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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 30 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, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 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 19 lakh plus views on New Drug Approvals Blog in 216 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 antibiotic Xenleta (lefamulin) to treat community-acquired bacterial pneumonia


FDA approves new antibiotic  Xenleta (lefamulin) to treat community-acquired bacterial pneumonia

The U.S. Food and Drug Administration today approved Xenleta (lefamulin) to treat adults with community-acquired bacterial pneumonia.

“This new drug provides another option for the treatment of patients with community-acquired bacterial pneumonia, a serious disease,” said Ed Cox, M.D., M.P.H., director of FDA’s Office of Antimicrobial Products. “For managing this serious disease, it is important for physicians and patients to have treatment options. This approval reinforces our ongoing commitment to address treatment of infectious diseases by facilitating the development of new antibiotics.”

Community-acquired pneumonia occurs when someone develops pneumonia in the community (not in a hospital). Pneumonia is a type of lung infection that can range in severity from mild to severe illness and can affect people of all ages. According to data from the Centers from Disease Control and Prevention, each year in the United States, about one million people are hospitalized with community-acquired pneumonia and 50,000 people die from the disease.

The safety and efficacy of Xenleta, taken either orally or intravenously, was evaluated in two clinical trials with a total of 1,289 patients with CABP. In these trials, treatment with Xenleta was compared to another antibiotic, moxifloxacin with or without linezolid. The trials showed that patients treated with Xenleta had similar rates of clinical success as those treated with moxifloxacin with or without linezolid.

The most common adverse reactions reported in patients taking Xenleta included diarrhea, nausea, reactions at the injection site, elevated liver enzymes and vomiting. Xenleta has the potential to cause a change on an ECG reading (prolonged QT interval). Patients with prolonged QT interval, patients with certain irregular heart rhythms (arrhythmias), patients receiving treatment for certain irregular heart rhythms (antiarrhythmic agents), and patients receiving other drugs that prolong the QT interval should avoid Xenleta. In addition, Xenleta should not be used in patients with known hypersensitivity to lefamulin or any other members of the pleuromutilin antibiotic class, or any of the components of Xenleta. Based on findings of fetal harm in animal studies, pregnant women and women who could become pregnant should be advised of the potential risks of Xenleta to a fetus. Women who could become pregnant should be advised to use effective contraception during treatment with Xenleta and for two days after the final dose.

Xenleta received FDA’s Qualified Infectious Disease Product (QIDP) designation. The QIDP designation is given to antibacterial and antifungal drug products intended to treat serious or life-threatening infections under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act. As part of QIDP designation, Xenleta was granted Priority Review under which the FDA’s goal is to take action on an application within an expedited time frame.

The FDA granted the approval of Xenleta to Nabriva Therapeutics.

A key global challenge the FDA faces as a public health agency is addressing the threat of antimicrobial-resistant infections. Among the FDA’s other efforts to address antimicrobial resistance, is the focus on facilitating the development of safe and effective new treatments to give patients more options to fight serious infections.

LINK

http://s2027422842.t.en25.com/e/er?utm_campaign=081919_PR_FDA%20approves%20new%20antibiotic%20to%20treat%20community-acquired%20bacterial%20pneumonia&utm_medium=email&utm_source=Eloqua&s=2027422842&lid=9299&elqTrackId=AC98B5F2F3FDA7EADC5780AB18C8861A&elq=a5d6c9e321e34425b20035738f0e4edf&elqaid=9185&elqat=1

//////////Xenleta,  Nabriva Therapeutics, Qualified Infectious Disease Product, QIDP, fda 2019, Generating Antibiotic Incentives Now, GAIN, lefamulin, community-acquired bacterial pneumonia, antibacterial, Priority Review

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FDA approves new treatment for hospital-acquired and ventilator-associated bacterial pneumonia


The U.S. Food and Drug Administration today approved a new indication for the previously FDA-approved drug, Zerbaxa (ceftolozane and tazobactam) for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) in patients 18 years and older. The FDA initially approved Zerbaxa in 2014 to treat complicated intra-abdominal infections and for complicated urinary tract infections.

“A key global challenge we face as a public health agency is addressing the threat of antimicrobial-resistant infections,” said FDA Principal Deputy Commissioner Amy Abernethy, M.D., Ph.D. “Hospital-acquired and ventilator-associated bacterial pneumonia are serious infections that can result in death in some patients. New therapies to treat these infections are important to …

https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-hospital-acquired-and-ventilator-associated-bacterial-pneumonia?utm_campaign=060319_PR_FDA%20approves%20treatment%20for%20hospital-acquired%20and%20ventilator-associated%20bacterial%20pneumonia&utm_medium=email&utm_source=Eloqua

June 03, 2019

The U.S. Food and Drug Administration today approved a new indication for the previously FDA-approved drug, Zerbaxa (ceftolozane and tazobactam) for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) in patients 18 years and older. The FDA initially approved Zerbaxa in 2014to treat complicated intra-abdominal infections and for complicated urinary tract infections.

“A key global challenge we face as a public health agency is addressing the threat of antimicrobial-resistant infections,” said FDA Principal Deputy Commissioner Amy Abernethy, M.D., Ph.D. “Hospital-acquired and ventilator-associated bacterial pneumonia are serious infections that can result in death in some patients. New therapies to treat these infections are important to meet patient needs because of increasing antimicrobial resistance. That’s why, among our other efforts to address antimicrobial resistance, we’re focused on facilitating the development of safe and effective new treatments to give patients more options to fight life-threatening infections.”

HABP/VABP occur in patients in hospitals or other health care facilities and can be caused by a variety of bacteria. According to data from the U.S. Centers for Disease Control and Prevention, HABP and VABP are currently the second most common type of hospital-acquired infection in the United States, and are a significant issue in patients in the intensive care unit (ICU).

The safety and efficacy of Zerbaxa for the treatment of HABP/VABP, administered via injection, was demonstrated in a multinational, double-blind study that compared Zerbaxa to another antibacterial drug in 726 adult patients hospitalized with HABP/VABP. The study showed that mortality and cure rates were similar between Zerbaxa and the comparator treatment.

The most common adverse reactions observed in the HABP/VABP trial among patients treated with Zerbaxa were elevated liver enzyme levels, renal impairment or failure, and diarrhea.
Zerbaxa should not be used in patients with known serious hypersensitivity to components of Zerbaxa, as well as hypersensitivity to piperacillin/tazobactam or other members of the beta lactam class of antibacterial drugs.

Zerbaxa received FDA’s Qualified Infectious Disease Product (QIDP) designation for the treatment of HABP/VABP. The QIDP designation is given to antibacterial and antifungal drug products intended to treat serious or life-threatening infections under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act. As part of QIDP designation, the Zerbaxa marketing application for the HABP/VABP indication was granted Priority Review under which the FDA’s goal is to take action on an application within an expedited time frame.

The FDA granted the approval of Zerbaxa for the treatment of HABP/VABP to Merck & Co., Inc.

//////////////ceftolozane,  tazobactam, FDA 2019,  Zerbaxa,  HABP/VABP, Merck , Qualified Infectious Disease Product,  (QIDP),  Priority Review

FDA approves new drug Aemcolo (rifamycin), to treat travelers’ diarrhea


FDA approves new drug to treat travelers’ diarrhea
The U.S. Food and Drug Administration today approved Aemcolo (rifamycin), an antibacterial drug indicated for the treatment of adult patients with travelers’ diarrhea caused by noninvasive strains of Escherichia coli (E. coli), not complicated by fever or blood in the stool.
“Travelers’ diarrhea affects millions of people each year and having treatment options for this condition can help reduce symptoms of the condition,” said Edward Cox, M.D., M.P.H., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.
Travelers’ diarrhea is the most common travel-related illness, affecting an estimated 10 to 40 percent of travelers worldwide each year. Travelers’ diarrhea is defined by …

November 16, 2018

Release

The U.S. Food and Drug Administration today approved Aemcolo (rifamycin), an antibacterial drug indicated for the treatment of adult patients with travelers’ diarrhea caused by noninvasive strains of Escherichia coli (E. coli), not complicated by fever or blood in the stool.

“Travelers’ diarrhea affects millions of people each year and having treatment options for this condition can help reduce symptoms of the condition,” said Edward Cox, M.D., M.P.H., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

Travelers’ diarrhea is the most common travel-related illness, affecting an estimated 10 to 40 percent of travelers worldwide each year. Travelers’ diarrhea is defined by having three or more unformed stools in 24 hours, in a person who is traveling. It is caused by a variety of pathogens, but most commonly bacteria found in food and water. The highest-risk destinations are in most of Asia as well as the Middle East, Africa, Mexico, and Central and South America.

The efficacy of Aemcolo was demonstrated in a randomized, placebo-controlled clinical trial in 264 adults with travelers’ diarrhea in Guatemala and Mexico. It showed that Aemcolo significantly reduced symptoms of travelers’ diarrhea compared to the placebo.

The safety of Aemcolo, taken orally over three or four days, was evaluated in 619 adults with travelers’ diarrhea in two controlled clinical trials. The most common adverse reactions with Aemcolo were headache and constipation.

Aemcolo was not shown to be effective in patients with diarrhea complicated by fever and/or bloody stool or diarrhea due to pathogens other than noninvasive strains of E. coli and is not recommended for use in such patients. Aemcolo should not be used in patients with a known hypersensitivity to rifamycin, any of the other rifamycin class antimicrobial agents (e.g. rifaximin), or any of the components in Aemcolo.

The FDA granted Aemcolo a Qualified Infectious Disease Product (QIDP)designation. QIDP designation is given to antibacterial and antifungal drug 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 QIDP designation, the Aemcolo marketing application was granted Priority Review under which the FDA’s goal is to take action on an application within an expedited time frame.

The FDA granted approval of Aemcolo to Cosmo Technologies, Ltd.

///////////////// Aemcolo, rifamycin, fda 2018, qidp, priority review

FDA approves a new antibacterial drug to treat a serious lung disease using a novel pathway to spur innovation


FDA approves a new antibacterial drug to treat a serious lung disease using a novel pathway to spur innovation

First drug granted approval under FDA’s Limited Population Pathway for Antibacterial and Antifungal Drugs, instituted to spur development of antibiotics for unmet medical needs

The U.S. Food and Drug Administration today approved a new drug, Arikayce (amikacin liposome inhalation suspension), for the treatment of lung disease caused by a group of bacteria, Mycobacterium avium complex (MAC) in a limited population of patients with the disease who do not respond to conventional treatment (refractory disease).

MAC is a type of nontuberculous mycobacteria (NTM) commonly found in water and soil. Symptoms of disease in patients with MAC include persistent cough, fatigue, weight loss, night sweats, and occasionally shortness of breath and coughing up of blood.

September 28, 2018

Release

The U.S. Food and Drug Administration today approved a new drug, Arikayce (amikacin liposome inhalation suspension), for the treatment of lung disease caused by a group of bacteria, Mycobacterium avium complex (MAC) in a limited population of patients with the disease who do not respond to conventional treatment (refractory disease).

MAC is a type of nontuberculous mycobacteria (NTM) commonly found in water and soil. Symptoms of disease in patients with MAC include persistent cough, fatigue, weight loss, night sweats, and occasionally shortness of breath and coughing up of blood.

“As bacteria continue to grow impervious to currently available antibiotics, we need to encourage the development of drugs that can treat resistant infections. That means utilizing novel tools intended to streamline development and encourage investment into these important endeavors,” said FDA Commissioner Scott Gottlieb, M.D. “This approval is the first time a drug is being approved under the Limited Population Pathway for Antibacterial and Antifungal Drugs, and it marks an important policy milestone. This pathway, advanced by Congress, aims to spur development of drugs targeting infections that lack effective therapies. We’re seeing a lot of early interest among sponsors in using this new pathway, and it’s our hope that it’ll spur more development and approval of antibacterial drugs for treating serious or life-threatening infections in limited populations of patients with unmet medical needs.”

Arikayce is the first drug to be approved under the Limited Population Pathway for Antibacterial and Antifungal Drugs, or LPAD pathway, established by Congress under the 21st Century Cures Act to advance development and approval of antibacterial and antifungal drugs to treat serious or life-threatening infections in a limited population of patients with unmet need. Approval under the LPAD pathway may be supported by a streamlined clinical development program. These programs may involve smaller, shorter or fewer clinical trials. As required for drugs approved under the LPAD pathway, labeling for Arikayce includes certain statements to convey that the drug has been shown to be safe and effective only for use in a limited population.

Arikayce also was approved under the Accelerated Approval pathway. Under this approach, the FDA may approve drugs for serious or life-threatening diseases or conditions where the drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. The approval of Arikayce was based on achieving three consecutive negative monthly sputum cultures by month six of treatment. The sponsor of Arikayce will be required by the FDA to conduct an additional, post-market study to describe the clinical benefits of Arikayce.

The safety and efficacy of Arikayce, an inhaled treatment taken through a nebulizer, was demonstrated in a randomized, controlled clinical trial where patients were assigned to one of two treatment groups. One group of patients received Arikayce plus a background multi-drug antibacterial regimen, while the other treatment group received a background multi-drug antibacterial regimen alone. By the sixth month of treatment, 29 percent of patients treated with Arikayce had no growth of mycobacteria in their sputum cultures for three consecutive months compared to 9 percent of patients who were not treated with Arikayce.

The Arikayce prescribing information includes a Boxed Warning regarding the increased risk of respiratory conditions including hypersensitivity pneumonitis (inflamed lungs), bronchospasm (tightening of the airway), exacerbation of underlying lung disease and hemoptysis (spitting up blood) that have led to hospitalizations in some cases. Other common side effects in patients taking Arikayce were dysphonia (difficulty speaking), cough, ototoxicity (damaged hearing), upper airway irritation, musculoskeletal pain, fatigue, diarrhea and nausea.

The FDA granted this application Fast Track, Breakthrough Therapy, Priority Review, and Qualified Infectious Disease Product (QIDP) designations. QIDP 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. Arikayce also received Orphan Drug designation, which provides additional incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted approval of Arikayce to Insmed, Inc. of Bridgewater, NJ.

