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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Idelalisib ….US FDA Accepts NDA for Gilead’s Idelalisib for the Treatment of Refractory Indolent Non-Hodgkin’s Lymphoma


Idelalisib

An antineoplastic agent and p110delta inhibitor

(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one

Icos (Originator)

  • CAL-101
  • GS-1101
  • Idelalisib
  • UNII-YG57I8T5M0

M.Wt: 415.43
Formula: C22H18FN7O

CAS No.: 870281-82-6
CAL-101 Solubility: DMSO ≥80mg/mL Water <1.2mg/mL Ethanol ≥33mg/mL

5-Fluoro-3-phenyl-2-[(1S)-1-(7H-purin-6-ylamino)propyl]-4(3H)-quinazolinone

idelalisib

Idelalisib (codenamed GS-1101 or CAL-101) is a drug under investigation for the treatment of chronic lymphocytic leukaemia. It is in Phase III clinical trials testing drug combinations with rituximab and/or bendamustine as of 2013. The substance acts as aphosphoinositide 3-kinase inhibitor; more specifically, it blocks P110δ, the delta isoform of the enzyme phosphoinositide 3-kinase.[1][2]

GDC-0032 is a potent, next-generation beta isoform-sparing PI3K inhibitor targeting PI3Kα/δ/γ with IC 50 of 0.29 nM/0.12 nM/0.97nM,> 10 fold over Selective PI3K [beta].

GS-1101 is a novel, orally available small molecule inhibitor of phosphatidylinositol 3-kinase delta (PI3Kdelta) develop by Gilead and is waiting for registration in U.S. for the treatment of patients with indolent non-Hodgkin’s lymphoma that is refractory (non-responsive) to rituximab and to alkylating-agent-containing chemotherapy and for the treatment of chronic lymphocytic leukemia. The compound is also in phase III clinical evaluation for the treatment of elderly patients with previously untreated small lymphocytic lymphoma (SLL) and acute myeloid leukemia. Clinical trials had been under way for the treatment of inflammation and allergic rhinitis; however, no recent development has been reported. Preclinical studies have shown that GS-1101 has desirable pharmaceutical properties. The compound was originally developed by Calistoga Pharmaceuticals, acquired by Gilead on April 1, 2011.

clinical trials, click link

http://clinicaltrials.gov/search/intervention=CAL-101%20OR%20GS-1101%20OR%20Idelalisib

FOSTER CITY, Calif.–(BUSINESS WIRE)–Jan. 13, 2014– Gilead Sciences, Inc. (Nasdaq: GILD) announced today that the U.S. Food and Drug Administration (FDA) has accepted for review the company’s New Drug Application (NDA) for idelalisib, a targeted, oral inhibitor of PI3K delta, for the treatment of refractory indolent non-Hodgkin’s lymphoma (iNHL). FDA has granted a standard review for the iNHL NDA and has set a target review date under the Prescription Drug User Fee Act (PDUFA) of September 11, 2014.

The NDA for iNHL, submitted on September 11, 2013, was supported by a single arm Phase 2 study (Study 101-09) evaluating idelalisib in patients with iNHL that is refractory (non-responsive) to rituximab and to alkylating-agent-containing chemotherapy. Following Gilead’s NDA submission for iNHL, FDA granted idelalisib a Breakthrough Therapy designation for relapsed chronic lymphocytic leukemia (CLL). The FDA grants Breakthrough Therapy designation to drug candidates that may offer major advances in treatment over existing options. Gilead submitted an NDA for idelalisib for the treatment of CLL on December 6, 2013.

About Idelalisib

Idelalisib is an investigational, highly selective oral inhibitor of phosphoinositide 3-kinase (PI3K) delta. PI3K delta signaling is critical for the activation, proliferation, survival and trafficking of B lymphocytes and is hyperactive in many B-cell malignancies. Idelalisib is being developed both as a single agent and in combination with approved and investigational therapies.

Gilead’s clinical development program for idelalisib in iNHL includes Study 101-09 in highly refractory patients and two Phase 3 studies of idelalisib in previously treated patients. The development program in CLL includes three Phase 3 studies of idelalisib in previously treated patients. Combination therapy with idelalisib and GS-9973, Gilead’s novel spleen tyrosine kinase (Syk) inhibitor, also is being evaluated in a Phase 2 trial of patients with relapsed or refractory CLL, iNHL and other lymphoid malignancies.

Additional information about clinical studies of idelalisib and Gilead’s other investigational cancer agents can be found at http://www.clinicaltrials.gov. Idelalisib and GS-9973 are investigational products and their safety and efficacy have not been established.

About Indolent Non-Hodgkin’s Lymphoma

Indolent non-Hodgkin’s lymphoma refers to a group of largely incurable slow-growing lymphomas that run a relapsing course after therapy and can lead ultimately to life-threatening complications such as serious infections and marrow failure. Most iNHL patients are diagnosed at an advanced stage of disease, and median survival from time of initial diagnosis for patients with the most common form of iNHL, follicular lymphoma, is 8 to 10 years. The outlook for refractory iNHL patients is significantly poorer.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North and South America, Europe and Asia Pacific.

The delta form of PI3K is expressed primarily in blood-cell lineages, including cells that cause or mediate hematologic malignancies, inflammation, autoimmune diseases and allergies. By specifically inhibiting only PI3K delta, a therapeutic effect is exerted without inhibiting PI3K signalling that is critical to the normal function of healthy cells. Extensive studies have shown that inhibition of other PI3K forms can cause significant toxicities, particularly with respect to glucose metabolism, which is essential for normal cell activity.

In 2011, orphan drug designation was assigned to GS-1101 in the U.S. for the treatment of CLL. In 2013, several orphan drug designations were assigned to the compound in the E.U. and U.S.: for the treatment of follicular lymphoma, for the treatment of mucosa-associated lymphoid tissue lymphoma (MALT), for the treatment of nodal marginal zone lymphoma, for the treatment of splenic marginal zone lymphoma, and for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma. Orphan drug designation was also assigned in the U.S. for the treatment of lymphoplasmacytic lymphoma with or without Walenstom’s macroglobulinemia and, in the E.U., for the treatment of Waldenstrom’s macroglobulinemia (lymphoplasmacytic lymphoma).

Later in 2013, some of these orphan drug designations were withdrawn in the E.U.; for the treatment of chronic lymphocytic leukemia / small lymphocytic lymphoma, for the treatment of extranodal marginal-zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), for the treatment of of nodal marginal-zone lymphoma and for the treatment of splenic marginal-zone lymphoma. In 2013, the FDA granted a breakthrough therapy designation for the treatment of chronic lymphocytic leukemia.

  1.  H. Spreitzer (13 May 2013). “Neue Wirkstoffe – Ibrutinib und Idelalisib”. Österreichische Apothekerzeitung (in German) (10/2013): 34.
  2.  Wu, M.; Akinleye, A.; Zhu, X. (2013). “Novel agents for chronic lymphocytic leukemia”.Journal of Hematology & Oncology 6: 36. doi:10.1186/1756-8722-6-36.PMC 3659027PMID 23680477.

idelalisib

CAL-101 is an Oral Delta Isoform-Selective PI3 Kinase Inhibitor.

CAL-101 (GS 1101) is a potent PI3K p110δ inhibitor with an IC50 of 65 nM. PI3K-delta inhibitor CAL-101 inhibits the production of the second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3), preventing the activation of the PI3K signaling pathway and thus inhibiting tumor cell proliferation, motility, and survival. Unlike other isoforms of PI3K, PI3K-delta is expressed primarily in hematopoietic lineages. The targeted inhibition of PI3K-delta is designed to preserve PI3K signaling in normal, non-neoplastic cells. [3][4]
Reference:
[3] Blood 2011, 117, 591-594.
[4] Blood, 2010, 116, 2078-2088.
5. WO 2005113556
6. WO 2005113554
7. WO 2010057048
8. WO 2011156759
9. WO 2012125510
10. WO 2013134288
11. US 2013274198
12. J Med Chem. 2013 Mar 14;56(5):1922-39. doi: 10.1021/jm301522m
US8207153 6-27-2012 QUINAZOLINONES AS INHIBITORS OF HUMAN PHOSPHATIDYLINOSITOL 3-KINASE DELTA
US2012015964 1-20-2012 QUINAZOLINONES AS INHIBITORS OF HUMAN PHOSPHATIDYLINOSITOL 3-KINASE DELTA
US2011306622 12-16-2011 METHODS OF TREATING HEMATOLOGICAL DISORDERS WITH QUINAZOLINONE COMPOUNDS IN SELECTED SUBJECTS
US7932260 4-27-2011 Quinazolinones as Inhibitors of Human Phosphatidylinositol 3-Kinase Delta
US2011044942 2-25-2011 METHODS OF TREATMENT FOR SOLID TUMORS
US2010256167 10-8-2010 QUINAZOLINONES AS INHIBITORS OF HUMAN PHOSPHATIDYLINOSITOL 3-KINASE DELTA
US2010202963 8-13-2010 THERAPIES FOR HEMATOLOGIC MALIGNANCIES
WO2005113556A1 * 12 May 2005 1 Dec 2005 Icos Corp Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta
WO2005117889A1 * 12 Nov 2004 15 Dec 2005 Didier Bouscary Methods for treating and/or preventing aberrant proliferation of hematopoietic
WO2005120511A1 * 4 Jun 2005 22 Dec 2005 Joel S Hayflick Methods for treating mast cell disorders
WO2006089106A2 * 16 Feb 2006 24 Aug 2006 Icos Corp Phosphoinositide 3-kinase inhibitors for inhibiting leukocyte accumulation
US20060106038 * 25 May 2005 18 May 2006 Icos Corporation Methods for treating and/or preventing aberrant proliferation of hematopoietic cells
……………………….
synthesis

The synthesis of a compound in accordance with formula I is first exemplified using steps A-E below, which provide a synthetic procedure for compound 107, the structure of which is shown below.

Figure imgf000150_0001

(107) is idelalisib

……………….

Synthesis of 2-fluoro-6-nitro-N-phenyl-benzamide (108)

Step A: A solution of 2-fluoro-6- nitrobenzoic acid (100 g, 0.54 mol) and dimethylformamide (5 mL) in dichloromethane (600 mL) was treated dropwise with oxalyl chloride (2 M in dichloromethane, 410 mL, 0.8 mol, 1.5 eq) over 30 min. After stirring 2 h at room temperature, the reaction was concentrated to an orange syrup with some solids present. The syrup was dissolved in dry dioxane (80 mL) and slowly added to a suspension of aniline (49 mL, 0.54 mol, 1 eq) and sodium bicarbonate (90 g, 1.08 mol, 2 eq) in a mixture of dioxane (250 mL) and water (250 mL) at 6 0C. The temperature reached 27°C at the end of the addition. After 30 min, the reaction mixture was treated with water (1.2 L). The precipitate was collected by vacuum filtration, washed with water (300 mL) , air dried in the funnel, and dried in vacuo at 50°C for 24 h to afford an off-white solid product (139 g, 99%). 1H NMR (300 MHz, DMSO-d6) δ 10.82 (s, IH), 8.12 (d, J = 7.7 Hz, IH), 7.91-7.77 (m, 2H), 7.64 (d, J = 7.7 Hz, 2H), 7.38 (t, J = 7.9 Hz, 2H), 7.15 > (t, J = 7.4 Hz, IH), ESI-MS m/z 261 (MH+). The reaction described above and compound 108 are shown below.

Figure imgf000151_0001

………………………..

Synthesis of(S) – [1- (2-fluoro-6-nitro-benzoyl) -phenyl-aminocarbonyl] – propyl-carbamic acid tert-butyl ester (109)

Step B: A suspension of compound 108 (0.5 mol) and dimethylformamide (5 mL) in thionyl chloride (256 mL, 2.5 mol, 5 eq) was stirred at 85°C for 5 hours. The reaction mixture was concentrated in vacuo to a brown syrup. The syrup was dissolved in dichloromethane (200 mL) and was slowly added to a solution of N-BOC-L-2-aminobutyric acid (112 g, 0.55 mol, 1.1 eq) and triethylamine (77 mL, 0.55 mol, 1.1 eq) in dichloromethane (600 mL) at 10 0C. After stirring at room temperature for 3 h, salts were removed by filtration, and the solution was washed with 100 mL of water, saturated sodium bicarbonate, water, 5% citric acid, and saturated sodium chloride. The organic phase was dried with magnesium sulfate and concentrated to a red syrup. The syrup was dissolved in dichloromethane (450 mL) and purified by flash chromatography on a silica gel plug (15 x 22 cm, 4 L dry silica) eluted with hexanes/ethyl acetate (10%, 8 L; 15%, 8 L; 20%, 8 L; 25%, 4 L) to yield the compound 109 as an off-white solid (147 g, 66%). 1H NMR (300 MHz, DMSO-d6) δ 8.13 (d, J = 8.0 Hz, IH), 7.84 (t, J = 8.6 Hz, IH), 7.78- 7.67 (m, IH), 7.65-7.49 (m, 3H), 7.40-7.28 ( m, 2H), 7.19 (d, J = 7.5 Hz, IH), 4.05 (broad s, IH), 1.75- 1.30 (m, 2H), 1.34 (s, 9H), 0.93 (broad s, 3H). ESI- MS m/z 446.3 (MH+) . The reaction described above and compound 109 are shown below.

