FLAGS AND HITS
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
FACEBOOK
...................................................................Join me on twitter
..................................................................Join me on google plus
GoogleplusMYSELF
FDA approves Gazyva for chronic lymphocytic leukemia
Drug is first with breakthrough therapy designation to receive FDA approval
The U.S. Food and Drug Administration today approved Gazyva (obinutuzumab) for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL).
read all at
http://www.pharmalive.com/fda-approves-roche-s-gazyva
my old article cut paste
Roche’s new leukaemia drug, Obinutuzumab, superior to Rituxan in clinical trial
JULY 25, 2013 12:52 AM / 6 COMMENTS / EDIT
July 24 2013 | By Márcio Barra
Roche has announced that its experimental leukemia drug GA101, or obinutuzumab, used in combination with chemotherapy, was better than Rituxan at helping people with chronic lymphocytic leukemia live longer without their disease worsening, according to the results from the second phase of the clinical trial. Both drugs were tested and compared in combination with chlorambucil.
Roche’s Phase III leukemia drug Obinutuzumab (GA101) yields positive results
- GA101 is the first glycoengineered, type II anti-CD20 mAb.
Roche’s Phase III leukemia drug Obinutuzumab (GA101) yields positive results
Obinutuzumab (GA101)
| FORMULA | C6512H10060N1712O2020S44 |
|---|
GA101 is the first glycoengineered, type II anti-CD20 monoclonal antibody (mAb) that has been designed for increased antibody-dependent cellular cytotoxicity (ADCC) and Direct CellDeath.1 This agent is being investigated in collaboration with Biogen Idec.
Swiss pharmaceutical company Roche has announced that its early Phase III trial of Leukemia drug obinutuzumab (GA101) demonstrated significantly improved progression-free survival in people with chronic lymphocytic leukemia (CLL).
The positive results yield from stage 1 of a three-arm study called CLL11, designed to investigate the efficacy and safety profile of obinutuzumab (GA101) plus chlorambucil, a chemotherapy, compared with chlorambucil alone in people with previously untreated chronic lymphocytic leukemia (CLL).
This phase of the study met its primary endpoint and an improvement in progression-free survival was achieved; obinutuzumab plus chlorambucil significantly reduced the risk of disease worsening or death compared to chlorambucil alone.
Roche chief medical officer and global product development head Hal Barron said; “the improvement in progression-free survival seen with GA101 is encouraging for people with CLL, a chronic illness of older people for which new treatment options are needed.”
“GA101 demonstrates our ongoing commitment to the research and development of new medicines for this disease.”
Obinutuzumab is Roche’s most advanced drug in development for the treatment of hematological malignancies.
It has been specifically designed as the first glycoengineered, type 2 anti-CD20 monoclonal antibody in development for B cell malignancies.
Afutuzumab is a monoclonal antibody being developed by Hoffmann-La Roche Inc. for the treatment of lymphoma.[1] It acts as an immunomodulator.[2][3] It was renamed obinutuzumab in 2009.[4]
References
- Robak, T (2009). “GA-101, a third-generation, humanized and glyco-engineered anti-CD20 mAb for the treatment of B-cell lymphoid malignancies”. Current opinion in investigational drugs (London, England : 2000) 10 (6): 588–96. PMID 19513948.
- Statement On A Nonproprietary Name Adopted By The Usan Council – Afutuzumab,American Medical Association.
- International Nonproprietary Names for Pharmaceutical Substances (INN), World Health Organization.
- International Nonproprietary Names for Pharmaceutical Substances (INN), World Health Organization.
-
OBINUTUZUMAB ISMONOCLONAL ANTIBODY TYPE Whole antibody SOURCE Humanized (from mouse) TARGET CD20
Biosimilar drugs in Portugal
November 1 ,2013 | By Márcio Barra
What follows is a list of Biosimilar drugs available in Portugal. This data has been compiled from the INFOMED database, managed by the Portuguese National Competent Authrority on Medicines, INFARMED. The Portuguese Marketing approval date was also provided. In the Market Status, you may find “no data” on some drugs. This means that the drug in question has no information displayed on the INFOMED database, save for its name.
View original post 486 more words
Cempra’s Taksta secures FDA orphan drug status for prosthetic joint infections treatment
FUSIDIC ACID, 6990-06-3
2-[(1S,2S,5R,6S,7S,10S,11S,13S,14Z,15R,17R)-13-(acetyloxy)-5,17-dihydroxy-2,6,10,11-tetramethyltetracyclo[8.7.0.02,7.011,15]heptadecan-14-ylidene]-6-methylhept-5-enoic acid
Taksta (CEM-102)
Clinical-stage pharmaceutical firm Cempra has secured orphan drug status from the US Food and Drug Administration (FDA) for its drug candidate Taksta (CEM-102) to treat patients with prosthetic joint infections (PJI).
Cempra’s Taksta secures FDA orphan drug status for prosthetic joint infections treatment
TAKSTATM (CEM-102)
Fusidic acid is a bacteriostatic antibiotic that is often used topically in creams and eyedrops, but may also be given systemically as tablets or injections. The global problem of advancing antimicrobial resistance has led to a renewed interest in its use recently.
Fusidic acid acts as a bacterial protein synthesis inhibitor by preventing the turnover ofelongation factor G (EF-G) from the ribosome. Fusidic acid is effective primarily ongram-positive bacteria such as Staphylococcus species, Streptococcus species, and Corynebacterium species. Fusidic acid inhibits bacterial replication and does not kill the bacteria, and is therefore termed bacteriostatic.
Fusidic acid is a true antibiotic, derived from the fungus Fusidium coccineum and was developed by Leo Laboratories in Ballerup, Denmark and released for clinical use in the 1960s. It has also been isolated from Mucor ramannianus and Isaria kogana. The drug is licensed for use as its sodium salt sodium fusidate, and it is approved for use under prescription in South Korea, Japan, UK, Canada, Europe, Australia, New Zealand, Thailand, India and Taiwan. A different oral dosing regimen, based on the compound’s Pharmacokinetic/pharmacodynamic (PK-PD) profile is in clinical development in the U.S. as Taksta.
Fusidic acid (TAKSTATM, CEM-102) is an antibiotic with a long history of safety and efficacy outside the United States. Cempra has exclusive rights to the supply of the compound for the U.S. market. Fusidic acid is orally active against gram-positive bacteria, including all S. aureus strains such as HA-MRSA and CA-MRSA. A novel dosing regimen has been successfully evaluated in a Phase II trial in patients with acute bacterial skin and skin structure infections (aBSSSI). Cempra is conducting a Phase II trial of TAKSTA for patients with prosthetic joint infections.
Profile of TAKSTA (CEM-102)
Prosthetic joint infections (PJI) occur in about 1% of hip replacements and 2% of knee replacements, translating to an incidence rate of about 10,000 per year in the U.S. at current hip and knee arthroplasty rates. There are few good options to treat these serious staphylococcal, often MRSA infections, which require long-term antibiotic treatment. Current therapy in the U.S. is with intravenous antibiotics such as vancomycin. An oral drug that can be safely administered for a long period of time could improve care and quality of life for these patients.
TAKSTA has shown potent activity against a large number of S. aureus strains, including CA-MRSA, HA-MRSA and linezolid-resistant strains, isolated in the U.S over a 10 year period. Its broad S. aureus coverage makes it useful for a broad range of clinical applications. Because of its safety and tolerability profile, TAKSTA could be ideal for patients suffering from staphylococcal infections that require long-term therapy such as patients with PJIs.
Cempra has developed a unique oral loading dose regimen to optimize key pathogen coverage and minimize drug resistance development. This regimen is incorporated in our Phase II trial to treat PJIs with TAKSTA in combination with rifampin, which is commonly used with injectible antibiotics such as vancomycin to treat PJIs.
Research on TAKSTA
Publications
The links for the articles go to subscription-based sites and may require a fee to view the article.
