New Drug Approvals

Home » FDA 2016 (Page 2)

Category Archives: FDA 2016

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

Blog Stats

  • 3,984,314 hits

Flag and hits

Flag Counter

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

Join 2,728 other followers
Follow New Drug Approvals on WordPress.com

Archives

Categories

Recent Posts

Flag Counter

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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

Join 2,728 other followers
DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, 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 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

Personal Links

Verified Services

View Full Profile →

Archives

Categories

Flag Counter

Pimavanserin


ChemSpider 2D Image | Pimavanserin | C25H34FN3O2

Pimavanserin

  • MF C25H34FN3O2
  • MW 427.555

Pimavanserin, ACP 103, ACP-103; BVF-048

N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N’-(4-(2-methylpropyloxy)phenylmethyl)carbamide,

706779-91-1 (Pimavanserin )
706782-28-7 (Pimavanserin Tartrate)

For treatment of psychotic symptoms in patients with Parkinson’s disease

WATCH OUT AS THIS POST IS UPDATED………..

Trade Name:Nuplazid®

MOA:5-HT2A inverse agonist

Indication:Hallucinations and delusions associated with Parkinson’s disease psychosis

Company:Acadia (Originator)

Mikkel Thygesen, Nathalie Schlienger, Bo-Ragnar Tolf, Fritz Blatter, Jorg Berghausen
Applicant Acadia Pharmaceuticals Inc.

APPROVED US FDA 2016-04-29, ACADIA PHARMS INC, (NDA) 207318

To treat hallucinations and delusions associated with psychosis experienced by some people with Parkinson’s disease

Image result for pimavanserin tartrate


706782-28-7 (tartrate)
Molecular Weight 1005.2
Formula (C25H34FN3O2)2 ● C4H6O6

Urea, N-[(4-fluorophenyl)methyl]-N-(1-methyl-4-piperidinyl)-N’-[[4-(2-methylpropoxy)phenyl]methyl]-, (2R,3R)-2,3-dihydroxybutanedioate (2:1)

Image result for pimavanserin tartrate

Pimavanserin Tartrate was approved by the U.S. Food and Drug Administration (FDA) on Apr 29, 2016. It was developed by Acadia, then marketed as Nuplazid® by Acadia in US.

Pimavanserin Tartrate is a 5-HT2A receptor inverse agonists, used to treat hallucinations and delusions associated with psychosis experienced by some people with Parkinson’s disease.

Nuplazid® is available as tablet for oral use, containing 17 mg of pimavanserin. Recommended dose is 34 mg, taken orally as two tablets once daily.

Pimavanserin (INN), or pimavanserin tartate (USAN), marketed under the trade name Nuplazid, is a non-dopaminergic atypical antipsychotic[2] developed by Acadia Pharmaceuticals for the treatment of Parkinson’s disease psychosis and schizophrenia. Pimavanserin has a unique mechanism of action relative to other antipsychotics, behaving as a selective inverse agonist of theserotonin 5-HT2A receptor, with 40-fold selectivity for this site over the 5-HT2C receptor and no significant affinity or activity at the5-HT2B receptor or dopamine receptors.[1] The drug has met expectations for a Phase III clinical trial for the treatment ofParkinson’s disease psychosis,[3] and has completed Phase II trials for adjunctive treatment of schizophrenia alongside anantipsychotic medication.[4]

Pimavanserin is expected to improve the effectiveness and side effect profile of antipsychotics.[5][6][7] The results of a clinical trial examining the efficacy, tolerability and safety of adjunctive pimavanserin to risperidone and haloperidol were published in November 2012, and the results showed that pimavanserin potentiated the antipsychotic effects of subtherapeutic doses ofrisperidone and improved the tolerability of haloperidol treatment by reducing the incidence of extrapyramidal symptoms.[8]

On September 2, 2014, the United States Food and Drug Administration granted Breakthrough Therapy status to Acadia’s New Drug Application for pimavanserin.[9] It was approved by the FDA to treat hallucinations and delusions associated with psychosis experienced by some people with Parkinson’s disease on April 29, 2016.[10]

Image result for pimavanserin tartrate

Clinical pharmacology

Pimavanserin acts as an inverse agonist and antagonist at serotonin 5-HT2A receptors with high binding affinity (Ki 0.087 nM) and at serotonin 5-HT2C receptors with lower binding affinity (Ki 0.44 nM). Pimavanserin shows low binding to σ1 receptors (Ki 120 nM) and has no appreciable affinity (Ki >300 nM) to serotonin 5-HT2B, dopaminergic (including D2), muscarinic, histaminergic, oradrenergic receptors, or to calcium channels.[2]

Image result for Pimavanserin

Pimavanserin tartrate, 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)urea L-hemi-tartrate, has the following chemical structure:

Pimavanserin tartrate was developed by Acadia Pharmaceuticals and was approved under the trade name NUPLAZID® for use in patients with Parkinson’s disease psychosis.

Pimavanserin free base and its synthesis are disclosed in US 7,601,740 (referred to herein as US ‘740 or the ‘740 patent) and US 7,790,899 (referred to herein as US ‘899 or the ‘899 patent). US ‘740 discloses the synthesis of Pimavanserin free base (also referred to herein as“Compound A”), which includes O-alkylation followed by ester hydrolysis, and then in situ azidation. This process suffers from low process safety, and utilizes the hazardous reagent diphenylphosphoryl azide. The process is illustrated by the following Scheme 1.

Scheme 1:

US ‘899 describes another process, which includes O-alkylation followed by aldehyde reductive amination to obtain an intermediate which is then reacted with the hazardous reagent phosgene. This process is illustrated by the following Scheme 2:

Scheme 2:

Both of the above processes for the preparation of Pimavanserin include a reaction between 1-isobutoxy-4-(isocyanatomethyl)benzene, a benzyl isocyanate intermediate, and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine. Processes for preparing benzyl isocyanate derivatives are generally described in the literature, such as in US ‘740; US ‘899; Bioorganic & Medicinal Chemistry, 21(11), 2960-2967, 2013; JP 2013087107; Synthesis (12), 1955-1958, 2005; and Turkish Journal of Chemistry, 31(1), 35-43, 2007. These processes often use the hazardous reagents like phosgene derivatives or diphenylphosphoryl azide.

Image result for Pimavanserin

synthetic route:

First, reduction of the ketone and a secondary amine to amine condensation after S-3 . 4- hydroxybenzaldehyde etherification, followed by condensation with hydroxylamine to give the oxime S-. 7 , which is then reduced by hydrogenation to the amine S-. 8 , S.8- light gas reaction to give the isocyanate S-. 9 , S. 9- react with the primary amine can be obtained Nuplazid ( pimavanserin ).Kg product can be obtained by this route.

WO2006036874

https://www.google.com/patents/WO2006036874A1?cl=en

Example 1 : Preparation of N-(4-fluorobenzyl)-N-( 1 -methylpiperidin-4-yl)-N’ -( 4-(2- methylpropyloxy)phenylmethyl)carbamide a) Preparation of

Figure imgf000021_0001

Tπacetoxy borohydπde (6.5 kg) was added over 1.5 h to a solution of N- methylpiperid-4-one (3.17 kg) and 4-fluorobenzylamme (3.50 kg) in methanol (30 1), maintaining the temperature under 27 0C. The reaction mixture was stirred for 15 h at 22 0C. The residual amine was checked by gel chromatography (4-fluorobenzylamine: < 5%). A solution of 30% sodium hydroxide (12.1 kg) in water (13.6 kg) was added in 75 minutes (min) maintaining the temperature under 20 0C. Methanol was distilled off to a residual volume of 26 litters. Ethyl acetate was added (26 L), the solution was stirred for 15 min, the phases were decanted over 15 min and the lower aqueous phase was discarded. Ethyl acetate was distilled under reduced pressure from the organic phase at 73-127 0C. At this stage the residue was mixed with a second crude batch prepared according to this method. The combined products were then distilled at 139-140 0C / 20 mbar to yield 11.2 kg product (> 82%). b) Preparation of

Figure imgf000022_0001

4-Hydroxybenzaldehyde (4.0 kg) and ethanol (20 1) were added to a solution of isobutyl bromide (9.0 kg) in ethanol (15 1). Potassium carbonate (13.6 kg) was added and the suspension was refluxed (74-78 0C) for 5 days. The residual 4- hydroxybenzaldehyde was checked by HPLC (< 10%). The suspension was cooled to 20 0C and used in the next step.

c) Preparation of

Figure imgf000022_0002

] Hydroxylamine (50% in water, 8.7 kg) was added to the product from previous step b)(174 1, 176 kg) and ethanol (54 1). The suspension was refluxed (77 0C) for 3 h. Unreacted residual amounts of the compound of step b was checked by HPLC (< 5%). The suspension was cooled to 30 0C, filtered and the filter was washed with ethanol (54 1). The solution was concentrated by distillation under reduced pressure at 30 0C to a residual volume of 67 litters. The solution was cooled to 25 0C and water (110 1) was added. The suspension was concentrated by distillation under reduced pressure at 30 0C to a residual volume of 102 litters. Petrol ether (60-90 fraction, 96 1) was added and the mixture was heated to reflux (70 0C). The solution Λvas cooled to 40 0C and crystallization was initiated by seeding. The suspension was cooled to 5 0C and stirred for 4h. The product was centrifuged and the cake was washed with petrol ether (60-90 fraction, 32 1). The wet cake was dried at about 40 0C to yield 16kg product (63%).

d) Preparation of

Figure imgf000022_0003

[0105] The product from previous step c) (15.7 kg) was dissolved in ethanol (123 1). Acetic acid (8.2 kg) and palladium on charcoal 5% wet (1.1 kg) were added. The oxime was hydxogenated at 22 0C and 1.5 bar for 4h. Consumption of oxime was checked by HPLC (for information). The catalyst was filtered and the solvent was distilled under reduced pressure at 36 0C to a final volume of 31 1. Ethyl acetate (63 1) was added and the mixture was heated to reflux (75 0C) until dissolution. The solution was cooled to 45 0C and the crystallization was initiated by seeding. The suspension was cooled to 6-10 0C and stirred for 2.5h. The product was centrifuged and the cake was washed with 2 portions of ethyl acetate (2 x 0.8 1). The wet cake was dried at a temperature of about 40 0C to yield 8 kg (41%).

e) Preparation of

Figure imgf000023_0001

Aqueous sodium hydroxide (30%, 5.0 kg) was added to a suspension of the product from previous step d) (7.9 kg) in heptane (41 1). The solution was heated to 47 0C, stirred for 15 mm and decanted o~ver 15 mm. The pH was checked (pH>12) and the aqueous phase was separated. The solvent was removed by distillation under reduced pressure at 47-650C. Heptane was added (15 1) and it was removed by distillation under reduced pressure at 58-65 0C. Heptane was added (7 1), the solution was filtered and the filter was washed with heptane (7 1). The solvent was removed by distillation under reduced pressure at 28-60 0C. Tetrahydrofuran (THF, 107 1) and tπethylamme (TEA, 6.8 kg) were added and the temperature was fixed at 22 0C. In another reactor, phosgene (5.0 kg) was introduced in tetrahydrofuran (88 1) previously cooled to -3 0C. The THF and TEA s olution was added to the solution of phosgene in 3h 50 mm maintaining the temperature at -3 0C. The reactor was washed with tetrahydrofuran (22 1). The mixture was stirred for 45 min at 20 0C and then for 90 min at reflux (65 0C). The solvent was distilled under reduced pressure at 25-30 0C to a residual volume of 149 1. The absence of phosgene was controlled. At this stage, there still was phosgene and the suspension was degassed by bubbling nitrogen through it. After this operation the level of phosgene above the solution was below 0.075 ppm. The suspension was filtered and washed with tetrahydrofuran (30 1). The solvent was distilled under reduced pressure at 20-25 0C to a residual volume of 40 1. Tetrahydrofuran (51 1) was added and the solvent was distilled under reduced pressure at 20-25 0C to a residual volume of 40 1. The final volume was adjusted to about 52 litters by addition of tetrahydrofuran (11 1). The solution was analysed and used in the next step. f) Preparation of the title compound of formula I

Figure imgf000024_0001

The product from previous step e) (51 1) was added in 1 h to a solution of the product from step a) (7.3 kg) in tetrahydrofuian (132 1) at 17 0C. The line was washed with tetrahydrofuran (12 1) and the mixture was stirred for 15h. Residual product from the first step was checked by HPLC The solvent was removed by distillation under reduced pressure at 20-38 0C to a residual volume of 165 1. Charcoal (Noπt SXl-G, 0 7 kg) was added, the mixture was stirred for 15 mm and filtered. The lme was washed with tetrahydrofuran (7 1) and the solvent was removed by distillation under reduced pressure at 20-25 0C to a residual volume of 30 1. Isopropyl acetate (96 1) was added to obtain a solution of the title compound of formula I, which contains a small amount of impurities, which were mainly side products from the previous reactions. Removal of the solvent from a sample yields a substantially amorphous solid

g) Preparation of N-(4-fluorobenzyl)-N-(l-methylpipeπdm-4-yl)-N’-(4-(2-methylpropyloxy)phe- nylmethyl)carbamide hemi-tartrate

To the solution of the compound of Formula I in isopropyl acetate (96 1) from step f was added at 23 0C a previously prepared solution of tartaric acid (1 7 kg) in water (1.7 1) and tetrahydrofuran (23 1) The residual suspension was stirred for 2.5 days at 22 0C The tartrate crude product was centrifuged and the cake was washed with 4 portions of isopropyl acetate (4 x 23 1). A total of 107 kg of mother liquors was saved for later use in obtaining the tartrate salt The wet cake was dπed at about 40 0C to yield 8.3 kg (50%) product.

h) First Purification

The tartrate crude product of step g) (8.1 kg) was dissolved m demmeralized water (41 1) at 22 0C. Isopropyl acetate (40 L), 30% aqueous sodium hydroxide (4.3 kg) and sodium chloride (2 kg) were added. The pH was checked (>12) and the solution was stirred for 15 mm. The solution was decanted over 15 mm and the aqueous phase was separated. The aqueous phase was re-extracted with isopropyl acetate (12 1) Demmeralized water (20 1) and sodium chloride (2 0 kg) were added to the combined organic phases, the solution was stirred for 15 mm, decanted over 15 mm and the aqueous phase was discarded. Charcoal (0.4 kg) was added, the mixture was stirred for 20 mm and filtered. After a line wash with isopropyl acetate (12 1), the solvent was removed under reduced pressure at 20-25 0C Heptane (49 1) was added and the suspension was stirred for 15 mm at 40 °C. Then, 8 1 of solvent was removed by distillation under reduced pressure at 38-41 0C The slurry was cooled to 20 0C and stirred for 1 h. The product was centrifuged and the cake was washed with heptane (5 1) The wet compound of Forrnu-la I (5.5 kg) was dissolved m ethanol (28 1) at 45 0C. A solution of tartaric acid (0.72 kg) m ethanol (11 1) was added at 45 0C and the line was washed with ethanol (91). The solution was cooled to 43 0C, seeded with the tartrate salt of the compound o f Formula I, then the slurry was cooled to 350C m 30 mm, stirred at this temperature for 1 h and cooled to -5 0C After 14 h at this temperature the product was centrifuged and washed with two portions of ethanol (2×6 1) The wet cake was dried at about 45 0C for 76 h to yield 4 kg of the herm-tartrate

i) Re -crystallization

150 O g of herm-tartrate obtained m h) was dissolved under stirring at 65 0C m 112 ml absolute ethanol and then cooled under stirring to 48 0C at a cooling rate of 1 °C/mm Crystallization started after a few minutes at this temperature and the suspension turned to a thick paste withm 1 h. The suspension was heated again to 60 0C and then cooled to 480C at a rate of 1 °C/mm The obtained suspension was stirred and was cooled to 15 0C at a cooling rate of 3 °C/h. The crystalline precipitate was separated by filtration and the bottle was washed with 10 ml absolute ethanol cooled to 5 0C. The crystalline residue was dried under vacuum and 40 0C for 50 hours to yield 146 g crystalline pure herm-tartrate.

j) Second purification

15 78 g of the tartrate salt prepared from step i) was dissolved 121 130 ml water 500 ml TBME was added and the pH -was adjusted to 9 8 by addition of 2 ISf NaOH solution. After precipitation of a white solid, the aqueous phase was extracted 5 times by 500 ml TBME The organic phases were concentrated until a volume of about 400 ml remained. The solution was stored at 60C. The precipitate was filtered, washed with TBME and finally dried m vacuum for 5 hours. Yield: 8.24 g of a white poΛvder. The mother liquor was concentrated to a fourth and stored at 60C. The precipitate was filtered and dried m vacuum for 18 hours. Yield: 1.6 g of a white powder.

PXRD revealed a crystalline compound of formula I. No Raman peaks from tartaric acid were found. The first scan of DSC (-500C to 2100C5 10°K/mm) revealed a melting point at 123.6°C. Above about 19O0C, the sample started to decompose. Example 2. Preparation of N-(4-fluoroben2yl)-N-(l-methylpiperidin-4-yl)-N’-(4-(2- methylpropγloxy)phenylmethyl)carbamide citrate of formula FV

a) 90 mg of the product from Example 1 and 40 mg citnc acid were suspended m 5.0 ml ethylacetate. The suspension was stirred at 60 0C for 15 minutes (mm), cooled to 23±2 0C, and then stored for 30 mm at 23±2 0C. The precipitate was filtered off and dried in air for 30 mm to yield 52 mg of a crystalline white powder. Optical microscopy shows that the obtained solid was crystalline

b) 182 mg of the product from Example 2 and 78.4 mg citric acid were suspended m 10.0 ml ethyl acetate The suspension was stirred at 60 0C for 30 mm, then stirred at 40 0C for 90 mm, and finally stirred for 60 mm at 23 0C The suspension was filtered and washed with heptane, yielding 237 mg of a white crystalline powder -with an endothermic peak near 153 0C (enthalpy of fusion of about 87 J/g), determined by differential scanning caloπmetry at a rate of 10K/mm (DSC). Thermogravimetry (TG-FTIR) showed a mass loss of about 0.7% between 60 and 160 0C, which was attributed to absorbed water Decomposition started at about 170 0C Solubility m water was about 14 mg/ml The crystalline powder remained substantially unchanged when stored for 1 week at 60 0C and about 75% r_h. m an open container (HPLC area was 99.4% compared to reference value of 99.9%). Elemental analysis and 1H-NMR complies with an 1 : 1 stoichiometry.

PATENT

http://www.google.im/patents/WO2008144326A2?cl=en

Figure imgf000011_0004

Example 1 : Preparation of N-(4-fluorobenzyl)-N-Cl-methylpiperidin-4-yl)-N’-(4-f2- methylpropyloxy)phenylmethγl)carbamide a) Preparation of

Figure imgf000032_0001

Triacetoxy borohydride (6.5 kg) was added over 1.5 h to a solution of N- methylpiperid-4-one (3.17 kg) and 4-fluorobenzylamine (3.50 kg) in methanol (30 L) maintaining the temperature under 27 0C. The reaction mixture was stirred for 15 h at 22 0C. The residual amine was checked by gel chromatography (4-fluorobenzylamine: < 5%). A solution of 30% sodium hydroxide (12.1 kg) in water (13.6 kg) was added in 75 minutes (min) maintaining the temperature under 20 0C. Methanol was distilled off to a residual volume of 26 litres. Ethyl acetate was added (26 L), the solution was stirred for 15 min, the phases were decanted over 15 min and the lower aqueous phase was discarded. Ethyl acetate was distilled under reduced pressure from the organic phase at 73-127 0C. At this stage the residue was mixed with a second crude batch prepared according to this method. The combined products were then distilled at 139-140 0C / 20 mbar to yield 11.2 kg product (> 82%). b) Preparation of

Figure imgf000033_0001

4-Hydroxybenzaldehyde (4.0 kg) and ethanol (20 L) were added to a solution of isobutyl bromide (9.0 kg) in ethanol (15 L). Potassium carbonate (13.6 kg) was added and the suspension was refluxed (74-78 0C) for 5 days. The residual 4- hydroxybenzaldehyde was checked by HPLC (< 10%). The suspension was cooled to 20 °C and used in the next step.

c) Preparation of

Figure imgf000033_0002

[0117] Hydroxylamine (50% in water, 8.7 kg) was added to the product from previous step b) (174 L5 176 kg) and ethanol (54 L). The suspension was refluxed (77 0C) for 3 h. Unreacted residual was checked by HPLC (< 5%). The suspension was cooled to 30 °C, filtered and the filter was washed with ethanol (54 L). The solution was concentrated by distillation under reduced pressure at 30 0C to a residual volume of 67 litters. The solution was cooled to 25 0C and water (1 10 L) was added. The suspension was concentrated by distillation under reduced pressure at 30 °C to a residual volume of 102 litters. Petrol ether (60-90 fraction, 96 L) was added and the mixture was heated to reflux (70 °C). The solution was cooled to 40 0C and crystallization was initiated by seeding. The suspension was cooled to 5 0C and stirred for 4h. The product was centrifuged and the cake was washed with petrol ether (60-90 fraction, 32 L). The wet cake was dried at about 40 °C to yield 16kg product (63%). d) Preparation of

Figure imgf000034_0001

The product from previous step c) (15.7 kg) was dissolved in ethanol (123 L). Acetic acid (8.2 kg) and palladium on charcoal 5% wet (1.1 kg) were added. The oxime was hydrogenated at 22 0C and 1.5 bar for 4h. Consumption of oxime was checked by HPLC. The catalyst was filtered and the solvent was distilled under reduced pressure at 36 °C to a final volume of 31 L. Ethyl acetate (63 L) was added and the mixture was heated to reflux (75 0C) until dissolution. The solution was cooled to 45 0C and the crystallization was initiated by seeding. The suspension was cooled to 6-10 °C and stirred for 2.5h. The product was centrifuged and the cake was washed with 2 portions of ethyl acetate (2 x 0.8 L). The wet cake was dried at a temperature of about 40 0C to yield 8 kg (41%).

e) Preparation of

Figure imgf000034_0002

Aqueous sodium hydroxide (30%, 5.0 kg) was added to a suspension of the product from previous step d) (7.9 kg) in heptane (41 L). The solution was heated to 47 °C, stirred for 15 min and decanted over 15 min. The pH was checked (pH>12) and the aqueous phase was separated. The solvent was removed by distillation under reduced pressure at 47-65 °C. Heptane was added (15 L) and then removed by distillation under reduced pressure at 58-65 0C. Heptane was added (7 L), the solution was filtered, and the filter was washed with heptane (7 L). The solvent was removed by distillation under reduced pressure at 28-60 0C. Tetrahydrofuran (THF, 107 L) and triethylamine (TEA, 6.8 kg) were added and the temperature was fixed at 22 0C. In another reactor, phosgene (5.0 kg) was introduced in tetrahydrofuran (88 L) previously cooled to -30C. The THF and TEA solution was added to the solution of phosgene in 3h 50 min, maintaining the temperature at – 3 0C. The reactor was washed with tetrahydrofuran (22 L). The mixture was stirred for 45 min at 20 0C and then for 90 min at reflux (65 0C). The solvent was distilled under reduced pressure at 25-30 0C to a residual volume of 149 L. The absence of phosgene was controlled. At this stage, phosgene was still present and the suspension was degassed by bubbling nitrogen through it. After this operation, the level of phosgene above the solution was below 0,075 ppm. The suspension was filtered and washed with tetrahydrofuran (30 L). The solvent was distilled under reduced pressure at 20-25 0C to a residual volume of 40 L. Tetrahydrofuran (51 L) was added and the solvent was distilled under reduced pressure at 20- 25 0C to a residual volume of 40 L. The final volume was adjusted to about 52 litters by addition of tetrahydrofuran (1 1 L). The solution was analysed and used in the next step.

f) Preparation of the title compound of formula I

Figure imgf000035_0001

The product from previous step e) (51 L) was added in 1 h to a solution of the product from step a) (7.3 kg) in tetrahydrofuran (132 L) at 17 0C. The line was washed with tetrahydrofuran (12 L) and the mixture was stirred for 15h. Residual product from the first step was checked by HPLC. The solvent was removed by distillation under reduced pressure at 20-38 0C to a residual volume of 165 L. Charcoal (Norit SXl-G5 0.7 kg) was added, the mixture was stirred for 15 min and filtered. The line was washed with tetrahydrofuran (7 L) and the solvent was removed by distillation under reduced pressure at 20-25 0C to a residual volume of 30 L. Isopropyl acetate (96 L) was added to obtain a solution of the title compound of formula I, which contains a small amount of impurities (mainly side products from the previous reactions.) Removal of the solvent from a sample yields a substantially amorphous solid.

The solution with the crude product was used for the direct preparation of the hemi-tartrate and simultaneously for the purification of the free base via the hemi-tartrate through crystallization from suitable solvents.

Example 5: Preparation of the hemi-tartrate of formula IV from crude free base of formula I

Crude product according to Example l(f) (4.3 kg) was dissolved at 45 0C in ethanol (23 L). A solution of (+)-L-tartaric acid (0.58 kg) in ethanol was added at 45 0C and the line was washed with 6 L of ethanol. The solution was stirred for 20 min (formation of solid precipitate) and the slurry was cooled to 35 0C over 30 min. The slurry was stirred at this temperature for 1 hour and then cooled to -5 0C. After 14 hours stirring at this temperature, the product was centrifuged and washed with 2 portions of ethanol (2 x 4 L). The wet cake was dried at 45 0C for 80 hours yielding 3.3 kg of product (85%, based on tartaric acid). PXRD of the product revealed that polymorph A was formed.

PATENT

WO2014085362A1.

CN101031548A

CN101035759A

CN102153505A

CN1816524A

US2008280886A1.

WO0144191

PATENT

WO-2016141003

Scheme 4:

The reaction depicted in Scheme 4 can be carried out in a suitable organic solvent such as acetone at rather mild conditions (e.g.40-50°C). If necessary, the R1 substituent may subsequently be converted to an isobutoxy group to obtain Pimavanserin or a salt thereof.

An overview about certain processes for preparation of Pimavanserin is shown in Scheme 5 below.

