, M.D., acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and director of the FDA’s Oncology Center of Excellence. “In addition, patients treated with Hemlibra reported an improvement in their physical functioning.”

Hemophilia A is an inherited blood-clotting disorder that primarily affects males. According to the National Institutes of Health, hemophilia affects one in every 5,000 males born in the United States, approximately 80 percent of whom have hemophilia A. Patients with hemophilia A are missing a gene which produces Factor VIII, a protein that enables blood to clot. Patients may experience repeated episodes of serious bleeding, primarily into their joints, which can be severely damaged as a result. Some patients develop an immune response known as a FVIII inhibitor or antibody. The antibody interferes with the effectiveness of currently available treatments for hemophilia.

Hemlibra is a first-in-class therapy that works by bridging other Factors in the blood to restore blood clotting for these patients. Hemlibra is a preventative (prophylactic) treatment given weekly via injection under the skin (subcutaneous).

The safety and efficacy of Hemlibra was based on data from two clinical trials. The first was a trial that included 109 males aged 12 and older with hemophilia A with FVIII inhibitors. The randomized portion of the trial compared Hemlibra to no prophylactic treatment in 53 patients who were previously treated with on-demand therapy with a bypassing agent before enrolling in the trial. Patients taking Hemlibra experienced approximately 2.9 treated bleeding episodes per year compared to approximately 23.3 treated bleeding episodes per year for patients who did not receive prophylactic treatment. This represents an 87 percent reduction in the rate of treated bleeds. The trial also included patient-reported Quality of Life metrics on physical health. Patients treated with Hemlibra reported an improvement in hemophilia-related symptoms (painful swellings and joint pain) and physical functioning (pain with movement and difficulty walking) compared to patients who did not receive prophylactic treatment.

The second trial was a single arm trial of 23 males under the age of 12 with hemophilia A with FVIII inhibitors. During the trial, 87 percent of the patients taking Hemlibra did not experience a bleeding episode that required treatment.

Common side effects of Hemlibra include injection site reactions, headache, and joint pain (arthralgia).

The labeling for Hemlibra contains a boxed warning to alert healthcare professionals and patients that severe blood clots (thrombotic microangiopathy and thromboembolism) have been observed in patients who were also given a rescue treatment (activated prothrombin complex concentrate) to treat bleeds for 24 hours or more while taking Hemlibra.

The FDA granted this application Priority Review and Breakthrough Therapydesignations. Hemlibra also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Hemlibra to Genentech, Inc.

///////Hemlibra, emicizumab-kxwh, FDA 2017, hemophilia A, Priority Review and Breakthrough Therapy designation,  Orphan Drug designation

 

 

“NEW DRUG APPROVALS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

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FDA approves Mepsevii (vestronidase alfa-vjbk) for treatment for rare genetic enzyme disorder


FDA approves treatment for rare genetic enzyme disorder

The U.S. Food and Drug Administration today approved Mepsevii (vestronidase alfa-vjbk) to treat pediatric and adult patients with an inherited metabolic condition called mucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome. MPS VII is an extremely rare, progressive condition that affects most tissues and organs. Continue reading.

 

 

November 15, 2017

Summary

First FDA approved treatment for pediatric and adult patients with MPS VII

Release

The U.S. Food and Drug Administration today approved Mepsevii (vestronidase alfa-vjbk) to treat pediatric and adult patients with an inherited metabolic condition called mucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome. MPS VII is an extremely rare, progressive condition that affects most tissues and organs.

“This approval underscores the agency’s commitment to making treatments available to patients with rare diseases,” said Julie Beitz, M.D., director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research (CDER). “Prior to today’s approval, patients with this rare, inherited condition had no approved treatment options.”

MPS VII is an inherited, rare genetic condition and impacts less than 150 patients worldwide. The features of MPS VII vary widely from patient to patient, but most patients have various skeletal abnormalities that become more pronounced with age, including short stature. Affected individuals can also develop heart valve abnormalities, enlarged liver and spleen, and narrowed airways which can lead to lung infections and trouble breathing. The life expectancy of individuals with MPS VII depends on the severity of symptoms. Some affected individuals do not survive infancy, while others may live into adolescence or adulthood. Heart disease and airway obstruction are major causes of death in people with MPS VII. Affected individuals may have developmental delay and progressive intellectual disability.

MPS VII is a lysosomal storage disorder caused by deficiency of an enzyme called beta-glucuronidase, which causes an abnormal buildup of toxic materials in the body’s cells. Mepsevii is an enzyme replacement therapy that works by replacing the missing enzyme.

The safety and efficacy of Mepsevii were established in clinical trial and expanded access protocols enrolling a total of 23 patients ranging from 5 months to 25 years of age. Patients received treatment with Mepsevii at doses up to 4 mg/kg once every two weeks for up to 164 weeks. Efficacy was primarily assessed via the six-minute walk test in ten patients who could perform the test. After 24 weeks of treatment, the mean difference in distance walked relative to placebo was 18 meters. Additional follow-up for up to 120 weeks suggested continued improvement in three patients and stabilization in the others. Two patients in the Mepsevii development program experienced marked improvement in pulmonary function. Overall, the results observed would not have been anticipated in the absence of treatment. The effect of Mepsevii on the central nervous system manifestations of MPS VII has not been determined.

The most common side effects after treatment with Mepsevii include infusion site reactions, diarrhea, rash and anaphylaxis.

The FDA granted this application Fast Track designation, which seeks to expedite the development and review of drugs that are intended to treat serious conditions where initial evidence showed the potential to address an unmet medical need. Mepsevii also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The sponsor is receiving a Rare Pediatric Disease Priority Review Voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. A voucher can be redeemed by a sponsor at a later date to receive Priority Review of a subsequent marketing application for a different product. This is the twelfth rare pediatric disease priority review voucher issued by the FDA since the program began.

The FDA is requiring the manufacturer to conduct a post-marketing study to evaluate the long-term safety of the product.

The FDA granted approval of Mepsevii to Ultragenyx Pharmaceutical, Inc.

/////////Mepsevii, vestronidase alfa-vjbk, fda 2017

FDA approves first treatment Zelboraf (vemurafenib)for certain patients with Erdheim-Chester Disease, a rare blood cancer


FDA approves first treatment for certain patients with Erdheim-Chester Disease, a rare blood cancer

The U.S. Food and Drug Administration today expanded the approval of Zelboraf (vemurafenib) to include the treatment of certain adult patients with Erdheim-Chester Disease (ECD), a rare cancer of the blood. Zelboraf is indicated to treat patients whose cancer cells have a specific genetic mutation known as BRAF V600. This is the first FDA-approved treatment for ECD. Continue reading.

//////Zelboraf, vemurafenib, fda 2017, Erdheim-Chester Disease,

 

Vemurafenib
Vemurafenib structure.svg
Vemurafenib ball-and-stick model.png
Clinical data
Pronunciation /ˌvɛməˈræfənɪb/ VEM-ə-RAF-ə-nib
Trade names Zelboraf
Synonyms PLX4032, RG7204, RO5185426
AHFS/Drugs.com Monograph
MedlinePlus a612009
License data
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
Routes of
administration
By mouth (tablets)
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
ECHA InfoCard 100.226.540
Chemical and physical data
Formula C23H18ClF2N3O3S
Molar mass 489.92 g/mol
3D model (JSmol)

Vemurafenib (INN, marketed as Zelboraf) is a B-Raf enzyme inhibitor developed by Plexxikon (now part of Daiichi-Sankyo) and Genentech for the treatment of late-stage melanoma.[1] The name “vemurafenib” comes from V600E mutated BRAF inhibition.

