New Drug Approvals

Home » FDA 2018

Category Archives: FDA 2018

Advertisements
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

Blog Stats

  • 2,207,204 hits

Flag and hits

Flag Counter

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,273 other followers

Follow New Drug Approvals on WordPress.com

Categories

Flag Counter

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,273 other followers

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

Personal Links

Verified Services

View Full Profile →

Categories

Flag Counter
Advertisements

FDA approves first treatment Libtayo (cemiplimab-rwlc) for advanced form of the second most common skin cancer


FDA approves first treatment for advanced form of the second most common skin cancer

New drug targets PD-1 pathway

The U.S. Food and Drug Administration today approved Libtayo (cemiplimab-rwlc) injection for intravenous use for the treatment of patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation. This is the first FDA approval of a drug specifically for advanced CSCC.

September 28, 2018

Release

The U.S. Food and Drug Administration today approved Libtayo (cemiplimab-rwlc) injection for intravenous use for the treatment of patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation. This is the first FDA approval of a drug specifically for advanced CSCC.

Libtayo works by targeting the cellular pathway known as PD-1 (protein found on the body’s immune cells and some cancer cells). By blocking this pathway, the drug may help the body’s immune system fight the cancer cells.

“We’re continuing to see a shift in oncology toward identifying and developing drugs aimed at a specific molecular target. With the Libtayo approval, the FDA has approved six immune checkpoint inhibitors targeting the the PD-1 / PD-L1 pathway for treating a variety of tumors, from bladder to head and neck cancer, and now advanced CSCC,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This type of cancer can be difficult to treat effectively when it is advanced and it is important that we continue to bring new treatment options to patients.”

CSCC is the second most common human cancer in the United States with an estimated annual incidence of approximately 700,000 cases. The most common form of skin cancer is basal cell cancer. Squamous cells are thin, flat cells that look like fish scales and are found in the tissue that forms the surface of the skin. CSCC usually develops in skin areas that have been regularly exposed to the sun or other forms of ultraviolet radiation. While the majority of patients with CSCC are cured with surgical resection, a small percentage of patients will develop advanced disease that no longer responds to local treatments including surgery and radiation. Advanced CSCC may cause disfigurement at the site of the tumor and local complications such as bleeding or infection, or it may spread (metastasize) to local lymph nodes, distant tissues and organs and become life-threatening.

The safety and efficacy of Libtayo was studied in two open label clinical trials. A total of 108 patients (75 with metastatic disease and 33 with locally-advanced disease) were included in the efficacy evaluation. The study’s primary endpoint was objective response rate, or the percentage of patients who experienced partial shrinkage or complete disappearance of their tumor(s) after treatment. Results showed that 47.2 percent of all patients treated with Libtayo had their tumors shrink or disappear. The majority of these patients had ongoing responses at the time of data analysis.

Common side effects of Libtayo include fatigue, rash and diarrhea. Libtayo must be dispensed with a patient Medication Guide that describes uses of the drug and its serious warnings. Libtayo can cause the immune system to attack normal organs and tissues in any area of the body and can affect the way they work. These reactions can sometimes become severe or life-threatening and can lead to death. These reactions include the risk of immune-mediated adverse reactions including lung problems (pneumonitis), intestinal problems (colitis), liver problems (hepatitis), hormone gland problems (endocrinopathies), skin (dermatologic) problems and kidney problems. Patients should also be monitored for infusion-related reactions.

Libtayo can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception.

The FDA granted this application Breakthrough Therapy and Priority Reviewdesignations.

The FDA granted the approval of Libtayo to Regeneron Pharmaceuticals, Inc.

////////////Libtayo, cemiplimab-rwlc, FDA 2018,  Breakthrough Therapy,  Priority Review
Advertisements

Sarecycline , サレサイクリン


Sarecycline.svg

ChemSpider 2D Image | Sarecycline | C24H29N3O8

Sarecycline

サレサイクリン

MW 487.5024, MF C24H29N3O8 FREE FORM

Paratek  INNOVATOR

FDA 2018/10/1 APPROVED SEYSARA, ALMIRALL, for the oral treatment of inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 9 years of age and older

(4S,4aS,5aR,12aS)-4-(dimethylamino)-3,10,12,12a-tetrahydroxy-7-[(methoxymethylamino)methyl]-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide
(4S,4aS,5aR,12aS)-4-(Dimethylamino)-3,10,12,12a-tetrahydroxy-7-{[methoxy(methyl)amino]methyl}-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-tetracenecarboxamide
1035654-66-0 [RN] FREE FORM
2-Naphthacenecarboxamide, 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-7-[(methoxymethylamino)methyl]-1,11-dioxo-, (4S,4aS,5aR,12aS)-
94O110CX2E
9743

P005672, 

  • P 005672

Sarecycline hydrochloride.png

CAS 1035979-44-2 HCl

Molecular Formula C24 H29 N3 O8 . Cl H
 Molecular Weight 523.963

P-005672
PTK-AR-01
SC-1401
WC-3035

Sarecycline (trade name Seysara; development code WC-3035) is a tetracycline-derived antibiotic. In the United States, it was approved by the FDA in October 2018 for the treatment of moderate to severe acne vulgaris.[1]

Paratek Pharmaceuticals, Inc. licensed the US rights to sarecycline for the treatment of acne in the United States to Actavis, a subsidiary of Allergan, while retaining rights in the rest of the world.[2]

Allergan initiated a Phase 3 study in December 2014 evaluating the efficacy and safety of sarecycline tablets 1.5 mg/kg per day taken orally for 12 weeks versus placebo in the treatment of acne vulgaris.[3] Two phase 3 randomized, multi-center, double-blind, placebo-controlled studies evaluating the efficacy and safety of sarecycline in moderate to severe acne reported positive results on 27 March 2017.[4]

SYN

US 2016/0200671

PATENT

WO 2008079363

PATENT

WO 2008079339

PATENT

WO 2012155146

EXAMPLES

[00104] The following examples illustrate the synthesis of the compounds described herein.

Synthesis of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,ll-dioxo-l,4,4a,5,5a,6,ll,12a-octahydro-naphthacene-2-carboxylic acid amide (“the free base”).

[00105] A solution of 7-formylsancycline TFA salt (2.23 g) and N,0-dimethylhydroxylamine hydrochloride (780 mg) in N,N-dimethylacetamide (15 mL) was stirred for 10 minutes at room temperature under argon atmosphere. To this solution was added sodium cyanoborohydride (302 mg). The solution was stirred for 5 minutes and monitored by LC-MS. The reaction mixture was poured into diethyl ether, and the resulting precipitates were collected by filtration under vacuum. The crude product was purified by prep-HPLC using a C18 column (linear gradient 10-40% acetonitrile in 20 mM aqueous triethanolamine, pH 7.4). The prep-HPLC fractions were collected, and the organic solvent (acetonitrile) was evaporated under reduced pressure. The resulting aqueous solution was loaded onto a clean PDVB SPE column, washed with distilled water, then with a 0.1 M sodium acetate solution followed by distilled water. The product was eluted with

acetonitrile. The eluent was concentrated under reduced pressure, 385 mg was obtained as free base.

Synthesis of crystalline mono hydrochloride salt of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,ll-dioxo-l,4,4a,5,5a,6,ll,12a-octahydro-naphthacene-2-carboxylic acid amide (the “Crystalline Mono Hydrochloride Salt”).

[00106] Crude (4S,4aS,5aR,12aS)-4-dimethylamino-3, 10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l ,ll-dioxo-l,4,4a,5,5a,6,l l ,12a-octahydro-naphthacene-2-carboxylic acid amide (lOOg, app. 35% assay) was purified on preparative column chromatography. The desired fractions (8-10 liters) were combined and the pH was adjusted to 7.0-7.5 using ammonium hydroxide. This aqueous solution was extracted 3 times with dichloromethane (4 liters each time). The dichloromethane layers were combined and concentrated under reduced pressure. The residue was suspended in ethanol (800 ml) and 20 ml water was added. The pH was gradually adjusted to pH 1.6-1.3 using 1.25M hydrochloric acid in methanol and the mixture was stirred for 20-60 minutes at which point the free base was completely dissolved. The solution was concentrated under reduced pressure to 200-250 ml and was seeded with (4S,4aS,5aR,12aS)-4-dimethylamino-3,10, 12, 12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]- 1, 11-dioxo-l,4,4a,5,5a,6,l l,12a-octahydro-naphthacene-2-carboxylic acid amide mono HQ crystals (100-200 mg). The stirring was continued for 2-18 hours while the slurry was kept at <5°C. The resulting crystals were filtered, washed with ethanol (50 mL) and dried under reduced pressure to a constant weight. 20g crystalline (4S,4aS,5aR,12aS)-4-dimethylamino-3,10, 12, 12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]- 1, 11-dioxo-l,4,4a,5,5a,6,l l,12a-octahydro-naphthacene-2-carboxylic acid amide mono hydrochloride was isolated in > 90% purity and > 90% assay.

Synthesis of crystalline mono mesylate salt of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,ll-dioxo-l,4,4a,5,5a,6,ll,12a-octahydro-naphthacene-2-carboxylic acid (the “Crystalline Mesylate Salt”).

[00107] (4S,4aS,5aR,12aS)-4-dimethylamino-3, 10,12, 12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,ll-dioxo-l,4,4a,5,5a,6,l l,12a-octahydro-naphthacene-2-carboxylic acid amide free base (74mg) was suspended in ethanol (740μ1) and heated with stirring to 60°C (bath temperature). Methane sulfonic acid (1.1 eq, 167μ1 as 1M solution in THF) was added and most of the solid dissolved. After five minutes, the suspension was cooled to ambient temperature over approximately 1.75 hours (uncontrolled in oil bath). By 53 °C, solid had precipitated which was filtered at ambient temperature under reduced pressure. A further portion of ethanol (200μ1) was added to aid filtration, as the suspension was viscous. The cake was washed with n-hexane (400μ1) and air dried on filter for approximately 30 minutes to yield 59 mg (67% yield) of yellow solid.

Synthesis of crystalline mono sulfate salt of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,ll-dioxo-l,4,4a,5,5a,6,ll,12a-octahydro-naphthacene-2-carboxylic acid (the “Crystalline Sulfate Salt”).

[00108] (4S,4aS,5aR,12aS)-4-dimethylamino-3, 10,12, 12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,l l-dioxo-l,4,4a,5,5a,6,l l,12a-octahydro-naphthacene-2-carboxylic acid amide free base (86mg) was suspended in ethanol (500μ1) and heated with stirring to 63 °C (bath temperature) at which temperature most of the free base had dissolved. Sulfuric acid (1.1 eq, 194μ1 as 1M solution in water) was added and all of the solid dissolved. The solution was cooled to ambient temperature over approximately 1.75 hours (uncontrolled in oil bath) at which temperature no solid had precipitated. Methyl t-butyl ether (MtBE) was added as an antisolvent (4 x 50μ1). Each addition caused a cloud point, but the solid re-dissolved on stirring. The solution was stirred with a stopper for approximately 3 hours after which time solid precipitated. The solid was filtered under reduced pressure and washed with MtBE (3 x 200μ1) and air dried on filter for

approximately 45 minutes to yield 93 mg (90% yield) of yellow solid.

COMPARATIVE EXAMPLE 1

Synthesis of amorphous bis hydrochloride salt of (4S,4aS,5aR,12aS)-4-dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,ll-dioxo-l,4,4a,5,5a,6,ll,12a-octahydro-naphthacene-2-carboxylic acid amide.

[00109] (4S,4aS,5aR,12aS)-4-dimethylamino-3, 10,12, 12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,l l-dioxo-l,4,4a,5,5a,6,l l,12a-octahydro-naphthacene-2-carboxylic acid amide free base (1 g) was suspended in methanol (50 mL). The freebase was converted to the hydrochloride salt by adding an excess of methanolic HCl followed by under reduced pressure evaporation to give 1.1 g yellow solid: MS (Mz+1 = 488). 1H NMR (300 MHz, CD30D) δ 7.46 (d, 1H, J = 8.6 Hz), 6.81 (d, 1H, J = 8.6 Hz), 4.09 (d, 1H, J = 1.0 Hz), 3.79 (d, 1H, J = 13.1 Hz), 3.73 (d, 1H, J = 13.1 Hz), 3.36 (m, 1H), 3.27 (s, 3H), 3.08-2.95 (8H), 2.61 (s, 3H), 2.38 (t, 1H, J = 14.8), 2.22 (m, 1H), 1.64 (m, 1H). An XRPD pattern is shown in Figure 10 and a TGA and DSC curve overlaid are shown in Figure 11.

COMPARATIVE EXAMPLE 2

Synthesis of amorphous mono hydrochloride salt of (4S,4aS,5aR,12aS)-4- dimethylamino-3,10,12,12a-tetrahydroxy-7-[(methoxy(methyl)amino)-methyl]-l,ll- dioxo-l,4,4a,5,5a,6,ll,12a-octahydro-naphthacene-2-carboxylic acid amide.

[00110] A sample of Crystalline Mono Hydrochloride Salt (2.09 g) was dissolved in water (250 ml, 120 vols), filtered and frozen in a -78°C bath. Water was removed from the solidified sample using a lyophilizer for 110 hours to yield the amorphous mono hydrochloride salt as a fluffy yellow solid, that was confirmed to be amorphous by XRPD analysis .

PATENT

US 20130302442

PATENT

WO 2015153864

PATENT

WO 2018051102

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2003075857

References

External links

Sarecycline
Sarecycline.svg
Clinical data
Trade names Seysara
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C24H29N3O8
Molar mass 487.51 g·mol−1
3D model (JSmol)

////////////Sarecycline, Seysara, WC-3035 FDA 2018, サレサイクリン , P-005672 , PTK-AR-01 , SC-1401, WC-3035,

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,

Glycopyrrolate Tosylate


Glycopyrrolate Tosylate.pngFigure US20130211101A1-20130815-C00001

Glycopyrrolate Tosylate

Molecular Formula: C26H35NO6S
Molecular Weight: 489.627 g/mol

(1,1-dimethylpyrrolidin-1-ium-3-yl) 2-cyclopentyl-2-hydroxy-2-phenylacetate;4-methylbenzenesulfonate

CAS 873295-46-6 , C19 H28 N O3 . C7 H7 O3 S, Pyrrolidinium, 3-[(2-cyclopentyl-2-hydroxy-2-phenylacetyl)oxy]-1,1-dimethyl-, 4-methylbenzenesulfonate (1:1)

Glycopyrronium tosylate monohydrate

Molecular Formula, C19-H28-N-O3.C7-H8-O3-S.H2-O, Molecular Weight, 508.6522

https://chem.nlm.nih.gov/chemidplus/structure/1624259-25-1?maxscale=30&width=300&height=300

CAS 1624259-25-1, C19 H28 N O3 . C7 H7 O3 S . H2 O, Pyrrolidinium, 3-[(2-cyclopentyl-2-hydroxy-2-phenylacetyl)oxy]-1,1-dimethyl-, 4-methylbenzenesulfonate, hydrate (1:1:1)

Dermira (Originator)

DRM-04
DRM-04B

  • DRM-04 tosylate monohydrate
  • DRM04
  • DRM04 tosylate
  • Glycopyrronium tosylate
  • Glycopyrronium tosylate monohydrate
  • Glycopyrronium tosylate [USAN]
  • UNII-1PVF6JLU7B
  • UNII-X2N5209428

In 2018, the product was approved in the U.S. for the treatment of primary axillary hyperhidrosis in adult and pediatric patients 9 years of age and older.

In 2016, Maruho signed an exclusive license agreement with Dermina for product development and marketing in Japan for the treatment of axillary hyperhidrosis.

PATENT

https://patents.google.com/patent/US8558008B2/en

PATENT

https://patents.google.com/patent/US20130211101A1/en

  • Glycopyrrolate is a quaternary ammonium cation of the muscarinic anticholinergic group. Glycopyrrolate, typically as a bromide salt, has been used in the treatment of a variety of conditions including diarrhea (U.S. Pat. Nos. 6,214,792 and 5,919,760), urinary incontinence (U.S. Pat. Nos. 6,204,285 and 6,063,808), and anxiety (U.S. Pat. No. 5,525,347). Additionally, U.S. Pat. No. 5,976,499 discloses a method for diagnosing cystic fibrosis in a patient by, in part, stimulating sweat production through the injection of a glycopyrrolate solution into a patient. Glycopyrrolate has also been used for the treatment of hyperhidrosis in US 20100276329.
  • [0002]
    Glycopyrrolate has previously been made available as a bromide salt or an acetate salt. The bromide salt of glycopyrrolate is sold as Rubinol®. The term “glycopyrrolate” as used in the label for Rubinol® refers to the bromide salt which is more formally referred to as glycopyrronium bromide.
    • Example 6 Glycopyrrolate Tosylate

    • [0124]
      In a dark room, silver tosylate (3.5 g) was dissolved in water (˜100 mL) by sonication. The solution was heated to approximately 40° C. and additional water was added (˜15 mL). An equimolar amount of glycopyrrolate bromide (5 g) (mixture of R,S and S,R diastereomers) was added and immediately resulted in a yellow precipitate. The slurry was stirred at approximately 40° C. overnight, and then slowly cooled while stirring to ambient temperature. At ambient temperature, the solids were vacuum filtered and the wet cake was washed three times with approximately 10 mL of water. The mother liquor was collected and filtered two times through a 0.2 μm nylon filter with glass microfiber (GMF). A clear solution was observed after filtration and was lyophilized at approximately −50° C. After 6 days, a mixture of white, needle-like and slightly sticky, glassy solids was observed. Toluene (˜20 mL) was added, and the slurry was briefly sonicated and then stirred at ambient temperature. Additional toluene (˜80 mL) was added for easier stirring, and the mixture was allowed to stand at ambient conditions for 1 day. Solids of glycopyrrolate tosylate were collected by vacuum filtration and vacuum drying at ambient temperature for 1 day.

Example 7 Preparation of Glycopyrrolate Tosylate

    • [0125]
      A slurry of equimolar amounts of glycopyrrolate acetate and p-toluenesulfonic acid was prepared in isopropanol (1 mL). The mixture was stirred at ambient temperature. Additional isopropanol (0.5 mL) was added to improve stirring, and the mixture was stirred overnight. Solids of glycopyrrolate tosylate were isolated by vacuum filtration and analyzed.