Scheme 5:

Compound A L-Tartaric acid

Hemi-tartrate salt *Compound A is Pimavanserin

Scheme 10:

Compound 1 Compound 2 Pimavanserin

Scheme 13:

An overview about synthetic routes to Pimavanserin via Compound XVI is shown in the following Scheme 14:

Scheme 14:

Example 16: Preparation of hemi-tartrate salt of Pimavanserin

To a 25 mL seal tube, equipped with a stir bar, was charged 344.4 mg of the above crude PMV (1.0 mmol in theory), 75 mg of L-tartaric acid (FW: 150.09, 0.5 mmol, 0.5 equiv.), and 7 mL (16.4 vol.) of absolute ethanol. The tube was sealed and heated to 70°C to afford a clear solution, then cooled down gradually to room temperature. The product precipitated, and the batch was further cooled down to 0-5°C and stirred at this temperature for 0.5 hour. The product was collected by vacuum filtration, and the filter cake was washed with 2 × 1 mL (2.3 vol.) of EtOH. The product was dried in the Buchner funnel under vacuum overnight, affording 177.6 mg of salt, representing a 35.4% yield in 99.6 A% purity. 1H NMR (CDCl3, 400 MHz): δ = 1.01 (d, J = 6.4 Hz, 6 H), 1.79-1.82 (m, 2H), 2.02-2.19 (m, 3H), 2.63 (brs, 5H), 3.38-3.47 (m, 2H), 3.67 (d, J = 6.4 Hz, 2H), 4.25 (d, J = 4.8 Hz, 2H), 4.32 (s, 1H), 4.38 (s, 2H), 4.58 (brs, 2H), 6.77 (d, J = 8.0 Hz, 2H), 6.95-6.99 (m, 4H), 7.17 (d, J = 7.2 Hz, 2H).

Example 21: Preparation of Pimavanserin via compound V as dihydrochloride salt

Step 1: Preparation of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine dihydrochloride (Compound V x 2HCl)

The reaction was performed in 300 mL reactor. The reactor was purged with N2, then Argon. 4-Fluorobenzylamine (10 g; 80 mmol, 1.0 eq) was dissolved in dry MeCN (100 mL), then 1-methylpiperidin-4-one (10.9 g; 96 mmol, 1.2 eq) was added and the reaction mixture was stirred at ambient temperature for 18h. Then, the reaction mixture was cooled to 0°C and 25.4 g of NaBH(OAc)3 (25.4 g; 120 mmol, 1.5 eq) was added in portions over 20 min and the reaction was allowed to stir to room temperature. After 1h, the reaction was quenched by the addition of 200 ml of water, pH was adjusted to 2 with 5M HCl and then extracted using 3 x 250 mL of DCM. Basification of the aqueous layer to pH 9.5 with 30% sol. NaOH and extraction 3 x 300 ml of DCM followed. The organic layers were collected and dried over anh. Na2SO4, filtered and evaporated to dryness yielding 17.24 g (92%) of oily product, N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (Compound V).

To a 250 mL, three necked, round bottom flask, equipped with a stir bar and thermometer, N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (10 g; 0.045 mol) and DCM (50 mL) were charged and cooled to 10-15 °C. To the resulting solution, 5-6 N HCl in 2-PrOH (3 equiv., 0.135 mmol) was added dropwise over 25 min., white crystals formed, and the solution then cooled to 0-5 °C for 2 hours. Crystals were filtered off, washed with 50 mL of DCM, dried at 50°C/10 mbar for 10 hours yielding 12.8 g (96.4%) of N-(4-fluorobenzyl)-1-methylpiperidin-4-amine dihydrochloride (Compound V x 2HCl).

Step 2: Preparation of 4-isobutoxybenzaldehyde (Compound XIII)

4-Hydroxybenzaldehyde (10 g; 0.082 mol), potassium carbonate (33.95 g; 0.246 mol) and potassium iodide (1.36 g; 0.008 mol) were suspended in N,N-dimethylformamide (50 mL). Isobutyl bromide (26.7 mL; 0.246 mol) was added and the reaction was heated at 70°C under nitrogen for 3 hours. The reaction was cooled down, diluted by using 150 mL of water and extracted by using 300 mL of ethyl acetate. The organic layer was extracted five times by using 150 mL of 10% NaCl solution, dried under Na2SO4, filtered and concentrated which resulted in 14.3 g (98%) of yellow oily product of 4-isobutoxybenzaldehyde

(Compound XIII).

Step 3: Preparation of (4-isobutoxyphenyl)methanamine hydrochloride (Compound XI x HCl)

[0142] To a solution of 4-isobutoxybenzaldehyde (Compound XIII) (19.9 g; 0.112 mol) in methanol (90 mL), Raney nickel (6 g) and 7N methanol ammonia solution (90 mL) were added. The reaction mixture was stirred under hydrogen atmosphere (0.5 bar) at 10-15°C for 24 hours. The reaction solution was filtered through Celite to remove the catalyst. Methanol was distilled off and toluene (500 mL) was added. The solution was concentrated to 250 mL and 5-6 N HCl in 2-PrOH (30 mL; 0.15 mol) was added dropwise at ambient temperature. The resulting suspension was then cooled to 5 °C and stirred for additional 2 hours. Crystals were filtered off, washed with 60 mL of toluene, dried at 50°C/10 mbar for 10 hours yielding 20.88 g (86.7%) of (4-isobutoxyphenyl)methanamine hydrochloride (Compound XI x HCl). The product was analyzed by PXRD– form I was obtained, the PXRD pattern is shown in Figure 3.

Step 4: Option 1: Preparation of 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)urea (Pimavanserin

Part a: Preparation of Compound VI-a:

To a 250 mL, three necked, round bottom flask, equipped with a stir bar, condenser and thermometer, (4-isobutoxyphenyl)methanamine hydrochloride (Compound XI x HCl) (5 g, 0.023 mol), CDI (6.01 g; 0.037 mol) and acetonitrile (40 mL) were charged. The resulting solution was stirred for 1 h at 65-70 °C and monitored by HPLC until full conversion to Compound VI-a.

Part b: Preparation of Pimavanserin:

N-(4-fluorobenzyl)-1-methylpiperidin-4-amine (Compound V) (7.73 g; 0.035 mol) was added to Compound VI-a obtained above. After 2h, complete conversion was observed. Upon completion, the reaction solution was cooled to 50 °C and water was added dropwise in a 1:3 ratio (120 mL). After addition of a whole amount of water, crystals were formed and suspension was allowed to cool to ambient temperature. The crystals were filtered off, washed with 2 x 40 mL solution of CH3CN:H2O 1:3, then 40 mL of water, dried at 45°C/10 mbar for 10 hours yielding 9.35 g (94.4%) of 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)urea (Pimavanserin).

Step 4– option 2: Preparation of 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)urea (Pimavanserin)

Part a: Preparation of Compound VI-a:

To a 500 mL, three necked, round bottom flask, equipped with a stir bar, condenser and thermometer, (4-isobutoxyphenyl)methanamine hydrochloride (Compound XI x HCl) (10 g; 0.046 mol), CDI (11.28 g; 0.07 mol) and acetonitrile (100 mL) were charged. The resulting solution was stirred for 1 h at 65-70 °C and monitored by HPLC until full conversion to Compound VI-a.

Part b: Preparation of Pimavanserin:

[0146] The reaction solution containing Compound VI-a obtained above was cooled to 30°C and N-(4-fluorobenzyl)-1-methylpiperidin-4-amine dihydrochloride (Compound V x 2HCl) (20.53 g; 0.07 mol) and K2CO3 (9.61 g; 0.07 mol) were added. The reaction mixture was heated to 65-70 °C and stirred for next 18 hours. Upon completion, the reaction solution was cooled to 50 °C, pH of solution was adjusted to 10.5 with 6N NaOH solution, and water was added dropwise in ratio 1:3 (300 mL). After addition of a whole amount of water, crystals were formed, and suspension was allowed to cool to ambient temperature, and then cooled on ice-bath (0-5°C) for 1.5 hour. The crystals were filtered off, washed with 2 x 100 mL solution of CH3CN:H2O 1:3, then 100 mL of water, dried at 45°C/10 mbar for 10 hours yielding 18.797 g (95.6%) of 1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)urea (Pimavanserin).

Example 26: One pot preparation of Pimavanserin (without isolation of Compound 1)

Step 1: Preparation of 2-(4-isobutoxyphenyl)acetic acid

To a 250 mL, 3 neck, round bottom flask, equipped with thermocouple and nitrogen sweep, was charged 10 g of 4-hydroxy phenyl acetic acid (Molecular weight (FW): 152.15, 65.7 mmol, 1.0 equiv.), 30 g of potassium carbonate (FW: 138.21, 216.8 mmol, 3.3 equiv.), 1.1 g of potassium iodide (KI, FW: 166, 6.57 mmol, 0.1 equiv.), followed by 100 mL (10 vol.) of DMF. After stirring for 5 minutes at room temperature, 15.7 mL of isobutyl bromide (FW: 137.02, 144.6 mmol, 2.2 equiv.) was charged into the batch. The mixture was then heated to 75°C and kept stirring at the same temperature for 2 days until no limited starting material remaining as determined by HPLC. The reaction was cooled down to room temperature, and quenched by charging with 100 mL of deionized (DI) water. The pH of the reaction mixture was adjusted to less than 1 by charging 100 mL of 2N HCl. The product was extracted with 150 mL of ethyl acetate. After partitioning, the upper organic layer was washed with additional 100 mL of DI water, concentrated to dryness on the rotary evaporator under vacuum. The residue was dissolved in 100 mL each of THF (10 vol) and DI water (10 vol). After charging 20 g of lithium hydroxide, the mixture was heated to reflux for 3 hours until complete reaction. The batch was cooled to room temperature, concentrated on rotary

evaporator to remove THF. The residue was acidified with 300 mL of 2N HCl and 45 mL of 6N HCl aqueous solution until pH <1. The product was extracted with 2×250 mL of methylene chloride, dried over sodium sulfate, and filtered on Buchner funnel. The filtrate was concentrated to dryness on rotary evaporator under vacuum to afford 10.18 g of 2-(4-isobutoxyphenyl)acetic acid, representing a 74.4% yield in 98.5 A% purity. 1H NMR (d6-DMSO, 400 MHz): δ = 0.97 (d, J = 6.8 Hz, 6 H), 1.96-2.02 (m, 1H), 3.47 (s, 2H), 3.71 (d, J = 6.4 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.8 Hz, 2H).

Step 2: Preparation of Pimavanserin

To a 50 mL, single neck, round bottom flask, equipped with thermocouple and nitrogen sweep, was charged 333.2 mg of 2-(4-isobutoxyphenyl)acetic acid (FW: 208.25, 1.6 mmol, 1.0 equiv.), 311.3 mg of CDI (FW: 162.15, 1.92 mmol, 1.2 equiv.), and 3.3 mL of CH3CN (10 vol.). After stirring at room temperature for 1 hour, this was charged 139 mg (FW: 69.5, 2.0 mmol, 1.25 equiv.) of NH2OH.HCl and stirred for additional 15-18 hours at room temperature. Additional 518.9 mg of CDI (FW: 162.15, 3.2 mmol, 2.0 equiv.) was charged and the batch turned from a slurry to a clear solution again. This was followed by charging a solution of 334 mg of Compound V (FW: 222.3, 1.5 mmol, 0.94 equiv.), and heating up to 60 oC. The reaction was stirred at this temperature for approximately 5 hour before cooling back to room temperature. The reaction was quenched with 20 mL of DI water, and concentrated on rotary evaporator to remove acetonitrile. The aqueous residue was diluted with 40 mL of ethyl acetate, and washed with 2×20 mL of brine. The organic phase was concentrated to dryness on rotary evaporator under vacuum. The residue was purified by chromatography (160 g RediSep Alumina column), eluting with 0-5% of methanol in dichloromethane to afford 305 mg of Pimavanserin, representing a 47.6% yield in 99.3 A% purity.1H NMR (CDCl3, 400 MHz): δ = 1.01 (d, J = 6.8 Hz, 6 H), 1.62-1.73 (m, 4H), 2.03-2.09 (m, 3H), 2.25 (s, 3H), 2.84-2.87 (m, 2H), 3.68 (d, J = 6.4 Hz, 2H), 4.27-4.34 (m, 5H), 4.45-4.48 (m, 1H), 6.67-6.79 (m, 2H), 6.99-7.02 (m, 4H), 7.16-7.27 (m, 2H). HRMS-ESI (m/z): [M+1]+ Calcd for C25H35F1N3O2: 428.2708; found 428.2723.

Example 27: Preparation of Pimavanserin (with isolation of Compound 1)

Step 1: Preparation of Compound 1

To a 100 mL, single neck, round bottom flask, equipped with thermocouple and nitrogen sweep, was charged 1 g of Compound XV (FW: 208.25, 4.8 mmol, 1.0 equiv.), 934.0 mg of CDI (FW: 162.15, 5.76 mmol, 1.2 equiv.), followed by 10 mL (10 vol.) of acetonitrile. After stirring for 45 minutes at room temperature, 417 mg of NH2OH.HCl (FW: 69.5, 6.0 mmol, 1.25 equiv.) was charged into the batch. The mixture was kept stirring at the ambient temperature overnight and turned into a thick slurry. HPLC determined 1.6 A% of starting material remaining. The batch was diluted with 6 mL of acetonitrile (6 vol.) and 16 mL (16 vol.) of DI water, and cooled down to 0-5 ºC. After stirring at the same temperature for additional 1 hour, the batch was filtered on the Buchner funnel. The filter cake was washed with 2×10 mL (10 vol.) of DI water, and dried in the funnel under vacuum overnight to afford 774.1 mg of hydroxamic acid Compound 1, representing a 72% yield in 99.6 A% purity. 1H NMR (CDCl3, 400 MHz): δ = 0.96 (d, J = 6.8 Hz, 6 H), 1.95-2.02 (m, 1H), 3.19 (s, 2H), 3.70 (d, J = 6.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 8.80 (s, 1H), 10.61 (s, 1H).

Step 2: Synthesis of Pimavanserin

To a 50 mL sealed tube, equipped with nitrogen sweep, was charged 250 mg of compound 1 (FW: 223.27, 1.12 mmol, 1.0 equiv.), 217.9 mg of CDI (FW: 162.15, 1.34 mmol, 1.2 equiv.), and 1.7 mL of acetonitrile (6.8 vol.). After stirring at room temperature for 40 minutes, the batch was heated to 60 oC and kept stirring at the same temperature for additional 10 minutes. This was followed by charging 373.5 mg of Compound 3 (FW: 222.3, 1.68 mmol, 1.5 equiv.). The container of Compound V was rinsed with 0.5 mL (2 vol.) of acetonitrile, and the wash was combined with the batch. The reaction was monitored by HPLC and complete in 2 hours. The batch was cooled down to room temperature, diluted with 5 mL (20 vol.) of ethyl acetate, which was washed with 3×5 mL (20 vol.) of DI water. After partitioning, the upper organic layer was concentrated to dryness on rotary evaporator. The residue was re-dissolved into 3 mL (12 vol.) of ethyl acetate after heating up to reflux to afford a slightly milky solution. This was charged with 12 mL (48 vol.) of heptane, and cooled down to 0-5oC. The batch was kept stirring at the same temperature for 1 hour and filtered on a Buchner funnel. The filter cake was washed with 2×5 mL (20 vol.) of heptane, and dried in the funnel with a nitrogen sweep for 1 hour to afford 270.8 mg of Pimavanserin as a white solid, representing a 56.6% yield in 98.8 A% purity. 1H NMR (CDCl3, 400 MHz): δ = 1.01 (d, J = 6.8 Hz, 6 H), 1.62-1.73 (m, 4H), 2.03-2.09 (m, 3H), 2.25 (s, 3H), 2.84-2.87 (m, 2H), 3.68 (d, J = 6.4 Hz, 2H), 4.27-4.34 (m, 5H), 4.45-4.48 (m, 1H), 6.67-6.79 (m, 2H), 6.99-7.02 (m, 4H), 7.16-7.27 (m, 2H). HRMS-ESI (m/z): [M+1]+ Calcd for C25H35F1N3O2: 428.2708; found 428.2723.

Example 34: Preparation of Pimavanserin from Compound 2

To a 25 mL, three neck, round bottom flask, equipped with a stir bar, condenser and thermocouple, Compound 2, 0.210 g, was charged (FW: 249.26, 0.84 mmol, 1.0 equiv.). This was followed 3 mL of acetonitrile, anhydrous, 99.8%. The mixture was stirred at 60°C for 4 h. Then, to the reaction mixture, Compound V, 0.375 g (FW: 222.30, 1.69 mmol, 2.0 equiv.), was added. After 1h, complete conversion was observed. The reaction was diluted with EtOAc (20 mL) and washed twice with a saturated solution of NH4Cl (2 x 15 mL), then H2O (10 mL) and finally with a saturated NaCl solution (10 mL). The organic layer was dried over anh. sodium sulfate, filtered and concentrated under partial vacuum to about 5 mL of EtOAc. To this solution, n-heptane (10 ml) was added with vigorous stirring, in a dropwise manner, over half an hour. A white precipitate was formed, followed by filtration and drying in vacuum at 45°C for 3h, affording 0.188 g of Pimavanserin. HPLC-MS (m/z) [M+1]+ 428.2; 1H NMR (CDCl3, 400 MHz): δ = 1.01 (d, J = 6.7 Hz, 6 H), 1.68-1.77 (m, 4H), 2.03-2.10 (m, 3H), 2.30 (s, 3H), 2.91-2.97 (m, 2H), 3.67(d, J = 6.7 Hz, 2H), 4.27 (d, J = 5.4 Hz, 2H), 4.31-4.43 (m, 3H), 4.50 (brt, J = 5.5 Hz, 1H), 6.74-6-79 (m, 2H), 6.95-7.05 (m, 4H), 7.14-7.22 (m, 2H).

Example 38: Preparation of Pimavanserin from Compound and Compound V x 2HCl

250 mL reactor was charged with N-hydroxy-2-(4-isobutoxyphenyl)acetamide (Compound 1) (10 g, 0.045 mol), CDI (10.53 g, 0.076 mol) and 100 mL of MeCN, p.a. The resulting solution was stirred for 1.5 h at 60-65 °C and monitored by HPLC. Upon full conversion to the corresponding isocyanate, reaction solution was cooled to 35 °C and N-(4- fluorobenzyl)-1-methylpiperidin-4-amine dihydrochloride (Compound V x 2HCl) (22.48 g, 0.065 mol) and K2CO3 (6.19 g, 0.045 mol) were added. Reaction mixture was heated up to 60-65 °C and stirred for 6 hours and followed by 17 h at ambient temperature.

Upon completion, the reaction solution was cooled to 20 °C and water was added dropwise in ratio 1:3 (300 mL) with adjustment of pH to 11 with 6N NaOH solution. After addition of whole amount of water, crystals were formed and suspension was stirred at 20 °C for 2 h and 0-5°C for next 2 hour. Crystals were filtered off, washed with 2 x 100 mL solution of MeCN:H2O 1:3, then 100 mL of H2O, dried at 30°C/10 mbar for 24 hours yielding 17.56 g (91.7%) of Pimavanserin.

 

PAPER

Bioorg. Med. Chem. Lett. 2015, 25, 1053–1056.

11C-labeling and preliminary evaluation of pimavanserin as a 5-HT2A receptor PET-radioligand

  • a Neurobiology Research Unit, Rigshospitalet and University of Copenhagen, Blegdamsvej 9, 2100 Copenhagen, Denmark
  • b Center for Integrated Molecular Brain Imaging, University of Copenhagen Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark
  • c Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark

Pimavanserin is a selective serotonin 2A receptor (5-HT2AR) inverse agonist that has shown promise for treatment of psychotic symptoms in patients with Parkinson’s disease. Here, we detail the 11C-labeling and subsequently evaluate pimavanserin as a PET-radioligand in pigs. [11C]Pimavanserin was obtained by N-methylation of an appropriate precursor using [11C]MeOTf in acetone at 60 °C giving radiochemical yields in the range of 1–1.7 GBq (n = 4). In Danish Landrace pigs the radio ligand readily entered the brain and displayed binding in the cortex in accordance with the distribution of 5-HT2ARs. However, this binding could not be blocked by either ketanserin or pimavanserin itself, indicating high nonspecific binding. The lack of displacement by the 5-HT2R antagonist and binding in the thalamus suggests that [11C]pimavanserin is not selective for the 5-HT2AR in pigs.


Graphical abstract

Image for unlabelled figure

Clip

THURSDAY Oct. 31, 2013 — Many people living with Parkinson’s disease suffer from hallucinations and delusions, but an experimental drug might offer some relief without debilitating side effects.

READ ALL AT

http://www.drugs.com/news/new-shows-early-promise-treating-parkinson-s-psychosis-48630.html

The drug — pimavanserin — appears to significantly relieve these troubling symptoms, according to the results of a phase 3 trial to test its effectiveness.

Pimavanserin (ACP-103) is a drug developed by Acadia Pharmaceuticals which acts as an inverse agonist on the serotonin receptor subtype 5-HT2A, with 40x selectivity over 5-HT2C, and no significant affinity or activity at 5-HT2B or dopamine receptors.[1] As of September 3 2009, pimavanserin has not met expectations for Phase III clinical trials for the treatment of Parkinson’s disease psychosis,[2] and is in Phase II trials for adjunctive treatment of schizophrenia alongside an antipsychotic medication.[3] It is expected to improve the effectiveness and side effect profile of antipsychotics.[4][5][6]

3-D MODEL OF DRUG PIMAVANSERIN, THE DEVELOPMENT OF WHICH HAS BEEN EXPEDITED BY THE FDA

Psychiatrist Herb Meltzer sadly watched the agitated woman accuse her son of trying to poison her. Although not her physician, Dr. Meltzer certainly recognized the devastating effects of his mother-in-law’s Parkinson’s disease psychosis (PDP). Occurring in up to half of all patients with Parkinson’s, symptoms of the psychotic disorder may include hallucinations and delusions. The development of PDP often leads to institutionalization and increased mortality.

“I was on the sidelines,” explains Dr. Meltzer, professor of psychiatry and physiology and director of the Translational Neuropharmacology Program at Northwestern University Feinberg School of Medicine. “I told my brother-in-law it was the disease talking, not his mother.”

Ironically, Dr. Meltzer has been far from the sidelines and right on the PDP playing field for quite a while. In fact, he may soon see a drug he helped develop become the first approved treatment for the disorder. In early April, Dr. Meltzer celebrated, along with colleagues at ACADIA Pharmaceuticals in San Diego for which he has been a clinical advisor, the stunning announcement: the Food and Drug Administration (FDA) had expedited the company’s path to filing a new drug application (NDA) for pimavanserin, a selective serotonin 5-HT2Areceptor blocker. Typically, the FDA requires data from two successful pivotal Phase III clinical studies affirming a drug candidate’s safety and efficacy before the agency will even consider an NDA. Just as ACADIA was planning to launch another Phase III study this spring to fulfill this requirement, the FDA decided the company had amassed enough data to support an NDA filing.

HERBERT MELTZER, MD, DESIGNED ACADIA PHARMACEUTICAL’S INITIAL PROOF OF CONCEPT TRIAL OF THE DRUG PIMAVANSERIN TO TREAT PARKINSON’S DISEASE PSYCHOSIS.

“This action on the part of the FDA is extremely unusual,” says Dr. Meltzer, who designed ACADIA’s initial proof-of-concept trial of pimavanserin, a drug he had initially suggested ACADIA develop to treat schizophrenia, with PDP as a secondary indication. “The FDA staff decided that results from my small clinical study and the first successful Phase III study were sufficient to establish efficacy and safety.”

Bringing a safe and effective drug to market is a monumental achievement. Pimavanserin is not yet there but has significantly moved within striking distance with this recent nod from the regulatory agency.

24 YEARS IN THE MAKING

The neuropharmacologist’s collaboration with ACADIA began in 2000. The company wanted to develop a drug targeting the serotonin 5-HT 2A receptor, a neurotransmitter ACADIA believed played a key role in schizophrenia based upon basic research from Meltzer and their own studies. A distinguished schizophrenia investigator, then at Case Western Reserve University, he welcomed ACADIA’s offer to translate his ideas about developing safer and more effective drug treatments for psychosis. Through his provocative and groundbreaking research, Dr. Meltzer originally championed the idea that blocking the 5-HT2A receptor would lead to better antipsychotic drugs with fewer side effects. Existing drugs often impaired motor function because they targeted the dopamine D2 receptor. Of the 14 different types of serotonin receptors in this complex area of study, Dr. Meltzer zeroed in on the 5-HT2A type—the same receptor that leads to hallucinogenic properties of LSD and mescaline. It was an ideal target to complement weak D2 receptor blockade in schizophrenia and as a standalone treatment for PD psychosis.

External links

References

  1.  Friedman, JH (October 2013). “Pimavanserin for the treatment of Parkinson’s disease psychosis”. Expert Opinion on Pharmacotherapy. 14 (14): 1969–1975.doi:10.1517/14656566.2013.819345. PMID 24016069.
  2. ^ Jump up to:a b c “Nuplazid (pimavanserin) Tablets, for Oral Use. U.S. Full Prescribing Information” (PDF). ACADIA Pharmaceuticals Inc. Retrieved 1 May 2016.
  3. Jump up^ ACADIA Pharmaceuticals. “Treating Parkinson’s Disease – Clinical Trial Pimavanserin – ACADIA”. Archived from the original on February 25, 2009. Retrieved 2009-04-11.
  4. Jump up^ “ACADIA Announces Positive Results From ACP-103 Phase II Schizophrenia Co-Therapy Trial” (Press release). ACADIA Pharmaceuticals. 2007-03-19. Retrieved 2009-04-11.
  5. Jump up^ Gardell LR, Vanover KE, Pounds L, Johnson RW, Barido R, Anderson GT, Veinbergs I, Dyssegaard A, Brunmark P, Tabatabaei A, Davis RE, Brann MR, Hacksell U, Bonhaus DW (Aug 2007). “ACP-103, a 5-hydroxytryptamine 2A receptor inverse agonist, improves the antipsychotic efficacy and side-effect profile of haloperidol and risperidone in experimental models”. The Journal of Pharmacology and Experimental Therapeutics. 322 (2): 862–70. doi:10.1124/jpet.107.121715.PMID 17519387.
  6. Jump up^ Vanover KE, Betz AJ, Weber SM, Bibbiani F, Kielaite A, Weiner DM, Davis RE, Chase TN, Salamone JD (Oct 2008). “A 5-HT2A receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model”. Pharmacology, Biochemistry, and Behavior. 90 (4): 540–4. doi:10.1016/j.pbb.2008.04.010. PMC 2806670free to read.PMID 18534670.
  7. Jump up^ Abbas A, Roth BL (Dec 2008). “Pimavanserin tartrate: a 5-HT2A inverse agonist with potential for treating various neuropsychiatric disorders”. Expert Opinion on Pharmacotherapy. 9 (18): 3251–9.doi:10.1517/14656560802532707. PMID 19040345.
  8. Jump up^ Meltzer HY, Elkis H, Vanover K, Weiner DM, van Kammen DP, Peters P, Hacksell U (Nov 2012). “Pimavanserin, a selective serotonin (5-HT)2A-inverse agonist, enhances the efficacy and safety of risperidone, 2mg/day, but does not enhance efficacy of haloperidol, 2mg/day: comparison with reference dose risperidone, 6mg/day”. Schizophrenia Research. 141 (2-3): 144–152. doi:10.1016/j.schres.2012.07.029. PMID 22954754.
  9. Jump up^ “ACADIA Pharmaceuticals Receives FDA Breakthrough Therapy Designation for NUPLAZID™ (Pimavanserin) for Parkinson’s Disease Psychosis”. Press Releases. Acadia. 2014-09-02.
  10. Jump up^ “Press Announcements — FDA approves first drug to treat hallucinations and delusions associated with Parkinson’s disease”. U.S. Food and Drug Administration. Retrieved1 May 2016.

NUPLAZID contains pimavanserin, an atypical antipsychotic, which is present as pimavanserin tartrate salt with the chemical name, urea, N-[(4-fluorophenyl)methyl]-N-(1-methyl-4-piperidinyl)-N’-[[4-(2- methylpropoxy)phenyl]methyl]-,(2R,3R)-2,3-dihydroxybutanedioate (2:1). Pimavanserin tartrate is freely soluble in water. Its molecular formula is (C25H34FN3O2)2•C4H6O6 and its molecular weight is 1005.20 (tartrate salt). The chemical structure is:

NUPLAZID™ (pimavanserin) Structural Formula Illustration

The molecular formula of pimavanserin free base is C25H34FN3O2 and its molecular weight is 427.55.

NUPLAZID tablets are intended for oral administration only. Each round, white to off-white, immediaterelease, film-coated tablet contains 20 mg of pimavanserin tartrate, which is equivalent to 17 mg of pimavanserin free base. Inactive ingredients include pregelatinized starch, magnesium stearate, and microcrystalline cellulose. Additionally, the following inactive ingredients are present as components of the film coat: hypromellose, talc, titanium dioxide, polyethylene glycol, and saccharin sodium.

WO2006036874A1 * 26 Sep 2005 6 Apr 2006 Acadia Pharmaceuticals Inc. Salts of n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n’-(4-(2-methylpropyloxy)phenylmethyl)carbamide and their preparation
WO2006037043A1 * 26 Sep 2005 6 Apr 2006 Acadia Pharmaceuticals Inc. Synthesis of n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n’-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms
WO2007133802A2 * 15 May 2007 22 Nov 2007 Acadia Pharmaceuticals Inc. Pharmaceutical formulations of pimavanserin
US20060205780 * 3 May 2006 14 Sep 2006 Thygesen Mikkel B Synthesis of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N’-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms
US20060205781 * 3 May 2006 14 Sep 2006 Thygesen Mikkel B Synthesis of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N’-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms
US20070260064 * 15 May 2007 8 Nov 2007 Bo-Ragnar Tolf Synthesis of n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n’-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms
Reference
1 * WANG, Y. ET AL: “ACP-103: 5-HT2A receptor inverse agonist treatment of psychosis treatment of sleep disorders” DRUGS OF THE FUTURE , 31(11), 939-943 CODEN: DRFUD4; ISSN: 0377-8282, 2006, XP002446571
Pimavanserin
Pimavanserin structure.svg
Systematic (IUPAC) name
N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N’-(4-(2-methylpropyloxy)phenylmethyl)carbamide
Clinical data
Trade names Nuplazid
Routes of
administration
Oral (tablets)
Legal status
Legal status
Pharmacokinetic data
Protein binding 94–97%[1]
Metabolism Hepatic (CYP3A4, CYP3A5,CYP2J2)[2]
Biological half-life 54–56 hours[1]
Identifiers
CAS Number 706779-91-1 Yes
706782-28-7 (tartrate)
ATC code None
PubChem CID 10071196
DrugBank DB05316 
ChemSpider 8246736 
UNII JZ963P0DIK Yes
KEGG D08969 
ChEBI CHEBI:133017 
ChEMBL CHEMBL2111101 
Synonyms ACP-103
Chemical data
Formula C25H34FN3O2
Molar mass 427.553 g/mol
Jeffrey Cummings, Stuart Isaacson, Roger Mills, Hilde Williams, Kathy Chi-Burris, Anne Corbett, Rohit Dhall, Clive Ballard.
Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial.
The Lancet, Volume 383, Issue 9916, Pages 533 – 540, 8 February 2014.
Findings: Between Aug 11, 2010, and Aug 29, 2012, we randomly allocated 199 patients to treatment groups. For 90 recipients of placebo and 95 recipients of pimavanserin included in the primary analysis, pimavanserin was associated with a −5·79 decrease in SAPS-PD scores compared with −2·73 for placebo (difference −3·06, 95% CI −4·91 to −1·20; p=0·001; Cohen’s d 0·50). Ten patients in the pimavanserin group discontinued because of an adverse event (four due to psychotic disorder or hallucination within 10 days of start of the study drug) compared with two in the placebo group. Overall, pimavanserin was well tolerated with no significant safety concerns or worsening of motor function.This study is registered with ClinicalTrials.gov, number NCT01174004.Bo-Ragnar Tolf, Nathalie Schlienger, Mikkel Boas Thygesen.
Synthesis of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms.
US patent number:US7790899 B2
Also published as:CA2692001A1, CN101778821A, EP2146960A2, US20070260064, WO2008144326A2, WO2008144326A3.
Publication date:Sep 7, 2010.
Original Assignee:Acadia Pharmaceuticals, Inc.Tolf, Bo-Ragmar; Schlienger, Nathalie; Thygesen, Mikkel Boas.
Preparation of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N’-[4-(2-methylpropyloxy)phenylmethyl]carbamide and its tartrate salt and crystalline forms.
PCT Int. Appl. (2008), WO2008144326 A2 20081127.Tolf, Bo-Ragnar; Schlienger, Nathalie; Thygesen, Mikkel Boas.
Synthesis of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N’-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms.
U.S. Pat. Appl. Publ. (2007), US20070260064 A1 20071108.Pyke, Robert; Ceci, Angelo.
Pharmaceutical compositions for the treatment and/or prevention of schizophrenia and related diseases.
PCT Int. Appl. (2006), WO2006096439 A2 20060914.Wang, Y.; Bolos, J.; Serradell, N.ACP-103:
5-HT2A receptor inverse agonist treatment of psychosis treatment of sleep disorders.
Drugs of the Future (2006), 31(11), 939-943.Roberts, Claire.
Drug evaluation: ACP-103, a 5-HT2A receptor inverse agonist.
Current Opinion in Investigational Drugs (Thomson Scientific) (2006), 7(7), 653-660.hygesen, Mikkel; Schlienger, Nathalie; Tolf, Bo-Ragnar; Blatter, Fritz; Berghausen, Jorg.
Process for preparation of salts of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N’-(4-(2-methylpropyloxy) phenylmethyl)carbamide.
PCT Int. Appl. (2006), WO2006036874 A1 20060406.Clip

FDA approves first drug to treat hallucinations and delusions associated with Parkinson’s disease

For Immediate Release

April 29, 2016

Release

The U.S. Food and Drug Administration today approved Nuplazid (pimavanserin) tablets, the first drug approved to treat hallucinations and delusions associated with psychosis experienced by some people with Parkinson’s disease.

Hallucinations or delusions can occur in as many as 50 percent of patients with Parkinson’s disease at some time during the course of their illness. People who experience them see or hear things that are not there (hallucinations) and/or have false beliefs (delusions). The hallucinations and delusions experienced with Parkinson’s disease are serious symptoms, and can lead to thinking and emotions that are so impaired that the people experiencing them may not relate to loved ones well or take appropriate care of themselves.

“Hallucinations and delusions can be profoundly disturbing and disabling,” said Mitchell Mathis, M.D., director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research. “Nuplazid represents an important treatment for people with Parkinson’s disease who experience these symptoms.”

An estimated 50,000 Americans are diagnosed with Parkinson’s disease each year, according to the National Institutes of Health, and about one million Americans have the condition. The neurological disorder typically occurs in people over age 60, when cells in the brain that produce a chemical called dopamine become impaired or die. Dopamine helps transmit signals between the areas of the brain that produce smooth, purposeful movement — like eating, writing and shaving. Early symptoms of the disease are subtle and occur gradually. In some people Parkinson’s disease progresses more quickly than in others. As the disease progresses, the shaking, or tremor, which affects the majority of people with Parkinson’s disease, may begin to interfere with daily activities. Other symptoms may include depression and other emotional changes; hallucinations and delusions; difficulty in swallowing, chewing, and speaking; urinary problems or constipation; skin problems; and sleep disruptions.

The effectiveness of Nuplazid was shown in a six-week clinical trial of 199 participants. Nuplazid was shown to be superior to placebo in decreasing the frequency and/or severity of hallucinations and delusions without worsening the primary motor symptoms of Parkinson’s disease.

As with other atypical antipsychotic drugs, Nuplazid has a Boxed Warning alerting health care professionals about an increased risk of death associated with the use of these drugs to treat older people with dementia-related psychosis. No drug in this class is approved to treat patients with dementia-related psychosis.

In clinical trials, the most common side effects reported by participants taking Nuplazid were: swelling, usually of the ankles, legs, and feet due to the accumulation of excessive fluid in the tissue (peripheral edema); nausea; and abnormal state of mind (confused state).

Nuplazid was granted breakthrough therapy designation for the treatment of hallucinations and delusions associated with Parkinson’s disease. Breakthrough therapy designation is a program designed to expedite the development and review of drugs that are intended to treat a serious condition and where preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint. The drug was also granted a priority review. The FDA’s priority review program provides for an expedited review of drugs that offer a significant improvement in the safety or effectiveness for the treatment, prevention, or diagnosis of a serious condition.

Nuplazid is marketed by Acadia Pharmaceuticals Inc. of San Diego, California.

//////////Pimavanserin, FDA 2016,  Nuplazid®,  Acadia , Breakthrough Therapy, PRIORITY REVIEW, 

FDA grants accelerated approval to first drug for Duchenne muscular dystrophy


Image result for Exondys 51

Image result for eteplirsen

CAS 1173755-55-9
eteplirsen, eteplirsén [Spanish], étéplirsen [French] , eteplirsenum [Latin], этеплирсен [Russian], إيتيبليرسان [Arabic]

Structure credit http://lgmpharma.com/eteplirsen-still-proves-efficacious-duchenne-drug/

FDA grants accelerated approval to first drug for Duchenne muscular dystrophy
New therapy addresses unmet medical need

The U.S. Food and Drug Administration today approved Exondys 51 (eteplirsen) injection, the first drug approved to treat patients with Duchenne muscular dystrophy (DMD). Exondys 51 is specifically indicated for patients who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, which affects about 13 percent of the population with DMD.

Read more

Image result for Duchenne muscular dystrophy

FDA grants accelerated approval to first drug for Duchenne muscular dystrophy

September 19, 2016

Release

The U.S. Food and Drug Administration today approved Exondys 51 (eteplirsen) injection, the first drug approved to treat patients with Duchenne muscular dystrophy (DMD). Exondys 51 is specifically indicated for patients who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, which affects about 13 percent of the population with DMD.

“Patients with a particular type of Duchenne muscular dystrophy will now have access to an approved treatment for this rare and devastating disease,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “In rare diseases, new drug development is especially challenging due to the small numbers of people affected by each disease and the lack of medical understanding of many disorders. Accelerated approval makes this drug available to patients based on initial data, but we eagerly await learning more about the efficacy of this drug through a confirmatory clinical trial that the company must conduct after approval.”

DMD is a rare genetic disorder characterized by progressive muscle deterioration and weakness. It is the most common type of muscular dystrophy. DMD is caused by an absence of dystrophin, a protein that helps keep muscle cells intact. The first symptoms are usually seen between three and five years of age, and worsen over time. The disease often occurs in people without a known family history of the condition and primarily affects boys, but in rare cases it can affect girls. DMD occurs in about one out of every 3,600 male infants worldwide.

People with DMD progressively lose the ability to perform activities independently and often require use of a wheelchair by their early teens. As the disease progresses, life-threatening heart and respiratory conditions can occur. Patients typically succumb to the disease in their 20s or 30s; however, disease severity and life expectancy vary.

Exondys 51 was approved under the accelerated approval pathway, which provides for the approval of drugs that treat serious or life-threatening diseases and generally provide a meaningful advantage over existing treatments. Approval under this pathway can be based on adequate and well-controlled studies showing the drug has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit to patients (how a patient feels or functions or whether they survive). This pathway provides earlier patient access to promising new drugs while the company conducts clinical trials to verify the predicted clinical benefit.

The accelerated approval of Exondys 51 is based on the surrogate endpoint of dystrophin increase in skeletal muscle observed in some Exondys 51-treated patients. The FDA has concluded that the data submitted by the applicant demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit in some patients with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping. A clinical benefit of Exondys 51, including improved motor function, has not been established. In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease for these children and the lack of available therapy.

Under the accelerated approval provisions, the FDA is requiring Sarepta Therapeutics to conduct a clinical trial to confirm the drug’s clinical benefit. The required study is designed to assess whether Exondys 51 improves motor function of DMD patients with a confirmed mutation of the dystrophin gene amenable to exon 51 skipping. If the trial fails to verify clinical benefit, the FDA may initiate proceedings to withdraw approval of the drug.

The most common side effects reported by participants taking Exondys 51 in the clinical trials were balance disorder and vomiting.

The FDA granted Exondys 51 fast track designation, which is a designation to facilitate the development and expedite the review of drugs that are intended to treat serious conditions and that demonstrate the potential to address an unmet medical need. It was also granted priority review and orphan drug designation.Priority review status is granted to applications for drugs that, if approved, would be a significant improvement in safety or effectiveness in the treatment of a serious condition. Orphan drug designation provides incentives such as clinical trial tax credits, user fee waiver and eligibility for orphan drug exclusivity to assist and encourage the development of drugs for rare diseases.

The manufacturer received a rare pediatric disease priority review voucher, which comes from a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. This is the seventh rare pediatric disease priority review voucher issued by the FDA since the program began.

Exondys 51 is made by Sarepta Therapeutics of Cambridge, Massachusetts.

Image result for Exondys 51 (eteplirsen) injection

ChemSpider 2D Image | eteplirsen | C364H569N177O122P30

CAS 1173755-55-9 [RN]
eteplirsén [Spanish] [INN]
étéplirsen [French] [INN]
eteplirsenum [Latin] [INN]
этеплирсен [Russian] [INN]
إيتيبليرسان [Arabic] [INN]
Eteplirsen
Systematic (IUPAC) name
(P-deoxy-P-(dimethylamino)](2′,3′-dideoxy-2′,3′-imino-2′,3′-seco)(2’a→5′)(C-m5U-C-C-A-A-C-A-m5U-C-A-A-G-G-A-A-G-A-m5U-G-G-C-A-m5U-m5U-m5U-C-m5U-A-G),5′-(P-(4-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)carbonyl)-1-piperazinyl)-N,N-dimethylphosphonamidate) RNA
Clinical data
Routes of
administration
Intravenous infusion
Legal status
Legal status
  • Investigational
Identifiers
CAS Number 1173755-55-9
ATC code None
ChemSpider 34983391
UNII AIW6036FAS Yes
Chemical data
Formula C364H569N177O122P30
Molar mass 10305.738

///////////Exondys 51, Sarepta Therapeutics, Cambridge, Massachusetts, eteplirsen,  Orphan drug designationPriority reviewfast track designation, Duchenne muscular dystrophy, этеплирсен ,  إيتيبليرسان ,

VELPATASVIR (GS-5816), GILEAD SCIENCES, велпатасвир, فالباتاسفير , 维帕他韦 ,


img

VELPATASVIR (GS-5816), GILEAD SCIENCES

CAS 1377049-84-7

Molecular Formula: C49H54N8O8
Molecular Weight: 883.00186 g/mol

Hepatitis C virus NS 5 protein inhibitors

KEEP WATCHING AS I ADD MORE DATA, SYNTHESIS……………

Gilead Sciences, Inc. INNOVATOR

Elizabeth M. Bacon, Jeromy J. Cottell, Ashley Anne Katana, Darryl Kato, Evan S. Krygowski, John O. Link, James Taylor, Chinh Viet Tran, Martin Teresa Alejandra Trejo, Zheng-Yu Yang, Sheila Zipfel,

Elizabeth Bacon

Senior Research Associate II at Gilead Sciences

Methyl {(2S)-1-[(2S,5S)-2-(5-{2-[(2S,4S)-1-{(2R)-2- [(methoxycarbonyl)amino]-2-phenylacetyl}-4- (methoxymethyl)pyrrolidin-2-yl]-1 ,1 1 dihydroisochromeno[4′,3′:6,7]naphtho[1 ,2-d]imidazol-9-yl}-1 H-imidazol-2-yl)-5- methylpyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl}carbamate

methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

methyl {(2S)-1 – [(2S,5S)-2-(5-{2-[(2S,4S)-l- {(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl} -4-(methoxymethyl) pyrrolidin-2-yl]-l,l 1 dihydroisochromeno [4′,3′:6,7]naphtho[l,2-d]imidazol-9-yl}-lH-imidazol-2-yl)- 5-methylpyrrolidin-l-yl]-3-methyl-l -oxobutan-2-yl}carbamate

str1

Research Scientist I at Gilead Sciences

{(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(Méthoxycarbonyl)amino]-2-phénylacétyl}-4-(méthoxyméthyl)-2-pyrrolidinyl]-1H-imidazol-4-yl}-1,11-dihydroisochroméno[4′,3′:6,7]naphto[1,2-d]imidazol-2-yl)-5 -méthyl-1-pyrrolidinyl]-3-méthyl-1-oxo-2-butanyl}carbamate de méthyle
Carbamic acid, N-[(1R)-2-[(2S,4S)-2-[4-[1,11-dihydro-2-[(2S,5S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-5-methyl-2-pyrrolidinyl][2]benzopyrano[4′,3′:6,7]naphth[1,2-d]imidazol-9-yl]-1H- imidazol-2-yl]-4-(methoxymethyl)-1-pyrrolidinyl]-2-oxo-1-phenylethyl]-, methyl ester

Methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-4-yl}-1,11-dihydro[2]benzopyrano[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

str1

Velpatasvir.png

.

str1

Description Pan-genotypic HCV NS5A inhibitor
Molecular Target HCV NS5A protein
Mechanism of Action HCV non-structural protein 5A inhibitor
Therapeutic Modality Small molecule
Latest Stage of Development Phase II
Standard Indication Hepatitis C virus (HCV)
Indication Details Treat HCV genotype 1 infection; Treat HCV infection
  • Gilead Sciences
  • Class Antivirals; Carbamates; Chromans; Imidazoles; Naphthols; Phenylacetates; Phosphoric acid esters; Pyrimidine nucleotides; Pyrrolidines; Small molecules
  • Mechanism of Action Hepatitis C virus NS 5 protein inhibitors
  • Registered Hepatitis C

Most Recent Events

  • 14 Jul 2016 Registered for Hepatitis C in Canada (PO)
  • 08 Jul 2016 Registered for Hepatitis C in Liechtenstein, Iceland, Norway, European Union (PO)
  • 30 Jun 2016 Gilead Sciences plans a phase III trial for Hepatitis C (Combination therapy, Treatment-experienced) in Japan (PO (NCT02822794)

 

Darryl Kato works on a hepatitis treatment at Gilead Sciences Inc.’s lab

Velpatasvir, also known as GS-5816, is a potent and selective Hepatitis C virus NS5A inhibitor. GS-5816 has demonstrated pan-genotypic activity and a high barrier to resistance in HCV replicon assays. GS-5816 demonstrated pangenotypic antiviral activity in patients with genotype 1-4 HCV infection. It will be further evaluated in combination with other pangenotypic direct-acting antivirals to achieve the goal of developing a well-tolerated, highly effective treatment for all HCV genotypes.

WO 2013/075029. Compound I has the formula:


methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate

.

PAPER

Patent Highlights: Recently Approved HCV NS5a Drugs

Cidara Therapeutics, 6310 Nancy Ridge Dr., Suite 101, San Diego, California 92121, United States
Org. Process Res. Dev., Article ASAP

Abstract

Five inhibitors of the NS5a enzyme have been approved as part of oral regimens for the treatment of hepatitis C virus, including daclatasvir (Bristol-Myers Squibb), ledipasvir (Gilead Sciences), ombitasvir (AbbVie), elbasvir (Merck), and velpatasvir (Gilead Sciences). This article reviews worldwide patents and patent applications that have been published on synthetic routes and final forms for these five drugs.

 

PATENT

https://google.com/patents/WO2013075029A1?cl=en

Example NP

Methyl {(2S)-1-[(2S,5S)-2-(5-{2-[(2S,4S)-1-{(2R)-2- [(methoxycarbonyl)amino]-2-phenylacetyl}-4- (methoxymethyl)pyrrolidin-2-yl]-1 ,1 1 dihydroisochromeno[4′,3′:6,7]naphtho[1 ,2-d]imidazol-9-yl}-1 H-imidazol-2-yl)-5- methylpyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl}carbamate

Methyl {(2S)-l-[(2S,5S)-2-(5-{2-[(2S,4S)-l-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4- (methoxymethyl)pyrrolidin-2-yl]-l,ll dihydroisochromeno [4′,3′:6,7]naphtho[l,2-d]imidazol-9- yl}-lH-imidazol-2-yl)-5-methylpyrrolidin-l-yl]-3-methyl-l-oxobutan-2-yl}carbamate

The synthesis of this compound was prepared according to the procedure of example LR-1 with the following modification. During the Suzuki coupling, (2S)-l-[(2S,5S)-2-(5-iodo-lH-imidazol- 2-yl)-5-methylpyrrolidin-l-yl]-2-[(l-meth^ was used in lieu of

(2S)-l -[(2S)-2-(5-bromo-lH-imidazol-2-yl)pyrrolidin-l-yl]-2-[(l-methoxyethenyl)amino]-3- methylbutan-l-one. The crade material was purified by preparative HPLC to provide methyl {(2S)-1 – [(2S,5S)-2-(5-{2-[(2S,4S)-l- {(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl} -4-(methoxymethyl) pyrrolidin-2-yl]-l,l 1 dihydroisochromeno [4′,3′:6,7]naphtho[l,2-d]imidazol-9-yl}-lH-imidazol-2-yl)- 5-methylpyrrolidin-l-yl]-3-methyl-l -oxobutan-2-yl}carbamate as a white solid (17 mg, 0.019 mmol, 17%). lU NMR (400 MHz, cd3od) δ 8.63 (s, 1H), 8.19 (d, 1H), 8.04 (m, 1H), 7.87 (m, 2H), 7.66 (m, 2H), 7.52 – 7.39 (m, 6H), 5.50 (m, 2H), 5.32 (s, 2H), 5.16 (m, 1H), 4.12 (m, 1H), 3.80 (m, 4H), 3.66 (s, 6H), 3.43 (m, 4H), 3.23 (s, 3H), 2.72-1.99 (m, 9H), 1.56 (d, 3H), 1.29 (m, 1H), 0.99 (d, 3H), 0.88 (d, 3H).

PATENT

US 20150361073 A1

Scheme 1

Compound (J)

Compound (I) H CO- Com pound (G)

st alkylation: Conversion of Compound (I-a) to Compound (G-a)

Compound (I-a) (45 g, 1.0 equiv.), Compound (J-a) (26.7g, 1.03 equiv.) and potassium carbonate (20.7g, 1.5 equiv.) in dichloromethane (450 mL) were stirred at about 20 °C for approximately 3-4 hours. After the completion of the reaction, water (450 mL) was charged into the reactor and the mixture was stirred. Layers were separated, and the aqueous layer was extracted with dichloromethane (200 mL). The combined organic layers were washed with 2 wt% NaH2PO4/10wt% NaCl solution (450 mL). The organic layer was then concentrated and the solvent was swapped from dichloromethane into tetrahydrofuran. A purified sample of Compound (G-a) has the following spectrum: ¾ NMR (400 MHz,

CDC13) δ 7.90-7.94 (m, 1H), 7.81-7.85 (m, 1H), 7.72 (s, 1H), 7.69 (s, 1H), 7.66 (s, 1H), 5.19-5.56 (2dd, 2H), 5.17 (s, 2H), 4.73 (t, 1H), 4.39-4.48 (m, 1H), 3.70-3.77 (m, 1H), 3.37-3.45 (m, 2H), 3.33-3.35 (d, 3H), 3.28-3.32 (m, 1H), 3.20-3.25 (dd, 1H), 2.92-2.96 (dt, 1H), 2.44-2.59 (m, 4H), 1.97-2.09 (m, 1H), 1.44 (d, 9H).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative starting material may be Compound (I) where X may be -CI, -Br, -OTs, -OS02Ph, -OS02Me, -OS02CF3, -OS02R, , and -OP(0)(OR)2 and Y may be -CI, -Br, -OTs, -OS02Ph, -OS02Me, -OS02CF3, -OS02R, and -OP(0)(OR)2. R may be alkyl, haloalkyl, or an optionally substituted aryl.

Various bases may also be employed, such as phosphate salts (including but not limited to KH2P04, K3P04, Na2HP04, and Na3P04) and carbonate salts (including but not limited to Na2C03,Cs2C03, and NaHC03). Where the starting material is Compound (J), KHC03 or preformed potassium, sodium, and cesium salts of Compound (J) may also be used.

Alternative solvents can include 2-methyltetrahydrofuran, tetrahydrofuran, isopropyl acetate, ethyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, dimethylformamide, acetone, MEK, and MIBK.

The reaction temperature may range from about 10 °C to about 60 °C.

” alkylation: Conversion of Compound (G-a) to Compound (B-a):

A solution of Compound (G-a) (prepared as described earlier starting from 45 g of Compound (I-a)) was mixed with Compound (H) (42.9g, 1.5 equiv.), and cesium carbonate (26. lg, 0.8 equiv.). The reaction mixture was stirred at about 40-45 °C until reaction was complete and then cooled to about 20 °C. Water (450 mL) and ethyl acetate (225 mL) were added and the mixture was agitated. Layers were separated, and the aqueous layer was extracted with ethyl acetate (150 mL). Combined organic phase was concentrated and solvent was swapped to toluene. A purified sample of Compound (B-a) has the following spectrum: ¾ NMR (400 MHz, CDC13) 57.90-7.93 (m, 1H), 7.81-7.83 (m, 1H), 7.73 (s, 1H), 7.63-7.64 (d, 1H), 7.59-7.60 (d, 1H), 5.52-5.63 (m, 1H), 5.30-5.43 (q, 1H), 5.13-5.23 (s+m, 3H), 4.56-4.64 (m, 2H), 4.39-4.48 (m, 1H), 4.20-4.27 (m, 1H), 3.62-3.79 (m, 2H), 3.66 (s, 2H), 3.36-3.45 (m, 2H), 3.34-3.35 (d, 3H), 3.07-3.25 (m, 3H), 2.59-2.37 (m, 5H), 1.97-2.16 (m, 3H), 1.60 (s, 3H), 1.38-1.45 (m, 12H), 0.91-1.03 (m, 6H).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative starting material may include Compound (G) where Y may be -CI, -Br, -OTs, -OS02Ph, -OS02Me, -OS02CF3, -OS02R, , or -OP(0)(OR)2. where R is alkyl, aryl, or substituted aryl. In some embodiments, the substituted aryl may be an aryl having one or more substituents, such as alkyl, alkoxy, hydroxyl, nitro, halogen, and others as discussed above.

Various bases may be employed. Non-limiting examples can include phosphate salts (including but not limited to KH2P04, K3P04, Na2HP04, and Na3P04) and carbonate salts (including but not limited to K2C03 or Na2C03). If Compound (H) is used as the starting material, Li2C03 or preformed potassium, sodium, and cesium salt of Compound (H) may be employed.

Alternative solvents may include 2-methyltetrahydrofuran, dichloromethane, toluene, mixtures of THF/Toluene, isopropyl acetate, ethyl acetate, l-methyl-2-pyrrolidinone, Ν,Ν-dimethylacetamide, acetone, MEK,and MIBK. An alternative additive may be

potassium iodide, and the reaction temperature may range from about 40 °C to about 60 °C or about 40 °C to about 50 °C.

A toluene solution of Compound (B-a) (604 g solution from 45 g of Compound (I-a)) was charged to a reaction vessel containing ammonium acetate (185.2 g) and isopropanol (91.0 g). The contents of the reactor were agitated at about 90 °C until the reaction was complete (about 16 to 24 hours). The reaction mixture was cooled to about 45 °C, and then allowed to settle for layer separation. Water (226 g) was added to the organic phase, and the resulting mixture was separated at about 30 °C. Methanol (274 g), Celite (26.9 g) and an aqueous solution of sodium hydroxide (67.5 g, 50%) and sodium chloride (54.0 g) in water (608 g) were added to the organic phase, and the resulting mixture was agitated for a minimum of 30 minutes. The mixture was then filtered through Celite and rinsed forward with a mixture of toluene (250 g) and isopropanol (1 1 g). The biphasic filtrate was separated and water (223 g) was added to the organic phase, and the resulting mixture was agitated at about 30 °C for at least 15 minutes. The mixture was filtered through Celite and rinsed forward with toluene (91 g). The organic layer was concentrated by vacuum distillation to 355 g and was added over 30 minutes to another reactor containing w-heptane (578 g). The resulting slurry is filtered, with the wetcake was washed with w-heptane (450 mL) and dried in a vacuum oven to afford Compound (C-a). A purified sample of Compound (C-a) has the following spectrum: *H NMR (400 MHz, CDC13) δ 12.27-11.60 (m, 1 H), 1 1.18-10.69 (m, 1 H), 7.83 – 7.44 (m, 4 H), 7.36 (d, J = 7.9 Hz, 1 H), 7.28 – 7.05 (m, 1 H), 5.65 – 5.25 (m, 1H), 5.25 – 4.83 (m, 4 H), 4.34 – 4.03 (m, 2 H), 3.93 – 3.63 (m, 4 H), 3.52 (s, 1 H), 3.35 (d, J = 2.4 Hz, 4 H), 3.19 – 2.94 (m, 4 H), 2.88 (dd, J = 12.0, 7.9 Hz, 3 H), 2.66 – 1.85 (m, 5 H), 1.79 (s, 5 H), 1.37 – 1.12 (m, 6H), 1.04-0.98 (m, 6 H), 0.82 (t, J = 7.7 Hz, 2 H).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative reagents, in lieu of ammonium acetate, can include hexamethyldisilazane, ammonia, ammonium formate, ammonium propionate, ammonium hexanoate, and ammonium octanoate. Various solvents, such as toluene, xylene, an alcohol

(including but not limited to isopropanol, 1-propanol, 1-butanol, 2-butanol, 2-methoxyethanol, and glycols, such as ethylene glycol and propylene glycol) may be employed. Alternative catalyst/additives may include magnesium stearate, acetic acid, propionic acid, and acetic anhydride. The reaction temperature may range from about 60 °C to about 110 °C or about 85 °C to about 95 °C.

D

Preparation of Compound (D-a) using DDQ as oxidant:

A solution of Compound (C-a) (255.84 g) in 2-methyltetrahydrofuran (1535 mL) was cooled to about 0 °C and acetic acid (0.92 mL) was added. To this mixture was added a solution of DDQ (76.98 g) in 2-methyltetrahydrofuran (385 mL) over about 30 minutes. Upon reaction completion, a 10 wt% aqueous potassium hydroxide solution (1275 mL) was added over about 30 minutes and the mixture was warmed to about 20 °C. Celite (101.5 g) was added and the slurry was filtered through Celite (50.0 g) and the filter cake was rinsed with 2-methyltetrahydrofuran (765 mL). The phases of the filtrate were separated. The organic phase was washed successively aqueous potassium hydroxide solution (1020 mL, 10 wt%), aqueous sodium bisulfite solution (1020 mL, 10 wt%), aqueous sodium bicarbonate solution (1020 mL, 5 wt%) and aqueous sodium chloride solution (1020 mL, 5 wt%). The organic phase was then concentrated to a volume of about 650 mL. Cyclopentyl methyl ether (1530 mL) was added and the resulting solution was concentrated to a volume of about 710 mL. The temperature was adjusted to about 40 °C and Compound (D-a) seed (1.0 g) was added. The mixture was agitated until a slurry forms, then methyl tert-butyl ether (2300 mL) was added over about 3 hours. The slurry was cooled to about 20 °C over about 2 hours and filtered. The filter cake was rinsed with methyl tert-butyl ether (1275 mL) and dried in a vacuum oven at about 40 °C to provide Compound (D-a). A purified sample of Compound (D-a) has the following spectrum: ¾ NMR (400 MHz, CDC13) δ 13.05-10.50 (comp m, 2H), 8.65-6.95 (comp m, 8H), 5.50-5.35 (m, 2H), 5.25^1.60 (comp m, 3H), 4.35-4.20 (m, 1H), 4.00-3.65 (comp m, 4H), 3.60-3.45 (m, 1H), 3.45-3.25 (comp m, 4H), 3.25-3.00 (comp m, 2H), 2.95-1.65 (comp m, 6H), 1.47 (br s, 9H), 1.40-1.25 (comp m, 2H), 1.20-0.70 (comp m, 9H).

Alternative Preparation of Compound (D-a) using Mn02 as oxidant:

A mixture of Compound (C-a) (50.0 g), manganese (IV) oxide (152.8 g) and dichloromethane (500 mL) is stirred at about 20 °C. Upon completion of the reaction, Celite (15 g) was added. The resulting slurry was filtered through Celite (20 g) and the filter cake was rinsed with dichloromethane (500 mL). The filtrate was concentrated and solvent exchanged into cyclopentyl methyl ether (250 mL). The resulting solution was warmed to about 60 °C and treated with an aqueous potassium hydroxide solution (250 mL, 10wt%). The biphasic mixture is stirred at about 45 °C for about 12 hours. The phases are then separated and the organic phase is concentrated to a volume of about 150 mL. The concentrate is filtered, seeded with Compound (D-a) seed and agitated at about 40 °C to obtain a slurry. Methyl tert-butyl ether (450 mL) was added to the slurry over 30 minutes and the resulting mixture was cooled to about 20 °C. The precipitated solid was filtered, rinsed with methyl tert-butyl ether (250 mL) and dried in a vacuum oven at about 40 °C to obtain Compound (D-a).

Alternative Preparation of Compound (D-a) through catalytic dehydrogenation

A mixture of Compound (C-a) (2.5 g, 2.7 mmol, 1 equiv), 5% Pd/Al203 (2.5 g) and 1-propanol (25 mL, degassed) was stirred at reflux under inert environment for about 5.5 hours. The reaction mixture was then cooled to ambient temperature and filtered through Celite, and the residue rinsed with 1-propanol (2 x 5 mL) to obtain a solution of Compound (D-a).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, in a reaction scheme employing stoichiometric oxidants, alternative oxidants may include manganese(IV) oxide, copper(II) acetate, copper(II) trifluoroacetate, copper(II) chloride, copper(II) bromide, bromine (Br2), iodine (I2), N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, 1 ,4-benzoquinone, tetrachloro-l,4-benzoquinone (chloranil), eerie ammonium nitrate, hydrogen peroxide, tert-butyl hydroperoxide, άϊ-tert-butyl peroxide, benzoyl peroxide, oxygen ((¾), sodium hypochlorite, sodium hypobromite, tert-butyl hypochlorite, Oxone, diacetoxyiodobenzene, and bis(trifluoroacetoxy)iodobenzene. Various additives may be employed, and non-limiting examples may be carbonate bases (e.g., potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, and the like), amines (e.g., triethylamine, diisopropylethylamine and the like), and acids (e.g., trifluoroacetic acid, trichloroacetic acid, benzoic acid, hydrochloric acid, sulfuric acid, phosphoric acid, ara-toluenesulfonic acid, methanesulfonic acid), sodium acetate, potassium acetate, and the like). The reaction temperature may range from about -10°C to 80 °C. The reaction may take place in solvents, such as halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, etc.), aromatic solvents (e.g., toluene, xylenes, etc.), ethereal solvents (tetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, 1 ,2-dimethoxyethane, diglyme, triglyme, etc.), alcoholic solvents (e.g., methanol, ethanol, w-propanol, isopropanol, n-butanol, tert-butanol, tert-amyl alcohol, ethylene glycol, propylene glycol, etc.), ester solvents (e.g., ethyl acetate, isopropyl acetate, tert-butyl acetate, etc.), ketone solvents (e.g., acetone, 2-butanone, 4-methyl-2-pentanone, etc.), polar aprotic solvents (e.g., acetonitrile, Ν,Ν-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidinone, pyridine, dimethyl sulfoxide, etc.), amine solvents (e.g., triethylamine, morpholine, etc.), acetic acid, and water.

In reaction schemes employing catalytic oxidants, alternative catalysts may include palladium catalysts (e.g., palladium(II) acetate, palladium(II) trifluoroacetate, palladium(II) chloride, palladium(II) bromide, palladium(II) iodide, palladium(II) benzoate, palladium(II) sulfate, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(tri-iert-butylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, bis(acetonitrile)palladium(II) chloride, bis(benzonitrile)palladium(II) chloride, palladium on carbon, palladium on alumina, palladium on hydroxyapatite, palladium on calcium carbonate, palladium on barium sulfate, palladium(II) hydroxide on carbon), platinum catalysts (e.g., platinum on carbon, platinum(IV) oxide, chloroplatinic acid, potassium chloroplatinate), rhodium catalysts (e.g., rhodium on carbon, rhodium on alumina,

bis(styrene)bis(triphenylphosphine)rhodium(0)), ruthenium catalysts (e.g., ruthenium(II) salen, dichloro(para-cymene)ruthenium(II) dimer), iridium catalysts (e.g., iridium(III) chloride, (l,5-cyclooctadiene)diiridium(I) dichloride, bis(l,5-cyclooctadiene)iridium(I) tetrafluoroborate, bis(triphenylphosphine)(l,5-cyclooctadiene)iridium(I) carbonyl chloride, bis(triphenylphosphine)(l,5-cyclooctadiene)iridium(I) tetrafluoroborate), copper catalysts (e.g., copper(I) chloride, copper(II) chloride, copper(I) bromide, copper(II) bromide, copper(I) iodide, copper(II) iodide, copper(II) acetate, copper(II) trifluoroacetate, copper(I) trifluoromethanesulfonate, copper(II) trifluoromethanesulfonate, copper(II) sulfate), iron catalysts (e.g., iron(II) sulfate, iron(II) chloride, iron(III) chloride), vanadium catalysts (e.g., dichloro(ethoxy)oxovanadium, dichloro(isopropoxy)oxovanadium), manganese catalysts (e.g., manganese(rV) oxide, manganese(III) (salen) chloride), cobalt catalysts (e.g., cobalt(II) acetate, cobalt(II) chloride, cobalt(II) salen), indium(III) chloride, silver(I) oxide, sodium tungstate, quinone catalysts (e.g., 2,3-dichloro-5,6-dicyano-l,4-benzoquinone, 1,4-benzoquinone, and tetrachloro-l,4-benzoquinone (chloranil)).

Alternative co-oxidants can include, but are not limited to, sodium nitrite, copper(II) acetate, sodium persulfate, potassium persulfate, ammonium persulfate, sodium perborate, nitrobenzenesulfonate, 2,2,6,6-tetramethylpiperidine-l-oxyl (TEMPO), pyridine-N-oxide, hydrogen peroxide, tert-butyl hydroperoxide, di-tert-butyl peroxide, benzoyl peroxide, oxygen (02), sodium hypochlorite, sodium hypobromite, tert-butyl hypochlorite, oxone, diacetoxyiodobenzene, and bis(trifluoroacetoxy)iodobenzene.

Varoius hydrogen acceptors may be employed. Non-limiting examples can include unsaturated hydrocarbons (e.g., tert-butylethylene, tert-butyl acetylene, 2-hexyne, cyclohexene, and the like), acrylate esters (e.g., methyl acrylate, ethyl acrylate, isopropyl acrylate, tert-butyl acrylate, and the like), maleate esters (e.g., dimethyl maleate, diethyl maleate, diisopropyl maleate, dibutyl maleate, and the like), fumarate esters (e.g., dimethyl fumarate, diethyl fumarate, diisopropyl fumarate, dibutyl fumarate, and the like), and quinones (e.g. chloranil, 1 ,4-benzoquinone, etc.).

Alternative additives may be employed, such as carbonate bases (e.g., potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, etc.), amine bases (e.g., triethylamine, diisopropylethylamine, etc.), phosphines (e.g., triphenylphosphine, tri(ort zotolyl)phosphine, tricyclohexylphosphine, tri-w-butylphosphine, tri-tert-butylphosphine, etc.), acids (e.g., trifluoroacetic acid, trichloroacetic acid, benzoic acid, hydrochloric acid, sulfuric acid, phosphoric acid, ara-toluenesulfonic acid, methanesulfonic acid, etc.), sodium acetate, N-hydroxyphthalimide, salen, 2,2 ‘-bipyri dine, 9,10-phenanthroline, and quinine.

The reaction can proceed at temperatures ranging from about 10 °C to about 120 °C. Various solvents can be employed, including but not limited to halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, and the like), aromatic solvents (e.g., toluene, xylenes, and the like), ethereal solvents (tetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, 1,2-dimethoxyethane, diglyme, triglyme, and the like), alcoholic solvents (e.g., methanol, ethanol, w-propanol, isopropanol, w-butanol, tert-butanol, tert-amyl alcohol, ethylene glycol, propylene glyco, and the like), ester solvents (e.g., ethyl acetate, isopropyl acetate, tert-butyl acetate, and the like), ketone solvents (e.g., acetone, 2-butanone, 4-methyl-2-pentanone, and the like), polar aprotic solvents (e.g., acetonitrile, Ν,Ν-dimethylformamide, Ν,Ν-dimethylacetamide, N-methyl-2-pyrrolidinone, pyridine, dimethyl sulfoxide, and the like), amine solvents (e.g., triethylamine, morpholine, and the like), acetic acid, and water.

Acetyl chloride (135 mL, 5 equiv.) was added slowly to methanol (750 mL) under external cooling maintaining reaction temperature below 30 °C. The resulting methanolic hydrogen chloride solution was cooled to about 20 °C, and added slowly over about 1 hour to a solution of Compound (D-a) (300 g, 1 equiv.) in methanol (750 mL) held at about 60 °C, and rinsed forward with methanol (300 mL). The reaction mixture was agitated at about 60 °C until reaction was complete (about 1 hour), and then cooled to about 5 °C. The reaction mixture was adjusted to pH 7-8 by addition of sodium methoxide (25 wt. % solution in methanol, 370 mL) over about 20 minutes while maintaining reaction temperature below about 20 °C. Phosphoric acid (85 wt. %, 26 mL, 1 equiv.) and Celite (120 g) were added to the reaction mixture, which was then adjusted to about 20 °C, filtered, and the filter cake was rinsed with methanol (1050 mL). The combined filtrate was polish filtered and treated with phosphoric acid (85 wt. %, 104 mL, 4 equiv.). The mixture was was adjusted to about 60 °C, seeded with Compound (E-a) seed crystals (1.5 g), aged at about 60 °C for 4 hours and cooled slowly to about 20 °C over about 7.5 hours. The precipitated product was filtered, washed with methanol (2 x 600 mL), and dried in a vacuum oven at about 45 °C to provide

Compound (E-a). !H NMR (400 MHz, D20) δ 7.53-6.77 (comp m, 8H), 5.24-4.80 (comp m, 3H), 4.59-4.38 (comp m, 2H), 4.15-3.90 (m, 1H), 3.65-3.38 (comp m, 5H), 3.36-3.14 (comp m, 4H), 2.75 (s, 1H), 2.87-2.66 (m, 1H), 2.29-1.60 (comp m, 6H), 1.27 (d, 3H), 0.76 (m, 6H).

Alternative reagents and reaction conditions to those disclosed above may also be employed. Various deprotection agents are well known to those skilled in the art and include those disclosed in T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis (4th edition) J. Wiley & Sons, 2007, hereby incorporated by reference in its entirety. For example, a wide range of acids may be used, including but not limited to phosphoric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 4-bromobenzenesulfonic acid, thionyl chloride,and trimethylsilyl chloride. A wide range of solvents may be employed, including but not limited to water, ethanol, acetonitrile, acetone, tetrahydrofuran, 1 ,4-dioxane, and toluene. Deprotection may proceed at temperatures ranging from about 20 °C to about 110 °C or from about 55 °C to about 65 °C.

A wide range of bases may be employed as a neutralization reagent. Non-limiting examples can include sodium phosphate dibasic, potassium phosphate dibasic, potassium bicarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, triethylamine, N, N-diisopropylethylamine, and 4-methylmorpholine. Various solvents may be used for neutralization, such as water, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, acetone, acetonitrile, 2-butanone, 4-methyl-2-pentanone, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethyl acetate, isopropyl acetate, dichloromethane, and dichloroethane.

Neutralization may proceed at temperatures ranging from about -20 °C to about 60 °C or about 5 °C to about 15 °C.

Various crystallization reagents can be employed. Non-limiting examples may be hydrochloric acid, hydrobromic acid, sulfuric acid, ethanesulfonic acid, benzenesulfonic acid, 4-bromobenzenesulfonic acid, oxalic acid, and glucuronic acid. Solvents for crystallization can include, but is not limited to, water, ethanol, 1-propanol, 2-propanol, and acetonitrile. Crystallization may proceed at temperatures ranging from about -20 °C to about 100 °C.

Free-Basing of Compound (E-a) to Prepare Compound (E)

ompound (E-a) OCH, H3CO- Compound (E)

Compound (E-a) (10.0 g, 10.1 mmol) was dissolved in water (100 g) and then dichloromethane (132 g) and 28% ammonium hydroxide (7.2 g) were added sequentially. The biphasic mixture was stirred for 45 minutes. Celite (2.2 g) was added, the mixture was filtered through a bed of additional Celite (5.1 g), and the phases were then separated. The lower organic phase was washed with water (50 g), filtered, and then concentrated by rotary evaporation to produce Compound (E). ‘H NMR (400 MHz, CD3OD) δ 8.35-7.17 (m, 8H), 5.6^1.68 (m, 3H), 4.41-3.96 (m, 2H), 3.96-3.72 (br s, 1H), 3.74-3.48 (m, 2H), 3.42 (d, 2H), 3.33 (s, 3H), 3.28 (s, 1H), 3.19-3.01 (m, 1H), 3.00-2.79 (m, 1H), 2.69-1.82 (m, 6H), 1.80-1.45 (m, 3H), 1.21-0.73 (m, 8H).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, tris-hydrochloride salts of Compound (E) may be used. Various bases may be employed, such as sodium carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide. Various solvents, such as 2-methyltetrahydrofuran and ethyl acetate, may be employed. The temperature may range from about 15 °C to about 25 °C.

Alternative Free-Basing of Compound (E-b) to Prepare Compound (E)

Compound (E-b) (15.2 g) was dissolved in water (100 g) and then dichloromethane

(132 g) and 28% ammonium hydroxide (7.4 g) were added sequentially. The biphasic mixture was stirred for about 45 minutes. Celite (2.1 g) was added, the mixture was filtered through a bed of additional Celite (5.2 g), and the phases were then separated. The lower organic phase was washed with water (50 g), filtered, and then concentrated by rotary evaporation to produce Compound (E). *H NMR (400 MHz, CD3OD) δ 7.92-6.73 (m, 8H), 5.51-4.90 (m, 2H), 4.63-4.30 (m, 3H), 4.21-3.78 (m, 1H), 3.73-3.46 (m, 5H), 3.40-3.19 (m, 4H), 3.07-2.49 (m, 3H), 2.41-1.61 (m, 6H), 1.44-1.14 (m, 2H), 1.04-0.55 (m, 7H).

Salt Conversion of Compound (E-a) to Compound (E-b)

A solution of Compound (E-a) (10.0 g, 10.1 mmol), a solution of 37% HCI (10 g) in water (20 g), and acetonitrile (30 g)was warmed to about 50 °C and agitated for about lh. The solution was cooled to about 20 °C and acetonitrile (58 g) was charged to the reactor during which time a slurry formed. The slurry was stirred for about 21 h and then additional acetonitrile (39 g) was added. The slurry was cooled to about 0 °C, held for about 60 min and the solids were then isolated by filtration, rinsed with 7% (w/w) water in acetonitrile (22 g) previously cooled to about 5 °C. The wet cake was partially deliquored to afford

Compound (E-b). *H NMR (400 MHz, D20) δ 7.92-6.73 (m, 8H), 5.51^1.90 (m, 2H),

4.63-4.30 (m, 3H), 4.21-3.78 (m, 1H), 3.73-3.46 (m, 5H), 3.40-3.19 (m, 4H), 3.07-2.49 (m, 3H), 2.41-1.61 (m, 6H), 1.44-1.14 (m, 2H), 1.04-0.55 (m, 7H).

A flask was charged sequentially with 2-chloro-4,6-bis[3-(perfluorohexyl)propyloxy]-1,3,5-triazine (“CDMT”) (2.2 giv) and methanol (8.9 g) and the slurry was cooled to about 0 °C. To the mixture was added NMM (1.3 g) over about 5 minutes, maintaining an internal temperature of less than 20 °C. The solution was stirred for about 20 minutes to produce a solution of 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride in methanol.

To a solution of Compound (E) (7.1 g) in dichloromethane (170 g) was added

Compound (Γ) (2.8 g). The solution of 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride in methanol was added over 2 minutes followed by a rinse of methanol (1.1 g). After about 2.5 h, the completed reaction solution was washed sequentially with aqueous 10% potassium bicarbonate solution (40 mL), 3% hydrochloric acid (40 mL), and aqueous 10% potassium bicarbonate solution (40 mL). The lower organic phase was washed with water (40 mL), filtered, and then concentrated by rotary evaporation to produce Compound (A). ¾ NMR (400 MHz, CD3OD) δ 8.56-6.67 (m, 13H), 5.76^1.94 (m, 4H), 4.86-4.67 (m, 1H), 4.47-3.98 (m, 1H), 3.98-2.72 (m, 15H), 2.74-1.77 (m, 7H), 1.77-1.40 (m, 2H), 1.39-0.53 (m, 8H).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, tris-phosphate salts or tris-hydrochloride salts of Compound (G) may be used as alternative starting material. The reaction may take place at a temperature range of from about 10 °C to about 20 °C. Alternative coupling agents include, but are not limited to, EDC/HOBt, HATU, HBTU, TBTU, BOP, PyClOP, PyBOP, DCC/HOBt, COMU, EDCLOxyma, T3P, and 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium tetrafluoroborate. An alternative bases that may be employed can be diisopropylethylamine. The reaction may proceed in DMF and at temperatures ranging from about -20 °C to about 30 °C.

Salt Formation and Crystallization of Compound (A)

Crystallization of Compound (A-a)

A flask was charged with Compound (A) (10 g) and ethanol (125 mL) and was then warmed to about 45 °C. Concentrated hydrochloric acid (2.3 mL) was added followed by Compound (A-a) seed crystals (5 mg). The mixture was cooled to about 20 °C over about 5 h and held for about an additional 1 1 h. The solids were isolated by filtration, washed with ethanol (2 x 20 mL), and deliquored to produce Compound (A-a). !H NMR (400 MHz, CD3OD) δ 8.94-7.22 (m, 14H), 5.78-5.1 1 (m, 5H), 4.53-4.04 (m, 1H), 3.99-3.57 (m, 10H), 3.57-3.41 (m, 2H), 2.99-2.24 (m, 5H), 2.24-1.85 (m, 3H), 1.80-1.50 (m, 2H), 1.39-0.73 (m, 8H).

Alternative Crystallization of Compound (A-b)

A reaction vessel was charged with Compound (A) (25.0 g) followed by ethanol (125 mL) and 10% H3PO4 (250 mL). The solution was seeded with Compound (A-b) (100 mg) and stirred for about 17.5 h. The solids were isolated by filtration, washed with ethanol (2 x 5 mL), deliquored, and dried in a vacuum oven to produce Compound (A-b). JH NMR (400 MHz, D20) δ 7.76-6.48 (m, 13H), 5.53^1.90 (m, 3H), 4.60-4.32 (m, 2H), 4.29-3.76 (m, 1H), 3.70-2.75 (m, 14H), 2.66-1.51 (m, 8H), 1.51-1.09 (m, 3H), 1.05-0.45 (m, 7H).

Alternative reagents and reaction conditions to those disclosed above may also be employed. For example, alternative acids may be hydrochloric acid, hydrobromic acid, L-tartaric acid. Various solvents may be employed, such as methanol, ethanol, water, and isopropanol. The reaction may proceed at temperatures ranging from about 5 °C to about 60 °C.

Free-Basing of Compound (A)

Free-Basing of Compound (A-a) to Prepare Compound (A)

A reaction vessel was charged with Compound (A-a) (18.2 g) followed by ethyl acetate (188 g) and 10% potassium bicarbonate (188 g) and the mixture was stirred for about 25 minutes. The phases were separated and the upper organic phase was then washed with water (188 mL). The resulting organic solution was concentrated, ethanol (188 g) was added, and the solution was evaporated to produce a concentrate (75 g). The resulting concentrate added into water (376 g) to produce a slurry. The solids were isolated by filtration, washed with water (38 g), de liquored and dried in a vacuum oven at about 50 °C to produce

Compound (A).

Alternative Free-Basing of Compound (A-b) to Prepare Compound (A)

om poun –

A reaction vessel was charged with Compound (A-b) (3.0 g) followed by EtOAc (15 mL) and 10% KHCO3 (15 mL) and agitation was initiated. After about 5 h, the phases were separated and the organic phase was washed with water (15 mL) and then concentrated by rotary evaporation under vacuum. The residue was taken up in EtOH (4.5 mL) and then added to water (30 mL) to produce a slurry. After about 15 min, the solids were isolated by filtration rinsing forward water (3 x 3 mL). The solids were dried at about 50 to 60 °C vacuum oven for about 15 h to produce Compound (A).

CLIP AND ITS REFERENCES

Synthetic Route—Final Steps

The final steps to velpatasvir from backbone dibromide 62 (Scheme 14) are described and claimed in a process chemistry patent application.(43) The bond disconnections are the same as described in the composition of matter patents.(44)
The phenacyl bromide of 62 is selectively alkylated with the chiral methoxylmethyl proline 63 using K2CO3 in CH2Cl2 to provide intermediate64. After aqueous workup, the solvent is switched into THF for the alkylation of the secondary bromide with the 2-methylproline-Moc-l-valine dipeptide 65 using Cs2CO3 to afford bis-ester 66.
Formation of the bis-imidazole 67 is conducted using NH4OAc in toluene/i-PrOH, conditions similar to those originally described for daclatasvir  and also used for ledipasvir  except that i-PrOH is added as cosolvent, likely for increased solubility. Dehydrogenation to the aromatic core 68 is accomplished with DDQ and HOAc in 2-MeTHF solvent.
Deprotection of the Boc group with HCl/MeOH affords the bis-amine 69 which is crystallized as a triphosphate salt.
The final amide coupling with the chiral phenylglycine carbamate fragment 70 mediated by CDMT affords velpatasvir. No yields are provided in the experimental section of the patent and characterization is limited to generalized 1H NMR data, ie, the aromatic region of velpatasvir is reported as δ 8.56–6.67 (m, 13H).(43)
 STR1
STR1
Synthetic RouteEarly Steps. Multiple routes to intermediates 62, 63, and 65 are described in the process
patent application but are not claimed.43 The route to 2-methylproline-Moc-valine fragment 65 is outlined in Scheme 15.45
str1
N-Boc (S)-pyroglutamic acid ethyl ester is ring-opened with methylmagnesium bromide to form Boc-amine 71. Deprotection with TFA and reductive amination with NaBH(OAc)3 are conducted in a one-pot reaction. Hydride transfer to the intermediate imine occurs on the face opposite to the ethoxycarbonyl group to afford cis-pyrrolidine
72, which is isolated as the tosylate salt. Amide coupling with Moc-L-valine followed by hydrolysis affords the dipeptide 65.
Three routes are described for the synthesis of fragment 63. The first route, and the only chemistry in the patent that is
described on a multikilo scale, is outlined in Scheme 16.
str1
Dimethyl N-Boc-L-glutamate is formylated at low temperature with acetic formic anhydride, which is cyclized to the enamine 73 with TFA. The patent scheme shows both Boc groups present in structure 73, so it is not clear if this is an error or if the Boc groups remain intact upon TFA treatment and whether imine formation can occur with the Boc-protected amine.
Hydrogenation of the double bond is carried out with Pd/C;then the ester is reduced to the primary alcohol 74 with
NaBH4. Deprotection of both Boc groups is followed by reprotection of the nitrogen to afford 75. After methylation, the dicyclohexylamine salt of 63 is crystallized, presumably to remove the trans-diastereomer formed during the hydrogenation. After salt break, 63 free acid is crystallized from hexane/CH2Cl2.
The second approach to 63 starts with N-Boc-cis-4-cyano-Lproline methyl ester and converts the cyano group to the
methoxymethyl group in 4−5 steps (Scheme 17).
str1
The stereochemistry appears to be maintained at both chiral centers through the sequence. Methanolysis of the cyano group to the methyl ester occurs with concomitant deprotection of the Boc group, so reprotection is necessary. The ester at the 4-position is then selectively hydrolyzed with 1.4 equiv of NaOH in THF at −1 °C to afford ester-acid 76. No yield is provided so no information is available for the selectivity of hydrolysis at the 4-position vs the more hindered 2-position, except that hydrolysis later in the sequence requires a temperature of 20 °C.
Reduction of the carboxylic acid to the primary alcohol is accomplished with borane−dimethyl sulfide followed by
hydrolysis of the methyl ester, then alkylation of the primary alcohol with MeI to afford 63, which is purified by
crystallization from i-PrOH/water. Alternatively, hydrolysis of the ester and alkylation can be carried out in a single pot reaction with 63 crystallized from toluene/heptane.
A number of routes to backbone 62 are described, but all rely on an alkylation/C−H activation sequence as outlined in
Scheme 18.
str1
An alternate bond disconnection for the synthesis of velpatasvir is described in a Chinese patent application in which left (77) and right-hand (78) fragments are more fully elaborated and then the tetracyclic backbone is constructed at a stereochemistry appears to be maintained at both chiral centers through the sequence. Methanolysis of the cyano group to the methyl ester occurs with concomitant deprotection of the Bocgroup, so reprotection is necessary. The ester at the 4-position is then selectively hydrolyzed with 1.4 equiv of NaOH in THF
at −1 °C to afford ester-acid 76. No yield is provided so no information is available for the selectivity of hydrolysis at the 4-position vs the more hindered 2-position, except that hydrolysis later in the sequence requires a temperature of 20 °C.
Reduction of the carboxylic acid to the primary alcohol is accomplished with borane−dimethyl sulfide followed by
hydrolysis of the methyl ester, then alkylation of the primary alcohol with MeI to afford 63, which is purified by
crystallization from i-PrOH/water. Alternatively, hydrolysis of the ester and alkylation can be carried out in a single pot reaction with 63 crystallized from toluene/heptane.
A number of routes to backbone 62 are described, but all rely on an alkylation/C−H activation sequence as outlined in
Scheme 18. An alternate bond disconnection for the synthesis of velpatasvir is described in a Chinese patent application in which left (77) and right-hand (78) fragments are more fully elaborated and then the tetracyclic backbone is constructed at a late stage.46 This route is more convergent than the Gilead route but overall requires a similar number of steps (Scheme19).
str1
Final Form.
A patent application describes and claims 19 crystal forms of velpatasvir, including free base (1 form), bis-HCl salt (5 forms), phosphate salt (9 forms), bis-HBr salt (1form), L-tartrate salt (2 forms), and D-tartrate salt (1 form).47
Two patent applications describe solid dispersion formulations of velpitasvir alone and as a combination with sofosbuvir,48 suggesting that velpitasvir is rendered amorphous during the formulation process. According to the patent applications,several forms of velpitasvir API are suitable for use in the solid dispersion process although a specific claim is made for a spraydried process of free base in ethanol.48
(43) Allan, K. M.; Fujimori, S.; Heumann, L. V.; Huynh, G. M.;Keaton, K. A.; Levins, C. M.; Pamulapati, G. R.; Roberts, B. J.; Sarma,K.; Teresk, M. G.; Wang, X.; Wolckenhauer, S. A. Processes for Preparing Antiviral Compounds. U.S. Patent Application 2015/0361073 A1, December 17, 2015.
(44) (a) Bacon, E. M.; Cottrell, J. J.; Katana, A. A.; Kato, D.;Krygowski, E. S.; Link, J. O.; Taylor, J.; Tran, C. V.; Martin, T. A. T.;Yang, Z.-Y.; Zipfel, S. Antiviral Compounds. U.S. Patent 8,575,135 B2,November 5, 2013. (b) Bacon, E. M.; Cottrell, J. J.; Katana, A. A.;Kato, D.; Krygowski, E. S.; Link, J. O.; Taylor, J.; Tran, C. V.; Martin, T. A. T.; Yang, Z.-Y.; Zipfel, S. Antiviral Compounds. U.S. Patent 8,921,341 B2, December 30, 2014.
(45) The process patent43 appears to contain an error in structure Va,which should not contain a Boc group.
(46) Mu, X.; Liu, N. Velpatasvir Intermediate and PreparationMethod Thereof. Chinese Patent Application CN 105294713 A,February 3, 2016.
(47) Lapina, O. V.; Shi, B.; Wang, F.; Wolckenhauer, S. A. SolidForms of an Antiviral Compound. U.S. Patent Application 2015/0361085 A1, December 17, 2015.
(48) (a) Gorman, E.; Mogalian, E.; Oliyai, R.; Stefanidis, D.; Zia, V.Solid Dispersion Formulation of an Antiviral Compound. U.S. PatentApplication 2015/0064252 A1, March 5, 2015. (b) Gorman, E.;Mogalian, E.; Oliyai, R.; Stefanidis, D.; Wiser, L.; Zia, V. CombinationFormulation of Two Antiviral Compounds.

PATENT

US 2015/0361085

https://patentscope.wipo.int/search/en/detail.jsf?docId=US153621930&redirectedID=true

Compound I Form I
      An additional stable form screen was performed using the same procedure as described above but included a crystalline intermediate (Compound II shown below) as seeds.


      Compound II can be synthesized according to the methods described in WO 2013/075029 or U.S. Provisional Application No. 62/010,813. Needle-like particles were formed in butyronitrile, propionitrile, MEK/toluene, MEK/IPE and 2-pentanone/toluene. XRPD patterns of the wet solids were mostly consistent with each other with minor shifting in the peaks. The new form is named Compound I Form I, which is believed to be isostructural channel solvates with the respective solvents. After air drying all solids afforded amorphous XRPD patterns.
      Another stable form screen was performed using carbon (Darco G-60) treated Compound I, solvents, antisolvent (diisopropyl ether (IPE)), and seeds of Compound I Form I. This screen afforded crystalline solids from additional solvents as summarized in Table 1. The XRPD patterns of all of these solvates are consistent with Form I. The solvates were observed to convert to amorphous solids after drying. The XRPD patterns of Compound I were obtained in the experimental setting as follows: 45 kV, 40 mA, Kα1=1.5406 Å, scan range 2-40°, step size 0.0167°, counting time: 15.875 s.

[TABLE-US-00002]

TABLE 1
Stable form screen of carbon treated Compound I
Solvents PLM Comments
Water Amorphous Slurry
Water/EtOH Amorphous Sticky phase coating
ACN/IPE Birefringent Slurry of needles
MeOH/IPE Solution Seeds dissolved
EtOH/IPE Solution Seeds dissolved
Acetone/IPE Birefringent Thick slurry of
needles
IPA/IPE Amorphous Sticky coating
MEK/IPE Birefringent Thick slurry of
needles
MIBK/IPE Birefringent White paste
DCM/IPE Birefringent Thick slurry of small
needles
THF/IPE Solution Seeds dissolved
2-MeTHF/IPE Amorphous slurry
EtOAc/IPE Birefringent Thick slurry of
needles
IPAc/IPE Amorphous slurry
Toluene Amorphous Sticky coating
      The crystallinity of Compound I Form I can be improved by using a butyronitrile/butyl ether (BN/BE) mixture according to the following procedure.
      The crystallization experiment was started with 40 to 75 mg Compound I in 1.1 to 3.0 mL of a BN/BE in a ratio of 7:4 (anhydrous solvents). The sample was held at RT over P2O5 for 23 days without agitation, and crystals formed in the solution. Afterwards, the liquid phase was replaced with butyl ether and the solids were obtained by centrifuge. These solids, corresponding to Compound I Form I, were used for the subsequent step as seed.
      Purified Compound I (709.8 mg) was prepared from reflux of ethanol solution with Darco G-60 and was added to a new vial via a filter. While stirring, 7 mL of anhydrous butyronitrile (BN) was added. A clear orange solution was obtained. While stirring, 4 mL of anhydrous butyl ether (BE) was added slowly. To the solution was added 7.7 mg of Compound I Form I (from previous BN:BE crystallization experiment) as seed. The solution became cloudy and the seeds did not dissolve. The sample was stirred for ˜10 minutes before the agitation was stopped. The vial was capped and placed into a jar with some P2O5 solids at room temperature. After 6 days, a thin layer of bright yellow precipitate was observed on the wall and the bottom of the vial. The liquid phase was withdrawn and 3 mL of anhydrous butyl ether was added. Solids were scraped down with a spatula from the vial. The suspension was heated to about 30° C. for over half hour period and was held for ˜1 hour before cooling to 20° C. at about 0.1° C./min (without agitation). The sample was stored in ajar with P2O5 solids for 5 days. The sample was vacuum filtered using 0.22 μm nylon filter, washed with 2×200 μL of anhydrous butyl ether, and air dried under reduced pressure for about 5 minutes.
      XRPD analysis of the sample showed good very sharp peaks as shown in FIG. 1. The XRPD analysis setting was as follows: 45 kV, 40 mA, Kα1=1.5406 Å, scan range 1-40°, step size 0.0167°, counting time: 36.83 s. The characteristic peaks of crystalline Compound I Form I include: 2.9, 3.6, 4.8, 5.2, 6.0° 2θ (FIG. 1). The XRPD pattern of Form I was successfully indexed, indicating that Form I is composed primarily of a single crystalline phase. Extremely large unit cell volume containing up to ˜60 API molecules in the unit cell was observed. The amorphous halo observed in the XRPD pattern could be a result of the size of the unit cell. Butyl ether stoichiometry could not be estimated. Two alternative indexing solutions were found: monoclinic and orthorhombic.
      DSC and TGA data confirmed that Form I is a solvated form. DSC shows a broad endotherm with onset at 109° C. and small endotherm with onset at 177° C. (FIG. 2). TGA shows 22% weight loss below 150° C. (FIG. 3).

PATENT

CN 105294713

https://www.google.com/patents/CN105294713A?cl=en

https://patentimages.storage.googleapis.com/pdfs/2601c633c50937ffb780/CN105294713A.pdf

str1

str1

Example 12

str1

Under nitrogen, was added l〇2g1 said, adding methylene burn 500 blood dissolved, 4mol / L fertilizer 1 1,4-dioxane SOOmL, football for 1 hour at room temperature, of the C (already burned: ethyl acetate 1: 1) point in the control board, the starting material spot disappeared, the reaction was stopped, the solvent was concentrated, was added (R & lt) -2- (methoxy several yl) -2-phenylacetic acid 29g, COMU60g, DMF blood 500, diisopropylethylamine 223M1,25 ° C reaction I h, ethyl acetate was added IL diluted, purified water is added IL painted twice, dried over anhydrous sulfate instrument, and concentrated, methanol was added SOOmL temperature 60 ° C dissolved, 250mL of purified water was slowly added dropwise, to precipitate a solid, the addition was completed, cooled to 50 ° C for 1 hour, cooled to room temperature, filtered, and concentrated to give Velpatasvir (GS-5816) product 90. 5g, 78. 2〇 yield / billion. H-NMR (400MHz, CDs isolated) 5 7. 94 – 7.67 (m, 4H), 7.59 of J = 9.1 Hz, 1H), 7. 52 (S, 1H), 7.48 – 7. 33 (m, 4H) , 7.11 of J = 18. 7Hz, 1H), 5.68 of J = 6.3Hz, 1H), 5.48 – 5.33 (m, 1H), 5.23 (dd, J = 24.1, 15.7Hz, 1H), 5.17 -5.03 (m, 3H), 4.22 (dd, J = 17.0, 9.6Hz, 1H), 4.16 – 4.01 (m, 1H), 3.91 (d, J = 24. 1 Hz, 1H), 3 83 -. 3. 68 (m, 1H), 3 68 -. 3. 59 (m, 3H), 3 59 -. 3. 49 (m, 3H), 3.38 (ddd, J = 15.9, 9.6, 5.7Hz, 2H), 3.28 – 3.14 (m, 5H), 3.10 (dd, J = 14.0, 8.2 Hz, 1H), 3.00 (dd, J = 17.8, 9.6Hz, 1H), 2.92 (dd, J = 14.5, 6.7 Hz, 1H), 2.73 – 2.41 (m, 2H), 2.40 – 2.11 (m, 2H), 2. 11 – 1.83 (m, 2H), 1.54 deduction J = 9. 7 Hz, 2H), 1.24 of J = 6.2Hz, 1H), 1.06 (t, J = 8.0 Hz, 1H), 0.99 of J = 6.8 Hz, 1H), 0. 94 (d, J = 6. 6Hz, 2H), 0. 85 (d, J = 6. 7Hz, 2H ).

str1

Construction

str1

str1

str1

str1

str1

str1

str1

str1

str1

str1

str1

str1

Clip and foot notes

Velpatasvir only got its name last year and was previously known as GS-5816. That compound was only announced back in 2013 when Gilead showed the initial in vitrostudies on a handful of posters. [1]  [2]  Very little information is available on this follow-up compound. The following was pretty much the summary of their poster presentation.

To understand the medical significance of this study, Sofosbuvir is the best-in-class NS5B inhibitor from Gilead (see link for more information). [3] These inhibitors work the fastest when paired with a NS5A inhibitor like Daclatasvir or Ledipasvir (making up the Sofosbuvir+Ledipasvir = Harvoni combination) or the Viekira Pak combo. Disclosure: I am an employee of Bristol-Myers Squibb which produces Daclatasvir. However, HCV comprises of 7 different genotypes. Harvoni and Viekira Pak are approved against genotypes 1a, 1b. Harvoni is indicated for genotypes 4, 5, and 6. For the treatment of genotypes 2 and 3, sofosbuvir is generally combined with ribavirin or interferon which has notable side effects. While 70% of patients have genotype 1, for the remainder of patients with the other variants, they are still stuck with the more risky (and more expensive and longer) therapy.

I think this is the structure of GS-5816. It’s not yet published in any journal.  [4]

For comparison, here is the structure of Ledipasvir, the first generation NS5A inhibitor used in Harvoni. Structurally speaking, they are pretty similar so it seems like GS-5816 is the product of good old fashioned medchem.

The clearest summary of the 4 Phase III trials can be found on Gilead’s website. [5]ASTRAL-1 was run on genotypes 1, 2, 4, 5, 6. [6]  ASTRAL-2 focused on genotype 2. ASTRAL-3 focused on genotype 3. [7]  ASTRAL-4 focused on HCV patients with Child-Pugh cirrhosis. [8] These patients previously had interferon treatment but had a poor response and are generally very sick.

I think that a few interesting things stand out. ASTRAL-1 occurred from July 2014 to December 2014 but upon a request from the FDA, ASTRAL-2 and 3 were started in September 2014-July 2015 in order to have an isolated study on genotypes 2 and 3. For a 24 week study that’s incredibly fast. As discussed elsewhere, clinical trials are often limited by the speed of patient enrollment and these studies can take years. [9] Here, they were able to find volunteers for a 1000 patient study within weeks. An interesting note about the clinical trial design, the ASTRAL-1 team knew that the historical cure rate was 85% and were able to correctly power the trial to get a statistically significant study on the first try. Also, deep sequencing was used to identify and stratify the HCV genotypes. In ASTRAL-1, 42% of the patients had NS5A resistance and 9% had NS5B resistance.

The market impact may be significant to Achillion which was a former partner of Gilead and a potential acquisition target. Achillion was working with Janssen on its own second generation NS5A inhibitor, odalasvir. This announcement may kill the market for a competing product as well as remove the acquisition hype.

How did Gilead come up with Velpatasvir? It really sounds like good solid science. Ledipasvir was developed to be a best-in-class NS5A inhibitor and it was recognized that it worked well with NS5B inhibitors. It was also understood that most of the NS5A inhibitors specific only towards certain N5SA genotypes and that there was a clear unmet need for patients with HCV genotypes 2 and 3. With the help of some computational modeling  [10]Gilead developed assays for all of the HCV genotypes to screen for a pan-genotype NS5A inhibitor to follow up to their 2014 Ledipasvir trials and leveraging their strategic advantage in the HCV market, were able to quickly ramp up 4 major clinical trials to demonstrate the clinical efficacy of their next gen drug combination.

That’s really good science. Not long ago, Gilead stated that it was planning on eradicating HCV. This compound is a part of the Gilead license with Indian generic manufacturers but it seems like MSF is contesting that decision. [11]  [12] With this drug Gilead is now another step closer towards that goal. [13]

Footnotes

[1] GS-5816, a Second-Generation HCV NS5A Inhibitor With Potent Antiviral Activity, Broad Genotypic Coverage, and a High Resistance Barrier

[2] Page on journal-of-hepatology.eu

[3] Christopher VanLang’s answer to How was Sovaldi (the drug now being marketed by Gilead), first discovered by Pharmasset?

[4] CAS # 1377049-84-7, Velpatasvir, GS 5816, Methyl [(2S)-1-[(2S,5S)-2-[9-[2-[(2S,4S)-1-[(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl]-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate

[5] Page on gilead.com

[6] Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection — NEJM

[7] Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection — NEJM

[8] Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis — NEJM

[9] Why do clinical trials for new drugs take several years? Remarkably, 72% of Americans are willing to be in them.

[10] Inhibition of hepatitis C virus NS5A by fluoro-olefin based γ-turn mimetics.

[11] Page on gilead.com

[12] MSF response to Gilead announcement on inclusion of hepatitis C drug GS-5816 in voluntary licence

[13] Gilead and Georgia to attempt Hep C eradication by Christopher VanLang on Making Drugs

09338-acsnews1-gileadcxd

SAVING LIVES
The Gilead team responsible for Harvoni: Front row, from left: John Link, Chris Yang, Rowchanak Pakdaman, Bob Scott, and Benjamin Graetz. Back row, from left: Erik Mogalian and Bruce Ross. Not pictured: Michael Sofia.
Credit: Gilead Sciences

Gilead’s Harvoni is a combination of two antiviral agents, sofosbuvir and ledipasvir. “In hepatitis C, the virus mutates so rapidly that to overcome resistance, we use a combination of drugs, and each one pulls their own weight in the process,” says John Link, who discovered ledipasvir.

Link says that the amount of interdisciplinary collaboration on the drug was unprecedented for the company. “Once ledipasvir was discovered, the process chemists were right there with us understanding the kinds of things we were doing, and medicinal chemists and process chemists worked on making material to scale for preclinical studies,” he says. “We all realized this was our moment to make a difference for patients with hepatitis C.”

Harvoni is the first once-a-day pill for treatment of chronic hepatitis C, and it has a cure rate in the U.S. of 94-99%. The drug is an alternative to injected interferon treatment, which has been associated with significant side effects.

“The high cure rates that we saw in our clinical trials are really amazing,” Link says. “Before we had these compounds, I had only hoped that we could equal something like interferon-type regimens in cure rates, without all the horrible side effects. To dramatically exceed them is important for patients.”

Harvoni patients can attest to the drug’s effectiveness. Mark Melancon, who had contracted hepatitis C 25 years ago, says that after taking Harvoni, he now has no trace of the virus in his body, and his liver is beginning to repair itself. “Four weeks into it, and the virus was gone. Not detectable,” he says. “To have this virus hanging over my head for 25 years and then it was just gone, I can’t explain the feeling. The people who worked hard on this medication, they need to know that I appreciate it.”

Print

REFERENCES

https://www.eiseverywhere.com/file_uploads/c2a2b5664a374fe807c0b95bb546321d_JordanFeld.pdf

WO2013075029A1 * Nov 16, 2012 May 23, 2013 Gilead Sciences, Inc. Condensed imidazolylimidazoles as antiviral compounds

References

1: Kanda T. Interferon-free treatment for HCV-infected patients with decompensated cirrhosis. Hepatol Int. 2016 Jun 9. [Epub ahead of print] Review. PubMed PMID: 27282879.

2: Gane EJ, Schwabe C, Hyland RH, Yang Y, Svarovskaia E, Stamm LM, Brainard DM, McHutchison JG, Stedman CA. Efficacy of the Combination of Sofosbuvir, Velpatasvir, and the NS3/4A Protease Inhibitor GS-9857 in Treatment-naïve or Previously Treated Patients with HCV Genotype 1 or 3 Infections. Gastroenterology. 2016 May 27. pii: S0016-5085(16)34513-9. doi: 10.1053/j.gastro.2016.05.021. [Epub ahead of print] PubMed PMID: 27240903.

3: Schreiber J, McNally J, Chodavarapu K, Svarovskaia E, Moreno C. Treatment of a patient with genotype 7 HCV infection with sofosbuvir and velpatasvir. Hepatology. 2016 May 14. doi: 10.1002/hep.28636. [Epub ahead of print] PubMed PMID: 27177605.

4: Feld JJ, Zeuzem S. Sofosbuvir and Velpatasvir for Patients with HCV Infection. N Engl J Med. 2016 Apr 28;374(17):1688-9. PubMed PMID: 27135095.

5: Curry MP, Charlton M. Sofosbuvir and Velpatasvir for Patients with HCV Infection. N Engl J Med. 2016 Apr 28;374(17):1688. PubMed PMID: 27135094.

6: Assy N, Barhoum M. Sofosbuvir and Velpatasvir for Patients with HCV Infection. N Engl J Med. 2016 Apr 28;374(17):1687. doi: 10.1056/NEJMc1601160#SA1. PubMed PMID: 27119243.

7: Foster GR, Mangia A, Sulkowski M. Sofosbuvir and Velpatasvir for Patients with HCV Infection. N Engl J Med. 2016 Apr 28;374(17):1687-8. doi: 10.1056/NEJMc1601160. PubMed PMID: 27119242.

8: Smolders EJ, de Kanter CT, van Hoek B, Arends JE, Drenth JP, Burger DM. Pharmacokinetics, Efficacy, and Safety of Hepatitis C Virus Drugs in Patients with Liver and/or Renal Impairment. Drug Saf. 2016 Jul;39(7):589-611. doi: 10.1007/s40264-016-0420-2. Review. PubMed PMID: 27098247.

9: Majumdar A, Kitson MT, Roberts SK. Systematic review: current concepts and challenges for the direct-acting antiviral era in hepatitis C cirrhosis. Aliment Pharmacol Ther. 2016 Jun;43(12):1276-92. doi: 10.1111/apt.13633. Epub 2016 Apr 18. Review. PubMed PMID: 27087015.

10: Kahveci AS, Tahan V. Sofosbuvir and Velpatasvir: A complete pan-genotypic treatment for HCV patients. Turk J Gastroenterol. 2016 Mar;27(2):205-6. doi: 10.5152/tjg.2016.160000. PubMed PMID: 27015627.

11: Younossi ZM, Stepanova M, Feld J, Zeuzem S, Jacobson I, Agarwal K, Hezode C, Nader F, Henry L, Hunt S. Sofosbuvir/velpatasvir improves patient-reported outcomes in HCV patients: Results from ASTRAL-1 placebo-controlled trial. J Hepatol. 2016 Jul;65(1):33-9. doi: 10.1016/j.jhep.2016.02.042. Epub 2016 Mar 5. PubMed PMID: 26956698.

12: Gentile I, Scotto R, Zappulo E, Buonomo AR, Pinchera B, Borgia G. Investigational direct-acting antivirals in hepatitis C treatment: the latest drugs in clinical development. Expert Opin Investig Drugs. 2016 May;25(5):557-72. doi: 10.1517/13543784.2016.1161023. Epub 2016 Mar 21. PubMed PMID: 26934419.

13: Asselah T, Boyer N, Saadoun D, Martinot-Peignoux M, Marcellin P. Direct-acting antivirals for the treatment of hepatitis C virus infection: optimizing current IFN-free treatment and future perspectives. Liver Int. 2016 Jan;36 Suppl 1:47-57. doi: 10.1111/liv.13027. Review. PubMed PMID: 26725897.

14: Bourlière M, Adhoute X, Ansaldi C, Oules V, Benali S, Portal I, Castellani P, Halfon P. Sofosbuvir plus ledipasvir in combination for the treatment of hepatitis C infection. Expert Rev Gastroenterol Hepatol. 2015;9(12):1483-94. doi: 10.1586/17474124.2015.1111757. Epub 2015 Nov 23. PubMed PMID: 26595560.

15: Foster GR, Afdhal N, Roberts SK, Bräu N, Gane EJ, Pianko S, Lawitz E, Thompson A, Shiffman ML, Cooper C, Towner WJ, Conway B, Ruane P, Bourlière M, Asselah T, Berg T, Zeuzem S, Rosenberg W, Agarwal K, Stedman CA, Mo H, Dvory-Sobol H, Han L, Wang J, McNally J, Osinusi A, Brainard DM, McHutchison JG, Mazzotta F, Tran TT, Gordon SC, Patel K, Reau N, Mangia A, Sulkowski M; ASTRAL-2 Investigators; ASTRAL-3 Investigators. Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection. N Engl J Med. 2015 Dec 31;373(27):2608-17. doi: 10.1056/NEJMoa1512612. Epub 2015 Nov 17. PubMed PMID: 26575258.

16: Feld JJ, Jacobson IM, Hézode C, Asselah T, Ruane PJ, Gruener N, Abergel A, Mangia A, Lai CL, Chan HL, Mazzotta F, Moreno C, Yoshida E, Shafran SD, Towner WJ, Tran TT, McNally J, Osinusi A, Svarovskaia E, Zhu Y, Brainard DM, McHutchison JG, Agarwal K, Zeuzem S; ASTRAL-1 Investigators. Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection. N Engl J Med. 2015 Dec 31;373(27):2599-607. doi: 10.1056/NEJMoa1512610. Epub 2015 Nov 16. PubMed PMID: 26571066.

17: Curry MP, O’Leary JG, Bzowej N, Muir AJ, Korenblat KM, Fenkel JM, Reddy KR, Lawitz E, Flamm SL, Schiano T, Teperman L, Fontana R, Schiff E, Fried M, Doehle B, An D, McNally J, Osinusi A, Brainard DM, McHutchison JG, Brown RS Jr, Charlton M; ASTRAL-4 Investigators. Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis. N Engl J Med. 2015 Dec 31;373(27):2618-28. doi: 10.1056/NEJMoa1512614. Epub 2015 Nov 16. PubMed PMID: 26569658.

18: Pianko S, Flamm SL, Shiffman ML, Kumar S, Strasser SI, Dore GJ, McNally J, Brainard DM, Han L, Doehle B, Mogalian E, McHutchison JG, Rabinovitz M, Towner WJ, Gane EJ, Stedman CA, Reddy KR, Roberts SK. Sofosbuvir Plus Velpatasvir Combination Therapy for Treatment-Experienced Patients With Genotype 1 or 3 Hepatitis C Virus Infection: A Randomized Trial. Ann Intern Med. 2015 Dec 1;163(11):809-17. doi: 10.7326/M15-1014. Epub 2015 Nov 10. PubMed PMID: 26551263.

19: Everson GT, Towner WJ, Davis MN, Wyles DL, Nahass RG, Thuluvath PJ, Etzkorn K, Hinestrosa F, Tong M, Rabinovitz M, McNally J, Brainard DM, Han L, Doehle B, McHutchison JG, Morgan T, Chung RT, Tran TT. Sofosbuvir With Velpatasvir in Treatment-Naive Noncirrhotic Patients With Genotype 1 to 6 Hepatitis C Virus Infection: A Randomized Trial. Ann Intern Med. 2015 Dec 1;163(11):818-26. doi: 10.7326/M15-1000. Epub 2015 Nov 10. PubMed PMID: 26551051.

20: Mogalian E, German P, Kearney BP, Yang CY, Brainard D, McNally J, Moorehead L, Mathias A. Use of Multiple Probes to Assess Transporter- and Cytochrome P450-Mediated Drug-Drug Interaction Potential of the Pangenotypic HCV NS5A Inhibitor Velpatasvir. Clin Pharmacokinet. 2016 May;55(5):605-13. doi: 10.1007/s40262-015-0334-7. PubMed PMID: 26519191.

Patent ID Date Patent Title
US2013309196 2013-11-21 ANTIVIRAL COMPOUNDS
US8575135 2013-11-05 Antiviral compounds
US2013164260 2013-06-27 ANTIVIRAL COMPOUNDS
Patent ID Date Patent Title
US2015064252 2015-03-05 SOLID DISPERSION FORMULATION OF AN ANTIVIRAL COMPOUND
US2015064253 2015-03-05 COMBINATION FORMULATION OF TWO ANTIVIRAL COMPOUNDS
US8940718 2015-01-27 Antiviral compounds
US8921341 2014-12-30 Antiviral compounds
US2014357595 2014-12-04 METHODS OF PREVENTING AND TREATING RECURRENCE OF A HEPATITIS C VIRUS INFECTION IN A SUBJECT AFTER THE SUBJECT HAS RECEIVED A LIVER TRANSPLANT
US2014343008 2014-11-20 HEPATITIS C TREATMENT
US2014316144 2014-10-23 ANTIVIRAL COMPOUNDS
US2014309432 2014-10-16 ANTIVIRAL COMPOUNDS
US2014212491 2014-07-31 COMBINATION FORMULATION OF TWO ANTIVIRAL COMPOUNDS
US2014018313 2014-01-16 ANTIVIRAL COMPOUNDS
Patent ID Date Patent Title
US2016083394 2016-03-24 ANTIVIRAL COMPOUNDS
US9221833 2015-12-29 Antiviral compounds
US2015361073 2015-12-17 PROCESSES FOR PREPARING ANTIVIRAL COMPOUNDS
US2015361085 2015-12-17 SOLID FORMS OF AN ANTIVIRAL COMPOUND
US2015361087 2015-12-17 ANTIVIRAL COMPOUNDS
US2015353529 2015-12-10 ANTIVIRAL COMPOUNDS
US2015299213 2015-10-22 ANTIVIRAL COMPOUNDS
US2015175646 2015-06-25 SOLID FORMS OF AN ANTIVIRAL COMPOUND
US2015150897 2015-06-04 METHODS OF TREATING HEPATITIS C VIRUS INFECTION IN SUBJECTS WITH CIRRHOSIS
US2015141326 2015-05-21 ANTIVIRAL COMPOUNDS
Velpatasvir
Velpatasvir structure.svg
Systematic (IUPAC) name
(2S)-2-{[hydroxy(methoxy)methylidene]amino}-1-[(2S,5S)-2-(17-{2-[(2S,4S)-1-[(2R)-2-{[hydroxy(methoxy)methylidene]amino}-2-phenylacetyl]-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-21-oxa-5,7-diazapentacyclo[11.8.0.0³,¹¹.0⁴,⁸.0¹⁴,¹⁹]henicosa-1(13),2,4(8),6,9,11,14(19),15,17-nonaen-6-yl)-5-methylpyrrolidin-1-yl]-3-methylbutan-1-one
Identifiers
CAS Number 1377049-84-7
PubChem CID 67683363
ChemSpider 34501056
UNII KCU0C7RS7Z Yes
Chemical data
Formula C49H54N8O8
Molar mass 883.02 g·mol−1

//////////////VELPATASVIR, GS-5816, GILEAD SCIENCES, Epclusa , FDA 2016, велпатасвир,فالباتاسفير  ,              维帕他韦  , велпатасвир, فالباتاسفير , 维帕他韦 , Elizabeth Bacon, Sheila Zipfel

UNII:KCU0C7RS7Z

C[C@H]1CC[C@H](N1C(=O)[C@H](C(C)C)NC(=O)OC)C2=NC3=C(N2)C=CC4=CC5=C(C=C43)OCC6=C5C=CC(=C6)C7=CN=C(N7)[C@@H]8C[C@@H](CN8C(=O)[C@@H](C9=CC=CC=C9)NC(=O)OC)COC

/////

FDA approves Adlyxin (lixisenatide) 利西拉 to treat type 2 diabetes


 

 

07/28/2016 07:53 AM EDT
The U.S. Food and Drug Administration approved Adlyxin (lixisenatide), a once-daily injection to improve glycemic control (blood sugar levels), along with diet and exercise, in adults with type 2 diabetes.

July 28, 2016

Release

The U.S. Food and Drug Administration approved Adlyxin (lixisenatide), a once-daily injection to improve glycemic control (blood sugar levels), along with diet and exercise, in adults with type 2 diabetes.

“The FDA continues to support the development of new drug therapies for diabetes management,” said Mary Thanh Hai Parks, M.D., deputy director, Office of Drug Evaluation II in the FDA’s Center for Drug Evaluation and Research. “Adlyxin will add to the available treatment options to control blood sugar levels for those with type 2.”

Type 2 diabetes affects more than 29 million people and accounts for more than 90 percent of diabetes cases diagnosed in the United States. Over time, high blood sugar levels can increase the risk for serious complications, including heart disease, blindness and nerve and kidney damage.

Adlyxin is a glucagon-like peptide-1 (GLP-1) receptor agonist, a hormone that helps normalize blood sugar levels. The drug’s safety and effectiveness were evaluated in 10 clinical trials that enrolled 5,400 patients with type 2 diabetes. In these trials, Adlyxin was evaluated both as a standalone therapy and in combination with other FDA-approved diabetic medications, including metformin, sulfonylureas, pioglitazone and basal insulin. Use of Adlyxin improved hemoglobin A1c levels (a measure of blood sugar levels) in these trials.

In addition, more than 6,000 patients with type 2 diabetes at risk for atherosclerotic cardiovascular disease were treated with either Adlyxin or a placebo in a cardiovascular outcomes trial. Use of Adlyxin did not increase the risk of cardiovascular adverse events in these patients.

Adlyxin should not be used to treat people with type 1 diabetes or patients with increased ketones in their blood or urine (diabetic ketoacidosis).

The most common side effects associated with Adlyxin are nausea, vomiting, headache, diarrhea and dizziness. Hypoglycemia in patients treated with both Adlyxin and other antidiabetic drugs such as sulfonylurea and/or basal insulin is another common side effect. In addition, severe hypersensitivity reactions, including anaphylaxis, were reported in clinical trials of Adlyxin.

The FDA is requiring the following post-marketing studies for Adlyxin:

  • Clinical studies to evaluate dosing, efficacy and safety in pediatric patients.
  • A study evaluating the immunogenicity of lixisenatide.

Adlyxin is manufactured by Sanofi-Aventis U.S. LLC, of Bridgewater, New Jersey.

END……………….

 

 

lixisenatide;Lixisenatide|Lixisenatide Acetate;Lixisenatide Acetate
CAS: 320367-13-3
MF: C215H347N61O65S
MW: 4858.53

C215 H347 N61 O65 S

L-Lysinamide, L-histidylglycyl-L-α-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-leucyl-L-seryl-L-lysyl-L-glutaminyl-L-methionyl-L-α-glutamyl-L-α-glutamyl-L-α-glutamyl-L-alanyl-L-valyl-L-arginyl-L-leucyl-L-phenylalanyl-L-isoleucyl-L-α-glutamyl-L-tryptophyl-L-leucyl-L-lysyl-L-asparaginylglycylglycyl-L-prolyl-L-seryl-L-serylglycyl-L-alanyl-L-prolyl-L-prolyl-L-seryl-L-lysyl-L-lysyl-L-lysyl-L-lysyl-L-lysyl-

L-Histidylglycyl-L-α-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-α-aspartyl-L-leucyl-L-seryl-L-lysyl-L-glutaminyl-L-methionyl-L-α-glutamyl-L-α-glutamyl-L-α-glutamyl-L-alanyl-L-valyl-L-arginyl-L-leucyl-L-phenylalanyl-L-isoleucyl-L-α-glutamyl-L-tryptophyl-L-leucyl-L-lysyl-L-asparaginylglycylglycyl-L-prolyl-L-seryl-L-serylglycyl-L-alanyl-L-prolyl-L-prolyl-L-seryl-L-lysyl-L-lysyl-L-lysyl-L-lysyl-L-lysyl-L-lysinamide

 

827033-10-3.png

Lixisenatide

Lixisenatide

 

827033-10-3; Lixisenatide [INN]; UNII-74O62BB01U; DesPro36Exendin-4(1-39)-Lys6-NH2;   DesPro36Exendin-4(1-39)-Lys6-NH2
Molecular Formula: C215H347N61O65S
Molecular Weight: 4858.49038 g/mol
IUPAC Condensed

H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-NH2

from PubChem
LINUCS

[][L-Lys-NH2]{[(1+2)][L-Lys]{[(1+2)][L-Lys]{[(1+2)][L-Lys]{[(1+2)][L-Lys]{[(1+2)][L-Lys]{[(1+2)][L-Ser]{[(1+2)][L-Pro]{[(1+2)][L-Pro]{[(1+2)][L-Ala]{[(1+2)][Gly]{[(1+2)][L-Ser]{[(1+2)][L-Ser]{[(1+2)][L-Pro]{[(1+2)][Gly]{[(1+2)][Gly]{[(1+2)][L-Asn]{[(1+2)][L-Lys]{[(1+2)][L-Leu]{[(1+2)][L-Trp]{[(1+2)][L-Glu]{[(1+2)][L-Ile]{[(1+2)][L-Phe]{[(1+2)][L-Leu]{[(1+2)][L-Arg]{[(1+2)][L-Val]{[(1+2)][L-Ala]{[(1+2)][L-Glu]{[(1+2)][L-Glu]{[(1+2)][L-Glu]{[(1+2)][L-Met]{[(1+2)][L-Gln]{[(1+2)][L-Lys]{[(1+2)][L-Ser]{[(1+2)][L-Leu]{[(1+2)][L-Asp]{[(1+2)][L-Ser]{[(1+2)][L-Thr]{[(1+2)][L-Phe]{[(1+2)][L-Thr]{[(1+2)][Gly]{[(1+2)][L-Glu]{[(1+2)][Gly]{[(1+2)][L-His]{}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}

from PubChem
Sequence

HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK

from PubChem
PLN

H-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK-[NH2]

from PubChem
HELM

PEPTIDE1{H.G.E.G.T.F.T.S.D.L.S.K.Q.M.E.E.E.A.V.R.L.F.I.E.W.L.K.N.G.G.P.S.S.G.A.P.P.S.K.K.K.K.K.K.[am]}$$$$

Sanofi (formerly sanofi-aventis, formerly Aventis), under license from Zealand Pharma, has developed and launched lixisenatide

Lixisenatide (trade name Lyxumia) is a once-daily injectable GLP-1 receptor agonist for the treatment of diabetes, discovered by Zealand Pharma A/S of Denmark and licensed and developed by Sanofi.[1] Lixisenatide was accepted for review by the US FDA on February 19, 2013, and approved by the European Commission on February 1, 2013.[2] On September 12, 2013, Sanofi delayed the approval process in the US, citing internal data from a cardiovascular risk study. The drug will likely be resubmitted for approval in 2015.

Lixisenatide is a once-daily injectable GLP-1 receptor agonist discovered by Zealand Pharma A/S of Denmark and licensed and developed by Sanofi. As of September 2010 it is in clinical trials for diabetes. Lixisenatide was accepted for review by the US FDA on February 19, 2013, and approved by the European Commission on February 1, 2013. The drug will likely be resubmitted for approval in 2015.

Mechanism of action

GLP-1 is a naturally-occurring peptide that is released within minutes of eating a meal. It is known to suppress glucagon secretion from pancreatic alpha cells and stimulate insulin secretion by pancreatic beta cells. GLP-1 receptor agonists are used as an add-on treatment for type 2 diabetes and their use is endorsed by the European Association for the Study of Diabetes, the American Diabetes Association, the American Association of Clinical Endocrinologists and the American College of Endocrinology.

Physical and chemical properties

Lixisenatixe has been described as “des-38-proline-exendin-4 (Heloderma suspectum)-(1–39)-peptidylpenta-L-lysyl-L-lysinamide”, meaning it is derived from the first 39 amino acids in the sequence of the peptide exendin-4, found in the Gila monster (Heloderma suspectum), omitting proline at position 38 and adding six lysine residues. Its complete sequence is:[3]

H–HisGlyGlu–Gly–ThrPhe–Thr–SerAspLeu–Ser–LysGlnMet–Glu–Glu–Glu–AlaValArg–Leu–Phe–Ile–Glu–Trp–Leu–Lys–Asn–Gly–Gly–Pro–Ser–Ser–Gly–Ala–Pro–Pro–Ser–Lys–Lys–Lys–Lys–Lys–Lys–NH2

PATENT

US 20110313131

http://www.google.co.in/patents/US20110313131

 

PATENT

CN 105713082

The title method comprises the steps of: (1) coupling Fmoc-Lys(Boc)-OH and resin to obtain Fmoc-Lys(Boc)-resin, (2) protecting amino acid with Fmoc, conducting solid-phase synthesis to obtain lixisenatide wholly protected 20-44-peptide resin, (3) conducting solid-phase synthesis to obtain wholly protected 15-19-peptide resin, (4) coupling the wholly protected 20-44-peptide resin and wholly protected 15-19-peptide resin, (5) coupling other amino acids till solid-phase synthesis finishes, (6) cracking lixisenatide peptide resin to obtain crude peptide, and (7) purifying through RP-HPLC.  The method improves crude peptide purity and purifn. yield.

PATENT

CN104211801A

MACHINE TRANSLATION FROM CHINESE, PL BEAR WITH SOME IREGULARITES IN GRAMMAR

利西拉, the English name: Lixisenatide, is a polypeptide containing 44 amino acids, the structural formula is as follows: peptide sequence as follows:

Figure CN104211801AD00031

H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Al a-Val-Arg-Leu-Phe-IIe-Glu -Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pr O-Ser-Lys-Lys-Lys-Lys-Lys-Lys-NH 2 Li Xila to (Lixisenatide ) by Sanofi-Aventis developed once a day subcutaneously with glucagon-like peptide -I (GLP-I) receptor agonists, for the treatment of type II diabetes, on February 1, 2013 Sanofi Lee Division -Aventis of exenatide is approved EMEA, for the adjuvant treatment of poorly stable dose of basal insulin (or metformin) in the treatment of type II diabetes to improve HbAlc and postprandial blood glucose levels.

CN201210030151. 2 used in a pure solid phase sequential coupling method synthetic peptides. The method amino resin as the carrier, using conventional coupling sequence, the final cut to give Li Xila.

 US6528486 patent for the compound, synthetic methods mentioned it to phase condensation method Fmoc / tBu strategy.

The [0005] W02005058954 synthesis method including the gradual condensation process Fmoc / tBu strategy, Boc strategy of gradual condensation methods and genetic engineering.

The  W02001004156 synthesis method for the gradual condensation process Fmoc / tBu strategy.

 Since Li Xila abroad mostly used to synthesize Fmoc solid phase synthesis method, a gradual shrinking gradually synthesis step more, resulting in more types of product impurities, US 20130284912 Special Report polypeptide impurity: Di-Ser33- Leisy pull and Di-Ala35- Li Xila come, Di-Ser 33- Li Xila come and Di-Ala35- Li Xila to atmosphere amino acid sequence as follows: Di-Ser33- Li Xila to the amino acid sequence: H-His -Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Al a-Val-Arg-Leu-Phe-IIe-Glu-Trp- Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Ser-Gly-Ala-Pr 〇-Pr〇-Ser-Lys_Lys_Lys_Lys_Lys_LyS-NH2 Di-Ala35- Li Xila to the amino acid sequence: H-His-Gly- Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Al a-Val-Arg-Leu-Phe-IIe-Glu-Trp-Leu-Lys -Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Ala-Pr 〇-Pr〇-Ser-Lys_Lys_Lys_Lys_Lys_LyS-NH2 toxicity of these impurities are impurities larger, and very difficult to separate from the main peak , the presence of the impurities seriously affect 利西拉 to content and the use of safety. Hence the need to find an effective way to remove it and to reach the high standard level of 0.1% or less. The present inventors have found that this impurity is difficult to remove by means of the prior art, although there are ways to remove part of, but removal is not ideal, it is difficult to achieve high quality standards is likely to cause 利西拉 level while reducing their yield.

In summary, the existing Li Xila to the solid phase synthesis, low yield of the synthesis, impurities, in particular, are not well controlled impurity Di-Ser 33- Li Xila come and Di-Ala35 – Li Xila to, does not apply to industrial production

Example i ^ a: Preparation 利西拉 to fine peptide acetate Weigh 利西拉 above 44. 70g to 45L crude peptide was dissolved in water, purified by C18 column, the first purification conditions: mobile phase: A phase: 0 I% TFA; B phase: acetonitrile; gradient program was: 15% B, 60 minutes to 60% B; detection wavelength 220 nm; peak fraction collection purposes. The second purification conditions: mobile phase was: A phase: 0 3% HAC; B phase: acetonitrile; gradient program was: 10% B, 60 minutes to 60% B; detection wavelength 220 nm; peak fraction collection purposes. Desalting conditions: Mobile phase: A phase: an aqueous solution of 20 mmol / L ammonium acetate: acetonitrile = 95: 5; B phase: water: acetonitrile = 95: 5; C phase: 0.03% aqueous solution of acetic acid: acetonitrile = 95 : 5; D phase: 0.03% aqueous solution of acetic acid: acetonitrile = 50: 50; gradient program: mobile phase A isocratic for 15 minutes, convert isocratic mobile phase B for 10 minutes, is converted into the flow Phase C isocratic 10 minutes, converted into a mobile phase D isocratic 25 minutes; detection wavelength 220 nm; peak fraction collection purposes; rotary evaporation concentrated and lyophilized to give Li Xila acetate fine peptide 22. 65g which HPLC spectrum shown in Figure 5, HPLC purity of 99.75% (area normalization method), Di-Ser33- Li Xila come to 0.03% (area normalization method), Di-Ala35- Li Xila to the content of 0.05% (area normalization method). Purification total yield of 51%, total yield 41%. Its mass spectrum as shown in Figure 6, [M + H] + = 4858. 691, 利西拉 precise molecular weight to the theoretical: 4857.53, the sample mass is consistent with the theoretical molecular weight.

PATENT

CN 103709243

MACHINE TRANSLATION FROM CHINESE, PL BEAR WITH SOME IREGULARITES IN GRAMMAR

Example 2: Preparation 利西拉 to crude peptide

利西拉 [0116] Example 24 was prepared to be placed 125.4g peptide resin cleavage reaction to 10ml / g resin ratio added lysis reagent (TFA: thioanisole: EDT: TIS: water = 86: 5 : 5: 3: 1 (V / V)), stirred at room temperature 2.5h. The reaction was purified by frit funnel filtration, the filtrate was collected, the resin was washed 3 times and then a small amount of TFA, the combined filtrates concentrated under reduced pressure. Frozen precipitation in anhydrous ether was added, washed three times with anhydrous diethyl ether, and dried in vacuo to give a white solid powder, i.e. Li Xila to crude peptide 47.lg, by weight of the crude peptide yield 97.2%, HPLC purity 63.8% 0

利西拉 to crude peptide preparation: 27 patients [0117] Example

利西拉 [0118] The Example 25 was prepared to be placed 123.7g peptide resin cleavage reaction to 10ml / g resin ratio added lysis reagent (TFA: thioanisole: EDT: TIS: water = 86: 5 : 5: 3: 1 (V / V)), stirred at room temperature 2.5h. The reaction was purified by frit funnel filtration, the filtrate was collected, the resin was washed 3 times and then a small amount of TFA, the combined filtrates concentrated under reduced pressure. Frozen precipitation in anhydrous ether was added, washed three times with anhydrous diethyl ether, and dried in vacuo to give a white solid powder, i.e. Li Xila to crude peptide 46.9g, yield the crude peptide by weight 96.5%, HPLC purity 64.2% 0

28 Example 2: Preparation 利西拉 to fine peptide acetate

 Example weighed 26 to 27 after 利西拉 to any 30.0g crude peptide was dissolved in 3000ml of water using Waters2545RP-HPLC system, wavelength 230nm, 50 X 250mm column of reverse phase C18 column, 0.2% TFA conventional / acetonitrile mobile phase were fractionated peaks of fractions, refined peptide purity greater than 98.5%. The fine peptide solution using Waters2545RP-HPLC system, 50 X 250mm column was C18 reverse phase column, 0.1% acetic acid / acetonitrile mobile phase transfer salt, the purpose of peak fractions were collected, concentrated by rotary evaporation and lyophilized to give Li Xila acetate fine salt peptide> 9.0g, RP-HPLC purity ≥98.5%. Purification Yield ≥30%, total yield ≥29.0%.

PATENT

CN 102875663

MACHINE TRANSLATION FROM CHINESE, PL BEAR WITH SOME IREGULARITES IN GRAMMAR

http://www.google.at/patents/CN102875663B?cl=en

Example 9

[0239] The crude peptide Li Xila to 4000g (including Li Xila to 1139g) was dissolved with purified water 100L, collected by filtration and the filtrate set aside.

[0240] purification chromatographic conditions:

[0241] HPLC Model: Novasep LC450

 Column: 450X250mm, built-phenyl silane bonded silica gel as stationary phase filler, the filler particle size of 10 μ m0

 flow rate: 5000ml / min.

The detection wavelength: 280nm.

 Mobile phase A phase: 10% 30mM D- 30mM sodium tartrate and disodium hydrogenphosphate in methanol / 90% aqueous (v / v), adjusted to pH 2.5 with phosphoric acid.

[0246] Mobile phase A phase preparation process: Weigh 1280g 2070g D- sodium tartrate and disodium hydrogenphosphate, after an appropriate amount of purified water was dissolved through 0.45 μ m membrane filter, the filtrate collected all 300L tank, added 30L chromatographically pure After methanol was added to the 300L scale purification of water, adjusted to pH 2.5 with phosphoric acid. Repeat preparation run.

[0247] The mobile phase B phase: HPLC grade acetonitrile.

Figure CN102875663BD00132

[0249] sample volume: 250.0g (6250ml).

[0250] Purification: column equilibration the sample so that after 5 minutes, run a gradient purification, monitoring and staging purposes peak fractions were collected. The collected fractions (chromatographic conditions purity testing to the same conditions as above 利西拉 determination to area normalization method measured) purity test, the purity of greater than or equal to 98% of the fractions after removing most of the acetonitrile in turn salt; purity of 70% or more less than 98% of the fraction recovered after removal of most of the acetonitrile and the purification procedure is repeated, again collected purity greater than or equal to 98% of the fraction after removal of most of the acetonitrile are also used to turn salt; purity of less than 70 % of fractions by waste disposal.

[0251] points and 16 injections, repeat the above operation.

[0252] turn salt chromatographic conditions:

[0253] HPLC Model: Novasep LC450

[0254] Column: 450 X 250mm, built-C8 reversed-phase chromatography packing, the particle size of the filler is 10 μ m.

[0255] flow rate: 5000ml / min.

[0256] The detection wavelength: 280nm.

[0257] Mobile phase A phase: 0.2% acetic acid (v / v) solution.

[0258] The mobile phase B phase: HPLC grade acetonitrile.

[0259] gradient

Figure CN102875663BD00141

[0260] sample volume: 2500ml.

[0261] Purification: The column equilibration the sample for 5 minutes, run a gradient purification, monitoring and collecting the target peak fractions. The purpose of the peak fractions were concentrated by rotary evaporation under reduced pressure to 9000ml after lyophilization.

[0262] After the freeze-dried to give a white powder refined peptide 704g. Purity of 98.39%, the impurity content of less than 0.5%. Purification yield 61.8% (in crude Li Xila to content), total yield of 17.6%.

PATENT

CN 102558338

MACHINE TRANSLATION FROM CHINESE, PL BEAR WITH SOME IREGULARITES IN GRAMMAR

Preparation of Fmoc-Lys (Boc) -Lys (Boc) -Lys (Boc) -Lys (Boc) -Rink Amide-MBHAResin:

[0096] To the resulting Fmoc-Lys (Boc) -Lys (Boc) -Lys (Boc) -RinkAmide-MBHAResin mouth of a 20% strength piperidine / DMF solution for 10 minutes, the reaction was drained, washed with DMF Resin 6 (50ml * 6). Weigh Fmoc-Lys (Boc) -〇H3.52g, H0Bt1.01g, HBTU2.84g, TMP1.98ml, DMF50ml added to dissolve slowly with stirring under ice-cooling for 3 minutes, at room temperature for 2 hours, the reaction Ninhydrin detection method completed, pumping off the reaction solution, DMF the resin was washed twice (50mlX2), DCM the resin was washed twice (50mlX2), to give Fmoc-Lys (B oc) -Lys (Boc) -Lys (Boc) -Lys (Boc) -RinkAmide-MBHAResin. As used in the above operation Fmoc-Lys (Boc) -OH: HOBt: HBTU: TMP ratio is 1: 1: 1: 2, wherein Fmoc-Lys (Boc) -OH is the number of moles of Fmoc-RinkAmide-MBHAResin number of moles 3 times.

[0097] Li Xila fully protected side chain was prepared to -Rink Amide-MBHA Resin:

[0098] To the resulting Fmoc-Lys (Boc) -Lys (Boc) -Lys (Boc) -Lys (Boc) -RinkAmide-MBHA Resin added 20% piperidine / DMF solution for 10 minutes, drained reaction solution, washed 6 times with DMF. Weigh Jie 111〇 (3-1 ^ 8 billion (3) -0 13.528, 1 (»Shu 1.018,01 (:!! 1.391111 added 50,111,101 ^ dissolve slowly stirring for 3 minutes in an ice bath, poured into the solid phase resin is mixed with the reaction column, at room temperature for 2 hours, the reaction Ninhydrin detection method is completed, the reaction solution was deprived, DMF the resin was washed twice (50ml X 2), DCM the resin was washed twice (50ml X 2), to give Fmoc-Lys ( Boc) -Lys (Boc) -Lys (Boc) -Lys (Boc) -Lys (Boc) -Rink Amide-MBHAResin above operation used by the Fmoc-Lys (Boc) -〇H:. HOBt: DIC ratio is 1: 1: L2, which Fmoc-Lys (Boc) is three times the number of moles -〇H Fmoc-Rink Amide-MBHA Resin moles of repeat after the coupling step, followed by the completion of the 39 lysine to first. connecting protected amino acids histidine, followed by addition of 20% piperidine / DMF solution for 10 minutes, the reaction was drained, DMF the resin was washed six times (50ml X 6), DCM the resin was washed six times (50ml X 6 ), MeOH contraction of the resin three times with MeOH 50ml, each contraction 5min. After the resin was dried in vacuo to give a full side-chain protected peptide resin to the Li Xila 27. 5g, weight resin 17. 5g.

[0099] Li Xila to crude peptide preparation:

[0100] Weigh side chains fully protected Li Xila to -Rink Amide-MBHA Resin 27. 5 grams, into a round bottom flask.Configuration 275 ml lysis buffer, wherein trifluoroacetic acid: thioanisole: ethanedithiol: anisole, phenol = 93: 4: 1: 1.5: 2 (volume ratio). Lysate in the refrigerator after the pre-freeze 1 hour before Sheng Youli put to Silas to -Rink Amide-MBHA Resin round bottom flask, stirred at room temperature for 2 hours. The reaction mixture was filtered, the resin was washed with 20ml TFA and the combined filtrate.

[0101] The volume of the filtrate was slowly poured into 2,750 ml of diethyl ether frozen (frozen advance ether), a white precipitate appears, at 3000 rpm / centrifuged 5 minutes, the resulting solid was washed twice with ether, then the solid was dried under vacuum to give Li Xila trifluoroacetate crude peptide to 15. 3g.

[0102] Li Xila to large scale production of fine peptide:

[0103] Sample Preparation: The crude peptide was dissolved in water, the sample was completely dissolved by membrane filtration, the filtrate was collected for use.

[0104] Purification conditions: Column: octadecyl silane bonded silica gel as stationary phase column, the column diameter and length: 300_X250mm. Mobile phase: A phase: 35mm〇l / L phosphoric acid solution adjusted with triethylamine to pH 6. 7; B phase: acetonitrile, flow rate: 2200ml / min, Gradient: B%: 12% ~32%, detection wavelength: 280nm . The injection volume was 75g. Purification process: the column with 50% acetonitrile rinse clean after balance sample, sample amount is 75g. Linear gradient 120min, the purpose of collecting peaks will be collected 利西拉 solution was concentrated by rotary evaporation under reduced pressure to about 80mg / ml and reserve the water temperature exceeds 40 ° C without conditions.

[0105] turn salt: turn salt conditions: Column: octadecyl silane bonded silica gel as stationary phase column, the column diameter and length: 300mmX250mm. Mobile phase: A phase: mass concentration of 0.2% aqueous acetic acid; B phase: HPLC grade acetonitrile, flow rate: 2200ml / min, detection wavelength: 280nm. Gradient: B%: 6% ~36%. The injection volume was 48-60g. Salt transfer process: the column with 50% acetonitrile rinse clean after the sample, the sample volume is 1600ml sample solution. Linear gradient 90min, the purpose of collecting peaks collected Li Xila to solutions were concentrated by rotary evaporation to about 80ml / g after go to the appropriate size vials, then freeze-dried to obtain the purity of greater than 99.5% The Li Xila come.

Old post

https://newdrugapprovals.org/2013/09/13/sanofi-to-withdraw-the-lixisenatide-new-drug-application-nda-in-the-u-s-the-company-plans-to-resubmit-the-nda-in-2015-after-completion-of-the-elixa-cv-study/

lixisenatide

Sanofi Provides Update on Lixisenatide New Drug Application in U.S.

Paris, France – September 12, 2013 – Sanofi (EURONEXT: SAN and NYSE: SNY) announced today its decision to withdraw the lixisenatide New Drug Application (NDA) in the U.S., which included early interim results from the ongoing ELIXA cardiovascular (CV) outcomes study. The company plans to resubmit the NDA in 2015, after completion of the ELIXA CV study.

The decision to withdraw the lixisenatide application follows discussions with the U.S. Food and Drug Administration (FDA) regarding its proposed process for the review of interim data. Sanofi believes that potential public disclosure of early interim data, even with safeguards, could potentially compromise the integrity of the ongoing ELIXA study. Sanofi’s decision is not related to safety issues or deficiencies in the NDA………………………read all at

http://www.pharmalive.com/sanofi-pulls-diabetes-drug-nda

 

EU

US20070037807 * 29 Oct 2004 15 Feb 2007 Satoru Oi Pyridine compounds as inhibitors of dipeptidyl peptidase IV
US20070191436 * 12 Sep 2006 16 Aug 2007 Valerie Niddam-Hildesheim Diastereomeric purification of rosuvastatin
EP0708179A2 * 13 Oct 1995 24 Apr 1996 Eli Lilly And Company Glucagon-like insulinotropic peptide analogs, compositions, and methods of use
Citing Patent Filing date Publication date Applicant Title
CN102584982A * 10 Feb 2012 18 Jul 2012 深圳翰宇药业股份有限公司 Method for purifying solid-phase synthetic coarse liraglutide
WO2013117135A1 * 29 Jan 2013 15 Aug 2013 Hybio Pharmaceutical Co., Ltd. Method for purifying solid-phase synthetic crude liraglutide
WO2014077802A1 * 13 Nov 2012 22 May 2014 Ipsen Pharma S.A.S. Purification method of a glp-1 analogue
WO2014118797A1 1 Jul 2013 7 Aug 2014 Neuland Health Sciences Private Limited Purification of organic compounds using surrogate stationary phases on reversed phase columns
CN1839155A 18. Aug. 2004 27. Sept. 2006 诺沃挪第克公司 Purification of glucagon-like peptides
WO2006041945A2 4. Okt. 2005 20. Apr. 2006 Novetide, Ltd. A counterion exchange process for peptides

References

  1.  Christensen, M; Knop, FK; Holst, JJ; Vilsboll, T (2009). “Lixisenatide, a novel GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus”. IDrugs : the investigational drugs journal 12 (8): 503–13. PMID 19629885.
  2.  “Sanofi New Drug Application for Lixisenatide Accepted for Review by FDA”. Drugs.com/PR Newsire. 19 February 2013.
  3.  “International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended INN: List 61” (PDF). WHO Drug Information 23 (1): 66f. 2009.
Lixisenatide
Clinical data
Trade names Lyxumia
License data
Routes of
administration
Subcutaneous injection
Legal status
Legal status
  • UK: POM (Prescription only)
Identifiers
CAS Number 827033-10-3
ATC code A10BX10 (WHO)
PubChem CID 16139342
IUPHAR/BPS 7387
ChemSpider 17295846
ChEBI CHEBI:85662
Chemical data
Formula C215H347N61O65S
Molar mass 4858.49 g/mol

///////FDA 2016, SANOFI, FDA,  approves , Adlyxin, lixisenatide, type 2 diabetes, Sanofi-Aventis U.S. LLC, Bridgewater, New Jersey, Lyxumia,  利西拉, PEPTIDE, 

CCC(C)C(C(=O)NC(CCC(=O)O)C(=O)NC(Cc1c[nH]c2c1cccc2)C(=O)NC(CC(C)C)C(=O)NC(CCCCN)C(=O)NC(CC(=O)N)C(=O)NCC(=O)NCC(=O)N3CCCC3C(=O)NC(CO)C(=O)NC(CO)C(=O)NCC(=O)NC(C)C(=O)N4CCCC4C(=O)N5CCCC5C(=O)NC(CO)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)N)NC(=O)C(Cc6ccccc6)NC(=O)C(CC(C)C)NC(=O)C(CCCNC(=N)N)NC(=O)C(C(C)C)NC(=O)C(C)NC(=O)C(CCC(=O)O)NC(=O)C(CCC(=O)O)NC(=O)C(CCC(=O)O)NC(=O)C(CCSC)NC(=O)C(CCC(=O)N)NC(=O)C(CCCCN)NC(=O)C(CO)NC(=O)C(CC(C)C)NC(=O)C(CC(=O)O)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C(Cc7ccccc7)NC(=O)C(C(C)O)NC(=O)CNC(=O)C(CCC(=O)O)NC(=O)CNC(=O)C(Cc8cnc[nH]8)N

AND

CCC(C)C(C(=O)NC(CCC(=O)O)C(=O)NC(CC1=CNC2=CC=CC=C21)C(=O)NC(CC(C)C)C(=O)NC(CCCCN)C(=O)NC(CC(=O)N)C(=O)NCC(=O)NCC(=O)N3CCCC3C(=O)NC(CO)C(=O)NC(CO)C(=O)NCC(=O)NC(C)C(=O)N4CCCC4C(=O)N5CCCC5C(=O)NC(CO)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)NC(CCCCN)C(=O)N)NC(=O)C(CC6=CC=CC=C6)NC(=O)C(CC(C)C)NC(=O)C(CCCNC(=N)N)NC(=O)C(C(C)C)NC(=O)C(C)NC(=O)C(CCC(=O)O)NC(=O)C(CCC(=O)O)NC(=O)C(CCC(=O)O)NC(=O)C(CCSC)NC(=O)C(CCC(=O)N)NC(=O)C(CCCCN)NC(=O)C(CO)NC(=O)C(CC(C)C)NC(=O)C(CC(=O)O)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C(CC7=CC=CC=C7)NC(=O)C(C(C)O)NC(=O)CNC(=O)C(CCC(=O)O)NC(=O)CNC(=O)C(CC8=CN=CN8)N

FDA approves first MRI-guided focused ultrasound device to treat essential tremor


Exablate Neuro – non-invasive, image-guided alternative for deep brain lesioning

 

 

07/11/2016 11:28 AM EDT
The U.S. Food and Drug Administration today approved the first focused ultrasound device to treat essential tremor in patients who have not responded to medication. ExAblate Neuro uses magnetic resonance (MR) images taken during the procedure to deliver focused ultrasound to destroy brain tissue in a tiny area thought to be responsible for causing tremors.

FDA approves first MRI-guided focused ultrasound device to treat essential tremor

Release

The U.S. Food and Drug Administration today approved the first focused ultrasound device to treat essential tremor in patients who have not responded to medication. ExAblate Neuro uses magnetic resonance (MR) images taken during the procedure to deliver focused ultrasound to destroy brain tissue in a tiny area thought to be responsible for causing tremors.

“Patients with essential tremor who have not seen improvement with medication now have a new treatment option that could help them to avoid more invasive surgical treatments,” said Carlos Peña, Ph.D., M.S., director of the division of neurological and physical medicine devices in the FDA’s Center for Devices and Radiological Health. “As with other treatments for essential tremor, this new device is not a cure but could help patients enjoy a better quality of life.”

Essential tremor, also called benign essential tremor, is the most common form of tremor. According to the National Institute of Neurological Disorders and Stroke, several million Americans, usually those over age 40, are affected by the condition. Essential tremor may be treated with beta blockers or anticonvulsant drugs. If medications fail to control symptoms, the condition may also be treated with surgery (thalamotomy) or a deep brain stimulation device to destroy the tiny part of the brain (thalamus) that controls some involuntary movements.

To determine if the ExAblate Neuro treatment is appropriate, patients should first have MR and computerized tomography (CT) scans. Those undergoing treatment with the MRI-guided device lie in an MRI scanner that takes images to help a doctor identify the targeted area in the brain’s thalamus for treatment. Treatment with transcranial focused ultrasound energy is administered with incremental increases in energy until patients achieve a reduction of tremor. Patients are awake and responsive during the entire treatment.

Data supporting the safety and effectiveness of the device system included a double-blind control trial involving 76 patients with essential tremor who had not responded to medication therapy. Fifty-six of the patients were randomly selected to receive the ExAblate Neuro treatment and 20 received a fake treatment. Patients in the control group were able to cross over into the treatment group three months later.

Patients treated with the ExAblate Neuro showed nearly a 50 percent improvement in their tremors and motor function (composite tremor/motor function score) three months after treatment compared to their baseline score. Patients in the control group had no improvement, and some experienced a slight worsening after the sham procedure before they crossed over into the treatment group. At 12 months post-procedure, the treatment group retained a 40 percent improvement in these scores compared to baseline.

Adverse events for the ExAblate Neuro are consistent with those reported for thalamotomy surgery, including numbness/tingling of the fingers, headache, imbalance/unsteadiness, loss of control of body movements (ataxia) or gait disturbance. Other side effects identified as possibly related to treatment with MR-guided focused ultrasound treatments include tissue damage in an area other than the treatment area, hemorrhage in the treated area requiring emergency treatment, skin burns with ulceration of the skin, skin retraction and scar formation and blood clots.

The ExAblate Neuro treatment is contraindicated for patients who cannot have MR imaging, including those who have a non-MRI compatible implanted metallic device, such as a cardiac pacemaker, those with allergies to MR contrast agents or those with body size limitations for MR.

The treatment should also not be used in women who are pregnant, patients with advanced kidney disease or on dialysis, those with unstable heart conditions or severe hypertension, patients exhibiting any behavior consistent with ethanol or substance abuse or patients with a history of abnormal bleeding, hemorrhage and/or blood clotting disorders (coagulopathy). Patients currently taking anticoagulant drugs or drugs known to increase the risk of hemorrhage, patients with a history of cerebrovascular disease (strokes) or brain tumors and patients who are not able to tolerate the prolonged stationary position during treatment also should not have the procedure.

ExAblate Neuro is manufactured by InSightec in Dallas, Texas.

http://www.insightec.com/clinical/neurosurgery/

InSightec, maker of MRI-guided interventional ultrasound systems, received clearance in Europe for its ExAblate Neuro system to treat Parkinson’s disease, .

/////fda 2016, ExAblate Neuro, InSightec , Dallas, Texas, MRI-guided focused ultrasound device,  essential tremor

FDA approves new medication for dry eye disease, Xiidra (lifitegrast ophthalmic solution)


lifitegrast

 

Xiidra (lifitegrast ophthalmic solution)

07/12/2016 08:48 AM EDT
The U.S. Food and Drug Administration approved Xiidra (lifitegrast ophthalmic solution) for the treatment of signs and symptoms of dry eye disease, on Monday, July 11, 2016. Xiidra is the first medication in a new class of drugs, called lymphocyte function-associated antigen 1 (LFA-1) agonist, approved by the FDA for dry eye disease.

FDA approves new medication for dry eye disease

July 12, 2016

Release

The U.S. Food and Drug Administration approved Xiidra (lifitegrast ophthalmic solution) for the treatment of signs and symptoms of dry eye disease, on Monday, July 11, 2016. Xiidra is the first medication in a new class of drugs, called lymphocyte function-associated antigen 1 (LFA-1) agonist, approved by the FDA for dry eye disease.

“Normal tear production is needed for clear vision and eye health,” said Edward Cox, M.D., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research. “This approval will provide a new treatment option for patients with dry eye disease.”

Dry eye disease includes a group of conditions in which the eye does not produce an adequate volume of tears or when the tears are not of the correct consistency. The chance of experiencing dry eye increases with age, affecting approximately five percent of the adult population age 30-40 and 10 to 15 percent of adults over age 65, and is more common among women. When severe and left untreated, this condition can lead to pain, ulcers or scars on the part of the eye called the cornea. Dry eye can make it more difficult to perform some activities, such as using a computer or reading for an extended period of time, and it can decrease tolerance for dry environments, such as the air inside an airplane.

The safety and efficacy of Xiidra was assessed in over a thousand patients, in four separate, randomized, controlled studies. These studies included patients 19–97 years of age, of which the majority were female (76 percent). Patients were randomized equally to receive either Xiidra eyedrops or placebo eyedrops, which were used twice a day for twelve weeks. The studies found that groups treated with Xiidra demonstrated more improvement in both the signs and the symptoms of eye dryness than the groups treated with placebo.

The most common side effects of Xiidra include eye irritation, discomfort or blurred vision and an unusual taste sensation (dysgeusia).

Dry eye disease does not routinely occur in children. Safety and efficacy in pediatric patients below the age of 17 years has not been studied.

Xiidra is manufactured by Shire US Inc., of Lexington, Massachusetts.

ref https://newdrugapprovals.org/2014/09/04/lifitegrast-sar-1118-effective-inhibitor-of-lfa-1-interactions-with-icam-1/

Common name: Lifitegrast, SAR 1118

Trademarks: Lifitegrast
Molecular Formula: C29H24Cl2N2O7S
CAS Registry Number: 1025967-78-5
Molecular Weight: 615.49
Activity: SAR 1118 is a potent novel small molecule lymphocyte function-associated antigen-1 (LFA-1/ICAM-1) antagonist for a broad range of ocular inflammatory conditions including dry eye and diabetic macular edema.
Intermediates:
Lifitegrast Synthesis: US20110092707A1
References:
1. Burnier, J. Crystalline Pharmaceutical and Methods of Preparation and Use Thereof. US20110092707A1
2. Zhong, M.; et. al. Discovery of tetrahydroisoquinoline (THIQ) derivatives as potent and orally bioavailable LFA-1/ICAM-1 antagonists. Bioorg. Med. Chem. Lett. 20 (2010) 5269-5273.
3. Zeller, J. R.; et. al. Lfa-1 inhibitor and polymorph thereof. WO2014018748A1
4. Zhong, M.; et. al. Modulators of cellular adhesion. WO2005044817A1
///////Xiidra,  Shire US Inc., Lexington, Massachusetts,  fda 2016, lifitegrast ophthalmic solution, FDA,  approves,  new medication , dry eye disease

FDA approves vaccine Vaxchora to prevent cholera for travelers


06/10/2016 04:22 PM EDT
The U.S. Food and Drug Administration today approved Vaxchora, a vaccine for the prevention of cholera caused by serogroup O1 in adults 18 through 64 years of age traveling to cholera-affected areas. Vaxchora is the only FDA-approved vaccine for the prevention of cholera.

June 10, 2016

Release

The U.S. Food and Drug Administration today approved Vaxchora, a vaccine for the prevention of cholera caused by serogroup O1 in adults 18 through 64 years of age traveling to cholera-affected areas. Vaxchora is the only FDA-approved vaccine for the prevention of cholera.

Cholera, a disease caused by Vibrio cholerae bacteria, is acquired by ingesting contaminated water or food and causes a watery diarrhea that can range from mild to extremely severe. Often the infection is mild; however, severe cholera is characterized by profuse diarrhea and vomiting, leading to dehydration. It is potentially life threatening if treatment with antibiotics and fluid replacement is not initiated promptly. According to the World Health Organization, serogroup O1 is the predominant cause of cholera globally.

“The approval of Vaxchora represents a significant addition to the cholera-prevention measures currently recommended by the Centers for Disease Control and Prevention for travelers to cholera-affected regions,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research.

While cholera is rare in the U.S., travelers to parts of the world with inadequate water and sewage treatment and poor sanitation are at risk for infection. Travelers to cholera-affected areas have relied on preventive strategies recommended by the CDC to protect themselves against cholera, including safe food and water practices and frequent hand washing.

Vaxchora is a live, weakened vaccine that is taken as a single, oral liquid dose of approximately three fluid ounces at least 10 days before travel to a cholera-affected area.

Vaxchora’s efficacy was demonstrated in a randomized, placebo-controlled human challenge study of 197 U.S. volunteers from 18 through 45 years of age. Of the 197 volunteers, 68 Vaxchora recipients and 66 placebo recipients were challenged by oral ingestion of Vibrio cholerae, the bacterium that causes cholera. Vaxchora efficacy was 90 percent among those challenged 10 days after vaccination and 80 percent among those challenged three months after vaccination.  The study included provisions for administration of antibiotics and fluid replacement in symptomatic participants. To prevent transmission of cholera into the community, the study included provisions for administration of antibiotics to participants not developing symptoms.

Two placebo-controlled studies to assess the immune system’s response to the vaccine were also conducted in the U.S. and Australia in adults 18 through 64 years of age. In the 18 through 45 year age group, 93 percent of Vaxchora recipients produced antibodies indicative of protection against cholera. In the 46 through 64 years age group, 90 percent produced antibodies indicative of protection against cholera. The effectiveness of Vaxchora has not been established in persons living in cholera-affected areas.

The safety of Vaxchora was evaluated in adults 18 through 64 years of age in four randomized, placebo-controlled, multicenter clinical trials; 3,235 study participants received Vaxchora and 562 received a placebo. The most common adverse reactions reported by Vaxchora recipients were tiredness, headache, abdominal pain, nausea/vomiting, lack of appetite and diarrhea.

The FDA granted the Vaxchora application fast track designation and priority review status. These are distinct programs intended to facilitate and expedite the development and review of medical products that address a serious or life-threatening condition. In addition, the FDA awarded the manufacturer of Vaxchora a tropical disease priority review voucher, under a provision included in the Food and Drug Administration Amendments Act of 2007. This provision aims to encourage the development of new drugs and biological products for the prevention and treatment of certain tropical diseases.

Vaxchora is manufactured by PaxVax Bermuda Ltd., located in Hamilton, Bermuda.

Company PaxVax Inc.
Description Live attenuated vaccine against Vibrio cholerae
Molecular Target
Mechanism of Action Vaccine
Therapeutic Modality Preventive vaccine: Viral vaccine
Latest Stage of Development Registration
Standard Indication Cholera
Indication Details Prevent cholera infection; Treat cholera
Regulatory Designation U.S. – Fast Track (Prevent cholera infection);
U.S. – Priority Review (Prevent cholera infection)

FDA Approves Vaxchora, PaxVax’s Single-Dose Oral Cholera Vaccine

Vaxchora™ is the only approved vaccine in the U.S. for protection against cholera

June 10, 2016 04:32 PM Eastern Daylight Time

REDWOOD CITY, Calif.—-PaxVax, today announced that it has received marketing approval from the United States (U.S.) Food and Drug Administration (FDA) for Vaxchora, a single-dose oral, live attenuated cholera vaccine indicated for use in adults 18 to 64 years of age. Vaxchora is the only vaccine available in the U.S. for protection against cholera and the only single-dose vaccine for cholera currently licensed anywhere in the world.

FDA Approves Vaxchora, PaxVax’s Single-Dose Oral Cholera Vaccine

“FDA approval of a new vaccine for a disease for which there has been no vaccine available is an extremely rare event. The approval of Vaxchora is an important milestone for PaxVax and we are proud to provide the only vaccine against cholera available in the U.S.,” said Nima Farzan, Chief Executive Officer and President of PaxVax. “We worked closely with the FDA on the development of Vaxchora and credit the agency’s priority review program for accelerating the availability of this novel vaccine. In line with our social mission, we have also begun development programs focused on bringing this vaccine to additional populations such as children and people living in countries affected by cholera.”

“As more U.S. residents travel globally, there is greater risk of exposure to diseases like cholera,” added Lisa Danzig, M.D., Vice President, Clinical Development and Medical Affairs. “Cholera is an underestimated disease that is found in many popular global travel destinations and is thought to be underreported in travelers. Preventative measures such as food and water precautions can be challenging to follow effectively and until now, U.S. travelers have not had access to a vaccine to help protect against this potentially deadly pathogen.”

Cholera is an acute intestinal diarrheal infection acquired by ingesting contaminated water and food. Annually, millions of people around the world are impacted by this extremely virulent disease1 which can cause death in less than 24 hours if left untreated2. More than 80 percent of reported U.S. cases3 are associated with travel to one of the 69 cholera-endemic countries4 in Africa, Asia and the Caribbean. A recent report from the Centers for Disease Prevention and Control suggests that the true number of cholera cases in the U.S. is at least 30 times higher than observed by national surveillance systems5. The currently recommended intervention to prevent cholera infection is the avoidance of contaminated water and food, but studies have shown that 98 percent of travelers do not comply with these precautions when travelling6.

“This important FDA decision is the culmination of years of dedicated work by many researchers,” said Myron M. Levine, MD, DTPH, the Simon and Bessie Grollman Distinguished Professor at the University of Maryland School of Medicine (UM SOM). “For travelers to the many parts of the world where cholera transmission is occurring and poses a potential risk, this vaccine helps protect them from this disease. It is a wonderful example of how public-private partnerships can develop medicines from bench to bedside.” Dr. Levine is co-inventor of the vaccine, along with James B. Kaper, PhD, Chairman of the UM SOM Department of Microbiology and Immunology. In addition, the Center for Vaccine Development at UM SOM worked closely with PaxVax during the development of Vaxchora.

The attenuated cholera vaccine strain used in Vaxchora is CVD 103-HgR, which was in-licensed from the Center for Vaccine Development at UM SOM in 2010. Vaxchora is expected to be commercially available in Q3 2016. Vaxchora will be distributed through PaxVax’s U.S. marketing and sales organization, which currently commercializes Vivotif®, an FDA-approved oral typhoid fever vaccine.

About Vaxchora (Cholera Vaccine, Live, Oral)

Vaxchora is an oral vaccine indicated for active immunization against disease caused by Vibrio cholerae serogroup O1. Vaxchora is approved for use in adults 18 through 64 years of age traveling to cholera-affected areas. The effectiveness of Vaxchora has not been established in persons living in cholera-affected areas or in persons who have pre-existing immunity due to previous exposure to V. cholerae or receipt of a cholera vaccine. Vaxchora has not been shown to protect against disease caused by V. cholerae serogroup O139 or other non-O1 serogroups.

The FDA approval of Vaxchora is based on positive results from a 10 and 90-day cholera challenge trial, as well as two safety and immunogenicity trials in healthy adults that demonstrated efficacy of more than 90 percent at 10 days and 79 percent at 3 months post vaccination7. The most common adverse reactions were tiredness, headache, abdominal pain, nausea/vomiting, lack of appetite and diarrhea. More than 3,000 participants were enrolled in the Phase 3 clinical trial program that evaluated Vaxchora at sites in Australia and the United States.

For the full Prescribing Information, please visit www.vaxchora.com.

Young man drinking contaminated water. Close-up of vibrio cholerae bacteria.
A bacterial disease causing severe diarrhoea and dehydration, usually spread in water

About PaxVax

PaxVax develops, manufactures and commercializes innovative specialty vaccines against infectious diseases for traditionally overlooked markets such as travel. PaxVax has licensed vaccines for typhoid fever (Vivotif) and cholera (Vaxchora), and vaccines at various stages of research and clinical development for adenovirus, anthrax, hepatitis A, HIV, and zika. As part of its social mission, PaxVax is also working to make its vaccines available to broader populations most affected by these diseases. PaxVax is headquartered in Redwood City, California and maintains research and development and Good Manufacturing Practice (GMP) facilities in San Diego, California and Bern, Switzerland and other operations in Bermuda and Europe. More information is available at www.PaxVax.com.

References:

1 Centers for Disease Control and Prevention. Cholera: General Information. November 2014. http://www.cdc.gov/cholera/general. Accessed June 2016.

2 World Health Organization website. Cholera Fact Sheet. July 2015. http://www.who.int/mediacentre/factsheets/fs107/en/. Accessed June 2016.

3 Loharikar A et al. Cholera in the United States, 2001-2011: a reflection of patterns of global epidemiology and travel. Epidemiol Infect. 2015;143(4):695-703. doi:10.1017/S0950268814001186.

4 Ali M et al. Updated global burden of cholera in endemic countries. PLoS Negl Trop Dis. 2015; 9: e0003832 doi: 10.1371/journal.pntd.0003832.

5 Scallan E et al. Foodborne Illness Acquired in the United States –Major Pathogens. Emerg Infect Dis. 2011. http://dx.doi.org/10.3201/eid1701.P11101.

6 Kozicki M et al. Boil it, cook it, peel it or forget it’: does this rule prevent travellers’ diarrhoea?. Int J. Epidemiol. 1985; 14(1):169-72.

7 Chen WH et al. Single-Dose Live Oral Cholera Vaccine CVD 103-HgR Protects Against Human Experimental Infection with Vibrio cholerae O1 El Tor. Clinical Infectious Diseases 2016. 62 (11) 1329-1335. doi: 10.1093/cid/ciw145.

Contacts

PaxVax Inc.
Colin Sanford, 415-870-9188
colin.sanford@W2comm.com

/////FDA.  vaccine,  Vaxchora, choleram  travelers, PaxVax Bermuda Ltd.,Hamilton, Bermuda.

FDA approves new diagnostic imaging agent FLUCICLOVINE F-18 to detect recurrent prostate cancer


FLUCICLOVINE F-18

Cyclobutanecarboxylic acid, 1-amino-3-(fluoro-18F)-, trans- [

  • Molecular FormulaC5H818FNO2
  • Average mass132.124 Da
Axumin (fluciclovine F 18)
fluciclovinum (18F)
GE-148
NMK36
trans-1-Amino-3-(18F)fluorcyclobutancarbonsäure [German] [ACD/IUPAC Name]
trans-1-Amino-3-(18F)fluorocyclobutanecarboxylic acid [ACD/IUPAC Name]
UNII-38R1Q0L1ZE
anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid
cas 222727-39-1
PMDA JAPAN 2021, 2021/3/23, Axumin
05/27/2016 11:27 AM EDT
The U.S. Food and Drug Administration today approved Axumin, a radioactive diagnostic agent for injection. Axumin is indicated for positron emission tomography (PET) imaging in men with suspected prostate cancer recurrence based on elevated prostate specific antigen (PSA) levels following prior treatment.

May 27, 2016

Release

The U.S. Food and Drug Administration today approved Axumin, a radioactive diagnostic agent for injection. Axumin is indicated for positron emission tomography (PET) imaging in men with suspected prostate cancer recurrence based on elevated prostate specific antigen (PSA) levels following prior treatment.

Prostate cancer is the second leading cause of death from cancer in U.S. men. In patients with suspected cancer recurrence after primary treatment, accurate staging is an important objective in improving management and outcomes.

“Imaging tests are not able to determine the location of the recurrent prostate cancer when the PSA is at very low levels,” said Libero Marzella, M.D., Ph.D., director of the Division of Medical Imaging Products in the FDA’s Center for Drug Evaluation and Research. “Axumin is shown to provide another accurate imaging approach for these patients.”

Two studies evaluated the safety and efficacy of Axumin for imaging prostate cancer in patients with recurrent disease. The first compared 105 Axumin scans in men with suspected recurrence of prostate cancer to the histopathology (the study of tissue changes caused by disease) obtained by prostate biopsy and by biopsies of suspicious imaged lesions. Radiologists onsite read the scans initially; subsequently, three independent radiologists read the same scans in a blinded study.

The second study evaluated the agreement between 96 Axumin and C11 choline (an approved PET scan imaging test) scans in patients with median PSA values of 1.44 ng/mL. Radiologists on-site read the scans, and the same three independent radiologists who read the scans in the first study read the Axumin scans in this second blinded study. The results of the independent scan readings were generally consistent with one another, and confirmed the results of the onsite scan readings. Both studies supported the safety and efficacy of Axumin for imaging prostate cancer in men with elevated PSA levels following prior treatment.

Axumin is a radioactive drug and should be handled with appropriate safety measures to minimize radiation exposure to patients and healthcare providers during administration. Image interpretation errors can occur with Axumin PET imaging. A negative image does not rule out the presence of recurrent prostate cancer and a positive image does not confirm the presence of recurrent prostate cancer. Clinical correlation, which may include histopathological evaluation of the suspected recurrence site, is recommended.

The most commonly reported adverse reactions in patients are injection site pain, redness, and a metallic taste in the mouth.

Axumin is marketed by Blue Earth Diagnostics, Ltd., Oxford, United Kingdom

Patent

http://www.google.com/patents/WO2014023775A1?cl=en

The non-natural amino acid [ F]-l-amino-3-fluorocyclobutane-l-carboxylic acid

([18F]-FACBC, also known as [18F]-Fluciclovine) is taken up specifically by amino acid transporters and has shown promise for tumour imaging with positron emission tomography (PET).

A known synthesis of [18F]-FACBC begins with the provision of the protected precursor compound 1 -(N-(t-butoxycarbonyl)amino)-3 –

[((trifluoromethyl)sulfonyl)oxy]-cyclobutane-l-carboxylic acid ethyl ester. This precursor compound is first labelled with [18F]-fluoride:

II before removal of the two protecting groups:

IT III

EP2017258 (Al) teaches removal of the ethyl protecting group by trapping the [18F]- labelled precursor compound (II) onto a solid phase extraction (SPE) cartridge and incubating with 0.8 mL of a 4 mol/L solution of sodium hydroxide (NaOH). After 3 minutes incubation the NaOH solution was collected in a vial and a further 0.8 mL 4 mol/L NaOH added to the SPE cartridge to repeat the procedure. Thereafter the SPE cartridge was washed with 3 mL water and the wash solution combined with the collected NaOH solution. Then 2.2 mL of 6 mol/L HCl was then added with heating to 60°C for 5 minutes to remove the Boc protecting group. The resulting solution was purified by passing through (i) an ion retardation column to remove Na+ from excess NaOH and Cl~ from extra HCl needed to neutralise excess of NaOH to get a highly acidic solution before the acidic hydrolysis step, (ii) an alumina column, and (iii) a reverse-phase column. There is scope for the deprotection step(s) and/or the

purification step in the production of [18F]-FACBC to be simplified.

Example 1: Synthesis of f FIFACBC

No-carrier- added [18F]fluoride was produced via the 180(p,n)18F nuclear reaction on a GE PETtrace 6 cyclotron (Norwegian Cyclotron Centre, Oslo). Irradiations were performed using a dual-beam, 30μΑ current on two equal Ag targets with HAVAR foils using 16.5 MeV protons. Each target contained 1.6 ml of > 96% [180]water (Marshall Isotopes). Subsequent to irradiation and delivery to a hotcell, each target was washed with 1.6 ml of [160]water (Merck, water for GR analysis), giving approximately 2-5 Gbq in 3.2 ml of [160]water. All radiochemistry was performed on a commercially available GE FASTlab™ with single-use cassettes. Each cassette is built around a one-piece-moulded manifold with 25 three-way stopcocks, all made of polypropylene. Briefly, the cassette includes a 5 ml reactor (cyclic olefin copolymer), one 1 ml syringe and two 5 ml syringes, spikes for connection with five prefilled vials, one water bag (100 ml) as well as various SPE cartridges and filters. Fluid paths are controlled with nitrogen purging, vacuum and the three syringes. The fully automated system is designed for single-step fluorinations with cyclotron-produced [18F]fluoride. The FASTlab was programmed by the software package in a step-by-step time-dependent sequence of events such as moving the syringes, nitrogen purging, vacuum, and temperature regulation. Synthesis of

[18F]FACBC followed the three general steps: (a) [18F]fluorination, (b) hydrolysis of protection groups and (c) SPE purification.

Vial A contained K222 (58.8 mg, 156 μπιοΐ), K2C03 (8.1 mg, 60.8 μπιοΐ) in 79.5% (v/v)

MeCN(aq) (1105 μΐ). Vial B contained 4M HC1 (2.0 ml). Vial C contained MeCN

(4.1ml). Vial D contained the precursor (48.4 mg, 123.5 μιηοΐ) in its dry form (stored at -20 °C until cassette assembly). Vial E contained 2 M NaOH (4.1 ml). The 30 ml product collection glass vial was filled with 200 mM trisodium citrate (10 ml). Aqueous

[18F]fluoride (1-1.5 ml, 100-200 Mbq) was passed through the QMA and into the 180-

H20 recovery vial. The QMA was then flushed with MeCN and sent to waste. The trapped [18F]fluoride was eluted into the reactor using eluent from vial A (730 μΐ) and then concentrated to dryness by azeotropic distillation with acetonitrile (80 μΐ, vial C). Approximately 1.7 ml of MeCN was mixed with precursor in vial D from which 1.0 ml of the dissolved precursor (corresponds to 28.5 mg, 72.7 mmol precursor) was added to the reactor and heated for 3 min at 85°C. The reaction mixture was diluted with water and sent through the tC18 cartridge. Reactor was washed with water and sent through the tC18 cartridge. The labelled intermediate, fixed on the tC18 cartridge was washed with water, and then incubated with 2M NaOH (2.0 ml) for 5 min after which the 2M NaOH was sent to waste. The labelled intermediate (without the ester group) was then eluted off the tC18 cartridge into the reactor using water. The BOC group was hydrolysed by adding 4M HC1 (1.4 ml) and heating the reactor for 5 min at 60 °C. The reactor content with the crude [18F]FACBC was sent through the HLB and Alumina cartridges and into the 30 ml product vial. The HLB and Alumina cartridges were washed with water (9.1 ml total) and collected in the product vial. Finally, 2M NaOH (0.9 ml) and water (2.1 ml) was added to the product vial, giving a purified formulation of [18F]FACBC with a total volume of 26 ml. Radiochemical purity was measured by radio-TLC using a mixture of MeCN:MeOH:H20:CH3COOH (20:5:5: 1) as the mobile phase. The radiochemical yield (RCY) was expressed as the amount of radioactivity in the [18F]FACBC fraction divided by the total used [18F]fluoride activity (decay corrected). Total synthesis time was 43 min.

The RCY of [18F]FACBC was 62.5% ± 1.93 (SD), n=4.

/////FDA,  diagnostic imaging agent,  recurrent prostate cancer, fda 2016, Axumin, marketed, Blue Earth Diagnostics, Ltd., Oxford, United Kingdom, fluciclovine F 18

C1[C@@](C[C@H]1[18F])(N)C(=O)O

UPDATE

FLUCICLOVINE

Image result for FLUCICLOVINE

LINK https://newdrugapprovals.org/2016/05/28/fda-approves-new-diagnostic-imaging-agent-fluciclovine-f-18-to-detect-recurrent-prostate-cancer/

SEE EMA

Axumin : EPAR – Summary for the public EN = English 06/07/2017

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004197/human_med_002100.jsp&mid=WC0b01ac058001d124

Marketing-authorisation holder Blue Earth Diagnostics Ltd
Revision 0
Date of issue of marketing authorisation valid throughout the European Union 22/05/2017

Contact address:

Blue Earth Diagnostics Ltd
215 Euston Road
London NW1 2BE
United Kingdom

Manufacture, characterisation and process controls

The active substance fluciclovine (18F) is prepared from the precursor AH113487 by nucleophilic substitution
of a triflate group by 18F-fluoride, followed by two deprotection steps. Due to the short half-life of the 18Ffluorine
radioisotope, each batch is prepared on the day of clinical use.
The active substance is prepared in a proprietary automated synthesiser unit. The synthesiser module is
computer-controlled. A fluid path for synthesis is provided in the form of a single use cassette (FASTlab). The
cassette contains 3 reagent vials and 3 solid phase cartridges. Two other reagent vials are supplied
separately as they have a recommended storage temperature of 2-8°C. These 2 vials are inserted into the
cassette on the day of production.
Assessment report
EMA/237809/2017 Page 13/90
Fluciclovine (18F) is produced in a continuous operation from the precursor AH113487. Due to the radioactive
nature of the process, and the short half-life of [18F] fluorine, intermediates are not isolated and there is no
opportunity for operator intervention or in-process testing. Control of the synthesis of fluciclovine (18F) from
the precursor is achieved through the automated synthesis platform, which is pre-programmed with
synthesis parameters optimised for the process. On-board detectors record transfers of radioactivity through
the fluid path at critical points and monitor temperature and pressure as appropriate so that the operator
may track the progress of the synthesis.
The active substance fluciclovine (18F) progressses immediately to purification, formulation and dispensing as
the finished product within a single, continuous operation. Validation of the manufacturing process for
fluciclovine (18F) is therefore described as part of finished product validation.
The characterisation of the active substance is in accordance with the EU guideline on chemistry of new
active substances.
As mentioned, the manufacture of the active substance and finished product takes place in a single,
continuous process. The active substance is not isolated at any point. Therefore, relevant information about
impurities is given only for the finished product.
For the same reason, information for the container closure system is provided only for the finished product.http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004197/WC500230836.pdf

FDA issues rule for data collection of antimicrobial sales and distribution by animal species


05/10/2016 09:28 AM EDT
Additional data help further target efforts to ensure judicious use of medically important antimicrobials
The U.S. Food and Drug Administration (FDA) finalized a rule today that revises its annual reporting requirements for drug sponsors of all antimicrobials sold or distributed for use in animals intended for human consumption or food-producing animals. Companies are now required to provide estimates of sales broken down by major food-producing species (cattle, swine, chickens and turkeys) in addition to the overall estimates they already submit on the amount of antimicrobial drugs they sell or distribute for use in food-producing animals.

May 10, 2016

Release

The U.S. Food and Drug Administration finalized a rule today that revises its annual reporting requirements for drug sponsors of all antimicrobials sold or distributed for use in animals intended for human consumption or food-producing animals. Companies are now required to provide estimates of sales broken down by major food-producing species (cattle, swine, chickens and turkeys) in addition to the overall estimates they already submit on the amount of antimicrobial drugs they sell or distribute for use in food-producing animals.

The new sales data will improve the agency’s understanding of how antimicrobials are sold and distributed for use in major food-producing species and help further target efforts to ensure judicious use of medically important antimicrobials.

Section 105 of the Animal Drug User Fee Amendments of 2008 (ADUFA 105) requires antimicrobial drug sponsors to annually report to the FDA the amount of all antimicrobial drugs they sell and distribute for use in food-producing animals, including those antibiotics that are not used in human medicine. ADUFA 105 also requires the FDA to prepare summary reports of sales and distribution information received from drug sponsors each year, by antimicrobial class for classes with three or more distinct sponsors, and to provide those summaries to the public. Prior to finalizing this rule, animal drug sponsors were not required to submit sales or distribution data by particular species.

Adding the requirement for sponsors to report species-specific sales estimates will also complement the data collection plan the FDA is developing, as part of the National Strategy for Combating Antibiotic-Resistant Bacteria (CARB), with the U.S. Department of Agriculture and the Centers for Disease Control and Prevention, to obtain additional on-farm use and resistance data. The collection of data from multiple sources, including enhanced sales data from antimicrobial animal drug sponsors, is important for providing a comprehensive and science-based picture of antimicrobial drug use and resistance in animal agriculture.

“This information will further enhance FDA’s ongoing activities related to slowing the development of antimicrobial resistance to help ensure that safe and effective antimicrobial new animal drugs will remain available for use in human and animal medicine,” said Dr. William T. Flynn, D.V.M., M.S., deputy director for science policy in the FDA’s Center for Veterinary Medicine.

The final rule also includes a provision to improve the timeliness of annual reports by requiring the FDA to publish its summary report of the antimicrobial sales and distribution information it collects for each calendar year by Dec. 31 of the following year.

The rule was proposed in May 2015, and takes into consideration hundreds of public comments from the veterinary community, animal feed manufacturing and livestock production associations, drug manufacturers, consumer groups and other stakeholders. Drug sponsors are required to comply with the reporting requirements in the final rule when submitting their reports covering the period of calendar year 2016.

///////FDA ,  data collection, antimicrobial sales, distribution, animal species

Albutrepenonacog alfa


1YNSGKLEEFV QGNLERECME EKCSFEEARE VFENTERTTE FWKQYVDGDQ
51CESNPCLNGG SCKDDINSYE CWCPFGFEGK NCELDVTCNI KNGRCEQFCK
101NSADNKVVCS CTEGYRLAEN QKSCEPAVPF PCGRVSVSQT SKLTRAETVF
151PDVDYVNSTE AETILDNITQ STQSFNDFTR VVGGEDAKPG QFPWQVVLNG
201KVDAFCGGSI VNEKWIVTAA HCVETGVKIT VVAGEHNIEE TEHTEQKRNV
251IRIIPHHNYN AAINKYNHDI ALLELDEPLV LNSYVTPICI ADKEYTNIFL
301KFGSGYVSGW GRVFHKGRSA LVLQYLRVPL VDRATCLRST KFTIYNNMFC
351AGFHEGGRDS CQGDSGGPHV TEVEGTSFLT GIISWGEECA MKGKYGIYTK
401VSRYVNWIKE KTKLTPVSQT SKLTRAETVF PDVDAHKSEV AHRFKDLGEE
451NFKALVLIAF AQYLQQCPFE DHVKLVNEVT EFAKTCVADE SAENCDKSLH
501TLFGDKLCTV ATLRETYGEM ADCCAKQEPE RNECFLQHKD DNPNLPRLVR
551PEVDVMCTAF HDNEETFLKK YLYEIARRHP YFYAPELLFF AKRYKAAFTE
601CCQAADKAAC LLPKLDELRD EGKASSAKQR LKCASLQKFG ERAFKAWAVA
651RLSQRFPKAE FAEVSKLVTD LTKVHTECCH GDLLECADDR ADLAKYICEN
701QDSISSKLKE CCEKPLLEKS HCIAEVENDE MPADLPSLAA DFVESKDVCK
751NYAEAKDVFL GMFLYEYARR HPDYSVVLLL RLAKTYETTL EKCCAAADPH
801ECYAKVFDEF KPLVEEPQNL IKQNCELFEQ LGEYKFQNAL LVRYTKKVPQ
851VSTPTLVEVS RNLGKVGSKC CKHPEAKRMP CAEDYLSVVL NQLCVLHEKT
901PVSDRVTKCC TESLVNRRPC FSALEVDETY VPKEFNAETF TFHADICTLS
951EKERQIKKQT ALVELVKHKP KATKEQLKAV MDDFAAFVEK CCKADDKETC
1001FAEEGKKLVA ASQAALGL

Albutrepenonacog alfa

recombinant factor IX

(Idelvion®)Approved, 2016-03-04 USFDA

A recombinant albumin-human coagulation factor IX (FIX) fusion protein indicated for the treatment and prevention of bleeding in patients with hemophilia B.

Research Code CSL-654

CAS 1357448-54-4
Blood- coagulation factor IX (synthetic human) fusion protein with peptide (synthetic linker) fusion protein with serum albumin (synthetic human)
Type Recombinant coagulation factor
Source Human
Molecular Formula C5077H7846N1367O1588S67
Molecular Weight ~125000

Other Names

  • Albutrepenonacog alfa

Protein Sequence

Sequence Length: 1018modified (modifications unspecified)

  • Originator CSL Behring
  • Class Albumins; Antihaemorrhagics; Blood coagulation factors; Recombinant fusion proteins
  • Mechanism of Action Blood coagulation factor replacements; Factor X stimulants
  • Orphan Drug Status Yes – Haemophilia B
  • Marketed Haemophilia B

Most Recent Events

  • 21 Mar 2016 Launched for Haemophilia B (In adolescents, In children, In adults) in USA (IV) – First global launch
  • 07 Mar 2016 Preregistration for Haemophilia B in Australia (IV) before March 2016
  • 04 Mar 2016 Registered for Haemophilia B (In children, In adolescents, In adults) in USA (IV)
Company CSL Ltd.
Description Fusion protein linking recombinant coagulation Factor IX with recombinant albumin
Molecular Target Factor IX
Mechanism of Action
Therapeutic Modality Biologic: Fusion protein
Latest Stage of Development Approved
Standard Indication Hemophilia
Indication Details Treat and prevent bleeding episodes in hemophilia B patients; Treat hemophilia B
Regulatory Designation U.S. – Orphan Drug (Treat and prevent bleeding episodes in hemophilia B patients);
EU – Orphan Drug (Treat and prevent bleeding episodes in hemophilia B patients);
Switzerland – Orphan Drug (Treat and prevent bleeding episodes in hemophilia B patients)
  • BNF Category:
    Antifibrinolytic drugs and haemostatics (02.11)
    Pharmacology: Albutrepenonacog alfa is a recombinant factor IX (rIX-FP) albumin fusion protein, designed to exhibit an extended half-life. Factor IX has a short half-life which necessitates multiple injections.
    Epidemiology: Haemophilia B is a genetic disorder caused by missing or defective factor IX, a clotting protein. It has a prevalence of around 1 in 50,000 live births in the UK and is more common in males. In 2012-13, there were 476 hospital admissions in England due to haemophilia B, accounting for 508 finished consultant episodes and 125 bed days.
    Indication: Haemophilia B

Albutrepenonacog alfa was approved by the U.S. Food and Drug Administration (FDA) on March 4, 2016. It was developed and marketed as Idelvion® by CSL Behring.

Albutrepenonacog alfa is a recombinant albumin-human coagulation factor IX (FIX) fusion protein, which replaces the missing FIX needed for effective hemostasis. It is indicated for the treatment and prevention of bleeding in children and adults with hemophilia B.

Idelvion® is available as injection (lyophilized powder) for intravenous use, containing 250 IU, 500 IU, 1000 IU or 2000 IU of albutrepenonacog alfa in single-use vials. In control and prevention of bleeding episodes and perioperative management, the required dosage is determined using the following formulas: Required Dose (IU) = Body Weight (kg) x Desired Factor IX rise (% of normal or IU/dL) x (reciprocal of recovery (IU/kg per IU/dL)). In routine prophylaxis, the recommended dose is 25-40 IU/kg (for patients ≥12 years of age) or 40-55 IU/kg (for patients <12 years of age) every 7 days.

EMA

On 25 February 2016, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product IDELVION, intended for treatment and prophylaxis of bleeding in patients with Haemophilia B. IDELVION was designated as an orphan medicinal producton 04 February 2010. The applicant for this medicinal product is CSL Behring GmbH.

IDELVION will be available as 250 IU, 500 IU, 1000 IU and 2000 IU Powder and solvent for solution for injection. The active substance of IDELVION is albutrepenonacog alfa, an antihaemorrhagic, blood coagulation factor IX, (ATC code: B02BD04). It works as replacement therapy and temporarily increases plasma levels of factor IX, helping to prevent and control bleeding.

The benefits with IDELVION are its ability to stop the bleeding when given on demand and prevent bleeding when used as routine prophylaxis or for surgical procedures. The most common side effects are injection site reaction and headache.

The full indication is: “the treatment and prophylaxis of bleeding in patients with Haemophilia B (congenital factor IX deficiency)”. Idelvion can be used in all age groups. It is proposed that IDELVION be prescribed by physicians experienced in the treatment of haemophilia B.

Detailed recommendations for the use of this product will be described in the summary of product characteristics (SmPC), which will be published in the European public assessment report (EPAR) and made available in all official European Union languages after the marketing authorisation has been granted by the European Commission.

Name Idelvion
INN or common name albutrepenonacog alfa
Therapeutic area Hemophilia B
Active substance albutrepenonacog alfa
Date opinion adopted 25/02/2016
Company name CSL Behring GmbH
Status Positive
Application type Initial authorisation

//////Albutrepenonacog alfa, CSL-654,  Idelvion; Recombinant factor IX – CSL Behring,  Recombinant factor IX fusion protein linked with human albumin,  rFIX-FP – CSL Behring; rIX-FP, Orphan Drug Status,  Haemophilia B, recombinant factor IX , FDA 2016

update

Human medicines European public assessment report (EPAR): Idelvion, albutrepenonacog alfa, Hemophilia B, 11/05/2016, Orphan, 9, Authorised
%d bloggers like this: