AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

Daratumumab

 Uncategorized  Comments Off on Daratumumab
Apr 262016
 

Daratumumab

(Darzalex®)Approved

An anti-CD38 monoclonal antibody used to treat multiple myeloma.

Research Code HuMax-CD-38; HuMaxCD-38

CAS No.

Daratumumab (HuMax®-CD38)

Daratumumab (Darzalex) is an anti-cancer drug. It binds to CD38.[1] Daratumumab was originally developed by Genmab, but it is now being jointly developed by Genmab along with the Johnson & Johnson subsidiary Janssen Biotech, which acquired worldwide commercialization rights to the drug from Genmab.[2]

Clinical trials

Encouraging preliminary results were reported in June 2012 from a Phase 1/2 clinical trial in relapsed multiple myeloma patients.[3]Updated trial results presented in December 2012 indicate daratumumab is continuing to show promising single-agent anti-myeloma activity.[4] A 2015 study compared monotherapy 8 and 16mg/kg at monthly to weekly intervals.[5]

In November 2015, the U.S. Food and Drug Administration approved daratumumab for treatement of multiple myeloma.[6]

Interference with blood compatibility testing

Daratumumab can also bind to CD38 present on red blood cells and interfere with antibody testing. Patients will show a panreactive antibody panel, including a positive auto-control. Treatment of the antibody panel cells with dithiothreitol (DTT) and repeating testing will effectively negate the binding of daratumumab to CD38 on the RBC surface; however, DTT also inactivates/destroys many antigens on the RBC surface by disrupting disulfide bonds. Fortunately, the only antigen system affected that is associated with common, clinically significant antibodies is Kell, making K-negative RBCs a reasonable alternative when urgent transfusion is indicated.[7]

Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through programmed cell death, or apoptosis, and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity.

Daratumumab is approved in the United States for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.

In May 2013, daratumumab received Fast Track Designation and Breakthrough Therapy Designation from the US FDA for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a PI and an immunomodulatory agent or who are double refractory to a PI and an immunomodulatory agent.  Breakthrough Therapy Designation is a program intended to expedite the development and review of drugs to treat serious or life-threatening diseases in cases where preliminary clinical evidence shows that the drug may provide substantial improvements over available therapy. Daratumumab has also received Orphan Drug Designation from the US FDA and the EMA for the treatment of multiple myeloma.

Five Phase III clinical studies with daratumumab in relapsed and frontline settings are currently ongoing. Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma and non-Hodgkin’s lymphoma.

Genmab announced a global license and development agreement for daratumumab with Janssen Biotech, Inc. in August 2012.  The agreement became effective in September 2012.

DARZALEX® (daratumumab) Approved by U.S. FDA: First Human Anti-CD38 Monoclonal Antibody Available for the Treatment of Multiple Myeloma

First-in-class immunotherapy approved for multiple myeloma patients who have received three or more prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double refractory to a PI and immunomodulatory agent
HORSHAM, PA, November 16, 2015 – Janssen Biotech, Inc., a Janssen Pharmaceutical Company of Johnson & Johnson, announced today the U.S. Food and Drug Administration (FDA) has approved DARZALEX® (daratumumab) injection for intravenous infusion for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.1 This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Multiple myeloma is an incurable blood cancer that occurs when malignant plasma cells grow uncontrollably in the bone marrow.2,3 Refractory cancer occurs when a patient’s disease is resistant to treatment or in the case of multiple myeloma, the disease progresses within 60 days of their last therapy.4,5 Relapsed cancer means the disease has returned after a period of initial, partial or complete remission.6

DARZALEX is the first human anti-CD38 monoclonal antibody (mAb) approved anywhere in the world. CD38 is a surface protein that is expressed by most, if not all, multiple myeloma cells.7 DARZALEX is believed to induce tumor cell death through multiple immune-mediated mechanisms of action,8,9 in addition to apoptosis, in which a series of molecular steps in a cell lead to its death.10 Its approval comes just two months after the Biologics License Application (BLA) was accepted for Priority Review by the FDA in September 2015.11 DARZALEX received Breakthrough Therapy Designation from the FDA for this indication in May 2013.12

“Multiple myeloma is a highly complex disease and remains incurable, with almost all patients relapsing or becoming resistant to therapy,” said DARZALEX clinical trial investigator Paul G. Richardson, M.D., Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute. “With DARZALEX, we have a promising new immunotherapy, which has shown pronounced efficacy as a single agent with an acceptable adverse event profile. This is especially important for treating these heavily pre-treated patients in whom all of the major classes of currently available medicines have failed.”

The pivotal open-label Phase 2 MMY2002 (SIRIUS) study showed treatment with single-agent DARZALEX resulted in an overall response rate (ORR) of 29.2 percent (95% CI; 20.8, 38.9) in patients who received a median of five prior lines of therapy, including a PI and an immunomodulatory agent.1

Stringent complete response (sCR) was reported in 2.8 percent of patients, very good partial response (VGPR) was reported in 9.4 percent of patients, and partial response (PR) was reported in 17 percent of patients.1 These efficacy results were based on ORR as determined by the Independent Review Committee assessment using IMWG (International Myeloma Working Group) criteria and the range for median duration of response.

For responders, the median duration of response was 7.4 months (range 1.2-13.1+ months).1 At baseline, 97 percent of patients were refractory to their last line of therapy, 95 percent were refractory to both a PI and an immunomodulatory agent, and 77 percent were refractory to alkylating agents.1 Additional efficacy data from the Phase 1/2 GEN501 monotherapy study – published in The New England Journal of Medicine in August 2015 – also support this approval.1

“The responses we saw in clinical trials that led to today’s approval were striking, especially considering that these patients received a median of five prior lines of therapy,” said MMY2002 investigator Sagar Lonial, M.D., Chief Medical Officer, Winship Cancer Institute of Emory University and Professor and Executive Vice Chair, Department of Hematology and Medical Oncology, Emory University School of Medicine. “It appears the mechanism of action for daratumumab (DARZALEX) may play an important role in its single-agent activity among this group of advanced-stage multiple myeloma patients.”

“Living with multiple myeloma is challenging, both physically and emotionally, especially as the disease progresses and treatment options become more limited,” said Debby Graff, a patient enrolled in a clinical trial at Dana-Farber Cancer Institute. “I am encouraged by emerging treatments for multiple myeloma, and I have a new outlook on my path forward.”

“While there have been considerable improvements over the past decade in the treatment of people living with multiple myeloma, these patients face a long, hard road – especially those whose disease has relapsed or is no longer responding to current therapies,” said Walter M. Capone, President and Chief Executive Officer of the Multiple Myeloma Research Foundation (MMRF). “With the approval of daratumumab, a new antibody option targeting CD38, along with ongoing work to advance the development of novel classes of therapies by both Janssen and MMRF, we are ushering in a new era of myeloma therapy focused on individualized treatment approaches for patients with significant unmet needs.”

“Our focus is developing transformational medicines for people living with hard-to-treat cancers, such as multiple myeloma,” said Peter F. Lebowitz, M.D., Ph.D., Global Oncology Head, Janssen. “The rapid development and approval of DARZALEX – the first human anti-CD38 monoclonal antibody – is a great example of this commitment and our ongoing work in developing immunotherapies. We will continue to study this compound as both a mono- and a combination therapy to understand its full clinical benefit for patients across the treatment continuum in multiple myeloma and other tumor types.”

The warnings and precautions for DARZALEX include infusion reactions, interference with serological testing and interference with determination of complete response (see Important Safety Information).1 The most frequently reported adverse reactions (incidence ≥20%) were: fatigue, nausea, back pain, pyrexia, cough and upper respiratory tract infection.1

In data from three pooled clinical studies including a total of 156 patients, four percent of patients discontinued treatment due to adverse reactions.1 Infusion reactions were reported in approximately half of all patients treated with DARZALEX.1 Common (≥5 percent) symptoms of infusion reactions included nasal congestion, chills, cough, allergic rhinitis, throat irritation, dyspnea (shortness of breath) and nausea.1 Severe infusion reactions, including bronchospasm, dyspnea, hypoxia and hypertension (<2 percent each).1

The recommended dose of DARZALEX is 16 mg/kg body weight administered as an intravenous infusion.1 The dosing schedule begins with weekly administration (weeks 1-8) and reduces in frequency over time to every two weeks (weeks 9-24) and ultimately every four weeks (week 25 onwards until disease progression).1

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive license to develop, manufacture and commercialize DARZALEX.13 Janssen is currently the global sponsor of all but one clinical study. DARZALEX will be commercialized in the U.S. by Janssen Biotech, Inc.

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that occurs when malignant plasma cells grow uncontrollably in the bone marrow.2,3 Multiple myeloma is the third most common blood cancer in the U.S., following only leukemia and lymphoma.14 Approximately 26,850 new patients will be diagnosed with multiple myeloma, and approximately 11,240 people will die from the disease in the U.S. in 2015.15 Globally, it is estimated that 124,225 people will be diagnosed, and 87,084 will die from the disease in 2015.16,17 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms which can include bone problems, low blood counts, calcium elevation, kidney problems or infections.18 Patients who relapse after treatment with standard therapies (including PIs or immunomodulatory agents) typically have poor prognoses and few remaining options.3

Access to DARZALEX® (daratumumab) Injection, for Intravenous Infusion
DARZALEX (daratumumab) injection for intravenous infusion will be available for distribution in the U.S. within two weeks following FDA approval. Janssen Biotech offers comprehensive access and support information, resources and services to assist U.S. patients in gaining access to DARZALEX through the Janssen CarePath Program. For more information, health care providers or patients can contact: 1-844-55DARZA (1-844-553-2792). Information will also be available at www.DARZALEX.com. Dedicated case coordinators are available to work with both healthcare providers and patients.

Patients with private or commercial insurance may be eligible for the Janssen CarePath Savings Program for DARZALEX. Information on the enrollment process will be available online at www.darzalex.com/access-and-cost-support#affordability.

About DARZALEX® (daratumumab) Injection, for Intravenous Infusion
DARZALEX® (daratumumab) injection for intravenous infusion is indicated for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.1 This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. DARZALEX is the first human anti-CD38 monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (FDA) approval to treat multiple myeloma. DARZALEX is believed to induce tumor cell death through apoptosis, in which a series of molecular steps in a cell lead to its death1,10 and multiple immune-mediated mechanisms of action, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).1,8 More information will be available atwww.DARZALEX.com.

References

  1.  World Health Organization (2009). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 101” (PDF). WHO Drug Information 23 (2).
  2.  “‘Janssen Biotech Announces Global License and Development Agreement for Investigational Anti-Cancer Agent Daratumumab'”. Janssen Biotech. Retrieved 2013-01-31.
  3.  “ASCO: Drug Shows Promise in Myeloma”. MedPage Today.
  4.  “‘Daratumumab Continues To Show Promise For Relapsed/Refractory Myeloma Patients (ASH 2012)'”. The Myeloma Beacon. Retrieved 2013-01-31.
  5.  Lokhorst, Henk M.; Plesner, Torben; Laubach, Jacob P.; Nahi, Hareth; Gimsing, Peter; Hansson, Markus; Minnema, Monique C.; Lassen, Ulrik; Krejcik, Jakub (2015-09-24). “Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma”. The New England Journal of Medicine 373 (13): 1207–1219. doi:10.1056/NEJMoa1506348. ISSN 1533-4406. PMID 26308596.
  6.  http://www.medscape.com/viewarticle/854548?nlid=91686_3663&src=wnl_edit_newsal&uac=78316PX&impID=890536&faf=1
  7.  Chapuy, CI; Nicholson, RT; Aguad, MD; Chapuy, B; Laubach, JP; Richardson, PG; Doshi, P; Kaufman, RM (June 2015). “Resolving the daratumumab interference with blood compatibility testing.”. Transfusion 55 (6 Pt 2): 1545–54. PMID 25764134.
Daratumumab
Monoclonal antibody
Type Whole antibody
Source Human
Target CD38
Legal status
Legal status
Identifiers
CAS Number 945721-28-8 
ATC code none
ChemSpider none
UNII 4Z63YK6E0E Yes
Chemical data
Formula C6466H9996N1724O2010S42
Molar mass 145,391.67 g·mol−1

////Daratumumab

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Idarucizumab

 Uncategorized  Comments Off on Idarucizumab
Apr 262016
 

 

Idarucizumab

(Praxbind®) Approved

An antidote for rapid reversal of dabigatran-induced anticoagulation indicated for emergency surgery (urgent procedures) and life-threatening or uncontrolled bleeding in patients treated with dabigatran.

BI-655075

CAS No.1362509-93-0

1-​225-​Immunoglobulin G1, anti-​(dabigatran) (human-​Mus musculus γ1-​chain) (225→219′)​-​disulfide with immunoglobulin G1, anti-​(dabigatran) (human-​Mus musculus κ-​chain)

Other Names

  • BI 655075
  • Idarucizumab
  • Praxbind

Protein Sequence

Sequence Length: 444, 225, 219multichain; modified (modifications unspecified)

Idarucizumab, sold under the brand name Praxbind, is a monoclonal antibody designed for the reversal of anticoagulant effects ofdabigatran.[1][2]

This drug was developed by Boehringer Ingelheim Pharmaceuticals. A large study sponsored by the manufacturer found that idarucizumab effectively reversed anticoagulation by dabigatran within minutes.[3] It was FDA approved in October 2015.[4] In the United States the wholesale cost is $3500 US.[5]

On October 16, 2015, the U. S. Food and Drug Administration granted accelerated approval to idarucizumab (Praxbind  Injection, Boehringer Ingelheim Pharmaceuticals, Inc.) for the treatment of patients treated with dabigatran (Pradaxa) when reversal of the anticoagulant effects of dabigatran is needed for emergency surgery/urgent procedures, or in life-threatening or uncontrolled bleeding.
The approval was based on three randomized, placebo-controlled trials enrolling a total of 283 healthy volunteers who received either dabigatran and idarucizumab or dabigatran and placebo.  The primary endpoint in healthy volunteer trials was the reduction of unbound dabigatran to undetectable levels after the administration of 5 g idarucizumab.  This reduction of dabigatran plasma concentration was observed over the entire 24 hour observation period.
These trials are supported by an ongoing open-label trial in which data from 123 patients receiving dabigatran who had life-threatening or uncontrolled bleeding, or who required emergency surgery/urgent procedures was available for evaluation.  This open-label trial continues to enroll and follow patients. The primary endpoint is the reversal of dabigatran’s anticoagulant effect (measured by ecarin clotting time or dilute thrombin time) in the first four hours after administration of 5 g idarucizumab. In these 123 patients, the anticoagulant effect of dabigatran was completely reversed in more than 89% of patients within four hours of receiving idarucizumab.  Between 12 and 24 hours after idarucizumab administration, elevated coagulation parameters have been observed in a limited number of patients.
Safety data were evaluated in 224 healthy volunteers who received at least one dose of idarucizumab and 123 patients who received idarucizumab. Headache was the most common adverse event reported in more than 5% of healthy volunteers.  Among the 123 patients treated with idarucizumab in the ongoing open-label trial, adverse events reported in more than 5% of patients were hypokalemia, delirium, constipation, pyrexia and pneumonia.
Praxbind is the first approved reversal agent. It is specific for dabigatran.
Continued approval for this indication may be contingent upon the results of completion of the ongoing open-label trial.
The recommended dose for idarucizumab is 5 g (2.5g per vial) administered intravenously as two consecutive 2.5 g infusions or bolus injection by injecting both vials consecutively one after another via syringe.

References

  1.  Statement On A Nonproprietary Name Adopted By The USAN Council – Idarucizumab, American Medical Association.
  2.  World Health Organization (2013). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 109” (PDF). WHO Drug Information 27 (2).
  3.  Pollack, Charles V.; Reilly, Paul A.; Eikelboom, John; Glund, Stephan; Verhamme, Peter; Bernstein, Richard A.; Dubiel, Robert; Huisman, Menno V.; Hylek, Elaine M. (2015-08-06).“Idarucizumab for Dabigatran Reversal”. The New England Journal of Medicine 373 (6): 511–520. doi:10.1056/NEJMoa1502000. ISSN 1533-4406. PMID 26095746.
  4.  “Press Announcements – FDA approves Praxbind, the first reversal agent for the anticoagulant Pradaxa”. www.fda.gov. Retrieved 2015-10-17.
  5.  Elia, Joe. “Dabigatran-Reversal Agent Price Set”. Retrieved 20 October 2015.
Idarucizumab
Monoclonal antibody
Type Fab fragment
Source Humanized (from mouse)
Target Dabigatran
Clinical data
Trade names Praxbind
Identifiers
CAS Number 1362509-93-0
ATC code V03AB37 (WHO)
IUPHAR/BPS 8298
ChemSpider none
Chemical data
Formula C2131H3299N555O671S11
Molar mass 47.8 kg/mol

/////Idarucizumab

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Asfotase alfa

 Uncategorized  Comments Off on Asfotase alfa
Apr 262016
 

 STR1

> Asfotase Alfa Sequence
LVPEKEKDPKYWRDQAQETLKYALELQKLNTNVAKNVIMFLGDGMGVSTVTAARILKGQL
HHNPGEETRLEMDKFPFVALSKTYNTNAQVPDSAGTATAYLCGVKANEGTVGVSAATERS
RCNTTQGNEVTSILRWAKDAGKSVGIVTTTRVNHATPSAAYAHSADRDWYSDNEMPPEAL
SQGCKDIAYQLMHNIRDIDVIMGGGRKYMYPKNKTDVEYESDEKARGTRLDGLDLVDTWK
SFKPRYKHSHFIWNRTELLTLDPHNVDYLLGLFEPGDMQYELNRNNVTDPSLSEMVVVAI
QILRKNPKGFFLLVEGGRIDHGHHEGKAKQALHEAVEMDRAIGQAGSLTSSEDTLTVVTA
DHSHVFTFGGYTPRGNSIFGLAPMLSDTDKKPFTAILYGNGPGYKVVGGERENVSMVDYA
HNNYQAQSAVPLRHETHGGEDVAVFSKGPMAHLLHGVHEQNYVPHVMAYAACIGANLGHC
APASSLKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV
KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE
KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKDIDDDD
DDDDDD

Asfotase alfa

Indicated for the treatment of patients with perinatal/infantile and juvenile onset hypophosphatasia (HPP).

(Strensiq®)Approved

A mineralized tissue targeted fusion protein used to treat hypophosphatasia.

Research Code ALXN-1215; ENB-0040; sALP-FcD-10

CAS No.1174277-80-5

180000.0

C7108H11008N1968O2206S56

Company Alexion Pharmaceuticals Inc.
Description Fusion protein incorporating the catalytic domain of human tissue non-specific alkaline phosphatase (TNSALP; ALPL) and a bone-targeting peptide
Molecular Target
Mechanism of Action Enzyme replacement therapy
Therapeutic Modality Biologic: Fusion protein
Latest Stage of Development Approved
Standard Indication Metabolic (unspecified)
Indication Details Treat hypophosphatasia (HPP); Treat hypophosphatasia (HPP) in children; Treat hypophosphatasia (HPP) in patients whose first signs or symptoms occurred prior to 18 years of age; Treat perinatal, infantile and juvenile-onset hypophosphatasia (HPP)
Regulatory Designation U.S. – Breakthrough Therapy (Treat hypophosphatasia (HPP) in children);
U.S. – Breakthrough Therapy (Treat hypophosphatasia (HPP) in patients whose first signs or symptoms occurred prior to 18 years of age);
U.S. – Fast Track (Treat hypophosphatasia (HPP));
U.S. – Orphan Drug (Treat hypophosphatasia (HPP));
U.S. – Priority Review (Treat hypophosphatasia (HPP) in children);
EU – Accelerated Assessment (Treat hypophosphatasia (HPP));
EU – Accelerated Assessment (Treat hypophosphatasia (HPP) in children);
EU – Orphan Drug (Treat hypophosphatasia (HPP));
Japan – Orphan Drug (Treat hypophosphatasia (HPP));
Australia – Orphan Drug (Treat hypophosphatasia (HPP)

Asfotase Alfa is a first-in-class bone-targeted enzyme replacement therapy designed to address the underlying cause of hypophosphatasia (HPP)—deficient alkaline phosphatase (ALP). Hypophosphatasia is almost always fatal when severe skeletal disease is obvious at birth. By replacing deficient ALP, treatment with Asfotase Alfa aims to improve the elevated enzyme substrate levels and improve the body’s ability to mineralize bone, thereby preventing serious skeletal and systemic patient morbidity and premature death. Asfotase alfa was first approved by Pharmaceuticals and Medicals Devices Agency of Japan (PMDA) on July 3, 2015, then approved by the European Medicine Agency (EMA) on August 28, 2015, and was approved by the U.S. Food and Drug Administration (FDA) on October 23, 2015. Asfotase Alfa is marketed under the brand name Strensiq® by Alexion Pharmaceuticals, Inc. The annual average price of Asfotase Alfa treatment is $285,000.

Hypophosphatasia (HPP) is a rare inheritable disease that results from loss-of-function mutations in the ALPL gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). Therapeutic options for treating the underlying pathophysiology of the disease have been lacking, with the mainstay of treatment being management of symptoms and supportive care. HPP is associated with significant morbidity and mortality in paediatric patients, with mortality rates as high as 100 % in perinatal-onset HPP and 50 % in infantile-onset HPP. Subcutaneous asfotase alfa (Strensiq(®)), a first-in-class bone-targeted human recombinant TNSALP replacement therapy, is approved in the EU for long-term therapy in patients with paediatric-onset HPP to treat bone manifestations of the disease. In noncomparative clinical trials in infants and children with paediatric-onset HPP, asfotase alfa rapidly improved radiographically-assessed rickets severity scores at 24 weeks (primary timepoint) as reflected in improvements in bone mineralization, with these benefits sustained after more than 3 years of treatment. Furthermore, patients typically experienced improvements in respiratory function, gross motor function, fine motor function, cognitive development, muscle strength (normalization) and ability to perform activities of daily living, and catch-up height-gain. In life-threatening perinatal and infantile HPP, asfotase alfa also improved overall survival. Asfotase alfa was generally well tolerated in clinical trials, with relatively few patients discontinuing treatment and most treatment-related adverse events being of mild to moderate intensity. Thus, subcutaneous asfotase alfa is a valuable emerging therapy for the treatment of bone manifestations in patients with paediatric-onset HPP.

 

FDA

October 23, 2015

Release

 Today, the U.S. Food and Drug Administration approved Strensiq (asfotase alfa) as the first approved treatment for perinatal, infantile and juvenile-onset hypophosphatasia (HPP).

HPP is a rare, genetic, progressive, metabolic disease in which patients experience devastating effects on multiple systems of the body, leading to severe disability and life-threatening complications. It is characterized by defective bone mineralization that can lead to rickets and softening of the bones that result in skeletal abnormalities. It can also cause complications such as profound muscle weakness with loss of mobility, seizures, pain, respiratory failure and premature death. Severe forms of HPP affect an estimated one in 100,000 newborns, but milder cases, such as those that appear in childhood or adulthood, may occur more frequently.

“For the first time, the HPP community will have access to an approved therapy for this rare disease,” said Amy G. Egan, M.D., M.P.H., deputy director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research (CDER). “Strensiq’s approval is an example of how the Breakthrough Therapy Designation program can bring new and needed treatments to people with rare diseases.”

Strensiq received a breakthrough therapy designation as it is the first and only treatment for perinatal, infantile and juvenile-onset HPP. The Breakthrough Therapy Designation program encourages the FDA to work collaboratively with sponsors, by providing timely advice and interactive communications, to help expedite the development and review of important new drugs for serious or life-threatening conditions. In addition to designation as a breakthrough therapy, the FDA granted Strensiq orphan drug designation because it treats a disease affecting fewer than 200,000 patients in the United States.

Orphan drug designation provides financial incentives, like clinical trial tax credits, user fee waivers, and eligibility for market exclusivity to promote rare disease drug development. Strensiq was also granted priority review, which is granted to drug applications that show a significant improvement in safety or effectiveness in the treatment of a serious condition. In addition, the manufacturer of Strensiq was granted a rare pediatric disease priority review voucher – a provision intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. Development of this drug was also in part supported by the FDA Orphan Products Grants Program, which provides grants for clinical studies on safety and/or effectiveness of products for use in rare diseases or conditions.

Strensiq is administered via injection three or six times per week. Strensiq works by replacing the enzyme (known as tissue-nonspecific alkaline phosphatase) responsible for formation of an essential mineral in normal bone, which has been shown to improve patient outcomes.

The safety and efficacy of Strensiq were established in 99 patients with perinatal (disease occurs in utero and is evident at birth), infantile- or juvenile-onset HPP who received treatment for up to 6.5 years during four prospective, open-label studies. Study results showed that patients with perinatal- and infantile-onset HPP treated with Strensiq had improved overall survival and survival without the need for a ventilator (ventilator-free survival). Ninety-seven percent of treated patients were alive at one year of age compared to 42 percent of control patients selected from a natural history study group. Similarly, the ventilator-free survival rate at one year of age was 85 percent for treated patients compared to less than 50 percent for the natural history control patients.

Patients with juvenile-onset HPP treated with Strensiq showed improvements in growth and bone health compared to control patients selected from a natural history database. All treated patients had improvement in low weight or short stature or maintained normal height and weight. In comparison, approximately 20 percent of control patients had growth delays over time, with shifts in height or weight from the normal range for children their age to heights and weights well below normal for age. Juvenile-onset patients also showed improvements in bone mineralization, as measured on a scale that evaluates the severity of rickets and other HPP-related skeletal abnormalities based on x-ray images. All treated patients demonstrated substantial healing of rickets on x-rays while some natural history control patients showed increasing signs of rickets over time.

The most common side effects in patients treated with Strensiq include injection site reactions, hypersensitivity reactions (such as difficulty breathing, nausea, dizziness and fever), lipodystrophy (a loss of fat tissue resulting in an indentation in the skin or a thickening of fat tissue resulting in a lump under the skin) at the injection site, and ectopic calcifications of the eyes and kidney.

Strensiq is manufactured by Alexion Pharmaceuticals Inc., based in Cheshire, Connecticut.

 

Patent Number Pediatric Extension Approved Expires (estimated)
US7763712 No 2004-04-21 2026-07-15

STRENSIQ is a formulation of asfotase alfa, which is a soluble glycoproteincomposed of two identical polypeptide chains. Each chain contains 726amino acids with a theoretical mass of 161 kDa. Each chain consists of the catalytic domain of human tissue non-specific alkaline phosphatase (TNSALP), the human immunoglobulin G1 Fc domain and a deca-aspartatepeptide used as a bone targeting domain. The two polypeptide chains are covalently linked by two disulfide bonds.

STRENSIQ is a tissue nonspecific alkaline phosphatase produced byrecombinant DNA technology in a Chinese hamster ovary cell line. TNSALP is a metallo-enzyme that catalyzes the hydrolysis of phosphomonoesters with release of inorganic phosphate and alcohol. Asfotase alfa has a specific activity of 620 to 1250 units/mg. One activity unit is defined as the amount of asfotase alfa required to form 1 μmol of p-nitrophenol from pNPP per minute at 37°C.

STRENSIQ (asfotase alfa) is a sterile, preservative-free, nonpyrogenic, clear, slightly opalescent or opalescent, colorless to slightly yellow, with few small translucent or white particles, aqueous solution for subcutaneous administration. STRENSIQ is supplied in glass single-use vials containing asfotase alfa; dibasic sodium phosphate, heptahydrate; monobasic sodium phosphate, monohydrate; and sodium chloride at a pH between 7.2 and 7.6. Table 5 describes the content of STRENSIQ vial presentations.

Table 5: Content of STRENSIQ Vial Presentations

 

INGREDIENT QUANTITY PER VIAL
ASFOTASE ALFA 18 MG/0.45 ML 28 MG/0.7 ML 40 MG/ML 80 MG/0.8 ML
Dibasic sodium phosphate, heptahydrate 2.48 mg 3.85 mg 5.5 mg 4.4 mg
Monobasic sodium phosphate, monohydrate 0.28 mg 0.43 mg 0.62 mg 0.5 mg
Sodium chloride 3.94 mg 6.13 mg 8.76 mg 7.01 mg

 

REFERNCES

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003794/WC500194340.pdf

  1. Whyte MP: Hypophosphatasia – aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2016 Apr;12(4):233-46. doi: 10.1038/nrendo.2016.14. Epub 2016 Feb 19. [PubMed:26893260 ]
  2. Whyte MP, Rockman-Greenberg C, Ozono K, Riese R, Moseley S, Melian A, Thompson DD, Bishop N, Hofmann C: Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile Hypophosphatasia. J Clin Endocrinol Metab. 2016 Jan;101(1):334-42. doi: 10.1210/jc.2015-3462. Epub 2015 Nov 3. [PubMed:26529632 ]
  3. Whyte MP, Greenberg CR, Salman NJ, Bober MB, McAlister WH, Wenkert D, Van Sickle BJ, Simmons JH, Edgar TS, Bauer ML, Hamdan MA, Bishop N, Lutz RE, McGinn M, Craig S, Moore JN, Taylor JW, Cleveland RH, Cranley WR, Lim R, Thacher TD, Mayhew JE, Downs M, Millan JL, Skrinar AM, Crine P, Landy H: Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med. 2012 Mar 8;366(10):904-13. doi: 10.1056/NEJMoa1106173. [PubMed:22397652 ]

//////Asfotase alfa, Strensiq, treat hypophosphatasia, ALXN-1215,  ENB-0040,  sALP-FcD-10, FDA 2015

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Reslizumab

 Uncategorized  Comments Off on Reslizumab
Apr 252016
 

Reslizumab

(Cinqair®) Approved Active, FDA 2016-03-23

An interleukin-5 (IL-5) antagonist used to treat severe asthma.

CAS  241473-69-8

Research Code CDP-835; CEP-38072; CTx-55700; SCH-5570; SCH-55700; TRFK-5,

Anti-interleukin-5 monoclonal antibody – Celltech/Schering-Plough

Reslizumab was approved by the U.S. Food and Drug Administration (FDA) on March 23, 2016. It was developed and marketed as Cinqair® by Teva.

Reslizumab is an interleukin-5 antagonist, which binds to human IL-5 and prevents it from binding to the IL-5 receptor, thereby reducing eosinophilic inflammation. It is indicated for the maintenance treatment of patients with severe asthma in patients aged 18 years and older.

Cinqair® is available as injection for intravenous infusion, containing 100 mg of reslizumab in 10 mL solution in single-use vials. The recommended dose is 3 mg/kg once every four weeks.

  • Originator Celltech R&D; Schering-Plough
  • Developer Celltech R&D; Teva Pharmaceutical Industries
  • Class Antiasthmatics; Monoclonal antibodies
  • Mechanism of Action Interleukin 5 receptor antagonists
  • Orphan Drug Status Yes – Oesophagitis

 

  • 23 Mar 2016 Registered for Asthma in USA (IV) – First global approval
  • 04 Mar 2016 Pooled efficacy data from two phase III trials in Asthma presented at the 2016 Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI-2016)
  • 10 Dec 2015 Preregistration for Asthma in Canada (IV)

 

Reslizumab (trade name Cinqair) is a humanized monoclonal antibody intended for the treatment of eosinophil-meditated inflammations of the airways, skin and gastrointestinal tract.[1] The FDA approved reslizumab for use with other asthma medicines for the maintenance treatment of severe asthma in patients aged 18 years and older on March 23, 2016. Cinqair is approved for patients who have a history of severe asthma attacks (exacerbations) despite receiving their current asthma medicines.[2]

Teva Announces FDA Acceptance of the Biologics License Application for Reslizumab

Investigational Biologic for the Treatment of Inadequately Controlled Asthma in Patients with Elevated Blood Eosinophils Accepted for Review

JERUSALEM–(BUSINESS WIRE)–Jun. 15, 2015– Teva Pharmaceutical Industries Ltd., (NYSE: TEVA) announced today that the U.S. Food and Drug Administration (FDA) has accepted for review the Biologics License Application (BLA) for reslizumab, the company’s investigational humanized monoclonal antibody (mAb) which targets interleukin-5 (IL-5), for the treatment of inadequately controlled asthma in adult and adolescent patients with elevated blood eosinophils, despite an inhaled corticosteroid (ICS)-based regimen.

“Despite currently available medicines, uncontrolled asthma remains a serious problem for patients, physicians and healthcare systems, highlighting the need for targeted new treatment options,” said Dr. Michael Hayden, President of Global R&D and Chief Scientific Officer at Teva Pharmaceutical Industries Ltd. “The reslizumab BLA filing acceptance represents a significant milestone for Teva as we work toward serving a specific asthma patient population that is defined by elevated blood eosinophil levels and inadequately controlled symptoms despite standard of care therapy. In clinical trials, patients treated with reslizumab showed significant reductions in the rate of asthma exacerbations and significant improvement in lung function. If approved, we believe reslizumab will serve as an important new targeted treatment option to achieve better asthma control for patients with eosinophil-mediated disease.”

The BLA for reslizumab includes data from Teva’s Phase III BREATH clinical trial program. The program consisted of four separate placebo-controlled Phase III trials involving more than 1,700 adult and adolescent asthma patients with elevated blood eosinophils, whose symptoms were inadequately controlled with inhaled corticosteroid-based therapies. Results from these studies demonstrated that reslizumab, in comparison to placebo, reduced asthma exacerbation rates by at least half and provided significant improvement in lung function and other secondary measures of asthma control when added to an existing ICS-based therapy. Common adverse events in the reslizumab treatment group were comparable to placebo and included worsening of asthma, nasopharyngitis, upper respiratory infections, sinusitis, influenza and headache. Two anaphylactic reactions were reported and resolved following medical treatment at the study site.

Results from the reslizumab BREATH program were recently presented at the American Thoracic Society 2015 Annual Meeting and the American Academy of Allergy, Asthma and Immunology 2015 Annual Meeting, in addition to being published in The Lancet Respiratory Medicine. The BLA for reslizumab has been accepted for filing by the FDA for standard review, with FDA Regulatory Action expected in March 2016.

About Reslizumab

Reslizumab is an investigational humanized monoclonal antibody which targets interleukin-5 (IL-5). IL-5 is a key cytokine involved in the maturation, recruitment, and activation of eosinophils, which are inflammatory white blood cells implicated in a number of diseases, such as asthma. Elevated levels of blood eosinophils are a risk factor for future asthma exacerbations. Reslizumab binds circulating IL-5 thereby preventing IL-5 from binding to its receptor.

About Asthma

Asthma is a chronic (long term) disease usually characterized by airway inflammation and narrowing of the airways, which can vary over time. Asthma may cause recurring periods of wheezing (a whistling sound when you breathe), chest tightness, shortness of breath and coughing that often occurs at night or early in the morning. Without appropriate treatment, asthma symptoms may become more severe and result in an asthma attack, which can lead to hospitalization and even death.

About Eosinophils

Eosinophils are a type of white blood cell that are present at elevated levels in the lungs and blood of many asthmatics. Evidence shows that eosinophils play an active role in the pathogenesis of the disease. IL-5 has been shown to play a crucial role in maturation, growth and activation of eosinophils. Increased levels of eosinophils in the sputum and blood have been shown to correlate with severity and frequency of asthma exacerbations.

About Teva

Teva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA) is a leading global pharmaceutical company that delivers high-quality, patient-centric healthcare solutions to millions of patients every day. Headquartered in Israel, Teva is the world’s largest generic medicines producer, leveraging its portfolio of more than 1,000 molecules to produce a wide range of generic products in nearly every therapeutic area. In specialty medicines, Teva has a world-leading position in innovative treatments for disorders of the central nervous system, including pain, as well as a strong portfolio of respiratory products. Teva integrates its generics and specialty capabilities in its global research and development division to create new ways of addressing unmet patient needs by combining drug development capabilities with devices, services and technologies. Teva’s net revenues in 2014 amounted to $20.3 billion. For more information, visit www.tevapharm.com.

USFDA

The U.S. Food and Drug Administration today approved Cinqair (reslizumab) for use with other asthma medicines for the maintenance treatment of severe asthma in patients aged 18 years and older. Cinqair is approved for patients who have a history of severe asthma attacks (exacerbations) despite receiving their current asthma medicines.

Asthma is a chronic disease that causes inflammation in the airways of the lungs. During an asthma attack, airways become narrow making it hard to breathe. Severe asthma attacks can lead to asthma-related hospitalizations because these attacks can be serious and even life-threatening. According to the Centers for Disease Control and Prevention, as of 2013, more than 22 million people in the U.S. have asthma, and there are more than 400,000 asthma-related hospitalizations each year.

“Health care providers and their patients with severe asthma now have another treatment option to consider when the disease is not well controlled by their current asthma therapies,” said Badrul Chowdhury, M.D., Ph.D., director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research.

Cinqair is administered once every four weeks via intravenous infusion by a health care professional in a clinical setting prepared to manage anaphylaxis. Cinqair is a humanized interleukin-5 antagonist monoclonal antibody produced by recombinant DNA technology in murine myeloma non-secreting 0 (NS0) cells. Cinqair reduces severe asthma attacks by reducing the levels of blood eosinophils, a type of white blood cell that contributes to the development of asthma.

The safety and efficacy of Cinqair were established in four double-blind, randomized, placebo‑controlled trials in patients with severe asthma on currently available therapies. Cinqair or a placebo was administered to patients every four weeks as an add-on asthma treatment. Compared with placebo, patients with severe asthma receiving Cinqair had fewer asthma attacks, and a longer time to the first attack. In addition, treatment with Cinqair resulted in a significant improvement in lung function, as measured by the volume of air exhaled by patients in one second.

Cinqair can cause serious side effects including allergic (hypersensitivity) reactions. These reactions can be life-threatening. The most common side effects in clinical trials for Cinqair included anaphylaxis, cancer, and muscle pain.

Cinqair is made by Teva Pharmaceuticals in Frazer, Pennsylvania.

 

References

 

 

Reslizumab
Monoclonal antibody
Type Whole antibody
Source Humanized (from rat)
Target IL-5
Clinical data
Trade names Cinquil
Identifiers
ATC code R03DX08 (WHO)
ChemSpider none

/////////CDP-835,  CEP-38072,  CTx-55700,  SCH-5570,  SCH-55700,  TRFK-5, Reslizumab, Cinqair®, teva, interleukin-5 (IL-5) antagonist, severe asthma, FDA 2016, Orphan Drug StatuS

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Lobeglitazone Sulfate

 Uncategorized  Comments Off on Lobeglitazone Sulfate
Apr 252016
 

Lobeglitazone.svg

 

Lobeglitazone Sulfate, CKD-501

(Duvie®) Approved

Chong Kun Dang (Originator)

A dual PPARα and PPARγ agonist used to treat type 2 diabetes.

Trade Name：Duvie®MOA：Dual PPARα and PPARγ agonistIndication：Type 2 diabetes

CAS No. 607723-33-1(FREE)

763108-62-9(Lobeglitazone Sulfate)

2,4-Thiazolidinedione, 5-((4-(2-((6-(4-methoxyphenoxy)-4- pyrimidinyl)methylamino)ethoxy)phenyl)methyl)-, sulfate (1:1);

Lobeglitazone sulfate.png

Lobeglitazone (trade name Duvie, Chong Kun Dang) is an antidiabetic drug in the thiazolidinedione class of drugs. As an agonistfor both PPARα and PPARγ, it works as an insulin sensitizer by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin.[3]

Lobeglitazone sulfate was approved by the Ministry of Food and Drug Safety (Korea) on July 4, 2013. It was developed and marketed as Duvie® by Chong Kun Dang Corporation.

Lobeglitazone is an agonist for both PPARα and PPARγ, and it works as an insulin sensitizer by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin. It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

Duvie® is available as tablet for oral use, containing 0.5 mg of free Lobeglitazone. The recommended dose is 0.5 mg once daily.

Lobeglitazone which was reported in our previous works belongs to the class of potent PPARα/γ dual agonists (PPARα EC50:  0.02 μM, PPARγ EC50:  0.018 μM, rosiglitazone; PPARα EC50:  >10 μM, PPARγ EC50:  0.02 μM, pioglitazone PPARα EC50:  >10 μM, PPARγ EC50:  0.30 μM). Lobeglitazone has excellent pharmacokinetic properties and was shown to have more efficacious in vivo effects in KKAy mice than rosiglitazone and pioglitazone.17 Due to its outstanding pharmacokinetic profile, lobeglitazone was chosen as a promising antidiabetes drug candidate.

Medical uses

Lobeglitazone is used to assist regulation of blood glucose level of diabetes mellitus type 2 patients. It can be used alone or in combination with metformin.[4]

Lobeglitazone was approved by the Ministry of Food and Drug Safety (Korea) in 2013, and the postmarketing surveillance is on progress until 2019.[4][5]

SYNTHESIS

STR1

 

 

PAPER

Org. Process Res. Dev. 2007, 11, 190-199.

Process Development and Scale-Up of PPAR α/γ Dual Agonist Lobeglitazone Sulfate (CKD-501)

Process Research and Development Laboratory, Chemical Research Group, Chong Kun Dang Pharmaceutical Cooperation, Cheonan P. O. Box 74, Cheonan 330-831, South Korea, and Department of Chemistry, Korea University, 5-1-2, Anam-Dong, Seoul 136-701, Korea
Org. Process Res. Dev., 2007, 11 (2), pp 190–199
DOI: 10.1021/op060087u

http://pubs.acs.org/doi/abs/10.1021/op060087u

Abstract Image

A scaleable synthetic route to the potent PPARα/γ dual agonistic agent, lobeglitazone (1), used for the treatment of type-2 diabetes was developed. The synthetic pathway comprises an effective five-step synthesis. This process involves a consecutive synthesis of the intermediate, pyrimidinyl aminoalcohol (6), from the commercially available 4,6-dichloropyrimidine (3) without the isolation of pyrimidinyl phenoxy ether (4). Significant improvements were also made in the regioselective 1,4-reduction of the intermediate, benzylidene-2,4-thiazolidinedione (10), using Hantzsch dihydropyridine ester (HEH) with silica gel as an acid catalyst. The sulfate salt form of lobeglitazone was selected as a candidate compound for further preclinical and clinical study. More than 2 kg of lobeglitazone sulfate (CKD-501, 2) was prepared in 98.5% purity after the GMP batch. Overall yield of 2 was improved to 52% from 17% of the original medicinal chemistry route.

 

Silica gel TLC Rf = 0.35 (detection:  iodine char chamber, ninhydrin solution, developing solvents:  CH2Cl2/MeOH, 20:1); mp 111.4 °C; IR (KBr) ν 3437, 3037, 2937, 2775, 1751, 1698, 1648, 1610, 1503, 1439, 1301, 1246, 1215, 1183 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.09 (m, 4H), 3.29 (m, 1H), 3.76 (s, 3H), 3.97 (m, 2H), 4.14 (m, 2H), 4.86 (m, 1H), 6.06 (bs, 1H), 6.86 (m, 2H), 7.00 (m, 2H), 7.13 (m, 4H), 8.30 (s, 1H), 11.99 (s, NH); 13C NMR (100 MHz, CDCl3) δ 37.1, 38.2, 53.7, 53.8, 56.3, 62.2, 65.8, 86.0, 115.1, 116.0, 123.0, 129.8, 131.2, 145.7, 153.4, 157.9, 158.1, 161.1, 166.5, 172.4, 172.5, 176.3, 176.5; MS (ESI)m/z (M + 1) 481.5; Anal. Calcd for C24H26N4O9S2:  C, 49.82; H, 4.53; N, 9.68; S, 11.08. Found:  C, 49.85; H, 4.57; N, 9.75; S, 11.15.

PATENT

WO03080605A1.

References

  1. Lee JH, Noh CK, Yim CS, Jeong YS, Ahn SH, Lee W, Kim DD, Chung SJ. (2015). “Kinetics of the Absorption, Distribution, Metabolism, and Excretion of Lobeglitazone, a Novel Activator of Peroxisome Proliferator-Activated Receptor Gamma in Rats.”.Journal of Pharmaceutical sciences 104 (9): 3049–3059.doi:10.1002/jps.24378. PMID 25648999.
  2.  Kim JW, Kim JR, Yi S, Shin KH, Shin HS, Yoon SH, Cho JY, Kim DH, Shin SG, Jang IJ, Yu KS. (2011). “Tolerability and pharmacokinetics of lobeglitazone (CKD-501), a peroxisome proliferator-activated receptor-γ agonist: a single- and multiple-dose, double-blind, randomized control study in healthy male Korean subjects.”. Clinical therapeutics 33 (11): 1819–1830.doi:10.1016/j.clinthera.2011.09.023. PMID 22047812.
  3.  Lee JH, Woo YA, Hwang IC, Kim CY, Kim DD, Shim CK, Chung SJ. (2009). “Quantification of CKD-501, lobeglitazone, in rat plasma using a liquid-chromatography/tandem mass spectrometry method and its applications to pharmacokinetic studies.”. Journal of Pharmaceutical and Biomedical Analysis 50 (5): 872–877.doi:10.1016/j.jpba.2009.06.003. PMID 19577404.
  4.  “MFDS permission information of Duvie Tablet 0.5mg”(Release of Information). Ministry of Food and Drug Safety. Retrieved2014-10-23.
  5.  “국내개발 20번째 신약‘듀비에정’허가(20th new drug developed in Korea ‘Duvie Tablet’ was approved)”. Chong Kun Dang press release. 2013-07-04. Retrieved 2014-10-23.
Lobeglitazone
Lobeglitazone.svg
Systematic (IUPAC) name
5-[(4-[2-([6-(4-Methoxyphenoxy)pyrimidin-4-yl]-methylamino)ethoxy]phenyl)methyl]-1,3-thiazolidine-2,4-dione
Clinical data
Trade names Duvie
Routes of
administration		 Oral
Legal status
Legal status
Pharmacokinetic data
Protein binding >99%[1]
Metabolism liver (CYP2C9, 2C19, and 1A2)[1]
Biological half-life 7.8–9.8 hours[2]
Identifiers
CAS Number 607723-33-1
PubChem CID 9826451
DrugBank DB09198 Yes
ChemSpider 8002194
Synonyms CKD-501
Chemical data
Formula C24H24N4O5S
Molar mass 480.53616 g/mol

///Lobeglitazone Sulfate, CKD-501, Duvie®,  Approved KOREA, Chong Kun Dang, A dual PPARα and PPARγ agonist , type 2 diabetes.

CN(CCOC1=CC=C(C=C1)CC2C(=O)NC(=O)S2)C3=CC(=NC=N3)OC4=CC=C(C=C4)OC.OS(=O)(=O)O

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Blinatumomab

 MONOCLONAL ANTIBODIES, Uncategorized  Comments Off on Blinatumomab
Apr 252016
 

Blinatumomab, AMG-103,  MEDI-538,  MT-103,

(Blincyto®) Approved

A bispecific CD19-directed CD3 T-cell engager used to treat philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

Immunoglobulin, anti-​(human CD19 (antigen)​) (single-​chain) fusion protein with immunoglobulin, anti-​(human CD3 (antigen)​) (clone 1 single-​chain) (9CI)

Other Names

1: PN: WO2005052004 SEQID: 1 claimed protein

cas 853426-35-4

 BLINCYTO (blinatumomab) for injectionBlinatumomab (trade name Blincyto, previously known as AMG103) is a biopharmaceutical drug used as a second-line treatmentfor Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia. It belongs to a class of constructedmonoclonal antibodies, bi-specific T-cell engagers (BiTEs), that exert action selectively and direct the human immune system to act against tumor cells. Blinatumomab specifically targets the CD19 antigen present on B cells.[1] In December 2014 it was approved by the US Food and Drug Administration under the accelerated approval program; marketing authorization depended on the outcome of clinical trials that were ongoing at the time of approval.[2][3] When it launched, blinatumomab was priced at $178,000 per year in the United States; only about 1,000 people were eligible to take the drug, based on its label.[4]

 

Medical use

Blinatumomab is used as a second-line treatment for Philadelphia chromosome-negative relapsed or refractory Bcell precursor acute lymphoblastic leukemia.[2]

Mechanism of action

Blinatumomab linking a T cell to a malignant B cell.

Blinatumomab enables a patient’s T cells to recognize malignant B cells. A molecule of blinatumomab combines two binding sites: aCD3 site for T cells and a CD19 site for the target B cells. CD3 is part of the T cell receptor. The drug works by linking these two cell types and activating the T cell to exert cytotoxic activity on the target cell.[5] CD3 and CD19 are expressed in both pediatric and adult patients, making blinatumomab a potential therapeutic option for both pediatric and adult populations.[6]

History

The drug was developed by a German-American company Micromet, Inc. in cooperation with Lonza; Micromet was later purchased byAmgen, which has furthered the drug’s clinical trials. In July 2014, the FDA granted breakthrough therapy status to blinatumomab for the treatment of acute lymphoblastic leukemia (ALL).[7] In October 2014, Amgen’s Biologics License Application for blinatumomab was granted priority review designation by the FDA, thus establishing a deadline of May 19, 2015 for completion of the FDA review process.[8]

On December 3, 2014, the drug was approved for use in the United States to treat Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia under the FDA‘s accelerated approval program; marketing authorization depended on the outcome of clinical trials that were ongoing at the time of approval.[2][9]

Cost

When blinatumomab was approved, Amgen announced that the price for the drug would be $178,000 per year, which made it the most expensive cancer drug on the market. Merck’s pembrolizumab was priced at $150,000 per year when it launched; unlike that drug and others, only about 1,000 people can be given the drug, based on its label.[4]

Peter Bach, director of the Center for Health Policy and Outcomes at Memorial Sloan-Kettering Cancer Center, has calculated that according to “value-based pricing,” assuming that the value of a year of life is $120,000 with a 15% “toxicity discount,” the market price of blinaumomab should be $12,612 a month, compared to the market price of $64,260 a month. A representative of Amgen said, “The price of Blincyto reflects the significant clinical, economic and humanistic value of the product to patients and the health-care system. The price also reflects the complexity of developing, manufacturing and reliably supplying innovative biologic medicines.”[10]

Patent

WO 2010052013

http://www.google.co.in/patents/WO2010052013A1?cl=en

Examples:

1. CD19xCD3 bispecific single chain antibody

The generation, expression and cytotoxic activity of the CD19xCD3 bispecific single chain antibody has been described in WO 99/54440. The corresponding amino and nucleic acid sequences of the CD19xCD3 bispecific single chain antibody are shown in SEQ ID NOs. 1 and 2, respectively. The VH and VL regions of the CD3 binding domain of the CD19xCD3 bispecific single chain antibody are shown in SEQ ID NOs. 7 to 10, respectively, whereas the VH and VL regions of the CD19 binding domain of the CD19xCD3 bispecific single chain antibody are shown in SEQ ID NOs 3 to 6, respectively.

PATENT

http://www.google.com.ar/patents/WO2010052014A1?cl=en

PATENT

WO 2015006749

http://www.google.com/patents/WO2015006749A2?cl=un

PATENT

CN 104861067

http://www.google.com/patents/CN104861067A?cl=zh

WO1998008875A1 * 18 Aug 1997 5 Mar 1998 Viva Diagnostika Diagnostische Produkte Gmbh Novel combination preparations and their use in immunodiagnosis and immunotherapy
WO1999054440A1 21 Apr 1999 28 Oct 1999 Micromet Gesellschaft Für Biomedizinische Forschung Mbh CD19xCD3 SPECIFIC POLYPEPTIDES AND USES THEREOF
WO2004106381A1 26 May 2004 9 Dec 2004 Micromet Ag Pharmaceutical compositions comprising bispecific anti-cd3, anti-cd19 antibody constructs for the treatment of b-cell related disorders
WO2007068354A1 29 Nov 2006 21 Jun 2007 Micromet Ag Means and methods for the treatment of tumorous diseases

References

  1.  “blinatumomab” (PDF). United States Adopted Names Council » Adopted Names.American Medical Association. 2008. N08/16.(registration required)
  2.  Blinatumomab label Updated 12/2014
  3.  Food and Drug Administration December 3, 2014 FDA Press release: Blinatumomab
  4.  Tracy Staton for FiercePharmaMarketing. December 18, 2014 Amgen slaps record-breaking $178K price on rare leukemia drug Blincyto
  5.  Mølhøj, M; Crommer, S; Brischwein, K; Rau, D; Sriskandarajah, M; Hoffmann, P; Kufer, P; Hofmeister, R; Baeuerle, PA (March 2007). “CD19-/CD3-bispecific antibody of the BiTE class is far superior to tandem diabody with respect to redirected tumor cell lysis”.Molecular Immunology 44 (8): 1935–43. doi:10.1016/j.molimm.2006.09.032.PMID 17083975.Closed access
  6.  Amgen (30 October 2012). Background Information for the Pediatric Subcommittee of the Oncologic Drugs Advisory Committee Meeting 04 December 2012 (PDF) (PDF). Food and Drug Administration. Blinatumomab (AMG 103).
  7.  “Amgen Receives FDA Breakthrough Therapy Designation For Investigational BiTE® Antibody Blinatumomab In Acute Lymphoblastic Leukemia” (Press release). Amgen. 1 July 2014.
  8.  “Amgen’s BiTE® Immunotherapy Blinatumomab Receives FDA Priority Review Designation In Acute Lymphoblastic Leukemia” (Press release). Amgen. 9 October 2014.
  9. “Business: Antibody advance”. Seven Days. Nature (paper) 516 (7530): 149. 11 December 2014. doi:10.1038/516148a.open access publication - free to read
  10.  Peter Loftus (June 18, 2015). “How Much Should Cancer Drugs Cost? Memorial Sloan Kettering doctors create pricing calculator that weighs factors such as side effects, extra years of life”. The Wall Street Journal. Retrieved 22 June 2015.
Blinatumomab
Monoclonal antibody
Type Bi-specific T-cell engager
Source Mouse
Target CD19, CD3
Clinical data
Trade names Blincyto
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration		 intravenous
Legal status
Legal status
Pharmacokinetic data
Bioavailability 100% (IV)
Metabolism degradation into small peptides and amino acids
Biological half-life 2.11 hours
Excretion urine (negligible)
Identifiers
CAS Number 853426-35-4 
ATC code L01XC19 (WHO)
ChemSpider none
UNII 4FR53SIF3A Yes
Chemical data
Formula C2367H3577N649O772S19
Molar mass 54.1 kDa

///////

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Istradefylline

 Uncategorized  Comments Off on Istradefylline
Apr 252016
 

Istradefylline.svg

Istradefylline, KW-6002

(Nouriast®) Approved

A selective adenosine A2A receptor antagonist used to treat Parkinson’s disease.

KW-6002

CAS No. 155270-99-8

Istradefylline; 155270-99-8; KW-6002; KW 6002; 8-[(E)-2-(3,4-Dimethoxyphenyl)ethenyl]-1,3-diethyl-7-methyl-purine-2,6 -dione; (E)-8-(3,4-Dimethoxystyryl)-1,3-diethyl-7-methyl-1H-purine-2,6(3H,7H)-dione;

Molecular Formula: C20H24N4O4
Molecular Weight: 384.42896 g/mol

Istradefylline (KW-6002) is a selective antagonist at the A2A receptor. It has been found to be useful in the treatment of Parkinson’s disease.[1] Istradefylline reduces dyskinesia resulting from long-term treatment with classical antiparkinson drugs such as levodopa. Istradefylline is an analog of caffeine.

Istradefylline.png

Kyowa Hakko Kirin is developing istradefylline, a selective adenosine A2A receptor antagonist, for the once-daily oral treatment of Parkinson’s disease (PD). Adenosine A2A receptors are considered to be present particularly in the basal ganglia of the brain; the degeneration or abnormality observed in PD is believed to occur in the basal ganglia, which is recognized to play a significant role in motor control.

Commercially available dopamine replacement therapies effectively treat the early motor symptoms of PD; however, these agents are associated with development of motor complications, limiting usefulness in late stages of the disease. Istradefylline is proposed to possess a clearly distinct action site from existing agents which act on dopamine metabolism or dopamine receptors. Kyowa Hakko Kirin has received approval for istradefylline in the adjunctive treatment of PD in Japan. A New Drug Application was filed in the USA, but the FDA issued a non-approvable letter in February 2008.

PATENT

US5484920A

http://www.google.co.in/patents/US5484920

PAPER

http://www.sciencedirect.com/science/article/pii/S0960894X13003983

Synthesis of KW 6002 (2). Reagents and conditions: (i) acetic anhydride, 80°C, ...

Scheme 1.

Synthesis of KW 6002 (2). Reagents and conditions: (i) acetic anhydride, 80 °C, 2 h, 83%; (ii) sodium nitrite, 50% acetic acid, 60 °C, 15 min, 86%; (iii) sodium dithionite, NH4OH solution (12.5% (w/v)), 60 °C, 30 min, 98%; (iv) SOCl2, toluene, 75 °C, 2 h, 97%; (v) pyridine, DCM, rt, 16 h, 66%; (vi) HMDS, cat. (NH4)2SO4, CH3CN, 160 °C, microwave, 5 h, 100% followed by (vii) MeI, K2CO3, DMF, rt, 2 h, 75%.

Chemical structures of some important adenosine receptor antagonists and their ...

Synthesis

(E)-8-(3,4-Dimethoxystyryl)-1,3-diethyl-7-methyl-1H-purine-2,6(3H,7H)-dione (2)3

  1. J. Hockemeyer; J. C. Burbiel; C. E. Müller, J. Org. Chem. 2004, 69, 3308.

(E)-8-(3,4-Dimethoxystyryl)-1,3-diethyl-1H-purine-2,6(3H,7H)-dione (1.11 g, 3.00 mmol) was taken up in dimethylformamide (15 mL) and potassium carbonate (828 mg, 6.00 mmol). To the milky white mixture was added iodomethane (468 µL, 7.50 mmol) and it was allowed to stir at room temperature for 2 h. The mixture was then filtered and washed with water (100 mL), leaving the title compound 2 as a pale yellow solid which was dried in the oven at 110 °C (863 mg, 75%), mp: 192 °C (lit.3 191 °C). 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 15.7 Hz, 1H), 7.18 (dd, J = 8.4, 1.9 Hz, 1H), 7.09 (d, J = 1.9 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 15.7 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.12 – 4.04 (m, 5H), 3.95 (s, 3H), 3.93 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 155.0 (C), 150.8 (C), 150.4 (C), 150.3 (C), 149.2 (C), 148.2 (C), 138.1 (CH), 128.6 (C), 121.2 (CH), 111.2 (CH), 109.5 (CH), 109.3 (CH), 108.0 (C), 55.98 (CH3), 55.97 (CH3), 38.4 (CH2), 36.3 (CH2), 31.5 (CH3), 13.43 (CH3), 13.39 (CH3). LCMS: m/z (ESI 20 V) 385.2 (MH+, 100).

 

PATENT

http://www.google.com/patents/CN103254194A?cl=en

Specific synthetic route is as follows:

 

Figure CN103254194AD00071

the above reaction is a synthetic Parkinson’s disease clinical drug KW-6002 against a yield of 83%.

Example 26 (a new synthetic method for anti-Parkinson’s disease in clinical drug KW-6002):

In addition to use in place of 3,4-dimethoxy-styryl boronic acid (0.4mmol, i.e., in formula IV, R5 is 3,4_-dimethoxy-styryl) benzene boronic acid in Example 23 and 1,3 – two-ethyl-8-phenylthio-9-methyl-xanthine (0.4mmol, i.e., Formula I, R1 is methyl, R2 and R3 are ethyl, R4 is a phenyl group) in place of Example 23 in 1 , 3,9-trimethyl xanthine -8- phenylthio, the remaining steps in Example 23 to give a white solid, yield 83%, mp = 101~103 ° C I1H NMR (⑶CI3, 600MHz): δ 7.71 (d, J = 15.6Hz, 1H), 7.17 (dd, J = 8.2,1.9Hz, 1H), 7.07 (d, J = L 9Hz, 1H), 6

• 88 (d, J = 8.2Hz, 1H), 6.74 (d, J = 15.8Hz, 1H), 4.19 (q, J = 7Hz, 2H), 4.07 (q, J = 7Hz, 2H), 4.03 (s , 3H), 3.93 (s, 3H), 3.90 (s, 3H), 1.36 (t, J = 7Hz, 3H), 1.23 (t, J = 7Hz, 3H); 13C NMR (150MHz, CDCl3): 155.1, 150.8,150.4,150.2,149.2,148.2,138.2,128.6,121.2, 111.2,109.5,109.3,108.0,56.0,55.9,38.4,36.3,31.5,13.4,13.4; HRMS: calcd for C20H25N4O4 (M + H) +385.187

6, Found385.1879. It indicates that the white solid was 8- (3,4-dimethoxy-styryl) structural formula shown KW-6002 (E) -1,3_ diethyl-7-methylxanthine.

 

Figure CN103254194AD00162

 In contrast, KW-6002 is a new drug to treat Parkinson’s disease developed by Kyowa Hakko in Japan, Japan and the United States is currently the second phase of clinical trials. Literature (. J.Hockemeyer, JCBurbiel andC.E.Muller, J.0rg.Chem, 2004,69,3308) through the following synthetic route:

 

Figure CN103254194AD00171

The synthetic route requires five steps, with a total yield of 33%, and there is the use of environmentally unfriendly halogenated solvent methylene chloride, the reaction requires high pressure high temperature (170~180 ° C) and other shortcomings. By comparison, the present invention starting from 8- phenylthio xanthine coupling reaction catalyzed by palladium simple, a yield of 83% was synthesized KW6002, it is currently the most efficient synthesis route KW-6002’s. In particular, the multi-step synthesis route to avoid the complex operation of the reactor, but under relatively mild conditions (60 ° C) conduct, simple operation, suitable for scale synthesis.

PATENT

http://www.google.com/patents/CN104744464A?cl=en

itraconazole theophylline (Istradefylline, KW6002), the chemical name 8 – [(E) -2- (3, 4- dimethoxyphenyl) ethenyl] -1,3-diethyl -7 – methyl-purine-2,6-dione, CAS number: 155270-99-8, structural formula shown below.

 

Figure CN104744464AD00031

 itraconazole Theophylline is a selective adenosine A2a receptor antagonist, by changing the activity of neurons in Parkinson’s disease patients to improve motor function, for the treatment of Parkinson’s disease and Parkinson’s disease improve early dyskinesia.

The invention and JPH0940652A European Patent 0,590,919 discloses a method for preparing itraconazole and theophylline. WO 2004/099207 published good solubility stability of a particle size of less than 50 micrometers 8 – [(E) -2- (3, 4- dimethoxyphenyl) ethenyl] -1,3- diethyl-7-methyl-purine-2,6-dione crystallites.

Example 1 Preparation of theophylline itraconazole  Example

 

Figure CN104744464AD00051

ships equipped with a mechanical stirrer, a thermometer, a 2L 4-neck flask was added 30g8 – [(E) -2- (3, 4- dimethoxyphenyl) ethenyl] -1,3-diethyl- -7- hydrogen – purine-2,6-dione (Intermediate A), 400mL N, N- dimethylformamide and 15g of potassium carbonate, and 25g of methyl iodide and heated to 80 ° C after the reaction was stirred 8h, added 200mL water, cooled to room temperature, and stirring was continued crystallization 2h. The resulting suspension was suction filtered, washed with water after the cake was 800mL sash, 50 ° C under blast drying 24h, 32g give a pale yellow solid, for each polymorph of itraconazole theophylline preparation example the following examples.

References

  1.  Peter A. LeWitt, MD, M. Guttman, James W. Tetrud, MD, Paul J. Tuite, MD, Akihisa Mori, PhD, Philip Chaikin, PharmD, MD, Neil M. Sussman, MD (2008). “Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces off time in Parkinson’s disease: A double-blind, randomized, multicenter clinical trial (6002-US-005)”. Annals of Neurology 63 (3): 295–302. doi:10.1002/ana.21315. PMID 18306243.

1. EP0590919A1.

2. US5484920A.

3. US5543415A.

4. J. Org. Chem. 2004, 69, 3308-3318.

5. Bioorg. Med. Chem. Lett. 1997, 7, 2349-2352.

6. Bioorgan. Med. Chem. 2003, 11, 1299-1310.

7. Bioorg. Med. Chem. Lett. 2013, 23, 3427-3433.

8. Chinese Journal of Pharmaceuticals 2010, 41, 241-243.

9. JP0940652A.

10. Org. Biomo. Chem. 2010, 8, 4155-4157.

1. Chem. Commun. 2012, 48, 2864-2866.

2. CN103254194A.

CN104744464A * Nov 15, 2013 Jul 1, 2015 南京华威医药科技开发有限公司 Istradefylline crystal forms
  1. Istradefylline
    Istradefylline.svg
    Systematic (IUPAC) name
    8-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione
    Identifiers
    CAS Number 155270-99-8 Yes
    ATC code none
    PubChem CID 5311037
    IUPHAR/BPS 5608
    ChemSpider 4470574 Yes
    UNII 2GZ0LIK7T4 Yes
    KEGG D04641 Yes
    ChEMBL CHEMBL431770 Yes
    Chemical data
    Formula C20H24N4O4
    Molar mass 384.429 g/mol

//////Istradefylline, KW-6002, Nouriast®, Approved, A selective adenosine A2A receptor antagonist, Parkinson’s disease,

O=C2N(c1nc(n(c1C(=O)N2CC)C)\C=C\c3ccc(OC)c(OC)c3)CC

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Polmacoxib, CG-100649

 Uncategorized  Comments Off on Polmacoxib, CG-100649
Apr 222016
 

Polmacoxib.svg

Polmacoxib, CG-100649

(Acelex®)Approved

A COX-2 inhibitor used to treat osteoarthritis.

  • OriginatorCrystalGenomics
  • ClassAntirheumatics; Benzene derivatives; Fluorobenzenes; Furans; Nonsteroidal anti-inflammatories; Small molecules; Sulfonamides
  • Mechanism of ActionCarbonic anhydrase inhibitors; Cyclo-oxygenase 2 inhibitors
  • 12 Jan 2016Polmacoxib licensed to TR-Pharm for commercialisation in Turkey and Middle East and North Africa region
  • 01 Sep 2015Launched for Osteoarthritis in South Korea (PO)
  • 12 Aug 2015Polmacoxib licensed to Dong-A ST for commercialisation in South Korea
Molecular Formula: C18H16FNO4S
Molecular Weight: 361.387343 g/mol

CAS No.301692-76-2

Polmacoxib.png

4-[3-(3-fluorophenyl)-5,5-dimethyl-4-oxofuran-2-yl]benzenesulfonamide

STR1

Polmacoxib (Acelex) is a nonsteroidal anti-inflammatory drug (NSAID) used to treat osteoarthritis. It was developed as CG100649 and approved for use in South Korea in February 2015.[1] It inhibits the enzymes carbonic anhydrase and COX-2. A study in healthy volunteers showed drug effects on urinary prostaglandin metabolites for both CG100649 and celecoxib that suggest a similar cardiovascular risk profile.[2] Further work by this group developed dose-exposure relationsships of CG100649 to guide clinical development strategies. [3]

Dual-acting cyclooxygenase-2 (COX-2) and carbonic anhydrase inhibitor
Molecular Target Cyclooxygenase-2 (COX-2) ; Carbonic anhydrase l (CAI)
Mechanism of Action Cyclooxygenase-2 (COX-2) inhibitor; NSAID

KOREA FDA APPROVED ACELEX ® (POLMACOXIB) FOR THE TREATMENT OF OSTEOARTHRITIS

01 FEB

KOREA FDA APPROVED ACELEX ® (POLMACOXIB) FOR THE TREATMENT OF OSTEOARTHRITIS

CrystalGenomics, announced today that it has received approval for Acelex® (polmacoxib) from the Korean Ministry of Food and Drug Safety (MFDS) for the treatment of osteoarthritis.

The company said that “Pre-commercialization will commence immediately and a commercial launch partner for the Korean market will be announced very shortly.”

Acelex® (polmacoxib) is the first, tissue-specific once-a-day osteoarthritis drug with a novel mode of action that specifically targets affected joints to relieve pain and restore mobility, while simultaneously preserving the integrity and safety of the gastrointestinal and cardiovascular systems. The results from the Phase 3 study suggest that Acelex 2mg once-a-day provides more rapid onset of relief from the signs and symptoms of osteoarthritis in comparison to celecoxib 200mg once-a-day, without added safety risk.

Polmacoxib is a first-in-class NSAID drug candidate that is a dual inhibitor of COX-2 and carbonic anhydrase (CA). Polmacoxib’s interaction with CA in red blood cells provides it with a novel ’tissue-specific’ transport mechanism that is designed to deliver sustained levels of drug to inflamed tissues, while maintaining low systemic exposure. Its unique dual COX-2 and CA binding properties are designed to provide potentially superior safety to cardiovascular, renal, and gastrointestinal tissues compared to traditional NSAIDs or COX-2 inhibitor drugs.

Acelex® is expected to rapidly capture at least 10% of the arthritis market in Korea that is estimated to be worth more than KRW 500 billion per year as of 2013. Osteoarthritis is quite common in Korea, as it affects about 50% of the population aged 65 years or older. Moreover, the overall number of patients is growing rapidly due to an aging population coupled with an increasing prevalence of obesity.

Nonsteroidal antiinflammatory drugs (NSAIDs) have been widely used over 100 years to alleviate symptoms of arthritis, arthritis-associated disorders, fever, post-operative pain, migraine, and so on. Despite their widespread use and desirable therapeutic efficacy for the treatment of inflammation and inflammation-associated disorders, NSAIDs are generally regarded to have life-threatening toxicity in the gastrointestinal (GI) tract. Severity of the GI toxicity is well illustrated by a report that 16 500 patients on NSAIDs therapy died due to the GI toxicity in the year of 1994 alone in the US. Frequently, the gastric toxicity of perforation, ulceration, and bleeding (PUB) is not noticed by patients before hospitalization, leading to such a high mortality rate upon chronic use of NSAIDs.
Despite the huge amount of efforts directed to reduce the GI toxicity of NSAIDs, it was only about a decade ago that the origin of the GI toxicity began to be understood through the discovery of an inducible isoform of cyclooxygenases. There are at least two kinds of cyclooxygenases, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX-1 is constitutively expressed in various tissues including the GI tract, the kidneys, and the platelets. COX-1 is known to be responsible for bodily homeostasis such as the gastrointestinal integrity, vascular dilatation, renal functions, and so on. Overt inhibition of COX-1 can, therefore, elicit undesirable side effects such as gastric PUB and blood thinning. In the meantime, COX-2 is induced upon inflammatory stimuli and is known to be responsible for progression of inflammation. Traditional NSAIDs, such as aspirin, naproxen, piroxicam, ibuprofen, diclofenac, etc., inhibit both COX-1 and COX-2, which accounts for NSAIDs’ antiinflammatory effects as well as their notorious side effects of GI toxicity and blood thinning. Thus, selective inhibition of COX-2 over COX-1 should be useful for treatment of inflammation without incurring the side effects associated with inhibition of COX-1.
A study with COX-2 knockout mice suggests that complete inhibition of COX-2 could lead to peritonitis secondary to intestinal toxicity. Animal safety data for COX-2 inhibitors indicated that the intestinal toxicity was the dose-limiting toxicity in the dog and the rat. However, primates seem to possess robust intestinal tolerance to selective inhibition of COX-2. Indeed, COX-2 inhibitors are regarded to have better gastrointestinal safety profiles than traditional NSAIDs.
Long term use of traditional NSAIDs has been known to elicit cardiorenal toxicity such as edema and worsening blood pressure. There have been some attempts to assess cardiorenal safety of COX-2 inhibitors; however, more clinical data are needed to estimate the cardiorenal safety of COX-2 inhibitors. Considering that COX-2 inhibitors are supposed to be chronically taken mostlyby elderly arthritis patients, the importance of the long-term cardiorenal safety can never be overemphasized. COX-2 is constitutively expressed in the glomerular region and the small blood vessels of the kidneys in primates including the human, suggesting that the smaller inhibition of renal COX-2 could lead to smaller renal and consequently cardiovascular adverse effects. Given that only protein-unbound drug molecules are subject to glomerular filtration, a drug with higher plasma protein binding is expected to exert a smaller renal effect for a given lipophilicity or hydrophilicity of drug.
There are already several COX-2 inhibitors being prescribed for chronic indications, and they mostly maintain a tricyclic structure as in rofecoxib, celecoxib, valdecoxib, and etoricoxib.

Prostaglandins are known to play an important role in the inflammation.

Since prostaglandins are produced from arachidonic acid by cyclooxygenases, inhibition of prostagalndin synthesis by cyclooxygenases, especially synthesis of PGE2, PGG2, and PGH2, leads to the treatment of inflammation.

There are at least two kinds of cyclooxygenases, cyclooxygenase-1

(abbreviated as COX-1) and cyclooxygenase-2 (abbreviated as COX-2). COX-1 is constitutively present in the gastrointestinal tract and the kidney, and is implicated to be responsible for the maintenance of the physiological homeostasis, such as gastrointestinal integrity and renal function. Interruption of COX-1 activity can lead to life-threatening toxicities to the gastrointestinal tract, such as ulceration and bleeding. In the meantime, COX-2 is induced upon inflammatory stimuli and known to be responsible for progression of inflammation. Thus, selective inhibition of COX-2 over COX-1 is useful for the treatment of inflammation and inflammation-associated disorders without incurring gastrointestinal toxicities.

Conventional non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, naproxen, ketoprofen, ibuprofen, piroxicam, diclofenac etc, inhibit both COX-1 and COX-2, which would demonstrate their gastrointestinal toxicities as well as anti-inflammatory potency. However, they possess serious life-threatening gastrointestinal toxicities of bleeding and ulceration arising from their inhibition of COX-1, which limit their clinical use. Thus, a selective inhibitor of COX-2 can be useful as an anti-inflammatory therapeutic agent without the gastrointestinal toxicities, frequently occurring upon chronic use of conventional NSAIDs.

COX-2 inhibitors are implicated to possess a broad therapeutic spectrum besides anti-inflammatory, analgesic, and antipyretic activity. For example inhibition of COX-2 can prevent growth of certain types of cancer, especially colon cancer [J. Clin. Invest. 100. 1 (1997)]. Another application of a COX-2 inhibitor can be found in the treatment of degenerative chronic neurological disorders, such as Alzheimer’s disease [Neurology 4£, 626 (1997)]. COX-2 inhibition would be useful in reducing the infarct volume accompanying the stroke [J. Neuroscience 17, 2746 (1997)].

Recently two of COX-2 selective antiinflammatory drugs, celecoxib and rofecoxib, were introduced into the clinic for arthritic indications. Celecoxib and rofecoxib show anti-inflammatory potency comparable to conventional NSAIDs without COX-2 selectivity. In the meantime, these drugs show appreciably lower gastrointestinal toxicities than conventional NSAIDs without COX-2 selectivity over COX-1. Thus, COX-2 selective inhibition itself can be enough for anti-arthritic potency and the inhibition of COX-1 is largely responsible for the gastro-intestinal toxicities associated with conventional NSAIDs without COX-2 selectivity.

.s-l,2-Diaryl-alkenes or its structural-equivalents are known to be a pharmacophore for achieving selective COX-2 inhibition over COX-1 [Ann. Rep. Med. Chem. 22, 211 (1997)]. In case of celecoxib and rofecoxib, pyrazole and 2(JH)-furanone correspond to the scaffold, respectively.

Celecoxib Rofecoxib By adopting an appropriate scaffold for the c/s-alkene pharmacophore, it would be possible to modulate both in vitro and in vivo characteristics of such inhibitors, such as dosing regimen, daily dose, clinical indications arising from tissue distribution characteristics, safety profile, and so on.

In this invention, 3(2H)-furanone is adopted as a scaffold for COX-2 inhibitors.

3(2H)-furanone derivatives were prepared for use in the treatment of glaucoma [EP 0

737 476 A2]. However, there is no precedent case that 3(2H)-furanone derivatives have been ever used as COX-2 inhibitors. There is no reported case of 4,5-diaryl-3(2H)-furanone derivatives, either.

The 4,5-diaryl-3(2H)-furanone derivatives disclosed herein selectively inhibit COX-2 over COX-1 and relieve the effects of inflammation. 4,5-Diaryl-3(2H)-furanone derivatives of this invention do not show substantial inhibition of COX-1 and consequently show reduced gastrointestinal side effects. Thus, 4,5-diaryl-3(2H)-furanone derivatives of this invention are found useful as anti -inflammatory agents with significantly reduced gastrointestinal side effects, when compared with conventional NSAIDs.

Paper

Shin, Song Seok; Journal of Medicinal Chemistry 2004, V47(4), P792-804

In Vitro Structure−Activity Relationship and in Vivo Studies for a Novel Class of Cyclooxygenase-2 Inhibitors:  5-Aryl-2,2-dialkyl-4-phenyl-3(2H)furanone Derivatives

Drug Discovery, AmorePacific R&D Center, 314-1 Bora-ri, Kiheung-eup, Yongin-si, Kyounggi-do 449-729, South Korea
J. Med. Chem., 2004, 47 (4), pp 792–804
DOI: 10.1021/jm020545z
Abstract Image

5-Aryl-2,2-dialkyl-4-phenyl-3(2H)furanone derivatives were studied as a novel class of selective cyclooxygenase-2 inhibitors with regard to synthesis, in vitro SAR, antiinflammatory activities, pharmacokinetic considerations, and gastric safety. 1f, a representative compound for methyl sulfone derivatives, showed a COX-2 IC50 comparable to that of rofecoxib. In case of 20b, a representative compound for sulfonamide derivatives, a potent antiinflammatory ED50 of 0.1 mg kg-1 day-1 was observed against adjuvant-induced arthritis by a preventive model, positioning20b as one of the most potent COX-2 inhibitors ever reported. Furthermore, 20b showed strong analgesic activity as indicated by its ED50 of 0.25 mg/kg against carrageenan-induced thermal hyperalgesia in the Sprague−Dawley rat. 3(2H)Furanone derivatives showed due gastric safety profiles as selective COX-2 inhibitors upon 7-day repeat dosing. A highly potent COX-2 inhibitor of the 3(2H)furanone scaffold could be considered suitable for a future generation COX-2 selective arthritis medication with improved safety profiles.

STR1

PATENT

WO 2015080435 

non-steroidal anti-inflammatory drugs (nonsteroidal ant i- inf lammatory drug, NSAID) has a problem that causes serious side effects such as renal toxicity or distress Gastrointestinal. NSAID is to inhibit the activity of the enzyme cyclo-oxy-related prostaglandin G / H synthesis to tyrosinase (cyclooxygenase, COX) inhibits the biosynthesis of prostaglandins in the stomach and kidney, as well as inflammation. C0X is present in the two types of C0X C0X-1 and-2.

