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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Kyowa Hakko Kirin Korea begins patient recruitment in phase I/II study of BIW-8962 in lung cancer


Kyowa Hakko Kirin Korea begins patient recruitment in phase I/II study of BIW-8962 in lung cancer

http://www.kyowa-kirin.com/news_releases/2011/pdf/e20110802_04.pdf

http://clinicaltrials.gov/ct2/show/NCT01898156

Kyowa Hakko Kirin Korea Co., Ltd

This Phase 1/2 study is designed to assess the following: safety and tolerability of BIW-8962, Dose Limiting Toxicities (DLTs), Maximum Tolerated Dose (MTD), Recommended Phase 2 Dose (RP2D) in Phase 1 and preliminary efficacy in Phase 2 in subjects with advanced/recurrent lung cancer or mesothelioma.

http://www.myeloma.org.uk/patient-information/drug-development/hcp-drug-scanner/biw-8962/

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UK regulator approves access to Revolade drug after three-year process


25 July 2013

The National Institute for Health and Care Excellence (NICE) in the UK has recommended immune disorder drug Revolade for use on the NHS after a process of three and a half years.

The GSK once-daily oral treatment is now available to adult patients in England and Wales living with chronic immune (idiopathic) thrombocytopenic purpura (cITP), an immune disorder associated with low-blood platelet counts.

In patients with cITP, the immune system prematurely destroys platelets or impairs their production so that platelets are lost from the circulation faster than they can be replaced from the bone marrow, where they are made.

This results in patients developing mild bruising or serious bleeding, which affects their quality of life and, in some instances, may be fatal.

It is estimated that cITP currently affects 50 in 100,000 people in the UK.

The only other licensed TPO-RA recommended by NICE is romiplostim, which is given in the form of a weekly injection.

The Royal London Hospital’s clinical director for pathology Prof Adrian Newland said: “I was very pleased to see that NICE has recognised the clinical value and cost-effectiveness of eltrombopag in their guidance.

“We now have an important addition to the treatment options for patients with severe or refractory disease.”

“With eltrombopag, we hope to ultimately make a meaningful difference in the quality of life of cITP patients and contribute to potential savings for the NHS.”

Revolade is an oral thrombopoietin receptor agonist (TPO-RA) that stimulates the growth and maturation of cells in the bone marrow (megakaryocytes) that produce platelets, increasing platelet production.

When added to conventional immunosuppressive therapy, Revolade, also known as eltrombopag, increases response rates compared with placebo and in some patients.

GlaxoSmithKline UK general manager Erik Van Snippenberg said: “This has been a lengthy three and a half year long appraisal process. We are pleased that NICE has recommended eltrombopag and that the small number of cITP patients in England and Wales are granted access to an alternative treatment option offering the benefit of oral convenience.

“With eltrombopag, we hope to ultimately make a meaningful difference in the quality of life of cITP patients and contribute to potential savings for the NHS.”

 

Compound Suffocates Tumors


Scientists have discovered a new molecule that prevents cancer cells from responding and surviving when starved of oxygen and which could be developed into new treatments for the disease, according to new research published in the Journal of the American Chemical Society.

Cancer Research UK scientists at the University of Southampton found that this molecule targets the master switch—HIF-1—that cancer cells use to adapt to low oxygen levels, a common feature in the disease.

read all at

http://www.dddmag.com/news/2013/07/compound-suffocates-tumors?et_cid=3389792&et_rid=523035093&type=cta

http://www.pharmaceutical-technology.com/news/newsnew-molecule-that-can-suffocate-cancer-cells-discovered?WT.mc_id=DN_News

Find out more:

Hepatitis B


Hepatitis B


Key facts

  • Hepatitis B is a viral infection that attacks the liver and can cause both acute and chronic disease.
  • The virus is transmitted through contact with the blood or other body fluids of an infected person.
  • About 600 000 people die every year due to the consequences of hepatitis B.
  • Hepatitis B is an important occupational hazard for health workers.
  • Hepatitis B is preventable with the currently available safe and effective vaccine.


Hepatitis B is a potentially life-threatening liver infection caused by the hepatitis B virus. It is a major global health problem. It can cause chronic liver disease and chronic infection and puts people at high risk of death from cirrhosis of the liver and liver cancer.

More than 240 million people have chronic (long-term) liver infections. About 600 000 people die every year due to the acute or chronic consequences of hepatitis B.

A vaccine against hepatitis B has been available since 1982. Hepatitis B vaccine is 95% effective in preventing infection and its chronic consequences, and was the first vaccine against a major human cancer.

Geographical distribution

Hepatitis B virus can cause an acute illness with symptoms that last several weeks, including yellowing of the skin and eyes (jaundice), dark urine, extreme fatigue, nausea, vomiting and abdominal pain. Hepatitis B prevalence is highest in sub-Saharan Africa and East Asia. Most people in these regions become infected with the hepatitis B virus during childhood and between 5–10% of the adult population is chronically infected.

High rates of chronic infections are also found in the Amazon and the southern parts of eastern and central Europe. In the Middle East and the Indian subcontinent, an estimated 2–5% of the general population is chronically infected. Less than 1% of the population in western Europe and North America is chronically infected.

Transmission

In highly endemic areas, HBV is most commonly spread from mother to child at birth, or from person to person in early childhood.

Perinatal or early childhood transmission may also account for more than one third of chronic infections in areas of low endemicity, although in those settings, sexual transmission and the use of contaminated needles, especially among injecting drug users, are the major routes of infection.

The hepatitis B virus can survive outside the body for at least seven days. During this time, the virus can still cause infection if it enters the body of a person who is not protected by the vaccine.

The hepatitis B virus is not spread by contaminated food or water, and cannot be spread casually in the workplace.

The incubation period of the hepatitis B virus is 75 days on average, but can vary from 30 to 180 days. The virus may be detected 30 to 60 days after infection and persists for variable periods of time.

Symptoms

Most people do not experience any symptoms during the acute infection phase. However, some people have acute illness with symptoms that last several weeks, including yellowing of the skin and eyes (jaundice), dark urine, extreme fatigue, nausea, vomiting and abdominal pain.

In some people, the hepatitis B virus can also cause a chronic liver infection that can later develop into cirrhosis of the liver or liver cancer.

More than 90% of healthy adults who are infected with the hepatitis B virus will recover and be completely rid of the virus within six months.

Who is at risk for chronic disease?

The likelihood that infection with the hepatitis B virus becomes chronic depends upon the age at which a person becomes infected. Children less than 6 years of age who become infected with the hepatitis B virus are the most likely to develop chronic infections:

  • 80–90% of infants infected during the first year of life develop chronic infections;
  • 30–50%% of children infected before the age of 6 years develop chronic infections.

In adults:

  • <5% of otherwise healthy adults who are infected will develop chronic infection;
  • 15–25% of adults who become chronically infected during childhood die from hepatitis B-related liver cancer or cirrhosis.

