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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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

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Talazoparib, MDV3800


Talazoparib.svg

Talazoparib, BMN-673, MDV-3800

(2S,3S)-methyl-7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate

(8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one

(8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one

CAS 1207456-01-6
Chemical Formula: C19H14F2N6O
Exact Mass: 380.11972

BMN673, BMN673, BMN-673, LT673, LT 673, LT-673,  Talazoparib

BioMarin Pharmaceutical Inc

phase 3

Poly ADP ribose polymerase 2 inhibitor; Poly ADP ribose polymerase 1 inhibitor

cancer

(85,9R)-5-fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one toluenesulfonate salt

CAS 1373431-65-2(Talazoparib Tosylate)

1H NMR DMSOD6

str1

13C NMR DMSOD6

str1

HMBC NMR

str1

HSQC NMR

str1

Talazoparib (BMN-673) is an investigational drug that acts as a PARP inhibitor. It is in clinical trials for various cancers.

Talazoparib.png

Medivation, under license from BioMarin Pharmaceuticals, following its acquisition of LEAD Therapeutics, is developing a PARP-1/2 inhibitor, talazoparib, for treating cancer, particularly BRCA-mutated breast cancer. In February 2016, talazoparib was reported to be in phase 3 clinical development

Talazoparib, also known as BMN-673, is an orally bioavailable inhibitor of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) with potential antineoplastic activity (PARP1 IC50 = 0.57 nmol/L). BMN-673 selectively binds to PARP and prevents PARP-mediated DNA repair of single strand DNA breaks via the base-excision repair pathway. This enhances the accumulation of DNA strand breaks, promotes genomic instability and eventually leads to apoptosis. PARP catalyzes post-translational ADP-ribosylation of nuclear proteins that signal and recruit other proteins to repair damaged DNA and is activated by single-strand DNA breaks. BMN-673 has been proven to be highly active in mouse models of human cancer and also appears to be more selectively cytotoxic with a longer half-life and better bioavailability as compared to other compounds in development. Check for active clinical trials or closed clinical trials using this agent.

Talazoparib is C19H14F2N6O.

Talazoparib tosylate is C26H22F2N6O4S.[1]

Approvals and indications

None yet.

Mechanism of action

Main article: PARP inhibitor

Clinical trials

After trials for advanced hematological malignancies and for advanced or recurrent solid tumors.[2] it is now in phase 3 for metastatic germline BRCA mutated breast cancer.[3] Trial estimated to complete in June 2016.[4]

As of January 2016 it in 14 active clinical trials.[5]

WO2010017055,  WO2015069851, WO 2012054698, WO 2011130661, WO 2013028495, US 2014323725, WO 2011097602

PAPER

Discovery and Characterization of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a Novel, Highly Potent, and Orally Efficacious Poly(ADP-ribose) Polymerase-1/2 Inhibitor, as an Anticancer Agent

BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, California 94949, United States
J. Med. Chem.201659 (1), pp 335–357
DOI: 10.1021/acs.jmedchem.5b01498
Publication Date (Web): December 10, 2015
Copyright © 2015 American Chemical Society
*Phone: 1-415-506-3319. E-mail: bwang@bmrn.com.

Abstract

Abstract Image

We discovered and developed a novel series of tetrahydropyridophthlazinones as poly(ADP-ribose) polymerase (PARP) 1 and 2 inhibitors. Lead optimization led to the identification of (8S,9R)-47 (talazoparib; BMN 673; (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one). The novel stereospecific dual chiral-center-embedded structure of this compound has enabled extensive and unique binding interactions with PARP1/2 proteins. (8S,9R)-47 demonstrates excellent potency, inhibiting PARP1 and PARP2 enzyme activity with Ki = 1.2 and 0.87 nM, respectively. It inhibits PARP-mediated PARylation in a whole-cell assay with an EC50 of 2.51 nM and prevents proliferation of cancer cells carrying mutant BRCA1/2, with EC50 = 0.3 nM (MX-1) and 5 nM (Capan-1), respectively. (8S,9R)-47 is orally available, displaying favorable pharmacokinetic (PK) properties and remarkable antitumor efficacy in the BRCA1 mutant MX-1 breast cancer xenograft model following oral administration as a single-agent or in combination with chemotherapy agents such as temozolomide and cisplatin. (8S,9R)-47 has completed phase 1 clinical trial and is currently being studied in phase 2 and 3 clinical trials for the treatment of locally advanced and/or metastatic breast cancer with germline BRCA1/2 deleterious mutations.

http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.5b01498

http://pubs.acs.org/doi/suppl/10.1021/acs.jmedchem.5b01498/suppl_file/jm5b01498_si_001.pdf

Preparation of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one Tosylate Salt ((8S,9R)-47 Tosylate Salt)

A suspension of (8S,9R)-47 (BMN 673) (400 mg, 1.05 mmol) in a mixture of acetone (27 mL) and THF (13 mL) was heated to reflux until the suspension became clear. TsOH (220 mg, 1.16 mmol) was then added to the solution. White solids started to precipitate out from the solution shortly after the addition of TsOH. After stirring at 25 °C for 30 min, the mixture was filtered to collect the white crystal solids, which were washed with a mixture of acetone (10 mL) and 1,4-dioxane (4 mL) and then dried under vacuum at 45 °C for 3 days. This afforded the product as a white crystalline solid (540 mg, yield 93%). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 2.29 (s, 3H), 3.67 (s, 3H), 4.97–5.06 (m, 2H), 6.91–6.94 (dd, J1 = 2.0 Hz, J2 = 10.8 Hz, 1H), 7.06–7.19 (m, 5H), 7.19–7.51 (m, 4H), 7.74 (s, 1H), 7.87 (s, 1H), 10.32 (brs, 1H), 12.36 (s, 1H). LC-MS (ESI)m/z: 381 (M + H)+. Anal. Calcd for C19H14F2N6O·toluene sulfonic acid: C, 56.52; H, 4.01; N, 15.21. Found: C, 56.49; H, 3.94; N, 15.39.

(8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (8S,9R)-47 or BMN 673 and (8R,9S)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one (8R,9S)-47

Compound 47 was dissolved in DMF, and chiral resolution was performed using supercritical-fluid chromatography (SFC) with a CHIRALPAK IA chiral column and methanol (20% with 0.1% DEA) and CO2 (80%) as the eluents. Yield 90%. For (8S,9R)-47 (BMN 673): retention time 8.8 min and ee 99.3%. For (8R,9S)-47: retention time 10.2 min and ee 99.2%.
Alternatively, compound (8S,9R)-47 could also be made using (2S,3R)-60a as a starting material and employing the same procedure described for the conversion of 60a to 47.
The optical rotation for both (8S,9R)-47 and (8R,9S)-47 was measured using a RUDOLPH (AUTOPOL V) automatic polarimeter at a concentration of 6.67 mg/mL in MeOH/MeCN/DMF = 0.5:0.5:1 at 20 °C. The specific rotation for (8S,9R)-47 was +92.2°, whereas it was −93.4° for (8R,9S)-47.

PATENT

WO-2016019125

WO2016019125

The compound (85,9R)-5-fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one toluenesulfonate salt (Compound (A))

Compound (A)

is an inhibitor of poly(ADP-ribose)polymerase (PARP). Methods of making it are described in WO2010017055, WO2011097602, and WO2012054698. However, the disclosed synthetic routes require chiral chromatography of one of the synthetic intermediates in the route to make Compound (A), methyl 7-fluoro-2-(4-fluorophenyl)-3-(l -methyl- lH-1, 2,4-triazol-5-yl)-4-oxo- 1 ,2,3,4-tetrahydroquinoline-5-carboxylate (Intermediate (A)),

Intermediate (A)

to yield the chirally pure (2S,35)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(l-methyl-lH- 1,2,4-triazol-5-yl)-4-oxo-l,2,3,4-tetrahydroquinoline-5-carboxylate (Compound (1))

Compound (1).

Using conventional chiral chromatography is often solvent and time intensive.

Use of more efficient chromatography methods, such as simulated moving bed (SMB) chromatography still requires the use of expensive chiral chromatography resins, and is not practical on a large scale to purify pharmaceutical compounds. Also, maintaining

Compound (1) in solution for an extended time period during chromatography can lead to epimerization at the 9-position and cleavage of the methyl ester group in Compound (1). Replacing the chromatography step with crystallization step(s) to purify Compound (1) is desirable and overcomes these issues. Therefore, it is desirable to find an alternative to the use of chiral chromatography separations to obtain enantiomeric Compound (1).

Scheme 1 below describes use of Ac49 as a coformer acid for the preparation of Compound (la) and for the chiral resolution of Compound (1).

Scheme 1

Compound (1 )

Example 2 – Preparation of Compound (1) Using Scheme 1

Step la

Intermediate (A) (5 g, 12.5 mmol) was dissolved in 9: 1 v/v MIBK/ethanol (70 mL, 14 vol.) at 50 °C with stirring and dissolution was observed in less than about 5 minutes. [(lS)-en<io]-(+)-3-bromo-10-camphor sulfonic acid monohydrate (4.1 g, 12.5 mmol) was added and dissolution was observed in about 10-20 minutes. Seeding was then performed with Compound (la) (95% e.e., 5 mg, 0.1% w.) and the system was allowed to equilibrate for about 1 hour at 50 °C, was cooled to about 20 °C at 0.15 °C/min, and then equilibrated at 20 °C for 2 hours. The solid phase was isolated by filtration, washed with ethanol, and dried at about 50 °C and 3 mbar for about 2 to 3 hours to yield Compound (la) as a 0.6 molar equiv. EtOH solvate and 0.6 molar equiv. hydrate (93.4% e.e.).

Step lb

Compound (la) was then suspended in MIBK/ethanol 95/5% by volume (38 mL, 10 vol.) at 50 °C with stirring. After about 2 hours at 50 °C, the suspension was cooled to about 5 °C for 10 to 15 hours. The solid phase was recovered by filtration and dried at about 50 °C and 3 mbar for about 3 hours. Compound (la) (97.4% e.e.) was recovered. Step 2

000138] Compound (1) was released by suspending Compound (la) (3.9 g, 5.5 mmoi), without performing the optional reslurrying in Step 1, in 20 mL of water at room temperature and treating with 5M sodium hydroxide in water (1.3 mL, 1.2 mol). The mixture was kept at room temperature for about 15 hours and the solid was isolated by filtration and dried at 50 °C and 3 mbar for about 3 hours. Compound (1) was recovered (94.4% e.e.).

Example 3 – Large Scale Preparation of Compound (1) Using Scheme 1

The procedure of Example 1 was followed using 3.3 kg of Intermediate (A) and the respective solvent ratios to provide 95.7% e.e. in Step la; 99.2% e.e. in Step lb; and 99.2% e.e. in Step 2.

Example 4 – Alternative Preparation of Compound (1) Using Scheme 1

Step la

Intermediate (A) (751 mg, 1.86 mmol)) was dissolved in 9: 1 v/v

MIBK/ethanol (7.5 mL, 10 vol.) at 50 °C with stirring. [(15)-eni o]-(+)-3-bromo-10-camphor sulfonic acid monohydrate (620 mg, 1.88 mmol, 1 equiv.) was added. Formation of a precipitate was observed at about 1 hour at 50 °C. The system was then cooled to about 5 °C at 0.1 °C/min, and then equilibrated at 5 °C for about 60 hours. The solid phase was isolated by filtration and dried at about 50 °C and 3 mbar for about 2 hours to yield

Compound (la)(92% e.e.). See Figures 1-4 for XRPD (Figure 1), chiral HPLC (Figure 2), Ή NMR (Figure 3), and TGA/DSC analyses (Figure 4). The XRPD pattern from the material in Example 3 is similar to that in Example 1 with some slight shifts in the positions of specific diffraction peaks (highlighted by black arrows in Figure l). The ‘H NIVIR was consistent with a mono-salt of Compound (la) containing 0.5 molar equivalent of EtOH and 0.6% by weight residual MIBK. The TGA analysis showed a stepwise mass loss of 3.5% between 25 and 90 °C (potentially representing loss of the 0.5 molar equivalent of EtOH) and a gradual mass loss of 1.2% between 90 and 160 °C (potentially representing the loss of adsorbed water). The DSC analysis had a broad endotherm between 25 and 90 °C

representing desolvation and an endotherm at 135 °C representing melt/degradation.