C0X-1 is induced by the other hand to adjust the height of the above features and is expressed in normal cells, it is C0X-2 mitogen or inflammation occurred in inflammation and other immune banung cytokines. To avoid the toxicity of the NSAID due to the inhibitory action of coexisting C0X-1 which, has been the selective inhibitors of the study C0X-2.

To 4- (3- (3-fluoro-phenyl) -5, 5-dimethyl-4-oxo-4, 5-dihydro-furan-2-yl) benzenesulfonamide represented by the general formula (1), such as 4, 5- diaryl-3- (0-furanones and derivatives thereof are compounds, wherein the by-1 do not inhibit the C0X standing substantially inhibit only C0X-2 selectively – represents a reduced gastrointestinal side effects while showing the inflammatory effect.

In addition, the compound of Formula 1 has C0X-2, as well as CA carbonic anhydrase) in inhibitory effect shown, in the CA-rich than C0X-2 tissues such as the gastrointestinal tract is to neutralize the inhibitory activity of C0X-2 gastrointestinal bleeding, such as side effects and more while the reduction, the less the distribution of the CA, such as joint tissue has a characteristic showing the effect to inhibit only C0X eu 2. Thus, 4, 5-diaryl-3- (0-furanones derivatives compared to conventional NSAIDs significantly reduced gastrointestinal side effects having an anti-inflammatory substance is useful as a.

Compounds and their derivatives of the formula (1) are of various inflammatory diseases; Pain accompanying diseases; viral infection; It is useful in the relief of inflammation, pain and fever, and the like accompanying surgery; diseases such as diabetes. Sikimyeo compounds and their derivatives of the formula (1) and they also inhibit the growth of cancer, including colorectal cancer C0X- parameter, reducing the infarction area of ​​reperfusion injuries to (reperfusion injury) caused by the stroke, treatment of neurodegenerative diseases, including Alzheimer’s disease it is useful. Diabetes accompanying retinopathy (retinopathy) in the treatment of useful and eu C0X-mediated vascularization (angiogenesis) to engage it (Mart in SG et al., Oral surgery oral medicine oral pathology, 92 (4), 2001, 399; James RH et al., oral surgery oral medicine oral pathology, 97 (2), 2004, 139; RE Harris et al., Inflammopharmacology, 12,2009, 55;

K. Oshima et al. , J. Invest. Surg. , 22 (4), 2009, 239; The Journal of

Pharmacology and Experimenral Therapeutics, 318 (3), 2006, 1248; JM. SL et al. , Int. J. Geriatr. Psychiatry, 2011; Jennifer L. et al. , Invest.

Ophthalmol. Vis. Sci. March, 44 (3), 2003, 974; K. M. Leahy et al. , Current Medicinal Chemistry, 7, 2000, 1163).

Method for producing a compound of formula I is disclosed in the International Patent Publication W0 00/615 sign, are incorporated herein by reference in their entirety.However, using the -78-butyllithium, which discloses in the above production method ° banung in C is not a m- chloroperoxybenzoic acid not suitable for commercial use it is difficult to practically carried out, as well as the yield for each step to be low, there are also overall yield is very low, so that problems 2.22%. ”

Therefore, the way to mass production of a compound of formula 1 without problems, such as the high yield and a low cost has been desired still.

o provide the production method ol compound represented by Formula 1:

[Formula 4]

[Formula 5]

[Formula 8]

[Formula 9]

4- (3- (3-fluorophenyl) -5,5-dimethyl-4-oxo-4, 5-dihydro-furan-2-yl) -benzenesulfonamide The total yield by the method represented by Reaction Scheme 1 It is very easy to about 46% of the high yield and can be economically mass-produced:

Or less, on the basis of the example embodiments The invention will be described in more detail. The following examples are not be the only, and the scope of the invention to illustrate the present invention be limited to these.

Example 1: 2- (3-fluorophenyl) Preparation of the acetyl chloride

2- (3-fluorophenyl) acetic acid (305.5 g, 1.98 mol), thionyl chloride (500 mL, 6.85 mol) to dissolve by stirring the solution in a catalytic amount of dimethylformamide (2.1 mL, 25.83让ol) to the It was. This solution banung 110 ° and heated to sikimyeo C was stirred under reflux for 3 hours. After nyaenggak banung the solution to room temperature, the excess thionyl chloride under reduced pressure using a concentrator was removed by distillation. The stage was distilled off under reduced pressure to about 5mm¾ burgundy red oily objective compound (323 g, 94.4%) was obtained.

Example 2: 2- (3-fluorophenyl) -1- [4- (methylthio) phenyl] ethanone discussed prepared

Aluminum chloride (225 g, 1.91 mol) in dichloromethane (2500 mL), and then the suspension to 5 ° C a solution banung 2- (3-fluorophenyl) acetyl chloride (305 g in cooling,

It was added 1.77 mol). The reaction was stirred for about 5 minutes after the common compounds, the liquid Ndo of banung

5 ° while keeping the C was added dropwise the thio Enigma sol (237 g, 1.91 mol). After stirring for 3 hours banung common compounds at room temperature, it was slowly poured into cold aqueous hydrochloric acid solution. After separation the organic layer was washed with saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous magnesium sulfate. After removing the anhydrous magnesium sulfate by filtration chest and diluted to a concentration under reduced pressure to concentrate the nucleic acid (1,000 mL). The diluted solution was 10 ° after the nyaenggak C to crystallize, it was stirred for 1 hour and then filtered and washed with a nucleic acid (1,000 mL). The filtered solid 50 ° and vacuum-dried for 2 hours in the target compound C (406 g, 88.3%) was obtained.

mp: 94.5 – 95.5 ° C

¾-NMR (CDCls, 300 MHz): δ 2.52 (s, 3H), 4.23 (s, 2H), 6.95-7.05 On, 3H), 7.25-7.30 (m, 3H), 7.92 (d, J = 8.7 Hz , 2H)

Example 3: 2,2-dimethyl-eu 4- (3-phenyl pool Luo) -5- [4- (methylthio) phenyl] -3 () – furanyl discussed prepared

Eu 2 (3-fluorophenyl) – 1- [4- (methylthio) phenyl] was cooled 30 minutes with stirring at ice-water was dissolved ethanone (512 g, 1.97 mol) in tetrahydrofuran (3,900 mL) . Sodium hydride in the reaction solution (60%, 180 g, 7.5 mol) was added to the subdivision for at least 15 minutes, the common banung compounds was stirred for 30 minutes at room temperature. The reaction common compounds 5 ° after nyaenggak in C, the 2-bromo butyryl cattle feeders cyanide (403 g, 2.29 mol) was added dropwise while maintaining the temperature. After the addition the solution was slowly stirred for 5 hours banung to room temperature. Banung ^ the compounds 5 ° and cooled to C, and then slowly added to de-ionized water and neutralized with acetic acid (122 g). After concentration under reduced pressure the banung solution was extracted with dichloromethane (2, 500 mL) and deionized water (2, 000 mL). The organic layer was washed with brine and then dried over anhydrous magnesium sulfate and filtered.

Filtered and concentrated under reduced pressure then gave a precipitate is dissolved with stirring in methanol (700 mL). After filtering the precipitate is washed with acid and methane. The filtered solid 50 ° and vacuum-dried for 2 hours at C, to give the desired compound (534.7 g, 82.8%). mp: 106 ° C

NMR-¾ ​​(CDCI 3 , 300 MHz): δ 1.55 (s, 6H), 2.50 (s, 3H), 6.97-7.11 (m, 3H), 7.18 (d, J = 9.0 Hz, 2H), 7.26-7.36 (m, 1H), 7.55 ( d, J = 9.0 Hz, 2H)

Example 4: [4- (3- (3-fluoro-phenyl) -5, 5-dimethyl-4-oxo-4, 5-dihydro-furan-2-yl) phenylsulfonyl] Preparation of methyl acetate

2,2-dimethyl-eu eu eu 4 (3_ fluorophenyl) _5- [4- (methylthio) phenyl] -3 (0 furanones (5.5 Kg) and acetonitrile (27.2 Kg) and dichloromethane (45.43 Kg) after heunhap dissolved in a solvent, the compounds banung common -5 ° was cooled to C. to binary dissolved in acetic acid solution to the other reaction by injecting a peracetic acid (18%) and injection of dichloromethane and 23.4 Kg 13.9 Kg acetonitrile a common hapaek was prepared. hapaek prepared common to -5 ° keeping the C and slowly 0-5 was added to the reaction common compounds for 2 h ° and stirred for 30 to 90 minutes in the C. and the reaction common compounds with purified water 109.2 L separating the washed organic layer was then washed with aqueous sodium thiosulfate and aqueous sodium bicarbonate solution. the organic layer is concentrated 4- (3-fluorophenyl eu) eu 2,2-dimethyl-5- (4-eu

(Methyl sulfinyl) phenyl) furan -3 (2H) – one to give the as an oil form.

NiP: 143-144 ° C

¾-NMR (CDCls, 300 腿 ζ): δ 1.58 (s, 6Η), 2.76 (s, 3H), 7.26-7.08 (m, 3H), 7.30-7.38 (111, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.80 (d, J = 8.2 Hz, 2H)

After the thus obtained compound was dissolved in acetic anhydride (42.3 Kg) was added anhydrous sodium acetate (5.1 Kg). A liquid banung 130 ° under reflux for 12 hours at C and then cooled to room temperature after stirring. By filtration, washed with acetic anhydride solution banung the filtrate was 55 ° and concentrated in C. 63.5 Kg of purified water to the acid concentrate and 20.7

Injecting L and 10 ° after a nyaenggak C, it was added oxone 32.3 Kg followed by stirring for 3 hours. A liquid banung 50 ° and then concentrated in C until the residual liquid was added ½ and purified water (89.5 L) was stirred for 3 hours. The precipitated compound was filtered and then, washed with purified water and heptane and 50 °followed by drying for 12 hours at C, to give the desired compound (6.4 Kg, 91.3%).

¾ -赚(DMS0-d 6 (300 MHz): δ 8.01 (d, 2H), 7.83 (d, 2H), 7.43 (q, 1H), 7.20 (t, 1H), 7.07 (q, 1H), 5.47 (s, 2H), 2.06 ( s, 3H), 1.52 (s, 6H)

Example 5: Preparation of sodium 4- (3- (3-fluorophenyl) -5,5-dimethyl-4-oxo-4,5-dihydro-2-yl) Preparation of benzene sulfinate

[4- (3- (3-fluoro-phenyl) -5, 5-dimethyl-4-oxo-eu 4, 5-dihydro-furan-2-yl) phenylsulfonyl] methyl acetate (6.4 Kg) in tetrahydrofuran was dissolved in (34.3 Kg) and ethanol (15.3 Kg), the liquid temperature banung 0 ° was cooled to C. It was dissolved in sodium hydroxide (0.7 Kg) in purified water (16.1 L) to the other reaction section was prepared the solution cooled to C. It was added slowly for 5 hours, the prepared aqueous sodium hydroxide solution to the reaction solution, further stirring the reaction solution after about 1 hour and concentrated at 45 ° C. After concentration is completed, when added to absolute ethanol (10.0 Kg) and the toluene (11.0 Kg) was dissolved in concentrated 5C C. When concentration is complete, and then the absolute ethanol (10.0 Kg) was dissolved was added to toluene (10.1 Kg) and concentrated in 5C C. When the concentration is completed with absolute ethanol (7.7 Kg) was dissolved in 50 was added to toluene (8.4 Kg) ° was repeated in the course of concentration C twice. After re-concentrated solution of absolute ethanol (4.6 Kg) and the dissolution was added to toluene (5.1 Kg) to 50 ° and concentrated in C. Rouen (20.7 When the concentrate is completed,

Kg) was added and the resultant mixture was stirred for 2 hours, filtered and the washed with toluene (12.5 Kg). Was added to 20.7 Kg of toluene to the obtained solid was filtered after stirring for one to two hours. The filtered solid to a toluene (11.9 Kg) and washed with heptane (11.9 Kg) and then 45 ° was obtained in a quantitative and dried for 12 hours in C.

¾- 赚 (DMSO-de, 300 MHz): δ 7.52 (s, 4H), 7.40 (m, 1H), 7. 19-7.02

‘ (M, 3H), 1.49 (s, 6H) .

Example 6: 4- (3- (3-fluoro-phenyl) -5, 5-dimethyl-4-oxo-4, 5-dihydro-furan-2-yl) Preparation of benzenesulfonamide

Sodium 4- (3 eu (3_-fluorophenyl) -5, 5-dimethyl-4-oxo-4, 5-dihydro-furan-2-yl eudi) after the benzene sulfinate (6.0 Kg) was dissolved in dichloromethane – 5 ° and cooled to C. After stirring for another part banung ^ the combined dichloromethane (6.0 Kg) and sulfonic sulfuryl chloride (2. 1 Kg), 0 to the reaction solution obtained in the above ° was added slowly for 1 hour under C. A common banung hapaek eu 5 ° and after stirring for 4 hours at C and the organic layer was separated and washed with brine. After filtering the organic layer was dried over sodium sulfate (4.2 Kg), the filtrate was 40 ° and concentrated in C or less to give the intermediates of sulfonyl chloride compounds.

Tetrahydrofuran (36.3 Kg) and aqueous ammonia (16.9K the other part banung g were combined for common) was nyaenggak to 0 ° C. By dissolving the obtained sulfonic ponal chloride compound in 8.9 Kg of tetrahydrofuran 5 ° , while maintaining the below C was added slowly to the prepared aqueous ammonia solution for 1 hour.This solution banung -5 ° was concentrated after stirring for 30 to 120 minutes in the C. Once completed, the concentrated, purified water 40.2 L

It was added and stirred for 1 to 2 hours. Filtered and the resulting solid was then washed with purified water (16.9 L) and heptane (11.4 Kg). The filtered solid 45 °followed by drying for 12 hours at C, to give the desired compound (4.3 Kg, 73%).

mp: 204-205 ° C

¾-NMR (CDCls, 300 MHz): δ 1.57 (s, 6H), 4.96 (br s, 2H), 6.78 (m,

1H), 6.82 (m, 2H), 7.78 (d, J = 8.7 Hz, 2H), 7.96 (d, J = 8.7 Hz, 2H) IR (cm- 1 ): 3267, 1686, 1218, 1160

Example 7: Preparation of 2-bromo butyryl cattle feeders cyanide

Was added trimethylsilyl cyanide (283.4 g, 2.86 mol) in 2-bromo cattle feeders butyryl bromide (557 g, 2.24 mol). This solution banung 90 ° After stirring at C for 3 hours to nyaenggak to room temperature. Banung completed under reduced pressure (79画¾), 66 to 75 ° to fractional distillation under a C, to give the desired compound (384 g, 90.04%).

-醒(CDC1 3) 300 MHz): δ 1.97 (s, 6H)

PATENT

WO 2000061571

STR1

 

Patent ID Date Patent Title
US2010069483 2010-03-18 DUAL INHIBITION OF CYCLOOXYGENASE-2 AND CARBONIC ANHYDRASE
US2008306146 2008-12-11 Dosing Regimens for Cox-2 Inhibitor
US2005222251 2005-10-06 Dual inhibition of cyclooxygenase-2 and carbonic anhydrase
US6492416 2002-12-10 4,5-diaryl-3(2H)-furanone derivatives as cyclooxygenase-2 inhibitors
WO0061571 2000-10-19 4,5-DIARYL-3(2H)-FURANONE DERIVATIVES AS CYCLOOXYGENASE-2 INHIBITORS

References

  1.  “CrystalGenomics Receives MFDS Approval for Acelex® (Polmacoxib)”. PR Newswire.
  2.  Skarke, C.; Alamuddin, N.; Lawson, J. A.; Cen, L.; Propert, K. J.; Fitzgerald, G. A. (2012). “Comparative impact on prostanoid biosynthesis of celecoxib and the novel nonsteroidal anti-inflammatory drug CG100649”. Clinical Pharmacology & Therapeutics 91 (6): 986–93. doi:10.1038/clpt.2012.3.PMC: 3740579. PMID 22278334.
  3.  Hirankarn, S.; Barrett, J.S.; Alamuddin, N.; Fitzgerald, G. A.; Skarke, C. (2013). “GCG100649, A Novel Cyclooxygenase-2 Inhibitor, Exhibits a Drug Disposition Profile in Healthy Volunteers Compatible With High Affinity to Carbonic Anhydrase-I/II: Preliminary Dose–Exposure Relationships to Define Clinical Development Strategies”. Clinical Pharmacology in Drug Development 2 (4): 379–386. doi:10.1002/cpdd.47.
Polmacoxib
Polmacoxib.svg
Systematic (IUPAC) name
4-(3-(3-Fluorophenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)-benzenesulfonamide
Clinical data
Trade names Acelex
Identifiers
CAS Number 301692-76-2
PubChem CID 9841854
ChemSpider 8017569
UNII IJ34D6YPAO
ChEMBL CHEMBL166863
Synonyms CG100649
Chemical data
Formula C12H16FNO4S
Molar mass 361.3914 g/mol

///////Polmacoxib, CG-100649, 301692-76-2

CC1(C(=O)C(=C(O1)C2=CC=C(C=C2)S(=O)(=O)N)C3=CC(=CC=C3)F)C

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NEW PATENT, WOCKHARDT LIMITED, WO 2016055918, ISAVUCONAZOLE

 PATENTS  Comments Off on NEW PATENT, WOCKHARDT LIMITED, WO 2016055918, ISAVUCONAZOLE
Apr 222016
 

 

WO2016055918) NOVEL STABLE POLYMORPHS OF ISAVUCONAZOLE OR ITS SALT THEREOF

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

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

The present invention relates to novel stable novel stable polymorphs of Isavuconazole or its salt thereof, having purity more than 90 % when measured by HPLC. In particular the present invention directs process for the preparation of solid amorphous and crystalline form of Isavuconazole base. In a further embodiment present invention directs to crystalline form Isavuconazole Hydrobromide salt and oxalate salt of 2-(2,5-difluoro- phenyl)-1-[1,2,4]triazol-1-yl-butane-2,3-diol.

Isavuconazole, Isavuconazonium, Voriconazole, and Ravuconazole are azole derivatives and known as antifungal drugs for treatment of systemic mycoses as reported in US 5,648,372, US 5,792,781, US 6,300,353 and US 6,812,238.

The US patent No. 6,300,353 discloses Isavuconazole and its process. It has chemical name [(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl)]-l -(lH-l,2,4-triazol-l-yl)-2-(2,5-difluorophenyl)43utan-2-ol; and has the structural formula I:

Formula I

The ‘353 described the process for the preparation Isavuconazole, involve the use of 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l-yl-butane-2,3-diol (referred herein after “diol base”) in an oil form, which is difficult to isolate and purify. The use of 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l-yl-butane-2,3-diol base, without purification, reflects the purity of Isavuconazole and Isavuconazonium sulfate. However, the reported process not feasible industrially.

Thus, an object of the present invention is to provide simple, cost effective and industrially feasible processes for preparation of Isavuconazole or its salt thereof in enhanced yield as well as purity. In a particular present invention directs to novel stable polymorphs of Isavuconazole or its salt thereof.

Examples

Example-1: Preparation of Amorphous Isavuconazole

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

Yield: 26.5 gm

HPLC purity: 92.7%

Example-2: Preparation of crystalline Isavuconazole Base

Charged methylene dichloride (250 ml) and 25.0 gm Isavuconazole Hydrobromide compound of formula-II into 1.0 L flask and stirred. Added aqueous solution of sodium bi carbonate in to the reaction mass to obtained clear solution. The layers were separated and organic layer was washed with dilute hydrochloric acid solution followed by saturated solution of sodium chloride. Finally, Organic layer was concentrated under vacuum to get titled product.

Yield: 18.5 gm

HPLC Purity: 97%

Example-3: Preparation of crystalline Isavuconazole Hydrobromide

Charged isopropanol alcohol (250 ml) followed by thioamide compound (25.0 gm) and 4-cyano phenacyl bromide (18.4 gm) into 1.0 L flask. The reaction mixture was stirred and heated to 50 C, after completion of reaction the precipitated material was filtered and washed with isopropanol alcohol (25 ml). The wet cake is dried under vacuum for 4-5 hrs at 40 C to obtain off-white solid product.

Yield: 26.5 gm

HPLC Purity: 97.3%

Exaniple-4: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate

Dissolved crude 50 gm 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l -yl-butane-2,3-diol base compound in 150 ml of ethyl acetate. Oxalic acid dihydrate 25 gm was added into the reaction mixture and stirred. Heat the reaction mixture for 1 hour at 50-55 °C. The reaction mixture was cooled to 25°C to 35°C. Toluene 300 ml was added into the reaction mixture to precipitate the solid. The precipitate was washed with toluene and dried under vacuum to obtain the solid crystalline form of titled compound.

Yield: 58 g

HPLC Purity: 76%

Exaniple-5: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate salt

Exemplified procedure in example 1 with the replacement ethyl acetate solvent with tetrahydrofuran and antisolvent toluene with petroleum ether were used to get the title compound.

Exaniple-6: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate

Exemplified procedure in example 1 with the replacement ethyl acetate solvent with isopropyl acetate and antisolvent toluene with diisopropyl ether were used to get the title compound.

Exaniple-7: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate

Exemplified procedure in example 1 wherein diethyl ether is used in place of ethyl acetate and toluene or heptane was used as antisolvent to get the title compound.

Example-8: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate

Exemplified procedure in example 1 wherein diethyl ether is used in place of ethyl acetate and isolation of the product were done by means of partial removal of the solvent under vacuum.

Example-9: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate

Exemplified procedure in example 1 wherein ethyl acetate is replaced with isopropyl acetate and further, the reaction mass was stirred at lower temperatures to about 10°C to about 15°C for 3-5 hours and subsequently precipitated product was isolated and dried.

Example-10: Synthesis of 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l-yl-butane-2,3-diol base

Stirring the suspension of 260 ml water and 65 gm 2-(2,5-difluoro-phenyl)-l-[l,2,4] triazol-l-yl-butane-2,3-diol oxalate salt were added. The reaction mixture pH was adjusted by addition of 10 % aqueous sodium carbonate solution. The pH was maintained to about pH 7 to about 8, 300 ml dichloro methane was added into the reaction mixture with stirring. The layers were separated and dichloromethane layer was collected. Aqueous layer was extracted with 150 ml dichloromethane. Dichloromethane layer was combined and washed with water. Dichloromethane was distilled out to get titled compound.

Yield: 35 gm

Purity: 87%

 

Wockhardt Ltd chairman Habil Khorakiwala.

 

 

/////////NEW PATENT, WOCKHARDT LIMITED, WO 2016055918, ISAVUCONAZOLE

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“7th Annual Clinical Trials Summit 2016” “A critical guide for successfully conducting clinical trials” 24th May 2016, The Lalit Hotel, Mumbai, India

 Uncategorized  Comments Off on “7th Annual Clinical Trials Summit 2016” “A critical guide for successfully conducting clinical trials” 24th May 2016, The Lalit Hotel, Mumbai, India
Apr 212016
 

Deepak Raj

Deepak Raj

Delegate & Sponsorship Sales

 

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Virtue Insight

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“7th Annual Clinical Trials Summit 2016”

“A critical guide for successfully conducting clinical trials”

24th May 2016, The Lalit Hotel, Mumbai, India

str1

 

Greeting From Virtue Insight,

I am happy to invite you and your colleagues to be a sponsor/ delegate for our upcoming “7th Annual Clinical Trials Summit 2016”. The conference will be held on 24th May 2016, The Lalit Hotel, Mumbai, India. Please find the detailed agenda for the same with this email.

KEY SPEAKERS:-

  • ANKA G. EHRHARDT, Director Clinical Cytometry, Biomarker Technologies, ECTR, Bristol-Myers Squibb (USA)
  • JOHN LAMBERT, Chief Medical Officer Early Phase, PAREXEL International (UK)
  • SUMIT MUNJAL, Medical Director Lead, Global Medical Safety , Head of Mature Established products, Takeda Pharmaceuticals (UK)
  • ARUN BHATT, Consultant – Clinical Research & Development
  • BHASWAT CHAKRABORTY, Senior VP & Chair, Research and Development, Cadila
  • HEMA BAJAJ, Head of Clinical Quality & Medical Compliance – Affiliate Quality Officer, Sanofi Aventis
  • ANISH DESAI, Director Medical Affairs, Clinical Operations & Device Safety, Johnson & Johnson
  • KAVYA KADAM, Head – Global Clinical Operations, Cipla
  • PIYUSH GUPTA, Associate Director, GNH India
  • SAMBIT PATNAIK, CEO & Medical Director, Clintech India
  • KEDAR SUVARNAPATHAKI, Head-Regulatory Affairs, Boehringer Ingelheim
  • CHANDRA SEKHAR, Vice President Quality (Pharma), Reliance Life Sciences
  • ROHIT ARORA, Head – Medical & Scientific Affairs, Abbott
  • NARESH TONDARE, Head – India and Nepal Regulatory Affairs, Glenmark Pharmaceuticals
  • MURTUZA BUGHEDIWALA, Associate Director, Project Management & Strategic Initiatives, Sanofi
  • MILIND ANTANI, Partner In-Charge – Pharma LifeSciences, Nishith Desai Associates
  • YASHESH MEHTA, Director Delivery Partner, Sciformix
  • SHILPA RAUT, Regional Training Head – Asia, Middle East and Africa Cluster, Novartis
  • DEEPTI SANGHAVI, Assistant Manager-Medical Writing, Tata Consultancy Services
  • UMAKANTA SAHOO, Director, Cytel
  • AMEY MANE, General Manager – Medical Affairs, Janssen India (Pharmaceutical companies of Johnson & Johnson)
  • SANKET SAWANT, Strategy & Business Development Partner, SIRO Clinpharm
  • ASHWANI PANDITA, Dy. General Manager Quality Management & Training, Global Clinical Research Operations, Glenmark Pharmaceuticals

Plus Many More..

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We also have some sponsorship opportunities available for the event which gives you an opportunity to speak/exhibit and create brand awareness. In addition, the networking opportunities in focused and relevant industry gathering provide the personal contact necessary for business development efforts.

In case you or any of your colleagues might be interested in participating in the same, please let me know and I will be happy to call you and help you with the registration.

Thank you for your time and consideration. I look forward to hearing from you.

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Deepak Raj

Best Regards,

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Virtue Insight

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Tel –      + 91 44 65515693

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