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TEGOBUVIR ..IN PHASE II FOR HEPATITIS C

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TEGOBUVIR

A non-structural protein 5B polymerase inhibitor
for Treatment of chronic hepatitis C

5-[6-[2,4-Bis(trifluoromethyl)phenyl]pyridazin-3-ylmethyl]-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine

CHEMICAL NAMES

1. 5H-Imidazo[4,5-c]pyridine, 5-[[6-[2,4-bis(trifluoromethyl)phenyl]-3-pyridazinyl]methyl]-
2-(2-fluorophenyl)-

2. 5-({6-[2,4-bis(trifluoromethyl)phenyl]pyridazin-3-yl}methyl)-2-(2-fluorophenyl)-5H-
imidazo[4,5-c]pyridine

MOLECULAR FORMULA C25H14F7N5

MOLECULAR WEIGHT 517.4

MANUFACTURER Gilead Sciences, Inc.

CODE DESIGNATION

  • GS 333126
  • GS 9190
  • GS-333126
  • GS-9190
  • Tegobuvir
  • UNII-5NOK5X389M

CAS REGISTRY NUMBER 1000787-75-6

GS-9190, an RNA-directed RNA polymerase (NS5B) inhibitor, is in phase II clinical evaluation at Gilead for the treatment of hepatitis C virus (HCV) infection. A clinical trial with GS-9190 in combination with peginterferon alfa-2a and ribavirin and with GS-9451 or with GS-9256 in treatment-naive subjects with chronic genotype 1 HCV infection was discontinued due to serious adverse events.

Gilead (Originator)
Katholieke Universiteit Leuven (Originator)

……………………………………….

tegobuvir

PATENTS

WO 2005063744

WO 2008005519

WO 2009009001

WO 2010151488

WO 2010151487

WO 2010151472

WO 2011072370

WO 2011156757

WO 2012087596

WO 2013101550

The HCV non-nucleoside inhibitor Tegobuvir utilizes a novel mechanism of action to inhibit NS5B polymerase function.

Hebner CM, Han B, Brendza KM, Nash M, Sulfab M, Tian Y, Hung M, Fung W, Vivian RW, Trenkle J, Taylor J, Bjornson K, Bondy S, Liu X, Link J, Neyts J, Sakowicz R, Zhong W, Tang H, Schmitz U.

PLoS One. 2012;7(6):e39163. doi: 10.1371/journal.pone.0039163. Epub 2012 Jun 13.

Tegobuvir (GS-9190) potency against HCV chimeric replicons derived from consensus NS5B sequences from genotypes 2b, 3a, 4a, 5a, and 6a.

Wong KA, Xu S, Martin R, Miller MD, Mo H.

Virology. 2012 Jul 20;429(1):57-62. doi: 10.1016/j.virol.2012.03.025. Epub 2012 Apr 28.

The protease inhibitor, GS-9256, and non-nucleoside polymerase inhibitor tegobuvir alone, with ribavirin, or pegylated interferon plus ribavirin in hepatitis C.

Zeuzem S, Buggisch P, Agarwal K, Marcellin P, Sereni D, Klinker H, Moreno C, Zarski JP, Horsmans Y, Mo H, Arterburn S, Knox S, Oldach D, McHutchison JG, Manns MP, Foster GR.

Hepatology. 2012 Mar;55(3):749-58. doi: 10.1002/hep.24744.

Mechanistic characterization of GS-9190 (Tegobuvir), a novel nonnucleoside inhibitor of hepatitis C virus NS5B polymerase.

Shih IH, Vliegen I, Peng B, Yang H, Hebner C, Paeshuyse J, Pürstinger G, Fenaux M, Tian Y, Mabery E, Qi X, Bahador G, Paulson M, Lehman LS, Bondy S, Tse W, Reiser H, Lee WA, Schmitz U, Neyts J, Zhong W.

Antimicrob Agents Chemother. 2011 Sep;55(9):4196-203. doi: 10.1128/AAC.00307-11. Epub 2011 Jul 11.

……………………..
http://www.google.com/patents/WO2013040492A2
ompound 1 can be prepared using synthetic methods and intermediates like those described in US 7,754,720. Compound 1 can also be prepared as described in the following Example.
Compound 1 is:

Figure US20130243726A1-20130919-C00001

Compound 1 may also be referred to as 5-((6-(2,4-bis(trifluoromethyl)phenyl)pyridazin-3-yl)methyl)-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine, 5-[[6-[2,4-bis (trifluoromethyl)phenyl]pyridazin=3-yl]methyl]-2-(2-fluorophenyl).

Example 1 : 5-({6-[2,4-bis(trifluoromethyl)phenyl]pyridazin-3-yl}methyl)-2-(2-fluorophenyl)-5H- imidazo[4,5-c]pyridi

Figure imgf000059_0001
Figure imgf000059_0002

Compound 103 was dissolved in dimethoxyethane (DME). To this solution was added 2,4-bis(trifluromethyl)phenylboronic acid 105 and a 2N aq. Na2C03 solution. To the resulting biphasic mixture was added Pd(PPh3)4 and the reaction was then heated at 80°C for 72 hrs. The reaction was cooled to room temperature and filtered through Celite and the Celite washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified on 6g Si02 using MeOH/CH2CI2 to elute compound. The compound thus obtained was contaminated with PPh3(0). The product was repurified on a 1 mm Chromatotron plate with 0 to 5%

MeOH/CH2CI2 in 1 % steps. The pure fractions were combined and concentrated in vacuo, then dried on high vacuum for 12 hrs. 11.8 mg of the free base of compound 1 was obtained with no PPh3 contamination. 1H NMR (300MHz,CD3OD) δ 6.20 (s, 2), 7.32 (m, 3), 7.52 (m, 1 ), 7.78 (d, 1), 7.89 (d, 1), 7.95 (s, 2), 8.15 (m, 3), 8.35 (d, 1), 9.12 (s, 1); LC/MS M+H = 518.

The intermediate compound 104 was prepared as follows, a. Preparation of Compound 10

Figure imgf000060_0001

101 102

Figure imgf000060_0003

To a solution of the commercially available starting material 101 in CHCI3, trichloroisocyanuric acid (TCCA) was added at 60°C. Then the solution was stirred for 1.5 hrs, cooled, and filtered with HiFlo-Celite. The filtrate was concentrated and dried with vacuum. The yield was 5.037 g of compound 102. b. Preparation of Compound 104.

Figure imgf000060_0002

102 104

Figure imgf000060_0004

To a solution of compound 103 in DMF (dimethylformamide), NaOH was added.

Compound 102 was dissolved in DMF (20 mL) and added to the solution slowly. The reaction was stirred for 3 hrs, was diluted with water and extracted with EtOAc. The organic layer was dried with Na2S0 . The solvent was removed and the product recrystallized with

dichloromethane. The yield was 5.7 g of compound 103.

……………………………
US7754720
Example 1a Synthesis of 5-({6-[2,4-bis(trifluoromethyl)phenyl]pyridazin-3-yl}methyl)-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridineIn this method, dimethoxyethane or its related solvents, all having the general formula R1OR2O(R4O)aRwherein each of R1, R2, Rand Rare independently selected from C1-C6 alkyl and a is 0 or 1, have been found to be particularly advantageous over the conventional solvent DMF. Typically, each of R1, R2, Rand Rare independently C1-Calkyl and usually a is 0. C1-Calkyl includes fully saturated primary, secondary or tertiary hydrocarbon groups with 1 to 6 carbon atoms and thereby includes, but is not limited to methyl, ethyl, propyl, butyl, etc.Step 1

Figure US07754720-20100713-C00008
Figure US07754720-20100713-C00009
Figure US07754720-20100713-C00010
Compound MW Amount mmoles Equivalents
SM 128.56 5 g 38.9 1
TCCA 232.41 3.62 g 15.6 0.4
CHCl3 130 ml

To a solution of the commercially available starting material (SM) in CHCl3, trichloroisocyanuric acid (TCCA) was added at 60° C. Then the solution was stirred for 1.5 hrs., cooled down and filtered with HiFlo-Celite. The filtrate was concentrated and dried with vacuum. The yield was 5.037 g.

Step 2

Figure US07754720-20100713-C00011
Figure US07754720-20100713-C00012
Figure US07754720-20100713-C00013
Compound MW Amount mmoles Equivalents
S.M. 163 5.073 g 31.12 1
Core 213.2 6.635 g 31.12 1
NaOH (10%) 40 1.245 g 31.12 1
DMF 320 ml

To a solution of core (obtained as described in literature in DMF (dimethylformamide), NaOH was added. Then SM for this step (obtained from step 1) was dissolved in DMF (20 ml) and added to the solution slowly. The reaction was stirred for 3 hrs, was diluted with water and extracted with EtOAc. The organic layer was dried with Na2SO4. The solvent was removed and the product recrystallized with DCM (dichloromethane). The yield was 5.7 g.

Step 3

Figure US07754720-20100713-C00014
Figure US07754720-20100713-C00015
Figure US07754720-20100713-C00016
Compound MW Amount Moles Equivalents
A 453.79 95 mg 0.209 1
DME 500 ul
2 N aq. Na2CO3 313ul 0.626 3
2,4-bisCF3 257.93 80.9 mg 0.313 1.5
phenylboronic
acid
Pd(PPh3)4 1155 12 mg 0.0104 0.05

Compound A was dissolved in dimethoxyethane (DME). To this solution was added 2,4-bis(trifluromethyl)phenylboronic acid and a 2N aq. Na2COsolution. To the resulting biphasic mixture was added Pd(PPh3)and the reaction was then heated at 80° C. for 72 hrs. The reaction was cooled to room temperature and filtered through Celite and the Celite washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified on 6 g SiO2 using MeOH/CH2Cl2 to elute compound. The compound thus obtained was contaminated with PPh3(O). The product was repurified on a 1 mm Chromatotron plate with 0 to 5% MeOH/CH2Clin 1% steps. The pure fractions were combined and concentrated in vacuo, then dried on high vacuum for 12 hrs. 11.8 mg of the free base of compound (1) was obtained with no PPhcontamination.

1H NMR (300 MHz, CD3OD)

6.20 (s, 2)

7.32 (m, 3)

7.52 (m, 1)

7.78 (d, 1)

7.89 (d, 1)

7.95 (s, 2)

8.15 (m, 3)

8.35 (d, 1)

9.12 (s, 1)

LC/MS M+H=518

Example 1b Synthesis of 5-({6-[2,4-bis(trifluoromethyl)phenyl]pyridazin-3-yl}methyl)-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridineThis example is directed to an additional method for making compound (1), employing the following schemes.

Figure US07754720-20100713-C00017

Methanesulfonic acid was added to 2-fluorobenzoic acid in a reactor with active cooling keeping T≦50° C. 3,4-Diaminopyridine was then added portionwise to this cooled slurry, keeping T≦35° C. The contents of the reactor were then heated to 50° C. Phosphorus pentoxide was added in a single charge. The reaction was then heated at 90-110° C. for at least 3 hours. The reaction was sampled for completion by HPLC analysis. The reaction was cooled to ambient temperature and water was added portionwise slowly to quench the reaction. The reaction was then diluted with water. In solubles were removed by filtration. The pH of the filtrate was adjusted to 5.5-5.8 with ammonium hydroxide. The reaction was allowed to self-seed and granulate for ˜4 hours at ambient temperature. The pH was then adjusted to 8.0-9.3 with ammonium hydroxide. The slurry was held at ambient temperature for at least 2 hours. The solids were isolated by filtration and washed with water, followed by IPE. The wet cake was dried in vacuo at not more than 60° C. until ≦1% water remains. The dry product is core (2).

Summary of Materials M.W. Wt. Ratio Mole ratio
3,4-Diaminopyridine 109.13 1.0 1.0
2-Fluorobenzoic acid 140.11 1.4 1.1
Methanesulfonic acid 96.1 7.0 8.0
Phosphorus pentoxide 141.94 1.3 1.0
Water 18.02 40
Isopropyl ether 102.17 5.0
Ammonium hydroxide 35.09 ~10
Figure US07754720-20100713-C00018

A solution of compound (2a) in 1,2-dichloroethane was heated to 40-45° C. Trichloroisocyanuric acid was added and the mixture was heated at 60-70° C. for at least 2 hours. The reaction was sampled for completion by HPLC analysis. The reaction was cooled to ambient temperature. Celite was added to absorb insolubles, then solids were removed by filtration. The filtrate was washed with 0.5 N sodium hydroxide solution. The organic layer was concentrated to lowest stirrable volume and displaced with DMF. Core (2) and 10% aqueous sodium hydroxide solution were added. The reaction was stirred at ambient temperature for at least 8 hours. The reaction was sampled for completion by HPLC analysis. An additional 10% charge of 10% sodium hydroxide solution was added to the reaction. The reaction was then charged into water to isolate the crude product. After granulating for at least 1 hour, the solids were isolated and washed with water and isopropyl ether. Ethyl acetate was added and refluxed (internal T=70-77° C.) for 1-5 hours to dissolve product, then cooled to 18-23° C. slowly over 4-8 hours. The reactor contents were agitated at 18-23° C. for 8-20 hours and solids collected by filtration and rinsed with ethyl acetate. Low melt (i.e., DSC about 220 degrees C.) amorphous compound (1) was discharged. Amorphous compound (1) was dissolved in ethyl acetate by heating at reflux (internal T=70-77° C.) for 1-5 hours. Water content is controlled to about 0.2% by azeotropically removing water (with ethyl acetate the upper limit on water content is about 0.6% by weight; at about 0.9% by weight water the amorphous material will reprecipitate and crystals will not be obtained). The reactor contents are cooled slowly to 18-23° C. over 4-8 hours, then agitated at 18-23° C. for 8-20 hours and solids collected by filtration. The solids were rinsed with ethyl acetate and dried in vacuo at not more than 60° C. to obtain the dry crystalline compound (1).

Summary of Materials M.W. Wt. Ratio Mole ratio
3-chloro-6-methylpyridazine 128.56 1.0 1.0
2,4bis(trifluromethyl)phenylboronic 257.93 4.0 2.0
acid
X-Phos 476.72 0.18 0.05
Palladium acetate 224.49 0.04 0.025
1,2-Dimethoxyethane 90.12 16.7
Potassium carbonate 138.21 2.15 2.0
Water 18.02 7.8
Copper iodide 190.45 0.037 0.025
Celite 0.25
Heptane 100.2 22.4

Nuclear Magnetic Resonance (1H-, 13C-, and 19F-NMR) SpectraNuclear magnetic resonance (NMR) spectra of compound (1) is consistent with the proposed structure. The 13C, 19F, and 1H-NMR spectra of compound (1) in DMSO-dwere measured using a Varian UnityInova-400 FT-NMR spectrometer. Spectra are shown in the table below. The NMR chemical shift assignments were established using 2D correlation experiments (COSY, HSQC, HMBC and HSQCTOCSY).

1H- and 13C-NMR Chemical Shift Assignments for Compound (1) Reference Standard

Atom δC/ppm (DMSO-d6) δF/ppm (DMSO-d6) δH/ppm (DMSO-d6)
1A 140.16
2A 128.32 (qa, JCF = 32 Hz)
3A 123.61, m 8.24 (m, 1 H)
4A 130.27 (q, JCF = 34 Hz)
5A 129.54 (q, JCF = 3 Hz) 8.22 (m, 1 H)
6A 133.36 7.88 (m, 1 H)
7A 123.20 (q, JCF = 273 Hz) −56.4b
8A 123.02 (q, JCF = 275 Hz) −62.0b
1B 158.76
2B 128.16 8.01 (d, 1 H, J = 8.4 Hz)
3B 126.20 7.95 (d, 1 H, J = 8.8 Hz)
4B 157.70
5B  60.49 6.17 (s, 2 H)
2C 131.86 8.31 (m, 1 H)
3C 112.63 7.86 (m, 1 H)
4C 155.44
6C 168.11 (d, JCF = 6 Hz)
8C 145.08
9C 133.06 9.25 (s, 1 H)
1D 123.11 (d, JCF = 10 Hz)
2D 160.46 (d, JCF = 254 Hz) −111.7
3D 116.59 (d, JCF = 22 Hz) 7.29 (m, 1 H)
4D 130.84 (d, JCF = 8 Hz) 7.46 (m, 1 H)
5D 124.13 (d, JCF = 4 Hz) 7.31 (m, 1 H)
6D 131.72 (d, JCF = 2 Hz) 8.35 (m, 1 H)
amultiplicity, s: singlet, d: doublet, q: quartet, m: multiplet
binterchangeable signals

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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

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