In Vitro Activity of CEM-102 (Fusidic Acid) Against Prevalent Clones and Resistant Phenotypes of Staphylococcus aureus
DF Sahm, J Deane, CM Pillar, P Fernandes
Antimicrobial Agents and Chemotherapy. June 2013 57: 4535-4346
http://aac.asm.org/content/57/9/4535
Efforts to Support the Development of Fusidic Acid in the United States
P Fernandes, D Pereira
Clinical Infectious Disease. June 2011 52:S542-6
http://www.ncbi.nlm.nih.gov/pubmed/21546632
Case report: Treatment of Chronic Osteomyelitis
CR Wolfe
Clinical Infectious Disease. June 2011 52:S538-41
http://cid.oxfordjournals.org/content/52/suppl_7/S538.long
The Safety Record of Fusidic Acid in Non-US markets: A Focus on Skin Infections
CN Kraus, BW Burnstead
Clinical Infectious Disease. June 2011 52:S527-37
http://cid.oxfordjournals.org/content/52/suppl_7/S527.long
A Randomized, Double-Blind Phase 2 Study Comparing the Efficacy and Safety of an Oral Fusidic Acid Loading-Dose Regimen to Oral Linezolid in the Treatment of Acute Bacterial Skin and Skin Structure Infections
JC Craft, SR Moriarty, K Clark, D Scott, TP Degenhardt, JG Still, GR Corey, A Das, P Fernandes
Clinical Infectious Disease. June 2011 52:S520-26
http://cid.oxfordjournals.org/content/52/suppl_7/S520.long
Application of Pharmacokinetic-Pharmacodynamic Modeling and the Justification of a Novel Fusidic Acid Dosing Regimen: Raising Lazarus from the Dead
BT Tsuji, OO Okusanya, JB Bulitta, A Forrest, SM Bhavnani, P Fernandes, PG Ambrose
Clinical Infectious Disease. June 2011 52:S513-19
http://cid.oxfordjournals.org/content/52/suppl_7/S513.long
Pharmacokinetics and Safety of Single, Multiple, and Loading Doses of Fusidic Acid in Healthy Subjects
JG Still, K Clark, TP Degenhardt, D. Scott, P. Fernandes, M. J. Gutierrez
Clinical Infectious Disease. June 2011 52:S504-12
http://cid.oxfordjournals.org/content/52/suppl_7/S504.long
Activity of Fusidic Acid Against Extracellular and Intracellular Staphylococcus aureus: Influence of pH and Comparison with Linezolid and Clindamycin
S Lemaire, F Van Bambeke, D Pierard, PC Appelbaum, PM Tulkens
Clinical Infectious Disease. June 2011 52:S493-503
http://cid.oxfordjournals.org/content/52/suppl_7/S493.long
Characterization of Global Patterns and the Genetics of Fusidic Acid Resistance
DJ Farrell, M Castanheira, I Chopra
Clinical Infectious Disease. June 2011 52:S487-92
http://cid.oxfordjournals.org/content/52/suppl_7/S493.long
In Vitro Antimicrobial Findings for Fusidic Acid Tested Against Contemporary (2008-2009) Gram-Positive Organisms Collected in the United States
RN Jones, RE Mendes, HS Sader, M Castanheira
Clinical Infectious Disease. June 2011 52:S477-86
http://cid.oxfordjournals.org/content/52/suppl_7/S477.long
New Rules for Clinical Trials in Patients with Acute Bacterial Skin and Skin Structure Iinfections: Do not Let the Perfect be the Enemy of the Good
GR Corey, ME Stryjewski
Clinical Infectious Disease. June 2011 52:S469-76
http://cid.oxfordjournals.org/content/52/suppl_7/S469.long
Introduction: Fusidic Acid Enters the United States
RC Moellering, GR Corey, ML Grayson
Clinical Infectious Disease. June 2011 52:S467-8
http://cid.oxfordjournals.org/content/52/suppl_7/S467.long
Evaluation of the Pharmacokinetics-Pharmacodynamics of Fusidic Acid Against Staphylococcus aureus and Streptococcus pyogenes Using In Vitro Infection Models: Implications for Dose Selection
OO Okusanya, BT Tsuji, JB Bulitta, A Forrest, CC Bulik, SM Bhavnani, P Fernandes, PG Ambrose
Diagnostic Microbiology & Infectious Disease. June 2011 70:101-11
http://www.ncbi.nlm.nih.gov/pubmed/21513848
In Vitro Activity of Fusidic Acid (CEM-102, Sodium Fusidate) Against Staphylococcus aureus Isolated from Cystic Fibrosis Patients and its Effect on the Activities of Tobramycin and Amikacin against Pseudomonas aeruginosa and Burkholderia cepacia
P McGhee, K Credito, L Beachel, PC Appelbaum, K Kosowaska-Shick
Antimicrobial Agents and Chemotherapy. June 2011 55:2417-19
http://www.ncbi.nlm.nih.gov/pubmed/21513848
Occurrence and Molecular Characterization of Fusidic Acid Resistance Mechanisms Among Staphylococcus spp. From European Countries (2008)
Castanheira, M., AA Watters, RE Mendes, DJ Farrell, RN Jones
Antimicrobial Agents and Chemotherapy. April 2010 65:1353-8
http://jac.oxfordjournals.org/content/65/7/1353.long
Update on Fusidic Acid (CEM-102) Tested Against Neisseria gonorrhoeae and Chlamydia trachomatis
R Jones, D Biedenbach, P Roblin, S Kohlhoff, M Hammerschlag
Antimicrobial Agents and Chemotherapy. October 2010 54: 4518-4519
http://aac.asm.org/cgi/content/citation/54/10/4518
Fusidic Acid Resistance Rates and Prevalence of Resistance Mechanisms Among Staphylococcus spp. Isolated in North America and Australia, 2007-2008
M Castanheira, AA Watters, JM Bell, JD Turnidge, RN Jones
Antimicrobial Agents and Chemotherapy. September 2010 54: 3614-3617
http://www.ncbi.nlm.nih.gov/pubmed/20566766
Spectrum of Activity, Mutation Rates, Synergistic Interactions, and the Effects of pH and Serum Proteins for Fusidic Acid (CEM-102)
D Biedenbach, P Rhomberg, R Mendes, R Jones
Diagnostic Microbiology & Infectious Disease. March 2010 66: 301-307
http://www.dmidjournal.com/article/S0732-8893(09)00424-6/abstract
Performance of Fusidic Acid (CEM-102) Susceptibility Testing Reagents: Broth Microdilution, Disk Diffusion, and Etest Methods as Applied to Staphylococcus aureus
R Jones, M Castanheira, P Rhomberg, L Woosley, M Pfaller
Journal of Clinical Microbiology. March 2010 48: 972-976
http://jcm.asm.org/cgi/content/abstract/48/3/972
Evaluation of the Activity of Fusidic Acid Tested Against Contemporary Gram-Positive Clinical Isolates From the USA and Canada
M Pfaller, M Castaneira, H Sader, R Jones
International Journal of Antimicrobial Agents. March 2010 35: 282-287
http://www.ijaaonline.com/article/S0924-8579(09)00510-X/abstract
Quantitative and qualitative assessment of antibiotic activity against Staphylococcus aureus biofilm.
Siala, W., M. P. Mingeot-Leclercq, P. M. Tulkens, and F. Van Bambeke.
Abstr. 6th Am. Soc. Microbiol. Conf. Biofilms, abstr A-179.
Download Poster 
Activity of Fusidic Acid Against Methicillin-resistant Staphylococcus Aureus (MRSA) Isolated from CF Patients
Prabhavathi Fernandes, Donald Anderson, K. Kosowska-Shick, P. McGhee, L. Beachel and P.C. Appelbaum
Download Abstract | Download Poster
Evaluation of L6 Ribosomal Protein Alterations in Fusidic Acid-Resistant Staphylococcus aureus: Fitness Cost and Time Kill Analysis
M Castanheira, RN Jones, LN Woosley, RE Mendes, GJ Moet, DJ Farrell
Download Abstract
Fusidic Acid Activity and Coverage of Gram-positive Pathogens Associated with Acute Bacterial Skin and Skin Structure Infections (ABSSSI) in the USA (2008-2010)
RN Jones, DJ Farrell, HS Sader, M Castanheira
Download Abstract | Download Poster
Activity of Fusidic Acid Tested Against Contemporary Staphylococcus aureus Collected from United States Hospitals
M. Castanheira, R.E. Mendes, P.R. Rhomberg, R.N. Jones
Download Abstract | Download Poster
Pharmacokinetics-Pharmacodynamics (PK-PD) of CEM- 102 (Sodium Fusidate) Against Streptococcus pyogenes Using In Vitro Pharmacodynamic Models (IVPM)
B. T. Tsuji, A. Forrest, P. A. Kelchlin, T. Brown, P. N. Holden, O. O. Okusanya, S. M. Bhavnani, P. Fernandes, P. G. Ambrose
Download Abstract | Download Poster
Activity of CEM-102 (sodium fusidate) against 40 MRSA from Cystic Fibrosis Patients
Cynthia Todd, Pamela Mcghee, and Peter Appelbaum
Download Abstract | Download Poster
Ability of CEM-102 (Fusidic Acid), Linezolid, Daptomycin to Select Resistant S.aureus Mutants at Steady-state Serum Levels
K. Kosowska-Shick, P. Mcghee, L. Beachel, P. C. Appelbaum;
Download Abstract | Download Poster
CEM-102 (Fusidic Acid) Maintains Potency against Resistant MRSA and Prevalent Hospital Acquired, Community Acquired,and Epidemic MRSA Clones
C.M. Pillar, M.K. Torres, D.F. Sahm and P. Fernandes
Download Abstract | Download Poster
In Vitro Activity Of Fusicic Acid (CEM-102) Against Resistant Strains Of Staphylococcus aureus
J. dubois, P. Fernandes
Download Abstract | Download Poster
Trade names and preparations
- Fucidin (of Leo in Canada and the US)
- Fucidin H (topical cream with corticosteroid – Leo)
- Fucidin (of Leo in UK/ Leo-Ranbaxy-Croslands in India)
- Fucidine (of Leo in France)
- Fucidin (of Leo in Norway)
- Fucidin (of Adcock Ingram, licenced from Leo, in South Africa)
- Fucithalmic (of Leo in the UK, the Netherlands, Denmark and Portugal)
- Fucicort (topical mixture with hydrocortisone)
- Fucibet (topical mixture with betamethasone)
- Ezaderm (topical mixture with betamethasone)(of United Pharmaceutical “UPM” in Jordan)
- Fuci (of pharopharm in Egypt)
- Fucizon (topical mixture with hydrocortisone of pharopharm in Egypt)
- Foban (topical cream in New Zealand)
- Betafusin (cream mixture with betamethasone valerate in Greece)
- Fusimax (of Schwartz in India)
- Fusiderm (topical cream and ointment by indi pharma in India)
- Fusid (in Nepal)
- Fudic (topical cream in India)
- Fucidin (후시딘, of Dong Wha Pharm in South Korea)
- Stanicid (in Serbia)
- Dermy (Topical cream of W.Woodwards in Pakistan)
- Fugen Cream (膚即淨軟膏 in Taiwan)
- Phudicin Cream (in China; 夫西地酸[24])
- Dermofucin cream ,ointment and gel (in Jordan)
- Optifucin viscous eye drops (of API in Jordan)
- Verutex (of Roche in Brazil)
- TAKSTA (of Cempra in U.S.)
- Futasole (of Julphar in Gulf and north Africa)
- Stanicid (2% ointment of Hemofarm in Serbia)
- Fuzidin (tablets of Biosintez in Russia)
- Fuzimet (ointment with methyluracil of Biosintez in Russia)
- Axcel Fusidic Acid(2% cream and ointment of Kotra Pharma, Malaysia)
MORE INFO
Fusidic acid (FA) is a tetracyclic triterpenoid or fusidane (steroidal) antibiotic derived from the fungus Fusidium coccineum that inhibits bacterial protein synthesis. FA is effective against gram-positive bacteria such as Staphylococcusspecies and Corynebacterium species (L. Verbist, J. Antimicro. Chemo. 25, Suppl. B, 1-5 (1990); A. Bryskier, Fusidic Acid, Chapter 23, in Antimicrobial Agents: Antibacterials and Antifungals (Andre Bryskier, Ed., ASM Press, Washington, USA, 2005)). FA also has moderate activity against Group A beta-hemolytic streptococci, or Streptococcus pyogenes (L. Verbist, J. Antimicro. Chemo. 25, Suppl. B, 1-5 (1990); A. Bryskier, Fusidic Acid, Chapter 23, inAntimicrobial Agents: Antibacterials and Antifungals (Andre Bryskier, Ed., ASM Press, Washington, USA, 2005); Skov et al., Diag. Micro. Infect. Dis. 40:111-116 (2001)).
-
Fusidic acid, chemically (3α, 4α, 8α, 9α, 11α, 13α, 14α, 16α, 17Z)-16-(Acetyloxy)-3,11-dihydroxy-29-nordammara-17(20), 24-dien-21-oic acid, is an antibacterial agent. It is a well-known antibiotic with a unique steroid-like tetracyclic ring system structure, and it is the most potent of a small family of steroidal antibiotics, the fusidanes. It is produced by fermentation under controlled conditions of the fungus Fusidium Coccineum.
-
The excellent distribution in various tissues, low degree of toxicity and allergic reactions and the absence cross-resistance with other clinically used antibiotics has made fusidic acid a highly valuable antibiotic,especially for skin and eye infections. The drug is used clinically both in its acid form, and as the sodium salt (Fusidin®), however Fusidin® is more favored one because of its better solubility in water, enabling a fast absorption from gastro-intestinal tract. As a result, it is more preferable to use sodium salt of fusidin in oral solid forms.
-
Fusidin® has the actions and uses of fusidic acid, and it has been shown that it ameliorates the course of several organ-specific immuno-inflammatory diseases such as chronic uveitis, Behcet’s disease, type I diabetes mellitus, Guillain-Barre syndrome, hepatitis, sepsis, pancreatitis, formalin-induced edema, multiple sclerosis, and scleroderma, whereby fucidin formulations have a great importance in pharmaceutical production.
-
Fusidin® can be presented in various formulations that differ significantly in their pharmacokinetic behaviors such as oral tablets, oral suspensions, intravenous formulations and topical preparation. Considering oral tablets, many of the early clinical studies were performed with capsule containing sodium fusidate. This was also the formulation marketed for many years in several countries. It is currently available as an oral tablet containing the sodium salt. Originally the sodium salt was available as an enteric-coated form but later it was reformulated as a film-coated tablet that appears to be better tolerated and gives higher blood levels.
-
Fusidic acid sodium salt was used in capsules as well as in tablets which were coated enterically. However by this enteric coating, the active fusidic acid sodium salt was not released before the tablets reached the part of the gastrointestinal tract in which the enteric coating would be dissolved. Depending on the time of passage through the stomach together with the food and the pH in the gastrointestinal tract, this led to unpredictable variations in the blood concentration of the patient undergoing treatment. Because of these adverse differences in blood concentration, the tablets without enteric coating were produced. Now, sodium fusidate is available in tablet, oral solution and injection form
-
PCT/WO9603128 A (LEO PHARMACEUTICALS PRODUCTS LTD. ET.AL.) describes the preparation of fusidic acid sodium salt tablets without an enteric coating by using dry granulation method in which a roller compactor was used. The compacted material so produced was size reduced to form a granulate having a bulk density in the range 0.45 to 0.9 g/m3 which was then formed into tablets.
FA was developed for clinical use in the 1960s and it is approved for human use outside of the United States, such as in the UK, Canada, Europe, Israel, Australia and New Zealand. It is typically prescribed at doses of 500 mg TID for treating skin and skin structure infections caused by Staphylococcus aureus (A. Bryskier,Fusidic Acid, Chapter 23, in Antimicrobial Agents: Antibacterials and Antifungals(Andre Bryskier, Ed., ASM Press, Washington, USA, 2005); Collignon et al., Int’l J. Antimicrobial Agents 12:S45-S58 (1999); D. Spelman, Int’l J. Antimicrobial Agents 12:S59-S66 (1999)), although some physicians have routinely prescribed the compound at 500 mg BID for treating skin and skin structure infections due to the long half-life of the compound (Fusidic Acid, in Principles and Practice of Infectious Diseases, 6th ed. (Mandell et al. eds., Elsevier, 2006)).
Treatment using FA has been well studied and it is generally regarded as safe when administered to humans, as evidenced by the fact that the drug has been in continuous use for more than 40 years. There are, however, several characteristics of FA that have prevented use of the drug against a wider spectrum of bacteria and in the treatment in additional types of infection. For example, approved dosing regimens have been shown to select for bacterial resistance, such as in S. aureus. Approved dosing regimens provide low multiples of the MIC and as a result, S. aureus resistant mutants can be selected after the first day of dosing. Once resistance has developed, FA is not effective against the resistant strains. Resistance is reported to occur if FA is used as a single drug as the resistance frequency at 4 and 8 times the MIC is in the range of 10−6 or 10−8 (Evans et al., J. Clin. Path. 19:555-560 (1966); Hansson et al., J. Mol. Biol.348:939-949 (2005), Jensen et al., Acta Pathol Microbiol Scand. 60:271-284 (1964); Besier et al., Antimicrob. Agents Chemo., 49(4):1426-1431 (2005); Gemmell et al., J. Antimicrobial Chemo. 57:589-608 (2006)).
The dosage of the drug cannot be simply increased as a means of avoiding development of resistance. It is difficult to achieve high concentrations of FA in the blood due to the substantial protein binding of the drug (approximately 95-97%) (K. Christiansen, International Journal of Antimicrobial Agents 12:S3-S9 (1999); Coutant et al., Diagn Microbiol Infect Dis 25:9-13 (1996); D. Reeves, J. Antimicrob. Chemo. 20:467-476 (1987); J. Turnidge, Int’l J. Antimicrobial Agents12:S23-S34 (1999); Rieutord et al., Int’l J. Pharmaceutics 119:57-64 (1995)). Moreover, high dosages of FA are not well-tolerated by patients receiving the drug. High doses of FA (e.g., 1 gram TID) are required if the drug is to be used in the treatment of bone and joint infections, less susceptible bacteria and other serious infections. However, treatment regimens using high doses of the drug induce nausea and vomiting and are rejected by patients (Fusidic Acid, inPrinciples and Practice of Infectious Diseases, 6th ed. (Mandell et al. eds., Elsevier, 2006); K. Christiansen, International Journal of Antimicrobial Agents 12:S3-S9 (1999); Nordin et al., Eur. J. Clin. Res. 5:97-106 (1994)).
In view of the tremendous costs associated with the de novo development of new anti-bacterials, expanding the indications for drugs that have already been demonstrated to be safe and effective is strongly needed. Overcoming the limitations on the uses of FA would broaden the population of bacterial infections against which it could be used and thus meet this need.
In a specific commercial pharmaceutical formulation, fusidic acid is presently marketed [see Monographs in the European Pharmacopeia 5.0] as a hemihydrate, which is the only hemihydrate form which has been described.
Patent GB 930,786 discloses salts of fusidic acid with organic and inorganic bases, solvates of fusidic acid, namely a benzene solvate and a methanol solvate. This patent further discloses an unspecified fusidic acid form with IR absorption bands (KBr) at 1265, 1385, 1695, 1730 and 3450 cm“1 and having a specific rotation [α]D 22 of minus 9 degrees (1% solution in CHCI3) obtainable by crystallisation of the methanol solvate of fusidic acid from ether. However, this form is distinct from the form of the present invention evident from the depicted IR spectrum in GB 930,786 which indicates that this form actually corresponds to the presently marketed hemihydrate form.
Solvates and salts of fusidic acid have also been disclosed in British patent GB 999,794. Patent ES 2208110 discloses two solvent free crystalline forms offusidic acid called Form I and Form II, and a crystalline hemihydrate called Form III which is identical to the presently marketed hemihydrate, respectively. The crystalline forms were identified and characterised by IR spectroscopy, differential scanning calorimetry, X-ray diffraction and melting points.
Patent WO 96/03128 discloses tablets containing a sodium salt form of fusidicacid and WO 86/03966 describes an ophthalmic gel composition comprising an undefined form of suspended fusidic acid.
Pimavanserin …New Drug Shows Early Promise in Treating Parkinson’s Psychosis
Pimavanserin, ACP 103
N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N’-(4-(2-methylpropyloxy)phenylmethyl)carbamide, 706779-91-1 cas
 706782-28-7 (tartrate) |
THURSDAY Oct. 31, 2013 — Many people living with Parkinson’s disease suffer from hallucinations and delusions, but an experimental drug might offer some relief without debilitating side effects.
READ ALL AT
http://www.drugs.com/news/new-shows-early-promise-treating-parkinson-s-psychosis-48630.html
The drug — pimavanserin — appears to significantly relieve these troubling symptoms, according to the results of a phase 3 trial to test its effectiveness.
Pimavanserin (ACP-103) is a drug developed by Acadia Pharmaceuticals which acts as an inverse agonist on the serotonin receptor subtype 5-HT2A, with 40x selectivity over 5-HT2C, and no significant affinity or activity at 5-HT2B or dopamine receptors.[1] As of September 3 2009, pimavanserin has not met expectations for Phase III clinical trials for the treatment of Parkinson’s disease psychosis,[2] and is in Phase II trials for adjunctive treatment of schizophrenia alongside an antipsychotic medication.[3] It is expected to improve the effectiveness and side effect profile of antipsychotics.[4][5][6]
3-D MODEL OF DRUG PIMAVANSERIN, THE DEVELOPMENT OF WHICH HAS BEEN EXPEDITED BY THE FDA
- Friedman, JH (October 2013). “Pimavanserin for the treatment of Parkinson’s disease psychosis”. Expert Opinion on Pharmacotherapy 14 (14): 1969–1975.doi:10.1517/14656566.2013.819345. PMID 24016069.
- ACADIA Pharmaceuticals. “Treating Parkinson’s Disease – Clinical Trial Pimavanserin – ACADIA”. Retrieved 2009-04-11.[dead link]
- “ACADIA Announces Positive Results From ACP-103 Phase II Schizophrenia Co-Therapy Trial” (Press release). ACADIA Pharmaceuticals. 2007-03-19. Retrieved 2009-04-11.
- Gardell LR, Vanover KE, Pounds L, Johnson RW, Barido R, Anderson GT, Veinbergs I, Dyssegaard A, Brunmark P, Tabatabaei A, Davis RE, Brann MR, Hacksell U, Bonhaus DW (August 2007). “ACP-103, a 5-hydroxytryptamine 2A receptor inverse agonist, improves the antipsychotic efficacy and side-effect profile of haloperidol and risperidone in experimental models”. J Pharmacol Exp Ther 322 (2): 862–70.doi:10.1124/jpet.107.121715. PMID 17519387.
- Vanover KE, Betz AJ, Weber SM, Bibbiani F, Kielaite A, Weiner DM, Davis RE, Chase TN, Salamone JD (October 2008). “A 5-HT2A receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model”. Pharmacol Biochem Behav 90 (4): 540–4. doi:10.1016/j.pbb.2008.04.010. PMC 2806670.PMID 18534670.
- Abbas A, Roth BL (December 2008). “Pimavanserin tartrate: a 5-HT2A inverse agonist with potential for treating various neuropsychiatric disorders”. Expert Opin Pharmacother9 (18): 3251–9. doi:10.1517/14656560802532707. PMID 19040345.