Example 8 Preparation of Glycopyrrolate Tosylate Form D

    • [0126]
      Glycopyrrolate tosylate (1.0569 g) made from Example 6 was dissolved in 4 mL ACN/H2O (50/50 vol/vol) by sonication. The solution was filtered through 0.2 μm nylon filter into a clean vial. The solvent was allowed to partially evaporate from an open vial under ambient conditions. Further evaporation was subsequently performed under nitrogen gas flow. A gel resulted which was vacuum dried at 40° C. for 1 day. Toluene (5 mL) was added and the mixture was sonicated for approximately 10 minutes causing white solids to precipitate. The mixture was stirred at ambient temperature for 1 day. The solids were isolated by vacuum filtration and the wet cake was washed with approximately 10 mL of toluene. The solids were vacuum dried at ambient temperature for 1 day. After vacuum drying the solids were placed in a vial which remained uncapped and placed inside a relative humidity chamber (˜97%). The chamber was placed inside an oven at 41° C. After 6 days, the solids were analyzed by XRPD showing Form D.

Example 9 Single Crystal Preparation of Form D

    • [0127]
      Glycopyrrolate tosylate (54.9 mg) made from Example 6 was dissolved in EtOAc/DMF (87/13 vol/vol) at approximately 55° C. at 24 mg/ml. The solution was hot filtered through a 0.2 μm nylon filter into a pre-warmed vial. The vial containing the solution was first placed in a dry ice/acetone bath and then in a freezer (approximately −25 to −10° C.). After 3 days, the solution was re-heated to approximately 50° C. and additional EtOAc was added for 96/4 EtOAc/DMF (vol/vol) at 7 mg/ml. The solution was quickly removed from elevated temperature and placed in the freezer. Solids were isolated by decanting the solvent and drying the solids under ambient conditions.
    • [0128]
      Single Crystal Data Collection
    • [0129]
      A colorless chunk of C26H37NO7S [C7H7O3S, C19H28NO3, H2O] having approximate dimensions of 0.23×0.20×0.18 mm, was mounted on a fiber in random orientation. Preliminary examination and data collection were performed with Cu Kα radiation (λ=1.54184 Å) on a Rigaku Rapid II diffractometer equipped with confocal optics. Refinements were performed using SHELX97.

Example 10 Preparation of Dehydrated Form D

    • [0130]
      A mixture of glycopyrrolate tosylate solids, including Form C and Form D, and a trace amount of silver tosylate was kept over P2Oat ambient temperature for 18 days. The resulting solids were composed of a mixture of dehydrated Form D with a trace of silver tosylate as shown by XRPD analysis.

Example 11 Preparation of Form C Glycopyrrolate Tosylate

    • [0131]
      Glycopyrrolate tosylate Form D, containing trace amounts of Form C and silver tosylate, was heated on an Anton Paar TTK 450 stage and XRPD patterns were collected in situ in the range 3.5-26° (2θ). All heating steps were at approximately 10° C./min. The stage was heated in incremental steps of 20° C. from 25 to 125° C. At each step, an XRPD pattern was collected over approximately 4 minutes. The stage was then heated to 135° C. and an XRPD pattern was collected over approximately 16 minutes and after heating further to 145° C., a pattern was collected in approximately 31 minutes. The sample was subsequently cooled to 25° C. at approximately 24° C./min, upon which a final XRPD pattern was collected over approximately 16 min. The XRPD pattern of this final pattern was indexed as Form C.

Example 12 Preparation of Form C Glycopyrrolate Tosylate

    • [0132]
      Glycopyrrolate tosylate Form D from Example 6 was heated to an approximate temperature in the range 143-149° C. under a continuous nitrogen purge for approximately 3.3 hours. The vial containing the solids was capped, placed on a lab bench and allowed to cool down to room temperature. At room temperature, the vial was placed in a jar containing P2O5. The sample was prepared for XRPD analysis under nitrogen which confirmed production of Form C.

Example 13 Preparation of Form C Glycopyrrolate Tosylate

    • [0133]
      Glycopyrrolate tosylate (59.5 mg) from Example 6 was dissolved in acetone at approximately 50° C. at 27 mg/ml. The solution was hot filtered through a 0.2 μm nylon filter into a pre-warmed vial. The vial was capped and left on the hot plate which was subsequently turned off to allow the sample to cool slowly to ambient temperature. At ambient temperature the solution was stirred causing white solids to precipitate. The solids were isolated by vacuum filtration and the wet cake was washed with approximately 2 ml of acetone. XRPD analysis resulted in Form C.

Example 14 Amorphous Glycopyrrolate Tosylate

  • [0134]
    Glycopyrrolate tosylate from Example 6 was melted and cooled repeatedly until the majority of the solids had the appearance of a glass by microscopy. XRPD analysis indicated that the “glassy” sample was observed to be amorphous. A 2.2% weight loss was observed by TGA from 25 to 250° C. of the amorphous glycopyrrolate tosylate. The onset of the glass transition temperature was measured at 11.6° C.

In a dark room, silver tosylate (3.5 g) was dissolved in water (~ 100 mL) by sonication. The solution was heated to approximately 40°C. and additional water was added (-15 mL). An equimolar amount of glycopyrrolate bromide (5 g) (mixture of R,S and S,R diastereomers) was added and imme diately resulted in a yellow precipitate. The slurry was stirred at approximately 40°C. overnight, and then slowly cooled while stirring to ambient temperature. At ambient tempera ture, the solids were vacuum filtered and the wet cake was washed three times with approximately 10 mL of water. The mother liquor was collected and filtered two times through a 0.2 pm nylon filter with glass microfiber (GMF). A clear solution was observed after filtration and was lyophilized at approximately -50°C. After 6 days, a mixture of white, needle-like and slightly sticky, glassy solids was observed. Toluene (-20 mL) was added, and the slurry was briefly sonicated and then stirred at ambient temperature. Additional toluene (-80 mL) was added for easier stirring, and the mix ture was allowed to stand at ambient conditions for 1 day. Solids of glycopyrrolate tosylate were collected by vacuum filtration and vacuum drying at ambient temperature for 1 day. Glycopyrrolate Tosylate.

PAtent

https://patents.google.com/patent/CN103159659A/en

Image result for Glycopyrronium bromide synthesis

glycopyrrolate (I)

Methyl ethyl ketone (20mL) IOOmL three-necked flask was added 8 (4.6g, 15mmol) was, at (Γ5 ° C was added dropwise dibromomethane (2.9g, 30mmol) in butanone (5 mL) was added dropwise completed, continued The reaction was stirred for 15min, and a white solid precipitated, was allowed to stand 36h at room temperature, filtered off with suction, the filter cake was sufficiently dried to give crude ketone was recrystallized twice to give a white powdery crystals I (3.9g, 66%) mp 191~193 ° C chromatographic purity 99.8% [HPLC method, mobile phase: lmol / L triethylamine acetate – acetonitrile – water (1: 150: 49); detection wavelength: 230nm, a measurement of the area normalization method] .MS m / z: 318 ( m-BrO 1HNMR (CD3OD) δ:! 1.33~1.38 (m, 2H), 1.55~1.70 (m, 6H), 2.11~2.21 (m, 1H), 2.67~2.80 (m, 1H), 3.02 (m, 1H), 3.06 (s, 3H), 3.23 (s, 3H), 3.59~3.71 (m, 3H), 3.90 (dd, /=13.8,1H), 5.47 (m, 1H), 7.27 (t, 1H) , 7.35 (t, 2H), 7.62 (dd, 2H) .13C bandit R (DMSO) δ: 27.0, 27.4, 28.0, 31.3, 47.8, 53.8, 54.3, 66.0, 71.3, 74.6, 81.1, 126.9,128.7,129.3 , 143.2 17 5.00

Patent

https://patents.google.com/patent/WO2016204998A1/en

Image result for Glycopyrronium bromide synthesis

PAPER

https://link.springer.com/article/10.1007/s41981-018-0015-4

Sequential α-lithiation and aerobic oxidation of an arylacetic acid – continuous-flow synthesis of cyclopentyl mandelic acid

Open Access

Communications

Image result for Glycopyrronium bromide synthesis

The medicinal properties of glycopyrronium bromide (glycopyrrolate, 4) were first identified in the late 1950s [1]. Glycopyrrolate is an antagonist of muscarinic cholinergic receptors and is used for the treatment of drooling or excessive salivation (sialorrhea) [2], excess sweating (hyperhidrosis) [3], and overactive bladder and for presurgery treatment. In addition, it has recently been introduced as an effective bronchodilator for the treatment of chronic obstructive pulmonary disease (COPD) for asthma patients [4]. Glycopyrrolate displays few side effects because it does not pass through the blood brain barrier. Cyclopentyl mandelic acid (CPMA, 1), or its corresponding ester derivatives, are key intermediates in the synthetic routes to 4. CPMA (1) reacts with 1-methyl-pyrrolidin-3-ol (2) to form tertiary amine 3N-Methylation of 3 by methyl bromide gives quaternary ammonium salt glycopyrrolate 4 as a racemate (Scheme 1) [5].

Scheme 1

Synthesis of glycopyrrolate 4 from CPMA (1)

CPMA (1) is a synthetically challenging intermediate to prepare (Scheme 2). Routes A to D are most likely to be the commercially applied methods because these procedures are described in patents [5]. The published descriptions for the yields of 1 range from 28 to 56% for routes A to D. Ethyl phenylglyoxylate is reacted with cyclopentyl magnesium bromide to form an ester which is then hydrolyzed (route A) [6]. Phenylglyoxylic acid can be reacted in a similar manner with cyclopentyl magnesium bromide to directly form 1 (route B) [7]. Alternatively, the inverse addition of phenyl-Grignard reagent to cyclopentyl glyoxylic acid ester is reported (route C) [8]. Cyclopentyl glyoxylic acid ester can also be reacted with cyclopentadienyl magnesium bromide which is followed by an additional hydrogenation step with Pd/C and H2 to afford 1 (route D) [910].

Scheme 2

Existing synthetic pathways to CPMA (1)

Publication numberPriority datePublication dateAssigneeTitle
WO2014134510A1 *2013-02-282014-09-04Dermira, Inc.Glycopyrrolate salts
US8859610B22013-02-282014-10-14Dermira, Inc.Crystalline glycopyrrolate tosylate
US9006462B22013-02-282015-04-14Dermira, Inc.Glycopyrrolate salts
US20160052879A1 *2014-08-202016-02-25Dermira, Inc.Process for production of glycopyrronium tosylate
Family To Family Citations
WO2018026869A12016-08-022018-02-08Dermira, Inc.Processes for making, and methods of using, glycopyrronium compounds
Patent ID

Title

Submitted Date

Granted Date

US9440056 DEVICE AND METHOD FOR DISPENSING A DRUG
2015-09-29
2016-03-31
US2016058735 METHODS OF TREATING HYPERHIDROSIS
2015-08-27
2016-03-03
Patent ID

Title

Submitted Date

Granted Date

US2017157088 GLYCOPYRROLATE SALTS
2017-02-21
US9610278 Glycopyrrolate Salts
2016-01-07
2016-04-28
US2016052879 PROCESS FOR PRODUCTION OF GLYCOPYRRONIUM TOSYLATE
2015-08-19
2016-02-25
US9006461 CRYSTALLINE GLYCOPYRROLATE TOSYLATE
2013-09-11
2014-08-28
US2016243345 DEVICE AND METHOD FOR DISPENSING A DRUG
2016-05-04
2016-08-25
Patent ID

Title

Submitted Date

Granted Date

US2016354315 DOSAGE FORMS AND USE THEREOF
2016-06-03
US9259414 Glycopyrrolate Salts
2015-03-10
2015-07-16
US9006462 Glycopyrrolate Salts
2014-08-29
2014-12-18
US8558008 Crystalline glycopyrrolate tosylate
2013-02-28
2013-10-15
US8859610 Crystalline glycopyrrolate tosylate
2013-09-11
2014-10-14

///////////Glycopyrrolate Tosylate, DRM-04 , DRM-04B , FDA 2018, Qbrexza

CC1=CC=C(C=C1)S(=O)(=O)[O-].C[N+]1(CCC(C1)OC(=O)C(C2CCCC2)(C3=CC=CC=C3)O)C

FDA approves new kind of treatment Lumoxiti (moxetumomab pasudotox-tdfk) for hairy cell leukemia


The U.S. Food and Drug Administration today approved Lumoxiti (moxetumomab pasudotox-tdfk) injection for intravenous use for the treatment of adult patients with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Lumoxiti is a CD22-directed cytotoxin and is the first of this type of treatment for patients with HCL.

September 13, 2018

Release

The U.S. Food and Drug Administration today approved Lumoxiti (moxetumomab pasudotox-tdfk) injection for intravenous use for the treatment of adult patients with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Lumoxiti is a CD22-directed cytotoxin and is the first of this type of treatment for patients with HCL.

“Lumoxiti fills an unmet need for patients with hairy cell leukemia whose disease has progressed after trying other FDA-approved therapies,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This therapy is the result of important research conducted by the National Cancer Institute that led to the development and clinical trials of this new type of treatment for patients with this rare blood cancer.”

HCL is a rare, slow-growing cancer of the blood in which the bone marrow makes too many B cells (lymphocytes), a type of white blood cell that fights infection. HCL is named after these extra B cells which look “hairy” when viewed under a microscope. As the number of leukemia cells increases, fewer healthy white blood cells, red blood cells and platelets are produced.

The efficacy of Lumoxiti was studied in a single-arm, open-label clinical trial of 80 patients who had received prior treatment for HCL with at least two systemic therapies, including a purine nucleoside analog. The trial measured durable complete response (CR), defined as maintenance of hematologic remission for more than 180 days after achievement of CR. Thirty percent of patients in the trial achieved durable CR, and the overall response rate (number of patients with partial or complete response to therapy) was 75 percent.

Common side effects of Lumoxiti include infusion-related reactions, swelling caused by excess fluid in body tissue (edema), nausea, fatigue, headache, fever (pyrexia), constipation, anemia and diarrhea.

The prescribing information for Lumoxiti includes a Boxed Warning to advise health care professionals and patients about the risk of developing capillary leak syndrome, a condition in which fluid and proteins leak out of tiny blood vessels into surrounding tissues. Symptoms of capillary leak syndrome include difficulty breathing, weight gain, hypotension, or swelling of arms, legs and/or face. The Boxed Warning also notes the risk of hemolytic uremic syndrome, a condition caused by the abnormal destruction of red blood cells. Patients should be made aware of the importance of maintaining adequate fluid intake, and blood chemistry values should be monitored frequently. Other serious warnings include: decreased renal function, infusion-related reactions and electrolyte abnormalities. Women who are breastfeeding should not be given Lumoxiti.

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

The FDA granted the approval of Lumoxiti to AstraZeneca Pharmaceuticals.

///////////// Lumoxiti, moxetumomab pasudotox-tdfk, fda 2018, Fast Track, Priority Review designations,  Orphan Drug designation,

Lanadelumab, ラナデルマブ


(Heavy chain)
EVQLLESGGG LVQPGGSLRL SCAASGFTFS HYIMMWVRQA PGKGLEWVSG IYSSGGITVY
ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAYRR IGVPRRDEFD IWGQGTMVTV
SSASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ
SSGLYSLSSV VTVPSSSLGT QTYICNVNHK PSNTKVDKRV EPKSCDKTHT CPPCPAPELL
GGPSVFLFPP KPKDTLMISR TPEVTCVVVD VSHEDPEVKF NWYVDGVEVH NAKTKPREEQ
YNSTYRVVSV LTVLHQDWLN GKEYKCKVSN KALPAPIEKT ISKAKGQPRE PQVYTLPPSR
EEMTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP PVLDSDGSFF LYSKLTVDKS
RWQQGNVFSC SVMHEALHNH YTQKSLSLSP G
(Light chain)
DIQMTQSPST LSASVGDRVT ITCRASQSIS SWLAWYQQKP GKAPKLLIYK ASTLESGVPS
RFSGSGSGTE FTLTISSLQP DDFATYYCQQ YNTYWTFGQG TKVEIKRTVA APSVFIFPPS
DEQLKSGTAS VVCLLNNFYP REAKVQWKVD NALQSGNSQE SVTEQDSKDS TYSLSSTLTL
SKADYEKHKV YACEVTHQGL SSPVTKSFNR GEC
(dimer; dishulfide bridge: H22-H96, H149-H205, H225-L213, H231-H’231, H234-H’234, H266-H326, H372-H430, H’22-H’96, H’149-H’205, H’225-L’213, H’266-H’326, H’372-H’430, L23-L88, L133-L193, L’23-L’88, L’133-L’193)

Lanadelumab

DX 2930

Fda approved 2018/8/23, Takhzyro

Formula
C6468H10016N1728O2012S48
Cas
1426055-14-2
Mol weight
145714.225

Peptide, Monoclonal antibody
Prevention of angioedema in patients with hereditary angioedema

Immunomodulator, Plasma kallikrein inhibitor

breakthrough therapyUNII: 2372V1TKXK

Image result for Lanadelumab

Image result for Lanadelumab

Lanadelumab (INN) (alternative identifier DX-2930[1]) is a human monoclonal antibody (class IgG1 kappa)[2] that targets plasma kallikrein (pKal)[1] in order to promote prevention of angioedema in patients with hereditary angioedema.[3][4] In phase 1 clinical trialsLanadelumab was well tolerated and was reported to reduce cleavage of kininogen in the plasma of patients with hereditary angioedeman and decrease the number of patients experiencing attacks of angioedema.[1][5][6][7] As of 2017 ongoing trials for Lanadelumab include two phase 3 studies focused on investigating the utility of Lanadelumab in preventing of acute angioedema attacks in hereditary angioedema patients[8][9]

Image result for Lanadelumab

This drug was produced by Dyax Corp and currently under development by Shire.[10] Lanadelumab has been designated by the U.S. Food and Drug Administration (FDA) as a breakthrough therapy.[11]