Diagnosis

It is not possible, on clinical grounds, to differentiate hepatitis B from hepatitis caused by other viral agents and, hence, laboratory confirmation of the diagnosis is essential. A number of blood tests are available to diagnose and monitor people with hepatitis B. They can be used to distinguish acute and chronic infections.

Laboratory diagnosis of hepatitis B infection centres on the detection of the hepatitis B surface antigen HBsAg. WHO recommends that all blood donations are tested for this marker to avoid transmission to recipients.

  • Acute HBV infection is characterized by the presence of HBsAg and immunoglobulin M (IgM) antibody to the core antigen, HBcAg. During the initial phase of infection, patients are also seropositive for HBeAg.
  • Chronic infection is characterized by the persistence (>6 months) of HBsAg (with or without concurrent HBeAg). Persistence of HBsAg is the principal marker of risk for developing chronic liver disease and hepatocellullar carcinoma (HCC) later in life.
  • The presence of HBeAg indicates that the blood and body fluids of the infected individual are highly contagious

Treatment

There is no specific treatment for acute hepatitis B. Care is aimed at maintaining comfort and adequate nutritional balance, including replacement of fluids that are lost from vomiting and diarrhoea.

Some people with chronic hepatitis B can be treated with drugs, including interferon and antiviral agents. Treatment can slow the progression of cirrhosis, reduce incidence of HCC and improve long term survival. Treatment, however, is not readily accessible in many resource-constrained settings.

Liver cancer is almost always fatal and often develops in people at an age when they are most productive and have family responsibilities. In developing countries, most people with liver cancer die within months of diagnosis. In high-income countries, surgery and chemotherapy can prolong life for up to a few years.

People with cirrhosis are sometimes given liver transplants, with varying success.

Prevention

The hepatitis B vaccine is the mainstay of hepatitis B prevention. WHO recommends that all infants receive the hepatitis B vaccine as soon as possible after birth, preferably within 24 hours.

The birth dose should be followed by 2 or 3 doses to complete the primary series. In most cases, 1 of the following 2 options is considered appropriate:

  • a 3-dose schedule of hepatitis B vaccine, with the first dose (monovalent) being given at birth and the second and third (monovalent or combined vaccine) given at the same time as the first and third doses of DTP vaccine; or
  • 4 doses, where a monovalent birth dose is followed by 3 monovalent or combined vaccine doses, usually given with other routine infant vaccines.

The complete vaccine series induces protective antibody levels in more than 95% of infants, children and young adults. Protection lasts at least 20 years and is possibly lifelong.

All children and adolescents younger than 18 years old and not previously vaccinated should receive the vaccine if they live in countries where there is low or intermediate endemicity. In those settings it is possible that more people in high risk groups may acquire the infection and they should also be vaccinated. They include:

  • people who frequently require blood or blood products, dialysis patients, recipients of solid organ transplantations;
  • people interned in prisons;
  • injecting drug users;
  • household and sexual contacts of people with chronic HBV infection;
  • people with multiple sexual partners, as well as health-care workers and others who may be exposed to blood and blood products through their work; and
  • travellers who have not completed their hepatitis B vaccination series should be offered the vaccine before leaving for endemic areas.

The vaccine has an excellent record of safety and effectiveness. Since 1982, over one billion doses of hepatitis B vaccine have been used worldwide. In many countries, where 8–15% of children used to become chronically infected with the hepatitis B virus, vaccination has reduced the rate of chronic infection to less than 1% among immunized children.

As of July 2011, 179 Member States vaccinate infants against hepatitis B as part of their vaccination schedules. This is a major increase compared with 31 countries in 1992, the year that the World Health Assembly passed a resolution to recommend global vaccination against hepatitis B. Furthermore, as of July 2011, 93 Member States have introduced the hepatitis B birth dose.

In addition, implementation of blood safety strategies, including quality-assured screening of all donated blood and blood components used for transfusion can prevent transmission of HBV. Safe injection – unnecessary as well as unsafe injections – practices can protect against HBV transmission. Furthermore, safer sex practices, including minimizing the number of partners and using barrier protective measures (condoms), protect against transmission.

WHO response

WHO is working in the following areas to prevent and control viral hepatitis:

  • raising awareness, promoting partnerships and mobilizing resources;
  • formulating evidence-based policy and data for action;
  • preventing of transmission; and
  • executing screening, care and treatment.

WHO also organizes World Hepatitis Day on July 28 every year to increase awareness and understanding of viral hepatitis.

 

Cabergoline therapy for cushing disease throughout pregnancy


CABERGOLINE

Obstet Gynecol. 2013 Aug;122(2 Pt 2):485-7. doi: 10.1097/AOG.0b013e31829e398a.

http://www.ncbi.nlm.nih.gov/pubmed/23884269
.
Woo I, Ehsanipoor RM.
Source
Department of Gynecology and Obstetrics and Division of Maternal-Fetal Medicine, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Abstract
BACKGROUND:
Cushing disease during pregnancy is rare and is associated with significant maternal and fetal morbidity and mortality. Transsphenoidal pituitary surgery is the first-line therapy; however, in cases of failed surgery or in patients who are not surgical candidates, medical therapy has been used to control symptoms.
CASE:
A 29-year-old woman with Cushing disease and a noncurative transsphenoidal pituitary surgery was successfully treated with cabergoline, a dopamine agonist. After approximately 1 year of therapy, she became pregnant. She was maintained on high-dose cabergoline throughout her pregnancy and had an uncomplicated antenatal course. She went into spontaneous labor at 38 weeks of gestation and delivered a healthy female neonate.
CONCLUSION:
Cabergoline can be used to manage Cushing disease successfully during pregnancy with an opportunity for a favorable outcome.

Cabergoline (brand names Dostinex and Cabaser), an ergot derivative, is a potent dopamine receptor agonist on D2 receptors. In vitro, rat studies show cabergoline has a direct inhibitory effect on pituitary lactotroph (prolactin) cells.[1] It is frequently used as a first-line agent in the management of prolactinomas due to higher affinity for D2 receptor sites, less severe side effects, and more convenient dosing schedule than the older bromocriptine.

History

Cabergoline was invented by scientists working for the Italian drug company Farmitalia-Carlo Erba SpA in Milan in 1981/82,[2] who were experimenting with semisynthetic derivatives of the ergot alkaloids. Farmitalia-Carlo Erba was acquired by Pharmacia in 1992, which in turn was acquired by Pfizer in 2002. The drug was approved by the FDA on December 23, 1996. It went generic in late 2005 following US patent expiration.

Intellectual property

Farmitalia filed a patent application for Cabergoline in 1982, and U.S. Patent 4,526,892 issued in July 1985.