Figure imgf000152_0001
…………………….

Synthesis of(S) – [1- (5-fluoro-4-oxo-3-phenyl-3 , 4-dihydro-quinazolin-2- yl) -propyl] -carbamic acid tert-butyl ester (110)

Step C: A solution of compound 109 (125 mmol, 1 eq) in acetic acid (500 mL) was treated with zinc dust (48.4 g, 740 mmol, 6 eq) added in 3 portions, and the reaction mixture was allowed to cool to below 35°C between additions. After stirring for 2 h at ambient temperature, solids were filtered off by vacuum filtration and washed with acetic acid (50 mL) . The filtrate was concentrated in vacuo, dissolved in EtOAc (400 mL) , washed with water (300 mL) , and the water layer was extracted with EtOAc (300 mL) . The combined organic layers were washed with water (200 mL) , sat’d sodium bicarbonate (2 x 200 mL) , sat’d NaCl (100 mL) , dried with MgSO4, and concentrated to a syrup. The syrup was dissolved in toluene (200 mL) and purified by flash chromatography on a silica gel plug (13 x 15 cm, 2 L dry silica) eluted with hexanes/ethyl acetate (10%, 4 L; 15%, 4 L; 17.5%, 8 L; 25%, 4 L) to yield compound 110 as an off-white foamy solid (33.6 g, 69%). 1H NMR (300 MHz, DMSO-d6) δ 7.83 (td, J = 8.2, 5.7 Hz, IH), 7.64-7.48 (m, 5H), 7.39 (broad d, J = 7.6 Hz, IH), 7.30 (dd, J = 8.3 Hz, IH), 7.23 (d, J = 7.6 Hz, IH), 4.02-3.90 (m, IH), 1.76-1.66 (m, IH), 1.62-1.46 (m, IH), 1.33 (s, 9H), 0.63 (t, J= 7.3 Hz, 3H). ESI-MS m/z 398.3 (MH+). The reaction described above and compound 110 are shown below.

Figure imgf000153_0001

…………..

Syn of (S) -2- (1-amino-propyl) -5-fluoro-3-phenyl-3H-quinazolin-4- one (111)

Step D: A solution of compound 110 (85 mmol) in dichloromethane (60 mL) was treated with trifluoroacetic acid (60 mL) . The reaction mixture was stirred for 1 h, concentrated in vacuo, and partitioned between dichloromethane (150 mL) and 10% K2CO3 (sufficient amount to keep the pH greated than 10) . The aqueous layer was extracted with additional dichloromethane (100 raL) , and the combined organic layers were washed with water (50 mli) and brine (50 mL) . After drying with Mg SO4, the solution was concentrated to provide compound 111 as an off-white solid (22 g, 88%) . 1H NMR (300 MHz,

CDCl3) δ 7.73-7.65 (m, IH), 7.62-7.49 (m, 4H), 7.32- 7.22 (m, 2H), 7.13-7.06 (m, IH), 3.42 (dd, J= 7.5, 5.2 Hz, IH), 1.87-1.70 (m, IH), 1.58-1.43 (m, IH), 0.80 (t, J = 7.4 Hz, 3H) . ESI-MS m/z 298.2 (MH+) . The reaction described above and compound 111 are shown below.

Figure imgf000154_0001

………………

syn of (S) -5-fluoro-3-phenyl-2- [1- (9H-purin-6-ylamino) -propyl] – 3H-quinazolin-4-one (107)

Step E: A suspension of compound 111(65.6 mmol, 1 eq) , 6-bromopurine (14.6 g, 73.4 mmol, 1.1 eq) , and DIEA (24.3 mL, 140 mmol, 2 eq) in tert- butanol (40 mL) was stirred for 24 h at 800C. The reaction mixture was concentrated in vacuo and treated with water to yield a solid crude product that was collected by vacuum filtration, washed with water, and air dried. Half of the obtained solid crude product was dissolved in MeOH (600 mL) , concentrated onto silica gel (300 mL dry) , and purified by flash chromatography (7.5 x 36 cm, eluted with 10 L of 4% MeOH/CH2Cl2) to yield a solid product. The solid product was then dissolved in EtOH (250 mL) and concentrated in vacuo to compound 107 idelalisib as a light yellow solid (7.2 g, 50%).

1H NMR (300 MHz, 80 0C, DMSO-d5) δ 12.66 (broad s, IH), 8.11 (s, IH), 8.02 (broad s, IH), 7.81-7.73 (m, IH),7.60-7.42 (m, 6H), 7.25-7.15 (m, 2H), 4.97 (broad s, IH), 2.02-1.73 (m, 2H), 0.79 (t, J= 7.3 Hz, 3H).

ESI-MS m/z 416.2 (MH+).

C, H, N elemental analysis (C22Hi8N7OF-EtOH- 0.4 H2O).

Chiral purity 99.8:0.2 (S:R) using chiral HPLC (4.6 x 250 mm Chiralpak ODH column, 20 °C, 85:15 hexanes : EtOH, 1 rnL/min, sample loaded at a concentration of 1 mg/mL in EtOH) . The reaction described above and compound 107 idelalisib are shown below.

Figure imgf000155_0001
WO2001030768A1 * 26 Oct 2000 3 May 2001 Gustave Bergnes Methods and compositions utilizing quinazolinones
WO2001081346A2 * 24 Apr 2001 1 Nov 2001 Icos Corp Inhibitors of human phosphatidyl-inositol 3-kinase delta
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Sprout Pharmaceuticals Appeals FDA Decision on NDA for Flibanserin to Treat Hypoactive Sexual Desire Disorder in Premenopausal Women


Flibanserin, girosa
167933-07-5
 cas no

147359-76-0 (monoHCl)

Flibanserin, BIMT-17-BS, BIMT-17
1 – [2 – [4 – [3 – (Trifluoromethyl) phenyl] piperazin-1-yl] ethyl] -2,3-dihydro-1H-benzimidazol-2-one
1-[2-(4-(3-trifluoromethyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one
C20-H21-F3-N4-O, 390.412, Boehringer Ingelheim (Originator)
  • Bimt 17
  • BIMT 17 BS
  • Bimt-17
  • Flibanserin
  • Girosa
  • UNII-37JK4STR6Z
Boehringer Ingelheim (Originator)
Antidepressants, Disorders of Sexual Function and Reproduction, Treatment of, ENDOCRINE DRUGS, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, Treatment of Female Sexual Dysfunction, 5-HT1A Receptor Agonists, 5-HT2A Antagonists
Patents
EP 526434, JP 94509575, US 5576318, WO 9303016.
 WO2010/128516 , US2007/265276
Papers
Pharmaceutical Research, 2002 ,  vol. 19,  3,   pg. 345 – 349
Naunyn-Schmiedeberg’s Archives of Pharmacology, 1995 ,  vol. 352, 3  pg. 283 – 290
Journal of Pharmaceutical and Biomedical Analysis, v.57, 2012 Jan 5, p.104(5)
FLIBANSERIN
…………………….

December 11, 2013 – Sprout Pharmaceuticals today announced that it has received and appealed the Food and Drug Administration’s (FDA) Complete Response Letter (CRL) for flibanserin through the Formal Dispute Resolution process.

Flibanserin is an investigational, once-daily treatment for Hypoactive Sexual Desire Disorder, or HSDD, in premenopausal women. HSDD is the most commonly reported form of female sexual dysfunction

read all here picture    animation

A new drug being developed by Boehringer Ingelheim could give a boost to the sex drive of women with low libido. The drug, known as flibanserin, has been shown in clinical trials to increase their sexual desire when taken once a day at bedtime.

The results from four pivotal Phase III clinical trials on women with hypoactive sexual desire disorder (HSDD) were presented this week at the European Society for Sexual Medicine’s congress in Lyon, France. The trials showed that participants taking flibanserin had a significant improvement in their sexual desire compared to those given a placebo. They also experienced less of the distress associated with sexual dysfunction.

The drug was initially being investigated as a treatment for depression, and acts on the serotonin receptors in the brain – it is both a 5-HT1A receptor agonist and a 5-HT2A receptor antagonist. It is also a partial agonist at the dopamine D4 receptor.

Neurotransmitters such as serotonin are believed to be involved in sexual function, and antidepressants are commonly associated with a loss of libido, so this was an obvious side-effect to look out for during clinical trials in depression. But far from suppressing the libido in women, it appeared to have the opposite effect, so trials in women with HSDD were initiated.

Hormone replacement can improve the libido of women who have had their ovaries removed, but there is no available drug to treat those who have not. There have been accusations that pharma companies invent new diseases like HSDD in order to sell more medicines, but according to Kathleen Segraves, an assistant professor at Case Western Reserve University in the US who has worked in the field of sexual functioning for many years, this is not the case here. HSDD is a very real disorder, she says, and the potential for a treatment for these women is very exciting.

Mona Lisa Painting animation

Flibanserin (code name BIMT-17; proposed trade name Girosa) is a drug that was investigated by Boehringer Ingelheim as a novel, non-hormonal treatment for pre-menopausal women with Hypoactive Sexual Desire Disorder (HSDD).[1][2] Development was terminated in October 2010 following a negative report by the U.S. Food and Drug Administration.[3]

HSDD is the most commonly reported female sexual complaint and characterized by a decrease in sexual desire that causes marked personal distress and/or personal difficulties. According to prevalence studies about 1 in 10 women reported low sexual desire with associated distress, which may be HSDD.[4] The neurobiological pathway of female sexual desire involves interactions among multiple neurotransmitters, sex hormones and various psychosocial factors. Sexual desire is modulated in distinct brain areas by a balance between inhibitory and excitatory neurotransmitters, serotonin acting as an inhibitor while dopamine and norepinephrine act as a stimulator of sexual desire.[5][6]Flibanserin is a 5-HT1A receptor agonist and 5-HT2A receptor antagonist that had initially been investigated as an antidepressant. Preclinical evidence suggested that flibanserin targets these receptors preferentially in selective brain areas and helps to restore a balance between these inhibitory and excitatory effects.[6] HSDD has been recognized as a distinct sexual function disorder for more than 30 years.

The proposed mechanism of action refers back to the Kinsey dual control model. Several sex steroids, neurotransmitters, and hormones have important excitatory or inhibitory effects on the sexual response. Among the neurotransmitters, the excitatory activity is driven by dopamine and norepinephrine, while the inhibitory activity is driven by serotonin. The balance between these systems is relevant for a healthy sexual response. By modulating these neurotransmitters in selective brain areas, flibanserin, a 5-HT1A receptoragonist and 5-HT2A receptor antagonist, is likely to restore the balance between these neurotransmitter systems.[6]

Several large pivotal Phase III studies with Flibanserin were conducted in the USA, Canada and Europe. They involved more than 5,000 pre-menopausal women with generalized acquired Hypoactive Sexual Desire Disorder (HSDD). The results of the Phase III North American Trials demonstrated that

Although the two North American trials that used the flibanserin 100 mg qhs dose showed a statistically significant difference between flibanserin and placebo for the endpoint of [satisfying sexual events], they both failed to demonstrate a statistically significant improvement on the co-primary endpoint of sexual desire. Therefore, neither study met the agreed-upon criteria for success in establishing the efficacy of flibanserin for the treatment of [Hypoactive Sexual Desire Disorder].

These data were first presented on November 16, 2009 at the congress of the European Society for Sexual Medicine in Lyon, France. The women receiving Flibanserin reported that the average number of times they had “satisfying sexual events” rose from 2.8 to 4.5 times a month. However, women receiving placebo reported also an increase of “satisfying sexual events” from 2.7 to 3.7 times a month.

Evaluation of the overall improvement of their condition and whether the benefit was meaningful to the women, showed a significantly higher rate of a meaningful benefit in the flibanserin-treated patient group versus the placebo group.The onset of the Flibanserin effect was seen from the first timepoint measured after 4 weeks of treatment and maintained throughout the treatment period.

The overall incidence of adverse events among women taking flibanserin was low, the majority of adverse events being mild to moderate and resolved during the treatment. The most commonly reported adverse events included dizziness, nausea, fatigue, somnolence and insomnia.

On June 18, 2010, a federal advisory panel to the U.S. Food and Drug Administration (FDA) unanimously voted against recommending approval of Flibanserin.

Earlier in the week, a FDA staff report also recommended non-approval of the drug. While the FDA still might approve Flibanserin, in the past, negative panel votes tended to cause the FDA not to approve.

On October 8, 2010, Boehringer Ingelheim announced that it would discontinue its development of flibanserin in light of the FDA advisory panel’s recommendation.

On June 27, 2013, Sprout Pharmaceuticals confirmed they had resubmitted flibanserin for FDA approval.

Flibanserin, chemically 1 -[2-(4-(3-trifluoromethylphenyl)piperazin-1 – yl)ethyl]-2,3-dihydro-1 H-benzimidazole-2-one was disclosed in form of its hydrochloride in European Patent No. 526,434 (‘434) and has the following chemical structure:

Figure imgf000002_0001

Process for preparation of flibanserin were disclosed in European Patent No. ‘434, U.S. Application Publication No. 2007/0032655 and Drugs of the future 1998, 23(1): 9-16.

According to European Patent No. ‘434 flibanserin is prepared by condensing 1-(2-chloroethyl)-2,3-dihydro-1 H-benzimidazol-one with m- trifluoromethyl phenyl piperazine. According to U.S. Application Publication No. 2007/0032655 flibanserin is prepared by condensing 1-[(3-trifluoromethyl)phenyl]-4-(2- chloroethyl)piperazine with 1 -(2-propenyl)-1 ,3-dihydro-benzimidazol-2H-one.

According to Drugs of the future 1998, 23(1): 9-16 flibanserin is prepared by reacting 1-(2-chloroethyl)-2,3-dihydro-1 H-benzimidazol-one with m- trifluoromethylphenylpiperazine.

…………………

EP0526434A1

1-[2-(4-(3-trifluoromethyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one

Compound 3

  • Hydrochloride salt (isopropanol) M.p. 230-231°C

Analysis

  • Figure imgb0022

    ¹H NMR (DMSO-d₆/CDCL₃ 5:2) 11.09 (b, 1H), 11.04 (s, 1H), 7.5-6.9 (8H), 4.36 (t, 2H), 4.1-3.1 (10H)

…………………………………

 drawing   animation

The compound 1-[2-(4-(3-trifluoromethyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1 H- benzimidazol-2-one (flibanserin) is disclosed in form of its hydrochlorid in European Patent Application EP-A-526434 and has the following chemical structure:

Figure imgf000003_0001

Flibanserin shows affinity for the 5-HTιA and 5-HT2-receptor. It is therefore a promising therapeutic agent for the treatment of a variety of diseases, for instance depression, schizophrenia, Parkinson, anxiety, sleep disturbances, sexual and mental disorders and age associated memory impairment.

EXAMPLE……… EP1518858A1

375 kg of 1-[(3-trifluoromethyl)phenyl]-4-(2-cloroethyl)piperazin are charged in a reactor with 2500 kg of water and 200 kg of aqueous Sodium Hydroxide 45%. Under stirring 169.2 kg of 1-(2-propenyl)-1,3-dihydro-benzimidazol-2H-one, 780 kg of isopropanol, 2000 kg of water and 220 kg of aqueous Sodium Hydroxide 45% are added. The reaction mixture is heated to 75-85° C. and 160 kg of concentrated hydrochloric acid and 200 kg of water are added.

The reaction mixture is stirred at constant temperature for about 45 minutes. After distillation of a mixture of water and Isopropanol (about 3000 kg) the remaining residue is cooled to about 65-75° C. and the pH is adjusted to 6.5-7.5 by addition of 125 kg of aqueous Sodium Hydroxide 45%. After cooling to a temperature of 45-50° C., the pH value is adjusted to 8-9 by addition of about 4 kg of aqueous Sodium Hydroxide 45%. Subsequently the mixture is cooled to 30-35° C. and centrifuged. The residue thus obtained is washed with 340 l of water and 126 l of isopropanol and then with water until chlorides elimination.

The wet product is dried under vacuum at a temperature of about 45-55° C. which leads to 358 kg of crude flibanserin polymorph A. The crude product thus obtained is loaded in a reactor with 1750 kg of Acetone and the resulting mixture is heated under stirring until reflux. The obtained solution is filtered and the filtrate is concentrated by distillation. The temperature is maintained for about 1 hour 0-5° C., then the precipitate solid is isolated by filtration and dried at 55° C. for at least 12 hours.

The final yield is 280 kg of pure flibanserin polymorph A.

………………………….

Flibanserin may be prepared by reacting 1-(phenylvinyl)-2,3-dihydro-1H-benzimidazol-2-one (I) with 1,2-dichloroethane (II) in the presence of NaH in warm dimethylformamide. The resulting 1-(2-chloroethyl)-2,3-dihydro-1H-benzimidazol-one (III) is in turn coupled with commercially available m-trifluoromethylphenylpiperazine hydrochloride (IV) in the presence of sodium carbonate and catalytic potassium iodide in refluxing ethanol. The crude flibanserin hydrochloride (V) is then dissolved in aqueous ethanol and the pure base is precipitated upon addition of sodium hydroxide.

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1-(1-phenylvinyl)-1,3-dihydro-2H-benzimidazol-2-one (I)
1,2-dichloroethane (II)
1-(2-chloroethyl)-1,3-dihydro-2H-benzimidazol-2-one (III)
1-[3-(trifluoromethyl)phenyl]piperazine; N-[3-(trifluoromethyl)phenyl]piperazine (IV)
1-(2-[4-[3-(trifluoromethyl)phenyl]piperazino]ethyl)-1,3-dihydro-2H-benzimidazol-2-one (V)

………………………..

WO2010128516A2

A process for the preparation of a compound of formula X or a salt thereof:
Figure imgf000026_0001
wherein R2 is hydrogen or an amino protecting group which comprises reacting the compound of formula VII
Figure imgf000026_0002

wherein R2 is as defined in formula X; with a compound of formula Xl:

Figure imgf000026_0003

According to another aspect of the present invention there is provided a novel compound or a salt thereof selected from the compounds of formula I, IV and VII:

Figure imgf000014_0001
Figure imgf000014_0002

Wherein R is hydrogen or an amino protecting group.

Preferable the amino protecting groups are selected from butyl, 1 ,1- diphenylmethyl, methoxymethyl, benzyloxymethyl, trichloroethoxymethyl, pyrrolidinomethyl, cyanomethyl, pivaloyloxymethyl, allyl, 2-propenyl, t- butyldimethylsilyl, methoxy, thiomethyl, phenylvinyl, 4-methoxyphenyl, benzyl, A- methoxybenzyl, 2,4-dimethoxybenzyl, 2-nitrobenzyl, t-butoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl, 4-chlorophenoxycarbonyl, A- nitrophenoxycarbonyl, methoxycarbonyl and ethoxycarbonyl. Still more preferable protecting groups are selected from t- butoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl, phenylvinyl and 2-propenyl.

R1 is independently selected from chlorine, bromine, iodine, methanesulphonate, trifluoromethanesulphonate, paratoluenesulphonate or benzenesulphonate. Preferable R1 is independently selected from chlorine, bromine or iodine and more preferable R1 is chlorine.

Wherein R2 is hydrogen or an amino protecting group.

The amino protecting group may be any of the groups commonly used to protect the amino function such as alkyl, substituted alkyl, hetero substituted alkyl, substituted or unsubstituted unsaturated alkyl, alkyl substituted hetero atoms, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, alkyoxy carbonyl groups and aryloxy carbonyl groups.

Preferable the amino protecting groups are selected from butyl, 1 ,1 – diphenylmethyl, methoxymethyl, benzyloxymethyl, trichloroethoxymethyl, pyrrolidinomethyl, cyanomethyl, pivaloyloxymethyl, allyl, 2-propenyl, t- butyldimethylsilyl, methoxy, thiomethyl, phenylvinyl, 4-methoxyphenyl, benzyl, A- methoxybenzyl, 2,4-dimethoxybenzyl, 2-nitrobenzyl, t-butoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl, 4-chlorophenoxycarbonyl, A- nitrophenoxycarbonyl, methoxycarbonyl and ethoxycarbonyl. Still more preferable protecting groups are selected from t- butoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl, phenylvinyl and 2-propenyl. The following examples are given for the purpose of illustrating the present invention and should not be considered as limitations on the scope and spirit of the invention.

EXAMPLES Example 1

A mixture of sodium hydroxide (47 gm) and i-(α-methylvinyl) benzimidazol-2-one (100 gm) in dimethylformamide (400 ml) was .stirred for 1 hour at room temperature. Dibromoethane (217 gm) was slowly added to the mixture and stirred at 1 hour 30 minutes. The resulting solution after addition water (500 ml) was extracted with ethyl acetate. The combined ethyl acetate extract washed with water. After drying the solvent was removed under vacuum to yield 132 gm of 1 ,3-dihydro-1-(2-bromoethyl)-3-isopropenyl-2H-benzimidazol- 2-one as a yellow oily liquid.

Example 2 A mixture of 1 ,3-dihydro-1-(2-bromoethyl)-3-isopropenyl-2H- benzimidazol-2-one (100 gm), diethanolamine (175 ml), sodium carbonate (40 gm) and potassium iodide (10 gm) was heated to 90 to 95 deg C and stirred for 2 hours. The reaction mass was cooled to room temperature and added water (500 ml). The resulting mixture extracted into ethyl acetate and the organic layer washed with water. After drying the solvent was removed under vacuum to yield 105 gm of 1 ,3-dihydro-1-[2-[N-bis-(2-hydroxyethyl)amino]ethyl]-3-isopropenyl- 2H-benzimidazol-2-one as a thick yellow oily liquid.

Example 3

To the mixture of 1 ,3-dihydro-1-[2-[N-bis-(2-hydroxyethyl)amino]ethyl]-3- isopropenyl-2H-benzimidazol-2-one (100 gm) obtained as in example 2 and chloroform (300 ml), thionyl chloride (95 ml) was slowly added. The mixture was heated to reflux and stirred for 2 hours. The excess thionyl chloride and chloroform was distilled off to yield 98 gm of 1 ,3-dihydro-1-[2-[N-[bis-(2- chloroethyl)amino]ethyl]-3-isopropenyl-2H-benzimidazol-2-one as a brown coloured sticky residue.

Example 4

1 ,3-dihydro-1-[2-[N-[bis-(2-chloroethyl)amino]ethyl]-3-isopropenyl-2H- benzimidazol-2-one (98 gm) obtained as in example 3 was added to water (500 ml) and concentrated hydrochloric acid (200 ml) mixture. The mixture was heated to 60 to 65 deg C and stirred for 1 hour. The contents of the flask cooled to room temperature and pH of the solution adjusted to 9 – 10 with 10% sodium hydroxide solution. The resulting solution extracted with ethyl acetate and washed the organic layer with water. Evaporate the solvent under reduced pressure to yield 82 gm of 1 ,3-dihydro-1-[2-[N-bis-(2-chloroethyl)amino]ethyl]- 2H-benzimidazol-2-one as a dark brown coloured oily liquid

Example 5

A mixture of 1 ,3-dihydro-1-[2-[N-bis-(2-chloroethyl)amino]ethyl]-1,2-H- benzimidazol-2-one (82 gm) obtained as in example 4, xylene (300 ml) and m- trifluoromethyl aniline (58 gm) was refluxed for 64 hours. The reaction mass was cooled to room temperature and filtered to obtain 1-[2-(4-(3- thfluoromethylphenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1 H-benzimidazole-2-one hydrochloride (Flibanserin hydrochloride) as a light brown coloured solid.

The crude flibanserin hydrochloride was purified in isopropyl alcohol to give 85 gm of pure flibanserin hydrochloride as off white solid.

Example 6

Piperazine (12 gm), toluene(60 ml) and tetra butyl ammonium bromide (1 gm) mixture was heated to 60 deg C, added 1 ,3-dihydro-1-(2-bromoethyl)-3- isopropenyl-2H-benzimidazol-2-one (10 gm) and stirred for 4 hours at 90 to 95 deg C. The mixture was cooled to 60 deg C and added water (50 ml). The separated toluene layer distilled under vacuum to give 8.5 gm of 1 ,3-dihydro-1- (2-piperazinyl)ethyl-3-isopropenyl-2H-benzimidazol-2-one as a white solid.