Psychiatrist Herb Meltzer sadly watched the agitated woman accuse her son of trying to poison her. Although not her physician, Dr. Meltzer certainly recognized the devastating effects of his mother-in-law’s Parkinson’s disease psychosis (PDP). Occurring in up to half of all patients with Parkinson’s, symptoms of the psychotic disorder may include hallucinations and delusions. The development of PDP often leads to institutionalization and increased mortality.
“I was on the sidelines,” explains Dr. Meltzer, professor of psychiatry and physiology and director of the Translational Neuropharmacology Program at Northwestern University Feinberg School of Medicine. “I told my brother-in-law it was the disease talking, not his mother.”
Ironically, Dr. Meltzer has been far from the sidelines and right on the PDP playing field for quite a while. In fact, he may soon see a drug he helped develop become the first approved treatment for the disorder. In early April, Dr. Meltzer celebrated, along with colleagues at ACADIA Pharmaceuticals in San Diego for which he has been a clinical advisor, the stunning announcement: the Food and Drug Administration (FDA) had expedited the company’s path to filing a new drug application (NDA) for pimavanserin, a selective serotonin 5-HT2Areceptor blocker. Typically, the FDA requires data from two successful pivotal Phase III clinical studies affirming a drug candidate’s safety and efficacy before the agency will even consider an NDA. Just as ACADIA was planning to launch another Phase III study this spring to fulfill this requirement, the FDA decided the company had amassed enough data to support an NDA filing.
HERBERT MELTZER, MD, DESIGNED ACADIA PHARMACEUTICAL’S INITIAL PROOF OF CONCEPT TRIAL OF THE DRUG PIMAVANSERIN TO TREAT PARKINSON’S DISEASE PSYCHOSIS.
“This action on the part of the FDA is extremely unusual,” says Dr. Meltzer, who designed ACADIA’s initial proof-of-concept trial of pimavanserin, a drug he had initially suggested ACADIA develop to treat schizophrenia, with PDP as a secondary indication. “The FDA staff decided that results from my small clinical study and the first successful Phase III study were sufficient to establish efficacy and safety.”
Bringing a safe and effective drug to market is a monumental achievement. Pimavanserin is not yet there but has significantly moved within striking distance with this recent nod from the regulatory agency.
24 YEARS IN THE MAKING
The neuropharmacologist’s collaboration with ACADIA began in 2000. The company wanted to develop a drug targeting the serotonin 5-HT 2A receptor, a neurotransmitter ACADIA believed played a key role in schizophrenia based upon basic research from Meltzer and their own studies. A distinguished schizophrenia investigator, then at Case Western Reserve University, he welcomed ACADIA’s offer to translate his ideas about developing safer and more effective drug treatments for psychosis. Through his provocative and groundbreaking research, Dr. Meltzer originally championed the idea that blocking the 5-HT2A receptor would lead to better antipsychotic drugs with fewer side effects. Existing drugs often impaired motor function because they targeted the dopamine D2 receptor. Of the 14 different types of serotonin receptors in this complex area of study, Dr. Meltzer zeroed in on the 5-HT2A type—the same receptor that leads to hallucinogenic properties of LSD and mescaline. It was an ideal target to complement weak D2 receptor blockade in schizophrenia and as a standalone treatment for PD psychosis.
………………………………………….
Veterinary- Atipamezole
Atipamezole
4-(2-Ethyl-1,3-dihydroinden-2-yl)-3H-imidazole, Atipamezole, cas 104054-27-5
hydrochloride cas no 104075-48-1
- MPV 1248 (IS: FarmosGroupLt)
- UNII-03N9U5JAF6 (IS)
- UNII-2W4279571X (IS)
Atipamezole is a synthetic alpha2-adrenergic antagonist, indicated for the reversal of the sedative and analgesic effects of dexmedetomidine and medetomidine in dogs. It has also been researched in humans as a potential anti-Parkinsonian drug.Atipamezole is more potent than yohimbine; it is very selective for alpha2-adrenergic vs alpha1sites, but not selelctive for alpha2 – subtypes.
Atipamezole (brand name Antisedan, Pfizer) is a synthetic alpha2–adrenergic antagonist, indicated for the reversal of the sedative and analgesic effects of dexmedetomidine andmedetomidine in dogs.[1] It has also been researched in humans as a potential anti-Parkinsonian drug.[2]
- Pfizer Animal Health ANTISEDAN Product Overview
- Pertovaara A, Haapalinna A, Sirviö J, Virtanen R (2005). “Pharmacological properties, central nervous system effects, and potential therapeutic applications of atipamezole, a selective alpha2-adrenoceptor antagonist”. CNS Drug Reviews 11 (3): 273–88.doi:10.1111/j.1527-3458.2005.tb00047.x. PMID 16389294.
- ANTISEDAN product information page (Pfizer Animal Health)
- Drugs Future, vol. 15, no. 5, 1990, “Atipamezole“, pages 448-452, see page 449
Synonyms
1H-imidazole, 4-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-
1H-imidazole, 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-
5-(2-Ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole
Atipamezole
4-(2-Ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole
4-(2-Ethyl-2-indanyl)imidazole
4-(2-Ethyl-indan-2-yl)-1H-imidazole(Atipamezole)
4-(2-ethylindan-2-yl)imidazole
Antisedan
Antisedan
Atipamezol
Atipamezolum
Atipamezole Hydrochloride CAS 104075-48-1
………………………………
Atipamezole is a selective alpha2 – adrenoceptor antagonist which is currently marketed under the trademark Antisedan® for the reversal of sedative- analgesic veterinary drugs. Atipamezole has been disclosed e.g. in the European Patent EP 183492 as useful for the reversal of detomidine. European Patent EP 0589957 discloses the use of atipamezole for the treatment of male sexual impotence. In US 4698692 the use of atipamezole for the attenuation of ethyl alcohol intoxication is disclosed.
US Patent No. US6543389 discloses insecticidal pet collars for dogs comprising amitraz and atipamezole. Atipamezole in the collar provides amelioration of amitraz toxicosis in combination with the amitraz in case the dogs ingests the collar. The pet collar comprises 0.01 to 1%, preferably 0.1 to 1 %, by weight of atipamezole. Safe, effective ways to eliminate ectoparasites are desired for the companion animal’s well-being, for the well-being and comfort of its human associate and for the prevention of losses in livestock
A substantial amount of work has been devoted to identifying the neurotransmitters involved in the facilitation and inhibition of male sexual behaviour (see e.g. Bitran and Hull 1987, Neuroscience and Behavioral reviews 11 , 365-389). Noradrenergic neuro-transmission seems to have an important role.
Atipamezole is a selective and potent a2*-adrenoceptor antagonist which is currently marketed for the reversal of sedative-analgesic veterinary drugs. Atipamezole has been disclosed e.g. in the European Patent EP 183492 as useful for the reversal of detomidine.
We have now found that this compound is also very effective in increasing male sexual capacity in a monkey model. These findings suggest that atipamezole would be an effective therapy in male impotence in humans as well.
Another a2-adrenoreceptor antagonist, yohimbine, is currently used for the treatment of male impotence. Yohimbine increases noradrenergic neurotransmission and has been reported to facilitate the sexual capacity of male animals, although the results of different studies are conflicting.
Atipamezole is, however clearly advantageous over yohimbine for this use because of its excellent selectivity. The a2/a-|selectivity ratio of atipamezole is
200-300 times higher than that of yohimbine.
- EP 0310745 B (FARMOS OY) 1989.04.12. disclosed preparation of 5-(2-ethyl-2,3-dihydro-1 H-inden-2-yl)-1 H-imidazole salt by two synthetic routes.
-
First synthetic route as starting material was used 2-acetyl-1-indanone, which was alkylated with ethylbromide in acetone in the presence of sodium carbonate to 2-acetyl-2-ethyl-1-indanone. The acetyl group was brominated with bromine in methanol and to imidazole by heating in formamide. Then the intermediate was hydrogenated in 2N hydrochloric acid in the presence of 10% palladium on carbon.
-
Second synthetic route disclosed in the same patent is following, as starting material was used 2,3-dihydro-1H-indene-2-carboxylic acid methyl ester, which was prepared by methylation of 2,3-dihydro-1H-indene-2-carboxylic acid in the presence of sulphuric acid. The 2,3-dihydro-1H-indene-2-carboxylic acid methyl ester was reacted with N-isopropylcyclohexylamide and ethylbromide yielding 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid, then thionyl chloride was added and 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid chloride was obtained. In the next step ethoxymagnesiummalonic acid ethyl ester in dry ether was added to 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid chloride and reaction mixture was treated with sulphuric acid, and 1-(2,3-dihydro-2-ethyl-1H-inden-2-yl)ethanone was obtained, then the intermediate was stirred in methylene chloride and bromine was added by giving a new intermediate 2-bromo-1-(2,3-dihydro-2-methyl-1H-inden-2-yl)ethanone, to which was thereafter added formamide and hydrochloric acid yielding crude product of 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole. The last step involved hydrogenation of the crude product of 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1 H-imidazole with 10% palladium on carbon.
-
EP 0247764 B (ORION-YHTYMÄ OY) 1987.02.12. disclosed the following process for preparation of 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole hydrochloride. The process starts by reaction of alpha, alpha-dibromo-o-xylene with 4-penten-2-one to obtain 1-(2,3-dihydro-2-vinyl-1H-inden-2-yl)ethanone. The obtained intermediate was brominated, e.g. with bromine, methylene chloride was used as solvent and 2-bromo-1-(2,3-dihydro-2-vinyl-1H-inden-2-yl)-ethanone was obtained, which is thereafter reacted with formamide in excess formamide to give a 4(5)-(2,3-dihydro-2-vinyl-1H-inden-2-ylimidazole hydrochloride. As the last step the vinyl group was catalytically hydrogenated to an ethyl group so as to form a product 4(5)-(2,3-dihydro-2-ethyl-1 H-inden-2-yl) imidazole.
-
Another synthetic route for obtaining 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole is disclosed in WAI, Wonf, et al. A Concise Synthesis of Atipamezole. Synthesis. 1995, no.2, p.139-140. The cyclization of alpha, alpha’-dibromo-o-xylene with acetylacetone by means of NaOH and tetrabutylammonium bromide in toluene/water at 80°C under phase-transfer conditions gives the unstable diacetyl derivative, which presumably undergoes cleavage to afford 2-acetylindane. The alkylation of 2-acetylindane with ethyl iodide and potassium tert-butoxide yields 2-acetyl-2-ethylindan, which is brominated with Br2 to give 2-bromoacetyl-2-ethylindan. Finally, this compound is cyclised with formamide at 160°C (some 2-ethyl-2-(4-oxazolyl)indane is also formed but easily eliminated); the cyclization can also be carried out with formamidine in liquid ammonia. Although the substitution of formamide by formamidine acetate eliminates the oxazole formation, it does not increase the yield of Atipamezole (<30%) WAI, Wonf, et al. A Concise Synthesis of Atipamezole. Synthesis. 1995, no.2, p.139-140 in the final step.