Step lb

Compound (la) (100.3 mg, 0.141 mmol) was re-suspended in 95:5 v/v MIBK EtOH (1 mL, 10 vol.) at 50 °C and stirred for 1 hour before cooling to 5 °C at

0.1 °C/min. The solid (99.4% e.e.) was recovered by filtration after 1 night at 5 °C. Shifts in the XRPD diffraction peaks were no longer detected (Figure 5; compare Figure 1). Figure 6 shows the chiral HPLC for Compound (la).

Step 2

Compound (la) (100.2 mg, 0.141 mmol) from Step la was suspended in water (2 mL, 20 vol.) at 50 °C and 5 M NaOH in water (34 μL·, 1.2 molar equiv) was added. The resulting suspension was kept at 50 °C for one night, cooled to room temperature

(uncontrolled cooling) and filtered to yield Compound (1) (92% e.e.). The chiral purity was not impacted by this step and no [(15)-enJo]-(+)-3-bromo-10-camphor sulfonic acid was detected by NMR. Figure 7 compares the XRPD of Compound (1) in Step 2 with

Intermediate (A), the starting material of Step 1. Figure 8 shows the NMR of Compound (1) in Step 2 with Intermediate (A), the starting material of Step 1.

Example 5 – Alternative Preparation of Compound (1) Using Scheme 1 Step la

000144] Intermediate (A) (1 equiv.) was added with stirring to a solution of MIBK (12-13 vol), ethanol (1-1.5 vol), and water (0.05-0.10 vol) and the reaction was heated within 15 minutes to an internal temperature of about 48 °C to about 52 °C . [(lS)-endo]-(+)-3-bromo- 10-camphor sulfonic acid (1 equiv) was added and the reaction was stirred for about 5-10 mins at an internal temperature of about 48 °C to about 52 °C until dissolution occurred. Seed crystals of Compound (la) were added and the reaction was allowed to proceed for 1 hour at an internal temperature of about 48 °C to about 52 °C. The reaction was cooled at a rate of 0.15 °C /min to about 19-21 °C. The suspension was stirred for 2 hours at an internal temperature of about 19 °C to 21 °C and then was collected by filtration and washed twice with ethanol. The product was characterized by 1H NMR and 13C NMR (Figures 13a and 13b), IR Spectrum (Figure 14), DSC (Figure 15), and chiral HPLC (Figure 16).

Step 2a

To Compound (la) (1 equiv.) was added acetone (1.1 vol), IPA (0.55 vol), and methanol (0.55 vol) and the reaction was heated to an internal temperature of about 38 °C to 42 °C. Aqueous ammonia (25%) (1.3 equiv) was added and the reaction was stirred for about 10 minutes. The pH of the reaction was confirmed and the next step performed if > 7. Water was added (0.55 vol), the reaction was cooled to an internal temperature of about 35 °C, seed crystals of Compound (1) were added, and the reaction was stirred for about 10 mins. Water was added (3.3 vol) dropwise within about 30 minutes, the suspension was cooled within 30 minutes to an internal temperature of about 0 °C to 5 °C, and the reaction was stirred for 15 minutes. The solid was collected by filtration and washed three times with water.

Step 2b

To the product of Step 2a) was added acetone (4 vol), ΓΡΑ (1 vol), and methanol (1 vol) and the reaction was heated to an internal temperature of about 38 °C to 42 °C resulting in a clear solution. Water (2 vol) and seed crystals of Compound (1) were added and the system was stirred for about 15 minutes at an internal temperature of about 35 °C. Water (342 mL) was added dropwise in about 30 minutes. The suspension was then cooled in 30 min to an internal temperature of about 0 °C to 5 °C and was stirred for an additional 15 minutes. The solid was collected by filtration, washed twice with water, and chiral purity was determined. If > 99% e.e., then the solid was dried at an internal temperature of about 60 °C under reduced pressure to yield Compound (1). The product was characterized by Ή NMR (Figure 19), 13C NMR (Figure 20), IR (Figure 21), DSC (Figure 22), chiral HPLC (Figure 23).

Scheme 2 below describes use of Acl 10 as a coformer acid for the preparation of Compound (lb) and the chiral resolution of Compound (1).

Intermediate (A)

Compound (1 b)

Intermediate (A)

Compound (1 b)

Compound (1 )

Example 6 – Preparation of Compound (1) Using Scheme 2

Step la

Intermediate (A) (102 mg, 0.256 mmol) was dissolved in MIBK (1 mL, 10 vol.) at 65 °C with stirring. (lS)-phenylethanesulfonic acid, prepared using procedures known to one of skill in the art, in MIBK (3.8 M, 80 μί, 1 molar equiv.) was added and a suspension was observed after 30 minutes at 65 °C. The system was kept at 65 °C for another 30 minutes before cooling to 5 °C at 0.1 C/min. After one night at 5 °C, the solid was filtered, dried at 50 °C, 3 mbar pressure for about 2 hours to yield Compound (lb). See Figures 9-12 for XRPD (Figure 9), chiral HPLC (Figure 10), Ή NMR (Figure 11), and TGA/DSC analyses (Figures 12a and 12b). The XRPD diffraction pattern of the solid obtained in Example 5 differed from the XRPD pattern obtained with the solid from in the salt screen of Example 1 and was consistent with the production of different solids in Examples 1 and 5. The Ή NMR was consistent with the mono-salt with a 0.3% by weight residue of dioxane. In Figure 12a, the thermal behavior was consistent with a non-solvated form exhibiting a melt/degradation at 201 °C. Figure 12b compares the melt pattern of Compound (lb) in Example 5 with Compound (lb) in Example 1.

Steps lb and 2 can be carried out using procedures similar to those used in Examples 2-5.

Example 7 – Polymorphism of Compound (la)

Compound (1) (92% e.e., 10 mg, mmol) was placed in 1.5 mL vials and the solvents (1 mL or less) of Table 3 were added at 50 °C until dissolution was achieved. [(1S)-eni o]-(+)-3-bromo-10-camphorsulfonic acid was added as a solid at 50 °C. The samples were kept at 50 °C for about 1 hour prior to being cooled to room temperature overnight

(uncontrolled cooling rate). Clear solutions were successively cooled to 4 °C, -20 °C and evaporated at room temperature. Any gum obtained after evaporation was re-suspended in diethyl ether. The solid phases generated were characterized by XRPD and if relevant, by Ή NMR and TGA/DSC.

Table 3. Compound (la) Polymorphism Conditions

C.S. means clear solution and Susp. means suspension. “A” means the XRPD diffraction pattern was new but similar to that for Ac49 in

Example 1. “B” means the XRPD diffraction pattern was the same as that for Ac49 in Example 1. “M.E.” means molar equiv.

Page 38 of 64

NAI- 1500460480V I

Each of the seven solvents in which solvates were observed (heterosolvates not included) were mixed with MIBK (90% vol). Solutions of Intermediate (A) were prepared in the solvent mixtures (10 vol) at 50 C and [(15)-en<io]-(+)-3-bromo-10-camphor sulfonic acid (1 molar equivalent) was added. The resulting clear solutions were cooled to 5 °C at 0.2 C/min. Surprisingly, no crystallization was reported in any sample. Seeding was performed with a few crystals of each solvate at about 25 °C. The solid phases were analyzed by XRPD and the liquid phases were analyzed by chiral HPLC. See Table 4 for a summary of the results (where “Dias 2” is the (2R, 3R) diastereomer of Compound (la)) .

Table 4. Compound (la) Solvate Analysis

As seen in Table 4 above, the ethanol/MIBK system yielded 93% pure Compound (la) which demonstrates that Compound (la) does crystallize in a very pure form as an ethanolate solvate.

Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following description. It should be understood, however, that the description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the present description will become apparent from this detailed description.

All publications including patents, patent applications and published patent applications cited herein are hereby incorporated by reference for all purposes.

PATENT

US 2011196153

http://www.google.co.ve/patents/US20110237581

STR1.jpg

Patent

US 2011237581

PATENTSTR1.jpg

PATENT

http://www.google.com/patents/WO2015069851A1?cl=en

SYNTHETIC EXAMPLES

Example 1

\ , 

(1 a) (2) (3) (la) (5)

To a flask was added N-methyl-l,2,4-triazole (la)(249.3 g, 3.0 mol, 1 equiv.),

2-methyl-THF (1020 mL, about 1 :4 m/v), and DMF (2)(230.2 g, 3.15 mol, 1.05 equiv.), in any order. The solution was cooled to an internal temperature of about -5 to 0 °C. To the flask was added LiHMDS (3) as a 20% solution in 2-methyl-THF (3012 g, 3.6 mol, 1.2 equiv.) dropwise within about 60 minutes. During the addition of the LiHMDS (3), the desired Compound (la) was precipitated as the 2-methyl-THF solvate, and the flask was cooled to about -30 °C. The reaction was stirred for about 30 minutes at an internal temperature of about -5 to 0 °C.

The precipitated crystals were removed from the reaction mixture by filtration and washed with 2-methyl-THF. The product, Compound (la) as the 2-methyl-THF solvate, was dried under vacuum at an internal temperature of about 60 °C (about 72.5% as measured by NMR) to yield Compound (la).

Example 2

As shown in Example 2, the Compounds of Formula I are useful in the synthesis of more complex compounds. See General Scheme 1 for a description of how the first step can be accomplished. Compounds of Formula I can be reacted with compound (6) to yield Compounds of Formula II. In Example 2, Compound (la) can be reacted with

Compound (6) to yield Compound (7). The remaining steps are accomplished using procedures known to one of ordinary skill in the art, for example, as disclosed in

WO2010017055 and WO2011097602 to yield Compound (12).

PATENT

US 2014323725/http://www.google.com/patents/WO2011097602A1

5-fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5-yl)-8,9- dihydro-2H-pyrido[4,3,2-Je]phthalazin-3(7H)-one, as shown in formula (1), and its enantiomer compounds, as shown in formulas (la) and (lb):

Figure imgf000003_0001

Example 1

(Z)-6-Fluoro-3-(( 1 -methyl- IH- 1 ,2,4-triazol-5 -yl)methylene)-4-nitroisobenzofuran- 1 (3H)-one (3)

Figure imgf000013_0001

[0053] To a 80 L jacketed glass reactor equipped with a chiller, mechanical stirrer, thermocouple, and nitrogen inlet/outlet, at 15 – 25 °C, anhydrous 2-methyl-tetrahydrofuran (22.7 kg), 6-fluoro-4- nitroisobenzofuran-l(3H)-one (2) (2.4 kg, 12.2 mol, 1.00 eq.), and 2-methyl-2H-l,2,4-triazole-3- carbaldehyde (49.6 – 52.6 % concentration in dichloromethane by GC, 3.59 – 3.38 kg, 16.0 mol, 1.31 eq.) were charged consecutively. Triethylamine (1.50 kg, 14.8 mol, 1.21 eq.) was then charged into the above reaction mixture. The reaction mixture was stirred for another 10 minutes. Acetic anhydride (9.09 – 9.10 kg, 89.0 – 89.1 mol, 7.30 eq.) was charged into the above reaction mixture at room temperature for 20 – 30 minutes. The reaction mixture was heated from ambient to reflux temperatures (85 – 95 °C) for 80 – 90 minutes, and the mixture was refluxed for another 70 – 90 minutes. The reaction mixture was monitored by HPLC, indicating compound (2) was reduced to < 5 %. The resulting slurry was cooled down to 5 – 15 °C for 150 – 250 minutes. The slurry was aged at 5 – 15 °C for another 80 – 90 minutes. The slurry was filtered, and the wet cake was washed with ethyl acetate (2L x 3). The wet cake was dried under vacuum at 40 – 50 °C for 8 hours to give 2.65 – 2.76 kg of (Z)-6-fluoro-3-((l -methyl-lH-l ,2,4-triazol-3- yl)methylene)-4-nitroisobenzofuran-l(3H)-one (3) as a yellow solid (2.66 kg, yield: 75.3 %, purity: 98.6 – 98.8 % by HPLC). LC-MS (ESI) m/z: 291 (M+l)+. Ή-ΝΜΡ (400 MHz, DMSO-d6) δ (ppm): 3.94 (s, 3H), 7.15 (s, 1H), 8.10 (s, 1H), 8.40-8.42 (dd, Jx = 6.4 Hz, J2 = 2.4 Hz, 1H), 8.58-8.61 (dd, Jx = 8.8 Hz, J2 = 2.4 Hz, 1H).

Example 2

Methyl 5- enzoate (4)

Figure imgf000014_0001

Example 2A

[0054] (¾-6-Fluoro-3-((l-methyl-lH-l,2,4-taazol-3-yl)m (3) (177 g, 0.6 mol, 1.0 eq.), and HC1 (2 N in methanol, 3 L, 6 mol, 10 eq.) were charged into a 5 L 3-neck flask equipped with mechanical stirrer, thermometer, and nitrogen inlet/outlet. The reaction mixture was stirred at room temperature for 25 hours. The reaction mixture was monitored by HPLC, indicating 0.8 % compound (3) remained. The reaction mixture was concentrated under vacuum at 40 °C to dryness, and methyl 5-fluoro-2-(2-(l -methyl- lH-l,2,4-triazole-3-yl)acetyl)-3-nitrobenzoate hydrochloride (4) was obtained as a yellow solid (201 g, yield: 93.4 %). It was used for the next step without further purification. LC-MS (ESI) m/z: 323 (M+l)+ ¾-NMR (400 MHz, DMSO-J6) δ (ppm): 3.89 (s, 3H), 3.92 (s, 3H), 4.60 (s, 2H), 7.85 (s, 1H), 8.25-8.28 (dd, Jx = 8.4 Hz, J2 = 2.8 Hz, 2H), 8.52-8.54 (dd, Jx = 8.4 Hz, J2 = 2.8 Hz, 2H).

Example 2B

An alternative workup procedure to that illustrated in Example 2A follows. Instead of evaporating the reaction mixture to dryness, it was condensed to 2 volumes, followed by solvent exchange with 12 volumes of THF, and then 12 volumes of heptane. The slurry mixture was concentrated to 2 volumes and filtered to give the product. As such, 1.8 kilograms of (Z)-6-fluoro-3-((l-methyl-lH-l,2,4-triazol-3- yl)methylene)-4-nitroisobenzofuran-l(3H)-one (3) gave 2.15 kilograms (yield 96.4 %) of the product methyl 5-fluoro-2-(2-(l -methyl- lH-l,2,4-triazole-3-yl)acetyl)-3-nitrobenzoate hydrochloride (4).

Example 3

Methyl 7-fluoro-2-(4-fluorophenyl)-3-(l-methyl-lH-l,2,4-triazol-5-yl)-4-oxo-l,2,3,4- tetrahydroquinoline-5 -carboxylate (5)

Figure imgf000015_0001

Example 3A

To a suspension of methyl 5-fluoro-2-(2-(l-methyl-lH-l,2,4-triazol-5-yl)acetyl)-3-nitrobenzoate (4) (5 g, 15.5 mmol, leq.) and 4-fluorobenzaldehyde (3.6 g, 29 mmol, 1.87 eq.) in a mixture of solvents tetrahydrofuran (30 mL) and MeOH (5 mL) was added titanium(III) chloride (20 % w/w solution in 2N Hydrochloric acid) (80 mL, 6 eq.) dropwise with stirring at room temperature. The reaction mixture was allowed to stir at 30~50°C for 2 hours. The mixture was then diluted with water (160 mL), and the resulting solution was extracted with ethyl acetate (100 mL x 4). The combined organic layers were washed with saturated NaHC03 (50 mL x 3) and aqueous NaHS03 (100 mL x 3), dried by Na2S04, and concentrated to dryness. This afforded a crude solid, which was washed with petroleum ether (120 mL) to obtain the title compound as a yellow solid (5.9 g, yield: 95 %, purity: 97 %). LC-MS (ESI) m/z: 399 (M+l)+. ^-NMR (400 MHz, CDCla) δ (ppm): 3.58 (s, 3H), 3.87 (s, 3H), 4.16-4.19 (d, J2=13.2 Hz, 1H), 4.88 (s, 1H), 5.37-5.40 (d, J2=13.2 Hz, 1H), 6.47-6.53 (m, 2H) , 6.97-7.01 (m, 2H), 7.37-7.41 (m, 2H), 7.80 (s, 1H).

Example 3B

An alternative workup procedure to that illustrated in Example 3A follows. After the completion of the reaction, the mixture was extracted with isopropyl acetate (20 volumes x 4) without water dilution. The product was isolated by solvent exchange of isopropyl acetate with heptanes followed by re-slurry with MTBE and filtration. As such, 3 kilograms of methyl 5-fluoro-2-(2-(l-methyl-lH-l,2,4-triazol-5- yl)acetyl)-3-nitrobenzoate (4) afforded 2.822 kilograms of the title compound (5) (yield 81 %).

Example 3C

To a stirred solution of methyl 5-fluoro-2-(2-(l-methyl-lH-l,2,4-triazol-5-yl)acetyl)-3- nitrobenzoate (4) (580 mg, 2 mmol) and 4-fluorobenzaldehyde (488 mg, 4 mmol) in methanol (0.75 mL) and tetrahydrofuran (4.5 mL) was added concentrated HC1 solution (w/w 37 %, 6 mL), then reductive powdered Fe (672 mg, 12 mmol) was added slowly to the reaction system. After the addition was complete, the resulting mixture was heated to 60 °C and kept at this temperature for 3 hours. After the disappearance of the starting material (4) as monitored by LC-MS, the reaction mixture was partitioned between ethyl acetate (30 mL) and water (30 mL) and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried with Na2S04, concentrated in vacuo and purified by column chromatography (ethyl acetate: petroleum ether = 1 : 1) to give the title compound (5) as a pale yellow solid (300 mg, yield 40 %). LC-MS (ESI) m/z: 399 (M+l)+LH-NMR (400 MHz, CDC13) δ (ppm): 3.58 (s, 3H), 3.87 (s, 3H), 4.17 (d, 1H), 4.87 (s, 1H), 5.38 (d, 1H), 6.50 (dd, 2H), 6.99 (dd, 2H), 7.38 (dd, 2H), 7.80 (s, 1H).

Example 3D

To a stirred solution of methyl 5-fluoro-2-(2-(l-methyl-lH-l,2,4-triazol-5-yl)acetyl)-3- nitrobenzoate (4) (580 mg, 2 mmol) and 4-fluorobenzaldehyde (488 mg, 4 mmol) in methanol (0.75 mL) and tetrahydrofuran (4.5 mL) was added SnCl2 (2.28 g, 12 mmol) and concentrated HC1 (w/w 37 %, 6 mL), the resulting mixture was reacted at 45 °C for 3 hours, until LC-MS indicating the disappearance of the starting material (4) and about 50 % formation of the product. The mixture was then partitioned between ethyl acetate (30 mL) and water (30 mL) and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried with Na2S04, concentrated in vacuo and purified by column chromatography (ethyl acetate: petroleum ether = 1 : 1) to give the title compound (5) as a pale yellow solid (10 mg, yield 1.3 %). LC-MS (ESI) m/z: 399 (M+l)+LH-NMR (400 MHz, CDC13) δ (ppm): 3.58 (s, 3H), 3.87 (s, 3H), 4.17 (d, 1H), 4.87 (s, 1H), 5.38 (d, 1H), 6.50 (dd, 2H), 6.99 (dd, 2H), 7.38 (dd, 2H), 7.80 (s, 1H).

Example 3E

A solution of methyl 5-fluoro-2-(2-(l-methyl-lH-l,2,4-triazol-5-yl)acetyl)-3-nitrobenzoate (4) (580 mg, 2 mmol) and 4-fluorobenzaldehyde (488 mg, 4 mmol) in methanol (20 mL) and acetic acid (1 mL) was stirred at room temperature for 24 hours under hydrogen (1 barr) in the presence of a catalytic amount of 10 % Pd/C (212 mg, 0.2 mmol). After the reaction was complete, the catalyst was removed by filtration through a pad of Celite, the solvent was removed in vacuo, and the residue was purified by column chromatography (ethyl acetate: petroleum ether = 1 : 1) to give the title compound (5) as a pale yellow solid (63 mg, yield 8 %). LC-MS (ESI) m/z: 399 (M+l)+ . 1HNMR (400 MHz, DMSO-d6) δ (ppm): 3.56 (s, 3H), 3.86 (s, 3H), 7.02 (dd, 2H), 7.21 (dd, 2H), 7.90 (s, 1H), 8.08 (s, 1H), 8.26 (dd, 1H), 8.56 (dd, 1H).

Example 4

5-Fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-

Figure imgf000016_0001

 Methyl 7-fluoro-2-(4-fluorophenyl)-3-(l -methyl-lH-l ,2,4-triazol-5-yl)-4-oxo-l,2,3,4- tetrahydroquinoline-5-carboxylate (5) (150 g, 0.38 mol, 1.0 eq.) and methanol (1.7 L) were charged into a 3 L 3-neck flask equipped with a mechanical stirrer, thermometer, and nitrogen inlet/outlet. The resulted suspension was stirred at room temperature for 15 minutes. Hydrazine hydrate (85 % of purity, 78.1 g, 1.33 mol, 3.5 eq.) was charged dropwise into the above reaction mixture within 30 minutes at ambient temperature. The reaction mixture was stirred at room temperature overnight. The reaction was monitored by HPLC, showing about 2 % of compound (5) left. The obtained slurry was filtered. The wet cake was suspended in methanol (2 L) and stirred at room temperature for 3 hours. The above slurry was filtered, and the wet cake was washed with methanol (0.5 L). The wet cake was then dried in vacuum at 45 – 55 °C for 12 hours. This afforded the title compound as a pale yellow solid (112 g, yield: 78.1 %, purity: 95.98 % by HPLC). LC-MS (ESI) m/z: 381 (M+l)+. ^-NMR (400 MHz, DMSO-J6) δ (ppm): 3.66 (s, 3H), 4.97-5.04 (m, 2H), 6.91-6.94 (dd, Jx = 2.4, J2 = 11.2 Hz, 1H), 7.06-7.09 (dd, Jx = 2.4, J2 = 8.8 Hz, 1H), 7.14-7.18 (m, 3H), 7.47-7.51 (m, 2H), 7.72 (s, 1H), 7.80 (s, 1H), 12.35 (s, 1H).

Example 5

5 -Amino-7-flu in- 1 (2H)-one

Figure imgf000017_0001

To a solution of 6-fluoro-3-((l-methyl-lH-l,2,4-triazol-3-yl)methylene)-4-nitroiso-benzofuran- l(3H)-one (3) (4.0 g, 135 mmol) in THF (100 mL) was added hydrazine monohydrate (85 %) (6 mL) at room temperature under nitrogen atmosphere. The mixture was stirred for 2 hours, then acetic acid (6 mL) was added and the mixture was heated to and kept at 60 °C for 18 hours. The resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic layer was dried over anhydrous Na2S04 and evaporated to dryness to afford the title compound as a yellow solid (1.6 g, yield 42 %). LC-MS (ESI) m/z: 275(M+1)+.