Example 7

To the mixture of concentrated hydrochloric acid (20 ml) and water (100 ml) was added 1 ,3-dihydro-1-(2-piperazinylethyl)-3-isopropenyl-2H- benzimidazol-2-one (10 gm) obtained as in example 6 and heated to 60 to 65 deg C 1 hour. The mixture was cooled to room temperature and pH of the solution was adjusted to 9 – 10 with 10% sodium hydroxide solution, extracted with ethyl acetate and the organic layer was washed with water. After drying the solvent was removed under vacuum to yield 8.5 gm of 1 ,3-dihydro-1-(2- piperazinyl ethyl)-2H-benzimidazol-2-one as a white solid.

Example 8

3-trifluoromethylaniline (40 gm) and hydrobromic acid (85 ml; 48- 50%w/w) mixture was cooled to 0 to 5 deg C. To this mixture added sodium nitrite solution (18.5 gm in 25 ml of water) at 5 to 10 deg C and copper powder (1 gm). The temperature was slowly raised to 50 to 55 deg C and stirred for 30 minutes. Added water (200 ml) to reaction mass and applied steam distillation, collected m-trifluoromethylbromobenzene as oily liquid. The oily liquid washed with sulfuric acid for two times (2 X 10 ml) followed by washed with water (2 X 20 ml) and dried the liquid with sodium sulphate to give 22 gm of m- trifluoromethylbromobenzene.

Example 9

To a mixture of 1 ,3-dihydro-1-(2-piperazinyl ethyl)-2H-benzimidazol-2- one (10 gm) obtained as in example 7, m-trifluoromethylbromobenzene (9 gm) obtained as in example 8, sodium tert-butoxide (5.5 gm), palladium acetate (4.5 mg) and xylene (80 ml) was added tri-tert.-butylphosphine (0.2 ml). The mixture was heated to 120 deg C and stirred for 3 hours. The reaction mass was cooled, added water (100 ml) and extracted with ethyl acetate and the organic layer was washed with water. After drying the solvent was removed under vacuum to yield

10 gm of 1-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1 H- benzimidazole-2-one (Flibanserin).

Example 10

To a mixture of 1 ,3-dihydro-1-[2-[N-bis-(2-hydroxyethyl)amino]ethyl]-3- isopropenyl-2H-benzimidazol-2-one (100 gm) obtained as in example 3, cyclohexane (400 ml) and sodium carbonate (35 gm) was added benzene sulfonyl chloride (116 gm) at room temperature. The mixture was heated to 80 to

85 deg C and stirred for 8 hours . The contents were cooled to room temperature and added water (500 ml). Distilled the organic layer to give 182 gm of 1 ,3-dihydro-1-[2-[N-[bis-(2-benzenesulfonyloxy)- ethyl]amino]ethyl]-3- isopropenyl- 2H-benzimidazol-2-one.

Example 11

1 ,3-dihydro-1 -[2-[N-[bis-(2-benzenesulfonyloxy)- ethyl]amino]ethyl]-3- isopropenyl- 2H-benzitηidazol-2-one (100 gm) obtained as in example 10, dimethylformamide (500 ml) and sodium corbonate (18 gm) was mixed and heated to 70 deg C. To the mixture was added m-trifluoromethyl aniline (27 gm) and heated to 80 to 85 deg C, stirred for 5 hours. The reaction mass was cooled and added water (2000 ml), filtered the solid to yield 1 ,3-dihydro-1-[2-[4-(3- trifluoromethylphenyl)piperazinyl]ethyl]-3-isopropenyl-2H benzimidazol-2-one. Example 12

1 ,3-dihydro-1-[2-[N-[bis-(2-benzenesulfonyloxy)- ethyl]amino]ethyl]-3- isopropenyl- 2H-benzimidazol-2-one (100 gm) obtained as in example 11 added to the mixture of water (500 ml) and concentrated hydrochloric acid (200 ml), heated to 65 deg C and stirred for 1 hour. The reaction mass was cooled to room temperature and pH adjusted to 10 to 10-5 with 10% sodium hydroxide solution. The resulting mixture was extracted with ethyl acetate and the organic

 layer was washed with water. After drying the solvent was removed under vacuum to yield 87 gm of 1-[2-(4-(3-trifluoromethylphenyl)piperazin-1-yl)ethyl]- 2,3-dihydro-1 H-benzimidazole -2-one (Flibanserin).

…………………..

Paper

Journal of Pharmaceutical and Biomedical Analysis, v.57, 2012 Jan 5, p.104(5)

Isolation and structural elucidation of flibanserin as an adulterant in a health supplement used for female sexual performance enhancement

Low, Min-Yong et al

http://www.sciencedirect.com/science/article/pii/S0731708511004833

Full-size image (5 K)

This proposed formula and structure was further confirmed by 1H and 13C NMR data which indicated the presence of 20 carbon atoms and 21 protons.

1H NMR

Inline image 6

13C NMR

Inline image 5

1D and 2DNMR data were used to assign the protons and carbon atoms.

Inline image 2

In the1H NMR spectrum , a sharp singlet at 10.00 ppm integrating for one
proton is a typical proton attached to nitrogen. HMBC correlated this proton to C-2, C-4, and C-9 suggesting that it was H-3.

Complex signals were observedbetween 7.00 to 7.31 ppm, integrating for eight protons. A triplet at 7.31 ppm,integrating for a proton has a coupling constant of 8.0 Hz. HMBC correlated thisproton with C-16, C-19, and C-21 suggesting that it was H-20.

A double-doubletsplitting pattern at chemical shift 7.11 ppm, integrating for a proton, has couplingconstants of 6.3 Hz and 1.6 Hz.

HMBC correlated this proton to C-6, C-7, and C-9 showing that it was H-8. Overlapped signals were observed from 7.04 ppm to7.10 ppm, integrating for five protons. A double-doublet splitting pattern at 7.01ppm with coupling constant 8.0 Hz and 2.0 Hz, integrating for a proton was
observed.

HMBC correlated this proton to C-17 suggesting that it was either H-19or H-21. Four triplet signals were also observed from 2.73 ppm to 4.08 ppm,integrating for a total of twelve protons.

Two of these triplet signals at 2.74 ppmand 3.22 ppm integrated for four protons each, suggesting overlapping signals ofmethylene protons. This was further confirmed by 13C and DEPT NMR.

13C and DEPT NMR data showed the signals of four methylene, eight methineand six quaternary carbon atoms. The DEPT signals at 53.1 ppm and 48.6 ppmhave intensities which were double of those from the rest of the methylene carbonsignals, suggesting two methylene carbon atoms each contributing to the signal at 53.1 ppm and 48.6 ppm.

DEPT

Inline image 4

HMQC results further indicated that these two methylene carbon signals at 53.1 ppm and 48.6 ppm were correlated to the protons signal at 2.73 ppm and 4.08 ppm respectively, which corresponded to four protons each. The finding confirmed overlapping methylene carbon signals (at 53.1 ppm and 48.6 ppm) and methylene proton signals (at 2.73 ppm and 4.08 ppm). Hence, the unknown compound has six methylene carbon atoms with a total of twelve methylene protons.

The chemical shifts of the twelve methylene protons suggested that they were attached to relatively electronegative atoms. It was speculated that the six methylene groups were attached to the nitrogen atoms and the electron withdrawing effect of these electronegative nitrogen atoms resulted in the deshielding of the protons. HMBC and COSY correlations were used to assign the rest of the protons

The 13C NMR data  showed that there were two quaternary carbon at
155.6 ppm and 151.3 ppm. The carbon with chemical shift 155.6 ppm was C-2. Inthe structure of imidazolone, carbonyl carbon C-2 was attached to two nitrogenatoms which helped to withdraw electrons from oxygen to C-2. Hence, C-2 wasless deshielded as compared to a normal carbonyl carbon which has chemical shiftabove 170 ppm.

Eight methine carbons and two quaternary carbons with chemicalshifts above 108 ppm suggested the presence of two aromatic rings. Thequaternary carbon with chemical shift 125.4 ppm was C-22 which was attached tothree fluorine atoms. Due to the strong electron withdrawing effect of the fluorineatoms, C-22 was highly deshielded and had a high chemical shift.

The IR spectrum of the isolated compound showed absorption bands of amide (νC=O 1685 cm-1, νN-H (stretch) 3180 cm-1, νN-H (bending) 1610 cm-1), alkyl fluoride (νC-F1077 cm-1, 1112 cm-1, 1158 cm-1), aromatic ring (ν Ar-H 3028 cm-1, 3078 cm-1 andνC=C 1401 cm-1, 1446 cm-1, 1453 cm-1, 1468 cm-1, 1487 cm-1) and alkane (νC-H2891 cm-1, 2930 cm-1 2948 cm-).

Inline image 1

COSY

Inline image 3

……………………………….

US5576318, 1996

1 H NMR (DMSO-d6 /CDCL3 5:2) 11.09 (b, 1H), 11.04 (s, 1H), 7.5-6.9 (SH), 4.36 (t, 2H), 4.1-3.1 (10 H)

,,,,,,,,,,,,,,,,,,

  1.  Borsini F, Evans K, Jason K, Rohde F, Alexander B, Pollentier S (summer 2002). “Pharmacology of flibanserin”. CNS Drug Rev. 8 (2): 117–142. doi:10.1111/j.1527-3458.2002.tb00219.xPMID 12177684.
  2.  Jolly E, Clayton A, Thorp J, Lewis-D’Agostino D, Wunderlich G, Lesko L (April 2008). “Design of Phase III pivotal trials of flibanserin in female Hypoactive Sexual Desire Disorder (HSDD)”. Sexologies 17 (Suppl 1): S133–4. doi:10.1016/S1158-1360(08)72886-X.
  3.  Spiegel online: Pharmakonzern stoppt Lustpille für die Frau, 8 October 2010 (in German)
  4.  Nygaard I (November 2008). “Sexual dysfunction prevalence rates: marketing or real?”. Obstet Gynecol 112 (5): 968–9.doi:10.1097/01.AOG.0000335775.68187.b2PMID 18978094.
  5.  Clayton AH (July 2010). “The pathophysiology of hypoactive sexual desire disorder in women”Int J Gynaecol Obstet 110 (1): 7–11.doi:10.1016/j.ijgo.2010.02.014PMID 20434725.
  6.  Pfaus JG (June 2009). “Pathways of sexual desire”. J Sex Med 6 (6): 1506–33. doi:10.1111/j.1743-6109.2009.01309.x.PMID 19453889.
EP0200322A1 * Mar 18, 1986 Nov 5, 1986 H. Lundbeck A/S Heterocyclic compounds
BE904945A1 * Title not available
GB2023594A * Title not available
US3472854 * May 29, 1967 Oct 14, 1969 Sterling Drug Inc 1-((benzimidazolyl)-lower-alkyl)-4-substituted-piperazines
US4954503 * Sep 11, 1989 Sep 4, 1990 Hoechst-Roussel Pharmaceuticals, Inc. 3-(1-substituted-4-piperazinyl)-1H-indazoles

Chelsea Therapeutics Announces FDA Acceptance of NORTHERA(TM) (droxidopa) NDA Resubmission


Droxidropa

 

FDA Deems Resubmission a Complete Response; PDUFA Date Set as
February 14, 2014

CHARLOTTE, N.C., Sept. 4, 2013 (GLOBE NEWSWIRE) — Chelsea Therapeutics International, Ltd. (Nasdaq:CHTP) today announced that the U.S. Food and Drug Administration (FDA) has acknowledged receipt of the New Drug Application (NDA) resubmission seeking approval to market NORTHERA(TM) (droxidopa), an orally active synthetic precursor of norepinephrine

read all at

http://www.pharmalive.com/chelsea-therapeutics-announces-fda-acceptance-of-northera-nda-resubmission

UPDATE………………….