Approvals

Vemurafenib received FDA approval for the treatment of late-stage melanoma on August 17, 2011,[2] making it the first drug designed using fragment-based lead discovery to gain regulatory approval.[3]

Vemurafenib later received Health Canada approval on February 15, 2012.[4]

On February 20, 2012, the European Commission approved vemurafenib as a monotherapy for the treatment of adult patients with BRAF V600E mutation positive unresectable or metastatic melanoma, the most aggressive form of skin cancer.[5]

Mechanism of action

Vemurafenib causes programmed cell death in melanoma cell lines.[6] Vemurafenib interrupts the B-Raf/MEK step on the B-Raf/MEK/ERK pathway − if the B-Raf has the common V600E mutation.

Vemurafenib only works in melanoma patients whose cancer has a V600E BRAF mutation (that is, at amino acid position number 600 on the B-Raf protein, the normal valine is replaced by glutamic acid).[7] About 60% of melanomas have this mutation. It also has efficacy against the rarer BRAF V600K mutation. Melanoma cells without these mutations are not inhibited by vemurafenib; the drug paradoxically stimulates normal BRAF and may promote tumor growth in such cases.[8][9]

Resistance

Three mechanisms of resistance to vemurafenib (covering 40% of cases) have been discovered:

Clinical trials

In a phase I clinical study, vemurafenib (then known as PLX4032) was able to reduce numbers of cancer cells in over half of a group of 16 patients with advanced melanoma. The treated group had a median increased survival time of 6 months over the control group.[13][14][15][16]

A second phase I study, in patients with a V600E mutation in B-Raf, ~80% showed partial to complete regression. The regression lasted from 2 to 18 months.[17]

In early 2010 a Phase I trial[18] for solid tumors (including colorectal cancer), and a phase II study (for metastatic melanoma) were ongoing.[19]

A phase III trial (vs dacarbazine) in patients with previously untreated metastatic melanoma showed an improved rates of overall and progression-free survival.[20]

In June 2011, positive results were reported from the phase III BRIM3 BRAF-mutation melanoma study.[21] The BRIM3 trial reported good updated results in 2012.[22]

Further trials are planned including a trial of vemurafenib co-administered with GDC-0973 (cobimetinib), a MEK-inhibitor.[21] After good results in 2014 the combination was submitted to the EC and FDA for marketing approval.[23]

In January 2015 trial results compared vemurafenib with the combination of dabrafenib and trametinib for metastatic melanoma.[24]

Side effects

At the maximum tolerated dose (MTD) of 960 mg twice a day 31% of patients get skin lesions that may need surgical removal.[1] The BRIM-2 trial investigated 132 patients; the most common adverse events were arthralgia in 58% of patients, skin rash in 52%, and photosensitivity in 52%. In order to better manage side effects some form of dose modification was necessary in 45% of patients. The median daily dose was 1750 mg, 91% of the MTD.[25]

A trial combining vemurafenib and ipilimumab was stopped in April 2013 because of signs of liver toxicity.[26]

References

  1. Jump up to:a b c PDB3OG7​; Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, Spevak W, Zhang C, Zhang Y, Habets G, et al. (September 2010). “Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma”Nature467 (7315): 596–599. doi:10.1038/nature09454PMC 2948082Freely accessiblePMID 20823850.
  2. Jump up^ “FDA Approves Zelboraf (Vemurafenib) and Companion Diagnostic for BRAF Mutation-Positive Metastatic Melanoma, a Deadly Form of Skin Cancer” (Press release). Genentech. Retrieved 2011-08-17.
  3. Jump up^ Bollag G, Tsai J, Zhang J, Zhang C, Ibrahim P, Nolop K, Hirth P (November 2012). “Vemurafenib: the first drug approved for BRAF-mutant cancer”. Nat Rev Drug Discov11 (11): 873–86. doi:10.1038/nrd3847PMID 23060265.
  4. Jump up^ Notice of Decision for ZELBORAF
  5. Jump up^ Hofland P (February 20, 2012). “First Personalized Cancer Medicine Allows Patients with Deadly Form of Metastatic Melanoma to Live Significantly Longer”Onco’Zine. The International Cancer Network.
  6. Jump up^ Sala E, Mologni L, Truffa S, Gaetano C, Bollag GE, Gambacorti-Passerini C (May 2008). “BRAF silencing by short hairpin RNA or chemical blockade by PLX4032 leads to different responses in melanoma and thyroid carcinoma cells”. Mol. Cancer Res6 (5): 751–9. doi:10.1158/1541-7786.MCR-07-2001PMID 18458053.
  7. Jump up^ Maverakis E, Cornelius LA, Bowen GM, Phan T, Patel FB, Fitzmaurice S, He Y, Burrall B, Duong C, Kloxin AM, Sultani H, Wilken R, Martinez SR, Patel F (2015). “Metastatic melanoma – a review of current and future treatment options”. Acta Derm Venereol95 (5): 516–524. doi:10.2340/00015555-2035PMID 25520039.
  8. Jump up^ Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, Ludlam MJ, Stokoe D, Gloor SL, Vigers G, Morales T, Aliagas I, Liu B, Sideris S, Hoeflich KP, Jaiswal BS, Seshagiri S, Koeppen H, Belvin M, Friedman LS, Malek S (February 2010). “RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth”. Nature464 (7287): 431–5. doi:10.1038/nature08833PMID 20130576.
  9. Jump up^ Halaban R, Zhang W, Bacchiocchi A, Cheng E, Parisi F, Ariyan S, Krauthammer M, McCusker JP, Kluger Y, Sznol M (February 2010). “PLX4032, a Selective BRAF(V600E) Kinase Inhibitor, Activates the ERK Pathway and Enhances Cell Migration and Proliferation of BRAF(WT) Melanoma Cells”Pigment Cell Melanoma Res23(2): 190–200. doi:10.1111/j.1755-148X.2010.00685.xPMC 2848976Freely accessiblePMID 20149136.
  10. Jump up^ Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee MK, Attar N, Sazegar H, Chodon T, Nelson SF, McArthur G, Sosman JA, Ribas A, Lo RS (November 2010). “Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation”Nature468 (7326): 973–977. doi:10.1038/nature09626PMC 3143360Freely accessiblePMID 21107323Lay summary – Genetic Engineering & Biotechnology News.
  11. Jump up^ Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, Davis A, Mongare MM, Gould J, Frederick DT, Cooper ZA, Chapman PB, Solit DB, Ribas A, Lo RS, Flaherty KT, Ogino S, Wargo JA, Golub TR (July 2012). “Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion”Nature487 (7408): 500–4. doi:10.1038/nature11183PMC 3711467Freely accessiblePMID 22763439.
  12. Jump up^ Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, Peng J, Lin E, Wang Y, Sosman J, Ribas A, Li J, Moffat J, Sutherlin DP, Koeppen H, Merchant M, Neve R, Settleman J (July 2012). “Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors”Nature487 (7408): 505–9. doi:10.1038/nature11249PMC 3724525Freely accessiblePMID 22763448.
  13. Jump up^ “Drug hope for advanced melanoma”. BBC News. 2009-06-02. Retrieved 2009-06-07.
  14. Jump up^ Harmon, Amy (2010-02-21). “A Roller Coaster Chase for a Cure”The New York Times.
  15. Jump up^ Garber K (December 2009). “Melanoma drug vindicates targeted approach”. Science326 (5960): 1619. doi:10.1126/science.326.5960.1619PMID 20019269.
  16. Jump up^ Flaherty K. “Phase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer”2009 ASCO Annual Meeting Abstract, J Clin Oncol 27:15s, 2009 (suppl; abstr 9000).
  17. Jump up^ Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O’Dwyer PJ, Lee RJ, Grippo JF, Nolop K, Chapman PB (August 2010). “Inhibition of mutated, activated BRAF in metastatic melanoma”. N. Engl. J. Med363 (9): 809–19. doi:10.1056/NEJMoa1002011PMID 20818844Lay summary – Corante: In the Pipeline.
  18. Jump up^ “Safety Study of PLX4032 in Patients With Solid Tumors”. ClinicalTrials.gov.
  19. Jump up^ “A Study of RO5185426 in Previously Treated Patients With Metastatic Melanoma”. ClinicalTrials.gov. 2010-02-15.
  20. Jump up^ “Plexxikon Announces First Patient Dosed in Phase 3 Trial of PLX4032 (RG7204) for Metastatic Melanoma” (Press release). Plexxikon. 2010-01-08.
  21. Jump up to:a b “Plexxikon and Roche Report Positive Data from Phase III BRAF Mutation Melanoma Study”. 6 June 2011.
  22. Jump up^ “Vemurafenib Improves Overall Survival in Patients with Metastatic Melanoma”.
  23. Jump up^ Cobimetinib at exelixis.com
  24. Jump up^ “MEK/BRAF Inhibitor Combo Reduces Death by One-Third in Melanoma”. 2015.
  25. Jump up^ “BRIM-2 Upholds Benefits Emerging with Vemurafenib in Melanoma”Oncology & Biotech News5 (7). July 2011.
  26. Jump up^ “Getting close and personal”The Economist. January 4, 2014. ISSN 0013-0613. Retrieved 2016-04-15.

Secnidazole, секнидазол , سيكنيدازول , 塞克硝唑 ,


Secnidazole.svg ChemSpider 2D Image | Secnidazole | C7H11N3O3

Secnidazole

  • Molecular FormulaC7H11N3O3
  • Average mass185.180 Da
1-(2-Methyl-5-nitroimidazol-1-yl)-2-propanol
1H-Imidazole-1-ethanol, α,2-dimethyl-5-nitro- [ACD/Index Name]
222-134-0 [EINECS]
3366-95-8 [RN]
a,2-Dimethyl-5-nitro-1H-imidazole-1-ethanol
UNII:R3459K699K
секнидазол [Russian] [INN]
سيكنيدازول [Arabic] [INN]
塞克硝唑 [Chinese] [INN]
RP-14539, PM-185184, Flagentyl

Solosec (secnidazole) ; Symbiomix Therapeutics; For the treatment of bacterial vaginosis , Approved September 2017

Company: Symbiomix Therapeutics

Approval Status: Approved FDA September 2017

Specific Treatments: bacterial vaginosis

Therapeutic Areas Obstetrics/Gynecology (Women’s Health)

Infections and Infectious Diseases

 

Secnidazole is a second-generation 5-nitroimidazole antimicrobial that is structurally related to other 5-nitroimidazoles including Metronidazole and Tinidazole, but displays improved oral absorption and longer terminal elimination half-life than antimicrobial agents in this class [1]. Secnidazole is selective against many anaerobic Gram-positive and Gram-negative bacteria and protozoa. In September 2017, FDA granted approval to secnidazole under the market name Solosec as a single-dose oral treatment for bacterial vaginosis, which is a common vaginal infection in women aged 15 to 44 years. The antimicrobial therapy is only intended to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria [FDA Label].

Title: Secnidazole
CAS Registry Number: 3366-95-8
CAS Name: a,2-Dimethyl-5-nitro-1H-imidazole-1-ethanol
Additional Names: 1-(2-hydroxypropyl)-2-methyl-5-nitroimidazole; 1-(2-methyl-5-nitroimidazol-1-yl)-2-propanol
Manufacturers’ Codes: PM-185184; RP-14539
Trademarks: Flagentyl (Rh>e-Poulenc)
Molecular Formula: C7H11N3O3
Molecular Weight: 185.18
Percent Composition: C 45.40%, H 5.99%, N 22.69%, O 25.92%
Literature References: Analog of metronidazole, q.v. Prepn: FR M3270 (1965 to Rhône-Poulenc), C.A. 63, 11571d (1965); C. Cosar et al., Arzneim.-Forsch. 16, 23 (1966). Anti-amebic and trichomonacidal activities: F. Benazet, L. Guillaume, Bull. Soc. Pathol. Exot. Ses Fil. 69, 309 (1976), C.A. 90, 145922v (1979). Serum half-life: J. Symonds, J. Antimicrob. Chemother. 5, 484 (1979). Therapeutic use: D. Videau et al., Br. J. Vener. Dis. 54, 77 (1978).
Properties: Cryst from toluene, mp 76° (Cosar).
Melting point: mp 76° (Cosar)
Therap-Cat: Antiamebic. Antiprotozoal (Trichomonas).
Keywords: Antiamebic; Antiprotozoal (Trichomonas).

Secnidazole (trade names FlagentylSindoseSecnil) is a nitroimidazole anti-infective. Effectiveness in the treatment of dientamoebiasis has been reported.[1] It has also been tested against Atopobium vaginae.[2]

Mechanism of Action

Solosec (secnidazole) is a 5-nitroimidazole antimicrobial. 5-nitroimidazoles enter the bacterial cell as an inactive prodrug where the nitro group is reduced by bacterial enzymes to radical anions. It is believed that these radical anions interfere with bacterial DNA synthesis of susceptible isolates.

DE 2107405; FR 2079880; GB 1278757; JP 49080066

The condensation of (I) with propylene oxide (A) in ethanol at 20 C gives 1-(2-hydroxypropyl)-2-methylimidazole (III), which is acetylated with acetyl chloride in refluxing acetonitrile yielding the corresponding acetate (IV). The nitration of (IV) by means of HNO3 and P2O5 affords 1-(2-acetoxypropyl)-2-methyl-4-nitroimidazole (V), which is finally hydrolyzed with 4N HCl at 90 C

CH 513177; DE 2107423; FR 2079879; GB 1278758; NL 7101641

The reaction of (I) with chloroacetone (C) by means of K2CO3 in refluxing acetone gives (2-methylimidazol-1-yl)acetone (VI), which is nitrated with HNO3 and P2O5 affording the corresponding nitro compound (VII). Finally, this product is reduced with NaBH4 in methanol at room temperature.

Drugs Fut 1979,4(4),280, Arzneim-Forsch Drug Res 1966,16(1),23-29

The nitration of (I) with HNO3 and H2SO4 gives 2-methyl-4(5)-nitroimidazole (II), which is then condensed with refluxing 1-chloroisopropanol (B) or with propylene oxide in 85% formic acid (A).

References

  1. Jump up^ Girginkardeşler, N.; Coşkun, S.; Cüneyt Balcioğlu, I.; Ertan, P.; Ok, U. Z. (2003). “Dientamoeba fragilis, a neglected cause of diarrhea, successfully treated with secnidazole”. Clinical Microbiology and Infection9 (2): 110–113. PMID 12588330doi:10.1046/j.1469-0691.2003.00504.x.
  2. Jump up^ De Backer, E.; Dubreuil, L.; Brauman, M.; Acar, J.; Vaneechoutte, M. (2009). “In vitro activity of secnidazole against Atopobium vaginae, an anaerobic pathogen involved in bacterial vaginosis”. Clinical Microbiology and Infection16 (5): 470–472. PMID 19548924doi:10.1111/j.1469-0691.2009.02852.x.

External links

  • Gillis, J. C.; Wiseman, L. R. (1996). “Secnidazole. A review of its antimicrobial activity, pharmacokinetic properties and therapeutic use in the management of protozoal infections and bacterial vaginosis”. Drugs51 (4): 621–38. PMID 8706597doi:10.2165/00003495-199651040-00007.
Secnidazole
Secnidazole.svg
Clinical data
Synonyms PM 185184, RP 14539
AHFS/Drugs.com International Drug Names
Routes of
administration
Oral
ATC code
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
ECHA InfoCard 100.020.123
Chemical and physical data
Formula C7H11N3O3
Molar mass 185.180 g/mol
3D model (JSmol)

////////////Secnidazole, секнидазол سيكنيدازول 塞克硝唑 , FDA 2017, RP-14539, PM-185184, Flagentyl

CC1=NC=C(N1CC(C)O)[N+](=O)[O-]

DISCLAIMER

“NEW DRUG APPROVALS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This is a compilation for educational purposes only. P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

FDA approves new treatment for adults with mantle cell lymphoma


FDA approves new treatment for adults with mantle cell lymphoma

The U.S. Food and Drug Administration today granted accelerated approval to Calquence (acalabrutinib) for the treatment of adults with mantle cell lymphoma who have received at least one prior therapy.

“Mantle cell lymphoma is a particularly aggressive cancer,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “For patients who have not responded to treatment or have relapsed, Calquence provides a new treatment option that has shown high rates of response for some patients in initial studies.” Continue reading.

FDA approves CAR-T cell therapy Yescarta (axicabtagene ciloleucel) to treat adults with certain types of large B-cell lymphoma


FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma

Yescarta is the second gene therapy product approval in the U.S.

The U.S. Food and Drug Administration today approved Yescarta (axicabtagene ciloleucel), a cell-based gene therapy, to treat adult patients with certain types of large B-cell lymphoma who have not responded to or who have relapsed after at least two other kinds of treatment. Yescarta, a chimeric antigen receptor (CAR) T cell therapy, is the second gene therapy approved by the FDA and the first for certain types of non-Hodgkin lymphoma (NHL). Continue reading.

/////////FDA, CAR-T cell therapy,  large B-cell lymphoma, fda 2017, Yescarta, axicabtagene ciloleucel,

FDA clears first 7T magnetic resonance imaging device


FDA clears first 7T magnetic resonance imaging device

Today, the U.S. Food and Drug Administration cleared the first seven tesla (7T) magnetic resonance imaging (MRI) device, more than doubling the static magnetic field strength available for use in the United States. The Magentom Terra is the first 7T MRI system cleared for clinical use in the United States. Continue reading.

FDA approves implantable device to treat moderate to severe central sleep apnea


 

 

 

FDA approves implantable device to treat moderate to severe central sleep apnea

The U.S. Food and Drug Administration today approved a new treatment option for patients who have been diagnosed with moderate to severe central sleep apnea. The Remedē System is an implantable device that stimulates a nerve located in the chest that is responsible for sending signals to the diaphragm to stimulate breathing. Continue reading.

FDA approves new treatment for certain advanced or metastatic breast cancers


FDA approves new treatment for certain advanced or metastatic breast cancers

The U.S. Food and Drug Administration today approved Verzenio (abemaciclib) to treat adult patients who have hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer that has progressed after taking therapy that alters a patient’s hormones (endocrine therapy). Verzenio is approved to be given in combination with an endocrine therapy, called fulvestrant, after the cancer had grown on endocrine therapy. It is also approved to be given on its own, if patients were previously treated with endocrine therapy and chemotherapy after the cancer had spread (metastasized). Continue reading

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm578071.htm

Abemaciclib.svg

(abemaciclib)

September 28, 2017

Release

The U.S. Food and Drug Administration today approved Verzenio (abemaciclib) to treat adult patients who have hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer that has progressed after taking therapy that alters a patient’s hormones (endocrine therapy). Verzenio is approved to be given in combination with an endocrine therapy, called fulvestrant, after the cancer had grown on endocrine therapy. It is also approved to be given on its own, if patients were previously treated with endocrine therapy and chemotherapy after the cancer had spread (metastasized).

“Verzenio provides a new targeted treatment option for certain patients with breast cancer who are not responding to treatment, and unlike other drugs in the class, it can be given as a stand-alone treatment to patients who were previously treated with endocrine therapy and chemotherapy,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

Verzenio works by blocking certain molecules (known as cyclin-dependent kinases 4 and 6), involved in promoting the growth of cancer cells. There are two other drugs in this class that are approved for certain patients with breast cancer, palbociclib approved in February 2015 and ribociclib approved in March 2017.

Breast cancer is the most common form of cancer in the United States. The National Cancer Institute at the National Institutes of Health estimates approximately 252,710 women will be diagnosed with breast cancer this year, and 40,610 will die of the disease. Approximately 72 percent of patients with breast cancer have tumors that are HR-positive and HER2-negative.

The safety and efficacy of Verzenio in combination with fulvestrant were studied in a randomized trial of 669 patients with HR-positive, HER2-negative breast cancer that had progressed after treatment with endocrine therapy and who had not received chemotherapy once the cancer had metastasized. The study measured the length of time tumors did not grow after treatment (progression-free survival). The median progression-free survival for patients taking Verzenio with fulvestrant was 16.4 months compared to 9.3 months for patients taking a placebo with fulvestrant.

The safety and efficacy of Verzenio as a stand-alone treatment were studied in a single-arm trial of 132 patients with HR-positive, HER2-negative breast cancer that had progressed after treatment with endocrine therapy and chemotherapy after the cancer metastasized. The study measured the percent of patients whose tumors completely or partially shrank after treatment (objective response rate). In the study, 19.7 percent of patients taking Verzenio experienced complete or partial shrinkage of their tumors for a median 8.6 months.

Common side effects of Verzenio include diarrhea, low levels of certain white blood cells (neutropenia and leukopenia), nausea, abdominal pain, infections, fatigue, low levels of red blood cells (anemia), decreased appetite, vomiting and headache.

Serious side effects of Verzenio include diarrhea, neutropenia, elevated liver blood tests and blood clots (deep venous thrombosis/pulmonary embolism). Women who are pregnant should not take Verzenio because it may cause harm to a developing fetus.

The FDA granted this application Priority Review and Breakthrough Therapydesignations.

The FDA granted the approval of Verzenio to Eli Lilly and Company.

//////////Verzenio, abemaciclib, fda 2017, metastatic breast cancers, Eli Lilly ,  Priority Review,  Breakthrough Therapy designations, antibodies

Vaborbactam, Ваборбактам , فابورباكتام , 法硼巴坦 ,


Vaborbactam.svg

 Image result for VaborbactamImage result for Vaborbactam
Vaborbactam 
RN: 1360457-46-0
UNII: 1C75676F8V
Molecular Formula. C12-H16-B-N-O5-S
Molecular Weight. 297.1374
1,2-Oxaborinane-6-acetic acid, 2-hydroxy-3-((2-(2-thienyl)acetyl)amino)-, (3R,6S)-
B1([C@H](CC[C@H](O1)CC(=O)O)NC(=O)Cc2cccs2)O
RPX7009
A beta-lactamase inhibitor.
Treatment of Bacterial Infection
{(3R,6S)-2-Hydroxy-3-[(2-thienylacetyl)amino]-1,2-oxaborinan-6-yl}acetic acid
2-[(3R,6S)-2-hydroxy-3-[(2-thiophen-2-ylacetyl)amino]oxaborinan-6-yl]acetic acid
1,2-Oxaborinane-6-acetic acid, 2-hydroxy-3-[[2-(2-thienyl)acetyl]amino]-, (3R,6S)-
Ваборбактам [Russian]
فابورباكتام [Arabic]
法硼巴坦 [Chinese]
  • Originator Rempex Pharmaceuticals
  • Developer The Medicines Company; US Department of Health and Human Services
  • Class Antibacterials; Pyrrolidines; Small molecules; Thienamycins
  • Mechanism of Action Beta lactamase inhibitors; Cell wall inhibitors

Highest Development Phases

  • Registered Urinary tract infections
  • Phase III Bacteraemia; Gram-negative infections; Pneumonia; Pyelonephritis

Most Recent Events

  • 29 Aug 2017 Registered for Urinary tract infections (Treatment-experienced, Treatment-resistant) in USA (IV) – First global approval
  • 29 Aug 2017 Updated efficacy and safety data from a phase III trial in Gram-negative infections released by The Medicines Company
  • 09 Aug 2017 Planned Prescription Drug User Fee Act (PDUFA) date for Urinary tract infections (Treatment-experienced, Treatment-resistant) in USA (IV) is 2017-08-29
 
Rapidly rising resistance to multiple antimicrobial agents in Gram-negative bacteria, commonly related to healthcare-associated infections, is an emerging public health concern in U.S. hospitals. While the cephalosporin class of β-lactams was the mainstay of treatment in the 1980s, the dissemination of extended-spectrum β-lactamases (ESBLs) over the past 2 decades has dramatically weakened the utility of this class and brought about a corresponding reliance on the carbapenems.(1) Although carbapenems are widely recognized as a safe and effective class of antimicrobials, carbapenem-resistant Enterobacteriaceae (CRE) due to the Klebsiella pneumoniaecarbapenemase (KPC) and other β-lactamases now threatens the usefulness of all β-lactam antibiotics.(2) The Centers for Disease Control (CDC) considers CRE to be an urgent antimicrobial resistance threat that now has been detected in nearly every U.S. state, with an alarming increase in incidence over the past 5 years.(3) The failure to develop antimicrobial agents to manage CRE threatens to have a catastrophic impact on the healthcare system.(4)
A proven strategy to overcome resistance to β-lactam antibiotics has been to restore their activity by combining them with an inhibitor of the β-lactamase enzymes responsible for their degradation. Examples of clinically important β-lactamase inhibitors (Figure 1) include clavulanic acid (combined with amoxicillin), sulbactam (with ampicillin), and tazobactam (with piperacillin). The KPC β-lactamase is poorly inhibited by these β-lactamase inhibitors, and thus, they have no usefulness in the treatment of infections due to CRE. More recently, the diazabicyclooctane inhibitors avibactam (NXL-104)(5) and relebactam (MK-7655)(6) have entered clinical development, in combination with ceftazidime and imipenem, respectively. Both compounds display a broad spectrum of β-lactamase inhibition that includes the KPC enzyme.

Image result for VaborbactamNext generation β-lactamase inhibitors recently approved or in clinical trials. A. Avibactam. B. Relebactam. C. Vaborbactam.

Vaborbactam (INN)[1] is a non-β-lactam β-lactamase inhibitor discovered by Rempex Pharmaceuticals, a subsidiary of The Medicines Company. While not effective as an antibiotic by itself, it restores potency to existing antibiotics by inhibiting the beta-lactamase enzymes that would otherwise degrade them. When combined with an appropriate antibiotic it can be used for the treatment of gram-negative bacterial infections.[2]

According to a Medicines Company press release, as of June 2016 a combination of vaborbactam with the carbapenem antibiotic meropenem had met all pre-specified primary endpoints in a phase III clinical trial in patients with complicated urinary tract infections.[3] The company planned to submit an NDA to the FDAin early 2017.

Biochemistry

Carbapenemases are a family of β-lactamase enzymes distinguished by their broad spectrum of activity and their ability to degrade carbapenem antibiotics, which are frequently used in the treatment of multidrug-resistant gram-negative infections.[4] Carbapenemases can be broadly divided into two different categories based on the mechanism they use to hydrolyze the lactam ring in their substrates. Metallo-β-lactamases contain bound zinc ions in their active sites and are therefore inhibited by chelating agents like EDTA, while serine carbapenemases feature an active site serine that participates in the hydrolysis of the substrate.[4] Serine carbapenemase-catalyzed hydrolysis employs a three-step mechanism featuring acylation and deacylation steps analogous to the mechanism of protease-catalyzed peptide hydrolysis, proceeding through a tetrahedral transition state.[4][5]

Boronic acids are unusual in their ability to reversibly form covalent bonds with alcohols such as the active site serine in a serine carbapenemase. This property enables them to function as transition state analogs of serine carbapenemase-catalyzed lactam hydrolysis and thereby inhibit these enzymes. Based on data from Hecker et al., vaborbactam is a potent inhibitor of a variety of β-lactamases, exhibiting a 69-nanomolar {\displaystyle K_{i}}K_{i} against the KPC-2 carbapenemase and even lower inhibition constants against CTX-M-15 and SHV-12.[2]

Given their mechanism of action, the possibility of off-target effects brought about through inhibition of endogenous serine hydrolases is an obvious possible concern in the development of boronic acid β-lactamase inhibitors, and in fact boronic acids like bortezomib have previously been investigated or developed as inhibitors of various human proteases.[2] Vaborbactam, however, is a highly specific β-lactamase inhibitor, with an IC50 >> 1 mM against all human serine hydrolases against which it has been tested.[2] Consistent with its high in vitro specificity, vaborbactam exhibited a good safety profile in human phase I clinical trials, with similar adverse events observed in both placebo and treatment groups.[6] Hecker et al. argue this specificity results from the higher affinity of human proteases to linear molecules; thus it is expected that a boron heterocycle will have zero effect on them.

SYN

WO 2015171430

 

 

PATENT

Image result for Rempex Pharmaceuticals, Inc.

Inventors Gavin HirstRaja ReddyScott HeckerMaxim TotrovDavid C. GriffithOlga RodnyMichael N. DudleySerge BoyerLess «
Applicant Rempex Pharmaceuticals, Inc.
WO 2012021455

Antibiotics have been effective tools in the treatment of infectious diseases during the last half-century. From the development of antibiotic therapy to the late 1980s there was almost complete control over bacterial infections in developed countries. However, in response to the pressure of antibiotic usage, multiple resistance mechanisms have become widespread and are threatening the clinical utility of antibacterial therapy. The increase in antibiotic resistant strains has been particularly common in major hospitals and care centers. The consequences of the increase in resistant strains include higher morbidity and mortality, longer patient hospitalization, and an increase in treatment costs

[0003] Various bacteria have evolved β-lactam deactivating enzymes, namely, β-lactamases, that counter the efficacy of the various β-lactams. β-lactamases can be grouped into 4 classes based on their amino acid sequences, namely, Ambler classes A, B, C, and D. Enzymes in classes A, C, and D include active-site serine β-lactamases, and class B enzymes, which are encountered less frequently, are Zn-dependent. These enzymes catalyze the chemical degradation of β-lactam antibiotics, rendering them inactive. Some β-lactamases can be transferred within and between various bacterial strains and species. The rapid spread of bacterial resistance and the evolution of multi- resistant strains severely limits β-lactam treatment options available.

[0004] The increase of class D β-lactamase-expressing bacterium strains such as Acinetobacter baumannii has become an emerging multidrug-resistant threat. A. baumannii strains express A, C, and D class β-lactamases. The class D β-lactamases such as the OXA families are particularly effective at destroying carbapenem type β-lactam antibiotics, e.g., imipenem, the active carbapenems component of Merck’s Primaxin® (Montefour, K.; et al. Crit. Care Nurse 2008, 28, 15; Perez, F. et al. Expert Rev. Anti Infect. Ther. 2008, 6, 269; Bou, G.; Martinez-Beltran, J. Antimicrob. Agents Chemother. 2000, 40, 428. 2006, 50, 2280; Bou, G. et al, J. Antimicrob. Agents Chemother. 2000, 44, 1556). This has imposed a pressing threat to the effective use of drugs in that category to treat and prevent bacterial infections. Indeed the number of catalogued serine-based β- lactamases has exploded from less than ten in the 1970s to over 300 variants. These issues fostered the development of five “generations” of cephalosporins. When initially released into clinical practice, extended- spectrum cephalosporins resisted hydrolysis by the prevalent class A β-lactamases, TEM-1 and SHV-1. However, the development of resistant strains by the evolution of single amino acid substitutions in TEM-1 and SHV-1 resulted in the emergence of the extended- spectrum β-lactamase (ESBL) phenotype.

[0005] New β-lactamases have recently evolved that hydrolyze the carbapenem class of antimicrobials, including imipenem, biapenem, doripenem, meropenem, and ertapenem, as well as other β-lactam antibiotics. These carbapenemases belong to molecular classes A, B, and D. Class A carbapenemases of the KPC-type predominantly in Klebsiella pneumoniae but now also reported in other Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. The KPC carbapenemase was first described in 1996 in North Carolina, but since then has disseminated widely in the US. It has been particularly problematic in the New York City area, where several reports of spread within major hospitals and patient morbidity have been reported. These enzymes have also been recently reported in France, Greece, Sweden, United Kingdom, and an outbreak in Germany has recently been reported. Treatment of resistant strains with carbapenems can be associated with poor outcomes.

[0006] Another mechanism of β-lactamase mediated resistance to carbapenems involves combination of permeability or efflux mechanisms combined with hyper production of beta-lactamases. One example is the loss of a porin combined in hyperproduction of ampC beta-lactamase results in resistance to imipenem in Pseudomonas aeruginosa. Efflux pump over expression combined with hyperproduction of the ampC β-lactamase can also result in resistance to a carbapenem such as meropenem.

[0007] Because there are three major molecular classes of serine-based β- lactamases, and each of these classes contains significant numbers of β-lactamase variants, inhibition of one or a small number of β-lactamases is unlikely to be of therapeutic value. Legacy β-lactamase inhibitors are largely ineffective against at least Class A carbapenemases, against the chromosomal and plasmid-mediated Class C cephalosporinases and against many of the Class D oxacillinases. Therefore, there is a need for improved β-lactamase inhibitors.

The following compounds are prepared starting from enantiomerically pure (R)-tert-butyl 3-hydroxypent-4-enoate (J. Am. Chem. Soc. 2007, 129, 4175-4177) in accordance with the procedure described in the above Example 1.

5

[0192] 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-l,2-oxaborinan-6-yl)acetic acid 5. 1H NMR (CD3OD) δ ppm 0.97-1.11 (q, IH), 1.47-1.69 (m, 2H), 1.69-1.80 (m, IH), 2.21-2.33 (td, IH), 2.33-2.41 (dd, IH), 2.58-2.67 (m, IH), 3.97 (s, 2H), 4.06-4.14 (m, IH), 6.97-7.04 (m, IH), 7.04-7.08 (m, IH), 7.34-7.38 (dd, IH); ESIMS found for Ci2Hi6BN05S m/z 28 -H20)+.

PATENT
WO 2013122888

The following compounds are prepared starting from enantiomerically pure (R)-tert-butyl 3-hydroxypent-4-enoate (J. Am. Chem. Soc. 2007, 129, 4175-4177) in accordance with the procedure described in the above Example 1.

Figure imgf000091_0001

5

[0175] 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-l,2-oxaborinan-6- yl)acetic acid 5. 1H NMR (CD3OD) δ ppm 0.97-1.11 (q, 1H), 1.47-1.69 (m, 2H), 1.69-1.80 (m, 1H), 2.21-2.33 (td, 1H), 2.33-2.41 (dd, 1H), 2.58-2.67 (m, 1H), 3.97 (s, 2H), 4.06-4.14 (m, 1H), 6.97-7.04 (m, 1H), 7.04-7.08 (m, 1H), 7.34-7.38 (dd, 1H); ESIMS found for Ci2Hi6BN05S m/z 280 (100%) (M-H20)+.