Image result for Lanadelumab

References

  1. Jump up to:a b c Banerji, Aleena; Busse, Paula; Shennak, Mustafa; Lumry, William; Davis-Lorton, Mark; Wedner, Henry J.; Jacobs, Joshua; Baker, James; Bernstein, Jonathan A. (2017-02-23). “Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis”. The New England Journal of Medicine376 (8): 717–728. doi:10.1056/NEJMoa1605767ISSN 1533-4406PMID 28225674.
  2. Jump up^ Kenniston, Jon A.; Faucette, Ryan R.; Martik, Diana; Comeau, Stephen R.; Lindberg, Allison P.; Kopacz, Kris J.; Conley, Gregory P.; Chen, Jie; Viswanathan, Malini (2014-08-22). “Inhibition of Plasma Kallikrein by a Highly Specific Active Site Blocking Antibody”The Journal of Biological Chemistry289 (34): 23596. doi:10.1074/jbc.M114.569061PMC 4156074Freely accessiblePMID 24970892.
  3. Jump up^ Statement On A Nonproprietary Name Adopted By The USAN Council – LanadelumabAmerican Medical Association.
  4. Jump up^ World Health Organization (2015). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 114”(PDF). WHO Drug Information29 (4).
  5. Jump up^ Chyung, Yung; Vince, Bradley; Iarrobino, Ryan; Sexton, Dan; Kenniston, Jon; Faucette, Ryan; TenHoor, Chris; Stolz, Leslie E.; Stevens, Chris (2014-10-01). “A phase 1 study investigating DX-2930 in healthy subjects”. Annals of Allergy, Asthma & Immunology113 (4): 460–466.e2. doi:10.1016/j.anai.2014.05.028ISSN 1534-4436PMID 24980392.
  6. Jump up^ “A Single Increasing Dose Study to Assess Safety and Tolerability of DX-2930 in Healthy Subjects – Full Text View – ClinicalTrials.gov”clinicaltrials.gov. Retrieved 2017-03-24.
  7. Jump up^ “Double-Blind, Multiple Ascending Dose Study to Assess Safety, Tolerability and Pharmacokinetics of DX-2930 in Hereditary Angioedema (HAE) Subjects – Full Text View – ClinicalTrials.gov”clinicaltrials.gov. Retrieved 2017-03-24.
  8. Jump up^ “Efficacy and Safety Study of DX-2930 to Prevent Acute Angioedema Attacks in Patients With Type I and Type II HAE – Full Text View – ClinicalTrials.gov”clinicaltrials.gov. Retrieved 2017-03-24.
  9. Jump up^ “Long-term Safety and Efficacy Study of DX-2930 to Prevent Acute Angioedema Attacks in Patients With Type I and Type II HAE – Full Text View – ClinicalTrials.gov”clinicaltrials.gov. Retrieved 2017-03-24.
  10. Jump up^ “Lanadelumab – AdisInsight”adisinsight.springer.com. Retrieved 2017-03-24.
  11. Jump up^ “Dyax Corp. Receives FDA Breakthrough Therapy Designation for DX-2930 for Prevention of Attacks of Hereditary Angioedema”http://www.businesswire.com. Retrieved 2017-03-24.
Lanadelumab
Monoclonal antibody
Type Whole antibody
Source Human
Target kallikrein
Clinical data
Synonyms DX-2930
ATC code
  • none
Identifiers
CAS Number
ChemSpider
  • none
UNII
Chemical and physical data
Formula C6468H10016N1728O2012S47
Molar mass 145.7 kDa

///////////Lanadelumab, Peptide, Monoclonal antibody, FDA 2018, ラナデルマブ ,Immunomodulator, Plasma kallikrein inhibitor, DX 2930,  breakthrough therapy, Takhzyro

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

Sodium zirconium cyclosilicate, ナトリウムジルコニウムシクロケイ酸塩


242800-27-7.png

ZS-9 structure.png

Image result for Sodium zirconium cyclosilicate

str1

Sodium zirconium cyclosilicate

ZS-9, ZS 9, UZSi-9

CAS 242800-27-7, H2 O3 Si . x H2 O . 2/3 Na . 1/3 Zr, Sodium zirconium cyclosilicate; Silicic acid (H2SiO3), Sodium zirconium(4+) salt (3:2:1), hydrate

USAN CAS 17141-74-1, H6 O9 Si3 . 2 Na . Zr, Silicic acid (H2SiO3), sodium zirconium(4+) salt (3:2:1), hydrate, Sodium zirconium silicate (Na2ZrSi3O9) hydrate

ナトリウムジルコニウムシクロケイ酸塩

ZrH4O6. 3H4SiO4. 2H2O. 2Na, 561.6068, AS IN kegg

Molecular Formula, H6-O9-Si3.2Na.Z, Molecular Weight, 371.5004 as in chemid plus

APPROVED FDA 2018/5/18, LOKELMA, NDA 207078

APPROVED EMA 2018/3/22, LOKELMA

ATC code: V03AE10

UNII-D652ZWF066

TREATMENT
selective cation exchanger
Treatment of hyperkalemia

Sodium zirconium cyclosilicate (ZS-9) is a selective oral sorbent that traps potassium ions throughout the gastrointestinal tract. It is being developed by ZS Pharma and AstraZeneca for the treatment of hyperkalemia (elevated serum potassium levels).[1]

The product was originated at ZS Pharma, a wholly owned subsidiary of AstraZeneca. In 2015, ZS Pharma was acquired by AstraZeneca.

Hyperkalaemia is the presence of an abnormally high concentration of potassium in the blood. Most data on the occurrence of hyperkalaemia have been obtained from studies of hospitalised patients, and the incidence ranges from 1 to 10%. There is no agreed definition of hyperkalaemia, since the raised level of potassium at which a treatment should be initiated has not been established. The European Resuscitation Council guidelines consider hyperkalaemia to be a serum potassium (S-K) level > 5.5 mmol/L, with mild elevations defined as 5.5 to 5.9 mmol/L, moderate as 6.0-6.4 mmol/L, and severe as ≥ 6.5 mmol/L. The guidelines also note that extracellular potassium levels are usually between 3.5 and 5.0 mmol/L, which is considered the normal range for adults. However, a number of recent retrospective studies have shown the risk of mortality is increased even with only modest elevations of S-K. Mortality risk has been shown to be significantly higher in chronic kidney disease (CKD) patients with S-K levels > 5.0 mmol/L. In acute myocardial infarction patients, a mean postadmission S-K ≥ 5.5 mmol/L during hospitalisation corresponded to a 12-fold increase in death compared with S-K levels between 3.5 and 4.5 mmol/L but, more importantly, S-K levels between 4.5 and 5.0 mmol/L, which is within the normal range, were associated with a 2-fold increased risk of mortality compared with S-K between 3.5 and 4.5 mmol/L.

Sodium zirconium cyclosilicate (ZS) has been developed as treatment for hyperkalaemia. The indication applied for is: Treatment of hyperkalaemia in adult patients, acute and extended use. ZS is an inorganic cation exchange crystalline compound. ZS has a high capacity to selectively entrap monovalent cations, specifically excess potassium and ammonium ions, over divalent cations such as calcium and magnesium, in the gastrointestinal tract. The high specificity of ZS for potassium is attributable to the chemical composition and diameter of the micro pores, which act in an analogous manner to the selectivity filter utilized by physiologic potassium channels. The exchange with potassium ions occurs throughout the gastrointestinal tract with onset in the upper part of the gastrointestinal tract. The trapped potassium ions are excreted from the body via the faeces, thereby reducing any excess and resolving hyperkalaemia. As claimed by the applicant, ZS demonstrates improved capacity, selectivity, and speed for entrapping excess potassium over currently available options for the treatment of hyperkalaemia. The proposed commercial formulation of ZS is a non-absorbed, insoluble, white crystalline powder for suspension with a specific particle size distribution profile. The proposed starting dose of ZS for reversal of hyperkalaemia (when serum potassium is > 5.0 mmol/l) is up to 10 g/day, divided in 3 doses (TID) to achieve normokalaemia.

EMA

The chemical name of the active substance is hydrogen sodium zirconium (IV) silicate hydrate. Due to the natural variability in the manufacturing process of the active substance, it is expected to have the formula Na~1.5H~0.5ZrSi3O9 • 2–3 H2O and relative molecular mass in the range of 390.5 – 408.5. The WHO chose not to designate an INN for the active substance, and a USAN sodium zirconium cyclosilicate is used throughout the dossier and this CHMP AR. The active substance has the following structure:

str1

Figure 1. Stick-and-ball (left) and polyhedral (right) unit cell structural representation of the main framework of the microporous sodium zirconium cyclosilicate active substance. Red = zirconium, green = silicon, blue = oxygen atoms. Cations are not pictured.

The structure of sodium zirconium cyclosilicate is a cubic cell arrangement of octahedrally coordinated Zr and tetrahedrally coordinated Si units that interconnect through oxygen bridges as Zr–O–Si and Si–O–Si. The two types of units are observed in a ratio 1:3, respectively, and repeat orderly to form a three-dimensional framework characteristic of the compound. The framework acquires its negative charge from the octahedral fractions, [ZrO6]2– , and features channels and cavities that interconnect and locate the positive ions that counter-balance the negative charge of the framework. Electrostatic interactions between the framework and the cations allow for mobility and possibility of exchange with other cations that would fit and pass the free pore openings of ~ 3.0 Å. The uniform micropore structure allows a high exchange capacity and selectivity for potassium (K+) and ammonium (NH4 +) cations, providing the compound with its distinctive ion-exchange selectivity features responsible for its mode of action. In vitro characterisation of ion selectivity of sodium zirconium cyclosilicate was provided by the applicant and considered satisfactory

The structure of sodium zirconium cyclosilicate was confirmed using synchrotron powder diffraction, standard X-ray powder diffraction, 29Si magic angle spinning solid nuclear magnetic resonance studies (29Si-MASNMR), Fourier transform infrared spectroscopy, inductive coupled plasma-optical emission spectrometry, wave dispersive X-ray microprobe analysis and thermo-gravimetric analysis. Calculations using proprietary software were also used for structure elucidation. The active substance is a white crystalline powder. Bonding interactions in the main framework are considered primarily of covalent nature, with some ionic contribution due to the difference in electronegativity between Si–O and Zr–O. The covalent bonding interactions in all directions within the crystals make sodium zirconium cyclosilicate a compound insoluble in water or in organic solvents. It is neither hygroscopic nor sensitive to light and it is resistant to heat. During the hydrothermal synthesis, the possibility that other crystalline phases are formed exists. The observed crystalline forms are controlled by the manufacturing process parameters and release specifications. Sodium zirconium cyclosilicate is considered to be a new active substance. The applicant demonstrated that neither it, nor its derivatives have ever been active substances in medicinal products authorised in the EU………http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004029/WC500246776.pdf

TGA

DOC]Australian Public Assessment Report for Sodium zirconium … – TGA

Jan 29, 2018 – The sponsor has submitted an application to register a new chemical entity Lokelma,sodium zirconium cyclosilicate hydrate powder for …

The chemical formula of sodium zirconium cyclosilicate hydrate is Na~1.5H~0.5ZrSi3O9.2-3H2O.

str1

The drug substance ‘sodium zirconium cyclosilicate hydrate’ (abbreviated to ZS) is a white crystalline powder. The structure of ZS is summarised as a cubic cell arrangement of octahedrally coordinated zirconium Zr ([ZrO6]2-) and tetrahedrally coordinated silicon Si ([SiO4]0) units that interconnect through oxygen bridges as Zr-O-Si and Si-O-Si. The two types of units are observed in a ratio of 1:3, respectively, and repeat orderly to form a three dimensional framework characteristic of the compound. The framework acquires its negative charge from the octahedral fractions, [ZrO6]2- and features channels and cavities that interconnect and locate the positive ions (sodium, Na+, and hydrogen, H+) that counter balance the negative charge of the framework.

The manufacturing process is tightly controlled in terms of order of addition of starting material, reaction and crystallisation temperatures, mixing speeds and times, and minimum number of rinses, in order to meet expected yields of the drug substance of an expected quality. In process quality control tests [information redacted] are applied during the manufacturing process to ensure the formation of the correct crystalline structure and batch to batch consistency.

Sodium zirconium cyclosilicate hydrate is completely insoluble.

The drug substance forms part of a family of zirconium silicates that have specific ion exchange properties. Its mechanism of action is based on the cations within its porous crystalline structure, and their ability to freely exchange with a select group of monovalent cations, most specifically the potassium (K+) and ammonium (NH4+) cations. The pore size within the three dimensional crystalline structure has been measured at ~3Å (2.4 x 3.5 Å[1]), which is sufficiently wide enough to trap the potassium monovalent cations which have an approximate ionic diameter of 2.98Å.

The particle size of the drug substance is controlled to maintain a non-systemic mode of action. The sponsor adequately justified not routinely controlling the size of larger particles in the drug substance as differences in particle size were shown to not affect performance as measured by potassium ion exchange capacity (KEC), and there was no correlation between KEC and D90 for clinical lots manufactured.

There are two alternate zirconium silicate crystalline phases which may be formed in the reaction process; Crystalline Phase A (CPA) and Crystalline Phase B (CPB). These layered, two-dimensional structures also exhibit ion exchange properties, although their ion selectivity is less specific for the potassium K+ cations compared to the desired drug substance. PXRD techniques are used to differentiate between the desired drug substance and levels of CPA and CPB. Appropriate limits are applied in the drug substance specification to limit the content of these crystalline phases in the drug substance/drug product.

The quality of the drug substance is controlled by an acceptable specification that includes test and limits for Appearance, Identification (by FTIR and PXRD), KEC , Crystalline Phase A , Crystalline Phase B , Zirconium content , Silicon content , Hafnium content , Moisture content , Particle Size , and Elemental Impurities.

[1] 1 Å = 0.1 nm.

Image result for Sodium zirconium cyclosilicate

Background

Hyperkalemia occurs in 3 to 10% of hospitalized patients[2] but is often mild. Hyperkalemia can arise from impaired renal functionpotassium-sparing diuretics and renin–angiotensin system blockers (e.g., ACE inhibitorsangiotensin receptor blockersspironolactone) and diabetes mellitus.[2][3][4][5]

There is no universally accepted definition of what level of hyperkalemia is mild, moderate, or severe.[6] However, if hyperkalemia causes any ECG change it is considered a medical emergency[6] due to a risk of potentially fatal abnormal heart rhythms (arrhythmia) and is treated urgently.[6] serum potassium concentrations greater than 6.5 to 7.0 mmol/L in the absence of ECG changes are managed aggressively.[6]

Hyperkalemia, particularly if severe, is a marker for an increased risk of death.[2] However, there is disagreement regarding whether a modestly elevated serum potassium level directly causes significant problems. One viewpoint is that mild to moderate hyperkalemia is a secondary effect that denotes significant underlying medical problems.[2] Accordingly, these problems are both proximate and ultimate causes of death,[2] and adjustment of potassium may not be helpful. Alternatively, hyperkalemia may itself be an independent risk factorfor cardiovascular mortality.[7]

Several approaches are used in the treatment of hyperkalemia.[6] In October 2015, the U.S. Food and Drug Administration (FDA) approved patiromer which works by binding free potassium ions in the gastrointestinal tract and releasing calcium ions for exchange. Previously, the only approved product was sodium polystyrene sulfonate (Kayexalate),[8] an organic ion-exchange resin that nonspecifically binds cations (e.g., calciumpotassiummagnesium) in the gastrointestinal tract. The effectiveness of sodium polystyrene sulfonate has been questioned: a study in healthy subjects showed that laxatives alone were almost as effective in increasing potassium secretion as laxatives plus Kayexalate.[9] In addition, use of sodium polystyrene sulfonate, particularly if formulated with high sorbitol content, is uncommonly but convincingly associated with colonic necrosis.[6][8][10][11]

Mechanism of action

Cross-sections of ZS-9 pores with three different ions (K⁺ = potassium, Na⁺ = sodium, Ca²⁺ = calcium). The specificity for potassium is thought to be caused by the diameter and composition of the pores, which resembles potassium channels.

ZS-9 is a zirconium silicate. Zirconium silicates have been extensively used in medical and dental applications because of their proven safety.[12] 11 zirconium silicates were screened by an iterative optimization process. ZS-9 selectively captures potassium ions, presumably by mimicking the actions of physiologic potassium channels.[13] ZS-9 is an inorganic cation exchanger crystalline with a high capacity to entrap monovalent cations, specifically potassium and ammonium ions, in the GI tract. ZS-9 is not systemically absorbed; accordingly, the risk of systemic toxicity may be minimized.

Clinical studies

phase 2 clinical trial in 90 patients with chronic kidney disease and mild-to-moderate hyperkalemia found a significantly greater reduction in serum potassium with ZS-9 than placebo. ZS-9 was well tolerated, with a single adverse event (mild constipation).[14]

double-blindphase 3 clinical trial in 753 patients with hyperkalemia and underlying chronic kidney diseasediabetescongestive heart failure, and in patients on renin–angiotensin system blockers compared ZS-9 with placebo.[15] Patients were randomly assigned to receive either ZS-9 (1.25 g, 2.5 g, 5 g, or 10 g) or placebo 3 times daily for 48 hours (acute phase). Patients who achieved normokalemia (serum potassium of 3.5-4.9 mmol/L) were randomly assigned to receive ZS-9 or placebo once daily for 12 additional days (maintenance phase). At the end of the acute phase, serum potassium significantly decreased in the 2.5 g, 5 g, and 10 g ZS-9 groups. During the maintenance phase, once daily 5 g or 10 g ZS-9 maintained serum potassium at normal levels. Adverse events, including specifically gastrointestinal effects, were similar with either ZS-9 or placebo.[15]

double-blindphase 3 clinical trial in 258 patients with hyperkalemia and underlying chronic kidney diseasediabetescongestive heart failure, and in patients on renin–angiotensin system blockers compared ZS-9 with placebo.[16] All patients received 10 g ZS-9 three times daily for 48 hours in the initial open-label phase. Patients who achieved normokalemia (serum potassium 3.5-5.0 mEq/L) were randomly assigned to receive either ZS-9 (5 g, 10 g, or 15 g) or placebo once daily for 28 days (double-blind phase). 98% of patients (n=237) achieved normokalemia during the open-label phase. During the double-blind phase, once daily 5 g, 10 g, and 15 g ZS-9 maintained serum potassium at normal levels in a significantly higher proportion of patients (80%, 90%, and 94%, respectively) than placebo (46%). Adverse events were generally similar with either ZS-9 or placebo. Hypokalemiaoccurred in more patients in the 10 g and 15 g ZS-9 groups (10% and 11%, respectively), versus none in the 5 g ZS-9 or placebo groups.[16]

Regulatory

In the United States, regulatory approval of ZS-9 was rejected by the Food and Drug Administration in May 2016 due to issues associated with manufacturing.[17] On May 18th, 2018, the FDA approved ZS-9 (now known as Lokelma®) for treatment of adults with hyperkalemia.[18]

PATENT

WO 2012109590

PATENT

WO 2015070019

https://patents.google.com/patent/WO2015070019A1/en

The present invention relates to novel zirconium silicate (“ZS”) compositions which are preferably sodium zirconium cyclosilicates having an elevated level of ZS-9 crystalline form relative to other forms of zirconium cyclosilicates (i.e., ZS-7) and zirconium silicates (i.e., ZS-8, ZS-11). The ZS compositions are preferably sodium zirconium cyclosilicate compositions where the crystalline form has at least 95% ZS-9 relative to other crystalline forms of zirconium silicate. The ZS compositions of the present invention unexpectedly exhibit a markedly improved in vivo potassium ion absorption profile and rapid reduction in elevate levels of serum potassium.