/////////////////// Arikayce, amikacin liposome inhalation suspension, fda 2018, Fast Track, Breakthrough Therapy, Priority Review, and Qualified Infectious Disease Product, QIDP, Generating Antibiotic Incentives Now, GAIN,

Isavuconazonium sulfate, Изавуконазониев сулфат


Image result for isavuconazonium
ChemSpider 2D Image | Isavuconazonium sulfate | C35H36F2N8O9S2
Isavuconazonium sulfate
Изавуконазониев сулфат
MOLECULAR FORMULA: C35H36F2N8O9S2
MOLECULAR WEIGHT: 814.837 g/mol
BAL-8557-002, BAL 8557
[2-[1-[1-[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-1,2,4-triazol-4-ium-4-yl]ethoxycarbonyl-methylamino]pyridin-3-yl]methyl 2-(methylamino)acetate;hydrogen sulfate
UNII:31Q44514JV
(2-{[(1-{1-[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-1H-1,2,4-triazol-4-ium-4-yl}ethoxy)carbonyl](methyl)amino}pyridin-3-yl)methyl N-methylglycinate hydrogen sulfate
(2-{[(1-{1-[(2R,3R)-3-[4-(4-Cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-1H-1,2,4-triazol-4-ium-4-yl}ethoxy)carbonyl](methyl)amino}-3-pyridinyl)methyl N-methylglycinate hydrog en sulfate
FDA 2015, EU 2015, BAL8557-002, BCS CLASS I, RO-0098557 , AK-1820
fast track designation
QIDP
ORPHAN DRUG EU
Image result for Isavuconazonium sulfate
1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3- thiazol-2-yl]-2-(2,5-difluoro-phenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl] oxy}methyl) pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium monosulfate (IUPAC), corresponding to the molecular formula C35H35F2N8O5S·HSO4 and has a relative molecular mass of 814.84 g/mol. The relative molecular mass of isavuconazole is 437.47.
Isavuconazonium is a second-generation triazole antifungal approved on March 6, 2015 by the FDA for the treatment of invasive aspergillosis and invasive mucormycosis, marketed by Astellas under the brand Cresemba. It is the prodrug form of isavuconazole, the active moiety, and it is available in oral and parenteral formulations. Due to low solubility in waterof isavuconazole on its own, the isovuconazonium formulation is favorable as it has high solubility in water and allows for intravenous administration. This formulation also avoids the use of a cyclodextrin vehicle for solubilization required for intravenous administration of other antifungals such as voriconazole and posaconazole, eliminating concerns of nephrotoxicity associated with cyclodextrin. Isovuconazonium has excellent oral bioavailability, predictable pharmacokinetics, and a good safety profile, making it a reasonable alternative to its few other competitors on the market.
Originally developed at Roche, the drug candidate was subsequently acquired by Basilea. In 2010, the product was licensed to Astellas Pharma by Basilea Pharmaceutica for codevelopment and copromotion worldwide, including an option for Japan, for the treatment of fungal infection.
03/06/2015 02:10 PM EST
The U.S. Food and Drug Administration today approved Cresemba (isavuconazonium sulfate), a new antifungal drug product used to treat adults with invasive aspergillosis and invasive mucormycosis, rare but serious infections.

Syn……https://newdrugapprovals.org/2013/10/02/isavuconazole-basilea-reports-positive-results-from-study/

PRODUCT PATENT

https://patents.google.com/patent/US6300353

InventorTadakatsu HayaseShigeyasu IchiharaYoshiaki IsshikiPingli LiuJun OhwadaToshiya SakaiNobuo ShimmaMasao TsukazakiIsao UmedaToshikazu Yamazaki

Current Assignee Basilea Pharmaceutica International Ltd Original

AssigneeBasilea Pharmaceutica AG Priority date 1998-03-06

https://patents.google.com/patent/WO1999045008A1/en

POLYMORPHS OF BASE

WO 2016055918

https://patents.google.com/patent/WO2016055918A1/en

PATENT

IN 2014MU03189

WOCKHARDT

Isavuconazole, isavuconazonium, Voriconazole, and Ravuconazole are azole derivatives and known as antifungal drugs for treatment of systemic mycoses as reported in US 5,648,372, US 5,792,781, US 6,300,353 and US 6,812,238. The US patent No. 6,300,353 discloses Isavuconazole and its process. It has chemical name [(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl)]-1-(1H-1,2,4-triazol-1-yl)-2-(2,5- difluorophenyl)-butan-2-ol;

The Isavuconazonium iodide hydrochloride and Isavuconazonium sulfate can be prepared according to known methods, e.g. pending Indian Patent Applications IN 2424/MUM/2014 and IN 2588/MUM/2014.

Example-1: Preparation of Amorphous Isavuconazole

str1

4-cyano Phenacyl bromide F F N N N OH N S CN Formula-I Formula-III In a round bottomed flask charged ethanol (250 ml), thioamide compound of formula-II (25.0 gm) and 4-cyano phenacyl bromide (18.4 gm) under stirring. The reaction mixture were heated to 70 0C. After completion of reaction the solvent was removed under vacuum distillation and water (250 ml) and Ethyl acetate (350 ml) were added to reaction mass. The reaction mixture was stirred and its pH was adjusted between 7 to 7.5 by 10 % solution of sodium bicarbonate. The layer aqueous layer was discarded and organic layer was washed with saturated sodium chloride solution (100 ml) and concentrated under vacuum to get residue. The residue was suspended in methyl tert-butyl ether (250 ml) and the reaction mixture was heated to at 40°C to make crystals uniform and finally reaction mass is cooled to room temperature filtered and washed with the methyl tert-butyl ether. The product was isolated dried to get pale yellowish solid product. Yield: 26.5 gm HPLC purity: 92.7%

CLIP

March 6, 2015

Release

The U.S. Food and Drug Administration today approved Cresemba (isavuconazonium sulfate), a new antifungal drug product used to treat adults with invasive aspergillosis and invasive mucormycosis, rare but serious infections.

Aspergillosis is a fungal infection caused by Aspergillus species, and mucormycosis is caused by the Mucorales fungi. These infections occur most often in people with weakened immune systems.

Cresemba belongs to a class of drugs called azole antifungal agents, which target the cell wall of a fungus. Cresemba is available in oral and intravenous formulations.

“Today’s approval provides a new treatment option for patients with serious fungal infections and underscores the importance of having available safe and effective antifungal drugs,” said Edward Cox, M.D., M.P.H, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

Cresemba is the sixth approved antibacterial or antifungal drug product designated as a Qualified Infectious Disease Product (QIDP). This designation is given to antibacterial or antifungal drug 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, Cresemba was given priority review, which provides an expedited review of the drug’s application. The QIDP designation also qualifies Cresemba for an additional five years of marketing exclusivity to be added to certain exclusivity periods already provided by the Food, Drug, and Cosmetic Act. As these types of fungal infections are rare, the FDA also granted Cresemba orphan drug designations for invasive aspergillosis and invasive mucormycosis.

The approval of Cresemba to treat invasive aspergillosis was based on a clinical trial involving 516 participants randomly assigned to receive either Cresemba or voriconazole, another drug approved to treat invasive aspergillosis. Cresemba’s approval to treat invasive mucormycosis was based on a single-arm clinical trial involving 37 participants treated with Cresemba and compared with the natural disease progression associated with untreated mucormycosis. Both studies showed Cresemba was safe and effective in treating these serious fungal infections.

The most common side effects associated with Cresemba include nausea, vomiting, diarrhea, headache, abnormal liver blood tests, low potassium levels in the blood (hypokalemia), constipation, shortness of breath (dyspnea), coughing and tissue swelling (peripheral edema).  Cresemba may also cause serious side effects including liver problems, infusion reactions and severe allergic and skin reactions.

Cresemba is marketed by Astellas Pharma US, Inc., based in Northbrook, Illinois.

str0

The active substance is isavuconazonium sulfate, a highly water soluble pro-drug of the active triazole isavuconazole. The chemical name of the active substance isavuconazonium sulfate is 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3- thiazol-2-yl]-2-(2,5-difluoro-phenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl] oxy}methyl) pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium monosulfate (IUPAC), corresponding to the molecular formula C35H35F2N8O5S·HSO4 and has a relative molecular mass of 814.84 g/mol. The relative molecular mass of isavuconazole is 437.47. The active substance has the following structure:

STR1.JPG

The structure of the active substance has been confirmed by elemental analysis, mass spectrometry, UV, IR, 1H-, 13C- and 19F-NMR spectrometry, and single crystal X-ray analysis, all of which support the chemical structure. It appears as a white, amorphous, hygroscopic powder. It is very soluble in water and over the pH range 1-7. It is also very soluble in methanol and sparingly soluble in ethanol. Two pKa values have been found and calculated to be 2.0 and 7.3. Its logPoct/wat calculated by software is 1.31.

Isavuconazonium sulfate has three chiral centres. The stereochemistry of the active substance is introduced by one of the starting materials which is controlled by appropriate specification. The two centres, C7 and C8 in the isavuconazole moiety and in an intermediate of the active substance, have R configuration. The third chiral centre, C29, is not located on isavuconazole moiety and has both the R and S configurations. The nondefined stereo centre at C29 has been found in all batches produced so far to be racemic. Erosion of stereochemical purity has not been observed in the current process. The active substance is a mixture of two epimers of C29.

An enantiomer of drug substance was identified as C7 (S), C8 (S) and C29 (R/S) structure. The control of the stereochemistry of isavuconazonium sulfate is performed by chiral HPLC on the active substance and its two precursors. Subsequent intermediates are also controlled by relevant specification in the corresponding steps. Two crystal forms have been observed by recrystallisation studies. However the manufacturing process as described yields amorphous form only.

Two different salt forms of isavuconazonuium (chloride and sulfate) were identified during development. The sulfate salt was selected for further development. A polymorph screening study was also performed. None of the investigated salts could be obtained in crystalline Form………http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002734/WC500196130.pdf

Image result for isavuconazonium

str1str2str3

Clip

Isavuconazonium (Cresemba ) is a water-soluble prodrug of the triazole antifungal isavuconazole (BAL4815), a 14-a-demethylase inhibitor, under development byBasilea Pharmaceutica International Ltd and Astellas Pharma Inc. Isavuconazonium, in both its intravenous and oral formulations, was approved for the treatment of invasive aspergillosis and invasive mucormycosis (formerly termed zygomycosis) in the US in March 2015. Isavuconazonium is under regulatory review in the EU for invasive aspergillosis and mucormycosis. It is also under phase III development worldwide for the treatment of invasive candidiasis and candidaemia. This article summarizes the milestones in the development of isavuconazonium leading to the first approval for invasive spergillosis and mucormycosis.

Introduction

The availability of both an intravenous (IV) and an oral formulation of isavuconazonium (Cresemba ), as a result of its water solubility, rapid hydrolysis to the active entity isavuconazole and very high oral bioavailability, provides maximum flexibility to clinicians for treating seriously ill patients with invasive fungal infections [1]. Both the IV and oral formulations have been approved by the US Food and Drug Administration (FDA) to treat adults with invasive aspergillosis and invasive mucormycosis [2]. The recommended dosages of each formulation are identical, consisting of loading doses of 372 mg (equivalent to 200 mg of isavuconazole) every eight hours for six doses, followed by maintenance therapy with 372 mg administered once daily [3]. The Qualified Infectious Disease Product (QIDP) designation of the drug with priority review status by the FDA isavuconazonium in the US provided and a five year extension of market exclusivity from launch. Owing to the rarity of the approved infections,

isavuconazonium was also granted orphan drug designation by the FDA for these indications [2]. It has also been granted orphan drug and QIDP designation in the US for the treatment of invasive candidiasis [4]. In July 2014, Basilea Pharmaceutica International Ltd submitted a Marketing Authorization Application to the European Medicines Agency (EMA) for isavuconazonium in the treatment of invasive aspergillosis and invasive mucormycosis, indications for which the EMA has granted isavuconazonium orphan designation [5, 6]. Isavuconazonium is under phase III development in many countries worldwide for the treatment of invasive candidiasis and candidaemia.

1.1 Company agreements

In 2010, Basilea Pharmaceutica International Ltd (a spinoff from Roche, founded in 2000) entered into a licence agreement with Astellas Pharma Inc in which the latter would co-develop and co-promote isavuconazonium worldwide, including an option for Japan. In return for milestone payments, Astellas Pharma was granted an exclusive right to commercialize isavuconazonium, while Basilea Pharmaceutica retained an option to co-promote the drug in the US, Canada, major European countries and China [7]. The companies amended their agreement in 2014, making Astellas Pharma responsible for all regulatory filings, commercialization and manufacturing of isavuconazonium in the US and Canada. Basilea Pharmaceutica waived its right to co-promote the product in the US and Canada, in order to assume all rights in the rest of the world [8]. However, Astellas Pharma remains as sponsor of the multinational, phase III ACTIVE trial in patients with invasive candidiasis.

2 Scientific Summary

Isavuconazonium (as the sulphate; BAL 8557) is a prodrug that is rapidly hydrolyzed by esterases (mainly butylcholinesterase) in plasma into the active moiety isavuconazole

(BAL 4815) and an inactive cleavage product (BAL 8728).

References

1. Falci DR, Pasqualotto AC. Profile of isavuconazole and its potential in the treatment of severe invasive fungal infections. Infect Drug Resist. 2013;6:163–74.

2. US Food and Drug Administration. FDA approves new antifungal drug Cresemba. 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm437106.htm. Accessed 12 Mar 2015.

3. US Food and Drug Administration. Cresemba (isavuconazonium sulfate): US prescribing information. 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207500Orig1s000lbl.pdf. Accessed 18 Mar 2015.

4. Astellas Pharma US Inc. FDA grants Astellas Qualified Infectious Disease Product designation for isavuconazole for the treatment of invasive candidiasis (media release). 2014. http://newsroom astellas.us/2014-07-16-FDA-Grants-Astellas-Qualified-Infectious-Disease-Product-Designation-for-Isavuconazole-for-the-Treatmentof-Invasive-Candidiasis.

5. European Medicines Agency. Public summary of opinion on orphan designation: isavuconazonium sulfate for the treatment of invasive aspergillosis. 2014. http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2014/07/WC500169890.pdf. Accessed 18 Mar 2015.

European Medicines Agency. Public summary of opinion on orphan designation: isavuconazonium sulfate for the treatment of mucormycosis. 2014. http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2014/07/WC500169714.pdf. Accessed 18 Mar 2015.

7. Basilea Pharmaceutica. Basilea announces global partnership with Astellas for its antifungal isavuconazole (media release).2010. http://www.basilea.com/News-and-Media/Basilea-announcesglobal-partnership-with-Astellas-for-its-antifungal-isavuconazole/343.

8. Basilea Pharmaceutica. Basilea swaps its isavuconazole North American co-promote rights for full isavuconazole rights outside of North America (media release). 2014. http://www.basilea.com/News-and-Media/Basilea-swaps-its-isavuconazole-North-Americanco-promote-rights-for-full-isavuconazole-rights-outside-

CLIP

Image result for Isavuconazonium sulfate

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http://www.jpharmsci.org/article/S0022-3549(15)00035-0/pdf

A CLIP

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207500Orig1207501Orig1s000ChemR.pdf

EMA

On 4 July 2014 orphan designation (EU/3/14/1284) was granted by the European Commission to Basilea Medical Ltd, United Kingdom, for isavuconazonium sulfate for the treatment of invasive aspergillosis.

Update: isavuconazonium sulfate (Cresemba) has been authorised in the EU since 15 October 2015. Cresemba is indicated in adults for the treatment of invasive aspergillosis.

Consideration should be given to official guidance on the appropriate use of antifungal agents.

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002734/WC500196130.pdf

The active substance is isavuconazonium sulfate, a highly water soluble pro-drug of the active triazole isavuconazole. The chemical name of the active substance isavuconazonium sulfate is 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3- thiazol-2-yl]-2-(2,5-difluoro-phenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl] oxy}methyl) pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium monosulfate (IUPAC), corresponding to the molecular formula C35H35F2N8O5S·HSO4 and has a relative molecular mass of 814.84 g/mol. The relative molecular mass of isavuconazole is 437.47. The active substance has the following structure

str1

It appears as a white, amorphous, hygroscopic powder. It is very soluble in water and over the pH range 1-7. It is also very soluble in methanol and sparingly soluble in ethanol. Two pKa values have been found and calculated to be 2.0 and 7.3. Its logPoct/wat calculated by software is 1.31.