 PATENT
WO 2015171430 

EXAMPLES

Example 1 – Synthesis of Intermediate Compound 10

[0191] The compound of Formula 10 was synthesized as shown in Scheme 3, below:

Scheme 3

95%

80% for 2 steps

(i?)-t-butyl 3-(trimethysilyloxy)-pent-4-enoate (7)

[0192] Chlorotrimethylsilane (4.6 mL, 36.3 mmol, 1.25 eq) was added to a solution of (R)-t-butyl 3-hydroxy-pent-4-enoate (1, 5 g, 29 mmol) and triethylamine (5.3 mL, 37.3 mmol, 1.3 eq) in dichloromethane (25 mL) keeping the temperature below 30 °C. After completion of the addition, the white heterogeneous mixture was stirred at rt for 20 minutes (TLC, GC, note 2) then quenched with MeOH (352 μί, 0.3 eq). After stirring at rt for 5 minutes, the white heterogeneous reaction mixture was diluted with heptane (25 mL). The salts were filtered off and rinsed with heptane (2 x 10 mL). The combined turbid filtrates were washed with a saturated solution of NaHC03 (2 x 25 mL) and concentrated to dryness. The residual oil was azeotroped with heptane (25 mL) to give a colorless oil that was used immediately.

QSVt-butyl 3-(trimethylsilyloxy)-5-(4,4,5,5-tetramethyl-[L3,21dioxaborolan-2-yl)-pentanoate (8)

[0193] A solution of bis-diphenylphosphino-ethane (46.3 mg, 0.2 mol%) and [Ir(COD)Cl]2 (39 mg, 0.1 mol%) in CH2C12 (5 mL) was added to a refluxing solution of crude TMS-protected pentenoate 7. Pinacol borane (9.3 mL,l .l eq) was added to the

refluxing solution. After stirring at reflux for 3 h, the reaction mixture was cooled to room temperature, concentrated to dryness and taken up in heptane (50 mL). The insolubles were filtered over Celite and rinse with heptane (10 mL).

Ethanolamine-boronic acid salt (10)

[0194] A mixture of fully protected boronate 8 (5.0 g, 13.4 mmol), 0.5 N HC1 (5 mL) and acetone (0.5 mL) was stirred vigorously at room temperature, providing intermediate 9. After complete consumption of the starting material, a solution of NaI04 (3.44 g, 1.2 eq) in water (15 mL) was added slowly keeping the temperature <30 °C. Upon the completion of the addition (30 min), the reaction mixture was allowed to cool to room temperature. After consumption of all pinacol, MTBE (5 mL) was added. After stirring at room temperature for 10 min, the white solids were filtered off and rinsed with MTBE (2 x 5 mL). The filtrate was partitioned and the aqueous layer was extracted with MTBE (10 mL). The combined organic extracts were washed sequentially with a 0.1 M NaHS03 solution (2 x 5 mL), a saturated NaHC03 solution (5 mL) and brine (5 mL). The organic layer was concentrated to dryness. The residue was taken up in MTBE (15 mL) and the residual salts filtered off. The filtrate was concentrated to dryness and the residue was taken up in MTBE (10 mL) and acetonitrile (1.7 mL). Ethanolamine (0.99 mL, 1.1 eq) was added. After stirring at room temperature for 1 hour, the heterogeneous mixture was stirred at 0 °C. After stirring at 0 °C for 2 hours, the solids were collected by filtration, rinsed with MTBE (2 x 5 mL), air dried then dried under high vacuum to give Compound 10 as a white granular powder.

Example 2 – Preparation of Beta-Lactamase Inhibitor (15)

[0195] The compound of Formula 15 was synthesized as shown in Scheme 4 below:

Scheme 4

Synthesis of pinanediol boronate (12)

[0196] Ethanolammonium boronate 11 (15 g, 61.7 mmol) and pinanediol (10.5 g, 61.7 mmol, 1 eq) were suspended in MTBE (75 mL). Water (75 mL) was added and the yellow biphasic heterogeneous mixture was stirred at room temperature. After stirring for 2 hours at room temperature, some pinanediol was still present and stirring was continued overnight. The layers were separated and the organic layer was washed with brine, concentrated under reduced pressure and azeotroped with MTBE (2 x 30 mL). The residual oil was taken up in dichloromethane (40 mL). In another flask, TBSC1 (1 1.6 g, 77.1 mmol, 1.25 eq) was added to a solution of imidazole (9.66 g, 141.9 mmol, 2.3 eq) in dichloromethane (25 mL). The white slurry was stirred at room temperature. After 5 minutes, the solution of pinanediol boronate was added to the white slurry and the flask was rinsed with dichloromethane (2 x 5 mL). The heterogeneous reaction mixture was heated at reflux temeprature. After stirring at reflux for 8 hours, the reaction mixture was cooled to 30 °C and TMSC1 (330 \JL) was added. After stirring 30 minutes at 30 °C, MeOH (15 mL) was added. After stirring at room temperature overnight, the reaction mixture was washed sequentially with 0.5 N HC1 (115 niL), 0.5 N HC1 (60 n L) and saturated NaHC03 (90 niL). The organic layer was concentrated under reduced pressure and azeotroped with heptane (150 n L) to give 12 as a yellow oil (27.09 g, 94.1%) which was used without purification.

Synthesis of chloroboronate (13)

[0197] A solution of n-butyllithium (2.5 M in hexane, 29.6 niL, 74.1 mmol, 1.3 eq) was added to THF (100 mL) at -80 °C. The resulting solution was cooled to -100 °C. A solution of dichloromethane (14.6 mL, 228 mmol, 4 eq) in THF (25 mL) was added via syringe pump on the sides of the flask keeping the temperature < -95 °C. During the second half of the addition a precipitate starts to appear which became thicker with the addition of the remaining dichloromethane solution. After stirring between -100 and -95 °C for 30 min, a solution of 12 (26.59 g, 57 mmol) in THF (25 mL) was added by syringe pump on the sides of the flask while maintaining the batch temperature < -95 °C to give a clear yellow solution. After stirring between -100 and -95 °C for 30 min, a solution of zinc chloride (1 M in ether, 120 mL, 120 mmol, 2.1 eq) was added keeping the temperature < -70 °C. The reaction mixture was then warmed to room temperature (at about -18 °C the reaction mixture became turbid/heterogeneous). After stirring at room temperature for 2 hours, the reaction mixture was cooled to 15 °C and quenched with 1 N HC1 (100 mL). The layers were separated and the organic layer was washed sequentially with 1 N HC1 (100 mL) and water (2 x 100 mL), concentrated to oil and azeotroped with heptane (3 x 150 mL) to provide 13 as a yellow oil (30.03 g, 102%) which was used without purification.

Synthesis of (14)

[0198] LiHMDS (1 M in THF, 63 mL, 62.7 mmol, 1.1 eq) was added to a solution of 13 (29.5 g, 57 mmol) in THF (60 mL) while maintaining the batch temperature at < -65 °C. After stirring at -78 °C for 2 hours, additional LiHMDS (5.7 mL, 0.1 eq) was added to consume the remaining starting material. After stirring at -78 °C for 30 minutes, the tan reaction mixture was warmed to room temperature. After stirring at room temperature for one hour, the solution of silylated amine was added via cannula to a solution of HOBT ester of 2-thienylacetic acid in acetonitrile at 0 °C (the solution of HOBT ester was prepared by adding EDCI (16.39 g, 85.5 mmol, 1.5 eq) to a suspension of recrystallized 2-thienylacetic acid (9.73 g, 68.4 mmol, 1.2 eq) and HOBT.H20 (11.35 g, 74.1 mmol, 1.3 eq) in acetonitrile (10 mL) at 0 °C. The clear solution was stirred at 0 °C for 30 minutes prior to the addition of the silylated amine). After stirring at 0 °C for one hour, the heterogeneous reaction mixture was placed in the fridge overnight. Saturated aqueous sodium bicarbonate (80 mL) and heptane (80 mL) were added, and after stirring 30 minutes at room temperature, the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate (2 x 80 mL) and filtered through Celite. The filtrate was concentrated under reduced pressure and the tan oil was azeotroped with heptane (3 x 1 10 mL). The residue was taken up in heptane (60 mL) and seeds were added. After stirring at room temperature for one hour, the reaction mixture became heterogeneous. After stirring 4 hours at 0 °C, the solids were collected by filtration and washed with ice cold heptane (3 x 20 mL), air dried then dried under high vacuum to give 14 as an off white powder (10.95 g, 31%).