 

L-DOPS.svg

DROXIDOPA

ORPHAN DRUG,

CAS 23651-95-8, 3916-18-5

ROTATION   –FORM

(2S,3R)-2-amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid
223-480-5 [EINECS],
L-Tyrosine, β,3-dihydroxy-, (βR)-, L-Tyrosine, β,3-dihydroxy-, threo-
Northera [Trade name]
threo-b,3-Dihydroxy-L-tyrosine
1-14-00-00685 [Beilstein]L-threo-3-(3,4-Dihydroxyphenyl)serine, L-Dihydroxyphenylserine, L-DOPS;DOPS, \
Northera, C, L-DOPS|Northera®, |SM-5688, L-threo-dihydroxyphenylserine, L-Threodops
L-threo-droxidopa, threo-2-Amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropionic acid
THREO-DIHYDROXYPHENYLSERINE
threo-Dopaserine
UNII:24A0V01WKS
UNII:J7A92W69L7
FDA 2/18/2014, FDA approves Northera to treat neurogenic orthostatic hypotension
Properties: Crystals from ethanol and ether, mp 232-235° (dec).
[a]D20 -39° (c = 1 in 1N aq HCl).
Also cited as crystals from water and L-ascorbic acid, mp 229-232° (dec) (Ohashi). [a]D20 -42.0° (c = 1 in 1N aq HCl).
Melting point: mp 232-235° (dec); mp 229-232° (dec) (Ohashi)
Optical Rotation: [a]D20 -39° (c = 1 in 1N aq HCl); [a]D20 -42.0° (c = 1 in 1N aq HCl)
On February 18th 2014 the FDA approved Droxidopa (tarde name Northera™) for the treatment of neurogenic orthostatic hypotension (NOH). NOH is a rare, chronic and often debilitating drop in blood pressure upon standing, and is associated with Parkinson’s disease, multiple-system atrophy, and pure autonomic failure. Symptoms of NOH include dizziness, light-headedness, blurred vision, fatigue and fainting when a person stands.
Active Ingredient: DROXIDOPA
Proprietary Name: NORTHERA
Dosage Form; Route of Administration: CAPSULE; ORAL
Strength: 100MG
Reference Listed Drug: No
TE Code:
Application Number: N203202
Product Number: 001
Approval Date: Feb 18, 2014
Applicant Holder Full Name: LUNDBECK NA LTD
Marketing Status:  Prescription
str1
Image result for DROXIDOPA

Droxidopa (INN; trade name Northera; also known as L-DOPS, Lthreo-dihydroxyphenylserine, L-threo-DOPS and SM-5688) is a synthetic amino acid precursor which acts as a prodrug to the neurotransmitter norepinephrine (noradrenaline).[1] Unlike norepinephrine, droxidopa is capable of crossing the protective blood–brain barrier (BBB).[1]

CLIP

Image result for DROXIDOPA

REF http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203202Orig1s000ChemR.pdf

Distribution
Droxidopa exhibits plasma protein binding of 75% at 100 ng/mL and 26% at 10,000 ng/mL with an apparent volume of distribution of about 200 L.

Dosage

Droxidopa starting dose is 100mg three times daily (which can be titrated to a maximum of 600 mg three times daily). One dose should be taken in late afternoon at least 3 hours prior to bedtime to reduce the potential for supine hypertension during sleep.

Indications

History

Droxidopa was developed by Sumitomo Pharmaceuticals for the treatment of hypotension, including NOH,[2] and NOH associated with various disorders such as MSA, FAP, and PD, as well as IDH. The drug has been used in Japan and some surrounding Asianareas for these indications since 1989. Following a merge with Dainippon Pharmaceuticals in 2006, Dainippon Sumitomo Pharmalicensed droxidopa to Chelsea Therapeutics to develop and market it worldwide except in Japan, Korea, China, and Taiwan. In February 2014, the Food and Drug Administration approved droxidopa for the treatment of symptomatic neurogenic orthostatic hypotension.[3]

Image result for DROXIDOPA

Clinical trials

Chelsea Therapeutics obtained orphan drug status (ODS) for droxidopa in the U.S. for NOH, and that of which associated with PD, PAF, and MSA. In 2014, Chelsea Therapeutics was acquired by Lundbeck along with the rights to droxidopa which was launched in the US in Sept 2014.[4]

REGULATORY

str1

CLICK ON IMAGE TO VIEW

FDA agreement on overall development program (Sep 2007)

• FDA agreement on Study 301 design under a Special Protocol Assessment (Feb 2008) – Included agreement: length of patient exposure was adequate for the safety evaluation

• FDA agreement on changing primary endpoint of Study 301 while it was ongoing and prior to any unblinding (Nov 2009) – From dizziness to the OHQ – SPA remained intact

• FDA agrees to NDA package (Dec 2010) – Studies 301, 302, 303, 304 and 305 – Renal safety study conducted post-marketing

• FDA accepts droxidopa NDA and grants priority review (Sep 2011)

Pharmacology

Droxidopa is a prodrug of norepinephrine used to increase the concentrations of these neurotransmitters in the body and brain.[1][What, if any, are the other neurotransmitters droxidopa increases concentrations of? “These neurotransmitters” implies multiple(see above)] It ismetabolized by aromatic L-amino acid decarboxylase (AAAD), also known as DOPA decarboxylase (DDC). Patients with NOH have depleted levels of norepinephrine which leads to decreased blood pressure or hypotension upon orthostatic challenge.[5] Droxidopa works by increasing the levels of norepinephrine in the peripheral nervous system (PNS), thus enabling the body to maintain blood flow upon and while standing.

Droxidopa can also cross the blood–brain barrier (BBB) where it is converted to norepinephrine from within the brain.[1] Increased levels of norepinephrine in the central nervous system (CNS) may be beneficial to patients in a wide range of indications. Droxidopa can be coupled with a peripheral aromatic L-amino acid decarboxylase inhibitor (AAADI) orDOPA decarboxylase inhibitor (DDC) such as carbidopa (Lodosyn) to increase central norepinephrine concentrations while minimizing increases of peripheral levels.

Side effects

With over 20 years on the market, droxidopa has proven to have few side effects of which most are mild. The most common side effects reported in clinical trials include headache, dizziness nausea, hypertension and fatigue.[6][7][8][8]

L-threo-dihydroxyphenylserine, also known as droxidopa, L-threo-DOPS, or L-DOPS, is an orally active synthetic precursor of norepinephrine. Droxidopa thus replenishes depleted norepinephrine, allowing for re-uptake of norepinephrine into peripheral nervous system neurons. This reuptake, in turn, stimulates receptors for vasoconstriction, providing physiological improvement in symptomatic neurogenic orthostatic hypotension patients. It has also shown efficacy in other diseases, such as Parkinson’s disease and depression.

Droxidopa has been used in Japan for many years for the treatment of orthostatic hypotension. It was originally approved in 1989 for the treatment of frozen gait or dizziness associated with Parkinson’s disease and for the treatment of orthostatic hypotension, syncope or dizziness associated with Shy-Drager syndrome and Familial Amyloidotic Polyneuropathy.

Marketing approval was later expanded to include treatment of vertigo, dizziness and weakness associated with orthostatic hypotension in hemodialysis patients.

The preparation of droxidopa generally involves a multi-step synthesis. Typically, one or more of the necessary steps in the synthesis requires that reactive sites other than that site targeted for reaction are temporarily protected. Thus, the synthesis of droxidopa typically comprises at least one protecting and associated deprotecting step. For example, the catechol moiety, the amine moiety, and/or the carboyxyl moiety may require protection and subsequent deprotection, depending upon the synthetic route and the reagents used in the preparation of droxidopa.

U.S. Patent Nos. 4,319,040 and 4,480,109 to Ohashi et al. describe processes for the preparation of optically active D- and L- threo-DOPS by optically resolving a racemic mixture of threo-2-(3,4-methylenedioxyphenyl)-N-carbobenzyloxyserine or threo-2-(3,4-dibenzyloxy-phenyl)- N-carbobenzyloxyserine, respectively. Following optical resolution of these racemic mixtures to give the desired L-enantiomer, the methylene or benzyl groups must be removed from the catechol moiety and the carbobenzyloxy (CBZ) group must be removed from the amine group to give droxidopa. The methylene group can be readily removed by reaction with a Lewis acid {e.g., aluminum chloride). The CBZ group (and the benzyl catechol protecting groups, where applicable) is removed from the amine by hydrogenolysis to give the desired compound. The hydrogenolysis step is noted to be carried out by treating the optically resolved salt with hydrogen in the presence of a catalyst, e.g., palladium, platinum, nickel, or the like.

However, for large-scale production of pharmaceutical compounds, hydrogenolysis may not be desirable. For example, hydrogenolysis requires expensive, specialized equipment, which represents a large capital investment. Labor costs are also high, as the process requires careful handling and disposal of certain compounds (e.g., the pyrophoric catalyst). Further, due to the hazards associated with both the reagents and the high pressure system required for hydrogenolysis, it is desirable to avoid synthetic methods that require hydrogenolysis.

In an alternative method for the production of droxidopa, taught by U.S. Patent No.

4,562,263 to Ohashi et al, hydrogenation is not required. In this process, the amine group is protected via a phthaloyl group. Following optical resolution, the phthaloyl group is removed from the droxidopa precursor by hydrazine.

However, hydrazine is known to be genotoxic and has been classified by the EPA as a

Group B2 probable human carcinogen. Thus, it is desirable to remove even trace amounts of hydrazine from pharmaceutical compounds. In practice, the method described in the ‘263 patent suffers from the inability to remove 100% of the hydrazine from the final product. Thus, there is some level of contamination by hydrazine using this method. The Food and Drug Administration has established a maximum genotoxic impurity level of 1.5 micrograms per day. Therefore, based on the maximum daily dose of droxidopa (1.8 g), the maximum allowable hydrazine level therein is 0.8 ppm. Accordingly, it would be advantageous to find a new synthetic route for the preparation of droxidopa that avoids the use of hydrogenolysis and also avoids the use of hydrazine

PATENT

https://www.google.ch/patents/WO2013142093A1?cl=en

The synthetic route for the preparation of droxidopa comprises the following steps: a) converting piperonal to 2-amino-3-(benzo-l,3-diox-5-yl)-3-hydroxypropanoic acid

Figure imgf000004_0001

c) optical resolution and separation of the desired isomer

Figure imgf000004_0002
Figure imgf000005_0001
Figure imgf000005_0002

Experimental Section

Example 1 : Screening of Deprotection Strategies for Phthaloyl Group

Figure imgf000015_0001

Example 2: Exemplary Synthesis of Droxidopa

The synthesis of droxidopa according to the methods provided herein can be conducted as a continuous process or can be conducted in a series of individual steps. Both processes are intended to be encompassed by the present disclosure.

Synthesis of N-carbomethoxy phthalimide

Figure imgf000015_0002

3-Methoxy phthalimide 1 (120 kg) is added to a vessel containing dimethylformamide (420 L) and stirred (95 ± 10 RPM) at 25 – 30 °C for 30 min. The contents are cooled to 18 – 20 °C and triethylamine (124 L) is added. The contents are further cooled to -10 °C to -5 °C and

methylchloroformate 2 (85 kg) is added. The reaction temperature is maintained in the range of -10 °C to 0 °C to control the exothermicity during the addition of methylchloroformate. The temperature of the mixture is maintained at 0 – 5 °C for 1 h after the addition of

methylchloroformate .

The reaction mixture is then heated to 25 – 30 °C for 1 h. An in-process sample is taken to confirm a phthalimide content limit <2.5%. The mixture is sampled again to confirm a phthalimide content <0.5%. The mixture is transferred to another reactor, cooled to 0 – 5 °C, and the reaction is quenched with the addition of demineralized water (1260 ± 10 L) at a temperature of 10 ± 5 °C. The mixture is then heated at 25 – 30 °C for 1 h.

The material is centrifuged for 2 h and the wet cake is washed three times with

demineralized water (360 L). The wet cake is dried at a temperature of 55 – 60 °C and a sample is taken after 12 h of drying to confirm water content <1.0% w/w.

Expected yield of N-carbomethoxy phthalimide (3): 144-158 kg. This material is not isolated and is used directly in the next step.

Synthesis of 2-amino-3-(benzo-l ,3-dioxol-5-yl)-3-hydroxypropanoic acid

Figure imgf000016_0001

Piperonal 4 (229 ± 1 kg) is added to toluene (310 ± 5 L) in a reactor and the mixture is stirred (85 – 95 RPM) until a clear solution is obtained (approximately 30 min). The piperonal solution is transferred to a vessel for later use. Methanol (415 ± 5 L) is added to the reactor followed by the addition of potassium hydroxide (85 kg). The mixture is stirred for approximately 30 min at 25 – 30 °C to provide a clear solution. The potassium hydroxide solution is cooled to 20 – 25 °C, and then glycine 5 (52 ± 1 kg) and toluene (310 ± 5 L) are added while stirring at 20 – 25 °C. The contents of the reactor are cooled to 15 – 20 °C. The solution of piperonal in toluene is slowly added to the reactor while maintaining the temperature at 15 – 20 °C. The reactor temperature is increased to 20 – 25 °C and maintained for 18 h. An in-process sample is taken to determine glycine content by TLC (limit <5.0%).

The reaction mass is transferred to another reactor, the temperature is increased to 40 °C, and the solvents (toluene and methanol) are distilled off under vacuum until the mixture becomes thick. Additional toluene (210 ± 5L) is added to the reaction mass three times and distilled out for complete removal of methanol and toluene. The reaction mixture is kept under vacuum at 40 °C. After 3 h, the reaction mixture is cooled to 18 – 22 °C and a dilute hydrochloric acid solution (230 ± 5L hydrochloric acid and 1145 ± 10 L demineralized water) is added and mixed for 30 min.