Isavuconazonium sulfate has three chiral centres. The stereochemistry of the active substance is introduced by one of the starting materials which is controlled by appropriate specification. The two centres, C7 and C8 in the isavuconazole moiety and in an intermediate of the active substance, have R configuration. The third chiral centre, C29, is not located on isavuconazole moiety and has both the R and S configurations. The nondefined stereo centre at C29 has been found in all batches produced so far to be racemic. Erosion of stereochemical purity has not been observed in the current process. The active substance is a mixture of two epimers of C29. An enantiomer of drug substance was identified as C7 (S), C8 (S) and C29 (R/S) structure. The control of the stereochemistry of isavuconazonium sulfate is performed by chiral HPLC on the active substance and its two precursors.

FDA Orange Book Patents

US 6812238

US 7459561

FDA ORANGE BOOK PATENTS: 1 OF 2
Patent 7459561
Expiration Oct 31, 2020
Applicant ASTELLAS
Drug Application N207500 (Prescription Drug: CRESEMBA. Ingredients: ISAVUCONAZONIUM SULFATE)
FDA ORANGE BOOK PATENTS: 2 OF 2
Patent 6812238
Expiration Oct 31, 2020
Applicant ASTELLAS
Drug Application N207500 (Prescription Drug: CRESEMBA. Ingredients: ISAVUCONAZONIUM SULFATE)

FREE FORM

Isavuconazonium.png

Isavuconazonium; Isavuconazonium ion; Cresemba;  BAL-8557; 742049-41-8;

[2-[1-[1-[(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-1,2,4-triazol-4-ium-4-yl]ethoxycarbonyl-methylamino]pyridin-3-yl]methyl 2-(methylamino)acetate

MOLECULAR FORMULA: C35H35F2N8O5S+
MOLECULAR WEIGHT: 717.773 g/mol

Patent IDDatePatent Title

US20102494262010-09-30STABILIZED PHARMACEUTICAL COMPOSITION

US74595612008-12-02N-substituted carbamoyloxyalkyl-azolium derivativesUS71898582007-03-13N-phenyl substituted carbamoyloxyalkyl-azolium derivatives

US71511822006-12-19Intermediates for N-substituted carbamoyloxyalkyl-azolium derivatives

US68122382004-11-02N-substituted carbamoyloxyalkyl-azolium derivatives

REF

http://www.drugbank.ca/drugs/DB06636

////////// , QIDP designation, Cresemba , priority review, FDA 2015, EU 2015, BAL8557-002, BCS CLASS I, orphan designation,  invasive aspergillosis, invasive mucormycosis,  RO-0098557 , AK-1820, fast track designation, QIDP, 946075-13-4

CC(C1=NC(=CS1)C2=CC=C(C=C2)C#N)C(CN3C=[N+](C=N3)C(C)OC(=O)N(C)C4=C(C=CC=N4)COC(=O)CNC)(C5=C(C=CC(=C5)F)F)O

CC(C1=NC(=CS1)C2=CC=C(C=C2)C#N)C(CN3C=[N+](C=N3)C(C)OC(=O)N(C)C4=C(C=CC=N4)COC(=O)CNC)(C5=C(C=CC(=C5)F)F)O.OS(=O)(=O)[O-]

UPDATE NEW PATENT

WOCKHARDT, WO 2016016766, ISAVUCONAZONIUM SULPHATE, NEW PATENT

(WO2016016766) A PROCESS FOR THE PREPARATION OF ISAVUCONAZONIUM OR ITS SALT THEREOF

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016016766&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

WOCKHARDT LIMITED [IN/IN]; D-4, MIDC Area, Chikalthana, Aurangabad 431006 (IN)

KHUNT, Rupesh Chhaganbhai; (IN).
RAFEEQ, Mohammad; (IN).
MERWADE, Arvind Yekanathsa; (IN).
DEO, Keshav; (IN)

The present invention relates to a process for the preparation of stable Isavuconazonium or its salt thereof. In particular of the present invention relates to process for the preparing of isavuconazonium sulfate, Isavuconazonium iodide hydrochloride and Boc-protected isavuconazonium iodide has purity more than 90%. The process is directed to preparation of solid amorphous form of isavuconazonium sulfate, isavuconazonium iodide hydrochloride and Boc-protected isavuconazonium iodide. The present invention process of Isavuconazonium or its salt thereof is industrially feasible, simple and cost effective to manufacture of isavuconazonium sulfate with the higher purity and better yield.

Isavuconazonium sulfate is chemically known l-[[N-methyl-N-3-[(methylamino) acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl]butyl]-lH-[l,2,4]-triazo-4-ium Sulfate and is structurally represented by formula (I):

Formula I

Isavuconazonium sulfate (BAL8557) is indicated for the treatment of antifungal infection. Isavuconazonium sulfate is a prodrug of Isavuconazole (BAL4815), which is chemically known 4-{2-[(lR,2R)-(2,5-Difluorophenyl)-2-hydroxy-l-methyl-3-(lH-l ,2,4-triazol-l-yl)propyl]-l ,3-thiazol-4-yl}benzonitrile compound of Formula II

Formula II

US Ppatent No. 6,812,238 (referred to herein as ‘238); 7,189,858 (referred to herein as ‘858); 7,459,561 (referred to herein as ‘561) describe Isavuconazonium and its process for the preparation thereof.

The US Pat. ‘238 patent describes the process of preparation of Isavuconazonium chloride hydrochloride.

The US Pat. ‘238 described the process for the Isavuconazonium chloride hydrochloride, involves the condensation of Isavuconazole and [N-methyl-N-3((tert-butoxycarbonyl methylamino) acetoxymethyl) pyridine-2-yl]carbamic acid 1 -chloro-ethyl ester. The prior art reported process require almost 15-16 hours, whereas the present invention process requires only 8-10 hours. Inter alia prior art reported process requires too many step to prepare isavuconazonium sulfate, whereas the present invention process requires fewer steps.

Moreover, the US Pat. ‘238 describes the process for the preparation Isavuconazonium hydrochloride, which may be used as the key intermediate for the synthesis of isavuconazonium sulfate, compound of formula I. There are several drawbacks in the said process, which includes the use of anionic resin to prepare Isavuconazonium chloride hydrochloride, consequently it requires multiple time lyophilization, which makes the said prior art process industrially, not feasible.

The inventors of the present invention surprisingly found that Isavuconazonium or a pharmaceutically acceptable salt thereof in yield and purity could be prepared by using substantially pure intermediates in suitable solvent.

Thus, an object of the present invention is to provide simple, cost effective and industrially feasible processes for manufacture of isavuconazonium sulfate. Inventors of the present invention surprisingly found that isavuconazonium sulfate prepared from isavuconazonium iodide hydrochloride, provides enhanced yield as well as purity.

The process of the present invention is depicted in the following scheme:

Formula I

Formula-IA

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

Examples

Example-1: Synthesis of l-[[N-methyl-N-3-[(t-butoxycarbonylmethylamino) acetoxymethyl]pyridin-2-yl]carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3 – [4-(4-cyanophenyl)thiazol-2-yl]butyl] – 1 H-[ 1 ,2,4] -triazo-4-ium iodide

Isavuconazole (20 g) and [N-methyl-N-3((tert-butoxycarbonylmethylamino)acetoxy methyl)pyridine-2-yl]carbamic acid 1 -chloro-ethyl ester (24.7 g) were dissolved in acetonitrile (200ml). The reaction mixture was stirred to add potassium iodide (9.9 g). The reaction mixture was stirred at 47-50°C for 10-13 hour. The reaction mixture was cooled to room temperature. The reaction mass was filtered through celite bed and washed acetonitrile. Residue was concentrated under reduced pressure to give the crude solid product (47.7 g). The crude product was purified by column chromatography to get its pure iodide form (36.5 g).

Yield: 84.5 %

HPLC Purity: 87%

Mass: m/z 817.4 (M- 1)+

Example-2: Synthesis of l-[[N-methyl-N-3-[(methylamino)acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl) thiazol-2-yl]butyl]-lH-[l ,2,4]-triazo-4-ium iodide hydrochloride

l-[[N-methyl-N-3-[(t-butoxycarbonylmethylamino)acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl) thiazol-2-yl]butyl]-lH-[l ,2,4]-triazo-4-ium iodide (36.5 g) was dissolved in ethyl acetate (600 ml). The reaction mixture was cooled to -5 to 0 °C. The ethyl acetate hydrochloride (150 ml) solution was added to reaction mixture. The reaction mixture was stirred for 4-5 hours at room temperature. The reaction mixture was filtered and obtained solid residue washed with ethyl acetate. The solid dried under vacuum at room temperature for 20-24 hrs to give 32.0 gm solid.

Yield: 93 %

HPLC Purity: 86%

Mass: m/z 717.3 (M-HC1- 1)

Example-3: Preparation of Strong anion exchange resin (Sulfate).

Indion GS-300 was treated with aqueous sulfate anion solution and then washed with DM water. It is directly used for sulfate salt.

Example-4: Synthesis of l-[[N-methyl-N-3-[(methylamino)acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl) thiazol-2-yl]butyl]-lH-[l ,2,4]-triazo-4-ium Sulfate

Dissolved 10.0 g l-[[N-methyl-N-3-[(methylamino)acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl) thiazol-2-yl]butyl]-lH-[l ,2,4]-triazo-4-ium iodide hydrochloride in 200 ml deminerahzed water and 30 ml methanol. The solution was cooled to about 0 to 5°C. The strong anion exchange resin (sulfate) was added to the cooled solution. The reaction mixture was stirred to about 60-80 minutes. The reaction was filtered and washed with 50ml of demineralized water and methylene chloride. The aqueous layer was lyophilized to obtain

(8.0 g) white solid.

Yield: 93 %

HPLC Purity: > 90%

Mass: m/z 717.4 (M- HS04+

PATENT

CN 105288648

PATENT

CN 106883226

https://patents.google.com/patent/CN106883226A/en

PATENT

CN 107982221

PAPER

Title: Introduction of New Drugs Approved by the U.S. FDA in 2015
Author: Ma Shuai; Wenying Ling; Zhou Weicheng;
Source: China Pharmaceutical Industry
Publisher: Tongfangzhiwang Beijing Technology Co., Ltd.
Year of publication:
DOI code: 10.16522/j.cnki.cjph.2016.01.022
Registration Time: 2016-02-19 02:04:15

///////////////

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.

//////////////FDA,  antibacterial drug,  Vabomere, meropenem, vaborbactam, fda 2017, Rempex Pharmaceuticals, qualified infectious disease product, QIDP, Generating Antibiotic Incentives Now, GAIN, priority review

Biafungin, CD 101, a Novel Echinocandin for Vulvovaginal candidiasis


STR1

str1

str1as  CH3COOH salt

UNII-W1U1TMN677.png

CD 101

Several structural representations above

Biafungin™; CD 101 IV; CD 101 Topical; CD101; SP 3025, Biafungin acetate, Echinocandin B

UNII-G013B5478J FRE FORM,

CAS 1396640-59-7 FREE FORM

MF, C63-H85-N8-O17, MW, 1226.4035

Echinocandin B,

1-((4R,5R)-4-hydroxy-N2-((4”-(pentyloxy)(1,1′:4′,1”-terphenyl)-4-yl)carbonyl)-5-(2-(trimethylammonio)ethoxy)-L-ornithine)-4-((4S)-4-hydroxy-4-(4-hydroxyphenyl)-L-allothreonine)-

Treat and prevent invasive fungal infections; Treat and prevent systemic Candida infections; Treat candidemia

2D chemical structure of 1631754-41-0

Biafungin acetate

CAS 1631754-41-0 ACETATE, Molecular Formula, C63-H85-N8-O17.C2-H3-O2, Molecular Weight, 1285.4472,

C63 H85 N8 O17 . C2 H3 O2
1-[(4R,5R)-4-hydroxy-N2-[[4”-(pentyloxy)[1,1′:4′,1”-terphenyl]-4-yl]carbonyl]-5-[2-(trimethylammonio)ethoxy]-L-ornithine]-4-[(4S)-4-hydroxy-4-(4-hydroxyphenyl)-L-allothreonine]-, acetate (1:1)

UNII: W1U1TMN677

CD101 – A novel echinocandin antifungal C. albicans (n=351) MIC90 = 0.06 µg/mL C. glabrata (n=200) MIC90 = 0.06 µg/mL  Echinocandins have potent fungicidal activity against Candida species

  • Originator Seachaid Pharmaceuticals
  • Developer Cidara Therapeutics
  • Class Antifungals; Echinocandins; Small molecules
  • Mechanism of Action Glucan synthase inhibitors

 

BIAFUNGIN, CD 101

Watch this space as I add more info…………….

U.S. – Fast Track (Treat candidemia);
U.S. – Fast Track (Treat and prevent invasive fungal infections);
U.S. – Orphan Drug (Treat and prevent invasive fungal infections);
U.S. – Orphan Drug (Treat candidemia);
U.S. – Qualified Infectious Disease Program (Treat candidemia);
U.S. – Qualified Infectious Disease Program (Treat and prevent invasive fungal infections)

Fungal infections have emerged as major causes of human disease, especially among the immunocompromised patients and those hospitalized with serious underlying disease. As a consequence, the frequency of use of systemic antifungal agents has increased significantly and there is a growing concern about a shortage of effective antifungal agents. Although resistance rates to the clinically available antifungal agents remains low, reports of breakthrough infections and the increasing prevalence of uncommon fungal species that display elevated MIC values for existing agents is worrisome. Biafungin (CD101, previously SP 3025) is a novel echinocandin that displays chemical stability and long-acting pharmacokinetics that is being developed for once-weekly or other intermittent administration (see posters #A-693 and A- 694 for further information). In this study, we test biafungin and comparator agents against a collection of common Candida and Aspergillus species, including isolates resistant to azoles and echinocandins.

The echinocandins are an important class of antifungal agents, but are administered once daily by intravenous (IV) infusion. An echinocandin that could be administered once weekly could facilitate earlier hospital discharges and could expand usage to indications where daily infusions are impractical. Biafungin is a highly stable echinocandin for once-weekly IV administration. The compound was found to have a spectrum of activity and potency comparable to other echinocandins. In chimpanzees single dose pharmacokinetics of IV and orally administered biafungin were compared to IV anidulafungin, which has the longest half-life (T1/2 ) of the approved echinocandins.

Background  Vulvovaginal candidiasis (VVC) is a highly prevalent mucosal infection  VVC is caused by Candida albicans (~85%) and non-albicans (~15%)  5-8% of women have recurrent VVC (RVVC) which is associated with a negative impact on work/social life  Oral fluconazole prescribed despite relapse, potential DDIs and increased risk to pregnant women  No FDA-approved therapy for RVVC and no novel agent in >20 years

str1

Cidara Therapeutics 6310 Nancy Ridge Drive, Suite 101 San Diego, CA 92121

The incidence of invasive fungal infections, especially those due to Aspergillus spp. and Candida spp., continues to increase. Despite advances in medical practice, the associated mortality from these infections continues to be substantial. The echinocandin antifungals provide clinicians with another treatment option for serious fungal infections. These agents possess a completely novel mechanism of action, are relatively well-tolerated, and have a low potential for serious drug–drug interactions. At the present time, the echinocandins are an option for the treatment of infections due Candida spp (such as esophageal candidiasis, invasive candidiasis, and candidemia). In addition, caspofungin is a viable option for the treatment of refractory aspergillosis. Although micafungin is not Food and Drug Administration-approved for this indication, recent data suggests that it may also be effective. Finally, caspofungin- or micafungin-containing combination therapy should be a consideration for the treatment of severe infections due to Aspergillus spp. Although the echinocandins share many common properties, data regarding their differences are emerging at a rapid pace. Anidulafungin exhibits a unique pharmacokinetic profile, and limited cases have shown a potential far activity in isolates with increased minimum inhibitory concentrations to caspofungin and micafungin. Caspofungin appears to have a slightly higher incidence of side effects and potential for drug–drug interactions. This, combined with some evidence of decreasing susceptibility among some strains ofCandida, may lessen its future utility. However, one must take these findings in the context of substantially more data and use with caspofungin compared with the other agents. Micafungin appears to be very similar to caspofungin, with very few obvious differences between the two agents.

Echinocandins are a new class of antifungal drugs[1] that inhibit the synthesis of glucan in the cell wall, via noncompetitive inhibition of the enzyme 1,3-β glucan synthase[2][3] and are thus called “penicillin of antifungals”[4] (a property shared with papulacandins) as penicillin has a similar mechanism against bacteria but not fungi. Beta glucans are carbohydrate polymers that are cross-linked with other fungal cell wall components (The bacterial equivalent is peptidoglycan). Caspofungin, micafungin, and anidulafungin are semisynthetic echinocandin derivatives with clinical use due to their solubility, antifungal spectrum, and pharmacokinetic properties.[5]

List of echinocandins:[17]

  • Pneumocandins (cyclic hexapeptides linked to a long-chain fatty acid)
  • Echinocandin B not clinically used, risk of hemolysis
  • Cilofungin withdrawn from trials due to solvent toxicity
  • Caspofungin (trade name Cancidas, by Merck)
  • Micafungin (FK463) (trade name Mycamine, by Astellas Pharma.)
  • Anidulafungin (VER-002, V-echinocandin, LY303366) (trade name Eraxis, by Pfizer)

History

Discovery of echinocandins stemmed from studies on papulacandins isolated from a strain of Papularia sphaerosperma (Pers.), which were liposaccharide – i.e., fatty acid derivatives of a disaccharide that also blocked the same target, 1,3-β glucan synthase – and had action only on Candida spp. (narrow spectrum). Screening of natural products of fungal fermentation in the 1970s led to the discovery of echinocandins, a new group of antifungals with broad-range activity against Candida spp. One of the first echinocandins of the pneumocandin type, discovered in 1974, echinocandin B, could not be used clinically due to risk of high degree of hemolysis. Screening semisynthetic analogs of the echinocandins gave rise to cilofungin, the first echinofungin analog to enter clinical trials, in 1980, which, it is presumed, was later withdrawn for a toxicity due to the solvent system needed for systemic administration. The semisynthetic pneumocandin analogs of echinocandins were later found to have the same kind of antifungal activity, but low toxicity. The first approved of these newer echinocandins was caspofungin, and later micafungin and anidulafungin were also approved. All these preparations so far have low oral bioavailability, so must be given intravenously only. Echinocandins have now become one of the first-line treatments for Candida before the species are identified, and even as antifungal prophylaxis in hematopoietic stem cell transplant patients.

CIDARA THERAPEUTICS DOSES FIRST PATIENT IN PHASE 2 TRIAL OF CD101 TOPICAL TO TREAT VULVOVAGINAL CANDIDIASIS

SAN DIEGO–(BUSINESS WIRE)–Jun. 9, 2016– Cidara Therapeutics, Inc. (Nasdaq:CDTX), a biotechnology company developing novel anti-infectives and immunotherapies to treat fungal and other infections, today announced that the first patient has been dosed in RADIANT, a Phase 2 clinical trial comparing the safety and tolerability of the novel echinocandin, CD101, to standard-of-care fluconazole for the treatment of acute vulvovaginal candidiasis (VVC). RADIANT will evaluate two topical formulations of CD101, which is Cidara’s lead antifungal drug candidate.

“There have been no novel VVC therapies introduced for more than two decades, so advancing CD101 topical into Phase 2 is a critical step for women with VVC and for Cidara,” said Jeffrey Stein, Ph.D., president and chief executive officer of Cidara. “Because of their excellent safety record and potency against Candida, echinocandin antifungals are recommended as first line therapy to fight systemic Candida infections. CD101 topical will be the first echinocandin tested clinically in VVC and we expect to demonstrate safe and improved eradication of Candida with rapid symptom relief for women seeking a better option over the existing azole class of antifungals.”

RADIANT is a Phase 2, multicenter, randomized, open-label, active-controlled, dose-ranging trial designed to evaluate the safety and tolerability of CD101 in women with moderate to severe episodes of VVC. The study will enroll up to 125 patients who will be randomized into three treatment cohorts. The first cohort will involve the treatment of 50 patients with CD101 Ointment while a second cohort of 50 patients will receive CD101 Gel. The third cohort will include 25 patients who will be treated with oral fluconazole.

The primary endpoints of RADIANT will be the safety and tolerability of a single dose of CD101 Ointment and multiple doses of CD101 Gel in patients with acute VVC. Secondary endpoints include therapeutic efficacy in acute VVC patients treated with CD101. Treatment evaluations and assessments will occur on trial days 7, 14 and 28.

The RADIANT trial will be conducted at clinical trial centers across the United States. More information about the trial is available at www.clinicaltrials.gov, identifier NCT02733432.

About VVC and RVVC

Seventy-five percent of women worldwide suffer from VVC in their lifetime, and four to five million women in the United Statesalone have the recurrent form of the infection, which is caused by Candida. Many women will experience recurrence after the completion of treatment with existing therapies. Most VVC occurs in women of childbearing potential (the infection is common in pregnant women), but it affects women of all ages. In a recent safety communication, the U.S. Food and Drug Administration(FDA) advised caution in the prescribing of oral fluconazole for yeast infections during pregnancy based on a published study concluding there is an increased risk of miscarriage. The Centers for Disease Control and Prevention (CDC) guidelines recommend using only topical antifungal products to treat pregnant women with vulvovaginal yeast infections. Vaginal infections are associated with a substantial negative impact on day-to-day functioning and adverse pregnancy outcomes including preterm delivery, low birth weight, and increased infant mortality in addition to predisposition to HIV/AIDS. According to the CDC, certain species of Candida are becoming increasingly resistant to existing antifungal medications. This emerging resistance intensifies the need for new antifungal agents.

About CD101 Topical

CD101 topical is the first topical agent in the echinocandin class of antifungals and exhibits a broad spectrum of fungicidal activity against Candida species. In May 2016, the FDA granted Qualified Infectious Disease Product (QIDP) and Fast Track Designation to CD101 topical for the treatment of VVC and the prevention of RVVC.

About Cidara Therapeutics

Cidara is a clinical-stage biotechnology company focused on the discovery, development and commercialization of novel anti-infectives for the treatment of diseases that are inadequately addressed by current standard-of-care therapies. Cidara’s initial product portfolio comprises two formulations of the company’s novel echinocandin, CD101. CD101 IV is being developed as a once-weekly, high-exposure therapy for the treatment and prevention of serious, invasive fungal infections. CD101 topical is being developed for the treatment of vulvovaginal candidiasis (VVC) and the prevention of recurrent VVC (RVVC), a prevalent mucosal infection. In addition, Cidara has developed a proprietary immunotherapy platform, Cloudbreak™, designed to create compounds that direct a patient’s immune cells to attack and eliminate pathogens that cause infectious disease. Cidara is headquartered inSan Diego, California. For more information, please visit www.cidara.com.

REF http://ir.cidara.com/phoenix.zhtml?c=253962&p=irol-newsArticle&ID=2176474

CLIP

Cidara Therapeutics raises $42 million to develop once-weekly anti-fungal therapy

Cidara Therapeutics (formerly K2 Therapeutics) grabbed $42 million in a private Series B funding round Wednesday to continue developing its once-weekly anti-fungal therapy. Just in June 2014, the company completed a $32 million Series A financing led by 5AM Ventures, Aisling Capital, Frazier Healthcare and InterWest Partners, which was the fourth largest A round in 2014 for innovative startups[1]. FierceBiotech named the company as one of 2014 Fierce 15 biotech startups.

Cidara has an impressive executive team. The company was co-founded by Kevin Forrest, former CEO of Achaogen (NASDAQ: AKAO), and Shaw Warren. Jeffrey Stein, former CEO of Trius Therapeutics (NASDAQ: TSRX) and Dirk Thye, former president of Cerexa, have joined Cidara as CEO and CMO, respectively. Trius successfully developed antibiotic tedizolid and was acquired in 2013 by Cubist Pharmaceuticals (NASDAQ: CBST) for $818 million.

Cidara’s lead candidate, biafungin (SP3025), was acquired from Seachaid Pharmaceuticals for $6 million. Biafungin’s half-life is much longer than that of similar drugs known as echinocandins (e.g., caspofungin, micafungin, anidulafungin), which may allow it to be developed as a once-weekly therapy, instead of once daily. The company is also developing a topical formulation of biafungin, namely topifungin. Cidara intends to file an IND and initiate a Phase I clinical trial in the second half of 2015.

Merck’s Cancidas (caspofungin), launched in 2001, was the first of approved enchinocandins. The drug generated annual sales of $596 million in 2008. The approved echinocandins must be administered daily by intravenous infusion. Biafungin with improved pharmacokinetic characteristics has the potential to bring in hundreds of millions of dollars per year.

[1] Nat Biotechnol. 2015, 33(1), 18.

CLIP

Biafungin is a potent and broad-spectrum antifungal agent with excellent activity against wild-type and troublesome azole- and echinocandin-resistant strains of Candida spp. The activity of biafungin is comparable to anidulafungin. • Biafungin was active against both wild-type and itraconazole-resistant strains of Aspergillus spp. from four different species. • In vitro susceptibility testing of biafungin against isolates of Candida and Aspergillus may be accomplished by either CLSI or EUCAST broth microdilution methods each providing comparable results. • The use of long-acting intravenous antifungal agents that could safely be given once a week to select patients is desirable and might decrease costs with long-term hospitalizations. Background: A novel echinocandin, biafungin, displaying long-acting pharmacokinetics and chemical stability is being developed for once-weekly administration. The activities of biafungin and comparator agents were tested against 173 fungal isolates of the most clinically common species. Methods: 106 CAN and 67 ASP were tested using CLSI and EUCAST reference broth microdilution methods against biafungin (50% inhibition) and comparators. Isolates included 27 echinocandin-resistant CAN (4 species) with identified fks hotspot (HS) mutations and 20 azole nonsusceptible ASP (4 species). Results: Against C. albicans, C. glabrata and C. tropicalis, the activity of biafungin (MIC50, 0.06, 0.12 and 0.03 μg/ml, respectively by CLSI method) was comparable to anidulafungin (AND; MIC50, 0.03, 0.12 and 0.03 μg/ml, respectively) and caspofungin (CSP; MIC50, 0.12, 0.25 and 0.12 μg/ml, respectively; Table). C. krusei strains were very susceptible to biafungin, showing MIC90 values of 0.06 μg/ml by both methods. Biafungin (MIC50/90, 1/2 μg/ml) was comparable to AND and less potent than CSP against C. parapsilosis using CLSI methodology. CLSI and EUCAST methods displayed similar results for most species, but biafungin (MIC50, 0.06 μg/ml) was eight-fold more active than CSP (MIC50, 0.5 μg/ml) against C. glabrata using the EUCAST method. Overall, biafungin was two- to four-fold more active against fks HS mutants than CSP and results were comparable to AND. Biafungin was active against A. fumigatus (MEC50/90, ≤0.008/0.015 μg/ml), A. terreus (MEC50/90, 0.015/0.015 μg/ml), A. niger (MEC50/90, ≤0.008/0.03 μg/ml) and A. flavus (MEC50/90, ≤0.008/≤0.008 μg/ml) using CLSI method. EUCAST results for ASP were also low for all echinocandins and comparable to CLSI results. Conclusions: Biafungin displayed comparable in vitro activity with other echinocandins against common wild-type CAN and ASP and resistant subsets that in combination with the long-acting profile warrants further development of this compound. 1. Arendrup MC, Cuenca-Estrella M, Lass-Florl C, Hope WW (2013). Breakpoints for antifungal agents: An update from EUCAST focussing on echinocandins against Candida spp. and triazoles against Aspergillus spp. Drug Resist Updat 16: 81-95. 2. Castanheira M, Woosley LN, Messer SA, Diekema DJ, Jones RN, Pfaller MA (2014). Frequency of fks mutations among Candida glabrata isolates from a 10-year global collection of bloodstream infection isolates. Antimicrob Agents Chemother 58: 577-580. 3. Clinical and Laboratory Standards Institute (2008). M27-A3. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts: third edition. Wayne, PA: CLSI. 4. Clinical and Laboratory Standards Institute (2008). M38-A2. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi: Second Edition. Wayne, PA: CLSI. 5. Clinical and Laboratory Standards Institute (2012). M27-S4. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts: 4th Informational Supplement. Wayne, PA: CLSI. 6. European Committee on Antimicrobial Susceptibility Testing (2014). Breakpoint tables for interpretation of MICs and zone diameters. Version 4.0, January 2014. Available at: http://www.eucast.org/clinical_breakpoints/. Accessed January 1, 2014. 7. Pfaller MA, Diekema DJ (2010). Epidemiology of invasive mycoses in North America. Crit Rev Microbiol 36: 1-53. 8. Pfaller MA, Diekema DJ, Andes D, Arendrup MC, Brown SD, Lockhart SR, Motyl M, Perlin DS (2011). Clinical breakpoints for the echinocandins and Candida revisited: Integration of molecular, clinical, and microbiological data to arrive at species-specific interpretive criteria. Drug Resist Updat 14: 164-176. ABSTRACT Activity of a Novel Echinocandin Biafungin (CD101) Tested against Most Common Candida and Aspergillus Species, Including Echinocandin- and Azole-resistant Strains M CASTANHEIRA, SA MESSER, PR RHOMBERG, RN JONES, MA PFALLER JMI Laboratories, North Liberty, Iowa, USA C

PATENT

https://www.google.com/patents/WO2015035102A2?cl=en

BIAFUNGIN ACETATE IS USED AS STARTING MATERIAL

Example 30b: Synthesis of Compound 31

Step a. Nitration of Biafungin Acetate

To a stirring solution of biafungin (1 00 mg, 0.078 mmol) in glacial acetic acid(1 .5 ml_) was added sodium nitrite (1 1 mg, 0.159 mmol) and the reaction was stirred at ambient temperature for 20 hours. The mixture was applied directly to reversed phase H PLC (Isco CombiFlash Rf; 50g RediSep C1 8 column, 5 to 95% acetonitrile in Dl water containing 0.1 % formic acid: 15 minute gradient). The pure fractions were pooled and lyophilized to yield 85 mg of the desired product as a light yellow solid, formate salt. 1 H-NMR (300 M Hz, Methanol-d4) δ 8.58 (d, 1 H, J = 1 1 .7 Hz), 8.47 (t, 2H, J = 8.7Hz), 8.05 (d, 1 H, J = 2.1 Hz), 7.99 (d, 2H, J = 9.3 Hz), 7.82 (d, 2H, J = 8.7 Hz), 7.79-7.60 (m, 12H), 7.1 7 (d, 1 H, J = 8.7 Hz), 7.03 (d, 2H, J = 9 Hz), 5.48 (d, 1 H, J = 6 Hz), 5.08 (dd, 1 H, J = 1 .2, 5.7 Hz), 4.95-4.73 (m, 5H), 4.68-4.56 (m, 2H), 4.53 (d, 1 H, J = 5.7 Hz), 4.48-4.39 (m, 2H), 4.31 -3.79 (m, 6H), 4.04 (t, 2H, J = 5.7 Hz), 3.72-3.44 (m,3H), 3.1 8 (s, 9H), 2.60-1 .99 (m, 5H), 1 .83 (m, 2H, J = 8.7 Hz), 1 .56-1 .35 (m, 5H), 1 .28 (d, 6H, J = 4.2 Hz), 1 .09 (d, 3H, J = 1 0.2 Hz), 0.99 (t, 3H, J = 8.7 Hz) ; LC/MS, [M/2+H]+: 635.79, 635.80 calculated.