Synthesis of (15)

[0199] A mixture of 14 (10 g, 16.1 mmol), boric acid (1.3 g, 20.9 mmol, 1.3 eq), dioxane (20 mL), and 1 M sulfuric acid (10 mL) was heated at 75 °C. After stirring 7 hours at 75 °C, the cooled reaction mixture was diluted with water (10 mL) and MTBE (30 mL) and the residual mixture was cooled to 0 °C. The pH was adjusted to 5.0 with a solution of 2 N NaOH (14 mL). The layers were separated and the aqueous layer was extracted with MTBE (2 x 30 mL) then concentrated to dryness. The residue was taken up in water (10 mL) and the solution was filtered through a 0.45 μηι GMF syringe filter. The flask and filter were rinsed with water (7.5 mL). The pH of the filtrate was lowered to 4.0 with 2 M H2SO4 and seeds (5 mg) were added. After stirring at room temperature for 10 minutes, the pH was lowered to 1.9 over 1 hour with 2 M H2S04 (total volume 3.5 mL). After stirring at room temperature for 2 hours, the solids were collected by filtration. The filtrate was recirculated twice to rinse the flask and the cake was washed with water (2 x 12 mL), air dried then dried under high vacuum to give 15 as a white powder (3.63 g, 76%).

PAPER
 
Journal of Medicinal Chemistry (2015), 58(9), 3682-3692
Discovery of a Cyclic Boronic Acid β-Lactamase Inhibitor (RPX7009) with Utility vs Class A Serine Carbapenemases
 Rempex Pharmaceuticals, Inc., A Subsidiary of The Medicines Company, 3033 Science Park Rd., Suite 200, San Diego, California 92121, United States
 Molsoft L.L.C., 11199 Sorrento Valley Road, San Diego, California 92121, United States
§ Beryllium, 3 Preston Court, Bedford, Massachusetts 01730, United States
J. Med. Chem.201558 (9), pp 3682–3692
DOI: 10.1021/acs.jmedchem.5b00127
Publication Date (Web): March 17, 2015
Copyright © 2015 American Chemical Society
*Phone: 858-875-6678. E-mail: scott.hecker@themedco.com.
Abstract
The increasing dissemination of carbapenemases in Gram-negative bacteria has threatened the clinical usefulness of the β-lactam class of antimicrobials. A program was initiated to discover a new series of serine β-lactamase inhibitors containing a boronic acid pharmacophore, with the goal of finding a potent inhibitor of serine carbapenemase enzymes that are currently compromising the utility of the carbapenem class of antibacterials. Potential lead structures were screened in silico by modeling into the active sites of key serine β-lactamases. Promising candidate molecules were synthesized and evaluated in biochemical and whole-cell assays. Inhibitors were identified with potent inhibition of serine carbapenemases, particularly the Klebsiella pneumoniae carbapenemase (KPC), with no inhibition of mammalian serine proteases. Studies in vitro and in vivo show that RPX7009 (9f) is a broad-spectrum inhibitor, notably restoring the activity of carbapenems against KPC-producing strains. Combined with a carbapenem9f is a promising product for the treatment of multidrug resistant Gram-negative bacteria.
 
 
1 to 4 of 4
Patent ID
Patent Title
Submitted Date
Granted Date
CYCLIC BORONIC ACID ESTER DERIVATIVES AND THERAPEUTIC USES THEREOF
2013-07-29
2013-12-26
Cyclic boronic acid ester derivatives and therapeutic uses thereof
2011-08-08
2014-03-25
CYCLIC BORONIC ACID ESTER DERIVATIVES AND THERAPEUTIC USES THEREOF
2013-03-15
2013-12-12
METHODS OF TREATING BACTERIAL INFECTIONS
2013-02-11
2015-04-30
from PubChem
 
 

References

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Vaborbactam
Vaborbactam.svg
Clinical data
Routes of
administration
IV
ATC code
  • None
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C12H16BNO5S
Molar mass 297.13 g·mol−1
3D model (JSmol)

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FDA approves new antibacterial drug Vabomere (meropenem, vaborbactam)

Image result for meropenem

Meropenem

Beta-lactamase inhibitor vaborbactam
08/29/2017
The U.S. Food and Drug Administration today approved Vabomere for adults with complicated urinary tract infections (cUTI), including a type of kidney infection, pyelonephritis, caused by specific bacteria. Vabomere is a drug containing meropenem, an antibacterial, and vaborbactam, which inhibits certain types of resistance mechanisms used by bacteria.

The U.S. Food and Drug Administration today approved Vabomere for adults with complicated urinary tract infections (cUTI), including a type of kidney infection, pyelonephritis, caused by specific bacteria. Vabomere is a drug containing meropenem, an antibacterial, and vaborbactam, which inhibits certain types of resistance mechanisms used by bacteria.

“The FDA is committed to making new safe and effective antibacterial drugs available,” said Edward Cox, M.D., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research. “This approval provides an additional treatment option for patients with cUTI, a type of serious bacterial infection.”

The safety and efficacy of Vabomere were evaluated in a clinical trial with 545 adults with cUTI, including those with pyelonephritis. At the end of intravenous treatment with Vabomere, approximately 98 percent of patients treated with Vabomere compared with approximately 94 percent of patients treated with piperacillin/tazobactam, another antibacterial drug, had cure/improvement in symptoms and a negative urine culture test. Approximately seven days after completing treatment, approximately 77 percent of patients treated with Vabomere compared with approximately 73 percent of patients treated with piperacillin/tazobactam had resolved symptoms and a negative urine culture.

The most common adverse reactions in patients taking Vabomere were headache, infusion site reactions and diarrhea. Vabomere is associated with serious risks including allergic reactions and seizures. Vabomere should not be used in patients with a history of anaphylaxis, a type of severe allergic reaction to products in the class of drugs called beta-lactams.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of antibacterial drugs, Vabomere should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

Vabomere was designated as a qualified infectious disease product (QIDP). This designation is given to antibacterial products that treat serious or life-threatening infections under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act. As part of its QIDP designation, Vabomere received a priority review.

The FDA granted approval of Vabomere to Rempex Pharmaceuticals.

Image result for VaborbactamMoxalactam synthesis

Latamoxef (or moxalactam)

http://www.wikiwand.com/en/Latamoxef

////////////////RPX7009, RPX 7009, VABORBACTAM, Vaborbactam, Ваборбактам ,   فابورباكتام ,   法硼巴坦 , FDA 2017

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