The preparation of atipamezole hydrochloride salt is described in U.S. Patent 4,689,339, wherein atipamezole obtained from the hydrogenation step is first recovered from alkaline solution as free base. After the evaporation of methylene chloride solvent to dryness the isolated crystalline product is converted into its hydrochloride salt by treatment with dry hydrogen chloride in ethyl acetate
Other compounds having alpha-2 adrenoceptor antagonist properties which may be useful in accordance with the present invention include idazoxan related compounds [Reckitt & Colman] Doxey, et al., Br. J. Parmacol., Vol. 78, p.489-505 (1983); imiloxan [Syntex] Michel, et al., Br. J. Pharmacol., Vol. 74, p.255-256 (1981); WY 26703 and related compounds [Wyeth] Latimer, et al., Naunvn Schmiedeberg’s Arch. Pharmacol., Vol. 327, p. 312-318 (1984); CH-38083 [Chinoin] Vizi, et a., J. Pharmacol. Exp. Ther., Vol. 238, p. 701-706 (1986); GR 50360A and related compounds [Glaxo] Halliday, et al., Br. J. Pharmacol., Vol. 95, p. 715 (1988); DG 5128 and related compounds of Daiichi Seiyaku Co., Ltd., Tokyo, Japan; and Yohimbine [Sigma].
………………………………….
-
- 1. an essential process for obtaining 5-(2-ethyl-2,3-1H-inden-2-yl)-1H-imidazole, without bromination in any step of process, thus preventing the possibility of brominated by-products;
- 2. This process has given superior yields, compared to patents cited above;
- 3. This process is amenable to large scale production which does not require specialized equipment.
-
The condensing of commercially available 1-trityl-1H-imidazole-4-carboxaldehyde (I) with phtalide to form 2-(1-trityl-1H-imidazole-4-yl)indan-1,3-dione (II) is performed under the conditions that are similar to those used for synthesis of 4-(indane-1,3-dionyl) pyridine J. Org. Chem. 1971, vol.36, p.1563. surprisingly, the bulky 1-trityl-1H-imidazole-4-carboxaldehyde (I) reacted as expected and produced 2-(1-trityl-1H-imidazole-4-yl)indan-1,3-dione (II) in over 67% yield. Both ethyl acetate and dioxane can be used as reaction media.
-
The alkylation of (II) by ethyl iodide is performed in boiling acetone with potassium carbonate as basic agent. 2-Ethyl-2-(1-trityl-1H-imidazole-4-yl)indan-1,3-dione (III) is formed in over 67% yield and easily isolated from the acetone solution by concentrating it and diluting with water. A high purity (III) is obtained after crystallization from methanol or ethanol.
-
Removing the trityl group of 2-ethyl-2-(1-trityl-1H-imidazole-4-yl)indan-1,3-dione by acid hydrolysis to yield the deprotected 2-ethyl-2-(1H-imidazol-2-yl)indan-1,3-dione.
-
The reduction of (IV) to 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole hydrochloride (V) is performed in hydrogenation apparatus with Pd/C catalyst under hydrogen pressure in HCI solution. The reaction proceeds under variable pressure and temperature conditions, but a pressure of about 3 bar and the temperature of about 80-85°C is preferable. After removing the catalyst the product crystallizes on chilling in over 77% yield. It can be purified by additional crystallization.
-
EP 0310745 B (FARMOS OY) 1989.04.12. disclosed preparation of 5-(2-ethyl-2,3-dihydro-1 H-inden-2-yl)-1 H-imidazole salt by two synthetic routes.
-
First synthetic route as starting material was used 2-acetyl-1-indanone, which was alkylated with ethylbromide in acetone in the presence of sodium carbonate to 2-acetyl-2-ethyl-1-indanone. The acetyl group was brominated with bromine in methanol and to imidazole by heating in formamide. Then the intermediate was hydrogenated in 2N hydrochloric acid in the presence of 10% palladium on carbon.
-
Second synthetic route disclosed in the same patent is following, as starting material was used 2,3-dihydro-1H-indene-2-carboxylic acid methyl ester, which was prepared by methylation of 2,3-dihydro-1H-indene-2-carboxylic acid in the presence of sulphuric acid. The 2,3-dihydro-1H-indene-2-carboxylic acid methyl ester was reacted with N-isopropylcyclohexylamide and ethylbromide yielding 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid, then thionyl chloride was added and 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid chloride was obtained. In the next step ethoxymagnesiummalonic acid ethyl ester in dry ether was added to 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid chloride and reaction mixture was treated with sulphuric acid, and 1-(2,3-dihydro-2-ethyl-1H-inden-2-yl)ethanone was obtained, then the intermediate was stirred in methylene chloride and bromine was added by giving a new intermediate 2-bromo-1-(2,3-dihydro-2-methyl-1H-inden-2-yl)ethanone, to which was thereafter added formamide and hydrochloric acid yielding crude product of 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole. The last step involved hydrogenation of the crude product of 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1 H-imidazole with 10% palladium on carbon.
-
EP 0247764 B (ORION-YHTYMÄ OY) 1987.02.12. disclosed the following process for preparation of 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole hydrochloride. The process starts by reaction of alpha, alpha-dibromo-o-xylene with 4-penten-2-one to obtain 1-(2,3-dihydro-2-vinyl-1H-inden-2-yl)ethanone. The obtained intermediate was brominated, e.g. with bromine, methylene chloride was used as solvent and 2-bromo-1-(2,3-dihydro-2-vinyl-1H-inden-2-yl)-ethanone was obtained, which is thereafter reacted with formamide in excess formamide to give a 4(5)-(2,3-dihydro-2-vinyl-1H-inden-2-ylimidazole hydrochloride. As the last step the vinyl group was catalytically hydrogenated to an ethyl group so as to form a product 4(5)-(2,3-dihydro-2-ethyl-1 H-inden-2-yl) imidazole.
-
Another synthetic route for obtaining 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole is disclosed in WAI, Wonf, et al. A Concise Synthesis of Atipamezole. Synthesis. 1995, no.2, p.139-140. The cyclization of alpha, alpha’-dibromo-o-xylene with acetylacetone by means of NaOH and tetrabutylammonium bromide in toluene/water at 80°C under phase-transfer conditions gives the unstable diacetyl derivative, which presumably undergoes cleavage to afford 2-acetylindane. The alkylation of 2-acetylindane with ethyl iodide and potassium tert-butoxide yields 2-acetyl-2-ethylindan, which is brominated with Br2 to give 2-bromoacetyl-2-ethylindan. Finally, this compound is cyclised with formamide at 160°C (some 2-ethyl-2-(4-oxazolyl)indane is also formed but easily eliminated); the cyclization can also be carried out with formamidine in liquid ammonia. Although the substitution of formamide by formamidine acetate eliminates the oxazole formation, it does not increase the yield of Atipamezole (<30%) WAI, Wonf, et al. A Concise Synthesis of Atipamezole. Synthesis. 1995, no.2, p.139-140 in the final step.
…………………………….
US Patent 8,431,717
Atipamezole [5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole, 1] is a veterinary drug that has been investigated for treating Parkinson’s disease in humans. V. Lusis and co-inventors summarize several ways to synthesize 1. Some routes give a low yield of 1 and produce large quantities of an oxazole byproduct. Other processes involve a sluggish bromination reaction that leads to many byproducts.
The inventors’ process is intended to overcome these problems. In particular, it does not use the bromination reaction and thus avoids forming brominated byproducts. The process, outlined in the figure, begins with the reaction of imidazole 2 with i-PrMgCl to form iodo Grignard reagent 3, which is treated with DMF to give 4. This intermediate is not isolated but is treated with aq NH4Cl to give aldehyde 5, isolated in 73.2% yield. The aldehyde is condensed with phthalide (6) in the presence of NaOMe to produce imidazolylindane 7, recovered in crude form in 67.2% yield.
In the next stage, compound 7 is alkylated with EtI in the presence of K2CO3. Product 8 is isolated in 50.9% yield after being recrystallized from EtOH. Product1 can be produced directly from 8 by making its HCl salt and hydrogenating the salt over Pd/C. Crude atipamezole is isolated as its HCl salt in 26.6% yield.
Alternatively, acid hydrolysis of 8 removes the trityl group to form dione 9, recovered as a white crystalline solid in 76.2% yield. The HCl salt of 9 is then hydrogenated to 1·HCl.
The patent’s claims cover the process to make 1 and new compounds 7 and 8. The overall yield of compound 1 is poor, partly because of the low yield from the hydrogenation step. The inventors claim, however, that the yield is higher than from earlier methods. They point out that the process is amenable to large-scale production without the use of specialized equipment. (JSC Grindeks [Riga, Latvia]. US Patent 8,431,717, April 30, 2013; Keith Turner), View the full-text here.
………………………………
nmr
Atipamezole Hydrochloride CAS 104075-48-1 HNMR
……………………………………………………….
GADODIAMIDE, OMNISCAN Drug Patent Expiration, 1 st oct 2013
GADODIAMIDE
GE HEALTHCARE, OMNISCAN
Drug Patent Expiration
1 st oct 2013, US5560903, CAS 122795-43-1
| GADODIAMIDE | INJECTABLE; INJECTION | 287MG/ML | RX | NDA 020123 |
Gadodiamide is a gadolinium-based MRI contrast agent, used in MR imaging procedures to assist in the visualization of blood vessels. It is commonly marketed under the trade name Omniscan.
For intravenous use in MRI to visualize lesions with abnormal vascularity (or those thought to cause abnormalities in the blood-brain barrier) in the brain (intracranial lesions), spine, and associated tissues.
Gadodiamide is a contrast medium for cranial and spinal magnetic resonance imaging (MRI) and for general MRI of the body after intravenous administration. The product provides contrast enhancement and facilitates visualisation of abnormal structures or lesions in various parts of the body including the central nervous system (CNS). It does not cross an intactblood brain barrier but might give enhancement in pathological conditions.