Pharmacology

Although cabergoline is commonly described principally as a dopamine D2 receptor agonist, it also possesses significant affinity for the D3, D4, 5-HT1A, 5-HT2A, 5-HT2B, 5-HT2C, α2B receptors, and moderate/low affinity for the D1 and 5-HT7 receptors. Cabergoline functions as an agonist at all of these receptors except for 5-HT7 and α2B, where it acts as an antagonist.[3]

Following a single oral dose, resorption of cabergoline from the gastrointestinal (GI) tract is highly variable, typically occurring within 0.5 to 4 hours. Ingestion with food does not alter its absorption rate. Human bioavailability has not been determined since the drug is intended for oral use only. In mice and rats the absolute bioavailability has been determined to be 30 and 63 percent, respectively. Cabergoline is rapidly and extensively metabolized in the liver and excreted in bile and to a lesser extent in urine. All metabolites are less active than the parental drug or inactive altogether. The human elimination half-life is estimated to be 63 to 68 hours in patients with Parkinson’s disease and 79 to 115 hours in patients with pituitary tumors. Average elimination half-life is 80 hours.

The therapeutic effect in treatment of hyperprolactinemia will typically persist for at least 4 weeks after cessation of treatment.

Mechanism of action

Cabergoline is a long-acting dopamine D2 receptor agonist and in vitro rat studies show a direct inhibitory effect on the prolactin secretion in the pituitary’s lactotroph cells. Cabergoline decreased serum prolactin levels in reserpinized rats.

Receptor binding studies indicate a low affinity for dopamine D1 receptors, α1-adrenergic receptors, and α2-adrenergic receptors.[1]

  • Dostinex at www.rxlist.com”. Retrieved 2007-04-27.
  • 2 US Patent 4526892 – Dimethylaminoalkyl-3-(ergoline-8′.beta.carbonyl)-ureas
  • 3  Sharif NA, McLaughlin MA, Kelly CR, Katoli P, Drace C, Husain S, Crosson C, Toris C, Zhan GL, Camras C (March 2009). “Cabergoline: Pharmacology, ocular hypotensive studies in multiple species, and aqueous humor dynamic modulation in the Cynomolgus monkey eyes”. Experimental Eye Research 88 (3): 386–97. doi:10.1016/j.exer.2008.10.003. PMID 18992242.
  • National Institute ofMental Health. PDSD Ki Database (Internet) [cited 2013 Jul 24]. ChapelHill (NC): University of North Carolina. 1998-2013. Available from: http://pdsp.med.unc.edu/pdsp.php
  •  Sayyah-Melli, M; Tehrani-Gadim, S; Dastranj-Tabrizi, A; Gatrehsamani, F; Morteza, G; Ouladesahebmadarek, E; Farzadi, L; Kazemi-Shishvan, M (2009). “Comparison of the effect of gonadotropin-releasing hormone agonist and dopamine receptor agonist on uterine myoma growth. Histologic, sonographic, and intra-operative changes”. Saudi medical journal 30 (8): 1024–33. PMID 19668882edit

Sankaran, S.; Manyonda, I. (2008). “Medical management of fibroids”. Best Practice & Research Clinical Obstetrics & Gynaecology 22 (4): 655. doi:10.1016/j.bpobgyn.2008.03.001. PMID 18468953. edit http://www.britishfibroidtrust.org.uk/journals/bft_Sankaran.pdf

CUSHING DISEASE VIDEO

BEST WAYS TO COLON CLEANING


colon cleaning

 

LUMACAFTOR an Orphan drug in clinical trial for oral the treatment of cystic fibrosis


Lumacaftor

3-[6-[1-(2,2-Difluoro-1,3-benzodioxol-5-yl)cyclopropylcarboxamido]-3-methylpyridin-2-yl]benzoic acid

3-{6-{[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino}-3-methylpyridin-2-yl}benzoic acid

VRT-826809
VX-809

US patents:  US8124781, US8461342
Indication:Cystic fibrosis
Developmental status:Phase III (US, UK, EU)
Developer:Vertex

Vertex Pharmaceuticals
Company Vertex Pharmaceuticals Inc.
Description Small molecule cystic fibrosis transmembrane conductance regulator (CFTR) corrector
Molecular Target Cystic fibrosis transmembrane conductance regulator (CFTR)
Mechanism of Action CFTR stabilizer
Latest Stage of Development Phase III
Indication Cystic fibrosis (CF)
cas  936727-05-8

http://www.ama-assn.org/resources/doc/usan/lumacaftor.pdf  for all data

see……http://orgspectroscopyint.blogspot.in/2015/03/lumacaftor.html

Lumacaftor (USAN, codenamed VX-809) is an experimental drug for the treatment of cystic fibrosis being developed by Vertex Pharmaceuticals. The drug is designed to be effective in patients that have the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), the defective protein that causes the disease. F508del, meaning that the amino acid phenylalanine in position 508 is missing, is found in about 60% of cystic fibrosis patients in Europe,[1] and in about 90% of persons with some mutation in the CFTR gene.

A corrector molecule, one of two new classes of ion channel modulators. The corrector modulators enhance the number of channels of the CFTR protein at the cell surface. in combination with ivacaftor in homozygous F508del pts

Results from a Phase II clinical trial indicate that patients with the most common form of genetic mutation causing cystic fibrosis—homozygous F508del—had a mean increase of 7.4% in lung function (FEV1) on a combination of lumacaftor and ivacaftor.[2]

VX-809 is an investigational corrector compound in a phase II clinical trial for oral the treatment of cystic fibrosis. The trial will evaluate single and multiple doses of VX-809 in healthy volunteers. This compound has resulted from a collaboration with the Cystic Fibrosis Foundation Therapeutics, Inc. (CFFT) . In 2010, orphan drug designation was assigned in the E.U. and the U.S. for the treatment of CF.

VX-809 may act to restore the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, the defective cell membrane protein responsible for the progression of CF. VX-809 and other corrector compounds were designed to increase the amount of DF508-CFTR on the surface of cells lining the airway, which may result in an increase in chloride transport across the cell surface in patients with the DF508-CFTR mutation.

On January 11, 2013, the combination regimen of Lumacaftor (VX-809) and Kalydeco (Ivacaftor) was awarded by U.S. FDA with Breakthrough Therapy Designation as part of the agency’s efforts to accelerate the development and approval of drugs for serious and life-threatening disease.Breakthrough Therapy Designation for the combination regimen of VX-809 with ivacaftor was based on the Phase II combination data announced in 2012. Vertex Pharmaceuticals will report results from two Phase III trials (NCT01807949 (TRANSPORT) and NCT01807923 (TRAFFIC)) of the combination of Kalydeco + VX-809 in the middle of 2014. Positive data from TRAFFIC and TRANSPORT could open up a market with peak sales of approximately $6 billion, estimate analysts.

Lumacaftor skeletal.svg

  • 1      Merk; Schubert-Zsilavecz. Pharmazeutische Zeitung (in German) 156 (37): 24–27.
  • 2      Wilschanski, M. (2013). “Novel therapeutic approaches for cystic fibrosis”. Discovery medicine 15 (81): 127–133. PMID 23449115

see……http://orgspectroscopyint.blogspot.in/2015/03/lumacaftor.htm

…………………………

PATENT

 http://www.google.com/patents/EP2639222A1?cl=en

  • CFTR correctors useful in the treatment of cystic fibrosis. Such compounds include 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (hereinafter “Compound 1”) which has the structure below:

  • Compound 1 and pharmaceutically acceptable compositions thereof are useful for treating or lessening the severity of a variety of CFTR mediated diseases.
  • Scheme 1. Synthesis of the acid chloride moiety.

Scheme 2. Synthesis of the amine moiety.

Scheme 3. Formation of an acid salt of 3-(6-(1-(2,2-difluorobcnzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid.

  • Synthesis of 3-(6-(1-(2,2-difluorobenzord[d][1,3]dioxol-5-yl) cyclopropancearboxamido)-3-methylpyridin-2-yl)benzoic acid • HCl.
  • [0238]
    Acid Chloride Moiety
  • Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-methanol (Compound 18).

  • Commercially available 2,2-difluoro-1,3-benzodioxole-5-carboxylic acid (1.0 eq) is slurried in toluene (10 vol). Vitride® (2 eq) is added via addition funnel at a rate to maintain the temperature at 15-25 °C. At the end of addition the temperature is increased to 40 °C for 2 h then 10% (w/w) aq. NaOH (4.0 eq) is carefully added via addition funnel maintaining the temperature at 40-50 °C. After stirring for an additional 30 minutes, the layers are allowed to separate at 40 °C. The organic phase is cooled to 20 °C then washed with water (2 x 1.5 vol), dried (Na2SO4), filtered, and concentrated to afford crude Compound 18 that is used directly in the next step.
  • Synthesis of 5-chloromethyl-2,2-difluoro-1,3-benzodioxole (Compound 19).

  • Compound 18 (1.0 eq) is dissolved in MTBE (5 vol). A catalytic amount of DMAP (1 mol %) is added and SOCl2 (1.2 eq) is added via addition funnel. The SOCl2 is added at a rate to maintain the temperature in the reactor at 15-25 °C. The temperature is increased to 30 °C for 1 hour then cooled to 20 °C then water (4 vol) is added via addition funnel maintaining the temperature at less than 30 °C. After stirring for an additional 30 minutes, the layers are allowed to separate. The organic layer is stirred and 10% (w/v) aq. NaOH (4.4 vol) is added. After stirring for 15 to 20 minutes, the layers are allowed to separate. The organic phase is then dried (Na2SO4), filtered, and concentrated to afford crude Compound 19 that is used directly in the next step.
  • Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile (compound 20).

  • A solution of Compound 19 (1 eq) in DMSO (1.25 vol) is added to a slurry of NaCN (1.4 eq) in DMSO (3 vol) maintaining the temperature between 30-40 °C. The mixture is stirred for 1 hour then water (6 vol) is added followed by MTBE (4 vol). After stirring for 30 min, the layers are separated. The aqueous layer is extracted with MTBE (1.8 vol). The combined organic layers are washed with water (1.8 vol), dried (Na2SO4), filtered, and concentrated to afford crude compound 20 (95%) that is used directly in the next step.
  • Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile (compound 21).

  • A mixture of compound 20 (1.0 eq), 50 wt % aqueous KOH (5.0 eq) 1-bromo-2-chloroethane (1.5 eq), and Oct4NBr (0.02 eq) is heated at 70 °C for 1 h. The reaction mixture is cooled then worked up with MTBE and water. The organic phase is washed with water and brine then the solvent is removed to afford compound 21.
  • Synthesis of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (compound 22).

  • Compound 21 is hydrolyzed using 6 M NaOH (8 equiv) in ethanol (5 vol) at 80 °C overnight. The mixture is cooled to room temperature and ethanol is evaporated under vacuum. The residue is taken into water and MTBE, 1 M HCl was added and the layers are separated. The MTBE layer was then treated with dicyclohexylamine (0.97 equiv). The slurry is cooled to 0 °C, filtered and washed with heptane to give the corresponding DCHA salt. The salt is taken into MTBE and 10% citric acid and stirred until all solids dissolve. The layers are separated and the MTBE layer was washed with water and brine. Solvent swap to heptane followed by filtration gives compound 22 after drying in a vacuum oven at 50 °C overnight.
  • Synthesis of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonyl chloride (compound 7).

  • Compound 22 (1.2 cq) is slurried in toluene (2.5 vol) and the mixture heated to 60 °C. SOCl2 (1.4 eq) is added via addition funnel. The toluene and SOCl2 are distilled from the reaction mixture after 30 minutes. Additional toluene (2.5 vol) is added and distilled again.
  • Synthesis of 14C-(2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile (compound 23).

  • A solution of Compound 19 (1 eq) in DMSO (1.25 vol) is added to a slurry of Na14 CN (1.4 eq) in DMSO (3 vol) maintaining the temperature between 30-40 °C. The mixture is stirred for 1 hour then water (6 vol) is added followed by MTBE (4 vol). After stirring for 30 min, the layers are separated. The aqueous layer is extracted with MTBE (1.8 vol). The combined organic layers are washed with water (1.8 vol), dried (Na2SO4), filtered, and concentrated to afford crude compound 23 that is purified by chromatography.
  • Synthesis of 14C-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile (compound 24).

  • A mixture of compound 23 (1.0 eq) and 1,2-dibromoethane (1.8 eq) in THF (3 vol) is cooled to -10 °C via external chiller. 1 M LHMDS in THF (2.5 eq) is added via an addition funnel and at a rate to maintain the temperature in the reactor below 10 °C. One hour after addition is complete, 20% w/v aq. citric acid (13 vol) is added via addition funnel maintaining the temperature in the reactor below 20 C. The external chiller is turned off and after stirring for 30 min the layers are separated. The organic layer is filtered and concentrated to afford crude compound 24 that is purified by chromatography.
  • Synthesis of 14C-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid (compound 25).

  • Compound 24 is hydrolyzed using 6 M NaOH (8 equiv) in ethanol (5 vol) at 80 °C overnight. The mixture is cooled to room temperature and ethanol is evaporated under vacuum. The residue is taken into water and MTBE. 1 M HCl is added to the mixture and the organic layer is filtered and concentrated to afford compound 25.
  • Synthesis of 14C-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonyl chloride (compound 26).

  • A mixture of Compound 25, 4-dimethylaminopyridine, and thionyl chloride (SOCl2) in CH2Cl2 is stirred to produce compound 26, which may be further reacted with compound 6 without isolation.
  • Amine Moiety
  • Synthesis of tert-butyl-3-(3-methylpyridin-2-yl)benzoate (compound 4).

  • 2-Bromo-3-methylpyridine (1.0 eq) is dissolved in toluene (12 vol). K2CO3 (4.8 eq) is added followed by water (3.5 vol) and the mixture heated to 65 °C under a stream of N2 for 1 hour. 3-(t-Butoxycarbonyl)phenylboronic acid (1.05 eq) and Pd(dppf)Cl2-CH2Cl2 (0.015 eq) are then added and the mixture is heated to 80 °C. After 2 hours, the heat is turned off, water is added (3.5 vol) and the layers are allowed to separate. The organic phase is then washed with water (3.5 vol) and extracted with 10% aqueous methanesulfonic acid (2 eq MsOH, 7.7 vol). The aqueous phase is made basic with 50% aqueous NaOH (2 eq) and extracted with EtOAc (8 vol). The organic layer is concentrated to afford crude compound 4 (82%) that is used directly in the next step.
  • Synthesis of 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide (compound 5).

  • Compound 4 (1.0 eq) is dissolved in EtOAc (6 vol). Water (0. 3 vol) is added followed by urea-hydrogen peroxide (3 cq). The phthalic anhydride (3 cq) is added portion-wise as a solid to maintain the temperature in the reactor below 45 °C. After completion of phthalic anhydride addition, the mixture is heated to 45 °C. After stirring for an additional 4 hours, the heat is turned off. 10% w/w aqueous Na2SO3 (1.5 eq) is added via addition funnel. After completion of Na2SO3 addition, the mixture is stirred for an additional 30 minutes and the layers separated. The organic layer is stirred and 10% w/w aq. Na2CO3 (2 eq) is added. After stirring for 30 minutes, the layers are allowed to separate. The organic phase is washed 13% w/v aq NaCl. The organic phase is then filtered and concentrated to afford crude compound 5 (95%) that is used directly in the next step.
  • Synthesis of tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate (compound 6).

  • A solution of compound 5 (1 eq) and pyridine (4 eq) in MeCN (8 vol) is heated to 70 °C. A solution of methanesulfonic anhydride (1.5 eq) in MeCN (2 vol) is added over 50 min via addition funnel maintaining the temperature at less than 75 °C. The mixture is stirred for an additional 0.5 hours after complete addition. The mixture is then allowed to cool to ambient. Ethanolamine (10 eq) is added via addition funnel. After stirring for 2 hours, water (6 vol) is added and the mixture is cooled to 10 °C. After stirring for NLT 3 hours, the solid is collected by filtration and washed with water (3 vol), 2:1 MeCN/water (3 vol), and MeCN (2×1.5 vol). The solid is dried to constant weight (<1% difference) in a vacuum oven at 50 °C with a slight N2 bleed to afford compound 6 as a red-yellow solid (53% yield).
  • Synthesis of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (compound 8).

  • Compound 7 is dissolved in toluene (2.5 vol based on acid chloride) and added via addition funnel to a mixture of compound 6 (1 eq), dimethylaminopyridine (DMAP, 0.02 eq), and triethylamine (3.0 cq) in toluene (4 vol based on compound 6). After 2 hours, water (4 vol based on compound 6) is added to the reaction mixture. After stirring for 30 minutes, the layers are separated. The organic phase is then filtered and concentrated to afford a thick oil of compound 8 (quantitative crude yield). MeCN (3 vol based on crude product) is added and distilled until crystallization occurs. Water (2 vol based on crude product) is added and the mixture stirred for 2 h. The solid is collected by filtration, washed with 1:1 (by volume) MeCN/water (2 x 1 vol based on crude product), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 °C with a slight N2 bleed to afford 3-(6-(1-(2,2-difluorobenzo[d] [1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate as a brown solid.
  • Syntheisis of Syntheisis of 3-(6-(1-(2,2-difluorobenzo[d] [1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid • HCL salt (compound 9).

  • To a slurry of compound 8 (1.0 eq) in MeCN (3.0 vol) is added water (0.83 vol) followed by concentrated aqueous HCl (0.83 vol). The mixture is heated to 45 ± 5 °C. After stirring for 24 to 48 hours the reaction is complete and the mixture is allowed to cool to ambient. Water (1.33 vol) is added and the mixture stirred. The solid is collected by filtration, washed with water (2 x 0.3 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 °C with a slight N2 bleed to afford compound 9 as an off-white solid.
  • Synthesis of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1).

  • A slurry of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid • HCl (1 eq) in water (10 vol) is stirred at ambient temperature. A sample is taken after stirring for 24 hours. The sample is filtered and the solid washed with water (2 x). The solid sample is submitted for DSC analysis. When DSC analysis indicates complete conversion to Compound 1, the solid is collected by filtration, washed with water (2 x 1.0 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 °C with a slight N2 bleed to afford Compound 1 as an off-white solid (98% yield).
  • Synthesis of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1) using water and base.

  • To a slurry of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid • HCl (1 eq) in water (10 vol) stirred at ambient temperature is added 50% w/w aq. NaOH (2.5 eq). The mixture is stirred for NLT 15 min or until a homogeneous solution. Concentrated HCl (4 eq) is added to crystallize Compound 1. The mixture is heated to 60 °C or 90 °C if needed to reduce the level of the t-butylbenzoate ester. The mixture is heated until HPLC analysis indicates NMT 0.8% (AUC) t-butylbenzoate ester. The mixture is then cooled to ambient and the solid is collected by filtration, washed with water (3 x 3.4 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 °C with a slight N2 bleed to afford Compound 1 as an off-white solid (97% yield).
  • Synthesis of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1) directly from benzoate.

  • A solution of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (1.0 eq) in formic acid (3.0 vol) is heated to 70 ± 10 °C. The reaction is continued until the reaction is complete (NMT 1.0% AUC 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate) or heating for NMT 8 h. The mixture is allowed to cool to ambient. The solution is added to water (6 vol) heated at 50 °C and the mixture stirred. The mixture is then heated to 70 ± 10 °C until the level of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate is NMT 0.8% (AUC). The solid is collected by filtration, washed with water (2 x 3 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 °C with a slight N2 bleed to afford Compound 1 as an off-white solid.
  • 1HNMR spectra of Compound 1 are shown in Figures 9-11 (Figures 9 and 10 depict Compound 1 in Form I in a 50 mg/mL, 0.5 methyl cellulose-polysorbate 80 suspension, and Figure 11 depicts Compound 1 as an HCl salt).
  • Table 3 below recites additional analytical data for Compound 1.
  • Table 3.

    Cmpd. No. LC/MS M+1 LC/RTmin NMR
    1 453.3 1.93 H NMR (400 MHz, DMSO-d6) 9.14 (s, 1H), 7.99-7.93 (m, 3H), 7.80-7.78 (m, 1H), 7.74-7.72 (m, 1H), 7.60-7.55 (m, 2H), 7.41-7.33 (m, 2H), 2.24 (s, 3H), 1.53-1.51 (m, 2H), 1.19-1.17 (m, 2H)

WO2002096421A1 * May 22, 2002 Dec 5, 2002 Neurogen Corp 5-substituted-2-arylpyridines as crf1 modulators
WO2004072038A1 * Feb 10, 2004 Aug 26, 2004 Vertex Pharma Processes for the preparation of n-heteroaryl-n-aryl-amines by reacting an n-aryl carbamic acid ester with a halo-heteroaryl and analogous processes
WO2007056341A1 Nov 8, 2006 May 18, 2007 Vertex Pharma Heterocyclic modulators of atp-binding cassette transporters
 see……http://orgspectroscopyint.blogspot.in/2015/03/lumacaftor.htm

References

David Andrew Siesel;Processes for producing cycloalkylcarboxamido-pyridine benzoic acids,US patent number US8124781 B2 ;Also published as   CA2707494A1, CN101910134A, EP2231606A2, EP2231606B1, EP2639222A1, EP2639223A1, EP2639224A1, US8592602, US20090176989, US20120190856, WO2009076142A2, WO2009076142A3;Filing date:Dec 4, 2008;Original Assignee:Vertex Pharmaceuticals Incorporated

David Andrew Siesel;Processes for producing cycloalkylcarboxamido-pyridine benzoic acids,US patent number US8461342 B2  ;Also published as  US20100036130, US20120203006, US20130274477, WO2010138484A2, WO2010138484A3;Original Assignee:Vertex Pharmaceuticals Incorporated

Van Goor, Fredrick F. et al;Pharmaceutical compositions in the treatment of CFTR-mediated diseases such as cystic fibrosis;PCT Int. Appl., WO2011133956

Van Goor, Fredrick F. et al;Pharmaceutical compositions in the treatment of CFTR-mediated diseases such as cystic fibrosis.PCT Int. Appl., WO2011133951

Van Goor, Fredrick F. et al;Pharmaceutical compositions for treatment of CFTR-mediated diseases;PCT Int. Appl., WO2011133953

Verwijs, Marinus Jacobus et al;Preparation and pharmaceutical compositions of Lumacaftor for the treatment of cystic fibrosis and other diseases associated with CFTR mutations;PCT Int. Appl., WO2011127241

Keshavarz-Shokri, Ali et al;Preparation of Lumacaftor for therapeutical use;PCT Int. Appl., WO2011127290

Siesel, David;A process for the preparation of solid forms of (((difluorobenzodioxolyl)cyclopropanecarboxamido)methylpyridinyl)benzoic acid;U.S. Pat. Appl. Publ., US20100036130

Siesel, David;A process for the preparation of solid forms of (((difluorobenzodioxolyl)cyclopropanecarboxamido)methylpyridinyl)benzoic acid;PCT Int. Appl., WO2010138484

Young, Christopher;Dosage units of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid;PCT Int. Appl., WO2010037066

Hadida-Ruah, Sara et al;paration of N-pyridinyl carboxamide derivatives as modulators of ATP-binding cassette transporters;U.S. Pat. Appl. Publ., 20080019915

Siesel, David;A process for the preparation of solid forms of (((difluorobenzodioxolyl)cyclopropanecarboxamido)methylpyridinyl)benzoic acid;PCT Int. Appl., WO2009076142

Hadida Ruah, Sara et al;Preparation of N-pyridinyl carboxamide derivatives as modulators of ATP-binding cassette transporters;PCT Int. Appl., WO2007056341

video on cystic fibrosis

second video

Update on 26 mar 2015


LUMACAFTOR
VX 809

3-[6-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-3-methylpyridin-2-yl]benzoic Acid
CAS No.: 936727-05-8
Synonyms:
  • VX-809 (Lumacaftor);
  • VX-809;
  • Lumacaftor;
  • 3-(6-{[1-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-cyclopropanecarbonyl]-amino}-3-methyl-pyridin-2-yl)-benzoic acid;
  • 3-(6-(1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid;
Formula: C24H18F2N2O5
Exact Mass: 452.11800

SMILLES….    Cc1ccc(nc1c2cccc(c2)C(=O)O)NC(=O)C3(CC3)c4ccc5c(c4)OC(O5)(F)F

NMR…………….http://file.selleckchem.com/downloads/nmr/S156503-VX-809-HNMR-Selleck.pdf

 PATENT
  • Synthesis of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1) directly from benzoate.
    Figure imgb0101
  • A solution of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (1.0 eq) in formic acid (3.0 vol) is heated to 70 ± 10 °C. The reaction is continued until the reaction is complete (NMT 1.0% AUC 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate) or heating for NMT 8 h. The mixture is allowed to cool to ambient. The solution is added to water (6 vol) heated at 50 °C and the mixture stirred. The mixture is then heated to 70 ± 10 °C until the level of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate is NMT 0.8% (AUC). The solid is collected by filtration, washed with water (2 x 3 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 °C with a slight N2 bleed to afford Compound 1 as an off-white solid.
  • 1HNMR spectra of Compound 1 are shown in Figures 9-11 (Figures 9 and 10 depict Compound 1 in Form I in a 50 mg/mL, 0.5 methyl cellulose-polysorbate 80 suspension, and Figure 11 depicts Compound 1 as an HCl salt).
  • Table 3 below recites additional analytical data for Compound 1.
  • Table 3.
    Cmpd. No. LC/MS M+1 LC/RTmin NMR
    1 453.3 1.93 H NMR (400 MHz, DMSO-d6) 9.14 (s, 1H), 7.99-7.93 (m, 3H), 7.80-7.78 (m, 1H), 7.74-7.72 (m, 1H), 7.60-7.55 (m, 2H), 7.41-7.33 (m, 2H), 2.24 (s, 3H), 1.53-1.51 (m, 2H), 1.19-1.17 (m, 2H)

logo
1H NMR PREDICT

 3-[6-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-3-methylpyridin-2-yl]benzoic acid NMR spectra analysis, Chemical CAS NO. 936727-05-8 NMR spectral analysis, 3-[6-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-3-methylpyridin-2-yl]benzoic acid H-NMR spectrum
13C NMR PREDICT3-[6-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-3-methylpyridin-2-yl]benzoic acid NMR spectra analysis, Chemical CAS NO. 936727-05-8 NMR spectral analysis, 3-[6-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-3-methylpyridin-2-yl]benzoic acid C-NMR spectrumCAS NO. 936727-05-8, 3-[6-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-3-methylpyridin-2-yl]benzoic acid C-NMR spectral analysisCOSY PREDICT

13C NMR PREDICT

WO2002096421A1 * May 22, 2002 Dec 5, 2002 Neurogen Corp 5-substituted-2-arylpyridines as crf1 modulators
WO2004072038A1 * Feb 10, 2004 Aug 26, 2004 Vertex Pharma Processes for the preparation of n-heteroaryl-n-aryl-amines by reacting an n-aryl carbamic acid ester with a halo-heteroaryl and analogous processes
WO2007056341A1 Nov 8, 2006 May 18, 2007 Vertex Pharma Heterocyclic modulators of atp-binding cassette transporters
Patent

http://www.google.co.in/patents/US8124781

Figure US08124781-20120228-C00074

Figure US08124781-20120228-C00075

Figure US08124781-20120228-C00076

Synthesis of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic Acid (Compound 1)

Figure US08124781-20120228-C00093
A slurry of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid.HCl (1 eq) in water (10 vol) is stirred at ambient temperature. A sample is taken after stirring for 24 hours. The sample is filtered and the solid washed with water (2×). The solid sample is submitted for DSC analysis. When DSC analysis indicates complete conversion to Compound 1, the solid is collected by filtration, washed with water (2×1.0 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60° C. with a slight Nbleed to afford Compound 1 as an off-white solid (98% yield).

Synthesis of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic Acid (Compound 1) Using Water and Base

Figure US08124781-20120228-C00094
To a slurry of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid.HCl (1 eq) in water (10 vol) stirred at ambient temperature is added 50% w/w aq. NaOH (2.5 eq). The mixture is stirred for NLT 15 min or until a homogeneous solution. Concentrated HCl (4 eq) is added to crystallize Compound 1. The mixture is heated to 60° C. or 90° C. if needed to reduce the level of the t-butylbenzoate ester. The mixture is heated until HPLC analysis indicates NMT 0.8% (AUC) t-butylbenzoate ester. The mixture is then cooled to ambient and the solid is collected by filtration, washed with water (3×3.4 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60° C. with a slight Nbleed to afford Compound 1 as an off-white solid (97% yield).

Synthesis of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic Acid (Compound 1) Directly from Benzoate

Figure US08124781-20120228-C00095
A solution of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (1.0 eq) in formic acid (3.0 vol) is heated to 70±10° C. The reaction is continued until the reaction is complete (NMT 1.0% AUC 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate) or heating for NMT 8 h. The mixture is allowed to cool to ambient. The solution is added to water (6 vol) heated at 50° C. and the mixture stirred. The mixture is then heated to 70±10° C. until the level of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate is NMT 0.8% (AUC). The solid is collected by filtration, washed with water (2×3 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60° C. with a slight Nbleed to afford Compound 1 as an off-white solid.
……………….
WO2011127241

Compound 1

Compound 1 is used as the starting point for the other solid state forms and can be prepared by coupling an acid chloride moiety with an amine moiety according to Schemes 1-4.

Scheme 1. Synthesis of the acid chloride moiety.

1. NaCN

2. H20

socio

Scheme 1 depicts the preparation of l-(2,2-difluorobenzo[d][l,3]dioxol-5- yl)cyclopropanecarbonyl chloride, which is used in Scheme 3 to make the amide linkage of Compound 1.

The starting material, 2,2-difluorobenzo[d][l,3]dioxole-5-carboxylic acid, is commercially available from Saltigo (an affiliate of the Lanxess Corporation). Reduction of the carboxylc acid moiety in 2,2-difluorobenzo[d][l ,3]dioxole-5-carboxylic acid to the primary alcohol, followed by conversion to the corresponding chloride using thionyl chloride (SOCl2), provides 5-(chloromethyl)-2,2-difluorobenzo[d][l,3]dioxole, which is subsequently converted to 2-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)acetonitrile using sodium cyanide. Treatment of 2-(2,2- difluorobenzo[d][l,3]dioxol-5-yl)acetonitrile with base and l-bromo-2-chloroethane provides 1- (2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarbonitrile. The nitrile moiety in l-(2,2- difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarbonitrile is converted to a carboxylic acid using base to give l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxylic acid, which is converted to the desired acid chloride using thionyl chloride.

Scheme 2. Alternative synthesis of the acid chloride moiety.

Touene, H20, 70 °C3 N HC1,

DMSO,

75 °C

Scheme 2 depicts an alternative synthesis of the requisite acid chloride. 5- bromomethyl-2,2-difluoro-l,3-benzodioxole is coupled with ethyl cyanoacetate in the presence of a palladium catalyst to form the corresponding alpha cyano ethyl ester. Saponification of the ester moiety to the carboxylic acid gives the cyanoethyl compound. Alkylation of the cyanoethyl compound with l-bromo-2-chloro ethane in the presence of base gives the cyanocyclopropyl compound. Treatment of the cyanocyclopropyl compound with base gives the carboxylate salt, which is converted to the carboxylic acid by treatment with acid. Conversion of the carboxylic acid to the acid chloride is then accomplished using a chlorinating agent such as thionyl chloride or the like.

Scheme 3. Synthesis of the amine moiety.

ptBu urea-hydrogen peroxide hthalic anhydride EtOAc, water

Scheme 3 depicts the preparation of the requisite tert-butyl 3-(6-amino-3- methylpyridin-2-yl)benzoate, which is coupled with l-(2,2-difluorobenzo[d][l,3]dioxol-5- yl)cyclopropanecarbonyl chloride in Scheme 3 to give Compound 1. Palladium-catalyzed coupling of 2-bromo-3-methylpyridine with 3-(tert-butoxycarbonyl)phenylboronic acid gives tert-butyl 3-(3-methylpyridin-2-yl)benzoate, which is subsequently converted to the desired compound. Scheme 4. Formation of an acid salt of 3-(6-(l-(2,2-difluorobenzo[d] [l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid.

Scheme 4 depicts the coupling of l-(2,2-difluorobenzo[d][l,3]dioxol-5- yl)cyclopropanecarbonyl chloride with tert-butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate using triethyl amine and 4-dimethylaminopyridine to initially provide the tert-butyl ester of Compound 1.

……………………..

WO2010037066

http://www.google.im/patents/WO2010037066A2?cl=en

Syntheisis of 3-(6-(l-(2,2-difluorobenzo[d] [l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid • HCL salt.

HCl

To a slurry of 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (1.0 eq) in MeCN (3.0 vol) is added water (0.83 vol) followed by concentrated aqueous HCl (0.83 vol). The mixture is heated to 45 ± 5 0C. After stirring for 24 to 48 hours the reaction is complete and the mixture is allowed to cool to ambient. Water (1.33 vol) is added and the mixture stirred. The solid is collected by filtration, washed with water (2 x 0.3 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 0C with a slight N2 bleed to afford 3-(6-(l-(2,2- difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2- yl)benzoic acid • HCl as an off-white solid.

Synthesis of 3-(6-(l-(2,2-difluorobenzo[d] [l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1 in Form I).

HCl

Compound 1 in Form I

A slurry of 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid • HCl (1 eq) in water (10 vol) is stirred at ambient temperature. A sample is taken after stirring for 24 hours. The sample is filtered and the solid washed with water (2 x). The solid sample is submitted for DSC analysis. When DSC analysis indicates complete conversion to Compound 1, the solid is collected by filtration, washed with water (2 x 1.0 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 0C with a slight N2 bleed to afford Compound 1 as an off-white solid (98% yield).

Synthesis of 3-(6-(l-(2,2-difluorobenzo[d] [l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1 in Form I) using water and base.

Compound 1 in Form I

To a slurry of 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid • HCl (1 eq) in water (10 vol) stirred at ambient temperature is added 50% w/w aq. NaOH (2.5 eq). The mixture is stirred for NLT 15 min or until a homogeneous solution. Concentrated HCl (4 eq) is added to crystallize Compound 1. The mixture is heated to 60 0C or 90 0C if needed to reduce the level of the t-butylbenzoate ester. The mixture is heated until HPLC analysis indicates NMT 0.8% (AUC) t-butylbenzoate ester. The mixture is then cooled to ambient and the solid is collected by filtration, washed with water (3 x 3.4 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 0C with a slight N2 bleed to afford Compound 1 as an off-white solid (97% yield).

Synthesis of 3-(6-(l-(2,2-difluorobenzo[d] [l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid (Compound 1 in Form I) directly from benzoate.

Compound 1 in Form I

A solution of 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (1.0 eq) in formic acid (3.0 vol) is heated to 70 ± 10 0C. The reaction is continued until the reaction is complete (NMT 1.0% AUC 3-(6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate) or heating for NMT 8 h. The mixture is allowed to cool to ambient. The solution is added to water (6 vol) heated at 50 0C and the mixture stirred. The mixture is then heated to 70 ± 10 0C until the level of 3- (6-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin- 2-yl)-t-butylbenzoate is NMT 0.8% (AUC). The solid is collected by filtration, washed with water (2 x 3 vol), and partially dried on the filter under vacuum. The solid is dried to constant weight (<1% difference) in a vacuum oven at 60 0C with a slight N2 bleed to afford Compound 1 in Form I as an off-white solid.

 

First in Class Once-Daily Dual Bronchodilator Ultibro® Breezhaler® (QVA149) Gains Positive CHMP Opinion for the Treatment of COPD


The developer: Novartis, Vectura
Peak projections: $2 billion-$5 billion

TOKYO, July 27, 2013 /CNW/ –

http://www.newswire.ca/en/story/1203847/first-in-class-once-daily-dual-bronchodilator-ultibro-breezhaler-qva149-gains-positive-chmp-opinion-for-the-treatment-of-copd

  • QVA149 (indacaterol/glycopyrronium) is the first once-daily fixed-dose combination of both a LABA and a LAMA bronchodilator to gain positive CHMP opinion
  • Pivotal Phase III IGNITE data showed QVA149 significantly improved lung function and patient-reported outcomes including breathlessness and rescue medication use, compared to current standard of care[1]
  • QVA149 demonstrated significantly reduced rates of COPD exacerbations and improved health-related quality of life compared to open-label tiotropium 18 mcg and glycopyrronium 50 mcg[2],[3]

Sosei Group Corporation (“Sosei”; TSE Mothers Index: 4565) confirms the information released by Novartis that the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for approval of once-daily Ultibro® Breezhaler®(indacaterol 85 mcg/glycopyrronium 43 mcg delivered dose, equivalent to 110 mcg/50 mcg metered dose per capsule), as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Ultibro Breezhaler was developed under the name of QVA149.

QVA149 is an investigational fixed dose combination of two bronchodilators, indacaterol, a long-acting beta2-adrenergic agonist (LABA) and glycopyrronium, a long-acting muscarinic antagonist (LAMA).http://www.newswire.ca/en/story/1203847/first-in-class-once-daily-dual-bronchodilator-ultibro-breezhaler-qva149-gains-positive-chmp-opinion-for-the-treatment-of-copd

QVA149 is an inhaled fixed dose combination product for the treatment of COPD, an irreversible and chronic obstruction of the airways. The product combinesNVA237, the long acting muscarinic antagonist (LAMA) licensed to Novartis by Sosei in 2005, together with Novartis’ long acting beta agonist (LABA), indacaterol, now approved in more than 80 countries, including EU, Japan and the USA.

Both NVA237 and indacaterol are once-daily bronchodilators but act on different receptors in the lung thereby offering the potential in combination to provide additional patient benefit.

Phase III studies (IGNITE: Indacaterol and GlycopyrroNium bromide clInical sTudiEs) for QVA149 is one of the largest international patient registration programs in COPD comprising 10 studies and including more than 7,000 subjects across 42 countries. Up to date, Novartis announced positive results of five Phase III studies: SHINE, BRIGHT, ENLIGHTEN, ILLUMINATE and SPARK. IGNITE data demonstrated the efficacy of QVA149 and showed a superior effect on lung function and patient-reported outcomes versus comparators.

>> More

QVA149 was filed for approval in Europe in October, and in Japan in November 2012. The US filing is expected at the end of 2014.

About COPD

COPD is a chronic obstruction of the airways which in the developed world is caused primarily by smoking. Symptoms include chronic bronchitis and/or emphysema which slowly progress and eventually lead to a largely irreversible loss of lung function. Worldwide, COPD is estimated to affect a total of 210 million people and is projected to become the third leading cause of death by 2020.

Market Overview

COPD is a large and fast expanding market which is estimated to be worth around $9 billion (2008) and is expected to reach $14 billion by 2014 as a result of better recognition of the disease and improved treatment options.

indacaterol

glycoprronium

 

US OK for Forest/Pierre Fabre antidepressant fetzima, levomilnacipran


File:Levomilnacipran.svg

levomilnacipran

The US Food and Drug Administration has approved Forest Laboratories and Pierre Fabre’s Fetzima for major depressive disorder.

Fetzima (levomilnacipran extended-release), a once-daily serotonin and norepinephrine reuptake inhibitor, has been given the green light based on Phase III studies of adults with MDD and statistically significant and clinically meaningful improvement in depressive symptoms across three doses (40, 80, and 120 mg).

read all at

http://www.pharmatimes.com/Article/13-07-26/US_OK_for_Forest_Pierre_Fabre_antidepressant.aspx

Levomilnacipran (F2695) is an antidepressant currently under development by Forest Laboratories for the treatment of depression in the United States and Canada.[1][2][3] As of 2009 it is in phase III clinical trials.[4] Levomilnacipran is an active enantiomer of milnacipran and therefore has similar effects and pharmacology, acting as a serotonin-norepinephrine reuptake inhibitor.[2][5] On 20 January 2011, Forest and Pierre Fabre Medicament announced that levomilnacipran was no better than placebo in a late-stage clinical trial. Two other late-stage trials will be finished in mid-2011.

References

Vifor gets FDA approval for Injectafer


Switzerland’s Vifor Pharma is celebrating after getting the thumbs-up from US regulators for Injectafer for the treatment of iron deficiency anaemia.

The US Food and Drug Administration has approved the treatment, sold in Europe as Ferinject (ferric carboxymaltose) since getting the green light in 2007. Specifically, Injectafer will be available for the treatment of IDA in adults who have had an unsatisfactory response or are intolerant to oral iron.

The approval is based on two large trials conducted by Vifor’s US partner Luitpold Pharmaceuticals which studied more than 3,500 patients, of which 1,800 were treated with Injectafer.

read all at

http://www.pharmatimes.com/Article/13-07-26/Vifor_gets_FDA_approval_for_Injectafer.aspx

Ferric carboxymaltose
Chemical structure
The active substance of FERINJECT is a complex of polynuclear iron(III)-hydroxide with 4(R)-(poly-(1→4)-
O-α-D-glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hexanoate. The relative molecular weight is
approximately 150,000 Da, corresponding to the empirical formula:
[FeOx(OH)y(H2O)z]n [{(C6H10O5)m (C6H12O7)}l]k, where n ≈ 103, m ≈ 8, l ≈ 11, and k ≈ 4.
CAS-Number
9007-72-1

http://www.tga.gov.au/pdf/auspar/auspar-ferric.pdf     for structure

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