Step b. Reduction of Nitro-Biafungin To Amino-Biafungin

To a stirring solution of Nitro-Biafungin (1 00 mg, 0.075 mmol) in glacial acetic acid(1 .5 ml_) was added zinc powder (50 mg, 0.77 mmol) and the reaction was stirred at ambient temperature for 1 hour. The mixture was filtered and applied directly to reversed phase HPLC (Isco CombiFlash Rf, 50g Redisep C18 column; 5 to 95% acetonitrile in Dl water containing 0.1 % formic acid: 15 minute gradient). The pure fractions were pooled and lyophilized to yield 55 mg of the desired product as a white solid, formate salt. 1 H-NMR (300 MHz, Methanol-d4) 5 8.47 (bs, 1 H), 7.99 (d, 2H, J = 1 0.8Hz), 7.82 (d, 2H, J = 7.5 Hz), 7.80-7.67 (m, 6H), 7.62 (d, 2H, J = 8.7 Hz), 7.03 (d, 2H, J = 7.5 Hz), 6.77 (d, 1 H, J = 1 .9 Hz), 6.68 (d, 1 H, J = 8.2 Hz), 6.55 (dd, 2H, J = 8.2, 1 .9 Hz), 5.43 (d, 1 H, J = 2.5 Hz), 5.05 (d, 1 H, J = 3 Hz), 4.83-4.73 (m, 2H), 4.64- 4.56 (m, 2H), 4.43-4.34 (m, 2H), 4.31 -4.15 (m, 4H), 4.03-4.08 (m, 1 H), 4.1 1 -3.89 (m, 8H), 3.83 (d, 1 H, J = 1 0.8 Hz), 3.68-3.47 (m, 3H), 3.1 7 (s, 9H), 2.57-2.42 (m, 2H), 2.35-2.27 (m, 1 H), 2.14-1 .98 (m, 2H), 1 .83 (m, 2H, J = 6 Hz), 1 .56-1 .38 (m, 4H), 1 .28 (dd, 6H, J = 6.5, 2 Hz), 1 .09 (d, 3H, J = 7 Hz), 0.986 (t, 3H, J = 7 Hz); High Res LC/MS: [M+H]+ 1241 .61 63; 1241 .6136 calculated.

Step c. Reaction of Amino-Biafungin with lnt-2 to Produce Compound 31

To a stirring solution of Amino-Biafungin (50 mg, 0.04 mmol) in DM F (1 ml_) was added formyl-Met-Leu-Phe- -Ala-OSu (lnt-2) (36 mg, 0.06 mmol) and DI PEA (7 uL, 0.04 mmol). The reaction was stirred at ambient temperature for 1 8 hours. The mixture was applied directly to reversed phase HPLC (Isco CombiFlash Rf; 50g Redisep C1 8 column; 5 to 95% acetonitrile in Dl water containing 0.1 % formic acid: 15 minute gradient). The pure fractions were pooled and lyophilized to yield 26 mg of a white solid as a formate salt. 1 H-NMR (300 M Hz, Methanol-d4) 5 8.55 (bs, 1 H), 8.44 (t, 1 H, J = 10 Hz), 8.1 8 (d, 1 H, J = 6 Hz), 8.1 1 (s, 1 H), 7.99 (d, 2H, J = 1 0 Hz), 7.84-7.70 (m, 6H), 7.63 (d, 2H, J = 7.8 Hz), 7.32-7.1 9 (m, 6H), 7.03 (d, 4H, J = 9 Hz), 6.87 (d, 1 H, J = 8.1 Hz), 5.44 (d, 1 H, J = 1 0.5 Hz), 5.05 (d, 1 H, J = 4.5 Hz), 4.83-4.74 (m, 2H), 4.66-4.50 (m, 6H), 4.45-4.29 (m, 10H), 4.1 9-3.82 (m, 1 0H), 3.67-3.57 (m, 6H), 3.1 7 (s, 9H), 2.64-2.46 (m, 6 H), 2.14-1 .92 (m, 6H), 1 .84 (m, 4H, J = 6 Hz), 1 .62-1 .40 (m, 8H), 1 .32-1 .22 (m, 6H), 1 .09 (d, 3H, J = 9 Hz), 0.99 (t, 3H, J = 7.5 Hz), 0.88 (m, 6H, J = 6.8 Hz) ; High Res LC/MS, [M/2+H]+ 865.4143, 865.4147 calculated.

REFERENCES

  1. Denning, DW (June 2002). “Echinocandins: a new class of antifungal.”. The Journal of antimicrobial chemotherapy 49 (6): 889–91. doi:10.1093/jac/dkf045. PMID 12039879.
  2.  Morris MI, Villmann M (September 2006). “Echinocandins in the management of invasive fungal infections, part 1”. Am J Health Syst Pharm 63 (18): 1693–703.doi:10.2146/ajhp050464.p1. PMID 16960253.
  3. Morris MI, Villmann M (October 2006). “Echinocandins in the management of invasive fungal infections, Part 2”. Am J Health Syst Pharm 63 (19): 1813–20.doi:10.2146/ajhp050464.p2. PMID 16990627.
  4. ^ Jump up to:a b “Pharmacotherapy Update – New Antifungal Agents: Additions to the Existing Armamentarium (Part 1)”.
  5.  Debono, M; Gordee, RS (1994). “Antibiotics that inhibit fungal cell wall development”.Annu Rev Microbiol 48: 471–497. doi:10.1146/annurev.mi.48.100194.002351.

17 Eschenauer, G; Depestel, DD; Carver, PL (March 2007). “Comparison of echinocandin antifungals.”. Therapeutics and clinical risk management 3 (1): 71–97. PMC 1936290.PMID 18360617.

///////////Biafungin™,  CD 101 IV,  CD 101 Topical,  CD101,  SP 3025, PHASE 2, CIDARA, Orphan Drug, Fast Track Designation, Seachaid Pharmaceuticals,  Qualified Infectious Disease Product, QIDP, UNII-G013B5478J, 1396640-59-7, 1631754-41-0, Vulvovaginal candidiasis, Echinocandin B, FUNGIN

FREE FORM

CCCCCOc1ccc(cc1)c2ccc(cc2)c3ccc(cc3)C(=O)N[C@H]4C[C@@H](O)[C@H](NC(=O)[C@@H]5[C@@H](O)[C@@H](C)CN5C(=O)[C@@H](NC(=O)C(NC(=O)[C@@H]6C[C@@H](O)CN6C(=O)C(NC4=O)[C@@H](C)O)[C@H](O)[C@@H](O)c7ccc(O)cc7)[C@@H](C)O)OCC[N+](C)(C)C

AND OF ACETATE

CCCCCOc1ccc(cc1)c2ccc(cc2)c3ccc(cc3)C(=O)N[C@H]4C[C@@H](O)[C@H](NC(=O)[C@@H]5[C@@H](O)[C@@H](C)CN5C(=O)[C@@H](NC(=O)C(NC(=O)[C@@H]6C[C@@H](O)CN6C(=O)[C@@H](NC4=O)[C@@H](C)O)[C@H](O)[C@@H](O)c7ccc(O)cc7)[C@@H](C)O)OCC[N+](C)(C)C.CC(=O)[O-]

Three antifungal drugs approved by the United States Food and Drug Administration, caspofungin, anidulafungin, and micafungin, are known to inhibit β-1 ,3-glucan synthase which have the structures shown below.

caspofungin

Anidulafungin

Other exemplary p-1 ,3-glucan synthase inhibitors include,

echinocandin B

cilofungin

pneumocandin A0

pneumocandin B0

L-705589

L-733560

A-174591

or a salt thereof,

Biafungin


or a salt thereof,

Amino-biafungin


or a salt thereof,

Amino-AF-053

ASP9726

Yet other exemplary p-1 ,3-glucan synthase inhibitors include, without limitation:

Papulacandin B

Ergokonin

//////////////

MK 7655, RELEBACTAM, a β-Lactamase inhibitor


Image result for RELEBACTAM

MK 7655, RELEBACTAM

(1R,2S,5R)-7-Oxo-N-(4-piperidinyl)-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamide

(1R,2S,5R)-7-oxo-2-((piperidin-4-yl)carbamoyl)-1,6-diazabicyclo(3.2.1)octan-6-yl hydrogen sulfate monohydrate

Sulfuric acid, mono((1R,2S,5R)-7-oxo-2-((4-piperidinylamino)carbonyl)-1,6-diazabicyclo(3.2.1)oct-6-yl) ester, hydrate (1:1)

MF C12H22N4O7S
MW 366.39068 g/mol

CAS 1174020-13-3

β-Lactamase inhibitor

MK-7655 is a beta-lactamase inhibitor in phase III clinical studies at Merck & Co for the treatment of serious bacterial infections…….See clinicaltrials.gov, trial identifier numbers NCT01505634 and NCT01506271.

In 2014, Qualified Infectious Disease Product (QIDP) and Fast Track designations were assigned by the FDA for the treatment of complicated urinary tract infections, complicated intra-abdominal infections and hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia.

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PAPER

A concise synthesis of a beta-lactamase inhibitor
Org Lett 2011, 13(20): 5480

http://pubs.acs.org/doi/abs/10.1021/ol202195n

http://pubs.acs.org/doi/suppl/10.1021/ol202195n/suppl_file/ol202195n_si_001.pdf

 

Abstract Image

MK-7655 (1) is a β-lactamase inhibitor in clinical trials as a combination therapy for the treatment of bacterial infection resistant to β-lactam antibiotics. Its unusual structural challenges have inspired a rapid synthesis featuring an iridium-catalyzed N–H insertion and a series of late stage transformations designed around the reactivity of the labile bicyclo[3.2.1]urea at the core of the target.

H NMR (400 MHz, DMSO-d6): δ 8.30 (br s, 2H), 8.20 (d, J = 7.8 Hz, 1H), 4.01 (s, 1H), 3.97-3.85 (m, 1H), 3.75 (d, J = 6.5 Hz, 1H), 3.28 (dd, J = 12.9, 2.5 Hz, 2H), 3.05-2.93 (m, 4H), 2.08-1.97 (m, 1H), 1.95-1.79 (m, 3H), 1.73-1.59 (m, 4H);

13C NMR (DMSO-d6, 100 MHz) δ 169.7, 166.9, 59.8, 58.3, 46.9, 44.3, 42.9, 28.5, 28.3, 20.8, 18.9;

HRMS calculated for C12H20N4O6S (M+H): 349.1182, found: 349.1183.

[α]D 25 = -23.3 (c = 1.0, CHCl3)

sc1

sc2

PATENT

WO 2009091856

http://www.google.com/patents/WO2009091856A2?cl=en

EXAMPLE IA

(2S ,5 R)-7-Oxo-N-piperidin-4-yl-6-(sulfooxy)- 1 ,6-diazabicyclo [3.2.1 ]octane-2-carboxamide

Figure imgf000063_0001

Step 1 : tert-butyl 4-({[(2S,5R)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1]oct-2- yljcarbonyl } amino)piperidine- 1 -carboxylate : To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-l,6-diazabicyclot3.2.1]octane-

2-carboxylic acid (1.484 g, 5.37 mmol) in dry dichloromethane (60 ml) was added triethylamine (1.88 ml, 13.49 mmol), 2-chloro-l-methylpyridinium iodide (1.60 g, 6.26 mmol), and 4-amino-l- BOC-piperidine (1.30 g, 6.49 mmol) sequentially at room temperature under nitrogen. The reaction was then heated to 500C for 1 hour. The reaction mixture was concentrated under vacuum and purified by silica gel chromatography on an Isco Combiflash (40 g silica gel, 40 mL/min, 254 nM, 15% to 100% EtOAc/hexane over 14 column volumes then 100% EtOAc for 4 column volumes; title compuond eluted at 65% ethyl acetate/hexane) to afford the title compound as a pale orange solid.

Step 2: tert-butyl 4-({[(2S,5R)-6-hydroxy-7-oxo-l ,6-diazabicyclo[3.2.1]oct-2- yl] carbonyl } amino)piρeridine- 1 -carboxylate:

Palladium on carbon (394 mg; 10% Pd/C) was added to a solution of the product of step 1 (1.81 g, 3.95 mmol) in methanol (50.6 mL) and the resulting mixture was stirred under hydrogen (balloon) overnight. LC/MS analysis indicated the reaction was not complete. Acetic acid (6 drops) and additional catalyst (159 mg of 10% Pd/C) were added to the reaction and the resulting mixture was stirred under hydrogen (balloon) for an additional 90 minutes. Additional catalyst (0.2085 g of 10% Pd/C) was added to the reaction and stirring under hydrogen was continued for an additional 2.5 hours at which time the reaction was judged complete by LC-MS analysis. The reaction was filtered through a celite pad and the collected solid was washed well wtih MeOH. The filtrate was concentrated under vacuum to afford the title compound as a colorless oil which was used without purification in the next step.

Step 3 : tert-butyl-4-({ [(2S,5R)-7-oxo-6-(sulfooxy)- 1 ,6-diazabicyclo[3.2.1 ]oct-2- yl] carbonyl } amino)ρiperidine- 1 -carboxylate:

To a solution of the product of step 2 (1.455 g, 3.95 mmol; theoretical yield of step 2) in dry pyridine (30 mL) was added sulfur trioxide pyridine complex (3.2 g, 20.11 mmol) at room temperature under nitrogen. The resulting thick mixture was stirred over the weekend.

The reaction was filtered and the white insoluble solids were washed well with dichloromethane. The filtrate was concentrated in vacuo. The residue was further azeotroped with toluene to remove excess pyridine to afford the title compound which was used without purification in the next step.

Step 4: (2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfooxy)-l,6-diazabicyclo[3.2.1]octane-2- carboxamide:

To a mixture of the product of step 3 (1.772 g, 3.95 mmol; theoretical yield of step 3) in dry dichloromethane (30 ml) at 00C under nitrogen was slowly added trifluoroacetic acid (6.1 ml, 79 mmol). Immediately the reaction became a solution. After 1 hour, additional trifluoroacetic acid (8 ml) was added to the reaction. The reaction was stirred at 00C until judged complete by LC-MS analysis then concentrated in vacuo. The residue was triturated with ether (3X) to remove excess TFA and organic impurities. The resulting white insoluble solid was collected via centrifugation, dried in vacuo, then purified by preparative HPLC (250X21.2 mm Phenomenex Synergi Polar-RP 80A column; 10 micron; 35 mL/min.; 210 nM; 0% to 30% methanol/water over 15 minutes; title compound eluted at 10% methanol/water). Fractions containing the title compound were combined and Iyophilized overnight to afford the title compound as a white solid. LC-MS (negative ionization mode) m/e 347 (M-H).

PAPER

Discovery of MK-7655, a beta-lactamase inhibitor for combination with Primaxin
Bioorg Med Chem Lett 2014, 24(3): 780

http://www.sciencedirect.com/science/article/pii/S0960894X13014856

Image for unlabelled figure

PATENT

WO 2014200786

http://www.google.dj/patents/WO2014200786A1?cl=en

 

 

 

Exemplary Scheme

– 50% isolated yield overall from 1 to 5

O via crystallization

XAMPLE 1

(2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfooxy)- 1 ,6-diazabicyclo[3.2.1 ]octane-2-carboxamide

Preparation of (15′,45)-5-((2-nitrophenyl)sulfonyl)-2-oxa-5-azabicyclo[2.2.2]octan-3 one (2)

To a reactor (R-1) equipped with an additional funnel, nitrogen inlet and agitator was charged (2S,5S)-5-hydroxypiperidine-2-carboxylic acid (77.3 wt%) (50.0 g, 344 mmol), and water (150 mL). Agitation was begun, the pH adjusted to 10-11 by addition of 10 N NaOH (~ 46.5 mL) and the reactor charged with acetone (50.0 mL).

In a separate reactor (R-2) equipped with an agitator and nitrogen inlet was charged 2-nitrobenzene-l-sulfonyl chloride (97%) (106.0 g, 478 mmol) and acetone (80 mL). The contents of R-2 were transferred to R-1 at 23-30 °C while the pH of the solution was maintained at 10-11 by simultaneously addition of 10 N NaOH. After 15 to 30 min, the pH was adjusted to about 6 by addition of 12 N HC1. The solution was charged with EtOAc (500 mL) and the pH adjusted to 3.0 by addition of 12 N HC1. The layers were separated and the aqueous back-extracted with EtOAc (150 mL x 2).

To a separate reactor (R-3) was charged product la in the combined organic layers, 2-nitrobenzene-l-sulfonyl chloride (73.0 g, 329 mmol), and triethylamine (130 mL). The batch in R-3 was agitated at 20-28°C for 30 min. The solution was charged with water (100 mL), the layers separated, and the aqueous back extracted with EtOAc (150 mL x 2). The combined EtOAc layer was washed with 10% NaHC03 (100 mL) and brine (100 mL). The organic phase was concentrated to 150 mL upon which a crystalline slurry was formed. The concentrated solution was agitated at 13-18°C for 2-3 hours followed by filtration of crystalline solids. The resulting wet cake was washed with EtOAc (60 mL) and then dried under vacuum oven at 25-30°C to afford 2 (65.6 g, 79% yield), m.p. 126.0-126.7 °C. 1H NMR (CDC13, 400 MHz) δ: 8.02 (m, 1 H), 7.80-7.71 (m, 2 H), 7.66 (m, 1 H), 4.88 (m, 1 H), 4.55 (dd, J= 3.8, 2.7 Hz, 1 H), 3.78 (dt, J= 11.2, 3.0 Hz, 1 H), 3.66 (dd, J = 11.2, 1.1 Hz, 1 H), 2.44 (m, 1 H), 2.11 (m, 2 H), 1.91 (m, 1 H); 13C NMR (CDC13, 100 MHz) δ: 168.4, 148.3, 134.4, 132.1, 131.0, 130.7, 124.2, 73.5, 51.4, 48.0, 25.1, 23.2

Preparation oftert-butyl 4-((25*,55)-l-((2-nitrophenyl)sulfonyl)-5-(((2- nitrophenyl)sulfony l)oxy)piperidine-2-carboxamido)piperidine- 1 -carboxylate (3)

To a reactor (R-l) was charged lactone 2 (65.5 g, 210 mmol), THF (131 mL) and tert-butyl 4-aminopiperidine-l -carboxylate (44.5 g, 222 mmol). The stirred solution was heated to reflux (typical temperature 72 °C) for ~18 hr. The reaction was cooled to 25-35 °C and then charged with THF (325 mL) and 4-dimethylaminopyridine (40.1 g, 328 mmol) followed by agitation for 30 minutes.

To a separate reactor (R-2) was charged 2-nitrobenzene-l-sulfonyl chloride (60.9 g,

275 mmol) and THF (200 mL). The contents of R-2 were added to R-l over the course of 45 to 75 minutes maintaining batch temperature of 20 to 30°C. The batch in R-l was agitated for 2 to 4 hours at a temperature of 20 to 30°C.

To a separate reactor (R-3) was charged water (600 mL) and methanol (600 mL). The contents of R-3 were charged to the main batch over the course of 45 to 75 minutes with agitation while maintaining temperature of 20 to 30°C. The batch was cooled to 5 to -5°C and then agitated at 5 to -5°C for at least 4 hours. The solids were filtered and then washed twice with methanol (130 mL x 2). The wet cake was dried in a vacuum oven at 40 to 50°C to afford 3 (144.0 g, 98% yield), m.p. 131.8-133.1 °C. 1H NMR (CDC13, 400 MHz) δ: 8.14 (m, 2 H), 7.83-7.74 (m, 6 H), 6.50 (d, J= 7.9 Hz, 1 H), 4.69 (m, 1 H), 4.43 (s, 1H), 4.11 (dd, , J= 13.7, 4.9 Hz, 1H), 3.95 (m, 2H), 3.83 (m, 1H), 3.47 (s, 1H), 3.10 (dd, J= 13.7, 11.0 Hz, 1H), 2.81 (m, 2H), 2.51 (m, 1H), 2.12 (m, 1H), 1.85-1.72 (m, 4H), 1.45 (s, 9H), 1.26 (m, 1H); 13C NMR (CDC13, 100 MHz) δ: 166.9, 154.6, 148.2, 147.6, 135.2, 134.8, 132.6, 132.5, 131.9, 131.6, 131.4, 129.7, 124.9, 124.7, 79.8, 76.5, 55.0, 47.1, 46.0, 31.8, 31.5, 28.4, 27.3, 24.4.

Preparation of N-4-nitrobenzene sulfonyl-O-benzylhydroxylamine

To a reactor (R-l) was charged O-benzylhydroxylamine hydrochloride (61.0g, 382 mmol) and pyridine (400 mL). The solution cooled to 5 to -5°C.

To a separate reactor (R-2) was charged 4-nitrobenzenesulfonyl chloride (89.0 g, 402 mmol) and pyridine (200 mL). The contents of R-2 were transferred to R-l at a rate to maintain temperature range of -5 to -5°C. The batch in R-l was agitated at 5 to -5 °C for 15 to 45 minutes then warmed to 20 to 30°C for 45 to 75 minutes. Water (250 mL) was then added at a rate to maintain 20 to 30°C and agitated 5 to 15 minutes. The solids were filtered and the wet cake washed with water (100 mL x 3). The wet cake was dried in vacuum oven at 50°C to afford N-4-nitrobenzenesulfonyl-O-benzylhydroxylamine (113.3 g, 96% yield), m.p. 128.4-130.0 °C. 1H NMR (CDCls, 400 MHz) δ: 8.36 (d, J = 8.9 Hz, 2 H), 8.11 (d, J = 8.9 Hz, 2 H), 7.36 (m, 5H), 7.11 (s, 1H), 5.02 (s, 2H); 13C NMR (CDC13, 100 MHz) δ: 151.0, 142.5, 134.9, 130.2, 129.7, 129.3, 128.9, 124.5, 80.2.

Step C. Preparation of tert-butyl 4-((2S,5R)-5-((benzyloxy)amino)piperidine -2-carboxamido)piperidine- 1 -carboxylate (4)

Boc

To a reactor (R-l) was charged tert-butyl 4-((2R,5R)-l-((2-nitrophenyl)sulfonyl)-5-(((2-nitrophenyl)sulfonyl)oxy)piperidine-2-carboxamido)piperidine-l -carboxylate (3) (110 g, 158 mmol), N-4-nitrobenzene sulfonyl-O-benzylhydroxylamine (58 g, 188 mmol), potassium carbonate (25.9 g, 187 mmol) and dimethylacetamide (440 mL). The stirred solution was heated to 60 to 70°C for 24 – 32 hours. The batch was cooled to 20 to 30°C and charged with toluene (660 mL). The batch was extracted with 1 N sodium hydroxide (3×220 mL) then washed with water (220 mL).

The toluene solution was azotropically distilled at ~50°C to about 1/3 volume. The solution was solvent-switched to MeOH at 45-55°C, adjusted to 237 mL.

The batch was cooled to 20-25°C, charged with thioglycolic acid (57.9 g, 629 mmol) at 10 °C, and then charged with K2CO3 anhydrous (172.0 g, 1225 mmol). The batch was agitated at 10-15°C for 0.5 h, warmed to 20-25°C, agitated at 20-25°C for 10-15 h, and heated at 48-53°C for 3-6 h.

The batch was charged with 10 wt% sodium chloride (1.10 L) and toluene (880 mL) at about 40°C. The layers were separated and the aq. layer back-extracted with toluene (3 x440 mL). The combined organic layer was washed with 10% NaHC03 (2 x220 mL). The batch was concentrated at 40-50°C to 165 mL, then cooled to 35-40°C. The batch was charged with seed (50 mg) and agitated for 1 h at 35-40°C. The batch was charged with heptanes (110 mL) at 35-40°C over 1 h, then slowly cooled to 15-20°C over 1 h. The batch was agitated for 3 h and the solids filtered. The wet cake was washed with toluene/heptanes (137.5 mL) then dried in vacuum oven at 30 °C for 3-8 h to affored 4. (47.3 g, 70% overall yield from 3), m.p. 117.5-118.0 °C. 1H NMR (CDC13, 500 MHz) δ: 7.37-7.29 (m, 5 H), 6.64 (d, J= 8.2 Hz, 1 H), 5.36 (brs, 1 H), 4.67 (s, 2 H), 4.00 (m, 2 H), 3.90 (m, 1 H), 3.28 (ddd, J= 11.8, 4.0, 1.7 Hz, 1 H), 3.12 (dd, J= 10.2, 3.2 Hz, 1 H), 2.95 (m, 1 H), 2.86 (m, 2 H), 2.46 (dd, J= 11.8, 9.5 Hz, 1 H), 2.10 (m, 1 H), 1.93-1.83 (m, 3 H), 1.58 (brs, 1 H), 1.45 (s, 9 H), 1.41 (m, 1 H), 1.35-1.23 (m, 3 H); 13C NMR (CDC13, 125 MHz) δ: 172.8, 154.7, 137.7, 128.4 (4 C), 127.9, 79.6, 76.9, 59.8, 57.0, 49.2, 46.1, 42.8 (br, 2 C), 32.0 (2 C), 28.4 (3 C), 28.3, 27.2.

Step D: Preparation of tert-butyl 4-((lR,2S,5R)-6-(benzyloxy)-7-oxo-l,6-diazabicyclo[3.2.1 ]octane-2-carboxamido)piperidine- 1 -carboxylate (5)

To a reactor (R-l) was charged tert-butyl 4-((2S,5R)-5-((benzyloxy)amino)piperidine-2-carboxamido)piperidine-l-carboxylate (4) (46.3 g, 107 mmol), dichloromethane (463 mL), and Hunig’s base (58.0 mL). The batch was cooled to -18°C and then charged with triphosgene in four portions (25.1 g total; 85 mmol) at <-8°C. The batch was agitated at -5 to 0°C for 0.5 h then charged with 11.4 wt% aqueous H3P04 at -5 to 0 °C (347 g, 3541 mmol). The batch was agitated at 20-25°C for 15-20 h then phase cut. The aqueous layer was back-extracted with dichloromethane (138 mL). The combined organic layer was washed with 10% NaHC03 (115 mL), then water (115 mL). The organic solution was concentrated at atmospheric pressure to ~80

mL, then charged with MTBE (347 mL) at 35-45 °C over 0.5 h, then concentrated at 35-45 °C to 231 mL two times to form a slurry.

The slurry was charged with heptanes (139 mL) at 35-45 °C over 2 h, then slowly cooled to 15-20°C over 1 h. The batch was agitated at 15-20°C for 6-8 h. Solids were filtered and the wet cake washed with MTBE/heptanes (1.4 : 1 , 185 mL) then dried under vacuum at 25-30°C for 5-10 hours to afford 5 (43.7 g, 92% yield), m.p. 161.3-161.8 °C. 1H NMR (CDC13, 500 MHz) δ: 7.45-7.32 (m, 5 H), 6.55 (d, J= 8.2 Hz, 1 H), 5.05 (d, J= 11.6 Hz, 1 H), 4.90 (d, J= 11.6 Hz, 1 H), 4.02 (m, 2 H), 3.90 (m, 2 H), 3.30 (m, 1 H), 2.99 (dt, J= 11.7, 1.1 Hz, 1 H), 2.86 (m, 2 H), 2.64 (d, J = 11.7 Hz, 1 H), 2.37 (dd, J= 14.6, 6.9 Hz, 1 H), 2.04-1.82 (m, 4 H), 1.58 (m, 1 H), 1.45 (s, 9 H), 1.30 (m, 2 H); 13C NMR (CDC13, 125 MHz) δ: 168.3, 167.5, 154.7, 135.6, 129.2 (2 C), 128.8, 128.6 (2 C), 79.7, 78.3, 60.4, 57.8, 47.5, 46.8, 42.5 (br, 2 C), 32.0, 31.7, 28.4 (3 C), 20.8, 17.2.

Step E: Preparation of tert-butyl 4-((2S,5R)-6-hydroxy-7-oxo-l,6-diazabicyclo[3.2.1|octane- 2-carboxamido) iperidine- 1 -carboxylate

tert-butyl 4-((2S,5R)-6-hydroxy-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-l -carboxylate (9.2 g, 20.1 mmol) was charged to a glass bottle, and the solids were dissolved in THF (150 mL). The solution was then charged to a hydrogenation reactor along with Pd/Al203 (10 wt%, 1.5 g). The reaction was purged three times with hydrogen and then set to a hydrogen pressure of 50 psi. The reaction temperature was adjusted to 25°C and the reaction was allowed to agitate for 22 hours. After the reaction was complete as determined by HPLC analysis, the solution was filtered through SOLKA-FLOC® (Interational Fiber Corporation, North Tonawanda, NY) to remove the catalyst and the filter cake was washed with THF. The filtrate and washes were then solvent switched by vacuum distillation to iPrOAc to a final volume of 40 mL. The resulting iPrOAc slurry was aged at room temperature for 1 hour. The solids were then filtered and washed with iPrOAc (20 mL) and dried under vacuum and N2 at 40°C to afford the title product (6.62 g., 17.97 mmol, 90% isolated yield). Spectral data matched the reference compound.