[004] Preferably ZS compositions of the present invention are specifically formulated at particular dosages to remove select toxins, e.g., potassium ions or ammonium ions, from the gastrointestinal tract at an elevated rate without causing undesirable side effects. The preferred formulations are designed to remove and avoid potential entry of particles into the bloodstream and potential increase in pH of urine in patients. The formulation is also designed to release less sodium into the blood. These compositions are particularly useful in the therapeutic treatment of hyperkalemia and kidney disease. The present invention also relates to pharmaceutical granules, tablets, pill, and dosage forms comprising the microporous ZS as an active ingredient. In particular, the granules, tablets, pills or dosage forms are compressed to provide immediate release, delayed release, or specific release within the subject. Also disclosed are microporous ZS compositions having enhanced purity and potassium exchange capacity (“KEC”). Methods of treating acute, sub-acute, and chronic hyperkalemia have also been investigated. Disclosed herein are particularly advantageous dosing regimens for treating different forms of hyperkalemia using the microporous ZS compositions noted above. In addition, the present invention relates to methods of co-administering microporous ZS compositions in combination with other pharmacologic drugs that are known to induce, cause, or exacerbate the hyperkalemic condition.

Patent

Publication numberPriority datePublication dateAssigneeTitle
US3329480A *1963-10-181967-07-04Union Oil CoCrystalline zircono-silicate zeolites
US4581141A *1978-02-271986-04-08Purdue Research FoundationDialysis material and method for removing uremic substances
US20050220752A1 *2004-03-302005-10-06Dominique CharmotIon binding polymers and uses thereof
US20110097401A1 *2009-06-122011-04-28Meritage Pharma, Inc.Methods for treating gastrointestinal disorders
US20120213847A1 *2011-02-112012-08-23ZS Pharma, Inc.Microporous zirconium silicate for the treatment of hyperkalemia
CA2084086C *1990-05-282002-10-08Steven M. KuznickiLarge-pored molecular sieves containing at least one octahedral site and tetrahedral sites of at least one type
US5338527A *1992-08-201994-08-16UopZirconium silicate composition, method of preparation and uses thereof
US5891417A *1997-04-081999-04-06Uop LlcZirconium silicate and zirconium germanate molecular sieves and process using the same
US5888472A *1997-04-081999-03-30Uop LlcZirconium silicate molecular sieves and process using the same
EP1038580B1 *1999-03-262005-05-25Uop LlcAmmonium ion adsorption process using zirconium silicate and zirconium germanate molecular sieves
US6332985B1 *1999-03-292001-12-25Uop LlcProcess for removing toxins from bodily fluids using zirconium or titanium microporous compositions
WO2002062356A3 *2001-02-062002-09-26Ash Medical Systems IncMonovalent-selective cation exchangers as oral sorbent therapy
CN104968336A *2012-07-112015-10-07Zs制药公司Microporous zirconium silicate for the treatment of hyperkalemia in hypercalcemic patients and improved calcium-containing compositions for the treatment of hyperkalemia
KR20150074053A *2012-10-222015-07-01제트에스 파마, 인코포레이티드Microporous zirconium silicate for treating hyperkalemia
Publication numberPriority datePublication dateAssigneeTitle
WO2017066128A1 *2015-10-142017-04-20ZS Pharma, Inc.Extended use zirconium silicate compositions and methods of use thereof
Family To Family Citations
US20160038538A1 *2013-11-082016-02-11ZS Pharma, Inc.Microporous zirconium silicate for the treatment of hyperkalemia

References

  1. Jump up^ “ZS-9. A selective potassium binder”. ZS-Pharma.
  2. Jump up to:a b c d e Elliott, M. J.; Ronksley, P. E.; Clase, C. M.; Ahmed, S. B.; Hemmelgarn, B. R. (2010). “Management of patients with acute hyperkalemia”Canadian Medical Association Journal182 (15): 1631–5. doi:10.1503/cmaj.100461PMC 2952010Freely accessiblePMID 20855477.
  3. Jump up^ Stevens, M. S.; Dunlay, R. W. (2000). “Hyperkalemia in hospitalized patients”. International Urology and Nephrology32 (2): 177–80. doi:10.1023/A:1007135517950PMID 11229629.
  4. Jump up^ Navaneethan, S. D.; Yehnert, H.; Moustarah, F.; Schreiber, M. J.; Schauer, P. R.; Beddhu, S. (2009). “Weight Loss Interventions in Chronic Kidney Disease: A Systematic Review and Meta-analysis”Clinical Journal of the American Society of Nephrology4 (10): 1565–74. doi:10.2215/CJN.02250409PMC 2758256Freely accessiblePMID 19808241.
  5. Jump up^ Tamirisa, K. P.; Aaronson, K. D.; Koelling, T. M. (2004). “Spironolactone-induced renal insufficiency and hyperkalemia in patients with heart failure”. American Heart Journal148(6): 971–8. doi:10.1016/j.ahj.2004.10.005PMID 15632880.
  6. Jump up to:a b c d e f Taal, M.W.; Chertow, G.M.; Marsden, P.A.; Skorecki, K.; Yu, A.S.L.; Brenner, B.M. (2012). Brenner and Rector’s The Kidney (Chapter 17, page 672, 9th ed.). Elsevier. ISBN 978-1-4160-6193-9.
  7. Jump up^ Fang, J.; Madhavan, S.; Cohen, H.; Alderman, M. H. (2000). “Serum potassium and cardiovascular mortality”Journal of General Internal Medicine15 (12): 885–90. doi:10.1046/j.1525-1497.2000.91021.xPMC 1495719Freely accessiblePMID 11119186.
  8. Jump up to:a b Watson, M.; Abbott, K. C.; Yuan, C. M. (2010). “Damned if You Do, Damned if You Don’t: Potassium Binding Resins in Hyperkalemia”. Clinical Journal of the American Society of Nephrology5 (10): 1723–6. doi:10.2215/CJN.03700410PMID 20798253.
  9. Jump up^ Emmett, M.; Hootkins, R. E.; Fine, K. D.; Santa Ana, C. A.; Porter, J. L.; Fordtran, J. S. (1995). “Effect of three laxatives and a cation exchange resin on fecal sodium and potassium excretion”. Gastroenterology108 (3): 752–60. doi:10.1016/0016-5085(95)90448-4PMID 7875477.
  10. Jump up^ Sterns, R. H.; Rojas, M.; Bernstein, P.; Chennupati, S. (2010). “Ion-Exchange Resins for the Treatment of Hyperkalemia: Are They Safe and Effective?”. Journal of the American Society of Nephrology21 (5): 733–5. doi:10.1681/ASN.2010010079PMID 20167700.
  11. Jump up^ Kamel, K. S.; Schreiber, M. (2012). “Asking the question again: Are cation exchange resins effective for the treatment of hyperkalemia?”. Nephrology Dialysis Transplantation27(12): 4294–7. doi:10.1093/ndt/gfs293PMID 22989741.
  12. Jump up^ Denry I, Kelly JR. State of the art of zirconia for dental applications. Dental Materials. Volume 24, Issue 3, March 2008, Pages 299–307
  13. Jump up^ =Stavros, F (2014). “Characterization of Structure and Function of ZS-9, a K⁺ Selective Ion Trap”PLOS ONE9 (12): e114686. doi:10.1371/journal.pone.0114686PMC 4273971Freely accessiblePMID 25531770.
  14. Jump up^ Ash SR, et al. “Safety and efficacy of ZS-9, a novel selective cation trap, for treatment of hyperkalemia in CKD patients.” American Society of Nephrology 2013 conference, Late-Breaking Abstract.
  15. Jump up to:a b Packham DK, et al. (2014). “Sodium zirconium cyclosilicate in hyperkalemia”. New England Journal of Medicine372 (3): 222–31. doi:10.1056/NEJMoa1411487PMID 25415807.
  16. Jump up to:a b Kosiborod M, et al. (2014). “Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia”. Journal of the American Medical Association312 (21): 2223–33. doi:10.1001/jama.2014.15688PMID 25402495.
  17. Jump up^ Ben Adams (May 27, 2016). “AstraZeneca’s $2.7B hyperkalemia drug ZS-9 rejected by FDA”. FierceBiotech.
  18. Jump up^ https://www.drugs.com/history/lokelma.html
Sodium zirconium cyclosilicate
ZS-9 structure.png

Crystal structure of ZS-9. Blue spheres  =  oxygen atoms, red spheres  =  zirconium atoms, green spheres  =  silicon atoms.
Clinical data
Trade names Lokelma
Routes of
administration
Oral
ATC code
  • none
Legal status
Legal status
  • US: Rx-only
Pharmacokinetic data
Bioavailability Not absorbed
Excretion Stool
Identifiers
CAS Number
UNII
KEGG

//////////////Sodium zirconium cyclosilicate,  ナトリウムジルコニウムシクロケイ酸塩 , FDA 2018, EMA, 2018, EU 2018, ZS 9, UZSi-9

O[Si]1(O[Si](O[Si](O1)(O)O)(O)O)O.[Na+].[Na+].[Zr

Stiripentol, スチリペントール


D05928.pngStiripentol.pngChemSpider 2D Image | Stiripentol | C14H18O3Stiripentol structure.svg

Stiripentol

スチリペントール

STIRIPENTOL; Diacomit; 49763-96-4; BCX 2600; Estiripentol; Stiripentolum

CAS: 137767-55-6 49763-96-4

(E)-1-(1,3-benzodioxol-5-yl)-4,4-dimethylpent-1-en-3-ol

Molecular Formula: C14H18O3
Molecular Weight: 234.295 g/mol

UNII

R02XOT8V8I, Diacomit
fda approval 2018/8/20

Stiripentol (marketed as Diacomit by Laboratoires Biocodex) is an anticonvulsant drug used in the treatment of epilepsy. It is approved for the treatment of Dravet syndrome, an epilepsy syndrome. It is unrelated to other anticonvulsants and belongs to the group of aromatic allylic alcohols.

Medical use

It is used in some countries as an add-on therapy with sodium valproate and clobazam for treating children with Dravet syndromewhose seizures are not adequately controlled.[1][2][3] As of 2017 it was not known whether stiripentol remains useful as children become adolescents nor as they become adults.[4]

Adverse effects

Very common (more than 10% of people) adverse effects include loss of appetite, weight loss, insomnia, drowsiness, ataxiahypotonia, and dystonia.[3]

Common (between 1% and than 10% of people) adverse effects include neutropenia (sometimes severe), aggressiveness, irritability, behavior disorders, opposing behavior, hyperexcitability, sleep disorders, hyperkinesias, nausea, vomiting, and elevated gamma-glutamyltransferase.[3]

Interactions

Stiripentol inhibits several cytochrome P450 isoenzymes and so interacts with many anticonvulsants and other medicines.[3]

Pharmacology

As with most anticonvulsants, the precise mechanism of action is unknown. Regardless, stiripentol has been shown to have anticonvulsant effects of its own.

Stiripentol increases GABAergic activity. At clinically relevant concentrations, it enhances central GABA neurotransmission through a barbiturate-like effect, since it increases the duration of opening of GABA-A receptor channels in hippocampal slices.[5] It has also been shown to increase GABA levels in brain tissues by interfering with its reuptake and metabolism.[6] Specifically, it has been shown to inhibit lactate dehydrogenase, which is an important enzyme involved in the energy metabolism of neurons. Inhibition of this enzyme can make neurons less prone to fire action potentials, likely through activation of ATP-sensitive potassium channels.[7]

Stiripentol also improves the effectiveness of many other anticonvulsants, possibly due to its inhibition of certain enzymes, slowing the drugs’ metabolism and increasing blood plasma levels.[3]

Chemistry

Stiripentol is an α-ethylene alcohol; its chemical formula is 4,4-dimethyl-1-[3,4-(methylendioxy)-phenyl]-1penten-3-ol. It is chiral and is marketed as an equimolar racemic mixture. The R enantiomer appears to be around 2.5 times more active than the S enantiomer.[8]

Paper

Synthesis of the antiepileptic (R)-Stiripentol by a combination of lipase catalyzed resolution and alkene metathesis

The enantiopure (ee >99%) antiepileptic (R)-(+)-Stiripentol has been stereoselectively synthesized via cross metathesis of 5-vinylbenzo[d][1,3]dioxole 1 and (R)-(+)-4,4-dimethylpent-1-en-3-ol (R)-(+)-2. A novel one-pot two-step pathway for the synthesis of 5-vinylbenzo[d][1,3]dioxole 1 starting from 3,4-dihydroxycinnamic acid has been introduced. A lipase catalyzed kinetic resolution access to enantiopure (R)-(+)-4,4-dimethylpent-1-en-3-ol (R)-(+)-2 (ee >99%) has also been developed.

Image result for Stiripentol synthesis

Image result for Stiripentol synthesis

Stiripentol (CAS NO.: 49763-96-4), with other name of 4,4-Dimethyl-1-[(3,4-methylenedioxy)phenyl]-1-penten-3-ol, could be produced through many synthetic methods.

Following is one of the reaction routes:

Synthesis of Stiripentol

The synthesis of [14]-labeled stiripentol has been published:The reaction of 3,4-methylenedioxybromobenzene (I) with 14CO2 by means of butyllithium in ether gives 3,4-methylenedioxybenzoic acid (II), which is reduced with LiAlH4 to the corresponding benzyl alcohol (III). Oxidation of (III) with CrO3-pyridine affords the aldehyde (IV), which is condensed with methyl tert-butyl ketone (V) by means of NaOH in refluxing ethanol to give the labeled pentanone (VI). Finally, this compound is reduced to [14C]-labeled stiripentol with NaBH4 in methanol

合成路线图解说明:The condensation of 3,4-methylenedioxybenzaldehyde (I) with 3,3-dimethyl-2-butanone (II) by means of NaOH in ethanol-water gives 4,4-dimethyl-1-[(3,4-methylenedioxy)phenyl]-1-penten-3-one (III), which is reduced with NaBH4 in methanol.
合成路线图解说明:The synthesis of [14]-labeled stiripentol has been published: The reaction of 3,4-methylenedioxybromobenzene (I) with 14CO2 by means of butyllithium in ether gives 3,4-methylenedioxybenzoic acid (II), which is reduced with LiAlH4 to the corresponding benzyl alcohol (III). Oxidation of (III) with CrO3-pyridine affords the aldehyde (IV), which is condensed with methyl tert-butyl ketone (V) by means of NaOH in refluxing ethanol to give the labeled pentanone (VI). Finally, this compound is reduced to [14C]-labeled stiripentol with NaBH4 in methanol.

History

Stiripentol was discovered in 1978 by scientists at Biocodex and clinical trials started over the next few years.[8] It was originally developed for adults with focal seizures, but failed a Phase III trial.[4]

In December 2001 the European Medicines Agency (EMA) granted stiripentol orphan drug status (designation number EU/3/01/071) for the treatment of severe myoclonic epilepsy of infancy (SMEI, also known as Dravet’s syndrome) in children and in 2007, the EMA granted the drug a marketing authorisation for use of the drug as an add-on to other anti-seizure drugs.[3] It was approved in Canada for this use in 2012.[9] As of 2017 it was also approved for this use in Japan.[2]

As of 2014 it was not approved in the US, and parents of children with Dravets were paying around $1,000 for a month supply to obtain it from Europe.[10]

Stiripentol
Stiripentol structure.svg
Clinical data
Trade names Diacomit
AHFS/Drugs.com International Drug Names
License data
Routes of
administration
Oral
ATC code
Legal status
Legal status
  • AU: Unscheduled
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ECHA InfoCard 100.051.329 Edit this at Wikidata
Chemical and physical data
Formula C14H18O3
Molar mass 234.30 g·mol−1
3D model (JSmol)

References

  1. Jump up^ Brigo, F; Igwe, SC; Bragazzi, NL (18 May 2017). “Antiepileptic drugs for the treatment of infants with severe myoclonic epilepsy”. The Cochrane Database of Systematic Reviews5: CD010483. doi:10.1002/14651858.CD010483.pub4PMID 28521067.
  2. Jump up to:a b Nickels, KC; Wirrell, EC (May 2017). “Stiripentol in the Management of Epilepsy”. CNS drugs31 (5): 405–416. doi:10.1007/s40263-017-0432-1PMID 28434133.
  3. Jump up to:a b c d e f “Diacomit (stiripentol) SPC” (PDF). EMA. 8 January 2014. Retrieved 1 October 2017. For updates see EMA index page
  4. Jump up to:a b Nabbout, R; Camfield, CS; Andrade, DM; Arzimanoglou, A; Chiron, C; Cramer, JA; French, JA; Kossoff, E; Mula, M; Camfield, PR (April 2017). “Treatment issues for children with epilepsy transitioning to adult care”. Epilepsy & Behavior69: 153–160. doi:10.1016/j.yebeh.2016.11.008PMID 28188045.
  5. Jump up^ Quilichini PP, Chiron C, Ben-Ari Y, Gozlan H (2006). “Stiripentol, a putative antiepileptic drug, enhances the duration of opening of GABA-A receptor channels”Epilepsia47 (4): 704–16. doi:10.1111/j.1528-1167.2006.00497.xPMID 16650136.
  6. Jump up^ Trojnar MK, Wojtal K, Trojnar MP, Czuczwar SJ (2005). “Stiripentol. A novel antiepileptic drug” (PDF). Pharmacological reports : PR57 (2): 154–60. PMID 15886413.
  7. Jump up^ Sada N, Lee S, Katsu T, Otsuki T, Inoue T (2015). “Targeting LDH enzymes with a stiripentol analog to treat epilepsy”Science347 (6228): 1362–67. doi:10.1126/science.aaa1299PMID 25792327.
  8. Jump up to:a b “Scientific evaluation” (PDF). EMA. 2007.
  9. Jump up^ “Stiripentol (Diacomit): For Severe Myoclonic Epilepsy in Infancy (Dravet Syndrome)” (PDF). Canadian Agency for Drugs and Technologies in Health. April 2015.
  10. Jump up^ Kossoff, E (January 2014). “Stiripentol for dravet syndrome: is it worth it?”Epilepsy Currents14 (1): 22–3. doi:10.5698/1535-7597-14.1.22PMC 3913306Freely accessiblePMID 24526870.