Based on the behavior of protons when placed in a strong magnetic field, which is interpreted and transformed into images by magnetic resonance (MR) instruments. Paramagnetic agents have unpaired electrons that generate a magnetic field about 700 times larger than the proton’s field, thus disturbing the proton’s local magnetic field. When the local magnetic field around a proton is disturbed, its relaxation process is altered. MR images are based on proton density and proton relaxation dynamics. MR instruments can record 2 different relaxation processes, the T1 (spin-lattice or longitudinal relaxation time) and the T2 (spin-spin or transverse relaxation time). In magnetic resonance imaging (MRI), visualization of normal and pathological brain tissue depends in part on variations in the radiofrequency signal intensity that occur with changes in proton density, alteration of the T1, and variation in the T2. When placed in a magnetic field, gadodiamide shortens both the T1 and the T2 relaxation times in tissues where it accumulates. At clinical doses, gadodiamide primarily affects the T1 relaxation time, thus producing an increase in signal intensity. Gadodiamide does not cross the intact blood-brain barrier; therefore, it does not accumulate in normal brain tissue or in central nervous system (CNS) lesions that have not caused an abnormal blood-brain barrier (e.g., cysts, mature post-operative scars). Abnormal vascularity or disruption of the blood-brain barrier allows accumulation of gadodiamide in lesions such as neoplasms, abscesses, and subacute infarcts.
1.Schenker MP, Solomon JA, Roberts DA. (2001). Gadolinium Arteriography Complicated by Acute Pancreatitis and Acute Renal Failure, Journal of vascular and interventional radiology 12(3):393.[1]
2 Unal O, Arslan H. (1999). Cardiac arrest caused by IV gadopentetate dimeglumine. AJR Am J Roentgenol 172:1141.[2]
3 Cacheris WP, Quay SC, Rocklage SM. (1990). The relationship between thermodynamics and the toxicity of gadolinium complexes, Magn Reson Imaging 8(6):467-81. doi:10.1016/0730-725X(90)90055-7
4 Canavese, C; Mereu, MC; Aime, S; Lazzarich, E; Fenoglio, R; Quaglia, M; Stratta, P (2008). “Gadolinium-associated nephrogenic systemic fibrosis: the need for nephrologists’ awareness”. Journal of nephrology 21 (3): 324–36. PMID 18587720.
COUNTRY PATENT APPROVED, EXPIRY
| United States | 5560903 | 1993-10-01 | 2013-10-01 |
| Canada | 1335819 | 1995-06-06 | 2012-06-06 |
| United States | 5362475 | 1994-11-08 | 2011-11-08 |
| Canada | 1335819 | 1995-06-06 | 2012-06-06 |
| United States | 5560903 | 1993-10-01 | 2013-10-01 |
Gadolinium contrast agents are used as contrast media to enhance magnetic resonance imaging as they are paramagnetic. This compound has a low incidence of adverse side effects, although there is a rare association with nephrogenic systemic fibrosis (NSF) when given to people with severe renal impairment (ie, GFRglomerular filtration rate <30mL/min/1·73m2).It seems to be related to the liberation of free gadolinium ions, and UK CHM advice is against using the least stable of the agents – Omniscan (gadodiamide) – in patients with severe renal impairment, and carefully considering whether to use others where renal function is impaired.
OMNISCAN (gadodiamide) Injection is the formulation of the gadolinium complex of diethylenetriamine pentaacetic acid bismethylamide, and is an injectable, nonionic extracellular enhancing agent for magnetic resonance imaging. OMNISCAN is administered by intravenous injection. OMNISCAN is provided as a sterile, clear, colorless to slightly yellow, aqueous solution. Each 1 mL contains 287 mg gadodiamide and 12 mg caldiamide sodium in Water for Injection.
The pH is adjusted between 5.5 and 7.0 with hydrochloric acid and/or sodium hydroxide. OMNISCAN contains no antimicrobial preservative. OMNISCAN is a 0.5 mol/L solution of aqua[5,8-bis(carboxymethyl)11-[2-(methylamino)-2-oxoethyl]-3-oxo-2,5,8,11-tetraazatridecan-13-oato (3-)-N5, N8, N11, O3, O5, O8, O11, O13] gadolinium hydrate, with a molecular weight of 573.66 (anhydrous), an empirical formula of C16H28GdN5O9•xH2O, and the following structural formula:
 |
Pertinent physicochemical data for OMNISCAN are noted below:
PARAMETER
| Osmolality (mOsmol/kg water) | @ 37°C | 789 |
| Viscosity (cP) | @ 20°C | 2 |
| @ 37°C | 1.4 | |
| Density (g/mL) | @ 25°C | 1.14 |
| Specific gravity | @ 25°C | 1.15 |
OMNISCAN has an osmolality approximately 2.8 times that of plasma at 37°C and is hypertonic under conditions of use.
gadodiamide, chemical name: [5,8 _ bis (carboxymethyl) -11 – [2_ (methylamino)-2_ ethyl] -3 – O 2 ,5,8, 11 – tetraazacyclododecane-decane -13 – oxo-(3 -)] gadolinium trihydrate. Its structure is shown in formula one.
[0003] Structural Formula:
[0004]
[0005] Magnetic resonance contrast agent gadodiamide resonance than ionic contrast agents safer generation of products, it is non-ionic structure significantly reduces the number of particles in solution, osmotic balance of body fluids is very small.Meanwhile, gadodiamide relatively low viscosity to bring the convenience of nursing staff, making it easier to bolus. In addition, gadodiamide pioneered the use of amide-substituted carboxyl part, not only reduces the toxicity of carboxyl groups and ensure the non-ionic nature of the product solution.
[0006] reported in the literature and their intermediates gadodiamide synthetic route is as follows:
[0007] 1. Compound III synthetic routes for its preparation in U.S. Patent No. US5508388 described as: In the synthesis process, the inventors using acetonitrile as solvent, acetic anhydride as dehydrating agent, pyridine as acid-binding agent, at 55 ~ 60 ° C, the reaction 18h. Anti-
See the reaction should be a process. The disadvantage of this synthesis are acetonitrile toxicity, not widely used.
[0008]
[0009] Reaction a
[0010] (2) Synthesis of Compound III in many articles are reported in the patent and its implementation method similar to the patent US5508388.
[0011] In US3660388, the diethylenetriamine pentaacetic acid (Compound II), pyridine, acetic anhydride, the mixture was reacted at 65 ° C or 20h at 125 ° C the reaction 5min, to give compound III.
[0012] In US4822594, the compounds II, pyridine, acetic anhydride mixture was reacted at 65 ° C 20h, to give compound III.
[0013] In US4698263, the compounds II, pyridine, acetic anhydride heated in a nitrogen or argon atmosphere under reflux for 18h, to give compound III. [0014] In the EPO183760B1, the compounds II, pyridine, acetic anhydride mixture was reacted at 55 ° C 24h, to give compound III.
[0015] In CN1894223A, the compounds II, pyridine, acetic anhydride, the mixture above 65 ° C the reaction mixture, and the pyridine of DTPA feed ratio is: 1: (0.5 to 3).
[0016] The above patents do not provide for the compound III is post-processing method.
[0017] 3 Synthesis of Compound IV.
[0018] In U.S. Patent US4859451, the diethylenetriamine pentaacetic acid dianhydride (compound III) and ammonia, methanol and the reaction of compounds IV, see Reaction Scheme II.
[0019]
[0020] Reaction two
[0021] In the patent US5087439, the compound III with methylamine in aqueous solution for several hours, or overnight reactions, see reaction formula III.
[0022]
[0023] Reactive three
[0024] These two patents using ammonia and methylamine, which can form explosive mixtures with air, in case of fire or high pressure can cause an explosion in the production process of great insecurity. Although raw material prices are lower, but higher production conditions (such as requiring sealed, low temperature, etc.). Compared to this synthesis process,
[0025] 4, gadodiamide (Compound I) synthesis.
[0026] In the patent US4859451, the use of gadolinium chloride with the compound IV is carried out under acidic conditions, complexing. Finally, tune
Section PH neutral, see reaction IV.
[0027]
[0028] Reaction formula tetrakis [0029] in the patent US5087439, the chlorides are used as reactants, and details of the post-processing method of Compound I.
[0030] In the patent US5508388, the use of gadolinium oxide with compound IV in acetonitrile, water with stirring, the resulting compound I.
[0032] The synthetic route is as follows:
[0033]
[0034] 1) Compound II (diethylenetriamine pentaacetic acid) in pyridine, acetic anhydride in the presence of a dehydration reaction into the acid anhydride, and the product was stirred with cold DMF, leaving the solid filtered, washed with ether reagents, drying , to obtain a white powdery solid compound III (diethylenetriamine pentaacetic acid anhydride);
[0035] 2) Compound III in DMF with methylamine hydrochloride, the reaction of the compound IV (5,8 _ bis carboxymethyl methyl-11 – [2 – (dimethylamino) -2 – oxoethyl] – 3 – oxo -2,5,8,11 – tetraazacyclododecane _13_ tridecyl acid); and the control compound III: MeNH2 · HCl molar ratio = 1: (1 to 4), control the temperature between 20 ~ 80 ° C, the reaction time is 4 ~ 6h, after the treatment, the method of distillation under reduced pressure to remove DMF, the product is dissolved in a polar solvent, methanol, and then adding a solvent polarity modulation, so that the target Compound IV from system completely precipitated;
[0036] 3) Compound IV with gadolinium oxide formed in the presence of hydrochloric acid of the complex, after the reaction, filtration and drying, to obtain a white powdery compound I, i.e. gadodiamide.
[0037] Existing gadodiamide Synthesis basically from the synthesis of Compound IV as a starting material, the present invention is first introduced to the compound II as a starting material to synthesize gadodiamide. Synthesis of the conventional method of gadodiamide, the present invention has the advantage of inexpensive starting materials, convenient and easy to get. In addition, the synthetic pathway intermediates are involved in the post-processing is simple, enabling continuous reaction, saving time and cost savings, the reaction becomes controlled step by step, and try to avoid the use of toxic reagents, reducing the possibility of operator injury , while also greatly reducing damage to the environment.
Covidien sells Confluent product line for $235 million
October 30, 2013 | By Anabela Farrica
Covidien announced yesterday that it has reached an agreement with Integra LifeSciences Corporation to sell its Confluent Surgical product line for $235 million in up-front cash, plus an additional $30 million in milestones. The transaction depends on a number of regulatory approvals, but it is expected to be finished by March 31, 2014.
View original post 152 more words
Sales of Biogen Idec’s multiple sclerosis drug Tecfidera soar
October 29 ,2013 | By Márcio Barra
Tecfidera (dymethil Fumarate), Biogen Idec’s prized multiple sclerosis drug, is fast approaching blockbuster status according to the recently released third-quarter numbers of Biogen Idec’s, beating along the way analyst expectation and pushing Biogen Idec’s net profit up 22%.