Preparation of (2S,5R)-7-oxo-N-piperidin-4-yl-6-(sulfooxy)- 1 ,6-diazabicyclo[3.2.1 ]octane-2-carboxamide

tert-butyl 4-((2S,5R)-6-hydroxy-7-oxo-l,6-diazabicyclo[3.2.1]octane-2-carboxamido)piperidine-l-carboxylate (20 g, 54.3 mmol), THF (200 mL), 2-picoline (10.9 mL, 309 mmol) and pyridine-S03 complex (30.2 g, 190 mmol) were charged to a flask under nitrogen. The heterogeneous mixture was allowed to stir overnight (~15 h). The reaction mixture was cooled to -10°C then DCM (200 mL) was added. 0.5 M K2HP04 (168 mL, 84 mmol) was added over 10 minutes. Bu4NHS04 (19.4 g, 57 mmol) was then added over 10 minutes. The biphasic mixture was stirred for 30 minutes, phase cut and the water layer was back extracted with 40 ml of DCM. The combined DCM solution was washed with water (120 ml), phase cut and the organic solution was solvent-switched to MeCN (320 ml) by vacuum distillation with 3 bed volumes of MeCN (total 1.0 L) and used as is in the next step. The solution of Bu4N+ OSO3 salt 7 in MeCN solution was used with an assumed yield of 100% (37.5 g, 54.3 mmol). The reaction mixture was cooled in an ice bath, and TMSI (10.26 ml, 70.7 mmol) was added via addition funnel over 30 minutes between 0°C and 5°C. The resulting mixture was agitated for 1-2 h and then quenched with H20:MeCN (1 :1, 6 ml) to afford a slurry. The slurry was warmed to room temperature and agitated for 12 h and after this time the pH of the supernatant was about 3.0. Tetrabutylammonium acetate (13.6 ml, 13.59 mmol) was slowly added over 30 min. The slurry was agitated for 1 h and pH of the supernatant was about 4.0. Solids were collected by filtration. The solid was washed with 60 mL of aqueous MeCN to afford 19.5 g of the crude product 8 in a 93% isolated yield from compound 6 .

At this stage, all byproducts (including hydro lyzation products of TMS-carbonate) and impurities were soluble in the organic phase.

The product was dissolved back into 140 ml of MeCN:H20 (1 :2) at room temperature. 1-Butanol (390 ml) as antisolvent was slowly added into the solution to afford a slurry. The slurry was agitated overnight. The white crystalline solid was filtered and washed with 3:1 IPA: water (40 ml) and dried under vacuum and nitrogen at room temperature to afford the title product in the form of a crystalline hydrate. (Yield = 16.3 g, 82%). Spectral data matched reference compound.

Preparation of (2S,5R)-7-oxo-2-(piperidin- 1 -ium-4-ylcarbamoyl)- 1 ,6-diazabicyclo[3.2.1 ]octan-6-yl sulfate (1).

tert-Butyl 4-( {[(25*,5i?)-6-hydroxy-7-oxo- 1 ,6-diazabicyclo[3.2.1 ]oct-2-yl]carbonyl}amino)piperidine-l-carboxylate 16 (0.54 g, 1.5 mmol), THF (5.4 mL), 2-picoline (0.29 mL, 2.9 mmol) and pyridine-S03 complex (0.70 g, 4.4 mmol) were charged to a vial under nitrogen. The heterogeneous mixture was allowed to stir overnight (~15 hr). The reaction mixture was cooled to -10°C then dichloromethane (5.4 mL) was added. 0.5 M K2HPO4 (4.5 mL, 2.3 mmol) was added over 10 minutes. BU4NHSO4 (0.53 g, 1.54 mmol) was then added over 10 min. The biphasic mixture was stirred for 30 min, phase cut and the water layer was back extracted with 1 ml of DCM. The combined DCM solution was washed with water (2.0 mL), phase cut and the organic solution was solvent-switched to MeCN (3.2 mL) by vacuum distillation with 3 bed volumes of MeCN. The product was used as is in the next step (water content less than 1000 ppm).

The solution of Bu4N+S04~~ salt 8 in MeCN solution was used with an assumed yield of 100% (1.0 g, 1.47 mmol). The reaction mixture was cooled in an ice bath, and Ν,Ο-bis(trimethylsilyl)trifluoroacetamide (BSTFA) (0.4 lg, 1.59 mmol) was added into the reaction and was allowed to stir for 10 min. TMSI (0.06g, 0.27 mmol) was added between 0°C and 5°C. The resulting mixture was allowed to agitate for 2 hr and then quenched with H2O (0.07g, 4.1 mmol) and acetic acid (0.08g, 1.5 mmol) to afford a slurry. The slurry was warmed to room temperature and agitated for 12 hr. Filter to collect the solid. The solid was washed with MeCN/water (94:6, 1 mL X 4) to afford the crystalline product 1 (0.38 g) in a 75% yield.

If NO-bis(trimethylsilyl)acetamide (BSA) (0.32g, 1.59 mmol) was applied, the reaction needed 24 hr to achieve full conversion.

Patent

WO2015033191

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015033191&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Scheme 1.

Formula (V)

Formula (VI)

Formula (I)

Scheme – 1

Example -1

Preparation of (2S, 5R)-Sulfuric acid mono-{2-[N’-(4-aminopiperidinyl)-carbonyl]-7-oxo- l,6-diaza-bicyclo[3.2.1]oct-6-yl} ester (I).

Step-1: Preparation of (2S, 5R)-tert-butyl { (6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate (IV):

To a 250 ml round bottom flask equipped with magnetic stirrer was charged a solution of (2S, 5R)-sodium 6-benzyloxy-7-oxo-l,6-diaza-bicyclo [3.2.1] octane-2-carboxylate (11.1 gm, 0.037 mol, prepared using a method disclosed in Indian Patent Application No 699/MUM/2013) in water (180 ml) followed by l-tert-butoxycarbonyl-4-amino-piperidine (7.8 gm, 0.039 mol), EDC hydrochloride (11 gm, 0.055 mol) and 1 -hydro ybenzotriazole (4.8 gm, 0.037 mol) at 30°C successively under stirring. The reaction mixture was stirred for 24 hours at 30°C to provide a suspension. The suspension was filtered under suction and washed with 45°C warm water (40 ml) to provide (2S, 5R)-tert-butyl { (6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate in 12.7 gm quantity in 74% yield after drying under vacuum.

Analysis

NMR: (CDC13,) = 7.36-7.44 (m, 5H), 6.56 (d,lH), 5.06 (d,lH), 4.91 (d, 1H), 4.03 (br s, 1H), 3.88-3.97 (m, 2H), 3.29 (s, 1H), 3.00 (d, 1H), 2.86 (t, 2H), 2.64 (d, 1H), 2.37 (dd, 1H), 1.85-2.01 (m, 4H), 1.54-1.62 (m, 2H), 1.45 (s, 9H), 1.25-1.36 (m, 2H).

MS (ES+) C24H34N405 = 459.5 (M+l).

Step-2: Preparation of (2S, 5R)-tert-butyl { (6-hydroxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate (V):

To a 100 ml single neck round bottom flask equipped with magnetic stirrer was charged a solution of (2S, 5R)-tert-butyl { (6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate (9 g, 19.5 mmol) in methanol (90 ml) followed by 10% palladium on carbon (2.7 g) at 35°C. The reaction mixture was stirred under 1 atm hydrogen pressure at 35°C for 2 hours. The catalyst was removed by filtering the reaction mixture under suction over a celite bed. The celite bed was washed with dichloromethane (50 ml). The combined filtrate was evaporated under vacuum below 35°C to provide (2S, 5R)-tert-butyl {(6-hydroxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate in 8.45 g quantity; it was used as such for the next reaction.

Analysis

NMR: (CDC13,) = 6.60 (d, 1H), 3.88-4.10 (m, 4H), 3.78 (s, 1H), 3.20 (d, 1H), 3.90 (t, 2H), 2.80 (d, 1H), 2.46 (dd, 1H), 2.1-2.2 (m, 1H), 2.85-2.20 (m, 4H), 1.70-1.80 (m, 1H), 2.47 (s, 9H), 1.30-1.41 (m, 3H).

MS (ES+) C17H28N405 = 369.4 (M+l).

Step-3: Preparation of Tetrabutyl ammonium salt of (2S, 5R)-tert-butyl {(6-sulfooxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate (VI):

To a 100 ml single neck round bottom flask equipped with magnetic stirrer was charged a solution of (2S, 5R)-tert-butyl {(6-hydroxy-7-oxo-l,6-diaza-bicyclo [3.2.1 ]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate (6.40 g, 7.6 mmol) in dichloromethane (90 ml), triethyl amine (9.3 ml), followed by pyridine – sulfur trioxide complex (5.4 g, 34.2 mmol) at 35°C under stirring. The reaction mixture was stirred for additional 4 hours at 35°C. The solvent was evaporated under vacuum below 40°C to provide a residue. The residue was stirred with 0.5N aqueous potassium dihydrogen phosphate solution (90 ml) for 1 hour. The resulting solution was extracted with dichloromethane (2 x 100 ml) to remove impurities. To the aqueous layer was added tetrabutyl ammonium hydrogen sulfate (6.9 g, 20.52 mmol) and the reaction mixture was stirred for 14 hours at 35°C. It was extracted with dichloromethane (3 x 30 ml). Combined organic layer was dried over sodium sulfate and evaporated under vacuum to provide tetrabutyl ammonium salt of (2S, 5R)-tert-butyl {(6-sulfooxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate in 8.0 g quantity in 62% yield.

Analysis

NMR: (CDC13,) – 6.64 (d, 1H), 4.36 (br s, 1H), 4.05(br s, 2H), 3.90-4.00 (m, 1H), 3.87 (d, 1H), 2.28-3.34 (m, 10H), 3.80-3.95 (m, 2H), 3.74 (d, 1H), 2.42 (dd, 1H), 2.15-2.24 (m, 1H), 1.82-1.97 (m, 4H), 1.61-1.74 (m, 14 H), 1.41-1.52 (m, 10 H), 1.02 (t, 12H).

MS (ES-) C17H27N408S. N(C4H9)4 = 447.4 (M-l) as a free sulfonic acid.

Step-4: Synthesis of (2S, 5R)- Sulfuric acid mono-{ [(4-aminopiperidin-4-yl) carbonyl]-7-oxo-l,6-diaza-bicyclo[3.2.1]-oct-6-yl} ester (I):

To a 100 ml round bottom flask equipped with magnetic stirrer was charged a solution of tetrabutyl ammonium salt of (2S, 5R)-tert-butyl {(6-sulfooxy-7-oxo-l,6-diaza-bicyclo[3.2.1]oct-2-yl-carbonyl) amino} piperidine-l-carboxylate (6.0 g) in dichloromethane (15 ml). The solution was cooled to -10°C under stirring and to it was added trifluoro acetic acid (15 ml) drop wise. The reaction mixture was stirred at -10°C for 1 hour. Solvents were evaporated under vacuum below 30°C to its 1/3 volume to provide a thick residue. The thick residue was stirred twice with diethyl ether (60 ml each time) to provide a precipitation. The solid obtained was filtered at suction and suspended in acetone (90 ml). To the suspension was added 10% solution of sodium-2-ethyl-hexanoate in acetone to adjust pH between 4.5 to 5.5. The suspension was stirred for 10 minutes and filtered under suction. The wet cake was washed with acetone and dried under vacuum below 40°C to provide 3 gm crude compound. The crude compound was stirred with aqueous isopropanol (3ml water: 21 ml iospropanol) for overnight to purify further. The resulting suspension was filtered under suction and washed with aqueous isopropanol (1 ml water: 7 ml IPA mixture). Finally the cake was dried under vacuum below 40°C to provide the title compound as a off-white solid in 1.8 g quantity in 65% yield.

Analysis

H1NMR (DMSO-d6, D20 exchange) = 8.19 (d, exchanges with D20), 3.99 (s, 1H), 3.82-3.92 (m, 1H), 3.72 (d, 1H), 2.24 (br d, 3H), 2.90-3.04 (m, 5H), 1.96-2.06 (m, 1H), 1.80-1.94 (m, 3H), 1.58-1.72 (m, 4H).

MS (ES+) C12H20N4O6S = 349.2 (M+l) as a free sulfonic acid;

Purity by HPLC: 99.2%

Specific rotation: [a] D -45.25 °, (c 0.3%, water)

SEE BACTAM SERIES…………..http://apisynthesisint.blogspot.in/p/bactam-series.html

//////

C1CC(N2CC1N(C2=O)OS(=O)(=O)O)C(=O)NC3CCNCC3.O

 

UPDATE,,,,,,,,,,

Improved Preparation of a Key Hydroxylamine Intermediate for Relebactam: Rate Enhancement of Benzyl Ether Hydrogenolysis with DABCO

Process R&D Department, MRL, Merck & Co., Inc., Rahway, New Jersey 07065, United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00381
Publication Date (Web): February 1, 2018
Copyright © 2018 American Chemical Society
Abstract Image

Previous methods to prepare a bicyclic N-hydroxyl urea intermediate in the synthesis of the potent β-lactamase inhibitor relebactam were effective, but deemed unsuitable for long-term use. Therefore, we developed an in situ protection protocol during hydrogenolysis and a robust deprotection/isolation sequence of this unstable intermediate employing a reactive crystallization. During the hydrogenation studies, we discovered a significant rate enhancement of O-benzyl ether hydrogenolysis in the presence of organic amine bases, especially DABCO. The broader utility of the application of organic bases on the hydrogenolysis of a range of O– and N-benzyl-containing substrates was demonstrated.

Figure

5 could be isolated by concentrating the filtrate and storing the solution at 5 °C overnight. 1H NMR (500 MHz, CDCl3): δ 6.58 (d, J = 7.9 Hz, 1H), 4.10–3.86 (m, 4H), 3.55 (bs, 1H), 3.14 (bd, J = 11.5 Hz, 1H), 2.86 (bt, J = 12.0 Hz, 2H), 2.76 (d, J = 11.5 Hz, 1H), 2.36 (dd, J = 15.1, 7.1 Hz, 1H), 2.12 (m, 1H), 2.00–1.82 (m, 3H), 1.66 (m, 1H), 1.44 (s, 9H), 1.31 (m, 2H), 0.25 (S, 9H). 13C NMR (125 MHz, CDCl3): δ 169.2, 168.3, 154.8, 79.8, 60.7, 60.0, 47.3, 46.9, 42.6 (br, 2C), 32.2, 31.9, 28.5 (3C), 20.5, 17.5, −0.75 (3C). (+)-ESI HRMS: calcd for C20H36N4NaO3Si (M + Na)+, 463.2347; found, 463.2348.

WCK 5222, Wockhardt receives QIDP status for its new drug WCK 5222 from USFDA


 

WCK 5222

Watch this post as I get to the structure…………..