////////////Stiripentol, fda 2018, Diacomit, 49763-96-4, BCX 2600, Estiripentol, Stiripentolum

CC(C)(C)C(C=CC1=CC2=C(C=C1)OCO2)O

Plazomicin sulfate, プラゾマイシン硫酸塩 ,


File:Plazomicin flat.svgPlazomicin structure.svgChemSpider 2D Image | Plazomicin | C25H48N6O10

Plazomicin

  • Molecular FormulaC25H48N6O10
  • Average mass592.683 Da
(2S)-4-Amino-N-[(1R,2S,3S,4R,5S)-5-amino-4-{[(2S,3R)-3-amino-6-{[(2-hydroxyéthyl)amino]méthyl}-3,4-dihydro-2H-pyran-2-yl]oxy}-2-{[3-désoxy-4-C-méthyl-3-(méthylamino)-β-L-arabinopyranosyl]oxy}-3-hyd roxycyclohexyl]-2-hydroxybutanamide [French][ACD/IUPAC Name]
1154757-24-0 [RN]
9522
ACHN-490

1380078-95-4.pngPlazomicin sulfate.png

Image result for Plazomicin sulfateImage result for Plazomicin sulfateImage result for Plazomicin sulfate

Plazomicin Sulfate

Molecular Formula: C25H50N6O14S
Molecular Weight: 690.763 g/mol
Plazomicin Sulfate; UNII-A78L6MT746; Plazomicin Sulfate [USAN]; A78L6MT746; 1380078-95-4; Plazomicin sulfate (USAN),

  • ACHN 490 sulfate

6′-(hydroxylethyl)-1-(haba)-sisomicin

Plazomicin is a neoglycoside antibiotic with activity against a broad range of Gram-positive and Gram-negive pathogens. Plazomicin showed potent in vitro activity against multidrug-resistant Klebsiella pneumoniae and Escherichia coli.

  • Mechanism of ActionProtein synthesis inhibitors
  • Orphan Drug StatusNo
  • New Molecular EntityYes

Highest Development Phases

  • MarketedUrinary tract infections
  • RegisteredPyelonephritis
  • PreregistrationBacteraemia; Nosocomial pneumonia
  • PreclinicalGram-negative infections
  • No development reportedRespiratory tract infections; Tularaemia; Yersinia infections

Most Recent Events

  • 27 Jun 2018Registered for Pyelonephritis (Treatment-resistant) in USA (IV)- First Global Approval
  • 27 Jun 2018Registered for Urinary tract infections (Treatment-resistant) in USA (IV)- First Global Approval
  • 26 Jun 2018Achaogen receives complete response letter from the FDA for Plazomicin in Bloodstream infection
Synonyms:   O-2-Amino-2,3,4,6-tetradeoxy-6-[(2-hydroxyethyl)amino]-α-D-glycero-hex-4-enopyranosyl-(1→4)-O-[3-deoxy-4-C-methyl-3-(methylamino)-β-L-arabinopyranosyl-(1→6)]-N1-[(2S)-4-amino-2-hydroxy-1-oxobutyl]-2-deoxy-D-streptamine; ACHN 490;
CAS Number:   1154757-24-0

Sulfate 1380078-95-4, プラゾマイシン硫酸塩;

Achaogen (USA)Phase II completed
Mol. Formula:   C25H48N6O10
Aminoglycosides, Broad-spectrum,
Mol. Weight:   592.68

FDA

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210303Orig1s000lbl.pdf

str1

Developed by Achaogen biopharmaceuticals, plazomicin is a next-generation aminoglycoside synthetically derived from [DB12604]. The structure of plazomicin was established via appending hydroxylaminobutyric acid to [DB12604] at position 1 and 2-hydroxyethyl group at position 6′ [A33942]. It was designed to evade all clinically relevant aminoglycoside-modifying enzymes, which contribute to the main resistance mechanism for aminoglycoside therapy [A33942]. However, acquired resistance of aminoglycosides may arise through over expression of efflux pumps and ribosomal modification by bacteria, which results from amino acid or rRNA sequence mutations [A33942]. Like other aminoglycosides, plazomicin is ineffective against bacterial isolates that produce 16S rRNA methyltransferases [FDA Label]. Plazomicin mediates the antibacterial activity against pathogens including carbapenem-resistant (CRE) and extended-spectrum beta-lactamase (ESBL) producing _Enterobacteriaceae_. It mediates the antibacterial activity by binding to bacterial 30S ribosomal subunit and inhibiting protein synthesis [FDA Label]. On June 28th, 2018, plazomicin sulfate was approved by the FDA for use in adult patients for the treatment of complicated urinary tract infections (cUTI) including Pyelonephritis. It is marketed as Zemdri and is administered via once-daily intravenous infusion.

Developed by Achaogen biopharmaceuticals, plazomicin is a next-generation aminoglycoside synthetically derived from Sisomicin. The structure of plazomicin was established via appending hydroxylaminobutyric acid to Sisomicin at position 1 and 2-hydroxyethyl group at position 6′ [1]. It was designed to evade all clinically relevant aminoglycoside-modifying enzymes, which contribute to the main resistance mechanism for aminoglycoside therapy [1]. However, acquired resistance of aminoglycosides may arise through over expression of efflux pumps and ribosomal modification by bacteria, which results from amino acid or rRNA sequence mutations [1]. Like other aminoglycosides, plazomicin is ineffective against bacterial isolates that produce 16S rRNA methyltransferases [Label]. Plazomicin mediates the antibacterial activity against pathogens including carbapenem-resistant (CRE) and extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae. It mediates the antibacterial activity by binding to bacterial 30S ribosomal subunit and inhibiting protein synthesis [Label]. On June 28th, 2018, plazomicin sulfate was approved by the FDA for use in adult patients for the treatment of complicated urinary tract infections (cUTI) including Pyelonephritis. It is marketed as Zemdri and is administered via once-daily intravenous infusion.

Plazomicin (INN,[1] ZEMDRI) is a next-generation aminoglycoside (“neoglycoside”) antibacterial derived from sisomicin by appending a hydroxy-aminobutyric acid (HABA) substituent at position 1 and a hydroxyethyl substituent at position 6′.[2][3]

Plazomicin has been reported to demonstrate in vitro synergistic activity when combined with daptomycin or ceftobiprole versus methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant S. aureus (VRSA) and against Pseudomonas aeruginosawhen combined with cefepimedoripenemimipenem or piperacillin/tazobactam.[3] It also demonstrates potent in vitro activity versus carbapenem-resistant Acinetobacter baumannii.[4]

In 2012, U.S. Food and Drug Administration granted fast track designation for the development and regulatory review of plazomicin.[5]

It is being developed by Achaogen, Inc. to treat serious bacterial infections due to multidrug-resistant Enterobacteriaceae, including carbapenem-resistant Enterobacteriaceae (CRE)[6] and was in Phase III clinical trials as of April 7, 2016.[7]

In June 2018 the FDA approved plazomicin (ZEMDRI) for adults with complicated urinary tract infections (cUTI), including pyelonephritis, caused by Escherichia coliKlebsiella pneumoniaeProteus mirabilis, or Enterobacter cloacae, in patients who have limited or no alternative treatment options. Zemdri is an intravenous infusion, administered once daily.[8][9] The FDA declined approval for treating bloodstream infections due to lack of effectiveness.[10]

To continue the development of plazomicin, the company has received a contract option of US$ 60M from the Biomedical Advanced Research and Development Authority (BARDA) to support a global Phase III clinical study. The study will evaluate plazomicin in treating patients with serious Gram-negative bacterial infections due to carbapenem-resistant Enterobacteriaceae. The study is expected to start in the fourth quarter of 2013 [4].

PATENT

WO 2009067692

WO 2010132770

PAPER

Synthesis and spectrum of the neoglycoside ACHN-490
Antimicrobial Agents and Chemotherapy (2010), 54, (11), 4636-4642

https://aac.asm.org/content/54/11/4636

FIG. 1.

FIG. 2.

FIG. 3.

PAPER

Plazomicin Retains Antibiotic Activity against Most Aminoglycoside Modifying Enzymes
ACS Infectious Diseases (2018), 4, (6), 980-987.

https://pubs.acs.org/doi/abs/10.1021/acsinfecdis.8b00001

PAPER

Effects of the 1-N-(4-Amino-2S-hydroxybutyryl) and 6′-N-(2-Hydroxyethyl) Substituents on Ribosomal Selectivity, Cochleotoxicity, and Antibacterial Activity in the Sisomicin Class of Aminoglycoside Antibiotics
ACS Infectious Diseases (2018), 4, (7), 1114-1120.

https://pubs.acs.org/doi/abs/10.1021/acsinfecdis.8b00052

Abstract Image

Syntheses of the 6′-N-(2-hydroxyethyl) and 1-N-(4-amino-2S-hydroxybutyryl) derivatives of the 4,6-aminoglycoside sisomicin and that of the doubly modified 1-N-(4-amino-2S-hydroxybutyryl)-6′-N-(2-hydroxyethyl) derivative known as plazomicin are reported together with their antibacterial and antiribosomal activities and selectivities. The 6′-N-(2-hydroxyethyl) modification results in a moderate increase in prokaryotic/eukaryotic ribosomal selectivity, whereas the 1-N-(4-amino-2S-hydroxybutyryl) modification has the opposite effect. When combined in plazomicin, the effects of the two groups on ribosomal selectivity cancel each other out, leading to the prediction that plazomicin will exhibit ototoxicity comparable to those of the parent and the current clinical aminoglycoside antibiotics gentamicin and tobramycin, as borne out by ex vivo studies with mouse cochlear explants. The 6′-N-(2-hydroxyethyl) modification restores antibacterial activity in the presence of the AAC(6′) aminoglycoside-modifying enzymes, while the 1-N-(4-amino-2S-hydroxybutyryl) modification overcomes resistance to the AAC(2′) class but is still affected to some extent by the AAC(3) class. Neither modification is able to circumvent the ArmA ribosomal methyltransferase-induced aminoglycoside resistance. The use of phenyltriazenyl protection for the secondary amino group of sisomicin facilitates the synthesis of each derivative and their characterization through the provision of sharp NMR spectra for all intermediates.

https://pubs.acs.org/doi/suppl/10.1021/acsinfecdis.8b00052/suppl_file/id8b00052_si_001.pdf

4 (19 mg, 40%). [α]D 25 = +46.5 (c = 0.01, H2O);

1 H NMR (600 MHz, D2O): δ 5.51 ( s, 1H, H-1ʹ), 5.16 (t, J = 3.5 Hz, H, H-4ʹ), 4.99 (d , J = 4.0 Hz, 1H, H-1ʹʹ), 4.11 (dd , J =9.4 Hz, 3.9 Hz, 1H, CH(OH)CH2CH2), 4.00 (d , J = 12.8 Hz, 1H, H-5ʹʹ), 3.99-3.93 (m, 1H, H-1), 3.84 (dd, J = 11.0 Hz, 4.0 Hz, 1H, H-2ʹʹ), 3.81 (t, J = 9.9 Hz, 1H, H-4), 3.77 (t, J = 5.3 Hz, 1H, H-2ʹ), 3.71 (t, J = 5.1 Hz, 2H, NHCH2CH2O), 3.69 – 3.65 (m, 2H, H-6, H-6ʹ), 3.64 – 3.44 (m , 2H, H-5, H-6ʹ), 3.35 – 3.26 (m , 1H, H-3), 3.24 (d, J = 12.8 Hz, 1H, H-5ʹʹ), 3.15 (d, J = 11.0 Hz, 1H, H-3ʹʹ), 3.09 – 3.06 (m, 2H, NHCH2CH2O), 3.01 (t, J = 7.2 Hz, 2H, CH(OH)CH2CH2), 2.74 (s, 3H, NCH3), 2.58 – 2.52 (m, 1H, H-3ʹ), 2.29 – 2.24 (m, 1H, H-3ʹ), 2.07 (dt, J = 13.2 Hz, 4.4 Hz, 1H, H-2), 2.04 – 1.98 (m, 1H, CH(OH)CH2CH2), 1.84 – 1.79 (m, 1H, CH(OH)CH2CH2), 1.64 (q, 1H, J = 12.5 Hz, H-2), 1.17 (s, 3H, 4ʹʹ-CH3);

13C NMR (151 MHz, D2O): δ 181.2 (s, CH3COOH), 175.4 (s, NHCO), 141.7 (s, C-5ʹ), 102.5 (s, C-4ʹ), 98.0 (s, C-1ʹʹ), 96.9 (s, C-1ʹ), 79.8 (s, C-4), 78.8 (s, C-6), 73.8 (s, C-5), 69.8 (s, C-4ʹʹ), 69.4 (s, CH(OH)CH2CH2), 66.8 (s, C-5ʹʹ), 65.9 (s, C-2ʹʹ), 64.2 (s, C-3ʹʹ), 56.4 (s, NHCH2CH2O), 48.8 (s, C-1), 48.31 (s, NHCH2CH2O), 48.26 (s, C-3), 47.9 (s, C-6ʹ), 45.9 (s, C2ʹ), 36.8 (s, CH(OH)CH2CH2), 34.9 (s, NCH3), 30.7 (s, CH(OH)CH2CH2), 30.4 (s, C-2), 23.1 (s, CH3COOH), 23.0 (s, C-3ʹ), 20.8 (s, 4ʹʹ-CH3).

ESI-HRMS: m/z calcd. for C25H49N6O10 [M+H]+ 593.3510, found: 593.3481.

PATENT

http://www.google.com/patents/US20100099661

Common Intermediates Sisomicin

Figure US20100099661A1-20100422-C00031

Amberlite IRA-400 (OH form) (200 g) was washed with MeOH (3×200 m1). To a stirring suspension of the washed resin in MeOH (150 mL) was added sisomicin sulfate (20.0 g, 0.029 mol) and the mixture was stirred overnight. The resin was then filtered and washed with MeOH (100 mL) and the combined organic layers were concentrated to dryness to yield the desired sisomicin (11.57 g, 0.026 mol, 89.6% yield): MS m/e [M+H]+ calcd 448.3, found 448.1.

Example 1 6′-(2-Hydroxy-ethyl)-1-(4-amino-2(S)-hydroxy-butyryl)-sisomicin

Figure US20100099661A1-20100422-C00074

6′-(2-tert-Butyldimethylsililoxy-ethyl)-2′,3,3″-triBoc-1-(N-Boc-4-amino-2(S)-hydroxy-butyryl)-sisomicin

2′,3,3″-triBoc-1-(N-Boc-4-amino-2(S)-hydroxy-butyryl)-sisomicin (0.10 g, 0.105 mmol) was treated with tert-butyldimethylsilyloxy acetaldehyde following Procedure 1-Method A to yield the desired 6′-(2-tert-butyldimethylsilyloxy-ethyl)-2′,3,3″-triBoc-1-(N-Boc-4-amino-2(S)-hydroxy-butyryl)-sisomicin (MS m/e [M+H]+ calcd 1107.6, found 1107.4), which was carried through to the next step without further purification.

Figure US20100099661A1-20100422-C00075

6′-(2-Hydroxy-ethyl)-1-(4-amino-2(S)-hydroxy-butyryl)-sisomicin

6′ -(2-tert-butyldimethylsililoxy-ethyl)-2′,3,3″-triBoc-1-(N-Boc-4-amino-2(S)-hydroxy-butyryl)-sisomicin (0.105 mmol) was submitted to Procedure 3-Method B for Boc removal to yield a crude, which was purified by RP HPLC Method 1-Column A to yield 6′-(2-hydroxy-ethyl)-1-(4-amino-2(S)-hydroxy-butyryl)-sisomicin: MS m/e [M+H]+ calcd 593.3, found 593.2, [M+Na]+615.3 ; CLND 97.5% purity.

  1. Achaogen. Study for the treatment of complicated urinary tract infection and acute pyelonephritis.Available online: http://www.clinicaltrials.gov/ct2/show/NCT01096849 (accessed on 11 April 2013).
  2. Zhanel, G.G.; Lawson, C.D.; Zelenitsky, S.; Findlay, B.; Schweizer, F.; Adam, H.; Walkty, A.; Rubinstein, E.; Gin, A.S.; Hoban, D.J.; et al. Comparison of the next-generation aminoglycoside plazomicin to gentamicin, tobramycin and amikacin. Expert Rev. Anti-Infect. Ther. 201210, 459–473, doi:10.1586/eri.12.25.
  3. Endimiani, A.; Hujer, K.M.; Hujer, A.M.; Armstrong, E.S.; Choudhary, Y.; Aggen, J.B.; Bonomo, R.A. ACHN-490, a neoglycoside with potent in vitro activity against multidrug-resistant Klebsiella pneumoniae isolates. Antimicrob. Agents Chemother. 200953, 4504–4507.
  4. Achaogen. Achaogen pipeline. Available online: http://www.achaogen.com (accessed on 30 August 2012).
  5. Achaogen. Achaogen Awarded $60M Contract Option by BARDA for the Clinical Development of Plazomicin. Available online: http://www.achaogen.com/news/151/15 (accessed on 19 June 2013).
  6. Achaogen. Achaogen announces all objectives met in Phase 2 Plazomicin complicated urinary tract infections study and start of first-in-human study with ACHN-975. Available online: http://www.achaogen.com/uploads/news/id148/Achaogen_PressRelease_2012–05–15.pdf (accessed on 10 April 2013).
  7. Achaogen. Achaogen Announces Agreement with FDA on a Special Protocol Assessment for a Phase 3 Clinical Trial of Plazomicin to Treat Infections Caused by Carbapenem-Resistant Enterobacteriaceae (CRE); Achaogen: San Francisco, CA, USA, 2013.
  8. Comparison of the next-generation aminoglycoside plazomicin to gentamicin, tobramycin and amikacin
  9. 4-23-2010
    ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS

Patent ID

Title

Submitted Date

Granted Date

US9688711 ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
2016-01-20
US9266919 ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
2014-07-17
2015-02-12
Patent ID

Title

Submitted Date

Granted Date

US8383596 ANTIBACTERIAL AMINOGLYCOSIDE ANALOGS
2010-04-22
US8822424 Antibacterial aminoglycoside analogs
2013-01-04
2014-09-02
US2012208781 AMINOGLYCOSIDE DOSING REGIMENS
2011-11-11
2012-08-16
US2012214759 TREATMENT OF KLEBSIELLA PNEUMONIAE INFECTIONS WITH ANTIBACTERIAL AMINOGLYCOSIDE COMPOUNDS
2011-11-11
2012-08-23
US2012214760 TREATMENT OF URINARY TRACT INFECTIONS WITH ANTIBACTERIAL AMINOGLYCOSIDE COMPOUNDS
2011-11-11
2012-08-23
US8318685 Nov 14, 2011 Nov 27, 2012 Achaogen, Inc. Antibacterial aminoglycoside analogs
US8367625 Apr 7, 2011 Feb 5, 2013 Achaogen, Inc. Antibacterial aminoglycoside analogs
US8372813 Apr 7, 2011 Feb 12, 2013 Achaogen, Inc. Antibacterial aminoglycoside analogs
US8377896 Mar 9, 2011 Feb 19, 2013 Isis Pharmaceuticals, Inc Antibacterial 4,6-substituted 6′, 6″ and 1 modified aminoglycoside analogs
US8399419 Mar 9, 2011 Mar 19, 2013 Achaogen, Inc. Antibacterial aminoglycoside analogs
US8481502 Apr 6, 2012 Jul 9, 2013 Achaogen, Inc. Antibacterial aminoglycoside analogs
US8492354 Nov 14, 2011 Jul 23, 2013 Achaogen, Inc. Antibacterial aminoglycoside analogs
US8524675 Nov 14, 2011 Sep 3, 2013 Achaogen, Inc. Antibacterial aminoglycoside analogs
US8524689 Nov 14, 2011 Sep 3, 2013 Achaogen, Inc. Antibacterial aminoglycoside analogs
US8569264 Jan 5, 2012 Oct 29, 2013 Isis Pharmaceuticals, Inc. Antibacterial 4,5-substituted aminoglycoside analogs having multiple substituents
US8653041 Oct 15, 2012 Feb 18, 2014 Achaogen, Inc. Antibacterial aminoglycoside analogs
US8653042 Nov 14, 2011 Feb 18, 2014 Achaogen, Inc. Antibacterial aminoglycoside analogs
US8658606 Nov 14, 2011 Feb 25, 2014 Achaogen, Inc. Antibacterial aminoglycoside analogs

References

  1. Jump up^ “WHO Drug Information, Vol. 26, No. 3, 2012. International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 68”(PDF). World Health Organization. p. 314. Retrieved 27 April 2016.
  2. Jump up^ Aggen, JB; Armstrong, ES; Goldblum, AA; Dozzo, P; Linsell, MS; Gliedt, MJ; Hildebrandt, DJ; Feeney, LA; Kubo, A; Matias, RD; Lopez, S; Gomez, M; Wlasichuk, KB; Diokno, R; Miller, GH; Moser, HE (30 August 2010). “Synthesis and Spectrum of the Neoglycoside ACHN-490” (PDF). Antimicrobial Agents and Chemotherapy54 (11): 4636–4642. doi:10.1128/AAC.00572-10PMC 2976124Freely accessiblePMID 20805391. Retrieved 27 April2016.
  3. Jump up to:a b Zhanel, GG; Lawson, CD; Zelenitsky, S; Findlay, B; Schweizer, F; Adam, H; Walkty, A; Rubinstein, E; Gin, AS; Hoban, DJ; Lynch, JP; Karlowsky, JA (10 January 2014). “Comparison of the Next-Generation Aminoglycoside Plazomicin to Gentamicin, Tobramycin and Amikacin”. Expert Review of Anti-infective Therapy10 (4): 459–73. doi:10.1586/eri.12.25PMID 22512755.
  4. Jump up^ García-Salguero, C; Rodríguez-Avial, I; Picazo, JJ; Culebras, E (October 2015). “Can Plazomicin Alone or in Combination Be a Therapeutic Option against Carbapenem-Resistant Acinetobacter baumannii?” (PDF). Antimicrobial Agents and Chemotherapy59 (10): 5959–66. doi:10.1128/AAC.00873-15PMC 4576036Freely accessible. Retrieved 27 April 2016.
  5. Jump up^ “Achaogen Announces Plazomicin Granted QIDP Designation by FDA”. GlobeNewswire, Inc. Retrieved 27 April 2016.
  6. Jump up^ “Achaogen — Plazomicin”. Achaogen, Inc. Retrieved 27 April2016.
  7. Jump up^ “Plazomicin — AdisInsight”. Springer International Publishing AG. Retrieved 27 April 2016.
  8. Jump up^ “Medscape Log In”http://www.medscape.com. Retrieved 2018-07-03.
  9. Jump up^ “BioCentury – FDA approves plazomicin for cUTI, but not blood infections”http://www.biocentury.com. Retrieved 2018-06-28.
  10. Jump up^ “Drugs@FDA: FDA Approved Drug Products”http://www.accessdata.fda.gov. Retrieved 2018-06-28.
Plazomicin
Plazomicin structure.svg
Names
IUPAC name

(2S)-4-Amino-N-[(1R,2S,3S,4R,5S)-5-amino-4-[[(2S,3R)-3-amino-6-[(2-hydroxyethylamino)methyl]-3,4-dihydro-2H-pyran-2-yl]oxy]-2-[(2R,3R,4R,5R)-3,5-dihydroxy-5-methyl-4-(methylamino)oxan-2-yl]oxy-3-hydroxycyclohexyl]-2-hydroxybutanamide
Other names

6′-(hydroxylethyl)-1-(HABA)-sisomicin
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
KEGG
PubChem CID
UNII
Properties
C25H48N6O
Molar mass 592.683 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F],

Achaogen is a clinical-stage biopharmaceutical company passionately committed to the discovery, development, and commercialization of novel antibacterials to treat multi-drug resistant, or MDR, gram-negative infections.

Achaogen Inc.jpg

Achaogen (a-KAY-o-jen) is developing plazomicin, its lead product candidate, for the treatment of serious bacterial infections due to MDR Enterobacteriaceae, including carbapenem-resistant Enterobacteriaceae, or CRE. In 2013, the Centers for Disease Control and Prevention identified CRE as a “nightmare bacteria” and an immediate public health threat that requires “urgent and aggressive action.” We expect to initiate a Phase 3 superiority trial of plazomicin in the first quarter of 2014.

CRE are one of many types of MDR gram-negative pathogens threatening patients. Bacteria such as Pseudomonas aeruginosaAcinetobacter baumannii, and extended-spectrum beta-lactamase producing Enterobacteriaceae each pose “serious” resistance threats, according to the CDC, and also drive a great need for new, safe, and effective antibiotics. We have assembled the chemistry and microbiology expertise and capabilities required to develop new agents for the treatment of gram-negative infections. Plazomicin was the first clinical candidate from our gram-negative antibiotic discovery engine. In addition, our research and development pipeline includes two antipseudomonal programs targeting P. aeruginosa—a program to discover and develop small molecule inhibitors of LpxC, which is an enzyme essential for the synthesis of the outer membrane of gram-negative bacteria, and a therapeutic antibody program. We are also pursuing small molecule research programs targeting other essential gram-negative enzymes.

Achaogen has built an exceptional research and development team with deep expertise in the discovery and development of new drugs from research through commercialization. Our executive team has over 60 years of combined industry experience, and a proven track record of leadership, global registration, and lifecycle management for over 20 products. Our facility is located on the shores of the San Francisco Bay, ten minutes from the San Francisco International Airport, and only fifteen minutes from downtown San Francisco.

Image result for Plazomicin sulfate

ZEMDRITM (plazomicin) Approved by FDA for the Treatment of Adults with Complicated Urinary Tract Infections (cUTI)

https://globenewswire.com/news-release/2018/06/26/1529573/0/en/ZEMDRITM-plazomicin-Approved-by-FDA-for-the-Treatment-of-Adults-with-Complicated-Urinary-Tract-Infections-cUTI.html

― ZEMDRI is a new treatment for patients with cUTI, including pyelonephritis, due to certain Enterobacteriaceae ―

― ZEMDRI is the only once-daily aminoglycoside therapy approved for use in cUTI ―


― ZEMDRI has microbiological activity against pathogens designated by the CDC as urgent and serious public health threats, including carbapenem-resistant (CRE) and extended spectrum beta-lactamase (ESBL)- producing Enterobacteriaceae ―

SOUTH SAN FRANCISCO, Calif., June 26, 2018 (GLOBE NEWSWIRE) — Achaogen, Inc. (NASDAQ:AKAO), a biopharmaceutical company developing and commercializing innovative antibacterial agents to address multidrug resistant (MDR) gram-negative infections, today announced that the U.S. Food and Drug Administration (FDA) has approved ZEMDRI™ (plazomicin) for adults with complicated urinary tract infections (cUTI), including pyelonephritis, caused by certain Enterobacteriaceae in patients who have limited or no alternative treatment options. ZEMDRI is an intravenous infusion, administered once daily.

“The approval of ZEMDRI marks a significant milestone for Achaogen and we are excited to offer healthcare practitioners a new treatment option for patients with certain serious bacterial infections. ZEMDRI is designed to retain its potent activity in the face of certain difficult-to-treat MDR infections, including CRE and ESBL- producing Enterobacteriaceae,” said Blake Wise, Achaogen’s Chief Executive Officer. “Today’s milestone was made possible by our employees, by patients and investigators involved in our clinical trials, and by BARDA, who contributed significant funding for the development of ZEMDRI. This marks an important step in our commitment to fighting MDR bacteria and we are excited to launch ZEMDRI, a much needed once-daily antibiotic.”

“Bacteria continue to circumvent existing antibiotics, making certain infections notoriously hard to treat and putting some patients at high risk for mortality,” said James A. McKinnell, Assistant Professor of Medicine at the David Geffen School of Medicine and LA Biomed at Harbor-UCLA. “Aminoglycosides are a familiar and very effective class of antibiotics. I look forward to adding plazomicin to my short list of available treatment options and to its potential impact on patient outcomes.”

Regarding the potential indication for plazomicin for the treatment of bloodstream infection (BSI), the FDA issued a Complete Response Letter (CRL) stating that the CARE study does not provide substantial evidence of effectiveness of plazomicin for the treatment of BSIThe Company intends to meet with the FDA to determine whether there is a feasible resolution to address the CRL.

Achaogen will work with hospitals, providers, and insurers to ensure patients are able to receive this treatment. Patients, physicians, pharmacists, or other healthcare professionals with questions about ZEMDRI should contact 1.833.252.6400 or visit www.ZEMDRI.com.

ZEMDRI Phase 3 Clinical Results
The approval of ZEMDRI is supported in part by data from the EPIC (Evaluating Plazomicin In cUTI) clinical trial, which was the first randomized controlled study of once-daily aminoglycoside therapy for the treatment of cUTI, including pyelonephritis.

In the Phase 3 EPIC cUTI trial, ZEMDRI demonstrated non-inferiority to meropenem for the co-primary efficacy endpoints of composite cure (clinical cure and microbiological eradication) in the microbiological modified intent-to-treat (mMITT; N=388) population at Day 5 and test-of-cure (TOC) visit (Day 17 + 2). Composite cure rates at Day 5 were 88.0% (168/191) for ZEMDRI vs 91.4% (180/197) for meropenem (difference -3.4%, 95% CI, -10.0 to 3.1). Composite cure rates at TOC were 81.7% (156/191) for ZEMDRI vs 70.1% (138/197) for meropenem (difference 11.6%, 95% CI, 2.7 to 20.3). Composite cure at the TOC visit in patients with concomitant bacteremia at baseline was achieved in 72.0% (18/25) of patients in the ZEMDRI group and 56.5% (13/23) of patients in the meropenem group. The most common side effects (≥1% of patients treated with ZEMDRI) were decreased kidney function, diarrhea, hypertension, headache, nausea, vomiting, and hypotension.1

The FDA approved a breakpoint of <= 2 mcg/mL; greater than 99% of Escherichia coliKlebsiella pneumoniae and Enterobacter cloacae in U.S. surveillance are susceptible to Zemdri when applying this breakpoint.2

About cUTI
cUTI is defined as a UTI occurring in a patient with an underlying complicating factor of the genitourinary tract, such as a structural or functional abnormality.3 Patients with pyelonephritis, regardless of underlying abnormalities of the urinary tract, are considered a subset of patients with cUTI.4 An estimated 3 million cases of cUTI are treated in the hospital setting in the US each year.5 Enterobacteriaceae are the most common pathogens causing cUTIs6, and resistance within this family is a global concern. High rates of resistance to previous mainstays of therapy necessitate alternative treatment options. Ineffectively managed cUTI can lead to increased treatment failure rates, recurrence of infection, increased re-hospitalization, and increased morbidity and mortality. cUTI infections place an economic burden on hospitals and payers.6,7

About ZEMDRI
ZEMDRI is an aminoglycoside with once-daily dosing that has activity against certain Enterobacteriaceae, including CRE and ESBL- producing Enterobacteriaceae. Achaogen’s EPIC clinical trial successfully evaluated the safety and efficacy of ZEMDRI in adult patients with cUTI, including pyelonephritis. ZEMDRI was engineered to overcome aminoglycoside-modifying enzymes, the most common aminoglycoside-resistance mechanism in Enterobacteriaceae, and has in vitro activity against ESBL- producing, aminoglycoside- resistant, and carbapenem- resistant isolates. The Centers for Disease Control and Prevention (CDC) has characterized ESBL- producing Enterobacteriaceae as a “serious threat” and CRE as “nightmare bacteria”, which is an immediate public health threat that requires urgent and aggressive action.

Working in the Lab
Working in the Lab
Working in the Lab
Achaogen, Inc.
Blake Wise, Chief Executive Officer at Achaogen
Blake Wise, Chief Executive Officer at Achaogen
Blake Wise, Chief Executive Officer at Achaogen
Achaogen, Inc.
High-Resolution Achaogen company logo
High-Resolution Achaogen company logo
High-Resolution Achaogen company logo
Achaogen, Inc.

/////////Plazomicin, ZEMDRI, FDA 2018, fast track designation, Plazomicin SULFATE, ACHN 490 sulfate, cUTI, Achaogen

CC1(COC(C(C1NC)O)OC2C(CC(C(C2O)OC3C(CC=C(O3)CNCCO)N)N)NC(=O)C(CCN)O)O

CN[C@@H]1[C@@H](O)[C@@H](O[C@H]2[C@@H](C[C@H](N)[C@@H](O[C@H]3OC(CNCCO)=CC[C@H]3N)[C@@H]2O)NC(=O)[C@@H](O)CCN)OC[C@]1(C)O

BINIMETINIB, биниметиниб , بينيميتينيب , 美替尼 , ビニメチニブ


Figure imgf000024_0001ChemSpider 2D Image | Binimetinib | C17H15BrF2N4O3

Binimetinib.svgBinimetinib.png

Binimetinib

MEK-162
биниметиниб [Russian] [INN]
بينيميتينيب [Arabic] [INN]
贝美替尼 [Chinese] [INN]
ビニメチニブ
5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide
5-(4-Bromo-2-fluorophenylamino)-4-fluoro-1-methyl-1H-benzimidazole-6-carbohydroxamic acid 2-hydroxyethyl ester
6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide
606143-89-9  CAS
C17H15BrF2N4O3, 441.227
UNII-181R97MR71
181R97MR71
1H-Benzimidazole-6-carboxamide, 5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-1-methyl-
tyrosine kinase inhibitor, antineoplastic

Array BioPharma Inc;PHASE 3 Cancer, ovary (serous)

Novartis PHASE 3 Melanoma

CAS 606143-89-9 [RN]
9764
ARRY-162
ARRY-438162, NVP-MEK162

MEK-1 protein kinase inhibitor; MEK-2 protein kinase inhibitor

Liver injury; Melanoma; Noonan syndrome; Ovary tumor; Solid tumor

On June 27, 2018, the Food and Drug Administration approved encorafenib and binimetinib in combination patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test

Binimetinib, also known as Mektovi and ARRY-162, is an anti-cancer small molecule that was developed by Array Biopharma to treat various cancers.[1] Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway.[2] Inappropriate activation of the pathway has been shown to occur in many cancers.[2] In June 2018 it was approved by the FDA in combination with encorafenib for the treatment of patients with unresectable or metastatic BRAF V600E or V600K mutation-positive melanoma.[3]

Binimetinib, also known as Mektovi, is a potent is a potent and selective oral mitogen-activated protein kinase 1/2 (MEK 1/2) inhibitor which is combined with Encorafenib [4],[8].

On June 27, 2018, the Food and Drug Administration approved the combination of Encorafeniband binimetinib (BRAFTOVI and MEKTOVI, from Array BioPharma Inc.) in combination for patients with unresectable or metastatic melanoma with the BRAF V600E or V600K mutations, as detected by an FDA-approved test [8].

Binimetinib was originally developed by Array BioPharma, then licensed to Novartis for worldwide development in 2010. But Array Biopharma regained full worldwide rights of the product in 2015. And in 2015, Pierre Fabre acquired exclusive rights to commercialize the product.