Example 6

(£’)-7-fluoro-5-(4-fluorobenzylideneamino)-4-((l -methyl- IH- 1 ,2,4-triazol-5-yl)methyl)phthalazin- 1 (2H)- one

Figure imgf000018_0001

(7)

To a suspended of 5-amino-7-fluoro-4-((l-methyl-lH-l,2,4-triazol-3-yl)methyl) phthalazin- l(2H)-one (7) (1.6 g, 5.8 mmol) in acetonitrile (50 mL) was added 4-fluorobenzaldehyde (2.2 g, 17.5 mmol). The mixture was stirred under reflux under nitrogen for 48 hours. The precipitate was filtered and washed with a mixture of solvents (ethyl acetate/hexane, 1 :1, 10 mL). After drying in vacuum, it afforded the title compound as a yellow solid (1.2 g, yield 52 %). LC-MS (ESI) m/z: 381(M+1)+.

Example 7

5-Fluoro-8 4-fluorophenyl)-9 l-methyl H-l,2,4-triazol-5-yl)-8,9-dihydro-2H^yrido[4,3,2-

Figure imgf000018_0002

(8) (1 )

To a suspension of (£’)-7-fluoro-5-(4-fluorobenzylideneamino)-4-((l-methyl-lH-l,2,4-triazol-5- yl)methyl)phthalazin-l(2H)-one (8) (2.0 g, 5.3 mmol) in THF (80 mL) was added cesium carbonate (3.4 g, 10.6 mmol). The reaction mixture was stirred at 55 °C for 4 hours and cooled down to room temperature. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous Na2S04 and evaporated to dryness to afford the title compound as a white solid (1.6 g, yield 80 %). LC-MS (ESI) m/z: 381(M+1)+. ^-NMR (400 MHz, DMSO- ) δ (ppm): 3.66 (s, 3H), 4.97-5.04 (m, 2H), 6.91-6.94 (dd, Jx = 2.4, J2 = 11.2 Hz, 1H), 7.06-7.09 (dd, Ji = 2.4, J2 = 8.8 Hz, 1H), 7.14-7.18 (m, 3H), 7.47-7.51 (m, 2H), 7.72 (s, 1H), 7.80 (s, 1H), 12.35 (s, 1H).

Example 8

(£)-Methyl 5-fluoro-2-(3-(4-fluorophenyl)-2-(l-methyl-lH-l,2,4-triazol-5-yl)acryloyl)-3-nitrobenzoate

(9)

Figure imgf000019_0001

To a stirred solution of methyl 5-fluoro-2-(2-(l-methyl-lH-l,2,4-triazol-5-yl)acetyl)-3- nitrobenzoate (4) (580mg, 2 mmol) and 4-fluorobenzaldehyde (488 mg, 4 mmol) in dimethylsulfoxide (2 mL) was added L-proline (230 mg, 2 mmol). The resulting mixture was kept with stirring at 45 °C for 48 hours. The reaction system was then partitioned between ethyl acetate (50 mL) and water (30 mL), and the organic phase was washed with water (20 mL x 3), dried with Na2S04, concentrated in vacuo, and purified by column chromatography (ethyl acetate: petroleum ether = 1 :3) to give the title compound (9) as a pale yellow foam (340 mg, yield 40 %). LC-MS (ESI) m/z: 429 (M+l)+. ^-NMR (400 MHz, DMSO-dg); δ (ppm): 3.56 (s, 3H), 3.86 (s, 3H), 7.02 (dd, 2H), 7.21 (dd, 2H), 7.90 (s, IH), 8.08 (s, IH), 8.26 (dd, IH), 8.56 (dd, IH).

Example 9

Methyl 7-fluoro-2-(4-fluorophenyl)- 1 -hydroxy-3-( 1 -methyl- IH- 1 ,2,4-triazol-5-yl)-4-oxo- 1 ,2,3,4- tetrahydroquinoline-5 -carboxylate (10)

Figure imgf000019_0002

To a solution of (£)-Methyl 5-fluoro-2-(3-(4-fluorophenyl)-2-(l-methyl-lH-l,2,4-triazol-5- yl)acryloyl)-3-nitrobenzoate (9) (200 mg, 0.467 mmol) in methanol (20 mL) was added 10 % Pd/C (24 mg). After the addition, the mixture was stirred under H2 (1 atm) at room temperature for 0.5 h. The reaction system was then filtered and evaporated under reduced pressure. The residue was purified by chromatography (ethyl acetate: petroleum ether = 1 :1) to give the title compound (10) (110 mg, yield 57 %) as an off-white foam. LC-MS (ESI) m/z: 415 (M+H)+. ¾-NMR (400 MHz, DMSO-d6) δ (ppm): 3.53 (s, 3H), 3.73 (s, 3H), 5.08 (d, 2H), 5.27 (d, 2H), 6.95 (dd, IH), 7.08 (dd, 2H), 7.15 (dd, IH), 7.42 (dd, 2H), 7.77 (s, IH), 9.92 (s, IH). Example 10

Methyl 7-fluoro-2-(4-fluorophenyl)-3-(l-methyl-lH-l,2,4-triazol-5-yl)-4-oxo-l,2,3,4-

Figure imgf000020_0001

(10) (5)

To a stirred solution of methyl 7-fluoro-2-(4-fluorophenyl)-l-hydroxy-3-(l-methyl-lH-l,2,4- triazol-5-yl)-4-oxo-l, 2,3, 4-tetrahydroquinoline-5 -carboxylate (10) (41.4 mg, 0.1 mmol) in methanol (5 mL) was added concentrated HCl solution (w/w 37 %, 1 mL) and reductive powdered Fe (56 mg, 1 mmol). The reaction mixture was refluxed for 3 hours. After the disappearance of compound (10) as monitored by LC-MS, the reaction system was partitioned between ethyl acetate (20 mL) and water (20 mL) and then the aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried with Na2S04, concentrated in vacuo and purified by column chromatography (ethyl acetate: petroleum ether = 1 :1) to give the title compound (5) as a pale yellow solid (12 mg, yield 30 %). LC-MS (ESI) m/z: 399 (M+l)+. ¾-NMR (400 MHz, CDC13) δ (ppm): 3.58 (s, 3H), 3.87 (s, 3H), 4.17 (d, 1H), 4.87 (s, 1H), 5.38 (d, 1H), 6.50 (dd, 2H), 6.99 (dd, 2H), 7.38 (dd, 2H), 7.80 (s, 1H).

Example 11

Methyl 7-fluoro-2-(4-fluorophenyl)-3-(l-methyl-lH-l,2,4-triazol-5-yl)-4-oxo-l,2,3,4-

Figure imgf000020_0002

To a solution of (£)-Methyl 5-fluoro-2-(3-(4-fluorophenyl)-2-(l-methyl-lH-l,2,4-triazol-5- yl)acryloyl)-3-nitrobenzoate (9) (214 mg, 0.5 mmol) in methanol (5 mL) was added concentrated HCl solution (w/w 37 %, 1 mL), then reductive Fe powder (140 mg, 2.5 mmol) was added slowly to the reaction system. After the addition was complete the resulting mixture was refluxed for 24 hours. The reaction mixture was then filtered, concentrated, neutralized with saturated NaHC03 (20 mL), and extracted with ethyl acetate (10 mL x 3). The residue was purified by chromatography (ethyl acetate: petroleum ether = 1 : 1) to give the title compound (5) (30 mg, yield 15 %) as an off-white foam. LC-MS (ESI) m/z: 399 (M+H)+. ^-NMR (400 MHz, DMSO-d6) δ (ppm): 3.56 (s, 3H), 3.86 (s, 3H), 7.02 (dd, 2H), 7.21 (dd, 2H), 7.90 (s, 1H), 8.08 (s, 1H), 8.26 (dd, 1H), 8.56 (dd, 1H).

Example 12

(8R,9S)-5-fluoro-8-(4-fluorophenyl)-9-(l-me

Je]phthalazin-3(7H)-one (la) and (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5-

Figure imgf000021_0001

(1) (la) (lb)

A chiral resolution of 5-fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5-yl)-8,9- dihydro-2H-pyrido[4,3,2-Je]phthalazin-3(7H)-one (1) (52.5 g) was carried out on a super-fluid chromatography (SFC) unit using a CHIRALPAK IA column and C02/methanol/diethylamine

(80/30/0.1) as a mobile phase. This afforded two enantiomers with retention times of 7.9 minute (23.6 g, recovery 90 %, > 98 % ee) and 9.5 minute (20.4 g, recovery 78 %, > 98 % ee) as analyzed with a CHIRALPAK IA 0.46 cm x 15 cm column and C02/methanol/diethylamine (80/30/0.1) as a mobile phase at a flow rate of 2 g/minute.

Example 13

(2R,3R)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(l-methyl-lH-l,2,4-triazol-5-yl)-4-oxo-l,2,3,4- tetrahydroquinoline-5-carboxylate (6a) and (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(l-methyl-lH-

Figure imgf000021_0002

(5) (6a) (6b)

Example 13A

The chiral resolution of compound (5) was carried out on a SFC unit with a CHIRALPAK®IC 3 cm (I.D.) x 25 cm, 5 μηι column, using C02/MeOH (80/20) as a mobile phase at a flow rate of 65 g/ minute while maintaining the column temperature at 35 °C and with a detection UV wavelength of 254 nm. As such, a racemate of compound (5) (5 g) in methanol solution was resolved, which resulted in two enantiomers with a retention times of 2.35 minute (2.2 g, 88 % recovery, >98 % ee) and 4.25 minute (2.3 g, 92 % recovery, >98 % ee), respectively when analyzed using CHIRALPAK®IC 0.46 cm x 15 cm column and CO2/MeOH(80/20) as a mobile phase at a flow rate of 2 mL/ minute.

Example 13B

The chiral resolution of compound (5) was carried out on a SFC unit with a CHIRALPAK®IC 5cm (I.D.) x 25 cm, 5 μηι column, using C02/MeOH (75/25) as a mobile phase at a flow rate of 200 mL/ minute while maintaining the column temperature at 40 °C and with a detection UV wavelength of 255 nm. As such, a racemate of compound (5) (1.25 kg) in methanol solution was resolved, which resulted in two enantiomers in about 83 % yield and 97.4 % purity.

Example 13C

Alternatively, the separation can also be achieved on a Simulated Moving Bed (SMB) unit with a CHIRALPAK®IC column and acetonitrile as a mobile phase. The retention times for the two enantiomers are 3.3 and 4.1 minutes, respectively. In certain embodiments, the productivity can be greater than 6 kg Feed/day/kg CSP.

Example 14

(8R,9S)-5-fluoro-8 4-fluorophenyl)-9<l-me

Je]phthalazin-3(7H)-one (la) and (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(l-methyl-lH-l,2,4-triazol-5- (lb)

Figure imgf000022_0001

Example 14A

To a solution of (2R,3R)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(l-methyl-lH-l,2,4-triazol-5-yl)- 4-oxo-l,2,3,4-tetrahydroquinoline-5-carboxylate (6a) or (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(l- methyl-lH-l,2,4-triazol-5-yl)-4-oxo-l,2,3,4-tetrahydroquinoline-5-carboxylate (6b) (400 mg, 1.0 mmol) in ethanol (8.0 mL) was added hydrazine monohydrate (85 %, 2.0 mL), and the solution stirred at room temperature for 2 hours. The resulting solution was then concentrated to a volume of 2 mL and filtered, and the resultant cake washed with ethanol (1 mL). After drying in vacuum at 50°C, this afforded the title compound as a white solid (209 mg, yield 55 %). LC-MS (ESI) m/z: 381(M+1)+. ^-NMR (400 MHz, DMSO-dg): δ (ppm): 3.681 (s, 3H), 4.99-5.06 (m, 2H), 6.92-6.96 (m, 1H), 7.08-7.11 (m, 1H), 7.16-7.21 (t, J= 8.8 Hz, 2H), 7.49-7.53 (m, 2H), 7.75 (s, 1H), 7.83 (s, 1H), 12.35 (s, 1H).

Example 14B

To a solution of (2R,3R)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(l-methyl-lH-l,2,4-triazol-5-yl)- 4-oxo-l,2,3,4-tetrahydroquinoline-5-carboxylate (6a) or (2S,3S)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(l- methyl-lH-l,2,4-triazol-5-yl)-4-oxo-l,2,3,4-tetrahydroquinoline-5-carboxylate (6b) (446 g) in acetonitrile (10 volume) was added hydrazine monohydrate (2.9 eq.), and the solution stirred at room temperature for 2 hours. The resulting solution was then concentrated to a volume of 2 mL and filtered. The crude product was re-slurried with water (3~5 volumes) at 15-16 °C. After drying in vacuum at 50 °C, this affords the title compound as a white solid (329 g, yield 77%, 99.93% purity). LC-MS (ESI) m/z:

381(M+1)+; ¾-NMR (400 MHz, DMSO-d6) δ (ppm): 3.681 (s, 3H), 4.99-5.06 (m, 2H), 6.92-6.96 (m, 1H), 7.08-7.11 (m, 1H), 7.16-7.21 (t, J= 8.8 Hz, 2H), 7.49-7.53 (m, 2H), 7.75 (s, 1H), 7.83 (s, 1H), 12.35 (s, 1H).

Talazoparib (BMN-673) is an orally available poly ADP ribose polymerase (PARP) inhibitor currently in development by Pfizer for the treatment of advanced breast cancer patients with germline BRCA mutations.[1] Talazoparib is similar to the first in class PARP inhibitor, olaparib.[2][3] However, talazoparib is thought to be more potent than olaparib.[3]

Mechanism of action

Talazoparib acts as an inhibitor of poly ADP ribose polymerase(PARP) which aids in single strand DNA repair. Cells that have BRCA1/2mutations are susceptible to the cytotoxic effects of PARP inhibitors because of an accumulation of DNA damage.[1] Talazoparib is theorized to have a higher potency than olaparib due to the additional mechanism of action called PARP trapping. PARP trapping is the mechanism of action where the PARP molecule is trapped on the DNA, which interferes with the cells ability to replicate. Talazoparib is found to be ~100 fold more efficient in PARP trapping than olaparib.[4] However, this increased potency may not translate directly to clinical effectiveness as many other factors must be considered.[3][4]

Commercialization

Talazoparib was originally developed by BioMarin Pharmaceutical Inc. However, Medivation Inc. acquired all worldwide rights to talazoparib in August 2015 to expand their global oncology franchise.[5] Medivation acquired talazoparib for $410 million with additional payments of up to $160 million in royalties and milestones. Under this agreement, Medivation assumed all financial responsibilities for the continued development, regulatory, and commercialization of talazoparib.[5][6]

Clinical trials

As of January 2016, talazoparib is in 14 active clinical trials [7] including a new arm of I-SPY 2.[8] These trials cover a variety of cancers types and combination therapies. The most notable clinical trials are the ABRAZO and EMBRACA studies.

ABRAZO

ABRAZO is a phase II study for the safety and efficacy of treatment of BRCA breast cancer patients with Talazoparib monotherapy. This study is for patients who have failed at least two prior chemotherapy treatments for metastatic breast cancer or been previously treated with a platinum regimen.[6][9][10] The original target enrollment for the study was 70 patients but Biomarin expanded the trial to 140 patients.[9][10] The estimated completion date is December 2016.[10]

EMBRACA

EMBRACA is a phase III study for the treatment of BRCA breast cancer patients with Talazoparib.[11][12][13] This trial is an open-label, randomized, parallel, 2-arm, multi-center comparison of talazaporib against physician’s preference for the treatment of patients with locally advanced or metastatic breast cancer. Patients must also have received prior chemotherapy regimens for metastatic breast cancer.[12][13] Patients participating in this study are randomly selected for either talazoparib or physician’s choice of chemotherapy at a 2:1 ratio to talazoparib.[6] The target enrollment for the study was 430 patients [12][13] and the estimated completion date is June 2017.[13]

References

  1. Jump up to:a b Medivation Inc. “Talazoparib”.
  2. Jump up^ FDA (19 December 2014). “FDA approves Lynparza to treat advanced ovarian cancer”FDA News Release.
  3. Jump up to:a b c Jessica Brown, Stan Kaye, Timothy Yap (29 March 2016). “PARP inhibitors: the race is on”British Journal of Cancer114: 713–5. doi:10.1038/bjc.2016.67PMC 4984871Freely accessiblePMID 27022824.
  4. Jump up to:a b Yuqiao Shen, Mika Aoyagi-Scharber, Bing Wang (June 2015). “Trapping Poly(ADP-Ribose) Polymerase”Journal of Pharmacology and Experimental Therapeutics.
  5. Jump up to:a b Biomarin (24 August 2015). “Medivation to Expand Global Oncology Franchise With the Acquisition of All Worldwide Rights to Talazoparib (BMN 673), a Potent PARP Inhibitor, From BioMarin”.
  6. Jump up to:a b c Silus Inman (25 August 2015). “Medivation Acquires BioMarin’s PARP Inhibitor Talazoparib”.
  7. Jump up^ BMN 673 trials registered
  8. Jump up^ I-SPY 2 TRIAL: Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer (I-SPY 2)
  9. Jump up to:a b “BioMarin Provides Program Update for Talazoparib in Metastatic Breast Cancer”. 20 July 2015.
  10. Jump up to:a b c “A Phase 2, 2-Stage, 2-Cohort Study of Talazoparib (BMN 673), in Locally Advanced and/or Metastatic Breast Cancer Patients With BRCA Mutation (ABRAZO Study)”ClinicalTrials.gov.
  11. Jump up^ “EMBRACA CLINICAL STUDY IS NOW ENROLLING”.
  12. Jump up to:a b c “A Study Evaluating Talazoparib (BMN 673), a PARP Inhibitor, in Advanced and/or Metastatic Breast Cancer Patients With BRCA Mutation (EMBRACA Study)”ClinicalTrials.gov.
  13. Jump up to:a b c d “BioMarin Initiates Phase 3 BMN 673 Trial for Metastatic gBRCA Breast Cancer”Benzinga.

External links

nmr……http://www.medkoo.com/uploads/product/Talazoparib__BMN-673_/qc/BMN673-QC-BBC20130523-Web.pdf

Patent                       Submitted                        Granted

PROCESSES OF SYNTHESIZING DIHYDROPYRIDOPHTHALAZINONE DERIVATIVES [US2014323725]2014-06-022014-10-30

CRYSTALLINE (8S,9R)-5-FLUORO-8-(4-FLUOROPHENYL)-9-(1-METHYL-1H-1,2,4-TRIAZOL-5-YL)-8,9-DIHYDRO-2H-PYRIDO[4,3,2-DE]PHTHALAZIN-3(7H)-ONE TOSYLATE SALT [US2014228369]2014-04-142014-08-14

Crystalline (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt [US8735392]2011-10-202014-05-27

DIHYDROPYRIDOPHTHALAZINONE INHIBITORS OF POLY(ADP-RIBOSE)POLYMERASE (PARP) [US8012976]2010-02-112011-09-06

DIHYDROPYRIDOPHTHALAZINONE INHIBITORS OF POLY(ADP-RIBOSE)POLYMERASE (PARP) FOR USE IN TREATMENT OF DISEASES ASSOCIATED WITH A PTEN DEFICIENCY [US2014066429]2013-08-212014-03-06

METHODS AND COMPOSITIONS FOR TREATMENT OF CANCER AND AUTOIMMUNE DISEASE [US2013184342]2013-03-132013-07-18

WO2012054698A1 Oct 20, 2011 Apr 26, 2012 Biomarin Pharmaceutical Inc. Crystalline (8s,9r)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1h-1,2,4-triazol-5-yl)-8,9-dihydro-2h-pyrido[4,3,2-de]phthalazin-3(7h)-one tosylate salt
WO2015069851A1 Nov 6, 2014 May 14, 2015 Biomarin Pharmaceutical Inc. Triazole intermediates useful in the synthesis of protected n-alkyltriazolecarbaldehydes
US8420650 Mar 31, 2011 Apr 16, 2013 Biomarin Pharmaceutical Inc. Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP)
US8541403 Feb 3, 2011 Sep 24, 2013 Biomarin Pharmaceutical Inc. Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP) for use in treatment of diseases associated with a PTEN deficiency
US8735392 Oct 20, 2011 May 27, 2014 Biomarin Pharmaceutical Inc. Crystalline (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt
US8765945 Feb 8, 2011 Jul 1, 2014 Biomarin Pharmaceutical Inc. Processes of synthesizing dihydropyridophthalazinone derivatives
US8999987 Mar 6, 2013 Apr 7, 2015 Biomarin Pharmaceutical Inc. Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP)
US9018201 Aug 21, 2013 Apr 28, 2015 Biomarin Pharmaceuticial Inc. Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP) for use in treatment of diseases associated with a PTEN deficiency

SEE………..http://orgspectroscopyint.blogspot.in/2016/02/talazoparib.html

http://apisynthesisint.blogspot.in/2016/02/talazoparib.html

Talazoparib
Talazoparib.svg
Systematic (IUPAC) name
(8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one
Clinical data
Legal status
  • Investigational
Chemical data
Formula C19H14F2N6O
Molar mass 380.35 g/mol
Talazoparib
Talazoparib.svg
Legal status
Legal status
  • Investigational
Identifiers
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C19H14F2N6O
Molar mass 380.35 g/mol
3D model (JSmol)

/////////////BMN 673, talazoparib, phase 3, BMN673, BMN673, BMN-673, LT673, LT 673, LT-673, Poly ADP ribose polymerase 2 inhibitor, Poly ADP ribose polymerase 1 inhibitor, cancer, MDV-3800 , MDV 3800

Cn1c(ncn1)[C@H]2c3c4c(cc(cc4N[C@@H]2c5ccc(cc5)F)F)c(=O)[nH]n3

O=C1NN=C2C3=C1C=C(F)C=C3N[C@H](C4=CC=C(F)C=C4)[C@H]2C5=NC=NN5C

Talazoparib tosylate タラゾパリブトシル酸塩;

str1

1373431-65-2.png

Talzenna

fda 2018/10/16

CAS: 1373431-65-2
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Nusinersen sodium, ヌシネルセンナトリウム


ヌシネルセンナトリウム
Nusinersen Sodium

C234H323N61Na17O128P17S17 : 7500.89
[1258984-36-9 , ヌシネルセン]

Nusinersen sodium

C234H323N61O128P17S17.17Na, 7500.8854

UNII 4CHB7QQU1Q

ISIS 396443

Nusinersen sodium was approved by the US Food and Drug Administration (FDA) on Dec 23, 2016, and approved by the European Medicines Agency’s (EMA) on May 30, 2017, and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on July 3, 2017.

JAPAN APPROVAL

2017/7/3 Nusinersen sodium Spinraza Biogen Japan

An antisense oligonucleotide that induces survival motor neuron (SMN) protein expression, it was approved by the U.S. FDA in December, 2016 as Spinraza for the treatment of children and adults with spinal muscular atrophy (SMA). It is adminstrated as direct intrathecal injection.Nusinersen sodium colored.svg

FREE FORM CAS: 1258984-36-9

Image result for nusinersen

CAS1258984-36-9

MFC234H340N61O128P17S17

ISIS-396443, ISIS-SMNRx, IONIS-SMNRx

RNA, (2′-0-(2-methoxyethyi))(p-thio)(m5u-c-a-c-m5u-m5u-m5u-c-a-m5ua- a-m5 u-g-c-m5u-g-g)

RNA, (2′-0-(2-METHOXYETHYI))(P-THIO)(M5U-C-A-C-M5U-M5U-M5U-C-A-M5UA- A-M5 U-G-C-M5U-G-G)

All-P-ambo-2′-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-P-thioadenylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-P-thioadenylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-P-thioadenylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-P-thioadenylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-P-thioguanylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-P-thioguanylyl-(3’¨5′)-2′-O-(2-methoxyethyl)guanosine

ISIS-SMNRx is a drug that is designed to modulate the splicing of the SMN2 gene to significantly increase the production of functional SMN protein. The US regulatory agency has granted Orphan Drug Designation with Fast Track Status to nusinersen for the treatment of patients with SMA. The European regulatory agency has granted Orphan Drug Designation to nusinersen for the treatment of patients with SMA.

Nusinersen,[1] marketed as Spinraza,[3] is a medication used in treating spinal muscular atrophy (SMA),[4] a rare neuromuscular disorder. In December 2016, it became the first approved drug used in treating this disorder. Nusinersen has orphan drugdesignation in the United States and the European Union.[5]

Image result for nusinersen

FDA

FDA approves first drug for spinal muscular atrophy

New therapy addresses unmet medical need for rare disease

The U.S. Food and Drug Administration today approved Spinraza (nusinersen), the first drug approved to treat children and adults with spinal muscular atrophy (SMA), a rare and often fatal genetic disease affecting muscle strength and movement. Spinraza is an injection administered into the fluid surrounding the spinal cord.

Read more.

For Immediate Release

December 23, 2016

The U.S. Food and Drug Administration today approved Spinraza (nusinersen), the first drug approved to treat children and adults with spinal muscular atrophy (SMA), a rare and often fatal genetic disease affecting muscle strength and movement. Spinraza is an injection administered into the fluid surrounding the spinal cord.

“There has been a long-standing need for a treatment for spinal muscular atrophy, the most common genetic cause of death in infants, and a disease that can affect people at any stage of life,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “As shown by our suggestion to the sponsor to analyze the results of the study earlier than planned, the FDA is committed to assisting with the development and approval of safe and effective drugs for rare diseases and we worked hard to review this application quickly; we could not be more pleased to have the first approved treatment for this debilitating disease.”

SMA is a hereditary disease that causes weakness and muscle wasting because of the loss of lower motor neurons controlling movement. There is wide variability in age of onset, symptoms and rate of progression. Spinraza is approved for use across the range of spinal muscular atrophy patients.

The FDA worked closely with the sponsor during development to help design and implement the analysis upon which this approval was based. The efficacy of Spinraza was demonstrated in a clinical trial in 121 patients with infantile-onset SMA who were diagnosed before 6 months of age and who were less than 7 months old at the time of their first dose. Patients were randomized to receive an injection of Spinraza, into the fluid surrounding the spinal cord, or undergo a mock procedure without drug injection (a skin prick). Twice the number of patients received Spinraza compared to those who underwent the mock procedure. The trial assessed the percentage of patients with improvement in motor milestones, such as head control, sitting, ability to kick in supine position, rolling, crawling, standing and walking.

The FDA asked the sponsor to conduct an interim analysis as a way to evaluate the study results as early as possible; 82 of 121 patients were eligible for this analysis. Forty percent of patients treated with Spinraza achieved improvement in motor milestones as defined in the study, whereas none of the control patients did.

Additional open-label uncontrolled clinical studies were conducted in symptomatic patients who ranged in age from 30 days to 15 years at the time of the first dose, and in presymptomatic patients who ranged in age from 8 days to 42 days at the time of first dose. These studies lacked control groups and therefore were more difficult to interpret than the controlled study, but the findings appeared generally supportive of the clinical efficacy demonstrated in the controlled clinical trial in infantile-onset patients.

The most common side effects found in participants in the clinical trials on Spinraza were upper respiratory infection, lower respiratory infection and constipation. Warnings and precautions include low blood platelet count and toxicity to the kidneys (renal toxicity). Toxicity in the nervous system (neurotoxicity) was observed in animal studies.

The FDA granted this application fast track designation and priority review. The drug also received orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The sponsor is receiving a rare pediatric disease priority review voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. A voucher can be redeemed by a sponsor at a later date to receive priority review of a subsequent marketing application for a different product. This is the eighth rare pediatric disease priority review voucher issued by the FDA since the program began.

Spinraza is marketed by Biogen of Cambridge, Massachusetts and was developed by Ionis Pharmaceuticals of Carlsbad, California.

Medical use

The drug is used to treat spinal muscular atrophy associated with a mutation in the SMN1 gene. It is administered directly to the central nervous system (CNS) using intrathecal injection.[2]

In clinical trials, the drug halted the disease progression. In around 60% of infants affected by type 1 spinal muscular atrophy, the drug also significantly improved motor function.[2]

Image result for Nusinersen sodium

Side effects

Like other antisense drugs, there is a risk of abnormalities in blood clotting and a reduction in platelets as well as a risk of kidney damage.[2]

In clinical trials, people treated with nusinersen had an increased risk of upper and lower respiratory infections and congestion, ear infections, constipation, pulmonary aspiration, teething, and scoliosis. One infant in a clinical trial had severe lowering of salt levels and several had rashes. There is a risk that growth of infants and children might be stunted. In older clinical trial subjects, the most common adverse events were headache, back pain, and adverse effects from the spinal injection.[2]

Some people may develop antibodies against the drug; as of December 2016 it was unclear what effect this might have on efficacy or safety.[2]

Pharmacology

Spinal muscular atrophy is caused by loss-of-function mutations in the SMN1 gene which codes for survival motor neuron (SMN) protein. Patients survive owing to low amounts of the SMN protein produced from the SMN2 gene. Nusinersen modulates alternate splicing of the SMN2 gene, functionally converting it into SMN1 gene, thus increasing the level of SMN protein in the CNS.[6]

The drug distributes to CNS and to peripheral tissues.[2]

The half-life is estimated to be 135 to 177 days in CSF and 63 to 87 days in blood plasma. The drug is metabolized via exonuclease (3’- and 5’)-mediated hydrolysis and does not interact with CYP450 enzymes.[2] The primary route of elimination is likely by urinary excretion for nusinersen and its metabolites.[2]

Chemistry

Nusinersen is an antisense oligonucleotide in which the 2’-hydroxy groups of the ribofuranosyl rings are replaced with 2’-O-2-methoxyethyl groups and the phosphate linkages are replaced with phosphorothioate linkages.[2][6]

History

Nusinersen was discovered in a collaboration between Adrian Krainer at Cold Spring Harbor Laboratory and Ionis Pharmaceuticals (formerly called Isis Pharmaceuticals).[7][8][9][10] Partial work was done at the University of Massachusetts Medical School funded by Cure SMA.[11]

Starting in 2012, Ionis partnered with Biogen on development and in 2015 Biogen acquired an exclusive license to the drug for a US$75 million license fee, milestone payments up to US$150 million, and tiered royalties thereafter; Biogen also paid the costs of development subsequent to taking the license.[12] The license to Biogen included licenses to intellectual property that Ionis had acquired from Cold Spring Harbor Laboratory and University of Massachusetts.[13]

In November 2016, the new drug application was accepted under the FDA’s priority review process on the strength of the Phase III trial and the unmet need, and was also accepted for review at the European Medicines Agency (EMA) at that time.[14][15] It was approved by the FDA in December 2016 and by EMA in May 2017 as the first drug to treat spinal muscular atrophy.[16][17] Subsequently, nusinersen was approved to treat SMA in Canada (July 2017),[18] Japan (July 2017),[19] Brasil (August 2017)[20] and Switzerland (September 2017).[21]

Controversy

Spinraza list price is US$125,000 per injection which puts the treatment cost at US$750,000 in the first year and US$375,000 annually after that. According to the New York Times, this places Spinraza “among the most expensive drugs in the world”.[15]

As of October 2017, Spinraza is reimbursed by health insurance providers in the United States and by the public healthcare systems in France (SMA type 1 and 2 patients only), Germany (all patients), Iceland (all patients), Italy (all patients) and Japan (SMA type 1 only).[3]

In October 2017, the authorities in Denmark recommended Spinraza for use only in a small subset of patients with SMA type 1 (young babies) and refused to offer it as a standard treatment in all other SMA patients quoting an “unreasonably high price” compared to the clinical effect.[22] Norwegian authorities rejected the funding in October 2017 because the price of the medicine was “unethically high”.[23] In February 2018 the funding was approved for patients under 18 years old.[23]

In January 2018 public funding of Spinraza was approved in Israel.

Nusinersen (formerly, IONIS-SMNRx, ISIS-SMNRx), intended to be marketed as Spinraza,[1] is an investigational drug for spinal muscular atrophy developed by Ionis Pharmaceuticals and Biogen with financial support from SMA Foundation and Cure SMA. It is a proprietary antisense oligonucleotide that modulates alternate splicing of the SMN2 gene, functionally converting it into SMN1 gene.

The drug is administered directly to the central nervous system using intrathecal injection once every 3–4 months.

Nusinersen has orphan drug designation in the United States and the European Union.[2]

In August 2016, a phase III trial in type 1 SMA patients was ended early due to positive efficacy data, with Biogen deciding to file for regulatory approval for the drug.[3]Consequently, the company submitted a New Drug Application to the FDA in September 2016[4] and a marketing authorisation application to the European Medicines Agency, under the centralised procedure,[5] in the following month. The company also announced an expanded access programme of nusinersen in type 1 SMA in selected countries.

In November 2016, a phase III clinical trial in type 2 SMA patients was halted after an interim analysis indicated the drug’s efficacy also in this SMA type.[6]

Image result for nusinersen

Image result for nusinersen

Image result for nusinersen

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

References

  1. Jump up to:a b “International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 74” (PDF). World Health Organization. pp. 413–14. Retrieved 13 March 2017.
  2. Jump up to:a b c d e f g h i j k “Nusinersen US Label” (PDF). FDA. December 2016. For updates see FDA index page for NDA 209531
  3. Jump up to:a b “Nusinersen”. AdisInsight. Retrieved 1 January 2017.
  4. Jump up^ Ottesen, Eric W. (2017-01-01). “ISS-N1 makes the first FDA-approved drug for spinal muscular atrophy”Translational Neuroscience8 (1): 1–6. doi:10.1515/tnsci-2017-0001ISSN 2081-6936PMC 5382937Freely accessiblePMID 28400976.
  5. Jump up^ “Nusinersen”. UK Specialist Pharmacy Service. Retrieved 31 December 2016.
  6. Jump up to:a b Zanetta, C; Nizzardo, M; Simone, C; Monguzzi, E; Bresolin, N; Comi, GP; Corti, S (1 January 2014). “Molecular Therapeutic Strategies for Spinal Muscular Atrophies: Current and Future Clinical Trials”. Clinical Therapeutics36 (1): 128–40. doi:10.1016/j.clinthera.2013.11.006PMID 24360800.
  7. Jump up^ Garber, K (11 October 2016). “Big win possible for Ionis/Biogen antisense drug in muscular atrophy”. Nature Biotechnology34 (10): 1002–1003. doi:10.1038/nbt1016-1002PMID 27727217.
  8. Jump up^ Wadman, Meredith (23 December 2016). “Updated: FDA approves drug that rescues babies with fatal neurodegenerative disease”Science.
  9. Jump up^ Offord, Catherine (December 1, 2016). “Oligonucleotide Therapeutics Near Approval”The Scientist.
  10. Jump up^ Tarr, Peter (24 December 2016). “CSHL FDA approval of life-saving SMA drug is hailed by its researcher-inventor at CSHL”Cold Spring Harbor Laboratory.
  11. Jump up^ “Therapeutic Approaches”http://www.curesma.org. Cure SMA. Retrieved 1 January 2017.
  12. Jump up^ “Biogen Shells Out $75M to Develop Ionis’ Nusinersen after Positive Phase III Results”Genetic Engineering News, August 1, 2016
  13. Jump up^ “Press release: Biogen and Ionis Pharmaceuticals Report Nusinersen Meets Primary Endpoint at Interim Analysis of Phase 3 ENDEAR Study in Infantile-Onset Spinal Muscular Atrophy | Biogen Media”Biogen. August 1, 2016.
  14. Jump up^ “Regulatory Applications for SMA Therapy Nusinersen Accepted in US, EU”. BioNews Services, LLC. Retrieved 2016-11-15.
  15. Jump up to:a b Katie Thomas (December 30, 2016). “Costly Drug for Fatal Muscular Disease Wins F.D.A. Approval”New York Times.
  16. Jump up^ Grant, Charley (2016-12-27). “Surprise Drug Approval Is Holiday Gift for Biogen”Wall Street JournalISSN 0099-9660. Retrieved 2016-12-27.
  17. Jump up^ “Spinraza (nusinersen)”European Medicines Agency. Retrieved 2017-10-27.
  18. Jump up^ “Biogen’s SPINRAZA™ (nusinersen) Receives Notice of Compliance from Health Canada for the Treatment of 5q Spinal Muscular Atrophy (SMA)”Cision. 2017-07-04.
  19. Jump up^ “Biogen to launch Spinraza in Japan soon”. 2017-07-10.
  20. Jump up^ “Remédio inédito para atrofia muscular espinhal é liberado” (in Portuguese). 2017-08-25.
  21. Jump up^ “Spinraza – Zulassung nun auch in der Schweiz” (in German). SMA Schweiz. 2017-09-30.
  22. Jump up^ Medicinrådet siger nej til lægemiddel til børn med muskelsvind: ‘Urimeligt’ dyrt Retrieved October 13 2017.
  23. Jump up to:a b Dette er uforståelig og utrolig urettferdig

Further reading

  • Finkel, Richard S; Chiriboga, Claudia A; Vajsar, Jiri; Day, John W; Montes, Jacqueline; De Vivo, Darryl C; Yamashita, Mason; Rigo, Frank; Hung, Gene; Schneider, Eugene; Norris, Daniel A; Xia, Shuting; Bennett, C Frank; Bishop, Kathie M (2016). “Treatment of infantile-onset spinal muscular atrophy with nusinersen: A phase 2, open-label, dose-escalation study”. The Lancet388 (10063): 3017. doi:10.1016/S0140-6736(16)31408-8.
Nusinersen
Nusinersen sodium colored.svg
Clinical data
Trade names Spinraza
Synonyms IONIS-SMNRx, ISIS-SMNRx
AHFS/Drugs.com Multum Consumer Information
License data
Routes of
administration
Injection into cerebrospinal fluid
ATC code
Legal status
Legal status
Pharmacokinetic data
Metabolism Exonuclease (3’- and 5’)-mediated hydrolysis
Biological half-life 135–177 days (in CSF), 63–87 days (in plasma)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
Chemical and physical data
Formula C234H323N61Na17O128P17S17[2]
Molar mass 7501 Da[2]
3D model (JSmol)

////////////////Nusinersen sodium, Spinraza, ヌシネルセンナトリウム, FDA 2016, EU 2017, JAPAN 2017

CC1=CN(C(=O)NC1=O)C2C(C(C(O2)CO)OP(=S)(O)OCC3C(C(C(O3)N4C=C(C(=NC4=O)N)C)OCCOC)OP(=S)(O)OCC5C(C(C(O5)N6C=NC7=C6N=CN=C7N)OCCOC)OP(=S)(O)OCC8C(C(C(O8)N9C=C(C(=NC9=O)N)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=O)NC1=O)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=O)NC1=O)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=O)NC1=O)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=NC1=O)N)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=NC2=C1N=CN=C2N)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=O)NC1=O)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=NC2=C1N=CN=C2N)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=NC2=C1N=CN=C2N)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=O)NC1=O)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=NC2=C1N=C(NC2=O)N)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=NC1=O)N)C)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=C(C(=O)NC1=O)C)OCCOC)OP(=O)(OCC1C(C(C(O1)N1C=NC2=C1N=C(NC2=O)N)OCCOC)OP(=S)(O)OCC1C(C(C(O1)N1C=NC2=C1N=C(NC2=O)N)OCCOC)O)S)OCCOC

FDA approves first drug Spinraza (nusinersen), for spinal muscular atrophy


New FDA Logo Blue

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FDA approves first drug for spinal muscular atrophy

New therapy addresses unmet medical need for rare disease

The U.S. Food and Drug Administration today approved Spinraza (nusinersen), the first drug approved to treat children and adults with spinal muscular atrophy (SMA), a rare and often fatal genetic disease affecting muscle strength and movement. Spinraza is an injection administered into the fluid surrounding the spinal cord.

Read more.

For Immediate Release

December 23, 2016

The U.S. Food and Drug Administration today approved Spinraza (nusinersen), the first drug approved to treat children and adults with spinal muscular atrophy (SMA), a rare and often fatal genetic disease affecting muscle strength and movement. Spinraza is an injection administered into the fluid surrounding the spinal cord.

“There has been a long-standing need for a treatment for spinal muscular atrophy, the most common genetic cause of death in infants, and a disease that can affect people at any stage of life,” said Billy Dunn, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “As shown by our suggestion to the sponsor to analyze the results of the study earlier than planned, the FDA is committed to assisting with the development and approval of safe and effective drugs for rare diseases and we worked hard to review this application quickly; we could not be more pleased to have the first approved treatment for this debilitating disease.”

SMA is a hereditary disease that causes weakness and muscle wasting because of the loss of lower motor neurons controlling movement. There is wide variability in age of onset, symptoms and rate of progression. Spinraza is approved for use across the range of spinal muscular atrophy patients.

The FDA worked closely with the sponsor during development to help design and implement the analysis upon which this approval was based. The efficacy of Spinraza was demonstrated in a clinical trial in 121 patients with infantile-onset SMA who were diagnosed before 6 months of age and who were less than 7 months old at the time of their first dose. Patients were randomized to receive an injection of Spinraza, into the fluid surrounding the spinal cord, or undergo a mock procedure without drug injection (a skin prick). Twice the number of patients received Spinraza compared to those who underwent the mock procedure. The trial assessed the percentage of patients with improvement in motor milestones, such as head control, sitting, ability to kick in supine position, rolling, crawling, standing and walking.

The FDA asked the sponsor to conduct an interim analysis as a way to evaluate the study results as early as possible; 82 of 121 patients were eligible for this analysis. Forty percent of patients treated with Spinraza achieved improvement in motor milestones as defined in the study, whereas none of the control patients did.

Additional open-label uncontrolled clinical studies were conducted in symptomatic patients who ranged in age from 30 days to 15 years at the time of the first dose, and in presymptomatic patients who ranged in age from 8 days to 42 days at the time of first dose. These studies lacked control groups and therefore were more difficult to interpret than the controlled study, but the findings appeared generally supportive of the clinical efficacy demonstrated in the controlled clinical trial in infantile-onset patients.

The most common side effects found in participants in the clinical trials on Spinraza were upper respiratory infection, lower respiratory infection and constipation. Warnings and precautions include low blood platelet count and toxicity to the kidneys (renal toxicity). Toxicity in the nervous system (neurotoxicity) was observed in animal studies.

The FDA granted this application fast track designation and priority review. The drug also received orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The sponsor is receiving a rare pediatric disease priority review voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. A voucher can be redeemed by a sponsor at a later date to receive priority review of a subsequent marketing application for a different product. This is the eighth rare pediatric disease priority review voucher issued by the FDA since the program began.

Spinraza is marketed by Biogen of Cambridge, Massachusetts and was developed by Ionis Pharmaceuticals of Carlsbad, California.

str1

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CAS1258984-36-9

MFC234H340N61O128P17S17

ISIS-396443, ISIS-SMNRx, IONIS-SMNRx

RNA, (2′-0-(2-methoxyethyi))(p-thio)(m5u-c-a-c-m5u-m5u-m5u-c-a-m5ua- a-m5 u-g-c-m5u-g-g)

RNA, (2′-0-(2-METHOXYETHYI))(P-THIO)(M5U-C-A-C-M5U-M5U-M5U-C-A-M5UA- A-M5 U-G-C-M5U-G-G)

All-P-ambo-2′-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-P-thioadenylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-P-thioadenylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-P-thioadenylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-P-thioadenylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-P-thioguanylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiocytidylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-5-methyl-P-thiouridylyl-(3’¨5′)-2′-O-(2-methoxyethyl)-P-thioguanylyl-(3’¨5′)-2′-O-(2-methoxyethyl)guanosine

ISIS-SMNRx is a drug that is designed to modulate the splicing of the SMN2 gene to significantly increase the production of functional SMN protein. The US regulatory agency has granted Orphan Drug Designation with Fast Track Status to nusinersen for the treatment of patients with SMA. The European regulatory agency has granted Orphan Drug Designation to nusinersen for the treatment of patients with SMA.

Image result for nusinersen

Nusinersen (formerly, IONIS-SMNRx, ISIS-SMNRx), intended to be marketed as Spinraza,[1] is an investigational drug for spinal muscular atrophy developed by Ionis Pharmaceuticals and Biogen with financial support from SMA Foundation and Cure SMA. It is a proprietary antisense oligonucleotide that modulates alternate splicing of the SMN2 gene, functionally converting it into SMN1 gene.

The drug is administered directly to the central nervous system using intrathecal injection once every 3–4 months.

Nusinersen has orphan drug designation in the United States and the European Union.[2]

In August 2016, a phase III trial in type 1 SMA patients was ended early due to positive efficacy data, with Biogen deciding to file for regulatory approval for the drug.[3]Consequently, the company submitted a New Drug Application to the FDA in September 2016[4] and a marketing authorisation application to the European Medicines Agency, under the centralised procedure,[5] in the following month. The company also announced an expanded access programme of nusinersen in type 1 SMA in selected countries.

In November 2016, a phase III clinical trial in type 2 SMA patients was halted after an interim analysis indicated the drug’s efficacy also in this SMA type.[6]

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References

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

//////////spinraza, nusinersen, fda 2016, Biogen, Cambridge, Massachusetts,  Ionis Pharmaceuticals of Carlsbad, California. spinal muscular atrophy, ISIS-396443, ISIS-SMNRx, IONIS-SMNRx, 1258984-36-9

FDA grants accelerated approval to new treatment for advanced ovarian cancer , Rubraca(rucaparib)


 

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The U.S. Food and Drug Administration today granted accelerated approval to Rubraca (rucaparib) to treat women with a certain type of ovarian cancer. Rubraca is approved for women with advanced ovarian cancer who have been treated with two or more chemotherapies and whose tumors have a specific gene mutation (deleterious BRCA) as identified by an FDA-approved companion diagnostic test.

Read more.

For Immediate Release

December 19, 2016

The U.S. Food and Drug Administration today granted accelerated approval to Rubraca (rucaparib) to treat women with a certain type of ovarian cancer. Rubraca is approved for women with advanced ovarian cancer who have been treated with two or more chemotherapies and whose tumors have a specific gene mutation (deleterious BRCA) as identified by an FDA-approved companion diagnostic test.

“Today’s approval is another example of the trend we are seeing in developing targeted agents to treat cancers caused by specific mutations in a patient’s genes,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and acting director of the FDA’s Oncology Center of Excellence. “Women with these gene abnormalities who have tried at least two chemotherapy treatments for their ovarian cancer now have an additional treatment option.”

The National Cancer Institute estimates that 22,280 women will be diagnosed with ovarian cancer in 2016 and an estimated 14,240 will die of this disease. Approximately 15 to 20 percent of patients with ovarian cancer have a BRCA gene mutation.

BRCA genes are involved with repairing damaged DNA and normally work to prevent tumor development. However, mutations of these genes may lead to certain cancers, including ovarian cancers. Rubraca is a poly ADP-ribose polymerase (PARP) inhibitor that blocks an enzyme involved in repairing damaged DNA. By blocking this enzyme, DNA inside the cancerous cells with damaged BRCA genes may be less likely to be repaired, leading to cell death and possibly a slow-down or stoppage of tumor growth.

Today, the FDA also approved the FoundationFocus CDxBRCA companion diagnostic for use with Rubraca, which is the first next-generation-sequencing (NGS)-based companion diagnostic approved by the agency. The NGS test detects the presence of deleterious BRCA gene mutations in the tumor tissue of ovarian cancer patients. If one or more of the mutations are detected, the patient may be eligible for treatment with Rubraca.

The safety and efficacy of Rubraca were studied in two, single-arm clinical trials involving 106 participants with BRCA-mutated advanced ovarian cancer who had been treated with two or more chemotherapy regimens. BRCA gene mutations were confirmed in 96 percent of tested trial participants with available tumor tissue using the FoundationFocus CDxBRCA companion diagnostic. The trials measured the percentage of participants who experienced complete or partial shrinkage of their tumors (overall response rate). Fifty-four percent of the participants who received Rubraca in the trials experienced complete or partial shrinkage of their tumors lasting a median of 9.2 months.

Common side effects of Rubraca include nausea, fatigue, vomiting, low levels of red blood cells (anemia), abdominal pain, unusual taste sensation (dysgeusia), constipation, decreased appetite, diarrhea, low levels of blood platelets (thrombocytopenia) and trouble breathing (dyspnea).  Rubraca is associated with serious risks, such as bone marrow problems (myelodysplastic syndrome), a type of cancer of the blood called acute myeloid leukemia and fetal harm.

The agency approved Rubraca under its accelerated approval program, which allows approval of a drug to treat a serious or life-threatening disease or condition based on clinical data showing the drug has an effect on a surrogate (substitute) endpoint that is reasonably likely to predict clinical benefit. The sponsor is continuing to study this drug in patients with advanced ovarian cancer who have BRCA gene mutations and in patients with other types of ovarian cancer. The FDA also granted the Rubraca application breakthrough therapy designation and priority review status. Rubraca also received orphan drug designation, which provides incentives such as tax credits, user fee waivers and eligibility for exclusivity to assist and encourage the development of drugs intended to treat rare diseases.

Rubraca is marketed by Clovis Oncology, Inc. based in Boulder, Colorado. The FoundationFocus CDxBRCA companion diagnostic is marketed by Foundation Medicine, Inc. of Cambridge, Massachusetts.

////////////Rubraca, rucaparib, Clovis Oncology, Boulder, Colorado, fda 2016, cancer, ovarian

ZINPLAVA (BEZLOTOXUMAB), Approved FDA


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BEZLOTOXUMAB

Biologic License Application (BLA): 761046
Company: MERCK SHARP DOHME

Drug Name(s):
• ZINPLAVA (BEZLOTOXUMAB)

http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761046s000lbl.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/761046Orig1s000ltr.pdf

Drug
Name
Active Ingredient Approval Date FDA-approved use on approval date
Zinplava bezlotoxumab 10/21/2016 To reduce the recurrence of Clostridium difficile infection in patients aged 18 years or older
Drug Trials Snapshot

Image result for BEZLOTOXUMAB

From Wikipedia, the free encyclopedia
Bezlotoxumab
Monoclonal antibody
Type ?
Source Human
Target Clostridium difficile
Clinical data
ATC code none
Identifiers
CAS Number 1245634-25-6
ChemSpider none
Chemical and physical data
Formula C6464H9974N1726O2014S46
Molar mass 145.6 kg/mol

Bezlotoxumab (proprietary name Zinplava) is a human monoclonal antibody designed for the prevention of recurrence ofClostridium difficile infection.[1]

Actoxumab and bezlotoxumab are fully human monoclonal antibodies which bind Clostridium difficile (C diff) toxins A and B, respectively.

This drug, along with actoxumab, was developed through Phase II efficacy trials by a partnership between Medarex Inc and MassBiologics of the University of Massachusetts Medical School.[2] The project was then licensed to Merck Sharp & Dohme Corp for further development and commercialization.[3]

A Phase III trial only showed a benefit from bezlotoxumab; the combination of actoxumab and bezlotoxumab worked no better to prevent recurrence of C.difficile associated diarrhea than bezlotoxumab alone.[4]

Progress towards FDA approval

On June 9, 2016, the US FDA’s Antimicrobial Drugs Advisory Committee (formerly known as the Anti-Infective Drugs Advisory Committee)[5] met to discuss bezlotoxumab and voted to recommend approval of Merck’s license application by a vote of 10 to 5, generally expressing a willingness to accept that the trials had proven that bezlotoxumab decreased recurrence of C.diff overall while tempering this acceptance with a robust discussion of whether or not the drug provide more marked benefit in some patient groups and concern over a potential safety signal in the group treated with bezlotoxumab. The data suggested that bezlotoxumab might have the most benefit in sicker, high-risk patients but did show a statistical benefit in all patient subgroups. Although the patient population as a whole contained many very sick individuals and thus there were many adverse events in both the subjects receiving placebo and those receiving bezlotoxumab, the panel focused on a small number of serious events in patients with pre-existing congestive heart failure. In this subset the patients receiving bezlotoxumab appeared to have a higher rate of negative outcomes than the placebo group, although there many have been imbalance in how sick the patients in those groups were.[6][7]

The Prescription Drug User Fee Act (PDUFA) action date for the FDA’s review of bezlotoxumab is July 23, 2016.[8]

Bezlotoxumab gained FDA approval in October 2016: “indicated to reduce the recurrence of Clostridium difficile infection (CDI) in patients 18 years of age or older who are receiving antibiotics for CDI and are at high risk for recurrence.”[9]

Mechanism of TcdB neutralization

By x-ray crystallized structure of N-terminal of Clostridium difficile toxin B (TcdB), the toxin was identified to consist of three domains: a GTD, a cysteine protease and a combined repetitive oligopeptides, CROP domain. The CROP domain consists of four different peptide units, B1, B2, B3 and B4. Bezlotoxumab specifically inhibits the CROP domain of TcdB. It recognizes a specific epitope on toxin TcdB and has high affinity for that region. The GTD domain does not interact with bezlotoxumab, but appears to interact with B1, which is representative of the entire CROP domain. Bezlotoxumab interacts with either B2 andB3 or the overlapping residues region between the two domains. The B4 fragment does not interact with the specific portion of the CROP domain. Characterization of peptide B1 as full CROP domain of TcdB suggests that the antibody specifically react with the B2 region of the CROP domain, leading to the conclusion that TcdB epitope lies within the N-terminus of the CROP domain.[10]

Image result for BEZLOTOXUMABImage result for BEZLOTOXUMABImage result for BEZLOTOXUMAB

References

  1. Jump up^ “Statement On A Nonproprietary Name Adopted By The USAN Council – Bezlotoxumab” (PDF). American Medical Association.
  2. Jump up^ Lowy I, Molrine DC, Leav BA, Blair BM, Baxter R, Gerding DN, Nichol G, Thomas WD, Leney M, Sloan S, Hay CA, Ambrosino DM (January 2010). “Treatment with monoclonal antibodies against Clostridium difficile toxins”. N. Engl. J. Med. 362 (3): 197–205. doi:10.1056/NEJMoa0907635. PMID 20089970.
  3. Jump up^ “Merck & Co., Inc., Medarex, Inc. and Massachusetts Biologic Laboratories Sign Exclusive Licensing Agreement for Investigational Monoclonal Antibody Combination for Clostridium Difficile Infection”. Press Release. Merck Sharp & Dohme Corp. April 21, 2009.
  4. Jump up^ http://www.businesswire.com/news/home/20150920005053/en/Pivotal-Phase-3-Studies-Bezlotoxumab-Merck%E2%80%99s-Investigational
  5. Jump up^ http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/default.htm
  6. Jump up^ http://www.medpagetoday.com/Washington-Watch/FDAGeneral/58433?xid=nl_mpt_DHE_2016-06-10&eun=g411987d0r
  7. Jump up^ http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Anti-InfectiveDrugsAdvisoryCommittee/ucm505289.htm
  8. Jump up^ FDA Advisory Panel Gives Nod to Zinplava. June 2016
  9. Jump up^ FDA Approves Zinplava for Recurrent C. difficile. Oct 25 2016
  10. Jump up^ Orth P, Hernandez LD, Reichert P, Sheth PR, Beaumont M, Yang XY, Murgolo N, Ermakov G, DiNunzio E, Racine F, Karczewskl J, Secore S, Ingram RN, Mayhood T, Strickland C, Therien AG (June 27, 2014). “Mechanism of Action and Epitopes of Clostridium difficile Toxin B-neutralizing Antibody Bezlotoxumab Revealed by X-ray Crystallography”. Biological Chemistry. 289 (26): 18008–18021. doi:10.1074/jbcM114.560748.
Bezlotoxumab
Monoclonal antibody
Type ?
Source Human
Target Clostridium difficile
Clinical data
ATC code none
Identifiers
CAS Number 1245634-25-6
ChemSpider none
Chemical and physical data
Formula C6464H9974N1726O2014S46
Molar mass 145.6 kg/mol

///////BEZLOTOXUMAB, FDA 2016,  MERCK SHARP DOHME

FDA approves Amjevita, a biosimilar to Humira


New FDA Logo Blue

FDA approves Amjevita, a biosimilar to Humira

The U.S. Food and Drug Administration today approved Amjevita (adalimumab-atto) as a biosimilar toHumira (adalimumab) for multiple inflammatory diseases.

Read more.

FDA approves Amjevita, a biosimilar to Humira

For Immediate Release

September 23, 2016

Release

The U.S. Food and Drug Administration today approved Amjevita (adalimumab-atto) as a biosimilar to Humira (adalimumab) for multiple inflammatory diseases.

Amjevita is approved for the following indications in adult patients:

  • moderately to severely active rheumatoid arthritis;
  • active psoriatic arthritis;
  • active ankylosing spondylitis (an arthritis that affects the spine);
  • moderately to severely active Crohn’s disease;
  • moderately to severely active ulcerative colitis; and
  • moderate to severe plaque psoriasis.

Amjevita is also indicated for moderately to severely active polyarticular juvenile idiopathic arthritis in patients four years of age and older.

Health care professionals should review the prescribing information in the labeling for detailed information about the approved uses.

“This is the fourth FDA-approved biosimilar. The biosimilar pathway is still a new frontier and one that we expect will enhance access to treatment for patients with serious medical conditions,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research.

Biological products are generally derived from a living organism and can come from many sources, including humans, animals, microorganisms or yeast. A biosimilar is a biological product that is approved based on a showing that it is highly similar to an already-approved biological product and has no clinically meaningful differences in terms of safety, purity and potency (i.e., safety and effectiveness) from the reference product, in addition to meeting other criteria specified by law.

The FDA’s approval of Amjevita is based on review of evidence that included structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates Amjevita is biosimilar to Humira. It has been approved as a biosimilar, not as an interchangeableproduct.

The most serious known side effects with Amjevita are infections and malignancies. The most common expected adverse reactions with Amjevita are infections and injection site reactions.

Like Humira, the labeling for Amjevita contains a Boxed Warning to alert health care professionals and patients about an increased risk of serious infections leading to hospitalization or death. The Boxed Warning also notes that lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor blockers, including adalimumab products. The drug must be dispensed with a patient Medication Guide that describes important information about its uses and risks.

Amjevita is manufactured by Amgen, Inc., of Thousand Oaks, California. Humira was approved in December 2002 and is manufactured by AbbVie Inc. of North Chicago, Illinois.

Image result for humira structure

 

 

Adalimumab
Adalimumab structure.png
Farmaceutische gegevens
t1/2 10–20 dagen
Databanken
CAS-nummer 331731-18-1
ATC-code L04AB04
DrugBank BTD00049
Farmacotherapeutisch Kompas Adalimumab
Chemische gegevens
Molaire massa 144190.3 g/mol

///////FDA, Amjevita, biosimilar, Humira, FDA 2016

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.

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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

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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, 

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


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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

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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

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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

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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.

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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
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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

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