DEC2015

Wockhardt has received Qualified Infectious Disease Product (QIDP) status for its new drug WCK 5222,  a product from its breakthrough New Drug Discovery program in Anti Infectives from the US Food and Drug Administration (FDA).
This is the fourth product from the company to receive this coveted status. During last year, the company has received approval for WCK 771 & WCK 2349 and in early this year approval was received for WCK 4873. The only company globally to receive QIDP status for 4 drugs from US FDA.
Wockhardt is one of the few companies with end to end integrated capabilities for its products, starting with the manufacture of the oral and sterile API’s, the dose forms and marketing through wholly owned subsidiary in the US, enabling the company to capture maximum value.

 

Ten compounds generally represented by a general Formula (I) were used and are as follows:

(a) Sodium salt of ir ns-7-oxo-6-sulphooxy-l ,6-diazabicyclo[3.2.1]-octane-2-carbonitrile (Compound A);

(b) trans-sulphuric acid mono-[2-(5-carboxamido)-[l ,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octan-6-yl] ester (Compound B);

(c) trans-sulphuric acid mono-[2-(5-(piperidin-4-yl)-[l ,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octan-6-yl] ester (Compound C);

(d) trans-sulphuric acid mono-[2-(5-azetidin-3-ylmethyl-[l ,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octan-6-yl] ester (Compound D);

(e) (25,5i?)-7-Oxo-6-sulphooxy-2-[N’-((i?)-piperidine-3-carbonyl)-hydrazinocarbonyl] -1,6-diaza-bicyclo[3.2.1]octane (Compound E);

(f) (25, 5i?)-7-Oxo-N-[(25)-pyrrolidin-2-ylmethoxy]-6-(sulfooxy)-l,6-diaza bicyclo [3.2.1] octane-2-carboxamide (Compound F);

(g) (25,5i?)-7-Oxo-6-sulphooxy-2-[N’-((i?)-pyrrolidine-3-carbonyl)-hydrazinocarbonyl]-l ,6-diaza -bicyclo[3.2.1]octane (Compound G);

(h) (25,5i?)-7-Oxo-N-[(25)-piperidine-2-ylmethyloxy]-6-(sulfooxy)-l ,6-diazabicyclo

octane-2-carboxamide (Compound H);

(i) trans-sulphuric acid mono-[2-(5-((5)-l-amino-ethyl)-[l ,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octan-6-yl] ester (Compound I); and

j) trans-sulphuric acid mono-[2-(5-((5)-pyrrolidin-2-yl)-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octan-6-yl] ester (Compound J).

////

WCK 2349 in phase II trials by Wockhardt


Figure imgf000002_0001. CH3SO3H
WCK 2349
Cas 948895-94-1  methane sulfonate
Base..706809-20-3
527.563., C22 H26 F N3 O5 . C H4 O3 S
8-[4-(L-Alanyloxy)piperidin-1-yl]-9-fluoro-5(S)-methyl-1-oxo-1,5,6,7-tetrahydropyrido[3,2,1-ij]quinoline-2-carboxylic acid methanesulfonate
S-​(-​)​-​9-​fluoro-​6,​7-​dihydro-​8-​(4-​L-​alaninyloxypiperidin-​1-​yl)​-​5-​methyl-​1-​oxo-​1H,​5H-​benzo[i,​j]​quinolizine-​2-​carboxylic acid methanesulfonate
(2’S, 5S)-9-fluoro-6,7-dihydro-8-(4-L-alaninyl-oxy-piperidin-l-yl)-5-methyl- l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid methanesulfonic acid salt
Oral broad-spectrum antibiotic
WO 2000068229, WO 2002009758, WO 2007102061, WO 2008053295, Indian (2015), IN 267210 , IN 2008MU00864,
Shetty, N.M.; Nandanwar, M.B.; Kamalavenkatesh, P.; et al.
WCK 2349: A novel fluoroquinolone (FQ) prodrug-13 week oral (PO) safety profile in cynomolgus monkeys
47th Intersci Conf Antimicrob Agents Chemother (ICAAC) (September 17-20, Chicago) 2007, Abst F1-2133a

8-{4-[2(S)-Amino-propionyloxy] piperidine-l-yl}-9-fluoro-5 (S)-methyl-ό, 7-dihydro-l- oxo-lH, 5H-benzo[i,j]quinolizine-2-carboxylic acid of structural Formula I can be used to treat bacterial Gram-positive, Gram-negative and anaerobic infections; especially infections caused by resistant Gram-positive organism and Gram-negative organism, mycobacterial infections and emerging nosocomial pathogen infections.

Figure imgf000002_0001

Formula I

U.S. Patent Nos. 6,750,224 and 7,247,642 describes optically pure S-(-)-benzoquinolizine carboxylic acids, their derivatives, salts, pseudopolymorphs, polymorphs and hydrates thereof, their processes of preparation and their pharmaceutical compositions.

PATENT

 

WO 2007102061

http://www.google.co.in/patents/WO2007102061A2?cl=en

Figure imgf000008_0001
Figure imgf000008_0002

Scheme 1

Experimental:

(S)-9-Fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[ij] quinolizine-2-carboxylic acid was prepared as per procedure described in Chem. Pharm. Bull. 1996, 44(4), 642-645.

Example-l

Preparation of (2’S,5S)-9-fluoro-6,7-dihydro-8-(4-(N-tert-butoxycarbonyI-L-aIaninyl- oxy)-piperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid:

Method-1 : To a mixture of N-tert-butoxycarbonyl-L-alanine (473 g) in dichloromethane (2 L), dicyclohexylcarbodiimide (515 g) dissolved in dichloromethane (2 L) was charged at -10 to 0 0C to provide a turbid suspension. To the turbid suspension, 300 g of (S)-9-fluoro-6,7- dihydro-8-(4-hydroxy-piperidin- 1 -yl)-5-methyl- 1-oxo- lH,5H-benzo[i,j]quinolizine-2- carboxylic acid was added followed by 4-N,N-dimethylamino pyridine (58 g) and the reaction mixture was stirred at -10 to 5 °C temperature over a period of 2 h. Suspension was filtered and solid was washed with 500 ml of dichloromethane. The filtrate was washed with water. Filtrate was dried over anhydrous sodium sulfate. Dried organic layer was then concentrated to its half volume where upon solid was precipitated. The solid was filtered and washed with 300 ml of dichloromethane. Clear organic filtrate was concentrated to dryness to provided an oily mass. Oily mass was triturated with diethyl ether (4 L) to provide white solid. The solid was filtered under suction and washed with diethyl ether (1 L) to provide title compound in 415 g (94%) quantity.

Method-2: To a mixture of triethylamine (98.0 ml) and N-tert-butoxycarbonyl-L-alanine (110 g) in tetrahydrofuran (1050 ml) and N,N-dimethyl formamide (350 ml) mixture, was added 2,4,6-trichlorobenzoyl chloride (100 ml). The resultant mixture was stirred at a temperature -5 to 0 °C for 5 h. To the > reaction mixture 4-N,N-dimethylamino pyridine (24g) and (S)-9-fluoro-6,7-dihydro-8-(4-hydroxy-piperidin-l-yl)-5-methyl-l-oxo-lH,5H- benzo[i,j]quinolizine-2-carboxylic acid (70 g) was added. The reaction mixture was stirred for additional 7 h at -5 to 0 0C temperature. The suspension was filtered at room temperature and the filtrate was extracted with ethyl acetate after addition of water. The evaporation of organic layer under reduced pressure provided a sticky solid, which upon triturating with diethyl ether provided a white solid in 85 g quantity.

Method-3: To a solution N-tert-butoxycarbonyl-L-alanine (7.9 g) in tetrahydrofuran (75 ml) and N,N-dimethyl formamide (25 ml) mixture at -10 to 0°C was added methanesulfonyl chloride (2.42 ml) dropwise. To the above solution triethylamine (8.7 ml) was added dropwise over 5 min. the reaction was stirred for 1.5 h maintaining the temperature between at -10 to 0 0C. To the reaction mixture (S)-9-fluoro-6,7-dihydro-8-(4-hydroxy-piperidin-l- yl)-5-methyl-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (5.01 g) and 4-N5N- dimethylamino pyridine (1.70 g) was added. The reaction mixture was stirred for additional 1 h at -5 to 0 °C temperature. The suspension was filtered at room temperature and the filtrate was diluted with water (300 ml) and extracted with ethyl acetate (150 ml x 2). The evaporation of organic layer under reduced pressure provided a sticky solid, which upon triturating with diethyl ether provided a white solid in 6.38 g (86%) quantity.

Example-2

Preparation of (2’S, 5S)-9-fluoro-6,7-dihydro-8-(4-L-alaninyl-oxy-piperidin-l-yl)-5-methyl- l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid methanesulfonic acid salt:

To a mixture of (2’S, 5S)-9-fluoro-6,7-dihydro-8-(4-N-tert-butoxycarbonyl-L-alaninyloxy- piperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid (415 g) in acetone (4.5 L) was charged methanesulfonic acid (66 ml). Reaction mixture was stirred at 65-67 °C temperature for overnight. The suspension was filtered at 40-45 0C. Solid was washed with acetone (1.5 L) followed by diethyl ether (1.5 L). Off white solid was dried under 40 to 45 mm vacuum at 55-60 °C temperature over the period of 3-4 h. Title compound was obtained as a free flowing off white material 383.0 g (93%).

For MF: C23H30FN3O8S, MS (ES+) m/z 432 (obtained as free base for MF: C22H26FN3O5);

M.P. 278.50 0C by DSC

PATENT

WO 2000068229
A S-(-)-optically pure benzoquinolizine carboxylic acid, its derivatives, its pharmaceutically acceptable salts, derivatives, pseudopolymorphs, polymorphs or hydrates thereof of formula I,
Figure imgf000066_0001
Formula I

Patent

WO 2011101710

PATENT

The tablets may optionally be coated with film forming agents and/or pharmaceutically acceptable excipients. Particularly suitable for use are commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® and Eudragit®. The coating layers over the tablet may be applied as solution/dispersion of coating ingredients using conventional techniques known in the art.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1 :

Table 1 provides the composition of batches of the present invention.

Table 1

Figure imgf000007_0001

Procedure: The compound of Formula I or pharmaceutically acceptable salts, esters or products thereof, lactose and croscannellose sodium were sifted and dry mixed in a rapid mixer granulator. The above mass was granulated by spraying aqueous solution of povidone. The granules were dried in a fluidized bed drier, sifted and oversize granules were milled in a Quadra mill. The resultant granules were mixed with talc, croscarmellose sodium, microcrystalline cellulose and sodium stearyl fumarate in a double cone blender. The lubricated granules were compressed into tablets using suitable tooling. Tablets were coated with aqueous dispersion of opadry.

Table 2 provides the dissolution data for the compound of formula I or pharmaceutically acceptable salts, esters or products thereof tablets prepared as per the formula given in Table 1. For determination of drug release rate, USP Type 2 Apparatus (rpm 50) was used wherein 0.1 N hydrochloric acid (900 ml) was used as a medium. Table 2: Dissolution data

Figure imgf000008_0001
//////////////////////////////
aChemical name: S-(–)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid L-arginine salt tetrahydrate. bChemical name: S-(–)-1-cyclopropyl-6-fluoro-8-methoxy-7-(4-amino-3, 3-dimethylpiperidin-1-yl)-1,4 dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride monohydrate. cChemical name: R-(+)-1-cyclopropyl-6-fluoro-8-methoxy-7-(4-amino-3,3-dimethylpiperidin-1-yl)-1,4 dihydro-4-oxo-quinoline-3-carboxylic acid hydrochloride monohydrate.
31 Aug, 2014,
NEW DELHI: Drug maker WockhardtBSE -1.83 % today said that two of its anti-infective drugs
have received Qualified Infectious Disease Product (QIDP) status from the US
health regulator.Two drugs – WCK 771 and WCK 2349 – have received QIDP
status, which allows fast-track review of the drug application by the US Food and Drug Administration (USFDA),
Wockhardt said in a statement.
Levonadifloxacin arginine salt, WCK 771
RN: 306748-89-0
  • C19-H21-F-N2-O4.C6-H14-N4-O2
  • MW: 534.5855
  • L-Arginine, mono((5S)-9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidinyl)-5-methyl-1-oxo-1H,5H-benzo(ij)quinolizine-2-carboxylate)
 WCK 771………..S-(–)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j] quinolizine-2-carboxylic acid L-arginine salt tetrahydrate
(-)-9-Fluoro-8-(4-hydroxypiperidin-1-yl)-5(S)-methyl-1-oxo-1,5,6,7-tetrahydropyrido[3,2,1-ij]quinoline-2-carboxylic acid L-arginine salt hydrate
 L-arginine salt of (S)-nadifloxacin
A chiral benzoquinolizine-2-carboxylic acid arginine salt active against vancomycin-resistant Staphylococcus aureus
J Med Chem 2005, 48(16): 5232
CN 102532131, WO 2005023805, WO 2002009758, WO 2001085095, WO 2000068229
WO1991012815A1 * Feb 25, 1991 Sep 5, 1991 Squibb Bristol Myers Co COMPOSITIONS AND METHODS FOR TREATING INFECTIONS CAUSED BY ORGANISMS SENSITIVE TO β-LACTAM ANTIBIOTICS
WO2000068229A2 * May 8, 2000 Nov 16, 2000 S K Agarwal (s)-benzoquinolizine carboxylic acids and their use as antibacterial agents
WO2001085095A2 * May 3, 2001 Nov 15, 2001 Shiv Kumar Agarwal Chiral fluoroquinolizinone arginine salt forms
WO2002009758A2 * Jul 31, 2001 Feb 7, 2002 Satish B Bhawsar Inhibitors of cellular efflux pumps of microbes
EP2062582A1 * Aug 14, 2007 May 27, 2009 Tianjin Hemey Bio-Tech Co., Ltd. The antibiotics composition comprising beta-lactam antibiotics and buffers
US4524073 * Jul 20, 1983 Jun 18, 1985 Beecham Group P.1.C. β-Lactam compounds
US6465428 * Aug 25, 2000 Oct 15, 2002 Aventis Pharma S.A. Pharmaceutical combinations based on dalfopristine and quinupristine, and on cefepime
US20040254381 * Aug 15, 2003 Dec 16, 2004 Day Richard A. Antibiotic compositions and methods of using the same
US20050148571 * Nov 29, 2002 Jul 7, 2005 Nancy Niconovich Method of treating bacterial infections using gemifloxacin or a salt thereof and a betha-Lactam antibiotic
US20090148512 * Apr 17, 2008 Jun 11, 2009 Lannett Co Inc Novel uses of chloramphenicol and analogous thereof
US20090232744 * Feb 26, 2009 Sep 17, 2009 Pari Pharma Gmbh Macrolide compositions having improved taste and stability
WO2002009758A2 * 31 Jul 2001 7 Feb 2002 Satish B Bhawsar Inhibitors of cellular efflux pumps of microbes
US6750224 17 Aug 2000 15 Jun 2004 Wockhardt Limited Antibacterial optically pure benzoquinolizine carboxylic acids, processes, compositions and methods of treatment

 

Mr Habil Khorakiwala, Chairman, Wockhardt Ltd.

 

///////////keywords  USFDA, Qualified Infectious Disease Product status, Wockhardt,  drugs,  WCK 2349, QIDP

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