Mechanism of action

Binimetinib is an orally available inhibitor of mitogen-activated protein kinase kinase (MEK), or more specifically, a MAP2K inhibitor.[4]MEK is part of the RAS pathway, which is involved in cell proliferation and survival. MEK is upregulated in many forms of cancer.[5]Binimetinib, uncompetitive with ATP, binds to and inhibits the activity of MEK1/2 kinase, which has been shown to regulate several key cellular activities including proliferation, survival, and angiogenesis.[6] MEK1/2 are dual-specificity threonine/tyrosine kinases that play key roles in the activation of the RAS/RAF/MEK/ERK pathway and are often upregulated in a variety of tumor cell types.[7] Inhibition of MEK1/2 prevents the activation of MEK1/2 dependent effector proteins and transcription factors, which may result in the inhibition of growth factor-mediated cell signaling.[8] As demonstrated in preclinical studies, this may eventually lead to an inhibition of tumor cell proliferation and an inhibition in production of various inflammatory cytokines including interleukin-1, -6 and tumor necrosis factor.[8]

Development

In 2015, it was in phase III clinical trials for ovarian cancer,[9] BRAF mutant melanoma,[10] and NRAS Q61 mutant melanoma.[11]

In December 2015, the company announced that the mutant-NRAS melanoma trial was successful.[12] In the trial, those receiving binimetinib had a median progression-free survival of 2.8 months versus 1.5 months for those on the standard dacarbazinetreatment.[13] NDA submitted Jun 2016,[14] and the FDA should decide by 30 June 2017.[15]

In April 2016, it was reported that the phase III trial for low-grade ovarian cancer was terminated due to lack of efficacy.[16]

Binimetinib was studied for treatment of rheumatoid arthritis, but a phase II trial did not show benefit.

In 2017, the FDA informed Array Biopharma that the phase III trial data was not sufficient and the New Drug Application was withdrawn.[17]

In June 2018 it was approved for the treatment of certain melanomas by the FDA in combination with encorafenib.[3]

Growth factor-mediated proliferative signals are transmitted from the extracellular environment to the nucleus through several pathways, including the RAS/RAF/ MEK pathway. The RAS/RAF/MEK kinase signal transduction pathway is activated through initial extracellular binding and stimulation of tyrosine receptor kinases (RTKs) by their respective cognate ligands. Upon autophosphorylation of specific tyrosine residues in the cytosolic domain of RTKs, the Grb2-Sos complex translocates to the plasma membrane, and converts the inactive RAS’GDP to active RAS’GTP. The interaction between the Grb2 docking protein and the activated kinases or the phosphorylated receptor associated proteins is mediated by the Src Homology (SH2) domain of the signaling protein that recognizes specific phosphotyrosine sequences. RAS undergoes a conformational change upon guanosine 5 ‘-triphosphate (GTP) binding and causes the recruitment of RAF- 1 to the cytoplasmic membrane where it is phosphorylated by several kinases and simultaneous disphosphorylated at key residues by protein phosphatase-2B. Activated RAF phosphorylates the mitogen- activated protein kinase kinase (MEK) on two serine residues in the activation loop, which results in the activation of this protein kinase. MEK then phosphorylates and activates extracellular signal-regulated kinase (ERK), allowing its translocation to the nucleus where it phosphorylates transcriptional factors permitting the expression of a variety of genes.

The RAS/RAF/MEK signal transduction pathway is deregulated, often through mutations that result in ectopic protein activation, in roughly 1/3 of human cancers. This deregulation in turn results in a wide array of cellular changes that are integral to the etiology and maintenance of a cancerous phenotype including, but not limited to, the promotion of proliferation and evasion of apoptosis (Dhillon et al., Oncogene, 2007, 26: 3279-3290).

Accordingly, the development of small molecule inhibitors of key members of the RAS/ RAF/ MEK signal transduction pathway has been the subject of intense effort within the pharmaceutical industry and oncology community.

MEK is a major protein in the RAS/ RAF/ MEK pathway, which signals toward cell proliferation and survival, and frequently activated in tumors that have mutations in the RAS or RAF oncogenes or in growth receptor tyrosine kinases. MEK is a key player in the RAS/RAF/MEK pathway as it is downstream of RAS and RAF. Despite being only rarely mutated in cancer (Murugan et al., Cell Cycle, 2009, 8: 2122-2124; Sasaki et al., J. Thorac. Oncol., 2010, 5: 597-600), inhibitors of the MEK1 and MEK2 proteins have also been targeted for small molecule inhibition owing to their central position within the RAS/ RAF/ MEK signal transduction pathway signaling cascade (Fremin and Meloche, J. Hematol.

Oncol., 2010, 3:8). Recently a potent MEK inhibitor failed to demonstrate efficacy in clinical trials in patients with advanced non-small cell lung cancer (Haura et al., Clin. Cancer Res., 2010, 16: 2450-2457). The reason for failure in this trial is not clear.

6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide (hereinafter, “Compound A”) is a benzimidazole compound that is a known potent and selective inhibitor of the MEK1 and MEK2 proteins, and useful in the treatment of hyperproliferative diseases, particularly cancer, in mammals. For example, in a recently published Phase I study of 28 patients suffering from unresectable, locally advanced or metastatic biliary cancer and who had received < 1 prior systemic therapy, oral Compound A treatment (60 mg twice daily) resulted in 1 complete regression, 1 partial regression and 11 stable disease diagnoses after at least 6 weeks of treatment (Finn et al., J. Clin. Oncol. 30, 2012 (Supplement 4, 2012 Gastrointestinal Cancers Symposium, Abstract No. 220). Compound A has also been demonstrated to be effective in the treatment of patients with either BRAFV600 or NRAS-mutant melanoma (Ascierto et al., J. Clin. Oncol. 30, 2012 (Supplement, 2012 ASCO Annual Meeting, Abstract No. 8511).

The compound, as well as a process for its preparation, is disclosed in PCT Pub. No. WO 03/077914

MEK-162, a potent, orally active MEK1/2 inhibitor, is in phase III clinical trials at Array BioPharma and licensee Novartis for the treatment of metastatic or unresectable cutaneous melanoma with NRAS mutations and in combination with LGX-818 in adult patients with BRAF V600. Phase III studies are also under way at Array BioPharma for the treatment of low grade serous carcinomas of the ovary, fallopian tube or primary peritoneum following at least one prior platinum-based chemotherapy regimen and no more than three lines of prior chemotherapy regimens. Novartis and Array BioPharma are also conducting phase II clinical studies for the treatment of locally advanced and unresectable or metastatic malignant cutaneous melanoma, harboring BRAFV600E mutations; in BRAF mutated melanoma in combination with AMG-479 and for the treatment of Noonan’s syndrome, and in non-small cell lung cancer harboring KRAS or EGFR mutation and in combination with erlotinib. MEK-162 is being evaluated in phase I/II as first line treatment of advanced biliary tract carcinoma and for the treatment of adult patients with mutant or wild-type RAS metastatic colorectal cancer. The product is in early clinical trials at Array Biopharma for the treatment of biliary cancer.

According to Array, MEK-162 may also provide broad therapeutic benefits in the treatment of chronic degenerative diseases. However, a phase II trial for the treatment of stable rheumatoid arthritis (RA) did not meet its primary endpoint. Based on these data, the company focused development of MEK-162 solely in oncology.

In 2010, MEK-162 was licensed to Novartis by Array BioPharma for worldwide development. In 2013, orphan drug designation was assigned in Japan for the treatment of malignant melanoma with NRAS or BRAF V600 mutation.

WO-2014063024 DEALS WITH Preparation, crystalline forms, and formulations comprising binimetinib. Binimetinib is a MEK-1/2 inhibitor originally claimed in WO03077914, which Array and Novartis are developing for the treatment of cancer, including melanoma, low-grade serous ovarian cancer, and other solid tumors, as well as Noonan syndrome hypertrophic cardiomyopathy and hepatic impairment. See also WO2014018725 for the most recent filing on the agent

SYNTHESIS

PATENT

WO 03/077914

http://www.google.com/patents/WO2003077914A1?cl=en

Schemes 1-4.

Scheme 1

Figure imgf000029_0001
Figure imgf000029_0002

Scheme la

Figure imgf000030_0001

Scheme 2

Figure imgf000031_0001

Scheme 3

Figure imgf000032_0001

17 18

Scheme 4

Figure imgf000033_0001

25

Scheme 5

Figure imgf000034_0001
Figure imgf000034_0002

General synthetic methods which may be referred to for preparing some of the compounds of the present invention are provided in PCT published application number WO 00/42022 (published July 20, 2000). The foregoing patent application is incorporated herein by reference in its entirety.

 similar ie chloro instead of fluoro

Example 52

Figure imgf000112_0001

6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5- carboxylic acid (2-hydroxy-ethoxy)-amide (lOcc) Step A: 3-Chloro-2,4-difluoro-5-nitro-benzoic acid 2a

3-Chloro-2,4-difluoro-benzoic acid la (3.00 g, 15.6 mmol) is added to a stirred solution of concentrated H2SO4 (16 mL) and fuming nitric acid (0.85 mL, 20.3 mmol). After 3 hours a precipitate forms. The yellow slurry is poured onto ice water (100 mL). The aqueous mixture is extracted with diethyl ether (3x). The organic extracts are dried (Na2SO4) and concentrated under reduced pressure to give 3.50 g (95%) of clean desired product as a pale yellow solid.

Step B: 4-Amino-3-chloro-2-fluoro-5-nitro-benzoic acid 3a

Ammonium hydroxide solution (6.88 g, -30% in water, 58.9 mmol) is added to a solution of 3-chloro-2,4-difluoro-5-nitro-benzoic acid 2a (3.5 g, 14.7 mmol) in water (16 mL) at 0 °C with stirring. Upon completion of the ammonium hydroxide addition the reaction mixture is warmed to room temperature. After 5 hours the reaction mixture is cooled to 0 °C and concentrated HCl is carefully added until the pH of the reaction mixture is near zero. The solid is collected by filtration and washed with water and diethyl ether. The solids are transferred to a round bottom flask as a solution in MeOH and EtOAc and concentrated under reduced pressure to give 2.96 g of a yellow solid. The filtrate is partitioned between diethyl ether and water and the organic layer is washed with brine. The combined organic extracts are dried (Na2SO ) and concentrated under reduced pressure to give 0.65 g of product. Recovered a total of 3.61 g (104%) of pure desired product, that is carried forward without further purification.

Step C: 4~Amino-3-chloro-2-fluoro-5-nitro-benzoic acid methyl ester 4a

To a stirred solution of 4-amino-3-chloro-2-fluoro-5-nitro-benzoic acid 3a (3.61 g, 15.4 mmol) in THF (30 mL) and MeOH (10 mL), TMS diazomethane (9.23 mL, 2.0 M solution in hexanes, 18.5 mmol) is added. After completion of reaction, the reaction mixture is concentrated via rotary evaporation with acetic acid in the trap. The recovered oily solid is triturated with diethyl ether to provide 1.51 g of a yellow solid. The filtrate is concentrated and triturated with diethyl ether to give an additional 0.69 g of yellow solid. A total of 2.20 g (57%) of pure desired product is recovered.

Step D: 4-Amino-3-chloro-5-nitro-2-phenylamino-benzoic acid methyl ester 5c

4-Amino-3-chloro-2-fluoro-5-nitro-benzoic acid methyl ester 4a (2.20 g, 8.84 mmol) is suspended in MeOH (9.4 mL) and aniline (3.22 mL, 35.4 mmol) is added. The reaction mixture is heated to reflux with stirring under a nitrogen atmosphere. After 19 hours, the reaction is complete. Distilled water (3.22 mL) is added to the reaction mixture and refluxing is continued for one hour. The reaction mixture is cooled to 0 °C in an ice bath for 20 minutes. The reaction mixture is filtered and washed with 3:10 distilled water/MeOH (65 mL total) and then with MeOH. The solid is dissolved with CH2C12 and concentrated under reduced pressure to give 2.40 g (84%) of pure desired product. MS APCI (-) m/z 320.3 (M-l) detected.

Step E: 4, 5-Diamino-3-chloro-2-phenylamino-benzoic acid methyl ester 6b

4-Amino-3-chloro-5-nitro-2-phenylamino-benzoic acid methyl ester 5c (0.50 g, 1.55 mmol) is dissolved into 2:1 EtOH/MeOH (15.5 mL). Saturated aqueous NH4C1 (15 mL), Zn powder (1.02 g, 15.6 mmol), and THF (10 mL) are added. After stirring for 20 hours, the reaction mixture is diluted with CH C12/THF and water. The organic layer is washed with water (3x). The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure. The solids are triturated with ether to give 0.32 g (70%) clean desired product. Step F: 7-Chloro-6-phenylamino-3H-benzoimidazole-5-carboxylic acid methyl ester 7c

4,5-Diamino-3-chloro-2-phenylamino-benzoic acid methyl ester 6b (0.32 g, 1.09 mmol) and formamidine acetate (72 mg, 1.64 mmol) in EtOH (36 mL) are heated, with stirring, to 80 °C. After 44 hours, the reaction mixture is cooled to room temperature and diluted with EtOAc and washed with water (3x), saturated NaHCO3, and brine. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure to give 0.33 g (99%) clean desired product as a solid. MS APCI (+) m/z 302.3 (M+l) detected.

Step G: 6-(4-Bromo-phenylamino)-7-chloro-3H-benzoimidazole-5-carboxylic acid methyl ester 8g

7-Chloro-6-phenylamino-3H-benzoimidazole-5-carboxylic acid methyl ester 7c (0.327 g, 1.08 mmol) is dissolved into DMF (16 mL) and NBS (0.193 g, 1.08 mmol) is added. After one hour, the reaction mixture is quenched by the addition of saturated aqueous NaHSO3. The reaction mixture is then partitioned between EtOAc/THF and water. The organic layer is washed with water and brine. The combined organic extracts are dried (Na2SO ) and concentrated under reduced pressure. The recovered solid is triturated with ether to give 0.225 g (54%) pure desired product. MS ESI (+) m/z 382, 384 (M+, Br pattern) detected.

Step H: 6-(4-Bromo-2-chloro-phenylamino)- 7 -chloro-3H-benzoimidazole-5 -carboxylic acid methyl ester lOdd 6-(4-Bromo-phenylamino)-7-chloro-3H-benzoimidazole-5-carboxylic acid methyl ester 8g (0.225 g, 0.591 mmol) is dissolved in DMF (2 mL) and NCS (79 mg, 0.591 mmol) is added. After the NCS is in solution concentrated HCl (0.005 mL, 0.059 mmol) is added. After 2 hours, sodium bicarbonate, water and NaHSO3 are added to the reaction mixture. Solids are filtered and washed with water and ether to give 0.141 g (57%) of clean desired product as a tan solid. MS APCI (-) m/z 414, 416 (M-, Br pattern) detected.

Step I: 6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5- carboxylic acid methyl ester lOee

6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3H-benzoimidazole-5-carboxylic acid methyl ester lOdd (0.141 g, 0.34 mmol), potassium carbonate (0.141 g, 1.02 mmol), and iodomethane (0.063 mL, 1.02 mmol) are dissolved in dimethylformamide (3 mL). After 20 hours, the reaction mixture is diluted with EtOAc and washed with water (3x), potassium carbonate, and brine. The organic layer is dried (Na2SO4) and concentrated to a brown oil. The N3 and Nl alkylated regioisomers are separated by flash chromatography (EtOAc). The recovery of the N3 alkylated regioisomer is 20.4 mg (28%). MS ESI (+) m/z 428, 430 (M+, Br pattern) detected.

Step J: 6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5- carboxylic acid 10 ff

6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5- carboxylic acid methyl ester lOee (21 mg, 0.048 mmol) is dissolved into 2:1 THF/water (1.2 mL) and NaOH (0.190 mL, 1.0 M aqueous solution, 0.190 mmol) is added. After stirring for 4 hours the reaction is diluted with water and acidified to pH 2 by addition of 1.0 M HCl. The mixture is then extracted with 3:1 EtOAc/THF (3x), dried (Na2SO ) and concentrated to give quantitative yield of desired prodcut as a white solid. MS APCI (+) m/z 414, 416 (M+, Br pattern) detected.

Step K: 6-(4-Bromo-2’chloro-phenylamino)- 7-chloro-3-methyl-3H-benzoimidazole-5- carboxylic acid (2-vinyloxy-ethoxy) -amide lOgg

6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5- carboxylic acid lOff (32 mg, 0.077 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (0.010 mL, 0.092 mmol), HOBt (13 mg, 0.093 mmol), triethylamine (0.011 mL, 0.077 mmol), and EDCI (19 mg, 0.10 mmol) are dissolved into dimethylformamide (1.0 mL) and allowed to stir under a nitrogen atmosphere at room temperature for 24 hours. The reaction mixture is diluted with EtOAc, washed with water (3x), 10% potassium carbonate (2x), saturated ammonium chloride, brine, dried (Na2SO4), and concentrated under reduced pressure to give 39 mg of 85% pure material. MS APCI (-) m/z 497, 501 (M-, Br pattern) detected.

Step L: 6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5- carboxylic acid (2-hydroxy-ethoxy)-amide lOcc

Hydrochloric acid (0.78 mL, 1.0 M aqueous solution, 0.78 mmol) is added to a suspension of 6-(4-bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H- benzoimidazole-5-carboxylic acid lOgg (2-vinyloxy-ethoxy)-amide (39 mg, 0.078 mmol) in MeOH (1 mL). After one hour, the reaction mixture is neutralized to pH 7 and concentrated under reduced pressure. The solids are dissolved in EtOAc, washed with brine, dried (Na SO4), and concentrated under reduced pressure. Flash chromatography (20:1 CH2Cl2/MeOH) provides 9 mg (23%) of pure product: MS APCI (+) m/z 473, 475 (M+, Br pattern) detected; 1H NMR (400 MHz, CDC13) δ 8.30 (s, IH), 8.08 (s, IH), 7.57

(d, IH), 7.15 (dd, IH), 6.21 (d, IH), 3.97 (s, 3H) 3.86 (m, 2H), 3.57 (m, 2H).

actual is below

Example 18

The following compounds are prepared by methods similar to those described in

Example 10 by using methyl ester 8d and the appropriate alkylating agent (Step A) and

the appropriate hydroxylamine (Step C):

Figure imgf000071_0002

PATENT

WO2014063024

http://patentscope.wipo.int/search/en/detail.jsf;jsessionid=E10680BCA177F821C7FEFA1AFC44A438.wapp2nA?docId=WO2014063024&recNum=6&maxRec=53841&office=&prevFilter=%26fq%3DICF_M%3A%22C07D%22&sortOption=Pub+Date+Desc&queryString=&tab=PCTDescription

COMPD A

Example 1. Preparation of 6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-

In an inertized (N2) reaction vessel at internal temperature 20°C and under exclusion of humidity and air, Compound 1 (1.0 eq.) and Compound 2 (1.2 eq.) are reacted in the presence of cesium carbonate (2.4 eq.), tris(dibenzylidenaceton) dipalladium(O) (0.035 eq.) and Xantphos (0.07 eq.) in a mixture of toluene and 1 ,4-dioxane at internal temperature of 99°C. After 8 hours, the mixture is cooled to internal temperature of 60°C.

Subsequently, dimethylformamide (DMF), filter aid (CEFOK) and activated charcoal (EKNS) are added, and the mixture is stirred and cooled to internal temperature of 35 °C. The solids are filtered off and washed with a mixture of dimethylformamide and toluene. To the filtrate, which contains the product Compound 3, is introduced at internal temperature of

25 °C hydrogen chloride gas (CLC) whereupon the HQ salt of Compound 3 crystallizes. The palladium residue mainly remains in solution. After warming to 60 °C and cooling to 0°C, the solids are filtered using a centrifuge and are washed with a mixture of toluene and dimethylformamide.

The damp Compound 3 HC1 salt is charged to a reactor (equipped with pH probe) together with dimethylformamide and is heated to 60°C. By adding a 4 wt% of aqueous tripotassium phosphate solution, the pH is adjusted to a pH range of 6.8-7.6 (with a target of pH 7.2) while Compound 3 crystallizes as free base. After cooling to 22°C and stirring, the solids are filtered using a centrifuge and are washed with drinking water. The moist solids are dried at 50 °C under vacuum to give dry, crude Compound 3.

In order to remove residual palladium, dry, crude Compound 3 is dissolved in dimethylformamide at internal temperature of 60°C and stirred together with Smopex-234 (commercially available from Johnson Matthey) and activated charcoal for 90 minutes. The solids are filtered off at internal temperature of 60°C and are washed with

dimethylformamide. To the filtrate are added drinking water and Compound 3 seed crystals. More drinking water is added while Compound 3 crystallizes. After cooling to internal temperature of 20 °C, the solids are filtered using a centrifuge and are washed with a mixture of deionized water and dimethylformamide and with deionized water. The moist solids are dried at 50°C under vacuum, providing 6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester (Compound 3).

Example 2. Preparation of 6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid-(2-tert-butoxyethoxy)-amide

A. “One-pot” Synthesis


In an inertized reaction vessel at internal temperature 20-25 °C under nitrogen, 6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester (Compound 3, 1.0 eq.) is added to a mixture of DMF and THF. To this slurry, a solution of potassium trimethylsilanolate (1.05 eq.) in THF is added to the mixture at internal temperature of 25 °C over a period of about 40 minutes, and the resulting mixture is stirred for about 1 hour, providing a potassium salt solution of Intermediate 1. A THF/methanol mixture is then sequentially distilled off from the mixture at 85-120°C during about 2 hours.

The potassium salt solution is then added to a suspension of CDI (1.25 eq.) and imidazole hydrochloride (1.40 eq.) in THF at internal temperature of 25 °C over a period of about 1 hour. The resulting mixture is then stirred for approximately 1 hour at 50°C, and the following imidazolide intermediate

The imidazolide intermediate is not further isolated.

Subsequently, 1.2 eq. of 0-(2-tert-butoxyethyl)hydroxylamine (Compound 4, CAS No. 1023742-13-3, available from suppliers such as Huhu Technology, Inc.®) is added over a period of about 30 minutes at 50°C and stirred for 1.5 hours. Demineralized water is then added at 50°C, producing a precipitate. After cooling to 20°C and stirring for about 3-16 hours, the slurry is filtered off, washed with THF/ demineralized water (1 :2) in 2 portions and with demineralized water in three portions, and dried at 50°C / <70 mbar for about 17 hours, providing 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid-(2-tert-butoxyethoxy)-amide (Compound 5) as monohydrate.

B. A synthesis method with isolation of the intermediate of step a) from the reaction mixture of step a) prior to the reaction of step b)

Alternatively, 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5 -carboxylic acid-(2-tert-butoxyethoxy)-amide (Compound 5) can be made by the synthesis method as shown below. Compound 3, which is a methyl ester, is first converted to a carboxylic acid, which is then isolated by a crystallization to form Compound

6. Compound 6 is then coupled with Compound 4 to form Compound 5 as monohydrate.

The crystallization step in this method removes starting materials such as Compound 1, process impurities, and the dba ligand from the prior catalyst before the coupling reaction with Compound 4, and at the same time maintains the overall yield of the synthesis.

6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-memy acid In an inertized (N2) reaction vessel at internal temperature of 60°C, Compound 3 (1.0 eq.) is dissolved in DMF and stirred with a fiber, which is sold under the trademark

SMOPEX 234, and activated charcoal for the removal of palladium to not more than 100 ppm. The fiber and activated charcoal are removed by filtration at 60°C and washed with DMF.

The filtrate (containing Compound 3) is transferred to a second inertized (N2) reaction vessel and cooled to an internal temperature of 30°C. A thin suspension can form at this point of time. 30% sodium hydroxide (1.1 eq.) and water (for rinsing) are added, and the resulting reaction mixture is vigorously stirred for 3 hours at an internal temperature of 30 °C. The methyl ester is saponified. Conversion is checked by an IPC (HPLC). As soon as the IPC criterion is met, a filter aid, which is sold under the trademark HYFLO, is added. The mixture is stirred for 15 minutes and then filtered at 30°C via a plate filter and polish filter to a third reaction inertized (N2) vessel.

An aqueous HC1 solution 7.5 % is added to the clear filtrate in the third vessel at an internal temperature of 30 °C until a pH value of 8 is reached. Then the solution is seeded at an internal temperature of 30°C with Compound 6, and an aqueous HC1 solution 7.5 % is added under vigorous stirring until a pH value of pH 2.8 is reached. The product gradually crystalizes. The suspension is cooled over 60 min to an internal temperature of 25 °C and

water is added. The suspension is stirred for at least 4 hours at an internal temperature of 25°C.

The resulting solid is collected by centrifugation or filtration. The filter cake is first washed with DMF/water 1 :1 (w/w) and then with water, discharged and dried in a vacuum at 50°C. The water content is controlled by IPC. The crystalline product Compound 6 is discharged as soon as the IPC criterion is met.

6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid- (2-tert-butoxyethoxy) – amide

An inertized (N2) reaction vessel is charged with Compound 6 (1.0 eq.), DMF, and

THF at room temperature. The suspension is heated to 25 °C under stirring with flow of nitrogen. After CDI (1.13 eq.) is added, the suspension can get thinner and slight evolution of gases can be observed. After the suspension finally becomes a solution, it is then monitored by IPC (HPLC).

As soon as the IPC (HPLC) criterion is met, the reaction mixture is heated to 50°C over 20 minutes and imidazole hydrochloride (0.3 eq.) is added, forming a solution of

Intermediate 2.

To the solution of Intermediate 2, Compound 4 (1.3 eq.) is added over 60 minutes at internal temperature of 50°C under stirring at a speed of 300 rpm with flow of nitrogen. As soon as the IPC (HPLC) criterion is met, the mixture is cooled to 20-25 °C over 30 minutes. The mixture is then stored at ambient temperature overnight under nitrogen without stirring. DMF is added to the mixture followed by heating it to 50 °C over 30 minutes. Complete conversion of Intermediate 2 to Compound 5 is confirmed by IPC (HPLC).

Water is added to the mixture at internal temperature of 50 °C over 20 minutes. Then the solution is seeded with Compound 5. After stirring at 50 °C for 60 minutes, more water is added to the suspension at 50 °C over 90 minutes. After vigorous stirring, the suspension is cooled to 20 °C over 2 hours and filtered. The filter cake is washed twice with THF/water (v/v: 1 :2) at 20 °C, and twice with water at 20 °C. Finally, the filter cake is dried at 50 °C under vacuum to provide 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid-(2-tert-butoxyethoxy)-amide (Compound 5) as monohydrate.

Example 3. Preparation of 6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide (Compound A)

Compound 5 Compound A

6-(4-Bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid-(2-tert-butoxyethoxy)-amide (Compound 5) monohydrate is added in 3 portions to a premixed solution of Acetonitrile and excess Phosphoric acid (85 % aqueous solution) at internal temperature 20-25 °C. After stirring for about 15 minutes, the suspension is heated to internal temperature 50-53 °C. The suspension is maintained at this temperature for 6 hours, cooled to internal temperature 20-25 °C. The mixture is then heated to internal temperature 35-37°C and diluted with Ethanol- Water (3 :1 v/v). EKNS and CEFOK are added, the reaction mixture is stirred approximately 15 minutes and filtered over a funnel coated with CEFOK. The filtrate is cooled to approximately 30°C. 3 N aqueous potassium hydroxide (ΚΟΗ) is added to the cooled filtrate over a period of 90 minutes until a pH- value of about 8.1 is reached. The suspension is heated to internal temperature 60-63 °C, stirred at this temperature for a period of about 2 hours, cooled to 20-23 °C over a period of about 45 minutes, filtered over a funnel, and dried at 50°C pressure <100 mbar over a period of about 17 hours, providing 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide (Compound A) as a white powder.

Example 4. Preparation of Crystallized 6-(4-bromo-2-fluorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxyethyoxy)-amide (Compound A) In a dry vessel at room temperature, Compound A is added to a premixed solvent solution of methanol/THF/water (35/35/30 w/w). The suspension is heated to internal temperature 53-55°C, and the resulting solution is hot filtered by deep and membrane filtration (via a paper filter and PTFE membrane) at internal temperature 53-56°C. The clear solution is stirred and cooled to 47-48°C, and the seed crystals suspension (i.e., seed crystals of crystallized Compound A in water, 10% m/m) is added (0.2 to 0.5% of crystallized Compound A expected yield mass). After about 20 minutes, water is slowly added within 25 hours (33.3% within 15 hours and 66.6% within 10 hours with at least 10 minute stirring after addition of water) to obtain a final ratio of methanol THF/water (20/20/60 w/w). After the water is added, the suspension is cooled down to internal temperature 3-5 °C within 10 hours and stirred for 0.5 hours. The white suspension is filtered over a sinter glass nutsche (75 ml, diameter = 6 cm, pore 3) suction filter and washed once with ice cold methanol/THF/water (15/15/70 w/w at 2-4 °C), and two times with ice cold water (2-4 °C). Drying takes place in a vacuum oven dryer at 20°C for 10 hours, and then at 40°C for 10 hours, and then at 60°C for at least 12 hours with pressure < lOmbar, providing crystallized Compound A.

CLIP

str1

http://blog.sina.com.cn/s/blog_de171b9b0101dvov.html

CLIP

https://www.pharmacodia.com/yaodu/html/v1/chemicals/675f9820626f5bc0afb47b57890b466e.html

References

  1. Jump up^ “Binimetinib”. Array Biopharma.
  2. Jump up to:a b Koelblinger P, Dornbierer J, Dummer R (August 2017). “A review of binimetinib for the treatment of mutant cutaneous melanoma”. Future Oncology13 (20): 1755–1766. doi:10.2217/fon-2017-0170PMID 28587477.
  3. Jump up to:a b Research, Center for Drug Evaluation and. “Approved Drugs – FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations”http://www.fda.gov. Retrieved 2018-07-17.
  4. Jump up^ Wu PK, Park JI (December 2015). “MEK1/2 Inhibitors: Molecular Activity and Resistance Mechanisms”Seminars in Oncology42 (6): 849–62. doi:10.1053/j.seminoncol.2015.09.023PMC 4663016Freely accessiblePMID 26615130.
  5. Jump up^ “Binimetinib”PubChem.
  6. Jump up^ Ascierto PA, Schadendorf D, Berking C, Agarwala SS, van Herpen CM, Queirolo P, Blank CU, Hauschild A, Beck JT, St-Pierre A, Niazi F, Wandel S, Peters M, Zubel A, Dummer R (March 2013). “MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study”. The Lancet. Oncology14(3): 249–56. doi:10.1016/S1470-2045(13)70024-XPMID 23414587.
  7. Jump up^ Mehdizadeh A, Somi MH, Darabi M, Jabbarpour-Bonyadi M (February 2016). “Extracellular signal-regulated kinase 1 and 2 in cancer therapy: a focus on hepatocellular carcinoma”. Molecular Biology Reports43 (2): 107–16. doi:10.1007/s11033-016-3943-9PMID 26767647.
  8. Jump up to:a b Woodfield SE, Zhang L, Scorsone KA, Liu Y, Zage PE (March 2016). “Binimetinib inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression”BMC Cancer16: 172. doi:10.1186/s12885-016-2199-zPMC 4772351Freely accessiblePMID 26925841.
  9. Jump up^ Clinical trial number NCT01849874 for “A Study of MEK162 vs. Physician’s Choice Chemotherapy in Patients With Low-grade Serous Ovarian, Fallopian Tube or Peritoneal Cancer” at ClinicalTrials.gov
  10. Jump up^ Clinical trial number NCT01909453 for “Study Comparing Combination of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in BRAF Mutant Melanoma (COLUMBUS)” at ClinicalTrials.gov
  11. Jump up^ Clinical trial number NCT01763164 for “Study Comparing the Efficacy of MEK162 Versus Dacarbazine in Unresectable or Metastatic NRAS Mutation-positive Melanoma” at ClinicalTrials.gov
  12. Jump up^ Hufford A (December 2015). “Array BioPharma Has Successful Trial for Cancer Drug Binimetinib”Wall Street Journal.
  13. Jump up^ “Array BioPharma announces Phase 3 binimetinib trial meets primary endpoint for NRAS-mutant melanoma”Metro Denver. December 2015.
  14. Jump up^ Array Bio submits marketing application in U.S. for lead product candidate in certain type of melanoma. June 2016
  15. Jump up^ House DW (1 September 2016). “FDA accepts Array Bio’s NDA for binimetinib, action date June 30”Seeking Alpha.
  16. Jump up^ House DW (1 April 2016). “Array bags Phase 3 study of binimetinib in ovarian cancer; shares down 4%”Seeking Alpha.
  17. Jump up^ Adams B (20 March 2017). “Losing Nemo: Array pulls skin cancer NDA for binimetinib”Fierce Biotech.
Binimetinib
Binimetinib.svg
Clinical data
ATC code
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
KEGG
ChEMBL
Chemical and physical data
Formula C17H15BrF2N4O3
Molar mass 441.23 g/mol
3D model (JSmol)
  1. Koelblinger P, Dornbierer J, Dummer R: A review of binimetinib for the treatment of mutant cutaneous melanoma. Future Oncol. 2017 Aug;13(20):1755-1766. doi: 10.2217/fon-2017-0170. Epub 2017 Jun 7. [PubMed:28587477]
  2. Queirolo P, Spagnolo F: Binimetinib for the treatment of NRAS-mutant melanoma. Expert Rev Anticancer Ther. 2017 Nov;17(11):985-990. doi: 10.1080/14737140.2017.1374177. Epub 2017 Sep 8. [PubMed:28851243]
  3. Dummer R, Schadendorf D, Ascierto PA, Arance A, Dutriaux C, Di Giacomo AM, Rutkowski P, Del Vecchio M, Gutzmer R, Mandala M, Thomas L, Demidov L, Garbe C, Hogg D, Liszkay G, Queirolo P, Wasserman E, Ford J, Weill M, Sirulnik LA, Jehl V, Bozon V, Long GV, Flaherty K: Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Apr;18(4):435-445. doi: 10.1016/S1470-2045(17)30180-8. Epub 2017 Mar 9. [PubMed:28284557]
  4. Bendell JC, Javle M, Bekaii-Saab TS, Finn RS, Wainberg ZA, Laheru DA, Weekes CD, Tan BR, Khan GN, Zalupski MM, Infante JR, Jones S, Papadopoulos KP, Tolcher AW, Chavira RE, Christy-Bittel JL, Barrett E, Patnaik A: A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor. Br J Cancer. 2017 Feb 28;116(5):575-583. doi: 10.1038/bjc.2017.10. Epub 2017 Feb 2. [PubMed:28152546]
  5. Gardner AM, Vaillancourt RR, Lange-Carter CA, Johnson GL: MEK-1 phosphorylation by MEK kinase, Raf, and mitogen-activated protein kinase: analysis of phosphopeptides and regulation of activity. Mol Biol Cell. 1994 Feb;5(2):193-201. [PubMed:8019005]
  6. Wang ZQ, Wu DC, Huang FP, Yang GY: Inhibition of MEK/ERK 1/2 pathway reduces pro-inflammatory cytokine interleukin-1 expression in focal cerebral ischemia. Brain Res. 2004 Jan 16;996(1):55-66. [PubMed:14670631]
  7. Cancer.gov link [Link]
  8. FDA approves encorafenib and binimetinib in combination for unresectable or metastatic melanoma with BRAF mutations [Link]
  9. A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor [Link]
  10. Binimetinib inhibits MEK and is effective against neuroblastoma tumor cells with low NF1 expression [Link]
  11. Binimetinib [File]
  12. EMA assessment [File]

/////////////BINIMETINIB, FDA 2018, MEK-162, биниметиниб بينيميتينيب , 美替尼 , ビニメチニブ , 606143-89-9 , 9764, ARRY-162, ARRY-438162, NVP-MEK162

CN1C=NC2=C(F)C(NC3=CC=C(Br)C=C3F)=C(C=C12)C(=O)NOCCO

https://cen.acs.org/articles/95/i23/Array-licenses-cancer-compounds-Ono.html

The structure of binimetinib.

Array BioPharma has licensed Japan’s Ono Pharmaceutical the right to develop two late-stage oncology compounds, binimetinib and encorafenib, in Japan and South Korea. Array will get $32 million up front and up to $156 million in milestone payments. The compounds are in Phase III studies of patients with BRAF-mutant cancers. Array recently struck a deal to assess binimetinib with two Bristol-Myers Squibb immuno-oncology agents.

%d bloggers like this: