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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 LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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JNJ-A07


str2

JNJ-A07

S + FORM

CAS 2135640-93-4 ROT (+)S

Butanoic acid, 4-[3-[[1-(4-chlorophenyl)-2-[2,3-dihydro-6-(trifluoromethoxy)-1H-indol-1-yl]-2-oxoethyl]amino]-5-methoxyphenoxy]-, (+)-

(+)-4-[3-[[1-(4-Chlorophenyl)-2-[2,3-dihydro-6-(trifluoromethoxy)-1H-indol-1-yl]-2-oxoethyl]amino]-5-methoxyphenoxy]butanoic acid

(+)-4-[3-([(1S)-1-(4-Chlorophenyl)-2-oxo-2-[6-(trifluoromethoxy)-2,3-dihydro-1H-indol-1-yl]ethyl]amino)-5-methoxyphenoxy]butanoic acidMolecular FormulaC28 H26 Cl F3 N2 O6Molecular Weight578.964

REF

Kaptein, S.J.F., Goethals, O., Kiemel, D. et al. A pan-serotype dengue virus inhibitor targeting the NS3–NS4B interaction. Nature (2021). https://doi.org/10.1038/s41586-021-03990-6

09938-scicon2-jnj.jpg

JNJ-018

CAS 2135640-91-2 +/-, R,S

CAS 2135640-92-3 ROT (-)R

Butanoic acid, 4-[3-[[1-(4-chlorophenyl)-2-[2,3-dihydro-6-(trifluoromethoxy)-1H-indol-1-yl]-2-oxoethyl]amino]-5-methoxyphenoxy]-, (-)-

(-)-4-[3-[[1-(4-Chlorophenyl)-2-[2,3-dihydro-6-(trifluoromethoxy)-1H-indol-1-yl]-2-oxoethyl]amino]-5-methoxyphenoxy]butanoic acid

  • Janssen (Originator)
  • Katholieke Universiteit Leuven (Originator)
  • NS4B Protease (Dengue Virus) Inhibitors
  • Serine Protease NS3/Non-Structural Protein NS4B Protease (Dengue Virus) Interaction Inhibitors

A pan-serotype dengue virus inhibitor targeting the NS3–NS4B interaction

https://www.nature.com/articles/s41586-021-03990-6

https://www.nature.com/articles/s41586-021-03990-6#citeas

Abstract

Dengue virus causes approximately 96 million symptomatic infections annually, manifesting as dengue fever or occasionally as severe dengue1,2. There are no antiviral agents available to prevent or treat dengue. Here, we describe a highly potent dengue virus inhibitor (JNJ-A07) that exerts nanomolar to picomolar activity against a panel of 21 clinical isolates that represent the natural genetic diversity of known genotypes and serotypes. The molecule has a high barrier to resistance and prevents the formation of the viral replication complex by blocking the interaction between two viral proteins (NS3 and NS4B), thus revealing a previously undescribed mechanism of antiviral action. JNJ-A07 has a favourable pharmacokinetic profile that results in outstanding efficacy against dengue virus infection in mouse infection models. Delaying start of treatment until peak viraemia results in a rapid and significant reduction in viral load. An analogue is currently in further development.

2-(4-Chlorophenyl)-1-(6-(trifluoromethoxy)indolin-1-yl)-ethanone (1)

127 A mixture of 6-(trifluoromethoxy)indoline ([CAS 959235-95-1], 2 g, 9.84 mmol), 2-(4-chlorophenyl)acetic acid 128 ([CAS 1878-66-6], 1.85 g, 10.8 mmol), HATU (5.6 g, 14.8 mmol) and diisopropylethylamine (4.9 mL, 29.5

129 mmol) in DMF (40 mL) was stirred at room temperature for 12 h. Water was added and the precipitate was

130 filtered off. The residue was taken up with EtOAc. The organic solution was washed with a 10 % aqueous

131 solution of K2CO3, brine, dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure. 132 The residue was purified by chromatography on silica gel (15-40 pm, 80 g, heptane/EtOAc gradient 90/10 to 133 60/40). The pure fractions were combined and the solvent was concentrated under reduced pressure to give 2-(4-

134 chlorophenyl)-1-(6-(trifluoromethoxy)indolin-1-yl)-ethanone 1 (3 g, yield: 86 %).

135 1 H NMR (400 MHz, DMSO-d6) d ppm 7.99 (s, 1 H), 7.37 – 7.41 (m, 2 H), 7.29 – 7.34 (m, 3 H), 6.97 (dd, J = 8.1, 1.3 Hz, 1 H), 4.25 (t, J = 8.6 Hz, 2 H), 3.88 (s, 2 H), 3.18 (t, J = 8.5 Hz, 2 H); 13

136 C NMR (101 MHz, 137 CHLOROFORM-d) δ ppm 168.91, 148.65, 148.63, 144.05, 133.16, 132.26, 130.63, 129.54, 128.93, 124.87, 120.50 (q, J=257.2 Hz), 116.38, 110.83, 77.26, 48.86, 42.52, 27.59; LC-MS: [M+H]+

138 728; purity 99 % (method LCMS2); Melting Point: 116-131 °C (DSC peak: 120.2 °C); HRMS (ESI+) m/z: [M]+ 139 calcd for C17H13ClF3NO2,

140 356.0660; found, 356.0657

141 2-Bromo-2-(4-chlorophenyl)-1- (6-(trifluoromethoxy)indolin-1-yl)ethanone (2)

142 At -78 °C, under nitrogen flow, LiHMDS (1.5 M in THF, 11.2 mL, 16.9 mmol) was added dropwise to a mixture 143 of 1 (3 g, 8.43 mmol) in THF (50 mL). The mixture was stirred for 15 min at -78 °C and a solution of N

144 bromosuccinimide (1.65 g, 9.3 mmol) in THF (30 mL) was added dropwise. After stirring for 2 h at -78 °C, the 145 reaction was quenched with a saturated aqueous solution of NH4Cl. The mixture was extracted with EtOAc. The 146 organic layer was separated, dried over MgSO4, filtered, and the solvent was evaporated under reduced pressure

147 to give 2-bromo-2-(4-chlorophenyl)-1- (6-(trifluoromethoxy)indolin-1-yl)ethanone 2 (3.6 g, yield: 98 %) as an 148 oil. The compound was used without further purification in the next step.

149 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.19 (s), 7.52 – 7.57 (m), 7.34 – 7.39 (m), 7.17 (d, J=8.2 Hz), 6.92 (dd, J=8.2, 1.1 Hz), 5.56 (s), 4.37 (td, J=10.1, 6.5 Hz), 4.09 (td, J=10.1, 6.7 Hz), 3.12 – 3.31 (m); 13

150 C NMR

151 (101 MHz, CHLOROFORM-d) δ ppm 164.90 (s), 148.68 (d, J=2.2 Hz), 143.75 (s), 135.46 (s), 133.99 (s), 152 130.52 (s), 129.79 (s), 129.10 (s), 125.01 (s), 117.20 (s), 120.47 (q, J=257.2 Hz), 111.36 (s), 48.88 (s), 46.61 (s), 27.65 (s); LC-MS: [M+H]+ 436; purity 100 % (method LCMS2); HRMS (ESI+) m/z: [M]+ 153 calcd for

154 C17H13O2NBrClF3, 433.9765; found, 433.9764

155 tert-Butyl 4-(3-amino-5-methoxyphenoxy)butanoate (3) 156 To a mechanically stirred solution of tert-butyl 4-bromobutanoate ([CAS 110661- 5 91-1], 42.3 g, 0.19 mol) in

157 DMF (600 mL) was added in portions a solid mixture of 3-amino-5-methoxyphenol ([CAS 162155-27-3], 26.4 158 g, 0.19 mol) and Cs2CO3 (123.6 g, 0.379 mol). The reaction mixture was stirred at 60 °C for 65 h, and allowed to

159 reach room temperature. The mixture was poured out into water (2.5 L). The product was extracted with Et2O (2 160 x). The combined organic layers were washed with brine, dried over MgSO4, and filtered. The solvent was

161 evaporated under reduced pressure, and then co-evaporated with toluene. The residue was purified by normal 162 phase HPLC (Stationary phase: silica gel 60A 25-40 pm (Merck), Mobile phase: gradient EtOAc/heptane 20/80 163 to 60/40), yielding tert-butyl 4-(3-amino-5-methoxyphenoxy)butanoate 3 as an oil (27 g, yield: 50 %).

164 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.89 – 5.92 (m), 5.86 (d, J=2.2 Hz), 3.92 (t, J=6.2 Hz), 3.73 (s), 3.66 (br s), 2.40 (t, J=7.4 Hz), 1.98 – 2.08 (m), 1.45 (s); 13

165 C NMR (101 MHz, CHLOROFORM-d) δ ppm 172.61 166 (s), 161.69 (s), 161.02 (s), 148.35 (s), 94.33 (s), 93.89 (s), 91.52 (s), 80.35 (s), 66.74 (s), 55.17 (s), 32.07 (s), 28.13 (s), 24.78 (s); LC-MS: [M+H]+ 282; purity 94 % (method LCMS2); HRMS (ESI+) m/z: [M]+

167 calcd for 168 C15H24O4N, 282.1700; found, 282.1695

169 tert-Butyl 4-(3-((1-(4-chlorophenyl)-2-oxo-2-(6-(trifluoromethoxy)indolin-1-yl)ethyl)amino)-5-

170 methoxyphenoxy)butanoate (4)

171 A mixture of 2 (3.6 g, 8.3 mmol), 3 (2.3 g, 8.3 mmol) and diisopropylethylamine (1.7 ml, 9.94 mmol) in CH3CN 172 (80 mL) was stirred at 70 °C for 4 h. The mixture was concentrated under reduced pressure, diluted with EtOAc,

173 and washed with 1 N aqueous HCl and water. The organic phase was separated, dried over MgSO4, filtered, and 174 the solvent was evaporated under reduced pressure. The compound was purified by flash chromatography on 175 silica gel (15-40 pm, 120 g, heptane/EtOAc 80/20). The pure fractions were combined and evaporated to dryness

176 to give, after crystallization from diisopropyl ether, tert-butyl 4-(3-((1-(4-chlorophenyl)-2-oxo-2-(6-

177 (trifluoromethoxy)indolin-1-yl)ethyl)amino)-5-methoxyphenoxy)butanoate 4 (2.6 g, yield: 49 %).

178 1 H NMR (400 MHz, DMSO-d6) d ppm 8.03 (s, 1 H), 7.55 (d, J = 8.6 Hz, 2 H), 7.43 (d, J = 8.6 Hz, 2 H), 7.33 (d, 179 J = 8.1 Hz, 1 H), 7.01 (dd, J = 8.1, 1.5 Hz, 1 H), 6.44 (d, J = 8.8 Hz, 1 H), 5.94 (d, J = 2.0 Hz, 2 H), 5.75 (t, J = 180 2.0 Hz, 1 H), 5.55 (d, J = 8.8 Hz, 1 H), 4.51 (td, J = 10.3, 6.5 Hz, 1 H), 4.04 (td, J = 10.3, 7.3 Hz, 1 H), 3.84 (t, J 6 181 = 6.3 Hz, 2 H), 3.62 (s, 3 H), 3.09 – 3.23 (m, 2 H), 2.31 (t, J = 7.3 Hz, 2 H), 1.86 (quin, J = 6.8 Hz, 2 H), 1.39 (s, 9 H); 13

182 C NMR (101 MHz, CHLOROFORM-d) δ ppm 172.57, 168.84, 161.66, 161.02, 148.65, 148.63, 147.68,

183 143.79, 135.66, 134.48, 129.58, 129.42, 129.38, 124.99, 116.92, 120.50 (q, J=257.2 Hz), 111.13, 93.02, 92.72, 91.06, 80.38, 77.25, 66.79, 59.74, 55.17, 48.31, 32.09, 28.15, 27.64, 24.77; LC-MS: [M+H]+

184 635; purity: 98 % (method LCMS3); Melting Point: 109-125 °C (DSC peak: 116.1 °C); HRMS (ESI+) m/z: [M]+ 185 calcd for 186 C32H34ClF3N2O6, 635.2130; found, 635.2127 187 (+)-4-(3-((1-(4-Chlorophenyl)-2-oxo2-(6-(trifluoromethoxy)indolin-1-yl)ethyl)amino)-5-

188 methoxyphenoxy)butanoic acid (JNJ-A07) 189 A solution of 4 (2.4 g, 3.8 mmol) in 4 M HCl in dioxane (24 mL) was stirred at 5 °C for 3 h and at room 190 temperature for 3 h. The precipitate was filtered off and dried to afford 4-(3-((1-(4-chlorophenyl)-2-oxo2-(6- 191 (trifluoromethoxy)indolin-1-yl)ethyl)amino)-5-methoxyphenoxy)butanoic acid as an HCl salt (racemic JNJ192 A07, 2 g, 0.8 eq. HCl, 0.07 eq. H2O). This salt was neutralized prior to chiral separation by dissolving it in 193 EtOAc and treating this solution with 1 N aqueous NaOH and evaporation of the organic layer under reduced 194 pressure.

The enantiomers were separated via preparative chiral SFC (Stationary phase: Chiralcel® OD-H 5 pm 195 250 x 30 mm, Mobile phase: 50 % CO2, 50 % iPrOH (+ 0.3 % iPrNH2)) and further purified via preparative 196 achiral SFC (Stationary phase: Cyano® 6 pm 150 x 21.2 mm, Mobile phase: 80 % CO2, 20 % MeOH (+ 0.3 % 197 iPrNH2)). The product fractions were combined and evaporated under reduced pressure. Each enantiomer was 198 taken up with EtOAc and washed with 1 N aqueous HCl. The organic layers were separated, dried over MgSO4, 199 filtered, and the solvent was evaporated under reduced pressure. The first eluted enantiomer was solidified from 200 diethyl ether/diisopropyl ether to give the epimer of JNJ-A07 (616 mg, yield: 28 %).

The second eluted

201 enantiomer was solidified from diethyl ether/diisopropyl ether to give JNJ-A07 (715 mg, yield: 32 %).

202 203 Epimer of JNJ-A07:

204 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.12 (br s, 1 H), 8.04 (br s, 1 H), 7.55 (br d, J = 8.2 Hz, 2 H), 7.44 (br d, 205 J = 8.5 Hz, 2 H), 7.34 (br d, J = 7.9 Hz, 1 H), 7.01 (br d, J = 7.6 Hz, 1 H), 6.45 (br s, 1 H), 5.95 (br d, J = 10.1 206 Hz, 2 H), 5.76 (s, 1 H), 5.57 (br s, 1 H), 4.47 – 4.57 (m, 1 H), 3.99 – 4.11 (m, 1 H), 3.85 (br t, J = 6.3 Hz, 2 H), 3.62 (s, 3 H), 3.08 – 3.27 (m, 2 H), 2.34 (br t, J = 7.3 Hz, 2 H), 1.87 (quin, J = 6.7 Hz, 2 H); 13

207 C NMR (101 MHz, 208 DMSO-d6) δ ppm 174.56, 169.79, 161.46, 160.71, 149.08, 147.64, 144.48, 137.28, 132.91, 131.95, 130.56, 209 128.89, 126.34, 120.58 (d, J=256.0 Hz), 116.69, 109.52, 93.08, 92.80, 90.23, 66.65, 58.69, 55.20, 48.65, 30.57, 27.48, 24.72; LC-MS: [M+H]+ 579; purity: 100 % (method LCMS1);

Chiral SFC: [M+H]+ 210 579; chiral purity 100 % (method SFC1); [a]D20 211 : -48.5° (589 nm, c 0.27 w/v %, DMF, 20 °C); Melting Point: 62-80 °C (DSC peak: 70.6 °C); HRMS (ESI+) m/z: [M]+ 212 calcd for C28H27O6N2ClF3, 579.1504; found, 579.1501 213 214

JNJ-A07: 215 1 H NMR (500 MHz, DMSO-d6) δ ppm 12.12 (brs, 1 H), 8.04 (br s, 1 H), 7.55 (br d, J = 8.2 Hz, 2 H), 7.44 (br d, 216 J = 8.2 Hz, 2 H), 7.34 (br d, J = 7.9 Hz, 1 H), 7.01 (br d, J = 7.9 Hz, 1 H), 6.45 (br s, 1 H), 5.95 (br d, J = 10.1 217 Hz, 2 H), 5.76 (br s, 1 H), 5.57 (s, 1 H), 4.46 – 4.59 (m, 1 H), 3.99 – 4.10 (m, 1 H), 3.85 (br t, J = 6.1 Hz, 2 H), 3.62 (s, 3 H), 3.09 – 3.27 (m, 2 H), 2.34 (br t, J = 7.3 Hz, 2 H), 1.87 (br t, J = 6.8 Hz, 2 H); 13

218 C NMR (101 MHz,

219 DMSO-d6) δ ppm 174.53 (C28), 169.79 (C10), 161.47 (C20), 160.72 (C22), 149.08 (C18), 147.65 (C6), 144.48 220 (C8), 137.29 (C12), 132.92 (C15), 131.95 (C3), 130.56 (C13, C17), 128.89 (C14, C16), 126.34 (C4), 120.58 (q, 221 J = 255.1 Hz, C9), 116.67 (C5), 109.51 (C7), 93.11 (C23), 92.81 (C21), 90.26 (C19), 66.66 (C25), 58.70 (C11), 55.21 (C24), 48.67 (C1), 30.57 (C27), 27.49 (C2), 24.72 (C26); LC/MS: [M+H]+

222 579; purity 100 % (method LCMS1); Chiral SFC: [M+H]+ 579; chiral purity 100 % (method SFC1); [a]D20

223 : +42.9° (589 nm, c 0.28 w/v %, 224 DMF, 20 °C); Melting point: 62-78 °C (DSC peak: 71.3 °C) ; HRMS (ESI+) m/z calcd for C28H27O6N2ClF3 [M]+ 225 , 579.1504, found 579.1500; Elemental analysis requires C, 58.09 %; H, 4.53 %; N, 4.84 % found C, 226 58.60 %; H, 4.59 %; N, 4.80 %

CLIP

https://www.bioworld.com/articles/512333-potent-selective-pan-serotype-dengue-inhibitor-developed

Blocking the interaction between two dengue virus (DENV) nonstructural proteins, NS3 and NS4B, with a newly developed small-molecule inhibitor resulted in potent antiviral activity in mouse models, according to an international collaborative study led by scientists at the University of Leuven (KU Leuven), CD3 the Centre for Drug Design and Discovery in Leuven, and Janssen Pharmaceutica in Beerse, Belgium.

This protein interaction represents a promising new target for the development of pan-serotype DENV inhibitors with a high barrier to resistance, with the potency of the inhibition warranting further development of these compounds, the authors reported in the October 6, 2021, edition of Nature.

“This is the first study to show that blocking the NS3/NS4B interaction has potent antiviral activity in mice warranting the further development of such inhibitors,” said study co-leader Johan Neyts, professor of virology at KU Leuven.

Dengue is currently among the leading threats to global public health, with an estimated 96 million individuals developing dengue disease, which is probably an underestimation.

In addition, the incidence of dengue has increased approximately 30-fold over the past 50 years. DENV is now endemic in the subtropical regions of 128 countries, with an estimated 4 billion people at risk of infection, predicted to increase to 6 billion by 2080.

This dengue upsurge is driven by various factors, most notably rapid urbanization and the spread of the Aedes mosquito vectors due to climate change.

The DENV has four serotypes that are further classified into genotypes, which are increasingly co-circulating in endemic regions. Antibodies to infection with one serotype can lead to a more severe second infection with a different serotype increases the risk of potentially life-threatening severe dengue.

The DENV vaccine Dengvaxia (Sanofi-Pasteur), which has been approved in several countries for individuals aged at least 9 years, is only recommended for those with previous DENV exposure.

Moreover, there are currently no available antiviral agents for dengue prevention or treatment, while development of pan-serotype DENV inhibitors has proven challenging.

“The major developmental challenge has been to obtain ultrapotent antivirals that also have equipotent activity against the four DENV serotypes,” Neyts told BioWorld Science.

Such drugs should lower viral loads during an ongoing infection, thereby reducing dengue-associated morbidity and mortality, as well as transmission.

In their new Nature study, researchers co-led by Neyts, Patrick Chaltin, managing director of CD3 the Centre for Drug Design and Discovery, and Marnix Van Loock, R&D Lead Emerging Pathogens, Janssen Global Public Health at Janssen Pharmaceutica, identified potential new DENV inhibitors using large-scale cell-based anti-DENV-2 screening.

“We screened tens of thousands of molecules and interesting hits were further optimized to eventually obtain JNJ-A07 and other ultrapotent and selective analogues, with roughly 2,000 analogues being synthesized and tested,” said Neyts.

Notably, the promising small molecule JNJ-A07 was demonstrated to have nanomolar to picomolar activity against a panel of 21 clinical isolates representing the natural genetic diversity of known DENV genotypes and serotypes.

The molecule was then shown to have a high barrier to resistance “by months of culturing the dengue virus in suboptimal concentrations of the inhibitor,” Neyts said.

JNJ-A07 was then shown to prevent formation of the viral replication complex by blocking the interaction between the nonstructural proteins NS3 and NS4B, thereby revealing a previously undescribed mechanism of antiviral action.

JNJ-A07 was further demonstrated to have a favorable pharmacokinetic (PK) profile resulting in outstanding efficacy against DENV infection in mouse models.

“JNJ-A07’s favorable PK profile resulted from optimization of the ADME [absorption, distribution metabolism and excretion] properties of the analogues within this chemical series,” Janssen’s Van Loock told BioWorld Science.

“This enabled us to administer the compound [twice daily] in mice and assess its efficacy, which resulted in a significantly reduced viral load and protected against mortality in a mouse lethal challenge model.”

However, “additional research will be required in preclinical models, to understand how these findings reflect those in humans, as currently no translational models are available to assess the potential effect in humans,” noted Van Loock.

Delaying treatment commencement until peak viremia had developed was shown to result in a rapid and significant reduction in viral load in the mouse models of infection.

This is an important finding, as “one wants an antiviral effect that is independent of how much [viral] replication is ongoing,” Van Loock said.

“In these mice, the reduction in viral load was also very pronounced if the treatment was initiated on the day of peak viral load, when the effect was quantified 24 hours later.”

On safety, said Neyts, as JNJ-A07 and its analogues “target specific viral proteins that have no homologues in eukaryotic cells, we expect a considerable safety window, with these agents being very well tolerated.” The safety and potency of DENV inhibition established in this study justifies the further development of these novel antivirals, with an analogue being currently in further development.

Further development will include “using our know-how to also develop drugs against the other member of the flavivirus family to which DENV belongs, including Japanese encephalitis, Zika, yellow fever, West Nile virus, et cetera,” said Neyts.

Meanwhile, “Janssen has moved the compound into clinical development and continues to work closely in this regard with teams at KU Leuven and elsewhere,” said Van Loock.

“We will be sharing information about progress of the compound’s clinical development during the American Society of Tropical Medicine and Hygiene meeting this November.”

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/////////////////////////////////////////////////////////////////////////////////////////////////////PatentWO2017167951https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017167951

  • IN201827040889
  • US2020299235
  • US2019112266
  • US10689340

Due to the presence of said chiral carbon atom, a “compound of formula (I)” can be the (R)-enantiomer, the (S)-enantiomer, the racemic form, or any possible combination of the two individual enantiomers in any ratio. When the absolute (R)-or (S)-configuration of an enantiomer is not known, this enantiomer can also be identified by indicating whether the enantiomer is dextrorotatory (+)- or levorotatory (-)- after measuring the specific optical rotation of said particular enantiomer.

In an aspect the present invention relates to a first group of compound of formula (I) wherein the compounds of formula (I) have the (+) specific rotation.

In a further aspect the present invention relates to a second ground of compounds of formula (I) wherein the compounds of formula (I) have the (-) specific rotation.

Example 4: synthesis of 4-(3-((1 -(4-chlorophenyl)-2-oxo-2-(6-(trifluoromethoxy)-indolin-1 -yl)ethyl)amino)-5-methoxyphenoxy)butanoic acid (Compound 4) and chiral separation into Enantiomers 4A and 4B.

Synthesis of intermediate 4a:

A mixture of 6-(trifluoromethoxy)indoline [CAS 959235-95-1] (2 g, 9.84 mmol), 2-(4-chlorophenyl)acetic acid [CAS 1878-66-6] (1 .85 g, 10.8 mmol), HATU (5.6 g, 14.8 mmol) and diisopropylethylamine (4.9 ml_, 29.5 mmol) in DMF (40 ml_) was stirred at room temperature for 12 h. Water was added and the precipitate was filtered off. The residue was taken up with EtOAc. The organic solution was washed with a 10% aqueous solution of K2CO3, brine, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel (15-40 μιτι, 80 g, heptane/EtOAc gradient 90/10 to 60/40). The pure fractions were combined and the solvent was concentrated under reduced pressure to give 2-(4-chlorophenyl)-1 -(6-(trifluoromethoxy)indolin-1 -yl)-ethanone 4a (3 g).

Synthesis of intermediate 4b:

At -78°C, under N2 flow, LiHMDS 1 .5 M in THF (1 1 .2 ml_, 16.9 mmol) was added dropwise to a mixture of 2-(4-chlorophenyl)-1 -(6-(trifluoromethoxy)indolin-1 -yl)-ethanone 4a (3 g, 8.43 mmol) in THF (50 ml_). The mixture was stirred for 15 min at -78°C and a solution of /V-bromosuccinimide (1 .65 g, 9.3 mmol) in THF (30 ml_) was added dropwise. After stirring for 2 h at -78°C, the reaction was quenched with a saturated solution of NH CI. The mixture was extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure to give 2-bromo-2-(4-chlorophenyl)-1 -(6-(trifluoromethoxy)indolin-1 -yl)ethanone 4b (3.6 g). The compound was used as such in the next step.

Synthesis of intermediate 4c:

A mixture of 2-bromo-2-(4-chlorophenyl)-1 -(6-(trifluoromethoxy)indolin-1 -yl)-ethanone 4b (3.6 g, 8.3 mmol), terf-butyl 4-(3-amino-5-methoxyphenoxy)-butanoate 1a (2.3 g, 8.3 mmol) and diisopropylethylamine (1 .7 mL, 9.94 mmol) in CH3CN (80 mL) was stirred at 70°C for 4 h. The mixture was concentrated under reduced pressure, diluted with EtOAc, and washed with 1 N HCI and water. The organic phase was separated, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. The compound was purified by flash chromatography on silica gel (15-40 μιτι, 120 g, heptane/EtOAc 80/20). The pure fractions were combined and evaporated to dryness to give, after crystallization from diisopropyl ether, te/t-butyl 4-(3-((1 -(4-chlorophenyl)-2-oxo-2-(6-(trifluoro-methoxy)indolin-1 -yl)ethyl)amino)-5-methoxyphenoxy)butanoate 4c (2.6 g).

Synthesis of Compound 4 and chiral separation into Enantiomers 4A and 4B: A solution of terf-butyl 4-(3-((1 -(4-chlorophenyl)-2-oxo-2-(6-(trifluoromethoxy)-indolin-1 -yl)ethyl)amino)-5-methoxyphenoxy)butanoate 4c (2.4 g, 3.8 mmol) in 4M HCI in dioxane (24 mL) was stirred at 5°C for 3 h and at room temperature for 3h. The precipitate was filtered off and dried to afford 4-(3-((1 -(4-chlorophenyl)-2-oxo-2-(6-(trifluoromethoxy)indolin-1 -yl)ethyl)amino)-5-methoxyphenoxy)butanoic acid as an HCI salt (Compound 4, 2 g, 0.8 equiv. HCI, 0.07 equiv. H2O). Compound 4 (2 g, HCI salt) was neutralized prior to chiral separation by treatment of a solution of Compound 4 (HCI salt) in ethylacetate with 1 N NaOH and evaporation of the organic layer under reduced pressure. The enantiomers were separated via Preparative Chiral SFC (Stationary phase: Chiralcel® OD-H 5 μηη 250 x 30 mm, Mobile phase: 50% CO2, 50% iPrOH (+ 0.3% iPrNH2)) and further purified via Preparative achiral SFC (Stationary phase: Cyano® 6 μιτι 150×21 .2mm, Mobile phase: 80% CO2, 20% MeOH (+ 0.3% iPrNH2)). The product fractions were combined and evaporated under reduced pressure. The two enantiomers were taken up with EtOAc and washed with 1 N HCI. The organic layers were separated, dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. The first eluted enantiomer was solidified from ether/diisopropyl ether to give Enantiomer 4A (616 mg). The second eluted enantiomer was solidified from ether/diisopropyl ether to give Enantiomer 4B (715 mg).

It is also possible to separate the enantiomers starting from the HCI salt of the racemate using the same conditions for chiral separation.

Compound 4:

1H NMR (500 MHz, DMSO-c/6) δ ppm 1 .87 (quin, J=6.9 Hz, 2 H) 2.34 (t, J=7.3 Hz, 2 H) 3.07 – 3.28 (m, 2 H) 3.62 (s, 3 H) 3.85 (t, J=6.5 Hz, 2 H) 4.04 (td, J=10.5, 7.1 Hz, 1 H) 4.52 (td, J=10.3, 6.5 Hz, 1 H) 5.57 (s, 1 H) 5.76 (t, J=2.2 Hz, 1 H) 5.90 – 6.00 (m, 2 H) 7.01 (dd, J=8.2, 1 .6 Hz, 1 H) 7.33 (d, J=8.2 Hz, 1 H) 7.41 – 7.48 (m, 2 H) 7.55 (d, J=8.5 Hz, 2 H) 8.03 (s, 1 H)

LC/MS (method LC-B): Rt 2.70 min, MH+ 579

Melting point: 150°C

Enantiomer 4A:

1H NMR (500 MHz, DMSO-c/6) δ ppm 1 .87 (quin, J=6.7 Hz, 2 H) 2.34 (br t, J=7.3 Hz, 2 H) 3.08 – 3.27 (m, 2 H) 3.62 (s, 3 H) 3.85 (br t, J=6.3 Hz, 2 H) 3.99 -4.1 1 (m, 1 H) 4.47 – 4.57 (m, 1 H) 5.57 (br s, 1 H) 5.76 (s, 1 H) 5.95 (br d, J=10.1 Hz, 2 H) 6.45 (br s, 1 H) 7.01 (br d, J=7.6 Hz, 1 H) 7.34 (br d, J=7.9 Hz, 1 H) 7.44 (br d, J=8.5 Hz, 2 H) 7.55 (br d, J=8.2 Hz, 2 H) 8.04 (br s, 1 H) 12.12 (br s, 1 H) LC/MS (method LC-A): Rt 2.95 min, MH+ 579

[a]D20: -48.5° (c 0.27, DMF)

Chiral SFC (method SFC-A): Rt 1 .13 min, MH+ 579, chiral purity 100%.

Enantiomer 4B:

1H NMR (500 MHz, DMSO-c/6) δ ppm 1 .87 (br t, J=6.8 Hz, 2 H) 2.34 (br t, J=7.3 Hz, 2 H) 3.09 – 3.27 (m, 2 H) 3.62 (s, 3 H) 3.85 (br t, J=6.1 Hz, 2 H) 3.99 -4.10 (m, 1 H) 4.46 – 4.59 (m, 1 H) 5.57 (s, 1 H) 5.76 (br s, 1 H) 5.95 (br d, J=10.1 Hz, 2 H) 6.45 (br s, 1 H) 7.01 (br d, J=7.9 Hz, 1 H) 7.34 (br d, J=7.9 Hz, 1 H) 7.44 (br d, J=8.2 Hz, 2 H) 7.55 (br d, J=8.2 Hz, 2 H) 8.04 (br s, 1 H) 12.12 (br s, 1 H) LC/MS (method LC-A): Rt 2.94 min, MH+ 579

[a]D20: +42.9° (c 0.28, DMF)

Chiral SFC (method SFC-A): Rt 2.13 min, MH+ 579, chiral purity 100%.

Patent

WO2021094563

The compounds of formula I according to the present invention may be synthesized according to methods described in the art, as disclosed in WO 2016/180696. The compounds of formula II according to the present invention may be prepared according to methods described in the art, as disclosed in WO2017/167951.

Compound (b) of the present invention was tested in AG129 mouse viremia model. The synthesis of compound (b) is described in WO 2017/167951, under Example 4.


compound (b)

PATENT

WO 2018215316

The compounds of formula (I) of the present invention all have at least one asymmetric carbon atom as indicated in the figure below by the carbon atom labelled with * :

Ref

https://doi.org/10.1038/s41586-021-03990-6

https://medicaldialogues.in/medicine/news/researchers-identify-first-drug-that-is-effective-against-dengue-infection-83187

////////////////////JNJ-A07, DENGUE, VIRUS, PRECLINICAL

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How the body fights against viruses


Lyra Nara Blog

How the body fights against viruses

Illustration “structure”: This is a model of the RNA-binding domain of ADAR1 (green), bound to double-stranded RNA (yellow). Transportin1, which mediates the nuclear transport of ADAR1, is depicted in gray. The structural model reveals that ADAR1 cannot enter the nucleus when bound to RNA, as RNA (yellow) and Transportin1 (gray) clash. Credit: PNAS

Scientists of the Max F. Perutz Laboratories of the University of Vienna and the Medical University of Vienna, together with colleagues of the ETH Zurich, have now shown how double stranded RNA, such as viral genetic information, is prevented from entering the nucleus of a cell. During the immune response against viral infection, the protein ADAR1 moves from the cell nucleus into the surrounding cytoplasm. There it modifies viral RNA to inhibit reproduction of the virus. But how is the human genome protected from inadvertent import of viral RNA into the nucleus?  The current study of the research…

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Amgen: Phase III Melanoma treatment, Talimogene Laherparepvec Improves Survival


Transmission electron micrograph of an unmodified herpes simplex virus

Talimogene Laherparepvec

Amgen Presents Interim Overall Survival Data From Phase 3 Study Of Talimogene Laherparepvec In Patients With Metastatic Melanoma

THOUSAND OAKS, Calif., Nov. 18, 2013 /PRNewswire/ — Amgen (NASDAQ:AMGN) today announced interim overall survival (OS) results from a pivotal Phase 3 trial evaluating talimogene laherparepvec in patients with unresected stage IIIB, IIIC or IV melanoma compared to granulocyte-macrophage colony-stimulating factor (GM-CSF). Results will be presented today during an oral session at the 2013 Society for Melanoma Research (SMR) Congress, in Philadelphia   read all at http://www.pharmalive.com/amgen-phase-iii-melanoma-drug-improves-survival
Talimogene laherparepvec (tal im’ oh jeen la her” pa rep’ vek), often simply called “T-VEC” is a cancer-killing (oncolytic) virus currently being studied for the treatment of melanoma and other advanced cancers. The drug was initially developed by BioVex, Inc. under the name OncoVEXGM-CSFuntil it was acquired by Amgen in 2011. With the announcement of positive results in March 2013, T-VEC is the first oncolytic virus to be proven effective in a Phase III clinical trial.
T-VEC was engineered from herpes simplex 1 (HSV-1), a relatively innocuous virus that normally causes cold sores. A number of genetic modifications were made to the virus in order to:

  • Attenuate the virus (so it can no longer cause herpes)
  • Increase selectivity for cancer cells (so it destroys cancer cells while leaving healthy cells unharmed)
  • Secrete the cytokine GM-CSF (a protein naturally secreted in the body to initiate an immune response)
Summary of genetic modifications
Modification Result
Use of new HSV-1 strain (JS1) Improved tumor cell killing ability compared with other strains
Deletion of ICP34.5 Prevents HSV infection of non-tumor cells, providing tumor-selective replication
Deletion of ICP47 Enables antigen presentation
Earlier insertion of US11 Increases replication and oncolysis of tumor cells
Insertion of human GM-CSF gene Enhances anti-tumor immune response by recruiting and stimulating dendritic cells to tumor site

T-VEC has a dual mechanism of action, destroying cancer both by directly attacking cancer cells and also by helping the immune system to recognize and destroy cancer cells. T-VEC is injected directly into a number of a patient’s tumors. The virus invades both cancerous and healthy cells, but it is unable to replicate in healthy cells and thus they remain unharmed. Inside a cancer cell, the virus is able to replicate, secreting GM-CSF in the process. Eventually overwhelmed, the cancer cell lyses (ruptures), destroying the cell and releasing new viruses, GM-CSF, and an array of tumor-specific antigens (pieces of the cancer cell that are small enough to be recognized by the immune system).

The GM-CSF attracts dendritic cells to the site. Dendritic cells are immune cells that process and present antigens to the immune system so that the immune system can then identify and destroy whatever produced the antigen. The dendritic cells pick up the tumor antigens, process them, and then present them on their surface to cytotoxic (killer) T cells. Now the T cells are essentially “programmed” to recognize the cancer as a threat. These T cells lead an immune response that seeks and destroys cancer cells throughout the body (eg, tumors and cancer cells that were not directly injected with T-VEC).

Talimogene laherparepvec MOA.jpg

In this way, T-VEC has both a direct effect on injected tumors and a systemic effect throughout the entire body. Because the adaptive immune system “remembers” a target once it has been identified, there is high likelihood that the effect of an oncolytic virus like T-VEC will be durable (eg, prevent relapse). And it is for this reason that T-VEC does not need to be injected into every tumor, just a few in order to start the immune process.

Clinical efficacy in unresectable melanoma has been demonstrated in Phase II and Phase III clinical trials.

The Phase II clinical trial was published in the Journal of Clinical Oncology in 2009. 50 patients with advanced melanoma (most of whom had failed previous treatment) were treated with T-VEC. The overall response rate (patients with a complete or partial response per RECIST criteria) was 26% (16% complete responses, 10% partial responses). Another 4% of patients had a surgical complete response, and another 20% had stable disease for at least 3 months. On an extension protocol, 3 more patients achieved complete responses, and overall survival was 54% at 1 year and 52% at 2 years—demonstrating that responses to T-VEC are quite durable.

Consistent with other immunotherapies, some patients exhibited initial disease progression before responding to therapy because of the time it takes to generate the full immune response. Responses were seen in both injected and uninjected tumors (including those in visceral organs), demonstrating the systemic immunotherapeutic effect of T-VEC. Treatment was extremely well tolerated, with only Grade 1 or 2 drug-related side effects, the most common being mild flu-like symptoms.

Senzer image of skin lesions after talimogene laherparepvec.jpg

Senzer image of internal lesions after talimogene laherparepvec.jpg

Amgen announced the initial results of the Phase III OPTiM trial on Mar. 19, 2013. This global, randomized, open-label trial compared T-VEC with subcutaneously administered GM-CSF (2:1 randomization) in 430 patients with unresectable stage IIIB, IIIC or IV melanoma. The primary endpoint was durable response rate (DRR), defined as a complete or partial tumor response lasting at least 6 months and starting within 12 months of treatment.

T-VEC was proven to offer superior benefits in metastatic melanoma. DRR was achieved in 16% of patients receiving T-VEC compared with only 2% in the GM-CSF control group (P<.0001). The greatest benefit was seen in patient with stage IIIB or IIIC melanoma, with a 33% DRR vs 0% with GM-CSF. The objective response rate (any response) with T-VEC was 26%, with an impressive 11% of patients experiencing a complete response (complete disappearance of melanoma throughout the body). This demonstrated once again that T-VEC has a systemic immune effect that destroys distant, uninjected tumors. According to Financial Times one of the investigators involved questioned the ethics of the trial design, as the control arm received subcutaneous GM-CSF instead of standard care 

A trend toward improved survival with T-VEC was observed in a pre-specified interim analysis of this endpoint, with the final survival data (event-driven) expected in late 2013. At the interim analysis, T-VEC was associated with a 21% reduced risk of death. The most common side effects with T-VEC were fatigue, chills, and fever. No serious side effect occurred in more than 3% of patients in either arm of the study.

The investigators concluded that “T-VEC represents a novel potential [treatment] option for melanoma with regional or distant metastases.” The success of T-VEC in the OPTiM trial represents the first Phase III proof of efficacy for a virus-based oncolytic immunotherapy.

Peregrine Pharmaceuticals Announces Results From Phase II Clinical Trial of Bavituximab in Stage IV Pancreatic Cancer


TUSTIN, CA  02/13/13 — Peregrine Pharmaceuticals  announced results from its 70 patient open-label, randomized Phase II clinical trial of bavituximab used in combination with gemcitabine in patients with previously untreated, advanced Stage IV pancreatic cancer. The trial included the enrollment of patients with advanced metastatic disease including significant liver involvement and poor performance status associated with rapid disease progression. Results showed that the combination of bavituximab and gemcitabine resulted in more than a doubling of overall response rates (ORR) and an improvement in overall survival (OS) when compared with gemcitabine alone (control arm). In the trial, patients treated with a combination of bavituximab and gemcitabine had a 28% tumor response rate as compared to 13% in the control arm. Median OS, the primary endpoint of the trial, was 5.6 months for the bavituximab plus gemcitabine arm and 5.2 months for the control arm (hazard ratio = 0.75).

Bavituximab binds to phosphatidylserine which is exposed on the surface of certain atypical animal cells, including tumour cells and cells infected with any of six different families of virus. These viral families contain the viruses hepatitis C, influenza A and B, HIV 1 and 2, measles, respiratory syncytial virus and pichinde virus, which is a model for the deadly Lassa virus.[2] Other cells are not affected since phosphatidylserine normally is only intracellular.[3]

Bavituximab binds to various aminophospholipids and is dependent on interaction with plasma protein beta-2 glycoprotein I to mediate binding.

These target aminophospholipids, usually residing only on the inner leaflet of the plasma membrane of cells, become exposed in virally infected, damaged or malignant cells, and more generally in most cells undergoing the process of apoptosis.

The antibody’s binding to phospholipids alerts the body’s immune system to attack the tumor endothelial cells, thrombosing the tumor’s vascular network and/or attacking free floating virally infected and metastatic cells while potentially minimizing side effects in healthy tissues.

  1. Statement on a nonproprietary name adopted by the USAN council
  2. Nature Medicine 14, 1357 – 1362 (2008)
  3. He, J.; Yin, Y.; Luster, T. A.; Watkins, L.; Thorpe, P. E. (2009). “Antiphosphatidylserine Antibody Combined with Irradiation Damages Tumor Blood Vessels and Induces Tumor Immunity in a Rat Model of Glioblastoma”. Clinical Cancer Research 15 (22): 6871–6880. doi:10.1158/1078-0432.CCR-09-1499. PMID 19887482edit
  4. New Progression-Free Survival Data From Peregrine’s Bavituximab in Phase II Refractory Breast Cancer
  5. Phase II Advanced Breast Cancer Data to Be Presented at ASCO Highlight Promising Tumor Response and Progression-Free Survival Data With Peregrine’s Bavituximab
  6. Pharma company completes humanization of 3G4 antibody
  7. He, J.; Luster, T. A.; Thorpe, P. E. (2007). “Radiation-Enhanced Vascular Targeting of Human Lung Cancers in Mice with a Monoclonal Antibody That Binds Anionic Phospholipids”. Clinical Cancer Research 13 (17): 5211–5218. doi:10.1158/1078-0432.CCR-07-0793. PMID 17785577. edit
  8. Ran; Downes, A.; Thorpe, P. E. (2002). “Increased exposure of anionic phospholipids on the surface of tumor blood vessels”. Cancer Research 62 (21): 6132–6140. PMID 12414638.

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