For Q3, Tecfidera sales garnered $286.4 million, far higher than the $217.2 million that analysts expected. It is now expected that Tecfidera will reach $3.5 billion in annual revenue by 2016, a no doubt impressive number for a drug that, in its first quarter in the market (the drug was launched in March 2013 in the US), posted $192.1 million in sales. This revenue mark pushed Biogen’s net profit up 22% to $488 million, up from $398 million last year.
View original post 302 more words
Atomoxetine
Atomoxetine
Atomoxetine hydrochloride (CAS NO.: 82248-59-7)
(R)-(-)-N-Methyl-gamma-(2-methylphenoxy)benzenepropanamine hydrochloride
| Patent No | PatentExpiry Date | |
|---|---|---|
| 5658590 | Nov 26, 2016 | |
| 5658590*PED | May 26, 2017 |
nda 021411 app 2002-11-26
TREATMENT OF ATTENTION-DEFICIT HYPERACTIVITY DISORDER
label
|
Country
|
Patent Number
|
Approved
|
Expires (estimated)
|
|---|---|---|---|
| United States | 5658590 | 1997-05-26 | 2017-05-26 |
The HCl salt of atomoxetine , with the (R)-configuration], which is marketed under the trade name Strattera, is used for treating attention-deficit hyperactivity disorder (ADHD
Atomoxetine is a drug approved for the treatment of attention-deficit hyperactivity disorder(ADHD).[1] It is a selective norepinephrine reuptake inhibitor (NRI),[1] not to be confused with serotonin norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs), both of which are currently the most prescribed form of antidepressants.
his compound is manufactured, marketed and sold in theUnited States under the brand name Strattera by Eli Lilly and Company as a hydrochloride salt (atomoxetine HCl), the original patent filing company, and current U.S. patent owner. Generics of atomoxetine are sold in all other countries; they are manufactured by Torrent Pharmaceuticals using the label Tomoxetin, Ranbaxy Laboratories (through its Division: Solus) using the label Attentin, Sun Pharmaceuticals(through its Division: Milmet Pharmaceuticals), and Intas Biopharmaceuticals There is currently no generic manufactured directly in the United States since it is under patent until 2017.[2]
On August 12, 2010, Lilly lost a lawsuit that challenged Lilly’s patent on Strattera, increasing the likelihood of an earlier entry of a generic into the US market.[3] On September 1, 2010, Sun Pharmaceuticals announced it would begin manufacturing a generic in the United States.[4] In a July 29, 2011 conference call, however, Sun Pharmaceutical’s Chairman stated “Lilly won that litigation on appeal so I think [generic Strattera]’s deferred.”[5]
Atomoxetine is designated chemically as (−)-N-methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride, and has a molecular mass of 291.82.[1] It has a solubility of 27.8 mg/mL in water.[1] Atomoxetine is a white solid that exists as a granular powder inside the capsule, along with pre-gelatinized starch and dimethicone.[1] The capsule shells contain gelatin, sodium lauryl sulfate, FD&C Blue No. 2, synthetic yellow iron oxide, titanium dioxide, red iron oxide, edible black ink, and trace amounts of other inactive ingredients.[1]
The compound (-)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine, or (-)-Λ/-methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride, is usually known by its adopted name “atomoxetine hydrochloride.” It is represented as shown in Formula 1 and is a selective norepinephrine reuptake inhibitor. A commercialatomoxetine hydrochloride product is sold as STRATTERA™ in the form of capsules containing 10, 18, 25, 40, 60, 80, or 100 mg of atomoxetine, for treating attention-deficit/hyperactivity disorder.
- “STRATTERA® (atomoxetine hydrochloride) CAPSULES for Oral Use. Full Prescribing Information.” Eli Lilly and Company, 2002, 2013. Revised August 5, 2013. [1]
- “Patent and Exclusivity Search Results”. Electronic Orange Book. US Food and Drug Administration. Retrieved 26 April 2009.
- “Drugmaker Eli Lilly loses patent case over ADHD drug, lowers revenue outlook”. Chicago Tribune.
- “Sun Pharma receives USFDA approval for generic Strattera capsules”. International Business Times.
- “Sun Pharma Q1 2011-12 Earnings Call Transcript 10.00 am, July 29, 2011”.
- Strattera by Eli Lilly and Company
- RxList.com – Strattera
- Detailed Strattera Consumer Information: Uses, Precautions, Side Effects
- All disclosed Lilly trials
- MSDS for Atomoxetine HCl
- Strattera Related Published Studies
Synthesis
Also known as: Atomoxetine hydrochloride, Strattera, Atomoxetine HCL, (R)-Tomoxetine hydrochloride, TOMOXETINE HYDROCHLORIDE, Tomoxetine, 82248-59-7
First step appears to be a Mannich reaction between acetophenone, paraformaldehyde and dimethylamine, although not formally written in the scheme.
Foster, B. J.; Lavagnino, E. R.; European Patent, 1982, EP 0052492.
Eli Lilly’s Strattera capsules.
Atomoxetine, designated chemically as (-)-N-methyl-3-phenyl-3-(0-tolyloxy)- propylamine hydrochloride, is structurally represented by the compound of Formula-I and is indicated for the potential treatment of attention-deficit hyperactivity disorder (ADHD). This compound is manufactured, marketed and sold in the United States under the brand name Strattera.
Formula-I Atomoxetine was first disclosed in US Patent No 4314081. The said patent disclosed Atomoxetine, its pharmaceutically acceptable salts and composition containing them.
4-hydroxy Atomoxetine, chemically known as R-(-)-N-methyl-3-(2-methyl-4- hydroxyphenyl)oxy)-3 -phenyl- 1-aminopropane, structurally represented by Formula-II, is a metabolite of Atomoxetine.
Fomnula-ll
4-hydroxy Atomoxetine hydrochloride was first disclosed in US Patent No 7384983, wherein 4-hydroxy Atomoxetine free base was dissolved in ethylacetate, treated the solution with 0.1N HC1; followed by lyophilization yielded a yellow solid which was dissolved in methanol and passed through a short column of activated carbon; the solvent was removed and finally the hydrochloride salt was recrystallized from water to afford 4-hydroxy Atomoxetine hydrochloride. However, this patent does not mention about the nature of the polymorph obtained through this process.
The asymmetric epoxidation of (E)-3-phenyl-2-propen-1-ol (I) by means of titanium tetraisopropoxide, (+)-diethyl tartrate (+)-(DET) and tBu-OOH in dichloromethane gives the chiral epoxide (II), which is opened by means of bis(2-methoxyethoxy)aluminum hydride (Red-Al) in DME to yield the chiral diol (III). The regioselective reaction of (III) with Ms-Cl and TEA in ethyl ether affords the primary mesylate (IV), which is condensed with 2-methylphenol (V) by means of PPh3 and DEAD in ethyl ether to provide the adduct (VI). Finally this compound is treated with methylamine in hot aq. THF to give rise to the target (R)-tomoxetine.
The reduction of omega-chloropropiophenone (I) with NaBH4 in ethanol gives 3-chloro-1-phenyl-1-propanol (II), which is treated with butyric anhydride and pyridine in dichloromethane to yield the corresponding racemic ester (III). The optical resolution of (III) with immobilized lipase B from Candida antarctica (CALB) affords a mixture of unreacted (S)-ester and (R)-alcohol (IV) that are separated by column chromatography. Condensation of th (R)-alcohol (IV) with 2-methylphenol (V) by means of PPh3 and diethyl azodicarboxylate (DEAD) in THF gives the corresponding ether (VI), which is finally treated with methylamine in refluxing ethanol.
more info
U.S. Patent No. 4,314,081 describes 3-Aryloxy-3-phenyl polyamines, which possess central nervous system activity. Atomoxetine is a member of the above class of compounds, and is a useful drug for the treatment of depression.Atomoxetine was claimed in U. S. Patent No. 4,314,081 and the patent describes a process for the preparation of atomoxetine and related compounds in two different ways as depicted below as Scheme A and Scheme B, respectively.
Scheme A
Atomoxetinc
Scheme B
The process illustrated in Scheme A involves the preparation of the atomoxetineusing 3-phenyl chloropropyl amine (Formula 5) as a starting material. The process involves bromination of said starting compound (Formula 5) by using N-bromosuccinimide. Further the bromo derivative is condensed with o-cresol to result in a compound of Formula 7, which is then subjected to amination using methylamine. Though the process looks very simple, it involves the following disadvantages: i) N-bromosuccinimide being a corrosive and sensitive chemical, its usage demands special care; ii) the workup of the compound formula 7 involves high vacuum (0.03 torr) distillation at 135-1450C, which is a tedious and cumbersome process to carry out at the plant level; and iii) the reaction conditions involved in some of the steps are harsh, for example the amination reaction is conducted at 14O0C. at pressures of 10 kg/cm2 for 12 hours in an autoclave.
All the above points make the process not viable for practicing on a commercial scale. Further, as described in U.S. Patent 4,314,081 , the free base compounds exist as high boiling oils, but form white crystalline salts.
On the other hand, Scheme B describes the preparation of atomoxetine using β-dimethylaminopropiophenone produced by a Mannich reaction; which is reduced to the hydroxy derivative having Formula 9 using diborane; further the hydroxy compound (Formula 9) is converted to the corresponding chloro derivative of Formula 10 using dry HCI gas and thionyl chloride and is followed by condensation with o-cresol.
The said reaction is carried out in methanol at reflux for a duration of five days to achieve the compound of formula 11 and is followed by demethylation using cyanogen bromide to end up with atomoxetine. As can be clearly understood the process is associated with the following problems: i) the use of costly reagents such as diborane makes the process uneconomical; ii) the passage of dry HCI gas followed by thionyl chloride addition is ^ very cumbersome and is not advisable in the plant; iii) this is a time-consuming process, involving a reaction which requires five days for its completion; and iv) use of cyanogen bromide, which is highly toxic, is not desirable.
All of the above-quoted drawbacks make the process unfriendly to practice in a production plant as well as to the environment.
Further, M. Srebnik et al., Journal of Organic Chemistry, Vol. 53, pages2916-2920 (1988); E. Corey et al., Tetrahedron Letters, Vol. 30, pages 5207-5210 (1989);
U.S. Patent No. 4,868,344; Y. Gao et al., Journal of Organic Chemistry, Vol. 53, pages 4081-4084 (1988); J. Deeter et al.,
Tetrahedron Letters, Vol. 31, pages 7101-7104 (1990);
and U.S. Patent No. 4,950,791 disclose stereospecific methods for the preparation of 3-aryloxy-3-phenylpropylamines; the enantiomers of 3-hydroxy-3-phenylpropylamines are prepared by the stereospecific reduction of the corresponding ketones. The thus obtained (S)-3-hydroxy-3-phenyl propylamines are subjected to condensation with aryl alcohols using the Mitsunobo reaction. As can be seen in Scheme C, the reaction involves two critical steps.
Scheme C
Dusopinocampheny) chloroborane
OH
,CH,
DEAD/ tn phenyl phosphine
The first critical step is an asymmetric reduction of the ketone to its corresponding alcohol. The second critical step involves the condensation of the obtained enantiomeric alcohol with the corresponding aryl alcohol. The process suffers from the following disadvantages:
1) the reagent used for the asymmetric reduction of the ketone is highly expensive;
2) the reagent diethyl azodicarboxylate (“DEAD”) is expensive;
3) the DEAD reagent is known to be highly carcinogenic, thus creating problems in handling; and
4) the reaction involves the use of triphenylphosphine and DEAD and the resulting byproducts formed in the reaction, phoshineoxide and a hydrazine derivative, are very difficult to remove.
Therefore, commercial applicability of the said process is limited owing to the above noted disadvantages.
International Patent Publication No. WO 00/58262 relates to a stereo- specific process for the preparation of atomoxetineusing nucleophilic aromatic displacement of an aromatic ring having a functional group, which can be converted to a methyl group. As can be seen, the process is very lengthy and involves many steps and is thus not commercially desirable.
U.S. Patent No. 5,847,214 describes the nucleophilic aromatic displacement reaction of 3-hydroxy-3-arylpropylamines with activated aryl halides, for example the reaction of N-methyl-3-phenyl-3-hydroxypropylamine with 4- triflouromethyl-1-cholro benzene has been reported; the success of this reaction is mainly due to electron withdrawing group on benzene ring of the aryl halides.
U.S. Patent No. 6,541 ,668 describes a process for the preparation of atomoxetine and its pharmaceutically acceptable addition salts which comprises reacting an alkoxide of N-methyl-3-phenyl-3-hydroxy propyl amine or an N protected derivative thereof, with 2-flouro toluene in the presence of 1 ,3-Dimethyl – 2-imidazolidinone (“DMI”) or N-Methyl-3-pyrrolidinone (“NMP”) as the solvent. The process disclosed in the said patent can be shown as Scheme D. Further, the process disclosed in the said patent restricts itself to the solvents DMI and NMP.
Scheme D
Nevertheless, a new crystalline form of N-methyl-3-phenyl-3-(o- tolyloxy)propylamine oxalate and an isolation technique of (±)-atmoxetine free base in a solid form, an intermediate useful in the synthesis of atomoxetine hydrochloride, is desirable.
http://www.sciencedirect.com/science/article/pii/S0040403906025068
There have been several methods reported for preparing (R)-(−)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine (Atomoxetine®). For example, U.S. Pat. No. 4,868,344 discloses a process as shown in the following scheme:
In this example, 3-chloropropiophenone is used as the starting material to be asymmetrically reduced with (−)-diisopinocamphenylchloroborane ((−)-IPc2BC1) to give the corresponding chiral alcohol. The resulting chiral alcohol is then reacted with o-cresol via Mitsunobu reaction to form the chiral ether compound. Subsequently, amination of the chiral ether compound with methylamine provided atomoxetine. In this process, the materials such as chiral-borane ((−)-IPc2BC1) and diethyl azodicarboxylate (DEAD) are expensive, and result in high manufacturing cost.
Further, WO 2006/009884 discloses another method for preparing atomoxetine, including the step of reacting N-methyl-3-phenyl-3-hydroxypropylamine with 2-fluorotoluene which is followed by resolution of the resulting product to provide optically pure atomoxetine as shown in the following scheme:
This process involving a chiral resolution step is inefficient due to low product yield, complicated and long time process that renders this process economically less competitive.
………………………………………………………………………………………………
see below
B.-F. Chen and co-inventors describe a synthesis of 5 that avoids costly reagents. It includes the preparation of the chiral amino alcohol 3 as a key intermediate. The route for preparing 5 starts with a Mannich reaction between benzophenone, N,O-dimethylhydroxylamine, and paraformaldehyde to give compound 1, isolated in 87.6% yield.
Ketone 1 is asymmetrically reduced to form alcohol 2 by using the chiral ruthenium catalyst RuCl2-[(S)-DMSEGPHOS)][(S)-DAIPEN]. The hydrogen pressure is described as “predetermined”, but no value is given. Product 2 is recovered as an oily product in 98.7% yield with 98.8% purity and 99% ee. It appears that the catalyst is not removed before the next step in which the oil is hydrogenated over a Raney nickel catalyst to form amino alcohol 3.
Intermediate 3 is also isolated as an oil in 96.4% yield, 96.5% % purity, and 99% ee. After recrystallization from toluene–heptane, the solid product is recovered with 100% ee. In the last step, 3 is treated with fluorotoluene 4 in the presence of t-BuOK to form atomoxetine, isolated as an oil in 91% yield with 97% ee. The purification of 5 and its conversion to the HCl salt are not described.
The inventors provide basic 1H-NMR data for all compounds except 5. The example describing the preparation of 1 lists one of the reactants as 2-acetylthiophene, which is clearly incorrect; and another reagent is called “32% hydrochloride”. These errors should have been spotted by anyone with a fundamental knowledge of chemistry who was involved in writing the patent—perhaps none were. (Sci Pharmtech [Taiwan]. US Patent 8,299,305, Oct. 30, 2012; Keith Turner)
View the full-text patent here.
| Patent Number: | US 8299305 |
| Title: | Process for preparation of atomoxetine |
| Inventor(s): | Chen, Bo-Fong; Li, Yan-Wei; Yeh, Jinun-Ban; Wong, Wei-Chyun |
| Patent Assignee(s): | SCI Pharmtech, Inc., Taiwan |
Bristol-Myers Squibb announced promising results from an expanded phase 1 dose-ranging study of its lung cancer drug nivolumab
NIVOLUMAB
Anti-PD-1;BMS-936558; ONO-4538
PRONUNCIATION nye vol’ ue mab
THERAPEUTIC CLAIM Treatment of cancer
CHEMICAL DESCRIPTION
A fully human IgG4 antibody blocking the programmed cell death-1 receptor (Medarex/Ono Pharmaceuticals/Bristol-Myers Squibb)
MOLECULAR FORMULA C6362H9862N1712O1995S42
MOLECULAR WEIGHT 143.6 kDa
SPONSOR Bristol-Myers Squibb
CODE DESIGNATION MDX-1106, BMS-936558
CAS REGISTRY NUMBER 946414-94-4
Bristol-Myers Squibb announced promising results from an expanded phase 1 dose-ranging study of its lung cancer drug nivolumab
Nivolumab (nye vol’ ue mab) is a fully human IgG4 monoclonal antibody designed for the treatment of cancer. Nivolumab was developed by Bristol-Myers Squibb and is also known as BMS-936558 and MDX1106.[1] Nivolumab acts as an immunomodulator by blocking ligand activation of the Programmed cell death 1 receptor.
A Phase 1 clinical trial [2] tested nivolumab at doses ranging from 0.1 to 10.0 mg per kilogram of body weight, every 2 weeks. Response was assessed after each 8-week treatment cycle, and were evaluable for 236 of 296 patients. Study authors concluded that:”Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non–small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use.”[3]
Phase III clinical trials of nivolumab are recruiting in the US and EU.[4]
- Statement On A Nonproprietary Name Adopted By The USAN Council – Nivolumab, American Medical Association.
- A Phase 1b Study of MDX-1106 in Subjects With Advanced or Recurrent Malignancies (MDX1106-03), NIH.
- Topalian SL, et al. (June 2012). “Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer”. New England Journal of Medicine 366. doi:10.1056/NEJMoa1200690. Lay summary – New York Times.
- Nivolumab at ClinicalTrials.gov, A service of the U.S. National Institutes of Health.
The PD-1 blocking antibody nivolumab continues to demonstrate sustained clinical activity in previously treated patients with advanced non-small cell lung cancer (NSCLC), according to updated long-term survival data from a phase I trial.
Survival rates at one year with nivolumab were 42% and reached 24% at two years, according to the median 20.3-month follow up. Additionally, the objective response rate (ORR) with nivolumab, defined as complete or partial responses by standard RECIST criteria, was 17% for patients with NSCLC. Results from the updated analysis will be presented during the 2013 World Conference on Lung Cancer on October 29.
“Lung cancer is very difficult to treat and there continues to be a high unmet medical need for these patients, especially those who have received multiple treatments,” David R. Spigel, MD, the program director of Lung Cancer Research at the Sarah Cannon Research Institute and one of the authors of the updated analysis, said in a statement.
“With nivolumab, we are investigating an approach to treating lung cancer that is designed to work with the body’s own immune system, and these are encouraging phase I results that support further investigation in larger scale trials.”
In the phase I trial, 306 patients received intravenous nivolumab at 0.1–10 mg/kg every-other-week for ≤12 cycles (4 doses/8 week cycle). In all, the trial enrolled patients with NSCLC, melanoma, renal cell carcinoma, colorectal cancer, and prostate cancer.
The long-term follow up focused specifically on the 129 patients with NSCLC. In this subgroup, patients treated with nivolumab showed encouraging clinical activity. The participants had a median age of 65 years and good performance status scores, and more than half had received three or more prior therapies. Across all doses of nivolumab, the median overall survival was 9.9 months, based on Kaplan-Meier estimates.
In a previous update of the full trial results presented at the 2013 ASCO Annual Meeting, drug-related adverse events of all grades occurred in 72% of patients and grade 3/4 events occurred in 15%. Grade 3/4 pneumonitis related to treatment with nivolumab emerged early in the trial, resulting in 3 deaths. As a result, a treatment algorithm for early detection and management was developed to prevent this serious side effect.
Nivolumab is a fully human monoclonal antibody that blocks the PD-1 receptor from binding to both of its known ligands, PD-L1 and PD-L2. This mechanism, along with early data, suggested an associated between PD-L1 expression and response to treatment.
In separate analysis presented at the 2013 World Conference on Lung Cancer, the association of tumor PD-L1 expression and clinical activity in patients with NSCLC treated with nivolumab was further explored. Of the 129 patients with NSCLC treated with nivolumab in the phase I trial, 63 with NSCLC were tested for PD-L1 expression by immunohistochemistry (29 squamous; 34 non-squamous).
DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
New Drug Approvals 