The mixture is allowed to settle for 30 min to separate into organic and aqueous layers. The aqueous layer is washed with toluene (310 ± 5 L) and separated. Glacial acetic acid (218 ± 2 kg) is added to the washed aqueous layer at 20-25 °C. Caustic solution (580 ± 5 L DM Water and 200 ± 1 kg caustic flakes) is slowly added into the reaction mass to bring the pH 5.0 to 5.1 while maintaining the temperature at 25 – 30 °C. The pH of the mixture is brought to 5.45 – 5.50 at 25 – 30 °C, while stirring for 30 min. The mixture is centrifuged for 8 h 30 min to 9 h and the resulting wet cake is washed with demineralized water (50 ± 5 L). The cake is dried at 50 – 55 °C under vacuum, and a sample is taken after 12 h to confirm that water content is <10% w/w. The purity is analyzed by HPLC (limit < 10%).

Expected yield of 2-amino-3-(benzo-l ,3-dioxol-5-yl)-3-hydroxypropanoic acid (6):

135 – 145 kg.

Synthesis of 2-phthalimido-3-hydroxy-3-(3,4-methylenedioxyphenvnpropionic acid

Figure imgf000017_0001

Intermediate 6 (140 kg) is added to a reactor containing demineralized water (1 120 L) and stirred (85-95 RPM) for 10 min at 20-25 °C. The contents are cooled to 15-20 °C and compound 3 (140 kg) is added followed by a sodium carbonate solution (63.5-68.3 kg sodium carbonate in 189-203 L demineralized water) within 45-60 min. The mixture is heated to 30-35 °C and held for 90 min. An in-process sample is taken to measure for Stage II (<2.5%) and Stage-I intermediate (<2.5 %). After acceptance criteria are met, the mixture is cooled to 15-20 °C. A dilute sulfuric acid solution (134 kg sulfuric acid in 1120 L demineralized water) at 15-20 °C is added to the mixture to bring the pH to 1.0-2.0. The mixture is maintained at this temperature and pH for 30 min, and then the mixture is heated to 20-25 °C for 2 h.

The mixture is centrifuged for 9 h and the resulting wet cake is washed twice with 518 L of demineralized water. The wet cake is removed from the centrifuge, washed in a reactor containing demineralized water (2590 L), and stirred for 1 h at 25-30 °C. The material is centrifuged for 9 h and the wet cake is washed twice with demineralized water (518 L). The final wet cake is dried at 45-50 °C under vacuum until water content is <1.0% w/w. Intermediate (6) output is considered as standard input and a mean of 140 kg is taken for all inputs.

Expected yield of 2-Phthalimido-3-hydroxy-3-(3,4-methylenedioxyphenyl)propionic acid (7): 187 – 208 kg.

Synthesis of L-threo (N-phthaloyl-3-(3,4-methylenedioxyphenyl)serine) norephedrine salt

Figure imgf000018_0001

L-Norephedrine 8 (89 kg) is added to a reactor containing methanol (296 L) and stirring (45-50 RPM) is started. The mixture is maintained at 25 – 30 °C for 15 – 20 min, and then transferred into a vessel for later use.

2-Phthalimido-3-hydroxy-3-(3,4-methylenedioxyphenyl)propionic acid 7 (197.5 kg) is added to a reactor containing methanol (395 L). The material is stirred for 15 – 20 min at 25 – 30 °C. The L-norephedrine solution is added and mixed for 3 h. If precipitation is not observed within 30 min of adding the L-norephedrine solution, it is seeded with L-threo(N-phthaloyl-3-(3,4- methylenedioxyphenyl) serine (approximately 50 g). After 3 h of mixing, the mixture is cooled to 10 – 15 °C and maintained for 1 h. An in-process sample is taken to check for purity by HPLC (>99.0% a/a). The mixture is centrifuged for 1 h to 1 h 30 min and the wet cake is washed with methanol (49 L) followed by isopropyl alcohol (197.5 L). The wet cake is checked for purity. If purity is <99% a/a, the wet cake is washed with a prechilled solution of methanol (197.5 L) followed by isopropyl alcohol (99 L). After achieving the required purity level, as measured by HPLC, the wet cake is removed from the centrifuge. The cake is dried at 45 – 50 °C until loss on drying <1.0% w/w.

Expected yield of L-threo (N-phthalpyl-3-(3,4-methylenedioxyphenyl)serine) norephedrine (9) salt: 85-99 kg.

Synthesis of L-threo flSi-phthaloyl-S-CS^-methylenedioxyphenvDserine)

Figure imgf000019_0001

Demineralized water (552 L) is added to a reactor and cooled to 10 – 15 °C. Sulfuric acid (20 kg) is added while maintaining the temperature below 30 °C and stirring for 15 – 20 min. The solution is cooled to 15 – 20 °C and 9 (92 kg) is slowly added while stirring and maintaining temperature. The solution is heated to 45 – 50 °C for 6 h, cooled to 25 – 30 °C, and held for 1 h. The pH is checked to confirm the solution is <2.0.

The mixture is centrifuged for 1 h and the wet cake is washed two times with demineralized water (138 L). The wet cake is removed and added to a reactor containing demineralized water (460 L). The temperature is maintained at 25 – 30 °C and stirred for 1 h. The material is centrifuged for 30 min and the wet cake is washed two times with demineralized water (138 L). The material is collected and placed into preweighed containers.

Expected yield of L-threo(N-phthaloyl-3-(3,4-methylenedioxyphenyl)serine) (10): 60-64 kg.

Synthesis of L-threo(N-phthaloyl-3-(3 ,4-dihydroxyphenyl serine)

Figure imgf000019_0002

Compound 10 (62 kg) wet cake is added to a reactor containing methylene chloride (1240 L) and stirred for 10 min. The mixture is heated to remove methylene chloride and water under azeotropic reflux. After methylene chloride (1550 L) is removed and no water remains in the distillate, the mixture is cooled to 25 – 30 °C. An in-process sample is taken to determine water content (limit <0.1 %).

Methylene chloride (186 L) is added to another reactor at 25-30 °C. An in-process sample is taken to check for water content (limit <0.2% w/w). Aluminum chloride (81 kg) is added and the contents are stirred at 25 – 30 °C for 10 – 15 min. The mixture is cooled to 10 – 15 °C and octanethiol (78 kg) is added. The mixture is cooled to -20 to -10 °C.

The slurry of 10 in methylene chloride controlled at -20 to -7 °C is added to the stirred mixture that is temperature controlled at -15 to -10 °C for 20 – 30 min. The mixture is heated to 10-15 °C for 1.5-2.5 h. An in-process sample is taken to determine 10 content (limit <3.5%). The mixture is further cooled to -20 to -10 °C and then transferred to another reactor containing oxalic acid (62 kg), methylene chloride (186 L), and demineralized water (744 L) while maintaining the temperature below -3 °C to quench the reaction. The quenched material is slowly heated to 25 – 30 °C and maintained at this temperature for 12 h. Methylene chloride is distilled out at 25 – 30 °C under vacuum until the mixture volume is reduced to 1364 L.

The mixture is centrifuged for 3 h and the wet cake is washed with demineralized water (62 L). The wet cake is added to a reactor containing oxalic acid (2.5 kg) and demineralized water (248 L) and the contents are stirred at 25-30 °C for 2 h to obtain a clear solution. The material is centrifuged for 1 h 15 min to 1 h 30 min and the wet cake is washed twice with demineralized water (186 L). The wet cake is added to a reactor containing demineralized water (248 L) at 25 – 30 °C and the contents are stirred for 2 h. The material is centrifuged for 1 h 30 min to 2 h and the wet cake is washed twice with demineralized water (186 L). The material is collected and placed into preweighed containers.

Expected yield of L-threo(N-phthaloyl-3-(3,4-dihydroxyphenyl)serine (11): 40-50 kg. Synthesis of L-threo (3,4-dihydroxyphenvP)serine

Figure imgf000021_0001

Methanol (360 L) is added to a reactor and cooled to 20 – 25 °C. Compound 11 (45 kg) is added to the reactor while stirring at 25 – 30 °C for 15 – 20 min. Demineralized water (225 L) and sodium bicarbonate (17 kg) are added to another reactor and cooled to 20 – 25 °C. Hydroxylamine hydrochloride (14 kg) is added and mixed for 15 – 20 min at 20 – 25 °C to obtain a clear solution. The solution of 11 in methanol is transferred through a sparkler filter into a reactor. The hydroxylamine and sodium bicarbonate solution is added to the reactor while maintaining the temperature at 25 – 30 °C. The reaction mixture is heated to 65 – 70 °C and refluxed for 16 h. An in-process sample is taken to determine 11 content (limit <3%). The material is cooled to 25-30 °C with mixing for 2 h.

The material is centrifuged for 1 h and the wet cake is washed three times with methanol (23 L). The wet cake is dried at 40 – 45 °C until water content is <1.0% w/w.

Expected yield of L-threo(3,4-dihydroxyphenyl)serine (12): 20-24 kg. Synthesis of L-threo(3,4-dihvdroxyphenyl)serine hydrochloride

Figure imgf000021_0002

L-threo (3,4-dihydroxyphenyl)serine 12 (22 kg) material is added to a reactor containing demineralized water (55 L) and stirred for 15-30 min. The material is cooled to 20-25 °C and concentrated hydrochloric acid (13 L) is added to form L-threo(3,4-dihydroxyphenyl)serine hydrochloride) (13). The mixture is stirred for 30^15 min until a white thick suspension is observed. The mixture is stirred for an additional 2.0 h ± 15 min. Isopropyl alcohol (132 L) is slowly added and the mixture is stirred for 5 hr ± 15 min. The mixture is cooled to 15-20 °C and stirred for 30^5 min. The mixture is centrifuged for 30 min and the wet cake is washed twice with chilled isopropyl alcohol (22 L) at 15-20 °C. The material is unloaded from the centrifuge and a sample is taken to check the individual impurity by HPLC (limit <0.05%) and purity by HPLC (limit >99.0%).

Reprocessing: If the individual impurity by HPLC does not meet the limit <0.05%, compound 13 is reprocessed by adding the material to a reactor containing demineralized water (28 L) and stirring for 15 – 30 min. Concentrated hydrochloric acid (3 L) is added at 20-25 °C and mixing is continued for 15 – 30 min. Continue mixing for 2 h ± 15 min at the same temperature. Isopropyl alcohol (74 L) is added over a period of 2 – 3 h at 25 – 30 °C. Mixing is continued at 25 – 30 °C for 5 h ± 15 min followed by cooling to 15 – 20 °C and mixing for 30 – 45 min. The mixture is centrifuged for 30 min and washed twice with chilled isopropyl alcohol (22 L) and checked for the individual impurity by HPLC (limit <0.05%).

Expected yield of L-threo(3,4-dihydroxyphenyl)serine hydrochloride) (13): 19-20 kg. Synthesis of L-threo(3,4-dihvdroxyphenyl)serine

Figure imgf000022_0001

Compound 13 (19.5 kg) is added to a reactor containing demineralized water (195 L) while stirring at 25 – 30 °C. Concentrated hydrochloric acid (6 L) is added and mixed for 25 – 30 min. For complete dissolution, the contents can be mixed for another 15 – 20 min. Activated carbon (1 kg) and celite (0.2 kg) are added and mixed for 30 – 40 min. The mixture is filtered through a sparkler filter and the filter is washed with demineralized water (1 X L). The filtrate is transferred to another reactor. A solution containing triethylamine (14 kg) and methanol (41 L) is slowly added to the reaction mass (reactor) while mixing. The pH of the filtrate is adjusted to 7.0 – 7.25 over a period of 3 h at 25 – 30 °C. The contents are stirred for 20-30 min. An in-process sample is taken to confirm the pH is 7.0 – 7.25. The mixture is stirred for 3 h. The mixture is centrifuged for 1 h and the wet cake is washed twice with demineralized water (19.5 L). The wet cake is removed from the centrifuge and kept for a slurry wash. The wet cake is added to a reactor containing methanol (58.5 L) while stirring at 25 – 30 °C for 30 – 40 min. The material is centrifuged for 1 h and the wet cake is washed with methanol (19.5 L). The wet cake is unloaded from the centrifuge and retained for water washing.

The wet cake is added to a reactor containing demineralized water (39 L) while stirring for 30 – 40 min. The material is centrifuged for 10 min and the wet cake is washed twice with methanol (19.5 L). The wet cake is unloaded and a sample is taken to check the chloride content (<200 ppm). The wet cake is dried at 40 – 45 °C until the water content is <0.1 % w/w. A sample is taken after 16 h of drying to confirm loss on drying is <0.1% w/w. The dry material is sieved through a sifter (400 micron) and packed. A sample is taken for quality control testing.

Expected yield of L-threo(3,4-dihydroxyphenyl)serine: 14-15 kg.

Scheme 1: Overview of Droxidopa Synthesis

a) converting piperonal to 2-amino-3-(benzo-l,3-diox-5-yl)-3-hydroxypropanoic acid

Figure imgf000009_0001

d) removal of the catechol protecting group

Figure imgf000009_0002
Figure imgf000010_0001

PATENT

https://www.google.com/patents/CN103086906A?cl=en

droxidopa, the English name Droxidopa, chemical name (_) _ (2S, 3R) _2_ amino _3_ hydroxy-3- (3,4-hydroxyphenyl) propionic acid, the formula is as follows:

Figure CN103086906AD00031

· It is a synthetic (-) _ norepinephrine precursor amino acids by intestinal absorption and metabolism of norepinephrine, in patients with Parkinson’s disease is mainly used to improve gait stiffness and postural dizziness, and for Treatment of orthostatic hypotension drugs.

 JP 09-031038 discloses droxidopa preparation, preparation process is as follows:

Figure CN103086906AD00032

That structural formula I obtained in the presence of a copper catalyst structure formulas II, and then the open-loop, elimination of R and X groups of structure III of droxidopa.

JP05 – 239025 also provides a droxidopa preparation, the preparation process is as follows.

Figure CN103086906AD00033

JP 59-055861 discloses a method of droxidopa preparation of optically active substances: Xi Qu racemic 多巴加 heat in water to form a saturated solution, the first addition to control the amount of optical after cooling Activity droxidopa as a seed, heat after the second cooling crystallize. JP 64-022849 discloses a method for purifying droxidopa: A mixture of alcohol solvents crude droxidopa was dissolved in water and inorganic acid, and then with an organic or inorganic base to neutralize, to precipitate crystals obtained purification. JP 59-055861 claims to obtain optically active by the method droxidopa, and JP64-022849 purification process is not considered to be heated, to avoid caused by heating droxidopa degradation.

Example 1

Preparation L- threo-3- (3,4-dihydroxyphenyl) serine 1: 300kg methanol successively and LN- carbonyl benzyloxy-3- (3,4-benzyloxyphenyl) serine Add 30kg 500L hydrogenation reactor, added dropwise 3mol / L hydrochloric acid to dissolve the solid, was added 5% palladium carbon 8kg, introducing hydrogen pressure was maintained at 0.02Mpa, the reaction temperature is controlled at 40 ± 5 ° C, 6 hours After discharge, the addition of concentrated hydrochloric acid 7kg and 0.3kg activated carbon and stirred for 20 minutes, filtration, the filtrate with 30% NaOH aqueous solution adjusted to pH 6-7, filtered crystallization two hours, that was (reaction formula below).

Figure CN103086906AD00061

L- Su _3_ (3,4-light-phenyl) Preparation of silk atmosphere acid 2:

Dad was added to the reaction in ethanol 100kg, was added under stirring L- threo-3- (3,4-light-phenyl) -3-light-2 phthalamide imino acid, stirred at room temperature until The solid was dissolved clear, liquid solution of hydrazine hydrate at 40-45 ° C, after completion of the addition of hydrazine hydrate, the reaction was refluxed for 16 hours, cooled to below 30 ° C, concentrated hydrochloric acid was added dropwise 30kg, maintaining 30 ° C under stirring for I hour, Rejection filter cake washed once with aqueous hydrochloric acid, and the filtrate with 30% NaOH solution pH was adjusted to 6_7, filtered crystallization two hours, that was (reaction formula below).

Figure CN103086906AD00062

CLIP

The condensation of 3,4-dimethoxybenzaldehyde (I ) with glycine (II) by means of KOH in hot methanol gives racemic threo-3- (3,4-dimethoxyphenyl) serine (III), which is acylated with N – (ethoxycarbonyl) phthalimide (IV) by means of Na2CO3 in water yielding the corresponding N-phthaloyl derivative (V) The reaction of (V) with AlCl3 and ethyl mercaptan in dichloromethane affords N-phthaloyl-3- (3,4-. dihydroxyphenyl) serine (VI), which is deprotected with hydrazine in refluxing ethanol to racemic threo-3- (3,4-dihydroxyphenyl) serine (VII). The resolution of the racemic form (VII) is performed through its benzyloxy derivative.

References

  1.  Goldstein, DS (2006). “L-Dihydroxyphenylserine (L-DOPS): a norepinephrine prodrug”. Cardiovasc Drug Rev. 24 (3-4): 189–203. doi:10.1111/j.1527-3466.2006.00189.x. PMID 17214596.
  2. Mathias, Christopher J (2008). “L-dihydroxyphenylserine (Droxidopa) in the treatment of orthostatic hypotension”. Clin Auton Res. 18 (Supplement 1): 25–29.doi:10.1007/s10286-007-1005-z.
  3.  “FDA grants accelerated approval to NORTHERA (droxidopa) for patients with symptomatic NOH”. news-medical.net. February 18, 2014.
  4.  http://investor.lundbeck.com/releasedetail.cfm?ReleaseID=846443http://lundbeck.com/upload/us/files/pdf/2014_Releases/NORTHERA%20Availability%20press%20release%209.2.14.pdf
  5.  Robertson, David (2008). “The pathophysiology and diagnosis of orthostatic hypotension”. Clin Auton Res. 18 (Supplement 1): 2–7. doi:10.1007/s10286-007-1004-0.
  6.  Kaufmann, Horacio; Freeman, Roy; Biaggioni, Italo; Low, Phillip; Pedder, Simon; Hewitt, L. Arthur; Mauney, Joe; Feirtag, Michael; Mathias, Christopher J. (2014). “Droxidopa for neurogenic orthostatic hypotension: a randomized placebo-controlled Phase 3 trial”.Neurology. 83 (4): 328–335. doi:10.1212/WNL.0000000000000615. PMC 4115605free to read.PMID 24944260.
  7.  Hauser, Robert A.; Isaacson, Stuart; Lisk, Jerome P.; Hewitt, L. Arthur; Rowse, Gerry (2015). “Droxidopa for the Short-Term Treatment of Symptomatic Neurogenic Orthostatic Hypotension in Parkinson’s Disease (nOH306B)”. Movement Disorders. 30 (5): 646–654.doi:10.1002/mds.26086.
  8.  http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/203202lbl.pdf
  9. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/203202Orig1s000ChemR.pdf
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Referenz
1 * Protection for the amino group” In: PETER G M WUTS; THEODORA W GREENE: “GREENE’S PROTECTIVE GROUPS IN ORGANIC SYNTHESIS,“, 2007, WILEY-Interscience,, HOBOKEN, NJ, USA, XP002685963, ISBN: 978-0-471-69754-1 page 696-700, 790-793, 799-802, the whole document
2 * A. ARIFFIN ET AL.: “Suggested Improved Method for the Ing-Manske and Related Reactions for the Second Step of Gabriel Synthesis of Primary Amines“, SYNTHETIC COMMUNICATIONS: AN INTERNATIONAL JOURNAL FOR RAPID COMMUNICATION OF SYNTHETIC ORGANIC CHEMISTRY, vol. 34, no. 24, 2004, pages 4439-4445, XP002695538, Taylor & Francis Inc. ISSN: 0039-7911
3 T. W. GREEN; P. G. M. WUTS: ‘Protective Groups in Organic Synthesis‘, vol. 583-584, 1999, WILEY-INTERSCIENCE pages 744 – 747

FDA NEWS RELEASE

For Immediate Release: Feb. 18, 2014
FDA approves Northera to treat neurogenic orthostatic hypotension

The U.S. Food and Drug Administration today approved Northera capsules (droxidopa) for the treatment of neurogenic orthostatic hypotension (NOH). NOH is a rare, chronic and often debilitating drop in blood pressure upon standing that is associated with Parkinson’s disease, multiple-system atrophy, and pure autonomic failure.

Symptoms of NOH include dizziness, lightheadedness, blurred vision, fatigue and fainting when a person stands.

“People with neurogenic orthostatic hypotension are often severely limited in their ability to perform routine daily activities that require walking or standing,” said Norman Stockbridge, M.D., Ph.D, director of the Division of Cardiovascular and Renal Drugs in the FDA’s Center for Drug Evaluation and Research. “There are limited treatment options for people with NOH and we are committed to helping make safe and effective treatments available.”

The FDA is approving Northera under the accelerated approval program, which allows for approval of a drug to treat a serious disease based on clinical data showing that the drug has an effect on an intermediate clinical measure (in this case, short-term relief of dizziness) that is reasonably likely to predict the outcome of ultimate interest (relief of dizziness during chronic treatment). This program provides patient access to promising drugs while the company conducts post-approval clinical trials to verify the drug’s clinical benefit, which for this approval is a long-term effect on patient symptoms in NOH, a chronic disease.

Northera has a boxed warning to alert health care professionals and patients about the risk of increased blood pressure while lying down (supine hypertension), a common problem that affects people with primary autonomic failure and can cause stroke. It is essential that patients be reminded that they must sleep with their head and upper body elevated. Supine blood pressure should be monitored prior to and during treatment and more frequently when increasing doses.

The most common adverse events reported by clinical trial participants taking Northera were headache, dizziness, nausea, high blood pressure (hypertension) and fatigue.

The effectiveness of Northera was shown through two-weeks in two clinical trials in people with NOH. People taking Northera reported a decrease in dizziness, lightheadedness, feeling faint, or feeling as if they might black out compared to those taking an inactive pill (placebo). Durability of the improvement in patient symptoms beyond two weeks has not been demonstrated.

Northera received orphan-product designation from the FDA because it is intended to treat a rare disease or condition.

Northera is made by Charlotte-based Chelsea Therapeutics Inc.

For more information:
FDA: Approved Drugs
FDA: Drug Innovation
National Institute of Neurological Disorders and Stroke: Orthostatic Hypotension

Droxidopa
L-DOPS.svg
Systematic (IUPAC) name
(2S,3R)-2-Amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid
Clinical data
Trade names Northera
Routes of
administration
Oral
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 90%
Metabolism Hepatic
Biological half-life 1.5 hours
Excretion Renal
Identifiers
CAS Number 23651-95-8 Yes
ATC code C01CA27 (WHO)
PubChem CID 6989215
ChemSpider 83927
UNII J7A92W69L7 Yes
ChEBI CHEBI:31524
ChEMBL CHEMBL2103827
Synonyms β,3-Dihydroxytyrosine
Chemical data
Formula C9H11NO5
Molar mass 213.18734 g/mol
Title: Droxidopa
CAS Registry Number: 23651-95-8
CAS Name: threo-b,3-Dihydroxy-L-tyrosine
Additional Names: L-threo-3-(3,4-dihydroxyphenyl)serine; (-)-(2S,3R)-2-amino-3-hydroxy-3-(3,4-dihydroxyphenyl)propionic acid;threo-dopaserine; L-threo-DOPS; L-DOPS
Manufacturers’ Codes: SM-5688
Trademarks: Dops (Sumitomo)
Molecular Formula: C9H11NO5
Molecular Weight: 213.19
Percent Composition: C 50.70%, H 5.20%, N 6.57%, O 37.52%
Literature References:
Synthetic amino acid precursor of norepinephrine, q.v. Prepn of racemate: K. W. Rosenmund, H. Dornsaft,Ber. 52B, 1734 (1919). Separation and resolution of diastereomers: B. Hegedüs et al., Helv. Chim. Acta 58, 147 (1975); B. Hegedüs, A. Krasso, US 3920728 (1975 to Hoffmann-La Roche). Improved process for production: N. Ohashi et al., US 4319040(1982 to Sumitomo). Pharmacology of stereoisomers: G. Bartholini et al., J. Pharmacol. Exp. Ther. 193, 523 (1975).
Clinical pharmacology of L-threo-form and clinical evaluation in familial amyloid polyneuropathy (FAP): T. Suzuki et al., Eur. J. Clin. Pharmacol. 17, 429 (1980).
Reversed-phase chromatography determn in plasma and urine: F. Boomsma et al., J. Chromatogr.427, 219 (1988). Pharmacokinetics in FAP: T. Suzuki et al., Eur. J. Clin. Pharmacol. 23, 463 (1982); in parkinsonism: T. Suzuki et al., Neurology 34, 1446 (1984).
Metabolism to norepinephrine: T. Suzuki et al., Life Sci. 36, 435 (1985).
Clinical studies in Parkinson’s disease: N. Ogawa et al., J. Med. 16, 525 (1985); H. Narabayashi et al., Adv. Neurol. 45, 593 (1986).
Properties: Crystals from ethanol and ether, mp 232-235° (dec).
[a]D20 -39° (c = 1 in 1N aq HCl).
Also cited as crystals from water and L-ascorbic acid, mp 229-232° (dec) (Ohashi). [a]D20 -42.0° (c = 1 in 1N aq HCl).
Melting point: mp 232-235° (dec); mp 229-232° (dec) (Ohashi)
Optical Rotation: [a]D20 -39° (c = 1 in 1N aq HCl); [a]D20 -42.0° (c = 1 in 1N aq HCl)
Therap-Cat: Antiparkinsonian.
RX LIST

NORTHERA capsules contain droxidopa, which is a synthetic amino acidprecursor of norepinephrine, for oral administration. Chemically, droxidopa is (–)-threo-3-(3,4- Dihydroxyphenyl)-L-serine. It has the following structural formula:

NORTHERA™ (droxidopa) Structural Formula Illustration

Droxidopa is an odorless, tasteless, white to off-white crystals or crystalline powder. It is slightly soluble in water, and practically insoluble in methanol, glacial acetic acid, ethanol, acetone, ether, and chloroform. It is soluble in dilute hydrochloric acid. It has a molecular weight of 213.19 and a molecular formula of C9H11NO5.

NORTHERA capsules also contain the following inactive ingredients: mannitol, corn starch, and magnesium stearate. The capsule shell is printed with black ink. The black inks contain shellac glaze, ethanol, iron oxide black, isopropyl alcohol, n-butyl alcohol, propylene glycol, and ammonium hydroxide. The capsule shell contains the following inactive ingredients: 100 mg – gelatin, titanium dioxide, FD&C Blue No. 2, black and red iron oxide; 200 mg – gelatin, titanium dioxide, FD&C Blue No. 2, black and yellow iron oxide; 300 mg – gelatin, titanium dioxide, FD&C Blue No. 1, FD&C Yellow No. 5 (tartrazine), and FD&C Red No. 40. NORTHERA capsules differ in size and color by strength

CLIP

//////////DROXIDOPA, Chelsea Therapeutics,  orphan drug status, FDA 2015, 3916-18-5,  NORTHERA, SUMITOMO, Antiparkinsonian

THESIS

http://ncl.csircentral.net/668/1/th1739.pdf

Review of Literature Literature search showed that there are only few reports available,42-44 which describe the synthesis of L-threo-DOPS (43) as detailed below. Kirk’s approach (2001)43 Kirk et. al have reported the synthesis of fluorinated analogue of L-threo-DOPS (49) starting from reaction of aldehyde 44 with isothiocyanate 45 in presence of LHMDS and Sn(OTf)2 to give ester 46 with d.r = 8.5:1. Subsequently, removal of chiral auxiliary with methoxymagnesium bromide followed by Boc protection of the thiocarbamate nitrogen was carried out. Thiocarbamate 46 was then converted to oxygen analogue 47 in 96% yield by treating it with Hg(OAc)2. This was followed by subsequent cleavage of 47 using Cs2CO3 and its Boc depotection gave the ester 48. Saponification of ester 48 followed by hydrogenation afforded fluoro analogue of L-threo-DOPS (49) (Scheme 13).

Sang-Ho’s approach (2007)44 Sang-Ho et. al have achieved an enzyme-catalyzed synthesis of L-threo-DOPS (43) by reacting in one-pot glycine, 3,4-dihydrobenzaldehyde, 2-mercaptoethanol, pyridoxal-5- phosphate solution, sodium sulfite and Triton X-100 in presence of E.coli at 15 °C

Yield: 94%; mp: 230-233 ºC; (lit.42 mp: 232-235 ºC); [α] 25 D: -38.7 (c 0.4, 1N aq. HCl); {lit.42 [α] 25 D: -39 (c 1, 1N HCl)}; IR (CHCl3, cm-1 ): 3018, 2399, 2366, 2345, 1652, 1519, 1215, 1018, 929, 756, 669; 1H NMR (200 MHz, DMSO-d6): δ 4.23 (d, J = 4.3 Hz, 1H), Droxidopa Chapter IV 226 5.10 (d, J = 3.8 Hz, 1H), 7.27-7.31 (m, 3H), 7.78 (br s, 1H), 8.40 (br s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 55.41, 70.70, 115.21, 116.51, 120.06, 130.09, 144.96, 146.06, 171.91; Analysis: C9H11NO5 requires C, 50.70; H, 5.20; N, 6.57%; found: C, 50.99; H, 5.01; N, 6.33%

42 Hegedus, V. B.; Krasso, A. F.; Noack, K.; Zeller, P. Helv. Chim. Acta 1975, 58, 147.

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by S George – ‎2009 – ‎Related articles

I here by declare that the thesis entitled “Enantioselective synthesis of bioactive molecules …. Section III Enantioselective synthesis of L-threo-DOPS (droxidopa).

History of drug approval -how misfortunes and tragedies has created the approval process


Sunovion Announces FDA Acceptance for Review of New Drug Application Resubmission for Stedesa (eslicarbazepine acetate)


eslicarbazepine

(S)-10-Acetoxy- 10,11-dihydro- 5H-dibenz[b,f]azepine- 5-carboxamide

 

Sunovion Announces FDA Acceptance for Review of New Drug Application Resubmission for Stedesa (eslicarbazepine acetate) as a Once-Daily Adjunctive Therapy for Partial-onset Seizures in Adults with Epilepsy

MARLBOROUGH, Feb 27, 2013

Sunovion Pharmaceuticals Inc. (Sunovion) today announced that the U.S. Food and Drug Administration (FDA) has accepted for review the Company’s New Drug Application (NDA) resubmission for Stedesa® (eslicarbazepine acetate) for use as a once-daily adjunctive therapy in the treatment of partial-onset seizures in patients 18 years and older with epilepsy. Stedesa is the proposed trade name for eslicarbazepine acetate.

“We are pleased to achieve this regulatory milestone for Stedesa, which, if approved, may offer adult patients living with epilepsy an effective, once-daily, adjunctive treatment option for managing partial-onset seizures,” said Fred Grossman, D.O., FAPA, Senior Vice President, Clinical Development and Medical Affairs at Sunovion. “Adequate seizure control of this most common form of epilepsy remains an unmet medical need for a significant number of patients and Sunovion is committed to providing a treatment option to help address this need.”

The NDA for Stedesa is supported by data from three Phase III randomized, double-blind, placebo-controlled 12-week maintenance trials of similar study design, which included more than 1,300 patients with partial-onset seizures in 35 countries, including the United States. Treatment with Stedesa demonstrated statistically significant reductions in standardized seizure frequency when used as adjunctive therapy. The most commonly reported adverse events in the clinical trials were dizziness, somnolence, headache, nausea, diplopia, vomiting, fatigue, ataxia, vision blurred, and vertigo.

The original NDA was submitted to the FDA in March 2009. This resubmission was prepared by Sunovion following receipt of the FDA’s April 2010 Complete Response Letter and subsequent correspondence requesting additional information. Eslicarbazepine acetate is currently marketed in Europe by BIAL-Portela & Cª, S.A and by BIAL´s licensee, Eisai Europe Limited, a UK subsidiary of Eisai Co., Ltd. under the trade name Zebinix®. Zebinix® was approved by the European Commission on April 21, 2009 as adjunctive therapy in adult patients with partial-onset seizures with or without secondary generalization.

Sunovion and BIAL are also conducting clinical trials to evaluate eslicarbazepine acetate as monotherapy in the treatment of partial-onset seizures in adult patients with epilepsy.

Epilepsy is one of the most common neurological disorders and, according to the Centers for Disease Control and Prevention, affects nearly 2.2 million people in the United States.1 It is characterized by abnormal firing of impulses from nerve cells in the brain.2 In partial-onset seizures, these bursts of electrical activity are initially focused in specific areas of the brain, but may become more widespread, with symptoms varying according to the affected areas.3,4

Stedesa (eslicarbazepine acetate) is an investigational voltage-gated sodium and T-type calcium channel blocker that has been evaluated in three Phase III clinical trials involving more than 1,300 patients with partial-onset epilepsy worldwide. BIAL-Portela & Cª, S.A., a privately held Portuguese research based pharmaceutical company, was responsible for the initial research and development of eslicarbazepine acetate. In late 2007, Sunovion Pharmaceuticals Inc., formerly known as Sepracor Inc., acquired the rights to further develop and commercialize eslicarbazepine acetate in the U.S. and Canadian markets from BIAL.

Sunovion is a leading pharmaceutical company dedicated to discovering, developing and commercializing therapeutic products that advance the science of medicine in the Psychiatry & Neurology and Respiratory disease areas and improve the lives of patients and their families. Sunovion’s drug development program, together with its corporate development and licensing efforts, has yielded a portfolio of pharmaceutical products including LATUDA® (lurasidone HCl) tablets, LUNESTA® (eszopiclone) tablets, XOPENEX® (levalbuterol HCI) inhalation solution, XOPENEX HFA® (levalbuterol tartrate) inhalation aerosol, BROVANA® (arformoterol tartrate) inhalation solution, OMNARIS® (ciclesonide) nasal spray, ZETONNA® (ciclesonide) nasal aerosol and ALVESCO® (ciclesonide) inhalation aerosol.

Sunovion, an indirect, wholly-owned subsidiary of Dainippon Sumitomo Pharma Co., Ltd., is headquartered in Marlborough, Mass. More information about Sunovion Pharmaceuticals Inc. is available at www.sunovion.com.

DSP is a multi-billion dollar, top-ten listed pharmaceutical company in Japan with a diverse portfolio of pharmaceutical, animal health and food and specialty products. DSP aims to produce innovative pharmaceutical products in the Psychiatry & Neurology field, which has been designated as one of the two key therapeutic areas. DSP is based on the merger in 2005 between Dainippon Pharmaceutical Co., Ltd., and Sumitomo Pharmaceuticals Co., Ltd. Today, DSP has more than 7,000 employees worldwide. Additional information about DSP is available through its corporate website at www.ds-pharma.com.

STEDESA is a registered trademark of Bial – Portela & Cª, S.A., used under license.

Sunovion Pharmaceuticals Inc. is a U.S. subsidiary of Dainippon Sumitomo Pharma Co., Ltd. © 2013 Sunovion Pharmaceuticals Inc.

For a copy of this release, visit Sunovion’s web site at www.sunovion.com

Eslicarbazepine acetate (BIA 2-093) is an antiepileptic drug. It is a prodrug which is activated to eslicarbazepine (S-licarbazepine), an active metabolite of oxcarbazepine.[1]

It is being developed by Bial[2] and will be marketed as Zebinix or Exalief by Eisai Co. in Europe and as Stedesa by Sepracor[3] in America.

The European Medicines Agency (EMA) has recommended granting marketing authorization in 2009 for adjunctive therapy for partial-onset seizures, with or without secondary generalisation, in adults with epilepsy.[1] The U.S. Food and Drug Administration (FDA) announced on 2 June 2009 that the drug has been accepted for filing.[3]

Eslicarbazepine acetate is a prodrug for S(+)-licarbazepine, the major active metabolite of oxcarbazepine.[4] Its mechanism of action is therefore identical to that of oxcarbazepine. [5] There may, however, be pharmacokinetic differences. Eslicarbazepine acetate may not produce as high peak levels of (S)-(+)-licarbazepine immediately after dosing as does oxcarbazepine which could theoretically improve tolerability.

Like oxcarbazepine, eslicarbazepine may be used to treat bipolar disorder and trigeminal neuralgia.

Patents

The first European patent to protect this drug is EP 0751129. The priority of this European patent is the Portuguese patent application PT 101732.

References

  1.  Dulsat, C., Mealy, N., Castaner, R., Bolos, J. (2009). “Eslicarbazepine acetate”. Drugs of the Future 34 (3): 189. doi:10.1358/dof.2009.034.03.1352675.
  2. Community register of medicinal products for human use: Exalief
  3.  Medical News Today: Sepracor’s STEDESA (Eslicarbazepine Acetate) New Drug Application Formally Accepted For Review By The FDA
  4.  Rogawski, MA (Jun 2006). “Diverse Mechanisms of Antiepileptic Drugs in the Development Pipeline”. Epilepsy Res 69 (3): 273–294. doi:10.1016/j.eplepsyres.2006.02.004. PMC 1562526. PMID 16621450.
  5. Rogawski MA, Löscher W (July 2004). “The neurobiology of antiepileptic drugs”. Nature Reviews Neuroscience 5 (7): 553–64. doi:10.1038/nrn1430. PMID 15208697.
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